AR113819A1 - Compuestos espirocíclicos como moduladores del receptor farnesoide x - Google Patents

Compuestos espirocíclicos como moduladores del receptor farnesoide x

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Publication number
AR113819A1
AR113819A1 ARP180103176A ARP180103176A AR113819A1 AR 113819 A1 AR113819 A1 AR 113819A1 AR P180103176 A ARP180103176 A AR P180103176A AR P180103176 A ARP180103176 A AR P180103176A AR 113819 A1 AR113819 A1 AR 113819A1
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Argentina
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independently
heterocyclyl
alkyl
nrcrc
nrbc
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ARP180103176A
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English (en)
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Gang Wu
Ying Wang
Yanting Huang
Joseph E Carpenter
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Bristol Myers Squibb Co
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Publication of AR113819A1 publication Critical patent/AR113819A1/es

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Abstract

Compuestos de la fórmula (1), o estereoisómeros, tautómeros, o sales o solvatos de aquellos aceptables desde el punto de vista farmacéutico, en donde todas las variables son como se definen en la presente. Estos compuestos modulan la actividad del receptor farnesoide X (FXR), por ejemplo, como agonistas. También composiciones farmacéuticas que comprenden estos compuestos y métodos para tratar una enfermedad, un trastorno o una afección asociados a la desregulación de FXR, tales como fibrosis patológica, rechazo de trasplante, cáncer, osteoporosis y trastorno inflamatorio, mediante el uso de compuestos y composiciones farmacéuticas. Reivindicación 1: Un compuesto caracterizado por la fórmula (1), o un estereoisómero, un tautómero, una sal o un solvato de aquel aceptables desde el punto de vista farmacéutico; en donde: X¹ y X⁴ son, cada uno independientemente, C o N; X² y X³ son, cada uno independientemente, CR⁵, N, NR⁶, O ó S; el anillo E es un carbociclilo o heterociclilo de 4 a 6 miembros, en donde el carbociclilo y el heterociclilo se sustituyen, cada uno independientemente, con 0 a 3 R³; * indica un átomo espiro de carbono; Y es CR⁷ o N; m y n son, cada uno independientemente, un entero de 0, 1 ó 2; f es un entero de 0, 1, 2 ó 3; Z es un arilo de 6 a 10 miembros, un heteroarilo de 5 a 10 miembros que contiene 1 a 3 heteroátomos seleccionados independientemente de N, O y S, un carbociclilo de 3 a 10 miembros, o un heterociclilo de 4 a 10 miembros que contiene 1 a 3 heteroátomos seleccionados independientemente de N, O y S, en donde el arilo, el heteroarilo, el carbociclilo y el heterociclilo se sustituyen independientemente con 0 a 5 R⁸; L¹ es un enlace covalente, O, S, -NR¹⁶-, -S(O)₂-, C₁₋₃ alquileno, C₁₋₃ heteroalquileno, C₂₋₄ alquenileno, C₂₋₄ alquinileno, arilo o un heteroarilo de 5 a 6 miembros que contiene 1 a 3 heteroátomos seleccionados independientemente de N, O y S que contienen 1 a 4 heteroátomos seleccionados independientemente de N, O y S; en donde el alquileno, alquenileno, arilo, heteroalquileno y heteroarilo se sustituyen, cada uno independientemente, con 0 a 3 R¹¹; L² es un enlace covalente, O, S, -NR¹⁷-, C₁₋₃ alquileno o C₁₋₃ heteroalquileno, en donde el alquileno y heteroalquileno se sustituyen independientemente con 0 a 3 R¹⁵; RX es L³-RZ; L³ es un enlace covalente, C₁₋₃ alquileno, -C(O)NR¹²-CH₂- o -OCH₂-, en donde el C₁₋₃ alquileno se sustituye con 0 a 3 R⁴; RZ es -CN, -C(O)OR¹³, -C(O)NR¹⁴ᵃR¹⁴ᵇ, o un resto del grupo de fórmulas (2); Rᵉ es C₁₋₆ alquilo, C₃₋₆ cicloalquilo, haloalquilo, hidroxialquilo, aminoalquilo, alcoxialquilo, haloalcoxialquilo o arilo; RY es cada uno independientemente hidrógeno, halo, ciano, hidroxilo, amino, C₁₋₆ alquilo, alquilamino, haloalquilo, hidroxialquilo, aminoalquilo, alcoxialquilo, haloalcoxialquilo, alcoxi o haloalcoxi; o de manera alternativa, dos RY, junto con los átomos de carbono a los que están unidos, forman una porción puente; y siempre que, cuando Y es N y RY está unido a un átomo de carbono adyacente a Y, entonces RY no sea halo, ciano, hidroxilo, amino, alcoxi o haloalcoxi; R¹ es C₁₋₆ alquilo, C₃₋₅ cicloalquilo o C₄₋₆ heterociclilo, en donde el alquilo, cicloalquilo y heterociclilo se sustituyen cada uno con 0 a 3 R⁹; R² es arilo de 6 a 10 miembros, heteroarilo de 5 a 10 miembros que contiene 1 a 3 heteroátomos seleccionados independientemente de N, O y S, carbociclilo de 3 a 10 miembros o heterociclilo de 4 a 10 miembros que contiene 1 a 3 heteroátomos seleccionados independientemente de N, O y S, en donde el arilo, heteroarilo, carbociclilo y heterociclilo se sustituyen independientemente con 0 a 5 R¹⁰; R³, R⁵, y R⁷ son, cada uno independientemente, hidrógeno, halo, ciano, hidroxilo, amino, C₁₋₆ alquilo, alquilamino, haloalquilo, hidroxialquilo, aminoalquilo, alcoxialquilo, haloalcoxialquilo, alcoxi o haloalcoxi; R⁴ es, cada uno independientemente, halo, oxo, ciano, hidroxilo, amino, alquilo, alcoxi o alquilamino; o de manera alternativa, dos R⁴, junto con los átomos a los que están unidos, forman una porción carbociclilo o heterociclilo; R⁶, R¹⁶ y R¹⁷ son cada uno independientemente hidrógeno, C₁₋₆ alquilo, haloalquilo, hidroxialquilo, aminoalquilo, alcoxialquilo, o haloalcoxialquilo; R⁸ y R¹⁰ son, cada uno independientemente, halo, ciano, hidroxilo, amino, oxo, -ORᵃ, -SRᵃ, =S, -NRᶜRᶜ, =NH, =N-OH, =NRᵃ, =N-ORᵃ, -NO₂, -S(O)₂Rᵃ, -S(O)₂NHRᵇ, -S(O)₂NRᶜRᶜ, -S(O)₂ORᵇ, -OS(O)₂Rᵇ, -OS(O)₂ORᵇ, -P(O)(ORᵇ)(ORᵇ), -C(O)Rᵇ, -C(NRᵇ)Rᵇ, -C(O)ORᵇ, -C(O)NRᶜRᶜ, -C(NRᵇ)NRᶜRᶜ, -OC(O)Rᵇ, -NRᵇC(O)Rᵇ, -OC(O)ORᵇ, -NRᵇC(O)ORᵇ, -NRᵇC(O)NRᶜRᶜ, -NRᵇC(NRᵇ)Rᵇ, -NRᵇC(NRᵇ)NRᶜRᶜ, C₁₋₆ alquilo, C₁₋₆ haloalquilo, arilo, arilalquilo, heteroarilo, carbociclilo o heterociclilo; en donde el alquilo, arilo, heteroarilo, carbociclilo y heterociclilo, en sí mismos o como parte de otro grupo, se sustituyen, cada uno independientemente, con 0 a 5 Rᵈ; Rᵃ es, cada uno independientemente, C₁₋₆ alquilo, haloalquilo, hidroxialquilo, aminoalquilo, alcoxialquilo, haloalcoxialquilo, arilo, arilalquilo, heteroarilo, heteroarilalquilo, carbociclilo, carbociclilalquilo, heterociclilo o heterociclilalquilo; Rᵇ es cada uno independientemente hidrógeno o Rᵃ; Rᶜ es, cada uno independientemente, Rᵇ o, de manera alternativa, los dos Rᶜ, junto con el átomo de nitrógeno al que están unidos, forman un heterociclilo de 4, 5, 6 ó 7 miembros que contiene 1 a 3 heteroátomos seleccionados independientemente de N, O y S; Rᵈ es cada uno independientemente Rᵃ, alcoxi, haloalcoxi, alquilamino, cicloalquilamino, heterociclilamino, haloalquilo, hidroxialquilo, aminoalquilo, cicloalcoxi, heterocicliloxi, haloalcoxi, alcoxialcoxi, haloalquilamino, alcoxialquilamino, haloalcoxialquilamino, arilamino, aralquilamino, ariloxi, aralquiloxi, heteroariloxi, heteroarilalquiloxi, alquiltio, halo, ciano, hidroxilo, amino, oxo, -ORᵃ, -SRᵃ, =S, -NRᶜRᶜ, =NH, =N-OH, =NRᵃ, =N-ORᵃ, -NO₂, -S(O)₂Rᵃ, -S(O)₂NHRᵇ, -S(O)₂NRᶜRᶜ, -S(O)₂ORᵇ, -OS(O)₂Rᵇ, -OS(O)₂ORᵇ, -P(O)(ORᵇ)(ORᵇ), -C(O)Rᵇ, -C(NRᵇ)Rᵇ, -C(O)ORᵇ, -C(O)NRᶜRᶜ, -C(NRᵇ)NRᶜRᶜ, -OC(O)Rᵇ, -NRᵇC(O)Rᵇ, -OC(O)ORᵇ, -NRᵇC(O)ORᵇ, -NRᵇC(O)NRᶜRᶜ, -NRᵇC(NRᵇ)Rᵇ, o -NRᵇC(NRᵇ)NRᶜRᶜ; R⁹ es, cada uno independientemente, halo, ciano, hidroxilo, amino o C₁₋₆ alquilo; R¹¹ y R¹⁵ son cada uno independientemente halo, oxo, ciano, hidroxilo, amino, C₁₋₆ alquilo, C₃₋₆ cicloalquilo, C₄₋₆ heterociclilo, alquilamino, haloalquilo, hidroxialquilo, aminoalquilo, alcoxialquilo, haloalcoxialquilo, alcoxi o haloalcoxi; R¹² es hidrógeno o C₁₋₄ alquilo; R¹³ es hidrógeno, C₁₋₁₀ alquilo, glucosilo o carboxi(trihidroxi)tetrahidropiranilo; y R¹⁴ᵃ y R¹⁴ᵇ son cada uno independientemente hidrógeno, C₁₋₆ alquilo, C₃₋₆ cicloalquilo, C₄₋₆ heterociclilo, alquilamino, haloalquilo, hidroxialquilo, aminoalquilo, alcoxialquilo, haloalcoxialquilo, alcoxi o haloalcoxi.
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