Bicyclic pyridine, pyrazine, and pyrimidine derivatives as PI3K beta inhibitors

A compound of Formula (I)

• a tautomer or a stereoisomeric form thereof, wherein
• X1 represents CH;
• X2 represents N;
• Y represents —CH2— or NH—;
• R2 represents
• R3 represents C1-4alkyl;
• —C(═O)—O—C1-4alkyl;
• —C(═O)—Het1;
• —CH(OH)—CH2—Rq;
• C1-4alkyl substituted on the same carbon atom with one OH and with one Het1;
• or C1-4alkyl substituted with one substituent selected from the group consisting of halo, —OH, —NH2, —O—(C═O)—C1-4alkyl, —(C═O)—O—C1-4alkyl, −NH-(C═O)—C1-4alkyl, —NH—(SO2)—C1-4alkyl,
• —N(CH3)—C1-4alkyl-SO2—CH3, —NH—C1-4alkyl-SO2—CH3, —N(CH3)—C1-4alkyl-OH,
• —N(C═O—C1-4alkyl)-C1-4alkyl-OH, —(C═O)—NH—C1-4alkyl-OH,
• —O—(C═O)—CH(NH2)—C1-4alkyl, —O—(C═O)—CH(NH2)—C1-4alkyl-Ar,
• —NH—C1-4alkyl-OH, Het1, —O—C(═O)—C1-4alkyl-Het1, —C(═O)—Het1, and —NH—C(═O)—Het1;
• Rq represents Het1, halo, —OH, —NH2, —O—(C═O)—C1-4alkyl, —NH—(C═O)—C1-4alkyl,
• NH—(SO2)—C7-4alkyl, —N(CH3)—C1-4alkyl-SO2—CH3, —NH—C1-4alkyl-SO2—CH3,
• N(CH3)—C1-4alkyl-OH, —O—(C═O)—CH(NH2)—C1-4alkyl,
• O—(C═O)—CH(NH2)—C1-4alkyl-Ar,
• or —NH—C1-4alkyl-OH;
• Ar represents phenyl optionally substituted with one hydroxy;
• R4a represents hydrogen, C1-4alkyl, Heta, or C1-4alkyl substituted with one or more substituents each independently selected from the group consisting of —OH, —NR5R6 and Heta;
• R4b represents hydrogen, halo, C1-4alkyl, or C1-4alkyl substituted with one or more halo substituents;
• or R4a and R4b are taken together to form together with the phenyl ring to which they are attached a structure of Formula (a-1), (a-2), (a-3), (a-4) or (a-5):
• X represents —NH—, —O—, —N(C1-3alkyl)-, or —N(hydroxyC1-3alkyl)-;
• both R7 substituents are the same and are selected from the group consisting of hydrogen, fluoro and methyl;
• or both R7 substituents are taken together to form together with the common carbon atom to which they are attached a cyclopropyl, cyclobutyl or oxetanyl;
• both R8 substituents are the same and are selected from the group consisting of hydrogen and methyl;
• or both R8 substituents are taken together to form together with the common carbon atom to which they are attached a cyclopropyl, cyclobutyl or oxetanyl;
• R5 represents hydrogen, C1-6alkyl, or C1-6alkyl substituted with one —OH;
• R6 represents hydrogen, C1-6alkyl, or C1-6alkyl substituted with one —OH;
• Het1 represents a 4-, 5- or 6-membered saturated heterocyclyl containing at least one heteroatom each independently selected from O, S, S(═O)p and N;
• said 4-, 5- or 6-membered saturated heterocyclyl is optionally substituted with one or two substituents each independently selected from the group consisting of halo, —NH2, C1-4alkyl,
• —S(═O)2—C1-6alkyl, —C1-4alkyl-S(═O)2—C1-6alkyl hydroxyl, C1-4alkyloxy, fluoro, cyano and C1-4alkyl substituted with one hydroxy;
• or two substituents on the same carbon atom of said 4-, 5- or 6-membered saturated heterocyclyl are taken together to form together with the common carbon atom to which they are attached Ring A;
• Ring A represents cyclobutyl, cyclopentyl, cyclohexyl or a 4-, 5- or 6-membered saturated heterocyclyl containing at least one heteroatom each independently selected from O, S,
• S(═O)p and N;
• said cyclobutyl, cyclopentyl, cyclohexyl or 4-, 5- or 6-membered saturated heterocyclyl is optionally substituted with one or two C1-4alkyl substituents, with one C1-4alkyl and one hydroxy substituent, or with one hydroxy substituent;
• each Heta independently represents a 4-, 5- or 6-membered saturated heterocyclyl containing at least one heteroatom each independently selected from O, S, S(═O)p and N;
• said 4-, 5- or 6-membered saturated heterocyclyl is optionally substituted with one or two substituents each independently selected from the group consisting of C1-4alkyl, —S(═O)2-C1-6alkyl, hydroxy, —C1-4alkyl-S(═O)2—C1-6alkyl, and C1-4alkyl substituted with one hydroxy;
• or two substituents on the same carbon atom of said 4-, 5- or 6-membered saturated heterocyclyl are taken together to form together with the common carbon atom to which they are attached Ring B;
• Ring B represents cyclobutyl, cyclopentyl, cyclohexyl or a 4-, 5- or 6-membered saturated heterocyclyl containing at least one heteroatom each independently selected from O, S, S(═O)p and N;
• said cyclobutyl, cyclopentyl, cyclohexyl or 4-, 5- or 6-membered saturated heterocyclyl is optionally substituted with one or two C1-4alkyl substituents, with one C1-4alkyl and one hydroxy substituent, or with one hydroxy substituent;
• p represents 1 or 2;
• or a N-oxide, a pharmaceutically acceptable addition salt thereof.