PYRROLOTRIAZINONE DERIVATIVES AS PI3K INHIBITORS

摘要

New pyrrolotriazinone derivatives having the chemical structure of Formula (I) are disclosed; as well as process for theft preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of Phosphoinositide 3-Kinases (PI3Ks).;

主权项

1. A compound of Formula (I), or a pharmaceutically acceptable salt, N-oxide, isotopically-labeled derivate thereof, comprising: wherein: n is 0, 1, 2 or 3; Ra and Rb are independently chosen from a hydrogen atom, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, and a linear or branched C1-C4 alkyl group; R1 is chosen from a C3-C13 cycloalkyl group, a C3-C10 group; a phenyl group; a 5- to 7-membered heteroaryl group containing at least one heteroatom chosen from O, S, and N; and a 5- to 7-membered heterocyclyl group containing at least one heteroatom chosen from O, S, and N; wherein the cycloalkyl, cycloalkenyl, phenyl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents chosen from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, and a C3-C4 cycloalkyl group, R2 and R3 are independently chosen from a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C4 cycloalkyl group, a C1-C4 alkoxy group, a —NH2 group, a —N(CH3)H group, and a —N(CH3)2 group; R7 and R8 are independently chosen from a hydrogen atom, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, and a linear or branched C1-C4 alkyl group; and a) R4 is chosen from a hydrogen atom, a C1-C4 alkoxy group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a —(CH2)0-3—S—(CH2)0-3-(phenyl group), a —(CH2)0-3—S—(CH2)0-3-(5- to 14-membered monocyclic or bicyclic heteroaryl group containing at least one heteroatom chosen from O, S, and N), a —(CH2)0-3—O—(CH2)0-3-(phenyl group), a —(CH2)0-3—O—(CH2)0-3-(5- to 14-membered monocyclic or bicyclic heteroaryl group containing at least one heteroatom chosen from O, S, and N), a —(CH2)0-3-(phenyl group), a —(CH2)0-3-(5- to 14-membered monocyclic or bicyclic heteroaryl group containing at least one heteroatom chosen from O, S, and N), and a linear or branched C1-C4 alkyl group, said alkyl group is unsubstituted or substituted by one or more substituents selected from a C1-C4 alkoxy group, a cyano group, a C3-C4 cycloalkyl group, a —C(O)—(CH2)0-3—R8 group, and a —C(O)—(CH2)0-3—NR7R8 group; wherein the phenyl and heteroaryl groups are unsubstituted or substituted by one or more substituents chosen from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, and a C1-C4 alkoxy group; R6 is chosen from a hydrogen atom; a halogen atom; a hydroxyl group; a cyano group; a C1-C4 alkoxy group; a C1-C4 haloalkyl group; a linear or branched C1-C4 hydroxyalkyl group; a C3-C7 cycloalkyl group; a —(CH2)0-3NR7R8 group; a —(CH2)1-3—O(C1-C4 alkyl group); a —(CH2)0-3—OC(O)—(C1-C4 alkyl group); a —(CH2)0-3—C(O)O—(C1-C4 alkyl group); a —C(O)—(CH2)0-3—NR7R8 group; a —(CH2)0-3—C(O)OH group; a —(CH2)0-3—S—(CH2)0-3-(phenyl group); a —(CH2)0-3—S—(CH2)0-3-(5- to 14-membered monocyclic or bicyclic heteroaryl group containing at least one heteroatom selected from O, S and N); a —(CH2)0-3—O—(CH2)0-3-(phenyl group); a —(CH2)0-3—O—(CH2)0-3-(5- to 14-membered monocyclic or bicyclic heteroaryl group containing at least one heteroatom chosen from O, S, and N); a —(CH2)0-3-(phenyl group); a —(CH2)0-3-(5- to 14-membered monocyclic or bicyclic heteroaryl group containing at least one heteroatom chosen from O, S, and N); a —(CH2)0-3-(5- to 14-membered monocyclic or bicyclic heterocyclyl group containing at least one heteroatom chosen from O, S, and N); a C2-C4 alkynyl group or a linear or branched C1-C4 alkyl group, said alkyl group is unsubstituted or substituted by one or more substituents chosen from a C1-C4 alkoxy group, a cyano group; and a C3-C4 cycloalkyl group; wherein the phenyl, heteroaryl, heterocyclyl and alkynyl groups are unsubstituted or substituted by one or more substituents chosen from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 alkoxy group, a —(CH2)0-3—NR7—(CH2)0-3—NR7R8 group, a —(CH2)0-3—C(O)—(CH2)0-3-(5- to 7-membered heteroaryl group containing at least one heteroatom chosen from O, S, and N), and a —(CH2)0-3-(5- to 7-membered heterocyclyl group containing at least one heteroatom chosen from O, S, and N); wherein the heteroaryl and heterocyclyl groups are unsubstituted or substituted by one or more substituents chosen from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, and a C1-C4 alkoxy group; R5 has formula (II-1), (II-2), (II-3), or (II-4): wherein:
R9, R11, R13, R14 and R15 are independently chosen from a hydrogen atom, a —(CH2)0-3CN group, a —(CH2)0-3NR′R″ group, and a linear or branched C1-C4 alkyl group; wherein R′ and R″ are independently chosen from a hydrogen atom, a hydroxyl group, a C1-C4 alkoxy group, a C1-C4 hydroxyalkyl group or a linear, and branched C1-C4 alkyl group;R10 and R12 are independently chosen from a phenyl group, or a 5- to 14-membered heteroaryl group containing at least one heteroatom chosen from O, S, and N, wherein the phenyl and heteroaryl groups are unsubstituted or substituted by one or more substituents chosen from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a linear or branched C1-C6 hydroxyalkyl group, a C3-C7 cycloalkyl group, a —(CH2)0-3-(phenyl group), a —(CH2)0-3-(5- to 14-membered heteroaryl group containing at least one heteroatom chosen from O, S, and N), a —(CH2)0-3-(5- to 14-membered heterocyclyl group containing at least one heteroatom chosen from O, S, and N), a —(CH2)1-3CN group, a —(CH2)0-3—O—(CH2)0-3—R′ group, a —C(O) group, a —(CH2)0-3 NR′R″ group, a —(CH2)0-3—C(O)—(CH2)1-3—CN group, a —(CH2)0-3—C(O)OH group, a —(CH2)0-3—C(O)—(CH2)0-3—R′ group, a —(CH2)0-3—C(O)—(CH2)0-3—NR′R″ group, a —(CH2)0-3NR′—C(O)—(CH2)0-3—NR′R″ group, a —(CH2)0-3NR′—C(O)—(CH2)0-3—R″ group, a —(CH2)0-3NR′—S(O)2—(CH2)0-3—R″ group, a —(CH2)0-3NR′—SO2—(CH2)0-3—NR′R″ group, a —(CH2)0-3—S(O)2—(CH2)0-3—R″ group, and a —(CH2)0-3—S(O)2(CH2)0-3NR′R″ group; wherein the phenyl, heterocyclyl, and heteroaryl groups are unsubstituted or substituted by one or more substituents chosen from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, a —NH2 group, a —NH(C1-C4 alkyl) group, a —N(C1-C4 alkyl)2 group, and a linear or branched C1-C6 hydroxyalkyl group; and wherein R′ and R″ are independently chosen from a hydrogen atom; a hydroxyl group; a C1-C4 haloalkyl group; a C1-C4 alkoxy group; a C1-C4 hydroxyalkyl group; a linear or branched C1-C4 alkyl group; a —N(C1-C4 alkyl)2 group; a 5- to 7-membered heteroaryl group containing at least one heteroatom chosen from O, S, and N; a 5- to 7-membered heterocyclyl group containing at least one heteroatom chosen from O, S, and N; a phenyl group, said phenyl group is unsubstituted or substituted by one or more substituents chosen from a halogen atom, a hydroxyl group, a cyano group, a C1-C4 hydroxyalkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, a C3-C4 cycloalkyl group, and a linear or branched C1-C4 alkyl group;
L is chosen from a direct bound or a linker selected from —O—, —S—, a —(CH2)0-3—SO2—(CH2)0-3 group, a —(CH2)0-3—SO2—NR′—(CH2)0-3, a —(CH2)0-3NR′—(CH2)0-3— group, a —C(O)—(CH2)0-3 group, a —C(O)—NR′—(CH2)0-3 group, a —(CH2)0-3NR′—C(O)—(CH2)0-3 group, a —(CH2)0-3—C(O)—O—(CH2)0-3 group, a —(CH2)0-3—O—C(O)—(CH2)0-3 group, and a —(CH2)1-4 group; wherein R′ is chosen from a hydrogen atom and a linear or branched C1-C4 alkyl group;Y is chosen from a —NR′— group; wherein R′ is chosen from a hydrogen atom and a linear or branched C1-C4 alkyl group; or b) R4 is chosen from a —(CH2)0-3—S—(CH2)0-3-(phenyl group), a —(CH2)0-3—S—(CH2)0-3-(5- to 14-membered monocyclic or bicyclic heteroaryl group containing at least one heteroatom chosen from O, S, and N), a —(CH2)0-3—O—(CH2)0-3-(phenyl group), a —(CH2)0-3—O—(CH2)0-3-(5- to 14-membered monocyclic or bicyclic heteroaryl group containing at least one heteroatom chosen from O, S, and N), a —(CH2)0-3-(phenyl group), and a —(CH2)0-3-(5- to 14-membered monocyclic or bicyclic heteroaryl group containing at least one heteroatom chosen from O, S, and N), wherein the phenyl and heteroaryl groups are unsubstituted or substituted by one or more substituents chosen from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, and a C1-C4 alkoxy group; R6 is chosen from a hydrogen atom; a halogen atom; a hydroxyl group; a cyano group; a C1-C4 alkoxy group; a C1-C4 haloalkyl group; a linear or branched C1-C4 hydroxyalkyl group; a C3-C7 cycloalkyl group; a —(CH2)0-3NR7R8 group; a —(CH2)1-3—O(C1-C4 alkyl group); a —(CH2)0-3—OC(O)—(C1-C4 alkyl group); a —(CH2)0-3—C(O)O—(C1-C4 alkyl group); a —C(O)—(CH2)0-3—NR7R8 group; a —(CH2)0-3—C(O)OH group; a —(CH2)0-3—S—(CH2)0-3-(phenyl group); a —(CH2)0-3—S—(CH2)0-3-(5- to 14-membered monocyclic or bicyclic heteroaryl group containing at least one heteroatom chosen from O, S, and N); a —(CH2)0-3—O—(CH2)0-3-(phenyl group); a —(CH2)0-3—O—(CH2)0-3-(5- to 14-membered monocyclic or bicyclic heteroaryl group containing at least one heteroatom chosen from O, S, and N); a —(CH2)0-3-(phenyl group); a —(CH2)0-3-(5- to 14-membered monocyclic or bicyclic heteroaryl group containing at least one heteroatom chosen from O, S, and N); a —(CH2)0-3-(5- to 14-membered monocyclic or bicyclic heterocyclyl group containing at least one heteroatom chosen from O, S, and N); a C2-C4 alkynyl group or a linear or branched C1-C4 alkyl group, said alkyl group is unsubstituted or substituted by one or more substituents chosen from a C1-C4 alkoxy group, a cyano group, and a C3-C4 cycloalkyl group; wherein the phenyl, heteroaryl, heterocyclyl and alkynyl groups are unsubstituted or substituted by one or more substituents chosen from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 alkoxy group, a —(CH2)0-3—NR7—(CH2)0-3—NR7R8 group, a —(CH2)0-3—C(O)—(CH2)0-3-(5- to 7-membered heteroaryl group containing at least one heteroatom chosen from O, S, and N), and a —(CH2)0-3-(5- to 7-membered heterocyclyl group containing at least one heteroatom chosen from O, S, and N); wherein the heteroaryl and heterocyclyl groups are unsubstituted or substituted by one or more substituents chosen from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, and a C1-C4 alkoxy group; R5 has formula (II-1), (II-2), (II-3), (II-4), (II-5), or (II-6): or c) R4 sent is chosen from a hydrogen atom, a C1-C4 alkoxy group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a —(CH2)0-3—S—(CH2)0-3-(phenyl group), a —(CH2)0-3—S—(CH2)0-3-(5- to 14-membered monocyclic or bicyclic heteroaryl group containing at least one heteroatom chosen from O, S, and N), a —(CH2)0-3—O—(CH2)0-3-(phenyl group), a —(CH2)0-3—O—(CH2)0-3-(5- to 14-membered monocyclic or bicyclic heteroaryl group containing at least one heteroatom chosen from O, S, and N), a —(CH2)0-3-(phenyl group), a —(CH2)0-3-(5- to 14-membered monocyclic or bicyclic heteroaryl group containing at least one heteroatom chosen from O, S, and N), and a linear or branched C1-C4 alkyl group, said alkyl group is unsubstituted or substituted by one or more substituents chosen from a C1-C4 alkoxy group, a cyano group, a C3-C4 cycloalkyl group, a —C(O)—(CH2)0-3—R8 group, and a —C(O)—(CH2)0-3—NR7R8 group; wherein the phenyl and heteroaryl groups are unsubstituted or substituted by one or more substituents chosen from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, and a C1-C4 alkoxy group; R6 is chosen from a —(CH2)0-3—S—(CH2)0-3-(phenyl group); a —(CH2)0-3—S—(CH2)0-3-(5- to 14-membered monocyclic or bicyclic heteroaryl group containing at least one heteroatom chosen from O, S, and N); a —(CH2)0-3—O—(CH2)0-3 (phenyl group); a —(CH2)0-3—O—(CH2)0-3-(5- to 14-membered monocyclic or bicyclic heteroaryl group containing at least one heteroatom chosen from O, S, and N); a —(CH2)0-3-(phenyl group); a —(CH2)0-3-(5- to 14-membered monocyclic or bicyclic heteroaryl group containing at least one heteroatom chosen from O, S, and N); a —(CH2)0-3-(5- to 14-membered monocyclic or bicyclic heterocyclyl group containing at least one heteroatom chosen from O, S, and N); and a C2-C4 alkynyl group; wherein the phenyl, heteroaryl, heterocyclyl and alkynyl groups are unsubstituted or substituted by one or more substituents chosen from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 alkoxy group, a —(CH2)0-3—NR7—(CH2)0-3—NR7R8 group, a —(CH2)0-3—C(O)—(CH2)0-3-(5- to 7-membered heteroaryl group containing at least one heteroatom chosen from O, S, and N) or a —(CH2)0-3-(5- to 7-membered heterocyclyl group containing at least one heteroatom chosen from O, S, and N); wherein the heteroaryl and heterocyclyl groups are unsubstituted or substituted by one or more substituents chosen from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, and a C1-C4 alkoxy group; R5 has formula (II-1), (II-2), (II-3), (II-4), (II-5), or (II-6):