AR096902A1 - Derivados de triazina y pirimidina como inhibidores de la idh1 y/o idh2 mutantes y su uso en el tratamiento del cáncer - Google Patents

Derivados de triazina y pirimidina como inhibidores de la idh1 y/o idh2 mutantes y su uso en el tratamiento del cáncer

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AR096902A1
AR096902A1 ARP140102587A ARP140102587A AR096902A1 AR 096902 A1 AR096902 A1 AR 096902A1 AR P140102587 A ARP140102587 A AR P140102587A AR P140102587 A ARP140102587 A AR P140102587A AR 096902 A1 AR096902 A1 AR 096902A1
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Argentina
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alkylene
alkyl
optionally substituted
phenyl
nhc
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ARP140102587A
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D Konteantis Zenon
Popovici-Muller Janeta
M Travins Jeremy
Cai Zhenwei
Zhou Ding
Zahler Robert
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Agios Pharmaceuticals Inc
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Application filed by Agios Pharmaceuticals Inc filed Critical Agios Pharmaceuticals Inc
Publication of AR096902A1 publication Critical patent/AR096902A1/es

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Abstract

Se proporcionan compuestos útiles para el tratamiento de cáncer y su uso en el tratamiento de cáncer. Reivindicación 1: Un compuesto que tiene la fórmula (1), o una sal o hidrato farmacéuticamente aceptable del mismo, en donde: el anillo A es un arilo monocíclico o heteroarilo monocíclico de 5 - 6 miembros opcionalmente sustituido; X es N, CH o C-halo; R¹, R³, R⁴ y R⁶ se seleccionan cada uno independientemente de hidrógeno, alquilo C₁₋₄, haloalquilo C₁₋₄, -O-alquilo C₁₋₄ y CN, en donde cada uno de dichos restos alquilo de R¹, R³, R⁴ y R⁶ se sustituye cada uno independientemente opcionalmente por -OH, -NH₂, -CN, -O- alquilo C₁₋₄, -NH(alquilo C₁₋₄) o -N(alquilo C₁₋₄)₂; cada R² y R⁵ se selecciona independientemente de: -(alquilo C₁₋₆), -(alquilo C₁₋₆)-C(O)-NH₂, -(alquilo C₁₋₆)-CO₂H, -(alquenilo o alquinilo C₂₋₆), -(alquileno C₁₋₆)-N(R⁶)-(alquileno C₁₋₆)-O-(alquilo C₁₋₆), -(alquileno C₁₋₆)-N(R⁶)-(alquileno C₀₋₆)-Q, -(alquileno C₁₋₆)-N(R⁶)(R⁶), -(alquileno C₁₋₆)-N(R⁶)-S(O)₁₋₂-(alquilo C₁₋₆), -(alquileno C₁₋₆)-N(R⁶)-S(O)₁₋₂-(alquilo C₀₋₆)-Q, -(alquileno C₁₋₆)-S(O)₁₋₂-N(R⁶)(R⁶), -(alquileno C₁₋₄)-S(O)₁₋₂-N(R⁶)-(alquileno C₁₋₆)-Q, -C(O)N(R⁶)-(alquileno C₁₋₆)-C(O)-(alquileno C₀₋₆)-O-(alquilo C₁₋₆), -C(O)N(R⁶)-(alquileno C₁₋₆)-C(O)-(alquileno C₀₋₆)-O-(alquileno C₀₋₆)-Q, -(alquileno C₁₋₆)-O-C(O)-(alquilo C₁₋₆), -(alquileno C₁₋₆)-O-C(O)-(alquilo C₀₋₆)-Q, -(alquileno C₁₋₆)-O-(alquilo C₁₋₆), -(alquileno C₁₋₆)-O-(alquileno C₁₋₆)-Q, -(alquileno C₀₋₆)-C(O)-(alquileno C₀₋₆)-O-(alquilo C₁₋₆), -(alquileno C₀₋₆)-C(O)-(alquileno C₀₋₆)-O-(alquileno C₁₋₆)-Q, -(alquileno C₁₋₆)-O-C(O)-(alquilo C₁₋₆), -(alquileno C₁₋₆)-O-C(O)-(alquileno C₀₋₆)-Q, -(alquileno C₀₋₆)-C(O)N(R⁶)-(alquilo C₁₋₆), -(alquileno C₀₋₆)-C(O)N(R⁶)-(alquileno C₀₋₆)-Q, -(alquileno C₁₋₆)-N(R⁶)C(O)-(alquilo C₁₋₆), -(alquileno C₁₋₆)-N(R⁶)C(O)-(alquileno C₀₋₆)-Q, -(alquileno C₀₋₆)-S(O)₀₋₂-(alquilo C₁₋₆), -(alquileno C₀₋₆)-S(O)₀₋₂-(alquileno C₀₋₆)-Q, -(alquileno C₁₋₆)-N(R⁶)-C(O)-N(R⁶)-(alquilo C₁₋₆), -(alquileno C₀₋₆)-Q, -(alquileno C₀₋₆)-C(O)-(alquilo C₁₋₆), -(alquileno C₀₋₆)-C(O)-(alquileno C₀₋₆)-Q, en donde: cualquier resto alquilo o alquileno presente en R² y R⁵ está opcionalmente sustituido por uno o más -OH, -O(alquilo C₁₋₄), -CO₂H o halo; cualquier resto metilo terminal presente en R² y R⁵ se reemplaza opcionalmente por -CH₂OH, CF₃, -CH₂F, -CH₂Cl, C(O)CH₃, C(O)CF₃, CN o CO₂H; R⁷ y R⁸ se seleccionan cada uno independientemente de hidrógeno y alquilo C₁₋₆; y Q se selecciona de arilo, heteroarilo, carbociclilo y heterociclilo, cualquiera de los cuales está opcionalmente sustituido; en donde R¹ y R³ opcionalmente se toman junto con el átomo de carbono al que están unidos para formar C(=O); o R⁴ y R⁶ opcionalmente se toman junto con el átomo de carbono al que están unidos para formar C(=O); o R¹ y R² opcionalmente se toman juntos para formar un carbociclilo opcionalmente sustituido o heterociclilo opcionalmente sustituido; o R⁴ y R⁵ opcionalmente se toman juntos para formar un carbociclilo opcionalmente sustituido, heterociclilo opcionalmente sustituido, un arilo opcionalmente sustituido o un heteroarilo opcionalmente sustituido; en donde: (i) cuando X es N y A es fenilo opcionalmente sustituido, entonces (a) ni N(R⁷)C(R⁴)(R⁵)(R⁶) ni N(R⁸)C(R¹)(R²)(R³) es NHCH₂CH₂OCH₂CH₂OCH₂CH₂NH₂, 4-[[2-(2-(2-aminoetoxi)etoxi]etil]amino] y (b) N(R⁷)C(R⁴)(R⁵)(R⁶) y N(R⁸)C(R¹)(R²)(R³) no son ambos NHEt, NH(n-propilo), NH(n-butilo), NH(n-docecilo), NH-[(4-metoxifenil)metilo], NHCH₂CH₂CHO, NHCH₂CH₂OCH₃, NHCH₂CH₂OH, NHCH₂CH(OH)CH₃, NHCH₂CH₂OC(O)fenilo, NHCH₂CH₂CH₂OH, NHCH₂CH₂CH₂N(CH₃)fenilo, NHCH₂C(O)OCH₃, NHCH₂C(O)OCH₂CH₃, NHCH₂-fenilo, NHCH(CH₃)CH₂CH₃ o NHCH₂CH₂OC(O)CH₃; (ii) cuando X es CH o C-Cl y A es fenilo opcionalmente sustituido por F, Cl o SO₂CH₃, entonces ni N(R⁷)C(R⁴)(R⁵)(R⁶) ni N(R⁸)C(R¹)(R²)(R³) es N(CH₃)CH₂C(O)NH-i-propilo, NHCH(CH₃)(CH₂)₃N(CH₂CH₃)₂, NHCH₂CH₂OH, NHCH₂CH₂OCH₃, NHCH₂CH₂OSO₃H, NHCH₂CH₂CH₂OCH₂CH₂O-fenilo, NHCH₂CH₂CH₂OH, NHCH₂CH₂CH₂OCH₃, NHCH₂CH(OH)CH₃, N(CH₂CH₃)₂, NH-i-propilo, NHCH₂CH₂NHC(O)OCH₃, NHCH₂CH₂NHC(O)CH₃, NHCH₂CH₂NH₂ o NHCH₂-fenilo; (iii) cuando X es CH y A es piridilo opcionalmente sustituido, entonces ni N(R⁷)C(R⁴)(R⁵)(R⁶) ni N(R⁸)C(R¹)(R²)(R³) es NHCH₂-fenilo, NHCH₂-(2,4- difluorofenilo), N(CH₃)CH₂CH₂C(O)OH, NHCH₂CH₂C(O)OH, NHCH₂CH₂C(O)OCH₂CH₃, NHCH₂CH₂C(O)O-t-butilo, NHCH₂CH₂C(O)NH₂, NHCH₂CH₂-fenilo, NHCH₂CH₂OH, NHCH₂CH₂NH₂, NHCH₂CH₂N(CH₃)₂ o NHCH₂CH₂CH₃; (iv) cuando X es CH y A es 1-imidazolilo opcionalmente sustituido, 1-pirazolilo opcionalmente sustituido, entonces ni N(R⁷)C(R⁴)(R⁵)(R⁶) ni N(R⁸)C(R¹)(R²)(R³) es NH(CH₂)₇CH₃, NHCH₂-(o-cloro-fenilo) o NHCH₂CH₂OH; (v) cuando X es N y A es un piridilo opcionalmente sustituido, entonces (A) ni N(R⁷)C(R⁴)(R⁵)(R⁶) ni N(R⁸)C(R¹)(R²)(R³) es NHC(O)-[2-cloro-4-(metilsulfonilo)], N(CH₃)₂, NHCH₂CH₂OCH₂CH₂SO₂CH₂CH₂Cl o NHCH₂CH₂SO₂CH₂CH₂Cl, (B) N(R⁷)C(R⁴)(R⁵)(R⁶) y N(R⁸)C(R¹)(R²)(R³) no son ambos NHC(O)C(CH₃)₃, NHC(O)CH=CH₂, NHC(O)C(CH₃)=CH₂, NHCH₂CH₂OH, NH-ciclohexilo, NHCH₂-fenilo, NHC(O)fenilo, NHC(O)(CH₂)₅NH₂, NHC(O)OCH₃, NHC(O)CH₃ y NHC(O)NH-fenilo opcionalmente sustituido y (C) cuando N(R⁷)C(R⁴)(R⁵)(R⁶) es NHC(CH₃)₃, entonces N(R⁸)C(R¹)(R²)(R³) no es NHCH₂-fenilo o NH-CH₂CH₃; (vi) cuando X es N y A es un heteroarilo opcionalmente sustituido, entonces N(R⁷)C(R⁴)(R⁵)(R⁶) y N(R⁸)C(R¹)(R²)(R³) no son ambos N(CH₂CH₃)₂, NHCH₂CH₂-i-propilo, NHCH₂CH(CH₃)₂ y NHC(O)CH₃, (vii) cuando X es CH y A es 2-piridinilo insustituido, entonces el anillo formado por R⁴ y R⁵ no es 5-metil-1H- pirazol-3-ilo, (viii) cuando A es 1-pirazolilo opcionalmente sustituido, entonces ni N(R⁷)C(R⁴)(R⁵)(R⁶) ni N(R⁸)C(R¹)(R²)(R³) es N(CH₃)₂, NHCH₃, NHAc, NH-isopropilo, NHCH₂CH₃, NHCH₂CH₂SO₃H o N(CH₂CH₃)₂, (ix) cuando X es N y A es fenilo, tienilo o piridinilo opcionalmente sustituido, entonces ni N(R⁷)C(R⁴)(R⁵)(R⁶) ni N(R⁸)C(R¹)(R²)(R³) es NH-ciclohexil-C(O)NHCH₂R, en donde R es fenilo o piridinilo que está sustituido por uno o más de OCF₃, OCH₃, cloro o CF₃, (x) cuando X es N, A es un fenilo opcionalmente sustituido y R⁴ y R⁵ forman un fenilo opcionalmente sustituido, entonces N(R⁸)C(R¹)(R²)(R³) no es NHCH₂(4-fluorofenilo), NHCH₂CO₂H, NHCH₂C(O)Cl, NHCH(CO₂H)(CH₂SCH₂ fenilo) o NHCH₂C(O)NHC(O)NHR o NHCH₂C(O)NHC(S)NHR, en donde R es fenilo o naftilo opcionalmente sustituido, (xi) cuando X es N, A es un oxadiazol sustituido por un piridinilo opcionalmente sustituido, entonces R⁴ y R⁵ no forman un fenilo opcionalmente sustituido, (xii) cuando A es 1-pira
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