ES2362369T3 - NEW LINES OF CANABINOID RECEPTORS, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM, AND PROCEDURES FOR THEIR PREPARATION. - Google Patents

Abstract

Un compuesto de la formula: ++Fórmula** una sal farmaceuticamente aceptable del mismo, un ester farmaceuticamente aceptable del mismo, un tautomero del mismo, un estereoisomero del mismo, un enantiomero del mismo o un diastereomero de los mismos en la que cada una de las lineas de puntos en formula (1) representa independientemente un enlace opcional; U y V son independientemente C o N; W, X e Y son independientemente C, N, O, S o -C(O)- con la condicion de que al menos dos de U, V, W, X o Y se seleccionan independientemente entre N, O, -C(O)- o S; en cada aparicion, R es independientemente alquilo sustituido o sin sustituir, arilo sustituido o sin sustituir o heteroarilo sustituido o sin sustituir; R1 y R2 pueden ser iguales o diferentes y son independientemente hidrogeno, nitro, ciano, formilo, acetilo, halogeno, -OR3, -SR3, oxo, tio, 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, cicloalquenilalquilo sustituido o sin sustituir, arilo sustituido o sin sustituir, arilalquilo sustituido o sin sustituir, heteroarilo sustituido o sin sustituir, heteroarilalquilo sustituido o sin sustituir, grupo heterociclico sustituido o sin sustituir, heterociclilalquilo sustituido o sin sustituir, -NR3R4, -C(=B)-R3, - C(O) O-R3, -C(C)NR3R4, -S(O)m-R3, -S(O)m-NR3R4 o un grupo protector o R1 y R2 pueden unirse para formar un anillo ciclico opcionalmente sustituido, saturado o insaturado de 3 a 7 miembros, que puede incluir opcionalmente al menos dos heteroatomos seleccionados entre O, NR3 o S; en cada aparicion, R3 y R4 pueden ser iguales o diferentes y son independientemente hidrogeno, nitro, halo, ciano, -ORa, -SRa, oxo, tio, 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, cicloalquenilalquilo sustituido o sin sustituir, arilo sustituido o sin sustituir, arilalquilo sustituido o sin sustituir, heteroarilo sustituido o sin sustituir, heteroarilalquilo sustituido o sin sustituir, grupo heterociclico sustituido o sin sustituir, heterociclilalquilo sustituido o sin sustituir, -C(=B)-Ra, -C(O)O-Ra, -C (O)NRaRb, -S(O)m-Ra, -S(O)m-NRaRb, -NRaRb o un grupo protector o R3 y R4, cuando se unen a un atomo en comun, pueden unirse entre si para formar un anillo ciclico opcionalmente sustituido, saturado o insaturado de 3 a 7 miembros, que puede incluir opcionalmente al menos dos heteroatomos seleccionados entre O, NR3 o S; cada aparicion de Ra y Rb pueden ser iguales o diferentes y son independientemente hidrogeno, halogeno, nitro, ciano, formilo, acetilo, oxo, tio, -C(O)-Rc, -C(O)O-Rc, -C(O)NRcRd, -S(O)m-Rc, -S(O)m-NRcRd, -NRcRd, - ORc, -SRc, un grupo protector, 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, cicloalquenilalquilo sustituido o sin sustituir, arilo sustituido o sin sustituir, arilalquilo sustituido o sin sustituir, heteroarilo sustituido o sin sustituir, grupo heterociclico sustituido o sin sustituir, heterociclilalquilo sustituido o sin sustituir o heteroarilalquilo sustituido o sin sustituir; cada aparicion de Rc y Rd pueden ser iguales o diferentes y son independientemente hidrogeno, halogeno, nitro, ciano, formilo, acetilo, oxo, tio, un grupo protector, 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, cicloalquenilalquilo sustituido o sin sustituir, arilo sustituido o sin sustituir, arilalquilo sustituido o sin sustituir, heteroarilo sustituido o sin sustituir, grupo heterociclico sustituido o sin sustituir, heterociclilalquilo sustituido o sin sustituir o heteroarilalquilo sustituido o sin sustituir; en cada aparicion, B es independientemente O, S o NR3; p es 1 o 2; en cada aparicion, m es independientemente 0, 1 o 2; A es cada una de las lineas de puntos en A representa independientemente un enlace opcional; R5, R6, R7, R8, R9 R10, R11, R12, R13 y R14son independientemente hidrogeno, nitro, ciano, formilo, acetilo, halogeno, -OR15 , -SR15, oxo, tio, 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, cicloalquenilalquilo sustituido o sin sustituir, arilo sustituido o sin sustituir, arilalquilo sustituido o sin sustituir, heteroarilo sustituido o sin sustituir, heteroarilalquilo sustituido o sin sustituir, grupo heterociclico sustituido o sin sustituir, heterociclilalquilo sustituid o sin sustituir, -NR15R16 , -C(=B)-R15 , - C(O)O-R15, -C(O)NR15R16, -S(O)m-R15, -S(O)m-NR15R16 o un grupo protector; R5 y R6 pueden unirse para formar un anillo mono- o bi- ciclico opcionalmente sustituido, saturado o insaturado de 3 a 11 miembros, que puede incluir opcionalmente al menos un heteroatomo seleccionado entre O, NR3 o S; R9y R10 pueden unirse entre si para formar un anillo mono- o bi- ciclico opcionalmente sustituido, saturado o insaturado de 3 a 11 miembros, que puede incluir opcionalmente al menos un heteroatomo seleccionado entre O, NR3 o S; en cada aparicion, R15 y R16 pueden ser iguales o diferentes y son independientemente hidrogeno, nitro, halo, ciano, -OR3, -SR3, oxo, tio, alquilo sustituido o sin sustituir, alquenilo sustituido o in sustituir, alquinilo sustituido o sin sustituir, cicloalquilo sustituido o sin sustituir, cicloalquilalquilo sustituido o sin sustituir, cicloalquenilo sustituido o sin sustituir, cicloalquenilalquilo sustituido o sin sustituir, arilo sustituido o sin sustituir, arilalquilo sustituido o sin sustituir, heteroarilo sustituido o sin sustituir, heteroarilalquilo sustituido o sin sustituir, grupo heterociclico sustituido o sin sustituir, heterociclilalquilo sustituido o sin sustituir, -C(=B)-R3, -C(O)O-R3, - C(O)NR3R4, -S(O)m-R3, -S(O)m-NR3R4, -NR3R4 o R15 y R16, cuando se unen a un atomo en comun, pueden unirse entre si para formar un anillo ciclico opcionalmente sustituido saturado o insaturado de 3 a 7 miembros, que puede incluir opcionalmente al menos dos heteroatomos seleccionados entre O, NR3 o S en las que R3 y R4 son como se han definido anteriormente; n es 1, 2, 3 o 4; y a, b, c, d y e son numeros enteros seleccionados independientemente de 0 a 4, con la condicion de que el compuesto no tenga la formula: **Fórmula** en la que R1 y R son como se han definido anteriormente, en la que los sustituyentes en grupo funcionales sustituido pueden ser iguales o diferentes y son uno o mas de hidroxi, halogeno, carboxilo, ciano, nitro, oxo (=O), tio (=S), alquilo C1-8, alcoxi C1-8, alquenilo C2-10, alquinilo C2- 12, arilo C6-14, arilalquilo, cicloalquilo, cicloalquenilo, amino, heteroarilo, anillo heterociclilalquilo, heteroarilalquilo, anillo heterociclico de 3-15 miembros, guanidina, -COORx, -C(O)Rx, C(S)Rx, -C(O)NRxRy, - C(O)ONRxRy, -NRxCONRyRz, -N(Rx)SORy, -N(Rx)SO2Ry, -(=N-N(Rx)Ry), -NRxC(O)ORy, -NRxRy, -NRxC(O)Ry, - NRxC(S)Ry, -NRxC(S)NRyRz, -SONRxRy, -SO2NRxRy, -ORx, ORxC(O)NRyRz, -ORxC(O)ORy, -OC(O)Rx, - OC(O)NRxRy, -RxNRyC(O)Rz, -RxORy, -RxC(O)ORy, -RxC(O)NRyRz, -RxC(O)Ry, - RxOC(O)Ry, -SRx, -SORx, - SO2Rx y ONO2, en los que Rx, Ry y Rz se seleccionan independientemente entre hidrogeno, alquilo C1-8, alcoxi C1-8, alquenilo C2-10, alquinilo C2-12, arilo C6-14, arilalquilo, cicloalquilo, cicloalquenilo, amino, heteroarilo, anillo heterociclilalquilo sustituido, heteroarilalquilo y anillo heterociclico de 3-15 miembros.A compound of the formula: ++ Formula ** a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable ester thereof, a tautomer thereof, a stereoisomer thereof, an enantiomer thereof or a diastereomer thereof in which each of the dotted lines in formula (1) independently represents an optional link; U and V are independently C or N; W, X and Y are independently C, N, O, S or -C (O) - with the proviso that at least two of U, V, W, X or Y are independently selected from N, O, -C ( O) - or S; in each occurrence, R is independently substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R1 and R2 may be the same or different and are independently hydrogen, nitro, cyano, formyl, acetyl, halogen, -OR3, -SR3, oxo, thio, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl , substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenyl alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, group substituted or unsubstituted heterocyclic, substituted or unsubstituted heterocyclyl alkyl, -NR3R4, -C (= B) -R3, - C (O) O-R3, -C (C) NR3R4, -S (O) m-R3, - S (O) m-NR3R4 or a protecting group or R1 and R2 may be joined to form an optionally substituted, saturated or unsaturated cyclic ring of 3 to 7 members, which may optionally include at least two heteroatoms selected from O, NR3 or S; in each occurrence, R3 and R4 may be the same or different and are independently hydrogen, nitro, halo, cyano, -ORa, -SRa, oxo, thio, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl , substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenyl alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, group substituted or unsubstituted heterocyclic, substituted or unsubstituted heterocyclylalkyl, -C (= B) -Ra, -C (O) O-Ra, -C (O) NRaRb, -S (O) m-Ra, -S (O ) m-NRaRb, -NRaRb or a protecting group or R3 and R4, when attached to a common atom, can be joined together to form an optionally substituted, saturated or unsaturated cyclic ring of 3 to 7 members, which may optionally include at least two heteroatoms are selected between O, NR3 or S; each occurrence of Ra and Rb may be the same or different and are independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, -C (O) -Rc, -C (O) O-Rc, -C ( O) NRcRd, -S (O) m-Rc, -S (O) m-NRcRd, -NRcRd, - ORc, -SRc, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted alkynyl or unsubstituted, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenyl alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group substituted, substituted or unsubstituted heterocyclylalkyl or substituted or unsubstituted heteroarylalkyl; each occurrence of Rc and Rd may be the same or different and are independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl substituted, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenyl alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group , substituted or unsubstituted heterocyclylalkyl or substituted or unsubstituted heteroarylalkyl; in each occurrence, B is independently O, S or NR3; p is 1 or 2; in each occurrence, m is independently 0, 1 or 2; A is each of the dotted lines in A independently represents an optional link; R5, R6, R7, R8, R9 R10, R11, R12, R13 and R14 are independently hydrogen, nitro, cyano, formyl, acetyl, halogen, -OR15, -SR15, oxo, thio, substituted or unsubstituted alkyl, substituted alkenyl or unsubstituted, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenyl alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl , substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclyl alkyl, -NR15R16, -C (= B) -R15, - C (O) O-R15, -C (O) NR15R16, -S (O) m-R15, -S (O) m-NR15R16 or a protecting group; R5 and R6 can be joined to form an optionally substituted, saturated or unsaturated mono- or bicyclic ring of 3 to 11 members, which may optionally include at least one heteroatom selected from O, NR3 or S; R9 and R10 can be joined together to form an optionally substituted, saturated or unsaturated mono- or bicyclic ring of 3 to 11 members, which may optionally include at least one heteroatom selected from O, NR3 or S; in each occurrence, R15 and R16 may be the same or different and are independently hydrogen, nitro, halo, cyano, -OR3, -SR3, oxo, thio, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl , substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenyl alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, group substituted or unsubstituted heterocyclic, substituted or unsubstituted heterocyclyl alkyl, -C (= B) -R3, -C (O) O-R3, - C (O) NR3R4, -S (O) m-R3, -S (O ) m-NR3R4, -NR3R4 or R15 and R16, when attached to a common atom, can be joined together to form an optionally substituted saturated or unsaturated cyclic ring of 3 to 7 members, which may optionally include at least two selected heteroatoms between or , NR3 or S in which R3 and R4 are as defined above; n is 1, 2, 3 or 4; ya, b, c, d and e are whole numbers independently selected from 0 to 4, with the proviso that the compound does not have the formula: ** Formula ** in which R1 and R are as defined above, in which the substituted functional group substituents may be the same or different and are one or more of hydroxy, halogen, carboxyl, cyano, nitro, oxo (= O), thio (= S), C1-8 alkyl, C1-8 alkoxy, alkenyl C2-10, C2-12 alkynyl, C6-14 aryl, arylalkyl, cycloalkyl, cycloalkenyl, amino, heteroaryl, heterocyclylalkyl ring, heteroarylalkyl, 3-15 membered heterocyclic ring, guanidine, -COORx, -C (O) Rx, C (S) Rx, -C (O) NRxRy, - C (O) ONRxRy, -NRxCONRyRz, -N (Rx) SORy, -N (Rx) SO2Ry, - (= NN (Rx) Ry), -NRxC (O ) ORy, -NRxRy, -NRxC (O) Ry, - NRxC (S) Ry, -NRxC (S) NRyRz, -SONRxRy, -SO2NRxRy, -ORx, ORxC (O) NRyRz, -ORxC (O) ORy, - OC (O) Rx, - OC (O) NRxRy, -RxNRyC (O) Rz, -RxORy, -RxC (O) ORy, -RxC (O) NRyRz, -RxC (O) Ry, - RxOC (O) Ry , -SRx, -SORx, - SO2Rx and ONO2, in which Rx, Ry and Rz are selected independently from hydrogen, C1-8 alkyl, C1-8 alkoxy, C2-10 alkenyl, C2-12 alkynyl, C6-14 aryl, arylalkyl, cycloalkyl, cycloalkenyl, amino, heteroaryl, substituted heterocyclyl ring, heteroarylalkyl and 3- heterocyclic ring 15 members

Description

La presente solicitud reivindica el beneficio de la Solicitud de Patente India Nº 659/MUM/2005 presentada el 2 de junio del 2005, Solicitud Provisional de los Estados Unidos Nº 60/696,433, presentada el 1 de julio del 2005, Solicitud de Patente India Nº 1370/MUM/2005, presentada el 10 de octubre del 2005, Solicitud de Patente India Nº 344/MUM/2006, presentada el 9 de marzo del 2006, Solicitud Provisional de los Estados Unidos Nº 60/744,071, presentada el 31 de marzo del 2006 y Solicitud de Patente India Nº 689/MUM/2006, presentada el 3 de mayo del 2006, las cuales se incorporan por referencia en su totalidad en el presente documento. The present application claims the benefit of the Indian Patent Application No. 659 / MUM / 2005 filed on June 2, 2005, Provisional Application of the United States No. 60 / 696,433, filed on July 1, 2005, Indian Patent Application No. 1370 / MUM / 2005, filed October 10, 2005, Indian Patent Application No. 344 / MUM / 2006, filed March 9, 2006, United States Provisional Application No. 60 / 744,071, filed March 31, 2006 and Indian Patent Application No. 689 / MUM / 2006, filed on May 3, 2006, which are incorporated by reference in their entirety herein.

Campo de la invención Field of the Invention

La presente invención se refiere a nuevos moduladores de receptores de canabinoides en particular moduladores de receptores de canabinoide 1 (CB1) o canabinoide 2 (CB2), y a usos de los mismos para el tratamiento de enfermedades, afecciones y/o trastornos modulados por un receptor de canabinoide (tales como trastornos del dolor, neurodegenerativos, trastornos alimenticios, pérdida o control de peso y obesidad). The present invention relates to new modulators of cannabinoid receptors in particular modulators of cannabinoid 1 (CB1) or cannabinoid 2 (CB2) receptors, and uses thereof for the treatment of diseases, conditions and / or disorders modulated by a receptor of cannabinoid (such as pain disorders, neurodegenerative, eating disorders, weight loss or control and obesity).

Antecedentes Background

El sistema canabinoide endógeno comprende dos receptores principales CB1 y CB2 y una serie de ligandos que incluyen anandamida y virodamina que demuestran la mayor actividad en el receptor de canabinoide (Jonathan A W & Louis J A, Obes Man., 5-19, 2005). La anandamida, que se produce postsinápticamente, es el ácido graso principal implicado en el sistema. Se introduce en el espacio extracelular y activa los receptores de canabinoides CB1 localizados en las terminaciones nerviosas presinápticas. Esta activación produce inhibición presináptica del ácido γ-aminobutírico o glutamato a través de la inhibición de los canales de calcio, interfiriendo simultáneamente la liberación de las vesículas y la activación de los canales de potasio. The endogenous cannabinoid system comprises two main CB1 and CB2 receptors and a series of ligands that include anandamide and virodamine that demonstrate the highest activity in the cannabinoid receptor (Jonathan A W & Louis J A, Obes Man., 5-19, 2005). Anandamide, which is produced postsynaptically, is the main fatty acid involved in the system. It is introduced into the extracellular space and activates CB1 cannabinoid receptors located in presynaptic nerve endings. This activation produces presynaptic inhibition of γ-aminobutyric acid or glutamate through the inhibition of calcium channels, simultaneously interfering with the release of vesicles and the activation of potassium channels.

Sin embargo, la anandamida tiende a una hidrólisis enzimática rápida. Esto representa un grave inconveniente en su uso como un fármaco porque, entre otras, sustancias que son susceptibles a escisión hidrolítica pueden experimentar cambios en el tracto gastrointestinal. However, anandamide tends to rapid enzymatic hydrolysis. This represents a serious inconvenience in its use as a drug because, among others, substances that are susceptible to hydrolytic excision can undergo changes in the gastrointestinal tract.

Los receptores CB1 se localizan predominantemente en el cerebro y en las neuronas, mientras que los receptores CB2 se localizan predominantemente en las células inmunitarias. Se sabe que la estimulación de estos receptores influye en la acción central y periférica sobre el metabolismo de los lípidos y glucosa en el tejido adiposo y más particularmente, ayuda a regular el consumo de alimentos, el equilibrio energético y la dependencia de nicotina así como a regular el miedo y la ansiedad. CB1 receptors are predominantly located in the brain and neurons, while CB2 receptors are predominantly located in immune cells. It is known that the stimulation of these receptors influences the central and peripheral action on the metabolism of lipids and glucose in adipose tissue and more particularly, helps regulate food consumption, energy balance and nicotine dependence as well as Regulate fear and anxiety.

Existen pruebas que sugieren que los agonistas o antagonistas de CB1, respectivamente, aumentan o disminuyen la motivación para surtir efecto en la ingesta agradable (Gallate J E y McGregor I S, Psychopharmacology, 142, 302308, 1999 y Gallate J E, Saharov T, Mallet P E y McGregor I S, Eur. J. Pharmacol., 370, 233-240, 1999). Los canabinoides parecen estimular directamente el consumo de alimentos mediante acciones sobre procesos relacionados con el apetito, provocando estímulos alimenticios más notables e induciendo rápidamente el consumo de alimentos incluso en animales saciados (Williams C M y Kirkham TC, Physiol. Behav., 76, 241-250, 2002). There is evidence to suggest that CB1 agonists or antagonists, respectively, increase or decrease the motivation to have an effect on pleasant intake (Gallate JE and McGregor IS, Psychopharmacology, 142, 302308, 1999 and Gallate JE, Saharov T, Mallet PE and McGregor IS, Eur. J. Pharmacol., 370, 233-240, 1999). Cannabinoids seem to directly stimulate food consumption through actions on appetite-related processes, causing more noticeable food stimuli and rapidly inducing food consumption even in satiated animals (Williams CM and Kirkham TC, Physiol. Behav., 76, 241- 250, 2002).

Datos actuales revelan que los canabinoides median la supresión de inflamación in vitro e in vivo mediante la estimulación de receptores CB2 (Ehrhart J, y col. J. Neuroinflammation, 2, 29, 2005). Los mediadores de la inflamación tales como óxido nítrico, citocinas y quimiocinas desempeñan una función importante en la lesión de las células neuronales asociada a las células microgliales. Las células microgliales activadas se han implicado en diversos trastornos neurodegenerativos, incluyendo enfermedad de Alzheimer, esclerosis múltiple, VIH y demencia. Current data reveal that cannabinoids mediate inflammation suppression in vitro and in vivo by stimulating CB2 receptors (Ehrhart J, et al. J. Neuroinflammation, 2, 29, 2005). Inflammation mediators such as nitric oxide, cytokines and chemokines play an important role in neuronal cell injury associated with microglial cells. Activated microglial cells have been implicated in various neurodegenerative disorders, including Alzheimer's disease, multiple sclerosis, HIV and dementia.

Los compuestos que pueden modular la actividad de receptores (CB) de canabinoides pueden usarse en el tratamiento de síndromes, enfermedades o trastornos mediados por receptores CB que incluyen apetito, diabetes, obesidad, presión intraocular asociada a glaucoma, trastornos anímicos, ataques, abuso de sustancias nocivas, trastornos relacionados con el aprendizaje, trastornos cognitivos, trastornos relacionados con la memoria, contracción de órganos, espasmos musculares, trastornos respiratorios, trastornos relacionados con la actividad locomotora, discinesias, trastornos inmunológicos, inflamación, trastornos del crecimiento celular, enfermedades oculares, alergias y reacciones alérgicas, dolor, ansiedad, aflicciones psicóticas, estados patológicos cerebrales, trastornos gastrointestinales, náuseas, vómitos, vértigos, problemas urinarios y de fertilidad, enfermedades cardiovasculares, patologías neuroinflamatorias, enfermedades del sistema nervioso central, síndromes, enfermedades y trastornos neurodegenerativos, enfermedades relacionadas con el sueño, trastornos dermatológicos, trastorno asociado con la activación de leucocitos, enfermedades autoinmunes, patologías nefrológicas, hipersensibilidad tardía o inmediata, enfermedades parasitarias, virales y bacterianas infecciosas. Compounds that can modulate the activity of cannabinoid receptors (CB) can be used in the treatment of syndromes, diseases or disorders mediated by CB receptors that include appetite, diabetes, obesity, glaucoma-associated intraocular pressure, mood disorders, seizures, abuse of harmful substances, learning-related disorders, cognitive disorders, memory-related disorders, organ contraction, muscle spasms, respiratory disorders, disorders related to locomotor activity, dyskinesias, immune disorders, inflammation, cell growth disorders, eye diseases, allergies and allergic reactions, pain, anxiety, psychotic afflictions, cerebral pathological conditions, gastrointestinal disorders, nausea, vomiting, dizziness, urinary and fertility problems, cardiovascular diseases, neuroinflammatory diseases, diseases of the central nervous system, syndromes, in neurodegenerative diseases and disorders, sleep-related diseases, dermatological disorders, disorder associated with the activation of leukocytes, autoimmune diseases, nephrological pathologies, late or immediate hypersensitivity, infectious parasitic, viral and bacterial diseases.

Hasta el momento, se han caracterizado diversos moduladores de CB como agonistas, agonistas inversos o antagonistas para los receptores CB1 y/o CB2. Estos moduladores incluyen naftalen-lil-(4-pentiloxi-naftalen-1il)metanona (que se cree que es SAB-378), 4-(2,4-diclorofenilamino)-N-(tetrahidro-piran-4ilmetil)-2-triflurometilSo far, various CB modulators have been characterized as agonists, inverse agonists or antagonists for CB1 and / or CB2 receptors. These modulators include naphthalen-lyl- (4-pentyloxy-naphthalen-1-yl) methanone (believed to be SAB-378), 4- (2,4-dichlorophenylamino) -N- (tetrahydro-pyran-4-methyl) -2- trifluromethyl

10 10

15 fifteen

20 twenty

25 25

30 30

benzamida (GW-842166X), N-(1-piperidinil)-5-(4-clorofenil)-1-(2,4-diclorofenil)-4-metilpirazol-3-carboxamida (SR141716A), 3-(4-clorofenil-N’-(4-clorofenil)sulfonil-N-metil-4-fenil-4,5-dihidro-1H-pirazol-1-carboxamida (SLV-319), y (R)-(+)-[2,3-dihidro-5-metil-3-[4-morfolinilmetil]-pirrolo-[1,2,3-de]-1,4-benzoxazin-6-il](1-naftil)metanona (WIN 55212-2). benzamide (GW-842166X), N- (1-piperidinyl) -5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methylpyrazol-3-carboxamide (SR141716A), 3- (4-chlorophenyl -N '- (4-chlorophenyl) sulfonyl-N-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-carboxamide (SLV-319), and (R) - (+) - [2, 3-dihydro-5-methyl-3- [4-morpholinylmethyl] -pyrrolo- [1,2,3-de] -1,4-benzoxazin-6-yl] (1-naphthyl) methanone (WIN 55212-2) .

imagen1image 1

Estos moduladores han alcanzado fases avanzadas de ensayos clínicos para el tratamiento del dolor, enfermedades neurodegenerativas, trastornos sicóticos, síndromes, enfermedades o trastornos neurológicos, trastornos alimenticios, enfermedad de Alzheimer, dependencia del alcohol, diabetes, obesidad y/o para dejar de fumar. These modulators have reached advanced phases of clinical trials for the treatment of pain, neurodegenerative diseases, psychotic disorders, syndromes, diseases or neurological disorders, eating disorders, Alzheimer's disease, alcohol dependence, diabetes, obesity and / or smoking cessation.

Las Patentes de Estados Unidos Nº 5.624.941, 6.028.084 y 6.509.367, las Publicaciones PCT Nº WO 98/31227, WO 98/41519, WO 98/43636 y WO 98/43635 y la Publicación Europea Nº EP 0 658 546 describen determinados pirazoles sustituidos que tienen actividad contra los receptores de canabinoides. Las Patentes de Estados Unidos Nº U.S. Patent Nos. 5,624,941, 6,028,084 and 6,509,367, PCT Publications No. WO 98/31227, WO 98/41519, WO 98/43636 and WO 98/43635 and European Publication No. EP 0 658 546 describe certain substituted pyrazoles that have activity against cannabinoid receptors. United States Patents No.

6.355.631 y 6.479.479 y las Publicaciones PCT Nº WO 01/64632, 01/64633 y 01/64634 desvelan determinados derivados de acetidina, que son antagonistas de canabinoides. 6,355,631 and 6,479,479 and PCT Publications No. WO 01/64632, 01/64633 and 01/64634 disclose certain acetidine derivatives, which are cannabinoid antagonists.

En las Patentes de Estados Unidos Nº 4.973.587, 5.013.837, 5.081.122, 5.112.820, 5.292.736 y 5.532.237 y en las Publicaciones PCT Nº WO97/29079,WO98/37061,WO99/02499, WO 00/10967, WO 00/10968, WO 01/58869, WO 01/70700, WO 02/076949, WO 03/026647, WO 03/026648, WO 03/027069, WO 03/027076, WO 03/027114, WO 03/077847, WO 03/088968, WO 04/13120, WO 04 /69837, WO 04/058145, WO 04/26301, WO 04/058744, WO 04/096763 y WO06/030124, se desvelan otros compuestos moduladores de receptores de canabinoides. In U.S. Patent Nos. 4,973,587, 5,013,837, 5,081,122, 5,112,820, 5,292,736 and 5,532,237 and in PCT Publications No. WO97 / 29079, WO98 / 37061, WO99 / 02499, WO 00 / 10967, WO 00/10968, WO 01/58869, WO 01/70700, WO 02/076949, WO 03/026647, WO 03/026648, WO 03/027069, WO 03/027076, WO 03/027114, WO 03 / 077847, WO 03/088968, WO 04/13120, WO 04/69837, WO 04/058145, WO 04/26301, WO 04/058744, WO 04/096763 and WO06 / 030124, other receptor modulating compounds are disclosed cannabinoids

Existe una necesidad insatisfecha para el tratamiento del abuso del alcohol. Los riesgos para la salud asociados con el alcoholismo incluyen deterioro del control motor y de la toma de decisiones, cáncer, enfermedad hepática, defectos congénitos, enfermedades cardiacas, interacciones fármaco/fármaco, pancreatitis y problemas interpersonales. Estudios realizados han sugerido que la modulación de canabinoides endógenos desempeña una función crítica en el control de la admisión del etanol. Se ha demostrado que el antagonista endógeno del receptor CB1, SR-141716A, bloquea la admisión voluntaria del etanol en ratas y ratones (Véase Arnone; M., y col., "Selective Inhibition of Sucrose and Ethanol Intakeby SR141716, an Antagonist of Central Cannabinoid (CB1) Receptors," Psychopharmacol, 132,104-106 (1997)). Para una revisión, véase, Hungund, B. L y B. S. Basavarajappa, "Are Anadamide and Cannabinoid Receptors involved in Ethanol Tolerance? A Review of the Evidence," Alcohol. & Alcoholism, 35(2) 126-133, 2000. There is an unmet need for the treatment of alcohol abuse. The health risks associated with alcoholism include impaired motor control and decision-making, cancer, liver disease, birth defects, heart disease, drug / drug interactions, pancreatitis and interpersonal problems. Studies have suggested that the modulation of endogenous cannabinoids plays a critical role in controlling the admission of ethanol. The endogenous CB1 receptor antagonist, SR-141716A, has been shown to block voluntary admission of ethanol in rats and mice (See Arnone; M., et al., "Selective Inhibition of Sucrose and Ethanol Intakeby SR141716, an Antagonist of Central Cannabinoid (CB1) Receptors, "Psychopharmacol, 132,104-106 (1997)). For a review, see, Hungund, B. L and B. S. Basavarajappa, "Are Anadamide and Cannabinoid Receptors involved in Ethanol Tolerance? A Review of the Evidence," Alcohol. & Alcoholism, 35 (2) 126-133, 2000.

Los tratamientos actuales para el abuso o dependencia del alcohol generalmente adolecen de incumplimiento o posible hepatotoxicidad. Existe una necesidad insatisfecha de tratamientos más eficaces de dependencia/abuso del alcohol. Current treatments for alcohol abuse or dependence generally suffer from non-compliance or possible hepatotoxicity. There is an unmet need for more effective alcohol dependence / abuse treatments.

También existe aún una necesidad de tratamientos terapéuticos más seguros y eficaces para enfermedades, afecciones y/o trastornos modulados por receptores de canabinoides (tales como dolor, obesidad), que incluyen los There is also a need for safer and more effective therapeutic treatments for diseases, conditions and / or disorders modulated by cannabinoid receptors (such as pain, obesity), which include

5 5

10 10

15 fifteen

20 twenty

25 25

30 30

35 35

40 40

45 Four. Five

modulados por los receptores CB1 o CB2. modulated by the CB1 or CB2 receptors.

Resumen de la Invención Summary of the Invention

La presente invención se refiere a moduladores del receptor canabinoide de la fórmula: The present invention relates to cannabinoid receptor modulators of the formula:

imagen2image2

y análogos de los mismos, sales farmacéuticamente aceptables de los mismos, ésteres farmacéuticamente aceptables de los mismos, tautómeros de los mismos, regioisómeros de los mismos, estereoisómeros de los mismos, enantiómeros de los mismos, diastereómeros de los mismos, polimorfos de los mismos y solvatos farmacéuticamente aceptables de los mismos, en los que cada una de las líneas de puntos en fórmula (1) representa independientemente un enlace opcional; U y V son independientemente C o N; W, Xe Y son independientemente C, N, O, S o -C(O)-con la condición de que al menos dos de U, V, W, X o Y se seleccionen independientemente entre N, O, -C(O)-o S; R, R1 y R2 pueden ser iguales o diferentes y son independientemente hidrógeno, nitro, ciano, formal, acetilo, halógeno, -OR3, -SR3, oxo, tio, 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, cicloalquenilalquilo sustituido o sin sustituir, arilo sustituido o sin sustituir, arilalquilo sustituido o sin sustituir, heteroarilo sustituido o sin sustituir, heteroarilalquilo sustituido o sin sustituir, grupo heterocíclico sustituido o sin sustituir, heterociclilalquilo sustituido o sin sustituir, -NR3R4, -C(=B)-R3, C(O)O-R3, -C(O)NR3R4, -S(O)m-R3, -S(O)m-NR3R4 o un grupo protector, o R1 y R2 pueden unirse para formar un anillo cíclico opcionalmente sustituido, saturado o insaturado de 3 a 7 miembros, que puede incluir opcionalmente al menos dos heteroátomos seleccionados entre O, NR3 o S; cada vez que aparecen R3 y R4 pueden ser iguales o diferentes y son independientemente hidrógeno, nitro, halo, ciano, -ORa, -SRa, oxo, tio, 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, cicloalquenilalquilo sustituido o sin sustituir, arilo sustituido o sin sustituir, arilalquilo sustituido o sin sustituir, heteroarilo sustituido o sin sustituir, heteroarilalquilo sustituido o sin sustituir, grupo heterocíclico sustituido o sin sustituir, heterociclilalquilo sustituido o sin sustituir, -C(=B)-Ra, -C(O)ORa, C(O)NRaRb, -S(O)m-Ra, -S(O)m-NRaRb -NR3Rb o un grupo protector, o R3 y R4, cuando se unen a un átomo en común, pueden unirse entre sí para formar un anillo cíclico opcionalmente sustituido, saturado o insaturado de 3 a 7 miembros, que puede incluir opcionalmente al menos dos heteroátomos seleccionados entre O, NR3 o S; cada vez que aparecen Ra y Rb pueden ser iguales o diferentes y son independientemente hidrógeno, halógeno, nitro, ciano, formilo, acetilo, oxo, tio, -C(O)-Rc, -C(O)O-Rc, -C(O)NRcRd , -S(O)m-Rc, -S(O)m-NRcRd, - NRcRd, -ORc, -SRc, un grupo protector, 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, cicloalquenilalquilo sustituido o sin sustituir, arilo sustituido o sin sustituir, arilalquilo sustituido o sin sustituir, heteroarilo sustituido o sin sustituir, grupo heterocíclico sustituido o sin sustituir, heterociclilalquilo sustituido o sin sustituir o heteroarilalquilo sustituido o sin sustituir; cada vez que aparecen Rc y Rd pueden ser iguales o diferentes y son independientemente hidrógeno, halógeno, nitro, ciano, formilo, acetilo, oxo, tio, un grupo protector, 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, cicloalquenilalquilo sustituido o sin sustituir, arilo sustituido o sin sustituir, arilalquilo sustituido o sin sustituir, heteroarilo sustituido o sin sustituir, grupo heterocíclico sustituido o sin sustituir, heterociclilalquilo sustituido o sin sustituir o heteroarilalquilo sustituido o sin sustituir; cada aparición de B es independientemente O, S o NR3; p y m son independientemente 0, 1 ó 2; A es and analogs thereof, pharmaceutically acceptable salts thereof, pharmaceutically esters. acceptable thereof, tautomers thereof, regioisomers thereof, stereoisomers thereof. same, enantiomers thereof, diastereomers thereof, polymorphs thereof and solvates pharmaceutically acceptable thereof, in which each of the dotted lines in formula (1) independently represents an optional link; U and V are independently C or N; W, X and Y are independently C, N, O, S or -C (O) - with the proviso that at least two of U, V, W, X or Y are independently selected from N, O, -C (O) -o S; R, R1 and R2 may be the same or different and are independently hydrogen, nitro, cyano, formal, acetyl, halogen, -OR3, -SR3, oxo, thio, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, alkynyl substituted or unsubstituted, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenyl alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclyl alkyl, -NR3R4, -C (= B) -R3, C (O) O-R3, -C (O) NR3R4, -S (O) m-R3, - S (O) m-NR3R4 or a protecting group, or R1 and R2 can join to form a optionally substituted, saturated or unsaturated cyclic ring of 3 to 7 members, which may include optionally at least two heteroatoms selected from O, NR3 or S; each time R3 and R4 appear they can be the same or different and are independently hydrogen, nitro, halo, cyano, -ORa, -SRa, oxo, thio, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, alkynyl substituted or unsubstituted, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenyl alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclyl alkyl, -C (= B) -Ra, -C (O) ORa, C (O) NRaRb, -S (O) m-Ra, -S (O) m -NRaRb -NR3Rb or a protecting group, or R3 and R4, when they bind to an atom in common, they can be joined together to form an optionally substituted, saturated or unsaturated cyclic ring of 3 to 7 members, which may optionally include at least two heteroatoms selected from O, NR3 or S; each time Ra and Rb appear they can be the same or different and are independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, -C (O) -Rc, -C (O) O-Rc, -C (O) NRcRd, -S (O) m-Rc, -S ( O) m-NRcRd, - NRcRd, -ORc, -SRc, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenyl alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group substituted, substituted or unsubstituted heterocyclylalkyl or substituted or unsubstituted heteroarylalkyl; each time Rc and Rd appear they can be the same or different and are independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, a protecting group, substituted or unsubstituted alkyl, alkenyl substituted or unsubstituted, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, cycloalkylalkyl substituted or unsubstituted, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenyl alkyl, aryl substituted or unsubstituted, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, group substituted or unsubstituted heterocyclic, substituted or unsubstituted heterocyclylalkyl or substituted heteroarylalkyl or without replacing; each occurrence of B is independently O, S or NR3; p and m are independently 0, 1 or 2; A is

imagen2image2

imagen2image2

5 5

10 10

15 fifteen

20 twenty

25 25

30 30

35 35

en las que: in which:

cada una de las líneas de puntos en A representa independientemente un enlace opcional; R5, R6, R7, R8, R9, R10, R11, R12, R13 y R14 son independientemente hidrógeno, nitro, ciano, formilo, acetilo, halógeno, -OR15 , -SR15, oxo, tio, 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, cicloalquenilalquilo sustituido o sin sustituir, arilo sustituido o sin sustituir, arilalquilo sustituido o sin sustituir, heteroarilo sustituido o sin sustituir, heteroarilalquilo sustituido o sin sustituir, grupo heterocíclico sustituido o sin sustituir, heterociclilalquilo sustituido o sin sustituir, -NR15R16 , -C(-B)-R15 , C(O)O-R15, -C(O)NR15R16, -S(O)m-R15, -S(O)m-NR15R16 o un grupo protector; R5 y R6 pueden unirse entre sí para formar un anillo mono-o bi-cíclico opcionalmente sustituido, saturado o insaturado de 3 a 11 miembros, que puede incluir opcionalmente al menos un heteroátomo seleccionado entre O, NR3 o S; R9 y R10 pueden unirse entre sí para formar un anillo mono-o bi-cíclico opcionalmente sustituido, saturado o insaturado de 3 a 11 miembros, que puede incluir opcionalmente al menos un heteroátomo seleccionado entre O, NR3 o S; R5 y R9 pueden unirse para formar un anillo mono-o bi-cíclico opcionalmente sustituido, saturado o insaturado de 3 a 11 miembros, que puede incluir opcionalmente al menos un heteroátomo seleccionado entre O, NR3 o S; R7 y R10 pueden unirse entre sí para formar un anillo mono-o bi-cíclico opcionalmente sustituido, saturado o insaturado de 3 a 11 miembros, que puede incluir opcionalmente al menos un heteroátomo seleccionado entre O, NR3 o S; cada vez que aparecen R15 y R16 pueden ser iguales o diferentes y son independientemente hidrógeno, nitro, halo, ciano, -OR3, -SR3, oxo, tio, 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, cicloalquenilalquilo sustituido o sin sustituir, arilo sustituido o sin sustituir, arilalquilo sustituido o sin sustituir, heteroarilo sustituido o sin sustituir, heteroarilalquilo sustituido o sin sustituir, grupo heterocíclico sustituido o sin sustituir, heterociclilalquilo sustituido o sin sustituir, -C(=B)-R3, -C(O)OR3, -C (O)NR3R4, -S(O)m-R3, -S(O)m-NR3R4, -NR3R4 o R15 y R16, cuando se unen a un átomo en común, pueden unirse entre sí para formar un anillo cíclico opcionalmente sustituido, saturado o insaturado de 3 a 7 miembros, que puede incluir opcionalmente al menos dos heteroátomos seleccionados entre O, NR3 o S, en el que R3 y R4 son como se han definido anteriormente; n es 1, 2,3 ó4; y a, b, c, d y e son números enteros seleccionados independientemente de 0 a 4. each of the dotted lines in A independently represents an optional link; R5, R6, R7, R8, R9, R10, R11, R12, R13 and R14 are independently hydrogen, nitro, cyano, formyl, acetyl, halogen, -OR15, -SR15, oxo, thio, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, alkynyl substituted or unsubstituted, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenyl alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclyl alkyl, -NR15R16, -C (-B) -R15, C (O) O-R15, -C (O) NR15R16, -S (O) m-R15, - S (O) m-NR15R16 or a protecting group; R5 and R6 can be joined together to form an optionally substituted, saturated or mono-or bi-cyclic ring unsaturated 3 to 11 members, which may optionally include at least one heteroatom selected from O, NR3 or S; R9 and R10 can be joined together to form an optionally substituted, saturated or mono-or bi-cyclic ring unsaturated 3 to 11 members, which may optionally include at least one heteroatom selected from O, NR3 or S; R5 and R9 can be joined to form an optionally substituted, saturated or unsaturated mono- or bi-cyclic ring 3 to 11 members, which may optionally include at least one heteroatom selected from O, NR3 or S; R7 and R10 can be joined together to form an optionally substituted, saturated or mono-or bi-cyclic ring unsaturated 3 to 11 members, which may optionally include at least one heteroatom selected from O, NR3 or S; each time R15 and R16 appear they can be the same or different and are independently hydrogen, nitro, halo, cyano, -OR3, -SR3, oxo, thio, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, alkynyl substituted or unsubstituted, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenyl alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclyl alkyl, -C (= B) -R3, -C (O) OR3, -C (O) NR3R4, -S (O) m-R3, -S (O) m-NR3R4, -NR3R4 or R15 and R16, when attached to a common atom, can be attached each other to form an optionally substituted, saturated or unsaturated cyclic ring of 3 to 7 members, which it may optionally include at least two heteroatoms selected from O, NR3 or S, wherein R3 and R4 are as defined above; n is 1, 2.3 or 4; Y a, b, c, d and e are whole numbers independently selected from 0 to 4.

con la condición de que el modulados no tenga la fórmula: with the proviso that the modulates do not have the formula:

imagen2image2

en la que R1 y R2 son como se han definido anteriormente. Se prefiere un compuesto de la fórmula general (1) en la que U y V son C. Se prefiereademás enel queYy Xson N yW es C. Se prefiere además en el que B en el grupo -C(B)NR1R2 es O. in which R1 and R2 are as defined above. A compound of the general formula (1) in which U and V are C is preferred. It is also preferred that Yy Xson N and W is C. It is further preferred in which B in the group -C (B) NR1R2 is O.

6 Se prefiere además en el que R es hidrógeno, alquilo sustituido o sin sustituir, arilo sustituido o sin sustituir. 6 It is further preferred in which R is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl.

Se prefiere además en el que R es metilo, fenilo, 2-clorofenilo, 4-clorofenilo, 2,4-diclorofenilo, 2-bromofenilo,4bromofenilo, 4-fluorofenilo, 2,4-difluorofenilo, 4-metilfenilo, 4-metoxifenilo, 2-(4-clorofenil)fenilo o 5-cloropiridin-2-ilo. It is further preferred in which R is methyl, phenyl, 2-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2-bromophenyl, 4bromophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 4-methylphenyl, 4-methoxyphenyl, 2- (4-chlorophenyl) phenyl or 5-chloropyridin-2-yl.

Se prefiere además en el que R1 es hidrógeno. It is further preferred in which R1 is hydrogen.

Se prefiere además en el que R2 es alquilo sustituido o sin sustituir; cicloalquilo sustituido o sin sustituir, cicloalquilalquilo sustituido o sin sustituir, arilo sustituido o sin sustituir, arilalquilo sustituido o sin sustituir, grupo heterocíclico sustituido o sin sustituir, grupo heteroarilo sustituido o sin sustituir, heteroarilalquilo sustituido o sin sustituir o NR3R4. It is further preferred in which R2 is substituted or unsubstituted alkyl; substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted heteroarylalkyl or NR3R4.

Se prefiere además en el que R2 es t-butilo, n-pentilo, ciclopentilo, ciclohexilo, adamantan-1-ilo, 2-metiladamantan-2ilo, 3-hidroxiadamantan-1-ilo, 1,3,3-trimetilbiciclo[2.2.1]hept-2-ilo, 1-fenilciclopropilo, ciclohexilmetilo, fenilo, 3clorofenilo, 4-clorofenilo, 3-bromofenilo; 2-metoxifenilo, 4-terc-butilfenilo, 2,4-difluorofenilo, bencilo, 2-clorobencilo, 4clorobencilo, 2,4-diclorobencilo, 2-fluorobencilo, 4-fluorobencilo, 2,4-difluorobencilo, 2,6-difluorobencilo, 2bromobencilo, 4-bromobencilo, 4-trifluorometilbencilo, 1-feniletilo, 1-metil-1-feniletilo, 2-feniletilo, 1-(2-clorofenil)etilo, 2(4-fluorofenil)etilo, 1-fenilpropilo, 1-etil-1-fenilpropilo, 1-(2-clorofenil)1-metiletilo, feniletanoato de metilo, 2-hidroxi-1feniletilo, piperidinilo, morfolinilo, piridinilo, 1,2,4-triazol-4-ilo, 2-piridilmetilo, 3-piridilmetilo o 4-piridilmetilo. It is further preferred in which R2 is t-butyl, n-pentyl, cyclopentyl, cyclohexyl, adamantan-1-yl, 2-methylamantan-2-yl, 3-hydroxyamantan-1-yl, 1,3,3-trimethylbicyclo [2.2. 1] hept-2-yl, 1-phenylcyclopropyl, cyclohexylmethyl, phenyl, 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl; 2-methoxyphenyl, 4-tert-butylphenyl, 2,4-difluorophenyl, benzyl, 2-chlorobenzyl, 4-chlorobenzyl, 2,4-dichlorobenzyl, 2-fluorobenzyl, 4-fluorobenzyl, 2,4-difluorobenzyl, 2,6-difluorobenzyl, 2-Bromobenzyl, 4-bromobenzyl, 4-trifluoromethylbenzyl, 1-phenylethyl, 1-methyl-1-phenylethyl, 2-phenylethyl, 1- (2-chlorophenyl) ethyl, 2 (4-fluorophenyl) ethyl, 1-phenylpropyl, 1-ethyl -1-phenylpropyl, 1- (2-chlorophenyl) 1-methyl ethyl, methyl phenylethanoate, 2-hydroxy-1-phenylethyl, piperidinyl, morpholinyl, pyridinyl, 1,2,4-triazol-4-yl, 2-pyridylmethyl, 3- pyridylmethyl or 4-pyridylmethyl.

Se prefiere además en el que R1 y R2 se unen entre sí para formar un anillo cíclico opcionalmente sustituido, saturado o insaturado de 3 a 7 miembros, que puede incluir opcionalmente al menos dos heteroátomos seleccionados entre O, NR3 o S. It is further preferred in which R1 and R2 join together to form an optionally substituted, saturated or unsaturated cyclic ring of 3 to 7 members, which may optionally include at least two heteroatoms selected from O, NR3 or S.

Se prefiere además en el que R1 y R2 junto con átomo de nitrógeno al que está unidos forman piperidin-1-ilo o morfolinilo (por ejemplo, morfolin-1-ilo). It is further preferred in which R1 and R2 together with the nitrogen atom to which they are attached form piperidin-1-yl or morpholinyl (for example, morpholin-1-yl).

Se prefiere además en el que R2 es NR3R4; en el que cada aparición de R3 y R4 pueden ser iguales o diferentes y son independientemente hidrógeno, alquilo sustituido o sin sustituir, cicloalquilo sustituido o sin sustituir, arilo sustituido o sin sustituir, heteroarilo sustituido o sin sustituir, o R3 y R4 se unen entre sí para formar un anillo cíclico opcionalmente sustituido, saturado o insaturado de 3 a 7 miembros, que puede incluir opcionalmente al menos dos heteroátomos seleccionados entre O, NR3 o S. It is further preferred in which R2 is NR3R4; wherein each occurrence of R3 and R4 may be the same or different and are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or R3 and R4 are linked between yes to form an optionally substituted, saturated or unsaturated cyclic ring of 3 to 7 members, which may optionally include at least two heteroatoms selected from O, NR3 or S.

Se prefiere además en el que R3 es hidrógeno, alquilo sustituido o sin sustituir, arilo sustituido o sin sustituir o cicloalquilo sustituido o sin sustituir. It is further preferred in which R 3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted cycloalkyl.

Se prefiere además en el que R3 es metilo, fenilo o ciclohexilo. It is further preferred in which R 3 is methyl, phenyl or cyclohexyl.

Se prefiere además en el que R4 se selecciona entre arilo sustituido o sin sustituir, heteroarilo sustituido o sin sustituir o cicloalquilo sustituido o sin sustituir. It is further preferred in which R4 is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted cycloalkyl.

R4R4

Se prefiere además en el que es fenilo, 2-clorofenilo, 4-clorofenilo, 2,4-diclorofenilo, 3,4-diclorofenilo, 2fluorofenilo, 3-fluorofenilo, 4-fluorofenilo, 2,4-difluorofenilo, 3,4-difluorofenilo, 2-bromofenilo, 3-cloropiridin-2-ilo, 5cloropiridin-2-ilo o ciclohexilo. It is further preferred where it is phenyl, 2-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl , 2-bromophenyl, 3-chloropyridin-2-yl, 5-chloropyridin-2-yl or cyclohexyl.

Se prefiere además en el que R2 es -NR3R4, en el que R3y R4 se unen entre sí para formar un anillo cíclico opcionalmente sustituido, saturado o insaturado de 3 a 7 miembros, que puede incluir opcionalmente al menos dos heteroátomos seleccionados entre O, NR3 o S; It is further preferred in which R2 is -NR3R4, in which R3 and R4 join together to form an optionally substituted, saturated or unsaturated cyclic ring of 3 to 7 members, which may optionally include at least two heteroatoms selected from O, NR3 or S;

Se prefiere además en el que R3 y R4 se unen entre sí para formar piperidin-1-ilo o morfolin-4-ilo. It is further preferred in which R3 and R4 join together to form piperidin-1-yl or morpholin-4-yl.

Se prefiere además en el que A es It is further preferred in which A is

imagen2image2

imagen2image2

en la que R5 a R14 son independientemente hidrógeno o metilo; y R8 es fenilo sin sustituir o sustituido. in which R5 to R14 are independently hydrogen or methyl; Y R8 is unsubstituted or substituted phenyl.

5 Se prefiere además en el que R8 es 4-clorofenilo. Se prefiere además en el que a = b = c = d = e = 1. Más preferentemente, U y V son C, X e Y son N, W es -C(O)NR1R2. Se prefiera demás p = 1. De acuerdo con una realización, cuando A es 1,7,7 trimetil-biciclo[2.2.1]heptano y p es 1, entonces R no representa 5 It is further preferred in which R8 is 4-chlorophenyl. It is further preferred in which a = b = c = d = e = 1. More preferably, U and V are C, X and Y are N, W is -C (O) NR1R2. Other p = 1 are preferred. According to one embodiment, when A is 1,7,7 trimethylbicyclo [2.2.1] heptane and p is 1, then R does not represent

fenilo sin sustituir. unsubstituted phenyl.

10 De acuerdo con una realización preferida, Y es N, U es C, uno de W, V y X es N y los dos C y B restantes en el grupo -C(B)NR1R2 es O, y A, R, R1 y R2 son como se han definido anteriormente. Otra realización un modulador de receptor canabinoide de Fórmula 1A. In accordance with a preferred embodiment, Y is N, U is C, one of W, V and X is N and the two remaining C and B in the group -C (B) NR1R2 is O, and A, R, R1 and R2 are as defined above. Another embodiment a cannabinoid receptor modulator of Formula 1A.

imagen2image2

o un análogo del mismos, sal farmacéuticamente aceptable del mismo, éster farmacéuticamente aceptable del or an analog thereof, pharmaceutically acceptable salt thereof, pharmaceutically acceptable ester of the

15 mismo, tautómero del mismo, regioisómero del mismo, estereoisómero del mismo, enantiómero del mismo, diastereómero del mismo, polimorfo del mismo o solvato farmacéuticamente aceptable del mismo, en la que R, R1 y R2 pueden ser iguales o diferentes y son independientemente hidrógeno, alquilo sustituido o sin sustituir, cicloalquilo sustituir o sin sustituir, cicloalquilalquilo sustituido o sin sustituir, arilo sustituido o sin The same, tautomer thereof, regioisomer thereof, stereoisomer thereof, enantiomer thereof, diastereomer thereof, polymorph thereof or pharmaceutically acceptable solvate thereof, in which R, R1 and R2 may be the same or different and are independently hydrogen. , substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl

20 sustituir, arilalquilo sustituido o sin sustituir, grupo heterocíclico sustituido o sin sustituir, grupo heteroarilo sustituido o sin sustituir o heteroarilalquilo sustituido o sin sustituir, o R1 y R2 pueden unirse para formar un anillo cíclico opcionalmente sustituido, saturado o insaturado de 3 a 7 miembros, que puede incluir opcionalmente al menos dos heteroátomos seleccionados entre O, NR3,S o NR3R4; cada aparición de R3 y R4 pueden ser iguales o diferentes y son independientemente hidrógeno, alquilo Substituted, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heteroaryl group or substituted or unsubstituted heteroarylalkyl, or R1 and R2 may be joined to form an optionally substituted, saturated or unsaturated cyclic ring of 3 to 7 members, which may optionally include at least two heteroatoms selected from O, NR3, S or NR3R4; Each occurrence of R3 and R4 can be the same or different and are independently hydrogen, alkyl

25 sustituido o sin sustituir, cicloalquilo sustituido o sin sustituir, arilo sustituido o sin sustituir, heteroarilo sustituido 25 substituted or unsubstituted, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted heteroaryl

o sin sustituir o grupo heterocíclico sustituido o sin sustituir o R3 y R4 pueden unirse para formar un anillo cíclico opcionalmente sustituido, saturado o insaturado de 3 a 7 miembros, que puede incluir opcionalmente al menos dos heteroátomos seleccionados entre O, NR3 o S; p es 1; y or unsubstituted or substituted or unsubstituted heterocyclic group or R3 and R4 may be joined to form an optionally substituted, saturated or unsaturated cyclic ring of 3 to 7 members, which may optionally include at least two heteroatoms selected from O, NR3 or S; p is 1; Y

30 A es en las que cada una de las líneas de puntos en A representa independientemente un enlace opcional, y en cada aparición, R5, R6, R7, R8, R9 R10, R11, R12, R13 y R14 son iguales o diferentes y se seleccionan entre hidrógeno, alquilo sustituido o sin sustituir o arilo sustituido o sin sustituir; con la condición de que el modulados no tenga la fórmula: 30 A is where each of the dotted lines in A independently represents an optional link, and at each occurrence, R5, R6, R7, R8, R9 R10, R11, R12, R13 and R14 are the same or different and are select from hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aryl; with the proviso that the modulates do not have the formula:

imagen2image2

imagen2image2

en la que R1 y R2 son como se han definido anteriormente. De acuerdo con una realización, cuando A es 1,7,7-trimetil-biciclo-[2.2.1]heptano y p es 1, entonces R no representa in which R1 and R2 are as defined above. According to one embodiment, when A is 1,7,7-trimethyl-bicyclo- [2.2.1] heptane and p is 1, then R does not represent

10 fenilo sustituido. 10 substituted phenyl.

De acuerdo con una realización preferida, R es arilo sustituido o sin sustituir. According to a preferred embodiment, R is substituted or unsubstituted aryl.

Se prefiere además en el que R es arilo sustituido con halógeno, alquilo sustituido o sin sustituir, alcoxi sustituido o It is further preferred in which R is halogen substituted aryl, substituted or unsubstituted alkyl, substituted alkoxy or

sin sustituir o arilo sustituido o sin sustituir. Se prefiere además en el que R es 2-clorofenilo, 4-clorofenilo, 2,4-diclorofenilo, 2-bromofenilo, 4-bromofenilo, 4unsubstituted or substituted or unsubstituted aryl. It is further preferred in which R is 2-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2-bromophenyl, 4-bromophenyl, 4

15 fluorofenilo, 2,4-difluorofenilo, 4-metilfenilo, 4-metoxifenilo o 2-(4-clorofenil)fenilo. 15 fluorophenyl, 2,4-difluorophenyl, 4-methylphenyl, 4-methoxyphenyl or 2- (4-chlorophenyl) phenyl.

Se prefiere además en el que R es 2,4-diclorofenilo o 2,4-difluorofenilo. It is further preferred in which R is 2,4-dichlorophenyl or 2,4-difluorophenyl.

Otra realización preferida es un modulador de receptor canabinoide de Fórmulas I(a) a I(g), en las que R, R1, R2 y R8 son como se han definido anteriormente y R en la fórmula 1(c) fenilo no es fenilo sin sustituir. Another preferred embodiment is a cannabinoid receptor modulator of Formulas I (a) to I (g), in which R, R1, R2 and R8 are as defined above and R in formula 1 (c) phenyl is not phenyl without replacing

imagen2image2

De acuerdo con una realización preferida, R es un grupo fenilo sustituido con al menos un átomo de halógeno. Más preferentemente, R es un grupo fenilo sustituido con uno o dos átomos de halógeno (por ejemplo, 2,4-difluorofenilo o 2,4-diclorofenilo). According to a preferred embodiment, R is a phenyl group substituted with at least one halogen atom. More preferably, R is a phenyl group substituted with one or two halogen atoms (for example, 2,4-difluorophenyl or 2,4-dichlorophenyl).

Otra realización más es un agonista selectivo de CB2 (es decir, un agonista de CB2 que no activa o inhibe sustancialmente el receptor de CB 1) que tiene la fórmula: Another embodiment is a selective CB2 agonist (i.e., a CB2 agonist that does not substantially activate or inhibit the CB 1 receptor) having the formula:

imagen2image2

10 en la que R, R1 y R2 son como se han definido anteriormente. R es preferentemente un arilo sustituido o sin sustituir, más preferentemente fenilo sustituido o sin sustituir, e incluso más preferentemente un fenilo sustituido. Aún más deseable, R es un grupo fenilo sustituido con uno o dos átomos de halógeno (por ejemplo, 2,4-difluorofenilo o 2,4diclorofenilo). Estos compuestos son particularmente útiles en el tratamiento de trastornos mediados por agonización del receptor de CB2, incluyendo, pero sin limitación, enfermedades oftálmicas, trastornos respiratorios, trastornos 10 in which R, R1 and R2 are as defined above. R is preferably a substituted or unsubstituted aryl, more preferably substituted or unsubstituted phenyl, and even more preferably a substituted phenyl. Even more desirable, R is a phenyl group substituted with one or two halogen atoms (for example, 2,4-difluorophenyl or 2,4-dichlorophenyl). These compounds are particularly useful in the treatment of disorders mediated by agonization of the CB2 receptor, including, but not limited to, ophthalmic diseases, respiratory disorders, disorders

15 inmunes (tales como trastornos autoinmunes), inflamación, dolor (tal como dolor neuropático) y síndromes relacionados neurodegenerativos. Por consiguiente, la presente invención también incluye procedimientos para tratar cualquiera de estos trastornos en un sujeto que lo necesita mediante la administración de una cantidad terapéuticamente eficaz de uno o más de los compuestos de fórmula 1(b). 15 immune (such as autoimmune disorders), inflammation, pain (such as neuropathic pain) and neurodegenerative related syndromes. Accordingly, the present invention also includes methods for treating any of these disorders in a subject in need thereof by administering a therapeutically effective amount of one or more of the compounds of formula 1 (b).

A continuación, se indican compuestos representativos de la presente invención sólo con carácter ilustrativo y no 20 limitan el alcancen de la invención. In the following, representative compounds of the present invention are indicated for illustrative purposes only and do not limit the scope of the invention.

101. 101.

N(7)-Piperidino-5-(2-bromofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxamida, N (7) -Piperidino-5- (2-bromophenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxamide,

102. 102

N(7)-Bencil-5-(2-bromofenil)-5,6-diazatetraciclo[7.3.1.13,11 .04,8]tetradeca-4(8),6-dieno-7-carboxamida, N (7) -Benzyl-5- (2-bromophenyl) -5,6-diazatetracycle [7.3.1.13.11 .04.8] tetradeca-4 (8), 6-diene-7-carboxamide,

103. 103.

N(7)-Morfolino-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11,04,8 tetradeca-4(8),6-dieno-7-carboxamida, N (7) -Morpholino-5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11,04,8 tetradeca-4 (8), 6-diene-7-carboxamide,

104. 104.

N(7)-(3-Piridilmetil)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,1104,8] tetradeca-4(8),6-dieno-7-carboxamida, N (7) - (3-Pyridylmethyl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,1104,8] tetradeca-4 (8), 6-diene-7-carboxamide,

105. 105.

N(7)-(4-Piridilmetil)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8] tetradeca-4(8),6-dieno-7-carboxamida, N (7) - (4-Pyridylmethyl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxamide,

106. 106.

N(7)-Ciclohexil-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,1104,8]tetradeca-4(8),6-dieno-7-carboxamida, N (7) -Cyclohexyl-5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,1104,8] tetradeca-4 (8), 6-diene-7-carboxamide,

107. 107.

N(7)-(N-Ciclohexil-N-metilamino)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7 N (7) - (N-Cyclohexyl-N-methylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7

carboxamida, carboxamide,

108. 108.

N(7)-Ciclohexilmetil-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11,04,7]tetradeca-4(8),6-dieno-7-carboxamida, N (7) -Cyclohexylmethyl-5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11,04,7] tetradeca-4 (8), 6-diene-7-carboxamide,

109. 109.

N(7)-(Adamantan-1-il)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-6-dieno-7 N (7) - (Adamantan-1-yl) -5- (4-chlorophenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8) -6-diene-7

carboxamida, carboxamide,

110. 110.

N(7)-(1S,2endo-1,3,3-Trimetil-biciclo[2.2.1]hept-2-il)-5-(4-clorofenil)-5,6diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-6-dieno-7-carboxamida, N (7) - (1S, 2endo-1,3,3-Trimethyl-bicyclo [2.2.1] hept-2-yl) -5- (4-chlorophenyl) -5,6diazatetracycle [7.3.1.13,11.04.8 ] tetradeca-4 (8) -6-diene-7-carboxamide,

111. 111.

N(7)-(2-Clorobencil)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxamida, N (7) - (2-Chlorobenzyl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxamide,

112. 112

N(7)-(4-Clorobencil)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-6-dieno-7-carboxamida, N (7) - (4-Chlorobenzyl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8) -6-diene-7-carboxamide,

113. 113.

N(7)-(4-Fluorobencil)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-6-dieno-7 N (7) - (4-Fluorobenzyl) -5- (4-chlorophenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8) -6-diene-7

carboxamida, carboxamide,

114. 114

N(7)-(2,4-Difluorobencil)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7 N (7) - (2,4-Difluorobenzyl) -5- (4-chlorophenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7

carboxamida, carboxamide,

115. 115

N(7)-(2,6-Difluorobencil)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7 N (7) - (2,6-Difluorobenzyl) -5- (4-chlorophenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7

carboxamida, carboxamide,

116. 116.

N(7)-(4-Trifluorometilbencil)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-di-eno-7 N (7) - (4-Trifluoromethylbenzyl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-di-eno-7

carboxamida, carboxamide,

117. 117.

N(7)-(1-Feniletil)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8] tetradeca-4(8),6-dieno-7-carboxamida, N (7) - (1-Phenylethyl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxamide,

118. 118.

N(7)-(R-1-Feniletil)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8] tetradeca-4(8),6-dieno-7-carboxamida, N (7) - (R-1-Phenylethyl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxamide,

119. 119.

N(7)-(1-Metil-1-feniletil)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-di-eno-7 N (7) - (1-Methyl-1-phenylethyl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-di-eno- 7

carboxamida, carboxamide,

120. 120.

N(7)-(2-Piridilmetil)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8] tetradeca-4(8),6-dieno-7-carboxamida, N (7) - (2-Pyridylmethyl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxamide,

121. 121.

N(7)-(N’-fenilamino)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7 N (7) - (N’-phenylamino) -5- (4-chlorophenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7

carboxamida, carboxamide,

122. 122.

Clorhidrato de N(7)-(N’-fenilamino)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno N (7) - (N’-phenylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene hydrochloride

7-carboxamida, 7-carboxamide,

123. 123

N(7)-(2-Clorofenilamino)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7 N (7) - (2-Chlorophenylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7

carboxamida, carboxamide,

124. 124.

Clorhidrato de N(7)-(2-Clorofenilamino)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6 N (7) - (2-Chlorophenylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6 hydrochloride

dieno-7-carboxamida, diene-7-carboxamide,

125. 125

N(7)-[4-clorofenilamino]-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7 N (7) - [4-chlorophenylamino] -5- (4-chlorophenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7

carboxamida, carboxamide,

126. 126.

N(7)-(2,4-Diclorofenilamino)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-di-eno-7 N (7) - (2,4-Dichlorophenylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-di-eno-7

carboxamida, carboxamide,

127. 127.

N(7)-[(2,4-Diclorofenil-N’-metilamino]-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6 N (7) - [(2,4-Dichlorophenyl-N’-methylamino] -5- (4-chlorophenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8), 6

dieno-7-carboxamida, diene-7-carboxamide,

128. 128.

Clorhidrato de N(7)-[(2,4-Diclorofenil-N’-metilamino]-5-(4-clorofenil)-5,6diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxamida, N (7) - [(2,4-Dichlorophenyl-N'-methylamino] -5- (4-chlorophenyl) -5,6diazatetracyclo [7.3.1.13.11.04.8] tetradeca-4 (8), 6- hydrochloride diene-7-carboxamide,

129. 129.

N(7)-(2,4-Diclorofenil-N’-ciclohexilamino)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6dieno-7-carboxamida, N (7) - (2,4-Dichlorophenyl-N'-cyclohexylamino) -5- (4-chlorophenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8), 6diene-7 -carboxamide,

130. 130.

N(7)-(4-Fluorofenilamino)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7carboxamida, N (7) - (4-Fluorophenylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7carboxamide,

131. 131.

Clorhidrato de N(7)-(4-Fluorofenilamino)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6dieno-7-carboxamida, N (7) - (4-Fluorophenylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxamide hydrochloride,

132. 132.

N(7)-(2,4-Difluorofenilamino]-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-di-eno-7carboxamida, N (7) - (2,4-Difluorophenylamino] -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-di-eno-7carboxamide,

133. 133

N(7)-(3-Fluorofenilamino)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7carboxamida, N (7) - (3-Fluorophenylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7carboxamide,

134. 134

N(7)-(3-Cloro-2-piridilamino)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-di-eno-7carboxamida, N (7) - (3-Chloro-2-pyridylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-di-eno- 7carboxamide,

135. 135

N(7)-(5-Cloro-2-piridilamino)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-di-eno-7carboxamida, N (7) - (5-Chloro-2-pyridylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-di-eno- 7carboxamide,

136. 136.

N(7)-(2-Feniletil)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8] tetradeca-4(8)-6-dieno-7-carboxamida, N (7) - (2-Phenylethyl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8) -6-diene-7-carboxamide,

137. 137.

N(7)-(N’,N’-Difenilamino)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7carboxamida, N (7) - (N ’, N’-Diphenylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7carboxamide,

138. 138.

N7-[1-(2-Clorofenil)etil]-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-di-eno-7carboxamida, N7- [1- (2-Chlorophenyl) ethyl] -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-di-eno-7carboxamide,

139. 139.

N(7)-Bencil-5-(4’-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-6-dieno-7-carboxamida, N (7) -Benzyl-5- (4’-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8) -6-diene-7-carboxamide,

140. 140.

N(7)-Piperidino-5-(4’-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8] tetradeca-4(8)-6-dieno-7-carboxamida, N (7) -Piperidino-5- (4’-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8) -6-diene-7-carboxamide,

141. 141.

7-(4’-Clorofenil)-6,7-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-5-dien-5-il-piperidinometanona, 7- (4’-Chlorophenyl) -6,7-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8) -5-dien-5-yl-piperidinometanone,

142. 142.

N(7)-Fenil-5-(4’-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-6-dieno-7-carboxamida, N (7) -Phenyl-5- (4’-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8) -6-diene-7-carboxamide,

143. 143.

N(7)-Piperidino-5-(2,4-difluorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8] tetradeca-4(8),6-dieno-7-carboxamida, N (7) -Piperidino-5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxamide,

144. 144.

N(7)-(Adamantan-1il)-5-(2,4-difluorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-6-dieno-7carboxamida, N (7) - (Adamantan-1-yl) -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8) -6-diene-7carboxamide,

145. 145.

N(7)-(1S,2endo-1,3,3-Trimetil-biciclo[2.2.1]hept-2il)-5-(2,4-difluorofenil)-5,6diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-6-dieno-7-carboxamida, N (7) - (1S, 2endo-1,3,3-Trimethyl-bicyclo [2.2.1] hept-2il) -5- (2,4-difluorophenyl) -5,6diazatetracycle [7.3.1.13,11.04,8 ] tetradeca-4 (8) -6-diene-7-carboxamide,

146 146

N(7)-(S-1-feniletil))-5-(2,4-difluorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7carboxamida, N (7) - (S-1-phenylethyl)) - 5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7carboxamide ,

147. 147.

N(7)-(R-1-feniletil)-5-(2,4-difluorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7carboxamida, N (7) - (R-1-phenylethyl) -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7carboxamide,

148. 148.

N(7)-(1-Metil-1-feniletil)-5-(2,4-difluorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-di-eno-7carboxamida, N (7) - (1-Methyl-1-phenylethyl) -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-di- eno-7carboxamide,

149. 149.

N(7)-(2-Clorobencil)-5-(2,4-difluorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7carboxamida, N (7) - (2-Chlorobenzyl) -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7carboxamide,

150. 150

N(7)-(2,4-Diclorofenilamino)-5-(2,4-difluorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno7-carboxamida, N (7) - (2,4-Dichlorophenylamino) -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene7-carboxamide,

151. 151.

N(7)-[1-(2-Clorofenil)etil]-5-(2,4-difluorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-di-eno-7carboxamida, N (7) - [1- (2-Chlorophenyl) ethyl] -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-di -eno-7carboxamide,

152. 152.

N(7)-[(S)-1-Fenilpropil]-5-(2,4-difluorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7carboxamida, N (7) - [(S) -1-Phenylpropyl] -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene- 7carboxamide,

153. 153.

N7-[1-(2-Clorofenil)-1-metiletil]-5-(2,4-difluorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4 (8),6-dieno7-carboxamida, N7- [1- (2-Chlorophenyl) -1-methylethyl] -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene7 -carboxamide,

154. 154

(2R)-2-[7-(2,4-Difluorofenil)-6,7-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),5-dien-5-ilcarboxamido]-2 (2R) -2- [7- (2,4-Difluorophenyl) -6,7-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8), 5-dien-5-ylcarboxamido] -2

feniletanoato de metilo, methyl phenylethanoate,

155. 155.

(2S)-2-[7-(2,4-diluorofenil)-6,7-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),5-dien-5-ilcarboxam-ido]-2feniletanoato de metilo, (2S) -2- [7- (2,4-dilorophenyl) -6,7-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8), 5-dien-5-ylcarboxam-gone] -2-phenylethanoate of methyl,

156. 156.

N7-(3-Hidroxiadamantan-1-il)-5-(2,4-difluorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7carboxamida, N7- (3-Hydroxiadamantan-1-yl) -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7carboxamide,

157. 157.

N(7)-(1-Metil-1-feniletil)-5-(4-fluorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7carboxamida, N (7) - (1-Methyl-1-phenylethyl) -5- (4-fluorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7carboxamide,

158. 158.

N(7)-(Adamantan-1-il)-5-(2,4-difluorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-6-dieno-7carboxamida, N (7) - (Adamantan-1-yl) -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8) -6-diene-7carboxamide,

158a N7-(Adamantan-2-il)-5-(4-fluorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7carboxamida, 158a N7- (Adamantan-2-yl) -5- (4-fluorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7carboxamide,

159. 159.

N7-(1,3,3-Trimetilbiciclo[2.2.1]hept-2il)-5-(4-fluorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6dieno-7-carboxamida, N7- (1,3,3-Trimethylbicyclo [2.2.1] hept-2il) -5- (4-fluorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6diene -7-carboxamide,

160. 160

N(7)-Piperidino-5-(4-metilfenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxamida, N (7) -Piperidino-5- (4-methylphenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxamide,

161. 161.

N(7)-(2,4-Diclorofenilamino)-5-(4-metilfenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-di-eno-7carboxamida, N (7) - (2,4-Dichlorophenylamino) -5- (4-methylphenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-di-eno-7carboxamide,

162. 162.

N(7)-(2-Clorobencil)-5-(4-metilfenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxamida, N (7) - (2-Chlorobenzyl) -5- (4-methylphenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxamide,

163. 163.

N(7)-Piperidino-5-(4-metoxifenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8] tetradeca-4(8),6-dieno-7-carboxamida, N (7) -Piperidino-5- (4-methoxyphenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxamide,

164. 164.

N7-(2-Clorobencil)-5-(4-metoxifenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxamida, N7- (2-Chlorobenzyl) -5- (4-methoxyphenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxamide,

165. 165.

N(7)-(2,4-Diclorofenilamino)-5-(4-metoxifenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7carboxamida, N (7) - (2,4-Dichlorophenylamino) -5- (4-methoxyphenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7carboxamide,

166. 166.

N(7)-Piperidino-5-[(2-clorofenil)fenil]-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7carboxamida, N (7) -Piperidino-5 - [(2-chlorophenyl) phenyl] -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7carboxamide,

167. 167.

N(7)-[(2,4-Diclorofenil)amino]-5-fenil-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7carboxamida, N (7) - [(2,4-Dichlorophenyl) amino] -5-phenyl-5,6-diazatetracycle [7.3.1.13,11.04.8] tetradeca-4 (8), 6-diene-7carboxamide,

168. 168.

N(7)-Fenil-5-fenil-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-6-dieno-7-carboxamida, N (7) -Phenyl-5-phenyl-5,6-diazatetracycle [7.3.1.13.11.04.8] tetradeca-4 (8) -6-diene-7-carboxamide,

169. 169.

N(7)-piperidino-5-fenil-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-6-dieno-7-carboxamida, N (7) -piperidino-5-phenyl-5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8) -6-diene-7-carboxamide,

170. 170.

N(7)-Bencil-5-fenil-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-6-dieno-7-carboxamida, N (7) -Benzyl-5-phenyl-5,6-diazatetracycle [7.3.1.13.11.04.8] tetradeca-4 (8) -6-diene-7-carboxamide,

171. 171.

N(7)-fenil-6,7-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-5-dien-5-il-piperidinometanona, N (7) -phenyl-6,7-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8) -5-dien-5-yl-piperidinometanone,

172. 172.

N(7)-(4-Fluorobencil)-5-(2,4-diclorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7carboxamida, N (7) - (4-Fluorobenzyl) -5- (2,4-dichlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7carboxamide,

173. 173.

N(7)-Fenilamino-5-(2,4-diclorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxamida, N (7) -Phenylamino-5- (2,4-dichlorophenyl) -5,6-diazatetracyclo [7.3.1.13.11.04.8] tetradeca-4 (8), 6-diene-7-carboxamide,

174. 174.

N(7)-(2-Clorofenilamino)-5-(2,4-diclorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-di-eno-7carboxamida, N (7) - (2-Chlorophenylamino) -5- (2,4-dichlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-di-eno-7carboxamide,

175. 175.

N(7)-(2,4-Diclorofenilamino)-5-(2,4-diclorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7carboxamida, N (7) - (2,4-Dichlorophenylamino) -5- (2,4-dichlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7carboxamide,

176. 176.

N(7)-(2-Bromofenilamino)-5-(2,4-diclorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-di-eno-7carboxamida, N (7) - (2-Bromophenylamino) -5- (2,4-dichlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-di-eno-7carboxamide,

177. 177.

N(7)-(N’,N’-Difenilamino)-5-(2,4-diclorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7carboxamida, N (7) - (N ', N'-Diphenylamino) -5- (2,4-dichlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene- 7carboxamide,

178. 178.

N(7)-(2-Feniletil)-5-(2,4-diclorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxamida, N (7) - (2-Phenylethyl) -5- (2,4-dichlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxamide,

179. 179.

N(7)-Bencil-5-(2’,4’-diclorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8] tetradeca-4(8)-6-dieno-7-carboxamida, N (7) -Benzyl-5- (2 ’, 4’-dichlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8) -6-diene-7-carboxamide,

180. 180

N(7)-piperidino-5-(2’,4’-diclorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxamida, N (7) -piperidino-5- (2 ’, 4’-dichlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxamide,

181. 181

N(7)-(2,4-Diclorofenilamino)-5-(2-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-di-eno-7carboxamida, N (7) - (2,4-Dichlorophenylamino) -5- (2-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-di-eno-7carboxamide,

182. 182.

N(7)-Bencil-5-(2’-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-6-dieno-7-carboxamida, N (7) -Benzyl-5- (2’-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8) -6-diene-7-carboxamide,

183. 183

N(7)-ciclohexil-5-(2-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-6-dieno-7-carboxamida, N (7) -cyclohexyl-5- (2-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8) -6-diene-7-carboxamide,

184. 184

N(7)-piperidino-5-(2’-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8] tetradeca-4(8)-6-dieno-7-carboxamida, N (7) -piperidino-5- (2’-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8) -6-diene-7-carboxamide,

185. 185.

N7-(2-Clorobencil)-5-(5-cloro-2-piridil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7carboxamida, N7- (2-Chlorobenzyl) -5- (5-chloro-2-pyridyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7carboxamide,

186. 186.

N(7)-Bencil-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-6-dieno-7-carboxamida, N (7) -Benzyl-5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8) -6-diene-7-carboxamide,

187. 187

N(7)-piperidino-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-6-dieno-7-carboxamida, N (7) -piperidino-5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8) -6-diene-7-carboxamide,

188. 188.

6,7-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-5-dien-5-il-piperidinometanona, 189a N(7)-piperidino-6-metil-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-6 dieno-7-carboxamida, 189b N(7)-piperidino-5-metil-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-6 dieno-7-carboxamida, 190a N(7)-(1-metil-1-feniletil)-6-pentil-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4,7-dieno-7-carboxamida, 190b N(7)-(1-metil-1-feniletil)-5-pentil-5,6-diazatetraciclo[7.3.1.13,11.04,8] tetradeca-4(8)-6-dieno-7-carboxamida, 191 N(7)-[(1R)-2-Hidroxi-1-feniletil]-5-(2,4-diflurofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno6,7-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8) -5-dien-5-yl-piperidinometanone, 189a N (7) -piperidino-6-methyl-5,6-diazatetracycle [7.3 .1.13,11.04,8] tetradeca-4 (8) -6 diene-7-carboxamide, 189b N (7) -piperidino-5-methyl-5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8) -6 diene-7-carboxamide, 190a N (7) - (1-methyl-1-phenylethyl) -6-pentyl-5,6-diazatetracycle [7.3.1.13.11.04.8] tetradeca-4.7 -diene-7-carboxamide, 190b N (7) - (1-methyl-1-phenylethyl) -5-pentyl-5,6-diazatetracyclo [7.3.1.13.11.04.8] tetradeca-4 (8) -6- diene-7-carboxamide, 191 N (7) - [(1R) -2-Hydroxy-1-phenylethyl] -5- (2,4-diflurophenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene

7-carboxamida, 7-carboxamide,

192. N(7)-[(1S)-2-Hidroxi-1-feniletil]-5-(2,4-difluorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno7-carboxamida, 192. N (7) - [(1S) -2-Hydroxy-1-phenylethyl] -5- (2,4-difluorophenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8 ), 6-diene7-carboxamide,

201. 201.

N(3)-Piperidino-1-fenil-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) -Piperidino-1-phenyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

202. 202.

N(3)-Ciclohexil-1-fenil-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) -Cyclohexyl-1-phenyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

203. 203

N(3)-Bencil-1-fenil-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) -Benzyl-1-phenyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

204. 204.

N(3)-Fenilamino-1-fenil-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) -Phenylamino-1-phenyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

205. 205.

N(3)-Piperidino-1-(2-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) -Piperidino-1- (2-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

206. 206.

N(3)-Ciclohexil-1-(2-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) -Cyclohexyl-1- (2-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

207. 207.

N(3)-Bencil-1-(2-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) -Benzyl-1- (2-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

208. 208.

N(3)-Fenilamino-1-(2-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) -Phenylamino-1- (2-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

209. 209

N(3)-Piperidino-1-(4-clorofenil)-4,5,6,7-tetrahidro=1H-4,7-metano-indazol-3-carboxamida, N (3) -Piperidino-1- (4-chlorophenyl) -4,5,6,7-tetrahydro = 1H-4,7-methane-indazol-3-carboxamide,

210. 210.

1-(4-Clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-il-piperidino metanona, 1- (4-Chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-yl-piperidino methanone,

211. 211.

N(3)-Ciclohexil-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) -Cyclohexyl-1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

212. 212.

N(3)-Ciclopentil-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) -Cyclopentyl-1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

213. 213

N(3)-[(N-Ciclohexil-N-metil)amino]-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - [(N-Cyclohexyl-N-methyl) amino] -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

214. 214.

N(3)-Fenil-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) -Phenyl-1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

215. 215.

N(3)-(3-Clorofenil)-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - (3-Chlorophenyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

216. 216.

N(3)-(4-Clorofenil)-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - (4-Chlorophenyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

217. 217

N(3)-(3-Bromofenil)-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - (3-Bromophenyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

218. 218.

N(3)-(2-Metoxifenil)-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - (2-Methoxyphenyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

219. 219.

N(3)-(4-terc-Butilfenil)-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - (4-tert-Butylphenyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

220. 220.

N(3)-Bencil-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7metano-indazol-3-carboxamida, N (3) -Benzyl-1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7methane-indazol-3-carboxamide,

221. 221

N(3)-(2-Clorobencil)-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - (2-Chlorobenzyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

222. 222

N(3)-(4-Clorobencil)-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - (4-Chlorobenzyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

223. 223

N(3)-(2,4-Diclorobencil)-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - (2,4-Dichlorobenzyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

224. 224

N(3)-(2,4-Diclorobencil)-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-indazol-3-carboxamida, N (3) - (2,4-Dichlorobenzyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-indazol-3-carboxamide,

225. 225.

N(3)-(4-Bromobencil)-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - (4-Bromobenzyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

226. 226

N(3)-(4-Fluorobencil)-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - (4-Fluorobenzyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

227. 227

N(3)-(4-Trifluorometilbencil)-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - (4-Trifluoromethylbenzyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

228. 228

N(3)-Fenilamino-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) -Phenylamino-1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

229. 229

N(3)-[(4-Clorofenil)amino]-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - [(4-Chlorophenyl) amino] -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

230. 230.

N(3)-[(2,4-Diclorofenil)amino]-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - [(2,4-Dichlorophenyl) amino] -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

231. 231.

N(3)-[(3,4-Diclorofenil)amino]-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - [(3,4-Dichlorophenyl) amino] -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

232. 232.

N(3)-[(2-Fluorofenil)amino]-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - [(2-Fluorophenyl) amino] -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

233. 233

N(3)-[(3-Fluorofenil)amino]-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - [(3-Fluorophenyl) amino] -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

234. 2. 3. 4.

N(3)-[(4-Fluorofenil)amino]-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - [(4-Fluorophenyl) amino] -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

235. 235

N(3)-[(2,4-Difluorofenil)amino]-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - [(2,4-Difluorophenyl) amino] -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

236. 236.

N(3)-(N’,N’-Difenilamino-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - (N ’, N’-Diphenylamino-1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

237. 237

N(3)-Ciclohexil-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) -Cyclohexyl-1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

238. 238.

N(3)-Ciclohexilmetil-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) -Cyclohexylmethyl-1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

239. 239

N(3)-(N,N-Diciclohexilamino)-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - (N, N-Dicyclohexylamino) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

240. 240.

N(3)-(4H-1,2,4-triazol-4-il)-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - (4H-1,2,4-triazol-4-yl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazole -3-carboxamide,

241. 241

N(3)-(1,3,3-Trimetil biciclo[2.2.1]hept-2-il)-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-in-dazol-3 N (3) - (1,3,3-Trimethyl bicyclo [2.2.1] hept-2-yl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4, 7-methane-in-dazol-3

carboxamida, carboxamide,

242. 242

N(3)-(Adamantan-1il)-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - (Adamantan-1il) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

243. 243

N(3)-Fenil-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) -Phenyl-1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

244. 244

N(3)-(2,4-Difluorofenil)-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - (2,4-Difluorophenyl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

245. 245

N(3)-(2-Fluorobencil)-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - (2-Fluorobenzyl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

246. 246

N(3)-(4-Fluorobencil)-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - (4-Fluorobenzyl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

247. 247

N(3)-(2,4-Difluorobencil)-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - (2,4-Difluorobenzyl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

248. 248

N(3)-(2,6-Difluorobencil)-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - (2,6-Difluorobenzyl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

249. 249

N(3)-(2-Clorobencil)-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - (2-Chlorobenzyl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

250. 250

N(3)-(4-Clorobencil)-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - (4-Chlorobenzyl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

251. 251

N(3)-(2,4-Diclorobencil)-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - (2,4-Dichlorobenzyl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

252. 252

N(3)-[S-(1-feniletil)]-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - [S- (1-phenylethyl)] - 1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

253. 253

N(3)-[R-(1-feniletil)]-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - [R- (1-phenylethyl)] - 1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

254. 254

N(3)-(2-feniletil)-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - (2-phenylethyl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

255. 255

N(3)-[2-(4-fluorofenil)etil]-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - [2- (4-fluorophenyl) ethyl] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

256. 256.

N(3)-Fenilamino-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) -Phenylamino-1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

257. 257

N(3)-[(2-Clorofenil)amino]-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - [(2-Chlorophenyl) amino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

258. 258

N(3)-[N-(2-Clorofenil)-N-metilamino]-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3 N (3) - [N- (2-Chlorophenyl) -N-methylamino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3

carboxamida, carboxamide,

259. 259

N(3)-[(4-Clorofenil)amino]-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - [(4-Chlorophenyl) amino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

260. 260.

N(3)-[(2,4-Diclorofenil)amino]-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - [(2,4-Dichlorophenyl) amino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

261. 261

N(3)-[(2,4-diclorofenil)-N-metilamino]-1-(2,4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3 N (3) - [(2,4-dichlorophenyl) -N-methylamino] -1- (2,4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3

carboxamida, carboxamide,

262. 262

N(3)-[3,4-Diclorofenil)amino]-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - [3,4-Dichlorophenyl) amino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

263. 263

N(3)-[(2-Bromofenil)amino]-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - [(2-Bromophenyl) amino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

264. 264

N(3)-[(2-Fluorofenil)amino]-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - [(2-Fluorophenyl) amino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

265. 265

N(3)-[(2,4-Difluorofenil)amino]-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - [(2,4-Difluorophenyl) amino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

266. 266

N(3)-[(3-Fluorofenil)amino]-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - [(3-Fluorophenyl) amino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

267. 267

N(3)-[(3-cloropiridin-2-il)amino]-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - [(3-Chloropyridin-2-yl) amino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3- carboxamide,

268. 268

N(5)-piperidino-3-(2’,4’-diclorofenil)-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxamida, N (5) -piperidino-3- (2 ’, 4’-dichlorophenyl) -3,4-diazatricyclo [5.2.1.02.6] deca-2 (6), 4-dien-5-carboxamide,

269. 269

N(5)-bencil-3-(2’,4’-diclorofenil)-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxamida, N (5) -benzyl-3- (2 ’, 4’-dichlorophenyl) -3,4-diazatricyclo [5.2.1.02.6] deca-2 (6), 4-dien-5-carboxamide,

270. 270.

N(3)-Piperidino-1-(2-bromofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) -Piperidino-1- (2-bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

271. 271

N(3)-Ciclohexil-1-(2-bromofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) -Cyclohexyl-1- (2-bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

272. 272

N(3)-Bencil-1-(2-bromofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) -Benzyl-1- (2-bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

273. 273

N(3)-Fenilamino-1-(2-bromofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) -Phenylamino-1- (2-bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

274. 274

N(3)-Piperidino-1-(4-bromofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) -Piperidino-1- (4-bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

275. 275

N(3)-Ciclohexil-1-(4-bromofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) -Cyclohexyl-1- (4-bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

276. 276

N(3)-Bencil-1-(4-bromofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) -Benzyl-1- (4-bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

277. 277

N(3)-Fenilamino-1-(4-bromofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) -Phenylamino-1- (4-bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

278. 278.

N(3)-[(2-Fluorofenil)amino]-1-(4-bromofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - [(2-Fluorophenyl) amino] -1- (4-bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

279. 279.

N(3)-Ciclohexil-1-(4-fluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) -Cyclohexyl-1- (4-fluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

280. 280.

N(3)-Bencil-1-(4-fluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) -Benzyl-1- (4-fluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

281. 281

N5-(Adamantan-2-il)-3-(4-fluorofenil)-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxamida, N5- (Adamantan-2-yl) -3- (4-fluorophenyl) -3,4-diazatricyclo [5.2.1.02.6] deca-2 (6), 4-dien-5-carboxamide,

282. 282

N5-(1-Metil-1-feniletil)-3-(4-fluorofenil)-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxamida, N5- (1-Methyl-1-phenylethyl) -3- (4-fluorophenyl) -3,4-diazatricyclo [5.2.1.02.6] deca-2 (6), 4-dien-5-carboxamide,

283. 283

N5-(Adamantan-1-il)-3-(4-fluorofenil)-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxamida, N5- (Adamantan-1-yl) -3- (4-fluorophenyl) -3,4-diazatricyclo [5.2.1.02.6] deca-2 (6), 4-dien-5-carboxamide,

284. 284

N(3)-Fenilamimo-1-(4-fluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) -Phenylamimo-1- (4-fluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

285. 285

N(3)-Fenilamino-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-1,7-metano-indazol-3-carboxamida, N (3) -Phenylamino-1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-1,7-methane-indazol-3-carboxamide,

286. 286

N(3)-[(2-Clorofenil)amino]-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - [(2-Chlorophenyl) amino] -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

287. 287

N(3)-[(2-Bromofenil)amino]-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - [(2-Bromophenyl) amino] -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

288. 288

N(3)-[(2-Fluorofenil)amino]-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - [(2-Fluorophenyl) amino] -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

289. 289

N(3)-Piperidino-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) -Piperidino-1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

290. 290.

N(3)-Ciclohexil-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) -Cyclohexyl-1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

291. 291.

N(3)-(Ciclohexilmetil)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - (Cyclohexylmethyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

292. 292

N(3)-[S-(1-Feniletil)]-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - [S- (1-Phenylethyl)] - 1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

293. 293

N(3)-(R-1-feniletil)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - (R-1-phenylethyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

294. 294

N(3)-(1-Metil-1-feniletil)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - (1-Methyl-1-phenylethyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

295. 295

N5-[1-(2-Clorofenil)-1-metiletil]-3-(2,4-difluorofenil)-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5 N5- [1- (2-Chlorophenyl) -1-methylethyl] -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5.2.1.02.6] deca-2 (6), 4-dien-5

carboxamida, carboxamide,

296. 296.

N(3)-(1,3,3-Trimetilbiciclo[2.2.1]hept-2-il)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-in-dazol-3 N (3) - (1,3,3-Trimethylbicyclo [2.2.1] hept-2-yl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7 -methane-in-dazol-3

carboxamida, carboxamide,

297. 297

N5-(2-Clorobencil)-3-(2,4-dfluorofenil)-3,4-diazatriciclo[2,2,1,02,6]deca-2(6),4-dien-5-carboxamida, N5- (2-Chlorobenzyl) -3- (2,4-dfluorophenyl) -3,4-diazatricyclo [2,2,1,02,6] deca-2 (6), 4-dien-5-carboxamide,

298. 298.

N5-(4-Clorobencil)-3-(2,4-difluorofenil)-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxamida, N5- (4-Chlorobenzyl) -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5.2.1.02.6] deca-2 (6), 4-dien-5-carboxamide,

299. 299.

N5-(1-Etil-1-fenilpropil)-3-(2,4-difluorofenil)-3,4-diazatriciclo[5.2.1.02 6]deca-2(6),4-dien-5-carboxamida, N5- (1-Ethyl-1-phenylpropyl) -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5.2.1.02 6] deca-2 (6), 4-diene-5-carboxamide,

300. 300

N5-[(1S)-1-Fenilpropil]-3-(2,4-difluorofenil)-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxamida, N5 - [(1S) -1-Phenylpropyl] -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5.2.1.02.6] deca-2 (6), 4-diene-5-carboxamide,

301. 301

(2S)-2-[5-(2,4-Difluorofenil)-4,5-diazatriciclo[5.2.1.0,2,6]deca-2(6),3-dien-3-ilcarboxamido]-2-feniletanoato de (2S) -2- [5- (2,4-Difluorophenyl) -4,5-diazatricyclo [5.2.1.0,2,6] deca-2 (6), 3-dien-3-ylcarboxamido] -2-phenylethanoate from

metilo, methyl,

302. 302

N5-[(1S)-2-Hidroxi-1-feniletil]-3-(2,4-difluorofenil)-3,4-diazatriciclo[5.2.1.0,2,6]deca-2(6),4-dien-5 N5 - [(1S) -2-Hydroxy-1-phenylethyl] -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5.2.1.0,2,6] deca-2 (6), 4-dien -5

carboxamida, carboxamide,

303. 303

N(3)-(terc-Butil)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - (tert-Butyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

304. 304.

(4R,7S)-o (4S,7R)-N(3)-(terc-Butil)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3 (4R, 7S) -o (4S, 7R) -N (3) - (tert-Butyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7- methane-indazol-3

carboxamida, carboxamide,

305. 305

(4S,7R) o (4R,7S) N(3)-(terc-Butil)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3 (4S, 7R) or (4R, 7S) N (3) - (tert-Butyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane- indazol-3

carboxamida, carboxamide,

306. 306

N5-n-Pentil-3-(2,4-difluorofenil)-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxamida, N5-n-Pentyl-3- (2,4-difluorophenyl) -3,4-diazatricyclo [5.2.1.02.6] deca-2 (6), 4-dien-5-carboxamide,

307. 307

N5-(2,4-Diclorobencil)-3-(2,4-difluorofenil)-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxamida, N5- (2,4-Dichlorobenzyl) -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5.2.1.02.6] deca-2 (6), 4-dien-5-carboxamide,

308. 308

N5-(1-fenilciclopropil)-3-(2,4-difluorofenil)-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxamida, N5- (1-phenylcyclopropyl) -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5.2.1.02.6] deca-2 (6), 4-dien-5-carboxamide,

309. 309

N5-(2-Adamantil)-3-(2,4-difluorofenil)-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxamida, N5- (2-Adamantyl) -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5.2.1.02.6] deca-2 (6), 4-dien-5-carboxamide,

310. 310.

N5-(2-Metil-2-adamantil)-3-(2,4-difluorofenil)-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxamida, N5- (2-Methyl-2-adamantyl) -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5.2.1.02.6] deca-2 (6), 4-diene-5-carboxamide,

311. 311

N7-(3-Hidroxiadamantan-1-il)-5-(2,4-difluorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7 N7- (3-Hydroxiadamantan-1-yl) -5- (2,4-difluorophenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7

carboxamida, carboxamide,

312. 312

4-[5-(2,4-Difluorofenil)-4,5-diazatriciclo[5.2.1.02,6]deca-2(6),3-dien-3-ilcarboxamido]morfolina, 4- [5- (2,4-Difluorophenyl) -4,5-diazatricyclo [5.2.1.02.6] deca-2 (6), 3-dien-3-ylcarboxamido] morpholine,

313. 313

N(3)-(terc-Pentil)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - (tert-Pentyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

314. 314

N(3)-Ciclopropanmetil-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) -Cyclopropanmethyl-1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

315. 315

N(3)-Ciclobutil-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) -Cyclobutyl-1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

316. 316

N(3)-(Tetrahidro-2H-4-piranmetil)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3 N (3) - (Tetrahydro-2H-4-pyranmethyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3

carboxamida, carboxamide,

317. 317

N(3)-Ciclopropil-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) -Cyclopropyl-1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

318. 318

N(3)-(4-metilpiperazino)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - (4-methylpiperazino) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

319. 319.

(2R)-2-[5-(2,4-difluorofenil)-4,5-diazatriciclo[5.2.1.0,2,6]deca-2(6),3-dien-3-ilcarboxamido]-2-feniletanoato (2R) -2- [5- (2,4-difluorophenyl) -4,5-diazatricyclo [5.2.1.0,2,6] deca-2 (6), 3-dien-3-ylcarboxamido] -2-phenylethanoate

de metilo, of methyl,

320. 320.

N(3)-[(1R)-2-Hidroxi-1-feniletil]-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - [(1R) -2-Hydroxy-1-phenylethyl] -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3 -carboxamide,

321. 321.

N(3)-(terc-Butil)-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - (tert-Butyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

322. 322

N(3)-(Tetrahidro-2-furanilmetil)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - (Tetrahydro-2-furanylmethyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

323. 323

N(3)-(terc-Butil)-1-(4-fluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - (tert-Butyl) -1- (4-fluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

324. 324

N(3)-(terc-Butil)-1-(4-bromofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - (tert-Butyl) -1- (4-bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

325. 325.

N(3)-(terc-Butil)-1-(3,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - (tert-Butyl) -1- (3,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

326. 326

(2S)-2-[5-(2,4-difluorofenil)-4,5-diazatriciclo[5.2.1.0,2,6]deca-2(6),3-dien-3-ilcarboxamido]-2-(4fluorofenil)etanoato de metilo, (2S) -2- [5- (2,4-difluorophenyl) -4,5-diazatricyclo [5.2.1.0,2,6] deca-2 (6), 3-dien-3-ylcarboxamido] -2- ( 4-Fluorophenyl) methyl ethanoate,

327. 327

N(3)-(terc-Buil)-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - (tert-Buil) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

328. 328

N(3)-(4-Hidroxifenil)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - (4-Hydroxyphenyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

329. 329.

N(3)-(terc-Butil)-1-(2-etoxi,4-fluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - (tert-Butyl) -1- (2-ethoxy, 4-fluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

330. 330.

N(3)-(2furilmetil)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida: N (3) - (2-Furylmethyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide:

331. 331.

N(3)-(2-tiofenometil)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida: N (3) - (2-thiophenomethyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide:

332. 332

N(3)-[(1S)-2-Hidroxi-1-(4-fluorofenil)etil]-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3carboxamida: N (3) - [(1S) -2-Hydroxy-1- (4-fluorophenyl) ethyl] -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7- methane-indazol-3carboxamide:

333. 333.

(2S)-2-[5-(2,4-difluorofenil)-4,5-diazatriciclo[5.2.1.0,2,6]deca-2(6),3-dien-3-ilcarboxamido]-4-metilpentanoato de metilo: (2S) -2- [5- (2,4-difluorophenyl) -4,5-diazatricyclo [5.2.1.0,2,6] deca-2 (6), 3-dien-3-ylcarboxamido] -4-methylpentanoate of methyl:

334. 334.

N(3)-(Adamantan-1il)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida: 335a. N(3)-(terc-butil)-1-(4-fluorobencil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida: 335b. N(3)-(terc-butil)-2-(4-fluorobencil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida: 336a. N(3)-(terc-butil)-1-(4-metilbencil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida: 336b. N(3)-(terc-butil)-2-(4-metilbencil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida: N (3) - (Adamantan-1yl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide: 335a. N (3) - (tert-butyl) -1- (4-fluorobenzyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide: 335b. N (3) - (tert-butyl) -2- (4-fluorobenzyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide: 336a. N (3) - (tert-butyl) -1- (4-methylbenzyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide: 336b. N (3) - (tert-butyl) -2- (4-methylbenzyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide:

337. 337.

N(3)-(2-Hidroxietil)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - (2-Hydroxyethyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

338. 338.

N(3)-(Tieniletil)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - (Thienylethyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

339. 339

N(3)-(Isopropil)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - (Isopropyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

340. 340.

N(3)-[(1S)-2-Metoxi-1-feniletil]-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) - [(1S) -2-Methoxy-1-phenylethyl] -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3 -carboxamide,

401. 401

N(3)-Fenil-1-(2,4-diclorofenil)-7,8,8-trimetil-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) -Phenyl-1- (2,4-dichlorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

402. 402

N(3)-[(2-Fluorofenil)amino]-1-(2,4-Diclorofenil)-7,8,8-trimetil-4,5,6,7-tetrahidro-1H-4,7-metano-in-dazol-3carboxamida, N (3) - [(2-Fluorophenyl) amino] -1- (2,4-Dichlorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methane- in-dazol-3carboxamide,

403. 403

N(3)-[(2,4-Difluorofenil)amino]-1-(2,4-Diclorofenil)-7,8,8-trimetil-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3carboxamida, N (3) - [(2,4-Difluorophenyl) amino] -1- (2,4-Dichlorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7- methane-indazol-3carboxamide,

404. 404.

N(3)-[(3-cloropiridin-2-il)amino]-1-(2,4-Diclorofenil)-7,8,8-trimetil-4,5,6,7-tetrahidro-1H-4,7-metano-indazol3-carboxamida, N (3) - [(3-Chloropyridin-2-yl) amino] -1- (2,4-Dichlorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4, 7-methane-indazol3-carboxamide,

405. 405

N(3)-(Adamantan-1il)-1-(2,4-difluorofenil)-7,8,8-trimetil-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3carboxamida, N (3) - (Adamantan-1yl) -1- (2,4-difluorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3carboxamide ,

406. 406

N(3)-(1,3,3-Trimetilbiciclo[2.2.1]hept-2-il)-1-(2,4-difluorofenil)-7,8,8-trimetil-4,5,6,7-tetrahidro-1H-4,7-metanoindazol-3-carboxamida, N (3) - (1,3,3-Trimethylbicyclo [2.2.1] hept-2-yl) -1- (2,4-difluorophenyl) -7,8,8-trimethyl-4,5,6,7 -tetrahydro-1H-4,7-methanoindazol-3-carboxamide,

407. 407

N(3)-(1-Metil-1-feniletil))-1-(2,4-difluorofenil)-7,8,8-trimetil-4,5,6,7-tetrahidro-1H-4,7-metano-in-dazol-3carboxamida, N (3) - (1-Methyl-1-phenylethyl)) - 1- (2,4-difluorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7- methane-in-dazol-3carboxamide,

408. 408

(4R,7S)-N(3)-terc-Butil-1-(2,4-difluorofenil)-7,8,8-trimetil-4,5,6,7-tetrahidro-1H-metano-indazol-3carboxamida, (4R, 7S) -N (3) -terc-Butyl-1- (2,4-difluorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-methane-indazol-3carboxamide ,

409. 409

(2R)-2-[1-(2,4-Difluorofenil)-7,8,8-trimetil-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamido]-2feniletanoato de metilo, (2R) -2- [1- (2,4-Difluorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamido] - 2-methylphenylethanoate,

410. 410.

N(3)-[(1R)-2-Hidroxi-1-feniletil]-1-(2,4-difluorofenil)-7,8,8-trimetil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol3-carboxamida, N (3) - [(1R) -2-Hydroxy-1-phenylethyl] -1- (2,4-difluorophenyl) -7,8,8-trimethyl) -4,5,6,7-tetrahydro-1H- 4,7-methane-indazol3-carboxamide,

411. 411

(4S,7R)N(3)-terc-Butil-1-(2,4-difluorofenil)-7,8,8-trimetil-4,5,6,7-tetrahidro-1H-metano-indazol-3(4S, 7R) N (3) -terc-Butyl-1- (2,4-difluorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-methane-indazol-3

carboxamida, carboxamide,

412. 412

N(3)-pentil-1-(2,4-difluorofenil)-7,8,8-trimetil-4,5,6,7-tetrahidro-1H-metano-indazol-3-carboxamida N (3) -pentyl-1- (2,4-difluorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-methane-indazol-3-carboxamide

501. 501

N(12)-Bencil-10-(2,4-diclorofenil)-10,11-diazatetraciclo[6.5.2.02,7.09,13]pentadeca-2,4,6,9(13),11-pentaeno12-carboxamida, N (12) -Benzyl-10- (2,4-dichlorophenyl) -10,11-diazatetracycle [6.5.2.02,7.09,13] pentadeca-2,4,6,9 (13), 11-pentaeno12-carboxamide,

502. 502

N(12)-Piperidino-10-(2,4-diclorofenil)-10,11-diazatetraciclo[6,5,202,7.09,13]pentadeca-2,4,6,9(13),11pentaeno-12-carboxamida, N (12) -Piperidino-10- (2,4-dichlorophenyl) -10,11-diazatetracyclo [6,5,202,7.09,13] pentadeca-2,4,6,9 (13), 11pentaeno-12-carboxamide,

503. 503

Clorhidrato de N(12)-Piperidino-10-(2,4-diclorofenil)-10,11-diazatetraciclo[6.5.2.02,7.09,13]pentadeca2,4,6,9(13),11-pentaen-12-carboxamida, N (12) -Piperidino-10- (2,4-dichlorophenyl) -10,11-diazatetracyclo [6.5.2.02,7.09,13] pentadeca2,4,6,9 (13), 11-pentaen-12- hydrochloride carboxamide,

504. 504

N(12)-[(N’-Ciclohexil-N’-metil)amino]-10-(2,4-diclorofenil)-10,11-diazatetraciclo[6.5.2.02,7.09,13]pentadeca2,4,6,9(13),11-pentaeno-12-carboxamida, N (12) - [(N'-Cyclohexyl-N'-methyl) amino] -10- (2,4-dichlorophenyl) -10,11-diazatetracycle [6.5.2.02,7.09,13] pentadeca2,4,6, 9 (13), 11-pentaeno-12-carboxamide,

505. 505

N(12)-{N’-[(2,4-Diclorofenil)-N’metil]amino}-10-(2,4-diclorofenil)-10,11diazatetraciclo[6.5.2.02,7,09,13]pentadeca-2,4,6,9(13),11-pentaeno-12-carboxamida, N (12) - {N '- [(2,4-Dichlorophenyl) -N'methyl] amino} -10- (2,4-dichlorophenyl) -10,11 diazatetracyclo [6.5.2.02,7,09,13] pentadeca -2,4,6,9 (13), 11-pentaeno-12-carboxamide,

506. 506

N(12)-(Adamantan-1il)-10-(2,4-diclorofenil)-10,11-diazatetraciclo[6.5.2.02,7.09,13]pentadeca-2,4,6,9(13),11pentaeno-12-carboxamida, N (12) - (Adamantan-1il) -10- (2,4-dichlorophenyl) -10,11-diazatetracycle [6.5.2.02,7.09,13] pentadeca-2,4,6,9 (13), 11pentaeno- 12-carboxamide,

507. 507

N12-(1,3,3-Trimetilbiciclo[2.2.1]hept-2-il)-10-(2,4-diclorofenil)-10,11diazatetraciclo[6.5.2.02,7.09,13]pentadeca-2(7),3,5,9(13),11-pentaeno-12-carboxamida, N12- (1,3,3-Trimethylbicyclo [2.2.1] hept-2-yl) -10- (2,4-dichlorophenyl) -10,11 diazatetracycle [6.5.2.02,7.09,13] pentadeca-2 (7) , 3,5,9 (13), 11-pentaeno-12-carboxamide,

508. 508

N12-(1-Metil-1-feniletil)-10-(2,4,diclorofenil)-10,11-diazatetraciclo[6.5.2.02,7.09,13]pentadeca-2,4,6,9(13),11pentaeno-12-carboxamida, N12- (1-Methyl-1-phenylethyl) -10- (2,4, dichlorophenyl) -10,11-diazatetracyclo [6.5.2.02,7.09,13] pentadeca-2,4,6,9 (13), 11pentaeno -12-carboxamide,

509. 509

N12-(1-Metil-1-feniletil)-10-(2,4-difluorofenil)-10,11-diazatetraciclo[6.5.2.02,7.09,13]pentadeca-2,4,6,9(13),11pentaeno-12-carboxamida, N12- (1-Methyl-1-phenylethyl) -10- (2,4-difluorophenyl) -10,11-diazatetracyclo [6.5.2.02,7.09,13] pentadeca-2,4,6,9 (13), 11pentaeno -12-carboxamide,

601. 601

N(12)-Bencil-16-(4-clorofenil)-10-(2,4-diclorofenil)-15,17-dioxo-10,11,16-triazapentaciclo[6.5.5.02,7 09,13.014,18]octadeca-2,4,6,9(13),11-pentaeno-12-carboxamida, N (12) -Benzyl-16- (4-chlorophenyl) -10- (2,4-dichlorophenyl) -15,17-dioxo-10,11,16-triazapentacyclo [6.5.5.02.7 09,13,014,18] octadeca-2,4,6,9 (13), 11-pentaeno-12-carboxamide,

602. 602

N(12)-Piperidino-16-(4-clorofenil)-10-(2,4-diclorofenil)-15,17-dioxo-10,11,16triazapentaciclo[6.5.5.02,7,09,13,014,18]octadeca-2,4,6,9(13),11-pentaeno-12-carboxamida, N (12) -Piperidino-16- (4-chlorophenyl) -10- (2,4-dichlorophenyl) -15,17-dioxo-10,11,16triazapentacyclo [6.5.5.02,7,09,13,014,18] octadeca -2,4,6,9 (13), 11-pentaeno-12-carboxamide,

701. 701

N12-Bencil-10-(2,4-difluorofenil)-10,11-diazatetraciclo[6.5.1.0.2,7.09,13] tetradeca-2,4,6,9(13),11-pentaeno-12carboxamida, N12-Benzyl-10- (2,4-difluorophenyl) -10,11-diazatetracyclo [6.5.1.0.2,7.09,13] tetradeca-2,4,6,9 (13), 11-pentane-12carboxamide,

702. 702

N(12)-terc-Butil-10-(2,4-difluorofenil)-10,11-diazatetraciclo[6.5.1.02,7.09,13]tetradeca-2,4,6,9(13),11-pentaeno12-carboxamida, N (12) -terc-Butyl-10- (2,4-difluorophenyl) -10,11-diazatetracycle [6.5.1.02,7.09,13] tetradeca-2,4,6,9 (13), 11-pentaeno12- carboxamide,

703. 703

N12-(1-Metil-1-feniletil)-10-(2,4-difluorofenil)-10,11-diazatetraciclo[6.5.1.02,7.09,13]tetradeca-2,4,6,9(13),11pentaeno-12-carboxamida, N12- (1-Methyl-1-phenylethyl) -10- (2,4-difluorophenyl) -10,11-diazatetracyclo [6.5.1.02,7.09,13] tetradeca-2,4,6,9 (13), 11pentaeno -12-carboxamide,

801. 801

N5-(terc-Butil)-3-(2,4-difluorofenil)-3,4-diazatriciclo[5.2.2.02,6]undeca-2(6),4-dien-5-carboxamida, N5- (tert-Butyl) -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5.2.2.02.6] undeca-2 (6), 4-dien-5-carboxamide,

802. 802.

N(5)-(terc-Pentil)-3-(2,4-difluorofenil)-3,4-diazatriciclo[5.2.2.2,6]undeca-2(6),4-dien-5-carboxamida. N (5) - (tert-Pentyl) -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5.2.2.2,6] undeca-2 (6), 4-dien-5-carboxamide.

imagen2image2

imagen2image2

imagen2image2

imagen2image2

imagen2image2

imagen2image2

imagen2image2

imagen2image2

imagen2image2

imagen2image2

imagen2image2

imagen2image2

imagen2image2

imagen2image2

imagen2image2

imagen2image2

imagen2image2

imagen2image2

imagen2image2

imagen2image2

imagen2image2

imagen2image2

imagen2image2

Otra realización de la invención es una composición farmacéutica que comprende al menos un compuesto de la presente invención y un excipiente farmacéuticamente aceptable (tal como un vehículo o diluyente farmacéuticamente aceptable). Preferentemente, la composición farmacéutica comprende una cantidad Another embodiment of the invention is a pharmaceutical composition comprising at least one compound of the present invention and a pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent). Preferably, the pharmaceutical composition comprises an amount

5 terapéuticamente eficaz del compuesto o compuestos de la presente invención. Therapeutically effective compound or compounds of the present invention.

Otra realización adicional es un procedimiento para prevenir, mejorar o tratar una enfermedad, trastorno o síndrome (tal como una enfermedad, trastorno o síndrome mediado por la interacción con el receptor CB1 o CB 2) mediado por receptores de canabinoides, en un sujeto que lo necesita, que comprende administrar al sujeto una cantidad terapéuticamente eficaz de un compuesto de la presente invención. Another additional embodiment is a procedure to prevent, ameliorate or treat a disease, disorder or syndrome (such as a disease, disorder or syndrome mediated by interaction with the CB1 or CB2 receptor) mediated by cannabinoid receptors, in a subject that it needs, which comprises administering to the subject a therapeutically effective amount of a compound of the present invention.

10 Dichas afecciones incluyen, pero sin limitación, trastornos relacionados con el apetito, trastornos metabólicos, trastornos catabólicos, diabetes, obesidad, enfermedades oftálmicas, enfermedades relacionadas con el ámbito social, trastornos anímicos, vértigos, abuso de sustancias nocivas, trastornos relacionados con el aprendizaje, trastornos cognitivos, trastornos relacionados con la memoria, contracción de órganos, espasmos musculares, trastornos y enfermedades respiratorias, trastornos relacionados con la actividad locomotora, discinesias, trastornos 10 Such conditions include, but are not limited to, appetite-related disorders, metabolic disorders, catabolic disorders, diabetes, obesity, ophthalmic diseases, social-related diseases, mood disorders, dizziness, harmful substance abuse, learning-related disorders , cognitive disorders, memory related disorders, organ contraction, muscle spasms, respiratory disorders and diseases, disorders related to locomotor activity, dyskinesias, disorders

15 inmunitarios, (tales como trastornos autoinmunitarios), inflamación, crecimiento celular, síndromes relacionados con dolor y neurodegenerativos. 15 immune, (such as autoimmune disorders), inflammation, cell growth, pain-related and neurodegenerative syndromes.

Una afección preferida es el dolor, enfermedades oftálmicas, trastornos respiratorios, trastornos inmunológicos (tales como trastornos autoinmunológicos), inflamación, crecimiento celular y síndromes neurodegenerativos relacionados. A preferred condition is pain, ophthalmic diseases, respiratory disorders, immunological disorders (such as autoimmune disorders), inflammation, cell growth and related neurodegenerative syndromes.

Otra realización adicional es un procedimiento para prevenir, mejorar o tratar un trastorno relacionado con el apetito, Another additional embodiment is a procedure to prevent, improve or treat an appetite-related disorder,

20 un trastorno relacionado con el ámbito social, un síndrome, trastorno o enfermedad autoinmunitario o relacionado con inflamación, dolor o neurodegenerativo, o abuso de sustancias nocivas, en un sujeto que lo necesita, administrando al sujeto una cantidad terapéuticamente eficaz de un compuesto de la presente invención. 20 a disorder related to the social field, an autoimmune syndrome, disorder or disease or related to inflammation, pain or neurodegenerative, or abuse of harmful substances, in a subject in need, administering to the subject a therapeutically effective amount of a compound of the present invention

Otra realización adicional es un procedimiento para prevenir, mejorar o tratar una enfermedad, trastorno o síndrome relacionado con el apetito, tal como obesidad, un estado de sobrepeso, anorexia, bulimia, caquexia, apetito mal regulado, un síndrome, trastorno, enfermedad o síntoma relacionado con obesidad (que incluye, pero sin limitación, obesidad como un resultado de un síndrome, trastorno o enfermedad genética, dieta, volumen de consumo de alimento, metabólico, trastorno o enfermedad hipotalámico, envejecimiento, distribución anómala de la masa adiposa, distribución anómala del compartimento adiposo, un trastorno alimenticio compulsivo o un trastorno motivacional que incluye el deseo de consumir azúcar, hidratos de carbono, alcohol o fármacos o cualquier ingrediente con valor hedónico y/o actividad reducida) en un sujeto que lo necesita, administrando al sujeto una cantidad terapéuticamente eficaz de un compuesto de la presente invención. Another additional embodiment is a procedure to prevent, ameliorate or treat an appetite-related disease, disorder or syndrome, such as obesity, an overweight state, anorexia, bulimia, cachexia, poorly regulated appetite, a syndrome, disorder, disease or symptom. related to obesity (which includes, but is not limited to, obesity as a result of a syndrome, disorder or genetic disease, diet, volume of food consumption, metabolic, disorder or hypothalamic disease, aging, abnormal distribution of fat mass, abnormal distribution of the adipose compartment, a compulsive eating disorder or a motivational disorder that includes the desire to consume sugar, carbohydrates, alcohol or drugs or any ingredient with hedonic value and / or reduced activity) in a subject in need, administering to the subject a therapeutically effective amount of a compound of the present invention.

Otra realización adicional es un procedimiento para prevenir, mejorar o tratar una enfermedad, trastorno o síndrome relacionado con el ámbito social, que incluye, pero sin limitación, depresión y sus tipos, depresión bipolar, depresión unipolar, episodios depresivos principales sencillos o recurrentes con o sin características psicóticas, características catatónicas, características melancólicas, características atípicas o que aparecen después del parto, trastorno afectivo estacional, trastornos distímicos con aparición temprana o tardía y con o sin características atípicas, depresión neurótica y fobia social, depresión acompañada de demencia, ansiedad, psicosis, trastornos afectivos sociales y/o trastornos cognitivos, en un sujeto que lo necesita, administrando al sujeto una cantidad terapéuticamente eficaz de un compuesto de la presente invención. Another additional embodiment is a procedure to prevent, ameliorate or treat a disease, disorder or syndrome related to the social field, which includes, but is not limited to, depression and its types, bipolar depression, unipolar depression, simple or recurrent major depressive episodes with or no psychotic characteristics, catatonic characteristics, melancholic characteristics, atypical characteristics or appearing after childbirth, seasonal affective disorder, dysthymic disorders with early or late onset and with or without atypical characteristics, neurotic depression and social phobia, depression accompanied by dementia, anxiety, psychosis, social affective disorders and / or cognitive disorders, in a subject in need thereof, administering to the subject a therapeutically effective amount of a compound of the present invention.

Otra realización adicional es un procedimiento para prevenir, mejorar o tratar una enfermedad, trastorno o síndrome autoinmune o relacionado con inflamación que incluye, pero sin limitación, psoriasis, lupus eritematoso, enfermedades del tejido conjuntivo, síndrome de Sjögren, espondiloartritis anquilosante; artritis reumatoide; artritis reactiva; espondiloartritis indiferenciada, enfermedad de Behcet, anemias hemolíticas autoinmunes, esclerosis múltiple, esclerosis amiotrófica lateral, amilosis, rechazo de injerto o enfermedades que afectan a la estirpe celular plasmática, enfermedades alérgicas (tales como hipersensibilidad tardía o inmediata, rinitis alérgica, dermatitis por contacto o conjuntivitis alérgica) enfermedades parasitarias, virales o bacterianas infecciosas (tales como SIDA y meningitis), enfermedades inflamatorias (tales como enfermedades de las articulaciones, que incluyen, pero sin limitación, artritis, artritis reumatoide, osteoartritis, espondilitis, gota, vasculitis, enfermedad de Crohn, enfermedad inflamatoria intestinal (EII), síndrome del intestino irritable (SII)) y osteoporosis, en un sujeto que lo necesita, administrando al sujeto una cantidad terapéuticamente eficaz de un compuesto de la presente invención. Another additional embodiment is a procedure to prevent, ameliorate or treat an autoimmune or inflammation-related disease, disorder or syndrome that includes, but is not limited to, psoriasis, lupus erythematosus, connective tissue diseases, Sjögren's syndrome, ankylosing spondyloarthritis; rheumatoid arthritis; reactive arthritis; undifferentiated spondyloarthritis, Behcet's disease, autoimmune hemolytic anemias, multiple sclerosis, lateral amyotrophic sclerosis, amylosis, graft rejection or diseases that affect plasma cell line, allergic diseases (such as late or immediate hypersensitivity, allergic rhinitis, contact dermatitis allergic conjunctivitis) infectious parasitic, viral or bacterial diseases (such as AIDS and meningitis), inflammatory diseases (such as joint diseases, including, but not limited to, arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis, disease of Crohn, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS) and osteoporosis, in a subject in need, administering to the subject a therapeutically effective amount of a compound of the present invention.

Otra realización adicional es un procedimiento para prevenir, mejorar o tratar el dolor o un síndrome, trastorno o enfermedad neurodegenerativo relacionado, que incluye, pero sin limitación, dolor mediado por la ruta central y periférica, dolor óseo y articular, dolor asociado con migraña, dolor por cáncer, dolor dental, dismenorrea, dolor por parto, dolor crónico de tipo inflamatorio, dolor asociado con alergias, artritis reumatoide, dermatitis o inmunodeficiencia, dolor crónico neuropático (que incluye dolor asociado con neuropatía diabética, ciática, dolor lumbar inespecífico, fibromialgia y neuropatía relacionada con el VIH), neuralgia postherpética, neuralgia trigémina, dolor resultante por traumatismo físico, amputación, cáncer, toxinas o afecciones crónicas inflamatorias, enfermedad de Hodgkin, miastenia grave, síndrome nefrótico, esclerodermia y tiroiditis, en un sujeto que lo necesita, administrando al sujeto una cantidad terapéuticamente eficaz de un compuesto de la presente invención. Another additional embodiment is a procedure to prevent, ameliorate or treat pain or a syndrome, related neurodegenerative disorder or disease, which includes, but is not limited to, pain mediated by the central and peripheral route, bone and joint pain, pain associated with migraine, cancer pain, dental pain, dysmenorrhea, labor pain, chronic inflammatory pain, pain associated with allergies, rheumatoid arthritis, dermatitis or immunodeficiency, chronic neuropathic pain (including pain associated with diabetic neuropathy, sciatica, non-specific low back pain, fibromyalgia and HIV-related neuropathy), postherpetic neuralgia, trigeminal neuralgia, pain resulting from physical trauma, amputation, cancer, toxins or chronic inflammatory conditions, Hodgkin's disease, myasthenia gravis, nephrotic syndrome, scleroderma and thyroiditis, in a subject in need , administering to the subject a therapeutically effective amount of a c of the present invention.

Otra realización adicional es un procedimiento para prevenir, mejorar o tratar un síndrome, trastorno o enfermedad relacionado con el abuso de sustancias nocivas, que incluye, pero sin limitación, abuso de sustancias nocivas y síndrome de abstinencia de sustancias nocivas, en el que, por ejemplo, la sustancia nociva de abuso o dependencia es alcohol, anfetaminas, sustancias similares a anfetaminas, cafeína, marihuana, cocaína, alucinógenos, inhalantes, opioides, nicotina (y/o productos relacionados con el tabaco), abuso de heroína, barbitúricos, fenciclidina (o compuestos similares a fenciclidina), hipnóticos sedantes, benzodiacepinas o combinaciones de sustancias nocivas, en un sujeto que lo necesita, administrando al sujeto una cantidad terapéuticamente eficaz de un compuesto de la presente invención. Another additional embodiment is a procedure to prevent, ameliorate or treat a syndrome, disorder or disease related to the abuse of harmful substances, which includes, but is not limited to, abuse of harmful substances and withdrawal of harmful substances, in which, by For example, the harmful substance of abuse or dependence is alcohol, amphetamines, amphetamine-like substances, caffeine, marijuana, ***e, hallucinogens, inhalants, opioids, nicotine (and / or tobacco-related products), heroin abuse, barbiturates, phencyclidine (or compounds similar to phencyclidine), sedative hypnotics, benzodiazepines or combinations of harmful substances, in a subject in need thereof, administering to the subject a therapeutically effective amount of a compound of the present invention.

Otra realización adicional es un procedimiento para reducir el deseo de fumar en un sujeto que lo necesita, administrando al sujeto una cantidad terapéuticamente eficaz de un compuesto de la presente invención. Another additional embodiment is a method of reducing the desire to smoke in a subject in need thereof, by administering to the subject a therapeutically effective amount of a compound of the present invention.

Otra realización adicional es un procedimiento para tratar la dependencia, adición, síndrome de abstinencia de la nicotina o para ayudar a dejar de fumar o abandonar el hábito del tabaco, en un sujeto que lo necesita, administrando al sujeto una cantidad terapéuticamente eficaz de un compuesto de la presente invención. Another additional embodiment is a procedure to treat dependence, addition, nicotine withdrawal syndrome or to help quit smoking or quit smoking in a subject in need, administering to the subject a therapeutically effective amount of a compound. of the present invention.

Otra realización más es un procedimiento para preparar un compuesto de fórmula (1), en la que Y es N, U es C, uno de W, V y X es N y los dos restantes son C, B es O, y A, R, R1, R2 y p son como se han definido anteriormente. El procedimiento incluye la etapa de acoplar una amina de la fórmula HNR1R2 con un compuesto de la fórmula: Another embodiment is a process for preparing a compound of formula (1), in which Y is N, U is C, one of W, V and X is N and the remaining two are C, B is O, and A, R, R1, R2 and p are as defined above. The process includes the step of coupling an amine of the formula HNR1R2 with a compound of the formula:

imagen2image2

en la que L2 es un grupo saliente, para formar el compuesto de fórmula (1). wherein L2 is a leaving group, to form the compound of formula (1).

Otra realización más es un procedimiento para preparar un compuesto de fórmula (1), en la que W e Y son N, U, V y X son C, B es O y A, R, R1, R2 y p son como se han definido anteriormente. El procedimiento incluye las etapas de: Another embodiment is a process for preparing a compound of formula (1), in which W and Y are N, U, V and X are C, B is O and A, R, R1, R2 and p are as defined previously. The procedure includes the steps of:

(a) oxidar un compuesto de fórmula K: (a) oxidize a compound of formula K:

para producir un compuesto de fórmula B: to produce a compound of formula B:

imagen2image2

(b) (b)

someter el compuesto de fórmula B a aminación reductora para formar la diamina vecinal de fórmula C: subject the compound of formula B to reductive amination to form the neighborhood diamine of formula C:

(c) (C)

monoacilar la diamina vecinal de fórmula C para formar una mono N-acil diamina de fórmula D: monoacrylate the neighborhood diamine of formula C to form an N-acyl diamine monkey of formula D:

imagen2image2

imagen2image2

en la que pg es a grupo protector; in which pg is the protecting group;

(d) (d)

someter el compuesto de fórmula D a ciclación para formar un compuesto de fórmula E: subject the compound of formula D to cyclization to form a compound of formula E:

(e) deshidrogenar el compuesto de fórmula E para formar un compuesto de fórmula F: (e) dehydrogenating the compound of formula E to form a compound of formula F:

(f) (F)

derivatizar el compuesto de la forma F para formar el compuesto G1, compuesto G2 o una mezcla de los mismos: derivatize the compound of form F to form compound G1, compound G2 or a mixture thereof:

(g) (g)

hidrolizar el compuesto G1, compuesto G2 o ambos para formar el compuesto H1, compuesto H2 o ambos: Hydrolyze compound G1, compound G2 or both to form compound H1, compound H2 or both:

imagen2image2

imagen2image2

imagen2image2

imagen2image2

y Y

(h) acoplar una amina de la fórmula HNR1R2 con el compuesto H1, compuesto H2 o ambos para formar el compuesto de fórmula (1). (h) coupling an amine of the formula HNR1R2 with compound H1, compound H2 or both to form the compound of formula (1).

Otra realización más es un procedimiento para preparar un compuesto de fórmula (1), en la que X e Y son N, U, V y W son C, B es O, y A, R, R1, R2 y p son como se han definido anteriormente. El procedimiento incluye las etapas de: Another embodiment is a process for preparing a compound of formula (1), in which X and Y are N, U, V and W are C, B is O, and A, R, R1, R2 and p are as they have been defined above. The procedure includes the steps of:

(a) (to)

desprotonar un compuesto de fórmula K: deprotonate a compound of formula K:

(b) (b)

hacer reaccionar el compuesto de fórmula L con una hidrazida que tiene la fórmula RNHNH2 para formar el compuesto M, compuesto N o ambos: reacting the compound of formula L with a hydrazide having the formula RNHNH2 to form compound M, compound N or both:

imagen2image2

seguido de acilación para producir un compuesto de fórmula L: followed by acylation to produce a compound of formula L:

imagen2image2

imagen2image2

y Y

(c) hidrolizar y acoplar el compuesto M, compuesto N o ambos con una amina de la fórmula HNR1R2 para formar el compuesto de fórmula (1). (c) hydrolyze and couple compound M, compound N or both with an amine of the formula HNR1R2 to form the compound of formula (1).

10 Otra realización más es un procedimiento para preparar un compuesto de fórmula (1), en la que V e Y son N, U, W, y X son C, B es O, p es 0 ó 1 y A, R, R1 y R2 son como se han definido anteriormente. El procedimiento incluye las etapas de: Another embodiment is a process for preparing a compound of formula (1), in which V and Y are N, U, W, and X are C, B is O, p is 0 or 1 and A, R, R1 and R2 are as defined above. The procedure includes the steps of:

(a) convertir un compuesto de fórmula O: (a) convert a compound of formula O:

imagen2image2

para dar un compuesto de fórmula P: to give a compound of formula P:

imagen2image2

(b) acoplar el compuesto P con una amina de la fórmula Q: (b) coupling compound P with an amine of the formula Q:

imagen2image2

para formar un compuesto de fórmula R: to form a compound of formula R:

imagen2image2

(c) desproteger el compuesto de fórmula R seguido de condensación para formar un compuesto de fórmula S: (c) deprotecting the compound of formula R followed by condensation to form a compound of formula S:

imagen2image2

y Y

(d) hidrolizar y acoplar el compuesto de fórmula S con una amina de la fórmula HNR1R2 para formar el 10 compuesto de fórmula (1). (d) hydrolyze and couple the compound of formula S with an amine of the formula HNR1R2 to form the compound of formula (1).

Breve descripción de los dibujos Brief description of the drawings

La Figura 1 es un gráfico de barras del porcentaje medio inverso de hiperalgesia neuropática (± ETM) medido mediante el modelo Seltzer (protocolo V), 0,5 y 1 hora después de la dosificación con vehículo, 100 mg/kg de gabapentina ó 0,01, 0,1, 0,3 ó 1 mg/kg del compuesto del Ejemplo 294. Figure 1 is a bar graph of the mean inverse percentage of neuropathic hyperalgesia (± ETM) measured by the Seltzer model (protocol V), 0.5 and 1 hour after dosing with vehicle, 100 mg / kg of gabapentin or 0 , 01, 0.1, 0.3 or 1 mg / kg of the compound of Example 294.

15 La Figura 2 es un gráfico de barras del porcentaje medio inverso de hiperalgesia neuropática (± ETM) medido mediante el modelo de lesión crónica por constricción del nervio ciático (protocolo VI), 0,5 y 1 hora después de la dosificación con vehículo, 100 mg/kg de gabapentina ó 0,1 mg/kg del compuesto del Ejemplo 15 Figure 2 is a bar graph of the mean inverse percentage of neuropathic hyperalgesia (± SEM) measured by the chronic sciatic nerve constriction lesion model (protocol VI), 0.5 and 1 hour after vehicle dosing, 100 mg / kg gabapentin or 0.1 mg / kg of the compound of Example

294. 294

5 5

10 10

15 fifteen

20 twenty

25 25

30 30

35 35

40 40

45 Four. Five

50 fifty

La Figura 3 es un gráfico de barras del porcentaje medio de máxima analgesia posible (MPE) (± ETM) medido mediante el procedimiento de sacudida de la cola (protocolo VII) 1, 3, 6, 12 y 18 horas después de la dosificación con vehículo, 3 mg/kg (i.p.) de WIN 55212-2 ó 0,3, 1 ó 3 mg/kg (i.p.) del compuesto del Ejemplo 294. Figure 3 is a bar graph of the average percentage of maximum possible analgesia (MPE) (± ETM) measured by the tail shaking procedure (protocol VII) 1, 3, 6, 12 and 18 hours after dosing with vehicle, 3 mg / kg (ip) of WIN 55212-2 or 0.3, 1 or 3 mg / kg (ip) of the compound of Example 294.

Descripción Detallada de la Invención Detailed description of the invention

Definiciones Definitions

El término "arilo" se refiere a radicales aromáticos que tienen de 6 a 14 átomos de carbono, tales como fenilo, naftilo, tetrahidro-naftilo, indanilo y bifenilo. The term "aryl" refers to aromatic radicals having from 6 to 14 carbon atoms, such as phenyl, naphthyl, tetrahydro-naphthyl, indanyl and biphenyl.

El término "arilalquilo" se refiere a un grupo arilo como se ha definido anteriormente unido directamente A un grupo alquilo como se ha definido anteriormente. por ejemplo, -CH2C6H5 y -C2H5C6H5. The term "arylalkyl" refers to an aryl group as defined above directly attached to an alkyl group as defined above. for example, -CH2C6H5 and -C2H5C6H5.

El término "anillo heterocíclico" se refiere a un radical de anillo de 3 a 15 miembros que consiste en átomos de carbono y de uno a cinco heteroátomos seleccionados entre nitrógeno, fósforo, oxígeno y azufre. Para los propósitos de la presente invención, el radical de anillo heterocíclico puede ser un sistema de anillo monocíclicos, bicíclicos o tricíclicos, que pueden incluir sistemas de anillos condensados, puenteados o espirales, y los átomos de nitrógeno, fósforo, carbono, oxígeno o azufre en el radical de anillo heterocíclico pueden oxidarse opcionalmente para dar diversos estados de oxidación. Además, el átomo de nitrógeno puede cuaternizarse opcionalmente; y el radical de anillo puede estar parcial o totalmente saturado (es decir, heterocíclico o heteroarilo). Los ejemplos de dichos radicales de anillo heterocíclicos incluyen, pero sin limitación, azetidinilo, acridinilo, benzodioxolilo, benzodioxanilo, benzofuranilo, carbazolilo, cinolinilo, dioxolanilo, indolizinilo, naftiridinilo, perhidroazepinilo, fenazinilo, fenotiazinilo, fenoxazinilo, ftalazinilo, piridil pteridinilo, purinilo, quinazolinilo, quinoxalinilo, quinolinilo, isoquinolinilo, tetrazolilo, imidazolilo, tetrahidroisouinolilo, piperidinilo, piperazinilo, 2-oxopiperazinilo, 2-oxopiperidinilo, 2-oxopirrolidinilo, 2oxoazepinilo, azepinilo, pirrolilo, 4-piperidonilo, pirrolidinilo, pirazinilo, pirimidinilo, piridazinilo, oxazolilo, oxazolinilo, oxazolidinilo, triazolilo, indanilo, isoxazolilo, isoxazolidinilo, morfolinilo, tiazolilo, tiazolinilo, tiazolidinilo, isotiazolilo, quinuclidinilo, isotiazolidinilo, indolilo, isoindolilo, indolinilo, isoindolinilo, octahidroindolilo, octahidroisoindolilo, quinolilo, isoquinolilo, decahidroisoquinolilo, bencimidazolilo, tia-diazolilo, benzopiranilo, benzotiazolilo, benzooxazolilo, furilo, tetrahidrofurilo, tetrahidropiranilo, tienilo, benzotienilo, tiamorfolinilo, sulfóxido de tiamorfolinilo, tiamorfolinil sulfona, dioxafosfolanilo, oxadiazolilo, cromanilo e isocromanilo. El radical de anillo heterocíclico puede estar unido a la estructura principal en cualquier heteroátomo o átomo de carbono que dé como resultado la creación de una estructura estable. The term "heterocyclic ring" refers to a 3 to 15-membered ring radical consisting of carbon atoms and one to five heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur. For the purposes of the present invention, the heterocyclic ring radical may be a monocyclic, bicyclic or tricyclic ring system, which may include condensed, bridged or spiral ring systems, and nitrogen, phosphorus, carbon, oxygen or sulfur atoms. in the heterocyclic ring radical they can optionally be oxidized to give various oxidation states. In addition, the nitrogen atom can optionally quaternize; and the ring radical may be partially or fully saturated (ie, heterocyclic or heteroaryl). Examples of such radicals heterocyclic ring include, but not limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl pteridinyl, purinyl, quinazolinyl , quinoxalinyl, quinolinyl, isoquinolinyl, tetrazolyl, imidazolyl, tetrahidroisouinolilo, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2oxoazepinilo, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl , oxazolidinyl, triazolyl, indanyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thia-diazolyl, be nzopyranyl, benzothiazolyl, benzooxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphospholanyl, oxadiazolyl, chromanyl and isochromanyl. The heterocyclic ring radical may be attached to the main structure in any heteroatom or carbon atom that results in the creation of a stable structure.

El término "heteroarilo" se refiere a una radical de anillo heterocíclico aromático. El radical de anillo heteroarilo puede estar unido a la estructura principal en cualquier heteroátomo o átomo de carbono que de como resultado la creación de una estructura estable. The term "heteroaryl" refers to an aromatic heterocyclic ring radical. The heteroaryl ring radical can be attached to the main structure in any heteroatom or carbon atom that results in the creation of a stable structure.

El término "heteroarilalquilo" se refiere a un radical de anillo heteroarilo unido directamente a un grupo alquilo. El radical heteroarilalquilo puede estar unido a la estructura principal en cualquier átomo de carbono del grupo alquilo que de como resultado la creación de una estructura estable. The term "heteroarylalkyl" refers to a heteroaryl ring radical attached directly to an alkyl group. The heteroarylalkyl radical can be attached to the main structure in any carbon atom of the alkyl group that results in the creation of a stable structure.

El término "heterociclilo" se refiere a un radical de anillo heterocíclico como se ha definido anteriormente. El radical de anillo heterocíclico puede estar unido a la estructura principal en cualquier heteroátomo o átomo de carbono que de como resultado la creación de una estructura estable. The term "heterocyclyl" refers to a heterocyclic ring radical as defined above. The heterocyclic ring radical may be attached to the main structure in any heteroatom or carbon atom that results in the creation of a stable structure.

El término "heterociclilalquilo" se refiere a un radical de anillo heterocíclico unido directamente a un grupo alquilo. El radical heterociclilalquilo puede estar unido a la estructura principal en cualquier átomo de carbono en el grupo alquilo que de como resultado la creación de una estructura estable. The term "heterocyclylalkyl" refers to a heterocyclic ring radical attached directly to an alkyl group. The heterocyclylalkyl radical can be attached to the main structure in any carbon atom in the alkyl group that results in the creation of a stable structure.

El término "alquilo" se refiere a un radical de cadena de hidrocarburo lineal o ramificada que consiste únicamente en átomos de hidrógeno y carbono, que no contiene insaturación, que tiene de uno a ocho átomos de carbono y que está unido al resto de la molécula por un enlace sencillo, por ejemplo, metilo, etilo, n-propilo, 1-metiletilo (isopropilo), n-butilo, n-pentilo y 1,1-dimetiletilo (t-butilo). The term "alkyl" refers to a linear or branched hydrocarbon chain radical consisting solely of hydrogen and carbon atoms, which does not contain unsaturation, which has one to eight carbon atoms and which is attached to the rest of the molecule. by a single bond, for example, methyl, ethyl, n-propyl, 1-methyl ethyl (isopropyl), n-butyl, n-pentyl and 1,1-dimethylethyl (t-butyl).

El término "alquenilo" se refiere a un grupo de hidrocarburo alifático que contiene un doble enlace carbono-carbono y que puede ser una cadena lineal o ramificada que tiene de 2 a aproximadamente 10 átomos de carbono, por ejemplo, etenilo, 1-propenilo, 2-propenil (alilo), iso-propenilo, 2-metil-1-propenilo, 1-butenilo y 2-butenilo. The term "alkenyl" refers to an aliphatic hydrocarbon group that contains a carbon-carbon double bond and can be a straight or branched chain having from 2 to about 10 carbon atoms, for example, ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-1-propenyl, 1-butenyl and 2-butenyl.

El término "alquinilo" se refiere a un radical hidrocarbilo de cadena lineal o ramificada que tiene al menos un triple enlace carbono-carbono, y que tiene de 2 a aproximadamente 12 átomos de carbono (prefiriéndose radicales que tienen de 2 a aproximadamente 10 átomos de carbono), por ejemplo, etinilo, propinilo y butinilo. The term "alkynyl" refers to a straight or branched chain hydrocarbyl radical having at least one carbon-carbon triple bond, and having from 2 to about 12 carbon atoms (with radicals having from 2 to about 10 carbon atoms being preferred carbon), for example, ethynyl, propynyl and butynyl.

El término "alcoxi" representa un grupo alquilo unido por un enlace de oxígeno al resto de la molécula. Los ejemplos representativos de dichos grupos son -OCH3 y -OC2H5. The term "alkoxy" represents an alkyl group linked by an oxygen bond to the rest of the molecule. Representative examples of such groups are -OCH3 and -OC2H5.

El término "cicloalquilo" representa un sistema de anillo no aromático mono o multicíclico de 3 a aproximadamente 12 átomos de carbono, tales como ciclopropilo, ciclobutilo, ciclopentilo y ciclohexilo. Los ejemplos de grupos cicloalquilo multicíclicos incluyen, pero sin limitación, grupo perhidronaftilo, adamantilo y norbornilo, grupos cíclicos puenteados o grupos espirobicíclicos, por ejemplo, esprio[4.4]non-2-ilo. The term "cycloalkyl" represents a mono or multicyclic non-aromatic ring system of 3 to about 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Examples of multicyclic cycloalkyl groups include, but are not limited to, perhydronaphthyl, adamantyl and norbornyl groups, bridged cyclic groups or spirobicyclic groups, for example, spium [4.4] non-2-yl.

El término "cicloalquilalquilo" se refiere a un radical que contiene un anillo cíclico, que tiene de 3 a aproximadamente 8 átomos de carbono, unidos directamente a un grupo alquilo. El grupo cicloalquilalquilo puede estar unido a la estructura principal en cualquier átomo de carbono en el grupo alquilo que de como resultado la creación de una estructura estable. Los ejemplos no limitantes de dichos grupos incluyen ciclopropilmetilo, ciclobutiletilo y ciclopentiletilo. The term "cycloalkylalkyl" refers to a radical containing a cyclic ring, having from 3 to about 8 carbon atoms, directly attached to an alkyl group. The cycloalkylalkyl group may be attached to the main structure in any carbon atom in the alkyl group that results in the creation of a stable structure. Non-limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl and cyclopentylethyl.

El término "cicloalquilarilo" se refiere a un radical que contiene un anillo cíclico, que tiene de 3 a aproximadamente 8 átomos de carbono, unidos directamente a un grupo arilo. Los ejemplos no limitantes de dicho grupos incluyen fenilciclopropilo, fenilciclobutilo y fenilciclopentilo. The term "cycloalkylaryl" refers to a radical containing a cyclic ring, having from 3 to about 8 carbon atoms, directly attached to an aryl group. Non-limiting examples of said groups include phenylcyclopropyl, phenylcyclobutyl and phenylcyclopentyl.

El término "cicloalquenilo" se refiere a un radical que contiene un anillo cíclico que tiene de 3 a aproximadamente 8 átomos de carbono con al menos un doble enlace carbono-carbono, tales como ciclopropenilo, ciclobutenilo y ciclopentenilo. The term "cycloalkenyl" refers to a radical containing a cyclic ring having from 3 to about 8 carbon atoms with at least one carbon-carbon double bond, such as cyclopropenyl, cyclobutenyl and cyclopentenyl.

A menos que se indique lo contrario, el término "sustituido", como se usa en la presente memoria, se refiere a sustitución con uno cualquiera o cualquier combinación de los siguientes sustituyentes: hidroxi, halógeno, carboxilo, ciano, nitro, oxo (=O), tio (=S), alquilo sustituido o sin sustituir, alcoxi sustituido o sin sustituir, alquenilo sustituido o sin sustituir, alquinilo sustituido o sin sustituir, arilo sustituido o sin sustituir, arilalquilo sustituido o sin sustituir, cicloalquilo sustituido o sin sustituir, cicloalquenilo sustituido o sin sustituir, amino sustituido o sin sustituir, arilo sustituido o sin sustituir, heteroarilo sustituido o sin sustituir, anillo heterociclilalquilo sustituido o sin sustituir, heteroarilalquilo sustituido o sin sustituir, anillo heterocíclico sustituido o sin sustituir, guanidina sustituida o sin sustituir, -COORx, -C(O)Rx, -C(S)Rx, -C(O)NRxRy, -C(O)ONRxRy, -NRxCONRyRz, -N(Rx)SORy, -N(Rx)SO2Ry, -(=NN(Rx)Ry), -NRxC(O)ORy, -NRxRy, -NRxC(O)Ry, -NRxC(S)Ry, -NRxC(S)NRyRz, -SONRxRy, -SO2NRxRy, -ORx, -ORxC(O)NRyRz, -ORxC(O)ORy, -OG(O)Rx, -OC(O)NRxRy, -RxNRyC(O)Rz, -RxORy, -RxC(O)ORy, -RxC(O)NRyRz, RxC(O)Ry, -RxOC(O)Ry, -SRx, -SORx, -SO2Rx y -ONO2, en los que Rx, Ry y Rz se seleccionan independientemente entre hidrógeno, alquilo sustituido o sin sustituir, alcoxi sustituido o sin sustituir, alquenilo sustituido o sin sustituir, alquinilo sustituido o sin sustituir, arilo sustituido o sin sustituir, arilalquilo sustituido o sin sustituir, cicloalquilo sustituido o sin sustituir, cicloalquenilo sustituido o sin sustituir, amino sustituido o sin sustituir, arilo sustituido o sin sustituir, heteroarilo sustituido o sin sustituir, anillo heterociclilalquilo sustituido, heteroarilalquilo sustituido o sin sustituir o anillo heterocíclico sustituido o sin sustituir. De acuerdo con una realización, los sustituyentes en los grupos "sustituidos" mencionados anteriormente no pueden estar sustituidos adicionalmente. Por ejemplo, cuando el sustituyente en "alquilo sustituido" es "arilo sustituido" el sustituyente en "arilo sustituido" no puede ser "alquenilo sustituido". Unless otherwise indicated, the term "substituted", as used herein, refers to substitution with any one or any combination of the following substituents: hydroxy, halogen, carboxyl, cyano, nitro, oxo (= O), thio (= S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl , substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted guanidine , -COORx, -C (O) Rx, -C (S) Rx, -C (O) NRxRy, -C (O) ONRxRy, -NRxCONRyRz, -N (Rx) SORy, -N (Rx) SO2Ry, - (= NN (Rx) Ry), -NRxC (O) ORy, -NRxRy, -NRxC (O ) Ry, -NRxC (S) Ry, -NRxC (S) NRyRz, -SONRxRy, -SO2NRxRy, -ORx, -ORxC (O) NRyRz, -ORxC (O) ORy, -OG (O) Rx, -OC ( O) NRxRy, -RxNRyC (O) Rz, -RxORy, -RxC (O) ORy, -RxC (O) NRyRz, RxC (O) Ry, -RxOC (O) Ry, -SRx, -SORx, -SO2Rx and -ONO2, in which Rx, Ry and Rz are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted arylalkyl or unsubstituted, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl alkyl, or substituted or unsubstituted heterocyclic ring. According to one embodiment, the substituents in the "substituted" groups mentioned above cannot be further substituted. For example, when the "substituted alkyl" substituent is "substituted aryl" the "substituted aryl" substituent cannot be "substituted alkenyl".

El término "grupo protector" o "GP" se refiere a un sustituyente que se emplea para bloquear o proteger una funcionalidad en particular. Otros grupos funcionales en el compuesto pueden permanecer reactivos. Por ejemplo, un "un grupo protector de amino" es un sustituyente unido a un grupo amino que bloquea o protege la funcionalidad amino en el compuesto. Los grupos protectores de amino adecuado incluyen, pero sin limitación, acetilo, trifluoroacetilo, t-butoxicarbonilo (BOC), benciloxicarbonilo (CBz) y 9-fluorenilmetilenoxicarbonilo (Fmoc). De forma análoga, un "un grupo protector de hidroxi" se refiere a un sustituyente de un grupo hidroxi que bloque o protege la funcionalidad hidroxi. Los grupos protectores de hidroxi adecuados incluyen, pero sin limitación, acetilo y sililo. Un "grupo protector de carboxi" se refiere a un sustituyente del grupo carboxi que bloquea o protege la funcionalidad carboxi. Los grupos protectores de carboxi adecuados incluyen, pero sin limitación, -CH2CH2SO2Ph, cianoetilo, 2(trimetilsilil)etilo, 2-(trimetilsilil)etoximetilo, 2-(p-toluenosulfonil)etilo, 2-(p-nitrofenilsulfenil)etilo, 2-(difenilfosfino)-etilo y nitroetilo. Para una descripción general de grupos protectores y sus usos, véase T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Nueva York, 1991. The term "protecting group" or "GP" refers to a substituent that is used to block or protect a particular functionality. Other functional groups in the compound may remain reactive. For example, an "amino protecting group" is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino protecting groups include, but are not limited to, acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethylene oxycarbonyl (Fmoc). Similarly, a "hydroxy protecting group" refers to a substituent of a hydroxy group that blocks or protects hydroxy functionality. Suitable hydroxy protecting groups include, but are not limited to, acetyl and silyl. A "carboxy protecting group" refers to a substituent of the carboxy group that blocks or protects the carboxy functionality. Suitable carboxy protecting groups include, but are not limited to, -CH2CH2SO2Ph, cyanoethyl, 2 (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrophenylsulfenyl) ethyl, 2- (diphenylphosphino) -ethyl and nitroethyl. For an overview of protective groups and their uses, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

La expresión “receptor de canabinoides” se refiere a cualquiera de los subtipos, hasta ahora conocidos o desconocidos, de la clase de receptores de canabinoides, que incluyen los receptores CB1 y/o CB2, que pueden unirse por un compuesto modulador de canabinoides de la presente invención. The term "cannabinoid receptor" refers to any of the subtypes, hitherto known or unknown, of the class of cannabinoid receptors, which include CB1 and / or CB2 receptors, which can be linked by a cannabinoid modulating compound of the present invention

El término “modulador” se refiere adicionalmente al uso de un compuesto de la invención como un agonista, agonista parcial, antagonista o agonista inverso de receptores CB (por ejemplo, CB1 y/o CB2). The term "modulator" further refers to the use of a compound of the invention as an agonist, partial agonist, antagonist or inverse agonist of CB receptors (eg, CB1 and / or CB2).

El término “tratar” o “tratamiento” de un estado, trastorno o afección incluye: The term "treat" or "treatment" of a state, disorder or condition includes:

(1) (one)

prevenir o retrasar la aparición de síntomas clínicos del estado, trastorno o afección que se desarrolla en un sujeto que puede parecer o que esta predispuesto al estado, trastorno o afección, pero que aún no padece ni presenta síntomas clínicos o subclínicos del estado, trastorno o afección; prevent or delay the onset of clinical symptoms of the condition, disorder or condition that develops in a subject that may appear or is predisposed to the condition, disorder or condition, but that does not yet suffer or present clinical or subclinical symptoms of the condition, disorder or condition;

(2) (2)

inhibir el estado, trastorno o afección, es decir, detener o reducir el desarrollo de la enfermedad o al menos de un síntoma clínico o subclínico de los mismos; o inhibit the condition, disorder or condition, that is, stop or reduce the development of the disease or at least one clinical or subclinical symptom thereof; or

(3) (3)

aliviar la enfermedad, es decir, causar la regresión del estado, trastorno o afección o al menos uno de sus síntomas clínicos o subclínicos. alleviate the disease, that is, cause regression of the condition, disorder or condition or at least one of its clinical or subclinical symptoms.

El beneficio para un sujeto que va a tratarse es estadísticamente significativo o al menos perceptible para el sujeto o para el médico. The benefit for a subject to be treated is statistically significant or at least noticeable to the subject or to the doctor.

El término “sujeto” incluye mamíferos (especialmente seres humanos) y otros animales, tales como animales domésticos (por ejemplo animales domésticos incluyendo gatos y perros) y animales no domésticos (tales como salvajes). The term "subject" includes mammals (especially humans) and other animals, such as domestic animals (for example domestic animals including cats and dogs) and non-domestic animals (such as wild animals).

Una” cantidad terapéuticamente eficaz” se refiere a la cantidad de un compuesto que, cuando se administra a un sujeto para tratar un estado, trastorno o afección, es suficiente para efectuar dicho tratamiento. La “cantidad terapéuticamente eficaz” variará dependiendo del compuesto, de la enfermedad y su gravedad, de la edad, peso, enfermedad física y respuesta al sujeto a tratar. A "therapeutically effective amount" refers to the amount of a compound that, when administered to a subject to treat a condition, disorder or condition, is sufficient to effect such treatment. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, age, weight, physical illness and response to the subject to be treated.

Las sales farmacéuticamente aceptables que forman parte de la presente invención incluyen sales derivadas de bases inorgánicas (tales como Li, Na, K, Ca, Mg, Fe, Cu, Zn y Mn), sales de bases orgánicas (tales como N,N’diacetiletilendiamina, glucamina, trietilamina, colina, diciclohexilamina, metformina, bencilamina, trialquilamina y tiamina), sales de bases quirales (tales como alquilfenilamina, glicinol y fenil glicinol), sales de aminoácidos naturales (tales como glicina, alanina, valina, leucina, isoleucina, norleucina, tirosina, cistina, cisteína, metionina, prolina, hidroxi prolina, histidina, ornitina, lisina, arginina y serina), sales de aminoácidos no naturales (tales como aminoácidos D-isómeros o sustituidos), sales de guanidina, sales de guanidina sustituidas (en las que los sustituyentes se seleccionan entre nitro, amino, alquilo, alquenilo o alquinilo) sales de amonio, sales de amonio sustituidas y sales de aluminio. Otras sales farmacéuticamente aceptables incluyen sales de adición de ácidos (cuando sea apropiado) tales como sulfatos, nitratos, fosfatos, percloratos, boratos, hidrohaluros, acetatos (tal como trifluoroacetato), tartratos, maleatos, citratos, fumaratos, succinatos, palmoatos, metanosulfonatos, benzoatos, salicilatos, bencenosulfonatos, ascorbatos, glicerofosfatos y cetoglutaratos. Otras sales farmacéuticamente aceptables incluyen, pero sin limitación, sales de amonio cuaternario de los compuestos de la invención con haluros de alquilo o sulfatos de alquilo (tales como MeI o (Me)2SO4). Pharmaceutically acceptable salts that are part of the present invention include salts derived from inorganic bases (such as Li, Na, K, Ca, Mg, Fe, Cu, Zn and Mn), salts of organic bases (such as N, N ' diacetylethylenediamine, glucamine, triethylamine, choline, dicyclohexylamine, metformin, benzylamine, trialkylamine and thiamine), chiral base salts (such as alkylphenylamine, glycine and phenyl glycol), natural amino acid salts (such as glycine, alanine, valine, leucine, leucine, leucine, leucine , norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxy proline, histidine, ornithine, lysine, arginine and serine), unnatural amino acid salts (such as D-isomeric or substituted amino acids), guanidine salts, guanidine salts substituted (in which the substituents are selected from nitro, amino, alkyl, alkenyl or alkynyl) ammonium salts, substituted ammonium salts and aluminum salts. Other pharmaceutically acceptable salts include acid addition salts (when appropriate) such as sulfates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates (such as trifluoroacetate), tartrates, maleates, citrates, smokers, succinates, palmoates, methanesulfonates, benzoates, salicylates, benzenesulfonates, ascorbates, glycerophosphates and ketoglutarates. Other pharmaceutically acceptable salts include, but are not limited to, quaternary ammonium salts of the compounds of the invention with alkyl halides or alkyl sulfates (such as MeI or (Me) 2SO4).

Los solvatos farmacéuticamente aceptables incluyen hidratos y otros disolventes de cristalización (tales como alcoholes). Los compuestos de la presente invención pueden formar solvatos con disolventes convencionales de bajo peso molecular mediante procedimientos conocidos en la técnica. Pharmaceutically acceptable solvates include hydrates and other crystallization solvents (such as alcohols). The compounds of the present invention can form solvates with conventional solvents of low molecular weight by methods known in the art.

Composiciones Farmacéuticas Pharmaceutical Compositions

La composición farmacéutica de la presente invención comprende al menos un compuesto de la presente invención y un excipiente farmacéuticamente aceptable (tal como un transportador o un diluyente farmacéuticamente aceptable). Preferentemente, la composición farmacéutica comprende una cantidad terapéuticamente eficaz del compuesto (o compuestos) de la presente invención. El compuesto de la presente invención puede asociarse con un excipiente farmacéuticamente aceptable (tal como un transportador o un diluyente) o diluirse mediante un transportador, o incluirse dentro de un transportador que puede estar en forma de una cápsula, sobrecito u otro artículo de envase. The pharmaceutical composition of the present invention comprises at least one compound of the present invention and a pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent). Preferably, the pharmaceutical composition comprises a therapeutically effective amount of the compound (or compounds) of the present invention. The compound of the present invention may be associated with a pharmaceutically acceptable excipient (such as a carrier or diluent) or be diluted by a carrier, or included within a carrier that may be in the form of a capsule, sachet or other package item.

Los ejemplos de transportadores adecuados incluyen, pero sin limitación, agua, soluciones salinas, alcoholes, polietilenglicoles, aceite de ricino poli(hidroxi-etoxilado), aceite de cacahuete, aceite de oliva, gelatina, lactosa, sulfato de calcio, sacarosa, dextrina, carbonato de magnesio, azúcar, ciclodextrina, amilosa, estearato de magnesio, talco, gelatina, agar, pectina, goma arábiga, ácido esteárico o éteres de celulosa de alquilo inferior, ácido silícico, ácidos grasos, aminas de ácidos grasos, monoglicéridos y diglicéridos de ácidos grasos, ésteres de ácidos grasos de pentaeritritol, polioxietileno, hidroximetilcelulosa y polivinilpirrolidona. Examples of suitable carriers include, but are not limited to, water, saline solutions, alcohols, polyethylene glycols, poly (hydroxy-ethoxylated) castor oil, peanut oil, olive oil, gelatin, lactose, calcium sulfate, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, gum arabic, stearic acid or cellulose ethers of lower alkyl, silicic acid, fatty acids, fatty acid amines, monoglycerides and diglycerides fatty acids, fatty acid esters of pentaerythritol, polyoxyethylene, hydroxymethyl cellulose and polyvinyl pyrrolidone.

El transportador o diluyente puede incluir un material de liberación prolongada tal como monoestearato de glicerilo o diestearato de glicerilo, en solitario o mezclado con una cera. The carrier or diluent may include an extended release material such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.

La composición farmacéutica también puede incluir uno o más agentes auxiliares farmacéuticamente aceptables, agente humectantes, agentes emulsionantes, agentes de suspensión, agentes conservantes, sales para ejercer influencia en la presión osmótica, tampones, agentes edulcorantes, agentes saporíferos, colorantes o cualquier combinación de los anteriores. Empleando procedimientos conocidos en la técnica, la composición farmacéutica de la presente invención puede formularse para proporcionar una liberación rápida, sostenida o prolongada del principio activo después de administrar al sujeto. The pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preservatives, salts for influencing osmotic pressure, buffers, sweetening agents, flavoring agents, colorants or any combination thereof. previous. Using methods known in the art, the pharmaceutical composition of the present invention can be formulated to provide a rapid, sustained or prolonged release of the active ingredient after administration to the subject.

Las composiciones farmacéuticas de la presente invención pueden prepararse mediante técnicas convencionales, como se describe, por ejemplo, en Remington: The Science and Practice of Pharmacy, 20ª Ed., 2003 (Lippincott Williams & Wilkins). Por ejemplo, el compuesto activo puede mezclarse con un transportador o diluirse mediante un transportador o incluirse dentro de un transportador, que puede estar en forma de una ampolla, cápsula, sobrecito, u otro artículo de envase. Cuando el transportador sirve como un diluyente, este puede ser un material sólido, semisólido o líquido que actúa como un vehículo, excipiente o medio para el compuesto activo. El compuesto activo puede adsorberse en un envase sólido granular, por ejemplo, en un sobrecito. The pharmaceutical compositions of the present invention can be prepared by conventional techniques, as described, for example, in Remington: The Science and Practice of Pharmacy, 20th Ed., 2003 (Lippincott Williams & Wilkins). For example, the active compound may be mixed with a carrier or diluted by a carrier or included in a carrier, which may be in the form of a vial, capsule, sachet, or other packaging article. When the carrier serves as a diluent, this may be a solid, semi-solid or liquid material that acts as a vehicle, excipient or medium for the active compound. The active compound can be adsorbed in a granular solid container, for example, in a sachet.

Las composiciones farmacéuticas pueden estar en formas convencionales, por ejemplo, cápsulas, comprimidos, aerosoles, soluciones, suspensiones o productos para aplicación tópica. The pharmaceutical compositions may be in conventional forms, for example, capsules, tablets, aerosols, solutions, suspensions or products for topical application.

La vía de administración puede ser cualquier vía que transporte eficazmente el compuesto activo de la invención al sitio de acción apropiado o deseado. Las vías de administración adecuadas incluyen, pero sin limitación, la vía oral, nasal, pulmonar, bucal, subdérmica, intradérmica, transdérmica, parenteral, rectal, por implante, subcutánea, intravenosa, intrauretral, intramuscular, intranasal, oftálmica (tal como con una solución oftálmica) o tópica (tal como con una pomada tópica). Se prefiere la vía oral. The route of administration may be any route that effectively transports the active compound of the invention to the appropriate or desired site of action. Suitable routes of administration include, but are not limited to, the oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, parenteral, rectal, implant, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic route (such as with a ophthalmic solution) or topical (such as with a topical ointment). The oral route is preferred.

Las formulaciones orales sólidas incluyen, pero sin limitación, comprimidos, cápsulas (de gelatina blanda o dura), grageas (que contienen el principio activo en forma de polvo o gránulo), obleas y pastillas para chupar. Los comprimidos, grageas o cápsulas que tienen talco y/o un transportador de carbohidrato o aglutinante o similar son particularmente adecuados para la aplicación oral. Los transportadores preferibles para comprimidos, grageas o cápsulas incluyen lactosa, almidón de maíz y/o almidón de patata. Puede emplearse un jarabe o elixir en casos en los que pueda usarse un vehículo edulcorado. Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active substance in powder or granule form), wafers and lozenges. Tablets, dragees or capsules having talc and / or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferable carriers for tablets, dragees or capsules include lactose, corn starch and / or potato starch. A syrup or elixir can be used in cases where a sweetened vehicle can be used.

Un comprimido típico que puede prepararse mediante técnicas de formación de comprimidos convencionales puede contener: (1) Núcleo: Compuesto activo (como compuesto libre o sal del mismo), 250 mg de dióxido de silicio coloidal (Aerosil®), 1,5 mg de celulosa microcristalina (Avicel®), 70 mg de goma de celulosa modificada (Ac-Di-Sol®) y 7,5 mg de estearato de magnesio; (2) Recubrimiento: HPMC, aprox. 9 mg de Mywacett 9-40 T y aprox. 0,9 mg de monoglicérido acilado. A typical tablet that can be prepared by conventional tabletting techniques may contain: (1) Core: Active compound (as free compound or salt thereof), 250 mg of colloidal silicon dioxide (Aerosil®), 1.5 mg of microcrystalline cellulose (Avicel®), 70 mg of modified cellulose gum (Ac-Di-Sol®) and 7.5 mg of magnesium stearate; (2) Coating: HPMC, approx. 9 mg of Mywacett 9-40 T and approx. 0.9 mg acylated monoglyceride.

Las formulaciones líquidas incluyen, pero sin limitación, jarabes, emulsiones, gelatina blanda y líquidos inyectables estériles, tales como suspensiones o soluciones líquidas acuosas o no acuosas. Liquid formulations include, but are not limited to, syrups, emulsions, soft gelatin and sterile injectable liquids, such as suspensions or aqueous or non-aqueous liquid solutions.

Para aplicación parenteral, son particularmente adecuadas las soluciones o suspensiones inyectables, preferentemente soluciones acuosas con el compuesto activo disuelto en aceite de ricino poli(hidroxilado). For parenteral application, injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in poly (hydroxylated) castor oil, are particularly suitable.

Procedimientos de Tratamiento Treatment Procedures

La presente invención proporciona compuestos y formulaciones farmacéuticas de los mismos que son útiles en el tratamiento, mejora y/o prevención de enfermedades, afecciones y/o trastornos modulados por un receptor de canabinoides (CB), especialmente los modulados por el receptor CB1 o CB2 que incluyen los descritos a continuación. The present invention provides compounds and pharmaceutical formulations thereof that are useful in the treatment, improvement and / or prevention of diseases, conditions and / or disorders modulated by a cannabinoid (CB) receptor, especially those modulated by the CB1 or CB2 receptor which include those described below.

La presente invención proporciona adicionalmente un procedimiento para tratar una enfermedad, afección y/o trastorno modulado por un receptor de canabinoides (CB), y en particular el receptor CB1 o CB2, en un sujeto que lo necesita, administrando al sujeto una cantidad terapéuticamente eficaz de un compuesto o una composición farmacéutica de la presente invención. The present invention further provides a method for treating a disease, condition and / or disorder modulated by a cannabinoid (CB) receptor, and in particular the CB1 or CB2 receptor, in a subject in need thereof, administering to the subject a therapeutically effective amount. of a compound or a pharmaceutical composition of the present invention.

Las enfermedades, afecciones y/o trastornos que un receptor CB modula, incluyen, pero sin limitación, trastornos relacionados con el apetito, trastornos metabólicos, trastornos catabólicos, diabetes, obesidad, trastornos relacionados con el ámbito social, trastornos anímicos, mareos, abuso de sustancias nocivas, trastornos relacionados con el aprendizaje, trastornos cognitivos, trastornos relacionados con la memoria, contracción de órganos, espasmos musculares, trastornos respiratorios, trastornos relacionados con la actividad locomotora, discinesias, trastornos inmunológicos (tales como trastornos autoinmunológicos), inflamación, crecimiento celular, dolor (tal como dolor neuropático) y síndromes, trastornos y enfermedades neurodegenerativas relacionados. The diseases, conditions and / or disorders that a CB receptor modulates, include, but are not limited to, appetite-related disorders, metabolic disorders, catabolic disorders, diabetes, obesity, social-related disorders, mood disorders, dizziness, abuse of harmful substances, learning-related disorders, cognitive disorders, memory-related disorders, organ contraction, muscle spasms, respiratory disorders, disorders related to locomotor activity, dyskinesias, immune disorders (such as autoimmune disorders), inflammation, cell growth , pain (such as neuropathic pain) and related neurodegenerative diseases and syndromes.

Los síndromes, enfermedades o trastornos relacionados con el apetito incluyen, pero sin limitación, obesidad, estados de sobrepeso, anorexia, bulimia, caquexia, apetito mal regulado y similares. Los síndromes, trastornos o enfermedades relacionados con la obesidad incluyen, pero sin limitación, obesidad como un resultado de un síndrome, enfermedad o trastorno genético, relacionado con la dieta, volumen de consumo de alimento, metabólico, trastorno o enfermedad hipotálamica, envejecimiento, distribución anómala de la masa adiposa, distribución anómala del compartimento adiposo, trastornos alimenticios compulsivos, trastornos motivacionales que incluyen el deseo de consumir azúcar, hidratos de carbono, alcohol o fármacos o cualquier ingrediente con valor hedónico y similares. Los síntomas asociados con síndromes, trastornos y enfermedades relacionadas con obesidad incluyen, pero sin limitación, actividad reducida. Syndromes, diseases or disorders related to appetite include, but are not limited to, obesity, overweight states, anorexia, bulimia, cachexia, poorly regulated appetite and the like. Syndromes, disorders or diseases related to obesity include, but are not limited to, obesity as a result of a syndrome, disease or genetic disorder, related to diet, volume of food consumption, metabolic, disorder or hypothalamic disease, aging, distribution anomalous adipose mass, abnormal distribution of the adipose compartment, compulsive eating disorders, motivational disorders that include the desire to consume sugar, carbohydrates, alcohol or drugs or any ingredient with hedonic value and the like. Symptoms associated with syndromes, disorders and diseases related to obesity include, but are not limited to, reduced activity.

Los síndromes, trastornos o enfermedades relacionados con el metabolismo incluyen, pero sin limitación, síndrome metabólico, dislipidemia, presión sanguínea elevada, sensibilidad o resistencia a insulina, hiperinsulinemia, hipercolesterolemia, hiperlipidemias, ateroesclerosis, hipertrigliceridemias, arterioesclerosis, otras enfermedades cardiovasculares, osteoartritis, enfermedades dermatológicas, enfermedades relacionadas con el sueño (modificaciones del ritmo circadiano, disomnio, insomnio, apnea del sueño y narcolepsia), colelitiasis, hepatomegalia, esteatosis, niveles anómalos de alanina aminotransferasa, enfermedad del ovario poliquístico, inflamación y similares. Syndromes, disorders or diseases related to metabolism include, but are not limited to, metabolic syndrome, dyslipidemia, elevated blood pressure, insulin sensitivity or resistance, hyperinsulinemia, hypercholesterolemia, hyperlipidemias, atherosclerosis, hypertriglyceridemias, atherosclerosis, other cardiovascular diseases, osteoarthritis, diseases dermatological, sleep-related diseases (modifications of the circadian rhythm, dysomnia, insomnia, sleep apnea and narcolepsy), cholelithiasis, hepatomegaly, steatosis, abnormal levels of alanine aminotransferase, polycystic ovarian disease, inflammation and the like.

Los síndromes, trastornos o enfermedades relacionados con la diabetes incluyen, pero sin limitación, mala regulación de glucosa, resistencia a insulina, intolerancia a glucosa, hiperinsulinemia, dislipidemia, hipertensión, obesidad, hiperglucemia y similares. Syndromes, disorders or diseases related to diabetes include, but are not limited to, poor glucose regulation, insulin resistance, glucose intolerance, hyperinsulinemia, dyslipidemia, hypertension, obesity, hyperglycemia and the like.

Los síndromes, trastornos o enfermedades relacionados con el catabolismo incluyen, pero sin limitación, catabolismo en relación con disfunción pulmonar y dependencia de respirador; disfunción cardiaca, asociada, por ejemplo, a enfermedad valvular, infarto de miocardio, hipertrofia cardiaca o insuficiencia cardiaca congestiva. Syndromes, disorders or diseases related to catabolism include, but are not limited to, catabolism in relation to pulmonary dysfunction and respirator dependence; cardiac dysfunction, associated, for example, with valvular disease, myocardial infarction, cardiac hypertrophy or congestive heart failure.

Las enfermedades oftálmicas incluyen, pero sin limitación, glaucoma, retinitis por depresión intraocular asociada con glaucoma, retinopatías, uveítis, lesión aguda en el tejido ocular (por ejemplo conjuntivitis). Ophthalmic diseases include, but are not limited to, glaucoma, retinitis due to intraocular depression associated with glaucoma, retinopathies, uveitis, acute injury to the ocular tissue (for example conjunctivitis).

Los síndromes, trastornos o enfermedades anímicos o relacionados con el ámbito social incluyen, pero sin limitación, depresión (que incluyen, pero sin limitación, depresión bipolar, depresión unipolar, episodios depresivos principales simples o recurrentes con o sin características psicóticas, características catatónicas, características melancólicas, características atípicas o que aparecen después del parto, trastorno afectivo estacional, trastornos distímicos con aparición temprana o tardía y con o sin características atípicas, depresión neurótica y fobia social, depresión acompañada por demencia, ansiedad, psicosis, trastornos sociales afectivos, trastornos cognitivos y similares). Syndromes, disorders or mood or social-related diseases include, but are not limited to, depression (including, but not limited to, bipolar depression, unipolar depression, major or recurrent major depressive episodes with or without psychotic characteristics, catatonic characteristics, characteristics melancholic, atypical characteristics or appearing after childbirth, seasonal affective disorder, dysthymic disorders with early or late onset and with or without atypical characteristics, neurotic depression and social phobia, depression accompanied by dementia, anxiety, psychosis, affective social disorders, cognitive disorders and the like).

Los síndromes, enfermedades o trastornos relacionados con el abuso de sustancias nocivas, incluyen, pero sin limitación, abuso de sustancias nocivas y síndrome de abstinencia. Las sustancias nocivas abusivas, incluyen, pero sin limitación, alcohol, anfetaminas (o sustancias similares a anfetaminas), cafeína, marihuana, cocaína, alucinógenos, inhalantes, opioides, nicotina (y/o productos relacionados con tabaco), abuso de heroína, barbitúricos, fenciclidina (o compuestos similares a fenciclidina), hipnóticos sedantes, benzodiacepinas o combinaciones de cualquiera de los anteriores. Los compuestos y composiciones farmacéuticas también pueden usarse para tratar síntomas de abstinencia y ansiedad inducida por sustancias nocivas o trastornos anímicos. Syndromes, diseases or disorders related to the abuse of harmful substances include, but are not limited to, abuse of harmful substances and withdrawal symptoms. Harmful abusive substances include, but are not limited to, alcohol, amphetamines (or amphetamine-like substances), caffeine, marijuana, ***e, hallucinogens, inhalants, opioids, nicotine (and / or tobacco-related products), heroin abuse, barbiturates , phencyclidine (or compounds similar to phencyclidine), sedative hypnotics, benzodiazepines or combinations of any of the above. The compounds and pharmaceutical compositions can also be used to treat withdrawal symptoms and anxiety induced by harmful substances or mood disorders.

Adicionalmente, la presente invención proporciona un procedimiento para tratar la dependencia, adición, abstinencia a la nicotina, o para ayudar a dejar de fumar o abandonar el hábito del tabaco en un sujeto que lo necesita, administrando al sujeto una cantidad terapéuticamente eficaz de un compuesto o una composición farmacéutica de la presente invención. Additionally, the present invention provides a method of treating nicotine dependence, addition, withdrawal, or to help quit smoking or quit smoking in a subject in need, administering to the subject a therapeutically effective amount of a compound. or a pharmaceutical composition of the present invention.

Los síndromes, trastornos o enfermedades relacionados con el aprendizaje, conocimiento o memoria que pueden tratarse con los compuestos de la presente invención incluyen, pero sin limitación, pérdida o incapacidad de memoria como resultado de envejecimiento, enfermedad, efectos secundarios de medicaciones (eventos adversos) Syndromes, disorders or diseases related to learning, knowledge or memory that can be treated with the compounds of the present invention include, but are not limited to, loss or inability of memory as a result of aging, disease, side effects of medications (adverse events)

o similares. La incapacidad de memoria es un síntoma primario de demencia y puede ser también un síntoma asociado a enfermedades tales como enfermedad de Alzheimer, esquizofrenia, enfermedad de Parkinson, enfermedad de Huntington, enfermedad de Pick, enfermedad de Creutzfeld-Jakob, VIH, enfermedad cardiovascular y traumatismo craneal así como deterioro cognitivo relacionado con el envejecimiento. Generalmente, las demencias son enfermedades que incluyen pérdida de memoria y disfunción intelectual adicional independiente de la memora. Los compuestos y composiciones farmacéuticas de la presente invención también son útiles en el tratamiento de disfunciones cognitivas relacionadas con falta de atención, tal como trastorno de falta de atención. or similar. Memory impairment is a primary symptom of dementia and may also be a symptom associated with diseases such as Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeld-Jakob disease, HIV, cardiovascular disease and head trauma as well as cognitive impairment related to aging. Generally, dementias are diseases that include memory loss and additional intellectual dysfunction independent of the memo. The compounds and pharmaceutical compositions of the present invention are also useful in the treatment of cognitive dysfunctions related to inattention, such as inattention disorder.

Los síndromes, trastornos o enfermedades espásmicos musculares incluyen, pero sin limitación, esclerosis múltiple, parálisis cerebral y similares. Musculoskeletal syndromes, disorders or diseases include, but are not limited to, multiple sclerosis, cerebral palsy and the like.

Los síndromes, trastornos o enfermedades relacionados con la actividad locomotora y discinesias, incluyen, pero sin limitación, ictus, enfermedad de Parkinson, esclerosis múltiple, epilepsia y similares. Syndromes, disorders or diseases related to locomotor activity and dyskinesias include, but are not limited to, stroke, Parkinson's disease, multiple sclerosis, epilepsy and the like.

Los síndromes, trastornos o enfermedades respiratorias incluyen, pero sin limitación, enfermedades del tracto respiratorio, enfermedad pulmonar obstructiva crónica, enfisema, asma, bronquitis y similares. Syndromes, respiratory disorders or diseases include, but are not limited to, respiratory tract diseases, chronic obstructive pulmonary disease, emphysema, asthma, bronchitis and the like.

La nefritis por disfunción renal que puede tratarse con los moduladores de la presente invención incluye, pero sin limitación, glomerulonefritis mesangial proliferativa, síndrome nefrítico, disfunción hepática (hepatitis, cirrosis). Renal dysfunction nephritis that can be treated with the modulators of the present invention includes, but is not limited to, proliferative mesangial glomerulonephritis, nephritic syndrome, liver dysfunction (hepatitis, cirrhosis).

Los síndromes, enfermedades o trastornos autoinmunológicos o relacionados con inflamación incluyen, pero sin limitación, psoriasis, lupus eritematoso, enfermedades del tejido conjuntivo, síndrome de Sjögren, espondiloartritis anquilosante artritis reumatoide, artritis reactiva, espondiloartritis indiferenciada, enfermedad de Behcet, anemias hemolíticas autoinmunológicas, esclerosis múltiple, esclerosis lateral amiotrófica, amilosis, rechazo de injerto o enfermedades que afectan a la estirpe celular plasmática; enfermedades alérgicas: hipersensibilidad tardía o inmediata, rinitis alérgica, dermatitis por contacto o conjuntivitis alérgica, enfermedades parasitarias, virales o bacterianas infecciosas (tales como SIDA y meningitis), enfermedades inflamatorias (tales como enfermedades de las articulaciones, que incluyen, pero sin limitación, artritis, artritis reumatoide, osteoartritis, espondilitis, gota, vasculitis, enfermedad de Crohn, enfermedad inflamatoria intestinal (EII), síndrome del intestino irritable (SII)) y osteoporosis. Autoimmune or inflammation-related syndromes, diseases or disorders include, but are not limited to, psoriasis, lupus erythematosus, connective tissue diseases, Sjögren's syndrome, ankylosing spondyloarthritis, rheumatoid arthritis, reactive arthritis, undifferentiated spondyloarthritis, Behcet's disease, anemologic hemolytic autoimmune multiple sclerosis, amyotrophic lateral sclerosis, amylosis, graft rejection or diseases that affect plasma cell lineage; allergic diseases: late or immediate hypersensitivity, allergic rhinitis, contact dermatitis or allergic conjunctivitis, infectious parasitic, viral or bacterial diseases (such as AIDS and meningitis), inflammatory diseases (such as joint diseases, including, but not limited to, arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis, Crohn's disease, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS)) and osteoporosis.

Los síndromes, enfermedades o trastornos relacionados con el crecimiento celular incluyen, pero sin limitación, proliferación celular no regulada en mamíferos, proliferación celular de cáncer de mama, proliferación celular de cáncer de próstata y similares. Syndromes, diseases or disorders related to cell growth include, but are not limited to, unregulated cell proliferation in mammals, breast cancer cell proliferation, prostate cancer cell proliferation and the like.

Los síndromes, enfermedades o trastornos relacionados con el dolor incluyen, pero sin limitación, dolor mediado por la ruta central y periférica, dolor óseo y articular, dolor asociado a migraña, dolor por cáncer, dolor dental, dismenorrea, dolor por parto, dolor crónico de tipo inflamatorio, alergias, artritis reumatoide, dermatitis, inmunodeficiencia, dolor neuropático crónico (por ejemplo, dolor asociado con neuropatía diabética, ciática, dolor lumbar inespecífico, fibromialgia; neuropatía relacionada con el VIH; neuralgia postherpética, neuralgia trigémina y dolor resultante por traumatismo físico, amputación, cáncer, toxinas o afecciones inflamatorias crónicas), enfermedad de Hodgkin, miastenia grave, síndrome nefrótico, esclerodermia, tiroiditis y similares. Syndromes, diseases or disorders related to pain include, but are not limited to, pain mediated by the central and peripheral route, bone and joint pain, migraine-associated pain, cancer pain, dental pain, dysmenorrhea, labor pain, chronic pain inflammatory type, allergies, rheumatoid arthritis, dermatitis, immunodeficiency, chronic neuropathic pain (for example, pain associated with diabetic neuropathy, sciatica, nonspecific low back pain, fibromyalgia; HIV-related neuropathy; postherpetic neuralgia, trigeminal neuralgia and pain resulting from trauma physical, amputation, cancer, toxins or chronic inflammatory conditions), Hodgkin's disease, myasthenia gravis, nephrotic syndrome, scleroderma, thyroiditis and the like.

Los síndromes, trastornos o enfermedades neurodegenerativas relacionadas incluyen, pero sin limitación enfermedad de Parkinson, esclerosis múltiple, epilepsia, isquemia o lesión bioquímica secundaria colateral a traumatismo craneal o lesión cerebral, inflamación cerebral, lesión ocular o ictus y similares. Related neurodegenerative syndromes, disorders or diseases include, but are not limited to Parkinson's disease, multiple sclerosis, epilepsy, ischemia or biochemical lesion secondary to head trauma or brain injury, brain inflammation, eye injury or stroke and the like.

Los compuestos de la presente invención también pueden usarse junto con otros agentes farmacéuticos para el tratamiento de enfermedades, afecciones y/o trastornos descritos en el presente documente. Por lo tanto, también se proporcionan procedimientos de tratamiento que incluyen administrar los compuestos de la presente invención en combinación con otros agentes farmacéuticos. Los agentes farmacéuticos adecuados que pueden usarse en combinación con los compuestos de la presente invención incluyen, pero sin limitación, agentes anti-obesidad tales como inhibidores de secreción de apolipoproteína-B/proteína de transferencia de triglicéridos microsomales (apo-B/MTP), inhibidores de la 11β-hidroxi esteroide deshidrogenasa-1 (11β-HSD de tipo 1), péptido YY3-36 o análogos de los mismos, agonistas de MCR-4, agonistas de colecistoquinina-A (CCK-A), inhibidores de la recaptación de monoamina (tal como sibutramina), agentes simpaticomiméticos, agonistas de receptores β3 adrenérgicos, agonistas de receptores de dopamina (tal como bromocriptina), análogos de receptores de la hormona estimulante de melanocitos, agonistas de receptores de 5HT2c, agonistas de la hormona concentradora de melanina, leptina (la proteína OB), análogos de leptina, agonistas de receptores de leptina, antagonistas de galanina, inhibidores de lipasa (tal como tetrahidrolipstatina, es decir orlistat), agentes anorécticos (tal como agonista de bombesina), antagonistas de receptores del neuropéptido Y, agentes tiromiméticos, deshidroepiandrosterona o un análogo de los mismos, agonistas o antagonistas de receptores de glucocorticoides, antagonistas de receptores de orexina, agonistas de receptores del péptido 1 similar a glucagón (GLP-1), inhibidores de Proteína Tirosina Fosfatasa (PTP1B), inhibidores de dipeptidil peptidasa IV (DPP-IV), factores neurotróficos ciliares (tales como Axokine ™ disponible de Regeneron Pharmaceuticals, Inc., Tarrytown, N. Y. y Procter & Gamble Company, Cincinnati, Ohio), inhibidores de la proteína humana relacionada agouti (AGRP), antagonistas de receptores de grelina, antagonistas o agonistas inversos de receptores de histamina 3 y agonistas de receptores de neuromedina U. Se conocen bien otros agentes antiobesidad que incluyen los agentes preferidos expuestos más adelante en este documento o serán fácilmente evidentes a la luz de la presente divulgación, para un experto en la materia. The compounds of the present invention can also be used together with other pharmaceutical agents for the treatment of diseases, conditions and / or disorders described herein. Therefore, treatment procedures are also provided that include administering the compounds of the present invention in combination with other pharmaceutical agents. Suitable pharmaceutical agents that can be used in combination with the compounds of the present invention include, but are not limited to, anti-obesity agents such as apolipoprotein-B secretion inhibitors / microsomal triglyceride transfer protein (apo-B / MTP), 11β-hydroxy steroid dehydrogenase-1 (11β-HSD type 1) inhibitors, YY3-36 peptide or analogs thereof, MCR-4 agonists, cholecystokinin-A (CCK-A) agonists, reuptake inhibitors of monoamine (such as sibutramine), sympathomimetic agents, β3 adrenergic receptor agonists, dopamine receptor agonists (such as bromocriptine), melanocyte stimulating hormone receptor analogues, 5HT2c receptor agonists, hormone concentrating agonists melanin, leptin (OB protein), leptin analogs, leptin receptor agonists, galanin antagonists, lipase inhibitors (such as tetrahydrolipstatin , ie orlistat), anorectic agents (such as bombesin agonist), neuropeptide Y receptor antagonists, thyromimetic agents, dehydroepiandrosterone or an analogue thereof, glucocorticoid receptor agonists or antagonists, orexin receptor antagonists, agonists glucagon-like peptide 1 receptors (GLP-1), Protein Tyrosine Phosphatase (PTP1B) inhibitors, dipeptidyl peptidase IV (DPP-IV) inhibitors, ciliary neurotrophic factors (such as Axokine ™ available from Regeneron Pharmaceuticals, Inc., Tarrytown , NY and Procter & Gamble Company, Cincinnati, Ohio), agouti-related human protein inhibitors (AGRP), ghrelin receptor antagonists, histamine 3 receptor antagonists or inverse agonists and U neuromedin receptor agonists. other anti-obesity agents that include the preferred agents set forth hereinbelow or will be readily apparent to the light of the present disclosure, for an expert in the field.

Se prefieren especialmente agentes antiobesidad tales como orlistat, sibutramina, bromocriptina, efedrina, leptina, péptido YY3-36 o un análogo de los mismos (que incluyen el péptido completo YY) y pseudoefedrina. Preferentemente, los compuestos de la presente invención y terapias de combinación se administran junto con una dieta equilibrada y ejercicio. Especially preferred are antiobesity agents such as orlistat, sibutramine, bromocriptine, ephedrine, leptin, peptide YY3-36 or an analogue thereof (including the complete peptide YY) and pseudoephedrine. Preferably, the compounds of the present invention and combination therapies are administered together with a balanced diet and exercise.

Los agentes antiobesidad para su uso en las combinaciones, composiciones farmacéuticas y procedimientos de la invención pueden prepararse usando procedimientos conocidos por un experto en la materia, por ejemplo, la sibutramina puede prepararse como se describe en la Patente de Estados Unidos Nº 4.929.629; la bromocriptina puede prepararse como se describe en las Patentes de Estados Unidos Nº 3.752.814 y 3.752.888; el orlistat puede prepararse como se describe en las Patentes de Estados Unidos Nº 5.274.143, 5.420.305, 5.540.917 y 5.643.874; y el PYY3-36 (incluyendo análogos) puede prepararse como se describe en la Publicación de Patente de Estados Unidos Nº 2002/0141985 y en la Publicación Internacional Nº WO 03/027637. Todas las referencias indicadas anteriormente se incorporan por referencia en el presente documento. Antiobesity agents for use in the combinations, pharmaceutical compositions and methods of the invention can be prepared using methods known to a person skilled in the art, for example, sibutramine can be prepared as described in US Patent No. 4,929,629; Bromocriptine can be prepared as described in US Pat. Nos. 3,752,814 and 3,752,888; Orlistat can be prepared as described in U.S. Patent Nos. 5,274,143, 5,420,305, 5,540,917 and 5,643,874; and PYY3-36 (including analogs) can be prepared as described in United States Patent Publication No. 2002/0141985 and International Publication No. WO 03/027637. All references indicated above are incorporated by reference herein.

Otros agentes farmacéuticos adecuados que pueden administrarse en combinación con los compuestos de la presente invención incluyen agentes diseñados para tratar el abuso del consumo de tabaco (por ejemplo, agonistas parciales de receptores de nicotina, hipoclorito de bupropión (conocido también con el nombre comercial Zyban ™) y sus terapias de sustitución de nicotina), agentes para tratar la disfunción eréctil (por ejemplo, agentes dopaminérgicos, tales como apomorfina), agentes ADD/ADHD (por ejemplo, Ritalin ™ (clorhidrato de metilfenidato), Strattera ™(clorhidrato de atomoxetina), Concerta ™ (clorhidrato de metilplienidato) y Adderall ™(aspartato de anfetamina; sulfato de anfetamina; sacarato de dextroanfetamina y sulfato de dextroanfetamina)) y agentes para tratar el alcoholismo, tales como antagonistas de opioides (por ejemplo, naltrexona (conocida también con el nombre comercial ReVia ™) y nalmefeno), disulfiram (conocido también con el nombre comercial Antabuse ™) y acamprosato (conocido también con el nombre comercial Campral ™)). Además, también pueden coadministrarse agentes para reducir los síntomas de abstinencia del alcohol, tales como benzodiacepinas, beta bloqueantes, clonidina, carbamacepina, pregabalina y gabapentina (Neurontin ™). El tratamiento para el alcoholismo se administra preferentemente en combinación con terapias conductuales que incluyen componentes tales como terapia de potenciación motivacional, terapia conductual cognitiva y recomendación a grupos de autoayuda, que incluyen Alcohólicos Anónimos (AA). Other suitable pharmaceutical agents that can be administered in combination with the compounds of the present invention include agents designed to treat tobacco abuse (for example, partial agonists of nicotine receptors, bupropion hypochlorite (also known under the trade name Zyban ™ ) and its nicotine replacement therapies), agents for treating erectile dysfunction (for example, dopaminergic agents, such as apomorphine), ADD / ADHD agents (for example, Ritalin ™ (methylphenidate hydrochloride), Strattera ™ (atomoxetine hydrochloride ), Concerta ™ (Methylplienidate Hydrochloride) and Adderall ™ (Amphetamine Aspartate; Amphetamine Sulfate; Dextroamphetamine Sulfate and Dextroamphetamine Sulfate)) and agents for treating alcoholism, such as opioid antagonists (e.g. naltrexone (also known under the trade name ReVia ™) and nalmefene), disulfiram (also known under the trade name An tabuse ™) and acamprosate (also known under the trade name Campral ™)). In addition, agents can also be coadministered to reduce alcohol withdrawal symptoms, such as benzodiazepines, beta blockers, clonidine, carbamazepine, pregabalin and gabapentin (Neurontin ™). The treatment for alcoholism is preferably administered in combination with behavioral therapies that include components such as motivational potentiation therapy, cognitive behavioral therapy and recommendation to self-help groups, which include Alcoholics Anonymous (AA).

Otros agentes farmacéuticos que pueden ser útiles incluyen agentes hipertensivos; antidepresivos (por ejemplo clorhidrato de fluoxetina (Prozac ™)); agentes de mejora cognitiva (por ejemplo, clorhidrato de donepezil (Aircept ™.) y otros inhibidores de acetilcolinesterasa); agentes neuroprotectores (por ejemplo, memantina); medicaciones antipsicóticas (por ejemplo, ziprasidona (Geodon ™), risperidona (Risperdal ™) y olanzapina (Zyprexa ™)); insulina y análogos de insulina (por ejemplo, insulina LysPro); GLP-1 (7-37) (insulinotropina) y GLP-1 (7-36)-NH2; sulfonilureas y análogos de los mismos; cloropropamida, glibenclamida, tolbutamida, tolazamida, acetohexamida, Glypizide®, glimepirida, repaglinida, meglitinida; biguanidas: metformina, fenformina, buformina; agonistas α2 e imidazolinas: midaglizol, isaglidol, deriglidol, idazoxan, efaroxan, fluparoxan; otros secretagogos de insulina: linoglirida, A-4166; glitazonas: ciglitazona, Actos® (pioglitazona), englitazona, troglitazona, darglitazona, Avandia® (BRL49653); inhibidores de la oxidación de ácidos grasos: clomoxir, etomoxir; inhibidores de α-glucosidasa: acarbosa, miglitol, emiglitato, voglibosa, MDL-25,637, camiglibosa, MDL-73,945; β-agonistas: BRL 35135, BRL 37344, RO 16-8714, ICI D7114, CL 316,243; inhibidores de fosfodiesterasa: L-386,398; agentes hipolipemiantes: benfluorex: fenfluramina; complejos de vanadato y vanadio (por ejemplo, Naglivan®) y complejos de peroxovanadio: antagonistas de amilina; antagonistas de glucagón; inhibidores de la gluconeogénesis; análogos de somatostatina; agentes antilipolíticos; ácido nicotínico, acipimox, WAG 994, pramlintida (Symlin ™), AC 2993, nateglinida, inhibidores de aldosa reductasa (por ejemplo, zopolrestat), inhibidores de glucógeno fosforilasa, inhibidores de sorbitol deshidrogenasa, inhibidores de intercambio sodio-hidrógeno de tipo 1 (NHE-1) y/o inhibidores de la biosíntesis del colesterol o inhibidores de la absorción del colesterol, especialmente un inhibidor de la HMG-CoA reductasa o un inhibidor de la HMG-CoA sintasa o un inhibidor de la expresión del gen de HMG-COA reductasa o sintasa, un inhibidor de CETP, un secuestrante de ácidos grasos, un fibrato, un inhibidor de ACAT, un inhibidor de escualeno sintetasa, un antioxidante Other pharmaceutical agents that may be useful include hypertensive agents; antidepressants (for example fluoxetine hydrochloride (Prozac ™)); cognitive enhancement agents (for example, donepezil hydrochloride (Aircept ™.) and other acetylcholinesterase inhibitors); neuroprotective agents (for example, memantine); antipsychotic medications (for example, ziprasidone (Geodon ™), risperidone (Risperdal ™) and olanzapine (Zyprexa ™)); insulin and insulin analogues (eg, insulin LysPro); GLP-1 (7-37) (insulinotropin) and GLP-1 (7-36) -NH2; sulfonylureas and analogues thereof; chloropropamide, glibenclamide, tolbutamide, tolazamide, acetohexamide, Glypizide®, glimepiride, repaglinide, meglitinide; biguanides: metformin, fenformin, buformin; α2 agonists and imidazolines: midaglizol, isaglidol, deriglidol, idazoxan, efaroxan, fluparoxan; other insulin secretagogues: linogliride, A-4166; glitazones: ciglitazone, Actos® (pioglitazone), englitazone, troglitazone, darglitazone, Avandia® (BRL49653); fatty acid oxidation inhibitors: clomoxir, ethomoxir; α-glucosidase inhibitors: acarbose, miglitol, emiglitate, voglibose, MDL-25,637, camiglibose, MDL-73,945; β-agonists: BRL 35135, BRL 37344, RO 16-8714, ICI D7114, CL 316,243; phosphodiesterase inhibitors: L-386,398; lipid lowering agents: benfluorex: fenfluramine; vanadate and vanadium complexes (eg, Naglivan®) and peroxovanadium complexes: amylin antagonists; glucagon antagonists; gluconeogenesis inhibitors; somatostatin analogues; antilipolytic agents; nicotinic acid, acipimox, WAG 994, pramlintide (Symlin ™), AC 2993, nateglinide, aldose reductase inhibitors (for example, zopolrestat), glycogen phosphorylase inhibitors, sorbitol dehydrogenase inhibitors, sodium-hydrogen exchange inhibitors type 1 ( NHE-1) and / or cholesterol biosynthesis inhibitors or cholesterol absorption inhibitors, especially an HMG-CoA reductase inhibitor or an HMG-CoA synthase inhibitor or an HMG-gene expression inhibitor COA reductase or synthase, a CETP inhibitor, a fatty acid sequestrant, a fibrate, an ACAT inhibitor, a squalene synthetase inhibitor, an antioxidant

o niacina. Los compuestos de la presente invención también pueden administrarse en combinación con un compuesto de origen natural que actúa para disminuir los niveles de colesterol en plasma. Dichos compuestos de origen natural se denominan comúnmente nutraceúticos e incluyen, por ejemplo, extracto de ajo, extractos del cactus Hoodia y niacina. or niacin. The compounds of the present invention can also be administered in combination with a naturally occurring compound that acts to lower plasma cholesterol levels. Such naturally occurring compounds are commonly called nutraceuticals and include, for example, garlic extract, Hoodia cactus extracts and niacin.

Los compuestos de la presente invención (incluyendo las composiciones farmacéuticas y procesos usados en las mismas) pueden usarse en solitario o en combinación con otros agentes farmacéuticos en la fabricación de un medicamento para las aplicaciones terapéuticas descritas en el presente documento. The compounds of the present invention (including the pharmaceutical compositions and processes used therein) can be used alone or in combination with other pharmaceutical agents in the manufacture of a medicament for the therapeutic applications described herein.

Procedimientos generales de preparación General Preparation Procedures

El compuesto de fórmula general (1) puede sintetizarse mediante los esquemas que se ilustran a continuación. The compound of general formula (1) can be synthesized by the schemes illustrated below.

Los compuestos de fórmula (1), en la queW e Y son N; U, V y X son C; B es O; p es 0 ó 1; y R, R1 R2 son como se han descrito en la descripción general, pueden sintetizarse como se muestra en el esquema 1, The compounds of formula (1), in which W and Y are N; U, V and X are C; B is O; p is 0 or 1; and R, R1 R2 are as described in the general description, can be synthesized as shown in scheme 1,

imagen2image2

En el esquema anterior, el compuesto de fórmula general K puede oxidarse (por ejemplo, con SeO2 (dióxido de selenio)) para dar un compuesto de fórmula general B, que después puede someterse a aminación reductora (por ejemplo, en condiciones convencionales (por ejemplo, hidrogenación en presencia de NH4OAc, Pd/C)) para obtener la diamina vecinal de fórmula general C. El compuesto C puede monoacilarse (por ejemplo, con un cloruro de ácido 5 de la fórmula, pgOCH2COCl o un anhídrido de la fórmula, por ejemplo, OCH2(O)2O (en la que pg es un grupo protector de alcohol, por ejemplo, bencilo o metoximetilo (MOM))) para obtener una mono N-acil diamina de fórmula general D. El compuesto de fórmula general D pueden someterse a ciclación intramolecular para dar el compuesto In the above scheme, the compound of general formula K can be oxidized (for example, with SeO2 (selenium dioxide)) to give a compound of general formula B, which can then be subjected to reductive amination (for example, under conventional conditions (for example, hydrogenation in the presence of NH4OAc, Pd / C)) to obtain the neighborhood diamine of general formula C. Compound C can be monoacylated (for example, with an acid chloride of the formula, pgOCH2COCl or an anhydride of the formula, for example, OCH2 (O) 2O (in which pg is an alcohol protecting group, for example, benzyl or methoxymethyl (MOM))) to obtain an N-acyl diamine mono of general formula D. The compound of general formula D they can undergo intramolecular cyclization to give the compound

E. El compuesto E puede deshidrogenarse (por ejemplo, usando un agente de oxidación (tal como nitrato amónico de cerio o 2,3-dicloro-5,6-diciano-1,4-benzoquinona (DDQ))) para producir el compuesto de fórmula general F. El 10 compuesto F se convierte en los compuestos G1 y/o G2. Por ejemplo, la derivatización de los compuestos F por acilación, alquilación o arilación proporcionaría compuestos de fórmula general G1 y/o G2 que pueden separarse. El compuesto de fórmula general G1 y/o G2 obtenida de esta manera pueden hidrolizarse para formar el compuesto (los compuestos) H1 y/o H2. Los compuestos H1 y/o H2 pueden acoplarse con una amina (por ejemplo, HNR1R2) para formar un compuesto de fórmula (1). Las aminas adecuadas incluyen, pero sin limitación, N,N’E. Compound E can be dehydrogenated (for example, using an oxidation agent (such as cerium ammonium nitrate or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ))) to produce the compound of general formula F. The compound F becomes the compounds G1 and / or G2. For example, derivatization of compounds F by acylation, alkylation or arylation would provide compounds of general formula G1 and / or G2 that can be separated. The compound of general formula G1 and / or G2 obtained in this way can be hydrolyzed to form the compound (compounds) H1 and / or H2. The compounds H1 and / or H2 can be coupled with an amine (for example, HNR1R2) to form a compound of formula (1). Suitable amines include, but are not limited to, N, N ’

15 dicliclohexilcarbodiimida (DCC), clorhidrato de 1-(3-dimetilaminopropil)-3-etil carbodiimida (EDC) y reactivo hexafluorofosfato de benzotriazol-1-iloxitris(dimetilamino)-fosfonio (BOP). 15 dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl) -3-ethyl carbodiimide hydrochloride (EDC) and benzotriazol-1-yloxytris (dimethylamino) -phosphonium hexafluorophosphate reagent (BOP).

En otra realización, los compuestos de la fórmula (1) en la que X e Y son N; U, V y W son C; B es O; p es 0 ó 1; R, R1 y R2 son como se han descrito en la descripción general, pueden sintetizarse como se muestra en el esquema 2. In another embodiment, the compounds of the formula (1) in which X and Y are N; U, V and W are C; B is O; p is 0 or 1; R, R1 and R2 are as described in the general description, they can be synthesized as shown in scheme 2.

imagen2image2

20 En el esquema anterior, el compuesto de fórmula general K puede desprotonarse, por ejemplo, usando una base (tal como LiHMDS o LDA), seguido de acilación, por ejemplo, usando oxalato de dietilo, para obtener un compuesto de fórmula general L. Después, el compuesto de fórmula general L puede tratarse con una hidrazina sustituida (tal como RNHNH2) para obtener el compuesto (los compuestos) de fórmula general M y/o N. El compuesto (los compuestos) de fórmula general M y/o N obtenidos de esta forma pueden hidrolizarse y acoplarse con una amina In the above scheme, the compound of general formula K can be deprotonated, for example, using a base (such as LiHMDS or LDA), followed by acylation, for example, using diethyl oxalate, to obtain a compound of general formula L. Then, the compound of general formula L can be treated with a substituted hydrazine (such as RNHNH2) to obtain the compound (compounds) of general formula M and / or N. The compound (compounds) of general formula M and / or N obtained in this way can be hydrolyzed and coupled with an amine

25 (por ejemplo, HNR1R2) para formar un compuesto de fórmula (1). Las aminas adecuadas incluyen, pero sin limitación, N,N’-diciclohexilcarbodiimida (DCC), clorhidrato de 1-(3-dimetilaminopropil)-3-etil carbodiimida (EDC) y reactivo hexafluorofosfato de benzotriazol-1-iloxitris(dimetilamino)-fosfonio (BOP). 25 (for example, HNR1R2) to form a compound of formula (1). Suitable amines include, but are not limited to, N, N'-dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl) -3-ethyl carbodiimide hydrochloride (EDC) and benzotriazol-1-yloxytris (dimethylamino) -phosphonium hexafluorophosphate reagent (BOP)

En otra realización más, los compuestos de la fórmula (1) en la que V e Y son nitrógeno; U, W y X son carbono; B es oxígeno; p es 0 ó 1 y R, R1 y R2 son como se han descrito en la descripción general, pueden sintetizarse como se In yet another embodiment, the compounds of the formula (1) in which V and Y are nitrogen; U, W and X are carbon; B is oxygen; p is 0 or 1 and R, R1 and R2 are as described in the general description, can be synthesized as

30 muestra en el esquema 3. 30 shows in scheme 3.

imagen2image2

En el esquema anterior, el compuesto de fórmula general O se convierte en un compuesto de fórmula general P. Después, el compuesto P se acopla con una amina de fórmula general Q, por ejemplo, térmicamente o catalizada por reactivos, tales como, Hg(OAC)2, para formar un compuesto de la fórmula general R. El compuesto R se desprotege y se condensa para formar compuesto de la fórmula general S. La desprotección y condensación intramolecular posterior del compuesto R se realiza preferentemente en presencia de un ácido (tal como p.TsOH, MsOH, TfOH o CF3COOH). El compuesto de fórmula general S puede hidrolizarse y acoplarse con una amina (por ejemplo, HNR1R2) para formar un compuesto de fórmula (1). Las aminas adecuadas incluyen, pero sin limitación, N,N’-diciclohexilcarbodiimida (DCC), clorhidrato de 1-(3-dimetilaminopropil)-3-etil carbodiimida (EDC) y reactivo hexafluorofosfato de benzotriazol-1-iloxitris(dimetilamino)-fosfonio (BOP). In the above scheme, the compound of general formula O is converted into a compound of general formula P. Next, compound P is coupled with an amine of general formula Q, for example, thermally or catalyzed by reagents, such as, Hg ( OAC) 2, to form a compound of the general formula R. The compound R is deprotected and condensed to form a compound of the general formula S. The subsequent intramolecular deprotection and condensation of the compound R is preferably carried out in the presence of an acid (such as p.TsOH, MsOH, TfOH or CF3COOH). The compound of general formula S can be hydrolyzed and coupled with an amine (for example, HNR1R2) to form a compound of formula (1). Suitable amines include, but are not limited to, N, N'-dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl) -3-ethyl carbodiimide hydrochloride (EDC) and benzotriazol-1-yloxytris (dimethylamino) -phosphonium hexafluorophosphate reagent (BOP)

Debe apreciarse que la presente invención abarca todos los isómeros de los compuestos de fórmula (I) y sus derivados farmacéuticamente aceptables, incluyendo todas las formas geométricas, tautoméricas y ópticas, y mezclas de los mismos (por ejemplo, mezclas racémicas). Cuando están presentes centros quirales adicionales en compuestos de fórmula (I), la presente invención incluye dentro de su alcance todos los posibles diastereoiómeros, incluyendo mezclas de los mismos. Las diferentes formas isómericas pueden separarse o resolverse unas de las otras por procedimientos convencionales, o cualquier isómero dado puede obtenerse por procedimientos sintéticos convencionales o por síntesis esteroespecífica o asimétrica. La presente invención también incluye compuestos marcados isotópicamente, que son idénticos a los indicados en las fórmulas I y siguientes, pero en los que uno o más átomos se reemplazan por un átomo que tiene una masa atómica o número másico diferente de la masa atómica o número másico que se encuentra normalmente en la naturaleza. Los ejemplos de isótopos que pueden incorporarse en compuestos de la invención incluyen isótopos de hidrógeno, carbono, nitrógeno, oxígeno, fósforo, flúor, yodo y cloro, tales como 3H, 11C, 14C, 18F, 123I y 125I. It should be appreciated that the present invention encompasses all isomers of the compounds of formula (I) and their pharmaceutically acceptable derivatives, including all geometric, tautomeric and optical forms, and mixtures thereof (eg, racemic mixtures). When additional chiral centers are present in compounds of formula (I), the present invention includes within its scope all possible diastereoiomers, including mixtures thereof. The different isomeric forms can be separated or resolved from each other by conventional procedures, or any given isomer can be obtained by conventional synthetic procedures or by stereospecific or asymmetric synthesis. The present invention also includes isotopically labeled compounds, which are identical to those indicated in formulas I and following, but in which one or more atoms are replaced by an atom having a different atomic mass or mass number of the atomic mass or number mass that is normally found in nature. Examples of isotopes that can be incorporated into compounds of the invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, iodine and chlorine isotopes, such as 3H, 11C, 14C, 18F, 123I and 125I.

Los compuestos de la presente invención y sales farmacéuticamente aceptables de los compuestos que contienen los isótopos mencionados anteriormente y/u otros isótopos de otros átomos están dentro del alcance de la presente invención. Compuestos marcados isotópicamente de la presente invención, por ejemplo aquellos en los que se incorporan isótopos radiactivos tales como 3H, 14C, son útiles en los ensayos de distribución de fármacos y/o sustratos en tejidos. Se prefieren particularmente isótopos tritriados, es decir, 3H y carbono-14, es decir, 14C, por su facilidad de preparación y detectabilidad. Son particularmente útiles isótopos 11C y 8F en PET (tomografía de emisión de positrones) y son particularmente útiles isótopos 125I en SPECT (tomografía computerizada de emisión fotónica simple), todos útiles en la formación de imágenes del cerebro. Además, la sustitución con isótopos más pesados tales como deuterio, es decir, 2H, pueden proporcionar ciertas ventajas terapéuticas resultantes de mayor estabilidad metabólica, por ejemplo incremento de la semivida in vivo o requerimientos de dosificación reducidos, e incluso e incluso pueden preferirse en algunas circunstancias. Pueden prepararse compuestos marcados isotópicamente de fórmula I y siguientes de la presente invención realizando los procedimientos descritos en los Esquemas y/o en los Ejemplos como se indica a continuación, sustituyendo un reactivo marcado isotópicamente fácilmente disponible por un reactivo no marcado isotópicamente. The compounds of the present invention and pharmaceutically acceptable salts of the compounds containing the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present invention. Isotopically labeled compounds of the present invention, for example those in which radioactive isotopes such as 3H, 14C are incorporated, are useful in the drug and / or substrate distribution assays in tissues. Tritiated isotopes, i.e. 3H and carbon-14, i.e. 14C, are particularly preferred because of their ease of preparation and detectability. 11C and 8F isotopes are particularly useful in PET (positron emission tomography) and 125I isotopes in SPECT (single photon emission computed tomography), all useful in brain imaging are particularly useful. In addition, substitution with heavier isotopes such as deuterium, i.e., 2H, may provide certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements, and even and may even be preferred in some circumstances. Isotopically labeled compounds of formula I and following of the present invention can be prepared by performing the procedures described in the Schemes and / or in the Examples as indicated below, substituting an easily available isotopically labeled reagent with an isotopically unlabeled reagent.

Los compuestos de fórmula (I) pueden prepararse en forma cristalina o no cristalina y, si es cristalina, puede hidratarse o solvatarse opcionalmente. La presente invención incluye dentro de su alcance solvatos o hidratos The compounds of formula (I) can be prepared in crystalline or non-crystalline form and, if it is crystalline, can optionally be hydrated or solvated. The present invention includes within its scope solvates or hydrates

5 5

10 10

15 fifteen

20 twenty

25 25

30 30

35 35

40 40

45 Four. Five

estequimétricos así como compuestos que contienen cantidades variables de agua y/o disolvente. stoichiometric as well as compounds containing varying amounts of water and / or solvent.

Se ilustran realizaciones de la presente invención mediante los siguientes ejemplos. Debe entenderse, sin embargo, que las realizaciones de la invención no se limitan a los detalles específicos de estos ejemplos, de manera que otras variaciones de los mismos se conocerán o serán evidentes a la luz de la presente divulgación, para un experto en la materia. Embodiments of the present invention are illustrated by the following examples. It should be understood, however, that the embodiments of the invention are not limited to the specific details of these examples, so that other variations thereof will be known or apparent in the light of the present disclosure, to a person skilled in the art. .

Sección experimental Experimental section

Abreviaturas y notaciones: Las siguientes abreviaturas y notaciones se han usado en el siguiente texto. P.M: punto de fusión. reactivo BOP: hexafluorofosfato de (benzotriazol-1-iloxi)tris(dimetilamino)fosfonio. FC: Cromatografía Ultrarrápida. J: Constantes de acoplamientos expresadas en unidades de Hz. THF: tertrahidrofurano. Et3N: trietil amina. BuLi: butil-litio. LiHMDS: hexametil disililazida de litio Abbreviations and notations: The following abbreviations and notations have been used in the following text. P.M: melting point. BOP reagent: (benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate. FC: Ultrafast Chromatography. J: Coupling constants expressed in units of Hz. THF: tertrahydrofuran. Et3N: triethyl amine. BuLi: butyl lithium. LiHMDS: lithium hexamethyl disililazide

Intermedio 1 Intermediate 1

Ácido 5-(2-bromofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxílico 5- (2-Bromophenyl) -5,6-diazatetracycle [7.3.1.13.11.04.8] tetradeca-4 (8), 6-diene-7-carboxylic acid

Etapa 1: 2-Oxo-(5-oxotriciclo[4,3,1,1,3,8]undec-4-il)acetato de etilo Stage 1: 2-Oxo- (5-oxotricyclo [4,3,1,1,3,8] undec-4-yl) ethyl acetate

Una sol. 1,6 M de n-BuLi en hexano se añadió a una solución de hexametildisilazano (1,27 ml, 5,4 mmol) en éter dietílico (10,0 ml) a -78 ºC y se agitó a esa temperatura durante 15 min. A esta mezcla se le añadió una solución de homoada-mantanona [900 mg, 5,4 mmol, preparada de acuerdo con: Black, R. M. y Gill, G. B., J. Chem. Soc. (C), 1970, 671] en éter dietílico (27,0 ml) y la agitación -78 ºC. se continuó durante 45 min. más. Se añadió oxalato de dietilo (0,98 ml, 6,5 mmol) y la mezcla se dejó calentar lentamente a 25 ºC. Después de agitar durante una noche, agua, se añadió agua (25 ml) a la solución y las fases se separaron. La fase acuosa se lavó dos veces con éter dietílico (20 ml), se acidificó con HCl 1 N y se extrajo con en éter dietílico (3 x 20 ml), la fase orgánica se secó sobre Na2SO4, se filtró y se evaporó. La cromatografía ultrarrápida (97:3 de éter de petróleo/acetato de etilo) dio el compuesto del título en forma de un aceite de color amarillo (589 mg, 36%). RMN 1H (δ ppm, CDCl3, 300 MHz): 15,75 (s, 1H); 4,33 (c, J = 7,2, 2H); 2,80 (t a, J= 6, 1H); 2,75-2,70 (m, 1H); 2,13-85 (m, 8H); 1,81-1,69 (m, 4 H); 1,36 (m, t, J = 7,2, 3H). IR (cm-1 puro): 3423 (a), 2982 (w), 2919 (s), 2851 (m), 1741 (s), 1599 (s, a). A sun. 1.6 M of n-BuLi in hexane was added to a solution of hexamethyldisilazane (1.27 ml, 5.4 mmol) in diethyl ether (10.0 ml) at -78 ° C and stirred at that temperature for 15 min . To this mixture was added a solution of homoada-mantanone [900 mg, 5.4 mmol, prepared according to: Black, RM and Gill, GB, J. Chem. Soc. (C), 1970, 671] in ether diethyl (27.0 ml) and stirring -78 ° C. It was continued for 45 min. plus. Diethyl oxalate (0.98 ml, 6.5 mmol) was added and the mixture was allowed to slowly warm to 25 ° C. After stirring overnight, water, water (25 ml) was added to the solution and the phases were separated. The aqueous phase was washed twice with diethyl ether (20 ml), acidified with 1 N HCl and extracted with in diethyl ether (3 x 20 ml), the organic phase was dried over Na2SO4, filtered and evaporated. Flash chromatography (97: 3 petroleum ether / ethyl acetate) gave the title compound as a yellow oil (589 mg, 36%). 1H NMR (δ ppm, CDCl3, 300 MHz): 15.75 (s, 1H); 4.33 (c, J = 7.2, 2H); 2.80 (t a, J = 6, 1H); 2.75-2.70 (m, 1 H); 2.13-85 (m, 8H); 1.81-1.69 (m, 4 H); 1.36 (m, t, J = 7.2, 3H). IR (pure cm-1): 3423 (a), 2982 (w), 2919 (s), 2851 (m), 1741 (s), 1599 (s, a).

Etapa 2: 5-(2-Bromofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxilato de etilo Stage 2: 5- (2-Bromophenyl) -5,6-diazatetracyclo [7.3.1.13.11.04.8] tetradeca-4 (8), ethyl 6-diene-7-carboxylate

Una solución del intermedio 1 (2,0 g, 7,56 mmol), clorhidrato de 2-bromofenilhidrazina (1,86 g, 8,32 mmol) y etanol (30 ml) se calentó a reflujo durante 1 h. Después de un periodo de refrigeración, el sólido precipitado se recogió por filtración y se secó para dar el producto del título en forma pura (2,04 g, 65%). RMN 1H (δ ppm, CDCl3, 300 MHz): 7,67 (dd, J = 7,8, 1,2, 1H); 7,42-7,26 (m, 3H); 4,40 (c, J = 7,2, 2H); 3,79 (t a, J = 5,4, 1H); 2,54 (t a, J = 7,2, 1H); 2,18 (s a, 2H); 2,14-1,92 (m, 4H); 1,92-1,60 (m, 6H); 1,39 (t, J = 7,2, 3H). A solution of intermediate 1 (2.0 g, 7.56 mmol), 2-bromophenylhydrazine hydrochloride (1.86 g, 8.32 mmol) and ethanol (30 ml) was heated at reflux for 1 h. After a period of cooling, the precipitated solid was collected by filtration and dried to give the title product in pure form (2.04 g, 65%). 1H NMR (δ ppm, CDCl3, 300 MHz): 7.67 (dd, J = 7.8, 1.2, 1H); 7.42-7.26 (m, 3H); 4.40 (c, J = 7.2, 2H); 3.79 (t a, J = 5.4, 1H); 2.54 (t a, J = 7.2, 1H); 2.18 (s at, 2H); 2.14-1.92 (m, 4H); 1.92-1.60 (m, 6H); 1.39 (t, J = 7.2, 3H).

Etapa 3: Ácido 5-(2-bromofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxílico Stage 3: 5- (2-Bromophenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxylic acid

Una solución de 5-(2-bromofenil)-5,6-diazatetraciclo[7.3.1.13,11.0 4,8]tetradeca-4(8),6-dieno-7-carboxilato de etilo en etanol:agua (20:1) se calentó a reflujo con KOH (270 mg, 4,82 mmol) durante 2 h. Después de la retirada del etanol, el residuo se disolvió en agua y se acidificó a pH 4,0 con HCl acuoso 1 N. El precipitado se filtró y se secó para dar el intermedio 1 puro (715 mg, 77%). RMN 1H (δ ppm, CDCl3, 300 MHz): 7,71 (dd, J = 7,8, 1,5, 1H); 7,50-7,32 (m, 3H); 3,79 (t a, J = 5,1, 1H); 2,56 (t a, J = 5,0, 1H); 2,19 (s, 2H); 2,12-1,90 (m, 4H); 1,90-1,66 (m, 6H). A solution of 5- (2-bromophenyl) -5,6-diazatetracyclo [7.3.1.13.11.0 4.8] tetradeca-4 (8), ethyl 6-diene-7-carboxylate in ethanol: water (20: 1 ) was heated at reflux with KOH (270 mg, 4.82 mmol) for 2 h. After ethanol removal, the residue was dissolved in water and acidified to pH 4.0 with 1 N aqueous HCl. The precipitate was filtered and dried to give pure intermediate 1 (715 mg, 77%). 1H NMR (δ ppm, CDCl3, 300 MHz): 7.71 (dd, J = 7.8, 1.5, 1H); 7.50-7.32 (m, 3H); 3.79 (t a, J = 5.1, 1H); 2.56 (t a, J = 5.0, 1H); 2.19 (s, 2 H); 2.12-1.90 (m, 4H); 1.90-1.66 (m, 6H).

Los intermedios 2 a 11 se prepararon de acuerdo con el procedimiento que se ha descrito en la etapas 2 y 3 del intermedio 1, usando 2-oxo-(5-oxotriciclo[4,3,1,1,3,8]undec-4-il)acetato de etilo, fenilo sustituido o sin sustituir adecuado o piridil hidrazina e Intermedio 2 alcalino Intermediates 2 to 11 were prepared according to the procedure described in steps 2 and 3 of intermediate 1, using 2-oxo- (5-oxotricyclo [4,3,1,1,3,8] undec- 4-yl) ethyl acetate, suitable substituted or unsubstituted phenyl or pyridyl hydrazine and alkaline Intermediate 2

Intermedio 2 Intermediate 2

ácido 5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxílico 5- (4-Chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxylic acid

Etapa 1: 5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.1 3,11.04,8]tetradeca-4(8),6-dieno-7-carboxilato de etilo Stage 1: 5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.1 3.11.04.8] tetradeca-4 (8), ethyl 6-diene-7-carboxylate

Rendimiento: 54%. RMN 1H (δ ppm, CDCl3; 300 MHz): 7,43, 7,30 (AB, J = 10, 4H); 4,40 (c, J = 7,5, 2H); 3,79 (t, J = 5,1, 1H); 3,0 (t, J = 5,4, 1H); 2,21 (s a, 2H); 2,06-1,77 (m, 10H); 1,40 (t, J =7,5, 3H). Yield: 54%. 1 H NMR (δ ppm, CDCl 3; 300 MHz): 7.43, 7.30 (AB, J = 10, 4H); 4.40 (c, J = 7.5, 2H); 3.79 (t, J = 5.1, 1H); 3.0 (t, J = 5.4, 1H); 2.21 (s at, 2H); 2.06-1.77 (m, 10H); 1.40 (t, J = 7.5, 3H).

Etapa 2: Ácido 5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxílico Stage 2: 5- (4-Chlorophenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxylic acid

Rendimiento: 89%. RMN 1H (δ ppm, DMSO-d6): 7,59 (d, J = 8,7, 2H); 7,39 (d, J =8,7, 2H); 3,76 (s a, 1H); 2,97 (s a, 1H); 2,14 (s a, 2H); 1,67-1,98 (m, 10H). Yield: 89%. 1H NMR (δ ppm, DMSO-d6): 7.59 (d, J = 8.7, 2H); 7.39 (d, J = 8.7, 2H); 3.76 (s a, 1 H); 2.97 (s at, 1 H); 2.14 (s a, 2H); 1.67-1.98 (m, 10H).

Intermedio 3 Intermediate 3

Ácido 5-(2,4dDifluorofenil)-5,6-diazatetraciclo[7,3,1:13,11.04,8]tetradeca-4(8),6-dieno-7-carboxílico 5- (2,4dDifluorophenyl) -5,6-diazatetracyclo [7,3,1: 13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxylic acid

Etapa 1: 5-(2,4-Difluorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxilato de etilo Stage 1: 5- (2,4-Difluorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), ethyl 6-diene-7-carboxylate

Rendimiento: 96%. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,50-7,40 (m, 1H); 7,02-6,90 (m, 2H); 4,38 (c, J = 7,2, 2H); 3,76 (s a, 1H); 2,66 (s a, 1H); 2,17 (s a, 2H); 2,05-1,70 (m, 10H), 1,37 (t, J = 7,2, 3H). Yield: 96%. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.50-7.40 (m, 1H); 7.02-6.90 (m, 2H); 4.38 (c, J = 7.2, 2H); 3.76 (s a, 1 H); 2.66 (s at, 1 H); 2.17 (s a, 2H); 2.05-1.70 (m, 10H), 1.37 (t, J = 7.2, 3H).

Etapa 2: Ácido 5-(2,4-difluorofenil)-5,6-diazatetraciclo[7.3.1.13,11,0 4,8]tetradeca-4(8),6-dieno-7-carboxílico Stage 2: 5- (2,4-Difluorophenyl) -5,6-diazatetracycle [7.3.1.13,11.0 4.8] tetradeca-4 (8), 6-diene-7-carboxylic acid

Rendimiento: 95%. RMN 1H (δ ppm, CDCl3, 300 MHz): 12,80 (s a, 1H); 7,70-7,55 (m, 2H); 7,30 (t a, J = 7,5, 1H); 3,66 (s a, 1H); 2,63 (s a, 1H); 2,13 (s, 2H); 2,00-1,71 (m, 10H). Yield: 95%. 1H NMR (δ ppm, CDCl3, 300 MHz): 12.80 (s at, 1H); 7.70-7.55 (m, 2H); 7.30 (t a, J = 7.5, 1H); 3.66 (s at, 1 H); 2.63 (s at, 1 H); 2.13 (s, 2H); 2.00-1.71 (m, 10H).

Intermedio 4 Intermediate 4

Ácido 5-(4-fluorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxílico 5- (4-fluorophenyl) -5,6-diazatetracyclo [7.3.1.13.11.04.8] tetradeca-4 (8), 6-diene-7-carboxylic acid

Etapa 1: 5-(4-Fluorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxilato de etilo Stage 1: 5- (4-Fluorophenyl) -5,6-diazatetracyclo [7.3.1.13.11.04.8] tetradeca-4 (8), ethyl 6-diene-7-carboxylate

Rendimiento: 55%. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,38-7,31 (m, 2H); 7,18-7,11 (m, 2H); 4,39 (c, J = 7,5, 2H); 3,78 (s a, 1H); 2,95 (s a, 1H); 2,20 (s a, 2H); 2,06-1,76 (m, 10H); 1,39 (t, J = 7,2, 3H). Yield: 55%. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.38-7.31 (m, 2H); 7.18-7.11 (m, 2H); 4.39 (c, J = 7.5, 2H); 3.78 (s a, 1 H); 2.95 (s at, 1 H); 2.20 (s a, 2H); 2.06-1.76 (m, 10H); 1.39 (t, J = 7.2, 3H).

Etapa 2: Ácido 5-(4-fluorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxílico Stage 2: 5- (4-fluorophenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxylic acid

Rendimiento: 81%. RMN 1H (δ ppm, DMSO-d6, 300 MHz): 12,60 (s a, 1H); 7,47-7,35 (m, 4H); 3,67 (s a, 1H); 2,91 (s a, 1H); 2,14 (s a, 2H); 1,98-1,71 (m, 10H). Yield: 81%. 1H NMR (δ ppm, DMSO-d6, 300 MHz): 12.60 (s at, 1H); 7.47-7.35 (m, 4H); 3.67 (s at, 1 H); 2.91 (s a, 1 H); 2.14 (s a, 2H); 1.98-1.71 (m, 10H).

Intermedio 5 Intermediate 5

Ácido 5-(4-metilfenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxílico 5- (4-Methylphenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxylic acid

Etapa 1: 5-(4-Metilfenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxilato de etilo Stage 1: 5- (4-Methylphenyl) -5,6-diazatetracycle [7.3.1.13.11.04.8] tetradeca-4 (8), ethyl 6-diene-7-carboxylate

Rendimiento: 91%. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,23 (s, 4H); 4,39 (c, J = 7,2, 2H); 3,79 (t a, J = 5,7, 1H); 3,00 (s a, 1H); 2,41 (s, 3H); 2,19 (s a, 2H); 2,07-1,95 (m, 2H); 1,95-1,73 (m, 8H); 1,40 (t, J =7,2, 3H). Yield: 91%. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.23 (s, 4H); 4.39 (c, J = 7.2, 2H); 3.79 (t a, J = 5.7, 1H); 3.00 (s at, 1 H); 2.41 (s, 3 H); 2.19 (s a, 2H); 2.07-1.95 (m, 2H); 1.95-1.73 (m, 8H); 1.40 (t, J = 7.2, 3H).

Etapa 2: Ácido 5-(4-metilfenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxílico Stage 2: 5- (4-methylphenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxylic acid

Rendimiento: 99%. RMN 1H (δ ppm, DMSO-d6, 300 MHz): 12,60 (s a, 1H); 7,34 (d, J = 8,1, 2H); 7,26 (d, J = 8,1, 2H); 3,68 (s a, 1H); 2,94 (s a, 1H); 2,37 (s, 3H); 2,12 (s a, 2H); 2,05-1,62 (m, 10H). Yield: 99%. 1H NMR (δ ppm, DMSO-d6, 300 MHz): 12.60 (s at, 1H); 7.34 (d, J = 8.1, 2H); 7.26 (d, J = 8.1, 2H); 3.68 (s at, 1 H); 2.94 (s a, 1 H); 2.37 (s, 3 H); 2.12 (s a, 2H); 2.05-1.62 (m, 10H).

Intermedio 6 Intermediate 6

Ácido 5-(4-metoxifenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxílico 5- (4-Methoxyphenyl) -5,6-diazatetracycle [7.3.1.13.11.04.8] tetradeca-4 (8), 6-diene-7-carboxylic acid

Etapa 1: 5-(4-Metoxifenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxilato de etilo Stage 1: 5- (4-Methoxyphenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), ethyl 6-diene-7-carboxylate

Rendimiento: 78%. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,29 (d, J = 9,0); 6,96 (d, J = 9,0, 2H); 4,39 (c, J = 7,2, 2H); 3,79 (t a, J = 5,0, 1H); 2,96 (s a, 1H); 2,19 (s a, 1H); 2,08-1,96 (m, 2H); 1,96-1,74 (m, 8H); 1,39 (t, J = 7,2, 3H). Yield: 78%. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.29 (d, J = 9.0); 6.96 (d, J = 9.0, 2H); 4.39 (c, J = 7.2, 2H); 3.79 (t a, J = 5.0, 1H); 2.96 (s at, 1 H); 2.19 (s a, 1 H); 2.08-1.96 (m, 2H); 1.96-1.74 (m, 8H); 1.39 (t, J = 7.2, 3H).

Etapa 2: Ácido 5-(4-metoxifenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxílico Stage 2: 5- (4-Methoxyphenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxylic acid

Rendimiento: 95%. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,28 (d, J = 9,0, 2H); 6,98 (d, J = 9,0, 2H); 3,86 (s, 3H); 3,78 (t, J = 5,4, 1H); 2,99 (s a, 1H); 2,21 (s a, 2H); 2,10-1,70 (m, 10H). Yield: 95%. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.28 (d, J = 9.0, 2H); 6.98 (d, J = 9.0, 2H); 3.86 (s, 3 H); 3.78 (t, J = 5.4, 1H); 2.99 (s at, 1H); 2.21 (s at, 2H); 2.10-1.70 (m, 10H).

Intermedio 7 Intermediate 7

Ácido 5-fenil-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxílico 5-Phenyl-5,6-diazatetracyclo acid [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxylic acid

Etapa 1: 5-Fenil-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxilato de etilo Stage 1: ethyl 5-Phenyl-5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxylate

Rendimiento: 63%. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,50-7,32 (m, 5H); 4,40 (c, J = 7,5, 2H); 3,80 (t, J = 5,4, 1H); 3,02 (t a, J = 4,8, 1H); 2,22 (s a, 2H); 2,07-1,95 (m, 2H); 1,95-1,76 (m, 8H); 1,40 (t, J = 7,5,3H). Yield: 63%. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.50-7.32 (m, 5H); 4.40 (c, J = 7.5, 2H); 3.80 (t, J = 5.4, 1H); 3.02 (t a, J = 4.8, 1H); 2.22 (s at, 2H); 2.07-1.95 (m, 2H); 1.95-1.76 (m, 8H); 1.40 (t, J = 7.5.3H).

Etapa 2: Ácido 5-fenil-5,6-diazatetraciclo[7.3.1.1,3,11.04,8]tetradeca-4(8),6-dieno-7-carboxílico Stage 2: 5-Phenyl-5,6-diazatetracyclo acid [7.3.1.1,3,11.04,8] tetradeca-4 (8), 6-diene-7-carboxylic acid

Rendimiento: 91%. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,58-7,42 (m, 3H); 7,37 (dd, J =7,8, 1,2, 2H); 3,80 (t, J = 5,4, 1H); 3,06 (s a, 1H); 2,22 (s a, 2H); 2,10-1,75 (m, 10H). Yield: 91%. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.58-7.42 (m, 3H); 7.37 (dd, J = 7.8, 1.2, 2H); 3.80 (t, J = 5.4, 1H); 3.06 (s at, 1 H); 2.22 (s at, 2H); 2.10-1.75 (m, 10H).

Intermedio 8 Intermediate 8

Ácido 5-(2,4-diclorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxílico 5- (2,4-Dichlorophenyl) -5,6-diazatetracycle [7.3.1.13.11.04.8] tetradeca-4 (8), 6-diene-7-carboxylic acid

Etapa 1: 5-(2,4-Diclorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxilato de etilo Stage 1: 5- (2,4-Dichlorophenyl) -5,6-diazatetracycle [7.3.1.13.11.04.8] tetradeca-4 (8), ethyl 6-diene-7-carboxylate

Rendimiento: 71%. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,52 (s, 1H); 7,34 (s, 2H); 4,39 (c, J = 6,9, 2H); 3,79 (t a, J = 5,4, 1H); 2,55 (t a, J = 4,6, 1H); 2,19 (s a, 2H); 2,10-1,60 (m, 10H); 1,39 (t, J = 6,9, 3H). Yield: 71%. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.52 (s, 1H); 7.34 (s, 2H); 4.39 (c, J = 6.9, 2H); 3.79 (t a, J = 5.4, 1H); 2.55 (t a, J = 4.6, 1H); 2.19 (s a, 2H); 2.10-1.60 (m, 10H); 1.39 (t, J = 6.9, 3H).

Etapa 2: Ácido 5-(2,4-diclorofenil)-5,6-diazatetraciclo[7.3.1.1 3,11.04,8]tetradeca-4(8),6-dieno-7-carboxílico Stage 2: 5- (2,4-Dichlorophenyl) -5,6-diazatetracycle [7.3.1.1 3.11.04.8] tetradeca-4 (8), 6-diene-7-carboxylic acid

Rendimiento: 95%. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,57 (d, J =1,8, 1H); 7,38 (dd, J = 8,4, 1,8, 1H); 7,32 (d, J = 8,4, 1H); 3,78 (t a, J = 5,4, 1H); 2,57 (t a, J = 4,6, 1H); 2,20 (s a, 2H); 2,10-2,65 (m, 10H). Yield: 95%. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.57 (d, J = 1.8, 1H); 7.38 (dd, J = 8.4, 1.8, 1H); 7.32 (d, J = 8.4, 1H); 3.78 (t a, J = 5.4, 1H); 2.57 (t a, J = 4.6, 1H); 2.20 (s a, 2H); 2.10-2.65 (m, 10H).

Intermedio 9 Intermediate 9

Ácido 5-(2-clorofenil)-5,6 diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxílico 5- (2-Chlorophenyl) -5.6 diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxylic acid

Etapa 1: 5-(2-Clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxilato de etilo Stage 1: 5- (2-Chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), ethyl 6-diene-7-carboxylate

Rendimiento: 56% RMN 1H (δ ppm, CDCl3, 300 MHz): 7,53-7,48 (m, 1H); 7,45-7,32 (m, 3H); 4,40 (c, J = 7,5, 2H); 3,80 (t, J = 5,7, 1H); 2,57 (t a, J =5,4, 1H); 2,17 (m, 2H); 2,08-1,65 (m, 10H); 1,39 (t, J =7,5, 3H). Yield: 56% 1H NMR (δ ppm, CDCl3, 300 MHz): 7.53-7.48 (m, 1H); 7.45-7.32 (m, 3H); 4.40 (c, J = 7.5, 2H); 3.80 (t, J = 5.7, 1H); 2.57 (t a, J = 5.4, 1H); 2.17 (m, 2H); 2.08-1.65 (m, 10H); 1.39 (t, J = 7.5, 3H).

Etapa 2: Ácido 5-(2-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxílico Stage 2: 5- (2-Chlorophenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxylic acid

Rendimiento: 96%. RMN 1H (δ ppm, DMSO-d6, 300 MHz): 12,66 (s a, 1H); 7,72 (d, J = 8,1, 1H); 7,70-7,51 (m, 3H); 3,68 (t, J =5,1, 1H); 2,46 (s a, 1H); 2,13 (s a, 2H); 2,03-1,64 (m, 10H). Yield: 96%. 1H NMR (δ ppm, DMSO-d6, 300 MHz): 12.66 (s at, 1H); 7.72 (d, J = 8.1, 1H); 7.70-7.51 (m, 3H); 3.68 (t, J = 5.1, 1H); 2.46 (s at, 1 H); 2.13 (s a, 2H); 2.03-1.64 (m, 10H).

Intermedio 10 Intermediate 10

Ácido 5-(5-cloropiridil)-5,6-diazatetraciclo[7.3.1.13,11 .04,8]tetradeca-4(8),6-dieno-7-carboxílico 5- (5-Chloropyridyl) -5,6-diazatetracycle [7.3.1.13.11 .04.8] tetradeca-4 (8), 6-diene-7-carboxylic acid

Etapa 1: 5-(5-Cloropiridil)-5,6-diazatetraciclo[7.3.1.13,11. 04,8]tetradeca-4(8), 6-dieno-7-carboxilato de etilo Stage 1: 5- (5-Chloropyridyl) -5,6-diazatetracycle [7.3.1.13.11. 04.8] tetradeca-4 (8), ethyl 6-diene-7-carboxylate

Rendimiento: 28%. RMN-1H (δ ppm, DMSO-d6, 300 MHz): 8,46-8,44 (d, J = 2,7, 1H); 8,08 (dd, J = 8,7, 2,7, 1H); 7,74 (d, J = 8,7, 1H); 4,21 (c, J = 6,9, 2H); 3,13-3,06 (m, 2H); 2,12-1,62 (m, 12H); 1,12 (t, J = 7,2, 3H). Yield: 28%. 1H NMR (δ ppm, DMSO-d6, 300 MHz): 8.46-8.44 (d, J = 2.7, 1H); 8.08 (dd, J = 8.7, 2.7, 1H); 7.74 (d, J = 8.7, 1H); 4.21 (c, J = 6.9, 2H); 3.13-3.06 (m, 2H); 2.12-1.62 (m, 12H); 1.12 (t, J = 7.2, 3H).

Etapa 2: Ácido 5-(5-cloropiridil)-5,6-diazatetraciclo[7.3.1.13,11, 04,8]tetradeca-4(8), 6-dieno-7-carboxílico Stage 2: 5- (5-Chloropyridyl) -5,6-diazatetracycle [7.3.1.13,11, 04,8] tetradeca-4 (8), 6-diene-7-carboxylic acid

Rendimiento: 78%. RMN 1H (δ ppm, DMSO-d6, 300 MHz): 13,25 (s a, 1H), 8,44 (d, J = 2,5, 1H); 8,06 (dd, J = 8,0, 2,5, 1); 7,70 (d, J = 8,1, 1H); 3 .22 (s a, 1H); 3,05 (s a, 1H); 2,12-1,64 (m, 12H). Yield: 78%. 1H NMR (δ ppm, DMSO-d6, 300 MHz): 13.25 (s a, 1H), 8.44 (d, J = 2.5, 1H); 8.06 (dd, J = 8.0, 2.5, 1); 7.70 (d, J = 8.1, 1H); 3.22 (s a, 1 H); 3.05 (s at, 1 H); 2.12-1.64 (m, 12H).

Intermedio 11 Intermediate 11

Ácido 5,6-diazatetrciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxílico 5,6-Diazatetrcycle acid [7.3.1.13.11.04.8] tetradeca-4 (8), 6-diene-7-carboxylic acid

Etapa 1: 5,6-Diazatetraciclo[7.3.1.1 3,11.04,8]tetradeca-4(8),6-dieno-7-carboxilato de etilo Stage 1: 5,6-Diazatetracycle [7.3.1.1 3.11.04.8] tetradeca-4 (8), ethyl 6-diene-7-carboxylate

Rendimiento: 97%. RMN 1H (δ ppm, CDCl3): 4,36 (c, J = 7,2, 2H); 3,61 (t a, J = 5,4, 1H); 3,10 (s a, 1H), 2,16 (s a, 2H);.2,08-1,95 (m, 4H); 1,85-1,70 (m, 6H); 1,38 (t, J = 7,2, 2H). Yield: 97%. 1H NMR (δ ppm, CDCl3): 4.36 (c, J = 7.2, 2H); 3.61 (t a, J = 5.4, 1H); 3.10 (s at, 1H), 2.16 (s at, 2H); 2.08-1.95 (m, 4H); 1.85-1.70 (m, 6H); 1.38 (t, J = 7.2, 2H).

Etapa 2: Ácido 5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxílico Stage 2: 5,6-diazatetracycle acid [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxylic acid

Rendimiento: 79%. RMN 1H (δ ppm, DMSO-d6): 12,78 (s a, 1H); 3,54 (s a, 1H); 2,97 (s a, 1H); 2,09 (s a, 2H); 1,971,85 (m, 4H); 1,77 (s a, 2H); 1,68 (t, J = 12,0, 4H). Yield: 79%. 1H NMR (δ ppm, DMSO-d6): 12.78 (s a, 1H); 3.54 (s at, 1 H); 2.97 (s at, 1 H); 2.09 (s a, 2H); 1,971.85 (m, 4H); 1.77 (s a, 2H); 1.68 (t, J = 12.0, 4H).

Intermedio 12a e Intermedio 12b Intermediate 12a and Intermediate 12b

6-Metil-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxilato etilo (intermedio 12a) y 5-Metil-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxilato etilo (Intermedio 12b): 6-Methyl-5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxylate ethyl (intermediate 12a) and 5-Methyl-5,6-diazatetracycle [7.3. 1.13.11.04.8] tetradeca-4 (8), ethyl 6-diene-7-carboxylate (Intermediate 12b):

Una solución de ácido 5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxílico (100 mg, 0,38 mmol) en DMF (2 ml) se trató con NaH (dispersión al 50% en aceite mineral, 20 mg, 0,4 mmol), se agitó a temperatura ambiente durante 45 minutos y después se añadió yodometano (60 mg, 0,026 mmol) a la mezcla. La agitación se continuó durante 1,5 h más. La mezcla se vertió en agua, se extrajo en acetato de etilo y se secó sobre sulfato sódico anhidro. La evaporación y la separación por cromatografía ultrarrápida dieron el Intermedio 12a y el Intermedio12b. A solution of 5,6-diazatetracycle [7.3.1.13.11.04.8] tetradeca-4 (8), 6-diene-7-carboxylic acid (100 mg, 0.38 mmol) in DMF (2 ml) was treated with NaH (50% dispersion in mineral oil, 20 mg, 0.4 mmol), stirred at room temperature for 45 minutes and then iodomethane (60 mg, 0.026 mmol) was added to the mixture. Stirring was continued for an additional 1.5 h. The mixture was poured into water, extracted into ethyl acetate and dried over anhydrous sodium sulfate. Evaporation and separation by flash chromatography gave Intermediate 12a and Intermediate12b.

Intermedio 12a: Rendimiento: 36%. RMN 1H (δ ppm, CDCl3): 4,37 (c, J = 7,2, 2H); 3,82 (s, 3H); 3,71 (t, J = 5,4, 1H); 3,00 (t a, J = 4,8, 1H); 2,18 (s a, 2H); 2,10-1,80 (m, 4H); 1,80 (t a, J = 12,3, 6H); 1,39 (t, J = 7,2, 3H). RMN-13C (δ ppm, CDCl3): 161,02, 158,50, 132,17, 127,49, 60,58, 39,36, 36,29, 35,35, 34,69, 32,41, 28,63, 27,15, 14,21. Intermediate 12a: Yield: 36%. 1H NMR (δ ppm, CDCl3): 4.37 (c, J = 7.2, 2H); 3.82 (s, 3 H); 3.71 (t, J = 5.4, 1H); 3.00 (t a, J = 4.8, 1H); 2.18 (s at, 2H); 2.10-1.80 (m, 4H); 1.80 (t a, J = 12.3, 6H); 1.39 (t, J = 7.2, 3H). NMR-13C (δ ppm, CDCl3): 161.02, 158.50, 132.17, 127.49, 60.58, 39.36, 36.29, 35.35, 34.69, 32.41, 28.63, 27.15, 14.21.

Intermedio 12b: Rendimiento: 36%.1H RMN (δ ppm, CDCl3): 4,34 (c, J = 7,2, 2H); 4,02 (s, 3H); 3,54 (t, J = 5,7, 1H); 3,03 (t, J = 5,1, 1H); 2,14 (s a, 2H); 2,07-1,93 (m, 4H); 1,84-1,67 (m, 6H); 1,37 (t, J = 7,2, 3H). RMN 13C (δ ppm, CDCl3): 163,32, 150,32, 136,54, 130,80, 60,32, 36,78, 36,14, 34,65, 33,65, 29,57, 28,68, 26,46, 14,40. Intermediate 12b: Yield: 36% .1H NMR (δ ppm, CDCl3): 4.34 (c, J = 7.2, 2H); 4.02 (s, 3 H); 3.54 (t, J = 5.7, 1H); 3.03 (t, J = 5.1, 1H); 2.14 (s a, 2H); 2.07-1.93 (m, 4H); 1.84-1.67 (m, 6H); 1.37 (t, J = 7.2, 3H). 13C NMR (δ ppm, CDCl3): 163.32, 150.32, 136.54, 130.80, 60.32, 36.78, 36.14, 34.65, 33.65, 29.57, 28 , 68, 26.46, 14.40.

Intermedio 13a e Intermedio 13b Intermediate 13a and Intermediate 13b

Ácido 6-pentil-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4,7-dieno-7-carboxílico (Intermedio 13a) y Ácido 5-pentil-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-6-dieno-7-carboxílico (Intermedio 13b) 6-Pentyl-5,6-diazatetracyclo acid [7.3.1.13,11.04.8] tetradeca-4,7-diene-7-carboxylic acid (Intermediate 13a) and 5-pentyl-5,6-diazatetracycle acid [7.3.1.13, 11.04.8] tetradeca-4 (8) -6-diene-7-carboxylic (Intermediate 13b)

Etapa 1: 6-pentil-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4,7-dieno-7-carboxilato de etilo(Intermedio 13aa) y 5-pentil-5,6-diazatetraciclo[7.3.1.13,11.04,8] tetradeca-4(8)-6-dieno-7-carboxilato de etilo (Intermedio 13bb): Stage 1: 6-pentyl-5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4,7-diene-7-carboxylate ethyl (Intermediate 13aa) and 5-pentyl-5,6-diazatetracycle [7.3 .1.13,11.04,8] tetradeca-4 (8) -6-diene-7-ethyl carboxylate (Intermediate 13bb):

Los intermedios 13aa y 13bb se prepararon por un procedimiento similar al descrito para los intermedios 12a y 12b, usando el intermedio 11 (1,00 g, 3,84 mmol), DMF (3 ml) y 1-bromo-n-pentano ((53 ml, 4,20 mmol). Intermediates 13aa and 13bb were prepared by a procedure similar to that described for intermediates 12a and 12b, using intermediate 11 (1.00 g, 3.84 mmol), DMF (3 ml) and 1-bromo-n-pentane ( (53 ml, 4.20 mmol).

Intermedios 13aa: RMN 1H (δ ppm, CDCl3, 300 MHz): 4,39-4,28 (m, 4H); 3,53 (t, J = 5,4, 1H); 3,04 (t, J = 5,4, 1H); 2,13 (s a, 2H); 2,04-1,94 (m, 4H); 1,84-1,66 (m, 8H); 1,37 (t, J = 6,9, 3H); 1,30-1,24 (m, 4H); 0,88 (t, J = 6,9, 3H). Intermediates 13aa: 1H NMR (δ ppm, CDCl3, 300 MHz): 4.39-4.28 (m, 4H); 3.53 (t, J = 5.4, 1H); 3.04 (t, J = 5.4, 1H); 2.13 (s a, 2H); 2.04-1.94 (m, 4H); 1.84-1.66 (m, 8H); 1.37 (t, J = 6.9, 3H); 1.30-1.24 (m, 4H); 0.88 (t, J = 6.9, 3H).

Intermedios 13bb: RMN 1H (δ ppm, CDCl3, 300 MHz): 4,37 (c, J = 6,9, 2H); 4,07 (t, J = 7,5, 2H); 3,71 (s a, 1H); 2,98 (s a, 1H); 2,18 (s a, 2H); 2,02-1,92 (m, 4H); 1,85-1,71 (m, 8H); 1,38 (t, J = 6,9, 3H); 1,40-1,24 (m, 4H); 0,89 (t, J = 7,2, 3H). Intermediates 13bb: 1H NMR (δ ppm, CDCl3, 300 MHz): 4.37 (c, J = 6.9, 2H); 4.07 (t, J = 7.5, 2H); 3.71 (s a, 1 H); 2.98 (s a, 1 H); 2.18 (s at, 2H); 2.02-1.92 (m, 4H); 1.85-1.71 (m, 8H); 1.38 (t, J = 6.9, 3H); 1.40-1.24 (m, 4H); 0.89 (t, J = 7.2, 3H).

Etapa 2: Ácido 6-pentil-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4,7-dieno-7-carboxílico (Intermedio 13a) y Ácido 5-pentil-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-6-dieno-7-carboxílico (Intermedio 13b) Stage 2: 6-pentyl-5,6-diazatetracyclo acid [7.3.1.13,11.04,8] tetradeca-4,7-diene-7-carboxylic acid (Intermediate 13a) and 5-pentyl-5,6-diazatetracycle acid [7.3 .1.13,11.04,8] tetradeca-4 (8) -6-diene-7-carboxylic (Intermediate 13b)

El intermedio 13aa (400 mg, 1,21 mmol) y el Intermedio 13bb (400 mg, 1,21 mmol), KOH (136 mg, 2,42 mmol), etanol (10 ml) y H2O (0,5 ml) produjeron el intermedio 13a (270 mg, 73%). RMN 1H (δ ppm, CDCl3, 300 MHz): 4,39 (t, J = 7,8, 2H); 3,64 (s a, 1H); 3,07 (s a, 1H); 2,14 (s a, 2H); 2,04-1,94 (m, 4H); 1,79-1,72 (m, 8H); 1,35-1,28 (m, 4H); 0,89 (t, J = 7,5, 3H) y el intermedio 13b (290 mg, 79%). RMN 1H (δ ppm, CDCl3, 300 MHz): 4,06 (t, J = 7,2, 2H); 3,70 (s a, 1H); 2,98 (s a, 1H); 2,18 (s a, 2H); 2,02-1,93 (m, 4H); 1,84-1,68 (m, 8H); 1,40-1,24 (m, 4H); 0,89 (t, J = 7,2, 3H), respectivamente. Intermediate 13aa (400 mg, 1.21 mmol) and Intermediate 13bb (400 mg, 1.21 mmol), KOH (136 mg, 2.42 mmol), ethanol (10 ml) and H2O (0.5 ml) produced intermediate 13a (270 mg, 73%). 1H NMR (δ ppm, CDCl3, 300 MHz): 4.39 (t, J = 7.8, 2H); 3.64 (s at, 1 H); 3.07 (s at, 1 H); 2.14 (s a, 2H); 2.04-1.94 (m, 4H); 1.79-1.72 (m, 8H); 1.35-1.28 (m, 4H); 0.89 (t, J = 7.5, 3H) and intermediate 13b (290 mg, 79%). 1H NMR (δ ppm, CDCl3, 300 MHz): 4.06 (t, J = 7.2, 2H); 3.70 (s at, 1 H); 2.98 (s a, 1 H); 2.18 (s at, 2H); 2.02-1.93 (m, 4H); 1.84-1.68 (m, 8H); 1.40-1.24 (m, 4H); 0.89 (t, J = 7.2, 3H), respectively.

Los intermedios 14 a 21 se prepararon de acuerdo con el procedimiento que se ha descrito en las etapas 1 y 2 del intermedio 1, usando 2-oxo-2(3-oxobiciclo[2.2.1]hept-2-il)acetato de etilo, fenilo sustituido o sin sustituir adecuado, hidracina y álcali. Intermediates 14 to 21 were prepared according to the procedure described in steps 1 and 2 of intermediate 1, using 2-oxo-2 (3-oxobicyclo [2.2.1] hept-2-yl) ethyl acetate , suitable substituted or unsubstituted phenyl, hydrazine and alkali.

Intermedio 14 Intermediate 14

Ácido 1-fenil-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxílico 1-Phenyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid

Etapa 1: 2-Oxo-2(3-oxobiciclo[2.2.1]hept-2-il)acetato de etilo Stage 1: 2-Oxo-2 (3-oxobicyclo [2.2.1] hept-2-yl) ethyl acetate

El producto del título se preparó por un procedimiento similar al descrito en la etapa 1 del intermedio 1, a partir de hexametildisilazano (4,2 ml, 20,0 mmol), éter (91 ml), nBuLi (2,3 M en hexano, 11,63 ml, 27,3 mmol), norcanfor (2,0 g, 18,2 mmol) y oxalato de dietilo (2,96 ml, 21,82 mmol), se obtuvo el producto del título. The title product was prepared by a procedure similar to that described in step 1 of intermediate 1, from hexamethyldisilazane (4.2 ml, 20.0 mmol), ether (91 ml), nBuLi (2.3 M in hexane , 11.63 ml, 27.3 mmol), norcanfor (2.0 g, 18.2 mmol) and diethyl oxalate (2.96 ml, 21.82 mmol), the title product was obtained.

Rendimiento: 56%. RMN 1H (δ ppm, CDCl3, 300 MHz): 11,41 (s a, 1H); 4,35 (c, J = 7,2, 2H); 3,81 (s a, 1H); 2,81 (s a, 1H); 2,05-1,85 (m, 3H); 1,80 (d a, J = 10,5, 1H); 1,59 (t a, J = 7,2, 2 H); 1,41 (t, J = 7,2, 3H). Yield: 56%. 1H NMR (δ ppm, CDCl3, 300 MHz): 11.41 (s at, 1H); 4.35 (c, J = 7.2, 2H); 3.81 (s at, 1 H); 2.81 (s at, 1 H); 2.05-1.85 (m, 3H); 1.80 (d a, J = 10.5, 1H); 1.59 (t a, J = 7.2, 2 H); 1.41 (t, J = 7.2, 3H).

Etapa 2: 1-Fenil-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxilato de etilo Stage 2: ethyl 1-Phenyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylate

Rendimiento: 52%. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,73 (d, J = 8,7, 2H); 7,47 (t, J = 7,2, 2H); 7,3 3 (t, J = 7,2, 1H); 4,42 (c, J = 7,2, 2H); 3,72 (s a, 1H); 3,68 (s a, 1H); 2,13 (d a, J = 8,7, 1H); 2,05-1,95 (m, 2H); 1,72 (d, J = 8,7, 1H); 1,42 (t, J = 7,2, 3H); 1,30-1,18 (m, 2H). Yield: 52%. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.73 (d, J = 8.7, 2H); 7.47 (t, J = 7.2, 2H); 7.3 3 (t, J = 7.2, 1H); 4.42 (c, J = 7.2, 2H); 3.72 (s a, 1 H); 3.68 (s at, 1 H); 2.13 (d a, J = 8.7, 1H); 2.05-1.95 (m, 2H); 1.72 (d, J = 8.7, 1H); 1.42 (t, J = 7.2, 3H); 1.30-1.18 (m, 2H).

Etapa 3: Ácido 1-fenil-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxílico Stage 3: 1-Phenyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid

Rendimiento: 79%. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,73 (d, J = 7,8, 2H); 7,50 (t, J = 7,8, 2H); 7,36 (t, J = 7,5, 1H); 3,75 (s, 1H); 3,72 (s, 1H); 2,17 (d a, J = 9,0, 1H); 2,10-1,93 (m, 2H); 1,74 (d, J = 8,7, 1H); 1,38-1,08 (m, 2H). Yield: 79%. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.73 (d, J = 7.8, 2H); 7.50 (t, J = 7.8, 2H); 7.36 (t, J = 7.5, 1H); 3.75 (s, 1 H); 3.72 (s, 1 H); 2.17 (d a, J = 9.0, 1H); 2.10-1.93 (m, 2H); 1.74 (d, J = 8.7, 1H); 1.38-1.08 (m, 2H).

Intermedio 15 Intermediate 15

Ácido 1-(2-Clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxílico 1- (2-Chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid

Etapa 1: 1-(2-Clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxilato de etilo Step 1: 1- (2-Chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylate ethyl

Rendimiento: 87%. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,72-7,60 (m, 2H); 7,41-7,33 (m, 2H); 4,42 (c, J = 7,2, 2H); 3,69 (s, 1H); 3,40 (s, 1H); 2,14 (d a, J = 9,0, 1H); 2,05-1,82 (m, 2H); 1,72 (d, J = 9,3, 1H); 1,30 (t, J = 7,2, 3H); 1,351,12 (m, 2H). Yield: 87%. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.72-7.60 (m, 2H); 7.41-7.33 (m, 2H); 4.42 (c, J = 7.2, 2H); 3.69 (s, 1 H); 3.40 (s, 1 H); 2.14 (d a, J = 9.0, 1H); 2.05-1.82 (m, 2H); 1.72 (d, J = 9.3, 1H); 1.30 (t, J = 7.2, 3H); 1,351.12 (m, 2H).

Etapa 2: Ácido 1-(2-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxílico Stage 2: 1- (2-Chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid

Rendimiento: 93%. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,59-7,50 (m, 2H); 7,45-7,33 (m, 2H); (dt, J = 8,7, 1,8, 2H); 3,72 (s, 1H); 3,42 (s, 1H); 2,17 (d a, J = 8,7, 1H); 2,10-1,85 (m, 2H); 1,74 (d, J = 8,7, 1H); 1,3 8-1,18 (m, 2H). Yield: 93%. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.59-7.50 (m, 2H); 7.45-7.33 (m, 2H); (dt, J = 8.7, 1.8, 2H); 3.72 (s, 1 H); 3.42 (s, 1 H); 2.17 (d a, J = 8.7, 1H); 2.10-1.85 (m, 2H); 1.74 (d, J = 8.7, 1H); 1.3 8-1.18 (m, 2H).

Intermedio 16 Intermediate 16

Ácido 1-(4-clorofenill)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxílico 1- (4-Chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid

Etapa 1: 1-(4-Clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxilato de etilo Stage 1: Ethyl 1- (4-Chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylate

Rendimiento: 72%. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,60 (d, J = 8,7, 2H); 7,43 (d, J = 8,7, 2H); 4,42 (c, J = 7,2, 2H); 3,69 (s a, 1H); 3,66 (s a, 1H); 2,14 (d a, J = 8,7, 1H); 2,10-1,95 (m, 2H); 1,72 (d a, J = 8,7, 1H); 1,42 (t, J = 7,2, 3H), 1,30-1,15 (m, 2H). IR (KBr, cm-1): 2977 (m), 2871 (m), 1716 (s), 1502 (s), 1373 (s), 1230 (s), 1092 (s), 831 (m). Yield: 72%. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.60 (d, J = 8.7, 2H); 7.43 (d, J = 8.7, 2H); 4.42 (c, J = 7.2, 2H); 3.69 (s a, 1 H); 3.66 (s at, 1 H); 2.14 (d a, J = 8.7, 1H); 2.10-1.95 (m, 2H); 1.72 (d a, J = 8.7, 1H); 1.42 (t, J = 7.2, 3H), 1.30-1.15 (m, 2H). IR (KBr, cm-1): 2977 (m), 2871 (m), 1716 (s), 1502 (s), 1373 (s), 1230 (s), 1092 (s), 831 (m).

Etapa 2: Ácido 1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxílico Stage 2: 1- (4-Chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid

Rendimiento: 74,5%. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,70 (d, J = 6,7, 2H); 7,50 (d, J = 6,7, 2H); 3,70 (s, 2H); 2,16 (d a, J = 8,7, 1H); 2,10-1,94 (m, 2H); 1,74 (d a, J = 8,7, 1H); 1,2 (m, 2H). IR (KBr, cm-1): 3460 (vs); 2943 (m), 2873 (m), 1705 (vs), 1684 (vs), 1500 (vs), 1357 (s?), 1252 (vs), 1093 (vs), 835 (s). Yield: 74.5%. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.70 (d, J = 6.7, 2H); 7.50 (d, J = 6.7, 2H); 3.70 (s, 2 H); 2.16 (d a, J = 8.7, 1H); 2.10-1.94 (m, 2H); 1.74 (d a, J = 8.7, 1H); 1.2 (m, 2H). IR (KBr, cm-1): 3460 (vs); 2943 (m), 2873 (m), 1705 (vs), 1684 (vs), 1500 (vs), 1357 (s?), 1252 (vs), 1093 (vs), 835 (s).

Intermedio 17 Intermediate 17

Ácido 1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxílico 1- (2,4-Dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid

Etapa 1: 1-(2,4-Diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxilato de etilo Step 1: 1- (2,4-Dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylate ethyl

Rendimiento: 51%. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,53 (d, J = 2,4, 1H); 7,49 (d, J = 8,4, 1H); 7,36 (dd, J = 8,4, 2,4, 1H); 4,41 (c, J = 7,2, 2H); 3,69 (s a, 1H); 3,38 (s a, 1H); 2,14 (d a, J = 9,0, 1H); 2,07-1,82 (m, 2H); 1,70 (d a, J = 9,0, 1H); 1,41 (t, J = 7,2, 3H); 1,29-1,13 (m; 2H). Yield: 51%. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.53 (d, J = 2.4, 1H); 7.49 (d, J = 8.4, 1H); 7.36 (dd, J = 8.4, 2.4, 1H); 4.41 (c, J = 7.2, 2H); 3.69 (s a, 1 H); 3.38 (s at, 1 H); 2.14 (d a, J = 9.0, 1H); 2.07-1.82 (m, 2H); 1.70 (d a, J = 9.0, 1H); 1.41 (t, J = 7.2, 3H); 1.29-1.13 (m; 2H).

Etapa 2: Ácido 1-(2, 4-Diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxílico Stage 2: 1- (2, 4-Dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid

Rendimiento: 87%. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,56 (d, J = 2,1, 1H); 7,48 (d, J = 8,4, 1H); 7,3 8 (dd, J = 8,4, 2,1, 1H); 3,71 (s a, 1H); 3 .41 (s a, 1H); 2,16 (d a, J = 8,7, 1 H); 2,07-1,82 (m, 2H); 1,72 (d a, J = 8,7, 1H); 1,31-1,14 (m, 2H). Yield: 87%. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.56 (d, J = 2.1, 1H); 7.48 (d, J = 8.4, 1H); 7.3 8 (dd, J = 8.4, 2.1, 1H); 3.71 (s a, 1 H); 3.41 (s a, 1 H); 2.16 (d a, J = 8.7, 1 H); 2.07-1.82 (m, 2H); 1.72 (d a, J = 8.7, 1H); 1.31-1.14 (m, 2H).

Intermedio 18 Intermediate 18

Ácido 1-(2-bromofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxílico 1- (2-Bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid

Etapa 1: 1-(2-Bromofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxilato de etilo Stage 1: 1- (2-Bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylate ethyl

Rendimiento: 79%. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,69 (dd, J = 7,8, 1,5, 1H); 7,50 (dd, J = 7,8, 2,1, 1H); 7,44 (td, J = 7,8, 1,5, 1H); 7,32 (td , J = 7,8, 2,1, 1H); 4,41 (c, J = 7,2, 2H); 3,69 (s a, 1H); 3,39 (s a, 1H); 2,18 (d a, J = 9,0, 1H); 2,05-1,81 (m, 2H); 1,70 (d, J = 8,7, 1H); 1,41 (t, J = 7,2, 3H); 1,30-1,12 (m, 2H). Yield: 79%. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.69 (dd, J = 7.8, 1.5, 1H); 7.50 (dd, J = 7.8, 2.1, 1H); 7.44 (td, J = 7.8, 1.5, 1H); 7.32 (td, J = 7.8, 2.1, 1H); 4.41 (c, J = 7.2, 2H); 3.69 (s a, 1 H); 3.39 (s at, 1 H); 2.18 (d a, J = 9.0, 1H); 2.05-1.81 (m, 2H); 1.70 (d, J = 8.7, 1H); 1.41 (t, J = 7.2, 3H); 1.30-1.12 (m, 2H).

Etapa 2: Ácido 1-(2-Bromofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxílico Stage 2: 1- (2-Bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid

Rendimiento: 92%. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,71 (dd, J = 8,4, 1,5, 1H); 7,53-7,40 (m, 2H); 7,34 (td, J = 7,8,2,1, 1H); 3,73 (s a, 1H); 3,41 (s a, 1H); 2,19 (d a, J = 8,7, 1H); 2,04-1,82 (m, 2H); 1,73 (d, J = 7,2,1,5,1H); 1,321,15 (m, 2H). Yield: 92%. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.71 (dd, J = 8.4, 1.5, 1H); 7.53-7.40 (m, 2H); 7.34 (td, J = 7.8.2.1, 1H); 3.73 (s a, 1 H); 3.41 (s at, 1 H); 2.19 (d a, J = 8.7, 1H); 2.04-1.82 (m, 2H); 1.73 (d, J = 7.2,1,5,1H); 1,321.15 (m, 2H).

Intermedio 19 Intermediate 19

Ácido 1-(4-bromofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxílico 1- (4-Bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid

Etapa 1: 1-(4-Bromofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxilato de etilo Stage 1: 1- (4-Bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylate ethyl

Rendimiento: 81%. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,65-7,50 (m, 4H); 4,42 (c, J = 7,2, 2H); 3,69 (s, 2H); 3,67 (s, 2H); 2,13 (d a, J = 8,7, 1H); 2,06-1,95 (m, 2H); 1,74 (d, J = 8,7, 1H); 1,42 (t, J = 7,2, 3H); 1,28-1,15, (m, 2H). Yield: 81%. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.65-7.50 (m, 4H); 4.42 (c, J = 7.2, 2H); 3.69 (s, 2 H); 3.67 (s, 2 H); 2.13 (d a, J = 8.7, 1H); 2.06-1.95 (m, 2H); 1.74 (d, J = 8.7, 1H); 1.42 (t, J = 7.2, 3H); 1.28-1.15, (m, 2H).

Etapa 2: Ácido 1-(4-bromofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxílico Rendimiento: 83%. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,62 (s, 4H); 3,71 (s, 2H); 2,17 (d a, J = 9,0, 1H); 2,06-2,01 (m, 2H); 1,75 (d, J = 9,0, 1H); 1,30-1,17 (m, 2H). Stage 2: 1- (4-Bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid Yield: 83%. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.62 (s, 4H); 3.71 (s, 2H); 2.17 (d a, J = 9.0, 1H); 2.06-2.01 (m, 2H); 1.75 (d, J = 9.0, 1H); 1.30-1.17 (m, 2H).

Intermedio 20 Intermediate 20

Ácido 1-(4-fluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxílico 1- (4-fluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid

Etapa 1: 1-(4-fluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxilato de etilo Stage 1: Ethyl 1- (4-fluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylate

5 5

10 10

15 fifteen

20 twenty

25 25

30 30

35 35

40 40

45 Four. Five

Rendimiento: 86%. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,69 (dd, J = 9,0, 4,8, 2H); 7,15 .(t, J = 9,0, 2H); 4,42 (c, J = 7,2, 2H); 3,67 (s a, 2H); 3,40 (s a, 1H); 2,16 (d a, J = 8,7, 1H); 2,03-1,85 (m, 2H); 1,72 (d a, J = 9,0, 1H); 1,43 (t, J = 7,2, 3H); 1,32-1,17 (m, 2H). Yield: 86%. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.69 (dd, J = 9.0, 4.8, 2H); 7.15. (T, J = 9.0, 2H); 4.42 (c, J = 7.2, 2H); 3.67 (s a, 2H); 3.40 (s at, 1 H); 2.16 (d a, J = 8.7, 1H); 2.03-1.85 (m, 2H); 1.72 (d a, J = 9.0, 1H); 1.43 (t, J = 7.2, 3H); 1.32-1.17 (m, 2H).

Etapa 2: Ácido 1-(4-fluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxílico Stage 2: 1- (4-fluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid

Rendimiento: 60%. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,70 (dd, J = 8,7, 4,8, 2H); 7,18 (t, J = 8,7, 2H); 3,70 (s, 2H); 2,17 (d a, J = 8,7, 1H); 2,10-1,90 (m, 2H); 1,74 (d, J = 8,7, 1H); 1,35-1,18 (m, 2H). Yield: 60%. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.70 (dd, J = 8.7, 4.8, 2H); 7.18 (t, J = 8.7, 2H); 3.70 (s, 2 H); 2.17 (d a, J = 8.7, 1H); 2.10-1.90 (m, 2H); 1.74 (d, J = 8.7, 1H); 1.35-1.18 (m, 2H).

Intermedio 21 Intermediate 21

Ácido 1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxílico 1- (2,4-Difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid

Etapa 1: 1-(2,4-Difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxilato de etilo Stage 1: 1- (2,4-Difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylate ethyl

Rendimiento: 81%. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,80-7,68 (m, 1H); 7,05-6,95 (m, 2H); 4,42 (c, J = 7,2, 2H); 3,67 (s a, 1H); 3,47 (s a, 1H); 2,12-2,08 (d a, J = 8,7, 1H); 2,03-1,90 (m, 2H); 1,72-1,65 (d a, J = 8,7, 1H); 1,41 (t, J = 7,2, 3H); 1,30-1,17 (m, 2H). Yield: 81%. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.80-7.68 (m, 1H); 7.05-6.95 (m, 2H); 4.42 (c, J = 7.2, 2H); 3.67 (s at, 1 H); 3.47 (s at, 1 H); 2.12-2.08 (d a, J = 8.7, 1H); 2.03-1.90 (m, 2H); 1.72-1.65 (d a, J = 8.7, 1H); 1.41 (t, J = 7.2, 3H); 1.30-1.17 (m, 2H).

Etapa 2: Ácido 1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxílico Stage 2: 1- (2,4-Difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid

Rendimiento: 78%. P.F.: 153-156 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,80-7,70 (m, 1H); 7,10-6,97 (m, 2H); 3,70 (s a, 1H); 3,50 (s a, 1H); 2,12 (d, J = 7,2, 1H); 2,08-1,86 (m, 2H); 1,72 (d, J = 8,7, 1H); 1,35-1,17 (m, 2H). Yield: 78%. P.F .: 153-156 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.80-7.70 (m, 1H); 7.10-6.97 (m, 2H); 3.70 (s at, 1 H); 3.50 (s at, 1 H); 2.12 (d, J = 7.2, 1H); 2.08-1.86 (m, 2H); 1.72 (d, J = 8.7, 1H); 1.35-1.17 (m, 2H).

Resolución Óptica de ácido 1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxílico: Optical Resolution of 1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid:

Intermedio 21 Intermediate 21

Intermedio 21a Intermediate 21a

Una suspensión del intermedio 21 (racémico, 15,0 g, 51,72 mmol) en acetonitrilo (calidad de LR) (150 ml) se trató con (S)-(-)-α-metilbenilamina (3,66 ml, 28,44 mmol), se agitó a TA durante 5-10 min y la mezcla se calentó a reflujo durante 15 min. Se añadió lentamente metanol (24 ml) hasta que apareció una solución transparente y se continuó calentando durante 30 min más, tiempo después del cual la mezcla se dejó enfriar lentamente a TA. Los cristales separados se recogieron por filtración y se lavaron con acetonitrilo/MeOH 9:1 (~15 ml). El ácido se recuperó de la sal diastereomérica por disolución en CH2Cl2 y extracción con HCl ac. 1 N. La reiteración de los mismos procedimientos varias veces produjo una mezcla (100 mg) enriquecida en el último enantiómero de elución [Intermedio 21a, Rt= 38,20 min. en una columna CHIRALCEL AS-H (dimensiones: 250 x 4,6 mm, tamaño de partícula: 5 µ) usando una mezcla 90:10:0,1 de n-hexano:isopropanol:ácido trifluoroacético como eluyente a 1 ml/min. caudal]. P.F.: 114-115 ºC; e.e = 92%. A suspension of intermediate 21 (racemic, 15.0 g, 51.72 mmol) in acetonitrile (LR quality) (150 ml) was treated with (S) - (-) - α-methylbenylamine (3.66 ml, 28 , 44 mmol), stirred at RT for 5-10 min and the mixture was heated at reflux for 15 min. Methanol (24 ml) was added slowly until a clear solution appeared and heating was continued for an additional 30 min, after which time the mixture was allowed to slowly cool to RT. The separated crystals were collected by filtration and washed with acetonitrile / MeOH 9: 1 (~ 15 ml). The acid was recovered from the diastereomeric salt by dissolution in CH2Cl2 and extraction with aq HCl. 1 N. Repeating the same procedures several times produced a mixture (100 mg) enriched in the last elution enantiomer [Intermediate 21a, Rt = 38.20 min. on a CHIRALCEL AS-H column (dimensions: 250 x 4.6 mm, particle size: 5 µ) using a 90: 10: 0.1 mixture of n-hexane: isopropanol: trifluoroacetic acid as eluent at 1 ml / min . flow]. P.F .: 114-115 ° C; e.e = 92%.

Intermedio 21b Intermediate 21b

Las aguas madre obtenidas en la primera etapa de los procedimientos descritos anteriormente se evaporaron, se distribuyeron entre CH2Cl2 y HCl ac. 1 N y las fases separaron. El secado (Na2SO4) y la evaporación de la fase orgánica dio una mezcla de los dos ácidos enantioméricos (9 g) enriquecida en el último enantiómero de elusión (Rt = 34,65 min. en las mismas condiciones que se han descrito anteriormente; e.e = 34%). La mezcla se enriqueció en este enantiómero a un e.e del 91% (Intermedio 21b, rendimiento = 72 mg), reemplazando (S)-(-)-α-metilbenilamina por (R)-(+)-α-metilbenilamina en el procedimiento descrito anteriormente para el último enantiómero de elusión. P.F.: 110-112 ºC. The mother liquors obtained in the first stage of the procedures described above were evaporated, distributed between CH2Cl2 and HCl aq. 1 N and the phases separated. Drying (Na2SO4) and evaporation of the organic phase gave a mixture of the two enantiomeric acids (9 g) enriched in the last elution enantiomer (Rt = 34.65 min. Under the same conditions as described above; ee = 34%). The mixture was enriched in this enantiomer at 91% ee (Intermediate 21b, yield = 72 mg), replacing (S) - (-) - α-methylbenylamine with (R) - (+) - α-methylbenylamine in the procedure described above for the last elution enantiomer. P.F .: 110-112 ° C.

Los intermedios 22 y 23 se prepararon de acuerdo con el procedimiento que se ha descrito en la etapa 2 y etapa 3 del intermedio 1, usando 2-(3-hidroxi-4,7,7-trimetilbiciclo[2.2.1]hept-2-en-2-il-2-oxoacetato de etilo, fenilo sustituido o sin sustituir adecuado hidrazina y álcali. Intermediates 22 and 23 were prepared according to the procedure described in step 2 and stage 3 of intermediate 1, using 2- (3-hydroxy-4,7,7-trimethylbicyclo [2.2.1] hept-2 -en-2-yl-2-oxoacetate ethyl, substituted or unsubstituted phenyl hydrazine and alkali.

Intermedio 22 Intermediate 22

Ácido 1-(2,4-diclorofenil)-7,8,8-trimetil-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxílico 1- (2,4-Dichlorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid

Etapa 1: 2-(3-Hidroxi-4,7,7-trimetilbiciclo[2.2.1]hept-2-en-2-il-2-oxoacetato de etilo Stage 1: 2- (3-Hydroxy-4,7,7-trimethylbicyclo [2.2.1] hept-2-en-2-yl-2-ethyl oxoacetate

Una solución de DL-canfor (5 g, 33 mmol) en tolueno (25 ml) se añadió a una suspensión de hidruro sódico (dispersión al 60%, 1,34 g, 56 mmol) y oxalato de dietilo (6,69 g, 49 mmol) en tolueno (30 ml) a 60 ºC y la mezcla se agitó a la misma temperatura durante 1 hora. La mezcla de reacción se inactivó en hielo, se acidificó con HCl 1 N, se extrajo con acetato de etilo, las fases orgánicas se secaron sobre Na2SO4 y el disolvente se retiró al vacío para dar el producto del título (7,3 g, 88%) que se usó sin purificación adicional para la siguiente etapa. A solution of DL-camphor (5 g, 33 mmol) in toluene (25 ml) was added to a suspension of sodium hydride (60% dispersion, 1.34 g, 56 mmol) and diethyl oxalate (6.69 g , 49 mmol) in toluene (30 ml) at 60 ° C and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was quenched on ice, acidified with 1N HCl, extracted with ethyl acetate, the organic phases dried over Na2SO4 and the solvent removed in vacuo to give the title product (7.3 g, 88 %) that was used without further purification for the next step.

Rendimiento: 88%. RMN 1H (δ ppm, CDCl3, 300 MHz): 11,39 (s a, 1H); 4,35 (c, J = 7,2, 2H); 3,29 (d, J = 4,2, 1H); 2,30-2,04 (m, 1H); 1,70-1,40 (m, 1H); 1,46 (d a, J = 8,7, 2H); 1,3 8 (t, J = 7,2, 3H); 1,01, 0,97, 0,83 (3s, 9H). Yield: 88%. 1H NMR (δ ppm, CDCl3, 300 MHz): 11.39 (s at, 1H); 4.35 (c, J = 7.2, 2H); 3.29 (d, J = 4.2, 1H); 2.30-2.04 (m, 1 H); 1.70-1.40 (m, 1 H); 1.46 (d a, J = 8.7, 2H); 1.3 8 (t, J = 7.2, 3H); 1.01, 0.97, 0.83 (3s, 9H).

Etapa 2: 1-(2,4-Diclorofenil)-7,8,8-trimetil-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxilato de etilo Stage 2: Ethyl 1- (2,4-Dichlorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylate

Rendimiento: 42%. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,53 (s, 1H); 7,36 (s, 2H); 4,40 (c, J = 7,2, 2H); 3,16 (d, J = 3,6, 1H); 2,13 (m, 1H); 1,40 (t, J = 7,2, 3H); 1,26 (m, 2H); 0,88 (s, 6H); 0,83 (s, 3H). Yield: 42%. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.53 (s, 1H); 7.36 (s, 2H); 4.40 (c, J = 7.2, 2H); 3.16 (d, J = 3.6, 1H); 2.13 (m, 1 H); 1.40 (t, J = 7.2, 3H); 1.26 (m, 2H); 0.88 (s, 6H); 0.83 (s, 3 H).

Etapa 3: Ácido 1-(2,4-diclorofenil)-7,8,8-trimetil-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxílico Stage 3: 1- (2,4-Dichlorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid

Rendimiento: 72%. RMN 1H (δ ppm, DMSO-d6, 300 MHz): 12,80 (s a, 1H); 7,95 (d, J = 2,1, 1H); 7,67 (d, J =8,7, 1H); 7,63 (dd, J = 8,7, 2,1, 1H); 3,01 (d, J = 3,6, 1H); 2,13-2,06 (m, 1H); 1,79 (t a, J = 8,7, 1H); 1,32 (t a, J = 9,3, 1H); 1,161,00 (m, 1H); 0,88 (s, 3H); 0,84 (s, 3H); 0,77 (s, 3H). Yield: 72%. 1H NMR (δ ppm, DMSO-d6, 300 MHz): 12.80 (s a, 1H); 7.95 (d, J = 2.1, 1H); 7.67 (d, J = 8.7, 1H); 7.63 (dd, J = 8.7, 2.1, 1H); 3.01 (d, J = 3.6, 1H); 2.13-2.06 (m, 1 H); 1.79 (t a, J = 8.7, 1H); 1.32 (t a, J = 9.3, 1H); 1,161.00 (m, 1 H); 0.88 (s, 3 H); 0.84 (s, 3 H); 0.77 (s, 3 H).

Intermedio 23 Intermediate 23

Ácido 3-(2,4-difluorofenil)-1,10,10-trimetil-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxílico 3- (2,4-Difluorophenyl) -1,10,10-trimethyl-3,4-diazatricyclo [5.2.1.02.6] deca-2 (6), 4-diene-5-carboxylic acid

Etapa 1: 3-(2,4-Difluorofenil)-1,10,10-trimetil-3,4-diazatriciclo[5.2.1.02,6] deca-2 (6),4-dien-5-carboxilato de etilo Stage 1: 3- (2,4-Difluorophenyl) -1,10,10-trimethyl-3,4-diazatricyclo [5.2.1.02.6] deca-2 (6), ethyl 4-dien-5-carboxylate

Rendimiento: 42%. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,58-7,48 (m, 1H); 7,03-6,80 (m, 2H); 4,40 (c, J = 7,2, 2H); 3,15 (d, J = 4,2, 1H); 2,20-2,08 (m, 1H); 1,88-1,76 (m, 1H); 1,40 (t, J = 7,2, 3H); 1,40-1,08 (m, 2H); 0,99, 0,92, 0,79 (3s, 9H). Yield: 42%. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.58-7.48 (m, 1H); 7.03-6.80 (m, 2H); 4.40 (c, J = 7.2, 2H); 3.15 (d, J = 4.2, 1H); 2.20-2.08 (m, 1 H); 1.88-1.76 (m, 1 H); 1.40 (t, J = 7.2, 3H); 1.40-1.08 (m, 2H); 0.99, 0.92, 0.79 (3s, 9H).

Etapa 2: Ácido 3-(2,4-difluorofenil)-1,10,10-trimetil-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxílico Stage 2: 3- (2,4-Difluorophenyl) -1,10,10-trimethyl-3,4-diazatricyclo [5.2.1.02.6] deca-2 (6), 4-diene-5-carboxylic acid

Rendimiento: 72%. RMN 1H (δ ppm, DMSO-d6, 300 MHz): 12,80 (s a, 1H); 7,80-7,57 (m, 2H); 7,29 (t a, J = 8,4, 1H); 3,01 (d, J = 3,6, 1H); 2,08-2,02 (m, 1H); 1,79 (t a, J = 9,6, 1H); 1,32 (t a, J = 9,0, 1H); 1,06 (t a, J = 9,0 1H); 0,91, 0,88, 0,73 (3s, 9H). Yield: 72%. 1H NMR (δ ppm, DMSO-d6, 300 MHz): 12.80 (s a, 1H); 7.80-7.57 (m, 2H); 7.29 (t a, J = 8.4, 1H); 3.01 (d, J = 3.6, 1H); 2.08-2.02 (m, 1 H); 1.79 (t a, J = 9.6, 1H); 1.32 (t a, J = 9.0, 1H); 1.06 (t a, J = 9.0 1H); 0.91, 0.88, 0.73 (3s, 9H).

Los intermedios 24 y 25 se prepararon de acuerdo con el procedimiento que se ha descrito en la etapa 2 y etapa 3 del intermedio 1, usando 2-oxo-2-(10-oxotriciclo[6.2.2.2,7]dodeca-2,4,6-trien-9-il)acetato de etilo, fenilo sustituido o sin sustituir adecuado hidrazina y álcali. Intermediates 24 and 25 were prepared according to the procedure described in stage 2 and stage 3 of intermediate 1, using 2-oxo-2- (10-oxotricyclo [6.2.2.2,7] dodeca-2,4 , 6-trien-9-yl) ethyl acetate, substituted or unsubstituted phenyl suitable hydrazine and alkali.

Intermedio 24 Intermediate 24

Ácido 10-(2,4-diclorofenil)-10,11-diazatetraciclo[6.5.2.02,7.09,13]pentadeca-2,4,6,9(13),11-pentaen-12-carboxílico 10- (2,4-Dichlorophenyl) -10,11-diazatetracycle [6.5.2.02,7.09,13] pentadeca-2,4,6,9 (13), 11-pentaen-12-carboxylic acid

Etapa 1: 2-Oxo-2-(10-oxotriciclo[6.2.2.02,7]dodeca-2,4,6-trien-9-il)acetato de etilo. Stage 1: 2-Oxo-2- (10-oxotricyclo [6.2.2.02.7] dodeca-2,4,6-trien-9-yl) ethyl acetate.

El producto del título se preparó por un procedimiento similar al descrito para la etapa 1 del intermedio 1. A partir de triciclo[6.2.2.02,7]dodeca-2,4,6-trien-9-ona [preparado por uno de los procedimientos disponibles en la técnica de síntesis orgánica, por ejemplo, como se describe en Hales y col. Tetrahedron, 1995, 51, 7777-7790] (2,5 g, 14,53 mmol), hexametildisilazano (4,9 ml, 23,2 mmol), n-BuLi 2,34 M (10 ml, 23,4 mmol) y oxalato de dietilo (3,18 ml, 21,18 mmol) se obtuvo el producto deseado (2,3 g, 63%). The title product was prepared by a procedure similar to that described for step 1 of intermediate 1. From tricycle [6.2.2.02.7] dodeca-2,4,6-trien-9-one [prepared by one of the procedures available in the organic synthesis technique, for example, as described in Hales et al. Tetrahedron, 1995, 51, 7777-7790] (2.5 g, 14.53 mmol), hexamethyldisilazane (4.9 ml, 23.2 mmol), n-BuLi 2.34 M (10 ml, 23.4 mmol ) and diethyl oxalate (3.18 ml, 21.18 mmol) the desired product (2.3 g, 63%) was obtained.

Rendimiento: 63%. RMN 1H (δ ppm, CDCl3, 400 MHz): 12,9 (s, 1H); 7,20-7,15 (m, 4H); 4,91 (s, 1H); 4,31 (c, J = 7,2, 2H); 3,79 (s, 1H); 2,00-1,90 (m, 2H); 1,73-1,60 (m, 2H); 1,34 (t, J = 7,2, 3H). Yield: 63%. 1H NMR (δ ppm, CDCl3, 400 MHz): 12.9 (s, 1H); 7.20-7.15 (m, 4H); 4.91 (s, 1 H); 4.31 (c, J = 7.2, 2H); 3.79 (s, 1 H); 2.00-1.90 (m, 2H); 1.73-1.60 (m, 2H); 1.34 (t, J = 7.2, 3H).

Etapa 2: 10-(2,4-Diclorofenil)-10,11-diazatetraciclo[6.5.2.02,709,13]pentadeca-2,4,6,9(13),11-pentaeno-12-carboxilato de etilo Stage 2: 10- (2,4-Dichlorophenyl) -10,11-diazatetracyclo [6.5.2.02,709,13] pentadeca-2,4,6,9 (13), 11-pentaeno-12-carboxylate ethyl

Rendimiento: 91%. RMN 1H (δ ppm, CDCl3, 400 MHz): 7,58 (d, J = 2,2, 1H); 7,45 (d, J = 8,5, 1H); 7,3 8 (dd, J = 8,5, 2,0, 1H); 7,33 (d a, J = 7,0, 1H); 7,16 (d a, J = 7,08, 1H); 7,13 (td, J = 7,6, 1,5, 1H); 7,08 (td, J = 7,5, 1,5, 1H); 4,91 (s, 1H); 4,45 (c, J = 7,2, 2H); 4,29 (s, 1H); 1,81-1,72 (m, 4H); 1,43 (t, J = 7,2, 3H). Yield: 91%. 1H NMR (δ ppm, CDCl3, 400 MHz): 7.58 (d, J = 2.2, 1H); 7.45 (d, J = 8.5, 1H); 7.3 8 (dd, J = 8.5, 2.0, 1H); 7.33 (d a, J = 7.0, 1H); 7.16 (d a, J = 7.08, 1H); 7.13 (td, J = 7.6, 1.5, 1H); 7.08 (td, J = 7.5, 1.5, 1H); 4.91 (s, 1 H); 4.45 (c, J = 7.2, 2H); 4.29 (s, 1 H); 1.81-1.72 (m, 4H); 1.43 (t, J = 7.2, 3H).

Etapa 3: Ácido 10-(2,4-diclorofenil)-10,11-diazatetraciclo[6.5.2.02,7.09,13]pentadeca-2,4,6,9(13),11-pentaeno-12carboxílico Stage 3: 10- (2,4-dichlorophenyl) -10,11-diazatetracycle [6.5.2.02,7.09,13] pentadeca-2,4,6,9 (13), 11-pentane-12 carboxylic acid

RMN 1H(δ ppm, CDCl3, 400 MHz): 7,60 (d, J = 2,1, 1H); 7,45 (d, J = 8,5, 1H); 7,41 (dd, J = 8,5, 2,1, 1H); 7,35 (d a, J = 6,8, 1H); 7,17 (d a, J = 7,2, 1H); 7,14 (td, J = 7,5, 1,3, 1H); 7,09 (td, J = 7,5, 1,3, 1H); 4,94 (s, 1H); 4,32 (s, 1H); 1,82-1,73 (m, 4H). 1H NMR (δ ppm, CDCl3, 400 MHz): 7.60 (d, J = 2.1, 1H); 7.45 (d, J = 8.5, 1H); 7.41 (dd, J = 8.5, 2.1, 1H); 7.35 (d a, J = 6.8, 1H); 7.17 (d a, J = 7.2, 1H); 7.14 (td, J = 7.5, 1.3, 1H); 7.09 (td, J = 7.5, 1.3, 1H); 4.94 (s, 1 H); 4.32 (s, 1 H); 1.82-1.73 (m, 4H).

Intermedio 25 Intermediate 25

Ácido 10-(2,4-difluorofenil)-10,11-diazatetraciclo[6.5.2.02,7.09,13]pentadeca-2,4,6,9(13),11-pentaeno-12carboxílico 10- (2,4-Difluorophenyl) -10,11-diazatetracycle [6.5.2.02,7.09,13] pentadeca-2,4,6,9 (13), 11-pentane-12 carboxylic acid

Etapa 1: 10-(2,4-Difluorofenil)-10,11-diazatetraciclo[6.5.2.02,7.09,13]pentadeca-2,4,6,9(13),11-pentaeno-12-carboxilato de etilo Stage 1: 10- (2,4-Difluorophenyl) -10,11-diazatetracycle [6.5.2.02,7.09,13] pentadeca-2,4,6,9 (13), ethyl 11-pentane-12-carboxylate

Rendimiento: 71%. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,67-7,57 (m, 1H); 7,34 (d, J = 6,9, 1H); 7,20-7,01 (m, 5H); 4,90 (s, 1H); 4,44 (c, J = 6,9, 2H); 4,39 (s a, 1H); 1,79 (s, 4H); 1,45 (t, J = 6,9, 3H). Yield: 71%. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.67-7.57 (m, 1H); 7.34 (d, J = 6.9, 1H); 7.20-7.01 (m, 5H); 4.90 (s, 1 H); 4.44 (c, J = 6.9, 2H); 4.39 (s a, 1 H); 1.79 (s, 4 H); 1.45 (t, J = 6.9, 3H).

Etapa 2: Ácido 10-(2,4-difluorofenil)-10,11-diazatetraciclo[6.5.2.02,7.09,13]pentadeca-2,4,6,9(13),11-pentaeno-12carboxílico Stage 2: 10- (2,4-Difluorophenyl) -10,11-diazatetracycle [6.5.2.02,7.09,13] pentadeca-2,4,6,9 (13), 11-pentane-12 carboxylic acid

Rendimiento: 86%. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,68-7,58 (m, 1H); 7,35 (d, J = 7,2, 1H); 7,21-7,04 (m, 5H); 4,94 (s, 1H); 4,41 (s a, 1H); 1,81 (s a, 4H) Yield: 86%. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.68-7.58 (m, 1H); 7.35 (d, J = 7.2, 1H); 7.21-7.04 (m, 5H); 4.94 (s, 1 H); 4.41 (s a, 1 H); 1.81 (s at, 4H)

El intermedio 26 se preparó de acuerdo con el procedimiento que se ha descrito en la etapa 2 y etapa 3 del intermedio 1, usando 9endo,13endo-2-[11-(4-clorofenil)-10,12,15-trioxo-11-azatetraciclo[6.5.2.02,7.09,13]pentadeca2,4,6-trien-14-il]-2-oxoacetato de etilo fenilo sustituido o sin sustituir adecuado hidrazina y álcali. Intermediate 26 was prepared according to the procedure described in step 2 and stage 3 of intermediate 1, using 9endo, 13endo-2- [11- (4-chlorophenyl) -10,12,15-trioxo-11 -azatetracycle [6.5.2.02,7.09,13] pentadeca2,4,6-trien-14-yl] -2-substituted or unsubstituted ethyl phenyl oxoacetate hydrazine and alkali.

Intermedio 26 Intermediate 26

Ácido 13endo,14endo-16-(4-clorofenil)-15,17-dioxo-10-(2,4-diclorofenil)-10,11,16-triazapentaciclo[6.5.5.02,7 09,13.014,18]octadeca-2,4,6,9(13),11-pentaeno-12-carboxílico Acid 13endo, 14endo-16- (4-chlorophenyl) -15,17-dioxo-10- (2,4-dichlorophenyl) -10,11,16-triazapentacyclo [6.5.5.02.7 09,13,014,18] octadeca- 2,4,6,9 (13), 11-pentaeno-12-carboxylic

Etapa 1: 9-Endo,13-endo-11-(4-clorofenil)-11-azatetraciclo[6.5.2.02,7,09,13]pentadeca-2,4,6-trieno-10,12,14-triona Stage 1: 9-Endo, 13-endo-11- (4-chlorophenyl) -11-azatetracycle [6.5.2.02,7,09,13] pentadeca-2,4,6-triene-10,12,14-trione

Una solución de 11-oxatetraciclo[6.5.2.02,7.09,13]pentadeca-2,4,6-trieno-10,12,14-triona [preparada como se describe en Takeda y col. Tetrahedron 1970, 26, 1435-1451] (1,0 g, 4,11 mmol), 4-cloroanilina (1,2 g, 9,05 mmoles) en xileno se calentó a reflujo durante 6 h. Se añadió agua a la mezcla de reacción y se extrajo con AcOEt. Las fases orgánicas se secaron Na2SO4 y el disolvente se evaporó. El residuo, después de FC (AcOEt-éter de petróleo 4:96→16:84) dio el producto del título (930 mg, 65%). A solution of 11-oxatetracycle [6.5.2.02,7.09,13] pentadeca-2,4,6-triene-10,12,14-trione [prepared as described in Takeda et al. Tetrahedron 1970, 26, 1435-1451] (1.0 g, 4.11 mmol), 4-chloroaniline (1.2 g, 9.05 mmol) in xylene was heated at reflux for 6 h. Water was added to the reaction mixture and extracted with AcOEt. The organic phases were dried Na2SO4 and the solvent was evaporated. The residue, after FC (AcOEt-petroleum ether 4: 96 → 16: 84) gave the title product (930 mg, 65%).

Rendimiento: 65%. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,40-7,222 (m, 6H); 6,47 (d, J = 8,7, 2H); 4,18 (dd, J = 3,3, 1H); 4,07-4,02 (m, 1H); 3,59 (dd, J = 8,7, 3,3, 1H); 3,49 (dd, J = 8,4, 3,3,1H); 2,56 (dd, J = 20,4, 2,1, 1H); 2,43 (dd, J = 20,4, 3,3, 1H). Yield: 65%. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.40-7.222 (m, 6H); 6.47 (d, J = 8.7, 2H); 4.18 (dd, J = 3.3, 1H); 4.07-4.02 (m, 1 H); 3.59 (dd, J = 8.7, 3.3, 1H); 3.49 (dd, J = 8.4, 3.3.1H); 2.56 (dd, J = 20.4, 2.1, 1H); 2.43 (dd, J = 20.4, 3.3, 1H).

Etapa 2: 9endo,13endo-2-[11-(4-clorofenil)-10,12,15-trioxo-11-azatetraciclo[6.5.2.02,7.09,13]pentadeca-2,4,6-trien-14il]-2-oxoacetato de etilo Stage 2: 9endo, 13endo-2- [11- (4-chlorophenyl) -10,12,15-trioxo-11-azatetracyclo [6.5.2.02,7.09,13] pentadeca-2,4,6-trien-14il] -2-ethyl oxoacetate

El producto del título se preparó por un procedimiento similar al descrito para la 1 del intermedio 1. Se obtuvo el producto a partir de 9-endo,13-endo-11-(4-clorofenil)-11-azatetraciclo[6.5.2.02,7.09,13]pentadeca-2,4,6-trieno10,12,14-triona (800 mg, 2,28, mmol), hexametildisilazano (0,68 ml, 3,2 mmol), n-BuLi (15% en hexano,1,31 ml, 3,1 mmol) y oxalato de dietilo (0,62 ml, 4,6 mmol) producto del título (530 mg, 52%) se obtuvo en forma pura después de FC. The title product was prepared by a procedure similar to that described for 1 of intermediate 1. The product was obtained from 9-endo, 13-endo-11- (4-chlorophenyl) -11-azatetracycle [6.5.2.02, 7.09.13] pentadeca-2,4,6-triene10,12,14-trione (800 mg, 2.28, mmol), hexamethyldisilazane (0.68 ml, 3.2 mmol), n-BuLi (15% in hexane, 1.31 ml, 3.1 mmol) and diethyl oxalate (0.62 ml, 4.6 mmol) title product (530 mg, 52%) was obtained in pure form after FC.

Rendimiento: 52%. RMN 1H (δ ppm, CDCl3, 300 MHz): 13,0 (s a, 1H); 7,36-7,20 (m, 6H); 6,47 (d, J = 7,2, 2H); 5,54 (s a, 1H); 4,49-4,38 (m, 3H); 3,54 (s a, 2H); 1,45 (t, J = 7,2, 3H); Yield: 52%. 1H NMR (δ ppm, CDCl3, 300 MHz): 13.0 (s at, 1H); 7.36-7.20 (m, 6H); 6.47 (d, J = 7.2, 2H); 5.54 (s a, 1 H); 4.49-4.38 (m, 3H); 3.54 (s a, 2H); 1.45 (t, J = 7.2, 3H);

Etapa 3: 13Endo,14endo-16-(4-clorofenil)-15,17-dioxo-10-(2,4-diclorofenil)-10,11,16-triazapentaciclo [6.5.5.02,7 .09,13.014,11]octadeca-2,4,6,9(13),11-pentaeno-12-carboxilato de etilo. Stage 3: 13Endo, 14endo-16- (4-chlorophenyl) -15,17-dioxo-10- (2,4-dichlorophenyl) -10,11,16-triazapentacyclo [6.5.5.02.7 .09,13,014.11 ] octadeca-2,4,6,9 (13), ethyl 11-pentaeno-12-carboxylate.

Rendimiento: 66%. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,63 (d, J = 2,4, 1H); 7,51 (d, J = 8,4, 1H); 7,47-7,35 (m, 3H); 7,30-7,15 (m, 4H); 6,44 (d, J = 9,0, 2H); 5,44 (d, J = 3,0, 1H); 4,83 (d, J = 2,7, 1H); 4,49 (c, J = 7,2, 2H); 3,56 (dd, J = 8,7, 3,3, 1H); 3,48 (d a, J = 8,7, 1H); 1,46 (t, J = 7,2, 3H). Yield: 66%. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.63 (d, J = 2.4, 1H); 7.51 (d, J = 8.4, 1H); 7.47-7.35 (m, 3H); 7.30-7.15 (m, 4H); 6.44 (d, J = 9.0, 2H); 5.44 (d, J = 3.0, 1H); 4.83 (d, J = 2.7, 1H); 4.49 (c, J = 7.2, 2H); 3.56 (dd, J = 8.7, 3.3, 1H); 3.48 (d a, J = 8.7, 1H); 1.46 (t, J = 7.2, 3H).

Etapa 4: Ácido 13endo, 14endo-16-(4-clorofenil)-15,17-dioxo-10-(2,4-diclorofenil)-10,11,16-triazapentaciclo[6.5.5.02,7.09,13.014,18]octadeca-2,4,6,9(13),11-pentaeno-12-carboxílico Stage 4: Acid 13endo, 14endo-16- (4-chlorophenyl) -15,17-dioxo-10- (2,4-dichlorophenyl) -10,11,16-triazapentacyclo [6.5.5.02,7.09,13,014,18] octadeca-2,4,6,9 (13), 11-pentaeno-12-carboxylic

Rendimiento: 76%. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,66 (d, J = 2,4, 1H); 7,54-7,40 (m, 3H); 7,28-7,19 (m, 5H); 6,45 (d, J = 8,7, 2H); 5,50 (d, J = 3,0, 1H); 4,87 (d, J = 3,0, 1H); 3,59 (dd, J = 8,7, 3,0, 1H); 3,50 (d a, J = 8,7, 1H). Yield: 76%. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.66 (d, J = 2.4, 1H); 7.54-7.40 (m, 3H); 7.28-7.19 (m, 5H); 6.45 (d, J = 8.7, 2H); 5.50 (d, J = 3.0, 1H); 4.87 (d, J = 3.0, 1H); 3.59 (dd, J = 8.7, 3.0, 1H); 3.50 (d a, J = 8.7, 1H).

Intermedio 27 Intermediate 27

Ácido 10-(2,4-Difluorofenil)-10,11-diazatetraciclo[6.5.1.02,7.09,13]tetradeca-2,4,6,9(13),11-pentaeno-12carboxílico 10- (2,4-Difluorophenyl) -10,11-diazatetracyclo [6.5.1.02,7.09,13] tetradeca-2,4,6,9 (13), 11-pentane-12 carboxylic acid

Etapa 1: 2-Oxo-2-(10-oxotriciclo[6.2.1.02,7]undeca-2(7),3,5-trien-9-il)acetato de etilo Stage 1: 2-Oxo-2- (10-oxotricyclo [6.2.1.02.7] undeca-2 (7), 3,5-trien-9-yl) ethyl acetate

El producto del título se preparó por un procedimiento similar al descrito para la etapa 1 del intermedio 22. A partir de benzonorbomanona (2,4 g, 15,18 mmol), hidruro sódico (dispersión al 60%, 619 mg, 25 mmol) y oxalato de dietilo (3,09 ml, 22,7 mmol) se obtuvo el producto del título (2,6 g, 52%). RMN 1H (δ ppm, CDCl3, 300 MHz): 10,63 (s a, 1H); 7,75-7,20 (m, 5H); 4,81 (d, J = 1,5, 1H); 4,35 (c, J = 7,2, 2H); 3,75 (d, J = 1,5, 1H); 2,57 (dt, J = 9,3, 1,8, 1 H); 2,42 (d, J = 8,7,1,5,1H); 1,43 (t, J = 7,2, 3H). The title product was prepared by a procedure similar to that described for step 1 of intermediate 22. From benzonorbomanone (2.4 g, 15.18 mmol), sodium hydride (60% dispersion, 619 mg, 25 mmol) and diethyl oxalate (3.09 ml, 22.7 mmol) the title product (2.6 g, 52%) was obtained. 1H NMR (δ ppm, CDCl3, 300 MHz): 10.63 (s at, 1H); 7.75-7.20 (m, 5H); 4.81 (d, J = 1.5, 1H); 4.35 (c, J = 7.2, 2H); 3.75 (d, J = 1.5, 1H); 2.57 (dt, J = 9.3, 1.8, 1 H); 2.42 (d, J = 8,7,1,5,1H); 1.43 (t, J = 7.2, 3H).

Etapa 2: 10-(2,4-Difluorofenil)-10,11-diazatetraciclo[6.5.1.02,7.09,13]tetradeca-2,4,6,9(13),11-pentaeno-12-carboxilato etilo Stage 2: 10- (2,4-Difluorophenyl) -10,11-diazatetracycle [6.5.1.02,7.09,13] tetradeca-2,4,6,9 (13), 11-pentaeno-12-carboxylate ethyl

El producto del título se preparó por un procedimiento similar al descrito para la etapa 3 del intermedio 20. A partir de (2Z)-hidroxi(10-oxotriciclo[6.2.1.02,7]undeca-2,4,6-trien-9-ilideno)acetato de etilo (1,0 g, 3,87 mmol), clorhidrato de 2,4-difluorofenilhidrazina (838 mg, 4,64 mmol) etanol (13,0 ml) y ácido acético (15,0 ml) se obtuvo el producto del título (1,21 g, 85%). RMN 1H (δ ppm, CDCl3, 300 MHz): 7,79-7,69 (m, 1H); 7,35-7,26 (m, 2H); 7,05-6,94 (m, 4H), 4,52 (s a, 1H), 4,41 (c, J = 7,5, 2H); 4,32 (s a, 1H); 3,00 (d a, J = 8,1, 1H); 2,85 (dt, J = 8,1,1,5, 1H); 1,41 (t, J = 7,5, 3H). The title product was prepared by a procedure similar to that described for step 3 of intermediate 20. From (2Z) -hydroxy (10-oxotricyclo [6.2.1.02.7] undeca-2,4,6-trien-9 -ylidene) ethyl acetate (1.0 g, 3.87 mmol), 2,4-difluorophenylhydrazine hydrochloride (838 mg, 4.64 mmol) ethanol (13.0 ml) and acetic acid (15.0 ml) the title product (1.21 g, 85%) was obtained. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.79-7.69 (m, 1H); 7.35-7.26 (m, 2H); 7.05-6.94 (m, 4H), 4.52 (s a, 1H), 4.41 (c, J = 7.5, 2H); 4.32 (s a, 1 H); 3.00 (d a, J = 8.1, 1H); 2.85 (dt, J = 8.1.1.5, 1H); 1.41 (t, J = 7.5, 3H).

Etapa 3: Ácido 10-(2,4-difluorofenil)-10,11-diazatetraciclo[6.5.1.02,7,09,13]tetradeca-2,4,6,9(13),11-pentaeno-12carboxílico Stage 3: 10- (2,4-Difluorophenyl) -10,11-diazatetracycle [6.5.1.02,7,09,13] tetradeca-2,4,6,9 (13), 11-pentane-12 carboxylic acid

El producto del título se preparó por un procedimiento similar al descrito para la etapa 3 del intermedio 1. A partir de The title product was prepared by a procedure similar to that described for step 3 of intermediate 1. From

10-(2,4-difluorofenil)-10,11-diazatetraciclo [6.5.1.02,7,09,13]tetradeca-2,4,6,9(13),11-pentaeno-12-carboxilato de etilo 10- (2,4-Difluorophenyl) -10,11-diazatetracycle [6.5.1.02,7,09,13] tetradeca-2,4,6,9 (13), ethyl 11-pentaeno-12-carboxylate

KOH (367 mg, 6,5 mmol), etanol (10,4 ml) y H2O (0,5 ml) se obtuvo el producto del título (810 mg, 73%). RMN 1H (δ ppm, DMSO-d6, 300 MHz): 12,95 (m, 1H); 7,78-7,57 (m, 2H); 7,32-7,25 (m, 3H); 6,98-6,89 (m, 2H); 4,43 (s, 2H); 2,89 (d, J = 8,1, 1H); 2,71 (d, J = 8,1, 1H). KOH (367 mg, 6.5 mmol), ethanol (10.4 ml) and H2O (0.5 ml) the title product (810 mg, 73%) was obtained. 1H NMR (δ ppm, DMSO-d6, 300 MHz): 12.95 (m, 1H); 7.78-7.57 (m, 2H); 7.32-7.25 (m, 3H); 6.98-6.89 (m, 2H); 4.43 (s, 2 H); 2.89 (d, J = 8.1, 1H); 2.71 (d, J = 8.1, 1H).

Los intermedios 28 a 30 se prepararon de acuerdo con los procedimientos descritos en la 2 y la etapa 3 del intermedio 1, usando 2-hidroxi-2-(3-oxabiciclo[2.2.2]octa-2-iliden)acetato de etilo fenilo sustituido o sin sustituir adecuado hidrazina y álcali. Intermediates 28 to 30 were prepared according to the procedures described in step 2 and step 3 of intermediate 1, using 2-hydroxy-2- (3-oxabicyclo [2.2.2] octa-2-ylidene) ethyl phenyl acetate substituted or unsubstituted suitable hydrazine and alkali.

Intermedio 28 Intermediate 28

Ácido 3-(2,4-difluorofenil)-3,4-diazatriciclo[5.2.2.02,6]undeca-2(6),4-dien-5-carboxílico 3- (2,4-Difluorophenyl) -3,4-diazatricyclo [5.2.2.02.6] undeca-2 (6), 4-diene-5-carboxylic acid

Etapa 1: 2-hidroxi-2-(3-oxabiciclo[2.2.2]octa-2-iliden)acetato de etilo Stage 1: 2-hydroxy-2- (3-oxabicyclo [2.2.2] octa-2-ylidene) ethyl acetate

Una solución de biciclo[2.2.2]octan-2-ona (2,4 g, 19,35 mmol) en tolueno (20 ml) se añadió a una suspensión de hidruro sódico (dispersión al 60%, 603 mg, 25,16 mmol) y oxalato de dietilo (3,15 ml, 23,22 mmol) en tolueno (10 ml) a 60 ºC y la mezcla se agitó a la misma temperatura durante 1 hora. La mezcla de reacción se inactivó en hielo, se acidificó con HCl 1 N, se extrajo con acetato de etilo, las fases orgánicas se secaron sobre Na2SO4 y el disolvente se retiró al vacío para dar Intermedio 28 (1,2 g, 27%) que se usó sin purificación adicional para la siguiente etapa. RMN 1H (δ ppm, CDCl3, 300 MHz): 13,80 (s a, 1H); 4,36 (c, J = 6,9, 2H); 3,57 (s a, 1H); 2,52 (s a, 1H);1,82-1,60 (m, 8H); 1,38 (t, J = 6,9, 3H). A solution of bicyclo [2.2.2] octan-2-one (2.4 g, 19.35 mmol) in toluene (20 ml) was added to a suspension of sodium hydride (60% dispersion, 603 mg, 25, 16 mmol) and diethyl oxalate (3.15 ml, 23.22 mmol) in toluene (10 ml) at 60 ° C and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was quenched on ice, acidified with 1 N HCl, extracted with ethyl acetate, the organic phases were dried over Na2SO4 and the solvent was removed in vacuo to give Intermediate 28 (1.2 g, 27%) which was used without further purification for the next stage. 1H NMR (δ ppm, CDCl3, 300 MHz): 13.80 (s at, 1H); 4.36 (c, J = 6.9, 2H); 3.57 (s a, 1 H); 2.52 (s at, 1 H); 1.82-1.60 (m, 8 H); 1.38 (t, J = 6.9, 3H).

Etapa 2: 3-(2,4-Difluorofenil)-3,4-diazatriciclo[5.2.2.02,6]undeca-2(6),4-dien-5-carboxilato de etilo: Stage 2: 3- (2,4-Difluorophenyl) -3,4-diazatricyclo [5.2.2.02.6] undeca-2 (6), ethyl 4-dien-5-carboxylate:

Rendimiento: 48%. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,70-7,60 (m, 1H); 7,06-6,94 (m, 2H); 4,43 (c, J = 7,2, 2H); 3,70 (s a, 1H); 3,15 (s a, 1H); 1,78 (d, 7,8, 4H); 1,45-1,36 (m, 7H). Yield: 48%. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.70-7.60 (m, 1H); 7.06-6.94 (m, 2H); 4.43 (c, J = 7.2, 2H); 3.70 (s at, 1 H); 3.15 (s a, 1 H); 1.78 (d, 7.8, 4H); 1.45-1.36 (m, 7H).

Etapa 3: Ácido 3-(2,4-difluorofenil)-3,4-diazatriciclo[5.2.2.02,6]undeca-2(6),4-dien-5-carboxílico: Stage 3: 3- (2,4-Difluorophenyl) -3,4-diazatricyclo [5.2.2.02.6] undeca-2 (6), 4-diene-5-carboxylic acid:

Rendimiento: 90%. 1H RMN (δ ppm, CDCl3, 300 MHz): RMN 1H (δ ppm, CDCl3, 300 MHz): 7,72-7,60 (m, 1H); 7,096,98 (m, 2H); 3,73 (s a, 1H); 3,18 (s a, 1H); 1,80 (d, J = 6,6, 4H); 1,40 (d, J = 7,8, 4H). Yield: 90%. 1H NMR (δ ppm, CDCl3, 300 MHz): 1H NMR (δ ppm, CDCl3, 300 MHz): 7.72-7.60 (m, 1H); 7,096.98 (m, 2H); 3.73 (s a, 1 H); 3.18 (s a, 1 H); 1.80 (d, J = 6.6, 4H); 1.40 (d, J = 7.8, 4H).

Intermedio 29 Intermediate 29

Ácido 3-(3,4-diclorofenil)-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxílico 3- (3,4-Dichlorophenyl) -3,4-diazatricyclo [5.2.1.02.6] deca-2 (6), 4-diene-5-carboxylic acid

Etapa 1: 3-(3,4-Diclorofenil)-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxilato de etilo Stage 1: 3- (3,4-Dichlorophenyl) -3,4-diazatricyclo [5.2.1.02.6] deca-2 (6), ethyl 4-diene-5-carboxylate

Rendimiento: 69%. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,90 (d, J = 2,1, 1H); 7,59 (dd, J. = 7,5, 2,1, 1H); 7,52 (d, J = 8,7, 1H); 4,42 (c, J = 7,5, 2H); 3,71 (s a, 1H); 3,66 (s a, 1H); 2,14 (d, J = 8,7, 1H); 2,00 (d, J = 8,4, 2H); 1,73 (d, J = 9,3, 1H); 1,42 (t, J = 7,5, 3H); 1,20 (d, J = 6,9, 2H). Yield: 69%. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.90 (d, J = 2.1, 1H); 7.59 (dd, J. = 7.5, 2.1, 1H); 7.52 (d, J = 8.7, 1H); 4.42 (c, J = 7.5, 2H); 3.71 (s a, 1 H); 3.66 (s at, 1 H); 2.14 (d, J = 8.7, 1H); 2.00 (d, J = 8.4, 2H); 1.73 (d, J = 9.3, 1H); 1.42 (t, J = 7.5, 3H); 1.20 (d, J = 6.9, 2H).

Etapa 2: Ácido 3-(3,4-diclorofenil)-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxílico Stage 2: 3- (3,4-Dichlorophenyl) -3,4-diazatricyclo [5.2.1.02.6] deca-2 (6), 4-diene-5-carboxylic acid

Rendimiento: 90%. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,92-7,87 (m, 1H); 7,62-7,52 (m, 2H); 3,73 (s a, 1H); 3,71 (s a, 1H); 2,16 (d, J = 6,6, 1H); 2,03 (d, J = 6,3, 2H); 1,76 (d, J = 8,7, 1H); 1,23 (d, J = 6,0, 2H). Yield: 90%. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.92-7.87 (m, 1H); 7.62-7.52 (m, 2H); 3.73 (s a, 1 H); 3.71 (s a, 1 H); 2.16 (d, J = 6.6, 1H); 2.03 (d, J = 6.3, 2H); 1.76 (d, J = 8.7, 1H); 1.23 (d, J = 6.0, 2H).

Intermedio 30 Intermediate 30

Ácido 3-(2-etoxi-4-fluorofenil)-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxílico 3- (2-Ethoxy-4-fluorophenyl) -3,4-diazatricyclo [5.2.1.02.6] deca-2 (6), 4-diene-5-carboxylic acid

Etapa 1: 3-(2-Etoxi-4-fluorofenil)-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxilato etilo Stage 1: 3- (2-Ethoxy-4-fluorophenyl) -3,4-diazatricyclo [5.2.1.02.6] deca-2 (6), ethyl 4-dien-5-carboxylate

RMN 1H(δ ppm, CDCl3, 300 MHz): 7,53 (c, J = 6,3, 1H); 6,78-6,66 (m, 2H); 4,40 (c, J = 6,9, 2H); 4,10-4,00 (m, 2H); 3,65 (s a, 1H); 3,35 (s a, 1H); 2,08 (d, J = 8,1, 1H); 2,00-1,80 (m, 2H); 1,66 (d, J = 9,0, 1H); 1,44-1,32 (m, 6H); 1,24 (d, J = 6,0, 2H). 1H NMR (δ ppm, CDCl3, 300 MHz): 7.53 (c, J = 6.3, 1H); 6.78-6.66 (m, 2H); 4.40 (c, J = 6.9, 2H); 4.10-4.00 (m, 2H); 3.65 (s a, 1 H); 3.35 (s at, 1 H); 2.08 (d, J = 8.1, 1H); 2.00-1.80 (m, 2H); 1.66 (d, J = 9.0, 1H); 1.44-1.32 (m, 6H); 1.24 (d, J = 6.0, 2H).

Etapa 2: Ácido 3-(2-etoxi-4-fluorofenil)-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxílico Stage 2: 3- (2-Ethoxy-4-fluorophenyl) -3,4-diazatricyclo [5.2.1.02.6] deca-2 (6), 4-diene-5-carboxylic acid

Rendimiento: 91%. RMN 1H (δ ppm, DMSO-d6, 300 MHz): 12,62 (s a, 1H); 7,48 (t, J = 7,8, 1H); 7,18 (d, J = 8,4, 1H); 6,94-6,86 (m, 1H); 4,17 (d, J = 6,6, 2H); 3,49 (s a, 1H); 3,34 (s a, 1H); 2,00-1,88 (m, 3H); 1,63 (d, J = 7,8, 1H); 1,30 (t, J = 6,6, 1H); 1,09 (t, J = 10,5, 2H). Yield: 91%. 1H NMR (δ ppm, DMSO-d6, 300 MHz): 12.62 (s a, 1H); 7.48 (t, J = 7.8, 1H); 7.18 (d, J = 8.4, 1H); 6.94-6.86 (m, 1 H); 4.17 (d, J = 6.6, 2H); 3.49 (s at, 1 H); 3.34 (s at, 1 H); 2.00-1.88 (m, 3H); 1.63 (d, J = 7.8, 1H); 1.30 (t, J = 6.6, 1H); 1.09 (t, J = 10.5, 2H).

Los intermedio 31a y 31b, 32a y 32b se prepararon de acuerdo con el procedimiento que se ha descrito para el intermedio 12a y 12 b seguido de hidrólisis como se ha descrito para los intermedio 13a y 13b, usando 2-oxo-2(3oxobiciclo[2.2.1]hept-2-il)acetato de etilo, hidrato de hidrazina, bromuro de 4-metilbencilo y bromuro de 4flurobencilo, respectivamente. Intermediates 31a and 31b, 32a and 32b were prepared according to the procedure described for intermediate 12a and 12b followed by hydrolysis as described for intermediates 13a and 13b, using 2-oxo-2 (3-oxobicycle [ 2.2.1] hept-2-yl) ethyl acetate, hydrazine hydrate, 4-methylbenzyl bromide and 4flurobenzyl bromide, respectively.

Intermedio 31a Intermediate 31a

Etapa 1: 4,5,6,7-Tetrahidro-1H-4,7-metano-indazol-3-carboxilato de etilo: Stage 1: Ethyl 4,5,6,7-Tetrahydro-1H-4,7-methane-indazol-3-carboxylate:

Rendimiento: 1,30 g, 66%. RMN 1H (δ ppm, CDCl3): 4,36 (c, J = 6,9, 2H); 3,58 (s a, 1H); 3,45 (s a, 1H), 2,02-1,92 (m, 3H); 1,71 (d, J = 9,0, 1H); 1,38 (t, J = 6,9, 3H); 1,30-1,20 (m, 2H). Yield: 1.30 g, 66%. 1H NMR (δ ppm, CDCl3): 4.36 (c, J = 6.9, 2H); 3.58 (s at, 1 H); 3.45 (s at, 1 H), 2.02-1.92 (m, 3 H); 1.71 (d, J = 9.0, 1H); 1.38 (t, J = 6.9, 3H); 1.30-1.20 (m, 2H).

Etapa 2: 1-(4-Metilbencil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxilato de etilo: (Intermedio 31aa) y 2-(4-metilbencil)-4,5,6,7-tetrahidro-2H-4,7-metano-indazol-3-carboxilato de etilo (Intermedio 31bb) Stage 2: 1- (4-Methylbenzyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylate ethyl: (Intermediate 31aa) and 2- (4-methylbenzyl) - Ethyl 4,5,6,7-tetrahydro-2H-4,7-methane-indazol-3-carboxylate (Intermediate 31bb)

Intermedio 31aa: RMN 1H (δ ppm, CDCl3, 300 MHz): 7,15 (s, 4H); 5,28 (d, J = 4,8, 2H); 4,38 (c, 7,2, 2H); 3,54 (s a, 1H); 2,97 (s a, 1H); 2,34 (s, 3H); 1,98-1,78 (m, 3H); 1,52 (d, J = 8,7, 1H); 1,39 (t, J = 6,9, 3H); 1,12-0,98 (m, 1H); 0,82-0,68 (m, 1H). Intermediate 31aa: 1H NMR (δ ppm, CDCl3, 300 MHz): 7.15 (s, 4H); 5.28 (d, J = 4.8, 2H); 4.38 (c, 7.2, 2H); 3.54 (s at, 1 H); 2.97 (s at, 1 H); 2.34 (s, 3 H); 1.98-1.78 (m, 3H); 1.52 (d, J = 8.7, 1H); 1.39 (t, J = 6.9, 3H); 1.12-0.98 (m, 1 H); 0.82-0.68 (m, 1 H).

Intermedio 31bb: RMN 1H (δ ppm, CDCl3, 300 MHz): 7,20-7,05 (m, 4H); 5,72 (d, J = 15,6, 1H); 5,49 (d, 14,7, 1H); 4,38-4,25 (m, 2H); 3,52 (s a, 1H); 3,41 (s a, 1H); 2,29 (s, 3H); 2,22 (s a, 1H); 1,99-1,80 (m, 2H); 1,66 (d, J = 7,2, 1H); 1,35 (t, J = 6,9, 3H); 1,26-1,19 (m, 2H) Intermediate 31bb: 1H NMR (δ ppm, CDCl3, 300 MHz): 7.20-7.05 (m, 4H); 5.72 (d, J = 15.6, 1H); 5.49 (d, 14.7, 1H); 4.38-4.25 (m, 2H); 3.52 (s at, 1 H); 3.41 (s at, 1 H); 2.29 (s, 3 H); 2.22 (s at, 1 H); 1.99-1.80 (m, 2H); 1.66 (d, J = 7.2, 1H); 1.35 (t, J = 6.9, 3H); 1.26-1.19 (m, 2H)

Etapa 3a:Ácido 3-(4-metilbencil)-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxílico: Stage 3a: 3- (4-methylbenzyl) -3,4-diazatricyclo [5.2.1.02.6] deca-2 (6), 4-diene-5-carboxylic acid:

Intermedio 31a (294 mg, 82%). RMN 1H (δ ppm, CDCl3, 300 MHz): 7,15 (s, 4H); 5,27 (d, J = 3,6, 2H); 3,57 (s a, 1H); 3,03 (s a, 1H); 2,34 (s, 3H); 1,96-1,81 (m, 2H); 1,74-1,65 (m, 1H); 1,55 (d, J = 9,0, 1H); 1,12-1,02 (m, 1H); 0,83-0,74 (m, 1H). Intermediate 31a (294 mg, 82%). 1H NMR (δ ppm, CDCl3, 300 MHz): 7.15 (s, 4H); 5.27 (d, J = 3.6, 2H); 3.57 (s a, 1 H); 3.03 (s at, 1 H); 2.34 (s, 3 H); 1.96-1.81 (m, 2H); 1.74-1.65 (m, 1 H); 1.55 (d, J = 9.0, 1H); 1.12-1.02 (m, 1 H); 0.83-0.74 (m, 1 H).

Etapa 3b: Ácido 2-(4-metilbencil)-4,5,6,7-tetrahidro-2H-4,7-metano-indazol-3-carboxílico: Step 3b: 2- (4-methylbenzyl) -4,5,6,7-tetrahydro-2H-4,7-methane-indazol-3-carboxylic acid:

Intermedio 31b: (68 mg, 85%). RMN 1H (δ ppm, CDCl3, 300 MHz): 7,10(d, J = 3,3, 4H); 5,72 (d, 15,0, 1H); 5,49 (d, J = 14,4, 1H); 3,58 (s a, 1H); 3,42 (s a, 1H); 2,29 (s, 3H); 1,99-1,88 (m, 3H); 1,67 (d, J = 8,7, 1H); 1,23 (d, J = 10,5, 2H). Intermediate 31b: (68 mg, 85%). 1H NMR (δ ppm, CDCl3, 300 MHz): 7.10 (d, J = 3.3, 4H); 5.72 (d, 15.0, 1H); 5.49 (d, J = 14.4, 1H); 3.58 (s at, 1 H); 3.42 (s at, 1 H); 2.29 (s, 3 H); 1.99-1.88 (m, 3H); 1.67 (d, J = 8.7, 1H); 1.23 (d, J = 10.5, 2H).

Intermedios 32a y 32b Intermediates 32a and 32b

Etapa 1: Stage 1:

1-(4-Fluorobencil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxilato de etilo(Intermedio 32aa) y 2-(4fluorobencil)-4,5,6,7-tetrahidro-2H-4,7-metano-indazol-3-carboxilato de etilo (Intermedio 32bb) Ethyl 1- (4-Fluorobenzyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylate (Intermediate 32aa) and 2- (4fluorobenzyl) -4,5,6, Ethyl 7-tetrahydro-2H-4,7-methane-indazol-3-carboxylate (Intermediate 32bb)

Intermedios 32aa: RMN 1H (δ ppm, CDCl3, 300 MHz): 7,28-7,20 (m, 2H); 7,03 (t, J = 8,7, 2H); 5,29 (d, J = 3,3, 2H); 4,38 (c, 6,9, 2H); 3,55 (s a, 1H); 3,02 (s a, 1H); 1,98-1,79 (m, 2H); 1,70-1,62 (m, 1H); 1,55 (d, J = 9,0, 1H); 1,39 (t, J = 6,9, 3H); 1,14-0,98 (m, 1H); 0,82-0,68 (m, 1H). Intermediates 32aa: 1H NMR (δ ppm, CDCl3, 300 MHz): 7.28-7.20 (m, 2H); 7.03 (t, J = 8.7, 2H); 5.29 (d, J = 3.3, 2H); 4.38 (c, 6.9, 2H); 3.55 (s at, 1 H); 3.02 (s at, 1 H); 1.98-1.79 (m, 2H); 1.70-1.62 (m, 1 H); 1.55 (d, J = 9.0, 1H); 1.39 (t, J = 6.9, 3H); 1.14-0.98 (m, 1 H); 0.82-0.68 (m, 1 H).

Intermedios 32bb: RMN 1H (δ ppm, CDCl3, 300 MHz): 7,24-7,17 (m, 2H); 6,95 (t, J = 8,4, 2H); 5,72 (d, J = 15,6, 1H); 5,48 (d, 15,0, 1H); 4,29 (c, J = 7,2, 2H); 3,51 (s a, 1H); 3,40 (s a, 1H); 1,94 (d, J = 6,0, 3H); 1,66 (d, J = 9,0, 1H); 1,35 (t, J = 7,2, 3H),1,28-1,18 (m, 2H). Intermediates 32bb: 1H NMR (δ ppm, CDCl3, 300 MHz): 7.24-7.17 (m, 2H); 6.95 (t, J = 8.4, 2H); 5.72 (d, J = 15.6, 1H); 5.48 (d, 15.0, 1H); 4.29 (c, J = 7.2, 2H); 3.51 (s at, 1 H); 3.40 (s at, 1 H); 1.94 (d, J = 6.0, 3H); 1.66 (d, J = 9.0, 1H); 1.35 (t, J = 7.2, 3H), 1.28-1.18 (m, 2H).

Etapa 2a:Ácido 1-(4-fluorobencil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxílico: Stage 2a: 1- (4-Fluorobenzyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid:

Intermedio 32a: (294 mg, 72%). RMN 1H (δ ppm, DMSO-d6, 300 MHz): 12,42 (s a, 1H); 7,36-7,25 (m, 2H); 7,20 (t, J = 9,0, 2H); 5,31 (s a, 2H); 3,39 (s a, 1H); 3,32 (s a, 1H); 1,90-1,70 (m, 3H); 1,55 (d, J = 8,7, 1H); 0,99-0,80 (m, 1H); 0,79-0,62 (m, 1H). Intermediate 32a: (294 mg, 72%). 1H NMR (δ ppm, DMSO-d6, 300 MHz): 12.42 (s a, 1H); 7.36-7.25 (m, 2H); 7.20 (t, J = 9.0, 2H); 5.31 (s a, 2H); 3.39 (s at, 1 H); 3.32 (s at, 1 H); 1.90-1.70 (m, 3H); 1.55 (d, J = 8.7, 1H); 0.99-0.80 (m, 1 H); 0.79-0.62 (m, 1 H).

Etapa 2b: Ácido 2-(4-Fluorobencil)-4,5,6,7 tetrahidro-2H-4,7-metano-indazol-3-carboxílico: Step 2b: 2- (4-Fluorobenzyl) -4,5,6,7 tetrahydro-2H-4,7-methane-indazol-3-carboxylic acid:

Intermedio 32b: (55 mg, 60%). RMN 1H (δ ppm, CDCl3, 300 MHz): 7,25-7,17 (m, 2H); 6,96 (t, J = 8,7, 2H); 5,72 (d, J = 14,4, 1H); 5,50 (d, 15,3, 1H); 3,59 (s a, 1H); 3,43 (s a, 1H); 1,84 (d, J = 6,9, 3H); 1,69 (d, J = 8,4, 1H); 1,23 (d, J = 10,2, 2H). Intermediate 32b: (55 mg, 60%). 1H NMR (δ ppm, CDCl3, 300 MHz): 7.25-7.17 (m, 2H); 6.96 (t, J = 8.7, 2H); 5.72 (d, J = 14.4, 1H); 5.50 (d, 15.3, 1H); 3.59 (s a, 1 H); 3.43 (s at, 1 H); 1.84 (d, J = 6.9, 3H); 1.69 (d, J = 8.4, 1H); 1.23 (d, J = 10.2, 2H).

Ejemplo 101 Example 101

N(7)-Piperidino-5-(2-bromofenil)-5,6-diazatetraciclo[7.3.1.13,11 .04,8]tetradeca-4(8),6-dieno-7-carboxamida. N (7) -Piperidino-5- (2-bromophenyl) -5,6-diazatetracycle [7.3.1.13.11 .04.8] tetradeca-4 (8), 6-diene-7-carboxamide.

Una solución del intermedio 1 (300 mg, 0,78 mmol) en DMF (3 ml), se trató con reactivo BOP (319 mg, 0,72 mmol) y Et3N (0,10 ml, 0,99 mmol) a temperatura ambiente durante 15 minutos periodo después del cual se añadió Naminopiperidina (80 µl, 0,90 mmol) a la mezcla y se agitó a temperatura ambiente durante 1 h. La mezcla se vertió en agua y el precipitado formado se recogió por filtración, se secó y se purificó por cromatografía ultrarrápida para obtener el compuesto del título puro (270 mg, 74%). P.F.: 244 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,72 (d, J = 7,6, 1H); 7,65 (s a, 1H); 7,50-7,30 (m, 3H; 3,97 (s a, 1H); 2,85 (s a, 4H); 2,51 (s a, 1H); 2,16 (s a, 2H); 2,10-1,50 (m, 14H); 1,40 (s a, 2H). IR (cm-1, KBr): 3311 (w), 2913 (s), 2844 (m), 2793 (m), 1687 (s), 1570 (w), 1522 (s), 1489 (m), 1479 (m), 1440 (m), 1352 (m), 1227 (m), 1214 (m). EM (m/z) 469,4 ([M+H]+). A solution of intermediate 1 (300 mg, 0.78 mmol) in DMF (3 ml), was treated with BOP reagent (319 mg, 0.72 mmol) and Et3N (0.10 ml, 0.99 mmol) at temperature ambient for 15 minutes after which Naminopiperidine (80 µl, 0.90 mmol) was added to the mixture and stirred at room temperature for 1 h. The mixture was poured into water and the precipitate formed was collected by filtration, dried and purified by flash chromatography to obtain the pure title compound (270 mg, 74%). P.F .: 244 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.72 (d, J = 7.6, 1H); 7.65 (s a, 1 H); 7.50-7.30 (m, 3H; 3.97 (sa, 1H); 2.85 (sa, 4H); 2.51 (sa, 1H); 2.16 (sa, 2H); 2, 10-1.50 (m, 14H); 1.40 (sa, 2H) IR (cm-1, KBr): 3311 (w), 2913 (s), 2844 (m), 2793 (m), 1687 (s), 1570 (w), 1522 (s), 1489 (m), 1479 (m), 1440 (m), 1352 (m), 1227 (m), 1214 (m) .MS (m / z) 469.4 ([M + H] +).

Ejemplo 102 Example 102

N(7)-Bencil-5-(2-bromofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxamida N (7) -Benzyl-5- (2-bromophenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 1 (300 mg, 0,78 mmol), DMF (3 ml), Et3N (0,10 ml, 0,99 mmol), reactivo BOP (319 µg, 0,72 mmol) y bencilamina (80 µl, 0,72 mmol) dieron compuesto del título (280 mg, 76%). P.F.: 201 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,70 (d, J = 7,5, 1H); 7,44 (dd, J = 7,5, 1,5, 1H); 7,41-7,20 (m, 8H); 4,63 (dd, J = 14,4, 6,0, 1H); 4,50 (dd, J = 16,5, 5,4, 1H); 4,00 (t a, J = 5,1, 1H); 2,52 (t a, J = 5,1, 1H); 2,13 (s a, 2H); 2,13-1,92 (m, 4H); 1,92-1,65 (m, 6H). IR (cm-1, KBr): 3428 (m), 2908 (s), 2845 (m), 1672 (s), 1566 (m), 1522 (s), 1498 (s), 1472 (s), 1351 (m), 1087 (m), 1024 (m), 1010 (m), 778 (m), 763 (m), 726 (m), 698 (m). EM (m/z): 476,4 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 1 (300 mg, 0.78 mmol), DMF (3 ml), Et3N (0.10 ml, 0.99 mmol), reagent BOP (319 µg, 0.72 mmol) and benzylamine (80 µl, 0.72 mmol) gave the title compound (280 mg, 76%). P.F .: 201 ºC. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.70 (d, J = 7.5, 1H); 7.44 (dd, J = 7.5, 1.5, 1H); 7.41-7.20 (m, 8H); 4.63 (dd, J = 14.4, 6.0, 1H); 4.50 (dd, J = 16.5, 5.4, 1H); 4.00 (t a, J = 5.1, 1H); 2.52 (t a, J = 5.1, 1H); 2.13 (s a, 2H); 2.13-1.92 (m, 4H); 1.92-1.65 (m, 6H). IR (cm-1, KBr): 3428 (m), 2908 (s), 2845 (m), 1672 (s), 1566 (m), 1522 (s), 1498 (s), 1472 (s), 1351 (m), 1087 (m), 1024 (m), 1010 (m), 778 (m), 763 (m), 726 (m), 698 (m). MS (m / z): 476.4 ([M + H] +).

Ejemplo 103 Example 103

N(7)-Morfolino-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxamida N (7) -Morpholino-5- (4-chlorophenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 2 (100 mg, 0,29 mmol), DMF (1,0 ml), Et3N (40 µl, 0,29 mmol), reactivo BOP (129 mg, 0,29 mmol) y N-aminomorfolina (28 µl, 0,29 mmol) produjo el compuesto del título (97 mg, 78%). P.F.: 220 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,75 (s a, 1H); 7,47 (d, J = 8,1, 2H); 7,29 (d, J = 8,1, 2H); 3,96 (s a, 1H); 3,85 (t, J = 4,5, 4H); 2,99 (s a, 1H); 2,95 (t, J = 4,5, 5H); 2,20 (s a, 2H); 2,10-1,76 (m, 10H). IR (KBr, cm-1): 2915 (s), 2848 (m), 1674 (s), 1532 (m), 1498 (s), 1304 (m), 1267 (m), 1219 (m), 1112 (s), 1091 (s), 895 (m), 838 (s). EM (m/z): 427,3 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 2 (100 mg, 0.29 mmol), DMF (1.0 ml), Et3N (40 µl, 0.29 mmol), reagent BOP (129 mg, 0.29 mmol) and N-aminomorpholine (28 µl, 0.29 mmol) produced the title compound (97 mg, 78%). P.F .: 220 ºC. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.75 (s at, 1H); 7.47 (d, J = 8.1, 2H); 7.29 (d, J = 8.1, 2H); 3.96 (s at, 1 H); 3.85 (t, J = 4.5, 4H); 2.99 (s at, 1H); 2.95 (t, J = 4.5, 5H); 2.20 (s a, 2H); 2.10-1.76 (m, 10H). IR (KBr, cm-1): 2915 (s), 2848 (m), 1674 (s), 1532 (m), 1498 (s), 1304 (m), 1267 (m), 1219 (m), 1112 (s), 1091 (s), 895 (m), 838 (s). MS (m / z): 427.3 ([M + H] +).

Ejemplo 104 Example 104

N(7)-(3-Piridilmetil)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxamida N (7) - (3-Pyridylmethyl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 2 (100 mg, 0,29 mmol), DMF (1,0 ml), Et3N (48 µl, 0,34 mmol), reactivo BOP (128 mg, 0,29 mmol) y 3-aminometil-piridina (30 µl, 0,29 mmol) produjo el compuesto del título (98 mg, 78%). P.F.: 180 ºC. RMN 1H (δ ppm, DMSO-d6, 300 MHz): 8,76 (t, J = 6,0, 1H); 8,52 (s a, 1H); 8,43 (dd, J = 4,8, 1,5, 1H); 7,70 (d, J = 8,1, 1H); 7,62 (d, J = 8,4, 2H); 7,46 (d, J = 8,4, 2H); 7,34 (dd, J = 8,1, 4,8, 1H); 4,39 (d, J = 6,0, 2H); 3,80 (s a, 1H); 2,95 (s a, 1H); 2,14 (s a, 2H), 2,00-1,69 (m, 10H). EM (m/z): 433,2 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 2 (100 mg, 0.29 mmol), DMF (1.0 ml), Et3N (48 µl, 0.34 mmol), reagent BOP (128 mg, 0.29 mmol) and 3-aminomethyl-pyridine (30 µl, 0.29 mmol) produced the title compound (98 mg, 78%). P.F .: 180 ºC. 1H NMR (δ ppm, DMSO-d6, 300 MHz): 8.76 (t, J = 6.0, 1H); 8.52 (s a, 1 H); 8.43 (dd, J = 4.8, 1.5, 1H); 7.70 (d, J = 8.1, 1H); 7.62 (d, J = 8.4, 2H); 7.46 (d, J = 8.4, 2H); 7.34 (dd, J = 8.1, 4.8, 1H); 4.39 (d, J = 6.0, 2H); 3.80 (s at, 1 H); 2.95 (s at, 1 H); 2.14 (s at, 2H), 2.00-1.69 (m, 10H). MS (m / z): 433.2 ([M + H] +).

Ejemplo 105 Example 105

N(7)-(4-Piridilmetil)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxamida N (7) - (4-Pyridylmethyl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 2 (100 mg, 0,29 mmol), DMF (1,0 ml), Et3N (48 µl, 0,34 mmol), reactivo BOP (128 mg, 0,29 mmol) y 4-aminometil-piridina ((30 µl, 0,29 mmol) produjo el compuesto del título (119 mg, 94%). P.F.: 167-168 ºC. RMN 1H (δ ppm, DMSO-d6, 300 MHz): 8,79 (t, J = 6,3, 1H); 8,48 (d, J = 4,5, 2H); 7,65 (dd, J = 7,5, 1,5, 2H); 7,48 (dd, J = 7,5,1,5, 2H); 7,27 (d, J = 4,5, 2H); 4,39 (d, J = 5,7, 2H); 3,80 (s a, 1H); 2,97 (s a, 1H); 2,14 (s a, 2H), 2,00-1,68 (m, 10H). IR (cm-1, KBr): 3212 (m), 2913 (s), 2850 (m), 1656 (s), 1529 (m), 1498 (s), 1419 (m), 1363 (m), 1232 (m), 1160 (m), 1084 (m), 842 (m). EM (m/z): 433,1([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 2 (100 mg, 0.29 mmol), DMF (1.0 ml), Et3N (48 µl, 0.34 mmol), reagent BOP (128 mg, 0.29 mmol) and 4-aminomethyl-pyridine ((30 µl, 0.29 mmol) produced the title compound (119 mg, 94%). MP: 167-168 ° C. 1 H NMR (δ ppm, DMSO-d6, 300 MHz): 8.79 (t, J = 6.3, 1H); 8.48 (d, J = 4.5, 2H); 7.65 (dd, J = 7, 5, 1.5, 2H); 7.48 (dd, J = 7.5, 1.5, 2H); 7.27 (d, J = 4.5, 2H); 4.39 (d, J = 5.7, 2H); 3.80 (sa, 1H); 2.97 (sa, 1H); 2.14 (sa, 2H), 2.00-1.68 (m, 10H). cm-1, KBr): 3212 (m), 2913 (s), 2850 (m), 1656 (s), 1529 (m), 1498 (s), 1419 (m), 1363 (m), 1232 (m ), 1160 (m), 1084 (m), 842 (m) MS (m / z): 433.1 ([M + H] +).

Ejemplo 106 Example 106

N(7)-Ciclohexil-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,1104,8]tetradeca-4(8),6-dieno-7-carboxamida N (7) -Cyclohexyl-5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,1104,8] tetradeca-4 (8), 6-diene-7-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 2 (100 mg, 0,29 mmol), DMF (1,0 ml), Et3N (40 µl, 0,29 mmol), reactivo BOP (129 mg, 0,29 mmol) y ciclohexilamina (40 µl, 0,29 mmol) dio el compuesto del título (110 mg, 89%). P.F.: 162 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,47 (d, J = 8,7, 2H); 7,30 (d, J = 8,7, 2H); 6,85 (d, J = 8,7, 1H); 4,01 (t a, J = 5,5, 1H); 4,00-3,80 (m, 1H); 2,99 (t a, J = 5,6, 1H); 2,20 (s a, 2H); 2,08-1,68 (m, 12H); 1,48-1,10 (m, 8H). IR (cm-1, KBr): 3336 (m), 2928 (s), 2909 (s), 2846 (m), 1649 (s), 1537 (s), 1498 (s), 1366 (m), 1231 (m), 1164 (m), 1088 (m), 838 (m). EM (m/z): 424,1 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 2 (100 mg, 0.29 mmol), DMF (1.0 ml), Et3N (40 µl, 0.29 mmol), reagent BOP (129 mg, 0.29 mmol) and cyclohexylamine (40 µl, 0.29 mmol) gave the title compound (110 mg, 89%). P.F .: 162 ºC. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.47 (d, J = 8.7, 2H); 7.30 (d, J = 8.7, 2H); 6.85 (d, J = 8.7, 1H); 4.01 (t a, J = 5.5, 1H); 4.00-3.80 (m, 1 H); 2.99 (t a, J = 5.6, 1H); 2.20 (s a, 2H); 2.08-1.68 (m, 12H); 1.48-1.10 (m, 8H). IR (cm-1, KBr): 3336 (m), 2928 (s), 2909 (s), 2846 (m), 1649 (s), 1537 (s), 1498 (s), 1366 (m), 1231 (m), 1164 (m), 1088 (m), 838 (m). MS (m / z): 424.1 ([M + H] +).

Ejemplo 107 Example 107

N(7)-(N-ciclohexil-N-metilamino)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-di-eno-7N (7) - (N-cyclohexyl-N-methylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-di-eno- 7 carboxamida carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 2 (250 mg, 0,72 mmol), DMF (3 ml), Et3N (0,22,0 ml, 1,60 mmol), reactivo BOP (322 mg, 0,72 mmol) y 3-N-ciclohexil-N-metil hidrazina (140 mg, 1,10 mmol) produjo el compuesto del título (215 mg, 65%). P.F.: 219 ºC.. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,64 (s a, 1H); 7,46 (d, J = 9,0, 2H), 7,31 (d, J = 9,0, 2,1, 2H), 3,97 (s a, 1H); 2,98 (s a, 1H), 2,69 (s, 3H), 2,62 (s a, 1H); 2,19 (s a, 2H); 2,05-1,70 (m, 14H); 1,40-1,00 (m, 6H).IR (cm-1, KBr): EM (m/z): 453,20 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 2 (250 mg, 0.72 mmol), DMF (3 ml), Et3N (0.22.0 ml, 1.60 mmol) , BOP reagent (322 mg, 0.72 mmol) and 3-N-cyclohexyl-N-methyl hydrazine (140 mg, 1.10 mmol) produced the title compound (215 mg, 65%). P.F .: 219 ° C. 1 H NMR (δ ppm, CDCl 3, 300 MHz): 7.64 (s at, 1 H); 7.46 (d, J = 9.0, 2H), 7.31 (d, J = 9.0, 2.1, 2H), 3.97 (s a, 1H); 2.98 (s at, 1 H), 2.69 (s, 3 H), 2.62 (s at, 1 H); 2.19 (s a, 2H); 2.05-1.70 (m, 14H); 1.40-1.00 (m, 6H) .IR (cm-1, KBr): MS (m / z): 453.20 ([M + H] +).

Ejemplo 108 Example 108

N(7)-Ciclohexilmetil-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11 .04,8]tetradeca-4(8),6-dieno-7-carboxamida N (7) -Cyclohexylmethyl-5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13.11 .04.8] tetradeca-4 (8), 6-diene-7-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 2 (100 mg, 0,29 mmol), Et3N (40 µl, 0,29 mmol), reactivo BOP (129 mg, 0,29 mmol) y ciclohexanometilamina (38 µl, 0,23 mmol) dio el compuesto del título (93 mg, 73%). P.F.: 117 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,46 (d, J = 8,1, 2H); 7,29 (d, J = 8,1, 2H); 7,03 (s a, 1H); 4,01 (s a, 1H), 3,22 (t, J = 6,6, 2H); 3,00 (s a, 1H); 2,20 (s a, 2H); 2,10-1,50 (m, 15H); 1,40-1,10 (m, 4H), 1,10-0,85 (m, 2H). IR (cm-1, KBr): 3441 (m), 2924 (s), 2849 (m), 1670 (s), 1528 (m), 1499 (s), 1477 (m), 1364 (m), 1214 (m), 1232 (m), 1162 (w), 1087 (m), 838 (m). EM (m/z): 438,2 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 2 (100 mg, 0.29 mmol), Et3N (40 µl, 0.29 mmol), BOP reagent (129 mg, 0.29 mmol) and cyclohexanomethylamine (38 µl, 0.23 mmol) gave the title compound (93 mg, 73%). P.F .: 117 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.46 (d, J = 8.1, 2H); 7.29 (d, J = 8.1, 2H); 7.03 (s a, 1 H); 4.01 (s a, 1H), 3.22 (t, J = 6.6, 2H); 3.00 (s at, 1 H); 2.20 (s a, 2H); 2.10-1.50 (m, 15H); 1.40-1.10 (m, 4H), 1.10-0.85 (m, 2H). IR (cm-1, KBr): 3441 (m), 2924 (s), 2849 (m), 1670 (s), 1528 (m), 1499 (s), 1477 (m), 1364 (m), 1214 (m), 1232 (m), 1162 (w), 1087 (m), 838 (m). MS (m / z): 438.2 ([M + H] +).

Ejemplo 109 Example 109

N(7)-(Adamantan-1-il)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-6-dieno-7-carboxamida N (7) - (Adamantan-1-yl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8) -6-diene-7-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 2 (120 mg, 0,35 mmol), DMF (1,0 ml), Et3N (58 µl, 0,42 mmol), reactivo BOP (154 mg, 0,35 mmol) y 1-adamantilamina (52 mg, 0,35 mmol) produjo el compuesto del título (117 mg, 70%). P.F.: 249-252 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,47 (d, J = 8,7, 2H); 7,29 (d, J = 8,7, 2H); 6,73 (s a, 1H); 4,00 (s a, 1H); 2,98 (s a, 1H); 2,23-1,54 (m, 27H). IR (cm-1 , KBr): 3389 (s), 2904 (s), 2849 (m), 1674 (s), 1561 (w), 1527 (s), 1499 (s), 1479 (m), 1455 (m), 1364 (m), 1356 (m), 1232 (m), 1219 (m), 1170 (w), 1090 (m), 1014 (w), 837 (m). EM (m/z): 476,2 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 2 (120 mg, 0.35 mmol), DMF (1.0 ml), Et3N (58 µl, 0.42 mmol), reagent BOP (154 mg, 0.35 mmol) and 1-adamantylamine (52 mg, 0.35 mmol) produced the title compound (117 mg, 70%). P.F .: 249-252 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.47 (d, J = 8.7, 2H); 7.29 (d, J = 8.7, 2H); 6.73 (s a, 1 H); 4.00 (s at, 1 H); 2.98 (s a, 1 H); 2.23-1.54 (m, 27H). IR (cm-1, KBr): 3389 (s), 2904 (s), 2849 (m), 1674 (s), 1561 (w), 1527 (s), 1499 (s), 1479 (m), 1455 (m), 1364 (m), 1356 (m), 1232 (m), 1219 (m), 1170 (w), 1090 (m), 1014 (w), 837 (m). MS (m / z): 476.2 ([M + H] +).

Ejemplo 110 Example 110

N(7)-(1S,2endo-1,3,3-Trimetil-biciclo[2.2.1]hept-2-il)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8] tetradeca-4(8)-6-dieno-7-carboxamida N (7) - (1S, 2endo-1,3,3-Trimethyl-bicyclo [2.2.1] hept-2-yl) -5- (4-chlorophenyl) -5,6-diazatetracycle [7.3.1.13,11.04 , 8] tetradeca-4 (8) -6-diene-7-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 2 (120 mg, 0,35 mmol), DMF (1,0 ml), Et3N (58 µl, 0,42 mmol), reactivo BOP (154 mg, 0,35 mmol) y 1,3,3-Trimetilbiciclo[2.2.1]hept-2-il amina (53 mg, 0,80 mmol) produjo el compuesto del título (135 mg, 80%). P.F.: 229 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,91(s, 1H); 7,47 (d, J = 8,7, 2H); 7,39 (d, J = 8,1, 2H); 7,34-7,20 (m, 3H); 6,99 (t, J = 8,8, 1H); 3,86 (t a, J =4,8, 1H); 3,35 (s, 3H); 3,00 (s a, 1H); 2,17 (s a, 2H); 2,00-1,70 (m, 10H). IR (cm-1, KBr): 3396 (s), 2909 (s), 2845 (m), 1685 (s), 1587 (m), 1563 (m), 1498 (s), 1475 (s), 1464 (s), 1438 (s), 1366 (m), 1223 (m), 1152 (m), 1092 (s), 1083 (m), 1014 (m), 837 (s). EM (m/z): 478,3 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 2 (120 mg, 0.35 mmol), DMF (1.0 ml), Et3N (58 µl, 0.42 mmol), reagent BOP (154 mg, 0.35 mmol) and 1,3,3-Trimethylbicyclo [2.2.1] hept-2-yl amine (53 mg, 0.80 mmol) produced the title compound (135 mg, 80%) . P.F .: 229 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 8.91 (s, 1H); 7.47 (d, J = 8.7, 2H); 7.39 (d, J = 8.1, 2H); 7.34-7.20 (m, 3H); 6.99 (t, J = 8.8, 1H); 3.86 (t a, J = 4.8, 1H); 3.35 (s, 3 H); 3.00 (s at, 1 H); 2.17 (s a, 2H); 2.00-1.70 (m, 10H). IR (cm-1, KBr): 3396 (s), 2909 (s), 2845 (m), 1685 (s), 1587 (m), 1563 (m), 1498 (s), 1475 (s), 1464 (s), 1438 (s), 1366 (m), 1223 (m), 1152 (m), 1092 (s), 1083 (m), 1014 (m), 837 (s). MS (m / z): 478.3 ([M + H] +).

Ejemplo 111 Example 111

N(7)-(2-Clorobencil)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxamida N (7) - (2-Chlorobenzyl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 2 (100 mg, 0,29 mmol), DMF (1,0 ml), Et3N (40 µl, 0,29 mmol), reactivo BOP (129 mg, 0,29 mmol) y 2-clorobencilamina (35 µl, 0,29 mmol) produjo el compuesto del título (102 mg, 75%). P.F.: 162-164 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,50-7,18 (m, 9H); 4,67 (d, J = 6,3, 2H); 3,99 (t a, J = 4,8, 1H); 3,00 (t a, J = 4,8, 1H); 2,20 (s a, 2H); 2,00-1,70 (m, 10H). IR (KBr, cm-1): 3422 (m), 2916 (s), 2845 (m), 1670 (s), 1564 (m), 1531 (s), 1497 (s), 1478 (s), 1442 (m), 1360 (m), 1249 (m), 1232 (m), 1163 (m), 1085 (s), 1047 (m), 1012 (m), 976 (m), 835 (m). EM (m/z): 466,0 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 2 (100 mg, 0.29 mmol), DMF (1.0 ml), Et3N (40 µl, 0.29 mmol), reagent BOP (129 mg, 0.29 mmol) and 2-chlorobenzylamine (35 µl, 0.29 mmol) produced the title compound (102 mg, 75%). P.F .: 162-164 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.50-7.18 (m, 9H); 4.67 (d, J = 6.3, 2H); 3.99 (t a, J = 4.8, 1H); 3.00 (t a, J = 4.8, 1H); 2.20 (s a, 2H); 2.00-1.70 (m, 10H). IR (KBr, cm-1): 3422 (m), 2916 (s), 2845 (m), 1670 (s), 1564 (m), 1531 (s), 1497 (s), 1478 (s), 1442 (m), 1360 (m), 1249 (m), 1232 (m), 1163 (m), 1085 (s), 1047 (m), 1012 (m), 976 (m), 835 (m). MS (m / z): 466.0 ([M + H] +).

Ejemplo 112 Example 112

N(7)-(4-Clorobencil)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-6-dieno-7-carboxamida N (7) - (4-Chlorobenzyl) -5- (4-chlorophenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8) -6-diene-7-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 2 (100 mg, 0,29 mmol), Et3N (40 µl, 0,29 mmol), reactivo BOP (129 mg, 0,29 mmol) y 4-clorobencilamina (36 µl, 0,29 mmol) dio el compuesto del título (115 mg, 85%). P.F.: 198 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,45 (d, J = 8,7, 2H); 7,40-7,20 (m, 7H); 4,54 (d, J = 6,3, 2H), 4,00 (s a, 1H); 3,00 (s a, 1H); 2,21 (s a, 2H); 2,10-1,95 (m, 2H); 1,95-1,70 (m, 8H). IR (cm-1, KBr): 3317 (m), 2914 (s), 2847 (m), 1657 (s), 1538 (s), 1498 (s), 1365 (m), 1247 (m), 1087 (m), 1015 (m); 839 (m). EM (m/z): 466,3 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 2 (100 mg, 0.29 mmol), Et3N (40 µl, 0.29 mmol), BOP reagent (129 mg, 0.29 mmol) and 4-chlorobenzylamine (36 µl, 0.29 mmol) gave the title compound (115 mg, 85%). P.F .: 198 ºC. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.45 (d, J = 8.7, 2H); 7.40-7.20 (m, 7H); 4.54 (d, J = 6.3, 2H), 4.00 (s a, 1H); 3.00 (s at, 1 H); 2.21 (s at, 2H); 2.10-1.95 (m, 2H); 1.95-1.70 (m, 8H). IR (cm-1, KBr): 3317 (m), 2914 (s), 2847 (m), 1657 (s), 1538 (s), 1498 (s), 1365 (m), 1247 (m), 1087 (m), 1015 (m); 839 (m). MS (m / z): 466.3 ([M + H] +).

Ejemplo 113 Example 113

N(7)-(4-Fluorobencil)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-6-dieno-7-carboxamida N (7) - (4-Fluorobenzyl) -5- (4-chlorophenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8) -6-diene-7-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 2 (100 mg, 0,29 mmol), DMF (1,0 ml), Et3N (40 µl, 0,29 mmol), reactivo BOP (129 mg, 0,29 mmol) y 4-fluorobencilamina (33 µl, 0,29 mmol) dio el compuesto del título (96 mg, 73%). P.F.: 201 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,44 (d, J = 8,4, 2H); 7,3,0-7,25 (m, 5H); 7,00 (t, J =8,4, 2H); 4,54 (d, J = 6,0, 2H), 4,01 (s a, 1H); 3,00 (s a, 1H); 2,20 (s a, 2H); 2,05-1,95 (m, 2H); 1,95-1,80 (m, 8H). IR (cm-1, KBr): 3345 (m), 2921 (s), 2900 (m), 2850 (m), 1648 (s), 1542 (s), 1508 (s), 1364 (m), 1354(m), 1258 (m), 1233 (m), 1217 (s), 1155 (m), 1087 (m), 834 (s). EM (m/z): 450,0 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 2 (100 mg, 0.29 mmol), DMF (1.0 ml), Et3N (40 µl, 0.29 mmol), reagent BOP (129 mg, 0.29 mmol) and 4-fluorobenzylamine (33 µl, 0.29 mmol) gave the title compound (96 mg, 73%). P.F .: 201 ºC. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.44 (d, J = 8.4, 2H); 7.3.0-7.25 (m, 5H); 7.00 (t, J = 8.4, 2H); 4.54 (d, J = 6.0, 2H), 4.01 (s a, 1H); 3.00 (s at, 1 H); 2.20 (s a, 2H); 2.05-1.95 (m, 2H); 1.95-1.80 (m, 8H). IR (cm-1, KBr): 3345 (m), 2921 (s), 2900 (m), 2850 (m), 1648 (s), 1542 (s), 1508 (s), 1364 (m), 1354 (m), 1258 (m), 1233 (m), 1217 (s), 1155 (m), 1087 (m), 834 (s). MS (m / z): 450.0 ([M + H] +).

Ejemplo 114 Example 114

N(7)-(2,4-Difluorobencil)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7carboxamida N (7) - (2,4-Difluorobenzyl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 2 (150 mg, 0,43 mmol), DMF (2,0 ml), Et3N (60 µl, 0,43 mmol), reactivo BOP (193 mg, 0,43 mmol) y 2,4-difluorobencilamina (52 µl, 0,43 mmol) produjo el compuesto del título (195 mg, 96%). P.F.: 185 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,49-7,27 (m, 6H); 6,90-6,75 (m, 2H); 4,57(d, J = 6,3, 2H), 3,98 (t, J = 5,7, 1H); 2,99 (t a, J = 5,4, 1H), 2,20 (s a, 2H), 2,05-1,80 (m, 10H). IR (cm-1, KBr): 3428 (s), 2920 (m), 2898 (m), 1673 (s), 1535 (s), 1500 (s), 1430 (s), 1229 (m), 1161 (m), 1064 (m), 986 (m), 835(m), 960 (m), 861 (m). EM (m/z): 468,10 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 2 (150 mg, 0.43 mmol), DMF (2.0 ml), Et3N (60 µl, 0.43 mmol), reagent BOP (193 mg, 0.43 mmol) and 2,4-difluorobenzylamine (52 µl, 0.43 mmol) produced the title compound (195 mg, 96%). P.F .: 185 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.49-7.27 (m, 6H); 6.90-6.75 (m, 2H); 4.57 (d, J = 6.3, 2H), 3.98 (t, J = 5.7, 1H); 2.99 (t a, J = 5.4, 1H), 2.20 (s a, 2H), 2.05-1.80 (m, 10H). IR (cm-1, KBr): 3428 (s), 2920 (m), 2898 (m), 1673 (s), 1535 (s), 1500 (s), 1430 (s), 1229 (m), 1161 (m), 1064 (m), 986 (m), 835 (m), 960 (m), 861 (m). MS (m / z): 468.10 ([M + H] +).

Ejemplo 115 Example 115

N(7)-(2,6-Difluorobencil)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7carboxamida N (7) - (2,6-Difluorobenzyl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 2 (150 mg, 0,43 mmol), DMF (2,0 ml), Et3N (60 µl, 0,43 mmol), reactivo BOP (193 mg, 0,43 mmol) y 2,6-difluorobencilamina (52 µl, 0,43 mmol) produjo el compuesto del título (178 mg, 87%). P.F.: 166-167 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,44 (d, J = 8,7, 2H); 7,30-7,20 (m, 3H); 6,88 (t, J = 7,8, 2H), 4,68 (d, J = 5,7, 2H), 4,00 (t a, J = 5,4, 1H); 2,98 (s a, 1H), 2,19 (s a, 2H), 2,05-1,60 (m, 10H). IR (cm-1, KBr): 3427 (m), 2930 (m), 2905 (m), 1681 (s), 1594 (m), 1563 (m), 1530 (s), 1499 (s), 1471 (s), 1364 (m), 1260 (m), 1161 (m), 1087 (s), 994 (s), 839 (m). EM (m/z): 468,10 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 2 (150 mg, 0.43 mmol), DMF (2.0 ml), Et3N (60 µl, 0.43 mmol), reagent BOP (193 mg, 0.43 mmol) and 2,6-difluorobenzylamine (52 µl, 0.43 mmol) produced the title compound (178 mg, 87%). P.F .: 166-167 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.44 (d, J = 8.7, 2H); 7.30-7.20 (m, 3H); 6.88 (t, J = 7.8, 2H), 4.68 (d, J = 5.7, 2H), 4.00 (t a, J = 5.4, 1H); 2.98 (s at, 1H), 2.19 (s at, 2H), 2.05-1.60 (m, 10H). IR (cm-1, KBr): 3427 (m), 2930 (m), 2905 (m), 1681 (s), 1594 (m), 1563 (m), 1530 (s), 1499 (s), 1471 (s), 1364 (m), 1260 (m), 1161 (m), 1087 (s), 994 (s), 839 (m). MS (m / z): 468.10 ([M + H] +).

Ejemplo 116 Example 116

N(7)-(4-Trifluorometilbencil)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7carboxamida N (7) - (4-Trifluoromethylbenzyl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 2 (100 mg, 0,29 mmol), Et3N (40 µl, 0,29 mmol), reactivo BOP (129 mg, 0,29 mmol) y 4-(trifluorometil)bencilamina (42 µl, 0,27 mmol) produjo el compuesto del título (115 mg, 79%). P.F.: 228 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,57 (d, J =8,6, 2H); 7,46-7,39 (m, 4H); 7,37 (t a, J = 5,4, 1H); 7,28 (d, J = 8,7, 2H); 4,63 (d, J = 6,0, 2H), 3,99 (t a, J = 4,2, 1H); 3,00 (s a, 1H); 2,21 (s a, 2H); 2,05-1,96 (m, 2H); 1,96-1,84 (m, 8H). IR (cm-1, KBr): 3350 (m), 2916 (s), 2850 (m), 1647 (s), 1618 (m), 1541 (s), 1498 (s), 1325 (s), 1256 (m), 1232 (m), 1159 (s), 1124 (s), 1112 (s), 1086 (s), 1065 (s), 1015 (m), 978 (m), 850 (m), 834 (m). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 2 (100 mg, 0.29 mmol), Et3N (40 µl, 0.29 mmol), BOP reagent (129 mg, 0.29 mmol) and 4- (trifluoromethyl) benzylamine (42 µl, 0.27 mmol) produced the title compound (115 mg, 79%). P.F .: 228 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.57 (d, J = 8.6, 2H); 7.46-7.39 (m, 4H); 7.37 (t a, J = 5.4, 1H); 7.28 (d, J = 8.7, 2H); 4.63 (d, J = 6.0, 2H), 3.99 (t a, J = 4.2, 1H); 3.00 (s at, 1 H); 2.21 (s at, 2H); 2.05-1.96 (m, 2H); 1.96-1.84 (m, 8H). IR (cm-1, KBr): 3350 (m), 2916 (s), 2850 (m), 1647 (s), 1618 (m), 1541 (s), 1498 (s), 1325 (s), 1256 (m), 1232 (m), 1159 (s), 1124 (s), 1112 (s), 1086 (s), 1065 (s), 1015 (m), 978 (m), 850 (m), 834 (m).

Ejemplo 117 Example 117

N(7)-(S-1-Feniletil)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7carboxamida N (7) - (S-1-Phenylethyl) -5- (4-chlorophenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 2 (150 mg, 0,43 mmol), DMF (2,0 ml), Et3N (60 µl, 0,43 mmol), reactivo BOP (193 mg, 0,43 mmol) y S-(-)-Feniletil-amina (58 µl, 0,43 mmol) produjo el compuesto del título (130 mg, 67%). P.F.: 85-86 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,50-7,40 (m, 5H); 736-7,20 (m, 4H); 5,27 (quintuplete, 7,2, 1H), 4,00 (t, J = 5,6, 1H); 2,98 (t, J = 5,6, 1H), 2,19 (s a, 2H), 2,10-1,75 (m, 10H), 1,57 (d, J = 6,9, 3H). IR (cm-1, KBr): 3410 (m), 2913 (s), 2845 (m), 1667 (s), 1526 (s), 1498 (s), 1478 (s), 1363 (m), 1219 (m), 1160 (m), 1084 (s), 1014 (m), 835 (m), 699 (m). EM (m/z): 446,10 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 2 (150 mg, 0.43 mmol), DMF (2.0 ml), Et3N (60 µl, 0.43 mmol), reagent BOP (193 mg, 0.43 mmol) and S - (-) - Phenylethyl amine (58 µl, 0.43 mmol) produced the title compound (130 mg, 67%). P.F .: 85-86 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.50-7.40 (m, 5H); 736-7.20 (m, 4H); 5.27 (quintuple, 7.2, 1H), 4.00 (t, J = 5.6, 1H); 2.98 (t, J = 5.6, 1H), 2.19 (sa, 2H), 2.10-1.75 (m, 10H), 1.57 (d, J = 6.9, 3H ). IR (cm-1, KBr): 3410 (m), 2913 (s), 2845 (m), 1667 (s), 1526 (s), 1498 (s), 1478 (s), 1363 (m), 1219 (m), 1160 (m), 1084 (s), 1014 (m), 835 (m), 699 (m). MS (m / z): 446.10 ([M + H] +).

Ejemplo 118 Example 118

N(7)-(R-1 Feniletil))-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8] tetradeca-4(8),6-dieno-7-carboxamida N (7) - (R-1 Phenylethyl)) - 5- (4-chlorophenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 2 (100 mg, 0,29 mmol), DMF (1,0 ml), Et3N (46 µl, 0,32 mmol), reactivo BOP (136 mg, 0,32 mmol) y R-1-feniletilamina (39 mg, 0,32 mmol) produjo el compuesto del título (90 mg, 69%). P.F.: 65-70 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,50-7,18 (m, 10H); 5,35-5,18 (m, 1H); 4,00 (s a, 1H); 2,98 (s a, 1H); 2,19 (s a, 2H); 2,10-1,71 (m, 10H); 1,57 (d, J = 6,9, 3H). IR (cm-1, KBr): 3408 (s), 3062 (w), 3029 (w), 2914 (s), 2845 (s), 1667 (s), 1596 (w), 1585 (w), 1526 (s), 1498 (s), 1478 (s), 1441 (s), 1406 (m), 1363 (m), 1353 (w), 1271 (m), 1232 (s), 1218 (m), 1159 (m), 1083 (s), 1033 (m), 1013, (m), 933 (w), 835 (m). EM (m/z): 446,3 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 2 (100 mg, 0.29 mmol), DMF (1.0 ml), Et3N (46 µl, 0.32 mmol), reagent BOP (136 mg, 0.32 mmol) and R-1-phenylethylamine (39 mg, 0.32 mmol) produced the title compound (90 mg, 69%). P.F .: 65-70 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.50-7.18 (m, 10H); 5.35-5.18 (m, 1 H); 4.00 (s at, 1 H); 2.98 (s a, 1 H); 2.19 (s a, 2H); 2.10-1.71 (m, 10H); 1.57 (d, J = 6.9, 3H). IR (cm-1, KBr): 3408 (s), 3062 (w), 3029 (w), 2914 (s), 2845 (s), 1667 (s), 1596 (w), 1585 (w), 1526 (s), 1498 (s), 1478 (s), 1441 (s), 1406 (m), 1363 (m), 1353 (w), 1271 (m), 1232 (s), 1218 (m), 1159 (m), 1083 (s), 1033 (m), 1013, (m), 933 (w), 835 (m). MS (m / z): 446.3 ([M + H] +).

Ejemplo 119 Example 119

N(7)-(1-Metil-1-feniletil))-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7carboxamida N (7) - (1-Methyl-1-phenylethyl)) - 5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 2 (100 mg, 0,29 mmol), DMF (1,0 ml), Et3N (46 µl, 0,32 mmol), reactivo BOP (136 mg, 0,32 mmol) y α,α-dimetilbencilamina (48 mg, 0,36 mmol) produjo el compuesto del título (90 mg, 67%). P.F.: 181 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,47 (d a, J = 8,7, 4H); 7,36-7,28 (m, 5H); 7,22 (t a, J = 7,2, 1H); 3,92, (s a, 1H); 3,35 (s, 3H); 2,99 (s a, 1H); 2,18 (s a, 2H); 2,00-1,74 (m, 10H); 1,79 (s, 6H). IR (cm-1, KBr): 3407 (m), 3090 (w), 3060 (w), 3024 (w), 2965 (w), 2898 (s), 2845 (m), 1675 (s), 1563 (w), 1497 (s), 1479 (s), 1438 (m), 1407 (w), 1379 (w), 1362 (m), 1340 (w), 1254 (w), 1231 (w), 1219 (w), 1194 (w), 1159 (w), 1085 (m), 1031 (w), 1015 (m), 834 (m). EM (m/z): 460,1 (25, [M+H]+); 342,3 (100). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 2 (100 mg, 0.29 mmol), DMF (1.0 ml), Et3N (46 µl, 0.32 mmol), reagent BOP (136 mg, 0.32 mmol) and α, α-dimethylbenzylamine (48 mg, 0.36 mmol) produced the title compound (90 mg, 67%). P.F .: 181 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.47 (d a, J = 8.7, 4H); 7.36-7.28 (m, 5H); 7.22 (t a, J = 7.2, 1H); 3.92, (s a, 1 H); 3.35 (s, 3 H); 2.99 (s at, 1H); 2.18 (s at, 2H); 2.00-1.74 (m, 10H); 1.79 (s, 6H). IR (cm-1, KBr): 3407 (m), 3090 (w), 3060 (w), 3024 (w), 2965 (w), 2898 (s), 2845 (m), 1675 (s), 1563 (w), 1497 (s), 1479 (s), 1438 (m), 1407 (w), 1379 (w), 1362 (m), 1340 (w), 1254 (w), 1231 (w), 1219 (w), 1194 (w), 1159 (w), 1085 (m), 1031 (w), 1015 (m), 834 (m). MS (m / z): 460.1 (25, [M + H] +); 342.3 (100).

Ejemplo 120 Example 120

N(7)-(2-Piridilmetil)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxamida N (7) - (2-Pyridylmethyl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 2 (100 mg, 0,29 mmol), DMF (1,0 ml), Et3N (48 µl, 0,34 mmol), reactivo BOP (128 mg, 0,29 mmol) y 2-aminometil-piridina ((30 µl, 0,29 mmol) dio el compuesto del título (98 mg, 78%). P.F.: 187 ºC. RMN 1H (δ ppm, DMSO-d6, 300 MHz): 8,66 (t, J = 6,0, 1H); 8,49 (d a, J = 5,1; 1H); 7,76 (td, J = 7,6, 1,8, 1H); 7,64 (d, J = 9,0, 2H); 7,51 (d, J = 9,0, 2H); 7,31 (d, J = 7,6, 1 H); 7,26 (m, 1H); 4,50 (d, J = 6,0, 2H); 3,82 (s a, 1H); 2,98 (s a, 1H); 2,15 (s a, 2H), 2,00-1,70 (m, 10H). IR (cm-1, KBr): 2918 (m), 2847 (m), 1781 (s), 1496 (s), 1443 (m), 1366 (m), 1230 (m), 1113 (m), 1089 (m), 1059 (m), 835 (m). EM (m/z): 433,2 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 2 (100 mg, 0.29 mmol), DMF (1.0 ml), Et3N (48 µl, 0.34 mmol), reagent BOP (128 mg, 0.29 mmol) and 2-aminomethyl-pyridine ((30 µl, 0.29 mmol) gave the title compound (98 mg, 78%). MP: 187 ° C. 1 H NMR (δ ppm, DMSO-d6, 300 MHz): 8.66 (t, J = 6.0, 1H); 8.49 (da, J = 5.1; 1H); 7.76 (td, J = 7.6, 1.8, 1H); 7.64 (d, J = 9.0, 2H); 7.51 (d, J = 9.0, 2H); 7.31 (d, J = 7.6, 1 H); 7.26 (m, 1H); 4.50 (d, J = 6.0, 2H); 3.82 (sa, 1H); 2.98 (sa, 1H); 2.15 (sa , 2H), 2.00-1.70 (m, 10H) IR (cm-1, KBr): 2918 (m), 2847 (m), 1781 (s), 1496 (s), 1443 (m) , 1366 (m), 1230 (m), 1113 (m), 1089 (m), 1059 (m), 835 (m) .MS (m / z): 433.2 ([M + H] +).

Ejemplo 121 Example 121

N(7)-(N’-fenilamino)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,1104,8]tetradeca-4(8),6-dieno-7-carboxamida N (7) - (N’-phenylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,1104,8] tetradeca-4 (8), 6-diene-7-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 2 (200 mg, 0,29 mmol), Et3N (80 µl, 0,58 mmol), reactivo BOP (258 mg, 0,58 mmol) y fenilhidrazina (60 µl, 0,58 mmol) dio el compuesto del título (185 mg, 73%). P.F.: 103-105 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,59 (s, 1H); 7,48 (d, J = 8,7, 2H); 7,33 (d, J = 8,7, 2H); 7,22 (t, J = 7,5, 2H); 6,94 (d, J =8,7, 2H); 6,88 (t, J = 7,5, 1H); 3,89 (t a, J = 4,7, 1H); 3,03 (s a, J = 3,5, 1H); 2,20 (s a, 2H); 2,00-1,75 (m, 10H). IR (cm-1, KBr): 3279 (m), 2912 (s), 2845 (m), 1678 (s), 1603 (m), 1497 (s), 1467 (m), 1353 (m), 1232 (m), 1090 (m), 1012 (m), 835 (m). EM (m/z): 433,1 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 2 (200 mg, 0.29 mmol), Et3N (80 µl, 0.58 mmol), BOP reagent (258 mg, 0.58 mmol) and phenylhydrazine (60 µl, 0.58 mmol) gave the title compound (185 mg, 73%). P.F .: 103-105 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 8.59 (s, 1H); 7.48 (d, J = 8.7, 2H); 7.33 (d, J = 8.7, 2H); 7.22 (t, J = 7.5, 2H); 6.94 (d, J = 8.7, 2H); 6.88 (t, J = 7.5, 1H); 3.89 (t a, J = 4.7, 1H); 3.03 (s a, J = 3.5, 1H); 2.20 (s a, 2H); 2.00-1.75 (m, 10H). IR (cm-1, KBr): 3279 (m), 2912 (s), 2845 (m), 1678 (s), 1603 (m), 1497 (s), 1467 (m), 1353 (m), 1232 (m), 1090 (m), 1012 (m), 835 (m). MS (m / z): 433.1 ([M + H] +).

Ejemplo 122 Example 122

Clorhidrato de N(7)-(N’-fenilamino)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,1104,8]tetradeca-4(8),6-dieno-7carboxamida N (7) - (N’-phenylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,1104,8] tetradeca-4 (8), 6-diene-7carboxamide hydrochloride

Una solución de ejemplo 121 (100 mg, 0,23 mmol) en éter seco (2,0 ml) se trató con una solución saturada de HCl en éter (2,0 ml) a TA, se agitó a TA durante 1 hora y el sólido precipitado se filtró para producir el compuesto del título (90 mg, 73%). P.F.: 135-136 ºC. RMN 1H (δ ppm, DMSO-d6 300 MHz): 9,95 (s, 1H); 7,65 (d, J = 9,0, 2H); 7,52 (d, J = 9,0, 2H); 7,13 (t, J = 7,8, 2H); 6,74 (d, J = 7,5, 2H); 6,69 (t, J = 7,5, 1H); 3,67 (s a,1H); 3,02 (s a, 1H); 2,15 (s a, 2H); 2,00-1,71 (m, 10H). IR (cm-1, KBr): 3419 (s a), 3020 (m), 1642(s), 1498 (m), 1216 (m), 1092 (w), 1014(w), 836 (m). EM (m/z): 433,3 ([M+H]+). An example solution 121 (100 mg, 0.23 mmol) in dry ether (2.0 ml) was treated with a saturated solution of HCl in ether (2.0 ml) at RT, stirred at RT for 1 hour and The precipitated solid was filtered to yield the title compound (90 mg, 73%). P.F .: 135-136 ° C. 1H NMR (δ ppm, DMSO-d6 300 MHz): 9.95 (s, 1H); 7.65 (d, J = 9.0, 2H); 7.52 (d, J = 9.0, 2H); 7.13 (t, J = 7.8, 2H); 6.74 (d, J = 7.5, 2H); 6.69 (t, J = 7.5, 1H); 3.67 (s at, 1 H); 3.02 (s at, 1 H); 2.15 (s a, 2H); 2.00-1.71 (m, 10H). IR (cm-1, KBr): 3419 (s a), 3020 (m), 1642 (s), 1498 (m), 1216 (m), 1092 (w), 1014 (w), 836 (m). MS (m / z): 433.3 ([M + H] +).

Ejemplo 123 Example 123

N(7)-(2-Clorofenilamino)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7carboxamida N (7) - (2-Chlorophenylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 2 (200 mg, 0,58 mmol), Et3N (90 µl, 0,64 mmol), reactivo BOP (258 mg, 0,58 mmol) y clorhidrato de 2-clorofenilhidrazina (104 mg, 0,58 mmol) produjo el compuesto del título (168 mg, 62%). P.F.: 155 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,60 (s, 1H); 7,49 (d, J = 8,7, 2H); 7,38-7,20 (m, 3H); 7,11 (t, J = 7,2, 1H); 7,04 (dd, J = 7,5, 1,5, 1H); 6,82 (t, J = 7,6, 1H); 6,56 (s a, 1H); 3,90 (s a, 1H); 3,03 (s a, 1H); 2,20 (s a, 2H); 2,01-1,70 (m, 10H). IR (cm-1, KBr): 3376 (m), 3310 (m), 2909 (m), 1683 (s), 1597 (m), 1563 (w), 1498 (s), 1470 (s), 1423 (w), 1364 (m), 1212 (m), 1088 (m), 1026 (m), 835 (m). EM (m/z): 467,9 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 2 (200 mg, 0.58 mmol), Et3N (90 µl, 0.64 mmol), BOP reagent (258 mg, 0.58 mmol) and 2-chlorophenylhydrazine hydrochloride (104 mg, 0.58 mmol) produced the title compound (168 mg, 62%). P.F .: 155 ºC. 1 H NMR (δ ppm, CDCl 3, 300 MHz): 8.60 (s, 1 H); 7.49 (d, J = 8.7, 2H); 7.38-7.20 (m, 3H); 7.11 (t, J = 7.2, 1H); 7.04 (dd, J = 7.5, 1.5, 1H); 6.82 (t, J = 7.6, 1H); 6.56 (s a, 1 H); 3.90 (s at, 1 H); 3.03 (s at, 1 H); 2.20 (s a, 2H); 2.01-1.70 (m, 10H). IR (cm-1, KBr): 3376 (m), 3310 (m), 2909 (m), 1683 (s), 1597 (m), 1563 (w), 1498 (s), 1470 (s), 1423 (w), 1364 (m), 1212 (m), 1088 (m), 1026 (m), 835 (m). MS (m / z): 467.9 ([M + H] +).

Ejemplo 124 Example 124

Clorhidrato de N(7)-(2-Clorofenilamino)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6dieno-7-carboxamida N (7) - (2-Chlorophenylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxamide hydrochloride

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 2 (250 mg, 0,73 mmol), DMF (3 ml), Et3N (0,12,0 ml, 0,86 mmol), reactivo BOP (322 mg, 0,73 mmol) y clorhidrato de N-(2clorofenil)-N-metilhidrazina (220 mg, 0,80 mmol) produjo el compuesto del título (210 mg, 60%). P.F.: 229 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,91(s, 1H); 7,47 (d, J = 8,7, 2H); 7,39 (d, J = 8,1, 2H); 7,34-7,20 (m, 3H); 6,99 (t, J = 8,8, 1H); 3,86 (t a, J = 4,8, 1H); 3,35 (s, 3H); 3,00 (s a, 1H); 2,17 (s a, 2H); 2,00-1,70 (m, 10H). IR (cm-1, KBr): 3396 (s), 2909 (s), 2845 (m), 1685 (s), 1587 (m), 1563 (m), 1498 (s), 1475 (s), 1464 (s), 1438 (s), 1366 (m), 1223 (m), 1152 (m), 1092 (s), 1083 (m), 1014 (m), 837 (s). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 2 (250 mg, 0.73 mmol), DMF (3 ml), Et3N (0.12.0 ml, 0.86 mmol) , BOP reagent (322 mg, 0.73 mmol) and N- (2-chlorophenyl) -N-methylhydrazine hydrochloride (220 mg, 0.80 mmol) produced the title compound (210 mg, 60%). P.F .: 229 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 8.91 (s, 1H); 7.47 (d, J = 8.7, 2H); 7.39 (d, J = 8.1, 2H); 7.34-7.20 (m, 3H); 6.99 (t, J = 8.8, 1H); 3.86 (t a, J = 4.8, 1H); 3.35 (s, 3 H); 3.00 (s at, 1 H); 2.17 (s a, 2H); 2.00-1.70 (m, 10H). IR (cm-1, KBr): 3396 (s), 2909 (s), 2845 (m), 1685 (s), 1587 (m), 1563 (m), 1498 (s), 1475 (s), 1464 (s), 1438 (s), 1366 (m), 1223 (m), 1152 (m), 1092 (s), 1083 (m), 1014 (m), 837 (s).

Ejemplo 125 Example 125

N(7)-[(4-clorofenil)amino)]-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,1104,8]tetradeca-4(8),6-dieno-7carboxamida N (7) - [(4-chlorophenyl) amino)] - 5- (4-chlorophenyl) -5,6-diazatetracycle [7.3.1.13,1104.8] tetradeca-4 (8), 6-diene-7carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 2 (100 mg, 0,29 mmol), Et3N (0,27 ml, 1,94 mmol), reactivo BOP (129 mg, 0,29 mmol) y clorhidrato de 4-clorofenilhidrazina (52 mg, 0,29 mmol) produjo el compuesto del título (105 mg, 77%). P.F.: 208-210 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,58 (s, 1H); 7,49 (d, J = 8,4, 2H); 7,33 (d, J = 8,4, 2H); 7,18 (d, J = 8,7, 2H); 6,88 (d, J = 8,7, 2H); 6,00 (s a, 1H); 3,87 (s a, 1H); 3,03 (s a, 1H); 2,20 (s, 2H); 2,00-1,70 (m, 10H). IR (cm-1, KBr): 3282 (m), 2912 (s), 2845 (m), 1670 (s), 1596 (m), 1498 (s), 1470 (s), 1253 (m), 1231 (m), 1091 (s), 1013 (m), 834 (m). EM (m/z): 467,2 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 2 (100 mg, 0.29 mmol), Et3N (0.27 ml, 1.94 mmol), BOP reagent (129 mg, 0 , 29 mmol) and 4-chlorophenylhydrazine hydrochloride (52 mg, 0.29 mmol) produced the title compound (105 mg, 77%). P.F .: 208-210 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 8.58 (s, 1H); 7.49 (d, J = 8.4, 2H); 7.33 (d, J = 8.4, 2H); 7.18 (d, J = 8.7, 2H); 6.88 (d, J = 8.7, 2H); 6.00 (s at, 1 H); 3.87 (s at, 1 H); 3.03 (s at, 1 H); 2.20 (s, 2 H); 2.00-1.70 (m, 10H). IR (cm-1, KBr): 3282 (m), 2912 (s), 2845 (m), 1670 (s), 1596 (m), 1498 (s), 1470 (s), 1253 (m), 1231 (m), 1091 (s), 1013 (m), 834 (m). MS (m / z): 467.2 ([M + H] +).

Ejemplo 126 Example 126

N(7)-(2,4-Diclorofenilamino)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,1104,8]-tetradeca-4(8),6-dieno-7carboxamida N (7) - (2,4-Dichlorophenylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,1104,8] -tetradeca-4 (8), 6-diene-7carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 2 (200 mg, 0,58 mmol), Et3N (90 µl, 0,65 mmol), reactivo BOP (258 mg, 0,58 mmol) y clorhidrato de 2,4-diclorofenilhidrazina (125 mg, 0,59 mmol) produjo el compuesto del título (226 mg, 77%). P.F.: 214-215 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,60 (s, 1H); 7,49 (d, J = 8,7, 2H); 7,40-7,22 (m, 3H); 7,11 (dd, J = 8,7, 2,4, 1H); 6,97 (d, J = 8,7, 1H); 6,49 (s a, 1H); 3,87 (t a, J = 4,61, 1H); 3,03 (s a, 1H); 2,20 (s a, 2H); 2,04-1,70 (m, 10H). IR (cm-1, KBr): 3300 (m), 2907 (m), 2845 (m), 1681 (s), 1498 (s), 1471 (s), 1232 (m), 1089 (m), 863 (m), 837(m). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 2 (200 mg, 0.58 mmol), Et3N (90 µl, 0.65 mmol), BOP reagent (258 mg, 0.58 mmol) and 2,4-dichlorophenylhydrazine hydrochloride (125 mg, 0.59 mmol) produced the title compound (226 mg, 77%). P.F .: 214-215 ° C. 1 H NMR (δ ppm, CDCl 3, 300 MHz): 8.60 (s, 1 H); 7.49 (d, J = 8.7, 2H); 7.40-7.22 (m, 3H); 7.11 (dd, J = 8.7, 2.4, 1H); 6.97 (d, J = 8.7, 1H); 6.49 (s a, 1 H); 3.87 (t a, J = 4.61, 1H); 3.03 (s at, 1 H); 2.20 (s a, 2H); 2.04-1.70 (m, 10H). IR (cm-1, KBr): 3300 (m), 2907 (m), 2845 (m), 1681 (s), 1498 (s), 1471 (s), 1232 (m), 1089 (m), 863 (m), 837 (m).

Ejemplo 127 Example 127

N(7)-[(2,4-Diclorofenil-N’-metilamino]-5-(4-clorofenil)-5,6-diazatetraciclo [7.3.1.13,11.04,8]tetradeca-4(8),6-dieno7carboxamida N (7) - [(2,4-Dichlorophenyl-N'-methylamino] -5- (4-chlorophenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8), 6- diene7carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 2 (300 mg, 0,88 mmol), DMF (3,0 ml), Et3N (0,15 ml, 1,05 mmol), reactivo BOP (387 mg, 0,88 mmol) y N-(2,4-diclorofenil)N-metilhidrazina (296 mg, 0,97 mmol) dio el compuesto del título (220 mg, 49%). P.F.: 192 ºC. RMN 1H (δ ppm, CDCl3, 400 MHz): 8,90 (s, 1H); 7,44 (dt, J = 8,8, 2,0, 2H); 7,29-7,26 (m, 4H); 7,17 (dd, J = 8,4, 2,4, 1H); 3,80 (s a, 1H); 3,30 (s, 3H); 2,97 (s a, 1H); 2,15 (s, 2H); 1,86-1,75 (m, 10H). IR (cm-1, KBr): 3396 (s), 2909 (s), 2845 (m), 1685 (s), 1587 (m), 1563 (m), 1498 (s), 1475 (s), 1464 (s), 1438 (s), 1366 (m), 1223 (m), 1152 (m), 1092 (s), 1083 (m), 1014 (m), 837 (s). EM (m/z): 514,9 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 2 (300 mg, 0.88 mmol), DMF (3.0 ml), Et3N (0.15 ml, 1.05 mmol) , BOP reagent (387 mg, 0.88 mmol) and N- (2,4-dichlorophenyl) N-methylhydrazine (296 mg, 0.97 mmol) gave the title compound (220 mg, 49%). P.F .: 192 ºC. 1H NMR (δ ppm, CDCl3, 400 MHz): 8.90 (s, 1H); 7.44 (dt, J = 8.8, 2.0, 2H); 7.29-7.26 (m, 4H); 7.17 (dd, J = 8.4, 2.4, 1H); 3.80 (s at, 1 H); 3.30 (s, 3 H); 2.97 (s at, 1 H); 2.15 (s, 2H); 1.86-1.75 (m, 10H). IR (cm-1, KBr): 3396 (s), 2909 (s), 2845 (m), 1685 (s), 1587 (m), 1563 (m), 1498 (s), 1475 (s), 1464 (s), 1438 (s), 1366 (m), 1223 (m), 1152 (m), 1092 (s), 1083 (m), 1014 (m), 837 (s). MS (m / z): 514.9 ([M + H] +).

Ejemplo 128 Example 128

Clorhidrato de N(7)-[(2,4-diclorofenil-N’-metilamino]-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-*carboxamida. N (7) - [(2,4-Dichlorophenyl-N'-methylamino] -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13.11.04.8] tetradeca-4 (8) hydrochloride, 6-diene-7- * carboxamide.

Una solución de ejemplo 127 (100 mg, 0,19 mmol) en éter (2,0 ml) se trató con éter saturado con HCl (2,0 ml), se mantuvo a TA durante 1 hora y el sólido precipitado se filtró para producir el compuesto del título (102 mg, 95%). P.F.: 203 ºC. RMN 1H (δ ppm, CDCl3, 400 MHz): 9,86 (s,1H); 7,53 (d, J = 7,2, 2H); 7,42-7,36 (m, 3H); 7,33 (d, J = 1,7, 1H);7,20 (dd, J = 8,8, 1,7, 1H); 3,29 (s, 3H); 2,99 (s a, 1H); 2,21 (s, 2H); 1,88 (m, 4H); 1,88-1,80 (m, 6H). IR (cm 1, KBr): 3386 m), 3197 (m), 2916 (s), 2901 (s), 2845 (m), 1687 (s), 1474 (s), 1439 (s), 1260 (m), 1323 (m), 1241 (m), 1124 (m), 1106 (m), 1089 (s), 1012 (m), 938 (m), 845 (m), 829 (m). EM (m/z): 515,0 ([M-HCl+H]+). An example solution 127 (100 mg, 0.19 mmol) in ether (2.0 ml) was treated with ether saturated with HCl (2.0 ml), maintained at RT for 1 hour and the precipitated solid was filtered to produce the title compound (102 mg, 95%). P.F .: 203 ° C. 1H NMR (δ ppm, CDCl3, 400 MHz): 9.86 (s, 1H); 7.53 (d, J = 7.2, 2H); 7.42-7.36 (m, 3H); 7.33 (d, J = 1.7, 1H); 7.20 (dd, J = 8.8, 1.7, 1H); 3.29 (s, 3 H); 2.99 (s at, 1H); 2.21 (s, 2H); 1.88 (m, 4 H); 1.88-1.80 (m, 6H). IR (cm 1, KBr): 3386 m), 3197 (m), 2916 (s), 2901 (s), 2845 (m), 1687 (s), 1474 (s), 1439 (s), 1260 (m ), 1323 (m), 1241 (m), 1124 (m), 1106 (m), 1089 (s), 1012 (m), 938 (m), 845 (m), 829 (m). MS (m / z): 515.0 ([M-HCl + H] +).

Ejemplo 129 Example 129

N(7)-(2,4-Diclorofenil-N’-ciclohexilamino)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6dieno-7-carboxamida N (7) - (2,4-Dichlorophenyl-N'-cyclohexylamino) -5- (4-chlorophenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8), 6diene-7 -carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 2 (200 mg, 0,58 mmol), Et3N (0,26 ml, 1,87 mmol), reactivo BOP (258 mg, 0,58 mmol) y clorhidrato de N-ciclohexil-N-(2,4diclorofenil)hidrazina (427 mg, 1,28 mmol) dio el compuesto del título (162 mg, 48%). P.F.: 95-96 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,72 (s, 1H); 7,47 (d, J = 8,4, 2H); 7,42 (d, J = 8,7, 1H); 7,40 -7,20 (m, 3H); 7,17 (dd, J = 8,7, 2,4, 1H), 3,86 (t a, J = 5,2, 1H); 3,75 (s a, 1H); 2,99 (s a, 1H); 2,17 (s, 2H), 2,00-1,70 (m, 14H), 1,43-1,10 (m, 6H). IR (cm-1, KBr): 3400 (m), 2919 (s), 2850 (s), 1683 (s), 1564 (w), 1498 (s), 1474 (s), 1363 (m), 1233 (m), 1218 (m), 1100 (m), 1062 (m), 833 (m), 753 (w). EM (m/z): 583,1 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 2 (200 mg, 0.58 mmol), Et3N (0.26 ml, 1.87 mmol), BOP reagent (258 mg, 0 , 58 mmol) and N-cyclohexyl-N- (2,4-dichlorophenyl) hydrazine hydrochloride (427 mg, 1.28 mmol) gave the title compound (162 mg, 48%). P.F .: 95-96 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 8.72 (s, 1H); 7.47 (d, J = 8.4, 2H); 7.42 (d, J = 8.7, 1H); 7.40-7.20 (m, 3H); 7.17 (dd, J = 8.7, 2.4, 1H), 3.86 (t a, J = 5.2, 1H); 3.75 (s a, 1 H); 2.99 (s at, 1H); 2.17 (s, 2H), 2.00-1.70 (m, 14H), 1.43-1.10 (m, 6H). IR (cm-1, KBr): 3400 (m), 2919 (s), 2850 (s), 1683 (s), 1564 (w), 1498 (s), 1474 (s), 1363 (m), 1233 (m), 1218 (m), 1100 (m), 1062 (m), 833 (m), 753 (w). MS (m / z): 583.1 ([M + H] +).

Ejemplo 130 Example 130

N(7)-(4-Fluorofenilamino)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7carboxamida N (7) - (4-Fluorophenylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 2 (200 mg, 0,58 mmol), Et3N (0,16 ml, 1,15 mmol), reactivo BOP (258 mg, 0,58 mmol) y clorhidrato de 4-fluorofenilhidrazina (95 mg, 0,58 mmol) dio el compuesto del título (218 mg, 83%). P.F.: 125-127 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,59 (s, 1H); 7,48 (d, J = 8,6, 2H); 7,32 (d, J = 8,6, 2H); 7,00-6,80 (m, 4H); 3,88 (s a, 1H); 3,03 (s a, 1H); 2,20 (s a, 2H); 2,05-1,70 (m, 10H). IR (cm-1, KBr): 3263 (m), 2912 (s), 2847 (m), 1671 (s), 1508 (s), 1498 (s), 1475 (m), 1234 (m), 1219 (m), 1088 (m), 884 (w), 831(m). EM (m/z): 451,0 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 2 (200 mg, 0.58 mmol), Et3N (0.16 ml, 1.15 mmol), BOP reagent (258 mg, 0 , 58 mmol) and 4-fluorophenylhydrazine hydrochloride (95 mg, 0.58 mmol) gave the title compound (218 mg, 83%). P.F .: 125-127 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 8.59 (s, 1H); 7.48 (d, J = 8.6, 2H); 7.32 (d, J = 8.6, 2H); 7.00-6.80 (m, 4H); 3.88 (s at, 1 H); 3.03 (s at, 1 H); 2.20 (s a, 2H); 2.05-1.70 (m, 10H). IR (cm-1, KBr): 3263 (m), 2912 (s), 2847 (m), 1671 (s), 1508 (s), 1498 (s), 1475 (m), 1234 (m), 1219 (m), 1088 (m), 884 (w), 831 (m). MS (m / z): 451.0 ([M + H] +).

Ejemplo 131 Example 131

Clorhidrato de N(7)-(4-fluorofenilamino)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6dieno-7-carboxamida. N (7) - (4-fluorophenylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxamide hydrochloride.

Una solución de ejemplo 130 (100 mg, 0,22 mmol) en éter (2,0 ml) se trató con una solución saturada de HCl en éter (2,0 ml) a TA, se agitó a TA durante 1 hora y el sólido precipitado se filtró y se lavó con éter para producir el compuesto del título (106 mg, 98%). P.F.: 175 ºC. RMN 1H (δ ppm, DMSO-d6, 300 MHz): 9,99 (s, 1H); 7,64 (d, J = 8,5, 2H); 7,50 (d, J = 8,5, 2H); 6,98 (t, J = 8,7, 2H); 6,74 (dd, J = 8,7, 4,8, 2H); 3,67 (s a, 1H); 3,01 (s a, 1H); 2,15 (s, 2H); 2,00-1,70 (m, 10H). IR (cm-1, KBr): 3247 (m a), 2916 (m), 2844 (m), 1694 (s), 1507 (s), 1498 (s), 1234 (s), 1089 (m), 1014 (m), 990 (w), 836 (m). EM (m/z): 451,0 ([M+H]+). An example solution 130 (100 mg, 0.22 mmol) in ether (2.0 ml) was treated with a saturated solution of HCl in ether (2.0 ml) at RT, stirred at RT for 1 hour and the Precipitated solid was filtered and washed with ether to yield the title compound (106 mg, 98%). P.F .: 175 ºC. 1H NMR (δ ppm, DMSO-d6, 300 MHz): 9.99 (s, 1H); 7.64 (d, J = 8.5, 2H); 7.50 (d, J = 8.5, 2H); 6.98 (t, J = 8.7, 2H); 6.74 (dd, J = 8.7, 4.8, 2H); 3.67 (s at, 1 H); 3.01 (s a, 1 H); 2.15 (s, 2H); 2.00-1.70 (m, 10H). IR (cm-1, KBr): 3247 (ma), 2916 (m), 2844 (m), 1694 (s), 1507 (s), 1498 (s), 1234 (s), 1089 (m), 1014 (m), 990 (w), 836 (m). MS (m / z): 451.0 ([M + H] +).

Ejemplo 132 Example 132

N(7)-(2,4-Difluorofenilamino]-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11-.04,8]tetradeca-4(8),6-dieno-7carboxamida N (7) - (2,4-Difluorophenylamino] -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11-.04,8] tetradeca-4 (8), 6-diene-7carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 2 (200 mg, 0,58 mmol), Et3N (22 µl, 1,58 mmol), reactivo BOP (258 mg, 0,58 mmol) y clorhidrato de 2,4difluorofenilhidrazina (105 mg, 0,58 mmol) dio el compuesto del título (225 mg, 82%). P.F.: 195-196 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,56 (s, 1H); 7,49 (d, J = 9,0, 2H); 7,32 (d, J = 9,0, 2H); 7,01 (m, 1H); 6,86-6,74 (m, 2H); 6,24 (s a, 1H), 3,87 (t a, J = 4,6, 1H); 3,03 (s a, 1H); 2,20 (s a, 2H); 2,02-1,78 (m, 10H). IR (cm-1, KBr): 3276 (w), 2912 (m), 2846 (w), 1683 (s), 1499 (s), 1467 (m), 1137 (m), 1114 (m), 848 (m), 836 (m). EM (m/z): 469,1 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 2 (200 mg, 0.58 mmol), Et3N (22 µl, 1.58 mmol), BOP reagent (258 mg, 0.58 mmol) and 2,4-difluorophenylhydrazine hydrochloride (105 mg, 0.58 mmol) gave the title compound (225 mg, 82%). P.F .: 195-196 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 8.56 (s, 1H); 7.49 (d, J = 9.0, 2H); 7.32 (d, J = 9.0, 2H); 7.01 (m, 1 H); 6.86-6.74 (m, 2H); 6.24 (s a, 1H), 3.87 (t a, J = 4.6, 1H); 3.03 (s at, 1 H); 2.20 (s a, 2H); 2.02-1.78 (m, 10H). IR (cm-1, KBr): 3276 (w), 2912 (m), 2846 (w), 1683 (s), 1499 (s), 1467 (m), 1137 (m), 1114 (m), 848 (m), 836 (m). MS (m / z): 469.1 ([M + H] +).

Ejemplo 133 Example 133

N(7)-(3-fluorofenilamino)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7carboxamida N (7) - (3-fluorophenylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 2 (250 mg, 0,72 mmol), DMF (3 ml), Et3N (0,22,0 ml, 1,60 mmol), reactivo BOP (322 mg, 0,72 mmol) y clorhidrato de 3fluorofenilhidrazina (119 µl, 0,72 mmol) produjo el compuesto del título (165 mg, 50%). P.F.: 203 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,58 (s, 1H); 7,51 (d, J = 9,0, 2H); 7,33 (d, J = 9,0, 2H), 7,16 (c, J = 6,6, 1H); 6,72-6,53 (m, 3H); 3,88 (s a, 1H); 3,03 (s a, 1H); 2,21 (s a, 2H); 2,05-1,80 (m, 10H). IR (cm-1, KBr): 3259 (m), 2913 (s), 1617 (s), 1601 (m), 1498 (s), 1442 (m), 1269 (m), 1234 (m), 1140 (m), 1089 (s), 1012 (m), 832 (m), 760 (m), 679 (m). EM (m/z): 451,10 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 2 (250 mg, 0.72 mmol), DMF (3 ml), Et3N (0.22.0 ml, 1.60 mmol) , BOP reagent (322 mg, 0.72 mmol) and 3fluorophenylhydrazine hydrochloride (119 µl, 0.72 mmol) produced the title compound (165 mg, 50%). P.F .: 203 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 8.58 (s, 1H); 7.51 (d, J = 9.0, 2H); 7.33 (d, J = 9.0, 2H), 7.16 (c, J = 6.6, 1H); 6.72-6.53 (m, 3H); 3.88 (s at, 1 H); 3.03 (s at, 1 H); 2.21 (s at, 2H); 2.05-1.80 (m, 10H). IR (cm-1, KBr): 3259 (m), 2913 (s), 1617 (s), 1601 (m), 1498 (s), 1442 (m), 1269 (m), 1234 (m), 1140 (m), 1089 (s), 1012 (m), 832 (m), 760 (m), 679 (m). MS (m / z): 451.10 ([M + H] +).

Ejemplo 134 Example 134

N(7)-(3-Cloro-2-piridilamino)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7carboxamida N (7) - (3-Chloro-2-pyridylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 2 (150 mg, 0,44 mmol), DMF (1,5 ml), Et3N (68 µl, 0,48 mmol), reactivo BOP (203 mg, 0,46 mmol) y 3-cloro-2hidrazinopiridina (69 mg, 0,48 mmol) produjo el compuesto del título (170 mg, 83%). P.F.: 200-203 ºC. RMN 1H (δ ppm, DMSO-d6, 300 MHz): 9,85 (s, 1H); 8,46 (s, 1H); 8,0 (dd, J = 4,5, 1,5, 1H); 7,69 (dd, J = 7,5, 1,5, 1H); 7,66 (d, J = 8,7, 2H); 7,51 (d, J = 9,0, 2H); 6,75 (dd, J = 7,8, 4,8, 1H); 3,73 (s a, 1H); 3,02 (s a, 1H); 2,15 (s a, 2H); 2,00-1,70 (m, 10H). IR (cm-1, KBr): 3382 (m), 2902 (m), 2846 (m), 1683 (m), 1664 (m); 1589 (s), 1498 (s), 1455 (s), 1401 (m), 1229 (m), 1117 (m), 1089 (m), 1030 (m), 833 (m). EM (m/z): 465,10 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 2 (150 mg, 0.44 mmol), DMF (1.5 ml), Et3N (68 µl, 0.48 mmol), reagent BOP (203 mg, 0.46 mmol) and 3-chloro-2-hydrazinopyridine (69 mg, 0.48 mmol) produced the title compound (170 mg, 83%). P.F .: 200-203 ° C. 1H NMR (δ ppm, DMSO-d6, 300 MHz): 9.85 (s, 1H); 8.46 (s, 1 H); 8.0 (dd, J = 4.5, 1.5, 1H); 7.69 (dd, J = 7.5, 1.5, 1H); 7.66 (d, J = 8.7, 2H); 7.51 (d, J = 9.0, 2H); 6.75 (dd, J = 7.8, 4.8, 1H); 3.73 (s a, 1 H); 3.02 (s at, 1 H); 2.15 (s a, 2H); 2.00-1.70 (m, 10H). IR (cm-1, KBr): 3382 (m), 2902 (m), 2846 (m), 1683 (m), 1664 (m); 1589 (s), 1498 (s), 1455 (s), 1401 (m), 1229 (m), 1117 (m), 1089 (m), 1030 (m), 833 (m). MS (m / z): 465.10 ([M + H] +).

Ejemplo 135 Example 135

N(7)-(5-Cloro-2-piridilamino)-5-(4-clorofenil)-5,6-diazatetraciclo[7,3,13,11.04,8]tetradeca-4(8),6-dieno-7carboxamida N (7) - (5-Chloro-2-pyridylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7,3,13,11.04,8] tetradeca-4 (8), 6-diene- 7carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 2 (150 mg, 0,44 mmol), DMF (1,5 ml), Et3N (68 µl, 0,48 mmol), reactivo BOP (203 mg, 0,46 mmol) y 5-cloro-2hidrazinopiridina (70 mg, 0,49 mmol) produjo el compuesto del título (170 mg, 83%). P.F.: 130-135 ºC. RMN 1H (δ The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 2 (150 mg, 0.44 mmol), DMF (1.5 ml), Et3N (68 µl, 0.48 mmol), reagent BOP (203 mg, 0.46 mmol) and 5-chloro-2-hydrazinopyridine (70 mg, 0.49 mmol) produced the title compound (170 mg, 83%). P.F .: 130-135 ° C. 1H NMR (δ

ppm, DMSO-d6, 300 MHz): 10,02 (s, 1H); 8,62 (s, 1H); 8,06 (d, J = 2,4, 1H); 7,66 (d, J = 8,5, 2H); 7,60 (dd, J = 8,7, 2,5, 1H); 7,51 (d, J = 8,5, 2H); 6,60 (d, J = 8,7, 1H); 3,69 (s a, 1H); 3,01 (s a, 1H); 2,15 (s a, 2H); 2,00-1,70 (m, 10H). IR (cm-1, KBr): 3285 (m), 2909 (s), 2847 (m), 1671 (s), 1595 (m), 1498 (s), 1477 (s), 1364 (m), 1255 (m), 1233 (m), 1089 (m), 1012 (m), 832 (m). EM (m/z): 468,10 ([M+H]+). ppm, DMSO-d6, 300 MHz): 10.02 (s, 1 H); 8.62 (s, 1 H); 8.06 (d, J = 2.4, 1H); 7.66 (d, J = 8.5, 2H); 7.60 (dd, J = 8.7, 2.5, 1H); 7.51 (d, J = 8.5, 2H); 6.60 (d, J = 8.7, 1H); 3.69 (s a, 1 H); 3.01 (s a, 1 H); 2.15 (s a, 2H); 2.00-1.70 (m, 10H). IR (cm-1, KBr): 3285 (m), 2909 (s), 2847 (m), 1671 (s), 1595 (m), 1498 (s), 1477 (s), 1364 (m), 1255 (m), 1233 (m), 1089 (m), 1012 (m), 832 (m). MS (m / z): 468.10 ([M + H] +).

Ejemplo 136 Example 136

N(7)-(2-Feniletil)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8] tetradeca-4(8)-6-dieno-7-carboxamida N (7) - (2-Phenylethyl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8) -6-diene-7-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 2 (100 mg, 0,29 mmol), Et3N (40 µl, 0,29 mmol), reactivo BOP (129 mg, 0,29 mmol) y fenetilamina (36 µl, 0,29 mmol) produjo el compuesto del título (105 mg, 81%). P.F.: 148 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,46 (d, J = 8,7, 2H); 7,35-7,18 (m, 7H); 7,07 (t a, J = 7,5, 1H); 3,99 (t a, J = 4,7, 1H); 3,63 (c, J = 7,5, 2H); 3,00 (t a, J = 4,7, 1H); 2,90 (t, J = 7,5, 2H); 2,20 (s a, 2H); 2,05-1,95 (m, 2H); 1,94-1,75 (m, 8H). IR (cm-1, KBr): 3398 (m), 2913 (s), 2843 (m), 1673 (s), 1538 (s), 1498 (s), 1483 (s), 1382 (m), 1231 (m), 1086 (m), 998 (m), 839 (m). EM (m/z): 446,1 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 2 (100 mg, 0.29 mmol), Et3N (40 µl, 0.29 mmol), BOP reagent (129 mg, 0.29 mmol) and phenethylamine (36 µl, 0.29 mmol) produced the title compound (105 mg, 81%). P.F .: 148 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.46 (d, J = 8.7, 2H); 7.35-7.18 (m, 7H); 7.07 (t a, J = 7.5, 1H); 3.99 (t a, J = 4.7, 1H); 3.63 (c, J = 7.5, 2H); 3.00 (t a, J = 4.7, 1H); 2.90 (t, J = 7.5, 2H); 2.20 (s a, 2H); 2.05-1.95 (m, 2H); 1.94-1.75 (m, 8H). IR (cm-1, KBr): 3398 (m), 2913 (s), 2843 (m), 1673 (s), 1538 (s), 1498 (s), 1483 (s), 1382 (m), 1231 (m), 1086 (m), 998 (m), 839 (m). MS (m / z): 446.1 ([M + H] +).

Ejemplo 137 Example 137

N(7)-(N’,N’-Difenilamino)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,1104,8]tetradeca-4(8),6-dieno-7carboxamida N (7) - (N ’, N’-Diphenylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,1104,8] tetradeca-4 (8), 6-diene-7carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 2 (300 mg, 0,88 mmol), DMF (3 ml), Et3N (0,27 ml, 1,94 mmol), reactivo BOP (387 mg, 0,88 mmol) y clorhidrato de N,Ndifenilhidrazina (192 mg, 0,87 mmol) dio el compuesto del título (370 mg, 83%). P.F.: 214 ºC. H RMN (δ ppm, CDCl3, 300 MHz): 9,04 (s, 1H); 7,47 (d, J = 8,4, 2H); 7,33 (d, J = 8,4, 2H); 7,28-7,20 (m, 8H); 7,00 (t, J = 8,4, 2H); 3,94 (s a, 1H); 3,03 (s a, 1H); 2,20 (s, 2H); 2,05-1,80 (m, 10H). IR (cm-1, KBr): 3384 (m), 2912 (m), 2900 (m), 1702 (s), 1591 (m), 1497 (s), 1466 (m), 1277 (w), 1235 (w), 1092 (m), 1012 (w). EM (m/z): 509,4 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 2 (300 mg, 0.88 mmol), DMF (3 ml), Et3N (0.27 ml, 1.94 mmol), reagent BOP (387 mg, 0.88 mmol) and N, N-diphenylhydrazine hydrochloride (192 mg, 0.87 mmol) gave the title compound (370 mg, 83%). P.F .: 214 ° C. H NMR (δ ppm, CDCl3, 300 MHz): 9.04 (s, 1H); 7.47 (d, J = 8.4, 2H); 7.33 (d, J = 8.4, 2H); 7.28-7.20 (m, 8H); 7.00 (t, J = 8.4, 2H); 3.94 (s a, 1 H); 3.03 (s at, 1 H); 2.20 (s, 2 H); 2.05-1.80 (m, 10H). IR (cm-1, KBr): 3384 (m), 2912 (m), 2900 (m), 1702 (s), 1591 (m), 1497 (s), 1466 (m), 1277 (w), 1235 (w), 1092 (m), 1012 (w). MS (m / z): 509.4 ([M + H] +).

Ejemplo 138 Example 138

N7-[1-(2-Clorofenil)etil]-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8] tetradeca-4(8),6-dieno-7-carboxamida N7- [1- (2-Chlorophenyl) ethyl] -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 2 (100 mg, 0,29 mmol), DMF (1,0 ml), Et3N (48 µl, 0,34 mmol), reactivo BOP (141 mg, 0,31 mmol) y (±)-1-(2clorofenil)etilamina (48 µl, 0,29 mmol) produjo el compuesto del título (104 mg, 77%)..P.F.: 198 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,48-7,18 (m, 8H); 5,27 (quintuplete, J = 7,2, 1H); 3,99 (s a, 1H); 2,98 (s a, 1H); 2,18 (s a, 2H); 2,06-1,74 (m, 10H); 1,56 (d, J = 7,2, 3H). IR (cm-1, KBr): 3400 (m), 2915 (s), 2880 (s), 1666 (s), 1498 (s), 1528 (s), 1480 (s), 1362(m), 1229 (m), 1085 (m), 1012(w), 834 (m), 696 (m). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 2 (100 mg, 0.29 mmol), DMF (1.0 ml), Et3N (48 µl, 0.34 mmol), reagent BOP (141 mg, 0.31 mmol) and (±) -1- (2-chlorophenyl) ethylamine (48 µl, 0.29 mmol) produced the title compound (104 mg, 77%). MP: 198 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.48-7.18 (m, 8H); 5.27 (quintuple, J = 7.2, 1H); 3.99 (s at, 1 H); 2.98 (s a, 1 H); 2.18 (s at, 2H); 2.06-1.74 (m, 10H); 1.56 (d, J = 7.2, 3H). IR (cm-1, KBr): 3400 (m), 2915 (s), 2880 (s), 1666 (s), 1498 (s), 1528 (s), 1480 (s), 1362 (m), 1229 (m), 1085 (m), 1012 (w), 834 (m), 696 (m).

Ejemplo 139 Example 139

N(7)-Bencil-5-(4’-clorofenil)-5,6 diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-6-dieno-7-carboxamida N (7) -Benzyl-5- (4’-chlorophenyl) -5.6 diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8) -6-diene-7-carboxamide

El compuesto del título se sintetizó como para el procedimiento descrito para el ejemplo 101 usando el intermedio 2 (100 mg, 0,29 mmol), DMF (1 ml), trietilamina (0,04 ml, 0,29 mmol), reactivo BOP (128 mg, 0,29 mmol) y bencilamina (0,031 ml, 0,291 mmol) para dar el compuesto del título (72 mg, 57%). P.F.: 164-166 ºC. RMN 1H (δ ppm, CDCl3): 7,45 (d, J = 8,4, 2H); 7,39-7,21 (m, 7H); 4,58 (d, J = 6,0, 2H); 4,02 (t, J = 5,4, 1H); 3,00 (t a, J = 4,7, 1H); 2,20 (d a, 2H); 2,04-1,77 (m, 10H). IR (cm-1, KBr): 3471(m), 3403 (m), 2919 (s), 2884 (m), 1672 (s), 1534 (m), 1499 (s). The title compound was synthesized as for the procedure described for example 101 using intermediate 2 (100 mg, 0.29 mmol), DMF (1 ml), triethylamine (0.04 ml, 0.29 mmol), BOP reagent (128 mg, 0.29 mmol) and benzylamine (0.031 ml, 0.291 mmol) to give the title compound (72 mg, 57%). P.F .: 164-166 ° C. 1H NMR (δ ppm, CDCl3): 7.45 (d, J = 8.4, 2H); 7.39-7.21 (m, 7H); 4.58 (d, J = 6.0, 2H); 4.02 (t, J = 5.4, 1H); 3.00 (t a, J = 4.7, 1H); 2.20 (d a, 2H); 2.04-1.77 (m, 10H). IR (cm-1, KBr): 3471 (m), 3403 (m), 2919 (s), 2884 (m), 1672 (s), 1534 (m), 1499 (s).

Ejemplo 140 Example 140

N(7)-Piperidino-5-(4’-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-6-dieno-7-carboxamida: N (7) -Piperidino-5- (4’-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8) -6-diene-7-carboxamide:

El compuesto del título se sintetizó como para el procedimiento descrito para el ejemplo 101 usando intermedio 2 (100 mg, 0,291 mmol), trietilamina (0,04 ml, 0,29 mmol), reactivo BOP (128 mg, 0,29 mmol) y 1-aminopiperidina (0,031 ml, 0,291 mmol) para dar el compuesto del título (85 mg, 68%). P.F.: 185-188 ºC. RMN 1H (δ ppm, CDCl3): 7,67, (s a, 1H); 7,46 (d, J = 8,7, 2H); 7,29 (d, J = 8,7, 2H); 3,99 (t a, J = 5,4, 1H); 2,99 (t a, 1H); 2,85 (s a, 4H); 2,19 (s a, 2H); 2,06-1,69 (m, 14H); 1,44-1,38 (m, 2H). IR (cm-1, KBr): 3436 (m), 3320 (m); 2921 (s), 2853 (m), 1694 (m), 1668 (s), 1499 (m). The title compound was synthesized as for the procedure described for example 101 using intermediate 2 (100 mg, 0.291 mmol), triethylamine (0.04 ml, 0.29 mmol), BOP reagent (128 mg, 0.29 mmol) and 1-aminopiperidine (0.031 ml, 0.291 mmol) to give the title compound (85 mg, 68%). P.F .: 185-188 ° C. 1H NMR (δ ppm, CDCl3): 7.67, (s a, 1H); 7.46 (d, J = 8.7, 2H); 7.29 (d, J = 8.7, 2H); 3.99 (t a, J = 5.4, 1H); 2.99 (t a, 1 H); 2.85 (s at, 4H); 2.19 (s a, 2H); 2.06-1.69 (m, 14H); 1.44-1.38 (m, 2H). IR (cm-1, KBr): 3436 (m), 3320 (m); 2921 (s), 2853 (m), 1694 (m), 1668 (s), 1499 (m).

Ejemplo 141 Example 141

7-(4’-Clorofenil)-6,7-diazatetraciclo[7.3.1.13,11 .04,8]tetradeca-4(8)-5-dien-5-il-piperidinometanona: 7- (4’-Chlorophenyl) -6,7-diazatetracyclo [7.3.1.13.11 .04.8] tetradeca-4 (8) -5-dien-5-yl-piperidinometanone:

El compuesto del título se sintetizó como para el procedimiento descrito para el ejemplo 101 usando intermedio 2 (100 mg, 0,291 mmol), trietilamina (0,04 ml, 0,29 mmol), reactivo BOP (128 mg, 0,29 mmol) y piperidina (0,028 ml, 0,291 mmol), para dar el compuesto del título (85 mg, 71%). P.F.: 151-153 ºC. RMN 1H (δ ppm, CDCl3): 7,43 (d, J = 9,0); 7,31 (d, J = 9,0); 3,70 (s a, 2H); 3,55 (t, J = 5,1, 2H); 3,00-3,10 (m, 2H); 2,21 (s a, 2H); 2,05-1,78 (m, 10H); 1,751,50 (m, 18H). IR (cm-1, KBr): 2913 (m), 1634 (s), 1498 (m). The title compound was synthesized as for the procedure described for example 101 using intermediate 2 (100 mg, 0.291 mmol), triethylamine (0.04 ml, 0.29 mmol), BOP reagent (128 mg, 0.29 mmol) and piperidine (0.028 ml, 0.291 mmol), to give the title compound (85 mg, 71%). P.F .: 151-153 ° C. 1H NMR (δ ppm, CDCl3): 7.43 (d, J = 9.0); 7.31 (d, J = 9.0); 3.70 (s at, 2H); 3.55 (t, J = 5.1, 2H); 3.00-3.10 (m, 2H); 2.21 (s at, 2H); 2.05-1.78 (m, 10H); 1,751.50 (m, 18H). IR (cm-1, KBr): 2913 (m), 1634 (s), 1498 (m).

Ejemplo 142 Example 142

N(7)-Fenil-5-(4’-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-6-dieno-7-carboxamida: N (7) -Phenyl-5- (4’-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8) -6-diene-7-carboxamide:

El compuesto del título se sintetizó como para el procedimiento descrito para el ejemplo 101 usando intermedio 2 (100 mg, 0,291 mmol), trietilamina (0,04 ml, 0,29 mmol), reactivo BOP (128 mg, 0,29 mmol) y anilina (0,026 ml, 0,29 mmol) para dar el compuesto del título (95 mg, 77%). P.F.: 188-190 ºC. RMN 1H (δ ppm, CDCl3): 8,78 (s a, 1H); 7,67 (d, J = 8,4, 2H); 7,50 (d, J = 8,7, 2H); 7,30-7,37 (m, 4H); 7,12 (t, J = 8,4, 1H); 4,05 (t, J = 5,4, 1H); 3,02 (t, J = 4,8, 1H); 2,22 (s a, 2H); 2,10-1,75 (m, 10H). IR (cm-1, KBr): 3365 (m), 2915 (m), 2844 (m), 1682 (s), 1532 (s), 1498 (s). The title compound was synthesized as for the procedure described for example 101 using intermediate 2 (100 mg, 0.291 mmol), triethylamine (0.04 ml, 0.29 mmol), BOP reagent (128 mg, 0.29 mmol) and aniline (0.026 ml, 0.29 mmol) to give the title compound (95 mg, 77%). P.F .: 188-190 ° C. 1H NMR (δ ppm, CDCl3): 8.78 (s a, 1H); 7.67 (d, J = 8.4, 2H); 7.50 (d, J = 8.7, 2H); 7.30-7.37 (m, 4H); 7.12 (t, J = 8.4, 1H); 4.05 (t, J = 5.4, 1H); 3.02 (t, J = 4.8, 1H); 2.22 (s at, 2H); 2.10-1.75 (m, 10H). IR (cm-1, KBr): 3365 (m), 2915 (m), 2844 (m), 1682 (s), 1532 (s), 1498 (s).

Ejemplo 143 Example 143

N(7)-Piperidino-5-(2,4-difluorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxamida N (7) -Piperidino-5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 3 (100 mg, 0,30 mmol), DMF (1,0 ml), Et3N (42 µl, 0,31 mmol), reactivo BOP (135 mg, 0,31 mmol) y N-aminopiperidina ((33 µl, 0,31 mmol) dio el compuesto del título (96 mg, 73%). P.F.: 215 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,61 (s a, 1H); 7,49-7,40 (m, 1H); 7,05-6,95 (m, 2H); 3,96 (s a, 1H); 2,86 (s a, 4H); 2,65 (s a, 1H); 2,18 (s a, 2H), 2,04-1,90 (m, 2H); 1,85-1,62 (m, 12H); 1,42 (s a, 2H). IR. (cm-1, KBr): EM (m/z): 427,20 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 3 (100 mg, 0.30 mmol), DMF (1.0 ml), Et3N (42 µl, 0.31 mmol), reagent BOP (135 mg, 0.31 mmol) and N-aminopiperidine ((33 µl, 0.31 mmol) gave the title compound (96 mg, 73%). MP: 215 ° C. 1 H NMR (δ ppm, CDCl 3, 300 MHz): 7.61 (sa, 1H); 7.49-7.40 (m, 1H); 7.05-6.95 (m, 2H); 3.96 (sa, 1H); 2, 86 (sa, 4H); 2.65 (sa, 1H); 2.18 (sa, 2H), 2.04-1.90 (m, 2H); 1.85-1.62 (m, 12H) ; 1.42 (sa, 2H) IR (cm-1, KBr): MS (m / z): 427.20 ([M + H] +).

Ejemplo 144 Example 144

N(7)-(Adamantan-1-il)-5-(2,4-difluorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-6-dieno-7carboxamida N (7) - (Adamantan-1-yl) -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8) -6-diene-7carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 3 (150 mg, 0,44 mmol), DMF (1,0 ml), Et3N (72 µl, 0,52 mmol), reactivo BOP (192 mg, 0,44 mmol) y 1-adamantilamina (65 mg, 0,44 mmol) produjo el compuesto del título (156 mg, 75%). P.F.: 221-224 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,50-7,38 (m, 1H); 7,06-6,93 (m, 2H); 6,68 (s a, 1H); 3,97 (s a, 1H); 3,35 (s a, 3H); 2,22-1,54 (m, 27H). IR (cm-1, KBr): 3394 (m), 2915 (s), 2850 (s), 1669 (s), 1611 (m), 1566 (m), 1520 (s), 1483 (m), 1440 (m), 1359 (m), 1353 (m), 1273 (m), 1225 (m), 1220 (m), 1140 (m), 1092 (m), 1082 (m), 966 (m), 850 (m). EM (m/z): 478,2 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 3 (150 mg, 0.44 mmol), DMF (1.0 ml), Et3N (72 µl, 0.52 mmol), reagent BOP (192 mg, 0.44 mmol) and 1-adamantylamine (65 mg, 0.44 mmol) produced the title compound (156 mg, 75%). P.F .: 221-224 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.50-7.38 (m, 1H); 7.06-6.93 (m, 2H); 6.68 (s a, 1 H); 3.97 (s at, 1 H); 3.35 (s a, 3H); 2.22-1.54 (m, 27H). IR (cm-1, KBr): 3394 (m), 2915 (s), 2850 (s), 1669 (s), 1611 (m), 1566 (m), 1520 (s), 1483 (m), 1440 (m), 1359 (m), 1353 (m), 1273 (m), 1225 (m), 1220 (m), 1140 (m), 1092 (m), 1082 (m), 966 (m), 850 (m). MS (m / z): 478.2 ([M + H] +).

Ejemplo 145 Example 145

N(7)-(1S,2endo-1,3,3-Trimetil-biciclo[2.2.1]hept-2-il)-5-(2,4-difluorofenil)-5,6diazatetraciclo[7.3.1.13,11·04,8]tetradeca-4(8)-6-dieno-7-carboxamida N (7) - (1S, 2endo-1,3,3-Trimethyl-bicyclo [2.2.1] hept-2-yl) -5- (2,4-difluorophenyl) -5,6diazatetracycle [7.3.1.13.11 04.8] tetradeca-4 (8) -6-diene-7-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 3 (150 mg, 0,44 mmol), DMF (1,0 ml), Et3N (72 µl, 0,52 mmol), reactivo BOP (192 mg, 0,44 mmol) y 2-amino-1,3,3-trimetilbiciclo[2.2.1]heptano (66 mg, 0,44 mmol) produjo el compuesto del título (176 mg, 84%). P.F.: 235-238 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,51-7,42 (m, 1H); 7,07-6,95 (m, 3H); 3,98 (s a, 1H); 3,72 (d, J = 6,0, 1H); 2,67 (s a, 1H); 2,18 (s a, 2H); 2,06-1,54 (m, 13H); 1,54-1,28 (m, 2H); 1,28-1,14 (m, 2H); 1,16, 1,10, 0,85 (3s, 9H). IR (cm-1, KBr): 3419 (s), 2927 (s), 2905 (s), 2870 (m), 1669 (s), 1567 (m), 1515 (s), 1480 (m), 1442 (m), 1366 (m), 1275 (m), 1226 (m), 1226 (m), 1097 (m), 1080 (m), 967 (m), 858 (m), 845 (m). EM (m/z): 480,3 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 3 (150 mg, 0.44 mmol), DMF (1.0 ml), Et3N (72 µl, 0.52 mmol), reagent BOP (192 mg, 0.44 mmol) and 2-amino-1,3,3-trimethylbicyclo [2.2.1] heptane (66 mg, 0.44 mmol) produced the title compound (176 mg, 84%). P.F .: 235-238 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.51-7.42 (m, 1H); 7.07-6.95 (m, 3H); 3.98 (s at, 1 H); 3.72 (d, J = 6.0, 1H); 2.67 (s at, 1 H); 2.18 (s at, 2H); 2.06-1.54 (m, 13H); 1.54-1.28 (m, 2H); 1.28-1.14 (m, 2H); 1.16, 1.10, 0.85 (3s, 9H). IR (cm-1, KBr): 3419 (s), 2927 (s), 2905 (s), 2870 (m), 1669 (s), 1567 (m), 1515 (s), 1480 (m), 1442 (m), 1366 (m), 1275 (m), 1226 (m), 1226 (m), 1097 (m), 1080 (m), 967 (m), 858 (m), 845 (m). MS (m / z): 480.3 ([M + H] +).

Ejemplo146 Example 146

N(7)-(S-1-feniletil))-5-(2,4-difluorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8] tetradeca-4(8),6-dieno-7-carboxamida N (7) - (S-1-phenylethyl)) - 5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7 -carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 3 (150 mg, 0,46 mmol), DMF (1,5 ml), Et3N (75 µl, 0,51 mmol), reactivo BOP (214 mg, 0,53 mmol) y S-1-feniletilamina (65 µl, 0,50 mmol) produjo el compuesto del título (120 mg, 58%). P.F.: 123-128 ºC. 7,50-7,13 (m, 7H); 7,06-6,94 (m, 2H); . 5,27 (quintuplete, J = 7,2, 1H); 3,97 (s a, 1H); 2,65 (s a, 1H); 2,17 (s a, 2H); 2,06-1,74 (m, 10H); 1,56 (d, J =7,2, 3H). IR (cm-1, KBr): 3404 (m); 2911 (s), 2846 (m), 1668 (s), 1519 (s), 1480 (m), 1439 (m), 1367 (w), 1352 (w), 1275 (m), 1227 (m), 1145 (m), 1081 (m), 966 (w), 854 (m). EM (m/z): 448,2 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 3 (150 mg, 0.46 mmol), DMF (1.5 ml), Et3N (75 µl, 0.51 mmol), reagent BOP (214 mg, 0.53 mmol) and S-1-phenylethylamine (65 µl, 0.50 mmol) produced the title compound (120 mg, 58%). P.F .: 123-128 ° C. 7.50-7.13 (m, 7H); 7.06-6.94 (m, 2H); . 5.27 (quintuple, J = 7.2, 1H); 3.97 (s at, 1 H); 2.65 (s at, 1 H); 2.17 (s a, 2H); 2.06-1.74 (m, 10H); 1.56 (d, J = 7.2, 3H). IR (cm-1, KBr): 3404 (m); 2911 (s), 2846 (m), 1668 (s), 1519 (s), 1480 (m), 1439 (m), 1367 (w), 1352 (w), 1275 (m), 1227 (m), 1145 (m), 1081 (m), 966 (w), 854 (m). MS (m / z): 448.2 ([M + H] +).

Ejemplo 147 Example 147

N(7)-(R-1-feniletil)-5-(2,4-difluorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8] tetradeca-4(8),6-dieno-7-carboxamida N (7) - (R-1-phenylethyl) -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7- carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 3 (150 mg, 0,46 mmol), DMF (1,5 ml),Et3N (75 µl, 0,51 mmol), reactivo BOP (214 mg,0,53 mmol) y R-1-feniletilamina (65 µl, 0,50 mmol) produjo el compuesto del título (125 mg, 61%). P.F.: 123-128 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,50-7,12 (m, 7H); 7,06-6,94 (m, 2H); 5,27 (quintuplete, J = 7,5, 1H); 3,97 (s a, 1H); 2,65 (s a, 1H); 2,17 (s a, 2H); 2,07-1,70 (m, 10H); 1,56 (d, J = 7,5, 3H). IR (cm-1, KBr): 3404 (m), 2911 (s), 2846 (m), 1669 (s), 1519 (s), 1480 (m), 1439 (m), 1367 (w), 1352 (w), 1275 (m), 1227 (m), 1145 (m), 1081 (w), 966 (m), 853 (m). EM (m/z): 448,2 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 3 (150 mg, 0.46 mmol), DMF (1.5 ml), Et3N (75 µl, 0.51 mmol), reagent BOP (214 mg, 0.53 mmol) and R-1-phenylethylamine (65 µl, 0.50 mmol) produced the title compound (125 mg, 61%). P.F .: 123-128 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.50-7.12 (m, 7H); 7.06-6.94 (m, 2H); 5.27 (quintuple, J = 7.5, 1H); 3.97 (s at, 1 H); 2.65 (s at, 1 H); 2.17 (s a, 2H); 2.07-1.70 (m, 10H); 1.56 (d, J = 7.5, 3H). IR (cm-1, KBr): 3404 (m), 2911 (s), 2846 (m), 1669 (s), 1519 (s), 1480 (m), 1439 (m), 1367 (w), 1352 (w), 1275 (m), 1227 (m), 1145 (m), 1081 (w), 966 (m), 853 (m). MS (m / z): 448.2 ([M + H] +).

Ejemplo 148 Example 148

N(7)-(1-Metil-1-feniletil)-5-(2,4-difluorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-di-eno-7carboxamida N (7) - (1-Methyl-1-phenylethyl) -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-di- eno-7carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 3 (150 mg, 0,46 mmol), DMF (1,5 ml), Et3N (75 µl, 0,51 mmol), reactivo BOP (214 mg, 0,53 mmol) y α,α-dimetilbencilamina (68 mg, 0,51 mmol) produjo el compuesto del título (70 mg, 33%). P.F.: 150-152 ºC. . RMN 1H (δ ppm, CDCl3, 300 MHz): 7,60-7,41 (m, 3H); 7,33 (t, J = 7,2, 2H); 7,22 (t, J = 7,2, 1H); 7,05-6,95 (m, 2H); 3,89 (s a, 1H); 2,65 (s a, 1H); 2,16 (s a, 2H); 2,00-1,54 (m, 10H); 1,78 (s, 6H). IR (cm-1, KBr): 3419 (m), 2906 (m), 1678 (s), 1519 (s), 1276 (m), 1261 (m), 11,34 (m), 968 (m), 848 (m). EM (m/z): 462,2 (100, [M+H]+), 344,1 (90). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 3 (150 mg, 0.46 mmol), DMF (1.5 ml), Et3N (75 µl, 0.51 mmol), reagent BOP (214 mg, 0.53 mmol) and α, α-dimethylbenzylamine (68 mg, 0.51 mmol) produced the title compound (70 mg, 33%). P.F .: 150-152 ° C. . 1H NMR (δ ppm, CDCl3, 300 MHz): 7.60-7.41 (m, 3H); 7.33 (t, J = 7.2, 2H); 7.22 (t, J = 7.2, 1H); 7.05-6.95 (m, 2H); 3.89 (s a, 1 H); 2.65 (s at, 1 H); 2.16 (s a, 2H); 2.00-1.54 (m, 10H); 1.78 (s, 6H). IR (cm-1, KBr): 3419 (m), 2906 (m), 1678 (s), 1519 (s), 1276 (m), 1261 (m), 11.34 (m), 968 (m) , 848 (m). MS (m / z): 462.2 (100, [M + H] +), 344.1 (90).

Ejemplo 149 Example 149

N(7)-(2-Clorobencil)-5-(2,4-difluorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7carboxamida N (7) - (2-Chlorobenzyl) -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito por ejemplos 101. El intermedio 3 (100 mg, 0,29 mmol), DMF (1,0 ml), Et3N (48 µl, 0,34 mmol), reactivo BOP (128 mg, 0,29 mmol) y 2-clorobencilamina ((55 µl, 0,46 mmol) dio el compuesto del título (152 mg, 71%). P.F.: 136 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,51-7,39 (m, 3H); 7,35 (dd, J = 7,5, 2,4, 1H); 7,24-7,18 (m, 2H); 7,05-6,95 (m, 2H); 4,67 (d, J = 6,0, 2H); 3,98 (t, J = 5,4, 1H); 2,67 (s a, 1H); 2,19 (s a, 2H), 2,10-1,95 (m, 2H); 1,95-1,65 (m, 10H). IR (cm-1, KBr): 3329 (m), 2918 (s), 2849 (m), 1648 (s), 1537 (m), 1515 (m), 1442 (m), 1220 (m), 1083 (m), 1051 (m), 750 (m). EM (m/z): 468,0 ([M+H]+). The title compound was synthesized by a procedure similar to that described by examples 101. Intermediate 3 (100 mg, 0.29 mmol), DMF (1.0 ml), Et3N (48 µl, 0.34 mmol), BOP reagent (128 mg, 0.29 mmol) and 2-chlorobenzylamine ((55 µl, 0.46 mmol) gave the title compound (152 mg, 71%). MP: 136 ° C. 1 H NMR (δ ppm, CDCl 3, 300 MHz): 7.51-7.39 (m, 3H); 7.35 (dd, J = 7.5, 2.4, 1H); 7.24-7.18 (m, 2H); 7, 05-6.95 (m, 2H); 4.67 (d, J = 6.0, 2H); 3.98 (t, J = 5.4, 1H); 2.67 (sa, 1H); 2.19 (sa, 2H), 2.10-1.95 (m, 2H); 1.95-1.65 (m, 10H). IR (cm-1, KBr): 3329 (m), 2918 (s), 2849 (m), 1648 (s), 1537 (m), 1515 (m), 1442 (m), 1220 (m), 1083 (m), 1051 (m), 750 (m). (m / z): 468.0 ([M + H] +).

Ejemplo 150 Example 150

N(7)-(2,4-Diclorofenilamino)-5-(2,4-difluorofenil)-5,6-diazatetraciclo-[7.3.1.13,11.04,8]tetradeca-4(8),6-di-eno-7carboxamida N (7) - (2,4-Dichlorophenylamino) -5- (2,4-difluorophenyl) -5,6-diazatetracyclo- [7.3.1.13,11.04,8] tetradeca-4 (8), 6-di-eno -7carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 3 (150 mg, 0,46 mmol), DMF (2,0 ml), Et3N (63 µl, 0,46 mmol), reactivo BOP (203 mg, 0,46 mmol) y clorhidrato de 2,4diclorofenilhidrazina (98 mg, 0,46 mmol) produjo el compuesto del título (107 mg, 47%). P.F.: 162 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,70 (s a, 1H); 7,48 (m, 1H); 7,30 (d, J = 1,2, 1H); 7,16-6,96 (m, H); 3,87 (s a, 1H); 2,71 (s a, 1H); 2,19 (s a, 2H), 2,05-1,70 (m, 10H). IR (cm-1, KBr): 3394 (s a, s), 2916 (s), 1683 (s), 1519 (m), 1274 (m), 1216 (m), 1145 (s), 1118 (s), 1099 (m), 967 (m), 850 (m), 817 (m). EM (m/z): 503,0 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 3 (150 mg, 0.46 mmol), DMF (2.0 ml), Et3N (63 µl, 0.46 mmol), reagent BOP (203 mg, 0.46 mmol) and 2,4-dichlorophenylhydrazine hydrochloride (98 mg, 0.46 mmol) produced the title compound (107 mg, 47%). P.F .: 162 ºC. 1H NMR (δ ppm, CDCl3, 300 MHz): 8.70 (s at, 1H); 7.48 (m, 1 H); 7.30 (d, J = 1.2, 1H); 7.16-6.96 (m, H); 3.87 (s at, 1 H); 2.71 (s at, 1 H); 2.19 (s at, 2H), 2.05-1.70 (m, 10H). IR (cm-1, KBr): 3394 (sa, s), 2916 (s), 1683 (s), 1519 (m), 1274 (m), 1216 (m), 1145 (s), 1118 (s) , 1099 (m), 967 (m), 850 (m), 817 (m). MS (m / z): 503.0 ([M + H] +).

Ejemplo 151 Example 151

N(7)-[1-(2-Clorofenil)etil]-5-(2,4-difluorofenil)-5,6-diazatetraciclo-[7.3.1.13,11.04,8]tetradeca-4(8),6-di-eno-7carboxamida N (7) - [1- (2-Chlorophenyl) ethyl] -5- (2,4-difluorophenyl) -5,6-diazatetracyclo- [7.3.1.13,11.04,8] tetradeca-4 (8), 6- di-eno-7carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 3 (100 mg, 0,29 mmol), DMF (1,0 ml), Et3N (48 µl, 0,34 mmol), reactivo BOP (141 mg, 0,31 mmol) y (±)-1-(2clorofenil)etilamina (48 µl, 0,29 mmol) produjo el compuesto del título (60 mg, 41%). P.F.: 143-146 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,46-7,14 (m, 5H); 7,04-6,94 (m, 2H); 5,26 (quintuplete, J = 7,2, 1H); 3,97 (s a, 1H); 2,65 (s a, 1H); 2,17 (s a, 2H); 2,04-1,70 (m, 10H); 1,56 (d, J = 7,2, 3H). IR (cm-1, KBr): 3419 (m), 2915 (s), 2847 (m), 1666 (s), 1612 (m), 1519 (s), 1481 (m), 1442 (m), 1368(w), 1353(w), 1273 (m), 1219(m), 1144 (m), 1082 (m), 967 (m), 852 (m). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 3 (100 mg, 0.29 mmol), DMF (1.0 ml), Et3N (48 µl, 0.34 mmol), reagent BOP (141 mg, 0.31 mmol) and (±) -1- (2-chlorophenyl) ethylamine (48 µl, 0.29 mmol) produced the title compound (60 mg, 41%). P.F .: 143-146 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.46-7.14 (m, 5H); 7.04-6.94 (m, 2H); 5.26 (quintuple, J = 7.2, 1H); 3.97 (s at, 1 H); 2.65 (s at, 1 H); 2.17 (s a, 2H); 2.04-1.70 (m, 10H); 1.56 (d, J = 7.2, 3H). IR (cm-1, KBr): 3419 (m), 2915 (s), 2847 (m), 1666 (s), 1612 (m), 1519 (s), 1481 (m), 1442 (m), 1368 (w), 1353 (w), 1273 (m), 1219 (m), 1144 (m), 1082 (m), 967 (m), 852 (m).

Ejemplo 152 Example 152

N(7)-[(S)-1-Fenilpropil]-5-(2,4-difluorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]-tetradeca-4(8),6-dieno-7carboxamida N (7) - [(S) -1-Phenylpropyl] -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] -tetradeca-4 (8), 6-diene -7carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 3 (100 mg; 0,29 mmol), DMF (1,0 ml), Et3N (48 µl, 0,34 mmol), reactivo BOP (141 mg, 0,31 mmol) y (s)-1-fenilpropilamina (41 µl, 0,29 mmol) produjo el compuesto del título (84 mg, 63%). P.F.: 127-129 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,50-7,10 (m, 1H); 7,34-7,15 (m, 6H); 7,05-6,90 (m, 2H); 4,99 (c, J = 7,5, 1H); 3,96 (t, J = 6,2, 1H); 2,64 (s a, 1H); 2,16 (s a, 2H); 2,04-1,70 (m, 12H); 0,94 (t, J = 7,2, 3H). IR (cm-1, KBr): 3410 (m), 3325 (m), 2916 (s), 2848 (m), 1666 (s), 1612 (m), 1519 (s), 1481 (m), 1442 (m), 1367 (w), 1353 (w), 1273 (m), 1226 (m), 1217 (m), 1144 (m), 1083 (m),1030 (w), 966 (w), 966 (m), 852 (w), 756 (s), 700 (m). EM (m/z): 462,1 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 3 (100 mg; 0.29 mmol), DMF (1.0 ml), Et3N (48 µl, 0.34 mmol), reagent BOP (141 mg, 0.31 mmol) and (s) -1-phenylpropylamine (41 µl, 0.29 mmol) produced the title compound (84 mg, 63%). P.F .: 127-129 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.50-7.10 (m, 1H); 7.34-7.15 (m, 6H); 7.05-6.90 (m, 2H); 4.99 (c, J = 7.5, 1H); 3.96 (t, J = 6.2, 1H); 2.64 (s at, 1 H); 2.16 (s a, 2H); 2.04-1.70 (m, 12H); 0.94 (t, J = 7.2, 3H). IR (cm-1, KBr): 3410 (m), 3325 (m), 2916 (s), 2848 (m), 1666 (s), 1612 (m), 1519 (s), 1481 (m), 1442 (m), 1367 (w), 1353 (w), 1273 (m), 1226 (m), 1217 (m), 1144 (m), 1083 (m), 1030 (w), 966 (w), 966 (m), 852 (w), 756 (s), 700 (m). MS (m / z): 462.1 ([M + H] +).

Ejemplo 153 Example 153

N7-[1-(2-Clorofenil)-1-metiletil]-5-(2,4-difluorofenil)-5,6-diazatetraciclo[7,3,13,11.04,8]tetradeca-4(8),6-dieno-7carboxamida N7- [1- (2-Chlorophenyl) -1-methyl ethyl] -5- (2,4-difluorophenyl) -5,6-diazatetracycle [7,3,13,11.04,8] tetradeca-4 (8), 6 -diene-7carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 3 (100 mg, 0,29 mmol), DMF (1,0 ml), Et3N (45 µl, 0,31 mmol), reactivo BOP (141 mg, 0,31 mmol) y 2-(2-clorofenil)-prop-2ilamina (73 mg, 0,43 mmol) produjo el compuesto del título (95 mg, 66%). P.F.: 145-147 ºC. RMN 1H (δ ppm, CDCl3, The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 3 (100 mg, 0.29 mmol), DMF (1.0 ml), Et3N (45 µl, 0.31 mmol), reagent BOP (141 mg, 0.31 mmol) and 2- (2-chlorophenyl) -prop-2-amine (73 mg, 0.43 mmol) produced the title compound (95 mg, 66%). P.F .: 145-147 ° C. 1H NMR (δ ppm, CDCl3,

300 MHz): 7,57 (dd, J = 7,5, 1,2, 1H); 7,52-7,39 (m, 2H); 7,32 (dd, J = 7,8, 1,5, 1H); 7,26-7,20 (m, 1H); 7,16 (td, J = 7,8, 1,5, 1H), 7,08-6,94 (m, 2H); 3,82 (t a, J = 6,2, 1H); 2,64 (s a, 1H); 2,14 (s a, 2H); 1,95-1,74 (m, 10H); 1,88 (s, 6H). IR (cm-1, KBr): 3419 (m), 2919 (m), 2892 (m), 2841 (m), 1674 (s), 1515 (s), 1441 (m), 1384 (w), 1362 (w), 1274 (m), 1249 (m), 1226 (m), 1139 (m), 1083 (m), 1039 (m), 967 (m), 843 (m), 727 (m). EM (m/z): 496,2 ([M+H]+). 300 MHz): 7.57 (dd, J = 7.5, 1.2, 1H); 7.52-7.39 (m, 2H); 7.32 (dd, J = 7.8, 1.5, 1H); 7.26-7.20 (m, 1 H); 7.16 (td, J = 7.8, 1.5, 1H), 7.08-6.94 (m, 2H); 3.82 (t a, J = 6.2, 1H); 2.64 (s at, 1 H); 2.14 (s a, 2H); 1.95-1.74 (m, 10H); 1.88 (s, 6H). IR (cm-1, KBr): 3419 (m), 2919 (m), 2892 (m), 2841 (m), 1674 (s), 1515 (s), 1441 (m), 1384 (w), 1362 (w), 1274 (m), 1249 (m), 1226 (m), 1139 (m), 1083 (m), 1039 (m), 967 (m), 843 (m), 727 (m). MS (m / z): 496.2 ([M + H] +).

Ejemplo 154 Example 154

(2R)-2-[7-(2,4-Difluorofenil)-6,7-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),5-dien-5-ilcarboxamido]-2feniletanoato de metilo (2R) -2- [7- (2,4-Difluorophenyl) -6,7-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8), methyl 5-dien-5-ylcarboxamido] -2-phenylethanoate

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 3 (200 mg, 0,58 mmol), DMF (2,0 ml), Et3N (193 µl, 1,39 mmol), reactivo BOP (282 mg, 0,64 mmol) y metil éster clorhidrato de (R)-(+)-2-fenilglicina (11,7 mg, 0,58 mmol) produjo el compuesto del título (140 mg, 57%). P.F.: 138-141 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,78 (d, J = 7,2, 1H); 7,49-7,30 (m, 6H); 7,10-6,90 (m, 2H); 5,72 (d, J = 7,5, 1H); 3,91 (t. J = 6,1, 1H); 3,74 (s, 3H); 2,66 (s a, 1H); 2,16 (s a, 2H); 2,00-1,70 (m, 10H). IR (cm-1, KBr): 3411 (m), 2915 (s), 2848 (m), 1744 (s), 1671 (s), 1613 (m), 1570 (m), 1519 (m), 1478 (m), 1478 (m), 1441 (m), 1352 (w), 1367 (w), 1352 (w), 1322 (m), 1273 (m),1209 (m), 1081 (m), 967 (w), 851 (w), 754 (m), 698 (m). EM (m/z): 492,1 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 3 (200 mg, 0.58 mmol), DMF (2.0 ml), Et3N (193 µl, 1.39 mmol), reagent BOP (282 mg, 0.64 mmol) and methyl ester hydrochloride of (R) - (+) - 2-phenylglycine (11.7 mg, 0.58 mmol) produced the title compound (140 mg, 57%). P.F .: 138-141 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.78 (d, J = 7.2, 1H); 7.49-7.30 (m, 6H); 7.10-6.90 (m, 2H); 5.72 (d, J = 7.5, 1H); 3.91 (t. J = 6.1, 1H); 3.74 (s, 3 H); 2.66 (s at, 1 H); 2.16 (s a, 2H); 2.00-1.70 (m, 10H). IR (cm-1, KBr): 3411 (m), 2915 (s), 2848 (m), 1744 (s), 1671 (s), 1613 (m), 1570 (m), 1519 (m), 1478 (m), 1478 (m), 1441 (m), 1352 (w), 1367 (w), 1352 (w), 1322 (m), 1273 (m), 1209 (m), 1081 (m), 967 (w), 851 (w), 754 (m), 698 (m). MS (m / z): 492.1 ([M + H] +).

Ejemplo 155 Example 155

(2S)-2-[7-(2,4-Difluorofenil)-6,7-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),5-dien-5-ilcarboxami-do]-2feniletanoato metilo (2S) -2- [7- (2,4-Difluorophenyl) -6,7-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8), 5-dien-5-ylcarboxyamido] -2-phenylethanoate methyl

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 3 (500 mg, 1,45 mmol), DMF (4,0 mI), Et3N (480 µl, 3,48 mmol), reactivo BOP (706 mg, 1,59 mmol) y metil éster clorhidrato de (S)-(+)-2-fenilglicina (293 mg, 1,45 mmol) produjo el compuesto del título (525 mg, 73%). P.F.: 132-135 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,78 (d, J = 6,9, 1H); 7,52-7,25 (m, 6H); 7,05-6,90 (m, 2H); 5,71 (d, J = 7,2, 1H); 3,90 (t. J = 6,2, 1H); 3,74 (s, 3H); 2,66 (s a, 1H); 2,16 (s a, 2H); 2,04-1,70 (m, 10H). IR (cm-1, KBr): 3432 (m), 3413 (m), 2919 (s), 2849 (m), 1755 (s), 1740 (s), 1672 (s), 1614 (m), 1570 (m), 1522 (s), 1479 (m), 1439 (m), 1223 (m), 1308 (m), 1326 (m), 1274 (m), 1259 (m), 1207 (m), 1161 (m), 1143 (m), 1082 (m), 1029 (w), 967 (m), 845 (m), 697, EM (m/z): 492,1 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 3 (500 mg, 1.45 mmol), DMF (4.0 mL), Et3N (480 µL, 3.48 mmol), reagent BOP (706 mg, 1.59 mmol) and methyl ester hydrochloride of (S) - (+) - 2-phenylglycine (293 mg, 1.45 mmol) produced the title compound (525 mg, 73%). P.F .: 132-135 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.78 (d, J = 6.9, 1H); 7.52-7.25 (m, 6H); 7.05-6.90 (m, 2H); 5.71 (d, J = 7.2, 1H); 3.90 (t. J = 6.2, 1H); 3.74 (s, 3 H); 2.66 (s at, 1 H); 2.16 (s a, 2H); 2.04-1.70 (m, 10H). IR (cm-1, KBr): 3432 (m), 3413 (m), 2919 (s), 2849 (m), 1755 (s), 1740 (s), 1672 (s), 1614 (m), 1570 (m), 1522 (s), 1479 (m), 1439 (m), 1223 (m), 1308 (m), 1326 (m), 1274 (m), 1259 (m), 1207 (m), 1161 (m), 1143 (m), 1082 (m), 1029 (w), 967 (m), 845 (m), 697, MS (m / z): 492.1 ([M + H] +).

Ejemplo156 Example156

N7-(3-Hidroxiadamantan-1-il)-5-(2,4-difluorofenil)-5, 6-diazatetraciclo [7.3.1.13,11,0,’8]tetradeca-4(8),6-di-eno-7carboxamida N7- (3-Hydroxiadamantan-1-yl) -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7.3.1.13,11,0, '8] tetradeca-4 (8), 6-di- eno-7carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 3 (200 mg, 0,58 mmol), DMF (2,0 ml), Et3N (88 µl, 0,63 mmol), reactivo BOP (282 mg, 0,63 mmol) y 3-amino-1-adamantanol (97 mg, 0,58 mmol) produjo el compuesto del título (143 mg, 51%). P.F.: 240-243 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,48-7,38 (m, 1H); 7,05-6,94 (m, 2H); 6,74 (s a, 1H); 3,94 (s a, 1H); 2,64 (s a, 1H), 2,28 (s a, 2H); 2,17 (s a, 2H); 2,11 (s a, 2H); 2,04-1,56 (m, 21H). IR (cm-1, KBr): 3385 (m), 2911 (s), 2849 (m), 1657 (s), 1610 (w), 1560 (w), 1520 (m), 1482 (m), 1441 (w), 1441 (w), 1362 (w), 1352 (w), 1273 (w), 1253 (w), 1227 (m), 1150 (m), 1132 (m), 1101 (w), 1084 (w), 1048 (w), 1025 (w), 966 (m), 872 (m). EM (m/z): 494,0 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 3 (200 mg, 0.58 mmol), DMF (2.0 ml), Et3N (88 µl, 0.63 mmol), reagent BOP (282 mg, 0.63 mmol) and 3-amino-1-adamantanol (97 mg, 0.58 mmol) produced the title compound (143 mg, 51%). P.F .: 240-243 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.48-7.38 (m, 1H); 7.05-6.94 (m, 2H); 6.74 (s a, 1 H); 3.94 (s a, 1 H); 2.64 (s at, 1 H), 2.28 (s at, 2 H); 2.17 (s a, 2H); 2.11 (s a, 2H); 2.04-1.56 (m, 21H). IR (cm-1, KBr): 3385 (m), 2911 (s), 2849 (m), 1657 (s), 1610 (w), 1560 (w), 1520 (m), 1482 (m), 1441 (w), 1441 (w), 1362 (w), 1352 (w), 1273 (w), 1253 (w), 1227 (m), 1150 (m), 1132 (m), 1101 (w), 1084 (w), 1048 (w), 1025 (w), 966 (m), 872 (m). MS (m / z): 494.0 ([M + H] +).

Ejemplo 157 Example 157

N(7)-(1-Metil-1-feniletil)-5-(4-fluorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7carboxamida N (7) - (1-Methyl-1-phenylethyl) -5- (4-fluorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 4 (100 mg, 0,30 mmol), DMF (1,5 ml), Et3N (50 µl, 0,36 mmol), reactivo BOP (148 mg, 0,33 mmol) y α,α-dimetilbencilamina (49 mg, 0,36 mmol) produjo el compuesto del título (92 mg, 68%). P.F.: 180-182 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,47 (d, J = 7,8, 2H); 7,38-7,14 (m, 8H); 3,91 (s a, 1H); 2,95 (s a, 1H); 2,17 (s a, 2H); 1,97-1,76 (m, 16H). IR (cm-1, KBr): 3412 (m), 3064 (w), 2981 (w), 2916 (s), 2846 (m), 1672 (s), 1565 (w), 1512 (s), 1482 (m), 1439 (m), 1382 (w), 1363 (w), 1257 (m), 1215 (s), 1155 (m), 1084 (m), 844 (m). EM (m/z): 443,9 (100%), 444,9 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 4 (100 mg, 0.30 mmol), DMF (1.5 ml), Et3N (50 µl, 0.36 mmol), reagent BOP (148 mg, 0.33 mmol) and α, α-dimethylbenzylamine (49 mg, 0.36 mmol) produced the title compound (92 mg, 68%). P.F .: 180-182 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.47 (d, J = 7.8, 2H); 7.38-7.14 (m, 8H); 3.91 (s at, 1 H); 2.95 (s at, 1 H); 2.17 (s a, 2H); 1.97-1.76 (m, 16H). IR (cm-1, KBr): 3412 (m), 3064 (w), 2981 (w), 2916 (s), 2846 (m), 1672 (s), 1565 (w), 1512 (s), 1482 (m), 1439 (m), 1382 (w), 1363 (w), 1257 (m), 1215 (s), 1155 (m), 1084 (m), 844 (m). MS (m / z): 443.9 (100%), 444.9 ([M + H] +).

Ejemplo 158 Example 158

N(7)-(Adamantan-1-il)-5-(4-fluorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-6-dieno-7-carboxamida N (7) - (Adamantan-1-yl) -5- (4-fluorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8) -6-diene-7-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 4 (150 mg, 0,46 mmol), DMF (1,5 ml), Et3N (76 µl, 0,55 mmol), reactivo BOP (223 mg, 0,50 mmol) y 1-adamantilamina (69 mg, 0,46 mmol) produjo el compuesto del título (150 mg, 71%). P.F.: 214-216 ºC. RMN 1H (α ppm, CDCl3, 300 MHz): 7,36-7,26 (m, 2H); 7,20-7,12 (m, 2H); 6,73 (s a, 1H); 3,99 (s a, 1H); 2,94 (s a, 1H), 2,19-1,55 (m, 27H). IR (cm-1, KBr): 3392 (m), 2905 (s), 2847 (m), 1671 (s), 1560 (w), 1529 (m), 1512 (s), 1481 (m), 1454 (w), 1441 (w), 1357 (m), 1219 (m), 1092 (m), 841 (m). EM (m/z): 460,3 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 4 (150 mg, 0.46 mmol), DMF (1.5 ml), Et3N (76 µl, 0.55 mmol), reagent BOP (223 mg, 0.50 mmol) and 1-adamantylamine (69 mg, 0.46 mmol) produced the title compound (150 mg, 71%). P.F .: 214-216 ° C. 1H NMR (α ppm, CDCl3, 300 MHz): 7.36-7.26 (m, 2H); 7.20-7.12 (m, 2H); 6.73 (s a, 1 H); 3.99 (s at, 1 H); 2.94 (s at, 1H), 2.19-1.55 (m, 27H). IR (cm-1, KBr): 3392 (m), 2905 (s), 2847 (m), 1671 (s), 1560 (w), 1529 (m), 1512 (s), 1481 (m), 1454 (w), 1441 (w), 1357 (m), 1219 (m), 1092 (m), 841 (m). MS (m / z): 460.3 ([M + H] +).

Ejemplo 158a Example 158a

N7-(Adamantan-2-il)-5-(4-fluorofenil)-5,6-diazatetraciclo[7.3.1.13,1104,8]tetradeca-4(8),6-dieno-7-carboxamida N7- (Adamantan-2-yl) -5- (4-fluorophenyl) -5,6-diazatetracycle [7.3.1.13,1104.8] tetradeca-4 (8), 6-diene-7-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 4 (100 mg, 0,36 mmol), DMF (1,0 ml), Et3N (124 µl, 0,88 mmol), reactivo BOP (170 mg, 0,38 mmol) y clorhidrato de 2adamantilamina (103 mg, 0,55 mmol) produjo el compuesto del título (120 mg, 80%). P.F.: 196-198 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,69-7,63 (m, 2H); 7,17 (t, J = 8,1, 2H); 4,23 (d, J = 8,4, 1H); 3,75 (s a, 1H); 3,65 (s a, 1H), 2,14-1,87 (m, 14H), 1,78-1,54 (m, 4H), 1,26-1,21 (m, 2H). IR (cm-1, KBr): 3414 (s), 2979 (w), 2901 (s), 2851 (s), 1663 (s), 1542 (s), 1517 (s),1488 (s), 1454 (m), 1445 (m), 1347 (w), 1255 (w), 1224 (m), 1213 (s), 1159 (m), 1126 (m),1091 (m), 953 (w), 833 (m). EM (m/z): 406,2 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 4 (100 mg, 0.36 mmol), DMF (1.0 ml), Et3N (124 µl, 0.88 mmol), reagent BOP (170 mg, 0.38 mmol) and 2adamantylamine hydrochloride (103 mg, 0.55 mmol) produced the title compound (120 mg, 80%). P.F .: 196-198 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.69-7.63 (m, 2H); 7.17 (t, J = 8.1, 2H); 4.23 (d, J = 8.4, 1H); 3.75 (s a, 1 H); 3.65 (s a, 1H), 2.14-1.87 (m, 14H), 1.78-1.54 (m, 4H), 1.26-1.21 (m, 2H). IR (cm-1, KBr): 3414 (s), 2979 (w), 2901 (s), 2851 (s), 1663 (s), 1542 (s), 1517 (s), 1488 (s), 1454 (m), 1445 (m), 1347 (w), 1255 (w), 1224 (m), 1213 (s), 1159 (m), 1126 (m), 1091 (m), 953 (w), 833 (m). MS (m / z): 406.2 ([M + H] +).

Ejemplo 159 Example 159

N7-(1,3,3-Trimetilbiciclo[2.2.1]hept-2-il)-5-(4-fluorofenil)-5,6-diazatetraciclo[7.3.1.13,1104,8]tetradeca-4(8),6dieno-7-carboxamida N7- (1,3,3-Trimethylbicyclo [2.2.1] hept-2-yl) -5- (4-fluorophenyl) -5,6-diazatetracycle [7.3.1.13.1104.8] tetradeca-4 (8) , 6 diene-7-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 4 (100 mg, 0,30 mmol), DMF (1,5 ml), Et3N (103 µl, 0,73 mmol), reactivo BOP (142 mg, 0,32 mmol) y 1S,2endo-amino1,3,3-trimetil-biciclo[2.2.1]heptano (86 mg, 0,46 mmol) produjo el compuesto del título (101 mg, 71%). P.F.: 139-141 ºC. RMN 1H δ ppm, CDCl3, 300 MHz): 7,38-7,31 (m, 2H); 7,21-7,04 (m, 3H); 4,00 (s a, 1H); 3,73 (d, J = 9,6, 1H); 2,98 (s a, 1H), 2,19 (s a, 1H), 2,05-1,66 (m, 14H), 1,51-1,39 (m, 2H), 1,25-1,08 (m, 1H), 1,21, 1,01, 0,85 (3s, 9H). IR (cm-1 , KBr): 3418 (s), 2927 (s), 2904 (s), 2870 (m), 1670 (s), 1607 (w), 1560 (m), 1510 (s), 1525 (s), 1479 (m), 1440 (m), 1375 (w), 1355 (w), 1365 (w), 1220 (m), 1159 (m),1151 (m), 1089 (m), 1029 (m), 838 (m). EM (m/z): 462,3 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 4 (100 mg, 0.30 mmol), DMF (1.5 ml), Et3N (103 µl, 0.73 mmol), reagent BOP (142 mg, 0.32 mmol) and 1S, 2endo-amino1,3,3-trimethyl-bicyclo [2.2.1] heptane (86 mg, 0.46 mmol) produced the title compound (101 mg, 71% ). P.F .: 139-141 ° C. 1 H NMR δ ppm, CDCl 3, 300 MHz): 7.38-7.31 (m, 2H); 7.21-7.04 (m, 3H); 4.00 (s at, 1 H); 3.73 (d, J = 9.6, 1H); 2.98 (sa, 1H), 2.19 (sa, 1H), 2.05-1.66 (m, 14H), 1.51-1.39 (m, 2H), 1.25-1, 08 (m, 1H), 1.21, 1.01, 0.85 (3s, 9H). IR (cm-1, KBr): 3418 (s), 2927 (s), 2904 (s), 2870 (m), 1670 (s), 1607 (w), 1560 (m), 1510 (s), 1525 (s), 1479 (m), 1440 (m), 1375 (w), 1355 (w), 1365 (w), 1220 (m), 1159 (m), 1151 (m), 1089 (m), 1029 (m), 838 (m). MS (m / z): 462.3 ([M + H] +).

Ejemplo 160 Example 160

N(7)-Piperidino-5-(4-metilfenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxamida N (7) -Piperidino-5- (4-methylphenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 5 (100 mg, 0,31 mmol), DMF (1,0 ml), Et3N (46 µl, 0,33 mmol); reactivo BOP (137 mg, 0,31 mmol) y 1-aminopiperidina (35 µl, 0,33 mmol) produjo el compuesto del título (70 mg, 56%). P.F.: 228-232 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,70 (s a, 1H); 7,28 (d, J = 9,0, 2H); 7,23 (d, J = 9,0, 2H); 3,99 (t a, J = 4,83, 1H); 2,99 (s a, 1H); 2,85 (s a, 4H); 2,42 (s, 3H); 2,18 (s a, 2H); 2,04-1,95 (m, 2H); 1,95-1,65 (m, 12H); 1,41 (s a, 2H). IR (cm-1, KBr): 3306 (m), 2949 (s), 2937 (s), 2911 (s), 2849 (s), 2790 (m), 1690 (s), 1563 (w), 1518 (s), 1488 (m), 1462 (m), 1349 (m), 1216 (m), 1127 (m), 1108 (m), 987 (m), 830 (m). EM (m/z): 405,20 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 5 (100 mg, 0.31 mmol), DMF (1.0 ml), Et3N (46 µl, 0.33 mmol); BOP reagent (137 mg, 0.31 mmol) and 1-aminopiperidine (35 µl, 0.33 mmol) produced the title compound (70 mg, 56%). P.F .: 228-232 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.70 (s at, 1H); 7.28 (d, J = 9.0, 2H); 7.23 (d, J = 9.0, 2H); 3.99 (t a, J = 4.83, 1H); 2.99 (s at, 1H); 2.85 (s at, 4H); 2.42 (s, 3 H); 2.18 (s at, 2H); 2.04-1.95 (m, 2H); 1.95-1.65 (m, 12H); 1.41 (s at, 2H). IR (cm-1, KBr): 3306 (m), 2949 (s), 2937 (s), 2911 (s), 2849 (s), 2790 (m), 1690 (s), 1563 (w), 1518 (s), 1488 (m), 1462 (m), 1349 (m), 1216 (m), 1127 (m), 1108 (m), 987 (m), 830 (m). MS (m / z): 405.20 ([M + H] +).

Ejemplo 161 Example 161

N(7)-(2,4-Diclorofenilamino)-5-(4-metilfenil)-5,6-diazatetraciclo(7,3,1,13,11.04,8]tetradeca-(8),6-dieno-7carboxamida N (7) - (2,4-Dichlorophenylamino) -5- (4-methylphenyl) -5,6-diazatetracyclo (7,3,1,13,11.04,8] tetradeca- (8), 6-diene-7carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 5 (100 mg, 0,31 mmol), DMF (1,0 ml), Et3N (46 µl, 0,33 mmol), reactivo BOP (137 mg, 0,31 mmol) y clorhidrato de 2,4diclorofenilhidrazina (7,0 mg, 0,32 mmol) dio el compuesto del título (110 mg, 73%). P.F.: 208-215 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 9,42 (s a, 1H); 7,38-7,20 (m, 7H); 7,14-7,00 (m, 1H); 3,96 (s a, 1H); 3,04 (s a, 1H); 2,45 (s, 3H); 2,40-1,80 (m, 12H). IR (cm-1, KBr): 3314 (m), 3247 (m), 2914 (s), 2846 (m), 1674 (s), 1661 (s), 1515 (s), 1477 (s), 1478 (s), 1390 (m), 1363 (m), 1254 (m), 1235 (m), 1216 (m), 1089 (m), 1079 (m), 862 (m), 825 (s). EM (m/z): 481,10 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 5 (100 mg, 0.31 mmol), DMF (1.0 ml), Et3N (46 µl, 0.33 mmol), reagent BOP (137 mg, 0.31 mmol) and 2,4-dichlorophenylhydrazine hydrochloride (7.0 mg, 0.32 mmol) gave the title compound (110 mg, 73%). P.F .: 208-215 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 9.42 (s at, 1H); 7.38-7.20 (m, 7H); 7.14-7.00 (m, 1 H); 3.96 (s at, 1 H); 3.04 (s at, 1 H); 2.45 (s, 3 H); 2.40-1.80 (m, 12H). IR (cm-1, KBr): 3314 (m), 3247 (m), 2914 (s), 2846 (m), 1674 (s), 1661 (s), 1515 (s), 1477 (s), 1478 (s), 1390 (m), 1363 (m), 1254 (m), 1235 (m), 1216 (m), 1089 (m), 1079 (m), 862 (m), 825 (s). MS (m / z): 481.10 ([M + H] +).

Ejemplo 162 Example 162

N(7)-(2-Clorobencil-5-(4-metilfenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8] tetradeca-4(8),6-dieno-7-carboxamida N (7) - (2-Chlorobenzyl-5- (4-methylphenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 5 (100 mg, 0,31 mmol), DMF (1,0 ml), Et3N (46 µl, 0,33 mmol), reactivo BOP (137 mg, 0,31 mmol) y 2-clorobencilamina (40 µl, 0,36 mmol) produjo el compuesto del título (80 mg, 58%). P.F.: 127-130 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,70 (s a, 1H); 7,48 (d a, J = 6,9, 1H); 7,38-7,16 (m, 7H); 4,68 (d, J = 6,0, 2H); 4,02 (t a, J = 4,6, 1H); 3,00 (s a, 1H); 2,42 (s, 3H); 2,20 (s a, 2H); 2,10-1,70 (m, 10H). IR (cm-1, KBr): 3410 (m), 2915 (s), 2904 (s), 2842 (m), 1663 (s), 1526 (s), 1517 (s), 1478 (s), 1465 (s), 1439 (s), 1365 (m), 1352 (m), 1232 (m), 1215 (m), 1085 (m), 829 (m), 756 (m). EM (m/z): 446,10 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 5 (100 mg, 0.31 mmol), DMF (1.0 ml), Et3N (46 µl, 0.33 mmol), reagent BOP (137 mg, 0.31 mmol) and 2-chlorobenzylamine (40 µl, 0.36 mmol) produced the title compound (80 mg, 58%). P.F .: 127-130 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.70 (s at, 1H); 7.48 (d a, J = 6.9, 1H); 7.38-7.16 (m, 7H); 4.68 (d, J = 6.0, 2H); 4.02 (t a, J = 4.6, 1H); 3.00 (s at, 1 H); 2.42 (s, 3 H); 2.20 (s a, 2H); 2.10-1.70 (m, 10H). IR (cm-1, KBr): 3410 (m), 2915 (s), 2904 (s), 2842 (m), 1663 (s), 1526 (s), 1517 (s), 1478 (s), 1465 (s), 1439 (s), 1365 (m), 1352 (m), 1232 (m), 1215 (m), 1085 (m), 829 (m), 756 (m). MS (m / z): 446.10 ([M + H] +).

Ejemplo 163 Example 163

N(7)-Piperidino-5-(4-metoxifenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxamida N (7) -Piperidino-5- (4-methoxyphenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 6 (100 mg, 0,27 mmol), DMF (2,0 ml), Et3N (44 µl, 0,32 mmol), reactivo BOP (129 mg, 0,32 mmol) y 1-aminopiperidina (29 The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 6 (100 mg, 0.27 mmol), DMF (2.0 ml), Et3N (44 µl, 0.32 mmol), reagent BOP (129 mg, 0.32 mmol) and 1-aminopiperidine (29

µl, 0,29 mmol) dio el compuesto del título (65 mg, 58%). P.F.: 156 ºC (se funde). RMN 1H (δ ppm, CDCl3, 300 MHz): 7,22 (d, J = 6,9, 3H); 6,98 (d, J = 6,9, 2H); 3,86 (s a, 3H); 3,74 (s a, 1H); 3,01 (s a, 1H), 2,38-1,70 (m, 20H). IR (cm-1 , KBr): 3284 (m), 2917 (s), 2849 (s), 1655 (s), 1609 (m), 1519 (s), 1471 (s), 1440 (s), 1353 (m), 1298 (m), 1256 (s), 1231 (s), 1147 (m), 1071 (m), 1010 (m), 891 (m), 814 (s). EM (m/z): 421,20 ([M+H]+). µl, 0.29 mmol) gave the title compound (65 mg, 58%). P.F .: 156 ºC (melts). 1H NMR (δ ppm, CDCl3, 300 MHz): 7.22 (d, J = 6.9, 3H); 6.98 (d, J = 6.9, 2H); 3.86 (s a, 3H); 3.74 (s a, 1 H); 3.01 (s at, 1H), 2.38-1.70 (m, 20H). IR (cm-1, KBr): 3284 (m), 2917 (s), 2849 (s), 1655 (s), 1609 (m), 1519 (s), 1471 (s), 1440 (s), 1353 (m), 1298 (m), 1256 (s), 1231 (s), 1147 (m), 1071 (m), 1010 (m), 891 (m), 814 (s). MS (m / z): 421.20 ([M + H] +).

Ejemplo 164 Example 164

N7-(2-Clorobencil)-5-(4-metoxifenil)-5,6-diazatetraciclo[7.3.1.13,11 .04,8]tetradeca-4(8),6-dieno-7-carboxamida N7- (2-Chlorobenzyl) -5- (4-methoxyphenyl) -5,6-diazatetracycle [7.3.1.13.11 .04.8] tetradeca-4 (8), 6-diene-7-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 6 (100 mg, 0,27 mmol), DMF (1,0 ml), Et3N (44 µl, 0,32 mmol), reactivo BOP (129 mg, 0,32 mmol) y 2-clorobencilamina (32 µl, 0,27 mmol) produjo el compuesto del título (85 mg, 69%). P.F.: 178 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,507,45 (m, 2H); 7,37-7,10 (m, 5H); 6,98 (d a, J = 7,5, 2H); 4,67 (s a, 2H); 4,00 (s a, 1H); 3,86 (s a, 3H); 2,96 (s a, 1H); 2,19 (s a, 2H), 2,10-1,40 (m, 10H). IR (cm-1, KBr): 3395 (s), 2904 (m), 2848 (m), 1667 (s), 1531 (s), 1515 (s), 1444 (s), 1353 (s), 1242 (s), 1230 (s), 1222 (s), 1231 (s), 1162 (m), 985 (m), 839 (m). EM (m/z): 462,10 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 6 (100 mg, 0.27 mmol), DMF (1.0 ml), Et3N (44 µl, 0.32 mmol), reagent BOP (129 mg, 0.32 mmol) and 2-chlorobenzylamine (32 µl, 0.27 mmol) produced the title compound (85 mg, 69%). P.F .: 178 ºC. 1H NMR (δ ppm, CDCl3, 300 MHz): 7,507.45 (m, 2H); 7.37-7.10 (m, 5H); 6.98 (d a, J = 7.5, 2H); 4.67 (s a, 2H); 4.00 (s at, 1 H); 3.86 (s a, 3H); 2.96 (s at, 1 H); 2.19 (s at, 2H), 2.10-1.40 (m, 10H). IR (cm-1, KBr): 3395 (s), 2904 (m), 2848 (m), 1667 (s), 1531 (s), 1515 (s), 1444 (s), 1353 (s), 1242 (s), 1230 (s), 1222 (s), 1231 (s), 1162 (m), 985 (m), 839 (m). MS (m / z): 462.10 ([M + H] +).

Ejemplo 165 Example 165

N(7)-(2,4-Diclorofenilamino)-5-(4-metoxifenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-di-eno-7carboxamida N (7) - (2,4-Dichlorophenylamino) -5- (4-methoxyphenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-di-eno-7carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 6 (100 mg, 0,36 mmol), DMF (1,0 ml), Et3N (44 µl, 0,32 mmol), reactivo BOP (125 mg, 0,28 mmol) y clorhidrato de 2,4diclorofenilhidrazina (57 mg, 0,27 mmol) produjo el compuesto del título (78 mg, 56%). P.F.: 199 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,75 (s a, 1H); 7,36-7,27 (m, 3H); 7,10 (dd, J = 9,0, 1,8, 1H); 7,06-6,94 (d, J = 9,0, 1H); 6,97 (s a,1H); 6,50 (s a, 1H); 3,87 (s a, 4H); 3,00 (s a, 1H); 2,19 (s a, 2H), 2,02-1,80 (m, 10H). IR (cm-1, KBr): 3359 (s), 3020 (w), 2912 (s), 2844 . (m), 1678 (s), 1517 (s), 1473 (s), 1247 (s), 1229 (s), 1075 (m), 1020 (m), 837 (s). EM (m/z): 497,10 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 6 (100 mg, 0.36 mmol), DMF (1.0 ml), Et3N (44 µl, 0.32 mmol), reagent BOP (125 mg, 0.28 mmol) and 2,4-dichlorophenylhydrazine hydrochloride (57 mg, 0.27 mmol) produced the title compound (78 mg, 56%). P.F .: 199 ºC. 1 H NMR (δ ppm, CDCl 3, 300 MHz): 8.75 (s at, 1 H); 7.36-7.27 (m, 3H); 7.10 (dd, J = 9.0, 1.8, 1H); 7.06-6.94 (d, J = 9.0, 1H); 6.97 (s a, 1 H); 6.50 (s at, 1 H); 3.87 (s a, 4H); 3.00 (s at, 1 H); 2.19 (s at, 2H), 2.02-1.80 (m, 10H). IR (cm-1, KBr): 3359 (s), 3020 (w), 2912 (s), 2844. (m), 1678 (s), 1517 (s), 1473 (s), 1247 (s), 1229 (s), 1075 (m), 1020 (m), 837 (s). MS (m / z): 497.10 ([M + H] +).

Ejemplo 166 Example 166

N(7)-Piperidino-5-[(2-clorofenil)fenil]-5,6-diazatetraciclo[7.3.1.13,11.04,8] tetradeca-4(8),6-dieno-7-carboxamida N (7) -Piperidino-5 - [(2-chlorophenyl) phenyl] -5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxamide

Una solución del ejemplo 101 (170 mg, 0,36 mmol) en dioxano (4,0 ml) se trató con ácido 4-clorofenilborónico (62 mg, 0,33 mmol), Pd(PPh3)2Cl2 (6 mg, 0,009 m ml) y carbonato sódico (115 mg, 1,08 mmol) y se sometió a reflujo durante 7 h. El disolvente se evaporó, el residuo se disolvió en AcOEt y se lavó con agua. La fase orgánica se secó sobre Na2SO4, se filtró y el disolvente se retiró. El residuo se sometió a FC para dar aprox. 70% (como se analizó por HPLC) de producto puro que se purificó adicionalmente TLC preparativa para proporcionar el compuesto del título (70 mg, 39%). pureza de HPLC: 99,8%. P.F.: 206 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,59-7,38 (m, 4H); 7,27 (d, J = 8,4, 2H); 6,99 (d, J = 8,4, 2H); 3,84 (s a, 1H); 3,35 (s, 3H); 2,89 (s a, 4H); 2,35 (s a, 1H); 2,00-1,70 (m, 18H). EM (m/z): 501,2 ([M+H]+). A solution of example 101 (170 mg, 0.36 mmol) in dioxane (4.0 ml) was treated with 4-chlorophenylboronic acid (62 mg, 0.33 mmol), Pd (PPh3) 2Cl2 (6 mg, 0.009 m ml) and sodium carbonate (115 mg, 1.08 mmol) and refluxed for 7 h. The solvent was evaporated, the residue was dissolved in AcOEt and washed with water. The organic phase was dried over Na2SO4, filtered and the solvent removed. The residue was subjected to FC to give approx. 70% (as analyzed by HPLC) of pure product which was further purified preparative TLC to provide the title compound (70 mg, 39%). HPLC purity: 99.8%. P.F .: 206 ºC. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.59-7.38 (m, 4H); 7.27 (d, J = 8.4, 2H); 6.99 (d, J = 8.4, 2H); 3.84 (s a, 1 H); 3.35 (s, 3 H); 2.89 (s at, 4H); 2.35 (s at, 1 H); 2.00-1.70 (m, 18H). MS (m / z): 501.2 ([M + H] +).

Ejemplo 167 Example 167

N(7)-[2,4-Diclorofenil)amino]-5-fenil-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8), 6-dieno-7-carboxamida N (7) - [2,4-Dichlorophenyl) amino] -5-phenyl-5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al que se ha descrito para el ejemplo 101 usando el intermedio 7 (100 mg, 0,33 mmol), DMF (1,0 ml), Et3N (50 µl, 0,36 mmol), reactivo BOP (151 mg, 0,34 mmol) y clorhidrato de 2,4-diclorofenilhidrazina (77 mg, 0,36 mmol) para dar el compuesto del título (110 mg, 71%). P.F.: 166170 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,60 (s, 1H); 7,56-7,42 (m, 3H); 7,39 (dd, J = 7,5, 2,1, 2H); 7,29 (d, J = 2,2, 2H); 7,12 (dd, J = 9,0, 2,2, 1H); 6,80 (d, J = 9,0, 1H); 6,55 (s a, 1H); 3,90 (t, J = 6,0, 1H), 3,15 (s a, 1H); 2,20 (s, 2H); 2,04 -1,74 (m, 10H). IR (cm-1, KBr): 3371 (s), 3307 (m), 2910 (s), 2848 (m), 1683 (s), 1596 (m), 1564 (m), 1501 (m), 1463 (s), 1450 (s), 1393 (m), 1361 (m), 1231 (m), 1214 (m), 1075 (m), 1018 (m), 872 (m). EM (m/z): 467,1 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101 using intermediate 7 (100 mg, 0.33 mmol), DMF (1.0 ml), Et3N (50 µl, 0.36 mmol ), BOP reagent (151 mg, 0.34 mmol) and 2,4-dichlorophenylhydrazine hydrochloride (77 mg, 0.36 mmol) to give the title compound (110 mg, 71%). P.F .: 166170 ° C. 1 H NMR (δ ppm, CDCl 3, 300 MHz): 8.60 (s, 1 H); 7.56-7.42 (m, 3H); 7.39 (dd, J = 7.5, 2.1, 2H); 7.29 (d, J = 2.2, 2H); 7.12 (dd, J = 9.0, 2.2, 1H); 6.80 (d, J = 9.0, 1H); 6.55 (s a, 1 H); 3.90 (t, J = 6.0, 1H), 3.15 (s at, 1H); 2.20 (s, 2 H); 2.04 -1.74 (m, 10H). IR (cm-1, KBr): 3371 (s), 3307 (m), 2910 (s), 2848 (m), 1683 (s), 1596 (m), 1564 (m), 1501 (m), 1463 (s), 1450 (s), 1393 (m), 1361 (m), 1231 (m), 1214 (m), 1075 (m), 1018 (m), 872 (m). MS (m / z): 467.1 ([M + H] +).

Ejemplo 168 Example 168

N(7)-Fenil-5-fenil-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-6-dieno-7-carboxamida: N (7) -Phenyl-5-phenyl-5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8) -6-diene-7-carboxamide:

El compuesto del título se sintetizó como para el procedimiento descrito para el ejemplo 101 usando el intermedio 7 (100 mg, 0,32 mmol), DMF (2 ml), trietilamina (0,05 ml, 0,35 mmol), reactivo BOP (151 mg, 0,34 mmol) y anilina (33 µl, 0,35 mmol) para dar el compuesto del título (70 mg, 56%). P.F.: 178-181 ºC. RMN 1H (δ ppm, CDCl3): 8,82 (s a, 1H); 7,67 (d, J = 7,8, 2H); 7,56-7,29 (m, 7H); 7,09 (t, J = 7,5); 4,06 (t a, J = 5, 1H); 3,07 (t a, J = 4,3, 1H); 2,22 (s a, 2H); 2,09-1,98 (m, 2H); 1,98-1,76 (m, 8H). IR (cm-1, KBr): 3449 (a, m), 3384(m), 2922 (m), 2904 (m), 2844 (m), 1689 (s), 1601 (m), 1591 (m), 1528 (s), 1502 (s). The title compound was synthesized as for the procedure described for example 101 using intermediate 7 (100 mg, 0.32 mmol), DMF (2 ml), triethylamine (0.05 ml, 0.35 mmol), BOP reagent (151 mg, 0.34 mmol) and aniline (33 µl, 0.35 mmol) to give the title compound (70 mg, 56%). P.F .: 178-181 ° C. 1H NMR (δ ppm, CDCl3): 8.82 (s a, 1H); 7.67 (d, J = 7.8, 2H); 7.56-7.29 (m, 7H); 7.09 (t, J = 7.5); 4.06 (t a, J = 5, 1H); 3.07 (t a, J = 4.3, 1H); 2.22 (s at, 2H); 2.09-1.98 (m, 2H); 1.98-1.76 (m, 8H). IR (cm-1, KBr): 3449 (a, m), 3384 (m), 2922 (m), 2904 (m), 2844 (m), 1689 (s), 1601 (m), 1591 (m) , 1528 (s), 1502 (s).

Ejemplo 169 N(7)-piperidino-5-fenil-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-6-dieno-7-carboxamida: Example 169 N (7) -piperidino-5-phenyl-5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8) -6-diene-7-carboxamide:

El compuesto del título se sintetizó como para el procedimiento descrito para el ejemplo 101 usando intermedio 7 (155 mg, 0,5 mmol), DMF (2 ml), trietilamina, (77 µl, 0,55 mmol), reactivo BOP (235 mg, 0,53 mmol) y 1aminopiperidina (60 ml, 0,55 mmol) para dar el compuesto del título (120 mg, .61%). RMN 1H (δ ppm, CDCl3): 7,69 (s a,1H); 7,53-7,32 (m, 5H); 4,00 (t a, J = 5,5, 1H); 3,02 (t a, J = 4,6, 1H); 2,84 (t a, J = 4,8, 4H); 2,19 (s a, 2H); 2,051,68 (m, 14H); 1,44-1,36 (m, 2H). IR (cm-1, KBr): 3345 (m), 3306(m), 2941 (s), 2920 (s), 2906 (s), 1687 (s), 1525 (m), 1500 (m). The title compound was synthesized as for the procedure described for example 101 using intermediate 7 (155 mg, 0.5 mmol), DMF (2 ml), triethylamine, (77 µl, 0.55 mmol), BOP reagent (235 mg, 0.53 mmol) and 1aminopiperidine (60 ml, 0.55 mmol) to give the title compound (120 mg, .61%). 1H NMR (δ ppm, CDCl3): 7.69 (s a, 1H); 7.53-7.32 (m, 5H); 4.00 (t a, J = 5.5, 1H); 3.02 (t a, J = 4.6, 1H); 2.84 (t a, J = 4.8, 4H); 2.19 (s a, 2H); 2,051.68 (m, 14H); 1.44-1.36 (m, 2H). IR (cm-1, KBr): 3345 (m), 3306 (m), 2941 (s), 2920 (s), 2906 (s), 1687 (s), 1525 (m), 1500 (m).

Ejemplo 170 Example 170

N(7)-Bencil-5-fenil-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-6-dieno-7-carboxamida: N (7) -Benzyl-5-phenyl-5,6-diazatetracycle [7.3.1.13.11.04.8] tetradeca-4 (8) -6-diene-7-carboxamide:

El compuesto del título se sintetizó como para el procedimiento descrito para el ejemplo 101 usando intermedio 7 (100 mg, 0,32 mmol), DMF (2 ml), trietilamina (0,05 ml, 0,35 mmol), reactivo BOP (151 mg, 0,34 mmol) y bencilamina (39 µl, 0,35 mmol) para dar el compuesto del título (70 mg, 55%). P.F.: 137-139 ºC. RMN 1H (δ ppm, CDCl3): 7,517,21 (m, 11 H); 4,58 (d, J = 5,7, 2H); 4,03 (t a, J = 5, 1H); 3,03 (t a, J = 4,3, 1H); 2,20 (s a, 2H); 2,08-1,98 (m, 2H); 1,98-1,76 (m, 8H). IR (cm-1, KBr): 3405 (m), 3361(m), 2916 (s), 2900 (s), 2844 (m), 1659 (s), 1541 (s), 1504 (m). The title compound was synthesized as for the procedure described for example 101 using intermediate 7 (100 mg, 0.32 mmol), DMF (2 ml), triethylamine (0.05 ml, 0.35 mmol), BOP reagent ( 151 mg, 0.34 mmol) and benzylamine (39 µl, 0.35 mmol) to give the title compound (70 mg, 55%). P.F .: 137-139 ° C. 1 H NMR (δ ppm, CDCl 3): 7.517.21 (m, 11 H); 4.58 (d, J = 5.7, 2H); 4.03 (t a, J = 5, 1H); 3.03 (t a, J = 4.3, 1H); 2.20 (s a, 2H); 2.08-1.98 (m, 2H); 1.98-1.76 (m, 8H). IR (cm-1, KBr): 3405 (m), 3361 (m), 2916 (s), 2900 (s), 2844 (m), 1659 (s), 1541 (s), 1504 (m).

Ejemplo 171 Example 171

N(7)-fenil-6,7-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-5-dien-5-il-piperidino-metanona N (7) -phenyl-6,7-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8) -5-dien-5-yl-piperidine-methanone

El compuesto del título se sintetizó como para el procedimiento descrito para el ejemplo 101 usando el intermedio 7 (100 mg, 0,32 mmol), DMF (2 ml), trietilamina (0,05 ml, 0,35 mmol), reactivo BOP (151 mg, 0,34 mmol) y piperidina (36 µl, 0,35 mmol) para dar el compuesto del título (50 mg, 50%). P.F.: 123-125 ºC. RMN 1H (δ ppm, CDCl3): 7,497,35 (m, 5 H); 3,71 (s a, 2H); 3,57 (t, J = 5,4, 2H); 3,11 (s a, 1H); 3,05 (s a, 1H); 2,21 (s a, 2H); 2,04-1,74 (m, 10H); 1,70-1,51 (m, 8H). IR (cm-1, KBr): 2916 (s), 2845 (m), 1630 (s), 1597 (m), 1500 (m). The title compound was synthesized as for the procedure described for example 101 using intermediate 7 (100 mg, 0.32 mmol), DMF (2 ml), triethylamine (0.05 ml, 0.35 mmol), BOP reagent (151 mg, 0.34 mmol) and piperidine (36 µl, 0.35 mmol) to give the title compound (50 mg, 50%). P.F .: 123-125 ° C. 1 H NMR (δ ppm, CDCl 3): 7,497.35 (m, 5 H); 3.71 (s a, 2H); 3.57 (t, J = 5.4, 2H); 3.11 (s a, 1 H); 3.05 (s at, 1 H); 2.21 (s at, 2H); 2.04-1.74 (m, 10H); 1.70-1.51 (m, 8H). IR (cm-1, KBr): 2916 (s), 2845 (m), 1630 (s), 1597 (m), 1500 (m).

Ejemplo 172 Example 172

N(7)-(4-Fluorobencil)-5-(2,4-diclorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7carboxamida N (7) - (4-Fluorobenzyl) -5- (2,4-dichlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 8 (100 mg, 0,28 mmol), DMF (1,0 ml), Et3N (41 µl, 0,29 mmol), reactivo BOP (123 mg, 0,28 mmol) y 4-fluorobencilamina (37 mg, 33 µl, 0,29 mmol) dio el compuesto del título (95 mg, 74%). P.F.: 68-70 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,54 (d, J = 2,4, 1H); 7,38-7,15 (m, 5H); 7,00 (t, J = 8,4, 2H); 4,53 (dd, J = 14,1, 5,7, 2H)); 3,98 (s a, 1H), 2,53 (s a, 1H); 2,18 (s a, 2H); 2,00-1,61 (m, 10H). IR (cm-1, KBr): 3415 (m), 3307 (m), 2913 (s), 2846 (m), 1667 (s), 1537 (s), 1509 (s), 1498 (s), 1441 (m), 1352 (m), 1220 (s), 1156 (m), 1088 (m), 1071 (m), 824 (s). EM (m/z): 484,1([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 8 (100 mg, 0.28 mmol), DMF (1.0 ml), Et3N (41 µl, 0.29 mmol), reagent BOP (123 mg, 0.28 mmol) and 4-fluorobenzylamine (37 mg, 33 µl, 0.29 mmol) gave the title compound (95 mg, 74%). P.F .: 68-70 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.54 (d, J = 2.4, 1H); 7.38-7.15 (m, 5H); 7.00 (t, J = 8.4, 2H); 4.53 (dd, J = 14.1, 5.7, 2H)); 3.98 (s at, 1 H), 2.53 (s at, 1 H); 2.18 (s at, 2H); 2.00-1.61 (m, 10H). IR (cm-1, KBr): 3415 (m), 3307 (m), 2913 (s), 2846 (m), 1667 (s), 1537 (s), 1509 (s), 1498 (s), 1441 (m), 1352 (m), 1220 (s), 1156 (m), 1088 (m), 1071 (m), 824 (s). MS (m / z): 484.1 ([M + H] +).

Ejemplo 173 Example 173

N(7)-Fenilamino-5-(2,4-diclorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxamida N (7) -Phenylamino-5- (2,4-dichlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 8 (100 mg, 0,28 mmol), DMF (1,0 ml), Et3N (41 µl, 0,29 mmol), reactivo BOP (123 mg, 0,29 mmol) y fenilhidrazina (29 µl, 0,29 mmol) dio el compuesto del título (80 mg, 65%). P.F.: 162-163 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,53 (s, 1H); 7,59 (d, J = 2,4, 1H); 7,42 (dd, J = 8,4, 2,1, 1H); 7,35 (d, J = 8,4, 1H); 7,22 (t, J = 8,4, 2H); 6,95 (d, J = 8,4, 2H); 6,89 (t, J = 7,2, 1H); 3,87 (s a, 1H), 2,57 (s a, 1H); 2,18 (s a, 2H); 2,00-1,67 (m, 10H). IR (cm-1, KBr): 3292 (m), 2911 (s), 2845 (m), 1670 (s), 1603 (m), 1566 (m), 1525 (m), 1496 (s), 1477 (m), 1441 (m), 1351 (m), 1232 (m), 1219 (m), 1133 (m), 1121 (m), 1104 (m), 1086 (m), 887(m) 825 (m). EM (m/z) 467,8 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 8 (100 mg, 0.28 mmol), DMF (1.0 ml), Et3N (41 µl, 0.29 mmol), reagent BOP (123 mg, 0.29 mmol) and phenylhydrazine (29 µl, 0.29 mmol) gave the title compound (80 mg, 65%). P.F .: 162-163 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 8.53 (s, 1H); 7.59 (d, J = 2.4, 1H); 7.42 (dd, J = 8.4, 2.1, 1H); 7.35 (d, J = 8.4, 1H); 7.22 (t, J = 8.4, 2H); 6.95 (d, J = 8.4, 2H); 6.89 (t, J = 7.2, 1H); 3.87 (s at, 1 H), 2.57 (s at, 1 H); 2.18 (s at, 2H); 2.00-1.67 (m, 10H). IR (cm-1, KBr): 3292 (m), 2911 (s), 2845 (m), 1670 (s), 1603 (m), 1566 (m), 1525 (m), 1496 (s), 1477 (m), 1441 (m), 1351 (m), 1232 (m), 1219 (m), 1133 (m), 1121 (m), 1104 (m), 1086 (m), 887 (m) 825 ( m). MS (m / z) 467.8 ([M + H] +).

Ejemplo 174 Example 174

N(7)-(2-Clorofenilamino)-5-(2,4-diclorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7carboxamida N (7) - (2-Chlorophenylamino) -5- (2,4-dichlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 8 (100 mg, 0,27 mmol), DMF (1,0 ml), Et3N (94 µl, 0,66 mmol), reactivo BOP (129 mg, 0,29 mmol) y clorhidrato de 2clorofenilhidrazina (52 mg, 0,29 mmol) dio el compuesto del título (88 mg, 66%). P.F.: 110 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,54 (s, 1H); 7,59 (d, J = 2,1, 1H); 7,42 (dd, J =8,4, 2,4, 1H); 7,34 (d, J = 8,4, 1H); 7,28 (dd, J = 8,1, 1,6, 1H); 7,15 (td, J = 8,1, 1,6, 1H); 7,04 (dd, J = 8,1, 1,5, 1H); 6,82 (td, J = 8,1, 1,5, 1H); 6,55 (s a, 1H); 3,87 (t a, J = 5,1, 1H); 2,58 (t a, J = 5,1, 1H); 2,18 (s a, 2H); 2,05-1,63 (m, 8H); 1,35-1,20 (m, 2H). IR (cm-1, KBr): 3217 (m), 2916 (s), 2847 (m), 1678 (s), 1668 (s), 1595 (m), 1498 (s), 1475 (s), 1441 (s), 1361 (m), 1232 (m), 1218 (m), 1133 (m), 1106 (m), 1084 (m), 1063 (m), 937 (w), 826 (m). EM (m/z) 501,0 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 8 (100 mg, 0.27 mmol), DMF (1.0 ml), Et3N (94 µl, 0.66 mmol), reagent BOP (129 mg, 0.29 mmol) and 2-chlorophenylhydrazine hydrochloride (52 mg, 0.29 mmol) gave the title compound (88 mg, 66%). P.F .: 110 ºC. 1H NMR (δ ppm, CDCl3, 300 MHz): 8.54 (s, 1H); 7.59 (d, J = 2.1, 1H); 7.42 (dd, J = 8.4, 2.4, 1H); 7.34 (d, J = 8.4, 1H); 7.28 (dd, J = 8.1, 1.6, 1H); 7.15 (td, J = 8.1, 1.6, 1H); 7.04 (dd, J = 8.1, 1.5, 1H); 6.82 (td, J = 8.1, 1.5, 1H); 6.55 (s a, 1 H); 3.87 (t a, J = 5.1, 1H); 2.58 (t a, J = 5.1, 1H); 2.18 (s at, 2H); 2.05-1.63 (m, 8H); 1.35-1.20 (m, 2H). IR (cm-1, KBr): 3217 (m), 2916 (s), 2847 (m), 1678 (s), 1668 (s), 1595 (m), 1498 (s), 1475 (s), 1441 (s), 1361 (m), 1232 (m), 1218 (m), 1133 (m), 1106 (m), 1084 (m), 1063 (m), 937 (w), 826 (m). MS (m / z) 501.0 ([M + H] +).

Ejemplo 175 Example 175

N(7)-(2,4-Diclorofenilamino)-5-(2,4-diclorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-di-eno-7N (7) - (2,4-Dichlorophenylamino) -5- (2,4-dichlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-di-eno- 7 carboxamida carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 8 (100 mg, 0,27 mmol), DMF (1,0 ml), Et3N (82 µl, 0,59 mmol), reactivo BOP (123 mg, 0,28 mmol) y clorhidrato de 2,4diclorofenilhidrazina (62 mg, 0,29 mmol) dio el compuesto del título (95 mg, 67%). P.F.: 153-156 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,52 (s a, 1H); 7,59 (d, J = 1,8, 1H); 7,42 (dd, J = 8,1, 1,8, 1H); 7,36-7,24 (m, 2H); 7,12 (dd, J = 8,7, 2,4, 1H); 6,97 (d, J = 8,7, 1H); 6,48 (s a, 1H); 3,85 (s a, 1H); 2,57 (s a, 1H); 2,18 (s a, 2H); 2,00-1,60 (m, 10H). IR (cm-1, KBr): 3307 (m), 2920 (s), 2905 (s); 2848 (m), 1682 (s), 1495 (s), 1469 (s), 1388 (m), 1353 (m), 890 (m), 864 (m). EM (m/z): 535,1 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 8 (100 mg, 0.27 mmol), DMF (1.0 ml), Et3N (82 µl, 0.59 mmol), reagent BOP (123 mg, 0.28 mmol) and 2,4-dichlorophenylhydrazine hydrochloride (62 mg, 0.29 mmol) gave the title compound (95 mg, 67%). P.F .: 153-156 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 8.52 (s at, 1H); 7.59 (d, J = 1.8, 1H); 7.42 (dd, J = 8.1, 1.8, 1H); 7.36-7.24 (m, 2H); 7.12 (dd, J = 8.7, 2.4, 1H); 6.97 (d, J = 8.7, 1H); 6.48 (s a, 1 H); 3.85 (s a, 1 H); 2.57 (s at, 1 H); 2.18 (s at, 2H); 2.00-1.60 (m, 10H). IR (cm-1, KBr): 3307 (m), 2920 (s), 2905 (s); 2848 (m), 1682 (s), 1495 (s), 1469 (s), 1388 (m), 1353 (m), 890 (m), 864 (m). MS (m / z): 535.1 ([M + H] +).

Ejemplo 176 Example 176

N(7)-(2-Bromofenilamino)-5-(2,4-diclorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7carboxamida N (7) - (2-Bromophenylamino) -5- (2,4-dichlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 8 (100 mg, 0,27 mmol), DMF (1,0 ml), Et3N (82 µl, 0,59 mmol), reactivo BOP (123 mg, 0,28 mmol) y clorhidrato de 2bromofenil-hidrazina (62 mg, 0,29 mmol) produjo el compuesto del título (70 mg, 48%). P.F.: 196-199 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,56 (s a, 1H); 7,59 (d, J = 1,8, 1H); 7,45 (t a, J = 8,1, 2H); 7,41 (d, J = 8,1, 1H); 7,19 (t, J = 7,8, 1H); 7,02 (d, J = 7,8, 1H); 6,75 (t, J = 7,8, 1H); 6,52 (s a, 1H); 3,87 (s a, 1H); 2,57 (s a, 1H); 2,18 (s a, 2H); 2,001,60 (m, 8H); 1,30-1,26 (m, 2H). IR (cm-1, KBr): 3216 (m), 2915 (s), 2847 (m), 1685 (s), 1595 (m), 1566 (m), 1497 (s), 1441(m), 1387 (m), 1352 (m), 1263 (m), 1232 (m), 1218 (m), 1129 (m), 1105 (m), 1085 (m), 1062 (m), 1019 (m), 936 (w), 889 (w), 866 (w), 825 (m). EM (m/z): 545,1 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 8 (100 mg, 0.27 mmol), DMF (1.0 ml), Et3N (82 µl, 0.59 mmol), reagent BOP (123 mg, 0.28 mmol) and 2-bromophenyl hydrazine hydrochloride (62 mg, 0.29 mmol) produced the title compound (70 mg, 48%). P.F .: 196-199 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 8.56 (s at, 1H); 7.59 (d, J = 1.8, 1H); 7.45 (t a, J = 8.1, 2H); 7.41 (d, J = 8.1, 1H); 7.19 (t, J = 7.8, 1H); 7.02 (d, J = 7.8, 1H); 6.75 (t, J = 7.8, 1H); 6.52 (s a, 1 H); 3.87 (s at, 1 H); 2.57 (s at, 1 H); 2.18 (s at, 2H); 2,001.60 (m, 8H); 1.30-1.26 (m, 2H). IR (cm-1, KBr): 3216 (m), 2915 (s), 2847 (m), 1685 (s), 1595 (m), 1566 (m), 1497 (s), 1441 (m), 1387 (m), 1352 (m), 1263 (m), 1232 (m), 1218 (m), 1129 (m), 1105 (m), 1085 (m), 1062 (m), 1019 (m), 936 (w), 889 (w), 866 (w), 825 (m). MS (m / z): 545.1 ([M + H] +).

Ejemplo 177 Example 177

N(7)-(N’,N’-Difenilamizo)-5-(2,4-diclorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7carboxamida N (7) - (N ', N'-Diphenylamizo) -5- (2,4-dichlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene- 7carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 8 (100 mg, 0,27 mmol), DMF (1,0 ml), Et3N (74 µl, 0,53 mmol), reactivo BOP (123 mg, 0,28 mmol) y clorhidrato de N,Ndifenilhidrazina (141 mg, 0,64 mmol) dio el compuesto del título (85 mg, 59%). P.F.: 176-180 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,96 (s, 1H); 7,57 (d, J = 2,1, 1H); 7,40 (dd, J = 8,4, 2,1, 1H); 7,35-7,21 (m, 9H); 7,01 (t a, J = 8,4, 2H); 3,91 (s a, 1H), 2,57 (s a, 1H); 2,18 (s a; 2H); 2,00 -1,73 (m, 10H). IR (cm-1, KBr): 3392 (m), 2915 (m), 2881 (m), 2845 (m), 1686 (s), 1590 (m), 1493 (s), 1462 (m), 1386 (m), 1354 (m), 1340(m), 1311 (m), 1292 (m), 1273(m), 1204 (m), 1150 (m), 1102 (m), 1088 (m), 1076 (w), 1028 (w), 866 (w), 822 (w). EM (m/z): 543,3 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 8 (100 mg, 0.27 mmol), DMF (1.0 ml), Et3N (74 µl, 0.53 mmol), reagent BOP (123 mg, 0.28 mmol) and N, N-diphenylhydrazine hydrochloride (141 mg, 0.64 mmol) gave the title compound (85 mg, 59%). P.F .: 176-180 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 8.96 (s, 1H); 7.57 (d, J = 2.1, 1H); 7.40 (dd, J = 8.4, 2.1, 1H); 7.35-7.21 (m, 9H); 7.01 (t a, J = 8.4, 2H); 3.91 (s at, 1 H), 2.57 (s at, 1 H); 2.18 (s at; 2H); 2.00 -1.73 (m, 10H). IR (cm-1, KBr): 3392 (m), 2915 (m), 2881 (m), 2845 (m), 1686 (s), 1590 (m), 1493 (s), 1462 (m), 1386 (m), 1354 (m), 1340 (m), 1311 (m), 1292 (m), 1273 (m), 1204 (m), 1150 (m), 1102 (m), 1088 (m), 1076 (w), 1028 (w), 866 (w), 822 (w). MS (m / z): 543.3 ([M + H] +).

Ejemplo 178 Example 178

N(7)-(2-Feniletil)-5-(2,4-diclorofenil)-5,6-diazatetraciclo[7.3.1.13,11 .04,8]tetradeca-4(8),6-dieno-7-carboxamida N (7) - (2-Phenylethyl) -5- (2,4-dichlorophenyl) -5,6-diazatetracycle [7.3.1.13.11 .04.8] tetradeca-4 (8), 6-diene-7- carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 8 (100 mg, 0,28 mmol), DMF (1,0 ml), Et3N (41 µl, 0,29 mmol), reactivo BOP (123 mg, 0,29 mmol) y fenetilamina (37 µl, 0,29 mmol) dio el compuesto del título (90 mg, 71%). P.F.: 63-66 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,56 (d, J = 2,1, 1H); 7,38 (dd, J = 8,4, 2,1, 1H); 7,40-7,18 (m, 6H); 7,02 (t, J = 7,2, 1H); 3,97 (s a, 1H); 3,61 (c, J = 7,2, 2H); 2,90 (t, J = 8,1, 2H); 2,54 (s a, 1H); 2,18 (s a, 2H); 2,00-1,65 (m, 10H). IR (cm-1, KBr): 3413 (m), 2912 (s), 2845 (m), 1667 (s), 1535 (s), 1497 (s), 1478 (s), 1352 (m), 1233 (m), 1219 (m), 1162 (m), 1103 (m), 1088 (m), 996 (m), 866 (w), 699 (m). EM (m/z): 480,1 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 8 (100 mg, 0.28 mmol), DMF (1.0 ml), Et3N (41 µl, 0.29 mmol), reagent BOP (123 mg, 0.29 mmol) and phenethylamine (37 µl, 0.29 mmol) gave the title compound (90 mg, 71%). P.F .: 63-66 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.56 (d, J = 2.1, 1H); 7.38 (dd, J = 8.4, 2.1, 1H); 7.40-7.18 (m, 6H); 7.02 (t, J = 7.2, 1H); 3.97 (s at, 1 H); 3.61 (c, J = 7.2, 2H); 2.90 (t, J = 8.1, 2H); 2.54 (s at, 1 H); 2.18 (s at, 2H); 2.00-1.65 (m, 10H). IR (cm-1, KBr): 3413 (m), 2912 (s), 2845 (m), 1667 (s), 1535 (s), 1497 (s), 1478 (s), 1352 (m), 1233 (m), 1219 (m), 1162 (m), 1103 (m), 1088 (m), 996 (m), 866 (w), 699 (m). MS (m / z): 480.1 ([M + H] +).

Ejemplo 179 Example 179

N(7)-Bencil-5-(2’,4’-diclorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-6-dieno-7-carboxamida N (7) -Benzyl-5- (2 ’, 4’-dichlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8) -6-diene-7-carboxamide

Una solución del intermedio 8 (100 mg, 0,27 mmol) en DMF (2 ml) se trató con reactivo BOP (123 mg, 0,28 mmol) y trietilamina (41 µl, 0,29 mmol) a temperatura ambiente durante 15 minutos, periodo después del cual se añadió bencilamina (32 µl, 0,29 mmol) a la mezcla y se agitó a temperatura ambiente durante 1 h. La mezcla se vertió en agua y el precipitado formado se recogió por filtración, se secó y se purificó por cromatografía ultrarrápida para obtener el compuesto del título puro (90 mg, 73%). P.F.: 65-66 ºC. 1H RMN(δ ppm, CDCl3): 7,54 (d, J = 2,4, 1H); 7,40-7,18 (m, 8H); 4,62 (dd, J = 14,7, 6,0, 1H); 4,52 (dd, J = 14,7, 6,0, 1H); 4,0 (t, J = 5,4, 1H); 2,53 (s a, 1H); 2,18 (s a, 2H); 1,05-2,10 (m, 10H). IR (cm-1, KBr): 3413 (m), 2914 (s), 2846 (m), 1664 (s), 1534 (s). A solution of intermediate 8 (100 mg, 0.27 mmol) in DMF (2 ml) was treated with BOP reagent (123 mg, 0.28 mmol) and triethylamine (41 µl, 0.29 mmol) at room temperature for 15 minutes, period after which benzylamine (32 µl, 0.29 mmol) was added to the mixture and stirred at room temperature for 1 h. The mixture was poured into water and the precipitate formed was collected by filtration, dried and purified by flash chromatography to obtain the pure title compound (90 mg, 73%). P.F .: 65-66 ° C. 1 H NMR (δ ppm, CDCl 3): 7.54 (d, J = 2.4, 1H); 7.40-7.18 (m, 8H); 4.62 (dd, J = 14.7, 6.0, 1H); 4.52 (dd, J = 14.7, 6.0, 1H); 4.0 (t, J = 5.4, 1H); 2.53 (s at, 1 H); 2.18 (s at, 2H); 1.05-2.10 (m, 10H). IR (cm-1, KBr): 3413 (m), 2914 (s), 2846 (m), 1664 (s), 1534 (s).

Ejemplo 180 Example 180

N(7)-piperidino-5-(2’,4’-diclorofenil)-5,6-diazatetraciclo[7.3.1.13,11.0 4,8] tetradeca-4(8),6-dieno-7-carboxamida N (7) -piperidino-5- (2 ’, 4’-dichlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.0 4.8] tetradeca-4 (8), 6-diene-7-carboxamide

El compuesto del título se sintetizó como para el procedimiento descrito para el ejemplo 101 usando intermedio 8 (160 mg, 0,42 mmol), DMF (2 ml), trietilamina (0,06 ml, 0,41 mmol), reactivo BOP (187 mg, 0,42 mmol) y 1aminopiperidina (0,05 ml, 0,46 mmol) para dar el compuesto del título (106 mg, 52%). P.F.: 101-104 ºC . RMN 1H (δ ppm, CDCl3): 7,58 (s a, 1H); 7,56 (d, J = 2,1, 1H); 7,38 (dd, J = 8,7, 2,4, 1H); 7,31 (d, J = 8,7, 1H); 3,96 (t a, J = 5,4, 1 H); 2,84 (s a, 4H); 2,53 (s a, 1H); 2,17 (s a, 2H); 1,05-2,10 (m, 14H); 1,72-1,9 (m, 2H). IR (cm-1, KBr): 3413 (m), 2914 (s), 2846 (m), 1664 (s), 1534 (s). The title compound was synthesized as for the procedure described for example 101 using intermediate 8 (160 mg, 0.42 mmol), DMF (2 ml), triethylamine (0.06 ml, 0.41 mmol), BOP reagent ( 187 mg, 0.42 mmol) and 1aminopiperidine (0.05 ml, 0.46 mmol) to give the title compound (106 mg, 52%). P.F .: 101-104 ° C. 1H NMR (δ ppm, CDCl3): 7.58 (s a, 1H); 7.56 (d, J = 2.1, 1H); 7.38 (dd, J = 8.7, 2.4, 1H); 7.31 (d, J = 8.7, 1H); 3.96 (t a, J = 5.4, 1 H); 2.84 (s at, 4H); 2.53 (s at, 1 H); 2.17 (s a, 2H); 1.05-2.10 (m, 14H); 1.72-1.9 (m, 2H). IR (cm-1, KBr): 3413 (m), 2914 (s), 2846 (m), 1664 (s), 1534 (s).

Ejemplo 181 Example 181

N(7)-(2,4-Diclorofenilamino)-5-(2-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7carboxamida N (7) - (2,4-Dichlorophenylamino) -5- (2-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 9 (100 mg, 0,29 mmol), DMF (1,0 ml), Et3N (45 µl, 0,32 mmol), reactivo BOP (136 mg, 0,31 mmol) y clorhidrato de 2,4diclorofenilhidrazina (69 mg, 0,32 mmol) dio el compuesto del título (95 mg, 65%). P.F.: 233-240 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,60 (s, 1H); 7,57 (dd, J = 7,6, 1,6, 2H); 7,48 (td, J = 8,8, 2,4, 1H); 7,47-7,37 (m, 2H); 7,29 (d, J = 2,4, 1H); 7,11 (dd, J = 8,8, 2,4, 1H); 6,98 (d, J = 8,8, 1H); 3,87 (t a, J = 5,6, 1H); 2,60 (t a, J = 5,6, 1H); 2,20 (s a, 2H); 2,10-1,60 (m, 10H). IR (cm-1, KBr): 3386 (m), 3343 (m), 2907 (m), 2870 (m), 2847 (m), 1694 (s), 1497 (m), 1469 (m), 1349 (m), 1277 (m), 1259 (m), 1232 (m), 1216 (m), 1087 (m), 1058 (m), 1014 (m), 859 (m). EM (m/z): 501,1 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 9 (100 mg, 0.29 mmol), DMF (1.0 ml), Et3N (45 µl, 0.32 mmol), reagent BOP (136 mg, 0.31 mmol) and 2,4-dichlorophenylhydrazine hydrochloride (69 mg, 0.32 mmol) gave the title compound (95 mg, 65%). P.F .: 233-240 ° C. 1 H NMR (δ ppm, CDCl 3, 300 MHz): 8.60 (s, 1 H); 7.57 (dd, J = 7.6, 1.6, 2H); 7.48 (td, J = 8.8, 2.4, 1H); 7.47-7.37 (m, 2H); 7.29 (d, J = 2.4, 1H); 7.11 (dd, J = 8.8, 2.4, 1H); 6.98 (d, J = 8.8, 1H); 3.87 (t a, J = 5.6, 1H); 2.60 (t a, J = 5.6, 1H); 2.20 (s a, 2H); 2.10-1.60 (m, 10H). IR (cm-1, KBr): 3386 (m), 3343 (m), 2907 (m), 2870 (m), 2847 (m), 1694 (s), 1497 (m), 1469 (m), 1349 (m), 1277 (m), 1259 (m), 1232 (m), 1216 (m), 1087 (m), 1058 (m), 1014 (m), 859 (m). MS (m / z): 501.1 ([M + H] +).

Ejemplo 182 Example 182

N(7)-Bencil-5-(2-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-6-dieno-7-carboxamida N (7) -Benzyl-5- (2-chlorophenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8) -6-diene-7-carboxamide

El compuesto del título se sintetizó como para el procedimiento descrito para el ejemplo 101 usando intermedio 9 (100 mg, 0,29 mmol), DMF (2 ml), trietilamina (46 µl, 0,32 mmol), reactivo BOP (136 mg, 0,32 mmol) y bencilamina (36 µl, 0,32 mmol) para dar el compuesto del título (83 mg, 65%). P.F.: 159-161 ºC. RMN 1H (δ ppm, CDCl3): 7,52 (d, J = 7,5, 1H); 7,47-7,24 (m, 8 H); 4,62 (dd, J =15,0, 6,0, 1H); 4,51 (dd, J = 15,0, 6,0, 1H); 4,01 (s a, 1H); 2,55 (s a, 1H), 2,18 (s a, 2H); 210-1,54 (m, 10 H). IR (cm-1, KBr): 3412 (m), 3427(m), 2909 (s), 2845 (m), 1672 (s), 1567 (m), 1524 (s), 1498 (s), 1474 (s); 1455(s). The title compound was synthesized as for the procedure described for example 101 using intermediate 9 (100 mg, 0.29 mmol), DMF (2 ml), triethylamine (46 µl, 0.32 mmol), BOP reagent (136 mg , 0.32 mmol) and benzylamine (36 µl, 0.32 mmol) to give the title compound (83 mg, 65%). P.F .: 159-161 ° C. 1H NMR (δ ppm, CDCl3): 7.52 (d, J = 7.5, 1H); 7.47-7.24 (m, 8 H); 4.62 (dd, J = 15.0, 6.0, 1H); 4.51 (dd, J = 15.0, 6.0, 1H); 4.01 (s at, 1 H); 2.55 (s at, 1H), 2.18 (s at, 2H); 210-1.54 (m, 10 H). IR (cm-1, KBr): 3412 (m), 3427 (m), 2909 (s), 2845 (m), 1672 (s), 1567 (m), 1524 (s), 1498 (s), 1474 (s); 1455 (s).

Ejemplo 183 Example 183

N(7)-Ciclohexil-5-(2-clorofenil)-5,6-diazatetraciclo[7.3.1.13,17.04,8]tetradeca-4(8)-6-dieno-7-carboxamida N (7) -Cyclohexyl-5- (2-chlorophenyl) -5,6-diazatetracycle [7.3.1.13.17.04.8] tetradeca-4 (8) -6-diene-7-carboxamide

El compuesto del título se sintetizó como para el procedimiento descrito para el ejemplo 101 usando intermedio 9 (100 mg, 0,29 mmol), DMF (2 ml), trietilamina (45 µl, 0,32 mmol), reactivo BOP (136 mg, 0,32 mmol) y ciclohexilamina (37 µl, 0,32 mmol) para dar el compuesto del título (95 mg, 77%). P.F.: 218-220 ºC. RMN-1H (δ ppm, CDCl3): 7,55-7,52 (m, 1H); 7,42-7,35 (m, 3 H); 6,80 (d a, J = 8,1, 1H); 4,00 (t a, J = 5,4, 1H); 3,97-3,83 (m, 1H); 2,54 (s a, 1H); 2,17 (s a, 2H);1,99 (s a, 6H); 1,92-1,52 (m, 8H); 1,55-1,05 (m, 6H). IR (cm-1, KBr): 3409 (m), 2921(s), 2904(s), 2849(m), 1667(s), 1567(m), 1527(s), 1494(s), 1479(s). The title compound was synthesized as for the procedure described for example 101 using intermediate 9 (100 mg, 0.29 mmol), DMF (2 ml), triethylamine (45 µl, 0.32 mmol), BOP reagent (136 mg , 0.32 mmol) and cyclohexylamine (37 µl, 0.32 mmol) to give the title compound (95 mg, 77%). P.F .: 218-220 ° C. 1H NMR (δ ppm, CDCl3): 7.55-7.52 (m, 1H); 7.42-7.35 (m, 3 H); 6.80 (d a, J = 8.1, 1H); 4.00 (t a, J = 5.4, 1H); 3.97-3.83 (m, 1 H); 2.54 (s at, 1 H); 2.17 (s at, 2H); 1.99 (s at, 6H); 1.92-1.52 (m, 8H); 1.55-1.05 (m, 6H). IR (cm-1, KBr): 3409 (m), 2921 (s), 2904 (s), 2849 (m), 1667 (s), 1567 (m), 1527 (s), 1494 (s), 1479 (s)

Ejemplo 184 Example 184

N(7)-piperidino-5-(2’-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8tetetradeca-4(8)-6-dieno-7-carboxamida N (7) -piperidino-5- (2’-chlorophenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8tetetradeca-4 (8) -6-diene-7-carboxamide

El compuesto del título se sintetizó como para el procedimiento descrito para el ejemplo 101 usando el intermedio 9 (100 mg, 0,29 mmol), DMF (2 ml), trietilamina (45 µl, 0,32 mmol), reactivo BOP (136 mg, 0,32 mmol) y 1aminopiperidina (35 µl, 0,32 mmol) para dar el compuesto del título (90 mg, 72%). P.F.: 251-254 ºC. RMN 1H (δ ppm, CDCl3): 7,62 (s a, 1H); 7,54 (d, J = 8,7, 1H); 7,53-7,35 (m, 3H); 3,98 (s a, 1H); 2,84 (t, J = 4,8, 4H); 2,54 (s a, 1H), 2,17 (s a, 2H); 1,98 (t, J = 12,6, 4H); 1,93-1,50 (m, 10H); 1,44-1,34 (m, 2H). IR (cm-1, KBr): 3314 (m), 2905 (s), 2844 (m), 2804 (m), 1686 (s), 1567 (m), 1525 (s), 1492 (s), 1480 (s). The title compound was synthesized as for the procedure described for example 101 using intermediate 9 (100 mg, 0.29 mmol), DMF (2 ml), triethylamine (45 µl, 0.32 mmol), BOP reagent (136 mg, 0.32 mmol) and 1aminopiperidine (35 µl, 0.32 mmol) to give the title compound (90 mg, 72%). P.F .: 251-254 ° C. 1H NMR (δ ppm, CDCl3): 7.62 (s a, 1H); 7.54 (d, J = 8.7, 1H); 7.53-7.35 (m, 3H); 3.98 (s at, 1 H); 2.84 (t, J = 4.8, 4H); 2.54 (s at, 1H), 2.17 (s at, 2H); 1.98 (t, J = 12.6, 4H); 1.93-1.50 (m, 10H); 1.44-1.34 (m, 2H). IR (cm-1, KBr): 3314 (m), 2905 (s), 2844 (m), 2804 (m), 1686 (s), 1567 (m), 1525 (s), 1492 (s), 1480 (s)

Ejemplo 185 Example 185

N7-(2-Clorobencil)-5-(5-cloro-2piridil)-5,6-diazatetraciclo[7.3.1.13,11.04,8] tetradeca-4(8),6-dieno-7-carboxamida N7- (2-Chlorobenzyl) -5- (5-chloro-2-pyridyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 10 (100 mg, 0,29 mmol), DMF (1,0 ml), Et3N (40 µl, 0,29 mmol), reactivo BOP (128 mg, 0,29 mmol) y 2-clorobencilamina (31 mg, 0,29 mmol) produjo el compuesto del título (64 mg, 49%). P.F.: 187-189 ºC. RMN 1H (δ ppm, DMSO-d6, 300 MHz): 8,81 (t, J = 6,3, 1H), 8,60 (d, J = 2,6, 1H); 8,19 (dd, J = 8,6, 2,6, 1H); 7,96 (d, 8,6, 1H); 7,467,42 (m, 1H); 7,38-7,27 (m, 3H); 4,48 (d, J = 6,0, 2H); 4,04 (s, 1H); 3,78 (m, 1H); 2,14 (s a, 2H); 1,95-1,68 (m, 10H). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 10 (100 mg, 0.29 mmol), DMF (1.0 ml), Et3N (40 µl, 0.29 mmol), reagent BOP (128 mg, 0.29 mmol) and 2-chlorobenzylamine (31 mg, 0.29 mmol) produced the title compound (64 mg, 49%). P.F .: 187-189 ° C. 1H NMR (δ ppm, DMSO-d6, 300 MHz): 8.81 (t, J = 6.3, 1H), 8.60 (d, J = 2.6, 1H); 8.19 (dd, J = 8.6, 2.6, 1H); 7.96 (d, 8.6, 1H); 7,467.42 (m, 1 H); 7.38-7.27 (m, 3H); 4.48 (d, J = 6.0, 2H); 4.04 (s, 1 H); 3.78 (m, 1 H); 2.14 (s a, 2H); 1.95-1.68 (m, 10H).

Ejemplo 186 Example 186

N(7)-Bencil-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-6-dieno-7-carboxamida: N (7) -Benzyl-5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8) -6-diene-7-carboxamide:

El compuesto del título se sintetizó como para el procedimiento descrito para el ejemplo 101 usando intermedio 11 (100 mg, 0,43 mmol), DMF (1 ml), trietilamina (0,06 ml, 0,43 mmol), reactivo BOP (190 mg, 0,43 mmol) y bencilamina (0,05 ml, 0,43 mmol) para dar el compuesto del título (96 mg, 69%). P.F.: 218-219 ºC. RMN 1H (δ ppm, DMSO-d6): 12,70 (s a, 1H); 8,44 (s a, 1H); 7,30 (m, 5H); 4,36 (s a, 2H); 3,71 (s a, 1H); 2,97 (s a, 1H); 2,10 (s a, 2H); 1,91 (s a, 4H); 1,77 (s a, 2H); 1,65 (t, J = 13,2, 110H). IR (cm-1, KBr):3434 (s), 2924 (s), 2854 (m), 1634 (m). The title compound was synthesized as for the procedure described for example 101 using intermediate 11 (100 mg, 0.43 mmol), DMF (1 ml), triethylamine (0.06 ml, 0.43 mmol), BOP reagent ( 190 mg, 0.43 mmol) and benzylamine (0.05 ml, 0.43 mmol) to give the title compound (96 mg, 69%). P.F .: 218-219 ° C. 1H NMR (δ ppm, DMSO-d6): 12.70 (s at, 1H); 8.44 (s a, 1 H); 7.30 (m, 5 H); 4.36 (s a, 2H); 3.71 (s a, 1 H); 2.97 (s at, 1 H); 2.10 (s a, 2H); 1.91 (s a, 4H); 1.77 (s a, 2H); 1.65 (t, J = 13.2, 110H). IR (cm-1, KBr): 3434 (s), 2924 (s), 2854 (m), 1634 (m).

Ejemplo 187 Example 187

N(7)-Piperidino-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-6-dieno-7 carboxamida N (7) -Piperidino-5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8) -6-diene-7 carboxamide

Una solución del intermedio 11 (160 mg, 0,68 mmol) en DMF (3 ml) se trató a temperatura ambiente con EPCI (198 mg, 1,02 mmol), HOBt (93 mg, 0,68 mmol), trietilamina (0,19 ml, 1,36 mmol), DMAP (8 mg) y 1-aminopiperidina (0,081 mg, 0,68 mmol) durante 16h. La dilución de la mezcla con agua, la extracción en acetato de etilo, el secado sobre Na2SO4, la evaporación y la purificación por cromatografía ultrarrápida dio el compuesto del título (134 mg, 63%). P.F.: 295-297 ºC. RMN 1H (δ ppm, DMSO-d6): 12,61 (s a, 1H); 8,61 (s a, 1H); 3,65 (s a, 1H); 3,00 (s a, 1H); 2,10 (s a, 2H); 1,99-1,51 (m, 14H); 1,33 (s a, 2H). IR (cm-1, KBr): 3314 (m), 3199(s), 3155 (m); 3085 (m), 3003 (m), 2907 (s), 2843 (s), 2805 (m),1653 (s), 1590 (m), 1543 (m), 1509 (m). A solution of intermediate 11 (160 mg, 0.68 mmol) in DMF (3 ml) was treated at room temperature with EPCI (198 mg, 1.02 mmol), HOBt (93 mg, 0.68 mmol), triethylamine ( 0.19 ml, 1.36 mmol), DMAP (8 mg) and 1-aminopiperidine (0.081 mg, 0.68 mmol) for 16h. Dilution of the mixture with water, extraction in ethyl acetate, drying over Na2SO4, evaporation and purification by flash chromatography gave the title compound (134 mg, 63%). P.F .: 295-297 ° C. 1H NMR (δ ppm, DMSO-d6): 12.61 (s a, 1H); 8.61 (s a, 1 H); 3.65 (s a, 1 H); 3.00 (s at, 1 H); 2.10 (s a, 2H); 1.99-1.51 (m, 14H); 1.33 (s at, 2H). IR (cm-1, KBr): 3314 (m), 3199 (s), 3155 (m); 3085 (m), 3003 (m), 2907 (s), 2843 (s), 2805 (m), 1653 (s), 1590 (m), 1543 (m), 1509 (m).

Ejemplo 188 Example 188

6,7-Diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-5-diet-5-il-piperidinonmetanona: 6,7-Diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8) -5-diet-5-yl-piperidinonmethanone:

El compuesto del título se sintetizó como para el procedimiento descrito para el ejemplo 101 usando el intermedio 11 (100 mg, 0,43 mmol), DMF (1 ml), trietilamina (0,06 ml, 0,43 mmol), reactivo BOP (190 mg, 0,43 mmol) y piperidina (43 µl, 0,43 mmol) para dar el compuesto del título (84 mg, 66%). P.F.: 263-264 ºC. RMN 1H (δ ppm, CDCl3): 3,57 (s a, 4H); 3,05 (s a, 1H); 2,92 (s a, 1H); 2,17 (s a, 2H); 2,10-1,50 (m, 16H). IR (cm-1, KBr): 3436 (m), 3198(s), 3155 (m); 2924 (s), 2905 (s), 2888 (s), 1607 (s), 1598 (s), 1583 (s). The title compound was synthesized as for the procedure described for example 101 using intermediate 11 (100 mg, 0.43 mmol), DMF (1 ml), triethylamine (0.06 ml, 0.43 mmol), BOP reagent (190 mg, 0.43 mmol) and piperidine (43 µl, 0.43 mmol) to give the title compound (84 mg, 66%). P.F .: 263-264 ° C. 1H NMR (δ ppm, CDCl3): 3.57 (s a, 4H); 3.05 (s at, 1 H); 2.92 (s at, 1 H); 2.17 (s a, 2H); 2.10-1.50 (m, 16H). IR (cm-1, KBr): 3436 (m), 3198 (s), 3155 (m); 2924 (s), 2905 (s), 2888 (s), 1607 (s), 1598 (s), 1583 (s).

Ejemplo 189a Example 189a

N(7)-Piperidino-6-metil-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-6-dieno-7-carboxamida N (7) -Piperidino-6-methyl-5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8) -6-diene-7-carboxamide

Una solución 0,27 M de KOH en etanol-agua 4:3 (3,5 ml) se añadió a una solución del intermedio 12a (123 mg, 0,45 mmol) y se sometió a reflujo durante 3 h. Después de la concentración de la mezcla a aprox. la mitad de su volumen inicial, se acidificó con HCl ac. 1 N y el sólido precipitado se filtró, se secó y se disolvió en DMF (3 ml). La solución se trató con DMAP (5 mg), EPCI (100 mg, 0,5 mmol), HOBt (47 mg, 0,35 mmol), 1-aminopiperidina (39 mg, 0,35 mmol) y trietilamina (0,08 ml, 0,56 mmol) a temperatura ambiente durante 15h. La dilución de la mezcla con agua, la extracción en acetato de etilo, el secado sobre Na2SO4 y la purificación por cromatografía ultrarrápida dio el compuesto del título (48 mg, 33%). P.F.: 188,9 ºC. RMN 1H (δ ppm, DMSO-d6): 6,27 (s a, 1H); 3,88 (s, 3H); 3,06-2,92 (m, 2H); 2,87 (t, J = 5,4, 4H); 2,15 (s a, 2H); 2,10-1,91 (m, 4H); 1,90-1,70 (10H); 1,55-1,40 (m, 2H). IR (cm-1, KBr): 3440 (a, m); 3227 (m), 2918(s), 2844 (s), 1636 (s), 1557 (m), 1532 (m). A 0.27 M solution of KOH in 4: 3 ethanol-water (3.5 ml) was added to a solution of intermediate 12a (123 mg, 0.45 mmol) and refluxed for 3 h. After concentration of the mixture at approx. half of its initial volume was acidified with ac HCl. 1 N and the precipitated solid was filtered, dried and dissolved in DMF (3 ml). The solution was treated with DMAP (5 mg), EPCI (100 mg, 0.5 mmol), HOBt (47 mg, 0.35 mmol), 1-aminopiperidine (39 mg, 0.35 mmol) and triethylamine (0, 08 ml, 0.56 mmol) at room temperature for 15h. Dilution of the mixture with water, extraction in ethyl acetate, drying over Na2SO4 and purification by flash chromatography gave the title compound (48 mg, 33%). P.F .: 188.9 ° C. 1H NMR (δ ppm, DMSO-d6): 6.27 (s at, 1H); 3.88 (s, 3 H); 3.06-2.92 (m, 2H); 2.87 (t, J = 5.4, 4H); 2.15 (s a, 2H); 2.10-1.91 (m, 4H); 1.90-1.70 (10H); 1.55-1.40 (m, 2H). IR (cm-1, KBr): 3440 (a, m); 3227 (m), 2918 (s), 2844 (s), 1636 (s), 1557 (m), 1532 (m).

Ejemplo 189b Example 189b

N(7)-Piperidino-5-metil-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-6-dieno-7-carboxamida N (7) -Piperidino-5-methyl-5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8) -6-diene-7-carboxamide

El compuesto del título se sintetizó como para el procedimiento descrito para el ejemplo 189a usando el intermedio 12b (173 mg, 0,63 mmol), etanol (2 ml), solución 0,27 M de KOH en etanol-agua 4:3 (3,5 ml), DMF (3 ml), DMAP (8 mg), EPCI (167 mg, 0,87 mmol), HOBt (78 mg, 0,58 mmol), 1-aminopiperidina (58 mg, 0,35 mmol) y trietilamina (0,13 ml, 0,93 mmol) para dar el compuesto del título en forma pura (148 mg, 72%). P.F.: 218,7 ºC. RMN 1H (δ ppm, DMSO-d6): 7,56 (s a, 1H); 3,89 (t, J = 5,4, 1H); 3,74(s, 3H); 2,97 (t, J = 5,1, 1H); 2,85 (t, J = 5,1, 4H); 2,162,00-1,88 (m, 4H); 1,90-1,66 (10H); 1,47-1,36 (m, 2H). The title compound was synthesized as for the procedure described for example 189a using intermediate 12b (173 mg, 0.63 mmol), ethanol (2 ml), 0.27 M solution of KOH in ethanol-water 4: 3 ( 3.5 ml), DMF (3 ml), DMAP (8 mg), EPCI (167 mg, 0.87 mmol), HOBt (78 mg, 0.58 mmol), 1-aminopiperidine (58 mg, 0.35 mmol) and triethylamine (0.13 ml, 0.93 mmol) to give the title compound in pure form (148 mg, 72%). P.F .: 218.7 ° C. 1H NMR (δ ppm, DMSO-d6): 7.56 (s at, 1H); 3.89 (t, J = 5.4, 1H); 3.74 (s, 3 H); 2.97 (t, J = 5.1, 1H); 2.85 (t, J = 5.1, 4H); 2,162.00-1.88 (m, 4H); 1.90-1.66 (10H); 1.47-1.36 (m, 2H).

Ejemplo 190a Example 190a

N(7)-(1-Metil-1-feniletil)-6-pentil-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4,7-dieno-7-carboxamida N (7) - (1-Methyl-1-phenylethyl) -6-pentyl-5,6-diazatetracycle [7.3.1.13,11.04.8] tetradeca-4,7-diene-7-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 189a. El Intermedio 13a (100 mg, 0,33 mmol), DMF (1,0 ml), Et3N (52 µl, 0,36 mmol), reactivo BOP (160 mg, 0,36 mmol) y α,αdimetilbencilamina (53 mg, 0,39 mmol) produjo el compuesto del título (100 mg, 72%). P.F.: 66-69 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,46-7,40 (m, 2H); 7,58 (t, J = 7,2, 2H); 7,30-7,20 (m, 2H); 5,83 (s a, 1H); 4,14 (t, J = 7,8, 2H); 3,11 (t a, J = 5,2 , 1H); 3,03 (t a, J = 5,2 , 1H); 2,15 (s a, 1H); 2,08-1,94 (m, 4H); 1,79 (s, 6H); 1,80-1,70 (m, 6H); 1,32-1,20 (m, 4H); 0,87 (t, J = 7,5, 3H). The title compound was synthesized by a procedure similar to that described for example 189a. Intermediate 13a (100 mg, 0.33 mmol), DMF (1.0 ml), Et3N (52 µl, 0.36 mmol), BOP reagent (160 mg, 0.36 mmol) and α, α-dimethylbenzylamine (53 mg , 0.39 mmol) produced the title compound (100 mg, 72%). P.F .: 66-69 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.46-7.40 (m, 2H); 7.58 (t, J = 7.2, 2H); 7.30-7.20 (m, 2H); 5.83 (s a, 1 H); 4.14 (t, J = 7.8, 2H); 3.11 (t a, J = 5.2, 1H); 3.03 (t a, J = 5.2, 1H); 2.15 (s at, 1 H); 2.08-1.94 (m, 4H); 1.79 (s, 6H); 1.80-1.70 (m, 6H); 1.32-1.20 (m, 4H); 0.87 (t, J = 7.5, 3H).

Ejemplo 190b Example 190b

N(7)-(1-Metil-1-feniletil)-5-pentil-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-6-dieno-7-carboxamida N (7) - (1-Methyl-1-phenylethyl) -5-pentyl-5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8) -6-diene-7-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 189b. El intermedio 13b (100 mg, 0,33 mmol), DMF (1,0 ml), Et3N (52 µl, 0,36 mmol), reactivo BOP (160 mg, 0,36 mmol) y α,αdimetilbencilamina (53 mg, 0,39 mmol) produjo el compuesto del título (95 mg, 68%). P.F.: 99-102 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,50-7,44 (m, 2H); 7,32 (t, J = 7,2, 2H); 7,24-7,16 (m, 2H); 3,97 (t, J = 7,5, 2H); 3,82 (s a, 1H); 2,94 (s a, 1H); 2,13 (s a, 2H); 2,00-1,84 (m, 4H); 1,78 (s, 6H); 1,80-1,68 (m, 6H); 1,40-1,24 (m, 4H); 0,91 (t, J = 7,2, 3H). The title compound was synthesized by a procedure similar to that described for example 189b. Intermediate 13b (100 mg, 0.33 mmol), DMF (1.0 ml), Et3N (52 µl, 0.36 mmol), BOP reagent (160 mg, 0.36 mmol) and α, α-dimethylbenzylamine (53 mg , 0.39 mmol) produced the title compound (95 mg, 68%). P.F .: 99-102 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.50-7.44 (m, 2H); 7.32 (t, J = 7.2, 2H); 7.24-7.16 (m, 2H); 3.97 (t, J = 7.5, 2H); 3.82 (s at, 1 H); 2.94 (s a, 1 H); 2.13 (s a, 2H); 2.00-1.84 (m, 4H); 1.78 (s, 6H); 1.80-1.68 (m, 6H); 1.40-1.24 (m, 4H); 0.91 (t, J = 7.2, 3H).

Ejemplo 191 Example 191

N(7)-[(1R)-2-Hidroxi-1-feniletil]-5-(2,4-difluorofenil)-5,6-diazatetraciclo [7.3.1.13,11.04,8]tetradeca-4(8), 6-dieno-7carboxamida N (7) - [(1R) -2-Hydroxy-1-phenylethyl] -5- (2,4-difluorophenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7carboxamide

A una solución del ejemplo 154 (290 mg, 0662 mmol) en THF (3 ml) se le añadió LiBH4 (32 mg, 1,52 mmol) y la mezcla se calentó a reflujo durante una noche. Después de la evaporación del disolvente, el residuo oleoso se diluyó con agua, se acidificó con HCl 1 N, se extrajo con acetato de etilo y las fases orgánicas combinadas se lavaron con salmuera y se secaron sobre Na2SO4. La FC (3:7 de AcOEt/éter de petróleo) dio el compuesto del título (150 mg, 61%). P.F.: 161-162 ºC. RMN 1H (δ ppm, DMSO-d6, 300 MHz): 8,24 (d, J = 7,5, 1H); 7,76-7,58 (m, 2H); 7,38-7,20 (m, 6H); 5,02-4,92 (m, 2H), 3,77 (s a, 1H); 3,70-3,64 (m, 2H); 2,62 (s a, 1H); 2,12 (s a, 2H); 1,98-1,68 (m, 10H). IR (cm-1 , KBr): 3403 (m), 3007 (w), 2916 (s), 2848 (m), 1656 (s), 1612 (w), 1519 (s), 1483 (m), 1443 (m), 1368 (m), 1353 (m), 1273 (m), 1225 (m) 1144 (m), 1082 (m), 966 (m), 851 (m). EM (m/z): 452,17(M+H+). To a solution of example 154 (290 mg, 0662 mmol) in THF (3 ml) was added LiBH4 (32 mg, 1.52 mmol) and the mixture was heated at reflux overnight. After evaporation of the solvent, the oily residue was diluted with water, acidified with 1 N HCl, extracted with ethyl acetate and the combined organic phases were washed with brine and dried over Na2SO4. FC (3: 7 AcOEt / petroleum ether) gave the title compound (150 mg, 61%). P.F .: 161-162 ° C. 1H NMR (δ ppm, DMSO-d6, 300 MHz): 8.24 (d, J = 7.5, 1H); 7.76-7.58 (m, 2H); 7.38-7.20 (m, 6H); 5.02-4.92 (m, 2H), 3.77 (s at, 1H); 3.70-3.64 (m, 2H); 2.62 (s at, 1 H); 2.12 (s a, 2H); 1.98-1.68 (m, 10H). IR (cm-1, KBr): 3403 (m), 3007 (w), 2916 (s), 2848 (m), 1656 (s), 1612 (w), 1519 (s), 1483 (m), 1443 (m), 1368 (m), 1353 (m), 1273 (m), 1225 (m) 1144 (m), 1082 (m), 966 (m), 851 (m). MS (m / z): 452.17 (M + H +).

Ejemplo 192 Example 192

N(7)-[(1S)-2-Hidroxi-1-feniletil]-5-(2,4-difluorofenil)-5,6-diazatetraciclo-[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7carboxamida N (7) - [(1S) -2-Hydroxy-1-phenylethyl] -5- (2,4-difluorophenyl) -5,6-diazatetracycle- [7.3.1.13,11.04,8] tetradeca-4 (8) , 6-diene-7carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 191. El producto del ejemplo 155 (400 mg, 0,81 mmol), THF (5 ml) y LiBH4 (35 mg, 1,62 mmol) produjo el compuesto del título (130 mg, 34%). P.F.: 158-159 ºC. RMN 1H (δ ppm, DMSO-d6, 300 MHz): 8,24 (d, J = 8,1, 1H); 7,71 (c, 8,4, 1H); 7,61 (t, J = 8,4, 1H); 7,38-7,20 (m, 6H); 5,00-4,94 (m, 2H), 3,78 (s a, 1H); 3,72-3,64 (m, 2H); 2,62 (s a, 1H); 2,11 (s a, 2H); 2,00-1,65 (m, 10H). EM (m/z): 452,17(M+H+). The title compound was synthesized by a procedure similar to that described for example 191. The product of example 155 (400 mg, 0.81 mmol), THF (5 ml) and LiBH4 (35 mg, 1.62 mmol) produced the title compound (130 mg, 34%). P.F .: 158-159 ° C. 1H NMR (δ ppm, DMSO-d6, 300 MHz): 8.24 (d, J = 8.1, 1H); 7.71 (c, 8.4, 1H); 7.61 (t, J = 8.4, 1H); 7.38-7.20 (m, 6H); 5.00-4.94 (m, 2H), 3.78 (s at, 1H); 3.72-3.64 (m, 2H); 2.62 (s at, 1 H); 2.11 (s a, 2H); 2.00-1.65 (m, 10H). MS (m / z): 452.17 (M + H +).

Ejemplo 201 Example 201

N(3)-Piperidino-1-fenil-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) -Piperidino-1-phenyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 14 (100 mg, 0,39 mmol), DMF (1,0 ml), Et3N (66 µl, 0,47 mmol), reactivo BOP (191 mg, 0,43 mmol) y 1-aminopiperidina (42 ml, 0,39 mmol) dio el compuesto del título (45 mg, 34%). P.F.: 144 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,68 (d, J = 7,8, 2H); 7,68 (s a, 1H); 7,48 (t, J = 7,8, 1H); 7,32 (t, J = 7,8, 1H); 3,75 (s a, 1H); 3,70 (s a, 1H); 2,91 (s a, 4H); 2,11 (d a, J = 8,1, 1H); 1,98 (d a, J = 9,3, 2H); 1,80-1,50 (m, 5H); 1,45 (s a, 2H); 1,24 (d a, J = 8,1, 2H). IR (KBr, cm 1): 3302 (m), 2987 (m), 2940 (s), 2856 (m), 2790 (m), 1686 (s), 1597 (m), 1537 (s), 1513 (s), 1489 (s), 1444 (m), 1339 (m), 1270 (m), 1225 (m), 1140 (m), 1127 (m), 1075 (w), 1036(w), 918 (m), 893 (m), 832 (w). EM (m/z): 337,1 [M+H]+. The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 14 (100 mg, 0.39 mmol), DMF (1.0 ml), Et3N (66 µl, 0.47 mmol), reagent BOP (191 mg, 0.43 mmol) and 1-aminopiperidine (42 ml, 0.39 mmol) gave the title compound (45 mg, 34%). P.F .: 144 ºC. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.68 (d, J = 7.8, 2H); 7.68 (s a, 1 H); 7.48 (t, J = 7.8, 1H); 7.32 (t, J = 7.8, 1H); 3.75 (s a, 1 H); 3.70 (s at, 1 H); 2.91 (s a, 4H); 2.11 (d a, J = 8.1, 1H); 1.98 (d a, J = 9.3, 2H); 1.80-1.50 (m, 5H); 1.45 (s at, 2H); 1.24 (d a, J = 8.1, 2H). IR (KBr, cm 1): 3302 (m), 2987 (m), 2940 (s), 2856 (m), 2790 (m), 1686 (s), 1597 (m), 1537 (s), 1513 ( s), 1489 (s), 1444 (m), 1339 (m), 1270 (m), 1225 (m), 1140 (m), 1127 (m), 1075 (w), 1036 (w), 918 ( m), 893 (m), 832 (w). MS (m / z): 337.1 [M + H] +.

Ejemplo 202 Example 202

N(3)-Ciclohexil-1-fenil-4,5,6,7-tetrahidro-1H-4,7-metano-imidazol-3-carboxamida N (3) -Cyclohexyl-1-phenyl-4,5,6,7-tetrahydro-1H-4,7-methane-imidazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 14 (100 mg, 0,39 mmol), DMF (1,0 ml), Et3N (66 µl, 0,48 mmol), reactivo BOP (191 mg, 0,43 mmol) y ciclohexilamina (45 ml, 0,39 mmol) produjo el compuesto del título (99 mg, 75%). P.F.: 107 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,68 (d, J = 8,1, 2H); 7,48 (t, J = 8,1, 2H); 7,33 (t, J = 7,8, 1H); 6,80 (d a, J = 8,4, 1H); 3,97-3,95 (m, 1H); 3,75 (s a,1H); 3,69 (s a, 1H); 2,12 (d a, J = 8,7, 1H); 2,11-1,90 (m, 4H); 1,79-1,65 (m, 4H); 1,48-1,15 (m, 7H). IR (KBr, cm 1):3327 (m), 2936 (m), 2856 (m), 1655 (s), 1595 (m), 1549 (s), 1508 (s), 1490 (s), 1462 (s), 1448 (m), 1352 (s), 1272 (m), 1249 (m), 1226 (m), 1164 (m), 1140 (m), 1121 (m). EM (m/z): 336,1([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 14 (100 mg, 0.39 mmol), DMF (1.0 ml), Et3N (66 µl, 0.48 mmol), reagent BOP (191 mg, 0.43 mmol) and cyclohexylamine (45 ml, 0.39 mmol) produced the title compound (99 mg, 75%). P.F .: 107 ºC. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.68 (d, J = 8.1, 2H); 7.48 (t, J = 8.1, 2H); 7.33 (t, J = 7.8, 1H); 6.80 (d a, J = 8.4, 1H); 3.97-3.95 (m, 1 H); 3.75 (s a, 1 H); 3.69 (s a, 1 H); 2.12 (d a, J = 8.7, 1H); 2.11-1.90 (m, 4H); 1.79-1.65 (m, 4H); 1.48-1.15 (m, 7H). IR (KBr, cm 1): 3327 (m), 2936 (m), 2856 (m), 1655 (s), 1595 (m), 1549 (s), 1508 (s), 1490 (s), 1462 ( s), 1448 (m), 1352 (s), 1272 (m), 1249 (m), 1226 (m), 1164 (m), 1140 (m), 1121 (m). MS (m / z): 336.1 ([M + H] +).

Ejemplo 203 Example 203

N(3)-Bencil-1-fenil-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) -Benzyl-1-phenyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 14 (100 mg, 0,39 mmol), DMF (1,0 ml), Et3N (66 µl, 0,48 mmol), reactivo BOP (191 mg, 0,43 mmol) y bencilo amina (45 µl, 0,39 mmol) dio el compuesto del título (87 mg, 65%). P.F.: 115 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,66 (d, J = 7,5, 2H); 7,47 (t, J = 7,8, 2H); 7,40-7,26 (m, 7H); 4,64 (d, J = 5,4, 2H), 3,78 (s a, 1H); 3,71 (s a, 1H); 2,15 (d a, J = 8,4, 1H); 2,00 (d a, J = 8,7, 2H); 1,73 (d a, J = 8,4, 1H); 1,30-1,14 (m, 2H). IR (KBr, cm-1): 3376 (m), 2995 (m), 2966 (m), 2948 (m), 2863 (m), 1652 (s), 1595 (s), 1552 (s), 1354 (s), 1277 (m), 1256 (m), 1235 (s), 1157 (m), 1122 (m), 1070 (m), 988 (m). EM (m/z): 344,1([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 14 (100 mg, 0.39 mmol), DMF (1.0 ml), Et3N (66 µl, 0.48 mmol), reagent BOP (191 mg, 0.43 mmol) and benzyl amine (45 µl, 0.39 mmol) gave the title compound (87 mg, 65%). P.F .: 115 ºC. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.66 (d, J = 7.5, 2H); 7.47 (t, J = 7.8, 2H); 7.40-7.26 (m, 7H); 4.64 (d, J = 5.4, 2H), 3.78 (s a, 1H); 3.71 (s a, 1 H); 2.15 (d a, J = 8.4, 1H); 2.00 (d a, J = 8.7, 2H); 1.73 (d a, J = 8.4, 1H); 1.30-1.14 (m, 2H). IR (KBr, cm-1): 3376 (m), 2995 (m), 2966 (m), 2948 (m), 2863 (m), 1652 (s), 1595 (s), 1552 (s), 1354 (s), 1277 (m), 1256 (m), 1235 (s), 1157 (m), 1122 (m), 1070 (m), 988 (m). MS (m / z): 344.1 ([M + H] +).

Ejemplo 204 Example 204

N-(3)-Fenilamino-1-fenil-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N- (3) -Phenylamino-1-phenyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 14 (100 mg, 0,39 mmol), DMF (1,0 ml), Et3N (66 µl, 0,48 mmol), reactivo BOP (191 mg, 0,43 mmol) y fenilhidrazina (38 The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 14 (100 mg, 0.39 mmol), DMF (1.0 ml), Et3N (66 µl, 0.48 mmol), reagent BOP (191 mg, 0.43 mmol) and phenylhydrazine (38

µl, 0,39 mmol) dio el compuesto del título (111 mg, 82%). P.F.: 189 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,59 (s a, 1H); 7,71 (d, J = 8,1, 2H); 7,50 (t, J = 8,1, 2H); 7,35 (t, J = 8,1, 1H); 7,24 (t, J = 7,8, 2H); 6,96 (d, J = 7,8, 2H); 6,90 (t, J = 7,8, 1H); 3,73 (s a, 2H); 2,14 (d a, J = 8,7, 1H); 1,90-2,10 (m, 2H); 1,73 (d, J = 8,4, 1H); 1,31-1,14 (m, 2H). IR (KBr, cm-1):3413 (m), 3393 (m), 3273 (s), 2970 (m), 2955 (m), 2868 (w), 1682 (s), 1599 (m), 1541 (m), 1506 (s), 1493 (s), 1476 (s), 1458 (s), 1349 (m), 1273 (m), 1226 (m), 1157 (m), 1132 (m), 1085 (m), 1066 (m), 895 (m). EM (m/z): 345,1 ([M+H]+). µl, 0.39 mmol) gave the title compound (111 mg, 82%). P.F .: 189 ºC. 1H NMR (δ ppm, CDCl3, 300 MHz): 8.59 (s at, 1H); 7.71 (d, J = 8.1, 2H); 7.50 (t, J = 8.1, 2H); 7.35 (t, J = 8.1, 1H); 7.24 (t, J = 7.8, 2H); 6.96 (d, J = 7.8, 2H); 6.90 (t, J = 7.8, 1H); 3.73 (s a, 2H); 2.14 (d a, J = 8.7, 1H); 1.90-2.10 (m, 2H); 1.73 (d, J = 8.4, 1H); 1.31-1.14 (m, 2H). IR (KBr, cm-1): 3413 (m), 3393 (m), 3273 (s), 2970 (m), 2955 (m), 2868 (w), 1682 (s), 1599 (m), 1541 (m), 1506 (s), 1493 (s), 1476 (s), 1458 (s), 1349 (m), 1273 (m), 1226 (m), 1157 (m), 1132 (m), 1085 (m), 1066 (m), 895 (m). MS (m / z): 345.1 ([M + H] +).

Ejemplo 205 Example 205

N(3)-Piperidino-1-(2-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) -Piperidino-1- (2-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 15 (100 mg, 0,35 mmol), DMF (1,0 ml), Et3N (58 µl, 0,42 mmol), reactivo BOP (169 mg, 0,38 mmol) y 1 aminopiperidina (38 µl, 0,35 mmol) dio el compuesto del título (100 mg, 78%). P.F.: 232 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,607,47 (m, 3H); 7,42-7,35 (m, 2H); 3,76 (s a, 1H); 3,37 (s a, 1H); 2,80 (s a, 4H); 2,13 (d a, J = 9,3, 1H); 2,11-1,86 (m, 2H); 1,75-1,62 (m, 5H); 1,42-1,18 (m, 4H). IR (KBr, cm-1):3314 (w), 2999 (w), 2938 (s), 2867 (w), 2781 (m), 1682 (s), 1540 (s), 1511 (s), 1484 (s), 1450 (m), 1342 (m), 1276 (w), 1257 (w), 1227 (m), 1123 (m), 1083 (m), 1035 (m), 987 (m), 893 (w). EM (m/z): 371,1([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 15 (100 mg, 0.35 mmol), DMF (1.0 ml), Et3N (58 µl, 0.42 mmol), reagent BOP (169 mg, 0.38 mmol) and 1 aminopiperidine (38 µl, 0.35 mmol) gave the title compound (100 mg, 78%). P.F .: 232 ºC. 1H NMR (δ ppm, CDCl3, 300 MHz): 7,607.47 (m, 3H); 7.42-7.35 (m, 2H); 3.76 (s a, 1 H); 3.37 (s at, 1 H); 2.80 (s at, 4H); 2.13 (d a, J = 9.3, 1H); 2.11-1.86 (m, 2H); 1.75-1.62 (m, 5H); 1.42-1.18 (m, 4H). IR (KBr, cm-1): 3314 (w), 2999 (w), 2938 (s), 2867 (w), 2781 (m), 1682 (s), 1540 (s), 1511 (s), 1484 (s), 1450 (m), 1342 (m), 1276 (w), 1257 (w), 1227 (m), 1123 (m), 1083 (m), 1035 (m), 987 (m), 893 (w). MS (m / z): 371.1 ([M + H] +).

Ejemplo 206 Example 206

N(3)-Ciclohexil-1-(2-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) -Cyclohexyl-1- (2-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 15 (100 mg, 0,35 mmol), DMF (1,0 ml), Et3N (58 µl, 0,42 mmol), reactivo BOP (169 mg, 0,38 mmol) y ciclohexil amina (40 µl, 0,39 mmol) produjo el compuesto del título (92 mg, 72%). P.F.: 171 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,50-7,45 (m, 2H); 7,45-7,35 (m, 2H); 6,73 (d a, J = 7,2, 1H); 3,95-3,82 (m, 1H); 3,77 (s a, 1H); 3,37 (s a,1H); 2,13 (d a, J = 9,3, 1H); 2,11-1,86 (m, 4H); 1,70-1,66 (m, 4H); 1,42-1,18 (m, 7H). IR (KBr, cm-1): 3407 (m), 3393 (m), 2996 (m), 2934 (s), 2850 (s), 1662 (s), 1549 (s), 1513 (s), 1506 (s), 1483 (s), 1447 (s), 1342 (s), 1223 (s), 1125 (s), 1085 (m), 965 (m), 950 (m). EM (m/z): 370,1([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 15 (100 mg, 0.35 mmol), DMF (1.0 ml), Et3N (58 µl, 0.42 mmol), reagent BOP (169 mg, 0.38 mmol) and cyclohexyl amine (40 µl, 0.39 mmol) produced the title compound (92 mg, 72%). P.F .: 171 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.50-7.45 (m, 2H); 7.45-7.35 (m, 2H); 6.73 (d a, J = 7.2, 1H); 3.95-3.82 (m, 1 H); 3.77 (s a, 1 H); 3.37 (s at, 1 H); 2.13 (d a, J = 9.3, 1H); 2.11-1.86 (m, 4H); 1.70-1.66 (m, 4H); 1.42-1.18 (m, 7H). IR (KBr, cm-1): 3407 (m), 3393 (m), 2996 (m), 2934 (s), 2850 (s), 1662 (s), 1549 (s), 1513 (s), 1506 (s), 1483 (s), 1447 (s), 1342 (s), 1223 (s), 1125 (s), 1085 (m), 965 (m), 950 (m). MS (m / z): 370.1 ([M + H] +).

Ejemplo 207 Example 207

N(3)-Bencil-1-(2-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) -Benzyl-1- (2-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 15 (100 mg, 0,35 mmol), DMF (1,0 ml), Et3N (58 µl, 0,42 mmol), reactivo BOP (169 mg, 0,38 mmol) y bencil amina (37 µl, 0,34 mmol) produjo el compuesto del título (60 mg, 46%). RMN 1H (δ ppm, CDCl3, 300 MHz): 7,55-7,15 (m, 10H); 4,60 (s a, 2H); 3,79 (s a, 1H); 3,38 (s a,1H); 2,16 (d a, J = 7,8, 1H); 1,99-1,88 (m, 2H); 1,70 (d, J = 8,7, 1H); 1,31-1,20 (m, 2H). IR (Puro, cm-1): 3414 (m), 2994 (m), 2968 (m), 2949 (m), 1664 (s), 1550 (s), 1513 (s), 1485 (s), 1455 (s), 1347 (m), 1275 (m), 1251 (m), 1235 (m), 1161 (m), 1141 (m), 1121 (m). EM (m/z): 378,1 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 15 (100 mg, 0.35 mmol), DMF (1.0 ml), Et3N (58 µl, 0.42 mmol), reagent BOP (169 mg, 0.38 mmol) and benzyl amine (37 µl, 0.34 mmol) produced the title compound (60 mg, 46%). 1H NMR (δ ppm, CDCl3, 300 MHz): 7.55-7.15 (m, 10H); 4.60 (s at, 2H); 3.79 (s a, 1 H); 3.38 (s at, 1 H); 2.16 (d a, J = 7.8, 1H); 1.99-1.88 (m, 2H); 1.70 (d, J = 8.7, 1H); 1.31-1.20 (m, 2H). IR (Pure, cm-1): 3414 (m), 2994 (m), 2968 (m), 2949 (m), 1664 (s), 1550 (s), 1513 (s), 1485 (s), 1455 (s), 1347 (m), 1275 (m), 1251 (m), 1235 (m), 1161 (m), 1141 (m), 1121 (m). MS (m / z): 378.1 ([M + H] +).

Ejemplo 208 Example 208

N(3)-Fenilamino-1-(2-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) -Phenylamino-1- (2-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 15 (100 mg, 0,35 mmol), DMF (1,0 ml), Et3N (58 µl, 0,42 mmol), reactivo BOP (169 mg, 0,38 mmol) y fenil hidrazina (34 µl, 0,34 mmol) dio el compuesto del título (105 mg, 80%). P.F.: 205 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,51 (s, 1H); 7,60-7,51 (m, 2H); 7,52-7,40 (m, 2H); 7,23 (t, J = 7,8, 2H); 6,95 (d, J = 7,8, 2H); 6,90 (t, J = 7,5, 1H); 3,74 (s a, 1H); 3,41 (s a, 1H); 2,15 (d a, J = 8,7, 1H); 2,00-1,85 (m, 2H); 1,70 (d a, J = 8,7, 1H) 1,32-1,20 (m, 2H). IR (KBr, cm 1): 3283 (s), 2993 (m), 2958 (m), 1675 (s), 1591 (m), 1603 (m), 1542 (m), 1513 (s),1497 (s),1439 (m), 1348 (m), 1281 (m), 1238 (m), 1137 (m), 1123 (m), 1082 (m),1062 (m), 889 (m). EM (m/z): 379,0 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 15 (100 mg, 0.35 mmol), DMF (1.0 ml), Et3N (58 µl, 0.42 mmol), reagent BOP (169 mg, 0.38 mmol) and phenyl hydrazine (34 µl, 0.34 mmol) gave the title compound (105 mg, 80%). P.F .: 205 ºC. 1H NMR (δ ppm, CDCl3, 300 MHz): 8.51 (s, 1H); 7.60-7.51 (m, 2H); 7.52-7.40 (m, 2H); 7.23 (t, J = 7.8, 2H); 6.95 (d, J = 7.8, 2H); 6.90 (t, J = 7.5, 1H); 3.74 (s a, 1 H); 3.41 (s at, 1 H); 2.15 (d a, J = 8.7, 1H); 2.00-1.85 (m, 2H); 1.70 (d a, J = 8.7, 1H) 1.32-1.20 (m, 2H). IR (KBr, cm 1): 3283 (s), 2993 (m), 2958 (m), 1675 (s), 1591 (m), 1603 (m), 1542 (m), 1513 (s), 1497 ( s), 1439 (m), 1348 (m), 1281 (m), 1238 (m), 1137 (m), 1123 (m), 1082 (m), 1062 (m), 889 (m). MS (m / z): 379.0 ([M + H] +).

Ejemplo 209 Example 209

N(3)-Piperidino-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) -Piperidino-1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 16 (100 mg, 0,35 mmol), DMF (1,0 ml), Et3N (48 µl, 0,35 mmol), reactivo BOP (152 mg, 0,35 mmol) y 1-amino piperidina (37 µl, 0,35 mmol) produjo el compuesto del título (68 mg, 53%). P.F.: 78-81 ºC: RMN 1H (δ ppm, CDCl3, 300 MHz): 7,63 (d, J = 8,7, 2H); 7,44 (d, J = 8,7, 2H); 3,75 (s, 1H); 3,67 (s, 1H); 2,91 (s a, 4H); 2,11 (d a, J = 8,7, 1H); 2,00 (d a, J = 9,6, 2H); 1,80-1,65 (m, 5H); 1,45 (m, 2H); 1,20 (m, 2H).IR (KBr, cm-1): 3408 (m), 2931 (m), 2871 (m), 2779 (m), 1692 (s), 1540 (m), 1506 (s), 1489 (s), 1347 (m), 1268 (m), 1227 (m), 1085 (m). EM (m/z): 371,2 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0 ml), Et3N (48 µl, 0.35 mmol), reagent BOP (152 mg, 0.35 mmol) and 1-amino piperidine (37 µl, 0.35 mmol) produced the title compound (68 mg, 53%). P.F .: 78-81 ° C: 1 H NMR (δ ppm, CDCl 3, 300 MHz): 7.63 (d, J = 8.7, 2H); 7.44 (d, J = 8.7, 2H); 3.75 (s, 1 H); 3.67 (s, 1 H); 2.91 (s a, 4H); 2.11 (d a, J = 8.7, 1H); 2.00 (d a, J = 9.6, 2H); 1.80-1.65 (m, 5H); 1.45 (m, 2 H); 1.20 (m, 2H) .IR (KBr, cm-1): 3408 (m), 2931 (m), 2871 (m), 2779 (m), 1692 (s), 1540 (m), 1506 ( s), 1489 (s), 1347 (m), 1268 (m), 1227 (m), 1085 (m). MS (m / z): 371.2 ([M + H] +).

Ejemplo 210 Example 210

1-(4-Clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-ilpiperidin metanona 1- (4-Chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-ylpiperidin methanone

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101: El Intermedio 16 (100 mg, 0,35 mmol), DMF (1,0 ml), Et3N (54 µl, 0,39 mmol), reactivo BOP (160 mg, 0,36 mmol) y piperidina (38 µl, 0,38 mmol) produjo el compuesto del título (80 mg, 65%). P.F.: 96-98 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,63 (d, J = 8,7, 2H); 7,41 (d, J = 8,7, 2H); 3,92-3,75 (m, 4H), 3,69 (s a, 1H), 3,57 (s, 1H), 2,13 (d, J = 6,9, 1H), 1,97 (d, J = 9,0, 2H), 1,80-1,60 (m, 7H), 1,24 (d, J = 8,7, 2H). IR (cm-1, KBr): 2932(s), 2861 (m), 1613 (s), 1503 (s), 1467 (m), 1422 (m), 1371 (m), 1352 (m), 1271 (m), 1246 (m), 1156 (w), 1132 (m), 1088 (m), 825 (m). EM (m/z) : 356,0 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101: Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0 ml), Et3N (54 µl, 0.39 mmol), reagent BOP (160 mg, 0.36 mmol) and piperidine (38 µl, 0.38 mmol) produced the title compound (80 mg, 65%). P.F .: 96-98 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.63 (d, J = 8.7, 2H); 7.41 (d, J = 8.7, 2H); 3.92-3.75 (m, 4H), 3.69 (sa, 1H), 3.57 (s, 1H), 2.13 (d, J = 6.9, 1H), 1.97 ( d, J = 9.0, 2H), 1.80-1.60 (m, 7H), 1.24 (d, J = 8.7, 2H). IR (cm-1, KBr): 2932 (s), 2861 (m), 1613 (s), 1503 (s), 1467 (m), 1422 (m), 1371 (m), 1352 (m), 1271 (m), 1246 (m), 1156 (w), 1132 (m), 1088 (m), 825 (m). MS (m / z): 356.0 ([M + H] +).

Ejemplo 211 Example 211

N(3)-Ciclohexil-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) -Cyclohexyl-1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 16 (100 mg, 0,35 mmol), DMF (1,0 ml), Et3N (48 µl, 0,35 mmol), reactivo BOP (152 mg, 0,35 mmol) y ciclohexilamina (39 µl, 0,35 mmol) para dar el compuesto del título (98 mg, 77%). P.F.: 155-158 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,64 (d, J = 8,7, 2H); 7,43 (d, J = 8,7, 2H); 6,76 (d a, J = 8,7, 1H); 4,02-3,87 (m, 1H); 3,75 (s,1H); 3,67 (s,1H); 2,12 (d a, J = 8,1, 1H); 2,10-1,90 (m, 4H); 1,80-1,57 (m, 4H); 1,48-1,18 (m, 7H) IR (KBr, cm-1): 3411 (m), 2926 (s), 2848 (m), 1666 (s), 1598 (w), 1545 (s),1505 (s), 1486 (s), 1349 (m), 1248 (w),1223 (m), 1159 (m),1122 (m),1086 (m), 829 (m), 506 (m). EM (m/z): 370,3 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0 ml), Et3N (48 µl, 0.35 mmol), reagent BOP (152 mg, 0.35 mmol) and cyclohexylamine (39 µl, 0.35 mmol) to give the title compound (98 mg, 77%). P.F .: 155-158 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.64 (d, J = 8.7, 2H); 7.43 (d, J = 8.7, 2H); 6.76 (d a, J = 8.7, 1H); 4.02-3.87 (m, 1 H); 3.75 (s, 1 H); 3.67 (s, 1 H); 2.12 (d a, J = 8.1, 1H); 2.10-1.90 (m, 4H); 1.80-1.57 (m, 4H); 1.48-1.18 (m, 7H) IR (KBr, cm-1): 3411 (m), 2926 (s), 2848 (m), 1666 (s), 1598 (w), 1545 (s) , 1505 (s), 1486 (s), 1349 (m), 1248 (w), 1223 (m), 1159 (m), 1122 (m), 1086 (m), 829 (m), 506 (m) . MS (m / z): 370.3 ([M + H] +).

Ejemplo 212 Example 212

N(3)-Ciclopentil-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) -Cyclopentyl-1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El Intermedio 16 (100 mg, 0,35 mmol), DMF (1,0 ml), Et3N (54 µl, 0,39 mmol), reactivo BOP (160 mg, 0,36 mmol) y ciclopentilamina (38 µl, 0,38 mmol) produjo el compuesto del título (95 mg, 77%). P.F.: 176-178 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,63 (d, J = 8,7, 2H); 7,43 (d, J = 8,7, 2H); 6,81 (d, J = 7,5, 1H); 4,38 (sext., J = 7,5, 1H); 3,76 (s, 1H), 3,66 (s, 1H), 2,20-1,90 (d, J = 8,7, 5H); 1,8-1,40 (m, 7H); 1,28-1,20 (m, 2H). IR (cm-1, KBr): 3288 (m), 2964 (s), 2868 (m), 1643 (s), 1552 (s), 1505 (s), 1489 (s), 1442 (m), 1406 (m), 1364 (m), 1347 (m), 1275 (m), 1252 (m), 1243 (m), 1158 (m), 1129 (m), 1089 (m), 1008 (m), 836 (m). EM (m/z): 356,0 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0 ml), Et3N (54 µl, 0.39 mmol), reagent BOP (160 mg, 0.36 mmol) and cyclopentylamine (38 µl, 0.38 mmol) produced the title compound (95 mg, 77%). P.F .: 176-178 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.63 (d, J = 8.7, 2H); 7.43 (d, J = 8.7, 2H); 6.81 (d, J = 7.5, 1H); 4.38 (sext., J = 7.5, 1H); 3.76 (s, 1H), 3.66 (s, 1H), 2.20-1.90 (d, J = 8.7, 5H); 1.8-1.40 (m, 7H); 1.28-1.20 (m, 2H). IR (cm-1, KBr): 3288 (m), 2964 (s), 2868 (m), 1643 (s), 1552 (s), 1505 (s), 1489 (s), 1442 (m), 1406 (m), 1364 (m), 1347 (m), 1275 (m), 1252 (m), 1243 (m), 1158 (m), 1129 (m), 1089 (m), 1008 (m), 836 (m). MS (m / z): 356.0 ([M + H] +).

Ejemplo 213 Example 213

N(3)-[(N-Ciclohexil-N-metil)amino]-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) - [(N-Cyclohexyl-N-methyl) amino] -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 16 (300 mg, 1,039 mmol), DMF (3 ml), Et3N (173 µl, 1,25 mmol), reactivo BOP (459 mg, 1,039 mmol) y N-metil-Nciclohexilhidrazina (132 mg, 1,04 mmol) produjo el compuesto del título (285 mg, 69%). P.F.: 62 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,63 (d, J = 8,7, 2H); 7,62 (s a, 1H); 7,44 (d, J = 9,0, 2H); 3,77 (s, 1H); 3,67 (s, 1H); 2,73 (s a, 3H); 2,13 (d a, J = 8,7, 1H); 2,10-1,90 (m, 4H); 1,72 (d a, J = 8,7, 1H); 1,80-1,15 (m, 11H). IR (KBr, cm-1) 3258 (m), 2930 (s), 2854 (s), 1678 (s), 1596 (m), 1544 (s), 1501 (s), 1447 (s), 1350 (s), 1274 (m), 1233 (m), 1159 (m), 1121 (m), 1090 (s), 1051 (m), 1006 (m), 915 (m), 866 (m), 831 (s). EM (m/z): 399,1 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 16 (300 mg, 1,039 mmol), DMF (3 ml), Et3N (173 µl, 1.25 mmol), BOP reagent (459 mg , 1,039 mmol) and N-methyl-N-cyclohexylhydrazine (132 mg, 1.04 mmol) produced the title compound (285 mg, 69%). P.F .: 62 ºC. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.63 (d, J = 8.7, 2H); 7.62 (s a, 1 H); 7.44 (d, J = 9.0, 2H); 3.77 (s, 1 H); 3.67 (s, 1 H); 2.73 (s a, 3H); 2.13 (d a, J = 8.7, 1H); 2.10-1.90 (m, 4H); 1.72 (d a, J = 8.7, 1H); 1.80-1.15 (m, 11H). IR (KBr, cm-1) 3258 (m), 2930 (s), 2854 (s), 1678 (s), 1596 (m), 1544 (s), 1501 (s), 1447 (s), 1350 ( s), 1274 (m), 1233 (m), 1159 (m), 1121 (m), 1090 (s), 1051 (m), 1006 (m), 915 (m), 866 (m), 831 ( s). MS (m / z): 399.1 ([M + H] +).

Ejemplo 214 Example 214

N(3)-Fenil-1-(4-clorofenill)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) -Phenyl-1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 16 (100 mg, 0,35 mmol), DMF (1,0 ml), Et3N (48 µl, 0,35 mmol), reactivo BOP (152 mg, 0,35 mmol) y anilina (31 µl, 0,35 mmol) dio el compuesto del título (80 mg, 64%). P.F.: 137-140 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,70 (s,1H); 7,69 (t, J = 9,9, 4H); 7,48 (d, J = 9,0, 2H); 7,36 (t, J = 7,9, 2H); 7,12 (t, J = 7,4, 1H); 3,80 (s, 1H); 3,71 (s,1H); 2,17 (d a, J = 9,0, 1H); 2,10-1,95 (m, 2H); 1,76 (d a, J = 9,0, 1H); 1,38-1,19 (m, 2H). IR (KBr, cm-1); 3283 (m), 2933 (w), 2865 (w), 1663 (s), 1597 (s), 1542 (s), 1500 (s), 1433 (m), 1350 (m), 1240 (m), 1089 (m), 833 (m), 759 (m), 507 (w). EM (m/z): 364,3 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0 ml), Et3N (48 µl, 0.35 mmol), reagent BOP (152 mg, 0.35 mmol) and aniline (31 µl, 0.35 mmol) gave the title compound (80 mg, 64%). P.F .: 137-140 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 8.70 (s, 1H); 7.69 (t, J = 9.9, 4H); 7.48 (d, J = 9.0, 2H); 7.36 (t, J = 7.9, 2H); 7.12 (t, J = 7.4, 1H); 3.80 (s, 1 H); 3.71 (s, 1 H); 2.17 (d a, J = 9.0, 1H); 2.10-1.95 (m, 2H); 1.76 (d a, J = 9.0, 1H); 1.38-1.19 (m, 2H). IR (KBr, cm-1); 3283 (m), 2933 (w), 2865 (w), 1663 (s), 1597 (s), 1542 (s), 1500 (s), 1433 (m), 1350 (m), 1240 (m), 1089 (m), 833 (m), 759 (m), 507 (w). MS (m / z): 364.3 ([M + H] +).

Ejemplo 215 Example 215

N(3)-(3-Clorofenil)-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) - (3-Chlorophenyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 16 (100 mg, 0,35 mmol), DMF (1,0 ml), Et3N (54 µl, 0,38 mmol), reactivo BOP (162 mg, 0,37 mmol) y 3-cloroanilina (49 mg, 0,38 mmol) produjo el compuesto del título (110 mg, 78%). P.F.: 158-161 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,71 (s a, 1H); 7,87 (t, J = 1,8, 1 H); 7,67 (d, J = 8,7, 2H); 7,54 (d a, J = 8,1, 1H); 7,48 (d, J = 8,7, 2H); 7,28 (t, J = 8,1, 1H); 7,09 (d a, J = 8,1, 1H); 3,80 (s a, 1H); 3,71 (s a, 1H); 2,17 (d a, J = 9,0, 1H); 2,12-1,97 (m, 2H); 1,76 (d, J = 8,7, 1H); 1,32-1,20 (m, 2H). IR (cm-1, KBr): 3295 (s), 3187 (w), 3059 (w), 2987 (m), 2960 (m), 2984 (m), 2866 (m), 1677 (s), 1593 (s), 1551 (m), 1497 (s), 1484 (s), 1410 (m), 1400 (m), 1355 (m), 1308 (m), 1297 (w), 1234 (m), 1220 (m), 1157 (w), 1141·(m), 1091 (m), 1077 (w), 1048 (w), 1008 (m), 997 (m) 875 (m), 825 (m). EM (m/z): 398,2 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0 ml), Et3N (54 µl, 0.38 mmol), reagent BOP (162 mg, 0.37 mmol) and 3-chloroaniline (49 mg, 0.38 mmol) produced the title compound (110 mg, 78%). P.F .: 158-161 ° C. 1 H NMR (δ ppm, CDCl 3, 300 MHz): 8.71 (s a, 1 H); 7.87 (t, J = 1.8, 1 H); 7.67 (d, J = 8.7, 2H); 7.54 (d a, J = 8.1, 1H); 7.48 (d, J = 8.7, 2H); 7.28 (t, J = 8.1, 1H); 7.09 (d a, J = 8.1, 1H); 3.80 (s at, 1 H); 3.71 (s a, 1 H); 2.17 (d a, J = 9.0, 1H); 2.12-1.97 (m, 2H); 1.76 (d, J = 8.7, 1H); 1.32-1.20 (m, 2H). IR (cm-1, KBr): 3295 (s), 3187 (w), 3059 (w), 2987 (m), 2960 (m), 2984 (m), 2866 (m), 1677 (s), 1593 (s), 1551 (m), 1497 (s), 1484 (s), 1410 (m), 1400 (m), 1355 (m), 1308 (m), 1297 (w), 1234 (m), 1220 (m), 1157 (w), 1141 (m), 1091 (m), 1077 (w), 1048 (w), 1008 (m), 997 (m) 875 (m), 825 (m). MS (m / z): 398.2 ([M + H] +).

Ejemplo 216 Example 216

N(3)-(4-Clorofenil)-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) - (4-Chlorophenyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 16 (100 mg, 0,35 mmol), DMF (1,0 ml), Et3N (54 µl, 0,39 mmol), reactivo BOP (160 mg, 0,36 mmol) y 4-cloroanilina (49 mg, 0,39 mmol) produjo el compuesto del título (80 mg, 58%). P.F.: 182-184 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,69 (s, 1H); 7,67 (d, J = 8,7, 4H); 7:47 (d, J = 8,7, 2H); 7,32 (d, J = 8,7, 2H); 3,80 (s, 1H), 3,71 (s, 1H), 2,16 (d, J = 8,7, 1H); 2,03 (d, J = 7,2, 2H); 1,76 (d; J = 8,7, 1H); 1,26 (d, J = 7,5, 2H). IR (cm-1, KBr): 3306 (m), 2989 (w), 2971 (w), 2945 (m), 2868 (w), 1673 (s), 1660 (s), 1594 (s), 1545 (s), 1498 (s), 1407 (s), 1397 (m), 1310 (m), 1284 (m), 1240 (m), 1089 (s), 1008 (m), 828 (s). EM (m/z): 398,0 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0 ml), Et3N (54 µl, 0.39 mmol), reagent BOP (160 mg, 0.36 mmol) and 4-chloroaniline (49 mg, 0.39 mmol) produced the title compound (80 mg, 58%). P.F .: 182-184 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 8.69 (s, 1H); 7.67 (d, J = 8.7, 4H); 7:47 (d, J = 8.7, 2H); 7.32 (d, J = 8.7, 2H); 3.80 (s, 1H), 3.71 (s, 1H), 2.16 (d, J = 8.7, 1H); 2.03 (d, J = 7.2, 2H); 1.76 (d; J = 8.7, 1H); 1.26 (d, J = 7.5, 2H). IR (cm-1, KBr): 3306 (m), 2989 (w), 2971 (w), 2945 (m), 2868 (w), 1673 (s), 1660 (s), 1594 (s), 1545 (s), 1498 (s), 1407 (s), 1397 (m), 1310 (m), 1284 (m), 1240 (m), 1089 (s), 1008 (m), 828 (s). MS (m / z): 398.0 ([M + H] +).

Ejemplo 217 Example 217

N(3)-(3-Bromofenil)-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) - (3-Bromophenyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 16 (100 mg, 0,35 mmol), DMF (1,0 ml), Et3N (54 µl, 0,39 mmol), reactivo BOP (160 mg, 0,36 mmol) y 3-bromoanilina (42 µl, 0,38 mmol) produjo el compuesto del título (90 mg, 59%). P.F.: 176-178 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,69 (s, 1H); 8,00 (d, J = 2,1, 1H); 7,66 (d, J = 7,5, 2H); 7,61 (d a, J = 7,5, 1H); 7,47 (d, J = 7,5, 2H); 7,25-7,17 (m, 2H); 3,80 (s, 1H), 3,71 (s, 1H), 2,16 (d, J = 8,7, 1H); 2,03 (d, J = 7,8, 2H); 1,76 (d, J = 8,7, 1H); 1,26 (d, J = 7,2, 2H). IR (cm-1, KBr): 3292 (m), 2987 (w), 2865 (w), 1675 (s), 1587 (s), 1497 (s), 1481 (s), 1409 (m), 1397 (m), 1355 (m), 1306 (m), 1233 (m), 1157 (m), 1091 (m), 874 (w), 825, The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0 ml), Et3N (54 µl, 0.39 mmol), reagent BOP (160 mg, 0.36 mmol) and 3-bromoaniline (42 µl, 0.38 mmol) produced the title compound (90 mg, 59%). P.F .: 176-178 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 8.69 (s, 1H); 8.00 (d, J = 2.1, 1H); 7.66 (d, J = 7.5, 2H); 7.61 (d a, J = 7.5, 1H); 7.47 (d, J = 7.5, 2H); 7.25-7.17 (m, 2H); 3.80 (s, 1H), 3.71 (s, 1H), 2.16 (d, J = 8.7, 1H); 2.03 (d, J = 7.8, 2H); 1.76 (d, J = 8.7, 1H); 1.26 (d, J = 7.2, 2H). IR (cm-1, KBr): 3292 (m), 2987 (w), 2865 (w), 1675 (s), 1587 (s), 1497 (s), 1481 (s), 1409 (m), 1397 (m), 1355 (m), 1306 (m), 1233 (m), 1157 (m), 1091 (m), 874 (w), 825,

Ejemplo 218 Example 218

N(3)-(2-Metoxifenil)-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) - (2-Methoxyphenyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 16 (100 mg, 0,35 mmol), DMF (1,0 ml), Et3N (48 µl, 0,35 mmol), reactivo BOP (153 mg, 0,35 mmol) y o-anisidina (39 µl, 0,35 mmol) dio el compuesto del título (100 mg, 74%). P.F.: 149-151 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 9,32 (s a, 1H); 8,54 (dd, J = 8,1, 2,1, 1H); 7,69 (d, J = 9,0, 2H); 7,47 (d, J = 9,0, 2H); 7,10-7,02 (m, 2H); 6,92 (dd, J = 7,8, 1,5, 1H); 3,94 (s, 3H); 3,81 (s a, 1H); 3,71 (s a, 1H); 2,17 (d, J = 7,8, 1H); 2,02 (d a, J = 8,4, 2H); 1,76 (d, J = 8,7, 1H); 1,40-1,18 (m, 2H). IR (KBr, cm-1): 3380 (m), 2873 (w), 1684 (s), 1601 (m), 1541 (s), 1499 (s), 1479 (s), 1461 (s), 1349 (m), 1247 (m), 1219 (m), 1118 (m), 1089 (m), 1044(m), 1027 (m), 838 (m). EM (m/z): 394,2 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0 ml), Et3N (48 µl, 0.35 mmol), reagent BOP (153 mg, 0.35 mmol) and o-anisidine (39 µl, 0.35 mmol) gave the title compound (100 mg, 74%). P.F .: 149-151 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 9.32 (s at, 1H); 8.54 (dd, J = 8.1, 2.1, 1H); 7.69 (d, J = 9.0, 2H); 7.47 (d, J = 9.0, 2H); 7.10-7.02 (m, 2H); 6.92 (dd, J = 7.8, 1.5, 1H); 3.94 (s, 3 H); 3.81 (s at, 1 H); 3.71 (s a, 1 H); 2.17 (d, J = 7.8, 1H); 2.02 (d a, J = 8.4, 2H); 1.76 (d, J = 8.7, 1H); 1.40-1.18 (m, 2H). IR (KBr, cm-1): 3380 (m), 2873 (w), 1684 (s), 1601 (m), 1541 (s), 1499 (s), 1479 (s), 1461 (s), 1349 (m), 1247 (m), 1219 (m), 1118 (m), 1089 (m), 1044 (m), 1027 (m), 838 (m). MS (m / z): 394.2 ([M + H] +).

Ejemplo 219 Example 219

N(3) (4-terc-Butilfenil)-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) (4-tert-Butylphenyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 16 (100 mg, 0,35 mmol), DMF (1,0 ml), Et3N (54 µl, 0,39 mmol), reactivo BOP (160 mg, 0,36 mmol) y 4-terc-butilanilina (62 µl, 0,38 mmol) produjo el compuesto del título (100 mg, 69%). P.F.: 76-78 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,65 (s,1H); 7,67 (d, J = 8,7, 2H); 7,63 (d, J = 8,7, 2H); 7,47 (d, J = 8,7, 2H); 7,37 (d, J = 9,0, 2H); 3,81 (s, 1H), 3,70 (s, 1H), 2,16 (d, J = 9,0, 1H); 2,02 (d, J = 8,4, 2H); 1,75 (d, J = 9,0, 1H); 1,33 (s, 9H); 1,40-1,20 (m, 2H). IR (cm-1 , KBr): 2962 (m), 2868 (m), 1685 (s), 1589 (m), 1537 (s), 1519 (s), 1492 (s), 1407 (m), 1349 (m), 1243 (m), 1219 (m), 1134 (w), 1121 (w), 1091 (s), 1047 (w), 1009 (w), 830 (s). EM (m/z): 420,1 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0 ml), Et3N (54 µl, 0.39 mmol), reagent BOP (160 mg, 0.36 mmol) and 4-tert-butylaniline (62 µl, 0.38 mmol) produced the title compound (100 mg, 69%). P.F .: 76-78 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 8.65 (s, 1H); 7.67 (d, J = 8.7, 2H); 7.63 (d, J = 8.7, 2H); 7.47 (d, J = 8.7, 2H); 7.37 (d, J = 9.0, 2H); 3.81 (s, 1H), 3.70 (s, 1H), 2.16 (d, J = 9.0, 1H); 2.02 (d, J = 8.4, 2H); 1.75 (d, J = 9.0, 1H); 1.33 (s, 9H); 1.40-1.20 (m, 2H). IR (cm-1, KBr): 2962 (m), 2868 (m), 1685 (s), 1589 (m), 1537 (s), 1519 (s), 1492 (s), 1407 (m), 1349 (m), 1243 (m), 1219 (m), 1134 (w), 1121 (w), 1091 (s), 1047 (w), 1009 (w), 830 (s). MS (m / z): 420.1 ([M + H] +).

Ejemplo 220 Example 220

N(3)-Bencil-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N (3) -Benzyl-1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 16 (100 mg, 0,35 mmol), DMF (1,0 ml), Et3N (48 µl, 0,35 mmol), reactivo BOP (152 mg, 0,35 mmol) y bencilamina (37 µl, 0,35 mmol) dio el compuesto del título (67 mg, 51%). P.F.: 112-115 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,61 (d, J = 9,0, 2H); 7,45-7,20 (m, 8H); 4,63 (d a, J = 5,7, 2H); 3,78 (s, 1H); 3,68 (s, 1H); 2,14 (d a, J = 8,5, 1H); 2,05-1,90 (m, 2H); 1,73 (d a, J = 8,5, 1H); 1,35-1,17 (m, 2H). IR (KBr, cm-1): 3318 (m), 2995 (m), 2930 (m), 1652 (s), 1548 (s), 1501 (s), 1352 (m), 1275 (m), 1239 (m), 1120 (m), 1089 (m), 830 (m), 701(w), 508 (w). EM (m/z): 378,3 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0 ml), Et3N (48 µl, 0.35 mmol), reagent BOP (152 mg, 0.35 mmol) and benzylamine (37 µl, 0.35 mmol) gave the title compound (67 mg, 51%). P.F .: 112-115 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.61 (d, J = 9.0, 2H); 7.45-7.20 (m, 8H); 4.63 (d a, J = 5.7, 2H); 3.78 (s, 1 H); 3.68 (s, 1 H); 2.14 (d a, J = 8.5, 1H); 2.05-1.90 (m, 2H); 1.73 (d a, J = 8.5, 1H); 1.35-1.17 (m, 2H). IR (KBr, cm-1): 3318 (m), 2995 (m), 2930 (m), 1652 (s), 1548 (s), 1501 (s), 1352 (m), 1275 (m), 1239 (m), 1120 (m), 1089 (m), 830 (m), 701 (w), 508 (w). MS (m / z): 378.3 ([M + H] +).

Ejemplo 221 Example 221

N(3)-(2-Clorobencil)-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) - (2-Chlorobenzyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 16 (100 mg, 0,35 mmol), DMF (1,0 ml), Et3N (48 µl, 0,35 mmol), reactivo BOP (152 mg, 0,35 mmol) y 2-clorobencilamina (41 µl, 0,35 mmol) dio el compuesto del título (91 mg, 64%). P.F.:119-122 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,63 (d, J = 9,0, 2H); 7,43 (d, J = 9,0, 2H); 7,51-7,20 (m, 5H); 4,72 (d, J = 6,3, 2H); 3,76 (s,1H); 3,67 (s, 1H); 2,12 (d a, J = 8,6, 1H); 2,10-1,90 (m, 2H); 1,73 (d a, J = 8,6, 1H); 1:35-1,19 (m, 2H). IR (KBr, cm-1): 3319 (m), 2955 (m), 2868 (m), 1651 (s), 1595 (m), 1547 (m), 1490 (s), 1442 (m), 1352 (m), 1277 (m), 1237 (m), 1160 (m), 1123 (m), 1091 (m), 1007 (m), 993 (m), 835 (m). EM (m/z): 412,0 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0 ml), Et3N (48 µl, 0.35 mmol), reagent BOP (152 mg, 0.35 mmol) and 2-chlorobenzylamine (41 µl, 0.35 mmol) gave the title compound (91 mg, 64%). P.F.:119-122 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.63 (d, J = 9.0, 2H); 7.43 (d, J = 9.0, 2H); 7.51-7.20 (m, 5H); 4.72 (d, J = 6.3, 2H); 3.76 (s, 1 H); 3.67 (s, 1 H); 2.12 (d a, J = 8.6, 1H); 2.10-1.90 (m, 2H); 1.73 (d a, J = 8.6, 1H); 1: 35-1.19 (m, 2H). IR (KBr, cm-1): 3319 (m), 2955 (m), 2868 (m), 1651 (s), 1595 (m), 1547 (m), 1490 (s), 1442 (m), 1352 (m), 1277 (m), 1237 (m), 1160 (m), 1123 (m), 1091 (m), 1007 (m), 993 (m), 835 (m). MS (m / z): 412.0 ([M + H] +).

Ejemplo 222 Example 222

N(3)-(4-Clorobencil)-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) - (4-Chlorobenzyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 16 (100 mg, 0,35 mmol), DMF (1,0 ml), Et3N (48 µl, 0,35 mmol), reactivo BOP (152 mg, 0,35 mmol) y 4-clorobencilamina (42 µl, 0,35 mmol) produjo el compuesto del título (104 mg, 73%). P.F.: 157-160 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,61 (d, J = 8,7, 2H); 7,42 (d, J = 8,7, 2H); 7,31 (s, 4H); 7,23 (s a, 1H); 4,59 (d, J = 5,6 , 2H); 3,77 (s, 1H); 3,68 (s,1H); 2,14 (d a, J = 8,6, 1H); 2,10-1,90 (m, 2H); 1,73 (d a, J = 8,6,1H); 1,35-1,18 (m, 2H).IR (KBr, cm-1): 3324 (m), 2979 (m), 2951 (m), 2875 (m), 1649 (s), 1560 (s), 1513 (s), 1444 (m), 1406 (m), 1354 (m), 1244 (m), 1160 (m), 1144 (m), 1092 (s), 1007 (m), 980 (m), 946 (m), 835 (s), 626 (m), 509 (w). EM (m/z): 412,0 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0 ml), Et3N (48 µl, 0.35 mmol), reagent BOP (152 mg, 0.35 mmol) and 4-chlorobenzylamine (42 µl, 0.35 mmol) produced the title compound (104 mg, 73%). P.F .: 157-160 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.61 (d, J = 8.7, 2H); 7.42 (d, J = 8.7, 2H); 7.31 (s, 4H); 7.23 (s a, 1 H); 4.59 (d, J = 5.6, 2H); 3.77 (s, 1 H); 3.68 (s, 1 H); 2.14 (d a, J = 8.6, 1H); 2.10-1.90 (m, 2H); 1.73 (d a, J = 8.6.1H); 1.35-1.18 (m, 2H) .IR (KBr, cm-1): 3324 (m), 2979 (m), 2951 (m), 2875 (m), 1649 (s), 1560 (s ), 1513 (s), 1444 (m), 1406 (m), 1354 (m), 1244 (m), 1160 (m), 1144 (m), 1092 (s), 1007 (m), 980 (m ), 946 (m), 835 (s), 626 (m), 509 (w). MS (m / z): 412.0 ([M + H] +).

Ejemplo 223 Example 223

N(3)-(2,4-Diclorobencil)-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) - (2,4-Dichlorobenzyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 16 (100 mg, 0,35 mmol), DMF (1,0 ml), Et3N (48 µl, 0,35 mmol), reactivo BOP (152 mg, 0,35 mmol) y 2,4diclorobencilamina (46 µl, 0,35 mmol) dio el compuesto del título (104 mg, 67%). P.F.: 108-111 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,62 (d, J = 8,7, 2H); 7,50-7,30 (m, 4H); 7,34 (s a, 1H); 4,70 (d, J = 6,3, 2H); 3,75 (s, 1H); 3,68 (s, 1H); 2,13 (d a, J = 9,0, 1H); 2,10-1,90 (m, 2H); 1,73 (d a, J = 9,0, 1H); 1,40-1,18 (m, 2H) IR (KBr, cm-1): 3294 (m), 2988 (w), 2949 (w), 1652 (s), 1554 (m), 1502 (s), 1491 (s), 1356 (m), 1252 (m), 1092 (m), 831 (s). EM (m/z): 447,9 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0 ml), Et3N (48 µl, 0.35 mmol), reagent BOP (152 mg, 0.35 mmol) and 2,4-dichlorobenzylamine (46 µl, 0.35 mmol) gave the title compound (104 mg, 67%). P.F .: 108-111 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.62 (d, J = 8.7, 2H); 7.50-7.30 (m, 4H); 7.34 (s a, 1 H); 4.70 (d, J = 6.3, 2H); 3.75 (s, 1 H); 3.68 (s, 1 H); 2.13 (d a, J = 9.0, 1H); 2.10-1.90 (m, 2H); 1.73 (d a, J = 9.0, 1H); 1.40-1.18 (m, 2H) IR (KBr, cm-1): 3294 (m), 2988 (w), 2949 (w), 1652 (s), 1554 (m), 1502 (s) , 1491 (s), 1356 (m), 1252 (m), 1092 (m), 831 (s). MS (m / z): 447.9 ([M + H] +).

Ejemplo 224 Example 224

N(3)-(2-Bromobencil)-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) - (2-Bromobenzyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 16 (100 mg, 0,35 mmol), DMF (1,0 ml), Et3N (0,10 ml, 0,69 mmol), reactivo BOP (0,153 g, 0,35 mmol) y clorhidrato de 2bromobencilamina (77 mg, 0,35 mmol) para dar el compuesto del título (105 mg, 67%). P.F.:141-142 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz):7,60-7,50 (m, 3H); 7,50-7,22 (m, 5H); 7,14 (td, J = 7,8, 1,5, 1H); 4,70 (d, J = 6,3, 2H); 3,80 (s, 1H); 3,70 (s, 1H); 2,14 (d a, J = 8,7, 1H); 2,10-1,80 (m, 2H); 1,70 (d a, J = 8,7, 1H); 1,35-1,15 (m, 2H). IR (KBr, cm-1): 3322 (m), 2954 (w), 2867 (w), 1651 (s), 1548 (m), 1503 (s), 1350 (m), 1277 (w), 1236 (w), 1091 (s), 835 (m). EM (m/z): 458,1 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0 ml), Et3N (0.10 ml, 0.69 mmol) , BOP reagent (0.153 g, 0.35 mmol) and 2-bromobenzylamine hydrochloride (77 mg, 0.35 mmol) to give the title compound (105 mg, 67%). P.F.:141-142 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.60-7.50 (m, 3H); 7.50-7.22 (m, 5H); 7.14 (td, J = 7.8, 1.5, 1H); 4.70 (d, J = 6.3, 2H); 3.80 (s, 1 H); 3.70 (s, 1 H); 2.14 (d a, J = 8.7, 1H); 2.10-1.80 (m, 2H); 1.70 (d a, J = 8.7, 1H); 1.35-1.15 (m, 2H). IR (KBr, cm-1): 3322 (m), 2954 (w), 2867 (w), 1651 (s), 1548 (m), 1503 (s), 1350 (m), 1277 (w), 1236 (w), 1091 (s), 835 (m). MS (m / z): 458.1 ([M + H] +).

Ejemplo 225 Example 225

N(3)-(4-Bromobencil)-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) - (4-Bromobenzyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 16 (100 mg, 0,35 mmol), DMF (1,0 ml), Et3N (0,096 ml, 0,69 mmol), reactivo BOP (0,153 g, 0,35 mmol) y clorhidrato de 4-bromobencilamina (77 mg.0,35 mmol) produjo el compuesto del título (118 mg, 64%). P.F.: 181-183 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,60 (d, J = 6,9, 2H); 7,50-7,40 (m, 4H); 7,30-7,20 (m, 2H); 4,60 (d a, J = 5,1, 2H); 3,80 (s, 1H); 3,70 (s, 1H); 2,14 (d a, J = 9,0, 1H); 2,07-1,92 (m, 2H); 1,70 (d a, J = 9,0, 1H); 1,30-1,15 (m, 2H).IR (KBr, cm-1): 3325 (m), 2979 (m), 2950 (m), 1648 (s), 1558 (m), 1505 (s), 1489 (s), 1353 (m), 1253 (m), 1092 (m), 835 (s).EM (m/z): 458,0 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0 ml), Et3N (0.096 ml, 0.69 mmol), reagent BOP (0.153 g, 0.35 mmol) and 4-bromobenzylamine hydrochloride (77 mg 0.35 mmol) produced the title compound (118 mg, 64%). P.F .: 181-183 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.60 (d, J = 6.9, 2H); 7.50-7.40 (m, 4H); 7.30-7.20 (m, 2H); 4.60 (d a, J = 5.1, 2H); 3.80 (s, 1 H); 3.70 (s, 1 H); 2.14 (d a, J = 9.0, 1H); 2.07-1.92 (m, 2H); 1.70 (d a, J = 9.0, 1H); 1.30-1.15 (m, 2H) .IR (KBr, cm-1): 3325 (m), 2979 (m), 2950 (m), 1648 (s), 1558 (m), 1505 (s ), 1489 (s), 1353 (m), 1253 (m), 1092 (m), 835 (s) .EM (m / z): 458.0 ([M + H] +).

Ejemplo 226 Example 226

N(3)-(4-Fluorobencil)-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) - (4-Fluorobenzyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 16 (100 mg, 0,35 mmol), DMF (1,0 ml), Et3N (48 µl, 0,35 mmol), reactivo BOP (152 mg, 0,35 mmol) y 4fluorobencilamina (39 µl, 0,35 mmol) produjo el compuesto del título (95 mg, 69%). P.F.:104-107 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,61 (d, J = 9,0, 2H); 7,42 (d, J = 9,0, 2H); 7,35 (dd, J = 8,6, 5,7, 2H); 7,21 (s a, 1H); 7,02 (t, J = 8,6, 2H); 4,59 (d, J = 6,0, 2H); 3,77 (s, 1H); 3,68 (s,1H); 2,13 (d a, J = 8,7, 1H); 2,10-1,90 (m, 2H); 1,73 (d a, J = 9,0, 1H); 1,40-1,18 (m, 2H).IR (KBr, cm-1): 3314 (m), 2968 (m), 2940 (m), 2872 (w), 1647 (s), 1554 (m), 1509 (s), 1357 (m), 1218 (m), 1091 (s), 832 (s), 626 (w), 564 (w). EM (m/z): 396,1([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0 ml), Et3N (48 µl, 0.35 mmol), reagent BOP (152 mg, 0.35 mmol) and 4fluorobenzylamine (39 µl, 0.35 mmol) produced the title compound (95 mg, 69%). P.F. 10:4-107 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.61 (d, J = 9.0, 2H); 7.42 (d, J = 9.0, 2H); 7.35 (dd, J = 8.6, 5.7, 2H); 7.21 (s a, 1 H); 7.02 (t, J = 8.6, 2H); 4.59 (d, J = 6.0, 2H); 3.77 (s, 1 H); 3.68 (s, 1 H); 2.13 (d a, J = 8.7, 1H); 2.10-1.90 (m, 2H); 1.73 (d a, J = 9.0, 1H); 1.40-1.18 (m, 2H) .IR (KBr, cm-1): 3314 (m), 2968 (m), 2940 (m), 2872 (w), 1647 (s), 1554 (m ), 1509 (s), 1357 (m), 1218 (m), 1091 (s), 832 (s), 626 (w), 564 (w). MS (m / z): 396.1 ([M + H] +).

Ejemplo 227 Example 227

N(3)-(4-Trifluorometilbencil)-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) - (4-Trifluoromethylbenzyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 16 (100 mg, 0,35 mmol) , DMF (1,0 ml), Et3N (48 µl, 0,35 mmol), reactivo BOP (152 mg, 0,35 mmol) y 4The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0 ml), Et3N (48 µl, 0.35 mmol), reagent BOP (152 mg, 0.35 mmol) and 4

trifluorometilbencilamina (49 µl, 0,35 mmol) proporcionaron el compuesto del título (104 mg, 68%). M. P.: 165-168 ºC.RMN 1H(δ ppm, CDCl3, 300 MHz): 7,67-7,57 (m, 4H); 7,48 (d, J = 8,7, 2H); 7,43 (d, J = 8,7, 2H);7,30 (t a, J = 6,0, 1H); 4,68 (d, J = 5,7, 2H); 3,77 (s, 1H); 3,69 (s, 1H); 2,13 (d a, J = 8,4, 1H); 2,10-1,90 (m, 2H); 1,73 (d a, J = 7,2, 1H); 1,30-1,18 (m, 2H). IR (KBr, cm-1):3323 (m), 2969 (m), 2953 (m), 2874 (w), 1648 (s), 1557 (m), 1504 (s), 1439 (m), 1406 (m), 1417 (m), 1325 (s), 1282 (m), 1245 (m), 1161 (s), 1122 (s), 1110 (s), 1092 (s), 1064 (s), 847 (m), 832 (m), 625 (w), 509 (w). EM (m/z): 446,0 ([M+H]+). Trifluoromethylbenzylamine (49 µL, 0.35 mmol) provided the title compound (104 mg, 68%). M.P .: 165-168 ° C. RMN 1H (δ ppm, CDCl3, 300 MHz): 7.67-7.57 (m, 4H); 7.48 (d, J = 8.7, 2H); 7.43 (d, J = 8.7, 2H); 7.30 (t a, J = 6.0, 1H); 4.68 (d, J = 5.7, 2H); 3.77 (s, 1 H); 3.69 (s, 1 H); 2.13 (d a, J = 8.4, 1H); 2.10-1.90 (m, 2H); 1.73 (d a, J = 7.2, 1H); 1.30-1.18 (m, 2H). IR (KBr, cm-1): 3323 (m), 2969 (m), 2953 (m), 2874 (w), 1648 (s), 1557 (m), 1504 (s), 1439 (m), 1406 (m), 1417 (m), 1325 (s), 1282 (m), 1245 (m), 1161 (s), 1122 (s), 1110 (s), 1092 (s), 1064 (s), 847 (m), 832 (m), 625 (w), 509 (w). MS (m / z): 446.0 ([M + H] +).

Ejemplo 228 Example 228

N(3)-Fenilamino-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) -Phenylamino-1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 16 (100 mg, 0,35 mmol), DMF (1,0 ml), Et3N (48 µl, 0,35 mmol), reactivo BOP (152 mg, 0,35 mmol) y fenilhidrazina (34 µl, 0,35 mmol) dieron el compuesto del título (92 mg, 70%). P.F.: 138-141 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,55 (s, 1H); 7,67 (d, J = 8,5, 2H); 7,46 (d, J = 8,5, 2H); 7,24 (t, J = 7,5, 2H); 6,95 (d, J = 8,4, 2H); 6,90 (t, J = 7,5); 3,71 (s a, 2H); 2,13 (d a, J = 8,1, 1H); 2,10-1,95 (m, 2H); 1,73 (d a, J = 8,7, 1H); 1,40-1,18 (m, 2H). IR (KBr, cm-1): 3258 (m), 2951 (m), 1660 (s), 1603 (s), 1500 (s), 1358 (m), 1306 (m), 1277 (m), 1127 (m), 1092 (s), 892 (w), 828 (m), 749 (m), 691 (m), 510 (m). EM (m/z): 379,0 ([M+H]+), The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0 ml), Et3N (48 µl, 0.35 mmol), reagent BOP (152 mg, 0.35 mmol) and phenylhydrazine (34 µl, 0.35 mmol) gave the title compound (92 mg, 70%). P.F .: 138-141 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 8.55 (s, 1H); 7.67 (d, J = 8.5, 2H); 7.46 (d, J = 8.5, 2H); 7.24 (t, J = 7.5, 2H); 6.95 (d, J = 8.4, 2H); 6.90 (t, J = 7.5); 3.71 (s a, 2H); 2.13 (d a, J = 8.1, 1H); 2.10-1.95 (m, 2H); 1.73 (d a, J = 8.7, 1H); 1.40-1.18 (m, 2H). IR (KBr, cm-1): 3258 (m), 2951 (m), 1660 (s), 1603 (s), 1500 (s), 1358 (m), 1306 (m), 1277 (m), 1127 (m), 1092 (s), 892 (w), 828 (m), 749 (m), 691 (m), 510 (m). MS (m / z): 379.0 ([M + H] +),

Ejemplo 229 Example 229

N(3)-[(4-Clorofenil)amino]-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) - [(4-Chlorophenyl) amino] -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 16 (100 mg, 0,35 mmol), DMF (1,0 ml), Et3N (48 µl, 0,35 mmol), reactivo BOP (152 mg, 0,35 mmol) y clorhidrato de 4clorofenilhidrazina (61 µg, 0,35 mmol) para dar el compuesto del título (98 mg, 69%). P.F.:202-205 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,60 (s, 1H); 7,66 (d, J = 9,0, 2H); 7,47 (d, J = 9,0, 2H); 7,18 (d, J = 8,6, 2H); 6,87 (d, J = 8,6, 2H); 3,71 (s, 2H); 2,13 (d a, J = 8,7, 1H); 2,10-1,90 (m, 2H); 1,73 (d a, J = 9,0, 1H); 1,38-1,18 (m, 2H). IR (KBr, cm-1): 3256 (m), 2995 (m), 2950 (m), 2870 (m), 1661 (s), 1595 (m), 1500 (s), 1357 (m), 1278 (m), 1236 (m), 1128 (m), 1092 (s), 894 (w), 826 (m), 658 (w), 610 (w), 503 (w). EM (m/z): 413,0 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0 ml), Et3N (48 µl, 0.35 mmol), reagent BOP (152 mg, 0.35 mmol) and 4-chlorophenylhydrazine hydrochloride (61 µg, 0.35 mmol) to give the title compound (98 mg, 69%). P.F.:202-205 ° C. 1 H NMR (δ ppm, CDCl 3, 300 MHz): 8.60 (s, 1 H); 7.66 (d, J = 9.0, 2H); 7.47 (d, J = 9.0, 2H); 7.18 (d, J = 8.6, 2H); 6.87 (d, J = 8.6, 2H); 3.71 (s, 2H); 2.13 (d a, J = 8.7, 1H); 2.10-1.90 (m, 2H); 1.73 (d a, J = 9.0, 1H); 1.38-1.18 (m, 2H). IR (KBr, cm-1): 3256 (m), 2995 (m), 2950 (m), 2870 (m), 1661 (s), 1595 (m), 1500 (s), 1357 (m), 1278 (m), 1236 (m), 1128 (m), 1092 (s), 894 (w), 826 (m), 658 (w), 610 (w), 503 (w). MS (m / z): 413.0 ([M + H] +).

Ejemplo 230 Example 230

N(3)-[(2,4-Diclorofenil)amino]-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) - [(2,4-Dichlorophenyl) amino] -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 16 (100 mg, 0,35 mmol), DMF (1,0 ml), Et3N (57 µl, 0,42 mmol), reactivo BOP (152 mg, 0,35 mmol) y clorhidrato de 2,4diclorofenilhidrazina (73 mg, 0,35 mmol) produjeron el compuesto del título (53 mg, 34%). M. P. = 180-182 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,54 (d, J = 3,0, 1H); 7,66 (d, J = 8,7, 2H); 7,47 (d, J = 8,7, 2H); 7,31 (d, J = 2,1, 1H); 7,11 (dd, J = 8,7, 2,1, 1H); 6,96 (d, J = 8,7, 1H); 6,51 (d, J = 3,0, 1H); 3,71 (s a, 2H); 2,13 (d a, J = 7,8, 1H); 2,0 (m, 2H); 1,74 (d a, J = 9,0, 1H); 1,232-1,25 (m, 2H). IR (KBr, cm-1): 3301 (m), 2993 (m), 2873 (m), 1674 (s), 1595 (w), 1542 (m), 1499 (s), 1352 (m), 1304 (m), 1232 (m), 1021 (m), 1049 (m), 814 (m). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0 ml), Et3N (57 µl, 0.42 mmol), reagent BOP (152 mg, 0.35 mmol) and 2,4-dichlorophenylhydrazine hydrochloride (73 mg, 0.35 mmol) produced the title compound (53 mg, 34%). M. P. = 180-182 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 8.54 (d, J = 3.0, 1H); 7.66 (d, J = 8.7, 2H); 7.47 (d, J = 8.7, 2H); 7.31 (d, J = 2.1, 1H); 7.11 (dd, J = 8.7, 2.1, 1H); 6.96 (d, J = 8.7, 1H); 6.51 (d, J = 3.0, 1H); 3.71 (s a, 2H); 2.13 (d a, J = 7.8, 1H); 2.0 (m, 2H); 1.74 (d a, J = 9.0, 1H); 1,232-1.25 (m, 2H). IR (KBr, cm-1): 3301 (m), 2993 (m), 2873 (m), 1674 (s), 1595 (w), 1542 (m), 1499 (s), 1352 (m), 1304 (m), 1232 (m), 1021 (m), 1049 (m), 814 (m).

Ejemplo 231 Example 231

N(3)-[(3,4-Diclorofenil)amino]-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) - [(3,4-Dichlorophenyl) amino] -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 16 (200 mg, 0,69 mmol), DMF (2,0 ml), Et3N (0,193 ml,.1,38 mmol), reactivo BOP (306 mg, 0,69 mmol) y clorhidrato de 3,4-diclorofenilhidrazina (148 mg, 0,69 mmol) dio el compuesto del título (222 mg, 64,5%). P.F.: 235-237 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,50 (s, 1H); 7,67 (d, J = 9,0, 2H); 7,48 (d, J = 9,0, 2H); 7,28 (d, J = 8,4, 1H); 7,05 (d, J = 2,4, 1H); 6,79 (dd, J = 8,4, 2,4, 1H); 6,19 (s a, 1H); 3,70 (s, 2H); 2,14 (d a, J = 8,5, 1H); 2,10-1,90 (m, 2H); 1,7 (d a, J = 8,5, 1H); 1,30-1,18 (m, 2H). IR (KBr, cm-1): 3250 (m), 2995 (w), 2968 (w), 2946 (w), 2869 (m), 1667 (s), 1650 (s), 1598 (m), 1500 (s), 1475 (s), 1353 (m), 1277 (m), 1092 (m), 828 (m), 610 (w). EM (m/z): 449,0 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 16 (200 mg, 0.69 mmol), DMF (2.0 ml), Et3N (0.193 ml,. 1.38 mmol), BOP reagent (306 mg, 0.69 mmol) and 3,4-dichlorophenylhydrazine hydrochloride (148 mg, 0.69 mmol) gave the title compound (222 mg, 64.5%). P.F .: 235-237 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 8.50 (s, 1H); 7.67 (d, J = 9.0, 2H); 7.48 (d, J = 9.0, 2H); 7.28 (d, J = 8.4, 1H); 7.05 (d, J = 2.4, 1H); 6.79 (dd, J = 8.4, 2.4, 1H); 6.19 (s a, 1 H); 3.70 (s, 2 H); 2.14 (d a, J = 8.5, 1H); 2.10-1.90 (m, 2H); 1.7 (d a, J = 8.5, 1H); 1.30-1.18 (m, 2H). IR (KBr, cm-1): 3250 (m), 2995 (w), 2968 (w), 2946 (w), 2869 (m), 1667 (s), 1650 (s), 1598 (m), 1500 (s), 1475 (s), 1353 (m), 1277 (m), 1092 (m), 828 (m), 610 (w). MS (m / z): 449.0 ([M + H] +).

Ejemplo 232 Example 232

N(3)-[(2-Fluorofenil)amino]-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) - [(2-Fluorophenyl) amino] -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 16 (200 mg, 0,69 mmol), DMF (2,0 ml), Et3N (0,193 ml, 1,38 mmol), reactivo BOP (306 mg, 0,69 mmol) y clorhidrato de 2-fluorofenilhidrazina (113 mg, 0,69 mmol) dieron el compuesto del título (240 mg, 87%). P.F.: 91 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,50 (s, 1H); 7,65 (d, J = 7,2, 2H); 7,46 (d, J = 7,2, 2H); 6,95-7,10 (m, 3H); 6,80-6,90 (m, 1H); 6,40 (s a, 1H); 3,70 (s a, 2H); 2,14 (d a, J = 9,0, 1H); 2,05-1,90 (m, 2H); 1,70 (d a, J = 9,0, 1H); 1,30-1,17 (m, 2H). IR (KBr, cm-1): 3292 (m), 2925 (m), 2870 (m), 1676 (s), 1502 (s), 1351 (m), 1276 (m), 1194 (m), 1091 (s), 831 (s). EM (m/z): 397,0 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 16 (200 mg, 0.69 mmol), DMF (2.0 ml), Et3N (0.193 ml, 1.38 mmol), reagent BOP (306 mg, 0.69 mmol) and 2-fluorophenylhydrazine hydrochloride (113 mg, 0.69 mmol) gave the title compound (240 mg, 87%). P.F .: 91 ºC. 1H NMR (δ ppm, CDCl3, 300 MHz): 8.50 (s, 1H); 7.65 (d, J = 7.2, 2H); 7.46 (d, J = 7.2, 2H); 6.95-7.10 (m, 3H); 6.80-6.90 (m, 1 H); 6.40 (s at, 1 H); 3.70 (s at, 2H); 2.14 (d a, J = 9.0, 1H); 2.05-1.90 (m, 2H); 1.70 (d a, J = 9.0, 1H); 1.30-1.17 (m, 2H). IR (KBr, cm-1): 3292 (m), 2925 (m), 2870 (m), 1676 (s), 1502 (s), 1351 (m), 1276 (m), 1194 (m), 1091 (s), 831 (s). MS (m / z): 397.0 ([M + H] +).

Ejemplo 233 Example 233

N(3)-[(3-Fluorofenil)amino]-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) - [(3-Fluorophenyl) amino] -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 16 (200 mg, 0,69 mmol), DMF (2,0 ml), Et3N (0,193 ml, 1,38 mmol), reactivo BOP (306 mg, 0,69 mmol) y clorhidrato de 3-fluorofenilhidrazina (113 mg, 0,69 mmol) produjo el compuesto del título (158 mg, 58%). P.F.: 199 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,50 (s, 1H), 7,70 (d, J = 9,0, 2H); 7,50 (d, J = 9,0, 2H); 7,30-7,10 (m, 1H); 6,70-6,50 (m, 3H); 6,20 (s a, 1H); 3,70 (s, 2H); 2,14 (d a, J = 9,0, 1H); 2,10-1,90 (m, 2H); 1,73 (d a, J = 9,0, 1H); 1,35-1,18 (m, 2H). IR (KBr, cm-1): 3257 (m), 2952 (w), 2872 (w), 1663 (s), 1619 (m), 1597 (m), 1501 (s), 1358 (m), 1266 (m), 1092 (m), 827 (m). EM (m/z): 397,1 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 16 (200 mg, 0.69 mmol), DMF (2.0 ml), Et3N (0.193 ml, 1.38 mmol), reagent BOP (306 mg, 0.69 mmol) and 3-fluorophenylhydrazine hydrochloride (113 mg, 0.69 mmol) produced the title compound (158 mg, 58%). P.F .: 199 ºC. 1H NMR (δ ppm, CDCl3, 300 MHz): 8.50 (s, 1H), 7.70 (d, J = 9.0, 2H); 7.50 (d, J = 9.0, 2H); 7.30-7.10 (m, 1 H); 6.70-6.50 (m, 3H); 6.20 (s a, 1 H); 3.70 (s, 2 H); 2.14 (d a, J = 9.0, 1H); 2.10-1.90 (m, 2H); 1.73 (d a, J = 9.0, 1H); 1.35-1.18 (m, 2H). IR (KBr, cm-1): 3257 (m), 2952 (w), 2872 (w), 1663 (s), 1619 (m), 1597 (m), 1501 (s), 1358 (m), 1266 (m), 1092 (m), 827 (m). MS (m / z): 397.1 ([M + H] +).

Ejemplo 234 Example 234

N(3)-[(4-Fluorofenil)amino]-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) - [(4-Fluorophenyl) amino] -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 16 (200 mg, 0,69 mmol), DMF (2,0 ml), Et3N (0,193 ml, 1,38 mmol), reactivo BOP (306 mg, 0,69 mmol) y clorhidrato de 4-fluorofenilhidrazina (113 mg, 0,69 mmol) produjo el compuesto del título (179 mg, 65%). P.F.: 212 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,50 (s, 1H); 7,70 (d, J = 9,0, 2H); 7,50 (d, J = 9,0, 2H); 7,00-6,80 (m, 4H); 3,70 (s, 2H); 2,14 (d a, J = 9,0, 1H); 2,07-1,90 (m, 2H); 1,73 (d a, J = 9,0, 1H); 1,35-1,18 (m, 2H). IR (KBr, cm-1): 3268 (m), 2986 (w), 2950 (w), 1663 (m), 1502 (s), 1359 (m), 1214 (w), 1092 (m), 827 (m), 504 (w). EM (m/z): 397,0 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 16 (200 mg, 0.69 mmol), DMF (2.0 ml), Et3N (0.193 ml, 1.38 mmol), reagent BOP (306 mg, 0.69 mmol) and 4-fluorophenylhydrazine hydrochloride (113 mg, 0.69 mmol) produced the title compound (179 mg, 65%). P.F .: 212 ºC. 1H NMR (δ ppm, CDCl3, 300 MHz): 8.50 (s, 1H); 7.70 (d, J = 9.0, 2H); 7.50 (d, J = 9.0, 2H); 7.00-6.80 (m, 4H); 3.70 (s, 2 H); 2.14 (d a, J = 9.0, 1H); 2.07-1.90 (m, 2H); 1.73 (d a, J = 9.0, 1H); 1.35-1.18 (m, 2H). IR (KBr, cm-1): 3268 (m), 2986 (w), 2950 (w), 1663 (m), 1502 (s), 1359 (m), 1214 (w), 1092 (m), 827 (m), 504 (w). MS (m / z): 397.0 ([M + H] +).

Ejemplo 235 Example 235

N(3)-[(2,4-Difluorofenil)amino]-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7 metano-indazol-3-carboxamida N (3) - [(2,4-Difluorophenyl) amino] -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7 methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 16 (200 mg, 0,69 mmol), DMF (2,0 ml), Et3N (0,19 ml, 1,38 mmol), reactivo BOP (306 mg, 0,69 mmol) y clorhidrato 2,4difluorofenilhidrazina (113 mg, 0,69 mmol) para dar el compuesto del título (160 mg, 56%). P.F.:118-120 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,50 (s a, 1H); 7,70 (d, J = 8,7, 2H); 7,50 (d, J = 8,7, 2H); 7,10-6,70 (m, 3H); 6,25 (s a, 1H); 3,70 (s, 2H); 2,14 (d a, J = 8,7, 1H); 2, 08-1,95 (m, 2H); 1,70 (d a, J = 8,7, 1H); 1,35-1,20 (m, 2H). IR (KBr, cm-1): 3422 (m), 3286 (m), 2925 (m), 2871 (w), 1666 (m), 1501 (s), 1093 (m), 961 (m), 831 (m). EM (m/z): 417,1 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 16 (200 mg, 0.69 mmol), DMF (2.0 ml), Et3N (0.19 ml, 1.38 mmol) , BOP reagent (306 mg, 0.69 mmol) and 2,4-difluorophenylhydrazine hydrochloride (113 mg, 0.69 mmol) to give the title compound (160 mg, 56%). P.F.:118-120 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 8.50 (s at, 1H); 7.70 (d, J = 8.7, 2H); 7.50 (d, J = 8.7, 2H); 7.10-6.70 (m, 3H); 6.25 (s a, 1 H); 3.70 (s, 2 H); 2.14 (d a, J = 8.7, 1H); 2, 08-1.95 (m, 2H); 1.70 (d a, J = 8.7, 1H); 1.35-1.20 (m, 2H). IR (KBr, cm-1): 3422 (m), 3286 (m), 2925 (m), 2871 (w), 1666 (m), 1501 (s), 1093 (m), 961 (m), 831 (m). MS (m / z): 417.1 ([M + H] +).

Ejemplo 236 Example 236

N(3)-(N’,N’-Difenilamino-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7metano-indazol-3-carboxamida N (3) - (N ’, N’-Diphenylamino-1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 16 (200 mg, 0,69 mmol), DMF (2,0 ml), Et3N (0,19 ml, 1,38 mmol), reactivo BOP (306 mg, 0,69 mmol) y clorhidrato de N,N-difenilhidrazina (113 mg, 0,69 mmol) dio el compuesto del título (250 mg, 79,4%). P.F.: 193-195 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,98 (s, 1H); 7,66 (d, J = 9,0, 2H); 7,45 (d, J = 9,0, 2H); 7,40-7,20 (m, 8H); 7,00 (m, 2H); 3,74 (s a, 1H); 3,71 (s a, 1H); 2,14 (d a, J = 8,7, 1H); 2,05-1,95 (m, 2H); 1,70 (d a, J = 8,7, 1H); 1,30-1,18 (m, 2H). IR (KBr, cm -1): 3232 (w), 2924 (m), 1664 (m), 1590 (m), 1497 (s), 1357 (m), 1223 (m), 1092 (m), 828 (w). EM (m/z): 455,0 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 16 (200 mg, 0.69 mmol), DMF (2.0 ml), Et3N (0.19 ml, 1.38 mmol) , BOP reagent (306 mg, 0.69 mmol) and N, N-diphenylhydrazine hydrochloride (113 mg, 0.69 mmol) gave the title compound (250 mg, 79.4%). P.F .: 193-195 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 8.98 (s, 1H); 7.66 (d, J = 9.0, 2H); 7.45 (d, J = 9.0, 2H); 7.40-7.20 (m, 8H); 7.00 (m, 2 H); 3.74 (s a, 1 H); 3.71 (s a, 1 H); 2.14 (d a, J = 8.7, 1H); 2.05-1.95 (m, 2H); 1.70 (d a, J = 8.7, 1H); 1.30-1.18 (m, 2H). IR (KBr, cm -1): 3232 (w), 2924 (m), 1664 (m), 1590 (m), 1497 (s), 1357 (m), 1223 (m), 1092 (m), 828 (w). MS (m / z): 455.0 ([M + H] +).

Ejemplo 237 Example 237

N(3)-Ciclohexil-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) -Cyclohexyl-1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 17 (100 mg, 0,31 mmol), DMF (1,0 ml), Et3N (43 µl, 0,31 mmol), reactivo BOP (136 mg, 0,31 mmol) y ciclohexilamina (33 µl, 0,31 mmol) dio el compuesto del título (104 mg, 83%). P.F.: 157-160 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,55 (s, 1H); 7,46 (d, J = 8,0, 1H); 7,37 (d, J = 8,0, 1H); 6,70 (d a, J = 8,1, 1H); 4,05 -3,85 (m, 1H); 3,75 (s a, 1H); 3,36 (s a, 1H); 2,13 (d, J = 8,1, 1H); 2,00-1,85 (m, 4H); 1,70-1,58 (m, 4H); 1,46-1,15 (m, 7H). IR (KBr, cm-1): 3398 (m), 2923 (m), 2850 (m), 1658 (s), 1543 (s), 1520 (s), 1485 (m), 1343 (m), 1249 (m), 1122 (m), 1105 (m), 836 (m). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0 ml), Et3N (43 µl, 0.31 mmol), reagent BOP (136 mg, 0.31 mmol) and cyclohexylamine (33 µl, 0.31 mmol) gave the title compound (104 mg, 83%). P.F .: 157-160 ° C. 1 H NMR (δ ppm, CDCl 3, 300 MHz): 7.55 (s, 1 H); 7.46 (d, J = 8.0, 1H); 7.37 (d, J = 8.0, 1H); 6.70 (d a, J = 8.1, 1H); 4.05-3.85 (m, 1 H); 3.75 (s a, 1 H); 3.36 (s at, 1 H); 2.13 (d, J = 8.1, 1H); 2.00-1.85 (m, 4H); 1.70-1.58 (m, 4H); 1.46-1.15 (m, 7H). IR (KBr, cm-1): 3398 (m), 2923 (m), 2850 (m), 1658 (s), 1543 (s), 1520 (s), 1485 (m), 1343 (m), 1249 (m), 1122 (m), 1105 (m), 836 (m).

Ejemplo 238 Example 238

N(3)-Ciclohexilmetil-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) -Cyclohexylmethyl-1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 17 (100 mg, 0,31 mmol), DMF (1,0 ml), Et3N (51 µl, 0,37 mmol), reactivo BOP (136 mg, 0,31 mmol) y ciclohexanometilamina (40 µl, 0,31 mmol) produjo el compuesto del título (90 mg, 69%). P.F.: 111-113 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,56 (s a, 1H); 7,45 (d, J = 8,7, 1H); 7,39 (d a, J = 8,7, 1H); 6,88 (t a, J = 6,3, 1H): 3,77 (s a, 1H); 3,36 (s a, 1H) ; 3,32-3,18 (m, 2H); 2,13 (d a, J = 8,6, 1H); 2,00-1,50 (m, 9H); 1,25-1,11 (m, 5H); 1,00-0,80 (m, 2H). IR (KBr, cm-1): 3291 (m), 2922 (s), 2948 (m), 1643 (s), 1553 (m), 1501 (s), 1486 (s), 1445 (m), 1351 (m), 1274 (m), 1241 (m), 1107 (m), 1074 (m), 869 (m), 831 (m), 800 (m), 623 (m). EM (m/z): 418,1 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0 ml), Et3N (51 µl, 0.37 mmol), reagent BOP (136 mg, 0.31 mmol) and cyclohexanomethylamine (40 µl, 0.31 mmol) produced the title compound (90 mg, 69%). P.F .: 111-113 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.56 (s at, 1H); 7.45 (d, J = 8.7, 1H); 7.39 (d a, J = 8.7, 1H); 6.88 (t a, J = 6.3, 1H): 3.77 (s a, 1H); 3.36 (s at, 1 H); 3.32-3.18 (m, 2H); 2.13 (d a, J = 8.6, 1H); 2.00-1.50 (m, 9H); 1.25-1.11 (m, 5H); 1.00-0.80 (m, 2H). IR (KBr, cm-1): 3291 (m), 2922 (s), 2948 (m), 1643 (s), 1553 (m), 1501 (s), 1486 (s), 1445 (m), 1351 (m), 1274 (m), 1241 (m), 1107 (m), 1074 (m), 869 (m), 831 (m), 800 (m), 623 (m). MS (m / z): 418.1 ([M + H] +).

Ejemplo 239 Example 239

N(3)-(N,N-Diciclohexilamino)-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7 metano-indazol-3-carboxamida N (3) - (N, N-Dicyclohexylamino) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7 methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 17 (100 mg, 0,31 mmol), DMF (1,0 ml), Et3N (51 µl, 0,37 mmol), reactivo BOP (136 mg, 0,31 mmol) y N,Ndiciclohexilhidrazina (121 mg, 0,31 mmol) dio el compuesto del título (70 mg, 45%) . P.F.: 127-130 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,56 (d, J = 2,1, 1H); 7,48 (d, J = 8,7, 1H); 7,35 (dd, J = 8,7, 2,1, 1H); 7,33 (s a, 1H); 3,78 (s, 1H); 3,37 (s, 1H); 2,84 (s a, 2H); 2,12 (d a, J = 8,4, 1H); 1,97-1,80 (m, 6H); 1,80-1,58 (m, 6H); 1,40-1,00 (m, 13H). IR (KBr, cm-1): 3328 (m), 2932 (s), 2854 (s), 1693 (s), 1537 (m), 1501 (m), 1482 (m), 1345 (m), 1229 (m), 1102 (m), 1079 (m), 867 (m), 837 (m). EM (m/z): 501,50 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0 ml), Et3N (51 µl, 0.37 mmol), reagent BOP (136 mg, 0.31 mmol) and N, Nicyclohexylhydrazine (121 mg, 0.31 mmol) gave the title compound (70 mg, 45%). P.F .: 127-130 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.56 (d, J = 2.1, 1H); 7.48 (d, J = 8.7, 1H); 7.35 (dd, J = 8.7, 2.1, 1H); 7.33 (s a, 1 H); 3.78 (s, 1 H); 3.37 (s, 1 H); 2.84 (s at, 2H); 2.12 (d a, J = 8.4, 1H); 1.97-1.80 (m, 6H); 1.80-1.58 (m, 6H); 1.40-1.00 (m, 13H). IR (KBr, cm-1): 3328 (m), 2932 (s), 2854 (s), 1693 (s), 1537 (m), 1501 (m), 1482 (m), 1345 (m), 1229 (m), 1102 (m), 1079 (m), 867 (m), 837 (m). MS (m / z): 501.50 ([M + H] +).

Ejemplo 240 Example 240

N(3)-(4H-1,2,4-triazol-4-il)-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7 metano-indazol-3-carboxamida N (3) - (4H-1,2,4-triazol-4-yl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7 methane-indazol- 3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 17 (100 mg, 0,31 mmol), DMF (1,0 ml), Et3N (42 µl, 0,31 mmol), reactivo BOP (136 mg, 0,31 mmol) y 4-amino-1,2,4triazol (26 mg, 0,31 mmol) dio el compuesto del título (38 mg, 32%). P.F.: 231-233 ºC. RMN 1H (δ ppm, DMSO-d6, 300 MHz): 11,95 (s, 1H); 8,72 (s, 2H); 8,0 (d, J = 2,1, 1H); 7,71 (d, J = 8,4, 1H); 7,67 (dd, J = 8,4, 2,1, 1H); 3,58 (s a, 1H); 3,41 (s, 1H); 2,05 (d a, J = 8,7, 1H); 1,98-1,90 (m, 2H); 1,71 (d, J = 8,7, 1H); 1,24-1,08 (m, 2H). IR (KBr, cm-1): 3125 (w), 3090 (m), 2997 (m), 2876 (m), 1699 (s), 1506 (s), 1350 (m), 1129 (m), 1065 (s), 923 (w), 826 (w). EM (m/z): 389,3 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0 ml), Et3N (42 µl, 0.31 mmol), reagent BOP (136 mg, 0.31 mmol) and 4-amino-1,2,4triazole (26 mg, 0.31 mmol) gave the title compound (38 mg, 32%). P.F .: 231-233 ° C. 1H NMR (δ ppm, DMSO-d6, 300 MHz): 11.95 (s, 1H); 8.72 (s, 2H); 8.0 (d, J = 2.1, 1H); 7.71 (d, J = 8.4, 1H); 7.67 (dd, J = 8.4, 2.1, 1H); 3.58 (s at, 1 H); 3.41 (s, 1 H); 2.05 (d a, J = 8.7, 1H); 1.98-1.90 (m, 2H); 1.71 (d, J = 8.7, 1H); 1.24-1.08 (m, 2H). IR (KBr, cm-1): 3125 (w), 3090 (m), 2997 (m), 2876 (m), 1699 (s), 1506 (s), 1350 (m), 1129 (m), 1065 (s), 923 (w), 826 (w). MS (m / z): 389.3 ([M + H] +).

Ejemplo 241 Example 241

N(3)-(1,3,3-Trimetilbiciclo[2.2.1]hept-2-il)-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7metano-indazol-3carboxamida N (3) - (1,3,3-Trimethylbicyclo [2.2.1] hept-2-yl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7methane -indazol-3carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 17 (100 mg, 0,31 mmol), DMF (1,0 ml), Et3N (51 µl, 0,37 mmol), reactivo BOP (136 mg, 0,31 mmol) y (1S)-2endo-amino1,3,3-trimetilbiciclo[2.2.1]heptano [preparado como se describe por Suchocki y col. en J. Med. Chem. 1991,34,10031010 (46 mg, 0,34 mmol)] dio el compuesto del título (76 mg, 54%). P.F.:156-159 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,56 (d, J = 2,1, 1H); 7,47 (d, J = 8,4, 1H); 7,38 (dd, J = 8,4, 2,1, 1H); 6,91 (d a, J = 8,4, 1H); 3,76 (s a, 2H); 3,38 (s a, 1H); 2,12 (d a, J = 7,5, 1H); 2,00-1,84 (m, 2H); 1,80-1,58 (m, 4H); 1,02 (m, 12H); 0,85 (s, 3H). IR (KBr, cm 1): 3420 (m), 2954 (s), 2869 (m), 1677 (s), 1538 (s), 1483 (s), 1386 (m), 1229 (m), 1161 (m), 1113 (m), 1078 (s), 823 (w), 798 (w). EM (m/z): 458,10 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0 ml), Et3N (51 µl, 0.37 mmol), reagent BOP (136 mg, 0.31 mmol) and (1 S) -2endo-amino1,3,3-trimethylbicyclo [2.2.1] heptane [prepared as described by Suchocki et al. in J. Med. Chem. 1991,34,10031010 (46 mg, 0.34 mmol)] gave the title compound (76 mg, 54%). P.F.:156-159 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.56 (d, J = 2.1, 1H); 7.47 (d, J = 8.4, 1H); 7.38 (dd, J = 8.4, 2.1, 1H); 6.91 (d a, J = 8.4, 1H); 3.76 (s a, 2H); 3.38 (s at, 1 H); 2.12 (d a, J = 7.5, 1H); 2.00-1.84 (m, 2H); 1.80-1.58 (m, 4H); 1.02 (m, 12H); 0.85 (s, 3H). IR (KBr, cm 1): 3420 (m), 2954 (s), 2869 (m), 1677 (s), 1538 (s), 1483 (s), 1386 (m), 1229 (m), 1161 ( m), 1113 (m), 1078 (s), 823 (w), 798 (w). MS (m / z): 458.10 ([M + H] +).

Ejemplo 242 Example 242

N(3)-(Adamantan-1il)-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) - (Adamantan-1il) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 17 (100 mg, 0,31 mmol), DMF (1,0 ml), Et3N (0,51 µl, 0,37 mmol), reactivo BOP (136 mg, 0,31 mmol) y 1-adamantilamina (46 µg, 0,31 mmol) produjo el compuesto del título (108 mg, 76%). P.F.: 201-204 ºC. RMN 1H (d ppm, CDCl3, 300 MHz): 7,55 (d, J = 1,8, 1H); 7,45 (d, J = 8,4, 2H); 7,37 (dd, J = 8,4, 1,8, 1H); 6,60 (s a, 1H); 3,75 (s a, 1H); 3,35 (s a, 1H); 2,13 (s a, 10H); 2,02-1,80 (m, 2H); 1,70 (s a, 7H); 1,40-1,13 (m, 2H). IR (cm-1, KBr): 3400 (s), 2907 (s), 2851 (m), 1667 (s), 1542 (s), 1516 (s), 1483 (s), 1452 (m), 1359 (m), 1289 (w), 1230 (m), 1105 (m), 862 (w), 832 (m). EM (m/z): 456,3 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0 ml), Et3N (0.51 µl, 0.37 mmol) , BOP reagent (136 mg, 0.31 mmol) and 1-adamantylamine (46 µg, 0.31 mmol) produced the title compound (108 mg, 76%). P.F .: 201-204 ° C. 1H NMR (d ppm, CDCl3, 300 MHz): 7.55 (d, J = 1.8, 1H); 7.45 (d, J = 8.4, 2H); 7.37 (dd, J = 8.4, 1.8, 1H); 6.60 (s at, 1 H); 3.75 (s a, 1 H); 3.35 (s at, 1 H); 2.13 (s a, 10H); 2.02-1.80 (m, 2H); 1.70 (s a, 7H); 1.40-1.13 (m, 2H). IR (cm-1, KBr): 3400 (s), 2907 (s), 2851 (m), 1667 (s), 1542 (s), 1516 (s), 1483 (s), 1452 (m), 1359 (m), 1289 (w), 1230 (m), 1105 (m), 862 (w), 832 (m). MS (m / z): 456.3 ([M + H] +).

Ejemplo 243 Example 243

N(3)-Fenil-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) -Phenyl-1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 17 (100 mg, 0,31 mmol), DMF (1,0 ml), Et3N (42 µl, 0,30 mmol), reactivo BOP (121 mg, 0,31 mmol) y anilina (28 µl, 0,31 mmol) dio el compuesto del título (90 mg, 71%). P.F.: 66-68 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,63 (s a, 1H); 7,68 (d, J = 8,1, 2H); 7,59 (d, J = .2,1, 1 H); 7,49 (d, J = 8,4, 1H); 7,41 (dd, J = 8,4, 2,1, 1H); 7,34 (t, J = 8,1, 2H); 7,11 (t, J = 7,5, 1H); 3,81 (s a, 1H); 3,39 (s a, 1H); 2,16 (d a, J = 9,0, 1H); 2,05-1,86 (m, 2H); 1,73 (d, J = 8,7, 1H); 1,351,15 (m, 2H). IR (KBr, cm-1): 3382 (m), 2948 (m), 2869 (m), 1681 (s), 1596 (s), 1542 (s), 1500 (s), 1434 (s), 1380 (m), 1347 (m), 1321 (m), 1282 (m), 1237 (m), 1218 (m), 1159 (m), 1096 (m), 1077 (m), 810 (m), EM (m/z): 398,1 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0 ml), Et3N (42 µl, 0.30 mmol), reagent BOP (121 mg, 0.31 mmol) and aniline (28 µl, 0.31 mmol) gave the title compound (90 mg, 71%). P.F .: 66-68 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 8.63 (s at, 1H); 7.68 (d, J = 8.1, 2H); 7.59 (d, J = .2.1, 1 H); 7.49 (d, J = 8.4, 1H); 7.41 (dd, J = 8.4, 2.1, 1H); 7.34 (t, J = 8.1, 2H); 7.11 (t, J = 7.5, 1H); 3.81 (s at, 1 H); 3.39 (s at, 1 H); 2.16 (d a, J = 9.0, 1H); 2.05-1.86 (m, 2H); 1.73 (d, J = 8.7, 1H); 1,351.15 (m, 2H). IR (KBr, cm-1): 3382 (m), 2948 (m), 2869 (m), 1681 (s), 1596 (s), 1542 (s), 1500 (s), 1434 (s), 1380 (m), 1347 (m), 1321 (m), 1282 (m), 1237 (m), 1218 (m), 1159 (m), 1096 (m), 1077 (m), 810 (m), MS (m / z): 398.1 ([M + H] +).

Ejemplo 244 Example 244

N(3)-(2,4-Difluorofenil)-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) - (2,4-Difluorophenyl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 17 (100 mg, 0,31 mmol), DMF (1,0 ml), Et3N (57 µl, 0,37 mmol), reactivo BOP (136 mg, 0,31 mmol) y 2,4-difluoroanilina (31 µl, 0,31 mmol) produjo el compuesto del título (62 mg, 46%). P.F.: 152-155 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,79 (s a, 1H); 8,50-8,40 (m, 1H); 7,59 (d, J = 2,1, 1H); 7,48 (d, J = 8,4, 1H); 7,41 (dd, J = 8,4, 2,1, 1H); 6,956,82 (m, 2H); 3,79 (s a, 1H); 3,40 (s a, 1H); 2,17 (d a, J = 8,7, 1H); 2,10-1,90 (m, 2H); 1,73 (d, J = 8,7, 1H); 1,35-1,15 (m, 2H). IR (KBr, cm-1): 3389 (s), 2993 (m), 2874 (m), 1685 (s), 1543 (s), 1505 (s), 1428 (m), 1345 (m), 1123 (m), 1102 (m), 1085 (m), 961 (w), 852 (w), 619 (w). EM (m/z): 434,0 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0 ml), Et3N (57 µl, 0.37 mmol), reagent BOP (136 mg, 0.31 mmol) and 2,4-difluoroaniline (31 µl, 0.31 mmol) produced the title compound (62 mg, 46%). P.F .: 152-155 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 8.79 (s at, 1H); 8.50-8.40 (m, 1 H); 7.59 (d, J = 2.1, 1H); 7.48 (d, J = 8.4, 1H); 7.41 (dd, J = 8.4, 2.1, 1H); 6,956.82 (m, 2H); 3.79 (s a, 1 H); 3.40 (s at, 1 H); 2.17 (d a, J = 8.7, 1H); 2.10-1.90 (m, 2H); 1.73 (d, J = 8.7, 1H); 1.35-1.15 (m, 2H). IR (KBr, cm-1): 3389 (s), 2993 (m), 2874 (m), 1685 (s), 1543 (s), 1505 (s), 1428 (m), 1345 (m), 1123 (m), 1102 (m), 1085 (m), 961 (w), 852 (w), 619 (w). MS (m / z): 434.0 ([M + H] +).

Ejemplo 245 Example 245

N(3)-(2-Fluorobencil)-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) - (2-Fluorobenzyl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 17 (100 mg, 0,31 mmol), DMF (1,0 ml), Et3N (51 µl, 0,37 mmol), reactivo BOP (136 mg, 0,31 mmol) y 2fluorobencilamina (35 µl, 0,31 mmol) dio el compuesto del título (55 mg, 41%). P.F.: 54 ºC (se funde). RMN 1H (δ ppm, CDCl3, 300 MHz): 7,55 (s a, 1H); 7,50-7,30 (m, 3H); 7,28-7,20 (m, 2H); 7,15-7,00 (m, 2H); 4,65 (d a, J = 5,1, 2H); 3,77 (s a, 1H); 3,37 (s a, 1H); 2,12 (d a, J = 7,5, 1H); 1,99-1,84 (m, 2H); 1,69 (d a, J = 8,4, 1H); 1,28-1,15 (m, 2H). IR (KBr, cm-1): 3419 (m), 2950 (m), 2874 (m), 1668 (s), 1548 (s), 1487 (s), 1455 (s), 1346 (m), 1275 (m), 1229 (s), 1107 (s), 832 (m). EM (m/z): 430,10 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0 ml), Et3N (51 µl, 0.37 mmol), reagent BOP (136 mg, 0.31 mmol) and 2fluorobenzylamine (35 µl, 0.31 mmol) gave the title compound (55 mg, 41%). P.F .: 54 ºC (melts). 1H NMR (δ ppm, CDCl3, 300 MHz): 7.55 (s at, 1H); 7.50-7.30 (m, 3H); 7.28-7.20 (m, 2H); 7.15-7.00 (m, 2H); 4.65 (d a, J = 5.1, 2H); 3.77 (s a, 1 H); 3.37 (s at, 1 H); 2.12 (d a, J = 7.5, 1H); 1.99-1.84 (m, 2H); 1.69 (d a, J = 8.4, 1H); 1.28-1.15 (m, 2H). IR (KBr, cm-1): 3419 (m), 2950 (m), 2874 (m), 1668 (s), 1548 (s), 1487 (s), 1455 (s), 1346 (m), 1275 (m), 1229 (s), 1107 (s), 832 (m). MS (m / z): 430.10 ([M + H] +).

Ejemplo 246 Example 246

N(3)-(4-Fluorobencil)-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) - (4-Fluorobenzyl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 17 (100 mg, 0,31 mmol), DMF (1,0 ml), Et3N (43 µl, 0,31 mmol), reactivo BOP (136 mg, 0,31 mmol) y 4fluorobencilamina (35 µl, 0,31 mmol) dio el compuesto del título (90 mg, 68%). P.F.: 106-108 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,55 (d, J = 2,1, 1H); 7,41 (d, J = 8,4, 1H); 7,39-7,25 (m, 3H); 7,15 (t a, J = 6,6, 1H); 7,00 (t, J = 8,7, 2H); 4,54 (dd, J = 17,0, 6,6, 1H); 4,59 (dd, J = 17,0, 6,6, 1H); 3,77 (s a, 1H); 3,36 (s a, 1H); 2,12 (d a, J = 9,0, 1H); 2,10-1,82 (m, 2H); 1,70 (d a, J = 9,0, 1H); 1,32-1,10 (m, 2H). IR (KBr, cm-1): 3277 (m), 2951 (m), 2979 (m), 2871 (m), 1648 (s), 1551(m), 1510 (s), 1350 (m), 1273 (m), 1223 (s), 1108 (m), 1076 (w), 833 (m). EM (m/z): 432,1 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0 ml), Et3N (43 µl, 0.31 mmol), reagent BOP (136 mg, 0.31 mmol) and 4fluorobenzylamine (35 µl, 0.31 mmol) gave the title compound (90 mg, 68%). P.F .: 106-108 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.55 (d, J = 2.1, 1H); 7.41 (d, J = 8.4, 1H); 7.39-7.25 (m, 3H); 7.15 (t a, J = 6.6, 1H); 7.00 (t, J = 8.7, 2H); 4.54 (dd, J = 17.0, 6.6, 1H); 4.59 (dd, J = 17.0, 6.6, 1H); 3.77 (s a, 1 H); 3.36 (s at, 1 H); 2.12 (d a, J = 9.0, 1H); 2.10-1.82 (m, 2H); 1.70 (d a, J = 9.0, 1H); 1.32-1.10 (m, 2H). IR (KBr, cm-1): 3277 (m), 2951 (m), 2979 (m), 2871 (m), 1648 (s), 1551 (m), 1510 (s), 1350 (m), 1273 (m), 1223 (s), 1108 (m), 1076 (w), 833 (m). MS (m / z): 432.1 ([M + H] +).

Ejemplo 247 Example 247

N(3)-(2,4-Difluorobencil)-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) - (2,4-Difluorobenzyl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 17 (100 mg, 0,31 mmol), DMF (1,0 ml), Et3N (51 µl, 0,37 mmol), reactivo BOP (136 mg, 0,31 mmol) y 2,4difluorobencilamina (36 µl, 0,31 mmol) dio el compuesto del título (93 mg, 67%). P.F.: 73-76 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,55 (d, J = 1,8, 1H); 7,40 (m, 3H); 7,20 (s a, 1H); 6,90-6,75 (m, 2H); 4,50-4,70 (m, 2H); 3,77 (s a, 1H); 3,36 (s a, 1H); 2,12 (d a, J = 8,7, 1H); 2,02-1,86 (m, 2H); 1,69 (d, J = 8,7, 1H); 1,14 (d a, J = 9,0, 2H). IR (KBr, cm -1): 3421 (w), 3283 (m), 2996 (m), 2926 (w), 1648 (s), 1552(m), 1505 (s), 1487 (s), 1455 (s), 1280 (m), 1138 (m), 1117 (m), 1098 (m), 832 (m), 964 (w), 851 (w), 832 (w). EM (m/z): 448,10 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0 ml), Et3N (51 µl, 0.37 mmol), reagent BOP (136 mg, 0.31 mmol) and 2,4-difluorobenzylamine (36 µl, 0.31 mmol) gave the title compound (93 mg, 67%). P.F .: 73-76 ºC. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.55 (d, J = 1.8, 1H); 7.40 (m, 3 H); 7.20 (s at, 1 H); 6.90-6.75 (m, 2H); 4.50-4.70 (m, 2H); 3.77 (s a, 1 H); 3.36 (s at, 1 H); 2.12 (d a, J = 8.7, 1H); 2.02-1.86 (m, 2H); 1.69 (d, J = 8.7, 1H); 1.14 (d a, J = 9.0, 2H). IR (KBr, cm -1): 3421 (w), 3283 (m), 2996 (m), 2926 (w), 1648 (s), 1552 (m), 1505 (s), 1487 (s), 1455 (s), 1280 (m), 1138 (m), 1117 (m), 1098 (m), 832 (m), 964 (w), 851 (w), 832 (w). MS (m / z): 448.10 ([M + H] +).

Ejemplo 248 Example 248

N(3)-(2,6-Difluorobencil)-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) - (2,6-Difluorobenzyl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 17 (100 mg, 0,31 mmol), DMF (1,0 ml), Et3N (0,51 ml, 0,37 mmol), reactivo BOP (136 mg, 0,31 mmol) y 2,6difluorobencilamina (36 mg, 0,31 mmol) produjo el compuesto del título (74 mg, 53%). P.F.: 130-133 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,50-7,33 (m, 2H); 7,29-7,06 (m, 2H); 6,94-6,82 (m, 2H); 4,78-4,61 (m, 2H); 3,78 (s a, 1H); 3,35 (s a, 1H); 2,10 (d a, J = 8,7, 1H); 2,04-1,81 (m, 2H); 1,68 (d, J = 8,7, 1H); 1,38-1,10 (m, 2H). IR (cm-1, KBr): 3305 (m), 2988 (w), 2971 (w), 2945 (w), 2868 (w), 1672 (s), 1660 (s), 1593 (s), 1545 (s), 1498 (s), 1406 (m), 1397 (m), 1355 (m), 1310 (w), 1240 (m), 1218 (w), 1120 (w), 1189 (s), 1048 (w), 1008 (w), 829 (s). EM (m/z): 448,1 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0 ml), Et3N (0.51 ml, 0.37 mmol) , BOP reagent (136 mg, 0.31 mmol) and 2,6-difluorobenzylamine (36 mg, 0.31 mmol) produced the title compound (74 mg, 53%). P.F .: 130-133 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.50-7.33 (m, 2H); 7.29-7.06 (m, 2H); 6.94-6.82 (m, 2H); 4.78-4.61 (m, 2H); 3.78 (s a, 1 H); 3.35 (s at, 1 H); 2.10 (d a, J = 8.7, 1H); 2.04-1.81 (m, 2H); 1.68 (d, J = 8.7, 1H); 1.38-1.10 (m, 2H). IR (cm-1, KBr): 3305 (m), 2988 (w), 2971 (w), 2945 (w), 2868 (w), 1672 (s), 1660 (s), 1593 (s), 1545 (s), 1498 (s), 1406 (m), 1397 (m), 1355 (m), 1310 (w), 1240 (m), 1218 (w), 1120 (w), 1189 (s), 1048 (w), 1008 (w), 829 (s). MS (m / z): 448.1 ([M + H] +).

Ejemplo 249 Example 249

N(3)-(2-Clorobencil)-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) - (2-Chlorobenzyl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 17 (100 mg, 0,31 mmol), DMF (1,0 ml), Et3N (43 µl, 0,31 mmol), reactivo BOP (136 mg, 0,31 mmol) y 2-clorobencilamina (37 µl, 0,31 mmol) dio el compuesto del título (102 mg, 74%). P.F.: 117-120 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,55 (d, J = 2,4, 1H); 7,50-7,30 (m, 4H); 7,30-7,16 (m, 3H); 4,67 (dd, J = 17, 6,3, 1H); 4,72 (dd, J = 17,0, 6,3, 1H); 3,77 (s a, 1H); 3,36 (s a, 1H); 2,12 (d a, J = 8,6, 1H); 2,00-1,86 (m, 2H); 1,68 (d a, J = 8,6, 1H); 1,31-1,13 (m, 2H). IR (KBr, cm-1): 3309 (m), 2998 (m), 2968 (m), 2951 (m), 2925 (m), 2869 (m), 1640 (s), 1564 (s), 1504 (s), 1487 (s), 1442 (m), 1346 (m), 1281 (m), 1241 (m), 1110 (m), 1056 (m), 870 (m), 832 (m). EM (m/z): 448,1 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0 ml), Et3N (43 µl, 0.31 mmol), reagent BOP (136 mg, 0.31 mmol) and 2-chlorobenzylamine (37 µl, 0.31 mmol) gave the title compound (102 mg, 74%). P.F .: 117-120 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.55 (d, J = 2.4, 1H); 7.50-7.30 (m, 4H); 7.30-7.16 (m, 3H); 4.67 (dd, J = 17, 6.3, 1H); 4.72 (dd, J = 17.0, 6.3, 1H); 3.77 (s a, 1 H); 3.36 (s at, 1 H); 2.12 (d a, J = 8.6, 1H); 2.00-1.86 (m, 2H); 1.68 (d a, J = 8.6, 1H); 1.31-1.13 (m, 2H). IR (KBr, cm-1): 3309 (m), 2998 (m), 2968 (m), 2951 (m), 2925 (m), 2869 (m), 1640 (s), 1564 (s), 1504 (s), 1487 (s), 1442 (m), 1346 (m), 1281 (m), 1241 (m), 1110 (m), 1056 (m), 870 (m), 832 (m). MS (m / z): 448.1 ([M + H] +).

Ejemplo 250 Example 250

N(3)-(4-Clorobencil)-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) - (4-Chlorobenzyl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 17 (100 mg, 0,31 mmol), DMF (1,0 ml), Et3N (43 µl, 0,31 mmol), reactivo BOP (136 mg, 0,31 mmol) y 4-clorobencilamina (37 µl, 0,31 mmol) dio el compuesto del título (108 mg, 78%). P.F.: 139-142 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,56 (d, J = 2,2, 1H); 7,42 (d, 8,4, 1H); 7,36 (dd, J = 8,4, 2,2, 1H); 7,29 (s, 4H); 7,16 (t a, J = 5,1, 1H); 4,65-4,47 (m, 2H); 3,77 (s a, 1H); 3,36 (s a, 1H); 2,12 (d a, J = 8,6, 1H); 2,0-1,85 (m, 2H); 1,70 (d a, J = 8,6, 1H); 1,32-1,15 (m, 2H). IR (KBr, cm-1); 3290 (m), 2934 (m), 2869 (m), 1652 (s), 1553 (s), 1489 (s), 1436 (m), 1351 (m), 1276 (m), 1249 (m), 1142 (m), 1076 (m), 851 (m), 799 (m), 707 (m), 654 (m), 623 (m). EM (m/z): 448,2 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0 ml), Et3N (43 µl, 0.31 mmol), reagent BOP (136 mg, 0.31 mmol) and 4-chlorobenzylamine (37 µl, 0.31 mmol) gave the title compound (108 mg, 78%). P.F .: 139-142 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.56 (d, J = 2.2, 1H); 7.42 (d, 8.4, 1H); 7.36 (dd, J = 8.4, 2.2, 1H); 7.29 (s, 4H); 7.16 (t a, J = 5.1, 1H); 4.65-4.47 (m, 2H); 3.77 (s a, 1 H); 3.36 (s at, 1 H); 2.12 (d a, J = 8.6, 1H); 2.0-1.85 (m, 2H); 1.70 (d a, J = 8.6, 1H); 1.32-1.15 (m, 2H). IR (KBr, cm-1); 3290 (m), 2934 (m), 2869 (m), 1652 (s), 1553 (s), 1489 (s), 1436 (m), 1351 (m), 1276 (m), 1249 (m), 1142 (m), 1076 (m), 851 (m), 799 (m), 707 (m), 654 (m), 623 (m). MS (m / z): 448.2 ([M + H] +).

Ejemplo 251 Example 251

N(3)-(1,4-Diclorobencil)-1-(1,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) - (1,4-Dichlorobenzyl) -1- (1,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 17 (100 mg, 0,31 mmol), DMF (1,0 ml), Et3N (43 µl, 0,31 mmol), reactivo BOP (136 mg, 0,31 mmol) y 2,4diclorobencilamina (41 µl, 0,31 mmol) dio el compuesto del título (118 mg, 79%). P.F.: 57-59 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,56 (s, 1H); 7,45-7,37 (m, 4H); 7,27-7,20 (m, 3H); 4,60 (d a, J = 4,8, 2H); 3,76 (s, 1H); 3,37 (s, 1H); 2,12 (d a, J = 8,4, 1H); 2,05-1,86 (m, 2H); 1,71-1,65 (d a, J = 8,4, 1H); 1,26-1,13 (m, 2H). IR (KBr, cm-1): 3337 (m), 2948 (m), 2870 (m), 1737 (m), 1666 (s), 1545 (s), 1483 (s), 1381 (m), 1347 (m), 1236 (s), 1104 (s), 1078 (m), 1046 (m), 865 (m), 832 (s). EM (m/z): 482,3 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0 ml), Et3N (43 µl, 0.31 mmol), reagent BOP (136 mg, 0.31 mmol) and 2,4-dichlorobenzylamine (41 µl, 0.31 mmol) gave the title compound (118 mg, 79%). P.F .: 57-59 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.56 (s, 1H); 7.45-7.37 (m, 4H); 7.27-7.20 (m, 3H); 4.60 (d a, J = 4.8, 2H); 3.76 (s, 1 H); 3.37 (s, 1 H); 2.12 (d a, J = 8.4, 1H); 2.05-1.86 (m, 2H); 1.71-1.65 (d a, J = 8.4, 1H); 1.26-1.13 (m, 2H). IR (KBr, cm-1): 3337 (m), 2948 (m), 2870 (m), 1737 (m), 1666 (s), 1545 (s), 1483 (s), 1381 (m), 1347 (m), 1236 (s), 1104 (s), 1078 (m), 1046 (m), 865 (m), 832 (s). MS (m / z): 482.3 ([M + H] +).

Ejemplo 252 Example 252

N(3)-[S-(1-feniletil)]-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) - [S- (1-phenylethyl)] - 1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 17 (100 mg, 0,31 mmol), DMF (1,0 ml), Et3N (51 µl, 0,37 mmol), reactivo BOP (136 mg, 0,31 mmol) y S-(-)-1feniletilamina (39 µl, 0,31 mmol) dio el compuesto del título (74 mg, 66%). P.F.: 91-94 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,56 (d, J = 2,1, 1H); 7,47-7,20 (m, 7H); 7,08 (d, J =7,5, 1H); 5,38-5,22 (m, 1H); 3,75 (s a, 1H); 3,35 (s a, 1H); 2,11 (t a, J = 8,7, 1H); 2,00-1,80 (m, 2H); 1,69 (s a, 1H), 1,58 (d, J = 6,9, 3H); 1,40-1,08 (m, 1H). EM (m/z): 426,10 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0 ml), Et3N (51 µl, 0.37 mmol), reagent BOP (136 mg, 0.31 mmol) and S - (-) - 1 phenylethylamine (39 µl, 0.31 mmol) gave the title compound (74 mg, 66%). P.F .: 91-94 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.56 (d, J = 2.1, 1H); 7.47-7.20 (m, 7H); 7.08 (d, J = 7.5, 1H); 5.38-5.22 (m, 1 H); 3.75 (s a, 1 H); 3.35 (s at, 1 H); 2.11 (t a, J = 8.7, 1H); 2.00-1.80 (m, 2H); 1.69 (s a, 1H), 1.58 (d, J = 6.9, 3H); 1.40-1.08 (m, 1 H). MS (m / z): 426.10 ([M + H] +).

Ejemplo 253 Example 253

N(3)-[R-(1-feniletil)]-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) - [R- (1-phenylethyl)] - 1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 17 (100 mg, 0,31 mmol), DMF (1,0 ml), Et3N (51 µl, 0,37 mmol), reactivo BOP (136 mg, 0,31 mmol) y R-(+)-1fenetilamina (33 µl, 0,31 mmol) dio el compuesto del título (66 mg, 50%). P.F.: 89-92 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,55 (d, J = 2,1, 1H); 7,50-7,20 (m, 7H); 7,08 (d, J = 7,8, 1H); 5,30 (m, 1H); 3,75 (s a, 1H); 3,35 (s a, 1H); 2,10 (t, J = 9,0, 1H); 2,00-1,80 (m, 2H); 169 (s a, 1H); 1,58 (d, J = 6,9, 3H); 1,40-1,10 (m, 2H). IR (KBr, cm-1): 3411 (m), 3247 (m), 2972 (m), 2952 (m), 2870 (m), 1638 (s), 1545 (m), 1502 (s), 1483 (s), 1448 (m), 1378 (m), 1359 (m), 1239 (m), 1262 (m), 1138 (m), 1101 (m), 1076 (m), 815 (w), 699 (m). EM (m/z): 426,0 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0 ml), Et3N (51 µl, 0.37 mmol), reagent BOP (136 mg, 0.31 mmol) and R - (+) - 1 phenethylamine (33 µl, 0.31 mmol) gave the title compound (66 mg, 50%). P.F .: 89-92 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.55 (d, J = 2.1, 1H); 7.50-7.20 (m, 7H); 7.08 (d, J = 7.8, 1H); 5.30 (m, 1 H); 3.75 (s a, 1 H); 3.35 (s at, 1 H); 2.10 (t, J = 9.0, 1H); 2.00-1.80 (m, 2H); 169 (s at, 1 H); 1.58 (d, J = 6.9, 3H); 1.40-1.10 (m, 2H). IR (KBr, cm-1): 3411 (m), 3247 (m), 2972 (m), 2952 (m), 2870 (m), 1638 (s), 1545 (m), 1502 (s), 1483 (s), 1448 (m), 1378 (m), 1359 (m), 1239 (m), 1262 (m), 1138 (m), 1101 (m), 1076 (m), 815 (w), 699 (m). MS (m / z): 426.0 ([M + H] +).

Ejemplo 254 Example 254

N(3)-(2-feniletil)-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) - (2-phenylethyl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 17 (100 mg, 0,31 mmol), DMF (1,0 ml), Et3N (43 µl, 0,31 mmol); reactivo BOP (136 mg, 0,31 mmol) y fenetilamina (38 µl, 0,31 mmol) dio el compuesto del título (70 mg, 53%) en forma de un sólido ceroso. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,55 (d, J = 1,8, 1H); 7,43 (d, J = 8,4, 1H); 7,36 (dd, J = 8,4, 1,8, 1H); 7,35-7,19 (m, 5H); 6,91 (s a, 1H); 3,75 (s a, 1H); 3,70-3,60 (m, 2H); 3,36 (s a, 1H); 2,90 (t, J = 7,2, 2H); 2,12 (d a, J = 8,6, 1H); 2,01-1,84 (m, 2H); 1,69 (d a, J = 8,6, 1H); 1,31-1,13 (m, 2H). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0 ml), Et3N (43 µl, 0.31 mmol); BOP reagent (136 mg, 0.31 mmol) and phenethylamine (38 µl, 0.31 mmol) gave the title compound (70 mg, 53%) as a waxy solid. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.55 (d, J = 1.8, 1H); 7.43 (d, J = 8.4, 1H); 7.36 (dd, J = 8.4, 1.8, 1H); 7.35-7.19 (m, 5H); 6.91 (s a, 1 H); 3.75 (s a, 1 H); 3.70-3.60 (m, 2H); 3.36 (s at, 1 H); 2.90 (t, J = 7.2, 2H); 2.12 (d a, J = 8.6, 1H); 2.01-1.84 (m, 2H); 1.69 (d a, J = 8.6, 1H); 1.31-1.13 (m, 2H).

Ejemplo 255 Example 255

N(3)-[2-(4-fluorofenil)etil]-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) - [2- (4-fluorophenyl) ethyl] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 17 (100 mg, 0,31 mmol), DMF (1,0 ml), Et3N (43 µl, 0,31 mmol), reactivo BOP (136 mg, 0,31 mmol) y 4fluorofenetilamina (40 µl, 0,31 mmol) produjo el compuesto del título, (100 mg, 73%) en forma de una pasta vidriosa. RMN 1H(δ ppm, CDCl3, 300 MHz): 7,56 (d, J = 2,1, 1H); 7,41 (d, J = 8,4, 1H); 7,37 (d, J = 8,4, 2,1, 1H); 7,19 (dd, J = 8,4, 5,4, 2H); 6,98 (t, J = 8,7, 2H); 6,90 (t a, J = 4,6, 1H); 3,75 (s a, 1H); 3,71-3,57 (m, 2H); 3,36 (s a, 1H); 2,90 (t, J = 7,5, 2H); 2,12 (d a, J = 8,7, 1H); 2,02-1,86 (m, 2H); 1,69 (d a, J = 8,7, 1H); 1,31-1,13 (m, 2H). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0 ml), Et3N (43 µl, 0.31 mmol), reagent BOP (136 mg, 0.31 mmol) and 4-fluorophenethylamine (40 µl, 0.31 mmol) produced the title compound, (100 mg, 73%) as a glassy paste. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.56 (d, J = 2.1, 1H); 7.41 (d, J = 8.4, 1H); 7.37 (d, J = 8.4, 2.1, 1H); 7.19 (dd, J = 8.4, 5.4, 2H); 6.98 (t, J = 8.7, 2H); 6.90 (t a, J = 4.6, 1H); 3.75 (s a, 1 H); 3.71-3.57 (m, 2H); 3.36 (s at, 1 H); 2.90 (t, J = 7.5, 2H); 2.12 (d a, J = 8.7, 1H); 2.02-1.86 (m, 2H); 1.69 (d a, J = 8.7, 1H); 1.31-1.13 (m, 2H).

Ejemplo 256 Example 256

N(3)-Fenilamino-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) -Phenylamino-1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 17 (100 mg, 0,31 mmol), DMF (1,0 ml), Et3N (51 µl, 0,37 mmol), reactivo BOP (136 mg, 0,31 mmol) y fenilhidrazina clorhidrato (30 µl, 0,31 mmol) dio el compuesto del título (84 mg, 66%). P.F.: 182-185 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,48 (s a, 1H); 7,58 (d, J = 1,8, 1H); 7,48 (d, J = 8,5, 1H); 7,40 (dd, J = 8,5, 1,8, 1H); 7,26-7,20 (m, 3H); 7,00-6,82 (m, 3H); 3,73 (s a, 1H); 3,40 (s a, 1H); 2,13 (d a, J = 8,1, 1H); 1,97-1,90 (m, 2H); 1,71 (d a, J = 9,0, 1H); 1,30-1,15 (m, 2H). IR (KBr, cm-1): 3251 (s), 2996 (m), 2947 (m), 2870 (m), 1663 (s), 1604 (m), 1542 (m), 1498 (s), 1483 (s), 1352 (m), 1279 (m), 1230 (m), 1231 (m), 1111 (m), 1083 (m), 1060 (m), 937 (m), 899 (m), 889 (m), 867 (m). EM (m/z): 413,0 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0 ml), Et3N (51 µl, 0.37 mmol), reagent BOP (136 mg, 0.31 mmol) and phenylhydrazine hydrochloride (30 µl, 0.31 mmol) gave the title compound (84 mg, 66%). P.F .: 182-185 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 8.48 (s at, 1H); 7.58 (d, J = 1.8, 1H); 7.48 (d, J = 8.5, 1H); 7.40 (dd, J = 8.5, 1.8, 1H); 7.26-7.20 (m, 3H); 7.00-6.82 (m, 3H); 3.73 (s a, 1 H); 3.40 (s at, 1 H); 2.13 (d a, J = 8.1, 1H); 1.97-1.90 (m, 2H); 1.71 (d a, J = 9.0, 1H); 1.30-1.15 (m, 2H). IR (KBr, cm-1): 3251 (s), 2996 (m), 2947 (m), 2870 (m), 1663 (s), 1604 (m), 1542 (m), 1498 (s), 1483 (s), 1352 (m), 1279 (m), 1230 (m), 1231 (m), 1111 (m), 1083 (m), 1060 (m), 937 (m), 899 (m), 889 (m), 867 (m). MS (m / z): 413.0 ([M + H] +).

Ejemplo 257 Example 257

N(3)-[(2-Clorofenil)amino]-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7 metano-indazol-3-carboxamida N (3) - [(2-Chlorophenyl) amino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7 methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 17 (100 mg, 0,31 mmol), DMF (1,0 ml), Et3N (107 µl, 0,77 mmol), reactivo BOP (136 mg, 0,31 mmol) y clorhidrato de 2clorofenilhidrazina (55 mg, 0,31 mmol) dio el compuesto del título (78 mg, 57%). P.F.: 180-183 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,49 (s a, 1H); 7,59 (d, J = 2,4, 1H); 7,48 (d, J = 8,4, 1H); 7,41 (dd, J = 8,4, 2,4, 1H); 7,29 (d, J = 8,0, 1H); 7,14 (t, J = 7,8, 1H); 7,03 (d, J = 8,1, 1H); 6,83 (t, J = 8,0, 1H); 6,55 (s a, 1H); 3,73 (s a, 1H); 3,40 (s a, 1H); 2,13 (d a, J = 9,0, 1H); 2,01-1,87 (m, 2H); 1,70 (d a, J = 9,0, 1H); 1,30-1,16 (m, 2H). IR (KBr, cm-1): 3255 (a, m), 2959 (w), 2874 (w), 1667 (s), 1508 (s), 1346 (m), 1279 (m), 1110 (m), 1079 (m), 1066 (m), 862 (w). EM (m/z): 448,9 ([M+H] +). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0 ml), Et3N (107 µl, 0.77 mmol), reagent BOP (136 mg, 0.31 mmol) and 2-chlorophenylhydrazine hydrochloride (55 mg, 0.31 mmol) gave the title compound (78 mg, 57%). P.F .: 180-183 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 8.49 (s at, 1H); 7.59 (d, J = 2.4, 1H); 7.48 (d, J = 8.4, 1H); 7.41 (dd, J = 8.4, 2.4, 1H); 7.29 (d, J = 8.0, 1H); 7.14 (t, J = 7.8, 1H); 7.03 (d, J = 8.1, 1H); 6.83 (t, J = 8.0, 1H); 6.55 (s a, 1 H); 3.73 (s a, 1 H); 3.40 (s at, 1 H); 2.13 (d a, J = 9.0, 1H); 2.01-1.87 (m, 2H); 1.70 (d a, J = 9.0, 1H); 1.30-1.16 (m, 2H). IR (KBr, cm-1): 3255 (a, m), 2959 (w), 2874 (w), 1667 (s), 1508 (s), 1346 (m), 1279 (m), 1110 (m) , 1079 (m), 1066 (m), 862 (w). MS (m / z): 448.9 ([M + H] +).

Ejemplo 258 Example 258

N(3)-[N-(2-Clorofenil)-N-metilamino]-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3carboxamida N (3) - [N- (2-Chlorophenyl) -N-methylamino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 17 (100 mg, 0,31 mmol), DMF (1,0 ml), Et3N (0,51 µl, 0,37 mmol), reactivo BOP (136 mg, 0,31 mmol) y clorhidrato de N(2-clorofenil)-N-metilhidrazina (59 mg, 0,31 mmol) produjo el compuesto del título (104 mg, 70%). P.F.: 121-124 ºC. RMN 1H(δ ppm, CDCl3, 300 MHz): 8,82 (s a, 1H); 7,56 (d, J = 2,1, 2H); 7,45 (d, J = 8,4, 1H); 7,42 (dd, J = 8,1,1,5, 1H); 7,38 (dd, J = 8,4, 2,1, 1H); 7,31 (dd, J = 8,1, 1,5, 1H); 7,24 (td, J = 8,1, 1,5, 1H); 6,99 (td, J = 8,1, 1,5 1H); 3,70 (s a, 1H); 3,37 (s a, 4H); 2,09 (d a, J = 8,4, 1H); 2,00-1,82 (m, 2H); 1,67 (d a, J = 8,7, 1H); 1,30-1,10 (m, 2H). IR (cm 1, KBr): 3404 (s), 3253 (m), 2951 (w), 2868 (w), 1654 (s), 1587 (w), 1545 (w), 1500 (s), 1484 (s), 1475 (s), 1443 (m), 1348 (w), 1276 (m), 1236 (m), 1122 (m), 1107 (m), 1052 (m), 832 (s). EM (m/z): 461,0 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0 ml), Et3N (0.51 µl, 0.37 mmol) , BOP reagent (136 mg, 0.31 mmol) and N (2-chlorophenyl) -N-methylhydrazine hydrochloride (59 mg, 0.31 mmol) produced the title compound (104 mg, 70%). P.F .: 121-124 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 8.82 (s at, 1H); 7.56 (d, J = 2.1, 2H); 7.45 (d, J = 8.4, 1H); 7.42 (dd, J = 8.1.1.5, 1H); 7.38 (dd, J = 8.4, 2.1, 1H); 7.31 (dd, J = 8.1, 1.5, 1H); 7.24 (td, J = 8.1, 1.5, 1H); 6.99 (td, J = 8.1, 1.5 1H); 3.70 (s at, 1 H); 3.37 (s at, 4H); 2.09 (d a, J = 8.4, 1H); 2.00-1.82 (m, 2H); 1.67 (d a, J = 8.7, 1H); 1.30-1.10 (m, 2H). IR (cm 1, KBr): 3404 (s), 3253 (m), 2951 (w), 2868 (w), 1654 (s), 1587 (w), 1545 (w), 1500 (s), 1484 ( s), 1475 (s), 1443 (m), 1348 (w), 1276 (m), 1236 (m), 1122 (m), 1107 (m), 1052 (m), 832 (s). MS (m / z): 461.0 ([M + H] +).

Ejemplo 259 Example 259

N(3)-[(4-Clorofenil)amino]-1-(2,4-diclorofenil)-4,5,6,7-tetrathidro-1H-4,7-metano-indazol-3-carboxamida N (3) - [(4-Chlorophenyl) amino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrathydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 17 (200 mg, 0,62 mmol), DMF (2,0 ml), Et3N (189 µl, 1,36 mmol), reactivo BOP (273 mg, 0,62 mmol) y clorhidrato de 4clorofenilhidrazina (110 mg, 0,62 mmol) dio el compuesto del título (195 mg, 70%). P.F.: 141-144 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,47 (s, 1H); 7,59 (d, J = 1,8, 1H); 7,48 (d, J = 8,3, 1H); 7,40 (dd, J = 8,3, 1,8, 1H); 7,18 (d, J = 8,7, 2H); 6,87 (d, J = 8,7, 2H); 6,17 (s a, 1H); 3,72 (s, 1H); 3,40 (s, 1H); 2,15 (d a, J = 8,7, 1H); 1,99-1,88 (m, 2H); 1,70 (d a, J = 8,7, 1H); 1,26-1,19 (m, 2H). IR (KBr, cm-1): 3271 (s), 2991 (m), 1667 (m), 1596 (m), 1505 (m), 1491 (m), 1348 (m), 1276 (m), 1230 (m), 1080 (m), 1065 (m), 889 (m), 824 (s). EM (m/z): 447,0 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 17 (200 mg, 0.62 mmol), DMF (2.0 ml), Et3N (189 µl, 1.36 mmol), reagent BOP (273 mg, 0.62 mmol) and 4-chlorophenylhydrazine hydrochloride (110 mg, 0.62 mmol) gave the title compound (195 mg, 70%). P.F .: 141-144 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 8.47 (s, 1H); 7.59 (d, J = 1.8, 1H); 7.48 (d, J = 8.3, 1H); 7.40 (dd, J = 8.3, 1.8, 1H); 7.18 (d, J = 8.7, 2H); 6.87 (d, J = 8.7, 2H); 6.17 (s a, 1 H); 3.72 (s, 1 H); 3.40 (s, 1H); 2.15 (d a, J = 8.7, 1H); 1.99-1.88 (m, 2H); 1.70 (d a, J = 8.7, 1H); 1.26-1.19 (m, 2H). IR (KBr, cm-1): 3271 (s), 2991 (m), 1667 (m), 1596 (m), 1505 (m), 1491 (m), 1348 (m), 1276 (m), 1230 (m), 1080 (m), 1065 (m), 889 (m), 824 (s). MS (m / z): 447.0 ([M + H] +).

Ejemplo 260 Example 260

N(3)-[(2,4-Diclorofenil)amino]-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) - [(2,4-Dichlorophenyl) amino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 17 (200 mg, 0,62 mmol), DMF (2,0 ml), Et3N (189 µl, 1,36 mmol), reactivo BOP (273 mg, 0,62 mmol) y clorhidrato de 2,4-diclorofenilhidrazina (132 mg, 0,62 mmol) para dar el compuesto del título (205 mg, 69%). P.F.: 187-190 ºC. RMN 1H(δ ppm, CDCl3, 300 MHz): 8,47 (d, J = 3,0, 1H); 7,59 (d, J = 2,1, 1H); 7,47 (d, J = 8,6, 1H); 7,40 (dd, J = 8,6, 2,1, 1H); 7,30 (d, J = 2,4, 1H); 7,11 (dd, J = 8,7, 1H); 6,95 (d, J = 9,0, 1H); 6,49 (d, J = 3,0, 1H); 3,71 (s, 1H); 3,39 (s, 1H); 2,12 (d a, J = 9,3, 1H); 1,97-1,90 (m, 2H); 1,70 (d a, J = 9,3, 1H); 1,25-1,15 (m, 2H). IR (KBr, cm-1): 3348 (m), 3191 (m), 2984 (m), 2968 (m), 2873 (w), 1661 (s), 1588 (m), 1557 (m), 1495 (s), 1343 (m), 1279 (m), 1108 (m), 1078 (m), 1068 (m), 861 (m). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 17 (200 mg, 0.62 mmol), DMF (2.0 ml), Et3N (189 µl, 1.36 mmol), reagent BOP (273 mg, 0.62 mmol) and 2,4-dichlorophenylhydrazine hydrochloride (132 mg, 0.62 mmol) to give the title compound (205 mg, 69%). P.F .: 187-190 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 8.47 (d, J = 3.0, 1H); 7.59 (d, J = 2.1, 1H); 7.47 (d, J = 8.6, 1H); 7.40 (dd, J = 8.6, 2.1, 1H); 7.30 (d, J = 2.4, 1H); 7.11 (dd, J = 8.7, 1H); 6.95 (d, J = 9.0, 1H); 6.49 (d, J = 3.0, 1H); 3.71 (s, 1 H); 3.39 (s, 1 H); 2.12 (d a, J = 9.3, 1H); 1.97-1.90 (m, 2H); 1.70 (d a, J = 9.3, 1H); 1.25-1.15 (m, 2H). IR (KBr, cm-1): 3348 (m), 3191 (m), 2984 (m), 2968 (m), 2873 (w), 1661 (s), 1588 (m), 1557 (m), 1495 (s), 1343 (m), 1279 (m), 1108 (m), 1078 (m), 1068 (m), 861 (m).

Ejemplo 261 Example 261

N(3)-[(2,4-diclorofenil)-N-metilamino]-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3carboxamida N (3) - [(2,4-dichlorophenyl) -N-methylamino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 17 (100 mg, 0,31 mmol), DMF (1,0 ml), Et3N (0,51 µl, 0,37 mmol), reactivo BOP (136 mg, 0,31 mmol) y N-(2,4The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0 ml), Et3N (0.51 µl, 0.37 mmol) , BOP reagent (136 mg, 0.31 mmol) and N- (2.4

diclorofenil)-N-metilhidrazina (59 mg, 0,31 mmol) produjo el compuesto del título (97 mg, 63%). P.F.: 135-138 ºC. RMN 1H(δ ppm, CDCl3, 300 MHz): 8,81 (s a, 1H); 7,57 (d, J = 1,8, 1H); 7,42 (d, J = 8,3, 1H); 7,40 (dd, J = 8,3, 1,8, 1H); 7,35 (d, J = 8,3, 1H); 7,31 (d, J = 2,4, 1H); 7,21 (dd, J = 8,3, 2,4, 1H); 3,69 (s a, 1H); 3,35 (s a, 4H); 2,09 (d a, J = 9,0, 1H); 2,00-1,80 (m, 2H); 1,67 (d a, J = 9,0, 1H); 1,35-1,20 (m, 2H). IR (cm-1, KBr): 3348 (s), 3081 (w), 2963 (m), 2871 (w), 1683 (s), 1586 (w), 1565 (w), 1533 (m), 1505 (s), 1482 (s), 1470 (s), 1438 (m), 1345 (m), 1122 (m), 1105 (m), 1085 (m), 1464 (s), 1049 (m), 814 (m). EM (m/z): 495,0 ([M+H]+). dichlorophenyl) -N-methylhydrazine (59 mg, 0.31 mmol) produced the title compound (97 mg, 63%). P.F .: 135-138 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 8.81 (s at, 1H); 7.57 (d, J = 1.8, 1H); 7.42 (d, J = 8.3, 1H); 7.40 (dd, J = 8.3, 1.8, 1H); 7.35 (d, J = 8.3, 1H); 7.31 (d, J = 2.4, 1H); 7.21 (dd, J = 8.3, 2.4, 1H); 3.69 (s a, 1 H); 3.35 (s a, 4H); 2.09 (d a, J = 9.0, 1H); 2.00-1.80 (m, 2H); 1.67 (d a, J = 9.0, 1H); 1.35-1.20 (m, 2H). IR (cm-1, KBr): 3348 (s), 3081 (w), 2963 (m), 2871 (w), 1683 (s), 1586 (w), 1565 (w), 1533 (m), 1505 (s), 1482 (s), 1470 (s), 1438 (m), 1345 (m), 1122 (m), 1105 (m), 1085 (m), 1464 (s), 1049 (m), 814 (m). MS (m / z): 495.0 ([M + H] +).

Ejemplo 262 Example 262

N-(3)-[(3,4-Diclorofenil)amino]-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N- (3) - [(3,4-Dichlorophenyl) amino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 17 (200 mg, 0,619 mmol), DMF (2,0 ml), Et3N (189 µl, 1,361 mmol), reactivo BOP (273 mg, 0,619 mmol) y clorhidrato 3,4-diclorofenilhidrazina (132 mg, 0,619 mmol) produjo el compuesto del título (205 mg, 69%) . P.F.: 176-179 ºC. RMN 1H(δ ppm, CDCl3, 300 MHz): 8,48 (s, 1H); 7,59 (d, J = 2,1, 1H); 7,48 (d, J = 8,4, 1H); 7,40 (dd, J = 8,4, 2,1, 1H); 7,26 (d, J = 8,7, 1H); 7,03 (d, J = 2,7, 1H); 6,77 (dd, J = 8,7, 2,7, 1H); 6,22 (s a, 1H); 3,72 (s a, 1H); 3,40 (s a, 1H); 2,13 (d a, J = 9,0, 1H); 2,03-1,88 (m, 2H); 1,70 (d a, J = 9,0, 1H); 1,30-1,16 (m, 2H). IR (KBr, cm-1): 3314 (m), 2951 (m), 2870 (m), 1678 (s), 1602 (m), 1511 (s), 1475 (s), 1384 (m), 1339 (m), 1253 (m), 1225 (m), 1126 (s), 1062 (s), 863 (m), 819 (s). EM (m/z): 481,0 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 17 (200 mg, 0.619 mmol), DMF (2.0 ml), Et3N (189 µl, 1.361 mmol), BOP reagent (273 mg , 0.619 mmol) and 3,4-dichlorophenylhydrazine hydrochloride (132 mg, 0.619 mmol) produced the title compound (205 mg, 69%). P.F .: 176-179 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 8.48 (s, 1H); 7.59 (d, J = 2.1, 1H); 7.48 (d, J = 8.4, 1H); 7.40 (dd, J = 8.4, 2.1, 1H); 7.26 (d, J = 8.7, 1H); 7.03 (d, J = 2.7, 1H); 6.77 (dd, J = 8.7, 2.7, 1H); 6.22 (s a, 1 H); 3.72 (s a, 1 H); 3.40 (s, 1H); 2.13 (d a, J = 9.0, 1H); 2.03-1.88 (m, 2H); 1.70 (d a, J = 9.0, 1H); 1.30-1.16 (m, 2H). IR (KBr, cm-1): 3314 (m), 2951 (m), 2870 (m), 1678 (s), 1602 (m), 1511 (s), 1475 (s), 1384 (m), 1339 (m), 1253 (m), 1225 (m), 1126 (s), 1062 (s), 863 (m), 819 (s). MS (m / z): 481.0 ([M + H] +).

Ejemplo 263 Example 263

N-(3)-[(3,4-Diclorofenil)amino]-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N- (3) - [(3,4-Dichlorophenyl) amino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 17 (100 mg, 0,31 mmol), DMF (1,0 ml), Et3N (103 µl, 0,74 mmol), reactivo BOP (136 mg, 0,31 mmol) y clorhidrato de 2bromofenilhidrazina (69 mg, 0,31 mmol) produjo el compuesto del título (115 mg, 76%). P.F.: 159 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,50 (d, J = 3,3, 1H); 7,59 (d, J = 2,4,1H); 7,50-7,39 (m, 3 H); 7,20 (t, J = 7,7, 1H); 7,01 (d, J = 6,9, 1H); 6,77 (t, J = 7,5, 1H); 6,52 (d, J = 3,3, 1H); 3,73 (s, 1H); 3,40 (s, 1H); 2,14 (d a, J = 8,7, 1H); 2,02-1,91 (m, 2H); 1,70 (d a, J = 8,7, 1H); 1,30-1,19 (m, 2H). IR (KBr, cm-1): 3256 (m), 2925 (m), 2859 (m), 1666 (s), 1505 (s), 1344 (m), 1278 (m), 1232 (m), 1110 (m), 1079 (m), 1064 (m), 742 (m). EM (m/z): 491:0 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0 ml), Et3N (103 µl, 0.74 mmol), reagent BOP (136 mg, 0.31 mmol) and 2-bromophenylhydrazine hydrochloride (69 mg, 0.31 mmol) produced the title compound (115 mg, 76%). P.F .: 159 ºC. 1H NMR (δ ppm, CDCl3, 300 MHz): 8.50 (d, J = 3.3, 1H); 7.59 (d, J = 2.4.1H); 7.50-7.39 (m, 3 H); 7.20 (t, J = 7.7, 1H); 7.01 (d, J = 6.9, 1H); 6.77 (t, J = 7.5, 1H); 6.52 (d, J = 3.3, 1H); 3.73 (s, 1 H); 3.40 (s, 1 H); 2.14 (d a, J = 8.7, 1H); 2.02-1.91 (m, 2H); 1.70 (d a, J = 8.7, 1H); 1.30-1.19 (m, 2H). IR (KBr, cm-1): 3256 (m), 2925 (m), 2859 (m), 1666 (s), 1505 (s), 1344 (m), 1278 (m), 1232 (m), 1110 (m), 1079 (m), 1064 (m), 742 (m). MS (m / z): 491: 0 ([M + H] +).

Ejemplo 264 Example 264

N-(3)-[(3,4-Diclorofenil)amino]-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N- (3) - [(3,4-Dichlorophenyl) amino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 17 (200 mg, 0,62 mmol), DMF (2,0 ml), Et3N (0,2,0 ml, 1,49 mmol), reactivo BOP (273 mg, 0,62 mmol) y clorhidrato 2fluorofenilhidrazina (100 mg, 0,62 mmol) dio el compuesto del título (96 mg, 72%). P.F.:131-134 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,51 (s a, 1H); 7,59 (d, J = 2,1, 1H); 7,48 (d, J = 8,6, 1H); 7,40 (dd, J = 8,6, 2,1, 1H); 7,10-6,95 (m, 3H); 6,90-6,80 (m, 1H); 3,73 (s a, 1H); 3,40 (s a, 1H); 2,14 (d a, J = 9,0, 1H); 2,02-1,85 (m, 2H); 1,70 (d, J = 9,0, 1H); 1,30-1,15 (m, 2H). IR (KBr, cm-1): 3256 (s a), 2989 (m), 2959 (m), 2873 (w), 1666 (s), 1618 (m), 1508 (s), 1456 (m), 1345 (m), 1279 (m), 1243(m), 1194 (m), 1099 (s), 1063 (m), 863 (m). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 17 (200 mg, 0.62 mmol), DMF (2.0 ml), Et3N (0.2.0 ml, 1.49 mmol), BOP reagent (273 mg, 0.62 mmol) and 2-fluorophenylhydrazine hydrochloride (100 mg, 0.62 mmol) gave the title compound (96 mg, 72%). P.F.:131-134 ° C. 1 H NMR (δ ppm, CDCl 3, 300 MHz): 8.51 (s a, 1 H); 7.59 (d, J = 2.1, 1H); 7.48 (d, J = 8.6, 1H); 7.40 (dd, J = 8.6, 2.1, 1H); 7.10-6.95 (m, 3H); 6.90-6.80 (m, 1 H); 3.73 (s a, 1 H); 3.40 (s at, 1 H); 2.14 (d a, J = 9.0, 1H); 2.02-1.85 (m, 2H); 1.70 (d, J = 9.0, 1H); 1.30-1.15 (m, 2H). IR (KBr, cm-1): 3256 (sa), 2989 (m), 2959 (m), 2873 (w), 1666 (s), 1618 (m), 1508 (s), 1456 (m), 1345 (m), 1279 (m), 1243 (m), 1194 (m), 1099 (s), 1063 (m), 863 (m).

Ejemplo 265 Example 265

N-(3)-[(3,4-Diclorofenil)amino]-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N- (3) - [(3,4-Dichlorophenyl) amino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 17 (150 mg, 0,46 mmol), DMF (2,0 ml), Et3N (154 µl, 1,11 mmol), reactivo BOP (205 mg, 0,46 mmol) y clorhidrato 2,4difluorofenilhidrazina (83 mg, 0,46 mmol) produjo el compuesto del título (143 mg, 69%). P.F.: 157-160 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,50 (s a, 1H); 7,59 (d, J = 1,8, 1H); 7,47 (d, J = 8,4, 1H); 7,39 (dd, J = 8,4, 1,8, 1H); 7,00 (dt, J = 9,0, 5,4, 1H); 6,82 (td, J = 8,4, 2,7, 1H); 6,72 (t a, J = 8,1, 1H); 3,72 (s a, 1H); 3,40 (s a, 1H); 2,13 (d a, J = 8,4, 1H); 2,05-1,85 (m, 2H); 1,70 (d, J = 8,4, 1H); 1,30-1,15 (m, 2H). IR (KBr, cm-1): 3358 (m), 3198 (m), 3061 (m), 2989 (m), 2874 (m), 1664 (s), 1565 (m), 1520 (s), 1468 (m), 1382 (m), 1320 (m), 1281 (m), 1262 (m), 1207 (m), 1123 (m), 1108 (m), 1077 (m), 959 (m), 798 (m). EM (m/z): 449,0 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 17 (150 mg, 0.46 mmol), DMF (2.0 ml), Et3N (154 µl, 1.11 mmol), reagent BOP (205 mg, 0.46 mmol) and 2,4-difluorophenylhydrazine hydrochloride (83 mg, 0.46 mmol) produced the title compound (143 mg, 69%). P.F .: 157-160 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 8.50 (s at, 1H); 7.59 (d, J = 1.8, 1H); 7.47 (d, J = 8.4, 1H); 7.39 (dd, J = 8.4, 1.8, 1H); 7.00 (dt, J = 9.0, 5.4, 1H); 6.82 (td, J = 8.4, 2.7, 1H); 6.72 (t a, J = 8.1, 1H); 3.72 (s a, 1 H); 3.40 (s at, 1 H); 2.13 (d a, J = 8.4, 1H); 2.05-1.85 (m, 2H); 1.70 (d, J = 8.4, 1H); 1.30-1.15 (m, 2H). IR (KBr, cm-1): 3358 (m), 3198 (m), 3061 (m), 2989 (m), 2874 (m), 1664 (s), 1565 (m), 1520 (s), 1468 (m), 1382 (m), 1320 (m), 1281 (m), 1262 (m), 1207 (m), 1123 (m), 1108 (m), 1077 (m), 959 (m), 798 (m). MS (m / z): 449.0 ([M + H] +).

Ejemplo 266 Example 266

N-(3)-[(3,4-Diclorofenil)amino]-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N- (3) - [(3,4-Dichlorophenyl) amino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 17 (100 mg, 0,31 mmol), DMF (1,0 ml), Et3N (103 µl, 0,74 mmol), reactivo BOP (136 mg, 0,31 mmol) y clorhidrato 3fluorofenilhidrazina (50 mg, 0,31 mmol) produjo el compuesto del título (98 mg, 74%). P.F.: 190 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,46 (s, 1H); 7,59 (d, J = 2,4, 1H); 7,49 (d, J = 8,4, 1H); 7,40 (dd, J = 8,7, 2,4, 1H); 7,21-7,13 (m, 1H); 6,77-6,47 (m, 3H); 6,20 (s a, 1H); 3,73 (s, 1H); 3,40 (s, 1H); 2,14 (d a, J = 8,6, 1H); 2,02-1,88 (m, 2H); 1,70 (d a, J = 8,6, 1H); 1,31-1,16 (m, 2H). IR (KBr, cm-1): 3411 (s), 3277 (s), 2986 (m), 2940 (m), 2870 (m), 1670 (s), 1615 (s), 1544 (s), 1504 (s), 1469 (s), 1444 (s), 1475 (s), 1341(m), 1273 (m), 1237 (m), 1105 (m), 1081 (m), 835 (m). EM (m/z): 431,1 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0 ml), Et3N (103 µl, 0.74 mmol), reagent BOP (136 mg, 0.31 mmol) and 3fluorophenylhydrazine hydrochloride (50 mg, 0.31 mmol) produced the title compound (98 mg, 74%). P.F .: 190 ºC. 1H NMR (δ ppm, CDCl3, 300 MHz): 8.46 (s, 1H); 7.59 (d, J = 2.4, 1H); 7.49 (d, J = 8.4, 1H); 7.40 (dd, J = 8.7, 2.4, 1H); 7.21-7.13 (m, 1 H); 6.77-6.47 (m, 3H); 6.20 (s a, 1 H); 3.73 (s, 1 H); 3.40 (s, 1H); 2.14 (d a, J = 8.6, 1H); 2.02-1.88 (m, 2H); 1.70 (d a, J = 8.6, 1H); 1.31-1.16 (m, 2H). IR (KBr, cm-1): 3411 (s), 3277 (s), 2986 (m), 2940 (m), 2870 (m), 1670 (s), 1615 (s), 1544 (s), 1504 (s), 1469 (s), 1444 (s), 1475 (s), 1341 (m), 1273 (m), 1237 (m), 1105 (m), 1081 (m), 835 (m). MS (m / z): 431.1 ([M + H] +).

Ejemplo 267 Example 267

N-(3)-[(3,4-Diclorofenil)amino]-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N- (3) - [(3,4-Dichlorophenyl) amino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 17 (100 mg, 0,30 mmol), DMF (1,0 ml), Et3N (51 µl, 0,32 mmol), reactivo BOP (129 mg, 0,32 mmol) y 3-cloro-2hidrazinopiridina (44 mg, 0,31 mmol) para dar el compuesto del título (50 mg, 36%). P.F.: 95 ºC (se funde), RMN 1H (δ ppm, CDCl3, 300 MHz): 9,40 (s a, 1H); 8,10 (d a, J = 4,8, 1H); 7,60 (d a, J = 7,8, 2H); 7,58-7,50 (m, 1H); 7,39 (d a, J = 8,1, 2H); 6,78 (dt, J = 7,5, 2,4, 1H); 3,72 (s a, 1H); 3,41 (s a, 1H); 2,15 (t, J = 8,7, 1H), 2,00-1,85 (m, 2H); 1,69 (d a, J = 8,7, 1H); 1,20-1,10 (m, 2H). IR (cm-1, KBr): 3368 (m a), 2954 (m), 2870 (m), 1677 (s), 1591 (s), 1537 (m), 1498 (s), 1470 (s), 1406 (m), 1252 (m), 1227 (m), 1125 (s), 1080 (m), 1033 (m), 866 (w), 832 (m). EM (m/z): 448,0 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 17 (100 mg, 0.30 mmol), DMF (1.0 ml), Et3N (51 µl, 0.32 mmol), reagent BOP (129 mg, 0.32 mmol) and 3-chloro-2-hydrazinopyridine (44 mg, 0.31 mmol) to give the title compound (50 mg, 36%). P.F .: 95 ° C (melts), 1H NMR (δ ppm, CDCl3, 300 MHz): 9.40 (s at, 1H); 8.10 (d a, J = 4.8, 1H); 7.60 (d a, J = 7.8, 2H); 7.58-7.50 (m, 1 H); 7.39 (d a, J = 8.1, 2H); 6.78 (dt, J = 7.5, 2.4, 1H); 3.72 (s a, 1 H); 3.41 (s at, 1 H); 2.15 (t, J = 8.7, 1H), 2.00-1.85 (m, 2H); 1.69 (d a, J = 8.7, 1H); 1.20-1.10 (m, 2H). IR (cm-1, KBr): 3368 (ma), 2954 (m), 2870 (m), 1677 (s), 1591 (s), 1537 (m), 1498 (s), 1470 (s), 1406 (m), 1252 (m), 1227 (m), 1125 (s), 1080 (m), 1033 (m), 866 (w), 832 (m). MS (m / z): 448.0 ([M + H] +).

Ejemplo 268 Example 268

N(5)-piperidilo-3-(2’,4’-diclorofenil)-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxamida: N (5) -piperidyl-3- (2 ’, 4’-dichlorophenyl) -3,4-diazatricyclo [5.2.1.02.6] deca-2 (6), 4-dien-5-carboxamide:

El compuesto del título se sintetizó como para el procedimiento descrito para el ejemplos 101 usando el intermedio 17 (100 mg, 0,31 mmol), DMF (1 ml), trietilamina (0,04 ml, 0,31 mmol), reactivo BOP (136 mg, 0,31 mmol) y 1aminopiperidina (0,033 ml, 0,31 mmol) para dar el compuesto del título (62 mg, 50%). RMN 1H (δ ppm, CDCl3): 7,56 (d, J = 2,1, 1H); 7,45 (d, J = 8,4, 1H); 7,37 (dd, J = 8,4, 2,1, 1H); 3,76 (s a, 1H); 3,36 (s a, 1H); 2,91 (s a, 4H); 2,12 (d a, J = 10,2, 1H); 2,04-1,82 (m, 2H); 1,81-1,56 (m, 5H); 1,50-1,38 (m, 2H); 1,34-1,10 (m, 2H). The title compound was synthesized as for the procedure described for examples 101 using intermediate 17 (100 mg, 0.31 mmol), DMF (1 ml), triethylamine (0.04 ml, 0.31 mmol), BOP reagent (136 mg, 0.31 mmol) and 1aminopiperidine (0.033 ml, 0.31 mmol) to give the title compound (62 mg, 50%). 1H NMR (δ ppm, CDCl3): 7.56 (d, J = 2.1, 1H); 7.45 (d, J = 8.4, 1H); 7.37 (dd, J = 8.4, 2.1, 1H); 3.76 (s a, 1 H); 3.36 (s at, 1 H); 2.91 (s a, 4H); 2.12 (d a, J = 10.2, 1H); 2.04-1.82 (m, 2H); 1.81-1.56 (m, 5H); 1.50-1.38 (m, 2H); 1.34-1.10 (m, 2H).

Ejemplo 269 Example 269

N(5)-bencil-3-(2’,4’-diclorofenil)-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxamida N (5) -benzyl-3- (2 ’, 4’-dichlorophenyl) -3,4-diazatricyclo [5.2.1.02.6] deca-2 (6), 4-dien-5-carboxamide

El compuesto del título se sintetizó como para el procedimiento descrito para el ejemplo 101 usando intermedio 17 (100 mg, 0,31 mmol), DMF(1 ml), trietilamina (0,04 ml, 0,31 mmol), reactivo BOP (136 mg, 0,31 mmol) y bencilamina (0,033 ml, 0,31 mmol) para dar el compuesto del título (94 mg, 74%). RMN 1H (δ ppm, CDCl3): 7,55 (d, J = 2,1, 1H); 7,42 (d, J = 8,4, 1H); 7,37-7,23 (m, 6H); 7,15 (s a, 1H); 4,63 (dd, J = 11,0, 5,0, 1H); 4,57 (dd, J = 11,0, 5,0, 1H); 3,78 (s a, 1H); 3,36 (s a, 1H); 2,13 (d a, J = 8,4, 1H); 2,04-1,82 (m, 2H); 1,70 (d a, J = 8,4, 1H); 1,35-1,11 (m, 2H). The title compound was synthesized as for the procedure described for example 101 using intermediate 17 (100 mg, 0.31 mmol), DMF (1 ml), triethylamine (0.04 ml, 0.31 mmol), BOP reagent ( 136 mg, 0.31 mmol) and benzylamine (0.033 ml, 0.31 mmol) to give the title compound (94 mg, 74%). 1H NMR (δ ppm, CDCl3): 7.55 (d, J = 2.1, 1H); 7.42 (d, J = 8.4, 1H); 7.37-7.23 (m, 6H); 7.15 (s a, 1 H); 4.63 (dd, J = 11.0, 5.0, 1H); 4.57 (dd, J = 11.0, 5.0, 1H); 3.78 (s a, 1 H); 3.36 (s at, 1 H); 2.13 (d a, J = 8.4, 1H); 2.04-1.82 (m, 2H); 1.70 (d a, J = 8.4, 1H); 1.35-1.11 (m, 2H).

Ejemplo 270 Example 270

N(3)-Piperidino-1-(2-bromofenil)-4,5,6,7-tetrathidro-1H-4,7-metano-indazol-3-carboxamida N (3) -Piperidino-1- (2-bromophenyl) -4,5,6,7-tetrathydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 18 (100 mg, 0,30 mmol), DMF (1,0 ml), Et3N (50 µl, 0,36 mmol), reactivo BOP (146 mg, 0,33 mmol) y 1-aminopiperidina (32 µl, 0,30 mmol) dio el compuesto del título (52 mg, 42%). P.F.: 236 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,73 (d, J = 8,4, 1H); 7,58 (s a, 1H); 7,39-7,46 (m, 2H); 7,36-7,30 (m, 1H); 3,77 (s a, 1H); 3,35 (s a, 1H); 2,85 (s a, 4H); 2,15 (d a, J = 7,8, 1H); 2,00-1,71 (m, 6H); 1,44-1,16 (m, 5H). IR (KBr, cm-1): 3308 (m), 3000 (m), 2940 (s), 2864 (m), 2793 (m), 1685 (s), 1540 (s), 1511 (s), 1484 (s), 1449 (m), 1340 (w), 1229 (m), 1133 (m), 1123 (m), 1036 (m), 986 (m), 904 (m), 832 (w). EM (m/z): 415,1 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 18 (100 mg, 0.30 mmol), DMF (1.0 ml), Et3N (50 µl, 0.36 mmol), reagent BOP (146 mg, 0.33 mmol) and 1-aminopiperidine (32 µl, 0.30 mmol) gave the title compound (52 mg, 42%). M.P .: 236 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.73 (d, J = 8.4, 1H); 7.58 (s a, 1 H); 7.39-7.46 (m, 2H); 7.36-7.30 (m, 1 H); 3.77 (s a, 1 H); 3.35 (s at, 1 H); 2.85 (s at, 4H); 2.15 (d a, J = 7.8, 1H); 2.00-1.71 (m, 6H); 1.44-1.16 (m, 5H). IR (KBr, cm-1): 3308 (m), 3000 (m), 2940 (s), 2864 (m), 2793 (m), 1685 (s), 1540 (s), 1511 (s), 1484 (s), 1449 (m), 1340 (w), 1229 (m), 1133 (m), 1123 (m), 1036 (m), 986 (m), 904 (m), 832 (w). MS (m / z): 415.1 ([M + H] +).

Ejemplo 271 Example 271

N(3)-Ciclohexil-1-(2-bromofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) -Cyclohexyl-1- (2-bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 18 (100 mg, 0,30 mmol), DMF (1,0 ml), Et3N (50 µl, 0,36 mmol), reactivo BOP (146 mg, 0,33 mmol) y ciclohexilamina (39 µl, 0,34 mmol) dio el compuesto del título (100 mg, 80%). P.F.:178 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,26 (d; J= 8,1, 1H); 7,51-7,40 (m, 2H); 7,33 (t a, J = 8,1, 1H); 6,73 (d a, J = 8,4, 1H); 3,85-4,05 (m, 1H); 3,77 (s a, 1H); 3,35 (s a, 1H); 2,15 (d a, J = 7,2, 1H); 2,00-1,85 (m, 4H); 1,80-1,65 (m, 4H); 1,50-1,14 (m, 7H). IR (KBr, cm-1): 3413 (m), 2938 (s), 2854 (m), 1662 (s), 1541 (s), 1512 (s), 1480 (s), 1450 (s), 1341 (m), 1299 (m), 1222 (m), 1159 (m), 1125 (m). EM (m/z): 414,0 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 18 (100 mg, 0.30 mmol), DMF (1.0 ml), Et3N (50 µl, 0.36 mmol), reagent BOP (146 mg, 0.33 mmol) and cyclohexylamine (39 µl, 0.34 mmol) gave the title compound (100 mg, 80%). P.F.:178 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.26 (d; J = 8.1, 1H); 7.51-7.40 (m, 2H); 7.33 (t a, J = 8.1, 1H); 6.73 (d a, J = 8.4, 1H); 3.85-4.05 (m, 1 H); 3.77 (s a, 1 H); 3.35 (s at, 1 H); 2.15 (d a, J = 7.2, 1H); 2.00-1.85 (m, 4H); 1.80-1.65 (m, 4H); 1.50-1.14 (m, 7H). IR (KBr, cm-1): 3413 (m), 2938 (s), 2854 (m), 1662 (s), 1541 (s), 1512 (s), 1480 (s), 1450 (s), 1341 (m), 1299 (m), 1222 (m), 1159 (m), 1125 (m). MS (m / z): 414.0 ([M + H] +).

Ejemplo 272 Example 272

N(3)-Bencil-1-(2-bromofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) -Benzyl-1- (2-bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 18 (100 mg, 0,30 mmol), DMF (1,0 ml), Et3N (50 µl, 0,36 mmol), reactivo BOP (146 mg, 0,33 mmol) y bencilamina (32 µl, 0,30 mmol) dio el compuesto del título (60 mg, 47%). P.F.:110 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,70 (d, J = 8,4, 1H); 7,45-7,16 (m, 9H); 4,61 (m, 2H); 3,79 (s a, 1H); 3,56 (s a, 1H); 2,16 (d a, J = 8,7, 1H); 2,05-1,80 (m, 2H); 1,70 (d a, J = 8,7, 1H); 1,35-1,15 (m, 2H). IR (KBr, cm-1): 3419 (w), 3020 (s), 2401 (w), 1661 (w), 1549 (w), 1516 (w), The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 18 (100 mg, 0.30 mmol), DMF (1.0 ml), Et3N (50 µl, 0.36 mmol), reagent BOP (146 mg, 0.33 mmol) and benzylamine (32 µl, 0.30 mmol) gave the title compound (60 mg, 47%). P.F.: 110 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.70 (d, J = 8.4, 1H); 7.45-7.16 (m, 9H); 4.61 (m, 2H); 3.79 (s a, 1 H); 3.56 (s at, 1 H); 2.16 (d a, J = 8.7, 1H); 2.05-1.80 (m, 2H); 1.70 (d a, J = 8.7, 1H); 1.35-1.15 (m, 2H). IR (KBr, cm-1): 3419 (w), 3020 (s), 2401 (w), 1661 (w), 1549 (w), 1516 (w),

1484 (w), 1427 (w), 1343 (w), 1216 (s). EM (m/z): 422,0 ([M+H]+). 1484 (w), 1427 (w), 1343 (w), 1216 (s). MS (m / z): 422.0 ([M + H] +).

Ejemplo 273 Example 273

N(3)-Fenilamino-1-(2-bromofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) -Phenylamino-1- (2-bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 18 (100 mg, 0,30 mmol), DMF (1,0 ml), Et3N (50 µl, 0,36 mmol), reactivo BOP (146 mg, 0,33 mmol) y fenilhidrazina (30 µl, 0,30 mmol) dio el compuesto del título (101 mg, 80%). P.F.: 219 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,51 (s a, 1H); 7,50 (d, J = 7,8, 1H); 7,60-7,41 (m, 2H); 7,36 (t a; J = 8,4, 1H); 7,34 (t, J = 7,8, 2H); 6,95 (d, J = 7,8, 2H); 6,89 (t, J = 7,5, 1H); 3,73 (s a, 1H); 3,39 (s a, 1H); 2,16 (d a, J = 7,2, 1H); 2,00-1,85 (m, 2H); 7,70 (d, J = 8,7, 1H); 1,28-1,20 (m, 2H). IR (KBr, cm-1): 3283 (m), 2992 (m), 2959 (m), 2863 (w), 1675 (s), 1603 (m), 1542 (m), 1511 (s), 1497 (s), 1438 (m), 1348 (m), 1281 (m), 1240 (m), 1136 (m), 1123 (m), 1084 (m), 1029 (m), 888 (m). EM (m/z): 423,0 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 18 (100 mg, 0.30 mmol), DMF (1.0 ml), Et3N (50 µl, 0.36 mmol), reagent BOP (146 mg, 0.33 mmol) and phenylhydrazine (30 µl, 0.30 mmol) gave the title compound (101 mg, 80%). P.F .: 219 ° C. 1 H NMR (δ ppm, CDCl 3, 300 MHz): 8.51 (s a, 1 H); 7.50 (d, J = 7.8, 1H); 7.60-7.41 (m, 2H); 7.36 (t a; J = 8.4, 1H); 7.34 (t, J = 7.8, 2H); 6.95 (d, J = 7.8, 2H); 6.89 (t, J = 7.5, 1H); 3.73 (s a, 1 H); 3.39 (s at, 1 H); 2.16 (d a, J = 7.2, 1H); 2.00-1.85 (m, 2H); 7.70 (d, J = 8.7, 1H); 1.28-1.20 (m, 2H). IR (KBr, cm-1): 3283 (m), 2992 (m), 2959 (m), 2863 (w), 1675 (s), 1603 (m), 1542 (m), 1511 (s), 1497 (s), 1438 (m), 1348 (m), 1281 (m), 1240 (m), 1136 (m), 1123 (m), 1084 (m), 1029 (m), 888 (m). MS (m / z): 423.0 ([M + H] +).

Ejemplo 274 Example 274

N(3)-Piperidino-1-(4-bromofenil)-4,5,6,7-tetrathidro-1H-4,7-metano-indazol-3-carboxamida N (3) -Piperidino-1- (4-bromophenyl) -4,5,6,7-tetrathydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 19 (100 mg, 0,30 mmol), DMF (1,0 ml), Et3N (50 µl, 0,36 mmol), reactivo BOP (146 mg, 0,33 mmol) y 1-aminopiperidina (33 µl, 0,30 mmol) produjo el compuesto del título (124 mg, 99%). P.F.: 173 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,60 (s a, 4H); 3,70 (s a, 1H); 3,65 (s a, 1H); 2,90 (s a, 4H); 2,20 (d a, J = 7,14, 1H); 2,00 (d a, J = 8,6, 2H); 1,90-1,60 (m, 6H); 1,30-1,20 (m, 3H). IR (KBr, cm-1): 3408 (w), 3308 (w), 2929 (s), 2859 (m), 2780 (m), 1692 (s), 1591 (m), 1541 (s), 1503 (s), 1489 (s), 1440 (m), 1401 (m), 1348 (s), 1268 (m), 1226 (s), 1154 (m), 1122 (s), 1064 (m), 1006 (m), 827 (s). EM (m/z): 415,1 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 19 (100 mg, 0.30 mmol), DMF (1.0 ml), Et3N (50 µl, 0.36 mmol), reagent BOP (146 mg, 0.33 mmol) and 1-aminopiperidine (33 µl, 0.30 mmol) produced the title compound (124 mg, 99%). M.P .: 173 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.60 (s at, 4H); 3.70 (s at, 1 H); 3.65 (s a, 1 H); 2.90 (s at, 4H); 2.20 (d a, J = 7.14, 1H); 2.00 (d a, J = 8.6, 2H); 1.90-1.60 (m, 6H); 1.30-1.20 (m, 3H). IR (KBr, cm-1): 3408 (w), 3308 (w), 2929 (s), 2859 (m), 2780 (m), 1692 (s), 1591 (m), 1541 (s), 1503 (s), 1489 (s), 1440 (m), 1401 (m), 1348 (s), 1268 (m), 1226 (s), 1154 (m), 1122 (s), 1064 (m), 1006 (m), 827 (s). MS (m / z): 415.1 ([M + H] +).

Ejemplo 275 Example 275

N(3)-Ciclohexil-1-(4-bromofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) -Cyclohexyl-1- (4-bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 19 (100 mg, 0,30 mmol), DMF (1,0 ml), Et3N (50 µl, 0,36 mmol), reactivo BOP (146 mg, 0,33 mmol) y ciclohexilamina (34 µl, 0,30 mmol) dio el compuesto del título (91 mg, 73%). P.F.: 164 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,58 (s, 4H); 6,75 (d a, J = 8,1, 1H); 3,93 (m, 1H); 3,75 (s a, 1H); 3,67 (s a, 1H); 2,12 (d a, J = 8,4, 1H); 2,10-1,90 (m, 4H); 1,80-1,70 (m, 3H); 1,60-1,20 (m, 8H). IR (KBr, cm-1): 3410 (m), 2922 (m), 2848 (m), 1667 (s), 1591 (w), 1546 (s), 1504 (s), 1486 (s), 1450 (m), 1349 (m), 1224 (m), 1160 (m), 1122 (m), 1065 (m), 1006 (m), 827 (m). EM (m/z): 414,1 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 19 (100 mg, 0.30 mmol), DMF (1.0 ml), Et3N (50 µl, 0.36 mmol), reagent BOP (146 mg, 0.33 mmol) and cyclohexylamine (34 µl, 0.30 mmol) gave the title compound (91 mg, 73%). P.F .: 164 ºC. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.58 (s, 4H); 6.75 (d a, J = 8.1, 1H); 3.93 (m, 1 H); 3.75 (s a, 1 H); 3.67 (s at, 1 H); 2.12 (d a, J = 8.4, 1H); 2.10-1.90 (m, 4H); 1.80-1.70 (m, 3H); 1.60-1.20 (m, 8H). IR (KBr, cm-1): 3410 (m), 2922 (m), 2848 (m), 1667 (s), 1591 (w), 1546 (s), 1504 (s), 1486 (s), 1450 (m), 1349 (m), 1224 (m), 1160 (m), 1122 (m), 1065 (m), 1006 (m), 827 (m). MS (m / z): 414.1 ([M + H] +).

Ejemplo 276 Example 276

N(3)-Bencil-1-(4-bromofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) -Benzyl-1- (4-bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 19 (100 mg, 0,30 mmol), DMF (1,0 ml), Et3N (50 µl, 0,36 mmol), reactivo BOP (146 mg, 0,33 mmol) y bencilo amina (33 µl, 0,30 mmol) produjo el compuesto del título (107 mg, 85%). P.F.: 89 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,56 (s a, 4H); 7,40-7,22 (m, 6H); 4,64 (d, J = 5,4, 2H); 3,80 (s a, 1H); 3,68 (s a, 1H); 2,14 (d a, J = 8,1, 1H); 2,00 (d a, J = 5,7, 2H); 1,74 (d, J = 8,4, 1H); 1,26-1,20 (m, 2H). IR (KBr, cm-1): 3321 (m), 2937 (m), 2868 (m), 1649 (s), 1590 (m), 1551 (s), 1499 (s), 1455 (m), 1347 (s), 1275 (m), 1241 (m), 1121 (m), 1070 (m), 1005 (m), 975 (m), 825 (m). EM (m/z): 422,1 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 19 (100 mg, 0.30 mmol), DMF (1.0 ml), Et3N (50 µl, 0.36 mmol), reagent BOP (146 mg, 0.33 mmol) and benzyl amine (33 µl, 0.30 mmol) produced the title compound (107 mg, 85%). P.F .: 89 ºC. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.56 (s at, 4H); 7.40-7.22 (m, 6H); 4.64 (d, J = 5.4, 2H); 3.80 (s at, 1 H); 3.68 (s at, 1 H); 2.14 (d a, J = 8.1, 1H); 2.00 (d a, J = 5.7, 2H); 1.74 (d, J = 8.4, 1H); 1.26-1.20 (m, 2H). IR (KBr, cm-1): 3321 (m), 2937 (m), 2868 (m), 1649 (s), 1590 (m), 1551 (s), 1499 (s), 1455 (m), 1347 (s), 1275 (m), 1241 (m), 1121 (m), 1070 (m), 1005 (m), 975 (m), 825 (m). MS (m / z): 422.1 ([M + H] +).

Ejemplo 277 Example 277

N(3)-Fenilamino-1-(4-bromofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) -Phenylamino-1- (4-bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 19 (100 mg, 0,30 mmol), DMF (1,0 ml), Et3N (50 µl, 0,36 mmol), reactivo BOP (146 mg, 0,33 mmol) y fenilhidrazina (29 µl, 0,30 mmol) produjo el compuesto del título (90 mg, 71%). P.F.: 138 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,54 (s a, 1H); 7,61 (s, 4H); 7,24 (t, J = 7,8, 2H); 6,95 (d, J = 8,4, 2H); 6,90 (t, J = 7,2, 1H); 3,72 (a, 2H); 2,13 (d a, J = 8,0, 1H); 1,99 (d a, J = 7,8, 2H); 1,73 (d a, J = 8,0, 1H); 1,40-1,15 (m, 2H). IR (KBr, cm-1): 3262 (m), 2948 (m), 2869 (m), 1666 (s), 1603 (s), 1591 (s), 1545 (m), 1497 (s), 1401 (m), 1357 (m), 1279 (m), 1252 (m), 1227 (m), 1124 (m), 1083 (m), 1070 (m), 1005 (m), 894 (m). EM (m/z): 422,9 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 19 (100 mg, 0.30 mmol), DMF (1.0 ml), Et3N (50 µl, 0.36 mmol), reagent BOP (146 mg, 0.33 mmol) and phenylhydrazine (29 µl, 0.30 mmol) produced the title compound (90 mg, 71%). M.P .: 138 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 8.54 (s at, 1H); 7.61 (s, 4H); 7.24 (t, J = 7.8, 2H); 6.95 (d, J = 8.4, 2H); 6.90 (t, J = 7.2, 1H); 3.72 (a, 2H); 2.13 (d a, J = 8.0, 1H); 1.99 (d a, J = 7.8, 2H); 1.73 (d a, J = 8.0, 1H); 1.40-1.15 (m, 2H). IR (KBr, cm-1): 3262 (m), 2948 (m), 2869 (m), 1666 (s), 1603 (s), 1591 (s), 1545 (m), 1497 (s), 1401 (m), 1357 (m), 1279 (m), 1252 (m), 1227 (m), 1124 (m), 1083 (m), 1070 (m), 1005 (m), 894 (m). MS (m / z): 422.9 ([M + H] +).

Ejemplo 278 Example 278

N(3)-[(2-Fluorofenil)amino]-1-(4-bromofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) - [(2-Fluorophenyl) amino] -1- (4-bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 19 (100 mg, 0,30 mmol), DMF (1,0 ml), Et3N (63 µl, 0,45 mmol), reactivo BOP (146 mg, 0,33 mmol) y clorhidrato de 2The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 19 (100 mg, 0.30 mmol), DMF (1.0 ml), Et3N (63 µl, 0.45 mmol), reagent BOP (146 mg, 0.33 mmol) and 2 hydrochloride

fluorofenilhidrazina (48 mg, 0,30 mmol) produjo el compuesto del título (50 mg, 38%). P.F.: 123 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,57 (s a, 1H); 7,61 (s, 4H); 7,10-6,70 (m, 3H); 7,00-6,80 (m, 1H); 3,71 (s, 2H); 2,17 (d a, J = 8,4, 1H); 2,10-1,90 (m, 2H); 1,73 (d, J = 8,7, 1H); 1,35-1,15 (m, 2H). EM (m/z): 441,1 ([M+H]+). Fluorophenylhydrazine (48 mg, 0.30 mmol) produced the title compound (50 mg, 38%). M.P .: 123 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 8.57 (s at, 1H); 7.61 (s, 4H); 7.10-6.70 (m, 3H); 7.00-6.80 (m, 1 H); 3.71 (s, 2H); 2.17 (d a, J = 8.4, 1H); 2.10-1.90 (m, 2H); 1.73 (d, J = 8.7, 1H); 1.35-1.15 (m, 2H). MS (m / z): 441.1 ([M + H] +).

Ejemplo 279 Example 279

N(3)-Ciclohexil-1-(4-fluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) -Cyclohexyl-1- (4-fluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 20 (100 mg, 0,37 mmol), DMF (1,0 ml), Et3N (61 µl, 0,44 mmol), reactivo BOP (178 mg, 0,40 mmol) y ciclohexilamina (42 µl, 0,37 mmol) dio el compuesto del título (72 mg, 56%). P.F.: 127 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,647,62 (m, 2H); 7,17 (t, J = 8,4, 2H); 6,75 (d a, J = 7,7, 1H); 4,05-3,80 (m, 1H); 3,75 (s a, 1H); 3,64 (s a, 1H); 2,20-1,90 (s a, 5H); 1,74-1,66 (m, 5H); 1,44-1,10 (m, 6H). IR (KBr, cm-1): 3352 (m), 3310 (w), 2934 (m), 2834 (m), 1656 (s), 1642 (s), 1517 (s), 1499 (s), 1451 (m), 1350 (m), 1276 (w), 1252 (w), 1223 (s), 1163 (m), 1123 (m), 842 (m). EM (m/z): 354,1 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 20 (100 mg, 0.37 mmol), DMF (1.0 ml), Et3N (61 µl, 0.44 mmol), reagent BOP (178 mg, 0.40 mmol) and cyclohexylamine (42 µl, 0.37 mmol) gave the title compound (72 mg, 56%). P.F .: 127 ºC. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.647.62 (m, 2H); 7.17 (t, J = 8.4, 2H); 6.75 (d a, J = 7.7, 1H); 4.05-3.80 (m, 1 H); 3.75 (s a, 1 H); 3.64 (s at, 1 H); 2.20-1.90 (s a, 5H); 1.74-1.66 (m, 5H); 1.44-1.10 (m, 6H). IR (KBr, cm-1): 3352 (m), 3310 (w), 2934 (m), 2834 (m), 1656 (s), 1642 (s), 1517 (s), 1499 (s), 1451 (m), 1350 (m), 1276 (w), 1252 (w), 1223 (s), 1163 (m), 1123 (m), 842 (m). MS (m / z): 354.1 ([M + H] +).

Ejemplo 280 Example 280

N(3)-Bencil-1-(4-fluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) -Benzyl-1- (4-fluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 20 (100 mg, 0,37 mmol), DMF (1,0 ml), Et3N (61 µl, 0,44 mmol), reactivo BOP (178 mg, 0,40 mmol) y bencilamina (39 µl, 0,36 mmol) dio el compuesto del título (43 mg, 33%). P.F.: 104 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,62 (s a, 2H); 7,38-7,00 (m, 8H); 4,63 (d a, J = 5,1, 2H); 3,78 (s a, 1H); 3,66 (s a, 1H); 2,12 (d a, J = 8,4, 1H); 1,90-2,10 (m, 2H); 1,73 (d, J = 8,4, 1H); 1,40-1,10 (m, 2H). IR (KBr, cm-1): 3411 (m), 3009 (w), 2869 (w), 1670 (s), 1543 (s), 1500 (s), 1492 (s), 1454 (m), 1416 (m), 1349 (s), 1276 (m), 1226 (s), 1212 (s), 1164 (m), 1124 (m), 954 (w); 835 (s). EM (m/z): 362,1 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 20 (100 mg, 0.37 mmol), DMF (1.0 ml), Et3N (61 µl, 0.44 mmol), reagent BOP (178 mg, 0.40 mmol) and benzylamine (39 µl, 0.36 mmol) gave the title compound (43 mg, 33%). P.F .: 104 ºC. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.62 (s at, 2H); 7.38-7.00 (m, 8H); 4.63 (d a, J = 5.1, 2H); 3.78 (s a, 1 H); 3.66 (s at, 1 H); 2.12 (d a, J = 8.4, 1H); 1.90-2.10 (m, 2H); 1.73 (d, J = 8.4, 1H); 1.40-1.10 (m, 2H). IR (KBr, cm-1): 3411 (m), 3009 (w), 2869 (w), 1670 (s), 1543 (s), 1500 (s), 1492 (s), 1454 (m), 1416 (m), 1349 (s), 1276 (m), 1226 (s), 1212 (s), 1164 (m), 1124 (m), 954 (w); 835 (s). MS (m / z): 362.1 ([M + H] +).

Ejemplo 281 Example 281

N5-(Adamantan-2-il)-3-(4-fluorofenil)-3,4-diazatriciclo[5-2,1,02,6]deca-2(6),4-dien-5-carboxamida N5- (Adamantan-2-yl) -3- (4-fluorophenyl) -3,4-diazatricyclo [5-2,1,02,6] deca-2 (6), 4-dien-5-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 20 (100 mg, 0,36 mmol), DMF (1,0 ml), Et3N (124 µl, 0,88 mmol), reactivo BOP (170 mg, 0,38 mmol) y clorhidrato 2adamantilamina (103 mg, 0,55 mmol) produjo el compuesto del título (1,20 mg, 80%). P.F.: 196-198 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,69-7,63 (m, 2H); 7,17 (t, J = 8,1, 2H); 4,23 (d, J = 8,4, 1H); 3,75 (s a, 1H); 3,65 (s a, 1H), 2,14-1,87 (m, 14H), 1,78-1,54 (m, 4H), 1,26-1,21 (m, 2H). IR (cm-1, KBr): 3414 (s), 2979 (w), 2901 (s), 2851 (s), 1663 (s), 1542 (s), 1517 (s), 1488 (s), 1454 (m), 1445 (m), 1347 (w); 1255 (w), 1224 (m), 1213 (s), 1159 (m), 1126 (m), 1,091 (m), 953 (w), 833 (m). EM (m/z): 406,2 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 20 (100 mg, 0.36 mmol), DMF (1.0 ml), Et3N (124 µl, 0.88 mmol), reagent BOP (170 mg, 0.38 mmol) and 2-mantylamine hydrochloride (103 mg, 0.55 mmol) produced the title compound (1.20 mg, 80%). P.F .: 196-198 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.69-7.63 (m, 2H); 7.17 (t, J = 8.1, 2H); 4.23 (d, J = 8.4, 1H); 3.75 (s a, 1 H); 3.65 (s a, 1H), 2.14-1.87 (m, 14H), 1.78-1.54 (m, 4H), 1.26-1.21 (m, 2H). IR (cm-1, KBr): 3414 (s), 2979 (w), 2901 (s), 2851 (s), 1663 (s), 1542 (s), 1517 (s), 1488 (s), 1454 (m), 1445 (m), 1347 (w); 1255 (w), 1224 (m), 1213 (s), 1159 (m), 1126 (m), 1,091 (m), 953 (w), 833 (m). MS (m / z): 406.2 ([M + H] +).

Ejemplo Example

N5-(1-Metil-1-feniletil)-3-(4-fluorofenil)-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxamida N5- (1-Methyl-1-phenylethyl) -3- (4-fluorophenyl) -3,4-diazatricyclo [5.2.1.02.6] deca-2 (6), 4-dien-5-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 20 (100,mg, 0,36 mmol), DMF (1,0 ml), Et3N (41 µl, 0,40 mmol), reactivo BOP (170 mg, 0,38 mmol) y α,α-dimetilbencilamina (75 mg, 0,55 mmol) produjo el compuesto del título (77 mg, 54%). P.F.: 119-122 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,68-7,62 (m, 2H); 7,51-7,46 (m, 2H); 7,37-7,30 (m, 2H); 7,27-7,13 (m, 3H); 3,70 (s a, 1H); 3,63 (s a, 1H); 2,08 (d, J = 9,0, 1H), 1,95 (d, J = 7,8, 2H); 1, 84 (s, 6H); 1,68 (d, J = 8,4, 1H), 1,23 (d, J = 12,0, 2H). IR (cm-1 , KBr): 3358 (m), 2972 (m), 2927 (m), 2870 (m), 1664 (s), 1605 (w), 1542 (m), 1515 (s), 1489 (m), 1383 (w), 1357 (m), 1276 (m) 1219 (m), 1136 (m), 1117 (m), 1093 (m), 1031 (w), 1088 (w), 949 (w), 858 (w), 839 (m). EM (m/z): 390,0 (M+H+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 20 (100, mg, 0.36 mmol), DMF (1.0 ml), Et3N (41 µl, 0.40 mmol), BOP reagent (170 mg, 0.38 mmol) and α, α-dimethylbenzylamine (75 mg, 0.55 mmol) produced the title compound (77 mg, 54%). P.F .: 119-122 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.68-7.62 (m, 2H); 7.51-7.46 (m, 2H); 7.37-7.30 (m, 2H); 7.27-7.13 (m, 3H); 3.70 (s at, 1 H); 3.63 (s a, 1 H); 2.08 (d, J = 9.0, 1H), 1.95 (d, J = 7.8, 2H); 1, 84 (s, 6H); 1.68 (d, J = 8.4, 1H), 1.23 (d, J = 12.0, 2H). IR (cm-1, KBr): 3358 (m), 2972 (m), 2927 (m), 2870 (m), 1664 (s), 1605 (w), 1542 (m), 1515 (s), 1489 (m), 1383 (w), 1357 (m), 1276 (m) 1219 (m), 1136 (m), 1117 (m), 1093 (m), 1031 (w), 1088 (w), 949 ( w), 858 (w), 839 (m). MS (m / z): 390.0 (M + H +).

Ejemplo 283 Example 283

N5-(Adamantan-1-il)-3-(4-fluorofenil)-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxamida N5- (Adamantan-1-yl) -3- (4-fluorophenyl) -3,4-diazatricyclo [5.2.1.02.6] deca-2 (6), 4-dien-5-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 20 (100 mg, 0,36 mmol), DMF (1,0 ml), Et3N (41 µl, 0,40 mmol), reactivo BOP (170 g, 0,38 mmol) y 1-adamantilamina (83 mg, 0,54 mmol) produjo el compuesto del título (127 mg, 85%). P.F.: 189-191 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,66-7,60 (m, 2H); 7,19-7,12 (m, 2H); 6,66 (s a, 1H); 3,74 (s a, 1H); 3,63 (s a, 1H); 2,15-2,10 (m, 9H); 1,97 (d, J 8,7, 2H); 1,75-1,68 (m, 8H); 1,30-1,20 (m, 2H). IR (cm-1, KBr): 3361 (m), 2986 (m), 2909 (s), 2849 (m), 1658 (s), 1517 (s), 1550 (s), 1493 (s), 1445 (m), 1412 (m), 1308 (w), 1289 (w), 1278 (w), 1256 (s), 1219 (s), 868 (m). EM (m/z): 406,1 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 20 (100 mg, 0.36 mmol), DMF (1.0 ml), Et3N (41 µl, 0.40 mmol), reagent BOP (170 g, 0.38 mmol) and 1-adamantylamine (83 mg, 0.54 mmol) produced the title compound (127 mg, 85%). P.F .: 189-191 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.66-7.60 (m, 2H); 7.19-7.12 (m, 2H); 6.66 (s a, 1 H); 3.74 (s a, 1 H); 3.63 (s a, 1 H); 2.15-2.10 (m, 9H); 1.97 (d, J 8.7, 2H); 1.75-1.68 (m, 8H); 1.30-1.20 (m, 2H). IR (cm-1, KBr): 3361 (m), 2986 (m), 2909 (s), 2849 (m), 1658 (s), 1517 (s), 1550 (s), 1493 (s), 1445 (m), 1412 (m), 1308 (w), 1289 (w), 1278 (w), 1256 (s), 1219 (s), 868 (m). MS (m / z): 406.1 ([M + H] +).

Ejemplo 284 Example 284

N(3)-Fenilamino-1-(4-fluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) -Phenylamino-1- (4-fluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 20 (100 mg, 0,37 mmol), DMF (1,0 ml), Et3N (61 µl, 0,44 mmol), reactivo BOP (178 mg, 0,40 mmol) y fenilhidrazina (36 µl, 0,37 mmol) dio el compuesto del título (72 mg, 54%). P.F.: 163 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,55 (s, 1H); 7,69 (dd, J = 9,3, 5,2, 2H); 7,27-7,16 (m, 4H); 6,95 (d, J = 7,5, 2H); 6,90 (t, J = 7,2, 1H); 3,73 (s a, 1H); 3,69 (s a, 1H); 2,15 (d a, J = 9,0, 1H); 2,06-1,99 (m, 2H); 1,73 (d, J = 8,7, 1H); 1,25 (d a, J = 7,2, 2H). IR (KBr, cm-1): 3376 (m), 2991 (m), 2952 (m), 2871 (m), 1674 (s), 1604 (s), 1517 (s), 1497 (s); 1441 (m), 1350 (m), 1279 (m), 1223 (s), 1154 (m), 1127(m), 1093 (m), 1083 (m), 1066 (m), 1041 (w), 889 (m), 841 (m). EM (m/z): 363,1 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 20 (100 mg, 0.37 mmol), DMF (1.0 ml), Et3N (61 µl, 0.44 mmol), reagent BOP (178 mg, 0.40 mmol) and phenylhydrazine (36 µl, 0.37 mmol) gave the title compound (72 mg, 54%). P.F .: 163 ºC. 1H NMR (δ ppm, CDCl3, 300 MHz): 8.55 (s, 1H); 7.69 (dd, J = 9.3, 5.2, 2H); 7.27-7.16 (m, 4H); 6.95 (d, J = 7.5, 2H); 6.90 (t, J = 7.2, 1H); 3.73 (s a, 1 H); 3.69 (s a, 1 H); 2.15 (d a, J = 9.0, 1H); 2.06-1.99 (m, 2H); 1.73 (d, J = 8.7, 1H); 1.25 (d a, J = 7.2, 2H). IR (KBr, cm-1): 3376 (m), 2991 (m), 2952 (m), 2871 (m), 1674 (s), 1604 (s), 1517 (s), 1497 (s); 1441 (m), 1350 (m), 1279 (m), 1223 (s), 1154 (m), 1127 (m), 1093 (m), 1083 (m), 1066 (m), 1041 (w), 889 (m), 841 (m). MS (m / z): 363.1 ([M + H] +).

Ejemplo 285 Example 285

N(3)-Fenilamino-1-(4-fluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) -Phenylamino-1- (4-fluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 21 (100 mg, 0,36 mmol), DMF (1,0 ml), Et3N (44 µl, 0,32 mmol), reactivo BOP (125 mg, 0,28 mmol) y fenilhidrazina (34 µl, 0,34 mmol) dio el compuesto del título (87 mg, 44%). P.F.: 161 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,50 (s a, 1H); 7,70 (m, 1H); 7,24 (t, J = 7,8, 2H); 7,09-6,99 (m, 2H); 6,99-6,86 (m, 3H); 3,72 (s a, 1H); 3,48 (s a, 1H); 2,09 (d a, J = 8,4, 1H), 1,97 (d a, J = 9,3, 2H); 1,69 (d a, J = 8,7, 1H); 1,27 (d a, J =9,3, 2H). IR (cm-1, KBr): 3274 (s), 2991 (m), 2957 (m), 1672 (s), 1605 (s), 1525 (s), 1497 (s), 1441 (m), 1352 (m), 1273 (s), 1230 (m), 1146 (m), 1126 (m), 1085 (m), 966 (m), 889 (m), 851 (m). EM (m/z): 381,0 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 21 (100 mg, 0.36 mmol), DMF (1.0 ml), Et3N (44 µl, 0.32 mmol), reagent BOP (125 mg, 0.28 mmol) and phenylhydrazine (34 µl, 0.34 mmol) gave the title compound (87 mg, 44%). P.F .: 161 ºC. 1H NMR (δ ppm, CDCl3, 300 MHz): 8.50 (s at, 1H); 7.70 (m, 1H); 7.24 (t, J = 7.8, 2H); 7.09-6.99 (m, 2H); 6.99-6.86 (m, 3H); 3.72 (s a, 1 H); 3.48 (s at, 1 H); 2.09 (d a, J = 8.4, 1H), 1.97 (d a, J = 9.3, 2H); 1.69 (d a, J = 8.7, 1H); 1.27 (d a, J = 9.3, 2H). IR (cm-1, KBr): 3274 (s), 2991 (m), 2957 (m), 1672 (s), 1605 (s), 1525 (s), 1497 (s), 1441 (m), 1352 (m), 1273 (s), 1230 (m), 1146 (m), 1126 (m), 1085 (m), 966 (m), 889 (m), 851 (m). MS (m / z): 381.0 ([M + H] +).

Ejemplo 286 Example 286

N(3)-[(2-Clorofenil)amino]-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) - [(2-Chlorophenyl) amino] -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 21 (100 mg, 0,34 mmol), DMF (1,0 ml), Et3N (114 µl, 0,83 mmol), reactivo BOP (152 mg, 0,34 mmol) y clorhidrato de 2clorofenilhidrazina (61 mg, 0,34 mmol) dio el compuesto del título (108 mg, 76%). P.F.:126-129 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,55 (s a, 1H); 7,75-7,65 (m, 1H); 7,29 (d, J = 7,2, 1H); 7,14 (t, J = 8,1, 1H); 7,04 (t a, J = 8,1, 3H); 6,83 (t, J = 6,9, 1H); 3,71 (s a, 1H); 3,49 (s a, 1H); 2,09 (d, J = 9,0, 1H); 1,97 (d, J = 9,0, 2H); 1,70 (d, J = 9,0, 1H); 1,26 (d a, J = 8,4, 2H). IR (KBr, cm-1): 3247 (m a), 2956 (m), 2873 (m), 1670 (s), 1595 (m), 1524 (s), 1494 (s), 1439 (m), 1349 (m), 1270 (s), 1254 (m), 1141(m), 1048 (m), 1034 (m), 964 (m), 887 (w), 848 (m), 750 (s). EM (m/z): 415,10 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0 ml), Et3N (114 µl, 0.83 mmol), reagent BOP (152 mg, 0.34 mmol) and 2-chlorophenylhydrazine hydrochloride (61 mg, 0.34 mmol) gave the title compound (108 mg, 76%). P.F.:126-129 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 8.55 (s at, 1H); 7.75-7.65 (m, 1 H); 7.29 (d, J = 7.2, 1H); 7.14 (t, J = 8.1, 1H); 7.04 (t a, J = 8.1, 3H); 6.83 (t, J = 6.9, 1H); 3.71 (s a, 1 H); 3.49 (s at, 1 H); 2.09 (d, J = 9.0, 1H); 1.97 (d, J = 9.0, 2H); 1.70 (d, J = 9.0, 1H); 1.26 (d a, J = 8.4, 2H). IR (KBr, cm-1): 3247 (ma), 2956 (m), 2873 (m), 1670 (s), 1595 (m), 1524 (s), 1494 (s), 1439 (m), 1349 (m), 1270 (s), 1254 (m), 1141 (m), 1048 (m), 1034 (m), 964 (m), 887 (w), 848 (m), 750 (s). MS (m / z): 415.10 ([M + H] +).

Ejemplo 287 Example 287

N(3)-[(2-bromofenil)amino]-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) - [(2-bromophenyl) amino] -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 21 (100 mg, 0,34 mmol), DMF (1,0 ml), Et3N (114 µl, 0,83 mmol), reactivo BOP (152 mg, 0,34 mmol) y clorhidrato de 2bromofenilhidrazina (76 mg, 0,34 mmol) dio el compuesto del título (125 mg, 79%). P.F.:134-137 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,57 (s a, 1H); 7,74-7,65 (m, 1H); 7,46 (d, J = 7,8, 1H); 7,19 (t, J = 7,8, 1H); 7,10-6,90 (m, 3H); 6,77 (t, J = 8,1, 1H); 3,72 (s a, 1H); 3,49 (s a, 1H); 2,12 (d a, J = 8,7, 1H); 1,97 (d a, J = 9,0, 2H); 1,70 (d a, J = 8,7, 1H); 1,27 (d a, J = 9,0, 2H). IR (KBr, cm-1): 3327 (s), 3295 (m), 2969 (m), 2869 (m), 1656 (s), 1609 (m), 1594 (m), 1524 (s), 1481 (s), 1449 (m), 1353 (m), 1271 (s), 1229 (m), 1093 (s), 1071 (m), 1046 (m), 1021 (m), 846 (s). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0 ml), Et3N (114 µl, 0.83 mmol), reagent BOP (152 mg, 0.34 mmol) and 2-bromophenylhydrazine hydrochloride (76 mg, 0.34 mmol) gave the title compound (125 mg, 79%). P.F.:134-137 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 8.57 (s at, 1H); 7.74-7.65 (m, 1 H); 7.46 (d, J = 7.8, 1H); 7.19 (t, J = 7.8, 1H); 7.10-6.90 (m, 3H); 6.77 (t, J = 8.1, 1H); 3.72 (s a, 1 H); 3.49 (s at, 1 H); 2.12 (d a, J = 8.7, 1H); 1.97 (d a, J = 9.0, 2H); 1.70 (d a, J = 8.7, 1H); 1.27 (d a, J = 9.0, 2H). IR (KBr, cm-1): 3327 (s), 3295 (m), 2969 (m), 2869 (m), 1656 (s), 1609 (m), 1594 (m), 1524 (s), 1481 (s), 1449 (m), 1353 (m), 1271 (s), 1229 (m), 1093 (s), 1071 (m), 1046 (m), 1021 (m), 846 (s).

Ejemplo 288 Example 288

N(3)-[(2-Fluorofenil)amino]-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) - [(2-Fluorophenyl) amino] -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 21 (100 mg, 0,34 mmol), DMF (1,0 ml), Et3N (114 µl, 0,83 mmol), reactivo BOP (152 mg, 0,34 mmol) y clorhidrato 2fluorofenilhidrazina (55 mg, 0,34 mmol) dio el compuesto del título (94 mg, 69%). P.F.:172-175 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,54 (s a, 1H); 7,71 (dt, J = 8,4, 2,4, 1H); 7,10-6,96 (m, 5H); 6,90-6,80 (m, 1H); 3,72 (s a, 1H); 3,49 (s a, 1H); 2,11 (d a, J = 7,2, 1H); 1,97 (d, J = 9,3, 2H); 1,71 (d, J = 9,0, 1H); 1,30-1,25 (m, 2H). IR (KBr, cm-1): 3339 (s), 2989 (m), 2871 (m), 1685 (s), 1614 (m), 1523 (s), 1498 (s), 1439 (s), 1271 (m), 1233 (m), 1192 (m), 1143(m), 1061 (m), 1027 (m), 966 (m), 862 (m). EM (m/z): 399,10 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0 ml), Et3N (114 µl, 0.83 mmol), reagent BOP (152 mg, 0.34 mmol) and 2-fluorophenylhydrazine hydrochloride (55 mg, 0.34 mmol) gave the title compound (94 mg, 69%). P.F.: 172-175 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 8.54 (s at, 1H); 7.71 (dt, J = 8.4, 2.4, 1H); 7.10-6.96 (m, 5H); 6.90-6.80 (m, 1 H); 3.72 (s a, 1 H); 3.49 (s at, 1 H); 2.11 (d a, J = 7.2, 1H); 1.97 (d, J = 9.3, 2H); 1.71 (d, J = 9.0, 1H); 1.30-1.25 (m, 2H). IR (KBr, cm-1): 3339 (s), 2989 (m), 2871 (m), 1685 (s), 1614 (m), 1523 (s), 1498 (s), 1439 (s), 1271 (m), 1233 (m), 1192 (m), 1143 (m), 1061 (m), 1027 (m), 966 (m), 862 (m). MS (m / z): 399.10 ([M + H] +).

Ejemplo 289 Example 289

N(3)-Piperidino-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) -Piperidino-1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 21 (100 mg, 0,34 mmol), DMF (1,0 ml), Et3N (58 µl, 0,42 mmol), reactivo BOP (166 mg, 0,38 mmol) y 1-aminopiperidina (37 µl, 0,34 mmol) dio el compuesto del título (42 mg, 33%). P.F.: 143 ºC. RMN 1H (δ ppm, CDCl3; 300 MHz): 7,727,61 (m, 1H); 7,58 (s a, 1H); 7,02 (t, J = 8,4, 2H); 3,75 (s a, 1H); 3,44 (s a, 1H), 2,88 (s a, 4H); 2,09 (d a, J = 8,7, 1H); 2,10-1,90 (m, 2H); 1,78-1,65 (m, 5H); 1,50-1,34 (m, 2H); 1,34-1,08 (m, 2H). IR (KBr, cm-1): 3263 (m), 2994 (m), 2942 (m), 2872 (m), 2853 (m), 1658 (s), 1611 (m), 1521 (s), 1444 (m); 1353 (m), 1269 (s), 1233 (m), 1143 (m), 1121 (m), 1089 (m), 965 (m), 907 (m). EM (m/z): 373,2 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0 ml), Et3N (58 µl, 0.42 mmol), reagent BOP (166 mg, 0.38 mmol) and 1-aminopiperidine (37 µl, 0.34 mmol) gave the title compound (42 mg, 33%). P.F .: 143 ºC. 1H NMR (δ ppm, CDCl3; 300 MHz): 7,727.61 (m, 1H); 7.58 (s a, 1 H); 7.02 (t, J = 8.4, 2H); 3.75 (s a, 1 H); 3.44 (s at, 1 H), 2.88 (s at, 4 H); 2.09 (d a, J = 8.7, 1H); 2.10-1.90 (m, 2H); 1.78-1.65 (m, 5H); 1.50-1.34 (m, 2H); 1.34-1.08 (m, 2H). IR (KBr, cm-1): 3263 (m), 2994 (m), 2942 (m), 2872 (m), 2853 (m), 1658 (s), 1611 (m), 1521 (s), 1444 (m); 1353 (m), 1269 (s), 1233 (m), 1143 (m), 1121 (m), 1089 (m), 965 (m), 907 (m). MS (m / z): 373.2 ([M + H] +).

Ejemplo 290 Example 290

N(3)-Ciclohexil-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) -Cyclohexyl-1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 21 (100 mg, 0,34 mmol), DMF (1,0 ml), Et3N (57 µl, 0,42 mmol), reactivo BOP (166 mg, 0,38 mmol) y ciclohexilamina (39 µl, 0,34 mmol) dio el compuesto del título (41 mg, 32%). P.F.: 119 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,707,60 (m, 1H); 7,01 (t, J = 7,8, 2H); 6,72 (d a, J = 8,1, 1H); 4,03-3,85 (m, 1H); 3,75 (s a, 1H), 3,44 (s a, 1H); 2,10-1,95 (m, 5H); 1,80-1,42 (m, 5H); 1,40-1,15 (m, 6H). IR (KBr, cm-1): 3294 (m), 2995 (m), 2933 (s), 2853 (m), 1641 (s), 1610 (m), 1548 (s), 1520 (s), 1499 (s), 1451 (m), 1352 (m), 1269 (m), 1251 (m), 1239 (m), 1160 (m), 1142 (m), 1122 (m), 1090 (m), 964 (m), 851 (m). EM (m/z): 372,1 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0 ml), Et3N (57 µl, 0.42 mmol), reagent BOP (166 mg, 0.38 mmol) and cyclohexylamine (39 µl, 0.34 mmol) gave the title compound (41 mg, 32%). P.F .: 119 ºC. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.707.60 (m, 1H); 7.01 (t, J = 7.8, 2H); 6.72 (d a, J = 8.1, 1H); 4.03-3.85 (m, 1 H); 3.75 (s at, 1 H), 3.44 (s at, 1 H); 2.10-1.95 (m, 5H); 1.80-1.42 (m, 5H); 1.40-1.15 (m, 6H). IR (KBr, cm-1): 3294 (m), 2995 (m), 2933 (s), 2853 (m), 1641 (s), 1610 (m), 1548 (s), 1520 (s), 1499 (s), 1451 (m), 1352 (m), 1269 (m), 1251 (m), 1239 (m), 1160 (m), 1142 (m), 1122 (m), 1090 (m), 964 (m), 851 (m). MS (m / z): 372.1 ([M + H] +).

Ejemplo 291 Example 291

N(3)-(Ciclohexilmetil)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) - (Cyclohexylmethyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 21 (100 mg,0,34 mmol), DMF(1,0 ml), Et3N (57 µl,0,41 mmol), reactivo BOP (152 mg,0,34 mmol) y 2-ciclohexilmetil amina (44 µl, 0,34 mmol) dio el compuesto del título (87 mg, 65%). P.F.: 94-97 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,67 (m, 1H); 7,01 (t, J = 8,1, 2H); 6,91 (s a, 1H); 3,75 (s a, 1H); 3,44 (s a, 1H); 3,26 (t, J = 6,6, 2H); 2,08 (d a, J = 8,7, 1H); 2,05-1,85 (m, 2H); 1,83-1,50 (m, 6H); 1,26-1,18 (m, 6H); 1,05-0,85 (m, 2H). IR (KBr, cm-1): 3379 (m), 2926 (s), 2848 (m), 1655 (s), 1556 (m), 1519 (s), 1499 (m), 1450 (m), 1271 (m), 1241 (m), 1142 (m), 1088 (m), 962 (w), 852 (w). EM (m/z): 386,20 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0 ml), Et3N (57 µl, 0.41 mmol), reagent BOP (152 mg, 0.34 mmol) and 2-cyclohexylmethyl amine (44 µl, 0.34 mmol) gave the title compound (87 mg, 65%). P.F .: 94-97 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.67 (m, 1H); 7.01 (t, J = 8.1, 2H); 6.91 (s a, 1 H); 3.75 (s a, 1 H); 3.44 (s at, 1 H); 3.26 (t, J = 6.6, 2H); 2.08 (d a, J = 8.7, 1H); 2.05-1.85 (m, 2H); 1.83-1.50 (m, 6H); 1.26-1.18 (m, 6H); 1.05-0.85 (m, 2H). IR (KBr, cm-1): 3379 (m), 2926 (s), 2848 (m), 1655 (s), 1556 (m), 1519 (s), 1499 (m), 1450 (m), 1271 (m), 1241 (m), 1142 (m), 1088 (m), 962 (w), 852 (w). MS (m / z): 386.20 ([M + H] +).

Ejemplo 292 Example 292

N(3)-[S-(1-Feniletil)]-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) - [S- (1-Phenylethyl)] - 1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 21 (100 mg, 0,34 mmol), DMF (1,0 ml), Et3N (57 µl, 0,41 mmol), reactivo BOP (152 mg, 0,34 mmol) y S-(-)-1fenetilamina (44 µl, 0,34 mmol) dio el compuesto del título (85 mg, 63%). P.F.: 54-57 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,66 (dt, J = 9,0, 5,7, 1H); 7,40-7,20 (m, 5H); 7,11 (d a, J = 7,5, 1H); 7,00 (t, J = 8,7, 2H); 5,35-5,28 (m, 1H); 3,74 (s a, 1H); 3,44 (s a, 1H); 2,07 (t a, J = 8,6, 1H); 1,94 (s a, 2H); 1,70-1,55 (m, 4H); 1,33-1,25 (m, 2H). IR (KBr, cm -1): 3412 (m), 3310 (w), 2971 (m), 2872 (m), 1664 (s), 1611 (m), 1523 (s), 1493 (s), 1447 (s), 1359 (m), 1271 (s), 1232 (m), 1180 (m), 1144 (s), 1121 (m), 1091 (m), 965 (m), 850 (m). EM (m/z): 394,0 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0 ml), Et3N (57 µl, 0.41 mmol), reagent BOP (152 mg, 0.34 mmol) and S - (-) - 1 phenethylamine (44 µl, 0.34 mmol) gave the title compound (85 mg, 63%). P.F .: 54-57 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.66 (dt, J = 9.0, 5.7, 1H); 7.40-7.20 (m, 5H); 7.11 (d a, J = 7.5, 1H); 7.00 (t, J = 8.7, 2H); 5.35-5.28 (m, 1 H); 3.74 (s a, 1 H); 3.44 (s at, 1 H); 2.07 (t a, J = 8.6, 1H); 1.94 (s a, 2H); 1.70-1.55 (m, 4H); 1.33-1.25 (m, 2H). IR (KBr, cm -1): 3412 (m), 3310 (w), 2971 (m), 2872 (m), 1664 (s), 1611 (m), 1523 (s), 1493 (s), 1447 (s), 1359 (m), 1271 (s), 1232 (m), 1180 (m), 1144 (s), 1121 (m), 1091 (m), 965 (m), 850 (m). MS (m / z): 394.0 ([M + H] +).

Ejemplo 293 Example 293

N(3)-(R-1-feniletil)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) - (R-1-phenylethyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 21 (100 mg, 0,34 mmol), DMF (1,0 ml), Et3N (54 µl, 0,38 mmol), reactivo BOP (152 mg, 0,36 mmol) y R-1-feniletil-amina (44 µl, 0,37 mmol) produjo el compuesto del título (75 mg, 56%). P.F.: 40-45 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,72-7,60 (m, 1H); 7,46-7,19 (m, 5H); 7,15-6,90 (m, 3H); 5,31 (s a, 1H); 3,74 (s a, 1H); 3,43 (s a, 1H); 2,07 (s a, 1H); 1,95 (s a, 2H); 1,72-1,51 (m, 4H); 1,44-1,17 (m, 2H). IR (cm-1, KBr): 3412 (s), 3062 (m), 3029 (m), 2970 (s), 29230 (s), 2872 (m), 1663 (s), 1610 (s), 1523 (s), 1493 (s), 1447 (s), 1358 (m), 1326 (m), 1270 (s), 1252 (s), 1232 (s), 1210 (m), 1160 (s), 1143 (s), 1121 (s), 1191 (s), 965 (m) 850 (m), 831(m). EM (m/z):394,2 (87, [M+H]+); 290,2 (100). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0 ml), Et3N (54 µl, 0.38 mmol), reagent BOP (152 mg, 0.36 mmol) and R-1-phenylethyl-amine (44 µl, 0.37 mmol) produced the title compound (75 mg, 56%). P.F .: 40-45 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.72-7.60 (m, 1H); 7.46-7.19 (m, 5H); 7.15-6.90 (m, 3H); 5.31 (s a, 1 H); 3.74 (s a, 1 H); 3.43 (s at, 1 H); 2.07 (s at, 1 H); 1.95 (s at, 2H); 1.72-1.51 (m, 4H); 1.44-1.17 (m, 2H). IR (cm-1, KBr): 3412 (s), 3062 (m), 3029 (m), 2970 (s), 29230 (s), 2872 (m), 1663 (s), 1610 (s), 1523 (s), 1493 (s), 1447 (s), 1358 (m), 1326 (m), 1270 (s), 1252 (s), 1232 (s), 1210 (m), 1160 (s), 1143 (s), 1121 (s), 1191 (s), 965 (m) 850 (m), 831 (m). MS (m / z): 394.2 (87, [M + H] +); 290.2 (100).

Ejemplo 294 Example 294

N(3)-(1-Metil-1-feniletil)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) - (1-Methyl-1-phenylethyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 21 (100 mg, 0,34 mmol), DMF (1,0 ml), Et3N (54 µl, 0,38 mmol), reactivo BOP (152 mg, 0,36 mmol) y α,α-dimetilbencilamina (56 mg, 0,41 mmol) produjo el compuesto del título (80 mg, 58%). P.F.: 105 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,69 (dt, J = 9,6, 6,0, 1H); 7,49 (d, J = 7,8, 2H); 7,34 (t, J = 7,8, 2H); 7,28-7,18 (m, 2H); 7,06-6,96 (m, 2H); 3,70 (s a, 1H); 3,43 (s a, 1H); 2,06 (d a, J = 8,7, 1H); 2,00-1,86 (m, 2H); 1,66 (d a, J = 8,4, 1H); 1,35-1,17 (m, 2H). IR (cm-1, KBr): 3334 (s), 2965 (s), 2929 (s), 2873 (m), 1656 (s), 1609 (s), 1522 (s), 1495 (s), 1449 (s), 1385 (m), 1362 (m), 1326 (w), 1308 (m), 1271 (s), 1252 (s), 1237 (s), 1194 (m), 1156 (w), 1143 (m), 1121 (m), 1106 (m), 1091 (m), 965 (m) 848 (m), 831(m). EM (m/z): 408,1 (40, [M+H]+); 290,3 (100). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0 ml), Et3N (54 µl, 0.38 mmol), reagent BOP (152 mg, 0.36 mmol) and α, α-dimethylbenzylamine (56 mg, 0.41 mmol) produced the title compound (80 mg, 58%). P.F .: 105 ºC. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.69 (dt, J = 9.6, 6.0, 1H); 7.49 (d, J = 7.8, 2H); 7.34 (t, J = 7.8, 2H); 7.28-7.18 (m, 2H); 7.06-6.96 (m, 2H); 3.70 (s at, 1 H); 3.43 (s at, 1 H); 2.06 (d a, J = 8.7, 1H); 2.00-1.86 (m, 2H); 1.66 (d a, J = 8.4, 1H); 1.35-1.17 (m, 2H). IR (cm-1, KBr): 3334 (s), 2965 (s), 2929 (s), 2873 (m), 1656 (s), 1609 (s), 1522 (s), 1495 (s), 1449 (s), 1385 (m), 1362 (m), 1326 (w), 1308 (m), 1271 (s), 1252 (s), 1237 (s), 1194 (m), 1156 (w), 1143 (m), 1121 (m), 1106 (m), 1091 (m), 965 (m) 848 (m), 831 (m). MS (m / z): 408.1 (40, [M + H] +); 290.3 (100).

Ejemplo 295 Example 295

N5-[1-(2-Clorofenil)-1-metiletil]-3-(2,4-difluorofenil)-3,4-diazatriciclo-[5.2.1.02,6]deca-2(6),4-dien-5-carboxamida N5- [1- (2-Chlorophenyl) -1-methyl ethyl] -3- (2,4-difluorophenyl) -3,4-diazatricyclo- [5.2.1.02.6] deca-2 (6), 4-dien- 5-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 21 (100 mg, 0,34 mmol), DMF (1,0 ml), Et3N (54 µl, 0,37 mmol), reactivo BOP (152 mg, 0,37 mmol) y 2-(2-clorofenil)prop-2-ilamina (87 mg, 0,51 mmol) produjo el compuesto del título (87 mg, 57%). P.F.: 176-179 ºC. RMN 1H (δ ppm, The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0 ml), Et3N (54 µl, 0.37 mmol), reagent BOP (152 mg, 0.37 mmol) and 2- (2-chlorophenyl) prop-2-ylamine (87 mg, 0.51 mmol) produced the title compound (87 mg, 57%). P.F .: 176-179 ° C. 1H NMR (δ ppm,

CDCl3, 300 MHz): 7,75-7,60 (m, 1H); 7,58 (d, J = 7,8, 1H); 7,41-7,12 (m, 4H); 7,06-6,95 (m, 2H); 3,64 (s, 1H); 3,42 (s, 1H); 2,04 (d, J = 8,4, 1H); 1,95-1,85 (m, 8H), 1,62 (d, J = 9,3, 1H), 1,23 (d, J = 9,0, 2H). IR (cm-1, KBr): 3413 (m), 2975 (m), 2871 (m), 1675 (s), 1613 (w), 1522 (s), 1491 (m), 1447 (m), 1383 (w), 1362 (w), 1270 (s), 1244 (m), 1144 (m), 1091 (w), 1037 (w), 965 (w), 853 (w), 755 (w). EM (m/z): 442,1 ([M+H]+). CDCl3, 300 MHz): 7.75-7.60 (m, 1H); 7.58 (d, J = 7.8, 1H); 7.41-7.12 (m, 4H); 7.06-6.95 (m, 2H); 3.64 (s, 1 H); 3.42 (s, 1 H); 2.04 (d, J = 8.4, 1H); 1.95-1.85 (m, 8H), 1.62 (d, J = 9.3, 1H), 1.23 (d, J = 9.0, 2H). IR (cm-1, KBr): 3413 (m), 2975 (m), 2871 (m), 1675 (s), 1613 (w), 1522 (s), 1491 (m), 1447 (m), 1383 (w), 1362 (w), 1270 (s), 1244 (m), 1144 (m), 1091 (w), 1037 (w), 965 (w), 853 (w), 755 (w). MS (m / z): 442.1 ([M + H] +).

Ejemplo 296 Example 296

N(3)-(1,3,3-Trimetilbiciclo[2.2.1]hept-2-il)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3carboxamida N (3) - (1,3,3-Trimethylbicyclo [2.2.1] hept-2-yl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7 -methane-indazol-3carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 21 (120 mg, 0,41 mmol), DMF (1,0 ml), Et3N (137 µl, 0,99 mmol), reactivo BOP (182 mg, 0,41 mmol) y clorhidrato 1S, 2endo-1,3,3-trimetil-biciclo[2.2.1]hept-2-ilamina (77 mg, 0,41 mmol) produjo el compuesto del título (86 mg, 49%). P.F.: 114-117 ºC. RMN 1H (δ ppm, DMSO-d6, 300 MHz): 7,86-7,76 (m, 1H), 7,60 (t a, J = 9,3, 1H); 7,29 (t a, J = 8,1, 1H); 7,00 (d, J = 9,6, 1H); 3,63 (d, J = 9,3, 1H); 3,52 (s a, 1H); 3,46 (s a, 1H); 2,05-1,85 (m, 3H); 1,75-1,55 (m, 4H); 1,50-1,35 (m, 2H); 1,25-0,95 (m, 10H); 0,77 (d, J = 5,1, 3H). IR (cm-1, KBr): 3390 (m), 2952 (s), 2873 (m), 1658 (s), 1607 (w), 1520 (s), 1496 (s), 1451 (m), 1475 (m), 1368 (w), 1329 (m), 1252 (m), 1232 (m), 1158 (m), 1148 (m), 964 (m), 822 (w). EM (m/z): 426,3 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 21 (120 mg, 0.41 mmol), DMF (1.0 ml), Et3N (137 µl, 0.99 mmol), reagent BOP (182 mg, 0.41 mmol) and 1S hydrochloride, 2endo-1,3,3-trimethyl-bicyclo [2.2.1] hept-2-ylamine (77 mg, 0.41 mmol) produced the title compound ( 86 mg, 49%). P.F .: 114-117 ° C. 1H NMR (δ ppm, DMSO-d6, 300 MHz): 7.86-7.76 (m, 1H), 7.60 (t a, J = 9.3, 1H); 7.29 (t a, J = 8.1, 1H); 7.00 (d, J = 9.6, 1H); 3.63 (d, J = 9.3, 1H); 3.52 (s at, 1 H); 3.46 (s at, 1 H); 2.05-1.85 (m, 3H); 1.75-1.55 (m, 4H); 1.50-1.35 (m, 2H); 1.25-0.95 (m, 10H); 0.77 (d, J = 5.1, 3H). IR (cm-1, KBr): 3390 (m), 2952 (s), 2873 (m), 1658 (s), 1607 (w), 1520 (s), 1496 (s), 1451 (m), 1475 (m), 1368 (w), 1329 (m), 1252 (m), 1232 (m), 1158 (m), 1148 (m), 964 (m), 822 (w). MS (m / z): 426.3 ([M + H] +).

Ejemplo 297 Example 297

N5-(2-Clorobencil)-3-(2,4-difluorofenil)-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxamida N5- (2-Chlorobenzyl) -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5.2.1.02.6] deca-2 (6), 4-dien-5-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 21 (100 mg, 0,34 mmol), DMF (1,0 ml), Et3N (57 µl, 0,41 mmol), reactivo BOP (167 mg, 0,37 mmol) y 2-clorobencilamina (41 µl, 0,34 mmol) produjo el compuesto del título (100 mg, 68%). P.F.: 102-105 ºC. RMN 1H (δ ppm, DMSO-d6, 300 MHz): 8,67-8,73 (m, 1H), 7,89-7,77 (m, 1H); 7,66-7,57 (m, 1H); 7,44 (d, J = 7,2, 1H); 7,34-7,30 (m, 4H); 4,49 (s a, 2H); 3,55 (s a, 1H); 3,47 (s a, 1H); 2,00-1,92 (m, 3H); 1,66 (d, J = 8,7, 1H); 1,17-1,05 (m, 2H). IR (cm-1, KBr): 3337 (m), 2965 (m), 2868 (w), 1657 (m), 1645 (s), 1623 (m), 1526 (s), 1271 (m), 1243 (w), 1234 (w), 1160 (m), 846 (m), 738 (w). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0 ml), Et3N (57 µl, 0.41 mmol), reagent BOP (167 mg, 0.37 mmol) and 2-chlorobenzylamine (41 µl, 0.34 mmol) produced the title compound (100 mg, 68%). P.F .: 102-105 ° C. 1H NMR (δ ppm, DMSO-d6, 300 MHz): 8.67-8.73 (m, 1H), 7.89-7.77 (m, 1H); 7.66-7.57 (m, 1 H); 7.44 (d, J = 7.2, 1H); 7.34-7.30 (m, 4H); 4.49 (s a, 2H); 3.55 (s at, 1 H); 3.47 (s at, 1 H); 2.00-1.92 (m, 3H); 1.66 (d, J = 8.7, 1H); 1.17-1.05 (m, 2H). IR (cm-1, KBr): 3337 (m), 2965 (m), 2868 (w), 1657 (m), 1645 (s), 1623 (m), 1526 (s), 1271 (m), 1243 (w), 1234 (w), 1160 (m), 846 (m), 738 (w).

Ejemplo 298 Example 298

NS-(4-Clorofenil)-3-(2,4-difluorofenil)-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxamida NS- (4-Chlorophenyl) -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5.2.1.02.6] deca-2 (6), 4-dien-5-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 21 (100 mg, 0,34 mmol), DMF (1,0 ml), Et3N (50 µl, 0,37 mmol), reactivo BOP (159 mg, 0,36 mmol) y 4-clorobencilamina (63 µl, 0,51 mmol) produjo el compuesto del título (96 mg, 67%). P.F.: 121-125 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,67-7,57 (m, 1H); 7,30-7,25 (m, 4H); 7,20-7,15 (m, 1H); 7,05-6,95 (m, 2H); 4,57 (d, J = 4,8, 2H); 3,76 (s a, 1H); 3,45 (s a, 1H), 2,09 (d, J = 9,0, 1H); 2,00-1,93 (m, 2H); 1,69 (d, J = 9,0, 1H); 1,28-1,24 (m, 2H). IR (cm-1, KBr): 3310 (m), 2964 (m), 2939 (m), 2874 (m), 1644 (s), 1607 (w), 1557 (s), 1520 (s), 1491 (s), 1454 (m), 1407 (w), 1358 (m), 1326 (w), 1272 (m), 1254 (m), 1232 (m), 1160 (m), 1142 (m), 1088 (m), 1013 (m), 962 (m), 853 (m). EM (m/z): 412,25 (100%), 414,2 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0 ml), Et3N (50 µl, 0.37 mmol), reagent BOP (159 mg, 0.36 mmol) and 4-chlorobenzylamine (63 µl, 0.51 mmol) produced the title compound (96 mg, 67%). P.F .: 121-125 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.67-7.57 (m, 1H); 7.30-7.25 (m, 4H); 7.20-7.15 (m, 1 H); 7.05-6.95 (m, 2H); 4.57 (d, J = 4.8, 2H); 3.76 (s a, 1 H); 3.45 (s a, 1 H), 2.09 (d, J = 9.0, 1 H); 2.00-1.93 (m, 2H); 1.69 (d, J = 9.0, 1H); 1.28-1.24 (m, 2H). IR (cm-1, KBr): 3310 (m), 2964 (m), 2939 (m), 2874 (m), 1644 (s), 1607 (w), 1557 (s), 1520 (s), 1491 (s), 1454 (m), 1407 (w), 1358 (m), 1326 (w), 1272 (m), 1254 (m), 1232 (m), 1160 (m), 1142 (m), 1088 (m), 1013 (m), 962 (m), 853 (m). MS (m / z): 412.25 (100%), 414.2 ([M + H] +).

Ejemplo 299 Example 299

NS-(1-Etil-1-fenilpropil)-3-(2,4-difluorofenil)-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxamida NS- (1-Ethyl-1-phenylpropyl) -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5.2.1.02.6] deca-2 (6), 4-diene-5-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 21 (100 mg, 0,34 mmol), DMF (1,0 ml), Et3N (54 µl, 0,37 mmol), reactivo BOP (152 mg, 0,34 mmol) y α,α-dietilbencilamina (72 mg, 0,44 mmol) produjo el compuesto del título (85 mg, 86%). P.F.: 45-48 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,76-7,66 (m, 1H), 7,42-7,10 (m, 6H); 7,07-6,96 (m, 2H); 3,70 (s a, 1H); 3,45 (s a, 1H); 2,23 (c, J = 7,2, 4H); 2,06 (d, J = 9,0, 1H); 1,93 (d, J = 8,4, 2H); 1,66 (d, J = 8,7, 1H); 1,26 (d, J = 5,4, 2H); 0,78 (t, J = 7,2, 6H). IR (cm-1, KBr): 3407 (m), 3059 (m), 2968 (s), 2975 (s), 2935 (s), 1681 (s), 1610 (m), 1583 (s), 1524 (s), 1491 (m), 1447 (m), 1377 (w), 1327 (w), 1270 (m), 1234 (m), 1144 (m), 1091 (m), 965 (m), 850 (m), 756 (m), 698 (m). EM (m/z): 436,0 [M+H]+. The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0 ml), Et3N (54 µl, 0.37 mmol), reagent BOP (152 mg, 0.34 mmol) and α, α-diethylbenzylamine (72 mg, 0.44 mmol) produced the title compound (85 mg, 86%). P.F .: 45-48 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.76-7.66 (m, 1H), 7.42-7.10 (m, 6H); 7.07-6.96 (m, 2H); 3.70 (s at, 1 H); 3.45 (s at, 1 H); 2.23 (c, J = 7.2, 4H); 2.06 (d, J = 9.0, 1H); 1.93 (d, J = 8.4, 2H); 1.66 (d, J = 8.7, 1H); 1.26 (d, J = 5.4, 2H); 0.78 (t, J = 7.2, 6H). IR (cm-1, KBr): 3407 (m), 3059 (m), 2968 (s), 2975 (s), 2935 (s), 1681 (s), 1610 (m), 1583 (s), 1524 (s), 1491 (m), 1447 (m), 1377 (w), 1327 (w), 1270 (m), 1234 (m), 1144 (m), 1091 (m), 965 (m), 850 (m), 756 (m), 698 (m). MS (m / z): 436.0 [M + H] +.

Ejemplo 300 Example 300

N5-[(1S)-1-Fenilpropil]-3-(2,4-difluorofenil)-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxamida N5 - [(1S) -1-Phenylpropyl] -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5.2.1.02.6] deca-2 (6), 4-diene-5-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 21 (100 mg, 0,34 mmol), DMF (1,0 ml), Et3N (54 µl, 0,37 mmol), reactivo BOP (152 mg, 0,34 mmol) y (s)-(α)-etilbencil amina (51 mg, 0,37 mmol) produjo el compuesto del título (70 mg, 50%). P.F.: 100-103 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,71-7,62 (m, 1H), 7,39-7,25 (m, 5H); 7,23-6,96 (m, 3H); 5,05 (quintuplete, J = 7,8, 1H); 3,72 (s a, 1H); 3,43 (s a, 1H); 2,10-1,85 (m, 5H); 1,66 (d, J = 9,0, 1H); 1,27-1,19 (m, 2H); 1,00-0,92 (m, 3H). IR (cm-1, KBr): 3282 (m), 2968 (m), 2874 (m), 1641 (s), 1614 (m), 1522 (s), 1494 (s), 1454 (m), 1359 (m), 1269 (m), 1231 (m) 1159 (m), 1140 (m), 1120 (m), 1094 (m), 963 (m), 847 (m), 701 (m). EM (m/z): 290 (100%), 408,2 (M+H+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0 ml), Et3N (54 µl, 0.37 mmol), reagent BOP (152 mg, 0.34 mmol) and (s) - (α) -ethylbenzyl amine (51 mg, 0.37 mmol) produced the title compound (70 mg, 50%). P.F .: 100-103 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.71-7.62 (m, 1H), 7.39-7.25 (m, 5H); 7.23-6.96 (m, 3H); 5.05 (quintuple, J = 7.8, 1H); 3.72 (s a, 1 H); 3.43 (s at, 1 H); 2.10-1.85 (m, 5H); 1.66 (d, J = 9.0, 1H); 1.27-1.19 (m, 2H); 1.00-0.92 (m, 3H). IR (cm-1, KBr): 3282 (m), 2968 (m), 2874 (m), 1641 (s), 1614 (m), 1522 (s), 1494 (s), 1454 (m), 1359 (m), 1269 (m), 1231 (m) 1159 (m), 1140 (m), 1120 (m), 1094 (m), 963 (m), 847 (m), 701 (m). MS (m / z): 290 (100%), 408.2 (M + H +).

5 5

15 fifteen

25 25

35 35

45 Four. Five

Ejemplo 301 Example 301

(2S)-2-[5-(2,4-Difluorofenil)-4,5-diazatriciclo[5.2.1.0,2,6]deca-2(6),3-dien-3-ilcarboxamido]-2-feniletanoato de metilo (2S) -2- [5- (2,4-Difluorophenyl) -4,5-diazatricyclo [5.2.1.0,2,6] deca-2 (6), 3-dien-3-ylcarboxamido] -2-phenylethanoate of methyl

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 21 (510 mg, 1,76 mmol), DMF (4,0 ml), Et3N (580 µl, 4,20 mmol), reactivo BOP (777 mg, 1,76 mmol) y metil éster clorhidrato de (S)-(+)-2-fenilglicina (354 mg, 1,76 mmol) produjo el compuesto del título (420 mg, 55%). P.F.: 72-75 ºC.RMN 1H(δ ppm, CDCl3, 300 MHz): 8,47 (d, J = 7,5, 1H), 7,86-7,81 (m, 1H); 7,61 (t, J = 8,4, 1H); 7,45-7,29 (m, 6H); 5,65 (d, J = 6,9, 1H); 3,66 (s, 3H); 3,52 (s a, 1H); 3,47 (s a, 1H);1,94 (s a, 3H); 1,67 (s a, 1H); 1,25-1,05 (m, 2H); IR (cm-1, KBr): 3412 (m), 2953 (m), 2872 (m), 1745 (s), 1674 (s), 1610 (m), 1524 (s), 1488 (s), 1452 (m), 1358 (m), 1328 (w), 1295 (w) 1270 (s), 1211 (m), 1160 (m), 1144 (m), 1121 (m), 1092 (m), 965 (m), 850 (w), 698 (m). EM (m/z): 438,2(M+H+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 21 (510 mg, 1.76 mmol), DMF (4.0 ml), Et3N (580 µl, 4.20 mmol), reagent BOP (777 mg, 1.76 mmol) and methyl ester hydrochloride of (S) - (+) - 2-phenylglycine (354 mg, 1.76 mmol) produced the title compound (420 mg, 55%). P.F .: 72-75 ° C. RMN 1H (δ ppm, CDCl3, 300 MHz): 8.47 (d, J = 7.5, 1H), 7.86-7.81 (m, 1H); 7.61 (t, J = 8.4, 1H); 7.45-7.29 (m, 6H); 5.65 (d, J = 6.9, 1H); 3.66 (s, 3 H); 3.52 (s at, 1 H); 3.47 (s at, 1H); 1.94 (s at, 3H); 1.67 (s at, 1 H); 1.25-1.05 (m, 2H); IR (cm-1, KBr): 3412 (m), 2953 (m), 2872 (m), 1745 (s), 1674 (s), 1610 (m), 1524 (s), 1488 (s), 1452 (m), 1358 (m), 1328 (w), 1295 (w) 1270 (s), 1211 (m), 1160 (m), 1144 (m), 1121 (m), 1092 (m), 965 ( m), 850 (w), 698 (m). MS (m / z): 438.2 (M + H +).

Ejemplo 302 Example 302

N5-[(1S)-2-Hidroxi-1-feniletil]-3-(2,4-difluorofenil)-3,4-diazatriciclo-[5.2.1.0,2,6]deca-2(6),4-dien-5-carboxamida N5 - [(1S) -2-Hydroxy-1-phenylethyl] -3- (2,4-difluorophenyl) -3,4-diazatricyclo- [5.2.1.0,2,6] deca-2 (6), 4- dien-5-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 191. A una solución del Ejemplo 301 (290 mg, 0662 mmol) en THF (3 ml) se le añadió LiBH4 (32 mg, 1,52 mmol) y la mezcla se calentó a reflujo durante una noche. Después de la evaporación del disolvente, el residuo oleoso se diluyó con agua y se acidificó con HCl 1 N, se extrajo con acetato de etilo y las fases orgánicas combinadas se lavaron con salmuera y se secaron sobre Na2SO4. La FC (3:7 de AcOEt/éter de petróleo) dio el compuesto del título (170 mg, 63%). P.F.: 91 ºC. RMN 1H(δ ppm, CDCl3, 300 MHz): 7,71-7,61 (m, 1H); 7,46-7,29 (m, 6H); 7,00 (t, J = 8,4, 2H); 5,23 (c a, J = 5,1, 1H), 3,98 (s a, 2H); 3,73 (s a, 1H); 3,44 (s a, 1H); 2,92 (s a, 1H); 2,14-1,93 (m, 3H); 1,69 (d, J = 8,7, 1H); 1,32-1,24 (m, 2H). EM (m/z): 410,1(M+H+). The title compound was synthesized by a procedure similar to that described for example 191. To a solution of Example 301 (290 mg, 0662 mmol) in THF (3 ml) was added LiBH4 (32 mg, 1.52 mmol) and The mixture was heated at reflux overnight. After evaporation of the solvent, the oily residue was diluted with water and acidified with 1 N HCl, extracted with ethyl acetate and the combined organic phases were washed with brine and dried over Na2SO4. FC (3: 7 AcOEt / petroleum ether) gave the title compound (170 mg, 63%). P.F .: 91 ºC. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.71-7.61 (m, 1H); 7.46-7.29 (m, 6H); 7.00 (t, J = 8.4, 2H); 5.23 (c a, J = 5.1, 1H), 3.98 (s a, 2H); 3.73 (s a, 1 H); 3.44 (s at, 1 H); 2.92 (s at, 1 H); 2.14-1.93 (m, 3H); 1.69 (d, J = 8.7, 1H); 1.32-1.24 (m, 2H). MS (m / z): 410.1 (M + H +).

Ejemplo 303 Example 303

N(3)-(terc-Butil)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) - (tert-Butyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

[N5-(terc-butil)-3-(2,4-difluorofenil)-3,4-diazatriciclo[5.2.1.026]deca-2(6),4-dien-5-carboxamida] [N5- (tert-butyl) -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5.2.1.026] deca-2 (6), 4-diene-5-carboxamide]

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 21 (100 mg, 0,34 mmol), DMF (1,0 ml), Et3N (57 µl, 0,40 mmol), reactivo BOP (165 mg, 0,37 mmol) y 2-amino-2metilpropano (36 µl, 0,34 mmol) produjo el compuesto del título (31 mg, 26%). P.F.: 109-111 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,71-7,62 (m, 1H), 7,04-6,97 (m, 2H); 6,74 (s a, 1H); 3,75 (s a, 1H); 3,43 (s a, 1H); 2,10-2,04 (m, 1H); 2,01-1,90 (m, 2H); 1,67 (d, J = 8,4, 1H); 1,46 (s, 9H); 1,33-1,19 (m, 2H). IR (cm-1, KBr): 3323 (m), 2968 (m), 1652 (s), 1609 (s), 1547 (s), 1522 (s), 1495 (w), 1448 (m), 1391 (w), 1360 (m), 1272 (m) 1258 (w), 1145 (w), 1109 (m), 965 (m), 849 (m). EM (m/z): 346,0(M+H+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0 ml), Et3N (57 µl, 0.40 mmol), reagent BOP (165 mg, 0.37 mmol) and 2-amino-2 methylpropane (36 µl, 0.34 mmol) produced the title compound (31 mg, 26%). P.F .: 109-111 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.71-7.62 (m, 1H), 7.04-6.97 (m, 2H); 6.74 (s a, 1 H); 3.75 (s a, 1 H); 3.43 (s at, 1 H); 2.10-2.04 (m, 1 H); 2.01-1.90 (m, 2H); 1.67 (d, J = 8.4, 1H); 1.46 (s, 9H); 1.33-1.19 (m, 2H). IR (cm-1, KBr): 3323 (m), 2968 (m), 1652 (s), 1609 (s), 1547 (s), 1522 (s), 1495 (w), 1448 (m), 1391 (w), 1360 (m), 1272 (m) 1258 (w), 1145 (w), 1109 (m), 965 (m), 849 (m). MS (m / z): 346.0 (M + H +).

Ejemplo 304 y Ejemplo 305 Example 304 and Example 305

(4R,7S) y (4S,7R)N(3)-(terc-Butil)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7 -metano-indazol-3-carboxamida (4R, 7S) and (4S, 7R) N (3) - (tert-Butyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane- indazol-3-carboxamide

Preparación I: El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 21a (último enantiómero de elusión, 100 mg, 0,34 mmol), DMF (1,0 ml), Et3N (57 µl, 0,41 mmol), reactivo BOP (167 mg, 0,37 mmol) y 2-amino-2-metilpropano (36 ml, 0,34 mmol) produjo el compuesto del título (91 mg, 76%). HPLC: Rt (columna CHIRALCEL OD-H, dimensiones: 250 x 4,6 mm, tamaño de partícula: 5 µ, eluyente: isopropanol al 0,2% en n-hexano, caudal: 1 ml/min.) = 26,59 min.; e.e = 92,3%. P.F.: 89-92 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,72-7,60 (m, 1H), 7,04-6,96 (m, 2H); 6,74 (s a, 1H); 3,75 (s a, 1H); 3,43 (s a, 1H); 2,07 (d, J = 8,1, 1H); 2,01-1,90 (m, 2H); 1,67 (d, J = 8,7, 1H); 1,46 (s, 9H); 1,33-1,19 (m, 2H). Preparation I: The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 21a (last elution enantiomer, 100 mg, 0.34 mmol), DMF (1.0 ml), Et3N (57 µl , 0.41 mmol), BOP reagent (167 mg, 0.37 mmol) and 2-amino-2-methylpropane (36 mL, 0.34 mmol) produced the title compound (91 mg, 76%). HPLC: Rt (CHIRALCEL OD-H column, dimensions: 250 x 4.6 mm, particle size: 5 µ, eluent: 0.2% isopropanol in n-hexane, flow rate: 1 ml / min.) = 26, 59 min .; e.e = 92.3%. P.F .: 89-92 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.72-7.60 (m, 1H), 7.04-6.96 (m, 2H); 6.74 (s a, 1 H); 3.75 (s a, 1 H); 3.43 (s at, 1 H); 2.07 (d, J = 8.1, 1H); 2.01-1.90 (m, 2H); 1.67 (d, J = 8.7, 1H); 1.46 (s, 9H); 1.33-1.19 (m, 2H).

Preparación II: El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 21b (enantiómero de elusión rápida, 70 mg, 0,24 mmol), DMF (1,0 ml), Et3N (38 µl, 0,28 mmol), reactivo BOP (118 mg, 0,26 mmol) y 2-amino-2-metilpropano (25 µl, 0,24 mmol) produjo el compuesto del título (63 mg, 75%). HPLC: Rt (columna CHIRALCEL OD-H, dimensiones: 250 x 4,6 mm, tamaño de partícula: 5 µ, eluyente: 0,2% isopropanol en n-hexano, caudal: 1 ml/min.) = 24,73 min.; e.e.: 90%. P.F.: 89-90 ºC. Ejemplo 305 fue criptoquiral a 25 ºC en cloroformo (C = 0,5). RMN 1H (δ ppm, CDCl3, 300 MHz): 7,72-7,62 (m, 1H), 7,00 (t, J = 10,8, 2H); 6,74 (s a, 1H); 3,75 (s a, 1H); 3,43 (s a, 1H); 2,07 (d, J = 8,4, 1H); 2,01-1,89 (m, 2H); 1,67 (d, J = 8,1, 1H); 1,46 (s, 9H); 1,331,19 (m, 2H). Preparation II: The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 21b (rapid elution enantiomer, 70 mg, 0.24 mmol), DMF (1.0 ml), Et3N (38 µl , 0.28 mmol), BOP reagent (118 mg, 0.26 mmol) and 2-amino-2-methylpropane (25 µl, 0.24 mmol) produced the title compound (63 mg, 75%). HPLC: Rt (CHIRALCEL OD-H column, dimensions: 250 x 4.6 mm, particle size: 5 µ, eluent: 0.2% isopropanol in n-hexane, flow rate: 1 ml / min.) = 24.73 min .; e .: 90%. P.F .: 89-90 ° C. Example 305 was cryptochiral at 25 ° C in chloroform (C = 0.5). 1H NMR (δ ppm, CDCl3, 300 MHz): 7.72-7.62 (m, 1H), 7.00 (t, J = 10.8, 2H); 6.74 (s a, 1 H); 3.75 (s a, 1 H); 3.43 (s at, 1 H); 2.07 (d, J = 8.4, 1H); 2.01-1.89 (m, 2H); 1.67 (d, J = 8.1, 1H); 1.46 (s, 9H); 1,331.19 (m, 2H).

Ejemplo 306 Example 306

N5-n-Pentil-3-(2,4-difluorofenil)-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxamida N5-n-Pentyl-3- (2,4-difluorophenyl) -3,4-diazatricyclo [5.2.1.02.6] deca-2 (6), 4-dien-5-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al que se ha descrito para el ejemplo 101. El intermedio 21 (100 mg, 0,34 mmol), DMF (1,0 ml), Et3N (54 µml, 0,37 mmol), reactivo BOP (152 mg; 0,34 mmol) y npentilamina (32 mg, 0,37 mmol) produjo el compuesto del título (50 mg, 40%). P.F.: 75-78 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,70-7,61 (m, 1H), 7,01 (t, J = 8,4, 2H), 6,83 (s a, 1H); 3,75 (s a, 1H); 3,43-3,36 (m, 3H); 2,08 (d, J = 8,7, 1H), 2,02-1,89 (m, 2H), 1,68 (d, J = 8,7, 1H), 1,62-1,56 (m, 2H); 1:38-1,24 (m, 6H); 0,94 (t, J = 7,2, 3H). IR (cm 1, KBr): 3338 (m), 2960 (m), 2932 (m), 2872 (m), 2857 (m), 1648 (s), 1607 (w), 1552 (s), 1453 (s), 1519 (m), 1356 (m), 1251 (m), 1235 (m) 1159 (m), 1142 (m), 1112 (w), 1144 (m), 1087 (m), 1013 (m),853 (m), 624 (m). EM (m/z): 360,1 (M+H+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0 ml), Et3N (54 µml, 0.37 mmol ), BOP reagent (152 mg; 0.34 mmol) and npentylamine (32 mg, 0.37 mmol) produced the title compound (50 mg, 40%). P.F .: 75-78 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.70-7.61 (m, 1H), 7.01 (t, J = 8.4, 2H), 6.83 (s at, 1H); 3.75 (s a, 1 H); 3.43-3.36 (m, 3H); 2.08 (d, J = 8.7, 1H), 2.02-1.89 (m, 2H), 1.68 (d, J = 8.7, 1H), 1.62-1.56 (m, 2H); 1: 38-1.24 (m, 6H); 0.94 (t, J = 7.2, 3H). IR (cm 1, KBr): 3338 (m), 2960 (m), 2932 (m), 2872 (m), 2857 (m), 1648 (s), 1607 (w), 1552 (s), 1453 ( s), 1519 (m), 1356 (m), 1251 (m), 1235 (m) 1159 (m), 1142 (m), 1112 (w), 1144 (m), 1087 (m), 1013 (m ), 853 (m), 624 (m). MS (m / z): 360.1 (M + H +).

Ejemplo 307 Example 307

N5-(2,4-Diclorobencil)-3-(2,4-difluorofenil)-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxamida N5- (2,4-Dichlorobenzyl) -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5.2.1.02.6] deca-2 (6), 4-dien-5-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 21 (100 mg, 0,34 mmol), DMF (1,0 ml), Et3N (54 µl, 0,37 mmol), reactivo BOP (152 mg, 0,34 mmol) y 2,4diclorobecilamina (66 mg, 0,34 mmol) produjo el compuesto del título (110 mg, 71%). P.F.: 105-108 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,69-7,60 (m, 1H), 7,44 (d, J = 7,8, 1H); 7,39 (d, J = 1,8, 2H); 7,29-7,19 (m, 2H); 7,00 (t, J = 8,1, 2H), 4,65 (d, J = 6,3, 2H); 3,74 (s a, 1H); 3,45 (s a, 1H), 2,08 (d, J = 8,4, 1H); 1,98-1,93 (m, 2H); 1,68 (d, J = 8,4, 1H); 1,56 (d, J = 8,4, 2H). IR (cm-1, KBr): 3394 (m), 2973 (m), 2933 (m), 2871 (m), 1660 (s), 1607 (w), 1551 (w), 1587 (m), 1519 (s), 1493 (m), 1350 (m), 1326 (w), 1270 (m) 1231 (m), 1162 (m), 1142 (m), 1125 (m), 1091 (m), 1050 (m), 985 (w), 961 (m), 856 (m), 824 (m). EM (m/z): 448,1 (M+H+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0 ml), Et3N (54 µl, 0.37 mmol), reagent BOP (152 mg, 0.34 mmol) and 2,4-dichlorobecylamine (66 mg, 0.34 mmol) produced the title compound (110 mg, 71%). P.F .: 105-108 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.69-7.60 (m, 1H), 7.44 (d, J = 7.8, 1H); 7.39 (d, J = 1.8, 2H); 7.29-7.19 (m, 2H); 7.00 (t, J = 8.1, 2H), 4.65 (d, J = 6.3, 2H); 3.74 (s a, 1 H); 3.45 (s a, 1 H), 2.08 (d, J = 8.4, 1 H); 1.98-1.93 (m, 2H); 1.68 (d, J = 8.4, 1H); 1.56 (d, J = 8.4, 2H). IR (cm-1, KBr): 3394 (m), 2973 (m), 2933 (m), 2871 (m), 1660 (s), 1607 (w), 1551 (w), 1587 (m), 1519 (s), 1493 (m), 1350 (m), 1326 (w), 1270 (m) 1231 (m), 1162 (m), 1142 (m), 1125 (m), 1091 (m), 1050 ( m), 985 (w), 961 (m), 856 (m), 824 (m). MS (m / z): 448.1 (M + H +).

Ejemplo 308 Example 308

N5-(1-fenilciclopropil)-3-(2,4-difluorofenil)-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxamida N5- (1-phenylcyclopropyl) -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5.2.1.02.6] deca-2 (6), 4-dien-5-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 21 (100 mg, 0,34 mmol), DMF (1,0 ml), Et3N (54 µl, 0,37 mmol), reactivo BOP (152 mg, 0,34 mmol) y α,αciclopropilbencilamina (59 mg, 0,44 mmol) produjo el compuesto del título (55 mg, 40%). P.F.: 90 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,72-7,61 (m, 1H), 7,51 (s a, 1H); 7,35-7,14 (m, 5H); 7,06-6,96 (m, 2H); 3,73 (s a, 1H); 3,44 (s a, 1H); 2,06 (d, J = 8,7, 1H); 2,00-1,92 (m, 2H); 1,67 (d, J = 8,7, 1H); 1,43-1,23 (m, 6H). IR (cm-1, KBr): 3407 (w), 3296 (m), 3088 (w), 3056 (w), 2953 (m), 1660 (s), 1607 (m), 1522 (s), 1491 (m), 1453 (m), 1355 (m), 1322 (w), 1270 (m), 1230 (m), 1158 (m), 1142 (m), 1089 (m), 965 (m), 851 (w). EM (m/z): 406,1 [M+H]+. The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0 ml), Et3N (54 µl, 0.37 mmol), reagent BOP (152 mg, 0.34 mmol) and α, α-cyclopropylbenzylamine (59 mg, 0.44 mmol) produced the title compound (55 mg, 40%). P.F .: 90 ºC. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.72-7.61 (m, 1H), 7.51 (s a, 1H); 7.35-7.14 (m, 5H); 7.06-6.96 (m, 2H); 3.73 (s a, 1 H); 3.44 (s at, 1 H); 2.06 (d, J = 8.7, 1H); 2.00-1.92 (m, 2H); 1.67 (d, J = 8.7, 1H); 1.43-1.23 (m, 6H). IR (cm-1, KBr): 3407 (w), 3296 (m), 3088 (w), 3056 (w), 2953 (m), 1660 (s), 1607 (m), 1522 (s), 1491 (m), 1453 (m), 1355 (m), 1322 (w), 1270 (m), 1230 (m), 1158 (m), 1142 (m), 1089 (m), 965 (m), 851 (w). MS (m / z): 406.1 [M + H] +.

Ejemplo 309 Example 309

N5-(2-Adamantil)-3-(2,4-difluorofenil)-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxamida N5- (2-Adamantyl) -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5.2.1.02.6] deca-2 (6), 4-dien-5-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 21 (100 mg, 0,34 mmol), DMF (1,0 ml), Et3N (54 µl, 0,37 mmol), reactivo BOP (152 mg, 0,34 mmol) y clorhidrato 2adamantanamina (71 mg, 0,37 mmol) produjo el compuesto del título (123 mg, 84%). P.F.: 159-161 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,74-7,64 (m, 1H), 7,21 (d, J = 7,8, 1H), 7,05-6,95 (m, 2H); 4,23 (d, J = 8,4, 1H); 3,73 (s a, 1H); 3,44 (s a, 1H); 2,10-1,79 (m, 13H); 1,77-1,55 (m, 7H). IR (cm-1, KBr): 3414 (m), 2909 (s), 2855 (m), 1659 (s), 1614 (w), 1603 (w), 1545 (s), 1530 (s), 1494 (m), 1470 (w), 1448 (w), 1346 (w) 1290 (s), 1272 (m), 1226 (m), 1154 (m), 1122 (m), 967 (m), 869 (m). EM (m/z): 424,3(M+H+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0 ml), Et3N (54 µl, 0.37 mmol), reagent BOP (152 mg, 0.34 mmol) and 2-mantanamine hydrochloride (71 mg, 0.37 mmol) produced the title compound (123 mg, 84%). P.F .: 159-161 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.74-7.64 (m, 1H), 7.21 (d, J = 7.8, 1H), 7.05-6.95 (m, 2H); 4.23 (d, J = 8.4, 1H); 3.73 (s a, 1 H); 3.44 (s at, 1 H); 2.10-1.79 (m, 13H); 1.77-1.55 (m, 7H). IR (cm-1, KBr): 3414 (m), 2909 (s), 2855 (m), 1659 (s), 1614 (w), 1603 (w), 1545 (s), 1530 (s), 1494 (m), 1470 (w), 1448 (w), 1346 (w) 1290 (s), 1272 (m), 1226 (m), 1154 (m), 1122 (m), 967 (m), 869 ( m). MS (m / z): 424.3 (M + H +).

Ejemplo 310 Example 310

N5-(2-Metil-2-adamantil)-3-(2,4-difluorofenil)-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxamida N5- (2-Methyl-2-adamantyl) -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5.2.1.02.6] deca-2 (6), 4-diene-5-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 21 (100 mg, 0,34 mmol), DMF (1,0 ml), Et3N (54 µl, 0,37 mmol), reactivo BOP (152 mg, 0,34 mmol) y 2-metil-2adamantilamina (73 mg, 0,44 mmol) produjo el compuesto del título (110 mg, 73%). P.F.: 60 ºC. RMN 1H δ ppm, CDCl3, 300 MHz): 7,71-7,63 (m, 1H), 7,02-6,95 (m, 2H); 6,82 (s a, 1H); 3,74 (s a, 1H); 3,44 (s a, 1H); 2,30 (s a, 2H); 2,04-1,79 (m, 9H); 1,73-1,62 (m, 10H); 1,25 (s, 3H). IR (cm-1, KBr): 3406 (m), 2920 (s), 2861 (s), 1672 (s), 1610 (m), 1543 (s), 1524 (s), 1493 (s), 1446 (s), 1377 (w), 1368 (w), 1353 (m), 1270 (s), 1256 (m), 1227 (m), 1161 (m), 1144 (m), 1105 (m),965 (m),849 (m), 815 (w), 578(m). EM (m/z): 438,1, The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0 ml), Et3N (54 µl, 0.37 mmol), reagent BOP (152 mg, 0.34 mmol) and 2-methyl-2-mantylamine (73 mg, 0.44 mmol) produced the title compound (110 mg, 73%). P.F .: 60 ºC. 1H NMR δ ppm, CDCl3, 300 MHz): 7.71-7.63 (m, 1H), 7.02-6.95 (m, 2H); 6.82 (s a, 1 H); 3.74 (s a, 1 H); 3.44 (s at, 1 H); 2.30 (s a, 2H); 2.04-1.79 (m, 9H); 1.73-1.62 (m, 10H); 1.25 (s, 3H). IR (cm-1, KBr): 3406 (m), 2920 (s), 2861 (s), 1672 (s), 1610 (m), 1543 (s), 1524 (s), 1493 (s), 1446 (s), 1377 (w), 1368 (w), 1353 (m), 1270 (s), 1256 (m), 1227 (m), 1161 (m), 1144 (m), 1105 (m), 965 (m), 849 (m), 815 (w), 578 (m). MS (m / z): 438.1,

Ejemplo 311 Example 311

N7-(3-Hidroxiadamatan-1-il)-5-(2,4-difluorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-di-eno-7carboxamida N7- (3-Hydroxiadamatan-1-yl) -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-di-eno-7carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 21 (200 mg, 0,68 mmol), DMF (2,0 ml), Et3N (110 µl, 0,82 mmol), reactivo BOP (335 mg, 0,75 mmol) y 3-amino-1adamantanol (115 mg, 0,68 mmol) produjo el compuesto del título (185 mg, 55%). P.F.: 180-182 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,70-7,61 (m, 1H); 7,04-6,96 (m, 2H); 6,69 (s a, 1H); 3,72 (s a, 1H); 3,43 (s a, 1H), 2,30 (s a, 2H); 2,13 (s a, 2H); 2,10-1,94 (m, 7H); 1,73-1,51 (m, 8H); 1,33-1,19 (m, 2H). IR (cm-1, KBr): 3418 (s), 3369 (s), 2913 (s), 2885 (s), 1651 (s), 1610 (m), 1548 (s), 1519 (s), 1495 (s), 1455 (m), 1421 (w), 1359 (m), 1341 (w), 1314 (m), 1270 (s), 1233 (s), 1145 (m), 1115 (m), 1102 (m), 1049 (w), 1032 (w), 965 (m), 846 (m). EM (m/z): 440,1 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 21 (200 mg, 0.68 mmol), DMF (2.0 ml), Et3N (110 µl, 0.82 mmol), reagent BOP (335 mg, 0.75 mmol) and 3-amino-1adamantanol (115 mg, 0.68 mmol) produced the title compound (185 mg, 55%). P.F .: 180-182 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.70-7.61 (m, 1H); 7.04-6.96 (m, 2H); 6.69 (s a, 1 H); 3.72 (s a, 1 H); 3.43 (s at, 1H), 2.30 (s at, 2H); 2.13 (s a, 2H); 2.10-1.94 (m, 7H); 1.73-1.51 (m, 8H); 1.33-1.19 (m, 2H). IR (cm-1, KBr): 3418 (s), 3369 (s), 2913 (s), 2885 (s), 1651 (s), 1610 (m), 1548 (s), 1519 (s), 1495 (s), 1455 (m), 1421 (w), 1359 (m), 1341 (w), 1314 (m), 1270 (s), 1233 (s), 1145 (m), 1115 (m), 1102 (m), 1049 (w), 1032 (w), 965 (m), 846 (m). MS (m / z): 440.1 ([M + H] +).

Ejemplo 312 Example 312

4[5-(2,4-Difluorofenil)-4,5-diazatriciclo[5.2.1.02,6]deca-2(6),3-dien-3-ilcarboxamido]morfolina 4 [5- (2,4-Difluorophenyl) -4,5-diazatricyclo [5.2.1.02.6] deca-2 (6), 3-dien-3-ylcarboxamido] morpholine

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 21 (100 mg, 0,34 mmol), DMF (1,0 ml), Et3N (53 µl, 0,37 mmol), reactivo BOP (159 mg, 0,36 mmol) y 4-morfolinamina (115 mg, 0,68 mmol) produjo el compuesto del título (100 mg, 78%). P.F.: 106-110 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,70-7,61 (m, 2H); 7,06-6,98 (m, 2H); 3,85 (t, J = 4,5, 4H); 3,74 (s a, 1H); 3,44 (s a, 1H); 2,96 (t, J = 4,5, 4H); 2,08 (d, J = 8,7, 1H); 1,97-1,94 (m, 2H); 1,69 (d, J = 9,0, 1H); 1,27-1,23 (m, 2H). IR (cm-1, KBr): 3435 (m), 3262 (m), 3085 (w), 2954 (m), 2925 (m), 2870 (m), 1670 (s), 1614 (m), 1523 (s), 1498 (m), 1450 (m), 1387 (w), 1357 (m), 1326 (w), 1269 (s), 1232 (s), 1145 (m), 1108 (m), 1093 (m), 1002 (m), 966 (m), 847 (m). EM (m/z): 375,2 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0 ml), Et3N (53 µl, 0.37 mmol), reagent BOP (159 mg, 0.36 mmol) and 4-morpholinamine (115 mg, 0.68 mmol) produced the title compound (100 mg, 78%). P.F .: 106-110 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.70-7.61 (m, 2H); 7.06-6.98 (m, 2H); 3.85 (t, J = 4.5, 4H); 3.74 (s a, 1 H); 3.44 (s at, 1 H); 2.96 (t, J = 4.5, 4H); 2.08 (d, J = 8.7, 1H); 1.97-1.94 (m, 2H); 1.69 (d, J = 9.0, 1H); 1.27-1.23 (m, 2H). IR (cm-1, KBr): 3435 (m), 3262 (m), 3085 (w), 2954 (m), 2925 (m), 2870 (m), 1670 (s), 1614 (m), 1523 (s), 1498 (m), 1450 (m), 1387 (w), 1357 (m), 1326 (w), 1269 (s), 1232 (s), 1145 (m), 1108 (m), 1093 (m), 1002 (m), 966 (m), 847 (m). MS (m / z): 375.2 ([M + H] +).

Ejemplo 313 Example 313

N(3)-(terc-Pentil)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida: N (3) - (tert-Pentyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide:

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 21 (100 mg, 0,34 mmol), DMF (1,0 ml), Et3N (53 µl, 0,37 mmol), reactivo BOP (159 mg, 0,36 mmol) y terc-amilamina (60 µl, 0,52 mmol) produjo el compuesto del título (109 mg, 88%). P.F.: 78-80 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,71-7,61 (m, 1H); 7,04-7,02 (m, 2H); 6,66 (s a, 1H); 3,74 (s a, 1H); 3,43 (s a, 1H), 2,07 (d, J = 8,4, 1H); 1,98-1,78 (m, 4H); 1,67 (d, J = 9,0, 1H); 1,41 (s, 6H); 1,26-1,20 (m, 2H); 0,91 (t, J = 7,2, 3H). EM (m/z): 360,2 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0 ml), Et3N (53 µl, 0.37 mmol), reagent BOP (159 mg, 0.36 mmol) and tert-amylamine (60 µl, 0.52 mmol) produced the title compound (109 mg, 88%). P.F .: 78-80 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.71-7.61 (m, 1H); 7.04-7.02 (m, 2H); 6.66 (s a, 1 H); 3.74 (s a, 1 H); 3.43 (s a, 1 H), 2.07 (d, J = 8.4, 1 H); 1.98-1.78 (m, 4H); 1.67 (d, J = 9.0, 1H); 1.41 (s, 6H); 1.26-1.20 (m, 2H); 0.91 (t, J = 7.2, 3H). MS (m / z): 360.2 ([M + H] +).

Ejemplo 314 Example 314

N(3)-Ciclopropanmetil-1-(2,4-diflurofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) -Cyclopropanmethyl-1- (2,4-diflurophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 21 (100 mg, 0,34 mmol), DMF (1,0 ml), Et3N (116 µl, 0,83 mmol), reactivo BOP (159 mg, 0,36 mmol) y clorhidrato de aminometil ciclopropano (55 mg, 0,51 mmol) produjo el compuesto del título (101 mg, 85%). P.F.: 113-115 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,72-7,62 (m, 1H); 7,06-6,92 (m, 3H); 3,75 (s a, 1H); 3,44 (s a, 1H), 3,28 (t, J = 5,7, 2H); 2,08 (d,7,8, 1H); 1,96 (s a, 2H); 1,68 (d, J = 9,3, 1H); 1,26 (s a, 2H); 1,06-1,02 (m, 1H); 0,52 (d, J = 7,5, 2H); 0,26 (d, J = 4,2, 2H). EM (m/z): 344,1 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0 ml), Et3N (116 µl, 0.83 mmol), reagent BOP (159 mg, 0.36 mmol) and aminomethyl cyclopropane hydrochloride (55 mg, 0.51 mmol) produced the title compound (101 mg, 85%). P.F .: 113-115 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.72-7.62 (m, 1H); 7.06-6.92 (m, 3H); 3.75 (s a, 1 H); 3.44 (s at, 1 H), 3.28 (t, J = 5.7, 2 H); 2.08 (d, 7.8, 1H); 1.96 (s at, 2H); 1.68 (d, J = 9.3, 1H); 1.26 (s at, 2H); 1.06-1.02 (m, 1 H); 0.52 (d, J = 7.5, 2H); 0.26 (d, J = 4.2, 2H). MS (m / z): 344.1 ([M + H] +).

Ejemplo 315 Example 315

N(3)-Ciclobutil-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) -Cyclobutyl-1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 21 (100 mg, 0,34 mmol), DMF (1,0 ml), Et3N (116 µl, 0,83 mmol), reactivo BOP (160 mg, 0,36 mmol) y clorhidrato de ciclobutil amina (115 mg, 0,68 mmol) produjo el compuesto del título (92 mg, 77%). P.F.: 123-125 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,70-7,62 (m, 1H); 7,06-6,96 (m, 3H); 4,56 (quintuplete, J = 7,5, 1H); 3,74 (s a, 1H); 3,43 (s a, 1H), 2,46-2,36 (m, 2H); 2,07 (d, J = 7,8, 1H), 2,04-1,95 (m, 5H); 1,78-1,60 (m, 2H); 1,25 (s a, 2H). EM (m/z): 344,2 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0 ml), Et3N (116 µl, 0.83 mmol), reagent BOP (160 mg, 0.36 mmol) and cyclobutyl amine hydrochloride (115 mg, 0.68 mmol) produced the title compound (92 mg, 77%). P.F .: 123-125 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.70-7.62 (m, 1H); 7.06-6.96 (m, 3H); 4.56 (quintuple, J = 7.5, 1H); 3.74 (s a, 1 H); 3.43 (s at, 1 H), 2.46-2.36 (m, 2 H); 2.07 (d, J = 7.8, 1H), 2.04-1.95 (m, 5H); 1.78-1.60 (m, 2H); 1.25 (s at, 2H). MS (m / z): 344.2 ([M + H] +).

Ejemplo 316 Example 316

N(3)-(Tetrahidro-2H-4-piranmetil)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3carboxamida: N (3) - (Tetrahydro-2H-4-pyranmethyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3carboxamide:

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 21 (100 mg, 0,34 mmol), DMF (1,0 ml), Et3N (54 µl, 0,37 mmol), reactivo BOP (160 mg, 0,36 mmol) y tetrahidro-2H-4piranilmetilamina (60 mg, 0,51 mmol) produjo el compuesto del título (103 mg, 77%). P.F.: 107-109 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,70-7,60 (m, 1H); 7,05-6,96 (m, 3H); 4,10-3,94 (m, 2H); 3,75 (s a, 1H); 3,46-3,29 (m, 5H), 2,12-2,02 (m, 1H); 2,00-1,62 (m, 5H); 1,44-1,20 (m, 5H). EM (m/z): 386,0 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0 ml), Et3N (54 µl, 0.37 mmol), reagent BOP (160 mg, 0.36 mmol) and tetrahydro-2H-4-pyranylmethylamine (60 mg, 0.51 mmol) produced the title compound (103 mg, 77%). P.F .: 107-109 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.70-7.60 (m, 1H); 7.05-6.96 (m, 3H); 4.10-3.94 (m, 2H); 3.75 (s a, 1 H); 3.46-3.29 (m, 5H), 2.12-2.02 (m, 1H); 2.00-1.62 (m, 5H); 1.44-1.20 (m, 5H). MS (m / z): 386.0 ([M + H] +).

Ejemplo 317 Example 317

N(3)-Ciclopropil-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) -Cyclopropyl-1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 21 (100 mg, 0,34 mmol), DMF (1,0 ml), Et3N (54 µl, 0,37 mmol), reactivo BOP (160 mg, 0,36 mmol) y ciclopropilamina (36 µl, 0,51 mmol) produjo el compuesto del título (103 mg, 86%). P.F.: 59-61 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,70-7,62 (m, 1H); 7,00 (t, J = 9,9, 2H); 6,90 (s a, 1H); 3,75 (s a, 1H); 3,43 (s a, 1H), 2,88-2,84 (m, 1H); 2,07 (d, J = 8,7, 1H); 2,02-1,90 (m, 2H); 1,68 (d, J = 8,7, 1H); 1,32-1,15 (m, 2H); 0,82 (d, J = 5,1, 2H); 0,62 (s a, 2H). EM (m/z): 328,0 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0 ml), Et3N (54 µl, 0.37 mmol), reagent BOP (160 mg, 0.36 mmol) and cyclopropylamine (36 µl, 0.51 mmol) produced the title compound (103 mg, 86%). P.F .: 59-61 ºC. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.70-7.62 (m, 1H); 7.00 (t, J = 9.9, 2H); 6.90 (s at, 1 H); 3.75 (s a, 1 H); 3.43 (s at, 1 H), 2.88-2.84 (m, 1 H); 2.07 (d, J = 8.7, 1H); 2.02-1.90 (m, 2H); 1.68 (d, J = 8.7, 1H); 1.32-1.15 (m, 2H); 0.82 (d, J = 5.1, 2H); 0.62 (s at, 2H). MS (m / z): 328.0 ([M + H] +).

Ejemplo 318 Example 318

N(3)-(4-metilpiperazino)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida: N (3) - (4-methylpiperazino) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide:

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 21 (100 mg, 0,34 mmol), DMF (1,0 ml), Et3N (51 µl, 0,37 mmol), reactivo BOP (165 mg, 0,37 mmol) y N-amino-Nmetilpiperazina (61 µl, 0,51 mmol) produjo el compuesto del título (97 mg, 72%). P.F.: 154-156 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,70-7,62 (m, 1H); 7,58 (s a, 1H); 7,08-6,96 (m, 2H); 3,74 (s a, 1H); 3,44 (s a, 1H); 3,03 (s a, 4H); 2,76 (s a, 4H); 2,41 (s, 3H); 2,08 (d, J = 9,3, 1H); 2:00-1,94 (m, 2H); 1,68 (d, J = 8,1, 1H); 1,30-1,24 (m, 2H). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0 ml), Et3N (51 µl, 0.37 mmol), reagent BOP (165 mg, 0.37 mmol) and N-amino-N-methylpiperazine (61 µl, 0.51 mmol) produced the title compound (97 mg, 72%). P.F .: 154-156 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.70-7.62 (m, 1H); 7.58 (s a, 1 H); 7.08-6.96 (m, 2H); 3.74 (s a, 1 H); 3.44 (s at, 1 H); 3.03 (s a, 4H); 2.76 (s at, 4H); 2.41 (s, 3 H); 2.08 (d, J = 9.3, 1H); 2: 00-1.94 (m, 2H); 1.68 (d, J = 8.1, 1H); 1.30-1.24 (m, 2H).

Ejemplo 319 Example 319

(2R)-2-[5-(2,4-Difluorofenil)-4,5-diazatriciclo[5.2.1.0,2,6]deca-2(6),3-dien-3-ilcarboxamido]-2-feniletanoato de metilo: (2R) -2- [5- (2,4-Difluorophenyl) -4,5-diazatricyclo [5.2.1.0,2,6] deca-2 (6), 3-dien-3-ylcarboxamido] -2-phenylethanoate of methyl:

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 21 (300 mg, 1,03 mmol), DMF (3,0 ml), Et3N (343 µl, 2,48 mmol), reactivo BOP (502 mg, 1,13 mmol) y clorhidrato R-(-)2-fenilglicinmetilester (208 mg, 1,03 mmol) produjo el compuesto del título (334 mg, 74%). P.F.: 61-63 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,78-7,64 (m, 2H); 7,45 (d, J = 7,8, 2H); 7,40-7,31 (m, 3H); 7,04-6,95 (m, 2H); 5,76 (dd, J = 2,1, 7,2, 1H); 3,76 (2s, 3H); 3,71 (s a, 1H); 3,44 (s a; 1H); 2,11-2,01 (m, 1H); 1,99-1,90 (m, 2H); 1,66 (d, J = 8,7, 1H); 1,30-1,21 (m, 2H). IR (cm-1, KBr): 3411 (m), 3065 (w), 2953 (m), 2872 (w), 1744 (s), 1672 (s), 1610 (m), 1541 (s), 1523 (s), 1489 (s), 1454 (m), 1358 (m), 1328 (w), 1295 (w), 1271 (s), 1213 (m), 1160 (m), 1145 (m), 1122 (m), 1093 (w), 966 (m), 851 (m). EM (m/z): 480,24([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 21 (300 mg, 1.03 mmol), DMF (3.0 ml), Et3N (343 µl, 2.48 mmol), reagent BOP (502 mg, 1.13 mmol) and R - (-) 2-phenylglycinmethyl ester hydrochloride (208 mg, 1.03 mmol) produced the title compound (334 mg, 74%). P.F .: 61-63 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.78-7.64 (m, 2H); 7.45 (d, J = 7.8, 2H); 7.40-7.31 (m, 3H); 7.04-6.95 (m, 2H); 5.76 (dd, J = 2.1, 7.2, 1H); 3.76 (2s, 3H); 3.71 (s a, 1 H); 3.44 (s at; 1 H); 2.11-2.01 (m, 1 H); 1.99-1.90 (m, 2H); 1.66 (d, J = 8.7, 1H); 1.30-1.21 (m, 2H). IR (cm-1, KBr): 3411 (m), 3065 (w), 2953 (m), 2872 (w), 1744 (s), 1672 (s), 1610 (m), 1541 (s), 1523 (s), 1489 (s), 1454 (m), 1358 (m), 1328 (w), 1295 (w), 1271 (s), 1213 (m), 1160 (m), 1145 (m), 1122 (m), 1093 (w), 966 (m), 851 (m). MS (m / z): 480.24 ([M + H] +).

Ejemplo 320 Example 320

N(3)-[(1R)-2-Hidroxi-1-feniletil]-1-(2,4-diflurofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida: N (3) - [(1R) -2-Hydroxy-1-phenylethyl] -1- (2,4-diflurophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3 -carboxamide:

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 191. Ejemplo 319 (235 mg, 0,54 mmol), THF (4 ml) y LiBH4 (24 mg, 1,09 mmol) produjo el compuesto del título (153 mg, 69%). P.F.: 68-70 ºC.RMN 1H(δ ppm, CDCl3, 300 MHz): 8,25 (d, J = 9,0, 1H); 7,87-7,82 (m, 1H); 7,63-7,58 (m, 1H); 7,36-7,22 (m, 6H); 5,05-4,94 (m, 2H), 3,73-3,67 (m, 2H); 3,50 (s a, 1H); 3,45 (s a, 1H); 2,05-1,84 (m, 3H); 1,70-1,62 (m, 1H); 1,24-1,20 (m, 2H). EM (m/z): 452,17(M+H+). The title compound was synthesized by a procedure similar to that described for example 191. Example 319 (235 mg, 0.54 mmol), THF (4 mL) and LiBH4 (24 mg, 1.09 mmol) produced the title compound (153 mg, 69%). P.F .: 68-70 ° C. RMN 1H (δ ppm, CDCl3, 300 MHz): 8.25 (d, J = 9.0, 1H); 7.87-7.82 (m, 1 H); 7.63-7.58 (m, 1 H); 7.36-7.22 (m, 6H); 5.05-4.94 (m, 2H), 3.73-3.67 (m, 2H); 3.50 (s at, 1 H); 3.45 (s at, 1 H); 2.05-1.84 (m, 3H); 1.70-1.62 (m, 1 H); 1.24-1.20 (m, 2H). MS (m / z): 452.17 (M + H +).

Ejemplo 321 Example 321

N(3)-(terc-Butil)-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida: N (3) - (tert-Butyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide:

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 16 (100 mg, 0,34 mmol), DMF (1,0 ml), Et3N (52 µl, 0,38 mmol), reactivo BOP (157 mg, 0,35 mmol) y 2-amino-2metilpropano (53 ml, 0,51 mmol) produjo el compuesto del título (56 mg, 47%). P.F.: 170-173 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,62 (d, J = 8,7, 2H); 7,43 (d, J = 8,7, 2H); 6,78 (s a, 1H); 3,75 (s a, 1H); 3,65 (s a, 1H); 2,08-1,99 (m, 1H); 2,02-1,94 (m, 2H); 1,70 (d, J = 8,4, 1H); 1,47 (s, 9H); 1,28-0,99 (m, 2H). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 16 (100 mg, 0.34 mmol), DMF (1.0 ml), Et3N (52 µl, 0.38 mmol), reagent BOP (157 mg, 0.35 mmol) and 2-amino-2-methylpropane (53 ml, 0.51 mmol) produced the title compound (56 mg, 47%). P.F .: 170-173 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.62 (d, J = 8.7, 2H); 7.43 (d, J = 8.7, 2H); 6.78 (s a, 1 H); 3.75 (s a, 1 H); 3.65 (s a, 1 H); 2.08-1.99 (m, 1 H); 2.02-1.94 (m, 2H); 1.70 (d, J = 8.4, 1H); 1.47 (s, 9H); 1.28-0.99 (m, 2H).

Ejemplo 322 Example 322

N(3)-(Tetrahidro-2-furanilmetil)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida: N (3) - (Tetrahydro-2-furanylmethyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide:

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 21 (100 mg, 0,34 mmol), DMF (1,0 ml), Et3N (54 µl, 0,37 mmol), reactivo BOP (160 mg, 0,36 mmol) y tetrahidro-2furanilmetilamina (54 µl, 0,51 mmol) produjo el compuesto del título (82 mg, 64%). P.F.: 91-93 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,74-.7,62 (m, 1H); 7,15 (s a, 1H); 7,08-6,94 (m, 2H); 4,12-4,00 (m, 1H); 3,94-3,86 (m, 1H); 3,803,68 (m, 3H); 3,50-3,30 (m, 2H), 2,10-1,85 (m, 6H); 1,72-1,58 (m, 1H); 1,25 (s a, 3H). EM (m/z): 374,2 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0 ml), Et3N (54 µl, 0.37 mmol), reagent BOP (160 mg, 0.36 mmol) and tetrahydro-2-furanylmethylamine (54 µl, 0.51 mmol) produced the title compound (82 mg, 64%). P.F .: 91-93 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.74-7.62 (m, 1H); 7.15 (s a, 1 H); 7.08-6.94 (m, 2H); 4.12-4.00 (m, 1 H); 3.94-3.86 (m, 1 H); 3,803.68 (m, 3 H); 3.50-3.30 (m, 2H), 2.10-1.85 (m, 6H); 1.72-1.58 (m, 1 H); 1.25 (s at, 3H). MS (m / z): 374.2 ([M + H] +).

Ejemplo 323 Example 323

N(3)-(terc-Butil)-1-(4-fluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) - (tert-Butyl) -1- (4-fluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 20 (100 mg, 0,36 mmol), DMF (1,0 ml), Et3N (54 µl, 0,40 mmol), reactivo BOP (170 g, 0,38 mmol) y t-butilamina (57 µl, 0,55 mmol) produjo el compuesto del título (102 mg, 85%). P.F.: 131-133 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,66-7,60 (m, 2H); 7,20-7,12 (m, 2H); 6,78 (s a, 1H); 3,76 (s a, 1H); 3,63 (s a, 1H); 2,15-2,10 (m, 1H); 2,00-1,92 (m, 2H); 1,74-1,68 (m, 1H); 1,47 (s, 9H); 1,30-1,16 (m, 2H). EM (m/z): 328,15 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 20 (100 mg, 0.36 mmol), DMF (1.0 ml), Et3N (54 µl, 0.40 mmol), reagent BOP (170 g, 0.38 mmol) and t-butylamine (57 µl, 0.55 mmol) produced the title compound (102 mg, 85%). P.F .: 131-133 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.66-7.60 (m, 2H); 7.20-7.12 (m, 2H); 6.78 (s a, 1 H); 3.76 (s a, 1 H); 3.63 (s a, 1 H); 2.15-2.10 (m, 1 H); 2.00-1.92 (m, 2H); 1.74-1.68 (m, 1 H); 1.47 (s, 9H); 1.30-1.16 (m, 2H). MS (m / z): 328.15 ([M + H] +).

Ejemplo 324 Example 324

N(3)-(terc-Butil)-1-(4-bromofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) - (tert-Butyl) -1- (4-bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 19 (100 mg, 0,30 mmol), DMF (1,0 ml), Et3N (45 µl, 0,33 mmol), reactivo BOP (139 mg, 0,31 mmol) y 2-amino-2metilpropano (47 µl, 0,45 mmol) produjo el compuesto del título (87 mg, 75%). P.F.: 157-159 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,57 (s, 4H); 6,78 (s a, 1H); 3,75 (s a, 1H); 3,65 (s a, 1H); 2,18-2,07 (m, 1H); 2,02-1,92 (m, 2H); 1,70 (d, J = 9,0, 1H); 1,47 (s, 9H); 1,28-0,99 (m, 2H). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 19 (100 mg, 0.30 mmol), DMF (1.0 ml), Et3N (45 µl, 0.33 mmol), reagent BOP (139 mg, 0.31 mmol) and 2-amino-2-methylpropane (47 µl, 0.45 mmol) produced the title compound (87 mg, 75%). P.F .: 157-159 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.57 (s, 4H); 6.78 (s a, 1 H); 3.75 (s a, 1 H); 3.65 (s a, 1 H); 2.18-2.07 (m, 1 H); 2.02-1.92 (m, 2H); 1.70 (d, J = 9.0, 1H); 1.47 (s, 9H); 1.28-0.99 (m, 2H).

Ejemplo 325 Example 325

N(3)-(terc-Butil)-1-(3,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida: N (3) - (tert-Butyl) -1- (3,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide:

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 29 (100 mg, 0,31 mmol), DMF (1,0 ml), Et3N (47 µl, 0,34 mmol), reactivo BOP (143 mg, 0,32 mmol) y 2-amino-2metilpropano (48 µl, 0,46 mmol) produjo el compuesto del título (77 mg, 66%). 205-207 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,83 (s, 1H); 7,52 (s, 2H); 6,77 (s a, 1H); 3,75 (s a, 1H); 3,67 (s a, 1H); 2,11 (d, J = 8,7, 1H); 1,99 (d, 6,3, 2H); 1,71 (d, J = 8,7, 1H); 1,48 (s, 9H); 1,28-1,16 (m, 2H). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 29 (100 mg, 0.31 mmol), DMF (1.0 ml), Et3N (47 µl, 0.34 mmol), reagent BOP (143 mg, 0.32 mmol) and 2-amino-2 methylpropane (48 µl, 0.46 mmol) produced the title compound (77 mg, 66%). 205-207 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.83 (s, 1H); 7.52 (s, 2H); 6.77 (s a, 1 H); 3.75 (s a, 1 H); 3.67 (s at, 1 H); 2.11 (d, J = 8.7, 1H); 1.99 (d, 6.3, 2H); 1.71 (d, J = 8.7, 1H); 1.48 (s, 9H); 1.28-1.16 (m, 2H).

Ejemplo 326 Example 326

(2S)-2-[5-(2,4-Difluorofenil)-4,5-diazatriciclo[5.2.1.0,2,6]deca-2(6),3-dien-3-ilcarboxamido]-2-(4fluorofenil)etanoato de metilo: (2S) -2- [5- (2,4-Difluorophenyl) -4,5-diazatricyclo [5.2.1.0,2,6] deca-2 (6), 3-dien-3-ylcarboxamido] -2- ( 4-Fluorophenyl) methyl ethanoate:

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 21 (400 mg, 1,37 mmol), DMF (4,0 ml), Et3N (450 µl, 3,31 mmol), reactivo BOP (670 mg, 1,51 mmol) y metil éster clorhidrato de (S)-(-)-2-(4-flurofenil)glicina (302 mg, 1,37 mmol) produjo el compuesto del título (543 mg, 86%). P.F.: 51-52 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,78-7,68 (m, 2H); 7,44-7,41 (m, 2H); 7,06-6,95 (m, 4H); 5,63 (d, J = 6,9, 1H); 3,77, 3,76 (2s, 3H); 3,70 (s a, 1H); 3,44 (s a, 1H); 2,10-2,02 (m, 1H); 2,00-1,90 (m, 2H); 1,67 (d, J = 7,8, 1H); 1,30-1,19 (m, 2H). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 21 (400 mg, 1.37 mmol), DMF (4.0 ml), Et3N (450 µl, 3.31 mmol), reagent BOP (670 mg, 1.51 mmol) and methyl ester hydrochloride of (S) - (-) - 2- (4-flurophenyl) glycine (302 mg, 1.37 mmol) produced the title compound (543 mg, 86 %). P.F .: 51-52 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.78-7.68 (m, 2H); 7.44-7.41 (m, 2H); 7.06-6.95 (m, 4H); 5.63 (d, J = 6.9, 1H); 3.77, 3.76 (2s, 3H); 3.70 (s at, 1 H); 3.44 (s at, 1 H); 2.10-2.02 (m, 1 H); 2.00-1.90 (m, 2H); 1.67 (d, J = 7.8, 1H); 1.30-1.19 (m, 2H).

Ejemplo 327 Example 327

N(3)-(terc-Butil)-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida: N (3) - (tert-Butyl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide:

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 17 (100 mg, 0,30 mmol), DMF (1,0 ml), Et3N (48 µl, 0,34 mmol), reactivo BOP (144 mg, 0,32 mmol) y 2-amino-2metilpropano (48 µl, 0,46 mmol) produjo el compuesto del título (90 mg, 77%). 129-131 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,55 (d, J = 2,4, 1H); 7,45 (d, J = 8,4, 1H); 7,37 (dd, J = 8,4, 2,1, 1H); 6,71 (s a, 1H); 3,76 (s a, 1H); 3,34 (s a, 1H); 2,11 (d, J = 9,0; 1H); 2,02-1,82 (m, 2H); 1,68 (d, J = 8,7, 1H); 1,45 (s, 9H); 1,33-1,12 (m, 2H). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 17 (100 mg, 0.30 mmol), DMF (1.0 ml), Et3N (48 µl, 0.34 mmol), reagent BOP (144 mg, 0.32 mmol) and 2-amino-2-methylpropane (48 µl, 0.46 mmol) produced the title compound (90 mg, 77%). 129-131 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.55 (d, J = 2.4, 1H); 7.45 (d, J = 8.4, 1H); 7.37 (dd, J = 8.4, 2.1, 1H); 6.71 (s a, 1 H); 3.76 (s a, 1 H); 3.34 (s at, 1 H); 2.11 (d, J = 9.0; 1H); 2.02-1.82 (m, 2H); 1.68 (d, J = 8.7, 1H); 1.45 (s, 9H); 1.33-1.12 (m, 2H).

Ejemplo 328 Example 328

N(3)-(4-Hidroxifenil)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida: N (3) - (4-Hydroxyphenyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide:

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 21 (100 mg, 0,34 mmol), DMF (1,0 ml), Et3N (51 µl, 0,37 mmol), reactivo BOP (160 mg, 0,36 mmol) y 4-amino-fenol (56 mg, 0,51 mmol) produjo el compuesto del título (112 mg, 85%). P.F.: 189-191 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,56 (s a, 1H); 7,75-7,64 (m, 1H); 7,52 (d, J = 9,3, 2H); 7,08-6,99 (m, 2H); 6,82 (d, J = 8,7, 2H); 5,30 (s a, 1H); 3,79 (s a, 1H); 3,47 (s a, 1H); 2,11 (d, J = 8,7, 1H); 2,00-1,94 (m, 2H); 1,71 (d, J = 8,7, 1H); 1,32-1,22 (m, 2H). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0 ml), Et3N (51 µl, 0.37 mmol), reagent BOP (160 mg, 0.36 mmol) and 4-amino-phenol (56 mg, 0.51 mmol) produced the title compound (112 mg, 85%). P.F .: 189-191 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 8.56 (s at, 1H); 7.75-7.64 (m, 1 H); 7.52 (d, J = 9.3, 2H); 7.08-6.99 (m, 2H); 6.82 (d, J = 8.7, 2H); 5.30 (s at, 1 H); 3.79 (s a, 1 H); 3.47 (s at, 1 H); 2.11 (d, J = 8.7, 1H); 2.00-1.94 (m, 2H); 1.71 (d, J = 8.7, 1H); 1.32-1.22 (m, 2H).

Ejemplo 329 Example 329

N(3)-(terc-Butil)-1-(2-etoxi,4-fluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida: N (3) - (tert-Butyl) -1- (2-ethoxy, 4-fluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide:

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 30 (100 mg, 0,31 mmol), DMF (1,0 ml), Et3N (50 µl, 0,34 mmol), reactivo BOP (146 mg, 0,33 mmol) y 2-amino-2metilpropano (40 µl, 0,37 mmol) produjo el compuesto del título (96 mg, 82%). P.F.: 117-120 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,54-7,44 (m, 1H), 6,82-6,69 (m, 3H); 4,12-4,00 (m, 2H); 3,73 (s a, 1H); 3,31 (s a, 1H); 2,.06 (d, J = 8,1, 1H); 1,98-1,82 (m, 2H); 1,65 (d, J = 8,4, 1H); 1,45 (s, 9H); 1,38 (t, J = 6,9, 3H); 1,28-1,20 (m, 2H). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 30 (100 mg, 0.31 mmol), DMF (1.0 ml), Et3N (50 µl, 0.34 mmol), reagent BOP (146 mg, 0.33 mmol) and 2-amino-2 methylpropane (40 µl, 0.37 mmol) produced the title compound (96 mg, 82%). P.F .: 117-120 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.54-7.44 (m, 1H), 6.82-6.69 (m, 3H); 4.12-4.00 (m, 2H); 3.73 (s a, 1 H); 3.31 (s at, 1 H); 2, .06 (d, J = 8.1, 1H); 1.98-1.82 (m, 2H); 1.65 (d, J = 8.4, 1H); 1.45 (s, 9H); 1.38 (t, J = 6.9, 3H); 1.28-1.20 (m, 2H).

Ejemplo 330 Example 330

N(3)-(2-furilmetil)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida: N (3) - (2-Furylmethyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide:

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 21 (100 mg, 0,34 mmol), DMF (1,0 ml), Et3N (57 µl, 0,41 mmol), reactivo BOP (167 mg, 0,37 mmol) y furfurilamina (38 µl, 0,41 mmol) produjo el compuesto del título (98 mg, 77%). P.F.: 99-100 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,71-7,61 (m, 1H); 7,36 (s a, 1H); 7,19-7,11 (m, 1H); 7,00 (t, J = 8,4, 2H); 6,30 (d, J = 7,5, 2H); 4,60 (d, J = 5,1, 2H); 3,76 (s a, 1H); 3,44 (s a, 1H); 2,08 (d, J = 7,5, 1H); 2,02-1,90 (m, 2H), 1,68 (d, J = 8,1, 1H); 1:32-1,22 (m, 2H). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0 ml), Et3N (57 µl, 0.41 mmol), reagent BOP (167 mg, 0.37 mmol) and furfurylamine (38 µl, 0.41 mmol) produced the title compound (98 mg, 77%). P.F .: 99-100 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.71-7.61 (m, 1H); 7.36 (s a, 1 H); 7.19-7.11 (m, 1 H); 7.00 (t, J = 8.4, 2H); 6.30 (d, J = 7.5, 2H); 4.60 (d, J = 5.1, 2H); 3.76 (s a, 1 H); 3.44 (s at, 1 H); 2.08 (d, J = 7.5, 1H); 2.02-1.90 (m, 2H), 1.68 (d, J = 8.1, 1H); 1: 32-1.22 (m, 2H).

Ejemplo 331 Example 331

N(3)-(2-tiofenometil)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida: N (3) - (2-thiophenomethyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide:

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 21 (100 mg, 0,34 mmol), DMF (1,0 ml), Et3N (57 µ, 0,37 mmol), reactivo BOP (167 mg, 0,37 mmol) y 2-tiofeno metilamina (42 µl, 0,41 mmol) produjo el compuesto del título (106 mg, 80%). P.F.: 103-105 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,70-7,58 (m, 1H); 7,24-7,12 (m, 2H); 7,05-6,94 (m, 4H); 4,78 (d, J = 4,5, 2H); 3,77 (s a, 1H); 3,44 (s a, 1H); 2,08 (d, J = 6,3, 1H); 2,02-1,89 (m, 2H), 1,69 (d, J = 9,0, 1H); 1,34-1,20 (m, 2H). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0 mL), Et3N (57 µ, 0.37 mmol), reagent BOP (167 mg, 0.37 mmol) and 2-thiophene methylamine (42 µl, 0.41 mmol) produced the title compound (106 mg, 80%). P.F .: 103-105 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.70-7.58 (m, 1H); 7.24-7.12 (m, 2H); 7.05-6.94 (m, 4H); 4.78 (d, J = 4.5, 2H); 3.77 (s a, 1 H); 3.44 (s at, 1 H); 2.08 (d, J = 6.3, 1H); 2.02-1.89 (m, 2H), 1.69 (d, J = 9.0, 1H); 1.34-1.20 (m, 2H).

Ejemplo 332 Example 332

N(3)-[(1S)-2-Hidroxi-1-(4-fluorofenil)etil]-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3carboxamida: N (3) - [(1S) -2-Hydroxy-1- (4-fluorophenyl) ethyl] -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7- methane-indazol-3carboxamide:

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 191. El ejemplo 326 (400 mg, 0,87 mmol), THF (6 ml) y LiBH4 (38 mg, 1,75 mmol) produjo el compuesto del título (288 mg, 76%). P.F.: 116119 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,65 (c, J = 8,4, 1H); 7,49-7,41 (m, 1H); 7,40-7,32 (m, 2H); 7,08-6,96 (m, 4H); 5,24-5,18 (m, 1H), 3,96 (d, J = 5,1, 2H); 3,72 (s a, 1H); 3,44 (s a, 1H); 2,12-2,02 (m, 2H); 1,99-1,92 (m, 2H); 1,68 (d, J = 8,7, 1H); 1,28-1,20 (m, 2H). The title compound was synthesized by a procedure similar to that described for example 191. Example 326 (400 mg, 0.87 mmol), THF (6 ml) and LiBH4 (38 mg, 1.75 mmol) produced the compound of titer (288 mg, 76%). P.F .: 116119 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.65 (c, J = 8.4, 1H); 7.49-7.41 (m, 1 H); 7.40-7.32 (m, 2H); 7.08-6.96 (m, 4H); 5.24-5.18 (m, 1H), 3.96 (d, J = 5.1, 2H); 3.72 (s a, 1 H); 3.44 (s at, 1 H); 2.12-2.02 (m, 2H); 1.99-1.92 (m, 2H); 1.68 (d, J = 8.7, 1H); 1.28-1.20 (m, 2H).

Ejemplo 333 Example 333

(2S)-2-[5-(2,4-difluorofenil)-4,5-diazatriciclo[5.2.1.0,2,6]deca-2(6),3-dien-3-ilcarboxamido]-4-metil-pentanoato de metilo: (2S) -2- [5- (2,4-difluorophenyl) -4,5-diazatricyclo [5.2.1.0,2,6] deca-2 (6), 3-dien-3-ylcarboxamido] -4-methyl -methyl pentanoate:

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 21 (100 mg, 0,34 mmol), DMF (1,0 ml), Et3N (104 µl, 0,74 mmol), reactivo BOP (159 mg, 0,37 mmol) y metil éster clorhidrato L-leucina (75 mg, 0,50 mmol) produjo el compuesto del título (87 mg, 60%) en forma de un sólido ceroso. RMN 1H(δ ppm, CDCl3, 300 MHz): 7,78-7,65 (m, 1H); 7,21-7,10 (m, 1H); 7,12-6,95 (m, 2H); 4,90-4,75 (m, 1H); 3,75 (s, 4H); 3,45 (s a, 1H); 2,12-2,02 (m, 1H); 2,00-1,90 (m, 2H); 1,80-1,60 (m, 6H); 1,34-1,18 (m, 2H), 1,02-0,90 (m, 4H). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0 ml), Et3N (104 µl, 0.74 mmol), reagent BOP (159 mg, 0.37 mmol) and methyl ester L-leucine hydrochloride (75 mg, 0.50 mmol) produced the title compound (87 mg, 60%) as a waxy solid. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.78-7.65 (m, 1H); 7.21-7.10 (m, 1 H); 7.12-6.95 (m, 2H); 4.90-4.75 (m, 1 H); 3.75 (s, 4H); 3.45 (s at, 1 H); 2.12-2.02 (m, 1 H); 2.00-1.90 (m, 2H); 1.80-1.60 (m, 6H); 1.34-1.18 (m, 2H), 1.02-0.90 (m, 4H).

Ejemplo 334 Example 334

N(3)-(Adamantan-1il)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida: N (3) - (Adamantan-1yl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide:

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 21 (100 mg, 0,34 mmol), DMF (1,0 ml), Et3N (50 µl, 0,37 mmol), reactivo BOP (159 mg, 0,36 mmol) y 1-adamantilamina (78 mg, 0,51 mmol) produjo el compuesto del título (88 mg, 60%). P.F.: 146-148 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,72-7,60 (m, 1H); 7,04-6,94 (m, 2H); 6,61 (s a, 1H); 3,73 (s a, 1H); 3,42 (s a, 1H); 2,20-2,03 (m, 10H); 1,981,92 (m, 2H); 1,80-1,52 (m, 4H); 1,44-1,19 (m, 5H). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0 ml), Et3N (50 µl, 0.37 mmol), reagent BOP (159 mg, 0.36 mmol) and 1-adamantylamine (78 mg, 0.51 mmol) produced the title compound (88 mg, 60%). P.F .: 146-148 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.72-7.60 (m, 1H); 7.04-6.94 (m, 2H); 6.61 (s a, 1 H); 3.73 (s a, 1 H); 3.42 (s at, 1 H); 2.20-2.03 (m, 10H); 1,981.92 (m, 2H); 1.80-1.52 (m, 4H); 1.44-1.19 (m, 5H).

Ejemplo 335a Example 335a

N(3)-(terc-butil)-1-(4-fluorobencil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida: N (3) - (tert-butyl) -1- (4-fluorobenzyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide:

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 32a (100 mg, 0,34 mmol), DMF (1,0 ml), Et3N (55 µl, 0,39 mmol), reactivo BOP (162 mg, 0,36 mmol) y 2-amino-2metilpropano (44 µl, 0,41 mmol) produjo el compuesto del título (85 mg, 71%) en forma de un aceite. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,24-7,14 (m, 2H); 7,04 (t, J = 8,4, 2H); 6,67 (s a, 1H); 5,18 (s, 2H); 3,64 (s a, 1H); 3,03 (s a, 1H); 1,98-1,65 (m, 3H), 1,55 (d, J = 8,7, 1H); 1,45 (s, 9H); 1,18-1,08 (m, 1H); 0,86-0,74 (m, 1H). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 32a (100 mg, 0.34 mmol), DMF (1.0 ml), Et3N (55 µl, 0.39 mmol), reagent BOP (162 mg, 0.36 mmol) and 2-amino-2-methylpropane (44 µl, 0.41 mmol) produced the title compound (85 mg, 71%) as an oil. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.24-7.14 (m, 2H); 7.04 (t, J = 8.4, 2H); 6.67 (s a, 1 H); 5.18 (s, 2H); 3.64 (s at, 1 H); 3.03 (s at, 1 H); 1.98-1.65 (m, 3H), 1.55 (d, J = 8.7, 1H); 1.45 (s, 9H); 1.18-1.08 (m, 1 H); 0.86-0.74 (m, 1 H).

Ejemplo 335b Example 335b

N(3)-(terc-butil)-2-(4-fluorobencil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida: N (3) - (tert-butyl) -2- (4-fluorobenzyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide:

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 32b (50 mg, 0,17 mmol), DMF (1,0 ml), Et3N (30 µl, 0,19 mmol), reactivo BOP (80 mg, 0,18 mmol) y 2-amino-2metilpropano (20 µl, 0,19 mmol) produjo el compuesto del título (40 mg, 67%). P.F.: 130-134 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,30-7,20 (m, 2H); 6,94 (t, J = 8,7, 2H); 5,80 (d, J = 14,7, 1H); 5,72 (s a, 1H); 5,43 (d, J = 14,4, 1H); 3,40 (s a, 1H); 3,29 (s a, 1H), 1,98-1,88 (m, 3H); 1,68 (d, J = 8,4, 1H); 1,42 (s, 9H); 1,21 (d, J = 9,6, 2H). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 32b (50 mg, 0.17 mmol), DMF (1.0 ml), Et3N (30 µl, 0.19 mmol), reagent BOP (80 mg, 0.18 mmol) and 2-amino-2 methylpropane (20 µl, 0.19 mmol) produced the title compound (40 mg, 67%). P.F .: 130-134 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.30-7.20 (m, 2H); 6.94 (t, J = 8.7, 2H); 5.80 (d, J = 14.7, 1H); 5.72 (s at, 1 H); 5.43 (d, J = 14.4, 1H); 3.40 (s at, 1 H); 3.29 (s at, 1 H), 1.98-1.88 (m, 3 H); 1.68 (d, J = 8.4, 1H); 1.42 (s, 9H); 1.21 (d, J = 9.6, 2H).

Ejemplo 336a Example 336a

N(3)-(terc-butil)-1-(4-metilbencil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida: N (3) - (tert-butyl) -1- (4-methylbenzyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide:

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 31a (100 mg, 0,35 mmol), DMF (1,0 ml), Et3N (55 µl, 0,39 mmol), reactivo BOP (164 mg, 0,37 mmol) y 2-amino-2metilpropano (56 µl, 0,53 mmol) produjo el compuesto del título (71 mg, 65%). RMN 1H (δ ppm, CDCl3, 300 MHz): 7,16 (d, J = 8,1, 2H); 7,10 (d, J = 8,1, 2H); 6,69 (s a, 1H); 5,17 (s, 2H); 3,63 (s a, 1H); 2,99 (s a, 1H); 2,34 (s, 3H), 1,94-1,78 (m, 2H); 1,72-1,64 (m, 1H); 1,53 (d, J = 8,7, 1H); 1,45 (s, 9H); 1,18-1,08 (m, 1H); 0,90-0,78 (m, 1H). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 31a (100 mg, 0.35 mmol), DMF (1.0 ml), Et3N (55 µl, 0.39 mmol), reagent BOP (164 mg, 0.37 mmol) and 2-amino-2-methylpropane (56 µl, 0.53 mmol) produced the title compound (71 mg, 65%). 1H NMR (δ ppm, CDCl3, 300 MHz): 7.16 (d, J = 8.1, 2H); 7.10 (d, J = 8.1, 2H); 6.69 (s a, 1 H); 5.17 (s, 2H); 3.63 (s a, 1 H); 2.99 (s at, 1H); 2.34 (s, 3H), 1.94-1.78 (m, 2H); 1.72-1.64 (m, 1 H); 1.53 (d, J = 8.7, 1H); 1.45 (s, 9H); 1.18-1.08 (m, 1 H); 0.90-0.78 (m, 1 H).

Ejemplo 336b Example 336b

N(3)-(terc-butil)-2-(4-metilbencil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida: N (3) - (tert-butyl) -2- (4-methylbenzyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide:

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 32b (68 mg, 0,24 mmol), DMF (1,0 ml), Et3N (38 µl, 0,26 mmol), reactivo BOP (111 mg, 0,25 mmol) y 2-amino-2metilpropano (38 ul, 0,41 mmol) produjo el compuesto del título (44 mg, 54%). P.F.: 142-144 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,18 (d, J = 7,8, 2H); 7,07 (d, J = 7,8, 2H); 5,80 (d, J = 14,7, 1H); 5,71 (s a, 1H); 5,41 (d, J = 14,7, 1H); 3,39 (s a, 1H); 3,28 (s a, 1H); 2,28 (s, 3H); 1,98-1,89 (m, 3H); 1,70-1,62 (m, 1H); 1,42 (s, 9H), 1,20 (d, J = 9,0, 2H). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 32b (68 mg, 0.24 mmol), DMF (1.0 ml), Et3N (38 µl, 0.26 mmol), reagent BOP (111 mg, 0.25 mmol) and 2-amino-2-methylpropane (38 ul, 0.41 mmol) produced the title compound (44 mg, 54%). P.F .: 142-144 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.18 (d, J = 7.8, 2H); 7.07 (d, J = 7.8, 2H); 5.80 (d, J = 14.7, 1H); 5.71 (s at, 1 H); 5.41 (d, J = 14.7, 1H); 3.39 (s at, 1 H); 3.28 (s at, 1 H); 2.28 (s, 3 H); 1.98-1.89 (m, 3H); 1.70-1.62 (m, 1 H); 1.42 (s, 9H), 1.20 (d, J = 9.0, 2H).

Ejemplo 401 Example 401

N(3)-Fenil-1-(2,4-diclorofenil)-7,8,8-trimetil-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida N (3) -Phenyl-1- (2,4-dichlorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 22 (100 mg, 0,27 mmol), DMF (1,0 ml), Et3N (43 µl, 0,30 mmol), reactivo BOP (127 mg, 0,29 mmol) y anilina (28 µl, 0,30 mmol) produjo el compuesto del título (85 mg, 71%). P.F.: 112-115 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,64 (s a, 1H); 7,67 (d, J = 7,8, 2H); 7,59 (s a, 1H); 7,47-7,25 (m, 4H); 7,09 (t, J = 7,5, 1H); 3,29 (d, J = 3,6, 1H); 2,22-2,08 (m, 1H); 1,83 (t a, J = 9,3, 1H); 1,43-1,20 (m, 2H); 0,93 (s, 6H); 0,85 (s, 3H). IR (cm-1, KBr): 3274 (s), 3251 (s), 2955 (m), 2928 (s), 2869 (m), 1663 (s), 1517 (s), 1546 (s), 1533 (m), 1596 (s), 1502 (s), 1474 (m), 1436 (s), 1388 (m), 1345 (m), 1323 (s), 1252 (m), 1220 (m), 1229 (m), 1129 (m), 1117 (m), 1102 (m), 1077 (m), 1062 (s), 1014 (m), 1001 (m). EM (m/z): 440,3 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 22 (100 mg, 0.27 mmol), DMF (1.0 ml), Et3N (43 µl, 0.30 mmol), reagent BOP (127 mg, 0.29 mmol) and aniline (28 µl, 0.30 mmol) produced the title compound (85 mg, 71%). P.F .: 112-115 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 8.64 (s at, 1H); 7.67 (d, J = 7.8, 2H); 7.59 (s a, 1 H); 7.47-7.25 (m, 4H); 7.09 (t, J = 7.5, 1H); 3.29 (d, J = 3.6, 1H); 2.22-2.08 (m, 1 H); 1.83 (t a, J = 9.3, 1H); 1.43-1.20 (m, 2H); 0.93 (s, 6H); 0.85 (s, 3H). IR (cm-1, KBr): 3274 (s), 3251 (s), 2955 (m), 2928 (s), 2869 (m), 1663 (s), 1517 (s), 1546 (s), 1533 (m), 1596 (s), 1502 (s), 1474 (m), 1436 (s), 1388 (m), 1345 (m), 1323 (s), 1252 (m), 1220 (m), 1229 (m), 1129 (m), 1117 (m), 1102 (m), 1077 (m), 1062 (s), 1014 (m), 1001 (m). MS (m / z): 440.3 ([M + H] +).

Ejemplo 402 Example 402

N(3)-[(2-Fluorofenil)amino]-1-(2,4-diclorofenil)-7,8,8-timetil-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3carboxamida N (3) - [(2-Fluorophenyl) amino] -1- (2,4-dichlorophenyl) -7,8,8-timethyl-4,5,6,7-tetrahydro-1H-4,7-methane- indazol-3carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 22 (100 mg, 0,27 mmol), DMF (1,0 ml), Et3N (43 µl, 0,30 mmol), reactivo BOP (127 mg, 0,29 mmol) y 2-fluorofenilo hidrazina (49 mg, 0,30 mmol) para dar el compuesto del título (85 mg, 83%). P.F.: 72-80 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,54 (s a, 1 H); 7,60 (s a, 1 H); 7,42 (d, J = 8,4, 1 H); 7,38 (d, J = 8,7, 1 H); 7,14-6,95 (m, 3H) 6,87-6,78 (m, 1H); 3,21 (d, J = 3,3, 1H); 2,20-2,06 (m, 1H); 1,82 (t a, J = 9,0,1H); 1,41-1,18 (m, 2H); 0,93 (s, 3H); 0,91 (s, 3H); 0,82 (s, 3H). IR (cm-1, KBr): 3413 (m), 2912 (s), 2845 (m), 1667 (s), 1535 (s), 1497 (s), 1478 (s), 1352 (m), 1233 (m), 1219 (m), 1162 (m), 1103 (m), 1088 (m), 996 (m), 866 (w). EM (m/z): 473,10 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 22 (100 mg, 0.27 mmol), DMF (1.0 ml), Et3N (43 µl, 0.30 mmol), reagent BOP (127 mg, 0.29 mmol) and 2-fluorophenyl hydrazine (49 mg, 0.30 mmol) to give the title compound (85 mg, 83%). P.F .: 72-80 ° C. 1 H NMR (δ ppm, CDCl 3, 300 MHz): 8.54 (s at, 1 H); 7.60 (s at, 1 H); 7.42 (d, J = 8.4, 1 H); 7.38 (d, J = 8.7, 1 H); 7.14-6.95 (m, 3H) 6.87-6.78 (m, 1H); 3.21 (d, J = 3.3, 1H); 2.20-2.06 (m, 1 H); 1.82 (t a, J = 9.0.1H); 1.41-1.18 (m, 2H); 0.93 (s, 3 H); 0.91 (s, 3 H); 0.82 (s, 3H). IR (cm-1, KBr): 3413 (m), 2912 (s), 2845 (m), 1667 (s), 1535 (s), 1497 (s), 1478 (s), 1352 (m), 1233 (m), 1219 (m), 1162 (m), 1103 (m), 1088 (m), 996 (m), 866 (w). MS (m / z): 473.10 ([M + H] +).

Ejemplo 403 Example 403

N(3)-[(2,4-Difluorofenil)amino]-1-(2,4-diclorofenil)-7,8,8-trimetil-4,5,6,7-tetrahidro-1H-4,7-metano-in-dazol-3carboxamida N (3) - [(2,4-Difluorophenyl) amino] -1- (2,4-dichlorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7- methane-in-dazol-3carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 22 (100 mg, 0,27 mmol), DMF (1,0 ml), Et3N (43 µl, 0,31 mmol), reactivo BOP (127 mg, 0,29 mmol) y clorhidrato de 3,5difluorofenilhidrazina (55 mg, 0,31 mmol) dio el compuesto del título (90 mg, 67%). P.F.: 145-148 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,78 (s a, 1H); 7,60 (d, J = 1,8, 1H); 7,45-7,35 (m, 2H); 7,10-6,98 (m, 1 H); 6,86-6,70 (m, 2H); 3,22 (d, J = 3,6, 1 H); 2,20-2,05 (m, 1H); 1,88-1,80 (m, 1H); 1,40-1,20 (m, 2H); 0,93, 0,88, 0,82 (3s, 9H). IR (cm-1 , KBr): 3339 (m), 3269 (m), 2979 (m), 2961 (m), 1678 (s), 1508 (s), 1472 (m), 1211 (m), 1132 (m), 1102 (m), 959 (m), 844 (m). EM (m/z): 491,10 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 22 (100 mg, 0.27 mmol), DMF (1.0 ml), Et3N (43 µl, 0.31 mmol), reagent BOP (127 mg, 0.29 mmol) and 3.5-difluorophenylhydrazine hydrochloride (55 mg, 0.31 mmol) gave the title compound (90 mg, 67%). P.F .: 145-148 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 8.78 (s at, 1H); 7.60 (d, J = 1.8, 1H); 7.45-7.35 (m, 2H); 7.10-6.98 (m, 1 H); 6.86-6.70 (m, 2H); 3.22 (d, J = 3.6, 1 H); 2.20-2.05 (m, 1 H); 1.88-1.80 (m, 1 H); 1.40-1.20 (m, 2H); 0.93, 0.88, 0.82 (3s, 9H). IR (cm-1, KBr): 3339 (m), 3269 (m), 2979 (m), 2961 (m), 1678 (s), 1508 (s), 1472 (m), 1211 (m), 1132 (m), 1102 (m), 959 (m), 844 (m). MS (m / z): 491.10 ([M + H] +).

Ejemplo 404 Example 404

N(3)-[(3-cloropiridin-2il)amino]-1-(2,4-diclorofenil)-7,8,8-trimetil-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3carboxamida N (3) - [(3-Chloropyridin-2-yl) amino] -1- (2,4-dichlorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7- methane-indazol-3carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 22 (100 mg, 0,27 mmol), DMF (1,0 ml), Et3N (43 µl, 0,31 mmol), reactivo BOP (127 mg, 0,29 mmol) y 3-cloro-2hidrazinopiridina (45 mg, 0,31 mmol) para dar el compuesto del título (75 mg, 56%). P.F.: 142-145 ºC. RMN 1H (δ ppm, DMSO-d6, 300 MHz): 9,88 (s a, 1H); 8,42 (s a, 1H); 8,00 (d, J = 9,6, 2H); 7,30-7,55 (m, 3H); 6,75 (s a, 1 H); 3,05 (s a, 1H); 2,09 (s a, 1 H); 1,80 (s a, 1H); 1,40-1,05 (m, 2H); 0,88, 0,86, 0,80 (3s, 9H). IR (cm-1 KBr): 3339 (m), 3269 (m), 2961 (m), 2979 (m), 1678 (s), 1508 (s), 1472 (m), 1437 (m), 1312 (m), 1211 (m), 1132 (m), 1102 (m), 959 (m), 844 (m). EM (m/z): 490,00 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 22 (100 mg, 0.27 mmol), DMF (1.0 ml), Et3N (43 µl, 0.31 mmol), reagent BOP (127 mg, 0.29 mmol) and 3-chloro-2-hydrazinopyridine (45 mg, 0.31 mmol) to give the title compound (75 mg, 56%). P.F .: 142-145 ° C. 1H NMR (δ ppm, DMSO-d6, 300 MHz): 9.88 (s at, 1H); 8.42 (s a, 1 H); 8.00 (d, J = 9.6, 2H); 7.30-7.55 (m, 3H); 6.75 (s a, 1 H); 3.05 (s at, 1 H); 2.09 (s at, 1 H); 1.80 (s at, 1 H); 1.40-1.05 (m, 2H); 0.88, 0.86, 0.80 (3s, 9H). IR (cm-1 KBr): 3339 (m), 3269 (m), 2961 (m), 2979 (m), 1678 (s), 1508 (s), 1472 (m), 1437 (m), 1312 ( m), 1211 (m), 1132 (m), 1102 (m), 959 (m), 844 (m). MS (m / z): 490.00 ([M + H] +).

Ejemplo 405 Example 405

N(3)-(Adamantan-1-il)-1-(2,4-difluorofenil)-7,8,8-trimetil-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3carboxamida N (3) - (Adamantan-1-yl) -1- (2,4-difluorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazole -3carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 23 (120 mg,0,36 mmol), DMF (1,0 ml), Et3N (60 µl, 0,43 mmol), reactivo BOP (159 mg,0,36 mmol) y 1-adamantilamina The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 23 (120 mg, 0.36 mmol), DMF (1.0 ml), Et3N (60 µl, 0.43 mmol), reagent BOP (159 mg, 0.36 mmol) and 1-adamantylamine

(54 mg, 0,36 mmol) produjo el compuesto del título (120 mg, 71%). P.F.: 162-165 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,50-7,40 (m, 1H); 7,03-6,93 (m, 2H); 6,59 (s, 1H); 3,21 (d, J = 3,6, 1H); 2,13-2,07 (m, 9H); 1,84-1,63 (m, 7H); 1,37-1,24 (m, 3H); 0,97 (s, 3H); 0,90 (s, 3H); 0,77 (s, 3H). IR (cm-1 KBr): 3299 (m), 2958 (m), 2910 (s), 1652 (s), 1614 (m), 1605 (m), 1548 (s), 1524 (s), 1499 (s), 1454 (m), 1358 (m), 1324 (w), 1269 (m), 1224 (s), 1202 (m), 1143 (m), 1121 (w), 1017 (w), 981 (w), 945 (w), 847 (m). EM (m/z): 466,2 ([M+H]+). (54 mg, 0.36 mmol) produced the title compound (120 mg, 71%). P.F .: 162-165 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.50-7.40 (m, 1H); 7.03-6.93 (m, 2H); 6.59 (s, 1 H); 3.21 (d, J = 3.6, 1H); 2.13-2.07 (m, 9H); 1.84-1.63 (m, 7H); 1.37-1.24 (m, 3H); 0.97 (s, 3 H); 0.90 (s, 3 H); 0.77 (s, 3 H). IR (cm-1 KBr): 3299 (m), 2958 (m), 2910 (s), 1652 (s), 1614 (m), 1605 (m), 1548 (s), 1524 (s), 1499 ( s), 1454 (m), 1358 (m), 1324 (w), 1269 (m), 1224 (s), 1202 (m), 1143 (m), 1121 (w), 1017 (w), 981 ( w), 945 (w), 847 (m). MS (m / z): 466.2 ([M + H] +).

Ejemplo 406 Example 406

N(3)-(1,3,3-Trimetilbiciclo[2.2.1]hept-2-il)-1-(2,4-difluorofenil)-7,8,8-trimetil-4,5,6,7-tetrahidro-1H-4,7-metanoindazol-3-carboxamida N (3) - (1,3,3-Trimethylbicyclo [2.2.1] hept-2-yl) -1- (2,4-difluorophenyl) -7,8,8-trimethyl-4,5,6,7 -tetrahydro-1H-4,7-methanoindazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 23 (120 mg, 0,36 mmol), DMF (1,0 ml), Et3N (120 µl, 0,86 mmol), reactivo BOP (159 mg, 0,36 mmol) y clorhidrato de 1S,2endo-1,3,3-trimetil-biciclo[2.2.1]hept-2-ilamina (68 mg, 0,36 mmol) produjo el compuesto del título (95 mg, 57%). P.F.: 171-173 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,56-7,45 (m, 1H), 7,05-6,90 (m, 2H); 6,89 (d, J = 9,0, 1H); 3,76 (d, J = 9,0, 1H); 3,22 (t, J = 3,9, 1H); 2,19-2,06 (m, 1H); 1,86-1,62 (m, 4H); 1,54-0,74 (m, 24H). IR (cm-1, KBr): 3419 (m), 2954 (s), 2871 (s), 1672 (s), 1612 (m), 1542 (s), 1521 (s), 1493 (s), 1388 (m), 1328 (w), 1318 (w), 1220 (m), 1176 (w), 1117 (s), 1087 (m), 1018 (m), 962(m), 859 (m), 791(w). EM (m/z): 468,3 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 23 (120 mg, 0.36 mmol), DMF (1.0 ml), Et3N (120 µl, 0.86 mmol), reagent BOP (159 mg, 0.36 mmol) and 1S hydrochloride, 2endo-1,3,3-trimethyl-bicyclo [2.2.1] hept-2-ylamine (68 mg, 0.36 mmol) produced the title compound (95 mg, 57%). P.F .: 171-173 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.56-7.45 (m, 1H), 7.05-6.90 (m, 2H); 6.89 (d, J = 9.0, 1H); 3.76 (d, J = 9.0, 1H); 3.22 (t, J = 3.9, 1H); 2.19-2.06 (m, 1 H); 1.86-1.62 (m, 4H); 1.54-0.74 (m, 24H). IR (cm-1, KBr): 3419 (m), 2954 (s), 2871 (s), 1672 (s), 1612 (m), 1542 (s), 1521 (s), 1493 (s), 1388 (m), 1328 (w), 1318 (w), 1220 (m), 1176 (w), 1117 (s), 1087 (m), 1018 (m), 962 (m), 859 (m), 791 (w). MS (m / z): 468.3 ([M + H] +).

Ejemplo 407 Example 407

N(3)-(1-Metil-1-feniletil))-1-(2,4-difluorofenil)-7,8,8-trimetil-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3carboxamida N (3) - (1-Methyl-1-phenylethyl)) - 1- (2,4-difluorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7- methane-indazol-3carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 23 (120 mg, 0,36 mmol), DMF (1,0 ml), Et3N (60 µl, 0,43 mmol), reactivo BOP (159 mg, 0,36 mmol) y 2-fenilprop-2ilamina (48 mg, 0,36 mmol) produjo el compuesto del título (107 mg, 66%). P.F.: 114-117 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,82-7,73 (m, 1H); 7,66-7,54 (m, 2H); 7,39 (d, J = 7,8, 2H); 7,35-7,26 (m, 3H); 7,22-7,15 (m, 1H); 2,95 (d a, J = 2,7, 1H); 2,12-2,05 (m, 1H); 1,85-1,74 (m, 1H); 1,65 (d, J = 9,6, 2H); 1,30-0,95 (m, 1H); 0,90 (s, 3H); 0,85 (s, 3H); 0,71, (s, 3H). IR (cm-1, KBr): 3390 (m), 2973 (m), 2931 (m), 2871 (m), 1605 (w), 1583 (w), 1542 (s), 1526(s), 1494 (s), 1446(m),1392(w),1378(w),1360(w), 1319(w), 1268 (m), 1108 (m), 928 (m),870(m), 766 (m).EM(m/z):450,0 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 23 (120 mg, 0.36 mmol), DMF (1.0 ml), Et3N (60 µl, 0.43 mmol), reagent BOP (159 mg, 0.36 mmol) and 2-phenylprop-2-amine (48 mg, 0.36 mmol) produced the title compound (107 mg, 66%). P.F .: 114-117 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.82-7.73 (m, 1H); 7.66-7.54 (m, 2H); 7.39 (d, J = 7.8, 2H); 7.35-7.26 (m, 3H); 7.22-7.15 (m, 1 H); 2.95 (d a, J = 2.7, 1H); 2.12-2.05 (m, 1 H); 1.85-1.74 (m, 1 H); 1.65 (d, J = 9.6, 2H); 1.30-0.95 (m, 1 H); 0.90 (s, 3 H); 0.85 (s, 3 H); 0.71, (s, 3H). IR (cm-1, KBr): 3390 (m), 2973 (m), 2931 (m), 2871 (m), 1605 (w), 1583 (w), 1542 (s), 1526 (s), 1494 (s), 1446 (m), 1392 (w), 1378 (w), 1360 (w), 1319 (w), 1268 (m), 1108 (m), 928 (m), 870 (m), 766 (m) .EM (m / z): 450.0 ([M + H] +).

Ejemplo 408 Example 408

N(3)-terc-Butil-1-(2,4-difluorofenil)-7,8,8-trimetil-4,5,6,7-tetrahidro-1H-metano-indazol-3-carboxamida N (3) -terc-Butyl-1- (2,4-difluorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-methane-indazol-3-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 23 (100 mg, 0,30 mmol), DMF (1,0 ml), Et3N (46 µl, 0,33 mmol), reactivo BOP (139 mg, 0,31 mmol) y terc-Butilamina (32 mg, 0,45 mmol) produjo el compuesto del título (90 mg, 77%). P.F.: 150-154 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,53-7,43 (m, 1H); 7,03-6,95 (m, 2H); 6,71 (s a, 1H); 3,22 (d, J = 3,9, 1H); 2,13-2,06 (m, 1H); 1,84-1,76 (m, 1H); 1,45 (s, 9H); 1,32-1,24 (m, 2H); 0,97, 0,90, 0,78 (3s, 9H). IR (cm-1, KBr): 3402 (s), 3070 (w), 2966 (s), 2873 (m), 1671 (s), 1613 (m), 1549 (m), 1500 (s), 1472 (w), 1448 (m), 1390 (m), 1364 (m), 1322 (m), 1268 (s), 1219 (m), 1139 (s), 1116 (m), 1090 (m), 1018 (m), 961 (m), 861 (m), 846 (m). EM (m/z): 388,2 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 23 (100 mg, 0.30 mmol), DMF (1.0 ml), Et3N (46 µl, 0.33 mmol), reagent BOP (139 mg, 0.31 mmol) and tert-Butylamine (32 mg, 0.45 mmol) produced the title compound (90 mg, 77%). P.F .: 150-154 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.53-7.43 (m, 1H); 7.03-6.95 (m, 2H); 6.71 (s a, 1 H); 3.22 (d, J = 3.9, 1H); 2.13-2.06 (m, 1 H); 1.84-1.76 (m, 1 H); 1.45 (s, 9H); 1.32-1.24 (m, 2H); 0.97, 0.90, 0.78 (3s, 9H). IR (cm-1, KBr): 3402 (s), 3070 (w), 2966 (s), 2873 (m), 1671 (s), 1613 (m), 1549 (m), 1500 (s), 1472 (w), 1448 (m), 1390 (m), 1364 (m), 1322 (m), 1268 (s), 1219 (m), 1139 (s), 1116 (m), 1090 (m), 1018 (m), 961 (m), 861 (m), 846 (m). MS (m / z): 388.2 ([M + H] +).

Ejemplo 409 Example 409

(2R)-2[1-(2,4-Difluorofenil)-7,8,8-trimetil-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxami-do]-2feniletanoato de metilo: (2R) -2 [1- (2,4-Difluorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxyamido] -2-methylphenylethanoate:

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 23 (300 mg, 0,90 mmol), DMF (4,0 ml), Et3N (284 µl, 0,33 mmol), reactivo BOP (418 mg, 0,94 mmol) y metiléster clorhidrato (R)-(-)-2-fenilglicina (272 mg, 1,35 mmol) produjo el compuesto del título (290 mg, 67%). P.F.: 107-109 ºC.RMN 1H(δ ppm, DMSO-d6, 300 MHz): 8,42-8,36 (m, 1H); 7,78-7,72 (m, 1H); 7,63-7,56 (m, 1H); 7,44-7,28 (m, 6H); 5,64 (d, J = 7,5, 1H); 3,65, 3,64 (2s, 3H); 3,03 (s a, 1H); 2,12-2,02 (m, 1H); 1,84-1,76 (m, 1H); 1,26-1,20 (m, 1H); 1,12-1,00 (m, 1H); 0,91, 0,88 (2s, 6H); 0,74, 0,70 (2s, 3H). EM (m/z): 480,24([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 23 (300 mg, 0.90 mmol), DMF (4.0 ml), Et3N (284 µl, 0.33 mmol), reagent BOP (418 mg, 0.94 mmol) and methyl ester hydrochloride (R) - (-) - 2-phenylglycine (272 mg, 1.35 mmol) produced the title compound (290 mg, 67%). P.F .: 107-109 ° C. RMN 1H (δ ppm, DMSO-d6, 300 MHz): 8.42-8.36 (m, 1H); 7.78-7.72 (m, 1 H); 7.63-7.56 (m, 1 H); 7.44-7.28 (m, 6H); 5.64 (d, J = 7.5, 1H); 3.65, 3.64 (2s, 3H); 3.03 (s at, 1 H); 2.12-2.02 (m, 1 H); 1.84-1.76 (m, 1 H); 1.26-1.20 (m, 1 H); 1.12-1.00 (m, 1 H); 0.91, 0.88 (2s, 6H); 0.74, 0.70 (2s, 3H). MS (m / z): 480.24 ([M + H] +).

Ejemplo 410 Example 410

N(3)-[(1R)-2-Hidroxi-1-feniletil]-1-(2,4-difluorofenil)-7,8,8-trimetil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3carboxamida: N (3) - [(1R) -2-Hydroxy-1-phenylethyl] -1- (2,4-difluorophenyl) -7,8,8-trimethyl) -4,5,6,7-tetrahydro-1H- 4,7-methane-indazol-3carboxamide:

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 192. El Ejemplo 409 (170 mg, 034 mmol), THF (3 ml) y LiBH4 (15 mg, 0,68 mmol) produjo el compuesto del título (120 mg, 75%). P.F.: 68-70 ºC.RMN 1H(δ ppm, CDCl3, 300 MHz): 7,52-7,42 (m, 1H); 7,40-7,30 (m, 6H); 7,04-6,94 (m, 2H); 5,26-5,16 (m, 1H), 4,04-3,94 (m, 2H); 3,20 (d, J = 3,6, 1H); 3,02 (s a, 1H); 2,13-2,06 (m, 1H); 1,84-1,76 (m, 1H); 1,34-1,20 (m, 2H);. 0,98, 0,91 (2s, 6H); 0,79, 0,76 (2s, 3H). EM (m/z): 452,17(M+H+). The title compound was synthesized by a procedure similar to that described for example 192. Example 409 (170 mg, 034 mmol), THF (3 ml) and LiBH4 (15 mg, 0.68 mmol) produced the title compound ( 120 mg, 75%). P.F .: 68-70 ° C. RMN 1H (δ ppm, CDCl3, 300 MHz): 7.52-7.42 (m, 1H); 7.40-7.30 (m, 6H); 7.04-6.94 (m, 2H); 5.26-5.16 (m, 1H), 4.04-3.94 (m, 2H); 3.20 (d, J = 3.6, 1H); 3.02 (s at, 1 H); 2.13-2.06 (m, 1 H); 1.84-1.76 (m, 1 H); 1.34-1.20 (m, 2H) ;. 0.98, 0.91 (2s, 6H); 0.79, 0.76 (2s, 3H). MS (m / z): 452.17 (M + H +).

Ejemplo 411 Example 411

(4S,7R)-N(3)-terc-Butil-1-(2,4-difluorofenil)-7,8,8-trimetil-4,5,6,7-tetrahidro-1H-metano-indazol-3-carboxamida: (4S, 7R) -N (3) -terc-Butyl-1- (2,4-difluorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-methane-indazol-3 -carboxamide:

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 23 (100 mg, 0,30 mmol), DMF (1,0 ml), Et3N (45 µl, 0,33 mmol), reactivo BOP (139 mg, 0,31 mmol) y 2-amino-2metilpropano (47 µl, 0,45 mmol) produjo el compuesto del título (65 mg, 56%). P.F.: 173-175 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,54-7,44 (m, 1H); 7,04-6,94 (m, 2H); 6,73 (s a, 1H); 3,22 (d, J = 3,6, 1H); 2,13-2,06 (m, 1H); 1,851,76 (m, 1H); 1,45 (s, 9H); 1,33-1,24 (m, 2H); 0,97, 0,90, 0,78 (3s, 9H). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 23 (100 mg, 0.30 mmol), DMF (1.0 ml), Et3N (45 µl, 0.33 mmol), reagent BOP (139 mg, 0.31 mmol) and 2-amino-2-methylpropane (47 µl, 0.45 mmol) produced the title compound (65 mg, 56%). P.F .: 173-175 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.54-7.44 (m, 1H); 7.04-6.94 (m, 2H); 6.73 (s a, 1 H); 3.22 (d, J = 3.6, 1H); 2.13-2.06 (m, 1 H); 1,851.76 (m, 1 H); 1.45 (s, 9H); 1.33-1.24 (m, 2H); 0.97, 0.90, 0.78 (3s, 9H).

Ejemplo 501 Example 501

N(12)-Bencil-10-(2,4-diclorofenil)-10,11-diazatetraciclo[6.5.2.02,7,09,13]pentadeca-2,4,6,9(13),11-pentaeno-12carboxamida N (12) -Benzyl-10- (2,4-dichlorophenyl) -10,11-diazatetracycle [6.5.2.02,7,09,13] pentadeca-2,4,6,9 (13), 11-pentaeno- 12 carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 24 (90 mg, 0,23 mmol), DMF (1,0 ml), Et3N (36 µl, 0,26 mmol), reactivo BOP (103 mg, 0,23 mmol) y bencilamina (25 µl, 0,23 mmol) produjo el compuesto del título (40 mg, 33%). P.F.: 164-166 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,60 (s, 1H); 7,40-7,22 (m, 8H); 7,20 -7,00 (m, 4 H); 5,06 (s, 1H); 4,60 (d, J = 6,3, 2H); 4,28 (s, 1H); 2,00-1,70 (m, 4H). EM (m/z): 474,0 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 24 (90 mg, 0.23 mmol), DMF (1.0 ml), Et3N (36 µl, 0.26 mmol), reagent BOP (103 mg, 0.23 mmol) and benzylamine (25 µl, 0.23 mmol) produced the title compound (40 mg, 33%). P.F .: 164-166 ° C. 1 H NMR (δ ppm, CDCl 3, 300 MHz): 7.60 (s, 1 H); 7.40-7.22 (m, 8H); 7.20-7.00 (m, 4 H); 5.06 (s, 1 H); 4.60 (d, J = 6.3, 2H); 4.28 (s, 1 H); 2.00-1.70 (m, 4H). MS (m / z): 474.0 ([M + H] +).

Ejemplo 502 Example 502

N(12)-Piperidino-10-(2,4-diclorofenil)-10,11-diazatetraciclo[6.5.2.02,7.09,13]pentadeca-2,4,6,9(13),11-pentaeno12-carboxamida N (12) -Piperidino-10- (2,4-dichlorophenyl) -10,11-diazatetracycle [6.5.2.02,7.09,13] pentadeca-2,4,6,9 (13), 11-pentaeno12-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 24 (90 mg, 0,23 mmol), DMF. (1,0 ml), Et3N (36 µl, 0,26 mmol), reactivo BOP (105 mg, 0,24 mmol) y 1-aminopiperidina (26 µl, 0,23 mmol) produjo el compuesto del título (40 mg, 37%). P.F.: 164-166 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,61 (s, 1H); 7,44-7,32 (m, 3H); 7,16 -7,05 (m, 4 H); 5,02 (s, 1H); 4,27 (s, 1H); 2,83 (s a, 4H); 2,20-1,70 (m, 8H); 1,41 (s a, 2H). IR (cm-1, KBr): 2934 (s), 2854 (m), 1648 (s), 1551 (m), 1509 (s), 1488 (s), 1441 (s), 1381 (m), 1355 (m), 1342 (m), 1146 (m), 1097 (m), 1070 (m), 898 (m), 818 (w). EM (m/z): 467,0 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 24 (90 mg, 0.23 mmol), DMF. (1.0 ml), Et3N (36 µl, 0.26 mmol), BOP reagent (105 mg, 0.24 mmol) and 1-aminopiperidine (26 µl, 0.23 mmol) produced the title compound (40 mg , 37%). P.F .: 164-166 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.61 (s, 1H); 7.44-7.32 (m, 3H); 7.16 -7.05 (m, 4 H); 5.02 (s, 1 H); 4.27 (s, 1 H); 2.83 (s at, 4H); 2.20-1.70 (m, 8H); 1.41 (s at, 2H). IR (cm-1, KBr): 2934 (s), 2854 (m), 1648 (s), 1551 (m), 1509 (s), 1488 (s), 1441 (s), 1381 (m), 1355 (m), 1342 (m), 1146 (m), 1097 (m), 1070 (m), 898 (m), 818 (w). MS (m / z): 467.0 ([M + H] +).

Ejemplo 503 Example 503

Clorhidrato de N(12)-Piperidino-10-(2,4-diclorofenil)-10,11-diazatetraciclo[6.5.2.02,7.09,13]pentadeca2,4,6,9(13),11-pentaeno-12-carboxamida N (12) -Piperidino-10- (2,4-dichlorophenyl) -10,11-diazatetracyclo [6.5.2.02,7.09,13] pentadeca2,4,6,9 (13), 11-pentaeno-12- hydrochloride carboxamide

Una solución de ejemplo 502 (250 mg, 0,53 mmol) en éter (5 ml) se trató con éter saturado con HCl (10 ml) y se mantuvo a TA durante 1 hora y el sólido precipitado se concentró para producir el compuesto del título (200 mg, 74%). P.F.: 100-110 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,61 (s, 1H); 7,58 (s a, 1H); 7,41 (s, 2H); 7,33 (d, J = 7,5, 1H); 7,15-7,00 (m, 3H); 5,03 (s a, 1H); 4,27 (s a, 1H); 2,86 (s a, 4H); 1,80-1,70 (m, 8H); 1,43 (s a, 2H). An example solution 502 (250 mg, 0.53 mmol) in ether (5 ml) was treated with ether saturated with HCl (10 ml) and maintained at RT for 1 hour and the precipitated solid was concentrated to yield the compound of the titer (200 mg, 74%). P.F .: 100-110 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.61 (s, 1H); 7.58 (s a, 1 H); 7.41 (s, 2H); 7.33 (d, J = 7.5, 1H); 7.15-7.00 (m, 3H); 5.03 (s at, 1 H); 4.27 (s a, 1 H); 2.86 (s at, 4H); 1.80-1.70 (m, 8H); 1.43 (s at, 2H).

Ejemplo 504 Example 504

N(12)-[(N’-Ciclohexil-N’-metil)amino]-10-(2,4-diclorofenil)-10,11-diazatetraciclo[6.5.2.02,7.09,13]penta-deca2,4,6,9(13),11-pentaeno-12-carboxamida N (12) - [(N'-Cyclohexyl-N'-methyl) amino] -10- (2,4-dichlorophenyl) -10,11-diazatetracycle [6.5.2.02,7.09,13] penta-deca2,4, 6.9 (13), 11-pentaeno-12-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 24 (100 mg, 0,26 mmol), DMF (1,0 ml), Et3N (40 µl, 0,29 mmol), reactivo BOP (121 mg, 0,27 mmol) y N-ciclohexil-Nmetil hidrazina (37 mg, 0,29 mmol) para dar el compuesto del título (70 mg, 55%). P.F.: 127-132 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,62 (s, 1H); 7,52 (s a, 1H); 7,42-7,20 (m, 3H); 7,20-7,00 (m, 3H); 5,05 (s, 1H); 4,28 (s, 1H); 2,69 (s, 3H); 2,82-2,55 (m, 1H); 1,96 (s a, 2H); 1,88-1,70 (m, 6H); 1,40-1,00 (m, 6H). IR (cm-1, KBr): 3422 (s), 2930 (s), 2854 (s), 1667 (s), 1508 (s), 1474 (s), 1381 (m), 1354 (m), 1280 (m), 1248 (w), 1134 (m), 1118 (m), 1083 (m), 1012 (m), 815 (m). EM (m/z): 495,1 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 24 (100 mg, 0.26 mmol), DMF (1.0 ml), Et3N (40 µl, 0.29 mmol), reagent BOP (121 mg, 0.27 mmol) and N-cyclohexyl-Nmethyl hydrazine (37 mg, 0.29 mmol) to give the title compound (70 mg, 55%). P.F .: 127-132 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.62 (s, 1H); 7.52 (s a, 1 H); 7.42-7.20 (m, 3H); 7.20-7.00 (m, 3H); 5.05 (s, 1 H); 4.28 (s, 1 H); 2.69 (s, 3 H); 2.82-2.55 (m, 1 H); 1.96 (s at, 2H); 1.88-1.70 (m, 6H); 1.40-1.00 (m, 6H). IR (cm-1, KBr): 3422 (s), 2930 (s), 2854 (s), 1667 (s), 1508 (s), 1474 (s), 1381 (m), 1354 (m), 1280 (m), 1248 (w), 1134 (m), 1118 (m), 1083 (m), 1012 (m), 815 (m). MS (m / z): 495.1 ([M + H] +).

Ejemplo 505 Example 505

N(12)-{N’-[(2,4-Diclorofenil)-N’-metil]amino}-10-(2,4-diclorofenil)-10,11-diazatetraciclo[6,5,2,2,7,09,13] pentadeca2,4,6,9(13),11-pentaeno-12-carboxamida N (12) - {N '- [(2,4-Dichlorophenyl) -N'-methyl] amino} -10- (2,4-dichlorophenyl) -10,11-diazatetracycle [6,5,2,2, 7.09.13] pentadeca2,4,6,9 (13), 11-pentaeno-12-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 24 (100 mg, 0,26 mmol), DMF (1,0 ml), Et3N (40 µl, 0,29 mmol), reactivo BOP (120 mg, 0,27 mmol) y N-(2,4diclorofenil)-N-metilhidrazina (88 mg, 0,46 mmol) para dar el compuesto del título (80 mg, 55%). P.F.: 220-223 ºC. RMN 1H(δ ppm, CDCl3, 300 MHz): 8,82 (s, 1H); 7,61 (d, J = 1,2, 1H); 7,42-7,24 (m, 6 H); 7,15-7,05 (m, 3H); 4,94 (s, 1H), 4,28 (s, 1H); 3,33 (s, 3H); 1,79-1,69 (m, 4H). IR (cm-1, KBr): 3376 (s), 3005 (w), 2964 (m), 2867 (m), 1682 (s), 1546 (m), 1500 s), 1471 (s), 1352 (m), 1271 (m), 1241 (m), 1116 (m), 1100 (m), 811 (m), 759 (m). EM (m/z) 556,9 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 24 (100 mg, 0.26 mmol), DMF (1.0 ml), Et3N (40 µl, 0.29 mmol), reagent BOP (120 mg, 0.27 mmol) and N- (2,4-dichlorophenyl) -N-methylhydrazine (88 mg, 0.46 mmol) to give the title compound (80 mg, 55%). P.F .: 220-223 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 8.82 (s, 1H); 7.61 (d, J = 1.2, 1H); 7.42-7.24 (m, 6 H); 7.15-7.05 (m, 3H); 4.94 (s, 1 H), 4.28 (s, 1 H); 3.33 (s, 3 H); 1.79-1.69 (m, 4H). IR (cm-1, KBr): 3376 (s), 3005 (w), 2964 (m), 2867 (m), 1682 (s), 1546 (m), 1500 s), 1471 (s), 1352 ( m), 1271 (m), 1241 (m), 1116 (m), 1100 (m), 811 (m), 759 (m). MS (m / z) 556.9 ([M + H] +).

Ejemplo 506 Example 506

N(12)-(Adamantan-1il)-10-(2,4-diclorofenil)-10,11-diazatetraciclo-[6.5.2.02,7.09,13]pentadeca-2,4,6,9(13),11pentaeno-12-carboxamida N (12) - (Adamantan-1il) -10- (2,4-dichlorophenyl) -10,11-diazatetracyclo- [6.5.2.02,7.09,13] pentadeca-2,4,6,9 (13), 11pentaeno -12-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 24 (100 mg, 0,26 mmol), DMF (1 ml), Et3N (40 µl, 0,28 mmol), reactivo BOP (121 mg, 0,27 mmol) y 1-adamantilamina (43 mg, 0,28 mmol) produjo el compuesto del título (80 mg, 59%). P.F.: 120-124 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,60 (s, 1H); 7,46-7,31 (m, 3H); 7,20-6,99 (m, 3H); 6,59 (s a, 3H); 5,04(s a, 1H); 4,26 (s a, 1H); 2,12 (s a, 9H); 1,90-1,54 (m, 10H). IR (cm-1, KBr): 3396 (m), 2906 (s), 2849 (s), 1670 (s), 1548 (s), 1537 (s), 1508 (s), 1483 (s), 1457 (m), 1356 (m), 1279 (w), 1167 (m), 1072 (m), 818 (m). EM (m/z): 540,2 (100, [M+Na]+), 518,2 (25, [M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 24 (100 mg, 0.26 mmol), DMF (1 ml), Et3N (40 µl, 0.28 mmol), BOP reagent ( 121 mg, 0.27 mmol) and 1-adamantylamine (43 mg, 0.28 mmol) produced the title compound (80 mg, 59%). P.F .: 120-124 ° C. 1 H NMR (δ ppm, CDCl 3, 300 MHz): 7.60 (s, 1 H); 7.46-7.31 (m, 3H); 7.20-6.99 (m, 3H); 6.59 (s a, 3H); 5.04 (s at, 1 H); 4.26 (s a, 1 H); 2.12 (s a, 9H); 1.90-1.54 (m, 10H). IR (cm-1, KBr): 3396 (m), 2906 (s), 2849 (s), 1670 (s), 1548 (s), 1537 (s), 1508 (s), 1483 (s), 1457 (m), 1356 (m), 1279 (w), 1167 (m), 1072 (m), 818 (m). MS (m / z): 540.2 (100, [M + Na] +), 518.2 (25, [M + H] +).

Ejemplo 507 Example 507

N12-(1,3,3-Trimetilbiciclo[2.2.1]hept-2-il)-10-(2,4-diclorofenil)-10,11-diazatetraciclo[6.5.2.02,7.09,13]pentadeca2(7),3,5,9(13),11-pentaeno-12-carboxamida N12- (1,3,3-Trimethylbicyclo [2.2.1] hept-2-yl) -10- (2,4-dichlorophenyl) -10,11-diazatetracycle [6.5.2.02,7.09,13] pentadeca2 (7) , 3,5,9 (13), 11-pentaeno-12-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 24 (100 mg, 0,26 mmol), DMF (1,0 ml), Et3N (40 µl, 0,28 mmol), reactivo BOP (120 mg, 0,27 mmol) y 1S,2endo-amino1,3,3-trimetil-biciclo[2.2.1]heptano (43 mg, 0,28 mmol) produjo el compuesto del título (95 mg, 70%). P.F.: 82-85 ºC. RMN 1H(δ ppm, CDCl3, 300 MHz): 7,60 (a, s, 1H), 7,43-7,07 (m, 6H); 6,92 (d, J = 7,8, 1H); 5,04 (s a, 1H), 4,29 (s a, 1H); 3,77 (s a, 1H); 1,92-1,58 (m, 8H); 1,42-0,76 (m, 12H). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 24 (100 mg, 0.26 mmol), DMF (1.0 ml), Et3N (40 µl, 0.28 mmol), reagent BOP (120 mg, 0.27 mmol) and 1S, 2endo-amino1,3,3-trimethyl-bicyclo [2.2.1] heptane (43 mg, 0.28 mmol) produced the title compound (95 mg, 70% ). P.F .: 82-85 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.60 (a, s, 1H), 7.43-7.07 (m, 6H); 6.92 (d, J = 7.8, 1H); 5.04 (s at, 1 H), 4.29 (s at, 1 H); 3.77 (s a, 1 H); 1.92-1.58 (m, 8H); 1.42-0.76 (m, 12H).

Ejemplo 508 Example 508

N12-(1-Metil-1-feniletil)-10-(2,4,diclorofenil)-10,11-diazatetraciclo[6.5.2.02,7.09,13]pentadeca-2,4,6,9(13),11pentaeno-12-carboxamida N12- (1-Methyl-1-phenylethyl) -10- (2,4, dichlorophenyl) -10,11-diazatetracyclo [6.5.2.02,7.09,13] pentadeca-2,4,6,9 (13), 11pentaeno -12-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 24 (100 mg, 0,26 mmol), DMF (1,0 ml), Et3N (41 µl, 0,28 mmol), reactivo BOP (120 mg, 0,27 mmol) y α,α-dimetilbencilamina (56 mg, 0,41 mmol) produjo el compuesto del título (70 mg, 53%). P.F.: 190 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,61 (s a, 1H); 7,45-7,05 (m, 12H); 4,98 (s a, 1H); 4,26 (s a, 1H); 1,80 (s, 3H); 1,77 (s, 3H); 1,75-1,58 (m, 4H). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 24 (100 mg, 0.26 mmol), DMF (1.0 ml), Et3N (41 µl, 0.28 mmol), reagent BOP (120 mg, 0.27 mmol) and α, α-dimethylbenzylamine (56 mg, 0.41 mmol) produced the title compound (70 mg, 53%). P.F .: 190 ºC. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.61 (s at, 1H); 7.45-7.05 (m, 12H); 4.98 (s a, 1 H); 4.26 (s a, 1 H); 1.80 (s, 3 H); 1.77 (s, 3 H); 1.75-1.58 (m, 4H).

Ejemplo 509 Example 509

N12-(1-Metil-1-feniletil)-10-(2,4-difluorofenil)-10,11-diazatetraciclo[6.5.2.02,7.09,13]pentadeca-2,4,6,9(13),11pentaeno-12-carboxiazida N12- (1-Methyl-1-phenylethyl) -10- (2,4-difluorophenyl) -10,11-diazatetracyclo [6.5.2.02,7.09,13] pentadeca-2,4,6,9 (13), 11pentaeno -12-carboxiazide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 25 (100 mg, 0,28 mmol), DMF (1,0 ml), Et3N (44 µl, 0,31 mmol), reactivo BOP (131 mg, 0,29 mmol) y α,α-dimetilbencilamina (58 mg, 0,42 mmol) produjo el compuesto del título (78 mg, 58%). P.F.: 175-178 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,64-7,54 (m, 1H); 7,43 (d, J = 7,5, 2H); 7,35-7,02 (m, 10H); 4,98 (s a, 1H); 4,35 (s a, 1H); 1,81, 1,77 (2s, 6H); 1,80-1,68 (m, 4H). IR (cm-1, KBr): 3403 (s), 3077 (m), 2961 (m), 2973 (m), 1665 (s), 1609 (m), 1526 (s), 1493 (s), 1471 (m), 1446 (m), 1383 (w), 1361 (w), 1328 (w), 1269 (m), 1256 (m), 1160 (m), 1146 (m), 1095 (m), 846 (m), 758 (m), 699 (m). EM (m/z): 470,2([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 25 (100 mg, 0.28 mmol), DMF (1.0 ml), Et3N (44 µl, 0.31 mmol), reagent BOP (131 mg, 0.29 mmol) and α, α-dimethylbenzylamine (58 mg, 0.42 mmol) produced the title compound (78 mg, 58%). P.F .: 175-178 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.64-7.54 (m, 1H); 7.43 (d, J = 7.5, 2H); 7.35-7.02 (m, 10H); 4.98 (s a, 1 H); 4.35 (s a, 1 H); 1.81, 1.77 (2s, 6H); 1.80-1.68 (m, 4H). IR (cm-1, KBr): 3403 (s), 3077 (m), 2961 (m), 2973 (m), 1665 (s), 1609 (m), 1526 (s), 1493 (s), 1471 (m), 1446 (m), 1383 (w), 1361 (w), 1328 (w), 1269 (m), 1256 (m), 1160 (m), 1146 (m), 1095 (m), 846 (m), 758 (m), 699 (m). MS (m / z): 470.2 ([M + H] +).

Ejemplo 601 Example 601

N(12)-Bencil-16-(4-clorofenil)-10-(2,4-diclorofenil)-15,17-dioxo-10,11,16triazapentaciclo[6.5.5.02,7.09,13,014,18]octadeca-2,4,6,9(13),11-pentaeno-12-carboxamida N (12) -Benzyl-16- (4-chlorophenyl) -10- (2,4-dichlorophenyl) -15,17-dioxo-10,11,16triazapentacyclo [6.5.5.02,7.09,13,014,18] octadeca-2 , 4,6,9 (13), 11-pentaeno-12-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 26 (100 mg, 0,29 mmol), DMF (1,0 ml), Et3N (49 µl, 0,35 mmol), reactivo BOP (130 mg, 0,29 mmol) y α,α-dimetilbencilamina (47 mg, 0,35 mmol) produjo el compuesto del título (90 mg, 67%). P.F.: 84-87 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,92-7,79 (m, 2H), 7,71-7,61 (m, 1H); 7,41-7,15 (m, 8H); 6,98-6,90 (m, 2H); 4,43 (s a, 1H); 4,36 ( s, 1H); 2,88 (d, J = 7,8, 1H); 2,70 (d, J = 7,5, 1H); 1,66,1,64 (2s, 6H); IR (cm-1, KBr): 3404 (m), 2974 (w), 2933 (w), 2867 (w), 1679 (s), 1608 (w), 1522 (s), 1507 (m), 1447 (m), 1382 (w), 1362 (w), 1347 (w), 1270 (m), 1257 (m), 1209 (m), 1133 (m), 1029 (w), 1006 (w), 965 (m), 847 (m), 786 (w), 761(m). EM (m/z): 456,2 [M+H]+); 338,1 (100). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 26 (100 mg, 0.29 mmol), DMF (1.0 ml), Et3N (49 µl, 0.35 mmol), reagent BOP (130 mg, 0.29 mmol) and α, α-dimethylbenzylamine (47 mg, 0.35 mmol) produced the title compound (90 mg, 67%). P.F .: 84-87 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.92-7.79 (m, 2H), 7.71-7.61 (m, 1H); 7.41-7.15 (m, 8H); 6.98-6.90 (m, 2H); 4.43 (s a, 1 H); 4.36 (s, 1 H); 2.88 (d, J = 7.8, 1H); 2.70 (d, J = 7.5, 1H); 1.66.1.64 (2s, 6H); IR (cm-1, KBr): 3404 (m), 2974 (w), 2933 (w), 2867 (w), 1679 (s), 1608 (w), 1522 (s), 1507 (m), 1447 (m), 1382 (w), 1362 (w), 1347 (w), 1270 (m), 1257 (m), 1209 (m), 1133 (m), 1029 (w), 1006 (w), 965 (m), 847 (m), 786 (w), 761 (m). MS (m / z): 456.2 [M + H] +); 338.1 (100).

Ejemplo 602 Example 602

N(12)-Piperidino-16-(4-clorofenil)-10-(2,4-diclorofenil)-15,17-dioxo-10,11,16-triazapentaciclo[6.5.5.02,7,09,13,014,18]octadeca-2,4,6,9(13),11-pentaeno-12-carboxamida N (12) -Piperidino-16- (4-chlorophenyl) -10- (2,4-dichlorophenyl) -15,17-dioxo-10,11,16-triazapentacyclo [6.5.5.02,7,09,13,014,18 ] octadeca-2,4,6,9 (13), 11-pentaeno-12-carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 26 (100 mg, 0,18 mmol), DMF (1,0 ml), Et3N (30 µl, 0,20 mmol), reactivo BOP (85 mg, 0,19 mmol) y 1-aminopiperidina (22 µl, 0,20 mmol) produjo el compuesto del título (35 mg, 31%). P.F.: 150 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 26 (100 mg, 0.18 mmol), DMF (1.0 ml), Et3N (30 µl, 0.20 mmol), reagent BOP (85 mg, 0.19 mmol) and 1-aminopiperidine (22 µl, 0.20 mmol) produced the title compound (35 mg, 31%). P.F .: 150 ºC. 1H NMR (δ ppm, CDCl3, 300 MHz):

7,66 (s, 1H); 7,60 (s a, 1H); 7,46-7,40 (m, 3H); 7,26 -7,17 (m, 5H); 6,44 (d, J = 8,4, 2H); 5,58 (d, J = 3,3, 1H); 4,81 (d, J = 3,3, 1H); 3,58 (dd, J =8,4, 3,3, 1H); 3,46 (dd, J = 8,1, 3,3, 1H); 2,89-1,20 (m, 10H). IR (cm-1, KBr): EM (m/z): 646,2 ([M+H]+). 7.66 (s, 1 H); 7.60 (s at, 1 H); 7.46-7.40 (m, 3H); 7.26-7.17 (m, 5H); 6.44 (d, J = 8.4, 2H); 5.58 (d, J = 3.3, 1H); 4.81 (d, J = 3.3, 1H); 3.58 (dd, J = 8.4, 3.3, 1H); 3.46 (dd, J = 8.1, 3.3, 1H); 2.89-1.20 (m, 10H). IR (cm-1, KBr): MS (m / z): 646.2 ([M + H] +).

Ejemplo 701 Example 701

N12-Bencil-10-(2,4-difluorofenil)-10,11-diazatetraciclo[6.5.1.02,7,09,13]tetradeca-2,4,6,9(13),11pentaeno-12carboxamida N12-Benzyl-10- (2,4-difluorophenyl) -10,11-diazatetracyclo [6.5.1.02,7,09,13] tetradeca-2,4,6,9 (13), 11pentaeno-12carboxamide

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 27 (100 mg, 0,29 mmol), DMF (1,0 ml), Et3N (49 µl, 0,35 mmol), reactivo BOP (130 mg, 0,29 mmol) y bencilo amina (32 µl, 0,29 mmol) produjo el compuesto del título (90 mg, 71%). P.F.: 65-67 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 8,70 (s a, 1H); 7,85-7,75 (m, 1H); 7,65 (t, J = 9,0, 1H); 7,23-7,30 (m, 8H); 6,95 (d a, J = 2,9, 2H); 4,39-4,47 (m, 4H); 2,89 (d, J = 7,5, 1H); 2,73 (d, J = 7,5, 1H). IR (cm-1, KBr): 3404 (m), 3063 (w), 2974 (w), 2933 (w), 2867 (w), 1679 (s), 1608 (w), 1522 (s), 1507 (s), 1447 (m), 1382 (w), 1362 (w), 1347 (w), 1270 (m), 1257 (m), 1209 (m), 1133 (m), 965 (m), 847 (w), 761 (m). EM (m/z): 428,2 [M+H]+. The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 27 (100 mg, 0.29 mmol), DMF (1.0 ml), Et3N (49 µl, 0.35 mmol), reagent BOP (130 mg, 0.29 mmol) and benzyl amine (32 µl, 0.29 mmol) produced the title compound (90 mg, 71%). P.F .: 65-67 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 8.70 (s at, 1H); 7.85-7.75 (m, 1 H); 7.65 (t, J = 9.0, 1H); 7.23-7.30 (m, 8H); 6.95 (d a, J = 2.9, 2H); 4.39-4.47 (m, 4H); 2.89 (d, J = 7.5, 1H); 2.73 (d, J = 7.5, 1H). IR (cm-1, KBr): 3404 (m), 3063 (w), 2974 (w), 2933 (w), 2867 (w), 1679 (s), 1608 (w), 1522 (s), 1507 (s), 1447 (m), 1382 (w), 1362 (w), 1347 (w), 1270 (m), 1257 (m), 1209 (m), 1133 (m), 965 (m), 847 (w), 761 (m). MS (m / z): 428.2 [M + H] +.

Ejemplo 702 Example 702

N(12)-terc-Butil-10-(2,4-difluorofenil)-10,11-diazatetraciclo[6.5.1.02,7,09,13]tetradeca-2,4,6,9(13),11-pentaeno-12carboxamida: N (12) -terc-Butyl-10- (2,4-difluorophenyl) -10,11-diazatetracycle [6.5.1.02,7,09,13] tetradeca-2,4,6,9 (13), 11- pentaeno-12carboxamide:

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 27 (100 mg, 0,29 mmol), DMF (1,0 ml), Et3N (49 µl, 0,35 mmol), reactivo BOP (143 mg, 0,32 mmol) y 2-amino-2metilpropano (31 µl, 0,29 mmol) produjo el compuesto del título (91 mg, 78%). P.F.: 59 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,72-7,62 (m, 1H); 7,41 (d, J = 5,7, 1H); 7,32-7,26 (m, 1H); 7,07-6,92 (m, 4H); 6,65 (s a, 1H).; 4,62 (s a, 1H); 4,29 (s a, 1H); 2,96 (d, J = 7,5, 1H); 2,82 (d, J = 7,5, 1H); 1,43 (s, 9H). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 27 (100 mg, 0.29 mmol), DMF (1.0 ml), Et3N (49 µl, 0.35 mmol), reagent BOP (143 mg, 0.32 mmol) and 2-amino-2 methylpropane (31 µl, 0.29 mmol) produced the title compound (91 mg, 78%). P.F .: 59 ºC. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.72-7.62 (m, 1H); 7.41 (d, J = 5.7, 1H); 7.32-7.26 (m, 1 H); 7.07-6.92 (m, 4H); 6.65 (s a, 1H) .; 4.62 (s a, 1 H); 4.29 (s a, 1 H); 2.96 (d, J = 7.5, 1H); 2.82 (d, J = 7.5, 1H); 1.43 (s, 9H).

Ejemplo 801 Example 801

N5-(terc-Butil)-3-(2,4-difluorofenil)-3,4-diazatriciclo[5.2.2.02,6]undeca-2(6),4-dien-5-carboxamida: N5- (tert-Butyl) -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5.2.2.02.6] undeca-2 (6), 4-dien-5-carboxamide:

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 28 (100 mg, 0,32 mmol), DMF (1,0 ml), Et3N (54 µl, 0,35 mmol), reactivo BOP (159 mg, 0,36 mmol) y 2-amino-2metilpropano (34 µl, 0,32 mmol) produjo el compuesto del título (96 mg, 81%). P.F.: 105-108 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,62-7,54 (m, 1H); 7,08-6,99 (m, 2H); 6,82 (s a, 1H); 3,83 (s a, 1H); 3,11 (s a, 1H); 1,75 (d, J = 6,6, 4H); 1,52-1,26 (m, 4H); 1,47 (s, 9H). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 28 (100 mg, 0.32 mmol), DMF (1.0 ml), Et3N (54 µl, 0.35 mmol), reagent BOP (159 mg, 0.36 mmol) and 2-amino-2 methylpropane (34 µl, 0.32 mmol) produced the title compound (96 mg, 81%). P.F .: 105-108 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.62-7.54 (m, 1H); 7.08-6.99 (m, 2H); 6.82 (s a, 1 H); 3.83 (s a, 1 H); 3.11 (s a, 1 H); 1.75 (d, J = 6.6, 4H); 1.52-1.26 (m, 4H); 1.47 (s, 9H).

Ejemplo 802 Example 802

N(5)-(terc-Pentil)-3-(2,4-difluorofenil)-3,4-diazatriciclo[5.2.2.02,6]undeca-2(6),4-dien-5-carboxamida: N (5) - (tert-Pentyl) -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5.2.2.02.6] undeca-2 (6), 4-dien-5-carboxamide:

El compuesto del título se sintetizó por un procedimiento similar al descrito para el ejemplo 101. El intermedio 28 (100 mg, 0,32 mmol), DMF (1,0 ml), Et3N (54 µl, 0,39 mmol), reactivo BOP (159 mg, 0,36 mmol) y terc-amil amina (38 µl, 0,32 mmol) produjo el compuesto del título (81 mg, 66%). P.F.: 102-105 ºC. RMN 1H (δ ppm, CDCl3, 300 MHz): 7,66-7,54 (m, 1H); 7,10-6,96 (m, 2H); 6,74 (s a, 1H); 3,82 (s a, 1H); 3,13 (s a, 1H); 1,89-1,70 (m, 6H); 1,42 (s, 6H); 1,48-1,43 (m, 2H); 1,30-1,20 (m, 2H); 0,92 (t, J = 7,2, 3H). EM (m/z): 374,1 ([M+H]+). The title compound was synthesized by a procedure similar to that described for example 101. Intermediate 28 (100 mg, 0.32 mmol), DMF (1.0 ml), Et3N (54 µl, 0.39 mmol), reagent BOP (159 mg, 0.36 mmol) and tert-amyl amine (38 µl, 0.32 mmol) produced the title compound (81 mg, 66%). P.F .: 102-105 ° C. 1H NMR (δ ppm, CDCl3, 300 MHz): 7.66-7.54 (m, 1H); 7.10-6.96 (m, 2H); 6.74 (s a, 1 H); 3.82 (s at, 1 H); 3.13 (s a, 1 H); 1.89-1.70 (m, 6H); 1.42 (s, 6H); 1.48-1.43 (m, 2H); 1.30-1.20 (m, 2H); 0.92 (t, J = 7.2, 3H). MS (m / z): 374.1 ([M + H] +).

Protocolos Protocols

I. Protocolo in vitro para la unión al receptor CB1 de rata usando membrana de cerebro I. In vitro protocol for rat CB1 receptor binding using brain membrane

En este ensayo, se usó [3H]SR141716A (5-(4-clorofenil)-1-(2,4-diclorofenil)-4-metil-N-(1-piperidil)pirazol-3carboxamida) para unirse el receptor CB1 presente en una preparación de membrana de cerebro de rata que puede desplazarse por ligandos no marcados que tienen afinidad por el receptor CB1. In this assay, [3H] SR141716A (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-N- (1-piperidyl) pyrazol-3carboxamide) was used to bind the present CB1 receptor in a rat brain membrane preparation that can be displaced by unlabeled ligands that have affinity for the CB1 receptor.

Este ensayo se realizó de acuerdo con el procedimiento modificado de Thomas y col., 1998 (JPET 285: 285-292). La mezcla de reacción total (250 ml) contenía tampón Tris-BSA (Tris 50 mM, pH 7,4 con BSA al 1,5%) o SR141716A no marcado (1 mM) o muestras de ensayo (1 mM), [3H] SR141716A (2 nM) y 100 mg de membrana de cerebro de rata. La unión no específica se definió por 1 mM de SR141716A. La mezcla de ensayo se incubó a 37 ºC durante 1 hora. Después la reacción se detuvo por filtración rápida al vacío usando una placa microfiltradora Whatman GF/B-96. Se añadió un cóctel de escintilación y los recuentos radiactivos se midieron usando un contador de escintilación Topcount beta. This test was performed according to the modified procedure of Thomas et al., 1998 (JPET 285: 285-292). The total reaction mixture (250 ml) contained Tris-BSA buffer (50 mM Tris, pH 7.4 with 1.5% BSA) or unlabeled SR141716A (1 mM) or test samples (1 mM), [3H ] SR141716A (2 nM) and 100 mg of rat brain membrane. Non-specific binding was defined by 1 mM of SR141716A. The test mixture was incubated at 37 ° C for 1 hour. Then the reaction was stopped by rapid vacuum filtration using a Whatman GF / B-96 microfilter plate. A scintillation cocktail was added and radioactive counts were measured using a Topcount beta scintillation counter.

Se realizaron diluciones de muestras patrón y de ensayo en un tapón de ensayo que contenía etanol o DMSO a una concentración final del 1%. Dilutions of standard and test samples were made in a test plug containing ethanol or DMSO at a final concentration of 1%.

El desplazamiento en porcentaje (%) mediante un ligando de ensayo se calculó comparando los valores unidos específicos. Los resultados del ensayo se muestran en la siguiente Tabla II. The percentage displacement (%) by a test ligand was calculated by comparing the specific bound values. The test results are shown in the following Table II.

II. Protocolo para ensayo in vitro usando membranas de células CHO que expresan hCB1 II. Protocol for in vitro assay using CHO cell membranes expressing hCB1

En este ensayo, se usó [3H]-CP-55,940 ((-)-3-[2-hidroxil-4-(1,1-dimetilheptil)-fenil]-4-[3-hidroxipropil]ciclohexan-1-ol) como radioligando para unirse a receptores CB1 humanos expresados en las membranas de células CHO (la estirpe celular hCB1-CHO se generó internamente) que pueden desplazarse por ligandos no marcados que tienen afinidad por el receptor CB1. In this test, [3 H] -CP-55,940 ((-) - 3- [2-hydroxy-4- (1,1-dimethylheptyl) -phenyl] -4- [3-hydroxypropyl] cyclohexan-1-ol was used ) as radioligand to bind to human CB1 receptors expressed in the CHO cell membranes (the hCB1-CHO cell line was generated internally) that can be displaced by unlabeled ligands that have affinity for the CB1 receptor.

El ensayo se realizó de acuerdo con el procedimiento modificado de Ross y col., 1999 (Br. J. Pharmacol. 128, 735743). La reacción se preparó en un volumen total de 200 µl en placas de filtro PEI (Poli(etileneimina)) (0,2%) previamente revestidas con Millipore GFB (Fibra de Vidrio-B). Se prepararon soluciones madre 1 mM de los compuestos de ensayo en DMSO y se ensayaron a una concentración final de 300 nM. La unión no específica se determinó mediante CP-55, 940 0,5 µM. La mezcla de reacción total contenía, tampón Tris-BSA (Tris 50 mM, MgCl2 5 mM, EDTA 1 mM, pH 7,4 con BSA al 0,1%), CP-55, 940 (0,5 µM) no marcado o muestras de ensayo, [3H]-CP-55, 940 (0,75 nM) y 50 µg de preparación de receptor CB1 humano. La mezcla de ensayo (con o sin el compuesto de ensayo) se incubó a 37 ºC durante 1 hora. La reacción se detuvo por filtración rápida al vacío y la radioactividad en los filtros se midió por recuento de escintilación líquido. Los resultados del ensayo se muestran en la siguiente Tabla The test was performed according to the modified procedure of Ross et al., 1999 (Br. J. Pharmacol. 128, 735743). The reaction was prepared in a total volume of 200 µl in PEI filter plates (Poly (ethyleneimine)) (0.2%) previously coated with Millipore GFB (Fiberglass-B). 1 mM stock solutions of the test compounds in DMSO were prepared and tested at a final concentration of 300 nM. Non-specific binding was determined by CP-55, 940 0.5 µM. The total reaction mixture contained, Tris-BSA buffer (50 mM Tris, 5 mM MgCl2, 1 mM EDTA, pH 7.4 with 0.1% BSA), CP-55, 940 (0.5 µM) unlabeled or test samples, [3H] -CP-55, 940 (0.75 nM) and 50 µg of human CB1 receptor preparation. The test mixture (with or without the test compound) was incubated at 37 ° C for 1 hour. The reaction was stopped by rapid vacuum filtration and the radioactivity in the filters was measured by liquid scintillation count. The test results are shown in the following Table

II. II.

III. Protocolo in vitro para la unión al receptor CB2 de rata usando membrana esplénica III. In vitro protocol for binding to rat CB2 receptor using splenic membrane

En este ensayo se usó [3H]CP55,940 para unirse al receptor CB2 presente en una preparación de membrana esplénica de rata que puede desplazarse por ligandos no marcados que tienen afinidad por el receptor CB2. [3H] CP55,940 was used in this assay to bind to the CB2 receptor present in a rat splenic membrane preparation that can be displaced by unlabeled ligands that have affinity for the CB2 receptor.

El ensayo se realizó de acuerdo con el procedimiento modificado de Rinaldi-Carmona y col., 1998 (JPET 284: 644650). La mezcla de reacción total (250 ml) contenía tampón Tris-BSA (Tris 50 mM, pH 7,4 con BSA al 1,5%) o SR144528 no marcado (N-[(1S)-endo-1,3,3-trimetil biciclo[2.2.1]heptan-2-il]-5-(4-cloro-3-metilfenil)-1-(4-metilbencil)pirazol-3-carboxamida]) (1 mM) o muestras de ensayo (300 nM), [3H]CP55,940 (1 nM) y 100 mg de membrana de cerebro de rata. La unión no específica se definió mediante 1 mM de SR144528. La mezcla de ensayo se incubó a 37 ºC durante 1 hora. Después la reacción se detuvo por filtración rápida al vacío usando una placa microfiltradora Whatman GF/B-96. Se añadió un cóctel de escintilación y se midieron recuentos radiactivos usando un contador de escintilación Topcount beta. The test was performed according to the modified procedure of Rinaldi-Carmona et al., 1998 (JPET 284: 644650). The total reaction mixture (250 ml) contained Tris-BSA buffer (50 mM Tris, pH 7.4 with 1.5% BSA) or unlabeled SR144528 (N - [(1S) -endo-1,3,3 -trimethyl bicyclo [2.2.1] heptan-2-yl] -5- (4-chloro-3-methylphenyl) -1- (4-methylbenzyl) pyrazol-3-carboxamide]) (1 mM) or test samples ( 300 nM), [3H] CP55,940 (1 nM) and 100 mg of rat brain membrane. Non-specific binding was defined by 1 mM of SR144528. The test mixture was incubated at 37 ° C for 1 hour. Then the reaction was stopped by rapid vacuum filtration using a Whatman GF / B-96 microfilter plate. A scintillation cocktail was added and radioactive counts were measured using a Topcount beta scintillation counter.

Se realizaron diluciones de muestras patrón y de ensayo en un tapón de ensayo que contenía etanol o DMSO a una concentración final del 1%. Dilutions of standard and test samples were made in a test plug containing ethanol or DMSO at a final concentration of 1%.

El desplazamiento en porcentaje (%) mediante un ligando de ensayo se calculó comparando los valores unidos específicos. Los resultados del ensayo se muestran en la siguiente Tabla II. The percentage displacement (%) by a test ligand was calculated by comparing the specific bound values. The test results are shown in the following Table II.

IV. Protocolo para ensayo in vitro usando membranas de células CHO que expresan hCB2: IV. Protocol for in vitro assay using CHO cell membranes expressing hCB2:

En este ensayo, se usó [3H]-CP-55,940 como el radioligando para unirse al receptor CB2 humano expresado en las membranas de células CHO (la estirpe celular hCB2-CHO se generó internamente) que puede desplazarse por ligandos no marcados que tienen afinidad por el receptor CB2. In this assay, [3H] -CP-55,940 was used as the radioligand to bind to the human CB2 receptor expressed in the CHO cell membranes (the hCB2-CHO cell line was generated internally) that can be displaced by unlabeled ligands that have affinity by the CB2 receiver.

El ensayo se realizó de acuerdo con el procedimiento modificado de Ross y col., 1999 (Br. J. Pharmacol. 128, 735743). La reacción se preparó en un volumen total de 200 µl en placas de filtro PEI (0,2%) previamente revestidas con Millipore GFB. Se prepararon soluciones madre 1 mM de los compuestos de ensayo en DMSO y se ensayaron a una concentración final de 300 nM. La unión no específica se determinó mediante CP-55, 940 0,5 µM. La mezcla de reacción total contenía, tampón Tris-BSA (Tris 50 mM, MgCl2 5 mM, EDTA 1 mM, pH 7,4 con BSA al 0,1%), CP-55, 940 (0,5 µM) no marcado o muestras de ensayo, [3H]-CP-55, 940 (0,75 nM ) y 25-50 µg de preparación de receptor CB2 humano. La mezcla de ensayo (con o sin el compuesto de ensayo) se incubó a 37 ºC durante 1 hora. La reacción se detuvo por filtración rápida al vacío y la radioactividad en los filtros se midió por recuento de escintilación líquido. The test was performed according to the modified procedure of Ross et al., 1999 (Br. J. Pharmacol. 128, 735743). The reaction was prepared in a total volume of 200 µl in PEI filter plates (0.2%) previously coated with Millipore GFB. 1 mM stock solutions of the test compounds in DMSO were prepared and tested at a final concentration of 300 nM. Non-specific binding was determined by CP-55, 940 0.5 µM. The total reaction mixture contained, Tris-BSA buffer (50 mM Tris, 5 mM MgCl2, 1 mM EDTA, pH 7.4 with 0.1% BSA), CP-55, 940 (0.5 µM) unlabeled or test samples, [3H] -CP-55, 940 (0.75 nM) and 25-50 µg of human CB2 receptor preparation. The test mixture (with or without the test compound) was incubated at 37 ° C for 1 hour. The reaction was stopped by rapid vacuum filtration and the radioactivity in the filters was measured by liquid scintillation count.

El desplazamiento en porcentaje (%) mediante un ligando de ensayo se calculó comparando los valores unidos específicos. Los resultados del ensayo se muestran en la siguiente Tabla II. The percentage displacement (%) by a test ligand was calculated by comparing the specific bound values. The test results are shown in the following Table II.

V. Modelo de Hiperalgesia Neuropática – Ligamiento Parcial del Nervio Ciático (modelo de Seltzer) V. Model of Neuropathic Hyperalgesia - Partial Ligation of the Sciatic Nerve (Seltzer Model)

Este protocolo se realizó con el compuesto del Ejemplo 294 a 0,01, 0,1, 0,3 y 1 mg/kg (I.P.) y gabapentina a 100 mg/kg (I.P.) para evaluar la capacidad del compuesto del Ejemplo 294 para reducir la hiperalgesia neuropática. El procedimiento de Seltzer también se describe en líneas generales en Seltzer y col., Pain 1990, 43: 205-18. This protocol was performed with the compound of Example 294 at 0.01, 0.1, 0.3 and 1 mg / kg (IP) and gabapentin at 100 mg / kg (IP) to assess the ability of the compound of Example 294 to reduce neuropathic hyperalgesia. The Seltzer procedure is also described in general in Seltzer et al., Pain 1990, 43: 205-18.

1. one.

Las ratas se anestesiaron usando ketamina/xilacina (40 / 5 mg/kg/ml, i.p.). Después de inducir la anestesia, el muslo izquierdo se rasuró y se limpió. The rats were anesthetized using ketamine / xylazine (40/5 mg / kg / ml, i.p.). After inducing anesthesia, the left thigh was shaved and cleaned.

2. 2.

El nervio ciático izquierdo se expuso a nivel de la mitad del muslo mediante una pequeña incisión. The left sciatic nerve was exposed at mid-thigh level through a small incision.

3. 3.

El nervio se liberó de la adhesión del tejido muscular. The nerve was released from adhesion of muscle tissue.

4. Four.

La mitad des espesor del nervio se ligó estrechamente justo después de la bifurcación del nervio ciático Half of the nerve thickness was tightly ligated just after the bifurcation of the sciatic nerve

5 5

15 fifteen

25 25

35 35

45 Four. Five

común usando suturas de seda 7,0. common using silk sutures 7.0.

5. 5.

La herida se cerró con suturas en músculo y piel y se aplicó povidona. The wound was closed with sutures in muscle and skin and povidone was applied.

6. 6.

Se dejó que los animales se recuperasen durante 12 a 15 días después del ligamiento. The animals were allowed to recover for 12 to 15 days after ligation.

7. 7.

Se examinó la hiperalgesia mecánica en el modelo de dolor neuropático en rata, usando la técnica de presión de la pata (Ugo Basile Analgesymeter, Nº Cat. 37215, Comerio, Italia). Mechanical hyperalgesia was examined in the rat neuropathic pain model, using the leg pressure technique (Ugo Basile Analgesymeter, Cat. No. 37215, Comerio, Italy).

8. 8.

Se registraron umbrales de retirada de la pata para las patas traseras ipsilaterales y contralaterales antes (predosis) y 0,5 y 1 hora después de la administración del fármaco o vehículo (postdosis). Paw withdrawal thresholds were recorded for ipsilateral and contralateral hind legs before (predose) and 0.5 and 1 hour after drug or vehicle administration (postdose).

9. 9.

El límite se estableció a una presión de 150 g y el punto final se tomó como retirada de la pata o vocalización. The limit was set at a pressure of 150 g and the end point was taken as leg withdrawal or vocalization.

Análisis de Datos: Analysis of data:

Los valores umbral de latencia de retirada (sin tratar, predosis y postdosis) se representan como media ± ETM. Véase Walker KM, Urban LA, Medhurst SJ, Patel S, Panesar M, Fox AJ and Mcintyre P., "The VR1 antagonist capsazepine reverses mechanical hyperalgesia in models of inflammatory and neuropathic pain", J. Pharmacol. Expt. Ther. 304: 56-62, 2003. El porcentaje inverso de hiperalgesia mecánica neuropática se calculó a partir de los valores umbral de latencia de retirada de acuerdo con la siguiente fórmula: The withdrawal latency threshold values (untreated, predose and postdose) are represented as mean ± SEM. See Walker KM, Urban LA, Medhurst SJ, Patel S, Panesar M, Fox AJ and Mcintyre P., "The VR1 antagonist capsazepine reverses mechanical hyperalgesia in models of inflammatory and neuropathic pain", J. Pharmacol. Expt Ther. 304: 56-62, 2003. The inverse percentage of neuropathic mechanical hyperalgesia was calculated from the withdrawal latency threshold values according to the following formula:

Postdosis ipsilateral – Predosis ipsilateral % Inverso = X 100 Predosis contralateral – Predosis ipsilateral Ipsilateral postdose - ipsilateral predose% Inverse = X 100 Contralateral predosis - ipsilateral predose

Se realizaron análisis estadísticos de los datos sobre los valores inversos en porcentaje mediante ANOVA de una vía seguido por el ensayo de Tukey después de esto, usando el soporte lógico GraphPad Prism. Statistical analyzes of the data on the inverse values in percentage were performed using one-way ANOVA followed by the Tukey test after this, using the GraphPad Prism software.

Los resultados se muestran en la Figura 1. En este modelo, 1 mg/kg del compuesto del Ejemplo 294 invirtió significativamente la hiperalgesia neuropática. The results are shown in Figure 1. In this model, 1 mg / kg of the compound of Example 294 significantly reversed neuropathic hyperalgesia.

VI. Lesión por Constricción Crónica (LCC) con Respecto al Modelo del Nervio Ciático (Modelo LCC) SAW. Chronic Constriction Injury (LCC) Regarding the Sciatic Nerve Model (LCC Model)

Este protocolo se realizó con el compuesto del Ejemplo 294 a 0,1 mg/kg (p.o.) y gabapentina a 100 mg/kg (i. p.) para evaluar la capacidad el compuesto del Ejemplo 294 para reducir la hiperalgesia neuropática. Este procedimiento se describe también en líneas generales en Miletic G y Miletic V, "Long-term changes in sciatic-evoked A-fiber dorsal horn field potentials accompany loose ligation of the sciatic nerve in rats," Pain 84: 353-359, 2000. This protocol was performed with the compound of Example 294 at 0.1 mg / kg (p.o.) and gabapentin at 100 mg / kg (i. P.) To assess the ability of the compound of Example 294 to reduce neuropathic hyperalgesia. This procedure is also described in general in Miletic G and Miletic V, "Long-term changes in sciatic-evoked A-fiber dorsal horn field potentials accompany loose ligation of the sciatic nerve in rats," Pain 84: 353-359, 2000 .

1. one.

Las ratas se anestesiaron usando ketamina/xilacina (40 / 5 mg/kg/ml, i.p.). Después de inducir la anestesia, el muslo izquierdo se rasuró y se limpió. The rats were anesthetized using ketamine / xylazine (40/5 mg / kg / ml, i.p.). After inducing anesthesia, the left thigh was shaved and cleaned.

2. 2.

El nervio ciático izquierdo se expuso a nivel de la mitad del muslo mediante una pequeña incisión. The left sciatic nerve was exposed at mid-thigh level through a small incision.

3. 3.

El nervio se liberó de la adhesión del tejido muscular. The nerve was released from adhesion of muscle tissue.

4. Four.

Se colocaron cuatro ligamientos laxos de hilo de sutura crómico Ethicon 4-0 (Johnson & Johnson) en un espacio de 1 mm alrededor del nervio después de la bifurcación del nervio ciático común. Four lax ligations of Ethicon 4-0 chromic suture thread (Johnson & Johnson) were placed in a 1 mm space around the nerve after the bifurcation of the common sciatic nerve.

5. 5.

La herida se cerró con suturas en músculo y piel y se aplicó povidona. The wound was closed with sutures in muscle and skin and povidone was applied.

6. 6.

Los animales se usaron para el experimento 7 días después del ligamiento. Animals were used for the experiment 7 days after ligation.

7. 7.

Se examinó la hiperalgesia mecánica en el modelo de dolor neuropático en rata, usando la técnica de presión de la pata (Ugo Basile Analgesymeter, Cat. No. 37215, Comerio, Italia). Mechanical hyperalgesia was examined in the rat neuropathic pain model, using the paw pressure technique (Ugo Basile Analgesymeter, Cat. No. 37215, Comerio, Italy).

8. 8.

Se registraron umbrales de retirada de la pata para las patas traseras ipsilaterales y contralaterales antes (predosis) y 0,5 y 1 hora después de la administración del fármaco o vehículo (postdosis). Paw withdrawal thresholds were recorded for ipsilateral and contralateral hind legs before (predose) and 0.5 and 1 hour after drug or vehicle administration (postdose).

9. 9.

El límite se estableció a una presión de 150 g y el punto final se tomó como retirada de la pata o vocalización. Los análisis de los datos se realizaron como se describe en el protocolo V. Los resultados se muestran en la Figura 2. The limit was set at a pressure of 150 g and the end point was taken as leg withdrawal or vocalization. Data analyzes were performed as described in protocol V. The results are shown in Figure 2.

VII. Ensayo de Analgesia de Sacudida de la Cola en Ratones VII. Tail Shake Analgesia Assay in Mice

Se midió la latencia de sacudida de la cola (basal) en ratones sin tratamiento previo a 55 ºC tratados con vehículo, WIN 55212-2 (un agonista del receptor CB1) (3 mg/kg i.p.) o Ejemplo 294 (0,3, 1, ó 3 mg/kg i.p.) usando un baño con agua (Julabo, Alemania). Véase Murielle R., Barth F., Congy C., Martinez S., Oustric D., Perio A., Poncelet M., Maruani J., Arnone M., Finance O., Soubrie P., and Le’Fur G., "SR147778 (5-(4-Bromophenyl)-1-(2,4dichlorophenyl)-4-ethyl-N-(1-piperidinyl)-1H-pyrazole-3-carboxam-ide), a New Potent and Selective Antagonist of the CB1 Cannabinoid Receptor:Biochemical and Pharmacological Characterization,"J. Pharmacol. Exp. Ther., 310: 905914, 2004. Se administró a los ratones una inyección de vehículo por vía intraperitoneal (i. p.), fármaco convencional Tail shake latency (baseline) was measured in mice without prior treatment at 55 ° C treated with vehicle, WIN 55212-2 (a CB1 receptor agonist) (3 mg / kg ip) or Example 294 (0.3, 1, or 3 mg / kg ip) using a water bath (Julabo, Germany). See Murielle R., Barth F., Congy C., Martinez S., Oustric D., Perio A., Poncelet M., Maruani J., Arnone M., Finance O., Soubrie P., and Le'Fur G ., "SR147778 (5- (4-Bromophenyl) -1- (2,4dichlorophenyl) -4-ethyl-N- (1-piperidinyl) -1H-pyrazole-3-carboxam-ide), to New Potent and Selective Antagonist of the CB1 Cannabinoid Receptor: Biochemical and Pharmacological Characterization, "J. Pharmacol Exp. Ther., 310: 905914, 2004. The mice were given a vehicle injection intraperitoneally (i. P.), A conventional drug

o de ensayo. La analgesia se evaluó midiendo la latencia de la sacudida de la cola (reacción) 1, 3, 6, 12 y 18 horas después de la dosificación. El límite de latencia se estableció a 10 segundos y el punto final se tomó como respuesta de sacudida de la cola. or trial. Analgesia was evaluated by measuring the latency of the tail shake (reaction) 1, 3, 6, 12 and 18 hours after dosing. The latency limit was set to 10 seconds and the end point was taken as a tail shake response.

Análisis de los Datos Data analysis

Los valores de latencia de sacudida de la cola (basal y reacción) se representan como media ± ETM. La analgesia máxima (% MPE) se calculó de acuerdo con la siguiente fórmula: The values of tail shake latency (baseline and reaction) are represented as mean ± SEM. Maximum analgesia (% MPE) was calculated according to the following formula:

5 5

10 10

15 fifteen

20 twenty

25 25

30 30

35 35

40 40

45 Four. Five

(Latencia de reacción – Latencia basal) % de efecto analgésico máximo posible = X 100 (Latencia del límite – Latencia basal) (Reaction latency - Basal latency)% of maximum possible analgesic effect = X 100 (Limit latency - Basal latency)

Los análisis de los datos se realizaron sobre los valores de MPE en porcentaje mediante ANOVA de una vía seguido por el ensayo de Tukey después de esto. Los resultados se muestran en la Figura 3. Data analyzes were performed on the MPE values in percentage by one-way ANOVA followed by the Tukey test after this. The results are shown in Figure 3.

VIII. Protocolo para el Ensayo de unión a GTPγS (ensayo funcional de CB1 en membrana de cerebelo de rata). VIII. Protocol for the GTPγS binding assay (functional test of CB1 in rat cerebellum membrane).

En este ensayo de unión a GTPγS, se determinó la unión total, basal y no específica. Véase Griffin G., Atkinson P. J., Showalter V. M., Martin B. R. and Abood M. E., "Evaluation of cannabinoid receptor agonists and antagonists using the Guanosine-5’-O-(3-(35S)thio)-triphosphate binding assay in rat cerebellar membranes," J Pharmacol Exp Ther 285: 553-560, 1998. Se usaron tres pocillos para la unión total, tres pocillos para la unión basal y tres pocillos para la unión no específica a una concentración de radioligando de 0,2 nM. La unión basal se definió mediante GDP (difosfato de Guanosina) 50 µM y la unión no específica se definió mediante GTPγS no marcada 10 µM. Se añadieron 10 µg de membrana de cerebelo de rata, 50 µM de GDP, WIN-55212-2 o compuesto de ensayo (1 µMo 300 nM), 10 µM de GTPγS, y 0,2 nM de [35S]GTPγS a una placa de 96 pocillos y el volumen final de la mezcla de reacción se preparó con tampón GTPγS (Tris 50 mM, MgCl2 anhidro 3 mM, EGTA 0,2 mM y NaCl 100 mM pH 7,4) hasta 200 µl. Las placas se incubaron a 30 ºC durante 1 hora. Después la reacción se detuvo por filtración usando una placa microfiltradora Whatman GF/B-96. Se realizaron tres lavados usando Tris-HCl. La radioactividad unida a la membrana del cerebro se retuvo sobre los discos de filtro a los que se añadió líquido de escintilación (Microscint PS). Después las placas se leyeron para realizar recuentos radiactivos usando un Contador de Escintilación Beta Líquido (Packard Instruments, IL, Estados Unidos). In this GTPγS binding assay, total, basal and non-specific binding was determined. See Griffin G., Atkinson PJ, Showalter VM, Martin BR and Abood ME, "Evaluation of cannabinoid receptor agonists and antagonists using the Guanosine-5'-O- (3- (35S) thio) -triphosphate binding assay in rat cerebellar membranes , "J Pharmacol Exp Ther 285: 553-560, 1998. Three wells were used for total binding, three wells for basal binding and three wells for non-specific binding at a radioligand concentration of 0.2 nM. Basal binding was defined by 50 µM GDP (Guanosine Diphosphate) and non-specific binding was defined by 10 µM unlabeled GTPγS. 10 µg of rat cerebellum membrane, 50 µM of GDP, WIN-55212-2 or test compound (1 µMo 300 nM), 10 µM of GTPγS, and 0.2 nM of [35S] GTPγS were added to a plate 96-well and the final volume of the reaction mixture was prepared with GTPγS buffer (50 mM Tris, 3 mM anhydrous MgCl2, 0.2 mM EGTA and 100 mM NaCl pH 7.4) up to 200 µl. The plates were incubated at 30 ° C for 1 hour. Then the reaction was stopped by filtration using a Whatman GF / B-96 microfilter plate. Three washes were performed using Tris-HCl. The membrane-bound radioactivity of the brain was retained on the filter discs to which scintillation fluid (Microscint PS) was added. The plates were then read to perform radioactive counts using a Beta Liquid Scintillation Counter (Packard Instruments, IL, United States).

La membrana de cerebelo de cerebro de rata se preparó de la siguiente manera: The rat brain cerebellum membrane was prepared as follows:

1. one.

La rata se sacrificó, se extirpó todo el cerebro y el cerebelo se separó, lo más rápido como fuera posible, y se conservó en hielo. The rat was sacrificed, the entire brain was excised and the cerebellum separated, as quickly as possible, and preserved on ice.

2. 2.

Se pesó el cerebelo y se homogeneizó en 30 ml de tampón de homogeneización (Tris-HCl 50 mM que contenía EDTA 1 mM y sacarosa al 5%, pH 7,5) usando un homogeneizador en frío. The cerebellum was weighed and homogenized in 30 ml of homogenization buffer (50 mM Tris-HCl containing 1 mM EDTA and 5% sucrose, pH 7.5) using a cold homogenizer.

3. 3.

Se centrifugó el cerebelo homogeneizado a 18000 rpm (38000 g) durante 15 minutos a 4 ºC. The homogenized cerebellum was centrifuged at 18,000 rpm (38,000 g) for 15 minutes at 4 ° C.

4. Four.

Se resuspendió el sedimento en 5 ml de Tris-HCl 50 mM que contenía EDTA 1 mM y se conservó en hielo durante 30 minutos. The pellet was resuspended in 5 ml of 50 mM Tris-HCl containing 1 mM EDTA and stored on ice for 30 minutes.

5. 5.

Para asegurar una suspensión uniforme, la membrana se hizo pasar a través de una jeringa con insulina. To ensure a uniform suspension, the membrane was passed through a syringe with insulin.

6. 6.

La membrana se centrifugó a 18000 rpm a 4 ºC durante 20 minutos. The membrane was centrifuged at 18000 rpm at 4 ° C for 20 minutes.

7. 7.

El sedimento se reconstituyó en 3 ml de tampón GTPγS y se calculó la proteína mediante el ensayo BCA y se conservó la membrana en alícuotas de 1000 µg de proteína. The pellet was reconstituted in 3 ml of GTPγS buffer and the protein was calculated by the BCA assay and the membrane was stored in 1000 µg aliquots of protein.

Ensayo de exploración de la actividad agonista y antagonista de CB1 CB1 agonist and antagonist activity screening assay

Los compuestos del ensayo se exploraron a una concentración final de 1 µM o 300 nM en ausencia y presencia de 1 µM de WIN 55,212-2 de la misma manera que se describe en el ensayo de unión a GTPγS. The test compounds were screened at a final concentration of 1 µM or 300 nM in the absence and presence of 1 µM of WIN 55,212-2 in the same manner as described in the GTPγS binding assay.

Un antagonista estimulará la unión a GTPγS sobre la basal. An antagonist will stimulate GTPγS binding at baseline.

Un antagonista inhibirá WIN-55212-2 (agonista de CB1) e inducirá la estimulación de la unión a GTPγS sin modificar significativamente la unión basal. An antagonist will inhibit WIN-55212-2 (CB1 agonist) and induce stimulation of GTPγS binding without significantly modifying basal binding.

Un agonista inverso disminuirá la unión a GTPγS basal y/o producirá una inhibición superior al 100% de la estimulación inducida por el agonista (WIN-55212-2). A reverse agonist will decrease baseline GTPγS binding and / or produce an inhibition greater than 100% of the agonist-induced stimulation (WIN-55212-2).

Normalmente un agonista parcial solo produce estimulación parcial sobre la basal y también inhibe parcialmente la estimulación de la unión a GTPγS inducida por el agonista (WIN-55212-2). Normally a partial agonist only produces partial stimulation on the baseline and also partially inhibits the stimulation of agonist-induced GTPγS binding (WIN-55212-2).

Análisis de los Datos: Data analysis:

Se calculó la estimulación en porcentaje de la unión a GTPγS por cada compuesto del ensayo a una concentración de 1 µM o 300 nM en ausencia y presencia de WIN 55,212-2, 1 µM comparándola con los valores basales específicos unidos (Unión basal – Unión no específica). The percentage stimulation of GTPγS binding for each test compound at a concentration of 1 µM or 300 nM in the absence and presence of WIN 55,212-2, 1 µM was calculated by comparing it with the specific baseline values bound (Basal Union - Non-Union specific).

Los resultados se muestran en la siguiente Tabla III. The results are shown in the following Table III.

IX. Ensayo para Determinar la Actividad Agonista y Antagonista con Respecto a los Receptores CB1 y CB2 IX. Test to Determine Agonist and Antagonist Activity Regarding CB1 and CB2 Receptors

1. Antagonismo de los receptores CB1/ CB2 expresados en células CHO. 1. CB1 / CB2 receptor antagonism expressed in CHO cells.

Se cultivaron células h-CB1/CHO o h-CB2/CHO en medio DMEM HAM F12 (Sigma) con SBF al 10% (Hyclone), solución de penicilina-estreptomicina al 1% y 400 µg/ml de G418 (Sigma). Se sembraron 5000 células por pocillo en una placa de 96 pocillos y se incubaron durante 24 horas a 37 ºC en CO2 al 5%. El día del ensayo, las células se lavaron con tampón Krebs caliente que contenía BSA sin ácidos grasos (SAG) al 0,1% (Sigma) y se resuspendieron 5 en el mismo tampón que contenía IBMX 1 mM. A las células se añadió antagonista de ensayo o compuesto de referencia (AM 251 (1-(2,4-diclorofenil)-5-(4-yodofenil)-4-metil-N-(1-piperidil)pirazol-3-carboxamida) para CB1 y SR 144528 para CB2) diluido en tampón BSASAG + IBMX + Krebs y se incubó durante 10 minutos a temperatura ambiente. A las células se añadió CP 55,940 (concentración final 30 nM para ensayar CB1 y 10 nM del mismo para ensayar CB2) seguido de forscolina (concentración final 10 µM) y se incubó durante 30 minutos a temperatura H-CB1 / CHO or h-CB2 / CHO cells were cultured in DMEM HAM F12 medium (Sigma) with 10% SBF (Hyclone), 1% penicillin-streptomycin solution and 400 µg / ml G418 (Sigma). 5000 cells were seeded per well in a 96-well plate and incubated for 24 hours at 37 ° C in 5% CO2. On the day of the assay, the cells were washed with hot Krebs buffer containing 0.1% BSA without fatty acids (SAG) (Sigma) and 5 were resuspended in the same buffer containing 1 mM IBMX. To the cells was added test antagonist or reference compound (AM 251 (1- (2,4-dichlorophenyl) -5- (4-iodophenyl) -4-methyl-N- (1-piperidyl) pyrazol-3-carboxamide ) for CB1 and SR 144528 for CB2) diluted in BSASAG + IBMX + Krebs buffer and incubated for 10 minutes at room temperature. To the cells was added CP 55,940 (final concentration 30 nM to test CB1 and 10 nM thereof to test CB2) followed by forscolin (final concentration 10 µM) and incubated for 30 minutes at temperature

10 ambiente. Al final de la incubación, se realizó la lisis de las células usando reactivo para lisis a partir de un kit de cálculo de AMPc y el AMPc se cuantificó mediante el procedimiento quimioluminiscente descrito en las instrucciones del fabricante (Discovery RX). Los valores de CE50 se calcularon a partir de curvas de respuesta a la dosis por análisis de regresión no lineal usando el soporte lógico PRISM. 10 environment. At the end of the incubation, lysis of the cells was performed using lysis reagent from a cAMP calculation kit and the cAMP was quantified by the chemiluminescent procedure described in the manufacturer's instructions (Discovery RX). The EC50 values were calculated from dose response curves by nonlinear regression analysis using the PRISM software.

2. Agonismo de los receptores CB1/ CB2 expresados en células CHO 2. Agonism of CB1 / CB2 receptors expressed in CHO cells

15 Se cultivaron células h-CB1/CHO o h-CB2/CHO en medio DMEM HAM F12 (Sigma) con SBF al 10% (Hyclone), solución de penicilina-estreptomicina al 1% y 400 µg/ml de G418 (Sigma). Se sembraron 5000 células por pocillo en una placa de 96 pocillos y se incubaron durante 24 horas a 37 ºC en CO2 al 5%. El día del ensayo, las células se lavaron con tampón Krebs caliente que contenía BSA sin ácidos grasos (SAG) al 0,1% (Sigma) y se resuspendieron en el mismo tampón que contenía IBMX 1 mM. A las células se añadió compuesto de ensayo o CP 55,940 como un 15 h-CB1 / CHO or h-CB2 / CHO cells were cultured in DMEM HAM F12 medium (Sigma) with 10% SBF (Hyclone), 1% penicillin-streptomycin solution and 400 µg / ml G418 (Sigma) . 5000 cells were seeded per well in a 96-well plate and incubated for 24 hours at 37 ° C in 5% CO2. On the day of the assay, the cells were washed with hot Krebs buffer containing 0.1% BSA without fatty acids (SAG) (Sigma) and resuspended in the same buffer containing 1 mM IBMX. To the cells was added test compound or CP 55,940 as a

20 compuesto de referencia (concentración final 30 nM para ensayar CB1 y 10 nM del mismo para ensayar CB2) diluido en tampón FFB + IBMX + Krebs seguido de forscolina (concentración final 10 µM) y se incubó durante 30 minutos a temperatura ambiente. Al final de la incubación, se realizó la lisis de las células usando reactivo para lisis a partir de un kit de cálculo de AMPc y el AMPc se cuantificó mediante el procedimiento quimioluminiscente descrito en las instrucciones del fabricante (Discovery RX). Los valores de CE50 se calcularon a partir de curvas de respuesta a la Reference compound (final concentration 30 nM to test CB1 and 10 nM thereof to test CB2) diluted in FFB + IBMX + Krebs buffer followed by forscolin (final concentration 10 µM) and incubated for 30 minutes at room temperature. At the end of the incubation, lysis of the cells was performed using lysis reagent from a cAMP calculation kit and the cAMP was quantified by the chemiluminescent procedure described in the manufacturer's instructions (Discovery RX). The EC50 values were calculated from response curves to the

25 dosis por análisis de regresión no lineal usando el soporte lógico PRISM. 25 doses per non-linear regression analysis using PRISM software.

Los resultados se muestran en la siguiente Tabla IV. The results are shown in the following Table IV.

Tabla II (cont.) (cont.) (cont.) (cont.) (cont.) (cont.) (cont.) Tabla-III (cont.) Table II (cont.) (Cont.) (Cont.) (Cont.) (Cont.) (Cont.) (Cont.) Table-III (cont.)

Ejemplo Nº Example No.

% de desplazamiento % displacement

Protocolo I Protocol I

Protocolo II Protocolo III Protocolo IV Protocol II Protocol III Protocol IV

101 101

28,8 -5,75 - 0 28.8 -5.75 - 0

102 102

27,3 18,56 - 0,74 27.3 18.56 - 0.74

103 103

22,2 0 - 6,99 22.2 0 - 6.99

104 104

- 5,41 - 20,24 - 5.41 - 20.24

105 105

- 15,03 - 22,35 - 15.03 - 22.35

106 106

78,6 15,07 - 75,06 78.6 15.07 - 75.06

107 107

97,4 82,49@1 - - 97.4 82.49 @ 1 - -

108 108

82,5 23,19 - 37,15 82.5 23.19 - 37.15

109 109

- 8,36 - 63,05 - 8.36 - 63.05

110 110

- 37,69 - 60,7 - 37.69 - 60.7

111 111

110,6 32,19 - - 110.6 32.19 - -

112 112

59,9 25,76 - - 59.9 25.76 - -

113 113

55,9 27,70 - 17,02 55.9 27.70 - 17.02

114 114

- 25,27 - 31,67 - 25.27 - 31.67

115 115

- 39,62 - - - 39.62 - -

116 116

24,9 1,85 - - 24.9 1.85 - -

Ejemplo Nº Example No.

% de desplazamiento % displacement

Protocolo I Protocol I

Protocolo II Protocolo III Protocolo IV Protocol II Protocol III Protocol IV

117 117

- 80,08 59,8 - - 80.08 59.8 -

118 118

- 45,43 - 61,23 - 45.43 - 61.23

119 119

- 89,21 85,2 - - 89.21 85.2 -

120 120

30,4 15,43 - 9,18 30.4 15.43 - 9.18

121 121

65,4 3,01 - 29,8 65.4 3.01 - 29.8

122* 122 *

66,4 80,08 - - 66.4 80.08 - -

123 123

89,0 - - 47,63 89.0 - - 47.63

124 124

80,1 66,41 - - 80.1 66.41 - -

125 125

52,7 22,07 - 5,04 52.7 22.07 - 5.04

126 126

118,0 - - - 118.0 - - -

127 127

85,3 - - - 85.3 - - -

128 128

83 37,28 - - 83 37.28 - -

129 129

65,2 19,78 - 62,85 65.2 19.78 - 62.85

130 130

60,6 12,32 - - 60.6 12.32 - -

131 131

85,2 22,78 - 10,84 85.2 22.78 - 10.84

132 132

64,5 16,09 - 3,94 64.5 16.09 - 3.94

133 133

59,7 65,9@1 - - 59.7 65.9 @ 1 - -

134 134

89,6 63,68 - - 89.6 63.68 - -

135 135

20,5 10,05 - 6,48 20.5 10.05 - 6.48

136 136

31,3 1,01 - 15,44 31.3 1.01 - 15.44

137 137

76,7 50,75 --, - 76.7 50.75 - -

138 138

- 79,4 - 67,99 - 79.4 - 67.99

139 139

62,4 - - - 62.4 - - -

140 140

50,4 57,85 - 15,79 50.4 57.85 - 15.79

141 141

17 - - - 17 - - -

142 142

25 - - 9,86 25 - - 9.86

143 143

102,2 81,7 - - 102.2 81.7 - -

144 144

- 40,13 -- 69,24 - 40.13 - 69.24

145 145

- 54,01 - 75,88 - 54.01 - 75.88

146 146

- 60,51 - 68,16 - 60.51 - 68.16

147 147

- 39,9 - 37,14 - 39.9 - 37.14

148 148

- 75,56 - 79,21 - 75.56 - 79.21

149 149

- 82,67 - - - 82.67 - -

150 150

- 78,72 - - - 78.72 - -

151 151

- 92,43 - 69,16 - 92.43 - 69.16

152 152

- 84,24 - 60,26 - 84.24 - 60.26

Ejemplo Nº Example No.

% de desplazamiento % displacement

Protocolo I Protocol I

Protocolo II Protocolo III Protocolo IV Protocol II Protocol III Protocol IV

153 153

- 96,92 - 99,46 - 96.92 - 99.46

154 154

- 96,1 - 70,19 - 96.1 - 70.19

155 155

- 96,65 - 72,38 - 96.65 - 72.38

156 156

- 86,37, - 89,29 - 86.37, - 89.29

157 157

- 84,84 - 88,5 - 84.84 - 88.5

158 158

- 70,12 - 95,4 - 70.12 - 95.4

158a 158th

- - - 94,62 - - - 94.62

159 159

- 81,31 - 97,65 - 81.31 - 97.65

160 160

10,0 7,32 - 20,75 10.0 7.32 - 20.75

161 161

27,9 22,54 - 39,35 27.9 22.54 - 39.35

162 162

38,9 9,52 - 33,8 38.9 9.52 - 33.8

163 163

- 17,3 - 14,46 - 17.3 - 14.46

164 164

8,2 19,15 - 13,15 8.2 19.15 - 13.15

165 165

14,2 6,64 - 45,27 14.2 6.64 - 45.27

166 166

- 8,7@1 - 18,16 - 8.7 @ 1 - 18.16

167 167

61,3 44,72 - 24,59 61.3 44.72 - 24.59

168 168

37 11,47 - - 37 11.47 - -

169 169

19 29,65 - - 19 29.65 - -

170 170

40,0 29,49 - 27,16 40.0 29.49 - 27.16

171 171

0 19,37 - 0,56 0 19.37 - 0.56

172 172

59,2 - - 25,11 59.2 - - 25.11

173 173

67,1 - - - 67.1 - - -

174 174

76,4 21,69 - 22,53 76.4 21.69 - 22.53

175 175

66 25,7 - 18,48 66 25.7 - 18.48

176 176

65,6 39,34 - 30,48 65.6 39.34 - 30.48

177 177

75,6 - - 15,26 75.6 - - 15.26

178 178

47 - - 6,04 47 - - 6.04

179 179

48 30,88 - 18,21 48 30.88 - 18.21

180 180

40,6 28,65 - 13,19 40.6 28.65 - 13.19

181 181

16,4 - - - 16.4 - - -

182 182

39,9 19,35 - 12,78 39.9 19.35 - 12.78

183 183

45,9 17,24 - 18,23 45.9 17.24 - 18.23

184 184

41 3,24 - 8,76 41 3.24 - 8.76

185 185

- 51,98 - 60,66 - 51.98 - 60.66

186 186

17,2 16,13 - 59,06 17.2 16.13 - 59.06

187 187

6,0 15,66 - 0,7 6.0 15.66 - 0.7

Ejemplo Nº Example No.

% de desplazamiento % displacement

Protocolo I Protocol I

Protocolo II Protocolo III Protocolo IV Protocol II Protocol III Protocol IV

188 188

19,5 12,5 - 36,01 19.5 12.5 - 36.01

189a 189a

7 21,2 - 0,81 7 21.2 - 0.81

189b 189b

3 24,03 - 2,56 3 24.03 - 2.56

190a 190a

- - - 0 - - - 0

190b 190b

- 100 - 96,07 - 100 - 96.07

191 191

- 78,71 - 62,18 - 78.71 - 62.18

192 192

- - - 19,12 - - - 19.12

201 201

9,0 24,91 - 19,79 9.0 24.91 - 19.79

202 202

28,2 16,53 - 70,13 28.2 16.53 - 70.13

203 203

-10,4 56,51 - - -10.4 56.51 - -

204 204

-10,3 23,84 - 10,53 -10.3 23.84 - 10.53

205 205

-12,7 22,27 - 15,93 -12.7 22.27 - 15.93

206 206

27,4 15,15 - 71,87 27.4 15.15 - 71.87

207 207

-1,2 9,39 - - -1.2 9.39 - -

208 208

-1,2 - - 0 -1.2 - - 0

209 209

23,5 30,35 - 50,52 23.5 30.35 - 50.52

210 210

12,6 11,58 - 17,69 12.6 11.58 - 17.69

211 211

27,6 19,47 - 80,4 27.6 19.47 - 80.4

212 212

68,4 72,25 - - 68.4 72.25 - -

213 213

48,5 17,57 - 71,8 48.5 17.57 - 71.8

214 214

10,1 9,01 - 41,3 10.1 9.01 - 41.3

215 215

- 1,38 - - - 1.38 - -

216 216

32,2 34,03 - 20,74 32.2 34.03 - 20.74

217 217

20,5 38,55 - 10,74 20.5 38.55 - 10.74

218 218

29,9 44,41 - - 29.9 44.41 - -

219 219

33,7 59,57 - - 33.7 59.57 - -

220 220

29,5 17,92 - 25,29 29.5 17.92 - 25.29

221 221

68,6 0 - 75,66 68.6 0 - 75.66

222 222

39,4 - - 15,72 39.4 - - 15.72

223 223

52,1 21,5 - 59,5 52.1 21.5 - 59.5

224 224

81,6 42,62 - - 81.6 42.62 - -

225 225

31,1 46,8 - - 31.1 46.8 - -

226 226

38,4 72,08 - - 38.4 72.08 - -

227 227

25,3 3,51 - - 25.3 3.51 - -

228 228

16,1 0 - 9,4 16.1 0 - 9.4

229 229

47,1 0,01 - 24,6 47.1 0.01 - 24.6

Ejemplo Nº Example No.

% de desplazamiento % displacement

Protocolo I Protocol I

Protocolo II Protocolo III Protocolo IV Protocol II Protocol III Protocol IV

230 230

87,2 72,54@ 1 µm - - 87.2 72.54 @ 1 µm - -

231 231

31,9 30,79 - - 31.9 30.79 - -

232 232

49,7 1,15 - 13,76 49.7 1.15 - 13.76

233 233

73,2 10,79 - 46,22 73.2 10.79 - 46.22

234 2. 3. 4

36,3 3,33 - 10,64 36.3 3.33 - 10.64

235 235

46,8 80,94 - - 46.8 80.94 - -

236 236

75,5 55,25 - - 75.5 55.25 - -

237 237

65,6 80,77 - - 65.6 80.77 - -

238 238

73,9 24,52 - - 73.9 24.52 - -

239 239

23,5 8,09 - 77,12 23.5 8.09 - 77.12

240 240

1,5 0 - 7,98 1.5 0 - 7.98

241 241

92,5 87,5 - - 92.5 87.5 - -

242 242

- 84,89 - - - 84.89 - -

243 243

23,5 1,74 - - 23.5 1.74 - -

244 244

- 1,7 - 88,35 - 1.7 - 88.35

245 245

- 30,82 - 84,79 - 30.82 - 84.79

246 246

46,0 - - 30,44 46.0 - - 30.44

247 247

- 22,75 - 79,12 - 22.75 - 79.12

248 248

- 40,11 - - - 40.11 - -

249 249

47,7 - - - 47.7 - - -

250 250

27,1 6,46 - 27,93 27.1 6.46 - 27.93

251 251

42,3 20,93 - 60,18 42.3 20.93 - 60.18

252 252

99,8 74,52 - - 99.8 74.52 - -

253 253

63,0 43,16 - - 63.0 43.16 - -

254 254

9,1 - - - 9.1 - - -

255 255

23:9 - - - 23: 9 - - -

256 256

63,3 7,71 - - 63.3 7.71 - -

257 257

73,5 30,69 - 83,94 73.5 30.69 - 83.94

258 258

- 61,78 - - - 61.78 - -

259 259

18,3 2,72 - 33,33 18.3 2.72 - 33.33

260 260

84,4 30,22 - 80,22 84.4 30.22 - 80.22

261 261

- 34,15 - - - 34.15 - -

262 262

-1,6 21,54 - 32,58 -1.6 21.54 - 32.58

263 263

69,1 26,73 - 79,04 69.1 26.73 - 79.04

264 264

85,6 60,85@ 1 µm - - 85.6 60.85 @ 1 µm - -

265 265

31,6 25,85 - 70,16 31.6 25.85 - 70.16

Ejemplo Nº Example No.

% de desplazamiento % displacement

Protocolo I Protocol I

Protocolo II Protocolo III Protocolo IV Protocol II Protocol III Protocol IV

266 266

34,5 23,00 - 61,98 34.5 23.00 - 61.98

267 267

90,0 60,43 - - 90.0 60.43 - -

268 268

41,0 74,52 - - 41.0 74.52 - -

269 269

47,7 57,25 - - 47.7 57.25 - -

270 270

-14,6 18,04 - 8,62 -14.6 18.04 - 8.62

271 271

11,7 17,7 - 45,96 11.7 17.7 - 45.96

272 272

-4,5 13,99 - 18,37 -4.5 13.99 - 18.37

273 273

-5,9 8,94 - 26,25 -5.9 8.94 - 26.25

274 274

25,7 7,83 - 35,42 25.7 7.83 - 35.42

275 275

38,8 7,02 - 72,28 38.8 7.02 - 72.28

276 276

25,3 3,97 - 14,11 25.3 3.97 - 14.11

277 277

-12,8 5,41 - 22,13 -12.8 5.41 - 22.13

278 278

- 26,86 - - - 26.86 - -

279 279

62,0 44,84 - - 62.0 44.84 - -

280 280

33,0 40,37 - - 33.0 40.37 - -

281 281

- - - 97,11 - - - 97.11

282 282

- - - 92,31 - - - 92.31

283 283

- 58,84 - 94,79 - 58.84 - 94.79

284 284

13,7 25,15 - 0,9 13.7 25.15 - 0.9

285 285

61,9 53,9@1 µm - - 61.9 53.9 @ 1 µm - -

286 286

- 32,35 - - - 32.35 - -

287 287

- 36,8 - - - 36.8 - -

288 288

- 1,05 - 60,78 - 1.05 - 60.78

289 289

71,3 40,2 - - 71.3 40.2 - -

290 290

80,3 70,03 - - 80.3 70.03 - -

291 291

- 64,44 - - - 64.44 - -

292 292

- 69,79 - - - 69.79 - -

293 293

- 51,88 - - - 51.88 - -

294 294

110,7 78,08 - - 110.7 78.08 - -

295 295

- 93 - 100 - 93 - 100

296 296

- 94,62 - 95,88 - 94.62 - 95.88

297 297

- 71,92 - 70,29 - 71.92 - 70.29

298 298

- 28,07 - 11,25 - 28.07 - 11.25

299 299

- 86,48 - 77,61 - 86.48 - 77.61

300 300

- 54,93 - 90,14 - 54.93 - 90.14

301 301

- 82,54 - 82,09 - 82.54 - 82.09

Ejemplo Nº Example No.

% de desplazamiento % displacement

Protocolo I Protocol I

Protocolo II Protocolo III Protocolo IV Protocol II Protocol III Protocol IV

302 302

- 2,43 - 71,77 - 2.43 - 71.77

303 303

- 9,41 - 89,67 - 9.41 - 89.67

304 304

- - - - - - - -

305 305

- - - - - - - -

306 306

- 3,56 - 62,9 - 3.56 - 62.9

307 307

- 26,11 - 70,32 - 26.11 - 70.32

308 308

- 91,26 - 86,58 - 91.26 - 86.58

309 309

- 92,57 - 98,49 - 92.57 - 98.49

310 310

- 96,75 - 94,25 - 96.75 - 94.25

311 311

- 69,58 - 94,38 - 69.58 - 94.38

312 312

- 10,97 - 4,47 - 10.97 - 4.47

313 313

- 65,99 - 98,17 - 65.99 - 98.17

314 314

- 23,25 - 64,87 - 23.25 - 64.87

315 315

- 36,78 - 64,23 - 36.78 - 64.23

316 316

- 13,83 - 66,65 - 13.83 - 66.65

317 317

- - - 16,92 - - - 16.92

318 318

- - - 30,99 - - - 30.99

319 319

- 88,02 - 86,68 - 88.02 - 86.68

320 320

- 39,42 - 67,77 - 39.42 - 67.77

321 321

- 11,78 - 92,91 - 11.78 - 92.91

322 322

- 16,74 - 43,44 - 16.74 - 43.44

323 323

- 4,25 - 82,49 - 4.25 - 82.49

324 324

- 7,23 - 88,53 - 7.23 - 88.53

325 325

- 50:42 - 99,64 - 50:42 - 99.64

326 326

- 73,99 - 99,18 - 73.99 - 99.18

327 327

- 70,23 - 99,99 - 70.23 - 99.99

328 328

- 2,00 - 64,39 - 2.00 - 64.39

329 329

- 11,58 - 88,50 - 11.58 - 88.50

330 330

- - - 64,88 - - - 64.88

331 331

- - - 75,26 - - - 75.26

332 332

- - - 70,06 - - - 70.06

333 333

- - - 100,00 - - - 100.00

334 334

- - - 100,00 - - - 100.00

335a 335th

- - - 96,49 - - - 96.49

335b 335b

- - - 8,70 - - - 8.70

336b 336b

- - - 26,46 - - - 26.46

Ejemplo Nº Example No.

% de desplazamiento % displacement

Protocolo I Protocol I

Protocolo II Protocolo III Protocolo IV Protocol II Protocol III Protocol IV

401 401

- 12,04 - - - 12.04 - -

402 402

- 16,52 - 2,66 - 16.52 - 2.66

403 403

- 26,52 - 13,35 - 26.52 - 13.35

404 404

- 24,34 - 23,79 - 24.34 - 23.79

405 405

- 63,21 - 87,87 - 63.21 - 87.87

406 406

- 72,49 - 94,3 - 72.49 - 94.3

407 407

- 87,28 - 88,44 - 87.28 - 88.44

408 408

- 24,93 - 61,92 - 24.93 - 61.92

409 409

- 85,98 - 65,34 - 85.98 - 65.34

410 410

- - - 15,5 - - - 15.5

411 411

- - - 49,68 - - - 49.68

501 501

82,5 70,15 - - 82.5 70.15 - -

502 502

81,3 52,76 - - 81.3 52.76 - -

503 503

81,2 56,25 - - 81.2 56.25 - -

504 504

79,7 62,9 - - 79.7 62.9 - -

505 505

90,6 77,51 - - 90.6 77.51 - -

506 506

- 0 - 52,4 - 0 - 52.4

507 507

- 76,33 - 91,7 - 76.33 - 91.7

508 508

- 95,97 - 67,67 - 95.97 - 67.67

509 509

- 93,35 - 67,18 - 93.35 - 67.18

601 601

2,8 - - 0,99 2.8 - - 0.99

602 602

4,1 - - 16,4 4.1 - - 16.4

701 701

- 46,7 - 28,34 - 46.7 - 28.34

702 702

- - - 33,00 - - - 33.00

802 802

- 81,33 - 100,00 - 81.33 - 100.00

PROTOCOLO-VIII PROTOCOL-VIII

Ejemplo Nº, % Example No.,%

Estimulación Per Se % de Inhibición de estimulación inducida por WIN-55212-2 Stimulation Per Se % inhibition of stimulation induced by WIN-55212-2

106 106

-10,0% 65,3% -10.0% 65.3%

107 107

4,0% 71,5% 4.0% 71.5%

111 111

6,1% 101,1% 6.1% 101.1%

121 121

16,0% 81,3% 16.0% 81.3%

122 122

1,2% 59,3% 1.2% 59.3%

123 123

13,5% 99,1% 13.5% 99.1%

126 126

-7,9% 104,1% -7.9% 104.1%

127 127

18,0% 100,2% 18.0% 100.2%

131 131

-1,7% 86,0% -1.7% 86.0%

132 132

7,2% 89,2% 7.2% 89.2%

137 137

13,0% 76,0% 13.0% 76.0%

139 139

-8,5% 109,1% -8.5% 109.1%

140 140

24,9% 71,9% 24.9% 71.9%

143 143

43,1% 45,0% 43.1% 45.0%

170 170

17,5% 80,3% 17.5% 80.3%

172 172

-18,3% 115,3% -18.3% 115.3%

173 173

1,3% 99,5% 1.3% 99.5%

174 174

-20,8% 75,5% -20.8% 75.5%

177 177

9,7% 109,1% 9.7% 109.1%

178 178

-0,7% 88,0% -0.7% 88.0%

179 179

7,8% 89,7% 7.8% 89.7%

180 180

10,0% 87,9% 10.0% 87.9%

183 183

13,0% 72,5% 13.0% 72.5%

184 184

9,5% 75,9% 9.5% 75.9%

212 212

-13,8% 97,4% -13.8% 97.4%

221 221

-16,7% 95,7% -16.7% 95.7%

224 224

5,0% 78,1% 5.0% 78.1%

230 230

42,4% 99,4% 42.4% 99.4%

233 233

-16,3% 79,5% -16.3% 79.5%

236 236

8,0% 83,0% 8.0% 83.0%

237 237

7,1% 74,7% 7.1% 74.7%

238 238

0,4% 59,1% 0.4% 59.1%

246 246

0,7% 98,9% 0.7% 98.9%

256 256

-21,5% 69,7% -21.5% 69.7%

257 257

-5,1% 48,3% -5.1% 48.3%

260 260

38,0% 78,8% 38.0% 78.8%

PROTOCOLO-VIII PROTOCOL-VIII

Ejemplo Nº, % Example No.,%

Estimulación Per Se % de Inhibición de estimulación inducida por WIN-55212-2 Stimulation Per Se % inhibition of stimulation induced by WIN-55212-2

264 264

-0,1% 94,5% -0.1% 94.5%

268 268

29,1% 55,3% 29.1% 55.3%

269 269

6,0% 91,4% 6.0% 91.4%

290 290

3,8% 35,3% 3.8% 35.3%

501 501

53,7% 40,1% 53.7% 40.1%

502 502

1,8% 91,1% 1.8% 91.1%

503 503

1,5% 92,0% 1.5% 92.0%

505 505

15,6% 94,4% 15.6% 94.4%

Los ejemplos anteriores se ensayaron a 1 uM The above examples were tested at 1 uM

117 117

4:4% 55,7% 4: 4% 55.7%

119 119

46,0% 38,9% 46.0% 38.9%

134 134

-6,0% 58,1% -6.0% 58.1%

162 162

-29,2% 72,0% -29.2% 72.0%

241 241

54,7% 32,9% 54.7% 32.9%

242 242

33,4% 22,9% 33.4% 22.9%

252 252

48,2 58,8 48.2 58.8

253 253

-9,3% 79,9% -9.3% 79.9%

267 267

12,3% 43,6% 12.3% 43.6%

294 294

102,8% 9,8% 102.8% 9.8%

Los ejemplos anteriores se ensayaron a 300 nM The above examples were tested at 300 nM

Tabla-IV (cont.) (cont.) Table-IV (cont.) (Cont.)

Ejemplo Nº Example No.

DATOS FUNCIONALES DEL ENSAYO FUNCTIONAL TEST DATA

hCB1 hCB1

hCB2 hCB2

Agonismo Agonism

Antagonismo Agonismo Antagonismo Antagonism  Agonism Antagonism

106 106

NE 0% 50,90% NE 0% 50.90%

109 109

NE 61,64% a 10 µM NE NE 61.64% at 10 µM NE

117 117

CI50 18,87 nM 14,91% NE IC50 18.87 nM 14.91% NE

119 119

CI50 38,33 nM 18,42% a 10 uM NE IC50 38.33 nM 18.42% at 10 uM NE

122* 122 *

NE 40,66% a 10 uM NE NE 40.66% at 10 uM NE

134 134

75,61% a 10 µM 17,53% a 10 uM NE 75.61% at 10 µM 17.53% at 10 uM NE

140 140

48,88% a 10 µM 19,31% a 10 uM NE 48.88% at 10 µM 19.31% at 10 uM NE

149 149

79,86% a 10 µM 15,98% a 10 uM NE 79.86% at 10 µM 15.98% at 10 uM NE

150 150

61,1% a 10 µM 42,93% a 10 uM NE 61.1% at 10 µM 42.93% at 10 uM NE

186 186

29,4% a 10 µM 0% a 10 uM CI50 8,51 nM 21 % a 10 uM 29.4% at 10 µM 0% at 10 uM IC50 8.51 nM 21% at 10 uM

Ejemplo Nº Example No.

DATOS FUNCIONALES DEL ENSAYO FUNCTIONAL TEST DATA

hCB1 hCB1

hCB2 hCB2

Agonismo Agonism

Antagonismo Agonismo Antagonismo Antagonism  Agonism Antagonism

202 202

0% a 10 µM 0% a 10 uM 16,79 0 0% at 10 µM 0% at 10 uM 16.79 0

206 206

NE NE CI50 10,52 nM 15,96 % a 10 uM NE NE IC50 10.52 nM 15.96% at 10 uM

211 211

16,87 a 10 µM 0% a 10 uM CI50 40,65 nM 20,33 % a 10 uM 16.87 to 10 µM 0% at 10 uM IC50 40.65 nM 20.33% at 10 uM

212 212

NE 39,13% a 10 uM NE NE 39.13% at 10 uM NE

213 213

0% a 10 µM 0% a 10 uM CI50 12,67 nM 22,05% a 10 uM 0% at 10 µM 0% at 10 uM IC50 12.67 nM 22.05% at 10 uM

219 219

NE 33,4% a 10 uM NE NE 33.4% at 10 uM NE

221 221

0% a 10 µM 0% a 10 uM CI50 36,43 nM 30,07,% a 10 uM 0% at 10 µM 0% at 10 uM IC50 36.43 nM 30.07% at 10 uM

223 223

NE 0% a 10 uM CI50 1,49 nM 24,37 % a 10 uM NE 0% at 10 uM IC50 1.49 nM 24.37% at 10 uM

226 226

NE 71,03% a 10 uM NE NE 71.03% at 10 uM NE

235 235

NE 59,85% a 10 uM NE NE 59.85% at 10 uM NE

238 238

NE 55,05% a 10 µM 24,54% a 10 uM NE 55.05% at 10 µM 24.54% at 10 uM

239 239

NE CI50 42,52 nM 64,1% a 10 uM NE IC50 42.52 nM 64.1% at 10 uM

244 244

0% a 10 µM 61,52% a 10 uM CI50 5,66 nM 25,33 % a 10 uM 0% at 10 µM 61.52% at 10 uM IC50 5.66 nM 25.33% at 10 uM

245 245

0% a 10 µM 70,67% a 10 uM CI50 50,42 nM 32,91 % a 10 uM 0% at 10 µM 70.67% at 10 uM IC50 50.42 nM 32.91% at 10 uM

247 247

0% a 10 µM 75,31% a 10 uM CI50 5,44 nM 29,24 % a 10 uM 0% at 10 µM 75.31% at 10 uM IC50 5.44 nM 29.24% at 10 uM

251 251

37% a 10 µM 0% a 10 uM CI50 40,24 nM 40,78 % a 10 uM 37% at 10 µM 0% at 10 uM IC50 40.24 nM 40.78% at 10 uM

257 257

0 0 CI50 3,7 nM 37,53 % a 10 uM 0 0 IC50 3.7 nM 37.53% at 10 uM

260 260

0 0 CI50 4,1 nM 34,83% a 10 uM 0 0 IC50 4.1 nM 34.83% at 10 uM

263 263

16,19% a 10 µM 72,13% a 1 uM CI50 2,5 nM 27,08% a 10 uM 16.19% at 10 µM 72.13% at 1 uM IC50 2.5 nM 27.08% at 10 uM

265 265

NE CI50 23,11 nM 27,24% a 10 uM NE IC50 23.11 nM 27.24% at 10 uM

266 266

12,14% a 10 µM 0 CI50 14 nM 27,71% a 10 uM 12.14% at 10 µM 0 IC50 14 nM 27.71% at 10 uM

268 268

50,9% a 1 uM 50.9% at 1 uM

275 275

16,42% a 10 µM 0% a 10 uM CI50 4,49 nM 19,14 % a 10 uM 16.42% at 10 µM 0% at 10 uM IC50 4.49 nM 19.14% at 10 uM

288 288

0% a 10 µM 55,26% a 10 uM CI50 4,76 nM 17,13 % a 0 uM 0% at 10 µM 55.26% at 10 uM IC50 4.76 nM 17.13% at 0 uM

302 302

199% a 10 µM NE CI50 9,75 nM 0 % a 10 uM 199% at 10 µM NE IC50 9.75 nM 0% at 10 uM

303 303

CI50 857 nM 0% a 10 uM CI50 0,61 nM 17,6 % a 10 uM IC50 857 nM 0% at 10 uM IC50 0.61 nM 17.6% at 10 uM

304 304

55% a 10 µM 0% a 10 uM CI50 0,93 nM 51,60 % a 10 uM 55% at 10 µM 0% at 10 uM IC50 0.93 nM 51.60% at 10 uM

305 305

20% a 10 µM 0% a 10 uM CI50 2,16 nM 37,45 % a 10 uM 20% at 10 µM 0% at 10 uM IC50 2.16 nM 37.45% at 10 uM

306 306

CI50 11,95 nM 14,36 % a 10 uM IC50 11.95 nM 14.36% at 10 uM

307 307

CI50 0,81 nM 21,64 % a 10 uM IC50 0.81 nM 21.64% at 10 uM

314 314

3,41% a 10 µM 0% a 10 uM CI50 8,52 nM 22,88 % a 10 uM 3.41% at 10 µM 0% at 10 uM IC50 8.52 nM 22.88% at 10 uM

315 315

12,59% a 10 µM 1% a 10 uM CI50 0,16-1,76 nM 16,09 % a 10 uM 12.59% at 10 µM 1% at 10 uM IC50 0.16-1.76 nM 16.09% at 10 uM

316 316

18,53% a 10 µM 2% a 10 uM CI50 1,2-4,27 nM 37,63 % a 10 uM 18.53% at 10 µM 2% at 10 uM IC50 1.2-4.27 nM 37.63% at 10 uM

320 320

29,08% a 10 µM 0% a 10 uM CI50 0,76-1,25 nM 22,48 % a 10 uM 29.08% at 10 µM 0% at 10 uM IC50 0.76-1.25 nM 22.48% at 10 uM

Ejemplo Nº Example No.

DATOS FUNCIONALES DEL ENSAYO FUNCTIONAL TEST DATA

hCB1 hCB1

hCB2 hCB2

323 323

0% a 10 uM 0% a 10 uM CI50 14,12 nM 18,03 % a 10 uM 0% at 10 uM 0% at 10 uM IC50 14.12 nM 18.03% at 10 uM

408 408

NE CI50 16,05 nM NE NE IC50 16.05 nM NE

506 506

NE 0% a 10 uM 80,15% a 10 uM NE 0% at 10 uM 80.15% at 10 uM

NE = No ensayado NE = Not tested

Aunque en el presente documento la invención se ha descrito con referencia a realizaciones particulares, debe entenderse que estas realizaciones son únicamente ilustrativas de los principios y aplicaciones de la presente invención. Por lo tanto debe entenderse que pueden realizarse numerosas modificaciones con respecto a las Although the invention has been described herein with reference to particular embodiments, it should be understood that these embodiments are only illustrative of the principles and applications of the present invention. Therefore it should be understood that numerous modifications can be made with respect to the

5 realizaciones ilustrativas y que pueden realizarse otros diseños sin ajearse del espíritu y el alcance de la presente invención como se reivindica en las reivindicaciones adjuntas. 5 illustrative embodiments and that other designs can be made without departing from the spirit and scope of the present invention as claimed in the appended claims.

Todas las publicaciones, patentes y solicitudes de patentes citadas en la presente memoria descriptiva se incorporan por referencia en el presente documento hasta la misma medida si cada publicación individual, patente o solicitud de patente individual se indicase específica e individualmente para incorporarse por referencia en el presente All publications, patents and patent applications cited herein are incorporated by reference herein to the same extent if each individual publication, patent or individual patent application is specifically and individually indicated to be incorporated by reference herein.

10 documento. 10 document

5 5

10 10

15 fifteen

20 twenty

25 25

30 30

35 35

40 40

45 Four. Five

Claims (67)

REIVINDICACIONES 1. Un compuesto de la fórmula: 1. A compound of the formula: imagen1image 1 una sal farmacéuticamente aceptable del mismo, un éster farmacéuticamente aceptable del mismo, un tautómero del mismo, un estereoisómero del mismo, un enantiómero del mismo o un diastereómero de los mismos en la que cada una de las líneas de puntos en fórmula (1) representa independientemente un enlace opcional; U y V son independientemente C o N; W, X e Y son independientemente C, N, O, S o -C(O)-con la condición de que al menos dos de U, V, W, X o Y se seleccionan independientemente entre N, O, -C(O)-o S; en cada aparición, R es independientemente alquilo sustituido o sin sustituir, arilo sustituido o sin sustituir o heteroarilo sustituido o sin sustituir; R1 y R2 pueden ser iguales o diferentes y son independientemente hidrógeno, nitro, ciano, formilo, acetilo, halógeno, -OR3, -SR3, oxo, tio, 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, cicloalquenilalquilo sustituido o sin sustituir, arilo sustituido o sin sustituir, arilalquilo sustituido o sin sustituir, heteroarilo sustituido o sin sustituir, heteroarilalquilo sustituido o sin sustituir, grupo heterocíclico sustituido o sin sustituir, heterociclilalquilo sustituido o sin sustituir, -NR3R4, -C(=B)-R3, C(O) O-R3, -C(C)NR3R4, -S(O)m-R3, -S(O)m-NR3R4 o un grupo protector o R1 y R2 pueden unirse para formar un anillo cíclico opcionalmente sustituido, saturado o insaturado de 3 a 7 miembros, que puede incluir opcionalmente al menos dos heteroátomos seleccionados entre O, NR3 o S; en cada aparición, R3 y R4 pueden ser iguales o diferentes y son independientemente hidrógeno, nitro, halo, ciano, -ORa, -SRa, oxo, tio, alquilo sustituido o sin sustituir, alquenilo sustituido o sin sustituir, alquinilo sustituido a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable ester thereof, a tautomer thereof, a stereoisomer thereof, an enantiomer thereof or a diastereomer thereof in which each of the dotted lines in formula (1) represents independently an optional link; U and V are independently C or N; W, X and Y are independently C, N, O, S or -C (O) - with the proviso that at least two of U, V, W, X or Y are independently selected from N, O, -C ( O) -o S; at each occurrence, R is independently substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R1 and R2 may be the same or different and are independently hydrogen, nitro, cyano, formyl, acetyl, halogen, -OR3, -SR3, oxo, thio, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl , substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenyl alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, group substituted or unsubstituted heterocyclic, substituted or unsubstituted heterocyclyl alkyl, -NR3R4, -C (= B) -R3, C (O) O-R3, -C (C) NR3R4, -S (O) m-R3, -S (O) m-NR3R4 or a protecting group or R1 and R2 may be joined to form an optionally substituted, saturated or unsaturated cyclic ring of 3 to 7 members, which may optionally include at least two heteroatoms selected from O, NR3 or S; at each occurrence, R3 and R4 may be the same or different and are independently hydrogen, nitro, halo, cyano, -ORa, -SRa, oxo, thio, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted alkynyl o sin sustituir, cicloalquilo sustituido o sin sustituir, cicloalquilalquilo sustituido o sin sustituir, cicloalquenilo sustituido o sin sustituir, cicloalquenilalquilo sustituido o sin sustituir, arilo sustituido o sin sustituir, arilalquilo sustituido o sin sustituir, heteroarilo sustituido o sin sustituir, heteroarilalquilo sustituido o sin sustituir, grupo heterocíclico sustituido o sin sustituir, heterociclilalquilo sustituido o sin sustituir, -C(=B)-Ra, -C(O)O-Ra, -C (O)NRaRb, -S(O)m-Ra, -S(O)m-NRaRb, -NRaRb o un grupo protector o R3 y R4, cuando se unen a un átomo en común, pueden unirse entre sí para formar un anillo cíclico opcionalmente sustituido, saturado o insaturado de 3 a 7 miembros, que puede incluir opcionalmente al menos dos heteroátomos seleccionados entre O, NR3 o S; cada aparición de Ra y Rb pueden ser iguales o diferentes y son independientemente hidrógeno, halógeno, nitro, ciano, formilo, acetilo, oxo, tio, -C(O)-Rc, -C(O)O-Rc, -C(O)NRcRd, -S(O)m-Rc, -S(O)m-NRcRd, -NRcRd, -ORc, -SRc, un grupo protector, 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, cicloalquenilalquilo sustituido o sin sustituir, arilo sustituido o sin sustituir, arilalquilo sustituido o sin sustituir, heteroarilo sustituido o sin sustituir, grupo heterocíclico sustituido o sin sustituir, heterociclilalquilo sustituido o sin sustituir o heteroarilalquilo sustituido o sin sustituir; cada aparición de Rc y Rd pueden ser iguales o diferentes y son independientemente hidrógeno, halógeno, nitro, ciano, formilo, acetilo, oxo, tio, un grupo protector, 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, cicloalquenilalquilo sustituido o sin sustituir, arilo sustituido o sin sustituir, arilalquilo sustituido o sin sustituir, heteroarilo sustituido o sin sustituir, grupo heterocíclico sustituido o sin sustituir, heterociclilalquilo sustituido o sin sustituir o heteroarilalquilo sustituido o sin sustituir; en cada aparición, B es independientemente O, S o NR3; p es 1 ó2; en cada aparición, m es independientemente 0, 1 ó 2; A es en las que: or unsubstituted, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenyl alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryl substitute, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -C (= B) -Ra, -C (O) O-Ra, -C (O) NRaRb, -S (O) m-Ra, - S (O) m-NRaRb, -NRaRb or a protecting group or R3 and R4, when attached to a common atom, can be joined together to form an optionally substituted, saturated or unsaturated 3 to 7-membered cyclic ring, which it may optionally include at least two heteroatoms selected from O, NR3 or S; each occurrence of Ra and Rb may be the same or different and are independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, -C (O) -Rc, -C (O) O-Rc, -C ( O) NRcRd, -S (O) m-Rc, -S (O) m-NRcRd, -NRcRd, -ORc, -SRc, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted alkynyl or unsubstituted, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenyl alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group substituted, substituted or unsubstituted heterocyclylalkyl or substituted or unsubstituted heteroarylalkyl; each occurrence of Rc and Rd may be the same or different and are independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl substituted, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenyl alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group , substituted or unsubstituted heterocyclylalkyl or substituted or unsubstituted heteroarylalkyl; at each occurrence, B is independently O, S or NR3; p is 1 or 2; at each occurrence, m is independently 0, 1 or 2; A is in which: imagen1image 1 5 5 10 10 15 fifteen 20 twenty 25 25 30 30 35 35 40 40 45 Four. Five cada una de las líneas de puntos en A representa independientemente un enlace opcional; R5, R6, R7, R8, R9 R10, R11, R12, R13 y R14son independientemente hidrógeno, nitro, ciano, formilo, acetilo, halógeno, -OR15 , -SR15, oxo, tio, 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, cicloalquenilalquilo sustituido o sin sustituir, arilo sustituido o sin sustituir, arilalquilo sustituido o sin sustituir, heteroarilo sustituido o sin sustituir, heteroarilalquilo sustituido o sin sustituir, grupo heterocíclico sustituido o sin sustituir, heterociclilalquilo sustituid o sin sustituir, -NR15R16 , -C(=B)-R15 , C(O)O-R15, -C(O)NR15R16, -S(O)m-R15, -S(O)m-NR15R16 o un grupo protector; R5 y R6 pueden unirse para formar un anillo mono-o bi-cíclico opcionalmente sustituido, saturado o insaturado de 3 a 11 miembros, que puede incluir opcionalmente al menos un heteroátomo seleccionado entre O, NR3 o S; R9y R10 pueden unirse entre sí para formar un anillo mono-o bi-cíclico opcionalmente sustituido, saturado o insaturado de 3 a 11 miembros, que puede incluir opcionalmente al menos un heteroátomo seleccionado entre O, NR3 o S; en cada aparición, R15 y R16 pueden ser iguales o diferentes y son independientemente hidrógeno, nitro, halo, ciano, -OR3, -SR3, oxo, tio, alquilo sustituido o sin sustituir, alquenilo sustituido o in sustituir, alquinilo sustituido each of the dotted lines in A independently represents an optional link; R5, R6, R7, R8, R9 R10, R11, R12, R13 and R14 are independently hydrogen, nitro, cyano, formyl, acetyl, halogen, -OR15, -SR15, oxo, thio, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, alkynyl substituted or unsubstituted, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenyl alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclyl alkyl, -NR15R16, -C (= B) -R15, C (O) O-R15, -C (O) NR15R16, -S (O) m-R15, - S (O) m-NR15R16 or a protecting group; R5 and R6 can be joined to form an optionally substituted, saturated or unsaturated mono- or bi-cyclic ring 3 to 11 members, which may optionally include at least one heteroatom selected from O, NR3 or S; R9 and R10 can be joined together to form an optionally substituted, saturated or mono-or bi-cyclic ring unsaturated 3 to 11 members, which may optionally include at least one heteroatom selected from O, NR3 or S; at each occurrence, R15 and R16 may be the same or different and are independently hydrogen, nitro, halo, cyano, -OR3, -SR3, oxo, thio, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted alkynyl o sin sustituir, cicloalquilo sustituido o sin sustituir, cicloalquilalquilo sustituido o sin sustituir, cicloalquenilo sustituido o sin sustituir, cicloalquenilalquilo sustituido o sin sustituir, arilo sustituido o sin sustituir, arilalquilo sustituido o sin sustituir, heteroarilo sustituido o sin sustituir, heteroarilalquilo sustituido o sin sustituir, grupo heterocíclico sustituido o sin sustituir, heterociclilalquilo sustituido o sin sustituir, -C(=B)-R3, -C(O)O-R3, C(O)NR3R4, -S(O)m-R3, -S(O)m-NR3R4, -NR3R4 o R15 y R16, cuando se unen a un átomo en común, pueden unirse entre sí para formar un anillo cíclico opcionalmente sustituido saturado o insaturado de 3 a 7 miembros, que puede incluir opcionalmente al menos dos heteroátomos seleccionados entre O, NR3 o S en las que R3 y R4 son como se han definido anteriormente; n es 1, 2,3 ó4; y a, b, c, d y e son números enteros seleccionados independientemente de 0 a 4, or unsubstituted, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenyl alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryl substitute, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclyl alkyl, -C (= B) -R3, -C (O) O-R3, C (O) NR3R4, -S (O) m-R3, -S (O) m-NR3R4, -NR3R4 or R15 and R16, when attached to a common atom, can be joined together to form an optionally substituted saturated or unsaturated cyclic ring of 3 to 7 members, which may optionally include at least two heteroatoms selected from O, NR3 or S in which R3 and R4 are as defined above; n is 1, 2.3 or 4; and a, b, c, d and e are whole numbers independently selected from 0 to 4, imagen2image2 en la que R1 y R son como se han definido anteriormente, en la que los sustituyentes en grupo funcionales sustituido pueden ser iguales o diferentes y son uno o más de hidroxi, halógeno, carboxilo, ciano, nitro, oxo (=O), tio (=S), alquilo C1-8, alcoxi C1-8, alquenilo C2-10, alquinilo C212, arilo C6-14, arilalquilo, cicloalquilo, cicloalquenilo, amino, heteroarilo, anillo heterociclilalquilo, heteroarilalquilo, anillo heterocíclico de 3-15 miembros, guanidina, -COORx, -C(O)Rx, C(S)Rx, -C(O)NRxRy, C(O)ONRxRy, -NRxCONRyRz, -N(Rx)SORy, -N(Rx)SO2Ry, -(=N-N(Rx)Ry), -NRxC(O)ORy, -NRxRy, -NRxC(O)Ry, -NRxC(S)Ry, -NRxC(S)NRyRz, -SONRxRy, -SO2NRxRy, -ORx, ORxC(O)NRyRz, -ORxC(O)ORy, -OC(O)Rx, -OC(O)NRxRy, -RxNRyC(O)Rz, -RxORy, -RxC(O)ORy, -RxC(O)NRyRz, -RxC(O)Ry, -RxOC(O)Ry, -SRx, -SORx, SO2Rx y ONO2, en los que Rx, Ry y Rz se seleccionan independientemente entre hidrógeno, alquilo C1-8, alcoxi C1-8, alquenilo C2-10, alquinilo C2-12, arilo C6-14, arilalquilo, cicloalquilo, cicloalquenilo, amino, heteroarilo, anillo heterociclilalquilo sustituido, heteroarilalquilo y anillo heterocíclico de 3-15 miembros. wherein R1 and R are as defined above, in which the substituted functional group substituents may be the same or different and are one or more of hydroxy, halogen, carboxyl, cyano, nitro, oxo (= O), thio (= S), C1-8 alkyl, C1-8 alkoxy, C2-10 alkenyl, C212 alkynyl, C6-14 aryl, arylalkyl, cycloalkyl, cycloalkenyl, amino, heteroaryl, heterocyclylalkyl ring, heteroarylalkyl, 3-15 membered heterocyclic ring , guanidine, -COORx, -C (O) Rx, C (S) Rx, -C (O) NRxRy, C (O) ONRxRy, -NRxCONRyRz, -N (Rx) SORy, -N (Rx) SO2Ry, - (= NN (Rx) Ry), -NRxC (O) ORy, -NRxRy, -NRxC (O) Ry, -NRxC (S) Ry, -NRxC (S) NRyRz, -SONRxRy, -SO2NRxRy, -ORx, ORxC (O) NRyRz, -ORxC (O) ORy, -OC (O) Rx, -OC (O) NRxRy, -RxNRyC (O) Rz, -RxORy, -RxC (O) ORy, -RxC (O) NRyRz, -RxC (O) Ry, -RxOC (O) Ry, -SRx, -SORx, SO2Rx and ONO2, in which Rx, Ry and Rz are independently selected from hydrogen, C1-8 alkyl, C1-8 alkoxy, C2 alkenyl -10, C2-12 alkynyl, C6-14 aryl, arylalkyl, cycloalkyl, cycloalkenyl, ami no, heteroaryl, substituted heterocyclylalkyl ring, heteroarylalkyl and 3-15 membered heterocyclic ring.

2. 2.

Un compuesto de acuerdo con la reivindicación 1, en el que U y V son C A compound according to claim 1, wherein U and V are C

3. 3.

Un compuesto de acuerdo con la reivindicación 1 ó 2, en el que W es C e Y y X son N. A compound according to claim 1 or 2, wherein W is C and Y and X are N.

4. Four.

Un compuesto de acuerdo con la reivindicación 1, 2 ó 3, en el que R es arilo sustituido con halógeno, alquilo sustituido o sin sustituir, alcoxi sustituido o sin sustituir o arilo sustituido o sin sustituir. A compound according to claim 1, 2 or 3, wherein R is halogen substituted aryl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy or substituted or unsubstituted aryl.

5. 5.

Un compuesto de acuerdo con la reivindicación 1, 2 ó 3, en el que R es metilo, fenilo, 2-cloro-fenilo, 4-clorofenilo, 2,4-diclorofenilo, 2-bromofenilo, 4-bromofenilo, 4-fluoro fenilo, 2,4-difluorofenilo, 4-metilfenilo, 4-metoxifenilo, 2-(4clorofenil)-fenilo o 5-cloropiridin-2-ilo. A compound according to claim 1, 2 or 3, wherein R is methyl, phenyl, 2-chloro-phenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2-bromophenyl, 4-bromophenyl, 4-fluoro phenyl , 2,4-difluorophenyl, 4-methylphenyl, 4-methoxyphenyl, 2- (4-chlorophenyl) -phenyl or 5-chloropyridin-2-yl.

6. 6.

Un compuesto de acuerdo con la reivindicación 1-4 ó 5, en el que R1 es hidrógeno. A compound according to claim 1-4 or 5, wherein R1 is hydrogen.

5 5 10 10 15 fifteen 20 twenty 25 25 30 30

7. 7.

Un compuesto de acuerdo con la reivindicación 1-5 ó 6, en la que R2 es alquilo sustituido o sin sustituir, cicloalquilo sustituido o sin sustituir, cicloalquilalquilo sustituido o sin sustituir, arilo sustituido o sin sustituir, arilalquilo sustituido o sin sustituir, grupo heterocíclico sustituido o sin sustituir, grupo heteroarilo sustituido o sin sustituir, heteroarilalquilo sustituido o sin sustituir o NR3R4. A compound according to claim 1-5 or 6, wherein R2 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, heterocyclic group substituted or unsubstituted, substituted or unsubstituted heteroaryl group, substituted or unsubstituted heteroarylalkyl or NR3R4.

8. 8.

Un compuesto de acuerdo con la reivindicación 7, en la que R2 es t-butilo, n-pentilo, ciclopentilo, ciclohexilo, adamantan-1-ilo, 2-metiladamantan-2-ilo, 3-hidroxi adamantan-1-ilo, 1,3,3-trimetilbiciclo[2.2.1]hept-2-ilo, 1fenilciclopropilo, ciclohexilmetilo, fenilo, 3-clorofenilo, 4-clorofenilo, 3-bromofenilo, 2-metoxifenilo, 4-terc-butilfenilo, 2,4-difluorofenilbencilo, 2-clorobencilo, 4-clorobencilo, 2,4-diclorobencilo, 2-fluorobencilo, 4-fluorobencilo, 2,4difluorobenzilo, 2,6-difluorobencilo, 2-bromobencilo, 4-bromobencilo, 4-trifluorometilbencilo, 1-feniletilo, 1-metil-1feniletilo, 2-feniletilo, 1-(2-clorofenil)etilo, 2-(4-fluorofenil)etilo, 1-fenilpropilo, 1-etil-1-fenilpropilo, 1-(2-clorofenil)1metiletilo, feniletanoato de metilo, 2-hidroxi-1-feniletilo, piperidinilo, morfolinilo, piridinilo, 1,2,4-triazol-4-ilo, 2piridilmetilo, 3-piridilmetilo o 4-piridilmetilo. A compound according to claim 7, wherein R2 is t-butyl, n-pentyl, cyclopentyl, cyclohexyl, adamantan-1-yl, 2-methyladamantan-2-yl, 3-hydroxy adamantan-1-yl, 1 , 3,3-trimethylbicyclo [2.2.1] hept-2-yl, 1-phenylcyclopropyl, cyclohexylmethyl, phenyl, 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 2-methoxyphenyl, 4-tert-butylphenyl, 2,4-difluorophenylbenzyl , 2-chlorobenzyl, 4-chlorobenzyl, 2,4-dichlorobenzyl, 2-fluorobenzyl, 4-fluorobenzyl, 2,4difluorobenzyl, 2,6-difluorobenzyl, 2-bromobenzyl, 4-bromobenzyl, 4-trifluoromethylbenzyl, 1-phenylethyl, 1 -methyl-1-phenylethyl, 2-phenylethyl, 1- (2-chlorophenyl) ethyl, 2- (4-fluorophenyl) ethyl, 1-phenylpropyl, 1-ethyl-1-phenylpropyl, 1- (2-chlorophenyl) 1-methylethyl, phenylethanoate methyl, 2-hydroxy-1-phenylethyl, piperidinyl, morpholinyl, pyridinyl, 1,2,4-triazol-4-yl, 2-pyridylmethyl, 3-pyridylmethyl or 4-pyridylmethyl.

9. 9.

Un compuesto de acuerdo con la reivindicación 7, en el que R2 es NR3R4; en el que R3 es hidrógeno, alquilo sustituido o sin sustituir, arilo sustituido o sin sustituir, o cicloalquilo sustituido o sin sustituir y R4 es arilo sustituido o sin sustituir, heteroarilo sustituido o sin sustituir, o cicloalquilo sustituido o sin sustituir. A compound according to claim 7, wherein R2 is NR3R4; wherein R3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted cycloalkyl and R4 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted cycloalkyl.

10. 10.

Un compuesto de acuerdo con la reivindicación 9, en el que R3 es metilo, fenilo o ciclohexilo y R4 es fenilo, 2clorofenilo, 4-clorofenilo,2,4-diclorofenilo, 3,4-diclorofenilo, 2-fluorofenilo, 3-fluorofenilo, 4-fluorofenilo, 2,4difluorofenilo, 3,4-difluorofenilo, 2-bromofenilo, 3-cloropiridin-2-ilo, 5-cloropiridin-2-ilo o ciclohexilo, o R3 y R4 se unen entre sí para formar piperidin-1-ilo o morfolin-4-ilo. A compound according to claim 9, wherein R3 is methyl, phenyl or cyclohexyl and R4 is phenyl, 2-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 2-bromophenyl, 3-chloropyridin-2-yl, 5-chloropyridin-2-yl or cyclohexyl, or R3 and R4 join together to form piperidin-1- ilo or morpholin-4-yl.

11. eleven.

Un compuesto de acuerdo con la reivindicación 1-4 ó 5, en el que R1 y R2 se unen entre sí para formar un anillo cíclico opcionalmente sustituido, saturado o insaturado de 3 a 7 miembros, que puede incluir opcionalmente al menos dos heteroátomos seleccionados entre O, NR3 o S. A compound according to claim 1-4 or 5, wherein R1 and R2 are joined together to form an optionally substituted, saturated or unsaturated cyclic ring of 3 to 7 members, which may optionally include at least two heteroatoms selected from O, NR3 or S.

12. 12.

Un compuesto de acuerdo con la reivindicación 11, en el que R1 y R2 se unen entre sí para formar piperidin-1-ilo A compound according to claim 11, wherein R1 and R2 join together to form piperidin-1-yl

o morfolin-1-ilo. or morpholin-1-yl.

13. 13.

Un compuesto de acuerdo con la reivindicación 1-11 ó 12, en el que A es A compound according to claim 1-11 or 12, wherein A is

14. 14.

Un compuesto de acuerdo con la reivindicación 13, en el que cada aparición de R5, R6, R7, R8, R9, R10, R11, R12 , R13 y R14 es independientemente hidrógeno, alquilo sustituido o sin sustituir o arilo sustituido o sin sustituir; a, b, c y d son 1 y cada una de las líneas de puntos en A representa un enlace opcional. A compound according to claim 13, wherein each occurrence of R5, R6, R7, R8, R9, R10, R11, R12, R13 and R14 is independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aryl; a, b, c and d are 1 and each of the dotted lines in A represents an optional link.

15. fifteen.

Un compuesto de acuerdo con la reivindicación 14, en el que cada uno de R5, R6, R7, R8, R9, R10, R11, R12, R13 y R14 representan independientemente hidrógeno o metilo. A compound according to claim 14, wherein each of R5, R6, R7, R8, R9, R10, R11, R12, R13 and R14 independently represent hydrogen or methyl.

16. 16.

Un compuesto de acuerdo con la reivindicación 14, en el que R8 representa 4-clorofenilo. A compound according to claim 14, wherein R8 represents 4-chlorophenyl.

17. 17.

Un compuesto de acuerdo con la reivindicación 1-13 ó 14, en el que B es oxígeno. A compound according to claim 1-13 or 14, wherein B is oxygen.

18. 18.

Un compuesto de Fórmula 1A A compound of Formula 1A

imagen1image 1 imagen1image 1 una sal farmacéuticamente aceptable del mismo, éster farmacéuticamente aceptable del mismo, tautómero del mismo, estereoisómero del mismo, enantiómero del mismo o diastereómero del mismo, en la que, en cada aparición, R es independientemente alquilo sustituido o sin sustituir, arilo sustituido o sin sustituir o heteroarilo a pharmaceutically acceptable salt thereof, pharmaceutically acceptable ester thereof, tautomer thereof, stereoisomer thereof, enantiomer thereof or diastereomer thereof, in which, at each occurrence, R is independently substituted or unsubstituted alkyl, substituted or unsubstituted aryl. substitute or heteroaryl 5 sustituido o sin sustituir; R1 y R2 pueden ser iguales o diferentes y son independientemente hidrógeno, alquilo sustituido o sin sustituir, cicloalquilo sustituido o sin sustituir, cicloalquilalquilo sustituido o sin sustituir, arilo sustituido o sin sustituir, arilalquilo sustituido o sin sustituir, grupo heterocíclico sustituido o sin sustituir, grupo heteroarilo sustituido o sin sustituir, o heteroarilalquilo sustituido o sin sustituir, o R1 y R2 pueden unirse para formar un anillo cíclico 5 substituted or unsubstituted; R1 and R2 may be the same or different and are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heteroaryl group, or substituted or unsubstituted heteroarylalkyl, or R1 and R2 may be joined to form a cyclic ring 10 opcionalmente sustituido, saturado o insaturado de 3 a 7 miembros, que puede incluir opcionalmente al menos dos heteroátomos seleccionados entre O, NR3 o S, o NR3R4; en cada aparición, R3 y R4 pueden ser iguales o diferentes y son independientemente hidrógeno, alquilo sustituido o sin sustituir, cicloalquilo sustituido o sin sustituir, arilo sustituido o sin sustituir, heteroarilo sustituido 10 optionally substituted, saturated or unsaturated from 3 to 7 members, which may optionally include at least two heteroatoms selected from O, NR3 or S, or NR3R4; at each occurrence, R3 and R4 may be the same or different and are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted heteroaryl o sin sustituir, o grupo heterocíclico sustituido o sin sustituir, o R3 y R4 pueden unirse para formar un anillo or unsubstituted, or substituted or unsubstituted heterocyclic group, or R3 and R4 can be joined to form a ring 15 cíclico opcionalmente sustituido, saturado o insaturado de 3 a 7 miembros, que puede incluir opcionalmente al menos dos heteroátomos seleccionados entre O, NR3 o S; p es 1; y A es Optionally substituted, saturated or unsaturated cyclic of 3 to 7 members, which may optionally include at least two heteroatoms selected from O, NR3 or S; p is 1; and A is imagen1image 1 en las que cada una de las líneas de puntos en A representa independientemente un doble enlace opcional, y en cada aparición, R5, R6, R7, R8, R9, R10, R11, R12, R13 y R14 son iguales o diferentes y se seleccionan entre hidrógeno, alquilo sustituido o sin sustituir, o arilo sustituido o sin sustituir; con la condición de que no tenga la fórmula: in which each of the dotted lines in A independently represents an optional double bond, and at each occurrence, R5, R6, R7, R8, R9, R10, R11, R12, R13 and R14 are the same or different and are selected between hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl; with the proviso that it does not have the formula: imagen1image 1 en la que R1 y R1 son como se han definido anteriormente, en la que R1 y R son como se han definido anteriormente, en la que los sustituyentes en grupos funcionales sustituidos pueden ser iguales o diferentes y son uno o más in which R1 and R1 are as defined above, in which R1 and R are as defined above, in which the substituents in substituted functional groups may be the same or different and are one or more 5 de hidroxi, halógeno, carboxilo, ciano, nitro, oxo (=O), tio (=S), alquilo C1-8, alcoxi C1-8, alquenilo C2-10, alquinilo C2-12, arilo C6-14, arilalquilo, cicloalquilo, cicloalquenilo, amino, arilo, heteroarilo, anillo heterociclilalquilo, heteroarilalquilo, anillo heterocíclico de 3-15 miembros en el anillo, guanidina, -COORx, -C(O)Rx, C(S)Rx, C(O)NRxRy, -C(O)ONRxRy, -NRxCON-RyRz, -N(Rx)SORy, -N(Rx)SO2, -(=N-N(Rx)Ry), -NRxC(O)ORy, -NRxRy, -NRxC(O)Ry, -NRxC(S)Ry, -NRxC(S)NRyRz, -SONRxRy, -SO2NRxRy, -ORx, ORxC(O)NRyRz, -ORxC(O)ORy, 5 hydroxy, halogen, carboxyl, cyano, nitro, oxo (= O), thio (= S), C1-8 alkyl, C1-8 alkoxy, C2-10 alkenyl, C2-12 alkynyl, C6-14 aryl, arylalkyl , cycloalkyl, cycloalkenyl, amino, aryl, heteroaryl, heterocyclylalkyl ring, heteroarylalkyl, 3-15 ring heterocyclic ring, guanidine, -COORx, -C (O) Rx, C (S) Rx, C (O) NRxRy , -C (O) ONRxRy, -NRxCON-RyRz, -N (Rx) SORy, -N (Rx) SO2, - (= NN (Rx) Ry), -NRxC (O) ORy, -NRxRy, -NRxC ( O) Ry, -NRxC (S) Ry, -NRxC (S) NRyRz, -SONRxRy, -SO2NRxRy, -ORx, ORxC (O) NRyRz, -ORxC (O) ORy, 10 OC(O)Rx, -OC(O)NRxRy, -RxNRyC(O)Rz, -RxORy, -RxC(O)ORy, -RxC(O)NRyRz, -RxC(O)Ry, -RxOC(O)Ry, -SRx, -SORx, -SO2Rx y -ONO2, en las que Rx, Ry y Rz se seleccionan independientemente entre hidrógeno, alquilo sustituido o sin sustituir, alcoxi sustituido o sin sustituir, alquenilo sustituido o sin sustituir, alquinilo sustituido o sin sustituir, arilo sustituido o sin sustituir, arilalquilo sustituido o sin sustituir, cicloalquilo sustituido o sin sustituir, cicloalquenilo sustituido o sin sustituir, amino sustituido o sin sustituir, arilo sustituido o sin sustituir, 10 OC (O) Rx, -OC (O) NRxRy, -RxNRyC (O) Rz, -RxORy, -RxC (O) ORy, -RxC (O) NRyRz, -RxC (O) Ry, -RxOC (O) Ry, -SRx, -SORx, -SO2Rx and -ONO2, in which Rx, Ry and Rz are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl substituted, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, 15 heteroarilo sustituido o sin sustituir, anillo heterociclilalquilo sustituido, heteroarilalquilo sustituido o sin sustituir y anillo heterocíclico sustituido o sin sustituir. 15 substituted or unsubstituted heteroaryl, substituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl and substituted or unsubstituted heterocyclic ring. 19. Un compuesto de acuerdo con la reivindicación 18, en el que el compuesto de Fórmula 1(A) es 19. A compound according to claim 18, wherein the compound of Formula 1 (A) is imagen3image3 en la que R es fenilo sustituido con al menos un halógeno; R1 y R2 pueden ser iguales o diferentes y son independientemente hidrógeno, alquilo sustituido o sin sustituir. in which R is phenyl substituted with at least one halogen; R1 and R2 may be the same or different and are independently hydrogen, substituted or unsubstituted alkyl. 5 5 10 10 15 fifteen 20 twenty 25 25 30 30 35 35 40 40 45 Four. Five

21. twenty-one.

Un compuesto de la reivindicación 20, en el que R es fenilo sustituido con uno o dos átomos de halógeno. A compound of claim 20, wherein R is phenyl substituted with one or two halogen atoms.

22. 22

Un compuesto de la reivindicación 20, en el que R1 es hidrógeno. A compound of claim 20, wherein R1 is hydrogen.

23. 2. 3.

Un compuesto de la reivindicación 20, en el que R2 se selecciona entre t-butilo, n-pentilo, ciclohexilmetilo, bencilo, 2-clorobencilo, 4-clorobencilo, 2,4-diclorobencilo, 2-fluorobencilo, 4-fluorobencilo, 2,4-difluorobencilo, 2,6difluorobencilo, 2-bromobencilo, 4-bromobencilo, 4-trifluorometilbencilo, 1-feniletilo, 1-metil-1-feniletilo, 2-feniletilo, 1(2-clorofenil)etilo, 2-(4-fluorofenil)etilo, 1-fenilpropilo, 1-etil-1-fenilpropilo, 1(2-clorofenil)-1-metiletilo, 2-hidroxi-1feniletilo, 2-piridilmetilo, 3-piridilmetilo o 4-piridilmetilo. A compound of claim 20, wherein R2 is selected from t-butyl, n-pentyl, cyclohexylmethyl, benzyl, 2-chlorobenzyl, 4-chlorobenzyl, 2,4-dichlorobenzyl, 2-fluorobenzyl, 4-fluorobenzyl, 2, 4-Difluorobenzyl, 2,6-difluorobenzyl, 2-bromobenzyl, 4-bromobenzyl, 4-trifluoromethylbenzyl, 1-phenylethyl, 1-methyl-1-phenylethyl, 2-phenylethyl, 1 (2-chlorophenyl) ethyl, 2- (4-fluorophenyl) ) ethyl, 1-phenylpropyl, 1-ethyl-1-phenylpropyl, 1 (2-chlorophenyl) -1-methylethyl, 2-hydroxy-1phenylethyl, 2-pyridylmethyl, 3-pyridylmethyl or 4-pyridylmethyl.

24. 24.

Un compuesto de acuerdo con la reivindicación 19, en el que el compuesto de Fórmula (1A) es A compound according to claim 19, wherein the compound of Formula (1A) is

imagen1image 1 una sal farmacéuticamente aceptable del mismo, un éster farmacéuticamente aceptable del mismo, un tautómero del mismo, un estereoisómero del mismo, un enantiómero del mismo o un diastereómero del mismo, en el que R es 2-clorofenilo, 4-clorofenilo, 2,4-diclorofenilo, 2-bromofenilo, 4-bromofenilo, 4-fluorofenilo, 2,4difluorofenilo, 4-metilfenilo, 4-metoxifenilo o 2-(4-clorofenil)fenilo; R1 es hidrógeno; y R2 es t-butilo, n-pentilo, ciclopentilo, ciclohexilo, adamantan-1-ilo, 2-metiladamantan-2-ilo, 3-hidroxiadamantan1-ilo, 1,3,3-trimetilbiciclo[2.2.1]hept-2-ilo, 1-fenilciclopropilo, ciclohexilmetilo, fenilo, 3-clorofenilo, 4-clorofenilo, 3-bromofenilo, 2-metoxifenilo, 4-terc-butilfenilo, 2,4-difluorofenilo, bencilo, 2-clorobencilo, 4-clorobencilo, 2,4diclorobencilo, 2-fluorobencilo, 4-fluorobencilo, 2,4-difluorobencilo, 2,6-difluorobencilo, 2-bromobencilo, 4bromobencilo, 4-trifluorometilbencilo, 1-feniletilo, 1-metil-1-feniletilo, 2-feniletilo, 1-(2-clorofenil) etilo, 2-(4fluorofenil)etilo, 1-fenilpropilo, 1-etil-1-fenilpropilo, 1-(2-clorofenil)-1-metiletilo, feniletanoato de metilo, 2-hidroxi1-feniletilo, piperidinilo, morfolinilo, piridinilo, 1,2,4-triazol-4-ilo, 2-piridilmetilo, 3-piridilmetilo o 4-piridilmetilo. a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable ester thereof, a tautomer thereof, a stereoisomer thereof, an enantiomer thereof or a diastereomer thereof, wherein R is 2-chlorophenyl, 4-chlorophenyl, 2,4 -dichlorophenyl, 2-bromophenyl, 4-bromophenyl, 4-fluorophenyl, 2,4difluorophenyl, 4-methylphenyl, 4-methoxyphenyl or 2- (4-chlorophenyl) phenyl; R1 is hydrogen; and R2 is t-butyl, n-pentyl, cyclopentyl, cyclohexyl, adamantan-1-yl, 2-methylamantan-2-yl, 3-hydroxyamantan-1-yl, 1,3,3-trimethylbicyclo [2.2.1] hept-2 -yl, 1-phenylcyclopropyl, cyclohexylmethyl, phenyl, 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 2-methoxyphenyl, 4-tert-butylphenyl, 2,4-difluorophenyl, benzyl, 2-chlorobenzyl, 4-chlorobenzyl, 2 , 4-dichlorobenzyl, 2-fluorobenzyl, 4-fluorobenzyl, 2,4-difluorobenzyl, 2,6-difluorobenzyl, 2-bromobenzyl, 4bromobenzyl, 4-trifluoromethylbenzyl, 1-phenylethyl, 1-methyl-1-phenylethyl, 2-phenylethyl, 1 - (2-Chlorophenyl) ethyl, 2- (4-fluorophenyl) ethyl, 1-phenylpropyl, 1-ethyl-1-phenylpropyl, 1- (2-chlorophenyl) -1-methylethyl, methyl phenylethanoate, 2-hydroxy-1-phenylethyl, piperidinyl , morpholinyl, pyridinyl, 1,2,4-triazol-4-yl, 2-pyridylmethyl, 3-pyridylmethyl or 4-pyridylmethyl.

25. 25.

Un compuesto de la reivindicación 24, en el que R es 2,4-difluorofenilo. A compound of claim 24, wherein R is 2,4-difluorophenyl.

26. 26.

Un compuesto de la reivindicación 24, en el que R es 4-clorofenilo. A compound of claim 24, wherein R is 4-chlorophenyl.

27. 27.

Un compuesto de la reivindicación 24, en el que R es 4-bromofenilo. A compound of claim 24, wherein R is 4-bromophenyl.

28. 28.

Un compuesto de la reivindicación 24, en el que R2 es t-butilo. A compound of claim 24, wherein R2 is t-butyl.

29. 29.

Un compuesto de acuerdo con la reivindicación 1, en el que R es arilo sustituido o sin sustituir. A compound according to claim 1, wherein R is substituted or unsubstituted aryl.

30. 30

Un compuesto de acuerdo con la reivindicación 1, en el que R es heteroarilo sustituido o sin sustituir. A compound according to claim 1, wherein R is substituted or unsubstituted heteroaryl.

31. 31.

Un compuesto de acuerdo con la reivindicación 29, en el que el arilo es fenilo. A compound according to claim 29, wherein the aryl is phenyl.

32. 32

Un compuesto de acuerdo con la reivindicación 1, en el que el compuesto se selecciona entre: A compound according to claim 1, wherein the compound is selected from:

N(7)-Piperidino-5-(2-bromofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetetradeca-4(8),6-dieno-7-carboxamida, N(7)-Bencil-5-(2-bromofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetetradeca-4(8),6-dieno-7-carboxamida, N(7)-Morfolino-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetetradeca-4(8),6-dieno-7-carboxamida, N(7)-(3-Piridilmetil)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetetradeca-4(8), 6-dieno-7-carboxamida, N(7)-(4-Piridilmetil)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetetradeca-4(8), 6-dieno-7-carboxamida, N(7)-Ciclohexil-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetetradeca-4(8), 6-dieno-7-carboxamida, N(7)-(N-ciclohexil-N-metilamino)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetetradeca-4(8),6-dieno-7carboxamida, N(7)-Ciclohexilmetil-5-(4-clorofenil)-5,6-diazatetraciclo [7.3.1.13,11.04,8]tetetradeca-4(8), 6-dieno-7-carboxamida, N(7)-(Adamantan-1-il)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11,04,8 tetetradeca-4(8)-6-dieno-7-carboxamida, N(7)-(1S,2endo-1,3,3-Trimetil-biciclo[2.2.1]hept-2-il)-5-(4-clorofenil)-5,6diazatetraciclo[7.3.1.13,11.04,8]tetetradeca-4(8)-6-dieno-7-carboxamida, N(7)-(2-Clorobencil)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetetradeca-4(8), 6-dieno-7-carboxamida, N(7)-(4-Clorobencil)-5-(4-clorofenil)-5,6-diazatetraciclo [7.3.1.13,11.04,8]tetetradeca-4 (8) -6-dieno-7-carboxamida, N(7)-(4-Fluorobencil)-5-(4-clorofenil)-5,6-diazoltraciclo[7.3.1.13,11.04,8]tetetradeca-4(8)-6-dieno-7-carboxamida, N(7)-(2,4-Difluorobencil)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetetradeca-4(8),6-dieno-7carboxamida, N(7)-(2,6-Difluorobencil)-5-(4-clorofenil)-5,6-diazoltraciclo[7.3.1.13,11.04,8]tetetradeca-4(8),6-dieno-7carboxamida, N (7) -Piperidino-5- (2-bromophenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetetradeca-4 (8), 6-diene-7-carboxamide, N (7) -Benzyl -5- (2-bromophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetetradeca-4 (8), 6-diene-7-carboxamide, N (7) -Morpholino-5- (4- chlorophenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetetradeca-4 (8), 6-diene-7-carboxamide, N (7) - (3-Pyridylmethyl) -5- (4-chlorophenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetetradeca-4 (8), 6-diene-7-carboxamide, N (7) - (4-Pyridylmethyl) -5- (4-chlorophenyl) -5 , 6-diazatetracycle [7.3.1.13,11.04,8] tetetradeca-4 (8), 6-diene-7-carboxamide, N (7) -Cyclohexyl-5- (4-chlorophenyl) -5,6-diazatetracycle [7.3 .1.13,11.04,8] tetetradeca-4 (8), 6-diene-7-carboxamide, N (7) - (N-cyclohexyl-N-methylamino) -5- (4-chlorophenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetetradeca-4 (8), 6-diene-7carboxamide, N (7) -Cyclohexylmethyl-5- (4-chlorophenyl) -5,6-diazatetracycle [7.3.1.13,11.04.8 ] tetetradeca-4 (8), 6-diene-7-carboxamide, N (7) - (Adamantan-1-yl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04 , 8 tetetradeca -4 (8) -6-diene-7-carboxamide, N (7) - (1S, 2endo-1,3,3-Trimethyl-bicyclo [2.2.1] hept-2-yl) -5- (4- chlorophenyl) -5,6diazatetracycle [7.3.1.13,11.04,8] tetetradeca-4 (8) -6-diene-7-carboxamide, N (7) - (2-Chlorobenzyl) -5- (4-chlorophenyl) -5 , 6-diazatetracyclo [7.3.1.13,11.04,8] tetetradeca-4 (8), 6-diene-7-carboxamide, N (7) - (4-Chlorobenzyl) -5- (4-chlorophenyl) -5.6 -diazatetracycle [7.3.1.13,11.04,8] tetetradeca-4 (8) -6-diene-7-carboxamide, N (7) - (4-Fluorobenzyl) -5- (4-chlorophenyl) -5,6-diazoltracycle [7.3.1.13,11.04,8] tetetradeca-4 (8) -6-diene-7-carboxamide, N (7) - (2,4-Difluorobenzyl) -5- (4-chlorophenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetetradeca-4 (8), 6-diene-7carboxamide, N (7) - (2,6-Difluorobenzyl) -5- (4-chlorophenyl) -5,6-diazoltracycle [7.3 .1.13,11.04,8] tetetradeca-4 (8), 6-diene-7carboxamide, N(7)-(4-Trifluorometilbencil-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetetradeca-4(8),6-dieno-7carboxamida, N(7)-(S-1-Feniletil)-5-(4-clorofenil)-5,6-diazatetraciclol[7.3.1.13,11.04,8]tetetradeca-4(8),6-dieno-7-carboxamida, N(7)-(R-1-Feniletil)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetetradeca-4(8), 6-dieno-7-carboxamida, N(7)-(1-Metil-1-feniletil)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetetradeca-4(8),6-dieno-7carboxamida, N(7)-(2-Piridilmetil)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetetradeca-4(8),b-dieno-7-carboxamida, N(7)-(N’-fenilamino)-5-(4-clorofenil)-5,6-dimetetraciclo[7.3.1.13,11.04,8]tetetradeca-4(8),6-dieno-7-carboxamida, Clorhidrato de N(7)-(N’-fenilamino)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetetradeca-4(8),6-dieno-7carboxamida, N(7)-(2-Clorofenilamino)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetetradeca-4(8),6-dieno-7carboxamida, Clorhidrato de N(7)-(2-Clorofenilamino)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetetradeca-4(8),6dieno-7-carboxamida, N(7)-[4-clorofenilamino]-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetetradeca-4(8),6-dieno-7carboxamida, N(7)-(2,4-Diclorofenilamino)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetetradeca-4(8),6-di-eno-7carboxamida, N(7)-[(2,4-Diclorofenil-N’-metilamino]-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetetradeca-4(8),6-dieno7-carboxamida, Clorhidrato de N(7)-[(2,4-diclorofenil-N’-metilamino]-5-(4-clorofenil)-5,6diazatetraciclo[7.3.1.13,11.04,8]tetetradeca-4(8),6-dieno-7-carboxamida, N(7)-(2,4-Diclorofenil-N’-ciclohexilamino)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetra-deca-4(8),6dieno-7-carboxamida, N(7)-(4-Fluorofenilamino)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetetradeca-4(8),6-dieno-7carboxamida, Clorhidrato de ClN(7)-(4-Fluorofenilamino)-S-(4-clorofenil)-S6-diazatetraciclo[7.3.1.13,11.04,8]tetetradeca-4(8),6di-eno-7-carboxamida clorhidrato, N(7)-(2,4-Difluorofenilamino]-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetetradeca-4(8),6-di-eno-7carboxamida, N(7)-(3-fluorofenilamino)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetetradeca-4(8),6-dieno-7carboxamida, N(7)-(3-Cloro-2-pirrilamino)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetetradeca-4(8),6-di-eno-7carboxamida, N(7)-(5-Cloro-2-pirilamino)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetetradeca-4(8),6-dieno-7carboxamida, N(7)-(2-Feniletil)-5-(4-clorofenil)-5,6 diazatetraciclo[7.3.1.13,11.04,8]tetetradeca-4(8)-6-dieno-7-carboxamida, N(7)-(N’,N’-Difenilamino)-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7carboxamida, N7-[1-(2-Clorofenil)etil]-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxamida, N(7)-Bencil-5-(4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-6-dieno-7-carboxamida, N(7)-Piperidino-5-(4’-clorofenilj-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-6-dieno-7-carboxamida, 7-(4’-Clorofenil)-6,7-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-5-dien-5-il-piperidinometanona, N(7)-Fenil-5-(4’-clorofenil)-5,6-diazatetraclo[7.3.1.13,11.04,8]tetradeca-4(8)-6-dieno-7-carboxamida, N(7)-Piperidino-5-(2,4-difluorofenil)-5,6-diazatetraciclo [7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxamida, N(7)-(Adamantan-1-il)-5-(2,4-difluorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-6-dieno-7carboxamida, N(7)-(1S,2endo-1,3,3-Trimetil-biciclo[2.2.1]hept-2-il)-5-(2,4-difuorofenil)-5,6diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-6-dieno-7-carboxamida, N(7)-(S-1-feniletil)-5-(2,4-difluorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxamida, N(7)-(R-1-feniletil)-5-(2,4-difluorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxamida, N(7)-(1-Metil-1-feniletil)-5-(2,4-difluorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-di-eno-7carboxamida, N(7)-(2-Clorobencil)-5-(2,4-difluorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7carboxamida, N(7)-(2,4-Diclorofenilamino)-5-(2,4-difluorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7carboxamida, N(7)-[1-(2-Clorofenil)-5-(2,4-difluorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7carboxamida, N(7)-[(S)-1-Fenilpropil]-5-(2,4-difluorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7carboxamida, N7[1-(2-Clorofenil)-1-metiletil-5-(2,4-difuorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7carboxamida, (2,R)-2-[7-(2,4-Difluorofenil)-6,7-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),5-dien-5-ilcarboxamido]-2feniletanoato de metilo, (2S)-2-[7-(2,4-Difluorofenil)-6,7-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),5-dien-5-ilcarboxam-ido]-2N (7) - (4-Trifluoromethylbenzyl-5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetetradeca-4 (8), 6-diene-7carboxamide, N (7) - (S-1-Phenylethyl) -5- (4-chlorophenyl) -5,6-diazatetracyclyl [7.3.1.13,11.04,8] tetetradeca-4 (8), 6-diene-7-carboxamide, N (7) - (R-1-Phenylethyl) -5- (4-chlorophenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetetradeca-4 (8), 6-diene-7-carboxamide, N (7) - (1-Methyl-1-phenylethyl) -5- (4-chlorophenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetetradeca-4 (8), 6-diene-7carboxamide, N (7) - (2-Pyridylmethyl) -5- (4-chlorophenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetetradeca-4 (8), b-diene-7-carboxamide, N (7) - (N '-phenylamino) -5- (4-chlorophenyl) -5,6-dimetetracycle [7.3.1.13,11.04,8] tetetradeca-4 (8), 6-diene-7-carboxamide, N (7) Hydrochloride - ( N'-phenylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetetradeca-4 (8), 6-diene-7carboxamide, N (7) - (2-Chlorophenylamino ) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetetradeca-4 (8), 6-diene-7carboxamide, N (7) Hydrochloride - (2-Chlorophenylamino) - 5- (4- chlorophenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetetradeca-4 (8), 6-diene-7-carboxamide, N (7) - [4-chlorophenylamino] -5- (4-chlorophenyl) -5 , 6-diazatetracyclo [7.3.1.13,11.04,8] tetetradeca-4 (8), 6-diene-7carboxamide, N (7) - (2,4-Dichlorophenylamino) -5- (4-chlorophenyl) -5.6 -diazatetracycle [7.3.1.13,11.04,8] tetetradeca-4 (8), 6-di-eno-7carboxamide, N (7) - [(2,4-Dichlorophenyl-N'-methylamino] -5- (4- chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetetradeca-4 (8), 6-diene7-carboxamide, N (7) hydrochloride - [(2,4-dichlorophenyl-N'-methylamino] -5- (4-chlorophenyl) -5,6diazatetracyclo [7.3.1.13,11.04,8] tetetradeca-4 (8), 6-diene-7-carboxamide, N (7) - (2,4-Dichlorophenyl-N ' -cyclohexylamino) -5- (4-chlorophenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetra-deca-4 (8), 6-diene-7-carboxamide, N (7) - (4-Fluorophenylamino ) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetetradeca-4 (8), 6-diene-7carboxamide, ClN Hydrochloride (7) - (4-Fluorophenylamino) - S- (4-chlorophenyl) -S6-diazatetracycle [7.3.1.13,11.04,8] tetetradeca-4 (8), 6di-eno-7-carboxy gives hydrochloride, N (7) - (2,4-Difluorophenylamino] -5- (4-chlorophenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetetradeca-4 (8), 6-di-eno -7carboxamide, N (7) - (3-fluorophenylamino) -5- (4-chlorophenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetetradeca-4 (8), 6-diene-7carboxamide, N (7) - (3-Chloro-2-pyrilamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetetradeca-4 (8), 6-di-eno-7carboxamide , N (7) - (5-Chloro-2-pyrylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetetradeca-4 (8), 6-diene-7carboxamide , N (7) - (2-Phenylethyl) -5- (4-chlorophenyl) -5.6 diazatetracycle [7.3.1.13,11.04,8] tetetradeca-4 (8) -6-diene-7-carboxamide, N ( 7) - (N ', N'-Diphenylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7carboxamide, N7- [1- (2-Chlorophenyl) ethyl] -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxamide, N ( 7) -Benzyl-5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8) -6-diene-7-carboxamide, N (7) -Piperidino-5 - (4'-chlorophenylj-5,6-d iazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8) -6-diene-7-carboxamide, 7- (4'-Chlorophenyl) -6,7-diazatetracycle [7.3.1.13,11.04,8] tetradeca- 4 (8) -5-dien-5-yl-piperidinometanone, N (7) -Phenyl-5- (4'-chlorophenyl) -5,6-diazatetraclo [7.3.1.13,11.04,8] tetradeca-4 (8 ) -6-diene-7-carboxamide, N (7) -Piperidino-5- (2,4-difluorophenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8), 6- diene-7-carboxamide, N (7) - (Adamantan-1-yl) -5- (2,4-difluorophenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8) - 6-diene-7carboxamide, N (7) - (1S, 2endo-1,3,3-Trimethyl-bicyclo [2.2.1] hept-2-yl) -5- (2,4-difuorophenyl) -5,6diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8) -6-diene-7-carboxamide, N (7) - (S-1-phenylethyl) -5- (2,4-difluorophenyl) -5.6 -diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) - (R-1-phenylethyl) -5- (2,4-difluorophenyl) -5 , 6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) - (1-Methyl-1-phenylethyl) -5- (2,4- difluorophenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8), 6-d i-eno-7carboxamide, N (7) - (2-Chlorobenzyl) -5- (2,4-difluorophenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8), 6- diene-7carboxamide, N (7) - (2,4-Dichlorophenylamino) -5- (2,4-difluorophenyl) -5,6-diazatetracycle [7.3.1.13.11.04.8] tetradeca-4 (8), 6- diene-7carboxamide, N (7) - [1- (2-Chlorophenyl) -5- (2,4-difluorophenyl) -5,6-diazatetracycle [7.3.1.13.11.04.8] tetradeca-4 (8), 6 -diene-7carboxamide, N (7) - [(S) -1-Phenylpropyl] -5- (2,4-difluorophenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8) , 6-diene-7carboxamide, N7 [1- (2-Chlorophenyl) -1-methylethyl-5- (2,4-difuorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8 ), 6-diene-7carboxamide, (2, R) -2- [7- (2,4-Difluorophenyl) -6,7-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8), 5- dien-5-ylcarboxamido] -2-methylphenylethanoate, (2S) -2- [7- (2,4-Difluorophenyl) -6,7-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 5 -dien-5-ilcarboxam-gone] -2 feniletanoato de metilo, N7-(3-Hidroxiadamantan-1-il)-5-(2,4-dfluorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7carboxamida, N(7)-(1-Metil-1-feniletil)-5-(4-fluorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7carboxamida, N(7)-(Adamantan-1-il)-5-(2,4-difluorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-6-dieno-7carboxamida, N7-(Adamantan-2-il)-5-(4-fluorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxamida, N7-(1,3,3-Trimetilbiciclo[2.2.1]hept-2-il)-5-(4-fluorofenil)-5,6-diazatetraciclo-[7.3.1.13,11.04,8]tetradeca-4(8),6dieno-7-carboxamida, N(7)-Piperidino-5-(4-metilfenil)-5,6-diazatetraciclo[7.3.1.1311.04,8]tetradeca-4(8),6-dieno-7-carboxamida, N(7)-(1,4-Diclorofenilamino)-5-(4-metilfenil)-5,6-diazatetraciclo[7.3.1.1311,048]tetradeca-4(8),6dieno-7carboxamida, N(7)-(2-Clorobencil)-5-(4-metilfenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6 dieno-7-carboxamida, N(7)-Piperidino-5-(4-metoxifenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxamida, N7-(2-Clorobencil)-5-(4-metoxifenil)-5,6-diazatetraciclo[7.3.1.1311.04,8]tetradeca-4(8), 6-dieno-7-carboxamida, N(7)-(2,4-Diclorofenilamino)-5-(4-metoxifenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7carboxamida, N(7)-Piperidino-5-[(2-clorofenil)fenil]-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxamida, N(7)-[(2,4-Diclorofenil)amino]-5-fenil-5,6-diazatetraciclo[7.3.1.1311.04,8]tetradeca-4(8), 6-dieno-7-carboxamida, N(7)-Fenil-5-fenil-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-6-dieno-7-carboxamida, N(7)-piperidino-5-fenil-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-6-dieno-7-carboxamida, N(7)-Bencil-5-fenil-5,6-diazatetraciclo[7.3.1.1311.04,8]tetradeca-4(8)-6-dieno-7-carboxamida; 7-Fenil-6,7-diazatetraciclo[7.3.1.1311.04,8]tetradeca-4(8)-5-dien-5-il-piperidinometanona; N(7)-(4-Fluorobencil)-5-(2,4-diclorofenil)-5,6-diazatetraciclo[7.3.1.1311.04,8]tetradeca-4(8),6-dieno-7carboxamida, N(7)-Fenilamino-5-(2,4-diclorofenil)-5,6-diazatetraciclo[7.3.1.1311.04,8]tetradeca-4(8),6-dieno-7-carboxamida, N(7)-(2-Clorofenilamino)-5-(2,4-diclorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7carboxamida, N(7)-(2,4-Diclorofenilamino)-5-(2,4-diclorofenil)-5,6-diazatetraciclo[7.3.1.1311.04,8]tetradeca-4(8),6-dieno-7carboxamida, N(7)-(2-Bromofenilamino)-5-(2,4-diclorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-di-eno-7carboxamida, N(7)-(N’,N’-Difenilamino)-5-(2,4-diclorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7carboxamida, N(7)-(2-Feniletil)-5-(2,4-diclorofenil)-5, 6-diazatetraciclo[7.3.1.1311.04,8]tetradeca-4(8), 6-dieno-7-carboxamida, N(7)-Bencil-5-(2,4’-diclorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-6-dieno-7-carboxamida. N(7)-piperidino-5-(2’,4’-diclorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6,-dieno-7-carboxamida, N(7)-(2,4-Diclorofenilamino)-5-(2-clorofenil)-5,6-diazatetraciclo[7.3.1.1311.04,8]tetradeca-4(8),6-dieno-7carboxamida, N(7)-Bencil-5-(2’-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-6-dieno-7-carboxamida, N(7)-ciclohexil-5-(2’-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-6-dieno-7-carboxamida, N(7)-piperidino-5-(2’-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4 (8)-6-dieno-7-carboxamida, N7-(2-Clorobencil)-5-(6-cloro-2-piridil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxamida, N(7)piperidino-5-metil-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-5-dieno-7-carboxamida, N(7)piperidino-3-metil-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-6-dieno-7-carboxamida, N(7)-(1-metil-1-feniletil)-6-pentil-5,6-diazatetraciclo[7.3.1.1311.04,8]tetradeca-4,7-dieno-7-carboxamida, N(7)-(1-metil-1-feniletil)-5-pentil-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-6-dieno-7-carboxamida, N(7)-[(1R)-2-Hidroxi-1-feniletil]-5-(2,4-difluorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4-(8),6-dieno-7carboxamida, N(7)-[(1S)-2-Hidroxi-1-feniletil]-5-(2,4-difluorofenil)-5,6-diazatetraciclo[7.3.1.1311.04,8]tetradeca-4(8),5-dieno-7carboxamida, N(3)-Piperidino-1-fenil-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carbaxamida, N(3)-Ciclohexil-1-fenil-4,5,5,7-tetrahidro-1H-4,7-metano-indazol-3-carbaxamida, N(3)-Bencil-1-fenil-4,5,5,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-Fenilamino-1-fenil-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-Piperidino-1-(2-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-Ciclohexil-1-(2-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-Bencil-1-(2-clorofenil)-4,5,5,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-Fenilamino-1-(2-clorofenil)-4,5,5,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-Piperidino-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, 1-(4-Clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-il-piperidinometanona, N(3)-Ciclohexil-1-(4-clorofenil)-4,5,5,7-tetrahidro-1H-4,7metano-indazol-3-carboxamida, N(3)-Ciclopentil-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-[(N-Ciclohexil-N-metilamino]-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-Fenil-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-(3-Clorofenil)-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-(4-Clorofenil)-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-(3-Bromofenil)-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-(2-Metoxifenil)-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-(4-terc-Butilfenil)-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-Bencil-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-(2-Clorobencil)-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-(4-Clorobencil)-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-(2,4-Diclorobencil)-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-(2-Bromobencil)-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-(4-Bromobencil)-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-(4-Fluorobencil)-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H4,7-metano-indazol-3-carboxamida, N(3)-(4-Trifluorometilbencil)-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-Fenilamino-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-[(4-Clorofenil)amino]-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-[(2,4-Diclorofenil)amino]-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-[(3,4-Diclorofenil)amino]-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-[(2-Fluorofenil)amino]-1-(4-clorofenil)-4,5,6,7-tetrahidra-1H-4,7-metano-indazol-3-carboxamida, N(3)-[(3-Fluorofenil)amino]-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H 4,7-metano-indazol-3-carboxamida, N(3)-[(4-Fluorofenil) amino]-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-[(2,4-Difluorofenil)amino]-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-(N’,N’-Difenilamino-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-Ciclohexil-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-Ciclohexilmetil-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indozol-3-carboxamida, N(3)-(N,N-Diciclohexilamino)-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-(4H1,2,4-triazol-4-il)-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-(1,3,3-Trimetilbiciclo[2,21]hept-2-il)-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3carboxamida, N(3)-(Adamantan-1-il)-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-Fenil-1-(1,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-(1,4-Difluorofenil)-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-(2-Fluorobencil)-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-(4-Fluorobencil)-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H 4,7-metano-indazol-3-carboxamida, N(3)-(2,4-Difluorobencil)-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H4,7-metano-indazol-3-carboxamida, N(3)-(2,6-Difluorobencil)-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-(2-Clorobencil)-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H4,7-metano-indazol-3-carboxamida, N(3)-(4-Clorobencil)-1-(1,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-(2,4-Diclorobencil)-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-[S-(1-Feniletil)]-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-[R-(1-Feniletil)]-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-(2-Feniletil)-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-[2-(4-fluorofenil)etil]-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-Fenilamino-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-[(2-Clorofenil)amino]-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-[N-(2-Clorofenil)-N-metilamino]-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3carboxamida, N(3)-[(4-Clorofenil)amino]-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-[(2,4-Diclorofenil)amino]-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-[(2,4-Diclorofenil)-N-metilamino]-1-(2,4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3carboxamida, N(3)-[(3,4-Diclorofenil)amino]-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-[(2-Bromofenil)amino]-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-[(2-Fluorofenil)amino]-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-[(2,4-Difluorofenil)amino]-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4, 7-metano-indazol-3-carboxamida, N(3)-[(3-Fluorofenil)amino]-1-(2,4-diclorofenil)-4,5,6,7 tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-[(3-Cloropiridin-2-il)amino]-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(5)-piperidino-3-(2’,4’-diclorofenil)-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxamida, N(5)-bencil-3-(2’,4’-diclorofenil)-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxamida, N(3)-Piperidino-1-(2-bromofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-Ciclohexil-1-(2-bromofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-Bencil-1-(2-bromofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-Fenilamino-1-(2-bromofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-Piperidino-1-(4-bromofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-Ciclohexil-1-(4-bromofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-Bencil-1-(4-bromofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-Fenilamino-1-(4-bromofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-[(2-Fluorofenil)amino]-1-(4-bromofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-Ciclohexil-1-(4-fluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-Bencil-1-(4-fluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N5-(Adamantan-2-il)-3-(4-fluorofenil)-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxamida, N5-(1-Metil-1-feniletil)-3-(4-fluorofenil)-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxamida, N5-(Adamantan-1-il)-3-(4-fluorofenil)-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxamida, N(3)-Fenilamino-1-(4-fluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-Fenilamino-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-[(2-Clorofenil)amino]-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-[(2-bromofenil)amino]-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-[(2-Fluorofenil)amino]-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-Piperidino-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-Ciclohexil-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-(Ciclohexilmetil)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-[5-(1-Feniletil)]-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-(R-1-feniletil)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-(1-Metil-1-feniletil)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N5-[1-(2-Clorofenil)-1-metiletil]-3-(2,4-difluorofenil)-3,4-diazatriciclo [5.2.1.02,6]deca-2(6),4-dien-5-carboxamida, N(3)-(1,3,3-Trimetilbiciclo[2.2.1]hept-2-il)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3carboxamida, N5(2-Clorofenil)-3-(2,4-difluorofenil)-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxamida, N5-(4-Clorobencil)-3-(2,4-difluorofenil)-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxamida, N5-(1-Etil-1-fenilpropil)-3-(2,4-difluorofenil)-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxamida, N5-[(1S)-1-Fenilpropil]-3-(2,4-difluorofenil)-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxamida, Metil(2S)-2-[5-(2,4-difluorofenil)-4,5-diazatriciclo[5.2.1.02,6]deca-2(6),3-dien-3-ilcarboxamido]-2-feniletanoato, N5-[(1S)-2-Hidroxi-1-feniletil]-3-(2,4-difluorofenil)-3,4-diazatriciclo [5.2.1.02,6]deca-2(6),4-dien-5-carboxamida, N(3)-(terc-Butil)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, (4R,7S)-N(3)-(terc-Butil)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, (4S,7R)-N(3)-(terc-Butil)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N5-n-Pentil-3-(2,4-difluorofenil)-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxamida, N5-(2,4-Diclorobencil)-3-(2,4-difluorofenil)-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxamida, N5-(1-fenilciclopropil)-3-(2,4-difluorofenil)-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxamida, N5-(2-Adamantil)-3-(2,4-difluorofenil)-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxamida, N5-(2-Metil-2-adamantil)-3-(2,4-difluorofenil)-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxamida, N7-(3-Hidroxiadamantan-1-il)-5-(1,4-difluorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7carboxamida, 4-[5-(2,4-Difluorofenil)-4,5-diazatriciclo[5.2.1.02,6]deca-2(6),3-dien-3-ilcarboxamido]morfolina, N(3)-(terc-Pentil)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-Ciclopropanmetil-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-Ciclobutil-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-(Tetrahidro-2H-4-piranmetil)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-Ciclopropil-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-(4-metilpiperazino)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, (2R)-2-[5-(2,4-difluorofenil)-4,5-diazatriciclo[5.2.1.0,2,6]deca-2(6),3-dien-3-ilcarbaxamido-2-feniletanoato de metilo, N(3)-[(1R)-2-Hidroxi-1-feniletil]-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metanoindazol-3-carboxamida, N(3)-(terc-Butil)-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-(Tetrahidro-2-furanilmetil)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-(terc-Butil)-1-(4-fluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-(terc-Butil)-1-(4-bromofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-(terc-Butil)-1-(3,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, (2S)-2-[5-(2,4-difluorofenil)-4,5-diazatriciclo[5.2.1.02,6]deca-2(6),3-dien-3-ilcarboxamido]-2-(4-fluorofenil)etanoato de metilo, N(3)-(terc-Butil)-1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-(4-Hidroxifenil)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-(terc-Butil)-1-(2-etoxi,4-fluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-(2-furilmetil)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-(2-tiofenometil)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-[(1S)-2-Hidroxi-1-(4-fluorofenil)etil]-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-in-dazol-3carboxamida, (2S)-2-[5-(2,4-difluorofenil)-4,5-diazatriciclo[5.2.1.0.2,6]deca-2(6),3-dien-3-ilcarboxamido]-4-metilpentanoato de metilo, N(3)-(Adamantan-lil)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-(terc-butil)-1-(4-fluorobencil)-4,5,5,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-(terc-butil)-2-(4-fluorobencil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-(terc-butil)-1-(4-metilbencil)-4, 5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-(2-Hidroxietil)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, methyl phenylethanoate, N7- (3-Hydroxiadamantan-1-yl) -5- (2,4-dfluorophenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene -7-carboxamide, N (7) - (1-Methyl-1-phenylethyl) -5- (4-fluorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene -7carboxamide, N (7) - (Adamantan-1-yl) -5- (2,4-difluorophenyl) -5,6-diazatetracycle [7.3.1.13.11.04.8] tetradeca-4 (8) -6-diene -7carboxamide, N7- (Adamantan-2-yl) -5- (4-fluorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxamide, N7- (1,3,3-Trimethylbicyclo [2.2.1] hept-2-yl) -5- (4-fluorophenyl) -5,6-diazatetracyclo- [7.3.1.13,11.04,8] tetradeca-4 (8 ), 6-diene-7-carboxamide, N (7) -Piperidino-5- (4-methylphenyl) -5,6-diazatetracycle [7.3.1.1311.04.8] tetradeca-4 (8), 6-diene-7- carboxamide, N (7) - (1,4-Dichlorophenylamino) -5- (4-methylphenyl) -5,6-diazatetracyclo [7.3.1.1311,048] tetradeca-4 (8), 6-diene-7carboxamide, N (7) - (2-Chlorobenzyl) -5- (4-methylphenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6 diene-7-carboxamide, N (7) -Piperidino- 5- (4-methoxy enyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxamide, N7- (2-Chlorobenzyl) -5- (4-methoxyphenyl) -5, 6-diazatetracycle [7.3.1.1311.04.8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) - (2,4-Dichlorophenylamino) -5- (4-methoxyphenyl) -5, 6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7carboxamide, N (7) -Piperidino-5 - [(2-chlorophenyl) phenyl] -5,6-diazatetracycle [7.3 .1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) - [(2,4-Dichlorophenyl) amino] -5-phenyl-5,6-diazatetracycle [7.3. 1,113.04.8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) -Phenyl-5-phenyl-5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 ( 8) -6-diene-7-carboxamide, N (7) -piperidino-5-phenyl-5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8) -6-diene-7-carboxamide , N (7) -Benzyl-5-phenyl-5,6-diazatetracycle [7.3.1.1311.04.8] tetradeca-4 (8) -6-diene-7-carboxamide; 7-Phenyl-6,7-diazatetracycle [7.3.1.1311.04.8] tetradeca-4 (8) -5-dien-5-yl-piperidinometanone; N (7) - (4-Fluorobenzyl) -5- (2,4-dichlorophenyl) -5,6-diazatetracycle [7.3.1.1311.04.8] tetradeca-4 (8), 6-diene-7carboxamide, N ( 7) -Phenylamino-5- (2,4-dichlorophenyl) -5,6-diazatetracycle [7.3.1.1311.04.8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) - ( 2-Chlorophenylamino) -5- (2,4-dichlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7carboxamide, N (7) - (2, 4-Dichlorophenylamino) -5- (2,4-dichlorophenyl) -5,6-diazatetracycle [7.3.1.1311.04.8] tetradeca-4 (8), 6-diene-7carboxamide, N (7) - (2- Bromophenylamino) -5- (2,4-dichlorophenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8), 6-di-eno-7carboxamide, N (7) - (N ' , N'-Diphenylamino) -5- (2,4-dichlorophenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7carboxamide, N (7) - ( 2-Phenylethyl) -5- (2,4-dichlorophenyl) -5, 6-diazatetracycle [7.3.1.1311.04.8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) -Benzyl -5- (2,4'-dichlorophenyl) -5,6-diazatetracyclo [7.3.1.13.11.04.8] tetradeca-4 (8) -6-diene-7-carboxamide. N (7) -piperidino-5- (2 ', 4'-dichlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6, -diene-7-carboxamide, N (7) - (2,4-Dichlorophenylamino) -5- (2-chlorophenyl) -5,6-diazatetracycle [7.3.1.1311.04.8] tetradeca-4 (8), 6-diene-7carboxamide, N (7 ) -Benzyl-5- (2'-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8) -6-diene-7-carboxamide, N (7) -cyclohexyl-5 - (2'-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8) -6-diene-7-carboxamide, N (7) -piperidino-5- (2'- chlorophenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8) -6-diene-7-carboxamide, N7- (2-Chlorobenzyl) -5- (6-chloro-2-pyridyl ) -5,6-diazatetracycle [7.3.1.13,11.04.8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) piperidino-5-methyl-5,6-diazatetracycle [7.3.1.13 , 11.04.8] tetradeca-4 (8) -5-diene-7-carboxamide, N (7) piperidino-3-methyl-5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8) -6-diene-7-carboxamide, N (7) - (1-methyl-1-phenylethyl) -6-pentyl-5,6-diazatetracycle [7.3.1.1311.04.8] tetradeca-4,7-diene- 7-carboxamide, N (7) - (1-methyl -1-phenylethyl) -5-pentyl-5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8) -6-diene-7-carboxamide, N (7) - [(1R) -2 -Hydroxy-1-phenylethyl] -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4- (8), 6-diene-7carboxamide, N (7) - [(1S) -2-Hydroxy-1-phenylethyl] -5- (2,4-difluorophenyl) -5,6-diazatetracycle [7.3.1.1311.04.8] tetradeca-4 (8), 5-diene- 7carboxamide, N (3) -Piperidino-1-phenyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carbaxamide, N (3) -Cyclohexyl-1-phenyl-4, 5,5,7-tetrahydro-1H-4,7-methane-indazol-3-carbaxamide, N (3) -Benzyl-1-phenyl-4,5,5,7-tetrahydro-1H-4,7-methane -indazol-3-carboxamide, N (3) -Phenylamino-1-phenyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) -Piperidino-1 - (2-Chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) -Cyclohexyl-1- (2-chlorophenyl) -4.5, 6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) -Benzyl-1- (2-chlorophenyl) -4,5,5,7-tetrahydro-1H-4,7 -methane-indazol-3-carboxamide, N (3) -Phenylamino-1- (2-chlorophenyl) -4,5,5,7-tetrahydro-1H-4,7-meta non-indazol-3-carboxamide, N (3) -Piperidino-1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, 1- ( 4-Chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-yl-piperidinometanone, N (3) -Cyclohexyl-1- (4-chlorophenyl) -4.5, 5,7-tetrahydro-1H-4,7methane-indazol-3-carboxamide, N (3) -Cyclopentyl-1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane -indazol-3-carboxamide, N (3) - [(N-Cyclohexyl-N-methylamino] -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazole -3-carboxamide, N (3) -Phenyl-1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - ( 3-Chlorophenyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (4-Chlorophenyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (3-Bromophenyl) -1- (4-chlorophenyl) -4 , 5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (2-Methoxyphenyl) -1- (4-chlorophenyl) -4,5,6,7- tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (4-tert-Butylphenyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro -1H-4,7-methane-indazol-3-carboxamide, N (3) -Benzyl-1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol- 3-carboxamide, N (3) - (2-Chlorobenzyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3 ) - (4-Chlorobenzyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (2,4- Dichlorobenzyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (2-Bromobenzyl) -1- (4 -chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (4-Bromobenzyl) -1- (4-chlorophenyl) -4,5 , 6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (4-Fluorobenzyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro- 1H4,7-methane-indazol-3-carboxamide, N (3) - (4-Trifluoromethylbenzyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazole -3-carboxamide, N (3) -Phenylamino-1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - [ (4-Chlorophenyl) amino] -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - [(2,4 -Dichlor Ofhenyl) amino] -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - [(3,4-Dichlorophenyl) amino] -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - [(2-Fluorophenyl) amino] -1 - (4-chlorophenyl) -4,5,6,7-tetrahydra-1H-4,7-methane-indazol-3-carboxamide, N (3) - [(3-Fluorophenyl) amino] -1- (4- chlorophenyl) -4,5,6,7-tetrahydro-1H 4,7-methane-indazol-3-carboxamide, N (3) - [(4-Fluorophenyl) amino] -1- (4-chlorophenyl) -4, 5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - [(2,4-Difluorophenyl) amino] -1- (4-chlorophenyl) -4.5, 6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (N ', N'-Diphenylamino-1- (4-chlorophenyl) -4,5,6,7- tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) -Cyclohexyl-1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane -indazol-3-carboxamide, N (3) -Cyclohexylmethyl-1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indozol-3-carboxamide, N ( 3) - (N, N-Dicyclohexylamino) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (4H1,2,4-triazol-4-yl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3- carboxamide, N (3) - (1,3,3-Trimethylbicyclo [2.21] hept-2-yl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4 , 7-methane-indazol-3carboxamide, N (3) - (Adamantan-1-yl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane- indazol-3-carboxamide, N (3) -Phenyl-1- (1,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3 ) - (1,4-Difluorophenyl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - ( 2-Fluorobenzyl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (4-Fluorobenzyl) - 1- (2,4-Dichlorophenyl) -4,5,6,7-tetrahydro-1H 4,7-methane-indazol-3-carboxamide, N (3) - (2,4-Difluorobenzyl) -1- (2 , 4-dichlorophenyl) -4,5,6,7-tetrahydro-1H4,7-methane-indazol-3-carboxamide, N (3) - (2,6-Difluorobenzyl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (2-Chlorobenzyl) -1- (2,4-dichlorophenyl) -4,5, 6,7-tetrahydro-1H4,7-methane-indazol-3- carboxamide, N (3) - (4-Chlorobenzyl) -1- (1,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3 ) - (2,4-Dichlorobenzyl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - [ S- (1-Phenylethyl)] - 1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - [R - (1-Phenylethyl)] - 1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (2- Phenylethyl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - [2- (4-fluorophenyl) ethyl] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) -Phenylamino-1- (2,4 -dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - [(2-Chlorophenyl) amino] -1- (2,4-dichlorophenyl ) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - [N- (2-Chlorophenyl) -N-methylamino] -1- (2, 4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3carboxamide, N (3) - [(4-Chlorophenyl) amino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-m ethane-indazol-3-carboxamide, N (3) - [(2,4-Dichlorophenyl) amino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7- methane-indazol-3-carboxamide, N (3) - [(2,4-Dichlorophenyl) -N-methylamino] -1- (2,4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4 , 7-methane-indazol-3carboxamide, N (3) - [(3,4-Dichlorophenyl) amino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7 -methane-indazol-3-carboxamide, N (3) - [(2-Bromophenyl) amino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane -indazol-3-carboxamide, N (3) - [(2-Fluorophenyl) amino] - (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3 -carboxamide, N (3) - [(2,4-Difluorophenyl) amino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4, 7-methane-indazol-3 -carboxamide, N (3) - [(3-Fluorophenyl) amino] -1- (2,4-dichlorophenyl) -4,5,6,7 tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - [(3-Chloropyridin-2-yl) amino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3- carboxamide, N (5) -piperidino-3- (2 ', 4'-dichlorophenyl) -3,4-diazatricyclo [5.2.1.02.6] deca-2 (6), 4-diene-5-carboxamide, N ( 5)- benzyl-3- (2 ', 4'-dichlorophenyl) -3,4-diazatricyclo [5.2.1.02.6] deca-2 (6), 4-dien-5-carboxamide, N (3) -Piperidino-1- (2-Bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) -Cyclohexyl-1- (2-bromophenyl) -4,5,6 , 7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) -Benzyl-1- (2-bromophenyl) -4,5,6,7-tetrahydro-1H-4,7- methane-indazol-3-carboxamide, N (3) -Phenylamino-1- (2-bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3 ) -Piperidino-1- (4-bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) -Cyclohexyl-1- (4-bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) -Benzyl-1- (4-bromophenyl) -4,5,6,7-tetrahydro- 1H-4,7-methane-indazol-3-carboxamide, N (3) -Phenylamino-1- (4-bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3 -carboxamide, N (3) - [(2-Fluorophenyl) amino] -1- (4-bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) -Cyclohexyl-1- (4-fluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) -Benci l-1- (4-fluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N5- (Adamantan-2-yl) -3- (4-fluorophenyl ) -3,4-diazatricyclo [5.2.1.02.6] deca-2 (6), 4-dien-5-carboxamide, N5- (1-Methyl-1-phenylethyl) -3- (4-fluorophenyl) -3 , 4-diazatricyclo [5.2.1.02.6] deca-2 (6), 4-dien-5-carboxamide, N5- (Adamantan-1-yl) -3- (4-fluorophenyl) -3,4-diazatricyclo [ 5.2.1.02.6] deca-2 (6), 4-dien-5-carboxamide, N (3) -Phenylamino-1- (4-fluorophenyl) -4,5,6,7-tetrahydro-1H-4, 7-methane-indazol-3-carboxamide, N (3) -Phenylamino-1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide , N (3) - [(2-Chlorophenyl) amino] -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - [(2-Bromophenyl) amino] -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3 ) - [(2-Fluorophenyl) amino] -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - Piperidino-1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) -Cyclohexyl-1- (2,4- diflu orophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (Cyclohexylmethyl) -1- (2,4-difluorophenyl) -4,5, 6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - [5- (1-Phenylethyl)] - 1- (2,4-difluorophenyl) -4,5,6 , 7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (R-1-phenylethyl) -1- (2,4-difluorophenyl) -4,5,6,7- tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (1-Methyl-1-phenylethyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro -1H-4,7-methane-indazol-3-carboxamide, N5- [1- (2-Chlorophenyl) -1-methylethyl] -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5.2.1.02 , 6] deca-2 (6), 4-dien-5-carboxamide, N (3) - (1,3,3-Trimethylbicyclo [2.2.1] hept-2-yl) -1- (2,4- difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3carboxamide, N5 (2-Chlorophenyl) -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5.2. 1.02.6] deca-2 (6), 4-dien-5-carboxamide, N5- (4-Chlorobenzyl) -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5.2.1.02.6] deca -2 (6), 4-dien-5-carboxamide, N5- (1-Ethyl-1-phenylpropyl) -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5.2.1.02.6] deca- 2 (6) , 4-dien-5-carboxamide, N5 - [(1S) -1-Phenylpropyl] -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5.2.1.02.6] deca-2 (6), 4-dien-5-carboxamide, Methyl (2S) -2- [5- (2,4-difluorophenyl) -4,5-diazatricyclo [5.2.1.02.6] deca-2 (6), 3-dien-3 -ylcarboxamido] -2-phenylethanoate, N5 - [(1S) -2-Hydroxy-1-phenylethyl] -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5.2.1.02.6] deca-2 ( 6), 4-dien-5-carboxamide, N (3) - (tert-Butyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane- indazol-3-carboxamide, (4R, 7S) -N (3) - (tert-Butyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane -indazol-3-carboxamide, (4S, 7R) -N (3) - (tert-Butyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7- methane-indazol-3-carboxamide, N5-n-Pentyl-3- (2,4-difluorophenyl) -3,4-diazatricyclo [5.2.1.02.6] deca-2 (6), 4-diene-5-carboxamide , N5- (2,4-Dichlorobenzyl) -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5.2.1.02.6] deca-2 (6), 4-dien-5-carboxamide, N5- (1-phenylcyclopropyl) -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5.2.1.02.6] deca-2 (6), 4-dien-5-carboxamide, N5- (2-Adamantil) -3- (2,4-dif luorophenyl) -3,4-diazatricyclo [5.2.1.02.6] deca-2 (6), 4-dien-5-carboxamide, N5- (2-Methyl-2-adamantyl) -3- (2,4-difluorophenyl ) -3,4-diazatricyclo [5.2.1.02.6] deca-2 (6), 4-dien-5-carboxamide, N7- (3-Hydroxiadamantan-1-yl) -5- (1,4-difluorophenyl) -5,6-diazatetracycle [7.3.1.13.11.04.8] tetradeca-4 (8), 6-diene-7carboxamide, 4- [5- (2,4-Difluorophenyl) -4,5-diazatricyclo [5.2.1.02 , 6] deca-2 (6), 3-dien-3-ylcarboxamido] morpholine, N (3) - (tert-Pentyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro -1H-4,7-methane-indazol-3-carboxamide, N (3) -Cyclopropanmethyl-1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane- indazol-3-carboxamide, N (3) -Cyclobutyl-1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3 ) - (Tetrahydro-2H-4-pyranmethyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) -Cyclopropyl-1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (4-methylpiperazino) -1- (2,4-Difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxam outbound, (2R) -2- [5- (2,4-difluorophenyl) -4,5-diazatricyclo [5.2.1.0,2,6] deca-2 (6), 3-dien-3-ylcarbaxamido-2- methyl phenylethanoate, N (3) - [(1R) -2-Hydroxy-1-phenylethyl] -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methanoindazole -3-carboxamide, N (3) - (tert-Butyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N ( 3) - (Tetrahydro-2-furanylmethyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (tert-Butyl) -1- (4-fluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (tert-Butyl) -1 - (4-bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (tert-Butyl) -1- (3,4-dichlorophenyl ) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, (2S) -2- [5- (2,4-difluorophenyl) -4,5-diazatricyclo [5.2 .1.02.6] deca-2 (6), 3-dien-3-ylcarboxamido] -2- (4-fluorophenyl) methyl ethanoate, N (3) - (tert-Butyl) -1- (2,4- dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (4-Hydroxyphenyl) -1- (2,4-difluorophenyl) -4, 5,6,7-tetrahi dro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (tert-Butyl) -1- (2-ethoxy, 4-fluorophenyl) -4,5,6,7-tetrahydro-1H -4,7-methane-indazol-3-carboxamide, N (3) - (2-furylmethyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7- methane-indazol-3-carboxamide, N (3) - (2-thiophenomethyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3 -carboxamide, N (3) - [(1S) -2-Hydroxy-1- (4-fluorophenyl) ethyl] -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4 , 7-methane-in-dazol-3carboxamide, (2S) -2- [5- (2,4-difluorophenyl) -4,5-diazatricyclo [5.2.1.0.2,6] deca-2 (6), 3 -dien-3-ylcarboxamido] -4-methyl methylpentanoate, N (3) - (Adamantan-lil) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7 -methane-indazol-3-carboxamide, N (3) - (tert-butyl) -1- (4-fluorobenzyl) -4,5,5,7-tetrahydro-1H-4,7-methane-indazol-3- carboxamide, N (3) - (tert-butyl) -2- (4-fluorobenzyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (tert-butyl) -1- (4-methylbenzyl) -4, 5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (2-Hydroxyethyl) -1 - (2,4-difluorofe nil) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N(3)-(Tieniletil)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-(Isopropil)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-[(1S)-2-Metoxi-1-feniletil]-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H4,7-metano-indazol-3-carboxamida, N(3)-(terc-butil)-2-(4-metilbencil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-Fenil-1-(2,4-diclorofenil)-7,8,8-trimetil-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida, N(3)-[(2-Fluorofenil)amino]-1-(2,4-Diclorofenil)-7,8,8-trimetil-4,5,6,7-tetrahidro-1H-4,7-metano-in-dazol-3carboxamida, N(3)-[(2,4-Difluorofenil)amino]-1-(2,4-diclorofenil)-7,8,8-trimetil-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3carboxamida, N(3)-[(3Ccloropiridin-2-il)amino]-1-(1,4-diclorofenil)-7,8,8-trimetil-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3carboxamida, N(3)-(Adamantan-1il)-1-(2,4-difluorofenil)-7,8,8-trimetil-4,5,6,7-tetrahidro-1H4,7-metano-indazol-3-carboxamida, N(3)-(1,3,3-Trimetilbiciclo[2.2.1]hept-2-il)-1-(2,4-difluorofenil)-7,8,8-trimetil-4,5,6,7-tetrahidro-1H-4,7-metanoindazol-3-carbaxamida, N(3)-(1-Metil-1-feniletil)-1-(2,4-difluorofenil)-7,8,8-trimetil-4,5,6,7-tetrahidro-1H-4,7-metano-in-dazol-3carboxomida, (4R,7S)-N(3)-terc-Butil-1-(2,4-difluorofenil)-7,8,8-trimetil-4,5,6,7-tetrahidro-1H-metano-inalazol-3-carboxamida, (2R)-2-[1-(2,4-difluorofenil)-7,8,8-trimetil-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamido]-2feniletanoato de metilo, N(3)-[(1R)-2-Hidroxi-1-feniletil]-1-(2,4-difluorofenil)-7,8,8-trimetil)-4,5,6,7-tetrahidro-1H-4,-7-metano-indazol-3carboxamida, N(3)pentil-1-(2,4-difluorofenil)-7,8,8-trimetil-4,5,6,7-tetrahidro-1H-metano-indazol-3-carboxamida, (4S,7R)-N-(3)-terc-Butil-1-(2,4-difluorofenil)-7,8,8-trimetil-4,5,6,7-tetrahidro-1H-metano-indazol-3-carboxamida, N(12)-Bencil-10-(2,4-diclorofenil)-10,11-diazatetraciclo[6.5.2.1.0.2,7.09,13]pentadeca-2,4,6,9(13),1-pentaeno-12carboxamida, N(12)-Piperidino-10-(2,4-diclorofenil)-10,11-diazatetraciclo[6.5.2.02,7.02,7.09,13]pentadeca-2,4,6,9(13),11pentaeno-12-carboxamida, Clorhidrato de N(12)-piperidino-10-(2,4-diclorofenil)-10,11-diazatetraciclo[6.5.2.02,7,09,13]pentadeca2,4,6,9(13),11-pentaeno-12-carboxamida, N(12)-[(N’-Ciclohexil-N’-metil)amino]-10-(2,4-diclorofenil)-10,11-diazatetraciclo[6.5.2.02,7,09,13]pentadeca2,4,6,9(13),11-pentaeno-12-carboxamida, N(12)-{N’-[2,4-Diclorofenil)-N’-metil]amino}-10-(2,4-diclorofenil)-10,11-diazatetraciclo[6.5.2.02,7.09,13]pentadeca2,4,6,9(13),11-pentaeno-12-carboxamida, N(12)-(Adamantan-1il)-10-(2,4-diclorofenil)-10,11-diazatetraciclo[6.5.2.02,7,09,13]pentadeca-2,4,6,9(13),11pentaeno-12-carboxamida, N12-(1,3,3-Trimetilbiciclo[2.2.1]hept-2-il)-10-(2,4-diclorofenil)-10,11-diazatetraciclo[6.5.2.02,7.09,13]pentadeca2(7),3,5,9(13),11-pentaeno-12-carboxamida. N12-(1-Metil-1-feniletil)-10-(2,4,diclorofenil)-10,11-diazatetraciclo[6.5.2.02,7.09,13]pentadeca-2,4,6,9(13),11pentaeno-12-carboxamida, N12-(1-Metil-1-feniletil-10-(2,4-difluorofenil)-10,11-diazatetraciclo[6.5.2.02,7,09,13]pentadeca-2,4,6,9(13),11pentaeno-12-carboxamida, N(12)-Bencil-16-(4-clorofenil)-10-(2,4-diclorofenil)-15,17-dioxo-10,11,16triazapentaciclo[6.5.2.02,7.09,13]octadeca-2,4,6,9(13),11-pentaeno-12-carboxamida o N(12)-Piperidino-16-(4clorofenil)-10-(2,4-diclorofenil)-15,17-dioxo-10,11,16-triazapentaciclo[6.5.2.02,7.09,13]octadeca-2,4,6,9(13),11pentaeno-12-carboxamida, N12-Bencil-10-(2,4-difluorofenil)-10,11-diazatetraciclo[6.5.2.02,7,09,13]tetradeca-2,4,6,9(13),11-pentaeno-12carboxamida, N12-(1-Metil-1-feniletil)-10-(2,4-difluorofenil)-10,11-diazatetraciclo[6.5.1.02,7,09,13]tetradeca-2,4,6,9(13),11pentaeno-12-carboxamida, N(12)-terc-Butil-10-(2,4-difluorofenil)-10,11-diazatetraciclo [6.5.1.02,709,13]tetradeca-2,4,6,9(13),11-pentaeno-12carboxamida, N5-(terc-Butil)-3-(2,4-difluorofenil)-3,4-diazatriciclo[5.2.2.02,6]undeca-2(6),4-dien-5-carboxamida, N(5)-(terc-Pentil)-3-(2,4-difluorofenil)-3,4-diazatriciclo[5.2.2.02,6]undeca-2(6),4-dien-5-carboxamida, Ácido 5-(2-bromofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxílico, Ácido 5-4-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxílico, Ácido 5-(2,4-difluorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxílico, Ácido 5-(4-fluorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxílico, Ácido 5-(4-metilfenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxílico, Ácido 5-(4-metoxifenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxílico, Ácido 5-fenil-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxílico, Ácido 5-(2,4-diclorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxílico, Ácido 5-(2-clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxílico, Ácido 5-(5-cloropiridil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxílico, Ácido 5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxílico, Ácido 6-pentil-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4,7-dieno-7-carboxílico, Ácido 5-pentil-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-6-dieno-7-carboxílico, N (3) - (Thienylethyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (Isopropyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - [(1S) -2-Methoxy-1-phenylethyl] -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H4,7-methane-indazol-3-carboxamide , N (3) - (tert-butyl) -2- (4-methylbenzyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) -Phenyl-1- (2,4-dichlorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - [(2-Fluorophenyl) amino] -1- (2,4-Dichlorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methane- in-dazol-3carboxamide, N (3) - [(2,4-Difluorophenyl) amino] -1- (2,4-dichlorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7- methane-indazol-3carboxamide, N (3) - [(3 Chloropyridin-2-yl) amino] -1- (1,4-dichlorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7- methane-indazol-3carboxamide, N (3) - (Adamantan-1yl) -1- (2,4-difluorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H4,7-methane-indazol-3-carboxamide , N (3) - (1,3,3-Trimethylbicyclo [2.2.1] hept-2-yl) -1- (2,4-difluorophenyl) -7,8,8-trimethyl-4,5,6,7 -tetrahydro-1H-4,7-methanoindazol-3-carbaxamide, N (3) - (1-Methyl-1-phenylethyl) -1- (2,4-difluorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methane -in-dazol-3carboxomide, (4R, 7S) -N (3) -terc-Butyl-1- (2,4-difluorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-methane-inalazol-3 -carboxamide, (2R) -2- [1- (2,4-Difluorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamido] - 2-methylphenylethanoate, N (3) - [(1R) -2-Hydroxy-1-phenylethyl] -1- (2,4-difluorophenyl) -7,8,8-trimethyl) -4,5,6,7-tetrahydro-1H- 4, -7-methane-indazol-3carboxamide, N (3) pentyl-1- (2,4-difluorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-methane-indazol-3-carboxamide, (4S, 7R) -N- (3) -terc-Butyl-1- (2,4-difluorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-methane-indazole- 3-carboxamide, N (12) -Benzyl-10- (2,4-dichlorophenyl) -10,11-diazatetracycle [6.5.2.1.0.2,7.09,13] pentadeca-2,4,6,9 (13), 1-pentaeno- 12carboxamide, N (12) -Piperidino-10- (2,4-dichlorophenyl) -10,11-diazatetracycle [6.5.2.02,7.02,7.09,13] pentadeca-2,4,6,9 (13), 11pentaeno-12- carboxamide, N (12) -piperidino-10- (2,4-dichlorophenyl) -10,11-diazatetracyclo [6.5.2.02,7,09,13] pentadeca2,4,6,9 (13), 11-pentane- hydrochloride 12-carboxamide, N (12) - [(N'-Cyclohexyl-N'-methyl) amino] -10- (2,4-dichlorophenyl) -10,11-diazatetracycle [6.5.2.02,7,09,13] pentadeca2,4, 6.9 (13), 11-pentaeno-12-carboxamide, N (12) - {N '- [2,4-Dichlorophenyl) -N'-methyl] amino} -10- (2,4-dichlorophenyl) -10,11-diazatetracyclo [6.5.2.02,7.09,13] pentadeca2 , 4,6,9 (13), 11-pentaeno-12-carboxamide, N (12) - (Adamantan-1il) -10- (2,4-dichlorophenyl) -10,11-diazatetracycle [6.5.2.02,7,09,13] pentadeca-2,4,6,9 (13), 11pentaeno-12-carboxamide, N12- (1,3,3-Trimethylbicyclo [2.2.1] hept-2-yl) -10- (2,4-dichlorophenyl) -10,11-diazatetracycle [6.5.2.02,7.09,13] pentadeca2 (7) , 3,5,9 (13), 11-pentaeno-12-carboxamide. N12- (1-Methyl-1-phenylethyl) -10- (2,4, dichlorophenyl) -10,11-diazatetracyclo [6.5.2.02,7.09,13] pentadeca-2,4,6,9 (13), 11pentaeno -12-carboxamide, N12- (1-Methyl-1-phenylethyl-10- (2,4-difluorophenyl) -10,11-diazatetracyclo [6.5.2.02,7,09,13] pentadeca-2,4,6,9 (13), 11pentaeno-12-carboxamide, N (12) -Benzyl-16- (4-chlorophenyl) -10- (2,4-dichlorophenyl) -15,17-dioxo-10,11,16triazapentacyclo [6.5.2.02,7.09,13] octadeca-2,4 , 6.9 (13), 11-pentaeno-12-carboxamide or N (12) -Piperidino-16- (4-chlorophenyl) -10- (2,4-dichlorophenyl) -15,17-dioxo-10,11,16 -triazapentacyclo [6.5.2.02.7.09.13] octadeca-2,4,6,9 (13), 11pentaeno-12-carboxamide, N12-Benzyl-10- (2,4-difluorophenyl) -10,11-diazatetracyclo [6.5.2.02,7,09,13] tetradeca-2,4,6,9 (13), 11-pentane-12carboxamide, N12- (1-Methyl-1-phenylethyl) -10- (2,4-difluorophenyl) -10,11-diazatetracyclo [6.5.1.02,7,09,13] tetradeca-2,4,6,9 (13) , 11pentaeno-12-carboxamide, N (12) -terc-Butyl-10- (2,4-difluorophenyl) -10,11-diazatetracyclo [6.5.1.02,709,13] tetradeca-2,4,6,9 (13), 11-pentaeno- 12carboxamide, N5- (tert-Butyl) -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5.2.2.02.6] undeca-2 (6), 4-dien-5-carboxamide, N (5) - (tert-Pentyl) -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5.2.2.02.6] undeca-2 (6), 4-dien-5-carboxamide, 5- (2-Bromophenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxylic acid, 5-4-Chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxylic acid, 5- (2,4-Difluorophenyl) -5,6-diazatetracyclo [7.3.1.13.11.04.8] tetradeca-4 (8), 6-diene-7-carboxylic acid, 5- (4-fluorophenyl) -5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxylic acid, 5- (4-Methylphenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxylic acid, 5- (4-Methoxyphenyl) -5,6-diazatetracycle [7.3.1.13.11.04.8] tetradeca-4 (8), 6-diene-7-carboxylic acid, 5-Phenyl-5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxylic acid, 5- (2,4-Dichlorophenyl) -5,6-diazatetracycle [7.3.1.13.11.04.8] tetradeca-4 (8), 6-diene-7-carboxylic acid, 5- (2-Chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6-diene-7-carboxylic acid, 5- (5-Chloropyridyl) -5,6-diazatetracycle [7.3.1.13.11.04.8] tetradeca-4 (8), 6-diene-7-carboxylic acid, 5,6-Diazatetracycle [7.3.1.13.11.04.8] tetradeca-4 (8), 6-diene-7-carboxylic acid, 6-pentyl-5,6-diazatetracyclo acid [7.3.1.13,11.04,8] tetradeca-4,7-diene-7-carboxylic acid, 5-pentyl-5,6-diazatetracyclo acid [7.3.1.13,11.04,8] tetradeca-4 (8) -6-diene-7-carboxylic acid, Ácido 1-fenil-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxílico, Ácido 1-(2-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxílico, Ácido 1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxílico, Ácido 1-(2,4-diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxílico, Ácido 1-(2-bromofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxílico, Ácido 1-(4-bromofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxílico, Ácido 1-(4-fluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxílico, Ácido 1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxílico, Ácido (R o S) 1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H4,7-metano-indazol-3-carboxílico, Ácido (S o R) 1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H4,7-metano-indazol-3-carboxílico, Ácido 1-(2,4-diclorofenil)-7,8,8-trimetil-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxílico, Ácido 3-(2,4-difluorofenil)-1,10,10-trimetil-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxílico, Ácido 10-(2,4-diclorofenil)-10,11-diazatetraciclo[6.5.2.02,7.09,13]pentadeca-2,4,6,9(13),11-pentaeno-12carboxílico, Ácido 10-(2,4-difluorofenil)-10,11-diazatetraciclo[6.5.2.02,7.09,13]pentadeca-2,4,6,9(13),11-pentaeno-12carboxílico, Ácido 13Endo,14endo-16-(4-clorofenil)-15,17-dioxo-10-(2,4-diclorofenil)-10,11,16triazapentaciclo[6.5.5.02,7,09,13,014,18]octadeca-2,4,6,9(13),11-pentaeno-12-carboxílico, Ácido 10-(2,4-difluorofenil)-10,11-diazatetraciclo[6.5.1.02,7,09,13]tetradeca-2,4,6,9(13),11-pentaeno-12carboxílico, Ácido 3-(2,4-difluorofenil)-3,4-diazatriciclo[5.2.2.02,6]undeca-2(6),4-dien-5-carboxílico, Ácido 3-(3,4-diclorofenil)-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxílico, Ácido 3-(2-etoxi-4-fluorofenil)-3,4-diazatriciclo[5,2,102,6]deca-2(6),4-dien-5-carboxílico, Ácido 2-(4-metilbencil)-4,5,6,7-tetrahidro-2H-4,7-metano-indazol-3-carboxílico, Ácido 3-(4-metilbencil)-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxílico, Ácido 2-(4-fluorobencil)-4,5,6,7-tetrahidro-2H-4,7-metano-indazol-3-carboxílico, Ácido 1-(4-fuorobencil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxílico, 5-(2-Bromofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxilato de etilo, 5-(4-Clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxilato de etilo, 5-(2,4-Difluorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxilato de etilo, 5-(4-Fluorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7 carboxilato de etilo, 5-(4-Metilfenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxilato de etilo, 5-(4-Metoxifenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6 dieno-7-carboxilato de etilo, 5-Fenil-5,6-diazatetraciclo[7.3.1.1 3,11, 04,8]tetradeca-4(8),6-dieno-7-carboxilato de etilo, 5-(2,4-Diclorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxilato de etilo, 5-(2-Clorofenil)-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxilato de etilo, 5-(5-Cloropiridil)-5,6-diazatetraciclo[7.3.1.1 3,11.04,8]tetradeca-4(8),6-dieno-7-carboxilato de etilo, 5,6-Diazatetraciclo[7.3.1.1 3,11.04,8]tetradeca-4(8),6-dieno-7-carboxilato de etilo, 6-Metil-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8),6dieno-7-carboxilato de etilo, 5-Metil-5,6-diazatetraciclo [7.3.1.13,11.04,8]tetradeca-4(8),6-dieno-7-carboxilato de etilo, 6-Pentil-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4,7-dieno-7-carboxilato de etilo, 5-Pentil-5,6-diazatetraciclo[7.3.1.13,11.04,8]tetradeca-4(8)-6-dieno-7-carboxilato de etilo, 1-Fenil-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxilato de etilo, 1-(2-Clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxilato de etilo, 1-(4-Clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxilato de etilo, 1-(2,4-Diclorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxilato de etilo, 1-(2-Bromofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxilato de etilo, 1-(4-Bromofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxilato de etilo, 1-(4-Fluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxilato de etilo, 1-(2,4-Difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxilato de etilo, 1-(2,4-Diclorofenil)-7,8,8-trimetil-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxilato de etilo, 3-(2,4-Difluorofenil)-1,10,10-trimetil-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxilato de etilo, 10-(2,4-Diclorofenil)-10,11-diazatetraciclo[6.5.2.02,7,09,13]pentadeca-2,4,6,9(13),11-pentaeno-12-carboxilato de etilo, 10-(2,4-Difluorofenil)-10,11-diazatetraciclo[6.5.2.02,7, 09,13]pentadeca-2,4,6,9(13),11-pentaeno-12-carboxilato de etilo, 13endo,14endo-16-(4-Clorofenil)-15,17-dioxo-10-(2,4-diclorofenil)-10,11,16triazapentaciclo[6.5.5.02,7.09,13.014,18]octadeca-2,4,6,9(13),11-pentaeno-12-carboxilato de etilo, 10-(2,4-Difluorofenil)-10,11-diazatetraciclo[6.5.1.02,7,09,13]tetradeca-2,4,6,9(13),11-pentaeno-12-carboxilato de etilo, 3-(2,4-Difluorofenil)-3,4-diazatriciclo[5.2.2.02,6]undeca-2(6),4-dien-5-carboxilato de etilo, 3-(3,4-Diclorofenil)-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxilato de etilo, 3-(2-Etoxi-4-fluorofenil)-3,4-diazatriciclo[5.2.1.02,6]deca-2(6),4-dien-5-carboxilato de etilo, 4,5,6,7-Tetrahidro-1H-4,7-metano-indazol-3-carboxilato de etilo, 2-(4-Metilbencil)-4,5,6,7-tetrahidro-2H-4,7-metano-indazol-3-carboxilato de etilo, 1-(4-Metilbencil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxilato de etilo, 1-Phenyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid, 1- (2-Chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid, 1- (4-Chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid, 1- (2,4-Dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid, 1- (2-Bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid, 1- (4-Bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid, 1- (4-fluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid, 1- (2,4-Difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid, (R or S) 1- (2,4-Difluorophenyl) -4,5,6,7-tetrahydro-1H4,7-methane-indazol-3-carboxylic acid, (S or R) 1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H4,7-methane-indazol-3-carboxylic acid, 1- (2,4-Dichlorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1 H-4,7-methane-indazol-3-carboxylic acid, 3- (2,4-Difluorophenyl) -1,10,10-trimethyl-3,4-diazatricyclo [5.2.1.02.6] deca-2 (6), 4-diene-5-carboxylic acid, 10- (2,4-Dichlorophenyl) -10,11-diazatetracyclo [6.5.2.02,7.09,13] pentadeca-2,4,6,9 (13), 11-pentane-12 carboxylic acid, 10- (2,4-Difluorophenyl) -10,11-diazatetracyclo [6.5.2.02,7.09,13] pentadeca-2,4,6,9 (13), 11-pentane-12 carboxylic acid, Acid 13Endo, 14endo-16- (4-chlorophenyl) -15,17-dioxo-10- (2,4-dichlorophenyl) -10,11,16triazapentacyclo [6.5.5.02,7,09,13,014,18] octadeca-2 , 4,6,9 (13), 11-pentaeno-12-carboxylic acid, 10- (2,4-Difluorophenyl) -10,11-diazatetracyclo [6.5.1.02,7,09,13] tetradeca-2,4,6,9 (13), 11-pentane-12 carboxylic acid, 3- (2,4-Difluorophenyl) -3,4-diazatricyclo [5.2.2.02.6] undeca-2 (6), 4-diene-5-carboxylic acid, 3- (3,4-Dichlorophenyl) -3,4-diazatricyclo [5.2.1.02.6] deca-2 (6), 4-diene-5-carboxylic acid, 3- (2-Ethoxy-4-fluorophenyl) -3,4-diazatricyclo [5,2,102.6] deca-2 (6), 4-diene-5-carboxylic acid, 2- (4-Methylbenzyl) -4,5,6,7-tetrahydro-2H-4,7-methane-indazol-3-carboxylic acid, 3- (4-Methylbenzyl) -3,4-diazatricyclo [5.2.1.02.6] deca-2 (6), 4-diene-5-carboxylic acid, 2- (4-Fluorobenzyl) -4,5,6,7-tetrahydro-2H-4,7-methane-indazol-3-carboxylic acid, 1- (4-Fuorobenzyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid, 5- (2-Bromophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), ethyl 6-diene-7-carboxylate, 5- (4-Chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), ethyl 6-diene-7-carboxylate, 5- (2,4-Difluorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), ethyl 6-diene-7-carboxylate, 5- (4-Fluorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), ethyl 6-diene-7 carboxylate, 5- (4-Methylphenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), ethyl 6-diene-7-carboxylate, 5- (4-Methoxyphenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), 6 ethyl diene-7-carboxylate, 5-Phenyl-5,6-diazatetracycle [7.3.1.1 3.11, 04.8] tetradeca-4 (8), ethyl 6-diene-7-carboxylate, 5- (2,4-Dichlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), ethyl 6-diene-7-carboxylate, 5- (2-Chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8), ethyl 6-diene-7-carboxylate, 5- (5-Chloropyridyl) -5,6-diazatetracyclo [7.3.1.1 3.11.04.8] tetradeca-4 (8), ethyl 6-diene-7-carboxylate, 5,6-Diazatetracycle [7.3.1.1 3.11.04.8] tetradeca-4 (8), ethyl 6-diene-7-carboxylate, 6-Methyl-5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8), ethyl diene-7-carboxylate, 5-Methyl-5,6-diazatetracycle [7.3.1.13,11.04,8] tetradeca-4 (8), ethyl 6-diene-7-carboxylate, Ethyl 6-Pentyl-5,6-diazatetracycle [7.3.1.13.11.04.8] tetradeca-4,7-diene-7-carboxylate, 5-Pentyl-5,6-diazatetracyclo [7.3.1.13,11.04,8] tetradeca-4 (8) -6-diene-7-ethyl carboxylate, Ethyl 1-Phenyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylate, Ethyl 1- (2-Chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylate, Ethyl 1- (4-Chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylate, Ethyl 1- (2,4-Dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylate, Ethyl 1- (2-Bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylate, Ethyl 1- (4-Bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylate, Ethyl 1- (4-Fluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylate, Ethyl 1- (2,4-Difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylate, Ethyl 1- (2,4-Dichlorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylate, 3- (2,4-Difluorophenyl) -1,10,10-trimethyl-3,4-diazatricyclo [5.2.1.02.6] deca-2 (6), ethyl 4-dien-5-carboxylate, 10- (2,4-Dichlorophenyl) -10,11-diazatetracyclo [6.5.2.02,7,09,13] pentadeca-2,4,6,9 (13), 11-pentaeno-12-carboxylate ethyl, 10- (2,4-Difluorophenyl) -10,11-diazatetracyclo [6.5.2.02,7, 09,13] pentadeca-2,4,6,9 (13), 11-pentaeno-12-carboxylate ethyl, 13endo, 14endo-16- (4-Chlorophenyl) -15,17-dioxo-10- (2,4-dichlorophenyl) -10,11,16triazapentacyclo [6.5.5.02,7.09,13,014,18] octadeca-2,4, 6.9 (13), ethyl 11-pentaeno-12-carboxylate, 10- (2,4-Difluorophenyl) -10,11-diazatetracyclo [6.5.1.02,7,09,13] tetradeca-2,4,6,9 (13), 11-pentaeno-12-carboxylate ethyl, 3- (2,4-Difluorophenyl) -3,4-diazatricyclo [5.2.2.02.6] undeca-2 (6), ethyl 4-dien-5-carboxylate, 3- (3,4-Dichlorophenyl) -3,4-diazatricyclo [5.2.1.02.6] deca-2 (6), ethyl 4-dien-5-carboxylate, 3- (2-Ethoxy-4-fluorophenyl) -3,4-diazatricyclo [5.2.1.02.6] deca-2 (6), ethyl 4-diene-5-carboxylate, Ethyl 4,5,6,7-Tetrahydro-1H-4,7-methane-indazol-3-carboxylate, Ethyl 2- (4-Methylbenzyl) -4,5,6,7-tetrahydro-2H-4,7-methane-indazol-3-carboxylate, Ethyl 1- (4-Methylbenzyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylate, 5 5 10 10 15 fifteen 20 twenty 25 25 30 30 35 35 40 40 45 Four. Five 2-(4-Fluorobencil)-4,5,6,7-tetrahidro-2H-4,7-metano-indazol-3-carboxilato de etilo, 1-(4-Fluorobencil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxilato de etilo, 2-Oxo-(5-oxotriciclo[4,3,1,1,3,8]undec-4-il)acetato, Etil 2-oxo-2(3-oxobiciclo[2.2.1]hept-2-il)acetato de etilo, 2-(3-Hidroxi-4,7,7-trimetil biciclo[2.2.1]hept-2-en-2-il-2-oxoacetato de etilo, 2-Oxo-2-(10-oxotriciclo[6.2.2.02,7]dodeca-2,4,6-trien-9-il)acetato de etilo, 9endo,13endo-2-[11-(4-Clorofenil)-10,12,15-trioxo-11-azatetraciclo[6.5.2.02,7,09,13]pentadeca-2,4,6-trien-14-il]-2oxoacetato de etilo, 2-Oxo-2-(10-oxotriciclo[6.2.1.02,7]undeca-2(7),3,5-trien-9-il)acetato de etilo, 2-Hidroxi-2-(3-oxabiciclo[2,2,2]octa-2-iliden)acetato de etilo, 9-Endo,13-endo-11-(4-clorofenil)-11-azatetraciclo[6.5.2.02,7,09,13]pentadeca-2,4,6 trieno-10,12,14-tri-ona, Ethyl 2- (4-Fluorobenzyl) -4,5,6,7-tetrahydro-2H-4,7-methane-indazol-3-carboxylate, Ethyl 1- (4-Fluorobenzyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylate, 2-Oxo- (5-oxotricyclo [4,3,1,1,3,8] undec-4-yl) acetate, Ethyl 2-oxo-2 (3-oxobicyclo [2.2.1] hept-2-yl) ethyl acetate, 2- (3-Hydroxy-4,7,7-trimethyl bicyclo [2.2.1] hept-2-en-2-yl-2-oxoacetate ethyl, 2-Oxo-2- (10-oxotricyclo [6.2.2.02.7] dodeca-2,4,6-trien-9-yl) ethyl acetate, 9endo, 13endo-2- [11- (4-Chlorophenyl) -10,12,15-trioxo-11-azatetracyclo [6.5.2.02,7,09,13] pentadeca-2,4,6-trien-14-il ] -2 ethylxoxoacetate, 2-Oxo-2- (10-oxotricyclo [6.2.1.02.7] undeca-2 (7), 3,5-trien-9-yl) ethyl acetate, 2-Hydroxy-2- (3-oxabicyclo [2,2,2] octa-2-ylidene) ethyl acetate, 9-Endo, 13-endo-11- (4-chlorophenyl) -11-azatetracycle [6.5.2.02,7,09,13] pentadeca-2,4,6 triene-10,12,14-tri-one, y sus sales farmacéuticamente aceptables. and its pharmaceutically acceptable salts.

33. 33.

Un compuesto de acuerdo con la reivindicación 1, en el que el compuesto se secciona entre: A compound according to claim 1, wherein the compound is sectioned between:

N(3)-(terc-Butil)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida o una sal farmacéuticamente aceptable de la misma, (4S,7R)N(3)-(terc-Butil)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida o una sal farmacéuticamente aceptable de la misma, N(3)-(terc-Butil)-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida o una sal farmacéuticamente aceptable de la misma, y N(3)-(terc-Butil)-1-(4-bromofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida. N (3) - (tert-Butyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide or a pharmaceutically acceptable salt of the same, (4S, 7R) N (3) - (tert-Butyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3 -carboxamide or a pharmaceutically acceptable salt thereof, N (3) - (tert-Butyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazole- 3-carboxamide or a pharmaceutically acceptable salt thereof, and N (3) - (tert-Butyl) -1- (4-bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane- indazol-3-carboxamide.

34. 3. 4.

Un agonista selectivo de CB2 que tiene la fórmula: A selective CB2 agonist that has the formula:

imagen1image 1 en la que en cada aparición, R es independientemente alquilo sustituido o sin sustituir, arilo sustituido o sin sustituir o heteroarilo sustituido o sin sustituir; R1 y R2 pueden ser iguales o diferentes y son independientemente hidrógeno, nitro, ciano, formilo, acetilo, halógeno, -OR3, -SR3, oxo, tio, 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, cicloalquenilalquilo sustituido o sin sustituir, arilo sustituido o sin sustituir, arilalquilo sustituido o sin sustituir, heteroarilo sustituido o sin sustituir, heteroarilalquilo sustituido o sin sustituir, grupo heterocíclico sustituido o sin sustituir, heterociclilalquilo sustituido o sin sustituir, -NR3R4, -C(=B)-R3, C(O) O-R3, -C(O)NR3R4, -S(O)m-R3, -S(O)m-NR3R4 o un grupo protector o R1 y R2 pueden unirse para formar un anillo cíclico opcionalmente sustituido, saturado o insaturado de 3 a 7 miembros, que puede incluir opcionalmente al menos dos heteroátomos seleccionados entre O, NR3 o S; en cada aparición, R3 y R4 pueden ser iguales o diferentes y son independientemente hidrógeno, nitro, halo, ciano, -ORa, -SRa, oxo, tio, alquilo sustituido o sin sustituir, alquenilo sustituido o sin sustituir, alquinilo sustituido in which at each occurrence, R is independently substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R1 and R2 may be the same or different and are independently hydrogen, nitro, cyano, formyl, acetyl, halogen, -OR3, -SR3, oxo, thio, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, alkynyl substituted or unsubstituted, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenyl alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclyl alkyl, -NR3R4, -C (= B) -R3, C (O) O-R3, -C (O) NR3R4, -S (O) m-R3, - S (O) m-NR3R4 or a protecting group or R1 and R2 can join to form a optionally substituted, saturated or unsaturated cyclic ring of 3 to 7 members, which may include optionally at least two heteroatoms selected from O, NR3 or S; at each occurrence, R3 and R4 may be the same or different and are independently hydrogen, nitro, halo, cyano, -ORa, -SRa, oxo, thio, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted alkynyl o sin sustituir, cicloalquilo sustituido o sin sustituir, cicloalquilalquilo sustituido o sin sustituir, cicloalquenilo sustituido o sin sustituir, cicloalquenilalquilo sustituido o sin sustituir, arilo sustituido o sin sustituir, arilalquilo sustituido o sin sustituir, heteroarilo sustituido o sin sustituir, heteroarilalquilo sustituido o sin sustituir, grupo heterocíclico sustituido o sin sustituir, heterociclilalquilo sustituido o sin sustituir, -C(=B)-Ra, -C(O)O-Ra, -C (O)NRaRb, -S(O)m-Ra, -S(O)m-NRaRb, -NRaRb o un grupo protector o R3 y R4, cuando se unen a un átomo en común, pueden unirse entre sí para formar un anillo cíclico opcionalmente sustituido, saturado o insaturado de 3 a 7 miembros, que puede incluir opcionalmente al menos dos heteroátomos seleccionados entre O, NR3 o S; en cada aparición, Ra y Rb pueden ser iguales o diferentes y son independientemente hidrógeno, halógeno, nitro, ciano, formilo, acetilo, oxo, tio, -C(O)-Rc, -C(O)O-Rc, -C(O)NRcRd, -S(O)m-Rc, -S(O)m-NRcRd, -NRcRd, -ORc, -SRc, un grupo protector, 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, cicloalquenilalquilo sustituido o sin sustituir, arilo sustituido o sin sustituir, arilalquilo sustituido o sin sustituir, heteroarilo sustituido o sin sustituir, grupo heterocíclico sustituido o sin sustituir, heterociclilalquilo sustituido o sin sustituir o heteroarilalquilo sustituido o sin sustituir; en cada or unsubstituted, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenyl alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryl substitute, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -C (= B) -Ra, -C (O) O-Ra, -C (O) NRaRb, -S (O) m-Ra, - S (O) m-NRaRb, -NRaRb or a protecting group or R3 and R4, when attached to a common atom, can be joined together to form an optionally substituted, saturated or unsaturated 3 to 7-membered cyclic ring, which it may optionally include at least two heteroatoms selected from O, NR3 or S; at each occurrence, Ra and Rb may be the same or different and are independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, -C (O) -Rc, -C (O) O-Rc, -C (O) NRcRd, -S (O) m-Rc, -S (O) m-NRcRd, -NRcRd, -ORc, -SRc, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted alkynyl or unsubstituted, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenyl alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl alkyl, substituted or unsubstituted heteroaryl, substituted or heterocyclic group unsubstituted, substituted or unsubstituted heterocyclylalkyl or substituted or unsubstituted heteroarylalkyl; in each aparición, Rc y Rd pueden ser iguales o diferentes y son independientemente hidrógeno, halógeno, nitro, ciano, formilo, acetilo, oxo, tio, un grupo protector, 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, cicloalquenilalquilo sustituido o sin sustituir, arilo sustituido o sin sustituir, arilalquilo sustituido o sin sustituir, heteroarilo sustituido o sin sustituir, grupo heterocíclico sustituido o sin sustituir, heterociclilalquilo sustituido o sin sustituir o heteroarilalquilo sustituido o sin sustituir; en cada aparición, B es independientemente O, S o NR3; y m es 0,1 ó 2, en los que los sustituyentes en los grupos funcionales sustituidos pueden ser iguales o diferentes y son uno o más de hidroxi, halógeno, carboxilo, ciano, nitro, oxo (=O), tio (=S), alquilo C1-8, alcoxi C1-8, alquenilo C2-10, alquinilo C2-12, arilo C6-14, arilalquilo, cicloalquilo, cicloalquenilo, amino, arilo, heteroarilo, anillo heterociclilalquilo, heteroarilalquilo, anillo heterocíclico de 3-15 miembros, guanidina, -COORx, -C(O)Rx, C(S)Rx, -C(O)NRxRy, -C(O)ONRxRy, -NRxCONRyRz, -N(Rx)SORy, -N(Rx)SO2Ry, -(=N-N(Rx)Ry), -NRxC(O)ORy, -NRxRy, - NRxC(O)Ry, -NRxC(S)Ry, -NRxC(S)NRyRz, -SONRxRy, -SO2NRxRy, -ORx, ORxC(O)NRyRz, -ORxC(O)ORy, - OC(O)Rx, -OC(O)NRxRy, -RxNRyC(O)Rz, -RxORy, -RxC(O)ORy, -RxC(O)NRyRz, -RxC(O)Ry, -RxOC(O)Ry, -SRx, - SORx, -SO2Rx y ONO2, en los que Rx, Ry y Rz se seleccionan independientemente entre hidrógeno, alquilo C1-8, alcoxi C1-8, alquenilo C2-10, alquinilo C2-12, arilo C6-14, arilalquilo, cicloalquilo, cicloalquenilo, amino, arilo, heteroarilo, anillo heterociclilalquilo sustituido, heteroarilalquilo y anillo heterocíclico de 3-15 miembros. appearance, Rc and Rd can be the same or different and are independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenyl alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group substituted, substituted or unsubstituted heterocyclylalkyl or substituted or unsubstituted heteroarylalkyl; at each occurrence, B is independently O, S or NR3; Y m is 0.1 or 2, in which the substituents in the substituted functional groups may be the same or different and are one or more hydroxy, halogen, carboxyl, cyano, nitro, oxo (= O), thio (= S), C1-8 alkyl, C1-8 alkoxy, C2-10 alkenyl, C2-12 alkynyl, C6-14 aryl, arylalkyl, cycloalkyl, cycloalkenyl, amino, aryl, heteroaryl, ring heterocyclylalkyl, heteroarylalkyl, 3-15 membered heterocyclic ring, guanidine, -COORx, -C (O) Rx, C (S) Rx, -C (O) NRxRy, -C (O) ONRxRy, -NRxCONRyRz, -N (Rx) SORy, -N (Rx) SO2Ry, - (= NN (Rx) Ry), -NRxC (O) ORy, -NRxRy , - NRxC (O) Ry, -NRxC (S) Ry, -NRxC (S) NRyRz, -SONRxRy, -SO2NRxRy, -ORx, ORxC (O) NRyRz, -ORxC (O) ORy, - OC (O) Rx, -OC (O) NRxRy, -RxNRyC (O) Rz, -RxORy, -RxC (O) ORy, -RxC (O) NRyRz, -RxC (O) Ry, -RxOC (O) Ry , -SRx, - SORx, -SO2Rx and ONO2, wherein Rx, Ry and Rz are independently selected from hydrogen, C1-8 alkyl, C1-8 alkoxy, alkenyl C2-10, C2-12 alkynyl, C6-14 aryl, arylalkyl, cycloalkyl, cycloalkenyl, amino, aryl, heteroaryl, ring substituted heterocyclylalkyl, heteroarylalkyl and 3-15 membered heterocyclic ring. 35, El agonista selectivo de CB2 de la reivindicación 34, en el que R es a arilo sustituido o sin sustituir. 35, The selective CB2 agonist of claim 34, wherein R is a substituted or unsubstituted aryl.

36. 36.

El agonista selectivo de CB2 de la reivindicación 34, en el que R es un grupo fenilo sustituido con uno o dos átomos de halógeno. The selective CB2 agonist of claim 34, wherein R is a phenyl group substituted with one or two halogen atoms.

37. 37.

Una composición farmacéutica que comprende un compuesto de acuerdo con cualquiera de las reivindicaciones 1-36 tanto en forma de base libre como en forma de sal farmacéuticamente aceptable y un excipiente farmacéuticamente aceptable. A pharmaceutical composition comprising a compound according to any of claims 1-36 both in the form of a free base and in the form of a pharmaceutically acceptable salt and a pharmaceutically acceptable excipient.

38. 38.

La composición farmacéutica de acuerdo con la reivindicación 37, en la que el excipiente farmacéuticamente aceptables es un vehículo o diluyente. The pharmaceutical composition according to claim 37, wherein the pharmaceutically acceptable excipient is a carrier or diluent.

39. 39.

Un procedimiento para la fabricación de una composición farmacéutica que comprende mezclar un compuesto de acuerdo con cualquiera de las reivindicaciones 1-36 ya sea como base libre o en forma de sal farmacéuticamente aceptable y un excipiente farmacéuticamente aceptable. A process for the manufacture of a pharmaceutical composition comprising mixing a compound according to any of claims 1-36 either as a free base or in the form of a pharmaceutically acceptable salt and a pharmaceutically acceptable excipient.

40. 40

El uso de un compuesto de acuerdo con cualquiera de las reivindicaciones 1-36 en la preparación de un medicamento para prevenir, mejorar o tratar una enfermedad, trastorno o síndrome mediado por receptores de canabinoides, en el que la enfermedad, trastorno y síndrome mediado por receptores de canabinoides se selecciona entre trastornos relacionados con el apetito, trastornos relacionados con el metabolismo, trastornos relacionados con el catabolismo, diabetes, obesidad, enfermedades oftálmicas, trastornos relacionados con el ámbito social, trastornos anímicos, mareos, abuso de sustancias nocivas, trastornos relacionados con el aprendizaje, trastornos cognitivos, trastornos de la memoria, contracción de órganos, espasmo muscular, trastornos y enfermedades respiratorias, trastornos de la actividad locomotora, discinesias, trastornos inmunológicos (tales como trastornos autoinmunológicos), inflamación, crecimiento celular, dolor y síndromes neurodegenerativos relacionados. The use of a compound according to any of claims 1-36 in the preparation of a medicament for preventing, ameliorating or treating a disease, disorder or syndrome mediated by cannabinoid receptors, wherein the disease, disorder and syndrome mediated by Cannabinoid receptors are selected from appetite-related disorders, metabolism-related disorders, catabolism-related disorders, diabetes, obesity, ophthalmic diseases, social-related disorders, mood disorders, dizziness, harmful substance abuse, related disorders with learning, cognitive disorders, memory disorders, organ contraction, muscle spasm, respiratory disorders and diseases, disorders of locomotor activity, dyskinesias, immunological disorders (such as autoimmune disorders), inflammation, cell growth, pain and neurodegenerative syndromes related.

41. 41.

El uso de la reivindicación 40, en el que la enfermedad, trastorno o síndrome mediado por receptores de canabinoides se selecciona entre trastornos relacionados con el apetito, trastornos relacionados con el ámbito social, trastornos y enfermedades autoinmunitarios o inflamación, dolor, síndromes neurodegenerativos relacionados y abuso de sustancias nocivas. The use of claim 40, wherein the disease, disorder or syndrome mediated by cannabinoid receptors is selected from appetite-related disorders, social-related disorders, autoimmune disorders and diseases or inflammation, pain, related neurodegenerative syndromes and abuse of harmful substances.

42. 42

El uso de la reivindicación 41, en el que la enfermedad, trastorno o síndrome relacionado con el apetito, incluye obesidad, estado de sobrepeso, anorexia, bulimia, caquexia, apetito mal regulado, síndromes, trastornos, enfermedades o síntomas que incluye; obesidad como un resultado de un síndrome, trastorno o enfermedad genética, dieta, volumen de consumo de alimento, síndrome metabólico, trastorno o enfermedad hipotalámico, envejecimiento, distribución anómala de la masa adiposa, distribución anómala del compartimento adiposo, un trastorno alimenticio compulsivo o un trastorno motivacional que incluye el deseo de consumir azúcar, hidratos de carbono, alcohol o fármacos o cualquier ingrediente con valor hedónico, actividad reducida. The use of claim 41, wherein the disease, disorder or syndrome related to appetite, includes obesity, overweight status, anorexia, bulimia, cachexia, poorly regulated appetite, syndromes, disorders, diseases or symptoms including; obesity as a result of a syndrome, disorder or genetic disease, diet, volume of food consumption, metabolic syndrome, disorder or hypothalamic disease, aging, abnormal distribution of fat mass, abnormal distribution of the adipose compartment, a compulsive eating disorder or a motivational disorder that includes the desire to consume sugar, carbohydrates, alcohol or drugs or any ingredient with hedonic value, reduced activity.

43. 43

El uso de la reivindicación 41, en el que la enfermedad, trastorno o síndrome relacionado con el ámbito social es depresión, que incluye depresión bipolar, depresión unipolar, episodios de depresión mayor simples o recurrentes con o sin características psicóticas, características catatónicas, características melancólicas, características atípicas o que aparecen después del parto, trastorno afectivo estacional, trastornos distímicos con aparición temprana o tardía y con o sin características atípicas, depresión neurótica y fobia social, depresión acompañada de demencia, ansiedad, psicosis, trastornos sociales afectivos, trastornos cognitivos. The use of claim 41, wherein the disease, disorder or syndrome related to the social field is depression, which includes bipolar depression, unipolar depression, major or recurrent major depression episodes with or without psychotic characteristics, catatonic characteristics, melancholic characteristics , atypical characteristics or appearing after childbirth, seasonal affective disorder, dysthymic disorders with early or late onset and with or without atypical characteristics, neurotic depression and social phobia, depression accompanied by dementia, anxiety, psychosis, affective social disorders, cognitive disorders.

44. 44.

El uso de la reivindicación 41, en el que la enfermedad, trastorno o síndrome autoimunológico o relacionado con inflamación incluye soriasis, lupus eritematoso, enfermedades del tejido conjuntivo, síndrome de Sjögren, The use of claim 41, wherein the autoimunologic or inflammation-related disease, disorder or syndrome includes psoriasis, lupus erythematosus, connective tissue diseases, Sjögren's syndrome,

5 5 10 10 15 fifteen 20 twenty 25 25 30 30 35 35 espondiloartritis anquilosante; artritis reumatoide; artritis reactiva; espondiloartritis indiferenciada, enfermedad de Behcet, anemias hemolíticas autoinmunes, esclerosis múltiple, esclerosis lateral amiotrófica, amilosis, rechazo de injerto o enfermedades que afectan a la estirpe celular plasmática, enfermedades alérgicas: hipersensibilidad tardía ankylosing spondyloarthritis; rheumatoid arthritis; reactive arthritis; undifferentiated spondyloarthritis, Behcet's disease, autoimmune hemolytic anemias, multiple sclerosis, amyotrophic lateral sclerosis, amylosis, graft rejection or diseases that affect plasma cell line, allergic diseases: late hypersensitivity o inmediata, rinitis alérgica, dermatitis por contacto o conjuntivitis alérgica, enfermedades infecciosas parasitarias, virales o bacterianas (tales como SIDA y meningitis), enfermedades inflamatorias (tales como enfermedades de las articulaciones que incluyen, pero sin limitación, artritis, artritis reumatoide, osteoartritis, espondilitis, gota, vasculitis, enfermedad de Crohn, enfermedad intestinal inflamatoria (EII) y síndrome del intestino irritable (SII) y osteoporosis. or immediate, allergic rhinitis, contact dermatitis or allergic conjunctivitis, parasitic, viral or bacterial infectious diseases (such as AIDS and meningitis), inflammatory diseases (such as joint diseases that include, but are not limited to, arthritis, rheumatoid arthritis, osteoarthritis , spondylitis, gout, vasculitis, Crohn's disease, inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) and osteoporosis.

45. Four. Five.

El uso de la reivindicación 41, en el que el dolor y los síndromes, trastornos y enfermedades neurodegenerativos relacionados incluyen dolor mediado por la ruta central y periférica, dolor óseo y articular, dolor asociado a migraña, dolor por cáncer, dismenorrea, dolor por parto, dolor crónico de tipo inflamatorio, alergias, artritis reumatoides, dermatitis, inmunodeficiencia, dolor crónico neuropático, que incluye dolor asociado con neuropatía diabética; ciática, dolor de lumbar no específico; fibromialgia; neuropatía relacionada con el VIH; neuralgia postherpética, neuralgia trigeminal; dolor resultante de traumatismo físico, dolor dental, amputación, cáncer, toxinas o afecciones inflamatorias crónicas, enfermedad de Hodgkin, miastenia grave, síndrome nefrótico, esclerodermia y tiroiditis. The use of claim 41, wherein the pain and syndromes, disorders and related neurodegenerative diseases include pain mediated by the central and peripheral route, bone and joint pain, migraine associated pain, cancer pain, dysmenorrhea, labor pain , chronic inflammatory pain, allergies, rheumatoid arthritis, dermatitis, immunodeficiency, chronic neuropathic pain, which includes pain associated with diabetic neuropathy; sciatica, non-specific low back pain; fibromyalgia; HIV-related neuropathy; postherpetic neuralgia, trigeminal neuralgia; pain resulting from physical trauma, dental pain, amputation, cancer, toxins or chronic inflammatory conditions, Hodgkin's disease, myasthenia gravis, nephrotic syndrome, scleroderma and thyroiditis.

46. 46.

El uso de la reivindicación 41, en el que los síndromes, trastornos o enfermedades relacionados con el abuso de sustancias nocivas incluyen, abuso de sustancias nocivas y abstinencia a las sustancias nocivas de abuso en el que las sustancias de abuso o de dependencia incluyen alcohol, anfetaminas, sustancias similares a anfetamina, cafeína, marihuana, cocaína, alucinógenos, inhalantes, opioides, nicotina, abuso de heroína, barbitúricos, fenciclidina o sus derivados, hipnóticos sedantes, benzodiacepinas, combinaciones de sustancias de abuso. The use of claim 41, wherein the syndromes, disorders or diseases related to the abuse of harmful substances include, abuse of harmful substances and withdrawal from harmful substances of abuse in which the substances of abuse or dependence include alcohol, amphetamines, substances similar to amphetamine, caffeine, marijuana, ***e, hallucinogens, inhalants, opioids, nicotine, heroin abuse, barbiturates, phencyclidine or its derivatives, sedative hypnotics, benzodiazepines, substance abuse combinations.

47. 47

El uso de la reivindicación 41, en el que las enfermedades oftálmicas incluyen glaucoma, presión intraocular asociada a glaucoma, retinitis, retinopatías, uveítis, lesión aguda del tejido ocular. The use of claim 41, wherein the ophthalmic diseases include glaucoma, intraocular pressure associated with glaucoma, retinitis, retinopathies, uveitis, acute ocular tissue injury.

48. 48.

El uso de la reivindicación 40 en el que el compuesto es un compuesto de acuerdo con cualquiera de las reivindicaciones 34-36 y la enfermedad, trastorno o síndrome mediado por receptores de canabinoides se selecciona entre una enfermedad oftálmica, trastorno respiratorio, trastorno inmunológico, inflamación, dolor y un síndrome neurodegenerativo asociado. The use of claim 40 wherein the compound is a compound according to any of claims 34-36 and the disease, disorder or syndrome mediated by cannabinoid receptors is selected from an ophthalmic disease, respiratory disorder, immune disorder, inflammation , pain and an associated neurodegenerative syndrome.

49. 49.

El uso de la reivindicación 48, en el que la enfermedad, trastorno o síndrome mediado por receptores de canabinoides es dolor. The use of claim 48, wherein the disease, disorder or syndrome mediated by cannabinoid receptors is pain.

50. fifty.

El procedimiento de la reivindicación 49, en el que el dolor es dolor neuropático. The method of claim 49, wherein the pain is neuropathic pain.

51. 51.

Un procedimiento para preparar un compuesto de la reivindicación 1, en el que Y es N, U es C, uno de W, V y X es N y los dos restantes son C, y B es O, que comprende la etapa de acoplar una amina de la fórmula HNR1R2 con un compuesto de la fórmula: A process for preparing a compound of claim 1, wherein Y is N, U is C, one of W, V and X is N and the remaining two are C, and B is O, which comprises the step of coupling a amine of the formula HNR1R2 with a compound of the formula:

imagen1image 1 en la que L2 es un grupo saliente, para formar el compuesto de fórmula (1). wherein L2 is a leaving group, to form the compound of formula (1). 52. Un procedimiento para preparar un compuesto de la reivindicación 1, en el que W e Y son N, U, V y X, y C y B son O, que comprende las etapas de: 52. A process for preparing a compound of claim 1, wherein W and Y are N, U, V and X, and C and B are O, comprising the steps of: (a) oxidar un compuesto de fórmula K: (a) oxidize a compound of formula K: para dar un compuesto de fórmula B: (b) someter al compuesto de fórmula B a aminación reductora para formar la diamina vecinal de fórmula C: To give a compound of formula B: (b) subject the compound of formula B to reductive amination to form the neighborhood diamine of formula C: imagen1image 1 imagen1image 1 imagen1image 1 (c) monoacilar la diamina vecinal de fórmula C para formar una mono N-acil diamina de fórmula D: (c) monoacylated the neighborhood diamine of formula C to form an N-acyl diamine monkey of formula D: imagen1image 1 en la que pg es un grupo protector; in which pg is a protective group;

(d) (d)

someter al compuesto de fórmula D a ciclación para formar un compuesto de fórmula E: subject the compound of formula D to cyclization to form a compound of formula E:

(e) (and)

deshidrogenar el compuesto de fórmula E para formar un compuesto de fórmula F: dehydrogenating the compound of formula E to form a compound of formula F:

(f) (F)

derivatizar el compuesto de la fórmula F para formar el compuesto G1, compuesto G2 o una mezcla de los mismos: derivatize the compound of formula F to form compound G1, compound G2 or a mixture thereof:

(g) (g)

hidrolizar el compuesto G1, el compuesto G2 o ambos para formar el compuesto H1, el compuesto H2 o ambos: Hydrolyze compound G1, compound G2 or both to form compound H1, compound H2 or both:

imagen1image 1 imagen1image 1 imagen1image 1 imagen1image 1 5y 5y (h) acoplar una amina de la fórmula HNR1R2 con el compuesto H1, el compuesto H2 o ambos para formar el compuesto de fórmula (1). (h) coupling an amine of the formula HNR1R2 with compound H1, compound H2 or both to form the compound of formula (1). 53. Un procedimiento para la preparación de compuestos de fórmula 1A: 53. A process for the preparation of compounds of formula 1A: imagen1image 1 10 en la que A, R, R1 y R7 son iguales a como se han definido en la reivindicación 1, que comprende las etapas de: 10 wherein A, R, R1 and R7 are the same as defined in claim 1, which comprises the steps of: (a) desprotonar un compuesto de fórmula K: (a) deprotonate a compound of formula K: imagen1image 1 seguido de acilación para dar un compuesto de fórmula L: followed by acylation to give a compound of formula L: imagen1image 1

(b) (b)

hacer reaccionar el compuesto de fórmula L con una hidrazina que tiene la fórmula RNHNH2 para formar el compuesto M, compuesto N o ambos: reacting the compound of formula L with a hydrazine having the formula RNHNH2 to form compound M, compound N or both:

y Y

(c) (C)

hidrolizar y acoplar el compuesto M, compuesto N o ambos con una amina de la fórmula HNR1R2 para formar el compuesto de fórmula (1). Hydrolyze and couple compound M, compound N or both with an amine of the formula HNR1R2 to form the compound of formula (1).

imagen1image 1 54. Un procedimiento para preparar un compuesto de fórmula 1, en el que V e Y son N, U, W y X son C, B es O y p es 1, que comprende las etapas de: 54. A process for preparing a compound of formula 1, wherein V and Y are N, U, W and X are C, B is O and p is 1, comprising the steps of: (a) convertir un compuesto de fórmula O: (a) convert a compound of formula O: imagen1image 1 a un compuesto de fórmula P: to a compound of formula P: imagen1image 1 (b) acoplar el compuesto P con una amina de la fórmula Q: (b) coupling compound P with an amine of the formula Q: imagen1image 1 para formar un compuesto de fórmula R: to form a compound of formula R: imagen1image 1 (c) desprotección del compuesto de fórmula R seguido de condensación para formar un compuesto de fórmula (c) deprotection of the compound of formula R followed by condensation to form a compound of formula S: S: imagen1image 1 5 5 10 10 15 fifteen 20 twenty 25 25 30 30 35 35 e and (d) hidrolizar y acoplar el compuesto de fórmula S con una amina de la fórmula HNR1R2 para formar el compuesto de fórmula (1). (d) hydrolyze and couple the compound of formula S with an amine of the formula HNR1R2 to form the compound of formula (1). 55. Un compuesto de la fórmula (Ib): 55. A compound of the formula (Ib): imagen1image 1 una sal farmacéuticamente aceptable del mismo, un éster farmacéuticamente aceptable del mismo, un estereoisómero del mismo, en la que R es 2-clorofenilo, 4-clorofenilo, 2,4-diclorofenilo, 2-bromofenilo, 4bromofenilo, 4-fluorofenilo, 2,4-difluorofenilo, 4-metilfenilo, 4-metoxifenilo o 2-(4-clorofenil)fenilo; R1 es hidrógeno; y R2 es t-butilo, n-pentilo, ciclopentilo, ciclohexilo, adamantan-1-ilo, 2-metiladamantan-2-ilo, 3-hidroxiadamantan1-ilo, 1,3,3-trimetilbiciclo[2.2.1]hept-2-ilo, 1-fenilciclopropilo, ciclohexilmetilo, fenilo, 3-clorofenilo, 4-clorofenilo, 3-bromofenilo, 2-metoxifenilo, 4-terc-butilfenilo, 2,4-difluorofenilo, bencilo, 2-clorobencilo, 4-clorobencilo, 2,4diclorobencilo, 2-fluorobencilo, 4-fluorobencilo, 2,4-difluorobencilo, 2,6-difluorobencilo, 2-bromobencilo, 4bromobencilo, 4-trifluorometilbencilo, 1-feniletilo, 1-metil-1-feniletilo, 2-feniletilo, 1-(2-clorofenil)etilo, 2-(4fluorofenil)etilo, 1-fenilpropilo, 1-etil-1-fenilpropilo, 1-(2-clorofenil)-1-metiletilo, feniletanoato de metilo, 2-hidroxi1-feniletilo, piperidinilo, morfolinilo, piridinilo, 1,2,4-triazol-4-ilo, 2-piridilmetilo, 3-piridilmetilo o 4-piridilmetilo. a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable ester thereof, a stereoisomer thereof, wherein R is 2-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2-bromophenyl, 4bromophenyl, 4-fluorophenyl, 2, 4-difluorophenyl, 4-methylphenyl, 4-methoxyphenyl or 2- (4-chlorophenyl) phenyl; R1 is hydrogen; and R2 is t-butyl, n-pentyl, cyclopentyl, cyclohexyl, adamantan-1-yl, 2-methylamantan-2-yl, 3-hydroxyamantan-1-yl, 1,3,3-trimethylbicyclo [2.2.1] hept-2 -yl, 1-phenylcyclopropyl, cyclohexylmethyl, phenyl, 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 2-methoxyphenyl, 4-tert-butylphenyl, 2,4-difluorophenyl, benzyl, 2-chlorobenzyl, 4-chlorobenzyl, 2 , 4-dichlorobenzyl, 2-fluorobenzyl, 4-fluorobenzyl, 2,4-difluorobenzyl, 2,6-difluorobenzyl, 2-bromobenzyl, 4bromobenzyl, 4-trifluoromethylbenzyl, 1-phenylethyl, 1-methyl-1-phenylethyl, 2-phenylethyl, 1 - (2-Chlorophenyl) ethyl, 2- (4fluorophenyl) ethyl, 1-phenylpropyl, 1-ethyl-1-phenylpropyl, 1- (2-chlorophenyl) -1-methylethyl, methyl phenylethanoate, 2-hydroxy-1-phenylethyl, piperidinyl , morpholinyl, pyridinyl, 1,2,4-triazol-4-yl, 2-pyridylmethyl, 3-pyridylmethyl or 4-pyridylmethyl.

56. 56.

El compuesto de la reivindicación 56, en el que R es 4-bromofenilo. The compound of claim 56, wherein R is 4-bromophenyl.

57. 57.

El compuesto de la reivindicación 56, en el que R2 es t-butilo. The compound of claim 56, wherein R2 is t-butyl.

58. 58.

El compuesto de la reivindicación 56, en el que R es 2,4-difluorofenilo. The compound of claim 56, wherein R is 2,4-difluorophenyl.

59. 59.

El compuesto de la reivindicación 56, en el que R2 es 4-clorofenilo. The compound of claim 56, wherein R2 is 4-chlorophenyl.

60. 60

Una composición farmacéutica que comprende un compuesto de acuerdo con cualquiera de las reivindicaciones 56-59 y un excipiente farmacéuticamente aceptable. A pharmaceutical composition comprising a compound according to any of claims 56-59 and a pharmaceutically acceptable excipient.

61. 61.

Uso de un compuesto de acuerdo con cualquiera de las reivindicaciones 56-60 en la preparación de un medicamento para el tratamiento del dolor. Use of a compound according to any of claims 56-60 in the preparation of a medicament for the treatment of pain.

62. 62

Uso de un compuesto de acuerdo con cualquiera de las reivindicaciones 56-60 en la preparación de un medicamento para el tratamiento de Esclerosis Múltiple. Use of a compound according to any of claims 56-60 in the preparation of a medicament for the treatment of Multiple Sclerosis.

63. 63.

Un compuesto seleccionado entre N(3)-(terc-Butil)-1-(4-bromofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3carboxamida o una sal farmacéuticamente aceptable de la misma; N(3)-(terc-Butil)-1-(2,4-difluorofenil)-4,5,6,7tetrahidro-1H-4,7-metano-indazol-3-carboxamida o una sal farmacéuticamente aceptable de la misma; (4S,7R) N(3)(terc-Butil)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida o una sal farmacéuticamente aceptable de la misma o; N(3)-(terc-Butil)-1-(4-clorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida o una sal farmacéuticamente aceptable de la misma. A compound selected from N (3) - (tert-Butyl) -1- (4-bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3carboxamide or a pharmaceutically acceptable salt of the same; N (3) - (tert-Butyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide or a pharmaceutically acceptable salt thereof ; (4S, 7R) N (3) (tert-Butyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide or a pharmaceutically acceptable salt thereof or; N (3) - (tert-Butyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide or a pharmaceutically acceptable salt thereof .

64. 64.

Una composición farmacéutica que comprende un compuesto de acuerdo con la reivindicación 63 y un excipiente farmacéuticamente aceptable. A pharmaceutical composition comprising a compound according to claim 63 and a pharmaceutically acceptable excipient.

65. 65

Uso de un compuesto de acuerdo con la reivindicación 63 en la preparación de un medicamento para el tratamiento del dolor. Use of a compound according to claim 63 in the preparation of a medicament for the treatment of pain.

66. 66.

Uso de un compuesto de acuerdo con la reivindicación 63 en la preparación de un medicamento para el tratamiento de Esclerosis Múltiple. Use of a compound according to claim 63 in the preparation of a medicament for the treatment of Multiple Sclerosis.

67. 67.

(4S,7R) N(3)-(terc-Butil)-1-(2,4-difluorofenil)-4,5,6,7-tetrahidro-1H-4,7-metano-indazol-3-carboxamida o una sal farmacéuticamente aceptable de la misma. (4S, 7R) N (3) - (tert-Butyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide or a pharmaceutically acceptable salt thereof.

68. 68.

Uso de un compuesto de acuerdo con la reivindicación 67 en la preparación de un medicamento para el tratamiento de dolor neuropático, dolor inflamatorio o dolor por cáncer. Use of a compound according to claim 67 in the preparation of a medicament for the treatment of neuropathic pain, inflammatory pain or cancer pain.

69. 69.

Un compuesto que tiene la fórmula (1 g): A compound having the formula (1 g):

imagen1image 1 en la que, in which, 10 R es fenilo sustituido con al menos un halógeno; R1 es hidrógeno; y R2 es t-butilo, n-pentilo, ciclopentilo, ciclohexilo, adamantan-1-ilo, 2-metiladamantan-2-ilo, 3-hidroxiadamantan1-ilo, 1,3,3-trimetilbiciclo[2.2.1]hept-2-ilo, 1-fenilciclopropilo, ciclohexilmetilo, fenilo, 3-clorofenilo, 4-clorofenilo, 3-bromofenilo, 2-metoxifenilo, 4-terc-butilfenilo, 2,4-difluorofenilo, bencilo, 2-clorobencilo, 4-clorobencilo, 2,4R 10 is phenyl substituted with at least one halogen; R1 is hydrogen; and R2 is t-butyl, n-pentyl, cyclopentyl, cyclohexyl, adamantan-1-yl, 2-methylamantan-2-yl, 3-hydroxyamantan-1-yl, 1,3,3-trimethylbicyclo [2.2.1] hept-2 -yl, 1-phenylcyclopropyl, cyclohexylmethyl, phenyl, 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 2-methoxyphenyl, 4-tert-butylphenyl, 2,4-difluorophenyl, benzyl, 2-chlorobenzyl, 4-chlorobenzyl, 2 ,4 15 diclorobencilo, 2-fluorobencilo, 4-fluorobencilo, 2,4-difluorobencilo, 2,6-difluorobencilo, 2-bromobencilo, 4bromobencilo, 4-trifluorometilbencilo, 1-feniletilo, 1-metil-1-feniletilo, 2-feniletilo, 1-(2-clorofenil) etilo, 2(4fluorofenil)etilo, 1-fenilpropilo, 1-etil-1-fenilpropilo, 1-(2-clorofenil)1-metiletilo, feniletanoato de metilo, 2-hidroxi1-feniletilo, piperidinilo, morfolinilo, piridinilo, 1,2,4-triazol-4-ilo, 2-piridilmetilo, 3-piridilmetilo o 4-piridilmetilo. Dichlorobenzyl, 2-fluorobenzyl, 4-fluorobenzyl, 2,4-difluorobenzyl, 2,6-difluorobenzyl, 2-bromobenzyl, 4bromobenzyl, 4-trifluoromethylbenzyl, 1-phenylethyl, 1-methyl-1-phenylethyl, 2-phenylethyl, 1 - (2-Chlorophenyl) ethyl, 2 (4fluorophenyl) ethyl, 1-phenylpropyl, 1-ethyl-1-phenylpropyl, 1- (2-chlorophenyl) 1-methylethyl, methyl phenylethanoate, 2-hydroxy-1-phenylethyl, piperidinyl, morpholinyl , pyridinyl, 1,2,4-triazol-4-yl, 2-pyridylmethyl, 3-pyridylmethyl or 4-pyridylmethyl.