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 PDFInfo
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- 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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- ylamino
- methyl
- oxo
- methylpyrimidin
- pyrimidin
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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:
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.
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.
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).
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
46
- 11-87
- 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
47
- II-102
- 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
48
- II-117
- 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
49
- II-132
- 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
Claims (1)
-
imagen1 imagen2 imagen3 imagen4 imagen5 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;156imagen6 imagen7 imagen8 imagen9 imagen10 imagen11 imagen12 imagen13 imagen14 imagen15 imagen16 imagen17 imagen18
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US241630P | 2009-09-11 | ||
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