AR103065A1 - FXR MODULATING COMPOUNDS (NR1H4) CONTAINING HYDROXY GROUPS - Google Patents

FXR MODULATING COMPOUNDS (NR1H4) CONTAINING HYDROXY GROUPS

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AR103065A1
AR103065A1 ARP150104132A ARP150104132A AR103065A1 AR 103065 A1 AR103065 A1 AR 103065A1 AR P150104132 A ARP150104132 A AR P150104132A AR P150104132 A ARP150104132 A AR P150104132A AR 103065 A1 AR103065 A1 AR 103065A1
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Argentina
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alkyl
alkylene
group
cycloalkyl
halo
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ARP150104132A
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Spanish (es)
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C Schmitt Aaron
Kremoser Claus
Kinzel Olaf
Gege Christian
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Gilead Sciences Inc
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Application filed by Gilead Sciences Inc filed Critical Gilead Sciences Inc
Priority to ARP150104132A priority Critical patent/AR103065A1/en
Publication of AR103065A1 publication Critical patent/AR103065A1/en

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Abstract

Compuestos que se unen al NR1H4 (FXR) y actúan como agonistas de FXR. Además, el uso de los compuestos para la preparación de un medicamento para el tratamiento de enfermedades y/o condiciones por unión de dichos compuestos a dicho receptor nuclear y un proceso para la síntesis de dichos compuestos. Reivindicación 1: Un compuesto caracterizado porque es de acuerdo con la fórmula (1), un enantiómero, diasterómero, tautómero, solvato, profármaco o sal farmacéuticamente aceptable del mismo, donde R se selecciona entre el grupo que consiste en hidrógeno, halógeno, C₁₋₆-alquilo, C₂₋₆-alquenilo, C₂₋₆-alquinilo, halo-C₁₋₆-alquilo, C₀₋₆-alquilen-R⁷, C₀₋₆-alquilen-O-R⁷, C₀₋₆-alquilan-CN, C₀₋₆-alquilen-NR⁷R⁸, O-C₃₋₁₀-cicloalquilo, O-C₁₋₆-alquilen-O-R⁷, O-C₃₋₁₀-heterocicloalquilo, C₀₋₆-alquilen-CO₂R⁷, C₀₋₆-alquilen-C(O)R⁷, C₀₋₆-alquilen-C(O)NR⁷R⁸, C₀₋₆-alquilen-C(O)NR⁷SO₂R⁷, C₀₋₆-alquilen-N(R⁷)C(O)R⁷, C₀₋₆-alquilen-SOˣ-R⁷, C₀₋₆-alquilen-SO₃H, C₀₋₆-alquilen-SO₂-NR⁷R⁸, C₀₋₆-alquilen-SO₂-NR⁸COR⁷, C₀₋₆-alquilen-N(R⁷)SO₂-R⁸, y C₀₋₆-alquilen-SO₂-C₃₋₁₀-heterocicloalquilo, donde alquileno, cicloalquilo, heterocicloalquilo y heteroarilo de 5 ó 6 miembros no están sustituidos o están sustituidos con 1 a 4 sustituyentes seleccionados en forma independiente entre el grupo que consiste en halógeno, CN, C₁₋₃-alquilo, halo-C₁₋₃-alquilo, OH, oxo, CO₂H, SO₃H, O-C₁₋₃-alquilo y O-halo-C₁₋₃-alquilo; R⁷ se selecciona en forma independiente entre el grupo que consiste en hidrógeno, C₁₋₆-alquilo, halo-C₁₋₆-alquilo, C₀₋₆-alquilen-C₃₋₈-cicloalquilo, C₀₋₆-alquilen-C₃₋₈-heterocicloalquilo, heteroarilo de 5 ó 6 miembros y fenilo, donde alquilo, alquileno, cicloalquilo, heterocicloalquilo, fenilo y heteroarilo no están sustituidos o están sustituidos con 1 a 6 sustituyentes seleccionados en forma independiente entre el grupo que consiste en halógeno, CN, OH, oxo, CO₂H, C₁₋₃-alquilo, halo-C₁₋₃-alquilo, O-C₁₋₃-alquilo, O-halo-C₁₋₃-alquilo, SO₃H y SO₂-C₁₋₃-alquilo; R⁸ se selecciona en forma independiente entre el grupo que consiste en hidrógeno, C₁₋₆-alquilo, halo-C₁₋₆-alquilo y C₃₋₆-cicloalquilo; o R⁷ y R⁸ cuando se toman junto con el nitrógeno al cual están unidos pueden formar un anillo de 3 a 8 miembros que contiene átomos de carbono y que contiene opcionalmente 1 ó 2 heteroátomos seleccionados entre O, S o N, donde el anillo no está sustituido o está sustituido con 1 a 4 sustituyentes seleccionados en forma independiente entre el grupo que consiste en fluoro, OH, oxo, C₁₋₄-alquilo y halo-C₁₋₄-alquilo; A es un arilo monocíclico o bicíclico de 6 - 10 miembros o un heteroarilo monocíclico o bicíclico de 5 - 10 miembros que contiene 1 a 5 heteroátomos seleccionados en forma independiente entre el grupo que consiste en N, O y S, donde arilo y heteroarilo no están sustituidos o están sustituidos con uno o dos grupos seleccionados en forma independiente entre el grupo que consiste en OH, halógeno, CN, O-C₁₋₆-alquilo, O-halo-C₁₋₆-alquilo, C₁₋₆-alquilo, halo-C₁₋₆-alquilo, C₃₋₆-cicloalquilo, C₅₋₆-heterocicloalquilo y halo-C₃₋₆-cicloalquilo; Q es un anillo C₃₋₁₀-cicloalquilo, o anillo C₅₋₁₀-cicloalquilo en puente donde el sustituyente -O-CH₂-Z no es directamente adyacente al sustituyente A, donde si Q es un sistema de anillos bicíclico o multicíclico, un átomo de carbono puede reemplazarse opcionalmente por un oxígeno, SOˣ o NR⁷; Z se selecciona entre el grupo de fórmulas (2), donde L se selecciona entre el grupo que consiste en una unión, C₁₋₃-alquileno y C₁₋₃-alquilen-O-; Y se selecciona entre el grupo que consiste en fenilo, piridilo, N-óxido de piridilo, pirimidilo, piridinonilo, pirimidinonilo, C₄₋₈-cicloalquilo y C₄₋₈-heterocicloalquilo, donde fenilo, piridilo, N-óxido de piridilo, pirimidilo, piridinonilo, pirimidinonilo, C₄₋₈-cicloalquilo y C₄₋₈-heterocicloalquilo están sustituidos con R² y R³ y opcionalmente sustituidos una o dos veces con un grupo seleccionado entre fluoro, cloro, CN, NH₂, NH(C₁₋₃-alquilo), N(C₁₋₃-alquil)₂, C₁₋₃-alquilo, fluoro-C₁₋₃-alquilo, OH, C₁₋₃-alcoxi, fluoro-C₁₋₃-alcoxi, C₃₋₆-cicloalquilo y fluoro-C₃₋₆-cicloalquilo; R¹ se selecciona entre el grupo que consiste en C₁₋₄-alquilo y C₃₋₆-cicloalquilo, donde C₁₋₄-alquilo no está sustituido o está sustituido con 1 á 3 sustituyentes seleccionados en forma independiente entre el grupo que consiste en fluoro, hidroxi, C₁₋₃-alcoxi y fluoro-C₁₋₃-alcoxi, y C₃₋₆-cicloalquilo no está sustituido o está sustituido con 1 a 3 sustituyentes seleccionados en forma independiente entre el grupo que consiste en fluoro, hidroxi, C₁₋₃-alquilo, fluoro-C₁₋₃-alquilo, C₁₋₃-alcoxi y fluoro-C₁₋₃-alcoxi; R² y R³ se seleccionan en forma independiente entre el grupo que consiste en hidrógeno, halógeno, C₁₋₃-alquilo, halo-C₁₋₃-alquilo, C₁₋₃-alcoxi, halo-C₁₋₃-alcoxi, ciclopropilo y fluoro-ciclopropilo; R⁴ se selecciona. en forma independiente entre el grupo que consiste en halógeno, C₁₋₃-alquilo, halo-C₁₋₃-alquilo, C₁₋₃-alcoxi, halo-C₁₋₃-alcoxi, C₁₋₃-cicloalquilo, C₁₋₃-alquilen-O-C₁₋₃-alquilo y fluoro-C₁₋₃-cicloalquilo; R⁵ se selecciona entre el grupo que consiste en hidrógeno, fluoro, CH₃, CHF₂ y CF₃; n se selecciona entre 0, 1, 2, 3 y 4; x se selecciona en forma independiente entre 0, 1 y 2.Compounds that bind to NR1H4 (FXR) and act as FXR agonists. In addition, the use of the compounds for the preparation of a medicament for the treatment of diseases and / or conditions by binding said compounds to said nuclear receptor and a process for the synthesis of said compounds. Claim 1: A compound characterized in that it is according to formula (1), an enantiomer, diasteromer, tautomer, solvate, prodrug or pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of hydrogen, halogen, C₁₋ ₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, halo-C₁₋₆-alkyl, C₀₋₆-alkylene-R⁷, C₀₋₆-alkylene-O-R⁷, C₀₋₆-alkyne-CN, C₀₋₆-alkylene-NR⁷R⁸, O-C₃₋₁₀-cycloalkyl, O-C₁₋₆-alkylene-O-R⁷, O-C₃₋₁₀-heterocycloalkyl, C₀₋₆-alkylene-CO₂R⁷, C₀₋₆-alkylene- C (O) R⁷, C₀₋₆-alkylene-C (O) NR⁷R⁸, C₀₋₆-alkylene-C (O) NR⁷SO₂R⁷, C₀₋₆-alkylene-N (R⁷) C (O) R⁷, C₀₋₆- alkylene-SOˣ-R⁷, C₀₋₆-alkylene-SO₃H, C₀₋₆-alkylene-SO₂-NR⁷R⁸, C₀₋₆-alkylene-SO₂-NR⁸COR⁷, C₀₋₆-alkylene-N (R⁷) SO₂-R⁸, and C₀ ₋₆-alkylene-SO₂-C₃₋₁₀-heterocycloalkyl, where alkylene, cycle 5 or 6-membered alkyl, heterocycloalkyl and heteroaryl are not substituted or substituted with 1 to 4 substituents independently selected from the group consisting of halogen, CN, C,-alkyl, halo-C₁₋₃-alkyl, OH , oxo, CO₂H, SO₃H, O-C₁₋₃-alkyl and O-halo-C₁₋₃-alkyl; R⁷ is independently selected from the group consisting of hydrogen, C₁₋₆-alkyl, halo-C₁₋₆-alkyl, C₀₋₆-alkylene-C₃₋₈-cycloalkyl, C₀₋₆-alkylene-C₃₋₈- heterocycloalkyl, 5- or 6-membered heteroaryl and phenyl, where alkyl, alkylene, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are not substituted or substituted with 1 to 6 substituents independently selected from the group consisting of halogen, CN, OH, oxo, CO₂H, C₁₋₃-alkyl, halo-C₁₋₃-alkyl, O-C₁₋₃-alkyl, O-halo-C₁₋₃-alkyl, SO₃H and SO₂-C₁₋₃-alkyl; R⁸ is independently selected from the group consisting of hydrogen, C₁₋₆-alkyl, halo-C₁₋₆-alkyl and C₃₋₆-cycloalkyl; or R⁷ and R⁸ when taken together with the nitrogen to which they are attached can form a 3- to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S or N, where the ring is not substituted or substituted with 1 to 4 substituents independently selected from the group consisting of fluoro, OH, oxo, C₁₋₄-alkyl and halo-C₁₋₄-alkyl; A is a 6-10 membered monocyclic or bicyclic aryl or a 5-10 membered monocyclic or bicyclic heteroaryl containing 1 to 5 heteroatoms independently selected from the group consisting of N, O and S, where aryl and heteroaryl do not are substituted or substituted with one or two groups independently selected from the group consisting of OH, halogen, CN, O-C₁₋₆-alkyl, O-halo-C₁₋₆-alkyl, C₁₋₆-alkyl, halo-C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₅₋₆-heterocycloalkyl and halo-C₃₋₆-cycloalkyl; Q is a C₃₋₁₀-cycloalkyl ring, or C₅₋₁₀-cycloalkyl ring where the substituent -O-CH sustitu-Z is not directly adjacent to substituent A, where if Q is a bicyclic or multicyclic ring system, an atom carbon can optionally be replaced by an oxygen, SOˣ or NR⁷; Z is selected from the group of formulas (2), where L is selected from the group consisting of a union, C₁₋₃-alkylene and C₁₋₃-alkylene-O-; And it is selected from the group consisting of phenyl, pyridyl, pyridyl N-oxide, pyrimidyl, pyridinonyl, pyrimidinonyl, C₄₋₈-cycloalkyl and C₄₋₈-heterocycloalkyl, where phenyl, pyridyl, pyridyl N-oxide, pyrimidyl, pyridinonyl, pyrimidinonyl, C₄₋₈-cycloalkyl and C₄₋₈-heterocycloalkyl are substituted with R² and R³ and optionally substituted once or twice with a group selected from fluoro, chloro, CN, NH₂, NH (C₁₋₃-alkyl), N (C₁₋₃-alkyl) ₂, C₁₋₃-alkyl, fluoro-C₁₋₃-alkyl, OH, C₁₋₃-alkoxy, fluoro-C₁₋₃-alkoxy, C₃₋₆-cycloalkyl and fluoro-C₃₋ ₆-cycloalkyl; R¹ is selected from the group consisting of C₁₋₄-alkyl and C₃₋₆-cycloalkyl, where C₁₋₄-alkyl is not substituted or substituted with 1 to 3 substituents independently selected from the group consisting of fluoro, hydroxy, C₁₋₃-alkoxy and fluoro-C₁₋₃-alkoxy, and C₃₋₆-cycloalkyl is not substituted or substituted with 1 to 3 substituents independently selected from the group consisting of fluoro, hydroxy, C₁₋₃ -alkyl, fluoro-C₁₋₃-alkyl, C₁₋₃-alkoxy and fluoro-C₁₋₃-alkoxy; R² and R³ are independently selected from the group consisting of hydrogen, halogen, C₁₋₃-alkyl, halo-C₁₋₃-alkyl, C₁₋₃-alkoxy, halo-C₁₋₃-alkoxy, cyclopropyl and fluoro- cyclopropyl; R⁴ is selected. independently from the group consisting of halogen, C₁₋₃-alkyl, halo-C₁₋₃-alkyl, C₁₋₃-alkoxy, halo-C₁₋₃-alkoxy, C₁₋₃-cycloalkyl, C₁₋₃-alkylene -O-C₁₋₃-alkyl and fluoro-C₁₋₃-cycloalkyl; R⁵ is selected from the group consisting of hydrogen, fluoro, CH₃, CHF₂ and CF₃; n is selected from 0, 1, 2, 3 and 4; x is independently selected between 0, 1 and 2.

ARP150104132A 2015-12-17 2015-12-17 FXR MODULATING COMPOUNDS (NR1H4) CONTAINING HYDROXY GROUPS AR103065A1 (en)

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