AR127836A1 - NULLED AND DERIVED 2-AMINO-3-CYANO THIOPHENES FOR THE TREATMENT OF CANCER - Google Patents

NULLED AND DERIVED 2-AMINO-3-CYANO THIOPHENES FOR THE TREATMENT OF CANCER

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Publication number
AR127836A1
AR127836A1 ARP220103296A ARP220103296A AR127836A1 AR 127836 A1 AR127836 A1 AR 127836A1 AR P220103296 A ARP220103296 A AR P220103296A AR P220103296 A ARP220103296 A AR P220103296A AR 127836 A1 AR127836 A1 AR 127836A1
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AR
Argentina
Prior art keywords
alkyl
group
membered heterocyclyl
cycloalkyl
alkoxy
Prior art date
Application number
ARP220103296A
Other languages
Spanish (es)
Inventor
Joachim Broeker
Jason Abbott
Jianwen Cui
Stephen W Fesik
Julian Fuchs
Andreas Gollner
Lorenz Herdeis
Tim Hodges
Andrew Little
Andreas Mantoulidis
Jason Phan
Juergen Ramharter
Dhruba Sarkar
Christian Alan Paul Smethurst
Kevin Sokol
Heinz Stadtmueller
Qi Sun
Matthias Treu
Alex Waterson
Birgit Wilding
Tobias Wunberg
Original Assignee
Boehringer Ingelheim Int
Univ Vanderbilt
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Boehringer Ingelheim Int, Univ Vanderbilt filed Critical Boehringer Ingelheim Int
Publication of AR127836A1 publication Critical patent/AR127836A1/en

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  • Plural Heterocyclic Compounds (AREA)

Abstract

Compuestos de la fórmula (1) en donde R¹ᵃ, R¹ᵇ, R²ᵃ, R²ᵇ, Z, R³ a R⁵, A, p, U, V y W tienen los significados dados en las reivindicaciones y la memoria descriptiva, su uso como inhibidores de KRAS, composiciones farmacéuticas y preparaciones que contienen dichos compuestos y su uso como medicamentos / usos médicos, especialmente como agentes para el tratamiento y/o la prevención de enfermedades oncológicas. Reivindicación 1: Un compuesto de la fórmula (1), caracterizado porque R¹ᵃ y R¹ᵇ se seleccionan independientemente del grupo que consiste en hidrógeno, C₁₋₄ alquilo, C₁₋₄ haloalquilo, C₁₋₄ alcoxi, C₁₋₄ haloalcoxi, halógeno, -NH₂, -NH(C₁₋₄ alquilo), -N(C₁₋₄ alquilo)₂, C₃₋₅ cicloalquilo y heterociclilo de 3 - 5 miembros; R²ᵃ y R²ᵇ se seleccionan independientemente del grupo que consiste en hidrógeno, C₁₋₄ alquilo, C₁₋₄ haloalquilo, C₁₋₄ alcoxi, C₁₋₄ haloalcoxi, halógeno, -NH₂, -NH(C₁₋₄ alquilo), -N(C₁₋₄ alquilo)₂, C₃₋₅ cicloalquilo y heterociclilo de 3 - 5 miembros; y/u, opcionalmente, uno de R¹ᵃ o R¹ᵇ y uno de R²ᵃ o R²ᵇ junto con los átomos de carbono a los que están unidos forman un anillo de ciclopropano; Z es -(CR⁶ᵃR⁶ᵇ)ₙ-; cada R⁶ᵃ y R⁶ᵇ se selecciona independientemente del grupo que consiste en hidrógeno, C₁₋₄ alquilo, C₁₋₄ haloalquilo, C₁₋₄ alcoxi, C₁₋₄ haloalcoxi, halógeno, -NH₂, -NH(C₁₋₄ alquilo), -N(C₁₋₄ alquilo)₂, C₃₋₅ cicloalquilo y heterociclilo de 3 - 5 miembros; o R⁶ᵃ y R⁶ᵇ junto con el átomo de carbono al que están unidos para formar un anillo de ciclopropano; n se selecciona del grupo que consiste en 0, 1 y 2; R³ se selecciona del grupo que consiste en halógeno, C₁₋₆ alquilo, C₁₋₆ haloalquilo, -N₃, C₃₋₁₀ cicloalquilo, heterociclilo de 3 - 11 miembros, C₆₋₁₀ arilo y heteroarilo de 5 - 10 miembros, en donde el C₁₋₆ alquilo, C₁₋₆ haloalquilo, C₃₋₁₀ cicloalquilo, heterociclilo de 3 - 11 miembros, C₆₋₁₀ arilo y heteroarilo de 5 - 10 miembros están todos opcional e independientemente sustituidos con uno o más R⁷ y/o R⁸ idénticos o diferentes; cada R⁷ se selecciona independientemente del grupo que consiste en -OR⁸, -NR⁸R⁸, halógeno, -CN, -C(=O)R⁸, -C(=O)OR⁸, -C(=O)NR⁸R⁸, -NHC(=O)OR⁸ y el sustituyente bivalente =O; cada R⁸ se selecciona independientemente del grupo que consiste en hidrógeno, C₁₋₆ alquilo, C₃₋₁₀ cicloalquilo, heterociclilo de 3 - 11 miembros, C₆₋₁₀ arilo y heteroarilo de 5 - 10 miembros, en donde el C₁₋₆ alquilo, C₃₋₁₀ cicloalquilo, heterociclilo de 3 - 11 miembros, C₆₋₁₀ arilo y heteroarilo de 5 - 10 miembros están todos opcionalmente sustituidos con uno o más R⁹ y/o R¹⁰ idénticos o diferentes; cada R⁹ se selecciona independientemente del grupo que consiste en -OR¹⁰, -NR¹⁰R¹⁰ y -C(O)NR¹⁰R¹⁰; cada R¹⁰ se selecciona independientemente del grupo que consiste en hidrógeno, C₁₋₆ alquilo, C₃₋₁₀ cicloalquilo, heterociclilo de 3 - 11 miembros y heteroarilo de 5 - 10 miembros, en donde el C₁₋₆ alquilo está opcionalmente sustituido con un sustituyente seleccionado del grupo que consiste en C₁₋₆ alcoxi, C₃₋₁₀ cicloalquilo y heterociclilo de 3 - 11 miembros opcionalmente sustituido con C₁₋₆ alquilo; W es nitrógeno (-N=) o -CH=; V es nitrógeno (-N=) o -CH=; U es nitrógeno (-N=) o -C(R¹¹)=; R¹¹ se selecciona de hidrógeno, halógeno y C₁₋₄ alcoxi; el anillo A es un anillo seleccionado del grupo que consiste en pirrol, furano, tiofeno, imidazol, pirazol, oxazol, isoxazol, tiazol, isotiazol y triazol; cada R⁴, si está presente, se selecciona independientemente del grupo que consiste en C₁₋₆ alquilo, C₁₋₆ haloalquilo, C₁₋₆ alcoxi, C₁₋₆ haloalcoxi, ciano-C₁₋₆ alquilo, halógeno, -OH, -NH₂, -NH(C₁₋₄ alquilo), -N(C₁₋₄ alquilo)₂, -CN, C₃₋₅ cicloalquilo y heterociclilo de 3 - 5 miembros; p se selecciona del grupo que consiste en 0, 1, 2 y 3; R⁵ es un heterociclilo de 3 - 11 miembros opcionalmente sustituido con uno o más C₁₋₆ alquilo, C₁₋₆ alcoxi o un heterociclilo de 5 - 6 miembros idénticos o diferentes, en donde el C₁₋₆ alquilo está opcionalmente sustituido con ciclopropilo; o R⁵ es -O-C₁₋₆ alquilo sustituido con un heterociclilo de 3 - 11 miembros, en donde el heterociclilo de 3 - 11 miembros está opcionalmente sustituido con uno o más R¹² idénticos o diferentes, cada R¹² se selecciona del grupo que consiste en C₁₋₆ alquilo, C₁₋₆ alcoxi, halógeno y heterociclilo de 3 - 11 miembros; o una sal de estos.Compounds of formula (1) wherein R¹ᵃ, R¹ᵇ, R²ᵃ, R²ᵇ, Z, R³ to R⁵, A, p, U, V and W have the meanings given in the claims and specification, their use as KRAS inhibitors , pharmaceutical compositions and preparations containing said compounds and their use as medicines/medical uses, especially as agents for the treatment and/or prevention of oncological diseases. Claim 1: A compound of formula (1), characterized in that R¹ᵃ and R¹ᵇ are independently selected from the group consisting of hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, halogen, - NH₂, -NH(C₁₋₄ alkyl), -N(C₁₋₄ alkyl)₂, C₃₋₅ cycloalkyl and 3-5 membered heterocyclyl; R²ᵃ and R²ᵇ are independently selected from the group consisting of hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, halogen, -NH₂, -NH(C₁₋₄ alkyl), -N( C₁₋₄ alkyl)₂, C₃₋₅ cycloalkyl and 3-5 membered heterocyclyl; and/or, optionally, one of R¹ᵃ or R¹ᵇ and one of R²ᵃ or R²ᵇ together with the carbon atoms to which they are attached form a cyclopropane ring; Z is -(CR⁶ᵃR⁶ᵇ)ₙ-; each R⁶ᵃ and R⁶ᵇ is independently selected from the group consisting of hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, halogen, -NH₂, -NH(C₁₋₄ alkyl), -N (C₁₋₄ alkyl)₂, C₃₋₅ cycloalkyl and 3-5 membered heterocyclyl; or R⁶ᵃ and R⁶ᵇ together with the carbon atom to which they are attached to form a cyclopropane ring; n is selected from the group consisting of 0, 1 and 2; R³ is selected from the group consisting of halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, -N₃, C₃₋₁₀ cycloalkyl, 3-11 membered heterocyclyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, wherein C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 3-11 membered heterocyclyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are all optionally and independently substituted with one or more R⁷ and/or R⁸ identical or different; each R⁷ is independently selected from the group consisting of -OR⁸, -NR⁸R⁸, halogen, -CN, -C(=O)R⁸, -C(=O)OR⁸, -C(=O)NR⁸R⁸, -NHC(=O )OR⁸ and the bivalent substituent =O; each R⁸ is independently selected from the group consisting of hydrogen, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 3-11 membered heterocyclyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, wherein the C₁₋₆ alkyl, C₃ ₋₁₀ cycloalkyl, 3-11 membered heterocyclyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are all optionally substituted with one or more identical or different R⁹ and/or R¹⁰; each R⁹ is independently selected from the group consisting of -OR¹⁰, -NR¹⁰R¹⁰ and -C(O)NR¹⁰R¹⁰; each R¹⁰ is independently selected from the group consisting of hydrogen, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 3-11 membered heterocyclyl and 5-10 membered heteroaryl, wherein the C₁₋₆ alkyl is optionally substituted with a selected substituent. from the group consisting of C₁₋₆ alkoxy, C₃₋₁₀ cycloalkyl and 3-11 membered heterocyclyl optionally substituted with C₁₋₆ alkyl; W is nitrogen (-N=) or -CH=; V is nitrogen (-N=) or -CH=; U is nitrogen (-N=) or -C(R¹¹)=; R¹¹ is selected from hydrogen, halogen and C₁₋₄ alkoxy; ring A is a ring selected from the group consisting of pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole and triazole; each R⁴, if present, is independently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₆ alkyl, halogen, -OH, -NH₂, -NH(C₁₋₄ alkyl), -N(C₁₋₄ alkyl)₂, -CN, C₃₋₅ cycloalkyl and 3-5 membered heterocyclyl; p is selected from the group consisting of 0, 1, 2 and 3; R⁵ is a 3-11 membered heterocyclyl optionally substituted with one or more C₁₋₆ alkyl, C₁₋₆ alkoxy or an identical or different 5-6 membered heterocyclyl, wherein the C₁₋₆ alkyl is optionally substituted with cyclopropyl; or R⁵ is -O-C₁₋₆ alkyl substituted with a 3-11 membered heterocyclyl, wherein the 3-11 membered heterocyclyl is optionally substituted with one or more identical or different R¹², each R¹² being selected from the group consisting of C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen and 3-11 membered heterocyclyl; or one of these salt.

ARP220103296A 2020-12-01 2022-11-30 NULLED AND DERIVED 2-AMINO-3-CYANO THIOPHENES FOR THE TREATMENT OF CANCER AR127836A1 (en)

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US202063284778P 2020-12-01 2020-12-01
US202163284754P 2021-12-01 2021-12-01

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AR127836A1 true AR127836A1 (en) 2024-03-06

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