AR101208A1 - Espirocicloheptanos como inhibidores de rock - Google Patents

Espirocicloheptanos como inhibidores de rock

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AR101208A1
AR101208A1 ARP150102245A ARP150102245A AR101208A1 AR 101208 A1 AR101208 A1 AR 101208A1 AR P150102245 A ARP150102245 A AR P150102245A AR P150102245 A ARP150102245 A AR P150102245A AR 101208 A1 AR101208 A1 AR 101208A1
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Argentina
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alkyl
heterocycle
carbocycle
alkoxy
substituted
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ARP150102245A
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Wang Yufeng
Hu Zilun
W Glunz Peter
Ladziata Vladimir
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Bristol Myers Squibb Co
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Abstract

Estos compuestos son inhibidores de ROCK selectivos. También composiciones farmacéuticas que comprenden estos compuestos y métodos para tratar trastornos cardiovasculares, trastornos relacionados con el músculo liso, trastornos oncológicos, trastornos neuropatológicos, trastornos autoinmunitarios, trastornos fibróticos y/o trastornos inflamatorios mediante su uso. Reivindicación 1: Un compuesto, caracterizado porque tiene la fórmula (1), o un estereoisómero, un tautómero o una sal de aquel aceptable desde el punto de vista farmacéutico, en donde: el anillo A es un carbociclo espiro bicíclico de 5 a 9 miembros; el anillo B se selecciona de C₅₋₆ carbociclo y heterociclo de 5 a 6 miembros; - - - - es un enlace opcional; M está ausente o se selecciona de N y CR¹⁰; L se selecciona de -(CR⁴R⁴)₀₋₁-, -(CR⁴R⁴)₀₋₁C₍O₎₋, ₋OC₍O₎₋, ₋NR⁶C(O)- y -NR⁶-; R¹ se selecciona de NR⁵R⁵, OR⁵, -(CR⁴R⁴)ₙ-C₃₋₁₀ carbociclo y -(CR⁴R⁴)ₙ-heterociclo de 4 a 15 miembros que comprende átomos de carbono y 1 - 4 heteroátomos seleccionados de N, NR⁸, O y S(O)ₚ; en donde el alquilo, carbociclo y heterociclo se sustituyen con 1 - 4 R⁷; R², en cada caso, se selecciona independientemente de halógeno, C₁₋₆ alquilo, C₁₋₄ alcoxi, C₁₋₄ alquiltio, C₁₋₄ haloalquilo, -OH, -CH₂OH, -OCH₂F, -OCHF₂, -OCF₃, CN, -NH₂, -NH(C₁₋₄ alquilo), -N(C₁₋₄ alquilo)₂, -CO₂H, -CH₂CO₂H, -CO₂(C₁₋₄ alquilo), -CO(C₁₋₄ alquilo), -CH₂NH₂, -CONH₂, -CONH(C₁₋₄ alquilo), -CON(C₁₋₄ alquilo)₂, -OCH₂CO₂H, -NHCO(C₁₋₄ alquilo), -NHCO₂(C₁₋₄ alquilo), -NHSO₂(C₁₋₄ alquilo), -SO₂NH₂, -C(=NH)NH₂, un carbociclo y un heterociclo, en donde el alquilo, alcoxi, alquiltio, haloalquilo, carbociclo y heterociclo se sustituyen con 0 - 4 R⁹; R³, en cada caso, se selecciona independientemente de halógeno, C₁₋₆ alquilo, C₁₋₄ alcoxi, C₁₋₄ alquiltio, C₁₋₄ haloalquilo, -CH₂OH, -OCH₂F, -OCHF₂, -OCF₃, CN, -NH, -NH(C₁₋₄ alquilo), -N(C₁₋₄ alquilo)₂, -CO₂H, -CH₂CO₂H, -CO₂(C₁₋₆ alquilo), -CO(C₁₋₄ alquilo), -CH₂NH₂, -CONH₂, -CONH(C₁₋₄ alquilo), -CON(C₁₋₄ alquilo)₂, -OCH₂CO₂H, -NHCO(C₁₋₄ alquilo), -NHCO₂(C₁₋₄ alquilo), -NHSO₂(C₁₋₄ alquilo), -SO₂NH₂, -C(=NH)NH₂, un carbociclo y un heterociclo, en donde el alquilo, alcoxi, alquiltio, haloalquilo, carbociclo y heterociclo se sustituyen con 0 - 4 R⁹; R⁴, en cada caso, se selecciona independientemente de H, OH, NH₂, CH₂NH₂, C₁₋₄-haloalquilo, OCH₂F, OCHF₂, OCF₃, -NH(C₁₋₄ alquilo), -N(C₁₋₄ alquilo)₂, C₁₋₄ alcoxi, CH₂OH, CH₂O(C₁₋₄ alquilo), CH₂CO₂H, CH₂CO₂(C₁₋₄ alquilo), C₁₋₄ alquilo, un carbociclo y un heterociclo, en donde el alquilo, alcoxi, haloalquilo, carbociclo y heterociclo se sustituyen con 0 - 4 R⁹; R⁵, en cada caso, se selecciona independientemente de H, C₁₋₄ alquilo, -(CR⁶R⁶)ₙ-C₃₋₁₀ carbociclo y -(CR⁶R⁶)ₙ-heterociclo de 4 a 10 miembros que comprende átomos de carbono y 1 - 4 heteroátomos seleccionados de N, NR⁸, O y S(O)ₚ, en donde el alquilo, carbociclo y heterociclo se sustituyen con 1 - 4 R⁷; alternativamente, R⁵ y R⁵ se toman junto con el átomo de nitrógeno al que están unidos para formar un heterociclo de 4 a 15 miembros sustituido con 1 - 4 R⁷; R⁶, en cada caso, se selecciona independientemente de H, C₁₋₄ alquilo, CH₂NH₂, C₁₋₄ haloalquilo, C₁₋₄ alcoxi, CH₂OH, CH₂O(C₁₋₄ alquilo), CH₂CO₂H, CH₂CO₂(C₁₋₄ alquilo), un carbociclo y un heterociclo, en donde el alquilo, alcoxi, haloalquilo, carbociclo y heterociclo se sustituyen con 0 - 4 R⁹; alternativamente, R¹ y R⁶ se toman junto con el átomo de nitrógeno al que están unidos para formar un heterociclo que comprende átomos de carbono y 1 - 4 heteroátomos seleccionados de N, NR⁸, O y S(O)ₚ, y se sustituye con 1 - 4 R⁷; R⁷, en cada caso, se selecciona independientemente de H, =O, NO₂, halógeno, C₁₋₄ alquilo, C₁₋₄, alquilo, C₂₋₄ alquenilo, C₂₋₄ alquinilo, C₁₋₄ alcoxi, CN, OH, CHF₂, CF₃, -(CH₂)ₙ-CO₂H, -(CH₂)ₙ-CO₂(C₁₋₄ alquilo), -(CH₂)ₙ-NR⁸R⁸, -NHCOH, -NHCO(C₁₋₄ alquilo), -NHCOCF₃, -NHCO₂(C₁₋₄ alquilo), -NHCO₂(CH₂)₂O(C₁₋₄ alquilo), -NHCO₂(CH₂)₃O(C₁₋₄ alquilo), -NHCO₂(CH₂)₂OH, -NHCO₂(CH₂)₂NH₂, -NHCO₂(CH₂)₂N(C₁₋₄ alquilo)₂, -NHCO₂CH₂CO₂H, -CH₂NHCO₂(C₁₋₄ alquilo), -NHC(O)NR⁸R⁸, -NHSO₂(C₁₋₄ alquilo), -S(O)ₚ(C₁₋₄ alquilo), -SO₂NH₂, -SO₂NH(C₁₋₄ alquilo), -SO₂N(C₁₋₄ alquilo)₂, -SO₂NH(CH₂)₂OH, -SO₂NH(CH₂)₂O(C₁₋₄ alquilo), -(CH₂)ₙ-CONR⁸R⁸, -O(CH₂)ₙ-carbociclo, -O(CH₂)ₙ-heterociclo, -NHCO-carbociclo, -NHCO-heterociclo, -(CH₂)ₙ-carbociclo y -(CH₂)ₙ-heterociclo que comprende átomos de carbono, y 1 - 4 heteroátomos seleccionados de N, NR⁸, O y S(O)ₚ, en donde el alquilo, alquenilo, alquinilo, alcoxilo, carbociclo y heterociclo se sustituyen con 0 - 4 R⁹; R⁸, en cada caso, se selecciona independientemente de H, C₁₋₆ alquilo, C₁₋₄ alquilo, C₂₋₄ alquenilo, C₂₋₄ alquinilo, -(CH₂)ₙ-C(O)C₁₋₄ alquilo, -(CH₂)ₙ-C(O)carbociclo, -(CH₂)ₙ-C(O)heterociclo, -(CH₂)ₙ-C(O)NRᵃRᵃ, -(CH₂)ₙ-NRᵃC(O)C₁₋₄ alquilo, -(CH₂)ₙ-C(O)OC₁₋₄ alquilo, -(CH₂)ₙ-C(O)C₁₋₄ alquilo, -(CH₂)ₙ-C(O)O-carbociclo, -(CH₂)ₙ-C(O)O-heterociclo, -(CH₂)ₙ-SO₂-alquilo, -(CH₂)ₙ-SO₂-carbociclo, -(CH₂)ₙ-SO₂-heterociclo, -(CH₂)ₙ-SO₂NRᵃRᵃ, -(CH₂)ₙ-carbociclo y -(CH₂)ₙ-heterociclo, en donde el alquilo, carbociclo y heterociclo se sustituyen con 0 - 4 R⁹; alternativamente, R⁸ y R⁸ se toman junto con el átomo de nitrógeno al que están unidos para formar un heterociclo de 4 a 10 miembros sustituido con 0 - 4 R⁹; R⁹, en cada caso, se selecciona independientemente de halógeno, OH, =O, CN, NO₂, CHF₂, CF₃, C₁₋₄ alquilo, C₁₋₄ alcoxi, CH₂OH, CO(C₁₋₄ alquilo), CO₂H, CO₂(C₁₋₄ alquilo), -(CHR¹⁰)ₙNRᵃRᵃ, -(CHR¹⁰)ₙCONRᵃRᵃ, -(CHR¹⁰)ₙNRᵃCO(C₁₋₄ alquilo), -O(CHR¹⁰)ₙ-carbonilo, -O(CHR¹⁰)ₙ-heterociclo, -O(CHR¹⁰)ₙNRᵃRᵃ y -(CR¹⁰R¹⁰)ₙ-heterociclo de 4 a 10 miembros, en donde el alquilo, alcoxi, carbociclo y heterociclo se sustituyen con 0 - 4 Rᵇ; R¹⁰ se selecciona de H y C₁₋₄ alquilo; Rᵃ, en cada caso, se selecciona independientemente de H, C₁₋₄ alquilo, -(CH₂)ₙOH, CO(C₁₋₄ alquilo), COCF₃, CO₂(C₁₋₄ alquilo), -CONH₂, -CONH-C₁₋₄ alquilen-CO₂(C₁₋₄ alquilo), C₁₋₄ alquilen-CO₂(C₁₋₄ alquilo), Rᶜ, CO₂Rᶜ y CONHRᶜ; alternativamente, Rᵃ y Rᵃ se toman junto con el átomo de nitrógeno al que están unidos para formar un heterociclo de 4 a 10 miembros, en donde el alquilo, alquileno y heterociclo se sustituyen con 0 - 4 Rᵇ; Rᵇ, en cada caso, se selecciona independientemente de =O, OH, halógeno, C₁₋₄ alquilo, C₁₋₄ alcoxi, OCF₃, OC(O)C₁₋₄ alquilo, NH₂, NO₂, N(C₁₋₄ alquilo)₂, CO(C₁₋₄ alquilo), CO(C₁₋₄ haloalquilo), CO₂(C₁₋₄ alquilo), CONH₂, -CONH(C₁₋₄ alquilo), -CON(C₁₋₄ alquilo)₂, -CONH-C₁₋₄ alquilen-O(C₁₋₄ alquilo), -CONH-C₁₋₄ alquilen-N(C₁₋₄ alquilo)₂, -CONH-C₁₋₄ alquilen-N(C₁₋₄ alquilo)₂, -C₁₋₄ alquilen-O-P(O)(OH)₂, -NHCO₂(C₁₋₄ alquilo), -Rᶜ, CORᶜ, CO₂Rᶜ y CONHRᶜ, en donde el alquilo y alcoxi se sustituyen con Rᵈ; Rᶜ, en cada caso, se selecciona independientemente de -(CH₂)ₙ-C₃₋₆ cicloalquilo, -(CH₂)ₙ-fenilo y -(CH₂)ₙ-heterociclo de 5 a 6 miembros que contiene átomos de carbono y 1 - 4 heteroátomos seleccionados del grupo que consiste en: N, NH, N(C₁₋₄ alquilo), O y S(O)ₚ; en donde cada porción del anillo se sustituye con 0 - 2 Rᵈ; Rᵈ, en cada caso, se selecciona independientemente de =O, halógeno, -OH, C₁₋₄ alquilo, NH₂, NH(C₁₋₄ alquilo), N(C₁₋₄ alquilo)₂, C₁₋₄ alcoxi y -NHCO(C₁₋₄ alquilo), y un heterociclo que contiene átomos de carbono y 1 - 4 heteroátomos seleccionados del grupo que consiste en: N, NH, N(C₁₋₄ alquilo), O y S(O)ₚ; n, en cada caso, se selecciona independientemente de 0, 1, 2, 3 y 4; y p, en cada caso, se selecciona independientemente de 0, 1 y 2.
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