ES2533788T3 - Compuestos inhibidores de PI3K de tipo purina y métodos de uso - Google Patents

Compuestos inhibidores de PI3K de tipo purina y métodos de uso Download PDF

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Publication number
ES2533788T3
ES2533788T3 ES09755767.2T ES09755767T ES2533788T3 ES 2533788 T3 ES2533788 T3 ES 2533788T3 ES 09755767 T ES09755767 T ES 09755767T ES 2533788 T3 ES2533788 T3 ES 2533788T3
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Prior art keywords
morpholino
purin
alkylene
methyl
heterocyclyl
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ES09755767.2T
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Georgette Castanedo
Irina Chuckowree
Adrian Folkes
Daniel P. Sutherlin
Nan Chi Wan
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F Hoffmann La Roche AG
Genentech Inc
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F Hoffmann La Roche AG
Genentech Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Un compuesto que tiene la estructura:**Fórmula** y estereoisómeros, isómeros geométricos, tautómeros o sales farmacéuticamente aceptables de los mismos, en la que: R1 se selecciona entre H, alquilo C1-C12 y -(alquileno C1-C12)-(heterociclilo C2-C20), en donde alquilo, alquileno y heterociclilo están opcionalmente sustituidos con uno o más grupos seleccionados independientemente entre F, Cl, Br, I, -CH3, -CH2OH, -CN, -CF3, -CO2H, -COCH3, -CO2CH3, -CONH2, -CONHCH3, -CON(CH3)2, -NO2, -NH2, -NHCH3, -NHCOCH3, -NHS(O)2CH3, -OH, -OCH3, -S(O)2N(CH3)2, -SCH3, -CH2OCH3 y -S(O)2CH3. R2 se selecciona entre alquilo C1-C12, alquenilo C2-C8, alquinilo C2-C8, -(alquileno C1-C12)-(carbociclilo C3-C12)-, -(alquileno C1-C12)-(heterociclilo C2-C20)-, -(alquileno C1-C12)-C(>=O)-(C2-C20 heterociclilo), -(alquileno C1-C12)-(arilo C6-C20)- y -(alquileno C1-C12)-(heteroarilo C1-C20), en donde alquilo, alquenilo, alquinilo, alquileno, carbociclilo, heterociclilo, arilo y heteroarilo están opcionalmente sustituidos con uno o más grupos seleccionados independientemente entre F, Cl, Br, I, -CH3, -CH2OH, -CN, -CF3, -CO2H, -COCH3, -CO2CH3, -CONH2, -CONHCH3, -CON(CH3)2, -NO2, -NHz, -NHCH3,-NHCOCH3, -NHS(O)2CH3, -OH, -OCH3, -S(O)2N(CH3)2, -SCH3, -CH2OCH3 y -S(O)2CH3; y R3 es un heteroarilo monocíclico seleccionado entre:**Fórmula** en las que la línea ondulada indica el sitio de la unión.

Description

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Las realizaciones ilustrativas incluyen la estructura:
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en la que R3 es un heteroarilo monocíclico seleccionado entre:
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en las que la línea ondulada indica el sitio de la unión, y en la que R1 se selecciona entre alquilo C1-C12, -(alquileno C1-C12)-(heterociclilo C2-C20)-, en la que alquilo, alquileno, y heterociclilo, están opcionalmente sustituidos con uno o
10 más grupos seleccionados independientemente entre F, Cl, Br, I, -CH3, -CH2OH, -CN, -CF3, -CO2H, -COCH3, -CO2CH3, -CONH2, -CONHCH3, -CON(CH3)2, -NO2, -NH2, -NHCH3, NHCOCH3, -NHS(O)2CH3, -OH, -OCH3, -S(O)2N(CH3)2, -SCH3, -CH2OCH3, y -S(O)2CH3.
Los compuestos de la invención pueden contener centros asimétricos o quirales, y por tanto existen en formas
15 estereoisoméricas diferentes. Se pretende que todas las formas estereoisoméricas de los compuestos de la invención, incluyendo, pero sin limitación, diastereómeros, enantiómeros y atropisómeros, así como mezclas de los mismos, tales como mezclas racémicas, formen parte de la presente invención.
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2-(2-(2-amino-4-metilpirimidin-5-il)-9-(2-hidroxietil)-6-morfolino-9Hpurin-8-il)propan-2-ol
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2-(2-(2-aminopirimidin-5-il)-9-butil-6-morfolino-9H-purin-8-il)propan -2-ol
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imagen16 2-(2-(2-aminopirimidin-5-il)-6-morfolino-9-propil-9H-purin-8-il) propan-2-ol
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3-(2-(2-aminopirimidin-5-il)-8-(2-hidroxipropan-2-il)-6-morfolino-9Hpurin-9-il)propan-1-ol
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imagen17 2-(2-(2-aminopirimidin-5-il)-9-(2-hidroxietil)-6-morfolino-9H-purin-8il)propan-2-ol
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1-(4-((2-(2-aminopirimidin-5-il)-6-morfolino-9H-purin-9-il)metil) piperidin-1-il)etanona
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1-(3-((2-(2-aminopirimidin-5-il)-6-morfolino-9H-purin-9-il)metil) pirrolidin-1-il)etanona
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imagen18 (R)-3-(2-(2-aminopirimidin-5-il)-6-morfolino-9H-purin-9-il)-1(3-hidroxipirrolidin-1-il)propan-1-ona
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(S)-3-(2-(2-aminopirimidin-5-il)-6-morfolino-9H-purin-9-il)-1(3-hidroxipirrolidin-1-il)propan-1-ona
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1-(3-(2-(2-aminopirimidin-5-il)-6-morfolino-9H-purin-9-il)propanoil)N-metilpiperidina-4-carboxamida
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3-(2-(2-aminopirimidin-5-il)-6-morfolino-9H-purin-9-il)-1(4-(metilsulfonil)piperazin-1-il)propan-1-ona
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3-(2-(2-aminopirimidin-5-il)-6-morfolino-9H-purin-9-il)-1-morfolino-1 -ona
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Ácido 3-(2-(2-aminopirimidin-5-il)-6-morfolino-9H-purin-9-il)propanoico
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5-(9-(4-(metilsulfonil)bencil)-6-morfolino-9H-purin-2-il)pirimidin-2amina
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4-((2-(2-aminopirimidin-5-il)-6-morfolino-9H-purin-9-il)metil) benzoato de metilo
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imagen19 5-(6-morfolino-9-(2-morfolinoetil)-9H-purin-2-il)pirimidin-2-amina
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5-(9-(3-metoxibencil)-6-morfolino-9H-purin-2-il)pirimidin-2-amina
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3-((2-(2-aminopirimidin-5-il)-6-morfolino-9H-purin-9-il)metil) benzoato de metilo
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imagen20 3-(2-(2-aminopirimidin-5-il)-6-morfolino-9H-purin-9-il)propan-1-ol
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2-(2-(2-aminopirimidin-5-il)-6-morfolino-9H-purin-9-il)etanol
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1-(2-(2-(2-aminopirimidin-5-il)-6-morfolino-9H-purin-9-il)acetil)-Nmetilpiperidina-4-carboxamida
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2-(2-(2-aminopirimidin-5-il)-6-morfolino-9H-purin-9-il)-1-(4(metilsulfonil)piperazin-1-il)etanona
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2-(2-(2-aminopirimidin-5-il)-6-morfolino-9H-purin-9-il)-1morfolinoetanona
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Ácido 2-(2-(2-aminopirimidin-5-il)-6-morfolino-9H-purin-9-il)acético
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2-(2-(2-aminopirimidin-5-il)-6-morfolino-9H-purin-9-il)acetato de metilo
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imagen21 5-(9-metil-6-morfolino-9H-purin-2-il)pirimidin-2-amina
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5-(9-metil-6-morfolino-9H-purin-2-il)piridin-2-amina
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4-(2-(1H-indazol-4-il)-9-metil-9H-purin-6-il)morfolina
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2-(2-(2-aminopirimidin-5-il)-9-metil-6-morfolino-9H-purin-8-il) propan-2-ol
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2-(2-(6-aminopiridin-3-il)-9-metil-6-morfolino-9H-purin-8-il)propan-2 -ol
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2-(2-(1H-indazol-4-il)-9-metil-6-morfolino-9H-purin-8-il)propan-2-ol
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4-(2-(1H-indazol-4-il)-9-(2-metoxietil)-8-((4-(metilsulfonil)piperazin1-il)metil)-9H-purin-6-il)morfolina
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N-(4-(9-metil-8-((4-(metilsulfonil)piperazin-1-il)metil)-6-morfolino-9 H-purin-2-il)fenil)acetamida
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5-(9-metil-8-((4-(metilsulfonil)piperazin-1-il)metil)-6-morfolino-9Hpurin-2-il)piridin-2-amina
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4-(2-(2-metoxipirimidin-5-il)-9-metil-8-((4-(metilsulfonil)piperazin-1il)metil)-9H-purin-6-il)morfolina
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4-(9-metil-8-((4-(metilsulfonil)piperazin-1-il)metil)-2-(piridin-3-il)-9Hpurin-6-il)morfolina
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4-(2-(1H-indazol-4-il)-9-metil-8-((4-(metilsulfonil)piperazin-1-il) metil)-9H-purin-6-il)morfolina
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4-(2-(2-(3-hidroxifenil)-6-morfolino-9H-purin-9-il)acetil)piperazin-2ona
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2-(2-(3-hidroxifenil)-6-morfolino-9H-purin-9-il)-N-metilacetamida
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3-(6-morfolino-9-(piridin-4-ilmetil)-9H-purin-2-il)fenol
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3-(9-(4-fluorobencil)-6-morfolino-9H-purin-2-il)fenol
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3-(9-bencil-6-morfolino-9H-purin-2-il)fenol
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3-(9-(2-hidroxietil)-6-morfolino-9H-purin-2-il)fenol
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3-(9-isobutil-6-morfolino-9H-purin-2-il)fenol
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5-(8-((4-(dimetilamino)piperidin-1-il)metil)-9-etil-6-morfolino-9Hpurin-2-il)pirimidin-2-amina
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5-(8-((4-(azetidin-1-il)piperidin-1-il)metil)-9-etil-6-morfolino-9Hpurin-2-il)pirimidin-2-amina
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5-(8-((4-(azetidin-1-il)piperidin-1-il)metil)-9-etil-6-morfolino-9Hpurin-2-il)-4-metilpirimidin-2-amina
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2-(4-((2-(2-amino-4-metilpirimidin-5-il)-9-etil-6-morfolino-9H-purin8-il)metil)piperazin-1-il)-2-metilpropanamida
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5-(8-((4-(dimetilamino)piperidin-1-il)metil)-9-etil-6-morfolino-9Hpurin-2-il)-4-metilpirimidin-2-amina
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imagen22 5-(8-(1,4’-bipiperidin-1’-ylmetil)-9-etil-6-morfolino-9H-purin-2-il)-4metilpirimidin-2-amina
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5-(8-(1,4’-bipiperidin-1’-ylmetil)-9-etil-6-morfolino-9H-purin-2-il) pirimidin-2-amina
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5-(9-etil-6-morfolino-8-((4-morfolinopiperidin-1-il)metil)-9H-purin-2 -il)-4-metilpirimidin-2-amina
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imagen23 5-(9-etil-6-morfolino-8-((4-morfolinopiperidin-1-il)metil)-9H-purin-2il)pirimidin-2-amina
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N-(1-((2-(2-amino-4-metilpirimidin-5-il)-9-etil-6-morfolino-9H-purin8-il)metil)piperidin-4-il)-N-metilmetanosulfonamida
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N-(1-((2-(2-aminopirimidin-5-il)-9-etil-6-morfolino-9H-purin-8-il) metil)piperidin-4-il)-N-metilmetanosulfonamida
ADMINISTRACIÓN DE LOS COMPUESTOS DE LA INVENCIÓN
Los compuestos de la invención pueden administrarse a través de cualquier vía adecuada para la afección a tratar. Las
5 vías adecuadas incluyen la vía oral, parenteral (que incluye subcutánea, intramuscular, intravenosa, intraarterial, intradérmica, intratecal y epidural), transdérmica, rectal, nasal, tópica (incluyendo bucal y sublingual), vaginal, intraperitoneal, intrapulmonar e intranasal. Para el tratamiento inmunosupresor local, los compuestos se pueden administrar mediante administración intralesional, incluyendo la perfusión o poniendo en contacto de otra forma el injerto con el inhibidor antes del trasplante. Se apreciará que la vía preferida puede variar, por ejemplo, con la dolencia
10 del receptor. Cuando el compuesto se administra por vía oral, se puede formular en forma de píldora, cápsula, comprimido, etc., junto con un vehículo o excipiente farmacéuticamente aceptable. Cuando el compuesto se administra por vía parenteral, se puede formular con un vehículo parenteral farmacéuticamente aceptable en una forma farmacéutica inyectable, como se detalla a continuación.
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Claims (1)

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ES09755767.2T 2008-05-30 2009-05-29 Compuestos inhibidores de PI3K de tipo purina y métodos de uso Active ES2533788T3 (es)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US57559 1987-06-03
US5755908P 2008-05-30 2008-05-30
PCT/US2009/045603 WO2009146406A1 (en) 2008-05-30 2009-05-29 Purine pi3k inhibitor compounds and methods of use

Publications (1)

Publication Number Publication Date
ES2533788T3 true ES2533788T3 (es) 2015-04-14

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US (2) US8158624B2 (es)
EP (1) EP2279188B1 (es)
JP (1) JP2011521968A (es)
KR (1) KR20110042153A (es)
CN (1) CN102105474B (es)
AU (1) AU2009251291B2 (es)
BR (1) BRPI0909614A2 (es)
CA (1) CA2721851A1 (es)
ES (1) ES2533788T3 (es)
IL (1) IL208838A0 (es)
MX (1) MX2010012583A (es)
RU (1) RU2509081C2 (es)
WO (1) WO2009146406A1 (es)
ZA (1) ZA201007524B (es)

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