AR119092A1 - TRICYCLIC COMPOUNDS AND THEIR USE - Google Patents

TRICYCLIC COMPOUNDS AND THEIR USE

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Publication number
AR119092A1
AR119092A1 ARP200101583A ARP200101583A AR119092A1 AR 119092 A1 AR119092 A1 AR 119092A1 AR P200101583 A ARP200101583 A AR P200101583A AR P200101583 A ARP200101583 A AR P200101583A AR 119092 A1 AR119092 A1 AR 119092A1
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Argentina
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alkyl
haloalkyl
heteroaryl
cycloalkyl
optionally substituted
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ARP200101583A
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Spanish (es)
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Wei Su
- Zhang Weihan Guo
Jinshui Li
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Hutchison Medipharma Ltd
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Publication of AR119092A1 publication Critical patent/AR119092A1/en

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Abstract

La presente se relaciona con compuestos tricíclicos y su uso. Más específicamente, la presente se relaciona con compuestos tricíclicos, composiciones farmacéuticas que contienen los mismos, métodos de preparación de los mismos y su uso en terapia. Reivindicación 1: Un compuesto de la fórmula (1), una sal farmacéuticamente aceptable del mismo, o solvatos, mezclas racémicas, enantiómeros, diasterómeros, o tautómeros del compuesto de la fórmula (1) o una sal farmacéuticamente aceptable de los mismos, en donde Z¹ y Z² son independientemente N ó C, y el resto de fórmula (2) es heteroarilo de 5 miembros que contiene 1, 2, 3 ó 4 heteroátomos de anillo seleccionados de N, O ó S; dicho heteroarilo de 5 miembros está opcionalmente sustituido con uno o más sustituyentes independientemente seleccionados de deuterio, halógeno, hidroxi, amino, -NH(C₁₋₆ alquilo), -N(C₁₋₆ alquilo)₂, -CN, mercapto, C₁₋₆ alquilo, C₂₋₆ alquenilo, C₂₋₆ alquinilo, C₁₋₆ alcoxilo, C₁₋₆ haloalquilo, -(C₁₋₆ alquil)-OH, y -(C₁₋₆ alquil)-O-(C₁₋₆ alquilo), en donde cada uno de dichos C₁₋₆ alquilo, C₁₋₆ alcoxilo, y C₁₋₆ haloalquilo está opcionalmente sustituido con uno o más deuterios; L está ausente, ó L es -NRᶜ, O, ó S; Rᶜ es hidrógeno ó C₁₋₆ alquilo; Ar es heteroarilo opcionalmente sustituido con uno o más sustituyentes independientemente seleccionados de deuterio, halógeno, hidroxi, amino, -NH(C₁₋₆ alquilo), -N(C₁₋₆ alquilo)₂, -CN, mercapto, C₁₋₆ alquilo, C₂₋₆ alquenilo, C₂₋₆ alquinilo, C₁₋₆ alcoxilo, C₁₋₆ haloalquilo, -(C₁₋₆ alquil)-OH, -(C₁₋₆ alquil)-O-(C₁₋₆ alquilo), C₃₋₈ cicloalquilo, heterociclilo de 3 - 8 miembros, fenilo, y heteroarilo, en donde cada uno de dichos C₁₋₆ alquilo, C₁₋₆ alcoxilo, C₁₋₆ haloalquilo, C₃₋₈ cicloalquilo, heterociclilo de 3 - 8 miembros, fenilo, y heteroarilo está opcionalmente sustituido con uno o más deuterios; R¹ está seleccionado de hidrógeno, C₁₋₆ alquilo opcionalmente sustituido con uno o más deuterios, C₂₋₆ alquenilo, C₂₋₆ alquinilo, C₁₋₆ haloalquilo, -(C₁₋₆ alquil)-OH, -(C₁₋₆ alquil)-O-(C₁₋₆alquilo), -(C₁₋₆ alquil)-(C₃₋₈ cicloalquilo), -(C₁₋₆ alquil)-(heterociclilo de 3 - 8 miembros), -(C₁₋₆ alquil)-fenilo, -(C₁₋₆ alquil)-heteroarilo, C₃₋₈ cicloalquilo, heterociclilo de 3 - 8 miembros, fenilo, y heteroarilo, en donde cada uno de dichos C₂₋₆ alquenilo, C₂₋₆ alquinilo, C₃₋₈ cicloalquilo, heterociclilo de 3 - 8 miembros, fenilo, y heteroarilo está opcionalmente sustituido con uno o más sustituyentes independientemente seleccionados de deuterio, halógeno, -CN, hidroxi, mercapto, amino, -NH(C₁₋₆ alquilo), -N(C₁₋₆ alquilo)₂, -(C₁₋₆ alquil)-OH, -(C₁₋₆ alquil)-O-(C₁₋₆ alquilo), C₃₋₈ cicloalquilo, heterociclilo de 3 - 8 miembros, fenilo, heteroarilo, C₁₋₆ alquilo opcionalmente sustituido con uno o más deuterios, C₁₋₆ alcoxilo, y C₁₋₆ haloalquilo; R² está seleccionado de hidrógeno, deuterio, halógeno, hidroxi, amino, -NH(C₁₋₆ alquilo), -N(C₁₋₆ alquilo)₂, -CN, mercapto, C₁₋₆ alquilo opcionalmente sustituido con uno o más deuterios, C₂₋₆ alquenilo, C₂₋₆ alquinilo, C₁₋₆ haloalquilo, -(C₁₋₆ alquil)-OH, -(C₁₋₆ alquil)-O-(C₁₋₆ alquilo), -(C₁₋₆ alquil)-(C₃₋₈ cicloalquilo), -(C₁₋₆ alquil)-(heterociclilo de 3 - 8 miembros), -(C₁₋₆ alquil)-fenilo, -(C₁₋₆ alquil)-heteroarilo, C₃₋₈ cicloalquilo, heterociclilo de 3 - 8 miembros, fenilo, y heteroarilo, en donde cada uno de dichos C₂₋₆ alquenilo, C₂₋₆ alquinilo, C₃₋₈ cicloalquilo, heterociclilo de 3 - 8 miembros, fenilo, y heteroarilo está opcionalmente sustituido con uno o más sustituyentes independientemente seleccionados de deuterio, halógeno, -CN, hidroxi, mercapto, amino, -NH(C₁₋₆ alquilo), -N(C₁₋₆ alquilo)₂, -(C₁₋₆ alquil)-OH, -(C₁₋₆ alquil)-O-(C₁₋₆ alquilo), C₁₋₆ alquilo, C₁₋₆ alcoxilo, C₁₋₆ haloalquilo, y oxo; Rᵃ y Rᵇ están independientemente seleccionados de hidrógeno, deuterio, halógeno, hidroxi, amino, -NH(C₁₋₆ alquilo), -N(C₁₋₆ alquilo)₂, -(C₁₋₆ alquil)-OH, -(C₁₋₆ alquil)-O-(C₁₋₆ alquilo), -CN, mercapto, C₁₋₆ alquilo, C₁₋₆ alcoxilo, y C₁₋₆ haloalquilo; ó Rᵃ y Rᵇ junto con el átomo de carbono al cual están unidos forman C₃₋₆ cicloalquilo o heterociclilo de 4 - 6 miembros, en donde cada uno de dichos C₃₋₆ cicloalquilo o heterociclilo de 4 - 6 miembros está opcionalmente sustituido con uno o más sustituyentes independientemente seleccionados de deuterio, halógeno, -CN, hidroxi, mercapto, amino, -NH(C₁₋₆ alquilo), -N(C₁₋₆ alquilo)₂, -(C₁₋₆ alquil)-OH, -(C₁₋₆ alquil)-O-(C₁₋₆ alquilo), C₁₋₆ alquilo, C₁₋₆ alcoxilo, y C₁₋₆ haloalquilo; ⁻ ⁻ ⁻ ⁻ ⁻ es enlace doble o enlace simple, y cuando ⁻ ⁻ ⁻ ⁻ ⁻ es enlace doble, R³ y R⁵ están ausentes; R³, R⁴, R⁵, R⁶, R⁷, y R⁸ están independientemente seleccionados de hidrógeno, deuterio, halógeno, hidroxi, -CN, mercapto, amino, -NH(C₁₋₆ alquilo), -N(C₁₋₆ alquilo)₂, -(C₁₋₆ alquil)-OH, -(C₁₋₆ alquil)-O-(C₁₋₆ alquilo), C₁₋₆ alquilo, -(C₁₋₆ alquil)-fenilo, C₁₋₆ alcoxilo, y C₁₋₆ haloalquilo; o cualesquiera dos de R³, R⁴, R⁵, R⁶, R⁷, y R⁸ junto con el átomo de carbono al cual están unidos y el anillo B forman un anillo de 8 - 13 miembros espirocíclico, fusionado o puenteado que contiene opcionalmente 1 - 3 heteroátomos de anillo independientemente seleccionados de N, O, ó S; en donde dicho anillo espirocíclico, fusionado o puenteado está opcionalmente sustituido con uno o más sustituyentes independientemente seleccionados de deuterio, halógeno, -CN, hidroxi, mercapto, amino, -NH(C₁₋₆ alquilo), -N(C₁₋₆ alquilo)₂, -(C₁₋₆ alquil)-OH, -(C₁₋₆ alquil)-O-(C₁₋₆ alquilo), C₁₋₆ alquilo, C₁₋₆ alcoxilo, y C₁₋₆ haloalquilo; ó R³ y R⁴ juntos, R⁵ y R⁶ juntos, ó R⁷ y R⁸ juntos son oxo; n es 0, 1, ó 2; m es 0, 1, 2, 3, 4, ó 5.This relates to tricyclic compounds and their use. More specifically, the present relates to tricyclic compounds, pharmaceutical compositions containing them, methods of preparing them, and their use in therapy. Claim 1: A compound of the formula (1), a pharmaceutically acceptable salt thereof, or solvates, racemic mixtures, enantiomers, diastereomers, or tautomers of the compound of the formula (1) or a pharmaceutically acceptable salt thereof, wherein Z¹ and Z² are independently N or C, and the moiety of formula (2) is 5-membered heteroaryl containing 1, 2, 3 or 4 ring heteroatoms selected from N, O or S; said 5-membered heteroaryl is optionally substituted with one or more substituents independently selected from deuterium, halogen, hydroxy, amino, -NH(C₁₋₆ alkyl), -N(C₁₋₆ alkyl)₂, -CN, mercapto, C₁₋ ₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, -(C₁₋₆ alkyl)-OH, and -(C₁₋₆ alkyl)-O-(C₁₋₆ alkyl) , wherein each of said C₁₋₆ alkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkyl is optionally substituted with one or more deuteriums; L is absent, or L is -NRᶜ, O, or S; Rᶜ is hydrogen or C₁₋₆ alkyl; Ar is heteroaryl optionally substituted with one or more substituents independently selected from deuterium, halogen, hydroxy, amino, -NH(C₁₋₆ alkyl), -N(C₁₋₆ alkyl)₂, -CN, mercapto, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, -(C₁₋₆ alkyl)-OH, -(C₁₋₆ alkyl)-O-(C₁₋₆ alkyl), C₃₋₈ cycloalkyl, 3-8 membered heterocyclyl, phenyl, and heteroaryl, wherein each of said C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl, 3-8 membered heterocyclyl, phenyl, and heteroaryl is optionally substituted with one or more deuteriums; R¹ is selected from hydrogen, C₁₋₆ alkyl optionally substituted with one or more deuteriums, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, -(C₁₋₆ alkyl)-OH, -(C₁₋₆ alkyl) -O-(C₁₋₆alkyl), -(C₁₋₆ alkyl)-(C₃₋₈ cycloalkyl), -(C₁₋₆ alkyl)-(3-8 membered heterocyclyl), -(C₁₋₆ alkyl)-phenyl , -(C₁₋₆ alkyl)-heteroaryl, C₃₋₈ cycloalkyl, 3-8 membered heterocyclyl, phenyl, and heteroaryl, wherein each of said C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, heterocyclyl 3-8 membered, phenyl, and heteroaryl is optionally substituted with one or more substituents independently selected from deuterium, halogen, -CN, hydroxy, mercapto, amino, -NH(C₁₋₆ alkyl), -N(C₁₋₆ alkyl )₂, -(C₁₋₆ alkyl)-OH, -(C₁₋₆ alkyl)-O-(C₁₋₆ alkyl), C₃₋₈ cycloalkyl, 3-8 membered heterocyclyl, phenyl, heteroaryl, C₁₋₆ alkyl optionally substituted with one or more deuteriums, C₁₋₆ alkoxy, and C₁₋₆ haloalkyl; R² is selected from hydrogen, deuterium, halogen, hydroxy, amino, -NH(C₁₋₆ alkyl), -N(C₁₋₆ alkyl)₂, -CN, mercapto, C₁₋₆ alkyl optionally substituted with one or more deuteriums, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, -(C₁₋₆ alkyl)-OH, -(C₁₋₆ alkyl)-O-(C₁₋₆ alkyl), -(C₁₋₆ alkyl)- (C₃₋₈ cycloalkyl), -(C₁₋₆ alkyl)-(3-8 membered heterocyclyl), -(C₁₋₆ alkyl)-phenyl, -(C₁₋₆ alkyl)-heteroaryl, C₃₋₈ cycloalkyl, heterocyclyl 3-8 membered, phenyl, and heteroaryl, wherein each of said C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, 3-8 membered heterocyclyl, phenyl, and heteroaryl is optionally substituted with one or more substituents independently selected from deuterium, halogen, -CN, hydroxy, mercapto, amino, -NH(C₁₋₆ alkyl), -N(C₁₋₆ alkyl)₂, -(C₁₋₆ alkyl)-OH, -(C₁₋ ₆ alkyl)-O-(C₁₋₆ alkyl), C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, and oxo; Rᵃ and Rᵇ are independently selected from hydrogen, deuterium, halogen, hydroxy, amino, -NH(C₁₋₆ alkyl), -N(C₁₋₆ alkyl)₂, -(C₁₋₆ alkyl)-OH, -(C₁₋ ₆ alkyl)-O-(C₁₋₆ alkyl), -CN, mercapto, C₁₋₆ alkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkyl; or Rᵃ and Rᵇ together with the carbon atom to which they are attached form a 4-6 membered C₃₋₆ cycloalkyl or heterocyclyl, wherein each of said 4-6 membered C₃₋₆ cycloalkyl or heterocyclyl is optionally substituted with one or more substituents independently selected from deuterium, halogen, -CN, hydroxy, mercapto, amino, -NH(C₁₋₆ alkyl), -N(C₁₋₆ alkyl)₂, -(C₁₋₆ alkyl)-OH, -(C₁ ₋₆ alkyl)-O-(C₁₋₆ alkyl), C₁₋₆ alkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkyl; ⁻ ⁻ ⁻ ⁻ ⁻ is double bond or single bond, and when ⁻ ⁻ ⁻ ⁻ ⁻ is double bond, R³ and R⁵ are absent; R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are independently selected from hydrogen, deuterium, halogen, hydroxy, -CN, mercapto, amino, -NH(C₁₋₆ alkyl), -N(C₁₋₆ alkyl)₂, -(C₁₋₆ alkyl)-OH, -(C₁₋₆ alkyl)-O-(C₁₋₆ alkyl), C₁₋₆ alkyl, -(C₁₋₆ alkyl)-phenyl, C₁₋₆ alkoxy, and C₁₋ ₆ haloalkyl; or any two of R³, R⁴, R⁵, R⁶, R⁷, and R⁸ together with the carbon atom to which they are attached and ring B form an 8-13 membered spirocyclic, fused or bridged ring optionally containing 1-3 heteroatoms ring independently selected from N, O, or S; wherein said fused or bridged spirocyclic ring is optionally substituted with one or more substituents independently selected from deuterium, halogen, -CN, hydroxy, mercapto, amino, -NH(C₁₋₆ alkyl), -N(C₁₋₆ alkyl) ₂, -(C₁₋₆ alkyl)-OH, -(C₁₋₆ alkyl)-O-(C₁₋₆ alkyl), C₁₋₆ alkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkyl; or R³ and R⁴ together, R⁵ and R⁶ together, or R⁷ and R⁸ together are oxo; n is 0, 1, or 2; m is 0, 1, 2, 3, 4, or 5.

ARP200101583A 2019-06-06 2020-06-04 TRICYCLIC COMPOUNDS AND THEIR USE AR119092A1 (en)

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