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AR086977A1 - Derivados heterociclicos nitrogenados utiles para el tratamiento del cancer y composiciones farmaceuticas que los contienen - Google Patents

Derivados heterociclicos nitrogenados utiles para el tratamiento del cancer y composiciones farmaceuticas que los contienen

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Publication number
AR086977A1
AR086977A1 ARP120102167A ARP120102167A AR086977A1 AR 086977 A1 AR086977 A1 AR 086977A1 AR P120102167 A ARP120102167 A AR P120102167A AR P120102167 A ARP120102167 A AR P120102167A AR 086977 A1 AR086977 A1 AR 086977A1
Authority
AR
Argentina
Prior art keywords
alkyl
alkylene
aryl
rent
heteroaryl
Prior art date
Application number
ARP120102167A
Other languages
English (en)
Inventor
Sheldon Cao
Janeta Popovici-Muller
Francesco G Salituro
Jeffrey Saunders
Xuefei Tan
Jeremy Travins
Shunqi Yan
Zhixiong Ye
Original Assignee
Agios Pharmaceuticals Inc
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Filing date
Publication date
Application filed by Agios Pharmaceuticals Inc filed Critical Agios Pharmaceuticals Inc
Publication of AR086977A1 publication Critical patent/AR086977A1/es

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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/650952—Six-membered rings having the nitrogen atoms in the positions 1 and 4
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    • 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
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    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
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    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
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    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D213/85—Nitriles in position 3
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    • 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
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    • 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
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    • 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
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    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oncology (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pyridine Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

Reivindicación 1: Un compuesto caracterizado porque tiene la fórmula estructural (1), o una sal aceptable farmacéuticamente de los mismos, donde: Y es -N(R5)-, -N(R5)-CH2-, -CH2-N(R5)- o -CH(R5)-; cada R1a y R1b es en forma independiente hidrógeno, -alquilo C1-4, -N(R7)(alquilen C1-4)-N(R7)(alquilo C1-4), arilo, heteroarilo, heterociclilo, -C(O)N(R7)-arilo, -N(R7)C(O)-arilo, -(alquilen C1-4)-arilo, -(alquilen C1-4)-heteroarilo, -O-(alquilen C0-4)-arilo, -O-(alquilen C0-4)-heteroarilo, -O-(alquilen C0-4)-heterociclilo, O-(alquilen C0-4)-carbociclilo, -N(R7)-arilo, o -N(R7)-heteroarilo, -N(R9)-arilo, -N(R9)-heteroarilo, -O-(alquenilen C1-4)-N(R7)C(O)O-(alquilen C1-4)-arilo, -N(R9)-C(O)-(alquenilo C2-4) donde: al menos uno de R1a y R1b no es hidrógeno ni metilo; cualquier unidad alquileno presente en R1a o R1b se sustituye opcionalmente con OH o F; cada R7 se selecciona en forma independiente entre hidrógeno y alquilo C1-4; y cualquier arilo, heteroarilo, o heterociclilo de R1a o R1b se sustituye opcionalmente con uno o más sustituyentes seleccionados entre -G-L-M, halo, alquilo C1-6, -CºN, =O, -CF3 y -OCF3; G es una unión o una cadena hidrocarbonada bivalente, saturada o insaturada, lineal o ramificada de C1-6 donde opcionalmente una, dos o tres unidades metileno de la cadena hidrocarbonada se reemplazan en forma independiente por -NR8-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO-, -SO2-, -C(=S)-, -C(=NR8)-, -N=N-, o -C(=N2)-; L es una unión covalente una cadena hidrocarbonada bivalente, saturada o insaturada, lineal o ramificada de C1-8, donde uno, dos o tres unidades metileno de L son opcionalmente y en forma independiente reemplazados por ciclopropileno, -NR8-, -N(R8)C(O)-, -C(O)N(R8)-, -N(R8)SO2-, SO2N(R8)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO-, -SO2-, -C(=S)-, -C(=NR8)-, -N=N-, o -C(=N2)-; M es E, o un anillo de 3 a 10 miembros monocíclico o bicíclico, saturado, parcialmente insaturado o aromático que tiene 0 - 3 heteroátomos seleccionados en forma independiente entre nitrógeno, oxígeno, o azufre, y donde dicho anillo se sustituye con 1 - 4 grupos seleccionados en forma independiente entre -D-E, oxo, NO2, halógeno, CN, alquilo C1-6, alquenilo C2-6, o alquinilo C2-6; D es una unión covalente o una cadena hidrocarbonada bivalente, saturada o insaturada, lineal o ramificada de C1-6, donde una o dos unidades metileno de D son opcionalmente y en forma independiente reemplazadas por NR8-, -S-, -O-, -C(O)-,-SO-, o -SO2-; E es hidrógeno, alquilo C1-6, alquenilo C2-6, o alquinilo C2-6, donde dicho alquilo, alquenilo o alquinilo se sustituye opcionalmente con oxo, halógeno, o CN; y cada R8 es en forma independiente hidrógeno, alquilo C1-6, alquenilo C2-6, alquinilo C2-6, alcoxi C1-6, -S(O)2-alquenilo C2-4, o un grupo opcionalmente sustituido seleccionado entre fenilo, un heterociclilo de 4 a 7 miembros que tiene 1 - 2 heteroátomos seleccionados en forma independiente entre nitrógeno, oxígeno, o azufre, o un heterociclilo de 5 - 6 miembros que tiene 1 - 4 heteroátomos seleccionados en forma independiente entre nitrógeno, oxígeno, o azufre; R2 se selecciona entre fenilo, un cicloalquilo de 3 - 7 miembros, alquilo C2-4, o CF3, donde el fenilo o cicloalquilo se sustituye opcionalmente con un sustituyente seleccionado entre metilo o fluoro; cada R3 se selecciona en forma independiente entre halo, -(alquilen C1-4)-O-(alquilo C1-4), -fluoroalquilo C1-4, -C(O)-O-(alquilo C1-4), -fenilo, -heteroarilo, cicloalquilo C3-7, -CH2-N(alquil C1-4)2, C(O)-N-(alquil C1-4)2, -C(O)-NH-(alquilo C1-4), -alquilo C1-4 opcionalmente sustituido con uno o más halo o -OH, o dos R3s son tomados juntos para formar un anillo saturado de 3 - 8 miembros o un fenilo fusionado donde dicho anillo saturado o fenilo fusionado se sustituye opcionalmente con 1 a 2 metilo; R4 se selecciona entre hidrógeno, -CN, halo, alcoxi C1-4, -CH2NH(alquilo C1-4), alquenilo C2-4, alquinilo C2-4, -(alquil C1-4)-O-(alquilo C1-4), fluoroalquilo C1-4, C(O)-N-(alquil C1-4)2, -C(O)-NH-(alquilo C1-4), -C(O)-O-(alquilo C1-4), -C(O)-OH, -S(O)2-(alquilo C1-4), y un heteroarilo de 5 miembros; R5 se selecciona entre: -C(O)-(alquilo C1-5), -C(O)-(alquenilo C2-6), -C(O)-(alquilen C0-2)-Q, -C(O)-(alquenilen C1-4)-Q, -C(O)-(alquilen C0-2)-N(R6)-(alquilen C0-2)-Q, -C(O)-O-(alquilen C0-2)-Q, -C(O)-(alquilen C1-2)-O-(alquilen C0-2)-Q, -C(O)-C(O)-Q, -S(O)2-Q, -C(O)-(alquilen C1-4)-O-C(O)-(alquilo C1-4), -C(O)-(alquilen C1-4)-C(O)-O-(alquilo C1-4), -C(O)-N(R6)-(alquilen C1-4)-O-C(O)-(alquilo C1-4), -C(O)-N(R6)-(alquilen C1-4)-C(O)-O-(alquilo C1-4), -C(O)-(alquilen C0-2)-N(R6)-(alquilo C1-6), -C(O)-(alquilen C0-2)N(R6)-(alquinilo C2-6), -C(O)-(alquilen C0-2)-N(R6)-(alquenilo C2-6), -C(O)-(alquilen C0-2)-N(R6)-(alquilen C0-2)-O-(alquilo C1-4), -C(O)-(alquilen C1-2)-O-(alquilo C1-4), -C(O)-(alquilen C1-2)-C(O)C(O)N(R)(alquilo C1-4), -C(O)-O-(alquilen C1-4)-O-(alquilo C1-4), -(alquilen C0-4)-O-C(O)-(alquilo C1-4), -(alquilen C0-4)-C(O)-O-(alquilo C1-4), -(alquilen C0-4)-O-(alquilo C1-4), -C(O)-(alquilen C1-2)S(O)0-2-(alquilo C1-4), -S(O)2-(alquilo C1-4), -C(O)-(alquilen C1-4)-C(O)C(O)N(R6)(alquilo C1-6), -C(O)-(alquilen C1-4)-N(R6)S(O)2-(alquilo C1-6), o -C(O)-(alquilen C1-4)N(R6)S(O)2Q, donde: cualquier unidad alquileno presente en R5 se sustituye opcionalmente con OCH3, OH o F; cualquier unidad metilo terminal presente en R5 se reemplaza opcionalmente con -CH2OH, CF3, -CH2F, -CH2CI, C(O)CH3, C(O)CF3, CN, -OCH3, -C(O)H, -OP(O)(OH)2, -OP(O)(alcoxi C1-4)2 o CO2H; cada R6 se selecciona en forma independiente entre hidrógeno y metilo; Q se selecciona entre arilo, heteroarilo, carbociclilo y heterociclilo, donde Q se sustituye opcionalmente con hasta 3 sustituyentes seleccionados en forma independiente entre alquilo C1-4, opcionalmente sustituido con OH, alcoxi C1-4, -C(O)O-(alquilo C1-4), -(alquilen C1-4)-(alcoxi C1-4), -CN, -OH, fluoro, cloro, y bromo; R9 se selecciona entre arilo y heteroarilo, donde cada arilo o heteroarilo se sustituye opcionalmente con uno o más sustituyentes seleccionados entre -G-L-M, halo, alquilo C1-6, -CºN, =O, -CF3 y -OCF3; o C(O)(alquenilo C2-4); y m es 0, 1, 2 ó 3.
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