AR127185A1 - PYRAZOLOPYRIDINE COMPOUNDS AS TAM INHIBITORS - Google Patents

PYRAZOLOPYRIDINE COMPOUNDS AS TAM INHIBITORS

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Publication number
AR127185A1
AR127185A1 ARP220102627A ARP220102627A AR127185A1 AR 127185 A1 AR127185 A1 AR 127185A1 AR P220102627 A ARP220102627 A AR P220102627A AR P220102627 A ARP220102627 A AR P220102627A AR 127185 A1 AR127185 A1 AR 127185A1
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AR
Argentina
Prior art keywords
heteroaryl
heterocyclyl
cycloalkyl
aryl
alkyl
Prior art date
Application number
ARP220102627A
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Spanish (es)
Inventor
Bin Jiang
Ming Zhang
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Antengene Discovery Ltd
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Publication date
Application filed by Antengene Discovery Ltd filed Critical Antengene Discovery Ltd
Publication of AR127185A1 publication Critical patent/AR127185A1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02Heterocyclic 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
    • C07D487/04Ortho-condensed systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D413/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D417/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic 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
    • C07D471/02Heterocyclic 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
    • C07D471/04Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D519/00Heterocyclic 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

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

La presente divulgación se refiere a compuestos de pirazolopiridina útiles como inhibidores de las cinasas TAM, en particular como inhibidores de las cinasas AXL y MER, así como a composiciones farmacéuticas que comprenden estos compuestos y métodos de tratamiento mediante la administración de estos compuestos o las composiciones farmacéuticas. Reivindicación 1: Un compuesto que tiene la fórmula (1) o una sal farmacéuticamente aceptable de este: caracterizado porque El anillo A es un heteroarilo de 5 miembros que comprende 1 o 2 átomos de nitrógeno; El anillo B es fenilo o heteroarilo de 6 miembros que comprende 1 o 2 átomos de nitrógeno, cada uno de los cuales está opcionalmente sustituido con uno o dos R²; El anillo C es cicloalquilo, heterociclilo, arilo o heteroarilo, cada uno de los cuales está opcionalmente sustituido con uno o más Rᵃ; R¹ es cicloalquilo, heterociclilo, arilo o heteroarilo, cada uno de los cuales está opcionalmente sustituido con uno o más Rᵇ; R² es halógeno, hidroxilo, ciano, amino, alquilo o haloalquilo; cada Rᵃ se selecciona independientemente del grupo que consiste en hidrógeno, halógeno, hidroxilo, ciano, amino, oxo, alquilo, cicloalquilo, heterociclilo, arilo, heteroarilo y -C(=O)Rᶜ; o dos Rᵃ adyacentes junto con los átomos a los que están unidos forman un cicloalquilo o heterociclilo; cada Rᵇ se selecciona independientemente de oxo, alquilo, alcoxilo, cicloalquilo, heterociclilo, arilo, heteroarilo o -C(O)NH-Rᶜ, donde cicloalquilo, heterociclilo, arilo y heteroarilo están opcionalmente sustituidos con uno o más grupos seleccionados independientemente de halógeno, hidroxilo, ciano, amino o alquilo; y Rᶜ es alquilo, cicloalquilo, heterociclilo, arilo o heteroarilo, donde el cicloalquilo, heterociclilo, arilo y heteroarilo están opcionalmente sustituidos con uno o más grupos seleccionados independientemente de halógeno, hidroxilo, ciano, amino o alquilo. Reivindicación 28: Un compuesto que tiene la fórmula (2) o una sal farmacéuticamente aceptable de este: caracterizado porque El anillo A es un fenilo o heteroarilo de 6 miembros que comprende 1 o 2 átomos de nitrógeno; El anillo B es fenilo o heteroarilo de 6 miembros que comprende 1 o 2 átomos de nitrógeno, cada uno de los cuales está opcionalmente sustituido con uno o dos R²; El anillo C es cicloalquilo, heterociclilo, arilo o heteroarilo, cada uno de los cuales está opcionalmente sustituido con uno o más Rᵃ; W es CH, N, O o S; R¹ es cicloalquilo, heterociclilo, arilo o heteroarilo, cada uno de los cuales está opcionalmente sustituido con uno o más Rᵇ; R² es halógeno, hidroxilo, ciano, amino o alquilo; R³ es nulo, hidrógeno, oxo, alquilo o haloalquilo; R⁴ es NH₂ o haloalquilo; cada Rᵃ se selecciona independientemente del grupo que consiste en hidrógeno, halógeno, hidroxilo, ciano, amino, alquilo, cicloalquilo, heterociclilo, arilo, heteroarilo y -C(=O)Rᶜ; o dos Rᵃ adyacentes junto con los átomos a los que están unidos forman un cicloalquilo o heterociclilo; cada Rᵇ se selecciona independientemente de oxo, hidroxilo, alquilo, alcoxilo, haloalquilo, haloalcoxilo, cicloalquilo, heterociclilo, arilo, heteroarilo o -C(O)NH-Rᶜ, donde cicloalquilo, heterociclilo, arilo y heteroarilo están opcionalmente sustituidos con uno o más grupos seleccionados independientemente de halógeno, hidroxilo, ciano, amino o alquilo; y Rᶜ es alquilo, cicloalquilo, heterociclilo, arilo o heteroarilo, donde el cicloalquilo, heterociclilo, arilo y heteroarilo están opcionalmente sustituidos con uno o más grupos seleccionados independientemente de halógeno, hidroxilo, ciano, amino o alquilo. Reivindicación 66: Un compuesto que tiene la fórmula (3) o una sal farmacéuticamente aceptable de este: caracterizado porque El anillo A es un heteroarilo de 5 miembros que comprende 1 o 2 átomos de nitrógeno; El anillo B es fenilo o heteroarilo de 6 miembros que comprende 1 o 2 átomos de nitrógeno, cada uno de los cuales está opcionalmente sustituido con uno o dos R²; El anillo C es cicloalquilo, heterociclilo, arilo o heteroarilo, cada uno de los cuales está opcionalmente sustituido con uno o más Rᵃ; R¹ es cicloalquilo, heterociclilo, arilo o heteroarilo, cada uno de los cuales está opcionalmente sustituido con uno o más Rᵇ; R² es halógeno, hidroxilo, ciano, amino, alquilo o haloalquilo; cada Rᵃ se selecciona independientemente del grupo que consiste en hidrógeno, halógeno, hidroxilo, ciano, amino, oxo, alquilo, cicloalquilo, heterociclilo, arilo, heteroarilo y -C(=O)Rᶜ; o dos Rᵃ adyacentes junto con los átomos a los que están unidos forman un cicloalquilo o heterociclilo; cada Rᵇ se selecciona independientemente de oxo, alquilo, alcoxilo, cicloalquilo, heterociclilo, arilo, heteroarilo o -C(O)NH-Rᶜ, donde cicloalquilo, heterociclilo, arilo y heteroarilo están opcionalmente sustituidos con uno o más grupos seleccionados independientemente de halógeno, hidroxilo, ciano, amino o alquilo; y Rᶜ es alquilo, cicloalquilo, heterociclilo, arilo o heteroarilo, donde el cicloalquilo, heterociclilo, arilo y heteroarilo están opcionalmente sustituidos con uno o más grupos seleccionados independientemente de halógeno, hidroxilo, ciano, amino o alquilo. Reivindicación 86: Un compuesto que tiene la fórmula (4) o una sal farmacéuticamente aceptable de este: caracterizado porque el anillo A es un heterociclilo de 6 miembros o un heteroarilo de 6 miembros, cada uno de los cuales comprende 1 o 2 átomos de nitrógeno y está opcionalmente sustituido con uno o más grupos seleccionados independientemente entre hidroxilo, halógeno, ciano, oxo, amino o alquilo; El anillo B es fenilo o heteroarilo de 6 miembros que comprende 1 o 2 átomos de nitrógeno, cada uno de los cuales está opcionalmente sustituido con uno o dos R²; El anillo C es cicloalquilo, heterociclilo, arilo o heteroarilo, cada uno de los cuales está opcionalmente sustituido con uno o más Rᵃ; R¹ es cicloalquilo, heterociclilo, arilo o heteroarilo, cada uno de los cuales está opcionalmente sustituido con uno o más Rᵇ; R² es halógeno, hidroxilo, ciano, amino, alquilo o haloalquilo; cada Rᵃ se selecciona independientemente del grupo que consiste en hidrógeno, halógeno, hidroxilo, ciano, amino, oxo, alquilo, cicloalquilo, heterociclilo, arilo, heteroarilo y -C(=O)Rᶜ; o dos Rᵃ adyacentes junto con los átomos a los que están unidos forman un cicloalquilo o heterociclilo; cada Rᵇ se selecciona independientemente de oxo, alquilo, alcoxilo, cicloalquilo, heterociclilo, arilo, heteroarilo o -C(O)NH-Rᶜ, donde cicloalquilo, heterociclilo, arilo y heteroarilo están opcionalmente sustituidos con uno o más grupos seleccionados independientemente de halógeno, hidroxilo, ciano, amino o alquilo; y Rᶜ es alquilo, cicloalquilo, heterociclilo, arilo o heteroarilo, donde el cicloalquilo, heterociclilo, arilo y heteroarilo están opcionalmente sustituidos con uno o más grupos seleccionados independientemente de halógeno, hidroxilo, ciano, amino o alquilo. Reivindicación 104: Un método para inhibir una cinasa TAM, caracterizado porque comprende poner en contacto la cinasa TAM con el compuesto de una cualquiera de las reivindicaciones 1 a 102, o una sal farmacéuticamente aceptable de este o la composición farmacéutica de la reivindicación 103. Reivindicación 105: Un método para inhibir las cinasas AXL y MER, caracterizado porque comprende poner en contacto las cinasas AXL y MER con el compuesto de una cualquiera de las reivindicaciones 1 a 102, o una sal farmacéuticamente aceptable de este o la composición farmacéutica de la reivindicación 103.The present disclosure relates to pyrazolopyridine compounds useful as inhibitors of TAM kinases, in particular as inhibitors of AXL and MER kinases, as well as to pharmaceutical compositions comprising these compounds and methods of treatment by administering these compounds or the compositions. pharmaceuticals. Claim 1: A compound having formula (1) or a pharmaceutically acceptable salt thereof: characterized in that Ring A is a 5-membered heteroaryl comprising 1 or 2 nitrogen atoms; Ring B is 6-membered phenyl or heteroaryl comprising 1 or 2 nitrogen atoms, each of which is optionally substituted with one or two R²; The C ring is cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which is optionally substituted with one or more Rᵃ; R¹ is cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which is optionally substituted with one or more Rᵇ; R² is halogen, hydroxyl, cyano, amino, alkyl or haloalkyl; each Rᵃ is independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, amino, oxo, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and -C(=O)Rᶜ; or two adjacent Rᵃ together with the atoms to which they are attached form a cycloalkyl or heterocyclyl; each Rᵇ is independently selected from oxo, alkyl, alkoxyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or -C(O)NH-Rᶜ, where cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino or alkyl; and Rᶜ is alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, where the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino or alkyl. Claim 28: A compound having formula (2) or a pharmaceutically acceptable salt thereof: characterized in that Ring A is a 6-membered phenyl or heteroaryl comprising 1 or 2 nitrogen atoms; Ring B is 6-membered phenyl or heteroaryl comprising 1 or 2 nitrogen atoms, each of which is optionally substituted with one or two R²; The C ring is cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which is optionally substituted with one or more Rᵃ; W is CH, N, O or S; R¹ is cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which is optionally substituted with one or more Rᵇ; R² is halogen, hydroxyl, cyano, amino or alkyl; R³ is null, hydrogen, oxo, alkyl or haloalkyl; R⁴ is NH₂ or haloalkyl; each Rᵃ is independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, amino, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and -C(=O)Rᶜ; or two adjacent Rᵃ together with the atoms to which they are attached form a cycloalkyl or heterocyclyl; each Rᵇ is independently selected from oxo, hydroxyl, alkyl, alkoxyl, haloalkyl, haloalkoxyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or -C(O)NH-Rᶜ, where cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino or alkyl; and Rᶜ is alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, where the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino or alkyl. Claim 66: A compound having formula (3) or a pharmaceutically acceptable salt thereof: characterized in that Ring A is a 5-membered heteroaryl comprising 1 or 2 nitrogen atoms; Ring B is 6-membered phenyl or heteroaryl comprising 1 or 2 nitrogen atoms, each of which is optionally substituted with one or two R²; The C ring is cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which is optionally substituted with one or more Rᵃ; R¹ is cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which is optionally substituted with one or more Rᵇ; R² is halogen, hydroxyl, cyano, amino, alkyl or haloalkyl; each Rᵃ is independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, amino, oxo, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and -C(=O)Rᶜ; or two adjacent Rᵃ together with the atoms to which they are attached form a cycloalkyl or heterocyclyl; each Rᵇ is independently selected from oxo, alkyl, alkoxyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or -C(O)NH-Rᶜ, where cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino or alkyl; and Rᶜ is alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, where the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino or alkyl. Claim 86: A compound having formula (4) or a pharmaceutically acceptable salt thereof: characterized in that ring A is a 6-membered heterocyclyl or a 6-membered heteroaryl, each of which comprises 1 or 2 nitrogen atoms and is optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, oxo, amino or alkyl; Ring B is 6-membered phenyl or heteroaryl comprising 1 or 2 nitrogen atoms, each of which is optionally substituted with one or two R²; The C ring is cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which is optionally substituted with one or more Rᵃ; R¹ is cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which is optionally substituted with one or more Rᵇ; R² is halogen, hydroxyl, cyano, amino, alkyl or haloalkyl; each Rᵃ is independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, amino, oxo, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and -C(=O)Rᶜ; or two adjacent Rᵃ together with the atoms to which they are attached form a cycloalkyl or heterocyclyl; each Rᵇ is independently selected from oxo, alkyl, alkoxyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or -C(O)NH-Rᶜ, where cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino or alkyl; and Rᶜ is alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, where the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino or alkyl. Claim 104: A method of inhibiting a TAM kinase, characterized in that it comprises contacting the TAM kinase with the compound of any one of claims 1 to 102, or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 103. Claim 103. 105: A method for inhibiting AXL and MER kinases, characterized in that it comprises contacting the AXL and MER kinases with the compound of any one of claims 1 to 102, or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 103.

ARP220102627A 2021-09-29 2022-09-29 PYRAZOLOPYRIDINE COMPOUNDS AS TAM INHIBITORS AR127185A1 (en)

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CN2021121727 2021-09-29
CN2022076711 2022-02-17
CN2022114179 2022-08-23

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WO (1) WO2023051464A1 (en)

Family Cites Families (6)

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Publication number Priority date Publication date Assignee Title
EP1730148A4 (en) * 2004-02-03 2009-08-19 Abbott Lab Aminobenzoxazoles as therapeutic agents
TW200815437A (en) * 2006-06-13 2008-04-01 Bayer Schering Pharma Ag Substituted aminopyrazolopyridines and salts thereof, pharmaceutical compositions comprising same, methods of preparing same and uses of same
TWI753892B (en) * 2016-03-28 2022-02-01 美商英塞特公司 Pyrrolotriazine compounds as tam inhibitors
CN110627796B (en) * 2018-06-21 2022-07-12 北京越之康泰生物医药科技有限公司 Nitrogenous heterocyclic derivative and application thereof in medicine
CN113683629B (en) * 2020-05-18 2023-07-04 北京范恩柯尔生物科技有限公司 Substituted heteroaryl compounds, compositions and uses thereof
WO2022007921A1 (en) * 2020-07-10 2022-01-13 北京范恩柯尔生物科技有限公司 Triazine compound and composition and use thereof

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CN116437918A (en) 2023-07-14

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