AR110740A1 - Compuestos bicíclicos como inhibidores alostéricos de shp2 - Google Patents

Compuestos bicíclicos como inhibidores alostéricos de shp2

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Publication number
AR110740A1
AR110740A1 ARP180100059A ARP180100059A AR110740A1 AR 110740 A1 AR110740 A1 AR 110740A1 AR P180100059 A ARP180100059 A AR P180100059A AR P180100059 A ARP180100059 A AR P180100059A AR 110740 A1 AR110740 A1 AR 110740A1
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AR
Argentina
Prior art keywords
alkyl
nr5s
cycloalkyl
heterocycle
nr5r6
Prior art date
Application number
ARP180100059A
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English (en)
Inventor
Adrian L Gill
Jie Jack Li
Christos Tzitzilonis
Gert Kiss
Walter S Won
Ashutosh S Jogalekar
Gang Wang
Jennifer Pitzen
Brian R Blank
Chris M Semko
Kevin T Mellem
Andreas Buckl
Naing N Aay
Elena S Koltun
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Revolution Medicines Inc
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Application filed by Revolution Medicines Inc filed Critical Revolution Medicines Inc
Publication of AR110740A1 publication Critical patent/AR110740A1/es

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

Se describen inhibidores de SHP2 y su uso en el tratamiento de enfermedades. También se describen composiciones farmacéuticas que los comprenden. Reivindicación 1: Un compuesto de la fórmula (1) o una sal, profármaco, solvato, hidrato, tautómero o isómero farmacéuticamente aceptable del mismo, caracterizado porque : R⁴ es H o un compuesto de fórmula (2); A es un cicloalquilo, heterocicloalquilo, arilo o heteroarilo monocíclico o policíclico de 5 a 12 miembros, siempre que el heteroarilo no sea un compuesto de fórmula (3) ó (4); R¹ es en forma independiente, en cada caso, -H, -D, -C₁₋₆ alquilo, -C₂₋₆ alquenilo, -C₄₋₈ cicloalquenilo, -C₂₋₆ alquinilo, -C₃₋₈ cicloalquilo, -OH, halógeno, -NO₂, -CN, -NR⁵R⁶, -SR⁵, -S(O)₂NR⁵R⁶, -S(O)₂R⁵, -NR⁵S(O)₂NR⁵R⁶, -NR⁵S(O)₂R⁶, -S(O)NR⁵R⁶, -S(O)R⁵, -NR⁵S(O)NR⁵R⁶, -NR⁵S(O)R⁶, -C(O)R⁵ o -CO₂R⁵, donde cada alquilo, alquenilo, cicloalquenilo, alquinilo o cicloalquilo está opcionalmente sustituido con uno o más -OH, halógeno, -NO₂, oxo, -CN, -R⁵, -OR⁵, -NRSR⁶, -SR⁵, -S(O)₂NR⁵R⁶, -S(O)₂R⁵, -NR⁵S(O)₂NR⁵R⁶, -NR⁵S(O)₂R⁶, -S(O)NR⁵R⁶, -S(O)R⁵, -NR⁵S(O)NR⁵R⁶, -NR⁵S(O)R⁶, heterociclo, arilo o heteroarilo; Y¹ es -S-, un enlace directo, -NH-, -S(O)₂-, -S(O)₂-NH-, -C(=CH₂)-, -CH- o -S(O)-; X¹ es N o C; X² es N o CH; B, incluyendo los átomos en los puntos de unión, es un heterociclo monocíclico o policíclico de 5 a 12 miembros o un heteroarilo de 5 a 12 miembros monocíclico o policíclico, en donde cada heterociclo o heteroarilo está sustituido opcionalmente con uno o más -C₁₋₆ alquilo, -OH, -NH₂, oxo, heteroarilo, heterociclilo, -(CH₂)ₙNH₂, -(CH₂)ₙOH, -CF₃, -CHF₂ o -CH₂F; R² es -H, -OH, -NR⁵R⁶, -C₁₋₆ alquilo, -C₂₋₆ alquenilo, -C₄₋₈ cicloalquenilo, -C₂₋₆ alquinilo, -NH₂, halógeno, -C₃₋₈ cicloalquilo o heterociclilo que contiene 1 - 5 heteroátomos seleccionados del grupo que consiste en N, S, P y O; en donde cada alquilo, alquenilo, cicloalquenilo, alquinilo, cicloalquilo o heterociclilo está sustituido opcionalmente con uno o más -OH, halógeno, -NO₂, oxo, -CN, -R⁵, -OR⁵, -NR⁵R⁶, -SR⁵, -S(O)₂NR⁵R⁶, -S(O)₂R⁵, -NR⁵S(O)₂NR⁵R⁶, -NR⁵S(O)₂R⁶, -S(O)NR⁵R⁶, -S(O)R⁵, -NR⁵S(O)NR⁵R⁶, -NR⁵S(O)R⁶, heterociclo, arilo o heteroarilo; y en donde el heterociclilo no está unido por medio de un átomo de nitrógeno; Y² es -NRᵃ-, -(CRᵃ₂)ₘ-, -C(O)-, -C(Rᵃ)₂NH-, -(CRᵃ₂)ₘO-, -C(O)N(Rᵃ)-, -N(Rᵃ)C(O)-, -S(O)₂N(Rᵃ)-, -N(Rᵃ)S(O)₂-, -N(Rᵃ)C(O)N(Rᵃ)-, -N(Rᵃ)C(S)N(Rᵃ)-, -C(O)O-, -OC(O)-, -OC(O)N(Rᵃ)-, -N(Rᵃ)C(O)O-, -C(O)N(Rᵃ)O-, -N(Rᵃ)C(S)-, -C(S)N(Rᵃ)- o -OC(O)O-; en donde el enlace sobre el lado izquierdo de Y², como se ilustra, está unido al anillo y el enlace sobre el lado derecho de la unidad Y², como se ilustra, está unido a R³; Rᵃ es en forma independiente, en cada caso, -H, -D, -OH, -C₃₋₈ cicloalquilo o -C₁₋₆ alquilo, donde cada alquilo o cicloalquilo está opcionalmente sustituido con uno o más -NH₂, donde 2 Rᵃ, junto con el átomo de carbono al cual ambos están unidos, se pueden combinar para formar un cicloalquilo de 3 a 8 miembros; Rᵇ es en forma independiente, en cada caso, -H, -D, -C₁₋₆ alquilo, -C₃₋₈ cicloalquilo, -C₂₋₆ alquenilo o heterociclilo con 1 - 5 heteroátomos seleccionados entre el grupo que consiste en N, S, P, y O; donde cada alquilo, cicloalquilo, alquenilo o heterociclo está opcionalmente sustituido con uno o más -OH, halógeno, -NO₂, oxo, -CN, -R⁵, -OR⁵, -NR⁵R⁶, -SR⁵, -S(O)₂NR⁵R⁶, -S(O)₂R⁵, -NR⁵S(O)₂NR⁵R⁶, -NR⁵S(O)₂R⁶, -S(O)NR⁵R⁶, -S(O)R⁵, -NR⁵S(O)NR⁵R⁶, -NR⁵S(O)R⁶, heterociclo, arilo, heteroarilo, -(CH₂)ₙOH, -C₁₋₆ alquilo, -CF₃, -CHF₂ o -CH₂F; R³ es -H, -C₁₋₆ alquilo, un heterociclo monocíclico o policíclico de 3 a 12 miembros, -C₃₋₈ cicloalquilo o -(CH₂)ₙ-Rᵇ, en donde cada alquilo, heterociclo o cicloalquilo está sustituido opcionalmente con uno o más -C₁₋₆ alquilo, -OH, -NH₂, -ORᵇ, -NHRᵇ, -(CH₂)ₙOH, heterociclilo o espiroheterociclilo; o R³ se puede combinar con Rᵃ para formar un heterociclo monocíclico o policíclico de 3 a 12 miembros o un espiroheterociclo de 5 a 12 miembros, en donde cada heterociclo o espiroheterociclo está sustituido opcionalmente con uno o más -C₁₋₆ alquilo, -OH, -NH₂, oxo, heteroarilo, heterociclilo, -(CH₂)ₙNH₂, -(CH₂)ₙOH, -CF₃, -CHF₂ o -CH₂F, siempre que el heterociclo formado por la combinación de R³ y Rᵃ no es un piperazinilo sustituido opcionalmente; R⁵ y R⁶ son en forma independiente, en cada caso, -H, -D, -C₁₋₆ alquilo, -C₂₋₆ alquenilo, -C₄₋₈ cicloalquenilo, -C₂₋₆ alquinilo, -C₃₋₈ cicloalquilo, un heterociclo monocíclico o policíclico de 3 a 12 miembros, -OR⁷, -SR⁷, halógeno, -NR⁷R⁸, -NO₂ o -CN; R⁷ y R⁸ son en forma independiente, en cada caso, -H, -D, -C₁₋₆ alquilo, -C₂₋₆ alquenilo, -C₄₋₈ cicloalquenilo, -C₂₋₆ alquinilo, -C₃₋₈ cicloalquilo o un heterociclo monocíclico o policíclico de 3 a 12 miembros, donde cada alquilo, alquenilo, cicloalquenilo, alquinilo, cicloalquilo o heterociclo esta opcionalmente sustituido con uno o más -OH, -SH, -NH₂, -NO₂ o -CN; m es en forma independiente, en cada caso, 1, 2, 3, 4, 5 ó 6; y n es en forma independiente, en cada caso, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 ó 10.
ARP180100059A 2017-01-23 2018-01-09 Compuestos bicíclicos como inhibidores alostéricos de shp2 AR110740A1 (es)

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US (1) US11739093B2 (es)
EP (1) EP3571199A1 (es)
JP (2) JP7240319B2 (es)
KR (1) KR20190111079A (es)
CN (2) CN110446709B (es)
AR (1) AR110740A1 (es)
AU (2) AU2018210770B2 (es)
BR (1) BR112019015075A2 (es)
CA (1) CA3051206A1 (es)
IL (2) IL296456A (es)
MX (2) MX2019008695A (es)
SG (1) SG11201906209SA (es)
TW (1) TWI820013B (es)
WO (1) WO2018136265A1 (es)

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AU2018210770B2 (en) 2022-03-24
IL268030A (en) 2019-09-26
IL268030B2 (en) 2023-02-01
MX2019008695A (es) 2019-09-11
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US20200017511A1 (en) 2020-01-16
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EP3571199A1 (en) 2019-11-27
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CN117327075A (zh) 2024-01-02
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