Pyrrolotriazinone derivatives as inhibitors P13K

Patent metadata

Field	Value
Publication number	US-9340547-B2
Application number	US-201214114541-A
Country	US
Kind code	B2
Filing date	Apr 26, 2012
Priority date	Apr 29, 2011
Publication date	May 17, 2016
Grant date	May 17, 2016

Abstract

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

First claim

The invention claimed is:

1. A compound of formula (I), or a pharmaceutically acceptable salt, or solvate, or N-oxide, or stereoisomer thereof;

wherein,
X is chosen from a nitrogen atom or a —CR 6 group;
n is chosen from 0, 1, 2 or 3;
R a and R b independently are chosen from a hydrogen atom, a C 1 -C 4 haloalkyl group, a C 1 -C 4 hydroxyalkyl group or a linear or branched C 1 -C 4 alkyl group;
R 1 is chosen from a hydrogen atom, a linear or branched C 1 -C 4 alkyl group, a C 1 -C 4 haloalkyl group, a C 3 -C 10 cycloalkyl group, a C 3 -C 10 cycloalkenyl group, a monocyclic or bicyclic C 6 -C 14 aryl group, a 5- to 14-membered monocyclic or bicyclic heteroaryl group containing at least one heteroatom chosen from O, S and N, or a 5- to 14-membered monocyclic or bicyclic heterocyclyl group containing at least one heteroatom chosen from O, S and N,
wherein the cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by at least one substituent chosen from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C 1 -C 4 alkyl group, a C 1 -C 4 haloalkyl group, a C 1 -C 4 hydroxyalkyl group, a C 3 -C 4 cycloalkyl group, a —(CH 2 ) 1-3 CN group, a —(CH 2 ) 0-3 OR 8 group, a —(CH 2 ) 0-3 NR 7 R 8 group, a —C(O)—(CH 2 ) 1-3 —CN group, a —C(O)—(CH 2 ) 0-3 —R 8 group, a —C(O)—(CH 2 ) 0-3 —NR 7 R 8 group, a —S(O) 2 (CH 2 ) 0-3 R 8 group, a —S(O) 2 (CH 2 ) 0-3 NR 7 R 8 group or a —(CH 2 ) 0-3 (phenyl)-OR 8 group;

R 2 and R 3 independently are chosen from a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a C 1 -C 4 alkoxy group, a C 1 -C 4 haloalkyl group, a C 1 -C 4 hydroxyalkyl group, a C 3 -C 7 cycloalkyl group, a —NR′R″ group, or a linear or branched C 1 -C 6 alkyl group, wherein the alkyl group is unsubstituted or substituted by at least one substituent chosen from a C 1 -C 4 alkoxy group, a cyano group or a C 3 -C 7 cycloalkyl group;
R 4 is chosen from a hydrogen atom, a C 1 -C 4 alkoxy group, a C 1 -C 4 haloalkyl group, a C 1 -C 4 hydroxyalkyl group, a C 3 -C 7 cycloalkyl group, a —(CH 2 ) 1-4 NR′R″ group, or a linear or branched C 1 -C 4 alkyl group, wherein the alkyl group is unsubstituted or substituted by at least one substituent chosen from a C 1 -C 4 alkoxy group, a cyano group, a C 3 -C 4 cycloalkyl group, a —C(O)—(CH 2 ) 0-3 —R′ group or a —C(O)—(CH 2 ) 0-3 —NR′R″ group;
R 6 is chosen from a hydrogen atom, halogen atom, a hydroxyl group, a cyano group, a C 1 -C 4 alkoxy group, a C 1 -C 4 haloalkyl group, a linear or branched C 1 -C 4 hydroxyalkyl group, a C 3 -C 7 cycloalkyl group, a —(CH 2 ) 0-3 NR′R″ group, a —(CH 2 ) 1-3 O(C 1 -C 4 alkyl group), a —(CH 2 ) 0-3 OC(O)—(C 1 -C 4 alkyl group), a —(CH 2 ) 0-3 C(O)O—(C 1 -C 4 alkyl group), a —C(O)—(CH 2 ) 0-3 —NR′R″ group, a —(CH 2 ) 0-3 C(O)OH group, a —(CH 2 ) 0-3 -(5- to 14-membered monocyclic or bicyclic heteroaryl group containing at least one heteroatom chosen from O, S and N), a —(CH 2 ) 0-3 —(5- to 14-membered monocyclic or bicyclic heterocyclyl group containing at least one heteroatom chosen from O, S and N), or a linear or branched C 1 -C 4 alkyl group, wherein the alkyl group is unsubstituted or substituted by at least one substituent chosen from a C 1 -C 4 alkoxy group, a cyano group or a C 3 -C 4 cycloalkyl group,
wherein the heteroaryl and heterocyclyl groups are unsubstituted or substituted by at least one substituents chosen from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C 1 -C 4 alkyl group or a C 1 -C 4 haloalkyl group;

R 7 and R 8 independently are chosen from a hydrogen atom, a C 1 -C 4 haloalkyl group, a C 1 -C 4 hydroxyalkyl group or a linear or branched C 1 -C 4 alkyl group, wherein the alkyl group is unsubstituted or substituted by at least one substituent chosen from a C 1 -C 4 alkoxy group, a cyano group or a C 3 -C 4 cycloalkyl group;
R′ and R″ independently are chosen from a hydrogen atom, a hydroxyl group, a C 1 -C 4 alkoxy group or a linear or branched C 1 -C 4 alkyl group;
R 5 is chosen from:

i) a group of formula (IIb-1),

ii) a group of formula (IIb-2),

iii) a group of formula (IIb-3),

iv) a group of formula (IIb-4), and

v) a group of formula (IIb-5),

wherein
Y is chosen from a —NR′— group, —O— or —S—;
(*) represents a point of attachment of R 5 to the remainder of formula (I); and
R 13 , R 14 , R 15 and R 16 independently are chosen from a hydrogen atom, a halogen atom, a C 1 -C 4 alkoxy group, a C 1 -C 4 haloalkyl group, a C 1 -C 4 hydroxyalkyl group, a C 3 -C 4 cycloalkyl group, a —(CH 2 ) 0-3 CN group, a —C(O)—(CH 2 ) 1-3 —CN group, a —C(O)—(CH 2 ) 0-3 —R′ group, a —C(O)—(CH 2 ) 0-3 —NR′R″, a —(CH 2 ) 0-3 NR′R″ group, or a linear or branched C 1 -C 4 alkyl group, wherein the alkyl group is unsubstituted or substituted by at least one substituent chosen from a C 1 -C 4 alkoxy group, a cyano group or a C 3 -C 4 cycloalkyl group.

2. The compound according to claim 1 , wherein
R 1 is chosen from a linear or branched C 1 -C 4 alkyl group, a C 3 -C 10 cycloalkyl group, a C 3 -C 10 cycloalkenyl group, a monocyclic or bicyclic C 6 -C 14 aryl group, a 5- to 14-membered monocyclic or bicyclic heteroaryl group containing at least one heteroatom chosen from O, S and N, or a 5- to 14-membered monocyclic or bicyclic heterocyclyl group containing at least one heteroatom chosen from O, S and N,
wherein the cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by at least one substituents chosen from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C 1 -C 4 alkyl group, a C 1 -C 4 haloalkyl group, a C 1 -C 4 hydroxyalkyl group, a C 3 -C 4 cycloalkyl group, a —(CH 2 ) 1-3 CN group, a —(CH 2 ) 0-3 OR 8 group, a —(CH 2 ) 0-3 NR 7 R 8 group, a —C(O)—(CH 2 ) 1-3 —CN group, a —C(O)—(CH 2 ) 0-3 —R 8 group, a —C(O)—(CH 2 ) 0-3 —NR 7 R 8 group, a —S(O) 2 (CH 2 ) 0-3 R 8 group or a —S(O) 2 CH 2 ) 0-3 NR 7 R 8 group;

R 6 is chosen from a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a C 1 -C 4 alkoxy group, a C 1 -C 4 haloalkyl group, a C 1 -C 4 hydroxyalkyl group, a C 3 -C 7 cycloalkyl group, a —(CH 2 ) 0-3 NR′R″ group, or a linear or branched C 1 -C 4 alkyl group, wherein the alkyl group is unsubstituted or substituted by at least one substituent chosen from a C 1 -C 4 alkoxy group, a cyano group or a C 3 -C 4 cycloalkyl group;
R 13 , R 14 , R 15 and R 16 independently are chosen from a hydrogen atom, a C 1 -C 4 alkoxy group, a C 1 -C 4 haloalkyl group, a C 1 -C 4 hydroxyalkyl group, a C 3 -C 4 cycloalkyl group, a —(CH 2 ) 0-3 CN group, a —C(O)—(CH 2 ) 1-3 —CN group,
a —C(O)—(CH 2 ) 0-3 —R′ group, a —C(O)—(CH 2 ) 0-3 —NR′R″, a —(CH 2 ) 0-3 NR′R″ group, or a linear or branched C 1 -C 4 alkyl group, wherein the alkyl group is unsubstituted or substituted by at least one substituent chosen from a C 1 -C 4 alkoxy group, a cyano group or a C 3 -C 4 cycloalkyl group.

3. The compound according to claim 1 , wherein R 1 is chosen from a hydrogen atom, C 1 -C 3 a

Assignees

• Bernal Anchuela Francisco Javier
• Carrascal Riera Marta
• Caturla Javaloyes Juan Francisco
• Gracia Ferrer Jordi
• Matassa Victor Giulio
• Terricabras Belart Emma
• Taltavull Moll Joan
• Erra Sola Montserrat
• Almirall Sa

Inventors

• Bernal Anchuela Francisco Javier
• Carrascal Riera Marta
• Caturla Javaloyes Juan Francisco
• Gracia Ferrer Jordi
• Matassa Victor Giulio
• Terricabras Belart Emma
• Taltavull Moll Joan
• Erra Sola Montserrat

Classifications

• A61P5/00

  Drugs for disorders of the endocrine system · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title