AR106770A1 - INHIBITING COMPOUNDS OF A QUINASA DE JANUS - Google Patents

INHIBITING COMPOUNDS OF A QUINASA DE JANUS

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Publication number
AR106770A1
AR106770A1 ARP160103562A ARP160103562A AR106770A1 AR 106770 A1 AR106770 A1 AR 106770A1 AR P160103562 A ARP160103562 A AR P160103562A AR P160103562 A ARP160103562 A AR P160103562A AR 106770 A1 AR106770 A1 AR 106770A1
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Argentina
Prior art keywords
alkyl
group
independently selected
cycloalkyl
optionally substituted
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ARP160103562A
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Spanish (es)
Inventor
Zhang Lei
Edward Zak Mark
Yuen Po
Wai Mendonca Rohan
Li Wei
Kellar Terry
Gibbons Paul
Xing Cheng Yun
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Hoffmann La Roche
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Publication of AR106770A1 publication Critical patent/AR106770A1/en

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Abstract

Los compuestos y las sales de los mismos son útiles como inhibidores de una o más quinasas de Janus. Se proporcionan también composiciones farmacéuticas que incluyen un compuesto y un vehículo, adyuvante o excipiente farmacéuticamente aceptable, y métodos para tratar o reducir la severidad de una enfermedad o estado patológico que responda a la inhibición de la actividad de una quinasa de Janus en un paciente. Reivindicación 1: Un compuesto de la fórmula (1), o una sal del mismo, en la que: R¹ es H, alquilo C₁₋₆, alquenilo C₂₋₆, alquinilo C₂₋₆, -(alquilo C₀₋₃)CN, -(alquilo C₀₋₃)ORᵃ, -(alquilo C₀₋₃)Rᵃ, -(alquilo C₀₋₃)SRᵃ, -(alquilo C₀₋₃)NRᵃRᵇ, -(alquilo C₀₋₃)OCF₃, -(alquilo C₀₋₃)CF₃, -(alquilo C₀₋₃)NO₂, -(alquilo C₀₋₃)C(O)Rᵃ, -(alquilo C₀₋₃)C(O)ORᵃ, -(alquilo C₀₋₃)C(O)NRᵃRᵇ, -(alquilo C₀₋₃)NRᵃC(O)Rᵇ, -(alquilo C₀₋₃)S(O)₁₋₂Rᵃ, -(alquilo C₀₋₃)NRᵃS(O)₁₋₂Rᵇ, -(alquilo C₀₋₃)S(O)₁₋₂NRᵃRᵇ, -(alquilo C₀₋₃)(heteroarilo de 5 - 6 eslabones) o -(alquilo C₀₋₃)fenilo, dicho R¹ está opcionalmente sustituido por uno o más restos elegidos con independencia entre el grupo formado por halógeno, alquilo C₁₋₃, oxo, -CF₃, -(alquilo C₀₋₃)ORᶜ y -(alquilo C₀₋₃)NRᶜRᵈ; Rᵃ es con independencia hidrógeno, alquilo C₁₋₆, cicloalquilo C₃₋₆, heterociclilo de 3 - 10 eslabones, heteroarilo de 5 - 6 eslabones, -C(O)Rᶜ, -C(O)ORᶜ, -C(O)NRᶜRᵈ, -NRᶜC(O)Rᵈ, -S(O)₁₋₂Rᶜ, -NRᶜS(O)₁₋₂Rᵈ o -S(O)₁₋₂NRᶜRᵈ, cualquiera de dichos cicloalquilo C₃₋₆, heterociclilo de 3 - 10 eslabones y heteroarilo de 5 - 6 eslabones de Rᵃ está opcionalmente sustituido por uno o más restos Rᵉ; Rᵇ es con independencia hidrógeno o alquilo C₁₋₃, dicho alquilo está opcionalmente sustituido por uno o más restos elegidos con independencia entre el grupo formado por halógeno y oxo; o Rᶜ y Rᵈ se eligen con independencia entre el grupo formado por hidrógeno, heterociclilo de 3 - 6 eslabones, cicloalquilo C₃₋₆ y alquilo C₁₋₃, uno cualquiera de dichos heterociclilo de 3 - 6 eslabones, cicloalquilo C₃₋₆ y alquilo C₁₋₃ de Rᶜ y Rᵈ está opcionalmente sustituido por uno o más restos elegidos con independencia entre el grupo formado por halógeno y oxo; o Rᶜ y Rᵈ junto con el átomo al que están unidos forman un heterociclilo de 3 - 6 eslabones, opcionalmente sustituido por uno o más restos elegidos con independencia entre el grupo formado por halógeno, oxo, -CF₃ y alquilo C₁₋₃; cada Rᵉ se elige con independencia entre el grupo formado por oxo, ORᶠ, NRᶠRᵍ, halógeno, heterociclilo de 3 - 10 eslabones, cicloalquilo C₃₋₆ y alquilo C₁₋₆, uno cualquiera de dichos cicloalquilo C₃₋₆ y alquilo C₁₋₆ de Rᵉ está opcionalmente sustituido por uno o más restos elegidos con independencia entre el grupo formado por ORᶠ, NRᶠRᵍ, halógeno, heterociclilo de 3 - 10 eslabones, oxo y ciano y uno cualquiera de dichos heterociclilos de 3 - 10 eslabones de Rᵉ está opcionalmente sustituido por uno o más restos elegidos con independencia entre el grupo formado por halógeno, oxo, ciano, -CF₃, NRʰRᵏ, heterociclilo de 3 - 6 eslabones y alquilo C₁₋₃ que está opcionalmente sustituido por uno o más restos elegidos con independencia entre el grupo formado por halógeno, oxo, ORᶠ y NRʰRᵏ; Rᶠ y Rᵍ se eligen en cada caso con independencia entre el grupo formado por hidrógeno, alquilo C₁₋₆, heterociclilo de 3 - 6 eslabones y cicloalquilo C₃₋₆, uno cualquiera de dichos alquilo C₁₋₆, heterociclilo de 3 - 6 eslabones y cicloalquilo C₃₋₆ de Rᶠ y Rᵍ está opcionalmente sustituido por uno o más Rᵐ; cada Rᵐ se elige con independencia entre el grupo formado por halógeno, ciano, oxo, cicloalquilo C₃₋₆, hidroxi y NRʰRᵏ, uno cualquiera de dicho cicloalquilo C₃₋₆ de Rᵐ está opcionalmente sustituido por uno o más restos elegidos con independencia entre el grupo formado por halógeno, oxo, ciano y alquilo C₁₋₃; Rʰ y Rᵏ se eligen en cada caso con independencia entre el grupo formado por hidrógeno y alquilo C₁₋₆ que está opcionalmente sustituido por uno o más restos elegidos con independencia entre el grupo formado por halógeno, ciano, heterociclilo de 3 - 6 eslabones y oxo; o Rʰ y Rᵏ junto con, el átomo al que están unidos forman un heterociclilo de 3 - 6 eslabones que está opcionalmente sustituido por uno o más restos elegidos con independencia entre el grupo formado por halógeno, ciano, oxo, -CF₃ y alquilo C₁₋₃ que está opcionalmente sustituido por uno o más restos elegidos con independencia entre el grupo formado por halógeno y oxo; R² es alquilo C₁₋₆, alquenilo C₂₋₆, alquinilo C₂₋₆, cicloalquilo C₃₋₆, heterociclilo de 3 - 6 eslabones, (cicloalquil C₃₋₆)alquilo C₁₋₆, (cicloalquil de 3 - 6 eslabones)alquilo C₁₋₆, -C(O)(cicloalquilo C₃₋₆) o -C(O)(heterociclilo de 3 - 6 eslabones), dicho R² está opcionalmente sustituido por uno o más halógenos; n es el número 0, 1 ó 2; R³ es H o NH₂; R⁴ es H o CH₃; y R⁵ es H o NH₂.The compounds and salts thereof are useful as inhibitors of one or more Janus kinases. Pharmaceutical compositions are also provided which include a compound and a pharmaceutically acceptable carrier, adjuvant or excipient, and methods for treating or reducing the severity of a disease or pathological condition that responds to the inhibition of the activity of a Janus kinase in a patient. Claim 1: A compound of the formula (1), or a salt thereof, wherein: R¹ is H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, - (C₀₋₃ alkyl) CN, - (C₀₋₃ alkyl) ORᵃ, - (C₀₋₃ alkyl) Rᵃ, - (C₀₋₃ alkyl) SRᵃ, - (C₀₋₃ alkyl) NRᵃRᵇ, - (C₀₋₃ alkyl) OCF₃, - (C₀₋ alkyl ₃) CF₃, - (C₀₋₃ alkyl) NO₂, - (C₀₋₃ alkyl) C (O) Rᵃ, - (C₀₋₃ alkyl) C (O) ORᵃ, - (C₀₋₃ alkyl) C (O) NRᵃRᵇ, - (C₀₋₃ alkyl) NRᵃC (O) Rᵇ, - (C₀₋₃ alkyl) S (O) ₁₋₂Rᵃ, - (C₀₋₃ alkyl) NRᵃS (O) ₁₋₂Rᵇ, - (C₀₋ alkyl ₃) S (O) ₁₋₂NRᵃRᵇ, - (C₀₋₃ alkyl) (5-6 link heteroaryl) or - (C₀₋₃ alkyl) phenyl, said R¹ is optionally substituted by one or more moieties independently selected from the group consisting of halogen, C₁₋₃ alkyl, oxo, -CF₃, - (C₀₋₃ alkyl) ORᶜ and - (C₀₋₃ alkyl) NRᶜRᵈ; Rᵃ is independently hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 3-10 link heterocyclyl, 5-6 link heteroaryl, -C (O) Rᶜ, -C (O) ORᶜ, -C (O) NRᶜRᵈ , -NRᶜC (O) Rᵈ, -S (O) ₁₋₂Rᶜ, -NRᶜS (O) ₁₋₂Rᵈ or -S (O) ₁₋₂NRᶜRᵈ, any of said cycloalkyl C₃₋₆, heterocyclyl of 3 - 10 links and 5-6 heteroaryl of Rᵃ links is optionally substituted by one or more R restos moieties; Rᵇ is independently hydrogen or C₁₋₃ alkyl, said alkyl is optionally substituted by one or more moieties independently selected from the group consisting of halogen and oxo; or Rᶜ and Rᵈ are independently selected from the group consisting of hydrogen, 3-6 link heterocyclyl, C₃₋₆ cycloalkyl and C₁₋₃ alkyl, any one of said 3-6 link heterocyclyl, C₃₋₆ cycloalkyl and C₁ alkyl ₋₃ of Rᶜ and Rᵈ is optionally substituted by one or more moieties independently selected from the group consisting of halogen and oxo; or Rᶜ and Rᵈ together with the atom to which they are attached form a 3-6 link heterocyclyl, optionally substituted by one or more moieties independently selected from the group consisting of halogen, oxo, -CF₃ and C₁₋₃ alkyl; each Rᵉ is independently selected from the group consisting of oxo, ORᶠ, NRᶠRᵍ, halogen, 3-10 link heterocyclyl, C₃₋₆ cycloalkyl and C₁₋₆ alkyl, any one of said C₃₋₆ cycloalkyl and C₁₋₆ alkyl of Rᵉ is optionally substituted by one or more moieties independently selected from the group consisting of ORᶠ, NRᶠRᵍ, halogen, heterocyclyl of 3-10 links, oxo and cyano and any one of said heterocyclyls of 3-10 links of Rᵉ is optionally substituted by one or more moieties independently selected from the group consisting of halogen, oxo, cyano, -CF₃, NRʰRᵏ, 3-6 link heterocyclyl and C₁₋₃ alkyl which is optionally substituted by one or more moieties independently selected from the group formed by halogen, oxo, ORᶠ and NRʰRᵏ; Rᶠ and Rᵍ are independently selected in each case from the group consisting of hydrogen, C₁₋₆ alkyl, 3-6-link heterocyclyl and C₃₋₆ cycloalkyl, any one of said C₁₋₆ alkyl, 3-6-link heterocyclyl and C₃₋₆ cycloalkyl of Rᶠ and Rᵍ is optionally substituted by one or more Rᵐ; each Rᵐ is independently selected from the group consisting of halogen, cyano, oxo, C₃₋₆ cycloalkyl, hydroxy and NRʰRᵏ, any one of said C₃₋₆ cycloalkyl of Rᵐ is optionally substituted by one or more moieties independently selected from the group formed by halogen, oxo, cyano and C₁₋₃ alkyl; Rʰ and Rᵏ are chosen in each case independently from the group consisting of hydrogen and C₁₋₆ alkyl which is optionally substituted by one or more moieties independently selected from the group consisting of halogen, cyano, 3-6 link heterocyclyl and oxo ; or Rʰ and Rᵏ together with, the atom to which they are attached form a 3-6 link heterocyclyl that is optionally substituted by one or more moieties independently selected from the group consisting of halogen, cyano, oxo, -CF₃ and C₁₋ alkyl ₃ which is optionally substituted by one or more moieties independently selected from the group consisting of halogen and oxo; R² is C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, 3-6 heterocyclyl, (C₃₋₆ cycloalkyl) C₁₋₆ alkyl, (3-6 link cycloalkyl) C₁ alkyl ₋₆, -C (O) (C₃₋₆ cycloalkyl) or -C (O) (3-6 heterocyclyl), said R² is optionally substituted by one or more halogens; n is the number 0, 1 or 2; R³ is H or NH₂; R⁴ is H or CH₃; and R⁵ is H or NH₂.

ARP160103562A 2015-11-23 2016-11-21 INHIBITING COMPOUNDS OF A QUINASA DE JANUS AR106770A1 (en)

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CN2015095310 2015-11-23

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