专利摘要:
Compounds of formula (I): wherein R1, R2, R5, R6, R7, R12, X, Y, A, E and n are as defined in the description. Drugs.
公开号:FR3037956A1
申请号:FR1555747
申请日:2015-06-23
公开日:2016-12-30
发明作者:Zoltan Szlavik；Zoltan Szabo；Marton Csekei；Attila Paczal；Andras Kotschy；Alain Bruno；Olivier Geneste；I-Jen Chen；James Edward Paul Davidson；James Brooke Murray；Levente Ondi；Gabor Radics；Szabolcs Sipos；Agnes Proszenyak；Sierra Francoise Perron；Balazs Balint
申请人:Laboratoires Servier SAS；Vernalis R&D Ltd；
IPC主号:

专利说明:

[0001] The present invention relates to novel amino 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 (Cosy 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 Bel-2 family are associated with numerous pathologies. The involvement of Bel-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, Mc1-1, 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. The present invention relates more particularly to compounds of formula (I): in which: A represents the group in which 1 is attached to the group -NI-I- and 2 is linked to the aromatic ring, 15-E represents a cycloalkyl group; , a heterocycloalkyl group, an aryl group or a heteroaryl group, - X represents a nitrogen atom or a group C-R4, - Y represents a nitrogen atom or a group C-R3, - R1 represents an atom halogen, 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 group hydroxy, 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, (C 1-6 alkyl) -NR 9 R 9 ', -O- (C 1 -C 6) alkyl C6) -NR9R9 ', -O- (C1-C6) alkyl-R10, -C (O) -OR9, -OC (O) -R9, -C (O) -NR9R9', -NR9-C (0) ) -R-9 ', -NR9-C (O) -OR9', - (C1-C6) alkyl-NR9-C (O) -R9 ', -SO2-NR9R9', -SO2- (C1-C6) alkyl at C6), - R2, R3, R4 and R5 independently of one another represent a hydrogen atom, a halogen atom, a linear or branched C1-C6 alkyl group or a linear C2-C6 alkenyl group; or branched, a linear or branched C 2 -C 6 alkynyl group, a linear or branched C 1 -C 6 polyhaloalkyl, a hydroxy group, a hydroxy (C 1 -C 6) alkyl group, a linear or branched C 1 -C 6 alkoxy group a -S- (C1-C6) alkyl group, a cyano group, a nitro group, - (C1-C6) alkyl -NR9R9 ', -O- (C1-C6) alkyl -NR9R9', -O - (C1-C6) alkyl-R10, -C (O) -OR9, -OC (O) -R9, -C (O) -NR9R9 ', -NR9-C (O) -R9', -NR9- C (O) -OR9 ', - (C1-C6) alkyl-NR9-C (O) -R9', -SO2-NR9R9 'or -SO2- (C1-C6) alkyl, or the substituents of the pair (R1, R2) together with the carbon atoms carrying them have 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 with 1 to 2 groups selected from halogen, linear or branched C1 to C6 alkyl, - (C1 to C6) alkyl-NR9R9 ', NRI1R11', - (C1 to C6) alkyl. C6) -Cyl or an oxo, 4. R6 represents a hydrogen atom, a halogen atom, a linear or branched C1-C6 alkyl group, a linear or branched C2-C6 alkenyl group, an alkynyl group linear or branched C2 to C6, a linear or branched C1 to C6 polyhaloalkyl group, a hydroxyl group, a linear or branched C1 to C6 alkoxy group, a -S- (C1 to C6) alkyl group, a group cyano, a nitro group, - (C 1 -C 6 alkyl) -NR 9 R 9 ', - (C 1 -C 6) alkyl-Cyl, u n - (C2-C6) alkenyl-C111- (C2-C6) alkynyl-Cyl, -O- (C1-C6) alkyl-R10, -C (O) -OR9, -OC (O) -R9 , -C (O) -NR9R9 ', -NR9-C (O) -R9', -NR9-C (O) -OR9 ', -30- (C1-C6) alkyl -NR9-C (O) -R9 , -SO2-NR9R9 'or -SO2- (C1-C6) alkyl, R7 represents a hydrogen atom, a linear or branched C1-C8 alkyl group, a group -CHRaRb, a grouping aryl, a heteroaryl group, an aryl-C 1-6 alkyl group or a heteroaryl (C 1-6 alkyl) group; R g represents a linear or branched C 1-6 alkyl group; a C 2-6 alkenyl group; Linear or branched C6, a linear or branched C2-C6 allcynyl group, -Cy2, a halogen atom, a cyan group, -C (O) -R11 OR -C (O) -NR1 1R11 ', -R9 and R9 'independently of one another is hydrogen, a linear or branched C1-C6 alkyl group, or the substituents of the pair (R9, R9') together with the az 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, it being understood that the nitrogen in question may be substituted with a group representing a hydrogen atom or a linear or branched C1-C6 alkyl group; - R10 represents -Cy3, -Cy3- (C1-C6) alkyl -Cy4, -C (O) -NR9R9 ', -NR9R9', -OR9, -NR9-C (O) -R9 ', -O- (C1-C6) alkyl-OR9, -SO2-R9, -C (O) -OR9 or -NH-C (O) -NH-R9, -R11 and R11 'independently of one another are hydrogen or optionally substituted linear or branched C1-C6 alkyl, - R12 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-R 'a group -O-C (O) -NR, Ra' or a group -O-P (O) (ORa) 2, - Ra and represent, independently of one another, a hydrogen atom, a linear or branched Ci-Cg alkyl group, a cycloalkyl 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 nitrogen atom carrying 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 It is understood that the nitrogen in question may be substituted by a group representing a linear or branched C1-C6 alkyl group. Cy1, Cy2, Cy3 and Cy4 represent, independently of each other, a cycloalkyl group, a heterocycloalkyl group, a group aryl or a heteroaryl group, n is an integer equal to 0, 1 or 2, with the proviso that: by "aryl", The term "phenyl, naphthyl, biphenyl" or "heteroaryl" is understood to mean any mono- or bi-cyclic group consisting of 5 to 10 members, having at least one aromatic group and containing from 1 to 3 heteroatoms selected from the group consisting of 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 bi-cyclic, 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 for the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups thus defined and the alkyl, alkenyl, alkynyl, alkoxy groups to be substituted with 1 to 4 groups selected from linear or branched C1 to C6 alkyls; optionally substituted, optionally substituted linear or branched C2 to C6 alkenyl, optionally substituted linear or branched C2 to C6 alkynyl, optionally substituted linear or branched C1 to C6 alkoxy, optionally substituted (C1 to C6) alkyl-S- hydroxy, hydroxy (C1-C6) alkyl, oxo (or N-oxide if appropriate), nitro, cyano, -C (O) -OR ', -O-C (O) -R', -C (O) ) -NR'R '-OC (O) -NR'R ", -NR'R", -O-P (O) (OR') 2, -O-P (O) (O-M4) 2, linear or branched C1-C6 polyhaloalkyl, trifluoromethoxy, halogen or an aldohexose of formula OR 'OR' or RIO where each R 'is independent; it being understood that R 'and R "represent, independently of one another, a hydrogen atom or an optionally substituted linear or branched C 1 -C 6 alkyl group, and M + represents a pharmaceutically acceptable monovalent cation, their enantiomers, diastereoisomers and atropisomers, and their addition salts with a pharmaceutically acceptable acid or base Advantageously, the present invention relates to compounds of formula (I), wherein: R 1 and R 2 independently represent one of other a halogen atom, a linear or branched C1-C6 alkyl group, a hydroxy group, a hydroxy (C1-C6) alkyl group, a linear or branched C1-C6 alkoxy group or the substituents of the pair (R 1, R 2) form together with the carbon atoms carrying them an aromatic 5- to 7-membered ring, which may contain from 1 to 3 nitrogen atoms, it being understood that the resulting cycle can It can be substituted with 1 to 2 groups selected from halogen, C1-C6 linear or branched alkyl or (C1-C6) alkyl-NR9R9 ', R3 represents a hydrogen atom, a halogen atom, a moiety linear or branched C1-C6 alkyl, hydroxy group, linear or branched C1-C6 alkoxy group or -O- (C1-C6) alkyl -NR9R9 ', - R4 and R5 independently represent one of other a hydrogen atom, a halogen atom, a linear or branched C1-C6 alkyl group, a hydroxy group, a linear or branched C1-C6 alkoxy group, R6 represents a hydrogen atom, a halogen atom, a linear or branched C1-C6 alkyl group, a linear or branched C1-C6 polyhaloalkyl group, a hydroxyl group, a linear or branched C1-C6 alkoxy group, a cyano group, a nitro group, - (C 1 -C 6) alkyl-NR 9 R 9 ', -C (C 6 -C 6) alkyl-Cyl, -O- (C 1 -C 6) alkyl C6) -R10 or -C (O) -NR9R9 ', - R7 represents a hydrogen atom, a linear or branched C1-C8 alkyl group, a -CHRaRb group or a heteroaryl (C1-C8) alkyl group; C6), - R8 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, -Cy2, a halogen atom or - C (O) -Ri i, -R9 and R9 'independently of one another represent a hydrogen atom, a linear or branched C1-C6 alkyl group, or the substituents of the pair (R9, R9' ) together with the nitrogen atom carrying 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 it being understood that the nitrogen in question may be substituted by a group representing a linear or branched C1-C6 alkyl group, - R10 represents -Cy3 or -Cy3- (C1-C6) alkyl -Cy4; -R11 represents a linear or branched C1-C6 alkyl group, with the possibility for the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups thus defined and the alkyl groups , alkenyl, alkynyl, alkoxy, to be substituted with 1 to 4 groups selected from optionally substituted linear or branched C1 to C6 alkyl, optionally substituted linear or branched C1 to C6 alkoxy, hydroxy, hydroxyalkyl C1 to C6), an oxo (or N-oxide if appropriate), -C (O) -OR ', -C (O) -NR'R' -OC (O) -NR'R ", - NR'R ", -O-P (O) (OR ') 2, -O-P (O) (O-M +) 2, a linear or branched C1-C6 polyhaloalkyl, a halogen or an aldohexose of formula: OR 'R`O o 4 R'0 - OR where each R' is independent; with the proviso that R 'and R "are independently of each other hydrogen or an optionally substituted linear or branched C1 to C6 alkyl group, and M + is a pharmaceutically acceptable monovalent cation. the pharmaceutically acceptable acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, 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, tert-butylamine, etc. More particularly, the compounds of formula (I) which are Preferred are the compounds wherein n is an integer of 1. In another embodiment of the invention, an advantageous possibility is the compounds of formula (1-a) in which A, E, R1, R2, R5, R6, R7, R12, X, Y and n are as defined for formula (I). 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 (55a) when X is a group C-R4 and Y is a group C-R3. Advantageously, at least one of the groups chosen from R2, R3, R4 and R5 does not represent a hydrogen atom. Preferably, R12 represents a hydrogen atom, a hydroxymethyl group or a hydroxyethyl group. More preferably, R12 represents a hydrogen atom. In the preferred compounds of the invention, R 1 represents a linear or branched C1-C6 alkyl group or a halogen atom. More preferably, R 1 represents a methyl group, an ethyl group, a bromine atom or a chlorine atom. Even more preferably, R 1 represents a methyl group. Advantageously, R2 represents a halogen atom, a hydroxyl group or a linear or branched C1-C6 alkoxy group. More preferably, R2 is methoxy, hydroxy, fluoro, bromo or chloro. Even more preferably, R2 represents a chlorine atom. In certain preferred embodiments of the invention, when the substituents of the (R1, R2) pair together with the aromatic ring carbon atoms, R5 is R15. Wherein R 13 represents a hydrogen atom, a linear or branched C 1 -C 6 alkyl group or - (C 1 -C 6 alkyl) -NR 9 R 9 'in which wherein R9 and R9 'are as defined for formula (I), and R14 represents a hydrogen atom, a halogen atom or a linear or branched C1-C6 alkyl group. Preferably, R13 represents a hydrogen atom, a methyl group or - (CH2) m -NR9R9 'wherein m is an integer of 2 or 3, and R9 and R1' represent a methyl group or substituents of the pair (R9, R9 ') together with the nitrogen atom carrying them a pyrrolidinyl, a piperidinyl, a morpholinyl or a 4-methyl-piperazin-1-yl. Advantageously, R14 represents a hydrogen atom, a bromine atom, an iodine atom, a chlorine atom or a methyl group. Preferably, R14 is substituted at position F3 with respect to the nitrogen atom. Preferably, X represents a group C-R4. In a preferred embodiment of the invention, Y represents a group C-R3. Advantageously, R3 represents a hydrogen atom, a linear or branched C1-C6 alkoxy group or -O- (C1-C6) alkyl -NR9R9 '. Preferably, R4 represents a hydrogen atom.
[0004] In certain preferred embodiments of the invention, R 9 0 represents where R 1, R 2, R 9 and R 9 'are as defined for formula (I). In the preferred compounds of the invention, where R9 and R9 'are as defined for formula (I). Preferably, R5 represents a hydrogen atom. In an advantageous embodiment, the substituents of the (R 1, R 5) pair are identical and the substituents of the (R 2, R 4) pair are identical. In the preferred compounds of the invention, the substituents of the (R 1, R 5) pair are identical and represent a C 1 to C 6 alkyl group, while the substituents of the (R 2, R 4) pair are identical and represent a hydrogen atom. halogen or a hydrogen atom.
[0005] In another embodiment of the invention, E represents a phenyl group, a pyridin-2-yl group, a cyclohexyl group, a pyrazol-1-yl group, a cyclopentyl group, an indol-4-yl group, a cyclopropyl group, a pyridin-3-yl group, an indol-3-yl group, a naphth-1-yl group, an imidazol-4-yl group or a pyridin-4-yl group. Advantageously, E represents a phenyl group. In the preferred compounds of the invention, R6 represents a hydrogen atom; a fluorine atom; a chlorine atom; a bromine atom; a methyl group; a trifluoromethyl group; a hydroxy group; a methoxy group; a linear C1-C6 alkoxy group substituted with halogen atoms, a group -C (O) -NR'R "or a group -NR'R"; a cyan; a nitro group; an aminomethyl group; a benzyl group; -O- (C1-C6) alkyl -Rio -C (O) -NR9R9 '. Preferably, R6 represents a methoxy group, a 2,2,2-trifluoroethoxy group or -O- (C1-C6) alkyl-R10. In another embodiment of the invention, an advantageous possibility consists in the compounds of formula (Ib): ## STR2 ## in which R 1, R 2, R 5, R 6, R 7, R 12, X, Y, A and n are as defined for formula (I). In another embodiment of the invention, an advantageous possibility consists in the compounds of formula (Ic): wherein R6, R7, R9, R9 ', R12 and A are as defined for formula (I) . Preferably, R7 represents a hydrogen atom, a -CI1RaRb group, an optionally substituted linear or branched C1 to C8 alkyl group or a heteroaryl (C1 to C6) alkyl group. Preferably, R7 represents a -CHRaRb group, where 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, R, ', where Re, and 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 atom nitrogen bearing them a non-aromatic 5- to 7-membered ring which may contain in addition to the nitrogen atom from 1 to 3 heteroatoms selected from oxygen and nitrogen; or a group -O-P (O) (OH) 2. Preferred R7 groups are: hydrogen; methyl; an ethyl; (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl. Even more preferably, R7 is hydrogen. In the preferred compounds of the invention, R8 represents a linear or branched C2-C6 alkynyl group, an aryl group or a heteroaryl group. More preferably, Rg is a prop-1-yrt-1-yl group, a phenyl group, or a furan-2-yl group. In a more preferred embodiment, R8 represents a prop-1-yn-1-yl group, a 4-fluorophenyl group or a 5-fluorofuran-2-yl group. Even more preferably, R8 represents a 4-fluorophenyl group. In the preferred compounds of the invention, R9 and R9 'are independently of each other a linear or branched C1-C6 alkyl group, or the substituents of the pair (119). , R9 ') together with the nitrogen atom carrying them a 5- to 7-membered non-aromatic ring which may contain in addition to the nitrogen atom from 1 to 5 heteroatoms selected from oxygen and nitrogen, it being understood that the nitrogen in question may be substituted by a linear or branched C 1 -C 6 alkyl group. More preferably, R 9 and R 9 'represent a methyl group, or the substituents of the (R 9, R 9') pair together form a 4-methyl-piperazinyl group. Advantageously, R10 represents -Cy3 or a toCy3- (C1-C6) alkyl-C4. Preferably, R19 is -Cy3 or -Cy3-Cy4. Preferably, Cy3 represents a cycloalkyl group, in particular a cyclopentyl group. In a preferred embodiment, Cy3 represents an aryl group, in particular a phenyl group. Advantageously, Cy3 represents a heteroaryl group, in particular a pyrimidinyl group, a pyrazolyl group or a pyridinyl group. More preferably, Cy3 represents a pyrimidin-4-yl group, a pyrazol-5-yl group or a pyridin-2-yl group. In the preferred compounds of the invention Cy3 represents a pyrimidin-4-yl group. In another embodiment of the invention, Cy3 represents a heteroaryl group which is substituted by an optionally substituted linear or branched C1 to C6 alkyl group, an optionally substituted linear or branched C1 to C6 alkoxy group or a poly group. -C1-C6 haloalkyl linear or branched. Preferably, Cy3 represents a heteroaryl group which is substituted by a 2,2,2-trifluoroethoxy group, a 2-methoxyethyl group, an ethoxy group; an tert-butyl group, an ethyl group, an n-butyl group, a 2,2,2-trifluoroethyl group or a methyl group. Preferably, Cy4 represents a phenyl group, a pyridinyl group, a pyridazinyl group, a pyrazinyl group, a pyrimidinyl group or a morpholinyl group. More preferably, Cy4 represents a phenyl group.
[0006] Other preferred compounds of the invention are those in which R 1 is R 15 where p is an integer of 0 or 1 and R 15 is hydrogen, hydroxy, an optionally substituted linear or branched C1-C6 alkyl group, a linear or branched C1-C6 alkoxy group, a -O- (CHR16-CHR17-0) q-R 'group, a -OP (O) group ( OR ') 2, a group -O-P (O) (O-MF) 2, a group -OC (O) -NR18R19, a di (C 1 -C 6) alkyl group amino (C 1 -C 6 alkoxy), a halogen atom or an aldohexose of formula: OR 'OR.' Where each R 'is independent, it being understood that: R' represents a hydrogen atom or a linear or branched C1-C6 alkyl group; R16 represents a hydrogen atom or a (C1-C6) alkoxy (C1-C6) alkyl group; R17 represents a hydrogen atom or a hydroxy (C1-C6) alkyl group; hydrogen atom or a (C 1 -C 6) alkoxy (C 1 -C 6) alkyl group, R 19 represents a (C 1 -C 6) alkoxy (C 1 -C 6) alkyl group, a - (C 1 -C 2) group, -NR9R9 'or a group - (C1-12), - O- (CHRI6-CHR17-0) q-R', - q is an integer equal to 1, 2 or 3 and r is an integer equal to 0 or 1, 25 - M + represents a pharmaceutically acceptable monovalent cation. The aldohexose according to the invention is preferably D-mannose. Advantageously, R 15 represents a methoxy group, a 2-methoxyethoxy group or a fluorine. Preferably, the group - (CH 2) p -R 1 s is located in the ortho position on the phenyl group.
[0007] Among the preferred compounds of the invention, there may be mentioned: N- [5- {3-chloro-2-methyl-442- (4-methyl-piperazin-1-yl) ethoxylphenyl} -6- (4-fluorophenylthieno) [2,3-d] pyrimidin-4-yl] -2 - [(1-methyl-1H-pyrazol-5-yl) methoxy] -D-phenylalanine, - N- [5- {3-chloro-2 Methyl-4- (2- (4-methyl-piperazin-1-yl) ethoxylphenyl-6- (4-fluorophenylthieno [2,3-d] pyrimidin-4-yl] -2 - [(2-ethoxypyrimidin-4-yl ) -methoxy] -D-phenylalanine, - N- [5- {3-chloro-2-methyl-4- [2- (4-methyl-piperazin-1-yl) ethoxy] phenyl} -6- fluorophenylthieno [2,3-cflpyrimidin-4-yl] -2 - {[2- (2-methoxyphenyl) -pyrimidin-4-yl] methoxy) -D-phenylalanine, N- [5- {3-chloro} 2-methyl-4- [2- (4-methyl-piperazin-1-ylethoxy) phenyl-6- (furan-2-yl) thieno [2,3-d] pyrimidin-4-yl] -2-methoxy-D- phenylalanine, N- [5- {3-chloro-2-methyl-442- (4-methyl-piperazin-1-yl-ethoxylphenyl) -645-fluorofuran-2-yl) -thieno [2,3-d] pyrimidine 4-yl] -2-methoxy-D-phenylalanine, N- [5- {3-chloro-2-meth Y1-442- (4-methyl-piperazin-1-ylethoxylphenyl) -6- (5-fluorofuran-2-yl) -thieno [2,3-cilpyrimidin-4-yl] -2- (2.2.2 trifluoroethoxy) -D-phenylalanine, N- [5- {3-chloro-2-methyl-442- (4-methyl-piperazin-1-yl) ethoxylphenyl} -6- (5-fluorofuran-2-yl) - thieno [2,3-d] pyrimidin-4-yl) -2- (pyridin-2-ylmethoxy) -D-phenylalanine, - N- [5- {3-chloro-2-methyl-4- [2- 4-methyl-piperazin-1-yl) ethoxy] phenyl} -645-fluorofuran-2-yl) -thieno -2 - [(1-methyl-1H-pyrazol-5-yl) methoxy] -D-phenylalanine, N- [5- {3-chloro-2-methyl-442- (4-methyl-piperazin-1-yl) -ethoxy} phenyl} -645-fluoro-furan-2-yl) -thieno [2,3-diol] d] pyrimidin-4-yl] - [(1-ethyl-1H-pyrazol-5-yl) methoxy] -D-phenylalanine, - N- [5- {3-chloro-2-methyl-442- 4-methylpiperazin-1-ylethoxylphenyl) -645-fluorofuran-2-yl) thieno [2,3-d] pyrimidin-4-yl] -2 - [(2-ethoxypyrimidin-4-ylmethoxy] -D- phenylalanine, 2 - [(1-butyl-1H-pyrazol-5-yl) methoxy] -N45- {3-chloro-2-methyl-4- [244-methylpiperidine] razin-1-yl) ethoxy] -phenyl} -6- (5-fluorofuran-2-yl) thieno [2,3-d] pyrimidin-4-yl-D-phenylalanine, - N- [5- {3 1-chloro-2-methyl-442- (4-methyl-piperazin-1-yl) ethoxylphenyl) -6- (5-fluorofuran-2-yl) -thieno [2,3-d] pyrimidin-4-yl] -2- {[2- (2,2,2-trifluoro-ethoxy) pytimidin-4-yl] methoxy} -D-phenylalanine, - N45- {3-chloro-2-methyl-442- (4-methyl -Piperazin-1-yloxyphenyl} -645-fluorofuran-2-yl) -thieno [2,3-d] pyrimidin-4-yl] -2- {[2- (2-methoxyphenyl) -pyrimidin-4-yl] methoxy) -D-phenylalanine, N- [5-13-chloro-2-methyl-442- (4-methyl-piperazin-1-yl) ethoxy] phenyl-6- (prop-1-yl) -yl) thieno [2,3-d] pyriinidin-4-yl] -2-methoxy-D-phenylalanine, 2 - [(1-tert-butyl-1H-pyrazol-5-yl) methoxy] -N [5- {3-chloro-2-methyl-442- (4-methylpiperazin-1-yl) -ethoxylphenyl} -6- (prop-1 -yn-1-hypthieno [2,3-d] pyrimidine) 4-yll-D-phenylalanine, N- [5- {3-chloro-2-methyl-442- (4-methyl-piperazin-1-yl-ethoxylphenyl) -6- (prop-1-yl) -ypthiéno [2,3 pyrimidin-4-yl] -2- [2- (2-methoxyethyl) pyrimidin-4-yl] methoxy] -D-phenylalanine; N- [5- {3-chloro-2-methyl-4- [1- (2-methoxyethyl) pyrimidin-4-yl]; 2- (4-methyl-piperazin-1-yloxy-phenyl) -6- (prop-1-yn-1-yl) thieno [2,3-d] pyrimidin-4-yl] -2- [1 - (2,2,2-trifluoroethyl) -1H-pyrazol-5-yl] methoxy} -D-phenylalanine, N- [5- {3-chloro-2-methyl-442- (4-methylpiperazine) 1-ypethoxy] phenyl-6- (prop-1-yn-1-yl) thieno [2,3-d] pyrimidin-4-yl] -2- {[2- (morpholin-4-) 71) pyrimidine 4-yl] methoxy} -D-phenylalanine, N- [5- {3-chloro-2-methyl-442- (4-methyl-piperaz-1-yl) -propylphenyl} -propylphenylalanine; N-1-ypthieno [2,3-d] pyrimidin-4-yl] -2 - {[2- (2,2,2-trifluoroethoxy) -pyrimidin-4-yl] methoxy} -D-phenylalanine, - N- [5- {3-chloro-2-methyl-4- [2- (4-methyl-piperazin-1-yloxy) phenyl} -6- (prop-1-yn-1-yl) thieno [2, 3-Cipyrimidin-4-yl] -2- [2- (2-methoxyphenyl) -pyrimidin-4-yl] methoxy} -D-phenylalanine, N- [5- {3-chloro-442- (dimethylamino)} ethoxy1-2-methylphenyl} -6 - (prop-1-yn-1-yl) thieno [2,3-d] pyrimidin-4-yl] -2 - {[1- (2,2,2-trifluoroethyl) -1H-pyrazol-5-yl} ] -methoxyl-D-phenylalanine, N- [5 - {3-chloro-442- (dimethylamino) ethoxy] -2-methylphenyl} -6- (prop-1-yn-1-ylthio) 2,3-4-pyrimidin-4-yl-2 - {[2- (morpholin-4-yl) pyrimidin-4-yl] methoxyl-D-phenylalanine, - N45- {3-chloro-442- (dimethylamino) ethoxy} 2-methylphenyl} -6- (prop-1-yn-1-yl) thieno [2,3-4-pyrimidin-4-yl] -2 - {[2- (2,2,2-trifluoroethoxy) pyrimidin} 4-yl] methoxy} -D-phenylalanine, N45- {3-chloro-442- (dimethylamino) ethoxy] -2-methylphenyl} -6- (prop-1-yn-1-yl) thio [2], 3-d] pyrimidin-4-yl] -2 - {[2- (2-methoxyphenyl) pyrimidin-4-yl] methoxy} -D-phenylalanine, N- [5- {3-chloro-442} (dimethylamino) ethoxy] -2-methylphenyl} -6- (4-fluorophenyl) thieno [2,3-cipyrimidin-4-yl] -2 - ({242- (2-methoxyethoxy) phenyl] pyrimidin-4-ylmethoxy) -D-phenylalanine; N-R5S ') -5- {3-chloro-2-methyl-442- (4-methyl-piperazin-1-yl) ethoxylphenyl} -6- (4-fluorophenylthieno [2,3-d] pyrimidin); Ethyl 4-yl] -2- {[2- (2-methoxyphenyl) -pyrimidin-4-yl] methoxy} -D-phenylalaninate; N-R5Sci) -5- {3-chloro-2- Methyl-4- (2- (4-methyl-piperazin-1-yl) ethoxylphenyl) -6- (prop-1-yn-1-yl) thieno [2,3-pyrimidin-4-yl] -2- {[2- Ethyl 2-methoxyphenyl) -pyrimidin-4-yl] methoxy} -D-phenylalaninate; N - [(58 H) -5- {3-chloro-4- [2- (dimethylamino) -ethoxy] -2-methylphenyl-6- (prop-1-yn-1-hyphenoyl) Ethyl 2,3-d] pyrimidin-4-yl -2- {[2- (2-methoxyphenyl) pyrimidin-4-yl] methoxy} -D-phenylalaninate The invention also relates to a process for the preparation of compounds of the formula (I), said process being characterized in that it uses, as starting compound, the compound of formula (II-a): ClA wherein Z is bromine or iodine and A is as defined for the formula (I) wherein 1 is bonded to the chlorine atom and 2 is bonded to the Z moiety, said compound of formula (II-a) being coupled with a compound of formula (III): ## STR2 ## R12 wherein R6, R12, E and n are as defined for formula (I), and Alk 5 represents a linear or branched C1-C6 alkyl group, to obtain the compound of formula (IV): R12 in which R6, R12, A, E and n are as defined for formula (I), e Z and Alk are as defined above, the compound of formula (IV) being further subjected to coupling with a compound of formula (V): XY R2 R5 R1, e- (V), B, RB20 ORB 3037956 In which R1, R2, R5, X and Y 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, to obtain the compound of formula (VI): Alk in which R1, R2, R5, R6, R12, X, Y, A, E and n are as defined for the formula (I) and Alk is as defined above, the function is: Alk-OC (O) - of the compound of formula (VI) being hydrolysed to give the carboxylic acid, which can optionally be reacted with an alcohol of formula R7-OH or a chlorinated compound of formula R7-Cl, where R7 is as defined for formula (I), to obtain the compound of formula (I), which can be puri It is prepared 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 by a conventional separation technique, it being understood that 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. synthesis. In another embodiment of the invention, compounds of formula (I) may be obtained by an alternative process, said process being characterized in that it uses, as the starting compound, the compound of formula (II) b): A (II-b) C1 wherein A is as defined in formula (I) wherein 1 is bonded to the chlorine atom and 2 is attached to the iodine atom said compound of formula (II-b) being coupled with a compound of formula (V): wherein R1, R2, R5, X and Y are as defined for formula (I), and RBI and RB2 represent a hydrogen atom, a linear or branched C1-C6 alkyl group, or RB1 and RB2 form with oxygen carrying an optionally methylated ring, To obtain the compound of formula (VII): wherein R1, R2, R5, A, X and Y are as defined in formula (1), said compound of formula (VII) being subjected to or to be coupled to a compound of formula (III): embedded image in which R 6, R 12, E and n are as defined for formula (I), and Alk represents an alkyl group C1 to C6 linear or branched, to obtain the compound of formula (VI): (VI) wherein R1, R2, R5, R6, R12, X, Y, A, E and n are as defined for the 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 R7 -OH or a chlorinated compound of formula R7-Cl, where R7 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 desired, into its addition salts with a pharmaceutically acceptable acid or base and which is optionally separated into its isomers according to a However, it is understood that at any time considered appropriate during the process described above, certain groups (hydroxy, amino, etc.) of the starting reagents or synthetic intermediates are used. can be protected, then deprotected and functionalized for the purposes of synthesis.
[0008] The compounds of formulas (II-a), (II-b), (III), (V), R7-OH and R7-Cl are either commercially available or are accessible to those skilled in the art by reactions. classical chemicals and described in the literature. 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 cancer treatments contemplated include, but are not limited to, the treatment of cancers of the bladder, brain, breast and uterus, chronic lymphoid leukemias, colon cancer, esophagus and liver, lymphoblastic leukemia, acute myeloid leukemia, lymphoma, melanoma, hematological malignancies, myeloma, ovarian cancer, non-small cell lung cancer, prostate cancer, cancer of the liver, pancreas 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 tablets or sugar-coated sachets, sachets, packets, capsules, glossettes, tablets, suppositories, creams, ointments, skin gels and oral or injectable ampoules.
[0009] 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. and 1 g per 24 hours in one or more administrations. In addition, the present invention also relates to the combination of a compound of formula (I) with an anti-cancer agent selected from genotoxic agents, mitotic poisons, anti-metabolites, 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. 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.
[0010] 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. 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.
[0011] 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 compound. association. The combination of a compound of formula (I) with an anticancer agent may be administered simultaneously or sequentially. The route of administration is preferably oral, and the corresponding pharmaceutical compositions may allow instantaneous 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.
[0012] The compounds 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 framework proteins that may or may not be related to monoclonal antibodies.
[0013] By antibody fragments are meant fragments of the type Fv, scFv, Fab, F (ab ') 2, F (ab'), scFv-Fc, or diabodies, which in general have the same binding specificity. than 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 using automatic peptide synthesizers for example, such as those provided by Applied Biosystems etc.
[0014] Structural proteins, which may or may not be related to monoclonal antibodies, are understood to mean 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 (Skerra A., J. Mol.Recogn., 2000, 13, 167-187): good phylogenetic conservation, robust architecture with a well-defined 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 may be, but not limited to, a structure selected from the group consisting of fibronectin and, preferably, the tenth type III domain of fibronectin (FNfn10), lipocalin, anticalin (Skeea, 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 a "repetition". ankyrin "(Kohl et al., PNAS, 2003, 100 (4), 17001705), 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 neuronal nitric oxide synthase (PIN) inhibitory proteins. The following preparations and examples illustrate the invention and in no way limit it.
[0015] 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. Flash chromatography was performed on an ISCO CombiFlash Rf 200i with pre-filled cartridges of silica gel (RediSep®Rf 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 MonoWave or CEM Discover® instrument.
[0016] Purifications by preparative HPLC were performed on an Armen Spot liquid chromatography system with a Gemini-NX® 10 el C18 column, 250 mm × 50 mm, at a flow rate of 118 ml min -1 with UV detection by diode array. (210 nm to 400 mu) using an aqueous solution of 25 mM NH4HCO3 and MeCN as eluents unless otherwise indicated.
[0017] 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 mode 3037956 -27 - or ionization negative by ionic electrospray. The scanning of the molecular weights ranges from 100 to 1350. A parallel UV detection was carried out at 210 nm and 254 nm. Samples were injected as a 1mM solution in ACN or THF / H20 (1/1) in a 5μl loop. LC-MS analyzes were performed on two instruments, one operating with basic eluents and the other with acidic eluents. Basic LC-MS: Gemini-NX column, 3 μm, C18, 50 mm x 3.00 min d.i. at 23 ° C, at a flow rate of 1 mi min-1 using 5 mM ammonium bicarbonate (solvent A) and acetonitrile (solvent B) with a gradient starting with 100% solvent A and ending with 100% solvent B for a certain variable duration. LC-MS acid: ZORBAX column Eclipse XDB-C18, 1.8 μm, 50 mm x 4.6 mm d.i. at 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. The 1H 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 (quadruplet), quint (quintuplet), m (multiplet), s large (singlet wide), dd (doublet of doublets) , td (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 Agitate 6850 gas chromatograph and an Agitent 5975C mass spectrometer using a 15 m × 0.25 mm column with a 0.25 pin coating. HP-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 a Shimadzu IT-TOF, ionic source temperature of 200 ° C, ESI +/-, ionization voltage: (+ -) 4.5 kV. Min. Mass resolution The elemental analyzes were carried out on a Thermo Flash EA 1112 elementary analyzer. List of abbreviations Abbreviation Name 2-Me-THF 2-methyl-tetrahydrofuran Ac acetyl Ad adamantyl AtaPhos bis (di-but-butyl) 4-dimethylaminophenyl) phosphine) dichloropalladium (II) BuPAd2 butyl-di (adamant-1-yl) phosphane cc. DAST concentrate trifluoride of diethylaminosulfur dba dibenzylideneacetone DCM methylene chloride DIPA diisopropylamine DMA dimethylacetamide DME 1,2-dimethoxyethane DMF dimethylformamide DMSO dimethylsulfoxide dppf 1,1 '-bis (diphenylphosphino) ferrocene eq. equivalent And ethyl HILIC hydrophilic interaction liquid chromatography HMDS hexamethyldisilazane Isopropyl iPr LDA lithium diisopropylamide Meth methyl MeCN acetonitrile MTBE methyl tert-butyl ether MW microwave NBS N-bromosuccinimide 3037956 - 29 - nBu n-butyl NCS N-chlorosuccinimide Ph phenyl P113u3 x HBF4 tri-tert-butyl phosphonium tetrafluoroborate PCy3 x HBF4 tricyclohexyl phosphonium tetrafluoroborate Q-Phos 1,2,3,4,5-pentaphenyl-1 '- (di-tert-butyl-phosphino) fenocene RT room temperature TBAF fluoride tetrabutylammonium tBu tent-butyl TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TIPSC1 triisopropylsilyl chloride XantPhos 4,5-bis (diphenylphosphino) -9,9-dimethyl-xanthene General procedure 1 eq. of appropriate 4-chloro-thieno [2,3-d] pyrimidine derivative, 2 eq. of suitable amino acid derivative and 2 eq. K2CO3 were mixed in the 13uOH / 4: 1 water mixture (4 mL / mmol) and stirred at reflux temperature (or in a MW reactor at 100 ° C if necessary) until no further conversion. The mixture was then diluted with water, acidified with 1M HCl solution (to pH = 1, or up to pH = 6 in the presence of a basic amino group) and extracted with water. EtOAc, or the precipitate formed after acidification was isolated by filtration. In the case of purification by extraction, the combined organic phases were washed with brine, dried over MgSO 4, filtered and the filtrate concentrated under reduced pressure. The crude product was purified by reverse phase preparative chromatography using 25 mM aqueous NH4HCO3 and acetonitrile as eluents unless otherwise noted.
[0018] General Procedure Ib: 1 eq. of appropriate 4-chloro-thieno [2,3-d] pyrimidine derivative, 2 eq. of suitable amino acid derivative and 3 eq. of K2CO3 were mixed in DMSO (10 ml / mmol) and stirred at 50 ° C until no further conversion was observed. The mixture was then diluted with water, acidified with 1M HCl solution (to pH 1, or to pH 6 in the presence of a basic amino group) and extracted with water. EtOAc, or the precipitate formed after acidification was isolated by filtration. In the case of extraction purification, the combined organic phases were washed with brine, dried over MgSO 4, filtered and the filtrate concentrated under reduced pressure. The crude product was purified by reverse phase preparative chromatography using 25 mM aqueous NH4HCO3 and acetonitrile as eluents unless otherwise noted. General procedure on: 10 1 eq. of appropriate 4-chloro-thieno [2,3-d] pyrimidine derivative, 1.5 eq. of the appropriate amino acid derivative and 1.5 eq. of Cs2CO3 were mixed in DMSO (6 ml / mmol) and stirred at 70 ° C until no further conversion was observed. The mixture was then diluted with water, acidified with 1M HCl solution (up to pH = 1, or up to pH = 6 in the presence of a basic amino group) and extracted with water. EtOAc, or the precipitate formed after acidification was isolated by filtration. In the case of extraction purification, the combined organic phases were washed with brine, dried over MgSO 4, filtered and the filtrate concentrated under reduced pressure. The crude product was purified by reverse phase preparative chromatography using 25mM aqueous NH4HCO3 and acetonitrile as eluents unless otherwise indicated. General procedure Ha: 1 eq. derivative of 5- or 6-iodo-thieno [2,3-dlpyrimidine appropriate and 3 eq. of appropriate boronic acid derivative were dissolved in DME (15 ml / mmol), then 5 eq. K2CO3, 0.2 eq. of Pd2dba3, 0.4 eq. BuPAd2 and water (5 ml / mmol) were added and the mixture was stirred at 60 ° C. in a MW reactor until no further conversion was observed. The residue was purified by reverse phase preparative chromatography, using an aqueous solution of 25 mM NH 4 HCO 3 and acetonitrile as eluents, unless otherwise indicated General procedure IIb: 1 derivative eq. appropriate 5-iodo-thieno [2,3-d] pyrimidine and 5 equivalents of the appropriate boronic acid derivative were dissolved in 2-Me-THF (8 ml / mmol) followed by 5 eq of K 2 CO 3, 0.1 eq of Q-Phos and 0.05 eq of Pd2dba3 were added and the mixture was stirred at 80 ° C until no further conversion was observed. celite buffer, and the filtrate was concentrated under reduced pressure The crude product was purified by chromatography flash using heptane and EtOAc as eluents unless otherwise indicated. General Procedure IIe: 10 1 eq. of the appropriate 5- or 6-iodo-thieno [2,3-d] pyrimidine derivative and 1.1 eq. of. Suitable boronic acid derivative was dissolved in 2-Me-THF (8 ml / mmol), then 1.1 eq. Ag2CO3 and 0.1 eq. of Pd (PPh3) 4 were added and the mixture was stirred at 100 ° C until no further conversion was observed. The mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography using heptane and EtOAc as eluents unless otherwise indicated. General procedure IId: 1 eq. appropriate 5-iodo-thieno [2,3-4pyrimidine derivative and 3 eq. of the appropriate boronic acid derivative were dissolved in the dioxane / water mixture 2/1 (10 ml / mmol), then 2 eq. of Cs2CO3, 5 mol% Pd (OAc) 2 and 0.2 eq. of PtBu3 x HBF4 were added and the mixture was stirred at 120 ° C in a MW reactor until no further conversion was observed. The mixture was neutralized with 1M HCl solution and extracted with DCM. The combined organic phases were dried over Na2SO4, filtered and the filtrate concentrated in vacuo. The crude product was purified by reverse phase preparative chromatography using 0.1% aqueous TFA solution and acetonitrile as eluants unless otherwise noted. General procedure Hia: 30 1 eq. appropriate 6-iodo-thieno [2,3-d] pyrimidine derivative and 4 eq. of appropriate boronic acid derivative were dissolved in the dioxane / water mixture 4/1 (10 ml / nunol), then 2.2 eq. of Cs2CO3 and 0.1 eq. Pd (dppf) C12 was added and the mixture was stirred at 40 ° C until no further conversion was observed. The mixture was then diluted with water and extracted with DCM. The combined organic phases were washed with water, dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase preparative chromatography using 25mM aqueous NH4HCO3 and acetonitrile as eluents unless otherwise noted. General procedure 1Mb: 1 eq. suitable 6-iodo-thieno [2,3-d] pyrimidine derivative and 3 eq. of the appropriate boronic acid derivative were dissolved in THF / water 1/1 (10 ml / mmol), then 3 eq. of Cs2CO3 and 0.1 eq. AtaPhos were added and the mixture was stirred at 100 ° C in a MW reactor until no further conversion was observed. The volatiles were evaporated under reduced pressure, and the residue was purified by reverse phase preparative chromatography using 25mM aqueous NH4HCO3 and acetonitrile as eluents unless otherwise noted. General procedure IVa: 1 eq. of Preparation 4i was dissolved in anhydrous THF (5 ml / mmol) and cooled to -78 ° C. A solution of LDA (1.2 eq.
[0019] 2M in THF, heptane, EtPh) was added dropwise under argon and the mixture was stirred for 1.5 hours. Then, 1.2 eq. of suitable electrophilic reagent either in solution (dissolved in 3 ml / mmol of anhydrous THF), or pure was added at -78 ° C and the mixture was allowed to warm to RT. It was left stirring until no longer observe conversion. The reaction mixture was quenched by cautious addition of a 25 cc solution of NH4Cl. The mixture was extracted with MTBE, the organic phase was washed with brine, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography using heptane and EtOAc as eluants unless otherwise indicated.
[0020] General Procedure Va: 1 eq. Appropriate acetal was stirred in 2M HCl solution (3 ml / mmol) at 60 ° C until no further conversion was observed. The reaction mixture was cooled to 0 ° C and then 5.7 eq. of NaOH were added in portions. The pH was adjusted to 8 using 10% K2CO3 solution, then 2 eq. of sodium borohydride were added portionwise keeping the temperature under 5 ° C. After addition, the mixture was stirred at 0 ° C until no further conversion was observed. The mixture was extracted with EtOAc, the combined organic phases were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography using heptane and EtOAc as eluants unless otherwise indicated.
[0021] General procedure Vb: Step A To a solution containing I eq. of suitable N-alkyl pyrazole in anhydrous THF (1.5 r / mmol), 1.1 eq. BuLi was added dropwise at -78 ° C. The mixture was stirred for 30 minutes, then allowed to warm to 0 ° C., at which temperature it was allowed to stir. for 30 minutes, then cooled again to -78 ° C. 1.1 eq of DMF was added dropwise, then the reaction mixture was allowed to warm to RT and it was The mixture was inactivated with a solution of NH 4 Cl cc, the phases were separated and the aqueous phase was extracted with EtOAc.The combined organic phases were dried over Na 2 SO 4, filtered and dried. the filtrate was concentrated under reduced pressure The residue was used in the next step without further purification Step B To a solution containing 1 eq of the appropriate crude aldehyde in EtOH (0.5 ml / mmol), 1.3 eq of sodium borohydride was added in portions to - 15 ° C and the reaction mixture was stirred at RT until no further conversion was observed. The mixture was poured onto crushed ice and stirred for 16 hours. The precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. The oily phase was separated, and the aqueous phase was extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure. The product was further purified by flash chromatography if necessary. General Procedure Vc: To a mixture containing 1.2 eq. of appropriate amidine salt and 1 eq. Preparation 8a in anhydrous methanol (0.5 ml immol), 1.2 eq. Sodium methoxide was added portionwise and the mixture was stirred at 75 ° C until no further conversion was observed. The reaction mixture was cooled and concentrated under reduced pressure. Water was added to the residue, and it was 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 flash chromatography using heptane and EtOAc as eluants unless otherwise indicated. General Procedure Vd: To a mixture containing 1.2 eq. hydrazine or hydrazine hydrochloride and 1 eq. Preparation 8a in anhydrous methanol (0.5 ml / minol), 1.2 eq. Sodium methoxide was added portionwise and the mixture was stirred at 75 ° C until no further conversion was observed. The reaction mixture was cooled and concentrated under reduced pressure. Water was added to the residue, and it was 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 flash chromatography using heptane and EtOAc as eluents unless otherwise indicated. General procedure Ve: 25 1 eq. Appropriate acetal was stirred with 1M HCl solution (3 ml / mmol) at 50 ° C until no further conversion was observed. The reaction mixture was cooled to 0 ° C, then 2.85 eq. solid NaOH were added portionwise. The pH was adjusted to 8 using 10% K2CO3 solution, then 2 eq. Sodium borohydride was added in portions maintaining the temperature at 5 ° C and the mixture was stirred at 0 ° C until no further conversion was observed. The mixture was extracted with EtOAc, the combined organic phases were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography using heptane and EtOAc as eluents unless otherwise indicated. General Procedure VI: 5 1 eq. of suitable phenol derivative, 2 eq. of appropriate alcohol derivative, and 3 eq. of PPh3 were dissolved in anhydrous toluene (7 ml / mmol) under an N2 atmosphere, then 3 eq. Di-tert-butyl azodicarboxylate was added at RT. Then the mixture was stirred at 50 ° C until no further conversion was observed. Volatiles were removed in vacuo and the residue was purified by flash chromatography using heptane and EtOAc (and MeOH, if necessary) as eluents. If necessary, the product was further purified by reverse phase preparative chromatography using 25mM aqueous NH4HCO3 and acetonitrile as eluents, unless otherwise noted.
[0022] General Procedure VII: 1 eq. of suitable ester derivative was dissolved in THF (15 ml / mmol), then 10 eq. LiOH x 1120 and water (15 ml / mmol) were added. The mixture was stirred at RT (or at 60 ° C if necessary) until no further conversion was observed. The pH was adjusted to 6 with 1M HCl solution, then the mixture was diluted with brine and extracted with DCM or EtOAc. The organic phase was dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase preparative chromatography using 25 mM aqueous NH4HCO3 and acetonitrile as eluents unless otherwise noted.
[0023] General Procedure VIII: 1 eq. of suitable indole derivative and 2 eq. of suitable alcohol derivative were dissolved in anhydrous toluene (8 ml / mmol) under N 2 atmosphere, and the mixture was cooled to 0 ° C, then 2 eq. 2- (tributyl-phosphanylidene) acetonitrile were added. Then, the mixture was heated to 100 ° C and allowed to stir until no further conversion was observed. The volatiles were removed under vacuum, then water (4 ml / mmol) and 2M NaOH solution (1 ml / ml) were added and the mixture was stirred until no longer observed. conversion. The mixture was then acidified with 1M HCl solution to pH = 6 and extracted with DCM. The combined organic phases were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase preparative chromatography using a 40 mM aqueous solution of NH40Ac (pH = 4, adjusted with AcOH) and acetonitrile as eluants unless otherwise indicated. General Procedure IXa: Step A 10 1 eq. Preparation 9b was dissolved in anhydrous toluene (8 ml / mmol), then 1.18 eq. of PPh3, 1.1 eq. of suitable alcohol derivative and 1.18 eq. diethyl azodicarboxylate (40% solution in toluene) was added at RT. The mixture was stirred at RT until no further conversion was observed. The resulting precipitate was removed by filtration and the filtrate was washed successively with 10% KHSO4 solution, water, saturated Nal1CO3 solution and water. The organic phase was dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was stirred with diethyl ether (5 ml / mmol), the insoluble material was removed by filtration and the filtrate was concentrated under reduced pressure to obtain the crude product.
[0024] Step B The product of Step A was treated with 10 eq. of a solution of HCl (4.9M in MeOH) and was stirred at RT until no further conversion was observed. Then, the mixture was concentrated under reduced pressure. The residue was partitioned between cold EtOAc and ice-cold water, the layers were separated and the organic phase was extracted with ice-cold 5% KFISO4 solution. The combined aqueous phase was basified with solid Na2CO3, and the product was extracted with EtOAc. The organic phase was dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to obtain the methyl ester of the title product.
[0025] Step C 1 eq. the methyl ester obtained in Step B was dissolved in MeOH (9 ml / mmol), then 1.05 eq. NaOH and water (1 mL / mmol) were added and the mixture was stirred at RT until no further conversion was observed. Methanol was removed under reduced pressure and the mixture was neutralized using 1M HCl solution and extracted with DCM. The organic phase was dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to obtain the 0-alkylated amino acid derivative which was used without further purification. General Procedure IXb: Step A 10 1 eq. Preparation 9b was dissolved in anhydrous DMF (10 ml / mmol) and 4 eq. of K2CO3 and 2 eq. of suitable alkylating agent were added at RT. The mixture was stirred at 50 ° C until no further conversion was observed. The mixture was diluted with water and extracted with DCM. The organic phase was dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography using DCM and methanol as eluents unless otherwise indicated. Step B and Step C are identical to those described in the general procedure IXa.
[0026] Preparation 1a: 5-bromo-4-chloro-6-iodo-tbino [2,3-d] pyrimidine Step A: 6-iodo-3H-thiena [2,3-clipyrimidin-4-one One round-bottomed flask 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-a] pyrimidin-4-one (0.46 mol), 51.9 g of periodic acid (0.23 mol) and 104 g of iodine (0, 41 mol) was added to the stirred solution, which was 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. NMR11 (500 MHz, DMSO-d6) δ 12.57 (bs, 1H), 8.09 (s, 1H), 7.65 (s, 1H). Step B 4-Chloro-6-todo-thieno [2,3-d] pyrimidine A 1 1 round-bottomed flask equipped with a mechanical stirrer, thermometer, reflux condenser and of a CaCl 2 tube was charged with 113 ml of phosphorous oxychloride and 35 ml of N, N-dimethylaniline (0.29 mol). 75.54 g of 6-iodo-3Hthieno [2,3-d] pyrimidin-4-one (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. A beige crystalline solid was obtained. 1 H NMR (400 MHz, DMSO-d 6) δ 8.89 (s, 114), 7.98 (s, 1H). Step C: 5-bromo-4-chloro-6-todo-thieno [2,3-d] pyrimidine A 21-bottom round bottom flask equipped with a mechanical stirrer, thermometer and bubbler was loaded with 600 ml of acetonitrile. 84.9 g of 4-chloro-6-iodothieno [2,3-d] pyrimidine (0.29 mol), 50.9 g of NBS (0.29 mol) and 8.5 ml of acidic complex tetrafluoroboric / diethyl ether were 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. The product was obtained as a beige crystalline solid. 1 H NMR (500 MHz, DMSO-d 6) δ 8.88 (s, 1H). Preparation lb: 4-chloro-5,6-diiodothiotho [2,3-dipyrimidine Step A: 5,6-diiodo-3H-thieno [2,3-clipyrimidin-4-one To a perfectly stirred suspension containing 61 3 g of 3H-thieno [2,3-d] pyrimidin-4-one (396 mmol), 92.4 g of periodic acid (405 mmol), 1 liter of acetic acid, 200 ml of water, 6 ml of sulfuric acid cc. and 203 g of iodine (799 mmol) was added. The reaction mixture was heated to 110 ° C and stirred for 3 hours. The suspension was cooled to RT. Then 940 ml of diethyl ether was added and the mixture was further stirred at 10 ° C for 30 minutes. The precipitate was removed by filtration, washed with a 2: 1 mixture of diethyl ether and ethanol (100 mL) and with diethyl ether (3 x 250 mL), then dried at room temperature. air to give the product in the form of a brown powder. 1H NMR (500 MHz, DMSO-d6) δ: 12.60 (brs, 1H), 8.13 (s, 1F1). Step B: 4-chloro-5,6-diiodothiotho12,3-cilpyrimidine To a perfectly stirred suspension containing 180 g of 5,6-diiodo-3H-thieno [2,3-d] pyrimidin-4-one ( 445 mmol) in 2.5 l of phosphorous oxychloride, 64 ml of N, N-dimethylaniline was added. The reaction mixture was heated to 105 ° C and stirred for 1.5 hours. The resulting slurry was cooled to RT and 1.5 L of hexane was added, and the mixture was stirred for a further 20 minutes. The precipitate was removed by filtration, washed with hexane (3 x 500 ml) and water (3 x 100 ml) and then air-dried to give the product as a crystalline solid. Grey. NMR Ili (400 MHz, DMSO-d6) δ: 8.88 (s, 1H). Preparation 1: 4-Chloro-5-iodo-thieno 2,3-dlpyrimidine 52.8 g of Preparation 1b (125 mmol) was dissolved in 400 ml of anhydrous THF and cooled to 0 ° C. 100 ml of 13 μMgCl (200 mmol, 2M in diethyl ether) was added over a period of 15 minutes. Then 50 ml of water was added and the solution was decanted and concentrated under reduced pressure. The crude product was sonicated in a mixture of acetonitrile and water (3/1) and collected by filtration. NMR 11-1 (400 MHz, DMSO-d 6) : 8.95 (s, 1H), 8.45 (s, 1H). Preparation 2a: 4-chloro-6-ethyl-5-iodothiotho [2,3-d] pyrimidine Step A: 6-ethyl-3H-thieno-12,3-clipyrimidin-4-one A mixture containing 701 g of Ethyl 2-amino-5-ethyl-thiophene-3-carboxylate (3.52 mol) and 2200 ml of formamide was heated to 200 ° C and the solvents with the lowest boiling points were removed by distillation. After 2 hours, an additional 250 ml of formamide was added and the mixture was stirred at the same temperature for an additional hour and then at RT for 16 hours. The resulting mixture was poured into 7.5 l of water and the precipitate was removed by filtration, washed with 1.5 l of toluene and 3 l of water, and air-dried to give the product. the form of a brown crystalline solid. 1 H NMR (500 MHz, DMSO-d 6) δ: 12.40 (bs, 1H), 8.05 (s, 1H), 7.11 (t, 111), 2.85 (qd, 2H), 1, 27 (t, 311). Step B: 6-Ethyl-5-iodo-3H-thieno [2,3-c] pyrimidin-4-one A mixture containing 301 g of 6-ethyl-3H-thieno [2,3-d] pyrimidin-4 -one (1.67 mol), 847 g of iodine (3.34 mol), 1040 g of silver sulphate (3.34 mol) and 1.7 l of ethanol were left stirring at RT for 3 days. The resulting precipitate was removed by filtration and washed with ethanol (3 x 400 ml). The product was eluted from the filter cake with the following procedure: the filter cake was allowed to stir with 800 ml of DMF at 50 ° C for 1 hour, then the suspension was filtered. This sequence was repeated 6 times. The combined organic phase was evaporated to dryness to give the product as a brown crystalline solid. Step C: 4-chloro-6-ethyl-5-iodothieno [2,3-d] pyrimidine A mixture containing 880 ml of phosphorous oxychloride and 102 ml of stirred N, N-dimethylaniline was heated to 95 ° C. ° C and 220 g of 6-ethyl-5-iodo-31H-thieno [2,3-d] pyrimidin-4-one (0.719 mol) were added rapidly at the same temperature and stirred for 15 minutes. The reaction mixture was cooled to 80 ° C and poured onto a stirred mixture containing water (1 L), crushed ice (2 kg) and DCM (700 ml). The resulting mixture was stirred for a further 30 minutes while maintaining the temperature under 20 ° C. The phases were separated, the inorganic phase was extracted with DCM (100 ml) and the organic phase was washed with water (100 ml). The combined organic phase was dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure to give the product as a brown crystalline solid. 1H NMR (400MHz, DMSO-d6) δ: 8.79 (s, 1H), 3.02 (q, 2H), 1.39 (t, 31-1). Preparation 2b: 5-bromo-4-chloro-6- (4-fluorophenyl) -thieno [2,3-d] pyrimidine 75.08 g of Preparation 1a (200 mmol), 53.63 g of 2- (4-fluorophenyl) -4,4,5,5-tetramethyl-1,3,2-dioxa-borolane (240 mmol), 130 g of cesium carbonate (400 mmol), 2,245 g of Pd (OAc) 2 (10 mmol) and 8.50 g of 13uX-Phos (20 mmol) were placed in a flask of 2 1. 600 ml of THF and 200 ml of water were added, and then left stirring overnight at 70 ° C. ° C under an argon atmosphere. THF was evaporated, and the product was collected by filtration. The crude product was sonicated in 250 ml of acetonitrile and filtered again. Then, Preparation 2b was crystallized from EtOH / THF (2/1). NMR11 (400 MHz, DMSO-d6) δ: 9.02 (s, 1H), 7.80-7.77 (m, 2H), 7.47-7.43 (m, 2H).
[0027] Preparation 2c: 4-chloro-5-iodo-6- (prop-1-ynyl) -thieno [2,3-dipyrimidine 42.24 g Preparation 1b (100 mmol), 3.509 g Pd (PPh 3) 2 Cl ( 5 mmol) and 1.904 g of Cul (10 mmol) were dissolved in 400 ml of DIPA, then propyne was bubbled into the reaction mixture, which was stirred at RT until no more conversion. Volatiles were evaporated under reduced pressure and the crude product was purified by flash chromatography using heptane / EtOAc as eluent. NMR (400 MHz, DMSO-d6) δ: 8.92 (s, 1H), 2.25 (s, 3H).
[0028] Preparation 2d: 4-chloro-5-iodo-6-isopropyl-thieno [2,3-dipyrimidine Step A 6-isopropyl-5-iodo-3H-thieno [2,3-a] pyrimidin-4-one A mixture containing 2.858 g (14.7 mmol) of 6-isopropyl-3H-thieno [2,3-d] pyrimidin-4-one, 7.468 g (29.4 mmol) of iodine, 9.175 g (29.4 mmol) of sulfate 20 ml of silver and 55 ml of ethanol was stirred at RT for 3 days. The mixture was diluted with Et2O, and the resulting precipitate was removed by filtration and used without further purification. NMR11 (400MHz, DMSO-d6) δ: 12.49 (bs, 1H), 8.11 (s, 1H), 3.35 (m, 1H, overlapping H 2 O signal), 1.28 (s. d, 6H).
[0029] MS (M-H): 319.0. Step B: 4-chloro-6-isopropyl-5-iodothieno [2,3-epyrimidine A mixture containing 15 ml (161 mmol) phosphorous oxychloride and 1.9 ml (14.7 mmol) N, N -dimethylaniline was heated to 95 ° C and 25.9 g (14.7 mmol) of 6-isopropyl-5-iodo-3H-thieno [2,3-cflpyrimidin-4-one (0.719 mol) were added rapidly and left stirring for another 15 minutes at this temperature. The reaction mixture was cooled to 80 ° C and poured into a stirred mixture containing ice-water (300 g) and EtOAc (200 ml). The resulting mixture was stirred for a further 30 minutes while maintaining the temperature under 20 ° C. The phases were separated, the inorganic phase was extracted with EtOAc (100 ml) and the organic phase was washed with water and NaHCO 3 solution. The combined organic phase was dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure and purified by flash chromatography using heptane and EtOAc as eluents to give the title product. 1 H NMR (400 MHz, CDCl 3) δ: 8.78 (s, 1H), 3.63 (septet, III), 1.41 (d, 6H). MS (M + H): 339.0.
[0030] Preparation 3a: (2R) -2-1 (6-ethyl-5-iodothieno [2,3-d] pyrimidin-4-ylaminol-3-phenylpropanoic acid Following general procedure 1a and taking Preparation 2a as the appropriate 4-chloro-thieno [2,3-d] pyrimidine derivative and D-phenylalanine as the appropriate amino acid derivative, Preparation 3a was obtained .1H NMR (500 MHz, DMSO). d6) δ: 8.44 (s, 1H), 7.45 (d, 1H), 7.30-7.20 (in, 5H), 5.07 (m, 1H), 3.35 (dd, 1H), 3.16 (dd, 1H), 2.82 (q, 211), 1.22 (t, 3H), high resolution mass (HRMS) calculated for C17H161N3O2S: 453,0008, found: 454,0064 ( M + H).
[0031] Preparation 4a: 4-Chloro-543-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxylphenyl-6-iodothiotho [2,3-d] pyrimidine Step A: 4-Chlaro-5-P -chlaro-2-methyl-4-P- (4-methyl-piperazin-1-Aethoxylphenyl) thiena [2,3-dipyrimidine Following general procedure Ha and taking Preparation ic as a derivative of 5-iodo thieno [2,3-ci] pyrimidine and Preparation B4 as the appropriate boronic acid derivative, and purifying the product by flash chromatography using DCM and MeOH as eluents, 4-chloro-543-chloro-2 Methyl-4- [2- (4-methylpiperazin-1-ylethoxy) phenyl] thieno [2,3-d] pyrimidine was obtained.1H NMR (400MHz, DMSO-d6) δ: 8.98 (s, 1H). ), 7.97 (s, 1H), 7.22 (d, 1H), 7.09 (s, 1H), 4.25-4.16 (m, 2H), 2.76 (t, 2H); , 2.54 (bs, 4H), 2.32 (bs, 4H), 2.14 (s, 3H), 2.06 (s, 3H) Step B: 4-chloro 5-P-chloro-2-methyl-4- [4- (4-methyl-piperazin-1-yl) ethoxy] phenyl] -6-iodothiotho [2,3-clipyrimid] 10.935 g of 4-chloro-543-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxy] -phenyl] thieno [2,3-d] pyrimidine (25 mmol) were dissolved in 250 ml of anhydrous THF and cooled to -78 ° C. 25 ml of a solution of LDA (50 mmol, 2M in THF, heptane, ethylbenzene) was added dropwise under an argon atmosphere and the mixture was stirred for 15 minutes. . Then 12.69 g (50 mmol) of iodine was added at -78 ° C and the mixture was allowed to warm to RT.
[0032] Then, the mixture was diluted with EtOAc and was washed with NI-14Cl solution then Na2S2O3 solution, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using DCM and MeOH as eluents to obtain Preparation 4a. 1 H NMR (500 MHz, DMSO-d6) δ: 8.93 (s, 1H), 7.15 (d, 1H), 7.13 (d, 1H), 4.22 (t, 2H), 2.77 (t, 21-1), 2.56 (bs, 4H), 2.34 (bs, 4H), 2.16 (s, 3H), 2.00 (s, 3H). Preparation 4b: 4-Chloro-5-13-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxy-phenyl-6- (2-fluoryl) thieno [2,3-d] pyrimidine Following general procedure IIa and taking Preparation 4a as the appropriate 6-iodo-thieno [2,3-d] pyrimidine derivative and 2- (2-fury1) -4,4,5,5-tetrahydrofuran. Methyl-1,3,2-dioxaborolane as the appropriate boronic acid derivative, Preparation 4b was obtained. MS: (M + H) = 503.0. Preparation 4c: 4-chloro-543-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxy] phenyl-6- (5-fluoro-2-furyl) thieno [2,3-d] ] pyrimidine Following the general procedure lila and taking Preparation 4a as the appropriate 6-iodothieno [2,3-dipyrimidine derivative and 2- (5-fluoro-2-fury1) -4,4,5,5 tetramethyl-1,3,2-dioxaborolane as the appropriate boronic acid derivative, Preparation 4c was obtained.
[0033] 1H NMR (500 MHz, DMSO-d6) δ: 8.93 (s, HI), 7.24 (d, 1H), 7.18 (d, 1H), 5.92 (dd, 1H), 5.68 (t, 1H), 4.23 (t, 2H), 2.79 (t, 21-1), 2.58 (bs, 4H), 2.38 (bs, 4H), 2. , 19 (s, 3H), 2.05 (s, 3H). High resolution mass (HRMS) calculated for C24H23N4O2FSC2O: 520.0903; found: 521.0972 (M + H). Preparation 4d: 2-Chloro-4- (4-chloro-6-iodothiotho [2,3-dipyrimidin-5-yl] -3-methylphenol Step A: 12-chloro-4- (4-chlorothieno) [2,3-d] pyrimidin-5-yl) -3-methyl-phenoxy-triisopropyl-silane Following general procedure IIa and taking Preparation ic as the appropriate 5-iodothieno [2,3-d] pyrimidine derivative and Preparation B3 as the appropriate boronic acid derivative, [2-chloro-4- (4-chloro-thieno [2,3-d] pyrimidin-5-yl) -3-methylphenoxy-triisopropyl-silane was got. 1 H NMR (400 MHz, DMSO-d 6) δ: 8.95 (s, 1H), 7.98 (s, 1H), 7.13 (d, 1H), 6.91 (d, 1H), 2.05. (s, 3H), 1.40-1.29 (in, 3H), 1.10 (dd, 18H).
[0034] Step B: P-Chloro-4- (4-chloro-6-iodothieno [2,3-d] pyrimidin-5-yl) -3-methylphenoxytriisopropyl silane 33.7 g of [2-chloro-4] - (4-Chlorothieno [2,3-dipyrimidin-5-yl] -3-methyl-phenoxy-triisopropyl-silane (72 mmol) were dissolved in 300 ml of anhydrous THF and cooled to -78 ° C. 43.2 ml of a solution of LDA (86.4 mmol, 2M in THF, heptane, ethyl benzene) was added dropwise under argon and the mixture was stirred for 15 minutes. minutes. Then 23.8 g of iodine (93.7 mmol) was added at -78 ° C and the mixture was allowed to warm to RT. Then, the mixture was diluted with EtOAc and was washed with NH4Cl solution and then with Na2S2O3 solution. The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. NMR11-1 (400MHz, DMSO-d6) δ: 8.91 (s, 1H), 7.05 (d, 1H), 6.97 (d, 111), 1.99 (s, 3H), 1H NMR (CDCl3) , 39-1.30 (in, 3H), 1.10 (dd, 181-1). Step C: 2-Chloro-4- (4-chloro-6-iodothieno [2,3-c-pyrimidin-5-yl] -3-methyl-phenol 10.0 g of [2-chloro-4- (4 -Chlom-6-iodothieno [2,3-d] pyrimidin-5-yl) -3-methylphenoxy} -fisopropyl-silane (16.85 nunol) were dissolved in 100 ml of anhydrous THF and 18.5 ml. A solution of TBAF (18.5 mmol, 1M in THF) was added and the mixture was stirred at RT for 10 minutes and then the mixture was diluted with EtOAc. and washed with 1M HCl solution and brine The organic phase was dried over Na 2 SO 4, filtered and concentrated under reduced pressure The crude product was purified by flash chromatography using heptane and brine. EtOAc as eluent to give Preparation 4d High resolution mass (HRMS) calculated for C13H7Cl · 11N2OS: 435.8701, found: 436.8780 (M + 1-1) Preparation 4e: 2-12-chloro-4- (4-Chloro-6-iodo-thieno [2,3-4-pyrimidin-5-yl] -3-methyl-phenoxy] -N, N-dimethyl-ethan By following General Procedure VI and taking Preparation 4d as the appropriate phenol derivative and N, N-dimethylethanolamine as the appropriate alcohol, Preparation 4e was obtained. MS (M + H): 508.0. Preparation 4f 2-Halo-14-chloro-6- (3-thienyl) -theno 12,3-4 pyrimidin-5-yl-3-methylphenol Following general procedure Ma and taking Preparation 4d as the appropriate 6-iodo-thieno [2,3-d] pyrimidine derivative and the thiophene-3-boronic acid pinacol ester as the appropriate boronic acid derivative, Preparation 4f was obtained. MS (M + H): 393.0.
[0035] Preparation 4g: 4-chloro-543-chloro-2-methyl-412- (4-methylpiperazin-1-ylethoxy) phenyl-6-thienypthieno [2,3-d] ppimidine Following General Procedure VI and taking Preparation 4f as the appropriate 6-iodo-thieno [2,3-c] pyrimidine derivative and 2- (4-methylpiperazin-1-yl) -ethanol as the appropriate alcohol, Preparation 4g was obtained. 1 H NMR (500 MHz, DMSO-d 6) δ: 8.94 (s, 111), 7.60 (dd, 1H), 7.56 (dd, 1H), 7.19 (d, 1H), 7.12 (d, 1H), 6.79 (dd, 1H), 4.21 (t, 1H), 2.77 (t, 1H), 2.56 (brs, 4H), 2.33 (brs, 4H), 2.15 (s, 3H), 2.04 (s, 31-1), high resolution mass (HRMS) calculated for C24H24Cl2N4O5S 518.0769, found: 519.0852 (M + H). 46- Preparation 4h: 4-1212-Halo-444-chloro-6- (3-thienyl) thi [o-2,3-d] pyrimidin-5-yl] -3-methyl-phenylethyl-ethyl-morpholine following General Procedure VI and taking Preparation 4f as the appropriate phenol derivative and 2-morpholinoethanol as the appropriate alcohol Preparation 4h 5 was obtained Preparation 4: 4-Ethyl-5- (1-naphthypthieno [2,3] pyrimidine Step A: Ethyl 2-amino-4- (1-naphthyl) thiophene-3-carboxylate 50.00 g of 1- (1-naphthyl) ethanone (293.8 mmol), 43.66 g of ethyl cyanoacetate (386.0 mmol), 18.84 g of sulfur (587.5 mmol), 8.4 ml of AcOH and 38.39 g of morpholine were dissolved in 300 ml of EtOH and stirred at 60 ° C until no further conversion was observed. The volatiles were removed in vacuo, and the residue was purified by flash chromatography using heptane and EtOAc as eluents to give 2-amino-4- (1-naphthypthiophene-3-carboxylate). Ethyl High resolution mass (HRMS) Calcd for C17H15NO2S: 297.0823 Found: 298.0891 (M + H) Step B: 5- (1-Naphthyl) -3H-thieno [2,3-dipyrimicliti-4] 9.40 g of ethyl 2-amino-4- (1-naphthypthiophene-3-carboxylate (31.6 mmol) were dissolved in 45 ml of formamide and stirred at 200 ° C. until the reaction was complete. The mixture was cooled to RT and poured into water The precipitated solid was filtered, washed with water and then dried to give 5- (1-naphthyl) - 3Hthieno [2,3-dipyrimidin-4-one High resolution mass (HRMS) calcd for CI6H10N2OS: 278.0514, found: 279.0582 (M + H) Step C: 4-chloro-5- (1- naphthylthieno [2,3-d] pyrimidine 8.50 g of 5- (1-naphthyl) -3H-thieno [2,3 1-pyrimidin-4-one (30.5 mmol), 4.07 g of N, N-dimethylaniline (33.6 mmol) and 22.8 ml of phosphorus oxychloride (244 mmol) were left under stirring at room temperature. 100 ° C for 1 hour. The mixture was cooled to RT and poured into ice-cold water with stirring. The precipitated solid was filtered and recrystallized from acetonitrile to obtain Preparation 4i. High resolution mass (HRMS) calculated for C16H9N2SC1: 296.0175; found: 297.0255 (M + H). Preparation 41: 4-Chloro-5- (3-chloro-2-methyl-phenyl) -6-ethyl-thieno [2,3-s] pyrimidine Following general procedure IIb and taking Preparation 2a as a derivative of Suitable iodo-thieno [2,3-d] pyrimidine and (3-chloro-2-methyl-phenyl) boronic acid as the appropriate boronic acid derivative, Preparation 4j was obtained. 1H NMR (400MHz, DMSO-d6) δ: 8.89 (s, 1H), 7.55 (dd, 1H), 7.33 (t, 1H), 7.23 (dd, 1H), 2H NMR (CDCl3) , 65 (m, 2H), 2.03 (s, 3H), 1.17 (t, 3H). High resolution mass (HRMS) calculated for C15H12Cl2N2S: 322.0098; found: 323.0164 (M + H). Preparation 4k: 4-chloro-6-ethyl-5- (1-naphthypthieno [2,3-4pyrimidine Following general procedure 11b and taking Preparation 2a as a derivative of 5-iodothieno [2,3-d] The appropriate pyrimidine and neopentyl glycol ester of 1-naphthaleneboronic acid as the appropriate boronic acid derivative, Preparation 4k was obtained NMR (400 MHz, DMSO-d6) 8: 8.91 (s, 1H) ), 8.07 (dd, 1H), 8.03 (dm, 1H), 7.63 (dd, 1H), 7.55 (tm, 111), 7.51 (dd, 1H), 7, 44 (tm, 1H), 7.33 (dm, 1H), 2.61 (q, 2H), 1.13 (t, 3H), High resolution mass (HRMS) calculated for C18H13ClN2S: 324.0488; 325.0562 (M + H).
[0036] Preparation 41: 4-Chloro-6-methyl-5- (1-naphthyl) thieno [2,3-dlpyrimidine Following general procedure IVa and taking methyl iodide as the appropriate electrophile, Preparation 41 was obtained. 1H NMR (400MHz, DMSO-d6) δ: 8.90 (s, 1H), 8.04 (dd, 2H), 7.63 (dd, 1H), 7.54 (td, 1H), 7, 49 (dd, 1H), 7.43 (td, 1H), 7.32 (d, 1H), 2.28 (s, 3H).
[0037] MS (M + H): 311.0. Preparation 4m: [4-chloro-5- (1-naphthyl) thieno [2,341] pyrimidin-6-ylimethanol Step A: 4-chloro-5- (1-naphthyl) thieno [2,3-clipyrimidine] 6-Carbaldehyde Following general procedure IVa and taking DMF as the appropriate electrophile, 4-chloro-5- (1-naphthypthieno [2,3-d] pyrimidine-6-carbaldehyde was obtained NMR (400 MHz , CDCl13) δ: 9.65 (s, 1H), 9.00 (s, 1H), 8.07 (d, 1H), 7.99 (d, 1H), 7.68-7.52; (m, 3H), 7.47 (t, 1H), 7.33 (d, 1H) Step B [4-chloro-5- (1-naphthyl) thieno [2,3-cilpyrimidin-6-ylimethanol 4-Chloro-5- (1-naphthypthieno [2,3-c] pyrimidine-6-carbaldehyde was dissolved in 1/1 THF / MeOH (4 ml / mmol) and 3 eq of NaBH4 was added. at 0 ° C. The mixture was stirred for 10 minutes, then inactivated with 1M citric acid The mixture was extracted with DCM, washed with NaHCO 3 solution and brine, dried over Na 2 SO 4, filtered and the filtrate was concentrated under vacuum. The crude solution was purified by flash chromatography using heptane and EtOAc as eluents to obtain Preparation 4m. NMR (400 MHz, DMSO-d6) δ: 8.92 (s, 1H), 8.06 (d, 1H), 5.99 (t, 1H), 8.03 (d, 1H), 4.54. (dd, 1H), 7.62 (in, 1H), 7.58-7.49 (m, 2H), 7.44 (m, 1H), 7.35 (d, 1H), (dd, 1H) ). 4.33 MS (M + H): 327.0. Preparation 4n1 and Preparation 4n2: 1-14-chloro-5- (1-naphthyl) thieno-pyrimidin-6-yl ethanol Following general procedure IVa and taking acetaldehyde as the appropriate electrophilic reagent, the crude product was obtained in the form of a mixture of diastereoisomers which were separated by sequential flash chromatography using the DCM / acetone mixture and the heptane / MTBE mixture as eluents. The order of elution of the diastereomeric pairs was identical with both eluent systems. Preparation 4n1 was obtained as the diastereoisomer eluted first (racemate).
[0038] NMR (400 MHz, CDCl3) δ: 8.85 (s, 1H), 7.99 (d, 1H), 7.95 (d, 1H), 7.60-7.49 (m, 2H), 7.46-7.34 (in, 3H), 4.84 (in, 1H), 2.06 (d, 1H) 1.53 (d, 3H). MS (M + H): 341.0. Preparation 4n2 was obtained as the last eluted diastereoisomer (racemate). 1H NMR (400MHz, CDCl3) δ: 8.85 (s, 1H), 7.99 (d, 1H), 7.94 (d, 1H), 7.60-7.49 (m, 2H), 7.46 (dd, 1H) 7.43-7.37 (m, 1H), 7.27 (overlap, 1H), 4.98 (m, 1H), 2.14 (d, 1H) 1, (D, 3H). MS (M + H): 341.0. Preparation 4o: 1 [4-chloro-5- (1-naphthyl) thieno [2,3-d] pyrimidin-6-yl] ethanone 157 mg of Dess-Martin reagent (0.37 minol) was dissolved in 2 ml of DCM, then a mixture containing Preparation 4n1 and Preparation 4n2 (120 mg, 0.35 mmol dissolved in 10 ml of DCM) was added and the mixture was stirred until no more conversion. Then, the mixture was diluted with DCM, washed with NaOH and NaHCO3S solution and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using heptane and EtOAc as eluents to obtain Preparation 40. NMRIII (500 MHz, DMSO-d5) δ: 9.09 (s, 1H), 8.16 (dd, 1H), 8.08 (d, 1H), 7.727.65 (m, 2H), 7.62 -7.57 (m, 1H), 7.52-7.43 (m, 2H), 1.71 (s, 3H). MS (M + H): 339.0.
[0039] Preparation 4n: 214-chloro-5- (1-naphthyl) thieno [2,3-4] pyrimidin-6-yl] propan-2-ol Following general procedure IVa and taking acetone as the appropriate electrophile Preparation 4p was obtained. NMR (400 MHz, CDCl3) δ: 8.80 (s, 1H), 7.98 (d, 1H), 7.92 (d, 1H), 7.59-7.46 (m, 2H), , 46-7.34 (m, 2H), 7.30 (d, 1H), 2.53 (brs, 1H), 1.54 (s, 1H), 1.21 (s, 3H).
[0040] MS (M + H): 355.0. Preparation 4α: 4-Chloro-6-isopropyl-5- (1-naphthyl) thieno [2,3-d] pyrimidine Step A: 6-Isopropyl-5- (1-naphthyl) -3H-thieno-12,3-dlpyrimidin-4 250 mg of Preparation 4p (0.705 mmol) and 1.75 ml of Et3SiH (10.9 mmol) were placed in a flask and treated with 10 ml of TFA at -10 ° C. The mixture was then diluted with DCM, neutralized with solid K 2 CO 3 and NaHCO 3 solution, and the phase was separated off. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give 6-isopropyl-5- (1-naphthyl) -3Hthieno [2,3-d] pyrimidin-4-one as a crude intermediate: MS (M + H): 321.0.
[0041] Step B 4-chloro-6-isopropyl-5- (1-naphthyl) thieno [2,3-dipyrimidine 2 ml phosphorous oxychloride and 0.161 ml N, N-dimethylaniline (1.27 mmol) were placed in A flask under argon and 1.22 g of 6-isopropyl-5- (1-naphthyl) -3Hthieno [2,3-d] pyrimidin-4-one was added to the mixture in portions over a period of 10 minutes. The reaction mixture was stirred at 100 ° C until no further conversion was observed. The mixture was cooled to RT and poured into ice-cold water with stirring. The aqueous medium obtained was neutralized by careful addition of solid NaHCO3. After stopping the evolution of gas, the product was extracted three times with DCM. The combined organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using heptane and EtOAc as eluents to obtain Preparation 4q. NMR (500 MHz, CDCl3) δ: 8.80 (s, 11-1), 7.97 (d, 1H), 7.94 (d, 1H), 7.57 (dd, 1H), 7.54. -7.49 (m, 111), 7.42-7.37 (m, 2H), 7.34 (d, 1H), 3.02 (septet, 1H), 1.31 (d, 3H), 1.20 (d, 3H).
[0042] MS (M + H): 339.0. Preparation 4r 4-Chloro-6- (difluoromethyl) -5- (1-naphthyl) thieno [2,341 pyrimidine 0.250 g of 4-chloro-5- (1-naphthyl) thieno [2,3-d] pyrimidine-6-carbaldehyde (intermediate of step A in the synthesis of Preparation 4m, 0.77 mmol) was dissolved in 7 ml of DCM, then 270 μl of DAST (1.16 mmol) was added. The mixture was stirred at RT until no further conversion was observed. The mixture was then diluted with DCM and washed with water, then with NaHCO 3 solution and brine. The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using heptane and EtOAc as eluents to obtain Preparation 4r. NMR III (500 MHz, CDCl3) δ: 8.97 (s, 11-1), 8.04 (d, 1H), 7.97 (d, 1H), 7.62-7.54 (m, 2H). ), 7.49-7.43 (m, 2H), 7.28 (d, 1H), 6.47 (t, 1H). MS (M + H): 347.0. Preparation 4s: 4-Chloro-6-iodo-5- (1-naphthylthio [2,3-d] pyrimidine Following general procedure IVa and taking iodine as the appropriate electrophilic reagent, Preparation 4s was obtained. (400MHz, DMSO-d6) δ: 8.94 (s, 1H), 8.10 (dm, 1H), 8.05 (dm, 1H), 7.66 (dm, 111), 7.56 (b.p. tm, 1H), 7.48 (dd, 1H), 7.44 (tm, 1H), 7.31 (dm, 1H), High resolution mass (HRMS) calculated for C16118-N2SC11: 421.9141; 422.9211 (M + H).
[0043] Preparation 4t: 4-Chloro-5- (3-chloro-2-methyl-phenyl) -6-iodothiotho [2,3-Mpyrimidine Step A 4-chloro-5- (3-chloro-2-methyl) -2- phenyl) thieno12,3-clipyrimidine Following the general procedure IIb and taking Preparation 1α as the appropriate 5-iodothieno [2,3-d] pyrimidine derivative and (3-chloro-2-methylphenyl) boronic acid as the As a suitable boronic acid derivative, 4-chloro-5- (3-chloro-2-methyl-phenyl) -thieno [2,3-d] pyrimidine was obtained. NMRIII (400 MHz, CDCl3) δ: 8.89 (s, 1H), 7.47 (dd, 1H), 7.43 (s, 1H), 7.20 (t, 1H), 7.14 (dd; , 1H), 2.14 (s, 311).
[0044] Step B: 4-Chtoro-5- (3-chloro-2-methyl-phenyl) -6-iodothieno [2,3-dipyrimidine Following general procedure IVa and taking 4-chloro-5- ( 3-chloro-2-methyl-phenypthieno [2,3-d] pyrimidine In place of Preparation 4i and iodine as the appropriate electrophilic reagent, Preparation 4t was obtained NMR 11-1 (400 MHz, 25 MHz). CDCl13) δ: 8.82 (s, 1H), 7.52 (dd, 1H), 7.25 (t, 1H), 7.05 (dd, 11-I), 2.09 (s, 3H); Preparation 4u: 4-Chloro-5- (3-chloro-2-methyl-phenyl) -6-isopropyl-thieno-12,3-dl pyrimidine Following general procedure IIb and taking Preparation 2d as a derivative of 5-iodo -thieno [2,3-d] pyrimidine and (3-chloro-2-methyl-phenyl) boronic acid as the appropriate boronic acid derivative, Preparation 4u was obtained. (400 MHz, DMSO-d6) E: 8.90 (s, 1H), 7.56 (dd, 1H), 7.34 (t, 1H), 7.297.22 (m, 1H), 2.94 ( septet, 1H), 2.04 (s, 3H), 1.26 (d, 3H), 1.22 (d, 3H), high resolution mass (HRMS) ca calcined for C16H14N2SCI2: 336.0255, found: 337.0335 (M + H).
[0045] Preparation 4v: 4-chloro-6-ethyl-5- (1H-indol-4-yl) -thieno-12.3-Mpyrimidine A mixture containing 0.664 g of Preparation 2a (2.0 mmol), 0.400 g of 1H acid -indo-4-ylboronic acid (1.2 eq, 2.4 mmol), 44.9 mg Pd (OAc) 2 (10 mol%, 0.2 mmol), 152 mg PCy3 x HBF4 (20% mole, 0.4 mmol), 1.96 g of Cs 2 CO 3 (3.0 eq, 6.0 mmol) in 7.3 ml of dimethoxyethane and 7.3 ml of water was heated in a 100 micron reactor. ° C until you no longer observe a conversion. The crude reaction mixture was filtered through a pad of celite, washed with 2 x 10 ml MTBE and 2 x 10 ml water. The two phases of the filtrate were separated and the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by reverse phase preparative chromatography using water (containing 0.1% TFA) and acetonitrile as eluents to obtain Preparation 4v. 1 H NMR (400 MHz, DMSO-d 6) δ: 11.22 (bs, 1H), 8.87 (s, 1H), 7.49 (dm, 1H), 7.32 (m, 1H), 7, 19 (dd, 1H), 6.95 (dm, 1H), 5.96 (m, 1H), 2.67 (m, 211), 1.14 (t, 3H). High resolution mass (HRMS) calculated for C16H12ClN3S: 313.0440; found 20 314.0508 (M + H). Preparation 4w: 4-chloro-5- (1-naphthyl) -6-vinylthieno [2,3-d] pyrimidine Following general procedure He and taking Preparation 4s as a derivative of 6-iodothieno [2,3 and the vinylboronic acid pinacol ester as the appropriate boronic acid derivative, Preparation 4w was obtained. NMRIII (500 MHz, DMSO-d6) δ: 8.95 (s, 1H), 8.09 (d, 1H), 8.05 (d, 1H), 7.65 (dd, 1H), 7.56. (t, 1H), 7.52 (dd, 1H), 7.45 (t, 1H), 7.35 (d, 1H), 6.34 (dd, 1H), 5.90 (d, 1H) 5.45 (d, 1H). High resolution mass (HRMS) calculated for C18H14Cl2: 322.0331; found 323.0415 (M + H). Preparation 4x: 4-chloro-5- (1-naphthyl) -6 - [(E / Z) -prop-1-enyl] thieno [2,3-d] pyrimidine Step A: .5,5-dimethyl -2-1 (Z / E) -prop-1-en-1,3,2-diamborinane To a solution containing 0.172 g of (Z) -prop-1-en-1-ylboronic acid (2.0 mmol A mixture of ZIE isomer 9/1) and 0.208 g of neopentyl glycol (2.0 mmol) in 6 ml of 2-Me-THF, 20 mg of amberlyst 15H + ion exchange resin were added and the mixture was left stirring at RT until no longer observe conversion. The conversion was followed by an 11-1-NMR measurement in a CDCl3 solution. The mixture was filtered through a pad of celite, washed with 2 x 3 ml of 2-Me-THF and the filtrate was concentrated in vacuo. The resulting crude material was sufficiently pure for the next step as a 87/13 mixture of Z / E isomers according to the NMR measurement. 1H NMR (400MHz, CDCl3): 6.57-6.43 (in, 1H), 5.39-5.27 (dd, 11-1), 3.67 (s, 4H), 1.95. -1.83 (dd, 31-1), 0.97 (s, 61-1).
[0046] Step B: 4-Chloro-5- (1-naphthyl) -6-1 (Z / E) -prop-1-enyl] thieno [2,3-d] pyrimidine Following general procedure IIc and taking the Preparation 4s as the appropriate 6-iodothieno [2,3-d] pyrimidine derivative and 5,5-dimethyl-2 - [(Z / E) -prop-1-enyl] -1,3,2-dioxaborinan (Z / E mixture, Step A) as the appropriate boronic acid derivative, Preparation 4x was obtained as a 63/37 mixture of Z / E isomers.
[0047] NMR111 (500 MHz, DMSO-d15) δ: 8.95-8.90 (s, 1H), 8.11-8.06 (m, 1H), 8.06-8.01 (nl, 1H) , 7.67-7.60 (m, 1H), 7.58-7.52 (m, 1H), 7.52-7.48 (in, 1H), 7.46-7.40 (m, 1H), 7.36-7.29 (m, 1H), 6.45-5.90 (m, 1H), 6.10-6.04 (m, 1H), 2.06-1.72 (m, 1H), dd, 3H). High resolution mass (HRMS) calculated for C19H13ClN2S: 336.0488; found 337.0541 (M + H).
[0048] Preparation 4v: 4-Chloro-6-isopropenyl-5- (1-naphthyl) -thieno [2,3-d] pyrimidine Following general procedure He and taking Preparation 4s as a derivative of 6-iodothieno [2, Suitable 3-djpyrirnidine and 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as the appropriate boronic acid derivative, Preparation 4y was obtained. 1 H NMR (500 MHz, DMSO-d 6) : 8.83 (s, 1H), 7.96 (d, 1H), 7.92 (d, 1H), 7.557.37 (m, 5H), 5.23. (Ni, 1H), 5.12 (m, 1H), 1.65 (dd, 3H). High resolution mass (HRMS) calculated for C19H13ClN2S: 336.0488; found 337.0551 (M + H). Preparation 4z: 4-chloro-5- (1-naphthyl) -6-RE) -prop-1-enylithieno [2,3-a] pyrimidine Step A: .5,5-Dimethyl-2-1 (E) -prop-1-enyl] -1,3,2-dioxa-borinane To a solution containing 0.172 g of (E) -prop-1-en-1-ylboronic acid (2.0 mmol) and 0.208 g of neopentyl glycol (2.0 mmol) in 6 ml of 2-Me-THF, 20 mg of 15H + amberlyst ion exchange resin was added and the mixture was stirred at RT until no further conversion was observed. The conversion was followed by 1 H-NMR measurement in a CDCl3 solution. The mixture was filtered through a pad of celite, washed with 2 x 3 ml of 2-Me-THF and the filtrate was concentrated in vacuo. The resulting raw material was sufficiently pure for the next step. It contained only the E isomer. NMR11-1 (400 MHz, CDCl3) δ: 6.57 (m, 1H), 5.39 (dd, 1H), 3.63 (s, 4H), 1.83 ( dd, 3H), 0.97 (s, 6H). Step B: 4-chloro-5- (1-naphthyl) -6-1 (E) -prop-1-enyl-thieno [2,3-d] pyrimidine Following General Procedure IIcIIIb and taking Preparation 4s as the appropriate 6-iodo-thieno [2,3-dipyrimidine derivative and 5,5-dimethyl-2 - [(E) -prop-1-enyl-1,3,2-dioxaborinane (Step A) as a derivative of the appropriate boronic acid, Preparation 4z was obtained. NMR (500MHz, DMSO-d6) δ: 8.90 (s, 1H), 8.09 (d, 1H), 7.34 (d, 1H), 8.04 (ci, 1H), 6.45. (m, 1H), 7.64 (dd, 1H), 7.58-7.53 (m, 1H), 7.50 (dd, 1H), 7.44 (m, 1H), 6.03 (m, 1H), 1.72 (dd, 3H).
[0049] High resolution mass (HRMS) calculated for C19H13ClN2S: 336.0488; found 337.0550 (M + H). Preparation 5a: (2R) -2-1 [5- (3-Chloro-2-methyl-phenyl) -6-iodothieno [2,3-d] pyrimidin-4-yl] amino] -3-phenyl-propanic acid Following general procedure 1b and taking Preparation 4t as the appropriate 4-chloro-thieno [2,3-d] pyrimidine derivative and D-phenylalanine as the appropriate amino acid derivative, Preparation 5a was synthesized. The crude product was purified by reverse phase preparative chromatography using 0.1% TFA solution and acetonitrile as eluants and Preparation 5a was obtained as a mixture. 1 of diastereoisomers. 1 H NMR (500 MHz, DMSO-d 5) δ: 13.15 (bs, 1H), 8.42-8.41 (s, 1H), 7.62-7.54 (d, 1H), 7.39-7.17 (t, 1H), 7.21-7.01 (nd, d, 1H), 7.21 (m, 4H), 6.82-6.79 (d, 1H), 5.15-5.11 (d, 1H), 4.82-4.76 (q, 1H), 3.23-3.14 (dd, 1H), 2.73-2.67 (dd, 1H) ), 2.02-1.80 (s, 3H). High resolution mass (HRMS) calculated for C221117N2O2SCII: 548.9775; found 549.9842 and 549.9864 (M + H).
[0050] Preparation 5b: (2R) -24R5S ') - 543-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxylphenyl] -6-iodo-tbieno [2,3-d] pyrimidin-4- yllamino1-3421 (2-methylpyrazo-3-yl) metboxy] phenyllpropandic Following general procedure 1b and taking Preparation 4a as the appropriate 4-chloro-thieno [2,3-d] pyrimidine derivative and Preparation Al as derivative of the appropriate amino acid, after purification by HILIC, Preparation 5b was obtained as the last eluted diastereoisomer. MS: (M + H) 802.0. Preparation 5c: (2R) -2 - [[513-Chloro-2-methyl-4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl] -6-iodo-thieno [2,3-d] py embedded image In accordance with general procedure 1b and taking Preparation 4a as a 4-chlorothieno [4-chlorothieno [4-chloro-thieno derivative] [4-chlorothieno [4-chloro-thieno]], [α] [[2-ethylpyrazol-3-yl] methoxy] phenyl] propand 2,3-d] pyrimidine and Preparation A7 as the appropriate amino acid derivative, after purification by HILIC, Preparation 5c was obtained as the last eluted diastereomer. MS: (M + H) = 816.0.
[0051] Preparation 6a: (2R) -24 [5-Bromo-6- (4-fluoro-phenyl) thieno [2,3-d] pyrimidin-4-yl] amino] -3- (2-hydroxy-phenyl) propanoic acid Following general procedure Ib and taking Preparation 2b as the appropriate 4-chloro-thieno [2,3-4pyrimidine derivative and (2R) -2-amino-3- (2-hydroxyphenyl) propanoic acid as a derivative. Amino acid suitable, Preparation 6a was obtained, isolated by filtration .1H NMR (400 MHz, DMSO-d6) δ: 12.90 (brs, 1H), 9.65 (brs, 1H) ), 8.41 (s, 1H), 7.70 (nl, 2H), 7.45-7.34 (nl, 311), 7.18 (dd, 1H), 7.04 (td, 1H) , 6.80 (d, 1H), 6.72 (t, 1H), 4.96 (m, 1H), 3.31 (dd, 1H), 3.08 (dd, 1H) MS (M + H) ): 488.0 Preparation 6b: (2R) -3- (2-Hydroxyphenyl) -2 - [(5-iodo-6-prop-1-ynylthieno [2,3-dipyrimidin-4-yl]) By following general procedure Ib and taking Preparation 2e as a derivative of 4-chloro-thieno [2,3-4ppimidine and (2R) -2-amino-3- (2-hydroxy-phenyl) acid) - 10 propanoic as d Suitable amino acid derivative, Preparation 6b was obtained. The product was isolated by filtration rather than by chromatography. MS: (M + H) - 480.0. Preparation 6c: Methyl (2R) -2.4 (6-ethyl-5-iodo-thieno [2,3-pyrimidin-4-aamino] -3-phenyl-propanoate 3,246 g of Preparation 2a (10 mmol), 3, 70 g of [(1R) -1-benzyl-2-methoxy-2-oxo-ethyl] ammonium chloride (17 mmol) and 13.03 g of Cs 2 CO 3 (40 mmol) were dissolved in 15 ml of DMSO and left behind. The mixture was then acidified with 2M HCl solution to pH = 1 and extracted with EtOAc (2 x 300 ml), stirring at RT under N 2 until no further conversion was observed. The combined organic phases were washed with NaHCO 3 solution, 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 obtain the preparation. 1H NMR (500 MHz, DMSO-d6) δ: 8.39 (s, 1H), 7.33 (d, 1H), 7.30 (nl, 2H), 7.257.22 (m, 3H), m.p. , 11 (m, 111), 3.69 (s, 31-1), 3.33 (dd, 111), 3.18 (dd, 1H), 2.82 (q, 2H), 1.2 (T, 3H) High resolution mass (HRMS) calculated for C18HgIN3O2S: 467.0164; found 468.0242 (M + H). Preparation 7a: (2R) -24 [5-13-chloro-2-methyl-4-12- (4-methylpiperazin-1-yl) ethoxy] phenyl-6- (4-fluorophenyl) thieno Ethyl [2,3-d] pyrimidin-4-yl aminol-2- (2-hydroxyphenyl) -propanoate Step A: (2R) -2- [15-P-chloro-2-methyl] acid 4-12- (4-methylpiperazin-1-yloxyphenyl-6- (47-fluorophenyl) -thieno [2,3-dipyrimidin-1-yliamino] -3- (2-hydroxyphenyl) propanoic acid Following the general procedure IId and taking Preparation Ga as the appropriate 5-iodo-thieno [2,3-4pyrimidine derivative and Preparation B4 as the appropriate boronic IO derivative, (2R) -2 - [[5- [3- chloro-2-methyl-4- [2- (4-methylpiperazin-1-yl) ethoxy] -phenyl-6- (4-fluorophenylthieno [2,3-d] pyrimidin-4-yl] amino] -3 - ( 2-hydroxyphenylpropanoic acid was obtained High resolution mass (HRMS) calculated for C35H35ClFN5O4S: 675.2082, found 676.2097 (M + H).
[0052] Step B (2R) -2-115-13-chloro-2-methyl-4-P- (4-methyl-piperazin-1-yl) ethoxylphenyl-6- (4-fluorophenyl) thieno [2,3-d] ] Pyrimidin-4-yllaminol-3- (2-hydroxyphenyl) -propanoic acid 2.3 g (2R) -24 [5 - [3-chloro-2-methyl-4- [2- (4) 1-methylpiperazin-1-yl) ethoxy] phenyl-6- (4-fluoro-phenyl) -thio [2,3-a-pyrimidin-4-yl] amino] -3- (2-hydroxy-phenyl) -propanoic acid ( 3.4 mmol) were dissolved in 20 ml of 1.25 M HCl in EtOH and left stirring at 40 ° C overnight. The mixture was then diluted with NaHCO 3 solution and extracted with DCM. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography using DCM and MeOH as eluents to obtain Preparation 7a.
[0053] High resolution mass (HRMS) calculated for C37-139C1FN5O4S: 703.2395; found 704.2417 (M + H). Preparation 7ad2: (2R) -21R5SO5-13-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxylphenyl-6,44-fluorophenyl) thieno [2,3-d] pyrimidin Ethyl 4-yljaminol-3- (2-hydroxyphenyl) propanoate Step A: (2R) -2 - [[(5S0) -5-P-chloro-2-methyl] - [2- (4-methylpiperazin) 1-yl) ethoxyl-phenyl-6- (4-fluoro-phenyl) thieno [2,3-d] pyrimidin-4-ylkmino] -3- (2-hydroxy-phenyl) -propanoic acid By following the general procedure IId and taking Preparation 6a as the appropriate 5-iodo-thieno [2,3-c] pyrimidine derivative and Preparation B4 as the appropriate boronic acid derivative, (2R) -24 [543-chloro-2-methyl] acid. 442- (4-methylpiperazin-1-yl) ethoxyl-phenyl] -6- (4-fluorophenylthieno [2,3-d] pyrimidin-4-yl] amino] -3- (2-hydroxyphenyl) propanoic acid was obtained under In the form of a mixture of diastereomers, the mixture was separated by flash chromatography using HILIC eluents The diastereoisomer eluted first was glue Prepared 7a1, MS (M + H): 676.2 The last eluted diastereoisomer was collected as Preparation 7a2. MS (M + H): 676.2. Step B: (2R) -2 - [[(5S,) - 5-P-chloro-2-methyl-2- [2- (2-methylpiperazin-1-yl) ethoxyl-phenyl] -6- (4-fluorophenyl) ethyl-2,3-dipyrimidin-4-yllamino] -3- (2-hydroxyphenyl) -propanoate 44.51 g of Preparation 7a2 (6.67 mmol) were dissolved in 85 ml of HCl 1 25M in EtOH and stirred at 40 ° C. overnight, then the mixture was carefully diluted with NaHCO 3 solution and extracted with DCM The combined organic phases were dried over Na 2 SO 4, filtered. and concentrated in vacuo The crude product was purified by flash chromatography using DCM and MeOH as eluents to obtain Preparation 7ad 2. NMR (500 MHz, DMSO-d 6) δ: 9.49 (s, 1H), 8 , 40 (s, 1H), 7.34 (d, H1), 7.277.21 (nl, 3H), 7.20-7.14 (m, 2H), 7.00 (td, 1H), 6, 71 (dd, 1H), 6.60 (td, 1H), 6.39 (dd, 1H), 5.03 (d, 1H), 4.92 (nl, 1H), 4.26 (t, 2I-1), 4.03 (nl, 2H), 3.03 (dd, 11-1), 2.78 (t, 2H), 2.54 (bs, 4H), 2.36 (dd, 1H), 2, 30 (bs, 4H), 2.12 (s, 3H), 1.83 (s, 3H), 1.10 (t, 3H). High resolution mass (HRMS) calculated for C37H39ClFN5O4S: 703.2395; found 704.2450 (M + H). Preparation 7b (2R) -2-11 (5S) -5-13-chloro-2-methyl-4-12- (4-methylpiperazin-1-yl) ethoxylphenyl-6-prop-1-ynylthienol 2 Ethyl 3-4pyrimidin-4-yllaminol-3- (2-hydroxyphenyl) propanoate Step A: (2R) -2-11 (5S) -5-P-chloro-2-methyl-4- acid [2- (4-methylpiperazin-1-yl) ethoxylphenyl] -6-prop-1-ynylthieno], 3- (4-pyrimidin-4-yl) quinolin-3- (2-hydroxyphenyl) propanoic acid Following the general procedure Rb and taking the preparation 6b as the appropriate 5-iodo-thieno [2,3-d] pyrimidine derivative and Preparation 114 as a suitable boronic acid derivative, Ataphos as a catalyst and THF / water mixture as a solvent, a mixture of The diastereoisomer eluted last was collected as a (2R) -2 - [[(5Sa) -543-chloro-2- acid) diastereoisomer was obtained by flash chromatography using HILIC eluents. Methyl- (4- (4-methylpiperazin-1-yl) ethoxy] phenyl-6-prop-1-ynylthieno [2,3-4 pyrimidin-4- yl] amino] -3- (2-hydroxyphenyl) propanoic acid MS: (M + H): 620.2.
[0054] Step B (2R) -2 - [[(5S) -5-13-Chloro-2-methyl-4-P- (4-methylpiperazin-1-yl) ethoxyl-phenyl-6-prop-1-ynyl) ethyl thieno [2,3-d] pyrimidin-4-yllamino-1-3- (2-hydroxyphenyl) propanoate 2.3 g of (2R) -2 - [[(5S)) - 513-chloro-2 acid methyl-442- (4-methylPiperazin-1-yl) ethoxy] phenyl] -6-prop-1-ynylthieno [2,3-d] pyrimidin-4-yl] amino] -3 - (2- Hydroxyphenylpropanoic acid (3.71 nunol) was dissolved in 20 ml of 1.25M HCl in EtOH and stirred at 40 ° C overnight. The mixture was then diluted with NaHCO 3 solution and extracted with DCM. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography using EtOAc or DCM and MeOH as eluents to obtain Preparation 7b. NMR (500 MHz, DMSO-d6) b: 9.47 (s, 11-1), 8.41 (s, 1H), 7.21 (s, 1H), 7.21 (s, 1H), 7 , 00 (td, 1H), 6.70 (dd, 1H), 6.60 (td, 1H), 6.34 (d, 1H), 5.11 (d, 1H), 4.89 (m, 1H), 4.377 (t, 2H), 4.03 (m, 2H), 3.06 (dd, 1H), 2.79 (t, 2H), 2.55 (brs), 4H), 2.40 (dd, 1H), 2.30 (bs, 4H), 2.12 (s, 311), 2.00 (s, 3H), 1.97 (s, 3H), 1H; , 11 (t, 3H). High resolution mass (HRMS) calculated for C34H38ClN4O4S: 647.2333; found 648.2385 (M + H).
[0055] Preparation 7c: (2R) -24 [5- [3-chloro-4- (2-dimethylaminoethyloxy) -2-methylphenyl] -6-prop-1-ynylthieno [2,3-dIpyrimidin-4- Step A: (2R) -2-11 (5Sa) -513-chloro-4- (2-dimethylethylmethyloxy) -2-methylphenyl-6-yl-amino-3- (2-hydroxyphenyl) -propanoate prop-1-yn-thienoP, 3-d] pyrimidin-4-yl] amino] -3- (2-hydroxyphenyl) propanoic acid Following general procedure IId and taking Preparation 6b as derivative of 5-iodothiothio [2]. , 3-d] pyrimidine and Preparation B5 as the appropriate boronic acid derivative, a mixture of diastereoisomers was obtained. They were separated by flash chromatography using HILIC eluents. The last eluted diastereoisomer was collected as (2R) -2 - [[(5S ()) - 543-chloro-4- (2-dimethyl-aminoethyloxy) -2-methyl-phenyl] -6- prop-1-ynylthieno [2,3-d] pyrimidin-4-yl] amin-3- (2-hydroxyphenyl) propanoic acid MS (M + H): 565.2.
[0056] Step B: (2R) -2-115-13-chloro-4- (2-dimethylaminoethyloxy) -2-methyl-phenyl] -6-prop-1-ynylthieno [2,3-dipyrimidin-4 -yliamino] -3- (2-hydroxyphenyl) propanoate 2.3 g of (2R) -2 - [[(5Sa) -5- [3-chloro-4- (2-dimethylaminoethyloxy)) acid 2-methylphenyl] -6-prop-1-ynyl-thieno [2,3-d] pyrimidin-4-ylamino-1,3- (2-hydroxyphenyl) propanoic acid (4.07 mmol) were dissolved in 20 ml of 1.25 M HCl in EtOI-1 and stirred at 40 ° C overnight. The mixture was then diluted with NaHCO 3 solution and extracted with DCM. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography using DCM and MeOH as eluents to obtain Preparation 7c.
[0057] NMR (500 MHz, DMSO-d6) δ: 9.45 (s, 1H), 8.41 (s, 1H), 7.21 (s, 1H), 7.21 (s, 1H), 7, 00 (td, 11-1), 6.70 (dd, 1H), 6.60 (td, 1H), 6.34 (d, 1H), 5.12 (d, 1H), 4.89 (m.p. , 1H), 4.266 (m, 2H), 4.03 (m, 2H), 3.06 (dd, 1H), 2.74 (t, 2H), 2.39 (dd, 1H), 2.27 (s, 6H), 2.01 (s, 3H), 1.97 (s, 3H), 1.11 (t, 3H). High resolution mass (HRMS) calculated for C 11133CIN 404S: 592.1911; found 593.1954 (M + H).
[0058] Preparation 7: Ethyl (2R) -2 - [[5-bromo-6- (4-fluorophenyl) -thieno [2,3-di] pyrimidin-4-yl] amino] -3- (2-hydroxyphenyl) -propanoate 2.5 g of Preparation 6a (5.1 mmol) was dissolved in 20 ml of 1.25 M HCl in EtOH and stirred at 40 ° C overnight. The resulting mixture was diluted with aqueous NaHCO 3 and extracted with DCM. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography using heptane and EtOAc as eluents to obtain Preparation 7d. RIVINIH (400 MHz, DMSO-d6) δ: 9.67 (s, 1H), 8.42 (s, 1H), 7.70 (m, 2H), 7.43-7.37 (m, 3H) , 7.14 (dd, 1H), 7.05 (td, 1H), 6.80 (dd, 1H), 6.72 (td, 1H), 5.01 (m, 1H), 4.12 (dd, 1H), (q, 2H), 3.26 (dd, 1H), 3.14 (dd, 1H), 1.17 (t, 3H). Preparation 7e: methyl (2R) -24 [6-ethyl-5- (4-hydroxy-2-methyl-phenyl) thieno [2,3-d] pyrimidin-4-yllaminol-3-phenylpropanoate 934 mg of Preparation 6c (2 mmol), 903 mg of Preparation B6 (2.4 mmol), 231 mg of Pd (PPh3) 4 (0.2 mmol), 662 mg of Ag2CO3 (2.4 mmol) and 81 μl of Methanol (2 mmol) was dissolved in 20 ml of 2-Me-THF and stirred in a MW reactor at 110 ° C until no further conversion was observed. The mixture was filtered through celite, diluted with 100 ml of EtOAc, then 2.5 ml of TBAF (1M solution in THF) was added and the mixture was stirred at RT until no more 25 conversion. The mixture was then washed with NH4Cl solution and brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography using heptane and EtOAc as eluents to obtain Preparation 7e as d a mixture of diastereoisomers. 1 H NMR (400 MHz, CDCl 3) δ: 8.43-8.43 (s, 1H), 7.26-6.80 (m, 7H), 6.76-6.64 (m, 2H), 5.18 (m, 1H), 5.03 (m, 1H), 3.66-3.65 (s, 3H), 3.16-3.13 (dd, 1H), 2.73 (dd, 1H), 2.57 (m, 2H), 2.07-1.80 (s, 3H), 1.18-1.17 (t, 3H). MS (M + H): 448.2. Preparation 7f: (2R) -21 [5- (3,5-dichloro-4-hydroxy-2-methyl-phenyl) -6-ethylthieno [2,3-d] pyrimidin-4-) Methyl pyrophenylate 402 mg of Preparation 7e (0.898 mmol) and 300 mg of NCS (2.245 mmol) were dissolved in 5 ml of THF and allowed to stir at 60 ° C. ° C until you no longer observe a conversion. The volatiles were removed in vacuo, and the residue was purified by flash chromatography using heptane and EtOAc as eluents to obtain the title product as a mixture of diastereoisomers. NMR 11-1 (500 MHz, DMSO-d6) 3: 10.46-10.44 (s, 1H), 8.40-8.38 (s, 1H), 7.29-7.24 (s). , 1H), 7.20 (m, 3H), 6.80-6.78 (d, 2H), 5.09-5.01 (d, 1H), 4.95 (m, 1H), 3, 59-3.58 (s, 3H), 3.15-3.13 (dd, 1H), 2.78-2.61 (dd, 1H), 2.53 (q, 2H), 2.02- 1.84 (s, 31-1), 1.11 (t, 3H). High resolution mass (HRMS) calculated for C251-123C12N303S: 515.0837; found 516.0908 (M + H).
[0059] Preparation 7g: (2R) -2415- (3-chloro-4-hydroxy-2-methyl-phenyl) -6-ethyl-thio [2,3-d] pyrimidin-4-yl-aminol) Methyl 3-phenylpropanoate Following General Procedure IIc and taking Preparation 6c as the appropriate 5-iodothieno [2,3-d] pyrimidine derivative and Preparation B2 as the appropriate boronic acid derivative, Preparation 7g was obtained as a mixture of diastereoisomers. MS (M + H): 482.1. Preparation 72 (11: (2R) -2 - [[(54-5- (3-chloro-4-hydroxy-2-methyl-phenyl) -6-ethylthieno [2,3-d] pyrimidin-4-yl The diastereoisomers of Preparation 7g were separated by flash chromatography using heptane and EtOAc as eluents, The last eluted diastereoisomer was collected as the eluent. as Preparation 7gd1.1H NMR (500 MHz, DMSO-d6) δ: 10.53 (s, 1H), 8.36 (s, 1H), 7.23 (m, 2H), 7.20 (m, 111), 7.04 (d, 1H), 6.98 (d, 1H), 6.80 (m, 2H), 5.11 (d, 1H), 4.90 (in, 1H). , 3.57 (s, 3H), 3.10 (dd, 1H), 2.63 (dd, 1I-1), 2.51-2.46 (m, 21-1), 1.86 (s, , 3H), 1.10 (t, 3H) High resolution mass (HRMS) calculated for C25H24ClN3O3S: 481.1277, found 482.1313 (Mill) Preparation 7h: (2R) -2-1 acid [16-ethyl-5- (111-indol-4-yl) thieno [2,3-d] pyrimidin-4-yl] amino] -3-phenylpropanoic acid Following general procedure Ib and taking Preparation 4v as a derivative of 4-chloro-thie No. [2,3-d] pyrimidine and (2R) -2-amino-3- (2-hydroxyphenyl) propanoic acid as the appropriate amino acid derivative, Preparation 7h was obtained in the form of of a mixture of diastereoisomers. 1 H NMR (500 MHz, DMSO-d 6) δ: 12.71-12.59 (bs, 1H), 11.48-11.37 (s, 1H), 8.35-8.30 (s, 1H) , 7.64-7.53 (d, 1H), 7.45-7.39 (dd, 1H), 7.30-7.08 (t, 1H), 7.17-6.33 (m, 6H), 6.07-6.01 (s, 1H), 5.27 (d, 1H), 4.59 / 4.50 (m, 1H), 2.98-2.83 (dd, Hi); , 2.56 (in, 2H), 2.35-2.15 (dd, 1H), 1.11-1.09 (t, 3H). High resolution mass (HRMS) calculated for C25H22N4O2S: 442.1463; found 443.1529 and 443.1538 (M + H). Preparation 7i: (2R) -2- [5- (3-chloro-lev-indol-4-yl) -6-ethyl-thieno-12,3-d] pyrimidin-4-ylamino] -3-phenyl-propanoate methyl Step A (2R) -2-1 [6-ethyl-5- (1H-indol-14-yl) thieno [2,3-dlpyrimidin-4-yl] arninol-3-phenylpropanoate) 8.87 g Preparation 7 h (20 minol) were dissolved in 60 ml MeOH and 5.88 ml H 2 SO 4 cc. (60 mmol) were added. The mixture was stirred at RT under N 2 atmosphere for 2 hours. The mixture was then poured into ice water, and the precipitate was filtered to obtain (2R) -24 [6-ethyl-5- (1H-indol-4-ylthieno [2,3-d] pyrimidine Methyl 4-yl-amino] -3-phenylpropanoate as a mixture of diastereoisomers.
[0060] 1 H-NMR (400 MHz, DMSO-d6) δ: 11.52-11.43 (s, 1H), 8.39-8.34 (s, 1H), 7.65-7.57 (d, 1H) , 7.47-7.42 (t, 1H), 7.30-7.11 (dd, 1H), 7.18-6.79 (m, 2H), 7.02 (m, 1H), 6 93 (m, 1H), 6.65 (m, 1H), 6.34 (m, 1H), 6.05 (dt, 1H), 5.28 (m, 1H), 4.71-4, 62 (m, 1H), 3.553.41 (s, 3H), 2.91-2.77 (dd, 1H), 2.57 (in, 2H), 2.37-2.23 (dd, 1H) , 1.11-1.10 (t, 3H). MS (M + H): 457.2 and 457.2. Step B: (2R) -2-115- (3-Chloro-1H-indol-4-yl) -6-ethyl-thieno [2,3-d] pyrimidin-21-yilaminol-3-phenyl-propanoate Methyl 8,477 g of (2R) -2 - [[6-ethyl-5- (1H-indol-4-yl) -thieno [2,3-d] pyrimidin-4-yl] amino] -3-phenyl- Methyl propanoate (18.5 mmol), 2.47 g of NCS (18.5 mmol) and 30 ml of absolute THF were stirred at RT until no further conversion was observed. was poured into ice water and extracted with EtOAc The combined organic layers 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 obtain Preparation 7i as a mixture of diastereoisomers.1H NMR (500 MHz, DMSO-d6) 6: 11.73-11.65 (d, 111), 8 , 35-8.31 (s, 1H), 7.637.56 (d, 1H), 7.62-7.54 (d, 1H), 7.44-7.15 (dd, 1H), 7.20 -7.03 (m, 3H), 7.04-6.84 (d, 1H), 6.70-6.44 (dm, 2H) , 5.09-4.98 (d, 1H), 4.80-4.72 (in, III), 3.51-3.38 (s, 3H), 2.93-2.81 (dd, 1H), 2.52 (m, 2H), 2.46-2.29 (dd, 1H), 1.10-1.09 (t, 3H).
[0061] High resolution mass (HRMS) calculated for C26H23ClN4O2S: 490.1230; found 491, 1282 and 491, 1316 (M + H). Preparation 7i 4-Chloro-5- (3-chloro-1H-indol-4-yl) -6-ethyl-thieno-12,3-dipyrimidine A mixture containing 1.099 g of Preparation 4v (3.5 mmol) and 0.572 g of NCS (4.2 mmol) in 20 ml of CCl4 was stirred at RT until no further conversion was observed. The mixture was then poured onto crushed ice and extracted with DCM. 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 4-chloro-5- (3-chloro-1H-indol-4-yl) -6-. ethyl-thieno [2,3-4-pyrimidine, Preparation 7j. NMR (400 MHz, CDCl3) δ: 8.79 (s, 1H), 8.33 (br s, 1H), 7.47 (dd, 1H), 7.31 (t, 1H), 7.18 (s, 1H), d, 1H), 7.03 (dd, 1H), 2.73 (nl, 2H), 1.24 (t, 3H). Preparation 8a: (E) -4- (dimethylamino) -1,1-dimethoxy-but-3-en-2-one 502.1 g of 1,1-dimethoxypropan-2-one (4.25 mol) and 506.4 g of 1,1-dimethoxy-N, N-dimethyl-methanamine (4.25 mol) were mixed in a flask of 21 and stirred at 105 ° C for 3 hours. The formed MeOH was removed continuously by distillation. When the formation of MeOH stopped (at a head temperature of 65 ° C), the reaction mixture was distilled under vacuum (slowly decreasing the pressure to 30 mbar) to remove the by-products and departure not having reacted. The crude product was distilled at 0.1 mbar. Fractions were collected at a head temperature between 107 ° C and 118 ° C (bath temperature 160 ° C to 165 ° C) to give a yellow oil. NMR11 (500 MHz, DMSO-d6) δ: 7.59 (d, 1H), 5.17 (d, 1H), 4.42 (s, 1H), 3.25 (s, 6H), 3.09; (s, 311), 2.78 (s, 3H) Preparation 81ze 4- (dimethoxymethyl) -2-methylsulfonyl-pyrimidine Step A: 4- (dimethoxymethyl) -2-methylsulfanyl-pyrimidine 198 g sodium methoxide (3 67 mmol) were dissolved in 3 l of MeOH and cooled to 0 ° C. 322 g of thiocarbamide (4.23 mol) were added portionwise and the mixture was stirred for 1 hour. Then 488 g of Preparation 8a (2.82 mol) was added dropwise at 0 ° C and then the mixture was heated to 70 ° C until no further conversion was observed. It was cooled to RT, 237 ml of methyl iodide (3.81 mol) was added dropwise, keeping the temperature under 28 ° C, and the resulting mixture was stirred for one night at TA. It was filtered, the filtrate was concentrated under reduced pressure, diluted with EtOAc, washed with water and brine. The combined aqueous phases were extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was dissolved in 500 ml Et 2 O, filtered through a pad of silica, using Et 2 O as eluent. The filtrate was concentrated under reduced pressure to give a light brown oil. 1H NMR (400MHz, DMSO-d6) δ: 8.69 (d, 1H), 7.23 (d, 1H), 5.22 (s, 1H), 3.33 (s, 611), , 52 (s, 3H). Step B: 4- (dimethoxymethyl) -2-methylsulfonyl-pyrimidine To a solution containing 180 g of 4- (dimethoxy-methyl) -2-methylsulfanylpyrimidine (940 mmol) in 1.5 L of methanol and 1.5 L of 752 g of Oxone® (potassium peroxymonosulfate, 1220 mmol) were added portionwise at -5 ° C and then stirred at 0 ° C overnight. The reaction mixture was concentrated under reduced pressure to half its volume using a bath at 30 ° C, then the mixture was filtered, and the precipitate was washed with DCM. The filtrate was extracted with DCM. The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure to give a light brown oil. 1 H NMR (400 MHz, CDCl 3) δ: 8.98 (d, 1H), 7.97 (d, 111), 5.36 (s, 111), 3.47 (s, 6H), 3.39 ( s, 3H).
[0062] Preparation 9a: methyl (2R) -2-amino-3- (2-hydroxyphenyl) propanoate hydrochloride 24.6 g (2R) -2-amino-3- (2-hydroxyphenyl) propanoic acid (136) mmol) were stirred at RT in 900 ml of a 13M HCl solution in methanol for 40 hours. The reaction mixture was concentrated under reduced pressure, keeping the bath temperature under 40 ° C. The residue was triturated with diethyl ether to give the product as a cream-colored glossy powder. High resolution mass (HRMS) calculated for C 16 H 15 NO 3 (free base): 209.1052; found 210.1188 (M + H).
[0063] Preparation 9b: (2R) -2- (t-butoxycarbonylamino) -3- (2-hydroxyphenyl) propanoate 16.7 g of Preparation 9a (73.0 mmol) were suspended in 180 ml of DCM. 30.5 ml (219 mmol) of TEA was added and the solution was cooled with a water-ice bath. A solution containing 15.6 g of di-tert-butyl bicarbonate (73.0 mmol) in 75 ml of DCM was added slowly (2.5 hours). The mixture was stirred overnight at RT. Then 100 ml of water was added and the organic phase was separated, washed with water, 1M HCl solution and finally again with water. The organic phase was dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to obtain the product as an oil. Preparation A1: (2R) -2-Amino-3- [2-1 (2-methyl-pyrazol-3-yl) methoxylphenyl] propanoic acid Following General Procedure IXa and taking (2-methylpyrazol-3 yl) methanol as the appropriate alcohol derivative, Preparation A1 was obtained. MS (M + H): 276.2 Preparation A2: (2R) -2-amino-342-1 (2-ethoxy-pyrimidin-4-yl) methoxylphenylpropandic acid Following general procedure IXa and taking Preparation C1 as the appropriate alcohol derivative, Preparation A2 was obtained. MS (M + H): 318.1.
[0064] Preparation A3: (2R) -2-amino-3421 (2-butyl-pyrazol-3-yl) -thoxylphenyl] propanoic acid Following General Procedure IXa and taking Preparation C2 as the appropriate alcohol derivative, Preparation A3 was obtained. MS (M + H): 318.2.
[0065] Preparation A4: (2R) -2-amino-3424 [2- (2-methoxyphenyl) pyrimidin-4-yl] methoxy] phenyl] propanoic acid Following General Procedure IXa and taking Preparation C3 as an alcohol derivative appropriate, Preparation A4 was obtained. MS (M + H): 380.2.
[0066] Preparation A5: (2R) -2-Amino-342- (2-pyridylmethoxy) phenylpropanoic acid Following General Procedure IXa and taking 2-pyridylmethanol as the appropriate alcohol derivative, Preparation A5 was obtained. MS (M + H): 273.1.
[0067] Preparation A6: (2R) -2-amino-312- (2,2,2-trifluoroethoxy) phenyl] propanoic acid Following General Procedure IXb and taking 2,2,2-trifluoroethyl trifluoromethanesulfonate as a reagent suitable alkylation, Preparation A6 was obtained. MS (M + H): 264.1.
[0068] Preparation A7: (2R) -2-amino-3424 (2-ethyl-pyrazol-3-amethoxylphenylpropanoic acid Following the general procedure IXa and taking (2-ethylpyrazol-3-yl) methanol as a derivative of Suitable alcohol, Preparation A7 was obtained High resolution mass (HRMS) calculated for C151-119N3O3: 289,1426, found: 290,1512 (M + H) Preparation A8: acid (2R) - 2-Amino-342 - [[2- (2,2,2-trifluoroethoxy) pyrimidin-4-yl] methoxy] phenyl] propandyl Following the general procedure IXa and taking Preparation C8 as the appropriate alcohol derivative, the Preparation A8 was obtained: MS (M + H): 372.1.
[0069] Preparation A9: (2R) -2-Amino-342-12- (dimethylamino) -2-oxo-ethoxylphenylpropanoic acid Following General Procedure IXb and taking 2-chloro-N, N-dimethylacetamide as the alkylating reagent Preparative A9 was obtained. MS (M + H): 267.1. Preparation A10: (2R) -2-amino-342- (2-cyclo-pentylethoxy) phenylpropanoiric acid Following General Procedure IXa and taking 2-cyclopentylethanol as the appropriate alcohol derivative, Preparation A10 was obtained. MS (M + H): 278.2.
[0070] Preparation Garlic: (2R) -2-Amino-3- (2-phenethyloxyphenyl) propanoic acid hydrochloride Following General Procedure IXa and taking 2-phenylethanol as the appropriate alcohol derivative, Preparation Ail been obtained. MS (M + H): 286.1.
[0071] Preparation Al2: (2R) -2-amino-3- [2- (3-phenyl-propoxy) phenyl] propanoic acid Following general procedure IXa and taking 3-phenylpropan-1-ol as an alcohol derivative Suitably, Preparation Al2 was obtained. MS (M + H): 300.2.
[0072] Preparation A13: (2R) -2-amino-3424 (3-chlorophenyl) methoxylphenylpropanoic acid Following General Procedure IXa and taking (3-chlorophenyl) methanol as the appropriate alcohol derivative, Preparation A13 was obtained. MS (M + I-1): 306.1. Preparation A14: (2R) -2-Amino-3-1242- (4-methyl-piperazin-1-yl) ethoxyl-phenyl] propanoic acid Following General Procedure IXa and taking 2- (4-methyl-piperazin-1-yl) ethoxy-phenyl] propanoic acid. -methylpiperazin-1-ypethanol as the appropriate alcohol derivative, Preparation A14 was obtained: MS (M + H): 308.2 Preparation Al5: (2R) -2-amino-3- [2- ( 2-dimethylaminoethyloxy) phenyl] propandyl Following the general procedure IXa and taking 2- (dimethylamino) ethanol as the appropriate alcohol derivative, Preparation Al5 was obtained: MS (M + H): 253.2. Preparation A16: (2R) -2-amino-3- [243- (dimethyl-amino) propoxylphenylpropanorec acid Following general procedure IXa and taking 3- (dimethylamino) propan-1-ol as a derivative of Suitable alcohol, Preparation A16 was obtained: MS (M + H): 267.2 Preparation B1: 3-Methyl-4- (3,3,4,4-tetramethyl-borolan-1-34) -1H- indole 1.87 g of 4-bromo-3-methyl-1H-indole (8.9 mmol), 5.028 g of bis (pinaco lato) dibore (19.6 mmol) and 2.65 g of potassium acetate (26.7 mmol) were dissolved in 35 ml of anhydrous DMF under argon, followed by 652 mg of [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (0.89 mmol) was added. The reaction mixture was heated to 85 ° C and allowed to stir until no further conversion was observed. Then, it was concentrated under reduced pressure and purified by flash chromatography using heptane and EtOAc as eluents to obtain Preparation B1. 1 H NMR (400 MHz, CDCl 3) δ: 7.92 (br s, 1H), 7.56 (d, 1H), 7.42 (dd, 1H), 7.16 (t, 1H), 7.01 (d, 1H), 2.47 (d, 3H), 1.40 (s, 12H). High resolution mass (HRMS) calculated for C15H20NO2B: 257.1587; found 30 258.1665 (M + H). Preparation B2: 2-Chloro-3-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-Aphenol Step A: (4-Bromo-2) 3-bromo-2-chloro-phenol (100 mmol) was dissolved in 150 ml of anhydrous THF, and then 24.2 g of HMDS (150 nunol) were dissolved in 150 ml of anhydrous THF. The reaction mixture was stirred at 85 ° C. under an argon atmosphere for 1.5 hours, then concentrated under reduced pressure, and the resulting crude product was used without further purification. CDCl3): 7.49 (d, 1H), 7.23 (dd, 1H), 6.75 (d, 1H), 0.26 (s, 9H) Step B: 4-bromo-2- chloro-3-methylphenol 48 ml of a solution of nBuLi (120 mmol, 2.5M in hexane) 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 bromo-2-chlorophenoxy) -trimethylsilane (100 mmol) was 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. The organic phase was dried over Na2SO4, filtered and the filtrate was 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 crude product which was used without further purification. 1 H NMR (200 MHz, CDCl 3): 7.32 (d, 1H), 6.76 (d, 1H), 5.62 (s, 1H), 2.49 (s, 3H). Step C: (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-methyl-phenol (86.0 mmol) in 150 ml of anhydrous THF. The mixture was stirred at 85 ° C under argon balloon for 1.5 hours and then concentrated under reduced pressure. The product obtained was used without further purification. 1H NMR (200 MHz, CDCl3): 7.30 (d, 1H), 6.63 (d, 1H), 2.50 (s, 31-1), 0.28 (s, 911). Step D: 2-chloro-3-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol A solution containing 25.2 g of (4-bromo-2) chloro-3-methyl-phenoxy) -trimethylsilane (86.0 mmol) in 250 ml of anhydrous TFIF was cooled to -78 ° C under argon, then 38 ml of a solution of "BuLi (94 6 mmol, 2.5M in hexane) was added dropwise After 5 minutes, 19.2 g of 2-isopropoxy-4,4,5,5-tetramethyl-1, 3, 2- Dioxaborolane (103 mmol) was added dropwise, the cooling bath was removed and the mixture was allowed to warm slowly to RT, then the mixture was added to 200 ml of NH4Cl solution and extracted with EtOAc The combined organic layers were concentrated under reduced pressure and passed through a pad of silica gel using hexane and EtOAc as eluents. recrystallized from a mixture of EtOAc and hexane to obtain the Pr B2, 1H NMR (500 MHz, DMSO-d6): 10.40 (s, 1H), 7.42 (d, 1H), 6.80 (d, 111), 2.49 (s, 3H), 1.27 (s, 12H). Preparation B3: [2-Cifloro-3-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-ylphenoxy) -triisopropyl-silane Step A: ( 4-bromo-2-chloro-phenoxy) -triisopropyl-silicon 200 g of 4-bromo-2-chloro-phenol (0.97 mol) and 126 ml of TIPSCI (1.18 mol) were dissolved in 1.6 1 ml of DCM, 167 g of imidazole (2.45 mol) was added and the mixture was stirred at RT for 2 hours, then the volatiles were evaporated under reduced pressure and the residue was dissolved. The mixture was washed with brine, dried over Na 2 SO 4, filtered and the filtrate was concentrated under reduced pressure The triisopropylsilyl hydroxide impurity was removed by distillation (120 ° C. 0.01 mmHg) The residue was filtered through a short pad of silica with hexane and concentrated under reduced pressure The product (colorless oil) was used in the next step without further purification. 1H (400MHz, CDCl3) δ: 7.49 (d, 1H), 7.21 (dd, 1H), 6.78 (d, 1H), 1.31 (sept, 3H), 1.14 (d, 1H), , 18H). MS (EI, 70 eV) m / z (relative intensity in%, [ion]): 63 (30), 79 (24), 93 (41), 170 (17), 235 (19), 251 (16), 265 (24), 293 (23), 319 (77), 321 (100), 323 (28), 362 (1, [M1). Step B: (4-Bromo-2-ethyl-3-methyl-phenoxy) -triisopropyl-silane 76.0 ml anhydrous DIPA (0.54 mol) was dissolved in 1.2 L of anhydrous THF under an atmosphere. of argon and 51.2 ml of a solution of SuLi (0.512 mol, 10M in hexane) was added dropwise at -78 ° C. The mixture was stirred for 45 minutes at the same temperature. Then 178 g of (4-bromo-2-chlorophenoxy) -triisopropyl-silane (0.488 mol) was added dropwise at -78 ° C and the white suspension was stirred until no longer observe conversion. Then, 36.5 ml of MeI (0.586 mmol) was added at this temperature and the reaction mixture was allowed to stir overnight without further cooling. Volatiles were evaporated under reduced pressure. The residue was dissolved in 1.5 L of EtOAc and washed with brine. The organic phase was dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The crude product was filtered through a short pad of silica using hexane as eluent and concentrated under reduced pressure to obtain the product as a pale yellow oil. NMR (400 MHz, CDCl3) δ: 7.30 (d, 1H), 6.68 (d, 1H), 2.53 (s, 3H), 1.32 (septet, 3H), 1.14 (d, 1H); , 18H).
[0073] Step C: P-Chloro-3-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy-triisopropyl silane 178 g (4-bromo) 2-chloro-3-methyl-phenoxy) -triisopropyl-silane (0.472 mol) were dissolved in 1.4 l of anhydrous THF under an argon atmosphere and 52 ml of a solution of nBuLi (0.52 mol, 10M in hexane) was added dropwise at -78 ° C.
[0074] The mixture was stirred for 5 minutes at this temperature. Then 116 ml of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.569 mol) was added and the mixture was allowed to warm to RT. Volatiles were evaporated under reduced pressure. The residue was dissolved in 1.5 L of EtOAc and washed with brine. The organic phase was dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-clioxaborolane impurity was removed by distillation (80 ° C to 0.01 mmHg). The crude product was triturated in MeOH to give Preparation B3 as a white solid. NMR111 (400 MHz, CDCl3) δ: 7.53 (d, 1H), 6.74 (d, 1H), 2.60 (s, 3H), 1.34 (s, 12H), m.p. 1.32 (m, 3H), 1.12 (d, 18H). Preparation B4: 1- [2- [2-chloro-3-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxylethyl] -4-methylpiperazine 0 g of Preparation B2 (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 added. dissolved in 100 ml of anhydrous toluene, 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 until no further conversion was observed. The volatiles were evaporated under reduced pressure and 100 ml of Et 2 O was added. The precipitated white crystals were removed by filtration 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 clear man-on oil was crystallized from hexane to give Preparation B4 as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ: 7.56 (d, 1H), 6.99 (d, 1H), 4.15 (t, 2H), 2.72 (t, 2H), 2, 51 (s, 3H), 2.50 (bs, 4H), 2.29 (bs, 4H), 2.13 (s, 3H), 1.29 (s, 12H). Preparation B5: 1-12-12-Chloro-3-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxylethyl] -4-methylpiperazine 0 g of Preparation B2 (37.2 mmol), 8.7 g of N, N-dimethylolamine (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 volatiles were evaporated under reduced pressure and 100 ml of Et 2 O was added. The precipitated white crystals were removed by filtration 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 Preparation B5. 1 H NMR (400 MHz, DMSO-d 6) δ: 7.56 (d, 1H), 6.99 (d, 1H), 4.13 (t, 2H), 2.66 (t, 2H), 2, 51 (s, 3H), 2.23 (s, 6H), 1.29 (s, 12H). Preparation B6: 14- (5,5-dimethyl-1,3,2-dioxaborinan-2-yl) -3-methyl-phenoxy-triisopropyl-silane Step A: 4- (5,5-dimethyl-1-yl) 3,2-dioxaborinan-2-yl-3-methyl-phenol 4.675 g of (4-hydroxy-2-methyl-phenyl) -boronic acid (30.76 mmol), 3.204 of neopentyl glycol (32.9 mmol) Amberlyst 15H÷ and 150 ml of 2-Me-THF were stirred at RT under N 2 until no further conversion was observed.The mixture was then filtered through Celite and the filtrate was filtered. It was concentrated under reduced pressure to give 4- (5,5-dimethyl-1,3,2-dioxaborinan-2-yl) -3-methyl-phenol 1H NMR (400MHz, CDCl3) δ: 7.64 (m.p. or, 1H), 6.60 (nl, 2H), 5.23 (s wide, 1H), 3.75 (s, 4H), 2.47 (s, 3H), 1.01 (s, 6H) Step B: [4- (5,5-Dimethyl-1,3,2-dioxaborinan-2-yl) -3-methylphenoxy] -triisopropyl silane 30.76 mmol 4- (5,5-dimethyl) -1,3,2-dioxaborinan-2-yl) -3-methyl-phenol, 8.56 ml TIPSCI (40 mmol) and 4.19 g irnidazole (61.52 mmol) were dissolved in 100 ml of DCM and stirred at RT under a N2 atmosphere until no further conversion. The imidazolium hydrochloride was removed by filtration, the filtrate was concentrated under reduced pressure and purified by flash chromatography using heptane and EtOAc as eluents to obtain Preparation B6. NMR (400 MHz, CDCl3) δ: 7.62 (d, 1H), 6.68-6.66 (nl, 2H), 3.76 (s, 4H), 2.47 (s, 3H), 1.32-1.21 (m, 3H), 1.11 (d, 18H), 1.03 (s, 6H). Preparation B7: 2- (3-bromo-2-methyl-phenyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane 2,362 g of 2,6-dibromo-toluene (9.45 mmol) ) were dissolved in 10 ml of anhydrous THF under an N 2 atmosphere and the mixture was cooled to -78 ° C. Then, 5.2 ml of BuLi (2.0M in pentane, 10.4 mmol) was added dropwise and the mixture was stirred for 15 minutes. isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (11.3 mmol) was added dropwise and the mixture was allowed to warm to RT. The mixture was inactivated with aqueous NH4Cl solution and then extracted with EtOAc.The combined organic phase was dried over Na2SO4, filtered and dried. the filtrate was concentrated under reduced pressure The crude product was purified by flash chromatography using heptane and EtOAc as eluents to obtain Preparation B7 NMR (400 MHz, CDCl3) δ: 7.67 ( d, 1H), 7.62 (d, 1H), 7.10 (t, 1H), 2.53 (s, 3H), 1.29 (s, 12H).
[0075] Preparation C1: (2-Ethoxypyrimidin-4-yl) methanol Step A: 4- (dimethoxymethyl) -2-ethaxy-pyrimidine 1500 mg Preparation 8b (6.46 mmol) was dissolved in 60 ml ethanol, followed by 10 527 ml. mg sodium ethoxide (7.75 mmol) was added and the mixture was stirred at RT for 1 hour. The volatiles were evaporated under reduced pressure and the residue was purified by flash chromatography using heptane and EtOAc as eluents to give 4- (dimethoxymethyl) -2-ethoxy-pyrimidine. MS (M + H): 199.2.
[0076] Step B: (2-Ethoxypyrimidin-4-yl) methanol Following general procedure Va and taking 4- (dimethoxymethyl) -2-ethoxy-pyrimidine as the appropriate acetal, Preparation C1 was obtained. MS (M + H): 155.2.
[0077] Preparation C2: (1-Butyl-1H-pyrazol-5-yl) methanol Following the general procedure Vb and taking 1-butylpyrazole as the appropriate alkylpyrazole, Preparation C2 was obtained. 1 H NMR (400 MHz, DMSO-d 6) 3: 7.30 (d, 1H), 6.12 (d, 1H), 5.23 (t, 1H), 4.49 (d, 25H), 4, Δ (t, 2H), 1.72 (m, 2H), 1.26 (m, 21-1), 0.88 (t, 3H). MS (M + H): 155.2. Preparation C3: [2- (2-Methoxyphenyl) pyrimidin-4-yl] methanol Step A: 4- (dimethoxymethyl) -2- (2-methoxyphenyl) -pyrimidine Following general procedure Vc and taking the sodium salt. 2-methoxybenzamidine acetic acid as the appropriate amidine salt, 4- (dimethoxymethyl) -2- (2-methoxyphenyl) pyrimidine was obtained. 1 H NMR (400 MHz, DMSO-d 6) δ: 8.93 (d, 1H), 7.55-7.44 (m, 3H), 7.16 (d, 1H), 7.06 (m.p. 1), 5.31 (s, 1H), 3.76 (s, 3H), 3.37 (s, 6H). Step B: [2- (2-Methoxyphenyl) pyrimidin-4-yl] methanol 261 mg of 4- (dimethoxymethyl) -2- (2-methoxyphenyl) -pyrimidine (1.00 nunol) were dissolved in 2 ml of HCl. in dioxane (4M solution), then 2 ml of water was added and this mixture was stirred at 50 ° C. for 16 hours The reaction mixture was cooled to 0 ° C. and then 320 mg of NaOH (8.0 mmol) was added portionwise The pH was adjusted to 8 using 10% aqueous K 2 CO 3, then 76 mg of sodium borohydride (2.0 mmol) was added and The mixture was stirred for 30 minutes at 0 ° C. The reaction mixture was diluted with 5 ml of water and extracted with EtOAc.The combined organic phases were dried over Na 2 SO 4, filtered and the filtrate was filtered. concentrated under reduced pressure The crude product was purified by flash chromatography using heptane and EtOAc as eluents for Preparation C3 NMR 111 (400 MHz, DMSO-d6) δ: 8.84 (d, 1H), 7.50-7.42 (m, 3H), 7.14 (d, 1H), 7, 03 (m, 1H), 5.66 (t, 1H), 4.58 (d, 2H), 3.75 (s, 3H). Preparation C4: (1-tert-butyl-1H-pyrazol-5-yl) methanol Step A: 1-tert-butyl-5- (dimethoxymethyl) -1H-pyrazole Following the general procedure Vd and taking the hydrochloride salt. butylhydrazine as the appropriate hydrazine hydrochloride, 1-tert-huty1-5- (dimethoxymethyl) -1H-pyrazole was obtained. NMR11-1 (400MHz, DMSO-d6) δ: 7.34 (d, 1H), 6.34 (d, 1H), 5.74 (s, 1H), 3.24 (s, 61-1); , 1.57 (s, 9H).
[0078] Note: 1-tert-butyl-3- (dimethoxymethyl) -1H-pyrazole was also obtained. 1 H NMR (400 MHz, DMSO-d 6) δ: 7.75 (d, 1H), 6.18 (d, 1H), 5.34 (s, 1H), 3.24 (s, 6H); , 1.50 (s, 9H). Step B: (1-tert-butyl-1H-pyrazol-5-yl) methanol Following general procedure Ve and taking 1-tert-butyl-5- (dimethoxymethyl) -1H-pyrazole as the appropriate acetal, the Preparation C4 was obtained. 1H NMR (400MHz, DMSO-d6) 7.27 (d, 1H), 6.19 (d, 1H), 5.31 (t, 1H), 4.61 (d, 2H), 1.56 (b.p. s, 9H). Preparation C5: [2- (2-Methoxyethyl) pyrimidin-4-yl] ethanol Step A: 4- (dimethoxymethyl) -2- (2-methoxyethyl) pyrimidine Following general procedure Vc and taking 3-chlorohydrate. methoxypropanamidine as the appropriate amidine hydrochloride, 4- (dimethoxymethyl) -2- (2-methoxyethylpyrimidine) was obtained: 1H NMR (400MHz, DMSO-d6) 8: 8.78 (d, 1H), 7.38; (d, 1H), 5.25 (s, 1H), 3.80 (t, 2H), 3.33 (s, 6H), 3.22 (s, 3H), 3.11 (t, 2H); Note: 2- [4- (Dimethoxymethylpyrimidin-2-yl) -N, N-dimethylethanamine was also obtained, MS (M + H): 226.2.
[0079] Step B: 12- (2-Methoxyethyl) pyrimidin-4-yl] methanol In. following the general procedure Va and taking 4- (dimethoxymethyl) -2- (2-methoxyethyl) pyrimidine as the appropriate acetal, Preparation C5 was obtained NMR11 (400 MHz, DMSO-d6): 8.70 (d, 1H) ), 7.39 (d, 1H), 5.60 (t, 1H), 4.52 (d, 2H), 3.78 (t, 2H), 3.22 (s, 3H), 3.06 (t, 2H).
[0080] Preparation C6: [1- (2,2,2-trifluoroethyl) -1H-pyrazol-5-yl] methanol Step A: 5- (Dimethoxymethyl) -1- (2,2,2-trifluoroethyl) -4,5-dihydro- 1H-pyrazol-5-ol Following the general procedure Vd in the absence of sodium methoxide and taking ethanol instead of methanol and 2,2,2-trifluoroethylhydrazine (70% w / w) in water) as the appropriate hydrazine, 5- (dimethoxymethyl) -1- (2,2,2-trifluoro-ethyl) -4,5-dihydro-1H-pyrazol-5-ol was obtained. MHz, DMSO-d6): 6.83 (t, 1H), 6.03 (s, 11-I), 4.30 (s, 1H), 3.95 (m, 1H), 3.47 ( or, 1H), 3.40 (d, 61-1), 2.88 (m, 1H), 2.50 (m, 1H) Step B [1- (2,2,2) -trifluoroethyl) -1H-pyrazol-5-ylmethanol Following the general procedure Ve and taking 5- (dimethoxymethyl) -1- (2,2,2-trifluoromethyl) -4,5-dihydro-1H-pyrazol-5 As the appropriate acetal, Preparation C6 was obtained: 1H NMR (400MHz, DMSO-d6) δ: 7.48 (d, 1H), 6.27 (d, 1H), 5.46 (t, 1H). ), 5.08 (q, 2H), 4.56 (d, 21-1) Preparation C7: (2- (Morpholin-4-apyrimidin-4-yl) -methanol Step A: 4- [4- (N-Methoxymethyl) pyrimidin-2-yl] kinoipholine 25.0 g Preparation 8b ( 107.6 mmol) were dissolved in 161 ml of morpholine and the mixture was stirred at RT until no further conversion was observed. Then, it was concentrated under reduced pressure and the crude product was purified by flash chromatography using heptane and EtOAc as eluents to obtain 4 [4- (dimethoxy-methyl) pyrimidin-2-yl ] morpholine.
[0081] Step B (2- (morpholin-4-yl) peimidin-4-acethanol Following General Procedure Va and taking 4- [4- (dimethoxymethyl) pyrimidin-2-yl] morpholine as the appropriate acetal, Preparation C7 RIVIN (400 MHz, DMSO-d6) 5: 8.35 (d, 1H), 6.75 (dm, 1H), 5.431 (t, 1H), 4.36 (dm, 2H), were obtained. 3.67 (nl, 4H), 3.63 (m, 4H) Preparation C8: 12- (2,2,2-Trifluoroethoxy) pyrimidin-4-ylmetbanol Step A. 4- (ditethoxymethyl) -2- (2H) 2,2-trifluoroethoxy) pylinidine 5.00 g of Preparation 8b (21.5 mmol) were dissolved in 54 ml of anhydrous acetonitrile followed by 5.95 g of K2CO3 (43.1 mmol) and 24 g of 2,2,2-trifluoroethanol (32.3 mmol) was added, and the mixture was stirred at 60 ° C until no further conversion was observed. The solid was filtered, washed with EtOAc, the filtrate was concentrated under reduced pressure, and the crude product was purified by flash chromatography. reading heptane and EtOAc as eluents to give 4- (dimethoxymethyl) -2- (2,2,2-trifluoroethoxy) pyrimidine. 1H NMR (400 MHz, DMSO-d6): 8.74 (d, 1H), 7.32 (d, 1H), 5.25 (s, 1H), 5.05 (b.p. q, 2H), 3.34 (s, 6H). Step 11: 12- (2,2,2-Trifluoroethoxy) pyrimidin-4-ylkmethanol Following general procedure Va and taking 4- (dimethoxymethyl) -2- (2,2,2-trifluoroethoxy) -pyrimidine as acetal, Preparation C8 was obtained. NMR (400 MHz, DMSO-d6) δ: 8.65 (d, 1H), 7.32 (d, 1H), 5.69 (t, 1H), 5.02 (q, 2H), 4.51. (d, 2H).
[0082] Preparation C9: 12- (2-Fluorophenylpyrimidin-4-ylimethanol Step A: 2-Fluoro-N'-hydroxy-benzamidine A mixture containing 11.48 g of hydroxylamine hydrochloride (165 mmol), 13.87 g of NaHCO3 (165 mmol) and 120 ml of MeOH was allowed to stir at RT for 30 minutes Then 10 g of 2-fluorobenzonitrile (82.6 mmol) was added and the mixture was stirred at 75 ° C. The solvent was partially evaporated under reduced pressure, and the residue was filtered and washed with MeOH.The filtrate was concentrated under reduced pressure, then diluted with water and extracted with water. The combined organic phases were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give 2-fluoro-N'-hydroxybenzamidine Step B: 2-fluorobenzamidine 12.67 g 2-fluoro-N'-hydroxy-benzamidine (81.55 mmol) was dissolved in 300 ml of AcOH at 0 ° C. 9.24 ml of Ac 2 O (97.86 mmol) were added The mixture was stirred at RT until no further conversion was observed. Then, 630 mg of 10% Pd / C was added and the mixture was stirred under H 2 (4 bar) until no further conversion was observed. The mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to give 2-fluorobenzamidine acetate.
[0083] MS (M (free base) + H): 139.4. Step C: 4- (dimethoxymethyl) -2- (2-fluorophenyl) -pyrimidine Following general procedure Vc and taking 2efluorobenzamidine as the appropriate amidine, 4- (dimethoxymethyl) -2- (2-fluorophenyl) pyrimidine was obtained. MS (M + H): 249.2.
[0084] Step D: 12- (2-fluorophenyl) pyrimidin-4-ylitnethanol Following general procedure Va and taking 4- (dimethoxymethyl) -2- (2-fluorophenyl) pyrimidine as the appropriate acetal, Preparation C9 was obtained . MS (M + H): 205.2.
[0085] Preparation C10: 12-E2- (2-methoxyethoxy) phenyl-pyrimidin-4-yl] methanol Step A: N'-Hydroxy-2-methoxyethoxy-benzathidine 2 eq. Hydroxylamine hydrochloride was dissolved in MeOH Oral / n = 011 and then 2 eq. of NaHCO3 were added. The mixture was stirred at RT for 20 minutes, then 1 eq. 2-methoxyethoxy-benzonitrile were added and the mixture was stirred under reflux until no further conversion was observed. The MeOH was partially evaporated, the residue was filtered and the filtrate was concentrated under reduced pressure. The resulting N'-hydroxy-2- (2-methoxyethoxy) -benzamidine was used without further purification. 1H NMR (400MHz, CDCl3) δ: 9.48 (s, 1H), 7.45 (m, 1H), 7.34 (m, 1H), 7.08 (d, 1H), 6.94 (m.p. td, 1H), 5.65 (bs, 2H), 4.17 (m, 2H), 3.67 (m, 2H), 3.31 (s, 3H). MS (M + H): 211.2.
[0086] Step B: 2-methoxyethoxybenzamidine 8.22 g of N'-hydroxy-2- (2-methoxyethoxy) -benzamidine (39.1 mmol) was dissolved in 80 ml of AcOH at 0 ° C, then 43 ml of Ac 2 O (46.92 mmol) was added dropwise. The mixture was stirred at RT until no further conversion was observed. 575 mg of 10% Pd / C was added and the mixture was stirred under H 2 (4 bar) until no further conversion was observed. The mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to give 2- (2-methoxyethoxy) benzamidine acetate. MS (M + H): 195.2. Step C: 4- (Dimethoxymethyl) -2-p-methoxyethoxy-phenylkyrimidine Following general procedure Vc and taking 2- (2-methoxyethoxy) benzamidine acetate as the appropriate amidine salt, the 4 (dimethoxymethyl) -242-methoxyethoxy-phenylpyrimidine was obtained. NMR (400 MHz, CDCl3) δ: 8.92 (d, 1H), 7.55 (nl, 1H), 7.47 (m, 1H), 7.45 (m, 1H), 7.17 (d, 1H); , 1H), 7.08 (m, 1H), 5.29 (s, 1H), 4.12 (m, 2H), 3.57 (m, 2H), 3.36 (s, 6H), 3 , (S, 31-I). MS (M + H): 305.0.
[0087] Step D: 12- [4-Methoxy-2- (trifluoromethyl) phenyl] -pyrimidin-4-ylmethanol Following general procedure Va and taking 4- (dimethoxymethyl) -242-methoxyethoxy-phenyl-pyrimidine as the appropriate acetal, Preparation C10 was obtained.
[0088] NMR (400MHz, CDCl3) δ: 8.84 (cl, 1H), 7.53 (m, 1H), 7.47 (nl, 1H), 7.43 (m, 1H), 7.14 (dec. d, 1H), 7.05 (td, 1H), 5.64 (t, 1H), 4.58 (d, 2H), 4.11 (nl, 2H), 3.57 (m, 211), 3.21 (s, 3H). MS (M + H): 261.0.
[0089] Example 1: N-1 (5S ') - 543-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxy] phenyl} -6- (4-fluorophenyl) thieno 12.3 1-pyrimidin-4-yl-2-methoxy-D-phenylalanine and Example 2: N - [(5R ') - 5-13-chloro-2-methyl-412- (4-methylpiperazin-1-yl) ethoxy] p henyl) -6- (4-fluorophenyl) -thieno 12,3-d] pyrimidin-1-yl] -2-methoxy-D-phenylalanine Following general procedure VI and taking Preparation 7a as Suitable phenol derivative and methanol as the appropriate alcohol and then hydrolyzing the intermediate formed according to general procedure VII, Example 1 was obtained as the diastereoisomer eluted first. High resolution mass (FIRMS) calculated for C36H37ClFN5O4S: 689.2240, found: 345.6182 (M + 2H). Example 2 was obtained as the last eluted diastereoisomer. High resolution mass (HRMS) calculated for C36H37ClFN5O4S: 689.2240, found: 345.6185 (M + 2H).
[0090] Example 3: N-R5S ') -5- {3-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxyl-phenyl] -6- (4-fluorophenyl) -thieno [2,3] d) pyrimidin-4-yl-2 - [(1-methyl-1H-pyrazol-5-yl) methoxy] -D-phenylalanine Following General Procedure VI and taking Preparation 7ad2 as the appropriate phenol derivative and (2-methylpyrazol-3-yl) methanol as the appropriate alcohol, and then hydrolyzing the intermediate formed according to general procedure VII, Example 3 was obtained. High resolution mass (HRMS) calculated for C401-141CIFN7O4S: 769.2613, found: 385.6378 (M + 2H). Example 4: N-R5S ') - 5- (3-Chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxy] phenyl} -6- (4-fluorophenyl) thieno [2,3-d] pyrimidin-4-yl] -2-4 (2-ethoxypyrimidin-4-yl) methoxyl-Dphenylalin and Example 5: N-R5Ra) -5- (3) 1-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxy] -phenyl} -6- (4-fluoro-phenyl) -thi o [2,3-dipyrimidin-4-yl] - 2- [(2-Ethoxypyrimidin-4-yl) methoxy] -D-phenylalanine Following the general procedure VI and taking Preparation 7a as the appropriate phenol derivative and Preparation C1 as the appropriate alcohol, and then hydrolyzing the intermediate formed according to general procedure VII, a mixture of diastereoisomers was obtained which were separated by preparative reverse phase chromatography using 40 mM aqueous NH 4 OAc solution (pH = 4, adjusted with AcOH) and acetonitrile as eluents, Example 4 was obtained as the diastereoisomer first high resolution mass (HRMS) calculated for C42H43C1FN705S. 811.2719, found: 406.6417 (M + 2H). Example 5 was obtained as the diastereoisomer eluted last.
[0091] High resolution mass (HRMS) calculated for C42H43ClFN7O5S: 811.2719, found: 406.6436 (M + 2H). Example 6: 2-1 (1-Butyl-1H-pyrazol-5-yl) metboxyl-N-R5Sa) -5- {3-chloro-2-methyl-4- (4-methylpiperazin) 1-yl) ethoxylphenyl} -6- (4-fluorophenyl) thieno [2,3-d] pyrimidin4-ylFD-phenylalanine Following General Procedure VI and taking Preparation 7ad2 as the appropriate phenol derivative and Preparation C2 as alcohol, and then hydrolyzing the intermediate formed according to general procedure VII, Example 6 was obtained. High resolution mass (HRMS) calculated for C43f147ClFN7O4S: 811.3082, found: 406.6616 (M + 2H).
[0092] Example 7: N-R5S (,) - 543-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxyl-phenyl-6- (4-fluorophenyl) -thieno [2,3] -d] pyrimidin-4-yl-2-1 [2- (2-methoxy-phenyl) -pyrimidin-4-yl] -methyl-D-phenylalanine Following General Procedure VI and taking Preparation 7ad2 as the appropriate phenol derivative and Preparation C3 as the appropriate alcohol, and then hydrolyzing the intermediate formed according to General Procedure VII, Example 7 was obtained. High resolution mass (HRMS) calculated for C47H45ClFN7O5S: 873.2875, found: 437.6498 (M + 2H). Example 8: N-R5S ') - 5- (3-chloro-2-methyl-4- [2- (4-methylpiperazin-1-Aethoxyphenyl) -6- (furan-2-yl) -thieno [ 2,3-dipyrimidin-4-yl] -2-methoxy-D-phenylalanine and Example 9: N-1 (5R ') - 5- {3-ebloro-2-methyl-4- [2- (4-methylpiperazine 1-yl) ethoxy] phenyl} -6- (furan-2-yl) -thieno [2,3-d] pyrimidin-4-yl) -2-methoxy-D-phenylalanine Following the general procedure taking Preparation 4b as the appropriate 4-chloro-thieno [2,3-d] pyrimidine derivative and (2R) -2-amino-3- (2-methoxyphenyl) propanoic acid as the amino acid derivative Suitably, Example 8 was obtained as the diastereoisomer eluted first.High resolution mass (HRMS) calculated for C341-136CIN505S: 661.2126, found: 662.2203 (M + FI). was obtained as the diastereoisomer eluted last.
[0093] High resolution mass (HRMS) calculated for C341-136C1N5O5S: 661.2126, found: 662.2203 (M + H). Example 10: 2-Chloro-N45- {3-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxylphenyl} -6- (furan-2-yl) -thieno [2], 3pyrimidin-4-yl-D-phenylalanine, diastereoisomer 1 Following general procedure 1c and taking Preparation 4b as the appropriate 4-chloro-thieno [2,3-cflpyrimidine derivative and (2R) -2-acid. amino-3- (2-chlorophenyl) propanoic acid as the appropriate amino acid derivative, Example 10 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C331-133C12N5O4S: 665.1630, found: 666.1670 (M + H).
[0094] Example 11: 2-Carbamoyl-N45-13-chloro-2-methyl-412- (4-methylpiperazin-1-yl) ethoxylphenyl-6- (furan-2-yl) -thieno12,3-dipyrimidin-4-yl -D-Phenylalanine Step A: 5-13-Chloro-2-methyl-4- (4-methylpiperazin-1-yl) ethoxylphenyl-4-fluoro-6- (2-formyl) thieno [2,3-d] pyrimidine A The mixture containing 150 mg of Preparation 4b (0.3 mmol) and 380 mg of silver fluoride (3.0 mmol) in 6 ml of toluene was heated at reflux temperature for 3 hours and then cooled. to TA, and the inorganic components were removed by filtration The filtrate was concentrated under reduced pressure to obtain the crude product which was used in the next step without further purification.
[0095] Step B: Example 11 A mixture containing 316 mg of 543-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxy] phenyl] -4-fluoro-6- (2-furypthieno [2,3-d] pyrimidine ( 0.65 mmol), 271 mg of (2R) -2-amino-3- (2-carbamoylphenyl) propanoic acid (1.30 mmol) and 424 mg of Cs 2 CO 3 (1.30 mmol) in 6 ml of DMSO was allowed to stir at 40 ° C. for 30 minutes The mixture was diluted with water, the pH was adjusted to 5 with a 1M solution of Ha, and the mixture was extracted with DCM The organic phase was dried over Na 2 SO 4, filtered, and the filtrate was concentrated under reduced pressure The crude product was purified by reverse phase preparative chromatography using a 0.1% aqueous TFA solution, and acetonitrile as eluents The diastereoisomer eluted first was collected as Example 11. High resolution mass (HRMS) calculated for C34H35ClN6O5S: 674.2078, found: 675.2146 (M + H). Example 12: N-1 (54-5- {3-chloro-2-methyl-412- (4-methylpiperazin-1-yl) ethoxy] phenyl) -6- (furan-2-yl) -thieno [2, 3-4 pyrimidin-4-yl-2- (py-ridin-2-ylmethoxy) -D-phenylalanine and Example 13: N-R5R ') - 5-13-chloro-2-methyl-442- ( 4-methylpiperazin-1-yl) ethoxyl phenyl-6- (furan-2-yl) -thieno, 34-pyrimidin-4-yl] -2- (py-ridin-2-yl-ethoxy) -D - Phenylalanine Following general procedure 1c and taking Preparation 4b as the appropriate 4-chloro-thieno [2,3-d] pyrimidine derivative and Preparation A5 as the appropriate amino acid derivative, Example 12 was obtained in the form of the diastereoisomer eluted last. High resolution mass (HRMS) calculated for C39H39ClN6O5S: 738.2391, found: 370.1269 (M + 2H). Example 13 was obtained as the diastereoisomer eluted first.
[0096] High resolution mass (HRMS) calculated for C39H39ClN6O5S: 738.2391, found: 370.1263 (M + 2H). Example 14: N - [(5S) -5- (3-chloro-2-methyl-4-12- (4-methylpiperazin-1-yl) ethoxyl-phenyl} -6- (5-fluorofuran-2-ylthieno) , 3-inpyrimidin-4-yl-2-hydroxy-D-phenylalanine Step A: (2R) -2 - [[(5-yl) -5-p-chloro-2-methyl-4-P- (4) methylpiperazine-1-Aethoxyl-phenyl-6-iodothieno [2,3-d] pyrimidin-4-ylquininyl] -3- (2-hydroxyphenyl) propanoic acid Following general procedure 1c and taking Preparation 4a as a derivative. Of 2-amino-3- (2-hydroxyphenyl) propanoic acid, a mixture of diastereoisomers was separated by HILIC chromatography (2R) -2 - [[(5Sa) -5- [3-chloro-2-methyl-442- (4-methylpiperazinyl-1-yl) ethoxy] -phenyl] -6-iodo thieno [2,3-d] pyrimidin-4-yl] amino] -3- (2-hydroxyphenyl) propanoic acid was obtained as the last eluted diastereoisomer, MS (M + H): 708.0. 86- Step B Example 14 Following the general procedure Mb and in taking (2R) -2 - [[(5S ') - 5- [3-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxy] phenyl] -6-iodothiothoic acid [ 2,3-4-pyrimidin-4-yl-amino-3- (2-hydroxyphenyl) -propanoic acid as the appropriate 6-iodothieno [2,3-d] pyrimidine derivative and 2- (5-fluoro-2- fury1) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane as the appropriate boronic ester derivative, Example 14 was obtained. High resolution mass (HRMS) calculated for C33H33ClFN5O5S: 665.1875, found: 333.6012 (M + 2H).
[0097] Example 15: N - [(5R ') - 5- (3-Chloro-2-methyl) -4-12- (4-methylpiperazin-1-yl) ethoxy] -phenyl] -5- 2-fluoro-2-yl) thieno [2,3-d] pyrimidin-4-yl] -2-methoxy-D-phenylalanine and Example 16: N - [(5Sa) -5- (3-chloroalanine) 2-methyl-4- [2- (4-ethylpiperazin-1-yl) ethoxy] phenyl} -6- (5-fluorofuran-2-yl) thieno [2,3-d] pyrimid in-4-yl] -2-methoxy-D-phenylalanine Following the general procedure II) and taking Preparation 4c as the appropriate 4-chlorothieno [2,3-4 pyrimidine derivative and acid (2R) 2-amino-3- (2-methoxyphenyl) propanoic acid as the appropriate amino acid derivative, Example 15 was obtained as the last eluted diastereoisomer High resolution mass (HRMS) calculated for C34H35ClFN5O5S: 679 , 2031, found: 680,2100 (M + H) Example 16 was obtained as the diastereoisomer eluted first High resolution mass (HRMS) calculated for C34H35ClFN5O5S: 679.2031, found: 680.2092 ( M + H). Example 17: N-R5S ') - 5-13-Chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxylphenyl] -6- (5-fluorofuran-2-yl) thieno [ 2,3-d] pyrimidin-4-yl] -2- (2,2,2-trifluoroethoxy) -D-phenylalanine Step A: (2R) -2-11- (55cd-5-p-chloro-2) Methyl-4- [2- (4-methylpiperazin-1-yl) ethoxyl-phenyl] -6-iodothiotho [2,3-d] pyrimidin-4-yllaminol-3- (2-hydroxyphenyl) propartoate ethyl 876 mg of (2R) -24 [(5S, 7) -5- [3-chloro-2-methyl-4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl] -6 -iodothieno [2,3-d] pyrimidin-4-yl} amino-3 - (2-hydroxy-phenyl) propanoic acid (1.24 mmol) were dissolved in 5 ml of ethanol, followed by 0.05 ml of concentrated sulfuric acid was added and the mixture was stirred at 70 ° C for 2 hours. Then, the mixture was diluted with water, the pH was adjusted to 5 with 1M NaHCO 3 solution and the mixture was extracted with DCM. The organic phase was dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography using DCM and MeOH as eluents to give (2R) -2 - [[(5S ') - 543-chloro-2-methyl-442- (4-methylpiperazin) Ethyl ethoxy (ethoxy) phenyl] -6-iodothieno [2,3-d] pyrimidin-4-yl amino] -3,42-hydroxyphenyl) propanoate. MS (M + H): 736.1.
[0098] Step B: (2R) -2-11 (5S) -5-P-chloro-2-methyl-4-P- (4-methylpiperazin-1-yl) ethoxy] phenyl-6-iodothiothio [ Ethyl 2,3-dipyrimidin-4-yllamino] -3-12- (2,2,2-trilluoroethoxy) phenylpropanoate 648 mg of (2R) -2 - [[(5Sa) -543-chloro-2-methyl] Ethyl-4,42- (4-methylpiperazin-1-yl) -ethoxy] phenyl] -6-iodothieno [2,3-d] pyrimidamino] -3- (2-hydroxyphenyl) propanoate (0.alpha. 88 minol) were dissolved in 10 ml of DMF, then 415 mg of K2CO3 (3.00 mmol) and 348 mg of 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.50 mmol) were added at RT. . The mixture was stirred at 50 ° C for 5 hours. The reaction mixture was diluted with brine and extracted with DCM. The organic phase was dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography using DCM and methanol as eluents to give (2R) -2 - [[(5Sa) -5- [3-chloro-2-methyl] -benzene). Ethyl (4-methylpiperazin-1-yl) ethoxy] phenyl] -6-iodothiotho [2,3-dipyrimidin-4-yl] amino] -342- (2,2,2-trifluoroethoxy) phenyl] propanoate. MS (M + H): 818.1. Step C: Example 17 (2R) -2 - {[(5S ') - 5-Chloro-2-methyl-4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl] -6 Ethyl iodo [2,3-d] pyrimidin-4-yl] amino] -3- (2,2,2-trifluoroethoxy) phenyl] propanoate was hydrolyzed according to General Procedure VII to give the (2R) -2 - [[(5Sa) -5-Chloro-2-methyl-412- (4-methylpiperazin-1-yl) ethoxy] phenyl] -6-iodothieno [2,3-a] pyrimidin 4-yl] amino-3- (2,2,2-trifluoroethoxy) phenylpropanoic acid. This compound was used as the appropriate 6-iodothieno [2,3-d] pyrimidine derivative and converted to Example 17 according to the general procedure II1b, taking 2- (5-fluoro-2-furyl) -4 , 4,5,5-tetramethyl-1,3,2-dioxaborolane as the appropriate boronic acid derivative. High resolution mass (HRMS) calculated for C351-134ClF4N5O5S: 747.1905, found: 374.6006 (M + 2H).
[0099] Example 18: N - [(5Ra) -543-chloro-2-methyl-4-12- (4-methylpiperazin-1-yl) ethoxylphenyl) -6- (5-fluorofuran-2-Athieno) al pyrimidin-4-yl-2- (pyridin-2-yl-methoxy) -D-phenylalanine and Example 19: N-R5S ') - 5- (3-chloro-2-methyl-4- [2- ( 4-methylpiperazin-1-yl) ethoxy] phenyl} -6- (5-fluorofuran-2-yl) thieno [2,3-d] pyrimidin-4-yl] -2- (pyridin-2-ylmethoxy) D-phenylalanine Following general procedure 1c and taking Preparation 4c as the appropriate 4-chloro-thieno [2,3-Mpyrimidine derivative and Preparation A5 as the appropriate amino acid derivative, Example 18 was obtained as the diastereoisomer eluted first High resolution mass (HRMS) calculated for C39H38ClFN6O5S: 756.2296, found: 379.1230 (M + 2H) Example 19 was obtained as the diastereoisomer eluted last High resolution mass (HRMS) calculated for C39H38ClFN5O5S: 756.2296, found: 379.1230 (M + 2H) Example 20: N4 (54-5-13-c) 2-chloro-methyl-412- (4-methylpiperazin-1-yl) ethoxylphenyl} -6- (5-fluorofuran-2-ylthieno [2,3-d] pyrimidin-4-yl] -2 - [(1-methyl) 1H-pyrazol-5-yl) methoxy] -D-phenylalanine Following general procedure Mb and taking Preparation 5b as the appropriate 6-iodothieno [2,3-d] pyrimidine derivative and 2- ( 5-fluoro-2-furyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane as the appropriate boronic acid derivative, Example 20 was obtained. High resolution mass (HRMS) calculated for C38H39ClFN7O5S: 759.2406, found: 380.6271 (M + 2H).
[0100] Example 21: N-K5S1) -5- {3-chloro-2-methyl-4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl} -6- (5-fluorofuran-2) yl) thieno12,3-dipyrimidin-4-yl-2 - [(1-ethyl-1H-pyrazol-5-yl) metboxy] -D-phenylalanine Following general procedure Mb and taking Preparation 5c as a derivative of 6 suitable iodo-thieno [2,3-4pyrimidine and 2- (5-fluoro-2-furyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane as the appropriate boronic acid derivative Example 21 was obtained. High resolution mass (HRMS) calculated for C39H41ClFN7O5S: 773.2562, found: 387.6358 (M + 2H). Example 22: N-R5S ') - 5-13-Chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxylphenyl} -6- (5-fluorofuran-2-yl) thieno [2] , 3-dlpyrimidin-4-yl] -2 - [(2-ethoxypyrimidin-4-yl) methoxy] -D-phenylalanine Following general procedure 1c and taking Preparation 4c as a derivative of 4-chlorothieno [2]. Suitable 3-d] pyrimidine and Preparation A2 as the appropriate amino acid derivative, Example 22 was obtained as the diastereoisomer eluted last. High resolution mass (HRMS) calculated for C40H4ICIFN7O6S: 801.2512, found: 401.6326 (M + 211). Example 23: 2-1 (1-Butyl-1H-pyrazol-5-yl) methoxyl-N - [(5H-5- (3-chloro-2-methyl-4- [2- (4-methylpiperazin)] 1-yl) ethoxy] phenyl} -6- (5-fluorofuran-2-371) thieno [2,3-d] pyrimidin-4-yl-D-phenylalanine and Example 24: 2- [ (1-Butyl-1H-pyrazol-5-yl) methoxy] -Nf (54-5- (3-chloro-2-methyl-4-12- (4-methylpiperazin-1-yl) ethoxylphenyl} -6- ( 5-figtorofuran-2-yl) thieno [2,3-Mpyrimidin-4-yl-D-phenylalanine Following general procedure 1c and taking Preparation 4e as a derivative of 4-chloro-thieno [2,3-dlpyrimidine] and Preparation A3 as the appropriate amino acid derivative, Example 23 was obtained as the diastereoisomer eluted first.High resolution mass (HRMS) calculated for C411145C1FN7O5S: 801.2875, found: 401.6502 (M. Example 24 was obtained as the last eluted diastereoisomer o High resolution mass (HRIVIS) calculated for C41H45ClFN7O5S: 801.2875, found: 401.6505 (M + 2H). Example 25: N-R5Ra) -5-13-Chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxy-phenyl) -6- (5-lluorofuran-2-yl) thieno [ 2,3-d] [2- (2,2,2-trifluoro-ethoxy) pyrimidin-4-yl] methoxy) -D-phenylalanine and Example 26: N-R5S ') - 5- {3- chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxyl [en]] - 6- (5-fluorofuran-2-yl) thieno [2,3-4 pyrimid-4-yl] 2- (12- (2,2,2-Trifluoroethoxy) pyrimidin-4-yl] ethoxy-D-phenylalanine By following the general procedure 1c and taking Preparation 4c as a derivative of appropriate 4-chloro-thieno [2,3-cilpyrimidine and Preparation A8 as the appropriate amino acid derivative, Example 25 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C40H38ClF4N7O6S: 855.2228, found: 428.6181 (M + 2H).
[0101] Example 26 was obtained as the last eluted diastereoisomer. High resolution mass (HRMS) calculated for C401138C1174N706S: 855.2228, found: 428.6193 (M + 2H). Example 27: N-1 (5S0-5- {3-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxy] phenyl} -6- (5-fluorofuran-2-yl) thieno [2,3-d] pyrimidin-4-yl] -2- ([242-methoxyphenyl) pyrimidin-4-yl] methoxy] -D-phenylalanine Step A: (2R) -2-1 [(5S, ) -5-13-Chloro-2-methyl-4-12- (4-methylpiperazin-1-yl) ethoxyl-phenyl-6- (5-fluoro-27-trifluoro) thieno [2,3-d] pyrimidin-4-yllaminol- Ethyl 3- (2-hydroxyphenyl) propanoate 0.97 g of Example 14 (1.46 mmol) was dissolved in 15 ml of a solution of HCl (1.25 M in EtOH). The mixture was cooled to RT, neutralized with aqueous NaHCO 3, and the mixture was extracted with DCM The organic phase was dried over Na 2 SO 4, filtered, and stirred at 40 ° C. overnight. and the filtrate was concentrated under reduced pressure The residue was purified by flash chromatography using DCM and MeOH as eluents to give (2R) -2 - [[(5Sa) -543-chloro-2-methyl] 442- (4-meth ylpiperazin-1-yl) ethoxy] -phenyl] -6- (5-fluoro-2-furyl) thieno [2,3-d] pyrimidin-4-yl amino] -3- (2-hydroxyphenyl) ) ethyl propanoate. 1 H NMR (400 MHz, DMSO-d 6) δ: 9.48 (bs, 1H), 8.39 (s, 1H), 7.30 (s, 2H), 7.01 (td, 1H), 6 , 72 (d, 1H), 6.64 (t, 1H), 6.41 (d, 1H), 5.83 (m, 1H), 5.56 (t, 1H), 5.08 (d, 1H), 4.94 (m, 1H), 4.30 (t, 2H), 4.03 (m, 2H), 3.07 (dd, 1H), 2.81 (t, 2H), 2, 56 (bs, 4H), 2.36 (dd, 1H), 2.32 (bs, 4H), 2.14 (s, 3H), 1.91 (s, 3H).
[0102] MS (M + H): 694.2. Step B: Example 27 Following general procedure VI and taking (2R) -2 - [[(5S ') - 543-chloro-2-methyl-442- (4-methylpiperazin-1-ypethoxylphenyl) -6- Ethyl (5-fluoro-2-furyl) -thieno [2,3-d] pyrimidin-4-ylamino] -3- (2-hydroxyphenyl) -propanoate as the appropriate phenol derivative and the C3 preparation as a derivative of suitable alcohol and then hydrolyzing the intermediate formed according to general procedure VII, Example 27 was obtained High resolution mass (HRMS) calculated for C45H43ClFN7O6S: 863.2668, found: 432.6414 (M + 2H) Example 28: N-1 (5S ()) - 5- (3-Chloro-4- [2- (dimethylamino) ethoxy] -2-methylphenyl-6- (5-fluorofuran-2-one) Yl) thieno [2,3-d] pyrimidin-4-yl] -2-hydroxy-D-phenylalanine Step A: 2-12-Chloro4- [4-chloro-6- (57-fluoro-2-finyl) -thieno] Methyl-phenoxyl-N, N-dimethylethanamine Following general procedure Mb and taking Preparation 4e as appropriate 6-iodothieno [2,3-d] pyrimidine derivative and 2- (5-fluoro-2-furyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane as the appropriate boronic acid derivative, 242-chloro-444-chloro-6. (5-Fluoro-2-furyl) thieno [2,3-a] pyrimidin-5-yl-3-methyl-phenoxy] -N, N-dimethylethanamine was obtained. Step B: Example 28 Following general procedure Ib and taking 212-chloro-444-chloro-6- (5-fluoro-2-furyl) thieno [2,3-d] pyrimidin-5-yl-3- methyl-phenoxy-N, N-dimethylethanamine as the appropriate 4-chloro-thieno [2,3-d] pyrimidine derivative and 2-hydroxy-D-phenylalanine as the appropriate amino acid derivative, Example 28 was obtained as the diastereoisomer eluted last. High resolution mass (HRMS) calculated for C30H28ClFN4O5S: 610.1453, found: 611.1503 (M + H).
[0103] Example 29: N-R5S ') - 5- (3-chloro-2-methyl-4- [4- (4-methylpiperazin-1-yl) ethoxy] phenyl] -6- (thiophen-3-yl) -thieno [ 2,3-d] pyrimidin-4-yl-3-pyridin-2-yl-D-alanine and Example 30: N-R5Ra) -5- (3-chloro-2-methyl-442- ( 4-methylpiperazin-1-yl) ethoxylphenyl) -6- (thiophen-3-yl) thieno [2,34] pyrimidin-4-yl] -3-pyridin-2-yl-Da n in e 25 Following General procedure Ic and taking Preparation 4g as the appropriate 4-chloro-thieno [2,3-4pyrimidine derivative and (2R) -2-amino-3- (2-pyridyl) propanoic acid as the acid derivative amine, a mixture of diastereoisomers has been obtained. They were separated by preparative reverse phase chromatography using a 40 mM aqueous solution of NH4OAc (pH = 4, adjusted with AcOH) and acetonitrile as eluents. Example 29 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C32H33ClN6O3S2: 648.1744, found: 649.1811 (M + H). Example 30 was obtained as the last eluted diastereoisomer. High resolution mass (HRMS) calculated for C32H33ClN6O3S2: 648.1744, found: 649.1816 (M + H).
[0104] Example 31: N-R5R ') - 5- {3-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxylphenyl} -6- (thiophen-3-yl) thieno 2,3-dlpyrimidin-4-yl-3-eohexyl-Da and Example 32: N4 (54-5- {3-chloro-2-methyl-4- [2- (4-methylpiperazin)}; 1-yl) ethoxy] phenyl} -6- (thiophen-3-yl) -thieno [2,3-d] pyrimidin-4-yl] -3-eelohexyl-D-alanine Following the general procedure Tc and taking Preparation 4g as the appropriate 4-chloro-thieno [2,3-d] pyrimidine derivative and (2R) -2-amino-3-cyclohexylpropanoic acid as the appropriate amino acid derivative, 31 was obtained as the diastereoisomer eluted first.High resolution mass (HRMS) calculated for C33H40ClN5O3S2: 653.2261, found: 327.6194 (M + 211).
[0105] Example 32 was obtained as the diastereoisomer eluted last. High resolution mass (HRMS) calculated for C331-140CIN503S2: 653.2261, found: 327.6195 (M + 2H). Example 33: N-R5Ra) -5-13-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxyl-phenyl-6- (thiophen-3-yl) -thieno [2.3- d] pyrimidin-4-yl] -2-fluoro-D-phenylalanine and Example 34: N4 (5S ') - 543-chloro-2-methyl-4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl-6- (thiophen-3-yl) -thienof-2,3,4 / 1-pyrimidin-4-yl-2-fluoro-D-phenylalanine Following general procedure Ic and taking Preparation 4g as a 4-chloro-4-chloro derivative. thieno [2,3-d] pyrimidine and (2R) -2-amino-3- (2-fluorophenyl) propanoic acid as the appropriate amino acid derivative, Example 33 was obtained in the form of of the diastereoisomer eluted last. High resolution mass (HRMS) calculated for C33H33ClFN5O3S2: 665.1677, found: 666.1776 (M + H). Example 34 was obtained as the diastereoisomer eluted first.
[0106] High resolution mass (HRMS) calculated for C33H33ClFN5O3S2: 665.1677, found: 666.1766 (M + H) Example 35: N-1 (5H-5- {3-chloro-2-methyl) -4-12- (Morpholin-4-yl) ethoxylphenyl} -6- (thiophen-3-yl) -thieno [2,3-d] pyrimidin-4-yl] -3-pyridin-2-yl-D-alanine and Example 36: N-1 (5S ') - 5- {3-chloro-2-methyl-442- (morpholin-4-yl) ethoxylphenyl} -6- (thiophen-3-yl) thieno [2,3] -d] pyrimidin-4-yl] -3-pyridin-2-yl-D-alanine Following General Procedure Ic and taking Preparation 4h as the appropriate 4-chloro-thieno [2,3-d] pyrimidine derivative and (2R) -2-amino-3- (2-pyridipopanoic acid as the appropriate amino acid derivative, Example 35 was obtained as the diastereoisomer eluted first.High resolution mass (HRMS) calculated for C3 1H30Cl2 → 1504S2: 635.1428, found: 636.1499 (M + H) Example 36 was obtained as the last eluted diastereoisomer High resolution mass (HRMS) calculated for C3 1H30ClN4O4S2: 635.1488, found: 636.1508 (M + H).
[0107] Example 37 2- (Aminomethyl) -N-R5Ra) -5- (3-chloro-2-methyl-442- (morpholin-4-yl) ethoxy] phenyl} -6- (thiophen-3-yl) thienol 2, 3-dipyrimidin-4-yl-D-phenylalanine and Example 38: 2- (Aminomethyl) -N-1 (5S ') - 543-chloro-2-methyl-442- (morpholin-4-yl) ethoxylphenyl (Thiophen-3-ylthio [2,3-Mpyrimidin-4-yl] -D-phenylalanine Following general procedure Ic and taking Preparation 4h as a derivative of 4-chlorothieno [2,3-d]). ] pyrimidine and (2R) -2-amino-3- [2 (aminomethyl) phenyl] propanoic acid as the appropriate amino acid derivative, Example 37 was obtained as the diastereoisomer eluted first. high resolution (HRMS) calcd for C33H34ClN4O482: 663.1741, found: 664.1808 (M + H).
[0108] Example 38 was obtained as the diastereoisomer eluted last. High resolution mass (HRMS) calculated for C33H34ClN4O4S2: 663.1741, found: 664.1825 (M + H). EXAMPLE 39: N-R5Sl-5- {3-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxy] phenyl} -6- (prop-1-yn) 1-yl) -thieno-py-rimid-4-yl] -2-m ethoxy-D-phenylalanine Following general procedure VI and taking Preparation 7b as the appropriate phenol derivative and methanol as a derivative of alcohol, and then hydrolyzing the intermediate formed according to general procedure VII, Example 39 was obtained. High resolution mass (HRMS) calculated for C33H36ClN4O4S: 633.2176, found: 317.6163 (M + 2H).
[0109] Example 40: 2 [(1-Fert -butyl-1H-pyrazol-5-yl) methoxyl-N - [(5S) -5- (3-chloro-2-methyl-4- [2- (4- methylpiperazin-1-yl) ethoxy [henyl] -6- (prop-1-yl-1-ylthieno [2,3-d] pyrimidin-4-yl-D-phenylalanine Following the procedure General VI and taking Preparation 7b as the appropriate phenol derivative and Preparation C4 as the appropriate alcohol derivative, and then hydrolyzing the intermediate formed according to General Procedure VII, Example 40 was obtained. HRMS) calcd for C 40 11 46 ClN 4 S 4: 755.3021 found: 378.6573 (M + 2H) Example 41: N - [(5Sa) -5- (3-chloro-2-methyl-4- [2- (4-methylpiperazine -1-yl) ethoxy] phenyl} -6- (prop-1-yn-1-yl) -thieno [2,3-d] pyrimidin-4-yl] -2-112- (2-methoxyethyl) pyrimidin-4-ylmethoxyl-D-phenylalanine Following General Procedure VI and taking Preparation 7b as the appropriate phenol derivative and Preparation C5 as the appropriate alcohol derivative and then hydrolysing the Intermediate formed according to general procedure VII, Example 41 was obtained. High resolution mass (HRMS) calculated for C 40 R 14 O 4 CIN 705 S: 769.2813, found: 385.6476 (M + 2H). Example 42: N-1 (55 ') - 5-13-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxy] -phenyl) -6- (p-p-p-1-yn) 1-yl) -thieno12,3-4 pyrimidin-4-yl] -2- {11- (2,2,2-trifluoroethyl) -1H-pyrazol-5-ylmethoxy) -D-phenylalanine Following the procedure General VI and taking Preparation 7b as the appropriate phenol derivative and Preparation C6 as the appropriate alcohol derivative, and then hydrolyzing the intermediate formed according to General Procedure VII, Example 42 was obtained. High resolution mass (HRMS) calculated for C381-139C1F31 ^ 1704S: 781.2425, found: 391.6300 (M + 2H).
[0110] Example 43: N-R5S (,) - 5- {3-Chloro-2-methyl-442- (4-methylpiperazitt-1-yl) ethoxy] phenyl-6- (prop-1-yn-1-yl) ) -thieno [2,3-dlpyrimidin-4-yl] -2 - ([2- (morpholin-4-yl) pyrimidin-4-yl] methoxy} -D-phenylalanine Following general procedure VI and taking the preparation 7b as the appropriate phenol derivative and Preparation C7 as the appropriate alcohol derivative and then hydrolyzing the intermediate formed according to general procedure VII, Example 43 was obtained High resolution mass (HRMS) calculated for C411-145CIN805S 796.2922, found: 399.1546 (M + 2H) Example 44: N - [(5S ') - 543-chloro-2-methyl-442- (4-methylpiperazin-1-yepethoxy) phenyl] 6- (prop-1-yn-1-yl) -thieno [2,3-dlpyrimidin-4-yl] -2- (12- (2,2,2-trifluoroethoxy) pyrimidin-4-ylmethoxy} -D-phenylalanine Following the general procedure VI and taking Preparation 7h as the appropriate phenol derivative and Preparation C8 as the appropriate alcohol derivative, and then hydrolyzing the Intermediate formed according to general procedure VII, Example 44 was obtained. High resolution mass (HRMS) calculated for C13Cl13C1F3N7O5S: 809.2374, found: 405.6262 (M + 2H). Example 45: N-R5S ') - 5- {3-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxyphenyl} -6- (prop-1-yn-1-yl) - thieno pyrimid-4-yl -2- {[2- (2-methoxypenyl) pyrimidin-4-yl] methoxy} -D-phenylalanin By following general procedure VI and taking the Preparation 7b as the appropriate phenol derivative and Preparation C3 as the appropriate alcohol derivative, and then hydrolyzing the intermediate formed according to General Procedure VII, Example 45 was obtained. High resolution mass (HRMS) calculated for C44H44ClN4O5S: 817.2813, found: 409.6494 (M + 2H). Example 46: N-R5S ') - 5- {3-chloro-442- (dimethylamino) -ethoxy] -2-methylphenyl} -6- (p rop-1-yn-1-yl} thieno [ 2,3-Di-pyrimidin-4-yl] -2 - {[1- (2,2,2-trifluoroethyl) -1H-pyrazol-5-yl] methoxyl-D-phenylalanine Following the general procedure VI and taking Preparation 7c as the appropriate phenol derivative and Preparation C6 as the appropriate alcohol derivative and then hydrolyzing the intermediate formed according to General Procedure VII, Example 46 was obtained High resolution mass (HRMS calcd for C35H34ClF3N6O4S: 726.2003, found: 727.2092 (M + H).
[0111] Example 47: N-R5S ') - 543-Chloro-4- [2- (dimethylamino) -ethoxy] -2-methylphenyl] -6- (prop-1-yn-1-yl) thieno [2,3-d] d] pyridin-4-yl] -2- ([2- (morpholin-4-yl) pyrimidin-4-yl] methoxy} -D-phenylalanine Following general procedure VI and taking Preparation 7c as a derivative of phenol and Preparation C7 as the appropriate alcohol derivative, and then hydrolyzing the intermediate formed according to general procedure VII, Example 47 was obtained.High resolution mass (HRMS) calculated for C381140C1N7O5S: 741.2500, found Mp: 371.6331 (M + 2H) Example 48: N-R5Sa) -5- {3-chloro-4-12- (dimethylamino) -ethoxyl-2-methylphenyl-6- (prop-1-yn) 1-yl) thieno [2,3-dlpyrimidin-4-yl] -2 - {[2- (2,2,2-trifluoroethoxy) pyrimidin-4-yl] methoxyl-D-phenylalanine Following general procedure VI and taking Preparation 7c as the appropriate phenol derivative and Preparation C8 as the appropriate alcohol derivative and then hydrolyzing the formed intermediate according to General Procedure VII, Example 48 was obtained. High resolution mass (HRMS) calculated for C36H34ClF3N6O58: 754.1952, found: 755.1971 (M + H). Example 49: N - [(5S) -5- {3-chloro-4- [1- (dimethylamino) -ethoxy] -2-methylphenyl} -6- (prop-1-yn-1-yl) thieno [2], 3-d] pyrimidin-4-yl-2 - ([2- (2-methoxyphenyl) pyrimidin-4-yl] methoxy) -D-phenylalanine Following General Procedure VI and taking Preparation 7c as a phenol derivative and Preparation C3 as the appropriate alcohol derivative, and then hydrolyzing the intermediate formed according to General Procedure VII, Example 49 was obtained. High resolution mass (HRMS) calculated for C411-139CIN605S: 762.2391, found: 371.6323 (M + 2H).
[0112] Example 50: N-R5S ') - 5- (3-chloro-442- (dimethylamino) -ethoxy-2-methylphenyl] -6- (4-fluorophenyl) thieno [2,3-Mpyrimidin-4-y] - [2- (2-Fluorophenyl) pyrimidin-4-yl] methoxy] -D-phenylalanine Step A: (2R) -2- [1-5-Bromo-6- (4-fluorophenyl) thiothi [2,3-d] Ethyl pyrimidin-4-yl] arninol-3-P-10 [12- (2-fluorophenyl) pyrimidin-1-ylmethoxylphenylpropyl) carbonate Following general procedure VI and taking Preparation 7d as the appropriate phenol derivative and the preparation. C9 as the appropriate alcohol derivative, (2R) -24 [5-bromo-6- (4-fluorophenylthieno [2,3-a] pyrimidin-4-yllamino] -342 - [[2- (2-fluorophenyl)] ethyl pyrimidin-4-yl] methoxylphenylpropanoate was obtained NMR (400 MHz, DMSO-d6) 3: 8.84 (d, 1H), 8.39 (s, 1H), 7.95 (td) , 1H), 7.58-7.52 (m, 3H), 7.39-7.24 (m, 8H), 7.13 (d, 1H), 6.95 (t, 1H), 5, 29-5.15 (m, 3H), 4.16 (q, 2H), 3.63 (dd, 114), 3.25 (dd, 1H), 1.19 (t, 3H), Step B: (2R) -2-11-5-P-ehloro-4- (2-dimethylaminoethyl-oxy) -2-methyl-ph nyll-6- (4 fhtorophényl 20) thieno [2,3-d] pyrimidin-4-yllatninol-3-P - [[2- (27fhtorophényl) -pyrimidin-4- ylJnéthoxy] ethyl phénylJpropanoate 1 eq. (2 / 0-24 [5-Bromo-6- (4-fluorophenylthieno [2,3-d] pyrimidin-4-yl] amino] -34- [[2- (2-fluorophenyl) -pyrimidin-4-yl] methoxy] phenyl] The ethyl propanoate and 1.2 eq of Preparation B5 were dissolved in dioxane (5 ml / mmol) followed by 5 mol% AtaPhos, 3 eq Cs 2 CO 3 and water (5 ml). / mmol) were added, and the mixture was stirred at 70 ° C under an argon atmosphere until no further conversion was observed, then the mixture was diluted with EtAOc and washed. The organic phase was dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure The crude product was purified by flash chromatography using DCM and MeOH as eluents to obtain (2R) 2 - [(543-Chloro-4- (2-dimethylaminoethyloxy) -2-methyl-phenyl] -6- (4-fluorophenyl) thieno [2,3-d] pyrimidin-4-yl] amino ] -342 [[2- (2-fluorophenyl) pyrimidin-4-yl] methoxy] phenyl] propanoate In the form of a mixture of diastereoisomers MS (M + H): 834.6. Step C: Example 50 Following General Procedure VII and taking (2R) -24 [513-chloro-4- (2-dimethylaminoethyloxy) -2-methyl-phenyl] -6- (4-fluorophenyl) thieno [2] Ethyl 3-cl! Pyrimidin-4-yl] amino] -3-12- [[2- (2-fluorophenyl) pyrimidin-4-yl] methoxy] phenyl] propanoate as the appropriate ester derivative. Example 50 was obtained as the diastereoisomer eluted last. High resolution mass (HRMS) calculated for C43H37ClF2N6O4S: 806.2254, found: 807.2343 (M + H). Example 51: N-R5S ') - 5- {3-chloro-41- [2- (dimethylamino) -ethoxy] -2-methylphenyl} -6- (4-fluorophenyl) thieno [2,3-d] pyrimidin 4-yl 2 - ({242- (2-methoxyethoxy) phenylipyrimidin-4-yl} methoxy) -D-phenylalanine Step A: (210-2-1f5-bromo-6- (4-fluorophenyl) thieno [2,3] Ethyl-dlpyrimidin-4-yl] amino] -3-12- [[2-p- (2-methoxy-ethoxy) phenyl] pyrimidin-4-ylmethoxylphenylpropanoate Following general procedure VI and taking Preparation 7d as the appropriate phenol derivative and Preparation C10 as the appropriate alcohol derivative, (2R) -2- [[5-bromo-6- (4-fluorophenyl) thieno [2,3-d] pyrimidin-4-yl] amin] -3424 [ Ethyl 24242-methoxyethoxy) -phenylpyrimidin-4-yl] methoxy] phenylpropanoate was obtained: NMR (400 MHz, DMSO-d6) δ: 8.80 (d, 1H), 8.41 (s, 114), 7.57-7.53 (m, 3H), 7.46-7.23 (in, 7H), 7.16 (d, 1H), 7.07 (d, 1H), 7.03 (t, 1H), 6.94 (t, 1H), 5.28-5.23 (m, 1H), 5.19 (dd, 2H), 4.18-4.11 (m, 4H), 3.61 -3.57 (in, 3H), 3.27 (dd, 1H), 3.21 (s, 3H), 1.19 (t, 3H).
[0113] Step B (2R) -2-11-5-13-Chloro-4- (2-Climethylaminoethyl-oxy) -2-methyl-phenyl] -6- (4-fluorophenyl) thieno [2,3-pyrimidin-4-yl] amin Ethyl 1,312-112-p- (2-methoxyethoxy) phenylpyrimidin-4-ylmethylphenylpropanoate 1 eq. (2R) -24 [5-Bromo-6- (4-fluorophenylthieno [2,3-cl] pyrimidin-4-yllaminol-3- [24 [242- (2-methoxyethoxy) phenyl] pyrimidin-4-ylmethoxy ] ethyl phenyl] propanoate and 1.2 eq of Preparation B5 were dissolved in dioxane (5 ml / mmol), then 5 mol% AtaPhos, 3 eq Cs2CO3 and water (5 ml). ml / mmol) was added, and the mixture was stirred at 70 ° C under an argon atmosphere until no further conversion was observed, then the mixture was diluted with water. EtOc and was washed with brine The organic phase was dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure The crude product was purified by flash chromatography using DCM and MeOH as eluents for obtain (2R) -24 [543-chloro-4- (2-dimethylaminoethyloxy) -2-methyl-phenyl] -6- (4-fluorophenyl) thieno [2,3-4 pyrimidin-4-yl] amino] -3- [24 [242- (2-methoxyethoxy) -phenyl] pyrimidin-4-yl] methoxylphenyl ethylpropanoate in the form of a mixture of diastereoisomers. MS (M-FH): 890.6.
[0114] Step C: Example 51 Following General Procedure VII and taking (2R) -24 [543-chloro-4- (2-dimethylaminoethyloxy) -2-methyl-phenyl] -6- (4-fluorophenyl) thieno [ Ethyl 2-, 3-4-pyrimidin-4-ylamino] -342-1 [242- (2-methoxyethoxy) -phenylpyrimidin-4-yl] methoxylphenylpropanoate as the appropriate ester derivative, Example 51 was obtained under the form of the diastereoisomer eluted last. High resolution mass (HRMS) calculated for C46H44ClFN6O6S: 862.2716, found: 432.1442 (M + 2H). Example 52: N-R5Ra) -5- (3,5-dichloro-4-hydroxy-2-methylphenyl) -6-ethylthieno [2,3-dipyridin-4-yl] -D-phenylalanine and Example 53 : N-RSS ') - 5- (3,5-dihydro-4-hydroxy-2-metlylplenyl) -6-ethylthieno [2,3-d] pyrimidin-4-yl] -D-phenylalanine Following general procedure VII and taking Preparation 7f as a suitable ester derivative, a mixture of diastereoisomers was obtained which were separated by reverse phase preparative chromatography using 0.1% aqueous TFA solution and acetonitrile as eluents. Example 52 was obtained as the diastereomer eluted first High resolution mass (HRMS) calculated for C24H21Cl2N3O3S: 501.0681, found: 502.0755 (M + H) Example 53 was obtained as of the diastereomer eluted lastly.High resolution mass (HRMS) calculated for C 2 Cl 2 Cl 2 N 2 O 3 S: 501.0681, found: 502.0772 (M + H) Example 54: N4 (5S ') - 5- {3, 5-diehloro-2- methyl-442- (4-methylpiperazin-lypethoxylphenyl-6-ethylthieno [2,3-d] pyrimidin-4-yl) -D-phenylalanine and Example 55: N4 (5Ra) -5- {3,5-dichloro-2 methyl-442- (4-methylpiperazin-1-ylethoxy) phenyl-6-ethylthieno [2,3-d] pyrimidin-4-yl) -ll-phenylalanine Following the general procedure VI and taking Preparation 7f as the appropriate phenol derivative and 2- (4-methylpiperazin-1-ypethanol as the appropriate alcohol derivative, and then hydrolyzing the intermediate formed according to General Procedure VII, Example 54 was obtained in the form of of the diastereoisomer eluted last. High resolution mass (HRMS) calculated for C 311-1135 C 12 N 5 O 3 S: 627.1838, found: 628.1935 (M + H). Example 55 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C31H35Cl2N5O3S: 627.1838, found: 628.1932 (M + H).
[0115] Example 56: N4 (5Sa) -513-chloro-4- (2-hydroxyethoxy) -2-methylphenyl] -6-ethylthieno12,3-dlpyrimidin-4-yl-D-phenylalanine Following general procedure VI and taking Preparation 701 as the appropriate phenol derivative and 10 eq. ethylene glycol as the appropriate alcohol derivative, and then hydrolyzing the intermediate formed according to general procedure VII, Example 56 was obtained. High resolution mass (HRMS) calculated for C26H26ClN3O4S: 511.1333, found: 512.1390 (M + H). Example 57: N - {(5S ') - 544- (carboxymethoxy) -3-chloro-2-methylphenyl] -6-ethylthieno [2,3-d] pyrimidin-4-yl) -D-phenylalanine 25 Following the general procedure VI and taking Preparation 7gd1 as the appropriate phenol derivative and 2-hydroxy-N, N-dimethylacetamide as the appropriate alcohol derivative, and then hydrolyzing the intermediate formed according to General Procedure VII, Example 57 was obtained. High resolution mass (HRMS) calculated for C261124ClN305S: 525.1115, found: 526.1127 (M + H). Example 58: N - ((5H-5- (3-chloro-442- (dimethylamino) ethoxyl-2-methylphenyl) -6-ethylthieno [2,3-dlpyrimidin-4-yl] L-phenylalanine and Example 59: N4 (54-5-13-Chloro-4- [2- (dimethylamino) ethoxy] -2-methylphenyl] -6-ethylthieno [2,3-d] pyrimidin-4- y1) -L-phenylalanine Following general procedure VI and taking Preparation 7g as the appropriate phenol derivative and 2- (dimethylamino) ethanol as the appropriate alcohol derivative and then hydrolyzing the intermediate formed according to General Procedure VII A mixture of diastereoisomers was obtained which were separated by preparative reverse phase chromatography using 40 mM aqueous NH40Ac (pH = 4, adjusted with AcOH) and acetonitrile as eluents. Example 58 was obtained as the diastereoisomer eluted first.High resolution mass (HRMS) calculated for C28H31ClN4O3S: 538.1805, found: 539.1869 (M + H). mple 59 was obtained as the diastereoisomer eluted last.
[0116] High resolution mass (HRMS) calculated for C281-131ClN403S: 538.1805, found: 539.1866 (M + H). Example 60: N4 (5S ') - 5- (3-Chloro-4- [3- (dimethylamino) propoxy] -2-methylphenyl] -6-ethylthieno [2,3-di] pyrimidin-4-yl ) -D-phenylalone Following general procedure VI and taking Preparation 7gd1 as the appropriate phenol derivative and 3- (dimethylamino) propanol as the appropriate alcohol derivative, and then hydrolyzing the intermediate formed according to the procedure General VII, Example 60 was obtained. High resolution mass (HRMS) calculated for C291133CIN4O3S: 552.1962, found: 553.2036 (M + H).
[0117] Example 61: N4 (54-5- {3-chloro-2-methyl-442- (morpholin-4-yl) ethoxylphenyl} -6-ethylthieno [2,3-dipyrimidin-4-yl] -D-phenylalanine following General Procedure VI and taking Preparation 7gd1 as the appropriate phenol derivative and 2-morpholinoethanol as the appropriate alcohol derivative, and then hydrolyzing the intermediate formed according to General Procedure VII, Example 61 was obtained. High resolution mass (HRMS) calculated for C301-133ClN4O4S: 580.1911, found: 581.1981 (M + H). Example 62: N4 (5S ') - 5- (3-Chloro-2-methyl-4-12- (4-methylpiperazin-1-yl) ethoxylphenyl] -6-ethylthieno [2,3-d] pyrimidin 4-yl) -D-phenylalanine and Example 63: N - ((5Ra) -543-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxy] phenyl] -6-ethylthieno [ 2,3-d] pyrimid-4-yl) -D-phenylalanine Following the general procedure VI and taking Preparation 7g as the appropriate phenol derivative and 2- (4-methylpiperazin-1-yl) ethanol. As a suitable alcohol derivative, and then hydrolyzing the intermediate formed according to general procedure VII, Example 62 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C 311-116 C N 50 S: 593.2227, found: 594.2313 (M + H). Example 63 was obtained as the diastereoisomer eluted last. High resolution mass (HRMS) calculated for C 311-116ClN 503S: 593.2227, found: 594.2304 (M + H).
[0118] Example 64 N4 (5S ') - 5- (3-Chloro-2-methyl-443- (4-methylpiperazin-1-yl) propoxy] phenyl] -6-ethylthieno [2,3-d] ppimidin-4- y1) -D-phenylalanine Following general procedure VI and taking Preparation 7gd1 as the appropriate phenol derivative and 3- (4-methylpiperazin-1-yl) propan-1-01 as the appropriate alcohol derivative, then by hydrolyzing the intermediate formed according to general procedure VII, Example 64 was obtained. High resolution mass (HRMS) calculated for C32H35ClN4O3S: 607.2384, found: 608.2444 (M + H). Example 65: N4 (5S) -5-13-chloro-2-methyl-412- (4-methylpiperazin-1-yl) ethoxylphenyl} -645- (methoxy-carbonyl) -4-methylfuran-2 -Litthieno [2,3-d] pyrimidin-4-yl) -2-methoxy-D-phenylalanine and Example 66: N4 (5R ') - 5-13-chloro-2-methyl-4- [ 2- (4-methylpiperazin-1-yl) ethoxy] phenyl} -6- [5- (methoxy-r-onyl) -4-methylfuran-2-yl] thieno [2,3-d] pyrimidin - 4-yl) -2-methoxy-D-phenylalanine Step A: 14-Chloro-5-p-chloro-2-methyl-4-12- (4-methylpiperazin-1-yl) ethoxylphenylthieno [2,3 pyrrolidin-6-yl-trimethylstannane 1.97 g of 4-chloro-543-chloro-2-methyl-412- (4-methylpiperazin-1-yl) ethoxylphenyl-thieno [2,3-d] pyrimidine ( 4.50 mmol, obtained in step A of Preparation 4a) was dissolved in 40 ml of anhydrous THF under an N 2 atmosphere, and the mixture was cooled to -78 ° C. Then, 4.5 ml of LDA (9 mmol, 2M solution in heptane, THF and ethylbenzene) was added and the mixture was stirred at -78 ° C for 1 hour. Then, 13.5 ml of a solution of Me3SnCl (13.5 mmol, 1M in hexane) was added and the mixture was allowed to warm to RT. The mixture was then diluted with a solution of NH 4 Cl and extracted with diethyl ether. The organic phase was dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Then, it was dissolved in 60 ml of EtOAc, and 40 ml of saturated NaF solution was added, and the mixture was stirred at RT overnight. Then it was filtered and the filtrate phases were separated. The aqueous phase was extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography using DCM and MeOH as eluents to give [4-chloro-5- [3-chloro-2-methyl-442- (4-methyl-piperazin-1-yl) ethoxy] phenyl] thieno [2,3-d] pyrimidin-6-yl) trimethyl-stannane. High resolution mass (HRMS) calculated for C23H30N4OSCl2Sn: 600.0539, found: 601.0584 (M + H).
[0119] Step B: 5- [4-Chloro-5- [3-chloro-2-methyl-4- [2- (4-methylpiperazin-1-yl) ethoxylphenylthieno [2,3-d] pyrimidin-6-yl] -3 methylmethylfuran-2-carboxylate 900 mg [4-chloro-543-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxy] phenyl] thieno [2,3-d] pyrimidin 6-yl] trimethyl-stannane (1.50 mmol), 657 mg of methyl 5-bromo-3-methyl-furan-2-carboxylate (3 mmol), 29 mg of CuI (0.15 mmol), 29 mg of Pd (PhCN) 2 Cl 2 (0.075 mmol), 46 mg of Ph 3 As (0.15 mmol) and 2 ml of NMP were stirred at 100 ° C. until no further conversion was observed. The aqueous phase was extracted with EtOAc, the combined organic phases were dried over Na2SO4, filtered and the filtrate was concentrated. The crude product was purified by flash chromatography using DCM and MeOH as eluents to obtain 5 [4-chloro-5 [3-chloro-2-methyl-4- [2- (4-methylpiperazin-1-yepethoxy] phenyl] thieno [2,3-d] pyrimidin-6-yl} - Methyl 3-methyl-furan-2-carboxylate. High resolution mass (HRMS) calculated for C27t128Cl2N4O4S: 574.1208, found: 575.1263 (M + H). Step C: Example 65 Following general procedure 1b and taking 544-chloro-543-chloro-2-methyl-442- (4-methylpiperazin-1-ylethoxy) phenyl] thieno [2,3-d] pyrimidine Methyl-6-yl] -3-methyl-furan-2-carboxylate as the appropriate 4-chloro-thieno [2,3-d] pyrimidine derivative and (2R) -2-amino-3- (2-methoxyphenyl) - ) propanoic acid as a suitable amino acid derivative, Example 65 was obtained as the diastereoisomer eluted first.High resolution mass (HRMS) calculated for C 371-140ClN 507S: 733.23369, found: 367.6263 (M. + 2H) Example 66 was obtained as the last eluted diastereoisomer High resolution mass (HRMS) calculated for C37H40ClN5O7S: 733.23369, found: 367.6223 (M + 2H).
[0120] Example 67: N- [6-ethyl-5- (5-hydroxy-2-methylphenyl) -thieno [2,3-d] pyrimidin-4-yl) -phenylalanine Following general procedure IId and taking Preparation 3a as a derivative of 5-iodo-thieno [2,3-d] pyrimidine and 2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol as As a suitable boronic acid derivative, Example 67 was obtained as a mixture of diastereoisomers. High resolution mass (HRMS) calculated for C24H23N3O3S: 433.1460, found: 434.1545 and 434.1535 (M + H). Example 68: N- [6-ethyl-5- (3-fluoro-2-methylphenyl) -thieno [2,3-4-pyrimidin-4-yl] -phenylalanine Following general procedure 11a and taking Preparation 3a as the appropriate 5-iodo-thieno [2,3-abyrimidine derivative and (3-fluoro-2-methyl-phenyl) boronic acid as the appropriate boronic acid derivative, Example 68 was obtained. in the form of a mixture of diastereomers. High resolution mass (HRMS) calculated for C24H22FN3O2S: 435.1417, found: 436.1489 and 436.1484 (M + H).
[0121] Example 69: N- [6-ethyl- (5S) -5- (3-fluoro-2-methyl-phenylthieno [2,3-d] pyrimidin-4-yl] -D-phenylalanine and Example 70: N46-ethyl- (5-O-5- (3-fluoro-2-methyl-phenyl) thieno [2,3-d] pyrimidin-4-ad-phenylalanine The diastereoisomers of Example 68 were separated by preparative reverse phase chromatography using an aqueous solution of 25 mM NH4HCO3 and acetonitrile as eluents Example 69 was obtained as the diastereoisomer eluted first High resolution mass (HRMS) calculated for C241-122FN302S: 435.1417, found: 436.1481 (M + H).
[0122] Example 70 was obtained as the last eluted diastereoisomer. High resolution mass (HRMS) calculated for C24H22FN3O2S: 435.1417, found: 436.1498 (M + H) Example 71: N-16-ethyl-5- (1H-indol-7-yl) thieno-12,3-dipyrimidin 4-yl-D-phenylalanine, diastereoisomer 1 and Example 72: N- [6-ethyl-5- (1H-indol-7-yl) thieno [2,3-d] pyrimidin-4-yl-D-phenylalanine, diastereoisomer Following the general procedure 11a and taking Preparation 3a as the appropriate 5-iodothieno [2,3-d] pyrimidine derivative and 7- (4,4,5,5-tetramethyl-1,3), 2- dioxaborolan-2-yl) -1H-indole as the appropriate boronic acid derivative, a mixture of diastereoisomers was obtained. They were separated by reverse phase preparative chromatography using an aqueous solution of 0.1% TFA and acetonitrile as eluents. Example 71 was obtained as the diastereoisomer eluted first.
[0123] High resolution mass (HRMS) calculated for C25H22N4O2S: 442.1463, found: 443.1540 (M + 11). Example 72 was obtained as the last eluted diastereoisomer. High resolution mass (HRMS) calculated for C25H22N4O2S: 442.1463, found: 443.1537 (M + H).
[0124] Example 73: N-16-ethyl- (5S ') - 5- (11-1-indol-4-Athieno [2,3-epyrimidin-4-yl] -D-phenylalanine and Example 74: N46-ethyl- ( 5R ') - 5- (1H-Indol-4-yl) thieno [2,3-d] pyrimidin-4-yl] -D-phenylalanine The diastereoisomers of Preparation 7h were separated by reverse phase preparative chromatography using an aqueous solution of 0.1% TFA and acetonitrile as eluents Example 73 was obtained as the diastereoisomer eluted first High resolution mass (HRMS) calculated for C25H22N4O2S: 442.1463, found: found: 443.1529 (M + H) Example 74 was obtained as the last eluted diastereoisomer High resolution mass (HRMS) calculated for C25H22N4O2S: 442.1463, found: 443.1538 (M + H) Example 75: N46-ethyl- (5Sa) -5- (3-methoxy-2-methyl-phenyl) thieno [2,3-d] pyrimidin-4-yl] -D-phenylalanine and Example 76: N - [6-ethyl- (5H-5- (3-methoxy-2-methyl-phenylthieno [2,3,4] pyrimidin-4-yl-D-phenylalan] By following the general procedure IIb and taking Preparation 3a as the appropriate 5-iodothieno [2,3-d] pyrimidine derivative and 2- (3-methoxy-2-methyltramethyl) -1,3,2 -dioxaborolane as the appropriate boronic acid derivative, using the 5: 1 DME / water mixture in place of 2-Me-THF, and separating the diastereoisomers by preparative reverse phase chromatography using 25% aqueous NH 4 HCO 3 solution. mM and acetonitrile as eluents, Example 75 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C25H25N3O3S: 447.1617, found: 448.1701 (M + H). Example 76 was obtained as the last eluted diastereoisomer. High resolution mass (HRMS) calculated for C25H25N3O3S: 447.1617, found: 448.1672 (M + H) Example 77: N-R5Ra) -5- (2-chloro-3-methylpyridin-4-yl) -6 ethylthieno [2,3-M-pyrimidin-4-yl] phenylalanine and Example 78: N-R5Sa) -5- (2-chloro-3-methylpyridin-4-yl) -6-ethylthieno [2,3-d] ] pyrimidin-4-yll-D-phenylalanine Following General Procedure IIb and taking Preparation 3a as the appropriate 5-iodothieno [2,3-d] pyrimidine derivative and 2-chloro-3-methyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine as the appropriate boronic acid derivative, using the 5: 1 DME / water mixture in place of the 2- Me-THF, and separating the diastereoisomers by reverse phase preparative chromatography using an aqueous solution of 0.1% TFA and acetonitrile as eluents, Example 77 was obtained as the diastereoisomer eluted as first. High resolution mass (HRMS) calculated for C231121 CINO: 452.1074, found: 453.1158 (M + H). Example 78 was obtained as the last eluted diastereoisomer. High resolution mass (HRMS) calculated for C23H21ICIN4O2S: 452.1074, found: 453.1165 (M + H). Example 79: N46-ethyl- (5S ') - 5- (naphthalen-1-ylthieno [2,3-d] pyrimidin-4-yl-D-phenylalanine Following general procedure IIb and taking Preparation 3a as a derivative of appropriate 5-iodothieno [2,3-d] pyrimidine and 4,4,5,5-tetramethyl-2- (1-naphthyl) -1,3,2-dioxaborolane as the appropriate boronic acid derivative, a mixture of of diastereoisomers was obtained, purified by reverse phase preparative chromatography using 0.1% aqueous TFA solution and acetonitrile as eluants, and Example 79 was obtained as a mixture of diastereoisomers.
[0125] High resolution mass (HRMS) calculated for C27H23N3O2S: 453.1511, found: 454.1580 and 454.1580 (M + H). Example 80: N46-Ethyl-5- (quinolin-5-371) thieno-12,3-d] pyrimidin-4-yl-Dp-enylalanine Using the general procedure Ha and taking Preparation 3a as a derivative suitable 5-iodo-thieno [2,3-d] pyrimidine and 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) quinolone as a derivative of boronic acid, a mixture of diastereoisomers was obtained. It was purified by reverse phase preparative chromatography using a 40 mM aqueous solution of NH40Ac (pH = 4, adjusted with AcOH) and acetonitrile as eluents. Example 80 was obtained as a mixture of diastereoisomers. High resolution mass (HRMS) calculated for C26H22N4O2S: 454.1463, found: 455.1554 and 455.1518 (M + H). Example 81: N- [6-ethyl- (5S) -5- (isoquinolin-4-yl) -thieno [2,3-t] pyrimidin-4-yl) -dphenylalanine and Example 82: N46-ethyl- (5Ra) -5- (isoquinolin-4-yl) -thieno-12,3-dlpyrimidin-4-yl-D-phenylalanine Step A: 4-Chloro-6-ethyl-5- (4-isoquinol) thieno [2,3-c] pyrimidine Following the general procedure IIc and taking Preparation 2a as a 5-iodothieno [2,3-d] pyrimidine derivative and 4- (4,4,5,5-tetramethyl) -1,3,2 As the appropriate boronic acid derivative, 4-chloro-6-ethyl-5- (4-isoquinolyl) thieno [2,3-4-pyrimidine was obtained. DMSO-d6) 3: 9.46 (s, 111), 8.93 (s, 1H), 8.50 (s, 1H), 8.26 (m, 11-I), 7.74 (m, 2H), 7.42 (m, 1H), 2.65 (q, 211), 1.14 (t, 3H).
[0126] High resolution mass (HRMS) calculated for C17ll12ClN3S: 325.0440; found 326.0502 (M + H). Step B: N [6-ethyl-5- (isoquinolin-4-yl) thieno [2,3-clipyrimidin-4-yl] -D-phenylalanine Following general procedure 1a, and taking the product from Step A as the appropriate 4-chloro-thieno [2,3-d] pyrimidine derivative and D-phenylalanine as the appropriate amino acid derivative, N46-ethyl-5- (isoquinolin-4-ylthieno [2,3-d] Pyrimidin-4-yll-D-phenylalanine was obtained as a mixture of diastereoisomers and was separated by reverse phase preparative chromatography using water and acetonitrile as eluents. Example 81 was obtained as the diastereoisomer eluted first High resolution mass (HRMS) calculated for C26H22N4O2S: 454.1463, found: 455.1526 (M + H).
[0127] Example 82 was obtained as the diastereoisomer eluted last. High resolution mass (HRMS) calculated for C26H22N4O2S: 454.1463, found: 455.1538 (M + H). Example 83: N46-ethyl- (5S ') - 5- (1-methyl-1H-indol-7-yl) thieno [2,3-d] pyrimidin-4-yl) D-phenylalanine and Example 84: N46 -ethyl- (5R ') - 5- (1-methyl-111-indol-7-yl) thieno [2,3-d] pyrimidin-4-yl] -diphenylalanine Following the general procedure Hb and taking the Preparation 3a as the appropriate 5-iodo-thieno [2,3-d] pyrimidine derivative and 1-methyl-7- (4,4,5,5-tetra-methyl-1,3,2-dioxaborolan-2-yl) ) indole as the appropriate boronic acid derivative, a mixture of diastereoisomers was obtained. They were separated by preparative reverse phase chromatography using a 40 mM aqueous solution of NH4OAc (pH = 4, adjusted with AcO11) and acetonitrile as eluents. Example 83 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C26H24N4O2S: 456.11620, found: 457.1671 (M + H). Example 84 was obtained as the diastereoisomer eluted last. High resolution mass (HRMS) calculated for C26H22N4O2S: 456.11620, found: 457.1701 (M + H).
[0128] Example 85: N- [6-ethyl- (5S ') - 5- (3-methyl-1H-in-4-yl) thieno [2,3-d] pyrimidin-4-yl] -D-phenylalanine and Example 86: N46-ethyl- (5R ') - 5- (3-methyl-1H-indol-4-yl) thieno [2,3-d] pyrimidin-4-yl] - D-Phenylalanine Following General Procedure IIc and taking Preparation 3a as the appropriate 5-iodothieno [2,3-d] pyrimidine derivative and 3-methyl-4- (4,4,5,5-tetra) 1-Methyl-1,3,2-dioxaborolan-2-yl) -1H-indole as the appropriate boronic acid derivative, a mixture of diastereoisomers was obtained. They were separated by preparative reverse phase chromatography using a 40 mM aqueous solution of NH40Ac (pH = 4, adjusted with AcOH) and acetonitrile as eluents. High resolution mass (HRMS) calculated for C26H24N4O2S: 456.11620, found: 457.1691 (M + H). Example 86 was obtained as the diastereoisomer eluted last. High resolution mass (HRMS) calculated for C26H24N4O2S: 456.11620, found: 457.1688 (M + H). Example 87: N46-Ethyl-5- (1-methyl-1H-indazol-4-yl) -thieno [2,3-d] pyrimidin-4-yl-D-phenylalanine Following general procedure IIa and taking Preparation 3a as the appropriate 5-iodo-thieno [2,3-d] pyrimidine derivative and 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2) -Dindazole as a suitable boronic acid derivative, Example 87 was obtained as a mixture of diastereoisomers High resolution mass (HRMS) calculated for C25H23N5O2S: 457.1572, found: 458.1646 and 458, 1648 (M + H) Example 88: N- [6-Etbyl- (5Sa) -5- (1-methyl-1H-indazol-7-yl) thieno [2,3-d] pyrimidin-4-yl) D-Phenylalanine 20 and Example 89: N- [6-ethyl- (5R ') - 5- (1-methyl-4H-indazol-7-yl) thieno [2,3-d] pyrimidin-4-yl) phenylalanine Following the general procedure Ha and taking Preparation 3a as the appropriate 5-iodothieno [2,3-d] pyrimidine derivative and (1-methylindazol-7-yl) boronic acid as the appropriate boronic acid derivative Example 88 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C25H23N2O2S: 457.1552, found: 458.1641 (M + H). Example 89 was obtained as the diastereoisomer eluted last. High resolution mass (HRMS) calculated for C25H23N2O2S: 457.1572, found: 458.1634 (M + H). Example 90: N-R5Sff) -5- (3-Chloro-4-hydroxy-2-methyl-phenyl) -6-ethylthieno [2,3-d] pyrimidin-4-yl] -D-phenyl- Alanine and Example 91: N - [(5R ') - 5- (3-Ethyl-4-hydroxy-2-methyl-phenyl) -6-ethylthieno [2,3-d] pyrimidin-4-yl] -D- phenyl-alanine 500 mg of Preparation 7e (1.12 mmol) and 157 mg of NCS (1.173 mmol) were dissolved in 30 ml of THF and the mixture was stirred at 60 ° C overnight. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography using heptane and EtOAc as eluents to obtain 2-1 [543-chloro-4-hydroxy-2-methylaphenyl] Methyl 6-ethyl-thieno [2,3-pyriimidin-4-yl-amino] -3-phenylpropanoate as a mixture of diastereoisomers (with other regioisomers). The crude mixture was hydrolysed according to general procedure VII. The diastereoisomers were purified and separated by reverse phase preparative chromatography using an aqueous solution of 25 mM NH4HCO3 and acetonitrile as eluents. Example 90 was obtained as the last eluted diastereoisomer. High resolution mass (HRMS) calculated for C24H22ClN3O3S: 467.1070, found: 468.1153 (M + H). Example 91 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C24H22ClN3O3S: 467.1070, found: 468.1143 (M + H). Example 92: N - [(5R ') - 5- (2,3-dichlorophenyl) -6-ethyl-thieno [2,3-ti] pyrimidin-4-34] -D-phenylalanine and Example 93: N - [( SSC 1) - 5- (2,3-dichlorophenyl) -6-ethyl-thieno [2,3-d] pyrimidin-4-yl-D-phenylalanine Following general procedure Ha and taking Preparation 3a as a derivative of Suitable 5-iodo-thieno [2,3-d] pyrimidine and (2,3-dichlorophenyl) boronic acid as the appropriate boronic acid derivative, using Xantphos instead of nBuPAd2, a mixture of diastereoisomers was obtained. They were separated by preparative reverse phase chromatography using 0.1% aqueous TFA and acetonitrile as eluents, and Example 92 was obtained as the diastereoisomer eluted first. . High resolution mass (HRMS) calcd for C31-119Cl2N3O2S: 471.0575, found: 472.0667 (M + H). Example 93 was obtained as the diastereoisomer eluted last. High resolution mass (HRMS) calculated for C23H19Cl2N3O2S: 471.0575, found: 5,472,0654 (M + H). Example 94: N-R5Ra) -5- (3,4-dichloro-2-methylphenyl) -6-ethylthieno [2,3-d] pyrimidin-4-yl-D-phenylalanine and Example 95: N-1 ( 5S, 7) -5- (3,4-dichloro-2-methylphenyl) -6-ethylthieno [2,3-d] pyrimidin-4-yl) D-phenylalanine Following general procedure IIb and taking Preparation 3a as a derivative of appropriate 5-iodothieno [2,3-d] pyrimidine and (3,4-dichloro-2-methyl-phenyl) boronic acid as the appropriate boronic acid derivative, using Xantphos as ligand instead of Q-Phos and the 4: 1 DME / water mixture in place of 2-Me-THF, a mixture of diastereoisomers was obtained. They were separated by reverse phase preparative chromatography using a 0.1% aqueous TFA solution and acetonitrile as eluents, and Example 94 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C241-121C12N3O2S: 485.0731, found: 486.0816 (M + H). Example 95 was obtained as the diastereoisomer eluted last. High resolution mass (HRMS) calculated for C241-121C12N3O2S: 485.0731, found: 486.0797 (M + H).
[0129] Example 96: N-1 (5R ') - 5- (3-bromo-2-methylphenyl) -6-ethylthieno [2,3-d] pyrimidin-4-yl-D-phenylalanine and Example 97: N- [ (5S ') - 5- (3-bromo-2-methylphenyl) -6-ethylthieno [2,3-d] pyrimidin-4-yl-D-phenylalanine Following the general procedure 11a and taking Preparation 3a as 5-iodo-thieno [2,3-d] pyrimidine derivative and Preparation B7 as the appropriate boronic acid derivative, a mixture of diastereoisomers was obtained. They were separated by reverse phase preparative chromatography using a 40 mM aqueous solution of NH4OAc (pH = 4, adjusted with AcOH) and acetonitrile as eluents. Example 96 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C24H22BrN3O2S: 495.0616, found: 496.0673 (M + H). Example 97 was obtained as the diastereoisomer eluted last. High resolution mass (HRMS) calculated for C24H22BrN3O2S: 495.0616, found: 496.0687 (M + H). Example 98: N- [6-ethyl-5- (1H-indazol-4-yl) thieno [2,3-d] pyrimidin-4-yl] -D-phenylalanine Following general procedure Ha and taking Preparation 3a as the appropriate 5-iodo-thieno [2,3-d] pyrimidine derivative and 1H-indazol-4-yl-boronic acid as the appropriate boronic acid derivative, and then purifying the crude product by reverse phase preparative chromatography. using an aqueous solution of 0.1% TFA and acetonitrile as eluents, Example 98 was obtained as a mixture of diastereoisomers. High resolution mass (HRMS) calculated for C241-12 IN502S: 443.1416, found: 444.1485 and 444.1481 (M + H).
[0130] Example 99: N46-Ethyl-5- (quinolin-8-yl) thieno [2,3-dipyrimidin-4-yl] -D-phenylalanine Following general procedure Hd and taking Preparation 3a as a derivative of 5-iodo -thieno [2,3-d] pyrimidine and 8-quinolylboronic acid as the appropriate boronic acid derivative, Example 99 was obtained as a mixture of diastereoisomers. High resolution mass (HRMS) calculated for C26H28N4O2S: 454.1463, found: 455.1558 (M-FH). Example 100: N46-ethyl- (5R ') - 5- (naphthalen-1-ylthieno [2,3-d] pyrimidin-4-yl] -Dphenylalanine and Example 101: N-16-ethyl- (5S) (,) - 5- (naphthalen-1-yl) thieno [2,3-di-pyrimidin-4-yl] -D-phenylalanine Separating the diastereoisomers of Example 79 by preparative reversed-phase chromatography using an aqueous solution of TFA at 0.1% and acetonitrile as eluents, Example 100 was obtained as the diastereoisomer eluted first.High resolution mass (HRMS) calculated for High resolution mass (HRMS) calculated for C271-123N302S: 453, 1511, found: 454.1596 (M + H) Example 101 was obtained as the last eluted diastereoisomer High resolution mass (HRMS) calculated for C27H23N3O2S: 453.1511, found: 454, 1577 (M + H) Example 102: N46-Ethenyl- (5S ') - 5- (naphthalen-1-yl) -thieno [2,3-d] pyrimidin-4-yl-D-phenylalanine and Example 103: N46 -éthényl- (5R ') - 5- (naphthalen-1-yl) -thiénol2,3- dlpyrimidin-4-yl] -13-phenylalanine Following general procedure 1a and taking Preparation 4w as the appropriate 4-chloro-thieno [2,3-d] pyrimidine derivative and D-phenylalanine as amino acid derivative Example 102 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C27H21N3O2S: 451.1354, found: 452.1411 (M + H). Example 103 was obtained as the diastereoisomer eluted last. High resolution mass (HRMS) calculated for C27112114302S: 451.1354, found: 452.1412 (M + H).
[0131] Example 104: N-1 (5S ') - 5- (napitalen-1-yl) -6 - ((1Z) -prop-1-en-1-yl) thieno [2,3-d] pyrimidin-4 11-D-phenylalanine and Example 105: N-1 (5R (1) -5- (naphthalen-1-yl) -64 (12) -prop-1-en-1-yl) thieno [2,3-d] d] - Pyrimidin-4-yl-D-phenylalanine Following general procedure Ib and taking Preparation 4X as the appropriate 4-chloro-thieno [2,3-4pyrimidine derivative and D-phenylalanine as derivative 3037956 - 116 - of appropriate amino acid, a mixture of diastereoisomers was obtained. They were separated by reverse phase preparative chromatography using a 40 mM aqueous solution of NH4OAc (pH = 4, adjusted with AcO F) and acetonitrile as eluents. Example 104 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C28H23N3O2S: 465.11511, found: 466.1577 (M + H). Example 104 also contains 55% of Example 108. Example 105 was obtained as the last eluted diastereoisomer. High resolution mass (HRMS) calculated for C281-123N302S: 465.11511, found: 466.1578 (M + H). Example 105 also contains 55% of Example 109. EXAMPLE 106: N-R5S (-) - 5- (naphthalen-1-yl) -6- (p-rop-1-en-2-yl) thieno [ 2,3-d] pyrimidin4-yl-D-phenylalanine and Example 107: N-R5R ') - 5- (naphthalen-1.11) -6- (prop-1-en-2-yl) thieno [2,3 d) pyrimidin-4-yl-D-phenylalanine Following general procedure 1a and taking Preparation 4y as the appropriate 4-chloro-thieno [2,3-d] pyrimidine derivative and D-phenylalanine as the acid derivative. amine, a mixture of diastereoisomers has been obtained. They were separated by preparative reverse phase chromatography using 40 mM aqueous NH4OAc (pH = 4, adjusted with AcOH) and acetonitrile as eluents. Example 106 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C28H23N3O2S: 465.11511, found: 466.1581 (M + H). Example 107 a. was obtained as the diastereoisomer eluted last. High resolution mass (HRMS) calculated for C28H23N3O2S: 465.11511, found: 466.1597 (M + H).
[0132] Example 108: N - ((5S ') - 5- (naphthalen-1-yl) -6 - [(1n-prop-1-en-1-ylthieno) -3,3-d] pyrimidin-4-yl} -D phenylalanine and Example 109: N - {(5Ra) -5- (naphthalen-1-yl) -6 - [(1E) -prop-1-en-1-yl] thieno], 3-diphidimidin 4-yl) -D-phenylalanine Following general procedure 1a and taking Preparation 4z as the appropriate 4-chloro-thieno [2,3-d] pyrimidine derivative and D-phenylalanine as the appropriate amino acid derivative a mixture of diastereoisomers was obtained which were separated by reverse phase preparative chromatography using a 40 mM aqueous NI140Ac solution (pH 4, adjusted with AcOH) and acetonitrile as eluents. Example 108 was obtained as the diastereoisomer eluted first.High resolution mass (HRMS) calculated for C28E123N302S: 465.11511, found: 466.1593 (M + H) Example 109 was obtained as the diastereoisomer eluted last High resolution mass (HRM S) calcd for C28H23N3O2S: 465.11511, found: 466.1581 (M + H).
[0133] Example 110: N45- (3-chloro-2-methylphenyl) -6-ethyl-thieno [2,3-d] pyrimidin-4-yl] -3- (1H-pyrazol-1-yl) alanine Following the procedure General Io and taking Preparation 4j as the appropriate 4-chloro-thieno [2,3-c] pyrimidine derivative and methyl 2-amino-3-pyrazol-1-ylpropanoate hydrochloride as the amino acid derivative and then hydrolyzing the intermediate formed according to general procedure VII, a mixture of diastereoisomers was obtained. It was purified by reverse phase preparative chromatography using a 0.1% aqueous TFA solution and acetonitrile as eluents, and Example 110 was obtained as a mixture of diastereoisomers. High resolution mass (HRMS) calculated for C21H20ClN2O2S: 441.1026, found: 442.1120 and 442.1123 (M + H).
[0134] Example 111: N - [(SR (,) - 5- (3-chloro-2-methylphenyl) -6-ethylthieno [2,3-4 pyrimidin-4-yl] -3-cyclopentyl-D-alanine and Example 112: N-R5S ') - 5- (3-chloro-2-methylphenyl) -6-ethylthieno [2,3-d] pyrimidin-4-yl] -3-cyclopentyl-D-alanine Following general procedure lb and by taking Preparation 4j as the appropriate 4-chloro-thieno [2,3-cilpyrimidine derivative and (2R) -2-amino-3-cyclo-pentyl-propanoic acid as the appropriate amino acid derivative a mixture of diastereoisomers was obtained. They were separated by reverse phase preparative chromatography using an aqueous solution of 0.1% TFA and acetonitrile as eluents. Example 111 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C23H26ClN3O2S: 443.1434, found: 444.1519 (M + H). Example 112 was obtained as the diastereoisomer eluted last. High resolution mass (HRMS) calculated for C23H26ClN3O2S: 443.1434, found: 444.1518 (M + H). Example 113: N-R5S ') - 5- (3-chloro-2-methylphenyl) -6-ethylthieno [2,3-d] pyrimidin-4-yl-D-phenylalanine and Example 114: N-1 (5 / Q-5- (3-chloro-2-methylphenyl) -6-ethylthieno [2,3-d] pyrimidin-4-yin-D-phenylalanine Following general procedure 11a and taking Preparation 3a as a derivative of 5-io-thieno [2,3-cf] pyrimidine and (3-chloro-2-methyl-phenyl) boronic acid as the appropriate boronic acid derivative, a mixture of diastereoisomers was obtained. were separated by preparative reverse phase chromatography using a 40 mM aqueous solution of NH40Ac (pH = 4, adjusted with AcOH) and acetonitrile as eluents Example 113 was obtained in the form of of the diastereoisomer eluted first High resolution mass (HRMS) calculated for C24H22ClN3O2S: 451.1111, found: 452.1192 (M + H) Example 114 was obtained as the last eluted diastereoisomer.
[0135] High resolution mass (HRMS) calculated for C24H22ClN3O2S: 451.1121, found: 452.1174 (M-FH). Example 115: N-R5Sa) -5- (3-chloro-2-methylphenyl) -6-ethylthieno [2,3-4-pyrimidin-4-yl] phenylalanine and Example 116: N-1 (5Ra) -5- (3-Chloro-2-methylphenyl) -6-ethylthieno [2,3-d] pyrimidin-4-yl-L-phenylalanine Following general procedure Ib and taking Preparation 4j as a 4-chloro derivative -thieno [2,3-d] pyrimidine and L-phenylalanine as the appropriate amino acid derivative, a mixture of diastereoisomers was obtained. They were separated by reverse phase preparative chromatography using an aqueous solution of 0.1% TFA and acetonitrile as eluents. Example 115 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C24H22ClN2O2S: 451.1111, found: 452.1207 (M + H).
[0136] Example 116 was obtained as the last eluted diastereoisomer. High resolution mass (HRMS) calculated for C241-122C1N302S: 451.1111, found: 452.1183 (MAI). Example 117: N-1 (5Ra) -5- (3-ethyl-2-methylphenyl) -6-ethylthieno [2,3-d] pyrimidin-4-yl] -cyclohexyl-D-alanine and Example 118: N - [(5Sa) -5- (3-bromo-2-methyl-phenyl) -6-ethylthieno [2,3-d] pyrimidin-4-yl] -3-cyclohexyl-D-alanine Following the procedure Ib and taking Preparation 4j as the appropriate 4-chloro-thieno [2,3-d] pyrimidine derivative and (2R) -2-amino-3-cyclohexylpropanoic acid as the acid derivative. amine, a mixture of diastereoisomers has been obtained. They were separated by reverse phase preparative chromatography using an aqueous solution of 0.1% TFA and acetonitrile as eluents. Example 117 was obtained as the diastereoisomer eluted first. High Resolution Mass (HRMS) calculated for C241-128C1N3O2S: 457,1591, found: 458,1672 (1 + 4) - Example 118 was obtained as the last eluted diastereoisomer. High resolution mass (HRMS) calculated for C24H28ClN3O2S: 457.1551, found: 458.1663 (M + H). Example 119: N-15- (3-Chloro-2-methylphenyl) -6-ethyl-thieno [2,3-pyrimidin-4-yl] alpha-methyl-D-phenylalanine Following general procedure Ib and taking Preparation 4j as the appropriate 4-chloro-thieno [2,3-d] pyrimidine derivative and (2R) -2-amino-2-methyl-3-phenylpropanoic acid as the appropriate amino acid derivative a mixture of diastereoisomers was obtained which was purified by reverse phase preparative chromatography using 0.1% aqueous TFA solution and acetonitrile as eluents Example 119 was obtained as a A mixture of diastereoisomers High resolution mass (HRMS) calculated for C 25 H 24 ClN 3 O 2 S: 465.1278, found: 466.1372 and 466.1356 (M + H).
[0137] Example 120: N-R5R11) -5- (3-chloro-2-methylphenyl) -6-ethylthieno [2,3-d] pyrimidin-4-yl) -2-hydroxy-D-phenylalanine and Example 121: N - [(5Sa) -5- (3-chloro-2-methylphenyl) -6-ethylthieno [2,3-4-pyrimidin-4-yl] -2-hydroxy-D-phenyl-alanine Following general procedure 1b , and taking Preparation 4j as the appropriate 4-chloro-thieno [2,3-d] pyrimidine derivative and (2R) -2-amino-3- (2-hydroxyphenyl) propanoic acid as the amino acid derivative A mixture of diastereoisomers has been obtained. They were separated by preparative reverse phase chromatography using 0.1% aqueous TFA solution and acetonitrile as eluents. Example 120 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C24H22ClN3O3S: 467.1070, found: 468.1135 (M + H). Example 121 was obtained as the diastereoisomer eluted last.
[0138] High resolution mass (HRMS) calculated for C24H22ClN3O3S: 467.1070, found: 468.1162 (M + H). Example 122: (13S) -N-R5Ra) -5- (3-chloro-2-methyl-phenyl) -6-ethylthieno-1,2,3-dlpyrimidin-4-yl-beta-hydroxy-D-phenylalanine 30 and 3037956 - 121 Example 123: ((3S) -N-1 (5S ') - 5- (3-Chloro-2-methyl-phenyl) -6-ethylthieno [2,3-d] pyrimidin-4-yl-beta-hydroxy -D-phenylalanine Following the general procedure Ib and taking Preparation 4j as the appropriate 4-chloro-thieno [2,3-d] pyrimidine derivative and (2R, 35) -3-phenyl-serine acid as 5 As a suitable amino acid derivative, a mixture of diastereoisomers was obtained which were separated by reverse phase preparative chromatography using 0.1% aqueous TFA solution and acetonitrile as eluents. was obtained as the diastereoisomer eluted first.High resolution mass (HRMS) calculated for C24H22ClN3O3S: 467.1070, found: 468.1151 (M + H).
[0139] Example 123 was obtained as the diastereoisomer eluted last. High resolution mass (HRMS) calculated for C241422 C1N303S: 467.1070, found: 468.1133 (M + H). Example 124: (1R) -N-R5R ') - 5- (3-chloro-2-methyl-phenyl) -6-ethylthieno-12,3-dichloropyrimidin-4-g-beta-hydroxy-L-phenylalanine and Example 125: (fIR) -N-R5Sa) -5- (3-chloro-2-methyl-phenyl) -6-ethylthieno-12,3-di-pyrimidin-4-A-beta-hydroxy-L-phenylalanine Following the General procedure 1b and taking Preparation 4j as the appropriate 4-chloro-thieno [2,3-a] pyrimidine derivative and (2S, 3R) -2-amino-3-hydroxy-3-phenylpropionic acid as a derivative of a suitable amino acid, a mixture of diastereoisomers has been obtained. They were separated by reverse phase preparative chromatography using an aqueous solution of 0.1% TFA and acetonitrile as eluents. Example 124 was obtained as the diastereoisomer eluted first.
[0140] High resolution mass (HRMS) calculated for C24H22ClN3O3S: 467.1070, found: 468.1144 (M + H). Example 125 was obtained as the diastereoisomer eluted last. High resolution mass (HRMS) calculated for C24H22ClN3O3S: 467.1070, found: 468.1153 (M + H). Example 126: N-R5Ra) -5- (3-chloro-2-methylphenyl) -6-ethylthieno12,3-dipyrimidin-4-yl-2-cyano-D-phenylalanine and Example 127: N - [(5S0-5- (3-chloro-2-methylphenyl) -6-ethylthieno [2,3-d] pyrimidin-4-yl] -2-cyano-D-phenylalanine Following the general procedure 1b and taking Preparation 4j as the appropriate 4-chloro-thieno [2,3-d] pyrimidine derivative and (2R) -2-amino-3- (2-cyanophenyl) -propanoic acid as the acid derivative In a suitable amine, a mixture of diastereoisomers was obtained which were separated by preparative reverse phase chromatography using 0.1% aqueous TFA solution and acetonitrile as eluants. the form of the diastereoisomer eluted first High resolution mass (HRMS) calculated for C25H21ClN4O2S: 476.1074, found: 477.1129 (M + H) Example 127 was obtained as the last eluted diastereoisomer.
[0141] High resolution mass (HRMS) calculated for C25H21ClN4O2S: 476.1074, found: 477.1134 (M + H). Example 128: N-R5R ') - 5- (3-chloro-2-methylphenyl) -6-ethylthieno [2,3-di-pyrimidin-4-yl] -2-methoxy-D-phenylalanine and Example 129 : N-R5S ') - 5- (3-chloro-2-methylphenyl) -6-ethylthieno12,3-djpyrimidin-4-yl] -2-methoxy-D-phenylalanine Following general procedure 1c and Preparation 4j as the appropriate 4-chloro-thieno [2,3-d] pyrimidine derivative and (2R) -2-amino-3- (2-methoxyphenyl) propanoic acid as the appropriate amino acid derivative a mixture of diastereoisomers was obtained. They were separated by reverse phase preparative chromatography using an aqueous solution of 0.1% TFA and acetonitrile as eluents. Example 128 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C25H24ClN3O3S: 481.1277, found: 482.1320 (M + H). Example 129 was obtained as the last eluted diastereoisomer. High resolution mass (HRMS) calculated for C25H24ClN3O3S: 481.1277, found: 482.1399 (M + H).
[0142] Example 130: N-R5Ra) -5- (3-chloro-2-methylphenyl) -6-ethylthieno [2,3-Mpyrimidin-4-yl] -2,6-difluoro-D-phenylalanine and Example 131: N R 5 S ') - 5- (3-chloro-2-methylphenyl) -6-ethylthieno [2,3-dlpyrimidin-4-yl] -2,6-difluoro-D-phenylalanine Following general procedure 1b and taking Preparation 4j as the appropriate 4-chloro-thieno {2,3-dipyrimidine derivative and (2R) -2-amino-3- (2,6-difluorophenyl) propanoic acid as the appropriate amino acid derivative, a mixture of diastereoisomers was obtained. They were separated by preparative reverse phase chromatography using 0.1% aqueous TFA solution and acetonitrile as eluents. Example 130 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C24H20ClF2N3O2S: 487.0933, found: 488.1009 (M + H). Example 131 was obtained as the last eluted diastereoisomer. High resolution mass (HRMS) calculated for C24H20ClF2N3O2S: 487.0933, found: 488.1020 (M + H). Example 132: (2R) -2-1 [(5H) -5- (3-chloro-2-methyl-phenyl) -6-ethylthieno [2,3-dlpyrimidin-4-yl] amino} -3 - (1H-indol-4-yl) propanoic acid and Example 133: (2R) -2- (R5Sa) -5- (3-chloro-2-methyl-phenyl) -6-ethylthieno [2,3-tHF pyrimidine] 4-yl] amino} -3- (1H-indol-4-yl) propanoki Following the general procedure Ib and taking Preparation 4j as the appropriate 4-chloro-thieno [2,3-d] pyrimidine derivative and (2R) -2-amino-3- (1H-indol-4-yl) propanoic acid hydrochloride as the appropriate amino acid derivative, a mixture of diastereoisomers was obtained. They were separated by preparative reverse phase chromatography using 0.1% aqueous TFA solution and acetonitrile as eluents. Example 132 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C 26 H 23 ClN 4 O 2 S: 490.1230, found: 491.1289 (M + H). Example 133 was obtained as the last eluted diastereoisomer. High resolution mass (HRMS) calculated for C26H23ClN4O2S: 490.11230, found: 491.1309 (M + H). Example 134: 2-Earbamoyl-N - [(5S ') - 5- (3-chloro-2-methylphenyl) -6-ethylthieno-pyrimidin-4-yl] -D-phenylalanine Following general procedure 1b and taking the Preparation 4j as the appropriate 4-chloro-thieno [2,3-4pyrimidine derivative and (2R) -2-amino-3- (2-carbamoylphenyl) propanoic acid as the appropriate amino acid derivative, a mixture of diastereoisomers was obtained. They were separated by reverse phase preparative chromatography using an aqueous solution of 0.1% TFA and acetonitrile as eluents. Example 134 was obtained as the diastereoisomer eluted last.
[0143] High resolution mass (HRMS) calculated for C25H23ClN4O3S: 494.1179, found: 495.1255 (M + H). Example 135: N - [(5R ') - 5- (3-Chloro-2-methylphenyl) -6-ethylthieno [2,3-apyrimidin-4-yl] -2-nitro-D-phenylalanine and Example 136: N-R5S ') - 5- (3-chloro-2-methylphenyl) -6-ethylthieno [2,3-dlpyrimidin-4-yl] -2-nitro-D-phenylalanine Following general procedure Ib and taking Preparation 4j as the appropriate 4-chloro-thieno [2,3-arbyrimidine derivative and (2R) -2-amino-3- (2-nitrophenyl) propanoic acid as the appropriate amino acid derivative a mixture of diastereoisomers was obtained. They were separated by reverse phase preparative chromatography using an aqueous solution of 0.1% TFA and acetonitrile as eluents. Example 135 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C24H21ClN4O4S: 496.0972, found: 497.1026 (M + H). Example 136 was obtained as the last eluted diastereoisomer. High resolution mass (HRMS) calculated for C241-121ClN4O4S: 496.0972, found: 497.1045 (M + H).
[0144] Example 137: N-R5R ') - 5- (3-chloro-2-methylphenyl) -6-ethylthieno [2,3-di-pyrimidin-4-yl] -2- (trifluoromethyl) -D-phenylalanine and Example 138: N-R5Sa) -5- (3-chloro-2-methylphenyl) -6-ethylthieno [2,3-dipyrimidin-4-yl] -2- (trifluoromethyl) -D-phenylalanine Following general procedure Ib and taking Preparation 4j as the appropriate 4-chloro-thieno [2,3-d] pyrimidine derivative and (2R) -2-amino-3- [2- (trifluoromethyl) phenyl] propanoic acid as the amino acid derivative A mixture of diastereoisomers has been obtained. They were separated by preparative reverse phase chromatography using 0.1% aqueous TFA solution and acetonitrile as eluents. Example 137 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C25H21ClF3N3O2S: 519.0995, found: 520.1068 (M + H). Example 138 was obtained as the last eluted diastereoisomer. High resolution mass (HRMS) calculated for C25H21ClF3N3O2S: 519.0995, found: 5201047 (M + H). Example 139: 2-Bromo-N-R5Ra) -5- (3-chloro-2-methyl-phenyl) -6-ethylthieno [2,3-d] pyrimidin-4-yl-D-phenylalanine and Example 140: 2-Bromo-N - [(5S ') - 5- (3-chloro-2-methyl-phenyl) -6-ethylthieno [2,3-dl-pyrimidin-4-yl] -ll-phenyl-alanine Following the general procedure Ib and taking Preparation 4j as the appropriate 4-chloro-thieno [2,3-c] pyrimidine derivative and (2R) -2-amino-342-bromophenylpropanoic acid as the appropriate amino acid derivative, a mixture of diastereoisomers was obtained. They were separated by reverse phase preparative chromatography using an aqueous solution of 0.1% TFA and acetonitrile as eluents. Example 139 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C24H21IBIBN3O2S: 529.0226, found: 530.0312 (M + H). Example 140 was obtained as the diastereoisomer eluted last. High resolution mass (HRMS) calculated for C24H21IBIBN3O2S: 529.0226, found: 530,0294 (M + H). Example 141: N-R5Ra) -5- (3-chloro-2-methyl-phenyl) -6-ethylthieno [2,3,4-pyrimidin-4-yl] -2-dimethylamino) -2-oxo-ethoxy] -D Example 142: N-1 (5S ') - 5- (3-chloro-2-methylphenyl) -6-ethylthieno [2,3-Mpyrimidin-4-yl] -2- (dimethylamino) -2- -oxoethoxyl-D-phenylalanine Following general procedure lb and taking Preparation 4j as the appropriate 4-chloro-thieno [2,3-d] pyrimidine derivative and Preparation A9 as the appropriate amino acid derivative, a mixture of diastereomers a been obtained. They were separated by reverse phase preparative chromatography using 0.1% aqueous TFA solution and acetonitrile as eluents. Example 141 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C28H29ClN4O4S: 552.1598, found: 553.1694 (M + H). Example 142 was obtained as the last eluted diastereoisomer.
[0145] High resolution mass (HRMS) calculated for C28H29ClN4O4S: 552.1598, found 553.1667 (M + H). Example 143: N4 (5R ') - 5- (3-Chloro-2-methylphenyl) -6-ethylthieno [2,3-d] pyrimidin-4-yl] -2- (2-eyelopenyl-ethoxy) -D Phenylalanine and Example 144: N-1 (5S) -5- (3-chloro-2-methylphenyl) -6-ethylthieno [2,3-d] pyrimidin-4-yl) -2- -eyclopentyl-etboxy) -D-phenylalanine Following General Procedure Ib and taking Preparation 4j as the appropriate 4-chloro-thieno [2,3-d] pyrimidine derivative and Preparation A10 as the appropriate amino acid derivative a mixture of diastereoisomers was obtained. They were separated by reverse phase preparative chromatography using an aqueous solution of 0.1% TFA and acetonitrile as eluents. Example 143 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C1311134C1N3O3S: 563.2009, found: 564.2106 (M + H). Example 144 was obtained as the last eluted diastereoisomer. High resolution mass (HRMS) calculated for C 31 C 13 C 13 N 3 O 3 S: 563.2009, found: 564.2101 (M + H). Example 145: N - [(5 R) -5- (3-chloro-2-methylphenyl) -6-ethylthieno [2,3-dIpyrimidin-4-yl] -2- (2-phenylethoxy) -D-phenylalanine and Example 146: N - [(5S ()) - 5- (3-Chloro-2-methylphenyl) -6-ethylthieno [2,3-d] pyrimidin-4-yl] -2- (2-phenylethoxy) -D By following general procedure Ib and taking Preparation 4j as the appropriate 4-chloro-thieno [2,3-4pyrimidine derivative and Preparation All as the appropriate amino acid derivative, a mixture of diastereoisomers was obtained. were separated by reverse phase preparative chromatography using a 0.1% aqueous TFA solution and acetonitrile as eluents Example 145 was obtained as the diastereoisomer eluted first. HRMS) calcd for C32F130C1N3O3S: 571.1666, found: 572.1769 (M + H) Example 146 was obtained as the last eluted diastereoisomer.
[0146] High resolution mass (HRMS) calculated for C32H30ClN3O3S: 571.1666, found: 572.1763 (M + H). Example 147: N-R5Ra) -5- (3-chloro-2-methylphenyl) -6-ethylthieno [2,3-dipyrimidin-4-yl] -2- (3-phenylpropoxy) -D-phenylalanine and Example 148 : N-R5Sa) -5- (3-chloro-2-methylphenyl) -6-ethylthieno [2,3-4 pyrimidin-4-yl] -2- (3-phenylpropoxy) -D-phenylalanine Following the general procedure 1b and taking Preparation 4j as the appropriate 4-chloro-thieno [2,3-d] pyrimidine derivative and Preparation A1 2 as the appropriate amino acid derivative, a mixture of diastereoisomers was obtained. They were separated by reverse phase preparative chromatography using an aqueous solution of 0.1% TFA and acetonitrile as eluents. Example 147 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C33H32ClN3O3S: 585.1853, found: 586.1917 (M + H). Example 148 was obtained as the last eluted diastereoisomer. High resolution mass (HRMS) calculated for C33H32ClN3O3S: 585.1853, found: 586.1906 (M + H). Example 149: 2 - [(3-Chlorobenzyl) oxy] -N-R5R ') - 5- (3-chloro-2-methylphenyl) -6-ethylthieno [2,3-d] pyrimidin-4-yl] D- phenylalanine and Example 150: 2-1 (3-chlorobenzyl) oxyl-N-R5 ') - 5- (3-chloro-2-methylphenyl) -6-ethylthieno [2,3-4-pyrimidin-4-yl] D-phenylalanine Following general procedure Ib and taking Preparation 4j as the appropriate 4-chloro-thieno [2,3-d] pyrimidine derivative and Preparation A13 as the appropriate amino acid derivative, a mixture of diastereoisomers was got. They were separated by preparative reverse phase chromatography using 0.1% aqueous TFA solution and acetonitrile as eluents. Example 149 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C31H27Cl2N3O3S: 591.11150, found: 592.1121 (M + H). Example 150 was obtained as the last eluted diastereoisomer.
[0147] High resolution mass (HRMS) calculated for C31H27Cl2N3O3S: 591.1115, found: 592.1244 (M + 11). Example 151: N-R5R ') - 5- (3-Chloro-2-methylphenyl) -6-ethylthieno [2,3-d] pyrimidin-4-yl] -3-pyridin-2-yl-11-alanine 25 and Example 152: N-R5S ') - 5- (3-chloro-2-methylplienyl) -6-ethylthieno [2,3-d] pyrimidin-4-yl] -3-pyridin-2-yl-D-alanine following the general procedure Ib and taking Preparation 4j as the appropriate 4-chloro-thieno [2,3-d] pyrimidine derivative and (2R) -2-amino-3- (2-pyridyl) propanoic acid as a derivative of a suitable amino acid, a mixture of diastereoisomers has been obtained. They were separated by reverse phase preparative chromatography using an aqueous solution of 0.1% TFA and acetonitrile as eluents. Example 151 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C23H21ClN4O2S: 452.1074, found: 453.1146 (WH). Example 152 was obtained as the diastereoisomer eluted last.
[0148] High resolution mass (HRMS) calculated for C23H21ICIN4O2S: 452.1074, found: 453.1135 (M + H). Example 153: N - [(5R ') - 5- (3-Chloro-2-methylphenyl) -6-ethylthieno [2,3-d] pyrimidin-4-yl] -2-12- (4-methylpiperazine 1-y-Ethoxyl-D-phenylalanine and Example 154: N - [(5S ()) - 5- (3-chloro-2-methylphenyl) -6-ethylthieno [2,3-di-pyrimidin-4-yl] 242- (4-methyl-piperazin-1-y) ethoxyl-D-phenylalanine Following general procedure Ib and taking Preparation 4j as the appropriate 4-chloro-thieno [2,3-d] pyrimidine derivative and Preparation A14 as As a suitable amino acid derivative, a mixture of diastereoisomers was obtained which were separated by reverse phase preparative chromatography using 0.1% aqueous TFA solution and acetonitrile as eluents. was obtained as the diastereoisomer eluted first.High resolution mass (HRMS) calculated for C31H36ClN5O3S: 593.2227, found: 594.2297 (M + H).
[0149] Example 154 was obtained as the diastereoisomer eluted last. High resolution mass (HRMS) calculated for C 311-116ClN 503S: 593.2227, found: 594.2289 (M + 1-1). Example 155: N-1 (5Ra) -5- (3-chloro-2-methylphenyl) -6-ethylthieno [2,3-d] pyrimidin-4-yl] -2-12- (dimethylamino) -ethoxyl-D phenylalanine and Example 156: N - [(55a) -5- (3-chloro-2-methylphenyl) -6-ethylthieno [2,3-dlpyrimidin-4-yl] -2- [2- (dimethylamino) ethoxy] ] -D-phenylalanine Following the general procedure Ib and taking Preparation 4j as the appropriate 4-chloro-thieno [2,3-d] pyrimidine derivative and Preparation A15 as the appropriate amino acid derivative, a mixture of diastereoisomers was obtained. They were separated by reverse phase preparative chromatography using 0.1% aqueous TFA and acetonitrile as eluents. Example 155 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C28H31ClN4O3S: 538.1805, found: 539.1890 (M + H). Example 156 was obtained as the last eluted diastereoisomer.
[0150] High resolution mass (HRMS) calculated for C281-131ClN4O3S: 538.1805, found: 539.1887 (M + H). Example 157: N-R5R ') - 5- (3-chloro-2-methylphenyl) -6-ethylthieno [2,3-d] pyrimidin-4-yl] -2- (dimethylamino) propoxyl-D-phenylalanine and Example 158: N - [(5S) -5- (3-chloro-2-methylphenyl) -6-ethylthieno [2,3-d] pyrimidin-4-yl] -243- (dimethylamino) -propoxyl-D- Phenylalanine Following general procedure Ib and taking Preparation 4j as the appropriate 4-chloro-thieno [2,3-d] pyrimidine derivative and Preparation A16 as the appropriate amino acid derivative, a mixture of diastereoisomers was obtained. . They were separated by reverse phase preparative chromatography using an aqueous solution of 0.1% TFA and acetonitrile as eluents. Example 157 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C29H33ClN4O3S: 552.1962, found: 553.2043 (M + H).
[0151] Example 158 was obtained as the last eluted diastereoisomer. High resolution mass (HRMS) calculated for C29H33ClN4O3S: 552.1962, found: 553.2053 (M + H). Example 159: 3-Cyclopropyl-N-16-ethyl-5- (naphthalen-1-ylthieno [2,3-d] pyrimidin-4-yl] -D-alanine Following general procedure Ib and taking Preparation 4k as the appropriate 4-chloro-thieno [2,3-d] pyrimidine derivative and (2R) -2-amino-3-cyclo-propylpropanoic acid as the appropriate amino acid derivative, a mixture of diastereoisomers was obtained. They were separated by reverse phase preparative chromatography using a 0.1% aqueous TFA solution and acetonitrile as eluants Example 159 was obtained as a mixture of diastereoisomers Mass 3037956 High resolution (HRMS) calcd for C24H23N3O2S: 417.11511, found: 418.1570 (M + H) Example 160: (2R) - {[6-ethyl-5- (naphthalen-1-yl)) thieno [2,3-4-pyrimidin-4-yl] -amino} (phenyl) -ethanoic acid, diastereoisomer 1 and Example 161: (2R) - ([6-ethyl-5- (naphthalen-1-yl) thieno) acid, 3-d] pyrimidin-4-yl] amino) (phenyl) -ethanoic e, diastereoisomer 2 Following general procedure Ib and taking Preparation 4k as the appropriate 4-chloro-thieno [2,3-d] pyrimidine derivative and (2R) -2-amino-2-phenyl- Acetic acid as the appropriate amino acid derivative, using DMA as the solvent instead of DMSO, a mixture of diastereoisomers was obtained. They were separated by reverse phase preparative chromatography using an aqueous solution of 0.1% TFA and acetonitrile as eluents. Example 160 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C 26 H 21 O 130 S: 439.1354, found: 440.1488 (M + H). Example 161 was obtained as the last eluted diastereoisomer. High resolution mass (HRMS) calculated for C26H21Cl2O2S: 439.1354, found: 440.1412 (M + H).
[0152] Example 162: N46-ethyl- (5S) -5- (naphthalen-1-yl) thieno [2,3-dipyrimidin-4-yl] -3-pyridin-3-yl-D-alanine and Example 163: N-16-ethyl- (5H-5- (naphthalen-1-yl) thieno [2,3-dipyrimidin-4-yl] -3-pyridin-3-yl-D-alanine Following the general procedure Ib and taking Preparation 4k as the appropriate 4-chloro-thieno [2,3-d] pytimidine derivative and (2R) -2-amino-3- (3-pyridyl) -propanoic acid as the acid derivative To a suitable amine, a mixture of diastereoisomers was obtained which were separated by preparative reverse phase chromatography using a 40 mM aqueous solution of NH 4 OAc (pH = 4, adjusted with AcOH) and acetonitrile Example 162 was obtained as the diastereoisomer eluted first High resolution mass (HRMS) calculated for C 26 H 22 N 4 O 2 S 454.1463, found: 455.1520 (M + H). 163 was obtained as the diastereoisomer eluted last. resolution (HRMS) calcd for C26H22N4O2S: 454.1463, found: 455.1536 (M + H). Example 164: 3-Eyelohexyl-N-16-ethyl-5- (naphthalen-1-yl) thieno [2,3-d] pyrimidin-4-yl) -D-alanine Following general procedure 1a and taking the preparation 4k as the appropriate 4-chloro-thieno [2,3-d] pyrimidine derivative and (2R) -2-amino-3-cyclohexylpropanoic acid as the appropriate amino acid derivative, a mixture of diastereoisomers was obtained. It was purified by reverse phase preparative chromatography using an aqueous solution of 0.02% HCOOH and acetonitrile as eluents. Example 164 was obtained as a mixture of diastereoisomers. High resolution mass (HRMS) calculated for C27H29N3O2S: 459.1980, found: 460.2042 (M + H). Example 165: 3-Eyelohexyl-N [6-ethyl- (5R ') - 5- (naphthalen-1-yl) thieno [2,3-d] pyrimidin-4-yl] -D-alanine and Example 166: 3-Cyclohexyl-N-16-ethyl- (54-5- (naphthalen-1-yl) thieno-1,2,3 d] pyrimidin-4-yl-D-alanine The diastereoisomers of Example 164 were separated by preparative chromatography reverse phase using 40 mM aqueous NH40Ac solution (pH = 4, adjusted with AcOH) and acetonitrile as eluants Example 165 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C27H29N3O2S: 459.1980, found: 460.2043 (M + H) Example 166 was obtained as the last eluted diastereoisomer High resolution mass (HRMS) calculated for C271 -129N302S: 459.1980, found: 460.2058 (M + H) Example 167: N46-Ethyl-5- (naphthalen-1-yl) thieno [2,3-d] pyrimidin-4 1-yl] -2-methyl-D-phenylalanine, diastereoisomer 1 and Example 168: N46-ethyl-5- (naphtha) talen-1-yl) thieno [2,3-d] pyrimidin-4-yl-2-methyl-D-phenylalanine, diastereoisomer 2 Following general procedure 1b and taking Preparation 4k as a derivative of 4- Suitable chloro-thieno [2,3-d] pyrimidine and D-2'-methylphenylalanine as the appropriate amino acid derivative, a mixture of diastereoisomers was obtained. They were separated by preparative reverse phase chromatography using a 40 mM aqueous solution of NH4OAc (pH 4, adjusted with AcOH) and acetonitrile as eluents. Example 167 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C281-125N302S: 467.1677, found: 468.1747 (M + H). Example 168 was obtained as the diastereoisomer eluted last.
[0153] High resolution mass (HRMS) calculated for C281-125N3O2S: 467.1677, found: 468.1748 (M + H). Example 169: (2R) -24 [6-ethyl-5- (naphthalen-1-yl) thieno [2,3-d] pyrimidin-4-yl] amino] -4-phenyl-butanoic acid Following the general procedure and taking Preparation 4k as the appropriate 4-chloro-thieno [2,3-d] pyrimidine derivative and (2R) -2-amino-4-phenylbutanoic acid as the appropriate amino acid derivative, a mixture of diastereoisomers was obtained. It was purified by reverse phase preparative chromatography using an aqueous solution of 0.02% HCOOH and acetonitrile as eluents. Example 169 was obtained as a mixture of diastereoisomers. High resolution mass (HRMS) calculated for C28H25N3O2S: 467.1677, found: 468.1731 (M + H). Example 170: (2R) -2-1 [6-ethyl- (5S) -5- (naphthalen-1-ylthieno [2,3-d] pyrimidin-4-yl) aminol-4-phenylbutanol, and 3037956 Example 171: (2R) -2 - ([6-ethyl- (5H-5- (naphthalen-1-yl) thieno [2,3-d] pyrimidin4-yllaminol-4-phenylbutanoic acid The diastereoisomers of Example 169 were separated by reverse phase preparative chromatography using a 40 mM aqueous solution of NH4OAc (pH 4, adjusted with AcOH) and acetonitrile as eluents Example 170 was obtained in the form of of the diastereoisomer eluted first High resolution mass (HRMS) calculated for C28H25N3O2S: 467.1677, found: 468.1733 (M + H) Example 171 was obtained as the last eluted diastereoisomer High resolution mass (HRMS) calcd for C281-125N3O2S: 467.1677, found: 468.1726 (M + H) Example 172: N46-ethyl- (5R ') - 5- (naphthalen-1-yl) thieno [2 , 3-d] pyrimidin-4-yl-Dtyrosine and Example 173: N46-ethyl- (5S ') - 5- (nap) 1-yl) thieno [2,3-d] pyrimidin-4-yl] -D-tyrosine Following general procedure Ib and taking Preparation 4k as a derivative of 4-chloro-thieno [2,3-d] pyrimidine and (2R) -2-amino-3- (4-hydroxyphenyl) propanoic acid as the appropriate amino acid derivative, using DMA as solvent in place of DMSO, a mixture of diastereoisomers was got. They were separated by reverse phase preparative chromatography using an aqueous solution of 0.1% TFA and acetonitrile as eluents. Example 172 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C27H23N3O3S: 469.1460, found: 470.1539 (M + H).
[0154] Example 173 was obtained as the last eluted diastereoisomer. High resolution mass (HRMS) calculated for C27F123N3O3S: 469.1460, found: 470.1534 (M + H). Example 174: N- [6-ethyl- (5S) -5- (naphthalen-1-yl) -thieno [2,3-d] pyrimidin-4-yl] -2-hydroxy-D-phenylalanine and 3037956 Example 175: N46-ethyl- (5H-5- (naphthalen-1-yl) -thieno12,3-d] pyrimidin-4-yl) -2-hydroxy-D-phenylalanine Following general procedure 1b and taking Preparation 4k as the appropriate 4-chloro-thieno [2,3-cilpyrimidine derivative and (2R) -2-amino-3- (2-hydroxyphenyl) propanoic acid as the appropriate amino acid derivative, A mixture of diastereoisomers was obtained which were separated by preparative reverse phase chromatography using a 40 mM aqueous solution of NH40Ac (pH 4, adjusted with AcOH) and acetonitrile as eluents. 174 was obtained as the diastereoisomer eluted first High resolution mass (HRMS) calculated for C271123N3O3S: 469.1460, found: 470.1546 (M + H) Example 175 was obtained as the diastereoisomer eluted last. High resolution (HRMS) calculated for C27E123N3O3S: 469.1460, found: 470.1520 (M + H).
[0155] Example 176: N-16-ethyl- (5H-5- (naphthalen-1-yl) thieno [2,3-dipyrimidin-4-yl] -4-fluoro-D-phenylalanine and Example 177: N- I6-ethyl- (54-5- (naphthalen-1-yl) thieno [2,3-d] pyrimidin-4-yl] -4-fluoro-D-phenylalanine Following general procedure lb and taking Preparation 4k as the appropriate 4-chloro-thieno [2,3-d] pyrimidin derivative and (2R) -2-amino-3- (4-fluorophenyl) propanoic acid as the appropriate amino acid derivative, using DMA as a solvent in place of DMSO, a mixture of diastereoisomers was obtained which were separated by reverse phase preparative chromatography using 0.1% aqueous TFA solution and acetonitrile as eluents. Example 176 was obtained as the diastereoisomer eluted first High resolution mass (HRMS) calculated for C27H22FN3O2S: 471.1417, found: 472.1493 (M + H) Example 177 was obtained as of the diastereoisomer eluted in der High resolution mass (HRMS) calculated for C27H22FN3O2S: 471.1417, found: 472.1494 (M + H). Example 178: N- [6-ethyl- (5H-5- (naphthalen-1-yl) thieno [2,3-d] pyrimidin-4-yl] -3-fluoro-D-phenylalanine and Example 179: N-16-ethyl- (5S0-5- (naphthalen-1-yl) thieno [2,3-d] pyrimidin-4-yl] -3-fluoro-D-phenylalanine Following the general procedure 1b and taking Preparation 4k as the appropriate 4-chloro-thieno [2,3-d] pyrimidine derivative and (2R) -2-amino-3- (3-fluorophenyl) propanoic acid as the amino acid derivative A mixture of diastereoisomers was obtained which were separated by reverse phase preparative chromatography using a 0.1% aqueous TFA solution and acetonitrile as eluants. Diastereoisomeric form eluted first High resolution mass (HRMS) calculated for C27H22FN3O2S: 471.1417, found: 472.1486 (M + H) Example 179 was obtained as the last eluted diastereoisomer.
[0156] High resolution mass (HRMS) calculated for C27H22I'N3O2S: 471.1417, found: 472.1482 (M + F). Example 180: N [6-ethyl- (5Ra) -5- (naphthalen-1-yl) thieno [2,3-d] pyrimidin-4-yl] -2-fluoro-D-phenylalanine and Example 181: N- (6-ethyl- (5Sa) -5- (naphthalen-1-yl) thieno-1,2,3-Mpyrimidin-4-yl-2-fluoro-D-phenylalanine Following general procedure Ib and taking Preparation 4k as a derivative of Suitable 4-chloro-thieno [2,3-c] pyrimidine and (2R) -2-amino-3- (2-fluorophenyl) propanoic acid as the appropriate amino acid derivative, using DMA as solvent in place of DMSO, a mixture of diastereoisomers was obtained which were separated by reverse phase preparative chromatography using 0.1% aqueous TFA solution and acetonitrile as eluents. was obtained as the diastereoisomer eluted first.High resolution mass (HRMS) calculated for C27F122FN3O2S: 471.1417, found: 472.1501 (M + H). the shape of the diastereoisomer played most recently resolution Mass (HRMS) calculated for C27F122FN302S. 471.1417, found: 472.1492 (M + H).
[0157] Example 182: N46-Ethyl-5- (naphthalen-1-yl) thieno [2,3-11] pyrimidin-4-yl] -2-methoxy-D-phenylalanine Following general procedure Ib and taking Preparation 4k as appropriate 4-chloro-thieno [2,3-a] pyrimidine derivative and (2R) -2-amino-3- (2-methoxyphenyl) propanoic acid as the appropriate amino acid derivative, a mixture of 10 diastereomers a been obtained. It was purified by reverse phase preparative chromatography using a 40 mM aqueous solution of NH4OAc (pH = 4, adjusted with AcOH) and acetonitrile as eluents. Example 182 was obtained as a mixture of diastereoisomers. High resolution mass (HRMS) calculated for C28H25N3O3S 483.1617, found: 484.1682 and 484.1695 (M + H).
[0158] Example 183: 2-Chloro-N-16-ethyl-5- (naphthalen-1-yl) -thieno [2,3-di-pyrimidin-4-yl] -D-phenylalanine Following general procedure Ib and taking Preparation 4k as the appropriate 4-chloro-thieno [2,3-d] pyrimidine derivative and (2R) -2-amino-3- (2-chlorophenyl) propanoic acid as the appropriate amino acid derivative, a mixture of diastereomers was obtained. It was purified by reverse phase preparative chromatography using 0.1% aqueous TFA solution and acetonitrile as eluents. Example 183 was obtained as a mixture of diastereoisomers. High resolution mass (HRMS) calculated for C27H22ClN2O2S: 487.1121, found: 488.1988 and 488.1999 (M + H). Example 184: N-16-ethyl- (5Ra) -5- (naphthalen-1-yl) thieno [2,3-dlpyrimidin-4-yl] -Dtryptophan and Example 185: N-16-ethyl- (5S ') - 5- (naphthalen-1-yl) thieno [2,3-dlpyrimidin-4-yl] -Dtryptopha Following the general procedure Ib and taking Preparation 4k as a derivative of 4-chlomthieno [ 2,3-cilpyrinaidine and (2R) -2-amino-3- (1H-indol-3-yl) propanoic acid as the appropriate amino acid derivative, using DMA as a solvent in place of the DMSO, a mixture of diastereoisomers was obtained. They were separated by reverse phase preparative chromatography using an aqueous solution of 0.1% TFA and acetonitrile as eluents. Example 184 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C29H24N4O2S: 492.11620, found 493.1693 (M + H). Example 185 was obtained as the last eluted diastereoisomer. High resolution mass (HRMS) calculated for C29H24N4O2S: 492.11620, found 493.1690 (M + H).
[0159] Example 186: N46-ethyl-5- (napitalen-1-yl) thieno [2,3-d] pyrimidin-4-yl-3-naphthalen-1-yl-D-alanine, diastereoisomer 1 and Example 187: N46 1-ethyl-5- (naphthen-1-yl) thieno [2,3-d] pyrimid-3-n-aphthalen-1-yl-D-alanine, diastereoisomer 2 Following general procedure Ib and taking Preparation 4k as the appropriate 4-chloro-thieno [2,3-dlpyrimidine derivative and (2R) -2-amino-3- (1-naphthyl) -propanoic acid as the appropriate amino acid derivative, using DMA as solvent instead of DMSO, a mixture of diastereoisomers was obtained. They were separated by preparative reverse phase chromatography using 0.1% aqueous TFA solution and acetonitrile as eluents. Example 186 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C31H25N3O2S: 503.1677, found: 504.1754 (M + H). Example 187 was obtained as the last eluted diastereoisomer. High resolution mass (HRMS) calculated for C 31 O 12 N 5 O 2 S: 503.1677, found: 504.1758 (M + H). Example 188: (2R) -biphenyl-2-yl ([6-ethyl-5- (naphthalen-1-yl) thieno [2,3-di-pyrimidin-4-yl] amino) -ethanoic acid, diastereoisomer 2 Following general procedure Ib and taking Preparation 4k as the appropriate 4-chloro-thieno [2,3-d] pyrimidine derivative and (R) -amino-biphenyl-2-yl-acetic acid as suitable amino acid derivative, a mixture of diastereoisomers was obtained. They were separated by reverse phase preparative chromatography using a 40 mM aqueous NI-140Ac solution (pH = 4, adjusted with AcOH) and acetonitrile as eluents. Example 188 was obtained as the last eluted diastereoisomer. High resolution mass (HRMS) calculated for C32H25N3O2S: 515.1677, found: 516.1747 (M + H). Example 189: (2R) -Biphenyl-3-yl ([6-ethyl-5- (naphthalen-1-yl) thieno [2,3-d] pyrimidin-4-yl amino) -ethanoic acid, diastereoisomer 1 Following the general procedure Ib and taking Preparation 4k as the appropriate 4-chloro-thieno [2,3-d] pyrimidine derivative and (R) -amino-biphenyl-3-yl-acetic acid as the appropriate amino acid derivative a mixture of diastereoisomers was obtained. They were separated by preparative reverse phase chromatography using 40 mM aqueous NH4OAc (pH = 4, adjusted with AcOH) and acetonitrile as eluents. Example 189 was obtained as the diastereoisomer eluted first.
[0160] High resolution mass (HRMS) calculated for C32H25N3O2S: 515.1677, found: 516.1743 (M + H). Example 190: N- [6-ethyl-5- (naphthalen-1-yl) thieno [2,3-4-pyrimidin-4-yl] -DH-histidine Following general procedure 1a and taking Preparation 4k as a derivative of 4 suitable chloro-thieno [2,3-d] pyrimidine and (2R) -2-amino-3- (1H-imidazol-4-yl) propanoic acid as the appropriate amino acid derivative, a mixture of diastereomers a been obtained. It was purified by reverse phase preparative chromatography using 0.1% aqueous TFA solution and acetonitrile as eluents. Example 190 was obtained as a mixture of diastereoisomers. High resolution mass (HRMS) calculated for C24H21O1502S: 443.1416, found: 444.1462 and 444.1471 for the two diastereoisomers (M1-H). EXAMPLE 191 N46-Ethyl-5- (naphthalen-1-yl) thieno [2,3-d] pyrimidin-4-yl] -3-pyridin-2-yl-D-alanine Following general procedure 1b and taking Preparation 4k as the appropriate 4-chloro-thieno [2,3-d] pyrimidine derivative and (2R) -2-amino-3- (2-pyridyl) -propanoic acid as the suitable amino acid derivative, a mixture of diastereoisomers was obtained. It was purified by reverse phase preparative chromatography using 0.1% aqueous TFA solution and acetonitrile as eluents. Example 191 was obtained as a mixture of diastereoisomers. High resolution mass (HRMS) calculated for C261-122N402S: 454.1463, found: 455.1537 and 455.1558 for both diastereoisomers (M + H). Example 192: N-16-ethyl-5- (naphthalen-1-yl) thieno [2,3-d] pyrimidin-4-yl] -3-pyridin-3-yl-D-alanine Following general procedure Ib and by taking Preparation 4k as the appropriate 4-chloro-thieno [2,3-d] pyrimidine derivative and 3- (3-pyridyl) -D-alanine as the appropriate amino acid derivative, a mixture of diastereoisomers was obtained. It was purified by reverse phase preparative chromatography using 0.1% aqueous TFA solution and acetonitrile as eluents. Example 192 was obtained as a mixture of diastereoisomers. High resolution mass (HRMS) calculated for C26H22N4O2S: 454.1445, found: 455.1545 and 455.1553 for both diastereoisomers (1 441) - Example 193: N- [6-ethyl-5- (naphthalene) -1 -yl) thieno [2,3-d] pyrimidin-4-yl-3-pyridin-4-yl-D-alanine Following the general procedure Ib and taking Preparation 4k as a 4-chloro derivative. -thieno [2,3-d] pyrimidine and (2R) -2-amino-3- (4-pyridyl) propanoic acid as the appropriate amino acid derivative, a mixture of diastereoisomers was obtained. It was purified by reverse phase preparative chromatography using 0.1% aqueous TFA solution and acetonitrile as eluents. Example 193 was obtained as a mixture of diastereoisomers. High resolution mass (HRMS) calculated for C26H21O 1402S: 454.1440, found: 455.1540 and 455.1545 for the two diastereoisomers (M + H). Example 194: N-16-ethyl-5- (naphthalen-1-yl) thieno [2,3-d] pyrimidin-4-yl) -1-methyl-Distiidine Following general procedure Ib and taking Preparation 4k as the appropriate 4-chloro-thieno [2,3-d] pyrimidine derivative and (2R) -2-amino-3- (1-methyl-imidazol-4-yepropanoic acid as a derivative of As a suitable amino acid, a mixture of diastereoisomers was obtained which was purified by reverse phase preparative chromatography using a 0.1% aqueous TFA solution and acetonitrile as eluents. the form of a mixture of diastereoisomers.
[0161] High resolution mass (HRMS) calculated for C25H23N5O2S: 457,1572, found: 458,1641 and 458,1654 for both diastereoisomers (M + H). Example 195: 1-Benzyl-N46-ethyl-5- (naphthalen-1-yl) -thieno-1,2-djpyrimidin-4-yl] -distien Following general procedure Ib and taking Preparation 4k as a derivative of 4- suitable hydrochloride and / or (2R) -2-amino-3- (1-benzylimidazol-4-yl) propanoic acid as the appropriate amino acid derivative, a mixture of diastereomers was obtained. It was purified by reverse phase preparative chromatography using 0.1% aqueous TFA solution and acetonitrile as eluents. Example 195 was obtained as a mixture of diastereoisomers. High resolution mass (HRMS) calculated for C 31 O 12 N 5 O 2 S: 533.1855, found: 534.1934 and 534.1934 for both diastereoisomers (M + H). Example 196: N- [6-Methyl-5- (naphthalen-1-yl) thieno [2,3-dipyrimidin-4-yl] -D-phenylalanine Following general procedure 1a and taking Preparation 41 as a derivative of appropriate 4-chloro-thieno [2,3-d] pyrimidine and D-phenylalanine as the appropriate amino acid derivative, a mixture of diastereoisomers was obtained. It was purified by reverse phase preparative chromatography using 0.1% aqueous TFA solution and acetonitrile as eluents. Example 196 was obtained as a mixture of diastereoisomers. High resolution mass (HRMS) calculated for C26H21N3O2S: 439.1354, found: 440.1481 and 440.1429 (M + H). Example 197: N46- (hydroxymethyl) - (5R ') - 5- (naphthalen-1-yl) thieno [2,3-d] pyrimidin4-yl] -O-phenylalanine and Example 198: N46- (hydroxymethyl) - (5S ') - 5- (naphthalen-1-yl) thieno [2,3-dlpyrimidin-4-yl] -D-phenylalanine Following general procedure 1a and taking Preparation 4m as a derivative of 4- Suitable chloro-thieno [2,3-a] pyrimidine and D-phenylalanine as the appropriate amino acid derivative, a mixture of diastereoisomers was obtained. They were separated by reverse phase preparative chromatography using an aqueous solution of 0.1% TFA and acetonitrile as eluents. Example 197 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C26H21N3O3S: 455.1304, found: 456.1356 (M + H). Example 198 was obtained as the last eluted diastereoisomer.
[0162] High resolution mass (HRMS) calculated for C26H21NO3O3S: 455.1304, found: 456.1390 (M + H). Example 199: N46-acetyl- (5Sa) -5- (naphthalen-1-34) -thieno [2,3-4-pyrimidin-4-yl] -D-phenylalanine and Example 200: N-16-acetyl- (5R ') -5- (naphthalen-1-yl) -thieno [2,3-di-pyrimidin-4-yl] -dphenylalanine Following general procedure 1a and taking Preparation 40 as a derivative of 4-chloro-thieno [2,3-cflpyrimidine] and D-phenylalanine as the appropriate amino acid derivative, a mixture of diastereoisomers was obtained. They were separated by preparative reverse phase chromatography using 40 mM aqueous NH4OAc (pH = 4, adjusted with AcOH) and acetonitrile as eluents. Example 199 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C27 121N303S: 467.1304, found: 468.1379 (M + H). Example 200 was obtained as the last eluted diastereoisomer. High resolution mass (HRMS) calculated for C27H21N3O3S: 467.1304, found: 468.1377 (M + H).
[0163] Example 201: N45- (naphthalen-1-yl) -6- (propan-2-yl) -thieno [2,3-dlpyrimidin-4-yl] -D-phenylalanine, diastereoisomer 1 and Example 202: N- [ 5- (naphthalen-1-yl) -6- (p roman-2-yl) -thieno [2,3-d] pyrimidin-4-yl-D-phenylalanine, diastereoisomer 2 Following the procedure General Ib and taking Preparation 4q as the appropriate 4-chloro-thieno [2,3-d] pyrimidine derivative and D-phenylalanine as the appropriate amino acid derivative, a mixture of diastereoisomers was obtained. They were separated by preparative reverse phase chromatography using a 40 mM aqueous solution of NH40Ac (pH = 4, adjusted with AcOH) and acetonitrile as eluents.
[0164] Example 201 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C28H25N3O2S: 467.1677, found: 468.1731 (M + H) - Example 202 was obtained as the last eluted diastereoisomer. High resolution mass (HRMS) calculated for C281I25N302S: 467.1677, found: 468.1720 (M + H). Example 203: N46- (1-Hydroxyethyl) -5- (naphthalen-1-yl) -thieno [2,34] pyrimidin-4-yl] -D-phenylalanine, diastereoisomer 1 and Example 204: N46- (1) -hydroxyethyl-5- (n-acetyl-1-yl) -thien-1212-di-pyrimidin-4-yl-D-phenylalanine, diastereoisomer 2 Following general procedure 1a and taking Preparation 4n1 as derivative of appropriate 4-chloro-thieno [2,3-d] pyrimidine and D-phenylalanine as the appropriate amino acid derivative, a mixture of diastereoisomers was obtained which were separated by reverse phase preparative chromatography using a 0.1% aqueous TFA solution and acetonitrile as eluents Example 203 was obtained as the diastereoisomer eluted first High resolution mass (HRMS) calculated for C27E123N3O3S: 469.1460 Found: 470.1511 (M + H) Example 204 was obtained as the last eluted diastereoisomer High resolution mass (HR MS) calcd for C27H23N3O3S: 469.1460, found: 5,470.1536 (M + H). Example 205: N46- (1-hydroxyethyl) -5- (naphthalen-1-yl) -thieno [2,3-d] pyrimidin-4-yl-D-phenylalanine, diastereoisomer 3 and Example 206: N46- (1) -hydroxyethyl) -5- (naphthalen-1-yl) -thieno-12,3-dipyrimidin-4-yl-D-phenylalanine, diastereoisomer 4 Following general procedure 1a and taking Preparation 4n2 as a 4-chloro-thieno derivative Suitable [2,3-d] pyrimidine and D-phenylalanine as the appropriate amino acid derivative, a mixture of diastereoisomers was obtained. They were separated by preparative reverse phase chromatography using 0.1% aqueous TFA solution and acetonitrile as eluents. Example 205 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C27E123N3O3S: 469.1460, found: 470.1539 (M + H). Example 206 was obtained as the diastereoisomer eluted last.
[0165] High resolution mass (HRMS) calculated for C27H33N3O3S: 469.1460, found: 470.1534 (M + H). Example 207: N [6- (difluoromethyl) -5- (naphthalen-1-yl) -thieno [2,3-d] pyrimidin-4-yl] -D phenylalanine, diastereoisomer 1 and Example 208: N- [6- ( difluoromethyl) -5- (naphthalen-1-yl) -thieno 12,3-dlpyrimidin-4-yl D-phenylalanine, diastereoisomer 2 Following general procedure 1a and taking Preparation 4r as a 4-chlorothieno derivative [ 2,3-d] pyrimidine and D-phenylalanine as the appropriate amino acid derivative, a mixture of diastereoisomers was obtained. They were separated by preparative reverse phase chromatography using a 40 mM aqueous solution of NH40Ac adjusted with AcOH) and acetonitrile as eluents. Example 207 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C26H0F2N3O2S: 475.1116, found: 476.1242 (M + H). Example 208 was obtained as the diastereoisomer eluted last.
[0166] High resolution mass (HRMS) calculated for C26H19F2N3O2S: 475.1116, found: 476.1244 (M + H). Example 209: N-46- (2-hydroxypropan-2-yl) - (5R ') - 5- (naphthalen-1-yl) thieno [2,3-Mpyrimidin-4-yl] -D-phenylalanine and Example 210 : NP- (2-hydroxypropan-2-yl) - (5S ') - 5- (naphthalen-1-yl) thieno12,34 / 1-pyrimidin-4-yl] -D-phenylalanine By following the procedure General 1a and taking Preparation 4p as the appropriate 4-chloro-thieno [2,3-d] pyrimidine derivative and D-phenylalanine as the appropriate amino acid derivative, a mixture of diastereoisomers was obtained. They were separated by reverse phase preparative chromatography using an aqueous solution of 0.1% TFA and acetonitrile as eluents. Example 209 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C28H25N3O3S: 483.1617, found: 484.1689 (M + H).
[0167] Example 210 was obtained as the last eluted diastereoisomer. High resolution mass (HRMS) calculated for C281125N303S: 483.1617, found: 484.1704 (M + H). Example 211: N46-iodo-5- (naphthalen-1-yl) thieno [2,3-d] pyrimidin-4-yl] -D-phenylalanine Following general procedure 1a and taking Preparation 4s as a derivative of 4 Suitable chloro-thieno [2,3-d] pyrimidine and D-phenylalanine as the appropriate amino acid derivative, using DMA as solvent in place of DMSO, a mixture of diastereoisomers was obtained. It was purified by reverse phase preparative chromatography using a 40 mM aqueous solution of NH4OAc (pH = 4, adjusted with AcOH) and acetonitrile as eluents. Example 211 was obtained as a mixture of diastereoisomers. High resolution mass (HRMS) calculated for C25H181N3O2S: 551.0164, found: 552.0258 (M + H). Example 212: N-R5Ra) -5- (3-chloro-2-methylphenyl) -6-ethenylthieno [2,3-d] pyrimidin-4-yl] -D-phenylalanine and Example 213: N-R5M-5- (3-Chloro-2-methylphenyl) -6-ethenylthieno [2,3-d] pyrimidin-4-yl) phenylalanine Following general procedure IIc and taking Preparation 5a as the derivative of 6-iodothieno [2,3-d] pyrimidine and the vinyl boronic acid pinacol ester as the appropriate boronic acid derivative, a mixture of diastereoisomers was obtained. They were separated by reverse phase preparative chromatography using an aqueous solution of 0.1% TFA and acetonitrile as eluents. Example 212 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C24H20ClN3O2S: 449.0965, found: 450.1038 (M + 11). Example 213 was obtained as the last eluted diastereoisomer. High resolution mass (HRMS) calculated for C241120C1N302S: 449.0965, found: 450.1050 (M + H).
[0168] Example 214: N-R5R ') - 5- (3-chloro-2-methylphenyl) -6- (prop-1-en-2-ylthieno [2,34]] pyrimidin-4-yl] -D- phenylalanine and Example 215: N-R5S ') - 5- (3-chloro-2-methylphenyl) -6- (prop-1-en-2-yl) thieno [2,341-pyrimidin-4-yl] -13 By following the general procedure IIc and taking Preparation 5a as appropriate 6-iodo-thieno [2,3-d] pyrimidine and 2-isopropenyl-4,4,5,5-tetramethyl-1, 3,2-dioxaborolane as the appropriate boronic acid derivative, a mixture of diastereoisomers was obtained. They were separated by preparative reverse phase chromatography using 0.1% aqueous TFA solution and acetonitrile as eluents. Example 214 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C25H22ClN3O2S: 463.1111, found: 464.1178 (M + H). Example 215 was obtained as the last eluted diastereoisomer. High resolution mass (HRMS) calculated for C25H22ClN3O2S: 463.1111, found: 464.1179 (M + H).
[0169] Example 216: N-R5Ra) -5- (3-chloro-2-methylphenyl) -6-eyelopropylthieno [2,3-4-pyrimidin-4-yl] -D-phenylalanine and Example 217: N -R5S ') - 5- (3-chloro-2-methylphenyl) -6-cyclopropylthieno [2,34] pyrimidin-4-yl-D-phenylalanine Following the general procedure Ha and taking the Preparation 5a as the appropriate 6-iodothieno [2,3-cipyrimidine derivative and cyclopropylboronic acid as the appropriate boronic acid derivative, and Bu4NOH in place of K2CO3, a mixture of diastereoisomers was obtained. They were separated by preparative reverse phase chromatography using 0.1% aqueous TFA solution and acetonitrile as eluents. Example 216 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C25H22ClN3O2S: 463.1111, found: 464.1177 (M + H). Example 217 was obtained as the last eluted diastereoisomer. High resolution mass (HRMS) calculated for C25H22ClN3O2S: 463.1121, found: 464.1182 (M + H). Example 218: N-1 (55 ') - 5- (3-chloro-2-methylphenyl) -6- (propan-2-yl) thieno12,341-pyrimidin-4-yl] -L-phenylalanine and 25 Example 219: N-1 (5H-5- (3-chloro-2-methylphenyl) -6- (propan-2-yl) thieno [2,3-d] pyrimidin-4-yl) phenylalanine Following general procedure Ib and taking Preparation 4u as appropriate 4-chloro-thieno [2,3-d] pyrimidine and L-phenylalanine as the appropriate amino acid derivative, a mixture of diastereoisomers was obtained. by reverse phase preparative chromatography using a 0.1% aqueous TFA solution and acetonitrile as eluents Example 218 was obtained as the diastereoisomer eluted first. (HRMS) calcd for C25H24ClN3O2S: 465.1278, found: 466.1371 (M + H) Example 219 was obtained as the last eluted diastereoisomer High resolution mass (HRMS) calculated for C25H24ClN2O2S: 465 12 78, found: 5,466,1361 (M + H) Example 220: N-R 5 R ') - 5- (3-chloro-2-methylphenyl) -6- (propan-2-yl) thieno-pyrimidin-4-yl -D-phenylalanine and Example 221: N1 (54-5- (3-chloro-2-methylphenyl) -6- (propan-2-yl) thieno [2,3-o] pyrimidin-4-ylFD By following general procedure Ib and taking Preparation 4u as the appropriate 4-chloro-thieno [2,3-d] pyrimidine and D-phenylalanine as the appropriate amino acid derivative, a mixture of diastereoisomers was obtained. They were separated by reverse phase preparative chromatography using 0.1% aqueous TFA solution and acetonitrile as eluents. Example 220 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C25H24ClN3O2S: 465.1278, found: 466.1348 (M + H). Example 221 was obtained as the diastereoisomer eluted last.
[0170] High resolution mass (HRMS) calculated for C25H24ClN3O2S: 465.1278, found: 466.1395 (M + H). Example 222: N - [(5R ') - 5- (3-chloro-2-methylphenantl) -6- (propan-2-yl) thieno [2,3-d] pyrimidin-4-yl] 2-methoxy-D-phenylalanine and Example 223: N-R5Sa) -5- (3-chloro-2-methylphenyl) -6- (propan-2-ylthieno [2,3-4-pyrimidin-4-yl] -2-methoxy-D-phenylalanine Following general procedure Ib and taking Preparation 4u as appropriate 4-chloro-thieno [2,3-di-pyrimidine and (2R) -2-amino acid no-3- (2-methoxyphenyl) propanoic acid as the appropriate amino acid derivative, a mixture of diastereoisomers was obtained which were separated by reverse phase preparative chromatography using an aqueous solution of 0.1% TFA and acetonitrile. Example 222 was obtained as the diastereoisomer eluted first.High resolution mass (HRMS) calculated for C 26 H 26 ClN 3 O 3 S 495.1383, found: 496.1460 (M + H). 223 was obtained as the diastereoisomer eluted last.
[0171] High resolution mass (HRMS) calculated for C261-126C1N3O3S: 495.1383, found: 496.1444 (M + H). Example 224: N-R5Ra) -5- (3-chloro-1H-indol-4-yl) -6-ethyl-thieno [2,3-dlpyrimidin-4-yl] -D-phenylalanine and Example 225: N -5S ') - 5- (3-chloro-1H-indol-4-yl) -6-ethyl-thieno-12,3-d] pyrimidin-4-yl-D-phenylalanine 522 mg Preparation 7h (1 mmol), 164 mg of NCS (1.2 mmol), 15 ml of CCl4 and 10 ml of THF were stirred at RT under N 2 atmosphere for 2 hours. Then, the mixture was poured into ice water and extracted with DCM. The combined organic phases were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The formed diastereoisomers were separated by preparative reverse phase chromatography using 40 mM aqueous NH4OAc (pH = 4, adjusted with AcOH) and acetonitrile as eluents.
[0172] Example 224 was obtained as the last eluted diastereoisomer. High resolution mass (HRMS) calculated for C25F121ClN4O2S: 476.1074, found: 477.1133 (M + H). Example 225 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C251-121CIN402S: 476.1074, found: 477.1137 (M + H). Example 226: N-1 (5S ') - 5- (3-bromo-1H-indol-4-yl) -6-ethylthieno [2,3-d] pyrimidin-4-yl) phenylalanine and Example 227: N4 (5H-5- (3-bromo-1H-indol-4-yl) -6-ethylthieno [2,3-d] pyrimidin-4-yl] -D-phenylalanine 522 mg Preparation 7h (1 nmol), 216 mg of NBS (1.2 mmol), 15 ml of CCl4 and 5 ml of THF were stirred at RT under N 2 atmosphere for 2 hours, then the mixture was poured into water. The combined organic phases were dried over Na 2 SO 4, filtered and the filtrate was concentrated under reduced pressure The diastereoisomers formed were separated by preparative reverse phase chromatography using an aqueous solution of NH 4 OAc. 40 mM (pH 4, adjusted with AcOH) and acetonitrile as eluents.
[0173] Example 226 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C25H21BrN4O2S: 520.0569, found: 521.0653 (M + H). Example 227 was obtained as the diastereoisomer eluted last. High resolution mass (HRMS) calculated for C25H21BrN4O2S: 520.0569, found: 521.0629 (M + H). Example 228: N-16-ethyl- (5S) -5- (3-di-1H-indol-4-yl) thieno [2,3-4-pyrimidin-4-yl] -Depenylalanine and Example 229: N- [6-ethyl- (5R ') - 5- (3-iodo-1H-in-4-yl) thieno [2,3-d] pyrimidin-4-yl] 13-phenylalanine 522 mg of Preparation 7h (1 mmol), 196 mg of KOH (3.5 mmol), 15 ml of DMF and 267 mg of iodine (1.05 mmol) were stirred at RT under N 2 atmosphere for 18 hours. hours. Then, the mixture was poured into ice water and saturated Na2S2O3 solution was added. The mixture was extracted with DCM, the combined organic phases were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The formed diastereoisomers were separated by preparative reverse phase chromatography using 40 mM aqueous NF140Ac (pH 4, adjusted with AcOH) and acetonitrile as eluents. Example 228 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C25H21N4O2S: 568.043, found: 569.0498 (M + H). Example 229 was obtained as the last eluted diastereoisomer. High resolution mass (HRMS) calculated for C25H21N4O2S: 568.043, found: 569.0502 (M + H).
[0174] Example 230: N4 (54-5- {3-chloro-142- (dimethylamino) ethyl-1H-indol-4-yl) -ethyl-thieno2,3-4 pyridin-4-yl ) -D-phenylal a and ne and Example 231: N - ((5Ra) -5- (3-chloro-1-12- (dimethylamino) ethyl-1H-indol-4-yl} -6-ethyl- thieno [2,3-di-pyri-4-yl) -D-phenylamine Following the general procedure VIII and taking Preparation 7i as the appropriate indole derivative and 2- (N, N-dimethylamino) ethanol as the appropriate alcohol, Example 230 was obtained as the diastereoisomer eluted first.High resolution mass (HRMS) calculated for C291-130C1N5O2S: 547.1809, found: 548.1902 (M + H).
[0175] Example 231 was obtained as the last eluted diastereoisomer. High resolution mass (HRMS) calculated for C291-13oClN2O2S: 547.1809, found: 548.1889 (M + H). Example 232: N - ((5R ') - 5- {3-chloro-142- (pyrrolidin-1-yl) ethyl-1H-indol-4-yl} -6-ethyl-thieno [2,3-d] ] pyrimidin-4-yl) -D-phenylalanine and Example 233: N - {(5S) -5- {3-chloro-1- [2- (pyrrolidin-1-yl) ethyl] -1Hindol-4-yl} - 6-ethyl-thieno [2,3-d] pyrimidin-4-yl) -D-phenylalanine Following general procedure VIII and taking Preparation 7i as the appropriate indole derivative and 2-pyrrolidin-1-ylethanol as the appropriate alcohol, Example 232 was obtained as the last eluted diastereoisomer. High resolution mass (HRMS) calcd for C 31 H 1332 ClN 2 O 2 S: 573.1965, found: 574.2059 (M + H). Example 233 was obtained as the diastereoisomer eluted first.
[0176] High resolution mass (HRMS) calcd for C 31 H 1332 ClN 2 O 2 S: 573.1965, found: 574.2060 (M + H). Example 234: N4 (5R ') - 5- {3-chloro-142- (piperidin-1-yl) ethyl) indol-4-yl] -6-ethylthieno [2,3-d] pyrimidin-4-yl ) -D-phenylalanine and Example 235: N - ((5S ()) - 5- {3-chloro-142- (piperidin-1-yl) ethyl-1H-indol-4-yl} -6-ethyl; thieno [2,3-d] pyrimidin-4-yl) -D-phenylalanine Following the general procedure VIII and taking Preparation 7i as the appropriate indole derivative and 2- (1-piperidyl) ethanol as alcohol. A mixture of diastereoisomers was obtained which were separated by reverse phase preparative chromatography using a 0.1% aqueous TFA solution and acetonitrile as eluents. Diastereoisomeric form eluted first High resolution mass (HRMS) calculated for C32H34ClN2O2S: 587.2122, found: 588.2201 (M + H) Example 235 was obtained as the diastereoisomer eluted last. resolution (HRMS) calculated for C32H34 CIN 502S: 587.2122, found: 588.2199 (M + H) Example 236: N - ((5R0) -5 {3-chloro-1.42- (morpholin-4-yl) ethyl-1H-in) 4-yl) -6-ethylbenzo [2,3-d] pyrimidin-4-yl) -D-phenylalanine and Example 237: N4 (5S ') - 5- (3-chloro-1-12- (morpholine) 4-yl) ethyl-1H-indol-4-yl} -6-ethyl-thieno [2,3-d] pyrimidin-4-yl) -D-phenylalanine Following general procedure VIII and taking the Preparation 7i as the appropriate indole derivative and 2-moepholinoethanol as the appropriate alcohol, Example 236 was obtained as the last eluted diastereoisomer. High resolution mass (HRMS) calcd for C 31 H 1332 ClN 50 S: 589.1914, found: 590.1998 (M + H). Example 237 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C 311-1132ClN 50 S: 589.1914, found: 590.1994 (M + H).
[0177] Example 238: N4 (551) -5- {3-chloro-1-12- (4-methyl-piperazin-1-ylmethyl-1H-indol-4-yl} -6-ethyl-thieno [2] , 3-d] pyrimidin-4-yl) -D-phenylalanine and Example 239: N-gR ') - 5- {3-chloro-142- (4-methylpiperazin-1-yl) ethyl] 1H-Indol-4-yl) -6-ethyl-thieno-12,3-4-pyrimidin-4-yl) -D-phenylalanine Following the general procedure VIII and taking Preparation 7 as a derivative of Suitable indole and 2- (4-methylpiperazin-1-yl) ethanol as the appropriate alcohol, Example 238 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C32H35ClN602S: 602.2231, found: 603.2312 (M + H). Example 239 was obtained as the diastereoisomer eluted last.
[0178] High resolution mass (HRMS) calculated for C32H35ClN6O2S: 602.2231, found: 603.2311 (M + H). Example 240: N4 (5S) -5- (3-chloro-143- (4-methyl-piperazin-1-apropy-1H-indol-4-yl) -6-ethyl-thieno [2,3-dipyrimidin] 4-yl) -D-phenylalanine and Example 241: N - ((5 / ta) -5- (3-chloro-1-13- (4-methyl-piperazin-1-ylpropyll-111-indol-4- Y11-6-ethyl-thieno [2,3-d] pyrimidin-4-yl) -D-phenylalanine Following General Procedure VIII and taking Preparation 7i as the appropriate indole derivative and 3- (4-methylpiperazine 1-yppropan-1-ol as the appropriate alcohol, Example 240 was obtained as the diastereoisomer eluted first.High resolution mass (HRMS) calculated for C33H37ClN6O2S: 616.2387, found: 617.2466 (M. + H) Example 241 was obtained as the last eluted diastereoisomer High resolution mass (HRMS) calculated for C33H37ClN6O2S: 616.2387, found: 617.2473 (M + H) Example 242: 3 -eyelohexyl-N [6-ethyl-5- (1H-indol-4-371) thieno [2,3-d] pyrimidin-4-yl) -D-alanine, diastereoisomer 1 and 3037956 - Example 24 3: 3-Cyclohexyl-N46-ethyl-5- (1H-indol-4-yl) thieno [2,3-dipyrimidin-4-yl] -D-alanine, diastereoisomer 2 Following general procedure 1a and taking the Preparation 4v as the appropriate 4-chloro-thieno [2,3-d] pyrimidine derivative and (2R) -2-amino-3-cyclohexylpropanoic acid as the appropriate amino acid derivative, a mixture of diastereoisomers was obtained. They were separated by reverse phase preparative chromatography using an aqueous solution of 0.1% TFA and acetonitrile as eluents. Example 242 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C25H281 · 1402S: 448.1933, found: 449.1994 (M + H). Example 243 was obtained as the last eluted diastereoisomer. High resolution mass (HRMS) calculated for C25H28N4O2S: 448.1933, found: 449.2006 (M + H).
[0179] Example 244: N - [(5S) -5- (3-chloro-1H-indol-4-yl) -6-ethyl-thieno [2,3,4] -pyrimidin-4-yl] -3-pyridin-2-one Y1-D-alanine and Example 245: N-R5R (,) - 5- (3-chloro-1H-indol-4-yl) -6-ethyl-thieno [2,3-dlpyrimidin-4-yl] -3 -pyridin-2-yl-D-alanine Following general procedure 1a and taking Preparation 7j as the appropriate 4-chloro-thieno [2,3-d] pyrimidine derivative and (2R) -2-acid. amino-3- (2-pyridyl) propanoic acid as the appropriate amino acid derivative, a mixture of diastereoisomers was obtained. They were separated by reverse phase preparative chromatography using a 40 mM aqueous solution of NH40Ac (pH 4, adjusted with AcOH) and acetonitrile as eluents. Example 244 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C24H20ClN5O2S: 477.1026, found: 478.1087 (M + H). Example 245 was obtained as the diastereoisomer eluted last. High resolution mass (HRMS) calculated for C24H20ClN2O2S: 477.1026, found: 478.1089 (M + H). Example 246: N4 (55α) -5-13-chloro-142- (morpholin-4-371) ethyl-1H-indol-4-yl] -6-ethyl-thieno [2,3-d] ] Pyrimidin-4-yl) -3-pyridin-2-yl-D-alanine Step A: (2R) -2-11- (55) -5- (3-Chlaro-1H-indol-4-yl) Methyl 6-ethyl-thieno-1,2,3-dlpyrimidin-4-yliaminol-3- (2-pyridyl) -propanoate 0.13 g of Example 244 (0.27 mmol) was dissolved in 13 ml MeOH; then 0.3 ml of cc H 2 SO 4 was added and the mixture was stirred at RT until no further conversion was observed, then it was concentrated under reduced pressure and a saturated aqueous solution of NaHCO 3 was added. The precipitate formed was collected by filtration to obtain (2R) -2 - [[(5Sa) -5- (3-chloro-1H-indol) -4-34) -6- Methyl ethyl-thieno [2,3-a] pyrimidin-4-yl-amino] -3- (2-pyridyppropanoate) Step B: Example 246 Following General Procedure VIII and taking (2R) -2- [ [(5Sa) -5- (3-chloro-1H-indol-4-yl) -6-ethyl-thieno [2,3-d] p As the appropriate indole derivative and 2-morpholinoethanol as the appropriate alcohol, Example 246 was obtained. High resolution mass (HRMS) calculated for C30H3ICIN603S: 590.1867, found: 591.1938 (M + H).
[0180] Example 247: N4 (51t) -5- {3-chloro-1-12- (morpholin-4-ylethyl) -1H-indol-4-yl) -6-ethyl-thieno [2,3-d] pyrimidin 4-34) -3-pyridin-2-yl-D-alanine Step A: (2R) -2 - [[(5R) -5- (3-chloro-1H-indol-4-yl) -6 Methyl-thieno [2,3-dlpyrimidin-4-yl] amino] -3- (2-pyridyl) -propionic acid 0.157 g of Example 245 (0.33 mmol) was dissolved in 15 ml of MeOH. then 0.3 ml of H2SO4 cc. was added and the mixture was stirred at RT until no further conversion was observed. Then, it was concentrated under reduced pressure and a saturated aqueous solution of NaHCO 3 was added and the mixture was stirred. The precipitate formed was collected by filtration to obtain (2R) -2 - [[(5Ra) -5- (3-chloro-1H-indol-4-yl) -6-ethyl-thieno [2,3-d]. d] Methyl pyrimidin-4-yl-amino] -3- (2-pyridyppropanoate) Step B: Example 247 Following general procedure VIII and taking (2R) -2 - [[(5. N-O-5- (3-chloro-1H-indol-4-yl) -6-ethyl-thieno [2,3-d] pyrimidin-4-ylamino] -3- (2-pyridyl) -propanoate; methyl as the appropriate amine and 2-mmpholinoethanol as the appropriate alcohol Example 247 was obtained High resolution mass (HRMS) calculated for C30H31ClN6O3S: 590.1867, found: 591.1918 (M + H) Example 248: N - ((5S) -5- (3-chloro-142- (4-methyl-piperazin-1-yl) ethyl-1H-indol-4-yl) -6-ethyl-thieno [2,3-d] pyrimidin 4-yl) -3-pyridin-2-yl-D-alanine Step A: (2R) -2 - [[(58,7) -5- (3-chloro-1H-indol-4-yl) Methyl 6-ethyl-thieno [2,3-d] pyrimidin-4-yllaminal-3- (2-pyridyl) -propanoate 0.13 g of Example 244 (0.27 mmol) was dissolved in 13 ml of Me0H, then 0 To 3 ml of H 2 SO 4 cc was added and the mixture was stirred at RT until no further conversion was observed. Then, it was concentrated under reduced pressure and a saturated aqueous solution of NaHCO 3 was added and the mixture was stirred. The precipitate formed was collected by filtration to obtain (2R) -2 - [[(5Sa) -5- (3-chloro-1H-indol-4-yl) -6-ethyl-thieno [2,3-d] ] Pyrimidin-4-yl-amino] -3- (2-pyridyl) propanoate methyl.
[0181] Step B: Example 248 Following general procedure VIII and taking (2R) -2 - [[(5S, 7) -5- (3-chloro-1H-indol-4-yl) -6-ethyl] methyl thieno [2,3-d] pyrimidin-4-yl] aminol-3 - (2-pyridyl) -propanoate as the appropriate indole derivative and 2- (4-methylpiperazin-1-yoethanol as the appropriate alcohol, Example 248 was obtained High resolution mass (HRMS) calculated for C31H34ClN2O2S 603.2183, found: 302.6172 (M + 2H) Example 249: N4 (51ZR) -5- (3- 1H-chloro-1- [2- (4-methyl-piperazin-1-yl) ethyl] -1H-indol-4-yl] -6-ethyl-thieno [2,3-pyrimidin-4-yl] -3-pyridin-2-yl] 1) -Alanine Step A: (2R) -2-11 (54-5- (3-chloro-1H-indol-4yl) -6-ethyl-thieno [2,3-dlpyrimidin-4-yl] aminol Methyl 3- (2-pyridyl) propanoate 0.157 g of Example 245 (0.33 mmol) was dissolved in 15 ml of MeOH, then 0.3 ml of H 2 SO 4 cc was added and the mixture was stirred at RT until no further conversion was observed, and then was concentrated in a press Reduced ion and a saturated aqueous solution of NaHCO3 was added and the mixture was stirred. The precipitate formed was collected by filtration to obtain (2R) -24K5Ra) -5- (3-chloro-1H-indol-4-yl) -6-ethyl-thieno [2,3-d] pyrimidin-4 Methyl 2-pyridyppropanoate Step B: Example 249 By following general procedure VIII and taking (2R) -2 - [[(5 / Q-5- (3-chloro)] Methyl 1H-indol-4-yl) -6-ethylthieno [2,3-d] pyrimidin-4-ylamino] -3- (2-pyridyl) -pyropanoate as the appropriate indole derivative and the (4-methylpiperazin-1-ypethanol as the appropriate alcohol, Example 249 was obtained High resolution mass (HRMS) calculated for C31H34ClN2O2S: 603.2183, found: 302.6164 (M + 2H).
[0182] Example 250: N-16- (difluoromethyl) - (5S ') - 5- (naphthalen-1-yl) thieno [2,3-d] pyrimidin-4-yl] -3-pyridin-2-yl-D- alanine and Example 251: N-16- (difluoromethyl) - (5R ') - 5- (naphthalen-1-yl) thieno [2,3-d] pyrimidin-4-yl] -3-pyridin-2-yl D-alanine Following general procedure 1a and taking Preparation 4r as the appropriate 4-chloro-thieno [2,3-dlpyrimidine derivative and (2R) -2-amino-3- (2-pyridyl) acid) propanoic acid as a suitable amino acid derivative, a mixture of diastereoisomers was obtained. They were separated by reverse phase preparative chromatography using a 40 mM aqueous solution of NH 4 OAc (pH = 4, adjusted with AcOH) and acetonitrile as eluents. Example 250 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C25H18F2N4O2S: 476.1199, found: 477.1195 (M + H). EXAMPLE 251 was obtained as the last eluted diastereoisomer. High resolution mass (HRMS) calculated for C251-118F2N4O2S: 476.1199, found: 477.1182 (M + H).
[0183] Example 252: N-R5S ') - 5- (naphthalen-1-yl) -6-propyl-thieno [2,3-d] pyrimidin-4-yl] -1) -phenylalanine 266 mg of Example 108 (0.57 mmol) were dissolved in 10 ml of MeOH and 2 ml of AcOH, then 61 mg of 10% Pd / C was added. The mixture was stirred under an H 2 atmosphere at 40 ° C for 2 hours. It was filtered through Celite and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative reverse phase chromatography using 40 mM aqueous NH40Ac (pH = 4, adjusted with AcOH) and acetonitrile as eluents to obtain Example 252. High mass resolution (HRMS) calculated for C28H25N3O2S: 467.1677, found: 468.1746 (M + H).
[0184] Example 253: N - [(51 (I) -5- (naphthalen-1-yl) -6-propyl-thieno [2,3-d] pyrimidin-4-yl) -dphenylalanine 266 mg Example 109 (0.57 mmol) was dissolved in 10 ml of MeOH and 2 ml of AcOH, followed by addition of 61 mg of 10% Pd / C The mixture was stirred under an atmosphere of H2 at 40 ° C. for 2 hours, was filtered through Celite and the filtrate was concentrated under reduced pressure The crude product was purified by reverse phase preparative chromatography using a 40 mM aqueous solution of NH40Ac (pH = 4, adjusted with AcOH) and acetonitrile as eluents to obtain Example 253. High resolution mass (HRMS) calculated for C28H25N3O2S: 467.1667, found: 468.1736 (M + H). 254: Methyl N-16-ethyl- (5S) -5- (naphthen-1-yl) thieno-12,3-djpyrimidin-4-yl) phenylalaninate 102 mg of Example 101 (0.225 mmol) was dissolved in 2 ml of MeOFI and the mixture was cooled to 0 ° C. under an N 2 atmosphere Then 135 μl of a solution of diazomethyl (trimethyl) silane (2M in Et 2 O) was added and the mixture was allowed to warm to RT. Then, the mixture was concentrated in vacuo and purified by flash chromatography using heptane and EtOAc as eluents to obtain Example 254. High resolution mass (HRMS) calculated for C2H NOS: 467, 1667, found: 468.1746 (M + H).
[0185] Example 255: Methyl N46-ethyl- (5R ') - 5- (naphthalen-1-yl) thieno12,3-dlpyrimidin-4-yl-D-phenylalaninate 102 mg of Example 100 (0.225 mmol) were dissolved in 2 ml of MeOH and the mixture was cooled to 0 ° C under N 2 atmosphere. Then, 135 μl of a solution of diazomethyl (trimethyl) silane (2M in Et2O) was added and the mixture was allowed to warm to RT. The mixture was concentrated in vacuo and purified by flash chromatography using heptane and EtOAc as eluents to obtain Example 255. High resolution mass (HRMS) calculated for C28H25N3O2S: 467.1677, found: 468, 1737 (M + H).
[0186] Example 256: N-R5S) -5- {3-chloro-2-methyl-4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl} -6- (4-fluorophenyl) thieno Ethyl [2,3-4-pyrimidin-4-yl] -2 - {[2- (2-methoxyphenyl) -pyrimidin-4-yl] methoxy} -D-phenylalaninate Example 7 was dissolved in a solution of HCl (20 ml / mmol, 1.25M in EtOH) and the mixture was stirred at RT overnight. Then, the mixture was neutralized with NaHCO 3 solution and extracted with DCM. The organic phase was dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase preparative chromatography using 25 mM aqueous NH4HCO3 and acetonitrile as eluents to give Example 256. High resolution mass (HRMS) calculated for C49H49ClFN7O5S: 901.3188 found: 902.3225 (M + H). Example 257: 2 - [(1-tert-Butyl-111-pyrazol-5-yl) -methoxy] -N-R5Sa) -5-13-chloro-2-methyl-4- [2- (4-methyl) Ethylpiperazin-1-yl) ethoxy] phenyl-6- (p-p-1-yn-1-yl) thieno [2,3-d] pyrimidin-4-yl-D-phenylalaninate Example 40 was dissolved in a solution of HCl (20 ml / ml, 1.25M in EtOH) and the mixture was stirred at RT overnight. Then, the mixture was neutralized with NaHCO 3 solution and extracted with DCM. The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase preparative chromatography using 25 mM aqueous NH4HCO3 solution and acetonitrile as eluents to give Example 257. High resolution mass (HRMS) calculated for C42H50ClN7O4S: 783.3334 found: 392.6744 (M + 2H). Example 258: N-R5S ') - 5- {3-chloro-2-methyl-4- P- (4-methylpiperazin-1-yl) ethoxy] phenyl} -6- (prop-1-yn-1-yl) - Ethyl [2,3-d] pyrimidin-4-yl] -2- {12- (2-methoxyphenyl) -pyrimidin-4-yl] methoxy} -D-phenylalaninate Example 45 was dissolved in a HCI solution (20 ml / mmol, 1.25M in EtOH) and the mixture was stirred at RT overnight. Then, the mixture was neutralized with NaHCO 3 solution and extracted with DCM. The organic phase was dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase preparative chromatography using an aqueous 25 mM NH4HCO3 solution and acetonitrile as eluents to give Example 258. High resolution mass (HRMS) calculated for C46H48ClN4O5S: 845.3126 found: 423.6650 (M + H). Example 259: N-R5S ') - 5- {3-chloro-442- (dimethylamino) ethoxy] -2-methylphenyl} -6- (prop-yl) thiem) [2,3-d] pyrimidin Ethyl 4-yl-2-[2- (2-methoxyphenyl) -pyrimidin-4-yl] ethoxy) -DH-enylalaninate Example 49 was dissolved in a solution of HCl (20 ml. / mmol, 1.25M in EtOH) and the mixture was stirred at RT overnight. Then, the mixture was neutralized with NaHCO 3 solution and extracted with DCM. The organic phase was dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase preparative chromatography using 25mM aqueous NH4HCO3 and acetonitrile as eluents to give Example 259. High resolution mass (HRMS) calculated for C43H43ClN6O5S: 790.2704, found: 396.1455 (M + 2H). Example 260: N-1- (54-5- {3-chloro-442- (dimethylamino) ethoxy] -2-methylphenyl} -6- (4-fluorophenyl) -thieno12,3-4 pyrimidin Ethyl 4-yl] -2 - ({212- (2-methoxy-ethoxy) phenyl] pyrimidin-4-yl} methoxy) -D-phenylalaninate Example 51 was dissolved in a solution of HCl (20 ml / mmol, 1.25M in EtOH) and the mixture was stirred at 60 ° C until no further conversion was observed, then the mixture was neutralized with NaHCO 3 solution. The organic phase was dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure The crude product was purified by reverse phase preparative chromatography using an aqueous solution of NEL4HCO3. mM and acetonitrile as eluents to obtain Example 260. High resolution mass (HRMS) calculated for C45H48ClFN6O5S: 890.3029, found: 891.3105 (M + H) Example 261: N-1 (55 ( ,) - 543-ehloro-442- (Sun ethyl-amino) ethoxyl-2-methylphenyl} -6- (4-fluorophenyl) thieno [2,3-d] pyrimidin-4-yl] -2 - ({212- (2-methoxyethoxy) -phenyl) (5-methyl-2-oxo-1,3-dioxo-4-yl) methyl enyl] pyrimidin-4-emethoxy) -D-phenylalaninate 1 eq. of Example 51 and 1.1 eq. 4- (Chloromethyl) -5-methyl-1,3-dioxol-2-one were dissolved in DMF (10 ml / mmol), followed by 2 eq. of NaI and 2 eq. of Cs2CO3 were added and the mixture was allowed to stir until no further conversion was observed.
[0187] Then, the mixture was injected directly and purified by reverse phase preparative chromatography using an aqueous 25 mM NH4HCO3 solution and acetonitrile as eluents to obtain Example 261. High resolution mass (HRMS) calculated for C511 -148CIFN6O9S: 974.2876, found: 975.2949 (M + H).
[0188] Example 262: N - [(5Sa) -5-P-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxy] phenyl} -6- (4-fluorophenyl) -thieno [2] 1H-Ethoxyearbonyl) oxyl ethyl 3-diphthyridin-4-yl] -2- {12- (2-methoxyphenyl) -pyrimidin-4-ylmethoxyl-D-phenyl-alaninate Example 263: N-R5S ') -5- { 3-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxylphenyl} -6- (4-fluoro-phenyl) thieno [2,3-dlpyrimidin-4-yl] -2- 1 - [(Dimethylearbamoyl) oxylethyl [2- (2-methoxyphenyl) -pyrimidin-4-yl] methoxy] -D-phenylalaninate Example 264: N - [(5S +) - 5- ( 3-Chloro-2-methyl-4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl} -6- (4-fluorophenyl) thieno [2,3-Mpyrimidin-4-yl] -2 - ({2-13- (hydroxymethyl) -phenyl] pyrimidin-4-yl} methoxy) -D-phenylalanine Example 265: N-R5S ') - 5- (3-chloro-2-methyl-4-yl) (4-methylpiperazin-1-yl) ethoxy] phenyl} -6- (4-fluorophenyl) -thieno-12,3-tilpyrimidin-4-yl] -2 - ({2- [2- (hydroxymethyl) -pyridine) 4-yl] pyrimidin-4-ylimethoxy) -D-phenylalanine Example 266: N - [(5S ') ) -5- {3-Chloro-2-methyl-4- [2- (4-methylpiperazin-1-yl) -10-ethoxy] phenyl} -6- (4-fluorophenyl) thieno [2,3-d] pyrimidin-4-yl-2- (1216- (hydroxymethyl) -pyridazin-4-yl] pyrimidin-4-ylimethoxy) -D-phenylalanine Example 267: N - [(5Sa) -5-13-chloro-2-methyl 4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl] -6- (4-fluorophenyl) thieno [2,3-d] pyrimidin-4-yl) -2- (2-16 15 (hydroxymethyl) -pyrazin-2-ylpyrimidin-4-amethoxy) -D-phenylalanine Example 268: N-R5S ') - 5- (3-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ) - ethoxylphenyl) -6- (4-fluorophenyl) -thieno [2,3-d] pyrimidin-4-yl] - ([2 '- (hydroxymethyl) -2,5'-bipyrimidin-4-yl] methoxy Example 269: N-1 (54-5- {3-Chloro-2-methyl-4- [2- (4-methylpiperazin-1-yl) -ethoxy] phenyl} -6- (4-methylphenylalanine) 1-Fluorophenyl) -thieno [2,3-d] pyrimidin-4-yl] -2 - ({244- (phosphonooxy) -phenyl] pyrimidin-4-yl} methoxy) -D-phenylalanine Example 270: N45- (3, 5-Dichloro-2,6-dimethyl-4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl} -6- (4-fluorophenyl) thieno [2,3-4] pyrimidin-4-yl-2 - ([2- (2-methoxyphenyl) -pyrimidin-4-yl] methoxy} -D-phenylalanine Example 271: N45- {2,6-dimethyl-442} (4-methyl-piperazin-1-yl) ethoxylphenyl} -6- (4-fluorophenyl) -thieno [2,3-d] pyrimidin-4-yl] -2 - {[2- (2-methoxyphenyl)} - pyrimidin-4-yl] methoxyl-D-phenylalanine Example 272: N-R5S, i) -5- {3-chloro-2-methyl-4- [2- (4-methylpiperazin-1-yl)} ethoxy] phenyl-6- (4-fluoro-phenyl) -thieno [2,3-d] pyrimidin-4-yl-b- (hydroxymethyl) -2- {[2- (2-methoxyphenyl) pyrimidin-4} Example 273: N-R5Sa) -5- {3-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxy] phenyl} -6- (4-fluorophenyl) -1- [1-yl] methoxy) phenylalanine -thieno [2,3-d] pyrimidin-4-yl] -b-hydroxy-2-1 [2- (2-methoxy-4-pentyl) pyrimidin-4-yl] -methylphenylalanine Example 274: N - [(5S (,) - 5- 13-Chloro-2-methyl-4-12- (4-methylpiperazin-1-yl) ethoxy-phenyl] -6- (4-fluorophenyl) -thieno-12,3-djpyrimidin-4-yl) - (2-hydroxyethyl) -2 - {[2- (2-methoxyphenyl) pyrimidin-4-yl] methoxy) phenylalan PHARMACOLOGICAL STUDY EXAMPLE A Inhibition of Mc1-1 by the Fluorescence Polarization Technique The relative binding activity of each compound was determined by fluorescence polarization (PF). The method employs a fluorescein-labeled ligand (fluorescein- (3Ala-Ahx-A-REIGAQLRRMADDLNAQY-OH; pm 2,765) which binds to the Mc1-1 protein (such as Mc1-1 corresponding to the accession number UniProtKB® primer: Q07820), resulting in increased anisotropy measured in milli-polarization unit (mP) by means of a reader The addition of a compound that competitively binds to the same site that the ligand will lead to an increase in the proportion of unbound ligand in the system, indicated by a decrease in mP units Process I: An 11-point serial dilution of each compound was prepared in DMSO and 2 gl were transferred to a 384-well flat-bottomed, low-binding plate (5% final DMSO concentration), 38 μl buffer (10 mM 4- (2-hydroxyethyl) -1-piperazinethanesulfonic acid). [HEPES], 150 mM NaCl, 0.05% Tween 20, pH 7.4) containing the fluorine-labeled ligand escin (final concentration of 1 nM) and Mc1-1 protein (final concentration of 5 nM) were then added. Assay plates were incubated for about 2 hours at room temperature before measuring PF with a Biomek Synergy2 reader (eg, 528 nm, Em 640 nm, 510 nm cut-off) and calculating the results. mP units. The binding of increasing doses of test compound was expressed as percent reduction in mP from a window set 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 are shown in Table 1 below; the 1050 inhibition of Mc1-1 obtained using method 1 are not underlined.
[0189] Method 2: 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 (final concentration of 5% DMSO). ). 38 μl of buffer (20 mM Na 2 PO 4, 1 mM EDTA, 50 mM NaCl 2, pH 7.4) containing fluorescein labeled ligand (final concentration of 10 nM) and Mc1-1 protein (concentration 10 nM final) were then added.
[0190] Assay plates were incubated for about 2 hours at room temperature before measuring PF with a Biomek Synergy2 reader (eg 528 nm, In-1, 640 nm, 510 nm cutoff), and calculate the units mP. The binding of increasing doses of test compound 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" ( 50 μM unlabeled ligand). 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 using method 2 are shown in Table 1 below; the Mc1-1 inhibition IC50s obtained using Method 2 are underlined. The results show that the compounds of the invention inhibit the interaction between the Mc1-1 protein and the fluorescent peptide described above.
[0191] EXAMPLE B Cytotoxicity in vitro The cytotoxicity studies were performed on the H929 multiple myeloma tumor line. The cells are distributed in microplates and exposed to the 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 1050 (compound concentration which 50% inhibits cell viability) and are shown in Table 1 below. The results show that the compounds of the invention are cytotoxic. Table 1: 1C50 of delV1c1-1 Inhibition (Fluorescence Polarization and Cytotoxicity Test for H929 Cells Note: IC50s of Mc1-1 inhibition obtained with Method 2 are underlined. 1050 (MM) Mc1-1 1050 (gM) 1050 (iM) Mc1-1 IC50 (gM) MTT F1929 MTP MTT H929 Example 1 0.127> 6.0E-07 Example 29 0.063 2.52E-06 Example 2 56.9 % @ 10 gM> 6.0E-07 Example 30 68.2% @ 10 gM> 3.75E-06 Example 3 0.114 3.18E-07 Example 31 16.7% @ 10 [tM> 3.75E-06 Example 4 0.005 2.15E-07 Example 32 0.007> 3.75E-06 Example 5 ND ND Example 33 54.9% ® 10 gM ND Example 6 0 013> 6.0E-07 Example 34 0.726 4.27E-06 Example 7 0.008 1.38E-08 Example 35 24.78%> 3.0E-05 10 gM Example 8 0.054 2.58E-07 Example 36 0.086> 7.50E-06 Example 9 2.697> 3.75E-06 Example 37 18.7% @ 10 gM> 3,75E-06 Example 10 72,75% @> 3,75E-06 Example 38 1,871> 3,75E-06 3,3 gM Example 11 35,55% ®> 3,75E-06 Example 39 0.025 4.01E-07 10 i.th4 Example 12 0.014 6.47E-07 Example 40 0.006 3.28E-08 Example 13 58% @ 10 gM> 3.75E-06 Example 41 0.006 7.38E-09 Example 14 0.038 7.21E-07 Example 42 0.010 6.1E-08 Example 15 40.05% ®> 3.75E-06 Example 43 0.006 1.25E-08 10gM Example 16 0.006 9.93E-08 Example 44 0.007 3.44E-09 Example 17 0.057 2.94E-07 Example 45 0.005 8.96E-10 Example 18 1.821 1.14E- Example 46 0.024 1.66E-07 Example 19 0.020 1.75E-07 Example 47 0.008 8.39E-08 Example 20 0.026 7.86E-08 Example 48 0.007 1.61E-08 Example 21 0.006 3.97E-08 Example 49 0.003 4.12E-09 Example 22 0.002 8.59E-09 Example 50 0.007> 1.50E-07 Example 23 41.27% to 1 gM> 6.0E-07 Example 51 0.005 2.33E-08 Example 24 0.008 4.73 E-08 Example 52 0.3301 ND Example 25 55.5% @ 10 pM> 6.0E-07 Example 53 0.020 ND Example 26 0.012 6.36E-09 Example 54 0.541 ND Example 27 0.011 2.09E-09 Example 55 8,839 ND Example 28 0,116> 1,88E-06 Example 56 0.019 ND 105095 1050 (pM) Mc1-1 1050 (pM) 1C50 (pM) Mc1-1 1050 (pM) NITT H929 MIT H929 PF Example 57 0.106 ND Example 88 1,225 ND Example 58 52.8% @ 10 pM N Example 89 72.13% @ ND 200 μM Example 59 0.127 ND Example 90 0.023 ND Example 60 0.092 ND Example 91 6.372 ND Example 61 0.036 ND Example 92 12.887 ND Example 62 0.060 ND Example 93 0.080 ND Example 63 12.18% @ ND Example 94 6.901 ND 10 pM Example 64 0.025 ND Example 95 0.077 ND Example 65 0.345> 2.78E-06 Example 96 1.628 ND Example 66 36.9% @ 10 μM> 3.75E-06 Example 97 0.073 ND Example 67 2.079 ND Example 98 2.873 ND Example 68 0.142 ND Example 99 28.3% @ ND 200 μM Example 69 0.110 ND Example 100 4.747 ND Example 70 0.974 ND Example 101 0.462 ND Example 71 39.015 ND Example 102 0.073 ND Example 72 12.007 ND Example 103 0.715 ND Example 73 0.276 ND Example 104 0.046 ND Example 74 0.621 ND Example 105 0.704 ND Example 75 0.280 ND Example 106 0.065 ND Example 76 3.177 ND Example 107 0.544 ND Example 77 75.45% @ ND Example 108 0.079 ND 200 μM Example 78 0.135 ND Example 109 1.858 ND Example 79 0.429 ND Example 110 0.839 ND Example 80 0.487 ND Example 111 4.452 ND Example 81 20.241 ND Example 112 0,104 ND Example 82 1,109 ND Example 113 0,045 ND Example 83 0,258 ND Example 114 0,981 ND Example 84 4,022 ND Example 115 1,753 ND Example 85 0,228 ND Example 116 1,059 ND Example 86 9,976 ND Example 117 2,603 ND Example 87 62,6 % @ 7.4 11M ND Example 118 0.056 ND 1C50 (gM) Me1-1 1050 (el) 1050 (pM) Md-1 1050 (pM) MTT MTT MT 1-1929 PF H929 Example 119 1.456 ND Example 150 0.528 ND Example 120 9.445 ND Example 151 71.3% @ ND 66.7 μM Example 121 0.167 ND Example 152 0.047 ND Example 122 10.215 ND Example 153 75.7% @ 50 μM ND Example 123 0.152 ND Example 154 2.316 2, 03E-05 Example 124 75.7% @ 50 pM ND Example 155 63.15% @ ND 50 itM Example 125 13.710 ND Example 156 0.309 ND Example 126 41.2% @ 50 pM ND Example 157 62.05% @ ND 50 pM Example 127 0.913 ND Example 158 0.104 ND Example 128 10.722 ND Example 159 1.770 ND Example 129 0.053 ND Example 160 11.725 ND Example 130 67.4% @ 50 gM ND Example 161 12.579 ND Example 131 0.495 ND Example 162 0.597 ND Exe mple 132 9,844 ND Example 163 8,375 ND Example 133 0,079 ND Example 164 0,227 ND Example 134 0,176 ND Example 165 0,315 ND Example 135 75,25% @ 50 pM ND Example 166 0,064 ND Example 136 0,146 ND Example 167 1,146 ND Example 137 71, 05% @ 50 pM ND Example 168 4,775 ND Example 138 0,664 ND Example 169 2,105 ND Example 139 32,75% @ 10 pM ND Example 170 0,955 ND Example 140 0,208 ND Example 171 2,775 ND Example 141 26,78% @, ND Example 172 28.849 ND 10 pM Example 142 0.335 ND Example 173 6,794 ND Example 143 68,85% @ ND Example 174 0,466 ND 50 μM Example 144 0,154 ND Example 175 3,856 ND Example 145 3,888 ND Example 176 8,409 ND Example 146 0,071 ND Example 177 0,957 ND Example 147 14,236 ND Example 178 3,232 ND Example 148 0,416 ND Example 179 0,881 ND Example 149 14,001 ND Example 180 2,104 ND 3037956 - 169 1050 (itM) 1V1c1-1 1050 (1M) IC50 (pM) Mc1-1 IC50 (pM) MTT PF MTT H929 PF H929 Example 181 0,299 ND Example 212 12,674 ND Example 182 0,407 ND Example 213 0,111 ND Example 183 2,044 ND Example 214 1,911 ND Example 184 76.8% @ 200 μM ND Example 215 0.015 ND Example 185 2.533 ND Example 216 58.95% @ 10 μM ND Example 186 7.880 ND Example 217 0.065 ND Example 187 1.385 ND Example 218 71.5% @ 50 1.0.4 ND Example 188 21,302 ND Example 219 10,940 ND Example 189 8,327 ND Example 220 31,7% @ 10 pM ND Example 190 34,602 ND Example 221 0,097 ND Example 191 0,171 ND Example 222 70% @ 50 itM ND Example 192 2,082 ND Example 223 0,086 ND Example 193 36,522 ND Example 224 8,607 ND Example 194 1,752 ND Example 225 0,053 ND Example 195 14,228 ND Example 226 0,069 ND Example 196 2,908 ND Example 227 3,312 ND Example 197 54.1% @ ND Example 228 0,025 ND 200 μM Example 198 9,862 ND Example 229 6,325 ND Example 199 0,298 ND Example 230 3,236 ND Example 200 5,440 ND Example 231 56,75% @ ND 50 μM Example 201 0,136 ND Example 232 62,2% @ 50 μM ND Example 202 0,751 ND Example 233 3.408 ND Example 203 71.85% @ ND Example 234 68.7% @ 50 μM ND 100 0 +, Example 204 44.8% @ ND Example 235 1,393 ND 100 μM Example 205 26,2% @ 100 μM ND Example 236 13,498 ND Example 206 8,844 ND Example 237 0,569 ND Example 207 0,136 ND Example 238 2,785 ND Example 208 0,632 ND Example 239 20,328 ND Example 209 56,85% @ ND Example 240 0.958 ND 200 μM Example 210 8.363 ND Example 241 14.334 ND Example 211 0.668 ND Example 242 0.091 NI) 3037956 - 170 - 1050 (gM) Mcl-1 1050 (pM) 1050 (pM) Md-1 IC50 (gM) MTT PF MTT 11929 PF 11929 Example 243 0.073 ND Example 259 1.347> 6.0E-07 Example 244 0.120 ND Example 260 1.982 ND Example 245 11.367 ND Example 261 ND ND Example 246 0.293> 1.50E-05 Example 262 ND ND Example 247 11.826 ND Example 263 ND ND Example 248 2,176 ND Example 264 ND ND Example 249 36,761 ND Example 265 ND ND Example 250 0,617 ND Example 266 ND ND Example 251 12,053 ND Example 267 ND ND Example 252 0,223 ND Example 268 ND ND Example 253 1,363 ND Example 269 ND ND Example 254 22.08% @ ND Example 270 ND ND 200 μM Example 255 41.08% @ ND Example 271 ND ND 200 μM Example 256 1.606> 6, 0E-07 Example 272 ND ND Example 257 57.15% @ NO Example 273 ND ND 10 μM Example 258 1.070 4.28E-07 Example 274 ND ND ND: Not determined For partial inhibitors, the percentage inhibition by polarization of fluorescence for a given concentration of the test compound is indicated. Therefore, 45.1% @ 10 μM means that fluorescence polarization inhibition of 45.1% is observed for a concentration of test compound equal to 10 ktM. EXAMPLE C Quantification of the cleaved form of PARP in vivo The ability of the compounds of the invention to induce apoptosis, by measuring cleaved PARP levels, is evaluated in a multiple myeloma cell xenograft model AMO- 1. 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 (presented in Table 2 below) show that the compounds of the invention are capable of inducing apoptosis of AMO-1 tumor cells in vivo.
[0192] Table 2: Quantification of PARP cleaved form in vivo PARP Cleavage Cleavage Cleavage multiplied by PARP multiplied by PAR multiplied by by Example 7 81.4 Example 43 114.6 Example 51 52.2 Exempt 22 222.2 Example 44 85.8 Example 256 99.5 Example 24 164.5 Example 45 103.7 Example 25S 132.3 Example 40 114.3 Example 49 138.8 Example 259 134.4 EXAMPLE D In vivo anti-tumor activity The activity Anti-tumor of the compounds of the invention is evaluated in a model of xenograft of AMO-1 multiple myeloma cells. 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 beginning of the treatment. The compounds of the invention possess antitumor (tumor regression) activities in the AMO-1 multiple myeloma model with AT / C (the parameter for qualifying the activity of a product, which is measured by subtracting the average tumor volume on the day of the last treatment of the average tumor volume on the day of the first treatment / tumor volume of the untreated control group on the last treatment day) from -1.5% to -24.5 %. The results obtained show that the compounds of the invention induce a significant regression of the tumors during the treatment period. EXAMPLE E: Pharmaceutical composition: tablets 1000 tablets containing a dose of 5 mg of a compound selected from Examples 1 to 274 5g Wheat starch 20 g Corn starch 20 g Lactose 30 g Magnesium stearate 2 g Silica 1 g Hydroxypropylcellulose 2 g 5

权利要求:
Claims (41)
[0001]
REVENDICATIONS1. Compounds of formula (I): in which: Rs - A represents the group in which 1 is bonded to the group --NH - and 2 is bonded to the aromatic ring, - E represents a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, - X represents a nitrogen atom or a group C-R4, - Y represents a nitrogen atom or a group C-R3, - R1 represents an atom of halogen, 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 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, - (C1-C6) alkyl, C6) -NR9R9 ', -O- (C1-C6) alkyl -NR9R9', -O- (C1-C6) alkyl-R10, -C (O) -OR9, -O-C (O) -R9, -C (O) -NR9R9 ', -NR9-C (O) -R9', -NR9-C (O) -OR9 ', - (alkyl) C1 to C6) -NR, -C (O) -R9 ', -SO2-NR9R9', -SO2- (C1-C6) alkyl, + R2, R3, R4 and R5 independently of one another represent an atom of hydrogen, 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 C1-C6 polyhaloalkyl group or branched, a hydroxy group, a hydroxy (C1-C6) alkyl group, a linear or branched C1-C6 alkoxy group, -S- (C1-C6) alkyl, a cyano group, a nitro group, - ( C1-C6 alkyl) -NR9R9 ', -O- (C1-C6) alkyl -NR9R9', -O- (C1-C6) alkyl-R10, -C (O) -OR9, -OC (O) ) -R9, -C (O) -NR9R9 ', -NR9-C (O) -R9', -NR9-C (O) -OR9 ', -C1-6alkyl -NR9-C (O) -R9 ', -SO2-NR9R9' or -SO2- (C1-C6) alkyl, or the substituents of the pair (R1, R2) together with the atonia carbon containing an aromatic or nonaromatic 5- to 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 1 to 2 groups selected from halogen, linear or branched C1-C6 alkyl, - (C1-C6) alkyl -NR9R9 ', -NR11R1 I - (C1-C6) alkylCyl or oxo, - R6 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 or a C1-polyhaloalkyl group; at linear or branched C6, a hydroxyl group, a linear or branched C1-C6 alkoxy group, a -S- (C1-C6) alkyl group, a cyano group, a nitro group, - (C1-C6) alkyl group -NR9R9 ', - (C1-C6) alkyl-C y1, - (C2-C6) alkenyl-C y1, - (C2-C6) alkynyl) -Cy1 , -O- (C1-C6) alkyl-R10, -C (O) -OR9, -O-C (O) -R9, -C (O) -NR9R9 ', -NR9-C (O) -R9 -NR9-C (O) -OR9 ', -C1-C6alkyl -NR9-C (O) -R9', -SO2-NR9R9 'or -SO2- (C1-C6) alkyl, -R7 represents a hydrogen atonia, a linear or branched C1-C8 alkyl group, a -CHRaRb group, an aryl group, a heteroaryl group, an aryl-C1-C6 alkyl group or a heteroaryl (C1-alkyl) group. at C6), - R8 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, -Cy2, a linear or branched C1-C6 alkenyl group; halogen, a cyano group, -C (O) -R11 or R9 and R9 'represent, independently of one another, a hydrogen atom, or a linear or branched C1-C6 alkyl group, or the substituents of the pair (R9, R9 ') together with the nitrogen atom carrying them an aromatic or non-aromatic ring consisting of 5 to 7 cha 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 nitrogen in question may be substituted by a group representing a hydrogen atom. hydrogen or a linear or branched C1-C6 alkyl group, - R10 represents -Cy3, -Cy3- (C1-C6) alkyl-C4, -C (O) -NR9R9 ', -NR9R9', -OR9, -NR9-C (O) -R9 ', -O- (C1-C6) alkyl-OR9, -802-R9, -C (O) -OR9 or -NH-C (O) -NH-R9, - R11 and R11 'independently of one another are hydrogen or an optionally substituted linear or branched C1-C6 alkyl group; R12 represents a hydrogen atom, a hydroxy group or a hydroxy group ( C1-C6 alkyl), - Ra represents a hydrogen atom or a linear or branched C1-C6 alkyl group; - Rb represents a group -O-C (O) -O-Ra, a group -O- C (O) -NRaR, or a group -O-P (O) (OR9) 2, -Ra and independently represent one of the other a hydrogen atom, a linear or branched C1-C8 alkyl group, a cycloalkyl group, a C1-C6 alkoxy group (C1-C6 alkyl), a C1-C6 alkoxy group; carbonyl (C1-C6) alkyl, or the substituents of the pair (Ra, Ra ') together with the nitrogen atom carrying them a non-aromatic ring consisting of 5 to 7 members, which may contain in addition to the nitrogen atom of 1 to 3 heteroatoms selected from oxygen and nitrogen, it being understood that the nitrogen in question may be substituted by a group representing a linear or branched C1-C6 alkyl group; 176 - Cy1, Cy2, Cy3 and Cy4 independently of one another represent a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, n is an integer equal to 0, 1 or 2, with the proviso that: "Aryl" means a phenyl, naphthyl or biphenyl group by "heteroaryl e "is understood to mean any mono- or bi-cyclic group consisting of 5 to 10 members, having at least one aromatic group and containing from 1 to 3 heteroatoms chosen from oxygen, sulfur and nitrogen, with" cycloalkyl "is meant any nonaromatic, mono- or bicyclic carbocyclic group containing from 3 to 10 members, -" heterocycloalkyl "means any nonaromatic, mono- or bi-cyclic carbocyclic group consisting of from 3 to 10 linkages and containing from 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, which may comprise fused, bridged or spiro ring systems, with the possibility for the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined and the alkyl, alkenyl, alkynyl, alkoxy groups to be substituted with 1 to 4 groups selected from optionally substituted linear or branched C1 to C6 alkyl, optionally substituted linear or branched C2 to C6 alkenyl; substituted, optionally substituted linear or branched C2 to C6 alkynyl, optionally substituted linear or branched C1 to C6 alkoxy, (C1 to C6) alkyl-S- optionally substituted, hydroxy, hydroxy (C1 to C6) alkyl, oxo (or N-oxide if appropriate), nitro, cyan, -C (O) -OR ', -OC (O) -R', -C (O) -NR'R ", -OC (O) - NR'R ", -NR'R", - (C = NR ') - OR ", -O-P (O) (OR') 2, -O-P (O) (01V1 +) 2, polyhaloalkyl in. Linear or branched C1 to C6, trifluoromethoxy, halogen or an aldohexose of formula: OR 'OR' R 'OR' L1 OR 'where each R' is independent; It being understood that R 'and R "represent, independently of one another, a hydrogen atom or an optionally substituted linear or branched C1 to C6 alkyl group, and 1 4 represents a pharmaceutically monovalent cation. acceptable, their enantiomers, diastereoisomers and atropisomers, and their addition salts with a pharmaceutically acceptable acid or base.
[0002]
2. Compound of formula (I) according to claim 1, in which: R1 and R2 represent, independently of each other, a halogen atom, a linear or branched C1-C6 alkyl group or a group. hydroxy, a group. Hydroxy (C1-C6) alkyl, a linear or branched C1-C6 alkoxy group, or the substituents of the (R1, R2) pair together with the carbon atoms carrying them a 5-7 membered aromatic ring which may contain 1 to 3 nitrogen atoms, it being understood that the resulting ring may be substituted with 1 to 2 groups selected from halogen, linear or branched C1 to Cc alkyl or (C1 to C6) alkyl - NR9R9 ', - R3 represents a hydrogen atom, a halogen atom, a linear or branched C1-C6 alkyl group, a hydroxyl group, a linear or branched C1-C6 alkoxy group or -O- (lower alkyl) C1 to C6) -NR9R9 ', - R4 and R5 represent, independently of each other, a hydrogen atom, a halogen atom, a linear or branched C1-C6 alkyl group, a hydroxyl group, a linear or branched C1-C6 alkoxy group; R6 represents a hydrogen atom, a halogen atom; , a linear or branched C1-C6 alkyl group, a linear or branched C1-C6 polyhaloalkyl group, a hydroxyl group, a linear or branched C1-C6 alkoxy group, a cyano group, a nitro group, - (alkyl) group, to C6-C6) -NR9R9 ', - (C1-C6) alkyl-Cyl, -O- (C1-C6) alkyl-R10 or -C (O) -NR9R9', - R7 represents a hydrogen atom , a linear or branched C1-C8 alkyl group, a -CHRaRb group or a heteroaryl (C1-C6) alkyl group; -R8 represents a linear or branched C1-C6 alkyl group, a C2-C6 alkenyl group; linear or branched, a linear or branched C2-C6 alkynyl group, -Cy2, a halogen atom or -C (O) -R11, R9 and R9 'independently represent one of another a hydrogen atom, a linear or branched C1-C6 alkyl group, or the substituents of the pair (R9, R9 ') together with the nitrogen atom carrying 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, it being understood that the nitrogen in question may be substituted by a group representing a linear or branched C1-C6 alkyl group, - R10 represents -Cy3 or -Cy3- (CO-C6 alkyl) -Cy4, -R11 represents a linear or branched C1-C6 alkyl group, with the possibility for the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups thus defined and the alkyl, alkenyl, alkynyl, alkoxy groups to be substituted with 1 to 4 groups chosen from an optionally substituted linear or branched C1 to C6 alkyl, an alkoxy optionally substituted linear or branched C1 to C6, hydroxy, oxo (or N-oxide if appropriate), -C (O) -OR ', -C (O) -NR'R ", -OC ( 0) -NR'R ", -NR'R", -OP (O) (OR ') 2, -O-P (O) (O-M +) 2, a linear polyhalo-C 1 -C 6 alkyl or branched, a halogen or an aldohexose of formula: OR OR 'OR' -'- 'OR' 20 where each R 'is independent; with the proviso that R 'and R "are independently of each other hydrogen or an optionally substituted linear or branched C1-C6 alkyl group, and IVI + represents a pharmaceutically acceptable monovalent cation.
[0003]
Compounds according to claim 1, wherein n is an integer of 1.
[0004]
4. Compounds according to claim 1, wherein at least one of R 2, R 3, R 4 and R 5 does not represent a hydrogen atom. 3037956 -179-
[0005]
Compounds according to claim 1, wherein R12 represents a hydrogen atom.
[0006]
6. Compounds according to claim 1, wherein R1 represents a linear or branched C1-C6 alkyl group or a halogen atom.
[0007]
Compounds according to claim 1, wherein R2 represents a linear or branched C1-C6 alkoxy group, a hydroxy group or a halogen atom. 10
[0008]
Compounds according to claim 1, wherein X represents a C-R 4 group.
[0009]
Compounds according to claim 1, wherein Y represents a C-R3 group. 15
[0010]
10. Compounds according to claim 1, wherein R4 and R5 represent a hydrogen atom.
[0011]
The compound of claim 1, wherein the substituents of the pair (R1, R5) are the same and the substituents of the (R2, R4) pair are the same.
[0012]
12. Compounds according to claim 1, wherein: represents R9 'where R1, R2, R9 and R9' are as defined in claim 1. 3037956 -180
[0013]
13. Compounds according to claim 1 wherein R9 and R9 'are as defined in claim 1.
[0014]
14. Compounds according to claim 1, in which E represents a phenyl group, a pyridin-2-yl, a cyclohexyl group, a pyrazol-1-yl group, a cyclopentyl group, an indol-4-yl group and a cyclopropyl group. a pyridin-3-yl group, an indol-3-yl group, a naphth-1-yl group, an imidazol-4-yl group or a pyridin-4-yl group.
[0015]
Compounds according to claim 1, which are compounds of formula (Ib): wherein R1, R2, R5, R6, R7, R12, X, Y, A and n are as defined for formula (I) . 3037956 -181-
[0016]
Compounds according to claim 1, wherein R6 represents a hydrogen atom; a fluorine atom; a chlorine atom; a bromine atom; a methyl group; a trifluoromethyl group; a hydroxy group; a methoxy group; a linear C1-C6 alkoxy group substituted with halogen atoms, a -C (O) -NR'R "group or a -NR'R" group; a cyano; a nitro group; an aminomethyl group; a benzyl group; -O- (C1-C6) alkyl-R10; -C (0) -NR9R9.
[0017]
17. Compounds according to claim 1, wherein R7 represents a hydrogen atom, an optionally substituted linear or branched C1-C6 alkyl group, a -CHRaRb group or a heteroaryl- (C1-C6) alkyl group.
[0018]
18. Compounds according to claim 1, wherein R8 represents a linear or branched C2-C6 alkynyl group, an aryl group or a heteroaryl group.
[0019]
19. Compounds according to claim 1, in which R9 and R9 'represent, independently of one another, a linear or branched C1-C6 alkyl group, or the substituents of the (R9, R9') pair together with the nitrogen atom carrying 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, it being understood that The nitrogen in question may be substituted with a linear or branched C1-C6 alkyl group.
[0020]
20. Compounds according to claim 1, wherein R10 represents -Cy3 or -Cy3- (C1-C6) alkyl -Cy4.
[0021]
Compounds according to claim 20, wherein Cy3 represents a cycloalkyl group, an aryl group or a heteroaryl group. 30
[0022]
22. Compounds according to claim 20, wherein Cy4 represents a phenyl group or a morpholinyl group. 3037956 - 182 -
[0023]
23. Compounds according to claim 20, in which R10 represents R15 in which p is an integer equal to 0 or 1 and R15 represents a hydrogen atom, a hydroxyl group or an optionally substituted linear or branched C1 to C6 alkyl group. substituted, a linear or branched C1-C6 alkoxy group, a group -O- (CHR16-CHR17-0) q-R ', a group -OP (O) (OR') 2, a group -O-P ( 0) (O14 +) 2, a group -O-C (O) -NRI8R19, a di (C1-C6) alkyl amino group (C1-C6 alkoxy), a halogen atom or an aldohexose of the formula : GOLD 'OR' OR GOLD. ' where each R 'is independent; It being understood that: R 'represents a hydrogen atom or a linear or branched C1-C6 alkyl group; - R16 represents a hydrogen atom or a (C1-C6) alkoxy (C1-C6) alkyl group; R17 represents a hydrogen atom or a hydroxy (C1-C6) alkyl group; R15 represents a hydrogen atom or a (C1-C6) alkoxy (C1-C6) alkyl group; R19 is (C1-C6) alkoxy- (C1-C6) alkyl, - (CH2), -NR9R9 'or - (CH2), - O- (CHR16-CHR17-0) 9R Wherein q is an integer of 1, 2 or 3 and r is an integer of 0 or 1, # M + is a pharmaceutically acceptable monovalent cation.
[0024]
24. Compounds according to claim 23, wherein the aldexose is D-mannose. 5
[0025]
25. Compounds according to claim 1 which are: N- [5- {3-chloro-2-methyl-442- (4-methyl-piperazin-1-yl) ethoxylphenyl} fluorophenyl) thieno d] pyrimidin-4-yl] -2 - [(1-methyl-1H-pyrazol-5-yl) methoxy] -D-phenylalanine, N- [5- {3-chloro-2 Methyl-4- [4- (4-methyl-piperazin-1-hypethoxylphenyl) -644-fluorophenylthieno [2,3-d] pyrimidin-4-yl] -2 - [(2-ethoxypyrimidin-4-yl) -methoxy] ] -D-Phenylalanine, N- [5- {3-chloro-2-methyl-442- (4-methyl-piperazin-1-yloxy) phenyl} -6- (4-fluorophenylthieno [2,3-h] d] pyrimidin-4-yl] -2- [2- (2-methoxyphenyl) -piperidin-4-yl] methoxy} -D-phenylalanine; N45- {3-chloro-2-methyl-442-; 4-methyl-piperazin-1-yl) ethoxylphenyl} -6- (furan-2-yl) thieno [2,3-d] pyrimidin-4-yl] -2-methoxy-D-phenylalanine, - N45- { 3-chloro-2-methyl-442- (4-methyl-piperazin-1-yl) ethoxy] phenyl} -645-fluoro-furan-2-yl) -thi eno [2,3-d] pyrimid in-4 -yl] -2-methoxyd-phenylalanine, 20- N- [5- { 3-chloro-2-methyl-442- (4-methylpiperazin-1-yepethoxy) phenyl} -645-tert-fluoruran-2-yl) -thi eno {2,3-4 pyrimidin-4-yl] 2- (2,2,2-trifluoroethoxy) -D-phenylalanine, N- [5- {3-chloro-2-methyl-442- (4-methyl-piperazin-1-yl) ethoxylphenyl} - 645-fluorofuran-2-yl) -thieno [2,3-d] pyrim -2- (pyridin-2-ylmethoxy) -D-phenylalanine, - N- [5- {3-chloro-2-methyl] 442- (4-methylpiperazin-1-yl) ethoxy] phenyl} -645-fluorofuran-2-yl) thieno [2,3-4 primidin-4-yl] -2 - [(1-methyl) 1H-pyrazol-5-yl) methoxy] -D-phenylalanine, N- [5- {3-chlom-2-methyl-1,4- (4-methyl-piperazin-1-yl) ethoxylphenyl} -645-fluorofuran 2-yl) -thieno [2,3-d] pyrimidin-4-yl] -2 - [(1-ethyl-11H-pyrazol-5-yl) methoxy] -D-phenylalanine, - N- [ 5- (3-Chloro-2-methyl-4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl} -645-fluorofuran-2-yl) thieno [2,3-a] pyrimidine 4-yl] -2 - [(2-ethoxypyrimidin-4-yl) methoxy] -D-phenylalanine, 24- (1-butyldi-1H-pyrazol-5-yl) Ethoxyl-N45- {3-chloro-2-methyl-442- (4-methylpiperazin-1-yepethoxy) -phenyl} -6- (5-fluorofuran-2-yl) thieno [2,3-d] pyrimidin-4 D-Phenylalanine, N- [5- {3-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxy] phenyl-6- (5-fluorofuran) -2- yl) -thieno [2,3-d] pyrimidin-4-yl-2 - {[2- (2,2,2-trifluoroethoxy) pyrimidin-4-yl] methoxyl-D-phenylalanine; [5- {3-Chloro-2-methyl-4- [2- (4-methyl-piperazin-1-yl) ethoxy] phenyl} -645-fluorofuran-2-yl) -thieno [2,3-d] pyrimidin-4-yl-2 - {[2- (2-methoxyphenyl) -pyrimidin-4-yl] methoxy} -D-phenylalanine, N- [5- {3-chloro-2-methyl-442- (4-methyl-piperazin-1-yl) ethoxylphenyl-6- (prop-1-yn-1-yl) thieno [2,3-d] pyrimidin-4-yl) -2-methoxy-D-phenylalanine; [(1-tert-butyl-1H-pyrazol-5-yl) methoxy] -N45- {3-chloro-2-methyl-4- [2- (4-methylpiperazin-1-yl) -ethoxy] phenyl} - 6- (prop-1-yn-1-yl) thi eno [2,3-d] pyrimidin-4-yl] -D-phenylalanine, N- [5- {3-chloro-2-methyl-4-yl] -N (4-methyl-piperazin-l-ypéthox y] phenyl-6- (prop-1-yn-1-yl) thieno [2,3-d] pyrimidin-4-yl] -2- [2- (2-methoxyethyl) pyrimidin-4-yl] methoxy] } -D-Phenylalanine, N- [5- {3-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxy] phenyl} -6- (prop-1-yn) 1-ylthieno [2,3-d] pyrimidin-4-yl] -2 - {[1- (2,2,2-trifluoromethyl) -1H-pyrazol-5-yl] methoxyl-D-phenylalanine; N- [5- (3-chloro-2-methyl-442- (4-methyl-piperazin-1-yl) ethoxy] phenyl} -6- (prop-1-yn-1-yl) thieno [2,3] pyrimidin-4-yl] -2- {[2- (molpholin-4-ylpyrimidin-4-yl) methoxy) -D-phenylalanine, - N- [5- {3-chloro-2-methyl-1-yl] -methyl) -2- 442- (4-methylpiperazin-1-yepethoxy) phenyl} -6- (prop-1-yn-1-yl) thieno [2,3-cl] pyrimidin-4-yl] -2- [ 2- (2,2,2-trifluoroethoxy) -pyrimidin-4-yl] methoxyl-D-phenylalanine, - N- {5- {3-chloro-2-methyl-442- (4-methyl-piperazin-1) 1-yl) ethoxy] phenyl} -6- (prop-1-yn-1-ylthieno [2,3-d] pyrimidin-4-yl] -2- {[2- (2-methoxyphenyl) -pyrimidin-4- yl] methoxy) -D-phenylalanine, N- [5- {3-chloro-4- [2- (dimethylamin) o) ethoxy] -2-methylphenyl 1-6- (prop-1-yn-1-ylthieno [2,3-4pyrimidin-4-yl] -2 - {[1- (2,2,2-trilluoroethyl) -1H) pyrazol-5-yl] -methoxyl-D-phenylalanine, N- [5- {3-chloro-4- [2- (dimethylamino) ethoxy] -2-methylphenyl} -6- ( prop-1-yn-lyOthieno [2,3-d] pyrimidin-4-yl] -2- [2- (moipolin-4-yl) pyrimidin-4-yl] methoxy} -D-phenylalanine, - N- [ 5- {3-chloro-442- (dimethylamino) ethoxy] -2-methylphenyl} -6- (prop-1-yn) -1-ylthio [2,3-pyrimidin-4-yl] -2- (2,2,2-trifluoroethoxy) pyrimidin-4-yl] -methoxyl-D-phenylalanine, - N- [5- (3-chloro-442- (dimethylamino) ethoxy] -2-methylphenyl) -6- ( prop-1-yn-1-yl) thieno [2,3-pyrimidin-4-yl] -2- [2- (2-methoxyphenyl) pyrimidin-4-yl] methoxy} -D-phenylalanine, N- {3- {3-chloro-442- (dimethylamino) ethoxy] -2-methylphenyl} -6- (4-fluorophenylthieno [2,3-d] pyrimidin-4-yl] -2-24 {242} (2H); methoxyethoxy) phenyl] pyrimidin-4-yl} methoxy) -D-phenylalanine - N-R5S ') - 5- {3-chloro-2-methyl-442- (4-methyl) -2- piperazin-1-ylethoxylphenyl-6- (4-fluorophenyl) thieno [2,3-d] pyrimidin-4-yl} -2- [2- (2-methoxyphenyl) -pyrimidin-4-yl] methoxyl -D-phenylalaninate ethyl; N-R5Si) -5- {3-chloro-2-methyl-442- (4-methyl-piperazin-1-yl) ethoxylphenyl-6- (prop-1-yn-1-hypthieno [2,3-d]} ] pyrimidin-4-yl] -2- {[2- (2-methoxyphenyl) -pyrimidin-4-yl] methoxy} -D-phenylalaninate; - N-R5Si) 5- {3 - chloro-442- (dimethylamino) -ethoxy] -2-methylphenyl} -6- (prop-1-yn-1-yl) thieno [2,3-d] pyrimidin-4-yl] -2- Ethyl 2- (2-methoxyphenylpyrimidin-4-yl) methoxyl-D-phenylalaninate.
[0026]
26. Process for the preparation of a compound of formula (I) according to claim 1, characterized in that it uses, as starting compound, the compound of formula (II-a): 25 A (11-a) Key Wherein Z is bromine or iodine and A is as defined for formula (I) wherein 1 is bonded to chlorine atom and 2 is bonded to group Z, said compound of formula (II) a) being coupled to a compound of formula (III): wherein R6, R12, E and n are as defined for formula (I), and Alk is a C1-alkyl group linear or branched C6, to obtain the compound of formula (IV): wherein R6, R12, A, E and n are as defined for formula (I), and Z and Alk are as defined above, wherein the compound of formula (IV) is further coupled to a compound of formula (V): wherein R 1, R 2, R 5, X and Y 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 an optionally methylated ring, obtain the compound of formula (VI): (VI) wherein R1, R2, R5, R6, R12, X, Y, A, E and n are as defined for formula (I) and Alk is as defined previously, 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 R7-OH or a chlorinated compound of formula R7 -Cl, where R7 is as defined for formula (I), to give the compound of formula (I), which can be purified according to a conventional separation technique, which is converted, if desired, into its salts of addition with a pharmaceutically acceptable acid or base and which is optionally separated into its isomers according to a technique conventional separation, it being understood that at any time deemed appropriate during the process described above, certain groups (hydroxy, amino, etc.) of the starting reagents or synthesis intermediates can be protected, then deprotected and functionalized for the purposes of synthesis.
[0027]
27. Process for the preparation of a compound of formula (I) according to claim 1, characterized in that it uses, as starting compound, the compound of formula (II-b): 3037956 -188-A (II) embedded image in which A is as defined in formula (I) in which 1 is bonded to the chlorine atom and 2 is bonded to the iodine atom, said compound of formula (II) b) being coupled with a compound of formula (V): wherein R1, R2, R5, X and Y are as defined for formula (I), and RB1 and RB2 represents a hydrogen atom, a linear or branched C1-C6 alkyl group, or RB I and RB2 form with oxygen carrying them an optional methylated ring, to obtain the compound of formula (VII): in which RI R 2, R 5, A, X and Y are as defined in formula (I), wherein said compound of formula (VII) is further subjected to coupling with a compound of formula (III): (V) 3037956 - 189 - Wherein R 6, R 12, E and n are as defined for formula (I), and Alk 5 represents a linear or branched C 1 -C 6 alkyl group, to obtain the compound of formula (VI): Alk (VI) wherein R1, R2, R5, R6, R12, X, Y, A, E and n are as defined for formula (I) and Alk is as previously defined, the function Alk-OC (O) ester of the compound of formula (VI) being hydrolyzed to give the carboxylic acid, which may optionally be reacted with an alcohol of formula R7-OH or a chlorinated compound of formula R7-C1, where R7 is as defined for formula (I), 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 understood that 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 needs of the synthesis. 5
[0028]
28. A pharmaceutical composition containing a compound of formula (I) according to any one of claims 1 to 25 or an addition salt thereof with a pharmaceutically acceptable acid or base in combination with one or more pharmaceutically acceptable excipients. 10
[0029]
29. The pharmaceutical composition of claim 28 for use as a pro-apoptotic agent.
[0030]
30. The pharmaceutical composition of claim 29 for use in the treatment of cancer and autoimmune diseases and the immune system.
[0031]
31. Pharmaceutical composition according to claim 30, 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. 25
[0032]
32. Use of a pharmaceutical composition according to claim 28 in the manufacture of medicaments for use as pro-apoptotic agents.
[0033]
33. Use of a pharmaceutical composition according to claim 28 in the manufacture of medicaments for use in the treatment of cancers and autoimmune diseases and the immune system. 3037956 - 191 -
[0034]
34. Use of a pharmaceutical composition according to claim 28, 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.
[0035]
35. Compound of formula (I) according to one of claims 1 to 25, or one of its addition salts with a pharmaceutically acceptable acid or base, for its use in the treatment of cancers of the bladder, of the brain. , breast and uterus, chronic lymphoid leukemias, colon cancer, esophagus and liver cancer, lymphoblastic leukemias, acute myeloid leukemias, lymphomas, melanomas, hematological malignancies, myeloma, cancer of the ovaries, non-small cell lung cancer, prostate cancer, pancreatic cancer and small cell lung cancer.
[0036]
36. Use of a compound of formula (1) according to any of claims 1 to 25, or a pharmaceutically acceptable acid or base addition salt thereof, in the manufacture of medicaments for 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, melanoma, hematological malignancies, myeloma, ovarian cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer and small cell lung cancer.
[0037]
37. Combination of a compound of formula (I) according to any one of claims 1 to 25 with an anti-cancer agent selected from genotoxic agents, mitotic poisons, antimetabolites, proteasome inhibitors, inhibitors of kinases and antibodies. 3037956 - 192 -
[0038]
38. A pharmaceutical composition comprising a combination according to claim 37 in combination with one or more pharmaceutically acceptable excipients.
[0039]
39. The combination of claim 37 for use in the treatment of cancers.
[0040]
40. Use of an association according to claim 37 in the manufacture of medicaments for use in the treatment of cancers. 10
[0041]
41. A compound of formula (1) according to any one of claims 1 to 25 for its use in the treatment of cancers requiring radiotherapy.

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FR1555747A|FR3037956B1|2015-06-23|2015-06-23|NOVEL AMINO ACID DERIVATIVES, PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME|FR1555747A| FR3037956B1|2015-06-23|2015-06-23|NOVEL AMINO ACID DERIVATIVES, PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME|

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GEAP201614679A| GEP20207075B|2015-06-23|2016-06-22|New aminoacid derivatives, a process for their preparation and pharmaceutical compositions containing them|

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PL16731158T| PL3313850T3|2015-06-23|2016-06-22|New aminoacid derivatives, a process for their preparation and pharmaceutical compositions containing them|

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CR20170590A| CR20170590A|2015-06-23|2016-06-22|NEW HYDROXY ACID DERIVATIVES, A PROCESS FOR THE PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|

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UAA201800620A| UA123267C2|2015-06-23|2016-06-22|New aminoacid derivatives, a process for their preparation and pharmaceutical compositions containing them|

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PT16731158T| PT3313850T|2015-06-23|2016-06-22|New aminoacid derivatives, a process for their preparation and pharmaceutical compositions containing them|

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PE2017002702A| PE20190111A1|2015-06-23|2016-06-22|NEW AMINO ACID DERIVATIVES, A PROCESS FOR THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM|

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PCT/EP2016/064436| WO2016207226A1|2015-06-23|2016-06-22|New aminoacid derivatives, a process for their preparation and pharmaceutical compositions containing them|

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SI201630123T| SI3313850T1|2015-06-23|2016-06-22|New aminoacid derivatives, a process for their preparation and pharmaceutical compositions containing them|

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RU2018102372A| RU2747673C2|2015-06-23|2016-06-22|Novel amino acid derivatives, a method for production thereof and pharmaceutical compositions containing them|

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CR20170571A| CR20170571A|2015-06-23|2016-06-22|NEW AMINO ACID DERIVATIVES, A PROCESS FOR THE PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.|

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KR1020187002016A| KR20180015261A|2015-06-23|2016-06-22|Novel amino acid derivatives, a method for producing the same, and a pharmaceutical composition containing the same|

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CUP2017000164A| CU20170164A7|2015-06-23|2016-06-22|N-TIENPYRIMIDINYL-D-PHENYLALANINE COMPOUNDS, METHOD FOR PREPARING THE SAME AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|

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EP16731158.8A| EP3313850B1|2015-06-23|2016-06-22|New aminoacid derivatives, a process for their preparation and pharmaceutical compositions containing them|

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US15/737,783| US10457687B2|2015-06-23|2016-06-22|Aminoacid derivatives, a process for their preparation and pharmaceutical compositions containing them|

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DK16731158.8T| DK3313850T3|2015-06-23|2016-06-22|NEW AMINO ACID DERIVATIVES, PROCEDURES FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|

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AU2016282837A| AU2016282837B2|2015-06-23|2016-06-22|New aminoacid derivatives, a process for their preparation and pharmaceutical compositions containing them|

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ES16731158T| ES2703997T3|2015-06-23|2016-06-22|New amino acid derivatives, a process for their preparation and pharmaceutical compositions containing them|

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LTEP16731158.8T| LT3313850T|2015-06-23|2016-06-22|New aminoacid derivatives, a process for their preparation and pharmaceutical compositions containing them|

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TNP/2017/000521A| TN2017000521A1|2015-06-23|2016-06-22|New aminoacid derivatives, a process for their preparation and pharmaceutical compositions containing them|

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CA2990089A| CA2990089C|2015-06-23|2016-06-22|New aminoacid derivatives, a process for their preparation and pharmaceutical compositions containing them|

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JP2017566280A| JP6741698B2|2015-06-23|2016-06-22|Novel amino acid derivative, method for producing the same, and pharmaceutical composition containing the same|

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BR112017027645-3A| BR112017027645A2|2015-06-23|2016-06-22|amino acid derivatives, processes for their preparation and pharmaceutical compositions containing them|

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MA42232A| MA42232B1|2015-06-23|2016-06-22|New amino acid derivatives, process for their preparation and pharmaceutical compositions containing them|

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TW105119598A| TWI631124B|2015-06-23|2016-06-22|New aminoacid derivatives, a process for their preparation and pharmaceutical compositions containing them|

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EA201890123A| EA034587B1|2015-06-23|2016-06-22|New aminoacid derivatives, process for their preparation and pharmaceutical compositions containing them|

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ARP160101879A| AR105101A1|2015-06-23|2016-06-23|AMINO ACID DERIVATIVES, A PROCESS FOR THE PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|

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IL256191A| IL256191A|2015-06-23|2017-12-07|New aminoacid derivatives, a process for their preparation and pharmaceutical compositions containing them|

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CL2017003163A| CL2017003163A1|2015-06-23|2017-12-11|New amino acid derivatives, a process for their preparation and pharmaceutical compositions that contain them|

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PH12017502266A| PH12017502266A1|2015-06-23|2017-12-11|New aminoacid derivatives, a process for their preparation and pharmaceutical compositions containing them|

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SV2017005588A| SV2017005588A|2015-06-23|2017-12-12|NEW AMINO ACID DERIVATIVES, A PROCESS FOR THE PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|

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CONC2017/0012830A| CO2017012830A2|2015-06-23|2017-12-13|Compounds of n-thieno [2,3-d] pyrimidinyl-d-phenylalanine, method of preparation thereof and pharmaceutical compositions containing them|

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ECIEPI201782546A| ECSP17082546A|2015-06-23|2017-12-14|NEW AMINO ACID DERIVATIVES, A PROCESS FOR THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM|

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HK18109702.0A| HK1250234A1|2015-06-23|2018-07-26|New aminoacid derivatives, a process for their preparation and pharmaceutical compositions containing them|

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HK18111502.8A| HK1252113B|2015-06-23|2018-09-06|New aminoacid derivatives, a process for their preparation and pharmaceutical compositions containing them|

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HRP20181806TT| HRP20181806T1|2015-06-23|2018-10-31|New aminoacid derivatives, a process for their preparation and pharmaceutical compositions containing them|

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CY181101321T| CY1120991T1|2015-06-23|2018-12-10|NEW AMINO ACID PRODUCTS, A METHOD FOR THEIR MANUFACTURE AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|