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ES2578404T3 - Moduladores de la indolamina 2,3-dioxigenasa, y métodos de uso de los mismos - Google Patents

Moduladores de la indolamina 2,3-dioxigenasa, y métodos de uso de los mismos Download PDF

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Publication number
ES2578404T3
ES2578404T3 ES12178315.3T ES12178315T ES2578404T3 ES 2578404 T3 ES2578404 T3 ES 2578404T3 ES 12178315 T ES12178315 T ES 12178315T ES 2578404 T3 ES2578404 T3 ES 2578404T3
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Prior art keywords
amino
methyl
crarb
nrg1rh1
hydroximino
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ES12178315.3T
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Inventor
Andrew P. Combs
Eddy W. Yue
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Incyte Holdings Corp
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Incyte Holdings Corp
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
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  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

Un compuesto de Fórmula:**Fórmula** o una sal farmacéuticamente aceptable del mismo, para su uso en el tratamiento del cáncer en combinación con un anticuerpo anti-PD-1, en el que: W, X1 y X2 se seleccionan independientemente entre (CRaRb)t, (CRaRb)uO(CRaRb)v, (CRaRb)uC(O)(CRaRb)v, (CRaRb)uC(O)NRc(CRaRb)v, (CRaRb)uC(O)O(CRaRb)v, (CRaRb)uC(S)(CRaRb)u, (CRaRb)uC(S)NRc(CRaRb)v, (CRaRb)uS(O)(CRaRb)v, (CRaRb)uS(O)NRc(CRaRb)v, (CRaRb)uS(O)2(CRaRb)v, (CRaRb)uS(O)2NRc(CRaRb)v, (CRaRb)uNRc(CRaRb)v, y (CRaRb)uC(>=NRd)NRc(CRaRb)v; R2 es H, alquilo C1-6 , o cicloalquilo C3-7; R3a y R5a se seleccionan independientemente entre alquilo C1-8, alquenilo C2-8, alquinilo C2-8, arilo, cicloalquilo, heteroarilo y heterocicloalquilo, cada uno opcionalmente sustituido con 1, 2, 3, 4 o 5 sustituyentes seleccionados independientemente entre halo, alquilo C1-6, alquenilo C2-6, alquinilo C2-6, haloalquilo C1-4, Cy1, CN, NO2, ORe1, SRe1, C(O)Rf1, C(O)NRg1Rh1, C(O)ORe1, OC(O)Rf1, OC(O)NRg1Rh1, NRg1C(O)NRg1Rh1, NRg1Rh1, NRg1C(O)Rf1, NRg1C(O)ORe1, C(>=NRi)NRg1Rb1, NRg1C(>=NR')NRg1Rb1, P(Rfl)2, P(ORe1)2, P(O)Re1Rf1, P(O)ORe1ORf1, S(O)Rf1, S(O)NRg1Rb1, S(O)2Rf1, y S (O)2NRg1Rh1; R3b es arilo o heteroarilo cada uno opcionalmente sustituido con 1, 2, 3, 4 o 5 sustituyentes seleccionados independientemente entre halo, alquilo C1-6, alquenilo C2-6, alquinilo C2-6, haloalquilo C1-4, hidroxialquilo C1-4, Cy2, CN, NO2, ORe1, SRe1, C(O)Rf1, C(O)NRg1Rh1, C(O)ORe1, OC(O)Rf1, OC(O)NRg1Rh1, NRg1C(O)NRg1Rh1, NRg1Rh1, NRg1C(O)Rf1, NRg1C(O)ORe1, C(>=NRi)NRg1Rh1, NRg1C(>=NRi)NRg1Rh1, P(Rf1)2, P(ORe1)2, P(O)Re1Rf1, P(O)ORe1ORf1, S(O)Rf1, S(O)NRg1Rh1, S (O)2Rf1, y S(O)2NRg1Rh1; R5b es H, alquilo C1-8, alquenilo C2-8, alquinilo C2-8, arilo, cicloalquilo, heteroarilo, o heterocicloalquilo donde dicho alquilo C1-8, alquenilo C2-8, alquinilo C2-8, arilo, cicloalquilo, heteroarilo, o heterocicloalquilo esta cada uno opcionalmente substituido por 1, 2, 3, 4 o 5 sustituyentes independientemente seleccionados entre halo, alquilo C1-6, alquenilo C2-6, alquinilo C2-6, haloalquilo C1-4, hidroxialquilo C1-4, Cy2, CN, NO2, ORe1, SRe1, C(O)Rf1, C(O)NRg1Rh1, C(O)ORe1, OC(O)Rf1, OC(O)NRg1Rh1, NRg1C(O)NRg1Rh1, NRg1Rh1, NRg1C(O)Rf1, NRg1C(O)ORe1, C(>=NRi)NRg1Rh1, NRg1C(>=NRi)NRg1Rh1, P(Rf1)2, P(ORe1)2, P(O)Re1Rf1, P(O)ORe1ORf1, S(O)Rf1, S(O)NRg1Rh1, S(O)2Rf1, y S(O)2NRg1Rh1; Cy1 y Cy2 son independientemente seleccionados entre arilo, heteroarilo, cicloalquilo y heterocicloalquilo, cada uno opcionalmente sustituido con 1, 2, 3, 4 o 5 sustituyentes seleccionados independientemente entre halo, alquilo C1-4, alquenilo C2-4, alquinilo C2-4, haloalquilo C1-4, CN, NO2, ORe3, SRe3, C(O)Rf3, C(O)NRg3Rh3, C(O)ORe3, OC(O)Rf3, OC(O)NRg3Rb3, NRg3Rh3, NRg3C(O)Rh3, NRg3C(O)ORe3, C(>=NRi)NRg1Rh1, NRg1C(>=NRi)NRg1Rh1, P(Rf3)2, P(ORe3)2, P(O)Re3Rf3, P(O)ORe3ORf3, S(O)Rf3, S(O)NRgRh3, S(O)2Rf3, y S(O)2NRg3Rh3; Ra y Rb se seleccionan independientemente entre H, halo, alquilo C1-6, alquenilo C2-6, alquinilo C2-6, haloalquilo C1-4, arilo, cicloalquilo, heteroarilo, heterocicloalquilo, arilalquilo, cicloalquilalquilo, heteroarilalquilo, heterocicloalquilalquilo, CN, NO2, ORe4, SRe4, C(O)Rf4, C(O)NR g4 R h4, C(O)ORe4, OC(O)Rf4, OC(O)NRg4Rh4, NRg4Rh4, NRg4C(O)Rh4, NRg4C(O)ORe4, C(>=NRi)NRg1Rh1, NRg1C(>=NRi)NRg1Rh1, P(Rf4)2, P(ORe4)2, P(O)Re4Rf4, P(O)ORe4ORf4, S(O)Rf4, S(O)NRg4Rh4, S(O)2Rf4, y S(O)2NRg4Rh4; Rc es H, alquilo C1-6, haloalquilo C1-6, alquenilo C2-6, alquinilo C2-6, arilo, cicloalquilo, arilalquilo, o cicloalquilalquilo; Rd es H, ORd1, CN o NO2; Rd1 es H, alquilo C1-6, haloalquilo C1-6, alquenilo C2-6, alquinilo C2-6, arilo, cicloalquilo, arilalquilo, o cicloalquilalquilo; Re1, Re3, y Re4 se seleccionan independientemente entre H, alquilo C1-6, haloalquilo C1-6, alquenilo C2-6, (alcoxiC1-6)-alquilo C1-6, alquinilo C2-6, arilo, cicloalquilo, heteroarilo, heterocicloalquilo, arilalquilo, cicloalquilalquilo, heteroarilalquilo y heterocicloalquilalquilo; Rf1, Rf3, y Rf4 se seleccionan independientemente entre H, alquilo C1-6, haloalquilo C1-6, alquenilo C2-6, alquinilo C2-6, arilo, cicloalquilo, heteroarilo y heterocicloalquilo; Rg1, Rg3, y Rg4 se seleccionan independientemente de H, alquilo C1-6, haloalquilo C1-6, alquenilo C2-6, alquinilo C2-6, arilo, cicloalquilo, arilalquilo, y cicloalquilalquilo; Rh1, Rh3, y Rh4 se seleccionan independientemente de H, alquilo C1-6, haloalquilo C1-6, alquenilo C2-6, alquinilo C2-6, arilo, cicloalquilo, arilalquilo, y cicloalquilalquilo; o Rg1 y Rh1 o junto con el átomo de N al que están unidos forman un grupo de 4, 5, 6 o 7 miembros de heterocicloalquilo; o Rg3 y Rh3 o junto con el átomo de N al que están unidos forman un grupo de 4, 5, 6 o 7 miembros de heterocicloalquilo; o Rg4 y Rh4 o junto con el átomo de N al que están unidos forman un grupo de 4, 5, 6 o 7 miembros de heterocicloalquilo; Ri es H, CN, o NO2; a es 0 o 1; b es 0 o 1; n es 0 o 1; p es 0 o 1; t es 1, 2, 3, 4, 5 o 6; u es 0,1, 2, 3, 4, 5 o 6; y v es 0, 1, 2, 3, 4, 5 o 6.

Description

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en un grado útil de pureza de una mezcla de reacción, y preferiblemente capaz de formulación en un agente terapéutico eficaz.
Se aprecia además que ciertas características de la invención, que están, para mayor claridad, descritas en el contexto de realizaciones separadas, también pueden proporcionarse en combinación en una única realización. A la inversa, diversas características de la invención que están, para mayor brevedad, descritas en el contexto de una única realización, también pueden proporcionarse separadamente o en cualquier subcombinación adecuada.
Tal como se utiliza aquí, el término "alquilo" se refiere a un grupo hidrocarbonado saturado que es de cadena lineal o ramificada. Ejemplos de grupos alquilo incluyen metilo (Me), etilo (Et), propilo (por ejemplo, n-propilo e isopropilo), butilo (por ejemplo, n-butilo, isobutilo, t-butilo), pentilo (por ejemplo, n-pentilo, isopentilo, neopentilo), y similares. Un grupo alquilo puede contener de 1 a aproximadamente 20, de 2 a aproximadamente 20, de 1 a aproximadamente 10, de 1 a aproximadamente 8, de 1 a aproximadamente 6, de 1 a aproximadamente 4, o de 1 a aproximadamente 3 átomos de carbono.
Como se usa en la presente memoria, "alquenilo" se refiere a un grupo alquilo que tiene uno o más dobles enlaces carbono-carbono. Ejemplos de grupos alquenilo incluyen etenilo, propenilo, y similares.
Como se usa en la presente memoria, "alquinilo" se refiere a un grupo alquilo que tiene uno o más triples enlaces carbono-carbono. Ejemplos de grupos alquinilo incluyen etinilo, propinilo, y similares.
Como se usa en este documento, "haloalquilo" se refiere a un grupo alquilo que tiene uno o más sustituyentes halógeno. Ejemplos de grupos haloalquilo incluyen CF3, C2F5, CHF2, CCl3, CHCl2, C2Cl5, y similares.
Como se usa en la presente memoria, los grupos "carbociclilo" son restos hidrocarbonados cíclicos saturados (es decir, que no contienen enlaces dobles o triples) o insaturados (es decir, que contienen uno o más enlaces dobles o triples). Los grupos carbociclilo pueden ser mono o policíclicos (por ejemplo, que tienen 2, 3 o 4 anillos fusionados o espirociclos). Ejemplos de grupos carbociclilo incluyen ciclopropilo, ciclobutilo, ciclopentilo, ciclohexilo, cicloheptilo, ciclopentenilo, 1,3-ciclopentadienilo, ciclohexenilo, norbornilo, norpinilo, norcarnilo, adamantilo, fenilo, y similares. Los grupos carbocíclico pueden ser aromáticos (por ejemplo, "arilo") o no aromáticos (por ejemplo, "cicloalquilo"). En algunas realizaciones, los grupos carbociclilo pueden tener de aproximadamente 3 a aproximadamente 30, de aproximadamente 3 a aproximadamente 20, de aproximadamente 3 a aproximadamente 10, o de aproximadamente 3 a aproximadamente 7 átomos de carbono.
Como se usa en este documento, "arilo" se refiere a hidrocarburos aromáticos monocíclicos o policíclicos (por ejemplo, que tienen 2, 3 o 4 anillos fusionados) tales como, por ejemplo, fenilo, naftilo, antracenilo, fenantrenilo, indanilo, indenilo, y similares . En algunas realizaciones, los grupos arilo tienen de 6 a aproximadamente 20 átomos de carbono.
Como se usa aquí, "cicloalquilo" se refiere a carbociclos no aromáticos incluyendo alquilo ciclado, alquenilo, y alquinilo. Los grupos cicloalquilo pueden incluir sistemas de anillos mono o policíclicos (por ejemplo, que tienen 2, 3 o 4 anillos fusionados), incluyendo espirociclos. En algunas realizaciones, los grupos cicloalquilo pueden tener de 3 a aproximadamente 20 átomos de carbono, de 3 a aproximadamente 14 átomos de carbono, de 3 a aproximadamente 10 átomos de carbono, o de 3 a 7 átomos de carbono. Los grupos cicloalquilo pueden tener además 0, 1, 2, o 3 dobles enlaces y/o 0, 1, o 2 enlaces triples. También se incluyen en la definición de cicloalquilo los restos que tienen uno o más anillos aromáticos fusionados (es decir, que tienen un enlace en común con) al anillo cicloalquilo, por ejemplo, derivados benzo de pentano, penteno, hexano, y similares. Uno o más átomos de carbono formadores de anillo de un grupo cicloalquilo pueden estar oxidados, por ejemplo, contando con un sustituyente oxo o sulfuro. Ejemplos de grupos cicloalquilo incluyen ciclopropilo, ciclobutilo, ciclopentilo, ciclohexilo, cicloheptilo, ciclopentenilo, ciclohexenilo, ciclohexadienilo, cicloheptatrienilo, norbornilo, norpinilo, norcarnilo, adamantilo, y similares.
Como se usa en este documento, "heterociclilo" o "heterociclo" se refiere a un grupo cíclico saturado o insaturado en el que uno o más de los átomos que forman el anillo son heteroátomos tales como O, S, o N. Los grupos heterociclilo incluyen sistemas de anillo mono o policíclicos. Los grupos heterociclilo pueden ser aromáticos (por ejemplo, "heteroarilo") o no aromáticos (por ejemplo, "heterocicloalquilo"). Los grupos heterociclilo pueden caracterizarse por tener 3-14, 3-12, 3-10, 3-7, o 3-6 átomos formadores de anillo. En algunas realizaciones, los grupos heterociclilo pueden contener, además de al menos un heteroátomo, de aproximadamente 1 a aproximadamente 13, aproximadamente 2 a aproximadamente 10, o aproximadamente 2 a aproximadamente 7 átomos de carbono y se pueden conectar/enlazar a través de un átomo de carbono o un heteroátomo. En realizaciones adicionales, el heteroátomo puede estar oxidado (por ejemplo, tener un sustituyente oxo o sulfido) o un átomo de nitrógeno pueden estar cuaternizado. Los ejemplos de grupos heterociclilo incluyen morfolino, tiomorfolino, piperazinilo, tetrahidrofuranilo, tetrahidrotienilo, 2,3-dihidrobenzofurilo, 1,3-benzodioxol, benzo-1 ,4-dioxano, piperidinilo, pirrolidinilo, isoxazolidinilo, isotiazolidinilo, pirazolidinilo, oxazolidinilo, tiazolidinilo, imidazolidinilo , y similares, así como cualquiera de los grupos enumerados a continuación para "heteroarilo" y "heterocicloalquilo".
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Las oximas adicionales amida se pueden sintetizar como se describe en el Esquema 5 (X es un grupo saliente). El reordenamiento de la oxima amida 7 puede dar 16 que se puede convertir a 17 con nitrito de sodio en HC1. La reacción de 17 con aminas puede dar compuestos tales como 18.
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Los compuestos adicionales pueden sintetizarse como se muestra en el Esquema 6. El acoplamiento de la amida 8 puede dar 19 que puede ser tratado con pentacloruro de fósforo y luego se reduce con un hidruro tal como
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TABLA 1
Ex. No .
Estructura Nombre Prep. Metodo MS (M+1)
71
N-{4 -[(E, Z) -[(3-clorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il}-ciclopentano carboxamida Ex. 35 350.0
72
N-{4 -[(E, Z) -[(3-clorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il)]] trifluoroacetato nicotinamida Ex. 35 359.0
73
N-{4 - [(E, Z) -[(3-clorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il}-isonicotinamida trifluoroacetato Ex. 35 359.0
74
N-{4 - [(E, Z) -[(3-clorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il}-2-metoxibenzamida Ex. 35 388.1
75
N-{4 - [(E, Z) -[(3-clorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il}-3-metoxibenzamida Ex. 35 387.9
TABLA 1
Ex. No.
Estructura Nombre Prep. Metodo MS (M+1)
76
N-{4 - [(E, Z) - [(3-clorofenil) amino] (hydroximino) metil] -1,2,5oxadiazol-3-il}-4-metoxibenzamida Ex. 35 388.0
77
2-Cloro-N-{4 - [(E, Z) - [(3-clorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il}-benzamida Ex.35 391.9
78
3-Cloro-N-{4 - [(E, Z) - [(3-clorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il}-benzamida Ex. 35 391.9
79
imagen48 4-Cloro-N-{4 - [(E, Z) - [(3-clorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il}-benzamida Ex. 35 391.9
80
N-{4 - [(E, Z) - [(3-cloro-fenil) amino] (hydroximino) metil] -1,2,5 oxadiazol-3-il} -3,3dimetilbutanamida Ex. 35 352.0
TABLA 1
Ex. No.
Estructura Nombre Prep. Metodo MS (M+1)
81
4-Amino-N-(3-bromofenil)-Nhidroxi-1 ,2,5-oxadiazole-3carboximidamida Ex. 1 298.0, 300.0
82
imagen49 4-Amino-N-(3-bromo-4metilfenil)-N'-hidroxi-1 ,2,5oxadiazole-3-carboximidamida Ex. 1 312.1, 314.1
83
imagen50 4-Amino-N-(3-cloro-4metoxifenil)-N'-hidroxi-1, 2,5 oxadiazol-3-carboximidamida Ex. 1 284.1
84
imagen51 4-Amino-N-(3,5diniethylphenyl)-N'-hidroxi-1 ,2,5-oxadiazole-3carboximidamida Ex. 1 248.2
85
4-Amino-N '-hidroxi-N-(2metilbenzil) -1,2,5-oxadiazole3-carboximidamida Ex. 1 248.2
TABLA 1
Ex. No.
Estructura Nombre Prep. Metodo MS (M+1)
86
4-Amino-N '-hidroxi-N-(3metilbenzil) -1,2,5-oxadiazole3-carboximidamida Ex. 1 248.2
87
4-Amino-N '-hidroxi-N-(4metilbenzil) -1,2,5-oxadiazole3-carboximidamida Ex. 1 248.2
88
4-Amino-N '-hidroxi-N-[2 - (trifluorometil)-benzil] -1,2,5oxadiazol-3-carboximidamida Ex. 1 302.1
89
4-Amino-N '-hidroxi-N-[4 - (trifluorometil)-benzil] -1,2,5oxadiazol-3-carboximidamida Ex. 1 302.1
90
4-Amino-N-(3-etilfenil)-N'hidroxi-1 ,2,5-oxadiazole-3carboximidamida Ex. 1 248.1
TABLA 1
Ex. No.
Estructura Nombre Prep. Metodo MS (M+1)
91
4-Amino-N-(3,4-diclorofenil)-N'hidroxi-1 ,2,5-oxadiazole-3carboximidamida Ex. 1 288.1
92
imagen52 4-Amino-N-(3,5-diclorofenil)-N'hidroxi-1 ,2,5-oxadiazole-3carboximidamida Ex. 1 288.1
93
4-Amino-N-bifenil-3-il-N '-hidroxi1 ,2,5-oxadiazole-3 carboximidamida Ex. 1 296.1
94
4-Amino-N-(2-fluorofenil)-N'hidroxi-1, 2,5 -oxadiazol-3carboximidamida Ex. 1 238.1
95
4-Amino-N-(3-cloro-4-metilbenzil)-N'-hidroxi-1 ,2,5oxadiazole-3-carboximidamida Ex.1 282.1
TABLA 1
Ex. No.
Estructura Nombre Prep. Metodo MS (M+1)
96
4-Amino-N-(4-fluorofenil)-N'hidroxi-1 ,2,5-oxadiazole-3carboximidamida Ex. 1 238.1
97
4-Amino-N-(2,3-dimetilfenil)N'-hidroxi-1 ,2,5-oxadiazole-3carboximidamida Ex. 1 248.2
98
imagen53 N-{4 - [(E, Z) - [(3-cloro-fenil) amino] (hidroxi-imino) metil] 1,2,5-oxadiazol-3-il}-4iodobenzamida Ex. 35 483.8
99
4-Amino-N-(4-cloro-3metilfenil)-N'-hidroxi-1 ,2,5oxadiazole-3-carboximidamida Ex. 1 268.2
100
4-Amino-N '-hidroxi-N-[3 (metiltio)fenil] -1,2,5oxadiazole-3-carboximidamida Ex. 1 266.0
TABLA 1
Ex. No.
Estructura Nombre Prep. Metodo MS (M+1)
101
4-Amino-N-(3-cloro-2-metilfenil)N'-hidroxi-1 ,2,5-oxadiazole-3carboximidamida Ex. 1 268.1
102
4-Amino-N-(3-fluoro-2metilfenil)-N'-hidroxi-1 ,2,5oxadiazole-3-carboximidamida Ex. 1 252.1
103
4-Amino-N '-hidroxi-N-(3vinilfenil) -1,2,5-oxadiazole-3carboximidamida Ex.1 246.1
104
imagen54 4-Amino-N-(3-etinilfenil)-N'hidroxi-1 ,2,5-oxadiazole-3carboximidamida Ex. 1 244.0
105
4-Amino-N-(4-fluoro-3metilfenil)-N'-hidroxi-1 ,2,5oxadiazole-3-carboximidamida Ex. 1 252.0
TABLA 1
Ex. No.
Estructura Nombre Prep. Meto do MS (M+1)
106
4-Amino-N '-hidroxi-N-(3-iodofenil) 1,2,5-oxadiazole-3-carboximidamida Ex. 1 345.9
107
4-Amino-N '-hidroxi-N-(3isopropilfenil) -1,2,5-oxadiazole-3carboximidamida Ex. 1 262.2
108
4-Amino-N-(3-bromo-4-fluorofenil)N'-hidroxi-1 ,2,5-oxadiazole-3carboximidamida Ex. 1 316.1
109
4-Amino-N '-hidroxi-N-(4-fenilbutil) 1,2,5-oxadiazole-3-carboximidamida Ex. 1 276.2
110
4-Amino-N '-hidroxi-N-[3 - (1,3oxazol-5-il) fenil] -1,2,5-oxadiazole3-carboximidamida Ex. 1 287.0
TABLA 1
Ex. No.
Estructura Nombre Prep. Metod o MS (M+1 )
111
N-{4 -[(E, Z) -[(3-cloro-fenil) amino] (hydroxyim ino) metil] -1,2,5-oxadiazol-3-il}-4cianobenzamida Ex. 35 382. 9
112
imagen55 4-Amino-N’-hydroxy-N-[1phenylethyl] -1,2,5-oxadiazole-3carboximidamide Ex. 1 248. 2
113
imagen56 4-Amino-N’-hydroxy-N-1-naphthyl1,2,5-oxadiazole-3carboximidamide Ex. 1 270. 2
114
imagen57 4-Amino-N '-hidroxi-N-2-naftil-1 ,2,5-oxadiazole-3-carboximidamida Ex. 1 270. 2
115
4-Amino-N-(3-chloro-2fluorophenyl)-N’-hydroxy-1,2,5oxadiazole-3-carboximidamide Ex. 1 272. 1
TABLA 1
Ex. No.
Estructura Nombre Prep. Metodo MS (M+1)
116
N-{4 - [(E, Z) - {[4-Fluoro-3 (trifluorometil) fenil] amino} (Hidroxi-imino) metil] -1,2,5 - oxadiazol-3-il} nicotinamida trifluoroacetato Ex. 35 411.1
117
N-{4 - [(E, Z) - {[4-Fluoro3 - (trifluorometil) fenil] amino} (Hidroximino) metil] -1,2,5 -oxadiazol-3-il} isonicotinamida trifluoroacetato Ex. 35 411.1
118
4-Amino-N-(3-ciclopropilfenil)N'-hidroxi-1,2,5-oxadiazole-3carboximidamida Ex. 1 260.2
119
imagen58 N-{4 - [(E, Z) - [(3-Bromo-4fluorofenil) amino] (hydroximino) metil] -1,2,5oxadiazol-3-il}-benzamida Ex. 35 420.0 , 421.9
120
N-{4 - [(E, Z) - [(3-Bromo-4fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il}-nicotinamida trifluoroacetato Ex. 35 420.9 , 422.9
TABLA 1
Ex. No.
Estructura Nombre Prep. Metodo MS (M+1)
121
N-{4 - [(E, Z) - [(3-Bromo-4fluorofenil) amino] (hydroximi no) metil] -1,2,5-oxadiazol-3-il}isonicotinamida trifluoroacetato Ex. 35 421.0, 422.9
122
N-{4 - [(E, Z) - [(3-Bromo-4fluorofenil) aminodroxyimino) metil] -1,2,5-oxadiazol-3-il}-4cianobenzamida Ex. 35 444.9, 446.9
123
N-{4 - [(E, Z) - [(3-Bromo-4fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il}-3cianobenzamida Ex. 35 445.0, 447.0
124
N-{4 - [(E, Z) - [(3-Bromo-4fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il}-2-naftamida Ex. 35 470.0, 472.0
125
N-{4 - [(E, Z) - [(3-Bromo-4fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il}-1-naftamida Ex. 35 470.0, 472.0
imagen59
TABLA 1
Ex. No.
Estructura Nombre Prep. Metodo MS (M+1)
131
terc-butil {4 - [({4 - [(E, Z) - [(3bromo-4-fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il} amino)carbonil ] benzil} carbamato Ex. 41 548.9, 551.0
132
imagen60 N-{4 - [(E, Z) - [(3-Bromo-4fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il}-1-benzotiofeno2-carboxamida Ex. 41 475.9, 477.9
133
N-{4 - [(E, Z) - [(3-Bromo-4fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il} -1,3-tiazole-4carboxamida Ex. 41 426.9, 428.9
134
imagen61 N-{4 - [(E, Z) - [(3-Bromo-4fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il}-1-benzotiofeno3-carboxamida Ex. 41 475.9, 477.9
135
N-{4 - [(E, Z) - [(3-Bromo-4fluorofenil) amino] (hidroxiimino) metil] -1,2,5-oxadiazol3-il}-tiofeno-3-carboxamida Ex. 41 425.8, 427.9
TABLA 1
Ex. No.
Estructura Nombre Prep. Metodo MS (M+1)
136
N-{4 - [(E, Z) - [(3-Bromo-4fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il}-1H-imidazole2carboxamide Ex. 41 409.9, 411.9
137
imagen62 N-{4 - [(E, Z) - [(3-Bromo-4fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il}-4-metil-1 ,2,3tiadiazole-5-carboxamida Ex. 41 441.9, 443.9
138
N-{4 - [(E, Z) - [(3,-Bromo-4- fluorofenil) mino] (hidroxiimino) metil] -1,2,5-oxadiazol3-il} carboxamida -1,2,3tiadiazole-4 Ex. 41 427.9, 429.9
139
N-{4 - [(E, Z) - [(3-Bromo-4fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il} -2,1benzisoxazole-3-carboxamida Ex. 41 460.9, 462.9
140
imagen63 4 - (aminometil)-N-{4 - [(E, Z) - [(3-bromo-4-f luorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il}-benzamida trifluoroacetato Ex. 41 448.9, 450.9
TABLA 1
Ex. No.
Estructura Nombre Prep. Metodo MS (M+1)
141
imagen64 N-(3-Bromo-4fluorofenil)-N'-hidroxi-4-({[(2feniletil) amino] carbonil}-amino) -1,2,5-oxadiazole-3- carboximidamida Ex. 43 463.0, 465.0
142
imagen65 N-(3-Bromo-4-fluorofenil) -4 - {[ (ciclopentilamino) carbonil] a mino}-N '-hidroxi-1 ,2,5oxadiazole-3-carboximidamida Ex. 43 426.9, 428.9
143
imagen66 N-(3-Bromo-4-fluoro-fenil) -4 - ({[ (3-cianof enil)-carbonil] amino} a mino)-N'-hidroxi-1, 2,5 - oxadiazol-3-carboximidamida Ex. 43 459.9, 461.9
144
imagen67 N-{4 - [(E, Z) - [(3-Bromo-4f luorof enil) amino] (hidroimino) metil] -1,2,5-oxadiazol-3-il}-3terc-butil-1-metil-1H-pirazole-5carboxamida Ex. 35 480.0, 482.0
145
imagen68 N-{4 - [(E, Z) - [(3-Bromo-4fluorofenil) amino] (hidroximino) metil] -1,2,5-oxadiazol-3-il}-2metoxiacetamida Ex. 35 387.9, 389.9
TABLA 1
Ex. No.
Estructura Nombre Prep. Metodo MS (M+1)
146
imagen69 N-{4 - [(E, Z) - [(3-Bromo-4fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il} ciclopentanocarboxamida Ex. 35 412.0, 413.9
147
N-{4 - [(E, Z) - [(3-Bromo-4fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il}-butanamida Ex. 35 385.9 388.0
148
N-{4 - [(E, Z) - [(3-Bromo-4fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il}-propanamida Ex. 35 386.0 387.9
149
N-{4 - [(E, Z) - [(3-Bromo-4fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il}-propanamida Ex. 35 371.9, 373.9
150
N-{4 - [(E, Z) - [(3-Bromo-4fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il} ciclohexanocarboxamida Ex. 35 426.0, 427.9
TABLA 1
Ex. No.
Estructura Nombre Prep. Metodo MS (M+1)
151
4-Amino-N-(2,3-diclorofenil)-N'-hidroxi-1,2,5-oxadiazol-3carboximidamida Ex. 47 288.0
152
4-Amino-N-(3-clorofenil)-N'hidroxi-N-metil-1,2,5oxadiazol-3 carboximidamida Ex.1 268.1
153
N-{4 - [(E, Z) - [(3-bromo-4fluorofenil) amino] (hidroximi no) metil] -1,2,5-oxadiazol-3il}-1H-bencimidazol-5carboxamida Ex. 35 460.0, 462.0
154
N-{4 - [(E, Z) - [(3-bromo-4fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il}-2fenoxiacetamida Ex. 35 449.9, 451.8
155
N-{4 - [(E, Z) - [(3-bromo-4fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il} ciclobutanocarboxamida Ex. 35 398.0, 400.0
TABLA 1
Ex. No.
Estructura Nombre Prep. Metodo MS (M+1)
156
imagen70 N-{4 - [(E, Z) - [(3-bromo-4fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il} - 3-metilbutanamida Ex. 35 400.0, 402.0
157
imagen71 N-{4 - [(E, Z) - [(3-bromo-4fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il} - 3-piridin-3-il propanamida trifluoroacetato Ex. 35 449.0, 450.9
158
imagen72 N-{4 - [(E, Z) - [(3-bromo-4fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il} quinolin-6-carboxamida Ex. 35 470.9, 472.9
159
imagen73 N-{4 - [(E, Z) - [(3-bromo-4fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il} - 2 - (4-clorofenoxi) acetamida Ex. 35 483.9, 485.9
160
imagen74 N-{4 - [(E, Z) - [(3-bromo-4fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il} -2 - (4bromofenoxi) acetamida Ex. 35 527.8, 529.9, 531.8
TABLA 1
Ex. No.
Estructura Nombre Prep. Metodo MS (M+1)
161
N-{4 - [(E, Z) - [(3-bromo-4fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il} -2 - (4fluorofenoxi) acetamida Ex. 35 468.0, 470.0
162
N-{4 - [(E, Z) - [(3-bromo-4fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il} -2 - (4-tercbutilfenoxi) acetamida Ex. 35 506.0, 508.0
163
N-{4 - [(E, Z) - [(3-bromo-4fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il} -2 - (3clorofenoxi) acetamida Ex. 35 483.9, 485.9
164
N-{4 - [(E, Z) - [(3-bromo-4fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il} -2 - (3,4diclorofenoxi) acetamida Ex. 35 518.4, 519.9, 522.0
165
N-{4 - [(E, Z) - [(3-bromo-4fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il} -2 - (2-naftiloxi) acetamida Ex. 35 500.1, 502.0
TABLA 1
Ex. No.
Estructura Nombre Prep. Metodo MS (M+1)
166
imagen75 N-{4 - [(E, Z) - [(3-bromo-4fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il} -2 - (2,3diclorofenoxi) acetamida Ex. 35 517.8, 519.8, 521.8
167
imagen76 N-{4 - [(E, Z) - [(3-bromo-4fluorofenil) amino] (hidrox imino) metil] -1,2,5-oxadiazol3-il} -2 - (4-clorofenoxi)-2metilpropanamida Ex. 35 511.9, 513.9
168
N-{4 - [(E, Z) - [(3-bromo-4fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il} -2 - (2clorofenoxi) acetamida Ex. 35 483.8, 485.9
169
N-{4 - [(E, Z) - [(3-bromo-4fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il} -2 - (3metoxifenoxi) acetamida Ex. 35 480.0, 481.9
TABLA 1
Ex. No.
Estructura Nombre Prep. Metodo MS (M+1)
170
imagen77 N-{4 - [(E, Z) - [(3-bromo-4fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il} -2 - (4metoxifenoxi) acetamida Ex. 35 479.9, 481.9
171
N-{4 - [(E, Z) - [(3-bromo-4fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il} -2 - (2metoxifenoxi) acetamida Ex. 35 480.0, 482.0
172
Bencil {4 - [(E, Z) - [(3-bromo4-fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il}carbamato Ex. 35 449.9, 451.9
173
N-{4 - [(E, Z) - [(3-bromo-4fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il}acetamida Ex. 35 357.9, 359.9
174
N-{4 - [(E, Z) - [(3-bromo-4fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il} piperidina-1carboxamida Ex. 48 427.0, 429.0
TABLA 1
Ex. No.
Estructura Nombre Prep. Metodo MS (M+1)
175
imagen78 N-(3-Bromo-4-fluorofenil) -4 - ({[(3-cianofenil) (metil) amino carbonilo coche]} amino)-N'hidroxi-1, 2,5 -oxadiazol-3carboximidamida Ex. 48 473.9, 476.0
176
imagen79 4-amino-N'-hidroxi-N-(6metilpiridin-2-il) -1,2,5oxadiazol-3-carboximidamida trifluoroacetato Ex. 45 235.1
177
imagen80 4 - ({[Bencil (metil) amino] de carbonoil} amino)-N-(3-bromo4-'fluorofenil)-N'-hidroxi-1,2,5oxadiazol-3-carboximidamida Ex. 48 463.0, 464.9
178
N-{4 - [(E, Z) - [(3-bromo-4fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il} -2fenilacetamida Ex. 35 434.0, 436.0
179
N-{4 - [(E, Z) - [(3-bromo-4fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il} -2 - (3metoxifenil) acetamida Ex.35 464.0, 466.0
TABLA 1
Ex. No.
Estructura Nombre Prep. Metodo MS (M+1)
180
N-(3-Bromo-4-fluorofenil) -4 - ({[(3-cianofenil) (metil) amino] carbonil} amino)-N'-hidroxi-1, 2,5 - oxadiazol-3carboximidamida Ex. 48 473.9, 476.0
181
imagen81 4-amino-N'-hidroxi-N-(6metilpiridin-2-il) -1,2,5oxadiazol-3 carboximidamida trifluoroacetato Ex. 45 235.1
182
imagen82 4 - ({[Bencil (metil) amino] de carbono il} amino)-N-(3-bromo-4'fluorofenil)-N'-hidroxi1,2,5-oxadiazol-3carboximidamida Ex. 48 463.0, 464.9
183
imagen83 N-{4 - [(E, Z) - [(3-bromo4-fluorofenil) amino] (hidroximino) metil] 1,2,5-oxadiazol-3-il} - 2-fenilacetamida Ex. 35 434.0, 436.0
184
N-{4 - [(E, Z) - [(3-bromo4-fluorofenil) amino] (hidroximino) metil] 1,2,5-oxadiazol-3-il} -2 - (3-metoxifenil) acetamida Ex.35 464.0, 466.0
TABLA 1
Ex. No.
Estructura Nombre Prep. Metodo MS (M+1)
185
N-{4 - [(E, Z) - [(3-bromo4-fluorofenil) amino] (hidroximino) metil] 1,2,5-oxadiazol-3-il} - 3 - (4-bromofenil) propanamida Ex. 35 525.8, 527.8, 529.8
186
imagen84 N-{4 - [(E, Z) - [(3-bromo4-fluorofenil) amino] (hidroximino) metil] 1,2,5-oxadinol-3-il} - 3 - (4-clorofenil) propanamida Ex. 35 481.9, 483.9
187
N-{4 - [(E, Z) - [(3-bromo4-fluorofenil) amino] (hidroximino) metil) 1,2,5-oxadiazol-3-il} - 3 - (3-clorofenil) propanamida Ex.35 481.9, 483.9
188
N-{4 - [(E, Z) - [(3-bromo4-fluorofenil) amino] (hidroximino) metil] 1,2,5-oxadiazol-3-il} - 3 - (2-fluorofenil) propanamida Ex. 35 466.0, 467.9
189
N-{4 - [(E, Z) - [(3-bromo4-fluorofenil) amino] (hidroximino) metil] 1,2,5-oxadiazol-3-il} - 3 - (3-fluorofenil) propanamida Ex. 35 465.9, 467.9
TABLA 1
Ex. No.
Estructura Nombre Prep. Metodo MS (M+1)
190
imagen85 N-{4 - [(E, Z) - [(3-bromo4-fluorofenil) amino] (hidroximino) metil] 1,2,5-oxadiazol-3-il} - 3 - (2-clorofenil) propanamida Ex. 35 481.9, 483.9
191
imagen86 N-{4 - [(E, 2) - [(3-bromo4-fluorofenil) amino] (hidroximino) metil] 1,2,5-oxadiazol-3-il} - 3 - (3-metilfenil) propanamida Ex. 35 462.0, 464.0
192
imagen87 N-{4 - [(E, Z) - [(3-bromo4-fluorofenil) amino] (hidroximino) metil] 1,2,5-oxadiazol-3-il} - 3 - (3 - (trifluorometil) fenil) propanamida Ex. 35 515.9, 517.9
193
imagen88 N-{4 - [(E, Z) - [(3-bromo4-fluorofenil) amino] (hidroximino) metil] 1,2,5-oxadiazol-3-il} - 3 - (4-fluorofenil) propanamida Ex. 35 465.9, 468.0
194
N-{4 - [(E, Z) - [(3-bromo4-fluorofenil) amino] (hidroximino) metil] 1,2,5-oxadiazol-3-il} - 3 - (2-metoxifenil) propanamida Ex. 35 477.9, 479.9
TABLA 1
Ex. No.
Estructura Nombre Prep. Metodo MS (M+1 )
195
imagen89 N-{4 - [(E, Z) - [(3bromo-4-fluorofenil) amino] (hidroximino) metil] -1,2,5-oxadiazol3-il} -3 - (3-metoxifenil) propanamida Ex. 35 477.9 480.0
196
imagen90 N-{4 - [(E, Z) - [(3bromo-4-fluorofenil) amino] (hidroximino) metil] -1,2,5-oxadiazol3-il} -3 - (4-metoxifenil) propanamida Ex. 35 477.9 479.9
197
N-{4 - [(E, Z) - [(3bromo-4-fluorofenil) amino] (hidroximino) metil] -1,2,5-oxadiazol3-il} -3 - (4-metilfenil) propanamida Ex. 35 462.0 463.9
198
N-{4 - [(E, Z) - [(3bromo-4-fluorofenil) amino] (hidroximino) metil] -1,2,5-oxadiazol3-il} -3 - [4 (trifluorometil) fenil] propanamida Ex. 35 515.9 517.9
199
3 - [2,5-bis (trifluorometil)fenil]-N{4 - [(E, Z) - [(3-bromo4-fluorofenil) amino] (hidroximino) metil] 1,2,5-oxadiazol-3-il} propanamida Ex. 35 583.9 585.9
TABLA 1
Ex. No.
Estructura Nombre Prep. Metodo MS (M+1)
200
imagen91 3 - [3,5-bis (trifluorometil) fenil]-N-{4 - [(E, Z) - [(3bromo-4-fluorofenil) amino] (hidroximino) metil] -1,2,5-oxadiazol-3il} propanamida Ex. 35 583.9, 585.9
201
N-{4 - [(E, Z) - [(3-bromo4-fluorofenil) amino] (hidroximino) metil] 1,2,5-oxadiazol-3-il} - 2-metil-3fenilpropanamida Ex. 35 462.0, 464.0
202
imagen92 2-bencil-N-{4 - [(E, Z) - [(3-bromo-4-fluorofenil) amino] (hidroximino) metil] -1,2,5-oxadiazol-3il} -3,3dimetilbutanamida Ex. 35 504.0, 506.0
203
imagen93 4-Amino-N-(5-cloro-2metoxifenil)-N-hidroxi1,2,5-oxadiazol-3carboximidamida Ex. 1 284.1
204
imagen94 4-Amino-N-(5-cloro-2-metilfenil)-N'-hidroxi1,2,5-oxadiazol-3carboximidamida Ex.1 Ex. 47 268.1 299.0
TABLA 1
Ex. No.
Estructura Nombre Prep. Metodo MS (M+1)
205
4-Amino-N-(5-cloro-2-nitrofenil)-N'-hidroxi1,2,5-oxadiazol-3carboximidamida Ex. 47 299.0
206
4-Amino-N-(5-cloro-2fluorofenil)-N'-hidroxi1,2,5-oxadiazol-3carboximidamida Ex. 47 272.1
207
N-{4 - [(E, Z) - [(3-bromo4-fluorofenil) amino] (hidroximino) metil] 1,2,5-oxadiazol-3-il} - 1 - [4 - (trifluorometil) pirimidin-2-il] piperidina4-carboxamida Ex. 35 573.0, 575.0
208
1-bencil-N-{4 - [(E, Z) - [(3-bromo-4-fluorofenil) amino] (no hidroximi) metil] -1,2,5-oxadiazol-3il}-3-terc-butil-1H-pirazol5-carboxamida Ex. 35 556.0, 558.0
209
2 - (benciloxi)-N-{4 - [(E, Z) - [(3-bromo-4 fluorofenil) amino] (hidroximino) metil] 1,2,5 -oxadiazol-3-il} acetamida Ex. 35 463.9, 466.0
TABLA 1
Ex. No.
Estructura Nombre Prep. Metodo MS (M+1)
210
imagen95 N-{4 - [(E, Z) - [(3-bromo4-fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il} -1 - (4clorofenil ) ciclopentano carboxamida Ex. 35 521.9, 523.9
211
imagen96 N-{4-[(E,Z)-[(3-Bromo-4fluorophenyl)amino](hidrox imino)methyl]-1,2,5oxadiazol-3-yl}-3phenoxybenzamide Ex. 35 511.9, 513.9
212
N-{4 - [(E, Z) - [(3-bromo4-fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il} -2,4,6trichlorobenzamide Ex. 35 521.8, 523.8, 525.8
213
N-{4 - [(E, Z) - [(3-bromo4-fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il)-2metoxibenzamida Ex. 35 449.9, 451.9
214
N-{4 - [(E, Z) - [(3-bromo4-fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il} - 3-metoxibenzamida Ex. 35 449.9, 451.9
TABLA 1
Ex. No.
Estructura Nombre Prep. Metodo MS (M+1)
215
imagen97 N-{4 - [(E, Z) - [(3-bromo-4fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il} - 2,2 difenilacetamida Ex. 35 510.0 512.0
216
N-{4 - [(E, Z) - [(3-bromo-4fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il} -4 - (trifluorometoxi) benzamida Ex. 35 503.9 505.9
217
N-{4 - [(E, Z) - [(3-bromo-4fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il} - 4-metoxibenzamida Ex. 35 449.9 451.8
218
imagen98 N-{4 - [(E, Z) - [(3-bromo-4fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il} - 3,4-dimetoxibenzamida Ex. 35 479.9 481.9
219
N-{4 - [(E, Z) - [(3-bromo-4fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il} -2 - (2nitrofenoxi) acetamida Ex. 35 494.9, 496.9
TABLA 1
Ex. No.
Estructura Nombre Prep. Metodo MS (M+1)
220
N-{4 - [(E, Z) - [(3-bromo4-fluorofenil) amino] (hidroximino) metil] 1,2,5-oxadiazol-3-il} - 2-cloronicotinamida trifluoroacetato Ex. 35 454.9 456.9
221
imagen99 N-{4 - [(E, Z) - [(3-bromo4-fluorofenil) amino] (hidroximino) metil] 1,2,5-oxadiazol-3-il} bifenil-4-carboxamida Ex. 35 496.0 497.9
222
imagen100 N-{4 - [(E, Z) - [(3-bromo4-fenilo fluoro)-amino] (hidroximino) metil] 1,2,5-oxadiazol-3-il} -2 - (2,6-diclorobencil) -1,3tiazol-4-carboxamida Ex. 35 584.8, 586.8, 588.8
223
imagen101 N-{4 - [(E, Z) - [(3-bromo4-fluorofenil) amino] (hidroximino) metil] 1,2,5-oxadiazol-3-il} -2,6dimetoxibenzamida Ex. 35 479.9, 482.0
224
N-{4 - [(E, Z) - [(3-bromo4-fluorofenil) amino] (hidroximino) metil] 1,2,5-oxadiazol-3-il}-4nitrobeozamide Ex. 35 464.9, 466.9
TABLA 1
Ex. No.
Estructura Nombre Prep. Metodo MS (M+1)
225
imagen102 5-Bromo-N-{4 - [(E, Z) -[(3-bromo-4-fluorofenil) amino] - (hidroximino) metil] -1,2,5-oxadiazol-3il}trifluoroacetato nicotinamida Ex. 35 498.8, 500.8, 502.8
226
imagen103 N-{4 - [(E, Z) - [(3-bromo4-fluorofenil) amino] - (hidroximino) metil] 1,2,5-oxadiazol-3-il} - 3,3-dimetilbutanamida Ex. 35 413.9, 415.9
227
N-{4 - [(E, Z) - [(3-bromo4-fluorofenil) amino] - (hidroximino) metil] 1,2,5-oxadiazol-3-il} - 2 - (2-tienil) acetamida Ex. 35 439.9, 441.9
228
N-{4 - [(E, Z) - [(3-bromo4-fluorofenil) amino] - (hidroiimino) metil] 1,2,5-oxadiazol-3-il} - 4-fenilbutanamida Ex. 35 462.0, 464.0
229
4-Amino-N-(2-bromo-5- clorofenil)-N'-hidroxi1,2,5-oxadiazol-3carboximidamida Ex. 47 332.0, 334.0
TABLA 1
Ex. No.
Estructura Nombre Prep. Metodo MS (M+1)
230
N-{4 - [(E, Z) - [(3-bromo-4fluorofenil) amino] - (hidroximino) metil] -1,2,5oxadiazol-3-il} - 2,2-dimetilpropanamida Ex. 35 400.0, 401.9
231
N-{4 - [(E, Z) - [(3-bromo-4fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il} - 4 - (morfolin-4-il-metil) Benzamida trifluoroacetate Ex. 35 519.0, 521.0
232
N-{4 - [(E, Z) - [(3-bromo-4fluorofenil) amino] - (hidroximino) metil] -1,2,5oxadiazol-3-il} - 4 - [(1,1 dioxidothiomorpholin-4-il) metil]benzamide trifluoroacetate Ex. 35 567.0, 569.0
233
N-{4 - [(E, Z) - [(3-bromo-4fluorofenil) amino] - (hidroximino) metil] -1,2,5oxadiazol-3-il} - 1 - (fenilacetil) piperidina4-carboxamida Ex. 53 545.0, 547.0
234
N-{4 - [(E, Z) - [(3-Bromo4-fluoro-fenil)amino] (hidroximino) metil] -1,2,5oxadiazol-3-il} -1 - (metilsulfonil) piperidina-4carboxamida Ex. 53 505.0, 507.0
TABLA 1
Ex. No.
Estructura Nombre Prep. Metodo MS (M+1)
235
N-{4 - [(E, Z) - [(3-Bromo4-fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il}-2-piridin-4il-1 ,3-tiazol-4 carboxamide trifluoroacetate Ex. 35 504.0, 506.0
236
N-{4 - [(E, Z) - [(3-Bromo4-fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il} - 2-nitrobenzamida Ex. 35 464.9, 466.9
237
N-{4 - [(E, Z) - [(3-Bromo4-fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il}-3nitrobenzamida Ex. 35 464.9, 466.9
238
N-{4 - [(E, Z) - [(3-Bromo4-fluorofenil) amino] (hidroximino) metil] -1,2,5trifoxadiazol-3-il}-1isopropylpiperidine-4carboxamida Ex. 55 469.0, 471.0
239
terc-butil 4 - {4 - [({4 - [(E, Z) - [(3 -bromo-4-f luorof enil) amino](hidroximino) metil] -1,2,5 -oxadiazol-3-il} amino) carbonil] -1,3tiazol-2-il}-piperidino-1carboxilato Ex. 51 510.0 512.0
TABLA 1
Ex. No.
Estructura Nombre Prep. Metodo MS (M+1)
240
imagen104 N-{4 - [(E, Z) - [(3-Bromo4-fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il} -2-fenil-1 ,3tiazol-4-carboxamida Ex. 35 502.9, 504.9
241
imagen105 N-{4 - [(E, Z) - [(3-Bromo4-fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il} -2-metil-1 ,3-tiazol-4-carboxamida Ex. 35 441.0, 443.0
242
imagen106 N-{4 - [(E, Z) - [(3-Bromo4-fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il}-2-piperidin4-il-1 ,3-tiazol-4 carboxamida cloridrato Ex. 52 510.0, 512.0
243
imagen107 N-{4 - [(E, Z) - [(3-Bromo4fluorofenil)amino](hidroxi mino) metil] -1,2,5oxadiazol-3-il} - 2 - (4-cianofenoxi)acetamida Ex. 57 475.0, 476.9
244
imagen108 terc-butil 3 - [({4 - [(E, Z) - [(3-bromo-4-fluorofenil) amino] (hidroximino) metil] -1,2,5-oxadiazol-3il}carbonil) amino]piperidina-1-carboxilato de etilo Ex. 51 527.0, 529.0
TABLA 1
Ex. No.
Estructura Nombre Prep. Metodo MS (M+1)
245
N-{4 - [(E, Z) - [(3-Bromo-4f luorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il}-3 - (3 nitrofenil) propanamida Ex. 51 493.0, 494.9
246
imagen109 N-{4 - [(E, Z) - [(3-Bromo-4f luorofenil) amino] (hidroximino)metil] -1,2,5oxadiazol-3-il} -2 - acetamida (3-nitrofenoxi) Ex. 51 494.9, 497.0
247
imagen110 N-{4 - [(E, Z) - [(3-Bromo-4 fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il} -2 - (4-nitrof enoxi) acetamida Ex. 51 494.9, 496.9
248
N-{4 - [(E, Z) - [(3-Bromo-4fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il}piperidina-3carboxamida trifluoroacetato Ex. 52 426.9, 429.0
249
N-{4 - [(E, Z) - [(3-Bromo-4f luorofenil) amino] (hidroximino)metil] -1,2,5oxadiazol-3-il} -4-metil-2piridin-3-il-1, 3 - tiazol-5carboxamida trifluoroacetato Ex. 57 518.0, 520.0
TABLA 1
Ex. No.
Estructura Nombre Prep. Metod o MS (M+1)
N-{4 - [(E, Z) - [(3-Bromo-4
250
imagen111 f luorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il} -4-metil-1 ,3tiazol-5- carboxamida Ex. 57 441.0 443.0
2-Amino-N-{4 - [(E, Z) - [(3
251
bromo-4-fluorofenil)amino] (hidroximino) metil] -1,2,5oxadiazol-3-il} - 1,3-tiazol-4carboxamida trifluoroacetato Ex. 57 442.0 444.0
N-{4 - [(E, Z) - [(3-Bromo-4
252
imagen112 fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il} -4-metil-2pirazin-2-il-1, 3 -tiazol-5carboxamida trifluoroacetato Ex. 51 519.0 521.0
N-{4 - [(E, Z) - [(3-Bromo-4
253
imagen113 f luorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il} -4-metil-2-[4 -(trifluorometil) fenil] -1,3tiazole-5-carboxamida Ex. 51 585.0 587.0
N-{4 - [(E, Z) - [(3-Bromo-4
254
f luorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il} -2,4-dimetil-1 ,3-tiazol-5-carboxamida Ex. 57 455.0 457.0
TABLA 1
Ex. No.
Estructura Nombre Prep. Metodo MS (M+1)
255
imagen114 1-Acetil-N-{4 - [(E, Z) - [(3bromo-4- fluorof enil) amino] - (hidroximino) metil] -1,2,5oxadiazol-3-il}-pirrolidina-2carboxamida Ex. 51 454.9, 456.9
256
imagen115 N-{4 - [(E, Z) - [(3-Bromo-4fluorofenil) amino] (hidroximino metil] -1,2,5oxadiazol-3-il} -1,5-dimetil1H-pirazole-3- carboxamida Ex. 35 437.9, 439.9
257
imagen116 N-{4 - [(E, Z) - [(3-Bromo-4fluorofenil) amino] (hidroximino) metil] -1,2,5 oxadiazol-3-il}-5-cloro-1 metil-1H-pirazole-4 carboxamida Ex. 35 457.9, 459.9
258
imagen117 N-{4 - [(E, Z) - [(3-Bromo-4f luorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il} -1,3-dimetil1H-pirazole-5-carboxamida Ex.35 438.0, 440.0
259
N-{4 - [(E, Z) - [(3-Bromo-4fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il}-1-metil-1Himidazol-2-carboxamida Ex. 51 424.1 426.0
TABLA 1
Ex. No.
Estructura Nombre Prep. Metodo MS (M+1)
260
4 - [(acetilamino) metil]-N-{4 - [(E,Z) - [(3-bromo-4-fluorofenil) amino] (hidroximino) metil] -1,2,5-oxadiazol-3-il}benzamida Ex. 56 491.0 493.0
261
N-{4 - [(E, Z) - [(3-Bromo-4fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il}-4 metilpiperidina-4carboxamida trifluoroacetato Ex. 58 441.0 443.0
262
1-Acetil-N-{4 - [(E, Z) - [(3bromo-4- f luorof enil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il}-piperidina-3carboxamida Ex. 53 469.0 471.0
263
1-Acetil-N-{4 - [(E, Z) - [(3bromo-4-f luorof enil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il}-4 metilpiperidina-4carboxamida Ex. 53 483.0 485.0
264
imagen118 1-Acetil-N-{4 - [(E, Z) - [(3bromo-4-f luorof enil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il}-4-fenilpiperidina-4-carboxamida Ex. 53 545.0 547.0
TABLA 1
Ex. No.
Estructura Nombre Prep. Meto do MS (M+1)
265
imagen119 4 - (benzilamino)-N-(3bromo-4-N'fluorofenil)hidroxi-1 ,2,5-oxadiazole-3carboximidamida Ex.49 406.1 408.0
266
imagen120 N-{4 - [(E, Z) - [(3-Bromo-4fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il} -1etilpiperidina-3-carboxamida trifluoroacetato Ex. 55 455.0 457.0
267
N-{4 - [(E, Z) - [(3-Bromo-4fluorofenil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il}-4-etilpiperazina-1 carboxamida trifluoroacetato Ex. 48 456.0 458.0
268
4-Acetil-N-{4 - [(E, Z) - [(3bromo-4-f luorof enil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il} piperazina-1 carboxamida Ex. 48 470.0 472.0
269
imagen121 N-{4 - [(E, Z) - [(3-Bromo-4-f luorof enil) amino] (hidroximino) metil] -1,2,5oxadiazol-3-il} -2 - (1etilpiperidin-4-il) -1,3 -tiazol4carboxamida trifluoroacetato Ex. 55 538.0 540.0
TABLA 1
Ex. No.
Estructura Nombre Prep. Metodo MS (M+1)
270
imagen122 4-Amino-N-(3-ciano-4fluorofenil)-N'-hidroxi-1, 2,5 -oxadiazol-3carboximidamida Ex. 1 263.1
271
imagen123 N-(3-Bromo4fluorofenil)-N'- hidroxi4-[(1,3-tiazol-4-il-metil) amino] -1,2,5 oxadiazole-3carboximidamida Ex. 60 413.0 415.0
272
imagen124 N-(3-Bromo-4fluorofenil) -4 - [(4 cianobenzil) amino]-Nhidroxi-1 ,2,5oxadiazole-3 carboximidamida Ex. 60 431.0 433.0
273
imagen125 4-Amino-N-(3-cloro-5fluoro-fenil)-N'-hidroxi-1 ,2,5-oxadiazole-3carboximidamida Ex. 1 272.0
274
4-Amino-N-[3 - (dif luorometil) fenil]-N 'hidroxi-1 ,2,5 oxadiazole-3carboximidamida Ex. 1 270.1
TABLA 1
Ex. No.
Estructura Nombre Prep. Metodo MS (M+1)
275
imagen126 N-(3-Bromo-4 fluorofenil)-N'-hidroxi-4{[(1-metil-piperidin-4-il) metil] amino} -1,2,5oxadiazole trifluoroacetato-3carboximidamida Ex. 60 427.0 429.0
276
imagen127 N-(3-Bromo-4fluorofenil)-N '-hidroxi-4{[4 - (piperazin-1-il-metil)benzil] amino} -1,2,5 - oxadiazol-3 carboximidamida bis (trifluoroacetato) Ex. 60 504.0 506.0
277
imagen128 N-(3-Bromo-4-fluorofenil) -4 - ({4 - [(4-etilpiperazin1-il) metil]benzil} amino)-N '-hidroxi-1 ,2,5 oxadiazole-3carboximidamida bis (trifluoroacetato) Ex. 60 532.2 534.2
278
imagen129 4-Amino-N '-hidroxi-N-(3 -hidroxifenil) -1,2,5oxadiazole- 3carboximidamida Ex. 1 236.1
279
4-Amino-N-(3-cloro-4- fluorofenil)-N' (isobutiriloxi) - 1,2,5 oxadiazole-3- carboximidamida Ex. 67 342.0
TABLA 1
Ex. No.
Estructura Nombre Prep. Metodo MS (M+1)
280
imagen130 4-Amino-N-(3-cloro-4- fluorofenil)-N'-[(3 - metilbutanoil)-oxi] -1,2,5 -oxadiazol-3carboximidamida Ex. 67 356.0
281
4-amino-N'-(benziloxi)-N(3 -cloro-4-fluorofenil) 1,2,5 - oxadiazol-3carboximidamida Ex. 67 376.0
282
4-Amino-N-(3-cloro-4- fluorofenil)-N'-[(2,2 - dimetilpropanoil) oxi] 1,2,5 -oxadiazol-3carboximidamida Ex. 67 356.0
283
4-Amino-N-[3 - (cianometil) fenil]-N 'hidroxi-1, 2,5 -oxadiazol3-carboximidamida Ex. 67 259.1
284
4-Amino-N-(3-cyano-2fluorophenyl)-N’-hydroxy1,2,5-oxadiazole-3carboximidamide Ex. 1 263.1
TABLA 1
Ex. No.
Estructura Nombre Prep. Metodo MS (M+1)
285
imagen131 4-Amino-N '-hidroxi-N-[3 - (metoximetil) fenil] - 1,2,5-oxadiazole-3carboximidamida Ex. 1 264.1
286
imagen132 4-Amino-N '-hidroxi-N-[3 - (3-metoxiprop-1-in-1-il) fenil] -1,2,5-oxadiazole3-carboximidamida Ex. 70 287.9
287
imagen133 4-Amino-N '-hidroxi-N-(2metil-1,3-benzoxazol-4-il) -1,2,5-oxadiazole-3carboximidamida Ex. 1 275.0
288
imagen134 4-anilino-N-(3-bromo-4- fluorofenil)-N'-hidroxi-1, 2,5 -oxadiazol-3carboximidamida Ex. 69 392.0, 394.0
289
imagen135 N-(3-Bromo-4fluorofenil)-N'-hidroxi-4[(piridin-4-ilmetil)amino] 1,2,5-oxadiazole-3- trifluoroacetato carboximidamida Ex. 63 406.9, 408.9
imagen136
imagen137
imagen138
imagen139
imagen140

Claims (1)

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