ES2589555T3 - Compuestos de benceno sustituidos con arilo o heteroarilo - Google Patents

Compuestos de benceno sustituidos con arilo o heteroarilo Download PDF

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Publication number
ES2589555T3
ES2589555T3 ES12719529.5T ES12719529T ES2589555T3 ES 2589555 T3 ES2589555 T3 ES 2589555T3 ES 12719529 T ES12719529 T ES 12719529T ES 2589555 T3 ES2589555 T3 ES 2589555T3
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alkyl
halo
cyano
amino
cycloalkyl
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ES12719529.5T
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Inventor
Kevin Wayne Kuntz
Richard Chesworth
Kenneth William Duncan
Heike KEILHACK
Natalie WARHOLIC
Christine KLAUS
Masashi Seki
Syuji SHIROTORI
Satoshi Kawano
Timothy James Nelson Wigle
Sarah Kathleen Knutson
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Epizyme Inc
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Epizyme Inc
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    • 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
    • A61K31/535—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
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    • 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
    • A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
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    • 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
    • A—HUMAN NECESSITIES
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    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • 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
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    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
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    • A—HUMAN NECESSITIES
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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
    • A—HUMAN NECESSITIES
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    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
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    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
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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
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    • 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
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    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
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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
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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Un compuesto de Fórmuila (I) o una sal farmacéuticamente aceptable del mismo**Fórmula** en donde, X1 es N o CR11; X2 es N o CR13; Z es NR7R8, OR7, S(O)nR7, o CR7R8R14, en que n es 0, 1 o 2; cada uno de R1, R5, R9 y R10, independientemente, es H o alquilo C1-C6 opcionalmente sustituido con uno o más sustituyentes seleccionados del grupo que consiste en halo, hidroxilo, COOH, C(O)O-alquilo C1-C6, 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 y heteroarilo de 5 ó 6 miembros; cada uno de R2, R3 y R4, independientemente, es -Q1-T1, en que Q1 es un enlace o enlazador de alquilo C1- C3 opcionalmente sustituido con halo, ciano, hidroxilo o alcoxi C1-C6, y T1 es H, halo, hidroxilo, COOH, ciano o RS1, en el que RS1 es alquilo C1-C3, alquenilo C2-C6, alquinilo C2-C6, alcoxi C1-C6, C(O)O-alquilo C1-C6, cicloalquilo C3-C8, arilo C6-C10, amino, mono-alquil C1-C6-amino, di-alquil C1-C6-amino, heterocicloalquilo de 4 a 12 miembros o heteroarilo de 5 ó 6 miembros, y RS1 está opcionalmente sustituido con uno o más sustituyentes seleccionados del grupo que consiste en halo, hidroxilo, oxo, COOH, C(O)O-alquilo C1-C6, ciano, alcoxilo C1-C6, amino, mono-alquil C1-C6-amino, di20 alquil C1-C6-amino, cicloalquilo C3-C8, arilo C6-C10, heterocicloalquilo de 4 a 12 miembros o heteroarilo de 5 ó 6 miembros; R6 es arilo C6-C10 o heteroarilo de 5 ó 6 miembros, cada uno de los cuales está opcionalmente sustituido con uno o más -Q2-T2, en que Q2 es un enlace o enlazador alquilo C1-C3 opcionalmente sustituido con halo, ciano, hidroxilo o alcoxi C1-C6, y T2 es H, halo, ciano, -ORa, -NRaRb, -(NRaRbRc)+A~, -C(O)Ra, -C(O)ORa, - C(O)NRaRb, -NRbC(O)Ra, -NRbC(O)ORa, -S(O)2Ra, -S(O)2NRaRb o RS2, en que cada uno de Ra, Rb y Rc es independientemente H o RS3, A~ es un anión farmacéuticamente aceptable, cada uno de RS2 y RS3, independientemente, es alquilo C1-C6, cicloalquilo C3-C8, arilo C6-C10, heterocicloalquilo de 4 a 12 miembros o heteroarilo de 5 ó 6 miembros, o Ra y Rb, junto con el átomo de N al que están unidos, forman un anillo de heterocicloalquilo de 4 a 12 miembros que tiene 0 o 1 heteroátomo adicional, y cada uno de RS2, RS3, y el anillo de heterocicloalquilo de 4 a 12 miembros formado por Ra y Rb 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 alcoxi C1-C6, y T3 se seleccionado 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 ó 6 miembros, ORd, COORd, -S(O)2Rd, -NRdRe y -C(O)NRdRe, siendo cada uno de Rd y Re, independientemente, H o alquilo C1-C6, o -Q3-T3 es oxo; o cualesquiera dos -Q2-T2 vecinos, junto con los átomos a los que están unidos, forman un anillo de 5 ó 6 miembros que contiene opcionalmente 1-4 heteroátomos seleccionados entre N, O y S y están opcionalmente sustituidos con uno o más sustituyentes seleccionados del grupo que consiste en halo, hidroxilo, COOH, C(O)O-alquilo C1-C6, 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 y heteroarilo de 5 ó 6 miembros; R7 es -Q4-T4, en donde Q4 es un enlace, enlazador alquilo C1-C4 o enlazador alquenilo C2-C4, estando cada enlazador opcionalmente sustituido con halo, ciano, hidroxilo o alcoxi C1-C6, y T4 es H, halo, ciano, NRfRg, - ORf, -C(O)Rf, -C(O)ORf, -C(O)NRfRg, -C(O)NRfORg, -NRfC(O)Rg, -S(O)2Rf o RS4, en que cada uno de Rf y Rg es, independientemente, H o RS5, cada uno de RS4 y RS5 es, independientemente, 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 cada uno de RS4 y RS5 está 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 que 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 4 a 12 miembros, heteroarilo de 5 ó 6 miembros, excepto cuando T5 es H, halo, hidroxilo o ciano; o -Q5-T5 es oxo; cada uno de R8, R11, R12 y R13, independientemente, es H, halo, hidroxilo, COOH, ciano, RS6, ORS6 o COORS6, en que RS6 es alquilo C1-C6, alquenilo C2-C6, alquinilo C2-C6, cicloalquilo C3-C8, heterocicloalquilo de 4 a 12 miembros, amino, mono-alquil C1-C6-amino o di-alquil C1-C6-amino, y RS6 está opcionalmente sustituido con uno o más sustituyentes seleccionados del grupo que consiste en halo, hidroxilo, COOH, C(O)O-alquilo C1-C6, ciano, alcoxilo C1-C6, amino, mono-alquil C1-C6-amino y di-alquil C1-C6-amino; o R7 y R8, junto con el átomo de N al que están unidos, forman un anillo heterocicloalquilo de 4 a 11 miembros que tiene 0 a 2 heteroátomos adicionales, o R7 y R8, junto con el átomo de C al que están unidos, forman cicloalquilo C3-C8 o un anillo heterocicloalquilo de 4 a 11 miembros que tiene 1 a 3 heteroátomos, y cada uno de los anillos heterocicloalquilo de 4 a 11 miembros o cicloalquilo C3-C8 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, Rm es H o alquilo C1-C6, y T6 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)pRp, en que p es 0, 1 o 2 y Rp 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 T6 está opcionalmente sustituido con uno o más sustituyentes seleccionados del grupo que consiste en 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 y heteroarilo de 5 ó 6 miembros, excepto cuando T6 es H, halo, hidroxilo o ciano; o -Q6-T6 es oxo; y R14 está ausente, H o alquilo C1-C6 opcionalmente sustituido con uno o más sustituyentes seleccionados del grupo que consiste en halo, hidroxilo, COOH, C(O)O-alquilo C1-C6, 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 y heteroarilo de 5 ó 6 miembros.
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