AR122628A1 - 2-oxoimidazolidin-4-carboxamidas como inhibidores de nav1.8 - Google Patents

2-oxoimidazolidin-4-carboxamidas como inhibidores de nav1.8

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AR122628A1
AR122628A1 ARP210101629A ARP210101629A AR122628A1 AR 122628 A1 AR122628 A1 AR 122628A1 AR P210101629 A ARP210101629 A AR P210101629A AR P210101629 A ARP210101629 A AR P210101629A AR 122628 A1 AR122628 A1 AR 122628A1
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Argentina
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alkyl
cycloalkyl
cycloheteroalkyl
heteroaryl
aryl
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ARP210101629A
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Ashok Arasappan
Ian M Bell
Christopher James Bungard
Christopher S Burgey
Jason M Cox
Michael J Kelly
Mark Eric Layton
Hong Liu
Jian Liu
James J Perkins
Akshay A Shah
Michael D Vanheyst
Zhe Wu
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Merck Sharp & Dohme
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Publication of AR122628A1 publication Critical patent/AR122628A1/es

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Abstract

Reivindicación 1: Un compuesto de fórmula estructural (1) o una sal farmacéuticamente aceptable de los mismos, en donde uno de A y B se selecciona de: 1) arilo, y 2) heteroarilo, en donde el arilo y el heteroarilo están sin sustituir o sustituidos con uno a cinco sustituyentes seleccionados de Rᵃ, y el otro de A y B se selecciona de: 1) arilo, 2) heteroarilo, 3) -alquil C₁₋₆-arilo, 4) -cicloalquil C₃₋₈-arilo, 5) -cicloheteroalquil C₂₋₈-arilo, 6) -alquil C₁₋₆-heteroarilo, 7) -cicloalquil C₃₋₈-heteroarilo, 8) -cicloheteroalquil C₂₋₈-heteroarilo, 9) -alquil C₁₋₆-O-arilo, 10) -alquil C₁₋₆-O-heteroarilo, 11) -cicloalquilo C₃₋₁₂, 12) -cicloheteroalquilo C₂₋₁₂, 13) -alquil C₁₋₆-cicloalquilo C₃₋₁₂, 14) -alquil C₁₋₆-cicloheteroalquilo C₂₋₁₂, 15) -alquil C₁₋₆-O-cicloalquilo C₃₋₁₂, 16) -alquil C₁₋₆-O-cicloheteroalquilo C₂₋₁₂, 17) -alquil C₀₋₆-arilo condensado con un cicloalquilo C₄₋₆ o cicloheteroalquilo C₄₋₆ que contiene 1 - 3 heteroátomos seleccionados independientemente de O, S y N(Rʰ)₂, 18) -alquil C₀₋₆-arilo condensado con un cicloalquenilo C₄₋₆ o cicloheteroalquenilo C₄₋₆ que contiene 1 - 3 heteroátomos seleccionados independientemente de O, S y N(Rʰ)₂, 19) -alquil C₀₋₆-heteroarilo condensado con cicloalquilo C₄₋₆ o cicloheteroalquilo C₄₋₆ que contiene 1 - 3 heteroátomos seleccionados independientemente de O, S y N(Rʰ)₂, y 20) -alquil C₀₋₆-heteroarilo condensado con cicloalquenilo C₄₋₆ o cicloheteroalquenilo C₄₋₆ que contiene 1 - 3 heteroátomos seleccionados independientemente de O, S y N(Rʰ)₂, en donde el alquilo, cicloalquilo, cicloheteroalquilo, cicloalquenilo, arilo y heteroarilo están sin sustituir o sustituidos con uno a cinco sustituyentes seleccionados de Rᵇ; R¹ se selecciona del grupo que consiste en: 1) hidrógeno, 2) -alquilo C₁₋₆, 3) -alquenilo C₃₋₆, 4) -alquinilo C₃₋₆, 5) -cicloalquilo C₃₋₁₀, 6) -cicloheteroalquilo C₂₋₁₀, 7) -alquil C₁₋₆-O-alquil C₁₋₆-, 8) -(CH₂)ₛC(O)Rʲ, 9) -(CH₂)ₛC(O)NRᵉRʲ, 10) -(CH₂)ₙNRᵉC(O)Rʲ, 11) -(CH₂)ₙNRᵉC(O)ORʲ, 12) -(CH₂)ₙNRᵉC(O)N(Rᵉ)₂, 13) -(CH₂)ₙNRᵉC(O)NRᵉRʲ, 14) -(CH₂)ₙNRᵉS(O)ₘRʲ, 15) -(CH₂)ₙNRᵉS(O)ₘN(Rᵉ)₂, 16) -(CH₂)ₙNRᵉS(O)ₘNRᵉRʲ, y 17) -(CH₂)ₙNRᵉRʲ, en donde cada CH₂, alquilo, alquenilo, alquinilo, cicloalquilo y cicloheteroalquilo está sin sustituir o sustituido con uno a cinco sustituyentes seleccionados de Rᶜ; R² se selecciona del grupo que consiste en: 1) hidrógeno, 2) -alquilo C₁₋₆, 3) -alquenilo C₃₋₆, 4) -alquinilo C₃₋₆, 5) -cicloalquilo C₃₋₁₀, 6) -cicloheteroalquilo C₂₋₁₀, 7) -alquil C₁₋₆-O-alquil C₁₋₆-, 8) -(CH₂)ₛC(O)Rʲ, 9) -(CH₂)ₛC(O)NRᵉRʲ, 10) -(CH₂)ₙNRᵉC(O)Rʲ, 11) -(CH₂)ₙNRᵉC(O)ORʲ, 12) -(CH₂)ₙNRᵉC(O)N(Rᵉ)₂, 13) -(CH₂)ₙNRᵉC(O)NRᵉRʲ, 14) -(CH₂)ₙNRᵉS(O)ₘRʲ, 15) -(CH₂)ₙNRᵉS(O)ₘN(Rᵉ)₂, 16) -(CH₂)ₙNRᵉS(O)ₘNRᵉRʲ, y 17) -(CH₂)ₙNRᵉRʲ, en donde cada CH₂, alquilo, alquenilo, alquinilo, cicloalquilo y cicloheteroalquilo está sin sustituir o sustituido con uno a cinco sustituyentes seleccionados de Rᵈ; R³ se selecciona del grupo que consiste en: 1) hidrógeno, 2) -alquilo C₁₋₆, 3) -alquenilo C₂₋₆, 4) -alquinilo C₂₋₆, 5) -cicloalquilo C₃₋₁₀, 6) -cicloheteroalquilo C₂₋₁₀, 7) -alquil C₁₋₆-O-alquil C₁₋₆-, 8) -(CH₂)ₛC(O)Rʲ, 9) -(CH₂)ₛC(O)NRᵉRʲ, 10) -(CH₂)ₛNRᵉC(O)Rʲ, 11) -(CH₂)ₛNRᵉC(O)ORʲ, 12) -(CH₂)ₛNRᵉC(O)N(Rᵉ)₂, 13) -(CH₂)ₛNRᵉC(O)NRᵉRʲ, 14) -(CH₂)ₛNRᵉS(O)ₘRʲ, 15) -(CH₂)ₛNRᵉS(O)ₘN(Rᵉ)₂, 16) -(CH₂)ₛNRᵉS(O)ₘNRᵉRʲ, y 17) -(CH₂)ₛNRᵉRʲ, en donde cada CH₂, alquilo, alquenilo, alquinilo, cicloalquilo y cicloheteroalquilo está sin sustituir o sustituido con uno a cinco sustituyentes seleccionados de Rᶠ, y en donde R³ y R⁴ y los átomos de carbono a los que están unidos pueden formar un anillo cicloalquilo -C₃₋₅; R⁴ se selecciona del grupo que consiste en: 1) hidrógeno, 2) -alquilo C₁₋₆, 3) -alquenilo C₂₋₆, 4) -alquinilo C₂₋₆, 5) -cicloalquilo C₃₋₁₀, 6) -cicloheteroalquilo C₂₋₁₀, 7) -alquil C₁₋₆-O-alquil C₁₋₆-, 8) -(CH₂)ₛC(O)Rʲ, 9) -(CH₂)ₛC(O)NRᵉRʲ, 10) -(CH₂)ₛNRᵉC(O)Rʲ, 11) -(CH₂)ₛNRᵉC(O)ORʲ, 12) -(CH₂)ₛNRᵉC(O)N(Rᵉ)₂, 13) -(CH₂)ₛNRᵉC(O)NRᵉRʲ, 14) -(CH₂)ₛNRᵉS(O)ₘRʲ, 15) -(CH₂)ₛNRᵉS(O)ₘN(Rᵉ)₂, 16) -(CH₂)ₛNRᵉS(O)ₘNRᵉRʲ, y 17) -(CH₂)ₛNRᵉRʲ, en donde cada CH₂, alquilo, alquenilo, alquinilo, cicloalquilo y cicloheteroalquilo está sin sustituir o sustituido con uno a cinco sustituyentes seleccionados de Rᵍ; R⁵ se selecciona del grupo que consiste en: 1) hidrógeno, y 2) -alquilo C₁₋₆, en donde cada alquilo está sin sustituir o sustituido con uno a cinco sustituyentes halógeno; R⁶ se selecciona del grupo que consiste en: 1) hidrógeno, 2) -alquilo C₁₋₆, 3) -cicloalquilo C₃₋₆, y 4) -cicloheteroalquilo C₂₋₆, en donde cada alquilo, cicloalquilo y cicloheteroalquilo está sin sustituir o sustituido con uno a cinco sustituyentes halógeno; R⁷ se selecciona del grupo que consiste en: 1) hidrógeno, 2) -alquilo C₁₋₆, 3) -alquenilo C₂₋₆, y 4) -alquinilo C₂₋₆, en donde cada alquilo, alquenilo y alquinilo está sin sustituir o sustituido con uno a cinco sustituyentes halógeno; cada Rᵃ se selecciona independientemente del grupo que consiste en: 1) -CF₃, 2) -OCF₃, 3) -CHF₂, 4) -OCHF₂, 5) -CH₂CF₃, 6) -OCH₂CF₃, 7) -CF₂CH₃, 8) CN, 9) oxo, 10) halógeno, 11) -S(O)₂alquilo C₁₋₆, 12) -alquilo C₁₋₆, 13) -alquenilo C₂₋₆, 14) -alquinilo C₂₋₆, 15) -cicloalquilo C₃₋₆, 16) -cicloheteroalquilo C₂₋₆, 17) arilo, 18) heteroarilo, 19) -alquil C₁₋₆-arilo, 20) -alquil C₁₋₆-heteroarilo, 21) -alquil C₁₋₆-cicloalquilo C₃₋₆, 22) -alquil C₁₋₆-cicloheteroalquilo C₂₋₆, 23) -alquenil C₂₋₆-cicloalquilo C₃₋₆, 24) -alquenil C₂₋₆-cicloheteroalquilo C₂₋₆, 25) -alquenil C₂₋₆-arilo, 26) -alquenil C₂₋₆-heteroarilo, 27) -alquinil C₂₋₆-cicloalquilo C₃₋₆, 28) -alquinil C₂₋₆-cicloheteroalquilo C₂₋₆, 29) -alquinil C₂₋₆-arilo, 30) -alquinil C₂₋₆-heteroarilo, 31) -OH, 32) -(CH₂)ₚ-O-alquilo C₁₋₆, 33) -(CH₂)ₚ-O-alquenilo C₂₋₆, 34) -(CH₂)ₚ-O-alquinilo C₂₋₆, 35) -(CH₂)ₚ-O-cicloalquilo C₃₋₆, 36) -(CH₂)ₚ-O-heterocicloalquilo C₂₋₆, 37) -(CH₂)ₚ-O-arilo, 38) -(CH₂)ₚ-O-heteroarilo, 39) -O-alquil C₁₋₆-cicloalquilo C₃₋₆, 40) -O-alquil C₁₋₆-heterocicloalquilo C₂₋₆, 41) -O-alquil C₁₋₆-arilo, 42) -O-alquil C₁₋₆-heteroarilo, 43) -S(O)ₘRⁱ, 44) -alquil C₁₋₆-S(O)ₘRⁱ, 45) -N(Rᵏ)₂, y 46) -NRᵏRL, en donde cada Rᵃ está sin sustituir o sustituido con uno a seis sustituyentes seleccionados de halógeno, CF₃, OH, alquilo C₁₋₆ y -O-alquilo C₁₋₆; cada Rᵇ se selecciona independientemente del grupo que consiste en: 1) -CF₃, 2) -OCF₃, 3) -CHF₂, 4) -OCHF₂, 5) -CH₂CF₃, 6) -OCH₂CF₃, 7) -CF₂CH3, 8) CN, 9) oxo, 10) halógeno, 11) -S(O)₂alquilo C₁₋₆, 12) -alquilo C₁₋₆, 13) -alquenilo C₂₋₆, 14) -alquinilo C₂₋₆, 15) -O-alquilo C₁₋₆, 16) -cicloalquilo C₃₋₆, 17) -O-cicloalquilo C₃₋₆, 18) -cicloheteroalquilo C₂₋₆, 19) arilo, 20) heteroarilo, 21) -alquil C₁₋₆-arilo, 22) -alquil C₁₋₆-heteroarilo, 23) -alquil C₁₋₆-cicloalquilo C₃₋₆, 24) -alquil C₁₋₆-cicloheteroalquilo C₂₋₆, 25) -alquenil C₂₋₆-cicloalquilo C₃₋₆, 26) -alquenil C₂₋₆-cicloheteroalquilo C₂₋₆, 27) -alquenil C₂₋₆-arilo, 28) -alquenil C₂₋₆-heteroarilo, 29) -alquinil C₂₋₆-cicloalquilo C₃₋₆, 30) -alquinil C₂₋₆-cicloheteroalquilo C₂₋₆, 31) -alquinil C₂₋₆-arilo, 32) -alquinil C₂₋₆-heteroarilo, 33) -OH, 34) -(CH₂)q-O-alquilo C₁₋₆, 35) -(CH₂)q-O-alquenilo C₂₋₆, 36) -(CH₂)q-O-alquinilo C₂₋₆, 37) -(CH₂)q-O-cicloalquilo C₃₋₆, 38) -(CH₂)q-O-heterocicloalquilo C₂₋₆, 39) -(CH₂)q-O-arilo, 40) -(CH₂)q-O-heteroarilo, 41) -O-alquil C₁₋₆-cicloalquilo C₃₋₆, 42) -O-alquil C₁₋₆-heterocicloalquilo C₂₋₆, 43) -O-alquil C₁₋₆-arilo, 44) -O-alquil C₁₋₆-heteroarilo, 45) -S(O)ₘRⁱ, 46) -alquil C₁₋₆-S(O)ₘRⁱ, 47) -C(O)RL, y 48) -NRᵏRL, en donde cada Rᵇ está sin sustituir o sustituido con uno a seis sustituyentes seleccionados de halógeno, CF₃, OCF₃, CN, CH₂CF₃, CF₂CH₃, -alquilo C₁₋₆ y -O-alquilo C₁₋₆; Rᶜ se selecciona de: 1) -alquilo C₁₋₆, 2) OH, 3) halógeno, y 4) -O-alquilo C₁₋₆, en donde el alquilo puede estar sin sustituir o sustituido con uno a tres halógenos; Rᵈ se selecciona de: 1) -alquilo C₁₋₆, 2) OH, 3) halógeno, y 4) -O-alquilo C₁₋₆, en donde el alquilo puede estar sin sustituir o sustituido con uno a tres halógenos; Rᵉ se selecciona de: 1) hidrógeno, y 2) alquilo C₁₋₆; Rᶠ se selecciona de: 1) -alquilo C₁₋₆, 2) OH, 3) halógeno, y 4) -O-alquilo C₁₋₆, en donde el alquilo puede estar sin sustituir o sustituido con uno a tres halógenos; Rᵍ se selecciona de: 1) -alquilo C₁₋₆, 2) OH, 3) halógeno, y 4) -O-alquilo C₁₋₆, en donde el alquilo puede estar sin sustituir o sustituido con uno a tres halógenos; Rʰ se selecciona de: 1) hidrógeno, y 2) alquilo C₁₋₆; Rⁱ se selecciona de: 1) hidrógeno, 2) alquilo C₁₋₆, 3) cicloalquilo C₃₋₆, 4) arilo, y 5) heteroarilo; Rʲ se selecciona de: 1) hidrógeno, 2) alquilo C₁₋₆, 3) alquenilo C₃₋₆, 4) alquinilo C₃₋₆, 5) cicloalquilo C₃₋₆, 6) cicloheteroalquilo C₂₋₅, 7) arilo, y 8) heteroarilo; Rᵏ se selecciona de: 1) hidrógeno, y 2) alquilo C₁₋₆; RL se selecciona de: 1) hidrógeno, 2) alquilo C₁₋₆, 3) cicloalquilo C₃₋₆, 4) arilo, y 5) heteroarilo; m se selecciona independientemente de 0 a 2; n se selecciona independientemente de 2 a 6; p se selecciona independientemente de 0 a 3; q se selecciona independientemente de 0 a 3; r se selecciona independientemente de 0 a 2; y s se selecciona independientemente de 0 a 6.
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