Xanthine derivative inhibitors of bet proteins

An inhibitor of a BET protein which is a xanthine derivative compound of general formula (I)

• wherein,
• X is an oxygen atom, —ORa, a sulphur atom, —SRb, a nitrogen atom, —NRa, or —NRcRd;
• wherein Ra, Rb, Rc and Rd each independently represent:
• a hydrogen atom,
• a C1-C6 alkyl, optionally substituted,
• a (C5-C12)aryl-(C1-C6)alkyl, said aryl being optionally substituted, or
• a (C1-C6)alkyl-(C5-C12)aryl, optionally substituted;
• Y is a nitrogen atom, —NReRf, an oxygen atom, ORg or a linker-ligand for the E3 ubiquitin ligase;
• wherein Re, Rf and Rg each independently represent:
• a hydrogen atom,
• a C1-C6 alkyl, optionally substituted,
• a C5-C12 aryl, optionally substituted,
• a (C5-C12)aryl-(C1-C6)alkyl, said aryl being optionally substituted,
• a (C1-C6)alkyl-(C5-C12)aryl, optionally substituted,
• —C(O)ORh, or
• —C(O)Rh;
• R1 represents a hydrogen atom or a lone pair;
• R3 represents:
• a lone pair,
• a hydrogen atom,
• a C1-C6 alkyl, optionally substituted,
• a C5-C12 aryl, optionally substituted,
• a (C5-C12)aryl-(C1-C6)alkyl, said aryl being optionally substituted,
• a (C1-C6)alkyl-(C5-C12)aryl, optionally substituted,
• —C(O)ORi,
• —C(O)Ri, or
• a linker-ligand for the E3 ubiquitin ligase;
• R7 represents:
• a lone pair,
• a hydrogen atom,
• a C1-C6 alkyl, optionally substituted,
• a C5-C12 aryl, optionally substituted,
• a (C5-C12)aryl-(C1-C6)alkyl, said aryl being optionally substituted,
• a (C1-C6)alkyl-(C5-C12)aryl, optionally substituted,
• —C(O)ORj, or
• —C(O)Rj;
• wherein Rh, Ri and Rj each independently represent a hydrogen atom, a C1-C6 alkyl optionally substituted, a C5-C12 aryl optionally substituted, a (C5-C12)aryl-(C1-C6)alkyl optionally substituted, a (C1-C6)alkyl-(C5-C12)aryl optionally substituted, a heteroaryl optionally substituted, an alkylheteroaryl optionally substituted, a heteroarylalkyl optionally substituted;
• R8 is a hydrogen atom, a halogen atom, a C1-C6 alkyl optionally substituted, a linker-ligand for the E3 ubiquitin ligase or -A-B;
• wherein A represents —(—CH2)n, a sulphur atom, —SO2—, —CH2-O—, —CH2—S—, —CH2—SO2—, an oxygen atom, or —N(H)—;
• wherein B represents:
• a hydrogen atom,
• —OH,
• a halogen atom,
• —SH,
• —CO2H,
• a C1-C6 alkyl, optionally substituted,
• a (C5-C12)aryl-(C1-C6)alkyl, optionally substituted,
• a (C1-C6)alkyl-(C5-C12)aryl, optionally substituted,
• a C5-C12 aryl, optionally substituted by one or more:
• C1-C6 alkyl groups,
• oxygen atoms,
• sulphur atoms,
• halogen atoms,
• amino groups,
• (C1-C4)alkanoic acid,
• —S(O2)—(C1-C4)alkyl,
• —S(O2)-piperidine,
• —S(O2)—(N,N)dimethylamine,
• —S(O2)-morpholine,
• nitro groups,
• —C(═O)—O—(C1-C4)alkyl,
• —S(O2)-N(H)—(C1-C4)alkyl,
• oxo-pyrazole optionally substituted by one or more (C1-C4)alkanoic acid, (C1-C4)alkyl, halogen atoms or —OH,
• ketone groups,
• pyrazole optionally substituted by one or more (C1-C4)alkanoic acid, (C1-C4)alkyl, halogen atoms or —OH,
• pyrrolidine optionally substituted by one or more (C1-C4)alkanoic acid, (C1-C4)alkyl, halogen atoms or —OH,
• phenyl,
• benzyl,
• oxy-phenyl,
• oxy-benzyl,
• thiazolidin optionally substituted by one or more (C1-C4)alkanoic acid, (C1-C4)alkyl, halogen atoms or —OH,
• —C(═O)—N(H)-benzyl,
• —N(H)-quinazolinone,
• —OH,
• thiophenyl optionally substituted by one or more (C1-C4)alkanoic acid, (C1-C4)alkyl, halogen atoms or —OH,
• methyl-tetrahydrofuran, or
• CH2-pyrazole optionally substituted by one or more (C1-C4)alkanoic acid, (C1-C4)alkyl, halogen atoms or —OH;
• a (C1-C6)alkyl-heteroaryl, optionally substituted;
• a heteroaryl-(C1-C6)alkyl, optionally substituted;
• a heteroaryl, optionally substituted by one or more:
• C1-C6 alkyl groups,
• halogen atoms,
• oxygen atoms,
• sulphur atoms,
• amino groups
• (C1-C4)alkanoic acid,
• —S(O2)—(C1-C4)alkyl,
• —S(O2)-piperidine,
• —S(O2)—(N,N)dimethylamine,
• —S(O2)-morpholine,
• nitro groups,
• —C(═O)—O—(C1-C4)alkyl,
• —S(O2)—N(H)—(C1-C4)alkyl,
• oxo-pyrazole optionally substituted by one or more (C1-C4)alkanoic acid, (C1-C4)alkyl, halogen atoms or —OH,
• ketone groups,
• pyrazole optionally substituted by one or more (C1-C4)alkanoic acid, (C1-C4)alkyl, halogen atoms or —OH,
• pyrrolidine optionally substituted by one or more (C1-C4)alkanoic acid, (C1-C4)alkyl, halogen atoms or —OH,
• phenyl,
• benzyl,
• oxy-phenyl,
• oxy-benzyl,
• thiazolidin optionally substituted by one or more (C1-C4)alkanoic acid, (C1-C4)alkyl, halogen atoms or —OH,
• —C(═O)—N(H)-benzyl,
• —N(H)-quinazolinone,
• —OH,
• thiophenyl optionally substituted by one or more (C1-C4)alkanoic acid, (C1-C4)alkyl, halogen atoms or —OH,
• methyl-tetrahydrofuran, or
• CH2-pyrazole optionally substituted by one or more (C1-C4)alkanoic acid, (C1-C4)alkyl, halogen atoms or —OH;
• wherein n represents an integer ranging from 0 to 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
• or R7 with R8 taken together form a cycle by forming a covalent bond between a R7 group and R8 group as defined above;
• or a pharmaceutically acceptable salt thereof and/or tautomeric form thereof.