AR116939A1 - 2-amino-n-heteroaril-nicotinamidas como inhibidores de nav1.8 - Google Patents

2-amino-n-heteroaril-nicotinamidas como inhibidores de nav1.8

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AR116939A1
AR116939A1 ARP190103169A ARP190103169A AR116939A1 AR 116939 A1 AR116939 A1 AR 116939A1 AR P190103169 A ARP190103169 A AR P190103169A AR P190103169 A ARP190103169 A AR P190103169A AR 116939 A1 AR116939 A1 AR 116939A1
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Argentina
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6alkyl
heteroaryl
aryl
6alkenyl
group
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ARP190103169A
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Merck Sharp & Dohme
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Abstract

Compuestos derivados de nicotinamida como inhibidores de la actividad de los canales de sodio Naᵛ1.8, composiciones farmacéuticas que los comprenden y su uso en el tratamiento o prevención del dolor, tales como el dolor agudo, dolor neuropático, dolor inflamatorio y trastornos de picazón aguda y crónica. Reivindicación 1: Un compuesto de la fórmula estructural [1], o una sal farmacéuticamente aceptable del mismo, en donde A es heteroarilo o heteroarilo fusionado con un anillo de 5 ó 6 miembros saturado o insaturado que contiene 0 - 3 heteroátomos seleccionados independientemente de O, S y N(Rʰ)q, en donde cada heteroarilo, anillo de 5 miembros y anillo de 6 miembros no está sustituido o está sustituido con uno a cinco sustituyentes seleccionados de Rᵃ; B es heteroarilo, en donde el heteroarilo no está sustituido o está sustituido con uno a tres sustituyentes seleccionados de Rᵇ; R¹ se selecciona del grupo que consiste en: (1) hidrógeno, (2) -SO₃H, (3) -SO₂NH₂, (4) -SO₂NRᵉC₁₋₆alquilo, (5) -SO₂NRᵉC(O)C₁₋₆alquilo, (6) -SO₂NRᵉC₂₋₆alquenilo, (7) -SO₂NRᵉC₃₋₆cicloalquilo, (8) -SO₂NRᵉC(O)C₃₋₆cicloalquilo, (9) -SO₂NRᵉC₂₋₆cicloheteroalquilo, (10) -SO₂NRᵉC(O)C₂₋₆cicloheteroalquilo, (11) -SO₂NRᵉ-arilo, (12) -SO₂NRᵉ-heteroarilo, (13) SO₂C₁₋₆alquilo, (14) -SO₂C₁₋₆alquenilo, (15) -SO₂C₃₋₆cicloalquilo, (16) -SO₂C₂₋₆cicloheteroalquilo, (17) -SO₂arilo, (18) -SO₂heteroarilo, (19) -S(O)Rʲ, (20) -SRʲ, (21) -C(O)NH₂, (22) -C(O)NRᵉRʲ, (23) -CO₂H, (24) -CO₂Rʲ, (25) -C(O)Rʲ, (26) -CN, (27) CF₃, (28) halógeno, (29) -OH, (30) -OC₁₋₆alquilo, (31) -OC₂₋₆alquenilo, (32) -OC₃₋₆cicloalquilo, (33) -OC₂₋₆cicloheteroalquilo, (34) -O-arilo, (35) -O-heteroarilo, (36) -OC(O)Rʲ, (37) -OC(O)NRᵉRʲ, (38) -OC(O)N(Rʲ)₂, (39) -C₁₋₆alquilo, (40) -C₂₋₆alquenilo, (41) -C₁₋₆cicloalquilo, (42) -C₂₋₆cicloheteroalquilo, (43) arilo, (44) heteroarilo, (45) -(CH₂)ₙNRᵉC(O)Rʲ, (46) -(CH₂)ₙNRᵉC(O)ORʲ, (47) -(CH₂)ₙNRᵉC(O)N(Rᵉ)₂, (48) -(CH₂)ₙNRᵉC(O)NRᵉRʲ, (49) -(CH₂)ₙNRᵉC(O)N(Rʲ)₂, (50) -(CH₂)ₙNRᵉS(O)ₘRʲ, (51) -(CH₂)ₙNRᵉS(O)ₘN(Rᵉ)₂, (52) -(CH₂)ₙNRᵉS(O)ₘNRᵉRʲ, (53) -(CH₂)ₙNRᵉS(O)ₘN(Rʲ)₂, y (54) -(CH₂)ₙNRᵉRʲ, en donde cada CH₂, alquilo, alquenilo, cicloalquilo, cicloheteroalquilo, arilo y heteroarilo no está sustituido o está sustituido con uno a cuatro sustituyentes seleccionados de Rᵈ; R² se selecciona del grupo que consiste en: (1) hidrógeno, y (2) -C₁₋₆alquilo; R³ se selecciona del grupo que consiste en: (1) un anillo de C₃₋₁₂cicloalquilo monocíclico, bicíclico o espirocíclico, y (2) un anillo de C₂₋₁₂cicloheteroalquilo monocíclico, bicíclico o espirocíclico, en donde el cicloheteroalquilo contiene 1 - 4 heteroátomos seleccionados independientemente de N(Rᵐ)ʳ, O y S, en donde cada anillo de cicloalquilo y cada anillo de cicloheteroalquilo se pueden fusionar con un arilo o heteroarilo, y en donde cada cicloalquilo, cicloheteroalquilo, arilo y heteroarilo no está sustituido o está sustituido con uno a ocho sustituyentes seleccionados de Rᶜ; cada Rᵃ se selecciona del grupo que consiste en: (1) -C₁₋₆alquilo, (2) -OC₁₋₆alquilo, (3) halógeno, (4) -OH, (5) oxo, (6) -CN, (7) -C₃₋₆cicloalquilo, y (8) -C₂₋₅cicloheteroalquilo, en donde cada alquilo, cicloalquilo y cicloheteroalquilo no está sustituido o está sustituido con uno a seis sustituyentes seleccionados de halógeno, OH, NH₂, NH(C₁₋₆alquilo) y N(C₁₋₆alquilo)₂; cada Rᵇ se selecciona independientemente del grupo que consiste en: (1) -CF₃, (2) -CF₂CF₃, (3) -CHF₂, (4) -OCHF₂, (5) -OCH₂CF₃, (6) -OCF₃, (7) CN, (8) halógeno, (9) -Si(C₁₋₆alquilo)₃, (10) -C₁₋₆alquil-O-Rᵏ, (11) -C₁₋₆alquilo, (12) -C₂₋₆alquenilo, (13) -C₂₋₆alquinilo, (14) -C₃₋₆cicloalquilo, (15) -C₂₋₆cicloheteroalquilo, (16) arilo, (17) heteroarilo, (18) -C₁₋₆alquil-C₃₋₆cicloalquilo, (19) -C₁₋₆alquil-C₂₋₆cicloheteroalquilo, (20) -C₁₋₆alquil-arilo, (21) -C₁₋₆alquil-heteroarilo, (22) C₂₋₆alquenil-C₃₋₆cicloalquilo, (23) -C₂₋₆alquenil-C₂₋₆cicloheteroalquilo, (24) -C₂₋₆alquenil-arilo, (25) -C₂₋₆alquenil-heteroarilo, (26) -C₂₋₆alquinil-C₃₋₆cicloalquilo, (27) -C₂₋₆alquinil-cicloheteroalquilo, (28) -C₂₋₆alquinil-arilo, (29) -C₂₋₆alquinil-heteroarilo, (30) NO₂, (31) -OH, (32) -(CH₂)ₚ-OC₁₋₆alquilo, (33) -(CH₂)ₚ-OC₂₋₆alquenilo, (34) -(CH₂)ₚ-OC₂₋₆alquinilo, (35) -(CH₂)ₚ-OC₃₋₆cicloalquilo, (36) -(CH₂)ₚ-OC₂₋₆heterocicloalquilo, (37) -(CH₂)ₚ-O-arilo, (38) -(CH₂)ₚ-O-heteroarilo, (39) -OC₁₋₆alquil-C₃₋₆cicloalquilo, (40) -OC₁₋₆alquil-C₂₋₆heterocicloalquilo, (41) -OC₁₋₆alquil-arilo, (42) -OC₁₋₆alquil-heteroarilo, (1) -S(O)ₘRᵏ, (43) -C₁₋₆alquil-S(O)ₘRᵏ, (44) -C(O)Rᵏ, (45) -N(Rⁱ)₂, y (46) -NRⁱRᵏ, en donde cada Rᵇ no está sustituido o está sustituido con uno a cinco sustituyentes seleccionados de Rᶠ; cada Rᶜ se selecciona independientemente del grupo que consiste en: (1) -CF₃, (2) -CH₂CF₃, (3) -CHF₂, (4) -OCHF₂, (5) -OCF₃, (6) CN, (7) oxo, (8) -OH, (9) halógeno, (10) -C₁₋₆alquilo, (11) -C₂₋₆alquenilo, (12) -C₂₋₆alquinilo, (13) -C₃₋₆cicloalquilo, (14) -C₂₋₆cicloheteroalquilo, (15) -C₁₋₆alquil-C₃₋₆cicloalquilo, (16) -C₁₋₆alquil-C₂₋₆cicloheteroalquilo, (17) -C₁₋₆alquil-arilo, (18) -C₁₋₆alquil-heteroarilo, (19) -C₁₋₆alquenil-C₃₋₆cicloalquilo, (20) -C₁₋₆alquenil-arilo, (21) -C₁₋₆alquenil-heteroarilo, (22) -C₁₋₆alquenil-C₂₋₆cicloheteroalquilo, (23) -C₂₋₆alquinil-C₃₋₆cicloalquilo, (24) -C₂₋₆alquinil-C₂₋₆cicloheteroalquilo, (25) -C₂₋₆alquinil-arilo, (26) -C₂₋₆alquinil-heteroarilo, (27) -OC₁₋₆alquilo, (28) -OC₂₋₆alquenilo, (29) -OC₂₋₆alquinilo, (30) -OC₃₋₆cicloalquilo, (31) -OC₂₋₆heterocicloalquilo, (32) -O-arilo, (33) -O-heteroarilo, (34) -OC₁₋₆alquil-cicloalquilo, (35) -OC₁₋₆alquil-cicloheteroalquilo, (36) -OC₁₋₆alquil-arilo, (37) -OC₁₋₆alquil-heteroarilo, (38) -S(O)ₘRL, (39) -S(O)RL, (40) -S-RL, (41) -C₁₋₆alquil-S(O)ₘRL, (42) -C(O)RL, (43) -C(O)C₁₋₆alquil-RL, (44) -OC(O)RL, (45) -CO₂RL, (46) arilo, y (47) heteroarilo, en donde cada Rᶜ no está sustituido o está sustituido con uno a cinco sustituyentes seleccionados de Rᵍ; Rᵈ se selecciona independientemente del grupo que consiste en: (1) hidrógeno, (2) halógeno, (3) OH, (4) oxo, (5) -C₁₋₆alquilo, (6) -OC₁₋₆alquilo, (7) NH₂, (8) NH(C₁₋₆alquilo), y (9) N(C₁₋₆alquilo)₂; cada Rᵉ se selecciona independientemente del grupo que consiste en: (1) hidrógeno, y (2) -C₁₋₆alquilo; cada Rᶠ se selecciona del grupo que consiste en: (1) halógeno, F, (2) -C₁₋₆alquilo, (3) -OH, (4) -OC₁₋₆alquilo, (5) -OC₃₋₆cicloalquilo, (6) -OC₂₋₆cicloheteroalquilo, (7) CN, (8) -NH₂, (9) -NH(C₁₋₆alquilo), (10) -NH(C₃₋₆cicloalquilo), (11) -NH(C₂₋₆cicloheteroalquilo), (12) -N(C₁₋₆alquilo)₂, (13) -N(C₃₋₆cicloalquilo)₂, y (14) -N(C₂₋₆cicloheteroalquilo)₂, en donde cada alquilo, cicloalquilo y cicloheteroalquilo no está sustituido o está sustituido con uno a tres sustituyentes seleccionados independientemente de: -OH, halógeno, ciano y -S(O)₂CH₃; cada Rᵍ se selecciona del grupo que consiste en: (1) halógeno, (2) C₁₋₆alquilo, (3) -OH, (4) -OC₁₋₆alquilo, (5) -S(O)ₘ-C₁₋₆alquilo, (6) -CN, (7) -CF₃, (8) -OCHF₂, y (9) -OCF₃, en donde cada alquilo no está sustituido o está sustituido con uno a tres sustituyentes seleccionados independientemente de: -OH, halógeno, ciano y -S(O)₂CH₃; cada Rʰ se selecciona independientemente del grupo que consiste en: (1) hidrógeno, y (2) -C₁₋₆alquilo; cada Rⁱ se selecciona independientemente del grupo que consiste en: (1) hidrógeno, y (2) -C₁₋₆alquilo; cada Rʲ se selecciona del grupo que consiste en: (1) -C₁₋₆alquilo, (2) -C₂₋₆alquenilo, (3) -C₃₋₆cicloalquilo, (4) -C₂₋₆cicloheteroalquilo, (5) arilo, y (6) heteroarilo, en donde cada alquilo, alquenilo, cicloalquilo, cicloheteroalquilo, arilo y heteroarilo no está sustituido o está sustituido con uno a tres sustituyentes seleccionados independientemente de: -C₁₋₆alquilo, -C₃₋₆cicloalquilo, -OH, -OC₁₋₆alquilo, -OC₃₋₆cicloalquilo, halógeno, ciano y -S(O)₂CH₃; cada Rᵏ se selecciona del grupo que consiste en: (1) -C₁₋₆alquilo, (2) -C₂₋₆alquenilo, (3) -C₃₋₆cicloalquilo, (4) -C₃₋₆cicloalquilo, (5) -C₂₋₆cicloheteroalquilo, (6) arilo, y (7) heteroarilo, en donde cada alquilo, alquenilo, cicloalquilo, cicloheteroalquilo, arilo y heteroarilo no está sustituido o está sustituido con uno a tres sustituyentes seleccionados independientemente de: -C₁₋₆alquilo, -C₃₋₆cicloalquilo, -OH, -OC₁₋₆alquilo, -OC₃₋₆cicloalquilo, halógeno, ciano y - S(O)₂CH₃; cada RL se selecciona del grupo que consiste en: (1) -C₁₋₆alquilo, (2) -C₂₋₆alquenilo, (3) -C₃₋₆cicloalquilo, (4) -C₂₋₆cicloheteroalquilo, (5) arilo, y (6) heteroarilo, en donde cada alquilo, alquenilo, cicloalquilo, cicloheteroalquilo, arilo y heteroarilo no está sustituido o está sustituido con uno a tres sustituyentes seleccionados independientemente de: -C₁₋₆alquilo, -C₃₋₆cicloalquilo, -OH, -OC₁₋₆alquilo, -OC₃₋₆cicloalquilo, halógeno, ciano y -S(O)₂CH₃; cada Rᵐ se selecciona independientemente del grupo que consiste en: (1) hidrógeno, y (2) -C₁₋₆alquilo; cada n es independientemente 0, 1, 2, 3 ó 4; cada m es independientemente 0, 1 ó 2; cada p es independientemente 0, 1, 2, 3 ó 4; cada q es independientemente 0 ó 1; y cada r es independientemente 0 ó 1.
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