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AR106720A1 - 2-REPLACED QUINAZOLINE COMPOUNDS THAT INCLUDE A SUBSTITUTED HETEROCYCLIC GROUP AND METHODS OF USE OF THE SAME - Google Patents

2-REPLACED QUINAZOLINE COMPOUNDS THAT INCLUDE A SUBSTITUTED HETEROCYCLIC GROUP AND METHODS OF USE OF THE SAME

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Publication number
AR106720A1
AR106720A1 ARP160103501A ARP160103501A AR106720A1 AR 106720 A1 AR106720 A1 AR 106720A1 AR P160103501 A ARP160103501 A AR P160103501A AR P160103501 A ARP160103501 A AR P160103501A AR 106720 A1 AR106720 A1 AR 106720A1
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AR
Argentina
Prior art keywords
alkyl
haloalkyl
aminylalkyl
alkynyl
cyano
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Application number
ARP160103501A
Other languages
Spanish (es)
Inventor
Li Liansheng
Feng Jun
Oliver Long Yun
Liu Yuan
Wu Tao
Liu Yi
Ren Pingda
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Araxes Pharma Llc
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Publication date
Application filed by Araxes Pharma Llc filed Critical Araxes Pharma Llc
Publication of AR106720A1 publication Critical patent/AR106720A1/en

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Compuestos con actividad inhibidora de la proteína KRAS mutante G12C. Métodos asociados con la preparación y uso de los compuestos, composiciones farmacéuticas que los comprenden y métodos para modular la actividad de la proteína KRAS mutante G12C para el tratamiento de trastornos tales como el cáncer. Reivindicación 1: Un compuesto caracterizado porque tiene la estructura de fórmula (1), o una sal farmacéuticamente aceptable, estereoisómero o profármaco del mismo, donde: A es N, CH o C-CN; G¹ y G² son en forma independiente entre sí N o CH; L¹ es una unión o NR⁷; L² es una unión o alquileno; R¹ es arilo o heteroarilo; R²ᵃ, R²ᵇ y R²ᶜ son en forma independiente entre sí H, amino, ciano, halo, hidroxilo, C₁₋₆ alquilo, C₁₋₆ alquilamino, C₁₋₆ haloalquilo, C₁₋₆ alcoxi, C₁₋₆ haloalcoxi; C₃₋₈ cicloalquilo, heterociclilalquilo, C₁₋₆ alquinilo, C₁₋₆ alquenilo, aminilalquilo, alquilaminilalquilo, cianoalquilo, carboxialquilo, aminilcarbonilalquilo, aminilcarbonilo, heteroarilo o arilo; R³ᵃ y R³ᵇ son, en cada caso, en forma independiente H, -OH, -NH₂, -CO₂H, halo, ciano, C₁₋₆ alquilo, C₁₋₆ haloalquilo, C₁₋₆ haloalcoxi, C₁₋₆ alquinilo, hidroxilalquilo, alcoxialquilo, aminilalquilo, alquilaminilalquilo, cianoalquilo, carboxialquilo, aminilcarbonilalquilo o aminilcarbonilo; o R³ᵃ y R³ᵇ se unen para formar oxo, un anillo carbocíclico o heterocíclico; o R³ᵃ es H, -OH, -NH₂, -CO₂H, halo, ciano, C₁₋₆ alquilo, C₁₋₆ haloalquilo, C₁₋₆ haloalcoxi, C₁₋₆ alquinilo, hidroxilalquilo, alcoxialquilo, aminilalquilo, alquilaminilalquilo, cianoalquilo, carboxialquilo, aminilcarbonilalquilo o aminilcarbonilo, y R³ᵇ se une con R⁴ᵇ para formar un anillo carbocíclico o heterocíclico; R⁴ᵃ y R⁴ᵇ son, en cada caso, en forma independiente H, -OH, -NH₂, -CO₂H, halo, ciano, C₁₋₆ alquilo, C₁₋₆ haloalquilo, C₁₋₆ haloalcoxi, C₁₋₆ alquinilo, hidroxilalquilo, alcoxialquilo, aminilalquilo, alquilaminilalquilo, cianoalquilo, carboxialquilo, aminilcarbonilalquilo o aminilcarbonilo; o R⁴ᵃ y R⁴ᵇ se unen para formar oxo, un anillo carbocíclico o heterocíclico; o R⁴ᵃ es H, -OH, -NH₂, -CO₂H, halo, ciano, C₁₋₆ alquilo, C₁₋₆ haloalquilo, C₁₋₆ haloalcoxi, C₁₋₆ alquinilo, hidroxilalquilo, alcoxialquilo, aminilalquilo, alquilaminilalquilo, cianoalquilo, carboxialquilo, aminilcarbonilalquilo o aminilcarbonilo, y R⁴ᵇ se une con R³ᵇ para formar un anillo carbocíclico o heterocíclico; R⁵ᵃ y R⁵ᵇ son, en cada caso, en forma independiente H, hidroxilo, halo o C₁₋₆ alquilo, o R⁵ᵃ y R⁵ᵇ se unen para formar oxo; R⁶ es amino, ciano, hidroxilo, alquilo, haloalquilo, hidroxilalquilo, alcoxi, aminilalquilo, C₁₋₆ alquilfosforilo, C₁₋₆ alquilfosforilaminilo, cicloalquilo, heterociclilo, arilo, heteroarilo, heteroarilalquiloxi o heteroarilalquilaminilo cuando X es una unión, -NR⁷- o -S-; o R⁶ es amino, ciano, C₁₋₆ alquilo, haloalquilo, hidroxilalquilo, alcoxi, -NRᵃRᵇ, C₁₋₆ alquilfosforilo, C₁₋₆ alquilfosforilaminilo, cicloalquilo, heterociclilo, arilo, heteroarilo, heteroarilalquiloxi o heteroarilalquilaminilo cuando X es -O-, donde Rᵃ es H o C₁₋₆ alquilo, y Rᵇ es C₁₋₆ alquilo, con la condición de que Rᵃ es H o C₂₋₆ alquilo, y Rᵇ es C₁₋₆ alquilo cuando n es 2 y uno de R³ᵃ, R³ᵇ, R⁴ᵃ o R⁴ᵇ es metilo; R⁷ es, en cada caso, en forma independiente H, C₁₋₆ alquilo, C₃₋₈ cicloalquilo o heterocicloalquilo; m¹ y m² son en forma independiente entre sí 1, 2 ó 3; n es un entero entre 0 y 6; X es una unión, -O-, -NR⁷- o -S-; y E es una unidad electrófila capaz de formar un enlace covalente con el residuo cisteína en la posición 12 de una proteína KRAS, HRAS o NRAS con una mutación G12C, donde cada instancia de alquilo, alquinilo, alquenilo, alquileno, alquinilo, arilo, heteroarilo, cicloalquilo, heterociclilo, alquilamino, haloalquilo, alcoxi, alcoxialquilo, haloalcoxi, cicloalquilo, hereociclilalquilo, aminilalquilo, alquilaminilalquilo, cianoalquilo, carboxialquilo, aminilcarbonilo, aminilcarbonilalquilo, alquilfosforilo, alquilfosforilaminilo, y anillos carbocíclico y heterocíclico está opcionalmente sustituida con uno o más sustituyentes salvo que se especifique lo contrario; y con la condición de que al menos una instancia de R³ᵃ, R³ᵇ, R⁴ᵃ o R⁴ᵇ no es H.Compounds with inhibitory activity of the G12C mutant KRAS protein. Methods associated with the preparation and use of the compounds, pharmaceutical compositions comprising them and methods to modulate the activity of the G12C mutant KRAS protein for the treatment of disorders such as cancer. Claim 1: A compound characterized in that it has the structure of formula (1), or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein: A is N, CH or C-CN; G¹ and G² are independently N or CH; L¹ is a union or NR⁷; L² is a bond or alkylene; R¹ is aryl or heteroaryl; R²ᵃ, R²ᵇ and R²ᶜ are independently of each other H, amino, cyano, halo, hydroxyl, C₁₋₆ alkyl, C₁₋₆ alkylamino, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy; C₃₋₈ cycloalkyl, heterocyclylalkyl, C₁₋₆ alkynyl, C₁₋₆ alkenyl, aminylalkyl, alkylaminolalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, aminylcarbonyl, heteroaryl or aryl; R³ᵃ and R³ᵇ are, in each case, independently H, -OH, -NH₂, -CO₂H, halo, cyano, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkynyl, hydroxylalkyl, alkoxyalkyl , aminylalkyl, alkylaminolalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl; or R³ᵃ and R³ᵇ join to form oxo, a carbocyclic or heterocyclic ring; or R³ᵃ is H, -OH, -NH₂, -CO₂H, halo, cyano, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkynyl, hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminolalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl, and R³ᵇ binds with R⁴ᵇ to form a carbocyclic or heterocyclic ring; R⁴ᵃ and R⁴ᵇ are, in each case, independently H, -OH, -NH₂, -CO₂H, halo, cyano, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkynyl, hydroxylalkyl, alkoxyalkyl , aminylalkyl, alkylaminolalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl; or R⁴ᵃ and R⁴ᵇ join to form oxo, a carbocyclic or heterocyclic ring; or R⁴ᵃ is H, -OH, -NH₂, -CO₂H, halo, cyano, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkynyl, hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminolalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl, and R⁴ᵇ binds with R³ᵇ to form a carbocyclic or heterocyclic ring; R⁵ᵃ and R⁵ᵇ are, in each case, independently H, hydroxyl, halo or C₁₋₆ alkyl, or R⁵ᵃ and R⁵ᵇ are joined to form oxo; R⁶ is amino, cyano, hydroxy, alkyl, haloalkyl, hydroxylalkyl, alkoxy, aminylalkyl, C₁₋₆ alkylphosphoryl, C₁₋₆ alkylphosphorylaminyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroarylalkyl, or heteroarylalkyl-amino when X is a bond, -NR⁷ S-; or R⁶ is amino, cyano, C₁₋₆ alkyl, haloalkyl, hydroxylalkyl, alkoxy, -NRᵃRᵇ, C₁₋₆ alkylphosphoryl, C₁₋₆ alkylphosphorylaminyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroarylalkyl or heteroarylalkyl amino when X is -O-, where Rᵃ is H or C₁₋₆ alkyl, and Rᵇ is C₁₋₆ alkyl, with the proviso that Rᵃ is H or C₂₋₆ alkyl, and Rᵇ is C₁₋₆ alkyl when n is 2 and one of R³ᵃ, R³ᵇ, R⁴ᵃ or R⁴ᵇ is methyl; R⁷ is, in each case, independently H, C₁₋₆ alkyl, C₃₋₈ cycloalkyl or heterocycloalkyl; m¹ and m² are independently 1, 2 or 3; n is an integer between 0 and 6; X is a union, -O-, -NR⁷- or -S-; and E is an electrophilic unit capable of forming a covalent bond with the cysteine residue at position 12 of a KRAS, HRAS or NRAS protein with a G12C mutation, where each instance of alkyl, alkynyl, alkenyl, alkylene, alkynyl, aryl, heteroaryl , cycloalkyl, heterocyclyl, alkylamino, haloalkyl, alkoxy, alkoxyalkyl, haloalkoxy, cycloalkyl, helocyclylalkyl, aminylalkyl, alkylaminolalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonyl, aminylcarbonylalkyl, and which is optionally substituted or substituted by alkyl-heterocyclic, with heterophosphorus or ring-substituted alkyl, and optionally alkyl-substituted alkyl with heterophosphorus, except for alkyl or heterocyclic rings otherwise specified; and with the proviso that at least one instance of R³ᵃ, R³ᵇ, R⁴ᵃ or R⁴ᵇ is not H.

ARP160103501A 2015-11-16 2016-11-16 2-REPLACED QUINAZOLINE COMPOUNDS THAT INCLUDE A SUBSTITUTED HETEROCYCLIC GROUP AND METHODS OF USE OF THE SAME AR106720A1 (en)

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US201562255879P 2015-11-16 2015-11-16

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AR106720A1 true AR106720A1 (en) 2018-02-14

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