ES2677043T3 - Derivados de pirazol como moduladores del canal de calcio activado por liberación de calcio - Google Patents
Derivados de pirazol como moduladores del canal de calcio activado por liberación de calcio Download PDFInfo
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- ES2677043T3 ES2677043T3 ES10779334.1T ES10779334T ES2677043T3 ES 2677043 T3 ES2677043 T3 ES 2677043T3 ES 10779334 T ES10779334 T ES 10779334T ES 2677043 T3 ES2677043 T3 ES 2677043T3
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- substituted
- unsubstituted
- pyrazol
- cyclopropyl
- trifluoromethyl
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Classifications
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- 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
- A61K31/433—Thidiazoles
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- A—HUMAN NECESSITIES
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- 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
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—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
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Un compuesto de fórmula**Fórmula** o un tautómero, N-óxido, éster farmacéuticamente 5 aceptable, o sal farmacéuticamente aceptable del mismo, en la que el Anillo Hy representa**Fórmula** 10 opcionalmente sustituidos con R'''; R1 es ciclopropilo; R2 se selecciona de CH3, CH2F, CHF2, CF3, cicloalquilo C(3-5) sustituido o sin sustituir, CH2-ORa, CH2-NRaRb , CN y COOH; el Anillo Ar se selecciona de**Fórmula** L1 y L2 representan juntos -NH-C(>=X)- o -C(>=X)NH; A está ausente o se selecciona de -(CR'R")- o -NRa ; R' y R" son iguales o diferentes y se seleccionan independientemente de hidrógeno, hidroxi, ciano, halógeno, -ORa, -COORa, -S(>=O)q-Ra, -NRaRb,-C(>=X)-Ra, grupo alquilo C(1-6) sustituido o sin sustituir, alquenilo C(1-6) sustituido o sin sustituir, alquinilo C(1-6) sustituido o sin sustituir, y cicloalquilo C(3-5) sustituido o sin sustituir, o R' y R" pueden unirse para formar un anillo saturado o insaturado sustituido o sin sustituir de 3-6 miembros, que puede incluir opcionalmente uno o más heteroátomos que pueden ser iguales o diferentes y se seleccionan de O, NRa y S; R''' se selecciona de hidrógeno, hidroxi, ciano, halógeno, -ORa, -COORa, - S(>=O)q-Ra, -NRaRb, -C(>=X)-Ra, grupo alquilo C(1-6) sustituido o sin sustituir, alquenilo C(1-6) sustituido o sin sustituir, alquinilo C(1-6) sustituido o sin sustituir, y cicloalquilo C(3-5) sustituido o sin sustituir. cada aparición de X se selecciona independientemente de O, S y -NRa; Cy se selecciona de**Fórmula** cada aparición de Ra y Rb es igual o diferente y se selecciona independientemente de hidrógeno, nitro, hidroxi, ciano, halógeno, -ORc,-S(>=O)q-Rc, -NRcRd, -C(>=Y)-Rc, -CRcRd-C(>=Y)-Rc, -CRcRd-Y-CRcRd-,-C(>=Y)- NRcRd-, -NRRd-C(>=Y)-NRcRd-, -S(>=O)q-NRcRd-, -NRcRd-S(>=O)q-NRcRd-, -NRcRd-NRcRd-, alquilo sustituido o sin sustituir, alquenilo sustituido o sin sustituir, alquinilo sustituido o sin sustituir, cicloalquilo sustituido o sin sustituir, cicloalquilalquilo sustituido o sin sustituir, cicloalquenilo sustituido o sin sustituir, heterociclilo sustituido o sin sustituir, heterociclilalquilo sustituido o sin sustituir, arilo sustituido o sin sustituir, arilalquilo sustituido o sin sustituir, heteroarilo sustituido o sin sustituir, y heteroarilalquilo sustituido o sin sustituir, o cuando Ra y Rb están unidos directamente al mismo átomo, pueden estar unidos para formar un anillo saturado 5 o insaturado sustituido o sin sustituir de 3-10 miembros, que puede incluir opcionalmente uno o más heteroátomos que pueden ser iguales o diferentes y se seleccionan de O, NRc y S; cada aparición de Rc y Rd puede ser igual o diferente y se selecciona independientemente de hidrógeno, nitro, hidroxi, ciano, halógeno, alquilo sustituido o sin sustituir, alquenilo sustituido o sin sustituir, alquinilo sustituido o sin sustituir, cicloalquilo sustituido o sin sustituir, cicloalquilalquilo sustituido o sin sustituir, cicloalquenilo sustituido o sin sustituir, grupo heterocíclico sustituido o sin sustituir, heterociclilalquilo sustituido o sin sustituir, o cuando dos sustituyentes Rc y/o Rd están unidos directamente al mismo átomo, pueden estar unidos para formar un anillo saturado o insaturado sustituido o sin sustituir de 3-10 miembros, que puede incluir opcionalmente uno o más heteroátomos que son iguales o diferentes y se seleccionan de O, NH y S; cada aparición de Y se selecciona de O, S y -NRa; y cada aparición de q representa independientemente 0, 1 o 2;
Description
DESCRIPCION
Derivados de pirazol como moduladores del canal de calcio activado por liberacion de calcio
5 Esta solicitud reivindica la prioridad de las Solicitudes de Patente Provisional de la India N.° 2440/CHE/2009, con fecha del 8 de octubre de 2009; 2636/CHE/2009, con fecha del 30 de octubre de 2009; 158/CHE/2010, con fecha del 25 de enero de 2010; 1513/CHE/2010, con fecha del 2 de junio de 2010; 1514/CHE/2010, con fecha del 2 de junio de 2010; y la Solicitud de Patente Provisional de Estados Unidos N.° 61/265,540, con fecha del 1 de diciembre de 2009.
10
CAMPO DE LA INVENCION
La presente invencion se refiere a inhibidores de los canales de calcio activados por la liberacion de calcio (CRAC) de formula I y sales farmaceuticamente aceptables de los mismos, a metodos para prepararlos, a composiciones 15 farmaceuticas que los contienen, y al compuesto de formula (I) para su uso en metodos de tratamiento con los mismos.
ANTECEDENTES DE LA INVENCION
20 La regulacion del calcio intracelular es un elemento clave en la transduccion de senales en y dentro de las celulas. Las respuestas celulares a factores de crecimiento, neurotransmisores, hormonas y una diversidad de moleculas senal diferentes se inician a traves de procesos dependientes de calcio. La importancia del ion de calcio como segundo mensajero se enfatiza por muchos mecanismos diferentes que trabajan juntos para mantener la homeostasis del calcio. Los cambios en la concentracion de iones de calcio libre intracelular representan el evento 25 de senalizacion mas extendido e importante para la regulacion de una pletora de respuestas celulares. Una ruta generalizada para la entrada de iones de calcio en la celula es a traves de canales dependientes de deposito (SOC), es decir, muchos tipos de celulas emplean la entrada de iones de calcio dependiente de deposito como su ruta principal para la afluencia de iones de calcio. Este mecanismo se activa despues de la liberacion de iones de calcio de los depositos, donde los depositos agotados conducen a la activacion de los canales de calcio activado por 30 liberacion de calcio (CRAC).
Los canales CRAC, una subfamilia de canales dependientes de deposito, se activan mediante la liberacion de calcio desde los depositos intracelulares, particularmente desde el retfculo endoplasmico (RE). Estos canales son factores clave en la regulacion de una amplia gama de funciones celulares, incluida la contraccion muscular, la secrecion de 35 protefnas y fluidos y el control sobre el crecimiento y la proliferacion celular y, por lo tanto, desempenan un papel esencial en diversas enfermedades tales como trastornos inmunitarios y respuestas alergicas. Entre varias corrientes bioffsicamente distintas dependientes de deposito, la mejor caracterizada y la mas selectiva de iones de calcio es la corriente de CRAC. Por lo tanto, los canales CRAC median funciones esenciales desde la secrecion a la expresion genica y el crecimiento celular y forman una red esencial para la activacion de las celulas inmunes que 40 establecen la respuesta inmune adaptativa. Recientemente, dos protefnas, la molecula de interaccion estromal (STIM1) y el modulador 1 de CRAC (CRACM1 u Orai1), se han identificado como los componentes esenciales que reconstituyen y amplifican completamente las corrientes de CRAC en sistemas de expresion heterologos con una huella biofisica similar. En los mamfferos, existen varios homologos de estas protefnas: STIM1 y STIM2 en el retfculo endoplasmico y CRACM1, CRACM2 y CRACM3 en la membrana plasmatica.
45
Las corrientes de CRAC se descubrieron inicialmente en linfocitos y mastocitos, y al mismo tiempo se han caracterizado en diversas lfneas celulares tales como S2 drosophila, linfocitos B DT40, hepatocitos, dendrfticas, megacarioticas y celulas de rinon canino Madin-Darby. En los linfocitos y en los mastocitos, la activacion a traves del antfgeno o los receptores de Fc inicia la liberacion de iones de calcio de los depositos intracelulares causada por el 50 segundo mensajero inositol(1,4,5)-trifosfato (Ins(1,4,5)P3), que a su vez conduce a la entrada de iones de calcio a traves de los canales CRAC en la membrana plasmatica. Las corrientes de Ca2+ dependientes de deposito caracterizadas por musculo liso, celulas epidermicas A431, celulas endoteliales de diversos tejidos, y lfneas celulares de cancer de prostata muestran caracterfsticas bioffsicas alteradas que sugieren un origen molecular distinto.
55
Por ejemplo, el influjo de iones de calcio a traves de la membrana celular es importante en la activacion de linfocitos y respuestas inmunes adaptativas. Se ha demostrado que las oscilaciones de [Ca2+] desencadenadas a traves de la estimulacion del TCR (receptor de antfgenos de linfocitos T) son prominentes, y parecen implicar solo una unica via de afluencia de iones calcio, el canal CRAC dependiente de deposito. Veanse, por ejemplo, Lewis "Calcium
signalling mechanisms in T lymphocytes", Annu. Rev. Immunol. 19, (2001), 497-521; Feske et al. "Ca++ calcineurin signalling in cells of the immune system", Biochem. Biophys. Res. Commun. 311, (2003), 1117-1132; Hogan et al. "Transcriptional regulation by calcium, calcineurin, and NFAT", Genes Dev. 17, (2003) 2205-2232.
5 Esta bien establecido ahora que el calcio intracelular desempena un papel importante en diversas funciones celulares, y que su concentration esta regulada por la afluencia de iones de calcio a traves de canales de calcio en la membrana celular. Los canales de iones de calcio, que se encuentran en los sistemas nervioso, endocrino, cardiovascular y esqueletico y estan modulados por el potencial de membrana, se denominan canales de Ca2+ dependientes de voltaje (VOC). Estos canales se clasifican en los subtipos L, N, P, Q, R y T. El influjo excesivo de 10 Ca2+ a traves de los canales VOC causa hipertension y disfuncion cerebral. Por el contrario, los canales de iones de calcio en las celulas inflamatorias, incluidos los linfocitos, los mastocitos y los neutrofilos, pueden activarse independientemente de su potencial de membrana. Se ha informado que este tipo de canal de iones de calcio actua en la crisis y la exacerbation de la inflamacion y las enfermedades autoinmunes. En los linfocitos T, se ha informado que las primeras fases de activation consisten en eventos pre y post Ca2+. La estimulacion de los receptores de 15 linfocitos T induce eventos pre-Ca2+, incluida la generation de IP3, seguido de la liberation de Ca2+ del retfculo endoplasmico (RE). En los eventos post-Ca2+, el agotamiento de Ca2+ en el RE induce la activacion de los canales CRAC, y la afluencia capacitativa de Ca2+ a traves del canal CRAC mantiene una alta concentracion intracelular de Ca2+ ([Ca2+]i). Este alto [Ca2+]i prolongado activa la transduction de senal citosolica para producir mediadores lipfdicos (por ejemplo, LTD4), citocinas [por ejemplo, interleucina-2 (IL-2)] y metaloproteinasas de matriz, que 20 participan en la patogenesis de la inflamacion y enfermedades autoinmunes.
Estos hechos sugieren que los moduladores del canal CRAC pueden ser utiles para el tratamiento de enfermedades causadas por la activacion de celulas inflamatorias sin efectos secundarios observados en esteroides. Dado que los moduladores del canal VOC causarfan eventos adversos en los sistemas nervioso y cardiovascular, puede ser 25 necesario que los moduladores del canal CRAC muestren una selectividad suficiente sobre los canales VOC si se van a usar como farmacos antiinflamatorios.
Por consiguiente, se ha dicho que los moduladores del canal CRAC son utiles en el tratamiento, prevention y/o mejora de enfermedades o trastornos asociados con el canal de calcio activado por la liberacion de calcio 30 incluyendo, pero sin limitation, inflamacion, glomerulonefritis, uveitis, enfermedades o trastornos hepaticos, enfermedades o trastornos renales, enfermedad pulmonar obstructiva cronica, artritis reumatoide, enfermedad inflamatoria intestinal, vasculitis, dermatitis, osteoartritis, enfermedad muscular inflamatoria, rinitis alergica, vaginitis, cistitis intersticial, esclerodermia, osteoporosis, eccema, trasplante alogenico o xenogenico, rechazo de injertos, enfermedad de injerto contra huesped, lupus eritematoso, diabetes tipo I, fibrosis pulmonar, dermatomiositis, 35 tiroiditis, miastenia gravis, anemia hemolftica autoinmune, fibrosis qufstica, hepatitis recurrente cronica, cirrosis biliar primaria, conjuntivitis alergica, hepatitis y dermatitis atopica, asma, sfndrome de Sjogren, cancer y otras enfermedades proliferativas, y enfermedades o trastornos autoinmunes. Veanse, por ejemplo, las Publicaciones Internacionales N.° WO 2005/009954 , WO 2005/009539, WO 2005/009954, WO 2006/034402, WO 2006/081389, WO 2006/081391, WO 2007/087429, WO 2007/087427, WO 2007087441, WO 200/7087442, WO 2007/087443, WO 40 2007/089904, WO 2007109362, WO 2007/112093, WO 2008/039520, WO 2008/063504, WO 2008/103310, WO 2009/017818, WO 2009/017819, WO 2009/017831, WO 2010/039238, WO 2010/039237, WO 2010/039236, WO 2009/089305 y WO 2009/038775, y las Publicaciones de Estados Unidos N.°: US 2006/0173006 y US 2007/0249051.
45 Los inhibidores del canal CRAC que se han identificado incluyen SK&F 96365 (1), Econazol (2) y L-651582 (3).
Sin embargo, estas moleculas carecen de potencia y selectividad suficientes sobre los canales VOC y, por lo tanto, no son adecuadas para uso terapeutico.
Publicaciones recientes de Taiji et al. (European Journal of Pharmacology, 560, 225-233, 2007) y Yasurio Yonetoky et al. (Bio. & Med. Chem., 16, 9457-9466, 2008) describen un inhibidor de canal CRAC selectivo codificado YM-
58483 que es capaz de inhibir la funcion de los linfocitos T y se propone que sea beneficioso en el tratamiento de enfermedades inflamatorias, incluyendo asma bronquial.
5 Yasurio Yonetoky et al. describen que YM-58483 es selectivo para los canales CRAC sobre los canales dependientes de voltaje (VOC) con un Indice selectivo de 31.
Otros moduladores del canal CRAC descritos incluyen diversos compuestos de biarilo y/o carboxanilida heteroclclico que incluyen, por ejemplo, PCT o solicitudes de patente de Estados Unidos asignadas a Synta Pharmaceuticals viz. 10 WO 2005/009954 , WO 2005/009539, WO 2005/009954, WO 2006/034402, WO 2006/081389, WO 2006/081391, WO 2007/087429, WO 2007/087427, WO 2007087441, WO 200/7087442, WO 2007/087443, WO 2007/089904, WO 2007109362, WO 2007/112093, WO 2008/039520, WO 2008/063504, WO 2008/103310, WO 2009/017818, WO 2009/017819, WO 2009/017831, WO 2010/039238, WO 2010/039237, WO 2010/039236, WO 2009/089305 y WO 2009/038775, US 2006/0173006 y US 2007/0249051.
15
Otras publicaciones de patente relacionadas con moduladores de canal CRAC incluyen solicitudes de Astellas, Queens Medical Centre, Calcimedica y otros viz., WO 2007 /121186, WO 2006/0502 14, WO 2007/139926, WO 2008/148108, US 7.452.675, US 2009/023177, WO 2007/139926, US 6.696.267 , US 6.348.480 , WO 2008/106731, US 2008/0293092, WO 2010/048559, WO 2010/027875, WO2010/025295, WO 2010/034011, WO2010/034003, WO 20 2009/076454, WO 2009/035818, US 2010/0152241, US 2010/0087415, US 2009/0311720 y WO 2004/078995.
La revision adicional y la divulgacion de la bibliografla en el area de los canales CRAC incluye Isabella Derler et al., Expert Opinion in Drug Discovery, 3(7), 787-800, 2008; Yousang G et al., Cell Calcium, 42, 145-156, 2007; Yasurio Yonetoky et.al., Bio. & Med. Chem., 14, 4750-4760,2006; y Yasurio Yonetoky et.al., Bio. & Med. Chem., 14, 537025 5383, 2006.
El cancer es un importante problema de salud publica en la India, EE. UU. y muchas otras partes del mundo. Actualmente, 1 de cada 4 muertes en la India se debe al cancer. El cancer de pulmon es la principal causa de muerte por cancer en todo el mundo debido a su alta incidencia y mortalidad, con estimaciones de supervivencia a 5 30 anos de ~10 % para el cancer de pulmon de celulas no pequenas (NSCLC). Se ha informado que se necesitan mas investigaciones sobre los mecanismos de tumorigenesis y quimiorresistencia del cancer de pulmon para mejorar la tasa de supervivencia (Jemal A, et al., Cancer Statistics, CA Cancer. J. Clin., 56, 106-130, 2006). Existen cuatro tipos principales de NSCLC, concretamente, adenocarcinoma, carcinoma de celulas escamosas, carcinoma broncoalveolar y carcinoma de celulas grandes. El adenocarcinoma y el carcinoma de celulas escamosas son los 35 tipos mas comunes de NSCLC en funcion de la morfologla celular (Travis et al., Lung Cancer Principles and Practice, Lippincott-Raven, Nueva York, 361-395, 1996). Los adenocarcinomas se caracterizan por una ubicacion mas periferica en el pulmon y a menudo tienen una mutacion en el oncogen K-ras (Gazdar et al., Anticancer Res., 14, 261-267, 1994). Los carcinomas de celulas escamosas son tlpicamente mas centricos y con frecuencia llevan mutaciones del gen p53 (Niklinska et al., Folia Histochem. Cytobiol., 39, 147-148, 2001).
40
La mayorla de los NSCLC se caracterizan por la presencia de la mutacion ras, lo que hace que el paciente sea relativamente insensible al tratamiento con inhibidores de cinasas conocidos. Como resultado, los tratamientos actuales del cancer de pulmon generalmente se limitan a medicamentos citotoxicos, cirugla y radioterapia. Existe la necesidad de tratamientos que tengan menos efectos secundarios y se dirijan mas especlficamente a las celulas 45 cancerosas, sean menos invasivos y mejoren el pronostico de los pacientes.
La identification de celulas iniciadoras de tumores pulmonares y marcadores asociados puede ser util para la optimization de enfoques terapeuticos y para la information predictiva y pronostica en pacientes con cancer de pulmon. Por consiguiente, sigue existiendo la necesidad de nuevos metodos de prediction, evaluation y tratamiento 50 de pacientes afectados de cancer de pulmon.
Todavla existe la necesidad insatisfecha y grave de moduladores de molecula pequena que tengan especificidad
hacia Stiml y/u Orail con el fin de regular y/o modular la actividad de los canales CRAC, particularmente para el tratamiento de enfermedades y trastornos asociados con el CRAC.
RESUMEN DE LA INVENCION
5
La presente invention se refiere a compuestos de formula (I), metodos para su preparation, composiciones farmaceuticas que los contienen, y metodos de tratamiento con estos.
En particular, los compuestos de formula (I) y sus sales farmaceuticamente aceptables son moduladores de los 10 canales de calcio activados por la liberation de calcio utiles en el tratamiento, prevention, inhibition y/o mejora de enfermedades o trastornos asociados con el canal de calcio activado por la liberacion de calcio.
En un aspecto, la presente invencion se refiere a un compuesto de formula (I):
15 o un tautomero del mismo, profarmaco del mismo, N-oxido del mismo, ester farmaceuticamente aceptable del mismo o sal farmaceuticamente aceptable del mismo, en la que
20
25
30
35
el Anillo Hy representa
opcionalmente sustituidos con R''';
R1 es ciclopropilo;
R2 se selecciona de CH3, CH2F, CHF2, CF3, cicloalquilo C(3-5) sustituido o sin sustituir, CH2-ORa, CH2- NRaRb, CN y COOH; el Anillo Ar se selecciona de
Li y L2 representan juntos -NH-C(=X)- o -C(=X)NH;
A esta ausente o se selecciona de -(CR'R")- o -NRa ;
R' y R son iguales o diferentes y se seleccionan independientemente de hidrogeno, hidroxi, ciano, halogeno, -ORa, -COORa, -S(=O)q-Ra, -NRaRb, -C(=X)-Ra, grupo alquilo C(i-6) sustituido o sin sustituir, alquenilo C(i-6) sustituido o sin sustituir, alquinilo C(i-6) sustituido o sin sustituir, y cicloalquilo C(3-5) sustituido o sin sustituir, o R' y R" pueden estar unidos para formar un anillo saturado o insaturado sustituido o sin sustituir de 3-6 miembros, que puede incluir opcionalmente uno o mas heteroatomos que pueden ser iguales o diferentes y se seleccionan de O, NRa y S;
R''' se selecciona de hidrogeno, hidroxi, ciano, halogeno, -ORa, -COORa, -S(=O)q-Ra, -NRaRb, -C(=X)-Ra, grupo alquilo C(i-6) sustituido o sin sustituir, alquenilo C(i-6) sustituido o sin sustituir, alquinilo C(i-6) sustituido o sin sustituir, y cicloalquilo C(3-5) sustituido o sin sustituir. cada aparicion de X se selecciona independientemente de O, S y -NRa;
Cy se selecciona de
cada aparicion de Ra y Rb es igual o diferente y se selecciona independientemente de hidrogeno, nitro, hidroxi, ciano, halogeno, -ORc, -S(=O)q-Rc, -NRcRd, -C(=Y)-Rc,-CRcRd-C(=Y)-Rc, -CRcRd-Y-CRcRd-, -C(=Y)- 5 NRcRd-, -NRRd-C(=Y)-NRcRd-, -S(=O)q-NRcRd-, -NRcRd-S(=O)q-NRcRd-, -NRcRd-NRcRd-, alquilo sustituido o
sin sustituir, alquenilo sustituido o sin sustituir, alquinilo sustituido o sin sustituir, cicloalquilo sustituido o sin sustituir, cicloalquilalquilo sustituido o sin sustituir, cicloalquenilo sustituido o sin sustituir, heterociclilo sustituido o sin sustituir, heterociclilalquilo sustituido o sin sustituir, arilo sustituido o sin sustituir, arilalquilo sustituido o sin sustituir, heteroarilo sustituido o sin sustituir, y heteroarilalquilo sustituido o sin sustituir, o 10 cuando Ra y Rb estan unidos directamente al mismo atomo, pueden estar unidos para formar un anillo
saturado o insaturado sustituido o sin sustituir de 3-10 miembros, que puede incluir opcionalmente uno o mas heteroatomos que pueden ser iguales o diferentes y se seleccionan de O, NRc y S; cada aparicion de Rc y Rd puede ser igual o diferente y se selecciona independientemente de hidrogeno, nitro, hidroxi, ciano, halogeno, alquilo sustituido o sin sustituir, alquenilo sustituido o sin sustituir, alquinilo 15 sustituido o sin sustituir, cicloalquilo sustituido o sin sustituir, cicloalquilalquilo sustituido o sin sustituir,
cicloalquenilo sustituido o sin sustituir, grupo heterocfclico sustituido o sin sustituir, heterociclilalquilo sustituido o sin sustituir, o cuando dos sustituyentes Rc y/o Rd estan unidos directamente al mismo atomo, pueden estar unidos para formar un anillo saturado o insaturado sustituido o sin sustituir de 3-10 miembros, que puede incluir opcionalmente uno o mas heteroatomos que son iguales o diferentes y se seleccionan de 20 O, NH y S;
cada aparicion de Y se selecciona de O, S y -NRa; y cada aparicion de q representa independientemente 0, 1 o 2;
En una realizacion preferida, R1 es ciclopropilo. 25
En una realizacion preferida, R2 es CF3.
30
Se prefiere adicionalmente un compuesto de formula (I) en la que Hy es
De acuerdo con una realizacion preferida, Ar es
Se prefiere adicionalmente un compuesto de formula (I) en la que Ar es
10 '
Se prefiere adicionalmente un compuesto de formula (I) en la que Ar es
5
15 Aun otra realization es un compuesto que tiene la formula (IA-III)
o un tautomero, N-oxido, ester farmaceuticamente aceptable, o sal farmaceuticamente aceptable del 20 mismo, en la que
tanto R1 como R2 son ciclopropilo, y uno de R1 y R2 es CF3 y el otro es ciclopropilo;
T es CF o N y U, V, W son independientemente CH, CF o N;
L1 y L2 representan juntos -NH-C(=X)-, -NH-S(=O)q-, -C(=X)NH-, o -S(=O)qNH- o -NH-CR'R"-;
A esta ausente o se selecciona de -(CR'R")- y -NRa;
25 cada aparicion de R' y R es igual o diferente y se selecciona independientemente de hidrogeno o un grupo
alquilo C(1-6) sustituido o sin sustituir, o R' y R pueden estar unidos para formar un anillo saturado o insaturado sustituido o sin sustituir de 3-6 miembros, que puede incluir opcionalmente uno o mas heteroatomos que pueden ser iguales o diferentes y se seleccionan de O, NRa y S;
R''' se selecciona de hidrogeno o halogeno;
30 cada aparicion de X se selecciona independientemente de O, S y -NRa;
Cy se selecciona de
5 cada aparicion de Ra y Rb es igual o diferente y se selecciona independientemente de hidrogeno, nitro,
hidroxi, ciano, halogeno, -ORc, -S(=O)q-Rc, -NRcRd, -C(=Y)-Rc,-CRcRd-C(=Y)-Rc, -CRcRd-Y-CRcRd-,-C(=Y)- NRcRd-, -NRRd-C(=Y)-NRcRd-, -S(=O)q-NRcRd-, -NRcRd-S(=O)q-NRcRd-, -NRcRd-NRcRd-, alquilo sustituido o sin sustituir, alquenilo sustituido o sin sustituir, alquinilo sustituido o sin sustituir, cicloalquilo sustituido o sin sustituir, cicloalquilalquilo sustituido o sin sustituir, cicloalquenilo sustituido o sin sustituir, heterociclilo 10 sustituido o sin sustituir, heterociclilalquilo sustituido o sin sustituir, arilo sustituido o sin sustituir, arilalquilo
sustituido o sin sustituir, heteroarilo sustituido o sin sustituir, y heteroarilalquilo sustituido o sin sustituir, o cuando los sustituyentes Ra y Rb estan unidos directamente al mismo atomo, pueden estar unidos para formar un anillo saturado o insaturado sustituido o sin sustituir de 3-10 miembros, que puede incluir opcionalmente uno o mas heteroatomos que pueden ser iguales o diferentes y se seleccionan de O, NRc y 15 S;
cada aparicion de Rc y Rd puede ser igual o diferente y se selecciona independientemente de hidrogeno, nitro, hidroxi, ciano, halogeno, alquilo sustituido o sin sustituir, alquenilo sustituido o sin sustituir, alquinilo sustituido o sin sustituir, cicloalquilo sustituido o sin sustituir, cicloalquilalquilo sustituido o sin sustituir, cicloalquenilo sustituido o sin sustituir, grupo heterocfclico sustituido o sin sustituir, heterociclilalquilo 20 sustituido o sin sustituir, o cuando dos sustituyentes Rc y/o Rd estan unidos directamente al mismo atomo,
pueden estar unidos para formar un anillo saturado o insaturado sustituido o sin sustituir de 3-10 miembros, que puede incluir opcionalmente uno o mas heteroatomos que son iguales o diferentes y se seleccionan de O, NH y S;
cada aparicion de Y se selecciona de O, S y -NRa; y 25 cada aparicion de q representa independientemente 0, 1 o 2.
Se prefiere adicionalmente un compuesto de formula (IA-III) en la que tanto R1 como R2 representan ciclopropilo.
Se prefiere adicionalmente un compuesto de formula (IA-III) en la que uno de R1 y R2 es CF3 y el otro es ciclopropilo.
30
Se prefiere adicionalmente un compuesto de formula (IA-III) en la que uno de R1 y R2 es CF3 y el otro es CH2F, CHF2.
Se prefiere adicionalmente un compuesto de formula (IA-III) en la que R1 es ciclopropilo y R2 es CF3.
35
Se prefiere adicionalmente un compuesto de formula (IA-III) en la que T es CF o N.
Se prefiere adicionalmente un compuesto de formula (IA-III) en la que U, V, W son CH, CF o N.
40 Se prefiere adicionalmente un compuesto de formula (IA-III) en la que L1 y L2 representan juntos -NH-C(=O)-, C(=O)NH- o -NH-CH2-;
Se prefiere adicionalmente un compuesto de formula (IA-III) en la que A esta ausente, es -NH- o -CH2-.
45 Los compuestos representativos de la presente invention incluyen los especificados a continuation y en la Tabla 1, y sales farmaceuticamente aceptables de los mismos. La presente invencion no debe interpretarse como limitada a los mismos.
N-[4-(3,5-diciclopropil-1H-pirazol-1-il)-3-fluorofenil]-4-metil-1,2,3-tiadiazol-5-carboxamida 50 N-[4-(3,5-diciclopropil-1H-pirazol-1-il)-3-fluorofenil]-4-metiltiazol-5-carboxamida
N-[4-(3,5-diciclopropil-1H-pirazol-1-il)-3-fluorofenil]-3,5-dimetilisoxazol-4-carboxamida
5
10
15
20
25
30
35
40
45
50
55
N-[4-(3,5-diciclopropil-1H-pirazol-1-il)-3-fluorofenil]-2-metilbenzamida
N-[4-(3,5-diciclopropil-1H-pirazol-1-il)-3-fluorofenil]-2,3-difluorobenzamida
N-[4-(3,5-diciclopropil-1H-pirazol-1-il)-3-fluorofenil]-2,6-difluorobenzamida
Clorhidrato de N-[4-(3,5-diciclopropil-1H-pirazol-1-il)-3-fluorofenil]nicotinamida
Clorhidrato de N-[4-(3,5-diciclopropil-1H-pirazol-1-il)-3-fluorofenil]isonicotinamida
N-[4-(3,5-diciclopropil-1H-pirazol-1-il)-3-fluorofenil]-4-metilpirimidin-5-carboxamida
N-[4-(4-cloro-3,5-diciclopropil-1H-pirazol-1-il)-3-fluorofenil]-4-metil-1,2,3-tiadiazol-5-carboxamida
Clorhidrato de N-[6-(3,5-diciclopropil-1H-pirazol-1-il)piridin-3-il]-4-metil-1,2,3-tiadiazol-5-carboxamida
Clorhidrato de N-[6-(3,5-diciclopropil-1H-pirazol-1-il)piridin-3-il]-4-metiltiazol-5-carboxamida
N-[6-(3,5-diciclopropil-1H-pirazol-1-il)piridin-3-il]-2,4-dimetiltiazol-5-carboxamida
N-[6-(3,5-diciclopropil-1H-pirazol-1-il)piridin-3-il]-3,5-dimetilisoxazol-4-carboxamida
6-(3,5-diciclopropil-1H-pirazol-1-il)-N-o-tolilnicotinamida
N-[6-(3,5-diciclopropil-1H-pirazol-1-il)piridin-3-il]-2-fluorobenzamida
Clorhidrato de N-[6-(3,5-diciclopropil-1H-pirazol-1-il)piridin-3-il]-2,3-difluorobenzamida
Clorhidrato de N-[6-(3,5-diciclopropil-1H-pirazol-1-il)piridin-3-il]-2,6-difluorobenzamida
Diclorhidrato de N-[6-(3,5-diciclopropil-1H-pirazol-1-il)piridin-3-il]nicotinamida
Diclorhidrato de N-[6-(3,5-diciclopropil-1H-pirazol-1-il)piridin-3-il]isonicotinamida
N-[6-(3,5-diciclopropil-1H-pirazol-1-il)piridin-3-il]-3-fluoroisonicotinamida
Clorhidrato de 3,5-dicloro-N-[6-(3,5-diciclopropil-1H-pirazol-1 -il)piridin-3-il]isonicotinamida
Clorhidrato de N-[6-(3,5-diciclopropil-1H-pirazol-1-il)piridin-3-il]-4-metilpirimidin-5-carboxamida
N-{4-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]fenil}-N,4-dimetiltiazol-5-carboxamida
N-{4-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]fenil}-2-(4-fluorofenil)acetamida
Clorhidrato de N-{4-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]fenil}-2-(piridin-2-il)acetamida
Clorhidrato de N-{4-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]fenil}-2-(piridin-3-il)acetamida
Clorhidrato de N-{4-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]fenil}-2-(piridin-4-il)acetamida
4-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]-N-[(4-metiltiazol-5-il)metil]anilina
1-{4-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]fenil}-3-(4-metil-1,2,3-tiadiazol-5-il)urea
1-{4-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]fenil}-3-(4-metiltiazol-5-il)urea
1-{4-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]fenil}-3-(4-metilpirimidin-5-il)urea
N-{4-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]-3-fluorofenil}-4-metil-1,2,3-tiadiazol-5-carboxamida
N-{4-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]-3-fluorofenil}-4-metiltiazol-5-carboxamida
N-{4-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]-3-fluorofenil}-5-metilisoxazol-4-carboxamida
N-{4-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]-3-fluorofenil}-3,5-dimetilisoxazol-4-carboxamida
N-{4-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]-3-fluorofenil}-2-metilbenzamida
N-{4-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]-3-fluorofenil}-2,3-difluorobenzamida
N-{4-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]-3-fluorofenil}-2,6-difluorobenzamida
Clorhidrato de N-{4-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]-3-fluorofenil}nicotinamida
Clorhidrato de N-{4-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]-3-fluorofenil} isonicotinamida
N-{4-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]-3-fluorofenil}-3-fluoroisonicotinamida
3,5-dicloro-N-{4-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]-3-fluorofenil}isonicotinamida
N-{4-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]-3-fluorofenil}-4-metilpirimidin-5-carboxamida
N-{4-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]-3-fluorofenil}-N,4-dimetilpirimidin-5-carboxamida
N-{4-[4-cloro-5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]-3-fluorofenil}-4-metil-1,2,3-tiadiazol-5-
carboxamida
Clorhidrato de N-{4-[4-cloro-5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]-3-fluorofenil}-2-(piridin-2- il)acetamida
1-{4-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]-3-fluorofenil}-3-(4-metilpirimidin-5-il)urea
N-{4-[5)-ciclopropil-3-(triflurometil)-1H-pirazol-1-il]3-flurofenil}-2,6-diclorobenzamida
4-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]-N-(2,3-difluorofenil)-3-fluorobenzamida
4-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]-N-(2,6-difluorofenil) -3-fluorobenzamida
N-{6-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]piridin-3-il}-4-metil-1,2,3-tiadiazol-5-carboxamida
Clorhidrato de N-{6-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]piridin-3-il}-4-metiltiazol-5-carboxamida
N-{6-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]piridin-3-il}-3,5-dimetilisoxazol-4-carboxamida
N-{6-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]piridin-3-il}-2-metilbenzamida
Clorhidrato de 2-cloro-N-{6-[5-ciclopropil-3-(trifluorometil)-1 H-pirazol-1-il]piridin-3-il}benzamida
N-(6-(5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il)piridin-3-il)-2-fluorobenzamida
N-{6-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]piridin-3-il}-2,3-difluorobenzamida
N-{6-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]piridin-3-il}-2,6-difluorobenzamida
N-{6-[5-ciclopropil-3-(trifluorometil)-1 H-pirazol-1 -il]piridin-3-il}picolinamida N-{6-[5-ciclopropil-3-
10
15
20
25
30
(trifluorometil)-1H-pirazol-1-il]piridin-3-il}-3-metilpicolinamida
Clorhidrato de N-{6-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]piridin-3-il}nicotinamida Clorhidrato de N-{6-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]piridin-3-il}-2-metilnicotinamida Clorhidrato de N-{6-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]piridin-3-il}isonicotinamida N-{6-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]piridin-3-il}-3-fluoroisonicotinamida
3.5- dicloro-N-{6-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]piridin-3-il}isonicotinamida N-{6-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]piridin-3-il}-4-metilpirimidin-5-carboxamida Clorhidrato de N-{6-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]piridin-3-il}-2-(piridin-2-il)acetamida Clorhidrato de N-{6-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]piridin-3-il}-2-(piridin-4-il)acetamida N-{4-[4-cloro-5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]-3-fluorofenil}-4-metilpirimidin-5-carboxamida 1-{6-[3-ciclopropil-5-(trifluorometil)-1H-pirazol-1-il]piridin-3-il}-3-(4-metiltiazol-5-il)urea 6-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]-N-(2,3-difluorofenil) nicotinamida 6-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]-N-(2,6-difluorofenil) nicotinamida N-{6-[4-cloro-5-ciclopropil-3-trifluorometil-1H-pirazol-1-il]piridin-3-il}-4-metiltiazol-5-carboxamida N-{2-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]pirimidin-5-il}-2,6-difluorobenzamida
3.5- dicloro-N-[4-(3,5-diciclopropil-1H-pirazol-1-il)-3-fluorofenil]isonicotinamida N-(2-cloro-6-fluorofenil)-4-[5- ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]-3-fluorobenzamida
N-{2-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]pirimidin-5-il}-4-metiltiazol-5-carboxamida N-{4-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]-3,5-difluorofenil}-4-metilpirimidin-5-carboxamida {4-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]-3-fluorofenil}-1-fenilciclobutanocarboxamida N-{4-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]-3-fluorofenil}-4-metiloxazol-5-carboxamida N-{2-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]pirimidin-5-il}-4-metilpirimidin-5-carboxamida 4-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]-3-fluoro-N-(4-metilpirimidin-5-il) benzamida o N-{4-[3-ciclopropil-5-(difluorometil)-1H-pirazol-1-il]-3-fluorofenil}-2,6-difluorobenzamida y N-{4-[5-ciclopropil- 3-(difluorometil)-1H-pirazol-1-il]-3-fluorofenil}-2,6-difluorobenzamida
o un tautomero, profarmaco, N-oxido, ester farmaceuticamente aceptable, o sal farmaceuticamente aceptable de los mismos.
Tabla 1
- 28
- V N / cfSs-N 41 67 , I N—\ J— NH >=\ F3C^N' W
- 29
- 42 69 Lv v f3c^n y~
- 30
- 43 70 NH W f3c>n
- 31
- f y—NH /=\ V F (3^—? 44 A N—^ F F N—^ / ^ 71 ' 3'-' ff~ 0
Claims (16)
- REIVINDICACIONES1. Un compuesto de formula
imagen1 5 o un tautomero, N-oxido, ester farmaceuticamente aceptable, o sal farmaceuticamente aceptable del mismo, en la que1015202530el Anillo Hy representaimagen2 opcionalmente sustituidos con R''';R1 es ciclopropilo;R2 se selecciona de CH3, CH2F, CHF2, CF3, cicloalquilo C(3-5) sustituido o sin sustituir, CH2-ORa, CH2-NRaRb , CN y COOH;el Anillo Ar se selecciona deimagen3 L1 y L2 representan juntos -NH-C(=X)- o -C(=X)NH;A esta ausente o se selecciona de -(CR'R")- o -NRa ;R' y R" son iguales o diferentes y se seleccionan independientemente de hidrogeno, hidroxi, ciano, halogeno, -ORa, -COORa, -S(=O)q-Ra, -NRaRb,-C(=X)-Ra, grupo alquilo C(i-6) sustituido o sin sustituir, alquenilo C(i-6) sustituido o sin sustituir, alquinilo C(i-6) sustituido o sin sustituir, y cicloalquilo C(3-5) sustituido o sin sustituir, o R' y R" pueden unirse para formar un anillo saturado o insaturado sustituido o sin sustituir de 3-6 miembros, que puede incluir opcionalmente uno o mas heteroatomos que pueden ser iguales o diferentes y se seleccionan de O, NRa y S;R''' se selecciona de hidrogeno, hidroxi, ciano, halogeno, -ORa, -COORa, - S(=O)q-Ra, -NRaRb, -C(=X)-Ra, grupo alquilo C(i-6) sustituido o sin sustituir, alquenilo C(i-6) sustituido o sin sustituir, alquinilo C(i-6) sustituido o sin sustituir, y cicloalquilo C(3-5) sustituido o sin sustituir. cada aparicion de X se selecciona independientemente de O, S y -NRa;Cy se selecciona deimagen4 cada aparicion de Ra y Rb es igual o diferente y se selecciona independientemente de hidrogeno, nitro, hidroxi, ciano, halogeno, -ORc,-S(=O)q-Rc, -NRcRd, -C(=Y)-Rc, -CRcRd-C(=Y)-Rc, -CRcRd-Y-CRcRd-,-C(=Y)- NRcRd-, -NRRd-C(=Y)-NRcRd-, -S(=O)q-NRcRd-, -NRcRd-S(=O)q-NRcRd-, -NRcRd-NRcRd-, alquilo sustituido o sin sustituir, alquenilo sustituido o sin sustituir, alquinilo sustituido o sin sustituir, cicloalquilo sustituido o sinsustituir, cicloalquilalquilo sustituido o sin sustituir, cicloalquenilo sustituido o sin sustituir, heterociclilo sustituido o sin sustituir, heterociclilalquilo sustituido o sin sustituir, arilo sustituido o sin sustituir, arilalquilo sustituido o sin sustituir, heteroarilo sustituido o sin sustituir, y heteroarilalquilo sustituido o sin sustituir, o cuando Ra y Rb estan unidos directamente al mismo atomo, pueden estar unidos para formar un anillo 5 saturado o insaturado sustituido o sin sustituir de 3-10 miembros, que puede incluir opcionalmente uno omas heteroatomos que pueden ser iguales o diferentes y se seleccionan de O, NRc y S; cada aparicion de Rc y Rd puede ser igual o diferente y se selecciona independientemente de hidrogeno, nitro, hidroxi, ciano, halogeno, alquilo sustituido o sin sustituir, alquenilo sustituido o sin sustituir, alquinilo sustituido o sin sustituir, cicloalquilo sustituido o sin sustituir, cicloalquilalquilo sustituido o sin sustituir, 10 cicloalquenilo sustituido o sin sustituir, grupo heteroclclico sustituido o sin sustituir, heterociclilalquilosustituido o sin sustituir, o cuando dos sustituyentes Rc y/o Rd estan unidos directamente al mismo atomo, pueden estar unidos para formar un anillo saturado o insaturado sustituido o sin sustituir de 3-10 miembros, que puede incluir opcionalmente uno o mas heteroatomos que son iguales o diferentes y se seleccionan de O, NH y S;15 cada aparicion de Y se selecciona de O, S y -NRa; ycada aparicion de q representa independientemente 0, 1 o 2; - 2. Un compuesto de la reivindicacion 1, en el que Hy es
imagen5 20 - 3. Un compuesto de una cualquiera de las reivindicaciones 1 o 2, en el que L1 y L2 representan juntos - NH-C(=O)-.
- 4. Un compuesto de una cualquiera de las reivindicaciones 1-3, en el que A esta ausente.25
- 5. Un compuesto de formula
imagen6 o un tautomero, N-oxido, ester farmaceuticamente aceptable, o sal farmaceuticamente aceptable del mismo, en la que 30tanto R1 como R2 son ciclopropilo, y uno de R1 y R2 es CF3 y el otro es ciclopropilo;T es CF o N y U, V, W son independientemente CH, CF o N;L1 y L2 representan juntos -NH-C(=X)-, -NH-S(=O)q-, -C(=X)NH-, o -S(=O)qNH- o -NH-CR'R"-;A esta ausente o se selecciona de -(CR'R")- y -NRa;35 cada aparicion de R' y R" es igual o diferente y se selecciona independientemente de hidrogeno o grupoalquilo C(1-6) sustituido o sin sustituir, o R' y R" pueden estar unidos para formar un anillo saturado o insaturado sustituido o sin sustituir de 3-6 miembros, que puede incluir opcionalmente uno o mas heteroatomos que pueden ser iguales o diferentes y se seleccionan de O, NRa y S;R''' se selecciona de hidrogeno o halogeno;40 cada aparicion de X se selecciona independientemente de O, S y -NRa;Cy se selecciona de51015202530354045imagen7 hidroxi, ciano, halogeno, -ORc,-S(=O)q-Rc, -NRcRd, -C(=Y)-Rc, -CRcRd-C(=Y)-Rc, -CRcRd-Y-CRcRd-,-C(=Y)- NRcRd-, -NRRd-C(=Y)-NRcRd-, -S(=O)q-NRcRd-, -NRcRd-S(=O)q-NRcRd-, -NRcRd-NRcRd-, alquilo sustituido o sin sustituir, alquenilo sustituido o sin sustituir, alquinilo sustituido o sin sustituir, cicloalquilo sustituido o sin sustituir, cicloalquilalquilo sustituido o sin sustituir, cicloalquenilo sustituido o sin sustituir, heterociclilo sustituido o sin sustituir, heterociclilalquilo sustituido o sin sustituir, arilo sustituido o sin sustituir, arilalquilo sustituido o sin sustituir, heteroarilo sustituido o sin sustituir, y heteroarilalquilo sustituido o sin sustituir, o cuando los sustituyentes Ra y Rb estan unidos directamente al mismo atomo, pueden estar unidos para formar un anillo saturado o insaturado sustituido o sin sustituir de 3-10 miembros, que puede incluir opcionalmente uno o mas heteroatomos que pueden ser iguales o diferentes y se seleccionan de O, NRc y S;cada aparicion de Rc y Rd puede ser igual o diferente y se selecciona independientemente de hidrogeno, nitro, hidroxi, ciano, halogeno, alquilo sustituido o sin sustituir, alquenilo sustituido o sin sustituir, alquinilo sustituido o sin sustituir, cicloalquilo sustituido o sin sustituir, cicloalquilalquilo sustituido o sin sustituir, cicloalquenilo sustituido o sin sustituir, grupo heterocfclico sustituido o sin sustituir, heterociclilalquilo sustituido o sin sustituir, o cuando dos sustituyentes Rc y/o Rd estan unidos directamente al mismo atomo, pueden estar unidos para formar un anillo saturado o insaturado sustituido o sin sustituir de 3-10 miembros, que puede incluir opcionalmente uno o mas heteroatomos que son iguales o diferentes y se seleccionan de O, NH y S;cada aparicion de Y se selecciona de O, S y -NRa; y cada aparicion de q representa independientemente 0, 1 o 2. - 6. Un compuesto de una cualquiera de las reivindicaciones 1 a 5, en el que L1 y L2 representan juntos -NH-C(=O)-, -C(=O)NH- o -NHCH2-.
- 7. Un compuesto de una cualquiera de las reivindicaciones 1 a 6, en el que A esta ausente.
- 8. Un compuesto de una cualquiera de las reivindicaciones 1 o 5 seleccionado de:N-[4-(3,5-diciclopropil-1H-pirazol-1-il)-3-fluorofenil]-2metil benzamidaN-[4-(3,5-diciclopropil-1H-pirazol-1-il)-3-fluorofenil]-2,3-difluorobenzamidaN-[4-(3,5-diciclopropil-1H-pirazol-1-il)-3-fluorofenil]-2,6-difluorobenzamidaN-[4-(3,5-diciclopropil-1H-pirazol-1-il)-3-fluorofenil]nicotinamida N-[4-(3,5-diciclopropil-1H-pirazol-1-il)-3-fluorofeniljisonicotinamidaN-[4-(3,5-diciclopropil-1H-pirazol-1-il)-3-fluorofenil]-4-metilpirimidin-5-carboxamida6-(3,5-diciclopropil-1H-pirazol-1-il)-N-o-tolilnicotinamidaN-[6-(3,5-diciclopropil-1H-pirazol-1-il)piridin-3-il]-2-fluorobenzamidaN-[6-(3,5-diciclopropil-1H-pirazol-1-il)piridin-3-il]-2,3-difluorobenzamidaN-[6-(3,5-diciclopropil-1H-pirazol-1-il)piridin-3-il]-2,6-difluorobenzamidaDiclorhidrato de N-[6-(3,5-diciclopropil-1H-pirazol-1-il)piridin-3-il]nicotinamidaN-[6-(3,5-diciclopropil-1H-pirazol-1-il)piridin-3-il]isonicotinamidaN-[6-(3,5-diciclopropil-1H-pirazol-1-il)piridin-3-il]-3-fluoroisonicotinamida3,5-dicloro-N-[6-(3,5-diciclopropil-1H-pirazol-1-il)piridin-3-il]isonicotinamidaN-[6-(3,5-diciclopropil-1H-pirazol-1-il)piridin-3-il]-4-metilpirimidin-5-carboxamidaN-{4-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]-3-fluorofenil}-2-metilbenzamidaN-{4-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]-3-fluorofenil}-2,3-difluorobenzamidaN-{4-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]-3-fluorofenil}-2,6-difluorobenzamidaN-{4-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]-3-fluorofenil}nicotinamida101520253035404550W-{4-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]-3-fluorofenil} isonicotinamida W-{4-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]-3-fluorofenil}-3-fluoroisonicotinamida
- 3.5- dicloro-W-{4-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]-3-fluorofenil}isonicotinamida W-{4-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]-3-fluorofenil}-4-metilpirimidin-5-carboxamida W-{4-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]-3-fluorofenil}-W,4-dimetilpirimidin-5-carboxamida W-{4-[4-cloro-5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]-3-fluorofenil}-2-(piridin-2-il)acetamida1- {4-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]-3-fluorofenil}-3-(4-metilpirimidin-5-il)urea W-{4-[5)-ciclopropil-3-(triflurometil)-1H-pirazol-1-il]3-flurofenil}-2,6-dicloro benzamida 4-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]-W-(2,3-difluorofenil)-3-fluorobenzamida 4-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]-W-(2,6-difluorofenil)-3-fluorobenzamida W-{6-(5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]piridin-3-il}-3,5-dimetilisoxazol-4-carboxamida W-{6-(5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]piridin-3-il}-2-metilbenzamida2- cloro-N-{6-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]piridin-3-il}benzamida N-(6-(5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il)piridin-3-il)-2-fluorobenzamida W-{6-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]piridin-3-il}-2,3-difluorobenzamida W-{6-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]piridin-3-il}-2,6-difluorobenzamida W-{6-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]piridin-3-il}picolinamida W-{6-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]piridin-3-il}-3-metilpicolinamida W-{6-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]piridin-3-il}nicotinamida W-{6-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]piridin-3-il}-2-metilnicotinamida W-{6-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-iljpiridin-3-il}isonicotinamida W-{6-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]piridin-3-il}-3-fluoroisonicotinamida
- 3.5- dicloro-W-{6-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]piridin-3-il}isonicotinamida W-{6-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]piridin-3-il}-4-metilpirimidin-5-carboxamida W-{6-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]piridin-3-il}-2-(piridin-2-il)acetamida W-{6-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]piridin-3-il}-2-(piridin-4-il)acetamida N-{4-[4-cloro-5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]-3-fluorofenil}-4-metilpirimidin-5-carboxamida 6-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]-W-(2,3-difluorofenil) nicotinamida 6-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]-W-(2,6-difluorofenil) nicotinamida W-{2-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]pirimidin-5-il}-2,6-difluorobenzamida
- 3.5- dicloro-A/-[4-(3,5-diciclopropil-1H-pirazol-1-il)-3-fluorofenil]isonicotinamida W-(2-cloro-6-fluorofenil)-4-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]-3-fluorobenzamida W-{4-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]-3,5-difluorofenil}-4-metilpirimidin-5-carboxamida {4-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]-3-fluorofenil}-1-fenilciclobutanocarboxamida N-{2-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]pirimidin-5-il}-4-metilpirimidin-5-carboxamida 4-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]-3-fluoro-W-(4-metilpirimidin-5-il) benzamida y W-{4-[3-ciclopropil-5-(difluorometil)-1H-pirazol-1-il]-3-fluorofenil}-2,6-difluorobenzamida y W-{4-[5-ciclopropil-3-(difluorometil)-1H-pirazol-1-il]-3-fluorofenil}-2,6-difluorobenzamidao un tautomero, N-oxido, ester farmaceuticamente aceptable, o sal farmaceuticamente aceptable de los mismos.
- 9. Un compuesto de una cualquiera de las reivindicaciones 1 o 5, que es W-{6-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]piridin-3-il}-2-metilbenzamida, o una sal farmaceuticamente aceptable de la misma.
- 10. Un compuesto de una cualquiera de las reivindicaciones 1 o 5, que es W-{6-[5-ciclopropil-3-(trifluorometil)-1H-pirazol-1-il]piridin-3-il}-3-fluoroisonicotinamida, o una sal farmaceuticamente aceptable de la misma.
- 11. Una composicion farmaceutica que comprende uno o mas compuestos de una cualquiera de las reivindicaciones 1 a 10 y un vehfculo farmaceuticamente aceptable.
- 12. Uso de un compuesto en una cualquiera de las reivindicaciones 1-10 para la fabricacion de un medicamento para el tratamiento del cancer.
- 13. Uso de un compuesto en una cualquiera de las reivindicaciones 1-10 para la fabricacion de un medicamento para el tratamiento de un trastorno autoinmune, en el que el trastorno autoinmune es enfermedad pulmonar obstructiva cronica, artritis reumatoide, enfermedad inflamatoria del intestino, rinitis alergica, asma, esclerosis multiple, psoriasis, enfermedad de Crohn, colitis, colitis ulcerosa, artritis, enfermedades oseas asociadas con una mayor resorcion osea, o enfermedad obstructiva cronica de las vfas respiratorias.
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