HK1250233B - New hydroxyacid derivatives, a process for their preparation and pharmaceutical compositions containing them - Google Patents

Description

Novel hydroxy acid derivatives, preparation methods thereof and pharmaceutical compositions containing the same

The present invention relates to novel hydroxy acid derivatives, methods for their preparation and pharmaceutical compositions containing them.

The compounds of the present invention are novel and possess very valuable pharmacological properties in the field of apoptosis and oncology.

Apoptosis, or programmed cell death, is a critical physiological process in embryonic development and the maintenance of tissue homeostasis.

Apoptotic cell death involves morphological changes such as nuclear condensation and DNA fragmentation, as well as biochemical phenomena such as caspase activation, which leads to damage to key structural components of the cell, thereby inducing its disassembly and death. The regulation of the apoptotic process is complex and involves the activation or inhibition of multiple intracellular signaling pathways (Cory S. et al., Nature Review Cancer, 2002, 2, 647-656).

Dysregulation of apoptosis is implicated in several pathological conditions. Increased apoptosis is associated with neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and ischemia. Conversely, defects in the execution of apoptosis play a significant role in the development of cancer and its chemoresistance, autoimmune diseases, inflammatory diseases, and viral infections. Therefore, lack of apoptosis is one of the phenotypic hallmarks of cancer (Hanahan D. et al., Cell 2000, 100, 57-70).

The anti-apoptotic proteins of the Bcl-2 family are associated with a wide range of pathological conditions. The involvement of Bcl-2 family proteins has been documented in a wide range of cancer types, such as colon cancer, breast cancer, small cell lung cancer, non-small cell lung cancer, bladder cancer, ovarian cancer, prostate cancer, chronic lymphoid leukemia, lymphoma, myeloma, acute myeloid leukemia, and pancreatic cancer. Overexpression of anti-apoptotic proteins of the Bcl-2 family has been implicated in tumorigenesis, resistance to chemotherapy, and clinical prognosis in cancer patients. Notably, the anti-apoptotic Bcl-2 family member Mcl-1 is overexpressed in a variety of cancer types (Beroukhim R. et al., Nature 2010, 899-905). Therefore, there is a therapeutic need for compounds that inhibit the anti-apoptotic activity of Bcl-2 family proteins.

The compounds of the invention, besides being novel, possess pro-apoptotic properties, making them useful in pathologies involving apoptosis defects, for example in the treatment of cancer and immune and autoimmune diseases.

The present invention particularly relates to compounds of formula (I), their enantiomers, diastereomers and atropisomers, and their addition salts with pharmaceutically acceptable acids or bases:

in:

◆A represents the group

Where 1 is connected to the oxygen atom and 2 is connected to the benzene ring,

◆R ₁ represents a straight chain or branched chain (C ₁ -C ₆ ) alkyl group, a straight chain or branched chain (C ₂ -C ₆ ) alkenyl group, a straight chain or branched chain (C ₂ -C ₆ ) alkynyl group, a straight chain or branched chain (C ₁ -C ₆ ) alkoxy group, -S-(C ₁ -C ₆ ) alkyl group, a straight chain or branched chain (C ₁ -C ₆ ) polyhalogenated alkyl group, a hydroxyl group, a hydroxyl (C ₁ -C ₆ ) alkyl group, a cyano group, -NR ₁₂ R ₁₂ ', -Cy ₅ or a halogen atom,

◆R ₂ , R ₃ , R ₄ and R ₅ independently represent a hydrogen atom, a halogen atom, a straight-chain or branched (C ₁ -C ₆ ) alkyl group, a straight-chain or branched (C ₂ -C ₆ ) alkenyl group, a straight-chain or branched (C ₂ -C ₆ ) alkynyl group, a straight-chain or branched (C ₁ -C ₆ ) polyhaloalkyl group, a hydroxyl group, a hydroxyl (C ₁ -C ₆ ) alkyl group, a straight-chain or branched (C ₁ -C ₆ ) alkoxy group, a -S-(C ₁ -C ₆ ) alkyl group, a cyano group, a nitro group, a -alkyl (C ₀ -C ₆ ) -NR ₁₀ R ₁₀ ', a -O-alkyl (C ₁ -C ₆ ) -NR ₁₀ R ₁₀ ', a -O-alkyl (C ₁ -C ₆ ) -R ₁₁ , a -C(O)-OR ₁₀ , -OC(O)-R ₁₀ , -C(O)-NR ₁₀ R ₁₀ ', -NR ₁₀ -C(O)-R ₁₀ ', -NR ₁₀ -C(O)-OR ₁₀ ', -alkyl(C ₁ -C ₆ )-NR ₁₀ -C(O)-R ₁₀ ', -SO ₂ -NR ₁₀ R ₁₀ ', -SO ₂ -alkyl(C ₁ -C ₆ ) or, when attached to two adjacent carbon atoms, the substituents of one of the pairs (R ₂ , R ₃ ), (R ₃ , R ₄ ), (R ₄ , R ₅ ) together with the carbon atom carrying them form an aromatic or non-aromatic ring consisting of 5 to 7 ring members, said ring may contain 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, it being understood that the ring formed may be selected from a linear or branched (C ₁ -C ₆ )alkyl, -NR ₁₂ R ₁₂ ', -alkyl(C ₀ -C ₆ )-Cy ₁ or oxo-substituted group,

◆R ₆ represents -O-alkyl (C ₁ -C ₆ )-R ₁₁ ,

◆ _R7 represents a hydrogen atom, a halogen atom, a straight-chain or branched-chain ( _C1 - _C6 ) alkyl group, a straight-chain or branched-chain ( _C2 - _C6 ) alkenyl group, a straight-chain or branched-chain ( _C2 - _C6 ) alkynyl group, a straight-chain or branched-chain ( _C1 - _C6 ) polyhaloalkyl group, a hydroxyl group, a straight-chain or branched-chain ( _C1 - _C6 ) alkoxy group, -S- _{( C1} - _C6 ) alkyl group, a cyano group, a nitro group, _-alkyl ( _C0 - _{C6 ) -NR10R10 '} , -O- _alkyl ( _C1 - _C6 ) _{-NR10R10 '} , -O-Cy1, -alkyl( _C0 - _C6 )-Cy1, -alkenyl(C2-C6) _-Cy1 , -alkynyl( _C2 - _C6 ) _-Cy1 , -O-alkyl(C ₁ -C ₆ )-R ₁₁ , -C(O)-OR ₁₀ , -OC(O)-R ₁₀ , -C(O)-NR ₁₀ R ₁₀ ′, -NR ₁₀ -C(O)-R ₁₀ ′, -NR ₁₀ -C(O)-OR ₁₀ ′, -alkyl(C ₁ -C ₆ )-NR ₁₀ -C(O)-R ₁₀ ′, -SO ₂ -NR ₁₀ R ₁₀ ′, -SO ₂ -alkyl(C ₁ -C ₆ ),

◆R ₈ represents a hydrogen atom, a linear or branched (C ₁ -C ₈ ) alkyl group, a -CHR _a R _b group, an aryl group, a heteroaryl group, an aralkyl group (C ₁ -C ₆ ) or a heteroarylalkyl group (C ₁ -C ₆ ),

◆R ₉ represents a straight-chain or branched (C ₁ -C ₆ ) alkyl group, a straight-chain or branched (C ₂ -C ₆ ) alkenyl group, a straight-chain or branched (C ₂ -C ₆ ) alkynyl group, -Cy ₃ , -alkyl(C ₁ -C ₆ )-Cy ₃ , -alkenyl(C ₂ -C ₆ )-Cy ₃ , -alkynyl(C ₂ -C ₆ )-Cy ₃ , -Cy ₃ -Cy ₄ , -alkynyl(C ₂ -C ₆ )-O-Cy ₃ , -Cy ₃ -alkyl(C ₀ -C ₆ )-O-alkyl(C ₀ -C ₆ )-Cy ₄ , a halogen atom, a cyano group, -C(O)-R ₁₃ or -C(O)-NR ₁₃ R ₁₃ ′,

◆R ₁₀ and R ₁₀ ' independently represent a hydrogen atom, a linear or branched (C ₁ -C ₆ ) alkyl group, or -alkyl (C ₀ -C ₆ )-Cy ₁ ,

or the substituent pair (R ₁₀ , R ₁₀ ′) together with the nitrogen atom carrying them forms an aromatic or non-aromatic ring composed of 5 to 7 ring members, said ring containing, in addition to the nitrogen atom, 1 to 3 heteroatoms chosen from oxygen, sulfur and nitrogen, it being understood that said nitrogen may be substituted by 1 to 2 groups independently representing a hydrogen atom or a linear or branched (C ₁ -C ₆ ) alkyl group, and it being understood that one or more carbon atoms of the possible substituents may be deuterated,

◆R ₁₁ represents -Cy ₅ -alkyl(C ₀ -C ₆ )-O-alkyl(C ₀ -C ₆ )-Cy ₆ , -Cy ₅ -alkyl(C ₀ -C ₆ )-Cy ₆ , -Cy ₅ -alkyl(C ₀ -C ₆ )-NR ₁₂ -alkyl(C ₀ -C ₆ )-Cy ₆ ,

◆R ₁₂ , R ₁₂ ′, R ₁₃ and R ₁₃ ′ independently represent a hydrogen atom or an optionally substituted linear or branched (C ₁ -C ₆ ) alkyl group,

◆R ₁₄ represents a hydrogen atom, a hydroxyl group or a hydroxy(C ₁ -C ₆ )alkyl group,

◆ _Ra represents a hydrogen atom or a linear or branched ( _C1 - _C6 ) alkyl group,

◆R _b represents a -OC(O)-OR _c group, a -OC(O)-NR _c R _c ' or a -OP(O)(OR _c ) ₂ group,

R _c and R _c ' independently represent a hydrogen atom, a linear or branched (C ₁ -C ₈ ) alkyl group, a cycloalkyl group, a (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkyl group, a (C ₁ -C ₆ ) alkoxycarbonyl (C ₁ -C ₆ ) alkyl group, or the substituent pair (R _c , R _c ') together with the nitrogen atom carrying them forms a non-aromatic ring consisting of 5 to 7 ring members, said ring may contain, in addition to the nitrogen atom, 1 to 3 heteroatoms chosen from oxygen and nitrogen, it being understood that said nitrogen may be substituted by a group representing a linear or branched (C ₁ -C ₆ ) alkyl group,

◆Cy ₁ , Cy ₂ , Cy ₃ , Cy ₄ and Cy ₅ independently represent cycloalkyl, heterocycloalkyl, aryl or heteroaryl,

◆Cy ₆ represents

or Cy ₆ represents a heteroaryl group which is substituted by a group selected from -OP(O)(OR ₂₀ ) ₂ ; -OP(O)(O ^- ) ₂ ; -(CH ₂ ) _p -O-(CHR ₁₈ -CHR ₁₉ -O) _q -R ₂₀ ; hydroxy; hydroxy(C ₁ -C ₆ )alkyl; -(CH ₂ ) _r -Y-(CH ₂ ) _s -heterocycloalkyl; or -Y-(CH ₂ ) _q -NR ₂₁ R ₂₁ ′,

◆R ₁₅ represents a hydrogen atom; a -(CH ₂ ) _p -O-(CHR ₁₈ -CHR ₁₉ -O) _q -R ₂₀ group; a straight-chain or branched (C ₁ -C ₆ )alkoxy (C ₁ -C ₆ )alkyl group; a -Y-(CH ₂ ) _q -NR ₂₁ R ₂₁ 'group; or a -(CH ₂ ) _r -Y-(CH ₂ ) _s -heterocycloalkyl group,

◆R ₁₆ represents a hydrogen atom; a hydroxyl group; a hydroxy(C ₁ -C ₆ )alkyl group; a -(CH ₂ ) _r -Y-(CH ₂ ) _s -heterocycloalkyl group; a (CH ₂ ) _r -YXOP(O)(OR ₂₀ ) ₂ group; a -OP(O)(O ^- ) ₂ group; a -(CH ₂ ) _p -O-(CHR ₁₈ -CHR ₁₉ -O) _q -R ₂₀ group; a -(CH ₂ ) _p -OC(O)-NR ₂₂ R ₂₃ group; or a -Y-(CH ₂ ) _q -NR ₂₁ R ₂₁ ' group,

◆R ₁₇ represents a hydrogen atom; a -(CH ₂ ) _p -O-(CHR ₁₈ -CHR ₁₉ -O) _q -R ₂₀ group; a -OP(O)(OR ₂₀ ) ₂ group; a -OP(O)(O ^- ) ₂ group; a hydroxyl group; a hydroxy(C ₁ -C ₆ )alkyl group; a -(CH ₂ ) _r -Y-(CH ₂ ) _s -heterocycloalkyl group; a -Y-(CH ₂ ) _q -NR ₂₁ R ₂₁ 'group; or an aldonic acid,

◆X represents a -(CH ₂ ) _s - group or a -C(O)- group,

◆Y represents a bond or oxygen atom,

◆R ₁₈ represents a hydrogen atom or a (C ₁ -C ₆ )alkoxy (C ₁ -C ₆ )alkyl group,

◆R ₁₉ represents a hydrogen atom or a hydroxy (C ₁ -C ₆ ) alkyl group,

◆R ₂₀ represents a hydrogen atom or a linear or branched (C ₁ -C ₆ ) alkyl group,

◆R ₂₁ and R ₂₁ ' independently represent a hydrogen atom, a linear or branched (C ₁ -C ₆ )alkyl group or a hydroxy (C ₁ -C ₆ )alkyl group,

or the substituent pair (R ₂₁ , R ₂₁ ′) together with the nitrogen atom carrying them forms an aromatic or non-aromatic ring composed of 5 to 7 ring members, said ring containing, in addition to the nitrogen atom, 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, it being understood that the ring formed may be substituted by a group representing a hydrogen atom or a linear or branched (C ₁ -C ₆ ) alkyl group,

◆R ₂₂ represents a (C ₁ -C ₆ )alkoxy (C ₁ -C ₆ )alkyl group, a -(CH ₂ ) _p -NR ₂₄ R ₂₄ ′ or a -(CH ₂ ) _p -O-(CHR ₁₈ -CHR ₁₉ -O) _q -R ₂₀ group,

◆R ₂₃ represents a hydrogen atom or a (C ₁ -C ₆ )alkoxy (C ₁ -C ₆ )alkyl group,

or the substituent pair (R ₂₂ , R ₂₃ ) together with the nitrogen atom carrying them forms an aromatic or non-aromatic ring consisting of 5 to 18 ring members, said ring containing, in addition to the nitrogen atom, 1 to 5 heteroatoms selected from oxygen, sulfur and nitrogen, it being understood that the ring formed may be substituted by a group representing a hydrogen atom, a linear or branched (C ₁ -C ₆ )alkyl group or a heterocycloalkyl group,

◆R ₂₄ and R ₂₄ ' independently represent a hydrogen atom or a linear or branched (C ₁ -C ₆ ) alkyl group,

or the substituent pair (R ₂₄ , R ₂₄ ′) together with the nitrogen atom carrying them forms an aromatic or non-aromatic ring composed of 5 to 7 ring members, said ring containing, in addition to the nitrogen atom, 1 to 3 heteroatoms chosen from oxygen, sulfur and nitrogen, it being understood that the ring formed may be substituted by a group representing a hydrogen atom or a linear or branched (C ₁ -C ₆ )alkyl group,

◆n is an integer equal to 0 or 1,

◆p is an integer equal to 0, 1 or 2,

q is an integer equal to 1, 2, 3 or 4,

r and s are independently integers equal to 0 or 1,

Provided that R ₁₅ , R ₁₆ and R ₁₇ cannot simultaneously represent hydrogen atoms, and when R ₁ represents a methyl group, R ₁₅ cannot represent a methoxyethoxy group,

It should be understood that:

- "aryl" means phenyl, naphthyl, biphenyl, indanyl or indenyl,

- "heteroaryl" means any monocyclic or bicyclic radical consisting of 5 to 10 ring members, having at least one aromatic moiety and containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen,

- "Cycloalkyl" refers to any monocyclic or bicyclic non-aromatic carbocyclic group containing from 3 to 10 ring members,

- "heterocycloalkyl" refers to any monocyclic or bicyclic non-aromatic carbocyclic group containing from 3 to 10 ring members and containing from 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, which may include fused, bridged or spiro ring systems,

The defined aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups, as well as alkyl, alkenyl, alkynyl and alkoxy groups may be replaced by 1 to 5 groups selected from optionally substituted straight-chain or branched (C ₁ -C ₆ )alkyl, optionally substituted straight-chain or branched (C ₂ -C ₆ )alkenyl, optionally substituted straight-chain or branched (C ₂ -C ₆ )alkynyl, optionally substituted straight-chain or branched (C ₁ -C ₆ )alkoxy, optionally substituted (C ₁ -C ₆ )alkyl-S-, hydroxy, oxo (or N-oxide where appropriate), nitro, cyano, -C(O)-OR', -OC(O)-R', -C(O)-NR'R", -NR'R", -(C＝NR')-OR", straight-chain or branched (C ₁ -C ₆ ) polyhaloalkyl, trifluoromethoxy or halogen, it being understood that R' and R" independently represent a hydrogen atom or an optionally substituted linear or branched (C ₁ -C ₆ ) alkyl group, and it being understood that one or more carbon atoms of the aforementioned possible substituents may be deuterated.

Among the pharmaceutically acceptable acids, there may be mentioned, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulfonic acid, camphoric acid, and the like.

Among the pharmaceutically acceptable bases, there may be mentioned, but not limited to, sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine and the like.

Advantageously, at least one radical selected from R ₂ , R ₃ , R ₄ and R ₅ does not represent a hydrogen atom.

In particular, preferred compounds of formula (I) are those wherein n is an integer equal to 1.

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

wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₁₄ and A are as defined for formula (I).

In preferred compounds of the present invention, R ₁ represents a linear or branched (C ₁ -C ₆ ) alkyl group or a halogen atom, more preferably, R ₁ represents a methyl group, an ethyl group, a bromine atom or a chlorine atom.

Atropisomers are stereoisomers resulting from hindered rotation about a single bond, where energy differences due to steric strain or other factors create a sufficiently high barrier to rotation that allows separation of the individual conformers. For the compounds of the present invention, atropisomers are as follows:

The preferred atropisomer is (5S _a ).

Advantageously, R ₁₄ represents a hydrogen atom, a hydroxyl group, a hydroxymethyl group or a hydroxyethyl group. Preferably, R ₁₄ represents a hydrogen atom.

Advantageously, _R2 represents a halogen atom, a hydroxyl group, a linear or branched ( _C1 - _C6 ) alkoxy group. More preferably, _R2 represents a methoxy group, a hydroxyl group, a fluorine atom, a bromine atom, or a chlorine atom. Even more preferably, _R2 represents a chlorine atom.

R ₃ preferably represents a hydrogen atom, a hydroxyl group, a linear or branched (C ₁ -C ₆ )alkoxy group or —O-alkyl(C ₁ -C ₆ )—NR ₁₀ R ₁₀ ′. Advantageously, R ₃ represents —O-alkyl(C ₁ -C ₆ )—NR ₁₀ R ₁₀ ′.

In some preferred embodiments of the present invention,

represent

wherein R ₁ , R ₁₀ and R ₁₀ ′ are as defined for formula (I).

Among the preferred compounds of the present invention,

represent

wherein R ₁₀ and R ₁₀ ′ are as defined for formula (I).

R ₄ and R ₅ preferably represent a hydrogen atom.

In an advantageous embodiment, the substituent pair (R ₁ , R ₅ ) is identical and the substituent pair (R ₂ , R ₄ ) is identical. In preferred compounds of the invention, the substituent pair (R ₁ , R ₅ ) is identical and represents a (C ₁ -C ₆ ) alkyl group, preferably a methyl group, and the substituent pair (R ₂ , R ₄ ) is identical and represents a halogen atom, preferably a chlorine atom or a hydrogen atom.

Among the preferred compounds of the present invention,

represent

wherein R ₁₁ is as defined for formula (I).

R ₇ preferably represents a hydrogen atom.

Preferably, R ₈ represents a hydrogen atom, a —CHR _a R _b group, an optionally substituted linear or branched (C ₁ -C ₈ )alkyl group or a heteroarylalkyl (C ₁ -C ₆ ) group. Preferably, R ₈ represents a -CHR _a R _b group, in which R _a represents a hydrogen atom or a methyl group and R _b represents a -OC(O)-O-(C ₁ -C ₈ )-alkyl group; a -OC(O)-O-cycloalkyl group; a -OC(O)-NR _c R _c ' group, in which R _c and R _c ' independently of one another represent a hydrogen atom, a straight-chain or branched (C ₁ -C ₈ )-alkyl group, a (C ₁ -C ₆ )-alkoxy(C ₁ -C ₆ )-alkyl group, a (C ₁ -C ₆ )-alkoxycarbonyl(C ₁ -C ₆ )-alkyl group, or a substituent pair (R _c , R _c ') which, together with the nitrogen atom carrying them, form a non-aromatic ring consisting of 5 to 7 ring members, which ring, in addition to the nitrogen atom, may also contain 1 to 3 heteroatoms chosen from oxygen and nitrogen; or a -OP(O)(OH) ₂ group. Preferred _R8 groups are as follows: hydrogen; methyl; ethyl; (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl; _-CHRaRb group, wherein _Ra represents a _methyl group and _Rb represents a -OC(O ₎ -O- _CH2CH3 group or a -OC(O)-N( _CH3 ) ₂ group. Further more preferably, _R8 represents hydrogen.

In preferred compounds of the present invention, _R represents a straight or branched (C ₁ -C ₆ ) alkyl, a straight or branched (C ₂ -C ₆ ) alkenyl, a straight or branched (C ₂ -C ₆ ) alkynyl, an aryl or heteroaryl group. Advantageously, _R represents a straight or branched (C ₂ -C ₆ ) alkynyl, an aryl or heteroaryl group. More preferably, _R represents prop-1-yn-1-yl, but-1-yn-1-yl, phenyl or furan-2-yl. In a more preferred embodiment, R represents _4- (benzyloxy)phenyl, 4-(pyridin-4-ylmethoxy)phenyl, 4-phenylbut-1-yn-1-yl, 4-fluorophenyl or 5-fluorofuran-2-yl. Even more preferably, _R represents 4-fluorophenyl.

In preferred compounds of the present invention, R ₁₀ and R ₁₀ 'are independently linear or branched (C ₁ -C ₆ ) alkyl, or the substituent pair (R ₁₀ , R ₁₀ ') together with the nitrogen atom carrying them form a non-aromatic ring consisting of 5 to 7 ring members, said ring containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen in addition to the nitrogen atom, it being understood that the nitrogen may be substituted with a group representing a hydrogen atom or a linear or branched (C ₁ -C ₆ ) alkyl group. More preferably, R ₁₀ and R ₁₀ 'are methyl, or the substituent pair (R ₁₀ , R ₁₀ ') together form 4-methyl-piperazinyl or 4-ethyl-piperazinyl. In a more preferred embodiment, the substituent pair (R ₁₀ , R ₁₀ ') together form 4-methyl-piperazinyl. In another preferred embodiment, R ₁₀ and R ₁₀ 'are methyl.

Advantageously, R ₁₁ represents -Cy ₅ -alkyl(C ₀ -C ₆ )-Cy ₆ . More particularly, R ₁₁ represents -Cy ₅ -Cy ₆ .

Cy ₅ preferably represents heteroaryl, in particular pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl or pyridinyl. More preferably, Cy ₅ represents pyrimidin-4-yl, pyrazol-5-yl, triazol-5-yl, pyrazin-2-yl or pyridin-4-yl. In preferred compounds of the present invention, Cy ₅ represents pyrimidin-4-yl.

In another embodiment of the present invention, Cy ₅ represents heteroaryl, which is substituted by optionally substituted linear or branched (C ₁ -C ₆ )alkyl, optionally substituted linear or branched (C ₁ -C ₆ )alkoxy, -NR'R" group or linear or branched (C ₁ -C ₆ )polyhaloalkyl, it being understood that R' and R" independently of each other represent a hydrogen atom or optionally substituted linear or branched (C ₁ -C ₆ )alkyl.

Preferably, Cy ₆ represents

Cy ₆ preferably represents 3-pyridyl, 4-pyridyl, pyridazin-4-yl, pyrazin-2-yl or pyrimidin-4-yl, it being understood that these heteroaryl groups are substituted by a group selected from -OP(O)(OR ₂₀ ) ₂ ; -OP(O)(O ^- ) ₂ ; -(CH ₂ ) _p -O-(CHR ₁₈ -CHR ₁₉ -O) _q -R ₂₀ ; hydroxy(C ₁ -C ₆ ) alkyl; -(CH ₂ ) _r -Y-(CH ₂ ) _s -heterocycloalkyl; or -Y-(CH ₂ ) _q -NR ₂₁ R ₂₁ '. More preferably, Cy ₆ represents 5-(hydroxymethyl)pyridin-3-yl or 2-(hydroxymethyl)pyrimidin-4-yl.

Advantageously, R ₁₆ and R ₁₇ represent a hydrogen atom and R ₁₅ represents a -(CH ₂ ) _p -O-(CHR ₁₈ -CHR ₁₉ -O) _q -R ₂₀ group; a linear or branched (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl group; a -Y-(CH ₂ ) _q -NR ₂₁ R ₂₁ 'group; or a -(CH ₂ ) _r -Y-(CH ₂ ) _s -heterocycloalkyl group, in which R ₁₈ , R ₁₉ , R ₂₀ , R ₂₁ , R ₂₁ ', Y, p, q, r and s are as defined for formula (I).

In preferred compounds of the present invention, R ₁₅ and R ₁₇ represent a hydrogen atom and R ₁₆ represents a hydroxyl group; a hydroxy(C ₁ -C ₆ )alkyl group; a -(CH ₂ ) _r -Y-(CH ₂ ) _s -heterocycloalkyl group; a -OP(O)(OR ₂₀ ) ₂ group; a -OP(O)(O ^- ) ₂ group; a -(CH ₂ ) _p -O-(CHR ₁₈ -CHR ₁₉ -O) _q -R ₂₀ group; a -(CH ₂ ) _p -OC(O)-NR ₂₂ R ₂₃ group; a (CH ₂ ) _r -YXOP(O)(OR ₂₀ ) ₂ group; or a -Y-(CH ₂ ) _q -NR ₂₁ R ₂₁ ' group, wherein R ₁₈ , R ₁₉ , R ₂₀ , R ₂₁ , R ₂₁ ', R ₂₂ , R ₂₃ , X, Y, p, q, r and s are as defined for formula (I).

In some preferred embodiments of the present invention, R ₁₅ and R ₁₆ represent a hydrogen atom and R ₁₇ represents a -(CH ₂ ) _p -O-(CHR ₁₈ -CHR ₁₉ -O) _q -R ₂₀ group; a -OP(O)(OR ₂₀ ) ₂ group; a -OP(O)(O ^- ) ₂ group; a hydroxyl group; a hydroxy(C ₁ -C ₆ )alkyl group; a -(CH ₂ ) _r -Y-(CH ₂ ) _s -heterocycloalkyl group; a -Y-(CH ₂ ) _q -NR ₂₁ R ₂₁ 'group; or an aldonic acid, wherein R ₁₈ , R ₁₉ , R ₂₀ , R ₂₁ , R ₂₁ ', Y, p, q, r and s are as defined for formula (I).

In a preferred embodiment of the present invention, "heterocycloalkyl" as defined for R ₁₅ , R ₁₆ and R ₁₇ represents any monocyclic or bicyclic non-aromatic carbocyclic group containing 3 to 10 ring members and 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, it being understood that the ring formed may be substituted by 1 to 5 groups selected from linear or branched (C ₁ -C ₆ )alkyl, linear or branched (C ₁ -C ₆ )alkoxy, hydroxy or hydroxy(C ₁ -C ₆ )alkyl.

Advantageously, R ₁₅ represents a -(CH ₂ ) _p -O-CH ₂ -CH(CH ₂ OH)-OH group; a -(CH ₂ ) _p -O-(CH ₂ -CH ₂ -O) _q -H group; a -(CH ₂ ) _p -O-(CH ₂ -CH ₂ -O) _q -CH ₃ group; a methoxymethyl group; a (2,2-dimethyl-1,3-dioxolan-4-yl)methoxy group; a (2,2-dimethyl-1,3-dioxolan-4-yl)methoxymethyl group; or a -Y-(CH ₂ ) _q -N(CH ₂ -CH ₂ -OH) ₂ group, wherein Y, p and q are as defined for formula (I).

In preferred compounds of the present invention, R ₁₆ represents a hydroxyl group; a hydroxymethyl group; a (2,2-dimethyl-1,3-dioxolan-4-yl)methoxy group; a -OP(O)(OH) ₂ group; a -(CH ₂ ) _p -O-CH ₂ -CH(CH ₂ OH)-OH group; a -(CH ₂ ) _p -O-(CH ₂ -CH ₂ -O) _q -H group; a -(CH ₂ ) _p -O-(CH ₂ -CH ₂ -O) _q -CH ₃ group, wherein p and q are as defined with respect to formula (I); a -O-CH(CH ₂ -OCH ₃ ) ₂ group; a -CH ₂ -OC(O)-NR ₂₂ R ₂₃ group, wherein R ₂₂ is as defined with respect to formula (I) and R ₂₃ represents a hydrogen atom, or wherein R ₂₂ and R ₂₃ represent a (C ₁ -C ₆ )alkoxy group (C ₁ -C ₆ )alkyl, or wherein the substituent pair (R ₂₂ , R ₂₃ ) together with the nitrogen atom carrying them forms a non-aromatic ring consisting of 5 to 18 ring members, said ring may contain, in addition to the nitrogen atom, 1 to 5 heteroatoms chosen from oxygen, sulfur and nitrogen, it being understood that the ring formed may be substituted by a group representing a linear or branched (C ₁ -C ₆ )alkyl or heterocycloalkyl group; a -O-(CH ₂ ) ₂ -NR ₂₁ R ₂₁ 'group; a -CH ₂ -NR ₂₁ R ₂₁ ' group, wherein R ₂₁ and R ₂₁ ' are as defined with respect to formula (I); a (CH ₂ ) _r -OXOP(O)(OR ₂₀ ) ₂ group, wherein X and r are as defined with respect to formula (I), and s is an integer equal to 1; or -(CH ₂ ) _r -Y-(CH ₂ ) _s -heterocycloalkyl, wherein Y is a bond, r and s are integers equal to 0, and heterocycloalkyl represents an aldohexose of the formula:

wherein each R ₂₀ is independent. More preferably, heterocycloalkyl represents an aldohexose of the formula:

wherein each R ₂₀ is independent.

In some preferred embodiments of the present invention, R ₁₇ represents a hydroxyl group; a hydroxymethyl group; a hydroxyethyl group; a -O-(CH ₂ -CH ₂ -O) _q -CH ₃ group; a -O-CH ₂ -CH(CH ₂ OH)-OH group; a -(CH ₂ ) _p -O-(CH ₂ -CH ₂ -O) _q -H group; a -OP(O)(OH) ₂ group; a -OP(O)(O ^- ) ₂ group; a -O-CH(CH ₂ -OCH ₃ ) ₂ group; a -O-(CH ₂ ) ₂ -NR ₂₁ R ₂₁ 'group; a -CH ₂ -NR ₂₁ R ₂₁ ' group, wherein R ₂₁ and R ₂₁ ' are as defined for formula (I); (2,2-dimethyl-1,3-dioxolan-4-yl)methoxy group; D-mannonic acid; or -(CH ₂ ) _r -Y-(CH ₂ ) _s -heterocycloalkyl, wherein Y is a bond, s is an integer equal to 0, r is as defined for formula (I), and heterocycloalkyl represents an aldohexose of the formula:

wherein each R ₂₀ is independent. More preferably, heterocycloalkyl represents an aldohexose of the formula:

wherein each R ₂₀ is independent.

Preferred compounds of the invention which may be mentioned are:

-(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(3-hydroxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid;

-(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(4-hydroxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid;

-(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-({2-[3-(hydroxymethyl)phenyl]pyrimidin-4-yl}methoxy)phenyl]propanoic acid;

-(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-({2-[4-(hydroxymethyl)phenyl]pyrimidin-4-yl}methoxy)phenyl]propanoic acid;

-(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid;

-(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{2-[2-(2-methoxyethoxy)ethoxy]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid;

-(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}phenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid;

-(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-({2-[2-(methoxymethyl)phenyl]pyrimidin-4-yl}methoxy)phenyl]propanoic acid;

-(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{2-[(2-methoxyethoxy)methyl]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid;

-(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{2-[(2-hydroxyethoxy)methyl]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid;

-(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-{[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]methyl}phenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid;

-(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{3-[(2-hydroxyethoxy)methyl]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid;

-(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{3-[(1,3-dimethoxyprop-2-yl)oxy]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid;

-(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{4-[(1,3-dimethoxyprop-2-yl)oxy]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid;

-(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-({2-[4-(2,3-dihydroxypropoxy)phenyl]pyrimidin-4-yl}methoxy)phenyl]propanoic acid;

-methyl 6-O-{3-[4-({2-[(2R)-2-carboxy-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}ethyl]phenoxy}methyl)pyrimidin-2-yl]phenyl}-α-D-mannopyranoside;

-methyl 6-O-{3-[4-({2-[(2R)-2-carboxy-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}ethyl]phenoxy}methyl)pyrimidin-2-yl]phenyl}-2,3,4-tri-O-methyl-α-D-mannopyranoside;

-methyl 6-O-{4-[4-({2-[(2R)-2-carboxy-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}ethyl]phenoxy}methyl)pyrimidin-2-yl]phenyl}-α-D-mannopyranoside;

-methyl 6-O-{4-[4-({2-[(2R)-2-carboxy-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}ethyl]phenoxy}methyl)pyrimidin-2-yl]phenyl}-2,3,4-tri-O-methyl-α-D-mannopyranoside;

-6-O-{4-[4-({2-[(2R)-2-carboxy-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}ethyl]phenoxy}methyl)pyrimidin-2-yl]phenyl}-D-mannopyranose;

-6-O-{2-[4-({2-[(2R)-2-carboxy-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}ethyl]phenoxy}methyl)pyrimidin-2-yl]phenyl}-D-mannonic acid;

-1,2-O-[(1R)-1-({4-[4-({2-[(2R)-2-carboxy-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}ethyl]phenoxy}methyl)pyrimidin-2-yl]benzyl}oxy)ethylidene]-β-D-mannopyranose;

-(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{4-[(α-D-mannopyranosyloxy)methyl]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid;

-(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-({2-[4-(2-hydroxyethyl)phenyl]pyrimidin-4-yl}methoxy)phenyl]propanoic acid;

-(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-({2-[2-(2,3-dihydroxypropoxy)phenyl]pyrimidin-4-yl}methoxy)phenyl]propanoic acid;

-(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-({2-[2-(2-hydroxyethoxy)phenyl]pyrimidin-4-yl}methoxy)phenyl]propanoic acid;

-(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{2-[(2,3-dihydroxypropoxy)methyl]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid;

-(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-({2-[3-(phosphonooxy)phenyl]pyrimidin-4-yl}methoxy)phenyl]propanoic acid;

-4-[4-({2-[(2R)-2-carboxy-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}ethyl]phenoxy}methyl)pyrimidin-2-yl]phenyl phosphate;

-(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-({2-[3-(2-hydroxyethoxy)phenyl]pyrimidin-4-yl}methoxy)phenyl]propanoic acid;

-(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{4-[2-(2-methoxyethoxy)ethoxy]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid;

-(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{4-[2-(2-hydroxyethoxy)ethoxy]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid;

-(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(4-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}phenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid;

-(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{4-[2-(dimethylamino)ethoxy]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid;

-(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{3-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid;

-(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-({2-[3-(15-hydroxy-3-oxo-2,7,10,13-tetraoxa-4-azapentadecan-1-yl)phenyl]pyrimidin-4-yl}methoxy)phenyl]propanoic acid;

-(2R)-3-(2-{[2-(3-{[(1,4'-bipiperidin-1'-ylcarbonyl)oxy]methyl}phenyl)pyrimidin-4-yl]methoxy}phenyl)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propanoic acid;

-(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(3-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}phenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid;

-(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{3-[2-(2-hydroxyethoxy)ethoxy]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid;

-(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{3-[2-(2-methoxyethoxy)ethoxy]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid;

-(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{3-[({[2-(4-methylpiperazin-1-yl)ethyl]carbamoyl}oxy)methyl]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid;

-(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{3-[({[2-(morpholin-4-yl)ethyl]carbamoyl}oxy)methyl]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid;

-(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{3-[({[2-(dimethylamino)ethyl]carbamoyl}oxy)methyl]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid;

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

-(2R)-3-[2-({2-[3-({[bis(2-methoxyethyl)carbamoyl]oxy}methyl)phenyl]pyrimidin-4-yl}methoxy)phenyl]-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propanoic acid;

-(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(3-{[(1,4,7,10,13-pentaoxa-16-azacyclooctadec-16-ylcarbonyl)oxy]methyl}phenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid;

-(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-({2-[3-(2,3-dihydroxypropoxy)phenyl]pyrimidin-4-yl}methoxy)phenyl]propanoic acid;

-(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(3-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}phenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid;

-(2R)-3-(2-{[2-(3-{2-[bis(2-hydroxyethyl)amino]ethoxy}phenyl)pyrimidin-4-yl]methoxy}phenyl)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propanoic acid;

-(2R)-2-{[(5S _a )-5-{2,3-dimethyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{3-[({[2-(piperidin-1-yl)ethyl]carbamoyl}oxy)methyl]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid;

-(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{3-[2-(morpholin-4-yl)ethoxy]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid;

-(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{3-[2-(dimethylamino)ethoxy]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid;

-(2R)-3-(2-{[2-(4-{2-[bis(2-hydroxyethyl)amino]ethoxy}phenyl)pyrimidin-4-yl]methoxy}phenyl)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propanoic acid;

-(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(4-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}phenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid;

-(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{4-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid;

-(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{4-[2-(morpholin-4-yl)ethoxy]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid;

- 4-[4-({2-[(2R)-2-carboxy-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}ethyl]phenoxy}methyl)pyrimidin-2-yl]phenyl phosphate disodium salt;

-1-[(ethoxycarbonyl)oxy]ethyl(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{3-[(1,3-dimethoxyprop-2-yl)oxy]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoate;

-(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-({2-[5-(hydroxymethyl)pyridin-3-yl]pyrimidin-4-yl}methoxy)phenyl]propanoic acid;

-(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2′-(hydroxymethyl)-2,5′-bipyrimidin-4-yl]methoxy}phenyl)propanoic acid.

The present invention also relates to a process for preparing a compound of formula (I), characterized in that a compound of formula (II) is used as starting material:

wherein A is as defined for formula (I), wherein 1 is attached to a chlorine atom and 2 is attached to a bromine atom, coupling of a compound of formula (II) with a compound of formula (III):

wherein R ₆ , R ₇ , R ₁₄ and n are as defined for formula (I), and Alk represents a linear or branched (C ₁ -C ₆ )alkyl group,

To generate a compound of formula (IV):

wherein R ₆ , R ₇ , R ₁₄ , A and n are as defined for formula (I) and Alk is as defined above, the compound of formula (IV) is further coupled with a compound of formula (V):

wherein R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are as defined for formula (I), and _RB1 and _RB2 represent a hydrogen atom, a linear or branched (C ₁ -C ₆ )alkyl group, or _RB1 and _RB2 form an optionally methylated ring with the oxygen carrying them,

To generate a compound of formula (VI):

wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₁₄ , A and n are as defined for formula (I) and Alk is as defined above,

The Alk-OC(O)-ester function of the compound of formula (VI) is hydrolyzed to form a carboxylic acid, which can optionally be reacted with an alcohol of formula R ₈ ′-OH or a chloro compound of formula R ₈ ′-Cl, wherein R ₈ ′ represents a linear or branched (C ₁ -C ₈ )alkyl group, _{a -CHRaRb} group, an aryl group, a heteroaryl group, an aralkyl (C ₁ -C ₆ ) group or a heteroarylalkyl (C ₁ -C ₆ ) group, and _Ra and _Rb are as defined for formula (I),

To produce a compound of formula (I), the compound of formula (I) can be purified according to conventional separation techniques, converted into its addition salt with a pharmaceutically acceptable acid or base if necessary, and optionally separated into its isomers according to conventional separation techniques,

It will be appreciated that at any time deemed appropriate during the above methods, some groups (hydroxyl, amino, . . . ) of the starting reagents or synthetic intermediates may be protected as required by the synthesis and subsequently deprotected and functionalized.

Compounds of formula (II), (III), (V), R ₈ ′-OH and R ₈ ′-Cl are commercially available or can be prepared by those skilled in the art using conventional chemical reactions described in the literature.

Pharmacological studies of the compounds of the present invention have demonstrated that they possess pro-apoptotic properties. The ability to reactivate the apoptotic process in cancer cells has significant therapeutic implications in the treatment of cancer, immune and autoimmune diseases.

More specifically, the compounds of the present invention are useful in the treatment of cancers that are resistant to chemotherapy or radiotherapy.

Among the cancer treatments of interest, mention may be made, without limitation, of the treatment of bladder cancer, brain cancer, breast cancer and uterine cancer, chronic lymphocytic leukemia, colon cancer, esophageal cancer and liver cancer, lymphoblastic leukemia, acute myeloid leukemia, lymphoma, melanoma, hematological malignancies, myeloma, ovarian cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer and small cell lung cancer.

The present invention also relates to pharmaceutical compositions 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, mention may be made more particularly of those which are suitable for oral, parenteral, nasal, percutaneous or transdermal, rectal, perlingual, ophthalmic or respiratory administration, in particular tablets or dragees, sublingual tablets, sachets, paquets, capsules, glossettes, lozenges, suppositories, creams, ointments, skin gels and drinkable or injectable ampoules.

The dosage may vary depending on the patient's sex, age and weight, route of administration, therapeutic indication or the nature of any related treatment, and ranges from 0.01 mg to 1 g per 24 hours, administered in one or more divided doses.

In addition, the present invention also relates to a combination of a compound of formula (I) and an anticancer drug selected from genotoxic agents, mitotic inhibitors, antimetabolites, proteasome inhibitors, kinase inhibitors and antibodies, and also relates to a pharmaceutical composition comprising such a combination and its use in the preparation of a medicament for treating cancer.

Advantageously, the present invention relates to combinations of compounds of formula (I) with EGFR inhibitors and pharmaceutical compositions comprising such combinations.

In another embodiment, the present invention relates to combinations of compounds of formula (I) with mTOR/PI3K inhibitors and pharmaceutical compositions comprising such combinations.

In a preferred embodiment, the present invention relates to combinations of compounds of formula (I) with MEK inhibitors and pharmaceutical compositions comprising such combinations.

Preferably, the present invention relates to combinations of compounds of formula (I) and HER2 inhibitors and pharmaceutical compositions comprising such combinations.

Advantageously, the present invention relates to combinations of compounds of formula (I) with RAF inhibitors and pharmaceutical compositions comprising such combinations.

In another embodiment, the present invention relates to combinations of compounds of formula (I) and EGFR/HER2 inhibitors and pharmaceutical compositions comprising such combinations.

In a preferred embodiment, the present invention relates to combinations of compounds of formula (I) and taxanes and pharmaceutical compositions comprising such combinations.

In another embodiment, the present invention relates to combinations of compounds of formula (I) with proteasome inhibitors, immunomodulators or alkylating agents and pharmaceutical compositions comprising such combinations.

The combination of a compound of formula (I) and an anticancer agent can be administered simultaneously or sequentially. The route of administration is preferably oral, and the corresponding pharmaceutical composition can release the active ingredient instantly or with a delayed release. The compound in the combination can be administered as two separate pharmaceutical compositions each containing one active ingredient, or as a single pharmaceutical composition in which the active ingredients are present as a mixture.

The compounds of the present invention may also be used in combination with radiotherapy to treat cancer.

Finally, the compounds of the invention may be linked to a monoclonal antibody or fragment thereof or to a scaffold protein which may or may not involve a monoclonal antibody.

Antibody fragments are understood to include Fv, scFv, Fab, F(ab')2, F(ab'), scFv-Fc type fragments or diabodies generally having the same binding specificity as the antibody from which they are derived. According to the present invention, the antibody fragments of the present invention can be obtained from antibodies by, for example, digestion with enzymes such as pepsin or papain; and/or cleavage of disulfide bonds by chemical reduction. Alternatively, the antibody fragments encompassed by the present invention can be obtained by genetic recombination techniques known to those skilled in the art, or by peptide synthesis using, for example, an automated peptide synthesizer (such as those provided by Applied Biosystems, etc.).

The backbone protein that may or may not be related to a monoclonal antibody should be understood to refer to a protein that contains or does not contain an immunoglobulin fold and produces a binding ability similar to that of a monoclonal antibody. Those skilled in the art know how to select a protein backbone. More specifically, it is known that the selected backbone should exhibit the following characteristics (Skerra A., J. Mol. Recogn., 2000, 13, 167-187): good conservation of the phylogenetic tree, a robust structural system with a fully known three-dimensional molecular composition (e.g., crystallography or NMR), a small size, no or only a low degree of post-translational modification, ease of production, expression and purification. Such protein backbones may be, but are not limited to, structures selected from the group consisting of fibronectin and preferably the tenth fibronectin type III domain (FNfn10), lipocalins, anticalins (Skerra A., J. Biotechnol., 2001, 74(4): 257-75), protein Z derivatives of domain B from staphylococcal protein A, thioredoxin A, or any protein with repeat domains such as "ankyrin repeats" (Kohl et al., PNAS, 2003, 100(4), 1700-1705), "armadillo repeats," "leucine-rich repeats," or "tetratricopeptide repeats." Backbone derivatives from toxins (e.g., scorpion, insect, plant or mollusk toxins) or protein inhibitors of neuronal nitric oxide synthase (PINs) may also be mentioned.

The following preparations and examples illustrate the present invention but are not intended to limit the invention in any way.

General Methods

All reagents were obtained from commercial sources and used without further purification. Anhydrous solvents were obtained from commercial sources and used without further drying.

Flash chromatography was performed using an ISCO CombiFlash Rf 200i equipped with pre-packed silica gel short columns ( _Rf Gold High Performance).

Thin layer chromatography was performed using 5 x 10 cm plates coated with Merck type 60F254 silica gel.

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

Preparative HPLC purification was performed on an Armen Spot liquid chromatography system using a 10 μM C18, 250 mm × 50 mm id column at a flow rate of 118 mL/min, UV diode array detection (210–400 nm), and 25 mM aqueous NH ₄ HCO ₃ solution and MeCN as eluents unless otherwise specified.

Analytical LC-MS: Compounds of the invention were characterized by high-performance liquid chromatography-mass spectrometry (HPLC-MS) on an Agilent HP1200 with an Agilent 6140 quadrupole LC/MS, operated in positive or negative electrospray ionization mode. The molecular weight scan range was 100 to 1350. Parallel UV detection was performed at 210 nm and 254 nm. Samples were supplied as 1 mM solutions in either ACN or THF/ _H₂O (1:1) and injected in 5 μL loops. LCMS analysis was performed on two instruments, one using a basic eluent and the other using an acidic eluent.

Basic LCMS: Gemini-NX, 3μm, C18, 50mm×3.00mm i.d. column, column temperature 23°C, flow rate 1mL/min, using 5mM ammonium bicarbonate (solvent A) and acetonitrile (solvent B), gradient: starting from 100% solvent A and ending with 100% solvent B at different/constant time.

Acidic LCMS: ZORBAX Eclipse XDB-C18, 1.8 μm, 50 mm × 4.6 mm i.d. column, column temperature 40 ° C, flow rate 1 mL / min, using 0.02% v / v formic acid in water (solvent A) and 0.02% v / v formic acid in acetonitrile (solvent B), gradient: starting from 100% solvent A at different / fixed time to 100% solvent B.

^1H -NMR measurements were performed on a Bruker Avance III 500 MHz spectrometer and a Bruker Avance III 400 MHz spectrometer, using DMSO- _d6 or _CDCl3 as the solvent. ^1H NMR data are presented as δ values in ppm, using the residual solvent peak (2.50 ppm for DMSO- _d6 and 7.26 ppm for _CDCl3 ) as the internal standard. Splitting patterns were designated as: s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet), br s (broad singlet), dd (double of doublet), td (triplet of doublets), dt (double of triplets), and ddd (double of doublets).

Combined gas chromatography and low-resolution mass spectrometry were performed on an Agilent 6850 gas chromatograph and an Agilent 5975C mass spectrometer, using a 15 m × 0.25 mm column with 0.25 μm HP-5MS coating and helium as the carrier gas. Ion source: EI ⁺ , 70 eV, 230°C, quadrupole: 150°C, interface: 300°C.

HRMS was performed on a Shimadzu IT-TOF with an ion source temperature of 200°C, ESI+/-, and an ionization voltage of (+-)4.5 kV. The minimum mass resolution was 10,000.

Elemental analysis was performed on a Thermo Flash EA 1112 elemental analyzer.

List of abbreviations

Abbreviation Name

Ac acetyl

AIBN 2-[(1-cyano-1-methyl-ethyl)azo]-2-methyl-propionitrile

AtaPhos Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride

DCM dichloromethane

DIPA diisopropylamine

DMF dimethylformamide

DSC N,N’-disuccinimidyl carbonate

eq. equivalent

Et ethyl

HMDS Hexamethyldisilazane

ⁱ Pr Isopropyl

Me methyl

MeCN Acetonitrile

NBS N-bromosuccinimide

ⁿ Bu n-butyl

Ph Phenyl

PPh ₃ triphenylphosphine

r.t. room temperature

^t Bu tert-butyl

^t BuXPhos 2-Di(tert-butylphosphino)-2',4',6'-triisopropylbiphenyl

TEA triethylamine

THF Tetrahydrofuran

General Procedure I

Step A

Place 1 equivalent of Preparation Example 1, 2 equivalents of the appropriate boronic acid derivative, 2 equivalents of cesium carbonate, and 0.1 equivalent of bis(PPh ₃ )palladium(II) chloride in a flask. 1,4-Dioxane and water (4:1, 10 mL/mmol) are added, and the resulting mixture is stirred at 60°C under an argon atmosphere until no further conversion is observed. The reaction mixture is diluted with brine and the pH is adjusted to 6 with 2M aqueous HCl, followed by extraction with DCM. The volatiles from the separated organic phase are evaporated under reduced pressure, and the crude product is purified by flash chromatography using DCM and methanol as eluents.

Step B

The resulting intermediate was dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 equivalents of LiOH x _H₂O were added. The mixture was stirred at room temperature until no further conversion was observed. It was then diluted with brine, neutralized with 2M aqueous HCl, and extracted with DCM. The combined organic phases were dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative reverse-phase chromatography using 5 mM _{aqueous NH₄HCO₃} and MeCN as eluents. The later eluting diastereomers were collected.

General Procedure II

Step A

One equivalent of Preparation 2 or 1 equivalent of Preparation 3, two equivalents of the appropriate alcohol (unless otherwise specified), and two equivalents of PPh ₃ were dissolved in dry toluene (phenol concentration was 20.2 M). Two equivalents of di-tert-butyl azodicarboxylate were added and the mixture was stirred at 60° C. under a nitrogen atmosphere until no further conversion was observed. The volatile materials were evaporated under reduced pressure and the crude intermediate was purified by flash chromatography using ethyl acetate and methanol as eluents.

Step B

The resulting intermediate was dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 equivalents of LiOH x _H₂O were added. The mixture was stirred at room temperature until no further conversion was observed. It was then diluted with brine, neutralized with 2M aqueous HCl, and extracted with DCM. The combined organic phases were dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative reverse-phase chromatography using 5 mM _{aqueous NH₄HCO₃} and MeCN as eluents. The later eluting diastereomers were collected.

General Procedure III

Step A

To a solution of 1 equivalent of Preparation 5 in dry acetonitrile (15 mL/mmol) was added 1.5 equivalents of DSC and 3 equivalents of TEA, and the mixture was stirred at room temperature for 1 hour. To the resulting mixture was added 2 equivalents of the appropriate amine, and stirring was continued at room temperature for 1 hour. The reaction mixture was injected directly onto a flash silica gel column (160 g/mmol, pre-treated with EtOAc) and chromatographed using EtOAc and MeOH (containing 1.2% NH ₃ ) as eluents.

Step B

The product from step A was dissolved in dioxane-water (1:1, 10 mL/mmol) and 10 equivalents of LiOH x _H₂O were added. The mixture was stirred at room temperature until no further conversion was observed. It was then neutralized with 2M HCl and injected directly onto an RP18 column and chromatographed using 5 mM _{aqueous NH₄HCO₃} and MeCN as eluents. The later eluting diastereomer was collected.

General Procedure IV

Step A

1 equivalent of the appropriate phenol derivative, 2 equivalents of the appropriate alcohol derivative and 2 equivalents of PPh ₃ were dissolved in dry toluene (phenol concentration was 0.2 M) under a nitrogen atmosphere, and then 2 equivalents of di-tert-butyl azodicarboxylate were added and the mixture was stirred at 60° C. until no further conversion was observed. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography using heptane and EtOAc as eluents.

Step B

Dissolve 1 equivalent of the phenol derivative obtained in Step A in dry THF. Cool the solution to -78°C under argon, then add 1.2 equivalents of ^n- BuLi (1.6 M in hexane) dropwise. After 15 minutes, add 1.5 equivalents of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane dropwise. Remove the cooling bath and slowly warm the mixture to room temperature. The mixture is then quenched with _NH4Cl solution and extracted with EtOAc. The combined organic layers are concentrated under reduced pressure, and the crude product is purified by flash chromatography using heptane and EtOAc as eluents.

General Procedure V

One equivalent of Preparation Example 1, three equivalents of the appropriate boronic acid derivative, 4.5 equivalents of cesium carbonate, and 0.15 equivalents of bis( _PPh3 )palladium(II) chloride were stirred in dioxane (30 mL/mmol) and water (15 mL/mmol) under a nitrogen atmosphere at 60°C until no further conversion was observed. The reaction mixture was cooled to room temperature, 20 equivalents of LiOH x _H2O (832 mg/mmol) were then added, and the mixture was stirred until no further conversion was observed. The reaction mixture was diluted with brine, the pH was adjusted to 6 with 1M HCl, the mixture was filtered, and the precipitate was washed with dioxane. The volatiles of the filtrate were evaporated under reduced pressure, and the residue was purified by preparative reverse phase chromatography using 25 mM _{aqueous NH4HCO3} and MeCN as eluents.

Preparation Example 1 : Ethyl (2R)-2-[5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy-3-[2-[(2-chloropyrimidin-4-yl)methoxy]phenyl]propanoate

Step A : 6-iodo-3H-thieno[2,3-d]pyrimidin-4-one

To a 2-L round-bottom flask equipped with a mechanical stirrer, thermometer, and reflux condenser was added a solution of 433 mL of acetic acid, 13 mL of sulfuric acid, and 87 mL of water. To the stirred solution were added 69.3 g of 3H-thieno[2,3-d]pyrimidin-4-one (0.46 mol), 51.9 g of periodic acid (0.23 mol), and 104 g of iodine (0.41 mol), and the mixture was heated to 60°C and stirred for 1 hour. The resulting suspension was cooled to room temperature, filtered, and washed with a mixture of acetic acid and water (5:1), followed by diethyl ether. The resulting beige crystalline solid was air-dried to yield 6-iodo-3H-thieno[2,3-d]pyrimidin-4-one.

¹ H NMR(500MHz, DMSO-d ₆ )δ12.57(br s,1H),8.09(s,1H),7.65(s,1H) ¹³ C NMR(125MHz,DMSO-d ₆ )δ168.3,155.9,146.1,130.8,126.7,76.4

Step B : 4-chloro-6-iodo-thieno[2,3-d]pyrimidine

To a 1 L round-bottom flask equipped with a mechanical stirrer, thermometer, reflux condenser, and _CaCl₂ tube, add 113 mL of phosphorus oxychloride and 35 mL of N,N-dimethylaniline (0.29 mol). Add 75.54 g of 6-iodo-3H-thieno[2,3-d]pyrimidin-4-one (from Step A) (0.27 mol) portionwise to the mixture over 5 minutes. Stir the reaction mixture at 105°C for 1 hour. Cool the resulting suspension to 10°C, filter, and wash with hexane. Add the crude product to ice water and stir for 10 minutes, filter, wash with cold water, diethyl ether, and air-dry to afford 4-chloro-6-iodo-thieno[2,3-d]pyrimidine as a beige crystalline solid.

¹ H NMR (500MHz, DMSO-d ₆ ) δ8.89 (s, 1H), 7.98 (s, 1H)

¹³ C NMR (125MHz, DMSO-d ₆ ) δ172.3,152.9,151.9,131.1,128.9,86.5

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

To a 2-L round-bottom flask equipped with a mechanical stirrer, thermometer, and bubbler was added 600 mL of MeCN. 84.9 g of 4-chloro-6-iodo-thieno[2,3-d]pyrimidine (from Step B) (0.29 mol), 50.9 g of NBS (0.29 mol), and 8.5 mL of tetrafluoroborate etherate were added. The reaction mixture was stirred at room temperature for 16 hours. An additional 22.9 g (0.12 mol) of NBS was added to the mixture in three portions. After the suspension was cooled to 0°C and stirred for an additional hour, the precipitate was filtered, washed with acetonitrile, and air-dried to yield 5-bromo-4-chloro-6-iodo-thieno[2,3-d]pyrimidine as a beige crystalline solid.

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.88 (s, 1H)

¹³ C NMR (100MHz, DMSO-d ₆ ) δ171.3,152.9,152.3,126.0,112.4,92.9

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

75.08 g of 5-bromo-4-chloro-6-iodo-thieno[2,3-d]pyrimidine (from Step C) (200 mmol), 53.63 g of 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (240 mmol), 130 g of cesium carbonate (400 mmol), 2.245 g of Pd(OAc) ₂ (10 mmol), and 8.50 g ^{of tBuXPhos} (20 mmol) were placed in a 2 L flask. 600 mL of THF and 200 mL of water were added, followed by stirring at 70°C under an argon atmosphere overnight. The THF was evaporated, and the product was collected by filtration. The crude product was sonicated in 250 mL of MeCN and filtered again. 5-Bromo-4-chloro-6-(4-fluorophenyl)thieno[2,3-d]pyrimidine was then crystallized from EtOH/THF (2:1). ¹ H NMR (400MHz, DMSO-d ₆ ):9.02(s,1H),7.80-7.77(m,2H),7.47-7.43(m,2H)

Step E : 2-(Bromomethyl)phenyl]acetate

60.07 g of 2-methylphenyl acetate (400 mmol) and 106.8 g of NBS (600 mmol) were placed in a 1 L flask. 500 mL of cyclohexane was added, followed by 3.284 g of AIBN (20 mmol) over 30 minutes with vigorous stirring. The mixture was stirred at 80°C until no further conversion was observed, then cooled to room temperature. The precipitate was filtered and washed with cyclohexane. The mother liquor was concentrated under reduced pressure, and the crude product was used directly in Step B without further purification.

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

23.10 g of anhydrous LiCl (545 mmol) and 65.36 g of anhydrous ZnCl ₂ (479.6 mmol) were placed in a 2 L flask and dried at 160° C. under 0.1 mmHg for 1 hour. After cooling to room temperature under an argon atmosphere, 26.49 g of magnesium turnings (1090 mmol) and 1 L of pre-cooled (0° C.) dry THF were added. The resulting mixture was immersed in an ice bath and then stirred for 30 minutes.

100 g of 2-(bromomethyl)phenyl acetate (from Step E) (~436 mmol) was dissolved in 120 mL of dry THF and added to the pre-cooled inorganics over 15 minutes. After the addition of the reagents was complete, the resulting mixture was stirred for 45 minutes while maintaining the temperature between 0-5°C. To the mixture was added 64.82 mL of ethyl 2-oxoacetate (654 mmol, 50% in toluene) over 5 minutes and the resulting mixture was stirred for an additional 15 minutes.

The remaining inorganics were removed by filtration from the mixture, and 500 mL of MeOH was added to the filtrate. The mixture was stirred until the intramolecular migration of the acetyl group from the phenol oxygen to the alkyl oxygen was complete. 30 mL of acetic acid was added to the mixture, and the volatile substances were evaporated under reduced pressure. 350 mL of water was added to the residue and extracted with EtOAc. The combined organic layers were washed with saturated NaHCO ₃ and brine, then dried over magnesium sulfate, filtered and evaporated under reduced pressure. 100 mL of hexane was added to the residue and stirred at 0° C. for 30 minutes. The white crystals formed were collected by filtration and washed with hexane to obtain 2-acetoxy-3-(2-hydroxyphenyl)-ethyl propionate (rac). ¹ H NMR (500MHz, DMSO-d ₆ )δ9.53(s,1H),7.06(t,1H),7.04(d,1H),6.79(d,1H),6.71(t,1H),5.10( dd,1H),4.05(q,2H),3.06(dd,1H),2.94(dd,1H),2.00(s,3H),1.09(t,3H)

Step G : Ethyl (2R)-2-acetoxy-3-(2-hydroxyphenyl)propionate and Ethyl (2S)-2-acetoxy-3-(2-hydroxyphenyl)propionate

The enantiomers of ethyl 2-acetoxy-3-(2-hydroxyphenyl)propanoate (from Step F) were separated by chiral chromatography. Column: OD; Eluent: heptane/EtOH; The first-eluting enantiomer collected was 99.8% ee of ethyl (2S)-2-acetoxy-3-(2-hydroxyphenyl)propanoate, and the later-eluting enantiomer collected was 99.9% ee of ethyl (2R)-2-acetoxy-3-(2-hydroxyphenyl)propanoate.

Step H : (4-Bromo-2-chloro-phenoxy)-trimethyl-silane

20.8 g of 4-bromo-2-chloro-phenol (100 mmol) was dissolved in 150 mL of dry THF, and then 24.2 g of HMDS (150 mmol) was added. The reaction mixture was stirred at 85°C under an argon atmosphere for 1.5 hours and then concentrated under reduced pressure. The product was used directly without further purification. ¹ H NMR (200 MHz, CDCl ₃ ): 7.49 (d, 1H), 7.23 (dd, 1H), 6.75 (d, 1H), 0.26 (s, 9H)

Step 1 : 4-Bromo-2-chloro-3-methyl-phenol

48 mL of a 2.5 M solution of ^n- BuLi in hexane (120 mmol) was added dropwise to a solution of 12.1 g of dry DIPA (120 mmol) in 250 mL of dry THF at -78°C under an argon atmosphere. The mixture was stirred at the same temperature for 30 minutes, followed by the dropwise addition of 28.0 g of (4-bromo-2-chloro-phenoxy)-trimethyl-silane (from Step H) (100 mmol). After 2.5 hours, 21.3 g of MeI (150 mmol) was added dropwise, the cooling bath was removed, and the mixture was stirred overnight. The reaction was quenched with 100 mL of _NH₄OH solution and 200 mL of _NH₄Cl solution, and the mixture was extracted with EtOAc, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting dark material was refluxed several times with hexane (150-150 mL aliquots) and decanted, leaving a black tar. The combined organic phases were concentrated under reduced pressure to give 19.0 g of 4-bromo-2-chloro-3-methyl-phenol, which was used as a crude product without further purification.

¹ H NMR (200MHz, CDCl ₃ ):7.32(d,1H),6.76(d,1H),5.62(s,1H),2.49(s,3H)

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

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

Step K : 2-chloro-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol

A solution of 25.2 g (4-bromo-2-chloro-3-methyl-phenoxy)-trimethyl-silane (from Step J) (86.0 mmol) in 250 mL of dry THF was cooled to -78°C under an argon atmosphere, followed by the dropwise addition of 38 mL of a 2.5 M solution of ^n- BuLi in hexane (94.6 mmol). After 5 minutes, 19.2 g of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (103 mmol) was added dropwise. The cooling bath was removed and the mixture was slowly warmed to room temperature. The mixture was then added to 200 mL of _NH₄Cl solution and extracted with EtOAc. The combined organic layers were concentrated under reduced pressure and filtered 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 give 2-chloro-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol. ¹ H NMR (500 MHz, DMSO-d ₆ ): 10.40 (s, 1H), 7.42 (d, 1H), 6.80 (d, 1H), 2.49 (s, 3H), 1.27 (s, 12H)

Step L : 1-[2-[2-chloro-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl]-4-methyl-piperazine

10.0 g of 2-chloro-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (from Step K) (37.2 mmol), 8.7 g of 2-(4-methylpiperazin-1-yl)ethanol (60.3 mmol), and 15.8 g _of PPh₃ (60.3 mmol) were dissolved in 100 mL of dry toluene, followed by the dropwise addition of 27 mL of diethyl azodicarboxylate (60.3 mmol, 40% solution in toluene). The mixture was stirred at 50°C under an argon atmosphere for 1.5 hours. The volatiles were evaporated under reduced pressure, and 100 mL of _Et₂O was added. The precipitated white crystals were filtered and washed with _Et₂O . The filtrate was concentrated under reduced pressure and purified by flash chromatography using _CHCl₃ and MeOH as eluents. The resulting light brown oil was crystallized from hexane to give 1-[2-[2-chloro-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl]-4-methyl-piperazine as an off-white solid. ¹ H NMR (500 MHz, DMSO-d ₆ ): 7.56 (d, 1H), 6.99 (d, 1H), 4.15 (t, 2H), 2.72 (t, 2H), 2.51 (s, 3H), 2.50 (br s, 4H), 2.29 (br s, 4H), 2.13 (s, 3H), 1.29 (s, 12H)

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

9.06 g of ethyl (2R)-2-acetoxy-3-(2-hydroxyphenyl)propanoate (from Step G, 36 mmol), 7.12 g of 2-chloro-4-(chloromethyl)pyrimidine (44 mmol), 5.97 g _{of K2CO3} (44 mmol), and 1.22 g of KI (1.22 mmol) were placed in a 250 mL flask. 70 mL of DMF was added and the mixture was stirred at room temperature under a nitrogen atmosphere until no further conversion was observed. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using heptane and EtOAc as eluents to give ethyl (2R)-2-acetoxy-3-[2-[(2-chloropyrimidin-4-yl)methoxy]phenyl]propanoate. ¹ H NMR (500MHz, DMSO-d ₆ )δ8.86(d,1H),7.69(d,1H),7.25(td,1H),7.23(dd,1H),7.03(d,1H),6.95(td,1H),5.30(d,1H),5 .25(d,1H),5.16-5.13(m,1H),4.07(qm,2H),3.28(dd,1H),3.09(dd,1H),2.00(s,3H),1.09(t,3H)

Step N : (2R)-3-[2-[(2-chloropyrimidin-4-yl)methoxy]phenyl]-2-hydroxy-propionic acid ethyl ester

8.568 g of (2R)-2-acetoxy-3-[2-[(2-chloropyrimidin-4-yl)methoxy]phenyl]propionic acid ethyl ester (derived from step M) (23 mmol) was dissolved in 100 mL of ethanol, and then 1.8 mL of sodium ethoxide solution (1.0 M in ethanol) was added and stirred until no further conversion was observed. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using heptane and EtOAc as eluents to give (2R)-3-[2-[(2-chloropyrimidin-4-yl)methoxy]phenyl]-2-hydroxy-propionic acid ethyl ester.

¹ H NMR (500MHz, DMSO-d ₆ )δ8.84(d,1H),7.70(d,1H),7.20(m,1H),7.19(dm,1H),7.00(dm,1H),6.91(m,1H),5.52(d,1H ),5.27(d,1H),5.24(d,1H),4.06(m,1H),4.04(m,1H),3.13(dd,1H),2.84(dd,1H),1.11(t,3H)

Step O : Preparation Example 1

17.18 g of 5-bromo-4-chloro-6-(4-fluorophenyl)thieno[2,3-d]pyrimidine (from step D, 50 mmol) and 18.52 g of (2R)-3-[2-[(2-chloropyrimidin-4-yl)methoxy]phenyl]-2-hydroxy-propionic acid ethyl ester (from step N, 55 mmol) were dissolved in 250 mL of dry THF, then 48.87 g _{of Cs2CO3} (150 mmol) were added and the mixture was stirred at 70°C under nitrogen atmosphere until no further conversion was observed. The reaction mixture was cooled to room temperature, and then 2.17 g of 1-[2-[2-chloro-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl]-4-methyl-piperazine (from step L, 55 mmol), 560 mg of AtaPhos (2.5 mmol) and 250 mL of H ₂ O were added and the mixture was stirred at 70° C. under a nitrogen atmosphere until no further conversion was observed. It was then diluted with EtOAc and brine. After separation of the phases, the aqueous phase was extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was separated by flash chromatography using EtOAc and MeOH (containing 1.2% NH ₃ ) as eluents. Preparation Example 1 was obtained in atropisomer form.

¹ H NMR (500MHz, DMSO-d ₆ )δ8.87(dd,1H),8.60(s,1H),7.69(dd,1H),7.35-7.26(m,2H),7.22(t,2H),7.20-7.10(m,2H),7.02-6.91(m,1H),6. 87(d,1H),6.72(t,1H),6.15(d,1H),5.47(dd,1H),5.22(s,2H),4.29-4.11(m,2H),4.10-4.00(m,2H),3.15-2.15(br s,8H),3.13(dd,2H),2.73-2.65(m,2H),2.09(s,3H),1.86(s,3H),1.06(t,3H)

(M+2H) ²⁺ =416.1197

Preparation Example 2 : Ethyl (2R)-2-[5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy-3-[2-[[2-(3-hydroxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoate

Preparation 2 was obtained as a mixture of diastereoisomers using General Procedure I, Step A and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol as the appropriate boronic acid derivative.

1H NMR(500MHz,DMSO-d6)δ9.65(br s,1H),8.95(d,1H),8.58(s,1H),7.88-7.80(m,2H),7.57(d,1H),7.3 3(d,1H),7.32-7.27(m,2H),7.3(t,1H),7.24-7.14(m,4H),7.05(d,1H ),6.94-6.90(dm,1H),6.78-6.73(tm,1H),6.30(dd,1H),5.51(dd,1H),5.30(d,1H),5.24(d,1H),4.26-4.00(m,4H),3.17(dd,1H),2.76(br s,2H),2.58(dd,1H),2.42(br s,3H),3.00-2.30(br s,8H),1.86(s,3H),1.06(t,3H)

(M+2H) ²⁺ ＝445.1524

Preparation Example 3 : Ethyl (2R)-2-[5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy-3-[2-[[2-(4-hydroxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoate

Using General Procedure I, Step A and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol as the appropriate boronic acid derivative, Preparation 3 was obtained as a mixture of diastereoisomers.

¹ H NMR (500MHz, DMSO-d ₆ )δ10.01(s,1H),8.86(d,1H),8.58(s,1H),8.24(d,2H),7.46(d,1H),7.33(d,1H),7.32-7.27(m,2H),7.21(t,2H),7. 21-7.15(m,2H),7.04(d,1H),6.87(d,2H),6.74(t,1H),6.29(d,1H),5.52(dd,1H),5.26(d,1H),5.20(d,1H),4.19(br s,2H),4.10-4.00(m,2H),3.16(dd,1H),3.03-2.41(m,13H),2.56(dd,1H),1.86(s,3H),1.05(t,3H)

(M+2H) ²⁺ =445.1517

Preparation Example 4a : 2-[2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Using General Procedure IV with 2-iodophenol as the appropriate phenol and (2,2-dimethyl-1,3-dioxolan-4-yl)methanol as the appropriate alcohol, Preparation 4a was obtained.

¹ H NMR (500MHz, DMSO-d ₆ )δ7.50(dd,1H),7.41(tm,1H),6.98(d,1H),6.93(td,1H),4.37-4.31(m,1H),4.08 -4.02(m,2H),4.03(dd,1H),3.96(dd,1H),1.36(s,3H),1.30(s,3H),1.27(s,12H)

Preparation Example 4b : 2-[2-[2-(2-methoxyethoxy)ethoxy]phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Using General Procedure IV with 2-iodophenol as the appropriate phenol and 2-(2-methoxyethoxy)ethanol as the appropriate alcohol, Preparation 4b was obtained.

¹ H NMR (500MHz, DMSO-d ₆ )δ7.48(dm,1H),7.42-7.37(m,1H),6.94(dm,1H),6.92-6.90(m,1H),4.05-4.01(m,2H ),3.76-3.72(m,2H),3.70-3.67(m,2H),3.46-3.43(m,2H),3.24(s,3H),1.26(s,12H)

Preparation Example 4c : 2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Using General Procedure IV with 2-iodophenol as the appropriate phenol and 2-[2-(2-methoxyethoxy)ethoxy]ethanol as the appropriate alcohol, Preparation 4c was obtained. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.48 (dm, 1H), 7.49-7.46 (m, 1H), 6.94 (dm, 1H), 6.93-6.89 (m, 1H), 4.04-4.01 (m, 2H), 3.75-3.72 (m, 2H), 3.71-3.39 (m, 8H), 3.22 (s, 3H), 1.26 (s, 12H)

Preparation 4d : 2-[2-(2-methoxyethoxymethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Step A : 1-bromo-2-(2-methoxyethoxymethyl)benzene

To 20 mL of 2-methoxyethanol (672 mmol, 20 eq) was added 4.03 g of sodium hydride (100.8 mmol, 60% dispersion in oil, 3 eq) in small portions at 0°C. After stirring for 30 minutes, 8.40 g of 1-bromo-2-(bromomethyl)benzene (33.6 mmol, 1 eq) was added. The reaction mixture was then removed from the cooling bath and stirred at room temperature until no further conversion was observed. The reaction mixture was diluted with EtOAc and brine. After extraction, the organic phase was washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using heptane and EtOAc as eluents to yield 1-bromo-2-(2-methoxyethoxymethyl)benzene. ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.60(d,1H),7.49(d,1H),7.39(t,1H),7.24(t,1H),4.52(s,2H),3.63(dd,2H),3.51(dd,2H),3.27(s,3H)

Step B : Preparation Example 4d

The product from Step A was converted to the appropriate boronate ester using General Procedure IV, Step B to provide Preparation 4d. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.80 (d, 1H), 7.50 (d, 1H), 7.43 (t, 1H), 7.28 (t, 1H), 4.85 (s, 2H), 3.66 (dd, 2H), 3.59 (dd, 2H), 3.41 (s, 3H), 1.36 (s, 12H)

Preparation Example 4e : 4,4,5,5-Tetramethyl-2-[2-(2-tetrahydropyran-2-yloxyethoxymethyl)phenyl]-1,3,2-dioxaborolane

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

To a solution of 2.34 g (2-iodophenyl)methanol (10 mmol, 1 eq) in 25 mL of dry DMF was added 440 mg of sodium hydride (11 mmol, 60% dispersion in oil, 1.1 eq) in small portions at 0°C. After stirring for 30 minutes, 2.5 g of 2-(2-bromoethoxy)tetrahydropyran (12 mmol, 1.2 eq) was added. The reaction mixture was then removed from the cooling bath and stirred at 50°C until no further conversion was observed. The mixture was diluted with EtOAc and brine. After extraction, the organic phase was washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using heptane and EtOAc as eluents to yield 2-[2-[(2-iodophenyl)methoxy]ethoxy]tetrahydropyran. ¹ H NMR (400MHz, CDCl ₃ )δ7.83(d,1H),7.50(d,1H),7.36(t,1H),6.99(t,1H),4.70(t,1H),4.59(s,2H),3.98-3.88(m,2H),3.79- 3.76(m,2H),3.73-3.68(m,1H),3.56-3.51(m,1H),1.94-1.83(m,1H),1.80-1.73(m,1H),1.70-1.52(m,4H)

Step B : Preparation Example 4e

To a solution of 1.0 g of the product from Step A (2.76 mmol, 1 eq) in 15 mL of dry THF was added 4.24 mL ^{of iPrMgCl} x LiCl (5.52 mmol, 1.3 M in THF, 2 eq) at 0°C over 2 minutes. After stirring for 10 minutes, 1.40 mL of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.9 mmol, 2.5 eq) was added, and the mixture was stirred at 0°C until no further conversion was observed. The reaction mixture was diluted with EtOAc and brine. After extraction, the organic phase was washed with brine and dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using heptane and EtOAc as eluents to provide Preparation Example 4e. ¹ H NMR (400MHz, CDCl ₃ )δ7.80(d,1H),7.53(d,1H),7.44(t,1H),7.28(t,1H),4.87(s,1H),4.68(t,2H),3.94-3.87(m,2 H),3.76-3.64(m,3H),3.54-3.49(m,1H),1.93-1.82(m,1H),1.78-1.71(m,1H),1.69-1.52(m,4H)

Preparation Example 4f : 2-[2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxymethyl]phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Step A : 4-[(2-bromophenyl)methoxymethyl]-2,2-dimethyl-1,3-dioxolane

To a solution of 1.3 mL of (2,2-dimethyl-1,3-dioxolan-4-yl)methanol (11 mmol, 1.1 eq) in 25 mL of dry DMF was added 440 mg of sodium hydride (11 mmol, 60% dispersion in oil, 1.1 eq) in small portions at 0°C. After stirring for 30 minutes, 2.5 g of 1-bromo-2-(bromomethyl)benzene (10 mmol, 1 eq) was added. The reaction mixture was then removed from the cooling bath and stirred at room temperature until no further conversion was observed. The reaction mixture was diluted with EtOAc and brine. After extraction, the organic phase was washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using heptane and EtOAc as eluents to yield 4-[(2-bromophenyl)methoxymethyl]-2,2-dimethyl-1,3-dioxolane.

¹ H NMR (400MHz, CDCl ₃ )δ7.55(d,1H),7.49(d,1H),7.33(t,1H),7.17(t,1H),4.65(dd,2H),4.36(qui,1H) ,4.11(dd,1H),3.82(dd,1H),3.67(dd,1H),3.59(dd,1H),1.46(s,3H),1.39(s,3H)

Step B : Preparation Example 4f

The product from Step A was converted to the appropriate boronate ester using General Procedure IV, Step B to provide Preparation 4f. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.65 (d, 1H), 7.45 (t, 1H), 7.41 (d, 1H), 7.29 (t, 1H), 4.68 (dd, 2H), 4.20 (qui, 1H), 3.98 (dd, 1H), 3.62 (dd, 1H), 3.51-3.42 (m, 2H), 1.30 (s, 3H), 1.30 (s, 12H), 1.26 (s, 3H)

Preparation Example 4g : 4,4,5,5-Tetramethyl-2-[3-(2-tetrahydropyran-2-yloxyethoxymethyl)phenyl]-1,3,2-dioxaborolane

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

To a solution of 2.34 g (3-iodophenyl)methanol (10 mmol, 1 eq) in 25 mL of dry DMF was added 440 mg of sodium hydride (11 mmol, 60% dispersion in oil, 1.1 eq) in small portions at 0°C. After stirring for 30 minutes, 2.5 g of 2-(2-bromoethoxy)tetrahydropyran (12 mmol, 1.2 eq) was added. The reaction mixture was then removed from the cooling bath and stirred at 50°C until no further conversion was observed. The reaction mixture was diluted with EtOAc and brine. After extraction, the organic phase was washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using heptane and EtOAc as eluents to yield 2-[2-[(3-iodophenyl)methoxy]ethoxy]tetrahydropyran. MS (EI, 70 eV) m/z (% relative intensity, [ion]): 85 (100), 217 (57), 233 (15), 278 (15), 362 (1)

Step B : Preparation Example 4g

To a solution of 1.0 g of the product from Step A (2.76 mmol, 1 eq) in 15 mL of dry THF was added 4.24 mL ^{of iPrMgCl} x LiCl (5.52 mmol, 1.3 M in THF, 2 eq) at 0°C over 2 minutes. After stirring for 10 minutes, 1.40 mL of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.9 mmol, 2.5 eq) was added, and the mixture was stirred at 0°C until no further conversion was observed. The reaction mixture was diluted with EtOAc and brine. After extraction, the organic phase was washed with brine and dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using heptane and EtOAc as eluents to obtain Preparation Example 4g. ¹ H NMR (400MHz, CDCl ₃ )δ7.79(s,1H),7.75(d,1H),7.51(d,1H),7.38(t,1H),4.67(t,1H),4.63(d,1H),4.59(d,1H ),3.95-3.83(m,2H),3.71-3.62(m,3H),3.55-3.48(m,1H),1.94-1.47(m,6H),1.37(s,12H)

Preparation Example 4h : 2-[3-[2-methoxy-1-(methoxymethyl)ethoxy]phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

To a solution of 880 mg (4 mmol, 1 eq) of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol and 1371 mg (5.0 mmol, 1.25 eq) of 2-methoxy-1-(methoxymethyl)ethyl 4-methylbenzenesulfonate in 16 mL of DMF was added 1954 mg (6.0 mmol, 1.5 eq) of cesium carbonate and stirred at 75°C for 16 hours, then at 85°C for 8 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. 25 mL of brine was added to the residue, and the mixture was extracted with 3 x 25 mL of ethyl acetate. The combined organic layers were dried over _MgSO₄ and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography using heptane and ethyl acetate as eluents to provide Preparation Example 4h. HRMS calculated for C ₁₇ H ₂₇ BO ₅ : 322.1952; found: 323.2025 (M+H)

Preparation Example 4i : 2-[4-[2-methoxy-1-(methoxymethyl)ethoxy]phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

To a solution of 880 mg (4 mmol, 1.0 eq) of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol and 1371 mg (5.0 mmol, 1.25 eq) of [2-methoxy-1-(methoxymethyl)ethyl]-4-methylbenzenesulfonate in 16 mL of DMF was added 1954 mg (6.0 mmol, 1.5 eq) of cesium carbonate and stirred at 75 ° C for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. 25 mL of brine was added to the residue and extracted with 3 x 25 mL of ethyl acetate. The combined organic layers were dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography using heptane and ethyl acetate as eluents to provide Preparation Example 4i. HRMS calculated for C ₁₇ H ₂₇ BO ₅ : 322.1952; found: 323.2036 (M+H)

Preparation Example 4j : [(2R)-4,5-diacetoxy-6-methoxy-2-[[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl]tetrahydropyran-3-yl]acetate

Step A : Methyl 2,3,4-tri-O-acetyl-α-D-mannopyranoside

2.25 g (4 mmol) of methyl 2,3,4-tri-O-acetyl-6-triphenylmethyl-α-D-mannopyranoside was dissolved in 30 mL of acetic acid at 85°C, followed by the addition of 15 mL of water and stirring at 90°C for 1 hour. The mixture was cooled to room temperature and then poured into ice-cold brine. The mixture was filtered and the filtrate was extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography using heptane and ethyl acetate as eluents to yield methyl 2,3,4-tri-O-acetyl-α-D-mannopyranoside. ¹ H NMR (500MHz, DMSO-d ₆ ):5.11-5.03(m,3H),4.85(t,1H),4.73(d,1H),3.65(m,1H),3.48(m,1H),3.42(m,1H),3.33(s,3H),2.11-1.91(s,9H)

Step B : Preparation Example 4j

Preparation 4j was prepared using General Procedure IV, Step A, starting from methyl 2,3,4-tri-O-acetyl-α-D-mannopyranoside and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol. ¹ H NMR (500 MHz, DMSO-d ₆ ): 7.31 (t, 1H), 7.26 (m, 1H), 7.15 (m, 1H), 7.06 (m, 1H), 5.25 (t, 1H), 5.12 (m, 1H), 5.11 (m, 1H), 4.79 (d, 1H), 4.13 (dd, 1H), 4.05 (dd, 1H), 3.99 (m, 1H), 3.36 (s, 3H), 2.15-1.92 (s, 9H), 1.29 (s, 12H)

Preparation Example 4k : 4,4,5,5-tetramethyl-2-[3-[[(2S)-3,4,5,6-tetramethoxytetrahydropyran-2-yl]methoxy]phenyl]-1,3,2-dioxaborolane

Step A : Methyl-6-triphenylmethyl 2,3,4-tri-O-methyl-α-D-mannopyranoside

To a solution of 8.08 g (18.51 mmol) of methyl 6-triphenylmethyl-α-D-mannopyranoside in 150 mL of DMF was added portionwise 2.89 g of sodium hydride (60% dispersion in mineral oil, 72.2 mmol, 3.9 eq) at 0°C and stirred at this temperature for 30 minutes. Then, 5.20 mL of MeI (11.8 g, 83.3 mmol, 4.5 eq) was added dropwise at 0°C and stirred at room temperature for 16 hours. 10 mL of MeOH was added to the reaction mixture, stirred for 15 minutes, and then concentrated under reduced pressure. The residue was diluted with 200 mL of water and extracted with DCM. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography using heptane and ethyl acetate as eluents to yield methyl 6-triphenylmethyl 2,3,4-tri-O-methyl-α-D-mannopyranoside. ¹ H NMR (500MHz, DMSO-d ₆ ):7.44-7.23(m,15H),4.85(d,1H),3.58(dd,1H),3.48(m,1H),3.39(s,3H),3.36(s, 3H),3.33(dd,1H),3.31(s,3H),3.28(t,1H),3.23(dd,1H),3.11(s,3H),3.1(dd,1H)

Step B : Methyl 2,3,4-tri-O-methyl-α-D-mannopyranoside

1.914 g of methyl-6-triphenylmethyl 2,3,4-tri-O-methyl-α-D-mannopyranoside (4.0 mmol) was dissolved in 30 mL of acetic acid at 85°C, followed by the addition of 15 mL of water and stirring at 90°C for 1 hour. The mixture was cooled to room temperature and poured into ice-cold brine. The mixture was filtered and the filtrate was extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography using heptane and ethyl acetate as eluents to yield methyl 2,3,4-tri-O-methyl-α-D-mannopyranoside. ¹ H NMR (500MHz, DMSO-d ₆ ): 4.72 (d, 1H), 4.63 (br s,1H),3.56(dd,1H),3.54(dd,1H),3.47(dd,1H),3.36(s,3H),3.34(s,3H),3.32(m,1H),3.32(s,3H),3.26(s,3H),3.24(m,1H),3.22(m,1H)

Step C : Preparation Example 4k

Preparation 4k was prepared using General Procedure IV, Step A, starting from methyl 2,3,4-tri-O-methyl-α-D-mannopyranoside and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol. ¹ H NMR (500MHz, DMSO-d ₆ ):7.31(dd,1H),7.25(dm,1H),7.19(m,1H),7.09(dm,1H),4.77(d,1H),4.14(dd,1H),4.09(dd,1H),3.60(m,1 H),3.59(dd,1H),3.41(t,1H),3.38(dd,1H),3.37(s,3H),3.36(s,3H),3.34(s,3H),3.33(s,3H),1.29(s,12H)

Preparation Example 41 : [(2R)-4,5-diacetoxy-6-methoxy-2-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl]tetrahydropyran-3-yl]acetate

Preparation 41 was prepared using General Procedure IV, Step A, starting from methyl 2,3,4-tri-O-acetyl-α-D-mannopyranoside (from Preparation 4j, Step A) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol. ¹ H NMR (500 MHz, DMSO-d ₆ ): 7.60 (m, 2H), 6.92 (m, 2H), 5.23 (t, 1H), 5.13 (dd, 1H), 5.11 (dd, 1H), 4.80 (d, 1H), 4.14 (dd, 1H), 4.06 (dd, 1H), 4.02 (m, 1H), 3.36 (s, 3H), 2.14-1.92 (s, 9H), 1.27 (s, 12H).

Preparation Example 4m : 4,4,5,5-tetramethyl-2-[4-[[(2S)-3,4,5,6-tetramethoxytetrahydropyran-2-yl]methoxy]phenyl]-1,3,2-dioxaborolane

Preparation 4m was prepared using General Procedure IV, Step A, starting from methyl 2,3,4-tri-O-methyl-α-D-mannopyranoside (from Preparation 4j, Step A) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol. ¹ H NMR (500 MHz, DMSO-d ₆ ): 7.61 (m, 2H), 6.96 (m, 2H), 4.77 (d, 1H), 4.16 (dd, 1H), 4.10 (dd, 1H), 3.61 (m, 1H), 3.60 (d, 1H), 3.38 (m, 2H), 3.37-3.28 (s, 12H), 1.27 (s, 12H)

Preparation Example 4n : [(2R)-4,5,6-triacetoxy-2-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl]tetrahydropyran-3-yl]acetate

Step A : 1,2,3,4-tetra-O-acetyl-α/β-D-mannopyranose

2.36 g of 1,2,3,4-tetra-O-acetyl-6-triphenylmethyl-α/β-D-mannopyranose (4.0 mmol) was dissolved in 30 mL of acetic acid at 65°C, followed by the addition of 15 mL of water and stirring at 65°C for 1 hour. The mixture was cooled to room temperature and poured into ice-cold brine. The mixture was filtered and the filtrate was extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography using heptane and ethyl acetate as eluents to yield 1,2,3,4-tetra-O-acetyl-α/β-D-mannopyranose. ¹ H NMR (500MHz, DMSO-d ₆ ):6.06-5.97(d,1H),5.20-5.06(t,1H),5.31-5.18(dd,1H),5.35-5.14(dd,1H ),4.89-4.87(t,1H),3.84-3.74(m,1H),3.52-3.34(m,2H),2.20-1.90(s,12H)

Step B : Preparation Example 4n

Preparation 4n was obtained as a mixture of stereoisomers using General Procedure IV, Step A, starting from 1,2,3,4-tetra-O-acetyl-α/β-D-mannopyranose and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol. ¹ H NMR (500 MHz, DMSO-d ₆ ): 7.60 (m, 2H), 6.91 (m, 2H), 6.15-6.00 (d, 1H), 5.43-5.15 (m, 3H), 4.23-4.20 (m, 1H), 4.14-4.00 (m, 2H), 2.19-1.92 (s, 12H), 1.27 (s, 12H)

Preparation Example 4o : [(3R,4S,6S)-3,4,5-triacetoxy-6-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxy]tetrahydropyran-2-yl]methyl acetate

and

Preparation Example 4p : [(2R,3aS,6R,7S)-6,7-diacetoxy-2-methyl-2-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxy]-5,6,7,7a-tetrahydro-3aH-[1,3]dioxolo[4,5-b]pyran-5-yl]methyl acetate

Step A : 1-Bromo-2,3,4,6-tetra-O-acetyl-α/β-D-mannopyranose

1 mL of acetic anhydride was added to 30 mL of a 33% HBr solution in acetic acid and stirred at room temperature for 16 hours. The mixture was cooled to 0°C and a solution of 7.50 g of 1,2,3,4,6-penta-O-acetyl-α/β-D-mannopyranose (19.2 mmol) in 30 mL of dichloromethane was added dropwise at 0°C. The reaction mixture was stirred at this temperature for 2 hours and then at room temperature for 16 hours. The mixture was cooled to 0°C and poured onto 100 mL of ice water. It was diluted with 120 mL of DCM and the phases were separated. The organic layer was washed with ice-cold water, saturated NaHCO ₃ , and then washed again with water. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield 1-bromo-2,3,4,6-tetra-O-acetyl-α/β-D-mannopyranose. ¹ H NMR (500MHz, DMSO-d ₆ ):6.77(d,1H),5.50(dd,1H),5.35(dd,1H),5.23(t,1H),4.17(m,1H),4.25 (dd,1H),4.08(dd,1H),2.13(s,3H),2.06(s,3H),2.03(s,3H),1.96(s,3H)

Step B : Preparation of 4o and 4p

To a solution of 819 mg of [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol (3.50 mmol, 1 eq), 2015 mg of 1-bromo-2,3,4,6-tetra-O-acetyl-α/β-D-mannopyranose (4.90 mmol, 1.4 eq), and 467 mg of 2,4,6-trimethylpyridine (3.85 mmol, 1.1 eq) in 100 mL of DCM was added dropwise a solution of 1708 mg of silver trifluoromethanesulfonate (6.65 mmol, 1.9 eq) in 15 mL of toluene at -78°C, and the mixture was stirred at that temperature for 10 minutes. The mixture was allowed to slowly warm to room temperature (3 hours) and then stirred for 10 hours. The mixture was filtered through a pad of celite, and the filtrate was concentrated. The residue was purified by flash silica gel chromatography using heptane and ethyl acetate as eluents to give the first eluting product Preparation Example 4o: ¹ H NMR (500 MHz, DMSO-d ₆ ): 7.69 (m, 2H), 7.39 (m, 2H), 5.15-5.10 (m, 3H), 4.96 (d, 1H), 4.71 (d, 1H), 4.57 (d, 1H), 4.15 (dd, 1H), 4.04 (dd, 1H), 3.96 (m, 1H), 2.12-1.91 (s, 12H), 1.29 (s, 12H);

And the later eluted product Preparation Example 4p: ¹ H NMR (500 MHz, DMSO-d ₆ ): 7.63 (m, 2H), 7.31 (m, 2H), 5.68 (d, 1H), 5.32 (dd, 1H), 5.05 (t, 1H), 4.59 (d, 1H) 4.54 (dd, 1H), 4.53 (d, 1H), 4.12 (dd, 1H), 4.03 (dd, 1H), 3.94 (m, 1H), 2.01-1.97 (s, 9H), 1.70 (s, 3H), 1.29 (s, 12H).

Preparation Example 4q : [5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]methanol

113 mg of (5-bromopyrimidin-2-yl)methanol (0.6 mmol) and 609 mg of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (2.4 mmol) were dissolved in 6 mL of dioxane, followed by the addition of 353 mg of KOAc (3.6 mmol) and 66 mg of PdCl ₂ ×dppf (0.09 mmol). The mixture was stirred at 60° C. under a nitrogen atmosphere for 2 hours. The resulting mixture was used directly without further purification. MS (M+H): 237.1

Preparation Example 5 : (2R)-2-[5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy-3-[2-[[2-[3-(hydroxymethyl)phenyl]pyrimidin-4-yl]methoxy]phenyl]propanoic acid ethyl ester

Preparation 5 was obtained as a mixture of diastereoisomers using General Procedure I, Step A and [3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol as the appropriate boronic acid ester. MS: [M+H] ⁺ = 903.2

Example 1: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(3-hydroxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid

Example 1 was prepared using General Procedure I, Step B, starting from Preparation 2. HRMS Calcd. for _{C 46} H ₄₂ ClFN ₆ O ₆ S: 860.2559; Found: 431.1349 (M+2H) ²⁺

Example 2: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(4-hydroxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid

Example 2 was prepared using General Procedure I, Step _{B, starting from Preparation 3. HRMS Calcd. for C46H42ClFN6O6S :} 860.2559; Found: 431.1371 (M _{+ 2H} ) ²⁺

Example 3: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-({2-[3-(hydroxymethyl)phenyl]pyrimidin-4-yl}methoxy)phenyl]propanoic acid

Example 3 was prepared starting from Preparation 1 and [3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol using General Procedure I. HRMS calculated for C ₄₇ H ₄₄ ClFN ₆ O ₆ S: 874.2715; found: 438.141 (M+2H) ²⁺

Example 4: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-({2-[4-(hydroxymethyl)phenyl]pyrimidin-4-yl}methoxy)phenyl]propanoic acid

Example 4 was prepared starting from Preparation 1 and [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol using General Procedure I. HRMS calculated for C ₄₇ H ₄₄ ClFN ₆ O ₆ S: 874.2715; found: 438.1449 (M+2H) ²⁺

Example 5: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid

Example 5 was prepared starting from Preparation 1 and Preparation 4a using General Procedure I. HRMS calculated for C ₅₂ H ₅₂ ClFN ₆ O ₈ S: 974.324; found: 488.1698 (M+2H) ²⁺

Example 6: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{2-[2-(2-methoxyethoxy)ethoxy]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid

Example 6 was prepared starting from Preparation 1 and Preparation _4b using General Procedure I. HRMS Calcd. _{for C51H52ClFN6O8S} : 962.324; Found: 482.1695 (M ₊ 2H) ²⁺

Example 7: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}phenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid

Example 7 was prepared starting from Preparation 1 and Preparation 4c using General Procedure I. HRMS calculated for _{C 53} H ₅₆ ClFN ₆ O ₉ S: 1006.3502; found: 504.1828 (M+2H) ²⁺

Example 8: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-({2-[2-(methoxymethyl)phenyl]pyrimidin-4-yl}methoxy)phenyl]propanoic acid

Example 8 was prepared starting from Preparation 1 and [2-(methoxymethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane using General Procedure I. HRMS calculated for C ₄₈ H ₄₆ ClFN ₆ O ₇ S: 888.2872; found: 445.1518 (M+2H) ²⁺

Example 9: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{2-[(2-methoxyethoxy)methyl]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid

Example 9 was prepared starting from Preparation 1 and Preparation 4d using General Procedure I. HRMS calculated for C ₅₀ H ₅₀ ClFN ₆ O ₇ S: 932.3134; found: 467.164 (M+2H) ²⁺

Example 10: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{2-[(2-hydroxyethoxy)methyl]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid

Following General Procedure I, starting from Preparations 1 and 4e, after the reaction in Step B was complete, the pH was adjusted to 1 with 2M aqueous HCl _and stirred until no further conversion was observed. It was then neutralized with 10% aqueous _K2CO3 , diluted with brine, and extracted with DCM. The combined organic phases were dried over magnesium sulfate, filtered, _and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative reverse phase chromatography using 5 _{mM aqueous NH4HCO3 and MeCN as eluents. The later eluting diastereomer was collected to provide Example 10. HRMS calculated for C49H48N6O7FSCl : 918.2978 ; found} : 460.1572 (M+2H) ²⁺

Example 11: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-{[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]methyl}phenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid

Example 11 was prepared starting from Preparation 1 and Preparation 4f using General Procedure I. HRMS Calcd. for _{C 53} H ₅₄ ClFN ₆ O ₈ S: 988.3397; Found: 495.1762 (M+2H) ²⁺

Example 12: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{3-[(2-hydroxyethoxy)methyl]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid

Following General Procedure I, starting from Preparations 1 and 4g, after the reaction in Step B was complete, the pH was adjusted to 1 with 2M aqueous HCl _and stirred until no further conversion was observed. It was then neutralized with 10% aqueous _K2CO3 , diluted with brine, and extracted with DCM. The combined organic phases were dried over magnesium sulfate, filtered, and the filtrate _was concentrated under reduced pressure. The crude product was purified by preparative _{reverse phase chromatography using 5mM aqueous NH4HCO3 and MeCN as eluents. The later eluting diastereomer was collected to provide Example 12. HRMS calculated for C49H48ClFN6O7S : 918.2978 ; found} : 460.1556 (M+2H) ²⁺

Example 13: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{3-[(1,3-dimethoxyprop-2-yl)oxy]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid

Example 13 was prepared starting from Preparation ₁ and Preparation _4h using General Procedure I. HRMS Calcd. for _{C51H52ClFN6O8S} : 962.324; Found: 482.1694 (M+ _2H ) ²⁺

Example 14: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{4-[(1,3-dimethoxyprop-2-yl)oxy]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid

Example 14 was prepared starting from Preparation 1 and Preparation _{4i using} General Procedure I. HRMS Calcd. for _{C51H52ClFN6O8S :} 962.324; Found: 482.1678 (M+2H) ²⁺

Example 15: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-({2-[4-(2,3-dihydroxypropoxy)phenyl]pyrimidin-4-yl}methoxy)phenyl]propanoic acid

Following General Procedure II, starting from Preparation 3 and (2,2-dimethyl-1,3-dioxolan-4-yl)methanol, after the reaction in Step B was completed, the pH was adjusted to 1 with 2M aqueous HCl and stirred until no further conversion was observed. It was then neutralized with 10% _{aqueous K2CO3} , diluted with brine, and extracted with DCM. The combined organic phases were dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative reverse phase chromatography using _{5mM aqueous NH4HCO3 and MeCN as eluents. The later eluting diastereomer was collected to provide Example 15. HRMS calculated for C49H48N6O8FSCl : 934.2927 ; found :} 468.1531 (M+2H) ²⁺

Example 16: Methyl 6-O-{3-[4-({2-[(2R)-2-carboxy-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}ethyl]phenoxy}methyl)pyrimidin-2-yl]phenyl}-α-D-mannopyranoside

Example 16 was prepared using General Procedure V starting from Preparation 1 and Preparation 4j. HRMS Calcd. for C ₅₃ H ₅₄ ClFN ₆ O ₁₁ S: 1036.3243; Found: 519.1696 (M+2H) ²⁺

Example 17: Methyl 6-O-{3-[4-({2-[(2R)-2-carboxy-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}ethyl]phenoxy}methyl)pyrimidin-2-yl]phenyl}-2,3,4-tri-O-methyl-α-D-mannopyranoside

Example 17 was prepared starting from Preparation 1 and Preparation 4k using General Procedure I. HRMS Calcd. for _{C 56} H ₆₀ ClFN ₆ O ₁₁ S: 1078.3713; Found: 540.1936 (M+2H) ²⁺

Example 18: Methyl 6-O-{4-[4-({2-[(2R)-2-carboxy-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}ethyl]phenoxy}methyl)pyrimidin-2-yl]phenyl}-α-D-mannopyranoside

Example 18 was prepared using General Procedure V starting from Preparation 1 and Preparation 41. HRMS Calcd. for C ₅₃ H ₅₄ ClFN ₆ O ₁₁ S: 1036.3243; Found: 519.1714 (M+2H) ²⁺

Example 19: Methyl 6-O-{4-[4-({2-[(2R)-2-carboxy-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}ethyl]phenoxy}methyl)pyrimidin-2-yl]phenyl}-2,3,4-tri-O-methyl-α-D-mannopyranoside

Example 19 was prepared starting from Preparation 1 and Preparation 4m using General Procedure I. HRMS calculated for C ₅₆ H ₆₀ ClFN ₆ O ₁₁ S: 1078.3713; found: 540.1925 (M+2H) ²⁺

Example 20: 6-O-{4-[4-({2-[(2R)-2-carboxy-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}ethyl]phenoxy}methyl)pyrimidin-2-yl]phenyl}-D-mannopyranose

and

Example 21: 6-O-{2-[4-({2-[(2R)-2-carboxy-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}ethyl]phenoxy}methyl)pyrimidin-2-yl]phenyl}-D-mannonic acid

Using General Procedure V, starting from Preparation 1 and Preparation 4n, the first eluting compound was Example 20. HRMS calculated for C ₅₂ H ₅₂ ClFN ₆ O ₁₁ S: 1022.3087; found: 512.1611 (M+2H) ²⁺

The late eluting compound obtained was Example 21. HRMS calculated for C ₅₂ H ₅₂ ClFN ₆ O ₁₂ S: 1038.3036; found: 520.1604 (M+2H) ²⁺

Example 22: 1,2-O-[(1R)-1-({4-[4-({2-[(2R)-2-carboxy-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}ethyl]phenoxy}methyl)pyrimidin-2-yl]benzyl}oxy)ethylidene]-β-D-mannopyranose

Example 22 was prepared using General Procedure V starting from Preparation 1 and Preparation _{4o .} HRMS Calcd. _{for C55H56ClFN6O12S} : 1078.335; Found: 1079.343 (M+H) ⁺

Example 23: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{4-[(α-D-mannopyranosyloxy)methyl]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid

Example 23 was prepared using General Procedure V starting from Preparation 1 and Preparation 4p. HRMS Calcd. for C ₅₃ H ₅₄ ClFN ₆ O ₁₁ S: 1036.3243; Found: 519.1682 (M+2H) ²⁺

Example 24: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-({2-[4-(2-hydroxyethyl)phenyl]pyrimidin-4-yl}methoxy)phenyl]propanoic acid

Example 24 was prepared starting from Preparation 1 and [4-(2-hydroxyethyl)phenyl]boronic acid using General Procedure I. HRMS Calcd. for C ₄₈ H ₄₆ N ₆ O ₆ FSCl: 888.2872; Found: 445.1512 (M+2H) ²⁺

Example 25: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-({2-[2-(2,3-dihydroxypropoxy)phenyl]pyrimidin-4-yl}methoxy)phenyl]propanoic acid

Following General Procedure I, starting from Preparations 1 and 4a, after the reaction in Step B was complete, the pH was adjusted to 1 with 2M aqueous HCl _and stirred until no further conversion was observed. It was then neutralized with 10% aqueous _K2CO3 , diluted with brine, and extracted with DCM. The combined organic phases were dried over magnesium sulfate, filtered, and the filtrate _was concentrated under reduced pressure. The crude product was purified by preparative _{reverse phase chromatography using 5 mM aqueous NH4HCO3 and MeCN as eluents. The later eluting diastereomer was collected to provide Example 25. HRMS calculated for C49H48ClFN6O8S : 934.2927 ; found} : 468.1536 (M+2H) ²⁺

Example 26: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-({2-[2-(2-hydroxyethoxy)phenyl]pyrimidin-4-yl}methoxy)phenyl]propanoic acid

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

A solution of 1.01 g of (2R)-3-[2-[(2-chloropyrimidin-4-yl)methoxy]phenyl]-2-hydroxy-propionic acid ethyl ester (from Step E of Preparation 1) (3 mmol, 1 equivalent), 1.17 g of [2-(2-methoxyethoxy)phenyl]boronic acid (6 mmol, 2 equivalents), 2.93 g of cesium carbonate (9 mmol, 3 equivalents), and 210 mg of Pd(PPh ₃ ) ₂ Cl ₂ in 30 mL of dioxane/H ₂ O (1:1) was stirred at 70° C. until no further conversion was observed. The reaction mixture was diluted with EtOAc and brine. After extraction, the organic phase was washed with brine and dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using heptane and EtOAc as eluents to give ethyl (2R)-2-hydroxy-3-[2-[[2-[2-(2-methoxyethoxy)phenyl]pyrimidin-4-yl]methoxy]phenyl]propanoate as a dry oil. ¹ H NMR (400MHz, DMSO-d ₆ )δ8.92(d,1H),7.60(dd,1H),7.59(d,1H),7.45(dd,1H),7.24-7.15(m,3H),7.08(t,1H),7.02(d,1H),6.91(t,1H),5.55(d,1H),5.27(d,1 H),5.23(d,1H),4.40-4.32m,1H),4.17-4.11(m,2H),4.06(q,2H),3.62-3.60(m,2H),3.22(s,3H),3.17(dd,1H),2.88(dd,1H),1.18(t,3H)

Step B : Ethyl (2R)-2-[5-bromo-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy-3-[2-[[2-[2-(2-methoxyethoxy)phenyl]pyrimidin-4-yl]methoxy]phenyl]propanoate

A suspension of 995 mg of the product obtained in Step A (2.2 mmol, 1.1 equiv), 687 mg of 5-bromo-4-chloro-6-(4-fluorophenyl)thieno[2,3-d]pyrimidine (from Preparation 1, Step D) (2 mmol, 1 equiv), and 1.95 g of cesium carbonate (6 mmol, 3 equiv) in 10 mL of dry THF was stirred at 70°C until no further conversion was observed. The reaction mixture was diluted with EtOAc and brine. After extraction, the organic phase was washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using heptane and EtOAc as eluents to yield ethyl (2R)-2-[5-bromo-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy-3-[2-[[2-[2-(2-methoxyethoxy)phenyl]pyrimidin-4-yl]methoxy]phenyl]propanoate. ¹ H NMR (400MHz, DMSO-d ₆ )δ8.90(d,1H),8.62(s,1H),7.77-7.72(m,2H),7.61(d,1H),7.55(dd,1H) ,7.49(dd,1H),7.45-7.38(m,3H),7.25(dd,1H),7.15(d,1H),7.09-7.01(m ,2H),6.94(t,1H),5.79(dd,1H),5.31(d,1H),5.25(d,1H),4.17(q,2H),4. 15-4.10(m,2H),3.64-3.56(m,3H),3.33(dd,1H),3.21(s,3H),1.14(t,3H)

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

To a solution of 760 mg of the product obtained in step B (1 mmol, 1 equivalent) in 10 mL of dry DCM was added 1 mL of BBr ₃ (1 mmol, 1 M in DCM, 1 equivalent) at room temperature, and the mixture was stirred until no further conversion was observed. The reaction mixture was diluted with EtOAc and brine. After extraction, the organic phase was washed with brine and dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using heptane and EtOAc as eluents to give (2R)-2-[5-bromo-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy-3-[2-[[2-[2-(2-hydroxyethoxy)phenyl]pyrimidin-4-yl]methoxy]phenyl]propanoic acid ethyl ester. ¹ H NMR (400MHz, CDCl ₃ )δ8.99(d,1H),8.53(s,1H),7.92(dd,1H),7.79(d,1H),7.69-7.62(m,2H),7.54-7.45(m,2H),7.27-7.12(m,5H),6.98(7,1H),6.9 4(d,1H),5.87(dd,1H),5.34(d,1H),5.29(d,1H),4.41(t,2H),4.29(q,2H),3.94(t,2H),3.72(dd,1H),3.42(dd,1H),1.28(t,3H)

Step D : Ethyl (2R)-2-[5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy-3-[2-[[2-[2-(2-hydroxyethoxy)phenyl]pyrimidin-4-yl]methoxy]phenyl]propanoate

To a solution of 200 mg of the product of step C (0.27 mmol, 1 eq) in 4 mL of dioxane/H ₂ O (1:1) was added 127 mg of 1-[2-[2-chloro-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl]-4-methyl-piperazine (from step L of Preparation 1) (0.32 mmol, 1.2 eq), 3.1 mg of Pd(OAc) ₂ (0.05 eq), 11 mg of AtaPhos (0.1 eq) and 262 mg of cesium carbonate (0.8 mmol, 3 eq) and stirred at 70° C. until no further conversion was observed. The reaction mixture was diluted with EtOAc and brine. After extraction, the organic phase was washed with brine and dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using EtOAc/MeOH (containing 1.2% NH ₃ ) as eluent to give (2R)-ethyl 2-[5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy-3-[2-[[2-[2-(2-hydroxyethoxy)phenyl]pyrimidin-4-yl]methoxy]phenyl]propanoate. MS: [M+H] ⁺ = 933.2

Step E : Example 26

To a solution of 120 mg of the product from Step D (0.13 mmol) in 4 mL of dioxane/H ₂ O (1:1) was added 100 mg of LiOH x H ₂ O (2.6 mmol, 20 equivalents) and stirred at room temperature until no further conversion was observed. The mixture was then neutralized with 2 M HCl and injected directly onto an RP18 column using 5 mM aqueous NH ₄ HCO ₃ and MeCN as eluents. The later eluting diastereomer was collected to provide Example 26. HRMS calculated for C ₄₈ H ₄₆ ClFN ₆ O ₇ S: 904.2821; found: 453.1496 (M+2H) ²⁺

Example 27: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{2-[(2,3-dihydroxypropoxy)methyl]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid

Following General Procedure I, starting from Preparations 1 and 4f, after the reaction in Step B was complete, the pH was adjusted to 1 with 2M aqueous HCl _and stirred until no further conversion was observed. It was then neutralized with 10% aqueous _K2CO3 , diluted with brine, and extracted with DCM. The combined organic phases were dried over magnesium sulfate, filtered, and the filtrate _was concentrated under reduced pressure. The crude product was purified by preparative _{reverse phase chromatography using 5 mM aqueous NH4HCO3 and MeCN as eluents. The later eluting diastereomer was collected to provide Example 27. HRMS calculated for C50H50ClFN6O8S : 948.3083 ; found} : 475.1621 (M+2H) ²⁺

Example 28: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-({2-[3-(phosphonooxy)phenyl]pyrimidin-4-yl}methoxy)phenyl]propanoic acid

To a solution of 444 mg of Preparation 2 (0.5 mmol, 1 eq) and 210 μL of TEA (1.5 mmol, ₃ eq) in 5 mL of dry THF was added dropwise 140 μL (1.5 mmol, 3 eq) of POCl₃ at room temperature. After stirring for 15 minutes, 5 mL of sodium hydroxide solution (10 mmol, 2 M in water) was added, and the mixture was stirred at 50°C until no further conversion was observed. The reaction mixture was injected directly onto a 220 g flash silica gel column preconditioned (EtOAc/MeOH [containing 1.2% _{NH₃ ]} - 80/20). A gradient elution using EtOAc/MeOH (containing 1.2% NH₃) was performed to provide the desired product as a mixture of diastereomers. The diastereomers were separated by preparative reverse-phase chromatography using 50 mM _{aqueous NH₄HCO₃} and MeOH as eluents. The later eluting diastereomer was collected to provide Example 28. HRMS calculated for C ₄₆ H ₄₃ N ₆ O ₉ FPSCl: 940.2222; found: 471.1194 (M+2H) ²⁺

Example 29: 4-[4-({2-[(2R)-2-carboxy-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}ethyl]phenoxy}methyl)pyrimidin-2-yl]phenyl phosphate

To a solution of 444 mg of Preparation 3 (0.5 mmol, 1 eq) and 210 μL of TEA (1.5 mmol, ₃ eq) in 5 mL of dry THF was added dropwise 140 μL (1.5 mmol, 3 eq) of POCl₃ at room temperature. After stirring for 15 minutes, 5 mL of sodium hydroxide solution (10 mmol, 2 M in water) was added, and the mixture was stirred at 50°C until no further conversion was observed. The reaction mixture was injected directly onto a 220 g flash silica gel column pre-conditioned (EtOAc/MeOH [containing 1.2% _NH₃ ] - 80/20). A gradient elution using EtOAc/MeOH (containing 1.2% _NH₃ ) was performed to provide the desired product as a mixture of diastereomers. The later eluting diastereomer was collected and lyophilized to provide Example 29. HRMS calculated for C ₄₆ H ₄₃ N ₆ O ₉ FPSCl: 940.2222; found: 471.1188 (M+2H) ²⁺

Example 30: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-({2-[3-(2-hydroxyethoxy)phenyl]pyrimidin-4-yl}methoxy)phenyl]propanoic acid

Step A : (2R)-ethyl 2-[5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy-3-[2-[[2-[3-[2-(p-tolylsulfonyloxy)ethoxy]phenyl]pyrimidin-4-yl]methoxy]phenyl]propanoate

To a DMF solution of 178 mg of Preparation Example 2 (0.2 mmol) were added 195 mg of cesium carbonate (0.6 mmol) and 222 mg of 2-(p-tolylsulfonyloxy)ethyl 4-methylbenzenesulfonate (0.6 mmol) and the mixture was stirred at 60° C. until no further conversion was observed. The reaction mixture was diluted with EtOAc and brine. After extraction, the organic phase was washed with brine and dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using EtOAc and MeOH (containing 1.2% NH ₃ ) as eluents to give (2R)-ethyl 2-[5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy-3-[2-[[2-[3-[2-(p-tolylsulfonyloxy)ethoxy]phenyl]pyrimidin-4-yl]methoxy]phenyl]propanoate. MS: [M+H] ⁺ = 1087.2

Step B : Example 30

To a solution of 120 mg of the product from Step A (0.11 mmol) in 4 mL of dioxane/H ₂ O (1:1) was added 92 mg of LiOH x H ₂ O (2.2 mmol) and stirred at 60° C. until no further conversion was observed. The mixture was then neutralized with 2 M HCl and injected directly onto an RP18 column, eluting with 5 mM aqueous NH ₄ HCO ₃ and MeCN. The later eluting diastereomer was collected to give Example 30. HRMS calculated for C ₄₈ H ₄₆ ClFN ₆ O ₇ S: 904.2821; found: 453.1475 (M+2H) ²⁺

Example 31: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{4-[2-(2-methoxyethoxy)ethoxy]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid

Example 31 was prepared using General Procedure II starting from Preparation 3 and 2-( _{2-methoxyethoxy)ethanol. HRMS Calcd. for C51H52N6O8FSCl : 962.324 ;} Found: 482.1703 (M+2H) ²⁺

Example 32: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{4-[2-(2-hydroxyethoxy)ethoxy]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid

Example 32 was prepared using General Procedure II starting from Preparation 3 and 10 equivalents _of 2-( _{2-hydroxyethoxy)ethanol. HRMS Calcd. for C50H50N6O8FSCl : 948.3083} ; Found: 475.1613 (M+2H) ²⁺

Example 33: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(4-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}phenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid

Example 33 was prepared using General Procedure II starting from Preparation 3 and 2-[ _2- ( ₂ -methoxyethoxy)ethoxy]ethanol. HRMS Calcd. for _{C53H56N6O9FSCl} : _1006.3502 ; Found: 504.183 (M+2H) ²⁺

Example 34: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{4-[2-(dimethylamino)ethoxy]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid

Example 34 was prepared using General Procedure II starting from Preparation 3 and 2-( _{dimethylamino} )ethanol _. HRMS Calcd. for _{C50H51N7O6FSCl} : _931.3294 ; Found: 466.6709 (M+2H) ²⁺

Example 35: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{3-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid

Example 35 was prepared using General Procedure II starting from Preparation 2 and (2,2-dimethyl-1,3-dioxolan-4-yl)methanol. HRMS Calcd. for _{C 52} H ₅₂ N ₆ O ₈ FSCl: 974.324; Found: 488.1677 (M+2H) ²⁺

Example 36: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-({2-[3-(15-hydroxy-3-oxo-2,7,10,13-tetraoxa-4-azapentadecan-1-yl)phenyl]pyrimidin-4-yl}methoxy)phenyl]propanoic acid

Example 36 was prepared using General Procedure III, starting from Preparation 5 and using 2-[2-[2-(2-aminoethoxy) _ethoxy ]ethoxy]ethanol as the appropriate _amine . HRMS Calcd. _{for C56H61ClFN7O11S} : 1093.3822; Found: 547.7006 (M+2H) ²⁺

Example 37: (2R)-3-(2-{[2-(3-{[(1,4'-bipiperidin-1'-ylcarbonyl)oxy]methyl}phenyl)pyrimidin-4-yl]methoxy}phenyl)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propanoic acid

Example 37 was prepared using General Procedure III starting from Preparation 5 and using 1-(4-piperidinyl ₎ piperidine as the appropriate amine _{. HRMS Calcd. for C58H62ClFN8O7S : 1068.4135} ; Found: 1069.419 (M+H) ⁺

Example 38: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(3-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}phenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid

Example 38 was prepared using General Procedure II starting from Preparation 2 and 10 equivalents of 2-[2-( ₂ - _{hydroxyethoxy} ) _ethoxy ]ethanol. HRMS Calcd. for _{C52H54ClFN6O9S} : 992.3345; Found: 497.1748 (M+2H) ²⁺

Example 39: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{3-[2-(2-hydroxyethoxy)ethoxy]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid

Example 39 was prepared using General Procedure II starting from Preparation 2 and 10 equivalents of 2-( _{2 -hydroxyethoxy)ethanol. HRMS Calcd. for C50H50ClFN6O8S : 948.3083} ; Found: 475.1604 (M+2H) ²⁺

Example 40: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{3-[2-(2-methoxyethoxy)ethoxy]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid

Example 40 was prepared using General Procedure II starting from Preparation 2 and 2-( ₂ - _{methoxyethoxy} )ethanol _{. HRMS Calcd. for C51H52ClFN6O8S :} 962.324; Found: 482.1675 (M+2H) ²⁺

Example 41: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{3-[({[2-(4-methylpiperazin-1-yl)ethyl]carbamoyl}oxy)methyl]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid

Example 41 was prepared using General Procedure III, starting from Preparation 5 and using 2-(4-methylpiperazin- ₁ -yl _{)ethanamine as the appropriate amine. HRMS Calcd. for C55H59ClFN9O7S : 1043.3931} ; Found: 522.7052 (M+2H) ²⁺

Example 42: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{3-[({[2-(morpholin-4-yl)ethyl]carbamoyl}oxy)methyl]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid

Example 42 was prepared using General Procedure III starting from Preparation 5 and using 2-(morpholin- ₄ -yl _{)ethanamine as the appropriate amine. HRMS Calcd. for C54H56ClFN8O8S : 1030.3615} ; Found: 516.1871 (M+2H) ²⁺

Example 43: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{3-[({[2-(dimethylamino)ethyl]carbamoyl}oxy)methyl]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid

Example 43 was prepared using General Procedure III, starting from Preparation 5 and using N',N'-dimethylethane- _1,2 -diamine as the appropriate amine. HRMS Calcd. _{for C52H54ClFN8O7S} : 988.3509; Found: 989.3586 (M+ _H ) ⁺

Example 44: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{3-[({[2-(pyrrolidin-1-yl)ethyl]carbamoyl}oxy)methyl]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid

Example 44 was prepared using General Procedure III, starting from Preparation 5 and using 2-pyrrolidin-1-ylethylamine as the _{appropriate amine. HRMS Calcd. for C54H56ClFN8O7S : 1014.3665 ;} Found: 508.1916 (M+2H) ²⁺

Example 45: (2R)-3-[2-({2-[3-({[bis(2-methoxyethyl)carbamoyl]oxy}methyl)phenyl]pyrimidin-4-yl}methoxy)phenyl]-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propanoic acid

Example 45 was prepared using General Procedure III starting from Preparation 5 and using 2- _methoxy -N-(2- _methoxyethyl )ethanamine as the appropriate amine. HRMS Calcd. for _{C54H57N7O9FSCl} : _1033.3611 ; Found: 517.6883 (M+2H) ²⁺

Example 46: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(3-{[(1,4,7,10,13-pentaoxa-16-azacyclooctadec-16-ylcarbonyl)oxy]methyl}phenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid

Example 46 was prepared using General Procedure III starting from Preparation 5 and using 1,4,7,10,13- _pentaoxa - ₁₆ -azacyclooctadecane as the appropriate amine. HRMS calculated for _{C60H67N7O12FSCl} : _1163.4241 ; found: 582.7187 (M+2H) ²⁺

Example 47: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-({2-[3-(2,3-dihydroxypropoxy)phenyl]pyrimidin-4-yl}methoxy)phenyl]propanoic acid

Following General Procedure II, starting from Preparation 2 and (2,2-dimethyl-1,3-dioxolan-4-yl)methanol, after the reaction in Step B was completed, the pH was adjusted to 1 with 2M aqueous HCl and stirred until no further conversion was observed. It was then neutralized with 10% _{aqueous K2CO3} , diluted with brine, and extracted with _{DCM. The combined organic phases were dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative reverse phase chromatography using 5mM aqueous NH4HCO3 and MeCN as eluents. The later eluting diastereomer was collected to provide Example 47. HRMS calculated for C49H48N6O8FSCl : 934.2927 ; found :} 468.1538 (M+2H) ²⁺

Example 48: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(3-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}phenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid

Example 48 was prepared using General Procedure II starting from Preparation 2 and 2-[2-(2-methoxyethoxy)ethoxy]ethanol. HRMS Calcd. for _{C 53} H ₅₆ N ₆ O ₉ FSCl: 1006.3502; Found: 504.1829 (M+2H) ²⁺

Example 49: (2R)-3-(2-{[2-(3-{2-[bis(2-hydroxyethyl)amino]ethoxy}phenyl)pyrimidin-4-yl]methoxy}phenyl)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propanoic acid

Example 49 was prepared using General Procedure II starting from Preparation 2 and 10 equivalents of 2-[bis(2-hydroxyethyl)amino]ethanol. HRMS Calcd. for C ₅₂ H ₅₅ N ₇ O ₈ FSCl: 991.3505; Found: 496.6833 (M+2H) ²⁺

Example 50: (2R)-2-{[(5S _a )-5-{2,3-dimethyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{3-[({[2-(piperidin-1-yl)ethyl]carbamoyl}oxy)methyl]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid

Example 50 was prepared using General Procedure III, starting from Preparation 5 and using N-(2-aminoethyl)piperidine as the appropriate amine. HRMS calculated for _{C 55} H ₅₈ ClFN ₈ O ₇ S: 1028.3822; found: 1029.3893 (M+H) ⁺

Example 51: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{3-[2-(morpholin-4-yl)ethoxy]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid

Example 51 was prepared using General Procedure II starting from Preparation 2 and N-(2-hydroxyethyl)morpholine. HRMS Calcd. for C ₅₂ H ₅₃ ClFN ₇ O ₇ S: 973.3400; Found: 487.6785 (M+2H) ²⁺

Example 52: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{3-[2-(dimethylamino)ethoxy]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid

Example 52 was prepared using General Procedure II starting from Preparation 2 and ₂ - _{dimethylaminoethanol . HRMS Calcd. for C50H51ClFN7O6S :} 931.3294; Found: 466.6722 (M+2H) ²⁺

Example 53: (2R)-3-(2-{[2-(4-{2-[bis(2-hydroxyethyl)amino]ethoxy}phenyl)pyrimidin-4-yl]methoxy}phenyl)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propanoic acid

Example 53 was prepared using General Procedure II starting from Preparation 3 and 2-[bis(2-hydroxyethyl)amino]ethanol. HRMS Calcd. for C ₅₂ H ₅₅ N ₇ O ₈ FSCl: 991.3505; Found: 496.6822 (M+2H) ²⁺

Example 54: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(4-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}phenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid

Example 54 was prepared using General Procedure II starting from Preparation 3 and 10 equivalents of triethylene glycol. HRMS Calcd. for C ₅₂ H ₅₄ N ₆ O ₉ FSCl: 992.3345; Found: 497.1743 (M+2H) ²⁺

Example 55: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{4-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid

Example 55 was prepared using General Procedure II starting from Preparation 3 and (2,2-dimethyl-1,3-dioxolan-4-yl)methanol. HRMS Calcd. for C ₅₂ H ₅₂ N ₆ O ₈ FSCl: 974.3240; Found: 488.1689 (M+2H) ²⁺

Example 56: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]

phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{4-[2-(morpholin-4-yl)ethoxy]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid

Example 56 was prepared using General Procedure II starting from Preparation 3 and N-(2-hydroxyethyl)morpholine. HRMS Calcd. for C ₅₂ H ₅₃ N ₇ O ₇ FSCl: 973.3400; Found: 487.6775 (M+2H) ²⁺

Example 57: 4-[4-({2-[(2R)-2-carboxy-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}ethyl]phenoxy}methyl)pyrimidin-2-yl]phenyl phosphate disodium salt

To a solution of 444 mg of Preparation 3 (0.5 mmol, 1 eq) and 210 μL of TEA (1.5 mmol, 3 eq) in 5 mL of dry THF was added dropwise 140 μL _of POCl₃ (1.5 mmol, 3 eq) at room temperature. After stirring for 15 minutes, 5 mL of sodium hydroxide solution (10 mmol, 2 M in water) was added, and the mixture was stirred at 50°C until no further conversion was observed. The pH was then adjusted to 6 with TFA, and the reaction mixture was injected directly onto an RP18 column, eluting with 50 mM _{aqueous NH₄HCO₃} and MeOH. The later eluting diastereomer was collected. After freeze-drying, the remaining white solid was suspended in 5 mL of dioxane/saturated _NH₄HCO₃ solution (1: ₁ ). After stirring at room temperature for 1 hour, the reaction mixture was injected directly onto an RP18 column, eluting with water and MeCN to provide Example 57. HRMS calculated for C ₄₆ H ₄₃ N ₆ O ₉ FPSCl: 940.2222; found: 469.1054 (M-2H) ^2- .

Example 58: (2R)-3-(2-{[2-(2-{2-[bis(2-hydroxyethyl)amino]ethoxy}phenyl)pyrimidin-4-yl]methoxy}phenyl)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propanoic acid

Example 59: (2R)-3-(2-{[2-(4-{[bis(2-hydroxyethyl)amino]methyl}phenyl)pyrimidin-4-yl]methoxy}phenyl)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propanoic acid

Example 60: (2R)-3-(2-{[2-(3-{[bis(2-hydroxyethyl)amino]methyl}phenyl)pyrimidin-4-yl]methoxy}phenyl)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propanoic acid

Example 61: (2R)-3-(2-{[2-(2-{[bis(2-hydroxyethyl)amino]methyl}phenyl)pyrimidin-4-yl]methoxy}phenyl)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propanoic acid

Example 62: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{4-[(2-hydroxyethoxy)methyl]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid

Example 63: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{2-[2-(2-hydroxyethoxy)ethoxy]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid

Example 64: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}phenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid

Example 65: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{3-[(phosphonooxy)methoxy]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoic acid

Example 66: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(3-{[(phosphonooxy)methoxy]methyl}phenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid

Example 67: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(3-{[(phosphonooxy)carbonyl]oxy}phenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid

Example 68: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-({2-[3-({[(phosphonooxy)carbonyl]oxy}methyl)phenyl]pyrimidin-4-yl}methoxy)phenyl]propanoic acid

Example 69: (2R)-1-[(ethoxycarbonyl)oxy]ethyl 2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{3-[(1,3-dimethoxyprop-2-yl)oxy]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoate

Step A : 1-Chloroethyl Ethyl Carbonate

Dissolve 1 equivalent of ethanol and 1.2 equivalents of pyridine in dichloromethane (1.2 mL/mmol). Slowly add 1.05 equivalents of 1-chloroethyl chloroformate at -78°C under a nitrogen atmosphere and stir the reaction mixture at -78°C for 3 hours. Filter the cooled mixture and concentrate the filtrate under reduced pressure. The crude product is used directly without further purification.

Step B : Example 69

One equivalent of Example 13 was dissolved in DMF (20 ml/mmol) under nitrogen. 6.7 equivalents of Cs ₂ CO ₃ and 8 equivalents of 1-chloroethyl ethyl carbonate from Step A were added. The reaction mixture was stirred at room temperature until no further conversion was observed. The mixture was diluted with brine and extracted with DCM, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative reverse phase chromatography using 5 mM aqueous NH ₄ HCO ₃ and acetonitrile as eluents to provide Example 69. HRMS calculated for C ₅₆ H ₆₀ ClFN ₆ O ₁₁ S: 1078.3713; found: 1079.3796 and 1079.3786 (M+H)

Example 70: (2R)-1-[(dimethylcarbamoyl)oxy]ethyl 2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{3-[(1,3-dimethoxyprop-2-yl)oxy]phenyl}pyrimidin-4-yl)methoxy]phenyl}propanoate

Example 71: (2R)-2-{[5-{2,6-dimethyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-({2-[3-(hydroxymethyl)phenyl]pyrimidin-4-yl}methoxy)phenyl]propanoic acid

Example 72: (2R)-2-{[5-{3,5-dichloro-2,6-dimethyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-({2-[3-(hydroxymethyl)phenyl]pyrimidin-4-yl}methoxy)phenyl]propanoic acid

Example 73: (2R)-2-{[5-{2,6-dimethyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-({2-[4-(phosphonooxy)phenyl]pyrimidin-4-yl}methoxy)phenyl]propanoic acid

Example 74: (2R)-2-{[5-{3,5-dichloro-2,6-dimethyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-({2-[4-(phosphonooxy)phenyl]pyrimidin-4-yl}methoxy)phenyl]propanoic acid

Example 75: 2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-hydroxy-3-[2-({2-[3-(hydroxymethyl)phenyl]pyrimidin-4-yl}methoxy)phenyl]propanoic acid

Example 76: 2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-4-hydroxy-3-[2-({2-[3-(hydroxymethyl)phenyl]pyrimidin-4-yl}methoxy)phenyl]butanoic acid

Example 77: 2-O-[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]-3,4-dideoxy-3-[2-({2-[3-(hydroxymethyl)phenyl]pyrimidin-4-yl}methoxy)phenyl]pentanoic acid

Example 78: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-({2-[2-(hydroxymethyl)pyridin-4-yl]pyrimidin-4-yl}methoxy)phenyl]propanoic acid

Example 79: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-({2-[5-(hydroxymethyl)pyridin-3-yl]pyrimidin-4-yl}methoxy)phenyl]propanoic acid

Example 79 was prepared using General Procedure I starting from Preparation 1 and [5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methanol. HRMS calculated for _{C 46} H ₄₃ ClFN ₇ O ₆ S: 875.2668; found: 438.6428 (M+2H) ²⁺

Example 80: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-({2-[6-(hydroxymethyl)pyridazin-4-yl]pyrimidin-4-yl}methoxy)phenyl]propanoic acid

Example 81: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-({2-[6-(hydroxymethyl)pyrazin-2-yl]pyrimidin-4-yl}methoxy)phenyl]propanoic acid

Example 82: (2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2'-(hydroxymethyl)-2,5'-bipyrimidin-4-yl]methoxy}phenyl)propanoic acid

Example 82 was prepared starting from Preparation 1 and Preparation 4q using General Procedure I. HRMS calculated for _{C 4 5} H _{4 2} ClFN ₈ O ₆ S: 876.2621; found: 439.1402 (M+2H) ²⁺

Pharmacological research

Example A: Detection of Mcl-1 inhibition using fluorescence polarization technology

The relative binding affinity of each compound was determined by fluorescence polarization (FP). This method utilizes a fluorescently labeled ligand (fluorescein-βAla-Ahx-A-A-REIGAQLRRMADDLNAQY-OH; mw 2,765), which binds to the Mcl-1 protein (Mcl-1 corresponding to accession number: Q07820), resulting in an increase in anisotropy measured in milli-polarization units (mP) using a reader. Addition of a compound that competitively binds to the same site on the ligand results in a greater proportion of unbound ligand in the system, which is reflected by a decrease in mP units.

An 11-point serial dilution of each compound was prepared in DMSO and 2 μL was transferred to a flat-bottom, low-binding 384-well plate (final DMSO concentration 5%). Then, 38 μL of buffer (10 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid [HEPES], 150 mM NaCl, 0.05% Tween 20, pH 7.4) containing fluorescein-labeled ligand (final concentration 1 nM) and Mcl-1 protein (final concentration 5 nM) was added.

The assay plates were incubated at room temperature for approximately 2 hours, after which the FP was measured on a Biomek Synergy2 reader (Ex. 528 nm, Em. 640 nm, cutoff wavelength 510 nm) and mP units were calculated. Binding of increasing doses of test compound was expressed as the percent reduction in mP compared to a window established between the "5% DMSO alone" and "100% inhibition" controls. Using XL Fit software, an 11-point dose-response curve was constructed using a four-parameter logistic model (sigmoidal dose-response model) and the inhibitor concentration that caused a 50% reduction in mP (IC ₅₀ ) was determined. The results are shown in Table 1 below.

The results showed that the compounds of the present invention inhibited the interaction between Mcl-1 protein and the fluorescent peptide as described above.

Example B: In vitro cytotoxicity

Cytotoxicity studies were performed on the H929 multiple myeloma tumor line.

Cells were plated on microplates and exposed to the test compounds for 48 hours. Cell viability was then quantified by a colorimetric assay, the microculture tetrazolium assay (Cancer Res., 1987, 47 , 939-942).

The results are expressed as _IC50 (the concentration of compound that inhibits cell viability by 50%) and are shown in Table 1 below.

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

Table 1: _IC50 of Mcl-1 inhibition (fluorescence polarization assay) and cytotoxicity on H929 cells

ND: Not determined

Example C: Quantification of cleaved forms of PARP in vivo

The ability of the compounds of the present invention to induce apoptosis was evaluated in an AMO-1 multiple myeloma cell xenograft model by measuring the level of cleaved PARP.

1.10 ⁷ AMO-1 cells were implanted subcutaneously into immunosuppressed mice (SCID strain). 12-14 days after implantation, animals were treated with various compounds intravenously or orally. Following treatment, tumor masses were recovered and lysed, and the cleaved form of PARP was quantified in the tumor lysate.

Quantification was performed using the "Meso Scale Discovery (MSD) ELISA platform" assay, which specifically detects the cleaved form of PARP. Activation factor was expressed as the ratio of the amount of cleaved PARP in treated mice divided by the amount of cleaved PARP in control mice.

The results show that the compounds of the present invention can induce apoptosis of AMO-1 tumor cells in vivo.

Example D: In vivo antitumor activity

The antitumor activity of the compounds of the present invention was evaluated in the AMO-1 multiple myeloma cell xenograft model.

1 x 10 ⁷ AMO-1 cells were implanted subcutaneously into immunosuppressed mice (SCID strain).

6-8 days after implantation, when tumor masses reached approximately 150 mm ³ , mice were treated with various compounds on a daily dosing schedule (treatment for 5 days). Tumor masses were measured twice a week from the start of treatment.

The results obtained (expressed as the ΔT/C ratio, an evaluation parameter of product activity, defined as the ratio of tumor volume of the treated group to the tumor volume of the untreated control group) show that the compounds of the invention induce significant tumor regression during the treatment period.

Example F: Pharmaceutical composition: Tablet

1000 tablets containing a 5 mg dose of a compound selected from Examples 1 to 82

Compound selected from Examples 1 to 82 ..................................5 g

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

Corn starch................................................20g

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

Magnesium stearate..................................2g

Silicon dioxide..................................................1g

Hydroxypropyl cellulose................................................2g

Claims (31)

1. Compounds of formula (I), their enantiomers, diastereomers and transisomers, and their addition salts with pharmaceutically acceptable acids or bases: in: ◆A represents a functional group In this case, 1 is connected to an oxygen atom and 2 is connected to a benzene ring. ◆ _R1 represents a straight-chain or branched ( _C1 - _C6 ) alkyl or halogen atom. ◆ _R2 represents a hydrogen atom, a halogen atom, a hydroxyl group, or a straight-chain or branched ( _C1 - _C6 ) alkoxy group. ◆R ₃ represents -O-alkyl (C ₁ -C ₆ )-NR ₁₀ R ₁₀ ', ◆R ₄ represents a hydrogen atom or a halogen atom. ◆R ₅ represents a hydrogen atom or a straight-chain or branched ( _C1 - _C6 ) alkyl group. ◆ _R6 represents -O-alkyl ( _C1 - _C6 ) _-R11 , ◆R ₇ represents a hydrogen atom. ◆R ₈ represents a hydrogen atom, a straight-chain or branched ( _C1 - _C8 ) alkyl group, _{a -CHRaRb} group, an aryl group, a heteroaryl group, an aralkyl group ( _C1 - _C6 ), or a heteroarylalkyl group ( _C1 - _C6 ). ◆R ₉ represents 4-fluoro-phenyl, ◆The substituent pairs ( _R10 , _R10 ') together with the nitrogen atom carrying them form a 4-methyl-piperazinyl group. ◆R ₁₁ represents -Cy ₅ -alkyl(C ₀ -C ₆ )-O-alkyl(C ₀ -C ₆ )-Cy ₆ , -Cy ₅ -alkyl(C ₀ -C ₆ )-Cy ₆ , -Cy ₅ -alkyl(C ₀ -C ₆ )-NR ₁₂ -alkyl(C ₀ -C ₆ )-Cy ₆ , ◆R ₁₄ represents a hydrogen atom, a hydroxyl group, or a hydroxyl ( _C1 - _C6 ) alkyl group. ◆ _Ra represents a hydrogen atom or a straight-chain or branched ( _C1 - _C6 ) alkyl group. ◆ _Rb represents the -OC(O) _-ORc group, -OC(O) _{-NRcRc '} , or -OP(O)( _ORc ) ₂ group. ◆ _Rc and _Rc ' independently represent a hydrogen atom, a straight-chain or branched ( _C1 - _C8 ) alkyl group, a cycloalkyl group, a ( _C1 - _C6 ) alkoxy ( _C1 - _C6 ) alkyl group, or a ( _C1 - _C6 ) alkoxycarbonyl ( _C1 - _C6 ) alkyl group. Alternatively, the substituent pairs ( _Rc , _Rc ') together with the nitrogen atom carrying them form a non-aromatic ring consisting of 5 to 7 ring members, wherein the ring may contain 1 to 3 heteroatoms selected from oxygen and nitrogen in addition to the nitrogen atom, wherein the nitrogen may be substituted by a group representing a straight-chain or branched ( _C1 - _C6 ) alkyl group. ◆Cy ₅ represents heteroaryl. ◆Cy ₆ represents Alternatively, _Cy6 represents a heteroaryl group substituted with a group selected from -OP(O)(OR ₂₀ ) ₂ ; -OP(O)( ^O- ) ₂ ; -(CH ₂ ) _p -O-(CHR ₁₈ -CHR ₁₉ -O) _q -R ₂₀ ; hydroxyl; hydroxyl (C ₁ -C ₆ ) alkyl; -(CH ₂ ) _r -Y-(CH ₂ ) _s - heterocyclic alkyl; or -Y-(CH ₂ ) _q -NR ₂₁ R ₂₁ '. ◆R ₁₅ represents a hydrogen atom; -(CH ₂ ) _p -O-(CHR ₁₈ -CHR ₁₉ -O) _q -R ₂₀ group; straight-chain or branched (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkyl; -Y-(CH ₂ ) _q -NR ₂₁ R ₂₁ 'group; or -(CH ₂ ) _r -Y-(CH ₂ ) _s - heterocyclic alkyl, ◆R ₁₆ represents a hydrogen atom; hydroxyl group; hydroxyl (C ₁ -C ₆ ) alkyl group; -(CH ₂ ) _r -Y-(CH ₂ ) _s - heterocyclic alkyl group; (CH ₂ ) _r -YXOP(O)(OR ₂₀ ) ₂ group; -OP(O)(O ^- ) ₂ group; -(CH ₂ ) _p -O-(CHR ₁₈ -CHR ₁₉ -O) _q -R ₂₀ group; -(CH ₂ ) _p -OC(O)-NR ₂₂ R ₂₃ group; or -Y-(CH ₂ ) _q -NR ₂₁ R ₂₁ ' group. ◆R ₁₇ represents a hydrogen atom; -(CH ₂ ) _p -O-(CHR ₁₈ -CHR ₁₉ -O) _q -R ₂₀ group; -OP(O)(OR ₂₀ ) ₂ group; -OP(O)(O ^- ) ₂ group; hydroxyl group; hydroxyl (C ₁ -C ₆ ) alkyl group; -(CH ₂ ) _r -Y-(CH ₂ ) _s - heterocyclic alkyl group; -Y-(CH ₂ ) _q -NR ₂₁ R ₂₁ 'group; or aldonic acid, ◆X represents a -( _CH2 ) _s- group or a -C(O)- group. ◆Y represents a bond or an oxygen atom. ◆R ₁₈ represents a hydrogen atom or a ( _C1 - _C6 )alkoxy ( _C1 - _C6 )alkyl atom. ◆R ₁₉ represents a hydrogen atom or a hydroxyl ( _C1 - _C6 ) alkyl group. ◆R ₂₀ represents a hydrogen atom or a straight-chain or branched ( _C1 - _C6 ) alkyl group. ◆R ₂₁ and R ₂₁ ' independently represent a hydrogen atom, a straight-chain or branched ( _C1 - _C6 ) alkyl or a hydroxyl ( _C1 - _C6 ) alkyl. Alternatively, the substituent pairs ( _R21 , _R21 ') together with the nitrogen atom carrying them form an aromatic or non-aromatic ring consisting of 5 to 7 ring members, wherein the ring may contain 1 to 3 heteroatoms selected from oxygen, sulfur, and nitrogen in addition to the nitrogen atom, wherein the formed ring may be substituted by groups representing hydrogen atoms or straight-chain or branched ( _C1 - _C6 ) alkyl groups. ◆R ₂₂ represents a (C ₁ -C ₆ )alkoxy (C ₁ -C ₆ )alkyl, -(CH ₂ ) _p -NR ₂₄ R ₂₄ ' or -(CH ₂ ) _p -O-(CHR ₁₈ -CHR ₁₉ -O) _q -R ₂₀ group, ◆R ₂₃ represents a hydrogen atom or a ( _C1 - _C6 )alkoxy ( _C1 - _C6 )alkyl atom. Alternatively, the substituent pairs ( _R22 , _R23 ) together with the nitrogen atom carrying them form an aromatic or non-aromatic ring consisting of 5 to 18 ring members, wherein the ring may contain 1 to 5 heteroatoms selected from oxygen, sulfur, and nitrogen in addition to the nitrogen atom, wherein the formed ring may be substituted by groups representing hydrogen atoms, straight-chain or branched ( _C1 - _C6 ) alkyl or heterocyclic alkyl groups. ◆R ₂₄ and R ₂₄ ' independently represent a hydrogen atom or a straight-chain or branched ( _C1 - _C6 ) alkyl group. Alternatively, the substituent pairs ( _R24 , _R24 ') together with the nitrogen atom carrying them form an aromatic or non-aromatic ring consisting of 5 to 7 ring members, wherein the ring may contain 1 to 3 heteroatoms selected from oxygen, sulfur, and nitrogen in addition to the nitrogen atom, wherein the formed ring may be substituted by groups representing hydrogen atoms or straight-chain or branched ( _C1 - _C6 ) alkyl groups. ◆n is an integer equal to 0 or 1. ◆p is an integer equal to 0, 1, or 2. ◆q is an integer equal to 1, 2, 3, or 4. ◆r and s are independent integers equal to 0 or 1. The conditions are that _R15 , _R16 , and _R17 cannot all represent hydrogen atoms, and when _R1 represents a methyl group, _R15 cannot represent a methoxy or ethoxy group. in: - "Aryl" refers to phenyl, naphthyl, biphenyl, indene, or indene. - "Heteroaryl" refers to any monocyclic or bicyclic group consisting of 5 to 10 ring members, having at least one aromatic moiety and containing 1 to 3 heteroatoms selected from oxygen, sulfur, and nitrogen. - "Cycloalkyl" refers to any monocyclic or bicyclic non-aromatic carbocyclic group containing 3 to 10 ring members. - "Heterocyclic alkyl" refers to any monocyclic or bicyclic non-aromatic carbocyclic group containing 3 to 10 ring members and 1 to 3 heteroatoms selected from oxygen, sulfur, and nitrogen, which may include fused ring, bridged ring, or spirocyclic systems. The aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups, as well as alkyl, alkenyl, alkynyl, and alkoxy groups, as defined, can be substituted with one to five groups selected from straight-chain or branched ( _C1 - _C6 ) alkyl, straight-chain or branched ( _C2 - _C6 ) alkenyl, straight-chain or branched ( _{C2 - C6} ) alkoxy, ( _C1 - _C6 ) alkyl- _S- , hydroxyl, oxo, N-oxide, nitro, cyano, -C(O)-OR', -OC(O)-R', -C(O)-NR'R”, -NR'R”, -(C＝NR')-OR”, straight-chain or branched ( _C1 - _C6 ) polyhalogenated alkyl, trifluoromethoxy, or halogen groups, wherein R' and R” independently represent a hydrogen atom or a straight-chain or branched ( _C1 - _C6) group. )alkyl, and one or more carbon atoms of the aforementioned possible substituents may be deuterated. 2. The compound according to claim 1, wherein n is an integer equal to 1. 3. The compound according to claim 1, wherein R ₁₄ represents a hydrogen atom, a hydroxyl group, a hydroxymethyl group, or a hydroxyethyl group. 4. The compound according to claim 1, wherein _R4 and _R5 represent hydrogen atoms. 5. The compound according to claim 1, wherein... represent _R1 , _R10 and _R10 ' are as defined in claim 1. 6. The compound according to claim 1, wherein represent Wherein R ₁₀ and R ₁₀ ' are as defined in claim 1. 7. The compound according to claim 1, wherein the substituent pairs ( _R1 , _R5 ) are identical and the substituent pairs ( _R2 , _R4 ) are identical. 8. The compound according to claim 1, wherein represent R ₁₁ is as defined in claim 1. 9. The compound according to claim 1, wherein _R8 represents a hydrogen atom, a -CHR _{a Rb} group, a straight-chain or branched ( _C1 - _C8 ) alkyl or heteroarylalkyl ( _C1 - _C6 ). 10. The compound of claim 1, wherein R ₁₁ represents -Cy ₅ -alkyl(C ₀ -C ₆ )-Cy ₆ . 11. The compound of claim 1, wherein Cy ₅ represents pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl or pyridinyl. 12. The compound according to claim 1, wherein Cy ₆ represents _R15 , _R16 and _R17 are as defined in claim 1. 13. The compound according to claim 1, wherein R ₁₆ and R ₁₇ represent hydrogen atoms and R ₁₅ represents a -(CH ₂ ) _p -O-(CHR ₁₈ -CHR ₁₉ -O) _q -R ₂₀ group; a straight-chain or branched (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkyl group; a -Y-(CH ₂ ) _q -NR ₂₁ R ₂₁ 'group; or a -(CH ₂ ) _r -Y-(CH ₂ ) _s - heterocyclic alkyl group. 14. The compound according to claim 1, wherein R ₁₅ and R ₁₇ represent hydrogen atoms and R ₁₆ represents a hydroxyl group; hydroxyl (C ₁ -C ₆ )alkyl; -(CH ₂ ) _r -Y-(CH ₂ ) _s -heterocyclic alkyl; -OP(O)(OR ₂₀ ) ₂ group; -OP(O)( ^O- ) ₂ group; -(CH ₂ ) _p -O-(CHR ₁₈ -CHR ₁₉ -O) _q -R ₂₀ group; -(CH ₂ ) _p -OC(O)-NR ₂₂ R ₂₃ group; (CH ₂ ) _r -YXOP(O)(OR ₂₀ ) ₂ group or -Y-(CH ₂ ) _q -NR ₂₁ R ₂₁ ' group. 15. The compound according to claim 1, wherein R ₁₅ and R ₁₆ represent hydrogen atoms and R ₁₇ represents -(CH ₂ ) _p -O-(CHR ₁₈ -CHR ₁₉ -O) _q -R ₂₀ group; -OP(O)(OR ₂₀ ) ₂ group; -OP(O)(O ^- ) ₂ group; hydroxyl group; hydroxyl (C ₁ -C ₆ ) alkyl group; -(CH ₂ ) _r -Y-(CH ₂ ) _s -heterocyclic alkyl group; -Y-(CH ₂ ) _q -NR ₂₁ R ₂₁ 'group; or aldonic acid. 16. Compounds, selected from: -(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(3-hydroxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propionic acid; -(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(4-hydroxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propionic acid; -(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-({2-[3-(hydroxymethyl)phenyl]pyrimidin-4-yl}methoxy)phenyl]propionic acid; -(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-({2-[4-(hydroxymethyl)phenyl]pyrimidin-4-yl}methoxy)phenyl]propionic acid; -(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{2-[(2,2-dimethyl-1,3-dioxacyclopentan-4-yl)methoxy]phenyl}pyrimidin-4-yl)methoxy]phenyl}propionic acid; -(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{2-[2-(2-methoxyethoxy)ethoxy]phenyl}pyrimidin-4-yl)methoxy]phenyl}propionic acid; -(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}phenyl)pyrimidin-4-yl]methoxy}phenyl)propionic acid; -(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-({2-[2-(methoxymethyl)phenyl]pyrimidin-4-yl}methoxy)phenyl]propionic acid; -(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{2-[(2-methoxyethoxy)methyl]phenyl}pyrimidin-4-yl)methoxy]phenyl}propionic acid; -(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{2-[(2-hydroxyethoxy)methyl]phenyl}pyrimidin-4-yl)methoxy]phenyl}propionic acid; -(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-{[(2,2-dimethyl-1,3-dioxacyclopentan-4-yl)methoxy]methyl}phenyl)pyrimidin-4-yl]methoxy}phenyl)propionic acid; -(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{3-[(2-hydroxyethoxy)methyl]phenyl}pyrimidin-4-yl)methoxy]phenyl}propionic acid; -(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{3-[(1,3-dimethoxyprop-2-yl)oxy]phenyl}pyrimidin-4-yl)methoxy]phenyl}propionic acid; -(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{4-[(1,3-dimethoxyprop-2-yl)oxy]phenyl}pyrimidin-4-yl)methoxy]phenyl}propionic acid; -(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-({2-[4-(2,3-dihydroxypropoxy)phenyl]pyrimidin-4-yl}methoxy)phenyl]propionic acid; -Methyl 6-O-{3-[4-({2-[(2R)-2-carboxy-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}ethyl]phenoxy}methyl)pyrimidin-2-yl]phenyl}-α-D-mannopyranoside; -Methyl 6-O-{3-[4-({2-[(2R)-2-carboxy-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}ethyl]phenoxy}methyl)pyrimidin-2-yl]phenyl}-2,3,4-tri-O-methyl-α-D-mannopyranoside; -Methyl 6-O-{4-[4-({2-[(2R)-2-carboxy-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}ethyl]phenoxy}methyl)pyrimidin-2-yl]phenyl}-α-D-mannopyranoside; -Methyl 6-O-{4-[4-({2-[(2R)-2-carboxy-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}ethyl]phenoxy}methyl)pyrimidin-2-yl]phenyl}-2,3,4-tri-O-methyl-α-D-mannopyranoside; -6-O-{4-[4-({2-[(2R)-2-carboxyl-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}ethyl]phenoxy}methyl)pyrimidin-2-yl]phenyl}-D-mannopyranose; -6-O-{2-[4-({2-[(2R)-2-carboxyl-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}ethyl]phenoxy}methyl)pyrimidin-2-yl]phenyl}-D-mannonic acid; -1,2-O-[(1R)-1-({4-[4-({2-[(2R)-2-carboxyl-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}ethyl]phenoxy}methyl)pyrimidin-2-yl]benzyl}oxy)ethide]-β-D-mannopyranose; -(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{4-[(α-D-mannopyranosyloxy)methyl]phenyl}pyrimidin-4-yl)methoxy]phenyl}propionic acid; -(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-({2-[4-(2-hydroxyethyl)phenyl]pyrimidin-4-yl}methoxy)phenyl]propionic acid; -(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-({2-[2-(2,3-dihydroxypropoxy)phenyl]pyrimidin-4-yl}methoxy)phenyl]propionic acid; -(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-({2-[2-(2-(2-hydroxyethoxy)phenyl]pyrimidin-4-yl}methoxy)phenyl]propionic acid; -(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{2-[(2,3-dihydroxypropoxy)methyl]phenyl}pyrimidin-4-yl)methoxy]phenyl}propionic acid; -(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-({2-[3-(phosphonooxy)phenyl]pyrimidin-4-yl}methoxy)phenyl]propionic acid; -4-(4-({2-[(2R)-2-carboxy-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}ethyl]phenoxy}methyl)pyrimidin-2-yl]phenyl ester; -(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-({2-[3-(2-hydroxyethoxy)phenyl]pyrimidin-4-yl}methoxy)phenyl]propionic acid; -(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{4-[2-(2-methoxyethoxy)ethoxy]phenyl}pyrimidin-4-yl)methoxy]phenyl}propionic acid; -(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{4-[2-(2-hydroxyethoxy)ethoxy]phenyl}pyrimidin-4-yl)methoxy]phenyl}propionic acid; -(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(4-{2-[2-(2-(2-methoxyethoxy)ethoxy]ethoxy}phenyl)pyrimidin-4-yl]methoxy}phenyl)propionic acid; -(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{4-[2-(dimethylamino)ethoxy]phenyl}pyrimidin-4-yl)methoxy]phenyl}propionic acid; -(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{3-[(2,2-dimethyl-1,3-dioxacyclopentan-4-yl)methoxy]phenyl}pyrimidin-4-yl)methoxy]phenyl}propionic acid; -(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-({2-[3-(15-hydroxy-3-oxo-2,7,10,13-tetraoxa-4-azapentadecan-1-yl)phenyl]pyrimidin-4-yl}methoxy)phenyl]propionic acid; -(2R)-3-(2-{[2-(3-{[(1,4'-bipiperidin-1'-ylcarbonyl)oxy]methyl}phenyl)pyrimidin-4-yl]methoxy}phenyl)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propionic acid; -(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(3-{2-[2-(2-(2-hydroxyethoxy)ethoxy]ethoxy}phenyl)pyrimidin-4-yl]methoxy}phenyl)propionic acid; -(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{3-[2-(2-hydroxyethoxy)ethoxy]phenyl}pyrimidin-4-yl)methoxy]phenyl}propionic acid; -(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{3-[2-(2-methoxyethoxy)ethoxy]phenyl}pyrimidin-4-yl)methoxy]phenyl}propionic acid; -(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{3-[({[2-(4-methylpiperazin-1-yl)ethyl]carbamoyl}oxy)methyl]phenyl}pyrimidin-4-yl)methoxy]phenyl}propionic acid; -(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{3-[({[2-(morpholin-4-yl)ethyl]carbamoyl}oxy)methyl]phenyl}pyrimidin-4-yl)methoxy]phenyl}propionic acid; -(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{3-[({[2-(dimethylamino)ethyl]carbamoyl}oxy)methyl]phenyl}pyrimidin-4-yl)methoxy]phenyl}propionic acid; -(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{3-[({[2-(pyrrolidin-1-yl)ethyl]carbamoyl}oxy)methyl]phenyl}pyrimidin-4-yl)methoxy]phenyl}propionic acid; -(2R)-3-[2-({2-[3-({[di(2-methoxyethyl)carbamoyl]oxy}methyl)phenyl]pyrimidin-4-yl}methoxy)phenyl]-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propionic acid; -(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(3-{[(1,4,7,10,13-pentaoxa-16-azacyclooctadecane-16-ylcarbonyl)oxy]methyl}phenyl)pyrimidin-4-yl]methoxy}phenyl)propionic acid; -(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-({2-[3-(2,3-dihydroxypropoxy)phenyl]pyrimidin-4-yl}methoxy)phenyl]propionic acid; -(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(3-{2-[2-(2-(2-methoxyethoxy)ethoxy]ethoxy}phenyl)pyrimidin-4-yl]methoxy}phenyl)propionic acid; -(2R)-3-(2-{[2-(3-{2-[di(2-hydroxyethyl)amino]ethoxy}phenyl)pyrimidin-4-yl]methoxy}phenyl)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propionic acid; -(2R)-2-{[(5S _a )-5-{2,3-dimethyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{3-[({[2-(piperidin-1-yl)ethyl]carbamoyl}oxy)methyl]phenyl}pyrimidin-4-yl)methoxy]phenyl}propionic acid; -(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{3-[2-(morpholin-4-yl)ethoxy]phenyl}pyrimidin-4-yl)methoxy]phenyl}propionic acid; -(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{3-[2-(dimethylamino)ethoxy]phenyl}pyrimidin-4-yl)methoxy]phenyl}propionic acid; -(2R)-3-(2-{[2-(4-{2-[di(2-hydroxyethyl)amino]ethoxy}phenyl)pyrimidin-4-yl]methoxy}phenyl)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propionic acid; -(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(4-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}phenyl)pyrimidin-4-yl]methoxy}phenyl)propionic acid; -(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{4-[(2,2-dimethyl-1,3-dioxacyclopentan-4-yl)methoxy]phenyl}pyrimidin-4-yl)methoxy]phenyl}propionic acid; -(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{4-[2-(morpholin-4-yl)ethoxy]phenyl}pyrimidin-4-yl)methoxy]phenyl}propionic acid; Disodium salt of 4-[4-({2-[(2R)-2-carboxy-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}ethyl]phenoxy}methyl)pyrimidin-2-yl]phenyl ester; -(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thiopheno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2-{3-[(1,3-dimethoxypropyl-2-yl)oxy]phenyl}pyrimidin-4-yl)methoxy]phenyl}propionic acid 1-[(ethoxycarbonyl)oxy]ethyl ester; -(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thiopheno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-({2-[5-(hydroxymethyl)pyridin-3-yl]pyrimidin-4-yl}methoxy)phenyl]propionic acid; and -(2R)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thiopheno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2'-(hydroxymethyl)-2,5'-bipyrimidin-4-yl]methoxy}phenyl)propionic acid. 17. A method for preparing the compound of formula (I) according to claim 1, characterized in that the compound of formula (II) is used as a starting material: Where A is as defined with respect to formula (I), where 1 is connected to a chlorine atom and 2 is connected to a bromine atom, coupling the compound of formula (II) with the compound of formula (III): Where _R6 , _R7 , _R14 and n are as defined with respect to formula (I), and Alk represents a straight-chain or branched ( _C1 - _C6 ) alkyl group. Compounds of formula (IV): Where _R6 , _R7 , _R14 , A and n are as defined with respect to equation (I) and Alk is as defined above. The compound of formula (IV) is further coupled with the compound of formula (V): _R1 , _R2 , _R3 , _R4 , and _R5 are as defined with respect to formula (I), and _RB1 and _RB2 represent hydrogen atoms, straight-chain or branched ( _C1 - _C6 ) alkyl groups, or _RB1 and _RB2 form optionally methylated rings with the oxygen carrying them. Compounds of formula (VI): Where _R1 , _R2 , _R3 , _R4 , _R5 , _R6 , _R7 , _R14 , A and n are as defined with respect to equation (I) and Alk is as defined above. Hydrolysis of the Alk-OC(O)-ester functional group of compound (VI) yields a carboxylic acid, which may optionally be reacted with an alcohol of formula _R8' -OH or a chlorinated compound of formula _R8' -Cl, wherein _{R8 '} represents a straight-chain or branched ( _C1 - _C8 ) alkyl, _-CHRaRb group, aryl, heteroaryl, aralkyl ( _C1 - _C6 ) group, or heteroarylalkyl ( _C1 - _C6 ) group, and _Ra and _Rb are as defined with respect to formula (I). Compounds of formula (I) can be purified using conventional separation techniques, if necessary, by conversion to their addition salts with pharmaceutically acceptable acids or bases, and optionally by separation into their isomers using conventional separation techniques. During the above process, at any time deemed suitable, some groups of the raw materials, reagents, or synthetic intermediates may be protected as needed for the synthesis, and subsequently deprotected and functionalized. 18. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 16, or an addition salt thereof with a pharmaceutically acceptable acid or base, and one or more pharmaceutically acceptable excipients. 19. The pharmaceutical composition according to claim 18, used as an apoptosis-promoting agent. 20. The pharmaceutical composition of claim 19, for treating cancer, autoimmune diseases, and immune system disorders. 21. The pharmaceutical composition of claim 20, for the treatment of bladder cancer, brain cancer, breast cancer and uterine cancer, chronic lymphocytic leukemia, colon cancer, esophageal cancer and liver cancer, primitive lymphocytic leukemia, acute myeloid leukemia, lymphoma, melanoma, hematologic malignancies, myeloma, ovarian cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer and small cell lung cancer. 22. Use of the pharmaceutical composition according to claim 18 in the preparation of a medicament used as an apoptosis-promoting agent. 23. Use of the pharmaceutical composition of claim 18 in the preparation of a medicament for treating cancer, autoimmune diseases and immune system disorders. 24. Use of the pharmaceutical composition according to claim 18 in the preparation of a medicament for treating the following diseases: bladder cancer, brain cancer, breast cancer and uterine cancer, chronic lymphocytic leukemia, colon cancer, esophageal cancer and liver cancer, primitive lymphocytic leukemia, acute myeloid leukemia, lymphoma, melanoma, hematologic malignancies, myeloma, ovarian cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer and small cell lung cancer. 25. A compound of formula (I) according to any one of claims 1 to 16, or an addition salt thereof with a pharmaceutically acceptable acid or base, for the treatment of bladder cancer, brain cancer, breast cancer and uterine cancer, chronic lymphocytic leukemia, colon cancer, esophageal cancer and liver cancer, primitive lymphocytic leukemia, acute myeloid leukemia, lymphoma, melanoma, hematologic malignancies, myeloma, ovarian cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer and small cell lung cancer. 26. Use of a compound of formula (I) according to any one of claims 1 to 16, or an addition salt thereof with a pharmaceutically acceptable acid or base, in the preparation of a medicament for treating bladder cancer, brain cancer, breast cancer and uterine cancer, chronic lymphocytic leukemia, colon cancer, esophageal cancer and liver cancer, primitive lymphocytic leukemia, acute myeloid leukemia, lymphoma, melanoma, hematologic malignancies, myeloma, ovarian cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer and small cell lung cancer. 27. A combination product of a compound of formula (I) according to any one of claims 1 to 16 and an anticancer drug, wherein the anticancer drug is selected from genotoxic agents, mitotic inhibitors, antimetabolites, proteasome inhibitors, kinase inhibitors and antibodies. 28. A pharmaceutical composition comprising the combination product of claim 27 and one or more pharmaceutically acceptable excipients. 29. A combination product according to claim 27 for the treatment of cancer. 30. Use of the combination product according to claim 27 in the preparation of a medicament for treating cancer. 31. A compound of formula (I) according to any one of claims 1 to 16 for the treatment of cancers requiring radiotherapy.