AR093035A1 - PIRROLOTRIAZINONA DERIVATIVES AS PI3K INHIBITORS - Google Patents

PIRROLOTRIAZINONA DERIVATIVES AS PI3K INHIBITORS

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AR093035A1
AR093035A1 ARP130103756A ARP130103756A AR093035A1 AR 093035 A1 AR093035 A1 AR 093035A1 AR P130103756 A ARP130103756 A AR P130103756A AR P130103756 A ARP130103756 A AR P130103756A AR 093035 A1 AR093035 A1 AR 093035A1
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Argentina
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group
alkyl
linear
branched
haloalkyl
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ARP130103756A
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Spanish (es)
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Gracia Ferrer Jordi
Carrascal Riera Marta
Erra Sola Montserrat
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Almirall Sa
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Abstract

Se describen derivados de pirrolotriazinona que tienen la estructura química de fórmula (1); así como un procedimiento para su preparación, composiciones farmacéuticas que los contienen y su uso en terapia como inhibidores de Fosfoinositido 3-quinasas (PI3Ks). Reivindicación 1: Un compuesto de fórmula (1), o una sal farmacéuticamente aceptable, o N-óxido, o derivado isotópicamente marcado del mismo; en donde, n representa 0, 1, 2 ó 3; X representa N o CH; cada uno de Rᵃ y Rᵇ representa independientemente un átomo de hidrógeno, un grupo haloalquilo C₁₋₄, un grupo hidroxialquilo C₁₋₄ o un grupo alquilo lineal o ramificado C₁₋₄; R¹ representa un grupo cicloalquilo C₃₋₁₀, un grupo cicloalquenilo C₃₋₁₀, un grupo arilo monocíclico o bicíclico C₆₋₁₄, un grupo heteroarilo monocíclico o bicíclico de 5 a 14 miembros que contiene al menos un heteroátomo seleccionado de O, S y N, un grupo heterocíclico monocíclico o bicíclico de 5 a 14 miembros que contiene al menos un heteroátomo seleccionado de O, S y N, en donde los grupos cicloalquilo, cicloalquenilo, arilo, heteroarilo y heterociclilo están no sustituidos o sustituidos con uno o más sustituyentes seleccionados de un átomo de halógeno, un grupo hidroxilo, un grupo ciano, un grupo alquilo lineal o ramificado C₁₋₄, un grupo haloalquilo C₁₋₄, un grupo hidroxialquilo C₁₋₄, un grupo cicloalquilo C₃₋₄, un grupo -(CH₂)₁₋₃CN, un grupo -(CH₂)₀₋₃OR⁹, un grupo -(CH₂)₀₋₃NR⁹R¹⁰, un grupo -C(O)-(CH₂)₁₋₃-CN, un grupo -C(O)-(CH₂)₀₋₃-R⁹, un grupo -C(O)-(CH₂)₀₋₃-NR⁹R¹⁰, un grupo -S(CH₂)₀₋₃R⁹, un grupo -S(O)(CH₂)₀₋₃R⁹, un grupo -S(O)(CH₂)₀₋₃NR⁹R¹⁰, un grupo -S(O)₂(CH₂)₀₋₃R⁹, un grupo -S(O)₂(CH₂)₀₋₃NR⁹R¹⁰ o un grupo -(CH₂)₀₋₃(fenil)-OR⁹; cada uno de R² y R³ representa independientemente un átomo de hidrógeno, un átomo de halógeno, un grupo hidroxilo, un grupo ciano, un grupo alquilo C₁₋₄ lineal o ramificado, un grupo haloalquilo C₁₋₄, un grupo hidroxialquilo C₁₋₄, un grupo cicloalquilo C₃₋₄, un grupo alcoxi C₁₋₄, un grupo -NH₂, un grupo -N(CH₃)H, o un grupo -N(CH₃)₂; R⁴ representa un átomo de hidrógeno, un grupo alquilo lineal o ramificado C₁₋₄, un grupo haloalquilo C₁₋₄, un grupo hidroxialquilo C₁₋₄, un grupo -(CH₂)₀₋₃-(cicloalquilo C₃₋₄), un grupo -(CH₂)₀₋₃-O(alquilo C₁₋₄), un grupo -(CH₂)₀₋₃-S-(CH₂)₀₋₃-(fenil), un grupo -(CH₂)₀₋₃-S-(CH₂)₀₋₃-(grupo heteroarilo de 5 a 7 miembros que contiene al menos un heteroátomo seleccionado de O, S y N), un grupo -(CH₂)₀₋₃-O-(CH₂)₀₋₃-(fenil), un grupo -(CH₂)₀₋₃-O-(CH₂)₃-(grupo heteroarilo de 5 a 7 miembros que contiene al menos un heteroátomo seleccionado de O, S y N), en donde los grupos fenilo y heteroarilo están no sustituidos o sustituidos con uno o más sustituyentes seleccionados de un átomo de halógeno, un grupo hidroxilo, un grupo ciano, un grupo alquilo lineal o ramificado C₁₋₄, un grupo haloalquilo C₁₋₄, un grupo hidroxialquilo C₁₋₄ o un grupo alcoxi C₁₋₄; R⁵ representa un átomo de hidrógeno, un átomo de halógeno, un grupo hidroxilo, un grupo ciano, un grupo alquilo lineal o ramificado C₁₋₄, un grupo haloalquilo C₁₋₄, un grupo hidroxialquilo C₁₋₄, un grupo -(CH₂)₀₋₃NR⁹R¹⁰, un grupo -(CH₂)₀₋₃-O(alquilo C₁₋₄), un grupo -(CH₂)₀₋₃-(cicloalquilo C₃₋₄), un grupo alquinilo C₂₋₄, un grupo -(CH₂)₀₋₃-(fenil), un grupo -(CH₂)₀₋₃-(grupo heteroarilo de 5 a 7 miembros que contiene al menos un heteroátomo seleccionado de O, S y N), un grupo -(CH₂)₀₋₃-S(O)₂(CH₂)₀₋₃-R¹¹, un grupo -(CH₂)₀₋₃-S(O)₂(CH₂)₀₋₃-(fenil), un grupo -(CH₂)₀₋₃-S(O)₂(CH₂)₀₋₃-(grupo heteroarilo de 5 a 7 miembros que contiene al menos un heteroátomo seleccionado de O, S y N), un grupo -(CH₂)₀₋₃-SH, un grupo -(CH₂)₀₋₃-S-(CH₂)₀₋₃-R¹¹, un grupo -(CH₂)₀₋₃-S-(CH₂)₃-(fenil), un grupo -(CH₂)₀₋₃-S-(CH₂)₀₋₃-(grupo heteroarilo de 5 a 7 miembros que contiene al menos un heteroátomo seleccionado de O, S y N), un grupo -(CH₂)₀₋₃-O-(CH₂)₀₋₃-(fenil), un grupo -(CH₂)₀₋₃-O-(CH₂)₀₋₃-(grupo heteroarilo de 5 a 7 miembros que contiene al menos un heteroátomo seleccionado de O, S y N), en donde los grupos fenilo y heteroarilo están no sustituidos o sustituidos con uno o más sustituyentes seleccionados de un átomo de halógeno, un grupo hidroxilo, un grupo ciano, un grupo alquilo lineal o ramificado C₁₋₄, un grupo haloalquilo C₁₋₄, un grupo hidroxialquilo C₁₋₄ o un grupo alcoxi C₁₋₄ y en donde el grupo alquinilo está no sustituido o sustituido con uno o más sustituyentes seleccionados de un grupo ciano, un grupo alquilo lineal o ramificado C₁₋₄, un grupo haloalquilo C₁₋₄, un grupo hidroxialquilo C₁₋₄, un grupo alcoxi C₁₋₄, un grupo -(CH₂)₀₋₄-C(O)-N(R)-(CH₂)₀₋₄-R, un grupo -(CH₂)₀₋₄-C(O)-(CH₂)₀₋₄-R; en donde cada uno de R y R independientemente representa un átomo de hidrógeno, un grupo hidroxilo, un grupo haloalquilo C₁₋₄, un grupo hidroxialquilo C₁₋₄, un grupo -(CH₂)₀₋₃-O(alquilo C₁₋₄), un grupo alquilo lineal o ramificado C₁₋₄, un grupo fenilo, un grupo -(CH₂)₀₋₃-(grupo heteroarilo de 5 a 7 miembros que contiene al menos un heteroátomo seleccionado de O, S y N), o un grupo -(CH₂)₀₋₃-(grupo heterociclilo de 5 a 7 miembros que contiene al menos un heteroátomo seleccionado de O, S y N); en donde los grupos fenilo, heteroarilo y heterocíclico están no sustituidos o sustituidos con uno o más sustituyentes seleccionados de un átomo de halógeno, grupo hidroxilo, o un grupo alquilo C₁₋₄ lineal o ramificado; cada uno de R⁶ y R⁷ representa independientemente un átomo de hidrógeno, un grupo -(CH₂)₀₋₃CN, un grupo -C(O)-(CH₂)₁₋₃-CN, un grupo -C(O)-(CH₂)₀₋₃-R, un grupo -C(O)-(CH₂)₀₋₃-NRR, un grupo -(CH₂)₀₋₃NRR, o un grupo alquilo lineal o ramificado C₁₋₄ en donde cada uno de R y R independientemente representa un átomo de hidrógeno, un grupo hidroxilo, un grupo haloalquilo C₁₋₄, un grupo hidroxialquilo C₁₋₄, un grupo -(CH₂)₀₋₃-O(alquilo C₁₋₄) o un grupo alquilo lineal o ramificado C₁₋₄; R⁸ representa un grupo arilo monocíclico o bicíclico C₆₋₁₄, un grupo heteroarilo de 5 a 14 miembros que contiene al menos un heteroátomo seleccionado de O, S y N, o un grupo bicíclico que es un grupo arilo monocíclico C₆₋₉ o un grupo heteroarilo de 5 a 9 miembros condensado con un grupo cicloalquilo o heterocíclico de 5 a 9 miembros, donde dicho grupo heteroarilo o heterocíclico contiene al menos un heteroátomo seleccionado de O, S y N, en donde los grupos arilo, heteroarilo y el grupo bicíclico que es un arilo monocíclico C₆₋₉ o grupo heteroarilo de 5 a 9 miembros condensado con un grupo cicloalquilo o heterocíclico de 5 a 9 miembros están no sustituidos o sustituidos con uno o más sustituyentes seleccionados de un átomo de halógeno, un grupo hidroxilo, un grupo ciano, un grupo alquilo lineal o ramificado C₁₋₄, un grupo haloalquilo C₁₋₄, un grupo hidroxialquilo C₁₋₄, un grupo -(CH₂)₀₋₃-O(alquilo C₁₋₄), un grupo -(CH₂)₀₋₃-O(haloalquilo C₁₋₄), un grupo -(CH₂)₀₋₃-O-(CH₂)₁₋₃-O(alquilo C₁₋₄), un grupoPyrrolotriazinone derivatives having the chemical structure of formula (1) are described; as well as a procedure for its preparation, pharmaceutical compositions containing them and their use in therapy as inhibitors of Phosphoinositide 3-kinases (PI3Ks). Claim 1: A compound of formula (1), or a pharmaceutically acceptable salt, or N-oxide, or isotopically labeled derivative thereof; where, n represents 0, 1, 2 or 3; X represents N or CH; each of Rᵃ and Rᵇ independently represents a hydrogen atom, a C₁₋₄ haloalkyl group, a C₁₋₄ hydroxyalkyl group or a C₁₋₄ linear or branched alkyl group; R¹ represents a C₃₋₁₀ cycloalkyl group, a C₃₋₁₀ cycloalkenyl group, a C₆₋₁₄ monocyclic or bicyclic aryl group, a 5 to 14 membered monocyclic or bicyclic heteroaryl group containing at least one heteroatom selected from O, S and N , a 5- to 14-membered monocyclic or bicyclic heterocyclic group containing at least one heteroatom selected from O, S and N, wherein the cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclyl groups are unsubstituted or substituted with one or more selected substituents of a halogen atom, a hydroxyl group, a cyano group, a linear or branched C₁₋₄ alkyl group, a C₁₋₄ haloalkyl group, a C₁₋₄ hydroxyalkyl group, a C₃₋₄ cycloalkyl group, a group - (CH₂ ) ₁₋₃CN, a group - (CH₂) ₀₋₃OR⁹, a group - (CH₂) ₀₋₃NR⁹R¹⁰, a group -C (O) - (CH₂) ₁₋₃-CN, a group -C (O) - (CH₂) ₀₋₃-R⁹, a group -C (O) - (CH₂) ₀₋₃-NR R¹⁰, a group -S (CH₂) ₀₋₃R⁹, a group -S (O) (CH₂) ₀₋₃R⁹, a group -S (O) (CH₂) ₀₋₃NR⁹R¹⁰, a group -S (O) ₂ ( CH₂) ₀₋₃R⁹, a group -S (O) ₂ (CH₂) ₀₋₃NR⁹R¹⁰ or a group - (CH₂) ₀₋₃ (phenyl) -OR⁹; each of R² and R³ independently represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C₁₋₄ alkyl group, a C₁₋₄ haloalkyl group, a C₁₋₄ hydroxyalkyl group, a C₃₋₄ cycloalkyl group, a C₁₋₄ alkoxy group, a -NH₂ group, a -N (CH₃) H group, or a -N (CH₃) ₂ group; R⁴ represents a hydrogen atom, a linear or branched C₁₋₄ alkyl group, a C₁₋₄ haloalkyl group, a C₁₋₄ hydroxyalkyl group, a group - (CH₂) ₀₋₃- (C₃₋₄ cycloalkyl), a group - (CH₂) ₀₋₃-O (C₁₋₄ alkyl), a group - (CH₂) ₀₋₃-S- (CH₂) ₀₋₃- (phenyl), a group - (CH₂) ₀₋₃-S - (CH₂) ₀₋₃- (5 to 7-membered heteroaryl group containing at least one heteroatom selected from O, S and N), a group - (CH₂) ₀₋₃-O- (CH₂) ₀₋₃- (phenyl), a group - (CH₂) ₀₋₃-O- (CH₂) ₃- (5 to 7-membered heteroaryl group containing at least one heteroatom selected from O, S and N), wherein the phenyl and heteroaryl are unsubstituted or substituted with one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C₁₋₄ alkyl group, a C₁₋₄ haloalkyl group, a C₁₋₄ hydroxyalkyl group or a C₁₋₄ alkoxy group; R⁵ represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched C₁₋₄ alkyl group, a C₁₋₄ haloalkyl group, a C₁₋₄ hydroxyalkyl group, a group - (CH₂) ₀₋₃NR⁹R¹⁰, a group - (CH₂) ₀₋₃-O (C₁₋₄ alkyl), a group - (CH₂) ₀₋₃- (C₃₋₄ cycloalkyl), a C₂₋₄ alkynyl group, a group - ( CH₂) ₀₋₃- (phenyl), a group - (CH₂) ₀₋₃- (5- to 7-membered heteroaryl group containing at least one heteroatom selected from O, S and N), a group - (CH₂) ₀ ₋₃-S (O) ₂ (CH₂) ₀₋₃-R¹¹, a group - (CH₂) ₀₋₃-S (O) ₂ (CH₂) ₀₋₃- (phenyl), a group - (CH₂) ₀ ₋₃-S (O) ₂ (CH₂) ₀₋₃- (5 to 7-membered heteroaryl group containing at least one heteroatom selected from O, S and N), a group - (CH₂) ₀₋₃-SH, a group - (CH₂) ₀₋₃-S- (CH₂) ₀₋₃-R¹¹, a group - (CH₂) ₀₋₃-S- (CH₂) ₃- (phenyl), a group - (CH₂) ₀₋ ₃-S- (CH₂) ₋₃- (5 to 7-membered heteroaryl group containing at least one heteroatom selected from O, S and N), a group - (CH₂) ₀₋₃-O- (CH₂) ₀₋₃- (phenyl), a group - (CH₂) ₀₋₃-O- (CH₂) ₀₋₃- (5 to 7-membered heteroaryl group containing at least one heteroatom selected from O, S and N), where the phenyl and heteroaryl groups are not substituted or substituted with one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched C₁₋₄ alkyl group, a C₁₋₄ haloalkyl group, a C₁₋₄ hydroxyalkyl group or an alkoxy group C₁₋₄ and wherein the alkynyl group is unsubstituted or substituted with one or more substituents selected from a cyano group, a linear or branched C₁₋₄ alkyl group, a C₁₋₄ haloalkyl group, a C₁₋₄ hydroxyalkyl group, a C alco alkoxy group, a group - (CH₂) ₀₋₄-C (O) -N (R) - (CH₂) ₀₋₄-R, a group - (CH₂) ₀₋₄-C (O ) - (CH₂) ₀₋₄-R; wherein each of R and R independently represents a hydrogen atom, a hydroxyl group, a C₁₋₄ haloalkyl group, a C₁₋₄ hydroxyalkyl group, a group - (CH₂) ₀₋₃-O (C₁₋₄ alkyl) , a linear or branched C₁₋₄ alkyl group, a phenyl group, a group ((CH₂) ₀₋₃- (5- to 7-membered heteroaryl group containing at least one heteroatom selected from O, S and N), or a group - (CH₂) ₀₋₃- (5- to 7-membered heterocyclyl group containing at least one heteroatom selected from O, S and N); wherein the phenyl, heteroaryl and heterocyclic groups are unsubstituted or substituted with one or more substituents selected from a halogen atom, hydroxyl group, or a linear or branched C₁₋₄ alkyl group; each of R⁶ and R⁷ independently represents a hydrogen atom, a group - (CH₂) ₀₋₃CN, a group -C (O) - (CH₂) ₁₋₃-CN, a group -C (O) - (CH₂ ) ₀₋₃-R, a group -C (O) - (CH₂) ₀₋₃-NRR, a group - (CH₂) ₀₋₃NRR, or a linear or branched alkyl group C grupo where each of R and R independently represents a hydrogen atom, a hydroxyl group, a C₁₋₄ haloalkyl group, a C₁₋₄ hydroxyalkyl group, a group - (CH₂) ₀₋₃-O (C₁₋₄ alkyl) or a linear alkyl group or branched C₁₋₄; R⁸ represents a monocyclic or bicyclic aryl group C₆₋₁₄, a 5-14 membered heteroaryl group containing at least one heteroatom selected from O, S and N, or a bicyclic group that is a C₆₋₉ monocyclic aryl group or a group 5 to 9-membered heteroaryl fused to a 5 to 9-membered cycloalkyl or heterocyclic group, wherein said heteroaryl or heterocyclic group contains at least one heteroatom selected from O, S and N, wherein the aryl, heteroaryl and bicyclic groups that is a C₆₋₉ monocyclic aryl or 5-9 membered heteroaryl group fused to a 5-9 membered cycloalkyl or heterocyclic group are unsubstituted or substituted with one or more substituents selected from a halogen atom, a hydroxyl group, a group cyano, a C alquilo linear or branched alkyl group, a C₁₋₄ haloalkyl group, a C₁₋₄ hydroxyalkyl group, a group - (CH₂) ₀₋₃-O (C₁₋₄ alkyl), a group - (CH ) ₀₋₃-O (haloalkyl C₁₋₄), a group - (CH₂) ₀₋₃-O- (CH₂) ₁₋₃-O (C₁₋₄ alkyl), a group

ARP130103756A 2012-10-16 2013-10-16 PIRROLOTRIAZINONA DERIVATIVES AS PI3K INHIBITORS AR093035A1 (en)

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