AR110443A1 - Inhibidores de histona metiltransferasas - Google Patents

Inhibidores de histona metiltransferasas

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Publication number
AR110443A1
AR110443A1 ARP170103662A ARP170103662A AR110443A1 AR 110443 A1 AR110443 A1 AR 110443A1 AR P170103662 A ARP170103662 A AR P170103662A AR P170103662 A ARP170103662 A AR P170103662A AR 110443 A1 AR110443 A1 AR 110443A1
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AR
Argentina
Prior art keywords
alkyl
heteroalkyl
halo
alkoxy
haloalkyl
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Application number
ARP170103662A
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English (en)
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Global Blood Therapeutics Inc
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Publication date
Application filed by Global Blood Therapeutics Inc filed Critical Global Blood Therapeutics Inc
Publication of AR110443A1 publication Critical patent/AR110443A1/es

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    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • A—HUMAN NECESSITIES
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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    • A—HUMAN NECESSITIES
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    • A61P25/00—Drugs for disorders of the nervous system
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic 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
    • C07D401/02—Heterocyclic 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 two hetero rings
    • C07D401/04—Heterocyclic 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 two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic 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
    • C07D401/02—Heterocyclic 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 two hetero rings
    • C07D401/12—Heterocyclic 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 two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic 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
    • C07D401/14—Heterocyclic 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
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
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    • 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
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    • 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
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    • 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
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Hematology (AREA)
  • Rheumatology (AREA)
  • Dermatology (AREA)
  • Oncology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Diabetes (AREA)
  • Neurology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pain & Pain Management (AREA)
  • Nutrition Science (AREA)
  • Biomedical Technology (AREA)
  • Transplantation (AREA)
  • Neurosurgery (AREA)
  • Obesity (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)

Abstract

Compuestos tricíclicos angulares que son inhibidores de las histona metiltransferasas G9a y/o GLP, y por ello son de utilidad para el tratamiento de enfermedades que son tratables por la inhibición de G9a y/o GLP, tales como cánceres y hemoglobinopatias (por ejemplo, b-talasemia y enfermedad de células falsiformes). También se proveen composiciones farmacéuticas que contienen dichos compuestos. Reivindicación 1: Un compuesto de la fórmula (1), donde: Z¹ y Z² son de manera independiente C (cuando R² o R³ está unido al mismo), CH o N; alk es alquileno en donde uno o dos átomos de carbono de la cadena alquileno están reemplazados opcionalmente por NR, O, S o SO₂ (donde R es hidrógeno o alquilo), y la cadena alquileno está sustituida opcionalmente con uno o dos sustituyentes seleccionados de manera independiente entre halo, haloalquilo, haloalcoxi, hidroxi y alcoxi, y en donde -alk-R¹ está unido al carbono (a) o (b); R¹ es -NR⁶R⁷ (donde R⁶ y R⁷ son de manera independiente hidrógeno, alquilo, hidroxialquilo, alcoxialquilo, haloalquilo o haloalcoxialquilo), heterociclilo no sustituido, heterociclilo sustituido con 1, 2 ó 3 de Rᵃ, Rᵇ, y Rᶜ, en donde Rᵃ, Rᵇ y Rᶜ se seleccionan de manera independiente entre alquilo, hidroxi, alcoxi, halo, haloalquilo, alquilcarbonilo y haloalquilcarbonilo, o espiroheterocicloamina en donde un átomo de nitrógeno de la espiroheterocicloamina está unido a alk; R² es hidrógeno, alquilo, cicloalquilo, halo, hidroxi, alcoxi, haloalcoxi o ciano; R³ es hidrógeno, alquilo, halo, alcoxi, alquilamino, dialquilamino o ciano; R⁴ es hidrógeno, deuterio, alquilo (opcionalmente sustituido con uno a nueve deuterios), cicloalquilo (opcionalmente sustituido con uno o dos sustituyentes seleccionados de manera independiente entre alquilo, hidroxi, halo, alcoxi, haloalquilo, y haloalcoxi), cicloalquenilo, fenilo (opcionalmente sustituido con uno o dos sustituyentes seleccionados de manera independiente entre alquilo, halo, hidroxi y alcoxi), heteroarilo (opcionalmente sustituido con uno o dos sustituyentes seleccionados de manera independiente entre alquilo, halo, hidroxi y alcoxi), heterociclilo (opcionalmente sustituido con uno o dos sustituyentes seleccionados de manera independiente entre alquilo, halo, hidroxi, alcoxi, haloalquilo y haloalcoxi), -ORᵈ (donde Rᵈ es hidrógeno, alquilo, haloalquilo, hidroxialquilo, alcoxialquilo, cicloalquilo, halocicloalquilo, cicloalquilalquilo, arilo, aralquilo, heteroarilo, heteroaralquilo, heterociclilo o heterociclilalquilo), o NRᵉRᶠ (donde Rᵉ es hidrógeno o alquilo y Rᶠ es hidrogeno, alquilo, alquilo deuterado, alquiltioalquilo, acilo, haloalquilo, hidroxialquilo, alcoxialquilo, aminoalquilo, cianoalquilo, carboxialquilo, alcoxicarbonilalquilo, cicloalquilo, cicloalquilalquilo, arilo, aralquilo, heteroarilo, heteroaralquilo, heterociclilo o heterociclilalquilo), en donde el cicloalquilo, el arilo, el heteroarilo, y el heterociclilo ya sea solos o como parte del cicloalquilalquilo, aralquilo, heteroaralquilo y heterociclilalquilo en Rᵈ y Rᶠ de manera independiente no están sustituidos o están sustituido con 1, 2 ó 3 de Rᵍ, Rʰ y Rⁱ, en donde Rᵍ, Rʰ y Rⁱ se seleccionan de manera independiente entre alquilo, hidroxi, alcoxi, halo, haloalquilo, ciano, carboxi, alcoxicarbonilo y haloalcoxi, y en donde el alquileno del aralquilo, heteroaralquilo, heterociclilalquilo y cicloalquilalquilo en Rᵈ y Rᶠ está sustituido opcionalmente con uno a nueve deuterios; X es carbono o nitrógeno; y el anillo B es fenilo, heteroarilo de 5 ó 6 miembros que contiene uno, dos o tres heteroátomos seleccionados de manera independiente entre nitrógeno, oxigeno y azufre, cicloalquilo de 5 ó 6 miembros, espirocicloalquilo, espiroheterocicloamina o heterociclilo saturado de 5, 6 ó 7 miembros, en donde cada de uno de los anillos del anillo B no está sustituido o está sustituido con 1, 2, 3 ó 4 de Rʲ, Rᵏ, Rˡ y Rᵐ, en donde Rʲ, Rᵏ, Rˡ y Rᵐ se seleccionan de manera independiente entre alquilo, hidroxi, ciano, alcoxi, halo, haloalquilo y haloalcoxi; o una sal farmacéuticamente aceptable del mismo; y en donde el compuesto de la fórmula (1) no es: 5-aminobenzo[f][1,7]naftiridin-8-metanamina o 10-etoxi-8-(morfolinometil)-1,2,3,4-tetrahidrobenzo[h][1,6]naftiridin-5-ol; o una sal del mismo.
ARP170103662A 2016-12-22 2017-12-22 Inhibidores de histona metiltransferasas AR110443A1 (es)

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US (2) US10829452B2 (es)
EP (2) EP3558971B1 (es)
JP (2) JP7091336B2 (es)
AR (1) AR110443A1 (es)
ES (1) ES2910108T3 (es)
TW (1) TW201829386A (es)
WO (1) WO2018119208A1 (es)

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018119208A1 (en) * 2016-12-22 2018-06-28 Global Blood Therapeutics, Inc. Histone methyltransferase inhibitors
CN118021814A (zh) 2017-04-21 2024-05-14 Epizyme股份有限公司 用ehmt2抑制剂进行的组合疗法
CA3079412A1 (en) * 2017-10-18 2019-04-25 Epizyme, Inc. Methods of using ehmt2 inhibitors in immunotherapies
MA50417A (fr) * 2017-10-18 2020-08-26 Epizyme Inc Procédés d'utilisation d'inhibiteurs de l'ehmt2 dans le traitement ou la prévention de troubles du sang
CN111196817B (zh) * 2018-11-19 2021-06-11 四川大学华西医院 作为brpf1抑制剂的三环化合物
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