ES2545610T3 - Inhibidores de Syk de imidazopirazina - Google Patents

Inhibidores de Syk de imidazopirazina Download PDF

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ES2545610T3
ES2545610T3 ES09832228.2T ES09832228T ES2545610T3 ES 2545610 T3 ES2545610 T3 ES 2545610T3 ES 09832228 T ES09832228 T ES 09832228T ES 2545610 T3 ES2545610 T3 ES 2545610T3
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phenyl
methoxyphenyl
hydroxy
optionally substituted
methoxy
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Scott A. Mitchell
Kevin S. Currie
Peter A. Blomgren
Jeffrey E. Kropf
Seung H. Lee
Jianjun Xu
Douglas G. Stafford
James P. Harding
Antonio J. Barbosa, Jr.
Zhongdong Zhao
David M Armistead
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Gilead Connecticut Inc
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
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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
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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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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • 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
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    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
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    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/91—Transferases (2.)
    • G01N2333/912—Transferases (2.) transferring phosphorus containing groups, e.g. kinases (2.7)
    • G01N2333/91205—Phosphotransferases in general

Abstract

Al menos una entidad química elegida de los compuestos de Fórmula (I):**Fórmula** y sales farmacéuticamente aceptables de los mismos, en la que R1 se elige de (1-hidroxiciclobutil)fenilo, (1,1,1-trifluoro-2-hidroxipropan-2-il)fenilo, (2,2,2-trifluoro-1- hidroxietil)fenilo, (1,1,1,3,3,3-hexafluoro-2-hidroxipropan-2-il)fenilo, (2-hidroxi-2-metilpropoxi)-3-metoxifenilo, (2- hidroxietil)(metil)amino)-3-metoxifenilo, (2-metoxietil)(metil)amino)-3-metoxifenilo, (1-hidroxietil)fenilo, 3,4- dimetoxifenilo, 3-metoxifenilo, 4-etoxi-3-metoxifenilo, 4-hidroximetil-3-metoxifenilo, 3-hidroximetil-4-metoxifenilo, 2-fluoro-4-metoxifenilo, 4-(dimetilamino)propoxi-3-metoxifenilo, 4-hidroxipropoxi-3-metoxifenilo, 4-(2-hidroxi-1,1- dimetiletil)fenilo, 4-(1-hidroxi-1-metiletil)fenilo, 4-metoxi-3-(pirrolidin-1-yl)fenilo, 3-metoxi-4-(pirrolidin-1-il)fenilo, 3- metoxi-4-(propan-2-iloxi)fenilo, 3-metoxi-4-(morfolin-4-il)fenilo, 4-(pirrolidin-1-il)fenilo, 4-(3-hidroxipirrolidinil)fenilo, 4-(4-hidroxipiperidinil)-3-metoxifenilo, 4-(3-hidroxiacetidinil)-3-metoxifenilo, 4-(3-hidroxipirrolidinil)-3-metoxifenilo, 4-(2-metoxipropan-2-il)fenilo, 4-(4-etilpiperazin-1-il)-3-metoxifenilo, 4-(4-etilpiperazin-1-il)fenilo, 4-(3-hidroxi-3- metilpiperidinil)fenilo, 3-hidroximetilfenilo, 3,4-dihidro-2H-benzo[b][1,4]oxazin-6-ilo, 4-metil-3,4-dihidro-2Hbenzo[ b][1,4]oxazin-6-ilo, 2,3,4,5-tetrahidrobenzo[b][1,4]oxazepin-7-ilo, 5-metil-2,3,4,5- tetrahidrobenzo[b][1,4]oxazepin-7-ilo, 2,3-dihidro-1H-indol-2-ona-6-ilo y 2,3-dihidro-1H-indol-2-ona-5-ilo; R2 se elige de 2-fluoropiridin-4-ilo, 5-metilpiridin-3-ilo, 5-cloropiridin-3-ilo y 2-aminopiridin-5-ilo; R3 se elige de hidrógeno, alquilo C1-C4 y halo; R4 se elige de hidrógeno y alquilo C1-C4; y R5 es hidrógeno.

Description

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resultante es heteroarilo, no arilo, como se define en el presente documento.
El término “ariloxi” se refiere al grupo -O-arilo.
5 El término “halo” incluye fluoro-, cloro-, bromo-y yodo-y el término “halógeno” incluye flúor, cloro, bromo y yodo.
“Heteroarilo” abarca:
anillos monocíclicos aromáticos de 5 a 7 miembros que contienen uno o más, por ejemplo, de 1 a 4, o en algunas
10 realizaciones, de 1 a 3, heteroátomos elegidos de N, O y S, con los átomos de carbono restantes siendo carbono; y anillos de heterocicloalquilo bicíclicos que contienen uno o más, por ejemplo, de 1 a 4, o en algunas realizaciones, de 1 a 3, heteroátomos elegidos de N, O y S, con los restantes átomos del anillo siendo carbono y en los que al menos un heteroátomo está presente en un anillo aromático.
15 Por ejemplo, heteroarilo incluye un anillo aromático de heterocicloalquilo de 5 a 7 miembros fusionado a un anillo de cicloalquilo de 5 a 7 miembros. Para tales sistemas de anillos de heteroarilo bicíclicos fusionados en los que sólo uno de los anillos contiene uno o más heteroátomos, el punto de unión puede estar en el anillo heteroaromático o en el anillo de cicloalquilo. Cuando el número total de átomos de S y de O en el grupo heteroarilo excede 1, esos
20 heteroátomos no están adyacentes entre sí. En algunas realizaciones, el número total de átomos de S y de O en el grupo heteroarilo no es más de 2. En algunas realizaciones, el número total de átomos de S y de O en el heterociclo aromático no es más de 1. Los ejemplos de los grupos heteroarilo incluyen, pero no están limitados a (como se numeran desde la prioridad asignada a la posición de unión 1), 2-piridilo, 3-piridilo, 4-piridilo, 2,3-pirazinilo, 3,4pirazinilo, 2,4-pirazinilo, 2,4-pirimidinilo, 3,5-pirimidinilo, 2,3-pirazolinilo, 2,4-imidazolinilo, isoxazolinilo, oxazolinilo,
25 tiazolinilo, tiadiazolinilo, tetrazolilo, tienilo, benzotiofenilo, furanilo, benzofuranilo, benzoimidazolinilo, indolinilo, piridizinilo, tiazolilo, quinolinilo, pirazolilo y 5,6,7,8-tetrahidroisoquinolina. Los radicales bivalentes derivados de los radicales de heteroarilo univalentes cuyos nombres acaban en “-ilo” por retirada de un átomo de hidrógeno del átomo con la valencia libre se nombran añadiendo “-ideno” al nombre del radical univalente correspondiente, por ejemplo, un grupo piridilo con dos puntos de unión es un piridilideno. El heteroarilo no abarca o se superpone con el
30 arilo como se define anteriormente.
Heteroarilo sustituido también incluye sistemas de anillos sustituidos con uno o más sustituyentes óxido (-O-), tales como N-óxidos de piridinilo.
35 El término “heteroariloxi” se refiere al grupo -O-heteroarilo.
Por “heterocicloalquilo” se entiende un anillo alifático único, normalmente con 3 a 7 átomos de carbono, que contiene al menos 2 átomos de carbono además de 1-3 heteroátomos independientemente seleccionados de oxígeno, azufre y nitrógeno, así como combinaciones que comprenden al menos uno de los anteriores heteroátomos. Los grupos
40 heterocicloalquilo adecuados incluyen, por ejemplo (como se numera desde la prioridad asignada a la posición de unión 1), 2-pirrolinilo, 2,4-imidazolidinilo, 2,3-pirazolidinilo, 2-piperidilo, 3-piperidilo, 4-piperidilo y 2,5-piperzinilo. Los grupos morfolino también se contemplan, incluyendo 2-morfolino y 3-morfolino (numerados en los que el oxígeno es la prioridad asignada 1). El heterocicloalquilo sustituido también incluye sistemas de anillos sustituidos con uno o más restos oxo, tales como N-óxido de piperidinilo, morfolinil-N-óxido, 1-oxo-1-tiomorfolinilo y 1,1-dioxo-1
45 tiomorfolinilo.
“Heterocicloalquilo” también incluye sistemas de anillos bicíclicos en los que ninguno de los anillos es aromático y en los que al menos uno de los anillos en el sistema de anillos bicíclico contiene al menos 2 átomos de carbono además de los 1-3 heteroátomos elegidos independientemente de oxígeno, azufre y nitrógeno.
50 El término “heterocicloalquiloxi” se refiere al grupo -O-heterocicloalquilo.
“el término “nitro” se refiere al grupo -NO2.
55 El término “fosfono” se refiere al grupo -PO3H2.
“Tiocarbonilo” se refiere al grupo -C(=O)SH.
La frase “tiocarbonilo opcionalmente sustituido” incluye los siguientes grupos: -C(=O)S-(alquilo (C1-C6)
60 opcionalmente sustituido), -C(=O)S-(arilo opcionalmente sustituido), -C(=O)S-(heteroarilo opcionalmente sustituido) y -C(=O)S-(heterocicloalquilo opcionalmente sustituido)
El término “sulfanilo” incluye los grupos: -S-(alquilo (C1-C6) opcionalmente sustituido), -S-(arilo opcionalmente sustituido), -S-(heteroarilo opcionalmente sustituido) y -S-(heterocicloalquilo opcionalmente sustituido). Por lo tanto,
65 el sulfanilo incluye el grupo alquilsulfanilo C1-C6.
9
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en el que A se elige de grupos arilo, cicloalquilo y heterocicloalquilo, cada uno de cuyos grupos que tiene de 5 a 7 átomos de anillo incluyendo los átomos compartidos con el anillo aromático de 6 miembros y cada uno de cuyos
5 grupos estando opcionalmente sustituidos; R2 se elige de arilo opcionalmente sustituido y de heteroarilo opcionalmente sustituido; R3 es hidrógeno; R4 es hidrógeno; y R5 es hidrógeno,
10 con la condición de que si R1 es 3-metoxi-4-metilfenilo, 4-metoxi-3-metilfenilo, 2-(dimetilamino)etoxi-3-metoxifenilo, 3-etoxi-4-metoxifenilo o 4etoxi-3-metoxifenilo, entonces R2 no está fenil sustituido con -(CO)NHR6 donde R6 es arilo opcionalmente sustituido; si R1 es 3,4-dimetoxifenilo, entonces R2 no está fenil sustituido con -(CO)NR8R9 donde R8 y R9 tomados juntos forman un heterocicloalquilo opcionalmente sustituido o un heteroarilo
15 opcionalmente sustituido o donde R8 es hidrógeno y R9 es arilo opcionalmente sustituido, cicloalquilo opcionalmente sustituido, heterocicloalquilo opcionalmente sustituido, alquilo opcionalmente sustituido o heteroarilo opcionalmente sustituido, o -(SO)NHR10 donde R10 es fenilo opcionalmente sustituido; si R1 es 4-(morfolin-4-il)fenilo, entonces R2 no es piridinilo, 2-fluorofenilo, benzo[d][1,3]dioxolilo, 2-metoxifenilo, 2,6
20 dimetoxifenilo, 3-acetamidofenilo, 3-carboxifenilo, 2-(hidroximetil)fenilo, furanilo o 3-(hidroxietilcarbamoil)fenilo; si R1 es clorofenilo, entonces R2 no está fenil sustituido con piperidin-1-il-carbonilo o NH(CO)NR12 donde R12 está fenil sustituido con trifluorometilo o uno o más halógenos; si R1 es piperazinilo opcionalmente sustituido entonces R2 no es 3-aminofenilo; si R1 es 4-clorofenilo, entonces R2 no es 4-carboxifenilo, 3-(2-(dimetilamino)etilcarbamoil)fenilo o 4-(2
25 (dimetilamino)etilcarbamoil)fenilo; y si R1 es 4-(2-hidroxi-etil)fenilo o 4-(hidroxietil)fenilo, entonces R2 no es 2-metoxifenilo o 2-fluorofenilo; y además con la condición de que R2 no está fenil sustituido con -NHC(O)R11 donde R11 es arilo opcionalmente sustituido.
Desvelado en el presente documento, R1 puede estar fenil sustituido con uno o dos grupos elegidos de
30 halo, hidroxi, carboxi, cicloalquilo opcionalmente sustituido con uno o dos grupos elegidos de hidroxi, alcoxi inferior y alquilo inferior,
35 heterocicloalquilo opcionalmente sustituido con uno o dos grupos elegidos de hidroxi, alcoxi inferior, alquilo inferior, alquilo inferior sustituido con hidroxi, amino opcionalmente sustituido y oxo, heteroarilo, amino opcionalmente sustituido con uno o dos grupos elegidos de alquilo inferior, alquilo inferior sustituido con halo, alquilo inferior sustituido con hidroxi y alquilo inferior sustituido con alcoxi inferior,
40 -C(O)NR6R7 en el que R6 y R7 se seleccionan independientemente de hidrógeno, alquilo inferior, alquilo inferior sustituido con hidroxi, alquilo inferior sustituido con amino opcionalmente sustituido, cicloalquilo, arilo, heteroarilo y heterocicloalquilo, o R6 y R7 junto con el nitrógeno al que están unidos forman un anillo de heterocicloalquilo de 3 a 7 miembros opcionalmente sustituido con uno o dos grupos elegidos de hidroxi, alquilo inferior y alquilo inferior sustituido con hidroxi,
45 -S(O)2NR6R7 donde R6 y R7 se seleccionan independientemente de hidrógeno, alquilo inferior, alquilo inferior sustituido con hidroxi, alquilo inferior sustituido con amino opcionalmente sustituido, cicloalquilo, arilo, heteroarilo y heterocicloalquilo, o R6 y R7 junto con el nitrógeno al que están unidos forman un anillo de heterocicloalquilo de 3 a 7 miembros opcionalmente sustituido con uno o dos grupos elegidos de hidroxi, alquilo inferior y alquilo inferior sustituido con hidroxi, con la condición de que al menos uno de R6 y R7 no sea hidrógeno,
50 alcoxi inferior opcionalmente sustituido con uno dos grupos elegidos de hidroxi, alcoxi inferior, amino opcionalmente sustituido, carboxi, aminocarbonilo y heterocicloalquilo, heteroariloxi, y alquilo inferior opcionalmente sustituido con uno o dos grupos elegidos de hidroxi, alcoxi inferior, halo, trifluorometilo, amino opcionalmente sustituido y heterocicloalquilo opcionalmente sustituido con alquilo inferior.
55 Desvelado en el presente documento, R1 puede estar fenil sustituido con uno o dos grupos elegidos de
halo, hidroxi, 60 heterocicloalquilo opcionalmente sustituido con uno o dos grupos elegidos de hidroxi, alcoxi inferior, alquilo inferior y alquilo inferior sustituido con hidroxi,
17
imagen15
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imagen19
imagen20
imagen21
imagen22
imagen23
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E09832228
18-08-2015
Estructura
Nombre [M+H]+
N-(4-etoxi-3-metoxifenil)-6-(2-fluoropiridin-4-il)imidazo[1,2a]pirazin-8-amina;
380,3
imagen25
N-(4-etoxi-3-metoxifenil)-6-(5-metilpiridin-3-il)imidazo[1,2a]pirazin-8-amina; 376,5
6-(5-cloropiridin-3-il)-N-(4-etoxi-3-metoxifenil)imidazo[1,2a]pirazin-8-amina;
396,2
5-{8-[(3,4-dimetoxifenil)amino]imidazo[1,2-a]pirazin-6il}piridin-2-amina;
363,2
N-[3-metoxi-4-(morfolin-4-il)fenil]-6-(6-metoxipiridin-3il)imidazo[1,2-a]pirazin-8-amina;
433,5
imagen26
N-[3-metoxi-4-(morfolin-4-il)fenil]-6-(5-metoxipiridin-3il)imidazo[1,2-a]pirazin-8-amina; 433,4
28
imagen27
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imagen30

Claims (1)

  1. imagen1
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ES09832228.2T 2008-12-08 2009-12-07 Inhibidores de Syk de imidazopirazina Active ES2545610T3 (es)

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