ES2555491T3 - Composiciones y métodos para la inhibición de la ruta de JAK - Google Patents

Composiciones y métodos para la inhibición de la ruta de JAK Download PDF

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Publication number
ES2555491T3
ES2555491T3 ES10701189.2T ES10701189T ES2555491T3 ES 2555491 T3 ES2555491 T3 ES 2555491T3 ES 10701189 T ES10701189 T ES 10701189T ES 2555491 T3 ES2555491 T3 ES 2555491T3
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Prior art keywords
ylamino
methyl
oxo
methylpyrimidin
pyrimidin
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ES10701189.2T
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Inventor
Hui Li
Thilo J. Heckrodt
Yan Chen
Darren John Mcmurtrie
Vanessa Taylor
Rajinder Singh
Pingyu Ding
Sambaiah Thota
Rose Yen
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Rigel Pharmaceuticals Inc
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Rigel Pharmaceuticals Inc
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    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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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 formula I:**Fórmula** o una sal del mismo, en el que: X e Y son cada uno independientemente O, S, S(O), SO2 o NR1; cada R1 es independientemente para cada aparición H, alquilo C1-6 opcionalmente sustituido, C(O)-alquilo C1-6, CO2- alquilo C1-6 o R50; cada R50 es C(R9)2-O-R10 o C(R9)2-S-R10; cada R9 es independientemente para cada aparición H, alquilo C1-6 opcionalmente sustituido, arilo C6-10 opcionalmente sustituido o arilalquilo C7-16 opcionalmente sustituido; o como alternativa, dos R9, junto con el carbono al que están unidos, forman un grupo cicloalquilo C3-8 opcionalmente sustituido o un heteroarilciclilo de 3-8 miembros opcionalmente sustituido 3-8; R10 es Ra o -P(O)(OR11)2; cada R11 es independientemente para cada aparición Ra o un grupo catiónico monovalente; o dos R11, junto con los átomos a los que están unidos, forman un grupo fosfato cíclico de 4-8 miembros, o dos R11 juntos representan un grupo catiónico divalente; el anillo A es un arilo C6-10 o un heteroarilo de 5-10 miembros; cada R2 es independientemente para cada aparición H, Re, Rb, Re sustituido con uno o más de los mismos o diferentes Ra y/o Rb, -ORe sustituido con uno o más de los mismos o diferentes Ra y/o Rb, -SRe sustituido con uno o más de los mismos o diferentes Ra y/o Rb, -C(O)Re sustituido con uno o más de los mismos o diferentes Ra y/o Rb, - N(Ra)Re en el que Re está sustituido con uno o más de los mismos o diferentes Ra y/o Rb, -S(O)2Re sustituido con uno o más de los mismos o diferentes Ra y/o Rb, -B(ORa)2, -B(N(Rc)2)2, -(C(Ra)2)m-Rb, -O-(C(Ra)2)m-Rb, -S-(C(Ra)2)m- Rb, -O-(C(Rb)2)m-Ra, -N(Ra)-(C(Ra)2)m-Rb, -O-(CH2)m-CH((CH2)mRb)Rb, -C(O)N(Ra)-(C(Ra)2)m-Rb, -O-(C(Ra)2)m- C(O)N(Ra)-(C(Ra)2)m-Rb,-N((C(Ra)2)mRb)2, -S-(C(Ra)2)m-C(O)N(Ra)-(C(Ra)2)m-Rb, -N(Ra)-C(O)-N(Ra) -(C(Ra)2)m-Rb25 , - N(Ra)-C(O)-(C(Ra)2)m-C(Ra)(Rb)2 o -N(Ra)-(C(Ra)2)m-C(O)-N(Ra)-(C(Ra)2)m-Rb; cada Ra es independientemente para cada aparición H, deuterio, alquilo C1-6, cicloalquilo C3-8, cicloalquilalquilo C4-11, arilo C6-10, arilalquilo C7-16, heteroalquilo de 2-6 miembros, heteroaliciclilo de 3-10 miembros, heteroaliciclilalquilo de 4-11 miembros, heteroarilo 5-15 miembros o heteroarilalquilo de 6-16 miembros; cada Rb es independientemente para cada aparición >=O, -ORa, -O-(C(Ra)2)m,-ORa, haloalquiloxi C1-3, >=S, -SRa, >=NRa, >=NORa, -N(Rc)2, halo, -CF3, -CN, -NC, -OCN, -SCN, -NO, -NO2, >=N2, -N3, -S(O)Ra, -S(O)2Ra, -SO3Ra, - S(O)N(Rc)2, -OS(O)Ra, -OS(O)2Ra, -OSO3Ra, -OS(O)2N(Rc)2, -C(O)Ra, -CO2Ra, -C(O)N(Rc)2, -C(NRa)-N(Rc)2, - C(NOH)-Ra, -C(NOH)-N(Rc)2, -OC(O)Ra, -OC(O)ORa, -OC(O)N(Rc)2, -OC(NH)-N(Rc)2, -OC(NRa)-N(Rc)2, - [N(Ra)C(O)]nRa, -[N(Ra)C(O)]nORa, -[N(Ra)C(O)]nN(Rc)2 o -[N(Ra)C(NRa)]n-N(Rc)2; cada Rc es independientemente para cada aparición Ra, o, como alternativa, se toman juntos dos Rc con el átomo de nitrógeno al que se enlazan para formar un heteroaliciclilo de 3 a 10 miembros o un heteroarilo de 5-10 miembros que opcionalmente puede incluir uno o más de los mismos o diferentes heteroátomos adicionales y que está opcionalmente sustituido con uno o más de los mismos o diferentes grupos Ra y/o Rd; cada Rd es >=O, -ORa, halo alquiloxi C1-3,alquilo C1-6, >=S, -SRa, >=NRa, >=NORa, -N(Ra)2, halo, -CF3, -CN, -NC, -OCN, - SCN, -NO, -NO2, >=N2, -N3, -S(O)Ra, -S(O2)Ra, -SO3Ra, -S(O)N(Ra)2, -S(O)2N(Ra)2, -OS(O)Ra, -OS(O)2Ra, -OSO3Ra, - OS(O)2N(Ra)2, -C(O)Ra, -CO2Ra, -C(O)N(Ra)2, -C(NRa)N(Ra)2, -C(NOH)Ra, -C(NOH)N(Ra)2, -OCO2Ra, -OC(O)N(Ra)2, -OC(NRa)N(Ra)2 -[N(Ra)C(O)]nRa, -(C(Ra)2)n-ORa, -N(Ra)-S(O)2Ra, -C(O)-haloalquilo C1-6, -S(O)2- haloalquilo C1-6, - OC(O)Ra, -O(C(Ra)2)m-ORa, -S(C(Ra)2)m-ORa, -N(Ra)-haloalquilo C1-6, -P(O)(ORa)2, -N(Ra)-(C(Ra)2)m-ORa, - [N(Ra)C(O)]nORa, -[N(Ra)C(O)]nN(Ra)2, -[N(Ra)C(NRa)]n(Ra)2 o -N(Ra)C(O)-haloalquilo C1-6; o dos Rd, tomados junto con el átomo o átomos a los que están unidos, se combinan para formar un anillo mono o bicíclico, parcial o totalmente saturado de 3-10 miembros, que contiene opcionalmente uno o más heteroátomos y está opcionalmente sustituido con uno o más Ra; cada Re es independientemente para cada aparición alquilo C1-6, cicloalquilo C3-8, cicloalquilalquilo C4-11, arilo C6-10, arilalcilo C7-16, heteroalquilo de 2-6 miembros, heteroaliciclilo de 3-10 miembros, heteroaliciclilalquilo de 4-11 miembros, heteroarilo de 5-15 miembros o heteroarilalquilo de 6-16 miembros; p es 0, 1, 2, 3 o 4; cada m es 1, 2 o 3; cada n es 0, 1,2 o 3; o dos grupos R2, tomados junto con el átomo o átomos a los que están unidos, se combinan para formar un anillo mono o bicíclico, parcial o totalmente saturado de 4-10 miembros, que contiene opcionalmente uno o más heteroátomos y está opcionalmente sustituido con uno o más Ra y/o Rb; Z1 y Z2 son cada uno independientemente CH, CR2 o N; R3 es H, alquilo C1-6 opcionalmente sustituido o R50; R4 es H, alquilo C1-6 opcionalmente sustituido o R50; y R5 es halo, -CN, alquilo C1-6 opcionalmente sustituido, alquinilo, hidroxi, alcoxi C1-6 opcionalmente sustituido, nitro, - N(Ra)2, -C(O)N(Ra)2, -CO2Ra o -C(O)Ra.

Description

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CF3, -CN, -S(O)2N(Rc)2, -S(O)2Ra, -C(O)Ra, -CO2Ra, -C(O)N(Rc)2, -C(Ra)2-N(Rc)2 o -[N(Ra)C(O)]nRa; y uno de R2a y R2b no sea H. En otra realización, cada uno de R2a y R2b es H, alquilo C1-6, -ORa, -OCF3, halo, -N(Rc)2, -CF3, -C(Ra)2N(Rc)2 o -CN. En otra realización, R2b es -CF3 o -CH3; y R2a es halo o -CH3. En otra realización, R2a es H, -CH3, -CF3, -ORa o -OCF3; y R2b es -N(Rc)2 o -C(Ra)2-N(Rc)2. En otra realización más, R2a es -N(Rc)2 o -C(Ra)2-N(Rc)2; y R2b es H, -CH3, -CF3, -ORa o -OCF3.
Aún en otra realización es un compuesto de fórmulas estructurales IA1 o IA2, en las que R2c y R2d son H, y R5 es F o CH3; R2a y R2b se toman junto con los carbonos a los que están unidos para formar un anillo mono o bicíclico, parcial
o totalmente saturado de 4-10 miembros, que contiene opcionalmente uno o más heteroátomos y opcionalmente sustituido con uno o más Ra y/o Rb. En una realización, este es un anillo de 5 miembros, y en una realización más específica el anillo de 5 miembros es ciclopentano, pirrolidina, imidazolidina, 1,3-dioxolano, oxazolidina o tetrahidrofurano; opcionalmente sustituido con uno o más Ra y/o Rb. En una realización específica, el anillo de 5 miembros es pirrolidina, y en una realización incluso más específica los compuestos están de acuerdo con fórmula IA3:
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en la que Rb es OH, alquilo C1-6, -CO2-alquilo C1-6, -C(O)-alquilo C1-6 o -S(O)2-alquilo C1-6. En otra realización, R2a y R2b se toman junto con los carbonos a los que están unidos para formar un anillo monocíclico parcial o totalmente saturado de 6, 7 u 8 miembros, que contiene opcionalmente uno o más heteroátomos y opcionalmente sustituido con uno o más Ra y/o Rb. En una realización, cuando el anillo es de 6 miembros, el anillo es ciclohexano, morfolina, piperidina, dioxano, oxatiazinano o piperazina; opcionalmente sustituido con uno o más Ra y/o Rb. En otra realización, cuando el anillo es de 7 miembros, el anillo es cicloheptano, ciclohepteno, azepano, tetrahidroazepina o diazepano; opcionalmente sustituido con uno o más Ra y/o Rb. En otra realización más, cuando el anillo es de 8 miembros, el anillo es ciclooctano, cicloocteno, azocano, hexahidroazocina, diazocano o hexahidrodiazocina; opcionalmente sustituido con uno o más Ra y/o Rb. Para cada una de las realizaciones anteriores, en las que R2a y R2b se toman junto con los carbonos a los que están unidos para formar un anillo monocíclico parcial o totalmente saturado de 5, 6, 7 u 8 miembros, hay una realización más específica en la que hay 0, 1, 2 o 3 en cada uno de Ra y Rb, y Ra es alquilo C1-6; y cada Rb es independientemente para cada aparición =O, -ORa, haloalquiloxi C1-3, -SRa, N(Rc)2, halo, -CF3, -CN, -S(O)2Ra, -C(O)Ra, -CO2Ra, -C(O)N(Rc)2 o -C(Ra)2-N(Rc)2. Por ejemplo, en una realización, hay al menos un Rb que es =O; y opcionalmente un Ra que es alquilo C1-6 opcionalmente sustituido. Ejemplos particulares de compuestos de acuerdo con la fórmula IA3, incluyen, pero sin limitación, se abarcan compuestos tales como IV-2, IV-10, IV-14 a través de IV-16, IV-18 a través de IV-34 y IV-50 (véase Tabla IV).
Algunas realizaciones incluyen compuestos en los que el anillo A es otro distinto de fenilo. En una realización específica, el anillo A es piridina o piridazina. Como se muestra en la fórmula I, y con respecto a esta realización, la piridina o piridazina puede tener diversas configuraciones regioquímicas y puntos de unión a la molécula precursora.
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en los que las variables de definen de la misma manera como para los de fórmula I, y además: Q1 y Q2 son cada uno independientemente N o CR2, con la condición de que al menos uno de Q1 y Q2 sea N; X e Y son cada uno independientemente O o NR1; cada R1 es independientemente para cada aparición H, alquilo C1-6 opcionalmente sustituido o R50; p es 0, 1, 2 o 3; y R5 es halo, -CN, alquilo C1-6 opcionalmente sustituido, nitro, -N(Ra)2, -C(O)N(Ra)2, -CO2Ra o -C(O)Ra.
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en la que cada uno de R2a, R2b, R2c y R2d (cuando están presentes) es independientemente para cada aparición como se define para R2
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Una realización es un compuesto de fórmula estructural IB1 o IB2, en la que X e Y son cada uno independientemente NR1. En una realización más específica, X e Y son cada uno independientemente NH o Nalquilo C1-6. EN una realización incluso más específica, X e Y son cada uno independientemente NH o NCH3. En una realización, en la que X e Y se definen más específicamente como se han mencionado, R5 es halo o alquilo C1-6; Z1 es CH, C-Halo o C-alquilo C1-6 opcionalmente sustituido; y Z2 es CH. En otra realización, R2a y R2d son H; y R5 es F o CH3. En otra realización, cada uno de R2b y R2c es independientemente para cada aparición H, alquilo C1-6, -ORa, -OCH2F, -OCF3, -SRa, -N(Rc)2, halo, -OCF2H, -CF3, -CN, -S(O)2Ra, -C(O)Ra, -CO2Ra, -C(O)N(Rc)2, -C(Ra)2-N(Rc)2 o [N(Ra)C(O)]nRa; y uno de R2b y R2c no es H. En tal otra realización, cada uno de R2b y R2c es independientemente para cada aparición H, alquilo C1-6, -N(Rc)2, halo, -CF3, -CN, -S(O)2Ra, -C(O)Ra, -CO2Ra, -C(O)N(Rc)2, o -C(Ra)2N(Rc)2. En otra realización, R2b es H, halo, -CF3, -CN o -CH3; y RZc es -N(Rc)2, -S(O)2Ra, -C(O)N(Rc)2 o -C(Ra)2N(Rc)2.
Otra realización es un compuesto de fórmula estructural IB1 o IB2, en la que X es O e Y es NR1. En una realización, R5 es halo o alquilo C1-6; Z1 es CH, C-Halo o C-alquilo C1-6 opcionalmente sustituido; y Z2 es CH. En otra realización, R2a y R2d son H; y R5 es F o CH3. En una realización más específica, cada uno de R2b y R2c es independientemente para cada aparición H, alquilo C1-6, -ORa, -OCF3, -SRa, -N(Rc)2, halo, -OCF2H, -OCH2F, -CF3, -CN, -S(O)2Ra, C(O)Ra, -CO2Ra, -C(O)N(Rc)2, -C(Ra)2-N(Rc)2 o -[N(Ra)C(O)nNRa; y uno de R2b y R2c no es H. En otra realización, cada uno de R2b y R2c es independientemente para cada aparición H, alquilo C1-6, -N(Rc)2, halo, -CF3, -CN, -S(O)2Ra, -C(O)Ra, -CO2Ra, -C(O)N(Rc)2, o -C(Ra)2-N(Rc)2. En una realización más específica R2b es H, halo, -CF3, -CN o -CH3; y R2c es -N(Rc)2, -S(O)2Ra, -C(O)N(Rc)2 o -C(Ra)2-N(Rc)2. En otra realización, R2b es H, halo, -CF3, -CN o -CH3; y R2c es -N(Rc)2 o -C(Ra)2-N(Rc)2.
Otra realización es un compuesto de fórmula estructural IB1 o IB2, en la que X es O; Y es NR1; Z1 es CH, C-Halo o C-alquilo C1-6 opcionalmente sustituido; Z2 es CH; R2a y R2d son H; y R5 es F o CH3, R2b y R2c se toman junto con los carbonos a los que están unidos para formar un anillo mono o bicíclico, parcial o totalmente saturado de 4-10 miembros, que contiene opcionalmente uno o más heteroátomos y opcionalmente sustituido con uno o más Ra y/o Rb. En una realización, el anillo es un anillo monocíclico, parcial o totalmente saturado de 5, 6, 7 u 8 miembros opcionalmente sustituido con uno o más Ra y/o Rb. En una realización, el anillo monocíclico, saturado de 5, 6, 7 u 8 miembros es ciclopentano, pirrolidina, imidazolidina, 1,3-dioxolano, oxazolidina, tetrahidrofurano, ciclohexano, morfolina, piperidina, dioxano, oxatiazinano, piperazina, cicloheptano, ciclohepteno, azepano, tetrahidroazepina, diazepano, ciclooctano, cicloocteno, azocano, hexahidroazocina, diazocano o hexahidrodiazocina; opcionalmente sustituido con uno o más Ra y/o Rb. Para cada uno de las realizaciones anteriores, en las que R2b y R2c se toman junto con los carbonos a los que están unidos para formar un anillo monocíclico, saturado de 5, 6, 7 u 8 miembros, hay una realización más específica en la que hay 0, 1, 2 o 3 cada uno de Ra y Rb, y Ra es alquilo C1-6; y cada Rb es independientemente para cada aparición =O, -ORa, haloalquiloxi C1-3, -SRa, -N(Rc)2, halo, -CF3, -CN, -S(O)2Ra, C(O)Ra, -CO2Ra, -C(O)N(Rc)2, o -C(Ra)2-N(Rc)2. Por ejemplo, en una realización, hay al menos un Rb que es =O; y opcionalmente un Ra que es alquilo C1-6 opcionalmente sustituido. En esta realización se abarcan compuestos tales como IV-45, IV-46 y IV-47 (véase Tabla IV).
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Una realización es un compuesto de fórmula estructural IB3, en la que X es O e Y es NR1. En una realización, R5 es halo o alquilo C1-6; Z1 es CH, C-Halo o C-alquilo C1-6 opcionalmente sustituido; y Z2 es CH. En otra realización, R2a es H; y R5 es F o CH3. En una realización más específica, cada uno de R2b y R2c es independientemente para cada aparición H, alquilo C1-6, -ORa, -OCF3, -SRa, -N(Rc)2, halo, -OCF2H, -OCH2F, -CF3, -CN, -S(O)2Ra, -C(O)Ra, -CO2Ra, C(O)N(Rc)2, -C(Ra)2-N(Rc)2 o -[N(Ra)C(O)]nRa; y uno de R2b y R2c no es H. En otra realización, cada uno de R2b y R2c es independientemente para cada aparición H, alquilo C1-6, -N(Rc)2, halo, -CF3, -CN, -S(O)2Ra, -C(O)Ra, -CO2Ra, C(O)N(Rc)2, o -C(Ra)2-N(Rc)2. En una realización más específica R2b es H, halo, -CF3, -CN o -CH3; y R2c es -N(Rc)2, S(O)2Ra, -C(O)N(Rc)2 o -C(Ra)2-N(Rc)2. En otra realización, R2b es H, halo, -CF3, -CN o -CH3; y R2c es -N(Rc)2 o C(Ra)2-N(Rc)2.
Otra realización es un compuesto de fórmula estructural IB3, en la que X es O; Y es NR1; Z1 es CH, C-Halo o Calquilo C1-6 opcionalmente sustituido; Z2 es CH; R2c y R2d son H; y R5 es F o CH3, R2b y R2c se toman junto con los carbonos a los que están unidos para formar un anillo mono o bicíclico, parcial o totalmente saturado de 4-10 miembros, que contiene opcionalmente uno o más heteroátomos y opcionalmente sustituido con uno o más Ra y/o Rb. En una realización, el anillo es un anillo monocíclico parcial o totalmente saturado de 5, 6, 7 u 8 miembros
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Tabla II
Cpd
X Y Z1 R5 R2a R2b R2c R2d
II-1
O NH CH CH3 H H -N(CH3)2 H
II-2
O NH CH CH3 H H H
II-3
O NH CH CH3 H H 1-metil-1,4-diazepan-4-ilo H
II-4
O N-(n-propil) CH CH3 H H 1-metilpiperazin-4-ilo H
II-5
O N-(n-propil) CH CH3 H H imagen44 H
II-6
O NH CH CH3 H H 4-metilpiperidin-1-ilo H
II-7
O N-(isopropil) CH CH3 H H 1-metilpiperazin-4-ilo H
II-8
O NH CH CH3 H H imagen44 H
II-9
O NH CH CH3 H H H
II-10
O NH CH CH3 H H piperazin-1-ilo H
II-11
O NH CH CH3 H H imagen45 H
II-12
O NH CH CH3 H H H
II-13
O NH CH CH3 H H 1-metilpiperazin-4-ilo H
II-14
O NH CH F H H 1-metilpiperazin-4-ilo H
II-15
NH NH CH CH3 H H 1-metilpiperazin-4-ilo H
II-16
NH NH CH F H H 1-metilpiperazin-4-ilo H
II-17
O NH CH CH3 H H morfolin-4-ilo H
II-18
O NH CH F H H morfolin-4-ilo H
II-19
NH NH CH F H H morfolin-4-ilo H
II-20
NCH3 NCH3 CH CH3 H H 1-metilpiperazin-4-ilo H
II-21
NCH3 NCH3 CH F H H 1 -metilpiperazin-4-ilo H
II-22
O NCH3 CH CH3 H H 1-metilpiperazin-4-ilo H
II-23
NCH3 O CH CH3 H H 1-metilpiperazin-4-ilo H
II-24
O NCH3 CH F H H 1-metilpiperazin-4-ilo H
II-25
NH O CH CH3 H H 1-metilpiperazin-4-ilo H
II-26
O NH CH CH3 H CH3 1-metilpiperazin-4-ilo H
II-27
NH NH CH CH3 H CH3 1-metilpiperazin-4-ilo H
II-28
O NH CH CH3 H CH3 H
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II-29
O NH CH F H CH3 H
II-30
O NH CH F H CH3 1-metilpiperazin-4-ilo H
II-31
O NH CH CH3 H H H
II-32
O NH CH CH3 H H H
II-33
O NH CH F H H H
II-34
O NH CH F H H H
II-35
O NH CH CH3 H H -N(H)-1-metilpiperidin-4-ilo H
II-36
O NH CH CH3 H H -N(H)-piperidin-4-ilo H
II-37
O NH CH CH3 H H H
II-38
O NH CH CH3 H H H
II-39
O NH CH CH3 H CF 3 1-metilpiperazin-4-ilo H
II-40
O NH CH CH3 H F H
II-41
O NH CH CH3 H H H
II-42
O NH CH CH3 H H H H
II-43
O NH CH CH3 H H S(O)2CH3 H
II-44
O NH CH CH3 H H H
II-45
O NH CH CH3 H H -C(O)-piperazin-1-ilo H
II-46
O NH CH CH3 H H H
II-47
O NH CH CH3 H H H
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II-48
O NH CH CH3 H F H
II-49
O NH CH CH3 H F H
II-50
O NH CH CH3 H F H
II-51
O NH CH CH3 H F H
II-52
O NH CH CH3 H F H
II-53
O NH CH CH3 H F H
II-54
O NH CH CH3 H F H
II-55
O NH CH CH3 H H H
II-56
O NH CH CH3 H H H
II-57
O NH CH CH3 H H H
II-58
O NH CH CH3 H H H
II-59
O NH CH CH3 H H 4,4-difluoropiperidin-1-ilo H
II-60
O NH CH CH3 H H 4,4-dimetilpiperidin-1-ilo H
II-61
O NH CH CH3 H CH3 imagen44 H
II-62
O NH CH CH3 H CH3 H
II-63
O NH CH CH3 H CH3 H
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II-64
O NH CH CH3 H CH3 H
II-65
O NH CH CH3 H CH3 H
II-66
O NH CH CH3 H CH3 H
II-67
O NH CH CH3 H CH3 imagen44 H
II-68
O NH CH CH3 H CH3 H
II-69
O NH CH CH3 H CH3 H
II-70
O NH CH CH3 H H H
II-71
O NH CH CH3 H H pirrolidin-1-ilo H
II-72
O NH CCH3 CH3 H H 1-metilpiperazin-4-ilo H
II-73
O NH CCH3 CH3 H H morfolin-4-ilo H
II-74
O NH CH CH3 H H -N(H)CH2-ciclopropil H
II-75
O NH CF CH3 H H 1-metilpiperazin-4-ilo H
II-76
O NH CF CH3 H H morfolin-4-ilo H
II-77
O NH CH CH3 H Br H H
II-79
O NCH3 CH CH3 H H -N(H)S(O)2CH3 H
II-80
O NH CH CH3 H H H
II-81
O NH CH CH3 H H H
II-82
O NH CH CH3 H H H
II-83
O NH CH CH3 H H H
II-84
O NH CH CH3 H H H
II-85
O NH CH CF3 H H 1-metilpiperazin-4-ilo H
II-86
O NH CH CH3 H H H
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O NH CH CH3 H H H
11-88
O NH CH CH3 H H H
11-89
O NH CH CH3 H H imagen44 H
11-90
O NH CH CH3 H H H
11-91
O NH CH CH3 H H H
II-92
O NH CH CH3 H H H
II-94
O NH CH CH3 H H H
II-95
O NH CH CH3 H H H
II-96
O NH CH CH3 H H H
II-97
O NH CH CH3 H H H
II-98
O NH CH CH3 H H H
II-99
O NH CH CH3 H H H
II-100
O NH CH CH3 H H imagen44 H
II-101
O NH CH CH3 H H H
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O NH CH CH3 H H H
II-103
O NH CH CH3 H H H
II-104
O NH CH CH3 H H H
II-105
O NH CH CH3 H H H
II-106
O NH CH CH3 H H imagen46 H
II-107
O NH CH CH3 H H H
II-108
O NH CH CH3 H H H
II-109
O NH CH CH3 H CF 3 imagen44 H
II-110
O NH CH CH3 H CF 3 1-etilpiperazin-4-ilo H
II-111
O NH CH CH3 H F 1-metilpiperazin-4-ilo H
II-112
O NH CH CH3 H F H
II-113
O NH CH CH3 H F H
II-114
O NH CH CH3 H F 1-etilpiperazin-4-ilo H
II-115
O NH CH CH3 H CN H
11-116
O NH CH CH3 H Cl 1 -metilpiperazin-4-ilo H
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O NH CH CH3 H H H
11-118
O NH CH CH3 H Cl imagen44 H
II-119
O NH CH CH3 H CF 3 H
11-120
O NH CH CH3 H H imagen44 H
II-121
O NH CH CH3 H H H
II-122
O NH CH CH3 H Cl H
II-123
O NH CH CH3 H H -OCH3 H
II-124
O NH CH CH3 H CF3 imagen44 H
II-125
O NH CH CH3 H F H
II-126
O NH CH CH3 H H H
II-127
O NH CH CH3 H H H
II-128
O NH CH CH3 H H H
II-129
O NH CH CH3 H H imagen47 H
II-130
O NH CH CH3 H H H
II-131
O NH CH CH3 H H H
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O NH CH CH3 H H H
II-133
O NH CH CH3 H H H
II-134
O NH CH CH3 H H H
II-135
O NH CH CH3 H H imagen44 H
II-136
O NH CH CH3 H H 1-isopropilpiperazin-4-ilo H
II-137
O NH CH CH3 H H H
II-138
O NH CH CH3 H H H
II-139
O NH CH CH3 H H H
11-140
O NH CH CH3 H OCH3 OCH3 H
II-141
O NH CH CH3 H OCH3 OCH3 H
II-142
O NH CH CH3 H H OCH2CH2OH H
II-143
O NH CH CH3 CH3 H 1 -metilpiperazin-4-ilo H
II-144
O NH CH CH3 H H OCH(CH3)2 H
II-145
O NH CH CH3 H H OCH2CH2OCH3 H
11-146
O NH CH CH3 H H OC(CH3)2C(O)NH2 H
II-147
O NH CH CH3 H CF 3 OCH3 H
11-148
O NH CH CH3 H H OCH2CH2CH2OH H
II-149
O NH CH CH3 H H OCH2CH2CH2OCH3 H
II-150
O NH CH CH3 H Cl H
II-151
O NH CH CH3 H H H
II-152
O NH CH CH3 H OCH3 H H
II-153
O NH CH CH3 H CH3 CH3 H
50
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Claims (1)

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    I-65 N2-((3-metilsulfonil)fenil)-N4-(3-metil-2-oxo-2,3-dihidrobenzo[d]oxazol-6-il)-5-metilpirimidin-2,4-diamina; I-66 N2-((4-metilsulfonil)fenil)-N4-(3-metil-2-oxo-2,3-dihidrobenzo[d]oxazol-6-il)-5-metilpirimidin-2,4-diamina; I-69 N2-((3-metilsulfonil)fenil)-N4-(3-metil-2-oxo-2,3-dihidrobenzo[d]oxazol-5-il)-5-metilpirimidin-2,4-diamina; I-70 N2-((4-metilsulfonil)fenil)-N4-(3-metil-2-oxo-2,3-dihidrobenzo[d]oxazol-5-il)-5-metilpirimidin-2,4-diamina; I-77 N2-((3-metilsulfonil)fenil)-N4-(3-metil-2-oxo-2,3-dihidrobenzo[d]oxazol-5-il)-5-fluoropirimidin-2,4-diamina; I-78 N2-((4-metilsulfonil)fenil)-N4-(3-metil-2-oxo-2,3-dihidrobenzo[d]oxazol-5-il)-5-fluoropirimidin-2,4-diamina; I-100 N2-((3-metilsulfonil)fenil)-N4-(2-oxo-2,3-dihidrobenzo[d]oxazol-6-il)-5-metilpirimidin-2,4-diamina; I-101 N2-((4-metilsulfonil)fenil)-N4-(2-oxo-2,3-dihidrobenzo[d]oxazol-6-il)-5-metilpirimidin-2,4-diamina; I-106 sal trifluoroacetato de N4-(benzoxazolin-2-on-5-il)-N2-(3-trifluorometoxifenil)-5-metilpirimidin-2,4-diamina; I-107 sal trifluoroacetato de N4-(benzoxazolin-2-on-5-il)-N2-(3-trifluorometoxifenil)-5-fluoropirimidin-2,4-diamina; I-108 sal trifluoroacetato de N4-(benzoxazolin-2-on-5-il)-N2-(4-trifluorometoxifenil)-5-metilpirimidin-2,4-diamina; I-109 sal trifluoroacetato de N4-(benzoxazolin-2-on-5-il)-N2-(4-trifluorometoxifenil)-5-fluoropirimidin-2,4-diamina; I-110 N4-(benzoxazolin-2-on-5-il)-N2-[3-trifluorometil-4-(4-etilpiperazin-1-il)fenil]-5-metilpirimidin-2,4-diamina; I-111 N4-(benzoxazolin-2-on-5-il)-N2-[3-metil-4-(4-metilpiperazin-1-il)fenil]-5-metilpirimidin-2,4-di-amina; I-115 N4-(benzoxazolin-2-on-5-il)-N2-(3,4,5-trimetoxifenil)-5-fluoropirimidin-2,4-diamina; I-116 N2-(3-(difluorometoxi)-4-metoxifenil)-N4-(benzo[d]oxazol-2(3H)-on-5-il)-5-metilpirimidin-2,4-diamina; I-117 N4-(benzo[d]oxazol-2(3H)-on-5-il)-N2-(4-trifluorometilsulfonil)fenil-5-metilpirimidin-2,4-diamina; I-118 N4-(benzo[d]oxazol-2(3H)-on-5-il)-N2-(3-trifluorometilsulfonil)fenil-5-metilpirimidin-2,4-diamina; I-119 N4-(benzo[d]oxazol-2(3H)-on-5-il)-N2-(3,4,5-trimetoxi)fenil-5-metilpirimidin-2,4-diamina; I-120 N4-(benzo[d]oxazol-2(3H)-on-5-il)-N2-((4-(1,4-diazabiciclo[3.2.2]nonan-4-il)-3-metil)fenil)-5-metilpirimidin-2,4diamina; I-121 N4-(benzo[d]oxazol-2(3H)-on-5-il)-N2-(4-(8-metil-8-azabiciclo[3.2.1]octan-3-ilamino)fenil)-5-metilpirimidin-2,4diamina; I-122 N4-(benzo[d]oxazol-2(3H)-on-5-il)-N2-((4-(dihidro-1H-pirido[1,2-a]pirazin-2(6H,7H,8H,9H,9aH)-il)-3-metil)fenil) 5-metilpirimidin-2,4-diamina; I-123 N4-(benzo[d]oxazol-2(3H)-on-5-il)-N2-(4-(8-metil-2,8-diazabiciclo[3.2.1]octan-2-il)fenil)-5-metil-pirimidin-2,4diamina; I-124 N4-(benzo[tf]oxazoNn-2(3H)-ona-5-il)-5-metil-N2-[3-(morfoNn-4-il)-4-trifluorometoxifenil]-2,4-pirimidindiamina; I-125 N4-(benzo[d]oxazolm-2(3H)-on-5-il)-N2-[3-trifluorometil-2-(4-metilpiperazm-1-il)piridin-5-il]-5-metilpirimidin-2,4 diamina; I-126 ácido 4-[5-Metil-4-(2-oxo-2,3-dihidro-benzooxazol-5-ilamino)-pirimidin-2-ilamino]-benzoico; I-127 N-(2-Dietilamino-etil)-4-[5-metil-4-(2-oxo-2,3-dihidro-benzooxazol-5-ilamino)-pirimidin-2-ilamino]-benzamida; I-128 5-{2-[4-(3-Dietilamino-pirrolidin-1-carbonil)-fenilamino]-5-metil-pirimidin-4-ilamino}-3H-benzooxazol-2-ona; I-129 5-[2-(4-Acetil-fenilamino)-5-metil-pirimidin-4-ilamino]-3H-benzooxazol-2-ona; I-130 5-[2-(3-Acetil-fenilamino)-5-metil-pirimidin-4-ilamino]-3H-benzooxazol-2-ona; I-131 2-Metil-5-[5-metil-4-(2-oxo-2,3-dihidro-benzooxazol-5-ilamino)-pirimidin-2-ilamino]-benzonitrilo; I-132 N,N-Dimetil-4-[5-metil-4-(2-oxo-2,3-dihidro-benzooxazol-5-ilamino)-pirimidin-2-ilamino]-benzamida; I-133 N-Metil-4-[5-metil-4-(2-oxo-2,3-dihidro-benzooxazol-5-ilamino)-pirimidin-2-ilamino]-benzamida; I-134 sal formiato de N-ciclopropil-4-[5-metil-4-(2-oxo-2,3-dihidro-benzooxazol-5-ilamino)-pirimidin-2-ilamino]-benzamida; I-135 4-[5-Metil-4-(2-oxo-2,3-dihidro-benzooxazol-5-ilamino)-pirimidin-2-ilamino]-N-fenil-benzamida; I-136 4-[5-Metil-4-(2-oxo-2,3-dihidro-benzooxazol-5-ilamino)-pirimidin-2-ilamino]-2-pirrolidin-1-il-benzamida; I-137 N-Etil-4-[5-metil-4-(2-oxo-2,3-dihidro-benzooxazol-5-ilamino)-pirimidin-2-ilamino]-benzamida; I-138 sal del ácido N-Ciclobutil-4-[5-metil-4-(2-oxo-2,3-dihidro-benzooxazol-5-ilamino)-pirimidin-2-ilamino]-benzamida formico; I-139 N-Isopropil-4-[5-metil-4-(2-oxo-2,3-dihidro-benzooxazol-5-ilamino)-pirimidin-2-ilamino]-benzamida; I-140 sal formiato de N-ciclopropil-4-[5-metil-4-(2-oxo-2,3-dihidro-benzooxazol-5-ilamino)-pirimidin-2-ilamino]-benzamida; I-141 2-Cloro-4-[5-metil-4-(2-oxo-2,3-dihidro-benzooxazol-5-ilamino)-pirimidin-2-ilamino]-benzamida; I-142 sal del ácido N-ciclopropil-4-[5-metil-4-(2-oxo-2,3-dihidro-benzooxazol-5-ilamino)-pirimidin-2-ilamino]benzamida trifluoroacético; I-143 N-Ciclopropil-4-[5-metil-4-(2-oxo-2,3-dihidro-benzooxazol-5-ilamino)-pirimidin-2-ilamino]-benzamida; I-144 N-Ciclobutil-4-[5-metil-4-(2-oxo-2,3-dihidro-benzooxazol-5-ilamino)-pirimidin-2-ilamino]-benzamida; I-145 4-[5-Metil-4-(2-oxo-3-propionil-2,3-dihidro-benzooxazol-5-ilamino)-pirimidin-2-ilamino]-benzamida; I-146 (5-(2-(4-carbamoilfenilamino)-5-metilpirimidin-4-ilamino)-2-oxobenzo[d]oxazol-3(2H)-il)metilfosfato de di-tercbutilo; I-147 dihidrogenofosfato de (5-(2-(4-carbamoilfenilamino)-5-metilpirimidin-4-ilamino)-2-oxobenzo [d]oxazol-3(2H)il)metilo; I-148 (5-(2-(4-carbamoilfenilamino)-5-metilpirimidin-4-ilamino)-2-oxobenzo[d]oxazol-3(2H)-il)metilfosfato sódico; I-150 dihidrogenofosfato de (5-(2-(4-(ciclobutilcarbamoil)fenilamino)-5-metilpirimidin-4-ilamino)-2-oxobenzo[d] oxazol3(2H)-il)metilo; I-151 (5-(2-(4-(ciclobutilcarbamoil)fenilamino)-5-metilpirimidin-4-ilamino)-2-oxobenzo[d]oxazol-3(2H)-il)metilfosfato de metilo; I-152 (5-(2-(4-(ciclobutilcarbamoil)fenilamino)-5-metilpirimidin-4-ilamino)-2-oxobenzo[d]oxazol-3(2H)-il)metilfosfato de di-terc-butilo; I-153 5-[2-(4-Cloro-3-trifluorometil-fenilamino)-5-metil-pirimidin-4-ilamino]-3H-benzooxazol-2-ona;
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