OA18892A - New hydroxyacid derivatives, a process for their preparation and pharmaceutical compositions containing them. - Google Patents

Abstract

Compounds of formula (I): <img file="OA18892A_A0001.tif"/> wherein R1, R2, R3, R4, R5, R6, R7, R8, R14, A and n are as defined in the description. Medicaments.

Description

NEW HYDROXYACID DERIVATIVES, A PROCESS FOR THEIR PREPARATION

AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

The present invention relates to new hydroxyacid dérivatives, to a process for their préparation and to pharmaceutical compositions containing them.

The compounds of the present invention are new and hâve very valuable pharmacological characteristics in the field of apoptosis and cancerology.

Apoptosis, or programmed cell death. is a physiological process that is crucial for embryonic development and maintenance of tissue homeostasis.

Apoptotic-type cell death involves morphological changes such as condensation of the nucléus, DNA fragmentation and also biochemical phenomena such as the activation of caspases which cause damage to key structural components of the cell, so inducing its disassembly and death. Régulation of the process of apoptosis is complex and involves the activation or repression of several intracellular signal!ing pathways (Cory S. et al., Nature Review Cancer 2002, 2, 647-656).

Deregulation of apoptosis is involved in certain pathologies. Increased apoptosis is associated with neurodegenerative diseases such as Parkinson’s disease, Alzheimer's disease and ischaemia. Conversely. déficits in the implémentation oi apoptosis play a significant rôle in the development of cancers and their chemoresistance. in auto-immune diseases, inflammatory diseases and viral infections. Accordingly. absence of apoptosis is one of the phenotypic signatures of cancer (Hanahan D. et al., Cell 2000, 100, 57-70).

The anti-apoptotic proteins of the Bcl-2 family are associated with numerous pathologies. The involvement of proteins ofthe Bcl-2 family is described in numerous 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 lymphoîd leukaemia, lymphoma, myeloma, acute myeloid leukemia, pancreatic cancer, etc. Overexpression of the antiapoptotic proteins of the Bcl-2 family is involved in tumorigenesis, in résistance to

ORIGINAL

-2chemotherapy and in the clinical prognosis of patients affected by cancer. Notably, Mcl-l, an anti-apoptotic BcI-2 family member, is overexpressed in various types of cancer (Beroukhim R. et al., Nature 2010, 899-905). There is, therefore, a therapeutic need for compounds that inhibit the anti-apoptotic activity of the proteins of the Bcl-2 family.

In addition to being new, the compounds of the présent invention hâve pro-apoptotic properties making it possible to use them in pathologies involving a defect in apoptosis, such as, for example, in the treatment of cancer and of immune and auto-immune diseases.

The présent invention relates more especially to compounds of formula (I):

wherein:

(D ♦ A represents the group

in which 1 is linked to the oxygen atom and 2 is linked to the phenyl ring, ♦ R] represents a linear or branched (Cj-Cf,)alkyl group, a linear or branched (C2-C&)alkenyl group, a linear or branched (C2-Ct,)alkynyl group, a linear or branched (Ci-C₆)alkoxy group, a -S-(C|-C₆)alkyl group, a linear or branched (Ci-C₆)polyhaloalkyl. a hydroxy group, a hydroxy(Ci-C₆)alkyl group. a cyano group, -NR|₂Ri2^!- -Cys, or a halogen atom, ♦ R₂, R₃, R4 and R5 independently of one another represent a hydrogen atom, a halogen atom, a linear or branched (C|-C₆)alkyl group, a linear or branched

ORIGINAL

- 3 (C₂-C₆)alkenyl group, a linear or branched (C₂-C₆)alkynyl group, a linear or branched (Cj-CôJpolyhaloalkyl, a hydroxy group, a hydroxy(C|-Cô)alkyI group, a linear or branched (Cj-Côjalkoxy group, a -S-(Ci-Cô)alkyl group, a cyano group, a nitro group, -alkyl(Co-C6)-NR|oR|_O\ -0-alkyl(C|-C₆)-NRioRio\ -O-alkyl(C|-C₆)-Ru, -C(O)-OR|₀, -O-C(O)-R,₀, -C(0)-NR_loRio', -NR|₀-C(O)-R_I0 ⁷, -NR_I0-C(O)-OR|₀’, -alkyl(C|-C₆)-NR_lo-C(0)-Rio’, -SO₂-NR_I0R_l0’₅ -SO₂-alkyl(C |-C_b), or the substituents of one of the pairs (R₂, R₃). (R₃, R₄), (Rj, R5), when grafted onto two adjacent carbon atoms, form together with the carbon atoms carrying them an aromatic or non-aromatic ring composed of from 5 to 7 ring members, which may contain from l to 3 heteroatoms selected from oxygen, sulphur and nitrogen, it being understood that resulting ring may be substituted by a group selected from a linear or branched (Ci-C₆)alkyl group, -NRi₂Ri₂\ -alkyl(Co-Cô)-Cyi, or an oxo, ♦ R_ft represents -O-alkyl(C |-C_b)-R| i.

♦ R7 represents a hydrogen atom, a halogen atom, a linear or branched (C|-C_b)alkyl group, a linear or branched (C₂-Cô)alkenyl group, a linear or branched (C₂-C₆)alkynyl group, a linear or branched (Ci-Cô)polyhaloalkyl, a hydroxy group, a linear or branched (Ci-Côjalkoxy group, a -S-(Ci-C₆)alkyl group, a cyano group. a nitro group, -alkyl(C_o-C6)-NR|₍)R|o'. -0-alkyl(C|-C6)-NR.i₀Rio\ -O-Cy_b -alkyl(Co-C6)-Cyi, -alkenyl(C₂-C₆)-Cyi, -aIkynyl(C₂-C₆)-Cyi, -O-alkyl(Ci-C6)-R[|, -C(O)-OR_I0, -O-C(O)-R|₀, -C(O)-NRi₀R|₀\ -NR_l0-C(O)-R_!0·, -NR|q-C(O)-OR₁₀'. -alkyl(C_l-C6)-NRio-C(O)-R_lo’,-S0₂-NR|_üR_Io'_!-S0₂-alkyl(C_l-C₆), ♦ R_K represents a hydrogen atom, a linear or branched (C,-Cgjalkyl group. a -CHR_aR_b group, an aryl group, a heteroaryl group. an arylalkyl(C|-C_b) group, or a heteroarylalkyl(Ci-C*) group, ♦ R₉ represents a linear or branched (C|-C₆)alkyl group, a linear or branched (C₂-C₆)alkenyl group, a linear or branched (C₂-C₆)alkynyl group, -Cy₃, -aIkyl(Ci-C₆)-Cy₃, -alkenyl(C₂-C₆)-Cy₃, -alkynyl(C₂-C₆)-Cy₃, -Cy₃-Cy₄, -alkynyI(C₂-C_f,)-O-Cy₃, -Cy₃-alkyl(Co-C₆)-0-alkyl(Co-C₆)-Cy₄, a halogen atom. a cyano group, -C(O)-Ri₃, or -C(O)-NR|₃R|₃’, ♦ Rio and Rio’ independently of one another represent a hydrogen atom, a linear or branched (Ci-C_b)alkyl group, -alkyl(Co-C₆)-Cyi,

ORIGINAL

-4or the substituents of the pair (Rio, Rio') form together with the nitrogen atom carrying them an aromatic or non-aromatic ring composed of from 5 to 7 ring members, which may contain in addition to the nitrogen atom from l to 3 heteroatoms selected from oxygen, sulphur and nitrogen, it being understood that the nitrogen in question may be substituted by from l to 2 groups representing a hydrogen atom, or a linear or branched (C|-Cé)alkyl group, and it being understood that one or more of the carbon atoms of the possible substituents, may be deuterated, ♦ Ru represents -Cy₅-a]kyl(C₀-C₆)-0-alkyl(Co-C₆)-Cy6, -Cy5-alkyl(Co-C6)-Cy₆, -Cy₅-alkyl(C₍₎-C₆)-NR_l2-alkyl(Co-C6)-Cy₍„ ♦ R12, Rb', Rij and R_t3' independently of one another represent a hydrogen atom or an optionally substituted linear or branched (Ci-Cèjalkyl group, ♦ Ru represents a hydrogen atom, a hydroxy group, or a hydroxy(C i-Côjalkyl group, ♦ R_a represents a hydrogen atom or a linear or branched (Ci-Cô)alkyl group.

♦ Ri, represents a -O-C(O)-O-R_c group, a -O-C(O)-NR_cR_c' group, or a -O-P(O)(OR_C)₂ group, ♦ R_c and R/ independently of one another represent a hydrogen atom, a linear or branched (Ci-Cg)alkyl group. a cycloalkyl group, a (Ct-C6)alkoxy(Ci-C₆)alkyl group, a (Ci-C6)alkoxycarbonyl(Ci-C6)alkyl group, or the substituents of the pair (R_t, R_c‘) form together with the nitrogen atom carrying them a non-aromatic ring composed of from 5 to 7 ring members, which may contain in addition to the nitrogen atom from l 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 (Ci-Cé)alkyl group, ♦ Cyi, Cy₂, Cy₃, Cy₄ and Cy> independently of one another, represent a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, ♦ Cy₆ represents

or Cyé represents a heteroaryl group which is substituted by a group selected from

ORIGINAL

	-O-P(O)(OR20)2; -O-P(O)(O)2; -(CH2)p-O-(CHRIg-CHR|9-O)q-R20: hydroxy; hydroxy(C|-C6)alkyl; -(CH2)r-Y-(CH2)s-heterocycloalkyl; or -Y-(CH2)q-NR2|R2|’, ♦ Ris represents a hydrogen atom; a -(CH2)p-O-(CHRI8-CHR|9-O)q-R2Q group; a iinear or branched (Cj-Cé)alkoxy(C|-Cé)alkyl group; a -Y-(CH2)q-NR2iR2r group;
5	or a -(CH2)r-Y-(CH2)s-heterocycloalkyl group, ♦ Rrepresents a hydrogen atom; a hydroxy group; a hydroxy(Cj-C6)alkyl group; a -(CH2)r-Y-(CII2)s-heterocycloalkyl group; a (CH2)rY-X-O-P(O)(OR20)2 group; a -O-P(O)(O')2 group; a -(CH2)p-0-(CHRi8-CHRj9-0)q-R2o group; a -(CH2)P-O-C(O)-NR22R23 group; or a -Y-(CH2)q-NR2iR2i’ group,
ΙΟ	♦ Ri7 represents a hydrogen atom; a -(CH2)p-0-(CHRi8-CI-IR|9-0)q-R2o group; a -0-P(0)(OR2o)2 group; a -O-P(O)(O‘)2 group; a hydroxy group; a hydroxy(Ci-C6)alkyl group; a -(CH2)r-Y-(CH2)s-heterocycloalkyi group; a -Y-(CH2)q-NR2|R2i' group; or an aldonic acid, ♦ X represents a -(CH2)S- group or a -C(O)- group,
15	♦ Y represents a bond or an oxygen atom, ♦ R|8 represents a hydrogen atom or a (Ci-Cé)alkoxy(C j-Cé)alkyl group, ♦ Riq represents a hydrogen atom or a hydroxy(C|-Cé)aIkyl group,
j	♦ R2q represents a hydrogen atom or a linear or branched (Ci-Cé)alkyl group, ♦ R2i and R2/ independently of one another represent a hydrogen atom, a linear or
u 20	branched (Cj-Cé)alkyl group, or a hydroxy(C[-Cé)alkyl group, or the substituents of the pair (R2|, R2i ) form together with the nitrogen atom
	carrying them an aromatic or non-aromatic ring composed of from 5 to 7 ring members, which may contain in addition to the nitrogen atom from 1 to 3
-	heteroatoms selected from oxygen, sulphur and nitrogen, it being understood that
25	the resulting ring may be substituted by a group representing a hydrogen atom or a
-	linear or branched (C|-Cé)alkyl group, ♦ R22 represents a (C|-Cé)alkoxy(C|-Cé)alkyl group, a -(CH2)P-NR24R24’ group, or
-	a -(CII2)p-O-(CHRis-CHRi9-O)q-R2n group, ♦ R23 represents a hydrogen atom or a (Ci-C6)alkoxy(C]-Cé)alkyl group.
30	or the substituents of the pair (R22, R22) form together with the nitrogen atom carrying them an aromatic or non-aromatic ring composed of from 5 to 18 ring
-	members, which may contain in addition to the nitrogen atom from 1 to 5

ORIGINAL

-6heteroatoms selected from oxygen, sulphur and nitrogen, it being understood that the resulting ring may be substituted by a group representing a hydrogen atom, a linear or branched (C i-C&)alkyl group or a heterocycloalkyl group, ♦ R24 and Ri-f independently of one another represent a hydrogen atom or a linear or branched (Ci-C&)alkyl group, or the substituents of the pair (R24, R24’) form together with the nitrogen atom carrying them an aromatic or non-aromatic ring composed of from 5 to 7 ring members, which may contain in addition to the nitrogen atom from one to 3 heteroatoms selected from oxygen, sulphur and nitrogen, it being understood that IO the resulting ring may be substituted by a group representing a hydrogen atom or a linear or branched (C i-Côjalkyl group, ♦ n is an integer equal to 0 or l, ♦ p is an integer equal to 0, l or 2, ♦ q is an integer equal to l, 2, 3 or 4, ♦ r and s are independently an integer equal to 0 or l,

J with the proviso that R]s, Ri₆ and Rj? cannot represent together a hydrogen atom and, when R[ represents a methyl group, R|> cannot represent a methoxyethoxy group, it being understood that:

►J

- aryl means a phenyl, naphthyl, biphenyl, indanyl or indenyl group,

- heteroaryl means any mono- or bi-cyclic group composed of from 5 to IO ring members, having at least one aromatic moiety and containing from l to 3 heteroatoms selected from oxygen, sulphur and nitrogen, cycloalkyl means any mono- or bi-cyclic non-aromatic carbocyclic group containing from 3 to IO ring members,

- “heterocycloalkyl'’ means any mono- or bi-cyclic non-aromatic carbocyclic group containing from 3 to IO ring members, and containing from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen, which may include fused, bridged or spiro ring Systems, it being possible for the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined

ORIGINAL

-7and the alkyl, alkenyl, alkynyl, alkoxy groups, to be substituted by from l to 5 groups selected from optionally substituted linear or branched (C i-Cô)alkyl, optionally substituted linear or branched (C₂-C₆)alkenyl group, optionally substituted linear or branched (C₂-C₆)alkynyl group, optionally substituted linear or branched (C|-C₆)alkoxy, optionally substituted (Ci-Câ)alkyl-S-, hydroxy, oxo (or Λ'-oxide where appropriate), nitro, cyano, -C(O)-OR’, -O-C(O)-R’, -C(O)-NR’R”, -NR’R”, -(C=NR’)-OR”, linear or branched (Ci-Cû)polyhaloalkyl, trifluoromethoxy, or halogen, it being understood that R’ and R” independently of one another represent a hydrogen atom or an optionally substituted linear or branched (Ci-Cô)alkyl group, and it being understood that one or more of the carbon atoms of the preceding possible substituents, may be deuterated, their enantiomers, diastereoisomers and atropisomers, and addition salts thereof with a pharmaceuticaily acceptable acid or base.

Among the pharmaceuticaily acceptable acids there may be mentioned, without implying any limitation, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, maionic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulphonic acid, camphoric acid etc.

Among the pharmaceuticaily acceptable bases there may be mentioned, without implying any limitation, sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine etc.

Advantageously, at least one of the groups selected from R₂, R₃. Rq and R5 does not represent a hydrogen atom.

More especially, compounds of formula (I) to which préférence is given are compounds wherein n is an integer equal to l.

In another embodiment of the invention, an advantageous possibility consists of compounds of formula (I-a):

ORIGINAL

wherein R), R₂, R₃, R4, R>, R₍„ R7, Rg, Ru and A are as defined for formula (I).

In lhe preferred compounds of the invention. Ri represents a linear or branched (C|-C6)alkyl group or a halogen atom. More preferably. Ri represents a methyl group, an 5 ethyl group, a bromine atom or a chlorine atom.

Atropisomers are stereoisomers arising because of hindered rotation about a single bond, where energy différences due to steric strain or other contributors create a barrier to rotation that is high enough to allow for isolation of individual confomiers. For compounds according to the invention, atropisomers are as follows:

IO

Preferred atropisomer is (5^).

Advantageously, R14 represents a hydrogen atom, a hydroxy group, a hydroxymethyl group or a hydroxyethyl group. Preferably, R14 represents a hydrogen atom.

Advantageously, R₂ represents a halogen atom, a hydroxy group, a linear or branched

ORIGINAL

-9(C|-C₆)alkoxy group. More preferably, R₂ represents a methoxy group, a hydroxy group, a fluorine atom, a bromine atom or a chlorine atom. Even more preferably, R₂ represents a chlorine atom.

R₃ advantageously represents a hydrogen atom, a hydroxy group, a linear or branched (Ci-Cû)alkoxy group or -0-alkyl(C]-C6)-NRjoRio’-0-alkyl(C|-C₆)-NR|oRio’.

In some preferred embodiment of the invention,

represents wherein R|, Rio and Rio' are as defined for formula (I).

In the preferred compounds of the invention,

represents wherein Rio and Rio' are as defined for formula (l).

R4 and R5 preferably represent a hydrogen atom.

Advantageously,

R₃ represents

Rio

ORIGINAL

- ΙΟIn an advantageous embodiment, the substituents of the pair (R|, R₅) are identical and the substituents of the pair (R₂, Rj are identical. In the preferred compounds of the invention, the substituents of the pair (R_b R,) are identical and represent a (Ci-C₆)alkyl group, preferably a methyl group, whereas the substituents of the pair (R₂, Rfl are identical and 5 represent a halogen atom, preferably a chlorine atom, or a hydrogen atom.

In the preferred compounds of the invention, represents wherein R| [ is as defined for formula (I).

R₇ preferably represents a hydrogen atom.

Preferably, R₈ represents a hydrogen atom, a -CHR_aR_b group, an optionally substituted linear or branched (C|-C₈)alkyl group, or a heteroarylalkyl(C|-C₆) group. Preferably. R₈ represents a -CHR_aR_h group in which R_a represents a hydrogen atom or a methyl group and Rb represents a -O-C(O)-O-(Ci-C₈)alkyl group; a -O-C(O)-O-cycloalkyl group; a -O-C(O)-NR_cR_c· group, in which R_c and R_c’ independently of one another represent a hydrogen atom, a linear or branched (C]-C₈)alkyl group, a (C|-C6)alkoxy(Ci-C₆)alkyl group. a (Ci-C6)alkoxycarbonyl(C|-Cft)alkyl group, or the substituents of the pair (R,. R_c‘) form together with the nitrogen atom carrying them a non-aromatic ring composed of from 5 to 7 ring members, which may contain in addition to the nitrogen atom from l to 3 heteroatoms selected from oxygen and nitrogen; or a -O-P(O)(OH)₂ group. Preferred R₈ groups are as follows: hydrogen; methyl; ethyl; (5-methyl-2-oxo-l,3-dioxol-4-yi)niethyl; a -CHR_aR_b group in which R_a represents a methyl group and R_b represents a -O-C(O)-O-CH₂CH3 group or a -O-C(O)-N(CTl3)₂ group. Even more preferably, R₈ represents hydrogen.

In the preferred compounds of the invention, R₉ represents a linear or branched

ORIGINAL

- Il (Ci-C₆)alkyl group, a linear or branched (C₂-C₆)alkenyl group, a linear or branched (C₂-C₆)alkynyl group, an aryl group or a heteroaryl group. Advantageously, R₉ represents a linear or branched (C₂-C₆)alkynyl group, an aryl group or a heteroaryl group. More preferably, R₉ represents a prop-l-yn-l-yl group, a but-l-yn-l-yl group, a phenyl group or a furan-2-yl group. In a more preferred embodiment, R₉ represents a 4-(benzyloxy)phenyl group, a 4-(pyridin-4-ylmethoxy)phenyl group, a 4-phenylbut-l-yn-l-yl group, a 4-fluorophenyl group or a 5-fluorofuran-2-yl group. Even more preferentially, R₉ represents a 4-fluorophenyl group.

In the preferred compounds of the invention, Rio and Rio’ independently of one another represent a linear or branched (Ci-Cft)alkyl group, or the substituents of the pair (Rio, Rio ) form together with the nitrogen atom carrying them a non-aromatic ring composed of from 5 to 7 ring members, which may contain in addition to the nitrogen atom from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen, it being understood that the nitrogen in question may be substituted by a group representing a hydrogen atom or a linear or branched (C]-C₆)alkyl group. More preferably, Rio and Rio’ represent a methyl group, or the substituents of the pair (R|₀, Rio’) form together a 4-methyl-pîperazinyl group or a 4-ethyl-piperazinyl group. In a more preferred embodiment, the substituents of the pair (Rio, Rio’) form together a 4-methyl-piperazinyl group. In another preferred embodiment, Rio and Rio' represent a methyl group.

Advantageously, Ru represents -Cy5-alkyl(Co-C₆)-Cy₆. More particularly. Ru represents -Cy₅-Cy₆.

Cys preferably represents a heteroaryl group, particularly, a pyrimidinyl group, a pyrazolyl group, a triazolyl group, a pyrazinyl group or a pyridinyl group. More preferably, Cy₅ represents a pyrimidin-4-yl group, a pyrazol-5-yl group, a triazol-5-yl group, a pyrazin-2-yl group or a pyridin-4-yl group. In the preferred compounds of the invention, Cy.s represents a pyrimidin-4-yl group.

In another embodiment of the invention, Cy> represents a heteroaryl group which is substituted by an optionally substituted linear or branched (Ci-CJalkyl group, an optionally substituted linear or branched (Ci-C₆)alkoxy group, a -NR’R” group, or a linear

ORIGINAL or branched (Ci-CôJpolyhaloalkyl group, it being understood that R' and R” independently of one another represent a hydrogen atom or an optionally substituted linear or branched (C]-C₆)alkyl group.

Preferably, Cy₆ represents

Cyt, advantageously represents a 3-pyridinyl group, a 4-pyridinyl group, a pyridazin-4-yl group, a pyrazin-2-yl group, or a pyrimidin-4-yl group, it being understood that these heteroaryl groups are substituted by a group selected from -0-P(0)(OR₂o)₂; -O-P(O)(O’)₂; -(CH₂)p-0-(CHRi8-CHR|₉-O)_q-R_2t); hydroxy(C_rC₆)alkyl;

-(CH₂)r-Y-(CH₂)_s-heterocycloalkyl; or -Y-(CH₂)_q-NR₂iR₂t'. More preferably, Cy& represents a 5-(hydroxymethyl)pyridin-3-yl group or a 2-(hydroxymethyl)pyrimidin-4yl group.

Advantageously, R|₆ and Rp represent a hydrogen atom and R|> represents a -(CH₂)p-0-(CHR]8-CHRi9-0)_q-R₂o group; a linear or branched (C|-C6)alkoxy(Cj-C6)alkyl group; a -Y-(CH₂)_q-NR_2lR_2l’ group; or a -(CH₂)_r-Y-(CH₂)_s-heterocycloalkyl group, in which Ris, R19, R₂o, R21, R₂i , Y, p, Q, r and s are as defined for formula (l).

In the preferred compounds of the invention, R15 and R_I7 represent a hydrogen atom and R|6 represents a hydroxy group; a hydroxyfCi-CôJalkyl group; a -(CH₂)_r-Y-(CH₂)_s-heterocycloalkyi group; a -O-P(O)(OR₂q)₂ group; a -O-P(O)(O’)₂ group; a -(CH₂)_p-0-(CHRi₈-CHRi9-0)_q-R₂o group; a -(CH₂)_P-O-C(O)-NR₂₂R₂3 group; a (CH₂)_r-Y-X-O-P(O)(OR₂₀)₂ group; or a -Y-(CH₂)_q-NR_2IR_2!’ group, in which R|₈, R19, R₂q, R₂i, R₂i^?, 1<22- R23, X, Y, P, q, r and s are as defined for formula (I).

In some preferred embodiment of the invention, R15 and R]₆ represent a hydrogen atom and Ri? represents a -(CH₂)_p-0-(CHRi₈-CHR[9-0)_q-R₂o group; a -0-P(0)(OR₂o)₂ group; a -O-P(O)(O’)₂ group; a hydroxy group; a hydroxy(C]-C6)alkyl group;

ORIGINAL

- 13 a -(CH₂)_rY-(CH2)_s-heterocycloalkyl group; a -Y-(CH₂)q-NR₂iR2r group; or an aldonic acid, in which R_!8, R_I9, R₂₀, R?i, R21’, Y, P, q, r and s are as defined for formula (I).

In a preferred embodiment of the invention, heterocycloalkyl as defined for R15, Rjô and Rn represents any mono- or bi-cyclic non-aromatic carbocyclic group containing from 3 to 5 IO ring members, and containing from l to 3 heteroatoms selected from oxygen, sulphur and nitrogen, it being understood that the resulting ring may be substituted by from l to 5 groups selected from linear or branched (Cj-C(,)alkyl, linear or branched (Ci-C'ôjalkoxy, hydroxy, or hydroxy(Ci-C₆)alkyl.

Advantageously, R15 represents a -(CH₂)p-O-CH₂-CH(CH₂OH)-OH group; IO a -(CH₂)_p-O-(CH₂-CTI₂-O)_q-H group; a -(CH₂)_P-O-(CH2-CH₂-O)_q-CH₃ group;

a methoxymethyl group; a (2,2-dimethyl-l,3-dioxolan-4-yl)methoxy group; a (2.2-dimethyl-l.3-dioxolan-4-yl)methoxymethyl group; or a -Y-(CH2)q“N(CH2-CH₂-OH)₂ group, in which Y, p and q are as defined for formula (I).

In the preferred compounds of the invention, Riô represents a hydroxy group; a 15 hydroxymethyl group; a (2,2-dimethyl-l,3-dioxolan-4-yl)methoxy group; a -O-P(O)(OH)₂ group; a -(CH₂)_P-O-CH₂-CH(CH2OH)-OH group; a -(CH₂)_P-O-(CH₂-CH₂-O)_q-H group; a -(CH₂)_p-O-(CH₂-CH₂-O)_q-CI-l3 group, in which p and q are as defined for formula (I); a -O-CH(CH₂-OC 113)2 group; a -CH₂-O-C(O)-NR₂₂R₂3 group, in which R₂₂ is as defined for formula (l) and R₂3 represents a hydrogen atom, or in which R₂₂ and R₂₃ represent a 20 (Ci-C6)alkoxy(C]-C₆)alkyl group, or in which the substituents of the pair (R22- R23) f°rm together with the nitrogen atom carrying them a non-aromatic ring composed of from 5 to 18 ring members, which may contain in addition to the nitrogen atom from 1 to 5 heteroatoms selected from oxygen, sulphur and nitrogen, it being understood that the resulting ring may be substituted by a group representing a linear or branched (C]-C₆)alkyl 25 group or a heterocycloalkyl; a -O-(CH₂)2-NR2]R₂i’ group; a -CHi-NR^iRii’ group, in which R₂i and R₂|’ are as defined for formula (I); a (CI-I₂)_r-0-X-0-P(0)(OR₂o)₂ group, în which X and r are as defined for formula (1), and s is integer equal to 1; or a -(CH₂)_r-Y(CH₂)_s-heteiOcycloalkyl group, in which Y is a bond, r and s are integers equal to 0 and the heterocycloalkyl group represents an aldohexose of formula:

ORIGINAL

in which each R₂₀ is independent. More preferably, the heterocycloalkyl group represents an aidohexose of formula:

in which each R₂q is independent.

In some preferred embodiment of the invention. Rn represents a hydroxy group; a hydroxy methyl group; a hydroxyethyl group; a -O-(CH₂-CH₂-O)_q-CH₃ group; a -O-CH₂-CH(CH₂OH)-OH group; a -(CH₂)p-O-(CH₂-CH₂-0)_q-H group; a -O-P(O)(OH)₂ group; a -O-P(O)(O')₂ group; a -O-CH(CH₂-OCH₃)₂ group; a -O-(CH₂)₂-NR₂iR₂f group;

a -CH₂-NR₃|R₂i’ group, in which R_2i and R₂T are as defined for formula (I);

a (2.2-dimethyl-l,3-dioxolan-4-yl)methoxy group; D-mannonic acid; or a -(CH₂)_r-Y-(CH₂)_s-heterocycloa!kyl group in which Y is a bond, s is an integer equal to 0, r is as defined for formula (!) and the heterocycloalkyl group represents an aidohexose of formula:

in which each R₂o is independent. More preferably, the heterocycloalkyl group represents an aidohexose of formula:

ORIGINAL

in which each R₂o is independent.

Among the preferred compounds of the invention there may be mentioned:

- (2 7?)-2- {[(5S_a)-5- {3-chloro-2-methy I-4-[3-(4-methylpiperazin-1 yl)propoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-(2-{[2(3-hydroxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid;

- (27?)-2-{[(5S_a)-5-{3-chloro-2-methyl-4-[3-(4-methylpiperazin-lyl)propoxy]phenyl} -6-(4-lluoropheny l )thieno[2,3-ô/]pyrimidin-4-yl]oxy} -3-(2- {[2(4-hydroxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid;

- (2/?)-2-{[(5S'_a)-5-{3-chloro-2-methyl-4-[3-(4-methylpiperazin-lyl)propoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i:/]pyrimidm-4-yl]oxy}-3-[2-({2[3-(hydroxymethyr)phenyl]pyrimidin-4-yl}methoxy)phenyl]propanoic acid;

- (2/?)-2- {[(5S_a)-5- {3 -chloro-2-methyl-4-[3-(4-methylpiperazin-1 yl)propoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-</]pyrimidin-4-yl]oxy}-3-[2-({2[4-(hydroxymethyl)phenyl]pyrimidin-4-yl)methoxy)phenyl]propanoic acid;

- (2/î)-2-{[(5.S'_a)-5-{3-chloro-2-methyl-4-[3-(4-methylpiperazin-l- yl )propoxy]phenyl}-6-(4-fluoropheny l)thieno[2,3-<7]pyrimidin-4-yl]oxy}-3-{2-[(2{2-[(2,2-dimethyl-l,3-dioxoIan-4-yl)methoxy]phenyl}pyrimidin-4yl)methoxy]phenyl}propanoic acid;

- (27?)-2-{[(5S_a)-5-{3-chloro-2-methyl-4-[3-(4-methylpiperazin-lyl)propoxy]phenyl )-6-(4- fluorophenyl)thieno[2,3 -i/]pyrimidin-4-yi]oxy) -3-{2-[(2{2-[2-(2-methoxyethoxy)ethoxy]phenyl}pyrimidin-4- yl)methoxy]phenyl} propanoic acid;

- (2R)-2-{ [( 5S_a)-5-{3-chloro-2-methyl-4-[3-(4-methylpiperazin-1 yl)propoxy]phenyl}-6-(4-fIuorophenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-(2-{[2(2- {2-[2-(2-methoxyethoxy)ethoxy]ethoxy} phenyl)pyrimidin-4yl]methoxy}phenyl)propanoic acid;

ORIGINAL

- (2Æ)-2- {[(5S_a)-5- {3-chloro-2-methyl-4-[3-(4-methylpiperazin-1 yl)propoxy]phenyl}-6-(4-iluorophenyl)thieno[2,3-iZ]pyrimidin-4-yl]oxy}-3-[2-({2[2-(methoxymelhyl)phenyl]pyrimidin-4-yl}methoxy)phenyl]propanoic acid;

- (2/?)-2-{[(5S_a)-5-{3-chloro-2-methyl-4-[3-(4-methylpiperazin-l-yl)propoxy] phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{2-[(2methoxyethoxy)methyl]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid;

- (2Æ)-2-{[(5S_a)-5-{3-chloro-2-methyl-4-[3-(4-methylpiperazin-l-yl)propoxyJ pheny]}-6-(4-fluorophenyl)thieno[2,3-t/]pyrimidin-4-yl]oxy}-3-{2-[(2-{2-[(2hydroxyethoxy)methyl]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoîc acid;

- (2Æ)-2-{[(5S_fl)-5-{3-chloro-2-methyl-4-[3-(4-methylpiperazin-ly [)propoxy]phenyl }-6-(4-fluorophenyl)thieno[2,3-c/]pyrimidin-4-yl]oxy}-3-(2- {[2(2- {[(2,2-dimethy I-1,3-dioxolan-4-y 1 )methoxy]methyl} phenyl )p yri ni id i n-4yl]methoxy}phenyl)propanoic acid;

- (2Æ)-2-{[(5S_e)-5-{3-chloro-2-methyl-4-[3-(4-methylpiperazin-l-yl)propoxyJ phenyl }-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-y1]oxy} -3 - {2-[(2- {3-[(2hydroxyethoxy)melhyl]phenyl}pyrimidin-4-yl)methoxy]phenyI}propanoic acid;

- (2/?)-2-{[(5S_fl)-5-{3-chloro-2-methyl-4-[3-(4-methylpiperazin-lyl)propoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-</Jpyrimidin-4-yl]oxy}-3-{2-[(2{3-[(l,3-dimethoxypropan-2-yl)oxy]phenyl}pyrimidin-4- yl)methoxy]phenyl}propanoic acid;

- (2Æ)-2- {[(5S_a)-5-{3-chloro-2-methyl-4-[3-(4-methylpiperazin-1 y|)propoxy]phenyl}-6-(4-fluorophenyi)thieno[2.3-i/]pyrimidin-4-yl]oxy}-3-{2-[(2{4-[(l,3-dimethoxypropan-2-yl)oxy]phenyl}pyrimidin-4yl)methoxy]phenyl} propanoic acid;

- (2/?)-2-{[(55^, _I,)-5-{3-chloro-2-methyl-4-[3-(4-meihylpiperazin-ly|)piOpoxy]pheny]}-6-(4-fluorophenyl)thieno[2,3-if|pyrimidin-4-yl]oxy}-3-[2-({2[4-(2,3-dihydroxypropoxy)phenyl]pyrimidin-4-y 1} methoxy)phenyl]propanoic acid;

- methyl 6-i9-{3-[4-({2-[(2Æ)-2-carboxy-2-{[(5A_a)-5-{3-chloro-2-methyl-4-[3-(4methylpiperazin-l-yl)propoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-iZ] pyrimidin-4-yl]oxy}ethyl]phenoxy}methyl)pyrimidin-2-y]]phenyl}-a-Dmannopyranoside;

&

ORIGINAL

- methyl 6-O-{3-[4-({2-[(2Æ)-2-carboxy-2-{[(5S«)-5-{3-chloro-2-methyl-4-[3-(4methylpiperazin-l-yl)propoxy]phenyl(-6-(4-fluorophenyl)lhieno[2,3-J] pyrimidin-4-yl]oxy} ethyl]phenoxy} methyl)pyrimidin-2-yl]phenyl} -2,3,4-tri-6>methyl-cc-D-mannopyranoside;

- methyl 6-O-{4-[4-({2-[(2Æ)-2-carboxy-2-{[(5S_o)-5-{3-chloro-2-methyl-4-[3-(4methylpiperazin-l-yl)propoxy]phenyl(-6-(4-fluorophenyl)thieno[2,3-i/] pyrimidin-4-yl]oxy(ethyl]phenoxy(methyl)pyrimidin-2-yl]phenyl(-ci-Dmannopyranoside;

- methyl 6-O-{4-[4-({2-[(2Æ)-2-carboxy-2-{[(5S_a)-5-{3-chloro-2-methyl-4-[3-(4- methylpiperazin-l-yl)propoxy]phenyl(-6-(4-fluorophenyl)thieno[2,3-i/] pyrimidin-4-yl]oxy}ethyl]phenoxy}methyl)pyrimidin-2-yl]phenyl}-2,3,4-tri-(9methyl-a-D-mannopyranoside;

_ 6-0-{4-[4-({2-[(2/?)-2-carboxy-2-{[(5S_a)-5-{3-chloro-2-methyl-4-[3-(4methylpiperazin-l-yl)propoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin15 4-yl]oxy }ethyl]phenoxy} methyl)pyrimidin-2-y l]pheny I} -D-mannopyranose;

. 6-O-{2-[4-({2-[(2/î)-2-carboxy-2-{[(5S_fl)-5-{3-chloro-2-methyl-4-[3-(4methylpiperazin-l-yl)propoxy]phenyl(-6-(4-11 uorophenyl)thieno[2.3-i/]pyrimidin4-yl]oxy(ethyl]phenoxy}methyl)pyrimidin-2-yl]phenyl(-D-mannonic acid;

- 1,2-(9-(( 1 /?)-1 -( {4-(4-( {2-[(27?)-2-carboxy-2- {[(5SJ-5-{3-chloro-2-methyl-4-[3-(4- methylpiperazin-l-yl)propoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i7] pyrimidin-4-yl]oxy( ethyl]phenoxy (methyl )pyrimidin-2-yl]benzyl(oxy)ethylidene]β-D-mannopyranose;

- (2Æ)-2-{[(5S„)-5-{3-chloro-2-methyl-4-[3-(4-methylpiperazin-l - y l)propoxy]pheny I} -6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy} -3- {2-((225 {4-((a-D-mannopyranosyloxy)methyl]phenyl}pyrimidin-4yl)methoxy]phenyl(propanoic acid;

- (2/?)-2-{[(5S₀)-5-{3-chloro-2-methyi-4-(3-(4-methylpiperazin-lyl)propoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-£7]pyrimidin-4-yl]oxy}-3-(2-({2[4-(2-hydroxyethyI )phenyl]pyrimidin-4-yl} methoxy)phenyl]propanoic acid;

- (27?)-2- {[(5S_a)-5-{ 3-chloro-2-methyl-4-[3-(4-methylpiperazin-1 yl)propoxy]phenyl(-6-(4-fluorophenyl)thieno[2,3-i/|pyrimidin-4-yl]oxy}-3-[2-({2(2-(2,3-dihydroxypropoxy)phenyl]pyrimidin-4-yl} methoxy)phenyl]propanoic acid;

ORIGINAL

-IS-

- (2Æ)-2-{[(5S_o)-5-{3-chloro-2-methyl-4-[3-(4-methylpiperazin-ly|)propoxy]pheny l}-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-(2-( {2[2-(2-hydroxyethoxy)phenyl]pyrimidin-4-yl}methoxy)phenyl]propanoic acid;

- (222)-2- {[(5SJ-5- {3-chloro-2-methyl-4-[3-(4-methylpiperazin-1 - yl)propoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-t/]pyrimidin-4-yl]oxy}-3-{2-[(2{2-[(2,3-dihydroxypropoxy)methyl]phenyI}pyrimidin-4yl)methoxy]phenyl}propanoic acid;

- (2Æ)-2-{[(5S_fl)-5-{3-chloro-2-methyl-4-[3-(4-methylpipeiazin-l- yI)propoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-[2-({2l o [3-(phosphonooxy)phenyl]pyrimidin-4-yl} methoxy)phenyl]propanoic acid;

. 4-[4-({2-[(2/?)-2-carboxy-2-{[(5S_e)-5-{3-chloro-2-methyl-4-[3-(4-melhyl piperazin-l-yl)propoxy]phenyl}-6-(4-lluorophenyl)thieno[2,3-iZ]pyrimidin-4yl]oxy}ethyl]phenoxy}methyl)pyrimidin-2-yl]phenyl phosphate;

- (27?)-2-{[(5S_o)-5-{3-chloro-2-methyl-4-[3-(4-methylpiperazin-l- yl)propoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-[2-({2[3-(2-hydroxyethoxy)phenyl]pyrimidin-4-yl} methoxy )phenyJ]propanoic acid;

- (2R)-2-{[(55_o)-5-{ 3-chloro-2-methyl-4-[3-(4-methylpiperazin-1 yl)propoxy]phenyl}-6-(4-fluorophenyl)lhieno[2,3-iZ]pyrimidin-4-yl]oxy}-3-{2-[(2{4-[2-(2-methoxyethoxy)ethoxy]phenyl} pyrimidin-4- yl)methoxy]phenyl}propanoic acid;

- (2/?)-2-{[(5S_fl)-5-{3-chloro-2-methyl-4-[3-(4-methylpiperazin-l-yl)propoxy] phenyl}-6-(4-fluorophenyl)thieno[2,3-rf]pyrimidin-4-yl]oxy}-3-{2-[(2-{4-[2-(2hydroxyethoxy)ethoxy]phenyi}pyrimidin-4-yl)methoxy]phenyl (propanoic acid;

- (222)-2-{[(5SJ-5- {3-chloro-2-methyl-4-[3-(4-methylpiperazin-l-

y])propoxy]phenyl}-6-(4-nuorophenyl)thieno[2,3W]pyrimidin-4-yl]oxy)-3-(2-{[2(4- {2-[2-(2-methoxyethoxy)ethoxy]ethoxy} pheny l)pyrimidin-4yl]methoxy}phenyl)propanoic acid;

- (2Æ)-2-{[(5S_a)-5-{3-chloro-2-methyI-4-[3-(4-methylpiperazin-l-yl)propoxy] phenyl}-6-(4-fluorophenyl )thieno[2,3-<7]pyrimidin-4-yl]oxy}-3-{ 2-((2-{4-[2- (dimethylamino)ethoxy]phenyI} pyrimidin-4-yl)methoxy]phenyl} propanoic acid;

- (2Λ)-2- {[(5SJ-5- {3-chloro-2-methyi-4-[3-(4-methylpiperazin-1 y|)propoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-J]pyrimidin-4-yl]oxy}-3-{2-[(2-

ORIGINAL

- 19{3 - [(2,2-dimethy l -1.3 -dioxolan-4-yl)methoxy]phenyl} pyrimidin-4yl)methoxy]phenyl} propanoic acid;

- (2Λ)-2- {[(5SJ-5- {3-chioro-2-methyl-4-[2-(4-methy Ipiperazin-1 -yl )ethoxy] phenyl}-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-[2-({2-[3-(15- hydroxy-3-oxo-2,7,l 0,13-tetraoxa-4-azapentadec-l-yl)phenyl]pyrimidin-4yl} methoxy)phenyl]propanoic acid;

- (2R)-3-(2-{[2-(3-{[(l,4'-bipiperidin-r-ylcarbonyl)oxy]methyl}phenyl) pyrimidin-4-yl]methoxy}phenyl)-2-{[(5S’_a)-5-{3-chloro-2-methyl-4-[2-(4methylpiperazin-l-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4- yl]oxy}propanoic acid;

- (2Æ)-2-{[(5S_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy] phenyl}-6-(4-fluorophenyl)thieno[2,3-c/]pyrimidin-4-yl]oxy}-3-(2-{[2-(3-{2-[2-(2hydroxyethoxy)ethoxy]ethoxy}phenyl)pyrimidin-4-yl]niethoxy}phenyl)propanoic acid;

- (2Λ)-2- {[<5S_a)-5- {3-chloro-2-methyl-4-[2-(4-melhylpiperazin-1 -y l)ethoxy ] phenyl} -6-(4-fluorophenyl)thieno[2,3-<7]pyrimidin-4-yl]oxy} -3-(2-((2- {3-(2-(2hydroxyethoxy)ethoxy]phenyl}pyrimidin-4-yl)inethoxy]phenyl}propanoic acid;

- (27?)-2-{[(5S_a)-5-{3-chIoro-2-methyl-4-[2-(4-methy Ipiperazin-l-yl)ethoxy] phenyl }-6-(4-fluorophenyl)lhieno[2,3-i/]pyriniidin-4-yl]oxy}-3-{2-[(2-{ 3-(2-(2- inethoxyethoxy)ethoxy]phenyl}pyrimidin-4-yl)methoxy]phenyl} propanoic acid;

- (2/?)-2-{[(5S_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy] phenyl }-6-(4-tluorophenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-{2-[(2-{3-[({ [2-(4methy Ipiperazin-1 -yl)ethyl]carbamoyl} oxy )methy 1 Jphenyl} pyrimidin-4yl)methoxy]phenyl} propanoic acid;

- (2Æ)-2-{[(5S_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l -yl)ethoxy] phenyl} -6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy} -3- {2 - [(2- {3 - [ ( {[2(morpholin-4-yl)ethyl]carbamoyl}oxy)inelhyl]phenyl}pyriniidin-4-yl)methoxy] phenyl}propanoic acid;

- (2Æ)-2-{[(5S_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy] phenyl}-6-(4-fluorophenyl)thieno[2,3-J]pyrimidin-4-yl]oxy}-3-{2-[(2-{3-[({[2(dimethylamino)ethyl]carbamoyl}oxy)methyl]phenyl}pyriinidin-4-yl)methoxy] phenyl}propanoic acid;

ORIGINAL

- (2À)-2-{ ((55^)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy] phenyl}-6-(4-tluorophenyl)thieno(2,3-i/]pyrimidin-4-yl]oxy}-3-{2-[(2-{3-[({[2(pynoIidin-l-yl)ethyl]carbamoyl}oxy)methyl]phenyl}pyrimidin-4-yl)methoxy] phenyl} propanoic acid;

- (27?)-3-[2-({2-[3-({[bis(2-methoxyethyl)carbamoyI]oxy}rnethyl)phenyl] pyrimidin-4-y I} methoxy)phenyl]-2- {[(55^)-5- {3-chloro-2-methyl-4-[2-(4methylpiperazin-l-yl)ethoxy]phenyl}-6-(4-fluorophenyl )thieno[2,3-i/]pyrimidîn-4yl]oxy}propanoic acid;

- (2/?)-2-{[(5₁S'_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy] phenyl}-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-(2-{[2-(3{[( l ,4,7,10,13-pentaoxa-16-azacyclooctadecan-16ylcarbonyl )oxy] methy l}phenyl)pyrimidin-4-yl]methoxy} phenyl )propanoic acid;

- (2R)-2-{| (55_ο)-5-{ 3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 -yl)ethoxy] phenyl} -

6-(4-fluorophenyl)thieno[2.3-i/]pyrimidin-4-yl]oxy}-3“[2( {2-(3-(2,3- dihydroxypropoxy)phenyl]pyrimidin-4-yI} methoxy)phenyl]propanoic acid;

- (2/?)-2-{[(55'_ci)-5-{3-chloro-2-methyl-4-[2-(4-meÎhvlpiperazin-1 -vl)ethoxyj

J phenyl} -6-(4-fluorophenyl)thieno(2,3-i/]pyrimidin-4-yl]oxy} -3-(2- {[2-(3- {2-(2-(2methoxyethoxy)ethoxy]ethoxy}phenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic U acid;

- (2Æ)-3-(2-{[2-(3-{2-(bis(2-hydroxyethyl)amino]ethoxy}phenyI)pyrimidin-4y 1] methoxy} phenyl)-2- {[(5^)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(4-fhiorophenyl)thieno[2,3-</]pyrimidin-4-yl]oxy} propanoic acid;

- (2/î)-2-{ [(55^)-5-{2,3-dimethyl-4-[2-(4-methylpiperazin-l-yl)ethoxy] phenyl}-6-(4- fluorophenyI)thieno[2,3-t7]pyrimidin-4-yl]oxy}-3-{2-[(2-{3-[( {[2-(piperidin-lyl)ethyl]carbanioyl }oxy)methy l]phenyl} pyrimidin-4-yl )methoxy]pheny I} propanoic acid;

- (27?)-2-{[(55_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy] phenyl} -6-(4-fl uorophenyl )thieno[2,3-iZ]pyrimidin-4-yl]oxy} -3- {2-[(2-{ 3- [2- (morpholin-4-yl )ethoxy]phenyl} pyrimidin-4-yl)methoxy]pheny 1} propanoic acid;

ORIGINAL

-2l ·

- (2Æ)-2-{ [(55^)-5-{3-chloro-2-methyl-4-[2-(4-rnethylpiperazin-l-yl)ethoxy] phenyl} -6-(4-fluorophenyl )thieno[2,3-r/]pyrimidin-4-yl]oxy} -3- {2-[ (2- {3-[2(dimethylamino)ethoxy]phenyl}pyrimidin-4-yl)methoxy]phenyl} propanoic acid;

- (2Æ)-3-(2-{[2-(4-{2-[bis(2-hydroxyethyl)amino]ethoxy}phenyl)pyrimidin-4- yl]methoxy}phenyl)-2-{[(5S'_fl)-5-{3-chloro-2-methyI-4-[2-(4-methyipiperazin-lyl)ethoxy]phenyl}-6-(4-fluoiOphenyl)thieno[2,3-t7]pyrimidin-4-yl]oxy} propanoic acid;

(2Æ)-2-{ [(55^)-5-{3-chloiO-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy] phenyl} -6-(4-fluoropheny I )thieno[2,3-i/]pyrimidin-4-yl]oxy} -3-(2- {[2-(4- {2-[2-( 210 hydroxyethoxy)ethoxy]ethoxy}phenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid;

- (2/?)-2-{[(5\,)-5-{3-chloiO-2-melhyl-4-[2-(4-methylpiperazin-l-yl)ethoxy| phenyl }-6-(4-fluorophenyl)thieno[2,3-<7]pyiïmidin-4-yl]oxy}-3-{2-[(2-{4-[(2,2dimethyl-1,3-dioxolan-4-yI)methoxy]pheny l} pyrimidin-4-yl)methoxy]phenyl} propanoic acid;

- (2£)-2-{[(5S_a)-5-{3-chloro-2-methyl-4-[2-(4-rnethylpiperazin-l-yl)ethoxy] phenyl }-6-(4-fluorophenyl)thieno[2.3-i/]pyrimidin-4-yl]oxy}-3-{2-[(2-{4-[2(morpholin-4-yl)ethoxy]pheny I} pyrîmidin-4-y l)methoxy]pheny l} propanoic acid;

4-[4-( {2-[(2/?)-2-carboxy-2- {[(5SJ-5- {3-chloro-2-methyl-4-[3-(4-methyl piperazin-l-yl)propoxy]phenyl}-6-(4-fluorophenyl)thieno[2.3-i/]pyrimidin-4yl]oxy}ethyl]phenoxy}inethyl)pyrimidin-2-yl]phenyl phosphate disodium sait;

l -[(ethoxycarbonyl)oxyjethy l (2R)-2- {[(5.^,)-5-13-011101^0-2-111011171-4-(2-(4methylpiperazin-l -yl)ethoxy |phenyI}-6-(4-fluoiOphenyl)thieno[2,3-i/]pyriinidin-4yl]oxy}-3-{2-[(2-{3-[(l,3-dimethoxypiOpan-2-yl)oxy]phenyl}pyrimidin-425 y] )methoxy]pheny 1} propanoate;

- (2Æ)-2-{[(5.S'j-5-{3-chloro-2-mcthyl-4-|2-(4-mcthYlpiperazin-l-yl)ethoxy] phenyl }-6-(4-fluorophenyl)thieno[2,3-i7]pyrimidin-4-y]|oxy}-3-[2-({2-[5-(hydroxy methyl)pyridin-3-yl]pyrimidin-4-yl}methoxy)phenyl]propanoic acid;

- (2Æ)-2-{[(5£_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy] phenyl}-6-(4-11 uorophenyI)thieno[2,3-i/]pyriinidin-4-yl]oxy}-3-(2-{[2'-(hydroxy methyl)-2,5'-bipyrimidin-4-yl]methoxy}phenyl)propanoic acid.

ORIGINAL

- 22 The invention relates also to a process for the préparation of compounds of formula (I), which process is characterised in that there is used as starting material the compound of formula (II):

Cl^/A^Br wherein A is as defined for formula (I) in which 1 is linked to the chlorine atom and 2 is linked to the bromine atom, which compound of formula (11) is subjected to coupling with a compound of formula (III):

Alk

(III) wherein R₍„ R7, Ru and n are as defined for formula (I), and Alk represents a linear or branched (Ci-C&)alkyl group, to yield the compound of formula (IV):

Alk

(IV) wherein R₆, R7, Ru, A and n are as defined for formula (I) and Alk is as defined before, compound of formula (IV) which is further subjected to coupling with compound of formula (V):

ORIGINAL

(V) wherein R_h R₂, R₃, R4 and R5 are as defined for formula (I), and R_B| and R_B2 represent a hydrogen atom, a linear or branched (Ci-C₆) alkyl group, or R_B, and R_B2 form with the oxygen carrying them an optionally methylated ring.

to yield the compound of formula (VI):

Alk

wherein Rj, R₂, R₃, R4, R5, R&. R7, Rm, A and n are as defined for formula (!) and Alk is as defined before, the Alk-O-C(O)- ester function of which compound of formula (VI) is hydrolysed to yield IO the carboxylic acid, which may optionally be reacted with an alcohol of formula R₈'-Oll or a chlorinated compound of formula Rs'-CI wherein R₈' represents a linear or branched (Ci-Ca)alkyl group, a -CHR_aRb group, an aryl group, a heteroaryl group, an arylalkykCj-Cô) group, or a heteroarylalkyKCi-Cc) group, R_a and Rb are as defined for formula (I), to yield the compound of formula (I), which may be purified according to a conventional séparation technique, which is converted, if desired, into its addition salts with a

ORIGINAL

-24pharmaceutically acceptable acid or base and which is optionally separated into its isomers according to a conventional séparation technique, it being understood that at any moment considered appropriate during the course of the process described above, some groups (hydroxy, amino...) of the starting reagents or of the synthesis intermediates can be protected. subsequently deprotected and functionalized, as required by the synthesis.

The compounds of formulae (II), (III), (V), R₈’-OH and Rs’-Cl are either commercially available or can be obtained by the person skilled in the art using conventional Chemical reactions described in the literature.

Pharmacological study of the compounds of the invention has shown that they hâve proapoptotic properties. The ability to reactîvate the apoptotic process in cancerous cells is of major therapeutic interest in the treatment of cancers and of immune and auto-immune diseases.

More especially, the compounds according to the invention will be useful in the treatment of cheino- or radio-resistant cancers.

Among the cancer treatments envisaged there may be mentioned, without implying any limitation, treatment of cancers of the bladder, brain. breast and utérus, chronic lymphoid leukaemias, cancer of the colon, œsophagus and liver. lymphoblastic leukaemias, acute myeloid leukaemias, lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer.

The present invention relates also to pharmaceutical compositions comprising al least one compound of formula (I) in combination with one or more pharmaceutically acceptable excipients.

Among the pharmaceutical compositions according to the invention there may be mentioned more especially those that are suitable for oral, parentéral, nasal, per- or

ORIGINAL

-25trans-cutaneous, rectal, perlingual, ocular or respïratory administration, especially tablets or dragées, sublingual tablets, sachets, paquets, capsules, glossettes, lozenges, suppositories, creams, ointments, dermal gels, and drinkable or injectable ampoules.

The dosage varies according to the sex, âge and weight of the patient, the administration 5 route, the nature of the therapeutic indication, or of any associated treatments, and ranges from 0.01 mg to l g per 24 hours in one or more administrations.

Furlhermore, the present invention relates also to the combination of a compound of formula (I) with an anticancer agent selected from genotoxic agents, mitotic poisons, antimetabolites, protéasome inhibitors, kinase inhibitors and antibodies, and also to 10 pharmaceutical compositions comprising that type of combination and their use in the manufacture of médicaments for use in the treatment of cancer.

Advantageously, the present invention relates to the combination of a compound of a ...

formula (I) with an EGFR inhibitor, and also to pharmaceutical compositions comprising j that type of combination.

In another embodiment. the present invention relates to the combination of a compound of formula (!) with a mTOR/PI3K inhibitor. and also to pharmaceutical compositions comprising that type of combination.

In a preferred embodiment, the present invention relates to the combination of a compound of formula (!) with a MEK inhibitor, and also to pharmaceutical compositions comprising 20 that type of combination.

Preferably, the present invention relates to the combination of a compound of formula (I) with a HER2 inhibitor, and also to pharmaceutical compositions comprising that type of combination.

Advantageously, the present invention relates to the combination of a compound of 25 formula (I) with a RAF inhibitor, and also to pharmaceutical compositions comprising that type of combination.

In another embodiment, the present invention relates to the combination of a compound of formula (I) with a EGFR/HER2 inhibitor, and also to pharmaceutical compositions comprising that type of combination.

ORIGINAL

-26In a preferred embodiment. the présent invention relates to the combination of a compound of formula (I) with a taxane, and also to pharmaceutical compositions comprising that type of combination.

In another embodiment, the présent invention relates to the combination of a compound of formula (I) with a protéasome inhibitor, an immunomodulator or an alkylating agent, and also to pharmaceutical compositions comprising that type of combination.

ΙΟ

The combination of a compound of formula (I) with an anticancer agent may be administered simultaneously or sequentially. The administration route is preferably the oral route, and the corresponding pharmaceutical compositions may allow the instantaneous or delayed release of the active ingrédients. The compounds of the combination may moreover be administered in the form of two separate pharmaceutical compositions, each containing one of the active ingrédients, or in the form of a single pharmaceutical composition, in which the active ingrédients are in admixture.

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 linked to monoclonal antibodies or fragments thereof or linked to scaffold proteins that can be related or not to monoclonal antibodies.

Antibody fragments must be understood as fragments of Fv, scFv, Fab, F(ab')2, F(ab’), scFv-Fc type or diabodies, which generally hâve the sanie specificity of binding as the antibody from which they are descended. According to the présent invention, antibody fragments of the invention can be obtained starting from antibodies by methods such as digestion by enzymes, such as pepsin or papain. and/or by cleavage of the disulfide bridges by Chemical réduction. In another manner, the antibody fragments comprised in the présent invention can be obtained by techniques of genetic recombination likewise well known to the person skilled in the art or else by peptide synthesis by means of, for example, automatic peptide synthesizers such as those supplied by the company Applied Biosystems, etc.

ORIGINAL

-27Scaffold proteins that can be related or not to monoclonal antibodies are understood to mean a protein that contains or not an immunoglobulin fold and that yields a binding capacity similar to a monoclonal antibody. The man skilled in the art knows how to select the protein scaffold. More particularly, it is known that, to be selected, such a scaffold 5 should display several features as follow (Skerra A., J. Mol. Recogn. 2000, J3. 167-187): phylogenetically good conservation, robust architecture with a well-known threedimensional molecular organization (such as, for example, crystallography or NMR), small size, no or only a low degree of post-translational modifications, easy to produce, express and purify. Such a protein scaffold can be, but without limitation, a structure selected from 10 the group consisting in fibronectin and preferentially the tenth fibronectin type III domain (FNfnlO). lipocalin, anticalin (Skerra A., J. Biotechnol. 2001, 74(4):257-75), the protein Z derivative from the domain B of staphylococcal protein A, thioredoxin A or any protein with a repeated domain such as an ankyrin repeat (Kohl et al., PNAS 2003, 100(4), 1700-1705), armadillo repeat, leucine-rich repeat or tetratricopeptide repeat. There 15 could also be mentioned a scaffold derivative from toxins (such as, for example, scorpion, insect, plant or mollusc toxins) or protein inhibilors of neuronal nitric oxide synthase (PIN),

The following Préparations and Examples illustrate the invention but do not limit it in any way.

General Procedures

Ail 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 ISCO CombiFlash Rf 200i with pre-packed 25 silica-gel cartridges (RedLSe/i&Af Gold High Performance),

ORIGINAL

-28Thin layer chromatography was conducted with 5 x 10 cm plates coated with Merck Type 60 F254 silica-gel.

Microwave heating was performed in an Anton Parr MonoWave or CEM Discover® instrument.

Préparative HPLC purifications were performed on an Armen Spot Liquid Chromatography System with a Gemini-NX* 10 μΜ Cl8. 250 mm * 50 mm i.d. column running at a flow rate of 118 mL min'¹ with UV diode array détection (210 - 400 nm) using 25 mM aqueous NH4HCO3 solution and MeCN as eluents unless specified otherwise.

Analytical LC-MS: The compounds of the présent invention were characterized by high performance liquid chromatography-mass spectroscopy (HPLC-MS) on Agilent PIPI200 with Agilent 6140 quadrupole LC/MS, operating in positive or négative ion electrospray 1 ionisation mode. Molecular weight scan range is 100 to 1350. Parallel UV détection was done at 210 nm and 254 nm. Samples were supplied as a 1 mM solution in ACN, or in 15 THF/H2O (1:1) with 5 pL loop injection. LCMS analyses were performed on two instruments, one of which was operated with basic. and the other with acidic eluents.

Basic LCMS: Gemini-NX, 3 pm, Cl8, 50 mm χ 3.00 mm i.d. column 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 from 100 % Solvent A and finishing at 100 % 20 Solvent B over various/certain duration of time.

Acidic LCMS: ZORBAX Eclipse XDB-C18, 1.8 pm, 50 mm ^x 4.6 mm i.d. column 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 from 100% Solvent A and finishing at 100 % Solvent B over various/certain duration of time.

'Η-NMR measurements were performed on Bruker Avance III 500 MHz spectrometer and Bruker Avance III 400 MHz spectrometer, using DMSO-d₆ or CDCI3 as solvent. ’l-I NMR data is in the form of delta values, given in part per million (ppm), using the residual peak of the solvent (2.50 ppm for DMSO-d₍₁ and 7.26 ppm for CDCI3) as internai standard.

ORIGINAL

-29Splitting patterns are designated as: s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet), br s (broad singlet), dd (doublet of doublets), td (triplet of doublets), dt (doublet of triplets), ddd (doublet of doublet of doublets).

Combination gas chromatography and low resolution mass spectrometry were performed 5 on Agilent 6850 gas chromatograph and Agilent 5975C mass spectrometer using I5m* 0,25 mm column with 0.25 pm HP-5MS coating and hélium as carrier gas. Ion source: ΕΓ, 70 eV. 230 °C, quadrupole: 150 °C, interface: 300 °C.

HRMS were determined on a Shimadzu 1T-TOF, ion source température 200 °C, ESI +/-, ionization voltage: (+-)4.5 kV. Mass resolution min. 10000.

Elementary analyses were performed on a Thermo Flash EA 1112 Elemental Analyzer.

	List of abbreviations
15	Abbreviation Naine Ac acetyl AIBN 2-[( l -cyano-1 -methyl-ethy l)azo]-2-methyI-propanenitrile AtaPhos bis(di-K?i7-butyl(4-dimethylaniinophenyl)phosphine)
20	dichloropalladium(ll) DCM methylene chloride DIPA diisopropylamine DMF dimethylformamide DSC AUV'-disuccinimidyl carbonate
25	eq. équivalent Et ethyl HMDS hexamethyldisilazane ’Pr isopropyl Me methyl
	MeCN acetonitrile

ORIGINAL

NBS	A/-bromosuccinimide
Bu	/î-butyl
Ph	phenyl
PPh3	triphenylphosphine
5 r.t.	room température
'Bu	/e/7-butyl
'BuXPhos	2-di(/i?/7-butylphosphino)-2',4',6,-triisopropylbiphenyl
TEA	triethylamine
THF	tetrahydrofurane

ΙΟ General procedure I

Step A l eq. of Préparation 1, 2 eq, of the appropriate boronic acid dérivative, 2 eq. césium carbonate and 0.1 eq. bis(PPh₃)palladium(II) dichloride were placed in a fiask. A mixture of 1,4-dioxane and water (4:1, 10 mL/mmol) was added and the resulting mixture was 15 stirred at 60 °C under argon atmosphère until no further conversion was observed. The reaction mixture was diluted with brine and the pH was set to 6 with 2M aqueous HCl solution, and then extracted with DCM. The volatiles from the separated organic phase were evaporated under reduced pressure and the crude product was purified by flash chromatography using DCM and methanol as eluents.

Step B

The obtained intermediate was dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq. LiOH x IFO was added. The mixture was stined at r.t. until no further conversion was observed. Then il was diluted with brine, neutralized with 2M aqueous HCl solution, extracted with DCM. The combined organic phases were dried over MgSO₄, filtered and 25 the filtrate was concentrated under reduced pressure. The crude product was purified via preparative reversed phase chromatography using 5 mM aqueous NH₄F1CO₃ solution and MeCN as eluents. The diastereoisomer eluting later was collected.

ORIGINAL

-3I General procedure II

Step A l eq. Préparation 2 or l eq. Préparation 3, 2 eq. of the appropriate alcohol (unless otherwise stated) and 2 eq. PPÎ13 were dissolved in dry toluene (0.2M for the phénol). 2 eq.

di-/£?r/-butyl azodicarboxylate was added and the mixture was stirred at 60 °C under nitrogen until no further conversion was observed. The volatiles were evaporated under reduced pressure and the crude intermediate was purified via flash chromatography using ethyl acetate and methanol as eluents.

Step B

IO The obtained intermediate was dissolved in dioxane-water l:l (10 mL/mmol) and 10 eq. LiOH x H₂O was added. The mixture was stirred at r.t. 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 MgSCL, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified via 15 préparative reversed phase chromatography using 5 mM aqueous NH4HCO3 solution and MeCN as eluents. The diastereoisomer eluting later was collected.

General procedure III

Step A

To a solution of 1 eq. Préparation 5 in dry acetonitrile (15 mL/mmol) 1.5 eq. DSC and 20 3 eq. TEA was added and the mixture was stirred for one hour at r.t. To the resulting mixture 2 eq. of the appropriate amine was added and was further stirred for 1 hour at r.t. The reaction mixture was injected directly onto a flash silica column (160 g/mmol, conditioned with EtOAc) and chromatographied using EtOAc and MeOH (containing

1.2 % NH3) as eluents.

Step B

The product of Step A was dissolved in dioxane-water (1:1, 10 mL/mmol) and 10 eq. LiOH x H₂O was added. The mixture was stirred at r.t. until no further conversion was

ORIGINAL

-32observed. Then it was neutralized with 2M HCl and directly injected onto an RP18 column and chromatographied using 5 mM aqueous ΝΗ₄Η€Ο₃ solution and MeCN as eluents. The diastereomer eluting later was collected.

General Procedure IV

Step A eq. of the appropriate phénol dérivative, 2 eq. of the appropriate alcohol dérivative, and eq. PPhj were dissolved in dry toluene (0.2M for the phénol) under N₂ atmosphère then 2 eq. di-/fr/-butyl azodicarboxylate was added and the mixture was stirred at 60 °C until no further conversion was observed. The reaction mixture was concentrated under reduced pressure and the residue was purified via flash chromatography using heptane and EtOAc as eluents.

Step B l eq. of the phénol dérivative obtained in Step A was dissolved in dry THF. The solution was cooled to -78 °C under argon and then 1.2 eq. BuLi (l.6M in hexane) was added 15 dropwise. After 15 minutes, 1.5 eq. 2-isopropoxy-4,4,5,5-tetramethyl-l ,3,2-dioxaborolane was added dropwise. The cooling bath was removed and the mixture was slowly allowed to warm up to r.t. Then the mixture was quenched with NH4CI solution and extracted with EtOAc. The combined organic layers were concentrated under reduced pressure and the crude product was purified via flash chromatography using heptane and EtOAc as eluents.

General procedure V l eq. Préparation 1, 3 eq. the appropriate boronic acid dérivative, 4.5 eq. césium carbonate and 0.15 eq. bisfPPhjjpalladiumflI) dichloride in dioxane (30 niL/nunol) and water (15 mL/mmol) were stirred under N₂ atmosphère at 60 °C until no further conversion was observed. The reaction mixture was cooled to r.t., then 20 eq. LiOH x H₂O 25 (832 mg/mmol) was added and the mixture was stirred until no further conversion was observed. The reaction mixture was diluted with brine, the pH was adjusted to 6 using IM HCl, then the mixture was filtered and the precipitate was washed with dioxan. The volatiles of the filtrate were evaporated under reduced pressure and the residue was

ORIGINAL

- 33 purified via preparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents.

Préparation 1: Ethyl (2/f)-2-[5-|3-chloro-2-methyl-4-[2-(4-methylpipcrazin-l-yl) ethoxy]phenyl|-6-(4-fluorophenyl)thieno[2,3-rf]pyrimidin-4-yl]oxy-3-|2-[(2“Chloro pyrimidin-4-yl)mcthoxy]phenyl]propanoate

Step A : 6-1οάο-3νϊ-ΐ0ΐβηο[2.3-ά]ρνηηιίά'ιη-4-οηβ

A 2 L round bottomed flask equipped with mechanical stirrer, thermometer and reflux condenser was charged with the solution of 433 mL acetic acid, 13 mL sulfuric acid and 87 mL water. 69.3 g 3/7-thieno[2,3-J]pyrimidin-4-one (0.46 mol), 51.9 g periodic acid 10 (0.23 mol) and 104 g iodine (0.41 mol) were added to the stirred solution heated to 60 °C for 1 hour. The resulting suspension was cooled to r.t., filtered off, washed with a mixture of acetic acid and water (5:1) and then with diethyl ether. The resulting beige crystalline solid was air dried to give 6-iodo-3/f-thieno[2,3-i/]pyrimidin-4-one.

‘H NMR (500 MHz, DMSO-d₆) 8 12.57 (br s, 1 H), 8.09 (s, 1 H), 7.65 (s, 1H ) 15 ^t3C NMR (125 MHz, DMSO-d₆) δ 168.3, 155.9, 146.1, 130.8, 126.7, 76.4

Step B: 4-Chloro-6-iodo-thieno[2.3-d]pyrimidine

A 1 L round bottomed flask equipped with mechanical stirrer, thermometer. reflux condenser and a CaCL-tube was charged with 113 mL phosphorous oxychloride and 35 mL A\jV-dimethylaniline (0.29 mol). 75.54g 6-iodo-3/7-thieno[2,3-<7]pyrimidin-4-one 20 (from Step A)(0.27 mol) was added to the mixture in portions during 5 minutes. The reaction mixture was stirred al 105 °C for 1 hour. The resulting suspension was cooled to 10 °C, filtered and washed with hexane. The crude product was added to ice water and stirred for 10 minutes, lîltered off, washed with cold water, diethyl ether and air dried to give 4-chloro-6-iodo-thieno[2,3-<7]pyrimidine as a beige crystalline solid.

'H NMR (500 MHz. DMSO-d₆) δ 8.89 (s, IH), 7.98 (s. IH) ¹³CNMR(125 MHz, DMSO-d_f,) ô 172.3, 152.9, 151.9, 131.1, 128.9, 86.5

Step C: 5-Bromo-4-chloro-6-iodo-thieno[2,3-d]pyrimidine

ORIGINAL

- 34 A 2 L round bottomed flask equipped with mechanical stirrer, thermometer and a bubbler was charged with 600 mL MeCN. 84.9 g 4-chloro-6-iodo-thieno[2,3-</]pyriniidine (from Step B) (0.29 mol), 50.9 g NBS (0.29 mol) and 8.5 mL tetrafluoroboric acid diethyl ether complex were added. The reaction mixture was stirred at r.t. for 16 hours. Further 22.9 g 5 (0.12 mol) NBS was added to the mixture in three portions. After cooling the suspension to °C and stirring for further l hour the precipitate was filtered off, washed with acetonitrile and air dried to give 5-bromo-4-chloro-6-iodo-thieno[2,3-i/]pyrimidine as beige crystalline solid.

'H NMR (400 MHz. DMSO-d₆) δ 8.88 (s, IH) ^l3C NMR (100 MHz, DMSO-d₆) δ 17L3, 152.9, 152.3, 126.0, 112.4, 92.9

Step D: 5-Bromo-4-chloro-6-(4-fluorophenyl)lhieno[2,3-d]pyrimidine

75.08 g 5-bromo-4-chloro-6-iodo-thieno[2,3-</]pyrimidine (from Step C) (200 mmol), 53.63 g 2-(4-fluoiOphenyl)-4,4,5,5-tetramethyl-l.3,2-dioxaborolane (240 mmol). 130 g césium carbonate (400 mmol), 2.245 g Pd(OAc)₂ (10 mmol) and 8.50 g 'BuXPhos 15 (20 mmol) were placed in a 2 L flask. 600 mL THF and 200 mL water were added, and then stirred overnight at 70 °C under argon atmosphère. THF was evaporated, and then the product was collected by filtration. Crude product was sonicated in 250 mL MeCN and filtered again. Then 5-bromo-4-chÎoro-6-(4-fluoiOphenyl)thieno[2.3-c/]pyrimidine was crystalized from EtOH/THF (2:l). ^]H NMR (400 MHz, DMSO-d₆): 9.02 (s, IH), 7.80-7.77 20 (m, 2H), 7.47-7.43 (m, 2H)

Step E: [2-(Bromomethyl)phenyl]acetate

60.07 g 2-methylphenyI acetate (400 mmol) and Ί 06.8 g NBS (600 mmol) were placed in a l L flask. 500 mL cyclohexane was added, and then with intensive stirring 3.284 g AIBN (20 mmol) was added over 30 minutes. The mixture was stirred at 80 °C until no further 25 conversion was observed, then cooled to r.t. The precipitate was filtered off and washed with cyclohexane. The mother liquor was concentrated under reduced pressure, and the crude product was used in Step B without further purification.

Step F: Ethyl 2-acetoxy-3-(2-hydroxyphenyl)propanoate

ORIGINAL

- 35 23.IO g anhydrous LiCI (545 mmol) and 65.36 g anhydrous ZnCF (479.6 mmol) were placed in a 2 L flask, then dried at 160 °C under O.l nimHg for l hour. After cooling to r.t. under argon atmosphère, 26.49 g magnésium tumings (1090 mmol) and l L dry pre-cooled (0 °C) THF were added. The resulting mixture was immersed into an ice-bath, and then 5 stirred for 30 minutes.

100 g [2-(bromomethyl)phenyl] acetate (from Step E) (~ 436 mmol) was dissolved in l20mL dry THF and was added to the precooled inorganics over 15 minutes. After addition of the reagent the resulting mixture was stirred for 45 minutes while keeping the température between 0-5 °C. To the mixture 64.82 mL ethyl 2-oxoacetate (654 mmol, 10 50 % in toluene) was added over 5 minutes and the resulting mixture was stirred for another 15 minutes.

From the mixture the remaining inorganics were removed by filtration, and then 500 mL MeOH was added to the filtrate. This mixture was stirred until the intramolecular acetyl group migration from the phenolic oxygen to the alkyl oxygen was completed. To the 15 mixture 30 mL acetic acid was added then the volatiles were evaporated under reduced pressure. To the residue 350 mL water was added and it was extracted with EtOAc. The combined organic layers were washed with saturated NaHCOa and with brine, and then dried over MgSO₄, fîltered and evaporated under reduced pressure. To the residue 100 mL hexane was added and it was stirred for 30 minutes at 0 °C. The formed while crystals 20 were collected by filtration and washed with hexane yielding ethyl 2-acetoxy-3-(2hydroxyphenyl)-(rac). 'H NMR (500 MHz. DMSO-d_(î) δ 9.53 (s. IH), 7.06 (t. IH), 7.04 (d. IH), 6.79 (d, IH), 6.71 (t, IH), 5.10 (dd, IH), 4.05 (q, 2H), 3.06 (dd. IH), 2.94 (dd. IH). 2.00 (s, 3H), l.09(t,3H)

Step G: Ethyl (2B.)-2-acetoxy-3-(2-hydroxyphenyl)propanoate and ethyl (2S)-2-acetoxy-32 5 (2-hydroxyphenyl)propanoate

Enantiomers of ethyl 2-acetoxy-3-(2-hydroxyphenyl)propanoate (from Step F) were separated via chiral chromatography. Column: OD; Eluents: heptane / EtOH; the enantiomer eluting earlier was collected as ethyl (2S)-2-acetoxy-3-(2-hydroxyphenyl) propanoate with 99.8 % ee and the enantiomer eluting later was collected as ethyl (27?)-230 acetoxy-3-(2-hydroxyphenyl)propanoate with 99.9 % ee.

ORIGINAL

- 36 Step H: (4-Broino-2-chloro-phenoxy)-triinethyl-silane

20.8 g 4-bromo-2-chloro-phenol ( 100 mmol) was dissolved in 150 mL dry THF then

24.2 g HMDS ( 150 mmol) was added. The reaction mixture was stirred at 85 °C under argon atmosphère for L5 hours then concentrated under reduced pressure resulting in the product used without further purification. *H NMR (200 MHz, CDClj): 7.49 (d, IH), 7.23 (dd, IH), 6.75 (d, IH), 0.26 (s, 9H)

Step 1: 4-Bromo-2-chtoro-3-methyl-phenol mL ⁿBuLi solution in hexanes (2.5M, 120 mmol) was added dropwise to a solution of

12.1 g dry DIPA (120 mmol) in 250 mL dry THF at -78 °C under argon atmosphère. The 10 mixture was stirred for 30 minutes at the same température then 28.0 g (4-bromo-2-chlorophenoxy)-trimethyl-silane (from Step H) (100 mmol) was added dropwise, After 2.5 hours

21.3 g Mel (150 mmol) was added dropwise then the cooling bath was removed and the mixture was stirred overnight. The reaction was quenched with 100 mL NH4OH solution and 200 mL NH₄C1 solution and extracted with EtOAc, dried over Na₂SO4, filtered and concentrated under reduced pressure. The resulting dark mass was refluxed with pure hexane several times (150-150 mL aliquots) and decanted leaving a black tar behind. Combined organic phases were concentrated under reduced pressure affording 19.0 g 4-bromo-2-chloro-3-methyl-phenol, the crude product used without further purification. 'H NMR (200 MHz, CDCI3): 7.32 (d, IH), 6.76 (d. IH), 5.62 (s, IH), 2.49 (s, 3H)

Step J: (4-Bromo-2-cMoro-3-methyl-phenoxy)-lrimethyl-sikine

20.8 g HMDS (129 mmol) was added to the solution of 19.0 g 4-bromo-2-chloro-3-methylphenol (from Step I) (86.0 mmol) in 150 mL dry THF. The mixture was stirred at 85 °C under argon balloon for 1.5 hours and then concentrated under reduced pressure. The obtained (4-bromo-2-chloro-3-inethyl-phenoxy)-trimethyl-silane was used without further 25 purification. ’H NMR (200 MHz, CDC1₃): 7.30 (d, 1 H), 6.63 (d, IH), 2.50 (s, 3H), 0.28 (s, 9H)

Step K: 2-Chloro-3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborohm-2-yl)phenol

A solution of 25.2 g (4-bromo-2-chloro-3-methyl-phenoxy)-trimethyl-silane (from Step J) (86.0 mmol) in 250 mL dry THF was cooled to -78 °C under argon and then 38 mL ⁿBuLi

ORIGINAL

-37in hexanes (2.5M, 94.6 mmol) was added dropwise. After 5 minutes, 19.2 g 2-isopropoxy-

4,4,5,5-tetramethyl-l,3,2-dioxaborolane (103 mmol) was added dropwise. The cooling bath was removed and the mixture was slowly aliowed to warm up to r.t. Then the mixture was added to 200 mL NH₄Cl solution and extracted with EtOAc. Combined organic layers 5 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 hexane to obtain 2-chloro-3-methyl-4-(4,4,5,5-tetramethyl-l.3,2-dioxaborolan2-yl) phénol. 'H NMR (500 MHz, DMSO-d_(i): 10.40 (s, IH), 7.42 (d. IH), 6.80 (d. IH), 2.49 (s, 3H), 1.27 (s, 12H)

Step L: J-[2-[2-Chloro-3-methyl-4-(4,4,5,5-telra>nethyl-l,3,2-dioxaborokm-2-yl)phenoxy] ethyl]-4-methyl-piperazine

10.0 g 2-chloro-3-methy 1-4-(4,4.5,5-tetramethy 1-1,3,2-dioxaborolan-2-yl)phenol (from Step K) (37.2 mmol). 8.7 g 2-(4-methylpiperazin-l-yl)ethanol (60.3 mmol) and 15.8 g PPhj (60.3 mmol) were dissolved in 100 mL dry toluene and then 27 mL diethyl j 15 azodicarboxylate (60.3 mmol, 40 % solution in toluene) was added dropwise. The mixture was stirred at 50 °C under argon for 1.5 hours. The volatiles were evaporated under reduced pressure and 100 mL Et₂O was added. The precipitated white crystals were filtered off and washed with Et₂O. The filtrate was concentrated under reduced pressure and purified via flash chromatography using CHCI3 and MeOH as eluents. The resulting light 20 brown oil was crystallized from hexane to give l-[2-[2-chloro-3-methyl-4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl]-4-methyl-piperazine as an off-white solid. 'H NMR (500 MHz, DMSO-d₍₎): 7.56 (d, IH), 6.99 (d, IH), 4.15 (t, 2H), 2.72 (t, 2H), 2.51 (s, 3H), 2.50 (br s, 4H), 2.29 (br s, 4H), 2.13 (s. 3H), 1.29 (s, 12H)

Step M: Ethyl (2R)-2-acetoxy-3-[2-](2-chloropyrunidin-4-yl)methoxy]phenyl]propanoate

9.06 g ethyl (2Æ)-2-acetoxy-3-(2-hydroxyphenyl)propanoate (from Step G. 36 mmol),

7.12 g 2-chloro-4-(chloromethyl)pyrimidine (44 mmol), 5.97 g K₂CO₃ (44 mmol) and

1.22 g Kl (1.22 mmol) were placed in a 250 mL llask. 70 mL DMF was added and the mixture was stirred at r.t. under N₂ until no further conversion was observed. Then the reaction mixture was diluted with water and then it was extracted with EtOAc. The 30 combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced

ORIGINAL

-38pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to give ethyl (2Æ)-2-acetoxy-3-[2-[(2-chloropyrimidin-4-yl)methoxy] phenyl]propanoate. ’H NMR (500 MHz, DMSO-d₆) δ 8.86 (d. IH), 7.69 (d. IH), 7.25 (td, IH), 7.23 (dd, IH), 7.03 (d. IH), 6.95 (td. IH), 5.30 (d, IH), 5.25 (d, IH), 5.16-5.13 (m, IH), 4.07 (qm. 2H), 3.28 (dd. IH), 3.09 (dd, IH), 2.00 (s, 3H), l.09 (t. 3H)

Step N: Ethyl (2R)-3-[2-[(2-chloropyrimidin-4-yl)methoxy]phenyl]-2-hydroxy-propanoate 8.568 g ethyl (27?)-2-acetoxy-3-[2-[(2-chloiOpyrimidin-4-yI)methoxy]phenyl]propanoate (from Step M) (23 mmol) was dissolved in 100 mL éthanol, then 1.8 mL sodium ethoxide solution (l.OM in éthanol) was added and it was stirred until no further conversion was observed. The réaction mixture was diluted with water and it was extracted with ethyl acetate. The combined organics were dried over Na₂SO4, fîitered and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to give ethyl (2/?)-3-[2-[(2-chloropyrimidin-4-yl)methoxy]pheny[]-2hydroxy-propanoate. 'H NMR (500 MHz, DMSO-d₆) δ 8.84 (d, IH), 7.70 (d, IH), 7.20 (m, IH), 7.19 (dm, IH), 7.00 (dm, IH), 6.91 (m, IH), 5.52 (d, l H), 5.27 (d, IH), 5.24 (d, IH), 4.06 (m, IH), 4.04 (m, lH),3.l3(dd, lH),2.84(dd, IH). l.ll (t, 3H)

Step O: Préparation l

17.18 g 5-bromo-4-chloro-6-(4-fluorophenyl)thieno[2,3-i/]pyriniidine (from Step D, 50 mmol) and 18.52 g ethyl (2Æ)-3-[2-[(2-chloiOpyrimidin-4-yl)methoxy]phenyl]-2hydroxy-propanoate (from Step N, 55 mmol) were dissolved in 250 mL dry THF, then 48.87 g Cs₂CO₂ (150 mmol) was added and the mixture was stirred at 70 °C under N₂ until no further conversion was observed. Reaction mixture was cooled down to r.t., then 2.17 g l-[2-[2-chloro-3-methyl-4-( 4,4.5,5-tetramethyl-l. 3,2-dioxaborolan-2-yl )phenoxy]ethyl]-4methyl-piperazine (from Step L, 55 mmol), 560 mg AtaPhos (2.5 mmol) and 250 mL H₂O were added, and the mixture was stirred under nitrogen at 70 °C until no further conversion was observed. Then it was diluted with EtOAc and brine. After phase séparation the aqueous phase was extracted with EtOAc. The organic layers were combined and dried over Na₂SO4, fîitered and concentrated under reduced pressure. The product was separated via flash chromatography using EtOAc and MeOH (containing l .2 % NHj) as eluents. Préparation l was obtained as a mixture of the atropisomers.

ORIGINAL

-39'l-l NMR (500 MHz. DMSO-d₆) δ 8.87(dd, IH), 8.60 (s, IH). 7.69 (dd, IH), 7.35-7.26 (m, 2H), 7.22 (t, 2H), 7.20-7.10 (m, 2H), 7.02-6.91 (m, IH), 6.87 (d, IH), 6.72 (t, IH), 6.15 (d, IH), 5.47 (dd, IH), 5.22 (s, 2H), 4.29-4.H (m, 2H), 4.10-4.00 (m, 2H), 3.I5-2.15 (br s, 8H), 3.13 (dd, 2H), 2.73-2.65 (m, 2H). 2.09 (s, 3H), l .86 (s, 3H), l .06 (t, 3H) (M+2H)²⁺ = 416.1197

Préparation 2: Ethyl (2Æ)-2-[5-|3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yI) ethoxy]phenyI]-6-(4-fluoiOphenyI)thieno[2,3-rf]pyrimidin-4-yî]oxy-3-[2-[|2-(3hydroxyphenyl)pyrimidin-4-yl] methoxy] phenyl]propanoate

Using General Procedure l Step A and 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-210 yl)phenol as the appropriate boronic acid dérivative. Préparation 2 was obtained as a mixture of the diastereoisomers.

IH NMR (500 MHz, DMSO-d6) δ 9.65 (br s. IH), 8.95 (d, IH), 8.58 (s, IH), 7.88-7.80 (m, 2H), 7.57 (d, IH), 7.33 (d. IH). 7.32-7.27 (m. 2H), 7.3 (t, IH), 7.24-7.14 (m. 4H), 7.05 (d, IH), 6.94-6.90 (dm, IH), 6.78-6.73 (tm. IH), 6.30 (dd, IH), 5.51 (dd. IH), 5.30 (d, IH), 15 5.24 (d, IH), 4.26-4.00 (m, 4H), 3.17 (dd, IH), 2.76 (br s, 2H), 2.58 (dd, IH), 2.42 (br s,

3H), 3.00-2.30 (br s, 8H), l .86 (s, 3H), l .06 (t, 3H) (M+2H)²' = 445.1524

Préparation 3: Ethyl (27f)-2-|5-[3-chloro-2-methyI-4-[2-(4-methylpiperazin-l-yl) ethoxy]plienyl]-6-(4-fluorophenyl)thieno|2,3-i/]pyrimidin-4-yI]oxy-3-[2-||2-(420 hydroxyphenyl)pyrimidin-4-yl|methoxy]phenyl|propanoate

Using General Procedure 1 Step A and 4-(4,4,5.5-tetramethyl-1,3,2-dioxaborolan-2yl)phenol as the appropriate boronic acid dérivative, Préparation 3 was obtained as a mixture of the diastereoisomers.

'H NMR (500 MHz, DMSO-d_f,) δ 10.01 (s, IH), 8.86 (d. 111), 8.58 (s, IH), 8.24 (d, 2H), 25 7.46 (d, IH), 7.33 (d, IH), 7.32-7.27 (m, 211), 7.21 (t. 2H), 7.21-7.15 (m, 2H), 7.04 (d, IH),

6.87 (d, 2H), 6.74 (t, IH), 6.29 (d, IH), 5.52 (dd, IH), 5.26 (d, IH), 5.20 (d, 1 H), 4.19 (br s, 2H), 4.10-4.00 (m, 2H), 3.16 (dd. IH), 3.03-2.41 (m, 13H). 2.56 (dd, IH), 1.86 (s, 3H), 1,05 (t, 3H) (M+2H)²⁺ = 445.1517

ORIGINAL

-40Préparation 4a: 2-I2-[(2,2-dimethyl-l,3-dioxolan-4-yl)mcthoxy]phenyl]-4,4,5,5tetramethyl-1,3,2-dioxaborolane

Using General Procedure IV, 2-iodophenol as the appropriate phénol and (2,2-dimethyl-

1,3-dioxolan-4-yl)methanol as the appropriate alcohol, Préparation 4a was obtained.

'H NMR (500 MHz, DMSO-d₆) δ 7.50 (dd, 1 H), 7.41 (tm, 1 H), 6.98 (d. 1 H), 6.93 (td. IH), 4.37-4.31 (m, IH), 4.08-4.02 (m, 2H), 4.03 (dd, IH), 3.96 (dd, IH), 1.36 (s, 3H), 1.30 (s, 3H), 1.27 (s, 12H)

Préparation 4b: 2-[2-[2-(2-methoxyethoxy)ethoxy]phenyl]-4,4,5,5-tetraniethyl-l,3,2dioxaborolane

Using General Procedure IV, 2-iodophenol as the appropriate phénol and 2-(2methoxyethoxy)ethanol as the appropriate alcohol. Préparation 4b was obtained. ’H NMR (500 MHz, DMSO-d₆) δ 7.48 (dm, IH), 7.42-7.37 (m. IH), 6.94 (dm, IH), 6.926.90 (m. IH). 4.05-4.01 (m, 2H), 3.76-3.72 (m. 2H), 3.70-3.67 (m, 2H), 3.46-3.43 (m, 2H),

3.24 (s, 3H), 1.26 (s, 12H)

J

Préparation 4c: 2-|2-I2-|2-(2-niethoxyethoxy)ethoxy]ethoxy]phenyl|-4,4,5,5tetramethyl-l,3,2-dioxaborolane

Using General Procedure IV, 2-iodophenol as the appropriate phénol and 2-(2-(2methoxyethoxy)ethoxy]ethanol as the appropriate alcohol, Préparation 4c was obtained. Tl NMR (500 MHz, DMSO-d₆) δ 7.48 (dm, IH), 7.49-7.46 (m, IH), 6.94 (dm. IH), 6.9320 6.89 (m, 1 H), 4.04-4.01 (m, 2H), 3.75-3.72 (m, 2H), 3.71-3.39 (m, 8H), 3.22 (s, 3H), 1.26 (s, 12H)

Préparation 4d: 2-[2-(2-niethoxyethoxyinethyl)phenyl|-4,4,5,5-tetraniethyl-l,3,2dioxaborolane

Step A: 1 -bromo-2-(2-methoxyethoxymethyl)benzene

To 20 mL of 2-methoxyethanol (672 mmol, 20 eq) 4.03 g sodium hydride (100.8 mmol, 60 % in oil, 3 eq.) was adde in small portions at 0 °C. After 30 minutes stirring, 8.40 g l-bromo-2-(bromomethyl)benzene (33.6 mmol, 1 eq.) was added, then the reaction mixture was removed from the cooling bath and further was stirred at r.t. until no further

ORIGINAL

-4l conversion was observed. Reaction mixture was diluted with EtOAc and brine. After extraction the organic phase was washed with brine and dried over MgSO4, filtered and concentrated under reduced pressure. Crude product was purified by flash chromatography using heptane and EtOAc as eluents to obtain 1-bromo-2-(2-methoxyethoxymethyl) 5 benzene. 'H NMR (400 MHz, DMSO-d₆) δ 7.60 (d, IH), 7.49 (d, IH), 7.39 (t. IH), 7.24 (t, IH), 4.52 (s, 2H), 3.63 (dd, 2H), 3.51 (dd, 2H), 3.27 (s, 3H)

Slep B: Préparation 4d

Product from Step A was converted to the appropriate boronic ester using General Procedure IV Step B to obtain Préparation 4d. ’H NMR (400 MHz, DMSO-df,) δ 7.80 (d, 10 IH), 7.50 (d, IH), 7.43 (t. IH), 7.28 (t, IH), 4.85 (s, 2H), 3.66 (dd, 2H), 3.59 (dd, 2H), 3.41 (s. 3H), 1.36 (s. 12H)

Préparation 4e: 4,4,5,5-tetramethyl-2-[2-(2-tetrahydropyran-2-yloxyethoxymethyl) phenyl]-!, 3,2-dioxaborolane

Step A; 2-[2-[(2-iodophenyl)methoxy]ethoxy]tetrahydropyran

To a solution of 2.34 g (2-iodophenyl)methanol (10 mmol, 1 eq.) in 25 mL dry DMF 440 mg sodium hydride (Il mmol, 60% in oil, 1.1 eq.) was added in small portions at 0 °C. After 30 minutes stirring, 2.5 g 2-(2-bromoethoxy)tetrahydropyran (12 mmol,

1.2 eq.) was added, then the reaction mixture was removed from the cooling bath and further was stirred at 50 °C until no further conversion was observed. Reaction mixture 20 was diluted with EtOAc and brine. After extraction the organic phase was washed with brine and dried over MgSO₄, filtered and concentrated under reduced pressure. Crude product was purified by flash chromatography using heptane and EtOAc as eluents to obtain 2-[2-[(2-iodophenyl)methoxy]ethoxy]tetrahydropyran. '1-1 NMR (400 MHz. CDC1₃) δ 7.83 (d, 1 Fl), 7.50 (d, IH), 7.36 (t, IH), 6.99 (t, IH), 4.70 (t, 111), 4.59 (s. 2H), 3.98-3.88 25 (m, 2H), 3.79-3.76 (m, 2H), 3.73-3.68 (m, IH), 3.56-3.51 (m, IH), 1.94-1.83 (m, 111),

1.80-1.73 (m, IH), 1.70-1.52 (m, 4H)

Step B: Préparation 4e

ORIGINAL

-42To a solution of l.O g product from Step A (2.76 mmol, l eq.) in 15 mL dry THF 4.24 mL 'PrMgCl x LiCl (5.52 mmol, l.3M in THF, 2 eq.) was added at 0 °C over 2 minutes. After 10 minutes stirring, 1.40 mL 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (6.9 mmol, 2.5 eq.) was added then it was stirred at 0 °C until no further conversion was observed. The reaction mixture was diluted with EtOAc and brine. After extraction the organic phase was washed with brine and dried over MgSO₄, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using heptane and EtOAc as eluents to obtain Préparation 4e. ’H NMR (400 MHz, CDCfi) δ

7.80 (d. I H), 7.53 (d, IH), 7.44 (t, IH), 7.28 (t, IH), 4.87 (s, IH), 4.68 (t. 2H), 3.94-3.87 (m, 2H), 3.76-3.64 (m, 3H), 3.54-3.49 (m, IH), 1.93-1.82 (m, IH), I.78-1.71 (m, IH), 1.69-1.52 (m, 4H)

Préparation 4f: 2-[2-[(2,2-dimcthyl-l,3-dioxolan-4-yl)metlioxymethyI|pheny!]-4,4,5,5tetramethyl-l,3,2-dioxaborolane

Step A: 4-[(2-brotnophenyl)methoxymethyl]-2.2-dimethyl-l,3-dioxolcme

To a solution of 1.3 mL (2,2-dimethyI-l,3-dioxolan-4-yl)methanol (11 mmol, 1.1 eq) in 25 mL dry DMF 440 mg sodium hydride (11 mmol, 60 % in oil, 1 · 1 eq.) was adde in small portions at 0 °C. After 30 minutes stirring, 2.5 g l-bromo-2-(bromomethyl)benzene (10 mmol. 1 eq.) was added, then the reaction mixture was removed from the cooling bath and was stirred at rt until no further conversion was observed. The réaction mixture was diluted with EtOAc and brine. After extraction the organic phase was washed with brine and dried over MgSO₄, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using heptane and EtOAc as eluents to obtain 4-[(2-bromophenyl)methoxymethyl]-2,2-dimethyl-l,3-dioxolane. ‘H NMR (400 MHz, CDCI3) δ 7.55 (d, IH), 7.49 (d, 1 H), 7.33 (t. IH), 7.17 (t. III), 4.65 (dd, 2H), 4.36 (qui, IH), 4.11 (dd, 1 H). 3.82 (dd, 11-1),3.67 (dd, IH), 3.59 (dd, III), 1.46 (s, 3H), 1.39 (s, 3H)

Step B: Préparation 4f

Product from Step A was converted to the appropriate boronic ester using General Procedure IV Step B to obtain Préparation 4f. 'H NMR (400 MHz, DMSO-df,) δ 7.65 (d,

ORIGINAL

-43IH), 7.45 (t, IH), 7.41 (d, IH), 7.29 (t, IH), 4.68 (dd. 2H). 4.20 (qui, IH), 3.98 (dd, IH), 3.62 (dd. IH), 3.51-3.42 (m, 2H), l.30(s,3H), l.30(s, 12H), l.26(s,3H)

Préparation 4g: 4,4,5,5-tetramethyl-2-[3-(2-tetrahydropyran-2-yIoxyethoxymethyl) phenyl]-l,3,2-dioxaborolane

Step A : 2-[2-[(3-iodophenyl)methoxy]ethoxy]tetrahydropyran

To a solution of 2.34 g (3-iodophenyl)niethanol (10 mmol, l eq.) in 25 mL dry DMF 440 mg sodium hydride (i l mmol, 60 % in oil, l.l eq.) was added in small portions at 0 °C. After 30 minutes stirring, 2.5 g 2-(2-bromoethoxy)tetrahydropyran (12 mmol, l .2 eq.) was added, then the reaction mixture was removed from the cooling bath and was 10 stirred at 50 °C until no further conversion was observed. Reaction mixture was diluted with EtOAc and brine. After extraction the organic phase was washed with brine and dried over MgSO-i, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using heptane and EtOAc as eluents to obtain 2-[2-[(3iodophenyl)methoxy]ethoxy]tetrahydropyran. MS (El, 70 eV) m/z (% relative intensity, 15 [ion]): 85 (100),217 (57),233 (15), 278 (15), 362 (I)

Step B: Préparation 4g

To a solution of 1.0 g product from Step A (2.76 mmol, 1 eq.) in 15 mL dry THF 4.24 mL 'PrMgCI x LiCl (5.52 mmol, 1.3M in THF, 2 eq.) was added at 0 °C over 2 minutes. After 10 minutes stirring, 1.40 mL 2-isopropoxy-4,4.5,5-tetramethyl-1.3,2-dioxaborolane 20 (6.9 mmol. 2.5 eq.) was added then it was stirred at 0 °C until no further conversion was observed. The reaction mixture was diluted with EtOAc and brine. After extraction the organic phase was washed with brine and dried over MgSO.), filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using heptane and EtOAc as eluents to obtain Préparation 4g. *H NMR (400 MHz, CDC1₃) Ô 25 7.79 (s, IH), 7.75 (d, IH), 7.51 (d, IH), 7.38 (t, IH), 4.67 (t, IH), 4.63 (d, IH), 4.59 (d,

IH), 3.95-3.83 (m, 2H), 3.71-3.62 (m, 3H), 3.55-3.48 (m, IH), 1.94-1.47 (m, 6H), 1.37 (s.

12H)

ORIGINAL

-44Préparation 4h: 2-|3-]2-methoxy-l-(methoxymethyI)ethoxy |phenyl]-4,4,5,5tetramethyl-l,3,2-dioxaborolane

To the solution oi'880 mg (4 mmol, l eq.) 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) phénol and 1371 mg (5.0 mmol, 1.25 eq.) [2-methoxy-l-(methoxymethyl)ethyl] 4-methylbenzenesulfonate in 16 mL DMF, 1954 mg (6.0 mmol, 1.5 eq.) césium carbonate was added and it was stirred at 75 °C for 16 hours, then at 85 °C for 8 hours. The reaction mixture was cooled to r.t. and it was concentrated under reduced pressure. To the residue 25 mL brine was added and it was extracted with 3 x 25 mL ethyl acetate. The combined organic layer was dried over MgSO₄ and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using heptane and ethyl acetate as eluents to give Préparation 4h. HRMS calculated for C17I-L7BO5: 322.1952; found 323.2025 (M+H)

Préparation 4i: 2-|4-[2-methoxy-l-(metlioxymethyl)ethoxy|phenyl]-4,4,5,5-tetra mcthy 1-1,3,2-dioxaborolane

To the solution of 880 mg (4 mmol, 1.0 eq.) 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)phenol and 1371 mg (5.0 mmol, 1.25 eq.) [2-methoxy-l-(methoxymethyl)ethyl] 4-methylbenzenesulfonate in 16 mL DMF, 1954 mg (6.0 mmol, 1.5 eq.) césium carbonate was added and it was stirred at 75 °C for 16 hours. The reaction mixture was cooled to r.t. and it was concentrated under reduced pressure. To the residue 25 mL brine was added and it was extracted with 3 x 25 mL ethyl acetate. The combined organic layer was dried over MgSO₄ and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using heptane and ethyl acetate as eluents to give Préparation 4i. HRMS calculated for C17H27BO5: 322.1952; found 323.2036 (M+H)

Préparation 4j: |(2/?)-4,5-diacetoxy-6-methoxy-2-j]3-(4,4,5,5-tetramethyl-I,3,2dioxaborolan-2-yl)phenoxy]methyl]tctraliydropyran-3-yI] acetate

Step A: Methyl 2,3,4-iri-O-acetyl-a-D-mannopyranoside

2.25 g (4 mmol) methyl 2,3,4-tri-(7-acetyl-6-triphenylniethyl-a-D-mannopyranoside was dissolved in 30 mL acetic acid at 85 °C, then 15 mL water was added and it was stirred at 90 °C for 1 hour. It was cooled to r.t. then it was poured into ice cold brine. The mixture

ORIGINAL

-45was fîltered and the filtrate was extracted with dichloromethane. The combined organic layer was dried over MgSOq, it was fîltered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using heptane and ethyl acetate as eluents to give methyl 2,3,4-tri-O-acetyl-a-D-mannopyranoside. 'H NMR (500 MHz, 5 DMSO-iU): 5.11-5.03 (m. 3H), 4.85 (t, IH), 4.73 (d, IH), 3.65 (m, lH), 3.48 (m, IH), 3.42 (m, l H), 3.33 (s, 3H), 2.1 M.91 (s, 9H)

Step B: Préparation 4j

Starting from methyl 2,3,4-tri-Oacetyl-a-D-mannopyranoside and 3-(4,4,5,5-tetramethyl- l,3,2-dioxaboroian-2-yl)phenol using General Procedure IV Step A, Préparation 4j was 10 obtained. ‘H NMR (500 MHz, DMSO-d₆): 7.31 (t, IH), 7.26 (m, IH), 7.15 (m. IH), 7.06 (m, IH), 5.25 (t, IH), 5.12 (m, IH), 5.H (m, IH), 4.79 (d, IH), 4.13 (dd, IH), 4.05 (dd, ^L ‘ IH), 3.99 (m, IH), 3.36 (s, 3H), 2.15-1.92 (s. 9H), 1.29 (s, 12H)

U

Préparation 4k: 4,4,5,5-tetramethyl-2-|3-[|(2S)-3,4,5,6-tetramethoxytetrahydropyran2-y 11 methoxy ] pheny I] -1,3,2-dioxaborolane

Step A : methyl-6-triphenyhnethyl 2,3,4-tri-O-methyl-a-V)-niannopyranoside

To the solution of 8.08 g (18.51 mmol) methyl 6-triphenyhnethyl-a-D-mannopyranoside in 150 mL DMF 2.89 g sodium hydride (60 % in minerai oil, 72.2 mmol. 3.9 eq.) was added portionwise at 0 °C and it was stirred at this température for 30 minutes. Then 5.20 mL Mel (11.8 g, 83.3 mmol, 4.5 eq.) was added dropwise at 0 °C and it was stirred at r.t. for 20 16 hours. To the reaction mixture 10 mL MeOH was added and it was stirred for minutes, then it was concentrated under reduce pressure. The residue was diluted with 200 mL water and extracted with DCM. The combined organic layer was dried over MgSOj, it was fîltered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using heptane and ethyl acetate as eluents to give 25 methyl-6-triphenylmethyl 2,3,4-tri-O-methyl-a-D-mannopyranoside. ^!H NMR (500 MHz, DMSO-d₆): 7.44-7.23 (m, 15H), 4.85 (d, IH), 3.58 (dd, IH), 3.48 (m, IH), 3.39 (s, 3H), 3.36 (s, 3H), 3.33 (dd, IH), 3.31 (s, 3H), 3.28 (t, IH), 3.23 (dd, IH), 3.11 (s, 3H), 3.1 (dd, IH)

ORIGINAL

-46Step B: methyl 2,3,4-tri~O~methyl-a-O-mannopyranoside

L914 g methyl-6-triphenylmethyl 2,3,4-tri-0-methyl-a-£>-mannopyranoside (4.0 mmol) was dissolved in 30 mL acetic acid at 85 °C, then 15 mL water was added and it was stirred at 90 °C for l hour. It was cooled to r.t. and it was poured into ice cold brine. The mixture was filtered and the filtrate was extracted with dichloromethane. The combined organic layer was dried over MgSO₄, it was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using heptane and ethyl acetate as eluents to give methyl 2,3,4-tri-O-methyl-a-jD-mannopyranoside. ’H NMR (500 MHz. DMSO-d_f)): 4.72 (d, IH), 4.63 (br s, IH), 3.56 (dd, IH), 3.54 (dd, IH), 3.47 (dd, IH), 3.36 (s, 3H), 3.34 (s, 3H), 3.32 (m, IH), 3.32 (s, 3H), 3.26 (s, 3H), 3.24 (m. IH),

3.22 (m, IH)

Step C: Préparation 4k

Starting from methyl 2,3,4-tri-Ü-methyl-a-D-mannopyranoside and 3-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)phenol using General Procedure IV Step A, Préparation 4k was obtained. 'H NMR (500 MHz, DMSO-d₆): 7.31 (dd, IH), 7.25 (dm, IH), 7.19 (m, IH), 7.09 (dm, IH), 4.77 (d, IH), 4.14 (dd, IH), 4.09 (dd, IH), 3.60 (m, IH), 3.59 (dd, IH), 3.41 (t. IH), 3.38 (dd, IH). 3.37 (s. 3H). 3.36 (s, 3H), 3.34 (s, 3H), 3.33 (s, 3H), 1.29 (s. 12H)

Préparation 4I: [(2Æ)-4,5-diacetoxy-6-methoxy-2-[[4-(4,4,5,5-tetramethyl-l ,3,2dioxaborolan-2-yl)phenoxy|methyl|tetrahydropyran-3-yl] acetate

Starting from methyl 2,3,4-tri-G-acetyl-a-i)-mannopyranoside (from Préparation 4j Step A) and 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol using General Procedure IV Step A. Préparation 41 was obtained. 'H NMR (500 MHz, DMSO-d(,): 7.60(m, 2H). 6.92 (m, 2H), 5.23 (t. IH), 5.13 (dd, IH), 5.11 (dd, IH), 4.80 (d, IH), 4.14 (dd, IH). 4.06 (dd, IH), 4.02 (m, IH), 3.36 (s, 3H), 2.14-L92 (s, 9H), 1.27 (s, 12H)

Préparation 4m: 4,4,5,5-tetramethyl-2-|4-[[(20)-3,4,5,6-tetramethoxytetraliydro pyran-2-yl]methoxy]phenyl|-l,3,2-dioxaborolane

Starting from methyl 2,3,4-tri-O-methyl-a-D-mannopyranoside (from Préparation 4j Step A) and 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol using General

ORIGINAL

-47Procedure IV Step A, Préparation 4m was obtained. ‘H NMR (500 MHz, DMSO-df,):

7.61 (m, 2H), 6.96 (m, 2H), 4.77 (d, IH). 4.16 (dd. IH). 4.10 (dd, IH), 3.61 (m, IH), 3.60 (d, HT), 3.38 (m, 2H), 3.37-3.28 (s, 12H), 1.27 (s, 12H)

Préparation 4n: |(27î)-4,5,6-triacetoxy-2-[I4-(4,4,5,5-tetramethyI-l,3,2-dioxaborolan2-yI)phenoxy]methyl|tetrahydropyran-3-yl] acetate

Step A: 1,2,3,4-tetra-O-acetyl-a/p-O-mannopyranose

2.36 g 1.2,3,4-tetra-(9-acetyl-6-triphenylmethyl-a/p-D-mannopyranose (4,0 mmol) was dissolved in 30 mL acetic acid at 65 °C, then 15 mL water was added and it was stirred at 65 °C for 1 hour. It was cooled to r.t. and it was poured into ice cold brine. The mixture was filtered and the filtrate was extracted with dichloromethane. The combined organic layer was dried over MgSO₄, it was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using heptane and ethyl acetate as eluents to give l,2,3,4-tetra-O-acetyl-a/p-D-mannopyranose. 'H NMR (500 MHz, DMSO-d₆): 6.06-5.97 (d, IH), 5.20-5.06 (t. 114), 5.31-5.18 (dd. IH), 5.35-5.14 (dd, IH), 4.89-4.87 (t, 1 H), 3.84-3.74 (m, 1 H), 3.52-3.34 (m, 2H). 2.20-1.90 (s. 12H)

Step B: Préparation 4n

Starting from l,2,3,4-tetra-(9-acetyl-a/p-D-mannopyranose and 4-(4,4,5,5-tetramethyl-

1.3.2- dioxaborolan-2-yl)phenol using General Procedure IV Step A, Préparation 4n was obtained as the mixture of stereoisomers. 'il NMR (500 MHz. DMSO-d₍₁): 7.60 (m, 2H), 6.91 (m, 2H), 6.15-6.00 (d, 114), 5.43-5.15 (m, 314). 4.23-4.20 (m. 114), 4.14-4.00 (m. 2H), 2.19-1.92 (s, 1214), 1.27 (s, 12H)

Préparation 4o: |(3/f,45,65)-3,4,5-triacetoxy-6-||4-(4,4,5,5-tctramethyI-l,3,2dioxaborolan-2-yl)phenyl|methoxy|tetrahydiOpyran-2-yl]methyl acetate and

Préparation 4p: |(2/î,3«5,67î,75)-6,7-diacetoxy-2-methyl-2-[|4-(4,4,5,5-tetramethyl-

1.3.2- dioxaborolan-2-yl)phenyl|methoxy|-5,6,7,7a-tetrahydro-3fl/f-[l,3|dioxolo[4,5-/»] pyran-5-yl] methyl acetate

ORIGINAL

-48Step A: 1 -bromo-2,3.4,6-tetra-O-acetyl-a/p-O-mannopyranose mL acetic anhydride was added to 30 mL HBr in acetic acid (33 %) and it was stirred at r.t. for 16 hours. It was cooled to 0 °C, and the solution of 7.50 g 1,2,3,4,6-penta-O-acetylα/β-D-mannopyranose (19.2 mmol) in 30 mL dichloromethane was added dropwise at 0 °C. The reaction mixture was stirred al this température for 2 hours then at r.t. for 16 hours. The mixture was cooled to 0 °C and it was poured onto 100 mL ice-water. Il was diluted with 120 mL DCM then the phases were seprated. Organic layer was washed with ice cold water, saturated NaHCO₃ and water again. The organic layer was dried over MgSO.|, it was filtered and concentrated under reduced pressure to give 1-bromo-2,3,4,6-tetra- O-acetyl-a/p-D-mannopyranose. *14 NMR (500 MHz, DMSO-d^):

6.77 (d, IH), 5.50 (dd, IH), 5.35 (dd, IH), 5.23 (t. IH), 4.17 (m, IH), 4.25 (dd. 114), 4.08 (dd. IH), 2.13 (s, 314),2.06 (s, 3H), 2.03 (s, 3H), 1.96 (s, 3H)

Step B: Préparations 4o and 4p

To the solution of 819 mg [4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl] methanol (3.50 mmol, 1 eq.), 2015 mg 1 -bromo-2,3,4,6-tetra-<7-acetyl-a/p-Dmannopyranose (4.90 mmol, 1.4 eq.), 467 mg s-collidine (3.85 mmol, 1.1 eq.) in 100 mL DCM 1708 mg silver trifluoromethanesulfonate (6.65 mmol, 1.9 eq.) in 15 mL toluene was added dropwise at -78 °C and the mixture was stirred at this température for 10 minutes. The mixture was let to warm slowly to r.t. (3 hours), then it was stirred for 10 hours. The mixture was filtered through a Celite pad. the fîltrate was concentrated. The residue was purified by flash chromatography on silica gel using heptane and ethyl acetate as eluents to give Préparation 4o as fîrst eluted product ’H NMR (500 MHz, DMSO-d₍,): 7.69 (m. 214),

7.39 (m, 214), 5.15-5.10 (m, 314), 4.96 (d, 114), 4.71 (d, 114), 4.57 (d, IH), 4.15 (dd, III). 4.04 (dd. IH), 3.96 (m, 114).2.12-1.91 (s, 1214), 1.29 (s, 1214);

and Préparation 4p as later eluted product. ¹H NMR (500 MI4z. DMSO-d<,): 7.63 (m, 214),

7.31 (m. 214), 5.68 (d. 114), 5.32 (dd, 114), 5.05 (t, 114), 4.59 (d, Ih) 4.54 (dd, 114), 4.53 (d, IH), 4.12 (dd, 114), 4.03 (dd, IH), 3.94 (m, 114), 2.01-1.97 (s, 914), 1.70 (s, 3H), 1.29 (s, 12H)

Préparation 4q: [5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidin-2-yl] methanol

ORIGINAL

-49113 mg (5-bromopyrimidin-2-yl)methanol (0.6 mmol) and 609 mg 4,4,5,5-tetramethyl-2(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3.2-dioxaborolane (2.4 mmol) were dissolved in 6 mL dioxane, then 353 mg KOAc (3.6 mmol) and 66 mg PdCI₂ ^xdppf (0.09 mmol) were added. The mixture was stirred under nitrogen at 60 °C for 2 hours. The resulting mixture was used without further manipulation. MS (M+H): 237.1

Préparation 5: Ethyl (2Æ)-2-|5-[3-chloro-2-methyl-4-|2-(4-methylpiperazin-l-yl) ethoxy|phenyl]-6-(4-fluorophenyl)thieno[2,3-rfJpyrimidin-4-yl]oxy-3-[2-|[2-[3(hydroxymethyl)phenyl]pyrimidin-4-yl]methoxy|pl]enyl|propanoate

Using General Procedure l Step A and [3-(4,4,5,5-tetramethyl-l ,3.2-dioxaborolan-210 yl)phenyl]methanol as the approprite boronic ester, Préparation 5 was obtained as a mixture diastereoisomers. MS: |M-H] = 903.2

Example 1 : (2/ï)-2-{|(5₁S^,„)-5-{3-chloro-2-methyl-4-|3-(4-niethylpiperazin-l-yl) propoxy[phenyl}-6-(4-fluoroplienyl)thieno|2,3-r/|pyrimidin-4-yl]oxy}-3-(2-{|2-(3hydroxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid

Starting from Préparation 2 using General procedure I Step B, Exaniple 1 was obtained. HRMS calculated for C₄₆H₄₂CIFN₆O₆S: 860.2559; found 431.1349 (M+2H)²⁺

Example 2: (2/f)-2-{|(55'_u)-5-{3-chloro-2-methyl-4-[3-(4-methylpiperazin-l-yl) propoxy|phenyl}-6-(4-fluorophenyl)thteno[2,3-i/]pyrimidin-4-yl|oxy}-3-(2-{[2-(4hydroxyphenyl)pyriniidin-4~yl]metlioxy}phenyl)propanoic acid

Starting from Préparation 3 using General procedure I Step B, Exaniple 2 was obtained. HRMS calculated for C₄6H-i2CIFN₆O₆S: 860.2559; found 431.1371 (M+2H)²⁺

Example 3: (2/f)-2-{|(55^, _rt)-5-{3-chloro-2-inethyi-4-|3-(4-methylpiperazin-l-yl) propoxy|phenyl}-6-(4-fluorophenyI)tliieno|2,3-r/|pyrimidin-4-yl]oxy}-3-|2-({2-[3( hydroxy methyI)phenyl|pyriniidin-4-yl}metlioxy)phenyd]propanoic acid

ORIGINAL

- 50Starting from Préparation 1 and [3-(4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2yl)phenyl]methanol using General procedure I, Example 3 was obtained. HRMS calculated for C47H44CIFN6O6S: 874.2715; found 438.141 (M+2H)²⁺

Example 4: (2/f)-2-{|(5_lS_fl)-5-{3-chloro-2-methyl-4-[3-(4-methyIpiperazin-I-yl) propoxy]phcnyl}-6-(4-fluorophenyl)thieno|2,3-r/|pyrimidin-4-yl]oxy}-3-|2-( {2-|4(hydroxymcthyl)phenyl]pynmidin-4-yl}methoxy)phenyl]propanoic acid

Starting from Préparation 1 and [4-(4,4,5,5-tetramethyl-l ,3.2-dioxaborolan-2yl)phenyl]methanol using General procedure 1, Exampie 4 was obtained. HRMS calculated for C₄7H44C1FN₆O₆S: 874.2715; found 438.1449 (M+2H)²⁺

Example 5: (2/i)-2-{|(5S'_fl)-5-{3-chloro-2-metliyl-4-|3-(4-inethylpiperazin-l-yl) propoxy|phenyl}-6-(4-fluorophenyI)thieno|2,3-i/|pyrimidin-4-ylloxy}-3-{2-|(2-{2-|(2,2dimethyl-l,3-dioxolan-4-yl)methoxy]phcnyl}pyrimidin-4-yl)metlioxy|phenyl} propanoic acid

Starting from Préparation 1 and Préparation 4a using General procedure I, Exampie 5 was obtained. HRMS calculated for CsiHîtCIFNôOsS: 974.324; found 488.1698 (M+2H)²⁺

Example 6: (2Æ)-2-{[(5₁S^, _(J)-5-{3-cliloro-2-mcthyl-4-[3-(4-methylpiperazin-l-yI) propoxy|plienyI}-6-(4-fluorophenyI)thicno|2,3-r/| pyrimidin-4-yl]oxy}-3-{2-|(2-{2-|2(2-methoxyethoxy)ethoxy]phenyl}pyrimidin-4-yl)methoxy|phcnyl} propanoic acid

Starting from Préparation 1 and Préparation 4b using General procedure I, Example 6 was obtained. HRMS calculated for CjjHsiCIFNôOsS: 962.324; found 482.1695 (M+2H)²⁺

Example 7: (2Æ)-2-{[(55_tf)-5-{3-chIoro-2-methyl-4-|3-(4-methylpiperazin-l-yl) propoxy]phenyl}-6-(4-fluorophenyl)tIiieno[2,3-rf|pyrimidin-4-yi]oxy}-3-(2-{[2-(2-{2[2-(2-methoxyethoxy)ethoxy]ethoxy}phenyl)pyrimidin-4-yl[metlioxy}phenyl) propanoic acid _

ORIGINAL

-5I Starting from Préparation 1 and Préparation 4c using General procedure I. Example 7 was obtained. HRMS calculated for C53H56CIFN6O9S: 1006.3502; found 504.1828 (M+2H)²⁺

Example 8; (2Æ)-2-{[(5S„)-5-{3-eliloro-2-methyl-4-J3-(4-methylpiperazin-l-yl) propoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-rf|pyrîm!din-4-yljoxy}-3-[2-({2-|2(methoxymethyl)phenyl|pyrimidin-4-yl}methoxy)phenyl|propanoic acid

Starting from Préparation 1 and [2-(methoxymethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2dioxaborolane using General procedure 1, Example 8 was obtained. HRMS calculated for C₄₈H₄₆CIFN₆O₇S: 888.2872; found 445.1518 (M+2H)²⁺

Example 9: (2/f)-2-{[(55„)-5-{3-chloro-2-methyl-4-|3-(4-methylpiperazin-l-yl) propoxy]phenyl}-6-(4-fluorophenyl)thieno|2,3-7| pyrimidin-4-yl|oxy}-3-{2-[(2-{2-|(2methoxyethoxy)metliyI|phenyl}pynmidin-4-yI)niethoxy|plienyl}propanoic acid

Starting from Préparation 1 and Préparation 4d using General procedure I, Example 9 was obtained. HRMS calculated for C5oH5oC1FN₆0₇S: 932.3134; found 467.164 (M+2H)²⁺

Example 10: (2Æ)-2-{[(5S„)-5-{3-chloro-2-methyl-4-|3-(4-methylpiperazin-l-yl) propoxy]phenyl}-6-(4-fluoroplienyl)thieno[2,3-7]pyrimidin-4-yl|oxy}-3-{2-((2-{2-|(2liydroxyethoxy)methyl]phenyl}pyrimidin-4-yl)methoxy|phenyl}propanoic acid

Starting from Préparation 1 and Préparation 4e using General procedure I, after 20 completion of the reaction in Step B the pH was set to 1 with 2M aqueous HCl solution and il was stirred until no further conversion was observed. Then it was neutralized with 10% aqueous K2CO3 solution, diluted with brine, 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 via preparative reversed phase 25 chromatography using 5 mM aqueous NH4HCO3 solution and MeCN as eluents. The diastereoisomer eluting later was collected to obtain Example 10. HRMS calculated for C₄₉H₄8N₆O₇FSC1: 918.2978; found 460.1572 (M+2H)²⁺

ORIGINAL

-52Example 11 : (2/?)-2-{[(55_a)-5-{3-chIoro-2-methyl-4-|3-(4-methylpiperazin-l-yI) propoxy|phenyl}-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-ylJoxy}-3-(2-{[2-(2{[(2,2-dimethyl-l,3-dioxolan-4-yl)methoxy|methyl}phenyl)pyrimidin-4-yl] methoxy} phcnyljpropanoic acid

Starting from Préparation 1 and Préparation 4f using General procedure l, Example 11 was obtained. HRMS calculated for C53H54CIFN6O8S: 988.3397; found 495.1762 (M+2H)²⁺

Example 12: (2/f)-2-{[(5S_fl)-5-{3-cliIoro-2-methyl-4-|3-(4-methyIpiperazin-l-yl) propoxy|plienyl}-6-(4-fIuorophenyI)thieno|2,3-f/]pyrimidin-4-yl|oxy}-3{2-|(2-{3-[(210 hydroxyethoxy)methyl]phenyl}pyrimidin-4-yl)methoxy|pIienyl}propanoic acid

Starting from Préparation 1 and Préparation 4g using using General procedure I, after completion of the reaction in Step B the pH was set to 1 with 2M aqueous HCl solution and it was stirred until no further conversion was observed. Then it was neulralized with 10% aqueous K.2CO3 solution, diluted with brine, extracted with DCM. The combined 15 organic phases were dried over MgSO₄, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified via préparative reversed phase chromatography using 5 mM aqueous NH₄HCO₃ solution and MeCN as eluents. The diastereoisomer eluting later was collected to obtain Example 12. HRMS calculated for C₄₉H_4SC1FN₆O₇S: 918.2978; found 460.1556 (M+2H)²⁺

Example 13: (2Æ)-2-{[(55„)-5-{3-chloro-2-methyl-4-[3-(4-methylpipcrazin-l-yl) propoxy|phenyl}-6-(4-fluorophenyl)tliieno[2,3-r/]pyrimidin-4-yl|oxy}-3-{2-I(2-{3-|(l,3dimethoxypropan-2-yI)oxy|phenyl}pyrimidin-4-yl)methoxy|phenyl}propanoic acid

Starting from Préparation 1 and Préparation 4h using General procedure I, Example 13 was obtained. HRMS calculated for CâiHsiClFNôOsS: 962.324; found 482.1694 (M+2H)²⁺

ORIGINAL

-53Example 14: (2/?)-2-{[(55_u)-5-{3-chloro-2-methyl-4-|3-(4-methylpiperazin-l-yl) propoxy]phenyl}-6-(4-fluorophenyl)thieno|2,3-iflpyrimidin-4-yl|oxy}'3-{2-|(2-{4-|(l,3dimethoxypropan-2-yl)oxy|phenyI}pyrimidin-4-yl)methoxy|phenyl}propanoic acid

Starting from Préparation 1 and Préparation 4i using General procedure 1, Example 14 was obtained. HRMS calculated for C5iH5₂CIFNèO₈S: 962.324; tound 482.1678 (M+2H)“⁺

Example 15: (2R)-2-{[(55_a)-5-{3-chioro-2-methyl-4-|3-(4-methylpiperazin-l-yl) propoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i/|pyrimidin-4-yl]oxy}-3-[2-({2-|4-(2,3dihydroxypropoxy)phenyl|pyriinidin-4-yl}methoxy)phenyl|propanoic acid

Starting from Préparation 3 and (2,2-dimethyl-l,3-dioxolan-4-yl)methanol using General procedure II after compietion of the reaction in Step B the pH was sel to 1 with 2M aqueous HCl solution and il was stirred until no further conversion was observed. Then it was neutralized with 10 % aqueous K₂CO₃ solution, diluted with brine, 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 via préparative reversed phase chromatography using 5 mM aqueous NH₄HCO₃ solution and MeCN as eluents. The diastereoisomer eluting later was collected to obtain Example 15. HRMS calculated for C₄₉H₄₈N₆O₈FSC1: 934.2927; found 468.1531 (M+2H)²⁺

Example 16: methyl 6-0-{3-[4-({2-|(2/i)-2-carboxy-2-{|(5S^, _i,)-5-{3-chloro-2-methyl-4[3-(4-methylpiperazin-l-yI)propoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-rf] pyrimidin-4-y]]oxy}ethyl]phenoxy}methyl)pyrimidin-2-yl|phenyl}-a-Dmannopyranoside

Starting from Préparation 1 and Préparation 4j using General procedure V, Example 16 was obtained. HRMS calculated for C5₃H5₄C1FN(>O| iS: 1036.3243; found 519.1696 (M+2H)²⁺

Example 17: methyl 6-O-{3-|4-({2-[(2Æ)-2-carboxy-2-{[(5S„)-5-{3-chloro-2-methyl-4|3-(4-methylpiperazin-l -yl)propoxy]phenyl}-6-(4-fluorophenyl)thieno|2,3-r/|

ORIGINAL

-54pyrimidin-4-yl]oxy}ethyl]phenoxy}methyl)pyrimidin-2-yl]phenyl}-2,3,4-tri-i?-methylα-D-mannopyranoside

Starting from Préparation 1 and Préparation 4k using General procedure I, Example 17 was obtained. HRMS calculated for CsôHgoCIFNôOhS: 1078.3713; found 540.1936 5 (M+2H)²⁺

Example 18: methyl 6-0-{4-|4-({2-[(2/i)-2-carboxy-2-{[(5S'„)-5-{3-chloro-2-methyl-4[3-(4-methylpiperazin-l-yl)propoxy]plienyl}-6-(4-fIuorophenyl)thieno[2,3-i/| pyrimidin-4-ylJoxy}cthyl]phenoxy}methyl)pyrimidin-2-yl|phenyI}-a-Dmannopyranoside

Starting from Préparation 1 and Préparation 41 using General procedure V, Example 18 was obtained. HRMS calculated for CsjH-^CIFNôOijS: 1036.3243; found 519.1714 (M+2H)²⁺

Example 19: methyl 6-O“{4-[4-({2-I(2fi)-2-carboxy-2-{[(5S_i,)-5-{3-chlorO'2’niethyl-4[3-(4-methylpiperazin-l-yl)propoxyjphenyl)-6-(4-fluorophenyl)thieno[2,3-rf] pyrimidin-4-yl]oxy}ethyl]phenoxy}metliyl)pyrimidin-2-yI]phenyl}-2,3,4-tri-O-methyla-D-mannopyranoside

Starting from Préparation 1 and Préparation 4m using General procedure I, Example 19 was obtained. HRMS calculated for CîôHôoCIFNôOijS: 1078.3713; found 540.1925 (M+2H)²⁺

Example 20: 6-0-{4-|4-({2-|(2/ί)-2-€3Ηΐοχγ-2-{|(55_(ί)-5-{3-ΗιΙθΓθ-2-ηιείΙιχΙ-4-|3-(4methylpiperazin-l-yl)propoxy]phenyl}-6-(4-fluorophenyl)thïeno[2,3-rf| pyrimidin-4yl]oxy}ethyI]phenoxy}methyl)pyrimidin-2-yl]phenyI}-D-mannopyranose and Example 21: 6-<9-{2-[4-({2-|(2/i)-2-carboxy-2-{((5S₍,)-5-{3-chIoro-2-methyl-4-[3-(425 methylpiperazin-l-yl)propoxy]phenyl}-6-(4-fluorophenyl)thieno|2,3-i7]pyrimidin-4yl]oxy}ethyl]phenoxy}methyl)pyrimidin-2-yl|phenyl}-D-mannonic acid

ORIGINAL

- 55 Starting from Préparation 1 and Préparation 4n using General procedure V, Example 20 was obtained as the earlier eluting compound. HRMS calculated for C52H52CIFN6O11S: 1022.3087; found 512.1611 (M+2H)²⁺

Example 21 was obtained as the later eluting compound. HRMS calculated for C₅2H52CIFN₆O₁₂S: 1038.3036; found 520.1604 (M+2H)²⁺

Example 22: l,2-t?-[(lÆ)-l-({4-[4-({2-[(2/f)-2-carboxy-2-{|(55_i,)-5-{3-chIoro-2-methyl4-[3-(4-methyIpiperazin-l-yl)propoxy]phenyl}-6-(4-fluorophenyI)thienoJ2,3-^l pyrimidin-4-yl|oxy}ethyl|plienoxy}mcthyl)pyrimidin-2-yl|benzyl}oxy)ethylidene]-pD-mannopyranosc

Starting from Préparation 1 and Préparation 4o using General procedure V, Example 22 was obtained. HRMS calculated for C₅₅H₅₍,ClFN₆0i2S: 1078.335; found 1079.343 (M+H)⁺

Example 23: (2Æ)-2-{|(55_a)-5-{3-chloro-2-methyl-4-[3-(4-methylpiperazin-l-yl) propoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-rf]pyrimidin-4-yl]oxy}-3-{2-[(2-{4-|(aD-mannopyranosyloxy)methyl]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid

Starting from Préparation 1 and Préparation 4p using General procedure V, Example 23 was obtained. FIRMS calculated for C53H54CIFN6O1 |S: 1036.3243; found 519.1682 (M+2H)²⁺

Example 24: (27?)-2-{|(5S„)-5-{3-chloro-2-methyl-4-[3-(4-methylpiperazin-l-yl) propoxy]phenyl}-6-(4-nuoroplienyl)thieiio|2,3-(7] pyrimidin-4-yl|oxy}-3-|2-({2-|4-(2hydroxyethyl)phenyl|pyrimidin-4-yl}methoxy)plienyl]propanoic acid

Starting from Préparation 1 and [4-(2-hydroxyethyl)phenyl]boronic acid using General procedure 1, Example 24 was obtained. HRMS calculated for C4_SH46N₆O₆FSC1: 888.2872; found 445.1512 (M+2H)²⁺

ORIGINAL

-56Example 25: (27f)-2-{|(5S'„)-5-{3-chloro-2-metIiyl-4-|3-(4-methylpiperazin-l-yl) propoxy]phenyl}-6-(4-fluorophenyl)thieno(2,3-rf|pyrimidin-4-yI|oxy}-3-[2-({2-[2-(2,3dihydroxypropoxy)phenyl|pyrimidin-4-yl}metlioxy)phenyI]propanoic acid

Starting from Préparation 1 and Préparation 4a using General procedure I after 5 completion of the reaction in Step B the pH was set to 1 with 2M aqueous HCl solution and it was stirred until no further conversion was observed. Then it was neutralized with 10% aqueous K?CO₃ solution, diluted with brine, 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 via préparative reversed phase 10 chromatography using 5 mM aqueous NH4HCO3 solution and MeCN as eluents. The diastereoisomer eluting later was collected to obtain Example 25. HRMS calculated for C₄₉H₄₈C1FN₆O₈S: 934.2927; found 468.1536 (M+2H)²⁺

Example 26: (2/?)-2-{|(55'„)-5-{3-chloro-2-inethyl-4-|3-(4-niethyi[)iperazin-l-yl) propoxy|phenyI}-6-(4-fluorophenyl)thieno[2,3-i/|pyrimidin-4-yl]oxy}-3-|2-( {2-(2-(215 hydroxyethoxy)phenyl]pynmidin-4-yl}methoxy)phenyl|propanoic acid

Step A: Ethyl (2R)-2-hydroxy-3-[2-[[2-[2-(2-methoxyethoxy)phenyl]pyrimidin-4-yl] methoxy]phenyl]propanoate

A solution of 1.01 g ethyl (2Æ)-3-[2-[(2-chloiOpyiïmidin-4-yl)methoxy]phenyl]-2hydroxy-propanoate (from Préparation 1 Step E) (3 mmol, 1 eq.), 1.17 g [2-(220 methoxyethoxy)phenyl]boronic acid (6 mmol, 2 eq.), 2.93 g césium carbonate (9 mmol.

eq.) and 210 mg PdæPhsbCb in 30 mL dioxane/H^O (1:1) were stirred at 70 °C until no further conversion was observed. The reaction mixture was diluted with EtOAc and brine. After extraction the organic phase was washed with brine and dried over MgSO₄, filtered and concentrated under reduced pressure. The crude product was purified by flash 25 chromatography using heptane and EtOAc as eluents to obtain ethyl (2Æ)-2-hydroxy-3-[2[[2-[2-(2-methoxyethoxy)phenyl]pyrimidin-4-yl]methoxy]phenyl]propanoate as colorless oil. 'H NMR (400 MHz. DMSO-d₆) δ 8.92 (d, IH), 7.60 (dd, IH). 7.59 (d, IH), 7.45 (dd, IH), 7.24-7.15 (m, 3H), 7.08 (t, IH). 7.02 (d, IH), 6.91 (t, IH), 5.55 (d, IH), 5.27 (d, IH),

ORIGINAL

5.23 (d, IH), 4.40-4.32 m, IH). 4.17-4.11 (m, 2H), 4.06 (q, 2H), 3.62-3.60 (m. 2H), 3.22 (s,3H),3.l7(dd, 1H),2.88 (dd, IH), 1.18 (t. 3H)

Step B: Ethyl (2R)-2-[5-bromo-6-(4-fliiorophenyl)thieno[2,3-à]pyrimidm-4-yl]oxy-3-[2[[2-[2-(2-m ethoxyethoxy)phenyl]pyrim idin-4 -yl]methoxy]phenyl]propanoate

A suspension of 995 mg product obtained in Step A (2.2 mmol, 1.1 eq.), 687 mg 5-bromo4-chloro-6-(4-fluorophenyl)thieno[2,3-</]pyrimidine (from Préparation 1 Step D) (2 mmol, 1 eq.) and 1.95 g césium carbonate (6 mmol, 3 eq.) in 10 mL dry THF were stirred at 70 °C until no further conversion was observed. The reaction mixture was diiuted with EtOAc and brine. After extraction the organic phase was washed with brine and dried over MgSO₄. filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using heptane and EtOAc as eluents to obtain ethyl (27?)2-[5-bromo-6-(4-fluorophenyl)thieno[2,3-i7]pyrimidin-4-yl]oxy-3-[2-[[2-[2-(2-methoxy ethoxy)phenyl]pyrimidin-4-yl]methoxy]phenyl]propanoate. ’H NMR (400 MHz, DMSOd₆) δ 8.90 (d, JH), 8.62 (s, IH), 7.77-7.72 (m, 2H), 7.61 (d, IH), 7.55 (dd, IH), 7.49 (dd,

IH), 7.45-7.38 (m, 3H), 7.25 (dd. IH), 7.15 (d. IH), 7.09-7.01 (m, 2H), 6.94 (t. IH), 5.79 (dd, IH), 5.31 (d, IH), 5.25 (d, IH), 4.17 (q, 2H), 4.15-4.10 (m, 2H), 3.64-3.56 (m, 3H),

3.33 (dd. IH), 3.21 (s,3H), 1.14 (t, 3H)

Step C: Ethyl (2R)-2-[5-bromo-6-(4-fhiorophenyl)thieno[2,3-à]pyrimidin-4-yl]oxy-3-[2[[2-[2-(2-hydroxyethoxy)phenyl]pyrimidin-4-yl]methoxy]phenyl]propanoate

To the solution of 760 mg product obtained in Step B (1 mmol. 1 eq.) in 10 mL dry DCM, 1 mL BBrj (1 mmol, IM in DCM, 1 eq.) was added dropwise at r.t.. then the mixture was stirred until no further conversion was observed. The reaction mixture was diiuted with EtOAc and brine. After extraction the organic phase was washed with brine and dried over MgSO₄, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using heptane and EtOAc as eluents to obtain ethyl (2/?)-2-[5bromo-6-(4-fluorophenyl)thieno[2,3-i7]pyrimidin-4-yl]oxy-3-[2-[[2-[2-(2-hydroxyethoxy) phenyl]pyrimidin-4-yl]methoxy]phenyl]propanoate. *H NMR (400 MHz, CDC1₃) δ 8.99 (d, IH), 8.53 (s, IH), 7.92 (dd, IH), 7.79 (d, IH), 7.69-7.62 (m, 2H). 7.54-7.45 (m, 2H), 7.27-7.12 (m, 5H), 6.98 (7, IH), 6.94 (d, IH), 5.87 (dd. IH), 5.34 (d, IH), 5.29 (d, 1 H),

4.41 (t, 2H), 4.29 (q, 2H). 3.94 (t, 2H), 3.72 (dd, 1 H), 3.42 (dd, 1 H), 1.28 (t, 3H)

ORIGINAL

-58Slep D: Ethyl (2^)-2-[5-[3-chloro-2-methyl-4-[2-(4-methylpiperazïn-!-yl)ethoxy]phenyl]-

6-(4-fluorophenyl)thieno[2.3-d]pyrimidin-4-yl]oxy-3-[2-[[2-[2-(2-hydroxyethoxy)phenyl] pyrimidm-4-yl]methoxy]phenyl]propanoate

To a solution of 200 mg of product Step C (0.27 mmol, l eq.) in 4 mL dioxane/H?O (l:l), 5 127 mg l-[2-[2-chloro-3-methyl-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)phenoxy] ethyl]-4-methyl-piperazine (from Préparation 1 Step L) (0.32 mmol, 1.2 eq.), 3.1 mg Pd(OAc)₂ (0.05 eq.), 11 mg AtaPhos (0.1 eq.) and 262 mg césium carbonate (0.8 mmol, 3 eq.) were stirred at 70 °C until no further conversion was observed. Reaction mixture was diluted with EtOAc and brine. After extraction the organic phase was washed with 10 brine and dried over MgSO₄, filtered and concentrated under reduced pressure. Crude product was purified by flash chromatography using EtOAc/MeOH (containing 1.2% NH₃) as eluents to obtain ethyl (2Æ)-2-[5-[3-chloiO-2-methyl-4-[2-(4-methylpiperazin-l-yl) ethoxyjphenyl |-6-(4-tluoiOphenyl)thieno[2.3-i7]pyrimidin-4-yl]oxy-3-[2-[[2-[2-(2-hydroxy ethoxy)phenyl]pyrimidin-4-yl]methoxy]phenyl]propanoate. MS: [M+H]⁺= 933.2

Step E: Example 26

To a solution of 120 mg product of Step D (0.13 mmol) in 4 mL dioxane/I-LO (1:1) 100 mg LiOH x H₂O (2.6 mmol, 20 eq.) was added and it was stirred at r.t. until no further conversion was observed. Then it was neutralized with 2M HCl and then directly was injected to an RI³18 column using 5 mM aqueous NH₄HCO₃ solution and MeCN as 20 eluents. The diastereoisomer eluting later was collected to obtain Example 26. HRMS calculated for C_4gH_4fiClEN₆O₇S: 904.2821 ; found 453.1496 (M+2H)²⁺

Example 27: (2/?)-2-{|(5Ν_η)-5-{3-€Η1οιο-2-πΐ€ίΙιγ1-4-|3-(4-ηιοίΙιγΙριρ€Γηζΐη-1-γΙ) propoxy]phenyl}-6-(4-iluorophenyl)thieno[2,3-rf| pyrimidin-4-yl|oxy}-3-{2-|(2-{2-|(2,3dihydroxypropoxy)mcthyl]phenyI}pyrimidin-4-yl)niethoxy|phenyl}propanoic acid

Starting from Préparation 1 and Préparation 4f using General Procedure 1, after completîon of the reaction in Step B the pH was set to 1 with 2M aqueous HCl solution and it was stirred until no further conversion was observed. Then it was neutralized with 10% aqueous K₂CO₃ solution, diluted with brine, extracted with DCM. The combined

ORIGINAL

-59organic phases were dried over MgSO₄. filtered and the filtrate was concentrated under reduced pressure. The crude product was purified via preparative reversed phase chromatography using 5 mM aqueous NH₄HCO₃ solution and MeCN as eluents. The diastereoisomer eluting later was collected to obtain Example 27. HRMS calculated for 5 C₅oH₅₀ClFN₆0₈S: 948.3083; found 475.1621 (M+2H)²⁺

Example 28: (2Λ)-2-{[(55„)-5-{3-^ι1θΓθ-2-Γη€ίΙιγ1-4-[3-(4-ηιείΙιγΙρΐρβ™ζπι-1-γ1) propoxy|phenyl}-6-(4-fluorophenyl)thieno[2,3-if| pyrimidin-4-yljoxy}-3-|2-({2-[3(phosphonooxy)phenyl]pyrimidin-4-yl}methoxy)phenyl| propanoic acid

To a THF solution of 444 mg Préparation 2 (0.5 mmol, l eq.) and 210 pL TEA 10 (l .5 mmol, 3 eq.) in 5 mL dry THF, 140 pL (1.5 mmol, 3 eq.) POCl₃ was added dropwise at r.t. After 15 minutes stirring, 5 mL sodium hydroxide (10 mmol, 2M in water) was added, and then it was stirred at 50 °C until no further conversion was observed. The reaction mixture was injected directly to a preconditioned (EtOAc/MeOH [containing l .2 % NH₃] - 80/20) 220 g flash silica gel column using EtOAc /MeOH (containing l .2 % 15 NH₃) as eluents with gradient method giving the desired product as a mixture of the diastereoisomers. The diastereoisomers were separated via preparative reversed phase chromatography using 50 mM aqueous NH₄HCO₃ solution and MeOH as eluents. The diastereoisomer eluting later was collected as Example 28. HRMS calculated for C₄₆H₄₃N₆O₉FPSC[: 940.2222; found 47l.l 194 (M+2H)²⁺

Example 29: 4-[4-({2-[(2/0-2-€3^οχγ-2-{|(55_(ί)-5-{3^Η1οιο-2-ηιοίΗγΙ-4-|3-(4-ηιεί1ινΙ pipcrazin-l-yl)propoxy]phenyl}-6-(4-fluorophenyl)tliieno|2,3-r/|pyrimidin-4-yl]oxy} ethyl |phenoxy}methyl)pyrimidin-2-yl] phenyl phosphate

To a THF solution of 444 mg ethyl Préparation 3 (0.5 mmol, l eq.) and 210 pL TEA (1.5 mmol, 3 eq.) in 5 mL dry THF, 140 pL (L5 mmol. 3 eq.) POCl₃ was added dropwise 25 at r.t. After 15 minutes stirring, 5 mL sodium hydroxide (10 mmol, 2M in water) was added, and then it was stirred at 50 °C until no further conversion was observed. The reaction mixture was injected directly to a preconditioned (EtOAc/MeOH [containing

1.2 % NH₃] - 80/20) 220 g flash silica gel column using EtOAc /MeOH (containing 1.2 %

ORIGINAL

-60NH₃) as eluents with gradient method giving the desired product as a mixture of the diastereoisomers. The diastereoisomer eluting later was collected as Example 29 after lyophylisation. HRMS calculated for C4₆H4₃N₆O₉FPSCI: 940.2222; found 471.H88 (M+2H)²⁺

Example 30: (2/f)-2-{[(55_a)-5-{3-chloro-2-methyl-4-|3-(4-methylpiperazin-l-yl) propoxy]phenyl}-6-(4-fluorophenyl)thicno[2,3-i/|pyrimidin-4-yl|oxy}-3-[2-({2-|3-(2hydroxyethoxy)phenyl|pyrimidin-4-yl}methoxy)phenyl]propanoic acid

Step A: Ethyl (2R)-2-[5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]6-(4-fluorophenyl)lhieno[2,3-d]pyrimidin-4-yl]oxy-3-[2-[[2-[3-[2-(p-tolylsiilfonyloxy) ethoxy]phenyl]pyrimidin-4-yl]methoxy]phenyl]propanoate

To a DMF solution of 178 mg Préparation 2 (0.2 mmol), 195 mg césium carbonate (0.6 mmol) and 222 mg 2-(p-tolylsulfonyloxy)ethyl 4-methylbenzenesultonale (0.6 mmol) were added and the mixture was stirred at 60 °C until no further conversion was observed. The reaction mixture was diluted with EtOAc and brine. Aller extraction the organic phase was washed with brine and dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using EtOAc and MeOH (containing l .2 % NH₃) as eluents to obtain ethyl (2Æ)-2-[5-[3-chloro-2-methyl-4[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6-(4-fiuorophenyl)thieno[2,3-i7]pyrimidin-4-yl| oxy-3-[2-[[2-[3-[2-(p-tolylsulfonyloxy)ethoxy]phenyl]pyrimidin-4-yl]methoxy]phenyl] propanoate. MS: [M+Hf = 1087.2

Step B: Example 30

To a solution of 120 mg product Step A (0.11 mmol) in 4 mL dioxane/HjO (1:1), 92 mg LiOH x I LO (2.2 mmol) was added and it was stirred at 60 °C until no further conversion was observed. Then it was neutralized with 2M HCl and then was injected directly to an RP 18 column using using 5 mM aqueous NH4HCO₃ solution and MeCN as eluents. The diastereoisomer eluting later was collected to obtain Example 30. HRMS calculated for C4_gH₄₆ClFN₆O₇S: 904.2821 ; found 453.1475 (M+2H)²⁺

ORIGINAL

-6I Example 31: (ZTQ-Z-iKSSaj-â-ÎS-chloro-Z-methyl^-IS-^-methylpiperazin-l-yl) propoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-rf| pyrimidin-4-yl|oxy}-3-{2-[(2-{4-|2(2-methoxyethoxy)ethoxy]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid

Starting from Préparation 3 and 2-(2-methoxyethoxy)ethanol using General procedure II,

Example 31 was obtained. HRMS calculated for CsiHjjNfeOgFSCl: 962.324; found 482.1703 (M+2H)²⁺

Example 32: (2/f)-2-{|(55_iJ-5-{3-chloiO-2-methyl-4-I3-(4-methylpipcrazin-l-yl) propoxy]phenyl}-6-(4-fluorophenyl)thieno|2,3-rf|pyrimidin-4-yI]oxy}-3-{2-[(2-{4-|2(2-hydroxyethoxy)ethoxy| phenyl} pyrimidin-4-yl)methoxy|phenyl} propanoic acid

Starting from Préparation 3 and 10 eq. of 2-(2-hydroxyethoxy)ethanol using General procedure 11, Example 32 was obtained. HRMS calculated for CîoHsoNôOsFSCI: 948.3083; found 475.1613 (M+2H)²⁺

Example 33: (2/?)-2-{[(5S'_(/)-5-{3-chloro-2-methyl-4-[3-(4-methylpiperazin-l-yl) propoxy]phenyl}-6-(4-fluoiOphenyI)thÎenol2,3-</]pyrimidin-4-yl]oxy}-3-(2-{[2-(4-{215 [2-(2-methoxyethoxy)ethoxy]ethoxy}phenyl)pyrimidin-4-yl|methoxy}phenyl) propanoic acid

Starting from Préparation 3 and 2-[2-(2-methoxyethoxy)ethoxy]ethanol using General procedure II, Example 33 was obtained. HRMS calculated for C53H56N6O9FSCI: 1006.3502; found 504.183 (M+2H)²⁺

Examplc 34: (2Æ)-2-{[(5S_a)-5-{3-chloro-2-inethyl-4-[3-(4-methylpiperazin-l-yl) propoxy|phenyl}-6-(4-fiuorophenyl)thieno[2,3-i/|pyrimidin-4-yl|oxy}-3-{2-[(2“{4-|2(dimethylamino)ethoxy|phenyl}pyrimidin-4-yl)niethoxy|phenyl}propanoic acid

Starting from Préparation 3 and 2-(dimethylamino)ethanol using General procedure 11, Example 34 was obtained. HRMS calculated for C50H51N7O6FSCI: 931.3294; found

466.6709 (M+2H)²⁺

ORIGINAL

-62Example 35: (21?)-2-{|(55_fl)-5-{3-chIoro-2-methyl-4-|3-(4-methylpiperazin-l-yl) propoxy]phenyl}-6-(4-fluorophenyl)tliieno[2,3-r/|pyrimidin-4-yI]oxy}-3-{2-|(2-{3-[(2,2dimethyl-l,3-dioxolan-4-yl)methoxy]phenyl}pyrimidin-4-yl)methoxy]phenyl} propanoic acid

Starting from Préparation 2 and (2,2-dimethyl-l,3-dioxolan-4-yl)methanol using General procedure II, Example 35 was obtained. HRMS calculated for CîtHîiNôOsFSCI: 974.324; found 488.1677 (M+2H)²⁺

Example 36: (2Æ)-2-{|(55_ü)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy| phenyl}-6-(4-fluorophenyl)thieno[2,3-r/lpyrimidin-4-yl]oxy}-3-|2-({2-|3-(15-hydroxy10 3-oxo-2,7,10,I3-tetraoxa-4-azapentadec-l-yl)phenyl|pyrimidin-4-yl}methoxy)phenyl] propanoic acid

Starting from Préparation 5 and 2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethanol as the appropriate amine using General procedure III, Example 36 was obtained. HRMS calculated for C56H₆iClFN₇O_itS: 1093.3822; found 547.7006 (M+2H)²⁺

Example 37: (2/f)-3-(2-{[2-(3-{[(I,4^,-bipiperidin-r-ylcarbonyl)oxy]mctliyl}plienyl) pyrimidin-4-yl|methoxy}plienyI)-2-{|(5S₀)-5-{3-chloro-2-methyl-4-[2-(4methylpiperazin-l-yl)ethoxy)pbenyi}-6-(4-fIuorophenyl)thieno|2,3-rf] pyrimidin-4yl]oxy}propanoic acid

Starting from Préparation 5 and 1 -(4-piperidyl )piperidine as the appropriate amine using 20 General procedure III, Example 37 was obtained. HRMS calculated for CjsHf^ClFNgOvS: 1068.4135; found 1069.419 (M+H)⁺

Example 38: (27f)-2-{[(55_e)-5-{3-chloro-2-methyl-4-|2-(4-methylpiperazin-l-yl)ethoxy| phenyI}-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-yl|oxy}-3-(2-{|2-(3-{2-[2-(2hydroxyethoxy)ethoxy]ethoxy}phenyl)pyrimidin-4-yl|methoxy}phenyl)propanoic acid

ORIGINAL

- 63 Starting from Préparation 2 and 10 eq. of 2-[2-(2-hydroxyethoxy)ethoxy]ethanol using General procedure II, Example 38 was obtained. HRMS calculated for C52H54CIFN6O9S: 992.3345; found 497.1748 (M+2H)²⁺

Example 39: (27?)-2-{[(55_fl)-5-{3-chloro-2-methyl-4-|2-(4-methylpiperazin-l-yI)ethoxy| 5 phenyl}-6-(4-fluorophenyl)thieno|2,3-i/]pyrimidin-4-yl]oxy}-3-{2-|(2-{3-[2-(2-hydroxy ethoxy)ethoxy|phenyl}pyrinudin-4-yl)methoxy|phenyl}propanoic acid

Starting from Préparation 2 and 10 eq. of 2-(2-hydroxyethoxy)ethanol using General procedure II, Example 39 was obtained. HRMS calculated for CsoHsoCIFNèOsS: 948.3083; found 475.1604 (M+2H)²⁺

Example 40: (2Æ)-2-{|(5Sj-5-{3-chloro-2-mcthyl-4-|2-(4-methylpiperazin-l-yl)ethoxy] phenyl}-6-(4-fluorophcnyl)thieno[2,3-rZ| pyrimidin-4-yl|oxy}-3-{2-|(2-{3-[2-(2-methoxy etlioxy)ethoxy|phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid

Starting from Préparation 2 and 2-(2-methoxyethoxy)ethanol using General procedure II, Example 40 was obtained. HRMS calculated for CijHÿiCIFNôOsS: 962.324; found

482.1675 (M+2H)²⁺

Example 41: (2/i)-2-{|(55„)-5-{3-chloro-2-metliyl-4-[2-(4-methylpiperazin-l-yl)cthoxy] phenyI}-6-(4-fluoroplienyI)thieno[2,3-rf|pyrimidin-4-yl]oxy}-3-{2-[(2-{3-|({I2-(4methylpiperazin-l-yl)ethyi]carbamoyl}oxy)methyi]phenyl}pyrimidin-4-yl)methoxy| phenyl}propanoic acid

Starting from Préparation 5 and 2-(4-methylpiperazin-1 -yl)ethanamine as the appropriate amine using General procedure III, Example 41 was obtained. HRMS calculated lor C₅₅H59C1FN₉O₇S; 1043.3931; found 522.7052 (M+2H)²⁴

Example 42: (27î)-2-{l(5Sa)-5-{3-chloro-2-niethyl-4-|2-(4-methylpiperazin-l-yl)ethoxy] phenyl}-6-(4-fluorophenyl)thieno|2,3-rf]pyrimidin-4-yl]oxy}-3-{2-[(2-{3-[({|2ORIGINAL

- 64 (morpholin-4-yI)ethy!lcarbamoyl}oxy)methyl|phenyI}pyrimidin-4-yl)methoxy| phenyl}propanoic acid

Starting from Préparation 5 and 2-morpholinoethanamine as the appropriate amine using

General procedure III, Exaniple 42 was obtained. HRMS calculated l'or Cj-jHâeClFNsOsS: 5 1030.3615; found 516.1871 (M+2H)²⁺

Exaniple 43: (2Æ)-2-{[(5S_a)-5-{3-chloro-2-niethyl-4-[2-(4-methyipiperazin-l-yl)ethoxy| phenyl}-6-(4-fluorophcnyl)thieno|2,3-i/|pyrini!din-4-yl]oxy}-3-{2-[(2-{3-[({[2(diniethylamino)ethyl]carbanioyl}oxy)niethyl|phenyI}pyrimidin-4-yl)methoxy| phenyl} propanoic acid

Starting from Préparation 5 and Æ',?/-dimethylethane-l,2-diamine as the appropriate amine using General procedure 111, Example 43 was obtained. HRMS calculated for C₅₂H₅₄C1FN₈O₇S: 988.3509; found 989.3586 (M+H)⁺

Example 44: (2/t)-2-{|(5S„)-5-{3-chIoro-2-methyl-4-[2-(4-methylpiperazin-l-yl)etlioxy| phenyl}-6-(4-fluorophenyl)thieno|2,3-rf|pyrimidm-4-yl]oxy}-3-{2-[(2-{3-|({[215 (pyrrolidin-l-yl)ethyl]carbanioyl}oxy)methyl]phenyl}pyriniidin-4-yl)methoxy| phenyljpropanoic acid

Starting from Préparation 5 and 2-pyrrolidin-l-ylethanamine as the appropriate amine using General procedure III, Example 44 was obtained. HRMS calculated for C₅₄H₅6C1FN₈O₇S: 1014.3665; found 508.1916 (M+2H)²⁺

Example 4S: (2Æ)-3-[2-({2-[3-({|bis(2-mcthoxyethyl)carbamoyl]oxy}methyl)phenyll pyrimidin-4-yl}inetlioxy)phenyl|-2-{|(55„)-5-{3-chloro-2-mcthyl-4-[2-(4niethy Ipiperazin-l-yl)ethoxy ]phenyl}-6-(4-fluoroplienyl)thieno [2,3-r/]py rimidin-4yl|oxy}propanoic acid

ORIGINAL

-65Starting from Préparation 5 and 2-inethoxy-7V-(2-methoxyethyl)ethanamine as the appropriate amine using General procedure III, Example 45 was obtained. HRMS calculated for C₅₄H₅7N₇O9FSCI: 1033.3611; found 517.6883 (M+2H)²⁺

Example 46: (27f)-2-{[(55_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)cthoxy| phenyl}-6-(4-fluorophenyl)thieno[2,3-i/|pyrimidin-4-yl|oxy}-3-(2-{|2-(3-{[(l,4,7,10,13pentaoxa-16-azacyclooctadecan-16-ylcarbonyl)oxy| methyl} phenyl)py rimidin-4yl]methoxy}phenyl)propanoic acid

Starting from Préparation 5 and l,4,7,10.13-pentaoxa-16-azacyclooctadecane as the appropriate amine using General procedure III, Example 46 was obtained. HRMS calculated for C₆oH₆7N₇Oi2FSCl: 1163.4241 ; found 582.7187 (M+2H)²⁺

Example 47: (2Æ)-2-{|(55_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl) ethoxy|phenyl}-6-(4-fluorophenyl)thïeno[2,3-//|pyrimidin-4-yl|oxy}-3-|2-({2-[3-(2,3dÎhydroxypropoxy)phenyl]pyrimidin-4-yl}methoxy)pl)enyl|propanoÎc acid

Starting from Préparation 2 and (2,2-dimelhyl-l ,3-dioxolan-4-yl)methanol using General procedure II. after completion of the reaction in Step B the pH was set to 1 with 2M aqueous HCl solution and it was stirred until no further conversion was observed. Then it was neutralized with 10 % aqueous K7CO3 solution, diluted with brine, 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 via preparative reversed phase chromatography using 5 mM aqueous NH4HCO3 solution and MeCN as eluents. The diastereoisomer eiuting later was collected to obtain Example 47. HRMS calculated for C₄9H₄₈N₆O_gFSCl: 934.2927; found 468.1538 (M+2H)²⁺

Example 48: (27f)-2-{[(5S_a)-5-{3-chloro-2-methyl-4-[2-(4-metliylpÎperazin--l-yl)ethoxy| phenyl}-6-(4-fluorophenyl)thicno|2,3-rf] pyrimidin-4-yl]oxy}-3-(2-{|2-(3-{2-[2-(2methoxyetlioxy)ethoxy|ethoxy}phenyl)pyi’imidiii-4-yl]methoxy}phenyl)propanoic acid '

ORIGINAL

-66Starting from Préparation 2 and 2-[2-(2-methoxyethoxy)ethoxy]ethanol using General procedure II, Example 48 was obtained. HRMS calculated for C53H56N6O9FSCI: 1006.3502; found 504.1829 (M+2H)²⁺

Example 49: (2/f)-3-(2-{[2-(3-{2-|bis(2-hydroxyethyl)amino]ethoxy}phenyl)pyrimidin5 4-yIJmethoxy}phenyl)-2-{[(5_lS'₍,)-5-{3-chIoro-2-methyl-4-|2-(4-niethylpiperazin-lyl)ethoxy]phenyl}-6-(4-fluoroplienyI)thieno[2,3-i/|pyrimidm-4-yl]oxy}propanoic acid

Starting from Préparation 2 and 10 eq. of 2-[bis(2-hydroxyethyl)amino]ethanol using General procedure II. Example 49 was obtained. HRMS calculated for C52H55N7O8FSCI: 991.3505; found 496.6833 (M+2H)²⁺

Example 50: (2Æ)-2-{j(55'_o)-5-{2,3-dimethyI-4-[2-(4-niethylpiperazin-l-yl)ethoxy] phenyl}-6-(4-fluorophenyI)thieno|2,3-i/|pyrimidin-4-yl]oxy}-3-{2-[(2-{3-|({[2(piperidin-l-yl)ethyl]carbamoyl}oxy)methyl|phenyl}pyrimidin-4-yl)methoxy|phcnyl} propanoic acid

J

Starting from Préparation 5 and /V-(2-aminoethyl)piperidine as the appropriate amine 15 using General procedure 111, Example 50 was obtained. FIRMS calculated for C55H58CIFN8O7S: 1028.3822; found 1029.3893 (M+H)⁺

Exaniple 51: (2Æ)-2-{|(5S_(J)-5-{3-chloro-2-metliyl-4-[2-(4-methylpiperazin-l-yl)ethoxy[ phenyl}-6-(4-fluorophcnyl)thieno|2,3-i/| pyrimidin-4-yl|oxy}-3-{2-[(2-{3-|2(morpholin-4-yl)ethoxy|phenyI}pyrimidin-4-yl)mctlioxy]phenyl} propanoic acid

Starting from Préparation 2 and A⁷-(2-hydroxyethyl)morpholine using General procedure II, Example 51 was obtained. HRMS calculated for C52H53CIFN7O7S: 973.3400; found 487.6785 (M+2H)²⁺

Examplc 52: (2/?)-2-{|(5S_a)-5-{3-chloro-2-methyl-4-[2-(4-metliylpiperazin-l-yl)ethoxy| phenyl}-6-(4-fluorophenyl)thieno|2,3-rf|pyrÎmïdin-4-yl|oxy}-3-{2-|(2-{3-|2-(diniethyl 25 amino)ethoxy|phenyl}pyriniidin-4-yl)methoxy]phenyl}propanoic acid

ORIGINAL

-67Starting from Préparation 2 and 2-dimethylaminoethanol using General procedure II, Example 52 was obtained. HRMS calculated for C50H51CIFN7O6S: 931.3294; found 466.6722 (M+2H)²⁺

Example 53: (2Æ)-3-(2-{[2-(4-{2-|bis(2-hydroxyethyl)amino|ethoxy}phenyl)pyrimidin4-yl]mcthoxy}phenyl)-2-{[(5A₍,)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy|plienyl}-6-(4-fluorophenyl)thieno[2,3-rf|pyrimidin-4-yl|oxy}propanoic acid

Starting from Préparation 3 and 2-[bis(2-hydroxyethyl)amino]ethanol using General procedure II, Example 53 was obtained. HRMS calculated for C52H55N7O8FSCI: 991.3505; found 496.6822 (M+2H)²⁺

Example 54: (2Æ)-2-{|(5S„)-5-{3-chloiO-2-methyl-4-[2-(4-methylpiperazin-I-yl)ethoxy] phenyl}-6-(4-fluorophenyl)thieno[2,3-i/j pyriniidin-4-yl|oxy}-3-(2-{|2-(4-{2-]2-(2hydroxyethoxy)ethoxy|ethoxy}phcnyI)pyrimidin-4-yljmethoxy}phenyl)propanoic acid

Starting from Préparation 3 and 10 eq. of triethyleneglycol using General procedure 11, Example 54 was obtained. HRMS calculated for C52H54N6O9FSCI: 992.3345; found 497.1743 (M+2H)²⁺

Example 55: (2/f)-2-{|(5S_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy| phenyl}-6-(4-fluorophenyl)thieno|2,3-//| pyrimidin-4-yl|oxy}-3-{2-|(2-{4-[(2,2dimethyl-l,3-dioxolan-4-yl)methoxy|phenyl}pyrimidin-4-yl)methoxy]phenyl} propanoic acid

Starting from Préparation 3 and (2,2-dimethyl-l,3-dioxolan-4-yl)methanol using General procedure II, Example 55 was obtained. HRMS calculated for CsiHjiNôOsFSCl: 974.3240; found 488.1689 (M+2H)²⁺

ORIGINAL

-68Example 56: (27?)-2-{[(5Æ„)-5-{3-chloro-2-methyL4-[2-(4-methylpipeiazin-l-yl)ethoxy] phenyl}-6-(4-fIuorophenyl)thieno[2,3-rf]pyrimidin-4-yI|oxy}-3-{2-[(2-{4-|2(morphoIin-4-yI)ethoxy]plienyI}pyrimidin-4-yl)methoxy|phenyl}propanoic acid

Starting from Préparation 3 and N-(2-hydroxyethyl)morpholine using General 5 procedure II, Example 56 was obtained. HRMS calculated for C52H53N7O7FSCI: 973.3400; found 487.6775 (M+2H)²⁺

Example 57: 4-|4-({2-|(27?)-2-ciii-b<j>xy-2-{[(5Λ\₇)-5-{3-€·Ιιloi<>-2-niethyI-4-[3-(4-nicthyl piperazin-l-yl)propoxy|phenyl}-6-(4-fiuorophenyl)thieno[2,3-rf]pyrimidin-4-yl|oxy} ethyl] phenoxy}methyI)pyrimidin-2-yl]phenyl phosphate disodium sait

To a THF solution of 444 mg Préparation 3 (0.5 mmol, l eq.) and 210 pL TEA (1.5 mmol, 3 eq.) in 5 mL dry THF, 140 pL POCl₃ (1.5 mmol, 3 eq.) was added dropwise at r.t. After 15 minutes stirring, 5 mL sodium hydroxide (IO mmol, 2M in water) was added, and then it was stirred at 50 °C until no further conversion was observed. Then the pH w^ras adjusted to 6 with TFA, and then this reaction mixture directly was injected to an

RP18 column using 50 mM aqueous NH4HCO3 solution and MeOH as eluents. The dîastereoisomer eluting later was collected. After liophilisation the remaining white solid was suspended in 5 mL dioxan / saturated NH4HCO3 (1:1 ). After 1 hour stirring at r.t., reaction mixture directly was injected to an RP 18 column using water and MeCN as eluents giving Examplc 57. HRMS calculated for C46H43N(,O₉FPSC1: 940.2222; found

469.1054 (M-2H)²’.

Example 58: (2/f)-3-(2-{[2-(2-{2-[bis(2-hydroxyetliyl)amino]ethoxy}phenyl) pyrimidin-4-yl]niethoxy}phenyl)-2-{|(5S„)-5-{3-chloro-2-methyL4-]2-(4methylpipcrazin-l-yl)ethoxy]phenyl}-6-(4-fluoropiicnyl)thieno|2,3-r/] pyrimidin-4yl]oxy}propanoic acid

Examplc 59: (2/i)-3-(2-{|2-(4-{[bis(2-hydroxyethyI)amino]methyl}phcnyl)pyrimidin4-yl|methoxy}phenyl)-2-{|(5S_fl)-5-{3-chIoro-2-methyL4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-r/]pyrimidin-4-yl|oxy}propanoic acid

ORIGINAL

-69Example 60: (2/f)-3-(2-{[2-(3-{|bis(2-hydroxyethyl)aniino|methyl}phenyl)pyrimidin4-yl|niethoxy}phenyl)-2-{[(55₀)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)cthoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-rf]pyriniidin-4-yl|oxy}propanoic acid

Example 61: (2R)-3-(2-{(2-(2-{|bis(2-hy(iroxyethyl)amino|niethyl}phcnyl)pyrimidin4-yI] methoxy}plienyl)-2-{ [(55^)-5-{3-chloro-2-niethyl-4-[2-(4-methylpiperazin-ly!)cthoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i/]pyriniidin-4-yl]oxy}propanoic acid

Example 62: (2Æ)-2-{[(5Sa)-5-{3-cliloro-2-methyl-4-|2-(4-niethylpiperazin-l-yl)ethoxy] phenyl}-6-(4-fluorophenyl)thieno|2,3-rf]pyriniidin-4-yl|oxy}-3-{2-[(2-{4-|(2-liydroxy ethoxy)metliyl]phcnyl}pynmidin-4-yl)methoxy]phenyl}propanoic acid

Example 63: (2/f)-2-{[(55₀)-5-{3-chloro-2-methyl-4-|2-(4-methylpiperazin-l-yl)ethoxy| phenyl}-6-(4-fluorophenyl)thieno|2,3-r/|pyriniidin-4-yl|oxy}-3-{2-[(2-{2-|2-(2-hydroxy ethoxy)ethoxy|phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid

Example 64: (27?)-2-{|(5S,_;)-5-{3-chloiO-2-niethyl-4-[2-(4-methylpiperazin-l-yl)ethoxy] phenyl}-6-(4-fluorophenyI)thîeno[2,3-r/| pyriniidin-4-yl]oxy}-3-(2-{[2-(2-{2-|2-(2hydroxyethoxy)ethoxy]ethoxy}phenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid

Exaniple 65: (2Æ)-2-{|(55_(i)-5-{3-cliloro-2-niethyl-4-[2-(4-mctliylpiperazin-l-yl)etlioxy| phenyl}-6-(4-fluorophenyl)thieno[2,3-rf|pyrimidin-4-yl]oxy}-3“{2-[(2-{3-[(phosphono oxy)inethoxy|phenyl}pyriniidin-4-yl)niethoxy|phenyl}propanoic acid

Exaniple 66: (2Æ)-2-{|(5,S„)-5-{3-chloro-2-methyl-4-|2-(4-methylpiperazin-l-yl)ethoxy] phenyI}-6-(4-fluorophenyl)thÎeno|2,3-i/]pyrimidin-4-yI]oxy}-3-(2-{[2-(3-{[(pliospliono oxy)methoxy|methyl}phenyl)pyrimidin-4-yl]niethoxy}phenyl)propanoic acid

Example 67: (2Æ)-2-{[(55„)-5-{3-cliloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy] phenyl}-6-(4-fluorophenyl)thieno|2,3-JJpyrimidin-4-yl|oxy}-3-(2-{|2-(3-{|(phosphono oxy)carbonyl|oxy}phenyl)pyriniidin-4-yl|niethoxy}plienyl)propanoic acid

ORIGINAL

-70Example 68: (2/?)-2-{[(5S_a)-5-{3-chloro-2-methyl-4-J2-(4-methyIpiperazin-l-yl)ethoxy] phenyl}-6-(4-fluorophenyl)thieno[2,3-rf]pyrimidm-4-yl|oxy}-3-|2-({2-[3-({|(phosphono oxy)carbonyl]oxy)methyl)phenyl]pyrimidin-4-yl}methoxy)phenyl|propanoic acid

Example 69: l-[(ethoxycarbonyl)oxy]ethyl (2/î)-2-{[(55’_a)-5-{3-chloro-2-mcthyl-4-[25 (4-methylpiperazin-l-yl)etiioxy|phcnyl}-6-(4-fluorophenyl)thieno[2,3-iZ|pyriniidin-4yl|oxy)-3-{2-[(2-{3-|(l,3-dimethoxypropan-2-yI)oxy|phenyl}pyrimidin-4-yl)metlioxy] phenyljpropanoatc

Step A : ethyl 1-chloroethyl carbonate eq. of éthanol and 1.2 eq. pyridine were dissolved in dichloromethane (1.2 mL/mmol). ‘^J 10 1.05 eq. 1 -chloroethyl chloroformate was slowly added at -78 °C under nitrogen and the reaction mixture was stirred at -78 °C for 3 hours, The cold mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was used without further purification.

Step B: Example 69

1 eq. of Example 13 was dissolved in DMF (20 ml/mmol) under nitrogen. 6.7 eq. Cs₂CO₃ and 8 eq. of ethyl 1 -chloroethyl carbonate from Step A was added. The reaction mixture was stirred at room température until no further conversion was observed. The mixture was diluted with brine and it was extracted with DCM, dried with Na₂SOj, filtered and concentrated under reduced pressure. The crude product was purified via préparative reverse phase chromatography using 5 mM aqueous NH4HCO3 solution and acetonitrile as eluents to obtain Example 69. HRMS calculated for C5₆H₍,oC1FN60hS: 1078.3713; found 1079.3796 and 1079.3786 (M+H)

Example 70: l-[(dimethylcarbamoyl)oxy|ethyl (2/?)-2-{|(5₁S'₍,)-5-{3-chloro-2-metliyl-4|2-(4-methylpiperazin-l-yl)ethoxy|phenyl}-6-(4-fiuorophenyl)thicno[2,3-i/]pyrimidin25 4-yl|oxy}-3-{2-((2-{3-j(l,3-dimethoxypropan-2-yI)oxy|phenyl}pyrimid!n-4yl)methoxy]phenyl}propanoate

ORIGINAL

-7l Example 71: (2/f)-2-{[5-{2,6-dimethyl-4-|2-(4-methylpiperazin-l-yl)ethoxy|phenyl}-6(4-fluorophenyI)thieno[2,3-rf]pyriniidin-4-yl]oxy}-3-|2-({2-[3-(hydroxymethyl)phenyl] pyrimidin-4-yl}methoxy)phenyl|propanoic acid

Example 72: (27f)-2-{(5-{3,5-dichloro-2,6-dimethyl-4-|2-(4-methylpiperazin-l-yl) 5 ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i/|pyrimidin-4-yl]oxy}-3-|2-({2-[3(hydroxy methyl)phenyl|pyrimidin-4-yI}methoxy)phenyl]propanoic acid

Example 73: (2/?)-2-{[5-{2,6-dimethyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyI}-6(4-fluorophenyl)thieno[2,3-i/|pyrimidin-4-yl|oxy}“3-[2-({2-[4-(phosphonooxy)phenyi] pyrimidin-4-yl}methoxy)phenyl]propanoic acid

Example 74: (2/i)-2-{|5-{3,5-dichloro-2,6-dimethyl-4-|2-(4-methylpiperazin-l-yl) ethoxy|phenyl)-6-(4-fluorophenyl)thieno|2,3-//]pyrimidin-4-yl|oxy}-3-[2-({2-|4(phosphonooxy)phenyl]pyrimidin-4-yl}mcthoxy)phcnyl]propanoic acid

Example 75: 2-{|(5S_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy| phenyl}-6-(4-fluorophenyl)thieno|2,3-i/]pyrinüdin-4-yl|oxy}-3-hydroxy-3-[2-({2-|315 (hydroxymethyI)phenyl]pyrimidin-4-yl}methoxy)phenyl|propanoic acid

Example 76: 2-{[(5S_a)-5-{3-chloro-2-inethyl-4-(2-(4-methylpiperazin-l-yl)etlioxy| phenyl}-6-(4-fluorophenyl)thieno|2,3-^|pyi'imidin-4-yl|oxy}-4-liydroxy-3-[2-({2-[3(hydroxymethyl)phenyl|pyrimidin-4-yl}inethoxy)phenyl]butanoic acid

Example 77: 2-O-|(5S_a)-5-{3-chloro-2-methyI-4-[2-(4-methylpiperazin-l-yl)ethoxy] 20 phcnyl}-6-(4-fluorophcnyl)thieno[2,3-rf|pyrimidin-4-yl|-3,4-dideoxy-3-|2-({2-[3(liydroxymethyl)phenyl|pyriniidin-4-yl}methoxy)phenyl]pentonic acid

Example 78: (2Æ)-2-{[(55_a)-5-{3-chloro-2-methyl-4-|2-(4-methylpiperazin-l-yl)ethoxy| phenyl}-6-(4-fluorophenyl)tlüeno[2,3-i/]pyrimidin-4-yl]oxy}-3-|2-({2-[2-(hydroxy methyl)pyridin-4-yl|pyrimidin-4-yl}methoxy)phenyl]propanoic acid

ORIGINAL

-72Example 79: (27î)-2-{|(5_lS'_a)-5-{3-chloro-2-niethyl-4-[2-(4-niethylpiperazin-l-yI)ethoxy| phenyl}-6-(4-fluorophenyl)thieno|2,3-i/]pynmidin-4-yl|oxy}-3-[2-({2-|5-(hydroxy methyl)pyridin-3-yl|pyrimidin-4-yl}methoxy)phcnyl| propanoic acid

Starting from Préparation 1 and [5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-35 pyridyl] methanol using General procedure I, Example 79 was obtained. HRMS calculated for C₄₆H₄₃CIFN₇O₆S: 875.2668; found 438.6428 (M+2H)²⁺

Example 80: (2Æ)-2-{[(5S_a)-5-{3-chloro-2-methyl-4-|2-(4-methylpipcrazin-l-yl)ethoxy| phenyI}-6-(4-fluorophenyl)thieno[2,3-i/|pyrimidin-4-yl|oxy}-3-[2-({2-[6-(hydroxy > methyl)pyridazin-4-yl|pyrimidin-4-yl}methoxy)phenyl|propanoic acid

O 10 Example 81: (2/f)-2-{[(55₍₍)-5-{3-chloro-2-nietliyL4-|2“(4-methylpiperazîn-l-yl)ethoxy| phenyl}-6“(4-fiuorophenyl)thieno[2,3“i/]pyrimidin-4-yl|oxy}-3-|2-({2-|6-(hydroxy methyI)pyrazin-2-yl]pyrimidin-4-yl}methoxy)phenyl|propanoic acid

Example 82: (2ff)-2-{[(55_ff)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy| phenyl}-6-(4-fluorophenyl)thieno|2,3-i/|pyrimidin-4-yl|oxy}-3-(2-{[2'-(hydroxy “ 15 metliyl)-2,5'-bipyrimidin-4-yIjmethoxy}phcnyI)propanoic acid

Starting from Préparation 1 and Préparation 4q using General procedure I, Example 82 was obtained. HRMS calculated for C₄₅H₄₂C1FN₈O₆S: 876.2621; found 439.1402 (M+2H)²⁺

ORIGINAL

-73 PHARMACOLOG1CAL STUDY

EXAMPLE A: Inhibition of Mcl-l by the fluorescence polarisation technique

The relative binding potency of each compound was determined via Fluorescence Polarisation (FP). The method utilised a Fluorescein labelled ligand (Fluorescein-pAlaAhx-A-REIGAQLRRMADDLNAQY-OH; mw 2,765) which binds to the Mcl-l protein (such that Mcl-l corresponds to the UniProtKB* primary accession number: Q07820) leading to an increased anisotropy measured in milli-polarisation (mP) units using a reader. The addition of a compound which binds competitively to the saine site as the ligand will resuit in a greater proportion of unbound ligand in the System indicated by a decrease in mP units.

An 11 point serial dilution of each compound was prepared in DMSO and 2 μΙ transferred into flat bottomed, low binding, 384-well plate (final DMSO concentration 5 %). 38 μΐ of buffer (10 mM 4-(2-hydroxyethyl)-l-piperazineethanesulfonic acid (HEPES], l50mM NaCl. 0.05 % Tween 20, pH 7.4). containing the Fluorescein labelled ligand (final concentration l nM) and Mcl-l protein (final concentration 5 nM) was then added.

Assay piales were încubated ~2 hours at r.t. before FP was measured on a Biomek Synergy2 reader (Ex. 528 nm. Em. 640 nm, Cut off 510 nm) and mP units calculated. The binding of increasing doses of test compound was expressed as a percentage réduction in mP compared to a window established between ‘5 % DMSO only' and ' 100 % inhibition' Controls. H-point dose response curves were plotted with XL-Fit software using a 4Parameter Logistic Model (Sigmoidal Dose-Response Model) and the inhibitory concentrations that gave a 50 % réduction in mP (IC50) were determined. Results obtained are presented in Table l below.

The results show that the compounds of the invention inhibit interaction between the Mcl-l protein and the fluorescent peptide described hereinbefore.

ORIGINAL

-74EXAMPLE B: In vitro cytotoxicity

The cytotoxicity studies were carried out on the H929 multiple myeloma tumour line.

The cells are distributed onto microplates and exposed to the test compounds for 48 hours.

The cell vîability is then quantified by a colorimétrie assay, the Microculture Tétrazolium 5 Assay (Cancer Res., 1987, 47. 939-942).

The results are expressed in IC50 (lhe concentration of compound that inhibits cell viability by 50%) and are presented in Table l below.

The results show that the compounds of the invention are cytotoxic.

Table 1: IQq of Mcl-I inhibition (fluorescence polarisation test) and of cytotoxicity' for H929 cells

	ICw(M) Mcl-I IP	IC» (Μ) M TT 11929		IC» (M) Mcl-I Fl’	Κ%(Μ}ΜΊΊΗ929
Exampie 1	8.4E-09	9.31E-09	Exampie 19	4.95E-09	2.47E-09
Exampie 2	1.32E-08	I.59E-08	Example 20	4.35E-09	5.68E-08
Example 3	4.05E-09	4.08E-09	Example 21	4.85E-09	>|.50E-07
Example 4	4.9E-09	3.64E-09	Exampie 22	5.5E-09	5.97E-09
Example 5	3.7E-09	1.65E-09	Example 23	2.7E-09	3.97E-08
Example 6	1.57E-08	3.25 E-09	Exampie 24	3.15 E-09	2.55E-09
Exampie 7	3.75E-09	4.45E-09	Example 25	3.45E-09	1.00E-08
Example 8	7.35E-09	2.07E-09	Example 26	3.45 E-09	1.72E-09
Example 9	8.15E-09	1-40E-09	Example 27	2.2E-09	1.39E-08
Example 10	1.09E-08	2.79E-09	Example 28	4.15E-09	4.84E-08
Example 11	4.05E-09	1.99E-09	Exampie 29	4.6E-09	2.27E-08
Example 12	4.25E-09	3.82E-09	Example 30	4.5E-09	3.60E-09
Exampie 13	5.1 E-09	3.59E-09	Example 31	3.85E-09	1.68E-09
Example 14	6.15E-09	3.37E-09	Example 32	1.53E-08	1.68E-09
Example 15	2.75E-09	3.59E-09	Exampie 33	2.24E-08	1.18E-09
Example 16	7.2E-09	3.7IE-08	Example 34	7.1 E-09	4.76E-09
Example 17	4.8E-09	3.03 E-09	Exampie 35	5.I5E-09	4.76E-09
Example 18	4.1 E-09	1.39E-08	Exampie 36	4.65 E-09	7.59E-08

ORIGINAL

	ICîoîMJMcI-I FP	ICW(M)MTT H‘J2‘)		FP	IC» (M) MTT H929
Example 37	6.3E-09	2.05E-08	Example 60	ND	ND
Example 38	2.8E-09	2.76E-09	Example 61	ND	ND
Example 39	3.05E-09	3.25E-09	Example 62	ND	ND
Example 40	3.75E-09	6.I5E-09	Example 63	ND	ND
Example 41	3.45E-09	9.08E-08	Example 64	ND	ND
Example 42	4.4 5 E-09	4.45E-08	Example 65	ND	ND
Example 43	4.55 E-09	3.1 lE-08	Example 66	ND	ND
Example 44	3.7E-O9	2.87E-08	Example 67	ND	ND
Example 45	3.2E-09	4.58E-09	Example 68	ND	ND
Example 46	2.5 5 E-09	2.34E-08	Example 69	7.6E-08	ND
Example 47	4.05E-09	I.82E-08	Example 70	ND	ND
Example 48	3.85E-09	ND	Example 71	ND	ND
Example 49	4.65E-09	ND	Example 72	ND	ND
Example 50	6.6E-09	ND	Example 73	ND	ND
Example 51	4.15E-09	ND	Example 74	ND	ND
Example 52	3.7E-09	ND	Example 75	ND	ND
Example 53	4.65E-9	ND	Example 76	ND	ND
Example 54	4.6E-09	ND	Example 77	ND	ND
Example 55	6.35E-09	ND	Example 78	ND	ND
Example 56	4.75 E-09	ND	Example 79	7.6E-09	ND
Example 57	4.6E-09	2.27E-08	Example 80	ND	ND
Example 58	ND	ND	Example 8I	ND	ND
Example 59	ND	ND	Example 82	7.7E-09	ND

ND: not determined

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 xenograft model of AMO-l multiple myeloma cells.

ORIGINAL

-76I.IO⁷ AMO-l cells are grafted sub-cutaneously into immunosuppressed mice (SCID strain). 12 to 14 days after the graft. the animais are treated by intraveinous or oral routes with the varions compounds. After treatment. the tumour masses are recovered and lysed, and the cleaved form of PARP is quantified in the tumour lysâtes.

The quantification is carried out using the Meso Scale Discovery (MSD) ELISA platform test, which specifically assays the cleaved form of PARP. Il is expressed in the form of an activation factor corresponding to the ratio between the quantity of cleaved PARP in the treated mice divided by the quantity of cleaved PARP in the control mice.

The results show that the compounds of the invention are capable of inducing apoptosis in ΙΟ AMO-l tumour cells in vivo.

EXAMPLE D: Anti-tumour activity in vivo

The anti-tumour activity of the compounds of the invention is evaluated in a xenograft model of AMO-l multiple myeloma cells.

IxlO⁷ AMO-l cells are grafted sub-cutaneously into immunosuppressed mice (SCID 15 strain).

to 8 days after the graft, when the tumour mass has reached about 150 mm³, the mice are treated with the various compounds in a daily schedule (5-day treatment). The tumour mass is measured twice weekly from the start of treatment.

The results obtained using ΔΤ/C (i.e. qualification parameter of the activity of a product, 20 which is defined as the ratio tumour volume of the treated group / tumour volume of the untreated control group) show that the compounds of the invention induce significant tumour régression during the treatment period.

ORIGINAL

-77EXAMPLE F: Pharmaceutical composition: Tablets

1000 tablets containing a dose of 5 mg of a compound selected from Examples l to 82............5g

Wheat starch.....................................................................................................................20g

Maize starch............................................................................... 20g

Lactose............................................................................................................................ 30g

Magnésium stéarate............................................................................................................2g

Silica.................................................................................... Ig

Hydroxypropylceliulose.................................... 2g

ORIGINAL

Claims (36)

1. Compound of formula (I):

wherein;

♦ A represents the group

in which 1 is linked to the oxygen atom and 2 is linked to the phenyl ring, ♦ R, represents a linear or branched (Ci-Cû)alkyl group, a linear or branched (C2-C(,)alkenyl group, a linear or branched (C2-C₆)alkynyl group, a linear or branched (C|-C₆)alkoxy group, a -S-(Ci-C₆)alkyl group, a linear or branched (Ci-Côjpolyhaloalkyl, a hydroxy group, a hydroxy(Ci-C₆)alkyl group, a cyano group, -NR_t2Ri₂’, -Cys, or a halogen atom, ♦ R₂, R₃, R4 and R> independently of one another represent a hydrogen atom, a halogen atom, a linear or branched (Ci-Cejalkyl group, a linear or branched (C?-C6)alkenyl group, a linear or branched (C2-C6>alkynyl group, a linear or branched (C[-C₆)polyhaloalkyl, a hydroxy group, a hydroxy(Ci-C&)alkyl group, a linear or branched (C]-C₆)alkoxy group, a -S-(Ci-C₆)alkyl group, a cyano group, a nitro group, -alkyl(Co-Cé)-NRioRio\ -0-alkyl(Ci-Cft)-NRioRio’, -O-alkyl(CrC₆)-Ri], -C(O)-OR|₀, -O-C(O)-R|₀, -C(O)-NR|₀R_IQ’, -NRk)-C(O)-R₁₀’, -NRio-C(0)-OR_to’, -aIkyl(C]-C₆)-NRio-C(0)-Rio’, -S0₂-NRioR_lo',

ORIGINAL

-79-SO₂-alkyl(Ci-C₆), or the substituents of one of the pairs (R₂, R₃), (R₃, R-i), (R₄, R5), when grafted onto two adjacent carbon atoms, form together with the carbon atoms carrying them an aromatic or non-aromatic ring composed of from 5 to 7 ring members, which may contain from l lo 3 heteroatoms selected from oxygen, sulphur and nitrogen, it being understood that resulting ring may be substituted by a group selected from a linear or branched (Ci-C₆)alkyl group, -NR12R12’, -aIkyl(Co-Cb)-Cyi, or an oxo, ♦ R(, represents -O-alkyl(Ci-Cû)-Ri 1, ♦ R₇ represents a hydrogen atom, a halogen atom, a linear or branched (C_t-C₆)alkyl group, a linear or branched (C₂-C(,)alkenyl group, a linear or branched (C₂-C6)alkynyl group, a linear or branched (C|-C(,)polyhaloalkyl, a hydroxy group, a linear or branched (C]-C&)alkoxy group, a -S-(C|-Cf,)alkyl group, a cyano group, a nitro group, -alkyl(Co-C₆)-NRioR_to’, -0-alkyl(C]-C6)-NRioRio\ -O-Cyj, -alkyl(C₀-C₆)-Cyi, -alkenyl(C₂-C₆)-Cyi, -alkynyl(C₂-C₆)-Cyi, -O-alkyl(C_rC6)-R| 1, -C(0)-ORio, -O-C(O)-R₁₀, -C(0)-NRi₀Rio’, -NR_l0-C(O)-R_l0\ -NR_l0-C(O)-OR₁₀’, -alkyl(C|-C₆)-NRio-C(0)-Rio', -S0₂-NRi₀Rio\ -SO₂-alkyl(C_rC₆), ♦ Rs represents a hydrogen atom, a linear or branched (Ci-Cg)alkyl group, a -CHR_aRb group, an aryl group, a heteroaryl group, an arylalkyl(C 1-Ce) group, or a heteroarylalkyl(C|-C(,) group, ♦ R9 represents a linear or branched (Ci-Cejalkyl group. a linear or branched (C₂-C6)alkenyl group, a linear or branched (C₂-C6)alkynyl group, -Cy₃, -alkyl(C,-C₆)-Cy₃, -alkenyl(C₂-C₆)-Cy₃, -alkynyl(C₂-C₆)-Cy₃, -Cy₃-Cy₄, -alkynyl(C₂-Cô)-O-Cy₃, -Cy₃-alkyl(Co-C₆)-0-alkyI(C₀-C6)-Cy₄, a halogen atom, a cyano group, -C(O)-Rj₃, or -C(O)-NR|₃Rt₃’, ♦ Rio and Rio* independently of one another represent a hydrogen atom, a linear or branched (Ci-Cô)alkyl group, -alkyl(Co-C6)-Cyi, or the substituents of the pair (Rio, Rio') form together with the nitrogen atom carrying them an aromatic or non-aromatic ring composed of from 5 to 7 ring members, which may contain in addition to the nitrogen atom from 1 lo 3 heteroatoms selected from oxygen, sulphur and nitrogen, it being understood that the nitrogen in question may be substituted by from 1 to 2 groups representing a hydrogen atom, or a linear or branched (Ci-Cb)alkyl group, and it being understood

ORIGINAL

-80that one or more of the carbon atoms of the possible substituents, may be deuterated, ♦ Ru represents -Cy5-alkyl(Co-C₆)-0-alkyl(Co-C6)-Cy₆, -Cy5-alkyl(Co-C6)-Cy6, -Cy₅-alkyl(C₀-C₆)-NRi2-alkyl(C₀-C₆)-Cy₆, ♦ R12, Ri₂’, Ri3 and Ru’ independently of one another represent a hydrogen atom or an optionally substituted linear or branched (C]-C₆)alkyl group, ♦ R14 represents a hydrogen atom, a hydroxy group, or a hydroxy(C_rC6)alkyl group, ♦ R_a represents a hydrogen atom or a linear or branched (Ci-C₆)alky! group, ♦ Rh represents a -O-C(O)-O-R_c group, a -O-CfOj-NR^R/ group, or a -O-P(O)(OR_C)₂ group, ♦ R- and R’ independently of one another represent a hydrogen atom, a linear or branched (Ci-Cs)alkyl group, a cycloalkyl group, a (C|-C₍₁)alkoxy(Ci-C₆)alkyl group, a (C|-C6)alkoxycarbonyl(C]-C6)alkyl group, or the substituents of the pair (R_t-, R/) form together with the nitrogen atom carrying them a non-aromatic ring composed of from 5 to 7 ring members, which may contain in addition to the nitrogen atom from 1 to 3 heteroatoms selected from oxygen and nitrogen, it being understood that the nitrogen in question may be substituted by a group representing a linear or branched (C]-C₆)alkyl group, ♦ Cyi, Cy₂, Cy₃, Cy4 and Cy_s independently of one another, represent a cycloalkyl group, a heterocycloalkyl group, an aryl group. or a heteroaryl group.

♦ Cy₆ represents

or Cy₆ represents a heteroaryl group which is substituted by a group selected from -O-P(O)(OR₂₀)₂; -O-P(O)(O')₂; -(CH₂)_p-0-(CHR_1!S-CHRi₉-0)_q-R₂o; hydroxy; hydroxy(C|-C6)alkyl; -(CH₂)_rY-(CI l₂)_s-heterocycloalkyl; or -Y-(CH₂)_q-NR₂|R₂i', ♦ R15 represents a hydrogen atom; a -(CH₂)_p-0-(CI-IRi8-CHRi9-0)_q-R₂o group; a linear or branched (C|-C6)alkoxy(Ci-C6)alkyl group; a -Y-(CH₂)_q-NR₂]R₂i’ group; or a -(CH₂)_r-Y-(CH₂)_s-heterocycloalkyl group, ♦ Rié represents a hydrogen atom; a hydroxy group; a hydroxy(C|-Cô)alkyl group;

ORIGINAL

-8l a -(CH₂)_r-Y-(CH₂)_s-heterocycloalkyl group; a (CH₂)_r-Y-X-0-P(0)(OR₂o)₂ group;

a -O-P(O)(O')₂ group; a -(CH₂)_p-0-(CHRi8-CHRi9-0)i₁-R₂o group;

a -(CH₂)p-O-C(O)-NR₂₂R23 group; or a -Y-(CH₂)_q-NR₂iR₂i' group, ♦ R17 represents a hydrogen atom; a -(CH₂)_p-0-(Cl-IRi8-CHRi9-0)q-R₂o group; a -0-P(0)(OR₂o)₂ group; a -O-P(O)(O’)₂ group; a hydroxy group; a hydroxy(C|-C6)aIkyl group; a -(CH₂)r-Y-(CH2)s-heterocycloalkyl group; a -Y-(CH₂)_q-NR2iR2i group; or an aldonic acid, ♦ X represents a -(CII₂)_s- group or a -C(O)- group, ♦ Y represents a bond or an oxygen atom, ♦ Rie represents a hydrogen atom or a (C|-C6)alkoxy(Ci-C6)alkyl group, ♦ R|q represents a hydrogen atom or a hydroxytCj-Côjalkyl group, ♦ R₂o represents a hydrogen atom or a linear or branched (C |-C(,)alkyl group, ♦ R₂t and R₂i’ independently of one another represent a hydrogen atom, a linear or branched (C i-C₍,)alkyI group, or a hydroxy(Ci-Cô)alkyl group, or the substituents of the pair (R₂i, R₂i ' ) form together with the nitrogen atom carrying them an aromatic or non-aromatic ring composed of from 5 to 7 ring members, which may contain in addition to the nitrogen atom from l to 3 heteroatoms selected from oxygen, sulphur and nitrogen, it being understood that the resulting ring may be substituted by a group representing a hydrogen atom or a linear or branched (Cj-Cfftalkyl group, ♦ R₂₂ represents a (C|-C6)alkoxy(C|-C₆)alkyl group, a -(CH₂)_P-NR₂₄R₂₄‘ group. or a -(CH₂)_p-O-(CHRi8-CHR_l9-O)_q-R₂₀ group, ♦ R₂3 represents a hydrogen atom or a (Ci-C6)alkoxy(C[-Cû)alkyl group, or the substituents of the pair (R₂₂, R₂₃) form together with the nitrogen atom carrying them an aromatic or non-aromatic ring composed of from 5 to 18 ring members, which may contain in addition to the nitrogen atom from I to 5 heteroatoms selected from oxygen. sulphur and nitrogen, it being understood that the resulting ring may be substituted by a group representing a hydrogen atom, a linear or branched (Ci-C_&)alkyl group or a heterocycloalkyl group, ♦ R₂₄ and R₂₄' independently of one another represent a hydrogen atom or a linear or branched (Ci-Cejalkyl group, or the substituents of the pair (R₂₄, R₂₄’) form together with the nitrogen atom

ORIGINAL

-82 carrying them an aromatic or non-aromatic ring composed of from 5 to 7 ring members, which may contain in addition to the nitrogen atom from one to 3 heteroatoms selected from oxygen, sulphur and nitrogen. it being understood that the resulting ring may be substituted by a group representing a hydrogen atom or a linear or branched (Ci-C₆)alkyl group, ♦ n is an integer equal to 0 or l, ♦ p is an integer equal to 0, l or 2, ♦ q is an integer equal to l, 2, 3 or 4, ♦ r and s are independently an integer equal to 0 or l, with the proviso that R|₅, R|₆ and R_]7 cannot represent together a hydrogen atom and, when Rj represents a methyl group. Ri? cannot represent a methoxyethoxy group, it being understood that:

aryl means a phenyl, naphthyl, biphenyl, indanyl or indenyl group, heteroaryl means any mono- or bi-cyclic group composed oi Irom 5 to 10 ring members. having at least one aromatic moiety and containing from l to 3 heteroatoms selected from oxygen, sulphur and nitrogen,

- cycloalkyl means any mono- or bi-cyclic non-aromatic carbocyclic group containing from 3 to 10 ring members,

- heterocycloalkyl” means any mono- or bi-cyclic non-aromatic carbocyclic group containing from 3 to 10 ring members, and containing from l to 3 heteroatoms selected from oxygen. sulphur and nitrogen, which may include fused, bridged or spiro ring Systems, it being possible ibr the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined and the alkyl, alkenyl, alkynyl, alkoxy groups. to be substituted by from l to 5 groups selected from optionally substituted linear or branched (C|-C(,)alkyl, optionally substituted linear or branched (C₂-C₆)alkenyl group, optionally substituted linear or branched (C₂-C₆)alkynyl group, optionally substituted linear or branched (Ci-Côjalkoxy, optionally substituted (Cj-Côlalkyl-S-, hydroxy, oxo (or Λ'-oxide where appropriate), nitro, cyano, -C(O)-OR’. -O-C(O)-R , -C(O)-NR’R’ . -NR R ,

ORIGINAL

-83-(C=NR')-OR, linear or branched (C_rC₆)polyhaloalkyl, trifluoromethoxy, or halogen. it being understood that R' and R independently of one another represent a hydrogen atom or an optionally substituted linear or branched (Cj-Côjalkyf group, and it being understood that one or more of the carbon atoms of the preceding possible substituents, may be deuterated, their enantiomers, diastereoisomers and atropisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.

2. Compounds according to claim l, wherein at least one of the groups selected from R₂, R₃, R and R₃ does not represent a hydrogen atom.

3. Compounds according to claim l, wherein n is an integer equal to l.

4. Compounds according to claim l. wherein R, represents a linear or branched (Ci-Cô)alkyl group or a halogen atom.

5. Compounds according to claim l, wherein Rj₄ represents a hydrogen atom, a hydroxy group, a hydroxymethyl group or a hydroxyethyl group.

6. Compounds according to claim l, wherein R₂ represents a halogen atom, a hydroxy group, a linear or branched (Ci-C₍,)alkoxy group.

7. Compounds according to claim l, wherein R₃ represents a hydrogen atom. a hydroxy group, a linear or branched (C]-C(,)alkoxy group or -0-alkyl(C|-C6)-NRioRio .

8. Compound according to claim l, wherein R₄ and R 5 represent a hydrogen atom

9. Compounds according to claim l, wherein

ORIGINAL

represents

wherein R_]t Rio and R₎₀' are as defined in claim I.

10. Compounds according to claim l, wherein

represents

5 wherein R_l0 and Rio’ are as defined in claim l.

11. Compound according to claim l, wherein the substituents of the pair (Ri, R5) are identical and the substituents oflhe pair (R₂. R4) are identical.

12. Compound according to claim 1, wherein ^R7 Ra represents

10 wherein Ru is as defined in claim 1.

ORIGINAL

13. Compound according to claim 1, wherein R₇ represents a hydrogen atom

14. Compounds according to claim 1, wherein Rg represents a hydrogen atom, a -CHR_aRb group, an optionally substituted linear or branched (Ci-Cg)alkyl group, or a heteroarylalkyl(Ci-C&) group.

5 15. Compounds according to claim 1, wherein R₉ represents a linear or branched (CrC₆)alkyI group, a linear or branched (C₂-C₆)alkenyl group, a linear or branched (C₂-C6)aikynyl group, an aryl group or a heteroaryl group.

16. Compounds according to claim 1, wherein Rio and Rio’ independently of one another represent a linear or branched (C|-C₆)alkyl group,

10 or the substituents of the pair (Rio, Rio’) form together with the nitrogen atom carrying them a non-aromatic ring composed of from 5 to 7 ring members, which may contain in addition to the nitrogen atom from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen, it being understood that the nitrogen in question may be substituted by a group representing a hydrogen atom or a linear or branched

15 (C|-C₆)alkyl group.

17. Compounds according to claim 1. wherein Ru represents -Cy5-alkyl(Co-C6)-Cy6.

18. Compounds according to claim 1. wherein Cy₃ represents a heteroaryl group, particularly, a pyrimidinyl group, a pyrazolyl group. a triazolyl group. a pyrazinyl group or a pyridinyI group.

20 19. Compounds according to claim 1, wherein Cy₆ represents

wherein Ris, Ru, and Rj₇ are as defined in claim 1.

ORIGINAL

20. Compounds according to claim l, wherein R,6 and R π represent a hydrogen atom and Ri5 represents a -(CH₂)_p-0-(CHRi8-CI-IRi₉-0)q-R₂o group; a linear or branched (C|-C₆)alkoxy(C|-C₆)alkyl group; a -Y-(CH₂)_q-NR₂iR₂₁’ group; or a -(CH2)r-Y-(CH₂)_s-heteiOcycloalkyl group.

21. Compounds according to claim 1, wherein R_]5 and R_n represent a hydrogen atom and Riô represents a hydroxy group; a hydroxy(Ci-C₆)alkyl group; a -(CH₂)_r-Y-(CH₂)_s-heterocyc!oalkyl group; a -0-P(0)(OR₂o)₂ group; a -O-P(O)(O )₂ group; a -(CH₂)_p-0-(CHR|8-CHRi9-0)q-R₂o group; a -(CH₂)_P-O-C(O)-NR₂₂R₂3 group; a (CH₂)_r-Y-X-O-P(O)(OR₂₀)₂ group or a -Y-(CH₂)_q-NR_2lR₂₁’ group.

22. Compounds according to claim 1, wherein Rus and R|₍, represent a hydrogen atom and Ri? represents a -(CH₂)p-0-(CHRi8-CHR|₉-0)q-R₂o group; a -0-P(0)(OR₂o)₂ group; a -O-P(O)(O)₂ group; a hydroxy group; a hydroxy(Ci-C₆)alkyl group; a -(CH₂)_r-Y-(CH₂)_s-heterocycloalkyl group; a -Y-(CH₂)_q-NR₂iR₂i' group; or an aldonic acid.

23. Compounds according to claim 1, which are:

- (27?)-2- {[(5SJ-5- {3-chloro-2-methyl-4-[ 3-(4-methylpiperazin-1 yl)propoxy]phenyl)-6-(4-fkiorophenyl)thieno[2,3-</]pyrimidin-4-yl]oxy}-3-(2-{[2(3-hydroxyphenyl)pyrimidin-4-yl]methoxy)phenyl)propanoic acid;

- (2/?)-2- {[( 5S_a)-5- {3-chloro-2-methyl-4-[3-(4-methylpiperazin-1 yl)propoxy]phenyl)-6-(4-fluoiOphenyl)thieno[2,3-J]pyrimidin-4-yl]oxy )-3-(2-{[2(4-hydroxyphenyl)pyrimidin-4-yl]methoxy)pheny!)propanoic acid;

- (27? )-2- {[(5Sa)-5-{ 3-chloro-2-methyl-4-[3-(4-methylpiperazin-1 yl)propoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-[2-({2[3-(hydroxymethyl)phenyl]pyrimidin-4-yl)methoxy)phenyl]propanoic acid;

- (27?)-2-{[(5S_e)-5-{3-diloro-2-methyl-4-[3-(4-methylpiperazin-l- yl )propoxy]phenyl )-6-(4-11 uorophenyl)thieno[2,3-rf]pyrimidin-4-yl]oxy}-3-[2-( {2[4-(hydroxymethyl)phenyl]pyrimidin-4-yl ) methoxy )phenyl]propanoic acid;

ORIGINAL

- (2/?)-2-{[(55_a)-5-{3-chloro-2-methyl-4-[3-(4-melhylpiperazin-l- y i)propoxy]phenyl} -6-(4-fluorophenyl )thieno[2,3-i/]pyrimidin-4-yl]oxy} -3- {2-[ (2{2-[(2,2-dimethyl-k3-dioxoIan-4-yl)methoxy]phenyl}pyrimidin-4yl)methoxy]phenyl} propanoic acid;

5 - (2R)-2- {[(5S_a)-5-{ 3-chloro-2-methy l-4-[3-(4-methylpiperazin-1 yl)propoxy]phenyI}-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-yI]oxy}-3-{2-[(2{2-[2-(2-methoxyethoxy)ethoxyjphenyl} pyriniidin-4yl)methoxy]phenyl} propanoic acid;

- (2/?)-2-{[(5S_a)-5-{3-chloro-2-methyl-4-[3-(4-melhylpiperazin-l-

10 yl)propoxy]phenyl}-6-(4-fluorophenyl)lhieno[2,3-i7]pyrimidin-4-yl]oxy}-3-(2-{[2(2-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}phenyl)pyrimidin-4yl]methoxy} phenyl)propanoic acid;

- (2/?)-2-{[(5S_a)-5-{3-chloro-2-methyl-4-[3-(4-methylpiperazin-l- y l )propoxy]pheny I} -6-(4-fluorophenyl )thieno[2,3-ô/]pyrimidin-4-yI]oxy} -3-[2-( {215 [2-(methoxymethyl)phenyl]pyrimidin-4-yl}methoxy)phenyl]piOpanoic acid;

- (2Æ)-2-{L(5S_i,)-5-{3-chloro-2-methyl-4-[3-(4-methylpiperazin-l-yl)propoxy] phenyl}-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-{2-[(2-{2-[(2methoxyethoxy)methyl]phenyl}pyrimidin-4-yi)methoxy] phenyl} propanoic acid;

- (2Æ)-2-{[(55_a)-5-{3-chloro-2-methyl-4-[3-(4-methylpiperazin-l-yl)propoxy]

20 phenyl}-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-{2-[(2-{2-[(2hydroxyelhoxy)methyl]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid;

- (2R)-2-{[(5S_o)-5- {3-chloro-2-methyl-4-|3-(4-methyipiperazin-1 - y I )propoxy ]phenyl} -6-(4-fluorophenyl)thieno| 2.3-c/]pyrimidin-4-y IJoxy} -3-(2- {[2(2-{[(2,2-dimethyl-l,3-dioxolan-4-yl)methoxy]methyl}phenyr)pyrimidin-425 yl]methoxy}phenyl)propanoic acid;

- (2Æ)-2-{[(55_a)-5-{3-chloro-2-methyl-4-[3-(4-methylpiperazin-1 -yl)propoxy] phenyl}-6-(4-fluorophenyl)lhieno[2,3-i/Jpyrimidin-4-yl]oxy}-3-{2-[(2-{3-[(2hydroxyethoxy)methyl]phenyI} pyrimidin-4-yl)methoxy]phenyI} propanoic acid;

- (2/f)-2-{[(5S_a)-5-{3-chloro-2-methyl-4-[3-(4-methylpiperazin-l-

30 yl)propoxy]phenyl}-6-(4-iluorophenyl)thieno[2.3-i/]pyrimidin-4-ylloxy}-3-{2-[(2{3-[(l,3-dimethoxypropan-2-yl)oxy]phenyl}pyrimidin-4yl)methoxy]phenyl} propanoic acid;

ORIGINAL

- (2/?)-2-{[(5S_fl)-5-{3-chloro-2-methyl-4-[3-(4-methylpiperazin-l- yi)propoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i/|py^ri^midiⁿ-4-yl]oxy}-3-{2-[(2{4-[ ( l ,3-dimethoxypropan-2-yl)oxy]phenyl} pyrimidin-4yl)methoxy]phenyl}propanoic acid;

- (2Æ)-2-{[(5S_fl)-5-{3-chloro-2-methyl-4-[3-(4-methylpiperazin-l- y!)propoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-[2-({2[4-(2,3-dihydroxypropoxy)phenyl]pyrimidin-4-yl} methoxy)phenyl]propanoic acid;

- methyl 6-O-{3-[4-({2-[(2Æ)-2-carboxy-2-{[(5S_<J)-5-{3-chloiO-2-methyl-4-[3-(4methylpiperazin-1-yl)propoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i/j pyrimidin-4-yl]oxy}ethyl]phenoxy}methyl)pyrimidin-2-yl]phenyl}-a-Dmannopyranoside;

- methyl 6-C?-{3-[4-({2-[(2Æ)-2-carboxy-2-{[(5S₀)-5-{3-chloro-2-methyl-4-[3-(4methylpiperazin-1 -yl)propoxy]phenyl} -6-(4-fluoropheny l )thieno[2,3-rf] pyrimidin-4-yl]oxy} ethyl]phenoxy} methyl )pyrimidin-2-yl]phenyl} -2,3,4-tri-Ûmethyl-a-D-mannopyranoside;

- methyl 6-O-{4-[4-({2-[(2Æ)-2-carboxy-2-{[(5S_fl)-5-{3-chloro-2-methyl-4-[3-(4methy Ipiperazin-1 -yl)propoxy]phenyl} -6-(4-fluorophenyl)thieno[2,3-t/| pyrimidin-4-yl]oxy}ethyl]phenoxy}methyl)pyrimidin-2-yl]phenyl}-cc-Dmannopyranoside;

- methyl 6-O-{4-[4-({2-[(2/f)-2-carboxy-2-{[(5S_fl)-5-{3-chloro-2-methyl-4-[3-(4methylpiperazin-l-yl)propoxy]phenyl}-6-(4-nuorophenyl)thieno[2,3-t7] pyrirnidin-4-yl]oxy}ethyl]phenoxy}methyl)pyrimidin-2-yl]phenyl}-2,3.4-tri-C>methyl-a-D-mannopyranoside;

. 6-a{4-l4-({2-[(2Æ)-2-carboxy-2-{[(55_fl)-5-{3-chloro-2-methyl-4-[3-(4methylpiperazin-l-yl)propoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin4-yl]oxy}ethyl]phenoxy}methyl)pyrimidin-2-yl]phenyl}-D-inannopyranose;

- 6-O-{2-[4-({2-|(2/?)-2-carboxy’2-{[(5S'_a)-5-{3-chloiO-2-methyl-4-[3-(4methylpiperazin-l-yl)propoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin4-yl]oxy}ethyl]phenoxy}methyl)pyrimidin-2-yl]phenyl}-D-mannonic acid;

- 1,2-Û-[( l R)-1 -({4- [4-( {2-[(2Æ)-2-carboxy-2- {[(5.SJ-5- {3-chloro-2-methy l -4- [3 -(4methylpiperazin-1-y l )propoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i7]

ORIGINAL

- 89pyrimidin-4-yl]oxy}ethyl]phenoxy}methyl)pyrimidin-2-yl]benzyi}oxy)ethylidene]β-D-mannopyranose;

- (2Λ)-2- {((5S_a)-5-{3-chloro-2-methyl-4-(3-(4-methylpiperazin-1 yl)propoxy]phenyl }-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-((2-

5 {4-[(a-D-mannopyranosyloxy)methyl]phenyl)pyrimidin-4yl)methoxy]phenyl (propanoic acid;

- (2R)-2-{[ ( 5SJ-5- {3-chloro-2-methyl-4-[3-(4-methy Ipiperazin-1 yl)propoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy }-j-(2-({2[4-(2-hydroxyethyl)phenyl]pyrimidin-4-yl(methoxy)phenyl]propanoic acid;

10 - (2Æ)-2-{[(5S_c)-5-{3-ehloro-2-methyl-4-[3-(4-methylpiperazin-lyl)propoxy]phenyl}-6-(4-fluoropheny!)thieno[2,3-i/lpyrimidin-4-yl]oxy}-3-[2-({2[2-(2,3-dihydroxypropoxy)phenyl]pyrimidin-4-yl(niethoxy)phenyl]propanoic acid;

- (2Æ)-2- {[(5S_a)-5-{ 3-chloro-2-methy l-4-[3-(4-methylpiperazin-1 - y l)propoxy] phenyl ( -6-(4-fluorophenyl)thieno[2,3-c/]pyrimidin-4-yl]oxy} -3-(2-( {215 [2-(2-hydroxyethoxy )phenyl]pyrimidin-4-yl} methoxy)phenyl]propanoic acid;

- (2Æ)-2-{[(5S_a)-5-{3-chloro-2-methyl-4-[3-(4-methylpiperazin-lyl)propoxy]phenyl(-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-{2-[(2{2-[(2,3-dihydroxypropoxy)methyl]phenyl(pyrimidin-4yl)methoxy]phenyl(propanoic acid;

20 - (2Æ)-2-{[(5S₀)-5-{3-chloro-2-methyl-4-[3-(4-methylpiperazin-ly!)propoxy]phenyl(-6-(4-fluoiOphenyl)thieno[2,3-J]pyrimidin-4-yl]oxy}-3-[2-({2[3-(phosphonooxy)phenyl]pyrimidin-4-yl( methoxy (phenyljpropanoic acid;

_ 4-(4-( {2-[(2Æ)-2-carboxy-2-{((5S_fl)-5-{3-chloro-2-methyl-4-[3-(4-methy!

piperazîn-1 -yl)propoxy]phenyl}-6-(4-iluorophenyl)lhieno[2,3-</]pyrimidin-425 yl]oxy(ethyl]phenoxy)methyI)pyrimidin-2-yl]phenyl phosphate;

- (2/î)-2-{((5S_a)-5-{3-chloro-2-methyl-4-[3-(4-methylpiperazin-lyl)propoxy]phenyl(-6-(4-fluorophenyl)thieno[2_î3-i/]pyrimidin-4-yl]oxy}-3-[2-({2[3-(2-hydiOxyethoxy)phenyl]pyrimidin-4-yl(methoxy)phenyl]propanoic acid;

- (2Æ)-2- {[(5SJ-5- {3-chloro-2-methyl-4-[3-(4-methylpiperazin-1 -

30 y|)propoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-J]pyrimidin-4-yl]oxy}-3-{2-[(2{4-(2-(2-methoxyethoxy)ethoxy]phenyl(pyrimidin-4yl(methoxy]phenyl(propanoic acid;

ORIGINAL

- (2A)-2-{[(5S_a)-5-{3-chloro-2-methyl-4-[3-(4-iTiethylpiperazin-l-yl)propoxy] phenyl} -6-(4-fluorophenyl)thieno[2,3-d]pyriinidin-4-yl]oxy} -3- {2-[(2- {4-[2-(2hydroxyethoxy)ethoxy]phenyl}pyrirnidin-4-yl)methoxy]phenyl}propanoic acid;

- (2/î)-2-{[(5S_e)-5-{3-chloro-2-methyi-4-[3-(4-methylpiperazin-l- yl)propoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-rf]pyriinidin-4-yl]oxy}-3-(2-{[2(4-{2-[2-(2-niethoxyethoxy)ethoxy]ethoxy}phenyl)pyrimidin-4yl]methoxy)phenyl)propanoic acid;

- (27?)-2-{[(5S_i/)-5-{3-chloro-2-methyl-4-[3-(4-methylpiperazin-l-yl)propoxy] phenyl }-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy} -3 - {2-[<2- {4-[2(dimethylaniino)ethoxy]phenyl}pyrimidin-4-yl)methoxy]phenyl) propanoic acid;

- (2Æ)-2-{[(5S_n)-5-{3-chloro-2-meÎhyl-4-[3-(4-methylpiperazin-lyl)propoxy]phenyl}-6-(4-tluoiOphenyl)thieno[2,3-i/]pyriiTiidin-4-yl]oxy}-3-{2-[(2{3-[(2,2-dimethyl-l,3-dioxolan-4-yl)methoxy]phenyl)pyrimidin-4- yl)inethoxy]phenyl} propanoic acid;

- (2Æ)-2-{ [(55_α)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l -y l)ethoxy] phenyl)-6-(4-fluorophenyl)thieno[2.3-rf]pyrimidin-4-yl]oxy}-3-[2-({2-[3-(l 5hydroxy-3-oxo-2,7,10,13-tetraoxa-4-azapentadec-1 -yl)phenyl]pyrimidin-4yl}methoxy)phenyl]propanoic acid;

- (2Æ)-3-(2- {12-(3 - {[( l ,4'-b ipip eridi η-1 ’-ylcarbony l)oxy]methyl }phenyl ) pyrimidin-4-yl]methoxy}phenyl)-2-{[(5S_u)-5-{3-chloro-2-methyl-4-[2-(4methylpiperazin-l -y!)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4yl]oxy)propanoic acid;

- (2Æ)-2-{[(5Sa)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)elhoxyJ phenyl}-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-(2-{[2-(3-{2-[2-(2hydroxyethoxy)ethoxy]ethoxy}phenyl)pyrimidin-4-yl]nielhoxy}phenyl)propanoic acid;

- (2À)-2-{[(5S_n)-5-{3-chloro-2-inethyl-4-[2-(4-inethylpiperazin-l-yl)ethoxy] phenyl} -6-(4-fluorophenyl)thieno [2,3-i/]pyrimidin-4-yl]oxy }-3- {2-[(2- {3-[2-(2hydroxyethoxy )ethoxy]phenyl} pyrimidin-4-yl Jmethoxy]phenyl} propanoic acid;

- (2/0-2-{[(5S_a)-5-{3-chIoro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy] phenyl }-6-(4-fluorophenyl)thieno[2,3-rf]pyriniidin-4-yl]oxy }-3-{2-[(2-{3-[2-(2rnethoxyethoxy)ethoxy]phenyl}pyrhnidin-4-yl)inethoxy]phenyl)propanoic acid;

ORIGINAL

-9l -

- (2R)-2-{ [(5^)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy] phenyl}-6-(4-lluorophenyl)thieno[2,3-J]pyrimidin-4-yl]oxy}-3-{2-[(2-{3-[({[2-(4methylpiperazin-l-yl)ethyl]carbamoyl}oxy)methyl]phenyl}pyrimidin-4yl)methoxy]phenyl}propanoic acid;

- (27î)-2-{[(5S^, _a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy] phenyl}-6-(4-fluorophenyl)thieno[2,3-tZ]pyrimidin-4-yl]oxy}-3-{2-[(2-{3-[({[2(morpholin-4-yl)ethyl]carbamoyl}oxy)methyl]phenyl}pyrimidin-4-yl)methoxy] phenyl}propanoic acid;

- (2Æ)-2-{[(5S_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy] phenyl}-6-(4-fluorophenyl)thieno[2,3-r/]pyrimidin-4-yl]oxy}-3-{2-|(2-{3-[({[2(dimethy lamino)ethyl]carbamoy I} oxy)methyl]phenyl} pyrimidin-4-yl )methoxy] phenyl}propanoic acid;

- (2R)-2-{[(5S_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy] phenyl}-6-(4-fluorophenyl)thieno[2,3-<7[pyrimidin-4-yl]oxy}-3-{2-[(2-{3-[({[2(pyrrolidin-1 -yl)ethyl]carbamoyl} oxy)methyl]phenyl} pyrimidin-4-yl)methoxy] phenyl}propanoic acid;

- (2 R)-3 - [2-( {2-[ 3-( {[bis(2-methoxyethyl )carbamoyl]oxy } methyl )phenyl] pyrimidin-4-yl}methoxy)phenyl]-2-{[(5S_a)-5-{3-chloro-2-methyl-4-[2-(4methylpiperazin-1 -yl )ethoxy]phenyl} -6-(4-fluorophenyl )thieno[2,3-i/]pyrimidin-4yljoxyjpropanoic acid;

- (2Æ)-2-{[(5S_a)-5-{3-chioro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy] phenyl }-6-(4-fluorophenyl)thieno[2,3-i7]pyrimidin-4-yl]oxy}-3-(2-{[2-(3- {[( l ,4.7,10,13-pentaoxa-16-azacyclooctadecan-16ylcarbonyI)oxy]methyl}phenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid;

- (2R)-2- { [(55_a)-5- {3-chloro-2-methyl-4-[2-(4-methy Ipiperazin-1 -yl)ethoxy]phenyl} 6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-[2-({2-[3-(2,3dihydroxypropoxy)phenyl]pyrimidin-4-yl}methoxy)phenyl]propanoic acid;

- (2i)-2-{[(5S_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy] phenyl }-6-(4-fluorophenyl)thieno[2,3-iZJpyrimidin-4-yI]oxy}-3-(2-{ [2-(3-{2-[2-(2methoxyethoxy)ethoxy]ethoxy}phenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid;

ORIGINAL

- (2Æ)-3-(2-{[2-(3-{2-[bis(2-hydroxyethyl)amino]ethoxy}phenyl)pyrimidin-4yl]methoxy} phenyl )-2-{[( 5SJ-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]pheny[}-6-(4-fluoiOphenyl)thieno[2.3-i/]pyrimidin-4-yl]oxy}propanoic acid;

- (27?)-2-{[(5S₀)-5-{2,3-dimethyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl}-6-(4iluorophenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy} -3- {2-[(2- {3 - [( {[2-(piperid in-1 - y l)ethyl]carbamoyl }oxy )methy l]phenyl} pyrimidin-4-yl)methoxy]phenyl} propanoic acid;

- (2/Q-2-{[(5S_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxyJ phenyl} -6-(4-iluoropheny l)thieno[2,3-i7]pyrimidin-4-yl]oxy} -3-{ 2-[(2- {3 - [2(morpholin-4-yl)ethoxy]phenyl}pyrimidin-4-yl)niethoxy]phenyl}propanoic acid;

- (27?)-2- {[ ( 55,)-5- {3-chloro-2-methyl-4-[2-(4-inethy Ipiperazin-1 -y l)ethoxy] phenyl}-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-{2-[(2-{3-[2(dimethylamino)ethoxy]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid;

- (2Æ)-3-(2-{[2-(4-{2-[bis(2-hydroxyethyT)amino]ethoxy}phenyl)pyrimidin-4yl]methoxy}phenyl)-2-{[(5S_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i/|pyrimidin-4-yl]oxy}propanoic acid;

- (2R)-2-{[(55/)-5- {3-chIoro-2-methy l-4-[2-(4-methylpiperazin-1 -yl)ethoxy] phenyl }-6-(4-fluorophenyl)thieno[2.3-//]pyrimidin-4-yl]oxy }-3-(2-{[2-(4-{ 2-[2-(2hydroxyethoxy)ethoxy]ethoxy}pheny])pyrimidin-4-yl]methoxy}phenyl)propanoic acid;

- (2J?)-2-{[(55,)-5-{3-chloro-2-methyl-4-[2-(4-niethylpiperazin-l-yI)ethoxy] phenyl }-6-(4-fluorophenyl)thieno[2,3-5jpyriinidin-4-yl]oxy}-3-{2-[(2-{4-[(2,2dimethy I-1,3-dioxolan-4-y l )methoxy]pheny I} pyrimidin-4-yl)inethoxy] phenyl} propanoîc acid;

- (2/Î)-2-{[(55_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy] phenyl }-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-{2-[(2-{4-[2(morpholin-4-yl)ethoxy]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid;

. 4-[4-({2-[(2Æ)-2-carboxy-2-{[(5S_a)-5-{3-chloro-2-methyl-4-[3-(4-methyl piperazin-l-yl)propoxy]phenyl}-6-(4-fl uorophenyl )thieno[2,3-i/]pyrimidin-4yl]oxy}ethyl]phenoxy}methyl)pyrimidin-2-yl]phenyl phosphate disodium sait;

ORIGINAL

-93 l-[(ethoxycarbonyl)oxy]ethyl (2/?)-2-{[(5S_a)-5-{3-chloro-2-methyl-4-[2-(4methylpiperazin-l-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4yl]oxy }-3- {2-[(2- {3-[( l ,3-dimethoxypropan-2-yl)oxy]phenyl} pyrimidin-4y l )methoxy]phenyl} propanoate;

- (27?)-2-{[(5S_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy] phenyl }-6-(4-fluorophenyl)thieno[2,3-</]pyrimidin-4-yl]oxy}-3-[2-({2-[5-(hydroxy methyl)pyridin-3-yl]pyrimidin-4-yl}methoxy)phenyl]propanoic acid;

- (2£)-2-{[(5S_fl)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy] phenyl} -6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy} -3-(2- {[2'-(hydroxy methyl)-2,5'-bipyrimidin-4-yl]methoxy}phenyl)propanoic acid.

24. Process for the préparation of a compound of formula (I) according to claim l, characterised in that there is used as starting material the compound of formula (II):

CI^Br <^H) wherein A is as defined for formula (!) in which 1 is linked to the chlorine atom and 2 is linked to the bromine atom.

which compound of formula (II) is subjected to coupling with a compound of formula (III):

Alk

R14 (ΠΙ) wherein Rf„ R₇, Rj₄ and n are as defined for formula (1), and Alk represents a linear or branched (Ci-C₆)alkyl group, to yield the compound of formula (IV):

ORIGINAL

(IV) wherein R_fl. R7, R,₄, A and n are as defined for formula (I) and Alk is as defined before, compound of formula (IV) which is further subjected to coupling with compound of

5 formula (V):

(V) wherein R_b R₂, R3. R4 and R, are as defined for formula (l), and R_Bi and R_B2 represent a hydrogen atom, a linear or branched (C|-Ct,) alkyl group, or R_Bi and R_B2 form with the oxygen carrying them an optionally methylated ring,

IO to yield the compound of formula (VI):

Alk

(VI) wherein R_t, R₂, R₃, R₄, R5, R/„ R7, Rj₄, A and n are as defined for formula (I) and Alk

ORIGINAL

-95is as defined before, the Alk-O-C(O)- ester fonction of which compound of formula (VI) is hydrolysed to yield the carboxylic acid, which may optionally be reacted with an alcohol of formula R₈ ^!-OH or a chlorinated compound of formula Rs’-Cl wherein Rs’ represents a linear or branched (C|-C₈)alkyl group, a -CHR_aR_b group, an aryl group, a heteroaryl group, an arylalkyl(Ci-Cô) group, or a heteroarylalkylfCj-Cô) group, R_a and R_b are as defined for formula (l), to yield the compound of formula (I), which may be purified according to a conventional séparation technique, which is converted, if desired, into its addition salis with a pharmaceutically acceptable acid or base and which is optionally separated into its isomers according to a conventional séparation technique, it being understood that at any moment considered appropriate during the course of the process described above, some groups (hydroxy, amino...) of the starting reagents or of the synthesis intermediates can be protected, subsequently deprotected and functionalized, as required by the synthesis.

25. Pharmaceutical composition comprising a compound of formula (I) according to any one of daims l to 23 or an addition sait thereof with a pharmaceutically acceptable acid or base in combination with one or more pharmaceutically acceptable excipients.

26. Pharmaceutical composition according to claim 25 tor use as pro-apoptotic agents.

27. Pharmaceutical composition according to claim 26 for use in the treatment of cancers and of auto-immune and immune System diseases.

28. Pharmaceutical composition according to claim 27 for use in the treatment oi cancers of the bladder, brain, breast and utérus, chronic lymphoid leukaemias, cancer of the colon, œsophagus and liver, lymphoblastic leukaemias, acute myeloid leukaemias, lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, nonsmall-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer.

ORIGINAL

29. Use of a pharmaceutical composition according to claim 25 in the manufacture of médicaments for use as pro-apoptotic agents.

30. Use of a pharmaceutical composition according to claim 25 in the manutacture of médicaments for use in the treatment of cancers and of auto-immune and immune

5 System diseases.

31. Use of a pharmaceutical composition according to claim 25 in the manulacture of médicaments for use in the treatment ot cancers of the bladder, brain, breast and utérus, chronic lymphoid leukaemias, cancer of the colon, œsophagus and liver, lymphoblastic leukaemias, acute myeloid leukaemias, lymphomas, melanomas,

10 malignant haemopathies, myelomas, ovarian cancer, non-small-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer.

32. Compound of formula (I) according to any one of daims 1 to 23 , or an addition sait thereof with a pharmaceutically acceptable acid or base, for use in the treatment of cancers of the bladder, brain. breast and utérus, chronic lymphoid leukaemias, cancer

15 of the colon, œsophagus and liver, lymphoblastic leukaemias. acute myeloid leukaemias, lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer.

33. Use of a compound of formula (1) according to any one of daims 1 to 23 or an

20 addition sait thereof with a pharmaceutically acceptable acid or base, in the manufacture of médicaments for use in the treatment of cancers of the bladder, brain, breast and utérus, chronic lymphoid leukaemias, cancer of the colon, œsophagus and liver. lymphoblastic leukaemias, acute myeloid leukaemias, lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small-cell lung cancer, 25 prostate cancer, pancreatic cancer and small-cell lung cancer.

34. Combination of a compound of formula (I) according to any one of daims 1 to 23 with

ORIGINAL

-97an anti-cancer agent selected from genotoxic agents, mitotic poisons, anti-metabolites, protéasome inhibitors, kinase inhibitors and antibodies.

35. Pharmaceutical composition comprising a combination according to claim 34 in combination with one or more pharmaceutically acceptable excipients.

36. Combination according to claim 34 for use in the treatment ot cancers.

37. Use of a combination according to claim 34 in the manufacture of médicaments for use in the treatment of cancers.

38. Compound of formula (I) according to any one of daims l to 23 for use in the treatment of cancers requiring radiotherapy.