AR101982A1 - COMBINED THERAPIES FOR THE TREATMENT OF CANCER AND COMPOSITIONS - Google Patents

COMBINED THERAPIES FOR THE TREATMENT OF CANCER AND COMPOSITIONS

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Publication number
AR101982A1
AR101982A1 ARP150103030A ARP150103030A AR101982A1 AR 101982 A1 AR101982 A1 AR 101982A1 AR P150103030 A ARP150103030 A AR P150103030A AR P150103030 A ARP150103030 A AR P150103030A AR 101982 A1 AR101982 A1 AR 101982A1
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Argentina
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alkyl
cyano
independently
hydroxylalkyl
co2h
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ARP150103030A
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Spanish (es)
Inventor
Liu Yi
Ren Pingda
Li Liansheng
Peter Patricelli Matthew
Robert Janes Matthew
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Araxes Pharma Llc
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Publication of AR101982A1 publication Critical patent/AR101982A1/en

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Abstract

Reivindicación 1: Un método para tratar un cáncer asociado a KRAS, HRAS o NRAS con una mutación G12C, caracterizado porque comprende administrar una cantidad eficaz de un compuesto apropiado para modular KRAS, HRAS o NRAS con una mutación G12C y de un agente terapéutico adicional en un sujeto que lo necesita. Reivindicación 2: El método de acuerdo con la reivindicación 1, caracterizado porque el agente terapéutico adicional es un inhibidor del receptor del factor de crecimiento epidérmico (EGFR), un inhibidor de la fosfatidilinositol quinasa (Pl3K), un inhibidor del receptor del factor de crecimiento similar a la insulina (IGF1R), un inhibidor de las quinasas Janus (JAK), un inhibidor de las quinasas Met (MET), un inhibidor de las quinasas de la familia SRC (SFK), un inhibidor de las quinasas de proteínas activadas por mitógenos (MEK), un inhibidor de las quinasas que son reguladas por señales extracelulares (ERK), un inhibidor del blanco del mecanismo de acción de la rapamicina (mTOR), un inhibidor de la topoisomerasa, un taxano, un agente que actúa sobre los metabolitos o un agente alquilante. Reivindicación 29: El método de cualquiera de las reivindicaciones 1 - 28, caracterizado porque el compuesto tiene la estructura de fórmula (1), o una sal farmacéuticamente aceptable, tautómero, profármaco o estereoisómero de la misma, donde: A es CR¹, CR²ᵇ, NR⁷ o S; B es una unión, CR¹ o CR²ᶜ; G¹ y G² son en forma independiente entre sí N o CH; W, X e Y son en forma independiente entre sí N, NR⁵ o CR⁶; Z es una unión, N o CR⁶ᵃ o Z es NH cuando Y es C=O; L¹ es una unión o NR⁷; L² es una unión o alquileno; R¹ es H, ciano, halo, heterociclilo, heteroarilo, ariloxi o arilo; R²ᵃ, R²ᵇ y R²ᶜ son en forma independiente entre sí H, halo, hidroxilo, C₁₋₆ alquilo, C₁₋₆ haloalquilo, C₁₋₆ alcoxi, C₃₋₈ cicloalquilo o arilo; R³ᵃ y R³ᵇ son, en cada caso, en forma independiente H, -OH, -NH₂, CO₂H, halo, ciano, C₁₋₆ alquilo, C₁₋₆ alquinilo, hidroxilalquilo, aminilalquilo, alquilaminilalquilo, cianoalquilo, carboxialquilo, aminocarbonilalquilo o aminocarbonilo; o R³ᵃ y R³ᵇ se unen para formar un anillo carbocíclico o heterocíclico; o R³ᵃ es H, -OH, -NH₂, -CO₂H, halo, ciano, C₁₋₆ alquilo, C₁₋₆ alquinilo, hidroxilalquilo, aminoalquilo, 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 alquinilo, hidroxilalquilo, aminilalquilo, alquilaminilalquilo, cianoalquilo, carboxialquilo, aminocarbonilalquilo o aminocarbonilo; o R⁴ᵃ y R⁴ᵇ se unen para formar un anillo carbocíclico o heterocíclico; o R⁴ᵃ es H, -OH, -NH₂, -CO₂H, halo, ciano, C₁₋₆ alquilo, C₁₋₆ alquinilo, hidroxilalquilo, aminilalquilo, alquilaminoalquilo, cianoalquilo, carboxialquilo, aminilcarbonilalquilo o aminilcarbonilo, y R⁴ᵇ se une con R³ᵇ para formar un anillo carbocíclico o heterocíclico; R⁵ es, en cada caso, en forma independiente H, C₁₋₆ alquilo o una unión a L¹; R⁶ es, en cada caso, en forma independiente H, oxo, ciano, cianoalquilo, amino, aminilalquilo, aminilalquilaminilo, aminocarbonilo, alquilaminilo, haloalquilamino, hidroxilalquilamino, amindinilalquilo, amidinilalcoxi, amindinilalquilaminilo, guanidinilalquilo, guanidinilalcoxi, guanidinilalquilaminilo, C₁₋₆ alcoxi, aminilalcoxi, alquilcarbonilaminilalcoxi, C₁₋₆ alquilo, heterociclilo, heterocicliloxi, heterociclilalquiloxi, heterociclilamino, heterociclilalquilamino, heteroarilo, heteroariloxi, heteroarilalquiloxi, heteroarilamino, heteroarilalquilamino, arilo, ariloxi, arilamino, arilalquilamino, arilalquiloxi o una unión a L¹; R⁶ᵃ es H, alquilo o una unión a L¹; R⁷ es H o C₁₋₆ alquilo; m¹ y m² son en forma independiente entre sí 1, 2 ó 3; ⁻ ⁻ ⁻ ⁻ ⁻ indica una unión simple o doble de manera de completar todas las valencias; y E es una unidad electrofílica capaz de formar un enlace covalente con el residuo cisteína en la posición 12 de una proteína KRAS, HRAS o NRAS mutante G12C, donde al menos uno de W, X, Y o Z es CR⁶ donde R⁶ es una unión a L¹ o al menos uno de W, X o Y es NR⁵, donde R⁵ es una unión a L¹. Reivindicación 30: El método de cualquiera de las reivindicaciones 1 - 28, caracterizado porque el compuesto tiene la estructura de fórmula (2), o una sal farmacéuticamente aceptable, tautómero, estereoisómero o profármaco de la misma, donde: R¹ es arilo o heteroarilo; R³⁰ᵃ y R³⁰ᵇ son, en cada caso, en forma independiente H, -OH, -NH₂, -CO₂H, ciano, cianoalquilo, C₁₋₆ alquilo, C₃₋₈ cicloalquilo, hidroxilalquilo, aminoalquilo, carboxilalquilo o aminocarbonilo; o R³⁰ᵃ y R³⁰ᵇ se unen para formar un anillo carbocíclico o heterocíclico; o R³⁰ᵃ es H, -OH, -NH₂, -CO₂H, ciano, C₁₋₆ alquilo, C₃₋₈ cicloalquilo, hidroxilalquilo, aminoalquilo, carboxilalquilo o aminocarbonilo y R³⁰ᵇ se une con R³¹ᵇ para formar un anillo carbocíclico o heterocíclico; R³¹ᵃ y R³¹ᵇ son, en cada caso, en forma independiente H, -OH, -NH₂, -CO₂H, ciano, cianoalquilo, C₁₋₆ alquilo, C₃₋₈ cicloalquilo, hidroxilalquilo, aminoalquilo, carboxilalquilo o aminocarbonilo; o R³¹ᵃ y R³¹ᵇ se unen para formar un anillo carbocíclico o heterocíclico; o R³¹ᵃ es H, -OH, -NH₂, CO₂H, ciano, C₁₋₆ alquilo, C₃₋₈ cicloalquilo, hidroxilalquilo, aminoalquilo, carboxilalquilo o aminocarbonilo y R³¹ᵇ se une con R³⁰ᵇ para formar un anillo carbocíclico o heterocíclico; R³²ᵃ y R³²ᵇ son, en cada caso, en forma independiente H, -OH, -NH₂, -CO₂H, ciano, cianoalquilo, C₁₋₆ alquilo, C₃₋₈ cicloalquilo, hidroxilalquilo, aminoalquilo, carboxilalquilo o aminocarbonilo; o R³²ᵃ y R³²ᵇ se unen para formar un anillo carbocíclico o heterocíclico; o R³²ᵃ es H, -OH, -NH₂, -CO₂H, ciano, C₁₋₆ alquilo, C₃₋₈ cicloalquilo, hidroxilalquilo, aminoalquilo, carboxilalquilo o aminocarbonilo y R³²ᵇ se une con R³³ᵇ para formar un anillo carbocíclico o heterocíclico; R³³ᵃ y R³³ᵇ son, en cada caso, en forma independiente H, -OH, -NH₂, -CO₂H, ciano, cianoalquilo, C₁₋₆ alquilo, C₃₋₈ cicloalquilo, hidroxilalquilo, aminoalquilo, carboxilalquilo o aminocarbonilo; o R³³ᵃ y R³³ᵇ se unen para formar un anillo carbocíclico o heterocíclico; o R³³ᵃ es H, -OH, -NH₂, -CO₂H, ciano, C₁₋₆ alquilo, C₃₋₈ cicloalquilo, hidroxilalquilo, aminoalquilo, carboxilalquilo o aminocarbonilo y R³³ᵇ se une con R³²ᵇ para formar un anillo carbocíclico o heterocíclico; L¹ es carbonilo, -NHC(=O)-, alquileno, alquenileno, heteroalquileno, heterocicloalquileno, heteroarileno, alquilencarbonilo, alquenilencarbonilo, heteroalquilencarbonilo, heterocicloalquilencarbonilo o heteroarilencarbonilo; L² es una unión o alquileno; G¹, G², G³ y G⁴ son en forma independiente entre sí N o CR, donde R es H, ciano, halo o C₁₋₆ alquilo; n¹, n², n³ y n⁴ son en forma independiente entre sí 1, 2 ó 3; y E es una unidad electrofílica capaz de formar un enlace covalente con el residuo cisteína en la posición 12 de una proteína KRAS, HRAS o NRAS mutante G12C. Reivindicación 31: El método de cualquiera de las reivindicaciones 1 - 28, caracterizado porque el compuesto tiene la estructura de fórmula (3), una sal farmacéuticamente aceptable, tautómero, estereoisómero o profármaco de la misma, donde: A es CR³⁷ᵇ, N o NR³⁸ᵃ; B es CR³⁷ᶜ, N, NR³⁸ᵇ o S; C es CR³⁷ᵈ, N, NR³⁸ᶜ o S; G³ y G⁴ son en forma independiente entre sí N o CR, donde R es H, ciano, halo o C₁₋₆ alquilo; L¹ᵃ es una unión, -NH-, alquileno o heteroalquileno; L² es una unión o alquileno; R³²ᵃ y R³²ᵇ son, en cada caso, en forma independiente H, -OH, -NH₂, -CO₂H, ciano, cianoalquilo, C₁₋₆ alquilo, C₃₋₈ cicloalquilo, hidroxilalquilo, aminoalquilo, carboxilalquilo o aminocarbonilo; o R³²ᵃ y R³²ᵇ se unen para formar un anillo carbocíclico o heterocíclico; o R³²ᵃ es H, -OH, -NH₂, -CO₂H, ciano, C₁₋₆ alquilo, C₃₋₈ cicloalquilo, hidroxilalquilo, aminoalquilo, carboxilalquilo o aminocarbonilo y R³²ᵇ se une con R³³ᵇ para formar un anillo carbocíclico o heterocíclico; R³³ᵃ y R³³ᵇ son, en cada caso, en forma independiente H, -OH, -NH₂, CO₂H, ciano, cianoalquilo, C₁₋₆ alquilo, C₃₋₈ cicloalquilo, hidroxilalquilo, aminoalquilo, carboxilalquilo o aminocarbonilo; o R³³ᵃ y R³³ᵇ se unen para formar un anillo carbocíclico o heterocíclico; o R³³ᵃ es H, -OH, -NH₂, CO₂H, ciano, C₁₋₆ alquilo, C₃₋₈ cicloalquilo, hidroxilalquilo, aminoalquilo, carboxilalquilo o aminocarbonilo y R³³ᵇ se une con R³²ᵇ para formar un anillo carbocíclico o heterocíclico; R³⁷ᵃ, R³⁷ᵇ, R³⁷ᶜ, R³⁷ᵈ y R³⁷ᵉ son en forma independiente entre sí H halo, oxo, hidroxilo, ciano, aminocarbonilo, formilo, C₁₋₆ alquilo, C₁₋₆ alquilsulfonilo, C₁₋₆ haloalquilo, C₃₋₈ cicloalquilo, C₁₋₆ alcoxi, C₁₋₆ hidroxilalquilo, C₁₋₆ alcoxialquilo, C₁₋₆ aminoalquilo, heterociclilo o arilo; R³⁸ᵃ, R³⁸ᵇ y R³⁸ᶜ son en forma independiente entre sí H, C₁₋₆ alquilo o arilo; n³ y n⁴ son en forma independiente entre sí 1, 2 ó 3; m es 0 ó 1; ⁻ ⁻ ⁻ ⁻ ⁻ es una unión simple o doble de manera de completar todas las valencias; y E es una unidad electrofílica capaz de formar un enlace covalente con el residuo cisteína en la posición 12 de una proteína KRAS, HRAS o NRAS mutante G12C.Claim 1: A method of treating a cancer associated with KRAS, HRAS or NRAS with a G12C mutation, characterized in that it comprises administering an effective amount of a compound suitable for modulating KRAS, HRAS or NRAS with a G12C mutation and an additional therapeutic agent in A subject that needs it. Claim 2: The method according to claim 1, characterized in that the additional therapeutic agent is an inhibitor of the epidermal growth factor receptor (EGFR), an inhibitor of phosphatidylinositol kinase (Pl3K), an inhibitor of the growth factor receptor insulin-like (IGF1R), an inhibitor of Janus kinases (JAK), an inhibitor of Met kinases (MET), an inhibitor of SRC family kinases (SFK), an inhibitor of protein kinases activated by mitogens (MEK), an inhibitor of kinases that are regulated by extracellular signals (ERK), a target inhibitor of the mechanism of action of rapamycin (mTOR), a topoisomerase inhibitor, a taxane, an agent that acts on metabolites or an alkylating agent. Claim 29: The method of any one of claims 1-28, characterized in that the compound has the structure of formula (1), or a pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof, wherein: A is CR¹, CR²ᵇ, NR⁷ or S; B is a union, CR¹ or CR²ᶜ; G¹ and G² are independently N or CH; W, X and Y are independently N, NR⁵ or CR⁶; Z is a junction, N or CR⁶ᵃ or Z is NH when Y is C = O; L¹ is a union or NR⁷; L² is a bond or alkylene; R¹ is H, cyano, halo, heterocyclyl, heteroaryl, aryloxy or aryl; R²ᵃ, R²ᵇ and R²ᶜ are independently of each other H, halo, hydroxyl, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl or aryl; R³ᵃ and R³ᵇ are, in each case, independently H, -OH, -NH₂, CO₂H, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkynyl, hydroxylalkyl, aminylalkyl, alkylaminolalkyl, cyanoalkyl, carboxyalkyl, aminocarbonylalkyl or aminocarbonyl; or R³ᵃ and R³ᵇ join to form a carbocyclic or heterocyclic ring; or R³ᵃ is H, -OH, -NH₂, -CO₂H, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkynyl, hydroxylalkyl, aminoalkyl, 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 alkynyl, hydroxylalkyl, aminylalkyl, alkylaminolalkyl, cyanoalkyl, carboxyalkyl, aminocarbonylalkyl or aminocarbonyl; or R⁴ᵃ and R⁴ᵇ join to form a carbocyclic or heterocyclic ring; or R⁴ᵃ is H, -OH, -NH₂, -CO₂H, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkynyl, hydroxylalkyl, aminylalkyl, alkylaminoalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl, and R⁴ᵇ binds with R³ᵇ to form a carbocyclic or heterocyclic ring; R⁵ is, in each case, independently H, C₁₋₆ alkyl or a binding to L¹; R⁶ is, in each case independently H, oxo, cyano, cyanoalkyl, amino, aminilalquilo, aminilalquilaminilo, aminocarbonyl, alquilaminilo, haloalkylamino, hidroxilalquilamino, amindinilalquilo, amidinilalcoxi, amindinilalquilaminilo, guanidinylalkyl, guanidinilalcoxi, guanidinilalquilaminilo, C₁₋₆ alkoxy, aminilalcoxi , alkylcarbonylaminylalkoxy, C₁₋₆ alkyl, heterocyclyl, heterocyclyloxy, heterocyclylalkyl, heterocyclylamino, heterocyclylalkylamino, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylamino, heteroarylalkylamino, aryl, aryloxy, arylamino, arylamino, arylamino, arylamino; R⁶ᵃ is H, alkyl or a bond to L¹; R⁷ is H or C₁₋₆ alkyl; m¹ and m² are independently 1, 2 or 3; ⁻ ⁻ ⁻ ⁻ ⁻ Indicates a single or double union to complete all valences; and E is an electrophilic unit capable of forming a covalent bond with the cysteine residue at position 12 of a mutant KRAS, HRAS or NRAS protein G12C, where at least one of W, X, Y or Z is CR⁶ where R⁶ is a junction to L¹ or at least one of W, X or Y is NR⁵, where R⁵ is a union to L¹. Claim 30: The method of any one of claims 1-28, characterized in that the compound has the structure of formula (2), or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof, wherein: R¹ is aryl or heteroaryl; R³⁰ᵃ and R³⁰ᵇ are, in each case, independently H, -OH, -NH₂, -CO₂H, cyano, cyanoalkyl, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl; or R³⁰ᵃ and R³⁰ᵇ join to form a carbocyclic or heterocyclic ring; or R³⁰ᵃ is H, -OH, -NH₂, -CO₂H, cyano, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl and R³⁰ᵇ binds with R³¹ᵇ to form a carbocyclic or heterocyclic ring; R³¹ᵃ and R³¹ᵇ are, in each case, independently H, -OH, -NH₂, -CO₂H, cyano, cyanoalkyl, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl; or R³¹ᵃ and R³¹ᵇ join to form a carbocyclic or heterocyclic ring; or R³¹ᵃ is H, -OH, -NH₂, CO₂H, cyano, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl and R³¹ᵇ binds with R³⁰ᵇ to form a carbocyclic or heterocyclic ring; R³²ᵃ and R³²ᵇ are, in each case, independently H, -OH, -NH₂, -CO₂H, cyano, cyanoalkyl, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl; or R³²ᵃ and R³²ᵇ join to form a carbocyclic or heterocyclic ring; or R³²ᵃ is H, -OH, -NH₂, -CO₂H, cyano, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl and R³²ᵇ binds with R³³ᵇ to form a carbocyclic or heterocyclic ring; R³³ᵃ and R³³ᵇ are, in each case, independently H, -OH, -NH₂, -CO₂H, cyano, cyanoalkyl, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl; or R³³ᵃ and R³³ᵇ join to form a carbocyclic or heterocyclic ring; or R³³ᵃ is H, -OH, -NH₂, -CO₂H, cyano, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl and R³³ᵇ binds with R³²ᵇ to form a carbocyclic or heterocyclic ring; L¹ is carbonyl, -NHC (= O) -, alkylene, alkenylene, heteroalkylene, heterocycloalkylene, heteroarylene, alkylenecarbonyl, alkenylenecarbonyl, heteroalkylenecarbonyl, heterocycloalkylenecarbonyl or heteroarylenecarbonyl; L² is a bond or alkylene; G¹, G², G³ and G⁴ are independently from each other N or CR, where R is H, cyano, halo or C₁₋₆ alkyl; n¹, n², n³ and n⁴ are independently of each other 1, 2 or 3; and E is an electrophilic unit capable of forming a covalent bond with the cysteine residue at position 12 of a G12C mutant KRAS, HRAS or NRAS protein. Claim 31: The method of any one of claims 1-28, characterized in that the compound has the structure of formula (3), a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof, wherein: A is CR³⁷ᵇ, N or NR³⁸ᵃ ; B is CR³⁷ᶜ, N, NR³⁸ᵇ or S; C is CR³⁷ᵈ, N, NR³⁸ᶜ or S; G³ and G⁴ are independently N or CR, where R is H, cyano, halo or C₁₋₆ alkyl; L¹ᵃ is a bond, -NH-, alkylene or heteroalkylene; L² is a bond or alkylene; R³²ᵃ and R³²ᵇ are, in each case, independently H, -OH, -NH₂, -CO₂H, cyano, cyanoalkyl, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl; or R³²ᵃ and R³²ᵇ join to form a carbocyclic or heterocyclic ring; or R³²ᵃ is H, -OH, -NH₂, -CO₂H, cyano, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl and R³²ᵇ binds with R³³ᵇ to form a carbocyclic or heterocyclic ring; R³³ᵃ and R³³ᵇ are, in each case, independently H, -OH, -NH₂, CO₂H, cyano, cyanoalkyl, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl; or R³³ᵃ and R³³ᵇ join to form a carbocyclic or heterocyclic ring; or R³³ᵃ is H, -OH, -NH₂, CO₂H, cyano, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl and R³³ᵇ binds with R³²ᵇ to form a carbocyclic or heterocyclic ring; R³⁷ᵃ, R³⁷ᵇ, R³⁷ᶜ, R³⁷ᵈ and R³⁷ᵉ are independently of each other H halo, oxo, hydroxyl, cyano, aminocarbonyl, formyl, C₁₋₆ alkyl, C₁₋₆ alkylsulfonyl, C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl, C₁₋ ₆ alkoxy, C₁₋₆ hydroxylalkyl, C₁₋₆ alkoxyalkyl, C₁₋₆ aminoalkyl, heterocyclyl or aryl; R³⁸ᵃ, R³⁸ᵇ and R³⁸ᶜ are independently of each other H, C₁₋₆ alkyl or aryl; n³ and n⁴ are independently of each other 1, 2 or 3; m is 0 or 1; ⁻ ⁻ ⁻ ⁻ ⁻ Is a single or double union to complete all valences; and E is an electrophilic unit capable of forming a covalent bond with the cysteine residue at position 12 of a G12C mutant KRAS, HRAS or NRAS protein.

ARP150103030A 2014-09-18 2015-09-18 COMBINED THERAPIES FOR THE TREATMENT OF CANCER AND COMPOSITIONS AR101982A1 (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112661986A (en) * 2020-12-07 2021-04-16 南京师范大学 Hydrogen sulfide driven nano motor based on zwitterion and preparation method and application thereof
WO2024017316A1 (en) * 2022-07-20 2024-01-25 益方生物科技(上海)股份有限公司 Pharmaceutical combination product and combination therapy

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112661986A (en) * 2020-12-07 2021-04-16 南京师范大学 Hydrogen sulfide driven nano motor based on zwitterion and preparation method and application thereof
CN112661986B (en) * 2020-12-07 2023-08-22 南京师范大学 Amphoteric ion-based hydrogen sulfide driven nanomotor and preparation method and application thereof
WO2024017316A1 (en) * 2022-07-20 2024-01-25 益方生物科技(上海)股份有限公司 Pharmaceutical combination product and combination therapy

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