AR113820A1 - Compuestos bicíclicos en puente como moduladores del receptor farnesoide x - Google Patents

Compuestos bicíclicos en puente como moduladores del receptor farnesoide x

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AR113820A1
AR113820A1 ARP180103177A ARP180103177A AR113820A1 AR 113820 A1 AR113820 A1 AR 113820A1 AR P180103177 A ARP180103177 A AR P180103177A AR P180103177 A ARP180103177 A AR P180103177A AR 113820 A1 AR113820 A1 AR 113820A1
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Argentina
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independently
alkyl
haloalkyl
nrcrc
aminoalkyl
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ARP180103177A
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Guohua Zhao
Ximao Wu
Ramesh Kumar Sistla
Rishikesh Narayan
Susheel Jethanand Nara
Wei Meng
Elizabeth Anne Jurica
Yanting Huang
Srinivas Cheruku
Rushith Kumar Anumula
David S Yoon
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Bristol Myers Squibb Co
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Publication of AR113820A1 publication Critical patent/AR113820A1/es

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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61K31/47—Quinolines; Isoquinolines
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D471/04—Ortho-condensed systems

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  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)
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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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, trastorno o afección asociados a la desregulación del 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: el anillo B es un cicloheteroalquilo o cicloalquilo en puente de 5 a 8 miembros; y el punto de unión a L¹ o Z es un átomo de carbono; X¹ y X⁴ son, cada uno independientemente, C o N; X² y X³ son, cada uno independientemente, CR³, N, NR⁴, O ó S; E¹ y E³ son, cada uno independientemente, un enlace covalente, O, S, N, NR⁶, CR⁵ o CR⁵ᵃR⁵ᵇ; E² es O, S, N, NR⁸, CR⁷ o CR⁷ᵃR⁷ᵇ; en donde (E¹ y E²) o (E³ y E²) forman un enlace simple o un enlace doble; siempre que [1] los enlaces entre (E¹ y E²) y (E³ y E²) no sean ambos enlaces dobles; y [2] no más de uno de E¹, E² y E³ sea O, S, N o NR⁸; L¹ es un enlace covalente, O, S, NR¹⁶, -C(S)NH-, 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 4 heteroátomos seleccionados independientemente de N, O y S; en donde el alquileno, heteroalquileno, arilo y heteroarilo se sustituyen, cada uno independientemente, con 0 a 3 R⁹; Z es arilo de 6 a 10 miembros, heteroarilo de 5 a 10 miembros, carbociclilo de 3 a 10 miembros o heterociclilo de 4 a 10 miembros, en donde el arilo, heteroarilo, carbociclilo y heterociclilo se sustituyen, independientemente, con 0 a 5 R¹⁰; L² son, cada uno independientemente, un enlace covalente, O, S, NR¹⁷, C₁₋₃ alquileno o C₁₋₃ heteroalquileno, en donde el alquileno y el heteroalquileno se sustituyen, independientemente, con 0 a 3 R¹¹; RX es -(CR¹²ᵃR¹²ᵇ)ₑ-RZ o -O(CR¹²ᵃR¹²ᵇ)ₑ-RZ; e es 0 ó 1; RZ se selecciona de -CN, -OH, -O(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 fenilo; R¹ es C₁₋₆ alquilo, C₃₋₅ cicloalquilo o C₄₋₆ heterociclilo, en donde el alquilo, cicloalquilo y heterociclilo se sustituyen, cada uno independientemente, con 0 a 3 R¹⁵; R² es arilo de 6 a 10 miembros, heteroarilo de 5 a 10 miembros, carbociclilo de 3 a 10 miembros o heterociclilo de 4 a 10 miembros, en donde el arilo, heteroarilo, carbociclilo y heterociclilo se sustituyen, independientemente, con 0 a 5 R¹⁶; R³ y R⁷ son, cada uno independientemente, hidrógeno, halo, ciano, hidroxilo, amino, C₁₋₆ alquilo, alquilamino, haloalquilo, hidroxialquilo, aminoalquilo, alcoxialquilo, haloalcoxialquilo, alcoxi o haloalcoxi; R⁴, R⁶, R⁸, R¹⁶ y R¹⁷ son, cada uno independientemente, hidrógeno, C₁₋₆ alquilo, haloalquilo, hidroxialquilo, aminoalquilo, alcoxialquilo o haloalcoxialquilo; R⁵ es hidrógeno, C₁₋₆ alquilo, haloalquilo, hidroxialquilo, aminoalquilo, alcoxialquilo o haloalcoxialquilo; R⁵ᵃ, R⁵ᵇ, R⁷ᵃ y R⁷ᵇ son, cada uno independientemente, hidrógeno, halo, ciano, hidroxilo, amino, C₁₋₆ alquilo, alquilamino, haloalquilo, hidroxialquilo, aminoalquilo, alcoxialquilo, haloalcoxialquilo, alcoxi o haloalcoxi; R⁹ y R¹¹ 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; a es un entero de 0, 1, 2 ó 3; R¹⁰ y R¹⁶ 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, -OC(O)NRᶜRᶜ, -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 se selecciona de C₁₋₆ alquilo, haloalquilo, hidroxialquilo, aminoalquilo, alcoxialquilo, haloalcoxialquilo, arilo, arilalquilo, heteroarilo, heteroarilalquilo, carbociclilo, carbociclilalquilo, heterociclilo y heterociclilalquilo; Rᵇ es, cada uno independientemente, hidrógeno o Rᵃ; Rᶜ es, cada uno independientemente, Rᵇ o, alternativamente, los dos Rᶜ se toman junto con el átomo de nitrógeno al que están unidos para formar un heterociclilo de 4, 5, 6 ó 7 miembros; Rᵈ se seleccionan, 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 y -NRᵇC(NRᵇ)NRᶜRᶜ; R¹²ᵃ y R¹²ᵇ son, cada uno independientemente, hidrógeno, halo, ciano, hidroxilo, amino, C₁₋₆ alquilo, alquilamino, haloalquilo, hidroxialquilo, aminoalquilo, alcoxialquilo, haloalcoxialquilo, alcoxi o haloalcoxi; o, alternativamente, R¹²ᵃ y R¹²ᵇ, junto con los átomos a los que están unidos, forman un anillo carbocíclico o heterocíclico de 3 ó 4 miembros; R¹³ es hidrógeno, C₁₋₁₀ alquilo o glucosilo; R¹⁴ᵃ y R¹⁴ᵇ son, cada uno independientemente, hidrógeno, C₁₋₆ alquilo, haloalquilo, hidroxialquilo, aminoalquilo, alcoxialquilo, haloalcoxialquilo, alcoxi o haloalcoxi; y R¹⁵ es hidrógeno, halo, ciano, hidroxilo, amino, C₁₋₆ alquilo, alquilamino, haloalquilo, hidroxialquilo, aminoalquilo, alcoxialquilo, haloalcoxialquilo, alcoxi o haloalcoxi.
ARP180103177A 2017-11-01 2018-10-31 Compuestos bicíclicos en puente como moduladores del receptor farnesoide x AR113820A1 (es)

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