专利摘要:
Compounds of formula (I): wherein R1, R2, R3, R4, R5, R6, R7, R8, R14, W, A and n are as defined in the description. Drugs.
公开号:FR3037959A1
申请号:FR1555750
申请日:2015-06-23
公开日:2016-12-30
发明作者:Balazs Balint；Marton Csekei；Zoltan Szabo；Zoltan Szlavik；Andras Kotschy；Maia Chanrion；Olivier Geneste；I-Jen Chen；James Edward Paul Davidson；James Brooke Murray；Szabolcs Sipos；Levente Ondi；Agnes Proszenyak
申请人:Laboratoires Servier SAS；Vernalis R&D Ltd；
IPC主号:

专利说明:

[0001] The present invention relates to novel bicyclic derivatives, process for their preparation and pharmaceutical compositions containing them. The compounds of the present invention are new and have very interesting pharmacological characteristics in the field of apoptosis and oncology. Apoptosis, or programmed cell death, is a crucial physiological process for embryonic development and maintenance of tissue homeostasis. Apoptotic cell death involves morphological changes, such as core condensation, DNA fragmentation, as well as biochemical phenomena, such as activation of caspases that will degrade key structural components of the cell to induce disassembly and death. The regulation of the apoptosis process is complex and involves the activation or repression of several intracellular signaling pathways (Cory S. et al., Nature Review Cancer, 2002, 2, 647-656).
[0002] Deregulation of apoptosis is implicated in certain pathologies. Increased apoptosis is linked to neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and ischemia. Conversely, deficiencies in the execution of apoptosis play an important role in the development of cancers and their chemoresistance, autoimmune diseases, inflammatory diseases and viral infections. Thus, the absence of apoptosis is part of the phenotypic signatures of cancer (Hanahan D. et al., Cell 2000, 100, 57-70). The anti-apoptotic proteins of the Bel-2 family are associated with numerous pathologies. The involvement of Bc1-2 family proteins is described in many types of cancer, such as colon cancer, breast cancer, small cell lung cancer, non-small cell lung cancer, bladder cancer, ovarian cancer, prostate cancer, chronic lymphocytic leukemia, lymphoma, myeloma, acute myeloid leukemia, pancreatic cancer, etc. Overexpression of anti-apoptotic proteins in the Bel-2 family is implicated in tumorigenesis, chemotherapy resistance, and clinical prognosis in cancer patients.
[0003] In particular, Mc1-1, a member of the anti-apoptotic Bc1-2 family, is overexpressed in various types of cancers (Beroukhim 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 their novelty, have pro-apoptotic properties allowing them to be used 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): ## STR5 ## wherein: A represents the group in which 1 is attached to the W group and 2 is attached to the phenyl ring, wherein: E represents a furyl, thienyl or pyrrolyl ring; X1, X3, X4 and X5 independently of one another represent a carbon atom or a nitrogen atom; X2 represents a C-R21 group or a nitrogen atom; and signifies that the ring is aromatic, R 1 represents a halogen atom, a linear or branched C 1 -C 6 alkyl group, a linear or branched C 2 -C 6 alkenyl group, a C 2 -C alkynyl group, C6 linear or branched, a linear or branched C 1 -C 6 polyhaloalkyl, a hydroxyl group, a hydroxy (C 1 -C 6) alkyl group, a linear or branched C 1 -C 6 alkoxy group, a -S- (alkyl) group, C1 to C6), a cyano group, a nitro group, - (alkyl e to C6-C6) -NR11R1 1 ', -O- (C1-C6) alkyl -NR11R11', -O- (C1-C6) alkyl -R12, -C (O) -OR11, -O-C (0) -R11, -C (O) -NR11R11 ', -NR11-C (O) -R1 -NR1-C (O) -OR1', -C1-C6alkyl -NR1 -SO2- (alkyl) C1 to C6), R1, R2, R3, R4 and R5 independently of one another represent a hydrogen atom, a halogen atom, a linear or branched C1 to C6 alkyl group, a C2 to C6 alkenyl group, Linear or branched C6, a linear or branched C2-C6 alkynyl group, a linear or branched C1-C6 polyhaloalkyl group, a hydroxy group, a hydroxy (C1-C6) alkyl group, a linear C1-C6 alkoxy group. or branched, a -S- (C 1 -C 6) alkyl group, a cyano group, a nitro group, - (C 1 -C 6 alkyl) -NRIIR 11 ', -O- (C 1 -C 6 alkyl) -NR 11 R 1 -O - (C1-C6) alkyl-R12, -C (O) -OR1 1, -OC (O) -R11, -C (O) -NRIIR1 ', -NRi iC (O) -Ri -NRI -C ( 0) -OR1 - (C1-C6) alkyl -NR1 -C (O) -R'-S2-NR1 R11 'or -SO2- (alk) C1 to C6), or the substituents of the (R1, R2) pair together with the carbon atoms carrying them an aromatic or nonaromatic 5-7 membered ring which may contain from 1 to 3 selected heteroatoms. among 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 - NR11R11 ', -NR13R13', - (C1-C6) alkylCyl or an oxo, - R6 and R7 independently of one another represent a hydrogen atom, a halogen atom, an alkyl group linear or branched C1 to C6, a linear or branched C2 to C6 alkenyl group, a linear or branched C2 to C6 alkynyl group, a linear or branched C1 to C6 polyhaloalkyl, a hydroxyl group or a C1 alkoxy group. at linear or branched C6, a -S- (C1-C6) alkyl group, a cyano group, a nitro, - (C 1 -C 6) alkyl-N, R 1 R 1, -O-C 1-6, -C 1-6 alkyl-Cyl, -C 2 -C 6 alkenyl -C 1 -C, -C 2 -C 6 alkynyl -Cyl, -O- (C1-C6 alkyl) -R12, -C (O) -OR11, -OC (O) -R11, -C1-C6 alkyl -NR1 iC (O) R 1 ', -SO 2 -NR 1 R 11' -SO 2 -C 1 -C 6 alkyl, or the substituents of the pair (R 6, R 7), when grafted onto two adjacent carbon atoms, together with the atoms form of carbon carrying them 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 a group chosen from a linear or branched C1-C6 alkyl group, -NR13R13 ', - (C1-C6) alkyl-Cyl or an oxo, W represents a group -NH- or an oxygen atom, - R8 represents a hydrogen atom, a linear or branched C1-C8 alkyl group, a group -CHRaRb, a groupem aryl, a heteroaryl group, an aryl-C 1-6 alkyl group or a heteroaryl (C 1-6 alkyl) group; R 9 represents a hydrogen atom, a linear or branched C 1-6 alkyl group; a linear or branched C2 to C6 alkenyl group, a linear or branched C2 to C6 alkynyl group, -Cy2, -C1 to C6 alkylCy2, - (C2 to C6 alkenyl) -Cy2, - ( C2-C6 alkynyl) -Cy2, -Cy2-Cy3, - (C2-C5) alkynyl-O-Cy2, -Cy2- (C1-C6) alkyl-O- (C1-C6) alkyl-C3, a halogen atom, a cyano group, -C (O) -R15 or -C (O) -NRI5R15 ', the Rio represents a hydrogen atonia, a linear or branched C1-C6 alkyl group, a group linear or branched C2-C6 alkenyl, linear or branched C2-C6 alkynyl group, aryl (C1-C6) alkyl group, cycloalkyl (C1-C6) alkyl group, linear C1-C6 polyhaloalkyl or branched, - (C1-C6) alkyl-O-CY4, or the substituents of the pair (R9, R10), when grafted on two adjacent carbon atoms, together with the carbon atoms carrying them form an aromatic or nonaromatic ring consisting of 5 to 7 members, which may contain from 1 to with 3 heteroatoms selected from oxygen, sulfur and nitrogen, R 11 and R 11 'independently of one another are hydrogen, linear or branched (C 1 -C 6) alkyl, or the substituents of the (R11, R11 ') pair together with the nitrogen atom carrying them an aromatic or nonaromatic 5-7 membered ring, which may contain in addition to the nitrogen of 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 or a linear C 1 -C 6 alkyl group or branched, - R12 represents -Cy5, -Cy5- (C1-C6) alkyl-O- (alkyl) C6-C6) -C6-, -C6- (C1-C6) alkyl-C6-, -C6- (C6-C6) alkyl-NR11- (C6-C6) alkyl -Cy6; -Cγ5-Cy6-O- (C1-C6) alkyl -Cy7, -C (O) -NR1 -NRHR1 ', -OR11> -NR11-C (O) -R11' -O- (C1-C6) alkyl ) -OR11, -SO2-R11, -C (O) -OR11, or -NH-C (O) -NH-R11, -R13, R13 ', R15 and R15' independently of one another are an atom of hydrogen or an optionally substituted linear or branched C1-C6 alkyl group; - R14 represents a hydrogen atom, a hydroxy group or a hydroxy (C1-C6) alkyl group; -R21 represents a hydrogen atom, an atom; halogen, a linear or branched C1-C6 alkyl group or a cyano group, - Ra represents a hydrogen atom or a linear or branched C1-C6 alkyl group, - Rb represents a group -O-C ( 0) -O-Re, a group -O-C (O) -NReRe 'or a group -O-P (O) (ORe) 2, 20 - Re and Re' represent, independently of one another, a hydrogen atom, a linear or branched C1-C8 alkyl group, a cycloalkyl group, a C1-C6 alkoxy group (alky C1 to C6), a (C1-C6) alkoxycarbonyl (C1-C6) alkyl group, or the substituents of the (Ra, Ra ') pair together with the nitrogen atom carrying a 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, it being understood that the nitrogen in question may be substituted by a group representing a linear or branched C1-C6 alkyl group, - Cyl, Cy2, Cy3, Cy4, Cy5, Cy6 and Cy7 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 or 1, with the proviso that: - "aryl" means a phenyl, naphthyl, biphenyl, indanyl or indenyl group, - "heteroaryl" means any group mono- or bi-cyclic 5 to 10-membered ring having at least one moiety 1 to 3 heteroatoms chosen from oxygen, sulfur and nitrogen, "cycloalkyl" means any nonaromatic, mono- or bicyclic carbocyclic group containing from 3 to 10 ring members, "heterocycloalkyl" means any nonaromatic, mono- or bi-cyclic, carbocyclic group consisting of 3 to 10 members and containing from 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, which may include bridged, 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 C 1 to C 4 alkyl; Optionally substituted linear or branched C6, optionally substituted linear or branched C2 to C6 alkenyl, optionally substituted linear or branched C2 to C6 alkynyl, linear C1 to C6 alkoxy or optionally substituted branched, optionally substituted (C1-C6) alkyl-S-, hydroxy, oxo (or N-oxide if appropriate), nitro, cyano, -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) (01/1 +) 2, linear or branched C 1 -C 6 polyhaloalkyl, trifluoromethoxy, halogen or an aldohexose of the formula: OR' OR 'R' OR 'OR R Where each R 'is independent; it being understood that R 'and R "independently of one another represent a hydrogen atom or an optionally substituted linear or branched C1-C6 alkyl group, and M + represents a pharmaceutically acceptable monovalent cation,. v. ------, - v., ----- 3y, HE 1 * ------ "X4 - ,,,, -", - .., - -A-3 provided that their enantiomers, diastereoisomers and atropisomers, and their addition salts with a pharmaceutically acceptable acid or base are not represented Advantageously, the present invention relates to compounds of formula (I), wherein: and R2 are independently of each other a halogen atom, a linear or branched C1-C6 alkyl group, a hydroxy group, a linear or branched C1-C6 alkoxy group, or the substituents of the pair. (R1, R2) form together with the carbon atoms carrying them a 5- to 7-membered aromatic ring, which may contain 1 to 3 nitrogen atoms; R 3 represents a hydrogen atom, a halogen atom, a linear or branched C 1 -C 6 alkyl group, a hydroxyl group, a linear or branched C 1 -C 6 alkoxy group or -O- (C1-C6) alkyl-NR1RI R4 and R5 represent, independently of each other, a hydrogen atom, a halogen atom, a linear or branched C1-C6 alkyl group or a hydroxyl group , a linear or branched C1-C6 alkoxy group, R6 and R7 represent, independently of one another, a hydrogen atom, a halogen atom, a linear or branched C1-C6 alkyl group, a linear or branched C1 to C6 polyhaloalkyl, a hydroxy group, a linear or branched C1 to C6 alkoxy group, a cyano group, a nitro group, - (C1 to C6) alkyl -NR1R '- (C1 to C6) alkyl C6) -Cy1, -O- (C1-C6) alkyl -R12 or -C (O) -NR1 iRi ', -R8 represents a hydrogen atom, an alkyl group C1 to C8 linear or branched or a -CHRaRb group, - R9 represents a hydrogen atom, a linear or branched C1 to C6 alkyl group, a linear or branched C2 to C6 alkenyl group, a C2 alkynyl group. at linear or branched C6, -Cy2 or a halogen atom, R10 represents a hydrogen atom, a linear or branched C1-C6 alkyl group, a linear or branched C2-C6 alkenyl group, a linear or branched C 2 -C 6 alkynyl group, an aryl (C 1 -C 6) alkyl group, a cycloalkyl (C 1 -C 6) alkyl group, a linear or branched C 1 -C 6 polyhaloalkyl or a C 1 -C 6 alkyl group; C6) -O-Cy4, or the substituents of the pair (R9, R10), when grafted on two adjacent carbon atoms, together with the carbon atoms carrying them form a non-aromatic ring consisting of 5 to 7 members, which may contain from 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, R 1 and R 11 'independently of one another represent a hydrogen atom, a linear or branched (C 1 -C 6) alkyl group, or the substituents of the pair (R 11, R 11 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, - R12 represents -Cy5 or -Cy5- (C2-C6 alkyl) -Cy6, 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 optionally substituted linear or branched C 1 -C 6 alkyl, alkoxy C1 to C6 linear or branched optionally substituted a hydroxy, an oxo (or an N-oxide if appropriate), -C (O) -OR ', -C (O) -NR'R ", -OC (O) -NR'R", -NR "R", -OP (O) (OR ') 2, -O-P (O) (O-M +) 2, a linear or branched C 1 -C 6 polyhaloalkyl, a halogen or an aldohexose of the formula: OR 'OR' where each R 'is independent; It being understood that R 'and R "represent, independently of each other, a hydrogen atom or an optionally substituted linear or branched C1-C6 alkyl group, and IVI ± represents a pharmaceutically acceptable monovalent cation. More particularly, the preferred compounds of formula (I) are the compounds wherein n is an integer of 1. In another embodiment of the invention, an advantageous possibility is the compounds of the formula Wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R14, X1, X2, X3 and W are as defined for formula (I). Preferred compounds of formula (Ia) are the compounds in which 15 is or more particularly the compounds of formula I which are preferred are those compounds in which OR 5 is realization of the According to the invention, an advantageous possibility consists in the compounds of formula (1-b): embedded image in which R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 6, R 9, R 14, X 1, X 2, X 3 and W are such that defined for formula (I). More particularly, the compounds of formula (Ib) which are given preference are the compounds wherein I X 2 represents In another embodiment of the invention, an advantageous possibility consists of the compounds of formula (1-c) wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R14, X1, X2, X3 and W are as defined for formula (1). More particularly, the compounds of formula (1-c) which are given preference are the compounds in which X represents More particularly, the compounds of formula (1-c) which are given preference are the compounds in which 15 L or N represents In another embodiment of the invention, an advantageous possibility consists of the compounds of formula (1-d): ## STR2 ## wherein R 1, R 2, R 3, R4, R5, R6, R7, R8, R9, R10, R14, X1, X2, X3 and W are as defined for formula (I). More particularly, the compounds of formula (Id) which are given preference are the compounds in which N or -N represents. In another embodiment of the invention, an advantageous possibility consists of the compounds of formula (1-e) Wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R14, X1, X2, X3 and W are as defined for formula (I). More particularly, the compounds of formula (I-e) which are given preference are the compounds in which 5 represents or The compounds of formula (I-a), (I-b) and (I-c) are particularly preferred. The compounds of formula (I-a) and (I-b) are even more preferred. In another embodiment of the invention, an advantageous possibility consists in the compounds of formula (I-1): embedded image in which E, R 1, R 2, R 3, R 4, R 5, R 6, R 7 , R5, R9, R10, R14, X1, X2, X3, X4, X5 and W are as defined for formula (I).
[0004] Atropisomers are stereoisomers that arise due to a twisted rotation around a single bond, the energy differences due to steric tension or other contributors creating a barrier to rotation that is high enough to allow the isolation of individual conformers. For example, for compounds of formula (Ib) (the same applies to compounds of formula (Ia), (Ic) and (Id)), the atropisomers are as follows: The preferred atropisomer is (5Sa) . Advantageously, at least one of R 2, R 3, R 4 and R 5 does not represent a hydrogen atom. Preferably, R14 represents a hydrogen atom. Preferably, R 21 represents a hydrogen atom, a fluorine atom, a methyl group or a cyano group. More preferably, R 21 represents a hydrogen atom or a fluorine atom. Even more preferably, R 21 represents a hydrogen atom. In the preferred compounds of the invention, R1 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 or an ethyl 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 embodiments of the invention, when the substituents of the pair (R 1, R 2) together with the carbon atoms carrying them an aromatic ring, advantageously represents R 3 represents a hydrogen atom, a group hydroxy, a linear or branched C1-C6 alkoxy group or -O- (C1-C6) alkyl-NR1R11 '. Advantageously, R3 represents -O- (C1-C6) alkyl-NR1R11 '. Preferably, R4 and R5 represent a hydrogen atom. In an advantageous embodiment, the substituents of the pair (R1, R5) are identical and the substituents of the pair (R2, R4) are identical. In the preferred compounds of the invention, the substituents of the (RI, R5) pair are identical and represent a C1-C6 alkyl group, while the substituents of the (R2, R4) pair are identical and represent a halogen atom or a hydrogen atom. In the preferred compounds of the invention, where R11 and R11 'are as defined for formula (I). In another embodiment of the invention, R6 represents a hydrogen atom, an optionally substituted linear or branched C1 to C6 alkoxy group or a group -O- (C1 to C6) alkyl-R12. Advantageously, R6 represents a 2,2-trifluoroethoxy group, a methoxy group or a -O- (C1-C6) alkyl-R12 group. Preferably, R7 represents a hydrogen atom.
[0005] In the preferred compounds of the invention, where R 12 is as defined for formula (I).
[0006] In another embodiment of the invention, an advantageous possibility consists of the compounds of formula (Ig) -C1 C 113 represents 3037959 in which R1, R6, R7, R8, R9, R10, R11, R11 ', R14, X1, X2, X3, X4, X5, W and E are as defined for formula (I).
[0007] Preferably R8 is hydrogen, -CHR1, R4, optionally substituted linear or branched C1 to C8 alkyl, or heteroaryl (C1 to C6) alkyl. Preferably, R8 is -CHR.Rb wherein Ra is hydrogen or methyl and Rb is -O-C (O) -O- (C1-C8) alkyl; a group -O-C (O) -O-cycloalkyl; a group -O-C (O) -NR6R4 ', in which Rc and represent, independently of one another, a hydrogen atom, a linear or branched C 1 to C 6 alkyl group or a (C 1 -C 4) alkoxy group; C6) (C1-C6) alkyl, (C1-C6) alkoxycarbonyl (C1-C6) alkyl, or the substituents of the (Rc, Rc ') 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; or a group -O-P (O) (OH) 2. Preferred R8 groups are: hydrogen; methyl; an ethyl; (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl. Even more preferably, R8 represents hydrogen.
[0008] In the preferred compounds of the invention, R 9 represents a hydrogen atom, a halogen atom, a linear or branched C 1 -C 6 alkyl group, a linear or branched C 2 -C 6 alkenyl group, a C 1 -C 6 alkynyl group, C2 to C6 linear or branched, an aryl group or a heteroaryl group. More preferably, R 9 is a prop-1-yn-1-yl group, a phenyl group or a furan-2-yl group. In a more preferred embodiment, R 9 is a prop-1-yn-1-yl group, a 4-fluorophenyl group or a 5-fluorofuran-2-yl group. Even more preferably, R 9 represents a 4-fluorophenyl group. In the advantageous possibility consisting of the compounds of formula (I-c), the preferred R10 groups are the following: hydrogen; methyl; isopropyl; 2,2,2-trifluoroethyl; benzyl; 4-methoxybenzyl; phenethyl; 3-phenylpropyl; cyclopropylmethyl; cyclopentylethyl; naphthalen-1-ylmethyl; 2- (naphthalen-1-yloxy) ethyl; a but-2-yn-1-yl; a prop-2-en-1-yl; or a goal-3-en-1-yl. In another embodiment, the substituents of the pair (R9, R9), when grafted onto two adjacent atoms, together with the carbon and nitrogen atoms, form a non-aromatic 5- to 6-membered ring. .
[0009] In the advantageous possibility consisting of the compounds of formula (I-d), Rto preferably represents a hydrogen atom or a halogen atom. In the preferred compounds of the invention, R11 and R11 'independently of one another represent a linear or branched (C1-C6) alkyl group, or the substituents of the (R11, R11') 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, sulfur and nitrogen, it being understood that the nitrogen in question may be substituted by a group representing a hydrogen atom or a linear or branched C1-C6 alkyl group. More preferably, R 11 and R 11 'are methyl, or the substituents in the (Ru, R 11') pair together form a 4-methyl-piperazinyl group or a 4-ethyl-piperazinyl group. In a more preferred embodiment, the substituents of the (R 11, R 11 ') pair together form a 4-methyl-piperazinyl group. In another preferred embodiment, R 11 and R 11 'represent a methyl group. Advantageously, R12 represents -Cy5 or -Cy5- (C1-C6) alkyl -Cy6. Preferably, R12 is -Cy5 or -Cy5-CY6. Preferably, Cy5 represents a heteroaryl group, in particular a pyrimidinyl group, a pyrazolyl group, a triazolyl group, a pyrazinyl group or a pyridinyl group. More preferably, Cy5 represents a pyrimidin-4-yl group, a pyrazol-5-yl group or a pyrazin-2-yl group. In the preferred compounds of the invention Cy5 represents a pyrimidin-4-yl group.
[0010] In another embodiment of the invention, Cy5 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, a NR'R "or a linear or branched C 1 -C 6 polyhaloalkyl group, it being understood that R 'and R" represent, independently of one another, a hydrogen atom or a linear or branched C 1 to C 6 alkyl group; optionally substituted, Preferably, Cy6 represents a phenyl group. The other preferred compounds of the invention are those in which R12 is where p is an integer of 0 or 1 and R16 is hydrogen, hydroxy, C1 to C4 alkyl. Optionally substituted linear or branched C6, a linear or branched C1-C6 alkoxy group, a -O- (CHR17-CHR18-O) q-R 'group, a -OP (O) (OR') 2 group, a group -O-P (O) (0-114 +) 2, a group -O-C (O) -NRi9R20, a di (C1-C6) alkyl amino group (C1-C6 alkoxy), an atony d halogen or aldohexose of the formula: OR 'OR' R'0 OR 0 where each R 'is independent; with the proviso that: - R 'represents a hydrogen atom or a linear or branched C1-C6 alkyl group, - R17 represents a hydrogen atom or a (C1-C6) alkoxy (C1-C6) alkyl group ), R 1 represents a hydrogen atom or a hydroxy (C 1 -C 6 alkyl) group, R 1 represents a hydrogen atom or a group (C 1 -C 6 alkoxy) (C 1 -C 6 alkyl), - R 2 O represents a (C1-C6) alkoxy (C1-C6) alkyl group, a - (CH2) group, - NR11R11 'group or - (CH2) group, - Q- (CHR17-CHRi8-0) q-R q is an integer of 1, 2 or 3 and r is an integer of 0 or 1; 15 - M + represents a pharmaceutically acceptable monovalent cation. The aldexose according to the invention is preferably D-mannose. Preferably, the group - (CH 2) 1, -R 16 is located in the ortho position of the phenyl group. Among the preferred compounds of the invention, mention may be made of: (2R) -2 - {[5- {3-chloro-2-methyl-4- [2- (4-methylpiperazin-1-yl)} ethoxy] phenyl} -6- (4-fluorophenyl) -furo [2,3-a] pyrimidin-4-yl] oxy} -3- (2 - {[2- (2-methoxyphenyl) pyrimidin); 4-yl] methoxy) phenyl) propane, - (2R) -2 - {[5- {3-chloro-2-ethyl-442- (4-methylpiperazin-1-yepethoxy) -phenyl} -6- (4-fluorophenyl) -furo [2,3-d] pyrimidin-4-yl} oxy} -3- (2 - {[2- (2-methoxyphenyl) pyrimidin-4-yl] methoxy} phenyl) propanoic acid 25 N- [5- {3-chloro-2-methyl-4- [2- (4-methylpiperazin-1-yepethoxy) phenyl] -6- (4-fluorophenyl) -furo [2,3-d] pyrimidin-4-yl] -2 - {[2- (2-inethoxyphenyl) -pyrimidin-4-yl] methoxy} -D-phenylalanine, - (2R) -2 - {[3- {3-chloro acid 2-methyl-4- (4- (4-methylpiperazin-1-yepethoxy) phenyl) -2- (4-fluorophenyl) -1-benzothiophen-4-yl] oxy} -3- (2- {[2- Methoxyphenyl) pyrimidin-4-yl] methoxyphenyl) propandyl, (2R) -2 - {[3- {3-chloro-2-methyl-442- (4-methylpiperazine) -l- ypethoxylphenyl) -2- (4-fluorophenyl) -1-benzofuran-4-yl] oxy) -3- (2 - {[2- (2-methoxyphenyl) -pyrimidin-4-yl] methoxy} phenyl) propanoic acid, - (2R) -2 - ([3- {3-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxylphenyl] -6-fluoro-2- (4-fluorophenyl) -1- benzofuran-4-yloxy} -3- (2 - {[2- (2-methoxyphenyl) -pyrimidin-4-yl] methoxy} phenyl) propanoic acid, - (2R) -2 - ([3- {3 1-chloro-2-methyl-442- (4-methylpiperazin-1-yepethoxy) phenyl} -2- (4-fluorophenyl) -1-methyl-11-indol-4-yloxy} -3- (2- {[2- (2-methoxyphenyl) -pyrimidin-4-yl] methoxylphenylpropanoic acid, 10 - (2R) -2 - {[3- {3-chloro-2-methyl-442- (4-methylpiperazin-1) - -y1) ethoxyl-phenyl-2- (4-fluorophenyl) -thieno [2,3-b] pyridin-4-yloxy} -3- (2 - {[2- (2-methoxyphenyl) pyrimidin-4-yl} ] methoxylphenyl) propanoic acid; (2R) -24543-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxylphenyl-6- (4-fluorophenyl) -7-methyl-pyrrolo [2,3-c] pyrimidine 4-yloxy-3- [2 - [[2- (2-methoxyphenyl) pyrimidin-4-yl] methoxy] phenyl] propanoic acid. The invention also relates to a process for the preparation of the compounds of formula (I), said process being characterized in that it uses, as starting compound, the compound of formula (II-a): LY A in which Z1 represents bromine or iodine, Z2 represents chlorine, bromine or hydroxy, and A is as defined for formula (1) in which 1 is attached to group Z2 and 2 is attached to group Z1, said compound of formula (II-a) being coupled to a compound of formula (III): wherein R6, R7, R14, W and n are as defined for formula (I), and Alk is a linear or branched C1-C6 alkyl group to give the compound of formula (IV): wherein R6, R7, R14, A, W and n are as defined for formula (I), and Z1 and Alk are as defined above, the compound of formula (IV) being further subjected to coupling with a compound of formula (V): (V) Wherein R1, R2, R3, R4 and R5 are as defined for formula (I), and RBI and RB2 represent a hydrogen atom, a linear or branched C1-C6 alkyl group, or RBI and RB2 form with oxygen carrying them an optionally methylated ring to obtain the compound of formula (VI): Alk O R14 (VI) wherein R1, R2, R3, R4, R5, R6, R7, R14, A, W and n are as defined for formula (I) and Alk is as defined above, the Alk-OC (O) ester function of the compound of formula (VI) being hydrolyzed to give the carboxylic acid, which can optionally be reacted with an alcohol of formula Rs-OH or a chlorinated compound of formula Rs-Cl, where R8 is as defined for formula (I), to obtain the compound of formula (1), 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 optionally separated into its isomers according to 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 reagents starting or synthetic intermediates can be protected, then deprotected and functionalized for the purposes of synthesis. In another embodiment of the invention, the compounds of formula (I) can be obtained by an alternative process, said process being characterized in that it uses, as starting compound, the compound of formula (II) b): wherein Z3 is iodine, Z4 is chloro, hydroxy, and A is as defined for formula (I) wherein 1 is attached to Z4 and 2 is linked to group Z3, said compound of formula (II-b) being coupled with a compound of formula (V): wherein R1, R2, R3, R4 and R5 are as defined for formula (I), and RBI and RB2 represent a hydrogen atom, a linear or branched C1-C6 alkyl group, or RBI and RB2 form with oxygen optionally bearing them Methyl, to obtain the compound of formula (VII): wherein R1, R2, R3, R4, R5 and A are as defined for has formula (I), and Z4 is as defined above, the compound of formula (VII) being further subjected to a coupling with a compound of formula (III): Alk R14 wherein R6, R7, R14, W and n are as defined for formula (I), and Alk represents a linear or branched C1-C6 alkyl group to give the compound of formula (VI): (VI) wherein R1, R2, R3> R4, R5, R6, R7, R14, A, W and n are as defined for the formula (D and Alk is as defined above, the Alk-OC (O) ester function of the compound of formula (VI) being hydrolyzed to give the carboxylic acid, which may optionally be reacted with an alcohol of the formula R8-OH or a chlorinated compound of the formula R8-Cl, where R8 is as defined for the formula (I), 3037959 - 26- 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 an acid or a pharmaceutically acceptable base which is optionally separated into its isomers according to a conventional separation technique, it being understood that at any time deemed appropriate during the process described above, certain groups (hydroxy, amino, etc.) .) starting reagents or synthetic intermediates can be protected, then deprotected and functionalized for the purposes of synthesis. The compounds of the formulas (II-a), (II-b), (III), (V), R8-OH and R8-Cl are either commercially available or 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 treatments for the cancers contemplated, mention may be made of, but not limited to, the treatment of cancers of the bladder, brain, breast and uterus, chronic lymphocytic leukemias, cancers 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 small cell lung cancer.
[0011] 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, percutaneous, trans-cutaneous, rectal, perlingual, ocular or respiratory administration and in particular simple tablets or coated tablets, sublingual tablets, sachets, packets, capsules, glossettes, lozenges, suppositories, creams, ointments, dermal gels and drinkable or injectable ampoules. The dosage varies according to the sex, age and weight of the patient, the route of administration, the nature of the therapeutic indication, or any associated treatments, and ranges from 0.01 mg to 1 g per dose. 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 the like. 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. 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.
[0012] 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. In another embodiment, the present invention relates to the combination of a compound of formula (I) with a proteasome inhibitor, an immunomodulator, or an alkylating agent, as well as pharmaceutical compositions comprising this type of combination. 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.
[0013] 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.
[0014] 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 bisulfide 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.
[0015] By framework proteins which may or may not be related to monoclonal antibodies is meant a protein which contains or does not contain an immunoglobulin fold and which provides a binding capacity similar to that of an antibody 3037959-29. - monoclonal. One skilled in the art knows how to select the framework protein. More particularly, it is known that, to be selected, such a framework must have several characteristics, such as the following ones (Skerra A., J. Mol.Recogn., 2000, 13, 167187): a good phylogenetic conservation, a robust architecture with a well-identified three-dimensional molecular organization (by crystallography or NMR, for example), small size, no or little post-translational modification (s), ease of production, expression and purification. Such a framework protein may be, but not limited to, a structure selected from the group consisting of fibronectin and, preferably, the tenth type III fibronectin domain (FNfn10), lipocalin, anticalin (Skerra A., J. Bioteclmol., 2001, 74 (4): 257-75), B domain-derived protein Z of staphylococcal protein A, thioredoxin A or any protein having a repetitive domain such as ankyrin repetition "(Kohl et al., PNAS, 2003, 100 (4), 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.
[0016] 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.
[0017] Purifications by preparative HPLC were performed on an Armen Spot liquid chromatography system with a 10 ktM C18 Gemini-NX® column, 250 mm × 50 mm, at a flow rate of 118 ml min -1 with UV detection by diode array. (210 nm at 400 nm) using an aqueous solution of 25 mM NH4HCO3 and MeCN as eluents unless otherwise indicated. Analytical LC-MS: The compounds of the present invention were characterized by high performance liquid chromatography-mass spectrometry (HPLC-MS) on an Agitate HP1200 with a LC / MS Quadrupole Shaker 6140, operating in either positive or negative mode. ionization 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. The samples were injected as a 1mM solution in ACN or THF / H20 (1/1) in a loop of 111. 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 min x 3.00 mm dia. at 23 ° C, at a flow rate of 1 ml 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 certain variable period. 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), in (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 Agite 6850 gas chromatograph and an Agitent 5975C mass spectrometer using a 15 mx 0.25 mm column with a 307959 coating. 0.25 gm HP-5MS and helium as carrier gas. Ionic source: Er, 70 eV, 230 ° C, quadrupole: 150 ° C, interface: 300 ° C. The high resolution masses (HRMS) were determined on a Shimadzu ITTOF, ionic source temperature of 200 ° C, ESI +/-, ionization voltage: 5 (+ -) 4.5 kV. Min. Mass resolution 10,000 Elemental analyzes were performed on a Thermo Flash Elemental Analyzer EA 1112. List of abbreviations Abbreviation Name 2-Me-THF 2-methyl-tetrahydrofuran abs. absolute Ac acetyl AIBN 2 - [(1-cyano-1-methyl-ethyl-azazo] -2-methyl-propanenitrile AiaPhos bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) BINAP (2,2'- bis (diphenylphosphino) -1,1'-binaphthyl) cc dibenzylideneacetone concentrate DCM methylene chloride DEAD diethyl azodicarboxylate DEE diethyl ether DIPA diisopropylamine DIPEA diisopropylethylamine DMA dimethylacetamide DME 1,2-dimethoxyethane DMF dimethylformamide DMSO dimethylsulfoxide dppf 1,1'- bis (diphenylphosphino) ferrocene DTAD di-tert-butyl azodicarboxylate EDC.HCl N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride eq equivalent And ethyl HILIC hydrophilic interaction liquid chromatography HMDS hexamethyldisilazane isopropyl LDA lithium diisopropylamide MCPBA meta-chloroperoxybenzoic acid Me methyl MeCN acetonitrile MTBE methyl tert-butyl ether MW microonde NBS N-bromosuccinimide Bu n-butyl NCS N-chlorosuccinimide Ph ph Enyl PPA polyphosphoric acid rac. racemic RT ambient temperature S2Me2 dimethyl disulfide SPhos 2-dicyclohexylphosphino-2 ', 6'-dimethoxy-biphenyl TBAF tetrabutylammonium fluoride TBAOH tetrabutylammonium hydroxide tert-butyl Bu TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TIPSCI triisopropylsilyl chloride TLC layer chromatography X-Phos 2-dicyclohexylphosphino-2 ', 4', 6'-triisopropylbiphenyl Thin-N-thylate General Procedure 1-Eq. Preparation 1, 2 eq. of the appropriate lactic ester derivative, 10 ml / mmol of tBuOH and 5 eq. of Cs2CO3 were placed in a flask and allowed to stir at 55 ° C until no further conversion was observed. Then, the mixture was concentrated under reduced pressure, neutralized with a 1M aqueous HCl solution, diluted with brine and 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.
[0018] 10 General Procedure Ib 1 eq. Preparation 1, 2 eq. of suitable amino acid derivative, 10 ml / mmol DMSO and 3 eq. K2CO3 were placed in a flask and allowed to stir at 45 ° C until no further conversion was observed. Then, the mixture was neutralized with an aqueous solution of 1M Ha, diluted with brine 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 via HILIC chromatography unless otherwise indicated. General Procedure II 20 Step A 1 eq. of a suitable 5-bromo-furo [2,3-dbyrimidyl-lactic ester derivative, 1.25 eq. of appropriate boronic acid derivative, 10 mol% AtaPhos and 3 eq. of Cs2CO3 were dissolved in a 1/1 mixture of dioxane and water (10 ml / mmol of 5-bromo-furo [2,3-4-pyrimidyl-lactic ester derivative] and left stirring at 105 ° C. ° C in a MW reactor until no longer observe conversion. Then, the mixture was neutralized with 1M aqueous HCl solution, diluted with brine and extracted with THF. The combined organic phases were dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase preparative chromatography using 25 mM aqueous NH4HCO3 and MeCN as eluents. Step B The resulting intermediate was dissolved in a 1/1 mixture of dioxane and water (25 ml / mmol) and 10 eq. LiOH x H2O was added. The mixture was stirred at RT until no further conversion was observed. Then it was diluted with brine, neutralized with 2M aqueous HCl and extracted with DCM. The combined organic phases were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The diastereoisomers were purified and separated by reverse phase preparative chromatography using a 25 mM aqueous NH4HCO3 solution and MeCN as eluents.
[0019] General Procedure HI 1 eq. of appropriate 4-chloro-pyrrolo [2,3-d] pyrimidine derivative, 3 eq. of suitable amino acid derivative, 10 ml / mmol of DMSO and 4 eq. K2CO3 were stirred at 150 ° C until no further conversion was observed. The mixture was acidified with a 1M aqueous HCl solution, the precipitate was filtered and purified by reverse phase preparative chromatography using 25mM aqueous NH4HCO3 and MeCN as eluents. General Procedure IVa 20 1 eq. of appropriate 5-bromo-pyrrolo [2,3-d] pyrimidine derivative, 3 eq. of appropriate boronic acid derivative, 3 eq. of TBAOH, 0.2 eq. palladium acetate, 0.4 eq. Tricyclohexyl phosphonium tetrafluoroborate and 3.5 ml / mmol of DME were stirred under an N 2 atmosphere at 120 ° C in a MW reactor until no further conversion was observed. Then, the mixture was filtered through celite and washed with MTBE and water. The phases were separated and the aqueous phase was washed with MTBE. The combined organic phases were washed with brine, dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase preparative chromatography using 40 mM aqueous NI140Ac (pH = 4) and MeCN as eluents.
[0020] General Procedure IVb 3037959 - 35- 1 eq. of appropriate 5-iodo-pyrrolo [2,3-d] pyrimidine derivative, 3 eq. of appropriate boronic acid derivative, 3 eq. of TBAOH, 0.2 eq. palladium acetate, 0.4 eq. of butyldi-1-adamantylphosphine and 7 ml / mmol of DME were stirred under a refluxing N 2 atmosphere until no further conversion was observed. Then, the mixture was filtered through celite and concentrated under reduced pressure. The residue was purified by flash chromatography using DCM and MeOH as eluents. General procedure V 1 eq. of the appropriate benzofuran-4-ol derivative, 2.5 eq. of the appropriate lactic ester derivative, 2.5 eq. DTAD and 2.5 eq. of PPh3 were dissolved in anhydrous toluene (20 ml / mmol) and stirred at 55 ° C until no further conversion was observed. Then, the mixture was concentrated and the residue was purified by flash chromatography using heptane and EtOAc as eluents.
[0021] 15 General Procedure VI 1 eq. of a suitable 3-bromo-benzofuran derivative, 2 eq. of appropriate boronic acid derivative, 2 eq. of Cs2CO3, 10 mol% Ataphos, 1.5 eq. tri-tert-butylphosphonium tetrafluoroborate and THF (10 ml / mmol) and water (4 ml / mmol) were stirred under an N 2 atmosphere at 110 ° C. in a MW 20 reactor. no longer observe conversion. Then, the mixture was acidified with a 1M aqueous HCl solution and extracted with DCM. The combined organic phases were washed with brine, dried over MgSO4, 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 MeCN as eluents. The resulting intermediate was dissolved in the dioxane / water mixture 1: 1 (10 ml / mmol), 10 eq. LiOH-1 × H2O was added and the mixture was stirred at RT until no further conversion was observed. Then, the mixture was diluted with water, acidified with 1M aqueous HCl and extracted with DCM. The combined organic phases were dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure. The crude product was purified by reverse phase preparative chromatography using an aqueous 25 mM NH4HCO3 solution and MeCN as eluents. Preparation 1a: 5-Broino-4-chloro-6- (4-fluorophenyl) -furo [2,3-dipyrimidine Step A: 2- (47-Fluorobenzoylpropanedinitrile) 81 ml of a 1M NaOEt solution in 1 ml EtOH (81 mmol) was cooled to 0 ° C and 6.14 g of malononitrile (93 mmol) was added The mixture was stirred at 0 ° C for 1 hour, then 16.8 g 2-bromo-1- (4-fluorophenyl) ethanone (77.4 mmol) was added The mixture was stirred at 0 ° C for 1 hour, then at RT until no further conversion was observed. The volatiles were removed under reduced pressure, and the residue was purified by flash chromatography using heptane and EtOAc as eluents to give 2- (4-fluoro benzylpropanedanitrile) 1H NMR (400 MHz , CDCl3): 8.1 (m, 2H), 7.24 (m, 2H), 4.41 (t, 1H), 3.75 (d, 2H).
[0022] Step B 2-Amina-5- (4111-tartarphenyl) -furran-3-carbonitrile 6.56 g of 2- (4-fluorobenzoyl) propanedinitrile (28.5 mmol) was dissolved in 140 ml of AcOH and 6 g of amberlite 15H + were added. The mixture was stirred at 90 ° C until no further conversion was observed. Then, the mixture was filtered, the filtrate was concentrated under reduced pressure. The residue was recrystallized from DCM to give 2-amino-5- (4-fluorophenyl) furan-3-carbonitrile, 1H NMR (400MHz, DMSO-d6): 7.69 (m, 2H), 7.24 (m.p. m, 2H), 6.96 (s, 1H) Step C: 6- (4-fluorophenyl) -3H-furro [2,3-d] pyrimidin-4-one 1290 mg of 2-amino-5- ( 4-fluorophenyl) furan-3-carbonitrile (6.38 mmol) and 25.5 ml of formic acid anhydride were placed in a flask and allowed to stir at RT for 30 minutes. The residue was dissolved in 51 ml of AcOH and heated in a MW reactor at 160 ° C. for 30 minutes and then at 180 ° C. for 15 minutes. TA, and the precipitate was filtered to give 6- (4-fluorophenyl) -3H-furo [2,3-d] pyrimidin-4-one, 1H NMR (500MHz, DMSO-d6): 12.66 (br s). , 1H), 8.15 (s, 1H), 7.99 (nl, 2H), 7.47 (s, 1H), 7.33 (br, 2H) Step D: 5-bromo -6- (4-fluorophény1) -3H-Firro [2,3-d ] pyrimidin-4-one 1704 mg of 6- (4-fluorophenyl) -3H-furo [2,3-a] pyrimidin-4-one (7.4 mmol) was dissolved in 74 ml of AcOH, then 1182. mg bromine (7.4 mmol) was added. The mixture was stirred at RT until no further conversion was observed. The mixture was then filtered, the filtrate was concentrated under reduced pressure. The residue was suspended in 15 ml MeOH, filtered and air dried to give 5-bromo-6- (4-fluorophenyl) -3H-furo [2,3-cilpyrimidin-4-one. MS: (M-H) + = 309.0. Step E: 5-bromo-4-chloro-6- (4-fluorophenylfuro [2,3-c] pyritnidine 1680 mg of 5-bromo-6- (4-fluorophenyl) -3H-furo [2,3-d] Pyrimidin-4-one (5.44 mmol) was dissolved in 12.7 ml of POCl3 (136 mmol) and 690 μl of DMA (5.44 mmol) was added. C. The mixture was then cooled to 0 ° C. and poured into ice-water melt The crude product was isolated by filtration and purified by flash chromatography. using heptane and EtOAc as eluents to obtain Preparation 1a NMR (400 MHz, DMSO-d6): 8.87 (s, 1H), 8.16 (m, 2H), 7, 47 (m, 2H) Preparation 1b: 5-Bromo-4-chloro-6-ethyl-7H-pyrrolo [2,3-d] pyrimidine Step A: 6-Amitio-5-1- (2-ethyl-1) 3-Diarolan-2-amethylpyrimidin-4-ol 257 mg of 6-amino-5 - [(2-ethyl-1,3-dioxolan-2-yl) methyl] -2-sulfanyl-pyrimidin-4-ol ( 0.1 mmol), 0.77 ml of an aqueous NH 3 cc solution, 768 mg of Ni from Ra Ney and 11 ml of water were placed in a flask under an N 2 atmosphere and refluxed until no further conversion was observed. The hot reaction mixture was then filtered through celite and washed with hot water. The filtrate was concentrated under reduced pressure. The crude product (6-amino-5 - [(2-ethyl-1,3-dioxolan-2-yl) methyl] pyrimidin-4-ol) was used without further purification. NMR (400 MHz, DMSO-d6) δ: 11.44 (br s, 1H), 7.70 (s, 1H), 6.07 (s, 2H), 3.89 (m, 4H), , 62 (s, 2H), 1.53 (m, 2H), 0.81 (t, 3H). MS (M + H): 226.2. Step B: 6-ethyl-7H-pyrrolo [2,3-d] pyrimidin-4-ol 4,193 g of 6-amino-5 - [(2-ethyl-1,3-dioxo-2-yl) -yl) -methyl] pyrimidin-4-ol (18.6 mmol) were dissolved in 280 ml of 0.2M aqueous HCl solution. The mixture was stirred at RT until no further conversion was observed. The precipitate was filtered, washed with water and dried to give 6-ethyl-7H-pyrrolo [2,3-d] pyrimidin-4-ol. 1H NMR (400MHz, DMSO-d6) δ: 11.67 (s, 111), 7.75 (s, 111), 6.12 (t, 1H), 2.56 (m, 2H), 1, 21 (t, 3H). MS (M + H): 164.2.
[0023] Step C: 5-bromo-6-ethyl-7H-pyrrolo [2,3-clipyrimidin-4-ol 1.63 g of 6-ethyl-7H-pyrrolo [2,3-a] pyrimidin-4-ol ( 10 mmol) was dissolved in 20 ml of DMF and cooled to 0 ° C. 1 ml of bromine (20 mmol) was added and the mixture was stirred at RT until no further conversion was observed. Then, it was diluted with water and an aqueous solution of Na2S2O3 and extracted with DCM. The combined organic layers were washed with brine, dried over MgSO4, filtered and the filtrate concentrated under reduced pressure to give 5-bromo-6-ethyl-71β-pyrrolo [2,3-d] pyrimidin-4- ol. 1 H NMR (400 MHz, DMSO-d 6) δ: 12.08 (s, 1 F 1), 11.83 (s, 1H), 7.80 (d, 1H), 2.60 (q, 2H), 1, 16 (t, 3H). MS (M + H): 243.8. Step D: 5-bromo-4-chloro-6-ethyl-7H pyrrolo [2,3-d] pyrimidine 1936 mg 5-bromo-6-ethyl-7H-pyrrolo [2,3-d] pyrimidine 4-ol (8 mmol), 4.5 ml of POCl3 and 969 mg of N, N-dimethylaniline (8 mmol) were placed in a flask and stirred at 100 ° C until no more conversion. The mixture was then poured into ice-water and extracted with DCM. The combined organic phases were washed with brine, dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure to obtain Preparation Ib.
[0024] 111 NMR (400 MHz, CDCl3) δ: 9.79 (s, 1H), 8.59 (s, 1H), 2.91 (q, 2H), 1.37 (t, 3H). MS (M + H): 260.0. Preparation 1: 3-Bromo-2- (4-formiorophenyl) benzofuran-4-ol Step A: 2- (47-Fluorophenyl) -benzofuran-4-ol 2.37 g of 2-bromoresorcinol (12.5 g) mmol) were dissolved in 30 ml of anhydrous THF under an N 2 atmosphere and 4.17 ml of TEA (30 nunol) and 1.92 ml of AcCl (27 mmol) were added, respectively. After stirring the mixture for 5 minutes, 2.4 g of 1-ethynyl-4-fluorobenzene (20 mmol), 561 mg of Pd (OAc) 2 (2.5 nunol), 1.45 g of tri-tetrafluoroborate were added. -butylphosphonium (5 nunol), 476 mg of Cul (2.5 mmol) and 10 ml of anhydrous DIPA were added and the mixture was stirred at 80 ° C until no further conversion was observed. Then 2 g of LiOH x H2O was added and the mixture was stirred at 80 ° C until no further conversion was observed. The mixture was then concentrated under reduced pressure and purified by reverse phase preparative chromatography using 25mM aqueous NH4HCO3 solution and MeCN as eluents to give 2- (4-fluorophenyl) benzofuran-4-ol. 1 H NMR (400 MHz, DMSO-d 6) δ: 10.00 (s, 1H), 7.91 (m, 2H), 7.38 (s, 111), 7.31 (t, 2H), 7 , (T, 1H), 7.04 (d, 1H), 6.63 (dd, 1H). Step B: P- (4-flitorophenyl) benzofuran-4-ylel acetate 456 mg of 2- (4-fluorophenyl) benzofuran-4-ol (2 mmol) was dissolved in 10 ml of anhydrous THF and then 156 μl of AcCl (2.2 mmol) and 306 of TEA (2.2 mmol) were added cautiously. The mixture was stirred under N 2 until no further conversion was observed. The solvent was then removed under reduced pressure, and the residue was purified by flash chromatography using heptane and EtOAc as eluents to give [2- (4-fluorophenyl) benzofuran-4 acetate. yl]. NMR11-1 (400 MHz, CDCl3) δ: 7.84 (m, 2H), 7.42 (d, 1H), 7.28 (t, 1H), 7.15 (t, 2H), 7.02 (d, 1H), 6.86 (s, 1H), 2.42 (s, 3H). Step C: P-bramo-2- (47-fluorophenyl-ericizoluran-4-yl) acetate 688 mg of [2- (4-fluorophenyl) benzofuran-4-yl] acetate (2.54 mmol) and 589 mg of NBS ( 3.31 mmol) were dissolved in 20 ml of MeCN and stirred at 70 ° C until no further conversion was observed.The solvent was then removed under reduced pressure, and the residue was purified. flash chromatography using heptane and EtOAc as eluents to give [3-bromo-2- (4-fluorophenyl) benzofuran-4-yl] acetate NMR (400 MHz, CDCl3): 8.11 (m, 2H), 7.44 (dd, 1H), 7.34 (t, 1H), 7.19 (m, 2H), 7.00 (dd, 1H), 2.45 (s). , 3H).
[0025] Step D: 3-bromo-2- (4-fluorophenyl) benzofuran-4-ol 175 mg [3-bromo-2- (4-fluorophenyl) benzofuran-4-yl] acetate (0.5 mmol) ) and 150 μl of a solution of 1M NaOEt in EtOH and 5 ml of EtOH were stirred at RT under N 2 until no further conversion was observed. The mixture was diluted with 50 ml of an aqueous NH4Cl cc solution. and extracted with DCM. The combined organic phases were dried over Na2SO4, filtered and the filtrate was concentrated to give Preparation 1c. 1H NMR (400 MHz, DMSO-d6) δ: 10.16 (bs, 1H), 8.08 (m, 2H), 7.38 (m, 2H), 7.17 (t, 11-1) , 7.08 (d, 1H), 6.70 (d, 1H) Preparation 1d: 3-bromo-6-fluoro-2 (4-fluorophenyl) -benzofuran-4-ol Step A: 57Fluoro-2-iado 1,3-dial-benzene 3.81 g (29.7 mmol) of 5-fluorobenzene-1,3-diol were dissolved in 600 ml of water and 8.08 g (31.8 mmol) of water. iodine was added at 0 ° C and the mixture was allowed to stir for 30 minutes. Then, the pH was adjusted to 3 with NaHCO 3 solution and the mixture was allowed to stir until no further conversion was observed. Then the pH was adjusted to 8 (with NaHCO 3 solution), 20 g of Na 2 S 2 O 3 was added and the mixture was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated and purified by flash chromatography using heptane and EtOAc as eluents to give 5-fluoro-2-iodobenzene-1 , 3-diol. NMR (400 MHz, DMSO-d6): 10.54 (s, 2H), 6.19 (d, 2H). Step B: (3-Acetoxy-5-fluoro-2-iodo-phenyl) acetate 4.78 g of 3-bromo-6-fluoro-2- (4-fluorophenyl) -benzofuran-4-01 (18.8 mmol) were dissolved in 150 ml of THF and 5.70 g of TEA (56.5 mmol) was added, then 4.267 g of Ac 2 O (41.4 mmol) was added dropwise at RT. . The mixture was allowed to stir until no further conversion was observed. The mixture was then concentrated under reduced pressure and purified by flash chromatography using heptane and EtOAc as eluents to obtain (3-acetoxy-5-fluoro-2-iodoacetate) acetate. phenyl). 1H NMR (400MHz, DMSO-d6): 7.24 (d, 2H), 2.34 (s, 6H).
[0026] Step C: 6: Flitoro-2- (4-fluorophenyl) benzofl-4-yr 5.9 g of (3-acetoxy-5-fluoro-2-iodophenyl) acetate (17.45 mmol) dissolved in 70 ml of anhydrous THF and 70 ml of anhydrous DIPA under an N 2 atmosphere, then 3.77 g of 1-ethynyl-4-fluorobenzene (31.4 mmol), 587 mg of Pd (OAc) 2 (2 , 62 mmol), 1.52 g of tri-tert-butylphosphonium tetrafluoroborate (5.24 mmol), and 500 mg of CuI (2.62 mmol) were added and the mixture was stirred at 60 °. C until no longer observe conversion. Then 2.93 g of LiOH x H2O was added and the mixture was stirred at 60 ° C until no further conversion was observed. The mixture was then concentrated under reduced pressure and purified by reverse phase preparative chromatography using 25mM aqueous NH4HCO3 and MeCN as eluents to give 6-fluoro-2- (4-fluorophenyl) benzofuran-4. -01. 1 H NMR (400 MHz, DMSO-d6): 10.60 (s, 1H), 7.89 (m, 2H), 7.38 (s, 1H), 7.32 (m, 2H), 6.99. (m, 1H), 6.48 (dd, 1H). Step D: [6-Fluoro-2- (4-fluorophenyl) benzofuran-4-yl] acetate 2.49 mg of 6-fluoro-2- (4-fluorophenyl) benzofuran-4-ol (10.1 mmol) ) were dissolved in 50 ml of anhydrous THF, followed by 791 μl of AcCl (11.1 mmol) and 1.55 ml of TEA (11.1 mmol) were added cautiously. The solvent was then removed under reduced pressure, and the residue was purified by flash chromatography using heptane and EtOAc as eluents to obtain the reaction mixture. [6-Fluoro-2- (4-fluorophenyl) benzo-furan-4-yl] acetate, 1H NMR (400 MHz, DMSO-d6): 7.95 (m, 2H), 7.57 (m, 1H). , 7.46 (s, 1H), 7.37 (m, 2H), 7.09 (dd, 1H), 2.40 (s, 311) Step E: P-bromo-6-flitoro acetate 2- (4-Fluoro-phenyl) benzofuran-4-yl] 2.96 g of [6-fluoro-2- (4-fluorophenyl) -benzofuran-4-yl] acetate (10.27 mmol) and 2.28 g of NBS (12.84 mmol) was dissolved in 120 ml of MeCN and the stirring at 60 ° C until no further conversion. The solvent was then removed under reduced pressure, and the residue was purified by flash chromatography using heptane and EtOAc as eluents to give [3-bromo-6-fluoroacetate. 2- (4-fluorophenyl) benzofuran-4-yl] acetate. 1H NMR (400MHz, DMSO-d6): 8.07 (m, 2H), 7.69 (dd, 1H), 7.44 (in, 1H), 7.19 (m, 2H), 7.09; (dd, 111), 2.41 (s, 31-1).
[0027] Step F: 3-bromo-6-fluoro-2- (4.1-fluorophenyl) benzo-furatt-4-ol 3.35 g of [3-bromo-6-fluoro-2- (4-fluoro) acetate phenyl-benzofuran-4-yl] (9.12 mmol) and 8.67 ml of a 1M NaOEt solution in EtOH and 90 ml of EtOH were stirred at RT under an N2 atmosphere. The mixture was diluted with 50 ml of a 1N aqueous solution of DCI and extracted with DCM The combined organic phases were dried over Na2SO4, filtered and the filtrate was concentrated to give the mixture. Preparation Id. NMR 111 (400 MHz, DMSO-d6): 10.78 (s, 1H), 8.06 (m, 21-1), 7.40 (m, 21-1), 7.06 (dd). , 1H), 6.54 (dd, 1H).
[0028] Preparation 2a: Ethyl (2R) -2-acetoxy-3- (2-hydroxyphenyl) -propanoate and Ethyl 2b (2S) -2-acetoxy-3- (2-hydroxyphenyl) -propanoate Preparation Step A: [2- (hromomethyl) phenyl acetate] 60.07 g of 2-methylphenyl acetate (400 mmol) and 106.8 g of NBS (600 mmol) were placed in a 1 1. 500 ml flask of Cyclohexane was added and then with intense stirring, 3.284 g of AJBN (20 mmol) was added over a period of 30 minutes. The mixture was stirred at 80 ° C until no conversion was observed, then cooled to RT. The precipitate was removed by filtration and washed with cyclohexane. The mother liquor was concentrated under reduced pressure, and the crude product was used in step B without further purification. Step B: Ethyl 2-acetoxy-3- (2-hydroxyphenyl) proparwate 23.10 g of anhydrous LiCl (545 mmol) and 65.36 g of anhydrous ZnCl 2 (479.6 mmol) were placed in a flask. of 2 1, then dried at 160 ° C under 0.1 mmHg for 1 hour. After cooling to RT under an argon atmosphere, 26.49 g of magnesium turnings (1090 mmol) and 1 l of anhydrous THF previously cooled (0 ° C) were added. The resulting mixture was immersed in an ice bath and then left stirring for 30 minutes. 100 g of [2- (bromomethyl) phenyl acetate] (crude product obtained in step A, -436 mmol) was dissolved in 120 ml of anhydrous THF and added to the inorganic substances previously cooled over a period of 15 minutes. . After adding the reagent, the resulting mixture was allowed to stir for 45 minutes while maintaining the temperature between 0 ° C and 5 ° C. Then, 64.82 ml of ethyl 2-oxoacetate (654 mmol, 50% in toluene) was added over a period of 5 minutes and the resulting mixture was allowed to stir for another 15 minutes. The remaining inorganic substances were removed by filtration, and the filtrate was diluted with 500 ml MeOH. This mixture was allowed to stir until the intramolecular migration of the acetyl group from the phenolic oxygen to the oxygen of the alkyl was complete. Then, 30 ml of acetic acid was added, and then the volatiles were evaporated under reduced pressure. 350 ml of water was added to the residue and the mixture was extracted with EtOAc. The combined organic phases were washed with saturated aqueous NaHCO3 and brine then dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. Then, 100 ml of hexane was added and the mixture was stirred for 30 minutes at 0 ° C. The white crystals formed were collected by filtration and washed with hexane. 1 H NMR (500 MHz, DMSO-d 6) δ: 9.53 (s, 1H), 7.06 (t, 1H), 7.04 (d, 111), 6.79 (d, 1H), 6.71. (t, 1H), 5.10 (dd, 114), 4.05 (q, 2H), 3.06 (dd, 114), 2.94 (dd, 1H), 2.00 (s, 3H). ), 1.09 (t, 3H). The enantiomers were separated by chiral chromatography. Column: OD; Eluents: heptane / EtOH; the first eluted enantiomer was collected as Preparation 2b at 99.8% and the last eluted enantiomer was collected as Preparation 2a at 99.9%.
[0029] Preparation 2c: Ethyl (2R) -2-hydroxy-3- [24 [2- (2-methoxyphenyl) pyrimidin-4-yl] methoxylphenyl] propanoate Step A: (2R) -2-hydroxy acid 3-3-112- (2-inethoxy-phenyl) pyrimidin-4-ylimethoxy-phenyl] propanoic acid 30.3 g of Preparation 2a (120 mmol), 38.9 g of Preparation 5b (180 mmol) and 47, 2 g of triphenyl phosphine (180 mmol) was dissolved in 120 ml of anhydrous toluene, then 82 ml. of DEAD (180 mmol, 40% in toluene) were added. The mixture was stirred at 50 ° C under a nitrogen atmosphere until no further conversion was observed. Volatiles were evaporated under reduced pressure. Then, 300 ml of DEE was added, the mixture was sonicated and filtered, then washed with DEE. The filtrate was concentrated under reduced pressure. The residue was dissolved in 125 ml of THF and then 24 g of NaOH (0.6 mol) dissolved in 125 ml of water was added. The mixture was stirred at 50 ° C until no further conversion was observed. The pH was adjusted to 5 with 1N HCl, and the volatiles were removed under reduced pressure. 100 ml of water and 350 ml of DCM were added, the mixture was stirred at 0 ° C and the precipitate was filtered, washed with cold water and DCM and dried under reduced pressure to obtain the mixture. (2R) -2-hydroxy-342 - [[2- (2-methoxyphenyl) pyrimidin-4-yl] methoxy] phenylFpropanoic acid. 1 H-NMR (400 MHz, DMSO-d6) δ: 8.88 (d, 1H), 7.80 (d, 1H), 7.55 (dd, 1H), 7.49-7.44 (m, 1H), 7.26 (dd, 1H), 7.17-7.11 (m, 2H), 7.06 (t, 1H), 6.98 (d, 1H), 6.88 (t, 1H). ), 5.22 (s, 211), 4.50 (d, 1H), 3.81 (dd, 1H), 3.77 (s, 3H), 3.73 (dd, 1H), 2, 44 (dd, 1H). Step B: Ethyl (2R) -2-hydroxy-3-P-112- (2-methoxyphenyl) -pyrimidin-iryllmethoxylphenylpropanoate 51.7 g of (2H) -2-hydroxy-342 - [[ 2- (2-methoxyphenyl) pyrimidin-4-yl] methoxy] phenyl] propanoic acid (136 mmol) was dissolved in 520 ml EtOH followed by 20 ml H 2 SO 4 cc. have been added. The mixture was stirred at 60 ° C until no further conversion was observed. Then, it was diluted with water, neutralized with a saturated aqueous solution of NaHCO 3 and extracted with dichloromethane. The combined organic phases were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure and purified by flash chromatography using EtOAc and MeOH as eluents to obtain Preparation 2c. High resolution mass (HRMS) calculated for C23H24N2O5: 408.1685, found: 409.1757 (M + H). Preparation 2d: Ethyl (2S) -2-hydroxy-3-12 - [[2- (2-methoxyphenyl) pyrimidin-4-yl] methoxylphenyl] propanoate Preparation 2d was synthesized in the same manner than Preparation 2c, but from Preparation 2b instead of Preparation 2a. Preparation 2: Ethyl (2R) -2-hydroxy-3- (2-methoxyphenyl) -PROPanoate and Preparation 2f: (2S) -2-Hydroxy-3- (2-methoxyphenyl) -propanoate ethyl The enantiomers of ethyl 2-hydroxy-3- (2-methoxyphenyl) -propanoate were separated by chiral chromatography; Column: AD, Eluent: 2-PrOH; the enantiomer eluted first was collected as Preparation 2e with an ee of 99.8%. The enantiomer eluted last was collected as Preparation 2f with a 97.8% ee.
[0030] Preparation 2g: Ethyl (2R) -2-hydroxy-3-12- (pyrazin-2-yl-nichloroethoxy) phenylpropanoate Step A: (2R) -2-Acetoxy-3-12- (pyrazin-2-ylmethoxy) ) -phenyl] ethyl propanoate 1 eq. Preparation 2a, 2 eq. pyrazin-2-ylmethanol and 2 eq. of triphenylphosphine were dissolved in anhydrous toluene (0.2M for phenol), then 2 eq. of DTAD have been added. The mixture was stirred at 50 ° C under a nitrogen atmosphere. After reaching an appropriate conversion, the volatiles were removed under reduced pressure. The crude intermediate was purified by flash chromatography using heptane and EtOAc as eluents to give (2R) -2-acetoxy-3 [2- (pyrazin-2-ylmethoxy) phenyl] propanoate. 'ethyl. Step B: Ethyl (2R) -2-hydroxy-3-P- (pyrazin-2-ylmethoxy) -pyrytylpropanoate (2R) -2-Acetoxy-3 [2- (pyrazin-2-ylmethoxy) -phenyl) propanoate Ethyl was dissolved in ethanol (0.5M) and then 2 mol% of a solution of NaOEt (1.0M in ethanol) was added. The resulting mixture was stirred at RT. More NaOEt solution was added if the conversion was not complete. The mixture was concentrated to half its volume, then water and brine were added, and it 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 methanol as eluents to obtain Preparation 2g. NMR III (400 MHz, DMSO-d6) δ: 8.88 (s, 1H), 8.64 (dd, 2H), 7.27-7.16 (m, 2H), 7.06 (d, 1H), 6.89 (t, 1H), 5.46 (d, 1H), 5.27 (dd, 2H), 4.29 (dq, 1H), 4.00 (q, 2H) , 3.09 (dd, 1H), 2.79 (dd, 1H), 1.08 (t, 3H). Preparation 2h: Ethyl (2S) -2-hydroxy-342- (2,2,2-trifluoro-ethoxy) phenyl] propanoate Step A: (25) -2-Hydroxy-3- (2-hydroxyphenyl) propanoate 13.633 g of Preparation 2b (54 mmol) were dissolved in 200 ml of anhydrous EtOH, then 30 ml of a solution of NaOEt (1M in EtOH) was added and the mixture was stirred at room temperature. YOUR. If necessary, the addition of the NaOEt solution was repeated until the cleavage of the acetyl group was complete. The mixture was diluted with 600 ml of water and extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The ethyl (25) -2-hydroxy-3- (2-hydroxyphenyl) propranoate obtained was used in the next step without further purification. Ethyl 2,2-trichloroethoxy) -phenyl] propanoate Ethyl (2S) -2-hydroxy-3- (2-hydroxyphenyl) -propanoate (9.18 g) (43.7 mmol) was dissolved in 130 ml. Anhydrous DMF followed by 6.040 g K2CO3 (43.7 mmol) was added, and after stirring for 5 minutes, 7.7 ml of 2,2,2-trifluoroethyl trifluoromethanesulfonate (48 nunol) was added to a solution. The resulting mixture was stirred until no further conversion was observed The reaction mixture was diluted with brine and extracted with EtOAc The combined organic phases were dried over Na 2 SO 4 The crude product was purified by flash chromatography using heptane and EtOAc as eluents. MHz, DMSO-d6) δ: 7.23 (t, 1H), 7.18 (d, 1H), 7.06 (d, 11-1), 6.95 (t, 1H), 5.50 (b.p. d, 1I-I), 4.75 (q, 211), 4.22 (m, 1H), 4.02 (q, 2H), 3.00 (dd, 11-I), 2.76 (dd; 114), 1.09 (t, 31-1) Preparation 3a: 2-Chloro-3-methyl-4- (4,41,5,5-tetramethyl-1,3,2-dioxaborolan-2) -y1) phenol Step A: (4-Bromo-2-chlorophenoxy) -trimethylsilane 20.8 g of 4-bromo-2-chlorophenol (100 mmol) were dissolved in 150 ml anhydrous THF, then 24.2 g of HMDS (150 mmol) was added. The reaction mixture was stirred at 85 ° C under an argon atmosphere for 1.5 hours and then concentrated under reduced pressure. The resulting crude product was used without further purification. NMRIII (200 MHz, CDCl3): 7.49 (d, 1H), 7.23 (dd, 1H), 6.75 (d, 1H), 0.26 (s, 9H). Step B: 4-Bromo-2-chloro-3-methyl-phenol 48 ml of a solution of SuLi in hexane (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 (4-bromo2-chloro-phenoxy) -trimethylsilane (100 mmol) was added dropwise. After 2.5 hours, 21.3 g of MeI (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 NH3 solution and 200 ml of saturated aqueous 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).
[0031] 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 in a flask for 1.5 hours and then concentrated under reduced pressure. The product obtained was used without further purification. 1 H NMR (200 MHz, CDCl 3): 7.30 (d, 1H), 6.63 (d, 1H), 2.50 (s, 3H), 0.28 (s, 9H). 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 (4 g) -bromo-2-chloro-3-methyl-phenoxy) -trimethylsilane (86.0 mmol) in 250 ml of anhydrous THF was cooled to -78 ° C under argon, followed by 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. saturated aqueous solution of NH 4 Cl and extracted with EtOAc The combined organic phases were concentrated under reduced pressure and passed through a pad of silica gel using hexane and EtOAc as eluents. The crude product was recrystallized from a mixture of EtOAc and hex to obtain Preparation 3a: NMRIII (500 MHz, DMSO-d6): 10.40 (s, 1H), 7.42 (d, 1H), 6.80 (d, 1H), 2.49 (s, 3H), 1.27 (s, 12H).
[0032] Preparation 3b: 142-12-Chloro-3-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-aphenoxylethyl) -4-methylpiperazine 10.0 g Preparation 3a (37.2 mmol), 8.7 g of 2- (4-methylpiperazin-1-yl) ethanol (60.3 mmol) and 15.8 g of PPh 3 (60.3 mmol) were dissolved in 100 ml. of anhydrous toluene, then 27 ml of DEAD (60.3 mmol, 40% solution in toluene) was added dropwise The mixture was stirred at 50 ° C under an argon atmosphere The volatiles were evaporated under reduced pressure and 100 ml of Et 2 O was added The precipitated white crystals were filtered off and washed with Et 2 O. The filtrate was concentrated The resulting light brown oil was crystallized from hexane to give Preparation 3b as a dichloroformate under reduced pressure and purified by flash chromatography using CHCl3 and MeOH as eluents. An off-white solid, 1 H NMR (500 MHz, DMSO-d 6): 7.56 (d, 1H), 6.99 (d, 11-1), 4.15 (t, 2H), 2.72 ( t, 21-1), 2.51 (s, 3H), 2.50 (bs, 41-1), 2.29 (bs, 41-1), 2.13 (s, 3H), 1 , 29 (s, 12H).
[0033] Preparation 3c: 2- (3-Chloro-2-methyl-phenyl) -5,5-dimethyl-1,3,2-dioxaborinane 4.94 g of (3-chloro-2-methylphenyl) boronic acid (29 mmol) and 3.021 g of neopentyl glycol (29 mmol) were stirred at RT in the presence of 15H + amberlite (dried with toluene) until no further conversion was observed. The mixture was then filtered through celite and washed with 2-Me-THF. The filtrate was concentrated under reduced pressure to obtain Preparation 3c. 1 H NMR (400 MHz, CDCl 3): 7.59 (dd, 1H), 7.38 (dd, 1H), 7.10 (t, 1H), 3.79 (s, 411), 2.57 (s). , 3H), 1.05 (s, 6H). Preparation 4: (2R) -2-15-Bromo-6- (4-fluorophenyl) furo [2,3-d] pyrimidin-4-yloxy-3-12-112- (2-methoxyphenyl) -pyrimidin-4- Ethyl Phenylphenylpropanoate Following the general procedure 1a and taking Preparation 2c as the appropriate lactic ester derivative, Preparation 4 was obtained. MS: (M + H) + = 700.4.
[0034] Preparation 5a: (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-dimethoxyN, N-dimethyl-methanamine (4.25 mol) were mixed in a 21-flask and allowed to stir at 105 ° C for 3 hours. The formed MeOH was continuously removed by distillation. When the formation of MeOH stopped (at a head temperature of 65 ° C), the reaction mixture was distilled under vacuum (decreasing the pressure slowly 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. 1H NMR (500 MHz, DMSO-d6) δ: 7.59 (d, 1H), 5.17 (d, 1H), 4.42 (s, 1H), 3.25 (s, 6H); , 3.09 (s, 3H), 2.78 (s, 3H). Preparation 5b: [2- (2-Methoxyphenyl) pyrimidin-4-yl-methanol Step A: 4- (dimethoxymethyl) -2- (2-methoxyphenyl) -pyritnidine To a mixture containing 1.2 eq. of acetic acid salt of 2-methoxybenzamidine and 1 eq. Preparation 5a in anhydrous methanol (0.5 ml / mmol), 1.2 eq. of NaOEt were added portionwise and the mixture was stirred at 75 ° C until no further conversion was observed. Then, 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 to give 4- (dimethoxymethyl) -2- (2-methoxyphenyl) pyrimidine. 1 H NMR (400 MHz, DMSO-d 6) δ: 8.93 (d, 1H), 7.55-7.44 (31-I), 7.16 (d, 1H), 7.06 (m, 1H), 5.31 (s, 1H), 3.76 (s, 31-1), 3.37 (s, 611).
[0035] Step B: [2- (2-Methoxyphenyl) pyrimidin-4-yl] methanol 261 mg of 4- (dimethoxymethyl) -2- (2-methoxyphenyl) -pyrimidine (1.00 mmol) was 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 solution, 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 5b: 1H NMR (400MHz, 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 6: (2R) -2-1- (7-Benzyl-5-bromo-6-ethyl-pyrrolo [1,2-d] yl) amino] -3-pbenyl-propanoic acid Step A: 7-benzyl-5-bromo 4-Chloro-6-ethyl-pyrrolo [2,3-d] pyrimidine 255 mg of NaH (6.38 mmol) and 50 ml of anhydrous THF were charged into a 50 ml Schlenk tube under N 2 atmosphere and the suspension was cooled to 0 ° C. Then 1.792 g of Preparation lb (5.8 mmol) was added. After stirring the mixture for 30 minutes at 0 ° C, 773 liters of benzyl bromide (6.38 mmol) was added and the mixture was allowed to warm to RT with stirring until no further conversion. The mixture was then diluted with saturated aqueous NH4Cl solution and extracted with DCM. The combined organic phases were washed with brine, 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 to give 7-benzyl-5-bromo-4-chloro-6-ethyl-pyrrolo [2,3]. d] pyrimidine. NMR (400 MHz, CDCl3) δ: 8.60 (s, 1H), 7.33-7.26 (in, 3H), 7.06-7.04 (m, 2H), 5.54 (s, 21-1), 2.79 (q, 2H), 1.07 (t, 3H).
[0036] MS (Mill): 351.8. Step B: (2R) -2-1- (7-Benzyl-5-bromo-6-ethyl-pyrrolo12,3-dipyrimidin-4-yl) -ininol-3-phenylpropanoic acid Following general procedure III and taking 7-benzyl-5-bromo-4-chloro-6-ethyl-pyrrolo [2,3-d] pyrimidine as the appropriate 4-chloro-pyrrolo [2,3-c /] pyrimidine derivative and D- phenylalanine as the appropriate amino acid derivative, Preparation 6 was obtained. MS (M + H): 279.2. Preparation 7a: N42-Benzyloxy-6- (2,2-dibromovinyl) -phenyl] -3-chloro-2-methyl-4-triisopropylsilyloxyaniline Step A: (4-Bromo-2-chloro-phenoxy) -triisopropyl -Silane 200 g of 4-bromo-2-chloro-phenol (0.97 mol) and 126 ml of TIPSC1 (1.18 mol) were dissolved in 1.6 l 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 in 1.5 L of EtOAc. The mixture was washed with brine, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The triisopropylsilyl hydroxide impurity was removed by distillation (120 ° C at 0.01 minHg). 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. NMR11-1 (400MHz, CDCl3) δ: 7.49 (d, 11-1), 7.21 (dd, 1H), 6.78 (d, 1H), 1.31 (septet, 3H), 1H NMR (CDCl3) , 14 (d, 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, [Mi). Step B: (4-Broino-2-chloro-3-methyl-phenoxy) -triisopropyl-silane 76.0 ml anhydrous DIPA (0.54 mol) was dissolved in 1.2 L anhydrous THF under an argon atmosphere and 51.2 ml of a solution of BuLi (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) were added dropwise at -78 ° C. and the white suspension After stirring until no further conversion was observed, 36.5 ml of Mei (0.586 mmol) was added at this temperature and the reaction mixture was left stirring overnight without further cooling. The residue was dissolved in 1.5 L of EtOAc and washed with brine The organic phase was dried over Na 2 SO 4 ltered 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. NMR111 (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).
[0037] Step C: N-benzyl-3-chloro-2-methyl-4-triisopropyl-silyloxyaniline 7.56 g of (4-bromo-2-chloro-3-methyl-phenoxy) -tri-isopropyl-silane ( 20 mmol) and 4.29 g of benzylamine (40 mmol) were dissolved in 16 ml of anhydrous toluene, then 450 mg of Pd2dba3 (0.5 mmol), 450 mg of X-Phos (1 mmol) and 9.77 g. Cs2CO3 (30 mmol) was added and the mixture was stirred at 100 ° C until no further conversion was observed. Then it was filtered through celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography using hexane and EtOAc as eluents to give N-benzyl-3-chloro-2-methyl-4-triisopropylsilyloxyaniline.
[0038] Step D: 3-chloro-2-methyl-4-triisopropylsilyloxyaniline 3.50 g of N-benzyl-3-chloro-2-methyl-4-triisopropylsilyloxyaniline (8.66 mmol) were dissolved in 100 ml of MeOH and 20 ml of EtOAc, then 80 mg of 10% Pd / C was added and the mixture was stirred under a 1 bar H 2 atmosphere until no further conversion was observed. . Then it was filtered through celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography using hexane and EtOAc as eluents to give 3-chloro-2-methyl-4-triisopropylsilyloxyaniline. NMRIII (400 MHz, DMSO-d6) δ: 6.58 (d, 1H), 6.50 (d, 111), 4.68 (s, 2H), 2.11 (s, 3H), 1.24 (m, 3H), 1.06 (d, 18H).
[0039] MS: (M + 11) + = 314.2. Step E: 3-benzylaxy-2-bromo-benzaldehyde 4.554 g of 2-bromo-3-hydroxybenzaldehyde (22.65 mmol), 4.262 g of benzyl bromide (24.92 mmol) and 4.696 g of K2CO3 (33.98 g) mmol) were dissolved in 20 ml of DMSO and stirred at 50 ° C until no further conversion was observed. The mixture was then poured into water. The precipitate was filtered to give 3-benzyloxy-2-bromo-benzaldehyde. MS (EI, 70 eV) m / z (relative intensity in%, [ion]): 65 (10), 91 (100), 290 (5, [M1), 292 (5, [M]).
[0040] Step F: 3-Benzyloxy-2- (3-chloro-2-methyl-4-triisopropylsilyloxyaniline) benzaldehyde 5.0 g of 3-benzyloxy-2-bromo-benzaldehyde (17.17 mmol), 5.391 g of 3-chloro-2-methyl-4-triisopropylsilyloxyaniline (17.17 mmol), 16.782 g of Cs 2 CO 3 (51.51 mmol), 393 mg of Pd 2 dba 3 (0.43 mmol) and 535 mg of BINAP rac. (0.86 mmol) were mixed in 85 ml of toluene and stirred at 120 ° C. until no further conversion was observed The volatiles were removed under reduced pressure and the residue was purified by flash chromatography using heptane and EtOAc as eluents to obtain 3-benzyloxy-2- (3-chloro-2-methyl-4-triisopropylsilyloxyanilino) benzaldehyde SM: (M + H) + 524.2.
[0041] Step G: N-12-Benzyloxy-6- (2,2-dibramovinyl) phenyl-3-chloro-2-methyl-4-triisopropylsilyloxyaniline 7.7 g of 3-benzyloxy-2- (3-chloro) 2-methyl-4-tri-isopropylsilyloxyanilino) benzaldehyde (14.69 mmol) and 7.308 g of carbon tetrabromide (22.03 mmol) were dissolved in 160 ml of DCM at 0 ° C, then 11, 56 g of PPh 3 (44.07 mmol) was added. The mixture was stirred at RT until no further conversion was observed. Then the solvent was removed under reduced pressure, and the residue was dissolved in Et2O. Then, heptane was added, the precipitate formed was filtered and the filtrate was concentrated under reduced pressure. Then, heptane was added, and the mixture was stirred for 10 minutes and filtered again. The filtrate was concentrated under reduced pressure and purified by flash chromatography using heptane and EtOAc as eluents to give Preparation 7a. 1H NMR (400MHz, DMSO-d6): 7.28-7.23 (m, 5H), 7.19 (s, 1H), 7.11 (dd, 2H), 7.05 (d, 1H); ), 6.60 (d, 1H), 6.41 (s, 1H), 6.22 (d, 11i), 5.08 (s, 2H), 2.30 (s, 3H), 1.25. (Ni, 3H), 1.05 (d, 18H). MS: (M + H) -F = 680.0.
[0042] Preparation 7b: (2R) -241-13-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxy-phenyl] -2- (4-fluorophenyl) -indol-7-yloxy-3- Ethyl (2-methoxyphenyl) propanoate Step A: [4- [7-Benzyloxy-2- (4-fluoro-phenyl) -dol-1-yl] -2-chloro-3-methyl-phenoxy-triisopropyl-silane 2720 mg. Preparation 7a (4 mmol), 1119 mg of 4-fluorophenylboronic acid (8 mmol), 4245 mg of K3PO4 (20 mmol), 90 mg of Pd (OAc) 2 (0.4 mmol) and 328 mg of SPhos (0). 8 mmol) were mixed in 60 ml of dry toluene under an N 2 atmosphere and stirred at 100 ° C until no further conversion was observed. Then, the solvent was removed under reduced pressure, the residue was purified by flash chromatography using heptane and EtOAc as eluents to give [447-benzyloxy-2- (4-fluorophenyl) ndol-1 2-chloro-3-methyl-phenoxy-triisopropyl-malon NMR h11 (400 MHz, CDCl3) δ: 7.33 (d, 2H), 7.29-t, 22 21-1 ), 7.18 (d, 1F1), 7.16 (d, 1H), 7.10 (t, 2H), 6.94 (d, 1H), 6.92-6.84 (nl, 4H) , 6.73 (s, 1H), 6.61 (d, 1H), 4.94 (d, 1H), 4.89 (d, 1H), 1.97 (s, 3H), 1.31. (m, 3H), 1.13 (t, 18H). Step B: 4-17-Benzyloxy-2- (4-fluorophenyl) incio-1-yl-2-chloro-3-methyl-phenol 2600 mg of [447-benzyloxy-2- (4-fluorophenyl) -indol-1 2-chloro-3-methylphenoxy-triisopropyl silane (2.96 mmol), 2.96 ml of TBAF solution (2.96 mmol, 1M in THF) and 50 ml of THF were left behind. stirring at RT until no longer observe conversion. The solvent was then removed under reduced pressure, the residue was purified by flash chromatography using heptane and EtOAc as eluents to give 4- [7-benzyloxy-2- (4- Fluorophenylindol-1-yl] -2-chloro-3-methyl-phenol, 1H NMR (400MHz, DMSO-d6) δ: 10.27 (bs, 1H), 7.28-7.18 (m, 6H). ), 7.10 (t, 2H), 7.07-6.99 (m, 2H), 6.85-6.77 (in, 311), 6.75 (s, 1H), 6.72 ( d, 1H), 4.95 (d, 1H), 4.90 (d, 1H), 1.75 (s, 311) MS: (M + H) + = 458.0 Step C: 7 benzyloxy-1β-chloro-2-methyl-4- [4- (4-methylpiperazin-1-yl) ethoxy] phenyl] -2- (4-fluorophenyl) indole 1.2 g of 4- [7-benzyloxy-2- (4-fluorophenyl) -indole) -1-yl] -2-chloro-3-methyl-phenol (2.1 mmol), 606 mg of 1- (2-hydroxyethyl) -4-methylpiperazine (4.2 mmol) and 2.1 g of PPh 3 ( 6.3 mmol) were dissolved in 50 ml of dry toluene under N 2 atmosphere and the mixture was cooled to 0 ° C. Then 1451 mg of DTAD (6.3 mmol) was added and the mixture was cha The mixture is stirred at 45 ° C. and left stirring until no further conversion is observed. The solvent was then removed under reduced pressure, and the residue was purified by flash chromatography using heptane and EtOAc and MeOH as eluents to give 7-benzyloxy-1- [3-chloro-2 Methyl-4- [4- (4-methylpiperazin-1-yepethoxy] phenyl] -2- (4-fluorophenyl) -indole MS: (M + H) + = 584.2.
[0043] Step D: 1-P-Chloro-2-methyl-4- (4- (4-methylpiperazin-1-ylethoxyphenyl) -2- (4-fluorophenyl) indol-7-ol 1280 mg of 7-benzyloxy-1- [3-Chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxy] phenyl] -2- (4-fluoro-phenyl) indole (2.19 mmol) was dissolved in 100 ml of water. EtOH, then 100 mg of 10% Pd / C was added The mixture was stirred under an F12 atmosphere of 1 bar at RT until no further conversion was observed, then the mixture was filtered. through Celite and the filtrate was concentrated to give 143-chloro-2-methyl-4- [2- (4-methylPiperazin-1-yl) -ethoxyphenyl] -2- (4-fluorophenyl) indol-7-ol. NMR (400 MHz, DMSO-d 6) δ: 9.04 (br s, 1H), 7.25 (dd, 2H), 7.17-7.03 (br, 4H), 6.94 (d, 1H), 6.86 (t, 1H), 6.70 (s, 111), 6.47 (d, 1H), 4.13 (m, 2H), 2.72 (t, 2H), 2, 58- 2.42 (bs, 4H), 2.40-2.17 (bs, 4H), 2.14 (s, 3H), 1.86 (s, 3H) MS: (M + H) ) + = 494.2 Step E (210-2-111-E-chloro-2-methoxy) ethyl 4-methyl-piperazin-1-yl) ethoxylphenyl-2- (4-fluorophenylindol-7-yloxy-3- (2-methoxyphenyl) propanoate 494 mg of 1 - [3-chloro] 2-methyl-4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl] -2- (4-fluorophenyl) indol-7-ol (1 mmol), 449 mg of Preparation 2 ( 2 mmol) and 786 mg of PPh 3 (3 mmol) were dissolved in 10 ml of dry toluene under N 2 atmosphere and the mixture was cooled to 0 ° C. Then 691 mg of DTAD (3 mmol) was added and the mixture was heated to 45 ° C and allowed to stir until no further conversion was observed. The solvent was then removed under reduced pressure, and the residue was purified by flash chromatography using heptane and EtOAc and MeOH as eluents to give Preparation 7b. 1 H NMR (500 MHz, DMSO-d 6): 7.43-6.98 (d, 1H), 7.28 (m, 2H), 7.23-7.24 (d, 1H), 7.17-7. , 18 (t, 1H), 7.14 (m, 2H), 7.12-6.88 (d, 1H), 6.95-6.94 (t, 1H), 6.91-6.91 (d, 1H), 6.79-6.78 (s, 1H), 6.73-6.75 (t, 1H), 6.52-6.60 (d, 1H), 6.40-6 , 46 (d, 1H), 4.85-4.76 (dd, 1H), 4.25-4.01 (m, 2H), 4.01-3.89 (m, 21-I), 3.77 (s, 3H), 2.75-2.60 (m, 2H), 2.69-2.64 (dd, 1H), 2.54-2.12 (bs, 8H), 2 , 42-2.43 (dd, 1H), 2.13-2.09 (s, 3H), 1.59-2.08 (s, 3H), 0.98 (t, 3H). MS: (M + H) + = 700.0.
[0044] Example 1: (2R) -2- (15- (3-chloro-2-methyl-442- (4-methylpiperazin-1-yl) -ethoxylphenyl] -6- (4-flamerophenyl) furo [2, 3-d] pyrimidin-4-yl] oxy} -3- (24 [242-methoxyphenyl] pyrimidin-4-yl] methoxy} phenyl) propanic Following the general procedure H and taking Preparation 4 as a 5-bromine derivative. Suitable furo [2,3-a] pyrimidine and Preparation 3b as the appropriate boronic acid derivative, Example 1 was obtained as a mixture of diastereoisomers High resolution mass (HRMS) calculated for C47H44ClFN607: 858, 2944, found: 430, 1547 and 430.1555 (M + 2H) Example 2: (2R) -2-115- {3-chlora-2-ethyl-442- (4-methylpiperazine) 1-yl) ethoxy-phenyl} -6- (4-fluorophenyl) -furo [2,3-d] pyrimidin-4-yl] oxy} -3- (2 - {[2- (2-methoxy-phenyl) pyrimidine) 4-Bromo-2-chloro-phenoxy) ethyl-4-methylpiperazine 10.373 g of 4-bromo-2-chlorophenol (50 mmol), 14.442 g of 4-bromo-2-chloro-phenoxy-ethyl-4-methylpiperazine 2- (4-methyl piperazine-yl) ethanol (100 mmol) and 26.229 g of PPh 3 (100 mmol) were dissolved in 250 ml of dry toluene under an N 2 atmosphere, then 23.027 g of DTAD (100 mmol) was added. The mixture was stirred at 50 ° C until no further conversion was observed. Volatiles were evaporated under reduced pressure and the residue was purified by flash chromatography using EtOAc and MeOH as eluents. MS (M + H): 333.0. Step B: 1- [2- (4-bromo-2-chloro-3-ethyl-phenoxy) -ethyl] -4-methyl-piperazine 2.0 g 142- (4-bromo-2-chloro-phenoxy) ethyl-4-methyl-piperazine (6 mmol) was dissolved in 50 ml of anhydrous THF under N 2 atmosphere and the mixture was cooled to -78 ° C. 6 ml of a solution of LDA (12 mmol in 2M THF) was added and the mixture was stirred for 3 hours, then 982 mg of iodoethane (6.3 mmol) was added and the mixture been allowed to warm up to 20 TA. It was inactivated with saturated aqueous NH4Cl solution and extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. MS (M + H): 360.8. Step C 1-12- [2-chloro-3-ethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy] -ethyl] -4-methyl- piperazine 2099 mg of 142- (4-bromo-2-chloro-3-ethyl-phenoxy) ethyl-4-methyl-piperazine (5.8 mmol) were dissolved in 30 ml of anhydrous THF under an N 2 atmosphere and the The mixture was cooled to -78 ° C. 4.65 ml of a solution of nBuLi (11.61 mmol in 2.5M THF) was added dropwise. The mixture was allowed to stir for 5 hours, then 2.6 ml of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (12.77 nunol) was added and The mixture was stirred for 30 minutes. Then it was allowed to warm to RT and concentrated under reduced pressure. The crude product was purified by flash chromatography using EtOAc and MeOH as eluents. MS (M + H): 409.2. Step D Example 2 Following General Procedure II and taking Preparation 4 as the appropriate 5-bromo-furo [2,3-dlpyrimidine derivative and 14242-chloro-3-ethyl-4- (4,4,5 5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxyl-ethyl-4-methyl-piperazine as the appropriate boronic acid derivative, Example 2 was obtained as a mixture of diastereoisomers. . High resolution mass (HRMS) calculated for C 48 H 46 ClFN 607: 872.3101, found: 437.1620 and 437.1620 (M + 211). Example 3: (2R) -24 [5- (3-Chloro-2-methyl-4-12- (4-methylpiperazin-1-yl) ethoxyl-phenyl] -6- (4-fluorophenyl) -furo pyrimidin-4-yloxy-3- (2-methoxyphiyl) -propanoic Step A: (2R) -2-15-Bromo-6- (47-fluorophenyl) -fitro [2,3-d] pyrimidin-4-yloxy Ethyl 3- (2-methoxyphenyl) propanoate Following general procedure 1a and taking Preparation 2e as the appropriate lactic ester derivative, (2R) -245-bromo-6- (4-fluorophenyl) furo [ Ethyl 2,3-d] pyrimidin-4-yl] oxy-3- (2-methoxyphenyl) propanoate was obtained NMRIII (400 MHz, DMSO-d6): 8.53 (s, 1E1), 8 , (M, 2H), 7.47-7.36 (in, 3H), 7.23 (m, 1H), 6.96 (in, 11-I), 6.89 (t, 1H), 5.58 (m, 1H), 4.12 (q, 2H), 3.79 (s, 3H), 3.36 (in, 1H), 3.21 (m, 1H), 1.11 (t , 3H).
[0045] Step B: Example 3 Following General Procedure II and taking (2R) -245-bromo-6- (4-fluorophenyl) furo [2,3-4-pyrimidin-4-yloxy-3- (2-methoxyphenyl) ethyl propanoate as the appropriate 5-bromo-furo [2,3-d] pyrimidine derivative and Preparation 3b as the appropriate boronic acid derivative, Example 3 was obtained as a mixture of diastereoisomers. High resolution mass (HRMS) calculated for C36H36ClFN4O6: 674.2307, found: 675.2367 and 675.2364 (M + H). Example 4: (2R) -2- {15- (3-Chloro-2-methyl-442- (4-methylpiperazin-1-yl) -ethoxy-phenyl] -6- (4-fluoro-phenyl) furo acid [2,3-dpyrimidin-4-yl] oxy] -3- [2- (pyrazin-2-ylmethoxy) phenyl] propanoic Step A: (2R) -2-P-bromo-6- (4-fluorophenyl) fiiro12, Ethyl 3-dlpyrimidin-4-yloxy-3-12- (pyrazin-2-ylmethoxy) phenylpropanoate Following general procedure 1a and taking Preparation 2g as the appropriate lactic ester derivative, the (2R) - Ethyl 245-bromo-6- (4-fluorophenyl) furo [2,3-a] pyrimidin-4-yloxy-342- (pyrazin-2-ylmethoxy) -phenylipropanoate was obtained.
[0046] MS: (M + H) + = 595.0. Step B: Example 4 Following general procedure II and taking (2R) -245-bromo-6- (4-fluorophenylfuro [2,3-d] pyrimidin-4-yl] oxy-3 - [2- ( ethyl pyrazin-2-ylmethoxy) phenyl] propanoate as the appropriate 5-bromo-furo [2,3-d] pyrimidine derivative and Preparation 3b as the appropriate boronic acid derivative, Example 4 was obtained as a mixture of diastereoisomers High resolution mass (HRMS) calculated for C40H38ClFN6O6: 752.2525, found: 753.2645 and 753.2606 (M + H).
[0047] EXAMPLE 5 (2R) -2 - ([6- (5-Chlorofuran-2-yl) -5- {3-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxyl-phenyl) Furo [2,3-dipyrimidin-4-yl] oxyl-342- (pyrazin-2-ylmethoxy) phenylpropanoic acid Step A: 2-P- (27fitryl) -2-oxo-ethyllpropanedinitrile 46.2 ml of a solution 1M NaOEt in EtOH (46.2mmol) and 400ml EtOH were cooled to 0 ° C and 3.2g malononitrile (48.4mmol) was added. The mixture was left stirring at 0 ° C. for 1 hour, then 8.35 g of 2-bromo-1- (2-furypethanone (44 mmol) was added, the mixture was stirred at 0 ° C. for 1 hour. The volatiles were removed under reduced pressure, and the residue was suspended in Et 2 O, filtered, and then purified by flash chromatography using DCM and methanol. EtOAc as eluents to give 242- (2-fury1) -2-oxo-ethyl] propanedinitrile MS: (M + H) + = 175, Step B: 2-Arnitio-5- (2-formyl) furan-3-carbanitrile 4.587 g of 242- (2-furyl) -2-oxo-ethyl-propane-dinitrile (26.34 mmol) dissolved in 150 ml of EtOH and 4.6 g of 15H + amberlite were added. The mixture was stirred at 90 ° C until no further conversion was observed. The mixture was then filtered, washed with DCM and EtOAc. The filtrate was concentrated under reduced pressure and purified by flash chromatography using heptane and EtOAc as eluents to give 2-amino-5- (2-furyl) furan-3-carbonitrile. MS: (M + H) + = 175.4.
[0048] Step C: 6- (27firty1) -311-furo [2,3-dipyrimidin-4-one 1310 mg of 2-amino-5- (2-furyl) furan-3-carbonitrile (7.52 mmol) and ml of formic acid anhydride was placed in a flask and stirred at RT for 30 minutes. Then the volatiles were evaporated under reduced pressure and the residue was dissolved in 60 ml of AcOH and irradiated at 180 ° C for 50 minutes. The mixture was cooled to RT, and the crude product was purified by flash chromatography using heptane and EtOAc as eluents to give 6- (2-furyl) -3H-furo [2, 3-d] pyrimidin-4-one. NMR11 (400 MHz, DMSO-d 5): 12.68 (bs, 1H), 8.14 (s, 1H), 7.84 (in, 1H), 7.08 (s, 1H), 6. , 94 (d, 1H), 6.67 (m, 1H).
[0049] Step D: 6- (5-chloro-2-formyl) -31-1-fir [2,3-dipyridnidin-4-one 1,183 g of 6- (2-furyl) -3H-furo d] pyrimidin-4-one (5.85 mmol) was dissolved in 55 ml of THF and 860 mg of NCS (6.44 mmol) was added. The mixture was stirred at 40 ° C until no further conversion was observed. The mixture was cooled to 0 ° C, and the precipitate was filtered and dried to give 6- (5-chloro-2-furyl) -3H-furo [2,3-d] pyrimidin-4- one. MS: (M + H) + = 237.0. Step E: 5-bromo-6- (5-chloro-2-filly1) -3H-3H, -41-pyrimidin-4-one 1000 mg of 6- (5-chloro-2-furyl) -3H-furo [2, 3-d] pyrimidin-4-one (4.23 mmol) was dissolved in 40 ml of AcOH and then 776 mg of bromine (4.86 mmol) was added. The mixture was stirred at 40 ° C until no further conversion was observed. Then the volatiles were removed under reduced pressure. The residue was suspended in DCM and filtered to give 5-bromo-6- (5-chloro-2-furyl) -3H-furo [2,3-d] pyrimidin-4-one. MS: (M-H) + = 314.8. Step F: 5-Bromo-4-chloro-6- (5-chloro-2-futyl) furo [2,3-dlpyrimidine 5,110 mg of 5-bromo-6- (5-chloro-2-yl) -3H -furo [2,3-d] pyrimidin-4-one (3.52 mmol) were dissolved in 8.21 ml of POCl3 (88.1 mmol), followed by 447 μl of DMA (3.52 mmol). been added. The mixture was stirred at 110 ° C until no further conversion was observed. The mixture was then cooled to -78 ° C and ice was added. The mixture was sonicated, then the precipitate was filtered. The crude product was purified by flash chromatography using heptane and EtOAc as eluents to give 5-bromo-4-chloro-6- (5-chloro-2-furypfuro [2,3-d] ] pyrimidine SM: (M + H) (= 335.0) Step G: (2R) -2-15-Bromo-6- (5-chloro-2-fluoryl) filr, 3-dlpyrimidin-4-yloxy Ethyl 3- (pyrazin-2-ylmethoxy) phenylpropanoate 1 eq of 5-bromo-4-chloro-6- (5-chloro-2-furypfuro [2,3-41pyrimidine, 2 eq. Preparation 2g, 10 ml / mmol tBuOH and 5 eq of Cs2CO3 were placed in a flask and stirred at 55 ° C until no further conversion was observed.The mixture was then concentrated under reduced pressure, diluted with brine, neutralized with 1M aqueous HCl solution and extracted with EtOAc The combined organic phases were dried over Na 2 SO 4, filtered and the filtrate was concentrated under reduced pressure. purified by flash chromatography using heptane and EtOA as eluents to give (2R) -245-bromo-6- (5-chloro-2-furypfuro [2,3-d] pyrimidin-4-yl] oxy-342- (pyrazin-2-ylmethoxy) phenyl] ethyl propanoate. MS: (M + H) + = 601.0.
[0050] Step H: Example 5 Following general procedure II and taking (2R) -245-bromo-6- (5-chloro-2-furypfuro [2,3-d] pyrimidin-4-yloxy-342- ( ethyl pyrazin-2-ylmethoxy) phenyl] propanoate as the appropriate 5-bromo-furo [2,3-4pyrimidine derivative and Preparation 3b as the appropriate boronic acid derivative, Example 5 was obtained in the form of of a mixture of diastereoisomers High resolution mass (ITEMS) calculated for C38H36Cl2N6O7: 758.2023, found: 759.2119 and 759.2156 (M + H) Example 6: acid (2R) -3- {2 - [(1-tert-butyl-1H-pyrazol-5-yl) methoxy] phenyl} -2 - {[543-chloro-4- [2- (dimethylamino) ethoxy} 2-methylphenyl) -6- (4-fluorophenyl) [[2,3-d] pyrimidin-4-yloxy} propanoic acid Step A: 1-tert-butyl-5- (dimethyl) -1H- pyrazole 1.2 eq. tert-butylhydrazine hydrochloride and 1 eq. Preparation Sa were dissolved in anhydrous methanol (0.5 ml / mmol), then 1.2 eq. of NaOEt were added portionwise and the mixture was stirred at 75 ° C for 2 hours. The reaction mixture was cooled and concentrated under reduced pressure. The residue was diluted with water and extracted with DCM. The combined organic phases were dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography using heptane and EtOAc as eluents to give 1-tert-butyl-5- (dimethoxymethyl) -1H-pyrazole. 1 H NMR (400 MHz, DMSO-d 6) δ: 7.34 (d, 1H), 6.34 (d, 1H), 5.74 (s, 1H), 3.24 (s, 6H), 1, 57 (s, 9H). We also obtained 1-t-butyl-3- (dimethoxy-methyl) -1H-pyrazole. 1 H NMR (400 MHz, DMSO-d6) δ: 7.75 (d, 1H), 6.18 (d, 1H), 5.34 (s, 1H), 3.24 (s, 6H), 1H NMR (CDCl3) , 50 (s, 9H).
[0051] Step B: (1-tert-butyl-1H-pyrazol-5-yl) methanol 1 eq. 1-Tert-butyl-5- (dimethoxymethyl) -1H-pyrazole was stirred with 1M aqueous HCl (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% aqueous K2CO3 solution, followed by 2 eq. Sodium borohydride was added in portions, keeping the temperature under 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 to give (1-iert-butyl-1H-pyrazol-5-yl) methanol. 1H NMR (400 MHz, DMSO-d6) δ: 7.27 (d, 1H), 6.19 (d, 1H), 5.31 (t, 1H), 4.61 (d, 2H), 1H NMR (CDCl3) , 56 (s, 9H). Step C: (2R) -3-12 - [(2-tert-butylpyrazolo-3-yl) -methoxylphenyl] -2-hydroxypropanoic acid 2.51 g of Preparation 2a (9.96 mmol), 2 0 g of (1-tert-butyl-1H-pyrazol-5-yl) methanol (13 mmol) and 3.39 g of triphenylphosphine (13 mmol) were dissolved in 12 ml of anhydrous toluene, followed by ml of DEAD (13 mol) were added. The mixture was stirred at 50 ° C under a nitrogen atmosphere until no further conversion was observed. Volatiles were evaporated under reduced pressure. Then, 30 ml of Et2O was added, and the mixture was sonicated and filtered (to remove PPh3 and PP30). The filtrate was concentrated under reduced pressure. The residue was dissolved in THF, then 2 g of NaOH dissolved in 8 ml of water was added. The mixture was stirred at 50 ° C until no further conversion was observed. Then, it was acidified with a 2M aqueous HCl solution, and the THF was removed under reduced pressure. The residue was extracted with DCM, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to obtain (2R) -342 - [(2-tert-butylpyrazol-3-yl) methoxy] - phény11-2-hydroxy-propanoic acid. MS (M + H): 319.0. Step D: Ethyl (2R) -3-P - [(2-butylpyrazol-3-yl) -methoxy] phenyl] -2-hydroxypropanoate 7.2 g of (2R) -3 acid - [24 (2-tert-Butylpyrazol-3-Amethoxy) phenyl] -2-hydroxypropanoic acid were dissolved in 75 ml of EtOH, then 2 ml of H 2 SO 4 cc was added. at 60 ° C until no further conversion, then diluted with water, neutralized with saturated aqueous NaHCO 3 solution and extracted with dichloromethane The combined organic phases were dried over Na 2 SO 4, filtered and the filtrate was concentrated under reduced pressure and purified by flash chromatography using EtOAc and MeOH as eluents to give (2R) -3- [2 - [(2-tert-butylpyrazol-3-yl) Ethyl methoxy] phenyl-2-hydroxy-proPanoate MS (M + H): 347.0 Step E: (2R) -2- [5-hromo-6- (4-fluorophenyl) formro [2 Ethyl 3-d] pyrimidin-4-yl] oxy-3-P - [(2-tertbutylpyrazol-3-yl) -methoxy] phenylpropanoate Following general procedure 1a and taking ethyl (2R) -342 - [(2-tert-butylpyrazol-3-ylmethoxy) -phenyl-2-hydroxypropanoate as the appropriate lactic ester derivative, the (2R) Ethyl -2- [5-bromo-6- (4-fluorophenylfuro [2,3-d] pyrimidin-4-yloxy-342 - [(2-tert-butyl-pyrazol-3-yepinoxy) phenyl] propanoate) was obtained. MS (M + H): 636.6-638.6. Step F: 2-P-chloro-3-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxyl-N, N-dimethylethanamine 10 0 g of Preparation 3a (37.2 mmol), 5.366 g of N, N-dimethylethanolamine (60.3 mmol) and 15.8 g of PPh 3 (60.3 mmol) were dissolved in 100 ml of anhydrous toluene, then 27 ml of DEAD (60.3 mmol, 40% solution in toluene) was added dropwise. The mixture was stirred at 50 ° C under an argon atmosphere 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 light brown oil was crystallized from hexane to give 2- [2-chloro-3-methyl-4- (4,4,5,5-tetramethyl) -1,3,2-dioxaborolan-2 -yl) phenoxy] -N, N-dimethylethanamine. NMR (200 MHz, CDCl3) δ: 7.63 (d, 1H), 6.75 (d, 1H), 4.15 (t, 2H), 2.81 (t, 2H), 2.60 (s). , 3H), 2.38 (s, 6H), 1.33 (s, 12H). MS (M + H): 340.1.
[0052] Step G: Example 6 Following General Procedure II and taking (2R) -245-bromo-6- (4-fluorophenyl) furo [2,3-cipyrimidin-4-yloxy-342 - [(2-tert) ethyl-butylpyrazol-3-yl) -methoxy] phenylpropanoate as the appropriate 5-bromo-furo [2,3-d] pyrimidine derivative and 242-chloro-3-methyl-4- (4,4,5 5-tetramethyl-1,3,2-dioxa-borolan-2-yl) phenoxy] -N, N-dimethylethanamine as the appropriate boronic acid derivative, Example 6 was obtained. High resolution mass (HRMS) calculated for C40H41ClFN5O6: 741.2729, found: 742.2813 and 742.2808 (M + H) for both diastereomers. Example 7: N45- (3-Chloro-2-methyl-442- (4-methyl-piperazin-1-yl) ethoxylphenyl) -6- (4-fluorophenyl) furo [2,3-dIpyrimidin-4-yl] -2 Methoxy-D-phenylalanine Step A: (2R) -2-1β-Bromo-6- (4-fluorophenyl) -firo [2,3-dipyrimidin-4-yl] amino] -3- (2-methoxyphenyl) By following the general procedure Ib and taking (2R) -2-amino-3- (2-methoxyphenyl) propanoic acid as the appropriate amino acid derivative, the acid (2R) -24 [5- bromo-6- (4-fluorophenyl) furo [2,3-d] pyrimidin-4-yliaminol-3- (2-methoxyphenyl) propanoic acid was obtained MS: (M + 11) + = 487.8. B: Example 7 1 eq of (2R) -2 - [{5-bromo-6- (4-fluorophenyl) -furo [2,3-d] pyrimidin-4-yl] amino] -3- (2-methoxyphenyl) -propanoic acid, 1.5 eq of Preparation 3b, 5 mol% of AtaPhos and 2 eq of Cs 2 CO 3 were stirred in a 1/1 mixture of THF and water (10 ml / mmol of 5-bromo-furo [2,3-d] pyrimidine derivative) and heated at 110 ° C in a MW reactor until no longer obs Afterwards, the mixture was diluted with brine, the pH was adjusted to 4 with a 1M aqueous HU solution, and the mixture was extracted with DCM. The combined organic phases were dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The resulting mixture of diastereoisomers was purified and separated by HILIC chromatography. Example 7 was obtained as the diastereoisomer eluted last. High resolution mass (HRMS) calculated for C361-137C1FN5O5: 673.2467, found: 337.6286 (M + 2H). Example 8: N-15- (3-Chloro-2-methyl-442- (4-methyl-piperazin-1-ylethoxy) phenyl] -6- (4-fluorophenyl) furo [2,3-d] pyrimidin-4 1- [2- (2-methoxyphenyl) -pyrimidin-4-yl] methoxy-D-phenylalanine and Example 9: N-1,5- {3-chloro-2-methyl-442- methyl-piperazin-1-yl) ethyloxylphenyl) -6- (4-fluoro-phenyl) furo [2,3-4-pyrimidin-1-y] [1-2- [2- (2- methoxyphenyl) -pyrimidin-4-yl] -methoxyl-D-phenylalanine Step A: (2R) -2-11-5-bromo-6- (4-fluorophenyl) -fitro [2,3-d] pyrimidine 4-yl] amino] -3- (2-hydroxyphenyl) propanoic acid Following general procedure Ib and taking D- (R) -2-amino-3- (2-hydroxy-phenyl) -propionic acid as a derivative of Suitable amino acid, (2R) -24 [5-bromo-6- (4-fluorophenyl) furo [2,3-d] pyrimidin-4-yl] amino] -3- (2-hydroxyphenyl) propanoic acid was obtained: MS: (M + H) + = 473.6 Step B: (210-2-115-bromo-6- (4-fluorophenypfttro [2,3-dipyrimidin-4-yl] amino] -312 -112- (2-methoxyphenyl) -pyrimidin-5-ylmethox ethyl ylphenylpropanoate 163 mg of (2R) -2 - [[5-bromo-6- (4-fluoro-phenypfuro [2,3-d] pyrimidin-4-yl] amino] -3- (2- hydroxy-phenyl) propanoic acid were dissolved in 3 ml of a solution of HCl (1.25M in EtOH) and stirred at 60 ° C until no further conversion was observed. The mixture was concentrated under reduced pressure and diluted with water. The precipitate was filtered and purified by flash chromatography using heptane and EtOAc as eluents to obtain (2R) -24 [5-bromo-6- (4-fluorophenypfuro [2,3-c]] pyrimidin-4-yl] aminol-3- (2-hydroxyphenyl) propanoate MS: (M + H) + = 501.6 Step C: (2R) -24 / 5-bromo-6- (4-fluorophenyl) ) Ethyl furo [2,3-d] pyrimidin-4-ylamino] -3- [2 - [[2- (2-methoxyphenyl) pyrimidin-5-ylmethoxylphenylpropanoate 500 mg of (2R) -2 - [[5-bromide] Ethyl 6- (4-fluorophenyl) furo [2,3-d] pyrimidin-4-yl] amino] -3- (2-hydroxyphenyl) -propanoate (1 mmol), 540 mg of Preparation 513 (2, 5 mmol) and 656 mg of PPh 3 (2.5 mmol) were dissolved in 20 ml of anhydrous toluene under N 2, then 576 mg of DTAD (2.5 mmol) was added. The mixture was then concentrated under reduced pressure and purified by flash chromatography using heptane and EtO at 60 ° C. until no conversion was observed. Ac as eluents to give (2R) -24 [5-bromo-6- (4-fluorophenyl) furo [2,3-d] pyrimidin-4-yliamino] -342 - [[2- (2-methoxyphenyl) pyrimidine] Ethyl 5-methoxyphenyl propanoate. HRMS (M + H) +: 698.1402. Step D: Examples 8 and 9 1 eq. (2R) -24 [5-Bromo-6- (4-fluorophenyl) Euro [2,3-d] pyrimidin-4-yl] amino] -3- [24 [2- (2-methoxy-phenyl) pyrimidine] Ethyl 5-yl] methoxyphenylpropanoate, 1.5 eq. Preparation 3b, 5 mole% AtaPhos and 2 eq. of Cs2CO3 were stirred in 1/1 THF-water (10 ml / mmol 5-bromo-furo [2,3-d] pyrimidine) and the mixture was heated to 70 ° C. left stirring until no longer observe conversion. Then, the mixture was diluted with brine, the pH was adjusted to 4 with a 1M aqueous HCl solution, and the mixture was extracted with DCM.
[0053] The combined organic phases were dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The crude intermediate was purified by flash chromatography using DCM and MeOH as eluents. Then, it was dissolved in the dioxane / water mixture 1: 1 (20 ml / mmol) and 10 eq. LiOHxH2O were added. The mixture was stirred at RT until no further conversion was observed. Then it was diluted with brine, neutralized with 2M aqueous HCl solution and extracted with DCM. The combined organic phases were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to obtain a mixture of diastereoisomers. They were separated and purified by reverse phase preparative chromatography using an aqueous solution of 25 mM NI-141-1CO3 and MeCN as eluents.
[0054] Example 8 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C47H45ClFN7O6: 857.3104, found: 429.6637 (M + 2H). Example 9 was obtained as the last eluted diastereoisomer. High resolution mass (HRMS) calculated for C47H45ClFN7O6: 857.3104, found: 429.6648 (M + 2H).
[0055] Example 10: N47-Methyl-5- (naphthalen-1-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] -D-phenylalanine Step A: 4-chloro-5-iodo-7-methyl pyrrolo [2,3-d] pyrimidine In a 50 ml Schlenk tube under N 2 atmosphere, 220 mg of NaH (5.5 mmol) and 40 ml of anhydrous THF were charged and the suspension was cooled. up to 0 ° C. Then 1471 mg of 4-chloro-5-iodo-7H-pyrrolo [2,3-d] pyrimidine (5 mmol) was added. After 30 minutes of stirring, 346 Mel (5.5 mmol) was added and the mixture was allowed to warm to RT, and allowed to stir until no further conversion was observed. The mixture was then diluted with saturated aqueous NH4Cl solution and extracted with DCM. The combined organic layers were washed with brine, dried over MgSO4, filtered and the filtrate concentrated under reduced pressure to give 4-chloro-5-iodo-7-methyl-pyrrolo [2,3-d] pyrimidine. 1H NMR (400MHz, DMSO-d6) δ: 8.65 (s, 1H), 7.98 (s, 1H), 3.83 (s, 3H). MS: (M + H) + = 294.0. Step B: 4-chloro-7-methyl-5- (1-naphthyl) pyrrolo [2,3-d] pyrimicline 10 eq. 4-chloro-5-iodo-7-methyl-pyrrolo [2,3-c] pyrimidine), 1.1 eq. of neopentyl glycol ester of 1-naphthalenboronic acid, 1.1 eq. of silver carbonate, 0.15 eq. of Pd (PPh3) 4 and 2-Me-THF (15 ml / mmol of 5-iodo-pyrro [2,3-d] pyrimidine derivative) were stirred under an N 2 atmosphere at 110 ° C until the reaction was complete. to no longer observe conversion. The mixture was diluted with brine, neutralized with a 1M aqueous HCl solution 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 flash chromatography using heptane and EtOAc as eluents to give 4-chloro-7-methyl-5- (1-naphthyl) pyrol [2,3-d] pyrimidine. MS: (M + H) + = 294.2.
[0056] Step C: Example 10 Following General Procedure III and taking 4-chloro-7-methyl-5- (1naphthyl) pyrTolo [2,3-c1] pyrimidate as a derivative of 4-chloro-pyTgolo [2,3 Suitable pyridine and D-phenylalanine as the appropriate amino acid derivative, Example 10 was obtained. High resolution mass (HRMS) calculated for C26H22N4O2: 422.1743, found: 423.1804 (M + H). Example 11: N-15- (naphthalen-1-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl-D-phenylalanine Step A: 7- (benzenesulbenyl) -4-chloro-5 In a 50 ml Schlenk tube under an N 2 atmosphere, 220 mg NaH (5.5 mmol) and 40 ml anhydrous THF were charged and the suspension was cooled. up to 0 ° C. Then 1471 mg of 4-chloro-5-iodo-7H-pyrrolo [2,3-d] pyrimidine (5 mmol) was added. After stirring for 30 minutes, 1.4 ml of benzenesulfonyl chloride (5.25 mmol) was added and the mixture was allowed to warm to RT and stir until no further conversion was observed. The mixture was then diluted with saturated aqueous NH4Cl solution and extracted with DCM. The combined organic phases were washed with brine, dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. Then the residue was suspended in MTBE and then filtered to give 7- (benzenesulfonyl) -4-chloro-5-iodo-pyrrolor2,3-4pyrimidine.
[0057] NMRIII (400 MHz, CDCl3) δ: 8.75 (s, 114), 8.22 (m, 2H), 7.95 (s, 1H), 7.67 (m, 1H), 7.56 (s, 1H), m, 2H). MS: (M + H) + 419.8. Step B: 7- (benzenesulfonyl) -4-chloro-5- (1-naphthyl) -1-pyrrolo [2,3-d] pyrimidine 1 eq. 7- (benzenesulfonyl) -4-chloro-5-iodo-pyrrolo [2,3-d] pyrimidine, 1.1 eq. of neopentyl glycol ester of 1-naphthalenboronic acid, 1.1 eq. of silver carbonate, 0.15 eq. of Pd (PPh3) 4 and 2-Me-THF (15 ml / mmol of 5-iodopyrrolo [2,3-c] pyrimidine derivative) were stirred under an N 2 atmosphere at 110 ° C until the reaction was complete. no longer observe conversion. The mixture was diluted with brine, neutralized with 1M aqueous HCl 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 flash chromatography using heptane and EtOAc as eluents to give 7- (benzenesulfonyl) -4-chloro-5- (1-naphthyl-p-tololo [2,3-a] primidine.
[0058] RIVINIH (400 MHz, CDCl3) δ: 8.82 (s, 1H), 8.31 (m, 2H), 7.94 (in, 2H), 7.84 (s, 1H), 7.71 (br. m, 1H), 7.60 (m, 2H), 7.56-7.48 (m, 31-1), 7.48-7.38 (m, 2H). MS: (M + 1-1) + = 420.0. Step C: Example 11 Following General Procedure III and taking 7- (benzenesulfonyl) -4-chloro-5- (1-naphthyl) pyrrolo [2,3-d] pyrimidine as a 4-chloro-4-chlorobenzene derivative. Suitable pyrrolo [2,3-d] pyrimidine and D-phenylalanine as the appropriate amino acid derivative, Example 11 was obtained. High resolution mass (HRMS) calculated for C 25 H 20 N 4 O 2: 408.1586, found: 409.1670 (M + H). Example 12: N-17-b-enzymethyl-5- (naphthalen-1-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl-D-phenylalanine and Example 13: N [7-Benzyl-6-ethyl-5- (naphthalen-1-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] -Finylalanine Following general procedure IVa and taking Preparation 6 as 5-bromo-pyrrolo [2,3-d] pyrimidine derivative and neopentyl glycol ester of 1-naphthaleneboronic acid as the appropriate boronic acid derivative, Example 12 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C34H30N4O2: 526.2369, found: 527.2431 (M + H). Example 13 was obtained as the diastereoisomer eluted last. High resolution mass (HRMS) calculated for C34H301.1402: 526.2369, found: 527.2423 (M + H). Example 14: N- (6-ethyl-5- (naphthalen-1-yl) -7- [2- (naphthalen-1-yloxy) ethyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl-D phenylalanine and Example 15: N- {6-ethyl-5- (naphthalen-1-yl) -7-12- (naphthalen-1-yloxy) ethyl] -7H-pyrrolo [2,3-d] pyrimidin-4 1-N-phenylalanine Step A: 5-Bromo-4-chloro-6-ethyl-7-P- (1-naphthyloxy) -heihylipyrrolo12,3-dipyrimidine 94 mg of 2- (1-naphthyloxy) ethanol (0) 5 mmol), 131 mg of PPh 3 (0.5 mmol) and 66 mg of Preparation 1b (0.25 mmol) were dissolved in 2.5 ml of anhydrous THF under an N 2 atmosphere and cooled to 0.degree. C. Then 230 μl of DEAD (0.5 mmol, 40% in toluene) was added dropwise The mixture was stirred at 40 ° C. until no more Then the volatiles were removed under reduced pressure and the residue was purified by flash chromatography using heptane and EtOAc as eluents to obtain 5-bromo-4-chloro-6- and hy1-742- (1-Naplityloxy) ethyl] pyrrolo [2,3-d] pyrimidine.
[0059] NMR (400 MHz, DMSO-d6) δ: 8.69 (s, 1H), 7.80 (dd, 21-1), 7.51-7.31 (in, 41-1), 6.94; (d, 1H), 4.90 (t, 2H), 4.52 (t, 2H), 3.08 (q, 2H), 1.26 (t, 3H). MS: (M + H) + - 430.0. Step B: (2R) -2-11-5-Bromo-6-ethyl-7-12- (1-thiaphthyloxy) ethyl-pyrrolo12,3-e-pyrimidin-4-yl-amino-3-phenyl-propanoic acid Following the procedure III and taking 5-bromo-4-chloro-6-ethyl-7- (1- (1-naphthyloxy) ethyl] -pyrrolo [2,3-4-pyrimidine as the derivative of 4-chloro-pyrrolo [2,3-al] suitable pyrimidine and D-phenylalanine as the appropriate amino acid derivative, (2R) -24 [5-bromo-6-ethyl-742- (1-naphthyloxy) ethyl] pyrrolo [2,3-d] acid; ] pyrimidin-4-yl] amino] -3-phenyl-propandyl was obtained. NMR (400 MHz, DMSO-d6) δ: 12.96 (bs, 1H), 8.24 (s, 1H), 7.88 (d, 1H), 7.82 (d, 1H), 7, 52-7.32 (nl, 4H), 7.29-7.15 (m, 5H), 6.94 (d, 1H), 6.38 (d, 1H), 4.94 (q, 1H); , 4.72 (t, 2H), 4.45 (t, 2H), 3.28 (nl, 1H), 3.18 (dd, 1H), 2.92 (q, 2H), 1.19 ( t, 3H). MS: (M + H) + = 559.2.
[0060] Step C: Examples 14 and 15 Following general procedure IVa and taking (2R) -24 [5-bromo-6-ethyl-17- (1- (naphthyloxy) -ethylipyrolo [2,3-en] d] pyrimidin-4-yl] amino-3-phenylpropane as the appropriate 5-bromo-pyrrolo [2,3-d] pyrimidine derivative and the neopentyl glycol ester of 1-naphthalenboronic acid as the acid derivative In a suitable boronic form, Example 14 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C39H34N4O3: 606.2631, found: 607.2711 (M + H). Example 15 was obtained as the diastereoisomer eluted last. High resolution mass (HRMS) calculated for C 39 H 34 N 4 O 3: 606.2631, found: 607.2705 (M + H). Example 16: N [6-ethyl-5- (napitalen-1-yl) -7- (2-phenyl-ethyl) -7H-pyrrolo [2,34] -pyrimidin-4-yl] -D phenylalanine and Example 17: N-16-ethyl-5- (naphthalen-1-yl) -7- (2-phenyl-ethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] -D Phenylalanine Step A: 5-Broino-4-chloro-6-ethyl-7-phenethyl-pyrrolo [2,3-dipepidine] 3,1 ml of 2-phenylethanol (25.9 mmol), 3.367 g of PPh 3 (12, 95 mmol) and 3.40 g of Preparation lb (12.95 mmol) were dissolved in 110 ml of anhydrous THF under a N 2 atmosphere and cooled to 0 ° C. Then 11.87 ml of DEAD (40% in toluene) was added dropwise. The mixture was stirred at 40 ° C until no further conversion was observed. Then, the volatiles were removed under reduced pressure and the residue was purified by flash chromatography using heptane and EtOAc as eluents to obtain 5-bromo-4-chloro-6-ethyl-7-. Phenethyl-pyrrolo [2,3-cipyrimidine]. RIVINIH (400 MHz, DMSO-d6) δ: 8.61 (s, 1H), 7.32-7.16 (m, 3H), 7.11 (nl, 2H), 4.51 (t, 21), 1), 3.06 (t, 21-1), 2.70 (q, 2H), 1.10 (t, 3H). MS: (M + H) + = 364.0.
[0061] Step B: (2R) -2-1 (5-Bromo-6-ethyl-7-phenethyl-pyrrolo [2,3-dipyrimidin-4-yl] -amino-3-phenylpropanoic acid Following the general procedure III and taking 5-bromo-4-chloro-6-ethyl-7-phenethyl-pyrrolo [2,3-d] pyrimidine as the appropriate 4-chloro-pyrrolo [2,3-4pyrimidine derivative and D-phenylalanine As the appropriate amino acid derivative, (2R) -2- [(5-bromo-6-ethyl-7-phenethyl-pyrrolo [2,3-4-pyrimidin-4-ylamino] -3-phenyl) propanoate was obtained NMR (400 MHz, DMSO-d6) δ: 12.80 (bs, 1H), 8.20 (s, 1H), 7.34-7.17 (m, 8H), 7, 13 (m, 2H), 6.45 (d, 1H), 4.91 (q, 1H), 4.33 (t, 2H), 3.31 (dd, 1H), 3.18 (dd, 1H). ), 3.00 (t, 2H), 2.55 (q, 2H), 1.04 (t, 3H).
[0062] MS: (M + H) + = 493.2. Step C: Examples 16 and 17 Following general procedure IVa and taking (2R) -2 - [(5-bromo-6-ethyl-7-phenethyl-pyrrolo [2,3-d]) acid ] pyrimidi n-4-yparni no] -3-phenyl-propanoic acid as the appropriate 5-bromo-pyrrolo [2,3-d] pyrimidine derivative and the neopentyl glycol ester of 1-naphthalene-boronic acid as As a suitable boronic acid derivative, Example 16 was obtained as the diastereoisomer eluted first.High resolution mass (HRMS) calculated for C 35 H 32 N 4 O 2: 540.2525, found: 541.2592 (M + H). Example 17 was obtained as the last eluted diastereoisomer High resolution mass (HRMS) calculated for C 35 H 32 N 4 O 2: 540.2525, found: 541.2619 (M + H).
[0063] Example 18: N46-Ethyl-5- (naphthalen-1-yl) -7- (3-phenyl-propyl) -7H-pyrrolo [2,3-Mpyrimidin-4-yl] -D phenyl-alanine and Example 19: N [6-ethyl-5- (naphthalen-1-yl) -7- (3-phenyl-propyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] -D-phenyl-alanine Step A: 5-Bromo-4-chloro-6-ethyl-7- (3-phenylpropyl) -pyrrolo [2,3-d] pyridine 3.52 ml 3-phenyl-propanol (25.9 mmol), 3.397 g of PPh 3 (12.95 mmol) and 3.4 g of Preparation lb (12.95 mmol) were dissolved in 110 ml of anhydrous THF under N 2 atmosphere and cooled to 0 ° C. Then 11.87 ml of DEAD (40% in toluene) was added dropwise. The mixture was stirred at 40 ° C until no further conversion was observed. Then, the volatiles were removed under reduced pressure and the residue was purified by flash chromatography using heptane and EtOAc as eluents to obtain 5-bromo-4-chloro-6-ethyl-7-. (3-phenylpropyl) pyrrolo [2,3-d] pyrimidine. 1H NMR (400MHz, DMSO-d6) δ: 8.60 (s, 1H), 7.31-7.22 (in, 2F), 7.21-7.13 (m, 3H), 4.32 (t, 2H), 2.85 (q, 211), 2.65 (t, 2H), 2.05 (m, 2H), 1.16 (t, 3H). MS: (M + H) + - 378.0. Step B: (2R) -2-115-bromo-6-ethyl-7- (3-phenyl-prapyl) pyrrolo [2,3-d] pyrimidin-4-yllaminol-3-phenyl-prop-micoic acid Following general procedure III and taking 5-bromo-4-chloro-6-ethyl-7- (3-phenylpropyl) pyrrolo [2,3-d] pyrimidine as a derivative of 4-chloro-pyrrolo [2, 3-d] -pyrimidine and D-phenylalanine as the appropriate amino acid derivative, (2R) -2 [[5-bromo-6-ethyl-7- (3-phenylpropyl) pyrro] o [ 2,3-d] pyrimidin-4-ylamino] -3-phenylpropanoic acid was obtained. NMR (400 MHz, DMSO-d6) δ: 12.95 (brs, 1H), 8.15 (s, 1H), 7.33-7.12 (m, 10H), 6.35 (d, 1H). ), 4.94 (q, 1H), 4.16 (t, 2H), 3.28 (dd, 1H), 3.16 (dd, 1H), 2.68 (q, 2H), 2, 61 (t, 2H), 1.97 (m, 2H), 1.09 (t, 3H). MS: (M + H) + = 507.2. Step C: Examples 18 and 19 Following general procedure IVa and taking (2R) -2 - [[5-bromo-6-ethyl-7- (3-phenylpropyl) -pyrrolo] d] pyrimidin-4-yl] amino] -3-phenylpropanoic acid as the appropriate 5-bromo-pyrrolo [2,3-d] pyrimidine derivative and the neopentyl glycol ester of 1-naphthaleneboronic acid as the acid derivative In the appropriate boronic form, Example 18 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C36H34N4O2: 554.2682, found: 555.2742 (M + H).
[0064] Example 19 was obtained as the diastereoisomer eluted last. High resolution mass (HRMS) calculated for C36H34N4O2: 554.2682, found: 555.2756 (M + H). Example 20: N-15- (3-Chloro-2-methylphenyl) -6-ethyl-7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -D-phenylalanine and Example 21: N (3- (3-Chloro-2-methylphenyl) -6-ethyl-7-methyl-7H-pyrrolo [2,3-4] pyrimidin-4-yl) -D-phenylalanine Step A: 5-bromo-4- chloro-6-ethyl-7-methyl-pyrrolo [2,3-dlpyrimidine 65 mg of Preparation Ib (0.25 mmol) were dissolved in 1 ml of anhydrous THF and then 20.3 μl of anhydrous MeOH ( 5 mmol) and 0.5 ml of a solution of cyanomethylenetributylphosphorane (0.5 mmol, 1M in toluene) were added. The mixture was stirred at RT until no further conversion was observed. Volatiles were removed under reduced pressure. The residue was purified by flash chromatography using heptane and EtOAc as eluents to give 5-bromo-4-chloro-6-ethyl-7-methyl-pyrrolo [2,3-d] pyrimidine.
[0065] 1H NMR (400MHz, CDCl3) δ: 8.56 (s, 3.84, (s, 3H), 2.91 (q, 2H), 1.26 (t, 3H) MS: (M +) 11) ÷ = 274.0 Step B: (2R) -2-1 [5-Bromo-6-ethyl-7-methyl-pyrrolo [2,3-d] pyrimidin-4-yllaminol-3-phenylpropanoic acid Following General Procedure III and taking 5-bromo-4-chloro-6-ethyl-7-methyl-pyrrolo [2,3-d] pyrimidine as a derivative of 4-chloro-pyrrolo [2,3-d] pyrimidine and D-phenylalanine as the appropriate amino acid derivative, (2R) -2 - [[5-bromo-6-ethyl-7-methyl-pyrrolo [2,3-d] pyrimidin-4- [1H] amino] -3-phenylpropanoic acid was obtained.1H NMR (500MHz, DMSO-d6) δ: 13.05 (bs, 1H), 8.17 (s, 1H), 7.32. -7.25 (m, 2H), 7.25-7.18 (m, 3H), 6.32 (d, 1H), 4.97 (m, 1H), 3.68, (s, 3H), 3.29 (dd, 1H), 3.18 (dd, 1H), 2.75 (q, 2H), 1.13 (t, 3H), MS: (M + H) + = 403, 0.
[0066] Step C: Examples 20 and 21 Following general procedure IVa and taking (2R) -24 [5-bromo-6-ethyl-7-methyl-pyrrolo [2,3-d] pyrimidin-4- acid 3.1] amino] -3-phenylpropanoic acid as the appropriate 5-bromo-pyrrolo [2,3-d] pyrimidine derivative and Preparation 3 as the appropriate boronic acid derivative, Example 20 was obtained under the form of the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C25H25ClN4O2: 448.1666, found: 449.1753 (M + H). Example 21 was obtained as the diastereoisomer eluted last. High resolution mass (HRMS) calculated for C25H25Cl2 · 1402: 448.1666, found: 449.1752 (M + H). Example 22: N45- (3-chloro-2-methylphenyl) -7- (elo-ethyl-propylmethyl) -6-ethyl-7H-pyrrolo12,3-dipyrimidin-4-yl-D-phenylalanine and Example 23: N45 (3-Chloro-2-methylphenyl) -7- (elo-prop-propylmethyl) -6-ethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -D-phenylalanine Step A: 5-bromo 4-chloro-7- (cyclopropylmethyl) -6-ethyl-pyrrolo [2,3-dlpyrimidine 65 mg of Preparation Ib (0.25 mmol) was dissolved in 1 ml of anhydrous THF, followed by 40 g of cyclopropanemethanol (0. 5 ml) and 0.5 ml of a solution of cyanomethylenetributylphosphorane (0.5 inmol, 1M in toluene) were added. The mixture was stirred at RT until no further conversion was observed. Volatiles were removed under reduced pressure. The residue was purified by flash chromatography using heptane and EtOAc as eluents to give 5-bromo-4-chloro-7- (cyclopropylmethyl) -6-ethyl-pyrrolo [2,3-d] pyrimidine 1H NMR (400 MHz, CDCl3) δ: 8.54 (s, 1H), 4.18 (d, 2H), 2.94 (q, 2H), 1.29 (t, 3H), 1H NMR (CDCl3): , 24-1.14 (in, 1H), 0.60-0.51 (in, 2H), 0.51-0.43 (m, 2H). MS: (M + H) + = 314.0. Step B: (2R) -2-ff5-bromo-7- (cyclopropylmethyl) -6-ethyl-pyrrolo [2,3-d] pyrimidin-4-yliamino] -3-phenyl-p-opioic acid Following the General procedure HI and taking 5-bromo-4-chloro-7- (cyclopropylmethyl) -6-ethyl-pyrrolo [2,3-cflpyrimidine as the appropriate 4-chloro-pyrrolo [2,3-Mpyrimidine derivative and the D-phenylalanine as the appropriate amino acid derivative, (2R) -2 - [[5-bromo-7- (cyclopropylmethyl) -6-ethyl-pyrrolo [2,3-d] pyrimidine) 4-aminamino] -3-phenylpropanoic acid was obtained. NMR (500 MHz, DMSO-d6) δ: 13.05 (bs, 1H), 8.15 (s, 111), 7.32-7.26 (m, 2H), 7.26-7.20. (in, 3H), 6.34 (d, 1H), 4.94 (m, 1H), 4.05 (d, 2H) 3.29 (dd, 1H), 3.18 (dd, 1H), 2.78 (q, 2H), 1.28-1.20 (m, 114), 1.16 (t, 3H), 0.47-0.42 (m, 2H), 0.42-0, 37 (m, 2H). MS: (M + H) + = 443.0. Step C: Examples 22 and 23 Following general procedure IVa and taking (2R) -21 [5-bromo-7- (cyclopropylmethyl) -6-ethyl-pyrrolo [2,3-a] d] pyrimino] -3-phenylpropanoic acid as the appropriate 5-bromo-pyrrolo [2,3-d] pyrimidine derivative and the preparation 3c as a suitable boronic acid derivative, Example 22 was obtained under form of the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C281129ClN402: 488.1979, found: 489.2064 (M + H). Example 23 was obtained as the diastereoisomer eluted last. High resolution mass (HRMS) calculated for C28H29ClN4O2: 488.1979, found: 489.2048 (M + H).
[0067] Example 24: N45- (3-ebloro-2-methylphenyl) -6-ethyl-7- (prop-2-en-1-yl) -7H-pyrrolo12,3-dlpyrimidin-4-yl) phenylalanine and Example 25 N45- (3-chloro-2-methylphenyl) -6-ethyl-7- (prop-2-en-1-yl) -7H-pyrrolo [2,3-dipyrimidin-4-yl] -D-phenylalanine A 7-allyl-5-bromo-4-chloro-6-ethylpyrrolo [2,3-d] pyrimidine 65 mg of Preparation Ib (0.25 mmol) was dissolved in 1 ml of anhydrous THF, then 34 ml of allyl alcohol (0.5 mmol) and 0.5 ml of a solution of cyanomethylenetributylphosphorane (0.5 mmol, 1M in toluene) were added. The mixture was stirred at RT until no further conversion was observed. Volatiles were removed under reduced pressure. The residue was purified by flash chromatography using heptane and EtOAc as eluents to give 7-allyl-5-bromo-4-chloro-6-ethyl-pyffolo [2,3-d] pyrimidine.
[0068] 1H NMR (400MHz, CDCl3) δ: 8.57 (s, 1H), 6.02-5.90 (in, 1H), 5.25-5.16 (m, 1H), 5min. 4.85 (m, 31-1), 2.87 (q, 2H), 1.26 (t, 3H). MS: (M + H) + = 300.0. Step B: (2R) -2-117-allyl-5-bromo-6-ethyl-pyrrolo [2,3-d] pyrimidin-4-yl] amino-3-phenylpropanaic acid Following general procedure III and taking 7-allyf-5-bromo-4-chloro-6-ethyl-pyrrolo [2,3-d] pyrimidine as the appropriate 4-chloro-pyrrolo [2,3-4pyrimidine derivative and D- phenylalanine as the appropriate amino acid derivative, (2R) -24 [7-allyl-5-bromo-6-ethyl-pyrrolo [2,3-dipyrimidin-4-yl] amino] -3-phenylpropanoic acid has been got. 1H NMR (500 MHz, DMSO-d6) δ: 13.06 (bs, 1H), 8.16 (s, 1H), 7.34-7.26 (m, 5H), 7.26-7; , 19 (m, 3H), 6.35 (d, 1H), 6.01-5.89 (m, 1H), 5.10 (dd, 1H), 5.01-4.93 (in, 1H). ), 4.87-4.73 (m, 3H), 3.29 (dd, 1H), 3.18 (dd, 1H), 2.70 (q, 2H), 1.12 (t, 3H); . MS: (M + 1-1) - 429.0. Step C: Examples 24 and 25 Following general procedure IVa and taking (2R) -24 [7-allyl-5-bromo-6-ethyl-pyrrolo [2,3-d] pyrimidin-4- acid yl] amino] -3-phenylpropanoic acid as the appropriate 5-bromo-pyrrolo [2,3-d] pyrimidine derivative and Preparation 3c as the appropriate boronic acid derivative, Example 24 was obtained as the eluted diastereoisomer first. High resolution mass (HRMS) calculated for C27H27ClN4O2: 474.1823, found: 475.1908. Example 25 was obtained as the last eluted diastereoisomer. High resolution mass (FIRMS) calculated for C271127ClN402: 474.1823, found: 475.1909. Example 26: N- [7- (But-2-yn-1-yl) -5- (3-chloro-2-methyl-phenyl) -6-ethyl-7H-pyrrolo [2,3-dlpyrimidin-4] 11-D-phenylalanine and Example 27: N-17- (but-2-yn-1-yl) -5- (3-chloro-2-methyl-phenyl) -6-ethyl-7H-pyrrolo [2,3-d] djpyrimidin-4-yl] -D-phenylalanine Step A: 5-Bromo-7-but-2-ynyl-4-chloro-6-ethyl-pyrrolo [2,3-dipyrimidine 37 μl of 2-butyn-1- ol (0.5 mmol), 131 mg of PPh 3 (0.5 mmol) and 66 mg of Preparation lb (0.25 mmol) were dissolved in 2.5 ml of anhydrous THF under N 2 atmosphere and cooled to room temperature. at 0 ° C. Then, 230 μl of DEAD (0.5 mmol, 40% in toluene) was added dropwise. The mixture was stirred at 40 ° C until no further conversion was observed. Then, the volatiles were removed under reduced pressure and the residue was purified by flash chromatography using heptane and EtOAc as eluents to obtain 5-bromo-7-but-2- 1-yl-4-chloro-6-ethyl-pyrrolo [2,3-pyrimidine. NMR11-1 (400MHz, CDCl3) δ: 8.59 (s, 1H), 5.03 (q, 2H), 2.99 (q, 2H), 1.77 (t, 3H), 1.33 (t, 31-1).
[0069] MS: (IVI + H) + = 312.0. Step B (2R) -2-f (5-bromo-7-but-2-yn) -6-ethyl-pyrrolo [2,3-dlpyrimidin-4-31) -aminol-3-phenylpropanoic acid Following the General procedure III and taking 5-bromo-7-but-2-ynyl-4-chloro-6-ethyl-pyrrolo [2,3-d] pyrimidine as a derivative of 4-chloro-pyrrolo [2,3-d]. 4-pyrimidine and D-phenylalanine as the appropriate amino acid derivative, (2R) -2 - [(5-bromo-7-but-2-yn) -6-ethyl-pyrrolo [2,3-a] d] pyrimidin-4-yl) amino] -3-phenylpropanoic acid was obtained. 1H NMR (500 MHz, DMSO-d6) δ: 13.25 (bs, 1H), 8.19 (s, 1H), 7.30-7.24 (m, 15H), 7.24-7. , 16 (m, 3H), 6.45 (d, 1H), 5.02-4.96 (m, 2H), 4.93 (q, 1H), 3.30 (dd, 1H), 3, 19 (dd, 1H), 2.80 (q, 2H), 1.74 (t, 3H), 1.19 (t, 3H). MS: (M + H) + = 441.0. Step C: Examples 26 and 27 Following general procedure IVa and taking (2R) -2 - [(5-bromo-7-but-2-yn) -6-ethyl-pyrrolo [2,3-a] d] pyrimidin-4-yDaminol-3-phenylpropanoate as the appropriate 5-bromo-pyrrolo [2,3-d] pyrimidine derivative and Preparation 3c as the appropriate boronic acid derivative, Example 26 was obtained under The form of the diastereoisomer eluted first High-resolution mass (HRMS) calculated for C 2 H 27 ClN 4 O 2: 486.1823, found: 487.1893 (M + H) Example 27 was obtained as the last eluted diastereoisomer. High resolution mass (HRMS) calculated for C28H27ClN4O2: 486.1823, found: 487.1893 (M + H) Example 28: N-15- (3-Chloro-2-methylphenyl) -6-ethyl-7- (2H) 2,2-trifluoroethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl-D-phenylalanine and Example 29: N-15- (3-chloro-2-methylphenyl) - 6-ethyl-7- (2,2,2-trifluoroethyl) -7H-pyrrolo [2,3-d] pyrionidin-4-yl-D-phenylalanine Step A: 5-bromo-4-chloro-6 ethyl-7- (2,2,2-trifluoroethyl) pyrrolo [beta] -3-dipyrimidine 72 t of trifluoroethanol (1 mmol), 262 mg of PPh 3 (1 mmol) and 130 mg of Preparation lb (0.5 mmol) ) were dissolved in 5 ml of anhydrous THF under an N 2 atmosphere and cooled to 0 ° C. Then 460 μl of DEAD (0.5 mmol, 40% in toluene) was added dropwise. The mixture was stirred at 40 ° C until no further conversion was observed. Then, the volatiles were removed under reduced pressure and the residue was purified by flash chromatography using heptane and EtOAc as eluents to give 5-bromo-4-chloro-6-ethyl-7 - (2,2,2-trifluoroethyl) pyrrolo [2,3-d] pyrimidine. NMR (400 MHz, CDCl3) δ: 8.62 (s, 1H), 4.90 (q, 2H), 2.94 (q, 2H), 1.28 (t, 3H).
[0070] MS: (M + H) + = 342.0. Step B: (2R) -2-1-1-5-Bromo-6-ethyl-7- (2,2,2-trifluoroethyl) pyrrolo [2,3-dlpyrimidin-1-yl] amino] -3-phenylpropanoic acid following general procedure III and taking 5-bromo-4-chloro-6-ethyl-7- (2,2,2-trifluoroethyl) -pyrrolo [2,3-d] pyrimidine as a 4-chloro suitable pyrrolo [2,3-4-pyrimidine and D-phenylalanine as the appropriate amino acid derivative, (2R) -24 [5-bromo-6-ethyl-7- (2,2,2 trifluoroethyl) -pynolo [2,3-d] pyrimidin-4-yl] amino] -3-phenylpropanoic acid has been obtained. 1H NMR (500MHz, DMSO-d6) δ: 13.11 (bs, 1H), 8.23 (s, 1H), 7.33-7.26 (m, 2H), 7.26-. 7.19 (m, 3H), 6.44 (d, 1H), 5.12 (q, 2H), 5.00-4.93 (m, 1H), 3.30 (dd, 1H), 3; , (Dd, 1H), 2.78 (q, 2H), 1.14 (t, 3H). MS: (M + H) + = 471.0. Step C: Examples 28 and 29 Following general procedure IVa and taking (2R) -24 [5-bromo-6-ethyl-7- (2,2,2-trifluoroethyl) pyrrolo [2] acid. , 3-Apyrimidin-4-yliamino] -3-phenylpropanoic acid as the appropriate 5-bromo-pyrrolo [2,3-d] pyrimidine derivative and the appropriate boronic acid derivative preparation, Example 28 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C26H24ClF3N4O2: 516.1540, found: 517.1624 (M + H). Example 29 was obtained as the last eluted diastereoisomer. High resolution mass (HRMS) calculated for C26H24ClF3N4O2: 516.1540, found: 517.1606 (M + H). Example 30: N-15- (3-chloro-2-methylphenyl) -7- (2-ethyl-pentylethyl) -6-ethyl-7H-pyrrolo [2,3-4-pyrimidin-4-yl] -D-phenylalanine and Example 31 N45- (3-chloro-2-methylphenyl) -7- (2-ethyl-pentylethyl) -6-ethyl-7H-pyrrole [2,341 pyrimidin-4-yl] -D-phenylalanine Step A: 5-bromine 4-chloro-7- (2-cyclopentylethyl) -6-ethyl-pyrrolo [2,3-dlpyrimidine 124 μl of 2-cyclopentylethanol (1 mmol), 262 mg of PPh 3 (1 mmol) and 130 mg of Preparation Ib ( 0.5 mmol) were dissolved in 5 ml of anhydrous THF under N 2 atmosphere and cooled to 0 ° C. Next, 460 μl of DEAD (0.5 mmol, 40% in toluene) was added dropwise. The mixture was stirred at 40 ° C until no further conversion was observed. Then the volatiles were removed under reduced pressure and the residue was purified by flash chromatography using heptane and EtOAc as eluents to give 5-bromo-4-chloro-7- (2- cyclopentylethyl) -6-ethyl-pyrrolo [2,3-djpyrirnidine. NMRIII (400 MHz, CDCl3): 8.55 (s, 1H), 4.31-4.20 (nl, 2H), 2.89 (q, 2H), 1.911.72 (m, 5H), 1H NMR (CDCl3): , 69-1.57 (m, 2H), 1.57-1.46 (m, 2H), 1.28 (t, 3H), 1.23-1.05 (m, 2H). MS: (M + H) + = 356.0.
[0071] Step B: (2R) -2 - [[5-Bromo-7- (2-cyclopentyl-ethyl) -6-ethyl-pyrrolo [2,3-pyridin-4-yl] amino] -3-phenyl- Propanoic By following general procedure III and taking 5-bromo-4-chloro-7- (2-cyclopentylethyl) -6-ethyl-pyrrolo [2,3-4pyrimidine as the derivative of 4-chloro-pyrrolo [2, 3-Ci] pyrimidine and D-phenylalanine as the appropriate amino acid derivative, (2R) -2 - [[5-bromo-7- (2-cyclopentylethyl) -6-ethyl-pyrrolo [ 2,3-a] pyrimidin-4-yliamino] -3-phenylpropanoic acid was obtained. IRNIFI (500 MHz, DMSO-d6) δ: 13.04 (bs, 1H), 8.17 (s, 1H), 7.32-7.26 (m, 2H), 7.25; -7.19 (m, 3H), 6.32 (d, 11I), 5.00-4.92 (m, 1H), 4.17-4.09 (in, 2H), 3.29 (dd); , 1H), 3.18 (dd, 111), 2.74 (q, 2H), 1.79-1.70 (m, 311), 1.70-1.62 (m, 211), 1, 60-1.50 (m, 2H), 1.501.42 (m, 2H), 1.15 (t, 3H), 1.12-1.01 (m, 2H).
[0072] MS: (M + H) + = 485.2. Step C: Examples 30 and 31 Following general procedure IVa and taking (2R) -24 [5-bromo-7- (2-cyclopentylethyl) -6-ethyl-pyrrolo [2,3-d] acid ] pyrimidin-4-yl] amino] -3-phenylpropanoic acid as the appropriate 5-bromo-pyrrolo [2,3-d] pyrimidine derivative and Preparation 3c as the appropriate boronic acid derivative, Example 30a. was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C 31 H 5 O 5 N 2 O 5: 530.2449, found: 531.2528 (M + H). Example 31 was obtained as the diastereoisomer eluted last. High resolution mass (HRMS) calcd. For C311135C1N4O2: 530.2449, found: 531.2547 (M + 11). Example 32: N- [5- (3-Chloro-2-methylphenyl) -6-ethyl-7- (naphthalen-1-ylmethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) -D-plienylalanine and Example 33: N- [5- (3-Chloro-2-methylphenyl) -6-ethyl-7- (naphthalen-1-ylmethyl) -7H-pyrrolof 2,34 / lpyrimidin-4-yl) -D phenylalanine Step A: 5 4-bromo-4-chloro-6-ethyl-7- (1-naphthylmethyl) pyrrolo [2,3-d] pyrimidine 158 mg of 1-naphthalenemethanol (1 mmol), 262 mg of PPh 3 (1 mmol) and 130 mg of Preparation 1b. (0.5 mmol) were dissolved in 5 ml of anhydrous THF under N 2 atmosphere and cooled to 0 ° C. Then 460 μl of DEAD (0.5 mmol, 40% in toluene) was added dropwise. The mixture was stirred at 40 ° C until no further conversion was observed. Then the volatiles were removed under reduced pressure and the residue was purified by flash chromatography using heptane and EtOAc as eluents to give 5-bromo-4-chloro-6-ethyl-7 - (1-naphthylmethyl) pyrrolo [2,3-d] pyrimidine. NMR (400 MHz, CDCl3) δ: 8.58 (s, 1H), 8.09 (d, 1H), 7.95-7.89 (in, 1H), 7.79 (d, 1H), 7.66-7.54 (m, 2H), 7.25 (t, 1H), 6.45 (dd, 1H), 6.03 (s, 2H), 2.76 (q, 2H); ), 1.08 (t, 3H). MS: (M + H) ÷ = 400.0.
[0073] Step B: (2R) -2-115-bromo-6-ethyl-7- (1-naphthyl-methyl) pyrrolo [2,3-d] pyrimidin-4-yl] amino-3-phenylpropanoic acid Following the General procedure III and taking 5-bromo-4-chloro-6-ethyl-7- (1-naphthylmethylpyrrolo [2,3-d] pyrimidine as a derivative of 4-chloro-pyrrolo [2,3-d] pyrimidine and D-phenylalanine as the appropriate amino acid derivative, (2R) -24 [5-bromo-6-ethyl-7- (1-naphthylmethyl) pyrrol o [2,3-4-pyrimidin-4] amino-3-phenyl-propanoic acid was obtained NMR (500 MHz, DMSO-d6) 5: 13.14 (brs, 1H), 8.27 (d, 1H), 8.15 (s, 1H), 7.98 (d, 1H), 7.83 (d, 1H), 7.66-7.56 (in, 2H), 7.37-7.20 (m, 6H), 6.48; (d, 11-I), 6.40 (d, 1H), 5.94 (s, 2H), 4.99 (q, 1H), 3.33 (dd, 1H), 3.22 (dd; , 1H), 2.62 (q, 2H), 0.89 (t, 3H) MS: (M + H) + = 529.0 Step C: Examples 32 and 33 Following general procedure IVa and (2R) -24 [5-Bromo-6-ethyl-7- (1-naphthylmethyl) -pyrrolo [2,3-pyrimidin-4-yl] aminol-3-phenyl-propa) -acid as the appropriate 5-bromo-pyrrolo [2,3-d] pyrimidine derivative and Preparation 3c as the appropriate boronic acid derivative, Example 32 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C35H31ClN4O2: 574.2136, found: 575.2211 (M + H). Example 33 was obtained as the last eluted diastereoisomer. High resolution mass (HRMS) calculated for C35H31ClN4O2: 574.2136, found: 575.2203 (M + H). Example 34: N- [5- (3-Chloro-2-methylphenyl) -6-ethyl-7- (4-methoxybenzyl) -7H-pyrrolo [2,3-Mpyrimidin-4-yl] -D-phenylalanine and 3037959; 84- Example 35: N15- (3-Chloro-2-methylphenyl) -6-ethyl-7- (4-methoxybenzyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] -13-phenylalanine Step A: 5-Bromo-4-chloro-6-ethyl-7 - [(4-methaxyphenyl) methyl] pyrrolo [2,3-p] pyrimidine 138 mg 4-methoxybenzyl alcohol (1 mmol), 262 mg PPh 3 (1 mmol) and 130 mg of Preparation Ib (0.5 mmol) were dissolved in 5 ml of anhydrous TE under N 2 and cooled to 0 ° C. Thereafter, 4601.t of DEAD (0.5 Mnol, 40% in toluene) was added dropwise, the mixture was stirred at 40 ° C until no further conversion was observed, and the volatiles were removed under reduced pressure. the residue was purified by flash chromatography using heptane and EtOAc as eluents to obtain 5-bromo-4-chlom-6- thy1-7 - [(4-methoxy-phenyl) methyl] pyrrolo [2,3-di-pyriamine. MS: (M + H) + = 380.0.
[0074] Step B: (2R) -2-11-5-Bromo-6-ethyl-7-114-methoxy-phenyl) methyl-2-vinyl [2,3-d] pyrimidin-4-yl-amino] -3-phenyl-propanoic acid Following the General procedure III and taking 5-bromo-4-chloro-6-ethyl-7 - [(4-methoxyphenyl) methyl] pyrrolo [2,3-Mpyrimidine as a derivative of 4-chloropyrrolo d] appropriate pyrimidine and D-phenylalanine as the appropriate amino acid derivative, (2R) -24 [5-bromo-6-ethyl-7 - [(4-methoxyphenyl) methyl] pyrrolo [2] 3-4-pyrimidin-4-yl] amino] -3-phenylpropanoic acid was obtained. 1 H NMR (500 MHz, DMSO-d 6) δ: 13.07 (br s, 1H), 8.20 (s, 111), 7.33-7.17 (br, 5H), 7.03 (d, 2H), 6.85 (d, 2H), 6.37 (d, 1H), 5.37 (s, 2H), 4.99 (q, 1H), 3.69 (s, 3H), 3, 31 (dd, 1H), 3.20 (dd, 11-1), 2.65 (q, 2H), 0.91 (t, 3H). MS: (M + H) + = 508.8. Step C: Examples 34 and 35 Following general procedure IVa and taking (2R) -2 - [[5-bromo-6-ethyl-7 - [(4-methoxyphenyl) -methyl] pyrrolo [2 , 3-d] pyrimidin-4-yliamino] -3-phenylpropanoic acid as the appropriate 5-bromo-pyrrolo [2,3-d] pyrimidine derivative and Preparation 3c as the appropriate boronic acid derivative, Example 34 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C32H31ClN4O3: 554.2085, found: 555.2176 (M + H). Example 35 was obtained as the diastereoisomer eluted last. High resolution mass (HRMS) calculated for C32H31ClN4O3: 554.2085, found: 555.2140 (M + H).
[0075] Example 36: N-17-Benzyl-5- (3-chloro-2-methylphenyl) -6-ethyl-71-1-pyrrolo [2,3-d] pyrimidin-4-yl] -D-phenylalanine and Example 37 N-17-benzyl-5- (3-chloro-2-methylphenyl) -6-ethyl-7H-pyrrolo [2,3-pyrimidin-4-yl] -D-phenylalanine Following general procedure IVa and by taking Preparation 6 as the appropriate 5-bromo-pyrrolo [2,3-dlpyrimidine derivative and Preparation 3c as the appropriate boronic acid derivative, Example 36 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C 31 C 12 -C 12 402: 524.1979, found: 525.2048 (M + H). Example 37 was obtained as the last eluted diastereoisomer. High resolution mass (HRMS) calculated for C31F129ClN402: 524.1979, found: 525.2064 (M + H). Example 38: N-15- (3-Chloro-2-methylphenyl) -6-ethyl-7- (propan-2-yl) -711-pyrrolo [2,3-d] pyrimidin-4-yl] -D- phenylalanine and Example 39: N45- (3-chloro-2-methylphenyl) -6-ethyl-7- (propan-2-yl) -7H-pyrrolo [2,3-Mpyrimidin-4-yl] -D-phenylalanine Step A: 5-bromo-4-chloro-6-ethyl-7-isopropyl-pyrrolo [2,3-d] pyrimidine 76 1.11 of 2-propanol (1 mmol), 262 mg of PPh 3 (1 mmol) and 130 mg of Preparation lb (0.5 mmol) was dissolved in 5 ml of anhydrous THF under an N 2 atmosphere and cooled to 0 ° C. Then 460 μl of DEAD (0.5 mmol, 40% in toluene) was added dropwise. The mixture was stirred at 40 ° C until no further conversion was observed. Then the volatiles were removed under reduced pressure and the residue was purified by flash chromatography using heptane and EtOAc as eluents to obtain 5-bromo-4-chloro-6- ethyl-7-isopropyl-pyrrolo [2,3-d] pyrimidine. 1H NMR (400MHz, CDCl3) δ: 8.53 (s, 1H), 4.71 (sp, 1H), 2.92 (q, 2H), 1.72 (d, 6H), 1.25 (s, 1H), t, 3H).
[0076] MS: (M + H) + = 302.0. Step B: (2R) -2 - [(5-bromo-6-ethyl-7-isopropyl-pyrrolo [2,3-d] pyrimidin-4-yl) -aminol-3-phenylpropanoic acid Following the general procedure HI and taking 5-bromo-4-chloro-6-ethyl-7-isopropyl-pyrrolo [2,3-d] pyrimidine as the appropriate 4-chloro-pyrrolo [2,3-d] pyrimidine derivative and D-phenylalanine as the appropriate amino acid derivative, (2R) -2 - [(5-bromo-6-ethyl-7-isopropyl-pyrrolo [2,3-d] pyrimidin-4-ylamino] -3-phenyl- Propanoic acid was obtained 1 H NMR (500 MHz, DMSO 3) 8: 13.04 (bs, 1H), 8.14 (s, 1H), 7.35-7.17 (m, 5H), 6.33 (d, 1H), 4.95 (q, 1H), 4.64 (sp, 1H), 3.28 (dd, 11-1), 3.17 (dd, 1H), 2.76 (q, 2H), 1.59 (d, 6H), 1.11 (t, 3H) MS: (M + H) + = 431.2 Step C: Examples 38 and 39 Following the general procedure IVa and taking (2R) -2 - {(5-bromo-6-ethyl-7-isopropyl-pyrrolo [2,3-Mpyrimidin-4-yl] amino-3-phenylpropanoic acid as a 5-bromo derivative. -pyrrolo [2,3-d] pyrimidine and Preparation 3c as a derivative With the appropriate boronic acid, Example 38 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C 27 H 29 ClN 4 O 2: 476.1979, found: 477.2057 (M + H). Example 39 was obtained as the diastereoisomer eluted last. High resolution mass (HRMS) calculated for C271-129ClN402: 476.1979, found: 477.2063 (M + H). Example 40: (2R) -2 - [(7-Benzyl-5- (3-chloro-2-methyl-412- (4-methylpiperazin-1-yl) ethoxylphenyl] -6-ethyl-7H acid pyrrolo [2,3-dipyrimidin-4-yl] oxyl-3-phenylpropanoic acid Step A: 7-Benzyl-5-bromo-4-chloro-6-ethyl-pyrrolo [2,3-d] pyrimidine 255 mg of NaH (6.38 mmol) and 50 ml of anhydrous TFIF were loaded into a 50 ml Schlenk tube under N 2 and the suspension was cooled to 0 ° C. Then 1.792 g of lbs (5.8 mmol) was added After stirring the mixture for 30 minutes at 0 ° C, 773 grams of benzyl bromide (6.38 mmol) was added and the mixture allowed to warm to room temperature. The mixture was then diluted with a saturated aqueous solution of NH 4 Cl and extracted with DCM The combined organic phases were washed with brine, dried over MgSO 4, filtered. and the filtrate was concentrated under pressure The crude product was purified by flash chromatography using heptane and EtOAc as eluents to give 7-benzyl-5-bromo-4-chloro-6-ethyl-pyrrolo [2,3]. d] pyrimidine. R1VINIII (400 MHz, CDCl3) δ: 8.58 (s, 1H), 7.35-7.20 (m, 3H), 7.106.96 (m, 2H), 5.52 (s, 2H), 2 , 78 (q, 2H), 1.05 (t, 3H). Step B: Methyl (2R) -2- (7-benzyl-5-bromo-6-ethyl-pyrrolo12,3-dlpyrimidin-4-yl) oxy-3-phenylpropanoate 1.639 g 7-benzyl-5 -bromo-4-chloro-6-ethyl-pyrrolo [2,3-4 pyrimidine (4.67 mmol) was dissolved in 47 ml of anhydrous DMSO, then 2.948 g of (2R) -2-hydroxy-3 Methyl phenyl propanoate (16.4 mmol) and 7.234 g of Cs 2 CO 3 (22.2 mmol) were added and the mixture was stirred at 100 ° C. under an atmosphere of N 2 until no more conversion. Then it was diluted with water and brine, 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 flash chromatography using heptane and iPr2O as eluents to obtain (2R) -2- (7-benzyl-5-bromo-6-ethyl-pyrrolo [2,3-en] Methyl alpyrimidin-4-yloxy-3-phenylpropanoate 1H NMR (400 MHz, CDCl3) δ: 8.29 (s, 1H), 7.47 (d, 2H), 7.36 -7.19 (m, 6H), 7.066.96 (m, 2H), 5.60 (dd, 1H), 5.47 (s, 2H), 3.73 (s, 3H), 3.28 (m, 2H), 2.72 (q, 2H), 1.03 (t, 3H) MS: (M + H) + = 494.2.
[0077] Step C: (2R) -2- [7-Benzyl- (5S) -5-P-chloro-2-methyl-4-hydroxphenyl] -6-ethyl-pyrrolo [3-pyrimidin-4-yl] -oxy-3- methyl phenylpropanoate A mixture containing 1.20 g of (2R) -2- (7-benzyl-5-bromo-6-ethyl-pyrrolo [2,3-4-pyrimidin-4-ypoxy-3-phenyl] methyl propanoate (2.43 mmol), 1.98 g of Preparation 3a (7.21 mmol), 110 mg of Pd (OAc) 2 (0.49 mmol), 350 mg of butyl-diadamantylphosphine (0.98 mmol). mmol) and 7.35 ml of 1M aqueous TBAOH in 18 ml of DME was heated under MW irradiation at 100 ° C until no further conversion was observed.The reaction mixture was filtered through celite. Water was added to the filtrate, and the mixture was acidified to pH = 4 and extracted with MTBE The combined organic phases were dried over Na 2 SO 4, filtered and the filtrate was concentrated under reduced pressure. in a mixture containing 10 ml of MeOH and 40 g of H 2 SO 4 cc until no longer observed conversion. The volatiles were removed under reduced pressure, the residue was diluted with water, the pH was adjusted to 5 and the mixture was 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 flash chromatography using heptane and EtOAc as eluents to give (2R) -247-benzyl- (5S) -5-P-chloro-2-methyl-4- Methyl hydroxphenyl-6-ethylpyrrolo [2,3-c] pyrimidin-4-yloxy-3-phenylpropanoate as the last eluted diastereoisomer. 1H NMR (500 MHz, DMSO-d6) δ: 10.14 (s, 1H), 8.27 (s, 1H), 7.34-7.27 (m, 21-I), 7.27-7. , 22 (in, 1H), 7.17-7.07 (in, 4H), 7.05 (d, 2H), 6.98 (dd, 1H), 6.64 (d, 2H), 5, 60 (d, 1H), 5.51 (d, 11-1), 5.43 (dd, 1H), 3.56 (s, 31-1), 3.00 (dd, 1H), 2.85 (dd, 1H), 2.60-2.51 (m, 11-1), 2.48-2.38 (in, 1H), 2.04 (s, 3H), 0.84 (t, 3H). ).
[0078] Step D: Example 40 139 mg of (2R) -247-benzyl- (5Sa) -543-chloro-2-methyl-4-hydroxphenyl] -6-ethylpyrrolo [2,3-d] pyrimidin-4-yloxy Methyl 3-phenyl-propanoate (0.25 mmol), 72 mg of 1- (2-hydroxyethyl) -4-methylpiperazine (0.50 mmol) and 166 mg of resin-bound PPh3 (0, 5 mmol) were dissolved in 3 ml of dry toluene under N 2 atmosphere, then 115 mg of DTAD (0.5 mmol) was added. The mixture was stirred at 50 ° C until no further conversion was observed. The mixture was then diluted with DCM, filtered and the filtrate concentrated under reduced pressure and purified by flash chromatography using heptane, EtOAc and MeOH as eluents. The resulting intermediate was dissolved in 10 ml MeOH, then 500 mg LiOH x H2O was added, and the mixture was stirred at 50 ° C until no further conversion was observed. The mixture was diluted with brine, neutralized with 1M aqueous HCl 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 40 mM aqueous NH40Ac (pH-4, adjusted with AcOH) and MeCN as eluents to obtain Example 40. Mass High resolution (HRMS) calculated for C38H42ClN4O4: 667.2925, found: 668.2992 (M + H). Example 41: N46-Bromo-7- (but-3-en-1-yl) -5- (3-chloro-2-methylphenyl) -7H-pyrrolo [2,3-dlpyrimidin-4-yl] -D-phenylalanine and Example 42: N- [6-Bromo-7- (but-3-en-1-yl) -5- (3-chloro-2-methylphenyl) -7H-pyrrolo [2,3-pyrimidin-4-y] D-phenylalanine Step A 7-but-3-en-4-chloro-5-iodo-pyrrole-12,3-clipyrimidine 5.0 g of 4-chloro-5-iodo-7H-pyrrolo [2,3-d] pyrimidine ( 17 mmol), 2,842 g of K 2 CO 3 (20.57 mmol), 2.15 ml of 4-bromo-1-butene (20.57 mmol) and 26 ml of anhydrous DMF were stirred at RT under an atmosphere. from N2 to no longer observe conversion. Then, the mixture was poured into water and extracted with EtOAc. 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 flash chromatography using heptane and EtOAc to give 7-but-3-enyl-4-chloro-5-iodo-pyrrolo [2,3-4pyrimidine. 1H NMR (400 MHz, CDCl3) δ: 8.62 (s, 1H), 7.38 (s, 1H), 5.82-5.69 (m, 1H), 5.08 (s, 1H), 5.04 (dd, 1H), 4.33 (t, 2H), 2.60 (q, 2H). MS: (M + H) + = 334.0.
[0079] Step B: (2R) -2-1 (7-But-3-Ethyl-5-locolo-pyrrolo [2,3-c-pyrimidin-4-yl] -aminoyl-3-phenyl-propanoic acid Following general procedure III and taking 7-but-3-en-4-chloro-5-iodopyrrolo [2,3-d] pyrimidine as the appropriate 4-chloro-pyrrolo [2,3-Mpyrimidine derivative and D-phenylalanine as a derivative of Suitable amino acid, (2R) -2 - [(7-but-3-enyl-5-iodo-pyrrolo [2,3-d] pyrimidin-4-yl] amino] -3-phenylpropanoic acid, R.MNIIT (400 MHz, CDCl3) δ: 8.32 (s, 1H), 7.38 (s, 1H), 7.35-7.28 (m, 311), 7.28-7. , 22 (m, 2H), 7.02 (s, 1H), 6.28 (d, 1H), 5.80-5.67 (in, 1H), 5.09-5.04 (in, 1H). ), 5.04-5.00 (s, 1H), 4.944.85 (m, 1H), 4.22 (t, 2H), 3.51 (dd, 1H), 3.30 (dd, 1H) , 2.54 (q, 2H).
[0080] Step C: (2R) -2-117-but-3-enyl-5- (3-chloro-2-methyl-phenyl) pyrrolo12,3-d] pyrimidin-4-ylamino] -3-phenylpropanaic acid Following the general procedure IVb and taking (2R) -2 - [(7-but-3-enin) -5-iodo-pyrrolo [2,3-d] pyrimidin-4-yDamino-3-phenyl-proPanoic acid as Suitable 5-iodopyiTolo [2,3-dipyrimidine derivative and Preparation 3c as the appropriate boronic acid derivative, (2R) -24 [7-but-3-eny1-5- (3-chloro-2) methyl-phenyl) pyrrolo [2,3-4-pyrimidin-4-yl] aminol-3-phenylpropanorec was obtained .MRNII (500 MHz, DMSOd6) 8: 12.86 (brs, 1H), 8 , 24 (s, 1H), 7.55-7.43 (nl, 1H), 7.33-6.95 (in, 6H), 6.89-6.80 (m, 21-1), , 84-5.40 (in, 1H), 5.08-4.93 (nl, 3H), 4.84 (bs, 1H), 4.37-4.15 (m, 2H), 3, 16 (d, 1H), 2.85 (dd, 1H), 2.56 (q, 2F1), 2.22-2.04 (s, 3H).
[0081] Step D Examples 41 and 42 512 mg of (2R) -2 - [[7-but-3-enyn] -5- (3-chloro-2-methyl-phenyl) pyrrolo [2,3-d] - pyrimidin-4-yl] amino] -3-phenylpropanoic acid (1 mmol) was dissolved in 4.5 ml of anhydrous DMF and 187 mg of NBS (1 mmol) was added. The mixture was stirred at RT until no further conversion was observed. The mixture was then poured into water and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase preparative chromatography using 0.1% aqueous TFA solution and MeCN as eluents to obtain Example 41 as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C26H24BrClN4O2: 538.0771, found: 541.0831 (M + H).
[0082] Example 42 was obtained as the last eluted diastereoisomer. High resolution mass (HRMS) calculated for C26H24BrClN402: 538.0771, found: 541.0835 (M + H). Example 43: N, 16-Bromo-5- (3-chloro-2-methylphenyl) -7- (proP-2-en-1-yl) -711-pyrrolo [2,3-d] pyrimidin-4-3 11-D-phenylalanine and Example 44: N-16-bromo-5- (3-chloro-2-methylphenyl) -7- (proP-2-en-1-yl) -7H-pyrrolo [2,3-d] ] pyrimidin-4-yl-D-phenylalanine Step A: 7-allyl-4-chloro-5-indo-pyrrolo12,3-dlpyrimidine 176.5 mg of 4-chloro-5-iodo-7H-pyiTolo [2, 3-d] pyrimidine (0.6 mmol), 100.7 mg of K 2 CO 3 (0.73 mmol), 63 g of allyl bromide (0.73 mmol) and 1 ml of anhydrous DMF were stirred at room temperature. TA under an atmosphere of N2 until no longer observe conversion. Then, the mixture was poured into water and extracted with EtOAc. 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 flash chromatography using heptane and EtOAc to give 7-allyl-4-chloro-5-iodo-pyrrolo [2,3-d] pyrimidine. MS: (M + H) ± 320.0. Step B: (2R) -21- (7-allyl-5-iodo-pyrrolo [213-dlpyrimidin-4-amino-3-phenylpropanoic acid Following general procedure III and taking 7-allyl-4- chloro-5-iodopyrrolo [2,3-Mpyrhnidine as the appropriate 4-chloro-pyrrolo [2,3-dlpyrimidine derivative] and D-phenylalanine as the appropriate amino acid derivative, (2R) -2 - [( 7-allyl-5-iodopyrrolo [2,3-d] pyrimidin-4-ylamino] -3-phenylpropanoic acid was obtained.
[0083] NMR14 (400 MHz, DMSO-d6) δ: 13.09 (bs, 1H), 8.20 (s, 1H), 7.43 (s, 1H), 7.34-7.18 (m, 5H), 6.52 (bd, 1H), 6.05-5.90 (m, 1H), 5.15 (dd, 1H), 5.07-4.94 (m, 2H), 4.74 (d, 2H), 3.38 (dd, 11-1), 3.15 (dd, 1H). MS: (M + H) + = 449.0. Step C: (2R) -2-177-allyl-5- (3-chloro-2-methyl-phenyl) pyrrolo12,3-dipyrimidin-4-yllaminol-3-phenyl-propanic acid Following the general procedure IVb and taking (2R) -2 - [(7-allyl-5-iodo-pyrrolo [2,3-d] pyrimidin-4-yDamino] -3-phenylpropanoic acid as the derivative of 5-iodopyrrolo [2, 3-d] pyrimidine and Preparation 3c as the appropriate boronic acid derivative, (2R) -2-1 [7-allyl-5- (3-chloro-2-methyl-phenyl) pyrrolo [2] , 3-d] pyrimidin-4-yl amino] -3-phenyl-propenoic was obtained.
[0084] 1H NMR (400MHz, DMSO-d6) δ: 12.89 (bs, 1H), 8.23 (s, 1H), 7.59-7.42 (bs, 1H), 7.10 (m, 6H), 6.91-6.81 (bs, 2H), 6.12-5.98 (m, 1H), 5.16 (dd, 1H), 5.09-4. , 96 (in, 214), 4.90-4.76 (bs, 3H), 3.17 (dd, 1H), 2.86 (dd, 1H), 2.23-2.04 (bs) , 3H). MS: (M + H) + = 447.0.
[0085] Step D: Examples 43 and 44 447 mg of (2R) -2 - [[7-allyl-5- (3-chloro-2-methyl-phenyl) pyrrolo [2,3-d] pyrimidin-4- acid yl] amino] -3-phenylpropanoic acid (1 mmol) was dissolved in 4.5 ml of anhydrous DMF and 187 mg of NBS (1 mmol) was added. The mixture was stirred at RT until no further conversion was observed. The mixture was then poured into water and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, 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 MeCN as eluents to obtain Example 43 as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C25H22BrClN402: 524.0615, found: 525.0675 (M + H). Example 44 was obtained as the diastereoisomer eluted last. High resolution mass (HRMS) calculated for C251122BrCIN402: 524.0615, found: 525.0674 (M + H) Example 45: (2R) -24 (7-Benzyl-5- (3-chloro) -2- methyl-442- (4-methylpiperazin-1-yl) ethoxylphenyl} -7H-pyrrolo [2,3-dlpyrimidin-4-yl] oxyl-3-phenylpropanoic acid Step A: 7-Benzyl-4-chloro-5-iodo-pyrrolo [ 2,3-d] pyrimidine 1.68 g of 4-chloro-5-iodo-7H-pyrrolo [2,3-d] pyrimidine (6 mmol), 1.24 ml of benzyl alcohol (12 mmol), 3.144 g of PPh 3 (12 mmol) and 60 ml of anhydrous THF were cooled to 0 ° C. under an N 2 atmosphere and then 5.5 ml of a DEAD solution (12 mmol, 40% in toluene). The mixture was stirred at 40 ° C until no further conversion was observed, then the mixture was poured into water and extracted with Et 2 O. 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 flash chromatography using heptane and EtOAc to give 7-benzyl-4-chloro-5-iodo-pyrrolo [2,3-d] pyrimidine. 1 H NMR (500 MHz, DMSO-d6) δ: 8.67 (s, 1H), 8.12 (s, 1H), 7.32 (t, 211), 7.28 (t, 1H), 7.28 (d, 2H), 5.47 (s, 2H). MS (M + H): 369.9. Step B: (2R) -2- (Methyl 7-benzyl-5-iodo-pyrrolo [2,3-d] pyrimidin-4-yl) oxy-3-phenylpropanoate 1 eq. 7-benzyl-4-chloro-5-iodo-pyrrolo [2,3-c] pyrimidine, 3 eq. methyl (2R) -2-hydroxy-3-phenylpropanoate, 3 eq. of Cs2CO3 and anhydrous DMSO (6 ml / mmol) were allowed to stir at 100 ° C until no further conversion was observed. The mixture was acidified with 1M aqueous HCl 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 flash chromatography using heptane and EtOAc as eluents to give (2R) -2- (7-benzyl-5-iodopyrrolo [2,3-d] pyrimidin-4- yl) methyl oxy-3-phenylpropanoate. MS (M + 11): 514.1. Step C: Example 45 Following General Procedure IVb and taking (2R) -2- (7-benzyl-5-iodo-pyrrolo [2,3-a] pyrimidin-4-ypoxy-3-phenyl-ProPanoate methyl as the appropriate 5-iodo-pyrrolo [2,3-a] pyrimidine derivative and Preparation 3b as the appropriate boronic acid derivative, (2R) -2 [7-benz, y-513- Methyl chloro-2-methyl-4- [2- (4-methylpiperazin-1-ylmethylphenyl) pyrrolo [2,3-d] pyrimidin-4-yleloxy-3-phenylpropanoate was obtained and dissolved in the dioxane / 1/1 water (20 ml / mmol) and 10 eq of LiOHxH 2 O were added, the mixture was stirred at RT until no conversion was observed, then it was diluted with brine, neutralized with a 2M aqueous HCl solution and extracted with DCM The combined organic phases were dried over Na 2 SO 4, filtered and the filtrate was concentrated under reduced pressure The crude product was purified by prep chromatography reverse phase arative using 0.1% aqueous TFA solution and MeCN as eluents to obtain Example 45. High resolution mass (FIRMS) calculated for C361138ClN4O4: 639.2612, found: 640.2654 (M. + H). Example 46: N-15- (3-chloro-2-methylphenyl) -7,8-dihydro-6H-pyrimido [5,4-1,1] pyrrolizin-4-yl) phenylalanine 210 mg d a 1/1 mixture of Examples 43 and 44 (mixture of the two diastereoisomers, 0.4 mmol) were dissolved in 3 ml of MeOH and 70 μl of 142SO4 cc. (1.2 mmol) were added. The mixture was stirred at RT until no further conversion was observed. The mixture was poured into ice water, neutralized with saturated aqueous NaHCO 3 solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. Then, it was dissolved in anhydrous THF (6 ml / mmol), and the mixture was cooled to 0 ° C. 5 eq. A solution of 9-borabicyclo [3,3,1] nonane (0.5M in THF) was added and the mixture was stirred at RT until no further conversion was observed. Then 20 eq. 2M aqueous NaOH solution and 20 mol% PdCl2 x dppf were added. The mixture was stirred at 80 ° C until no further conversion was observed. Then it was filtered through celite and washed with EtOAc. The filtrate phases were separated, the aqueous phase was acidified to pH 3 with a 2M aqueous HCl solution, and then 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 reverse phase preparative chromatography using 40 mM aqueous NH40Ac (pH = 4, adjusted with AcOH) and MeCN as eluents to obtain Example 46 under the form of a mixture of diastereoisomers. High resolution mass (HRMS) calculated for C25H23ClN402: 446.1510, found: 447.159 and 447.1591 (M-FH).
[0086] Example 47: N- [5- (3-Chloro-2-methylphenyl) -6,7,8,9-tetrahydropyrimido [5,443] -indolizin-4-yl-D-phenyl-alanine and Example 48: N-15 - (3-Chloro-2-methylphenyl) -6,7,8,9-tetrahydropyrimido-15,4-indolizin-4-yl) -phenyl-alanine 1.29 g of a 1/1 mixture of Examples 41 and 42 (mixture of the two diastereoisomers, 2.3 mmol) was dissolved in 10 ml MeOH and 0.4 ml H 2 SO 4 cc. (6.9 mmol) was added. The mixture was stirred at RT until no further conversion was observed. The mixture was poured into ice water, neutralized with saturated aqueous NaHCO 3 solution and extracted with EtOAc. The combined organic phases were washed with brine, dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. Then, it was dissolved in anhydrous THF (6 ml / mmol), and the mixture was cooled to 0 ° C. 5 eq. A solution of 9-borabicyclo [3,3,1] nonane (0.5M in THF) was added and the mixture was stirred at RT until no further conversion was observed. Then 20 eq. 2M aqueous NaOH solution and 20 mol% PdCl2 x dppf were added. The mixture was stirred at 80 ° C until no further conversion was observed. Then it was filtered through celite and washed with EtOAc. The filtrate phases were separated, the aqueous phase was acidified to pH 3 with a 2M aqueous HCl solution and then 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 reverse phase preparative chromatography using 0.1% aqueous TFA solution and MeCN as eluents. Example 47 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C261-125ClN402: 460.1666, found: 461.1747 (M + H). Example 48 was obtained as the diastereoisomer eluted last. High resolution mass (HRMS) calculated for C 26 H 25 ClN 4 O 2: 460.1666, found: 461.1752 (M + H). Example 49: (2R) -2- (13- (3-Chloro-4-hydroxy-2-methylphenyl) -2-ethyl-1-benzothiophen-4-yl] oxy} -3-phenylpropanoic acid and Example 50 (2R) -2-1 [3- (3-chloro-4-hydroxy-2-methylphenyl) -2-ethyl-1-benzothiophen-4-yl] oxy) -3-phenylpropanoic acid Step A: acid ( 2R) -2- (2-ethylbenzothiophen-4-yloxy-3-phenylpropanoic acid 270 mg of (2R) -2-hydroxy-3-phenylpropanoic acid (1.63 mmol), 40 mg of 21 mmol) and 325 mg of Cs2CO3 (1 mmol) were measured in a 7 ml vial equipped with a screw cap and a rubber septum The vial was purged with argon and 5 ml. 1 ml of anhydrous DMF and 288 mg of 2-ethyl-4-iodo-benzo [b] thiophene (1 mmol) were added using a syringe and the mixture was stirred at 110 ° C. 20 hours All the other steps were performed in the dark or under a red light, 10 ml of water was added and the pH was adjusted to 3 with 15 2M aqueous HCl solution Then 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 on a preparative TLC plate (silica layer, eluent toluene / AcOH 9/1) to obtain (2R) -2- (2-ethylbenzothiophen-4-yl) oxy-3-phenyl- propanoic. 1 H NMR (500 MHz, DMSO-d 6) δ: 12.53 (br s, 111), 7.42-7.36 (m, 3H), 7.30 (t, 2H), 7.25-7, 18 (in, 111), 7.13 (t, 1H), 7.07 (bs, 1H), 6.65 (d, 11-1), 4.98 (dd, 1H), 3.29 (b, 1H), dd, 11-1), 3.22 (dd, 1H), 2.89 (q, 2H), 1.30 (t, 3H). Step B: Methyl (2R) -2- (2-ethylbenzothiophen-4-yl) oxy-3-phenylpropanoate 1.434 g (2R) -2- (2-ethylbenzothiophen-4-yl) oxy- 3-phenylpropanoic acid (4.39 mmol) was dissolved in 20 ml MeOH and 20 μl H 2 SO 4 cc. have been added. The mixture was stirred at 80 ° C until no further conversion was observed. The mixture was concentrated under reduced pressure, then diluted with water, neutralized with saturated aqueous NaHCO 3 solution and extracted with DCM. The combined organic layers were washed with brine, dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure to give (2R) -2- (2-ethylbenzo-thiophen-4-yl) oxy-3 methyl phenyl propanoate. 1 H NMR (400 MHz, CDCl3) δ: 7.46-7.33 (m, 511), 7.33-3037959; 7.26 (in, 1H), 7.16 (bd, 1H), 7.13 (t, 1H), 6.65 (d, 1H), 4.99 (dd, 1H), 3, 75 (s, 3H), 3.463.32 (m, 2H), 3.01-2.91 (m, 2H), 1.42 (t, 3H). Step C: (2R) -2- (Methyl-2-ethyl-3-yl-benzothio-phenyl-4-yl) -oxy-3-phenyl-propanoate 1.278 g of (2R) -2- (2-ethylbenzothiophen-4) Methyl-3-phenyl-propanoate (3.75 mmol), 2.244 g of I2 (9 mmol) and 2.5 g of Ag2SO4 (8 mmol) were dissolved in 10 ml of EtOH and left behind. The mixture was then filtered, the filtrate was concentrated under reduced pressure and purified by flash chromatography using heptane and EtOAc as eluents to obtain 10 860 mg. Methyl (2R) -2- (2-ethyl-3,7-diiodobenzothiophen-4-yl) oxy-3-phenylpropanoate which were dissolved in 20 ml of THF, 150 mg of Pd / C 10% was added and the mixture was stirred at RT under a 4 bar atmosphere of 112 until no further conversion was observed, then it was filtered through Celite, the filtrate was concentrated under reduced pressure and purified by chromatography flash using heptane and EtOAc as eluents to obtain methyl (2R) -2- (2-ethyl-3-iodobenzothiophen-4-yl) oxy-3-phenylpropanoate. 1H NMR (500 MHz, DMSO-d6) δ: 7.53 (d, 1H), 7.49-7.41 (m, 2H), 7.34-7.27 (m, 2H), 7.26. -7.18 (m, 2H), 6.77 (d, 1H), 5.33 (dd, 1H), 3.61 (s, 3H), 3.43 (dd, 1H), 3.32 ( dd, 1H), 2.94-2.85 (m, 2H), 1.25 (t, 3H).
[0087] Step D: Examples 49 and 50 methyl (2R) -2- (2-ethyl-3-iodo-benzothiophen-4-yl) -oxy-3-phenylpropanoate (0.686 mmol) and 368 mg of Preparation 3a (1.37 mmol) was dissolved in 4 mL of 2-Me-THF under N 2, then 1.37 mL of TBAOH solution (1.37 mmol, 1M in THF) and 49 mg. AtaPhos (0.069 mmol) was added and the mixture was stirred at 90 ° C in a closed vial until no further conversion was observed. Then, it was diluted with 30 ml of DCM and washed with 10 ml of a 1M aqueous HCl solution. The organic phase was concentrated under reduced pressure and then dissolved in 5 ml of MeOH. 100 mg of LiOH x H2O was added, and the mixture was stirred at 50 ° C until no further conversion was observed. Then it was diluted with brine, neutralized with 1M aqueous HCl 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 inverted-phase preparative chromatography using 0.1% aqueous TFA solution and MeCN as eluents. Example 49 was obtained as the last eluted diastereoisomer. High resolution mass (HRMS) calculated for C26H23ClO4S: 466.1006, found: 465.0956 (M-H). Example 50 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C26H23ClO4S: 466.1006, found: 465.0971 (M-H). Example 51: (2R) -24 (3- {3-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxylphenyl} -2-ethyl-1-benzothiophen-4-yl) oxyl-3-acid phenylpropane Step A: methyl (2R) -2-P- (3-chloro-4-hydroxy-2-methyl-phenyl) -2-ethyl-bertzothiophen-4-yloxy-3-phenylpropartoate 140 mg Example 49 (0.3 mmol) was dissolved in 3 ml MeOH and 50 ul H 2 SO 4 cc. have been added. The mixture was stirred at 80 ° C until no further conversion was observed. The mixture was concentrated under reduced pressure and the residue was diluted with water, neutralized with saturated aqueous NaHCO 3 solution and extracted with DCM. The combined organic phases were washed with brine, 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 to give (2R) -2- [3- (3-chloro-4-hydroxy-2-methyl-phenyl) Methyl 2-ethylbenzothiophen-4-yl] oxy-3-phenylpropanoate. 1H NMR (500 MHz, DMSO-d6): 10.02 (s, 1H), 7.49 (d, 1H), 7.23-7.12 (m, 4H), 7.02 (d, 1H), 6.92 (d, 1H), 6.89-6.86 (m, 2H), 6.62 (d, 1H), 5.01 (dd, 1H), 3.50 (s, 3H), 2 , 72 (dd, 1H), 2.60-2.51 (m, 2H), 2.38 (dd, 1H), 1.96 (s, 3H), 1.12 (t, 3H).
[0088] Step B: Example 51 63 mg methyl (2R) -213- (3-chloro-4-hydroxy-2-methyl-phenyl) -2-ethyl-benzothiophen-4-yl] oxy-3-phenylpropanoate (0) 13 mmol), 23 mg of 1- (2-hydroxyethyl) -4-methylpiperazine (0.156 mmol) and 41 mg of PPh 3 (0.156 mmol) were dissolved in 2 ml of anhydrous TFIF under an N 2 atmosphere, followed by mg DTAD (0.156 mmol) was added. The mixture was stirred at 50 ° C until no further conversion was observed. The mixture was then concentrated under reduced pressure and purified by flash chromatography using Illetatie, EtOAc and MeOH as eluents. The resulting intermediate was dissolved in 5 ml of MeOH and then 100 mg of LiOH x H2O was added, and the mixture was stirred at 50 ° C until no further conversion was observed. Then, it was diluted with brine, neutralized with a 1M aqueous HCl 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 a 40 mM aqueous solution of NH4OAc (pH = 4, adjusted with AcOH) and MeCN as eluents to obtain Example 51. High resolution mass ( HRMS) calcd for C33H37ClN4O4S: 592.2163, found: 593.2238 (M + H). Example 52: (2R) -2 - ([3-13-Chloro-2-methyl-442- (4-methylpiperazin-1-yl) -ethoxylphenyl) -2- (4-fluoro-phenyl) -1-benzothiophenic acid 4-yloxy) -3- (2-112- (2-methoxyphenyl) pyrimidin-1-ylmethoxy} phenyl) propanoic acid and Example 53: (2R) -2 - {[3- (3-chloro-2-) - acid methyl-442- (4-methylpiperazin-1-yepethoxylphenyl) -2- (4-fluoro-phenyl) -1-benzothiopien-4-yloxy} -3- (2- (12, - (2-methoxy-4-pyrimidin) pyrimidin) Methyl phenoxypropanoic acid Step A: 3-bromophenyl N, N-diethylcarbamate 5.0 g 3-bromophenol (28.9 mmol) and 4.31 g diethylcarbamoyl chloride (31.8 mmol) were dissolved in 50 ml of pyridine and stirred at 100 ° C. until no further conversion was observed, then the mixture was concentrated under reduced pressure and purified by flash chromatography using heptane and EtOAc as eluents to give 3-bromophenyl N, N-diethylcarbamate SM (EI, 70 eV) rnlz (relative intensity in%, [ion]): 56 (9), 7 2 (42), 100 (100), 174 (4), 176 (4), 271 (4, [M1), 273 (4, [M +]). Step BN, 3-bromo-2-iodo-phenyl N, O-diethylearbamate 2.72 g of 3-bromophenyl N, N-diethylearbamate (10 mmol) was dissolved in 50 ml of anhydrous THF under N 2 atmosphere. cooled to -78 ° C. 6 ml of a solution of LDA (12 mmol, 2M in THF, heptane, ethylbenzene) was added and the mixture was stirred at -78 ° C for 30 minutes. Then, 3.18 g of 12 (12.5 mmol) was added and the mixture was stirred at -78 ° C for 30 minutes and then allowed to warm to RT. Then, the mixture was concentrated under reduced pressure and purified by flash chromatography using heptane and EtOAc as eluents to give 3-bromo-2-iodo-phenyl N, N-diethylcarbamate. 1 H NMR (400 MHz, DMSO-d 6) δ: 7.60 (dd, 1H), 7.35 (t, 11-1), 7.17 (dd, 1H), 3.47 (q, 2H), 3H NMR (CDCl3) , 31 (q, 2H), 1.27 (t, 3H), 1.14 (t, 31-1). Step C: 3-bromo-2- (4-fluorophenyl) ethynyliphenyl N, N-thiethylcarbamate 2.60 g of 3-bromo-2-iodophenyl N, N-diethylcarbamate (6.53 mmol), 863 mg of 1-ethynyl-4-fluoro-benzene (7.19 mmol), 229 mg of Pd (PPh 3) 2 Cl 2 (0.33 mmol), 130 mg of copper iodide (1) (0.65 mmol) and 1, 43 g of diethylamine (19.6 mmol) were dissolved in 25 ml of anhydrous DMF and stirred at 50 ° C. until no further conversion was observed.The mixture was diluted with water and extracted with EtOAc The combined organic phases were washed with brine, dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure The crude product was purified by flash chromatography using heptane and chloroform. EtOAc as eluents to give 3-bromo-242- (4-fluorophenyl) -ethynyl] phenyl N, N-diethylcarbamate MS (EI, 70 eV) m / z (relative intensity in%, [ion]): 56 (2), 72 (35), 100 (100), 261 (2), 263 (2), 389 (2, [M1 ), 391 (2, [M +]) Step D: 2-P- (4-Fluoro-phenyl) ethynyl-3-methylsternylphenyl N, N-diethylearbamate 2.5 g of 3-bromo N, N-diethylcarbamate -242- (4-fluorophenylphenyl) ethynyl) (6.56 mmol) were dissolved in 65 ml of anhydrous THF and cooled to -78 ° C, followed by 4.3 ml of a solution of IlBuLi (6.88 mmol, m.p. 1.6M in hexane) were added. The mixture was stirred at -78 ° C for 30 minutes. Then 742 mg of S2Me2 (7.87 mmol) was added and the mixture was stirred at -78 ° C for 30 minutes and then allowed to warm to RT. The mixture was then concentrated under reduced pressure and purified by flash chromatography using heptane and EtOAc as eluents to give 2- [2- (4-fluoro) -N, N-di-diethylcarbamate. -phenypethynyl-3-methylsulfanyl-phenyl MS (EI, 70 eV) m / z (relative intensity in%, [ion]): 56 (2), 72 (46), 100 (100), 342 (40), 357 (1, [M1) Step EN, 2- (4-fluorophenyl) -3-iodo-benzothiophen-4-yl N-diethylcarbane 1100 mg 242- (4-fluorophenyl) N, N-diethylcarbamate ethynyl] -3-methylsulfanyl-phenyl (3.08 mmol) and 937 mg of I2 (3.7 mmol) were dissolved in 20 ml of DCM and stirred at RT until no further conversion was observed. The mixture was then diluted with 10% aqueous Na2S2O3 solution and extracted with DCM The combined organic phases were washed with brine to give 2- (4-fluorophenyl) N, N-diethylcarbamate ) -3-iodo-benzothiophen-4-yl.1H NMR (400 MHz, CDCl 3 3) 8: 7.74 (dd, 1H), 7.56 (m, 2H), 7.40 (t, 1H), 7.18 (m, 2H), 7.12 (dd, 1H), 3 , 60 (q, 2H), 3.46 (q, 2H), 1.36 (t, 3H), 1.26 (t, 3H). MS (EI, 70 eV) m / z (relative intensity in%, [ion]): 72 (42), 100 (100), 170 (16), 342 (37), 369 (5), 469 (1, [M1).
[0089] Step F: 3-β-Ethyl-2-methyl-4- (4-methylpiperazin-1-yl) -ethoxyl-phenyl-2- (4-fluorophenyl) benzothiophen-4-yl e-N, N-diethylcarbamate . 2- (4-Fluoro-phenyl) -3-iodo-benzothiophen-4-yl N, N-diethylcarbamate, 2 eq. Preparation 3b, 2 eq. of Cs2CO3, 0.1 eq. Ataphos and THF / water 3/1 (10 ml / mmol benzothiophene derivative) were stirred under N 2 at 70 ° C until no further conversion was observed. The mixture was diluted with water and extracted with DCM. The organic phase was 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 to give 343-chloro-2-methyl-442- (4-methylpiperazine) N, N-diethylcarbamate. 1-yl) ethoxylphenyl] -2- (4-fluorophenyl) benzothiophen-4-yl. MS: (M + H) + = 610.2 Step G: 3-13-Chloro-2-methyl-4-P- (4-methylpiperazin-1-Aethoxylphenyl) -2- (4-fluorophenyl) benzothiophen-4-ol 1.8 g of 343-chloro-2-methyl-442- (4-methylpiperazin-1-yepethoxy-phenyl) -2- (4-fluorophenyl) benzothiophen-4-yl N, N-diethylcarbamate (3 mmol) was dissolved In 80 ml of EtOH and 1.2 g of NaOH (30 mmol) was added, the mixture was stirred at 80 ° C until no further conversion was observed. under reduced pressure and purified by flash chromatography using DCM and MeOH as eluents to obtain 343-chloro-2-methyl-4- [2- (4-methylpiperazin-1-yepethoxy) phenyl] -2- (4- fluorophenyl) benzothiophen-4-01 MS: (M + H) + = 511.2.
[0090] Step H: Example 52 470 mg of 313-chloro-2-methyl-442- (4-methyl-piperazin-1-yl) ethoxy] phenyl] -2- (4-fluorophenyl) benzothiophen-4-ol (m.p. 0.92 mmol), 1.12 g of Preparation 2d (2.76 mmol) and 726 mg of PPh 3 (2.76 mmol) were dissolved in 10 ml of anhydrous toluene, followed by 10 635 mg of DTAD (2.76 mmol). mmol) were added. The mixture was stirred at 50 ° C until no further conversion was observed. The mixture was then concentrated under reduced pressure and purified by flash chromatography using heptane and EtOAc as eluents. The formed intermediate was dissolved in 10 ml dioxane / water 1: 1, 400 mg LiOH x H2O was added, and the mixture was stirred at RT until no further conversion was observed. It was neutralized with 2M aqueous HCl 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 an aqueous 25 mM NH4HCO3 solution and MeCN as eluents. Example 52 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C49H46ClFN4O6S: 872.2811, found: 437.1457 (M + 2H). Example 53 was obtained as the diastereoisomer eluted last. High resolution mass (HRMS) calculated for C49H46ClFN4O6S: 872.2811, found: 437.1491 (M + 2H).
[0091] Example 54: 2-Benzyl-343- (3-chloro-4-hydroxy-2-methylphenyl) -2-ethyl-1-benzothiophen-4-ylpropanoic acid Step A: (Z) -2-Benzyl-3- ( Methyl 2-ethylbenzothiophen-4-yl) -prop-2-enoate 576 mg of 2-ethyl-4-iodo-benzo [b] thiophene (2 mmol), 717 mg of methyl 2-benzylacrylate (4 mmol) 556 μl of TEA (4 mmol) and 24 mg of PdCl2 (0.1 mmol) were dissolved in 10 ml DMF and stirred at 130 ° C. in a MW reactor until no further conversion was observed. The mixture was concentrated under reduced pressure and purified by flash chromatography using heptane and EtOAc as eluents to obtain (Z) -2-benzyl-3- (2-ethylbenzo-thiophene). Methyl 4-yl) propenoate. NMR111 (400 MHz, CDCl3) proportions of diastereoisomers 1.00 / 0.77 = majority / minority, 8: 8.06-8.28 (s, 1H), 7.68-7.76 (d, 1H), 7.44-6.98 (m, 8H), 4.25-3.93 (s, 2H), 3.78-3.82 (s, 3H), 2.97-2.99 (q, 211), 1.41-1.43 (t, 3H). Step B: Methyl 2-benzyl-3- (2-ethylbenzothiophen-4-yl) -propanoate 432 mg of (Z) -2-benzyl-3- (2-ethylbenzothiophen-4-yl) prop-2-enoate Methyl (1.28 mmol), 137 mg of 10% Pd / C, 5 ml of AcOH and 20 ml of MeOH were allowed to stir under an atmosphere of 1-12 of 4 bar at RT until no longer observe conversion. The mixture was filtered through celite, the filtrate was concentrated under reduced pressure and purified by flash chromatography using heptane and EtOAc as eluents to give 2-benzyl-3- (2-ethylbenzothiophen). -4-yl) methyl propanoate. NMR11 (400 MHz, CDCl3) δ: 7.61 (d, 1H), 7.38-7.05 (m, 7H), 6.80 (s, 1H), 3.50 (s, 3H), 3.28-3.18 (m, 1H), 3.11-3.00 (m, 311), 2.90 (q, 2H), 2.86-2.77 (m, 1H), 1, (T, 3H). Step C: Methyl 2-benzyl-3- (2-ethyl-3-iodo-benzothiophen-4-yl) propanoate 346 mg of methyl 2-benzyl-3- (2-ethylbenzothiophen-4-yl) -propanoate 20 (1.02 Immo), 305 mg of I2 (1.2 mmol) and 468 mg of Ag2SO4 (1.5 mmol) were dissolved in 5 ml of EtOH and stirred at RT until The mixture was filtered, the filtrate was concentrated under reduced pressure and purified by flash chromatography using heptane and EtOAc as eluents to give 2-benzyl-3- (2-ethyl) Methyl 3-iodo-benzothiophen-4-yl) propanoate 1H NMR (400MHz, CDCl3) δ: 7.67 (dd, 111), 7.28-7.06 (m, 7H), 4, 29-4.17 (m, 1H), 3.80-3.71 (in, 1H), 3.32 (s, 3H), 3.28-3.21 (in, 1H), 3.08- 3.00 (in, 2H), 2.97 (q, 2H), 1.35 (t, 3H) Step D: Example 54 1 eq of 2-benzyl-3- (2-ethyl-3-iodo) Methyl benzothiophen-4-yl) propanoate, 2 eq of Preparation 3a, 2 eq of a solution of TBAOH (1M in water), 0.1 eq of Ataphos and 2-Me- TH F (5 ml / mmol of benzothiophene derivative) was stirred under an N 2 atmosphere at 100 ° 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 formed intermediate was dissolved in MeOH (5 ml / mmol benzothiophene derivative), 10 eq. LiOH x H2O was added, and the mixture was stirred at RT until no further conversion was observed. It was neutralized with a 2M aqueous HCl solution 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 0.1% aqueous TFA and MeCN as eluents to give Example 54. High resolution mass (HRMS) calculated for C27H25ClO3S: 464.1123 found: 463.1158 (MH). Example 55: (2R) -2411-13-Chloro-2-methyl-4- [2- (4-methylpiperazin-1-yl) -ethoxylphenyl] -2- (4-fluoro-phenyl) -1H-indol-7-acid 2-methoxyphenylpropanoic acid and Example 56: (2R) -2-1 [1- {3-chloro-2-methyl-442- (4-methylpiperazin-1-yl)} - ethoxylphenyl) -2- (4-fluoro-phenyl) -1H-indol-7-yloxy-3- (2-methoxyphenyl) propanoic acid 600 mg of Preparation 7h (0.86 mmol) were dissolved in 20 ml of the mixture Dioxane / water 1: 1 and 600 mg of LiOH x H2O were added. The mixture was stirred at RT until no further conversion was observed. Then it was diluted with water, acidified with 1M aqueous HCl and extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure and purified by reverse phase preparative chromatography using a 25 mM aqueous solution of NH4HCO3 and MeCN as eluents. Example 55 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C38H39ClFN3O5: 671.2562, found: 672.2618 (M + H). Example 56 was obtained as the last eluted diastereoisomer. High resolution mass (HRMS) calculated for C38H39ClFN3O5: 671.2562, found: 672.2652 (M + H). EXAMPLE 57 (2R) -2-113-Chloro-1- {3-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxy] phenyl} -2- ( 4-fluoro (phenyl) -111-indol-7-yl] oxy} -3- (2-methoxyphenyl) -propanoic acid 240 mg of Preparation 7b (0.34 mmol) was dissolved in 3 ml of DCM and 5 ml. 46 mg of NCS (0.34 mmol) was added. The mixture was stirred at RT until no further conversion was observed. Then it was diluted with water and extracted with DCM. The combined organic phases were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Then, it was dissolved in 5 ml of dioxane / water 1: 1 and 140 mg of LiOH x 1420 was added. The mixture was stirred at RT until no further conversion was observed. Then it was diluted with water, acidified with 1M aqueous HCl 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 25 mM aqueous NH4HCO3 and MeCN as eluents. Example 57 was obtained as the last eluted diastereoisomer. High resolution mass (HRMS) calculated for C381-138C12FN3O5: 705.2173, found: 706.2227 (M + H). Example 58: (2R) -2 - {[1-13-Chloro-2-methyl-4- [2- (4-methylpiperazin-1-yl) -ethoxy] phenyl} -2- (furan-2-) acid Y1) -1H-indol-7-yl] oxy} -3- (2-methoxyphenyl) propanolic acid and Example 59: (2R) -2-1 [1- {3-chloro-2-methyl-442- (4 1-methylpiperazin-1-yl) -ethoxylphenyl} -2- (furan-2-yl) -1H-indol-7-yloxy) -3- (2-methoxyphenyl) propanoic acid and Example 60: (2R) -2- (11-O-Chloro-2-methyl-4124-methyl-piperazin-1-yl) ethoxy] phenyl} -245-fluoro-furan-2-yl) -1H-indol-7-yl] oxy} -3- (2- Step A: 4- [7-Benzyloxy-2- (5-flitero-2-fittyl) indol-1-yl] -2-chloro-3-methyl-phenol 1360 mg of Preparation 7a (2 mmol) (methoxypbenyl) propanoic ), 848 mg of 2- (5-fluoro-2-furyl) -4,4,5,5-tetramethyl-1,3,2-dioxa-borolane (4 mmol), 2123 mg of K3PO4 (10 mmol), 45 mg of Pd (OAc) 2 (0.2 mmol) and 164 mg of SPhos (0.4 mmol) were dissolved in 30 ml of anhydrous toluene and stirred at 75 ° C until the reaction was complete. no longer observe conversion. The solvent was then removed under reduced pressure and the residue was purified by flash chromatography using heptane and EtOAc as eluents. Then 2 ml of TBAF solution (2 mmol, 1M in THF) and 25 ml of THF were added and the mixture was stirred at RT until no further conversion was observed. Then, the mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography using heptane and EtOAc as eluents to give 4- [7-benzyloxy-2- (5-fluoro) 2-furyl) indol-1-y1] -2-chloro-3-methylphenol. MS: (M + H) + - 448.0.
[0092] Step B: 7-Benzyloxy-1β-chloro-2-methyl-4- (4-methylpiperazin-1-yl) ethoxy-2-phenyl-2- (57-fluoro-2-yl) indole 650 mg of 447-benzyloxy-2- (5- fluoro-2-furyl) -indol-1-yl-2-chloro-3-methylphenol (1.01 mmol), 288 mg of 1- (2-hydroxyethyl) -4-methylpiperazine (2 mmol) and 786 mg of PPh3 (3 mmol) was dissolved in 20 ml of anhydrous toluene. Then, 690 mg of DTAD (3 mmol) was added and the mixture was stirred at 45 ° C until no further conversion was observed. Then it was concentrated under reduced pressure and purified by flash chromatography using DCM and MeOH as eluents to give 7-benzyloxy-143-chloro-2-methyl-442- (4-methyl-piperazin-1) -y1) ethoxylphenyl] -2- (5-fluoro-2-furyl) indole. MS: (M + H) + = 574.2. Step C: Mixture of 1-P-chlora-2-methyl-4-12- (4-methylpiperazin-1-Aethoxylphenyl) -2- (2-finyl) indol-7-ol and 1-p-chloro-2-methyl-4- 12- (4-methylpiperazin-1-aelhoxylphenyl) -2- (5-atoro-2-furyl) indol-7-ol 1300 mg of 7-benzyloxy-143-chloro-2-methyl-44244-methylpiperazin-1-yl ) - ethoxylphenyl] -2- (5-fluoro-2-furypindole (2.26 mmol) were dissolved in 100 ml of MeOH and 100 mg of 10% Pd / C was added. under an H 2 atmosphere of 1 bar at rt overnight The mixture was filtered through celite and the filtrate was concentrated under reduced pressure to give a 7/3 mixture of 143-chloro-2-methyl- 442- (4-methylpiperazin-1-yl) ethoxy] phenyl] -2- (2-furypindol-7-01 (SM: (M + H) + = 466.2) and 143-chloro-2-methyl- 442- (4-methylpiperazin-1-yl) ethoxylphenyl-2- (5-fluoro-2-furypindol-7-ol (MS: (M-FH) + = 484.2) Step D: Examples 58, 59 and 60 465 mg of the 7/3 mixture containing 143-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxylphenyl-2 - (2-furypindol-7-O) and 1- [3-chloro-2-methyl-4- [2- (4 methyl (1 -ypethoxylphenyl-2,45-fluoro-2-furyl) indol-7-ol (1 mmol), 449 mg of ethyl (2S) -2-hydroxy-3-phenylpropanoate (2 mmol) and 786 mg of PPh 3 (3 mmol) was dissolved in 10 ml of anhydrous toluene. Then, 691 mg of DTAD (3 mmol) was added and the mixture was stirred at 45 ° C until no further conversion was observed. Then, it was concentrated under reduced pressure, and the residue was purified by flash chromatography using DCM and MeOH as eluents. Then, it was dissolved in 5 ml dioxane / water 1/1 and 140 mg LiOH x H2O were added. The mixture was stirred at RT until no further conversion was observed. Then it was diluted with water, acidified with 1M aqueous HCl 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 an aqueous 25 mM NH4HCO3 solution and MeCN as eluents. Example 58 was obtained as the diastereoisomer eluted first. High resolution mass (HRMS) calculated for C36H38ClN3O6: 643.2449, found: 644.2512 (M + H). Example 59 was obtained as the last eluted diastereoisomer. High resolution mass (HRMS) calculated for C36H38ClN3O6: 643.2449, found: 644.2521 (M + H). Example 60 was obtained as the last eluted diastereoisomer. High resolution mass (HRMS) calculated for C36H37ClFN3O6: 661.2355, found: 662.2411 (M + H).
[0093] Example 61: (2R) -2-1 [3-O-Chloro-2-methyl-4-12- (4-methylpiperazin-1-yl) -ethaxylphenyl) -2- (4-fluoro-phenyl) - 1-Benzofuran-4-yloxy) -3- (2-methoxyphenyl) -prapanoic acid and Example 62: (2R) -2- {13- {3-chloro-2-methyl-4-12- 4-methylpiperazin-1-yl) -ethoxylphenyl} -2- (4-fluoro-phenyl) -1-benzofuran-4-yloxy) -3- (2-methoxyphenyl) propanoic Step A: (2S) -3 Ethyl (2-methoxyphenyl) -2- (p-tolylsulfonyloxy) propanoylate 3000 mg of Preparation 2f (13.38 mmol) were dissolved in 10 ml of pyridine and 2933 mg of TsCl (15.38 mmol). were added at 0 ° C. The mixture was stirred at RT until. no longer observe conversion. Then, the mixture was diluted with water and extracted with EtOAc. The combined organic phases were washed with 1M aqueous citric acid solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give (2S) -3- (2-methoxyphenyl) -2- (ethyl ptolylsulfonyloxy) propanoate. MS (EI, 70 eV) m / z (relative intensity in%, [ion]): 65 (7), 77 (14), 91 (49), 123 (33), 133 (33), 165 (100) , 207 (65), 307 (13), 512 (7, [M1).
[0094] Step B: (2R) -2 (3-Rhomo-2-O-fluorophenyl) benzofitran-4-yloxy-342-methoxyphenyl) ethyl-prapanoate 1 eq. Preparation Ic, 1.5 eq. ethyl (2S) -3- (2-methoxyphenyl) -2- (p-tolylsulfonyloxy) propanoate, 2 eq. K2CO3 and DMSO (10 ml / mmol benzofuran derivative) were stirred at 60 ° C under N2 atmosphere until no further conversion was observed. Then, the mixture was diluted with brine, neutralized with 1M aqueous HCl 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 flash chromatography using heptane and EtOAc as eluents to give (2R) -2- [3-bromo-2- (4-fluorophenyl) benzofuran-4-yl] oxy- Ethyl 3- (2-methoxy-phenyl) propanoate MS (EI, 70 eV) trilz (relative intensity in%, [ion]): 91 (56), 133 (41), 165 (100), 207 ( 93), 281 (26), 305 (9), 512 (3, [M +]), 514 (3, Step C: Examples 61 and 62) 34 Following general procedure VI and taking (2R) -243- Ethyl bromo-2- (4-fluorophenyl) benzofuran-4-yl-oxy-3- (2-methoxyphenyl) propanoate as the appropriate 3-bromo-benzofuran derivative and Preparation 3b as the acid derivative 3037959 In the appropriate boronic form, Example 61 was obtained as the diastereoisomer eluted first.High resolution mass (HRMS) calculated for C38H38ClFN2O6: 672.2402, found: 673.2465 (M + H). obtained in the form of the last eluted diastereoisomer.High resolution mass (HRMS) calculated for C38H38ClFN2O6: 672.2402, found: 673.2486 (M + H). Example 63: (2R) -24 [3- {3-chloro-2-methyl-442- (4-methyl-piperazin-1-yl) -ethoxyl-phenyl-2- (4-fluoro-phenyl) -1-benzofuran-4-acid) -yljoxyl-3- (2 - {[2- (2-methoxyphenyl) pyrimidin-4-yl] methoxylphenyl) propandyl and Example 64: (2R) -24 [343-chloro-2-methyl-442- (4 methylpiperazin-1-yl) -ethoxyl-phenyl-2- (4-fluoro-phenyl) -1-benzofuran-4-yloxy-3- (2 - {[2- (2-methoxyphenyl) pyrimidine} 4-aminophenyl) propenoic acid Step A: (2R) -2-P-hromo-2- (4-fluorophenyl) benzofitran-4-yloxy-312-12- (2-methoxyphenyl) Ethyl pyrimidin-4-yloxy-phenylpropanoate Following General Procedure V and taking Preparation 1e as the appropriate benzofuran-4-ol derivative and Preparation 2d as the appropriate lactic ester derivative, the (2R) -243- Ethyl bromo-2- (4-fluoro-phenyl) benzofuran-4-yloxy-34242- (2-methoxyphenyl) -pyrimidin-4-yl] oxyphenylipropanoate was obtained. MS: (M + H) 4 = 699.2. Step B: Examples 63 and 64 Following general procedure VI and (2R) -2- [3-bromo-2- (4-fluorophenyl) benzofuran-4-yl] oxy-34242- (2-methoxy) phenyl) pyridin Ethyl 4-yljoxyphenyl] propanoate as the appropriate 3-bromo-benzofuran derivative and Preparation 3h as the appropriate boronic acid derivative, Example 63 was obtained as the diastereoisomer eluted first. HRMS) calcd for C49H46ClFN4O7: 856.3039, found: 429.1582 (M + 2H) Example 64 was obtained as the last eluted diastereoisomer High resolution mass (HRMS) calculated for C49H46ClFN4O7: 856, 3039, found: 429.1604 (M + 2H) Example 65: (2R) -2- [343-chloro-2-methyl-4-12- (4-methylpiperazin-1) acid ethoxyl phenyl-2- (4-fluoro-phenyl) -1-benzofuran-4-yl-oxy} -312- (2,2,2-trifluoroethoxy) phenyl] -propanolic acid Step A: (2R) ) -243-bromo-2- (4-fluorophenyl) benzofuran-4-yloxy-3-P- (2,2,2-t) Ethyl rifluoroethoxy) phenylipropanoate Following General Procedure V and taking Preparation 1α as the appropriate benzofuran-4-ol derivative and Preparation 2h as the appropriate lactic ester derivative, the (2R) -243-bromo-2- Ethyl (4-fluoro-phenyl) benzo-furan-4-yloxy-3,442,2,2-trifluoroethoxy) phenyl] propanoate was obtained. MS: (M + Na) + = 604.4. Step B: Example 65 Following general procedure VI and (2R) -243-bromo-2- (4-fluorophenyl) benzofuran-4-yl] oxy-342- (2,2,2-trifluoroethoxy) ethyl phenylpropanoate as the appropriate 3-bromo-benzofuran derivative and Preparation 3b as the appropriate boronic acid derivative, Example 65 was obtained as the last eluted diastereoisomer. High resolution mass (HRMS) calculated for C 39 H 37 ClF 4 N 2 O 6 740.2276, found: 741.2372 (M + H).
[0095] Example 66: (2R) -2 - ([343-Chloro-2-methyl-442- (4-methylpiperazin-1-yl) -ethoxylphenyl-6-fluoro-2- (4-fluorophenyl) -1-henzofuran) 4-ylloxyl-3-12- (2,2,2-trifluoroethoxy) phenylpropane Step A: (2R) -2- [3-bromo-67-fluoro-2- (47-fluorophenyl) -henzofur-1-yl] oxy-3 Ethyl P- (2,2,2-trifluoroethoxy) -phenyl] propatylate Following general procedure V and taking Preparation 1d as the appropriate benzofuran-4-ol derivative and Preparation 2h as ester derivative. Suitable lactic acid, (2R) -243-bromo-6-fluoro-2- (4-fluorophenyl) benzofuran-4-yloxy-3- [2- (2,2,2-trifluoroethoxy) phenyl] propanoate Ethyl was obtained NMR 11-1 (400 MHz, DMSO-d6): 8.07 (m, 2H), 7.43 (m, 311), 7.27 (in, 2H), 7.11 (m.p. in, 1H), 6.98 (m, 1H), 6.55 (cid, 1H), 5.23 (m, 111), 4.82 (q, 2H), 4.12 (q, 2H), 3.37 (in, 1H), 3.25 (m, 1H), 1.10 (t, 3H).
[0096] Step B: Example 66 Following general procedure VI and taking (2R) -243-bromo-6-fluoro-2- (4-fluorophenyl) benzo-furan-4-yloxy-342- (2,2, Ethyl 2-trifluoroethon) phenylpropanoate as the appropriate 3-bromo-benzofuran derivative and Preparation 3b as the appropriate boronic acid derivative, Example 66 was obtained as the last eluted diastereoisomer. High resolution mass (HRMS) calculated for C39H36ClF5N2O6: 758.2182, found: 759.2244 (M + H).
[0097] Example 67: (2R) -2 - {(3- {3-Chloro-2-methyl-4-12- (4-methylpiperazin-1-yl) -ethoxylphenyl} -6-fluoro-2- (4-) fluoroPhenyl) -1-benzofuran-4-yloxy} -3- (2- (2- [2- (2-methoxyphenyl) pyrimidin-4-yl] metboxy} phenyl) propanoic acid Step A: (2R) -2-13-bromo Ethylfluoro-2- (4-fluorophenyl) -henzofuran-4-yl] oxy-3-12-112- (2-methoxyphenyl) -pyrimidin-4-ylmethoxy] phenylpropanoate Following general procedure V and taking Preparation Id as the appropriate benzofuran-4-ol derivative and Preparation 2d as the appropriate lactic ester derivative, (2R) -243-bromo-6-fluoro-2- (4-fluorophenyl) benzofuran-4-yloxy Ethyl 34242- (2-methoxy-phenyl) pyrimidin-4-ylmethoxylphenyl] propanoate was obtained.
[0098] NMR (400MHz, DMSO-d6): 8.86 (d, 1H), 8.05 (m, 2H), 7.61 (d, 1H), 7.52 (dd, 1H), 7.48; -7.38 (m, 4H), 7.25 (in, 1H), 7.21 (m, 1H), 7.12 (n, 211), 7.03 (td, 1H), 6.94 ( td, 1H), 6.67 (dd, 1H), 5.40 (1H), 5.26 (s, 2H), 4.15 (q, 2H), 3.75 (s, 3H), 3.56 (m, 1H), 3.30 (nl, 1H), 1.12 (t, 3H).
[0099] Step B: Example 67 Following general procedure VI and taking (2R) -243-bromo-6-fluoro-2- (4-fluorophenyl) benzo-furan-4-yloxy-342 - [[2- ( Ethyl 2-methoxyphenyl) pyrimidin-4-yl] methoxy] phenylpropanoate as the appropriate 3-bromobenzofuran derivative and Preparation 3b as the appropriate boronic acid derivative, Example 67 was obtained as the diastereoisomer eluted last. High resolution mass (HRMS) calculated for C49H45ClF2N4O7: 874.2945, found: 438.1543 (M + 2H). Example 68: (2R) -2 - ([3-13-Chloro-2-methyl-442- (4-methylpiperazin-1-yl) -ethoxylphenyl] -2- (4-fluoro-phenyl) acid 1-methyl-1H-indol-4-yl] oxy-3- (2- {12- (2-methoxyphenyl) pyrimidin-4-yl] methoxy} phenyl) propandyl and Example 69: (2R) -24 [3- {acid 3-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxylphenyl} -2- (4-fluoro-phenyl) -1-methyl-1H-indol-4-yl] oxy} -3- - (T2- (2-Methoxyphenyl) pyrimidin-4-ylmethoxy) phenyl) propanoic Step A: 1- (Benzenesulfonyl) -4-benzyloxyindok 7.0 g 4-Benzyloxy-1H-indole (31.35 mmol) ) were dissolved in 60 ml of anhydrous DMF and 1.317 g of NaH (32.92 mmol, 60% in mineral oil) was added at 0 ° C. The mixture was stirred for 1 hour, then 6 minutes. 09 g of benzenesulfonyl chloride (34.48 mmol) was added dropwise and the mixture was stirred at 0 ° C until no further conversion was observed. 15 water and extracted with DCM The combined organic phases were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure and purified by flash chromatography using heptane and EtOAc as eluents to give 1- (benzenesulfonyl) -4-benzyloxy-indole. IZMNIH (400MHz, DMSO-d6) δ: 7.97 (d, 21-1), 7.72 (d, 11-1), 7.69 (t, 111), 7.59 (t, 20H). ), 7.54 (d, 1H), 7.47 (d, 2H), 7.39 (t, 2H), 7.33 (d, 1H), 7.27 (t, 1H), 6.89; (d, 1H), 6.85 (d, 1H), 5.20 (s, 2H). MS (EI, 70 eV) rn / z (relative intensity in%, [ion]): 77 (32), 91 (100), 141 (18), 222 (6), 272 (11), 363 (10, [M +]).
[0100] Step B: 1- (benzenesulfonyl) -4-benzyloxy-2-iadoindole 5.08 g of 1- (benzenesulfonyl) -4-benzyloxyindole (13.98 mmol) was dissolved in 140 ml of anhydrous THF . 8.54 ml of a solution of LDA (15.38 mmol, 1.8M in THF-heptane-ethylbenzene) was added at -78 ° C and the mixture was stirred for 1 hour. Then 4.26 g of iodine (16.8 mmol) was added and the mixture was stirred for 1 hour at -78 ° C. The mixture was quenched with saturated aqueous NH4Cl solution and extracted with EtOAc. The combined organic phases were washed with aqueous Na2S2O3 solution and water, then 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 to give 1- (benzenesulfonyl) -4-benzyloxy-2-iodoindole. NMR (400 MHz, DMSO-d6) δ: 7.86 (dd, 2H), 7.75 (d, 1H), 7.70 (d, 1H), 7.61 (t, 2H), 7.47; (dd, δ 2H), 7.39 (t, 2H), 7.33 (d, 1H), 7.23 (t, 1H), 7.18 (s, 1H), 6.90 (d, 1H). ), 5.20 (s, 2H) Step C: Mbenzenesulfonyl) -4-benzyloxy-2- (4-flitoro-preindole) 5.8 g of 1- (benzenesulfonyl) -4-benzyloxy-2-iodoindole (11) 86 mmol) and 4.16 g of 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) fluorobenzene (14.22 mmol) were dissolved in 75 ml. ml of THF, then 7.73 g of Cs2CO3 (23.72 mmol), 420 mg of Ataphos (0.59 mmol) and 25 ml of water were added and the mixture was stirred at 70 ° C. The mixture was then concentrated under reduced pressure and purified by flash chromatography using heptane and EtOAc as eluents to give 1- (benzenesulfonyl) - 4-Benzyloxy-2- (4-fluorophenyl) indole 1H NMR (400MHz, DMSO-d6) δ: 7.79 (d, 1H), 7.67 (m, 1H), 7.60-7. , 48 (m, 6H), 7.43-7.25 (in , 8H), 7.00 (d, 1H), 5.57 (s, 1H), 5.22 (s, 2H). Step D: 1- (benzenesulfonyl) -4-benzyloxy-2- (4-fluorophenyl) -3-iodoindole 4.92 g 1- (benzenesulfonyl) -4-benzyloxy-2- (4-fluorophenyl) indole (10.75 mmol), 3.69 g of Ag2SO4 (11.83 mmol) and 3.0 g of iodine (11.83 mmol) were stirred in 100 ml of EtOH at RT until the reaction was complete. The mixture was then concentrated under reduced pressure and purified by flash chromatography using heptane and EtOAc as eluents to give 1- (benzenesulfonyl) -4-benzyloxy-2-ene. (4-fluorophenyl) -3-iodoindole MS: (M + H) + = 584.2.
[0101] Step E: 1- (Benzenesulfonyl) -4-benzyloxy-3-p-chloro-2-methyl-4-12- (4-methylpiperazinylethoxyphenyl) -2- (4-fluorophenyl) indole 5.5 g. (benzenesulfonyl) -4-benzyloxy-2- (4-fluorophenyl) -3-iodo-indole (9.42 mmol), 4.46 g of Preparation 3b (11.31 mmol), 6.14 g of Cs2CO3 (18.4 g). 84 mmol) and 354 mg Ataphos (0.5 mmol) were dissolved in 100 ml THF / water 3/1 and stirred at 70 ° C under N 2 until no further conversion was observed. The mixture was concentrated under reduced pressure and purified by flash chromatography using heptane, EtOAc and MeOH as eluents to give 4- (benzenesulfonyl) -4-benzyloxy-343-chloro. 2-methyl-4- [4- (4-methylpiperazin-1-yepethoxy) phenyl] -2- (4-fluorophenyl) indindol NMR (400MHz, DMSO-d6) δ: 7.85 (d, 1H), 7.67 (t. , 1H), 7.61-6.90 (nl, 2H), 7.53-7.47 (in, 4H), 7.4 (t, 1H), 7.20-7.07 (m, 5H), 6.96 (d, 1H), 6.77 (d, 1H), 6.73 (d, 1H), 6.66 (d, 2H), 4.96 (d, III), 4, 86 (d, 1H) , 4.09 (m, 1H), 4.00 (in, 1H), 3.34 (bs, 4H), 2.75 (t, 2H), 2.58 (bs, 4H), 2, (S, 311), 1.81 (s, 3H). MS: (M + H) + = 724.2.
[0102] Step F: 4-Benzyloxy-3-β-chloro-2-methyl-4-12- (4-methylpiperazin-1-yl) ethoxylphenyl] -2- (4-fluorophenyl) -111-indole 6.5 g 1- (benzenesulfonyl) 4-Benzyloxy-343-chlom-2-methyl-442- (4-methylpiperazin-1-yepethoxy) -phenyl-2- (4-fluorophenyl) indole (8.97 mmol) was dissolved in 100 ml of THF and 100 ml MeOH followed by 28.3 g Ba (OH) 2 × 8 H 2 O (89.7 mmol) were added and the mixture was stirred at 70 ° C until no further conversion was observed. The mixture was then filtered, the filtrate was concentrated under reduced pressure and purified by flash chromatography using DCM and MeOH as eluents to give 4-benzyloxy-3 - [3-chloro-2-methyl-442- (4-methylpiperazin-1-yepethoxy) phenyl] -2- (4-fluorophenyl) -1H-indole MS: (M + H) + = 584.2.
[0103] Step G: 4-Benzyloxy-3-β-chloro-2-methyl-4-β- (4-methylpiperazin-1-yl) ethoxylphenyl-2- (4-flitorophenyl) -1-methyl-indok 1.626 g 4-benzyloxy 343-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxylphenyl-2- (4-fluoro-phenyl) -1H-indole (2.78 mmol) was dissolved in 25 ml. DMF anhydrous and cooled to 0 ° C. Then 123 mg of NaH (3.06 mmol, 60% in mineral oil) was added and the mixture was stirred for 1 hour and then 395 mg Methyl iodide (2.78 mmol) was added and the mixture was stirred for 1 hour The mixture was then poured into water and extracted with DCM 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 flash chromatography using DCM and MeOH as eluents to give 4-benzyloxy-343- chloro-2-m ethyl-442- (4-methylpiperazin-1-yl) -ethoxy-phenyl] -2- (4-fluorophenyl) -1-methylindole. 1H NMR (400MHz, DMSO-d6) δ: 7.31 (dd, 2H), 7.24-7.10 (m, 7H), 6.97 (d, 1H), 6.83-6.76. (in, 3H), 6.68 (dd, 1H), 5.01 (d, 1H), 4.93 (d, 1H), 4.14 (m, 1H), 4.06 (m, 1H) , 3.63 (s, 3H), 3.10-2.60 (bs, 8H), 2.84 (bs, 2H), 2.58 (s, 3H), 2.04 (s, 31). -1).
[0104] Step H: 3-13-Chloro-2-methyl-4- [2- (4-methylpiperazin-1-yl) oxypropyl] -2- (4-fluorophenyl) -1-methylindol-4-ol 1.6 g 4-Benzyloxy-343-chloro-2-methyl-442- (4-methylpiperazinyl-1-yl) ethoxylphenyl-2- (4-fluorophenyl) -1-methylindole (2.68 mmol) was dissolved in 10 ml DCM. and 1 eq of HBr (33% solution in AcOH) was added The mixture was stirred at RT until no further conversion was observed The mixture was then diluted with aqueous solution The combined organic phases were washed with brine, dried over MgSO 4, filtered and the filtrate was concentrated under reduced pressure The crude product was purified by flash chromatography using 10% K 2 CO 3 and extracted with DCM. DCM and MeOH as eluents, followed by reverse phase preparative chromatography using 25mM aqueous NH4HCO3 and MeCN as eluents to give 3- [3-chloro-2-methyl-4- [ 2- (4-methylpiperazin-1-yl) ethoxy] phenyl] -2- (4-fluorophenyl) -1-methylindol-4-ol. 1H NMR (400 MHz, DMSO-d 6) δ: 9.02 (s, 1H), 7.29-7.15 (m, 4H), 7.06-6.92 (m, 2H), 6 , 86 (d, 1H), 6.78 (d, 1H), 6.38 (dd, 1H), 4.07 (m, 2H), 3.58 (s, 3H), 2.70 (t, 2H), 2.58-2.40 (bs, 4H), 2.40-2.19 (bs, 4H), 2.19 (s, 3H), 2.09 (s, 3H). MS: (M + H) + = 508.2. Step I: (2S) -3-12-112- (2-methoxyphenyl) pyrimidin-4-ylmethylphenyl] -2- (p-tolylsulfonyloxy) ethylprapanoate 3.66 g Preparation 2 (1 (8.97 mmol) were dissolved in 12 ml of pyridine and 1.97 g of TsCl (10.31 mmol) was added at 0 ° C. The mixture was stirred at RT until no further conversion was observed. The combined organic phase was washed with 1M aqueous citric acid solution, dried over MgSO 4, filtered and the filtrate was concentrated under reduced pressure. to give ethyl (2S) -3424 [2- (2-methoxyphenyl) pyrimidin-4-yl] methoxy] phenyl] -2- (p-tolylsulfonyloxy) propanoate (NMR (400 MHz, DMSO-d6)) : 8.93 (d, 1H), 7.58 (dd, 1H), 7.52-7.43 (m, 21-1), 7.43-7.34 (m, 21-0.7, 26-7.15 (m, 4H), 7.13-7.04 (in, 2H), 6.93-6.83 (m, 21-1), 5.12 (d, 1H), 5, 03-4.92 (m, 2H), 4.01 (q, 21-I), 3.79 (s, 3H), 3.26 (dd, 1H), 3.01 (b.p. dd, 1H), 2.36 (s, 3H), 1.12 (t, 3H) MS: (M + H) + = 563.2. Step J: Examples 68 and 69 60 mg of 3 - [3-chloro-2-methyl-442- (4-methyl-piperazin-1-yl) ethoxy] phenyl] -2- (4-fluorophenyl) -1-methyl -indol-4-ol (0.12 mmol), 101 mg of (2S) -3- [2 - [[2- (2-methoxyphenylpyrimidin-4-yl) methoxylphenyl] -2- (p-tolylsulfonyloxy) propanoate of ethyl (0.18 mmol) and 80 mg of Cs 2 CO 3 (0.24 mmol) were dissolved in 2 ml of anhydrous DMF and stirred at 50 ° C. until no further conversion was observed. LiOH x H 2 O were added and the mixture was stirred at RT until no further conversion was observed.The mixture was concentrated and purified by reverse phase preparative chromatography using NI-141 aqueous solution. 25mM -1CO3 and MeCN as eluents to obtain Example 68 as the diastereoisomer eluted first High resolution mass (HRMS) calculated for C501-149CIFN506 869.3355, found: 435.6743 (M + 2H) Example 69 was obtained under Diastereoisomeric form eluted last High resolution mass (HRMS) calcd for C 50 H 49 ClFN 5 O 6: 869.3355, found: 435.6767 (M + 2H). Example 70: N-13- (3-chloro-2-methylphenyl) thienoP, 2-elpyridin-1-yl-D-phenylalanine Step A: 4-Bromo-N- (dimethoxymethyl) thiophene-3-carboxamide 5.01 g 4-bromothiophene-3-carboxylic acid (24.2 mmol) was dissolved in 25 ml of isopropyl acetate and 17.9 ml of SOCl 2 (242 mmol) was added and the mixture was stirred at room temperature. 50 ° C for 2 hours. Then, the excess SOC12 was distilled off and the residue was dissolved in 25 ml of isopropyl acetate and cooled to 10 ° C. 10.6 ml of DIPEA (60.5 mmol) and 4.0 ml of aminoacetaldehyde dimethyl acetal (36.3 mmol) were added. The mixture was allowed to warm to RT and stirred under N 2 overnight. The mixture was diluted with 10% aqueous H3PO4 and extracted with isopropyl acetate. The combined organic phases were washed with 10% aqueous KH2PO4 solution and brine, then dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure to give 4-bromo-N- (dimethoxymethyl) thiophene. 3-carboxamide.
[0105] 1H NMR (400 MHz, DMSO-d6) δ: 8.36 (t, 1H), 7.93 (d, 1H), 7.72 (d, 1H), 4.48 (t, 1H), 3, 31-3.28 (m, 8H). MS (M + H): 294.0. Step B: 3-bromo-511-thieno [3,2-c] pyridin-4-one 32 mg of 4-bromo-N- (dimethoxymethyl) thiophene-3-carboxamide (0.102 mmol) was dissolved in 1 ml of PPA and stirred at 100 ° C under an argon atmosphere until no further conversion. The mixture was then poured on ice, and the precipitate formed was filtered and washed with water to give 3-bromo-5Hthieno [3,2-c] pyridin-4-one. MS (M + 11): 229.9.
[0106] Step C: 3-bromo-4-chloro-thieno [3.2-e] pyridine 1.06 g of 3-bromo-5H-thieno [3,2-c] pyridin-4-one (4.4 mmol) ), 560 μl of N, N-dimethylaniline (4.4 mmol) and 8.37 ml of POCl3 (88 mmol) were stirred at 100 ° C until no further conversion was observed. The reaction mixture was then poured over ice and extracted with DCM. The combined organic phases were washed with saturated aqueous NaHCO 3 solution and brine, dried over Na 2 SO 4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography using heptane and EtOAc as eluents to obtain 3-bromo-4-chloro-thieno [3,2-c] pyridine. MS (M + H): 247.9.
[0107] Step D: 3,4-dibromothiena [3,2-c] pyridine 735 mg of 3-bromo-4-chloro-thieno [3,2-c] pyridine (2.8 mmol) and 2.288 g of bromotrimethylsilane (14 , 5 mmol) were dissolved in 15 ml of propionitrile and stirred at 100 ° C until no further conversion was observed. The reaction mixture was then concentrated under reduced pressure and purified by reverse phase preparative chromatography using a 40 mM aqueous solution of NH 4 OAc (pH = 4, adjusted with AcOH) and MeCN as eluents. to obtain 3,4-dibromothieno [3,2-c] pyridine. MS (M + H): 291.8. Step E: (210-2 - [(3-bromothiero [3,2-c] pyridin-1-yl) -amino] -3-phenylpropanoic acid 340 mg of 3,4-dibromothieno [3,2-dibromothieno] c] pyridine (1.16 mmol) and 718 mg of D-phenylalanine (4.35 mmol) were dissolved in 7.5 ml of sulfolane, followed by 421 mg of potassium fluoride (7.25 mmol) and 23 g of 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo [8.8.8] hexacosane (5.8 mmol) was added and the mixture was stirred at 175 ° C. The reaction mixture was injected directly and purified by reverse phase preparative chromatography using a 40 mM aqueous solution of NH 4 OAc (pH = 4, adjusted with of the AcOH) and MeCN as eluents to obtain (2R) -2 - [(3-bromo-thieno [3,2-c] pyridin-4-yl) aminol-3-phenylpropanoic acid.
[0108] Step F: Example 70 189 mg of (2R) -2 - [(3-bromothieno [3,2-e] pyridin-4-ylamine] -3-phenylpropanoic acid (0.5 mmol) and 341 mg of (3-chloro-2-methylphenyl) boronic acid (2 mmol) were dissolved in 3.5 ml of DME, then 72 mg of butyldi-1-adamantylphosphine (0.2 mmol), 22 mg of Pd ( OAc) 2 (0.1 mmol) and 389 mg of TBAOH (1.5 mmol) were added and the mixture was stirred at 100 ° C under an argon atmosphere until no further conversion was observed. Then, the mixture was poured into ice-cold water and extracted with MTBE The aqueous phase was acidified to pH 2 and extracted with DCM The combined organic phases were dried over Na 2 SO 4, filtered and filtered. The filtrate was concentrated under reduced pressure The crude product was purified by reverse phase preparative chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents to obtain Example 70. High solute mass n (HRMS) calculated for C23H19ClN2O2S: 422.0856, found: 423.0937 and 423.0919 for both diastereomers (M + H).
[0109] Example 71: (2R) -24 [3-13-Chloro-2-methyl-4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl} -2- (4-fluoro-phenyl) thieno acid [2,3-b] pyridin-4-yl] oxy} -3- (2- {12- (2-methoxyphenyl) pyrimidin-4-ylmethoxy) phenyl) propanoic acid. Step A: 2-chloro-3 In a dry flask, 3.85 g of 3-bromo-2-chloropyridine (20 mmol), 0.23 g of CuI (1.2 mmol) and 0, 42 g of PdCl2 (PPh3) 2 (0.6 mmol) was added to 40 ml of anhydrous TEA.
[0110] After stirring for 10 minutes, 2.64 g of 1-ethynyl-4-fluoro-benzene (22 mmol) was added and the solution was heated to 100 ° C and stirred overnight. The reaction mixture was cooled, diluted with water and extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using heptane and EtOAc as eluents to give 2-chloro-342- (4-fluorophenypetynynyl) pyridine NMR (500 MHz, DMSO-d6) S 8 , 44 (dd, 1H), 8.14 (dd, 1H), 7.68 (t, 2H), 7.51 (dd, 1H), 7.33 (t, 2H) Step B: 2- ( 4-fluorophenylthieno [2,3-b] pyridine 2.95 g of 2-chloro-342- (4-fluorophenylethynyl) pyridine (12.7 mmol) and 3.97 g of Na 2 S (51 mmol) were placed. In a 250 ml flask, 120 ml of DMF was added and the mixture was stirred at 130 ° C. for 2 hours, then the reaction mixture was cooled, diluted with water and extracted with water. 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 the 2- (4) -fluorophenyl) thieno [2,3-bpyridine] MS (M + H): 230.2. 2- (47-Fluorophenyl) -thieno [2,3-bipyridine-N-oxide N-Oxide 2- (4-fluorophenyl) thieno [2,3-b] pyridine (1. 8 mmol) was dissolved in DCM (50 ml) and cooled to 0 ° C. 3.12 g of MCPBA (12.6 mmol) was added portionwise and the mixture was stirred at RT for 6 hours. Then, it was concentrated under reduced first and the crude product was purified by flash chromatography using DCM and methanol as eluents. MS (M + H): 246.2.
[0111] Step D: 4-chloro-2- (4-fluorophenyl) thieno [2,3-b] pyridine 1.56 g 2- (4-fluorophenyl) -7-oxothiothio [2,3 β-pyridin-7-ium (6.4 mmol) was dissolved in 50 ml CHCl 3. 15.7 ml of P003 (25.76 g, 168 mmol) was added and the reaction mixture was stirred at reflux temperature for 3 hours. Then, it was cooled, ice and saturated aqueous NaHCO3 were added and the mixture was extracted with CHCl3. The combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using DCM and methanol as eluents to give 4-chloro-2- (4-fluorophenyl) thieno [2,3-b] pyridine. MS (M + H): 264.0.
[0112] Step E: 3-bromo-4-chloro-2- (4-fluorophenyl) thieno [2,3-bpyridine 1.15 g 13 r 2 (7.2 mmol) was added dropwise to a mixture containing 1.46 g of 4-chloro-2- (4-fluorophenyl) thieno [2,3-b] pyridine (5.5 mmol), 0.52 g of K 2 HPO 4 (3.0 mmol), 0.46 g of NaHCO3 (5.5 mmol) and 1.12 g of MgSO4 (9.2 mmol) in 20 ml of CHCl3. The mixture was stirred overnight at reflux temperature.
[0113] Then, the reaction was cooled and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography using DCM and methanol as eluents to obtain 3-bromo-4-chloro-2- (4-fluorophenyl) thieno [2,3-b] pyridine. 1H NMR (500 MHz, DMSO-d6) δ 8.59 (d, 1H), 7.76 (m, 2H), 7.71 (d, 1H), 7.42 (m, 2H).
[0114] Step F: 3-bromo-2- (4-fluorophenyl) thieno [2,3-bpyridin-4-ol] A mixture containing 0.206 g of 3-bromo-4-chloro-2- (4-fluorophenyl) thieno [2] 3- (3-b) pyridine (0.6 mmol), 0.492 g of sodium acetate (6 mmol), 12 ml of AcOH and 0.18 ml of H 2 O was heated at 150 ° C. under MW irradiation for 5 minutes. hours. Water was added and the product was collected by filtration. 1H NMR (500 MHz, DMSO-d6) δ 11.63 (br s, 1H), 8.30 (br s, 1H), 7.72 (in, 2H), 7.38 (m, 2H), 6.87 (s wide, 1H). Step G: (2R) -2-P-bromo-2- (47-fluorophenyl) thieno [2,3-bpyridin-4-yl] oxy-312-112- (2-methoxyphenyl) pyrimidin-1-ylimethoxylphenylpropanoate 0.324 3-bromo-2- (4-fluorophenyl) thieno [2,3-b] pyridin-4-ol (1 mmol), 0.613 g of Preparation 2d (1.5 mmol), 0.691 g of DTAD (3 mmol) and 0.787 g of PPh 3 (3 mmol) were dissolved in 10 ml of anhydrous THF under an N 2 atmosphere and the mixture was stirred at RT until no further conversion was observed. The solvent was then removed under reduced pressure, and the residue was purified by flash chromatography using heptane and EtOAc as eluents to give (2R) -213-bromo-2- ( 4-fluorophenyl) thieno [2,3-b] pyridin-4-yl] oxy-3 [[2- (2-methoxyphenyl) pyrimidin-4-yl] methoxy] phenyl] propanoate 1H NMR (500 MHz, DMSO) d6) δ8.86 (d, 1H), δ8.33 (d, 1H), 7.72 (nl, 2H), 7.61 (d, 1H), 7.51 (dd, 1H), 7.45 (td, 1H), 7.44 (d, 1H), 7.39 (m, 2H), 7.25 (td, 1H), 7.14 (d, 1H), 7.10 (d, 1H), , 111), 7.03 (td, 1H), 6.93 (t, 1H), 6.88 (d, 1H), 5.55 (dd, 1H), 5.30 (d, 1H), , 26 (d, 1H), 4.16 (m, 2H), 3.75 (s, 3H), 3.58 (dd, 1H), 3.35 (dd, 1H-1), 1.13 (d, 1H), t, 3H).
[0115] Step H: Example 71 0.288 g of (2R) -243-bromo-2- (4-fluorophenyl) -thieno [2,3-b] pyridin-4-yloxy-342- [[2- (2-methoxy) -2- phenylpyrimidin-4-yl] methoxy] phenylpropanoate (0.4 mmol), 0.472 g of Preparation 3b (1.2 mmol), 0.028 g of Ataphos (0.004 mmol) and 0.392 g of Cs 2 CO 3 (1.2 mmol) were dissolved in a mixture of dioxane (4 ml) and water (3 ml) and stirred under N 2 at 70 ° C. until no further conversion was observed, then the mixture was diluted with water The combined organic phases were dried over Na 2 SO 4 and concentrated under reduced pressure The crude product was purified by flash chromatography using DCM and methanol as eluants The resulting intermediate was dissolved in a mixture of dioxane (7 ml) and water (7 ml) and 0.168 g of LiOH x H 2 O (4 mmol) were added, the mixture was stirred at RT until no further conversion was observed. it was diluted with brine, neutralized with 2M aqueous HCl and extracted with DCM. The combined organic phases were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The diastereoisomers were purified and separated by reverse phase preparative chromatography using 5 mM aqueous NH4HCO3 solution and MeCN as eluents. The last eluted diastereomer was collected as Example 71. High resolution mass (HRMS) calculated for C48I-I45C1FN5O6S: 873.2763; found 437.6441 (M + 2H).
[0116] Example 72: (2R) -2- [543-Chloro-2-methyl-4-12- (4-methylpiperazin-1-yl) -ethoxylphenyl] -6- (4-fluoro-phenyl) -7-methyl-7-methyl-4-methyl-1-ylmethyl pyrrolo [2,3-d] pyrimidin-4-yloxy-342 - [[2- (2-methoxyphenyl) pyrimidin-4-ylmethoxylphenylpropanoic] Step A: 2-amino-5- (41-hrophenyl) -1H- ethylpyrrole-3-carboxylate A solution containing 3330 mg of ethyl 3-amino-3-imino-propanoate (20 mmol) and 4340 mg of 2-bromo-1- (4-fluorophenypethanone (20 mmol) in 40 ml of ethanol was stirred at RT for 30 minutes, then 20 ml of a 1M NaOEt solution in ethanol (20 mmol) was added at 0 ° C, and the mixture was left while stirring at 60 ° C. for 90 minutes, an additional 13 ml of the 1M NaOEt solution in ethanol (13 mmol) was added at room temperature and the mixture was stirred at 60 ° C. for an additional 1 hour. The reaction mixture was concentrated under pressure. duite, diluted with 40 ml of water and extracted with ethyl acetate. The combined organic phases were dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography using heptane and EtOAc as eluents to give ethyl 2-amino-5- (4-fluorophenyl) -1H-pyrrole-3-carboxylate. 1 H NMR (400 MHz, DMSO-d 6) δ: 10.75 (bs, 1H), 7.52 (nl, 2H), 7.14 (m, 2H), 6.44 (d, 1H), , 68 (bs, 2H), 4.14 (q, 2H), 1.25 (t, 3H). Step B 6- (4-fluorophenyl) -3,7-dihydropyrrolo [2,3-d] pyrimidin-4-one A solution containing 6.83 g of 2-amino-5- (4-fluorophenyl) -1H-pyrrole The ethyl carboxylate (27.5 mmol) and 12 ml of formic acid in 50 ml of formaldehyde and 24 ml of DMF were stirred at 160 ° C for 16 hours in a sealed reaction vessel. The reaction mixture was cooled to room temperature; 150 ml of 2-propanol was added. The precipitate was filtered, washed with heptane, and then dried under reduced pressure to give 6- (4-fluorophenyl) -3,7-dihydro-pyrrolo [2,3-d] pyrimidin-4-one. 1 H NMR (400 MHz, DMSO-d 6) δ: 12.36 (bs, 1H), 11.88 (bs, 1H), 7.88 (m, 3H), 7.27 (t, 2H), 6.93 (s, 1H). Step C 4-Chloro-6- (4-flitorophenyl) -7H-pyrrolo [7.3-dipyrimidine A solution containing 4.50 g of 6- (4-fluoro-phenyl) -3,7-dihydropyrrolo [2,3-dipyrimidine] M-pyrimidin-4-one (19.6 mmol) in 46 ml of POCl3 (491 mmol) was stirred at 90 ° C for 3 hours. It was concentrated under reduced pressure, and the residue was poured on ice. The pH was adjusted to 7 using solid K2CO3, then the mixture was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure to give 4-chloro-6- (4-fluorophenyl) -7H-pyrrolo d] pyrimidine. NMR11 (400 MHz, DMSO-d6) δ: 13.04 (bs, 1H), 8.60 (s, 1H), 8.08 (m, 2H), 7.37 (t, 2H), 7, (Cl, 1H). Step D: 4-chloro-6- (4-formrorophenyl) -7-methyl-pyrrolo12,3-d] pyrimidine To a solution containing 1.87 g of 4-chloro-6- (4-fluorophenyl) -7H-pyrrolo [2,3-4-pyrimidine (7.55 mmol) in 38 ml of DMF, 1.286 g of MeI (9.06 mmol) and then 1.15 g of K2CO3 (8.30 mmol) were added, and The mixture was stirred at RT for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was diluted with brine, and was extracted with dichloromethane. The combined organic layers were dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure, then the residue was purified by flash chromatography using heptane and ethyl acetate as eluents to obtain the 4-chloro-6- (4-fluorophenyl) -7-methylpyn-olo [2,3-d] pyrimidine. NMR (400 MHz, DMSO-d6) δ: 8.69 (s, 1H), 7.79 (m, 2H), 7.42 (m, 2H), 6.80 (s, 1H), 3.83 (s, 3H). Step E 5-Bromo-4-chloro-6- (4-fluorophenyl) -7-methyl-pyrrolo12,3-d] pyrimidine To a solution containing 1.36 g of 4-chloro-6- (4-fluorophenyl) 7-methyl-pyrrolo [2,3-dipyrimidine (5.20 mmol) in 16 ml of acetic acid, 5.46 ml of a 1M Bre solution in acetic acid (5.46 mmol) were was added dropwise at 0 ° C, then the reaction mixture was stirred at RT for 30 minutes. The reaction mixture was concentrated under reduced pressure, then the residue was diluted with saturated aqueous NaHCO 3 solution and extracted with ethyl acetate. 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 ethyl acetate as eluents to give 5-bromo-4-chloro-6- (4-fluoro-phenyl) -7-methyl-3-chloro-6- (4-fluoro-phenyl) -7-methyl- pyrrolo [2,3-4pyrimidine. 1 H NMR (400 MHz, DMSO-d 6) δ: 8.73 (s, 1H), 7.70 (m, 2H), 7.47 (m, 2H), 3.69 (s, 3H). Step F (2R) -2- [5-bromo-6- (4-fluorophenyl) -7-methyl-pyrrolo12,3-d] pyrimidin-4-yloxy3-12 - [(2- (2-methav-phenyl) ) ethyl pyrimidin-4-yl] methoxylphenyl] propanoate 845 mg of 5-bromo-4-chloro-6- (4-fluorophenyl) -7-methyl-pyrrolo [2,3-a] pyrimidine (2.48 mmol) and 1.27 g of Preparation 2c (3.11 mmol) were dissolved in 10 ml of DMF, then 2.43 g of Cs 2 CO 3 (7.44 mmol) were added and the mixture was allowed to stir at 60 ° C. for 6 hours The reaction mixture was concentrated under reduced pressure, diluted with brine, and the mixture was extracted with ethyl acetate The combined organic phases were dried over MgSO 4, filtered and the filtrate was concentrated under reduced pressure, then the residue was purified by flash chromatography using heptane and ethyl acetate as eluents to give (2R) -245-bromo-6- ( 4-fluorophenyl) -7-methyl-pyrrolo [2,3-d] pyrimidin-4-yl] ethyl oxy-3424 [2- (2-methoxy-phenyl) pyrimidin-4-yl] methoxylphenyl] propanoate. MS (M + H): 712.0. Step G: Example 72 Following General Procedure II and (2R) -245-bromo-6- (4-fluorophenyl) -7-methyl-pyrrolo [2,3-d] pyrimidin-4-yloxy Ethyl 342-P- (2-methoxyphenyl) -pyrimidin-4-yilmethoxy} phenylpropanoate in place of the 5-bromofuro [2,3-d] pyrimidyl-lactic ester, and the preparation 3b as a derivative of Suitable boronic acid, Example 72 was obtained as a mixture of diastereoisomers.
[0117] High resolution mass (HRMS) calculated for C48H47ClFN7O6: 871.3260; found 436.6703 and 436.6710 (M + 2H). Example 73: 2-1 [3-13,5-Dichloro-2,6-dimethyl-4- [4- (4-methylpiperazin-11 / l) -etboxylphenyl] -2- (4-fluoro-phenyl) thieno [2, 3-pyridin-4-yl] oxy} -3- (2- {12- (2-methoxyphenyl) pyrimidin-4-ylimethoxy} phenyl) propanoic acid. Example 74: 2 - {[3-12,6-dimethyl- 442- (4-methylpiperazin-1-yl) ethoxylphenyl} -2- (4-fluorophenylthieno [2,3-b] pyridin-4-yloxy) -3- (2-t [2- (2-methoxyphenyl)) pyrimidin-4-yl] methoxyphenyl) propanoic acid Example 75: 24 [3- {3-Chloro-2-methyl-442- (4-methyl-piperazin-1-yl) ethoxylphenyl} -2- 1- (4-Fluorophenyl) thieno [2,3-b] pyridin-4-yloxy) -3- (2 - {[2- (2-methoxyphenyl) -pyrimidin-4-yl] methoxy} phenyl) propanoate [(dimethylcarbamoyl) oxy] ethyl Example 76: 24 [3- {3-Chloro-2-methyl-442- (4-methyl-piperazin-1-yl) ethoxylphenyl} -2- (4-fluorophenyl) thieno [2 1 - [(ethoxycarbonyloxy) ethyl], 3-b] pyridin-4-yloxy} -3- (2- (12- (2-methoxyphenyl) -pyrimidin-4-ylmethoxy) phenyl) propanoate Example 77: Acid 2 - {[3 - {3-ch loro-2-methyl-4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl} -2- (4-fluorophenyl) thieno [2,3-b] pyridine; 4-yl] oxy} -3-hydoxy-3 - (2 - {[2- (2-methoxyphenyl) pyrimidin-4-yl] ethoxy} phenylpropanoic acid Example 78: 24 [3- {3-chloro acid 2-methyl-442- (4-methylpiperazin-1-yl) ethoxylphenyl} -2- (4-fluorophenyl) thieno [2,3-b] pyridin-4-yl] oxy} -4-hydroxy-3- (2-112- (2-methoxyphenyl) pyrimidin-4-ylmethoxy) phenyl) butane Example 79: 2-O-13-13-chloro-2-methyl-4- (4-methylpiperazin-1-yl) ) ethoxyl-phenyl) -2- (4-fluorophenyl) -thieno [2,3-b] pyridin-4-yl-3,4-dideoxy-3- (2 - {[2- (2-methoxyphenyl) pyrimidin); 4-yl] methoxylphenyl) pentone Example 80: 2-03- {3-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxyl-phenyl} -2- (4-fluorophenyl) thieno acid [2,3-b] pyridin-4-ylioxyl-3-12 - ({2-15- (hydroxy-methyl) pyridin-3-ylpyrimidin-4-yl} methoxy) phenylpropanoic acid Example 81: 2- acid 1 [3- {3-chloro-2-methyl-442- (4-rnéthylpipérazin-1-ypét Hoxy-phenyl) -2- (4-fluorophenyl) -thieno [2,3-b] pyridin-4-yloxy) -3- (2 - [(2- (2 - [(2-hydroxyethoxy) methyl] Example 82: 2 - {[3- (3-chloro-2-methyl-4- [4- (4-methylpiperazin-1-yl) ethoxylphenyl} -2- (b) phenylpyrimidin-4-amethoxylphenylpropanoic acid 4-fluorophenyl) -thieno [2,3-b] pyridin-4-yl] oxy} -3- (2 - [(2- {442- (dimethylamino) ethoxy] phenylpyrimidin-4-yl) methoxy] phenyl} propanoic acid Example 83: 2- [3- (3-chloro-2-methyl-4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl} -2- ( 4-fluoro-phenyl) -thieno [2,3-b] pyridin-4-yl] oxy] -3-12 - ({2- [3- (phosphonooxy) phenyl] pyrimidin-4-ylmethyloxy) plenyl Example 84: N43- (3-Chloro-2-methyl-4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl} -2- (4-fluorophenyl) thieno, m.p. [2,3-b] pyridin-4-yl] -2- ([2- (2-methoxyphenyl) -pyrimidin-4-yl] methoxy} phenylalanine Example 85: 24 [3- (3-chloro-2-methyl) acid -4-12- (4-methylpiperazin-1-yl) ethoxylphenyl} -2- (4-fluorophenyl) thieno [3,2-c] pyridin-4-yloxy-3- (2 - ([2- (2-methoxyphenyl) pyrimidin-4-yl] methoxy} phenyl) propanoic acid Example 86: N- [343-chloro] 2-methyl-442- (4-methyl-piperazin-1-yl) ethoxy] phenyll-2- (4-fluorophenyl) -thieno [3,2-c] pyridin-4-yl) -2- (2- (2- metboxyphenyl) -pyrimidin-4-yl] methoxylphenylalanine Example 87: 2- {13- {3-chloro-2-methyl-4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl} -2 - (4-fluorophenyl) -thieno [2,3-c] pyridin-4-yloxy) -3- (2 - {[2- (2-methoxyphenyl) pyrimidin-4-yl] methoxylphenyl) propanoic acid Example 88: N -13- {3-Chloro-2-methyl-412- (4-methylpiperazin-1-yl) ethoxy] phenyl} -2- (4-fluorophenyl) thieno [2,3-c] pyridin-4-yl ] -2 - {[2- (2-Methoxyphenyl) pyrimidin-4-yl] methoxy} phenylalanine Example 89: 2-113-13-Chloro-2-methyl-412- (4-methylpiperazin-1-yl) ethoxylate phenyl) -2- (4-fluorophenyl) -tbieno [2,3-d] pyridazin-4-yloxy} -3- (2- (12- (2-methoxy-phenyl) pyrimidin-4-ylmethoxy} phenyl) propanoic acid Example 90: N-1343-chloro-2-methyl-4-12- (4-m) thyl-piperazin-1-yl) ethoxylphenyl-2- (4-fluoropbienyl) thieno [2,3-d] pyridazin-4-yl] - ([2- (2-methoxyphenyl) -pyrimidin-4-yl) Methoxy} phenylalanine Example 91: 2- ([[5-13-Chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxylphenyl] -6- (4-fluorophenyl) thieno [2] 3- [2- (2-methoxyphenyl) pyrimidin-4-yl] methoxyphenyl) propanyl) Example 92: N- (3-c] pyridazin-4-yl] yl] -3- (2-1 [2- (2-methoxyphenyl) pyrimidin-4-yl] methylphenyl) propanamide 15- {3-chloro-2-methyl-4-12- (4-methyl-piperazin-1-yl) ethoxylphenyl) -6- (4-fluorophenyl) thieno [2,3-c] pyridazin-4 Example 93 2- (13- (3-chloro-2-methyl) -4- [2- (2- (2-methoxyphenyl) -pyrimidin-4-yl] methoxy) phenylalanine methylpiperazin-1-34) ethoxylphenyl) -2- (4-fluorophenyl) -furo [2,3-b] pyridin-4-yloxy} -3- (2 - ([2- (2-methoxyphenyl) pyrimidin-4-yl] methoxyphenyl) propanoic acid Example 94: N-13- {3-chloro-2-methyl-4- [2- (4-methylpiperazin-1-aethoxy) phenyl} -2- 4-fluorophenyl) furo [2,3-b] pyridin-4-yl] -2 - {[2- (2-methoxyphenyl) py Example 95: 2-113- [3-chloro-2-methyl-4- [4- (4-methylpiperazin-1-yl) ethoxyl-phenyl] -2- (4-fluorophenyl) -furoaldehyde [Methyl] phenylalanine [3,2-Clpyridin-4-yl] oxy} -3- (2-112- (2-methoxyphenyl) pyrimidin-4-ylmethoxylphenyl) propanoic Example 96: N- [343-chloro-2-methyl] 442- (4-methylpiperazin-1-yl) ethoxylphenyl} -2- (4-fluorophenyl) furo [3,2-c] pyridin-4-yl] -2 - {[2- (2-methoxyphenyl) pyrimidin} Example 97: 24 [3- {3-Chloro-2-methyl-4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl} -2- (4-fluorophenyl) imidazo [1,2-c] pyrimidin-5-yloxy} -3- (2 - {[2- (2-methoxyphenyl) pyrimidin-4-yl] methoxy} phenyl) propanoic acid Example 98: N- [3- { 3-chloro-2-methyl-442- (4-methyl-piperazin-1-yl) ethoxy] phenyl-2- (4-fluorophenyl) imidazo [1,2-c] pyrimidin-5-yl] - 2 - {[2- (2-methoxyphenyl) -pyrimidin-4-yl] methoxy} phenylalanine Example 99: 2 - ([3- {3-chlora-2-methyl-442- (4-methylpiperazine) -1-y1) éthoxylph 2- (4-fluorophenyl) imidazo [1,2-a] pyrazin-5-yl] oxy} -3 - (2- (2- (2-methoxyphenyl) pyrimidin); 4-yl] ethoxy] phenyl) propane Example 100: N-13- {3-chloro-2-methyl-4- [2- (4-methylpiperazin-1-yepethoxy] phenyl} 2- (4-Fluorophenyl) imidazo [1,2-a] pyrazin-5-yl] -2 - ([2- (2-methoxyphenyl) -pyrimidin-4-yl] methoxy} phenylalanine Example 101: Acid 24 [3- {3-Chloro-2-methyl-4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl} -2- (4-fluorophenyl) imidazo [1,2-a] pyridin-5-yl] oxy} -3- (2- {12- (2-methoxyphenyl) pyrimidin-4-ylmethoxy) phenyl) propanamide Example 102: N43- (3- chloro-2-methyl-4- [2- (4-methylpiperazin-1-yepethoxy) phenyl-2- (4-fluorophenyl) imidazo [1,2-a] pyrimidin-5-yl] -2- ([ 2- (2-Methoxyphenyl) -Pyrimidin-4-yl] metboxylphenylalanine Example 103: 2- [3- (3-Chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxyl-phenyl] -2- (4-fluorophenyl) imidazo [1,2-a] pyridin-5-yloxy) -3- (2 - {[2- (2-methoxyphenyl) pyrimidin-4-yl] metho Example 104: N13- {3-Chloro-2-methyl-442- (4-methyl-piperazin-1-yl) ethoxylphenyl} -2- (4-fluorophenyl) imidazo [1,2-a] py Ridin-5-yl-2 - {[2- (2-methoxyphenyl) pyrimidin-4-yl] methoxy) phenylalanine PHARMACOLOGICAL STUDY EXAMPLE A: Inhibition of Me1-1 by the polarization technique of Fluorescence 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 UniProtKBe primer: Q07820), which results in an increase of the anisotropy measured in milli-polarization unit (mP) by means of a reader The addition of a compound which competitively binds to the same site as the ligand will lead to an increase in the proportion of unbound ligand in the system, indicated by a decrease in mP units Method 1: an 11-point serial dilution of each compound was prepared in DMSO and 2 μl were transferred to a 384-well flat-bottomed, low-binding plate (final concentration of 5% DMSO), 38 μl of buffer (10 mM 4- (2-hydroxyethyl) -1-piperazinethanesulfonic acid [HEPES], 150 mM NaCl, 0.05% Tween 20, pH 7.4) containing the fluorescently labeled ligand eine (final concentration of 1 nM) and Mc1-1 protein (final concentration of 5 nM) were then added. The assay plates were incubated for about 2 hours at 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; Mc1-1 inhibition IC50s obtained using method 1 are not underlined.
[0118] Method 2: An 11-point serial dilution of each compound was prepared in DMSO and 2111 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 the fluorescein labeled ligand (final concentration of 10 nM) and Mc1-1 protein (final concentration 10 nM) were then added.
[0119] The assay plates were incubated for about 2 hours at room temperature before measuring FP 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 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 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 C159_ 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.
[0120] EXAMPLE B In Vitro Cytotoxicity Cytotoxicity studies were performed on the 11929 multiple myeloma tumor line. The cells are distributed in microplates and exposed to test compounds for 48 hours. Cell viability is then quantified by a colorimetric assay, Microculture Tetrazolium Assay (Cancer Res., 1987, 47, 939-942). The results are expressed as IC50 (concentration of compound which inhibits cell viability to 50%) and are presented in Table 1 below. The results show that the compounds of the invention are cytotoxic. Table 1: IC50 of Inhibition of Mc1-1 Fluorescence Olarization Assay and Cytotoxicity for H929 Cells Note: C1: 50 of Mcl-1 inhibition obtained with Method 2 are highlighted. IC50 (gM) Mc1-1C150 (gM) IC50 (gM) Mc1-1 PF C150 (gM) MTT PF MTT H929 1-1929 Example 1 3.8E-09 2.41E-08 Example 30 6.4E-06 ND Example 2 6.0E-09 1.45E-08 Example 31 7.9E-07 ND Example 3 1.7E-08 3.64E-07 Example 32 3.5E-06 ND Example 4 2.9E-08 3.29E Example 33 2,6E-07 ND Example 5 1,5E-08 6,19E-07 Example 34 6,4E-06 ND Example 6 8,9E-09 ND Example 2,9E-07 ND Example 7 1, 1E-07 7,57E-07 Example 36 6,5E-06 ND Example 8 6,6E-09 1,78E-08 Example 37 5,3E-07 ND Example 9 8,6E-08 6,89E-08 Exempt 38 67% @ 50 1.1M ND Example 10 1.8E-05 ND Example 39 77.75% @ 50 NM ND Example 11 3.4E-05 ND Example 40 8.6E-07 / 3.3E-08 ND Example 12 5 , 6E-07 ND Example 41 1 3E-05 ND Example 13 6.6E-07 ND Example 42 4.5E-07 ND Example 14 1.2E-05 ND Example 43 66.9% to 501IM ND Example 15 7.3E -06 ND Example 44 2.5E-06 ND Example 16 1.8E-06 ND Example 45 1.8E-06 ND Example 17 3.8E-06 ND Example 46 71% @ 50 tiM ND Example 18 3.1E-06 ND Example 47 1,1E-05 ND Example 19 3,3E-06 ND Example 48 5,9E-06 ND Example 2 0 64.8% (4 ND Example 49 3.9E-08 ND 50 tmM Example 21 8.7E-06 ND Example 50 65.85% @ 10 pM ND Example 22 74.2% @ ND Example 51 3.6E- 07 / 5.5E-09 1,10E-05 50gM Example 23 6,8E-06 ND Example 52 1,6E-06 ND Example 24 1,8E-05 ND Example 53 2,2E-08 2,53E-08 Example 25 9.1E-06 ND Example 54 1.2E-07 ND Example 26 5.9E-06 ND Example 55 55.35% @ 10 pM ND Example 27 3.3E-07 ND Example 56 4.7E-08 ND Example 28 63.25% nD Example 57 1.7E-07 ND 50 gM Example 29 8.5E-06 ND Example 58 51.9% @ 10 pM ND 3037959 - 132- C150 (11M) Mc1-1 IC50 (pM) C150 (pM) Mc1-1 PF C150 (iM) MTT MT MTT H929 11929 Example 59 3.6E-08 1.24E-06 Example 82 ND ND Example 60 1.9E-08 5.68E-07 Example 83 ND Example 61 52.8% Di ND Example 84 ND ND 10 itM Example 62 8.2E-07 ND Example 85 ND ND Example 63 1.7E-07 ND Example 86 ND ND Example 64 7.4E-09 4.71E-08 Example 87 ND ND Example 65 1,0E-06 ND Example 88 ND ND Example 66 1,6E-06 ND Example 89 ND ND Example 67 1,4E-08 8,36E-08 Example 90 ND ND Example 68 1,2E-06 ND Example 91 ND ND Example 69 2.4E-08 1.04E-07 Example 92 ND ND Example 70 13.55% @, ND Example 93 ND No. 101.1114 Example 71 ND 9.08E-09 Example 94 ND ND Example 72 1, 55E-08 3,2E-08 Example 95 ND ND Example 73 ND ND Example 96 ND ND Example 74 ND NU Example 97 ND ND Example 75 ND ND Example 98 ND ND Example 76 ND ND Example 99 ND ND Example 77 ND ND Example 100 Example 78 N / A Example 101 N / A Example 79 N / N Example 102 N / N Example 80 N / A Example 103 N / N Example 81 N / A Example 104 N / A N / A: Not determined For partial inhibitors, percent inhibition by polarization fluorescence for a given concentration of the test compound is indicated. Therefore, 45.1% @ 10 RM means that fluorescence polarization inhibition of 45.1% is observed for a concentration of test compound equal to 10 11.11. 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 model of xenograft myeloma cells. multiple 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.
[0121] 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 cleaved PARP in the treated mice divided by the amount of PARP cleaved in the control mice. The results (shown in Table 2 below) show that the compounds of the invention are capable of inducing apoptosis of AMO-1 tumor cells in vivo. Table 2: Quantification of PARP cleaved form in vivo Cleavage cleavage cleavage of PARP PARP PARP multiplied by multiplied by multiplied by Example 1 157.5 Example 8 55.4 Example 67 29.3 Example 2 216.3 Example 53 40 Example 72 15.7 EXAMPLE D In vivo anti-tumor activity The anti-tumor activity of the compounds of the invention is evaluated in a model of AMO-1 multiple myeloma cell xenograft. 1.107 AMO-1 cells are grafted under the skin of immunodepressed mice (strain SCID). Six to eight days after the graft, when the tumor mass reached about 150 mm3, the mice are treated with the various compounds according to a daily schedule (5-day treatment). The tumor mass is measured twice a week from the start of treatment. The compound of the invention has antitumor activity (tumor regression) 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 day of the last treatment) by -27%. 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 104 5 g Wheat starch 20 g Corn starch 20 g Lactose 30 g Magnesium stearate 2 g Silica 1 g Hydroxypropylcel lulo se 2 g 10

权利要求:
Claims (48)
[0001]
REVENDICATIONS1. A compound of formula (1): R14 (I) wherein: - A represents the group in which 1 is attached to the W group and 2 is attached to the phenyl ring, wherein: E represents a fuiyl, thienyl or pyrrolyl ring, 10 - X1, X3, X4 and X5 independently of one another are a carbon atom or a nitrogen atom, - X2 represents a C-R21 group or a nitrogen atom, and signifies that the ring is aromatic, - R1 represents a halogen atom, a. C1 to C4 alkyl group. Linear or branched C6, 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 hydroxy group, a hydroxy (C1-C6) alkyl group C6), a linear or branched C1-C6 alkoxy group, a -S- (C1-C6) alkyl group, a cyano group, a nitro group, - (C1-C6) alkyl -NRI1R11 1- (O-C 1-6 alkyl) -NR 11 R 11 ', -O-C 1-6 alkyl-R 12, -C (O) -OR 1, -OC (O) -R 11, 1', - NR1 -C (O) -R11 ', -NR11-C (O) -OR1', - (C1-C6) alkyl -NR11-C (O) -R11 ', -SO2-NRIIR11', -SO2- ( C1 to C6 alkyl), - R2, R3, R4 and R5 independently of one another represent a hydrogen atom, a halogen atom, a linear or branched C1-C6 alkyl group, a C2-alkenyl group, Linear or branched C6, a linear or branched C2 to C6 alkynyl group, a linear C1 to C6 polyhaloalkyl or a hydroxy 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-NR111211 ', -O- (C1-C6) alkyl-NR11R11', -O- (C1-C6) alkyl-R12, -C (O) -OR1 1, - OC (O) -R11, -C (O) -NR11R11 ', -NR1C (O) -ORII', - (C1-C6) alkyl -NR11-C (O) -R11 ', -SO2-NR11R11' or -SO2- (C1-C6) alkyl, or the substituents of the (R1, R2) pair together with the carbon atoms carrying them an aromatic or non-aromatic ring consisting of 5 to 7 members, which may contain from 1 to with 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-C6 alkyl, C6) -NRIIRI -N1113R13 ', - (C1-C6) alkyl) -Cyl or an oxo, - R6 and R7 independently represent one of the other a hydrogen atom, a halogen atom, a linear or branched C1-C6 alkyl group, a linear or branched C2-C6 alkenyl group, a linear or branched C2-C6 alkynyl group, a polyhaloalkyl group; C1 to C6 linear or branched, a hydroxyl group, a linear or branched C1 to C6 alkoxy group, a group -S- (C1 to C6) alkyl, a cyano group, a nitro group, - (C1 to C6 alkyl) C6) -NRHR11 ', -O-Cy1, -C6-C6alkyl -Cyl, -C2-C6alkenyl -Cy1-, -C2-C6alkynylC1i, -O- C1 to C6) -R12, -C (O) -OR11, -O-C (O) -Ri 1, -C (O) -NR1 'R1', -NR11-C (O) -R i ', - (C1-C6) alkyl -NR11-C (O) -R11 ', -SO2-NRIIRII', -SO2- (C1-C6) alkyl, or the substituents of the (R6, R7) pair, when they are grafted on two adjacent carbon atoms together with the carbon atoms carrying them an aromatic or non-aromatic ring consisting of 5-7 members, which may contain 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, it being understood that the resulting ring may be substituted by a group selected from a linear or branched C1-C6 alkyl group, -NR13R13 ', - ( C 1 -C 6 alkyl-Cyl or an oxo, W represents a group or an oxygen atom, R 8 represents a hydrogen atom, a linear or branched C 1 -C 6 alkyl group, a -CHRaRb group, an aryl group, a heteroaryl group, an arylC 1-6 alkyl group or a heteroarylC 1-6 alkyl group; R 9 represents a hydrogen atom, a linear C.sub.1 -C.sub.6 alkyl group or branched, linear or branched C2-C6 alkenyl group, linear or branched C2-C6 alkynyl group, -Cy2, -C1-C6alkylCy2-, -C2-C6alkenyl -Cy2- (C2-C6) alkynyl-C2y, -Cy2-Cy3, -C2-C6 alkynyl-O-Cy2, -Cy2- (C1-C6) alkyl-O- (C1-C6) alkyl -Cy3 , an atom halogen, a cyano group, -C (O) -R15 or -C (O) -NR.1512.15 ', 15 - Rio represents a hydrogen atom, a linear or branched C1-C6 alkyl group, a group linear or branched C2-C6 alkenyl, a linear or branched C2-C6 alkynyl group, an aryl C1-C6 alkyl group, a cycloalkyl (C1-C6) alkyl group, a linear C1-C6 polyhaloalkyl or branched, - (C1-C6) alkyl-O-Cy4, or the substituents of the pair (R9, R10), when grafted on two adjacent carbon atoms, together with the carbon atoms carrying them a ring 5- to 7-membered aromatic or nonaromatic compound, which may contain from 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, - R11 and R1 I 'represent, independently of one another, an atom of hydrogen, a linear or branched (C1-C6) alkyl group, or the substituents of the (R11, R11 ') pair together with the atom nitrogen carrying them an aromatic or 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, sulfur and nitrogen, being understood that the nitrogen in question can be substituted by a group representing a hydrogen atom or a linear or branched C1-C6 alkyl group; R12 represents -Cy5, -Cy5- (C1-C6) alkyl; ) -O- (C6-C6) alkyl-C6-C6-C6-C6 alkyl-C6-C6-C5-C6-C6 alkyl-N1 (11- (C1-C6) alkyl) - Cy6, -C15-Cy6-O- (C1-C6) alkyl-C17, n -NR11R11 ', -NR11C (O) -Rn-O- (C1-C6) alkyl-01 (11, -SO2 -R11, -C (O) -01 (ii) or -NH-C (O) -NH-Rit, 5-R13, R13 ', R15 and R15' independently of one another represent a hydrogen atom or a group optionally substituted linear or branched C1-C6 alkyl, - R14 represents a hydrogen atom, a hydroxy group or a hydroxy (C1-C6) alkyl group, 1 R21 represents a hydrogen atom, a halogen atom, a linear or branched C1-C6 alkyl group or a cyano group; Ra represents a hydrogen atom or a linear or branched C1-C6 alkyl group; R 1 represents a group -O-C (O) -O-Re, a group -O-C (O) -NReRe 'or a group -O-P (O) (ORc) 2, - Re and Re 'represent, independently of each other, a hydrogen atom, a linear or branched C1-C8 alkyl group, a cycloalkyl group, a (C1-C6) alkoxy (C1-C6) alkyl group, a group (C1-C6 alkoxy) carbonyl (C1-C6) alkyl, or the substituents of the (Ra, R0 ') pair together with the nitrogen atom carrying them a non-aromatic ring of 5-7 membered rings 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 grouping group linear or branched C1-C6 alkyl, 25-Cyl, Cy2, Cy3, Cy4, Cy5, Cy6 and Cy7 independently of one another represent a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, - n is a an integer equal to 0 or 1, it being understood that: "aryl" means a phenyl, naphthyl, biphenyl, indanyl or indenyl group, "heteroaryl" means any mono- or bi grouping; -cyclic compound consisting of 5 to 10 members, having at least one aromatic group and containing from 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, by "cycloalkyl" means any nonaromatic carbocyclic group, 5 mono or bicyclic, containing from 3 to 10 members, by "heterocycloalkyl" is meant any nonaromatic carbocyclic group, mono- or bi-cyclic, consisting of 3 to 10 members and containing from 1 to 3 heteroatoms chosen from oxygen, sulfur and l nitrogen, which may comprise fused, 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 optionally substituted linear or branched C1 to C6 alkyl, 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, (alkyl) C1 to C6) -S- optionally substituted, hydroxy, oxo (or N-oxide if appropriate), nitro, cyan, -C (O) -OR ', -O-C (O) -R', -C (0) -NR'R ", -O -C (O) -NR 'R", -NR'R ", - (C = NR') -OR", -O-P (O) (OR ') 2, -O-P (O) (O-M +) 2, linear or branched C1-C6 polyhaloalkyl, trifluoromethoxy, halogen or an aldohexose of the formula OR 'OR' 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 C 1 -C 6 alkyl group, and Ive represents a pharmaceutically acceptable monovalent cation, X represents not more than 3k21% ,, __, 2.1c4 E provided that 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 one another, a halogen atom, a linear or branched C1-C6 alkyl group, a hydroxyl group, a linear or branched C1-C6 alkoxy group, or the substituents of the pair (R1, R2) form together with the carbon atoms carrying them an aromatic ring consisting of 5 to 7 members, which may contain from 1 to 3 atoms nitrogen, - 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- (alkyl) C1 to C6) -NR111, R4 and R5 represent, independently of one another, 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 and R7 independently represent one of the other 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 C1-C6 alkoxy group or branched, a cyano group, a nitro group, - (C 1 -C 6 alkyl) -NR 11 R 11 ', - (C 1 -C 6) alkyl-Cyl, -O- (C 1 -C 6) alkyl-R 12 or -C (O) Embedded image, Rg represents a hydrogen atom, a linear or branched C1-C6 alkyl group or a -CHRaRb group, -R9- represents a hydrogen atom, a linear or branched C1-C6 alkyl group; a linear or branched C2 to C6 alkenyl group, a linear or branched C2 to C6 alkynyl group, -Cy2 or a halogen atom, - R1 represents a hydrogen atom or a linear C1 to C6 alkyl group. or branched, a linear or branched C2-C6 alkenyl group, a linear or branched C2-C6 alkynyl group, an aryl group C1-C6 alkyl), a cycloalkyl (C1-C6) alkyl group, a linear or branched C1-C6 polyhaloalkyl or - (C1-C6) alkyl-O-CY4, or the substituents of the (R9, R10), when they are grafted on two adjacent carbon atoms, together with the carbon atoms carrying them form a 5- to 7-membered non-aromatic ring, which may contain from 1 to 3 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, R11 and R11 'independently of one another represent a hydrogen atom, a linear or branched (C1-C6) alkyl group, or the substituents of the pair (R11 , R11 ') form 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 by a group representing a C1-alkyl group C6 linear or branched, R12 represents -Cy5 or -Cy5- (C1-C6) alkyl -Cy6, 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 an optionally substituted linear or branched C1 to C6 alkyl, an optionally substituted linear or branched C1 to C6 alkoxy, a hydroxy, an oxo (or an N-oxide if appropriate) , -C (O) -OR ', -C (O) -NR'R ", -O-C (O) -NR'R", -NR'R ", -OP (O) (OR') 2, -O-P (O) (O-M +) 2, a linear or branched C 1 -C 6 polyhaloalkyl, a halogen or an aldohexose of the formula OR 'OR' R'0 or OR '25 where each R' is independent; it being understood that R 'and R "independently of one another represent a hydrogen atom or an optionally substituted linear or branched C 1 -C 6 alkyl group, and M + represents a pharmaceutically acceptable monovalent cation.
[0003]
3. Compound of formula (I) according to claim 1, wherein n is an integer equal to 1.
[0004]
4. Compound of formula (I) according to claim 1, which is a compound of force (Ia): in which R1, R2, R3, R4, R5, R6, R7, R8, R9, R14, X1, X2, X3 and W are as defined in claim 1.
[0005]
5. Compound of formula (I) according to claim 1, which is a compound of formula (Ib): wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R14, X1 , X2, X3 and W are as defined in claim 1.
[0006]
6. Compound of formula (I) according to claim 1, which is a compound of formula (Ic): in which R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R14, XI, X2. , X3 and W are as defined in claim 1.
[0007]
The compound of claim 6 wherein R10 is hydrogen; methyl; isopropyl; 2,2,2-trifluoroethyl; benzyl; 4-methoxybenzyl; phenethyl; 3-phenylpropyl; cyclopropylmethyl; cyclopentylethyl; naphthalen-1-ylmethyl; 2- (naphthalen-1-yloxy) ethyl; a but-2-yn-1-yl; a prop-2-en-1-yl; or a goal-3-en-1-yl.
[0008]
A compound of formula (I) according to claim 1 which is a compound of formula (Id): wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R14, X1. , X2, X3 and -W are as defined in claim 1.
[0009]
The compound of claim 8, wherein R10 represents a hydrogen atom or a halogen atom.
[0010]
10. A compound of formula (I) according to claim 1, which is a compound of formula (Ie): wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R14, X1, X2, X3 and W are as defined in claim 1. 5
[0011]
The compound of claim 1, wherein at least one of R 2, R 3, R 4 and R 5 is not hydrogen.
[0012]
The compound of claim 1 wherein R14 is a hydrogen atom.
[0013]
13. A compound according to claim 1, wherein R21 represents a hydrogen atom, a fluorine atom, a methyl group or a cyano group. 15
[0014]
The compound of claim 1 wherein R 1 is a linear or branched C 1-6 alkyl group or a halogen atom.
[0015]
The compound of claim 1, wherein R2 is a linear or branched C1-C6 alkoxy group, a hydroxy group or a halogen atom. 20
[0016]
The compound according to claim 1, wherein R3 is hydrogen, hydroxy, linear or branched C1-C6 alkoxy or -O- (C1-C6) -NRI-3037959 -146. -
[0017]
17. The compound of claim 1, wherein R4 and R5 are hydrogen. 5
[0018]
18. A compound according to claim 1, wherein C) represents where R11 and R11 'are as defined in claim 1.
[0019]
The compound of claim 1, wherein the substituents of the (R1, R5) pair are the same and the substituents of the (R2, R4) pair are the same.
[0020]
20. A compound according to claim 1 wherein R6 is hydrogen, an optionally substituted linear or branched C1-C6 alkoxy group or a -O- (C1-C6) alkyl-R12 group.
[0021]
21. A compound according to claim 1, wherein R7 represents a hydrogen atom. 20
[0022]
22. A compound according to claim 1 wherein R12 is as defined in claim 1.
[0023]
The compound of claim 1, which is a compound of formula (1-g): wherein R 1, R 6, R 7, R 8, R 9, R 10, R 11, R 11, R 14, X 1, X 2, X 3, X 4, X 5 , W and E are as defined in claim 1.
[0024]
24. The compound according to claim 1, wherein R8 represents a hydrogen atom, a -CHRaRb group, an optionally substituted linear or branched C1-C8 alkyl group or a heteroaryl- (C1-C6) alkyl group.
[0025]
25. A compound according to claim 1, wherein R9 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, an aryl group or a heteroaryl group.
[0026]
26. A compound according to claim 1, wherein R11 and R11 'are independently of each other a linear or branched (C1-C6) alkyl group, or the substituents of the (R11, R11') pair form together with the nitrogen atom bearing them a 5- to 7-membered non-aromatic ring which may contain in addition to the nitrogen atom (1-g) of 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. 5
[0027]
27. A compound according to claim 1 wherein R12 is -Cy5 or -Cy5- (C1-C6) alkyl-C6.
[0028]
28. A compound according to claim 27, wherein Cy5 is a heteroaryl group.
[0029]
29. A compound according to claim 27, wherein Cy6 represents a phenyl group.
[0030]
30. Compounds according to claim 27, wherein R16 represents R12 in which p is an integer equal to 0 or 1 and R16 represents a hydrogen atom, a hydroxyl group, an optionally substituted linear or branched C1 to C6 alkyl group. substituted, a linear or branched C1-C6 alkoxy group, a group -O- (CHR17-CHR18-0) q-R ', a group -OP (O) (OR') 2, a group -O-P ( 0) (0-1V1 +) 2, a group -O-C (O) -NRI9R20, a di (C1-C6) alkylamino (C1-C6) alkoxy group, a halogen atom or an aldohexose of formula : OR 'OR' R10 OR 'or R10 ° R. Where each R 'is independent; with the proviso that: - R 'represents a hydrogen atom or a linear or branched C1-C6 alkyl group, - R17 represents a hydrogen atom or a (C1-C6) alkoxy (C1-C6) alkyl group R18 represents a hydrogen atom or a hydroxy (C1-C6) alkyl group; R19 represents a hydrogen atom or a (C1-C6) alkoxy (C1-C6) alkyl group; R20 represents a (C1-C6) alkoxy (C1-C6) alkyl group, a - (CH2) group, - NRIIRn 'or a - (CH2) group, .- O- (CHR17-CHR18-0) q -R ', - q is an integer equal to 1, 2 or 3 and r is an integer equal to 0 or 1, 15 - M ÷ represents a pharmaceutically acceptable monovalent cation.
[0031]
31. Compounds according to claim 30, wherein the aldexose is D-mannose.
[0032]
32. Compounds according to claim 1 which are: (2R) -2 - {[5- {3-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxy] phenyl} 6- (4-fluorophenyl) -furo [2,3-d] pyrimidin-4-yloxy) -3- (2 - {[2- (2-methoxyphenyl) pyrimidin-4-yl] methoxy} phenyl ) propanoic acid, - (2R) -2 - {[5- {3-chloro-2-ethyl-4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl} -6- fluorophenyl) -furo [2,3-d] pyrimidin-4-yl] oxy} -3- (2 - {[2- (2-methoxyphenyl) pyrimidin-4-ylimethoxy} phenyl) propanoic acid, - N [5- {3-chloro-2-methyl-442- (4-methyl-piperazin-1-ylethoxybenzyl} -6- (4-fluorophenyl) -furo [2,3-a] pyrimidin-4-yl] - 2 - {[2- (2-methoxyphenyl) -pyrimidin-4-yl] methoxy} -D-phenylalanine, - (2R) -2 - {[3- {3-chloro-2-methyl-442 (4-methylpiperazin-1-yepethoxy) phenyl) -2- (4-fluorophenyl) -1-benzothiophen-4-yl] oxy-342 - {[2- (2-methoxyphenyl) -pyrimidin-4-yl] methoxylphenylpropropandic acid , (2R) -2- {[3- {3-chloro-2-methyl-442- (4-methylpiperea) zin-1-yl) ethoxy] phenyl} -2- (4-fluorophenyl) -1-benzofuran-4-yloxy-3 - (2- [2- (2-methoxyphenyl) pyrimidin-4-yl] methoxy} phenyl) propanoic acid, - (2R) -2 - {[3- (3-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxyl-5-phenyl} -6-fluoroic acid; 2- (4-fluorophenyl) -1-benzofuran-4-yloxy) -3- (2 - {[2- (2-methoxyphenyl) pyrimidin-4-yl] methoxy} phenyl) propanoic acid, - (2R) acid -2 - {[3- {3-chloro-2-methyl-442- (4-methylPiperazin-1-yl) ethoxyl-phenyl} -2- (4-fluorophenyl) -1-methyl-1H-indol-4- Ylloxyl-3- (2 - {[2- (2-methoxyphenyl) -pyrimidin-4-yl] methoxylphenyl) propanoic acid, 10 - (2R) -2 - {[3- {3-chloro-2-methyl] acid 442- (4-methylPiperazin-1-yl) ethoxyl-phenyl-2- (4-fluorophenyl) -thieno [2,3-b] pyridin-4-yloxy) -3- (2- {[2- (2-yl)} -methoxyphenyl) pyrimidin-4-yl] methoxy} phenyl) propanoic acid; (2R) -21543-chloro-2-methyl-442- (4-methylpiperazin-1-yl) ethoxyl-phenyl] -6- (4-fluorophenyl) -7-methyl-pyrrolo [2,3-a d] Pyrimidin-4-yloxy-3- [2 - [[2- (2-methoxyphenyl) pyrimidin-4-yl] methoxylphenylpropanoic acid.
[0033]
33. 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): embedded image in which Z1 represents bromine or iodine, Z2 represents chlorine, bromine or hydroxy, and A is as defined for formula (I) wherein 1 is attached to group Z2 and 2 is attached to group Z1, said compound of formula (II-a) being coupled with a compound of formula (III): wherein R6, R7, R14, W and n are as defined for formula (I), and Alk represents a linear or branched C1-C6 alkyl group, to obtain the compound of formula (IV): Alk (IV) () A R14 in which R6, R7, R14, A, W and n are as defined for the formula (I), and Z1 and Alk are as defined above, the compound of formula (IV) being further subjected to a coupling with a compound of formula (V) (V). in which R1, R2, R3, R4 and R5 are as defined for formula (I), and RBI and RB2 represent a hydrogen atom, a linear or branched C1-C6 alkyl group, or RBI and RB2 form with oxygen carrying them an optionally methylated ring, to obtain the compound of formula (VI): Alk O R14 (VI) wherein R1, R2, R3, R4, R5, R6, R7, R14, A, W and n are as defined for formula (1) 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 reacting with an alcohol of formula R8-OH or a chlorinated compound of formula R8-C1, where R8 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 are optionally separated into its isomers according to 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 synthesis.
[0034]
34. 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): ## STR2 ## wherein Z 3 is iodine, Z 4 is chloro, hydroxy, and A is as defined for formula (I) wherein 1 is attached to the Z 4 moiety and 2 is attached to the Z 3 moiety, wherein wherein formula (II-b) is coupled to a compound of formula (V): wherein R1, R2, R3, R4 and R5 are as defined for formula (I), and Rat 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 ( VII): (VII) wherein R1, R2, R3, R4, R5 and A are as defined for formula (I), and Z4 is as defined above, the compound of wherein formula (VII) is further subjected to coupling with a compound of formula (III): wherein R6, R7, R14, W and n are as defined for formula (I), and Alk represents a linear or branched C1-C6 alkyl group, to obtain the compound of formula (VI): (VI) wherein R1, R2, R3, R4, R5, Rb, R7, R14, A, W and n are such defined for the formula (I) and Alk is as defined above, the ester function 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 R8-OH or a chlorinated compound of formula R8-C1, where R8 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, 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 synthesis. 10
[0035]
35. A pharmaceutical composition containing a compound of formula (1) according to any one of claims 1 to 32 or an addition salt thereof with a pharmaceutically acceptable acid or base in combination with one or more pharmaceutically acceptable excipients. 15
[0036]
36. Pharmaceutical composition according to claim 35, for its use as a pro-apoptotic agent.
[0037]
37. Pharmaceutical composition according to claim 36, for its use in the treatment of cancers and autoimmune diseases and the immune system. 20
[0038]
38. Pharmaceutical composition according to claim 37, 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.
[0039]
39. Use of a pharmaceutical composition according to claim 35 in the manufacture of medicaments for use as pro-apoptotic agents. 3037959 - 156-
[0040]
40. Use of a pharmaceutical composition according to claim 35 in the manufacture of medicaments for use in the treatment of cancer and autoimmune diseases and the immune system. 5
[0041]
41. Use of a pharmaceutical composition according to claim 35, 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.
[0042]
42. A compound of formula (1) according to one of claims 1 to 32, or one of its addition salts with a pharmaceutically acceptable acid or base, for its use in the treatment of cancers of the bladder, brain , breast and uterus, chronic lymphoid leukemias, colon cancer, esophagus and liver cancer, lymphoblastic leukemias, acute myeloid leukemias, lymphomas, melanomas, hematological malignancies, myeloma, cancer of the ovaries, non-small cell lung cancer, prostate cancer, pancreatic cancer and small cell lung cancer.
[0043]
43. Use of a compound of formula (I) according to one of claims 1 to 32, or an addition salt thereof with a pharmaceutically acceptable acid or base, in the manufacture of medicaments for use in the treatment of bladder, brain, breast and uterine cancers, chronic lymphoid leukemias, colon, esophageal and liver cancer, lymphoblastic leukemias, acute myeloid leukemias, lymphomas, melanoma, hematological malignancies, myeloma, ovarian cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer and small cell lung cancer. 30
[0044]
44. Association of a compound of formula (I) according to any one of claims 1 to 32 with an anticancer agent chosen from genotoxic agents, mitotic poisons, antimetabolites, proteasome inhibitors, kinase inhibitors and antibodies.
[0045]
45. A pharmaceutical composition containing a combination according to claim 44 in combination with one or more pharmaceutically acceptable excipients.
[0046]
46. Association according to claim 44 for its use in the treatment of cancers. 10
[0047]
47. Use of an association according to claim 44 in the manufacture of medicaments for use in the treatment of cancers.
[0048]
48. A compound of formula (1) according to any one of claims 1 to 32, for its use in the treatment of cancers requiring radiotherapy.

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RU2760554C1|2021-11-29|

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US10618909B2|2020-04-14|

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RS61179B1|2021-01-29|

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PH12017502315B1|2018-06-25|

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CU24466B1|2020-01-03|

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US20190248805A1|2019-08-15|

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LT3313817T|2020-11-25|

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HRP20201782T1|2021-01-22|

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FR3037959B1|2017-08-04|

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ES2831749T3|2021-06-09|

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MX2017016995A|2018-09-07|

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AR105102A1|2017-09-06|

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JO3674B1|2020-08-27|

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HUE051877T2|2021-03-29|

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CN108137497B|2021-06-15|

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AU2016282828B2|2020-07-16|

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CA2990084A1|2016-12-29|

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PT3313817T|2020-11-26|

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IL256375D0|2018-02-28|

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CL2017003205A1|2018-06-15|

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SI3313817T1|2021-01-29|

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UA122498C2|2020-11-25|

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ECSP17083003A|2018-02-28|

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PE20181491A1|2018-09-18|

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DK3313817T3|2020-12-14|

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IL256375A|2020-03-31|

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CO2017012832A2|2018-03-28|

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CU20170163A7|2018-05-08|

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SV2017005589A|2018-06-01|

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JP2018527297A|2018-09-20|

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MD3313817T2|2021-01-31|

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CR20170575A|2018-02-20|

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CA2990084C|2021-04-13|

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KR20180015264A|2018-02-12|

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EP3313817A1|2018-05-02|

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AU2016282828A1|2018-01-18|

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UY36734A|2016-12-30|

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EP3313817B1|2020-09-16|

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TW201712006A|2017-04-01|

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CN108137497A|2018-06-08|

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TN2017000524A1|2019-04-12|

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JP6741699B2|2020-08-19|

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MA42230A|2018-05-02|

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MA42230B1|2020-11-30|

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PH12017502315A1|2018-06-25|

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US20180258098A1|2018-09-13|

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法律状态:
2016-06-28| PLFP| Fee payment|Year of fee payment: 2 |

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2016-12-30| PLSC| Publication of the preliminary search report|Effective date: 20161230 |

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2017-06-27| PLFP| Fee payment|Year of fee payment: 3 |

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

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2020-06-22| PLFP| Fee payment|Year of fee payment: 6 |

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2021-06-29| PLFP| Fee payment|Year of fee payment: 7 |

优先权:

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申请号 | 申请日 | 专利标题

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FR1555750A|FR3037959B1|2015-06-23|2015-06-23|NOVEL BICYCLIC DERIVATIVES, PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME|FR1555750A| FR3037959B1|2015-06-23|2015-06-23|NOVEL BICYCLIC DERIVATIVES, PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME|

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TW105119604A| TW201712006A|2015-06-23|2016-06-22|New bicyclic derivatives, a process for their preparation and pharmaceutical compositions containing them|

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RS20201419A| RS61179B1|2015-06-23|2016-06-22|Bicyclic derivatives, a process for their preparation and pharmaceutical compositions containing them|

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PT167308543T| PT3313817T|2015-06-23|2016-06-22|New bicyclic derivatives, a process for their preparation and pharmaceutical compositions containing them|

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LTEP16730854.3T| LT3313817T|2015-06-23|2016-06-22|Bicyclic derivatives, a process for their preparation and pharmaceutical compositions containing them|

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UAA201800621A| UA122498C2|2015-06-23|2016-06-22|New bicyclic derivatives, a process for their preparation and pharmaceutical compositions containing them|

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US15/738,186| US10323041B2|2015-06-23|2016-06-22|Bicyclic derivatives, a process for their preparation and pharmaceutical compositions containing them|

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CU2017000163A| CU24466B1|2015-06-23|2016-06-22|COMPOUNDS DERIVED FROM D-PHENYLALANINE-N-SUBSTITUTED WITH AROMATIC BICYCLES, METHOD OF PREPARING THEM, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|

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PCT/EP2016/064418| WO2016207217A1|2015-06-23|2016-06-22|New bicyclic derivatives, a process for their preparation and pharmaceutical compositions containing them|

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CA2990084A| CA2990084C|2015-06-23|2016-06-22|Bicyclic derivatives, a process for their preparation and pharmaceutical compositions containing them|

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DK16730854.3T| DK3313817T3|2015-06-23|2016-06-22|BICYCLIC DERIVATIVES, MANUFACTURING PROCEDURES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THESE|

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AU2016282828A| AU2016282828B2|2015-06-23|2016-06-22|New bicyclic derivatives, a process for their preparation and pharmaceutical compositions containing them|

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TNP/2017/000524A| TN2017000524A1|2015-06-23|2016-06-22|New bicyclic derivatives, a process for their preparation and pharmaceutical compositions containing them|

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GEAP201614681A| GEP20207056B|2015-06-23|2016-06-22|New bicyclic derivatives, a process for their preparation and pharmaceutical compositions containing them|

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KR1020187002027A| KR20180015264A|2015-06-23|2016-06-22|Novel bicyclic derivatives, processes for their preparation and pharmaceutical compositions containing them|

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MA42230A| MA42230B1|2015-06-23|2016-06-22|Bicyclic derivatives, process for their preparation, and pharmaceutical compositions containing them|

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PE2017002717A| PE20181491A1|2015-06-23|2016-06-22|NEW BICYCLE DERIVATIVES, A PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM|

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SI201631022T| SI3313817T1|2015-06-23|2016-06-22|Bicyclic derivatives, a process for their preparation and pharmaceutical compositions containing them|

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EP16730854.3A| EP3313817B1|2015-06-23|2016-06-22|Bicyclic derivatives, a process for their preparation and pharmaceutical compositions containing them|

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PL16730854T| PL3313817T3|2015-06-23|2016-06-22|Bicyclic derivatives, a process for their preparation and pharmaceutical compositions containing them|

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MDE20180438T| MD3313817T2|2015-06-23|2016-06-22|Bicyclic derivatives, a process for their preparation and pharmaceutical compositions containing them|

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RU2018102368A| RU2760554C1|2015-06-23|2016-06-22|New bicyclic derivatives, method for their production and pharmaceutical compositions containing them|

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CR20170575A| CR20170575A|2015-06-23|2016-06-22|NEW BICYCLIC DERIVATIVES, A PROCESS FOR THE PREPARATION AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM.|

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CN201680048560.1A| CN108137497B|2015-06-23|2016-06-22|Bicyclic derivatives, process for their preparation and pharmaceutical compositions containing them|

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HUE16730854A| HUE051877T2|2015-06-23|2016-06-22|Bicyclic derivatives, a process for their preparation and pharmaceutical compositions containing them|

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EA201890126A| EA033566B1|2015-06-23|2016-06-22|New bicyclic derivatives, process for their preparation and pharmaceutical compositions containing them|

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PH12017502315A| PH12017502315A1|2015-06-23|2017-12-14|New bicyclic derivatives, a process for their preparation and pharmaceutical compositions containing them|

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CL2017003205A| CL2017003205A1|2015-06-23|2017-12-14|New bicyclic derivatives, a process for their preparation and pharmaceutical compositions that contain them.|

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ECIEPI201783003A| ECSP17083003A|2015-06-23|2017-12-15|NEW BICYCLIC DERIVATIVES, A PROCESS FOR THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|

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IL256375A| IL256375A|2015-06-23|2017-12-18|New bicyclic derivatives, a process for their preparation and pharmaceutical compositions containing them|

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HK18113624.7A| HK1254656A1|2015-06-23|2018-10-24|New bicyclic derivatives, a process for their preparation and pharmaceutical compositions containing them|

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US16/394,308| US10618909B2|2015-06-23|2019-04-25|Bicyclic derivatives, a process for their preparation and pharmaceutical compositions containing them|

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