专利摘要:
Compounds of formula (I): wherein R1, R2, R3, R4, R5, R6, R7, R8, R14, A and n are as defined in the description. Drugs.
公开号:FR3037958A1
申请号:FR1555753
申请日:2015-06-23
公开日:2016-12-30
发明作者:Zoltan Szlavik；Attila Paczal；Balazs Balint；Andras Kotschy；Maia Chanrion；Olivier Geneste；James Edward Paul Davidson；James Brooke Murray；Szabolcs Sipos；Agnes Proszenyak
申请人:Laboratoires Servier SAS；Vernalis R&D Ltd；
IPC主号:

专利说明:

[0001] The present invention relates to novel hydroxy acid derivatives, process for their preparation and pharmaceutical compositions containing them. The compounds of the present invention are new and have very interesting pharmacological characteristics in the field of apoptosis and oncology. Apoptosis, or programmed cell death, is a crucial physiological process for embryonic development and maintenance of tissue homeostasis. Apoptotic cell death involves morphological changes, such as core condensation, DNA fragmentation, as well as biochemical phenomena, such as activation of caspases that will degrade key structural components of the cell to induce disassembly and death. The regulation of the apoptosis process is complex and involves the activation or repression of several intracellular signaling pathways (Cory S. et al., Nature Review Cancer, 2002, 2, 647-656).
[0002] Deregulation of apoptosis is implicated in certain pathologies. Increased apoptosis is linked to neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and ischemia. Conversely, deficiencies in the execution of apoptosis play an important role in the development of cancers and their chemoresistance, autoimmune diseases, inflammatory diseases and viral infections. Thus, the absence of apoptosis is part of the phenotypic signatures of cancer (Hanahan D. et al., Cell 2000, 100, 57-70). The anti-apoptotic proteins of the Bc1-2 family are associated with numerous pathologies. The involvement of Bc1-2 family proteins is described in many types of cancer, such as colon cancer, breast cancer, small cell lung cancer, non-small cell lung cancer, bladder cancer, ovarian cancer, prostate cancer, chronic lymphocytic leukemia, lymphoma, myeloma, acute myeloid leukemia, pancreatic cancer, etc. Overexpression of anti-apoptotic proteins in the Bel-2 family is implicated in tumorigenesis, chemotherapy resistance, and clinical prognosis in cancer patients.
[0003] In particular, Me1-1, a member of the Bel-2 anti-apoptotic family, is overexpressed in various types of cancers (Beroulchim R. et al., Nature 2010, 899-905). There is therefore a therapeutic need for compounds that inhibit the anti-apoptotic activity of Bel-2 family proteins. The compounds of the present invention, in addition to novelty, have pro-apoptotic properties for use in pathologies involving a lack of apoptosis, for example in the treatment of cancer and autoimmune diseases and the immune system. More particularly, the present invention relates to compounds of formula (I): wherein: N - - A represents the group in which 1 is bonded to the oxygen atom and 2 is bonded to the phenyl ring; R1 represents a linear or branched C1-C6 alkyl group, a linear or branched C2-C6 alkenyl group, a linear or branched C2-C6 alkynyl group, a linear or branched C1-C6 alkoxy group, a linear or branched C1-C6 alkenyl group, S- (C1-C6) alkyl, a linear or branched C1-C6 polyhaloalkyl, a hydroxy group, a hydroxy (C1-C6) alkyl group, a cyano group, -NR12R12 ', -Cy5 or a d Halogen, R 3, R 3, R 4 and R 5 independently of one another represent a hydrogen atom, a halogen atom, a linear or branched C 1 -C 6 alkyl group, a C 2 -C 6 alkenyl group, Linear or branched C6, a linear or branched C2-C6 alkynyl group, a linear or branched C1-C6 polyhaloalkyl, a hydroxyl group, a hydroxy (C1-C6) alkyl group, a linear or branched C1-C6 alkoxy group, a -S- (C1-C6) alkyl group, a cyano group, a nitro group, - (C6-C6) alkyl -NR1oR1o ', -O- (C1-C6) alkyl -NR1oR1o', -O- (C1-C6) alkyl-R11, -C ( 0) -OR1 0, -OC (O) -R10, -C (O) -NRIOR1O, -NR10-C (O) -R1o ', -C1-C6alkyl -NR10-C (O) - R10 ', -SO2-NR10R10', -SO2- (C1-C6) alkyl, or the substituents of one of the pairs (R2, R3), (R3, R4), (R4, R5), when are grafted onto two adjacent carbon atoms together with the carbon atoms carrying them an aromatic or nonaromatic 5-7 membered ring which may contain from 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, it being understood that the resulting ring may be substituted by a group selected from a linear or branched C1 to C6 alkyl group; , -NR12R12 ', - (C1-C6) alkyl-Cyl or an oxo, - R6 represents -O- (C1-C6) alkyl -R11, -R7 represents a hydrogen atom, a halogen atom, a linear or branched C1-C6 alkyl group, a linear or branched C2-C6 alkenyl group, a linear or branched C2-C6 alkynyl group, a linear or branched C1-C6 polyhaloalkyl group, a hydroxyl group, a group linear or branched C1-C6 alkoxy, a -S- (C1-C6) alkyl group, a cyano group, a nitro group, - (C1-C6) alkyl -NR1oRio ', -O- (C1-C6) alkyl C6) -NR1oRio ', 25- (C1-C6) alkyl-Cyl, - (C2-C6) alkenyl-Cyl, - (C2-C6) alkynyl-Cyl, -O- (C1-C6) alkyl -R11, -C (O) -OR10, -O-C (O) -R13, -C (O) -NR1oRio ', -NR10-C (O) -R10', -NR10-C (O) -OR10 C1-C6 alkyl-NR10-C (O) -R10 ', -SO2- (C1-C6) alkyl; R8 is hydrogen, linear C1-C8 alkyl; or branched, a group -CHRaRb, u aryl group, a heteroaryl group, an arylC 1-6 alkyl group or a heteroaryl (C 1-6 alkyl) group; R 9 represents a linear or branched C 1 -C 6 alkyl group; linear or branched C2-C6 alkenyl group, a linear or branched C2-C6 alkynyl group, -Cy3, -C1-C6alkylCy3-, -C2-C6alkenylCy3-, alkynyl- C2 to C6) -CY3, -Cy3-Cy4, - (C2-C6) alkynyl-O-C373, -C3-C6-C6alkyl-O- (C6-C6alkyl) -Cy4, a halogen atom, a cyan group, -C (O) -R13 or -C (O) -NR13R13 ', - R10 and R10' represent, independently of one another, a hydrogen atom, an alkyl group or C1 to C6 linear or branched, - (C1-C6) alkyl-Cyl, or the substituents of the pair (R10, R10 ') together with the nitrogen atom carrying an aromatic or non-aromatic ring consisting of from 5 to 7 members, which may contain in addition to the nitrogen atom of 1 to 3 hours Eroatomes selected from oxygen, sulfur and nitrogen, it being understood that the nitrogen in question may be substituted with 1 or 2 groups representing a hydrogen atom or a linear or branched C1-C6 alkyl group, and being understood that one or more of the carbon atoms of the optional substituents may be deuterated, -R11 represents -Cy5- (C1-C6) alkyl-O- (C1-C6) alkyl -Cy6, -Cys- (C1-C6) alkyl; Co-C6) -Cy6, -Cy5- (C1-C6) alkyl-NR12- (C1-C6) alkyl -cy6, -R12, R12 ', R13 and R13' independently of one another represent an atom of hydrogen or an optionally substituted linear or branched C1-C6 alkyl group; - R14 represents a hydrogen atom, a hydroxy group or a hydroxy (C1-C6) alkyl group; - Ra represents a hydrogen atom or a linear or branched C1-C6 alkyl group; Rb represents a group -O-C (O) -O-Re, a group -O-C (O) -NReRe 'or a grouping -O-P (O) (ORc) 2, - Re and Re 'represent, independently of one another, a hydrogen atom, a linear or branched C1-C8 alkyl group, a cycloalkyl group, a group ( C1-C6 alkoxy) (C1-C6) alkyl, (C1-C6) alkoxycarbonyl (C1-C6) alkyl, or the substituents of the (Ru, Re ') pair together with the a nitrogen atom bearing them a 5- to 7-membered non-aromatic ring, which may contain in addition to the nitrogen atom from 1 to 3 heteroatoms selected from oxygen and nitrogen, being understood that the nitrogen in question may be substituted by a group representing a linear or branched C1-C6 alkyl group; - Cy1, Cy2, Cy3, Cy4 and Cy5 represent, independently of one another, a cycloalkyl group, a heterocycloalkyl group, a aryl group or a heteroaryl group, - Cy6 represents 10 or Cy6 represents a heteroaryl group which is substituted by a. group selected from -O-P (O) (OR2o) 2; -O-P (O) (O-) 2; - (CF12) p-O- (CH1R8-CHRI9-O) q-R20; a hydroxy; hydroxy (C1-C6) alkyl; - (CH2) rY- (CH2), - heterocycloalkyl; or -Y- (CH2) q-NR21R21 '; - R15 represents a hydrogen atom; a group - (CH2) 1 -O- (CHR18-CHR19-O) q-R20; a linear or branched (C1-C6) alkoxy (C1-C6) alkyl group; a group -Y- (C142) q-NR2IR21 '; or a group - (CH2), - Y- (CH2) s-heterocycloalkyl; - R16 represents a hydrogen atom; a hydroxy group; a hydroxy (C1-C6) alkyl group; a group - (CH2), - Y- (CH2), - heterocycloalkyl; a group (CH2), -Y-X-O-P (O) (OR2) 2; a group -O-P (0) (0-) 2; a group - (CH2) p-O- (CHR18-CHR19-O) q-R20; a group - (CH 2) p -O-C (O) -NR 22 R 23; or a group -Y- (CH2) q-NR2IR21 '; - R17 represents a hydrogen atom; a group - (CH2) p-O- (CHR18-CHR19-O) q-R20; a group -O-P (0) (OR20) 2; a group -O-P (O) (O-) 2; a hydroxy group; a hydroxy (C1-C6) alkyl group; a - (CH2) rY- (CH2) s-heterocycloalkyl group; a group -Y- (CH2) q-NR211Z21 '; or an aldonic acid; X represents a group - (C112) 5 or a group -C (O) -, - Y represents a bond or an oxygen atom; R15 represents a hydrogen atom or a (C1-C6) alkoxy (C1-C6) alkyl group; R19 represents a hydrogen atom or a hydroxy (C1-C6) alkyl group; R20 represents a hydrogen atom or a linear or branched C1-C6 alkyl group; R21 and R21 'represent, independently of each other, a hydrogen atom, a linear or branched C1-C6 alkyl group or a hydroxy (C1-C6) alkyl group, or the substituents of the pair ( R21, R21 ') together with the nitrogen atom carrying an aromatic or nonaromatic 5- to 7-membered ring which may contain in addition to the nitrogen atom from 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, it being understood that the resulting ring may be substituted by a group representing a hydrogen atom or a linear or branched C1 to C6 alkyl group; - R22 represents a (C1-C6) alkoxy (C1-C6) alkyl group, a - (CH2) p-NR24R24 'group or a - (CH2) e-04CHR15-CHR19-0) q-R2o group; R23 represents a hydrogen atom or a (C1-C6) alkoxy (C1-C6) alkyl group, or the substituents of the (R22, R23) pair together with the nitrogen atom bearing them a ring aromatic or nonaromatic compound consisting of 5 to 18 members, which may contain in addition to the nitrogen atom from 1 to 5 heteroatoms selected from oxygen, sulfur and nitrogen, it being understood that the resulting cycle may be substituted by a group representing a hydrogen atom, a linear or branched C1-C6 alkyl group or a heterocycloalkyl group; - R24 and R24 'represent independently of each other a hydrogen atom or a linear or branched C1-C6 alkyl group, or the substituents of the pair (R24, R24') together with the atom of nitrogen carrying them an aromatic or non-aromatic 5- to 7-membered ring which may contain in addition to the nitrogen atom from 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, being understood that the resulting ring may be substituted by a group representing a hydrogen atom or a linear or branched C1 to C6 alkyl group; n is an integer equal to 0 or 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; with the proviso that R15, R16 and R17 can not together represent a hydrogen atom and, when R1 represents a methyl group, R15 can not represent a methoxyethoxy group, it being understood that: "aryl" means a grouping phenyl, naphthyl, biphenyl, indanyl or indenyl, with "heteroaryl" is meant any mono- or bi-cyclic group consisting of 5 to 10 members, having at least one aromatic group and containing from 15 to 3 heteroatoms chosen from oxygen, sulfur and nitrogen, "cycloalkyl" means any nonaromatic, mono- or bi-cyclic carbocyclic group containing from 3 to 10 ring members, "heterocycloalkyl" means any nonaromatic carbocyclic group, mono or bicyclic, consisting of 3 to 10 members and containing from 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, which may comprise condensed, bridged or spiro ring systems, with the possibility of for the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups thus defined and the alkyl, alkenyl, alkynyl, alkoxy groups to be substituted with 1 to 5 groups selected from an optionally substituted linear or branched C1 to C6 alkyl group; optionally substituted linear or branched C2 to C6 alkenyl group, optionally substituted linear or branched C2 to C6 alkynyl group, optionally substituted linear or branched C1 to C6 alkoxy, optionally substituted (C1 to C6) alkyl, hydroxy , oxo (or NV oxide if appropriate), nitro, cyano, -C (O) -OR ', -OC (O) -R', -C (O) -NR'R ", -NR'R", - (C = NR ') - OR ", linear or branched C 1 -C 6 polyhaloalkyl, trifluoromethoxy or halogen, it being understood that R' and R" represent, independently of one another, a hydrogen atom or an optionally substituted linear or branched C1-C6 alkyl group, and being 3037958 It is understood that one or more of the carbon atoms of any of the foregoing substituents may be deuterated, their enantiomers, diastereoisomers and atropisomers, and their addition salts with a pharmaceutically acceptable acid or base.
[0004] Among the pharmaceutically acceptable acids, there may be mentioned, without limitation, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, lactic acid and the like. pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulfonic acid, camphoric acid, etc. Among the pharmaceutically acceptable bases, mention may be made, without limitation, of sodium hydroxide, potassium hydroxide, triethylamine, t-butylamine and the like. Advantageously, at least one of the groups selected from R2, R3, R4 and. R5 does not represent a hydrogen atom.
[0005] More particularly, the compounds of formula (I) which are given preference are the compounds wherein n is an integer of 1. In another embodiment of the invention, an advantageous possibility consists of compounds of formula (Ia): wherein R1, R2, R3, R4, R5, R65, R7, R5, R14 and A are as defined for formula (I). In the preferred compounds of the invention, R 1 represents a linear or branched C 1 -C 6 alkyl group or a halogen atom. More preferably, R 1 represents a methyl group, an ethyl group, a bromine atom or a chlorine atom. Atropisomers are stereoisomers that arise because of a twist around a single bond, the energy differences due to steric tension or other contributors create a barrier to rotation that is high enough to allow the isolation of individual conformers. For the compounds according to the invention, the atropisomers are as follows: The preferred atropisomer is (5Sa). Advantageously, R14 represents a hydrogen atom, a hydroxyl group, a hydroxymethyl group or a hydroxyethyl group. Preferably, R14 represents a hydrogen atom. Advantageously, R2 represents a halogen atom, a hydroxyl group or a linear or branched C1-C6 alkoxy group. Preferably, R2 represents a methoxy group, a hydroxyl group, a fluorine atom, a bromine atom or a chlorine atom. More preferably, R2 represents a chlorine atom. Advantageously, R3 represents a hydrogen atom, a hydroxyl group, a linear or branched C1-C6 alkoxy group or -O- (C1-C6) alkyl -NR1oR1 0 '. Advantageously, R3 represents -O- (C1-C6) alkyl-NR1oR10- In certain preferred embodiments of the invention, R5 represents R1, R10 and R10 'as defined for formula (I). In the preferred compounds of the invention, represents where R10 and R10 'are as defined for formula (1). Preferably, R4 and R5 represent a hydrogen atom. In an advantageous embodiment, the substituents of the (R1, R5) pair are identical and the substituents of the (R2, R4) pair are identical. In the preferred compounds of the invention, the substituents of the pair (R1, R5) are identical and represent a C1-C6 alkyl group, while the substituents of the pair (R2, R4) are identical and represent a hydrogen atom. halogen or a hydrogen atom.
[0006] In the preferred compounds of the invention, where R 11 is as defined for formula (I). Preferably, R7 represents a hydrogen atom. Preferably, Rg represents a hydrogen atom, a -CHRaRb group, an optionally substituted linear or branched C1 to C8 alkyl group or a heteroaryl (C1 to C6) alkyl group. Preferably, R8 represents a -CHRaRb group in which Ra represents a hydrogen atom or a methyl group and Rb represents a -O-C (O) -O- (C1-C8) alkyl group; a -O-C (O) -O-cycloalkyl group; a group -O-C (O) -NR, Re ', in which Re and K' independently of one another represent a hydrogen atom, a linear or branched C1-C8 alkyl group, a group (C1-C6 alkoxy) (C1-C6) alkyl, (C1-C6) alkoxycarbonyl (C1-C6) alkyl, or the substituents of the (Ra, Ra ') pair together with the a nitrogen atom bearing them a 5- to 7-membered non-aromatic ring, which may contain in addition to the nitrogen atom from 1 to 3 heteroatoms selected from oxygen and nitrogen, or a -OP group ( 0) (OH) 2. Preferred R8 groups are: hydrogen; methyl; an ethyl; (5-methyl-2-oxo-1,3-dioxo-4-yl) methyl. More preferably, Rg is hydrogen. In the preferred compounds of the invention, R 9 represents a linear or branched C 1 -C 6 alkyl group, a linear or branched C 2 -C 6 alkenyl group, a linear or branched C 2 -C 6 alkynyl group, an aryl group or a linear or branched C 1 -C 6 alkynyl group. heteroaryl group. Advantageously, R 9 represents a linear or branched C 2 -C 6 alkynyl group, an aryl group or a heteroaryl group. More preferably, R 9 is prop-1-yn-1-yl, but-1 -yn-1-yl, phenyl or furan-2-yl. In a more preferred embodiment, R 9 represents a 4- (benzyloxy) phenyl group, a 4- (pyridin-4-ylmethoxy) phenyl group, a 4-phenylbut-1-yn-1-yl group, a 4-membered group. -fluorophenyl or a 5-fluorofuran-2-yl group. Even more preferably, R 9 represents a 4-fluorophenyl group. In the preferred compounds of the invention, R10 and R10 'are independently of each other a linear or branched C1-C6 alkyl group, or the substituents of the (R10, R10') pair together with the nitrogen atom bearing them a 5- to 7-membered non-aromatic ring, which may contain, in addition to the nitrogen atom, 1 to 3 heteroatoms selected from oxygen, sulfur, and the like; nitrogen, it being understood that the nitrogen in question may be substituted by a group representing a hydrogen atom or a linear or branched C1-C6 alkyl group. More preferably, R 10 and R 10 'are methyl, or the substituents in the (R 10, R 10') pair together form a 4-methyl-piperazinyl group or a 4-ethyl-piperazinyl group. In a more preferred embodiment, the substituents of the (R10, R10 ') pair together form a 4-methylpiperazinyl moiety. In another preferred embodiment, R10 and R10 'represent a methyl group.
[0007] Advantageously, R11 is -Cy5- (C1-C6) alkyl-C6. More particularly, R11 represents -Cys-Cy6. Preferably, Cy5 represents a heteroaryl group, in particular a pyrimidinyl group, a pyrazolyl group, a triazolyl group, a pyrazinyl group or a pyridinyl group. More preferably, Cy5 represents a pyrimidin-4-yl group, a pyrazol-5-yl group, a triazol-5-yl group, a pyrazin-2-yl group or a pyridin-4-yl group. In the preferred compounds of the invention Cy5 represents a pyrimidin-4-yl group. In another embodiment of the invention, Cy5 represents a heteroaryl group which is substituted by an optionally substituted linear or branched C1-C6 alkyl group, an optionally substituted linear or branched C1-C6 alkoxy group, a NR'R "or a linear or branched C1-C6 polyhaloalkyl group, it being understood that R 'and R" represent, independently of one another, a hydrogen atom or an optionally linear or branched C1-C6 alkyl group substituted.
[0008] Preferably, Cy6 is advantageously Cy6 represents a 3-pyridinyl group, a 4-pyridinyl group, a pyridazin-4-yl group, a pyrazin-2-yl group or a 4- pyrimidine group. yle, it being understood that these heteroaryl groups are substituted with a group selected from -O-P (O) (OR2O2; -O-P (O) (O-) 2; 5 - (CH2) p-O- (CHR18- CH 1 -C 6) - (CH 2), - Y - (CH 2), - heterocycloalkyl, or - Y - (CH 2) q - NR 21 R 21 - advantageously, R 16 and R 17 represents a hydrogen atom and R 15 represents a - (CH 2) p -O- (CHR 18-CHR 19 --O) q-R 20 group, a linear (C 1 -C 6) -alkoxy (C 1 -C 6) alkyl group or branched; -Y- (CH2) q-NR21R21 '; or a group - (CH2), - Y- (CH2), - heterocycloalkyl, where R18, R19, R20, R21, R21', Y, p , q, r and s are as defined for formula (I) In the preferred compounds of the invention, R15 and R17 represent a hydrogen atom and R16 represents a hydroxy group; a hydroxy (C1-C6) alkyl group; a group - (CH2), - Y- (CH2), - heterocycloalkyl; a group -O-P (O) (OR2o) 2; a group -O-P (0) (0-) 2; a group - (CH2) p-O- (CHR1g-CHR19-0) q-R20; a group - (CH 2) p -O-C (O) -NR 22 R 23; a group (CH2), - Y-X-O-P (O) (OR2) 2; or a group -Y- (CH2) q -NR21R21 ', wherein R18, R19, R20, R21, R21', R22, R23, X, Y, p, q, r and s are as defined for formula (I ). In certain preferred embodiments of the invention, R15 and R16 are hydrogen and R17 is-(CH2) p-O- (CHR18-CHR19-O) q-R20; a group -O-P (O) (OR2O2; a group -O-P (O) (O-) 2; a hydroxyl group; a hydroxy- (C1-C6) alkyl group; a - (CH2) - (CH2), - heterocycloalkyl, a group -Y- (CH2) q-NR21R21 'or an aldonic acid, where R18, R19, R20, R21, R21', Y, p, q, r and s are such that defined for formula (I) In a preferred embodiment of the invention, "heterocycloalkyl" as defined for R15, R16 and R17 represents any nonaromatic, mono- or bi-cyclic carbocyclic group consisting of of 3 to 10 members and containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, it being understood that the resulting ring may be substituted with 1 to 5 groups selected from linear C1 to C6 alkyl or branched, linear or branched C1-C6 alkoxy, hydroxy or hydroxy (C1-C6) alkyl. Advantageously, R15 is - (CH2) pO-CH2-CH (CH2OH) - 011 a groupem ent - (CH 2) p -O- (CH 2 -CH 2 -O) q -H; a - (CH 2) p -O- (CH 2 -CH 2 -O) q-CH 3 group; a methoxymethyl group; a (2,2-dimethyl-1,3-dioxolan-4-yl) methoxy group; a (2,2-dimethyl-1,3-dioxolan-4-yl) methoxymethyl group; or a group -Y- (CH2) q-N (CH2-CI-12-OH) 2, where Y, p and q are as defined for formula (I). In the preferred compounds of the invention, R16 represents a hydroxy group; a hydroxy-methyl group; a (2,2-dimethyl-1,3-dioxolan-4-yl) methoxy group; a group -O-P (O) (OH) 2; a group - (CH 2) p -O-CH 2 -CH (CH 2 OH) -OH; a group - (CH 2) p -O- (CH 2 -CH 2 -O) q -H; a group - (CH 2) p -O- (CH 2 -CH 2 -O) q-CI-13, where p and q are as defined for formula (I); a group -O-0-1 (CH 2 -OCH 3) 2; a group -CH2-OC (O) -NR22R23, wherein R22 is as defined for formula (I) and R23 represents a hydrogen atom, or wherein R22 and R23 represent a (C1-C6) alkoxy group ( C1-C6 alkyl), or wherein the substituents of the pair (R22, R23) together with the nitrogen atom carrying them form a non-aromatic ring of 5 to 18 members, which may contain in addition to nitrogen atom of 1 to 5 heteroatoms selected from oxygen, sulfur and nitrogen, it being understood that the resulting ring may be substituted by a group representing a linear or branched C1 to C6 alkyl group or a heterocycloalkyl; A group -O- (CH 2) 2 -NR 2 / R 21 '; a group -CI-I2-NR2IR.21 ', wherein R21 and R21' are as defined for formula (I); a group (CH2), -O-X-O-P (O) (OR2O2), where X and r are as defined for formula (I), and s is an integer equal to 1, or a group - ( Wherein Y is a bond, r and s are integers equal to 0 and the heterocycloalkyl group represents an aldohexose of the formula: R20 is independent, More preferably the heterocycloalkyl moiety is an aldohexose of the formula: R200 OR20 OR20 wherein each R20 is independent In certain preferred embodiments of the invention, R17 is a hydroxyl group, a hydroxymethyl group; a hydroxyethyl group, a -O- (CH 2 -CH 2 -O) 4 CH 3 group, a -O-CH 2 -CH (CH 2 OH) -OH group, a - (CH 2) p -O- (CH 2 -CH 2 -O) group; qH, a group -O-P (O) (OH) 2, a group -O-P (O) (O-) 2, a group -O-CH (CH2-OCH3) 2, a group -O- ( CH2) 2-NR21R21 ', a group -CH2-NR211t21' where R 21 and R 21 'are as defined for formula (I); a (2,2-dimethyl-1,3-dioxolan-4-yl) methoxy group; D-mannonic acid; or a group - (CH 2), - Y- (CH 2), - heterocycloalkyl wherein Y is a bond, s is an integer equal to 0, r is as defined for formula (I) and the heterocycloalkyl represents an aldohexose of the formula: R200 or R200 R700 wherein each R20 is independent. More preferably, the heterocycloalkyl moiety represents an aldohexose of the formula: wherein each R20 is independent. Among the preferred compounds of the invention, there may be mentioned: (2R) -2 - {[(5%) - 5- {3-chloro-2-methyl-443- (4-methylpiperazin) 1-yl) -propoxylphenyl} -6- (4-fluoro-phenyl) thieno [2,3-cipyrimidin-4-yl] oxyl-3 - (2 - {[243-hydroxyphenyl] pyrimidin-4-yl] methoxy} phenyl] ) -propanoic; (2R) -2- {[(5S ()) - 5- {3-chloro-2-methyl-4-13- (4-methylpiperazin-1-yl) propoxy] phenyl} -6- fluoro-phenypthieno [2,3-a] pyrimidin-4-yloxy) -342- {[2- (4-hydroxyphenyl) pyrimidin-4-yl] methoxy} phenyl) propanoic acid; (2R) -2- {[(5S1a) -5- {3-chloro-2-methyl-443- (4-methylpiperazin-1-yl) propoxy] phenyl} -644-11 uoro-phenypthieno [2,3-c] pyrimidine; 4-yl] oxy} -3424 {243 - (hydroxymethyl) phenyl] pyrimidin-4-yl} methoxy) phenyl] propanoic acid - (2R) -2- {[(5Sa) -5- {3- 1-chloro-2-methyl-443- (4-methylpiperazin-1-yl) propoxylphenyl} -6- (4-fluoro-phenyl) thieno [2,3-d] pyrrotho-n-4-yl oxy} - 3- [2- ({244- (hydroxymethyl) phenyl] pyrimidin-4-yl} methoxy) phenyl] propanoic acid; (2R) -2- {[(5S) -5-3-chloro-2-methyl] acid; 443- (4-methylpiperazin-1-yl) propoxy] phenyl) -6- (4-fluoro-phenyl) thieno [2,3-d] pyrimidin-4-yl] oxy} -3- [(2- {2- [2,2-dimethyl-1,3-dioxo-lan-4-yl) methoxy] phenyl} -pyrimidin-4-yl) methoxylphenyl} - p ropanoic acid - (2R) -2 - {[(5S) -5- {3-chloro-2-methyl-4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} - 6- (4-Fluoro-phenyl) -thieno [2,3-d] pyrimidin-4-yl] oxy} -3- {2 - [(2- (24242-methoxyethoxy) ethoxylphenyl} pyrimidin-4-yl) methoxy] -methyl phenylpropanoic acid; (2R) -2 - {[(5Sa) -5- {3-chloro-2-methyl-4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -6- ( 4-fluoro-phenyl) thieno [2,3-d] pyrimidin-4-yl] oxy} -3 - (2 - {[2- (2- {242- (2-methoxyethoxy) ethoxy] ethoxy} phenyl ) pyrimidin-4-yl} methoxy} phenyl) propanoic acid; (2R) -2 - {[(5Sa) -5- {3-chloro-2-methyl-4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -6- (4-Fluoro-phenyl) thieno [2,3-d [yrimidin-4-yl] oxy] -3424 (242- (methoxymethyl) phenylipyrimidin-4-ylmethoxy) phenylpropanoic acid; (2R) -2 - {[(5S) -5- {3-chloro-2-methyl-443- (4-methylpiperazin-1-yl) propoxylphenyl} -6- -fluoro-phenypthieno [2,3-4-pyrimidin-4-yloxy] -3- {2 - [(2- {2 - [(2-methoxyethyloxy) methyl] phenyl} pyrimidin-4-yl) -methoxylphenyl} propanoic acid; (2R) -2 - {[(5S) -5- {3-chloro-2-methyl-4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -6- (4-Fluoro-phenyl) thieno [2,3-d] pyrimidin-4-yl] oxy] -3- {2 - [(2- {24 (2-hydroxyethoxy) methyl] phenyl] pyrimidin-4-yl} -methoxy} phenyl} propanoic acid - (2R) -2 - {[(5S) -5- {3-chloro-2-methyl-443- (4-methylpiperazin-1-yl) propoxy] phenyl} -6- Fluoro-phenypthieno [2,3-4-pyrimidin-4-yl] oxy} -3- (2 - {[2- (2 - {[(2,2-dimethyl-1,3-dioxolan-4-yl)} methoxy] methylphenyl) pyrimidin-4-ylmethoxy-phenylpropanoic acid; (2R) -2- {[(5S) -5- {3-chloro-2-methyl-443- 4-methylpiperazin-1-yl) propoxy] phenyl-6- (4-fluoro-phenyl) thieno [2,3-d] pyrimidin-4-yl] oxy} -3- {2 - [(2- {3 - [(2-hydroxyethox y) methyl] phenyl) pyrimidin-4-yl) methoxyphenyl} propanoic acid; (2R) -2 - {[(5S) -5- {3-chloro-2-methyl-443- (4-methylpiperazin-1-yl) propoxy] phenyl} -6- fluoro-phenypthieno [2,3-d] pyrimidin-4-yl] oxy} -3- {2 - [(2- {3 - [(1,3-dimethoxypropan-2-yloxy) phenyl] pyrimidin-4-yl) - methoxylphenyl} propanoic acid - (2R) -2 - {[(5S) -5- {3-chloro-2-methyl-443- (4-methylpiperazin-1-yl) propoxylphenyl] -4- Fluoro-phenypthieno [2,3-d] pyrimidin-4-yl] oxy] -3- {2 - [(2- (4 - [(1,3-dimethoxypropan-2-yloxy) phenyl] pyrimidin-4 (2R) -2 - {[(5S) -5- {3-chloro-2-methyl-4- [3- (4-methylpiperazin-1-yl)} - [(5S) -5- {3-chloro-2-methyl-4- [3- (4-methylpiperazin-1-yl)} ) - propoxy] phenyl-6- (4-fluoro-phenyl) thieno [2,3-d] pyrimoxy-3,42 - ({244- (2,3-dihydroxypropoxy) phenylpyrimidin-4-ylmethoxy) -phenylpropanoic acid; 6-0- {3 - [4 - ({2 - [(2R) -2-carboxy-2 - [(5S) -5- {3-chloro-2-methyl-443- (4-methylpip)} Erazin-1-yl) propoxyl-phenyl-6- (4-fluorophenylthieno [2,3-c] pyrimidin-4-yl] oxy} ethyllphenoxy} methylpyrimidin-2-yl] phenyl} -α-D-man methyl nopyranoside; 6-0- {3444 {2 - [(2R) -2-carboxy-2 - {[(5S) -5- {3-chloro-2-methyl-443- (4-methylpiperazine); 1-yppropoxy) -phenyl-6- (4-fluorophenyl) thieno [2,3-d] pyrimidin-4-yl] oxy} ethyl] phenoxy} methyl) pyrimidin-2-yl] phenyl} -2,3 Methyl 4-tri-O-methyl-α-D-mannopyranoside; 6-0- {444 - ({2 - [(2R) -2-carboxy-2 - {[(5S) -5- {3-chloro-2-methyl-443- (4-methylpiperazin)]; 1-yl) propoxyl-phenyl-6- (4-fluorophenyl) thieno [2,3-d] pyrimidin-4-yl-oxy} ethyllphenoxy} methylpyrimidin-2-aphenyl-α-D-mannopyranecylmethyl; 3037958 - 18 6-0- {444 - ({2 - [(2R) -2-carboxy-2 - {[(55 ') - 5- {3-chloro-2-methyl-413- (4-methylpiperazin)} 1-yppropoxy-phenyl} -6- (4-fluorophenyl) thieno [2,3- (4-pyrimidin-4-yl) -oxy} -ethyllylphenylmethyl) pyrimidin-2-yl] phenyl} -2,3,4- tri-O-methyl-α-D-mannopyrano methyl ester; 6-0- {4- [4 - ({2 - [(2R) -2-carboxy-2 - {[(5S ') - 5 - {3-Chloro-2-methyl-443- (4-methylpiperazin-1-yl) propoxy] -phenyl} -6- (4-fluorophenyl) thieno [2,3-d] pyrimidin-4-yloxy} ethyliphenoxylmethylpyrimidine; 2-ylphenyl} -D-mannopyranose; 6-0- {2- [4 - ({2 - [(2R) -2-carboxy-2 - {[(5S) -5- {3- chloro-2-methyl-443- (4-methylpiperazin-1-yl) propoxy] phenyl} -6- (4-fluorophenylthieno [2,3-pyrimidin-4-yloxy] ethyl] phenoxylmethylpyrimidine -2-yllphenyl} -D-mannonic 1,2-0 - [(1R) -1 - ({444 - ({2 - [(2R) -2-carboxy-2 - {[(58 ')) -5- {3-Chloro-2-methyl-4- [3- (4-methylpiperazin-1-ylpropoxy) phenyl} -6- (4-fluorophenyl) thieno [2,3-d] pyrimidin-4-yloxy} ethylphenophenylmethyl) primidin-2-ylbenzyloxy) ethylenedene] 43-D-mannopyranose; (2R) -2 - {[(55 ') - 5- {3-Chloro-2-methyl-4- [3- (4-methylpiperazin-1-yipropoxy] phenyl} -6- Fluoro-phenypthieno [2,3-d] pyrimidin-4-yl] oxy} -3- {2 - [(2- {4 - [(α-D-mannopyranosyloxy) methyl] phenyl} pyrimidin-4-yl) -methoxylphenyl} propanoic acid (2R) -2 - {[(5S) -5- {3-chloro-2-methyl-443- (4-methylpiperazin-1-yl) propoxylphenyl} -6- (4-fluoro) -acrylic acid; phenypthieno [2,3-dipyrimidin-4-yloxy] -3424 {2- [4- (2-hydroxyethyl) phenyl] pyrimidin-4-yl} methoxy) phenyl] propanoic acid; (2R) -2-acid - {[(55 ') - 5- {3-Chloro-2-methyl-443- (4-methylpiperazin-1-yl) propoxylphenyl} -6- (4-fluoro-phenyl) thieno [2,3-Mpyrimidin-4- (2 - [(2- [2- (2,3-dihydroxypropoxy) phenyl] pyrimidin-4-ylmethoxy) phenyl] propanoic acid; 3-chloro-2-methyl-443- (4-methylpiperazin-1-ylpoxyoxy) phenyl} -6- (4-fluoro-phenypthieno [2,3-d] pyrimidin-4-yl] oxy} -3- [ 2- ({242- (2-Hydroxyethoxy) phenyl] pyrimidin-4-ylmethoxy) phenyl] propanoic acid - (2R) -2- {R5S,) - 5- {3- acid chloro-2-methyl-4- [3- (4-methylpiperazin-1-yipropoxy) phenyl-6- (4-fluoro-phenyl) thieno [2,3-d] pyrimidin-4-yloxy-3-yl) - [(2- {2 - [(2,3-dihydroxypropoxy) methyl] phenyl} pyrimidin-4-yl) methoxy] phenyl} propanoic acid; (2R) -2 - {[(5S) -5- {3-chloro-2-methyl-443- (4-methylpiperazin-1-yl) propoxy] phenyl} -6- fluoro-phenyl) thieno [2,3-d] pyrimidin-4-yloxy) -3- [2 - ({243- (phosphonooxy) phenylipyrimidin-4-ylmethoxy) phenyl] propanoic acid; 4444 {2 - [(2R) -2-carboxy-2 - {[(5Sa) -5- (3-chloro-2-methyl-443- (4-methylpiperazin-1-apropoxyl) phosphate phenyl-6- (4-fluorophenyl) thieno [2,3-d] pyrimidin-4-yloxy} ethylphenoxy} methyl) pyrimidin-2-yliphenyl acid (2R) -2 - {[(5S ') -5- {3-Chloro-2-methyl-443- (4-methylpiperazin-1-yl) propoxylphenyl} -6- (4-fluoro-phenypthieno [2,3-d] pyrimidin-4-yl) -3- [2 - ({24342-hydroxyethoxy) phenyl} pyrimidin-4-yl} methoxy) phenylpropandic acid (2R) -2- {[(5S (7) -5- {3-chloro-2- Methyl-4- [3- (4-methylpiperazin-1-yipropoxy) phenyl] -6- (4-fluoro-phenylthieno [2,3-di-pyrimidin-4-yl] oxy} -3- {2 - [(2- {442} (2-methoxyethoxy) ethoxy] phenyl) pyrimidin-4-yl) methoxylphenyl} propanoic acid; (2R) -2- {[(5, S, ) - 2-methyl-4- [3- (4-methylpiperazin-1-yipropoxy) phenyl] -6- (4-fluoro-phenypthieno [2,3-4-pyrimidin-4-yl] oxyl-3 - {2 - [(2- {442- (2 hydroxyethyloxy) ethoxy] phenyl) pyrimidin-4-yl) methoxyphenylpropanoic acid; (2R) -2 - {[(5S0) -5- {3-chloro-2-methyl-443- (4-methylpiperazin-1-yl) propoxylphenyl} -6- (4-fluoro-phenyl) thieno [ 2,3-d] pyrimidin-4-yl] oxy} -3- (2 - {[2- (4- {2- [2- (2-methoxyethoxy) ethoxy] ethoxy} phenyl) pyrimidin-4-yl ] methoxy} phenyppropanoic acid; (2R) -2 - {[(5S) -5- {3-chloro-2-methyl-443- (4-methylpiperazin-1-yipropoxy) phenyl} -6- (4-fluoro) phenyl) thieno [2,3-d] pyrimidin-4-yloxy) -3- {2 - [(2- {442- (dimethylamino) ethoxy] phenyl} pyrimidin-4-ylmethoxy} -phenyl} propanoic acid (2R) -2 - {[(5S) -5- {3-chloro-2-methyl-4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} - 6- (4-Fluoro-phenyl) thieno [2,3-d] pyrimidin-4-yl] oxy} -3- {2 - [(2- {3 - [(2,2-dimethyl) -1,3- dioxolan-4-yl) methoxy] phenylpyrimidin-4-yl) methoxy] phenylpropanoic acid; (2R) -2 - {[(5Sa) -5- {3-chloro-2-methyl-442} acid; (4-methylpiperazin-1-yl) ethoxy] phenyl) -6- (4-fluoro-phenyl) thieno [2,3-d] pyrimidin-4-yloxy-3424 {2- [3- (15- hydroxy-3-oxo-2,7,10,13-tetraoxa-4-azapentadec-1-yl) phenyl] pyrimidin-4-yl} methoxy) phenyl] propanoic acid; (2R) -3- (2 - {[2- (3 - {[(1,4'-bipiperidin-1-ylcarbonyl) oxy] methylyllphenyl) pyrimidin-4-ylimethoxy} -phenyl) - 2- {[(5Sa) -5- (3-chloro-2-methyl-442- (4-methylpiperazin-1-yepethoxy) phenyl} -6- (4-fluorophenyl) thieno [2,3-d] pyrimidine 4-yloxy} -propanoic acid (2R) -2 - {[(5Sa) -5- {3-chloro-2-methyl-412- (4-methylpiperazin-1-yl)} ) ethoxy] phenyl-6- (4-fluoro-phenypthieno [2,3-d] pyrimidin-4-yl] oxy) -3 - (2- {[2- (3- (2- [2- (2- hydroxyethoxy) (ethoxyphenyl) phenyl) pyrimidin-4-ylmethoxy) phenylpropanoic acid (2R) -2- {[(5S) -5- {3-chloro-2-methyl-442- (4-methylpiperazine) 1- (5-yl) ethoxylphenyl-6- (4-fluoro-phenypthieno [2,3-4-pyrimidin-4-yl] oxy) -3- {2 - [(2- {3- [2- (2-hydroxyethoxy)} ethoxy] phenyl} pyrimidin-4-yl) methoxylphenyl} propanoic acid; (2R) -2- {[(54-5- {3-chloro-2-methyl-4- [2- (4- methylpiperazin-1-yl) ethoxy] phenyl} -6- (4-fluoro-phenyl) thieno [2,3-d] pyrimidin-4-yl] oxy) -3 - {24 (2- {3 4242-methox yethoxy) ethoxy] phenylpyrimidin-4-yl) metboxylphenylpropanoic acid; (2R) -2 - {[(5S ()) - 5- {3-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxy] phenyl} -6- 1-fluoro-phenyl) -thieno [2,3-d] pyrimidin-4-yloxy) -3- {2 - [(2- {3 - [({[2- (4-methylpiperazin-1-ylethyl) carbamoyl} oxy) -methyl-phenyl) pyrimidin-4-yl) methoxy] phenyl) propanoic acid; (2R) -2- (R5S0) -5- {3-chloro-2-methyl-4- [2- (4-methylpiperazin-1-yl) -ethoxy] phenyl} -6- fluoro-phenypthieno [2,3-d] pyrimidin-4-yl] oxyl-3- {2 - [(2- {3 - [({[2- (morpholin-4-ylethyl) carbamoyl) oxy} methyl] - phenyl pyrroth (n-4-yl) methoxylphenylpropanoic acid; (2R) -2 - {[(5Sa) -5- {3-chloro-2-methyl-442- (4-methyl) p-azazo] -y1) -ethoxy] phenyl} -6- (4-fluorophenyl) thieno [2,3-d] pyrimidin-4-yloxy) -3- {2- [2- {3- [({ [2- (dimethylamino) ethyl] carbamoyloxy) methyl] phenyl pyrimidin-4-yl) methoxylphenylpropanoic acid; (2R) -2 - [(5S) -5- {3-chloro-2-methyl-442- (4-methylpiperazin-1-yl) -ethoxy] phenyl} -6- (4-fluoro) Phenypthieno [2,3-d] pyrimidin-4-yl] oxy) -3- {2 - [(2- {3 - [({[2- (pyrrolidin-1-yl) ethyl] carbamoyl oxy} methyl ] -phenyl) pyrimidin-4-yl) methoxy] phenylpropanoic acid; (2R) -3- [2 - ({2- [3 - ({[bis (2-methoxyethyl) carbamoyl] oxy} methyl) phenyl] pyrimidin-4-yl} methoxy) phenyl] 2 - {[(5Sa) -5- {3-chloro-2-methyl-4- [2- (4-methylpiperazin-1-yepethoxy) phenyl) -6- (4-fluorophenyl) thieno [2,3-d]; d] pyrimidin-4-yl] oxylpropanoic acid; (2R) -2 - {[(5S ()) - 5- {3-chloro-2-methyl-442- (4-methylpiperazin-1-yl) -ethoxy] phenyl) -6- ( 4-fluoro-phenyl) thieno [2,3-4-pyrimidin-4-yl] oxy) -3- (2- {[2- (3)] - [- (1, 4, 7, 7, 10, 13- pentaoxa-16-azacyclooctadecan-16-ylcarbonyl) oxy] methylphenyl) pyrimidin-4-ylmethoxyphenyl) propanoic acid; (2R) -2 - {[(5S0) -5- {3-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxy] phenyl} -6- (4-fluoro-phenyl) thieno acid; [2,3-d] pyrimidin-4-yl] oxy} -3-P4 (24,342,3-hydroxypropoxy) phenylipyrimidin-4-ylmethyloxy) phenyl] propanoic acid; (2R) -2 - {[(5S0E) -5- {3-chloro-2-methyl-442- (4-methylpiperazin-lyOethoxy] phenyl} -6- (4-fluoro-phenyl) thieno [ 2,3-d] pyrimidin-4-yl] oxy} -342- [2- (3- {242- (2-methoxyethoxy) ethoxy] ethoxyphenylpyrimidin-4-ylimethoxy} phenyppropanoic acid - (2R) -3- (2 - {[243- {24bis (2-hydroxyethyl) aminolethoxy) phenyl) pyrimidin-4-ylmethoxy} -phenyl) -2 - {[(5S, 7) -5- {3-chloro-2-methyl) -2- 442- (4-methyl-piperazin-1-yepethoxyphenyl) -6- (4-fluorophenyl) thieno [2,3-d] pyrimidin-4-yloxy} propanoic acid, (2R) -2- {[(( 5, N-5- {2,3-dimethyl-442- (4-methylpiperazin-1-yl) ethoxy] phenyl} -6- (4-fluorophenylthieno [2,3-d] pyrimidin-4-yl] oxy-3- {2} [(2- {3 - [({[2- (Piperidin-y-ethyl) carbarnoyl} oxy) methyliplienyl-pyrimidin-4-yl) methoxy] phenyl} propanoic acid - (2R) -2- [- 5Sa) -5- {3-chloro-2-methyl-442- (4-methylpiperazin-1-yl) -ethoxylphenyl} -6- (4-fluoro-phenyl) thieno [2,3-d] pyrimidin-4 -yloxy} -3- {2 - [(2- {342- (morpholin-4-yl) ethoxylphenyl} pyrimid idin-4-yl) methoxyphenyl} propanoic acid - (2R) -2 - {[(5Sa) -5- {3-chloro-2-methyl-442- (4-methylpiperazin-1-yepethoxy) acid) phenyl-6- (4-fluoro-phenyl) thieno [2,3-d] pyrimidin-4-yl] oxy} -3- {2 - [(2- {3- [2- (dimethylamino) ethoxy] phenyl} pyrimine idin-4-yl) methoxyphenylpropanoic acid; (2R) -3 - (2 - {[2- (4- {2- [bis (2-hydroxyethypamino] ethoxy) phenyl) pyrimidin-4-ylimethoxy} -phenyl) -2- {[5S 5- (3-Chloro-2-methyl-442- (4-methyl-piperazin-1-yl) ethoxy] phenyl} -6- (4-fluorophenyl) thieno [2,3-d] pyrimidin-4 -ylyloxypropanoic; (2R) -2 - {[(5Sa) -5- {3-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxy] phenyl} -6- (4-fluoro) phenyl) thieno [2,3-d] pyrimidin-4-yl] oxy] -3- (2 - {[2- (4- {242- (2-hydroxyethoxy) ethyloxyethoxysilphenyl] pyrimidin-4-yl} methoxy} phenyl) propanoic acid (2R) -2 - {[(5S) -5- (3-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxy] phenyl} -6- -fluoro-phenypthieno [2,3-cl] pyrimidin-4-yl] oxy) -3- {2 - [(2- {4 - [(2,2-dimethyl-1,3-dioxolan-4-yl)} methoxy] phenyl-pyrimidin-4-yl) methoxylphenyl} -propanoic acid; (2R) -2 - {[(5S) -5- {3-chloro-2-methyl-4-yl) -propionic acid; [2- (4-methylpiperazin-1-yepethoxy) phenyl) -6- (4-fluoro-phenyl) thieno [2,3-d] -piperidin-4-yl] oxy} -3- {2 - [(2- {442- (Morpholin-4-yl) ethoxy} phenyl} pyrimidin-4-yl) methoxy] phenyl} propanoic acid; the disodium salt of 4- [4- (2 -) - (2R) -2- phosphate; carboxy-2 - {[(5Sa) -5- {3-chloro-2-methyl-443- (4-methylpiperazin-1-yl) propoxylphenyl} -6- (4-fluorophenyl) thieno [2,3-4 pyrimidin-4] -ylioxy} eth The invention relates to a process for the preparation of compounds of formula (I), said process being characterized in that it uses, as the starting compound, the compound of formula (I). formula (II): ## STR3 ## wherein A is as defined for formula (I) wherein 1 is bonded to the chlorine atom and 2 is bonded to the bromine atom, said compound of formula II) being coupled with a compound of formula (III): wherein R6, R7, R14 and n are as defined for formula (I), and Alk represents a linear or branched C1-C6 alkyl group to give the compound of formula (IV): embedded image in which R 6, R 7, R 14, A and n are as defined for formula (I) and Alk is as previously defined, wherein the compound of formula (IV) is further coupled to a compound of formula (V): wherein R1, R2, R3, R4 and R5 are as defined for formula (I), and RBI and RB2 represent a hydrogen atom, a linear or branched C1-C6 alkyl group, or RBI and RB2 form with oxygen carrying them an optionally methylated ring, for obtain the compound of formula (VI): wherein R1, R2, R3, R4, R5, R6, R7, R14, A and n are as defined for formula (I) and Alk is as defined above, the Alk-OC (O) ester function of the compound of formula (VI) being hydrolyzed to give the carboxylic acid, which may optionally be reacted with an alcohol of formula R8-OH or a chlorinated compound of formula R8-C1, wherein R8 is as defined for formula (I), to obtain the compound of formula (I), which can be purified by a conventional separation technique, which is converted, if it is desired in 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 time considered appropriate during the process described above, certain groups (hydroxy, amino, etc.) of the starting reagents or synthesis intermediates may be protected, then deprotected and functionalized for the purposes of synthesis. The compounds of formulas (II), (III), (V), R8-OH and R8-C1 are either commercially available or are accessible to those skilled in the art by conventional chemical reactions and described in the literature.
[0009] The pharmacological study of the compounds of the invention has shown that they possess pro-apoptotic properties. The ability to reactivate the apoptotic process in cancer cells represents a major therapeutic interest in the treatment of cancers and autoimmune diseases and the immune system. In particular, the compounds according to the invention will be useful in the treatment of chemo- or radio-resistant cancers. Among the treatments for the cancers envisaged, mention may be made of, but not limited to, the treatment of cancers of bladder, brain, breast and uterus, chronic lymphoid leukemias, cancers of the colon, esophagus and liver, lyrnphoblastic leukemias, acute myeloid leukemias, lymphomas, melanomas, hematologic diseases malignancies, myeloma, ovarian cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer and small cell lung cancer. The present invention also relates to pharmaceutical compositions containing at least one compound of formula (I) in combination with one or more pharmaceutically acceptable excipients. Among the pharmaceutical compositions according to the invention, mention may be made, more particularly, of those which are suitable for oral, parenteral, nasal, per- or trans-cutaneous, rectal, perlingual, ocular or respiratory administration and in particular simple or sugar-coated tablets. , sublingual tablets, sachets, packets, capsules, glossettes, lozenges, suppositories, creams, ointments, dermal gels and oral or injectable ampoules. The dosage varies according to the sex, age and weight of the patient, the route of administration, the nature of the therapeutic indication, or possibly associated treatments, and ranges from 0.01 mg to 1 g per 24 hours. hours in one or more 20 administrations. In addition, the present invention also relates to the combination of a compound of formula (I) with an anticancer agent chosen from genotoxic agents, mitotic poisons, antimetabolites, proteasome inhibitors, kinase inhibitors and antibodies, as well as pharmaceutical compositions containing this type of combination and their use for preparing medicaments for use in the treatment of cancer. Advantageously, the present invention relates to the combination of a compound of formula (I) with an EGFR inhibitor, as well as pharmaceutical compositions comprising this type of combination.
[0010] In another embodiment, the present invention relates to the combination of a compound of formula (I) with an inhibitor of mTOR / PI3K, as well as pharmaceutical compositions comprising this type of combination. In a preferred embodiment, the present invention relates to the combination of a compound of formula (I) with an MEK inhibitor, as well as pharmaceutical compositions comprising this type of combination. Preferably, the present invention relates to the combination of a compound of formula (I) with a HER2 inhibitor, as well as pharmaceutical compositions comprising this type of combination. Advantageously, the present invention relates to the combination of a compound of formula (I) with an RAF inhibitor, as well as pharmaceutical compositions comprising this type of combination.
[0011] In another embodiment, the present invention relates to the combination of a compound of formula (I) with an EGFR / HER2 inhibitor, as well as pharmaceutical compositions comprising this type of combination. In a preferred embodiment, the present invention relates to the combination of a compound of formula (I) with a taxane, as well as pharmaceutical compositions comprising this type of combination. In another embodiment, the present invention relates to the combination of a compound of formula (I) with a proteasome inhibitor, an immunomodulator or an alkylating agent, as well as pharmaceutical compositions comprising this type of combination.
[0012] The combination of a compound of formula (D) with an anticancer agent may be administered simultaneously or sequentially The route of administration is preferably oral, and the corresponding pharmaceutical compositions may allow the instant or delayed release of the active ingredients In addition, the compounds of the combination may be administered in the form of two separate pharmaceutical compositions, each containing one of the active ingredients, or in the form of a single pharmaceutical composition in which the active ingredients are mixed. of the invention may also be used in combination with radiotherapy in the treatment of cancer Finally, the compounds of the invention may be bound to monoclonal antibodies or fragments thereof or may be linked to proteins which may or may not be related to monoclonal antibodies. 7- By antibody fragments, we must understand fragments of the Fv, scFv, Fab, F (ab ') 2, F (ab'), scFv-Fc, or diabodies type, which in general have the same specificity of binding that the antibody from which they are derived. According to the present invention, the antibody fragments of the invention can be obtained from antibodies by methods such as digestion with enzymes, such as pepsin or papain, and / or by cleavage of the disulfide bridges by chemical reduction. In another way, the antibody fragments included in the present invention can be obtained by genetic recombination techniques also well known to those skilled in the art or by peptide synthesis by means of automatic peptide synthesizers for example, such as than those provided by Applied Biosystems etc. By framework proteins which may or may not be related to monoclonal antibodies is meant a protein which contains or does not contain immunoglobulin folding and which provides binding capacity similar to that of a monoclonal antibody. One skilled in the art knows how to select the framework protein. More particularly, it is known that, to be selected, such a framework must have several characteristics, such as the following ones (Skerra A., J. Mol.Recogn., 2000, 13, 167187): a good phylogenetic conservation, a robust architecture with a well-identified three-dimensional molecular organization (by crystallography or NMR, for example), small size, no or little post-translational modification (s), ease of production, expression and purification. Such a framework protein can be, but is not limited to, a structure selected from the group consisting of fibronectin and, preferably, the tenth type III domain of fibronectin (FNfill 0), lipocalin, anticalin ( Skerra A., J. Biotechnol., 2001, 74 (4): 257-75), B domain-derived protein Z of staphylococcal protein A, thioredoxin A or any protein having a repetitive domain such as ankyrin repetition "(Kohl et al., PNAS, 2003, 100 (4), 1700-1705), an" armadillo repeat ", a" leucine-rich repeat "or a" tetratricopeptide repeat ". One could also mention a framework derived from toxins (such as toxins from scorpions, insects, plants or molluscs, for example) or proteins inhibiting neuronal nitric oxide synthase (PIN).
[0013] The following preparations and examples illustrate the invention and in no way limit it. General Procedures All reagents obtained from commercial sources were used without further purification. Anhydrous solvents were obtained from commercial sources and used without further drying.
[0014] Flash chromatography was performed on an ISCO CombiFlash Rf 200i with pre-filled silica gel cartridges (RediSeeRf Gold High Performance). Thin layer chromatography was performed with Merck Type 60 F254 silica gel coated 5 x 10 cm plates. Microwave heating was performed in an Anton Parr 10 MonoWave or CEM Discover® instrument. Purifications by preparative HPLC were carried out on an Armen Spot liquid chromatography system with a 10 μm Gemini-I DC column, M C18, 250 mm × 50 mm, at a flow rate of 118 ml miril with UV detection by diode array. (210 nm to 400 nm) using an aqueous solution of 25 mM NH4HCO3 and MeCN as eluents unless otherwise indicated. Analytical LC-MS: The compounds of the present invention were characterized by high performance liquid chromatography-mass spectrometry (HPLC-MS) on an Agilent HP1200 with an Agilent 6140 quadrupole LC / MS, operating in positive or negative ionization mode by ionic electrospray. The molecular weight scans range from 100 to 1350. Parallel UV detection was performed at 210 nm and 254 nm. Samples were injected as a 1mM solution in ACN or THF / H20 (1/1) in a 5 'loop. LC-MS analyzes were performed on two instruments, one operating with basic eluents and the other with acidic eluents.
[0015] Basic LC-MS: Gemini-NX column, 3 ptm, C18, 50 mm x 3.00 mm d.i. at 23 ° C, at a flow rate of 1 ml min1 using 5 mM ammonium bicarbonate (solvent A) and acetonitrile (solvent B) with a gradient starting with 100% solvent A and ending with 100% of solvent B for a certain variable duration. LC-MS acid: ZORBAX column Eclipse XDB-C18, 1.81,1m, 50mm x 4.6mm d.i. 30 to 40 ° C, at a flow rate of 1 ml min-1 using 0.02% v / v aqueous formic acid (solvent A) and 0.02% v / v formic acid in acetonitrile (solvent B) with a gradient starting with 100% solvent A and ending with 100% solvent B for a variable length of time. 1 H NMR measurements were performed on a 500 MHz Bruker Avance III spectrometer and a 400 MHz Bruker Avance III spectrometer, using DMSO-d6 or CDCl3 as the solvent. The 1H NMR data are in the form of delta values, given in part per million (ppm), obtained with respect to the residual peak of the solvent (2.50 ppm for DMSO-d6 and 7.26 ppm for CDCl3) taken as internal standard. The separation profiles are named: s (singlet), d (doublet), t (triplet), q (quadruple), quint (quintuple), m (multiplet), s large (singlet wide), dd (doublet of doublets) , td 10 (triplet of doublets), dt (doublet of triplets), ddd (doublet of doublet of doublets). Gas chromatography and low resolution mass spectrometry in combination were performed on an Agilent 6850 gas chromatograph and an Agilent 5975C mass spectrometer using a 15 mx 0.25 mm column with 0.25 HP coating. -5MS and helium as carrier gas. Ionic source: EI +, 70 eV, 230 ° C, quadrupole: 150 ° C, interface: 300 ° C. The high resolution masses (HRMS) were determined on an ITTOF Shimadzu, ionic source temperature of 200 ° C, ESI +/-, ionisation voltage: (+ -) 4.5 kV. Min. Mass resolution 10,000. Elemental analyzes were performed on a Thermo 20 Flash EA 1112 elemental analyzer. List of abbreviations Abbreviation Name Ac acetyl AIBN 2 - [(1-cyano-1-methylethyl) azo] -2-methyl-propaneni tri AtaPhos bis (di-tert-butyl (4-dimethylamino-phenyl) phosphine) dichloropalladium (II) DCM methylene chloride DIPA diisopropylamine DMF dimethylformamide DSC N, N'-disuccinimidyl carbonate eq. Equivalent HMDS ethyl hexamethyldisilazane 'Pr isopropyl Me methyl MeCN acetonitrile NB S N-bromosuccinimide n-butyl Ph phenyl PPh3 triphenylphosphine TA room temperature tBu tent-butyl' BuXPhos 2-di (tert-butylphosphino) -2 ', 4 ', 6'-triisopropylbiphenyl TEA triethylamine THF tetrahydrofuran General procedure I And ape A 5 1 eq. of Preparation 1, 2 eq. of the appropriate boronic acid derivative, 2 eq. of cesium carbonate and 0.1 eq. of bis (PPh 3) palladium (II) dichloride were placed in a flask. A mixture of 1,4-dioxane and water (4/1, 10 ml / mmol) was added and the resulting mixture was stirred at 60 ° C under an argon atmosphere until no longer observed. conversion. The reaction mixture was diluted with brine and the pH was adjusted to 6 with 2M aqueous HCl and extracted with DCM. Volatiles from the separated organic phase were evaporated under reduced pressure and the crude product was purified by flash chromatography using DCM and methanol as eluents.
[0016] Step B The resulting intermediate was dissolved in dioxane-water 1/1 (10 ml / mmol) and 10 eq. Li0f1 x H2O were added. The mixture was stirred at RT until no further conversion was observed. Then it was diluted with brine, neutralized with 2M aqueous HCl solution, extracted with DCM. The combined organic phases were dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase preparative chromatography using 5 mM aqueous NH4HCO3 solution and MeCN as eluents. The diastereoisomer eluted subsequently was collected. General Procedure II Step A 10 1 eq. Preparation 2 or 1 eq. Preparation 3, 2 eq. appropriate alcohol (unless otherwise indicated) and 2 eq. of PPh3 were dissolved in anhydrous toluene (0.2M for phenol). 2 eq. Di-tert-butyl azodicarboxylate was added and the mixture was stirred at 60 ° C under nitrogen until no further conversion was observed. Volatiles were evaporated under reduced pressure and the crude intermediate was purified by flash chromatography using ethyl acetate and methanol as eluents. Step B The resulting intermediate was dissolved in dioxane-water 1/1 (10 ml / mmol) and 10 eq. LiOH x H2O were added. The mixture was stirred at RT until no further conversion was observed. Then it was diluted with brine, neutralized with 2M aqueous HCl and extracted with DCM. The combined organic phases were dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase preparative chromatography using 5mM aqueous NH4HCO3 and MeCN as eluents. The diastereoisomer eluted subsequently was collected. General Procedure III Step A To a solution of 1 eq. Preparation 5 in anhydrous acetonitrile (15 ml / mmol), 1.5 eq. of DSC and 3 eq. of TEA was added and the mixture was stirred for one hour at RT. To the resulting mixture, 2 eq. of the appropriate amine were added, and the mixture was again stirred for 1 hour at RT. The reaction mixture was injected directly onto a flash silica column (160 g / mmol, conditioned with EtOAc) and chromatographed using EtOAc and MeOH (containing 1.2% NH 3) as eluents. Step B The product of Step A was dissolved in the dioxane-water mixture (1/1, 10 ml / mmol) and 10 eq. Li01-1 x H2O were added. The mixture was stirred at RT until no further conversion was observed. Then, it was neutralized with 2M HCl and injected directly onto an RP18 column and chromatographed using an aqueous solution of 5mM N1-14HCO3 and MeCN as eluents. The diastereoisomer eluted subsequently was collected. General Procedure IV Step A 1 eq. of the appropriate phenol derivative, 2 eq. the appropriate alcohol derivative and 2 eq. of PPh3 were dissolved in anhydrous toluene (0.2M for phenol) under N2 atmosphere, then 2 eq. Di-tert-butyl azodi-carboxylate was added and the mixture was stirred at 60 ° C until no further conversion was observed. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography using heptane and EtOAc as eluents. Step B 25 1 eq. of the phenol derivative obtained in step A was dissolved in anhydrous THF. The solution was cooled to -78 ° C under argon, then 1.2 eq. nBuLi (1.6M in hexane) was added dropwise. After 15 minutes, 1.5 eq. 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was added dropwise. The cooling bath was removed and the mixture allowed to warm slowly to RT. Then, the mixture was inactivated with NH4Cl solution and extracted with EtOAc. The combined organic phases were concentrated under reduced pressure and the crude product was purified by flash chromatography using heptane and EtOAc as eluents. 3037958 -33- General procedure V 1 eq. Preparation 1, 3 eq. of the appropriate boronic acid derivative, 4.5 eq. of cesium carbonate and 0.15 eq. of bis (PPh 3) palladium (II) dichloride in dioxane 5 (30 ml / mmol) and water (15 ml / mmol) were stirred under an N 2 atmosphere at 60 ° C until no more observe conversion. The reaction mixture was cooled to RT, then 20 eq. LiOH x 1-120 (832 mg / mmol) was added and the mixture was stirred until no further conversion was observed. The reaction mixture was diluted with brine, the pH was adjusted to 6 with 1M HCl, then the mixture was filtered and the precipitate was washed with dioxane. Volatiles from the filtrate were evaporated under reduced pressure and the residue was purified by reverse phase preparative chromatography using 25 mM aqueous NH4HCO3 and MeCN as eluents.
[0017] Preparation 1: (2R) -2- [543-chloro-2-methyl-el-2- (4-methylpiperazin-1-yl) ethoxyl-phenyl-6- (4-fluorophenyl) -thieno [2,3-dipyrimidin-4-] Ethyl ylioxy-3- [2- [(2-chloro-pyrimidin-1-yl) methoxy] phenylpropanoate EIape A: 6-iodo-3H-thieno [2,3-d] pyrimidin-4-one A balloon With a round bottom of 21 equipped with a mechanical stirrer, a thermometer and a reflux condenser was charged with a solution containing 433 ml of acetic acid, 13 ml of sulfuric acid and 87 ml of water. 69.3 g of 3H-thieno [2,3-c] pyrimidin-4-one (0.46 mol), 51.9 g of periodic acid (0.23 mol) and 104 g of iodine (0, 41 mol) were added to the stirring solution heated at 60 ° C. for 1 hour The resulting slurry was cooled to RT, filtered, washed with a mixture of acetic acid and water (5 / 1) and then with diethyl ether The resulting beige crystalline solid was air-dried to give 6-iodo-3H-thieno [2,3-d] pyrimidin-4-one 1H NMR (500 MHz , DMSO-d6) δ 12.57 (bs, 1H), 8.09 (s, 1H), 7.65 (s, 1H) 13 C NMR (125 MHz, DMSO-d6) δ 168.3, 155.9 , 146.1, 130.8, 126.7, 76.4. Step B: 4-Chloro-6-iodothiotho [2,3-d] pyrimidine A 1: 1 round-bottomed flask equipped with a mechanical stirrer, a thermometer, a condenser. Reflux and CaCl2 tube was loaded with 113 ml of phosphorous oxychloride and 35 ml of N, N-dimethylaniline (0.29 mol). 75.54 g of 6-iodo-3H-thieno [2,3-cipyrimidin-4-one (obtained in step A) (0.27 mol) was added to the mixture in portions over a period of 5 minutes. . The reaction mixture was stirred at 105 ° C for 1 hour. The resulting slurry was cooled to 10 ° C, filtered and washed with hexane. The crude product was added to ice water and stirred for 10 minutes, removed by filtration, washed with cold water, diethyl ether and air-dried to give 4 g. 6-chloro-6-iodothieno [2,3-d] pyrimidine as a beige crystalline solid. NMR111 (500 MHz, DMSO-d6) δ 8.89 (s, 1H), 7.98 (s, 1H) 13 C NMR (125 MHz, DMSO-d6) δ 172.3, 152.9, 151.9, 131.1, 128.9, 86.5 Step C: 5-bromo-4-chloro-6-iodothiotho [2,3-dipyrimidine A 21-bottom round bottom flask equipped with a mechanical stirrer, a thermometer and a bubbler was charged with 600 ml of MeCN. 84.9 g of 4-chloro-6-iodothieno [2,3-d] pyrimidine (obtained in step B) (0.29 mol), 50.9 g of NBS (0.29 mol) and 8.5 ml of tetrafluoroboric acid / diethyl ether complex was added. The reaction mixture was stirred at RT for 16 hours. An additional 22.9 g (0.12 mol) of NBS was added to the mixture in three portions. After cooling the suspension to 0 ° C. and stirring for a further 1 hour, the precipitate was removed by filtration, washed with acetonitrile and air dried to give 5-bromo-4-chloro-6- iodo-thieno [2,3-d] pyrimidine as a beige crystalline solid.
[0018] NMR11-1 (400 MHz, DMSO-d6) δ 8.88 (s, 1H) 13 C NMR (100 MHz, DMSO-d6) δ 171.3, 152.9, 152.3, 126.0, 112, 4.92.9. Step D: 5-Bromo-4-chloro-6- (4-fluorophenyl) thieno [2,3-dipyridine] 75.08 g of 5-bromo-4-chloro-6-iodothieno [2,3-d] pyrimidine ( obtained in step C) (200 mmol), 53.63 g of 2- (4-fluorophenyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane (240 mmol), 130 g of cesium carbonate (400 mmol), 2.245 g of Pd (OAc) 2 (10 mmol) and 8.50 g of iBu) (Phos (20 mmol) were placed in a 2 liter flask. 600 ml 3037958 THF and 200 ml of water were added, stirred overnight at 70 ° C. under an argon atmosphere, THF was evaporated and the product was collected by filtration. It was sonicated in 250 ml of MeCN and further filtered and then 5-bromo-4-chloro-6- (4-fluorophenyl) thieno [2,3-d] pyrimidine was crystallized from EtOH / THF ( 2/1) NMR (400 MHz, DMSO-d6): 9.02 (s, 1H), 7.80-7.77 (m, 2H), 7.47-7.43 (m, 2H). Step E: [2- (bromomethyl) phenyl] acetate 60.07 g of 2-methylphenyl acetate (400 mmol) and 106.8 g of NBS (600 mmol) were placed in a 1 1 flask. 500 ml of cyclohexane was added, followed by intensive stirring, 3.244 g of AIBN (20 mmol) were added. added over a period of 30 minutes. The mixture was stirred at 80 ° C until no conversion was observed, then cooled to RT. The precipitate was removed by filtration and washed with cyclohexane. The mother liquor was concentrated under reduced pressure, and the crude product was used in step B without further purification. Step F: Ethyl 2-acetoxy-3- (2-hydroxyphenyl) propanoate 23.10 g of anhydrous LiCl (545 mmol) and 65.36 g of anhydrous ZnCl 2 (479.6 mmol) were placed in a flask of 2 1, then dried at 160 ° C under 0.1 mmHg for 1 hour.
[0019] After cooling to RT under an argon atmosphere, 26.49 g of magnesium turnings (1090 mmol) and 1 l of anhydrous THF previously cooled (0 ° C) THF were added. The resulting mixture was immersed in an ice bath and then left stirring for 30 minutes. 100 g of [2- (bromomethyl) phenyl acetate] (obtained in step E) (436 mmol) was dissolved in 120 ml of anhydrous THF and added to the inorganic substances previously cooled over a period of 15 minutes. After adding the reagent, the resulting mixture was allowed to stir for 45 minutes while maintaining the temperature between 0 ° C and 5 ° C. To the mixture, 64.82 ml of ethyl 2-oxoacetate (654 mmol, 50% in toluene) was added over a period of 5 minutes and the resulting mixture was allowed to stir for a further 15 minutes. The remaining inorganic substances were removed from the mixture by filtration and then 500 ml of MeOH was added to the filtrate. This mixture was allowed to stir until the intramolecular migration of the acetyl group from phenolic oxygen to oxygen of the alkyl was complete. To the mixture, 30 ml of acetic acid was added, and then the volatiles were evaporated under reduced pressure. To the residue, 350 ml of water was added and the mixture was extracted with EtOAc. The combined organic phases were washed with saturated NaHCO 3 and brine, then dried over MgSO 4, filtered and evaporated under reduced pressure. To the residue, 100 ml of hexane was added and the mixture was stirred for 30 minutes at 0 ° C. The formed white crystals were collected by filtration and washed with hexane to give ethyl-2-acetoxy-3- (2-hydroxyphenyl) - (rac). 1 H NMR (500 MHz, DMSO-d 6) δ 9.53 (s, 1H), 7.06 (t, 1H), 7.04 (d, 1H), 6.79 (d, 1H), 6.71. (t, 1H), 5.10 (dd, 1H), 4.05 (q, 2H), 3.06 (dd, 1H), 2.94 (dd, 11-1), 2.00 (s, 3H), 1.09 (t, 3H). Step G: Ethyl (2R) -2-acetoxy-3- (2-hydroxyphenyl) propanoate and Ethyl (2S) -2-acetoxy-3- (2-hydroxyphenyl) -proparwate The enantiomers of 2-acetoxy Ethyl 3- (2-hydroxyphenyl) propanoate (obtained in step F) was separated by chiral clu-omatography. Column: OD; Eluents: heptane / EtOH; the enantiomer eluted first was collected as ethyl (2S) -2-acetoxy-3- (2-hydroxyphenyl) propanoate having 99.8% ce and the last eluted enantiomer was collected in the form of ethyl (2R) -2-acetoxy-3- (2-hydroxyphenyl) propanoate having an ee of 99.9%. Step H: (4-bromo-2-chloro-phenoxy) -trimethyl-silane 20.8 g of 4-bromo-2-chlorophenol (100 mmol) was dissolved in 150 ml of anhydrous THF and then 24.2 ml. g HMDS (150 mmol) were added. The reaction mixture was stirred at 85 ° C under an argon atmosphere for 1.5 hours and then concentrated under reduced pressure to give the used product without further purification. 1H NMR (200 MHz, CDCl 3): 7.49 (d, 1H), 7.23 (dd, 1H), 6.75 (d, 1H), 0.26 (s, 9H). Step I. 4-bromo-2-chloro-3-methylphenol 48 ml of a solution of SuLi in hexane (2.5 M, 120 mmol) was added dropwise to a solution containing 12.1 g of anhydrous DIPA (120 mmol) in 250 ml of anhydrous THF at -78 ° C. under an argon atmosphere. The mixture was stirred for 30 minutes at the same temperature, then 28.0 g of (4-bromo-2-chlorophenoxy) -trimethylsilane (obtained in step H) (100 mmol). were added dropwise. After 2.5 hours, 21.3 g of Mel (150 mmol) was added dropwise, then the cooling bath was removed and the mixture was stirred overnight. The reaction was quenched with 100 ml of NH4OH solution and 200 ml of NH4Cl solution and extracted with EtOAc, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting black mass was refluxed in pure hexane several times (150 ml to 150 ml aliquots) and decanted to leave a black tar. The combined organic phases were concentrated under reduced pressure to give 19.0 g of 4-bromo-2-chloro-3-methyl-phenol, the crude product being used without further purification. NMR11 (200 MHz, CDCl3): 7.32 (d, 1H), 6.76 (d, 1H), 5.62 (s, 1H), 2.49 (s, 3H) Step J: (4-bromo) 2-chloro-3-methyl-phenoxy) -tri-methyl-silane 20.8 g of HMDS (129 mmol) was added to a solution containing 19.0 g of 4-bromo-2-chloro-3- methylphenol (obtained in stage I) (86.0 mmol) in 150 ml of anhydrous THF. The mixture was stirred at 85 ° C. under argon in a flask for 1.5 hours and then concentrated under reduced pressure. The (4-bromo-2-chloro-3-methyl-phenoxy) trimethyl silane obtained was used without further purification. NMR (200 MHz, CDCl3): 7.30 (d, 1H), 6.63 (d, 1H), 2.50 (s, 3H), 0.28 (s, 9H) Step K: 2-Chloro -3-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-phenol) A solution containing 25.2 g (4-bromo-2-chloro-3-methyl-phenoxy) ) -trimethylsilane (obtained in Step J) (86.0 mmol) in 250 ml of anhydrous THF was cooled to -78 ° C under argon, then 38 ml of SuLi in hexane (2.5M, 94%). 6 mmol) were added dropwise After 19 minutes, 19.2 g of 2-iso-propoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (103 mmol) was added. The cooling bath was removed and the mixture was allowed to warm slowly to RT, then the mixture was added to 200 ml NH4Cl solution and extracted with 30 ml. EtOAc The combined organic layers were concentrated under reduced pressure and passed through a pad of silica gel using hexane and EtOAc as eluents. was recrystallized from a mixture of EtOAc and hexane to obtain 2-chloro-3-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2). -yi) phenol. 1H NMR (500 MHz, DMSO-d6): 10.40 (s, 1H), 7.42 (d, 1H), 6.80 (d, 11-1), 2.49 (s, 3H), 1.27 (s, 12H).
[0020] Step L: 1-12-12-Chloro-3-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxylethyl-4-methylpiperazine 10.0 g of 2-chloro-3-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (obtained in Step K) ( 37.2 mmol), 8.7 g of 2- (4-methylpiperazin-1-yl) ethanol (60.3 mmol) and 15.8 g of PPh 3 (60.3 mmol) were dissolved in 100 ml of toluene. Anhydrous, then 27 ml of diethyl azodicarboxylate (60.3 mmol, 40% solution in toluene) was added dropwise. The mixture was stirred at 50 ° C under argon for 1.5 hours. The volatiles were evaporated under reduced pressure and 100 ml of Et 2 O was added. The precipitated white crystals were filtered and washed with Et2O. The filtrate was concentrated under reduced pressure and purified by flash chromatography using CHCl 3 and MeOH as eluents. The resulting light brown oil was crystallized from hexane to give 14242-chloro-3-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxylethyl. ] -4-methylpiperazine in the form of an off-white solid. 1 H NMR (500 MHz, DMSO-d 6): 7.56 (d, 1H), 6.99 (d, 1H), 4.15 (t, 211), 2.72 (t, 211), 2.51 (b.p. s, 3H), 2.50 (bs, 4H), 2.29 (bs, 4H), 2.13 (s, 3H), 1.29 (s, 1214) Step M (2R) -2 Ethyl-acetoxy-3- [2 - [(2-chloropyrimidin-4-yl) methoxylphenylpropanoate 9.06 g of ethyl (2R) -2-acetoxy-3- (2-hydroxyphenyl) -propanoate (obtained from step G, 36 mmol), 7.12 g of 2-chloro-4- (chloromethyl) pyrimidine (44 mmol), 5.97 g of K 2 CO 3 (44 mmol) and 1.22 g of ICI (1, 22 mmol) were placed in a 250 ml flask. 70 ml of DMF was added and the mixture was stirred at RT under N 2 until no further conversion was observed. Then, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using heptane and EtOAc as eluents to give ethyl (2R) -2-acetoxy-342 - [(2-chloropyrimidin-4-ylmethoxy) phenyl] propanoate. 1H NMR (500 MHz, DMSO-d6) 8.86 (d, 1H), 7.69 (d, 1H), 7.25 (td, 1H), 7.23 (dd, 1H), 3037958; 39-7.03 (d, 1H), 6.95 (td, 1H), 5.30 (d, 1H), 5.25 (d, 1H), 5.16-5.13 (m, 1H) 4.07 (qm, 2H), 3.28 (dd, 1H), 3.09 (dd, 1H), 2.00 (s, 3H), 1.09 (t, 3H). Ethyl 2R) -3-12 - [(2-chloropyrimidin-4-Amethoxyphenyl) -2-hydroxypropanoate 8.568 g of (2R) -2-acetoxy-342 - [(2-chloro-pyrimidin-4-yl) ethyl (methoxy) phenylpropanoate (obtained in step M) (23 mmol) were dissolved in 100 ml of ethanol, followed by 1.8 ml of a solution of sodium ethanolate (1.0M in ethanol) was added and the mixture was stirred until no further conversion was observed.The reaction mixture was diluted with water and extracted with acetic acid. The combined organic phases were dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using heptane and EtOAc as eluents to give (2R) -342 - [(2-chloropyrimidin-4-yl) methoxy] -phenyl] -2-hydroxy ethyl propanoate. NMR 11-1 (500 MHz, DMSO-d6) δ 8.84 (d, 1H), 7.70 (d, 1H), 7.20 (in, 1H), 7.19 (dm, 1H), 7.00 (dm, 1H), 6.91 (nl, 1H), 5.52 (d, 1H), 5.27 (d, 1H), 5.24 (d, 111), 4.06 (in , 1H), 4.04 (m, 1H), 3.13 (dd, 1H), 2.84 (dd, 1F1), 1.11 (t, 3H). Step O: Preparation I 17.18 g of 5-bromo-4-chloro-6- (4-fluorophenyl) -thieno [2,3-d] pyrimidine (obtained in step D, 50 mmol) and 18, 52 g of ethyl (2R) -3- [2 - [(2-chloropyrimidin-4-yl) methoxy] phenyl] -2-hydroxypropanoate (obtained in step N, 55 mmol) were dissolved in 250 ml of anhydrous THF, then 48.87 g of Cs 2 CO 3 (150 mmol) were added and the mixture was stirred at 70 ° C under N 2 until no further conversion was observed. The reaction mixture was cooled to RT, then 2.17 g of 14242-chloro-3-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl). phenoxy] -ethyl-4-methylpiperazine (obtained in step L, 55 mmol), 560 mg of AtaPhos (2.5 mmol) and 250 ml of H 2 O were added, and the mixture was allowed to stir under nitrogen at 70 ° C until no further conversion. Then it was diluted with EtOAc and brine.
[0021] After phase separation, the aqueous phase was extracted with EtOAc. The organic phases were combined and dried over Na2SO4, filtered and concentrated under reduced pressure. The product was separated by flash chromatography using EtOAc and MeOH (containing 1.2% NH 3) as eluents. Preparation 1 was obtained as a mixture of atropisomers. 1 H NMR (500 MHz, DMSO-d 6) δ 8.87 (dd, 1H), 8.60 (s, 1H), 7.69 (dd, 1H), 7.35-7.26 (m, 2H). ), 7.22 (t, 21I), 7.20-7.10 (m, 2H), 7.02-6.91 (m, 1H), 6.87 (d, 1H), 6.72 (b.p. t, 1H), 6.15 (d, 1H), 5.47 (dd, 1H), 5.22 (s, 2H), 4.29-4.11 (m, 211), 4.00 (m, 2H), 3.15-2.15 (bs, 8H), 3.13 (dd, 2H), 2.73-2.65 (m, 2H), 2.09 (s). , 3H), 1.86 (s, 311), 1.06 (t, 3H) (M + 2H) 2+ = 416.1179 Preparation 2: (2R) -2-15-13-chloro-2-methyl -4-12- (4-methylpiperazin-1-yl) ethoxyl-phenyl-6- (4-fluorophenyl) -thieno [2,3-d] pyrimidin-4-yl] oxy-3-124-yl Ethyl-hydroxyphenyl) pyrimidin-4-ylmethylphenyl] propanoate Following the general procedure I, step A, and taking 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan) 2-yl) phenol as the appropriate boronic acid derivative, Preparation 2 was obtained as a mixture of diastereomers.
[0022] 1 H-NMR (500 MHz, DMSO-d6) 9.65 (bs, 1H), 8.95 (d, 1H), 8.58 (s, 1H), 7.88-7.80 (m, 2H); ), 7.57 (d, 1H), 7.33 (d, 1H), 7.32-7.27 (m, 2H), 7.3 (t, 1H), 7.24-7.14 ( or, 4H), 7.05 (d, 1H), 6.94-6.90 (dm, 1H), 6.78-6.73 (tm, 1H), 6.30 (dd, 1H), , 51 (dd, 1H), 5.30 (d, 1H), 5.24 (d, 1H), 4.26-4.00 (in, 41-1), 3.17 (dd, 1H), 2.76 (bs, 2H), 2.58 (dd, 1H), 2.42 (bs, 311), 3.00-2.30 (bs, 8H), 1.86 (s, 3H); ), 1.06 (t, 3H). (M + 2H) 2 = 445.1524. Preparation 3: (2R) -2-15-P-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxyl-phenyl-6- (4-fluorophenyl) -thino [2, Ethyl 3- (pyrimidin-4-yl) oxy-3-12-1 [2- (4-hydroxyphenyl) pyrimin-4-yl] ethoxy] phenyl] propanoate Following the general procedure I, step A, and taking 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol as the appropriate boronic acid derivative, Preparation 3 was obtained in the form of a mixture of diastereomers. NMR 111 (500 MHz, DMSO-d6) δ 10.01 (s, 1H), 8.86 (d, 111), 8.58 (s, 1H), 8.24 (d, 2H), 7.46 (d, 1H), 7.33 (d, 1H), 7.32-7.27 (m, 2H), 7.21 (t, 2H), 7.21-7.15 (m, 2H), 7.04 (d, 111), 6.87 (d, 2H), 6.74 (t, 111), 6.29 (d, 1H), 5.52 (dd, 1H), 5.26 (d, 1H), d, 1H), 5.20 (d, 1H), 4.19 (bs, 2H), 4.10-4.00 (m, 211), 3.16 (dd, 1H), 3.03- 2.41 (m, 1311), 2.56 (dd, 1H), 1.86 (s, 3H), 1.05 (t, 3H). (M + 2H) 24. = 445.1517. Preparation 4a: 242 - [(2,2-dimethyl-1,3-dioxolan-4-yl) methoxy] phenyl] -4,4,5,5-tetramethyl-1,3,2-dioxa-borolane Following the procedure General IV, and taking 2-iodophenol as the appropriate phenol and (2,2-dimethyl-1,3-dioxolan-4-yl) methanol as the appropriate alcohol, Preparation 4a was obtained. 1H NMR (500 MHz, DMSO-d6) δ 7.50 (dd, 1H), 7.41 (tm, 1H-1), 6.98 (d, 1H), 6.93 (td, 1H), 4 , 37-4.31 (m, 1H), 4.08-4.02 (m, 2H), 4.03 (dd, 1H), 3.96 (dd, 1H), 1.36 (s, 3H) ), 1.30 (s, 3H), 1.27 (s, 12H).
[0023] Preparation 4b: 2-1242- (2-methoxyethoxy) ethoxy-phenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Following general procedure IV, and taking 2-iodophenol as Suitable phenol and 2- (2-methoxyethoxy) ethanol as the appropriate alcohol, Preparation 4b was obtained. NMR111 (500MHz, DMSO-d6) 7.48 (dm, 1H), 7.42-7.37 (m, 1H), 6.94 (dm, 1H), 6.92-6.90 (m.p. , 1H), 4.05-4.01 (m, 2H), 3.76-3.72 (m, 2H), 3.70-3.67 (m, 2H), 3.463.43 (m, 2H) ), 3.24 (s, 3H), 1.26 (s, 12H). Preparation 4c: 242-1242- (2-methoxyethoxy) ethoxy-ethoxy] phenyl] -4,4,5,5-tetramethyl-1,3,2-dioxaborolane Following general procedure IV, and taking 2- iodophenol as the appropriate phenol and 242- (2-methoxyethoxy) ethoxyethanol as the appropriate alcohol, Preparation 4c was obtained. RIVINIH (500 MHz, DMSO-d6) 7.48 (dm, 1H), 7.49-7.46 (m, 1H), 6.94 (dm, 1H), 6.93-6.89 (m.p. , 111), 4.04-4.01 (m, 2H), 3.75-3.72 (m, 2H), 3.71- 3.39 (m, 8H), 3.22 (s, 3H), 1.26 (s, 12H). Preparation 4d: 242- (2-methoxyethoxymethyl) phenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Step A: 1-Bramo-2- (2-methoxyethoxymethyl) benzene To 20 ml of 2-methoxyethanol (672 mmol, 20 eq.), 4.03 g of sodium hydride (100.8 mmol, 60% in oil, 3 eq.) Were added in small portions at 0 ° C. After 3037958 -42 Stirring for 30 minutes, 8.40 g of 1-bromo-2- (bromomethyl) benzene (33.6 mmol, 1 eq) was added and the reaction mixture was removed from the cooling bath and allowed to stir at room temperature. TA to no longer observe conversion The reaction mixture was diluted with EtOAc and brine After extraction, the organic phase was washed with brine and dried over MgSO 4, filtered and concentrated under pressure The crude product was purified by flash chromatography using heptane and EtOAc as eluents to give 1-bromo-2- (2-methoxyethoxymethyl) benzene. 400 MHz, DMSO-d6) δ 7.60 (d, 1H), 7.49 (d, 1H), 7.39 (t, 1H), 7.24 (t, 1H), 4.52 (s, 2H), 3.63 (dd, 2H), 3.51 (dd, 214), 3.27 (s, 3H).
[0024] Step B: Preparation 4d The product of Step A was converted to the appropriate boronic ester by following General Procedure W, Step B, to obtain Preparation 4d. 1H NMR (400MHz, DMSO-d6) δ 7.80 (d, 1H), 7.50 (d, 1H), 7.43 (t, 1H), 7.28 (t, 1H), 4.85. (s, 2H), 3.66 (dd, 15H), 3.59 (dd, 2H), 3.41 (s, 314), 1.36 (s, 12H). Preparation 4e: 4,4,5,5-tetramethyl-2,4- (2-tetrahydropyran-2-yloxyethoxymethyl) phenyl] -1,3,2-dioxa-borolane Step A: 2-P - [(2 (iodophenyl) methoxy] ethoxyltetrhydropyran To a solution containing 2.34 g of (2-iodo-phenyl) methanol (10 mmol, 1 eq) in 25 ml of anhydrous DMF, 440 mg of sodium hydride (11 mmol 60% in oil, 1.1 eq.) Were added in small portions at 0 ° C. After stirring for 30 minutes, 2.5 g of 2- (2-bromoethoxy) tetrahydropyran (12 mmol, 1.2 eq) was added and the reaction mixture was removed from the cooling bath and allowed to stir. at 50 ° C until no further conversion. The reaction mixture was diluted with EtOAc and brine. After extraction, the organic phase was washed with brine and dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using heptane and EtOAc as eluents to obtain 2- [2 - [(2-iodophenyl) methoxy] ethoxy] tetrahydropyran. NMR (400 MHz, CDCl 3) δ 7.83 (d, 1H), 7.50 (d, 1H), 7.36 (t, 1H), 6.99 (t, 11I), 4.70 (t, 1H), 1H), 4.59 (s, 2H), 3.98-8.88 (m, 2H), 3.79-3.76 (m, 2H), 3.73-3.68 (m.p. m, 1H), 3.56-3.51 (m, 1H), 1.94-1.83 (m, 1H), 1.80-1.73 (m, 11-1), 1.70- 1.52 (m, 4H). Step B: Preparation 4 To a solution containing 1.0 g of product of Step A (2.76 mmol, 1 eq) in 15 ml of anhydrous THF, 4.24 ml of iPrMgCl x LiCl (5, 52 mmol, 1.3M in THF, 2 eq.) Was added at 0 ° C over a period of 2 minutes. After stirring for 10 minutes, 1.40 ml of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.9 mmol, 2.5 eq) was added and was stirred at 0 ° C until no further conversion was observed. The reaction mixture was diluted with EtOAc and brine. After extraction, the organic phase was washed with brine and dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using heptane and EtOAc as eluents to obtain Preparation 4e. 1 H NMR (400 MHz, CDCl 3) δ 7.80 (d, 1H), 7.53 (d, 1H), 7.44 (t, 1H), 7.28 (t, 1H), 4.87 (s). , 11-1), 4.68 (t, 211), 3.94-3.87 (m, 2H), 3.76-3.64 (in, 3H), 3.54-3.49 (m.p. m, 1H), 1.93-1.82 (m, 1H), 1.78-1.71 (m, 111), 1.69-1.52 (m, 4H). Preparation 4f: 242-1 (2,2-dimethyl-1,3-dioxolan-4-yl) methoxymethyl-phenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Step A: 4-1 ( 2-bromophenylmethoxymethyl] -2,2-di-methyl-1,3-dioxolane To a solution containing 1.3 ml of (2,2-dimethyl-1,3-dioxolan-4-yl) methanol (11 mmol, 1 1 eq.) In 25 ml of anhydrous DMF, 440 mg of sodium hydride (11 mmol, 60% in oil, 1.1 eq.) Were added in small portions at 0 ° C. After 30 minutes After stirring, 2.5 g of 1-bromo-2- (bromomethyl) benzene (10 mmol, 1 eq) was added, then the reaction mixture was removed from the cooling bath and allowed to stir at room temperature. TA to no longer observe conversion The reaction mixture was diluted with EtOAc and brine After extraction, the organic phase was washed with brine and dried over MgSO4, filtered and concentrated under reduced pressure The crude product 30 was purified by flash chromatography using t heptane and EtOAc as eluents to give 4 - [(2-bromo-phenyl) methoxymethyl] -2,2-dimethyl-1,3-dioxolane. 1H NMR (400MHz, CDCl3) δ 7.55 (d, 1H), 7.49 (d, 1H), 7.33 (t, 1H), 7.17 (t, 1H), 4.653. 44 (dd, 2H), 4.36 (which, 1H), 4.11 (dd, 1H), 3.82 (dd, 1H), 3.67 (dd, 1H), 3.59 (dd, 1H), 1.46 (s, 31-1), 1.39 (s, 3H). Step B: Preparation 4f The product from Step A was converted to the appropriate boronic ester by following General Procedure IV, Step B, to obtain Preparation 4f. 1H NMR (400 MHz, DMSO-d 6) δ 7.65 (d, 1H), 7.45 (t, 1H), 7.41 (d, 1H), 7.29 (t, 1H), 4.68 (b.p. dd, 2H), 4.20 (which, 1H), 3.98 (dd, 1H), 3.62 (dd, 1H), 3.51-3.42 (m, 2H), 1.30 (s). , 3H), 1.30 (s, 12H), 1.26 (s, 3H).
[0025] Preparation 4g: 4,4,5,5-tetramethyl-2,443- (2-tetrahydropyran-2-yloxyethoxymethyl) phenyl] -1,3,2-dioxaborolane Step A 2-12 - [(3-iodophenyl) To a solution containing 2.34 g of (3-iodo-phenyl) methanol (10 mmol, 1 eq) in 25 ml of anhydrous DMF, 440 mg of sodium hydride (11 mmol, 60% in oil, 1.1 eq.) were added in small portions at 0 ° C. After stirring for 30 minutes, 2.5 g of 2- (2-bromoethoxy) tetrahydropyran (12 mmol, 1.2 eq.) Was added, then the reaction mixture was removed from the cooling bath and left undisturbed. stir at 50 ° C until no further conversion. The reaction mixture was diluted with EtOAc and brine. After extraction, the organic phase was washed with brine and dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using heptane and EtOAc as eluents to give 242 - [(3-iodophenyl) methoxy] ethoxyltetrahydropyran. MS (EI, 70 eV) in / z (% relative intensity, [ion]): 85 (100), 217 (57), 233 (15), 278 (15), 362 (1). Step B: Preparation 4g To a solution containing 1.0 g of product of Step A (2.76 mmol, 1 eq) in 15 ml of anhydrous THF, 4.24 ml of iPrMgCl x LiCl (5.52 mmol, 1.3M in THF, 2 eq.) were added at 0 ° C over a period of 2 minutes. After stirring for 10 minutes, 1.40 ml of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.9 mmol, 2.5 eq) was added, and the mixture was stirred at 0 ° C until no further conversion was observed. The reaction mixture was diluted with EtOAc and brine. After extraction, the organic phase was washed with brine and dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using heptane and EtOAc as eluents to obtain Preparation 4g. 1H NMR (400 MHz, CDCl3) δ 7.79 (s, 11-1), 7.75 (d, 1H), 7.51 (d, 111), 7.38 (t, 1H), 4, 67 (t, 1H), 4.63 (d, 1H), 4.59 (d, 1H), 3.95-3.83 (m, 2H), 3.71-3.62 (m, 3H) , 3.55-3.48 (m, 1H), 1.491.47 (m, 6H), 1.37 (s, 12H). Preparation 4h: 2- [3-12-methoxy-1- (methoxymethyl) ethoxylphenyl] -4,4,5,5-tetramethyl-1,3,2-dioxaborolane To a solution containing 880 mg (4mmol, 1 eq. .) 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol and 1371 mg (5.0 mmol, 1.25 eq) of 4-methylbenzene sulfonate. 2-methoxy-1- (methoxymethyl) ethyl] in 16 ml of DMF, 1954 mg (6.0 mmol, 1.5 eq) of cesium carbonate was added and the mixture was stirred at 75 °. C for 16 hours, then at 85 ° C. for 8 hours The reaction mixture was cooled to RT and concentrated under reduced pressure To the residue, 25 ml of brine was added and the mixture was extracted with 3 x 25 ml of ethyl acetate The combined organic phases were dried over MgSO 4 and concentrated under reduced pressure The residue was purified by flash chromatography on silica gel using heptane and acetate of ethyl as eluents to give Preparation 4h High resolution mass (HRMS) calculated for C17H27BO5: 322.1952; found 323.2025 (M + H). Preparation 4i: 24442-m ethoxy-1- (m ethoxymethyl) ethoxylphyl] -4,4,5,5-tetramethyl-1,3,2-dioxaborolane To the solution containing 880 mg (4 mmol, 1.0 eq.) of 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol and 1371 mg (5.0 mmol, 1.25 eq) of 4-methyl [2-methoxy-1- (methoxymethyl)] benzene sulphonate in 16 ml of DMF, 1954 mg (6.0 mmol, 1.5 eq) of cesium carbonate was added and the mixture was stirred at 75.degree. The reaction mixture was cooled to RT and concentrated under reduced pressure To the residue, 25 ml of brine was added and the mixture was extracted with 3 x 25 ml of acetate. The combined organic phases were dried over MgSO 4 and concentrated under reduced pressure The residue was purified by flash chromatography on silica gel using heptane and ethyl acetate as electors to give the Pr separation 4i High resolution mass (HRMS) calculated for C171-127B05: 322.1952; found 323.2036 (M + H).
[0026] Preparation 4i: 1 (2R) -4,5-Diacetoxy-6-methoxy-24 [3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy] acetate Methyltetrahydropyran-3-yl] Step A: Methyl Z3,4-tri-O-adtyl-α-D-mannopyranoside 2.25 g (4 mmol) 2,3,4-tri-O-acetyl-6-triphenylmethyl Methyl α-mannopyranoside was dissolved in 30 ml of acetic acid at 85 ° C, then 15 ml of water was added and the mixture was stirred at 90 ° C for 1 hour. The mixture was cooled to RT and then poured into ice-cold brine. The mixture was filtered and the filtrate was extracted with dichloromethane. The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using heptane and ethyl acetate as eluents to give methyl 2,3,4-tri-O-acetyl-α-Dmannopyranoside. NMR (500 MHz, DMSO-d6): 5.11-5.03 (m, 3H), 4.85 (t, 1H), 4.73 (d, 1H), 3.65 (m, 1H), 3.48 (m, 1H), 3.42 (m, 1H), 3.33 (s, 3H), 2.11-1.91 (s, 9H).
[0027] Step B: Preparation 4j From methyl 2,3,4-tri-O-acetyl-α-D-mannopyranoside and 344,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl phenol and following the general procedure IV, step A, Preparation 4j was obtained. IRNIFI (500 MHz, DMSO-d6): 7.31 (t, 1H), 7.26 (m, 1H), 7.15 (m, 1H), 7.06 (in, 1H), 5.25. (t, 1H), 5.12 (m, 1H), 5.11 (m, 1H), 4.79 (d, 1H), 4.13 (dd, 1H), 4.05 (dd, 1H) 3.99 (m, 1H), 3.36 (s, 3H), 2.15-1.92 (s, 9H), 1.29 (s, 12H). Preparations: 4,4,5,5-tetramethyl-2,443-1 [(2S) -3,4,5,6-tetramethoxytetrahydropyran-2-yl] methoxyl-phenyl] -1,3,2-dioxaborolane Step A: Methyl-6-triphenylmethyl 2,3,4-tri-O-methyl-α-mannopyranoside To a solution containing methyl 8-triphenylmethyl-α-D-mannopyranoside (8.08 g, 18.51 mmol) 150 ml of DMF, 2.89 g of sodium hydride (60% in mineral oil, 72.2 mmol, 3.9 eq.) Were added portionwise at 0 ° C. and the mixture was left undisturbed. stirring at this temperature for 30 minutes. Then 5.20 ml of MeI (11.8 g, 83.3 mmol, 4.5 eq) was added dropwise at 0 ° C and the mixture was stirred at RT for 16 hours. hours. To the reaction mixture, 10 ml of MeOH was added and allowed to stir for 15 minutes and then concentrated under reduced pressure. The residue was diluted with 200 ml of water and extracted with DCM. The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using heptane and ethyl acetate as eluents to give methyl 2,3,4-tri-O-methyl-α-D-mannopyranoside. 6-triphenyl-methyl. 1 H NMR (500 MHz, DMSO-d 6): 7.44-7.23 (m, 15H), 4.85 (d, 1H), 3.58 (dd, 1H), 3.48 (m, 1H); ), 3.39 (s, 3H), 3.36 (s, 3H), 3.33 (dd, 1H), 3.31 (s, 3H), 3.28 (t, 1H), 3.23 (s, 3H), (dd, 1H), 3.11 (s, 3H), 3.1 (dd, 1H).
[0028] Step B: methyl 2,3,4-tri-O-methyl-α-marmopyranoside 1,914 g of methyl-6-triphenylmethyl 2,3,4-tri-O-methyl-α-mannopyranoside (4.0 mmol) ) was dissolved in 30 ml of acetic acid at 85 ° C, then 15 ml of water was added and the mixture was stirred at 90 ° C for 1 hour. It was cooled to RT and poured into ice-cold brine. The mixture was filtered and the filtrate was extracted with dichloromethane. The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using heptane and ethyl acetate as eluents to give methyl 2,3,4-tri-O-methyl-α-D-mannopyranoside.
[0029] NMR (500 MHz, DMSO-d6): 4.72 (d, 1H), 4.63 (bs, 1H), 3.56 (dd, 111), 3.54 (dd, 1H), 3, 47 (dd, 111), 3.36 (s, 3H), 3.34 (s, 3H), 3.32 (m, 1H), 3.32 (s, 3H), 3.26 (s, 3H); ), 3.24 (m, 1H), 3.22 (m, 1H). Step C: Preparation 4k From methyl 2,3,4-tri-O-methyl-α-D-mannopyranoside and 344,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl) phenol and following the general procedure IV, step A, Preparation 4k was obtained. NMR111 (500 MHz, DMSO-d6): 7.31 (dd, 1H), 7.25 (dm, 1H), 7.19 (m, 1H), 7.09 (dm, 1H), 4.77 ( d, 1H), 4.14 (dd, 1H), 4.09 (dd, 1H), 3.60 (m, 1H), 3.59 (dd, 1H), 3.41 (t, 1H), 3.38 (dd, 1H), 3.37 (s, 3H), 3.36 (s, 3H), 3.34 (s, 3H), 3.33 (s, 3H), 1.29 (s). , 12H).
[0030] Preparation 41: [(2R) -4,5-Diacetoxy-6-methoxy-2 - [[4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) acetate) phenoxy] methyltetrahydropyran-3-yl] from methyl 2,3,4-tri-O-acetyl-α-D-mannopyranoside (obtained in Preparation 4j, step A) and from 4- (4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl) -phenol, and following the general procedure IV, step A, Preparation 41 was obtained. NMR (500 MHz, DMSO-d6): 7.60 (m, 2H), 6.92 (m, 2H), 5.23 (t, 1H), 5.13 (dd, 1H), 5.11 (m.p. (dd, 1F1), 4.80 (d, 1H), 4.14 (dd, 1H), 4.06 (dd, 1H), 4.02 (m, 1H), 3.36 (s, 3H); , 2.14-1.92 (s, 9H), 1.27 (s, 12H). Preparation 4m: 4,4,5,5-tetramethyl-2,444-11 (2S) -3,4,5,6-tetramethoxytetrahydropyran-2-ylimethoxy-phenyl] -1,3,2-dioxaborolane From 2, Methyl 3,4-tri-O-methyl-α-D-mannopyranoside (obtained in Preparation 4j, Step A) and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- Y-phenol, and following general procedure IV, step A, Preparation 4m was obtained.1H NMR (500 MHz, DMSO-d6): 7.61 (m, 2H), 6.96 (m, 2H) , 4.77 (cl, 1H), 4.16 (dd, 1H), 4.10 (dd, 25H), 3.61 (m, 1H), 3.60 (d, 1H), 3.38 (m, 2H), 3.37-3.28 (s, 12H), 1.27 (s, 12H) Preparation 4n: [(2R) -4,5,6-triacetoxy-2 - [[ 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -phenoxylmethyl] tetrahydropyran-3-yl] Step A: 1,2,3,4-tetra-O- acetyl-eD-mannopyranose 2.36 g of 1,2,3,4-tetra-O-acetyl-6-triphenyl-methyl-α / PD-mannopyranose (4.0 mmol) were dissolved in 30 ml of acid acetic acid at 65 ° C, then 15 ml of water was added and the mixture was added. left stirring at 65 ° C for 1 hour. The mixture was cooled to RT and poured into ice-cold brine. The mixture was filtered and the filtrate was extracted with dichloromethane. The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using heptane and ethyl acetate as eluants to give 1,2,3,4-tetra-O-acetyl-a-3-yl. D-mannopyranose. 1H NMR (500 MHz, DMSO-d6): 6.06-5.97 (d, 1H), 5.20-5.06 (t, 1H), 5.31-5.18 (dd, 1H), 5.35-5.14 (dd, 1H), 4.89-4.87 (t, 1H), 3.84-3.74 (in, 1H), 3.52-3.34 (m, 2H) ), 2.20-1.90 (s, 12H).
[0031] Step B: Preparation 4n From 1,2,3,4-tetra-O-acetyl-α / [3-D-mannopyranose and 444,4,5,5-tetramethyl-1,3,2-dioxaborolan -2-yl) phenol, and following general procedure IV, step A, Preparation 4n was obtained as the mixture of stereoisomers.
[0032] IRR (500 MHz, DMSO-d6): 7.60 (m, 2H), 6.91 (m, 2H), 6.15-6.00 (d, 1H), 5.43-5.15 ( m, 3H), 4.23-4.20 (m, 1H), 4.14-4.00 (m, 2H), 2.19-1.92 (s, 12H), 1.27 (s, 12H). Preparation 4o: [(3R, 4S, 6S) -3,4,5-triacetoxy-6414- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenylmethoxyltetrahydropyran-2-acetate Amyl 20 and Preparation 4p: R2R, 3aS, 6R, 7S) -6,7-diacetoxy-2-methyl-2 - [[4- (4,4,5,5-tetramethyl) -3-acetate) 2-dioxaborolan-2-yl) phenyl] methoxy] -5,6,7,7a-tetrahydro-3aH [1,3] dioxolo [4,5-b] pyran-5-ylmethyl Step A: 1-Bromo -2,3,4,6-tetra-O-acetyl-α-13-D-mannopyranose 1 ml of acetic anhydride was added to 30 ml of HBr in acetic acid (33%) and the mixture was stirred at RT for 16 hours. The mixture was cooled to 0 ° C, and a solution containing 7.50 g of 1,2,3,4,6-penta-O-acetyl-α / 13-Dmannopyranose (19.2 mmol) in 30 g. dichloromethane was added dropwise at 0 ° C. The reaction mixture was stirred at this temperature for 2 hours, then at RT for 16 hours. The mixture was cooled to 0 ° C and poured into 100 ml of ice water melt. It was diluted with 120 ml DCM, then the phases were separated. The organic phase was washed with ice-cold water, saturated NaHCO 3 and water. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to give 1-bromo-2,3,4,6-tetra-O-acetyl-α-β-Dmannopyranose. RivINIH (500 MHz, DMSO-d6): 6.77 (d, 1H), 5.50 (dd, 1H), 5.35 (dd, 5H), 5.23 (t, 1H), 4.17 (m, 1H), 4.25 (dd, 1H), 4.08 (dd, 1H), 2.13 (s, 311), 2.06 (s, 314), 2.03 (s, 3H). , 1.96 (s, 3H). Step B: Preparations 40 and 4p To a solution containing 819 mg of [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] methanol (3.50 mmol, 1 eq.), 2015 mg of 1-bromo-2,3,4,6-tetra-O-acetyl-α-β-D-mannopyranose (4.90 mmol, 1.4 eq.), 467 mg of s. -collidin (3.85 mmol, 1.1 eq) in 100 ml of DCM, 1708 mg of silver trifluoromethanesulfonate (6.65 mmol, 1.9 eq.) in 15 ml of toluene were added dropwise. -drained at -78 ° C, and the mixture was allowed to stir at this temperature for 10 minutes. The mixture was allowed to warm slowly to RT (3 hours) and then stirred for 10 hours. The mixture was filtered through a pad of celite, and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel using heptane and ethyl acetate as eluents to give Preparation 40 as first product eluted, 1H NMR (500 MHz, DMSO-d6) : 7.69 (m, 2H), 7.39 (m, 21-1), 5.15-5.10 (m, 3H), 4.96 (d, 1H), 4.71 (d, 1H), 4.57 (d, 1H), 4.15 (dd, 1H), 4.04 (dd, 1H), 3.96 (nl, 1H), 2.12-1.91 (s, 12H). ), 1.29 (s, 12H); and Preparation 4p as eluted product last. 1H NMR (500 MHz, DMSO-d6): 7.63 (m, 211), 7.31 (m, 2H), 5.68 (d, 1H), 5.32 (dd, 1H), 5, 05 (t, 1H), 4.59 (d, 1H) 4.54 (dd, 1H), 4.53 (d, 1H), 4.12 (dd, 1H), 4.03 (dd, 1H) , 3.94 (m, 1H), 2.01-1.97 (s, 9H), 1.70 (s, 31-1), 1.29 (s, 12H). Preparation 5: (2R) -245- [3-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxy] phenyl-6- (4-fluorophenyl) -thieno-12,3-djpyrimidin-4-yl] oxy-3 Ethyl [21 [2- [13-hydroxy-methylphenyl] pyrimidin-4-ylimethoxylphenyl] propanoate Following general procedure I, step A, and taking [3- (4,4,5,5-tetramethyl) -1, 3,2-dioxaborolan-2-yl) phenyl] methanol as the appropriate boronic ester, Preparation 5 was obtained as a mixture of diastereoisomers SM: [M + H] + = 903.2 .
[0033] Example 1: (2R) -2 - {[(54-5- {3-Chloro-2-methyl-443- (4-methylpiperazin-1-yl) propoxy] phenyl} -6- (4-fluorophenyl) Acid thieno [2,3-di-pyrimidin-4-yl] oxy} -3- (2-112- (3-hydroxyphenyl) pyrimidin-4-yl] methoxy) phenyl) -propanoic acid From Preparation 2 and following General Procedure I, Step B, Example 1 was obtained. High resolution mass (HRMS) calculated for C46H42ClFN6O6S: 860.2559; found 431.1399 (M + 2H) 2+. Example 2: (2R) -2 - {[(54-5- {3-Chloro-2-methyl-443- (4-methylpiperazin-1-yl) propoxylphenyl] -6- (4-fluorophenyl) thieno [2 acid, 3-dipyrimidin-4-yl] oxyl-3- (24 [2- (4-hydroxyphenyl) pyrimidin-4-yl] methoxy} phenyl) propanoic acid From Preparation 3 and following general procedure I, step B, Example 2 was obtained High resolution mass (HRMS) calculated for C46H42ClFN6O6S: 860.2559 found 431.1371 (M + 2H) 2 ÷ Example 3: Acid (2R) -2 - ([(5Sa 5- (3-chloro-2-methyl-443- (4-methylpiperazin-1-yl) propoxylphenyl} -6- (4-fluorophenyl) thieno [2,3-d] pyrimidin-4-yloxy) - 342- ((243- (hydroxymethyl) phenylipyrimidin-4-ylmethoxy) phenylpropanoic acid From Preparation 1 and [3- (4,4,5,5-tetramethyl) -1,3,2-dioxabomlan-2- yl) phenyl} methanol, and following general procedure 1, Example 3 was obtained High resolution mass (HRMS) calculated for C47H44ClFN6O6S: 874.2715, found 438.141 (M + 2H) 2+. Acid (2R) -2 - {[(54-5- {3- 2-chloro-methyl-4- [3- (4-methylpiperazin-1-yl) propoxylphenyl} -6- (4-fluorophenyl) thieno-12,3-d] pyrimidin-4-yloxy} -342- ({244- (hydroxymethyl) phenylipyrimidin-4-yl} } methoxy) phenylpropanoic acid From Preparation 1 and [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] methanol, and following the procedure General I, Example 4 was obtained. High resolution mass (HRMS) calculated for C47H44ClFN6O6S: 874.2715; found 438.1449 (M + 2H) 24-. Example 5: (2R) -2- (R5S ') - 5- {3-Chloro-2-methyl-4-P- (4-methylpiperazin-1-ylpropoxylphenyl) -6- (4-fluorophenyl) tbenzo [ 2,3-4-pyrimidin-4-yl] oxy} -3- (2 - [(2-12- [(2,2-dimethyl-1,3-dioxolan-4-yl) methoxy] phenyl-pyrimidin-4- Yl) methoxylphenylpropanoic acid From Preparation 1 and Preparation 4a, and following general procedure I, Example 5 was obtained High resolution mass (HRMS) calculated for C52H52ClFN6O8S: 974.324, found 488, 1698 (M + 2H) 2+ Example 6: (2R) -2 - {[((()) - 5- {3-Chloro-2-methyl-443- (4-methylpiperazin-1-yl) propoxy acid ] phenyl-6- (4-fluorophenylthieno [2,3-4-pyrimidin-4-yl] oxy} -3- {2- (2-12- (2-methoxyethoxy) ethoxylphenyl} pyrimidin-4-yl) -methoxy] Phenylpropanoic acid From Preparation 1 and Preparation 4b, and following general procedure I, Example 6 was obtained High resolution mass (HRMS) calculated for C 5 H 15 CIFN 608S: 962.324, found 482.1695 ( M + 2H) 2+ Example 7: Acid e (2R) -2 - {[(54-5- {3-chloro-2-methyl-4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -6- (4-fluorophenylthieno) [2,3-d] pyrimidin-4-yloxy-3- (2 - {[2- (2- {2- [2- (2-methoxyethoxy) ethoxy] ethoxy} phenyl) -pyrimidin-4-ylmethoxy} phenyl ) - Propanoic From Preparation 1 and Preparation 4c, and following General Procedure I, Example 7 was obtained. High resolution mass (HRMS) calculated for C53H56ClFN609S: 1006.3502; found 504.1828 (M + 2H) 24-. Example 8: (2R) -2 - {[(5S ') - 5- {3-Chloro-2-methyl-443- (4-methylpiperazin-1-yl) propoxylphenyl} -6- (4-fluorophenyl) thieno [2 acid] 3-4-pyrimidin-4-yloxyl-3- [2- (242- (methoxymethyl) phenylipyrimidin-4-ylmethoxy) -phenyl] propanoic acid From Preparation 1 and [2- (methoxy-methylphenyl) -4,4), 5,5-tetramethyl-1,3,2-dioxaborolane, and following General Procedure I, Example 8 was obtained High resolution mass (HRMS) calculated for C481-146C1FN6O7S: 888.2872; found 445.1518 (M + 2H) 2+ Example 9: (2R) -2- (R5S ()) - 5- {3-chloro-2-methyl-4-13- (4-methylpiperazin-1) acid 5 yl) propylphenyl) -6- (4-fluoroenyl) thi [o-2,3-d] pyrimidin-4-yloxy} -3-12- [(2- (2- [(2- Methoxyphenylmethylphenyl) pyrimidin-4-yl) methoxy] phenyl} propanic acid From Preparation 1 and Preparation 4d, and following General Procedure I, Example 9 was obtained. (HRMS) calcd for C50H50ClFN602S: 9 32.3134, found 467.164 (M + 2I-e.
[0034] Example 10: (2R) -2 - ([(5Sa) -5- {3-chloro-2-methyl-443- (4-methylpiperazin-1-yl) propoxy] phenyl} -6- (4-fluorophenyl) thienoic acid [2,3-d] pyrimidin-4-yloxy} -3- (2 - [(2- {2 - [(2-hydroxyethoxy) methyl] phenyl} pyrimidin-4-yl) methoxyphenyl} From Preparation 1 and Preparation 4e, and following General Procedure I, at the end of the reaction of Step B, the pH was adjusted to 1 with 2M aqueous HCl solution. and the mixture was stirred until no further conversion was observed, then the mixture was neutralized with 10% aqueous K 2 CO 3 solution, diluted with brine and extracted with DCM. were dried over MgSO 4, filtered and the filtrate was concentrated under reduced pressure The crude product was purified by reverse phase preparative chromatography using 5 mM aqueous NH4HCO3 solution and MeCN as eluents. The last eluted tereoisomer was collected to obtain Example 10. High resolution mass (HRMS) calculated for C491-148N602FSC1 918.2978; found 460.1572 (M + 2H) 2+.
[0035] Example 11: (2R) -2 - ([(54-5- {3-Chloro-2-methyl-4-13- (4-methylpiperazin-1-yl) propoxylphenyl] -6- (4-fluorophenylthieno [ 2,3-d] pyrimidin-4-yloxy) -3- (2- [2- (2- {[(2,2-dimethyl-1,3-dioxolan-4-yl) methoxy] methyl} -phenyl ) Pyrimidin-4-yl] methoxy} phenyl} propandol From Preparation 1 and Preparation 4f, and following General Procedure I, Example 11 was obtained High resolution mass (HRMS) calculated for C53H54C1FN608S 988.3397, found 495.1762 (M + 2H) 2+ Example 12: (2R) -2 - [(54-5-O-Chloro-2-methyl-443-) methylpiperazin-1-yl) p -opoxy] phenyl} -6- (4-fluorophenyl) thieno [2,3-d] pyrimidin-4-yl] oxy} -3- (2 4 (2 - ( 3- [(2-hydroxyethoxy) methyl] phenyl] pyrimidin-4-yl) -methoxylphenyl} propanic acid From Preparation 1 and Preparation 4g, and following General Procedure I, at the end of the reaction of the step B, the pH was adjusted to 1 with an aqueous solution of 2M HCl and melted nge was left stirring until no longer observe conversion. Then, it was neutralized with 10% aqueous K 2 CO 3 solution, diluted with brine and extracted with DCM. The combined organic phases were dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase preparative chromatography using 5 mM aqueous NH4HCO3 solution and MeCN as eluents. The last eluted diastereoisomer was collected to obtain Example 12. High resolution mass (HRMS) calculated for C49H48ClFN607S: 918.2978; Found 460.1556 (M + 2H) 2+ Example 13: (2R) -2- (k5S ') - 5- {3-chloro-2-methyl-443- (4-methylpiperazin-1-yl) propoxylphenyl) acid 6- (4-fluorophenyl) thieno [2,3-d] pyrimidin-4-yl] oxy} -3- [2-1 (2 - {3 - [(1,3-dimethyloxyperoxide) - 2-yl) oxy] phenyl} pyrimidin-4-yl) methoxy] phenyl} propanoic acid From Preparation 1 and Preparation 4h, and following General Procedure I, Example 13 was obtained. High resolution mass (HRMS) calculated for C511-152C1FN608S: 962.324; found 482.1664 (M + 2H) 2 ±. Example 14: (2R) -2- (k5Sa) -5-13-chloro-2-methyl-413- (4-methylpiperazin-1-yl) propoxylphenyl} -6- (4-fluorophenyl) thieno [2,3 acid] pyrimidin-4-yl] oxy} -3- {2 - [(2 - (4 - [(1,3-dimethoxypyram-2-yl) oxy] phenyl} pyrimidin-4-yl) methoxy phenylpropaneoic material From Preparation 1 and Preparation 4i, and following General Procedure I, Example 14 was obtained High resolution mass (HRMS) calculated for C511-152C1FN6O8S: 962.324 Found 482 1678 (M + 2H) 2+ Example 15: (2R) -2 - {[(54-5- {3-Chloro-2-methyl-443- (4-methylpiperazin-1-yl) acid ) propoxy] phenyl} -6- (4-fluoropbenyl) thieno [2,3-d] pyrimidin-4-yl] oxy] -342 - ({2- [4- (2,3-dihydroxypropoxy) phenyl] pyrimidin-4 -34} -methoxy) phenylpropanoic acid From Preparation 3 and (2,2-dimethyl-1,3-dioxolan-4-yl) methanol, and following general procedure II, at the end of the reaction of step B, the pH was adjusted to 1 with a 2M aqueous HCl solution and the The mixture was stirred until no further conversion was observed. Then, it was neutralized with 10% aqueous K 2 CO 3 solution, diluted with brine and extracted with DCM. The combined organic phases were dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase preparative chromatography using 5 mM aqueous NH4HCO3 solution and MeCN as eluents. The last eluted diastereoisomer was collected to obtain Example 15. High resolution mass (HRMS) calculated for C49H48N608FSC1: 934.2927; found 468.1531 (M-I-2H) 2+.
[0036] Example 16: 6-04344 - ({2 - [(2R) -2-carboxy-241 (54-5- (3-chloro-2-methyl-4- [3- (4-methylpiperazin-1-yl)} Methyl-propoxy] phenyl] -6- (4-fluorophenyl) thieno [2,3-d] pyrimidin-4-yloxy} ethyl [henoxy] methyl) pyrimidin-2-yliphenyl-α-mannopyranoside From Preparation 1 and Preparation 4j, and following general procedure V, Example 16 was obtained High resolution mass (HRMS) calculated for C53H54ClFN60 1S: 1036.3243, found 519.1666 (M + 2H) 2+. Example 17: 6-0- (344 - ({2 - [(2R) -2-carboxy-24 [(5S ') - 543-chloro-2-methyl-413- (4-methylpiperazin-1-yl)] propoxylphenyl} -6- (4-fluorophenyl) thieno [2,3-d] pyrimidin-4-yloxy} ethyl] phenoxy} methyl) pyrimidin-2-yl] phenyl} -2,3,4-tri-O-methyl-a- Methyl Dmannopyranoside From Preparation 1 and Preparation 4k, and following General Procedure I, Example 17 was obtained High resolution mass (HRMS) calculated for C56H60ClFN6OHS: 1078.3713, found 540.1936 (M + 2H) Example 18: 6-0- (4-14 - ({2 - [(2R) -2-carboxy-2 - {[(5S) -5-13-chloro-2-methyl] -4-13- (4-methylpiperazin-1-yl) -propoxylphenyl} -6- (4-fluorophenyl) thieno [2,3-d] pyrimidin-4-yl] oxy} ethylphenoxy} methylpyrimidin-2-yl] phenyl-α-D-mannopyranoside From Preparation 1 and Preparation 41, and following General Procedure V, Example 18 was obtained. High resolution mass (HRMS) calculated for C53H54ClFN601 1S: 1036.3243; found 519.1714 (M + 2H) 2+. Example 19: 6-O- (4-14 - ({2 - [(2R) -2-carboxy-2- (R5S ') -5- {3-chloro-2-methyl-413- (4-methylpiperazine) 1-yl) -propoxylphenyl} -6- (4-fluorophenyl) thieno [2,3-d] pyrimidin-4-yloxy} ethyllphenoxy} methylpyrimidin-2-yl] phenyl} -2,3,4-tri-O-methyl Methyl mannopyranoside Starting from Preparation 1 and Preparation 4m, and following General Procedure I, Example 19 was obtained High resolution mass (HRMS) calculated for C56H60ClFN6O11S: 1078.3713 found 540.1925 (M-F 2 H) 2 - Example 20: 6-0- {444 - ({2 - [(2R) -2-carboxy-2- (1 (54-5- {3-chloro} 2-methyl-4- [3- (4-methylpiperazin-1-yl) -propoxy] phenyl} -6- (4-fluorophenyl) thieno-1,2,3-a-pyridin-4-yl] oxy} ethyl] phenoxy} methylpyrimidin-2 -yl] phenyl} -D-mannopyranose and Example 21: 6-0-12-14- (12-1 (2R) -2-carboxy-2- (R5S ') - 5- {3-chloro-2 acid Methyl-4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl) -6- (4-fluorophenyl) thieno [2,3-d] pyrimidin-4-yloxy} ethylphenoxy} methylpyrimidin-2-yliphenyl] } -D-Mannon From Preparation 1 and Preparation 4n, and following General Procedure V, Example 20 was obtained as the eluted compound first. High resolution mass (HRMS) calculated for C52H52ClFN6011S: 1022.3087; found 512.1611 (M + 2H) 2+. Example 21 was obtained as the eluted compound last. High resolution mass (HRMS) calculated for C52H52ClFN6012S: 1038.3036; found 520,1604 (M + 2H) 2+. Example 22: 1,2-0 - [(1R) -1- "4-14 - ({2 - [(2R) -2-carboxy-2 - {[(5Sa) -5-{3 1-chloro-2-methyl-443- (4-methylpiperazin-1-yl) propoxy] phenyl} -6- (4-fluorophenylthieno [2,3-M-pyrimidin-4-yl] oxy} ethyl] phenoxy} methyl) pyrimidin-2-yl] benzyl) oxy) ethylidene-PD-mannopyranose From Preparation 1 and Preparation 40, and following General Procedure V, Example 22 was obtained. High resolution mass (HRMS) calculated for C55H56ClFN6O12S: 1078.335; Found 1079.343 (M + H) 4. EXAMPLE 23 (2R) -2- {1 (54-5- {3-Chloro-2-methyl-4-13- (4-methylpiperazin-1-10-oxopoxy)] phenyl-6- (4-fluorophenyl) thieno [2,344-pyrimidin-4-3 / 11oxy] -3- {2 - [(2- {4 - [(α-D-mannopyranosyloxy) methyl] phenyl} pyrimidin-4-yl) methoxylphenyl Propanoic From Preparation 1 and Preparation 4p, and following general procedure V, Example 23 was obtained High resolution mass (HRMS) calculated for C53H54ClFN6O11S: 1036.3243, found 519.1682 ( M + 2H) 2+ Example 24: (2R) -2 - {[(55a) -5- (3-chloro-2-methyl-443- (4-methylpiperazin-1-yl) propoxylphenyl} -6- (4-fluorophenyl) thieno [2,3-d] pyrimidin-4-yl] oxyl-342- (2-14- (2-hydroxyethyl) phenyl] pyrimidin-4-34) methoxy) phenylpropanoic acid From Preparation 1 and [4- (2-hydroxyethyl) phenyl] boronic acid, and following general procedure I, Example 24 was obtained High resolution mass (HRMS) calculated for C 48 H 46 N 6 O 6 FSC 1: 888.2872; 5,1512 (M + 2H) 2+ Example 25: (2R) -2 - ([(5 &) - 5- (3-Chloro-2-methyl-4-P) - (4-methylpiperazin) yppropoxylphenyl} -6- (4-fluorophenyl) thieno [2,3-d] pyrimidin-4-yl] oxy} -342- ({242- (2,3-dihydroxypropoxy) phenylipyrimidin-4-yl} methoxy) phenyl] propanoic acid From of Preparation 1 and Preparation 4a, and following General Procedure I, at the end of the reaction of Step B, the pH was adjusted to 1 with an aqueous solution of 2M HCl and the mixture stirred until no further conversion was observed. Then, it was neutralized with 10% aqueous K 2 CO 3 solution, diluted with brine and extracted with DCM. The combined organic phases were dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase preparative chromatography using 5 mM aqueous NH4HCO3 and MeCN as eluents. The last eluted diastereoisomer was collected to obtain Example 25. High resolution mass (HRMS) calculated for C49H48ClFN6OES: 934.2927; found 468.1536 (M + 2H) 2 ±.
[0037] Example 26: (2R) -2 - ([(5S ') - 5- (3-Chloro-2-methyl-443- (4-methylpiperazin-1-yl) p-oxo] phenyl] -6- ( 4-fluorophenyl) thieno-pyrimidoxy-3 - [24 (24242-hydroxyethoxy) phenylipyrimidin-4-yl} methoxy) phenyl] propanoic acid Step A: (2R) -2-hydroxy-3-f 2 -f [2- Ethyl 2- (2-methoxyethoxy) phenyl] pyrimidin-4-ylimethoxyl-phenylpropanoate A solution containing 1.01 g of (2R) -3- [2 - [(2-chloropyriniidin-4-yl) methoxy] phenyl] -2 ethylhydroxy-propanoate (obtained in Preparation 1, step E) (3 mmol, 1 eq.), 1.17 g of [2- (2-methoxyethoxy) phenyl] boronic acid (6 mmol, 2 eq. 2.93 g of cesium carbonate (9 mmol, 3 eq) and 210 mg of Pd (PP113) 2 Cl 2 in 30 ml of the dioxane / H 2 O mixture (1/1) were stirred at 70 °. C until no longer observe conversion. The reaction mixture was diluted with EtOAc and brine. After extraction, the organic phase was washed with brine and dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using heptane and EtOAc as eluents to obtain (2R) -2-hydroxy-3- [24 [242- (2-methoxyethoxy) phenyl] pyrimidine. Ethyl 4-yl] -methoxy] phenylpropanoate as a colorless oil. 1H NMR (400MHz, DMSO-d6) δ 8.92 (d, 1H), 7.60 (dd, 1H), 7.59 (d, 1H), 7.45 (dd, 1H), 7.24. -7.15 (m, 3H), 7.08 (t, 1H), 7.02 (d, 111), 6.91 (t, 1H), 5.55 (d, 1H), 5.27 (b, 1H), d, 1H), 5.23 (d, 1H), 4.40-4.32 (m, 1H), 4.17-4.11 (m, 2H), 4.06 (q, 2H), 3.62-3.60 (m, 2H), 3.22 (s, 3H), 3.17 (dd, 1H), 2.88 (dd, 1H), 1.18 (t, 3H). Step B: (2R) -2-P-bromo-6- (4-fittorophenyl) thieno [2,3-dlpyrimidin-4-yloxy-3-P-IPP- (2-methoxyethoxy) -phenyl] -1-pyrimidin-4-ylimethoxylphenylpropanoate A suspension containing 995 mg of the product obtained in step A (2.2 mmol, 1.1 eq), 687 mg of 5-bron-4-chloro-6- (4-fluorophenyl) thieno [2 , 3-cilpyrimidine (obtained in Preparation 1, step D) (2 mmol, 1 eq.) And 1.95 g of cesium carbonate (6 mmol, 3 eq.) In 10 ml of anhydrous THF were left stirring. at 70 ° C until no longer observing conversion. The reaction mixture was diluted with EtOAc and brine. After extraction, the organic phase was washed with brine and dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using heptane and EtOAc as eluents to give (2R) -245-bromo-6- (4-fluorophenyl) thieno [2,3-d] pyrimidine Ethyl 4-yloxy-3- [24 [242- (2-methoxyethoxy) -phenyl] pyrimidin-4-yl] methoxy] phenyl] propanoate. 1 H NMR (400 MHz, DMSO-d 6) δ 8.90 (d, 1H), 8.62 (s, 1H), 7.77-7.72 (m, 21-1), 7.61 (d, 1H); ), 7.55 (dd, 1H), 7.49 (dd, 1H), 7.45-7.38 (in, 3H), 7.25 (dd, 1H), 7.15 (d, 1H); , 7.09-7.01 (m, 2H), 6.94 (t, 1H), 5.79 (dd, 11-I), 5.31 (d, 111), 5.25 (d, 1H). ), 4.17 (q, 2H), 4.15-4.10 (in, 2H), 3.64-3.56 (in, 3H), 3.33 (dd, 1H), 3.21 (s, 3H), 1.14 (t, 3H). Step C: (2R) -2-15-Bromo-6- (4-fluorophenyl) Mieno [2,3-d] pyrimidin-4-yloxy-3-12-1-12- P- (2-hydroxyethoxy) - Ethyl phenyllpyrimidin-4-ylitomethoxylphenylpropanoate To the solution containing 760 mg of the product obtained in Step B (1 mmol, 1 eq) in 10 ml of anhydrous DCM, 1 ml of BBr3 (1 mmol, 1M in DCM). 1 eq.) Was added dropwise at RT, and the mixture was stirred until no further conversion was observed. The reaction mixture was diluted with EtOAc and brine. After extraction, the organic phase was washed with brine and dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using heptane and EtOAc as eluents to give (2R) -245-bromo-6- (4-fluorophenyl) thieno [2,3-d] pyrimidine Ethyl 4-yl] oxy-342 - [{242- (2-hydroxyethoxy) phenyl] pyrimidin-4-yl] methoxy] -phenyl] propanoate. 1 H NMR (400 MHz, CDCl 3) δ 8.99 (d, 1H), 8.53 (s, 1H), 7.92 (dd, 1H), 7.79 (d, 1H), 7.69-7. , 62 (in, 2H), 7.54-7.45 (m, 2H), 7.27-7.12 (m, 5H), 6.98 (7, 1H), 6.94 (d, 1H). ), 5.87 (dd, 1H), 5.34 (d, 1H), 5.29 (d, 1H), 4.41 (t, 2H), 4.29 (q, 2H), 3, 94 (t, 2H), 3.72 (dd, 1H), 3.42 (dd, 1H), 1.28 (t, 3H). Step D: (2R) -2-15-P-chloro-2-methyl-4- [2- (4-methyl-piperazin-1 -31) ethoxy] phenyl-6- (4-fluorophenyl) thieno [2, Ethyl 3-dipyrimidin-4-yl] oxy-3- [1- [1- [2- [2- (2-hydroxyethoxy) phenyl] pyrimidin-4-ylmethoxylphenyl] propanoate A solution containing 200 mg of the product of Step C (0, 27 mmol, 1 eq.) In 4 ml of the dioxane / H 2 O mixture (1/1), 127 mg of 14242-chloro-3-methyl-4- (4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl) phenoxylethyl-4-methyl-piperazine (obtained in Preparation 1, step L) (0.32 mmol, 1.2 eq.), 3.1 mg Pd (OAc) 2 (0.05 eq.), 11 mg of AtaPhos (0.1 eq) and 262 mg of cesium carbonate (0.8 mmol, 3 eq.) Were allowed to stir at 70 ° C. until no longer observe conversion. The reaction mixture was diluted with EtOAc and brine. After extraction, the organic phase was washed with brine and dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using EtOAc / MeOH (containing 1.2% NH 3) as eluent to give (2R) -21543-chloro-2-methyl-442- (4-methylpiperazin) -y1) ethoxylphenyl-6- (4-fluorophenyl) thieno [2,3-d] pyrimidin-4-yl] oxy-3 - [24 [242- (2-hydroxyethoxy) phenyl] pyrimidin-4-ylimethoxy] Ethyl phenyllpropanoate. SNI: [M + H] f = 933.2. Step E: Example 26 To a solution containing 120 mg of product of step D (0.13 mmol) in 4 ml of dioxane / H 2 O mixture (1/1), 100 mg of LiOH x H 2 O (2.6 mmol, 20 eq.) Were added and the mixture was stirred at RT until no further conversion was observed. Then, it was neutralized with 12M HCl, then injected directly onto an RP18 column using 5mM aqueous NH4HCO3 solution and MeCN as eluents. The last eluted diastereoisomer was collected to obtain Example 26. High resolution mass (HRMS) calculated for C48H46ClFN607S: 904.2821; found 453.1496 (M + 2H) 2+. Example 27: (2R) -2 - {[(5S ') - 543-Chloro-2-methyl-413- (4-methylpiperazin-1-propoxyl-phenyl) -6- (4-fluoro-phenyl) thieno [ 2,3-4 pyrimidin-4-yl] oxy} -3- (2 - [(2- {2 - [(2,3-dihydroxypropoxy) methyl] phenylipyrimidin-4-yl) methoxylphenyl) propandyl. Preparation 1 and Preparation 4f, and following General Procedure I, at the end of the reaction of Step B, the pH was adjusted to 1 with a 2M aqueous HCl solution and the mixture was left under agitation until no longer observe conversion. Then, it was neutralized with 10% aqueous K 2 CO 3 solution, diluted with brine and extracted with DCM. The combined organic phases were dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase preparative chromatography using 5 mM aqueous NH4HCO3 solution and MeCN as eluents. The last eluted diastereoisomer was collected to obtain Example 27. High resolution mass (HRMS) calculated for C50H50ClFN603S: 948.3083; found 475.1621 (M + 2H) 2+. Example 28: (2R) -2- (R5S ') - 5- {3-Chloro-2-methyl-4-13- (4-methylpiperazin-1-yl) propoxylphenyl] -6- (441-n-phenyl) thieno [2-acid] , 3-d] pyrimidin-4-yl] oxy} -3- [24 {243- (phosphonoxy) phenyl] methyloxy) phenylpropanoic acid To a solution in THF containing 444 mg of Preparation 2 (0.5 mmol, 1 eq) and 210 μl of TEA (1.5 mmol, 3 eq) in 5 ml of anhydrous THF, 140 μl (1.5 mmol, 3 eq) of POCl3 was added dropwise. drop to TA. After stirring for 15 minutes, 5 ml of sodium hydroxide (10 mmol, 2M in water) was added, and the mixture was stirred at 50 ° C until no further conversion was observed. The reaction mixture was injected directly onto a flash silica gel column 220 g previously conditioned (EtOAc / MeOH [containing 1.2% of NH3] - 80/20) using the EtOAc / MeOH mixture (containing 1.2% NH 3) as eluents with a gradient to give the desired product as a mixture of the diastereomers. The diastereoisomers were separated by reverse phase preparative chromatography using 50 mM NI-14HCO3 aqueous solution and MeOH as eluents. The last eluted diastereoisomer was collected as Example 28. High resolution mass (HRMS) calculated for C461-143N609FPSCI: 940.2222; found 471.1194 (M + 2H) 2+. Example 29: 444 - ({2-1 (2R) -2-carboxy-2 - {[(5S) -5-13-chloro-2-methyl-4- [3 - (4-methylpiperazine) Phosphate 1-Apropoxy] phenyl) -6- (4-fluoro-phenyl) thieno [2,3-d] pyrimidoxy) ethyl] -phenoxy) -methyl) pyrimidin-2-yl] phenyl 25-A a solution in THF containing 444 mg of Preparation 3 (0.5 mmol, 1 eq) and 210 g of TEA (1.5 mmol, 3 eq) in 5 ml of anhydrous THF, 140 kt.1 (1, 5 mmol, 3 eq.) Of POCl3 was added dropwise at RT. After stirring for 15 minutes, 5 ml of sodium hydroxide (10 mmol, 2M in water) was added, and the mixture was stirred at 50 ° C until no further conversion was observed. The reaction mixture was injected directly onto a flash silica gel 220 g column previously conditioned (EtOAc / MeOH [containing 1.2% NH3] - 80/20) using EtOAc / MeOH (1.2 g. % NH3) as eluents with a gradient giving the desired product as a mixture of the diastereomers. The last eluted diastereoisomer was collected as Example 29 after lyophilization. High resolution mass (HRMS) calculated for C46F143N609FPSC1: 940.2222; found 471.1188 (M + 2H) 2+.
[0038] Example 30: (2R) -2- (R5S ') - 5- (3-Chloro-2-methyl-4-13- (4-methylpiperazin-1-yl) propoxylphenyl] -6- (4-fluorophenyl) Acid thieno [2,3-d] pyrimidin-4-yloxy-3-12 - ({243- (2-hydroxyethoxy) phenylipyrimidin-4-yl} methoxy) -phenylpropanoic acid Step A: (2R) -215-1- 3-Chloro-2-methyl-4-P- (4-methyl-piperazin-1-yl) ethoxylphenyl-6- (4-fluorophenyl) thieno [2,3-dlpyrimidin-4-yloxy-3-12-1 Ethyl ethoxylphenyl kyrimidin-4-ylmethyloxyphenylpropanoate To a solution in DMF containing 178 mg of Preparation 2 (0.2 mmol), 195 mg of cesium carbonate (m.p. 0.6 mmol) and 222 mg of 2- (p-tolylsulfonyloxy) ethyl 4-methylbenzenesulfonate (0.6 mmol) were added and the mixture was stirred at 60 ° C until no more The reaction mixture was diluted with EtOAc and brine After extraction, the organic phase was washed with brine and dried over MgSO 4, filtered and treated. The crude product was purified by flash chromatography using EtOAc and MeOH (containing 1.2% NH 3) as eluants to give (2R) -24543-chloro-2-methyl 4- [2- (4-methylpiperazin-1-yepethoxy) phenyl] -6- (4-fluoro-phenyl) thieno [2,3-pyrimidin-4-yloxy-342 - [[243- [2- (p-tolylisulfonyloxy)] Ethoxy] phenylipyrimidin-4-yl] methoxy] phenyl] propanoate. MS: [M + H] + 1087.2.
[0039] Step B: Example 30 To a solution containing 120 mg of product of Step A (0.11 mmol) in 4 ml of the dioxane / H 2 O mixture (1/1), 92 mg of LiOH x H 2 O (2.2 mmol) ) were added and the mixture was stirred at 60 ° C until no further conversion was observed. Then, it was neutralized with 2M HCl and injected directly onto an RP18 column using 5mM aqueous NH4HCO3 solution and MeCN as eluents. The last eluted diastereoisomer was collected to obtain Example 30. High resolution mass (HRMS) calculated for C48H46ClFN607S: 904.2821; found 453.1475 (M + 2H) 24-. EXAMPLE 31 (2R) -2-11 (5S) -5- (3-Chloro-2-methyl-4-13- (4-methylpiperazin-1-yl) propoxylphenyl} -6- fluorophenyl) thieno [2,3-d] pyrimidin-4-yl] oxy} -3- {2 - [(2- (4- [2- (2-methoxyethoxy) ethoxy] phenyl} pyrimidin-4- Y1) -methoxy] phenyl} propanol From Preparation 3 and 2- (2-methoxyethoxy) ethanol, and following General Procedure II, Example 31 was obtained. HRMS) calcd for C511-152N6O8FSC1: 962.324, found 482.1703 (M + 2H) 2+.
[0040] Example 32: (2R) -24R5So) -5-13-Chloro-2-methyl-443- (4-methylpiperazin-1-yl) propoxylphenyl} -6- (4-fluorophenylthieno [2,3-4 pyrimidine] 4-yl] oxy} -3- {2 - [(2- {4- [2- (2-hydroxyethoxy) ethoxy] phenyl) pyrimidin-4-yl) methoxy} phenyl} propanoic acid from Preparation 3 and 10 eq. 2- (2-hydroxyethoxy) ethanol, and following General Procedure II, Example 32 was obtained. High resolution mass (HRMS) calculated for CS0Hs0N608FSC1: 948.3083; found 475.1613 (M + 2H) 2+. Example 33: (2R) -2 - ([(5Sa) -5- (3-Chloro-2-methyl-4- [3- (4-methylpiperazin-1-ylpropoxy) phenyl} -6- (4-fluorophenyl) Acid thieno [2,3-d] pyrimidin-4-yl] oxy} -3- (24 [2- (4- (2- [2- (2-methoxyethoxy) ethoxy] ethoxy} ph enyl) -pyrimidin-4-ylmethyloxyphenylpropandyl From Preparation 3 and 2- [2- (2-methoxyethoxy) ethoxy] ethanol, and following General Procedure II, the Example 33 was obtained High resolution mass (HRMS) calculated for C53H56N6O9FSC1: 1006.3502, found 504.183 (M + 2H) 2+.
[0041] Example 34: (2R) -2 - {[(5Sa) -5- (3-chloro-2-methyl-443- (4-methylpiperazin-1-yl) propoxy] phenyl} -6- (4-fluorophenyl) thiophenyl [2,3-4 pyrimidin-4-yloxy] -3- (24 (2-14- [2- (dimethylamino) ethoxy] pyrimidin-4-yl) ethoxy] phenyl} propanoic acid From Preparation 3 and 2- (dimethylamino) ethanol, and following General Procedure II, Example 34 was obtained High resolution mass (HRMS) calculated for C501-151N706FSC1: 931.3294 found 466, 6709 (M + 21-1) 2+ Example 35: (2R) -2- (1 (5S ()) - 5- {3-chloro-2-methyl-4-P- (4) - acid methylpiperazine-1-yl) propoxylphenyl} -6- (4-fluorophenyl) thieno [2,3-d] pyrimidin-4-yloxy} -3- (2 - [(2- (3 - [(2,2-dimethyl) -2- 1,3-dioxolan-4-yl) methoxy] phenyl] -pyrimidin-4-yl) methoxylphenyl} propanoic acid From Preparation 2 and (2,2-dimethyl-1,3-dioxolan-4-yl) methanol, and following General Procedure II, Example 35 was obtained High resolution mass (HRMS) calculated for C52H52N608FSC I: 974,324, found 488,1677 (M + 2H) 2 ÷ Example 36: (2R) -2 - {[(55 ') - 5-13-Chloro-2-methyl-442- (4-methylpiperazin) 1-yl) ethoxy] phenyl} -6- (4-fluorophenyl) thieno [2,3-d] pyrimidin-4-yloxy} -3-12- ({243- (15-hydroxy-3-oxo)} 2,7,14,13-tetraoxa-4-azapentadec-1-yiphenylpyrimidin-4-ylmethoxy) phenylpropanoic acid From Preparation 5 and taking 24242- (2-aminoethoxy) ethoxy] etboxylethanol as the appropriate amine, and following general procedure III, Example 36 was obtained. High resolution mass (HRMS) calculated for C561-161CIFN7011S: 1093.3822; found 547.7006 (M + 2H) 2 ÷. Example 37: (2R) -3- (2 - {[2- (3 - [(1,4'-bipiperidin-1-ylcarbonyl) oxy] methyl} -phenyl) pyrimid in-4- acid (2S, 1) -5- (3-chloro-2-methyl-442- (4-methyl-1-piperazin-1-yl) ethoxy] phenyl} -6- (4-Fluoro-phenyl) thieno [2,3-d] pyrimidin-4-yl] oxy) propanoic acid From Preparation 5 and taking 1- (4-piperidyl) piperidine as the appropriate amine, and following general procedure III, Example 37 was obtained. High resolution mass (HRMS) calculated for C58H62ClFN8O7S: 1068.4135; found 1069,419 (M + H) +. Example 38: (2R) -2- (k5Sa) -5- (3-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxylphenyl] -6- (4-fluorophenyl) acid thieno [2,3-Mpyrimidin-4-yl] oxy} -3- (2 - {[2- (3- {2- [2- (2-hydroxyethoxy) ethoxylethoxy} phenyl) -pyrimidin-4-ylmethoxy} phenyl) From Preparation 2 and 10 eq of 2- [2- (2-hydroxyethoxy) ethoxy] ethanol, and following General Procedure II, Example 38 was obtained High resolution mass (HRMS) Calcd for C52H54ClFN6O9S: 992.3345 Found 497.1748 (M + 2H) 2+ Example 39: (2R) -2-1 [(5S ') - 5- {3-Chloro-2-methyl-4-acid - [2- (4-methylpiperazin-1-yl) ethoxy] phenyl] -6- (4-fluorophenyl) thieno [2,3-d] pyrimidin-4-yl) oxyl -3- (24 (2-)) 342- (2-hydroxyethoxy) ethoxylphenyl) pyrimidin-4-yl) methoxylphenylpropanoic acid From Preparation 2 and 10 eq of 2- (2-hydroxyethoxy) ethanol, and following General Procedure II, Example 39 was obtained High resolution mass (HRMS) calculated for C 501150C1F1 1608S: 948.3083, found 475.1604 (M + 2H) 2+.
[0042] Example 40: (2R) -2- {1 (54-5-p-Chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxy] phenyl} -6- (4-flametophenyl) thieno Acid [2,3-d] pyrimidoxy} -3- {24 (2- {342- (2-methoxyethoxy) ethoxy] phenyl] pyrimidin-4-yl) -methoxylphenyl} propanoic acid From Preparation 2 and 2- (2 - -methoxy-ethoxy) ethanol, and following General Procedure II, Example 40 was obtained. High resolution mass (HRMS) calculated for C51M52CIFN6O8S: 962.324; found 482.1675 (M + 2H) 2+. Example 41: (2R) -2 - {[(5S ') - 5-13-Chloro-2-methyl-442- (4-methylpiperazin-1-ethoxy) pheny]} -6- (4-nitrophenyl) acid thieno [2,3-d] pyrimidin-4-yloxy) -3- {2 - [(2- {3 - M [2- (4-methylpiperazin-1-yl) ethyl] carbamoyl} oxy) - methyliphenyl) pyrimidin-4-yl) methoxylphenyl} propanoic acid From Preparation 5 and taking 2- (4-methylpiperazin-1-ylethanamine as the appropriate amine, and following general procedure III, Example 41 was obtained. High resolution mass (HRMS) calculated for C55H59ClFN907S: 1043.3931 found 522.7052 (M + 2H) 2+ Example 42: Acid (2R) -2 - {[(5S ') - 5 - {3-chloro-2-methyl-4-12- (4-methylpiperazin-1-yl) ethoxylphenyl-6- (4-fluorophenyl) thieno [2,3-d] pyrimidin-4-yl] ox} -3- { 24 (2- {3- 1 ({12- (Morpholin-4-yl) ethylcarbamoyl} oxy) methyl (phenyl) pyrimidin-4-yl) methoxylphenylpropanoic acid From Preparation 5 and taking 2-morpholinoethanamine as the appropriate amine , and following the procedure General III, Example 42 was obtained High resolution mass (HRMS) calculated for C54H56ClFN808S: 1030.3615; found 516.1871 (M + 2H) 2.f.
[0043] Example 43: (2R) -2- (R5Sa) -5-O-chloro-2-methyl-4-12- (4-methylpiperazin-1-yl) ethoxylphenyl} -6- (4-fluorophenyl) thieno [ 2,3-Di-pyrimidin-4-yl] oxy} -3 - {2 - [(2- {3 - [({[2- (dimethylamino) ethyl] carbamoyl} oxy) methylf-phenyl} pyrimidin-4-yl ) Methoxyl phenyl} propanol From Preparation 5 and taking N, N'-dimethylethane-1,2-diamine as the appropriate amine, and following General Procedure III, Example 43 was obtained. High resolution mass (HRMS) calculated for C521-154CIFF1807S: 988.3509; found 989.3586 (M-I-H) +. Example 44: (2R) -2 - {[(54-543-Chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxylphenyl} -6- (4-fluorophenyl) thieno [2,3-acid] pyrimidin-4-yloxy) -3- {2 - [(2- (3 - [({[2- (pyrrolidin-1-ylethyl) carbamoyl) oxy} methyl-phenyl) pyrimidin-4-yl) methoxy ] phenyl) propanoic acid From Preparation 5 and taking 2-pyrrolidin-1-ylethanamine as the appropriate amine, and following general procedure III, Example 44 was obtained.
[0044] High resolution mass (HRMS) calculated for C54H56ClFN807S: 1014.3665; found 508.1916 (M + 21-1) 2+. Example 45: (2R) -342 - ({2-P-Mbis (2-methoxy-ethyl) carbamoyloxy} methyl) -phenylipyrimidin-4-yl} -methoxy) phenyl] -2-yl acid (5S) 5- (3-Chloro-2-methyl-4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl} -6- (4-fluorophenyl) thieno [2,3-d] pyrimidin-4-yl] oxy} propanoyl From Preparation 5 and taking 2-methoxy-N- (2-methoxyethyl) ethanamine as the appropriate amine, and following general procedure III, Example 45 was obtained. High resolution mass (HRMS) calculated for C54H57N7O9FSCI: 1033.3611; found 517.6883 (M + 2H) 2+.
[0045] Example 46: (2R) -2 - {[(54-5- {3-Chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxy] phenyl} -6- (4-fluorophenyl) Acid thieno [2,3-d] pyrimidin-4-yl oxy} -3 - (2- {12- (3 - {[(1,4,7,10,13-pentaoxa-16-azacyclo) decan-16) 1-ylbenzyloxy) methyl] phenyl) pyrimidin-4-yl] ethoxy} phenyl) propanoic acid From Preparation 5 and taking 1,4,7,10,13-pentaoxa-16 - azacyclooctadecane as the appropriate amine, and following general procedure III, Example 46 was obtained High resolution mass (HRMS) calculated for C60H67N7O2FSC1: 1163.4241, found 582.7187 (M + 2H) 2 ±. 47: (2R) -2- (R5S ') - 5- {3-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxy] phenyl} -6- (4-fluorophenyl) thieno Acid [2,3-Dipyrimidin-4-yl] oxy} -342- ({243- (2,3-dihydroxypropoxy) phenyl] pyrimidin-4-yl} -methoxy) phenylpropanoic acid From Preparation 2 and (2, 2-dimethyl-1,3-dioxolan-4-yl) methanol, and following general procedure II, at the end of In the reaction of step B, the pH was adjusted to 1 with 2M aqueous HCl and the mixture was stirred until no further conversion was observed. Then, it was neutralized with 10% aqueous K 2 CO 3 solution, diluted with brine and extracted with DCM. The combined organic phases were dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase preparative chromatography using an aqueous solution of 5 mM NI-14HCO3 and MeCN as eluents. The last eluted diastereoisomer was collected to obtain Example 47. High resolution mass (HRMS) calculated for C491-481 1608FSCI: 934,2927; found 468.1538 (M + 2H) 2+. Example 48: (2R) -2- {R5Sa) -5- {3-chloro-2-methyl-4-p- (4-methylpiperazin-1-yl) ethoxyphenyl} -6,441 norophenyl acid thieno [2,3-d] oxy) -3- (2 - {[2- (3- {2- [2- (2-methoxyethoxy) ethoxy] ethoxy} phenyl) pyrimidin-4-yl] Methoxy phenylpropanoic acid From Preparation 2 and 242- (2-methoxyethoxy) ethoxy] ethanol, and following General Procedure II, Example 48 was obtained. High resolution mass (HRMS) calculated for C53H56N609FSC1: 1006.3502; found 504.1829 (M + 2H) 2+.
[0046] Example 49: (2R) -3- (24 [2- (3-124bis (2-hydroxyethyl) amino] ethoxylphenyl) -pyrimidin-4-ylimethoxybphenyl) -2 - ([(54-5- {3-chloro) 2-methyl-442- (4-methylpiperazin-1-yl) ethoxylphenyl-6- (4-fluorophenyl) thieno-1,2,3-pyrimidin-4-yloxy-propanoic acid From Preparation 2 and 10 eq of 2 - [bis (2-hydroxyethyl) amino] ethanol, and following General Procedure II, Example 49 was obtained High resolution mass (HRMS) calculated for C52H55N7O8FSC1: 991.3505, found 496.6833 (M +) 2H) 2'- Example 50: (2R) -2 - [[5S '] - 5- (43-Dimethyl-4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl] -6- (4-Fluoro-p-henyl) thieno [2,3-di-pyrimidin-4-yl] oxy} -3- {2 - [(2- {3 - [({12- (piperidin-1 y1) ethyl] (arbamoyloxy) methylphenyl) pyrimidin-4-yl) methoxy] phenyl} propanoic acid From Preparation 5 and taking N- (2-aminoethyl) piperidine as the appropriate amine, and following General procedure III, Example 50 was obtained. high resolution (HRMS) calculated for C551158CIFN807S: 1028.3822; found 1,029.3893 (M + H) +. Example 51: (2R) -2 - ([(5Sa) -5-13-Chloro-2-methyl-4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl} -6- fluorophenylthieno [2,3-d] pyrimidin-4-yl] oxy-3- {2 - [(2- (342- (morpholin-4-yl) ethoxylphenyl} pyrimidin-4-yl) methoxy] phenylpropanoic acid From the Preparation 2 and N- (2-hydroxyethyl) morpholine, and following general procedure II, Example 51 was obtained High resolution mass (HRMS) calculated for C52H53ClFN7O7S: 973.3400, found 487.6785 (M. Example 52: (2R) -2 - {[(5Sil) -5- {3-chloro-2-methyl-442- (4-methylpiperazin-1-yl) -ethoxyphenyl) -6-acid (2H) 2+ (4-fluorophenyl) thieno [2,3-d] pyrimidin-4-yl] oxy) -3- {2 - [(2-13-12- (dimethylamino) ethoxylphenyl} pyrimidin-4-yl) methoxylphenyl} Propanoic From Preparation 2 and 2-dimethylaminoethanol, and following general procedure II, Example 52 was obtained High resolution mass (HRMS) calculated for C50H51ClFN7O6S: 931.3294 found 466.6722 (M + 2H) 2+ Example 53: (2R) -3- (2- {12- (4- {2- [Bis (2-hydroxyethyl) amino] ethoxy} phenyl) pyrimidin-4-yl] methoxyl-phenyl) -2-acid [(54-543-Chloro-2-methyl-442- (4-methylpiperazin-1-yepethoxy) phenyl] -6- (4-fluorophenyl) thieno [2,3-d] pyrimidin-4-yl] oxy] From Preparation 3 and 24bis (2-hydroxyethypaminol ethanol, and following general procedure II, Example 53 was obtained. High resolution mass (HRMS) calculated for C52H551 1708FSC1: 991.3505; found 496.6822 (M + 2H) 2 ±. Example 54: (2R) -2 - {[(5Sn) -5-13-Chloro-2-methyl-4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl) -6- (4-Fluoro-phenyl) -thieno (2,3-d) pyrimidin-4-yl-oxy} -3- (2- (1244- {2- [2- (2-hydroxyethoxy) ethoxy] ethoxyethyl) en) Pyrimidin-4-ylmethyloxyphenylpropanoic acid From Preparation 3 and 10 eq of triethylene glycol and following general procedure II, Example 54 was obtained High resolution mass (HRMS) Calcd for C52H54N6O9FSCI: 992.3345, found 497.1743 (M + 2H) 2+.
[0047] Example 55: (2R) -2 - {[(5S ') - 5- (3-Chloro-2-methyl-4- (4-methylpiperazin-1-yl) ethyl] phenyl] -6- (4- fluorophenyl) thieno [2,3-d] pyrimidin-4-yloxy} -3- {2 - [(2- (4 - [(2,2-dimethyl-1,3-dioxolan-4-yl) methoxy] phenyl} ) -pyrimidin-4-amethoxylphenyl-propanoic acid From Preparation 3 and (2,2-dimethyl-1,3-dioxolan-4-yl) methanol, and following general procedure II, Example 55 was obtained. High resolution mass (HRMS) calculated for C52H52N608FSCI: 974.3240; found 488.1689 (M-F 2 H) 2+. EXAMPLE 56 (2R) -2 - {[(5S ') - 5- (3-Chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxy] phenyl} -6- (4) -fluorophenyl) thieno [2,3-d] pyrimidin-4-yloxy) -3-12- [(2-O42- (morpholin-4-yl) ethoxy] phenyl) pyrimidin-4-yl) -methoxylphenylpropanoic acid From Preparation 3 and N- (2-hydroxyethyl) moipholine, and following General Procedure II, Example 56 was obtained. High resolution mass (HRMS) calculated for C52H53N7O7FSC1: 973.3400; found 487.6775 (M + 2H) 2+. Example 57 Disodium salt of 4-14 - ({2-1 (2R) -2-carboxy-2 - {[(5-5-5) -chloro-2-methyl-443- (4-ethylpiperazin) 1-Apropoxylphenyl} -6- (4-fluorophenyl) thieno [2,3-d] pyrimidin-4-yloxyethyl] phenoxy} -methyl) pyrimidin-2-yl] phenyl To a solution of THF containing 444 mg of Preparation 3 (0.5 mmol, 1 eq) and 210 μl of TEA (1.5 mmol, 3 eq) in 5 ml of anhydrous THF, 140 μl of POCl 3 (1.5 mmol, 3 eq) were added dropwise. After stirring for 15 minutes, 5 ml of sodium hydroxide (10 mmol, 2M in water) was added and the mixture was stirred at 50 ° C until the reaction was complete. The pH was adjusted to 6 with TFA, and this reaction mixture was injected directly onto an RP18 column using an aqueous solution of 50 mM NFLIHCO3 and MeOH as eluents. eluted last was collected.After lyophilization, the remaining white solid was resuspended in 5 ml of saturated dioxane / NH4HCO3 mixture (1/1). After stirring for 1 hour at RT, the reaction mixture was injected directly onto an RP18 column using water and MeCN as eluents to obtain Example 57. High resolution mass (HRMS) calculated for C46R0N609FPSC1: 940, 2222; found 469.1054 (M-2F1) 2 -.
[0048] EXAMPLE 58 (2R) -3- (24 [2- (2- {2-ibis (2-hydroxyethyl) aminoethoxy) phenyl) pyrimidin-4-ylimethoxy} -phenyl) -2- ([(54-)) 5- {3-Chloro-2-methyl-4-12- (4-methylpiperazin-1-yl) ethoxylphenyl} -6- (4-fluorophenyl) thieno [2,3-pyrimidin-4-yl] oxy} propanoic acid EXAMPLE 59 (2R) -3- (2-1 [2- (4- [bis (2-hydroxyethyl) a-methyl] phenyl] pyrimidin-4-yl] methoxy] - acid phenyl) -2- (1 (5S) -5- (3-chloro-2-methyl-4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl} -6- (4-fluorophenyl) Example 60: (2R) -3- (24 [2- (3 - {[bis (2-hydroxyethyl) amino] methyl} phenyl) -pyrimidin-4-ylmethoxy} -acetate phenyl) -2-11 (5S) -5- {3-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxy] phenyl-6- (4-fluorophenyl) thieno 4-pyrimidin-4-yl] oxy} propanoic acid Example 61: (2R) -3- (2 - ([2- (2-Fibris (2-hydroxyethyl) a] methyl] phenyl) pyrimidin-4-ylmethoxy} acid -phenyl) -2-11 (54-5- (3-chloro-2-methyl-442- (4-methylpiperazin-1-ypetho) xylphenyl} -6- (4-fluorophenyl) thieno [2,3-d] pyrimidin-4-yl] oxy} propanoic acid Example 62: (2R) -2 - {[(55a) -5- {3-chloroacetic acid) 2-methyl-442- (4-methylpiperazin-1-yl) ethoxy] phenyl} -6- (4-fluorophenyl) thieno [2,3-d] pyrimidin-4-yl] oxy} -3- {2 - [(2- (4 - [(2-Hydroxyethoxy) methyl] phenyl} pyrimidin-4-yl) -methoxy] phenyl) propanoic acid. Example 63: (2R) -2- {1 (5S ') - Acid 5- (3-Chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxylphenyl} -6- (4-fluorophenyl) thieno [2,3-dlpyrimidin-4-yl] oxyl-3-12- [(2- (2- [2- (2-Hydroxyethoxy) ethoxy] phenyl] pyrimidin-4-yl) methoxy] phenyl} propanoic acid Example 64: (2R) -2 - {[(5S ') - 5- {3 1-chloro-2-methyl-4- [2- (4-methylpiperazin-1-yl) ethoxylphenyl] -6- (4-fluorophenyl) thieno [2,3-dipyrimidin-4-yl] oxy} -3- ( 2- (2- {2- [2- [2- (2-hydroxyethoxy) ethoxylethoxylphenyl) -pyrimidin-4-ylmethoxylphenyl} propanoic acid Example 65: (2R) -2 - ([(5S ') - 5- ( 3-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxy] phenyl} -6- (4-fluorophenypthi) eno [2,3-4-pyrimidin-4-yloxy) -3-12- [(2- {3 - [(pho -sulfonoxy) -methyleneoxy] phenyl} pyrimidin-4-yl) -methoxy] phenyl) Example 66: (2R) -2-11 (54-5- {3-Chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxy] phenyl} acid. 6- (4-fluorophenyl) thieno [2,3-d] pyrimidin-4-yl] oxyl-3- (2- {1243 - {[(phosphonooxy) methoxy] ethyllphenyl) pyrimidin-4- Example 67: (2R) -2 - {[(5S ') - 5- {3-Chloro-2-methyl-442- (4-methylpiperazin-lypethoxylphenyl)} -6-carboxylic acid (4-fluorophenyl) thieno [2,3-dlpyrimidin-4-yl] oxy} -3- (2 - {[2- (3 - {[(phosphonooxy) carbonyl} oxy} phenyl) pyrimidin-4-yl-methoxy} phenyl) propanoic acid Example 68: (2R) -2- {1 (5S ') - 5-13-Chloro-2-methyl-4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl} - acid 6- (4-fluorophenyl) thieno [2,3,4] pyrimidin-4-yloxy} -3424 {2-13 - ({[(phosphonooxy) carbonyl] oxy} methyl) phenyl-pyrimidin-4-yl} methoxy) phenyl] - propanoic Example 69: (2R) -2-f [(5S ') - 5- {3 1-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxy] phenyl} -6- (4-fluoro-phenyl) thieno [2,3-d] pyrimidin-4-yl] oxy} -3- (2 - [(2- [3 - [(1,3-dimethoxypro-2-yl) oxy] phenyl} pyrimidin-4-yl) -methoxy] phenyl} propanate Example 70: (2R) -2 - {[(5S ') - 5- (3-Chloro-2-methyl-4- [2- (4-methylpiperazin-1) -1- [(ethoxycarbonyl) oxylethyl] yl) ethoxy] phenyl) -6- (4-fluoro-phenypthieno [2,3-d] pyrimidin-4-yloxy} -342 - [(2- {3- (1,3-dimethoxypropan-2-yl)} 1H - [(dimethylcarbamoyl) -oxy] ethyl (1 - [(dimethylcarbamoyl) -oxy] ethyl oxyphenyl} pyrimidin-4-yl) methoxyphenyl} propanoate Example 71: (2R) -2-1 [5- {2,6-Dimethyl 4-12- (4-methylpiperazin-1-yl) ethoxylphenyl-6- (4-fluorophenyl) -thieno [2,3-dipyrimidin-4-yloxy] -342- ({243- (hydroxy-methyl) phenyl] pyrimidin-4 Example 72: (2R) -2 - ([543,5-Dichloro-2,6-dimethyl-442- (4-methylpiperazin-1-yl) ethoxylphenyl] -6- (4-fluorophenyl) -octyl ) thieno [2,3-d] pyrimidin-4-yl] oxy} -3-12- ({243- (hydroxymethyl) ph) enyl] pyrimidin-4-ylmethoxy) -phenylpropanoic acid Example 73: (2R) -2- ([5- (2,6-D) -methyl) -442- (4-methylpiperazin-1-yl) ethoxyacetic acid ] Phenyl-6- (4-fluorophenyl) -thieno [2,3-d] pyrimidin-4-yl] oxy} -3-12- ([214- (Phenoxyoxy) phenyl] pyrimidine Example 74: (2R) -2-115- {3,5-dichloro-2,6-dimethyl-442- (4-methylpiperazin-1-yl) ethoxylphenyl} -6-oxy-phenylpropanoic acid - (4-fluorophenylthieno [2,3-d] pyrimidin-4-yloxy) -342- ((2- [4- (phosphonooxy) phenyl] pyrimidin-4-yl} methoxy) phenylpropanoic acid. [(5S) -5- (3-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxylphenyl] -6- (4-fluoro-phenyl) thieno [2,3-d] pyrimidin-4- Example 76: 2- (R5Sa) -5- (3- (2- (R5Sa)) -5- (3-yl) oxy} -3-hydoxy-3- [24 {2- [3- (hydroxymethyl) phenyl] pyrimidin-4-yl} methoxy) phenylpropanoic acid chloro-2-methyl-4- [4- (4-methylpiperazin-1-yl) ethoxylphenyl] -6- (4-fluoro-phenyl) thieno [2,3-d] pyrimidin-4-yl] oxy} -4- hydroxy-3- [2- (12-13- (hydroxymethyl) Example 77: 2 - [(54-5- {3-Chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxy] phenyl} phenylpyrimidin-4-yl} methoxy) phenylbutanoic acid 6- (4-Fluoro-phenyl) thieno [2,3-d] pyrimidin-4-yl] -3,4-diisoxy-342- ({243- (hydroxymethyl) phenyl] pyrimidine Example 78: (2R) -2-11 (5S ') - 5- (3-Chloro-2-methyl-442- (4-methylpiperazinyl) -2-oxy) -phenyl] penton 1- (1-yl) ethoxy] phenyl) -6- (4-fluorophenylthieno [2,3-d] pyrimidin-4-yloxy} -3424 (242- (hydroxymethylpyridin-4-yl) pyrimidin-4-ylmethoxy) phenyl Example 79: (2R) -2 - ([(55a) -5-13-Chloro-2-methyl-4-12- (4-methylpiperazin-1-yl) ethoxylphenyl} -6 -ic acid (4-fluorophenyl) thieno [2,3-d] pyrimidin-4-yl] oxy} -342- ((245- (hydroxymethyl) pyridin-3-ylpyrimidin-4-yl} methoxy) phenyl] propanoic acid (2R) -2 - {[(55 ') - 5- {3-Chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxylphenyl] -6- (4-fluorophenyl) thieno [ 2,3-d] pyrimidin-4-yloxy) -3- [24 {246- (hydrate Roxymethyl) pyridazin-4-yl] pyrimidin-4-yl) -methyleneoxy) phenyl] propanoic acid Example 81: (2R) -2 - {[(54-5- (3-chloroacetic acid) -2-metyl-4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl} -6- (4-fluorophenyl) thieno [2,3-d] pyrimidin-4-yloxy) - 342 - ({2- [6- (hydroxymethyl) pyrazin-2-yl] pyrimidin-4-yl} methoxy) phenyl] propanoic acid Example 82: Acid (2R) -2- {1 (54-5- {3-chloro} 2-methyl-442- (4-methylpiperazin-1-yl) ethoxy] phenyl} -6- (4-fluorophenyl) thieno [2,3-dlpyrimidin-4-yl] oxy} -3- (2- 5 - (hydroxymethyl) -2,5'-bipyrimidin-4-ylmethoxyl-phenyl) propanoic acid PHARMACOLOGICAL STUDY EXAMPLE A: Inhibition of Mc1-1 by Fluorescence Polarization Technique The relative binding activity of each compound was determined by fluorescence polarization (PF). The method employs a fluorescein-labeled ligand (fluorescein-βAla-Ahx-A-REIGAQLRRMADDLNAQY-OH; pm 2,765) which binds to the Mc1-1 protein (such as Mc1-1 corresponding to the primary accession number UniProtKB®: Q07820), which results in an increase of the anisotropy measured in milli-polarization unit (mP) by means of a reader. The addition of a compound that competitively binds to the same site as the ligand will lead to an increase in the proportion of unbound ligand in the system, indicated by a decrease in rnP units. An 11-point serial dilution of each compound was prepared in DMSO and 2 μl was transferred to a 384-well flat-bottomed, low-binding plate (5% final DMSO concentration). 38 μl of buffer (10 mM 4- (2-hydroxyethyl) -1-piperazinethanesulfonic acid [HEPES], 150 mM NaCl, 0.05% Tween 20, pH 7.4) containing the labeled ligand. fluorescein (final concentration of 1 nM) and Mc1-1 protein (final concentration of 5 nM) were then added. The assay plates were incubated for about 2 hours at RT before measuring PF with a Biomek Synergy2 reader (eg, 528 nm, Em 640 nm, cutoff threshold 510 nm) and calculating the units. mP. The binding of increasing doses of test compounds was expressed as percent reduction in mP from a window established between a control group representing "5% DMSO only" and a control group representing "100% inhibition". The 11-point dose / response curves were plotted with the XL-Fit software using a 4-parameter logistic model (sigmoid dose / response model) and the inhibitory concentrations giving a 50% reduction in mP (IC50 ) have been determined. The results obtained are shown in Table 1 below. The results show that the compounds of the invention inhibit the interaction between the Mc1-1 protein and the fluorescent peptide described above. EXAMPLE B In Vitro Cytotoxicity Cytotoxicity studies were performed on the H929 multiple myeloma tumor line. The cells are distributed in microplates and exposed to test compounds for 48 hours. Cell viability is then quantified by a colorimetric assay, Microculture Tetrazolium Assay (Cancer Res., 1987, 47, 939-942). The results are expressed as IC50 (concentration of compound which inhibits cell viability to 50%) and are presented in Table 1 below. The results show that the compounds of the invention are cytotoxic.
[0049] Table 1: Cho of Fluorescence Olarization Test Inhibition and Cytotoxicity for H929 C13 Cells. (M) Mc1-1 PF C150 (pM) MTT H929 C150 (M) Mc1-1 PF CI (gM) MTT 11929 Example 1 8.4E-09 9.31E-09 Example 23 2.7E-09 3.97E -08 Example 2 1.32E-08 1.59E-08 Example 24 3.15E-09 2.55E-09 Example 3 4.05E-09 4.08E-09 Example 25 3.5E-09 1.00E-08 Example 4 4.9E-09 3.64E-09 Example 26 3.5E-09 1.72E-09 Example 5 3.7E-09 1.65E-09 Example 27 2.2E-09 1.39E-08 Example 6 1,57E-08 3,25E-09 Example 28 4,15E-09 4,84E-08 Example 7 3,75E-09 4,45E-09 Example 29 4,6E-09 2,27E-08 Example 8 7, 35E-09 2.07E-09 Example 30 4.5E-09 3.60E-09 Example 9 8.15E-09 1.40E-09 Example 31 3.85E-09 1.68E-09 Example 10 1.09E- 08 2,79E-09 Example 32 1,53E-08 1,68E-09 Example 11 4,05E-09 1,99E-09 Example 33 2,24E-08 1,18E-09 Example 12 4,25E-09 3 , 82E-09 Example 34 7.1E-09 4.76E-09 Example 13 5.1E-09 3.59E-09 Example 35 5.15E-09 4.76E-09 Example 14 6.15E-09 3.37E -09 Example 36 4,65E-09 7,59E-08 Example 15 2,75E-09 3,59E-09 Example 37 6.3E-09 2.05E-08 Example 16 7.2E-09 3.71E-08 Example 38 2.8E-09 2.76E-09 Example 17 4.8E-09 3.03 E-09 Example 39 3,05E-09 3,25E-09 Example 18 4,1E-09 1,39E-08 Example 40 3,75E-09 6,15E-09 Example 19 4,95E-09 2,47E- 09 Example 41 3,45E-09 9,08E-08 Example 20 4,35E-09 5,68E-08 Example 42 4,45E-09 4,45E-08 Example 21 4,85E-09> 1,50E-07 EXAMPLE 43 4.55E-09 3.11E-08 Example 22 5.5E-09 5.97E-09 Example 44 3.7E-09 2.87E-08 C150 (M) Mc1-1 PF Cl, (MM) MTT 11929 C130 (M) Mei-1 PF Cl (11M) MTT 11929 Example 45 3.2E-09 4.58E-09 Example 64 ND ND Example 46 2.55E-09 2.34E-08 Example 65 ND ND Example 47 4,05E-09 1,82E-08 Example 66 ND ND Example 48 3,85E-09 ND Example 67 ND ND Example 49 4,65E-09 ND Example 68 ND ND Example 50 6,6E- EXAMPLE 69 ND Example 51 4.15E-09 ND Example 70 ND Example 52 3.7E-09 ND Example 71 ND Example 53 4.65E-9 ND Example 72 ND Example 54 4.6E-09 ND Example 73 ND ND Example 55 6,35E-09 ND Example 74 ND ND Example 56 4,75E-09 ND Example 75 ND ND Example 57 4,6E-09 2,27E-08 Example 76 ND ND Example 58 ND ND Example 77 ND ND Example 59 ND ND Example 78 ND ND Example 60 ND ND Example 79 ND ND Example 61 ND ND Example 80 ND ND Example 62 ND ND Example 81 ND ND Example 63 ND ND Example 82 ND ND Example 63 ND ND ND: Not determined EXAMPLE C: Quantification of The in vivo cleaved form of PARP The ability of the compounds of the invention to induce apoptosis, by measuring cleaved PARP levels, is evaluated in a model of AMO-1 multiple myeloma cell xenograft. 1.107 AMO-1 cells are grafted under the skin of immunocompromised mice (strain SCID). 12 to 14 days after the transplant, the animals are treated intravenously or orally with the various compounds. After treatment, the tumor masses are removed and lysed, and the cleaved form of PARP is quantified in the tumor lysates. Quantification is performed using the Meso Scale Discovery (MSD) ELISA platform, which specifically measures the cleaved form of PARP. It is expressed as an activation factor corresponding to the ratio of the amount of PARP cleaved in the treated mice divided by the amount of cleaved PARP in the control mice. The results show that the compounds of the invention are capable of inducing apoptosis of AMO-1 tumor cells in vivo.
[0050] EXAMPLE D In Vivo Anti-tumor Activity The anti-tumor activity of the compounds of the invention is evaluated in a model of AMO-1 multiple myeloma cell xenograft. 1.107 AMO-1 cells are grafted under the skin of immunocompromised mice (strain SCID). 6 to 8 days after the grafting, when the tumor mass reached about 150 mm3, the mice are treated with the various compounds according to a daily schedule (treatment of 5 days). The tumor mass is measured twice a week from the start of treatment.
[0051] The results obtained using AT / C (i.e., the parameter for qualifying the activity of a product, which is defined as the volume ratio of the tumors of the treated group / volume of the tumors of the untreated control group) show that the compounds of the invention induce a significant regression of the tumors during the treatment period.
[0052] EXAMPLE F: Pharmaceutical composition: tablets 1000 tablets containing a dose of 5 mg of a compound selected from Examples 1 to 82 5g Wheat starch 20 g Corn starch 20 g Lactose 30 g Magnesium stearate 2 g Silica. 1 g Hydroxypropylcellulose 2 g

权利要求:
Claims (38)
[0001]
REVENDICATIONS1. Compound of formula (I): (I) in which: - A represents the group in which 1 is bonded to the oxygen atom and 2 is bonded to the phenyl ring; - R1 represents a linear C1 to C6 alkyl group; branched, a linear or branched C2-C6 alkenyl group, a linear or branched C2-C6 alkynyl group, a linear or branched C1-C6 alkoxy group, a -S- (C1-C6) alkyl group, a polyhaloalkyl group linear or branched C1 to C6, a hydroxyl group, a hydroxy (C1-C6) alkyl group, a cyano group, -NR12R12 ', -Cy5 or a halogen atom, - R2, R3, R4 and R5 represent independently from each other a hydrogen atom, a halogen atom, a linear or branched C1-C6 alkyl group, a linear or branched C2-C6 alkenyl group, a linear or branched C2-C6 alkynyl group, a linear or branched C1 to C6 polyhaloalkyl group, a hydroxy group, a hydroxyalkyl (C1-C6) alkyl, a linear or branched C1-C6 alkoxy group, a -S- (C1-C6) alkyl group, a cyano group, a nitro group, - (C1-C6) alkyl, C 1 -C 6) -NR 1 0 R 10 ', -O- (C 1 -C 6) alkyl-NR 1 R 10', -O- (C 1 -C 6) alkyl-R 11, -C (O) -ORO, -OC (O) - R 10, -C (O) -NRORR 0, -NR 10 -C (O) -R 1 o ', -NR 1 -C (O) -OR10', - (C 1 -C 6) alkyl -NR 0 -C ( 0) -R 0 ', -S 02-NR oR o', -SO2- (C1-C6) alkyl, or the substituents of one of the (R2, R3), (R3, RI) pairs, ( R4, R5), when grafted on two adjacent carbon atoms, together with the carbon atoms carrying them form an aromatic or nonaromatic 5-7 membered ring, which may contain from 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, it being understood that the resulting ring may be substituted by a group selected from a linear or branched C1-C6 alkyl group, -NR12R12 ', - (C1-C6) alkyl -Cyi or a "0, - R6 represents -O- (C1-C6) alkyl-R1, -R7 represents a hydrogen atom, a halogen atom, a linear or branched C1-C6 alkyl group, a linear C2-C6 alkenyl group or branched, linear or branched C2-C6 alkynyl group, linear or branched C1-C6 polyhaloalkyl, hydroxy group, linear or branched C1-C6 alkoxy group, -S- (C1-C6) alkyl group a cyan group, a nitro group, - (C 1 -C 6 alkyl) -NRioRio ', -O- (C 1 -C 6) alkyl -NR10R10', -O-CY1, - (C6-C6) alkylCyl C 1 -C 6 -alkenyl-Cyl, -C 2 -C 6 -alkynyl-Cyl, -O- (C 1 -C 6 -alkyl) -R11, -C (O) -OR10, -OC (O) -R10, -C (O) -NR1oR10 ', -NRIO-C (O) -R10% -NR10-C (O) -OR10', - (C1-C6) alkyl-NR10-C (O) -R1o Is a hydrogen atom, a linear or branched C 1 -C 8 alkyl group, a Hey teroaryl, an aryl-C 1-6 alkyl group or a heteroaryl (C 1-6 alkyl) group; R represents a linear or branched C 1-6 alkyl group, a linear or branched C 2-6 alkenyl group; a linear or branched C2-C6 alkynyl group, -Cy3, -C1-C6alkylCy3, -C2-C6alkenylCy3, -C2-C6alkynylCy3, -Cy3 -Cyl, - (C2-C6) alkynyl-O-Cy3, -Cy3- (C1-C6) alkyl-O- (C1-C6) alkyl -Cy4, halogen, cyan group, - C (O) -R13 01.1.-C (O) -NR13R13-R10 and R10 'represent, independently of one another, a hydrogen atom, a linear C1-C6 alkyl group or branched, - (C 1 -C 6) alkyl-CY 1, or the substituents of the pair (R 10, R 10 ') together with the nitrogen atom carrying them an aromatic or non-aromatic ring consisting of 5 to 7 members, which may contain in addition to the nitrogen atom from 1 to 3 heteroatoms selected from oxygen, the ufre and nitrogen, it being understood that the nitrogen in question may be substituted with 1 or 2 groups representing a hydrogen atom or a linear or branched C1-C6 alkyl group, and it being understood that one or more of the atoms of carbon of the optional substituents may be deuterated, - Ru represents -Cy5- (C6-C6) alkyl-O- (C6-C6) alkyl -Cy6, -Cy5- (C6-C6 alkyl) -Cy6, - Cy5- (C1-C6) alkyl-NR12- (C1-C6) alkyl-C6-R12, R12 ', R13 and R13' independently of one another are hydrogen or (C1-C6) alkyl. C6 linear or branched optionally substituted, - R14 represents a hydrogen atom, a hydroxy group or a hydroxy (C1-C6) alkyl group, - Ra represents a hydrogen atom or a linear C1 to C6 alkyl group or branched, - Rb represents a group -O-C (O) -O-R0, a group -O-C (O) -NR0Ro 'or a group -O-P (0) (OR0) 2, - Ro and Ro 'represent i Independently of each other is a hydrogen atom, a linear or branched C1-C8 alkyl group, a cycloalkyl group, a C1-C6 alkoxy (C1-C6) alkyl group, a (alkoxy) group, C1 to C6) carbonyl (C1-C6) alkyl, or the substituents of the pair (Ro, Ro ') together with the nitrogen atom carrying them a non-aromatic ring of 5 to 7 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 C1 to C6 alkyl group or branched, - Cy1, Cy2, Cy3, Cy4 and Cy5 independently of one another are cycloalkyl, heterocycloalkyl, aryl or heteroaryl, is substituted by a group selected from -O-P (0) ( 0R202; -O-P (0) (O-) 2; - (CH2) p-O- (CHR18-CHR19-O) q-R20; a hydroxy; hydroxy (C1-C6) alkyl; - (C112) r-Y- (CH2) s-heterocycloalkyl; or -Y- (CH2) q-NR21R21; - R15 represents a hydrogen atom; a group - (CH2) p-O- (CHR18-CHR19-O) q-R20; a linear or branched (C1-C6) alkoxy (C1-C6) alkyl group; a group -Y- (Cl-12) q-NR21R21 '; or a group - (CH2), - Y- (CH2) s-heterocycloalkyl; - R16 represents a hydrogen atom; a hydroxy group; a hydroxy (C1-C6) alkyl group; a group - (CH2), - Y- (CH2) s-heterocycloalkyl; a group (CH2), - Y-X-O-P (O) (OR2) 2; a group -O-P (0) (0-) 2; a group - (CH2) p-O- (CHR18-CHR19-O) q-R20; a group - (CH 2) p -O-C (O) -NR 22 R 23; or a group -Y- (CH2) q-NR21R21 '; - R17 represents a hydrogen atom; a group - (CH2) p-O- (CHR18-CHR19-O) q-R20; a group -O-P (O) (OR2O2, a group -O-P (O) (O-) 2, a hydroxyl group, a hydroxyl (C1-C6) alkyl group, a group - (C1-12) , -Y- (CFI2), - heterocycloalkyl, a group -Y- (CH2) q -NR2112.2 / 'or an aldonic acid; X represents a group - (CH2) s- or a group -C ( Y represents a bond or an oxygen atom; R 18 represents a hydrogen atom or a (C 1 -C 6) alkoxy (C 1 -C 6) alkyl group; R represents an atom of hydrogen or a hydroxy (C1-C6) alkyl group; R20 represents a hydrogen atom or a linear or branched C1-C6 alkyl group; R21 and R21 'independently represent one of the other a hydrogen atom, a linear or branched C1-C6 alkyl group or a hydroxy (C1-C6) alkyl group, or the substituents of the (R21, R21 ') pair together with the nitrogen atom the 5 bearing an aromatic or non-aromatic cycle consisting of 5- to 7-membered ring which may contain in addition to the nitrogen atom from 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, it being understood that the resulting ring may be substituted by a group representing an atom hydrogen or a linear or branched C1-C6 alkyl group; R22 represents a (C1-C6) alkoxy (C1-C6) alkyl group, a - (CH2) p-NR24R24 'group or a - (CH2) p -O- (CHRI8-CHR19-0) group; R23 represents a hydrogen atom or a C1-C6 alkoxy (C1-C6) alkyl group, or the substituents of the (R22, R23) pair together with the nitrogen atom 15 bearing an aromatic or nonaromatic ring consisting of 5 to 18 members, which may contain in addition to the nitrogen atom from 1 to 5 heteroatoms selected from oxygen, sulfur and nitrogen, it being understood that the The resulting ring may be substituted by a group representing a hydrogen atom, a linear or branched C1-C6 alkyl group or a heterocycloalkyl group. R24 and R24 'represent, independently of one another, a hydrogen atom or a linear or branched C1-C6 alkyl group, or the substituents of the pair (R24, R24 ') together with the nitrogen atom carrying them an aro ring 5- or 7-membered aromatic or nonaromatic compound which may contain, in addition to the nitrogen atom, from 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, it being understood that the resulting ring may be substituted with a group representing a hydrogen atom or a linear or branched C1-C6 alkyl group; n is an integer equal to 0 or 1, p is an integer equal to 0, 1 or 2; Q is an integer of 1, 2, 3 or 4; - r and s are independently an integer equal to 0 or 1, provided that R15, R16 and R17 can not together represent a hydrogen atom and, when R1 represents a methyl group, R15 can not represent a "methoxyethoxy" group, it being understood that: "aryl" means a phenyl, naphthyl, biphenyl, indanyl or indenyl group, "heteroaryl" means any mono- or bicyclic group consisting of 5 to 10 members, having at least one aromatic group and containing from 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, "cycloalkyl" means any nonaromatic, mono- or bi-cyclic carbocyclic group containing 3 with 10-membered "heterocycloalkyl" means any nonaromatic carbocyclic group, mono- or bicyclic, consisting of 3 to 10 members and containing from 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, who can 15 To form condensed, bridged or spiro ring systems, with the possibility for the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups thus defined and the alkyl, alkenyl, alkynyl, alkoxy groups to be substituted by 1 to 5 groups selected from an alkyl group. optionally substituted linear or branched C1 to C6, an optionally substituted linear or branched C2 to C6 alkenyl group, an optionally substituted linear or branched C2 to C6 alkynyl group, optionally substituted linear or branched C1 to C6 alkoxy, (alkyl) C1 to C6) -S- optionally substituted, hydroxy, oxo (or N-oxide if appropriate), nitro, cyano, -C (O) -OR ', -OC (O) -R', -C (O) ## STR5 ## wherein R 'and R "represent independently of one another a hydrogen atom or a C1-alkyl group linear or branched C6 ring optionally substituted, and it being understood that one or more of the carbon atoms of the possible substituents above may be deuterated, their enantiomers, diastereoisomers and atropisomers, and their addition salts with a pharmaceutically acceptable acid or base . 3037958 - 85 -
[0002]
2. Compounds according to claim 1, wherein at least one of R 2, R 3, R 4 and R 5 is not a hydrogen atom.
[0003]
Compounds according to claim 1, wherein n is an integer of 1. 5
[0004]
4. Compounds according to claim 1, wherein R1 represents a linear or branched C1-C6 alkyl group or a halogen atom.
[0005]
5. Compounds according to claim 1, wherein R14 represents a hydrogen atom, a hydroxy group, a hydroxymethyl group or a hydroxyethyl group.
[0006]
6. Compounds according to claim 1, wherein R2 represents a halogen atom, a hydroxyl group, a linear or branched C1-C6 alkoxy group. 15
[0007]
7. Compounds according to claim 1, wherein R3 represents a hydrogen atom, a hydroxy group, a linear or branched C1-C6 alkoxy group or -O- (C1-C6) alkyl -NR131R10-
[0008]
The compound of claim 1 wherein R4 and R5 are hydrogen.
[0009]
9. Compounds according to claim 1, wherein 25 represents R 1 R 10 where R 1, R 10 and R 10 'are as defined in claim 1.
[0010]
10. Compounds according to claim 1, wherein IR1 0 p R10 1 1 (represents where R10 and R10 'are as defined in claim 1.
[0011]
The compound of claim 1, wherein the substituents of the (R1, R5) pair are the same and the substituents of the (R2, R4) pair are the same. 10
[0012]
12. A compound according to claim 1 wherein R11 is as defined in claim 1.
[0013]
The compound of claim 1, wherein R7 represents a hydrogen atom. 20
[0014]
14. Compounds according to claim 1, wherein Rg represents a hydrogen atom, a -CHRaRb group, an optionally substituted linear or branched C1 to C8 alkyl group or a heteroaryl-C1 to C6 alkyl group. 3037958 -87-
[0015]
15. Compounds according to claim 1, in which R9 represents a linear or branched C1-C6 alkyl group, a linear or branched C2-C6 alkenyl group, a linear or branched C2-C6 alkynyl group, an aryl group or a linear or branched C1-C6 alkenyl group. heteroaryl group. 5
[0016]
Compounds according to claim 1, wherein R10 and R10 'are independently of each other a linear or branched C1-C6 alkyl group, or the substituents of the (R10, R10') pair together with the nitrogen atom bearing them a 5- to 7-membered non-aromatic ring which may contain in addition to the nitrogen atom from 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, being understood that the nitrogen in question may be substituted by a group representing a hydrogen atom or a linear or branched C1 to C6 alkyl group.
[0017]
17. Compounds according to claim 1, wherein R11 is -Cy5- (C1-C6) alkyl -Cy6.
[0018]
18. Compounds according to claim 1, wherein Cy5 represents a heteroaryl group, in particular a pyrimidinyl group, a pyrazolyl group, a triazolyl group, a pyrazinyl group or a pyridinyl group. 20
[0019]
19. Compounds according to claim 1, wherein Cy6 is wherein R15, R16 and R17 are as defined in claim 1.
[0020]
20. Compounds according to claim 1, wherein R16 and R17 represent a hydrogen atom and R15 represents a - (CH2) p-O- (CHRis-CHR19-0) o -R20 group; A linear or branched (C1-C6) alkoxy (C1-C6) alkyl group; a group -Y- (CH 2) q-NR 21 R 21 '; or a group - (CH 2), - Y- (CH 2) 5 heterocycloalkyl.
[0021]
21. Compounds according to claim 1, wherein R15 and R17 represent a hydrogen atom and R16 represents a hydroxyl group; a hydroxy (C1-C6) alkyl group; a - (CH2) 1Y- (CH2), - heterocycloalkyl group; a group -O-P (O) (OR2O2; a group -O-P (O) (O-) 2; a group - (CH2) p -O- (CHRI8-CHR19-0) q-R20; group - (CI-12) pOC (O) -NR22R23; a group (CI-12), -YX-O-P (O) (OR20) 2 or a group -Y- (CH2) q -NR21R21'- 10
[0022]
22. Compounds according to claim 1, wherein R15 and R16 represent a hydrogen atom and R17 represents a - (CH2) p -O- (CHR18-CH1119-0) q-R2o group -O-P (0) group. (0R202) a -O-P (O) (O-) 2 group, a hydroxyl group, a hydroxy (C1-C6) alkyl group, a - (CH2) group, - Y- (CH2) group, - heterocycloalkyl, a -Y- (CH2) q-NR21R21 'group or an aldonic acid.
[0023]
23. Compounds according to claim 1, which are: (2R) -2 - {[(5S) -5- {3-chloro-2-methyl-443- (4-methylpiperazin-1-yl)} ) propoxy] phenyl-6- (4-fluoro-phenyl) thieno-pyrimidin-4-yl] oxy} -3 - (2 - {[2- (3-hydroxyphenyl) pyrimidin-4-yl] methoxylphenyl) -propanoic acid) ; (2R) -2 - {[(5S) -5- {3-chloro-2-methyl-4-13- (4-methylpiperazin-10-propoxylphenyl) -6- (4-fluoro-phenypthieno [2 3-d] pyrimidin-4-yl] oxy} -3- (2 - {[2- (4-hydroxyphenyl) pyrimidin-4-yl] methoxy} phenyl) propanoic acid, (2R) -2 - {[(55 ') - 5- {3-Chloro-2-methyl-443- (4-methylpiperazin-1-yl) propoxy} phenyl} -6- (4-fluoro-phenyl) thieno [2,3-d] 4pyrimidin-4-yloxy} -3424 (243- (hydroxymethyl) phenyl] pyrimidin-4-yl} methoxy) phenylpropanoic acid, - (2R) -2 - {[(5S,) - 5- {3-) acid; chloro-2-methyl-4- [3- (4-methylpiperazin-1-ylpropoxy) phenyl) -6- (4-fluoro-phenypthieno [2,3-4-pyrimidin-4-yl] oxy} -342- (244-30) (2-hydroxymethyl) phenylpyrimidin-4-yl} methoxy) phenylpropionic acid; (2R) -2 - {[(5S) -5- {3-chloro-2-methyl-443- (4-methylpiperazin)} lyppropoxy] phenyl} -6- (4-fluoro-phenypthieno [2,3-d] pyrimidin-4-yl] oxy} -3- {2 - [(2 - {2- [2- [2,2 1-dimethyl-1,3-dioxolan-4-yl) methoxy] phenyl) pyrimidin-4-yl) methyloxy] phenylpropanoic acid; (2R) -2- {[(5Sa) acid; N- {3-chloro-2-methyl-443- (4-methylpiperazin-1-yl) propoxy] phenyl} -6- (4-fluoro-phenyl) thieno [2,3-cipyrimidin-4-yl] oxy} -3- {2 - [(2- {242- (2-methoxyethoxy) ethoxy] phenyl} pyrimidin-4-yl) methoxylphenyl} propanoic acid; (2R) -2 - {[(55,7) -5- {3-chloro-2-methyl-443- (4-methylpiperazin-1-yipropoxy) phenyl} -6- (4-fluoro-phenyl) acid; thieno [2,3-d] pyrimidin-4-yloxy) -3- (2 - {[242- {2- [2- (2-methoxyethoxy) ethoxy] ethoxy} phenyl) pyrimidin-4-ylmethoxy} phenyl) - propanoic; (2R) -2 - {[(5Sa) -5- {3-chloro-2-methyl-443- (4-methylpiperazin-1-yl) propoxylphenyl} -6- (4-fluoro-phenypthieno) [2,3-4-pyrimidin-4-yl] oxy} -3424 {242- (methoxymethylphenyl) pyrimidin-4-yl} methoxy) phenylpropanoic acid; (2R) -2- {[(5Sa) acid) -5- {3-Chloro-2-methyl-443- (4-methylpiperazin-1-yipropoxylphenyl) -6- (4-fluoro-phenyl) thieno [2,3-d] pyrimidin-4-yloxy} -3- { 24 (2- {2 - [(2-methoxyethoxy) methyl] phenylpyrimidin-4-yl) methoxy] phenyl} propanoic acid; (2R) -2- {[(5S ') - 5- {3 1-chloro-2-methyl-443- (4-methylpiperazin-1-yl) propoxy] phenyl} -6- (4-fluoro-phenypthieno [2,3-cflpyrimidin-4-yl] oxy} -3- [(2- {2 - [(2-Hydroxyethoxy) methyl] phenyl} pyrimidin-4-yl) -methoxylphenyl} propanoic acid; (2R) -2- {[(5Sa) -5- {3-chloro} 2-methyl-443- (4-methylpiperazin-1-yl) propoxylphenyl} -6- (11-fluoro-phenyl) thieno [2,3-a] pyrimidin-4-yloxy} -3- (2- {[2- (2- {[(2,2-dimethyl-1,3-dioxolan-4-yl) methoxy] methyl} phenyl) pyrimidin-4-yl] methoxy} p phenyl) propanoic acid - (2R) -2 - {[(5Sa) -5- {3-chloro-2-methyl-443- (4-methylpiperazin-1-yl) propoxy] phenyl} -6- ( 4-fluoro-phenyl) thieno [2,3-d] pyrimidin-4-yl] oxy} -3- {2 - [(2- {3 - [(2-hydroxyethoxy) methyl] phenyl} pyrimidin-4-yl) -methoxy] phenyl} propanoic acid; (2R) -2 - {[(5S) -5- {3-chloro-2-methyl-443- (4-methylpiperazin-1-yipropoxy) phenyl} -6- (4-fluoro-phenypthieno) [2,3-d] pyrimidin-4-yl] oxy} -3- {2 - [(2- {3 - [(1,3-dimethoxypropan-2-yloxy) phenyl} pyrimidin-4-yl) -methoxy } phenyl} propanoic acid - (2R) -2 - {[(5Sa) -5- {3-chloro-2-methyl-443- (4-methylpiperazin-1-yl) propoxy] phenyl} -6- ( 4-Fluoro-phenypthieno [2,3-4-pyrimidin-4-yloxy] -3- {2 - [(2- {4 - [(1,3-dimethoxypropan-2-yloxy) phenyl} pyrimidin-4-yl) methoxyphenyl} propanoic acid (2R) -2 - {[(5Sa) -5- {3-chloro-2-methyl-443- (4-methylpiperazin-1-yl) propoxy] phenyl} -methoxy-phenyl} -propanoic acid 6- (4-Fluoro-phenylthio [2,3-d] pyrimidin-4-yloxy-342- ({244- (2,3-dihydroxypropoxy) phenylipyrimidin-4-yl} methoxy) phenyl] propanoic acid; 6-O- {3- [4 - ({2 - [(2R) -2-carboxy-2 - {[(5S) -5- {3-chloro-2-methyl-443- (4-methylpiperazine) 1-yl) propoxyl-phenyl-6- (4-fluorophenyl) thieno [2,3-d] pyrimidin-4-yl-oxy] ethyl] phenoxy} methylpyrimidin-2-yl] phenyl} -α-manno methyl pyranoside; 6-0- {344 - ({2 - [(2R) -2-carboxy-2 - {[(5S) -5- {3-chloro-2-methyl-443- (4 methylpiperazin-1-yppropoxyl-phenyl} -6- (4-fluorophenylthieno [2,3-d] pyrimidin-4-yl] oxy} ethyliphenoxy} methylpropylmid-2-yl] phenyl} -2,3,4 methyl tri-O-methyl-α-mannopyranoside; 6-0- {444 - ({2 - [(2R) -2-carboxy-2 - {[(5Sa) -5- {3-chloro-2-methyl-443- (4-methylpiperazin)} yl) propoxy] -phenyl] -6- (4-fluorophenylthieno [2,3-d] pyrimidin-4-yl] oxy} ethyl] phenoxy} methyl) pyrimidin-2-yl] phenyl] -α-mannopyranoside methyl; 6-0- {4- [4 - ({24 (2R) -2-carboxy-2 - {[(5S) -5- {3-chloro-2-methyl-4- (3- (4-chloro-2-methyl-3- Methylpiperazin-1-yppropoxy] -phenyl} -6- (4-fluorophenylthieno [2,3-pyrimidin-4-yloxy] ethyl] phenoxy} methyl) pyrimidin-2-yliphenyl} -2,3,4 methyl tri-O-methyl-α-D-manno-pyranoside; 6-0- {4- [4- ({2 - [(2R) -2-carboxy-2 - {[(5Sa) -5- { 3-Chloro-2-methyl-4- [3 - (4-methylpiperazin-1-yipropoxy) -phenyl] -6- (4-fluorophenylthieno [2,3-pyrimidin-4-yl] oxyethyl] phenoxy} methyl ) pyrimidin-2-yllphenyl} -D-mannopyranose; 6-0- {244 - ({2 - [(2R) -2-carboxy-2- {[(5S)) -5- {3- 2-chloro-methyl-4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -6- (4-fluorophenylthieno [2,3-pyrimidin-4-yloxy] ethyl] phenoxylmethylpyrimidin-2-yliphenyl} - D-mannonic; 1,2-04 (1 R) -1 - ({444 - ({2 - [(2R) -2-carboxy-2 - {[(5S)) -5-chloro 2-methyl-4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -6- (4-fluorophenylthieno [2,3-d] pyrimidin-4-yl] oxy} ethyl] phenoxylmethyl) pyrimidine -2-yl] benzylloxy) ethylidene] -O-D-mannopyranose; (2R) -2 - {[(5Sa) -5- {3-chloro-2-methyl-443- (4-methylpiperazin-1-yl) propoxy] phenyl} -6- (4-fluoro) phenyl) thieno [2,3-d] pyrimidin-4-yl] oxy} -3- {2 - [(2- {4 - [(α-D-mannopyranosyloxy) methyl] phenyl} pyrimidin-4-yl) -methoxy] phenyl} propanoic acid; (2R) -2- (k5Sa) -5- (3-chloro-2-methyl-443- (4-methylpiperazin-1-yl) propoxy] phenyl-6- (4-fluoro) Phenypthieno [2,3-a] pyrimidin-4-yloxy) -3- [2- ((244- (2-hydroxyethyl) phenyl] pyrimidin-4-yl} methoxy) phenylpropanoic acid; 2 - {[(53s) -5- {3-chloro-2-methyl-4- [3- (4-methylpiperazin-1-ylpropoxylphenyl) -6- (4-fluoro-phenypthieno [2,3-d]; cis-pyrimidin-4-yl] oxy} -342- ({242- (2,3-dihydroxypropoxy) phenylpyrimidin-4-yl} methoxy) -phenyl] propanoic acid - (2R) -2- {R5S (7) -5- {3-chloro-2-methyl-413- (4-methylpiperazin-1-yl) propoxy] phenyl} -6- (4-fluoro-phenyl) thieno [2,3-d] pyrimidin-4-yl ] oxy} -342 - ({242- (2-hydroxyethoxy) phenylipyrimidin-4-yl} methoxy) phenylpropanoic acid; 2- (2R) -2 - {[(5S,) - 5- {3-) acid; chloro-2-methyl-443- (4-methylpiperazin-1-ylpropoxy) phenyl) -6- (4-fluoro-phenyl) thieno [2,3-a] pyrimidin-4-yloxy} -3- [2- [ (2- {2 - [(2,3-dihydroxypropoxy) methyl] phenylpyrimidin-4-yl) methoxy] phenyl} propandic acid (2R) -2 - {[(5S 5-{3-chloro-2-methyl-443- (4-methylpiperazin-1-yl) propoxylphenyl} -6- (4-fluoro-phenyl) thieno [2,3-c] pyrimidin-4-yloxy 3- [2- (2- [3- (Phosphonooxy) phenyl] pyrimidin-4-yl) methoxy) phenyl] propanoic acid; 444 - ({2 - [(2R) -2-carboxy-2 - {[(5Sa) -5- (3-chloro-2-methyl-4- [3- (4-methylpiperazin)] - phosphate, yl) propoxy] phenyl-6- (4-fluorophenylthieno [2,3-4-pyrimidin-4-yloxy] ethyl] phenoxylmethyl) pyrimidin-2-yl] phenyl; (2R) -2- {[(5S, ) -5- {3-Chloro-2-methyl-4- [3- (4-methylpiperazin-1-ylpropoxy) phenyl} -6- (4-fluoro-phenyl) thieno [2,3-d] pyrimidin); 4-yloxy-342- ({243- (2-hydroxyethoxy) phenylipyrimidin-4-yl} methoxy) phenylpropanoic acid; (2R) -2 - {[(5Sa) -5- {3-chloro} -2-methyl-4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -6- (4-fluoro-phenypthieno [2,3-b] pyrimidin-4-yloxy} -3- {2} [(2- (442- (2-methoxyethoxy) ethoxy] phenyl] pyrimidin-4-yl) methoxy] phenylpropano] acid (2R) -2 - {[(5Sa) -5- {3-chloro}} 2-methyl-4- [3- (4-methylpiperazin-1-yl) propoxylphenyl} -6- (4-fluoro-phenyl) thieno [2,3-d] pyrimidin-4-yl] oxy) -3- [2- [ (2- {4- [2- (2-Hydroxyethoxy) ethoxy] phenyl} pyrimidin-4-yl) methoxy] phenyl} propaneque acid (2R) -2- [(5Sa) -5- {3 chloro 2-methyl-443- (4-methylpiperazin-lyppropoxylphenyl-6- (4-fluom-phenyl) thieno [2,3-d] pyrimidin-4-yl] oxy} -3- (2 - ([2- ( 4- {2- [2- (2-methoxyethoxy) ethoxy] ethoxy} phenyl) pytimidin-4-yl] methoxy} phenyl) propanoic acid; (2R) -2 - {[(5Sa) -5- {3-chloro-2-methyl-413- (4-methylpiperazin-1-yipropoxy) phenyl} -6- (4-fluoro) phenypthieno [2,3-d] pyrimidin-4-yl] oxy} -3- {2 - [(2- {442- (dimethylamino) ethoxy] phenyl} pyrimidin-4-yl) methoxyphenylpropanoic acid; (2R) -2 - {[(5S) -5- (3-chloro-2-methyl-443- (4-methylpiperazin-1-yl) propoxy] phenyl} -6- (4-fluoro) Phenypthieno [2,3-d] pyrimidin-4-ylioxyl-3- {24 (243 - [(2,2-dimethyl-1,3-dioxol-4-yl) methoxy] phenyl} -pyrimidin-4 Methylphenyl} propanoic acid - (2R) -2 - [(5Sa) -5- {3-chloro-2-methyl-4- [2- (4-methylpiperazin-1-yl) ethoxylphenyl} -6- 1-fluoro-phenyl) thieno [2,3-c] pyrimidin-4-yloxy} -3- [2- (2- [3 - (15-hydroxy-3-oxo-2,7,10,13- tetraoxa-4-azapentadec-1-yl) phenyl] pyrimidin-4-yl} methoxy) phenyl] propanoic acid; (2R) -3- (2- {[2- (3- {[1, 4'-Bipiperidin-1'-ylcarbonypoxy] methyl-phenyl) -pyrimidin-4-yl] -methoxy-phenyl) -2 - {[(5Sa) -5- {3-chloro-2-methyl-442- (4-methyl) piperazin-1-yl) ethoxy] phenyl) -6- (4-fluorophenyl) -thieno [2,3-di-pyrimidin-4-yloxypropanoic acid; (2R) -2 - {[(5Sa) -5- {3-chloro-2-methyl-4- [2- (4-methylpiperazin-1-yepethoxy] phenyl} -6- fluoro-phenyl) thieno [2,3-d] pyrimidin-4-yl] oxy} -3- (2- [2- (3- {2- [2- (2-hydroxyethoxy) ethoxy] ethoxy} phenylpyrimidine 4-yl] methoxyphenyl) propanoic acid (2R) -2 - [(5Sa) -5- {3-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxylphenyl) 6- (4-Fluoro-phenylthio [2,3-a] pyrimidin-4-yloxy) -3- {2 - [(2- (3,4242-hydroxyethoxy) ethoxy] phenyl} pyrimidin-4-yl) methoxy] -phenyl} propanoic acid - (2R) -2 - {[(5Sa) -5- {3-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxy] phenyl} -6- (4-Fluoro-phenyl) thieno [2,3-d] pyrimidin-4-yl] oxy} -3- {24 (2- {34242-methoxyethoxy} ethoxy] phenyl} pyrimidin-4-yl) methoxy] phenylpropanoic acid; (2R) -2 - {[(5S ()) - 5- {3-chloro-2-methyl-4- [2- (4-methylpiperazin-1-yl) ethoxy] acid; phenyl-6- (4-fluom-phenyl) thieno [2,3-cipyrimidin-4-yl] oxy} -3- {24 (2- {3 - [({[2- (4-methylpiperazin-1 -ypét hyl] carbamoyloxy) methyl] phenyl} pyrimidin-4-yl) methoxy] phenylpropanoic acid; (2R) -2 - {[(5Sa) -5- {3-chloro-2-yl) ethyl-4- [2- (4-methylpiperazin-1-yl) -ethoxy] phenyl} -6 (4-Fluoro-phenyl) thieno [2,3-a] pyrimidin-4-yl] oxy} -3- {2 - [(2- {3 - [({[2- (morpholin-4-yl)} ethyl] carbamoyloxy) methyl-phenyl-pyrimidin-4-yl) methoxylphenylpropanoic acid; (2R) -2 - {[(5S) -5- {3-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxy] phenyl] -6- fluorophenyl) thieno [2,3-d] pyrimidin-4-yl] oxyl-3- {24 (2- {3 - [({[2- (dimethylamino) ethyl] carbamoyl} oxy) methyl} phenyl} pyrimidine. 4-yl) methoxy] phenyl} propanoic acid; (2R) -2 - {[(5S) -5- {3-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxy] phenyl} -6- (4-fluoro) -acrylic acid Phenypthieno [2,3-4-pyrimidin-4-yl] oxy} -3- {2 - [(2- {3 - [({[2- (pyrrolidin-1-yl) ethyl] carbamoyloxy) methyl] phenyl} pyrimidin-4-yl) methoxy] phenyl} propanoic acid (2R) -342 - ({2- [3 - ({[bis (2-methoxyethyl) carbamoyl] oxy} methyl) phenyl Pyrimidin-4-yl} methoxy) -phenyl] -2 - {[(5S) -5- {3-chloro-2-methyl-4- [2- (4-methylpiperazin-1-yl)} ethoxy] phenyl-6- (4-fluorophenylthieno [2,3-d] pyrimidin-4-yl] oxy) propanoic acid - (2R) -2 - {[(5S,) - 5- {3-chloro-2-methyl-442- (4-methylpiperazinyl-1-yl) ethoxylphenyl} -6- (4-fluoro-phenyl) thieno [2,3-c] pyrimidin-4-yl} oxy} -3 - (2- [2- (3-{[(1,4,7,10,13-Pentaoxa-16-azacyclooctadecan-16-ylcarbonyl) oxy] methyl} phenyl] pytimidin-4-yl] methoxy } -phenyl) propanoic acid - (2R) -2 - {[(5S) -5- {3-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxy] phenyl} -6- (4-fluoro-phénypth 1eno [2,3-cipyrimidin-4-yl] oxy) -3- [2- ({2- [3- (2,3-dihydroxypropoxy) phenyl] pyrimidin-4-yl} methoxy) phenyl} propanoic acid; (2R) -2 - {[(((()) - 5- {3-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxy] phenyl} -6- -fluoro-phenypthieno [2,3-4-pyrimidin-4-yloxy] -3- (2 - {[243- {242- (2-methoxyethoxy) ethoxy] ethoxy} phenyl) pyrimidin-4-yl] methoxy} phenyl) propanoic acid - (2R) -3 - (2- {[2- (3- {2- [bis (2-hydroxyethylamino) ethoxy} phenyl) pyrimidin-4-yl] methoxy} -phenyl) -2- [ (5S ') - 5- (3-Chloro-2-methyl-442- (4-methyl-piperazin-1-yl) ethoxy] phenyl-6- (4-fluorophenyl) thieno [2,3-4 pyrimidine] 4-yl] oxy} propanoic acid - (2R) -2 - {[(5Sa) -5- {2,3-dimethyl-442- (4-methylpiperazin-1-yl) ethoxy] phenyl} 6- (4-fluorophenyl) thieno [2,3-d] pyrimidin-4-yl] oxy} -3- {2 - [(2- {3 - [(([2- (piperidinyl)} ethyl carbamoyloxy) methylphenylpyrimidin-4-yl) methoxyphenylpropanoic acid; (2R) -2 - {[(5S) -5- {3-chloro-2-methyl-442- (4-methylpiperazine) acid; -1- (yl) ethoxy] phenyl) -6- (4-fluoro-phenyl) thieno [2,3-d] pyrimidin-4-yl] oxy} -3 - {2- [(2- {342- ( mor pholin-4-ypethoxylphenyl pyrimidin-4-yl) methoxyphenylpropanoic acid; (2R) -2- (R5S) -5- {3-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxy] phenyl} -6- 1,1-uoro-phenypthieno [2,3-4-pyrimidin-4-yloxy-3- {24 (2- {3- (dimethylamino) ethoxy] phenyl} pyrimidin-4-ylmethoxyl-phenyl} propanoic acid; 2R) -3- (2- [2- (4- {2- [bis (2-hydroxyethypaminoethoxy) phenyl) pyrimidin-4-ylimethoxy} -phenyl) -2 - {[(5Sa) -) 5- {3-Chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxy] phenyl} -6- (4-fluorophenyl) thieno [2,3-4pyrimidin-4-yl] oxy} propanoic acid - (2R) -2 - {[(5S, 7) -5- {3-chloro-2-methyl-442- (4-methylpiperazin-1-yloxyphenyl) -6- (4-fluoro-phenyl) -propanoic acid thieno [2,3-d] pyrimidin-4-yl] oxy-3- (2 - {[2- (4- {242- (2-hydroxyethoxy) ethoxy] ethoxylphenyl] pyrimidin-4-ylmethoxy} phenyl) propanoic acid, (2R) 2 - {[(53,7) -5- {3-chloro-2-methyl-442- (4-methylpiperazin-1-yl) -ethoxylphenyl-6- (4-fluoro-phenypthieno [2,3-b]) ] pyrimidin-4-yl] oxy} -3- {2 - [(2- {4 - [(2,2-dimethyl-1,3-dioxolan-4-yl) methoxylphen) (2R) -2- {[(58,7) -5- {3-chloro-2-methyl-442- (4-methylpiperazine) pyridin-4-yl) methoxy] phenylpropionic acid; 1- (yl) ethoxylphenyl) -6- (4-fluoro-phenypthieno [2,3-d] pyrimidin-4-yl] oxy} -3- {2 - [(2- {442- (morpholin-4- y1) ethoxy] phenylpyrimidin-4-yl) methoxylphenyl} propanoic acid; - the disodium salt of 444 - ({2 - [(2R) -2-carboxy-2 - {[(5S) -5- {3-chloro-methyl-443- (4-methylpiperazin-1-yipropoxy) ] phenyl-6- (4-fluorophenyl) thieno [2,3-alpyrimidin-4-yl] oxy} ethyliphenoxy} methyl) pyrimidin-2-yl] phenyl.
[0024]
24. Process for preparing a compound of formula (I) according to claim 1, characterized in that it uses, as starting compound, the compound of formula (II): A, (H) Cr 'Br 25 wherein A is as defined for formula (I) wherein 1 is bonded to the chlorine atom and 2 is bonded to the bromine atom, said compound of formula (II) being coupled with a compound of the formula (III) in which R6, R7, R14 and n are as defined for the formula (I), and Alk represents a linear or branched C1-C6 alkyl group, in which obtain the compound of formula (IV): R 14 in which R 6, R 7, R 14, A and n are as defined for formula (I) and Alk is as defined above, the compound of formula (IV) being subjected to in addition to coupling with a compound of formula (V): wherein R 1, R 2, R 3, R 4 and R 5 are as defined for formula (I), and RBI and RB2 represents a hydrogen atom, a linear or branched C1-C6 alkyl group, or RBI and RB2 form with oxygen carrying them an optionally methylated ring, to obtain the compound of formula (VI): Alk (VI) wherein R1, R2, R3, R4, R5, R6, R7, R14, A and n are as defined for formula (I) and Alk is as defined above, the ester function Alk-OC (O) - of the compound of formula (VI) being hydrolyzed to give the carboxylic acid, which may optionally be reacted with an alcohol of formula R8-OH or a chlorinated compound of formula R8-Cl, where Rg is as defined for formula (D, to obtain the compound of formula (I), which can 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, being At any time deemed appropriate during the process described above, certain groups (hydroxy, amino, etc.) of the starting reagents or synthetic intermediates can be protected, then deprotected and functionalized for the purposes of the invention. needs of synthesis.
[0025]
25. A pharmaceutical composition containing a compound of formula (I) according to any one of claims 1 to 23 or an addition salt thereof with an acid or a pharmaceutically acceptable base in combination with one or more excipients. pharmaceutically acceptable.
[0026]
26. The pharmaceutical composition of claim 25 for use as a pro-apoptotic agent.
[0027]
27. Pharmaceutical composition according to claim 26 for its use in the treatment of cancers and autoimmune diseases and the immune system. 10
[0028]
28. Pharmaceutical composition according to claim 27, for its use in the treatment of cancers of the bladder, brain, breast and uterus, chronic lymphoid leukemias, cancer of the colon, esophagus and liver, lymphoblastic leukemias, acute myeloid leukemias, lymphomas, melanomas, hematological malignancies, myelomas, ovarian cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer and cancer small cell lung.
[0029]
29. Use of a pharmaceutical composition according to claim 25 in the manufacture of medicaments for use as pro-apoptotic agents. 20
[0030]
30. Use of a pharmaceutical composition according to claim 25 in the manufacture of medicaments for use in the treatment of cancer and autoimmune diseases and the immune system. 25
[0031]
31. Use of a pharmaceutical composition according to claim 25, in the manufacture of medicaments for use in the treatment of cancers of the bladder, brain, breast and uterus, chronic lymphoid leukemias, colon cancer, esophagus and liver, lymphoblastic leukemias, acute myeloid leukemias, lymphomas, melanomas, hematological malignancies, myelomas, ovarian cancer, non-small cell lung cancer, prostate cancer , pancreatic cancer and small cell lung cancer. 3037958 -98-
[0032]
32. A compound of formula (I) according to any one of claims I to 23, or one of its addition salts with a pharmaceutically acceptable acid or base, for its use in the treatment of cancers of the bladder, brain , breast and uterus, chronic lymphoid leukemias, colon cancer, esophagus and liver cancer, lymphoblastic leukemias, acute myeloid leukemias, lymphomas, melanomas, hematological malignancies, myelomas, ovarian cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer and small cell lung cancer. 10
[0033]
33. Use of a compound of formula (I) according to one of claims 1 to 23, or an addition salt thereof with a pharmaceutically acceptable acid or base, in the manufacture of medicaments for use in the bladder, brain, breast and uterine cancers, chronic lymphoid leukemias, colon, esophagus and liver cancer, lymphoblastic leukemias, acute myeloid leukemias, lymphomas, melanoma, hematological malignancies, myeloma, ovarian cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer and small cell lung cancer.
[0034]
34. Combination of a compound of formula (I) according to any one of claims 1 to 23, with an anti-cancer agent chosen from genotoxic agents, mitotic poisons, antimetabolites, proteasome inhibitors, inhibitors of kinases and antibodies.
[0035]
35. A combination pharmaceutical composition according to claim 34 in combination with one or more pharmaceutically acceptable excipients.
[0036]
36. Association according to claim 34 for its use in the treatment of cancers. 30
[0037]
37. Use of an association according to claim 34 in the manufacture of medicaments for use in the treatment of cancers. 3037958 -99-
[0038]
38. Compound of formula (1) according to any one of claims 1 to 23 for its use in the treatment of cancers requiring radiotherapy.

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WO2020254299A1|2019-06-17|2020-12-24|Les Laboratoires Servier|Combination of a mcl-1 inhibitor and a standard of care treatment for breast cancer, uses and pharmaceutical compositions thereof|

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2018-06-26| PLFP| Fee payment|Year of fee payment: 4 |

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优先权:

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申请号 | 申请日 | 专利标题

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FR1555753|2015-06-23|

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FR1555753A|FR3037958B1|2015-06-23|2015-06-23|NOVEL HYDROXY ACID DERIVATIVES, PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|FR1555753A| FR3037958B1|2015-06-23|2015-06-23|NOVEL HYDROXY ACID DERIVATIVES, PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|

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UY0001036735A| UY36735A|2015-06-23|2016-06-16|NEW HYDROXY ACID DERIVATIVES, A PROCESS FOR THE PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|

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TNP/2017/000529A| TN2017000529A1|2015-06-23|2016-06-22|New hydroxyacid derivatives, a process for their preparation and pharmaceutical compositions containing them|

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BR112017027831A| BR112017027831A2|2015-06-23|2016-06-22|hydroxy acid derivatives, a process for their preparation and pharmaceutical compositions containing them|

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RU2018102361A| RU2745430C9|2015-06-23|2016-06-22|Novel hydroxy acid derivatives, a method for production thereof and pharmaceutical compositions containing them|

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PE2017002741A| PE20180949A1|2015-06-23|2016-06-22|NEW HYDROXIACID DERIVATIVES, A PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM|

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UAA201800619A| UA124759C2|2015-06-23|2016-06-22|New hydroxyacid derivatives, a process for their preparation and pharmaceutical compositions containing them|

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CN201680048558.4A| CN107922432B|2015-06-23|2016-06-22|Novel hydroxy acid derivatives, process for their preparation and pharmaceutical compositions containing them|

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TW105119603A| TWI715593B|2015-06-23|2016-06-22|New hydroxyacid derivatives, a process for their preparation and pharmaceutical compositions containing them|

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GEAP201614680A| GEP20207076B|2015-06-23|2016-06-22|New hydroxyacid derivatives, a process for their preparation and pharmaceutical compositions containing them|

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US15/738,601| US10322131B2|2015-06-23|2016-06-22|Hydroxyacid derivatives, a process for their preparation and pharmaceutical compositions containing them|

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AU2016282827A| AU2016282827B2|2015-06-23|2016-06-22|New hydroxyacid derivatives, a process for their preparation and pharmaceutical compositions containing them|

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EA201890124A| EA036503B1|2015-06-23|2016-06-22|Hydroxyacid derivatives, process for their preparation and pharmaceutical compositions containing them|

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CUP2017000162A| CU20170162A7|2015-06-23|2016-06-22|DERIVATIVES OF PHENYL-TIENOPIRIMIDINA-HIDROXIÁCID USEFUL IN THE TREATMENT OF CANCER AND AUTOIMMUNE DISEASES, METHOD OF PREPARATION OF THE SAME AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|

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CA2990083A| CA2990083C|2015-06-23|2016-06-22|Hydroxyacid derivatives, a process for their preparation and pharmaceutical compositions containing them|

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KR1020187002026A| KR20180015263A|2015-06-23|2016-06-22|NOVEL HYDROXYACIC ACID DERIVATIVE, METHOD FOR PRODUCING THE SAME, AND COMPOSITION CONTAINING THE SAME|

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MX2017017008A| MX2017017008A|2015-06-23|2016-06-22|New hydroxyacid derivatives, a process for their preparation and pharmaceutical compositions containing them.|

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PCT/EP2016/064417| WO2016207216A1|2015-06-23|2016-06-22|New hydroxyacid derivatives, a process for their preparation and pharmaceutical compositions containing them|

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MA042231A| MA42231A|2015-06-23|2016-06-22|NEW HYDROXYACID DERIVATIVES, THEIR PREPARATION PROCESS, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|

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JP2017566288A| JP6773695B2|2015-06-23|2016-06-22|A novel hydroxy acid derivative, a method for producing the same, and a pharmaceutical composition containing the same.|

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EP16731155.4A| EP3313849A1|2015-06-23|2016-06-22|New hydroxyacid derivatives, a process for their preparation and pharmaceutical compositions containing them|

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TW109118026A| TW202108590A|2015-06-23|2016-06-22|New hydroxyacid derivatives, a process for their preparation and pharmaceutical compositions containing them|

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ARP160101882A| AR105104A1|2015-06-23|2016-06-23|HYDROXYACID DERIVATIVES, A PROCESS FOR THE PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|

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SV2017005590A| SV2017005590A|2015-06-23|2017-12-14|NEW HYDROXIACIDE DERIVATIVES A PROCESS FOR THE PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|

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PH12017502314A| PH12017502314B1|2015-06-23|2017-12-14|New hydroxyacid derivatives, a process for their preparation and pharmaceutical compositions containing them|

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CONC2017/0012845A| CO2017012845A2|2015-06-23|2017-12-14|New hydroxy acid derivatives, a process for their preparation and pharmaceutical compositions containing them|

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IL256320A| IL256320D0|2015-06-23|2017-12-14|New hydroxyacid derivatives, a process for their preparation and pharmaceutical compositions containing them|

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ECIEPI201782825A| ECSP17082825A|2015-06-23|2017-12-15|NEW HYDROXIACID DERIVATIVES, A PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|

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DO2017000304A| DOP2017000304A|2015-06-23|2017-12-20|NEW HYDROXY ACID DERIVATIVES, A PROCESS FOR THE PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|

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CL2017003316A| CL2017003316A1|2015-06-23|2017-12-21|New hydroxy acid derivatives, a process for their preparation and pharmaceutical compositions containing them.|

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HK18109701.1A| HK1250233A1|2015-06-23|2018-07-26|New hydroxyacid derivatives, a process for their preparation and pharmaceutical compositions containing them|

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HK18113626.5A| HK1254477A1|2015-06-23|2018-10-24|New hydroxyacid derivatives, a process for their preparation and pharmaceutical compositions containing them|