OA18891A - New bicyclic derivatives, a process for their preparation and pharmaceutical compositions containing them. - Google Patents

Abstract

Compounds of formula (I);

Description

The present invention relates to new bicyciic dérivatives, to a process tor 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 homeostasîs.

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 ofthe process of apoptosis is complex and involves the activation or repression of several intracellular signalling 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 of 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 ofthe 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 lymphoid 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 chemotherapy and in the clinical prognosis of patients affected by cancer. Notably, Mcl-1, an anti-apoptotic Bcl-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.

ORIGINAL

- 2In 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:

♦ A represents the group

in which 1 is linked to the W group and 2 is linked to the phenyl ring, wherein:

- E represents a furyl, thienyl or pyrrolyl ring,

- X], X₃, X.I and X₅ independently of one another represent a carbon atom or a nitrogen atom,

- X? represents a C-R₂i group or a nitrogen atom, and

- ( ) means that the ring is aromatic,

R] represents a halogen atom, a linear or branched (Cj-Côjalkyl group, a linear or branched (C₂-C₆)alkenyi group, a linear or branched (C₂-C₆)alkynyl group, a linear or branched (C|-C₆)polyhaloalkyl group, a hydroxy group, a hydroxy(C|-C₆)alkyl group, a linear or branched (Cj-C&)alkoxy group, -S-(C|-Cé)alkyl, a cyano gioup, a nitro group, -alkylfCo-Côf-NRitRii’, -O-alkylfCi-Cej-NRnRn , -O-alkyl(Ci-C₆)-Ri₂, -C(0)-ORu, -O-C(O)-R_lb -C(O)-NRnRii’, -NR_n-C(O)-Rii’,

ORIGINAL

-NRii-C(O)-ORn’, -alkyl(Ci-C6)-NRii-C(O)-Rii\ -SCb-NRuRn’, -SO₂-alkyl(Cj-Cé), ♦ R₂, R₃, Ri and R₅ independently of one another represent a hydrogen atom, a halogen atom. a linear or branched (Ci-Cé)alkyl group, a linear or branched (C₂-C₆)alkenyl group, a linear or branched (C₂-C₆)alkynyl group, a linear or branched (C|-C₆)polyhaloalkyl, a hydroxy group, a hydroxy(Ci-C₆)alkyl group, a linear or branched (C,-C₆)alkoxy group, a -S-(C,-C₆)alkyl group, a cyano group, a nitro group, -alkyl(Co-Cé)-NR||Rn’, -0-alkyl(C|-C6)-NRnRn , -O-alkyl(C!-C₆)-R_l2, -C(O)-ORu, -O-C(O)-Rn, -C(O)-NRiiRh’, -NR_h-C(O)-Ru’, |0 -NRu-C(O)-ORn’, -alkyl(Ci-C6)-NRu-C(O)-Rir, -SCb-NRuRn’, or

-SO₂-alkyl(Ci-C₆), or the substituents of the pair (Ri, R₂) 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 ] 5 nitrogen. it being understood that resulting ring may be substituted by from l to 2 groups selected from halogen, linear or branched (Ci-Cé)alkyl, -alkyl(C₀-C₆)-NR_liRii’, -NR13R13’, -alkyl(C₀-C₆)-Cyi or oxo, ♦ Ré and R? independently of one another represent a hydrogen atom, a halogen atom, a linear or branched (C_rC₆)alkyl group, a linear or branched (C₂-C₆)alkenyl 20 group, a linear or branched (C₂-C₆)alkynyl group, a linear or branched (Ci-C₆)polyhaloalkyl, a hydroxy group, a linear or branched (Ci-C₆)alkoxy group, a -S-(Ci-C₆)alkyl group, a cyano group, a nitro group, -alkyl(Co-C₆)-NR|]Rn , -O-Cyi, -alkyl(C₀-C₆)-Cyi, -alkenyl(C₂-C₆)-Cy_l, -alkynyl(C2-C₆)-Cy₁₇ -O-alkyl(C|-C₆)-Ri2, -C(O)-OR_n, -O-C(O)-Rn, -C(O)-NRuR|i’, -NRu-C(O)-Rii’, 25 -NRh-C(O)-0Rii’, -alkyl(Ci-C₆)-NRn-C(O)-Rn’, -SO₂-NRhRh ,

-SO2-alkyl(CrC₆), or the substituents of the pair (Ré, R7), when grafted onto two adjacent carbon atoms, form together with the carbon atoms carrying them an aromatic or nonaromatic ring composed of from 5 to 7 ring members, which may contain from 1 to 30 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-Cé)alkyl group, -NRi₃Rb’, -alkyl(Co-Cé)-Cyi or an oxo,

ORIGINAL ♦ W represents a -CH₂- group, a -NH- group or an oxygen atom, ♦ R₈ represents a hydrogen atom, a linear or branched (C]-C₈)alkyl group, a -CHR_aRb group, an aryl group, a heteroaryl group, an arylalkyl(C]-C₆) group, or a heteroarylalkyl(Ci-C6) group, ♦ R₉ represents a hydrogen atom, a linear or branched (Cj -C₆)alkyl group, a linear or branched (C₂-C₆)alkenyl group, a linear or branched (C₂-C₆)alkynyl group, -Cy₂, -alkyl(CrC6)-Cy₂, -alkenyl(C₂-C₆)-Cy₂, -alkynyl(C₂-C₆)-Cy₂, -Cy₂-Cy₃, -alkynyl(C₂-C₆)-O-Cy₂, -Cy₂-alkyl(C₀-C₆)-0-alkyl(Co-C₆)-Cy₃, a halogen atom, a cyano group, -C(O)-R[j, or -C(O)-NR|₃R|5’, ♦Rio represents a hydrogen atom, a linear or branched (CpCôjalkyl group, a linear or branched (C₂-C₆)alkenyl group, a linear or branched (C₂-C₆)alkynyl group, an arylalkylfCi-Ce) group, a cycloalkylalkyl(Ci-C&) group, a linear or branched (C i-C₆)polyhaloalkyl, -alkyl(C i-C6)-O-Cy4, or the substituents of the pair (R₉, Rio), when grafted onto two adjacent carbon atoms, form together with the carbon atoms carrying them an aromatic or nonaromatic ring composed of from 5 to 7 ring members, which may contain from 1 to J heteroatoms selected from oxygen, sulphur and nitrogen, ♦ Ru and Ru’ independently of one another represent a hydrogen atom, a linear or branched (C |-Cô)alkyl group, or the substituents of the pair (Ru, Ru’) torm 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 trom 1 to j 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 (Ci-Côjalkyl group, r₁₂ represents -Cys, -Cys-alkyl(Co-C6)-0-alkyl(Co-C6)-Cy6, -Cy₅-alkyl(C₀-C6)-Cy₆, -Cy5-alkyl(C_o-C₆)-NR|i-alkyl(Co-C6)-Cy6.

-Cy₅-Cy₆-0-alkyl(Co-C6)-Cy7, -C(O)-NRhRii’, -NRnRn’, -OR₍i, -NRn-C(O)-Rn’, -O-alkyl(Ci-C₆)-ORii, -SO₂-Rn, -C(O)-ORn, or

-NH-C(O)-NH-R_n, ♦ Ri₃, R_î3’, R15 and Ri>’ independently of one another represent a hydrogen atom, or an optionally substituted linear or branched (C j-Côjalkyl group.

ORIGINAL ♦ R.|4 represents a hydrogen atom, a hydroxy group or a hydroxy(C]-C6)alkyl group, ♦ R₂j represents a hydrogen atom, a halogen atom, a linear or branched (Ci-C6)alkyl group, or a cyano group, ♦ R_a represents a hydrogen atom or a linear or branched (C i-Cr,)alkyl group, ♦ R_h 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 IV independently of one another represent a hydrogen atom, a linear or branched (Ci-C$)alkyl group, a cycloalkyl group, a (Ci-C₆)alkoxy(C|-C6)alkyl group, a(Ci-C₆)alkoxycarbonyl(Ci-C6)alkyl group, or the substituents of the pair (Rc, R/) form together with the nitrogen atom carrying them a non-aromatic ring composed oi 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 (Ci-Cé)alkyl group, ♦ Cyi, Cy₂, Cy₃, Cy₄, Cy₅, Cy₆ and Cy₇ independently of one another, represent a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, ♦ n is an integer equal to 0 or 1, it being understood that:

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

- “heteroaryl” means any mono- or bi-cyclic group composed of from 5 to 10 ring members, having at least one aromatic moiety and containing from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen,

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

- “heterocycloalkyl” means any mono- or bi-cyclic non-aromatic carbocyclic group containing from 3 to 10 ring members, and containing from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen, which may include fused, bridged or spiro ring Systems, it being possible for the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined and the alkyl, alkenyl, alkynyl, alkoxy groups, to be substituted by from 1 to 4 groups

ORIGINAL selected from optionally substituted linear or branched (Ci-C₆)alkyl, optionally substituted linear or branched (C₂-C₆)alkenyl, optionally substituted linear or branched (C₂-C₆)alkynyl, optionally substituted linear or branched (Ci-C₆)alkoxy, optionally substituted (C|-C₆)alkyl-S-, hydroxy, oxo (or A-oxide where appropriate), nitro, cyano, C(O)-OR’, -O-C(O)-R’, -C(O)-NR’R”, -O-C(O)-NR’R”, -NR’R”, -(C=NR’)-OR”, -OP(O)(OR’)₂, -O-P(O)(O'M⁺)₂, linear or branched (Ci-Côjpolyhaloalkyl, trifluoromethoxy, halogen, or an aldohexose of formula:

in which each R’ is independent;

it being understood that R’ and R” independently of one another represent a hydrogen atom or an optionally substituted linear or branched (C|-C₆)alkyl group, and M represents a pharmaceutically acceptable monovalent cation.

with the proviso that

their enantiomers, diastereoisomers and atropisomers, and addition salts thereof with a 15 pharmaceutical ly acceptable acid or base.

Advantageously, the présent invention relates to compounds of formula (I) wherein:

♦ R| and R₂ independently of one another represent a halogen atom, a linear or branched (C|-C₆)alkyl group, a hydroxy group, a linear or branched (C_rC₆)alkoxy group, or the substituents of the pair (Ri, R₂) form together with the carbon atoms carrying them an aromatic ring composed of from 5 to 7 ring members, which may contain

ORIGINAL

-7from l to 3 nitrogen atoms, ♦ R₃ represents a hydrogen atom, a halogen atom, a linear or branched (Ci-C₆)alkyi group, a hydroxy group, a linear or branched (Ci-Céjalkoxy group, or -O-alkyl(C rCej-NRi i Ri i ♦ R4 and R5 independently of one another represent a hydrogen atom, a halogen atom, a linear or branched (Ci-Cèjalkyl group, a hydroxy group, a linear or branched (CrC₆)alkoxy group, ♦ R₆ and R₇ independently of one another represent a hydrogen atom, a halogen atom, a linear or branched (CpCJalkyl group, a linear or branched (Ci-C₆)polyhaloalkyl group, a hydroxy group, a linear or branched (Ci-C₆)alkoxy group, a cyano group, a nitro group, -alkyl(Cû-C6)-NRuRu’, -alkyl(Co-C6)-Cyi, -O-alkyl(CrC₆)-Ri2, or -C(O)-NRnRn’, ♦ R_s represents a hydrogen atom, a linear or branched (Ci-C₈)alkyl group, or a -CHR_aRb group, ♦ R₉ represents a hydrogen atom, a linear or branched (Ci-C₆)alkyl group, a linear or branched (C₂-C₆)alkenyl group, a linear or branched (C₂-C₆)alkynyl group, -Cy₂, or a halogen atom, ♦ Rio represents a hydrogen atom, a linear or branched (Ci-C₆)alkyl group, a linear or branched (C₂-C₆)alkenyl group, a linear or branched (C₂-C₆)alkynyl group, an arylalkyl(Ci-C₆) group, a cycloalkylalkyl(Ci-C₆) group, a linear or branched (C|-C6)polyhaloalkyl, or -alkyl(Ci-C₆)-O-Cy4, or the substituents of the pair (R₉, Rio) when grafted onto two adjacent carbon atoms, form together with the carbon atoms carrying them a non-aromatic ring composed of from 5 to 7 ring members, which may contain from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen, ♦ Ru and Ru’ independently of one another represent a hydrogen atom, a linear or branched (C_rC₆)alkyl group, or the substituents of the pair (Ru, R11’) torm 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 (Ci-C^alkyl group,

ORIGINAL ♦ R12 represents -Cy, or -Cy5-alkyl(C₀-C6)-Cy6, ♦ W represents a -N H- group or an oxygen atom.

it being possible for the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined and the alkyl, alkenyl, alkynyl, alkoxy groups, to be substituted by from l to 4 groups selected from optionally substituted linear or branched (Cj-Céfalkyl, optionally substituted linear or branched (Ci-Ce)alkoxy, hydroxy, oxo (or /V-oxide where appropriate), -C(O)-OR’, -C(O)-NR’R”, -O-C(O)-NR’R”, -NR’R”, -O-P(O)(OR’h, -O-P(O)(O’M⁺)₂, linear or branched (Ci-Cèjpolyhaloalkyl, halogen, or an aldohexose of formula.

in which each R’ is independent;

it being understood that R’ and R” independently of one another represent a hydrogen atom or an optionally substituted linear or branched (C, -Cô)alkyl group and M represents a pharmaceutically acceptable monovalent cation.

More especially, compounds of formula (I) to which preference is given are compounds 15 wherein n is an integer equal to l.

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

ORIGINAL

wherein R_b R₂, R₃, R4, Rs, Rr„ R?. R«, R9, R«4, Χι, X2, X3 and W are as defined for formula (I). More especially, compounds of formula (l-a) to which preference is given are

More particularly, compounds of formula (I-a) to which preference is given are compounds wherein

IO

ORIGINAL

- ΙΟ-

In another embodiment of the compounds of formula (I-b):

invention, an advantageous possibility consists of

(Lb) wherein R_b R₂, R₃, Ri, R₅, Rô, R7, Rs, Ro, Ru, Xi, X2, X3 and W are as defined for formula (I). More especially, compounds of formula (I-b) to which preference is given are compounds wherein

ORIGINAL

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

(l-c) wherein Ri, R?, R3, R-ι, R5, Re- R7, R«, Ro, Rio, R14, Χι, X2, X3 and W are as defined for formula (I). More especially, compounds of formula (l-c) to which preference is given are compounds wherein

More particularly, compounds of formula (l-c) to which preference is given are compounds wherein

ORIGINAL

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

wherein R_h R₃, Rj, R4, R5, % R7, Rs, R9, Rio, Ru, Xi, X2, X3 and W are as defined for formula (I). More especially, compounds of formula (I-d) to which preterence is given are compounds wherein

In another embodiment of the invention, an advantageous possibility consists of 10 compounds of formula (l-e):

ORIGINAL

wherein R_h R₂, R₃, R+, Rs, R*, R7, Rs, Rg. Ri4, Xi, X2, X₃ and W are as defined for formula (I). More especially, compounds of formula (I-e) to which preterence is given are compounds wherein

Advantageously,

Compounds of formulae (I-a). (l-b), (ï-c) and (I-e) are particularly preferred. Compounds of formulae (I-a) and (I-b) are even more preferred.

IO ln another embodiment ol the invention, an advantageous possibility consists of compounds of formula (I-f):

ORIGINAL

wherein E, Rj, R₂, R3, R-i- R5, Ro, R7, Rs, R9- Rio, Ri4, Xi, X2, Xî, X-h X? and W are as defined for formula (I).

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 hîgh enough to allow for isolation of individual conformers. For example, for compounds of formula (I-b) (the same can be donc for compounds of formula (I-a), (I-c), (I-d) and (l-e)), atropisomers are as follows:

IO Preferred atropisomer is (S_a) for compounds of formula (I-a), (I-b), (I-c) and (I-d).

Preferred atropisomer is (R_a) for compounds of formula (l-e).

Advantageously, at least one of the groups selected from R₂, R3, R4 and R₅ does not represent a hydrogen atom.

ORIGINAL

Preferably, R|₄ represents a hydrogen atom.

R₂i represents preferably a hydrogen atom, a fluorine atom, a methyl group or a cyano group. More preferably, R₂₎ represents a hydrogen atom or a fluorine atom. Even more preferably, R₂j represents a hydrogen atom.

In the 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 ethyl group. a bromine atom or a chlorine atom. Even more preferably, R| represents a methyl group or an ethyl group.

Advantageously, R₂ represents a halogen atom, a hydroxy group, a linear or branched (Ci-Cô)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.

In some preferred embodiment of the invention, when the substituents oi the pair (Rj, R₂) form together with the carbon atoms carrying them an aromatic ring,

represents

R₃ advantageously represents a hydrogen atom, a hydroxy group, a linear or branched (Ci-C₆)alkoxy group or -O-alkyltCi-Cô/NRiiRn'. Advantageously, R₃ represents -O-alkyKCi-Côj-NRuRn’.

R, and R> preferably represent a hydrogen atom.

In an advantageous embodiment, the substituents of the pair (R|, R₅) are identical and the

ORIGINAL

- 16substituents of the pair (R₂, R4) are identical. In the preferred compounds of the invention, the substituents of the pair (Ri, R5) are identical and represent a (Cj-C^jalkyl group, preferably a methyl group, whereas the substituents of the pair (R?, R-ι) are identical and represent a halogen atom, preferably a chlorine atom, or a hydrogen atom.

In the preferred compounds of the invention,

wherein Ri i and Ru’ are as defined for formula (l).

In another embodiment of the invention, R& represents a hydrogen atom, an optionally substituted linear or branched (Ci-Cô)alkoxy group or a -O-alkyl(C|-C6)-Ri₂ group.

IO Advantageously, R_f) represents a 2,2,2-trifluoroethoxy group, a methoxy group, or a -O-alkyl(Ci-C₆)-Rt2 group.

R7 preferably represents a hydrogen atom.

In the preferred compounds of the invention,

represents

wherein R12 is as defined for formula (I).

In another embodiment of the invention, an advantageous possibility consists of

ORIGINAL

- 17compounds of formula (I-g):

wherein Rj, R&, R7, Rg, R₉, Rio> Rii, Rii'> R14· Xi, X2» X3, Χ4> X5, W ^and R ^{are as} defined for formula (I).

Preferably, Rg represents a hydrogen atom, a -CHR_aRb group, an optionally substituted linear or branched (Ci-Cg)alkyl group, or a heteroarylalkyl(Ci-C6) group. Preferably, Rg represents a -CHR_aR_b group in which R_a represents a hydrogen atom or a methyl group and R_b represents a -O-C(O)-O-(C,-C₈)alkyl group; a -O-C(O)-O-cycloalkyl group; a -O-C(O)-NR_cRJ group, in which R_c and RJ independently of one another represent a IO hydrogen atom, a linear or branched (Ci-Cg)alkyl group, a (Ci-CJalkoxylCi-Côjalkyl group, a (C_rC6)alkoxycarbonyl(Ci-C₆)alkyl group, or the substituants of the pair (R_c, RJ) 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 Rg groups are as follows: hydrogen; methyl; ethyl; (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl; 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(CH₃)₂ group. Even more preferably, Rg represents hydrogen.

In the preferred compounds of the invention, R₉ represents a hydrogen atom, a halogen atom, a linear or branched (C_rC₆)alkyl group, a linear or branched (C₂-C₆)alkenyl group, a

ORIGINAL

- 18linear 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 phenyl group or a furan-2-yl group. In a more preferred embodiment, R₉ represents a prop-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 advantageous possibility consisting in compounds of formula (l-c), preferred Rio sroups are as follows: hydrogen; methyl; isopropyl; 2,2,2-triiluoroethyl; benzyl, 4-methoxybenzyI; phenethyl; 3-phenyl-propyl; cyclopropylmethyl; cyclopentylethyl; naphthalen-l-ylmethyl; 2-(naphthalen-l-yloxy)ethyl; but-2-yn-l-yl; prop-2-en-lyl; but-3-en-l-yl. In another embodiment, the substituents of the pair (R₉, Rio) when grafted onto two adjacent atoms, form together with the carbon and nitrogen atoms carrying them a non-aromatic ring composed of from 5 to 6 ring members.

In the advantageous possibility consisting in compounds of formula (I-d), Rio preferably represents a hydrogen atom or a halogen atom.

In the preferred compounds of the invention. Ru and Ru independently of one another represent a linear or branched (Cj-Cojalkyl group, or the substituents of the pair (Ri i, Ru ) 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, a linear or branched (CrUjalkyl group. More preferably, Ru and Ru’ represent a methyl group, or the substituents of the pair (R_lt, Ru’) form together a 4-methyl-piperazinyl group or a 4-ethyl-piperazinyl group. In a more preferred embodiment, the substituents of the pair (Ru, Rii’) form together a 4-methyl-piperazinyl group. In another preferred embodiment, Ru and Ru’ represent a methyl group.

Advantageously, Ri? represents -Cy> or -Cy5-alkyl(Co-Câ)-Cy6. Preferably, Ri? represents -Cy₅ or -Cy₅-Cy₆.

ORIGINAL

- 19Cy₅ 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, or a pyrazin-2-yl group. In the preferred compounds ofthe invention, Cys represents a pyrimidin-4-yl group.

In another embodiment of the invention, Cy₅ represents a heteroaryl group which is substituted by an optionally substituted linear or branched (Ci-Côjalkyl group, an optionally substituted linear or branched (C]-Cô)alkoxy group, a -NR’R group, or a linear or branched (CrCôjpolyhaloalkyl group, it being understood that R’ and R” independently of one another represent a hydrogen atom or an optionally substituted linear or branched (Ci-C₆)alkyl group.

Cy₆ preferably represents a phenyl group.

Other compounds ofthe invention to which preference is given are those wherein.

R_l2 represents

in which p is an integer equal to 0 or l and Ri₆ represents a hydrogen atom, a hydroxy group, an optionally substituted linear or branched (C|-C₆)alkyl group, a linear or branched (C|-C₆)alkoxy group, a -O-(CHR|7-CHR|8-O)_q-R* group, a -O-P(O)(OR )₂ group, a -O-P(O)(O’M⁺)₂ group, a -O-C(O)-NR_]9R2() group, a di(C|-C₆)alkylamino(C|-C6)alkoxy group. a halogen atom, or an aldohexose of formula:

in which each R’ is independent;

ORIGINAL

-20it being understood that:

♦ R’ represents a hydrogen atom or a linear or branched (Cj-Côjalkyl group, ♦ R|7 represents a hydrogen atom or a (C]-C6)alkoxy(Ci-C₆)alkyl group, ♦ Rie represents a hydrogen atom or a hydroxy(C|-Cé)alkyl group, ♦ Rio represents a hydrogen atom or a (Ci-C6)alkoxy(C]-C6)alkyl group, ♦ R₂o represents a (Ci-Cô)alkoxy(C]-C₆)alkyl group, a -(CHaX-NRnRn’ group or a -(CHaJrO-ÎCHRn-CHRjg-Ojq-R’ group, ♦ q is an integer equal to 1, 2 or 3 and r is an integer equal to 0 or 1, ♦ M⁺ represents a pharmaceuticaily acceptable monovalent cation.

The aldohexose according to the invention is preferably D-mannose. Preferably, the group -(CIDp-Riô is located at ortho position of the phenyl group.

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

j - (2/î)-2-{[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yI)ethoxy]phenyl}-6-(4fluorophenyI)furo[2,3-r/]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl) pyrimidin-4-yl]methoxy}phenyl)propanoic acid;

- (27?)-2-{ [5- {3-chloro-2-ethyl-4-[2-(4-methylpiperazin-1 -yl)ethoxy]phenyl} -6-(4fluorophenyl)furo[2,3-(7|pyrimidin-4-yl]oxy} -3-(2- {[2-(2-methoxyphenyl) pyrimidin-4-yl]methoxy} phenyl)propanoic acid;

- A-[(5S„)-5-i 3-chloro-2-nicthyl-4-[2-(4-methylpiperazin-l -yl)ethoxv]phcnyl}-6-(4- fluorophenyl)furo[2,3-J]pyrirnidin-4-yl]-2- {[2-(2-methoxyphenyl)pyrirnidin-4-yl] methoxy} -Ώ-pheny lalanine;

(27î)-2-{ [(35^)-3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl}2-(4-fluorophenyl)-l-benzothiophen-4-yl]oxy}-3-(2-{[2-(2methoxyphenyl)pyrimidin-4-yl]methoxy} phenyl)propanoic acid;

- (2/?)-2-{[(3S_a)-3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl}2-(4-fluorophenyl)-l-benzofuran-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl jpyrimidin4-yl]methoxy}phenyl)propanoic acid;

ORIGINAL

- (2/?)-2-{[(3S_fl)-3-{3-chloro-2-methy1-4-[2-(4-niethylpiperazin-l-yl)ethoxy]phenyl}6-fluoro-2-(4-fluorophenyl)-1 -benzofuran-4-yl]oxy} -3-(2-{ [2-(2-methoxyphenyl) pyrimidin-4-yl]methoxy} phenyl)propanoic acid;

- (2/?)-2-{[3-{(3S_ÎI)-3-chloro-2-methyI-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl}-

2-(4-fluorophenyl)-1 -methyl-1 H-indol-4-yl]oxy} -3-(2-{[2-(2-methoxyphenyl) pyrimidin-4-yl]methoxy} phenyl)propanoic acid;

- (2Æ)-2-{[(3SJ-3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl)2-(4-fluorophenyl)thieno[2,3-à]pyridin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl) pyrimidin-4-yl]methoxy}phenyl)propanoic acid;

- (27Q-2-[5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 -yl)ethoxy]phenyl]-6-(4fluorophenyl)-7-methyl-pyrrolo[2,3-7]pyrimidin-4-yl]oxy-3-[2-[[2-(2-methoxy phenyl)pyrimidin-4-yl]methoxy]phenyl]propanoic acid;

l-[(dimethylcarbamoyl)oxy]ethyl (2Æ)-2-{[(3S_e)-3-{3-chloro-2-methyl-4-[2-(4methylpiperazin-l-yl)ethoxy]phenyl}-2-(4-fluoiOphenyl)thieno[2,3-Z>]pyridin-415 yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoate;

l-[(ethoxycarbonyl)oxy]ethyl (2/?)-2-{[(3S’_a)-3-{3-chloro-2-methyl-4-[2-(4methylpiperazin-l-yl)ethoxy]phenyl}-2-(4-fluorophenyl)thieno[2,3-6]pyridin-4yl]oxy}-3-(2-{[2-(2-methoxyphenyI)pyrimidin-4-yl]methoxy}phenyl)propanoate;

- ;V-[3- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 -yl)ethoxy]phenyl} -2-(4- fluorophenyl)thieno[2,3-6]pyridin-4-yl]-2- {[2-(2-methoxyphenyl)pyrimidin-4-yl] methoxy}-D-phenylalanine;

- A^f-[3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl}-2-(4fluorophenyl)thieno[3,2-c]pyridin-4-yl]-2-{[2-(2-methoxyphenyl)pyrimidin-4-yl] methoxy} phenylalanine;

- 2- {[(3 R_a)-3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 -yl)ethoxy]phenyl} -2-(4fluorophenyl)imidazo[ 1,2-c]pyrimidin-5-y l]oxy} -3-(2- {[2-(2-methoxyphenyl) pyrimidin-4-yl]methoxy} phenyl)propanoic acid.

The invention relates also to a process for the préparation of compounds of formula (1), which process is characterized in that there is used as starting material the compound of 30 formula (Il-a):

ORIGINAL

-22A.

/f Zi (Il-a) wherein Z| represents bromine or iodine, Z? represents chlorine, bromine or hydroxy, and A is as defined for formula (I) in which 1 is linked to the Z₂ group and 2 is linked to the Z| group, which compound of formula (Il-a) is subjected to coupling with a compound of formula (III):

Alk

(III) wherein R₆, R?, Ru, W and n are as defined for formula (I), and Alk represents a linear or branched (C j-C₆)alky1 group, to yield the compound of formula (IV):

Alk

(IV) wherein R₆, R₇, Rij. A, W and n are as defined for formula (1), and Zi and Alk are as defined before, compound of formula (IV) which is further subjected to coupling with compound of formula (V):

ORIGINAL

(V)

B r_b2o or_b1 wherein Ri, R₂, R₃, Ri and R₅ are as defined for formula (I), and R_B1 and R_B2 represent a hydrogen atom, a linear or branched (Ci-Cô) alkyl group, or Rm and R_B2 form ^ith the oxygen carrying them an optionally methylated ring, to yîeld the compound of formula (VI):

(VI) wherein R,, R₂, R₃ Rt, Rs, Rô, Rî, Ru, A, W and n are as defined for formula (I) and Alk is as defined before.

the Alk-O-C(O)- ester function of which compound of formula (VI) is hydrolyzed to yield the carboxylic acid, which may optionally be reacted with an alcohol of formula Rs’-OH or a chlorinated compound of formula Rg’-Cl wherein Rs represents a linear or branched (Ci-C₈)alkyl group, a -CHR_aR_b group, an aryl group, a heteroaryl group, an arylalkyl(Ci-C₆) group, or a heteroarylalkyl(Ci-C₆) group, R_a and R_b 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 ot the synthesis intermediates can be protected, subsequently deprotected and functionalized, as required by the synthesis.

In another embodiment of the invention, compounds of formula (I) may be obtained using an alternative process, which process is characterised in that there is used as starting materiai the compound of formula (Il-b):

ζ/^Λ\ν <^H-^b) wherein Z₃ represents iodine, Z₄ represents chlorine, hydroxy, and A is as defined for formula (I) in which 1 is linked to the Z₄ group and 2 is linked to the Z₃ group, which compound of formula (ΙΙ-b) is subjected to coupling with a compound of formula (V):

B ^ΒΒ2θ θ^ΒΙ wherein Ri, R?, R₃, R-i and R₅ are as defined for formula (I), and R_Bi and R_B2 represent a hydrogen atom, a linear or branched (CTCô) alkyl group, or R_Bi and R_B2 form with the oxygen carrying them an optionally methylated ring, to yield the compound of formula (VII):

ORIGINAL

R₂ (VII) wherein R₍, R₂, R₃ R4, R5 and A are as defined for formula (I), and Z₄ is as defined betore, compound of formula (Vil) which is further subjected to coupling with compound of formula (III):

(III) wherein R₆, R₇, R_u, W and n are as defined for formula (I), and Alk represents a linear or branched (Ci-C₆)alkyl group, to yield the compound of formula (VI):

(VI)

IO wherein R_h R₂, R₃ R4, Ri, R(>, R?, Ri4, A, W and n are as defined for formula (I) and Alk is as defined before,

ORIGINAL

-26the Alk-O-C(O)- ester function of which compound of formula (VI) is hydrolyzed to yield the carboxylic acid, which may optionally be reacted with an alcohol of formula Rg -OH or a chlorinated compound of formula Rg’-Cl wherein Rg’ represents a linear or branched (Ci-C₈)alkyl group, a -CHR_aR_b group, an aryl group, a heteroaryl group, an arylalkyl(Ci-C₆) group, or a heteroarylaikyl(Ci-C₆) group, R_a and R_b 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 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 intennediates can be protected, subsequently deprotected and functionalized, as required by the synthesis.

The compounds of formulae (Π-a), (ΙΙ-b), (III), (V), Rg’-OH and Rg -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 reactivate the apoptotic process in cancerous cells is of 20 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 chemo- or radio-resistant cancers.

Among the cancer treatments envisaged there may be mentioned, without implying any 25 limitation, treatment of cancers of the bladder, brain, breast and utérus, chronic lymphoid leukemia, cancer of the colon, esophagus and liver, lymphoblastic leukemia, acute myeloid

ORIGINAL

-27leukemia, 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 at 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 trans-cutaneous, rectal, perlingual, ocular or respiratory 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 route, the nature of the therapeutic indication, or ot any associated treatments, and ranges from 0.01 mg to l g per 24 hours in one or more administrations.

Furthermore, the present invention relates also to the combination ot 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 pharmaceutical compositions comprising that type of combination and their use in the manufacture of médicaments for use in the treatment ot cancer.

Advantageously, the présent invention relates to the combination ot a compound oi formula (I) with an EGFR, 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 mTOR/PI3K inhibitor, and also to pharmaceutical compositions comprising that type of combination.

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

ORIGINAL

-28Preferably, the présent 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 présent invention relates to the combination of a compound of formula (I) with a RAF inhibitor, 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 EGFR/HER2 inhibitor, and also to pharmaceutical compositions comprising that type of combination.

In 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 oi formula (I) with a protéasome inhibitor, an immunomodulator or an alkylating agent, and also to pharmaceutical compositions comprising that type of combination.

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 lorm ot 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 în 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 same specificity of binding as the

ORIGINAL

-29antibody 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 în the art or else by peptide synthesis by means of, for example, automatic peptide synthesîzers such as those supplîed by the company Applied Biosystems, etc.

Scaffold 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 should display several features as follow (Skerra A., J. Mol. Recogn. 2000,13, 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 the group consisting in fibronectin and preterentially 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 could also be mentioned a scaffold derivative from toxins (such as, for example, scorpion, insect, plant or mollusc toxins) or protein inhibitors of neuronal nitric oxide synthase (PIN).

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

General Procedures

ORIGINAL

- 30All 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 silica-gel cartridges (RediSep®.^ Gold High Performance).

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

Micro wave heating was performed in an Anton Parr Mono Wave 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 χ 50 mm i.d. colunm 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 Agitent HP 1200 with Agilent 6140 quadrupole LC/MS, operating in positive or négative ion electrospray 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 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 x 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% 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

ORIGINAL

-3I0.02% 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.

’H-NMR measurements were performed on Bruker Avance III 500 MHz spectrometer and Bruker Avance III 400 MHz spectrometer, using DMSO-d_& or CDCI3 as solvent. ^lH 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-dô and 7.26 ppm for CDCI3) as internai standard. Splitting 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 on Agilent 6850 gas chromatograph and Agilent 5975C mass spectrometer using 15 m* 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 IT-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

Abbreviation	N a me
2-Me-THF	2-methyl-tetrahydrofurane
abs.	absolute
Ac	acetyl
AIBN	2- [( 1 -cyano-1 -methyl -ethy 1 )azo] -2-methyl-propaneni t ri le
AtaPhos	bis(di-/É77-butyl(4-dimethylaminophenyl)phosphine) dichloropalladium(Il)
B1NAP	(2,2'-bis(diphenylphosphino)-1,1 ’-binaphthyl)

ORIGINAL

	-32-
cc.	concentrated
dba	dibenzylideneacetone
DCM	methylene chloride
DEAD	diethyl azodicarboxylate
DEE	diethyl ether
DIPA	diisopropylamine
DIPEA	diisopropylethylamine
DMA	dimethylacetamide
DME	l ,2-dimethoxyethane
DMF	d i methy l form am i de
DMSO	dimethyl sulfoxide
dppf	l, r-bis(diphenylphosphino)ferrocene
DTAD	di-ie/7-butyl azodicarboxylate
EDC.HCl	V-(3-dimethylaminopropyl)-7V'-ethylcarbodiimide hydrochloride
eq.	équivalent
Et	ethyl
H1L1C	hydrophilic interaction liquid chromatography
HMDS	hexamethyldisilazane
’Pr	isopropyl
LDA	lithium diisopropylamide
MCPBA	//ze/a-chloroperoxybenzoic acid
Me	methyl
MeCN	acetonitrile
MTBE	methyl ze/7-butyl ether
MW	microwave
NBS	A7-bromosuccinimide
nBu	n-butyl
NCS	V-chlorosuccinimide
Ph	phenyl
PPA	polyphospholic acid
rac.	racemic

ORIGINAL

	- jj-
r.t.	room température
S2Me2	dimethyl disulfide
SPhos	2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl
TBAF	tetrabutyl ammonium fluoride
TBAOH	tetrabutyl ammonium hydroxyde
lBu	rerCbutyl
TEA	triethylamine
TFA	trifluoroacetic acid
THF	tetrahydrofurane
TIPSCl	triisopropyIsilyl chloride
TLC	thin layer chromatography
Ts	tosyl
X-Phos	2-dicyclohexylphosphino-2’,4',6’-triisopropylbiphenyl

General Procedure la l eq. Préparation la, 2 eq. from the appropriate lactic ester derivative, 10 mL/mmol ‘BuOH and 5 eq. CS2CO3 were placed in a flask and stirred at 55 °C until no further conversion was observed. Then the mixture was concentrated under reduced pressure, neutralized with IM aqueous HCl solution, diluted with brine and extracted with EtOAc. The combined organic phases were dried over Na^SO^, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents unless otherwise stated.

General Procedure 1b l eq. Préparation la, 2 eq. from the appropriate amino acid derivative, IO mL/mmol DMSO and 3 eq. K2CO3 were placed in a flask and stirred at 45 °C until no further conversion was observed. Then the mixture was neutralized with l M aqueous HCl solution, diluted with brine and extracted with DCM. The combined organic phases were dried over Na₂SO4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified via HILIC chromatography unless otherwise stated.

ORIGINAL

- 34General Procedure II

Step A l eq. from the appropriate 5-bromo-furo[2,3-d]pyrimidyl-lactic ester dérivative, 1.25 eq. from the appropriate boronic acid dérivative, 10 mol% AtaPhos and 3 eq. CS2CO3 were dissolved in a l:l mixture of dioxane and water (10 mL/mmoI 5-bromo-furo[2,3-iZ] pyrimidyl-lactic ester dérivative) and stirred at 105 °C in a MW reactor until no further conversion was observed. Then the mixture was neutralized with IM aqueous HCl solution, diluted with brine and extracted with THF. The combined organic phases were dried over MgSÛ4, fîltered and the filtrate was concentrated under reduced pressure. The 10 crude product was purified using preparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents.

Step B

The obtained intermediate was dissolved in a l:l mixture of dioxane and water (25 mL/mmol) and 10 eq. LiOHxH₂O was added. The mixture was stirred at r.t. until no 15 further conversion was observed. Then it was diluted with brine, neutralized with 2M aqueous HCl, extracted with DCM. The combined organic phases were dried over Na₂SC>4, fîltered and the filtrate was concentrated under reduced pressure. The diastereoisomers were purified and separated by preparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents.

General Procedure III l eq. from the appropriate 4-chloro-pyrrolo[2,3-i/]pyrimidine dérivative, 3 eq. from the appropriate amino acid dérivative, 10 mL/mmol DMSO and 4 eq. K2CO3 were stirred at 15O°C until no further conversion was observed. The mixture was acidified with IM aqueous HCl solution, the precipitate was fîltered and purified via preparative reversed 25 phase chromatography using 25 mM aqueous NH4HCO₃ solution and MeCN as eluents.

General Procedure IVa l eq. from the appropriate 5-bromo-pyrrolo[2,3-i/]pyrimidine dérivative, 3 eq. from the appropriate boronic acid dérivative, 3 eq. TBAOH, 0.2 eq. palladium acetate, 0.4 eq.

ORIGINAL

- 35tricyclohexylphosphonium tetrafluoroborate and 3.5 mL/mmol DME were stirred under N₂ atmosphère at 120 °C in a MW reactor until no further conversion was observed. Then the mixture was filtered through Celite and washed with MTBE and water. The layers were separated, the aqueous layer was washed with MTBE. The combined organic layers were washed with brine, dried over MgSO₄, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified via preparative reversed phase chromatography using 40 mM aqueous NH₄()Ac (pH = 4) solution and MeCN as eluents.

General Procedure IVb l eq. from the appropriate 5-iodo-pyrrolo[2,3-/7] pyrimidine dérivative, 3 eq. from the appropriate boronic acid dérivative, 3 eq. TBAOH, 0.2 eq. palladium acetate, 0.4 eq. butyidi-l-adamantylphosphine and 7 mL/mmol DME were stirred under N₂ atmosphère at reflux until no further conversion was observed. Then the mixture was filtered through Celite and concentrated under reduced pressure. The residue was purified via flash chromatography using DCM and MeOH as eluents.

General Procedure V l eq. from the appropriate benzofuran-4-ol dérivative, 2.5 eq. from the appropriate lactic ester dérivative, 2.5 eq. DTAD and 2.5 eq. PPh₃ were dissolved in dry toluene (20 mL/mmol) and stirred at 55 °C until no further conversion was observed. Then the mixture was concentrated and the residue was purified via flash chromatography using heptane and EtOAc as eluents.

General Procedure VI eq. from the appropriate 3-bromo-benzofuran dérivative, 2 eq. from the appropriate boronic acid dérivative, 2 eq. Cs₂CO₃, 10 mol% Ataphos, 1.5 eq. tri-/e/7butylphosphonium tetrafluoroborate and THF (10 mL/mmol) and water (4 mL/mmol) were stirred under N₂ atmosphère at 110°C in a MW reactor until no further conversion was observed. Then the mixture was acidified with IM aqueous HCl solution and extracted with DCM. The combined organic layers were washed with brine, dried over MgSO₄, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified via preparative reversed phase chromatography using 25 mM aqueous NH₄HCO₃

ORIGINAL

-36solution and MeCN as eluents. The obtained intermediate was dissolved in dioxane:water l:l (10 mL / mmol), 10 eq. LiOHxH₂O was added and the mixture was stirred at r.t. until no further conversion was observed. Then the mixture was diiuted with water, acidified with IM aqueous HCl solution and extracted with DCM. The combined organic phases 5 were dried over Na₂SO4, filtered and the filtrate was concentrated under reduced pressure.

The crude product was purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents.

Préparation la: 5-bromo-4-chloro-6-(4-fluorophenyl)furo[2,3-rf]pyrimidine

Step À ; 2~(4-fluorobenzoyl)propanedinitrile

IO 8l mL IM NaOEt solution in EtOH (8l mmol) was cooled to 0 °C and 6.14 g malononitrile (93 mmol) was added. The mixture was stirred at 0 °C for l hour, then 16.8 g 2-bromo-l-(4-fluorophenyl)ethanone (77.4 mmol) was added. The mixture was stirred at 0 °C for l hour, then at r.t. until no further conversion was observed. The volatiles were removed under reduced pressure, and the residue was purified via flash chromatography using heptane and EtOAc as eluents to obtain 2-(4-fluorobenzoyl)propanedinitrile. ’H NMR (400 MHz. CDCI3): 8.1 (m, 2H), 7.24 (m, 2H), 4.41 (t, IH), 3.75 (d, 2H)

Step B: 2-amino-5-(4-fluorophenyl)furan-3-carbonitrile

6.56 g 2-(4-fluorobenzoyl)propanedinitrile (28.5 mmol) was dissolved in 140 mL AcOH and 6 g Amberlite 15H⁺ was added. The mixture was stirred at 90 °C until no further 20 conversion was observed. Then the mixture was filtered, the filtrate was concentrated under reduced pressure. The residue was recrystallized from DCM to obtain 2-amino-5-(4fluorophenyl)furan-3-carbonitrile. ^lH NMR (400 MHz, DMSO-dè): 7.69 (m, 2H), 7.24 (m, 211),6.96 (s, IH)

Step C: 6-(4-fluorophenyl)-3}3-furo[2,3-à]pyrimidin-4-one

1290 mg 2-amino-5-(4-lluorophenyl)furan-3-carbonitrile (6.38 mmol) and 25.5 mL acetic formic anhydride were placed in a flask and stirred at r.t. for 30 minutes. Then, the volatiles were evaporated under reduced pressure. The residue was dissolved in 51 mL

ORIGINAL

-37AcOH and heated in a MW reactor at l60°C for 30 minutes, then at 18O°C for 15 minutes. Then the mixture was cooled to r.t., and the precipitate was filtered to obtain 6-(4-fluorophenyl)-37/-furo[2,3-i/]pyrimidin-4-one. 'H NMR (500 MHz, DMSO-dû): 12.66 (br s, IH), 8.15 (s, IH), 7.99 (m, 2H), 7.47 (s, IH), 7.33 (m, 2H)

Step D: 5-bromo-6-(4-fluorophenyl)-3}3-furo[2,3-à]pyrimidin-4-one

1704 mg 6-(4-fluorophenyl)-3//-furo[2,3-i/]pyrimidin-4-one (7.4 mmol) was dissolved in 74 mL AcOH, then 1182 mg bromine (7.4 mmol) was added. The mixture was stirred at r.t. until no further conversion was observed. The mixture was then filtered, the filtrate was concentrated under reduced pressure. The residue was digerated with 15 mL MeOH, filtered and dried on air to obtain 5-bromo-6-(4-fluorophenyl)-3L/-furo[2,3-</]pyrimidin-4one. MS: (M-H)⁺ = 309.0

Step E: Préparation la

1680 mg 5-bromo-6-(4-fluorophenyl)-3/f-turo[2,3-i7]pyriniidin-4-one (5.44 mmol) was dissolved in 12.7 mL POCl₃ (136 mmol) and 690 pi. DMA (5.44 mmol) was added. The mixture was stirred at 110 °C until no further con\^rersion was observed. The mixture was then cooled to 0 °C and poured into ice-water. The crude product was isolated by filtration and purified via flash chromatography using heptane and EtOAc as eluents to obtain Préparation la. '14 NMR (400 MHz. DMSO-d_b): 8.87 (s, 114), 8.16 (m, 214), 7.47 (m, 2H)

Préparation lb: 5-bromo-4-chloro-6-ethyl-7H-pyrrolo|2,3-i/|pyrimidine

Step A: 6-amino-5-[(2-elhyl-l,3-dioxolan-2-yl)rneihylJpyriniidin-4-oI

257 mg 6-amino-5-[(2-ethyl-l ,3-dioxolan-2-yl)methyl]-2-sulfanyl-pyrimidin-4-ol (0.1 mmol), 0.77 mL aqueous cc. NH₃ solution, 768 mg Raney-Ni and 11 mL water were placed in a flask under N₂ atmosphère and heated to reflux until no further conversion was observed. The warm reaction mixture was then filtered through Celite and washed with warm water. The filtrate was concentrated under reduced pressure. The crude product (6-amino-5-[(2-ethyl-l,3-dioxolan-2-yl)niethyl]pyrimidin-4-oI) was used without further purification.

ORIGINAL

-38*H NMR (400 MHz. DMSO-d₆) δ: 11.44 (br s, IH), 7.70 (s, 1 H), 6.07 (s, 2H), 3.89 (m, 4H), 2.62 (s, 2H), 1.53 (m, 2H), 0.81 (t. 3H)

MS (M+H): 226.2

Step B: 6-ethyl- 7W-pyrrolo[2,3-d]pyrimidin-4-ol

4.193 g 6-amino-5-[(2-ethyl-l,3-dioxolan-2-yl)methyl]pyrimidin-4-ol (18.6 mmol) was dissolved in 280 mL 0.2M aqueous HCl solution. The mixture was stirred at r.t. until no further conversion was observed. The precipitate was fîitered, washed with water and dried to obtain 6-ethyl-7//-pyrrolo[2,3-i/]pyrimidin-4-ol.

'H NMR (400 MHz, DMSO-d₆) δ: 11.67 (s, IH), 7.75 (s, IH), 6.12 (t. IH), 2.56 (m. 2H),

1.21 (t,3H)

MS (M+H): 164.2

Step C: 5-bromo-6-ethyl- 7Y{-pyrrolo[2,3-d]pyrimidin-4-ol

1.63 g 6-ethyl-7/7-pyrrolo[2,3-i/]pyrimidin-4-ol (10 mmol) was dissolved in 20 mL DMF and cooled to 0 °C. 1 mL bromine (20 mmol) was added and the mixture was stirred at r.t. until no further conversion was observed. Then it was diluted with water and aqueous NaiSiCh solution and extracted with DCM. The combined organic layers were washed with brine, dried over MgSC>4, fîitered and the filtrate was concentrated under reduced pressure to obtain 5-bromo-6-ethyl-7F/-pyrrolo[2,3-iZ]pyrimidin-4-ol.

'H NMR (400 MHz, DMSO-d₆) δ: 12.08 (s, IH), 11.83 (s, IH), 7.80 (d. IH), 2.60 (q, 2H),

1.16 (t,3H)

MS (M+H): 243.8

Step D: Préparation 1b

1936 mg 5-bromo-6-ethyl-777-pyrrolo[2,3-i/]pyrimidin-4-ol (8 mmol), 4.5 mL POCI3 and 969 mg ÀGV-dirnethylaniline (8 mmol) were placed in a fîask and stirred at 100 °C until no further conversion was observed. The mixture was then poured into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over MgSÛ4, fîitered and the filtrate was concentrated under reduced pressure to obtain Préparation 1b.

'H NMR (400 MHz, CDC1₃) δ: 9.79 (s, 1 H), 8.59 (s, 1 H), 2.91 (q, 2H), 1.37 (t, 3H)

ORIGINAL

-39MS (M+H): 260.0

Préparation le: 3-bromo-2-(4-fluorophenyl)benzofuran-4-oi

Step A: 2-(4-fluorophenyl)benzofuran-4-ol

2.37 g 2-bromoresorcinol (12.5 mmol) was dissolved in 30 mL dry THF under N₂ atmosphère and 4.17 mL TEA (30 mmol) and 1.92 mL AcCI (27 mmol) were added respectively. After stirring the mixture for 5 minutes, 2.4 g l-ethynyl-4-fiuorobenzene (20 mmol), 561 mg Pd(OAc)₂ (2.5 mmol), 1.45 g tri-rm-butylphosphonium tetrafluoro borate (5 mmol), 476 mg Cul (2.5 mmol) and 10 mL dry DIP A were added and the mixture was stirred at 80 °C until no further conversion was observed. Then 2 g LiOHxH₂O was added and the mixture was stirred at 80 °C until no further conversion was observed. The mixture was then concentrated under reduced pressure and purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents to obtain 2-(4-fluorophenyl)benzofuran-4-ol. ^lH NMR (400 MHz, DMSO-dô) δ: 10.00 (s, IH), 7.91 (m, 2H), 7.38 (s, IH), 7.31 (t, 2H), 7.10 (t, IH), 7.04 (d, lH), 6.63 (dd, IH)

Step B: [2-(4-fluorophenyl)benzofuran-4-yl] acetate

456 mg 2-(4-fluorophenyl)benzofuran-4-ol (2 mmol) was dissolved in 10 mL dry THF then 156 pL AcCI (2.2 mmol) and then 306 pL TEA (2.2 mmol) were added carefully. The mixture was stirred under N₂ atmosphère until no further conversion was observed. The solvent was then removed under reduced pressure, and the residue was purified via flash chromatography using heptane and EtOAc as eluents to obtain [2-(4-fluorophenyl) benzofuran-4-yl] acetate. ¹H NMR (400 MHz, CDCI3) δ: 7.84 (m, 2H), 7.42 (d, IH), 7.28 (t, IH), 7.15 (t,2H), 7.02 (d, IH), 6.86 (s, 1 H), 2.42 (s, 3H)

Step C: [3-bromo-2-(4-fluorophenyl)benzofuran-4-yl] acetate

688 mg [2-(4-fluorophenyl)benzofuran-4-yl] acetate (2.54 mmol) and 589 mg NBS (3.31 mmol) were dissolved in 20 mL MeCN and stirred at 70 °C until no further conversion was observed. The solvent was then removed under reduced pressure, and the residue was purified via flash chromatography using heptane and EtOAc as eluents to

ORIGINAL

-40obtain [3-bromo-2-(4-fluorophenyl)benzofuran-4-yl] acetate. ’H NMR (400 MHz, CDCl₃) δ: 8.11 (m, 2H), 7.44 (dd, IH), 7.34 (t, IH), 7.19 (m, 2H), 7.00 (dd, IH), 2.45 (s, 3H)

Slep D: Préparation le

175 mg [3-bromo-2-(4-iluorophenyl)benzofuran-4-yl] acetate (0.5 mmol) and 150 pL IM NaOEt in EtOH solution and 5 mL EtOH were stirred at r.t. under N₂ atmosphère until no further conversion was observed. The mixture was diluted with 50 mL aqueous cc. NH4CI solution and extracted with DCM. The combined organic phases were dried over Na₂SO₄, filtered and the filtrate was concentrated to give Préparation le. 'H NMR (400 MHz, DMSO-df,) δ: 10.16 (br s, IH), 8.08 (m, 2H), 7.38 (m, 2H), 7.17 (t, IH), 7.08 (d, IH), 6.70 (d,lH)

Préparation Id: 3-bromo-6-fluoro-2-(4-fluorophenyl)benzofuran-4-ol

Step A: 5-fluoro-2-iodo-benzene-l,3-diol

3.81 g (29.7 mmol) 5-fluorobenzene-l,3-diol was dissolved in 600 mL water and 8.08 g (31.8 mmol) iodine was added at 0 °C and the mixture was stirred for 30 minutes. Then pH was adjusted to 3 with NaHCO₃ solution and the mixture was stirred until no further conversion was observed. Then pH was adjusted to 8 (with NaHCO₃ solution), 20 g Na₂S₂O₃ was added and the mixture was extracted with EtOAc. Combined organic phases were dried over Na₂SO4, filtered and the filtrate was concentrated and purified via flash chromatography using heptane and EtOAc as eluents to obtain 5-fluoro-2-iodo-benzene-

1,3-diol. 'H NMR (400 MHz, DMSO-d₆): 10.54 (s, 2H), 6.19 (d, 2H)

Step B: (3-acetoxy-5-fhioro-2-iodo-phenyl) acetate

4.78 g 3-bromo-6-fluoro-2-(4-fluorophenyl)benzofuran-4-ol (18.8 mmol) was dissolved in 150 mL THF and 5.70 g TEA (56.5 mmol) was added, then 4.267 g Ac₂O (41.4 mmol) was added dropwise at r.t. The mixture was stirred until no further conversion was observed. The mixture was then concentrated under reduced pressure and purified via flash chromatography using heptane and EtOAc as eluents to obtain (3-acetoxy-5-fluoro-2-iodophenyl) acetate. 'H NMR (400 MHz, DMSO-d₆): 7.24 (d, 2H), 2.34 (s, 6H)

ORIGINAL

-41Step C: 6-fluor0-2-(4-fliiorophenyl)benzofuran-4-ol

5.9 g (3-acetoxy-5-fluoro-2-iodo-phenyl) acetate ( 17.45 mmol) was dissolved in 70 mL dry THF and 70 mL dry DIPA under N₂ atmosphère, then 3.77 g l-ethynyl-4-fluorobenzene (31.4 mmol), 587 mg Pd(OAc)₂ (2.62 mmol), 1.52 g tri-/er/-butylphosphonîum tetrafluoroborate (5.24 mmol), and 500 mg Cul (2.62 mmol) were added and the mixture was stirred at 60 °C until no further conversion was observed. Then 2.93 g LiOH^xH₂O was added and the mixture was stirred at 60 °C until no further conversion was observed. The mixture was then concentrated under reduced pressure and purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents to obtain 6-fluoro-2-(4-fluorophenyl)benzofuran-4-ol. ’H NMR (400 MHz, DMSOd₆): 10.60 (s, IH), 7.89 (m, 2H), 7.38 (s, IH), 7.32 (m, 2H), 6.99 (m, IH), 6.48 (dd, IH)

Step D: [6-jhtoro-2-(4-fluoraphenyl)benzofuran-4-yl] acetate

2.49 mg 6-fluoro-2-(4-fluorophenyl)benzofuran-4-ol (10.1 mmol) was dissolved in 50 mL dry THF then 791 pL AcCl (11.1 mmol) and then 1.55 mL TEA (11.1 mmol) were added carefully. The mixture was stirred under N₂ atmosphère until no further conversion was observed. The solvent was then removed under reduced pressure, the residue was purified via flash chromatography using heptane and EtOAc as eluents to obtain [6-fluoro-2-(4fluorophenyl)benzofuran-4-yl] acetate. ’H NMR (400 MHz, DMSO-d₆): 7.95 (m, 2H), 7.57 (m, IH), 7.46 (s, IH), 7.37 (m, 2H), 7.09 (dd, IH), 2.40 (s, 3H)

Step E: [3-bromo-6-fluoro-2-(4-fluorophenyl)benzofuran-4-yl] acetate

2.96 g [6-fluoro-2-(4-fluorophenyl)benzofuran-4-yl] acetate (10.27 mmol) and 2.28 g NBS (12.84 mmol) were dissolved in 120 mL MeCN and stirred at 60 °C until no further conversion was observed. The solvent was then removed under reduced pressure, the residue was purified via flash chromatography using heptane and EtOAc as eluents to obtain [3-bromo-6-fluoro-2-(4-fluorophenyl)benzofuran-4-yl] acetate. ^[H NMR (400 MHz, DMSO-d₆): 8.07 (m, 2H), 7.69 (dd, IH), 7.44 (m, IH), 7.19 (m, 2H), 7.09 (dd, IH), 2.41 (s, 3H)

Step F: Préparation Id

ORIGINAL

3,35 g [3-bromo-6-fluoro-2-(4-fluorophenyl)benzofuran-4-yl] acetate (9.12 mmol) and

8.67 mL IM NaOEt in EtOH solution and 90 mL EtOH were stirred at r.t. under N₂ atmosphère until no further conversion was observed. The mixture was diluted with 50 mL aqueous cc, NH4CI solution and extracted with DCM. The combined organic phases were dried over Na₂SÛ4, filtered and the filtrate was concentrated to give Préparation Id. 'H NMR (400 MHz. DMSO-d_ti): 10.78 (s, IH), 8.06 (m, 2H), 7.40 (m, 2H), 7.06 (dd, IH), 6.54 (dd, IH)

Préparation 2a: Ethyl (2JÎ)-2-acetoxy-3-(2-hydroxyphenyI)propanoate and

Préparation 2b: Ethyl (2S)-2-acetoxy-3-(2-hydroxyphenyl)propanoatc

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

60.07 g 2-methylphenyl acetate (400 mmol) and 106.8 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 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 B: Préparations 2a and 2b

23.10 g anhydrous LiCl (545 mmol) and 65.36 g anhydrous ZnCl₂ (479,6 mmol) were placed in a 2 L flask, then dried at 160 °C under O.l mmHg 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 resuiting mixture was immersed into an ice-bath, and then stirred for 30 minutes. 100 g [2-(bromomethyl)phenyl] acetate (crude product from Step A, -436 mmol) was dissolved in 120 mL dry THF and was added to the precooled inorganics over 15 minutes. After addition of the reagent the resuiting mixture was stirred for 45 minutes while keeping the température between 0-5 °C. Then 64.82 mL ethyl 2-oxoacetate (654 mmol, 50 % in toluene) was added over 5 minutes and the resuiting mixture was stirred for another 15 minutes. The remaining inorganics were removed by filtration, and the filtrate was diluted with 500 mL MeOH. It was stirred until the

ORIGINAL

-43intramolecular acetyl group migration from the phenolic oxygen to the alkyl oxygen was complété. Then 30 mL acetic acid was added the volatiles were evaporated under reduced pressure. 350 mL water was added to the residue and it was extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaHCOj and with brine, and then dried over MgSO₄, filtered and the fîltrate was concentrated under reduced pressure. Then 100 mL hexane was added and it was stirred for 30 minutes at 0 °C. The formed whîte crystals were collected by filtration and washed with hexane. ’H NMR (500 MHz. DMSO-dô) 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)

The enantiomers were separated via chiral chromatography. Column: OD; Eluents: heptane / EtOH; the enantiomer eluting earlier was collected as Préparation 2b with

99.8 % ee and the enantiomer eluting later was collected as Préparation 2a with 99.9 % ee.

Préparation 2c: Ethyl (2Æ)-2-hydroxy-3-[2-|]2-(2-methoxyphenyl)pyriniidin-4-yl] methoxy] phenyl] propanoate

Step A: (2R)-2-hydroxy-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]niethoxy]phenyl] propanoic acid

30.3 g Préparation 2a (120 mmol), 38.9 g Préparation 5b (180 mmol) and 47.2 g triphenyl phosphine (180 mmol) were dissolved in 120 mL dry toluene, then 82 mL DEAD (180 mmol, 40 % in toluene) was added. The mixture was stirred at 50 °C under nitrogen atmosphère until no further conversion was observed. The volatiles were evaporated under reduced pressure. Then 300 mL DEE was added, the mixture was sonicated and filtered, washed with DEE. The fîltrate was concentrated under reduced pressure. The residue was dissolved in 125 mL THF, then 24 g NaOH (0.6 mol) dissolved in 125 mL water was added. The mixture was stirred at 50 °C until no further conversion was observed. The pl i was set to 5 with cc. HCl, and the volatiles were removed under reduced pressure. 100 mL water and 350 mL DCM were added, the mixture was stirred at 0 °C and the precipitate was filtered, washed with cold water and DCM and dried under reduced pressure to obtain (2Æ)-2-hydroxy-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoic acid. 'H-NMR (400 MHz, DMSO-d_f,) δ: 8.88 (d, IH), 7.80 (d, IH), 7.55 (dd, IH), 7.49-

ORIGINAL

-447.44 (m, IH), 7.26 (dd, IH), 7.17-7.H (m, 2H), 7.06 (t, IH), 6.98 (d, IH), 6.88 (t, IH),

5.22 (s, 2H), 4.50 (d, IH), 3.81 (dd. IH), 3.77 (s, 3H), 3.73 (dd, IH), 2.44 (dd, IH)

Step B: Préparation 2c

51.7 g (27?)-2-hydroxy-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl] propanoic acid (136 mmol) was dissolved in 520 mL EtOH, then 20 mL cc. H7SO4 was added. The mixture was stirred at 60 °C until no further conversion was observed. Then it was diluted with water, neutralized with aqueous saturated NaHCCfe solution and extracted with dichloromethane. The combined organic phases were dried over Na₂SO4, filtered and the filtrate was concentrated under reduced pressure and purified via flash chromatography using EtOAc and MeOH as eluents to obtain Préparation 2c. HRMS calculated for C₂3H₂₄N₂O₅: 408.1685, found: 409.1757 (M+H)

Préparation 2d: Ethyl (2A)-2-hy<lrox)-3-|2-||2-(2-inethoxyphenyl)pyrinii<iin-4-vl| methoxy]phenyl]propanoate

Préparation 2d was synthesized the way as Préparation 2c, but starting from Préparation 2b instead of Préparation 2a.

Préparation 2e: Ethyl (27ï)-2-hydroxy-3-(2-methoxyphenyl)propanoate and

Préparation 2f: Ethyl (2S)-2-hydroxy-3-(2-methoxyphcnyl)propanoate

The enantiomers of ethyl 2-hydroxy-3-(2-methoxyphenyl)propanoate were separated via chiral chromatography; Column: AD, Eluent: 2-PrOH; the enantiomer eluting earlier was collected as Préparation 2e with 99.8 % ee. The enantiomer eluting later was collected as Préparation 2f with 97.8 % ee.

Préparation 2g: Ethyl (27?)-2-hydroxy-3-[2-(pyrazin-2-ylinethoxy)phenyI|propanoate

Step A: Ethyl (2R)-2-acetoxy-3-[2-(pyrazin-2-ylmelhoxy)phenyl]propanoate eq. Préparation 2a, 2 eq. of pyrazin-2-ylmethanol and 2 eq. triphenylphosphine were dissolved in dry toluene (0.2M for the phénol), then 2 eq. DT AD was added. The mixture was stirred at 50 °C under nitrogen atmosphère. After reaching an appropriate conversion

ORIGINAL

-45the volatiles were removed under reduced pressure. The crude intermediate was purified via flash chromatography using heptane and EtOAc as eluents to obtain ethyl (2R)-2acetoxy-3-[2-(pyrazin-2-ylmethoxy)phenyl]propanoate.

Step B: Préparation 2g

Ethyl (2Æ)-2-acetoxy-3-[2-(pyrazin-2-ylmethoxy)phenyl]propanoate was dissolved in éthanol (0.5M) then 2 mol% NaOEt solution (l.OM in éthanol) was added. The resulting mixture was stirred at r.t. Additional NaOEt solution was added if conversion was not complété. The mixture was concentrated to half of its volume, then water and brine was added, and it was extracted with EtOAc. The combined organics were dried over Na2SÛ4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified via flash chromatography using DCM and methanol as eluents to obtain Préparation 2g. 'H NMR (400 MHz, DMSO-d₆) δ: 8.88 (s, IH), 8.64 (dd, 2H), 7.22-7.16 (m, 2H), 7.06 (d, IH), 6.89 (t, IH), 5.46 (d, IH), 5.27 (dd, 2H), 4.29 (dq, lH),4.00 (q, 2H), 3.09 (dd, IH), 2.79 (dd, IH), 1.08 (t, 3H)

Préparation 2h: Ethyl (2S)-2-hydroxy-3-[2-(2,2,2-trifluoroethoxy)phenyl|propanoate

Slep A: Ethyl (2S)-2-hydroxy-3-(2-hydroxyphenyl)propanoate

13,633 g Préparation 2b (54 mmol) was dissolved in 200 mL dry EtOH, then 30 mL NaOEt solution (IM in EtOH) was added and the mixture was stirred at r.t. If needed, the addition of the NaOEt solution was repeated until the cleavage of the acetyl group was complété. The mixture was diluted with 600 mL water and it was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The obtained ethyl (2S)-2-hydroxy-3-(2hydroxyphenyl)propanoate was used in the next step without further purification.

Slep B: Préparation 2h

9.18 g ethyl (2S^r)-2-hydroxy-3-(2-hydroxyphenyl)propanoate (43.7 mmol) was dissolved in 130 mL dry DMF, then 6.040 g K2CO3 (43.7 mmol) was added. After 5 minutes stirring

7.7 mL 2,2,2-trifluoroethyl trifluoromethanesulfonate (48 mmol) was added over 5 minutes. The resulting mixture was stirred until no further conversion was observed. The

ORIGINAL

-46reaction mixture was diluted with brine, then extracted with EtOAc. The combined organic layers were dried over Na₃SO4, fîltered and the filtrate was concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents. 'H NMR (500 MHz, DMSO-d₆) δ: 7.23 (t, IH), 7.18 (d, IH), 7.06 (d, IH), 6.95 (t, IH), 5.50 (d, IH), 4.75 (q, 2H), 4.22 (m, IH), 4.02 (q, 2H), 3.00 (dd, IH),

2.76 (dd, IH), l.09 (t, 3H)

Préparation 2i: (27?)-2-amino-3-|2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy| phenyl]propanoic acid

Step A: ethyl (2R)-2-amino-3-(2-hydroxyphenyl)propanoate hydrochloride

653 mg (27?)-2-amino-3-(2-hydroxyphenyl)propanoic acid hydrochloride (3.0 mmol) was dissolved in 6 mL HCl (I.25 M in EtOH) and stirred at 60 °C until no further conversion was observed. Then the reaction mixture was carefully diluted with 10% aqueous NaHCO₃ solution and extracted with DCM. The combined organic phase was dried over Na₂SO4, fîltered and the filtrate was concentrated under reduced pressure. The product should be stored in freezer.

’H NMR (500 MHz, DMSO-d₆) Ô: 7.05-6.95 (m, 2H), 6.72 (dm, IH), 6.69-6.63 (m, IH), 4.02 (q, 2H), 3.65 (dd. IH), 2.84 (dd, IH), 2.78 (dd, IH), l.12 (t, 3H)

HRMS calculated for C,, H j ₅NO₃: 209.1052; found: 210.1128 (M+H)

Step B: ethyl (2R)-2-amino-3-[2-[[2-(2-meihoxyphenyl)pyriniidin-4-yl]methoxy]phenyl] propanoate

3.96 g ethyl (2Æ)-2-amino-3-(2-hydroxyphenyl)propanoate hydrochloride (18.9 mmol) was dissolved in 200 mL dry toluene, then 5.69 g PPh₃ (21.7 mmol), 4.69 g Préparation 5b (21.7 mmol) were added and the mixture was heated to 35 °C, then 5.0 g DTAD (21.7 mmol) was added and the mixture was stirred at 45 °C until no further conversion was observed. Then the mixture was concentrated under reduced pressure and purified via flash chromatography using EtOAc and MeOH as eluents.

'H NMR (500 MHz, DMSO-d₆) δ: 8.92 (d, IH), 7.61 (d, IH), 7.55 (dd, IH), 7.46 (td, IH),

7.20 (td, IH), 7.17 (dd, IH), 7.15 (dd, IH), 7.06 (td, IH), 7.04 (dd, IH), 6.91 (td, IH),

ORIGINAL

-475.27/5.23 (d. 2H), 4.01 (q, 2H), 3.76 (s, 3H), 3.68 (dd, IH), 3.08 (br, 2H), 3.03/2.83 (dd, 2H), 1.07 (t, 3H)

HRMS calculated for C23H25N3O4: 407.1845; found: 408.1928 (M+H)

Step C: Préparation 2i

3.20 g ethyl (2/?)-2-ammo-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyI] propanoate (7.85 mmol) was dissolved in 10 mL THF, then 10 mL water and 420 mg LiOHxHjO (10 mmol) were added and the mixture was stirred at r.t. until the hydrolysis was complété. Then it was diluted with water and neutralized with 2 M aqueous HCl solution. The formed precipitate was filtered, washed with water and dried to obtain Préparation 2i.

’H NMR (500 MHz, DMSO-d₆) δ: 8.88 (d, IH), 7.82 (d, IH), 7.54 (dd, IH), 7.47 (m, IH), 7.27 (dd. IH), 7.23 (t, IH), 7.16 (d. IH), 7.06 (t. IH), 7.05 (d, IH), 6.93 (t, IH), 5.26 (s, 2H), 3.76 (s, 3H), 3.59 (dd, IH), 3.49/2.83 (dd, 2H)

HRMS calculated for C21H21N3O4: 379.1532; found: 380.1610 (M+H)

Préparation 3a: 2-Chloro-3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) phénol

Step A: (4-Bromo-2-chloro-phenoxy)-tnmelhyl-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 1.5 hours then concentrated under reduced pressure. The resulted crude product was used without further purification. 'H NMR (200 MHz, CDCI3): 7.49 (d, IH), 7.23 (dd, IH), 6.75 (d, 1 H), 0.26 (s, 9H)

Step B: 4-Bromo-2-chloro-3~methyl-phenol mL ⁿBuLi solution in hexanes (120 mmol, 2.5M in hexanes) 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 mixture was stirred for 30 minutes at the same température then 28.0 g (4-biOino-2-chloro-phenoxy)-trimethyl-silane (100 mmol) was added dropwise. After

2.5 hours, 21.3 g Mel (150 mmol) was added dropwise then the cooling bath was removed

ORIGINAL

-48and the mixture was stirred ovemight. The reaction was quenched with 100 mL aqueous NH₃ solution and 200 mL saturated aqueous NH4CI solution and extracted with EtOAc. The organic phase was dried over Na₂SO4, filtered and the filtrate was 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. The combined organic phases were concentrated under reduced pressure affording 19.0 g crude product, which was used without further purification. NMR (200 MHz, CDCl₃) δ: 7.32 (d, IH), 6.76 (d, l H), 5.62 (s, l H), 2.49 (s, 3H)

Step C: (4-Bromo-2-chloro-3-methyl-phenoxy)-trimethyl-silane

20.8 g HMDS (129 mmol) was added to the solution of 19.0 g 4-bromo-2-chloro-3-methylphenol (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 product was used without further purification. ’H NMR (200 MHz, CDCl₃) δ: 7.30 (d, IH), 6.63 (d. IH), 2.50 (s,3H), 0.28 (s, 9H)

Step D: Préparation 3a

A solution of 25.2 g (4-bromo-2-chloro-3-methyl-phenoxy)-trimethyl-silane (86.0 mmol) in 250 mL dry THF was cooled to -78 °C under argon and then 38 mL ⁿBuLi solution (94.6 mmol, 2.5M in hexanes) 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 allowed to warm up to r.t. Then the mixture was added to 200 mL saturated aqueous NH4CI solution and extracted with EtOAc. The combined organic layers were concentrated under reduced pressure and passed through a pad of silica gel using hexane and EtOAc as eluents. The crude product was recrystallized from a mixture of EtOAc and hexane to obtain Préparation 3a. ¹ FI NMR (500 MHz, DMSO-dû) δ: 10.40 (s, 1 H), 7.42 (d, IH), 6.80 (d, IH), 2.49 (s, 3H), 1.27 (s, 12H)

Préparation 3b: l-|2-[2-Chloro-3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yI)phenoxy]ethyl]-4-methyl-piperazine

10.0 g Préparation 3a (37.2 mmol,), 8.7 g 2-(4-methylpiperazin-l-yl)ethanol (60.3 mmol) and 15.8 g PPh₃ (60.3 mmol) were dissolved in 100 mL dry toluene and then 27 mL

ORIGINAL

-49DEAD (60.3 mmol, 40 % solution in toluene) was added dropwise. The mixture was stirred at 50 °C under argon atmosphère until no further conversion was observed. 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 CHCl₃ and MeOH as eluents. The resulting light brown oil was crystallized from hexane to give Préparation 3b as an off-white solid. 'H NMR (500 MHz, DMSO-de) δ: 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)

Préparation 3c: 2-(3-chloro-2-methy)-phenyl)-5,5-dimethyl-l,3,2-dioxaborinane

4.94 g (3-chloro-2-methylphenyl)boronic acid (29 mmol) and 3.021 g neopentyl-glycol (29 mmol) were stirred at r.t. in the presence of Amberlite 15IΓ (dried with toluene) until no further conversion was observed. The mixture was then filtered through Celite and washed with 2-Me-THF. The filtrate was concentrated under reduced pressure to obtain Préparation 3c. 'H NMR (400 MHz, CDCI3): 7.59 (dd, IH), 7.38 (dd, IH), 7.10 (t, IH),

3.79 (s, 4H), 2.57 (s, 3H), 1.05 (s, 6H)

Préparation 4: Ethyl (27î)-2-I5-bromo-6-(4-fluorophenyl)furo[2,3-rf]pyrimidin-4-yl] oxy-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl|methoxy|phenyl]propanoate

Using General procedure la and Préparation 2c as the appropriate lactic ester dérivative, Préparation 4 was obtained. MS: (M+H)⁺ =700.4

Préparation 5a: (E)-4-(Dimethylaniino)-l,l-dimethoxy-but-3-en-2-one

502.1 g i,l-dimethoxypropan-2-one (4.25 mol) and 506.4 g l.l-dimethoxy-AUV-dimethylmethanamine (4,25 mol) were mixed in a 2 L flask and stirred at 105 °C for 3 hours. The formed MeOH was removed continuously via distillation. When MeOH formation stopped (at 65 °C head température) the reaction mixture was vacuum distilled (decreasing the pressure slowly to 30 mbar) to remove side products and unreacted starting materials. The crude product was distilled at 0.1 mbar. Fractions were collected between 107-118 °C head température (bath température 160-165 °C) to give a yellow oil. NMR (500 MHz,

ORIGINAL

-50DMSO-d₆) δ: 7.59 (d, IH), 5.17 (d. IH), 4.42 (s, IH), 3.25 (s, 6H), 3.09 (s, 3H), 2.78 (s, 3H)

Préparation 5b: [2-(2-Methoxyphenyl)pyrimidin-4-yl]methanol

Step A: 4-(dimethoxymethyl)-2-(2-methoxyphenyl)pyrimidine

To the mixture of 1.2 eq. 2-methoxybenzamidine acetic acid sait and 1 eq. Préparation 5a in dry methanol (0.5 mL / mmol), 1.2 eq. NaOEt was added portionwise and the mixture was stirred at 75 °C until no further conversion was observed. Then the reaction mixture was cooled and concentrated under reduced pressure. Water was added to the residue and it was extracted with DCM. The combined organic layers were dried over MgSO₄, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to give 4-(dimethoxymethyl)-2-(2-methoxyphenyl)pyrimidine. 'H NMR (400 MHz. DMSO-d<,) δ:

8.93 (d, IH), 7.55-7.44 (m. 3H), 7.16 (d, IH), 7.06 (m, 1 H), 5.31 (s, 1 H), 3.76 (s, 3H), 3.37 (s, 6H)

Step B: Préparation 5b

261 mg 4-(dimethoxymethyl)-2-(2-metho.xyphenyl)pyrimidine (1.0 mmol) was dissolved in 2 mL HCI in dioxane (4M solution), then 2 mL water was added and this mixture was stirred at 50 °C for 16 hours. The reaction mixture was cooled to 0 °C. then 320 mg NaOH (8.0 mmol) was added portionwise. The pH was adjusted to 8 using 10 % aqueous K₂COj solution, then 76 mg sodium borohydride (2.0 mmol) was added and the mixture was stirred for 30 minutes at 0 °C. The reaction mixture was diluted with 5 mL water and extracted with EtOAc. The combined organic phases were dried over Na₂SO₄, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to give Préparation 5b. ‘H NMR (400 MHz, DMSO-d₆) Ô: 8.84 (d, IH), 7.50-7.42 (m, 3H), 7.14 (d, IH), 7.03 (m, IH), 5.66 (t, IH), 4.58 (d, 2H), 3.75 (s, 3H)

Préparation 6: (27î)-2-|(7-benzyl-5-bromo-6-ethyl-pyriOlo[2,3-r/]pyrimidin-4-yl) amino]-3-phenyl-propanoic acid

ORIGINAL

-5IStep A: 7-benzy!-5-bromo-4-chloro-6-elhyl-pyrrolo[2,3-d]pyrimidine

255 mg NaH (6.38 mmol) and 50 mL dry THF were charged into a 50 mL Schienk tube under N₂ atmosphère and the slurry was cooled to 0 °C. Then L792 g Préparation 1b (5.8 mmol) was added. After stirring the mixture for 30 minutes at 0 °C, 773 pL benzyl bromide (6.38 mmol) was added and the mixture was aliowed to warm up to r.t., and stirred until no further conversion was observed. The mixture was then diluted with saturated aqueous NH₄Cl solution, and extracted with DCM. The combined organic layers were washed with brine, dried over MgSO₄, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to obtain 7-benzyl-5-bromo-4-chloro~6-ethyl-pyrrolo[2,3-if[ pyrimidine.

'H NMR (400 MHz, CDCI3) δ: 8.60 (s, IH), 7.33-7.26 (m, 3H), 7.06-7.04 (m, 2H), 5.54 (s, 2H), 2.79 (q,2H), l .07 (t, 3H)

MS (M+H): 351.8

Step B: Préparation 6

Using General Procedure III and 7-benzyl-5-bromo-4-chloro-6-ethyl-pyrrolo[2,3-i/] pyrimidine as the appropriate 4-chloro-pyrrolo[2,3-i/]pyrimidine dérivative and D-phenylalanine as the appropriate amino acid dérivative, Préparation 6 was obtained. MS (M+H): 279.2

Préparation 7a: /V-|2-bcnzyloxy*6-(2,2-dibromovinyl)phenyl|-3-chloro-2-niethyI-4triisopropylsilyloxy-aniline

Step A: (4-Bromo-2-chloro-phenoxy)-triisopropyl-silane

200 g 4-bromo-2-chloro-phenol (0.97 mol) and 126 mL TIPSCI (Ί.18 mol) were dissolved in l .6 L DCM. 167 g îmidazole (2.45 mol) was added and the mixture was stirred at r.t. for 2 hours. Then the volatiles were evaporated under reduced pressure and the residue was dissolved in 1.5 L EtOAc. The mixture was washed with brine, dried over Na₂SO4, filtered and the filtrate was concentrated under reduced pressure. The triisopropylsilyl hydroxide impurity was removed by distillation (12O°C at 0.01 mmHg). The residue was filtered

ORIGINAL

-52through a short pad of silica with hexane and concentrated under reduced pressure. The product (colourless oil) was used in the next step without further purification.

'H NMR. (400 MHz. CDCI₃) ô: 7.49 (d. IH), 7.21 (dd, IH), 6.78 (d, IH), l.3l (septet, 3H),

I.l4 (d, 18H)

MS (El, 70 eV) m/z (% relative intensity, [ion]): 63 (30), 79 (24), 93 (41), 170 (17), 235 (19), 251 (16), 265 (24), 293 (23), 319 (77), 321 (100), 323 (28), 362 (l, [M⁺])

Step B: (4-Bromo-2-chloro-3-inethyl-phenoxy)-triisopropyl-silane

76.0 mL dry DIPA (0.54 mol) was dissolved in 1.2 L dry THF under argon atmosphère and

51.2 mL ⁿBuLi solution (0.512 mol, 10M in hexanes) was added dropwise at -78 °C. The mixture was stirred for 45 minutes at the same température. Then 178 g (4-bromo-2chloro-phenoxy)-triisopropyl-silane (0.488 mol) was added dropwise at -78 °C and the white suspension was stirred until no further conversion was observed. Then 36.5 mL Me! (0.586 mmol) was added at this température and the reaction mixture was stirred overnight without further cooling. The volatiles were evaporated under reduced pressure. The residue was dissolved in 1.5 L EtOAc, washed with brine. The organic phase was dried over Na₂SO4, filtered and the filtrate was concentrated under reduced pressure. The crude product was filtered through a short pad of silica using hexane as eluent and concentrated under reduced pressure to obtain the product as pale yellow oil. ’H NMR (400 MHz, CDCI3) ô: 7.30 (d, IH), 6.68 (d, IH), 2,53 (s, 3H), 1.32 (septet, 3H), 1.14 (d, 18H)

Step C: N-benzyl-3-chloro-2-niethyl-4-triisopropylsilyloxy-aniline

7.56 g (4-bromo-2-chloro-3-methyl-phenoxy)-triisopropyi-silane (20 mmol) and 4,29 g benzylamine (40 mmol) were dissolved in 16 mL dry toluene, then 450 mg Pd₂dba₃ (0.5 mmol), 450 mg X-Phos (l mmol) and 9.77 g Cs₂CO₃ (30 mmol) were added and the mixture was stirred at l00°C until no further conversion was observed. Then it was filtered through Celite, and the filtrate was concentrated under reduced pressure. The crude product was purified via flash chromatography using hexane and EtOAc as eluents to obtain A-benzyl-3-chloro-2-methyl-4-triisopropylsilyloxy-aniline.

Step D: 3-chloro-2-methyl-4-tnisopropyIsilyloxy-aniline

ORIGINAL

3.50 g jV-benzyl-3-chloro-2-methyl-4-triisopropylsilyloxy-aniline (8.66 mmol) was dissolved in 100 mL MeOH and 20 mL EtOAc, then 80 mg 10 % Pd/C was added and the mixture was stirred under 1 bar H₂ atmosphère until no further conversion was observed. Then it was fîitered through Celite, and the filtrate was concentrated under reduced pressure. The crude product was purified via flash chromatography using hexane and EtOAc as eluents to obtain 3-chloro-2-methyl-4-triisopropyIsilyloxy-aniline.

’H NMR (400 MHz, DMSO-d₆) δ: 6.58 (d, IH), 6.50 (d, IH), 4.68 (s, 2H), 2.11 (s, 3H),

1.24 (m,3H), 1.06 (d, 18H)

MS: (M+H)⁺ = 314.2

Step Et 3-benzyloxy-2-brotno-benzaldehyde

4.554 g 2-bromo-3-hydroxybenzaldehyde (22.65 mmol), 4.262 g benzyl bromide (24.92 mmol) and 4.696 g K₂CO₃ (33.98 mmol) were dissolved in 20 mL DMSO and stirred at 50 °C until no further conversion was observed. The mixture was then poured into water. The precipitate was fîitered to give 3-benzyloxy-2-bromo-benzaldehyde. MS (El, 70 eV) m/z (% relative intensity, [ion]): 65 (10), 91 (100), 290 (5, [M⁺]), 292 (5, [M⁺])

Step F; 3-benzyloxy-2-(3-chloro-2-tiieihyl-4-triisopropylsilyloxy-anilino)benzaldehyde

5.0 g 3-benzyloxy-2-bromo-benzaldehyde (17.17 mmol), 5.391 g 3-chloro-2-methyl-4triisopropylsilyloxy-aniline (17.17 mmol), 16.782 g Cs₂CO₃ (51.51 mmol), 393 mg Pd₂dba₃ (0.43 mmol) and 535 mg rac. BINAP (0.86 mmol) were mixed in 85 mL toluene and stirred at 120 °C until no further conversion was observed. The volatiles were removed under reduced pressure, the residue was purified via flash chromatography using heptane and EtOAc as eluents to obtain 3-benzyloxy-2-(3-chloro-2-methyl-4-triisopropylsilyloxyanilino) benzaldehyde. MS: (M+H/ = 524.2

Step G: Préparation 7a

7.7 g 3-benzyloxy-2-(3-chloro-2-methyl-4-triisopropylsilyloxy-anilino)benzaldehyde (14.69 mmol) and 7.308 g carbon tetrabromide (22.03 mmol) were dissolved in 160 mL DCM at 0 °C, then 11.56 g PPh₃ (44.07 mmol) was added. The mixture was stirred at r.t. until no further conversion was observed. Then the solvent was removed under reduced pressure, the residue was dissolved in Et₂O. Then heptane was added and the formed

ORIGINAL

-54precipitate was filtered, the filtrate was concentrated under reduced pressure. Then heptane was added, and the mixture was stirred for 10 minutes and filtered again. The filtrate was concentrated under reduced pressure and purified via flash chromatography using heptane and EtOAc as eluents to give Préparation 7a.

’H NMR (400 MHz, DMSO-d₆) δ: 7.28-7.23 (m, 5H), 7.19 (s, IH), 7.11 (dd, 2H), 7.05 (d, IH), 6.60 (d, IH), 6.41 (s, IH), 6.22 (d, IH), 5.08 (s, 2H), 2.30 (s, 3H), 1.25 (m, 3H), l.05 (d, 18H)

MS: (M+H)⁺ = 680.0

Préparation 7b: Ethyl (2Æ)-2-[l-[3-chIoro-2-methyl-4-[2-(4-methylpiperazin-l-yl) ethoxy]phenyl|-2-(4-fluorophenyl)indol-7-yl|oxy-3-(2-methoxyphenyl)propanoate

Step A: [4-[7-benzyloxy-2-(4-fliiorophenyl)indol-l-yl]-2-chloro-3-methyl-phenoxy]tri isopropyl -silane

2720 mg Préparation 7a (4 mmol), Hl9 mg 4-fluorophenylboronic acid (8 mmol), 4245 mg K.3PO4 (20 mmol), 90 mg Pd(OAc)₂ (0.4 mmol) and 328 mg SPhos (0.8 mmol) were mixed in 60 mL dry toluene under N₂ atmosphère and stirred at l00°C until no further conversion was observed. Then the solvent was removed under reduced pressure, the residue was purified via flash chromatography using heptane and EtOAc as eluents to give [4-[7-benzyloxy-2-(4-fluorophenyl)indol-1 -yl]-2-chloro-3-methyl-phenoxy]triisopropyl-silane. *H NMR (400 MHz, CDCI3) Ô: 7.33 (d, 2H), 7.29-1.22 (m, 2H), 7.18 (d, IH), 7.16 (d, IH), 7.10 (t. 2H), 6.94 (d, IH), 6.92-6.84 (m, 4H), 6.73 (s, IH), 6.61 (d, IH),

4.94 (d, 1 H), 4.89 (d, IH), 1.97 (s, 3H), 1.31 (m, 3H), 1.13 (t, 18H)

Step B: 4-[7-benzyloxy-2-(4-fluorophenyl)indol-l-yl]-2-chloro-3-methyl-phenol

2600 mg [4-[7-benzyloxy-2-(4-fluorophenyl)indol-1 -yl]-2-chloro-3-methy 1-phenoxy]triisopropyl-silane (2.96 mmol), 2.96 mL TBAF solution (2.96 mmol, IM in THF) and 50 mL THF were stirred at r.t. until no further conversion was observed. The solvent was then removed under reduced pressure, the residue was purified via flash chromatography using heptane and EtOAc as eluents to give 4-[7-benzyloxy-2-(4-fluorophenyl)indol-l-yl]2-chloro-3-methyl-phenol.

ORIGINAL

-55’HNMR (400 MHz. DMSO-dû) δ: 10.27 (br s, IH), 7.28-7.18 (m, 6H), 7.10 (t, 2H), 7.07-

6.99 (m, 2H), 6.85-6.77 (m,3H),6.75 (s, IH), 6.72 (d, lH), 4.95 (d, lH), 4.90 (d, IH), 1.75 (s, 3H)

MS: (M+H)⁺ = 458.0.

Step C: 7-benzyloxy-l -[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-2(4-fl uorophenyl) indol e

I.2 g 4-[7-benzyloxy-2-(4-fluorophenyl)indol-l-yl]-2-chIoro-3-methyl-phenol (2.1 mmol), 606 mg l-(2-hydroxyethyl)-4-methylpiperazine (4.2 mmol) and 2.1 g PPh₂ (6.3 mmol) were dissolved in 50 mL dry toluene under N₂ atmosphère and the mixture was cooled to 0 °C. Then I45l mg DTAD (6.3 mmol) was added and the mixture was heated to 45 °C and stirred until no further conversion was observed. The solvent was then removed under reduced pressure, the residue was purified via flash chromatography using heptane and EtOAc and MeOH as eluents to give 7-benzyioxy-l-[3-chloro-2-methyl-4-[2-(4methylpiperazin-l-yl)ethoxy]phenyl]-2-(4-fluorophenyl)indole. MS: (M+H)^T - 584.2

Step D: l-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-2-(4-fluoro phenylflndol- 7-ol

1280 mg 7-benzyloxy-l-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yI)ethoxy]phenyl]2-(4-fluorophenyl)indole (2.19 mmol) was dissolved in 100 mL EtOH, then 100 mg 10 % Pd/C was added. The mixture was stirred under l bar H₂ atmosphère at r.t. until no further conversion was observed. Then the mixture was filtered through Celite and the filtrate was concentrated to give l -[3-chloro-2-methyl-4-[2-(4-methylpiperazîn-l-yl)ethoxy]phenyl]-2(4-fluorophenyl)indol-7-ol.

‘H NMR (400 MHz, DMSO-d₆) δ: 9.04 (br s, IH), 7.25 (dd, 2H), 7.17-7.03 (m, 4H), 6.94 (d. IH), 6.86 (t, IH), 6.70 (s, IH), 6.47 (d, IH), 4.13 (m, 2H), 2.72 (t, 2H), 2.58-2.42 (br s, 4H), 2.40-2.17 (br s, 4H), 2.14 (s, 3H), l .86 (s, 3H)

MS: (M+H)⁺= 494.2

Step E: Préparation 7b

494 mg l -[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yI)ethoxy]phenyl]-2-(4-fluoro phenyl)indoI-7-ol (l mmol), 449 mg Préparation 2f (2 mmol) and 786 mg PPh₂ (3 mmol)

ORIGINAL

-56were dissolved in 10 mL dry toluene under N₂ atmosphère and the mixture was cooled to 0 °C. Then 691 mg DTAD (3 mmol) was added and the mixture was heated to 45 °C and stirred until no further conversion was observed. The solvent was then removed under reduced pressure, the residue was purified via flash chromatography using heptane and

EtOAc and MeOH as eluents to give Préparation 7b as a mixture of diastereoisomers.

‘H NMR (500 MHz, DMSO-d₆) δ: 7.43/6.98 (d, IH), 7.28 (m, 2H), 7.23/7.24 (d, IH), 7.17/7.18 (t, IH), 7.14 (m, 2H), 7.12/6.88 (d, IH), 6.95/6.94 (t, IH), 6.91/6.91 (d, 1 H), 6.79/6.78 (s, IH), 6.73/6.75 (t, IH), 6.52/6.60 (d, IH), 6.46/6.40 (d. IH), 4.85/4.76 (dd, IH), 4.25-4.01 (m, 2H), 4.01-3.89 (m, 2H), 3.77/3.76 (s, 3H), 2.70-2.60 (m, 3H), 2.54-2.30 (m, 5H), 2.21 (brs,4H), 2.13/2.09 (s, 3H), 1.59/2.08 (s, 3H), 0.99/0.98 (t, 3H)

MS: (M+H)⁺ = 700.0

Example 1 : (2Æ)-2-{[5-{3-chloro-2-methyl-4-|2-(4-methylpiperazin-l-yI)ethoxy] phenyl}-6-(4-nuorophenyI)furo[2,3-rf]pyriniidin-4-yi]oxy}-3-(2-{[2-(2-methoxyphenyl) pyrimidin-4-yl]methoxy}phenyl)propanoic acid

Using General Procedure II and Préparation 4 as the appropriate 5-bromo-furo[2,3-i/| pyrimidine dérivative and Préparation 3b as the appropriate boronic acid dérivative. Example 1 was obtained as a mixture of diastereoisomers. HRMS calculated for C47H44CIFN6O7: 858.2944, found: 430.1547 and 430.1555 (M+2H)

Example 2: (2Æ)-2-{|5-{3-chloro-2-ethvI-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl}20 6-(4-fluoroplienyl)furo|2,3-r/]pyrimidin-4-yI]oxy}-3-(2-{[2-(2-methoxyphenyl) pyrimidin-4-yl|methoxy}phenyl)propanoic acid

Siep A : l-[2-(4-bromo-2-chloro-phenoxy)ethyl]-4-methyl-piperazine

10.373 g 4-bromo-2-chlorophenol (50 mmol), 14.442 g 2-(4-methylpiperazin-l-yl)ethanol (100 mmol) and 26.229 g PPI13 (100 mmol) were dissolved in 250 mL dry toluene under 25 N₂ atmosphère, then 23.027 g DTAD (100 mmol) was added. The mixture was stirred at °C until no further conversion was observed. The volatiles were evaporated under

ORIGINAL

-57reduced pressure and the residue was purified via flash chromatography using EtOAc and MeOH as eluents. MS (M+H): 333.0

Step B'. l-[2-(4-bromo-2-chloro-3-ethyl-phenoxy)ethyl]-4-methyl-piperazine

2.0 g l-[2-(4-bromo-2-chloro-phenoxy)ethyl]-4-methyl-piperazine (6 mmol) was dissolved in 50 mL dry THF under N? atmosphère and was cooled to -78 °C. 6 mL LDA solution (12 mmol in 2M THF) was added and the mixture was stirred for 3 hours, then 982 mg iodoethane (6.3 mmol) was added and the mixture was allowed to warm up to r.t. It was quenched with saturated aqueous NH4CI solution, extracted with EtOAc. The combined organic layer was dried over Na2SO₄, filtered and the filtrate was concentrated under reduced pressure. MS (M+H): 360.8

Step C: l-[2-[2-chloro-3-ethyl-4-(4,4,5,5-letramethyl-i,3,2-dioxaborolan-2-yl)phenoxy] ethyI]-4-inethyl-pîperazme

2099 mg l-[2-(4-bromo-2-chloro-3-ethyl-phenoxy)ethyl]-4-methyl-piperazine (5.8 mmol) was dissolved in 30 mL dry THF under N2 atmosphère and was cooled to -78 °C. 4.65 mL ⁿBuLi solution (l L61 mmol in 2.5M THF) was added dropwise. It was stirred for 5 hours, then 2.6 mL 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaboroIane (12.77 mmol) was added and the mixture was stirred for 30 minutes. Then it was allowed to warm up to r.t. and it was concentrated under reduced pressure. The crude product was purified via flash chromatography using EtOAc and MeOH as eluents. MS (M+H): 409.2

Step D: Example 2

Using General Procedure II and Préparation 4 as the appropriate 5-bromo-furo[2,3-cZ] pyrimidine derivative and l-[2-[2-chloro-3-ethyl-4-(4,4,5,5-tetramethyl-1,3,2dioxaboro!an-2-yl)phenoxy]ethyl]-4-methyl-piperazine as the appropriate boronic acid derivative, Example 2 was obtained as a mixture of diastereoisomers. HRMS calculated for C48H4₆C1FN₆O₇: 872.3101, found: 437.1620 and 437.1620 (M+2H)

Example 3: (27?)-2-{|5-{3-chloro-2-mcthyl-4-[2-(4-mcthylpiperazin-l-yl)ethoxy| phenyl}-6-(4-fluorophenyl)furo[2,3-f/]pyrimidin-4-yl]oxy}-3-(2-rnethoxyphenyl) propanoic acid

ORIGINAL

-58Step A: Ethyl (2R)-2-[5-btx)mo-6-(4-fluorophenyl)fiiro[2,3-à]pyrimidm-4-yl]oxy-3-(2methoxyphenyl)propanoate

Using General procedure la and Préparation 2e as the appropriate lactic ester dérivative, ethyl (2Æ)-2-[5-bromo-6-(4-fluorophenyl)furo[2,3-i/]pyrimidin-4-yl]oxy-3-(2-methoxy phenyl)propanoate was obtained. NMR (400 MHz, DMSO-dô): 8.53 (s, IH), 8.10 (m, 2H), 7.47-7.36 (m, 3H), 7.23 (m, IH), 6.96 (m, IH), 6.89 (t, IH), 5.58 (m, IH), 4.12 (q, 2H), 3.79 (s, 3H), 3.36 (m, IH), 3.21 (m, 1 H), 1.11 (t, 3H)

Step B: Example 3

Using General Procedure II and ethyl (2Æ)-2-[5-bromo-6-(4-fluorophenyl)furo[2,3-c/] pyrimidin-4-yl]oxy-3-(2-methoxyphenyl)propanoate as the appropriate 5-bromo-furo [2,3-rf]pyrimidine dérivative and Préparation 3b as the appropriate boronic acid dérivative, Example 3 was obtained as a mixture of diastereoisomers. HRMS calculated for C36H36CIFN4O6: 674.2307, found: 675.2367 and 675.2364 (M+H)

Example 4: (2/f)-2-{[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy] phenyl}-6-(4-fluorophenyl)furo|2,3-i/|pyrimidin-4-yl|oxy}-3-|2-(pyrazin-2-ylmethoxy) phenyl]propanoic acid

Step A: Ethyl (2R)-2-[5-bromo-6-(4-flitorophenyl)furo[2,3-<3]pyrimidin-4-yl]oxy-3-[2(pyrazin-2-ylmethoxy)phenyl]propanoate

Using General procedure la and Préparation 2g as the appropriate lactic ester dérivative, ethyl (2/?)-2-[5-bromo-6-(4-fluorophenyl)furo[2,3-iZ]pyrimidin-4-yl]oxy-3-[2-(pyrazin-2ylmethoxy)phenyl]propanoate was obtained. MS: (M+H)⁺ = 595.0

Step B: Example 4

Using General Procedure II and ethyl (27?)-2-[5-bromo-6-(4-lluorophenyl)furo[2,3-if| pyrimidin-4-yl]oxy-3-[2-(pyrazin-2-ylmethoxy)phenyI]propanoate as the appropriate

5-bromo-furo[2,3-i/]pyrimidine dérivative and Préparation 3b as the appropriate boronic acid dérivative, Example 4 was obtained as a mixture of diastereoisomers. HRMS calculated for C4oH₃₈C1FN₆0₆: 752.2525, found: 753.2645 and 753.2606 (M+H)

ORIGINAL

-59Example 5: (2/f)-2-{[6-(5-chlorofuran“2-yl)-5-{3-chloro-2-methyl-4-|2-(4-methyl piperazin-l-yl)ethoxy|phenyl}furo[2,3-rf]pjTÏmidin-4-yl]oxy}-3-[2-(pyrazin-2-yl niethoxy)phenyl]propanoic acid

Step A: 2-[2-(2-furyl)-2-oxo-ethyl]propanedinitrile

46.2 mL IM NaOEt solution in EtOH (46.2 mmol) and 400 mL EtOH were cooled to 0 °C and 3.2 g malononitrile (48.4 mmol) was added. The mixture was stirred at 0 °C for l hour, then 8.35 g 2-bromo-l-(2-furyl)ethanone (44 mmol) was added. The mixture was stirred at 0 °C for l hour, then at r.t. until no further conversion was observed. The volatiles were removed under reduced pressure, the residue was digerated in Et₂O, fîltered, then purified 10 via flash chromatography using DCM and EtOAc as eluents to obtain 2-[2-(2-furyl)-2-oxoethyl]propanedînitrile. MS: (M+H)⁺ = 175.2

Step B: 2-amino-5-(2-furyl)furan-3-carbonitrile

4.587 g 2-[2-(2-furyl)-2-oxo-ethyl]propanedinitrile (26.34 mmol) was dissolved in 150 mL EtOH and 4.6 g Amberlite 15H was added. The mixture was stirred at 90 °C until no 15 further conversion was observed. The mixture was then fîltered, washed with DCM and EtOAc. The filtrate was concentrated under reduced pressure and purified via flash chromatography using heptane and EtOAc as eluents to obtain 2-amino-5-(2-furyl)furan-3carbonitrile. MS: (M+H)⁺ = 175.4

Step C: 6-(2-furyl)-3\d-furo[2,3-d]pyrûnidin-4-one

1310 mg 2-amino-5-(2-furyl)furan-3-carbonitrile (7.52 mmol) and 30 mL acetic formic anhydride were placed in a flask and stirred at r.t. for 30 minutes. Then the volatiles were evaporated under reduced pressure and the residue was dissolved in 60 mL AcOH, and irradiated at 180 °C for 50 minutes. The mixture was cooled to r.t., and the crude product was purified via flash chromatography using heptane and EtOAc as eluents to obtain

6-(2-furyl)-3/7-furo[2,3-i/]pyrimidin-4-one. ’H NMR (400 MHz, DMSO-d₆): 12.68 (br s, l H), 8.14 (s, l H), 7.84 (m, l H), 7.08 (s, l H), 6.94 (d, l H), 6.67 (m, l H)

Step D: 6-(5-chloro-2-furyl)-3H-furo[2,3-d]pyrimidin-4-one

ORIGINAL

-601.183 g 6-(2-furyl)-3i/-furo[2,3-J]pynmidin-4-one (5.85 mmol) was dissolved in 55 mL THF and 860 mg NCS (6.44 mmol) was added. The mixture was stirred at 40 °C until no further conversion was observed. The mixture was cooled to 0 °C, and the precipitate was filtered. and dried to obtain 6-(5-chloro-2-furyl)-3/7-furo[2,3-i7]pyrimidin-4-one. MS: (M+H)⁺ = 237.0

Step E: 5-bromo-6-(5-chloro-2-furyl)-3}3-furo[2,3-<3]pyrimidin-4-one)

1000 mg 6-(5-chloro-2-furyl)-3/7-furo[2,3-i/]pyrimidin-4-one (4.23 mmol) was dissolved in 40 mL AcOH, then 776 mg bromine (4.86 mmol) was added. The mixture was stirred at 40 °C until no further conversion was observed. Then the volatiles were removed under reduced pressure. The residue was digerated with DCM then filtered to obtain 5-bromo-6(5-chloro-2-furyl)-3//-furo[2,3-i/]pyriniidin-4-onc. MS: (M-H)⁺ = 314.8

Step F: 5-bromo-4-chloro-6-(5-chloro-2-fitryl)furo[2,3-à]pyrimidine

1110 mg 5-bromo-6-(5-chloro-2-furyl)-3i/-furo[2,3-i/|pyrimidin-4-one (3.52 mmol) was dissolved in 8.21 mL POC1₃ (88.1 mmol) then 447 pL DMA (3.52 mmol) was added. The mixture was stirred at 110 °C until no further conversion was observed. The mixture was then cooled to -78 °C and ice was added. It was sonicated then the precipitate was filtered. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to obtain 5-bromo-4-chloro-6-(5-chloro-2-furyl)furo[2,3-i/]pyrimidine. MS: (M+H)⁺ = 335.0

Step G: Ethyl (2R)-2-[5-bromo-6-(5-chloro-2-furyl)furo[2,3-à]pyrimidin-4-yl]oxy-3-[2(pyrazin-2-ylmelhoxy)phenyl]propanoate eq. 5-bromo-4-chloro-6-(5-chloro-2-furyl)furo[2,3-i7]pyrimidine, 2 eq. Préparation 2g.

mL/mmol 'BuOH and 5 eq. CS2CO3 were placed in a flask and stirred at 55 °C until no further conversion was observed. The mixture was then concentrated under reduced pressure, diluted with brine, neutralized with IM aqueous HCl solution, and extracted with EtOAc. The combined organic phases were dried over Na₂SO₄, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to give ethyl (2/?)-2-[5-bromo-6-(5ORIGINAL

-61chloro-2-furyl)furo[2,3-rf]pyrîmidin-4-yl]oxy-3-[2-(pyrazin-2-ylmethoxy)phenyl] propanoate. MS: (M+H)⁺ = 601.0

Step H: Example 5

Using General Procedure II and ethyl (2Æ)-2-[5-bromo-6-(5-chloro-2-furyl)furo[2,3-i/J pyrimidin-4-yl]oxy-3-[2-(pyrazin-2-ylmethoxy)phenyl]propanoate as the appropriate

5-bromo-furo[2,3-<7]pyrimidine derivative and Préparation 3b as the appropriate boronic acid derivative, Example 5 was obtained as a mixture of diastereoisomers. HRMS calculated for C₃₈H3₆Cl₂N₆O₇: 758.2023, found: 759.2119 and 759.2156 (M+H)

Example 6: (2Æ)-3-{2-[(l-/ert-buty l-lH-pyrazol-5-yl)methoxy]phenyl}-2-{|5-{3-chloro4-[2-(dimethylamino)ethoxy]-2-methylphenyl}-6-(4-fluorophenyl)furo[2,3-rf] pyrimidin-4-yl]oxy}propanoic acid

Step A: 1 -\ert-biityl-5-(dimethoxymethyl)-liï-pyrazole

1.2 eq. /erz-butylhydrazine hydrochloride and 1 eq. Préparation 5a was dissolved in dry methanol (0.5 mL/mmol), then 1.2 eq NaOEt was added portionwise and the mixture was stirred at 75 °C for 2 hours. The reaction mixture was cooled and concentrated under reduced pressure. The residue was diluted with water and it was extracted with DCM. The combined organic phases were dried over MgSCC, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to give l-/<?r/-butyl-5-(dimethoxymethyl)-l/Z-pyrazole. ‘H NMR (400 MHz, DMSO-d₆) δ: 7.34 (d, IH), 6.34 (d. IH), 5.74 (s, IH), 3.24 (s, 6H),

1.57 (s, 9H). We also obtained l-/e/7-butyl-3-(dimethoxymethyl)-l/7-pyrazole. 'H NMR (400 MHz, DMSO-dô) δ: 7.75 (d, IH), 6.18 (d, IH), 5.34 (s, IH), 3.24 (s, 6H), 1.50 (s, 9H)

Step B: (1 Aert-Butyl-lW-pyrazol-5-yl)methanol eq. l-/e/7-butyl-5-(dimethoxymethyl)-l/f-pyrazole was stirred with IM aqueous HCl solution (3 mL/mmol) at 50 °C until no further conversion was observed. The reaction mixture was cooled to 0 °C, then 2.85 eq. solid NaOH was added portionwise. The pH was adjusted to 8 using 10% aqueous K₂CO₃ solution, then 2 eq. sodium borohydride was added portionwise, keeping the température below 5 °C and stirred at 0 °C until no further

ORIGINAL

-62conversion was observed. The mixture was extracted with EtOAc, the combined organic phases were dried over Na₂SO₄, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc to obtain (l-/er/-butyl-lH-pyrazol-5-yl)methanol. ’H NMR (400 MHz, DMSO-d₆) δ: 7.27 (d, l H), 6.19 (d, l H), 5.31 (t, l H), 4.61 (d, 2H), l .56 (s, 9H)

Step C: (2R)-3-[2-[(2Aer(-butylpyrazol-3-yl)methoxy]phenyl]-2-hydroxy-propanoic acid

2.51 g Préparation 2a (9.96 mmol), 2.0 g (l-/e/7-butyl-lA-pyrazol-5-yl)methanol (l3 mmol) and 3.39 g triphenyl phosphine (13 mmol) were dissolved in 12 mL dry toluene, then 5.9 mL DEAD (13 mmol) was added. The mixture was stirred at 50 °C under nitrogen atmosphère until no further conversion was observed. The volatiles were evaporated under reduced pressure, Then 30 mL Et₂O was added, the mixture was sonicated and filtered (to remove PPh₃ and PPh₃O). The filtrate was concentrated under reduced pressure. The residue was dissolved in THF, and then 2 g NaOH dissolved in 8 mL water w^ras added. The mixture was stirred at 50 °C until no further conversion was observed. Then it was acidified with 2M aqueous HCl solution, and THF was removed under reduced pressure. The residue was extracted with DCM, dried over Na₂SO₄, filtered and the filtrate was concentrated under reduced pressure to obtain (2Æ)-3-[2-[(2-ie/7-butylpyrazol-3yl)methoxy]phenyl]-2-hydroxy-propanoic acid. MS (M+H): 319.0

Step D: Ethyl (2R)-3-[2-[(2-tecPbutylpyrazol-3-yl)methoxy]phenyl]-2-hydroxy-propanoate

7.2 g (2Æ)-3-[2-[(2-/e/7-butylpyrazol-3-yl)methoxy]phenyl]-2-hydroxy-propanoic acid was dissolved in 75 mL EtOH, then 2 mL cc. H₂SO₄ was added. The mixture was stirred at 60 °C until no further conversion was observed. Then it was diluted with water, neutralized with saturated aqueous NaHCO₃ solution and extracted with dichloromethane. The combined organic phases were dried over Na₂SO₄, filtered and the filtrate was concentrated under reduced pressure and purified via flash chromatography using EtOAc and MeOH as eluents to obtain ethyl (2Æ)-3-[2-[(2-ie/7-butylpyrazol-3-yl)methoxy] phenyl]-2-hydroxy-propanoate. MS (M+H): 347.0

Step E: Ethyl (2ty-2-[5-bromo-6-(4-fluorophenyl)furo[2,3-à]pyrimidin-4-yl]oxy-3-[2-[(2\ext-butylpyrazol-3-yl)niethoxy]phenyl]propanoate

ORIGINAL

-63Using General procedure la and ethyl (2/?)-3-[2-[(2-Zc/7-butylpyrazol-3-yl)methoxy] phcnylJ-2-hydroxy-propanoate as the appropriate lactic ester dérivative, ethyl (2Æ)-2-[5bromo-6-(4-fluorophenyl)furo[2,3-iT]pyrimidin-4-yl]oxy-3-[2-[(2-/e/7-butyl-pyrazol-3-yl) methoxy]phenyl]propanoate was obtained. MS (M+H): 636.6-638.6

Step F: 2-[2-chloro-3-methyl-4-(4,4,5,54etramethyl-l,3,2-dioxaborolan-2-yl)phenoxy]N. N -dimelhyl-ethanamine

10.0 g Préparation 3a (37.2 mmol), 5.366 g N,N-dimethylethanolamine (60.3 mmol) and

15.8 g PPh₃ (60.3 mmol) were dissolved in 100 mL dry toluene and then 27 mL DEAD (60.3 mmol, 40 % solution in toluene) was added dropwise. The mixture was stirred at 50 °C under argon atmosphère until no further conversion was observed. 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 CHCl₃ and MeOH as eluents. The resulting light brown oil was crystallized from hexane to give 2-[2-chloro-3methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy]-/V,V-dimethylethanamine.

’H NMR (200 MHz. CDCl₃) δ: 7.63 (d, IH), 6.75 (d, IH), 4.15 (t, 2H), 2.81 (t, 2H), 2.60 (s, 3H), 2.38 (s, 6H), 1.33 (s. 12H) MS (M+H): 340.1

Step G: Example 6

Using General Procedure II and ethyl (2/?)-2-[5-bromo-6-(4-fluorophenyl)furo[2,3-</] pyrimidin-4-yl]oxy-3-[2-[(2-/ei7-butylpyrazol-3-yl)methoxy]phenyl]propanoate as the appropriate 5-bromo-furo[2,3-d]pyrimidine dérivative and 2-[2-chloro-3-methyl-4(4,4,5,5-tetramethyl-l ,3.2-dioxaborolan-2-yl)phenoxy]-AOV-dimethyl-ethananiinc as the appropriate boronic acid dérivative, Example 6 was obtained. HRMS calculated for C₄oH4iClFN₅0₆: 741.2729, found: 742.2813 and 742.2808 (M+H) for the two diastereomers

Example 7: A^r-[(5S'_fl)-5-{3-chloro-2-methyl-4-|2-(4-methylpiperazin-lyl)ethoxy|phenyI}-6-(4-fluorophenyl)furo[2,3-rfJpyrimidin-4-yl]-2-methoxy-DORIGINAL

-64phenylalanine

Step A: (2K)-2-[[5-bromo-6-(4-fluorophenyl)furo[2,3-à]pyrimidin-4-yl]amino]-3-(2melhoxyphenyljpropanoic acid

Using General Procedure Ib and (27i)-2-amino-3-(2-methoxyphenyl)propanoic acid as the appropriate amino acid dérivative, (2/?)-2-[[5-bromo-6-(4-fluorophenyl)furo[2p-i/] pyrimidin-4-yI]amino]-3-(2-methoxyphenyl)propanoic acid was obtained. MS: (M+H)⁺ =

487.8

Step B: Example 1 eq. (27?)-2-[[5-bromo-6-(4-fluorophenyl)furo[2,3-i/]pyrimidin-4-yl]amino]-3-(2-methoxy phenyl)propanoic acid, 1.5 eq. Préparation 3b, 5 mol% AtaPhos and 2 eq. CS2CO3 were stirred in a 1:1 mixture of THF and water (10 mL/mmol 5-bromo-furo[2,3-i/]pyrimidine dérivative) and heated to 110°C in a MW reactor until no further conversion was observed. Then the mixture was diluted with brine, the pH was set to 4 with 1M aqueous HCl solution, and was extracted with DCM. The combined organic phases were dried over MgSO₄, filtered and the filtrate was concentrated under reduced pressure. The obtained mixture of diastereoisomers were purified and separated via HILIC chromatography. Example 7 was obtained as the later eluting diastereoisomer. HRMS calculated for C36H37CIFN5O5: 673.2467, found: 337.6286 (M+2H)

Exaniple 8: /V-[(55_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)etlioxy]phenyl}-6-(4-fluorophenyl)furo[2,3-if]pyrimidin-4-yl|-2-{[2-(2methoxyphenyl)pyrimidin-4-yl]methoxy}-Z)-phenylalanine and

Examplc 9: /V-[(5R_a)-5-{3-chloro-2-niethyl-4-|2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(4-f1uorophenyl)furo|2,3-i/|pyrimidin-4-yI]-2-{|2-(2methoxyphenyl)pyrimidin-4-yl|methoxy}-£>-phenyIalanine

Step A: (2ty-2-[[5d>romo-6-(4-fluorophenyl)furo[2,3-à]pyrimidin-4-yl]amino]-3-(2hydroxyphenyl)propani) ic acici

ORIGINAL

-65Using General Procedure Ib and D-(Æ)-2-amino-3-(2-hydroxy-phenyl)-propionic acid as the appropriate amino acid dérivative, (27î)-2-[[5-bromo-6-(4-fluorophenyl)furo[2,3-iZ] pyrimidin-4-yl]amino]-3-(2-hydroxyphenyl)propanoic acid was obtained, MS: (M+H) = 473,6

Step B: Ethyl (2V.)-2-[[5-bromo-6-(4-Jluorophenyl)furo[2,3-d]pyrimidin-4-yl] amino]-3-[2[[2-(2-methoxyphenyl)pyrimidin-5-yl]methoxy]phenyl]propanoate

163 mg (2Æ)-2-[[5-bromo-6-(4-fluorophenyl)furo[2,3-</]pyrimidin-4-yI]amino]-3-(2hydroxyphenyl)propanoic acid was dissolved in 3 mL HCl solution (1.25M in EtOH) and stirred at 60 °C until no further conversion was bserved. The mixture was concentrated under reduced pressure, diluted with water. The precipitate was filtered and purified via flash chromatography using heptane and EtOAc as eluents to obtain ethyl (27?)-2-[[5bromo-6-(4-fluorophenyl)furo[2,3-t/]pyrimidin-4-yl]amino]-3-(2-hydroxyphenyl) propanoate. MS: (M+H)⁺ = 501.6

Step C: Ethyl (2^)-2-[[5-bromo-6-(4-flttorophenyl)furo[2,3-d]pyrhnidin-4-yl]amino]-3-[2[[2 - (2-methoxyphenyl) pyrim idin-5 -y!] methoxy]phenyl]propa> loate

500 mg ethyl (2Æ)-2-[[5-bromo-6-(4-fluorophenyl)furo[2,3-</|pyrimidin-4-yl]amino]-3-(2hydroxyphenyl)propanoate (1 mmol), 540 mg Préparation 5b (2.5 mmol) and 656 mg PPh₃ (2.5 mmol) were dissolved in 20 mL dry toluene under N₂ atmosphère, then 576 mg DTAD (2.5 mmol) was added. The mixture was stirred at 60 °C until no further conversion was observed. The mixture was then concentrated under reduced pressure and purified via flash chromatography using heptane and EtOAc as eluents to give ethyl (2Æ)-2-[[5-bromo-

6-(4-fluorophenyl)furo[2,3-i/]pyrimidin-4-yl]amino]-3-[2-[[2-(2-methoxyphenyl) pyrimidin-5-yl]methoxy]phenyl]propanoate. HRMS (M+H)⁺: 698.1402

Step D: Examples 8 and 9 eq. ethyl (27?)-2-[[5-bromo-6-(4-fluoiOphenyl)furo[2,3-i/]pyrimidin-4-yl]amino]-3-[2[[2-(2-methoxyphenyl)pyrimidin-5-yl]methoxy]phenyI]propanoate, 1.5 eq.

Préparation 3b, 5 mol% AtaPhos and 2 eq. Cs₂CO₃ were stirred in a 1:1 mixture of THF and water (10 mL/mmol 5-bromo-furo[2,3-</]pyrimidine dérivative) and heated to 70 °C and stirred until no further conversion was observed. Then the mixture was diluted with

ORIGINAL

- 66brine, the pH was set to 4 with IM aqueous HCl solution, and was extracted with DCM. The combined organic phases were dried over MgSO₄, filtered and the filtrate was concentrated under reduced pressure. The crude intermediate was purified via flash chromatography using DCM and MeOH as eluents. Then it was dissolved in dioxaneiwater l:l (20 mL/mmol) and 10 eq. LiOH*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, extracted with DCM. The combined organic phases were dried over Na₂SO₄, filtered and the filtrate was concentrated under reduced pressure to obtain a mixture of diastereoisomers. They were separated and purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents. Example 8 was obtained as the earlier eluting diastereoisomer. HRMS calculated for C47H45CIFN7O6: 857.3104, found: 429.6637 (M+2H). Example 9 was obtained as the later eluting diastereoisomer. HRMS calculated for C₄7H₄5C1FN7O₆: 857.3104, found: 429.6648 (M+2H)

Example 10: /V-|7-methyl-5-(naplithalen-l-yl)-7//-pyrrolo|2,3-rf|pyrimidin-4-yl]-Z>phcnylalaninc

Step A : 4-chloro-5-iodo-7-methyl-pyrrolo[2,3-à]pyrimidine

Into a 50 mL Schlenk tube under N₂ atmosphère 220 mg NaH (5.5 mmol) and 40 mL dry THF were charged and the slurry was cooled to 0 °C. Then 1471 mg 4-chloro-5-iodo-7f/pyrrolo[2,3-i/]pyrimidine (5 mmol) was added. After 30 minutes stirring, 346 pL Mel (5.5 mmol) was added and the mixture was allowed to warrn up to r.t., and stirred until no further conversion was observed. The mixture was then diluted with saturated aqueous NH4CI solution, and extracted with DCM. The combined organic layers were washed with brine, dried over MgSO₄, filtered and the filtrate was concentrated under reduced pressure to obtain 4-chloro-5-iodo-7-methyl-pyrrolo[2,3-t/]pyrimîdme.

’H NMR (400 MHz, DMSO-d₆) δ: 8.65 (s, IH), 7.98 (s, IH), 3.83 (s, 3H) MS: (M+H)⁺ = 294.0

Step B: 4-chloro- 7-methyl-5-(/-naphthyl)pyrrolo[2,3-dJpyrimidine

ORIGINAL

-67l eq, 4-chloro-5-iodo-7-methyl-pyrrolo[2,3-c/]pyrimidine, l.l eq. l-naphthaleneboronic acid neopentyl glycol ester, l.l eq. silver carbonate, O.l5 eq, Pd(PPh₃)₄ and 2-Me-THF (l5mL/mmol 5-iodo-pyrrolo[2,3-fr]pyrimidine dérivative) were stirred under N₂ atmosphère at 110 °C until no further conversion was observed. The mixture was diiuted with brine, neutralized with IM aqueous HCl solution, and extracted with DCM. The combined organic phases were dried over Na₂SO₄, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to give 4-chloro-7-methyl-5-(lnaphthyl)pyrrolo[2,3-<7]pyrimidine. MS: (M+H)⁺ = 294.2

Step C: Example 10

Using General Procedure III and 4-chloro-7-methyl-5-(l-naphthyl)pyrrolo[2,3-i/] pyrimidine as the appropriate 4-chloro-pyrrolo[2,3-i/]pyrimidine dérivative and D-phenylalanine as the appropriate amino acid dérivative, Example 10 was obtained. HRMS calculated for C₂6H₂₂N₄O₂: 422.1743, found: 423.1804 (M+H)

Example 11: A'-|5-(naphthalen-l-yl)-7/7-pyrrolo|2,3-<'/|pyrimidin-4-yl|-Dphenylalanine

Step A: 7-(benzenesïtlfonyl)-4-chloro-5-iodo-pyrrolo[2.3-d]pyrimidine

Into a 50 mL Schlenk tube under N₂ atmosphère 220 mg NaH (5.5 mmol) and 40 mL dry THF were charged and the slurry was cooled to 0 °C. Then 1471 mg 4-chloro-5-iodo-7//pyrrolo[2,3-i/]pyrîmidine (5 mmol) was added. After 30 minutes stirring, 1.4 mL benzenesulfonyl chloride (5.25 mmol) was added and the mixture was allowed to warm up to r.t., and stirred until no further conversion was observed. The mixture was then diiuted with saturated aqueous NH₄CI solution, and extracted with DCM. The combined organic layers were washed with brine, dried over MgSO₄, filtered and the filtrate was concentrated under reduced pressure. Then it was digerated with MTBE, then filtered to obtain 7-(benzenesulfonyl)-4-chloro-5-iodo-pyrrolo[2,3-i/]pyrimidine, ’H NMR (400 MHz, CDC1₃) Ô: 8.75 (s, IH), 8.22 (m, 2H), 7.95 (s, IH), 7.67 (m, IH), 7.56 (m, 2H)

MS: (M+H)⁺ = 419.8

ORIGINAL

-68Step B: 7-(benzenesulfonyl)-4-chloro-5-(l~naphthyl)pyrrolo[2,3-à]pyrimidine l eq. 7-(benzenesulfonyl)-4-chloro-5-iodo-pyrrolo[2,3-i/]pyrimidine, l.l eq.

I-naphthaleneboronic acid neopentyl glycol ester, l.l eq. silver carbonate, 0.15 eq. Pd(PPh₃)₄ and 2-Me-THF (15 mL/mmol 5-iodo-pyirolo[2,3-i7]pyrimidine derivative) were stirred under N₂ atmosphère at 110 °C until no further conversion was observed. The mixture was diluted with brine, neutralized with IM aqueous HCl solution, and extracted with DCM. The combined organic phases were dried over Na₂SO₄, filtered and the fîltrate was concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to give 7-(benzenesulfonyl)-4-chloro-

5-( l -naphthyl)pyrrolo[2,3-i/]pyrimidine.

^!H NMR (400 MHz, CDCl₃) δ: 8.82 (s, IH), 8.31 (m, 2H), 7.94 (m, 2H), 7.84 (s, IH), 7.71 (m, IH), 7.60 (m, 2H), 7.56-7.48 (m, 3 H), 7.48-7.38 (m, 2H)

MS: (M+H)⁺= 420.0

Step C: Example 11

Using General Procedure III and 7-(benzenesulfonyl)-4-chloro-5-(l-naphthyl)pyrrolo [2,3-c/]pyrimidine as the appropriate 4-chloro-pyrrolo[2,3-^pyrimidine derivative and D-phenylalanine as the appropriate amino acid derivative, Example 11 was obtained. HRMS calculated for C₂₅H₂₀N₄O₂: 408.1586, found: 409.1670 (M+H)

Example 12: /V-I7-benzyl-6-ethyl-5-(naphthalen-l-yl)-7/7-pyrrolo[2,3-i/]pyrimidin-4yl]-Z)-phenylalanine, diastereoisomer 1 and

Exaniple 13: /V-|7-benzyl-6-ethyl-5-(naphthalen-l-yI)-7/f-pyrrolo[2,3-i/|pyrimidin-4yI]-D-phenylalanine, diastereoisomer 2

Using General Procedure IVa and Préparation 6 as the appropriate 5-bromo-pyrrolo [2,3-t7|pyrimidine derivative and 1-naphthaleneboronic acid neopentyl glycol ester as the appropriate boronic acid derivative, Example 12 was obtained as the earlier eluting diastereoisomer. HRMS calculated for CvjHkiN^L: 526.2369, found: 527.2431 (M+H).

ORIGINAL

-69Example 13 was obtained as the later eluting diastereoisomer. HRMS calculated for C34H30N4O2: 526.2369, found: 527.2423 (M+H)

Example 14: Aⁱ-{6-ethyl-5-(naphthalen-l-yl)-7-[2-(naphthalen-l-yIoxy)ethyl]-7/7pyrrolo[2,3-rf]pyrimidin-4-yI}-D-phenylalanine, diastereoisomer 1 and

Example 15: jV-{6-ethyl-5-(naphthalen-l-yI)-7-|2-(naphthalen-l-yloxy)ethyI]-7Hpyrrolo|2,3if]py^rimidin-4-yl)-£>-phenylalanine, diastereoisomer 2

Step A: 5-bronio-4-chloro-6-ethyl-7-[2-(l-naphthyloxy)ethyl]pyrrolo[2,3-d]pyrimidine mg 2-(l-naphthyloxy)ethanol (0.5 mmol), 131 mg PPh₃ (0.5 mmol) and 66 mg Préparation 1b (0.25 mmol) were dissolved in 2.5 mL dry THF under N₂ atmosphère and cooled to 0 °C. Then 230 pL DEAD (0.5 mmol, 40 % in toluene) was added dropwise. The mixture was stirred at 40 °C until no further conversion was observed. Then the volatiles were removed under reduced pressure and the residue was purified via flash chromatography using heptane and EtOAc as eluents to obtain 5-bromo-4-chloro-6-ethyl-

7-[2-( 1 -naphthyloxy)ethyl]pyrrolo[2,3-i/]pyrimidine.

’H NMR (400 MHz, DMSO-d₆) δ: 8.69 (s, IH), 7.80 (dd, 2H), 7.51-7.31 (m, 4H), 6.94 (d, IH), 4.90 (t, 2H), 4.52 (t, 2H), 3.08 (q, 2H), 1.26 (t, 3H)

MS: (M+H)⁺ = 430.0

Step B: (2R)-2-[[5-bromo-6-ethyl-7-[2-(l-naphthyloxy)eihyl]pyrrolo[2,3-d]pyrimidin-4yl]amino]-3-phenyl-propanoic acid

Using General Procedure III and 5-bromo-4-chloro-6-ethyl-7-[2-(l-naphthyloxy) ethyl]pyrrolo[2,3-c/|pyriniidine as the appropriate 4-chloro-pyrrolo[2,3-i/]pyrimidine dérivative and D-phenylalanine as the appropriate amino acid dérivative (2Æ)-2-[[5-bromo-

6-ethyl-7-[2-(l-naphthyloxy)ethyl]pyrrolo[2,3-i/]pyrimidin-4-yl]amino]-3-phenylpropanoic acid was obtained.

'H NMR (400 MHz, DMSO-d_fi) δ: 12.96 (br s, 1 H), 8.24 (s, IH), 7.88 (d, IH), 7.82 (d, IH), 7.52-7.32 (m, 4H), 7.29-7.15 (m, 5H), 6.94 (d, IH), 6.38 (d, IH), 4.94 (q, IH), 4.72 (t, 2H), 4.45 (t, 2H), 3.28 (m, IH), 3.18 (dd, 1 H), 2.92 (q, 2H), 1.19 (t,3H)

MS: (M+H)⁺ = 559.2

ORIGINAL

-70Step C: Examples 14 and 15

Using General Procedure IVa and (27î)-2-[[5-bromo-6-ethyl-7-[2-(l-naphthyloxy) ethyl]pyrrolo[2,3-i/]pyrimidin-4-yl]amino]-3-phenyl-propanoic acid as the appropriate

5-bromo-pyrrolo[2,3-c/]pyrimidine derivative and 1 -naphthaleneboronic acid neopentyl glycol ester as the appropriate boronic acid derivative, Example 14 was obtained as the earlier eluting diastereoisomer. HRMS calculated for C39H34N4O3: 606,2631, found. 607.2711 (M+H). Example 15 was obtained as the later eluting diastereoisomer. HRMS calculated for C39H34N4O3: 606.2631, found: 607.2705 (M+H)

Example 16: MI6-ethyl-5-(naphtha)en-l-yl)-7-(2-phenylethyl)-7H-pyrrolo[2,3-rf| pyrimidin-4-yl]-D-phenylalanine, diastereoisomer 1 and

Example 17: jV-[6-ethyl-5-(naphthalen-l-yl)-7-(2-phcnylethyl)-7/7-pyrrolo[2,3-rf] pyrimidin-4-yl]-D-phenylalanine, diastereoisomer 2

Step A: 5-bromo-4-chloro-6-ethyl-7-phenethyl-pyrrolo[2.3-d]pyrimidine

3.1 mL 2-phenylethanol (25.9 mmol), 3.397 g PPh₃ (12.95 mmol) and 3.40 g Préparation 1b (12.95 mmol) were dissolved in 110 mL dry THF under N₂ atmosphère and cooled to 0 °C. Then 11.87 mL DEAD (40% in toluene) was added dropwise. The mixture was stirred at 40 °C until no further conversion was observed. Then the volatiles were removed under reduced pressure and the residue was purified via flash chromatography using heptane and EtOAc as eluents to obtain 5-bromo-4-chloro-6-ethyl-

7-phenethyl-pyrrolo[2,3-J]pyrimidine.

'H NMR (400 MHz, DMSO-d₆) δ: 8.61 (s, 111), 7.32-7.16 (m, 3H), 7.11 (m, 2H), 4.51 (t, 2H), 3.06 (t, 2H), 2.70 (q, 2H), 1.10 (t, 3H)

MS: (M+H/ = 364.0

Step B: (2R)-2-[(5-bromo-6-ethyl-7-phenelhyl-pyrrolo[2,3-à]pyrimidin-4-yl)amino]-3phenyl-propanoic acid

Using General Procedure III and 5-bromo-4-chloro-6-ethyl-7-phenethyl-pyrrolo[2,3-ri] pyrimidine as the appropriate 4-chloro-pyrrolo[2,3-i/]pyrimidine derivative and

ORIGINAL

-71D-phenylalanine as the appropriate amino acid dérivative (2/?)-2-[(5-bromo-6-cthyl-7phenethyl-pyrrolo[2,3-i/]pyrimidin-4-yl)amino]-3-phenyl-propanoic acid was obtained.

’H NMR (400 MHz, DMSO-d₆) δ: 12.80 (br s, IH), 8.20 (s, IH), 7.34-7.17 (m, 8H), 7.13 (m, 2H), 6.45 (d, lH),4.9l (q, IH), 4.33 (t, 2H), 3.31 (dd, lH),3.!8(dd, IH), 3.00 (t. 2H), 2.55 (q, 2H), l .04 (t, 3H)

MS: (M+H)⁺= 493.2

Step C: Examples 16 and 17

Using General Procedure IVa and (2/î)-2-[(5-bromo-6-ethyl-7-phenethyl-pyrrolo[2,3-i/] pyrimidin-4-yl)amino]-3-phenyl-propanoic acid as the appropriate 5-bromo-pyrrolo[2,3-tZ] pyrimidine dérivative and 1-naphthaleneboronic acid neopentyl glycol ester as the appropriate boronic acid dérivative, Example 16 was obtained as the earlier eluting diastereoisomer. HRMS calculated tor C35H32N4O2: 540.2525, found: 541.2592 (M+H). Example 17 was obtained as the later eluting diastereoisomer. HRMS calculated for C35H32N4O2: 540.2525, found: 541.2619 (M+H)

Example 18: /V-[6-ethyl-5-(naphthalen-l-yl)-7-(3-phenylpropyl)-7H-pyrrolo[2,3-i/] pyrimidin-4-yl]-Z>-phenylalanine, diastereoisomer 1 and

Example 19: /V-|6-ethyl-5-(naphthalen-l-yl)-7-(3-phenylpropyl)-7//-pyrrolo[2,3-rf] pyrimidin-4-yl|-Z>-phenylalanine, diastereoisomer 2

Step A: 5-bromo-4-chloro-6-ethyl-7-(3-phenylpropyl)pyrrolo[2,3-à]pyrimidine

3.52 mL 3-phenyl-propanol (25.9 mmol), 3.397 g PPI13 (12.95 mmol) and 3.4 g Préparation 1b (12.95 mmol) were dissolved in 110 mL dry THF under N₂ atmosphère and cooled to 0 °C. Then 11.87 mL DEAD (40 % in toluene) was added dropwise. The mixture was stirred at 40 °C until no further conversion was observed. Then the volatiles were removed under reduced pressure and the residue was purified via flash chromatography using heptane and EtOAc as eluents to obtain 5-bromo-4-chloro-6-ethyl-

7-(3-phenylpropyl)pyrrolo[2,3-ô/]pyrimidine.

'H NMR (400 MHz, DMSO-d₆) δ: 8.60 (s, 1 H), 7.31-7.22 (m, 2H), 7.21-7.13 (m, 3H),

4.32 (t, 21-1), 2.85 (q, 2H), 2.65 (t, 2H), 2.05 (m, 2H), 1.16 (t, 3H)

ORIGINAL

-72MS: (M+H)⁺ = 378.0

Step B: (2R.)-2-[[5-bromo-6-ethyl-7-(3-phenylpropyl)pyrrolo[2,3-dJpyrimidin-4-yl] amino]-3-phenyl-propanoic acid

Using General Procedure III and 5-bromo-4-chloro-6-ethyl-7-(3-phenylpropyl)pyrrolo [2,3-t7]pyrimidine as the appropriate 4-chloro-pyrrolo[2,3-i/]pyrimidine dérivative and D-phenylalanine as the appropriate amino acid dérivative, (2/?)-2-[[5-bromo-6-ethyl-7-(3phenylpropyl)pyrrolo[2,3-i/]pyrimidin-4-yl]amino]-3-phenyl-propanoic acid was obtained. 'H NMR (400 MHz, DMSO-d₆) δ: 12.95 (br s, IH), 8.15 (s, IH), 7.33-7.12 (m, 10H), 6.35 (d, IH), 4.94 (q, IH), 4J6 (t, 2H), 3.28 (dd, IH), 3.16 (dd, IH), 2.68 (q, 2H), 2.61 (t, 2H),

1.97 (m.2H), l .09 (t, 3H)

MS: (M+H)⁺ = 507.2

Step C: Examples /8 and 19

Using General Procedure IVa and (27?)-2-[[5-bromo-6-ethyl-7-(3-phenylpropyl) pyrrolo[2,3-t/] pyrimidin-4-yl]amino]-3-phenyl-propanoic acid as the appropriate 5-bromopyrrolo[2,3-c/] pyrimidine dérivative and l-naphthaleneboronic acid neopentyl glycol ester as the appropriate boronic acid dérivative, Example 18 was obtained as the earlier eluting diastereoisomer. HRMS calculated for C36H34N4O2: 554.2682, found: 555.2742 (M+H). Example 19 was obtained as the later eluting diastereoisomer. HRMS calculated for C36H34N4O2: 554.2682, found: 555.2756 (M+H)

Example 20: A^r-[(57f_n)-5-(3-chloro-2-methyIphenyl)-6-ethyl-7-methyl-7/7-pyrrolo[2,3i/]pyrimidin-4-yl]-£>-plicnykilanine and

Example 21:7V-[(55'_<f)-5-(3-chloro-2-metliylphenyI)-6-ethyl-7-mcthyl-7/7-pyrroloj2,3rf]pyrïmidin-4-yl]-Z>-phenyIalanine

Step A: 5-bromo-4-chloro-6-ethyl-7-methyl-pyrrolo[2,3-d]pyrimidine mg Préparation 1b (0.25 mmol) was dissolved in I mL dry THF, then 20.3 pL dry MeOH (0.5 mmol) and 0.5 mL cyanomethylenetributylphosphorane solution (0.5 mmol, 1M in toluene) was added. The mixture was stirred at r.t. until no further conversion was

ORIGINAL

-73observed. The volatiles were removed under reduced pressure. The residue was purified via flash chromatography using heptane and EtOAc as eluents to obtain 5-bromo-4-chloro-

6-ethyl-7-methyl-pyrrolo[2,3-i/]pyrimidine.

H NMR (400 MHz, CDCl₃) Ô: 8.56 (s, IH), 3.84, (s, 3H), 2.91 (q, 2H), 1.26 (t, 3H)

MS: (M+H)⁺ = 274.0

Step B: (2R)-2-[[5-bromo-6-ethyl-7-methyl-pyrrolo[2,3-à]pyrimidin-4-yl]amino]-3phenyl-propanoic acid

Using General Procedure III and 5-bromo-4-chloro-6-ethyl-7-methyl-pyrrolo[2,3-t7] pyrimidine as the appropriate 4-chloro-pyrrolo[2,3-r(|pyrimidine dérivative and D-phenylalanine as the appropriate amino acid dérivative, (2/?)-2-[[5-bromo-6-ethyl-7methyl-pyrrolo[2,3-cf] pyrimidin-4-yl]amino]-3-phenyl-propanoic acid was obtained.

'H NMR (500 MHz, DMSO-d₆) δ: 13.05 (br s, IH), 8.17 (s, IH), 7.32-7.25 (m. 2H), 7.25-

7.18 (m, 3H), 6.32 (d, IH), 4.97 (m, IH), 3.68, (s, 3H), 3.29 (dd, IH), 3.18 (dd, IH), 2.75 (q,2H), 1.13 (t, 3H)

MS: (M+H)⁺ = 403.0

Step C: Examples 20 and 21

Using General Procedure IVa and (2A)-2-[[5-bromo-6-ethyl-7-methyl-pyrrolo[2,3-i/] pyrimidin-4-yl]amino]-3-phenyl-propanoic acid as the appropriate 5-bromo-pyrrolo[2,3-i/] pyrimidine derivative and Préparation 3c as the appropriate boronic acid dérivative, Example 20 was obtained as the earlier eluting diastereoisomer. HRMS calculated for C25H₂îC1N4O₃: 448.1666, found: 449.1753 (M+H). Example 21 was obtained as the later eluting diastereoisomer. HRMS calculated for C25H25CIN4O2: 448.1666, found: 449.1752 (M+H)

Example 22: jV-|(5/?_a)-5-(3-chloro-2-mcthylphenyl)-7-(cyclopropylmethyl)-6-ethyl-7//pyrrolo|2,3-rf]pyrimidin-4-yl]-Z)-plienylalanine and

Example 23: A^/-[(5S_fl)-5-(3-chloro-2-methylphenyl)-7-(cyclopropylmethyl)-6-ethyl-7Hpyrrolo|2,3-i/]pyrimidin-4-yl]-£>-phenylaIanine

ORIGINAL

- 74Step A: 5-bromo-4-chloro-7-(cyclopropylmethyl)-6-ethyl-pyrrolo[2,3-d]pyrimidine mg Préparation 1b (0.25 mmol) was dissolved in l mL dry THF, then 40 pL cyclopropanemethanol (0.5 mmol) and 0.5 mL cyanoinethyienetributylphosphorane solution (0.5 mmol, IM in toluene) was added. The mixture was stirred at r.t. until no further conversion was observed. The volatiles were removed under reduced pressure. The residue was purified via flash chromatography using heptane and EtOAc as eluents to obtain 5-bromo-4-chloro-7-(cyclopropylmethyl)-6-ethyl-pyrrolo[2,3-t/]pyrimidine.

'H NMR (400 MHz, CDClj) Ô: 8.54 (s, IH), 4.18 (d, 2H), 2.94 (q, 2H), 1.29 (t, 3H), l.24l.l4(m, lH), 0.60-0.51 (m, 2H), 0.51-0.43 (m,2H)

MS: (M+H)⁺= 314.0

Step B: (2R)-2-[[5-bromo-7-(cyctopropylmethyl)-6-ethyl-pyrrolo[2,3-d]pyrimidin-4-yl] amino]-3-phenyl-propanoic acid

Using General Procedure III and 5-bromo-4-chloro-7-(cyclopropylmethyl)-6-ethylpyrrolo[2,3-iZ]pyrimidine as the appropriate 4-chloro-pyrrolo[2,3-c/]pyrimidine dérivative and D-phenylalanine as the appropriate amino acid dérivative, (2/?)-2-[[5-bromo-7(cyclopropylmethyl)-6-ethyl-pyrrolo[2,3-i7]pyrimidin-4-yl]amino]-3-phenyl-propanoic acid was obtained.

'H NMR (500 MHz, DMSO-d₆) δ: 13.05 (br s, IH), 8.15 (s, IH), 7.32-7.26 (m, 2H), 7.26-

7.20 (m, 3H), 6.34 (d, IH), 4.94 (m. IH), 4.05 (d, 2H) 3.29 (dd, IH), 3.18 (dd, IH), 2.78 (q, 2H), 1.28-1.20 (m, 1 H), 1.16 (t, 3H), 0.47-0.42 (m, 2H), 0.42-0.37 (m, 2H)

MS: (M+H)⁺ = 443.0

Step C: Examples 22 and 23

Using General Procedure IVa and (27?)-2-[[5-bromo-7-(cyclopropylmethyl)-6-ethylpyrroio[2,3-i/]pyrimidin-4-yl]amino]-3-phenyl-propanoic acid as the appropriate 5-bromopyrrolo[2,3-t/]pyrimidine dérivative and Préparation 3c as the appropriate boronic acid dérivative, Example 22 was obtained as the earlier eluting diastereoisomer. HRMS calculated for C28H29CIN4O2: 488.1979, found: 489.2064 (M+H). Example 23 was obtained as the later eluting diastereoisomer. HRMS calculated for C28H29CIN4O2: 488.1979, found: 489.2048 (M+H)

ORIGINAL

-75Example 24: /V-[(57?_fl)-5-(3-chloro-2-methylphenyl)-6-ethyl-7-(prop-2-en-l-yl)-7//pvrrolo[2,3-rf]pyrimidin-4-yl]-D-phenylalanine and

Example 25: ?V-|(5S_n)-5-(3-chloro-2-methylphenyI)-6-ethyl-7-(prop-2-en-l-yl)-7//pyrrolo|2,3-r/|pyrimidin-4-yl]-£>-phenylalanine

Step A: 7~allyl-5-bromo-4-chloro-6-ethyl-pyrrolo[2,3-d]pyrimidine mg Préparation 1b (0.25 mmol) was dissolved in l mL dry THF, then 34 pL allylalcohol (0.5 mmol) and 0.5 mL cyanomethylenetributylphosphorane solution (0.5 mmol, l M in toluene) was added. The mixture was stirred at r.t. until no further conversion was observed. The volatiles were removed under reduced pressure. The residue was purified via flash chromatography using heptane and EtOAc as eluents to obtain 7-allyl-5-bromo-4chloro-6-ethyl-pyrrolo[2,3-i/]pyrimidine.

‘H NMR (400 MHz, CDCl₃) δ: 8.57 (s, IH), 6.02-5.90 (m, IH), 5.25-5.16 (m, IH), 5.00-

4.85 (m, 3H), 2.87 (q, 2H), l .26 (t, 3H) MS: (M+H)⁺ = 300.0

Step B: (2R)-2-[[7-allyl-5-bromo-6-ethyl-pyrrolo[2,3-d]pyriniidin-4~yl]amino]-3-phenylpropanoic acid

Using General Procedure [Il and 7-allyl-5-bromo-4-chloro-6-ethyl-pyrrolo[2,3-<7] pyrimidine as the appropriate 4-chloro-pyrrolo[2,3-r/]pyrimidine derivative and D-phenylalanine as the appropriate amino acid derivative, (2Æ)-2-[[7-allyl-5-bromo-6ethyl-pyrrolo[2,3-i/]pyrimidin-4-yl]amino]-3-phenyl-propanoic acid was obtained.

'H NMR (500 MHz, DMSO-d₆) δ: 13.06 (br s, IH), 8.16 (s, IH), 7.34-7.26 (m, 2H), 7.267.l9(m, 3H), 6.35 (d. I H), 6.01-5.89 (m, IH), 5.l0(dd, IH), 5.01-4.93 (m, IH), 4.87-4.73 (m, 3H), 3.29 (dd. IH), 3.18 (dd, IH), 2.70 (q, 2H), 1.12(1, 3H)

MS: (M+H)⁺= 429.0

Step C: Examples 24 and 25

Using General Procedure IVa and (2À)-2-[[7-allyl-5-bromo-6-ethyl-pyrrolo[2,3-r/] pyrimidin-4-yl]amino]-3-phenyl-propanoic acid as the appropriate 5-bromo-pyrroIo[2,3-c/j pyrimidine derivative and Préparation 3c as the appropriate boronic acid derivative,

ORIGINAL

-76Example 24 was obtained as the earlier eluting dîastereoisomer. HRMS calculated for C27H27CIN4O2: 474.1823, found: 475.1908. Example 25 was obtained as the later eluting dîastereoisomer. HRMS calculated for C27H27CIN4O2: 474,1823, found: 475.1909

Example 26:7V-|7-(but-2-yn-l-yl)-(5/f_a)-5-(3-chloro-2-methylphenyl)-6-ethyl-7£fpyrrolo[2,3-rf]pyrimidin-4-yl]-Z)-phenylalanine and

Example 27: ZV-|7-(but-2-yn-l-yl)-(55'_fl)-5-(3-chloro-2-methylphenyl)-6-ethyl-7Hpyrrolo|2,3-rf]pyrimidin-4-yl]-Z>-phenyIalanine

Step A: 5-bromo-7-but-2-ynyl-4-chloro-6-ethyl-pyrrolo[2,3-d]pyrimidine pL 2-butyn-l-ol (0.5 mmol), 131 mg PPha (0.5 mmol) and 66 mg Préparation 1b (0.25 mmol) were dissolved in 2.5 mL dry THF under N2 atmosphère and cooled to 0 °C. Then 230 pL DEAD (0.5 mmol, 40 % in toluene) was added dropwise. The mixture was stirred at 40 °C until no further conversion was observed. Then the volatiles were removed under reduced pressure and the residue was purified via flash chromatography using heptane and EtOAc as eluents to obtain 5-bromo-7-but-2-ynyI-4-chIoro-6-ethylpyrrolo[2,3-i/] pyrimidine.

'H NMR (400 MHz. CDCI3) Ô: 8.59 (s, IH), 5.03 (q, 2H), 2.99 (q, 2H), 1.77 (t, 3H), 1.33 (t, 3H)

MS: (M+H)⁺ = 312.0

Step B: (2R)-2-[(5-bromo- 7-but-2-ynyl-6-ethyl-pyrrolo[2,3-à]pyrimidin-4-yl)amino]-3phenyi-propanoic acid

Using General Procedure III and 5-broino-7-but-2-ynyl-4-chloro-6-ethyl-pyrrolo[2,3-tZ] pyrimidine as the appropriate 4-chloro-pyrrolo[2,3-i/]pyrimidine dérivative and D-phenylalanine as the appropriate amino acid dérivative (2Æ)-2-[(5-bromo-7-but-2-ynyl-

6-ethyl-pyrrolo[2,3-t/]pyrimidin-4-yl)amino]-3-phenyl-propanoic acid was obtained.

^fH NMR (500 MHz, DMSO-d₆) δ: 13.25 (br s, IH), 8.19 (s, 1 H), 7.30-7.24 (m, 2H), 7.24-

7.16 (m, 3H), 6.45 (d, IH), 5.02-4.96 (m, 2H), 4.93 (q, IH), 3.30 (dd, IH), 3.19 (dd, 1 H),

2.80 (q, 2H), 1.74 (t, 3H), 1.19 (t,3H)

MS: (M+H)⁺=441.0

ORIGINAL

-77Step C: Examples 26 and 2 7

Using General Procedure IVa and (2Æ)-2-[(5-bromo-7-but-2-ynyl-6-ethyi-pyrrolo[2,3-J] pyrimidin-4-yl)amino]-3-phenyl-propanoic acid as the appropriate 5-bromo-pyrrolo[2,3-c/] pyrimidine dérivative and Préparation 3c as the appropriate boronic acid dérivative, Example 26 was obtained as the earlier eluting diastereoisomer. HRMS calculated for C28H27CIN4O2: 486.1823, found: 487.1893 (M+H). Example 27 was obtained as the later eluting diastereoisomer. HRMS calculated for C28H27CIN4O2: 486.1823, found: 487.1893 (M+H)

Example 28: _JV-|(5/f„)-5-(3-chloro-2-methylphenyl)-6-ethyl-7-(2,2,2-trifluoroethyl)7H-pyrrolo[2,3-rf|pyrinndin-4-yl]-Z>-phenylalanine and

Example 29:7V-[(55^, _ü)-5-(3-chIoro-2-methylphenyl)-6-ethyl-7-(2,2,2-trifluoroethyI)-777pyrrolo[2,3-i/lpyrimidin-4-yl|-£>-phenylalanine

Step J; 5-bromo-4-chloro-6-ethyl-7-(2,2,2-trifluoroethyl)pyrrolo[2,3-à]pyrimidine pL trifluoroethanol (1 mmol), 262 mg PPhj (1 mmol) and 130 mg Préparation 1b (0.5 mmol) were dissolved in 5 mL dry THF under N2 atmosphère and cooled to 0 °C. Then 460 pL DEAD (0.5 mmol, 40 % in toluene) was added dropwise. The mixture was stirred at 40 °C until no further conversion was observed. Then the volatiles were removed under reduced pressure and the residue was purified via flash chromatography using heptane and EtOAc as eluents to obtain 5-bromo-4-chloro-6-ethy 1-7-(2,2,2-trifluoro ethyl)pyrrolo[2,3-i/J pyrimidine.

‘1-1 NMR (400 MHz, CDCI3) δ: 8.62 (s, IH), 4.90 (q, 2H), 2.94 (q, 2H), 1.28 (t, 3H)

MS: (M+H)⁺ = 342.0

Step B: (2R)-2-[[5-bromo-6-ethyl-7-(2,2,2-trifluoroethyl)pyrrolo[2,3-à]pyrimidin-4-yl] amino]-3-phenyl-propanoic acid

Using General Procedure III and 5-bromo-4-chloro-6-ethyl-7-(2,2,2-trifluoroethyl)pyrrolo [2,3-i/]pyrimidine as the appropriate 4-chloro-pyrrolo[2,3-i/]pyrimîdine dérivative and D-phenylalanine as the appropriate amino acid dérivative (27?)-2-[[5-bromo-6-ethyl-7ORIGINAL

-78(2,2,2-trifluoroethyl)pyrrolo[2,3-i/]pyrimidin-4-yl]amino]-3-phenyl-propanoic acid was obtained.

‘H NMR (500 MHz, DMSO-d₆) Ô: I3.l l (br s, IH), 8.23 (s, IH), 7.33-7.26 (m, 2H), 7.26-

7.19 (m, 3H), 6.44 (d, IH), 5.12 (q, 2H), 5.00-4.93 (m, IH), 3.30 (dd, IH), 3.20 (dd, IH), 2.78 (q, 2H), l.l4(t, 3H)

MS: (M+H/= 471.0

Step C: Examples 28 and 29

Using General Procedure IVa and (2À)-2-[[5-bromo-6-ethyl-7-(2,2,2-trifluoroethyl) pyrrolo[2,3-iZ|pyrimidin-4-yl]amino]-3-phenyl-propanoic acid as the appropriate 5-bromopyrrolo[2,3-i/]pyrimidine dérivative and Préparation 3c as the appropriate boronic acid dérivative, Example 28 was obtained as the earlier eluting diastereoisomer. HRMS calculated for C26H24CIF3N4O2: 516.1540, found: 517.1624 (M+H). Example 29 was obtained as the later eluting diastereoisomer. HRMS calculated for C26H24CIF3N4O2: 516.1540, found: 517.1606 (M+H)

Example 30:2V-[(5/t_a)-5-(3-chloro-2-methylphenyl)-7-(2-cyclopentv’lethyl)-6-ethyl-7Wpyrrolo[2,3-i/]pyrimidin-4-yl]-Z)-phenylalaninc and

Example 31 : j'V-|(55_a)-5-(3-chioiO-2-methylphenyl)-7-(2-cyclopentylethyl)-6-ethyl-7//pyrrolo[2,3-rf|pyrimïdin-4-yl]-Z>-phenylalanine

Step A : 5-bromo-4-chloro-7-(2-cyclopentylethyl)-6-ethyl-pyrrolo[2.3-à]pyrimidine

124 pL 2-cyclopentylethanol (1 mmol), 262 mg PPh₃ (1 mmol) and 130 mg Préparation lb (0.5 mmol) were dissolved in 5 mL dry THF under N₂ atmosphère and cooled to 0 °C. Then 460 pL DEAD (0.5 mmol, 40 % in toluene) was added dropwise. The mixture was stirred at 40 °C until no further conversion was observed. Then the volatiles were removed under reduced pressure and the residue was purified via flash chromatography using heptane and EtOAc as eluents to obtain 5-bromo-4-chloro-7-(2cyclopentylethyl)-6-ethyl-pyrrolo[2,3-c/]pyrimidine.

¹H NMR (400 MHz, CDCI3) δ: 8.55 (s, 1 H), 4.31 -4.20 (m, 2H), 2.89 (q, 2H), 1.91 -1.72 (m, 5H), 1.69-1.57 (m, 2H), 1.57-1.46 (m, 2H), 1.28 (t, 3H), 1.23-1.05 (m, 2H)

ORIGINAL

-79MS: (M+H)⁺ = 356.0

Step B: (2R)-2-[[5-bromo-7-(2-cyclopentylethyl)-6-ethyl-pyrrolo[2,3-à]pyrimidin-4-yl] am ino]-3~phenyl-propano ic acid

Using General Procedure III and 5-bromo-4-chloro-7-(2-cyclopentylethyl)-6-ethylpyrrolo[2,3-(/]pyrimidine as the appropriate 4-chloro-pyrrolo[2,3-</]pyrimidine dérivative and D-phenylalanine as the appropriate amino acid dérivative (2J?)-2-[[5-bromo-7-(2cyclopentylethyl)-6-ethyl-pyrrolo[2,3-i7]pyrimidin-4-yI]amino]-3-phenyl-propanoic acid was obtained.

'H NMR (500 MHz, DMSO-d₆) S: 13.04 (br s, IH), 8.17 (s, IH), 7.32-7.26 (m, 2H), 7.25-

7.19 (m, 3H), 6.32 (d, IH), 5.00-4.92 (m, IH), 4.17-4.09 (m. 2H), 3.29 (dd, 1 H), 3.18 (dd, IH), 2.74 (q, 2H), 1.79-1.70 (m, 3H), 1.70-1.62 (m, 2H), 1.60-1.50 (m, 2H), 1.50-1.42 (m, 2H), 1.15 (t,3H), 1.12-1.01 (m, 2H)

MS: (M+H)⁺ = 485.2

Step C: Examples 30 and 31

Using General Procedure IVa and (2Æ)-2-[[5-bromo-7-(2-cyclopentylethyl)-6-ethylpyrrolo[2,3-i/]pyrimidin-4-yl]amino]-3-phenyl-propanoic acid as the appropriate 5-bromopyrrolo[2,3-i/]pyrimidine dérivative and Préparation 3c as the appropriate boronic acid dérivative, Example 30 was obtained as the earlier eluting diastereoisomer. HRMS calculated for C31H35CIN4O2: 530.2449, found: 531.2528 (M+H). Example 31 was obtained as the later eluting diastereoisomer. HRMS calculated for C31H35CIN4O2: 530.2449, found: 531.2547 (M+H)

Example 32:7V-|(57?„)-5-(3-chloro-2-methylphenyl)-6-ethyl-7-(naphthalen-lylmethyl)-7H-pyrrolo [2,3-(/] pyrimidin-4-yl|-Z>-plienylalanme and

Example 33:7V-|(5S_a)-5-(3-chloro-2-methylphenyl)-6-ethyI-7-(naphthalen-l-ylmethyI)7//-pyrroIo|2,3-i/|pyrimidin-4-yl|-/)-phenylalanine

Step A: 5-bromo-4-chloro-6-ethyl-7-(l-naphthylmethyl)pyrrolo[2,3-à]pyrimidine

ORIGINAL

-80158 mg l-naphthalenemethanol (1 mmol), 262 mg PPhj (1 mmol) and 130 mg Préparation 1b (0.5 mmol) were dissolved in 5 mL dry THF under N₂ atmosphère and cooled to 0 °C. Then 460 pL DEAD (0.5 mmol, 40 % in toluene) was added dropwise. The mixture was stirred at 40°C until no further conversion was observed. Then the volatiles were removed under reduced pressure and the residue was purified via flash chromatography using heptane and EtOAc as eluents to obtain 5-bromo-4-chloro-6-ethyI-

7-( 1 -naphthylmethyl)pyrrolo[2,3-f/]pyrimidine.

‘H NMR (400 MHz, CDC1₃) δ: 8.58 (s, IH), 8.09 (d, IH), 7.95-7.89 (m, IH), 7.79 (d, IH), 7.66-7.54 (m, 2H), 7.25 (t. IH), 6.45 (dd, IH), 6.03 (s, 2H), 2.76 (q, 2H), 1.08 (t, 3H) MS: (M+H)⁺ = 400.0

Step B: (2R.)-2-[[5-bromo-6-ethyl-7-(l-naphlhylmethyl)pyrrolo[2,3-d]pyrinüdin-4-yl] amino]-3-phenyl-propanoic acid

Using General Procedure III and 5-bromo-4-chloro-6-ethyl-7-(l-naphthylmethyl)pyrrolo [2,3-i/]pyrimidine as the appropriate 4-chloro-pyrrolo[2,3-i/]pyrimidine dérivative and D-phenylalanine as the appropriate amino acid dérivative (2Æ)-2-[[5-bromo-6-ethyl-7-(lnaphthylmethyl)pyrrolo[2,3-c/]pyrimidin-4-yl]amino]-3-phenyl-propanoic acid was obtained.

'H NMR (500 MHz, DMSO-d₆) δ: 13.14 (br s, IH), 8.27 (d, IH), 8,15 (s, IH), 7.98 (d, IH), 7.83 (d, IH), 7.66-7.56 (m, 2H), 7.37-7.20 (m, 6H), 6.48 (d, IH), 6.40 (d, IH), 5.94 (s, 2H), 4.99 (q, IH), 3.33 (dd. IH), 3.22 (dd, IH), 2.62 (q, 2H), 0.89 (t, 3H) MS: (M+Hf = 529.0

Step C: Examples 32 and 33

Using General Procedure IVa and (2Æ)-2-[(5-bromo-6-ethyl-7-(l-naphthylmethyl)pyrrolo [2,3-i/]pyrimidin-4-yl]amino]-3-phenyl-propanoic acid as the appropriate 5-bromopyrrolo[2,3-i/]pyrimidine dérivative and Préparation 3c as the appropriate boronic acid dérivative, Examplc 32 was obtained as the earlier eluting diastereoisomer. HRMS calculated for C35H31CIN4O2: 574.2136, found: 575.221 1 (M+H). Example 33 was obtained as the later eluting diastereoisomer. HRMS calculated for C35H31CIN4O2: 574.2136, found: 575.2203 (M+H)

ORIGINAL

-81Examplc 34: /V-[(5Æ_a)-5-(3-chloro-2-methyIphenyl)-6-ethyl“7-(4-methoxybeiizyl)-7//pyrroIo[2,3-i/]pyrimidin-4-yl]-Z>-phenylalanine and

Examplc 35: A^r-|(5S_a)-5-(3-chloro-2-mcthylphenyl)-6-ethyl-7-(4-methoxybenzy 1)-7//pyrrolo(2,3-rf]pyrimidin-4-yl]-Z)-phenylaIanine

Step A: 5-bromo-4-cldoro-6-ethyl-7-[(4-methoxyphenyl)methyl]pyrrolo[2,3-à]pyrimidîne 138 mg 4-methoxybenzyl alcohol (1 mmol), 262 mg PPhj (1 mmol) and 130 mg Préparation 1b (0.5 mmol) were dissolved in 5 mL dry THF under N2 atmosphère and cooled to 0 °C. Then 460 pL DEAD (0.5 mmol, 40 % in toluene) was added dropwise. The mixture was stirred at 40 °C until no further conversion was observed. Then the volatiles were removed under reduced pressure and the residue was purified via flash chromatography using heptane and EtOAc as eluents to obtain 5-bromo-4-chloro-6-ethyl-

7-[(4-methoxyphenyl)methyl]pyrrolo[2,3-7]pyrimidine. MS: (M+H)⁺ = 380.0

Step B: (2Rj-2-[[5-bromo-6-ethyl-7-[(4-methoxyphenyl)methyl]pyrrolo[2,3-à]pyrimidin-4yl]amino]-3-phenyl-propanoic acid

Using General Procedure III and 5-bromo-4-chloro-6-ethyi-7-[(4-methoxyphenyl) methyl]pyrrolo[2,3-i/]pyrÎmidine as the appropriate 4-chloro-pyrrolo[2,3-7]pyrimidine dérivative and D-phenylalanine as the appropriate amino acid dérivative, (2Æ)-2-[[5bromo-6-ethyl-7-[(4-methoxyphenyl)methyl]pynolo[2,3-i7]pyrimidin-4-yl]aniino]-3phenyl-propanoic acid was obtained.

'H NMR (500 MHz. DMSO-d₆) δ: 13.07 (br s, IH), 8.20 (s, IH), 7.33-7.17 (m, 5H), 7.03 (d, 2H), 6.85 (d, 2H), 6.37 (d, IH), 5.37 (s, 2H), 4.99 (q, IH), 3.69 (s, 3H), 3.31 (dd, IH),

3.20 (dd, IH), 2.65 (q, 2H), 0.91 (t. 3H)

MS: (M+H)⁺ = 508.8

Step C: Examples 34 and 35

Using General Procedure IVa and (2/?)-2-[[5-bromo-6-ethyI-7-[(4-methoxyphenyl) methyl]pyrrolo[2,3-7]pyrimidin-4-yl]amino]-3-phenyl-propanoic acid as the appropriate

5-bromo-pyrrolo[2,3-7]pyriniidine dérivative and Préparation 3c as the appropriate boronic acid dérivative, Example 34 was obtained as the earlier eluting diastereoisomer.

ORIGINAL

- 82HRMS calculated for C3₂H3]CIN₄O3: 554.2085, found: 555.2176 (M+H). Example 35 was obtained as the later eluting diastereoisomer. HRMS calculated for C32H31CIN4O3: 554.2085, found: 555.2140 (M+H)

Example 36: jV-[7-benzyl-(5iï₍,)-5-(3-chloro-2-methylphenyl)-6-ethyl-7/7-pyrrolo[2,3rf]pyrimidin-4-yI]-Z>-phenylalanine and

Example 37: Aⁱ-[7-benzyl-(5X_fl)-5-(3-chloro-2-methylphenyI)“6-ethyl-7/f-pyrrolo[2,3-i/| pyrimidin-4-yl]-Z)-phenylalanine

Using General Procedure IVa and Préparation 6 as the appropriate 5-bromo-pyrrolo [2,3-i/|pyrimidine derivative and Préparation 3c as the appropriate boronic acid derivative, Example 36 was obtained as the earlier eluting diastereoisomer. HRMS calculated for C31H29CIN4O2: 524.1979, found: 525.2048 (M+H). Example 37 was obtained as the later eluting diastereoisomer. HRMS calculated for C31H29CIN4O2: 524.1979, found: 525.2064 (M+H)

Example 38: jV-|(5/f_a)-5-(3-chloro-2-methylphenyl)-6-etliyl-7-(propan-2-yl)-7/7pyrrolo[2,3-rf|pyrÎmidin-4-yl]-£)-phenylalanine and

Example 39: /V-|(55„)-5-(3-chloro-2-methylphenyl)-6-ethyl-7-(propan-2-yl)-7Hpyrrolo[2,3-rf|pyrimidin-4-yl]-£>-plienylalanine

Slep A : 5-bromo-4-chloro-6-ethyl-7-isopropyl-pyrrolo[2,3-d]pyrimidine pL 2-propanol (1 mmol), 262 mg PPI13 (1 mmol) and 130 mg Préparation 1b (0.5 mmol) were dissolved in 5 mL dry THF under N₂ atmosphère and cooled to 0 °C. Then 460 pL DEAD (0.5 mmol, 40 % in toluene) was added dropwise. The mixture was stirred at 40 °C until no further conversion was observed. Then the volatiles were removed under reduced pressure and the residue was purified via flash chromatography using heptane and EtOAc as eluents to obtain 5-bromo-4-chloro-6-ethyl-7-isopropyl-pyrrolo [2,3-i/]pyrimidine.

ORIGINAL

-83*H NMR (400 MHz. CDCl₃) 6: 8.53 (s, IH), 4.71 (sp, IH), 2.92 (q, 2H), 1.72 (d, 6H), 1.25 (t, 3H)

MS: (M+H)' =302.0

Step B: (2B.)-2-[(5-bromo-6-ethyl-7-isopropyl-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-3phenyl-propanoic acid

Using General Procedure III and 5-bromo-4-chloro-6-ethyl-7-isopropyl-pyrrolo[2,3-i7] pyrimidine as the appropriate 4-chloro-pyrrolo[2,3-iZ]pyrimidine derivative and D-phenylalanîne as the appropriate amino acid derivative (27?)-2-[(5-bromo-6-ethyl-7isopropyl-pyrrolo[2,3-i7]pyrimidin-4-yl)amino]-3-phenyl-propanoic acid was obtained.

‘H NMR (500 MHz. DMSO-d₆) δ: 13.04 (br s, IH), 8.14 (s, IH), 7.35-7.17 (m. 5H), 6.33 (d, IH), 4.95 (q, IH), 4.64 (sp, IH), 3.28 (dd, IH), 3.17 (dd, IH), 2.76 (q, 2H), 1.59 (d, 6H), 1.11 (t, 3H)

MS: (M+H)⁺ = 431.2

Step C: Examples 38 and 39

Using General Procedure IVa and (27?)-2-[(5-bromo-6-ethyl-7-isopropyl-pyrrolo[2,3-i/] pyrimidin-4-yl)amino]-3-phenyl-propanoic acid as the appropriate 5-bromo-pyrrolo[2,3-r/] pyrimidine derivative and Préparation 3c as the appropriate boronic acid derivative, Example 38 was obtained as the earlier eluting diastereoisomer. HRMS calculated for C27H29CIN4O2: 476.1979, found: 477.2057 (M+H). Example 39 was obtained as the later eluting diastereoisomer. HRMS calculated for C27H29CIN4O2: 476.1979, found: 477.2063 (M+H)

Example 40: (2/ï)-2-[(7-benzyl-(55'„)-5-{3-chloro-2-methyl-4-[2-(4-methylpipcrazin-lyI)ethoxy]phenyl}-6-ethyI-7H'-pyrrolo[2,3-rf| pyrimidm-4-yl)oxy]-3-phenylpropanoic acid

Step A: 7-benzyl-5-bronio-4-chloro-6-ethyl-pyirolo[2,3-àJpyrimidine

255 mg NaH (6.38 mmol) and 50 mL dry THF were charged into a 50 mL Schlenk tube under N₂ atmosphère and the slurry was cooled to 0 °C. Then 1.792 g Préparation 1b (5.8 mmol) was added. After stirring the mixture for 30 minutes at 0 °C, 773 pL benzyl

ORIGINAL

-84bromide (6.38 mmol) was added and the mixture was allowed to warm up to r.t., and stirred until no further conversion was observed. The mixture was then diluted with saturated aqueous NH4CI solution, and extracted with DCM. The combined organic layers were washed with brine, dried over MgSO₄, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to obtain 7-benzyl-5-bromo-4-chloro-6-ethyl-pyrrolo[2,3-i/] pyrimidine. 'H NMR (400 MHz, CDClj) δ: 8.58 (s, IH), 7.35-7.20 (m, 3H), 7.10-6.96 (m, 2H), 5.52 (s, 2H), 2.78 (q, 2H), 1.05 (t, 3H)

Step B: Methyl (2R)-2-(7-benzyl-5-bromo-6-ethyl-pyrrolo[2,3-8]pyrimidin-4-yl)oxy-3phenyl-propanoate

1.639 g 7-benzyl-5-bromo-4-chloro-6-ethyl-pyrrolo[2,3-i7]pyrimidine (4.67 mmol) was dissolved in 47 mL dry DMSO, then 2.948 g methyl (2Æ)-2-hydroxy-3-phenyl-propanoate (16.4 mmol) and 7.234 g Cs₂CO₃ (22.2 mmol) were added and the mixture was stirred at 100 °C under N₂ atmosphère until no further conversion was observed. Then it was diluted with water and brine, extracted with DCM. The organic layer was dried over Na₂SO₄, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and 'Pr₂O as eluents to obtain methyl (2Æ)-2-(7-benzyl-5-bromo-6-ethyl-pyrrolo[2,3-i/]pyrimidin-4-yl)oxy-3-phenyl-propanoate. ‘H NMR (400 MHz, CDC1₃) δ: 8.29 (s, IH), 7.47 (d, 2H), 7.36-7.19 (m, 6H), 7.06-6.96 (m, 2H), 5.60 (dd, IH), 5.47 (s, 2H), 3.73 (s, 3H), 3.41-3.28 (m, 2H), 2.72 (q, 2H), 1.03 (t, 3H) MS: (M - H)' = 494.2

Step C: Methyl (2R.)-2-[7-benzyl-(5S₃)-5-[3-chloro-2-methyl-4-hydroxphenyl]-6-ethylpyrrolo [2,3-8]pyrim idin-4 -yl] oxy-3 -phenyl-propanoate

A mixture of 1.20 g methyl (2Æ)-2-(7-benzyl-5-bromo-6-ethyl-pyrrolo[2,3-i(]pyrimidin-4yl)oxy-3-phenyl-propanoate (2.43 mmol), 1.98 g Préparation 3a (7.21 mmol), 110 mg Pd(OAc)₂ (0.49 mmol), 350 mg butyl-diadamantylphosphine (0.98 mmol), and 7.35 mL IM aqueous TBAOH in 18 mL DME was heated under MW irradiation at 100 °C until no further conversion was observed. The reaction mixture was filtered through Celite. Water was added to the filtrate, it was acidified to pH = 4 and extracted with MTBE. The

ORIGINAL

-85combined organic phases were dried over Na^SCL, filtered and the filtrate was concentrated under reduced pressure.

The residue was heated in a mixture of 10 mL MeOH and 40 pL cc. H2SO4 until no further conversion was observed. The volatiles were removed under reduced pressure, the residue 5 was diluted with water, the pH was set to 5, and it was extracted with DCM. The combined organic layers were dried over Na₂SO4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to obtain methyl (2Æ)-2-[7-benzyl-(5S’_ÎJ)-5-[3-chloro-2-methyl-4hydroxphenyl]-6-ethyl-pyrroIo[2,3-i7]pyrimidin-4-yl]oxy-3-phenyl-propanoate as the later I0 eiuting diastereoisomer. ^lH NMR (500 MHz, DMSO-d&) δ: 10.14 (s, IH), 8.27 (s, IH), 7.34-7.27 (m, 2H), 7.27-7.22 (m, IH), 7.17-7.07 (m, 4H), 7.05 (d, 2H), 6.98 (dd, IH), 6.64 (d, 2H), 5.60 (d, IH), 5.51 (d, IH), 5.43 (dd, IH), 3.56 (s, 3H), 3.00 (dd, IH), 2.85 (dd, IH), 2.60-2.51 (m, IH), 2.48-2.38 (m, IH), 2.04 (s, 3H), 0.84 (t. 3H)

Step D: Example 40

139 mg methyl (2/î)-2-[7-benzyl-(5S^, _a)-5-[3-chloro-2-methyl-4-hydroxphenyl]-6-ethylpyrrolo[2,3-i/]pyrimidin-4-yl]oxy-3-phenyl-propanoate (0.25 mmol), 72 mg l-(2-hydroxyethyl)-4-methylpiperazine (0.50 mmol) and 166 mg resin bound PPh₃ (0.5 mmol) were dissolved in 3 mL dry toluene under N₂ atmosphère, then 115 mg DTAD (0.5 mmol) was added. The mixture was stirred at 50 °C until no further conversion was 20 observed. The mixture was then diluted with DCM, filtered and the filtrate concentrated under reduced pressure, and purified via flash chromatography using heptane, EtOAc and MeOH as eluents. The obtained intermediate was dissolved in 10 mL MeOH, then 500 mg LiOHxH₂O was added, and the mixture was stirred at 50 °C until no further conversion was observed. The mixture was diluted with brine, neutralized with IM aqueous HCl 25 solution and extracted with DCM. The organic layer was dried over Na₂SÛ4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified via preparative reversed phase chromatography using 40 mM aqueous NH₄OAc solution (pH = 4, adjusted with AcOH) and MeCN as eluents to obtain Example 40. HRMS calculated for C3sH4₂ClN5O4: 667.2925, found: 668.2992 (M+H)

Example 41: iV-[6-bromo-7-(but-3-en-l-yl)-(5/f_fl)-5-(3-chloro-2-methylphenyl)-7/7ORIGINAL

-86pyrrolo[2,3-if]pyrimidin-4-yl]-Z)-phenylalanine and

Example 42: 7V-[6-bromo-7-(but-3-en-l-yl)-(55_ir)-5-(3-chloro-2-methylpiienyl)-7Hpyrrolo[2,3-i/]pyrimidin-4-yl]-Z)-phenylalanine

Step A: 7-but-3-enyl-4-chloro-5-iodo-pyrrolo[2,3-à]pyrimidine

5.0 g 4-chloro-5-iodo-7Z/-pyrrolo[2,3-i/]pyrimÎdine (17 mmol), 2.842 g K2CO3 (20.57 mmol), 2.15 mL 4-bromo-l-butene (20.57 mmol) and 26 mL dry DMF were stirred at r.t. under N₂ atmosphère until no further conversion was observed. Then the mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with water, dried over MgSOj, fîitered and the filtrate was concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc to obtain 7-but-3-enyl-4-chloro-5-iodo-pyrrolo[2,3-i/]pyrimidine.

'H NMR (400 MHz, CDCI3) Ô: 8.62 (s, IH), 7.38 (s, IH), 5.82-5.69 (m, IH), 5.08 (s, IH), 5.04 (dd, IH), 4.33 (t, 2H), 2.60 (q, 2H)

MS; (M+H)⁺ = 334.0

Step B: (2\A)-2-[(7-but-3-enyl-5-iodo-pyrrolo[2.3-<5]pyrimidin-4-yl)amino]-3-phenylpropanoic acid

Using General Procedure III and 7-but-3-enyl-4-chloro-5-iodo-pyrrolo[2,3-i7]pyrimidine as the appropriate 4-chloro-pyrrolo[2,3-i/]pyrimidine derivative and D-phenylalanine as the appropriate amino acid derivative, (2Â)-2-[(7-but-3-enyl-5-iodo-pyrrolo[2,3-i/]pyrimidin4-yl)amino]-3-phenyl-propanoic acid was obtained. ’H NMR (400 MHz, CDCI3) δ: 8.32 (s, IH), 7.38 (s, IH), 7.35-7.28 (m, 31-1), 7.28-7.22 (m, 2H), 7.02 (s, IH), 6.28 (d, IH), 5.80-

5.67 (m, IH), 5.09-5.04 (m, IH), 5.04-5.00 (s, IH), 4.94-4.85 (m, IH), 4.22 (t, 2H), 3.51 (dd, IH), 3.30 (dd, IH), 2.54 (q, 2H)

Step C: (2\k)-2-[[7-but-3-enyl-5-(3-chloro-2-methyl-phenyl)pyrrolo[2,3-d]pyrimidin-4-yl] ami) 10]-3 -phenyl-pi -opanoic acid

Using General Procedure IVb and (2Æ)-2-[(7-but-3-enyl-5-iodo-pyrrolo[2,3-i/]pyrimidin-4yl)amino]-3-phenyl-propanoic acid as the appropriate 5-iodo-pyrrolo[2,3-<f]pyrimidme derivative and Préparation 3c as the appropriate boronic acid derivative, (2Æ)-2-[[7-but-3ORIGINAL

- 87enyl-5-(3-chloro-2-methyl-phenyl)pyrrolo[2,3-i/]pyrimidin-4-yl]amino]-3-phenylpropanoic acid was obtained. 'H NMR (500 MHz, DMSO-dô) Ô: 12.86 (br s, IH), 8.24 (s, IH), 7.55-7.43 (m, IH), 7,33-6.95 (m, 6H), 6.89-6.80 (m, 2H), 5.84-5.40 (m. IH), 5.08-

4.93 (m, 3H), 4.84 (br s, IH), 4.37-4.15 (m, 2H), 3,l6(d, IH), 2.85 (dd, IH), 2.56 (q, 2H), 2.22-2.04 (s, 3H).

Step D: Examples 41 and 42

512 mg (2Æ)-2-[[7-but-3-enyl-5-(3-chloro-2-methyl-phenyl)pyrrolo[2,3-i/]pyrimidin-4-yl] amino]-3-phenyl-propanoic acid (1 mmol) was dissolved in 4.5 mL dry DMF and 187 mg NBS (i mmol) was added. The mixture was stirred at r.t. until no further conversion was observed. The mixture was then poured into water, extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified via préparative reversed phase chromatography using 0.1 % aqueous TFA solution and MeCN as eluents to obtain Example 41 as the earlier eluting diastereoisomer. HRMS calculated for C26H24BrClN4O₂: 538.0771, found: 541.0831 (M+H). Example 42 was obtained as the later eluting diastereoisomer. HRMS calculated for C₂6H₂4BrClN4O₂: 538.0771, found: 541.0835 (M+H)

Example 43: jV-[6-bronio-(5Æ_a)-5-(3-chloro-2-methylphenyl)-7-(prop-2-en-l-yl)-7//pyrrolo[2,3-//jpyiiniidin-4-vl|-£>-phenylalanine and

Example 44: 7V-|6-bromo-(55„)-5-(3-chloro-2-methylphenyl)-7-(prop-2-en-I-yl)-7/7pyrrolo|2,3-rf]pyriniidin-4-yl]-£)-phenylalanine

Step A: 7-allyl-4-chloro-5-iodo-pyirolo[2,3-d]pyrimidine

176.5 mg 4-chloro-5-iodo-7/7-pyiTolo[2,3-if|pyrimidine (0.6 mmol), 100.7 mg K₂CO₃ (0.73 mmol), 63 pL allyl bromide (0.73 mmol) and 1 mL dry DMF were stirred at r.t. under N₂ atmosphère until no further conversion was observed. Then the mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with water, dried over MgSO4. filtered and the filtrate was concentrated under reduced

ORIGINAL

-88pressure. The crude product was purified via flash chromatography using heptane and EtOAc to obtain 7-allyl-4-chloro-5-iodo-pyrrolo[2,3-</|pyrimidine. MS: (M+H)⁺ = 320.0

Step B: (2I3)-2-[(7-allyl-5-iodo-pyrrolo[2,3-à]pyrinûdin-4-yl)amino]-3-phenyl-propanoic acid

Using General Procedure III and 7-allyl-4-chloro-5-iodo-pyrrolo[2,3-i/]pyrimidine as the appropriate 4-chloro-pyrrolo[2,3-i/]pyrimidine dérivative and D-phenylalanine as the appropriate amino acid dérivative, (27î)-2-[(7-allyl-5-iodo-pyrrolo[2,3-i/]pyrimidin-4-yl) amino]-3-phenyl-propanoic acid was obtained.

‘H NMR (400 MHz, DMSO-d₆) δ: 13.09 (br s, IH), 8.20 (s, IH), 7.43 (s, IH), 7.34-7.18 (m, 5H), 6.52 (bd, IH), 6.05-5.90 (m, IH), 5.15 (dd. IH), 5.07-4.94 (m, 2H), 4.74 (d, 2H),

3.38 (dd, IH), 3.l5(dd, lH)

MS: (M+H)⁺ - 449.0

Step C: (2R)-2-[[7-allyl-5-(3-chloro-2-methyl-phenyl)pyrrolo[2,3-à]pyrimidin-4-yl] amino]-3-phenyl-propanoic acid

Using General Procedure IVb and (2Æ)-2-[(7-aliyl-5-iodo-pyrrolo[2,3-</]pyrimidin-4-yl) amino]-3-phenyl-propanoic acid as the appropriate 5-iodo-pyrrolo[2,3-t/]pyrimÎdine dérivative and Préparation 3c as the appropriate boronic acid dérivative, (2Æ)-2-[[7-allyl-

5-(3-chloro-2-methyl-phenyl)pyrrolo[2,3-i/]pyrimidin-4-yl]amino]-3-phenyl-propanoic acid was obtained.

'H NMR (400 MHz, DMSO-d₆) δ: 12.89 (br s, IH), 8.23 (s, IH), 7.59-7.42 (br, IH), 7.31-

7.10 (m, 6H), 6.91-6.81 (br, 2H), 6.12-5.98 (m, IH), 5.16 (dd, IH), 5.09-4.96 (m, 2H), 4.90-4.76 (br, 3H), 3.17 (dd, l H), 2.86 (dd. I H), 2.23-2.04 (br s, 3H)

MS: (M+H)⁺ = 447.0

Step D: Examples 43 and 44

447 mg (2/?)-2-[[7-allyl-5-(3-chloro-2-methyl-phenyl)pyrrolo[2,3-cf]pyrimidin-4-yl] amino]-3-phenyl-propanoic acid (l mmol) was dissolved in 4.5 mL dry DMF and 187 mg NBS (l mmol) was added. The mixture was stirred at r.t. until no further conversion was observed. The mixture was then poured into water, extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and the fîltrate was

ORIGINAL

-89concentrated under reduced pressure. The crude product was purified via préparative reversed phase chromatography using O.l % aqueous TFA solution and MeCN as eluents to obtain Example 43 as the earlier eluting diastereoisomer. HRMS calculated for C₂5H₂₂BrClN₄O₂: 524.0615, found: 525.0675 (M+H). Example 44 was obtained as the later eluting diastereoisomer. HRMS calculated for C₂5H₂₂BrClN₄O₂: 524.0615, found; 525.0674 (M+H)

Example 45; (2«)-2-[(7-benzyl-5-{3-chloro-2-mcthyl-4-[2-(4-methylpipcrazin-l-yl) ethoxy]phenyl}-7W-pyrrolo|2,3-rf]pyrimidin-4-yl)oxy]-3-phenylpropanoic acid

Step A: 7-benzyl-4-chloro-5-iodo-pyrrolo[2,3-d]pyrimidine

1.68 g 4-chloro-5-iodo-7/7-pyrrolo[2,3-i/]pyrimidine (6 mmol), 1.24 mL benzyl alcohol (12 mmol), 3.144 g PPh₃ (12 mmol) and 60 mL dry THF were cooled to 0 °C under N₂ atmosphère, then 5.5 mL DEAD solution (12 mmol, 40 % in toluene) was added and the mixture was stirred at 40 °C until no further conversion was observed. Then the mixture was poured into water and extracted with Et₂O. The combined organic layers were washed with water, dried over MgSO₄, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc to obtain 7-benzyl-4-chloro-5-iodo-pyrrolo[2,3-J]pyrimidine.

‘H NMR (500 MHz, DMSO-d₆) δ: 8.67 (s, IH), 8.12 (s, IH), 7.32 (t, 2H), 7.28 (t. IH),

7.28 (d, 2H), 5.47 (s, 2H)

MS (M+H): 369.9

Step B: Methyl (2^)-2d7-benzy4'5âodo-pyrrolo[2,3-à]pyiiimdin-4-yl)oxy-3-phenylpropanoate eq. 7-benzyl-4-chloro-5-iodo-pyrrolo[2,3-i7]pyrimidine, 3 eq. methyl (2/?)-2-hydroxy-3phenyl-propanoate, 3 eq. Cs₂CO₃ and dry DMSO (6 mL/mmol) were stirred at 100 C until no further conversion was observed. The mixture was acidified with IM aqueous HCl solution, and extracted with DCM. The organic layer was dried over Na₂SO₄, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to give methyl (2/?)-2-(7benzyl-5-iodo-pyrrolo[2,3-i/]pyrimidin-4-yl)oxy-3-phenyl-propanoate. MS (M+H): 514.1

ORIGINAL

-90Step C: Example 45

Using General Procedure IVb and methyl (27?)-2-(7-benzyl-5-iodo-pyrroIo[2,3-i7] pyrimidin-4-yl)oxy-3-phenyl-propanoate as the appropriate 5-iodo-pyrrolo[2,3-</] pyrimidine dérivative and Préparation 3b as the appropriate boronic acid dérivative, methyl (2tf)-2-[7-benzyl-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 -yl)ethoxy] phenyl]pyrrolo[2,3-i/]pyrimidin-4-yH oxy-3-phenyl-propanoate was obtained. It was dissolved in dioxane:water l:l (20 mL/mmol) and 10 eq. LiOH^HiO was added. The mixture was stirred at r.t. until no further conversion was observed. Then it was diiuted with brine, neutralized with 2M aqueous HCl solution, extracted with DCM. The combined organic phases were dried over Na₂SO₄, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified via préparative reversed phase chromatography using 0.1 % aqueous TFA solution and MeCN as eluents to obtain Example 45. HRMS calculated for C36H38CIN5O4: 639.2612, found: 640.2654 (M+H)

Example 46: /V-[5-(3-chIoro-2-mcthylphenyl)-7,8-(lihydro-6ff-pyrimido[5,4-i>] pyrrolizin-4-yll-i)-phenylalanine

210 mg 1:1 mixture of Examples 43 and 44 (mixture of the two diastereoisomers, 0.4 mmol) was dissolved in 3 mL MeOH and 70 pL cc. H2SO4 (1.2 mmol) was added. The mixture was stirred at r.t. until no further conversion was observed. The mixture was poured into icy water, neutralized with saturated aqueous NaHCO₃ solution and extracted with EtOAc. The combined organic phases were washed with brine, dried over MgSO₄, filtered and the filtrate was concentrated under reduced pressure. Then it was dissolved in dry THF (6 mL/mmol), and was cooled to 0 °C. 5 eq. 9-borabicyclo[3.3.1]nonane solution (0.5M in THF) was added and the mixture was stirred at r.t. until no further conversion was observed. Then 20 eq. 2M aqueous NaOH solution and 20 mol% PdC12^xdppf was added. The mixture was stirred at 80 °C until no further conversion was observed. Then it was filtered through Celite, washed with EtOAc. The layers of the filtrate were separated, the aqueous layer was acidified to pH 3 with 2M aqueous HCl solution, then extracted with EtOAc. The combined organic phases were dried over Na2SO₄, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified via préparative

ORIGINAL

-91reversed phase chromatography using 40 mM aqueous NH4OAC solution (pH = 4, adjusted with AcOH) and MeCN as eluents to obtain Example 46 as a mixture of diastereoisomers. HRMS calculated for C25H23CIN4O2: 446.1510, found: 447.159 and 447.1591 (M+H)

Example 47:7V-[(57î_a)-5-(3-chloro-2-methylphenyl)-6,7,8,9-tetrahydropyrimido|5,4-i»| indolizin-4-yl]-Z)-phenylalanine and

Example 48: A-[(5S„)-5-(3-chloro-2-niethylphenyl)-6,7,8,9-tetrahydropyriniido|5,4-/)| indolizin-4-yl]-Z>-phenylalanine

1.29 g 1:1 mixture of Examples 41 and 42 (mixture of the two diastereoisomers,

2.3 mmol) was dissolved in 10 mL MeOH and 0.4 mL cc. H2SO4 (6.9 mmol) was added. The mixture was stirred at r.t. until no further conversion was observed. The mixture was poured into icy water, neutralized with saturated aqueous NaHCO3 solution and extracted with EtOAc. The combined organic phases were washed with brine, dried over MgSO₄, filtered and the filtrate was concentrated under reduced pressure. Then it was dissolved in dry THF (6 mL/mmol), and was cooled to 0 °C. 5 eq. 9-borabicyclo[3.3.1]nonane solution (0.5M in THF) was added and the mixture was stirred at r.t. until no further conversion was observed. Then 20 eq. 2M aqueous NaOH solution and 20 mol% PdCl₂ ^xdppf was added. The mixture was stirred at 80 °C until no further conversion was observed. Then it was filtered through Celite, washed with EtOAc. The layers of the filtrate were separated, the aqueous layer was acidified to pH 3 with 2M aqueous HCl solution, then extracted with EtOAc. The combined organic phases were dried over Na₂SO4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified via préparative reversed phase chromatography using 0.1 % aqueous TFA solution and MeCN as eluents. Example 47 was obtained as the earlier eluting diastereoisomer. HRMS calculated for C₂6H₂5C1N4O₂: 460.1666, found: 461.1747 (M+H). Example 48 was obtained as the later eluting diastereoisomer. HRMS calculated for C₂6H₂5C!N4O₂: 460.1666, found: 461.1752 (M+H)

Example 49: (2Æ)-2-{|(3S_a)-3-(3-chloro-4-hydroxy-2-methylphenyl)-2-ethyl-lbenzothiophen-4-yl|oxy}-3-phenylpropanoic acid

ORIGINAL

-92and

Example 50: (2/?)-2-{|(37î_i,)-3-(3-chloro-4-hydroxy-2-methylphenyl)-2-ethyl-lbenzothiophen-4-yl]oxy}-3-phenylpropanoic acid

Step A: (2R)-2-(2-ethylbemothiophen-4-yl)oxy-3-phenyl-propanoic acid

270 mg (2Æ)-2-hydroxy-3-phenyl-propanoic acid (1.63 mmol), 40 mg Cul (0.21 mmol) and 325 mg CS2CO3 (l mmol) were measured into a 7 mL vial equipped with screw cap and rubber septum. The vial was purged with argon and 5 mL dry DMF and 288 mg 2-ethyl-4-iodo-benzo[6]thiophene (l mmol) were added by syringe. The mixture was stirred at HO °C in dark for 20 hours. Ail further steps were carried out in dark or at red 10 light. 10 mL water was added and the pH was set to 3 with 2M aqueous HCl solution. Then it was extracted with EtOAc. The combined organic layer was dried over Na₂SO4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified on a preparative TLC plate (siiica layer, toluene:AcOH 9:l eluent) to obtain (2/?)-2-(2ethylbenzothiophen-4-yl)oxy-3-phenyl-propanoic acid. ’H NMR. (500 MHz, DMSO-dô) δ: 15 12.53 (br s, IH), 7.42-7.36 (m, 3H), 7.30 (t, 2H), 7.25-7.18 (m, IH), 7.13 (t, IH), 7.07 (br,

IH), 6.65 (d, lH), 4.98 (dd, lH), 3.29 (dd, lH), 3.22 (dd, IH), 2.89 (q, 2H), I.30 (t,3H)

Step B: Methyl (2R)-2-(2-ethylbenzothiophen-4-yl)oxy-3-phenyl-propanoate

1.434 g (2/Î)-2-(2-ethylbenzothiophen-4-yl)oxy-3-phenyl-propanoic acid (4.39 mmol) was dissolved in 20 mL MeOH and 20 pL cc. H2SO4 was added. The mixture was stirred at 20 80 °C until no further conversion was observed. The mixture was concentrated under reduced pressure, then diluted with water, neutralized with saturated aqueous NaHCO3 solution and extracted with DCM. The combined organic phases were washed with brine, dried over MgSO₄, filtered and the filtrate was concentrated under reduced pressure to obtain methyl (27î)-2-(2-ethylbenzothiophen-4-yl)oxy-3-phenyl-propanoate. *H NMR (400 25 MHz. CDCI3) Ô: 7.46-7.33 (m, 5H), 7.33-7.26 (m, IH), 7.16 (bd, IH), 7.13 (t, IH), 6.65 (d, IH), 4.99 (dd, IH), 3.75 (s, 3H), 3.46-3.32 (m, 2H), 3.01-2.9I (m, 2H), 1.42 (t, 3H)

Step C: Methyl (2R.)-2-(2-ethyl-3-iodo-benzothiophen-4-yl)oxy-3-phenyl-propanoate

1.278 g methyl-(2R)-2-(2-ethylbenzothiophen-4-yl)oxy-3-phenyl-propanoate (3.75 mmol), 2.284 g I₂ (9 mmol), and 2.5 g Ag₂SO4 (8 mmol) were dissolved in 10 mL EtOH and

ORIGINAL

-93stirred at r.t. until no further conversion was observed. The mixture was then filtered, the filtrate was concentrated under reduced pressure and purified via flash chromatography using heptane and EtOAc as eluents to obtain 860 mg methyl (2/?)-2-(2-ethyl-3,7-diiodobenzothiophen-4-yl)oxy-3-phenyI-propanoate that was dissolved in 20 mL THF, 150 mg 10 % Pd/C was added and the mixture was stirred at r.t. under 4 bar H₂ atmosphère until no further conversion was observed. Then it was filtered through Celite, the filtrate was concentrated under reduced pressure and purified via flash chromatography using heptane and EtOAc as eluents to obtain methyl (2/?)-2-(2-ethyl-3-iodo-benzothiophen-4-yl)oxy-3phenyl-propanoate. ’H NMR (500 MFIz, DMSO-d₆) δ: 7.53 (d, IH), 7.49-7.41 (m, 2H), 7.34-7.27 (m, 2H), 7.26-7.18 (m, 2H), 6.77 (d, IH), 5.33 (dd, IH), 3.61 (s, 3H), 3.43 (dd, IH), 3.32 (dd, 1 H), 2.94-2.85 (m, 2H), 1.25 (t, 3H)

Step D: Examples 49 and 50

320 mg methyl (2/?)-2-(2-ethyl-3-iodo-benzothiophen-4-yl)oxy-3-phenyl-propanoate (0.686 mmol) and 368 mg Préparation 3a (1.37 mmol) were dissolved in 4 mL 2-Me-THF under N₂ atmosphère, then 1.37 mL TBAOH solution (1.37 mmol, IM in THF) and 49 mg AtaPhos (0.069 mmol) were added and the mixture was stirred at 90 °C in a closed vial until no further conversion was observed. Then it was diluted with 30 mL DCM, washed with 10 mL IM aqueous HCl solution. The organic layer was concentrated under reduced pressure, then dissolved in 5 mL MeOH. 100 mg LiOHxHiO was added, and the mixture was stirred at 50 °C until no further conversion was observed. Then it was diluted with brine, neutralized with IM aqueous HCl solution and extracted with DCM. The organic layer was dried over Na^SOj, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified via préparative reversed phase chromatography using 0.1 % aqueous TFA solution and MeCN as eluents. Example 49 was obtained as the later eluting diastereoisomer. HRMS calculated for C26H23CIO4S: 466.1006, found: 465.0956 (M-H). Example 50 was obtained as the earlier eluting diastereoisomer. HRMS calculated for C26H23CIO4S: 466.1006, found: 465.0971 (M-H)

Example 51 : (2Æ)-2-|((3_tS^TJ-3-{3-cliloiO-2-rnethyI-4-|2-(4-iiiethylpipei;izin-l-vl)ethoxy | phenyl}-2-ethyI-l-benzothiophen-4-yl)oxy]-3-phenylpropanoic acid

ORIGINAL

-94Step A: Methyl (2R)-2-[3-(3-chloro~4-hydroxy-2-methyl-phenyl)-2-ethyl-benzothiophen-4yl] oxy-3 -phenyl -propanoate

140 mg Example 49 (0.3 mmol) was dissolved in 3 mL MeOH and 50 pL cc. H2SO4 was added. The mixture was stirred at 80 °C until no further conversion was observed. The mixture was concentrated under reduced pressure and the residue was diluted with water, neutralized with saturated aqueous NaHCO₃ solution and extracted with DCM. The combined organic phases were washed with brine, dried over MgSÛ4, fîltered and the filtrate was concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to obtain methyl (2Æ)-2-[3-(3-chloro4-hydroxy-2-methyl-phenyl)-2-ethyl-benzothiophen-4-yl]oxy-3-phenyl-propanoate.

‘H NMR (500 MHz, DMSO-d₆) δ: 10.02 (s, IH), 7.49 (d, IH), 7.23-7.12 (m, 4H), 7.02 (d, IH), 6.92 (d, IH), 6.89-6.86 (m, 2H), 6.62 (d, IH), 5.01 (dd, IH), 3.50 (s, 3H), 2.72 (dd, lH), 2.60-2.51 (m, 2H), 2.38 (dd, lH), l .96 (s, 3H), l. 12 (t, 3H)

Step B: Example 51 mg methyl (2Æ)-2-[3-(3-chloro-4-hydroxy-2-methyl-phenyl)-2-ethyl-benzothiophen-4yl]oxy-3-phenyl-propanoate (0.13 mmol), 23 mg l-(2-hydroxyethy!)-4-methylpiperazine (0.156 mmol) and 41 mg PPh₃ (0.156 mmol) were dissolved in 2 mL dry THF under N₂ atmosphère, then 36 mg DTAD (0.156 mmol) was added. The mixture was stirred at 50 °C until no further conversion was observed. The mixture was then concentrated under reduced pressure, and purified via flash chromatography using heptane, EtOAc and MeOH as eluents. The obtained intermediate was dissolved in 5 mL MeOH, then 100 mg LiOHxH₂O was added, and the mixture was stirred at 50 °C until no further conversion was observed. Then it was diluted with brine, neutralized with 1 M aqueous HCl solution and extracted with DCM. The organic layer was dried over Na₂SO4, fîltered and the filtrate was concentrated under reduced pressure. The crude product was purified via preparative reversed phase chromatography using 40 mM aqueous NH4OAC solution (pH = 4, adjusted with AcOH) and MeCN as eluents to obtain Example 51. HRMS calculated for C₃₃H₃7C1N₂O₄S: 592.2163, found: 593.2238 (M+H)

Example 52: (2Æ)-2-{|(3/ï₍,)-3-{3-chloro-2-methyl-4-|2-(4-methylpiperazin-lyI)ethoxy]phenyl}-2-(4-fluorophenyl)-l-benzotliiophen-4-yl|oxy}-3-(2-{[2-(2ORIGINAL

-95methoxyphenyl)pyrimidin-4-yl] methoxy}phenyl)propanoic acid and

Example 53: (27î)-2-{[(35_(J)-3-{3-chloro-2-methyl-4-|2-(4-methyIpiperazin-l-yl)ethoxy] phenyI}-2-(4-fluorophenyl)-l-benzothiophen-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl) pyrimidin-4-yl]methoxy}phenyl)propanoic acid

Step A: (3-bromophenyl) N,N-diethylcarbamate

5.0 g 3-bromophenol (28.9 mmol) and 4.31 g diethylcarbamoyl chloride (31.8 mmol) were dissolved in 50 mL pyridine and stirred at l00°C until no further conversion was observed. Then the mixture was concentrated under reduced pressure and purified via flash chromatography using heptane and EtOAc as eluents to obtain (3-bromophenyl) Λζ/V-diethylcarbamate. MS (El, 70 eV) m/z (% relative intensity, [ion]): 56 (9), 72 (42), 100 (100), 174 (4), 176 (4), 271 (4, [M⁺]), 273 (4, [M⁺])

Step B: (3-bromo-2-iodo-phenyl) NN-diethylcarbamate

2.72 g (3-bromophenyl) AÇ/V-diethylcarbamate (10 mmol) was dissolved in 50 mL dry THF under N₂ atmosphère and cooled to -78 °C. 6 mL LDA solution (12 mmol, 2M in THF, heptane, ethyl benzene) was added and the mixture was stirred al -78 °C for 30 minutes. Then 3.18 g I₂ (12.5 mmol) was added and the mixture was stirred at -78 °C for 30 minutes then it was allowed to warm up to r.t. Then the mixture was concentrated under reduced pressure and purified via flash chromatography using heptane and EtOAc as eluents to obtain (3-bromo-2-iodo-phenyl) ZV,/V-diethylcarbamate. 'H NMR (400 MHz, DMSO-d₆) 5:

7.60 (dd, IH), 7.35 (t, IH), 7.17 (dd, IH), 3.47 (q, 2H), 3.31 (q, 2H), 1.27 (t. 3H), 1.14 (t, 3H)

Step C: [3-bromo-2-[2-(4-fluorophenyl)ethynyl]phenyl] N,N-dîelhylcarbamate

2.60 g (3-bromo-2-iodo-phenyl) MA-diethylcarbamate (6.53 mmol), 863 mg 1 -ethynyl-4fluorobenzene (7.19 mmol), 229 mg Pd(PPh3)₂Cl₂ (0.33 mmol), 130 mg copper(l) iodide (0.65 mmol) and 1.43 g diethylamine (19.6 mmol) were dissolved in 25 mL dry DMF and stirred at 50 °C until no further conversion was observed. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO₄, filtered and the filtrate was concentrated under reduced pressure. The

ORIGINAL

-96crude product was purified via flash chromatography using heptane and EtOAc as eluents to obtain [3-bromo-2-[2-(4-fluorophenyl)ethynyl]phenyl] AÇ/V-diethylcarbamate. MS (El, 70 eV) m/z (% relative intensity, [ion]): 56 (2), 72 (35), 100 (100), 261 (2), 263 (2), 389 (2, [M⁺]), 391 (2, [M⁺])

Step D: [2-[2-(4-fluorophenyl)ethynyl]-3-methylsulfanyl-phenyl] N,N-diethylcarbamate

2.5 g [3-bromo-2-[2-(4-fluorophenyl)ethynyl]phenyl] jV,/V-diethylcarbamate (6.56 mmol) was dissolved in 65 mL dry THF and cooled to -78 °C, then 4.3 mL ⁿBuLi solution (6.88 mmol, 1.6M in hexanes) was added. The mixture was stirred at -78 °C for 30 minutes. Then 742 mg S₂Me₂ (7.87 mmol) was added and the mixture was stirred at -78 °C for 30 minutes, then it was allowed to warm up to r.t. The mixture was then concentrated under reduced pressure and purified via flash chromatography using heptane and EtOAc as eluents to obtain [2-[2-(4-fiuorophenyl)ethynyl]-3-methylsulfanyl-phenyl] A’.jV-dicthylcarbamate. MS (El, 70 eV) m/z (% relative intensity, [ion]): 56 (2), 72 (46), 100 (100), 342 (40), 357 (1, [M⁺])

Step E: [2-(4-fluorophenyl)-3-iodo-benzothiophen-4-ylJ N.N-diethylcarbamate

1100 mg 2-[2-(4-fluorophenyl)ethynyl]-3-methylsulfanyl-phenyl] A’jV-dicthyicarbamate (3.08 mmol) and 937 mg 1₂ (3.7 mmol) were dissolved in 20 mL DCM and stirred at r.t. until no further conversion was observed. The mixture was then diluted with 10 % aqueous Na₂S₂O₃ solution and extracted with DCM. The combined organic layers were washed with brine, to give [2-(4-fluorophenyl)-3-iodo-benzothiophen-4-yl] /V./V-diethylcarbamate.

’H NMR (400 MHz, CDC1₃) δ: 7.74 (dd, IH), 7.56 (m. 2H), 7.40 (t, IH), 7.18 (m, 2H),

7.12 (dd, 1 H), 3.60 (q,2H), 3.46 (q, 2H), 1.36 (t, 3H), 1.26 (t.3H)

MS (El, 70 eV) m/z (% relative intensity, [ion]): 72 (42), 100 (100), 170 (16), 342 (37), 369(5), 469 (1, [M⁺])

Step F: [3-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-2-(4-fluoro phenyl)benzothiophen-4-yl] N.N-diethyÎcarbainate eq. [2-(4-fluorophenyl)-3-iodo-benzothiophen-4-yl] ?V,N-diethylcarbamate, 2 eq. Préparation 3b, 2 eq. Cs₂CO₃, 0.1 eq. Ataphos and THF:water 3:1 (10 mL/mmol benzothiophene dérivative) were stirred under N₂ atmosphère at 70 °C until no further

ORIGINAL

-97conversion was observed. The mixture was diluted with water and extracted with DCM. The organic phase was dried over MgSO₄, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to give [3-[3-chloro-2-methyl-4-[2-(4-methyipiperazin-lyl)ethoxy]phenyl]-2-(4-fluorophenyl)benzothiophen-4-yl] A,A/-diethylcarbamate. MS: (M+H)⁺= 610.2

Slep G: 3-[3-chloro-2-methylM-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-2-(4-fluoro phenyl)benzothiophen-4-ol

1.8 g [3-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-2-(4-fluoro phenyl)benzothiophen-4-yl] /V,A-diethylcarbamate (3 mmol) was dissolved in 80 mL EtOH and 1.2 g NaOH (30 mmol) was added. The mixture was stirred at 80 °C until no further conversion was observed. The mixture was concentrated under reduced pressure and purified via flash chromatography using DCM and MeOH as eluents to obtain 3-[3-chloro2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-2-(4-fluorophenyl)benzothiophen4-ol. MS:(M+H)⁺ = 511.2

Step H: Examples 52 and 53

470 mg 3-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-2-(4-fluoro phenyl)benzothiophen-4-ol (0.92 mmol), 1.12 g Préparation 2d (2.76 mmol) and 726 mg PPh₃ (2.76 mmol) were dissolved in 10 mL dry toluene, then 635 mg DTAD (2.76 mmol) was added. The mixture was stirred at 50 °C until no further conversion was observed. The mixture was then concentrated under reduced pressure and purified via flash chromatography using heptane and EtOAc as eluents. The formed intermediate was dissolved in 10 mL dioxane:water 1:1,400 mg LiOHxH₂O was added, and the mixture was stirred at r.t. until no further conversion was observed. It was neutralized with 2M aqueous HCl solution and extracted with DCM. The combined organic phases were dried over Na₂SO₄, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified via preparative reversed phase chromatography using 25 mM aqueous NH₄HCO₃ solution and MeCN as eluents. Example 52 was obtained as the earlier eluting diastereoisomer. HRMS calculated for C₄₉H₄6C1FN₄O6S: 872.2811, found: 437.1457

ORIGINAL

-98(M+2H). Example 53 was obtained as the later eluting diastereoisomer. HRMS calculated for C4₉H4₆ClFN₄O₆S: 872.2811, found: 437.1491 (M+2H)

Example 54: 2-benzyl-3-[3-(3-chloro-4-hydroxy-2-methylphenyl)-2-ethyl-lbenzothiophen-4-yl]propanoic acid

Step A: Methyl (Z)-2-benzyl-3-(2-ethylbenzothiophen-4-y!)prop-2-enoate

576 mg 2-ethyl-4-iodo-benzo[ô]thiophene (2 mmol), 717 mg methyl 2-benzylacrylate (4 mmol), 556 pL TE A (4 mmol) and 24 mg PdCl₂ (0.1 mmol) were dissolved in 10 mL DMF and stirred at 130 °C in a MW reactor until no further conversion was observed. The mixture was concentrated under reduced pressure and purified via flash chromatography using heptane and EtOAc as eluents to obtain methyl (Z)-2-benzyl-3-(2ethylbenzothiophen-4-yl)prop-2-enoate. '14 NMR (400 MHz, CDCI3) ratio of diastereoisomers 1.00 ! Ο.ΊΊ — major / minor, δ: 8.06-8.28 (s, IH), 7.68-7.76 (d, 111), 7.44-

6.98 (m, 8H), 4.25-3.93 (s, 2H), 3.78-3.82 (s, 3H), 2.97-2.99 (q, 214), 1.41-1.43 (t, 3H)

Step B: Methyl 2-benzyl-3-(2-eihylbenzothiophen-4-yl)propanoate

432 mg methyl (Z)-2-benzyl-3-(2-ethylbenzothiophen-4-yl)prop-2-enoate (1.28 mmol), 137mg 10% Pd/C, 5 mL AcOH and 20 mL MeOH were stirred under 4 bar FL atmosphère at r.t. until no further conversion was observed. The mixture was filtered through Celite, the filtrate was concentrated under reduced pressure and purified via flash chromatography using heptane and EtOAc as eluents to obtain methyl 2-benzyl-3-(2ethylbenzothiophen-4-yl)propanoate. *H NMR (400 MHz, CDCI3) Ô: 7.61 (d, IH), 7.j87.05 (m, 7H), 6.80 (s, 114), 3.50 (s, 3H), 3.28-3.18 (m, IH), 3.11-3.00 (m, 314), 2.90 (q, 214), 2.86-2.77 (m, IH), 1.35 (t, 3H)

Step C: Methyl 2-benzyl-3-(2-ethyl-3-iodo-benzothiophen-4-yl)propanoate

346 mg methyl 2-benzyl-3-(2-ethyibenzothiophen-4-yl)propanoate (1.02 mmol), 305 mg I₂ (1.2 mmol) and 468 mg Ag₂SO₄ (1-5 mmol) were dissolved in 5 mL EtOH and stirred at r.t. until no further conversion was observed. The mixture was filtered, the filtrate was concentrated under reduced pressure and purified via flash chromatography using heptane and EtOAc as eluents to obtain methyl 2-benzyl-3-(2-ethyl-3-iodo-benzothiophen-4OR1GINAL

-99yl)propanoate. ^lH NMR (400 MHz, CDCI3) δ: 7.67 (dd, IH), 7.28-7.06 (ni, 7H), 4.29-4.17 (m. IH), 3.80-3.71 (m, IH), 3.32 (s, 3H), 3.28-3.21 (m. IH), 3.08-3.00 (m, 2H), 2.97 (q, 2H), l.35(t,3H)

Step D: Example 54 l eq. methyl 2-benzyl-3-(2-ethyl-3-iodo-benzothiophen-4-yl)propanoate, 2 eq. Préparation 3a, 2 eq. TBAOH solution (IM in water), O.l eq. Ataphos and 2-Me-THF (5 mL/mmol benzothiophene dérivative) were stirred under N₂ atmosphère at 100 °C until no further conversion was observed. The mixture was diluted with water and extracted with DCM. The organic layer was dried over Na₂SO₄, filtered and the filtrate was concentrated under reduced pressure. The formed intermediate was dissolved in MeOH (5 mL/mmol benzothiophene dérivative), 10 eq. LiOH^xH₂O was added, and the mixture was stirred at r.t. until no further conversion was observed. It was neutralized with 2M aqueous HCl solution and extracted with DCM. The combined organic phases were dried over Na₂SO₄, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified using préparative reversed phase chromatography using 0.1 % aqueous TFA solution and MeCN as eluents to give Example 54. HRMS calculated for C₂₇H₂₅C1O₃S: 464.1213, found: 463.1158 (M-H)

Example 55: (2/Î)-2-{((lÆ_fl)-l-{3-chloro-2-methyl-4-12-(4-methylpiperazin-lyl)ethoxy]phenyl)-2-(4-fluorophenyl)-l//-indol-7-yl]oxy}-3-(2methoxyphenyl)propanoic acid and

Example 56: (2Æ)-2-{[(15_(/)-l-{3-chloro-2-niethyl-4-I2-(4-methylpiperazin-l-yl)ethoxy| phenyl)-2-(4-fluorophenyl)-l//-indol-7-yl]oxy}-3-(2-methoxyphenyl)propanoic acid

600 mg Préparation 7b (0.86 mmol) was dissolved in 20 mL dioxane:water 1:1 and 600 mg LiOHxFbO was added. The mixture was stirred at r.t. until no further conversion was observed. Then it was diluted with water, acidified with IM aqueous HCl solution and extracted with DCM. The combined organic phases were dried over Na₂SO₄, filtered and the filtrate was concentrated under reduced pressure and purified via préparative reversed phase chromatography using 25 mM aqueous NH₄HCO₃ solution and MeCN as eluents.

ORIGINAL

- 100Example 55 was obtained as the earlier eluting diastereoisomer. HRMS calculated for C38H39CIFN3O5: 671.2562, found: 672.2618 (M+H). Example 56 was obtained as the later eluting diastereoisomer. HRMS calculated for C38H39CÎFN3O5: 671.2562, found: 672.2652 (M+H)

Example 57: (2«)-2-{[3-chloro-(lS_a)-l-{3-chloro-2-methyI-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-2-(4-fluorophenyl)-l H-indol-7-yl|oxy}-3-(2methoxyphenyl)propanoic acid

240 mg Préparation 7b (0.34 mmol) was dissolved in 3 mL DCM and 46 mg NCS (0.34 mmol) was added. The mixture was stirred at r.t. until no further conversion was observed. Then it was diluted with water and extracted with DCM. The combined organic phases were dried over Na₂SO₄, filtered and the filtrate was concentrated under reduced pressure. Then it was dissolved in 5 mL dioxane:water 1:1 and 140 mg LiOH^xH₂O was added. The mixture was stirred at r.t. until no further conversion was observed. Then it was diluted with water, acidified with IM aqueous HCl solution and extracted with DCM. The combined organic phases were dried over NaiSCfr, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents. Example 57 was obtained as the later eluting diastereoisomer. HRMS calculated for C3sH3₈C12FN3O₅: 705.2173, found: 706.2227 (M+H)

Example 58: (2Æ)-2-{[(l/f_fl)-l-{3-chloro-2-mcthyl-4-|2-(4-inethylpiperazin-lyI)ethoxy]phenyl}-2-(furan-2-yl)-lH-indol-7-yl|oxy}-3-(2-methoxyphenyl)propanoic acid and

Example 59: (27f)-2-{[(lS_fl)-l-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy] phenyl}-2-(furan-2-yl)-l//-indol-7-yl]oxy}-3-(2-methoxyphenyl)propanoic acid and

Example 60: (27î)-2-{[(15_u)-l-{3-chloro-2-methyl-4-|2-(4-methylpiperazin-l-yl)ethoxy] phenyl}-2-(5-fluorofuran-2-yl)-lF7-indol-7-yl]oxy}-3-(2-methoxyphenyl)propanoic acid

ORIGINAL

- ΙΟΙStep A: 4-[7-benzyloxy-2-(5-fluoro-2-furyl)indol-1 -yl]-2-chloro-3-methyl-phenol

1360 mg Préparation 7a (2 mmol), 848 mg 2-(5-fluoro-2-furyl)-4,4,5,5-tetramethyl-1,3,2dioxaborolane (4 mmol), 2123 mg K3PO4 (10 mmol), 45 mg Pd(OAc)₂ (0.2 mmol) and 164 mg SPhos (0.4 mmol) were dissolved in 30 mL dry toluene and stirred at 75 °C until no further conversion was observed. The solvent was then removed under reduced pressure, the residue was purified via flash chromatography using heptane and EtOAc as eluents. Then 2 mL TBAF solution (2 mmol, IM in THF) and 25 mL THF were added and the mixture was stirred at r.t. until no further conversion was observed. Then the mixture was concentrated under reduced pressure, and the residue was purified via flash chromatography using heptane and EtOAc as eluents to give 4-[7-benzyloxy-2-(5-fiuoro-2furyl)indol-l-yl]-2-chloro-3-methyl-phenol. MS: (M+H)⁺ = 448.0

Step B: 7-benzyloxy-1 -[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 -yl)ethoxy]phenyl]-2(5-fluoro-2-fitryl)indole

650 mg 4-[7-benzyloxy-2-(5-fluoro-2-furyI)indol-l -yl]-2-chloro-3-methyl-phenol (1.01 mmol), 288 mg l-(2-hydroxyethyl)-4-methylpiperazine (2 mmol) and 786 mg PPI13 (3 mmol) were dissolved in 20 mL dry toluene. Then 690 mg DTAD (3 mmol) was added and the mixture was stirred at 45 °C until no further conversion was observed. Then it was concentrated under reduced pressure, and was purified via flash chromatography using DCM and MeOH as eluents to give 7-benzyloxy-l-[3-chloro-2-methyl-4-[2-(4-methyl piperazin-l-yl)ethoxy]phenyl]-2-(5-fluoro-2-furyl)indole. MS: (M+H)⁺ = 574.2

Step C: The mixture of 1 -[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l -yl)ethoxy]phenyl]2-(2-furyl)indol-7-ol and /-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 -yl)ethoxy] phenyl]-2-(5-fluoro-2-furyT)indol-7-ol

1300 mg 7-benzyloxy-1 -[3-chloiO-2-methyl-4-[2-(4-methylpiperazin-1 -yl)ethoxy]phenyl]2-(5-fluoro-2-furyl)indole (2.26 mmol) was dissolved in 100 mL MeOH and 100 mg 10 % Pd/C was added. The mixture was stirred under 1 bar H₂ atmosphère at r.t. overnight. The mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to give a 7:3 mixture of l-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl]-2-(2-furyl)indoI-7-ol (MS: (M+H)⁺ = 466.2) and l-[3-chloro-2-methylORIGINAL

- 1024-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-2-(5-fluoro-2-furyl)indol-7-ol (MS: (M+H)^T = 484.2).

Step D: Examples 58, 59 and 60

465 mg of the 7:3 mixture of l-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl]-2-(2-furyl)indol-7-ol and l -[3-chloro-2-methyl-4-[2-(4-methylpiperazinl-yl)ethoxy]phenyl]-2-(5-fluoro-2-furyl)indol-7-ol (l mmol), 449 mg ethyl (25)-2hydroxy-3-phenyl-propanoate (2 mmol) and 786 mg PPhj (3 mmol) were dissolved in 10 mL dry toluene. Then 691 mg DTAD (3 mmol) was added and the mixture was stirred at 45 °C until no further conversion was observed. Then it was concentrated under reduced pressure, and the residue was purified via flash chromatography using DCM and MeOH as eluents. Then it was dissolved in 5 mL dioxanerwater l:l and 140 mg LiOH^HiO was added. The mixture was stirred at r.t. until no further conversion was observed. Then it was diluted with water, acidified with l M aqueous HCl solution and extracted with DCM. The combined organic phases were dried over Na₂SÛ4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents. Example 58 was obtained as the earlier eluting dîastereoisomer. HRMS calculated for C3₆H3₈ClN3O6: 643.2449, found: 644.2512 (M+H). Example 59 was obtained as the later eluting dîastereoisomer. HRMS calculated for C36H38CIN3O6: 643.2449, found: 644.2521 (M+H). Example 60 was obtained as the later eluting dîastereoisomer. HRMS calculated for C36H3₇CIFN3O₆: 661.2355, found: 662.2411 (M+H)

Example 61: (2Æ)-2-{|(3/f_a)-3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-2-(4-fliiorophenyl)-l-benzofiiran-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid and

Example 62: (2Æ)-2-{[(35'„)-3-{3-chloro-2-methyI-4-[2-(4-methylpipcrazin-l-yl)ethoxy| phenyI}-2-(4-fluorophenyl)-l-benzofuran-4-yl|oxy}-3-(2-niethoxyphenyl)propanoic acid

Step A: Ethyl (2S>)-3-(2-methoxyphenyl)-2-(p-tolylsulfonyloxy)propanoate

ORIGINAL

- 1033000 mg Préparation 2f (13.38 mmol) was dissolved in 10 mL pyridine and 2933 mg TsCl (15.38 mmol) was added at 0 °C. The mixture was stirred at r.t. until no further conversion was observed. Then the mixture was diluted with water and extracted with EtOAc. The combined organic phases were washed with IM aqueous citric acid solution, dried over Na₂SO₄, filtered and the filtrate was concentrated under reduced pressure to give ethyl (2S)-3-(2-methoxyphenyl)-2-(p-tolylsulfonyloxy)propanoate. MS (El, 70 eV) m/z (% relative intensity, [ion]): 65 (7), 77 (14), 91 (49), 123 (33), 133 (33), 165 (100), 207 (65), 307(13),512(7, [M⁺])

Step B: Ethyl (2B]-2-[3-bromo-2-(4-fluorophenyl)benzofuran-4-yl]oxy-3-(2-methoxy phenyl)propanoate eq. Préparation le, 1.5 eq. ethyl (2S)-3-(2-rnethoxyphenyl)-2-(/?-tolylsulfonyloxy) propanoate, 2 eq. K₂CO₃ and DMSO (10 mL/mmol benzofurane dérivative) were stirred at 60 °C under N₂ atmosphère until no further conversion was observed. Then it was diluted with brine, neutralized with IM aqueous HCl solution and extracted with DCM. The combined organic phases were dried over Na₂SO₄, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to give ethyl (2Æ)-2-[3-bromo-2-(4fluoropheny[)benzofuran-4-yl]oxy-3-(2-methoxyphenyl)propanoate. MS (El, 70 eV) m/z (% relative intensity, [ion]): 91 (56), 133 (41), 165 (100), 207 (93), 281 (26), 305 (9), 512 (3, [M⁺]), 514 (3, [M⁺])

Step C: Examples 61 and 62

Using General Procedure VI and ethyl (2/î)-2-[3-bromo-2-(4-fluorophenyl)benzofuran-4yl]oxy-3-(2-methoxyphenyl)propanoate as the appropriate 3-bromo-benzofuran dérivative and Préparation 3b as the appropriate boronic acid dérivative, Examplc 61 was obtained as the earlier eluting diastereoisomer. HRMS calculated for C₃₈H₃₈C1FN₂O6: 672.2402, found: 673.2465 (M+H). Example 62 was obtained as the later eluting diastereoisomer, HRMS calculated for C₃₈H₃₈C1FN₂O₆: 672.2402, found: 673.2486 (M+H)

Exaniple 63: (27i)-2-{[(3/f_a)-3-{3-chloro-2-niethyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-2-(4-fluorophenyl)-l-benzofuran-4-yl]oxy}-3-(2-{[2-(2OR1GINAL

- 104methoxyphenyl)pyrimidin-4-y[]methoxy}phenyl)propanoic acid and

Example 64: (2ft)-2-{[(35a)-3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy] phenyl)-2-(4-fluorophenyl)-l-benzofuran-4-yl]oxy}-3-(2-{[2-(2-niethoxyphenyl) pyrimidin-4-yl]methoxy}phenyl)propanoic acid

Step A: Ethyl (2R)-2-[3-bromo-2-(4-fluorophenyl)benzofuran-4-yl]oxy-3-[2-[2-(2-methoxy phenyl)pyrimidin-4-yl]oxyphenyl]propanoate

Using General Procedure V and Préparation le as the appropriate benzofuran-4-ol dérivative and Préparation 2d as the appropriate lactic ester dérivative, ethyl (2Æ)-2-[310 bromo-2-(4-fIuorophenyl)benzofuran-4-yl]oxy-3-[2-[2-(2-methoxyphenyl)pyrimidin-4yl]oxyphenyl] propanoate was obtained. MS: (M+H)⁺ = 699.2

Step B: Examples 63 and 64

Using General Procedure VI and ethyl (2/?)-2-[3-bromo-2-(4-fluorophenyl)benzofuran-4yl]oxy-3-[2-[2-(2-methoxyphenyl)pyrimidin-4-yl]oxyphenyl]propanoate as the appropriate 15 3-bromo-benzofuran dérivative and Préparation 3b as the appropriate boronic acid dérivative, Example 63 was obtained as the earlier eluting diastereoisomer. HRMS calculated for C49H46CIFN4O7: 856.3039, found: 429.1582 (M+2H). Examplc 64 was obtained as the later eluting diastereoisomer. HRMS calculated for C49H46CIFN4O7: 856.3039, found: 429.1604 (M+2H)

Example 65: (2Æ)“2-{[(3S_a)-3-{3-chIoro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy] phcnyl}-2-(4-fiuorophenyl)-l-benzofuran-4-yl]oxy}-3-[2-(2,2,2-trifluoroethoxy) phenyijpropanoic acid

Step A: Ethyl (2R)-2-[3-bromo-2-(4-fluorophenyl)benzofuran-4-yl]oxy-3-[2-(2.2,2trifluoroethoxy)phenyl]propanoate

Using General Procedure V and Préparation le as the appropriate benzofuran-4-ol dérivative and Préparation 2h as the appropriate lactic ester dérivative, ethyl (27?)-2-[3bromo-2-(4-fluorophenyl)benzofuran-4-yl]oxy-3-[2-(2,2,2-trifluoroethoxy)phenyl] propanoate was obtained. MS: (M+Na)⁺ = 604.4

ORIGINAL

- 105Slep B: Example 65

Using General Procedure VI and ethyl (27?)-2-[3-bromo-2-(4-fluorophenyl)benzofuran-4yl]oxy-3-[2-(2,2,2-triiluoroethoxy)phenyl]propanoate as the appropriate 3-bromobenzofuran derivative and Préparation 3b as the appropriate boronic acid derivative, 5 Example 65 was obtained as the later eluting diastereoisomer. HRMS calculated for C39H37CiF₄N₂O₆: 740.2276, found: 74I.2372 (M+H)

Example 66: (2Æ)-2-{|(3S₀)-3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yI)ethoxy| phenyI}-6-fluoro-2-(4-fluorophenyl)-l-benzofuran-4-yl|oxy)-3-|2-(2,2,2-trifluoro ethoxy)phenyl| propanoic acid

Slep A: Ethyl (2R)-2-[3-bromo-6-fluoro-2-(4-fluorophenyl)benzofiiran-4-y}]oxy-3-[2(2,2,2-trifluoroethoxy)phenyl]propanoate

Using General Procedure V and Préparation Id as the appropriate benzofuran-4-ol derivative and Préparation 2h as the appropriate lactic ester derivative, ethyl (27?)-2-[3bromo-6-fluoro-2-(4-fluorophenyl)benzofuran-4-yl]oxy-3-[2-(2,2,2-trifluoroethoxy) phenyl]propanoate was obtained. ’H NMR (400 MHz. DMSO-d₆): 8.07 (m, 2H), 7.43 (m, 3H), 7.27 (m, 2H), 7.11 (m, IH), 6.98 (m, IH), 6.55 (dd, IH), 5.23 (m, IH), 4.82 (q, 2H),

4.12 (q, 2H), 3.37 (m, IH), 3.25 (m, IH), l. 10 (t, 3H)

Step B: Example 66

Using General Procedure VI and ethyl (2/?)-2-[3-biOmo-6-fluoro-2-(4-lluorophenyl) 20 benzofuran-4-yl]oxy-3-[2-(2,2,2-trifluoroethoxy)phenyl]propanoate as the appropriate

3-bromo-benzofuran derivative and Préparation 3b as the appropriate boronic acid derivative, Example 66 was obtained as the later eluting diastereoisomer. HRMS calculated for C39H36CIF5N2O6: 758.2182, found: 759.2244 (M+H)

Example 67: (2/ï)-2-{[(35'„)-3-{3-chloro-2-mcthyI-4-[2-(4-methylpiperazin-l-yl)ethoxy] 25 phenyl}-6-fluoro-2-(4-iluorophenyl)-l-benzofuran-4-yl]oxy}-3-(2-{|2-(2-methoxy phenyl)pyrimidin-4-yI]methoxy)phenyl)propanoic acid

ORIGINAL

- 106Sien A: Ethyl (2^)-2-[3-bromo-6-fluoro-2-(4-fluorophenyl)benzofuran-4-yl]oxy-3-[2-[[2(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoate

Using General Procedure V and Préparation Id as the appropriate benzofuran-4-ol dérivative and Préparation 2d as the appropriate lactic ester dérivative, ethyl (2Λ)-2-[3bromo-6-fluoro-2-(4-fluorophenyl)benzofuran-4-yl]oxy-3-[2-[[2-(2-methoxyphenyl) pyrimidin-4-yl]methoxy]phenyl]propanoate was obtained. ’H NMR (400 MHz, DMSOd₆): 8.86 (d, IH), 8.05 (m, 2H), 7.61 (d, IH), 7.52 (dd. IH), 7.48-7.38 (m, 4H), 7.25 (m, IH), 7.21 (m. IH), 7.12 (m, 2H), 7.03 (td, IH), 6.94 (td, IH), 6.67 (dd, IH), 5.40 (m, IH), 5.26 (s, 2H), 4.15 (q, 2H), 3.75 (s , 3H), 3.56 (m, IH), 3.30 (m, 1 H), 1.12 (t, 3H)

Step B: Example 67

Using General Procedure VI and ethyl (2Â)-2-[3-bromo-6-fluoro-2-(4-fluorophenyl) benzofuran-4-yl]oxy-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl] propanoate as the appropriate 3-bromo-benzofuran dérivative and Préparation 3b as the appropriate boronic acid dérivative, Example 67 was obtained as the later eluting diastereoisomer. HRMS calculated for C49H45CIF2N4O7: 874.2945, found: 438.1543 (M+2H)

Example 68: (27î)-2-{|(3/?₀)-3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]plienyl)-2-(4-fiuorophenyl)-l-methyl-l//-indol-4-yl]oxy}-3-(2-{|2-(2mcthoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid and

Example 69: (2ff)-2-{|(35_(f)-3-{3-chloro-2-methyi-4-|2-(4-methylpiperazin-l-yI)etlioxy| phenyl}-2-(4-fluoroplienyl)-l-metliyl-l/f-indol-4“yl]oxy}-3-(2-{|2-(2-methoxyphenyl) pyrimidin-4-yl|methoxy}phenyl)propanoic acid

Step A : l-(benzenesidfonyl)-4-benzyloxy-indole

7.0 g 4-benzyloxy-l/7-indole (31.35 mmol) was dissolved in 60 mL dry DMF and 1.317 g NaH (32.92 mmol, 60 % on minerai oil) was added at 0 °C. The mixture was stirred for 1 hour, then 6.09 g benzenesulfonyl chloride (34.48 mmol) was added dropwise and the mixture was stirred at 0 °C until no further conversion was observed. Then it was diluted with water and extracted with DCM. The combined organic phases were dried over

ORIGINAL

-107Na2SO4, filtered and the filtrate was concentrated under reduced pressure and purified via flash chromatography using heptane and EtOAc as eluents to obtain l-(benzenesulfonyl)-

4-benzyloxy-indole.

'H NMR (400 MHz, DMSO-d₆) δ: 7.97 (d, 2H), 7.72 (d. IH), 7.69 (t, IH), 7.59 (t, 2H), 7.54 (d, IH), 7.47 (d, 2H), 7.39 (t, 2H), 7.33 (d, IH), 7.27 (t,lH), 6.89 (d, IH), 6.85 (d, 1 H), 5.20 (s, 2H)

MS (El, 70 eV) m/z (% relative intensity, [ion]): 77 (32), 91 (100), 141 (18), 222 (6), 272 (11),363 (10, [M⁺])

Step B: 1 -(benzenesulfonyl)-4-benzyloxy-2-iodo-indole

5.08 g l-(benzenesulfonyl)-4-benzyloxy-indole (13.98 mmol) was dissolved in 140 mL dry THF. 8.54 mL LDA solution (15.38 mmol, 1.8M in THF-heptane-ethylbenzene) was added at -78 °C and the mixture was stirred for 1 hour. Then 4.26 g iodine (16.8 mmol) was added and the mixture was stirred for 1 hour at -78 °C. The mixture was quenched with saturated aqueous NH₄C1 solution, extracted with EtOAc. The combined organic phases were washed with aqueous NajSjOj solution and water, then dried over NaiSO4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to obtain l-(benzenesulfonyl)-4-benzyloxy-2-iodo-indole. 'H NMR (400 MHz, DMSO-dô) δ: 7.86 (dd, 2H), 7.75 (d, 1 H), 7.70 (d, IH), 7.61 (t, 2H), 7.47 (dd, 2H), 7.39 (t, 2H), 7.33 (d, IH),

7.23 (t, IH), 7.18 (s, 1 H), 6.90 (d, IH), 5.20 (s, 2H)

Step C: l-(benzenesidfonyl)-4-benzyloxy-2-(4-fltiorophenyl)indole

5.8 g l-(benzenesulfonyl)-4-benzyloxy-2-iodo-indole (11.86 mmol) and 3.16 g 4-(4,4,5,5tetramethyl-l,3,2-dioxaboroIan-2-yl)fluorobenzene (14.22 mmol) were dissolved in 75 mL THF, then 7.73 g CS2CO3 (23.72 mmol), 420 mg Ataphos (0.59 mmol) and 25 mL water were added and the mixture was stirred at 70 °C under N2 atmosphère until no further conversion was observed. The mixture was then concentrated under reduced pressure and purified via flash chromatography using heptane and EtOAc as eluents to obtain l-(benzenesulfonyl)-4-benzyloxy-2-(4-fluorophenyl)indole. 'El NMR (400 MHz, DMSO-dû) δ: 7.79 (d, IH), 7.67 (m, IH), 7.60-7.48 (m, 6H), 7.43-7.25 (m, 8H), 7.00 (d, IH), 5.57 (s, 1 H), 5.22 (s, 2H)

ORIGINAL

- 108Step D: 1-(benzenesulfanyl)-4-benzyloxy-2-(4-fluorophenyl)-3-iodo-indole

4.92 g l-(benzenesulfonyI)-4-benzyloxy-2-(4-fluorophenyl)indole (I0.75 mmol), 3.69 g Ag₂SO₄ (l 1.83 mmol) and 3.0 g iodine (l 1.83 mmol) were stirred in 100 mL EtOH at r.t. until no further conversion was observed. Then the mixture was concentrated under reduced pressure and purified via flash chromatography using heptane and EtOAc as eluents to obtain l-(benzenesulfonyl)-4-benzyloxy-2-(4-fluorophenyl)-3-iodo-indole. MS: (M+H)⁺ = 584.2

Step E: 1 -(benzenesidfonyl)-4d)enzyloxy-3-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl]-2-(4-fluorophenyl)indole

5.5 g l-(benzenesulfonyl)-4-benzyloxy-2-(4-fluorophenyl)-3-iodo-indole (9.42 mmol).

4.46 g Préparation 3b (11,31 mmol), 6.14 g Cs₂CO₃ (18.84 mmol) and 354 mg Ataphos (0.5 mmol) were dissolved in 100 mL THFrwater 3:1 and stirred at 70 °C under N₂ until no further conversion was observed. The mixture was concentrated under reduced pressure and purified via flash chromatography using heptane, EtOAc and MeOH as eluents to 15 obtain 1 -(benzenesulfonyl)-4-benzyloxy-3-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy] phenyl]-2-(4-fluorophenyl)indole.

’H NMR (400 MHz, DMSO-d₆) δ: 7.85 (d, IH), 7.67 (t, IH), 7.61-6.90 (m, 2H), 7.53-7.47 (m, 4H), 7.4 (t. IH), 7.20-7.07 (m, 5H), 6.96 (d, IH), 6.77 (d, IH), 6.73 (d, IH), 6.66 (d, 2H), 4.96 (d, IH), 4.86 (d, IH), 4.09 (m, IH), 4.00 (m, IH), 3.34 (br s, 4H), 2.75 (t, 2H), 20 2.58 (br s, 4H), 2.30 (s, 3H), 1.81 (s, 3H)

MS: (M : H)' - 724.2

Step F: 4-benzyloxy-3-[3-chloro-2-meihyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-2(4-fluorophenyl)-lW-indole

6.5 g 1 -(benzenesulfonyl)-4-benzyloxy-3-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 25 yl)ethoxy]phenyl]-2-(4-fluorophenyl)indole (8.97 mmol) was dissolved in 100 mL THF and 100 mL MeOH, then 28.3 g Ba(OH)₂ ^x8 H₂O (89.7 mmol) was added and the mixture was stirred at 70 °C until no further conversion was observed. The mixture was then filtered, the filtrate was concentrated under reduced pressure and purified via flash chromatography using DCM and MeOH as eluents to obtain 4-benzyloxy-3-[3-chloro-2-

ORIGINAL

- 109methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-2-(4-fluorophenyl)-lH-indole. MS: (M+H)⁺ = 584.2

Step G: 4-benzyloxy-3-[3-chloro-2-methyl-4-[2-(4-melhylpiperazin-l-yl)ethoxy]phenyl]-2(4-fh torophenyl)-!-methyl - indol e l .626 g 4-benzyloxy-3-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]2-(4-fluorophenyl)-l/f-indole (2.78 mmol) was dissolved in 25 mL dry DMF and cooled to 0 °C. Then 123 mg NaH (3.06 mmol, 60 % on minerai oil) was added and the mixture was stirred for l hour. Then 395 mg methyl iodide (2.78 mmol) was added and the mixture was stirred for l hour. The mixture was then poured into water and extracted with DCM. The combined organic phases were washed with brine, dried over MgSÛ4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified via flash chromatography using DCM and MeOH as eluents to obtain 4-benzyloxy-3-[3-chloro-2methyl-4-[2-(4-methylpiperazin-1 -yl)ethoxy]phenyl]-2-(4-fluorophenyl )-1 -methyl-indole.

’H NMR (400 MHz, DMSO-d₆) δ: 7.31 (dd, 2H), 7.24-7.10 (m, 7H), 6.97 (d, IH), 6.83-

6.76 (m, 3H), 6.68 (dd. IH), 5.01 (d, IH), 4.93 (d, IH), 4.14 (m, IH), 4.06 (m, IH), 3.63 (s, 3H), 3.10-2.60 (br s, 8H), 2.84 (br s, 2H), 2.58 (s, 3H), 2.04 (s, 3H)

Step H: 3-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-2-(4-fhioro phenyl)-}-methyl-indol-4-ol

1.6 g 4-benzyloxy-3-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)eihoxy]phenyl]-2(4-fluorophenyl)-l-methyl-indole (2.68 mmol) was dissolved in 10 mL DCM and l eq. HBr (33 % solution in AcOH) was added. The mixture was stirred at r.t. until no further conversion was observed. The mixture was then diluted with 10% aqueous K₂CO₃ solution and extracted with DCM. The combined organic phases were washed with brine, dried over MgSÛ4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified via flash chromatography using DCM and MeOH as eluents, then via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents to obtain 3-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl]-2-(4-fluorophenyl)-l-methyl-indol-4-ol.

ORIGINAL

- IIO’H NMR (400 MHz, DMSO-d₆) δ: 9.02 (s, IH), 7.29-7.15 (m, 4H), 7.06-6.92 (m, 2H),

6.86 (d, IH), 6.78 (d, IH), 6.38 (dd, IH), 4.07 (m, 2H), 3.58 (s, 3H), 2.70 (t, 2H), 2.58-2.40 (br s, 4H), 2.40-2.19 (br s, 4H), 2.19 (s, 3H), 2.09 (s, 3H)

MS: (M+H)⁺ = 508.2 ⁵ Step I: Ethyl (2S)-3-[2-[[2-(2-methoxyphenyî)pyrimidin-4-yl]methoxy]phenyl]-2-(p-tolyl sulfonyloxy)propanoate

3.668 g Préparation 2d (8.97 mmol) was dissolved in 12 mL pyridine and L97 g TsCI (10.31 mmol) was added at 0 °C. The mixture was stirred at r.t. until no further conversion was observed. Then the mixture was diluted with water and extracted with EtOAc. The 10 combined organic phases were washed with IM aqueous citric acid solution, dried over MgSO₄, filtered and the filtrate was concentrated under reduced pressure to give ethyl (2S)-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]-2-(/7-tolylsulfonyloxy) propanoate.

'H NMR (400 MHz, DMSO-d₆) δ: 8.93 (d, IH), 7.58 (dd. IH), 7.52-7.43 (m, 2H), 7.4315 7.34 (m, 2H), 7.26-7.15 (m, 4H), 7.13-7.04 (m, 2H), 6.93-6.83 (m, 2H), 5.12 (d, IH), 5.03-

4.92 (m, 2H), 4.01 (q, 2H), 3.79 (s. 3H), 3.26 (dd, IH), 3.01 (dd, IH), 2.36 (s, 3H), 1.12 (t, 3H)

MS: (M+H)⁺ = 563.2

Step J: Examples 68 and 69

60 mg 3-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 -yl)ethoxy]phenyl]-2-(4-fhioro phenyl)-l-methyl-indol-4-ol (0.12 mmol), 101 mg ethyl (2S)-3-[2-[[2-(2-methoxy phenyl)pyrimidin-4-yl]methoxy]phenyl]-2-(/>toly[sulfonyloxy)propanoate (0.18 mmol) and 80 mg Cs₂CO₃ (0.24 mmol) were dissolved in 2 mL dry DMF and stirred at 50 °C until no further conversion was observed. Then 2 eq. LiOH*H₂O was added and mixture was 25 stirred at r.t. until no further conversion was observed. The mixture was concentrated and purified by preparative reversed phase chromatography using 25 mM aqueous NH₄HCO₃ solution and MeCN as eluents to obtain Example 68 as the earlier eluting diastereoisomer.

HRMS calculated for C₅ûH49C1FN₅O₆: 869.3355, found: 435.6743 (M+2H). Example 69 was obtained as the later eluting diastereoisomer. HRMS calculated for C₅oH49C1FN₅0₆: 30 869.3355, found: 435.6767 (M+2H)

ORIGINAL

- mExample 70: jV-[3-(3-chloro-2-methylphenyI)thieno|3,2-c]pyridin-4-yl|-Z)phenylalanine

Step A : 4-bromo-YE(dimethoxymethyl)thiophene-3-carboxamide

5.01 g 4-bromothiophene-3-carboxylic acid (24.2 mmol) was dissolved in 25 mL isopropyl acetate and 17.9 mL SOCl₂ (242 mmol) was added and the mixture was stirred at 50 °C for 2 hours. Then the excess SOCl₂ was distilled and the residue was dissolved in 25 mL isopropyl acetate and cooled to l0°C. 10.6 mL DIPEA (60.5 mmol) and 4.0 mL aminoacetaldehyde dimethyl acetal (36.3 mmol) were added. The mixture was allowed to warni up to r.t. and stirred under N₂ atmosphère ovemight. The mixture was diluted with 10 % aqueous H3PO4 solution and extracted with isopropyl acetate. The combined organic phases were washed with 10% aqueous KH₂PO4 solution and brine, then dried over Na₂SC>4. fîitered and the filtrate was concentrated under reduced pressure to obtain 4-bromo-iV-(dimethoxymethyl)thiophene-3-carboxamide.

'H NMR (400 MHz, DMSO-d₆) δ: 8.36 (t, IH), 7.93 (d, IH), 7.72 (d, IH), 4.48 (t, IH), 3.31-3.28 (m, 8H)

MS (M+H): 294.0

Step Bt 3-bromo-5Y\-thierio[3,2-e.]pyridin-4-orie mg 4-bromo-/V-(dimethoxymethyl)thiophene-3-carboxamide (O.l02 mmol) was dissolved in l mL PPA and stirred at i00°C under argon atmosphère until no further conversion observed. The mixture was then poured into ice, the formed precipitate was fîitered and washed with water to obtain 3-bromo-5/7-thieno[3,2-c]pyridin-4-one. MS (M+H): 229.9

Step C: 3-bromo-4-chloro-thieno[3,2-c]pyridine l .06 g 3-brorno-5//-thieno[3,2-c]pyridin-4-one (4.4 mmol), 560 pL NJV-dimethylaniline (4.4 mmol) and 8.37 mL POCI3 (88 mmol) were stirred at I00 °C until no further conversion observed. The reaction mixture was then poured into ice and extracted with DCM. The combined organic phases were washed with saturated aqueous NaHCO3 solution and brine, dried over Na₂SC>4, fîitered and the filtrate was concentrated under

ORIGINAL

- H2reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to obtain 3-bromo-4-chloro-thieno[3,2-c]pyridine. MS (M+H): 247.9

Step D: 3,4-dibromothieno[3,2-cJpyridine

735 mg 3~bromo-4-chloro-thieno[3,2-c]pyridine (2.8 mmol) and 2.288 g bromotrimethylsilane (14.5 mmol) were dissolved in 15 mL propionitrile and stirred at 100 °C until no further conversion observed. The reaction mixture was then concentrated under reduced pressure and purified via preparative reversed phase chromatography using 40 mM aqueous NH4OAC solution (pH = 4, adjusted with AcOH) and MeCN as eluents to obtain 3,4-dibromothieno[3,2-c]pyridine. MS (M+H): 291.8

Step E: (2ty-2-[(3-bromothieno[3,2-c]pyridin-4-yl)ammo]-3-pheriyl-propanoic acid

340 mg 3,4-dibromothieno[3,2-c]pyridine (I.l6 mmoi) and 718 mg D-phenylalanine (4.35 mmol) were dissolved in 7.5 mL sulfolane, then 421 mg potassium fluoride (7.25 mmol) and 2.23 g 4,7,l3,l6,2l,24-hexaoxa-l,l0-diazabicyclo[8.8.8]hexacosane (5.8 mmol) were added and the mixture was stirred at 175 °C under argon atmosphère until no further conversion was observed. The reaction mixture was directly injected and purified via preparative reversed phase chromatography using 40 mM aqueous NH4OAC solution (pH = 4, adjusted with AcOH) solution and MeCN as eluents to obtain (27?)-2-|(3bromothieno[3,2-c]pyridin-4-yI)amino]-3-phenyl-propanoic acid.

Step F: Example 70

189 mg (2/?)-2-[(3-bromothieno[3,2-c]pyridin-4-yl)amino]-3-phenyl-propanoic acid (0.5 mmol), 341 mg (3-chloro-2-methylphenyl)boronic acid (2 mmol) were dissolved in 3.5 mL DME, then 72 mg butyldi-l-adamantylphosphine (0.2 mmol), 22 mg Pd(OAc)₂ (O.l mmol) and 389 mg TBAOH (1.5 mmol) were added and the mixture was stirred at !00°C under argon atmosphère until no further conversion was observed. Then the mixture was poured into icy water, extracted with MTBE. The aqueous phase was acidified to pH 2 and extracted with DCM. The combined organic phases were dried over Na₂SO4, fîltered and the filtrate was concentrated under reduced pressure. The crude product was purified via preparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents to obtain Example 70. HRMS calculated for

ORIGINAL

- H3C23H19CIN2O2S: 422.0856, found: 423.0937 and 423.0919 for the two diastereomers (M+H)

Example 71: (27?)-2-{[(35₍₍)-3-{3-cliloro-2-methyI-4-[2'(4-methylpiperazÎn-l-yI)ethoxy| phenyl}-2-(4-fluorophenyl)thieno[2,3-6]pyridm-4-ylJoxy}-3-(2-{[2-(2-methoxyphenyl) pyrimidin-4-yIjmethoxy}phenyl)propanoic acid

Step A: 2-chloro-3-[2-(4-fliiorophenyl)ethynyl]pyridine

In a dry flask 3.85 g 3-bromo-2-chloro-pyridine (20 mmol), 0.23 g Cul (1.2 mmol), 0.42 g PdCl2(PPlt3)2 (0.6 mmol) were added in 40 mL dry' TEA. After stirring for 10 minutes, 2.64 g l-ethynyl-4-fluoro-benzene (22 mmol) was added and the solution was heated to 100 °C and stirred ovemight. The reaction mixture was cooled down, diluted with water and then it was extracted with EtOAc. The combined organic layers were dried over Na2SO₄, filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to obtain 2-chloro-3-[2-(4fluorophenyl)ethynyl]pyridine. ’H NMR (500 MHz, DMSO-dô) δ 8.44 (dd, IH), 8.14 (dd, IH), 7.68 (t, 2H), 7.51 (dd, IH), 7.33 (t, 2H)

Step B: 2-(4-fluorophenyl)thieno[2,3-b]pyridine

2.95 g 2-chloro-3-[2-(4-fluorophenyl)ethynyl]pyridine (12.7 mmol) and 3.97 g Na₂S (51 mmol) were placed in a 250 mL flask. 120 mL DMF was added and the mixture was stirred at 130 °C for 2 hours. Then the reaction mixture was cooled down, diluted with water and then it was extracted with EtOAc. The combined organic layers were dried over Na2SO₄, filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to obtain 2-(4-fluorophenyl)thieno[2,3-Z>] pyridine. MS (M+H): 230.2

Step C: 2-(4-fluorophenyl)thieno[2,3-b]pyridine N-oxide

1.94 g 2-(4-fluorophenyl)thieno[2,3-ô]pyridine (8.4 mmol) was dissolved in DCM (50 mL) and cooled to 0 °C. 3.12 g MCPBA (12.6 mmol) was added portionwise and stirred at r.t. for 6 hours. Then it was concentrated under reduced pressure and the crude product was purified via flash chromatography using DCM and methanol as eluents. MS (M+H): 246.2

ORIGINAL

- 114Step D: 4-chloro-2-(4-fluorophenyl)thieno[2,3-\)]pyridine

1.56 g 2-(4-fluorophenyl)-7-oxido-thieno[2,3-ô]pyridin-7-ium (6.4 mmol) was dissolved in 50 mL CHCI3. 15.7 mL POCI3 (25.76 g, 168 mmol) was added and the reaction mixture was stirred at reflux température for 3 hours. Then it was cooled down, ice and saturated aqueous NaHCOs was added and it was extracted with CHCI3. The combined organic layers were dried over Na₂SO4, filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography using DCM and methanol as eluents to obtain 4-chloro-2-(4-fluorophenyl)thieno[2,3-ô]pyridine. MS (M+H): 264.0

Step E: 3-brotno-4-chloro-2-(4-fluorophenyl)thieno[2.3-b]pyridine

1.15 g Br? (7.2 mmol) was added dropwise to a mixture of 1.46 g 4-chloro-2-(4fluorophenyl)thieno[2,3-ô]pyridine (5.5 mmol), 0.52 g K2HPO4 (3.0 mmol), 0.46 g NaHCCfe (5.5 mmol) and 1.12 g MgSCL (9.2 mmol) in 20 mL CHCI3. The mixture was stirred overnight at reflux température. Then, the reaction was cooled down and filtered. The fîltrate was concentrated under reduced pressure. The crude product was purified via flash chromatography using DCM and methanol as eluents to obtain 3-bromo-4-chloro-2(4-fluorophenyl)thieno[2,3-6]pyridine. ^]H NMR (500 MHz, DMSO-d(,) δ 8.59 (d, IH),

7.76 (m, 2H), 7.71 (d, IH), 7.42 (m, 2H)

Step F: 3-bromo-2-(4-fluorophenyl)lhieno[2_t3-b]pyridin-4-ol

The mixture of 0.206 g 3-bromo-4-chloro-2-(4-iluorophenyl)thieno[2,3-A]pyridine (0.6 mmol), 0.492 g sodium acetate (6 mmol), 12 mL AcOH and 0.18 mL H?O was heated at 150 °C via MW irradiation for 5 hours. Water was added and the product was collected by filtration. 'H NMR (500 MHz, DMSO-d₆) δ 11.63 (br s, IH), 8.30 (br s, IH), 7.72 (m, 2H), 7.38 (m, 2H), 6.87 (br s, 1 H)

Step G: Ethyl (2R.)-2-[3-bromo-2-(4-jluorophenyl)thieno[2.3-b]pyridin-4-yl]oxy-3-[2-[[2(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoate

0.324 g 3-bromo-2-(4-fluorophenyl)thieno[2,3-6]pyridin-4-ol (1 mmol), 0.613 g Préparation 2d (1.5 mmol), 0.691 g DTAD (3 mmol) and 0.787 g PPh3 (3 mmol) were dissolved in 10 mL dry THF under N₂ atmosphère and the mixture was stirred at r.t. until

ORIGINAL

- Il5no further conversion was observed. The solvent was then removed under reduced pressure, the residue was purified via flash chromatography using heptane and EtOAc as eluents to give ethyl (27?)-2-[3-bromo-2-(4-fluorophenyl)thieno[2,3-ô]pyridin-4-yl]oxy-3[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoate. 'H NMR (500 MHz, DMSO-dù) ô 8.86 (d, IH), 8.33 (d, IH), 7.72 (m, 2H), 7.61 (d, IH), 7.51 (dd, IH), 7.45 (td, IH), 7.44 (d. IH), 7.39 (m, 2H), 7.25 (td, IH), 7.14 (d, IH), 7.10 (d, IH), 7.03 (td, IH), 6.93 (t, IH), 6.88 (d, IH), 5.55 (dd. IH), 5.30 (d, IH), 5.26 (d, IH), 4.16 (m, 2H), 3.75 (s, 3H), 3.58 (dd, IH), 3.35 (dd, IH), 1.13 (t, 3H)

Step H: Example 71

0.288 g (2£)-2-[3-bromo-2-(4-fluorophenyI)thieno[2,3-6]pyridin-4-yl]oxy-3-|2-[[2-(2methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoate (0.4 mmol), 0.472 g Préparation 3b (1.2 mmol), 0.028 g Ataphos (0.004 mmol) and 0.392 g Cs₂CO₃ (1.2 mmol) were dissolved in a mixture of dioxane (4 mL) and water (3 mL) and stirred under N₂ at 70 °C until no further conversion was observed. Then the mixture was diluted with water and extracted with DCM. The combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was purified was purified via flash chromatography using DCM and methanol as eluents. The obtained intermediate was dissolved in a mixture of dioxane (7 mL) and water (7 mL) and 0.168 g LiOHxH₂O (4 mmol) 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, extracted with DCM. The combined organic phases were dried over Na₂SO₄, filtered and the filtrate was concentrated under reduced pressure. The diastereoisomers were purified and separated by preparative reversed phase chromatography using 5 mM aqueous NH₄HCO₃ solution and MeCN as eluents. The diastereomer eluting later was collected as Example 71. HRMS calculated for C^^jCIFNjO^S: 873.2763; found 437.6441 (M+2H)

Example 72: (27?)-2-|5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy| phenyl|-6-(4-fluoroplienyl)-7-methyl-pyrrolo[2,3-i/]pyrimidin-4-yl]oxy-3-|2-[[2-(2methoxyphenyI)pyrimidin-4-yl|methoxyjphenyl|propanoic acid

Step A: Ethyl 2-amino-5-(4-fluorophenyl)-l\A-pyn‘ole-3-carhoxylate

ORIGINAL

-neThe solution of 3330 mg ethyl 3-amino-3-imino-propanoate (20 mmol) and 4340 mg 2-bromo-l-(4-fluorophenyl)ethanone (20 mmol) in 40 mL éthanol was stirred at r.t. for 30 minutes, then 20 mL l M NaOEt solution in éthanol (20 mmol) was added at 0 °C, then it was stirred at 60 °C for 90 minutes. Additional 13 mL IM NaOEt solution in éthanol (13 mmol) was added at room température and it was stirred at 60 °C for further l hour. The reaction mixture was concentrated under reduced pressure, diluted with 40 mL water then it was extracted with ethyl acetate. The combined organic phase was dried over MgSO₄, filtered and the filtrate was concentrated under reduced pressure. The residue was purified via flash chromatography using heptane and EtOAc as eluents to obtain ethyl 2-amino-5-(4-fluorophenyl)-l/7-pyrrole-3-carboxylate. NMR (400 MHz, DMSO-d₆) δ: 10.75 (br s, IH), 7.52 (m, 2H), 7.14 (m, 2H), 6.44 (d, IH), 5.68 (br s, 2H), 4.14 (q, 2H),

1.25 (t, 3H)

Step B: 6-(4-fliiorophenyl)-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one

The solution of 6.83 g ethyl 2-amino-5-(4-fluorophenyl)-l//-pyrrole-3-carboxylate (27.5 mmol) and 12 mL formic acid in 50 mL formamide and 24 mL DMF was stirred at 160 °C for I6 hours in a sealed reaction vessel. The reaction mixture was cooled to room température; 150 mL 2-propanol was added. The precipitate was filtered, washed with heptane, then it was dried under reduced pressure to obtain 6-(4-fluorophenyl)-3,7dihydropyrrolo[2,3-J]pyrimidin-4-one. 'H NMR (400 MHz. DMSO-dé) δ: 12.36 (br s, IH), H.88 (br s, lH), 7.88 (m. 3H), 7.27 (t, 2H), 6.93 (s, lH)

Step C: 4-chloro-6-(4-fluorophenyl)-7Y{-pyrrolo[2,3-d]pyrimidine

The solution of 4.50 g 6-(4-fluorophenyl)-3,7-dihydropyrrolo[2,3-i/]pyrimidin-4-one (Ί 9.6 mmol) in 46 mL POCI3 (491 mmol) was stirred al 90 °C for 3 hours. It was concentrated under reduced pressure, the residue was poured onto ice. The pH was adjusted to 7 using solid K2CO3, then the mixture was extracted with ethyl acetate. The combined organic phase was washed with brine, then it was dried over MgSO₄, filtered and the filtrate was concentrated under reduced pressure to give 4-chloro-6-(4-fIuorophenyl)7//-pyiTolo[2,3-i/]pyrimidine. 'H NMR (400 MHz, DMSO-d₆) ô: 13.04 (br s, IH), 8.60 (s, IH), 8.08 (m, 2H), 7.37 (t, 2H), 7.10 (d, IH)

ORIGINAL

- 1I7Step D: 4-chloro-6-(4-fluorophenyl)-7-methyl-pyrrolo[2,3-d]pyrimidine

To the solution of l .87 g 4-chloro-6-(4-fluorophenyl)-7/7-pyrrolo[2,3-</]pyrimÎdine (7.55 mmol) in 38 mL DMF L286 g Mel (9.06 mmol) then Ll5 g K₂CO₃ (8.30 mmol) was added and it was stirred at r.t. for l hour. The reaction mixture was concentrated under reduced pressure. The residue was diluted with brine, and it was extracted with dichloromethane. The combined organic phase was dried over MgSCL, filtered and the filtrate was concentrated under reduced pressure, then the residue was purified via flash chromatography using heptane and ethyl acetate as eluents to obtain 4-chIoro-6-(4fluorophenyl)-7-methyl-pyrrolo[2,3-d]pyrimidine. ¹11 NMR (400 MHz, DMSO-d₆) δ: 8.69 (s, l H), 7.79 (m, 2H), 7.42 (m, 2H), 6.80 (s, l H), 3.83 (s, 3H)

Step E: 5-bromo-4-chloro-6-(4-fliiorophenyl)-7-methyl-pyrrolo[2,3-d]pyrimidine

To the solution of 1.36 g 4-chloro-6-(4-fluorophenyl)-7-methyl-pyrrolo[2,3-i/]pyrimidine (5.20 mmol) in 16 mL acetic acid 5.46 mL IM Br₂ solution in acetic acid (5.46 mmol) was added dropwise at 0 °C, then the reaction mixture was stirred at r.t. for 30 minutes. The reaction mixture was concentrated under reduced pressure, then the residue was diluted with saturated aqueous NaHCO₃ solution and it was extracted with ethyl acetate. The combined organic phase was dried over MgSCL, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and ethyl acetate as eluents to obtain 5-bromo-4-chloro-6-(4-iluorophenyl)-7methyl-pyrrolo[2,3-<7]pyrimidine. ’H NMR (400 MHz, DMSO-dô) δ: 8.73 (s, IH), 7.70 (m, 2H), 7.47 (m, 2H), 3.69 (s, 3H)

Step F: Ethyl (2R)-2-[5-bromo-6-(4-jhtorophenyl)-7-methyl-pyrrolo[2,3-d]pyrimidin-4yl] oxy-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl] methoxy]phenyl]propanoate

845 mg 5-bromo-4-chloro-6-(4-lluorophenyl)-7-inethyl-pyrrolo[2,3-i.7]pyrimidine (2.48 mmol), 1.27 g Préparation 2c (3. H mmol) was dissolved in 10 mL DMF, then 2.43 g Cs₂CO₃ (7.44 mmol) was added and the mixture was stirred at 60 °C for 6 hours. The reaction mixture was concentrated under reduced pressure, it was diluted with brine, and then the mixture was extracted with ethyl acetate. The combined organic phase was dried over MgSCU filtered and the filtrate was concentrated under reduced pressure, then the residue was purified via flash chromatography using heptane and ethyl acetate

ORIGINAL

- usas eluents to obtain ethyl (2Æ)-2-[5-bromo-6-(4-fluorophenyl)-7-methyl-pyrrolo [2,3-J]pyrimidin-4-yl]oxy-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl] propanoate. MS (M+H): 712.0

Step G: Example 72

Using General Procedure II and ethyl (2Æ)-2-[5-bromo-6-(4-fluorophenyl)-7-methylpyrrolo[2,3-i/]pyrimidm-4-yl]oxy-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy] phenyl]propanoate instead of 5-bromo-furo[2,3-r/]pyrimidyl-lactic ester, and using Préparation 3b as the appropriate boronîc acid dérivative, Example 72 was obtained as a mixture of diastereoisomers. HRMS calculated for C48H47CIFN7O6: 871.3260; found 436.6703 and 436.6710 (M+2H)

Example 73: 2-{|3-{3,5-dichloro-2,6-dimethyl-4-[2-(4-methylpiperazin-l-yl)etlioxy| phenyl}-2-(4-fluorophenyl)thïeno|2,3-ô|pyridin-4-yl]oxy}-3-(2-{|2-(2-methoxyphenyl) pyrimidin-4-yl] methoxy)phenyl)propanoic acid

Example 74: 2-{[3-{2,6-dimethyl-4-|2-(4-methylpiperazin-l-yl)ethoxy]phenyl}-2-(4fluorophenyl)thieno I2,3-6| pyridin-4-yl]oxy )-3-(2-{| 2-(2-methoxyphenyl)pyrimidin-4yl] methoxy)phenyl)propanoïc acid

Example 75: l-j(dimethylcarbamoyl)oxy]ethyl (2/î)-2-{|(3S_rt)-3-{3-chloro-2-methyl-4[2-(4-methylpiperazin-l-yl)ethoxy]phenyl}-2-(4-fluorophenyl)thieno|2,3-h]pyridin-4yl]oxy)-3-(2-{[2-(2-niethoxyphenyl)pyrimidin-4-yl]methoxy}phcnyl)propanoate

591 mg dimethylamine hydrochloride (7.25 mmol) and 1.20 mL pyridine (14.9 mmol) were dissolved in 18 mL dry DCM under nitrogen atmosphère, then the mixture was cooled to -78 °C and 990 mg 1-chloroethyl chloroformate (6.9 mmol) was added. The reaction mixture was stirred at -78 °C until no further conversion was observed. The cold mixture was filtered and the filtrate was concentrated under reduced pressure (30 mbar) using a 30°C bath. Then it was dissolved in 2 mL dry DMF under nitrogen atmosphère, 60 mg Example 71 (0.069 mmol) and 223 mg Cs₂CO₃ (0.55 mmol) were added and the reaction mixture was stirred at r.t. until no further conversion was observed. Then the

ORIGINAL

- 119mixture was diluted with brine, extracted with EtOAc, The combined organic layer was dried over Na₂SÛ4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified via reversed phase chromatography using 5 mM aqueous NH4HCO3 solution and MeCN as eluents to obtain Example 75 as a mixture of diastereoisomers. HRMS calculated for C₅3H₅4ClFN₆O₈S: 988.3397; found: 495.1782 and 495.1772 (M+2H)

Example 76: l-[(ethoxycarbonyl)oxy|ethyl (27f)-2-{[(3S^, _a)-3-(3-chloro-2-methyl-4-[2(4-methylpiperazin-l-yl)ethoxy]phenyl}-2-(4-fIuorophenyl)thieno[2,3-ô]pyridin-4yl|oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl|methoxy}phenyl)propanoate

668 mg EtOH (14.5 mmol) and 1.26 g pyridine (15.6 mmol) were dissolved in 18 mL dry DCM under nitrogen atmosphère, then the mixture was cooled to -78 °C and 1.98 g l-chloroethyl chloroformate (13.8 mmol) was added. The reaction mixture was stirred at -78 °C until no further conversion was observed. The cold mixture was filtered and the filtrate was concentrated under reduced pressure (30 mbar) using a 30 °C bath. Then it was dissolved in 2 mL dry DMF under nitrogen atmosphère, 60 mg Example 71 (0.069 mmol) and 223 mg Cs₂CC>3 (0.55 mmol) were added and the reaction mixture was stirred at r.t. until no further conversion was observed. Then the mixture was filtered and the filtrate was purified via reversed phase chromatography using 5 mM aqueous NH4HCO3 solution and MeCN as eluents to obtain Example 76 as a mixture of diastereoisomers. HRMS calculated for C₅3H53C1FN₅O₉S: 989.3237; found: 990.3342 and 990.3314 (M+H).

Example 77: 2-{|3-{3-chloro-2-methyl-4-|2-(4-methylpiperazin-l-yl)ethoxy|phenyl}-2(4-fluorophenyl)tliieno[2,3-Z»|pyridin-4-yi]oxy}-3-hydroxy-3-(2-{[2-(2-methoxyphenyl) pyrimidin-4-yljmethoxy}phenyl)propanoic acid

Example 78: 2-{[3-{3-chloro-2-methyl-4-|2-(4-methylpiperazin-l-yI)ethoxy]phenyl}-2(4-nuorophenyl)thieno[2,3-0|pyridin-4-yl]oxy}-4-hydroxy-3-(2-{|2-(2-mcthoxyphenyl) pyrimidin-4-yI] methoxy}phcnyl)butanoic acid

ORIGINAL

- 120Example 79: 2-0-[3-{3-chloro-2-methyl-4-|2-(4-methylpiperazin-l-yI)ethoxy]phenyl}2-(4-fluorophenyl)thieno[2,3-/>]pyridin-4-yl]-3,4-dideoxy-3-(2-{)2-(2-methoxyphenyl) pyrimidin-4-yl]methoxy}phenyl)pentonic acid

Exaniple 80: 2-{[3-{3-chloro-2-metliyl-4-l2-(4-rnethylpiperazin-l-yI)ethoxy]phenyl}-2(4-fluorophenyl)thieno|2,3-#|pyridin-4-yl]oxy}-3-[2-({2-[5-(hydroxymethyl)pyridin-3yl]pyrimidin-4-yl}methoxy)phenyl]propanoic acid

Example 81: 2-{|3-{3-chloro-2-methyl-4-I2-(4-methylpiperazin-l-yl)cthoxy]phenyl}-2(4-fIuorophenyl)thieno|2,3-ô]pyridin-4-yl]oxy}-3-{2-[(2-{2-[(2-hydroxycthoxy)mcthyl| phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid

Example 82: 2-{|3-{3-chloro-2-methyl-4-|2-(4-methylpiperazin-l-yl)ethoxy|phcnyl}-2(4-fluorophenyl)thieno[2,3-i»]pyridin-4-yl]oxy}-3-{2-[(2-{4-[2-(dimethylamino)ethoxy| phenyl}pyrïmidin-4-yl)methoxy]phenyl}propanoic acid

Example 83: 2-{[3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl}-2(4-fluorophenyl)thieno[2,3-ô]pyridin-4-yl]oxy}-3-[2-({2-[3-(phosphonooxy)phenyl] pyrimidin-4-yl}methoxy)phenyl|propanoic acid

Example 84: _;V-[3-{3-chloro-2-mcthyl-4-|2-(4-niethylpiperazin-l-yl)cthoxy]phcnyl}-2(4-fluoroplienyl)thieno|2,3-/^>|pyridin-4-yl|-2-{[2-(2-methoxyplienyl)pyrimidin-4-ylJ methoxy}-D-phenylalanine

Step A: ethyl (2B,)-2-[[3-bromo-2-(4-fluorophenyl)thieno[2.3-'o]pyridin-4-yl]ammo]-3-[2[[2-(2-methoxyphenyl)pyrhnidin-4-yl]methoxy]phenyl]propanoale

343 mg 3-bromo-4-chloro-2-(4-fluorophenyl)thieno[2,3-6]pyridine (Step E in Example 71, 1.0 mmol) and 455 mg Préparation 2i (1.20 mmol) were dissolved in 5 mL dry DMSO, then 978 mg Cs₂CO₃ (3.0 mmol) was added and the mixture was stirred under nitrogen atmosphère at 100 °C until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M aqueous HCl solution, and extracted with DCM. The combined organic phase was dried over Na₂SO₄, filtered and the filtrate was

ORIGINAL

- I2lconcentrated under reduced pressure. Then it was dissolved l .5 mL l .25 M HCl solution in EtOH, and the mixture was stirred at 60 °C until the ester formation was complété. Then it was carefully neutralized with saturated aqueous NaHCCfe solution, extracted with DCM. The combined organic phase was dried over Na2SO₄, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents.

'H NMR (500 MHz, DMSO-d₆) δ: 8.77 (d, IH), 8.07 (d, IH), 7.6 (m, 2H), 7.52-6.88 (m, 8H), 7.37 (d, IH), 7.34 (m, 2H), 7.05 (d, IH), 6.57 (d, IH), 5.23/5.19 (d+d, 2H), 4.92 (m, IH), 4.12 (m, 2H), 3.73 (s, 3H), 3.44/3.25 (dd+dd. 2H), 1.14 (t, 3H)

HRMS calculated for CjôHjoBrFN^S: 712.1155; found: 357.0649 (M+2H)

Step B: ethyl (2R)-2-[[3-(3-chloro-4-hydroxy-2-methyl-phenyl)-2-(4-fuorophenyl)thieno [2,3-b]pyridin-4-yl]amino]-3-[2-[[2-(2-meihoxyphenyl)pyrimidin-4-yl]methoxy]phenyl] propanoate

178 mg ethyl (2Æ)-2-[[3-bromo-2-(4-fluorophenyl)thieno[2,3-/j]pyridin-4-yl]amino]-3-[2[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoate (0.249 mmol) and 107 mg Préparation 3a (0.4 mmol) were dissolved in l mL l,4-dioxane under nitrogen atmosphère, then 163 mg CS2CO3 (0.50 mmol), 0.5 mL water and 28 mg AtaPhos (0.04 mmol) were added and the mixture was stirred in a microwave reactor at 111 °C for 15 minutes. Then it was diluted with brine, neutralized with 2 M aqueous HCl solution, and extracted with DCM. The combined organic phase was dried over Na2SO₄, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to obtain ethyl (27?)-2-[[3-(3chloro-4-hydroxy~2-methyl-phenyl)-2-(4-fluorophenyl)thieno[2,3-/>]pyridin-4-yl]amino]-

3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]piOpanoate as a mixture of atropoisomers. HRMS calculated for C^HjôClFNuOsS: 774.2079; found: 388. H 13 (M+2H)

Step C: Example 84 mg ethyl (2/î)-2-[[3-(3-chloro-4-hydroxy-2-methyl-phenyl)-2-(4-fluorophenyl)thieno [2,3-/>]pyridin-4-yI]amino]-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl] propanoate (0.103 mmol), 43 mg 2-(4-methylpiperazin-l-yl)ethanol (0.30 mmol), and

ORIGINAL

- 12279 mg PPhj (0.30 mmol) were dissolved in l mL dry toluene, then 69 mg DTAD (0.30 mmol) was added and the mixture was stirred at 50 °C under nitrogen atmosphère until no further conversion was observed. Then the mixture was concentrated under reduced pressure and the residue was purified via flash chromatography using EtOAc and MeOH as eluents. The obtained ester dérivative was dissolved in l mL THF, then 80 mg LiOHxH₂O and I mL water were added and the mixture was stirred at r.t. until the hydrolysis was complété. Then it was diluted with brine, neutralized with 2 M aqueous HCl solution, and extracted with DCM. The combined organic phase was dried over Na₂SO4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified via reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents to obtain Example 84 as a 7:3 mixture of diastereoisomers. HRMS calculated for C₄8H46ClFN₆O₅S: 872.2923; found: 437.1540 and 437.1538 (M+2H)

Example 85: 2-{[3-{3-chloro-2-methyL4-|2-(4-methylpiperazin-l-yl)ethoxy]phenyl}-2(4-fluorophenyl)thieno[3,2-c]pyndin-4-yI]oxy}-3-(2-{|2-(2-methoxyphenyl)pyrimidin4-yl]methoxy}phenyl)propanoic acid

Example 86:7V-[3-{3-chloro-2-methyl-4-|2-(4-mcthy[piperazin-l-yl)ethoxy|phenyl}-2(4-fluorophenyl)thieno|3,2-c|pyridin-4-yl|-2-{|2-(2-methoxyphenyl)pyrimidin-4-yI] metlioxyjphenylalanine

Siep A: 3-bromo-4-chloro-2-iodo-thieno[3.2-c]pyridine

4.97 g 3-bromo-4-chloro-thieno[3,2-c]pyridine (20.0 mmol) was dissolved in 50 mL dry THF under argon atmosphère and the mixture was cooled to -45 °C. Then 22 mL Mg(TMP)Cl*LiCl solution (22 mmol, 1 M in THF) was added dropwise and the mixture was stirred for 1 hour at -45 °C, then 1 hour at 0 °C, then it was cooled to -45 °C again. Then 5.58 g iodine (22 mmol, dissolved in 20 mL dry, cold THF) was added dropwise and the mixture was stirred at -45 °C for 2 hours. Then it was allowed to warm up to r.t. and concentrated under reduced pressure. The residue was poured onto 300 mL brine, and extracted with EtOAc. The combined organic phase was washed with saturated aqueous Na₂S₂O3 solution, saturated aqueous NH4CI solution, then with water and then dried over

ORIGINAL

- 123Na₂SO₄, filtered and the fîltrate was concentrated under reduced pressure. The crude product was purified via flash chromatography using hexanes and EtOAc as eluents.

'H NMR (500 MHz, DMSO-dè) Ô: 8.27 (d, IH), 8.17 (d, IH)

HRMS calculated for C₇H₂BrClINS: 372.7824; found: 373.7916 (M+H)

Step B: 3-bromo-4-chloro-2-(4-fluorophenyl)thieno[3,2-c]pyridine

2.62 g 3-bromo-4-chloro-2-iodo-thieno[3,2-c]pyridine (7.0 mmol) and 2.33 g 2-(4fluorophenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (10.5 mmol) were dissolved in 18 mL THF under argon atmosphère, then 6.84 g Cs₂CO₃ (21 mmol), 18 mL water, 79 mg Pd(OAc)₂ (0.35 mmol) and 297 mg ‘BuXPhos (0.70 mmol) were added and the mixture was stirred at 70 °C until no further conversion was observed. Then the volatiles were evaporated under reduced pressure. The residue was diluted with water and extracted with EtOAc. The combined organic phase was washed with saturated aqueous NH₄C1 solution, then with brine and then dried over Na₂SO₄, filtered and the fîltrate was concentrated under reduced pressure. The crude product was purified via flash chromatography using hexanes and EtOAc as eluents.

‘H NMR (500 MHz, DMSO-d₆) δ: 8.35 (d, IH), 8.26 (d, IH), 7.74 (dd, 2H), 7.42 (t, 2H) HRMS calculated for Ci₃H₆BrClFNS: 340.9077; found: 341.9144 (M+H)

Step C: ethyl (2R)-2-[[3-bromo-2-(4-fliiorophenyl)thieno[3,2-c]pyridin-4-yl]amino]-3-[2[[2-(2-methoxy>phenyl)pyrhnidin-4-yl]methoxy]phenyl]propanoate

343 mg 3-bromo-4-chloro-2-(4-fluorophenyl)thieno[3,2-c]pyridine (1.0 mmol) and 455 mg

Préparation 2i (1,20 mmol) were dissolved in 5 mL dry DMSO, then 978 mg CS2CO3 (3.00 mmol) was added and the mixture was stirred under nitrogen atmosphère at 100 °C until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M aqueous HCl solution, and extracted with DCM. The combined organic phase was dried over Na2SO₄, filtered and the fîltrate was concentrated under reduced pressure. Then it was dissolved 1.5 mL 1.25 M HCl solution in EtOH, and the mixture was stirred at 60 °C until the ester formation was complété. Then it was carefully neutralized with saturated aqueous NaHCÛ3 solution, extracted with DCM. The combined organic phase was dried over Na₂SO₄, filtered and the fîltrate was concentrated under reduced pressure. The crude

ORIGINAL

- 124product was purified via flash chromatography using heptane and EtOAc as eluents. HRMS calculated for C^HaoBrEN^S: 712.1155; found: 713.1209 (M+H)

Step D: ethyl (2VL)-2-[[3-(3-chloro-4-hydroxy-2-methyl-phenyl)-2-(4-fluorophenyl)thieno [3,2-c]pyridin-4-yl]amino]-3-[2-[[2-(2-methoxyphenyl)pyrimldin-4-yl]methoxy]phenyl] propanoate mg ethyl (2/î)-2-[[3-bromo-2-(4-fluorophenyl)thieno[3,2-c]pyridtn-4-yl]amino]-3-[2[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoate (0.043 mmol) and 24 mg Préparation 3a (0.09 mmol) were dissolved in 0.5 mL 1,4-dioxane under nitrogen atmosphère, then 33 mg Cs₂CO₃ (0.10 mmol), 0.5 mL water and 9.4 mg AtaPhos 10 (0.013 mmol) were added and the mixture was stirred in a microwave reactor at 111 °C for minutes. Then it was diluted with brine, neutralized with 2 M aqueous HCl solution, and extracted with DCM. The combined organic phase was dried over Na2SO4, fîltered and the filtrate was concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to obtain ethyl (2Æ)-2-[[j-(j15 chloro-4-hydroxy-2-methyl-phenyl)-2-(4-fluorophenyl)thieno[3,2-c]pyridin-4-yl]amino]-3[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoate as a mixture ot atropoisomers. HRMS calculated for C₄₃H₃₆C1FN4O₅S: 774.2079; found: 775.2134 (M+H)

Step E: Example 86 mg ethyl (2/?)-2-[[3-(3-chloro-4-hydroxy-2-methyl-pheny!)-2-(4-fluorophenyl)thieno 20 [3,2-c]pyridin-4-yl]amino]-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl] propanoate (0.04 mmol), 15 mg 2-(4-methylpiperazin-l-yl)ethanol (0.10 mmol), and mg PPh₃ (0.10 mmol) were dissolved in 1 mL dry toluene, then 23 mg DTAD (0.10 mmol) was added and the mixture was stirred at 50 °C under nitrogen atmosphère until no further conversion was observed. Then the mixture was concentrated under 25 reduced pressure and the residue was purified via flash chromatography using EtOAc and

MeOH as eluents. The obtained ester dérivative was dissolved in 1 mL THF, then 80 mg LÎOH*H₂O and 1 mL water were added and the mixture was stirred at rt until the hydrolysis was complété. Then it was diluted with brine, neutralized with 2 M aqueous HCl solution, and extracted with DCM. The combined organic phase was dried over 30 Na₂SO₄, fîltered and the filtrate was concentrated under reduced pressure. The crude

ORIGINAL

- 125product was purified via reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents to obtain Example 86 as a 10:3 mixture of diastereoisomers. HRMS calculated for C₄₈H₄₆CIFN₆O₅S: 872.2923; found: 437.1549 and 437.1532 (M+2H)

Example 87: 2-{[3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl}-25 (4-f|uorophenyl)thieno[2,3-clpyridin-4-ylloxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin4-yllmethoxy}phenyl)propanoic acid

Example 88: /V-|3-{3-chloro-2-methyl-4-|2-(4-methylpiperazin-l-yl)ethoxylphenyl}-2(4-fluorophcnyl)tlneno[2,3-c|pyridin-4-yll-2-{[2-(2-niethoxyphenyl)pyrimidin-4-yl| methoxyjphenylalanine

Example 89: 2-{|3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy|phenyl}-2(4-fluorophenyl)thieno|2,3-i/]pyridazin-4-yl|oxy}-3-(2-{[2-(2-methoxyphenyl) pyrimi(lin-4-yl|methoxy}phenyl)propanoic acid

Example 90: A-[3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxylphenyl}-2(4-fluorophenyl)thieno[2,3-rf|pyridazin-4-yl]-2-{[2-(2-methoxyplienyl)pyrimidin-4-yl] methoxyjphenylalanine

Example 91: 2-{|5-{3-chloro-2-methyl-4-I2-(4-methylpiperazin-l-yl)ethoxy|phenyl}-6(4-fluorophenyl)thieno|2,3-c]pyridazin-4-yl]oxy}-3-(2-{|2-(2-methoxyphenyl) pyrimidin-4-yl|methoxy}plienyl)propanoic acid

Example 92: A-I5-{3-chloro-2-mcthyI-4-[2-(4-methylpiperazin-l-yl)etlioxy]phenyI}-620 (4-fluorophenyl)thieno[2,3-c|pyridazin-4-yl]-2“{[2-(2-niethoxyphenyl)pyrimidin-4-yl| methoxyjphenylalanine

Example 93: 2-{[3-{3-chloro-2-methyl-4-I2-(4-methylpiperazin-l-yl)ethoxy|phenyl}-2(4-fluorophenyl)furo|2,3-Z>]pyridin-4-yl)oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy}phenyl)propanoic acid

ORIGINAL

- 126Example 94: 7V-|3-{3-chloro-2-methyl-4-|2-(4-methyIpiperazin-l-yl)ethoxy]phenyl}-2(4-fluorophenyl)furo[2,3-i>]pyridin-4-yl]-2-{[2-(2-methoxyphenyl)pyrimidin-4-yl] methoxyjphcnylalanine

Example 95: 2-{|3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl}-25 (4-fluorophenyl)furo[3,2-c]pyridin-4-yl|oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy]phenyl)propanoic acid

Example 96:7V-[3-{3-chloro-2-methyl-4-|2-(4-methylpiperazin-l-yl)ethoxy]phenyl}-2(4-fluorophenyl)furo[3,2-c]pyridin-4-yl]-2-{|2-(2-methoxyphenyl)pyrimidin-4-yl| methoxy} phenylalanine

Example 97a: 2-{[(35„)-3-{3-chloro-2-methyl-4-|2-(4-methylpiperazin-lyl)ethoxy]phenyl}-2-(4-fluorophenyl)imidazo|l,2-c]pyrimidin-5-yl]oxy}-3-(2-{[2-(2.J» methoxyphenyl)pyrimidin-4-yI]methoxy}pheoyl)propanoic acid and j

Examplc 97b: 2-{[(3Æ_fl)-3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l15 yl)ethoxy|phenyl}-2-(4-fluorophenyI)imidazo|l,2-c]pyrimidin-5-yl]oxy}-3-(2-{|2-(2methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl)propanoic acid

Step A: 7-(2-bromo-l.1 -dimethoxy-ethyl)-4-fluoro-benzene

8.68 g 2-bromo-l-(4-fluorophenyl)ethanone (40.0 mmol) was dissolved in 80 mL MeOH, then 8.75 mL CH(OMe)j (80.0 mmol) and 380 mg TsOHxH₂O (2.00 mmol) was added 20 and the mixture was stirred at reflux température until no further conversion was observed.

Then it was concentrated under reduced pressure and diluted with Et₂O. It was washed with 10% aqueous K.2CO3 solution, dried over Na₂SO4, fîitered and the filtrate was concentrated under reduced pressure. ’H NMR (250 MHz. CDCI3) δ: 7.53-7.44 (m, 2H), 7.11-7.01 (m, 2H), 3.60 (s, 2H), 3.22 (s, 6H)

Step B: 5-chloro-2-(4-fluorophenyl)imidazo[],2-c]pyrimidine

A high pressure reaction vessel made of Steel was charged with 648 mg 2-chloropyrimidin-

4-amine (5.0 mmol), 1.58 g l-(2-bromo-l,l-dimethoxy-ethyl)-4-fluoro-benzene

ORIGINAL

- 127(6.0 mmol), 123 mg Sc(OTf)₃ (0.25 mmol) and 50 mL MeCN and the mixture was stirred at 120 °C for 24 hours. Then it was diluted with DCM and washed with saturated aqueous NaHCO₃ solution. The aqueous layer was extracted with DCM. The combined organic layer was dried over MgSC>4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified via flash chromatography using hexanes and EtOAc as eluents. HRMS calculated for CjJ-LClFNj: 247.0312; found: 248.0397 (M+H)

Step C: 3-bromo-5-chloro-2-(4-fluorophenyl)imidazo[l, 2-c]pyrimidine

198 mg 5-chloro-2-(4-fluorophenyl)imidazo[l,2-c]pyrimidine (0.80 mmol) was dissolved in 4.8 mL DMF then 142 mg NBS (0.80 mmol) was added and the mixture was stirred at r.t. until the consomption of the starting material. Then the mixture was poured onto saturated aqueous NaHCO₃ solution and the formed precipitate was filtered, washed with water. The crude product was purified via flash chromatography using hexanes and EtOAc as eluents.

'H NMR (500 MHz. DMSO-d₆) Ô: 8.03 (m, 2H), 7.90 (d, IH), 7.73 (d, IH), 7.39 (m, 2H) HRMS calculated for C₁₂H₆BrClFN₃: 324.9418; found: 325.9496 (M+H)

Step D: ethyl (2R)-2-[3-bromo-2-(4-fluorophenyl)imidazo[1.2-c]pyrimidin-5-yl]oxy-3-[2[[2-(2-methoxyphenyl)pyrimidin-4-yl] methoxy]phenyl]propanoate

102 mg 3-bromo-5-chloro-2-(4-fluorophenyl)imidazo[l,2-c]pyrimidine (0.312 mmol) and 140 mg Préparation 2c (0.344 mmol) were dissolved in 3 mL dry DMSO under nitrogen atmosphère, then 305 mg Cs₂CO₃ (0.936 mmol) was added and the mixture was stirred at r.t. until no further desired conversion was observed. Then it was diluted with brine and water, neutralized with 2 M aqueous HCl solution, and extracted with DCM. The combined organic phase was dried over Na₂SO4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents.

‘H NMR (500 MHz, DMSO-df,) δ: 8.20 (d, IH), 8.03 (m, 2H), 7.62 (d, IH), 7.56 (d, IH),

7.50 (dd, 111), 7.49 (dd, IH), 7.42 (ddd, IH), 7.35 (m, 2H), 7.27 (ddd, IH), 7.23 (d, IH),

7.13 (d, IH), 7.11 (d, IH), 7.01 (td, IH), 6.96 (td. IH), 5.80 (dd, IH), 5.31/5.27 (d+d, 2H), 4.18/4.15 (m+m, 2H), 3.75 (s, 3H), 3.62/3.36 (dd+dd, 2H), 1.12 (t, 3H)

HRMS calculated for CajHjgBrFNjO,: 697.1336; found: 698.1419 (M+H)

ORIGINAL

- 128Step E: ethyl (2R)-2-[3-(3-chloro-4-hydroxy-2-melhyl-phenyl)-2-(4-flnorophenyl)imidazo [l,2-c]pyrimidin-5-yl]oxy-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl] propanoate

150 mg ethyl (2/î)-2-[3-bromo-2-(4-fiuorophenyI)imidazo[l,2-c]pyrimidin-5-yl]oxy-3-[25 [[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoate (0.215 mmol) and

80.8 mg Préparation 3a (0.301 mmol) were dissolved in 1 mL THF under nitrogen atmosphère, then 140 mg Cs₂CO₃ (0.430 mmol), 0.2 mL water and 30.4 mg AtaPhos (0.043 mmol) were added and the mixture was stirred in a microwave reactor at 100 °C for 5 minutes. Then the mixture was diiuted with brine, neutralized with 2 M aqueous HCl solution and extracted with DCM. The combined organic phase was dried over Na₂SO₄, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to obtain a mixture of diastereoisomers. HRMS calculated for C₄₂H35C1FN5O₆: 759.2260; found: 760.2370 and 760.2344 (M+H)

Step F: Examples 97a and 97b

11.4 mg ethyl (2/?)-2-[3-(3-chloro-4-hydroxy-2-methyl-phenyl)-2-(4-fluorophenyl) imidazo[l,2-c]pyrimidin-5-yl]oxy-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy] phenyl]propanoate (0.015 mmol), 7.2 mg 2-(4-methylpiperazin-Lyl)ethanoI (0.050 mmol), and 13.1 mg PPh₃ (0.050 mmol) were dissolved in 1 mL dry toluene, then 11.5 mg DTAD (0.050 mmol) was added and the mixture was stirred at 50 °C under nitrogen atmosphère until no further conversion was observed. Then the mixture was concentrated under reduced pressure and the residue was purified via flash chromatography using EtOAc and MeOH as eluents. The obtained ester dérivative was dissolved in 1 mL THF, then 42 mg LiOH><H₂O and 1 mL water were added and the mixture was stirred at r.t. until the hydrolysis was complété. Then it was diiuted with brine, neutralized with 2 M aqueous HCl solution, and extracted with DCM. The combined organic phase was dried over Na₂SO₄, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified via reversed phase chromatography using 25 mM aqueous NH₄HCO3 solution and MeCN as eluents. Example 97a was obtained as the earlier eluting

ORIGINAL

- 129diastereoisomer. HRMS calculated for C47H45CIFN7O6: 857.3104; found: 429.6626 (M+2H)

Example 97b was obtained as the later eluting diastereoisomer. HRMS calculated for C₄7H45C1FN₇O₆: 857.3104; found: 429.6638 (M+2H)

Example 98: A^r-[3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yI)ethoxy]phenyl}-2(4-fluorophenyl)imidazo|l,2-c|pyrimidin-5-yl]-2-{[2-(2-methoxyphenyl)pyrimidin-4yljmethoxyjphenylalanine

Example 99: 2-{[3-{3-chi()r()-2-methvl-4-|2-(4-niethylpiperaziii-l-yl)ctlioxy|phenyli-2(4-fluorophenyl)imidazo[l,2-fl]pyrazin-5-yI]oxy}-3-(2-{|2-(2-methoxyphenyl) pyrimidin-4-y 1] methoxyjphenyl)propanoic acid

Example 100: 7V-[3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy|phcnyl}2-(4-fluorophenyl)imidazo[l,2-«]pyrazin-5-yl]-2-{|2-(2-methoxyphenyl)pyrimidin-4yl] methoxyjphenylalanine

Example 101: 2-{[3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl}2-(4-fluorophenyl)imidazo[l,2-fl]pyrimidin-5-yl|oxy}-3-(2-{[2-(2-methoxyphenyl) pyrimidin-4-y!]methoxy}phenyl)propanoic acid

Example 102: A^r-[3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yI)ethoxy|phenyl}2-(4-iluorophenyI)imidazo[l,2-«]pyrimidin-5-yl]-2-{|2“(2-methoxyphenyI)pyrinndin4-yl]mcthoxy}-D-phenylalanine

Step A: 2-(4-fluorophenyl)-1 \A-imidazo[1,2-ά]pyrimidin-5-one

10.0 g 2-amino-7//-pyrimidin-4-one (90.0 mmol) and 9.77 g 2-bromo-l-(4-fluorophenyl) ethanone (45.0 mmol) were dissolved in 100 mL DMF and the mixture was stirred at 120 °C until no further conversion was observed. Then it was concentrated under reduced pressure and was diluted with EtOAc. Celite was added and the volatiles were evaporated under reduced pressure. The mixture was purified via flash chromatography using heptane and EtOAc as eluents. The regioisomer eluting earlier was collected as 2-(4-fluorophenyl)OR1GINAL

- 130l/7-imidazo[l,2-iï]pyrimidin-5-one. ’H NMR (500 MHz, DMSO-de) δ: I2.98 (br s, IH),

8.14 (s, IH), 7.97 (m, 2H), 7.90 (d, IH), 7.27 (m, 2H), 5.57 (d, IH)

Step B: 5-chloro-2-(4-fluorophenyl)imidazo[l,2-a]pyrimidine

1.36 g 2'(4-fluorophenyl)-l//-imidazo[l,2</]pyrimidin-5-one (5.9 mmol) and 16.6 mL POCI3 was stirred at 93 °C for 90 minutes, then the mixture was cooled to r.t. and concentrated under reduced pressure. The residue was poured onto icy-water. After the ice melted the formed precipitate was filtered, washed with water. *H NMR (500 MHz, DMSO-d₆)ô: 8.65 (s, IH), 8.55 (d, IH), 8.l7(m, 2H), 7.45 (d, IH), 7.33 (m, 2H)

Step C: 3-bromo-5-chloro-2-(4yfluorophenyl)imidazo[l,2-a]pyrimidine

715 mg 5-chloro-2-(4-fluorophenyl)imidazo[l,2-iï]pyrimidÎne (2.89 mmol) was dissolved in 10 mL chloroform then 570 mg NBS (3.20 mmol) was added and the mixture was stirred at r.t. until the consumption of the starting material. Then the mixture was concentrated under reduced pressure and purified via flash chromatography using heptane and EtOAc as eluents.

'H NMR (500 MHz, DMSO-d₆) δ: 8.52 (d, IH), 8.10 (m, 2H), 7.39 (m, 2H), 7.38 (d, IH) HRMS calculated for C|₂H₆BrClFN₃: 324.9418; found: 325.9481 (M+H)

Step D: 5-chloro-3~[3-chloro-2-niethyl-4-[2-(4-melhylpiperazin-I-yl)elhoxy]phenyl]-2-(4fluorophenyl)imidazo[ 1,2-aJpyrimidine

620 mg 3-bromo-5-chloro-2-(4-fluorophenyl)imidazo[l,2-u|pyrimidine (1.93 mmol) and

2.37 g Préparation 3b (6.0 mmol) were dissolved in 10 mL THF under nitrogen atmosphère, then 1.30 g Cs₂CO₃ (4.00 mmol), 3 mL water and 273 mg AtaPhos (0.386 mmol) were added and the mixture was stirred in a microwave reactor at 110 °C for 10 minutes. Then the mixture was diluted with brine and extracted with DCM. The combined organic phase was dried over Na₂SO₄, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified via flash chromatography using EtOAc and MeOH as eluents. LRMS calculated for C₂6H₂6C1₂FN5O: 513.15; found: 514.1 (M+H)

Step E: Example 102

ORIGINAL

- I3l341 mg 5-chloro-3-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l -yl)ethoxy]phenyl]-2-(4fluorophenyl)imidazo[l,2-rt]pyrimidine (0.66 mmol) and 300 mg Préparation 2i (0.76 mmol) were dissolved in 3 mL dry DMSO under nitrogen atmosphère, then 652 mg Cs₂CO₃ (2.0 mmol) was added and the mixture was stirred in a microwave reactor at 160 °C for 10 minutes. Then it was diluted with brine and water, neutralized with 2 M aqueous HCl solution, and extracted with DCM. The combined organic phase was dried over Na₂SO₄, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified via reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents to obtain Example 102 as a mixture of diastereoisomers, HRMS calculated for C₄7H46C1FN₈O₅: 856.3264; found; 429.1687 and 429.1705 (M+2H)

Example 103: 2-{|3-{3-chloro-2-methyI-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl}2-(4-fluorophenyl)imidazo[l,2-fl]pyridin-5-yl]oxy}-3-(2-{[2-(2-methoxyphenyl) pyrimîdin-4-yl]methoxy}phenyI)propanoic acid

Example 104: A^r-|3-{3-chloro-2-methyl-4-i2-(4-methylpiperazin-l-yl)ethoxy]phcnyl}2-(4-fluorophenyl)imidazo[l,2-«|pyridin-5-yll-2-{[2-(2-methoxyphenyl)pyrimidin-4yl]niethoxy}phenylalanine

ORIGINAL

- 132PHARMACOLOGICAL 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-pAla5 Ahx-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 same site as the ligand will resuit in a greater proportion of unbound ligand in the System indicated by a decrease in 10 mP units.

Method 1: An 11 point serial dilution of each compound was prepared in DMSO and 2 μΐ transferred into fiat bottomed, low binding, 384-well plate (final DMSO concentration 5%). 38 μΙ of buffer (10 mM 4-(2-hydroxyethyl)-l-piperazineethanesulfonic acid [HEPES], 150 mM NaCl, 0.05 % Tween 20, pH 7.4), containing the Fluorescein labelled 15 ligand (final concentration 1 nM) and Mcl-l protein (final concentration 5 nM) was then added.

Assay plates were incubated ~2 hours at room température 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 increasîng doses of test compound was expressed as a 20 percentage réduction in mP compared to a window established between ‘5 % DMSO only’ and ‘100% inhibition’ Controls. 11-point dose response curves were plotted with XL-Fit software using a 4-Parameter Logistic Model (Sigmoidal Dose-Response Model) and the inhibitory concentrations that gave a 50 % réduction in mP (IC50) were determined. Results obtained using Method 1 are presented in Table 1 below; 1C_5Ü of Mcl-l inhibition obtained 25 using Method 1 are not underlined.

Method 2: An 11 point serial dilution of each compound was prepared in DMSO and 2 μΐ

ORIGINAL

- 133transferred into fiat bottomed, low binding, 384-well plate (final DMSO concentration

%). 38 μΐ of buffer (20 mM NaiHPO^, ImM EDTA, 50 mM NaCl, pH 7.4), containing the Fluorescein labelled ligand (final concentration lOnM) and Mcl-l protein (final concentration 10 nM) was then added.

Assay plates were incubated ~2 hours at room température before FP was measured on a Biomek Synergy2 reader (Ex. 528 nm. Em. 640 nm, Cut off 510 nm) and mP unîts 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 (50 μΜ unlabelled ligand). 11-point dose response curves were plotted with XL-Fit software using a 4-Parameter Logistic Model (Sigmoidal DoseResponse Model) and the inhibitory concentrations that gave a 50 % réduction in mP (lC₅o) were determined. Results obtained using Method 2 are presented in Table 1 below; IÇ5o of Mcl-l inhibition obtained using Method 2 are underlined.

The results show that the compounds of the invention inhibit interaction between the Mcl-1 protein and the fluorescent peptide described hereinbefore.

EXAMPLE B: In vitro cytotoxicity

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

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

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

The results are expressed in IC50 (the concentration of compound that inhibits cell viability by 50 %) and are presented in Table 1 below.

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

ORIGINAL

- 134Table 1: IÇ₅₀ of Mcl-1 inhibition (fluorescence polarisation test) and of cvtotoxicitv for H929 cells

Note: IC50 of Mcl-1 inhibition obtained using Method 2 are underlined.

	IC* (M) Mcl-1 FP	IC* (Μ) MTT H929		IC* (M) Mcl-1 FP	IC* (Μ) MTT H929
Example 1	3.8E-09	2.41E-08	Example 30	6.4E-06	ND
Example 2	6.0E-09	I.45E-08	Example 31	7.9E-07	ND
Example 3	1.7E-08	3.64E-07	Example 32	3.5E-06	ND
Example 4	2.9E-08	3.29E-07	Example 33	2.6E-07	ND
Example 5	1.5E-08	6.I9E-07	Example 34	6.4E-06	ND
Example 6	8.9E-09	ND	Example 35	2.9E-07	ND
Example 7	1.IE-07	7.57E-07	Example 36	6.5E-06	ND
Example 8	6.6E-09	I.78E-08	Example 37	5.3E-07	ND
Example 9	8.6E-08	6.89E-08	Example 38	67% @50 uM	ND
Example 10	I.8E-O5	ND	Example 39	77,75% @ 50 uM	ND
Example 11	3.4E-05	ND	Example 40	8.6E-07 / 3.3E-08	ND
Example 12	5.6E-07	ND	Example 41	1.3E-05	ND
Example 13	6.6E-07	ND	Example 42	4.5E-Q7	ND
Example 14	I.2E-05	ND	Example 43	66.9% @ 50 uM	ND
Example 15	7.3E-06	ND	Example 44	2.5E-06	ND
Example 16	1.8E-06	ND	Example 45	I.8E-06	ND
Example 17	3.8E-06	ND	Example 46	71% @ 50 uM	ND
Example 18	3.1E-06	ND	Example 47	1.IE-05	ND
Example 19	3.3E-06	ND	Example 48	5.9E-06	ND
Example 20	64.8% @ 50 iiM	ND	Example 49	3.9E-08	ND
Example 21	8.7E-06	ND	Example 50	65.85% @ 10 uM	ND
Example 22	74.2% @ 50 uM	ND	Example 51	3.6E-07 / 5.5E-09	I.I0E-05
Example 23	6.8E-06	ND	Example 52	1.6E-06	ND
Example 24	I.8E-05	ND	Example 53	2.2E-08	2.53E-08
Example 25	9.IE-06	ND	Example 54	1.2E-07	ND
Example 26	5.9E-06	ND	Example 55	55.35% @ 10 μΜ	ND
Example 27	3.3E-07	ND	Example 56	4.7E-08	ND
Example 28	63.25% @ 50 uM	ND	Example 57	1.7E-07	ND
Example 29	8.5E-06	ND	Example 58	51.9% @ 10 μΜ	ND

ORIGINAL

	IC» (M) Mcl-1 FP	ICW(M) MTT H929		ICm(M) Mcl-1 FP	IC» (M) MTT H929
Example 59	3.6E-O8	I.24E-06	Example 83	ND	ND
Example 60	1.9E-08	5.68E-07	Example 84	5.45E-09	I.09E-08
Example 61	52.8% @ 10 μΜ	ND	Examplc 85	ND	ND
Example 62	8.2E-07	ND	Example 86	3.05E-08	3.59E-08
Example 63	1.7E-07	ND	Examplc 87	ND	ND
Example 64	7.4E-09	4.7IE-08	Example 88	ND	ND
Examplc 65	1.0E-06	ND	Examplc 89	ND	ND
Example 66	1.6E-06	ND	Examplc 90	ND	ND
Examplc 67	I.4E-08	8.36E-08	Examplc 91	ND	ND
Example 68	I.2E-06	ND	Example 92	ND	ND
Examplc 69	2.4E-08	I.04E-07	Example 93	ND	ND
Examplc 70	13.55% @ 10 uM	ND	Examplc 94	ND	ND
Example 71	5.02E-09	9.08E-09	Examplc 95	ND	ND
Example 72	I.55E-08	3.2E-08	Examplc 96	ND	ND
Example 73	ND	ND	Example 97a	55% @ 10 μΜ	I.16E-05
Example 74	ND	ND	Examplc 97b	4.I0E-08	4.59E-07
Example 75	5.6 IE-07	7.55E-08	Examplc 98	ND	ND
Example 76	1.34E-07	1.01 E-08	Example 99	ND	ND
Examplc 77	ND	ND	Examplc 100	ND	ND
Example 78	ND	ND	Example 101	ND	ND
Examplc 79	ND	ND	Examplc 102	no curve	>3.00E-05
Example 80	ND	ND	Examplc 103	ND	ND
Example 81	ND	ND	Examplc 104	ND	ND
Examplc 82	ND	ND

ND: not determined

For partial inhibitors, the percentage fluorescence polarization inhibition for a given concentration of the test compound is indicated. Accordingly, 45.1% @10 μΜ means that 45.1% fluorescence polarization inhibition is observed for a concentration of test compound equal to 10 μΜ.

ORIGINAL

- 136EXAMPLE 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.

I.IO⁷ AMO-l cells are grafted sub-cutaneously into immunosuppressed mice (SC1D strain). 12 to 14 days after the graft, the animais are treated by intraveinous or oral routes with the various 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. It 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 (presented in Table 2 below) show that the compounds of the invention are capable of inducing apoptosis in AMO-l tumour cells in vivo.

Table 2: Quantification of the cleaved form of PARP in vivo

	PARP fold		PARP fold		PARP fold
Example l	I57.5	Example 8	55.4	Example 67	29.3
Example 2	216.3	Example 53	40.2	Example 72	15.7

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 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.

ORIGINAL

- I37The compound of the invention has anti-tumour activity (tumour régression) in the AMO-l multiple myeloma model with ΔΤ/C (qualification parameter of the activity of a product. which is measured by subtracting the médian tumor volume on the day of last treatment from the médian tumor volume on the day of fîrst treatment / tumour volume of the 5 untreated control group on the day of last treatment) of -27 %. The results obtained show that the compounds of the invention induce significant tumour régression during the treatment period.

EXAMPLE E: Pharmaceutical composition: Tablcts

1000 tablets containing a dose of 5 mg ofa compound selected from Examples l to 104..........5g

Wheat starch g

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

Lactose..........................„ τη

.. D\J

Magnésium stéarate......................... ?

Silica...................................................................,....................... ]g

Hydroxypropylcellulose.................................................,.................................... 2g

ORIGINAL

Claims (4)

1. Compound of formula (I):

♦ A represents the group

ΙΟ in which 1 is linked to the W group and 2 is linked to the phenyl ring, wherein:

- E represents a furyl, thienyl or pyrrolyl ring,

- X[, X₃, X4 and X5 independently of one another represent a carbon atom or a nitrogen atom.

- X₂ represents a C-R₂₁ group or a nitrogen atom, and

- I ) means that the ring is aromatic, ♦ R] represents a halogen atom, a linear or branched (Ci-C₆)alkyl group, a linear or branched (C₂-C₆)alkenyl group, a linear or branched (C₂-C₆)alkynyl group, a linear or branched (C|-C₆)polyhaloalkyl group, a hydroxy group, a hydroxyiCt-Côjalkyl group, a linear or branched (C|-C₆)alkoxy group, -S-(Ci-C₆)alkyl, a cyano group, a nitro group, -alkyl(Co-C₆)-NR[|Rii', -O-alkyl(Ci-C6)-NR_HRj|’, -O-alkyl(C_t-C₆)-R₁₂, -C(O)-OR_n, -O-C(O)-R_n, -C(O)-NRnR_lt’, -NRh-C(O)-Rii\ -NRn-CiOj-ORn’, -alkyl(C|-C₆)-NR||-C(O)-R|i’, -SO^NRuRji’,

ORIGINAL

-139-SO₂-alkyl(Ci-C₆), ♦ R?, R₃, R4 and R5 independently of one another represent a hydrogen atom, a halogen atom, a linear or branched (Ci-C^jalkyl group, a linear or branched (C2-C6)alkenyl group, a linear or branched (C₂-C6)alkynyl group, a linear or

5 branched (C|-C6)polyhaloalkyl, a hydroxy group, a hydroxytCi-C^Jalkyl group, a linear or branched (Ci-C&)alkoxy group, a -S-(C]-C6)alkyl group, a cyano group, a nitro group, -alkyl(Co-C₆)-NRi]R||’, -O-alkyl(C_rC₆)-NR||Rn’, -O-alkyl(Ci-C₆)-Ri2, -C(0)-ORn, -O-C(O)-R_U, -CiOj-NRnRn’, -NRn-CtOj-Rn’, -NR]|-C(O)-OR]|’, -alkyl(C|-C₆)-NRn-C(O)-Rir, -SO₂-NRiiR,r, or

IO -SO₂-alkyl(Ci-C₆), or the substituents of the pair (Rj, R₂) form together with the carbon atoms carrying them an aromatic or non-aromatic ring composed of from 5 to 7 ring members, which may contaîn from l to 3 heteroatoms selected from oxygen, sulphur and nitrogen, it being understood that resulting ring may be substituted by from l to 2 15 groups selected from halogen, linear or branched (Ci-CôJalkyl,

-alkyl(Co-C₆)-NRi]R||’, -NRi₃Ri₃’, -aIkyl(Co-C6)-Cyi or oxo, J ♦ R₆ and R7 independently of one another represent a hydrogen atom, a halogen atom, a linear or branched (Ci-Cô)alkyl group, a linear or branched (C₂-C6)alkenyl group, a linear or branched (C₂-C6)alkynyl group, a linear or branched

20 (Ci-C₆)polyhaloalkyl, a hydroxy group, a linear or branched (Ci-Céjalkoxy group, a -S-(C]-C6)alkyl group, a cyano group. a nitro group, -alkylfCo-Cftj-NRijRn’, -O-Cyi, -alkyl(Co-C₆)-Cyi, -alkenyl(C₂-C₆)-Cyi, -alkynyl(C₂-C₆)-Cyi, -O-alkyl(Ci-C₆)-R,₂, -C(O)-ORi], -O-C(O)-R_n, -CÎOJ-NRhR,,’, -NR_irC(O)-R|i\ -NR_irC(O)-ORir, -alkyl(C|-C₆)-NRn-C(O)-Rii·, -SO₂-NR||R_H’,

25 -SO₂-alkyl(C_rC₆), or the substituents of the pair (R₆, R₇), when grafted onto two adjacent carbon atoms, form together with the carbon atoms carrying them an aromatic or nonaromatic ring composed of from 5 to 7 ring members, which may contain from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen, it being understood thaï 30 resulting ring may be substituted by a group selected from a linear or branched (Ci-Côjalkyl group, -NRi₃Ri₃’, -alkyl(Co-C6)-Cyi or an oxo.

♦ W represents a -CH₂- group, a -NH- group or an oxygen atom,

ORIGINAL

- MO- ♦ R_s represents a hydrogen atom, a linear or branched (Ci-C₈)alkyl group, a -CHR_aR_h group, an aryl group, a heteroaryl group, an arylalkyKCj-Cô) group, or a heteroarylalkyl(Ci-C₆) group, ♦ R₉ represents a hydrogen atom, a linear or branched (C_rC₆)alkyl group, a linear or branched (C₂-C₆)alkenyl group, a linear or branched (C₂-C₆)alkynyl group, -Cy₂, -alkyl(Ci-C(,)-Cy₂, -alkenyl(C₂-Cé)-Cy₂, -alkynyl(C₂-C₆)-Cy₂, -Cy₂-Cy3, -alkynyl(C₂-C(,)-O-Cy₂, -Cy₂-alkyl(Co-C6)-0-alkyI(Co'C6)-Cy3, a halogen atom, a cyano group, -C(O)-R_l5, or -C(O)-NR|₅R|₅’, ♦ Rio represents a hydrogen atom, a linear or branched (C|-C6)alkyl group, a linear or branched (C₂-C₆)alkenyl group, a linear or branched (C₂-C₆)alkynyl group, an arylalkyl(C|-C₆) group, a cycloalkylalkylfCi-Cù) group, a linear or branched (Ci -C₆)polyhaloalkyl, -alkyl(C i -C₆)-O-Cy₄, or the substituents of the pair (R₉, Rio), when grafted onto two adjacent carbon atoms, form together with the carbon atoms carrying them an aromatic or nonaromatic ring composed of from 5 to 7 ring members, which may contain from l to 3 heteroatoms selected from oxygen, sulphur and nitrogen, ♦ Ru and Ru’ independently of one another represent a hydrogen atom, a linear or branched (C|-C₆)alkyl group, or the substituents of the pair (Ru, Ru’) 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 a group representing a hydrogen atom, or a linear or branched (C|-C₆)alkyl group, ♦ R_]2 represents -Cy₅, -Cy₅-alkyl(C₀-C₆)-0-alkyl(Co-C₆)-Cy₆,

-Cy₅-alkyi(C₀-C₆)-Cy₆, -Cys-alkyKCo-Càj-NRn-alkyKCo-Côj-Cyf,,

-Cy5-Cy₆-O-alkyl(C_O-C₆)-Cy7, -CfOj-NRnRn’, -NRuRh', -OR,., -NRii-C(O)-R_H’, -O-alkyl(C|-C₆)-ORn, -SO₂-Rn, -C(O)-ORh, or -NH-C(O)-NH-R_n, ♦ Ris, Ri₃\ Ris and R15’ independently of one another represent a hydrogen atom, or an optionally substituted linear or branched (Cj-Céjalkyl group, ♦ Rm represents a hydrogen atom, a hydroxy group, or a hydroxy(C]-C₆)alkyl group.

ORIGINAL

- I4l- ♦ Rji represents a hydrogen atom, a halogen atom, a linear or a branched (C|-C₆)alkyl group, or a cyano group, ♦ R_a represents a hydrogen atom or a linear or branched (C|-C₆)alkyi group, ♦ R_b represents a -O-C(O)-O-R_c group, a -O-QOj-NRcRç’ group, or a -O-P(O)(OR_e)₂

5 group, ♦ R_c and Rf independently of one another represent a hydrogen atom, a linear or branched (C_rC₈)alkyI group, a cycloalkyl group, a (C|-C₆)alkoxy(C_rC₆)alkyl group, a (C|-C₆)alkoxycarbonyl(Ci-C₆)alkyl group, or the substituents of the pair (R_c, Rc’) form together with the nitrogen atom ¹⁰ carrying them a non-aromatic ring composed of from 5 to 7 ring members, which may contain in addition to the nitrogen atom from 1 to 3 heteroatoms selected from oxygen 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, Cyj, Cy₄, Cy5, Cy6 and Cy₇ independently of one another, represent a

15 cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, ♦ n is an integer equal to 0 or 1, it being understood that:

- “aryl” means a phenyl, naphthyl, biphenyl, indanyl or indenyl group, heteroaryl” means any mono- or bi-cyclic group composed of from 5 to 10 ring 20 members, having at least one aromatic moiety and containing from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen, cycloalkyl means any mono- or bi-cyclic non-aromatic carbocyclic group containing from 3 to 10 ring members,

- heterocycloalkyl” means any mono- or bi-cyclic non-aromatic carbocyclic group

25 containing from 3 to 10 ring members, and containing from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen. which may include fused, bridged or spiro ring Systems, it being possible for the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined and the alkyl, alkenyl, alkynyl, alkoxy groups, to be substituted by from 1 to 4 30 groups selected from optionally substituted linear or branched (C|-C₆)alkyl, optionally

ORIGINAL

- 142substituted linear or branched (C₂-C6)alkenyl, optionally substituted linear or branched (C2-C₆)alkynyl, optionally substituted linear or branched (C|-C₆)alkoxy, optionally substituted (Ci-Cé)alkyl-S-, hydroxy, oxo (or jV-oxide where appropriate), nitro, cyano, -C(O)-OR’, -O-C(O)-R\ -C(O)-NR’R”, -O-C(O)-NR’R”, -NR’R”, -(C=NR’)-OR”, -O-P(O)(OR’)₂, -O-P(O)(O*M⁺)₂, linear or branched (Ci-Ce)polyhaloalkyl, trifluoromethoxy, halogen, or an aldohexose of formula:

in which each R' îs independent;

it being understood that R’ and R” independently of one another represent a hydrogen atom or an optionally substituted linear or branched (C_rC₆)alkyl group, and M⁺ represents a pharmaceutically acceptable monovalent cation.

their enantiomers, diastereoisomers and atropisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.

2. Compound of formula (!) according to claim l, wherein:

♦ Rj and R2 independently of one another represent a halogen atom. a linear or branched (Ci-C₆)alkyl group, a hydroxy group, a linear or branched (C|-C₆)alkoxy group, or the substituents of the pair (R_b R₂) form together with the carbon atoms carrying them an aromatic ring composed of from 5 to 7 ring members, which may contain from 1 to 3 nitrogen atoms,

ORIGINAL

- 143- ♦ Rj represents a hydrogen atom, a halogen atom, a linear or branched (C|-C&)alkyl group, a hydroxy group, a linear or branched (Ci-Cft)alkoxy group, or -O-alkyKC.-CôJ-NRnRn’, ♦ R4 and R5 independently of one another represent a hydrogen atom, a halogen

5 atom, a linear or branched (Ci-Côfalkyl group, a hydroxy group, a linear or branched (C|-C&)alkoxy group, ♦ R₆ and R7 independently of one another represent a hydrogen atom, a halogen atom, a linear or branched (Ci-Cô)alkyl group, a linear or branched (Ci-C₆)polyhaloalkyl group, a hydroxy group, a linear or branched (Ci-Cé)alkoxy

IO group, a cyano group, a nitro group, -alkyl(Co-C6)-NR||R]|’, -alkyl(Co-C6)-Cyi,

-O-alkyl(C_l-C₆)-Ri2, or -C(O)-NR| [R| f, ♦ Rs represents a hydrogen atom, a linear or branched (Ci-Cg)alkyl group, or a -CHR_aRb group, ♦ R₉ represents a hydrogen atom, a linear or branched (Ci-C₆)alkyl group, a linear or

15 branched (C₂-Cô)alkenyl group, a linear or branched (C₂-C₆)alkynyl group, -Cy₂, or a halogen atom, ♦ Rio represents a hydrogen atom, a linear or branched (C i -Côjalkyl group, a linear or branched (C₂-Cô)alkenyl group, a linear or branched (C₂-C₆)alkynyl group, an arylalkyl(Ci-Cô) group, a cycloalkylalkyl(C|-C₆) group, a linear or branched

20 (Ci-C₆)polyhaioalkyl, or -alkyl(Ci-C₆)-O-Cy4, or the substituents of the pair (R9, Rio) when grafted onto two adjacent carbon atoms, form together with the carbon atoms carrying them a 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,

25 ♦ R|| and Ru' independently of one another represent a hydrogen atom, a linear or branched (Ci-C&)alkyl group, or the substituents of the pair (Ru, Ru’) form together with lhe 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 30 oxygen and nitrogen, it being understood that the nitrogen in question may be substituted by a group representing a linear or branched (C i -Côjalkyl group, ♦ Rj₂ represents -Cy5 or -Cy5-alkyl(C(i-C₆)-Cy₆,

ORIGINAL

- I44♦ W represents a -NH- group or an oxygen atom, it being possible for the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined and the alkyl, alkenyl, alkynyl, alkoxy groups, to be substituted by from i to 4 groups selected from optionally substituted linear or branched (C_rC₆)alkyl, optionally 5 substituted linear or branched (C]-C₆)alkoxy, hydroxy, oxo (or N-oxide where appropriate), -C(O)-OR’, -C(O)-NR’R”, -O-C(O)-NR’R”, -NR’R”, -O-P(O)(OR’)₂, -O-P(O)(OM )₂, linear or branched (Ci-Côjpolyhaloalkyl, halogen, or an aldohexose of formula:

10 in which each R’ is independent;

it being understood that R’ and R” independently of one another represent a hydrogen atom or an optionally substituted linear or branched (Ci-C₆)alkyl group and M’ represents a pharmaceutically acceptable monovalent cation.

3. Compound of formula (I) according to claim l, wherein n is an integer equal to l.

15 4. Compound of formula (!) according to claim l, which is compound of formula (l-a);

ORIGINAL

- 145-

(I-a) wherein Rj, R₂, R3, R₄, R5, R<„ R₇, Rg, R₉, Ri₄, X_b X₂, X3 and W are as defined in claim l.

5. Compound of formula (I) according to claim L which is compound of formula (I-b):

(I-b) wherein R], R₂, R3, R4, R₅, R*, R₇, R_s, R₉, R_i4, X_b X₂, X₃ and W are as defined in claim l.

6. Compound of formula (I) according to claim l, which is compound of formula (I-c):

ORIGINAL

- I46-

wherein R_t, R₂, R3, R4, R5, Rr„ R7, Rs, R9, Rio, Ri4, Xi, X2, X3 and W are as defined in claim l.

7. Compound according to claim 6, wherein Rio represents hydrogen; methyl; isopropyl;

5 2,2,2-trifluoroethyl; benzyl; 4-methoxybenzyl; phenethyl; 3-phenyl-propyl;

cyciopropylmethyl; cyclopentylethyl; naphthalen-l-ylmethyl; 2-(naphthalen-lyloxy)ethyl; but-2-yn-l-yl; prop-2-en-lyl; or but-3-en-l-yl.

8. Compound of formula (!) according to claim l, which is compound of formula (I-d):

IO wherein R_b R₂, R₃, R4, R_5î R/,, R₇. R_s, R9, Rio, R14, X|, X2, X3 and W are as defined in

ORIGINAL

- 147claim I.

9. Compound according to claim 8, wherein R_l0 represents a hydrogen atom or a halogen atom.

10. Compound of formula (I) according to claim 1, which is compound of formula (I-e):

(i-e) wherein R|, R₂, R3, R4, R5, R₍,, R7, R_s, R_g, R₁₄, X_b X₂, X3 and W are as defined in claim 1.

11. Compound according to claim 1, wherein at least one of the groups selected from R₂, R3, R4 and R5 does not represent a hydrogen atom.

10 12. Compound according to claim 1, wherein Rj₄ represents a hydrogen atom.

13. Compound according to claim 1, wherein R₂j represents a hydrogen atom, a fluorine atom, a methyl group or a cyano group.

14. Compound according to claim 1, wherein R| represents a linear or branched (C|-C&)alkyl group or a halogen atom.

15 15. Compound according to claim 1, wherein R₂ represents a linear or branched (Cj-Côjalkoxy group, a hydroxy group or a halogen atom.

ORIGINAL

- I48-

16. Compound according to claim 1, wherein R₃ represents a hydrogen atom, a hydroxy group, a linear or branched (C|-C6)alkoxy group or -O-alkyl(Ci-C₆)-NR||Rn’.

17. Compound according to claim 1, wherein Rq and R₅ represent a hydrogen atom.

18. Compound according to claim 1, wherein

represents

wherein Rj t and R] 1 ’ are as defined in claim 1.

19. Compound according to claim 1, wherein the substituents of the pair (Ri, R5) are identical and the substituents of the pair (R₂, Rf) are identical.

20. Compound according to claim 1, wherein R_b represents a hydrogen atom, an optionally substituted linear or branched (Ci-C₆)alkoxy group or a -O-alkyI(C_rC₆)-R_I2 group.

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

22. Compound according to claim 1, wherein

ORIGINAL

- 149wherein Ru is as defined in claim l.

23. Compound according to claim l, which is compound of formula (I-g):

wherein R[, R_f>. R₇, R₈, R₉, R_l0, Ru, Ru’, R|₄, X|, X₂, X_3j X4, X₅₎ W and E are as 5 defined in claim l.

24. Compound according to claim l, wherein 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.

25. Compound according to claim l, wherein R₉ represents a hydrogen atom, a halogen

Ιθ atom, a linear or branched (Ci-C₆)alkyl group, a linear or branched (C2-C₆)alkenyl group, a linear or branched (C2-C_b)alkynyl group, an aryl group or a heteroaryl group.

26. Compound according to claim l, wherein Rj[ and Rn‘ independently of one another represent a linear or branched (Ci-Csjalkyl group, or the substituents of the pair (Ru, R|i’) torm together with the nitrogen atom carrying them a non-aromatic ring

15 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 a group representing a hydrogen atom, a linear or branched (Cj-C₆)alkyl group.

ORIGINAL

- ISO-

27. Compound according to daim l, wherein R_l2 represents -Cys or -Cy5-alkyl(Co-C6)-Cy6.

28. Compound according to claim 27, wherein Cys represents a heteroaryl group.

29. Compound according to claim 27, wherein Cyé represents a phenyl group.

5 30. Compounds according to claim 27 wherein

Ri₂ represents

in which p is an integer equal to 0 or l and R_l6 represents a hydrogen atom, a hydroxy group, an optionally substituted linear or branched (C|-C₆)alkyl group, a linear or branched (C_rC₆)alkoxy group, a -O-(CHR]7-CHRi₈-O)_q-R’ group, a -O-P(O)(OR’)₂ group, a -O-P(O)(QM⁺)₂ group, a -O-C(O)-NR|₉R₂₀ group, a di(C|-Cé)alkylamino(C|-C6)alkoxy group, a halogen atom, or an aldohexose of formula:

in which each R' is independent;

15 it being understood that:

♦ R’ represents a hydrogen atom or a linear or branched (Cj-C₆)alkyl group, ♦ R|₇ represents a hydrogen atom or a (C|-C₆)aikoxy(Ci-C₆)alkyl group.

ORIGINAL

- 151- ♦ Ri8 represents a hydrogen atom or a hydroxyiCj-CôJalkyl group, ♦ Ri₉ represents a hydrogen atom or a (Ci-C₆)alkoxy(C_rC₆)alkyl group, ♦ R₂₀ represents a (C_l-C₆)alkoxy(C_l-C₆)alkyl group, a -(CH₂)r-NR_HR||’ group or a -(CH₂)_r-O-(CHRi7~CHR]8-O)q-R’ group,

5 ♦ q is an integer equal to l, 2 or 3 and r is an integer equal to 0 or i, ♦ M⁺ represents a pharmaceutically acceptable monovalent cation.

31. Compounds according to claim 30, wherein the aldexose is D-mannose,

32. Compounds according to claim l, which are:

(2Æ)-2-{[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 -yl)ethoxy]phenyl }-6-(4^]0 fluorophenyl)furo[2,3-^pyrimidin-4-yI]oxy}-3-(2-{[2-(2-methoxyphenyl) pyrimidin-4-yl]methoxy}phenyl)propanoic acid; (2Æ)-2-{[5-{3-chloro-2-ethyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl}-6-(4fluorophenyl)furo[2,3-i/]pyrimidin-4-yl]oxy} -3-(2- {[2-(2-methoxyphenyl) pyrimidin-4-yl]methoxy}phenyl)propanoic acid;

15 - V-[(5S_iJ)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl}-6-(4fluorophenyl)furo[2,3-i/]pyrimidin-4-yl]-2-{[2-(2-methoxyphenyl)pyrimidin-4-yl] methoxy}-D-phenylalanine;

- (2Â)-2-{[(3xSj-3-{3-chloro-2-methyl-4-[2-(4-methyipiperazin-l-yl)ethoxy]phenyl}2-(4-fluorophenyl )-1 -benzothiophen-4-yl]oxy} -3-( 2-{[2-(2methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid;

- (2/?)-2-{[(3S_<I)-3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl}2-(4-fluorophenyl)-l-benzofuran-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin4-yl]methoxy}phenyl)propanoic acid;

(2 J?)-2-{ [(35^)-3- {3-chloro-2-methyI-4-[2-(4-methyipiperazin-1 -yl )ethoxy]phenyl} ²⁵ 6-fluoro-2-(4-fluorophenyl)-l-benzofuran-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl) pyrimidin-4-yl]methoxy}phenyl)propanoic acid;

(2 R)-2- {[3- {( jS_a)-3-chloro-2-methy l-4-[2-(4-methylpiperazin-1 -y 1 )ethoxy]phenyl} 2-(4-fluorophenyl)-1 -methyl-1 /f-indol-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl) pyrimidin-4-yl]methoxy}phenyl)propanoic acid;

ORIGINAL

- 152(2^)-2-{[(3S^, _a)-3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl}2-(4-fluorophenyl)thieno[2,3-6]pyridin-4-yl]oxy)-3-(2-{[2-(2-methoxyphenyl) pyrimidin-4-yl]methoxy} phenyl)propanoic acid;

- (2Æ)-2-[5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 -yl)ethoxy]phenyl]-6-(4fluorophenyl)-7-methyl-pyrrolo[2,3-i/]pyrimidin-4-yl]oxy-3-[2-[[2-(2-methoxy phenyl)pyrimidin-4-yl]methoxy]phenyl]propanoic acid;

- l-[(dimethylcarbamoyl)oxy]ethyl (2Æ)-2-{[(3S_a)-3-{3-chloro-2-methyl-4-[2-(4methylpiperazin-l-yl)ethoxy]phenyl}-2-(4-fluorophenyl)thieno[2,3-6]pyridin-4yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoate;

- I -[(ethoxycarbonyl)oxy]ethyl (2R)-2-{[(35'_a)-3-{3-chloro-2-methyl-4-[2-(4methylpiperazin-l-yl)ethoxy]phenyl}-2-(4-fiuorophenyl)thieno[2,3-ô]pyridin-4yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoate;

- A43-{3-chloro-2-melhyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl}-2-(4fluorophenyl)thieno[2,3-6]pyridin-4-yl]-2-{[2-(2-methoxyphenyl)pyrimidin-4-yl] methoxy }-D-phenylalanine;

- jV-[3-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyI}-2-(4fluorophenyl)thieno[3,2-c]pyridin-4-yl]-2-{[2-(2-methoxyphenyl)pyrimidin-4-yl] methoxy Jphenylalanine;

- 2-{[(3Æ_a)-3-{3-chloro-2-methyI-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl )-2-(4fluorophenyl)iniidazo[l,2-c]pyrimidin-5-yl]oxy)-3-(2-{[2-(2-methoxyphenyI) pyrimidin-4-yl]methoxy)phenyl)propanoic acid.

33. 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 (ll-a):

₇ ^^A\₇ (Il-a) wherein Zi represents bromine or iodine, Z₂ represents chlorine, bromine or hydroxy, and A is as defined for formula (I) in which l is linked to the Z? group and 2 is linked to the Zi group, which compound of formula (II-a) is subjected to coupling with a compound of formula (III):

ORIGINAL

- 153-

(III) wherein R₆, R₇, R_l4, W and n are as defined for formula (l), and Alk represents a linear or branched (C_rC₆)aikyl group, to yield the compound of formula (IV):

(IV) wherein K,. R₇, R_i4, A, W and n are as defined for formula (I), and Z] and Alk are as defined before, compound of formula (IV) which is further subjected to coupling with compound of formula (V):

(V) wherein R_t, R₂, R₃, R₄ and R₅ are as defined for formula (I), and R_B1 and R_B2 represent a hydrogen atom, a linear or branched (C,-C₆) alkyl group, or R_B, and R_B2 form with the oxygen carrying them an optionally methylated ring,

ORIGINAL

- I54to yield the compound of formula (VI):

(VI) wherein R_ls R₂, R₃ R-ι, Rs, R<„ R7, Ru, A, W and n are as defined for formula (I) and Alk îs as defined before, the Alk-O-C(O)- ester fonction of which compound of formula (VI) is hydrolyzed to yield the carboxylic acid, which may optionally be reacted with an alcohol of formula Rs’-OH or a chlorinated compound of formula R_s ^?-Cl wherein R_s’ represents a linear or branched (Ci-Cs)alkyl group, a -CHR_aR_b group, an aryl group, a heteroaryl group, an arylalkyl(C_rC₆) group, or a heteroarylalkyl(Cj-C₆) group, R_a and R_b are as defined for formula (I), to yield the compound of formula (l), which may be purified according to a conventional séparation technique, which is converted, if desired, into its addition salts with a pharmaceutically acceptable acid or base and which is optionally separated into its isomers according to a conventional séparation technique, it being understood thaï at any moment considered appropriate during the course ofthe 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.

34. 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 (ll-b):

₇ (Π-b)

Z.4 Z,₃

ORIGINAL

- 155wherein Z₃ represents iodine, Z₄ represents chlorine, hydroxy, and A is as defined for formula (I) in which 1 is linked to the Z₄ group and 2 is linked to the Z₃ group, which compound of formula (Π-b) is subjected to coupling with a compound of formula (V):

(V) wherein R_b R₂, R₃, R4 and R₃ are as defined for formula (I), and R_B| and R_B2 represent a hydrogen atom, a linear or branched (C i-C₆) alkyl group, or R_BI and R_B2 form with the oxygen carrying them an optionally methylated ring, to yield the compound of formula (VII):

(Vil) wherein R_b R₂, R₃ R|, R₅ and A are as defined for formula (I), and Z₄ is as defined before.

compound of formula (VII) which is further subjected to coupling with compound of formula (III):

ORIGINAL

- 156-

(ΠΙ) wherein R_ô, R7, R_f4, W and n are as defined for formula ([), and Alk represents a linear or branched (Ci-C^alkyl group, to yield the compound of formula (VI):

(VI) wherein R_ls R₂, R3 R_₍, R₅, R₆, R₇, R_i4, A, W and n are as defined for formula (I) and Alk is as defined before, the Alk-O-C(O)- ester fonction of which compound of formula (VI) is hydrolyzed to yield the carboxylic acid, which may optionally be reacted with an alcohol of formula 10 Rs'-OH or a chlorinated compound of formula R₈’-Cl wherein R₈’ represents a linear or branched (C|-C₈)alkyl group, a -CHR_aRi, group, an ary] group, a heteroaryl group, an aryIalkyl(C|-C6) group, or a heteroarylalkylfCi-Cô) group, R_a and R_b are as defined for formula (I), to yield the compound of formula (l), which may be purified according to a 15 conventional séparation technique, which is converted, if desired, into its addition salts with a pharmaceutically acceptable acid or base and which is optionally separated into its isomers according to a conventional séparation technique.

ORIGINAL

- 157it 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.

35. Pharmaceutical composition comprising a compound of formula (I) according to any one of daims l to 32 or an addition sait thereof with a pharmaceutically acceptable acid or base in combination with one or more pharmaceutically acceptable excipients.

36. Pharmaceutical composition according to claim 35 for use as pro-apoptotic agents.

37. Pharmaceutical composition according to claim 36 for use in the treatment of cancers and of auto-immune and immune System diseases.

38. Pharmaceutical composition according to claim 37 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, nonsmall-cell lung cancer, prostate cancer, pancreatîc cancer and small-cell lung cancer.

39. Use of a pharmaceutical composition according to claim 35 in the manufacture of médicaments for use as pro-apoptotic agents.

40. Use of a pharmaceutical composition according to claim 35 in the manufacture of médicaments for use in the treatment of cancers and of auto-immune and immune System diseases.

4L Use of a pharmaceutical composition according to claim 35 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,

ORIGINAL

- 158prostate cancer, pancreatic cancer and small-cell lung cancer.

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

43. Use of a compound of formula (I) according to any one of daims l to 32, or an addition sait thereof with a pharmaceuticaily 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, prostate cancer, pancreatic cancer and small-cell lung cancer.

44. Combination of a compound of formula (I) according to any one of daims l to 32 with an anti-cancer agent selected from genotoxic agents, mitotic poisons, anti-metabolites, protéasome inhîbitors, kinase inhibitors and antibodies.

45. Pharmaceutical composition comprising a combination according to daim 44 in combination with one or more pharmaceuticaily acceptable excipients.

46. Combination according to daim 44 for use in the treatment of cancers.

47. Use of a combination according to claim 44 in the manufacture of médicaments for use in the treatment of cancers.

48. Compound of formula (I) according to any one of daims l to 32 for use in the treatment of cancers requiring radiotherapy.