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AR071112A1 - Derivados de benzopirano y benzoxepina inhibidores de quinasaspi3k, utiles como agentes anticancer,y composiciones farmaceuticas que los contienen. - Google Patents

Derivados de benzopirano y benzoxepina inhibidores de quinasaspi3k, utiles como agentes anticancer,y composiciones farmaceuticas que los contienen.

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Publication number
AR071112A1
AR071112A1 ARP090101126A ARP090101126A AR071112A1 AR 071112 A1 AR071112 A1 AR 071112A1 AR P090101126 A ARP090101126 A AR P090101126A AR P090101126 A ARP090101126 A AR P090101126A AR 071112 A1 AR071112 A1 AR 071112A1
Authority
AR
Argentina
Prior art keywords
alkylene
nr10r11
co2h
ch2oh
heterocyclyl
Prior art date
Application number
ARP090101126A
Other languages
English (en)
Original Assignee
Genentech Inc
Hoffmann La Roche
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Genentech Inc, Hoffmann La Roche filed Critical Genentech Inc
Publication of AR071112A1 publication Critical patent/AR071112A1/es

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    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
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    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
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    • 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
    • A61K31/4365—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 having sulfur as a ring hetero atom, e.g. ticlopidine
    • 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
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
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    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
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    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
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    • 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
    • C07D513/12—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 three hetero rings
    • C07D513/14—Ortho-condensed systems

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  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Son utiles para inhibir quinasas lipídicas que incluyen p110 alfa y otras isoformas de PI3K, y para tratar trastornos tales como cáncer mediado por quinasas lipídicas. Reivindicacion 1: Un compuesto seleccionado de formula 1 y sus estereoisomeros, isomeros geométricos, tautomeros, o sales aceptables para uso farmacéutico, donde: Z1 es CR1 o N; Z2 es CR2 o N; Z3 es CR3 o N; Z4 es CR4 o N; donde (i) X1 es N y X2 es S, (ii) X1 es S y X2 es N, (iii) X1 es CR7 y X2 es S, o (iv) X1 es S y X2 es CR7; R1, R2, R3, R4, y R7 se seleccionan independientemente entre H, F, CI, Br, I, -CN, -CF3, -CH2OR10, -CH2R10, -alquileno C1-12NR10R11, -alquileno C1-12NR12C(=O)R10, -alquileno C1-12C(=O)OR10, -alquileno C1-12OR10, -CO2R10, -C(=O)N(R10)OR11, -NO2, -NR10R11, -OR10, -S(O)2R10, -C(=O)NR10R11, -C(=O)NR10(alquileno C1-12)NR10R11, -C(=O)NR10(alquileno C1-12)NR10C(=O)OR11, -C(=O)NR10(alquileno C1-12)NR10C(=O)R11, -C(=O)NR10(alquileno C1-12)R10, -C(=NR10)NR10R11, -NR12C(=O)R10, -NR12C(=O)OR11, -NR12C(=O)NR10R11, -NR12C(=O)(alquileno C1-12)NR10R11, -NR12(alquileno C1-12)NR10R11, -NR12(alquileno C1-12)OR10, -NR12(alquileno C1-12)C(=O)NR10R11, -C=CR10, -CH=CHR10, heterociclilo C2-20, heteroarilo C1-20, y fenilo, donde heterociclilo, heteroarilo, y fenilo están opcionalmente sustituidos con uno o más grupos seleccionados entre F, CI, Br, I, -CH2OH, -(CH2)2OH, -CH2CO2H, -CN, -CH2NH2, -(CH2)2N(CH3)2, -CH3, -C(=O)CH3, -C(=O)NHCH3, -CO2H, -CH2CO2CH3, -NH2, -OCH3, -S(O)2CH3, 4-metilpiperazin-1-ilo, y 4-morfolinilo, y donde alquileno está opcionalmente sustituido con uno o más F; A se selecciona entre -C(O)NR5R6, heterociclilo C2-20 y heteroarilo C1-20 donde heterociclilo C2-20 y heteroarilo C1-20 están opcionalmente sustituidos con uno o más grupos seleccionados independientemente entre F, CI, Br, I, -CH2OH, -CH2CO2H, -CH(CH3)CH2OCH3, -CN, alquilo C1-12, -alquileno C1-12NR10R11, -alquileno C1-12OR10, -CH3, -C(=O)CH3, -C(=O)NHCH3, -C(=O)N(CH3)2, -CO2H, -CO2CH3, -CH2CO2CH3, -NH2, -NHC(=O)CH3, -OCH3, -S(O)2CH3, 1-metilpiperid-4-ilo, 4-metilpiperazin-1-ilo, 4-morfolinilo, isopropilo, isobutilo, ciclopropilo, ciclopropilmetilo, ciclobutilo, triazolilmetilo, bencilo, y fenilo, donde alquilo, alquileno, bencilo y fenilo están opcionalmente sustituidos con uno o más grupos seleccionados independientemente entre F, CI, Br, I, -CF3, -CH2OH, -CH2CO2H, -CN, -CH2NH2, -CH3, -C(=O)CH3, -C(=O)NHCH3, -CO2H, -CH2CO2CH3, -NH2, -OH, -OCH3, -S(O)2CH3, 1-metilpiperid-4-ilo, (4-metilpiperazin-1-il)carboxamida, -CH2(1H-1,2,4-triazol-5-il), 4-metilpiperazin-1-ilo, y 4-morfolinilo; R5 se selecciona entre H, alquilo C1-12, opcionalmente sustituido con uno o más grupos seleccionados independientemente entre F, CI, Br, I, -CN, -CO2H, -CONH2, -CONHCH3, -NH2, -NO2, -N(CH3)2, -NHCOCH3, -NHS(O)2CH3, -OH, -OCH3, -OCH2CH3, -S(O)2NH2, y -S(O)2CH3; R6 se selecciona entre alquilo C1-12, carbociclilo C3-12, heterociclilo C2-20, heteroarilo C1-20, y arilo C6-20, cada uno opcionalmente sustituido con uno o más grupos seleccionados independientemente entre F, CI, Br, I, -CH2OH, - CH2C6H5, -CN, -CF3, -CO2H, -C(=O)NR10R11, -NH2, -NO2, -N(CH3)2, -NHCOCH3, -NHS(O)2CH3, -OH, -OCH3, -OCH2CH3, -S(O)2NH2, -S(O)2CH3, -C(=O)NR10(alquileno C1-12)NR10R11, morfolin-4-ilo, piperidin-1-ilo, piperazinilo, piperazin-4-il-2-ona, piperazin-4-il-3-ona, pirrolidin-1-ilo, tiomorfolin-4-ilo, S-dioxotiomorfolin-4-ilo, -C:::CR13, -CH=CHR13, y -C(=O)NR10R11 o R5 y R6 junto con el átomo de nitrogeno al cual están unidos forman morfolin-4-ilo, piperidin-1-ilo, piperazinilo, piperazin-4-il-2-ona, piperazin-4-iI-3-ona, pirrolidin-1-ilo, tiomorfolin-4-ilo o S-dioxotiomorfolin-4-ilo, cada uno opcionalmente sustituido con uno o más grupos seleccionados entre F, CI, Br, I, -CH2OH, -CH2C6H5, -CN, -CF3, -CO2H, -CONH2, -CONHCH3, -NO2, - N(CH3)2, -NHCOCH3, -NHS(O)2CH3, -OH, -OCH3, -OCH2CH3, -S(O)2NH2, y -S(O)2CH3; R7 se selecciona entre H y F; R10, R11 y R12 se seleccionan independientemente entre H, alquilo C1-12, alquilen C1-12-heterociclilo C2-20, alquilen C1-12-arilo C6-20, alquenilo C2-8, alquinilo C2-8, carbociclilo C3-12, heterociclilo C2-20, arilo C6-20, y heteroarilo C1-20, donde alquilo C1-12, alquenilo C2-8, alquinilo C2-8, carbociclilo C3-12, heterociclilo C2-20, arilo C6-20, y heteroarilo C1-20 están opcionalmente sustituidos con uno o más grupos seleccionados independientemente entre F, CI, Br, I, -CH2OH, -CH2C6H5, -CN, -CF3, -CO2H, -CONH2, -CONHCH3, -NO2, -N(CH3)2, -NHCOCH3, -NHS(O)2CH3, -OH, -OCH3, -OCH2CH3, 2-oxopirrolidin-1-ilo, -S(O)2NH2, y -S(O)2CH3; o R10 y R11 junto con el átomo de nitrogeno al cual están unidos forman un anillo de heterociclilo C2-20 o heteroarilo C1-20 cada uno opcionalmente sustituido con uno o más grupos seleccionados independientemente entre F, CI, Br, I, -CH3, -CH2OH, -CH2C6H5, -CN, -CF3, -CO2H, -CONH2, -CONHCH3, -NO2, -N(CH3)2, -NHCOCH3, -NHS(O)2CH3, -OH, oxo, -OCH3, -OCH2CH3, -S(O)2NH2, y -S(O)2CH3; y R13 se selecciona entre H, F, CI, Br, I, -CH3, -CH2CH3, -CN, -CF3, -CH2N(CH3)2, -CH2OH, -CO2H, -CONH2, -CON(CH3)2, -NO2, y -S(O)2CH3. Reivindicacion 32: Un compuesto seleccionado de la formula (2) y sus estereoisomeros, isomeros geométricos, tautomeros, o sales aceptables para uso farmacéutico, donde: R1, R2, R3, y R4 se seleccionan independientemente entre H, F, CI, Br, I, -CN, -CF3, -CH2OR10, -CH2R10, -CH2NR10R11, -(alquileno C1-12)C(=O)OR10, -CO2R10, -C(=O)N(R10)OR11, -NO2, -NR10R11, -OR10, -S(O)2R10, -C(=O)NR10R11, -C(=O)NR10(alquileno C1-12)NR10R11, -C(=O)NR10(alquileno C1-12)NR10C(=O)OR11, -C(=O)NR10(alquileno C1-12)NR10C(=O)R11, -C(=O)NR10(alquileno C1-12)R10, -NR12C(=O)R10, -NR12C(=O)OR11, -NR12C(=O)NR10R11, -NR12(alquileno C1-12)NR10R11, -NR12(alquileno C1-12)OR10, -NR12(alquileno C1-12)C(=O)NR10R11, -C:::CR10, -CH=CHR10, heterociclilo C2-20, heteroarilo C1-20, y fenilo, donde heterociclilo, heteroarilo, y fenilo están opcionalmente sustituidos con uno o más grupos seleccionados entre -CH2OH, -CH2CO2H, -CN, -CH2NH2, -C(=O)CH3, -CO2H, -CH2CO2CH3; -NH2, -S(O)2CH3, 4-metilpiperazin-1-ilo, y 4-morfolinilo; R5 se selecciona entre alquilo C1-12, opcionalmente sustituido con uno o más grupos seleccionados independientemente entre F, CI, Br, I, -CN, -CO2H, -CONH2, -CONHCH3, -NH2, -NO2, -N(CH3)2, -NHCOCH3, -NHS(O)2CH3, -OH, -OCH3, -OCH2CH3, -S(O)2NH2, y -S(O)2CH3; R6 se selecciona entre carbociclilo C3-12, heterociclilo C2-20, heteroarilo C1-20, y arilo C6-20, cada uno opcionalmente sustituido con uno o más grupos seleccionados independientemente entre F, CI, Br, I, -CH2OH, -CH2C6H5, -CN, -CF3, -CO2H, -CONHCH3, -NH2, -NO2, -N(CH3)2, -NHCOCH3, -NHS(O)2CH3, -OH, -OCH3, -OCH2CH3, -S(O)2NH2, -S(O)2CH3, morfolin-4-ilo, piperidin-1-ilo, piperazinilo, piperazin-4-il-2-ona, piperazin-4-il-3-ona, pirrolidin-1-ilo, tiomorfolin-4-ilo, S-dioxotiomorfolin-4-ilo, -C:::CR13, -CH=CHR13, y -C(=O)NR10R11 o R5 y R6 junto con el átomo de nitrogeno al cual están unidos forman morfolin-4-ilo, piperidin-1-ilo, piperazinilo, piperazin-4-il-2-ona, piperazin-4-iI-3-ona, pirrolidin-1-ilo, tiomorfolin-4-ilo, S-dioxotiomorfolin-4-ilo, cada uno opcionalmente sustituido con uno o más grupos seleccionados entre F, CI, Br, I, -CH2OH, -CH2C6H5, -CN, -CF3, -CO2H, -CONH2, -CONHCH3, -NO2, - N(CH3)2, -NHCOCH3, -NHS(O)2CH3, -OH, -OCH3, -OCH2CH3, -S(O)2NH2, y -S(O)2CH3;cada uno R7 se selecciona independientemente entre H, F, Cl, Br, I, -CH2OH, -CH3, -CN, -CF3, -CO2H, -CONH2, -CONHCH3, -NO2, -N(CH3)2, -NHCOCH3, -NHS(O)2CH3, -OH, -OCH3, -OCH2CH3, -S(O)2NH2, y -S(O)2CH3; o ambos R7 juntos son =O; R8 se selecciona entre H y F; R10, R11 y R12 se seleccionan independientemente entre H, alquilo C1-12, alquenilo C2-8, alquinilo C2-8, carbociclilo C3-12, heterociclilo C2-20, arilo C6-20, y heteroarilo C1-20, donde alquilo C1-12, alquenilo C2-8, alquinilo C2-8, carbociclilo C3-12, heterociclilo C2-20, arilo C6-20, y heteroarilo C1-20 están opcionalmente sustituidos con uno o más grupos seleccionados independientemente entre F, CI, Br, I, -CH2OH, -CH2C6H5, -CN, -CF3, -CO2H, -CONH2, -CONHCH3, -NO2, -N(CH3)2, -NHCOCH3, -NHS(O)2CH3, -OH, -OCH3, -OCH2CH3, -S(O)2NH2, y -S(O)2CH3; o R10 y R11 junto con el átomo de nitrogeno al cual están unidos forman un anillo de heterociclilo C2-20 opcionalmente sustituido con uno o más grupos seleccionados independientemente entre F, CI, Br, I, -CH3, -CH2OH, -CH2C6H5, -CN, -CF3, -CO2H, -CONH2, -CONHCH3, -NO2, -N(CH3)2, -NHCOCH3, -NHS(O)2CH3, -OH, oxo, -OCH3, -OCH2CH3, -S(O)2NH2, y -S(O)2CH3; R13 se selecciona entre H, F, CI, Br, I, -CH3, -CH2CH3, -CN, -CF3, -CH2N(CH3)2, -CH2OH, -CO2H, -CONH2, -CON(CH3)2, -NO2, y -S(O)2CH3; n es 1 o 2; y Y es O, S, N-NR10R11; con las siguientes condiciones: cuando n es 1, Y es O, y R1, R2, R3, R7, R8 son cada uno H, entonces R4 no es H o CH3 y cuando n es 1, entonces ambos R7 en forma conjunta no son =O.
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