ES2590489T3 - Compuestos de benceno sustituidos - Google Patents

Compuestos de benceno sustituidos Download PDF

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ES2590489T3
ES2590489T3 ES12716968.8T ES12716968T ES2590489T3 ES 2590489 T3 ES2590489 T3 ES 2590489T3 ES 12716968 T ES12716968 T ES 12716968T ES 2590489 T3 ES2590489 T3 ES 2590489T3
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alkyl
halo
membered heterocycloalkyl
amino
optionally substituted
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Kevin Wayne Kuntz
Richard Chesworth
Kenneth William DUNCAN
Heike KEILHACK
Natalie WARHOLIC
Christine KLAUS
Masashi Seki
Sarah K. KNUTSON
Timothy James Nelson WIGLE
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Epizyme Inc
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Epizyme Inc
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further 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
    • 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
    • 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
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur 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
    • 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
    • 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
    • C07D413/14—Heterocyclic 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
    • 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
    • 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
    • C07D491/08—Bridged 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
    • C07D491/10—Spiro-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
    • C07D491/10—Spiro-condensed systems
    • C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pyridine Compounds (AREA)
  • Peptides Or Proteins (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

Un compuesto de Fórmula (Ie) o una sal farmacéuticamente aceptable del mismo:**Fórmula** en donde Z es NR7R8 o S(O)aR7, en el que a es 0; R1 es H o alquilo C1-C6, opcionalmente sustituido con uno o más sustituyentes seleccionados de hidroxilo, alcoxiilo C1-C6, amino, mono-alquil C1-C6-amino, di-alquil C1-C6-amino y arilo C6-C10; cada uno de R2 y R4 independientemente, es -Q1-T1, en que Q1 es un enlace o enlazador alquilo C1-C3, opcionalmente sustituido con uno o más sustituyentes seleccionados de halo e hidroxilo, y T1 es H, halo o azido; R3 es H o halo; R5 es H o alquilo C1-C6; R6 es H, halo, ciano, azido, ORa, -NRaRb, -C(O)NRaRb , -S(O)bRa, en donde b es 0, 1 o 2, o RS2; en donde RS2 es alquilo C1-C6, alquenilo C2-C6, alquinilo C2-C6 o heterocicloalquilo de 4 a 12 miembros, y en donde cada uno de Ra y Rb, independientemente, es H, alquilo C1-C6 o heterocicloalquilo de 4 a 12 miembros; o Ra y Rb, junto con el átomo de N al que están unidos, forman un anillo heterocicloalquilo de 4 a 12 miembros que tiene 0 o 1 heteroátomo adicional; y cada uno de Ra, RS2 y el anillo de heterocicloalquilo de 4 a 12 miembros formado por Ra y Rb está opcionalmente sustituido con uno o más -Q2-T2; en donde Q2 es un enlace o enlazador alquilo C1-C3, y T2 es H, halo, -ORc , -NRcRd, -C(O)ORc, alquilo C1-C6, o RS4, en donde cada uno de Rc y Rd, independientemente, es H o alquilo C1-C6, RS4 es cicloalquilo C3-C8, arilo C6- C10, heterocicloalquilo de 4 a 12 miembros, o heteroarilo de 5 o 6 miembros, y RS4 está opcionalmente sustituido con uno o más -Q3-T3, en donde Q3 es un enlace o enlazador alquilo C1-C3, cada uno opcionalmente sustituido con halo, ciano, hidroxilo o alcoxilo C1-C6, y T3 se selecciona del grupo que consiste en halo, ciano, alquilo C1-C6, cicloalquilo C3-C8, arilo C6-C10, heterocicloalquilo de 4 a 12 miembros, heteroarilo de 5 o 6 miembros, ORe , COORe, -S(O)2Re, -NReRf y -C(O)NReRf , cada uno de Re y Rf son, independientemente, H o alquilo C1-C6 , o Rc y Rd, junto con el átomo de N al que están unidos, forman un anillo heterocicloalquilo de 4 a 12 miembros que tiene 0 o 1 heteroátomo adicional y opcionalmente está sustituido con alquilo C1-C6; R7 es -Q4-T4, en donde Q4 es un enlace o enlazador alquilo C1-C4 y T4 es H, alquilo C1-C6, cicloalquilo C3- C8, arilo C6-C10, C(O)-alquilo C1-6, C(O)-cicloalquilo C3-6 o heterocicloalquilo de 4 a 14 miembros, cada uno opcionalmente sustituido con uno o más -Q5-T5, en donde Q5 es un enlace, C(O), C(O)NRk, NRkC(O), S(O)2 o enlazador alquilo C1-C3, siendo Rk H o alquilo C1-C6, y T5 es H, halo, alquilo C1-C6, hidroxilo, ciano, alcoxilo C1-C6, amino, mono-alquil C1-C6-amino, di-alquil C1-C6-amino, cicloalquilo C3-C8, arilo C6-C10, heterocicloalquilo de 4 a 12 miembros, heteroarilo de 5 ó 6 miembros, o S(O)qRq, en donde q es 0, 1 o 2 y Rq es alquilo C1-C6, alquenilo C2-C6, alquinilo C2-C6, cicloalquilo C3-C8, arilo C6-C10, heterocicloalquilo de 4 a 12 miembros o heteroarilo de 5 ó 6 miembros, y T5 está opcionalmente sustituido con uno o más sustituyentes seleccionados del grupo que consiste en halo, alquilo C1-C6, hidroxilo, ciano, alcoxilo C1-C6 , amino, mono-alquil C1-C6-amino, di-alquil C1-C6-amino, cicloalquilo C3-C8, arilo C6-C10, heterocicloalquilo de a 12 miembros y heteroarilo de 5 ó 6 miembros, excepto cuando T5 es H, halo, hidroxilo o ciano; o -Q5- T5 es oxo; R8 es H, alquilo C1-C6 opcionalmente sustituido con halo, hidroxilo o alcoxilo C1-C6, alquenilo C2-C6, cicloalquilo C3-C8 o heterocicloalquilo de 4 a 7 miembros; o R7 y R8, junto con el átomo de N al que están unidos, forman un anillo heterocicloalquilo de 4 a 12 miembros que tiene 0 a 2 heteroátomos adicionales, y el anillo de heterocicloalquilo de 4 a 12 miembros formado por R7 y R8 está opcionalmente sustituido con uno o más -Q6-T6, en donde Q6 es un enlace, C(O), C(O)NRm, NRmC(O), S(O)2 o enlazador alquilo C1- C3, siendo Rm H o alquilo C1-C6, y T6 es H, halo, alquilo C1-C6, hidroxilo, ciano, alcoxilo C1-C6, amino, monoalquil C1-C6-amino, di-alquil C1-C6-amino, cicloalquilo C3-C8, arilo C6-C10, heterocicloalquilo de 4 a 12 miembros, heteroarilo de 5 ó 6 miembros, o S(O)pRp en que p es 0, 1 o 2 y Rp es C1 -C 6 alquilo, alquenilo C2-C6 , alquinilo C2-C6, cicloalquilo C3-C8, arilo C6-C10, heterocicloalquilo de 4 a 12 miembros o heteroarilo de 5 ó 6 miembros, y T6 está opcionalmente sustituido con uno o más sustituyentes seleccionados del grupo que consiste en halo, alquilo C1-C6 , hidroxilo, ciano, alcoxilo C1-C 6, amino, mono-alquil C1 -C6- amino, di-alquil C1-C6-amino, cicloalquilo C3-C8, arilo C6-C10, heterocicloalquilo de 4 a 12 miembros y heteroarilo de 5 ó 6 miembros, excepto cuando T6 es H, halo, hidroxilo, o ciano; o -Q6-T6 es oxo; y R12 es halo, alcoxilo C1-C6, alquenilo C2-C6 o alquilo C1-C6, opcionalmente sustituido con halo.
ES12716968.8T 2011-04-13 2012-04-13 Compuestos de benceno sustituidos Active ES2590489T3 (es)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US201161474825P 2011-04-13 2011-04-13
US201161474825P 2011-04-13
US201161505676P 2011-07-08 2011-07-08
US201161505676P 2011-07-08
PCT/US2012/033662 WO2012142513A1 (en) 2011-04-13 2012-04-13 Substituted benzene compounds

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US (2) US9376422B2 (es)
EP (3) EP3165520B1 (es)
JP (1) JP2014513084A (es)
KR (1) KR101975613B1 (es)
CN (1) CN104066718B (es)
AR (1) AR086839A1 (es)
AU (2) AU2012242604B2 (es)
BR (1) BR112013026308B1 (es)
CA (1) CA2832846C (es)
DK (1) DK2697198T3 (es)
ES (1) ES2590489T3 (es)
HK (1) HK1202534A1 (es)
HU (1) HUE030722T2 (es)
IL (1) IL228746B (es)
MX (1) MX344530B (es)
PL (1) PL2697198T3 (es)
PT (1) PT2697198T (es)
RU (2) RU2017126990A (es)
TW (2) TWI598336B (es)
WO (1) WO2012142513A1 (es)

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