ES2552989T3 - Compuestos de quinazolina como inhibidores de la cinasa de serina / treonina - Google Patents

Compuestos de quinazolina como inhibidores de la cinasa de serina / treonina Download PDF

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ES2552989T3
ES2552989T3 ES12769775.3T ES12769775T ES2552989T3 ES 2552989 T3 ES2552989 T3 ES 2552989T3 ES 12769775 T ES12769775 T ES 12769775T ES 2552989 T3 ES2552989 T3 ES 2552989T3
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alkyl
group
heterocyclyl
halogen
dmso
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James F. Blake
Huifen Chen
Mark Joseph Chicarelli
Jason Demeese
Rustam Ferdinand GARREY
John Gaudino
Lewis Gazzard
Robert J. Kaus
Samuel Kintz
Peter J. Mohr
David A. Moreno
Jacob Schwarz
Christopher S. SIEDEM
Eli M. Wallace
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Genentech Inc
Array Biopharma Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
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Abstract

Un compuesto de acuerdo con la fórmula I**Fórmula** en la que: R1 es heterociclilo o heteroarilo seleccionado de entre el grupo que consiste en pirazolilo, triazolilo oxadiazolilo, oxazolilo, imidazolilo, isoxazolilo, pirrolidinilo, piperidinilo o morfolinilo opcionalmente sustituidos con entre uno y tres sustituyentes seleccionados independientemente de entre el grupo que consiste en alquilo C1-6, hidroxialquilo C1-6, halógeno, hidroxilo y oxo; Ar es fenilo o piridinilo opcionalmente sustituidos con entre 1 y 5 grupos seleccionados independientemente de entre el grupo que consiste en alquilo C1-6, haloalquilo C1-6, alcoxi C1-6, cicloalquilo C1-6, halógeno, haloalcoxi C1-6, alquiltio C1-6, acilamino C1-6, ciano y nitro; R2 se selecciona de entre el grupo que consiste en (a) alquilo C1-10, (b) haloalquilo C1-6, (c) heterociclilo o heterociclil-alquilo C1-6 en donde dichos heterociclo o heterociclil-alquilo C1-6 se seleccionan de entre el grupo que consiste en tetrahidropiranilo, tetrahidrofuranilo, 2-oxabiciclo[2.2.1]heptan-5-ilo, oxetanilo, piperidinilo, N-alquilo C1-6-piperidinilo, 1,1-dioxotietan-3-ilo, tietan-3-ilo y N-alquilo C1-6-2-oxo-pirrolidinilo, y en donde dichos heterociclilo o heterociclil-alquilo C1-6 están opcionalmente sustituido con entre 1 y 3 grupos seleccionados independientemente de entre el grupo que consiste en alquilo C1-6, haloalquilo C1-6, aciloxi C1-4-alquilo C1-2, halógeno, hidroxilo, fenilo, hidroxialquilo C1-3 y oxo, (d) cicloalquilo C3-7 o cicloalquilo C3-7-alquilo C1-6 en donde dichos cicloalquilo o cicloalquilo C3-7-alquilo C1-6 están opcionalmente sustituidos con entre uno y tres grupos hidroxilo, alcoxi C1-3 o halo, (e) heteroalquilo C1-6 en donde la fracción heteroalquilo incluye al menos hidroxialquilo C1-6 o alcoxi C1-3-alcoxi C1-6, (f) heteroarilo en donde dicho heteroarilo se selecciona de entre el grupo que consiste en pirazolilo y piridinilo en donde dicho heteroarilo está opcionalmente independientemente sustituido con entre uno y tres grupos seleccionados de entre el grupo que consiste en grupos alquilo C1-6, haloalquilo C1-6 y halógeno, y (g) cianoalquilo C1-3; R3 es hidrógeno o halógeno; o, un estereoisómero, un tautómero o una sal farmacéuticamente aceptables de los mismos.

Description

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nomenclatura convencional que incluye los prefijos normal (n-), iso (i-), secundario (sec-), terciario (terc-) y neo-tiene su significado habitual cuando se usa con una fracción alquilo (J. Rigaudy y D. P. Klesney, Nomenclature in Organic Chemistry, IUPAC 1979 Pergamon Press, Oxford.).
5 COMPUESTOS Y PREPARACIÓN
Algunos ejemplos de los compuestos representativos en el ámbito de la invención se proporcionan en la siguiente Tabla. Estos ejemplos y las preparaciones que siguen se proporcionan para permitir que los expertos en la materia comprendan con más claridad y lleven a la práctica la presente invención. No deberían ser considerados como
10 limitantes del ámbito de la invención, sino simplemente como ilustrativos y representativos de la misma.
Si hubiera una discrepancia entre una estructura representada y un nombre proporcionado a esa estructura, se acuerda que la estructura representada debe tener más peso. Además, si la estereoquímica de una estructura o de una porción de una estructura no está indicada, por ejemplo, con unas líneas en negrita o discontinuas, debe
15 interpretarse que la estructura o la porción de la estructura engloba todos los estereoisómeros de la misma. En el presente documento se usa el siguiente sistema de numeración.
imagen19
TABLA I
Comp. Nº
Estructura CI501 (µM) EM2 RMN-1H
I -1
0,0025 469,2 (CDCl3) δ 9,02 (s, 1H), 7,82 (s, 1H), 7,73 (m, 2H), 7,40 (m, 1H), 7,18 (m, 3H), 6,71 (m, 1H), 6,33 (d, 1H), 5,46 (m, 1H), 4,27 (m, 1H), 3,89 (s, 3H), 3,85 (m, 1H), 3,72 (m, 1H), 1,34 (d, 3H), 1,25 (m, 1H)
I -2
0,0008 495,0 (CDCl3) δ 9,02 (s, 1H), 7,85 (s, 1H), 7,75 (d, 1H), 7,67 (d, 1H), 7,40 (t, 2H), 7,20 (m, 2H), 7,15 (d, 1H), 6,70 (d, 1H), 6,33 (d, 1H), 5,30 (m, 1H), 4,20 (m, 1H), 4,03 (m, 2H), 3,89 (s, 3H), 3,60 (t, 2H), 2,12 (d, 2H), 1,62 (m, 2H)
I -3
imagen20 0,0021 518,2 (CDCl3) δ 9,02 (s, 1H), 7,97 (s, 1H), 7,72 (m, 2H), 7,58 (m, 1H), 7,23 (m, 2H), 5,35 (d, 1H), 5,15 (dd, 1H), 4,26 (m, 1H), 4,04 (m, 2H), 3,62 (m, 2H), 3,55 (m a,, 1H), 3,05 (m, 1H), 2,94 (m, 1H), 2,14 (m, 2H), 2,02 (m, 1H), 1,74 (m, 6H)
I -4
0,0050 495,0 (CDCl3) δ 9,01 (s, 1H), 7,96 (s, 1H), 7,72 (dd, 2H), 7,65 (d, 1H), 7,34 (m, 2H), 7,22 (m, 2H), 6,28 (d, 1H), 6,07 (d, 1H), 5,26 (d, 1H), 4,24 (m, 1H), 4,03 (m, 2H), 3,92 (s, 3H), 3,61 (m, 2H), 2,12 (d, 2H), 1,62 (m, 2H)
I -5
0,0023 476,0
I -6
imagen21 0,0050 469,0
I -7
0,0018 518,1 (CDCl3) δ 9,01 (s, 1H), 7,89 (s, 1H), 7,73 (d, 1H), 7,66 (dd, 1H), 7,57 (m, 1H), 7,32 (s a, 1H), 7,29 (d, 1H), 7,18 (d, 1H), 5,30 (d, 1H), 5,05 (m, 1H), 4,24 (m, 1H), 4,04 (m, 2H), 3,62 (m, 3H), 2,90 (m, 2H), 2,14 (d, 2H), 1,86 (m, 1H), 1,62 (m, 6H)
I -8
0,0067 485,2
I -9
0,0067 485,2
I -10
0,0054 485,1
I -11
0,0064 485,1 (CDCl3) δ 8,94 (s, 1H), 7,87 (s, 1H), 7,60 (m, 2H), 7,53 (d, 1H), 7,32 (m, 1H), 7,07 (m, 1H), 5,41 (s a, 1H), 5,19 (m, 1H), 4,17 (s a, 1H), 4,00 (d, 2H), 3,56 (m, 2H), 3,44 (s a, 1H), 3,32 (m, 1H), 3,17 (m, 1H), 3,05 (m, 1H), 2,95 (m, 1H), 2,27 (m, 1H), 2,06 (m, 3H), 1,60 (m, 3H)
I -12
imagen22 0,0014 495,1 (CDCl3) δ 9,01 (s, 1H), 7,85 (s, 1H), 7,71 (dd, 2H), 7,40 (m, 2H), 7,19 (m, 2H), 7,15 (d, 1H), 6,72 (d, 1H), 6,33 (d, 1H), 5,30 (d, 1H), 4,20 (m, 1H), 4,02 (m, 2H), 3,89 (s, 3H), 3,59 (m, 2H), 2,12 (d, 2H), 1,61 (m, 2H)
I -13
0,0388 495,1 (CDCl3) δ 9,01 (s, 1H), 7,85 (s, 1H), 7,71 (dd, 2H), 7,40 (m, 2H), 7,19 (m, 2H), 7,15 (d, 1H), 6,72 (d, 1H), 6,33 (d, 1H), 5,30 (d, 1H), 4,20 (m, 1H), 4,02 (m, 2H), 3,89 (s, 3H), 3,59 (m, 2H), 2,12 (d, 2H), 1,61 (m, 2H)
I -14
0,0568 469,2
I -15
0,0012 469,2
I -16
503,1
I -17
0,0028 532,1 (CDCl3) δ 9,04 (s, 1H), 7,96 (s, 1H), 7,73 (dd, 2H), 7,56 (m, 1H), 7,20 (d, 1H),7,15 (d, 1H), 5,30 (d, 1H), 5,07 (m, 1H), 4,26 (m, 1H), 4,04 (m, 2H), 3,62 (m, 2H), 3,19 (m, 1H), 2,59 (m, 1H), 2,36 (s, 3H), 2,34 (m, 1H), 2,14 (d, 2H), 1,78 (m, 1H), 1,65 (m, 2H), 1,40 (m, 1H)
I -18
0,0128 509,0 (CDCl3) δ 9,02 (s, 1H), 7,86 (s, 1H), 7,72 (dd, 2H), 7,41 (m, 2H), 7,21 (s, 1H), 7,18 (m, 2H), 6,72 (d, 1H), 6,33 (d, 1H), 5,30 (d, 1H), 4,20 (m, 1H), 4,15 (c, 2H), 4,02 (m, 2H), 3,60 (m, 2H), 2,12 (d, 2H), 1,62 (m, 2H), 1,49 (t, 3H)
I -19
0,0024 509,1 (CDCl3) δ 9,02 (s, 1H), 7,86 (s, 1H), 7,72 (dd, 2H), 7,41 (m, 2H), 7,21 (s, 1H), 7,18 (m, 2H), 6,72 (d, 1H), 6,33 (d, 1H), 5,30 (d, 1H), 4,20 (m, 1H), 4,15 (c, 2H), 4,02 (m, 2H), 3,60 (m, 2H), 2,12 (d, 2H), 1,62 (m, 2H), 1,49 (t, 3H)
I -20
0,0020 495,0
I -21
0,069 495,0
I -22
0,0014 513,0 (CDCl3) δ 9,26 (s, 1H), 7,62 (s, 1H), 7,38 -7,43 (m, 2H), 7,29 7,34 (m, 1H), 7,19 (m, 1H), 7,15 (m, 1H), 6,67 (m, 1H), 6,31 (m, 1H), 5,40 (m, 1H), 4,20 (s, 1H), 4,00 -4,06 (m, 2H), 3,89 (s, 3H), 3,59 (m, 2H), 2,11 (m, 2H), 1,59 -1,68 (m, 2H)
I -23
imagen23 0,0023 484,0 (CDCl3) δ 9,01 (s, 1H), 7,88 (s, 1H), 7,70 (dd, 2H), 7,36 (m, 1H), 7,21 (dd, 2H), 7,12 (d, 1H), 5,29 (d, 1H), 5,01 (m, 1H), 4,24 (m, 1H), 4,04 (m, 2H), 3,60 (m, 2H), 3,56 (m, 1H), 2,87 (m, 2H), 2,13 (d, 2H), 1,87 (m, 1H), 1,60 (m, 4H)
I -24
0,0082 480
I -25
imagen24 0,0090 498,0 (d6-DMSO) δ 9,29 (s, 1H), 9,03 (m, 1H), 7,87 (m, 1H), 7,30 (m, 2H), 7,18 (m, 1H), 7,09 (m, 1H), 4,75 (m, 1H), 4,10 (m, 1H), 3,91 (m, 2H), 3,81 (s, 3H), 3,74 (s, 1H), 3,39 -3,49 (m, 4H), 2,71 -2,83 (m, 2H), 1,89 (m, 4H), 1,52 -1,71 (m, 4H)
I -26
0,002 464 (d6-DMSO) δ 9,13 (s, 1H), 8,97 (d, 1H), 7,90 (s, 1H), 7,82 (d, 1H), 7,54 (m, 1H), 7,48 (s a, 1H), 7,32 (m, 1H), 7,20 (m, 1H), 7,10 (m, 1H), 5,76 (m, 1H), 4,82 (m, 1H), 3,80 (s, 3H), 3,67 (m, 1H), 3,50 (m, 1H), 2,81 (m, 2H), 1,92 (m, 1H), 1,67 (m, 2H), 1,51 (m, 1H), 1,25 (d, 3H), 1,02 (m, 1H), 0,45 (m, 1H), 0,36 (m, 2H), 0,20 (m, 1H)
I -27
0,0158 513
I -28
0,0025 513 (d6-DMSO) δ 9,44 (d, 1H), 9,22 (s, 1H), 8,04 (s a, 1H), 7,90 (d, 1H), 7,67 (d, 1H), 7,58 (m, 2H), 7,49 (d, 1H), 7,38 (s, 1H), 7,32 (d, 1H), 6,32 (d, 1H), 4,88 (d a, 1H), 4,26 (d a, 1H), 4,03 (m, 1H), 3,93 (d, 1H), 3,79 (s, 3H), 3,56 (m, 2H), 2,00 (m, 1H), 1,70 (d, 1H)
I -29
imagen25 0,0038 513 (d6-DMSO) δ 9,46 (d, 1H), 9,22 (s, 1H), 8,06 (s a, 1H), 7,88 (d, 1H), 7,82 (s a, 1H), 7,66 (d, 1H), 7,58 (m, 1H), 7,58 (s, 1H), 7,49 (d, 1H), 7,38 (s, 1H), 7,32 (d, 1H), 6,33 (d, 1H), 4,61 (d a, 1H), 4,38 (s a, 1H), 4,04 (m, 1H), 3,86 (d, 1H), 3,80 (s, 3H), 3,50 (m, 2H), 2,06 (m, 1H), 1,65 (d, 1H)
I -30
0,0021 513 (d6-DMSO) δ 9,46 (d, 1H), 9,22 (s, 1H), 8,07 (s a, 1H), 7,88 (d, 1H), 7,66 (m, 1H), 7,58 (m, 2H), 7,49 (m, 1H), 7,38 (s, 1H), 7,32 (d, 1H), 6,32 (d, 1H), 4,61 (d a, 1H), 4,38 (s a, 1H), 4,04 (m, 1H), 3,86 (m, 1H), 3,80 (s, 3H), 3,45 (m, 2H), 2,06 (d a, 1H), 1,65 (m, 1 H)
I -31
0,0017 498,5 (CDCl3) δ 9,01 (s, 1H), 7,94 (s, 1H), 7,70 (m, 2H), 7,11 (m, 1H), 7,09 (m, 2H), 6,95 (m, 1H), 5,25 (m, 2H), 5,22 (m, 1H), 4,23 (m, 1H), 4,03 (m, 2H), 3,88 (s, 3H), 3,68 (m,, 1H), 3,61 (m, 2H), 3,39 (m, 1H), 2,93 (m, 1H), 2,13 (d, 2H), 2,00 (m, 1H), 1,62 (m, 2H)
I -32
0,0011 491 (d6-DMSO) δ 9,37 (d, 1H), 9,17 (s, 1H), 8,02 (s, 1H), 7,84 (m, 1H), 7,62 (m, 1H), 7,54 (m, 2H), 7,30 (m, 2H), 7,16 (m, 2H), 6,26 (m, 1H), 5,75 (m, 1H), 4,08 (s a, 1H), 3,90, (m, 2H), 3,82 (s, 3H), 3,79 (s, 3H), 3,42 (m, 2H), 1,90 (m, 2H), 1,58 (m, 2H),
I -33
imagen26 0,0015 509 (d6-DMSO) δ 9,41 (d, 1H), 9,30 (s, 1H), 7,93 -7,85 (m, 2H), 7,54 (s, 1H), 7,38 -7,25 (m, 3H), 7,22 -7,11 (m, 2H), 6,25 (d, 1H), 4,15 -4,05 (m, 1H), 3,93 -3,85 (m, 2H), 3,72 (s, 3H), 3,69 (s, 3H), 3,47 -3,38 (m, 2H), 1,93 -1,85 (m, 2H), 1,64 -1,53 (m, 2H)
I -34
0,0036 482,7 (d6-DMSO) δ 9,99 (d, 1H), 9,20 (s, 1H), 9,04 (s, 1H), 8,06 (s, 1H), 7,89 (d, 1H), 7,67 (m, 4H), 7,45 (d, 1H), 6,79 (d, 1H), 4,07 (s a, 1H), 3,90 (d, 2H), 3,42 (m, 2H), 1,89 (d, 2H), 1,57 (m, 2H)
I -35
imagen27 0,0020 498,0 (CDCl3) δ 9,01 (s, 1H), 7,88 (s, 1H), 7,69 (m, 2H), 7,37 (m, 1H), 7,16 (d, 1H), 7,01 (d, 1H), 5,28 (d, 1H), 5,01 (m, 1H), 4,24 (m, 1H), 4,04 (m, 2H), 3,61 (m, 2H), 3,58 (m, 1H), 3,22 (m, 1H), 2,13 (d, 2H), 1,80 (m, 2H), 1,62 (m, 2H), 1,57 (m, 4H), 1,11 (d, 3H)
I -36
0,0016 502,2
I -37
0,0736 502,1, 504,13
I -38
0,0654 502,2
I -39
0,0012 502,2
I -40
0,0073 497,0
I -41
0,00055 509,0 (CDCl3) δ 9,01 (s, 1H), 7,85 (s, 1H), 7,71 (m, 2H), 7,41 (m, 3H), 7,19 (s, 1H), 7,14 (m, 2H), 6,73 (d, 1H), 6,37 (d, 1H), 5,29 (d, 1H), 4,20 (m, 1H), 4,02 (m, 2H), 3,88 (s, 3H), 3,60 (m, 2H), 2,12 (d, 2H), 1,62 (m, 2H)
I -42
0,0072 525,2 (CDCl3) δ 9,03 (s, 1H), 7,86 (s, 1H), 7,72 (dd, 2H), 7,40 (m, 1H), 7,39 (s, 1H), 7,20 (s, 1H), 7,17 (m, 2H), 6,72 (d, 1H), 6,33 (d, 1H), 5,63 (d, 1H), 4,48 (m, 1H), 3,97 (m, 1H), 3,89 (s, 3H), 3,79 (m, 2H), 3,59 (m, 2H), 2,02 (m, 2H), 1,88 (m, 2H), 1,78 (m, 1H)
I -43
521,2 (DMSO) 9,33 (t, J = 10,4 Hz, 1H), 9,14 (d, J = 15,8 Hz, 1H), 8,01 (s, 1H), 7,89 -7,79 (m, 1H), 7,61 (t, J = 9,2 Hz, 1H), 7,56 -7,40 (m, 2H), 7,32 (d, J = 9,4 Hz, 1H), 7,26 (t, J = 11,7 Hz, 1H), 7,20 (d, J = 8,8 Hz, 1H), 7,12 (dd, J = 16,9, 8,4 Hz, 1H), 6,25 (t, J = 12,6 Hz, 1H), 4,60 (d, J = 19,4 Hz, 1H), 4,12 (d, J = 7,7 Hz, 1H), 3,95 (dd, J = 11,5, 3,8 Hz, 1H), 3,82 (s, 4H), 3,79 (s, 4H), 3,44 (dd, J =18,5, 7,7 Hz, 2H), 1,92 (dd, J = 29,5, 12,4 Hz, 2H), 1,51 (cd, J = 12,3, 4,5 Hz, 1H), 1,24 (c, J = 11,6 Hz, 1H)
I -44
0,001 507,2 (DMSO-d6) δ 9,40 (d, J = 8,5 Hz, 1H), 9,17 (s, 1H), 8,03 (s, 1H), 7,85 (d, J = 8,0 Hz, 1H), 7,63 (m, 1H), 7,58 -7,55 (m, 2H), 7,48 (d, J = 2,0 Hz, 1H), 7,38 -7,35 (m, 2H), 7,13 (d, J = 8,5 Hz, 1H), 6,27 (d, J = 8,5 Hz, 1H), 4,09 (m, 1H), 3,91 -3,89 (m, 2H), 3,84 (s, 3H), 3,80 (s, 3H), 3,44 -3,40 (m, 2H), 1,90 -1,88 (m, 2H), 1,61 1,54 (m, 2H)
I -45
0,022 502,1 (MeOH -d4) δ 9,11 (s, 1H), 8,00 (s, 1H), 7,87 -7,84 (m, 2H), 7,71 (s, 1H), 7,64 (m, 1H), 7,59 -7,56 (m, 2H), 7,45 (s, 1H), 6,44 (s, 1H), 4,19 (m, 1H), 4,03 -4,01 (m, 2H), 3,89 (s, 3H), 3,62 -3,57 (m, 2H), 2,07 2,05 (m, 2H), 1,69 -1,65 (m, 2H)
I -46
0,0042 521,2 (DMSO) 9,34 (d, J = 8,6 Hz, 1H), 9,19 (s, 1H), 8,01 (s, 1H), 7,86 (d, J = 8,3 Hz, 1H), 7,72 (d, J = 6,4 Hz, 1H), 7,64 (d, J = 8,3 Hz, 1H), 7,55 (d, J = 8,5 Hz, 1H), 7,35 -7,25 (m, 2H), 7,16 (dt, J = 17,2, 8,6 Hz, 2H), 6,27 (d, J = 8,5 Hz, 1H), 4,51 (s, 1H), 4,33 (s, 1H), 4,17 -3,94 (m, 2H), 3,82 (t, J = 11,8 Hz, 8H), 3,70 (dd, J = 16,9, 10,0 Hz, 2H), 1,83 (t, J = 14,8 Hz, 2H), 1,72 (d, J = 14,2 Hz, 1H), 1,59 -1,49 (m, 1H)
I -47
0,0014 525,5
I -48
0,0011 502,2
I -49
0,141 498,2
I -50
0,025 502,2
I -51
0,0028 510,2
I -52
imagen28 0,0026 527,2 RMN-1H (400 MHz, DMSO) δ 9,60 (d, J = 8,2 Hz, 1H), 9,30 (s, 1H), 7,89 (m, 2H), 7,63 (s, 1H), 7,33 (dd, J = 22,1, 10,8 Hz, 2H), 7,18 (dt, J = 17,2, 8,6 Hz, 2H), 6,44 (d, J = 8,4 Hz, 1H), 4,10 (m, 4H), 3,90 (d, J = 11,4 Hz, 2H), 3,82 (s, 3H), 3,42 (t, J = 11,3 Hz, 2H), 1,89 (m, 2H), 1,59 (cd, J = 12,0, 4,2 Hz, 2H)
I -53
0,0068 510,2
I -54
0,031 510,2
I -55
0,0027 495,2
I -56
0,0035 498,2
I -57
0,024 563,2 (DMSO) 9,34 (d, J = 8,6 Hz, 1H), 9,20 (s, 1H), 8,02 (s, 1H), 7,87 (d, J = 8,3 Hz, 1H), 7,78 (d, J = 6,5 Hz, 1H), 7,65 (d, J = 8,3 Hz, 1H), 7,54 (s, 1H), 7,36 -7,24 (m, 2H), 7,16 (dt, J = 17,2, 8,6 Hz, 2H), 6,26 (d, J = 8,5 Hz, 1H), 4,34 (s, 1H), 4,01 (ddd, J = 31,9, 17,1,7,3 Hz, 4H), 3,80 (d, J = 12,8 Hz, 7H), 3,73 (d, J = 11,2 Hz, 1H), 2,02 (s, 3H), 1,82 (d, J = 12,0 Hz, 2H), 1,75 (d, J = 13,5 Hz, 1H), 1,63 (dd, J = 17,0, 7,0 Hz, 1H)
I -58
0,020 483,2 (DMSO) 9,40 (d, J = 8,3 Hz, 1H), 9,29 (s, 1H), 7,91 (s, 1H), 7,82 (s, 1H), 7,54 (s, 1H), 7,36 (d, J = 10,3 Hz, 1H), 7,32 (s, 1H), 7,27 (dd, J = 12,6, 1,9 Hz, 1H), 7,21 -7,17 (m, 1H), 7,14 (t, J = 8,6 Hz, 1H), 6,25 (d, J = 8,4 Hz, 1H), 3,82 (s, 3H), 3,79 (s, 3H), 3,57 (m, 4H), 3,28 (s, 3H)
I -59
0,015 485,2 (DMSO) 9,40 (d, J = 8,4 Hz, 1H), 9,29 (s, 1H), 7,91 (s a, 2H), 7,54 (s, 1H), 7,36 (d, J = 10,6 Hz, 1H), 7,32 (s, 1H), 7,27 (dd, J = 12,6, 1,9 Hz, 1H), 7,20 (dd, J = 8,6, 1,8 Hz, 1H), 7,14 (t, J = 8,6 Hz, 1H), 6,25 (d, J = 8,4 Hz, 1H), 4,56 (dt, J = 47,4, 5,8 Hz, 2H), 3,82 (s, 3H), 3,79 (s, 3H), 3,49 (m, 2H), 2,10 1,87 (m, 2H)
I -60
0,006 479,2 (DMSO) 9,39 (d, J = 8,5 Hz, 1H), 9,28 (s, 1H), 7,92 (m, 2H), 7,54 (s, 1H), 7,34 (m, 2H), 7,27 (dd, J = 12,6, 1,9 Hz, 1H), 7,22 -7,17 (m, 1H), 7,14 (t, J = 8,6 Hz, 1H), 6,24 (d, J = 8,4 Hz, 1H), 3,82 (s, 3H), 3,79 (s, 3H), 3,25 (m, 2H), 1,15 (m, 1H), 0,49 -0,40 (m, 2H), 0,26 (m, 2H)
I -61
0,002 495,2 (DMSO) 9,41 (d, J = 8,5 Hz, 1H), 9,31 (s, 1H), 8,09 (s, 1H), 7,91 (s, 1H), 7,54 (s, 1H), 7,38 (d, J = 10,5 Hz, 1H), 7,33 (s, 1H), 7,27 (dd, J = 12,6, 1,8 Hz, 1H), 7,22 -7,17 (m, 1H), 7,14 (t, J = 8,6 Hz, 1H), 6,25 (d, J = 8,4 Hz, 1H), 4,51 (s, 1H), 3,94 (dd, J = 8,8, 6,1 Hz, 1H), 3,87 (dd, J = 15,2, 7,4 Hz, 1H), 3,82 (s, 3H), 3,79 (s, 3H), 3,75 (m, 1H), 3,64 (m, 1H), 2,20 (m, 7,6 Hz, 1H), 1,96 (m, 1H)
I -62
0,004 495,2 (DMSO) 9,41 (d, J = 8,5 Hz, 1H), 9,31 (s, 1H), 8,09 (s, 1H), 7,91 (s, 1H), 7,54 (s, 1H), 7,38 (d, J = 10,4 Hz, 1H), 7,32 (s, 1H), 7,27 (d, J = 12,7 Hz, 1H), 7,20 (d, J = 10,0 Hz, 1H), 7,14 (t, J = 8,5 Hz, 1H), 6,25 (d, J = 8,4 Hz, 1H), 4,50 (s, 1H), 3,96 -3,90 (m, 1H), 3,86 (t, J = 7,5 Hz, 1H), 3,82 (s, 3H), 3,79 (s, 3 H), 3,75 (m, 1H), 3,67 -3,59 (m, 1H), 2,20 (m, 1H), 1,97 (m, 1H)
I -63
0,004 495,2 (DMSO) 9,40 (d, J = 8,5 Hz, 1H), 9,29 (s, 1H), 8,02 (s, 1H), 7,92 (s, 1H), 7,54 (s, 1H), 7,37 (d, J = 10,4 Hz, 1H), 7,32 (s, 1H), 7,27 (dd, J = 12,6, 1,7 Hz, 1H), 7,20 (d, J = 8,6 Hz, 1H), 7,14 (t, J = 8,6 Hz, 1H), 6,25 (d, J = 8,4 Hz, 1H), 4,70 -4,62 (m, 2H), 4,37 (t, J = 5,9 Hz, 2H), 3,82 (s, 3H), 3,79 (s, 3H), 3,68 (t, J = 6,2 Hz, 2H), 3,26 (m, 1H)
I -64
0,006 495,2 (DMSO) 9,41 (d, J = 8,4 Hz, 1H), 9,33 (s, 1H), 8,30 (s, 1H), 7,81 (s, 1H), 7,53 (s, 1H), 7,41 (d, J = 10,4 Hz, 1H), 7,32 (s, 1H), 7,27 (dd, J = 12,6, 1,8 Hz, 1H), 7,21 -7,17 (m, 1H), 7,14 (t, J = 8,5 Hz, 1H), 6,24 (d, J = 8,4 Hz, 1H), 4,74 (d, J = 6,2 Hz, 2H), 4,46 (d, J = 6,2 Hz, 2H), 3,82 (s, 3H), 3,79 (s, 3H), 1,69 (s, 3H)
I -65
imagen29 0,0006 520,2
I -66
0,0006 525,2
I -67
0,005 521,2 (DMSO-d6) δ 9,10 (s, 1H), 7,97 (s, 1H), 7,86 (d, J = 9,0 Hz, 1H), 7,64 (d, J = 8,5 Hz, 1H), 7,56 (s, 1H), 7,44 (s, 1H), 7,22 (m, 2H), 7,13 (m, 1H), 6,36 (s, 1H), 4,22 (m, 3H), 4,03 (m, 2H), 3,89 (m, 5H), 3,61 (m, 2H), 2,07 (m, 2H), 1,68 (m, 2H)
I -68
0,0013 479,2 RMN-1H (400 MHz, DMSO) δ 9,46 (d, J = 8,4 Hz, 1H), 9,30 (s, 1H), 7,92 (s, 1H), 7,84 (s, 1H), 7,56 (s, 1H), 7,44 -7,33 (m, 3H), 7,30 -7,23 (m, 2H), 7,10 (td, J = 8,8, 2,4 Hz, 1H), 6,32 (d, J = 8,3 Hz, 1H), 4,10 (s a, 1 H), 3,90 (d, J = 11,1 Hz, 2H), 3,79 (s, 3 H), 3,42 (t, J = 11,1 Hz, 2H), 1,89 (d, J = 11,5 Hz, 2H), 1,59 (cd, J = 11,4, 4 Hz, 2H)
I -69
0,0012 523,2 RMN-1H (400 MHz, DMSO) δ 9,40 (d, J = 8,0 Hz, 1H), 9,25 (s, 1H), 7,91 (s, 1H), 7,68 (d a, J = 6,8 Hz, 1H), 7,54 (s, 1H), 7,33 (d, J = 9,6 Hz, 1H), 7,32 (s, 1H), 7,27 (dd, J = 12,6, 1,9 Hz, 1H), 7,20 (dd, J = 8,8, 1,6 Hz, 1H), 7,14 (t, J = 8,6 Hz, 1H), 6,25 (d, J = 8,4 Hz, 1H), 4,54 (d, J = 4,3 Hz, 1H), 3,88 -3,76 (m, 1H), 3,82 (s, 3H), 3,79 (s, 3H), 3,48 -3,37 (m, 1H), 1,98 -1,82 (m, 4H), 1,43 -1,20 (m, 4H)
I -70
0,004 527,2 RMN-1H (400 MHz, DMSO) δ 9,41 (d, J = 8,5 Hz, 1H), 9,35 (s, 1H), 7,93 (d, J = 8,5 Hz, 1H), 7,91 (s, 1H), 7,53 (s, 1H), 7,40 (d, J = 10,4 Hz, 1H), 7,33 (s, 1H), 7,28 (dd, J = 12,6, 1,8 Hz, 1H), 7,19 (d, J = 8,6 Hz, 1H), 7,14 (t, J = 8,5 Hz, 1H), 6,25 (d, J = 8,4 Hz, 1H), 4,88 (d, J = 48,8 Hz, 1H), 4,26 (m, 1H), 4,03 (t, J = 12,4 Hz, 1H), 3,93 (m, 1H), 3,82 (s, 3H), 3,79 (s, 3H), 3,69 -3,47 (m, 2H), 2,01 (m, 1H), 1,70 (d, J = 9,4 Hz, 1H)
1. Ensayo enzimático de la ERK-2 (Ejemplo 9) 2. APCI-pos m/z (M + 1) 3. m/z (M + 1), (M + 3)
Otros compuestos representativos en el ámbito de la presente invención están recogidos en la TABLA II. Estos ejemplos son ilustrativos y no deben ser interpretados como limitantes del ámbito de la invención, sino simplemente como representativos de la misma. Los compuestos de la TABLA II se preparan mediante el uso de una metodología descrita ampliamente en los Ejemplos que siguen y están completamente posibilitados.
TABLA II
Comp. Nº
Estructura EM CI501 (µM) RMN-1H (400 MHz, DMSO-d6)
II -1
521,1 0,0062 δ 9,44 (d, J = 8,4 Hz, 1H), 9,41 (s, 1H), 8,39 (s, 1H), 7,98 (s, 1H), 7,54 (s, 1H), 7,45 (d, J = 10,3 Hz, 1H), 7,32 (s, 1H), 7,28 (dd, J = 12,6, 1,8 Hz, 1H), 7,22 -7,17 (m, 1H), 7,14 (t, J = 8,6 Hz, 1H), 6,25 (d, J = 8,4 Hz, 1H), 5,07 (m, 1H), 3,82 (s, 3H), 3,79 (s, 3H), 1,40 (d, J = 7,0 Hz, 3H)
II -2
521,1 0,0136 δ 9,44 (d, J = 8,5 Hz, 1H), 9,41 (s, 1H), 8,40 (s, 1H), 7,96 (s, 1H), 7,54 (s, 1H), 7,45 (d, J = 10,4 Hz, 1H), 7,33 (s, 1H), 7,27 (dd, J = 12,6, 1,8 Hz, 1H), 7,20 (d, J = 8,6 Hz, 1H), 7,14 (t, J = 8,6 Hz, 1H), 6,24 (d, J = 8,4 Hz, 1H), 5,07 (m, 1H), 3,82 (s, 3H), 3,79 (s, 3H), 1,40 (d, J = 7,0 Hz, 3H)
II -3
511,1 0,0528 δ 9,40 (d, J = 8,5 Hz, 1H), 9,28 (s, 1H), 8,30 (s, 1H), 8,07 (s, 1H), 7,94 (d, J = 8,3 Hz, 1H), 7,72 (dd, J = 8,3, 1,3 Hz, 1H), 7,54 (s, 1H), 7,37 -7,24 (m, 2H), 7,17 (dt, J = 17,2, 8,6 Hz, 2H), 6,27 (d, J = 8,5 Hz, 1H), 4,61 (d, J = 9,3 Hz, 3H), 4,27 (dd, J = 9,7, 6,8 Hz, 2H), 3,82 (s, 3H), 3,79 (s, 3H)
II -4
509,2 0,0157
II -5
479,1 0,013 δ 9,37 (d, J = 8,6 Hz, 1H), 9,22 (s, 1H), 8,23 (d, J = 7,3 Hz, 1H), 8,05 (s, 1H), 7,88 (d, J = 8,3 Hz, 1H), 7,67 (dd, J = 8,3, 1,4 Hz, 1H), 7,55 (s, 1H), 7,35 -7,25 (m, 2H), 7,23 -7,18 (m, 1H), 7,14 (t, J = 8,6 Hz, 1H), 6,26 (d, J = 8,5 Hz, 1H), 5,34 (dd, J = 16,8, 8,4 Hz, 1H), 3,81 (d, J = 11,9 Hz, 6H), 3,51 (t, J = 9,1 Hz, 2H), 3,35 -3,32 (m, 2H)
II -6
509,2 0,157
II -7
479,1 0,0056 δ 9,41 (d, J = 8,5 Hz, 1H), 9,35 (s, 1H), 8,34 (s, 1H), 7,94 (s, 1H), 7,54 (s, 1H), 7,41 (d, J = 10,5 Hz, 1H), 7,33 (s, 1H), 7,27 (dd, J = 12,6, 1,9 Hz, 1H), 7,22 -7,18 (m, 1H), 7,14 (t, J = 8,6 Hz, 1H), 6,25 (d, J = 8,4 Hz, 1H), 4,32 (s, 1H), 3,82 (s, 3H), 3,79 (s, 3H), 3,08 -2,95 (m, 2H), 2,81 -2,63 (m, 3H)
II -8
477,1 0,0042 δ 9,34 (d, J = 8,6 Hz, 1H), 9,14 (s, 1H), 7,99 (s, 1H), 7,81 (t, J = 14,2 Hz, 2H), 7,61 (dd, J = 8,3, 1,3 Hz, 1H), 7,54 (s, 1H), 7,38 7,24 (m, 2H), 7,17 (dt, J = 29,9, 8,6 Hz, 2H), 6,26 (d, J = 8,5 Hz, 1H), 5,06 (d, J = 5,7 Hz, 1H), 3,90 (ddd, J = 22,1, 16,0, 7,9 Hz, 2H), 3,81 (d, J = 12,5 Hz, 6H), 2,71 -2,56 (m, 2H), 1,87 (ddd, J = 17,2, 8,6, 2,7 Hz, 2H)
II -9
477,2 0,0038 δ 9,35 (d, J = 8,6 Hz, 1H), 9,15 (s, 1H), 8,01 (s, 1H), 7,84 (d, J = 8,3 Hz, 2H), 7,62 (dd, J = 8,3, 1,3 Hz, 1H), 7,55 (s, 1H), 7,36 7,24 (m, 2H), 7,23 -7,11 (m, 2H), 6:26 (d, J = 8,6 Hz, 1H), 5,00 (d, J = 5,2 Hz, 1H), 4,47 (s, 1H), 4,34 (dd, J = 11,3, 6,0 Hz, 1H), 3,81 (d, J = 12,0 Hz, 6H), 2,32 -2,12 (m, 4H)
II -10
491,2 0,0138 δ 9,35 (d, J = 8,6 Hz, 1H), 9,15 (s, 1H), 7,99 (s, 1H), 7,84 (d, J = 8,3 Hz, 2H), 7,62 (dd, J = 8,3, 1,3 Hz, 1H), 7,54 (s, 1H), 7,37 7,24 (m, 2H), 7,17 (dt, J = 30,0, 8,6 Hz, 2H), 6,26 (d, J = 8,6 Hz, 1H), 4,09 (d, J = 8,0 Hz, 1H), 3,81 (d, J = 12,6 Hz, 6H), 3,64 (p, J = 7,2 Hz, 1H), 3,15 (s, 3H), 2,67 (t, J = 7,9 Hz, 2H), 1,89 (ddd, J = 16,9, 8,8, 2,7 Hz, 2H)
II -11
478,2 0,0139 δ 9,42 (d, J = 8,5 Hz, 1H), 9,35 (s, 1H), 8,15 (s, 1H), 7,95 (s, 1H), 7,54 (s, 1H), 7,42 (d, J = 10,4 Hz, 1H), 7,33 (s, 1H), 7,28 (dd, J = 12,6, 1,9 Hz, 1H), 7,20 (d, J = 8,6 Hz, 1H), 7,14 (t, J = 8,6 Hz, 1H), 6,25 (d, J = 8,2 Hz, 1H), 3,82 (s, 3H), 3,79 (s, 3H), 3,64 (s a, 2H), 2,88 (m, 2H)
II -12
479,2 0,0012 δ 9,46 (d, J = 8,4 Hz, 1H), 9,30 (s, 1H), 7,92 (s, 1H), 7,84 (s, 1H), 7,56 (s, 1H), 7,44 -7,33 (m, 3H), 7,30 -7,23 (m, 2H), 7,10 (td, J = 8,8, 2,4 Hz, 1H), 6,32 (d, J = 8,3 Hz, 1H), 4,10 (s a, 1H), 3,90 (d, J = 11,1 Hz, 2H), 3,79 (s, 3H), 3,42 (t, J = 11,1 Hz, 2H), 1,89 (d, J = 11,5 Hz, 2H), 1,59 (cd, J = 11,4, 4 Hz, 2H)
II -13
imagen30 523,2 0,0012 δ 9,40 (d, J = 8,0 Hz, 1H), 9,25 (s, 1H), 7,91 (s, 1H), 7,68 (d a, J = 6,8 Hz, 1H), 7,54 (s, 1H), 7,33 (d, J = 9,6 Hz, 1H), 7,32 (s, 1H), 7,27 (dd, J = 12,6, 1,9 Hz, 1H), 7,20 (dd, J = 8,8, 1,6 Hz, 1H), 7,14 (t, J = 8,6 Hz, 1H), 6,25 (d, J = 8,4 Hz, 1H), 4,54 (d, J = 4,3 Hz, 1H), 3,88 -3,76 (m, 1H), 3,82 (s, 3H), 3,79 (s, 3H), 3,48 -3,37 (m, 1H), 1,98 -1,82 (m, 4H), 1,43 -1,20 (m, 4H)
II -14
492,2 0,153 δ 9,39 (d, J = 8,2 Hz, 1H), 9,29 (s, 1H), 8,24 (d, J = 2,8 Hz, 1H), 7,92 (s, 1H), 7,83 (s, 1H), 7,55 (s, 1H), 7,45 (d, J = 8,6 Hz, 1H), 7,41 -7,34 (m, 2H), 7,34 (s, 1H), 6,29 (d, J = 8,2 Hz, 1H), 4,08 (m, 1H), 3,90 (m, 2H), 3,82 (s, 3H), 3,78 (s, 3H), 3,42 (t, J = 10,9 Hz, 2H), 1,89 (d, J = 11,7 Hz, 2H), 1,59 (cd, J = 12,0, 4,4 Hz, 2H)
II -15
527,2 0,0043
II -16
487,2 0,0021 δ 9,71 (s, 1H), 9,38 (d, J = 7,5 Hz, 2H), 8,15 (s, 1H), 8,00 (d, J = 8,4 Hz, 1H), 7,80 (d, J = 8,3 Hz, 1H), 7,53 (s, 1H), 7,39 (d, J = 1,7 Hz, 1H), 7,32 (s, 1H), 7,27 (d, J = 12,7 Hz, 1H), 7,16 (dt, J = 17,1,8,5 Hz, 2H), 6,40 (s, 1H), 6,27 (d, J = 8,5 Hz, 1H), 3,82 (s, 3H), 3,79 (d, J = 3,7 Hz, 3H), 3,73 (d, J = 11,7 Hz, 3H)
II -17
498,1 0,0048
II -18
501,2 0,0021 δ 9,64 (s, 1H), 9,38 (d, J = 8,8 Hz, 2H), 8,15 (s, 1H), 7,99 (d, J = 8,4 Hz, 1H), 7,79 (dd, J = 8,3, 1,2 Hz, 1H), 7,54 (s, 1H), 7,32 (s, 1H), 7,29 -7,24 (m, 1H), 7,20 (d, J = 10,2 Hz, 1H), 7,14 (t, J = 8,6 Hz, 1H), 6,27 (d, J = 8,4 Hz, 1H), 6,18 (s, 1H), 3,80 (d, J = 13,1 Hz, 6H), 3,63 (s, 3H), 2,14 (s, 3H)
II -19
imagen31 519,2 0,0068
II -20
imagen32 523 0,0097 δ 9,39 (d, J = 8,5 Hz, 1H), 9,26 (s, 1H), 7,88 (s, 1H), 7,70 (s, 1H), 7,54 (s, 1H), 7,32 (d, J = 10,4 Hz, 1H), 7,32 (s, 1H), 7,27 (d, J = 12,7 Hz, 1H), 7,19 (d, J = 9,8 Hz, 1H), 7,13 (t, J = 8,6 Hz, 1H), 6,55 (s, 1H), 6,24 (d, J = 8,4 Hz, 1H), 4,35 (d, J = 2,4 Hz, 1H), 3,87 (s, 1H), 3,82 (s, 3H), 3,79 (s, 3H), 3,76 (s, 1H), 1,86 -1,58 (m, 6H), 1,51 (t, J = 11,9 Hz, 2H)
II -21
483,1 0,0023 δ 9,38 (d, J = 8,4 Hz, 1H), 9,28 (s, 1H), 7,88 (s, 1H), 7,54 (s, 1H), 7,49 (s a, 1H), 7,34 (d, J = 10 Hz, 2H), 7,32 (s, 1H), 7,27 (d, J = 12,5 Hz, 1H), 7,19 (d, J = 9,9 Hz, 1H), 7,13 (t, J = 8,6 Hz, 1H), 6,25 (d, J = 8,5 Hz, 1H), 4,71 (t, J = 5,6 Hz, 1H), 4,12 (septuplete, J = 7 Hz, 1H), 3,82 (s, 3H), 3,79 (s, 3H), 3,53 (dt, J = 10,7, 5,4 Hz, 1H), 3,43 -3,35 (dt, J = 10,8, 5,2 Hz, 1H), 1,18 (d, J = 6,6 Hz, 3H)
II -22
491,1 0,0070 δ 9,37 (d, J = 8,5 Hz, 1H), 9,29 (s, 1H), 7,90 (s a, 1H), 7,79 (s a, 1H), 7,51 (s, 1H), 7,38 -7,30 (m, 4H), 6,91 (d, J = 8,7 Hz, 2H), 6,25 (d, J = 8,4 Hz, 1H), 4,07 (s a, 1H), 3,90 (d, J = 11,5 Hz, 1H), 3,79 (s, 3H), 3,74 (s, 3H), 3,42 (t, J = 10,8 Hz, 2H), 1,89 (d, J = 11,6 Hz, 2H), 1,59 (cd, J = 11,7, 4,3 Hz, 2H)
II -23
505,1 0,0108
II -24
505,1 0,0146 δ 9,62 (s, 1H), 9,43 (d, J = 8,3 Hz, 1H), 9,37 (s, 1H), 8,16 (s, 1H), 8,00 (d, J = 8,4 Hz, 1H), 7,79 (dd, J = 8,4, 1,6 Hz, 1H), 7,57 (t, J = 8,0 Hz, 2H), 7,47 (dd, J = 10,6, 2,0 Hz, 1H), 7,36 (s, 1H), 7,31 (dd, J = 8,3, 1,9 Hz, 1H), 6,33 (d, J = 8,3 Hz, 1H), 6,18 (s, 1H), 3,79 (s, 3H), 3,63 (s,3H), 2,14 (s, 3H)
II -25
491,0 0,0031 δ 9,69 (s, 1H), 9,43 (d, J = 8,3 Hz, 1H), 9,39 (s, 1H), 8,16 (s, 1H), 8,01 (d, J = 8,4 Hz, 1H), 7,80 (dd, J = 8,4, 1,5 Hz, 1H), 7,57 (t, J = 8,1 Hz, 2H), 7,47 (dd, J = 10,5, 2,0 Hz, 1H), 7,38 (d, J = 1,9 Hz, 1H), 7,36 (s, 1H), 7,31 (dd, J = 8,4, 1,9 Hz, 1H), 6,39 (d, J = 1,9 Hz, 1H), 6,32 (d, J = 8,3 Hz, 1H), 3,79 (s, 3H), 3,72 (s, 3H)
II -26
453,0 0,0056 δ 9,43 (d, J = 8,4 Hz, 1H), 9,28 (s, 1H), 7,89 (s, 1H), 7,57 (s, 1H), 7,46 (s, 1H), 7,40 (td, J = 8,2, 6,2 Hz, 1H), 7,3 5 (dd, J = 10,6, 1,0 Hz, 1H), 7,35 (s, 1H), 7,28 (d, J = 7,6 Hz, 1H), 7,26 (d, J = 10,8 Hz, 1H), 7,09 (td, J = 8,6,2,4 Hz, 1H), 6,32 (d, J = 8,4 Hz, 1H), 4,69 (t, J = 5,6 Hz, 1H), 4,19 -4,07 (m, 1H), 3,79 (s, 3H), 3,53 (dt, J = 10,8, 5,5 Hz, 1H), 3,44 -3,36 (m, 1H), 1,19 (d, J = 6,6 Hz, 3H)
II -27
501,2 0,96
II -28
491,2 0,003
II -29
509,2 0,0022
II -30
503,3 1
II -31
imagen33 479,1 0,015 δ 9,34 (d, J = 8,6 Hz, 1H), 9,16 (s, 1H), 8,00 (s, 1H), 7,84 (d, J = 8,3 Hz, 1H), 7,62 (dd, J = 8,3, 1,5 Hz, 1H), 7,54 (s, 1H), 7,39 7,24 (m, 3H), 7,16 (dt, J = 17,2, 8,6 Hz, 2H), 6,26 (d, J = 8,5 Hz, 1H), 4,37 -4,25 (m, 1H), 3,82 (s, 3H), 3,79 (s, 3H), 3,47 (dd, J = 9,4, 6,0 Hz, 1H), 3,41 -3,33 (m, 1H), 3,28 (s, 3H), 1,18 (d, J = 6,7 Hz, 3H)
II -32
497,2 0,0045 δ 9,40 (d, J = 8,4 Hz, 1H), 9,31 (s, 1H), 8,23 (s, 1H), 7,93 (s, 1H), 7,54 (s, 1H), 7,38 (d, J = 10,4 Hz, 1H), 7,32 (s, 1H), 7,27 (d, J = 12,7 Hz, 1H), 7,20 (d, J = 8,7 Hz, 1H), 7,14 (t, J = 8,6 Hz, 1H), 6,25 (d, J = 8,4 Hz, 1H), 5,29 (d, J = 56,8 Hz, 1H), 4,67 -4,54 (m, 1H), 3,82 (s, 3H), 3,79 (s, 3H), 2,64 -2,50 (m, 2H), 2,50 -2,38 (m, 2H)
II -33
imagen34 497,1 0,0038 δ 9,39 (d, J = 8,5 Hz, 1H), 9,31 (s, 1H), 8,19 (s, 1H), 7,88 (s, 1H), 7,54 (s, 1H), 7,38 (d, J = 10,4 Hz, 1H), 7,33 (s, 1H), 7,27 (d, J = 12,8 Hz, 1H), 7,19 (d, J = 8,6 Hz, 1H), 7,14 (t, J = 8,6 Hz, 1H), 6,24 (d, J = 8,4 Hz, 1H), 4,91 (d, J = 56,6 Hz, 1H), 4,12 -3,98 (m, 1H), 3,82 (s, 3H), 3,79 (s, 3H), 2,87 -2,75 (s, 2H), 2,34 -2,18 (m, 2H)
II -34
521,2 1
II -35
492,1 0,061 δ 9,39 (d, J = 8,3 Hz, 1H), 9,30 (s, 1H), 8,35 (d, J = 5,7 Hz, 1H), 7,93 (s, 1H), 7,84 (s, 1H), 7,58 (s, 1H), 7,39 -7,33 (m, 2H), 7,11 (d, J = 2,3 Hz, 1H), 6,89 (dd, J = 5,7, 2,4 Hz, 1H), 6,27 (d, J = 8,3 Hz, 1H), 4,10 (s, 1H), 3,90 (d, J = 11,3 Hz, 2H), 3,82 (s, 3H), 3,78 (s, 3H), 3,42 (t, J = 11,3 Hz, 2H), 1,89 (d, J = 12,1 Hz, 2H), 1,59 (m, 2H)
(500 MHz, CDCl3): δ9,15 (s, 1H),
7,99 (s, 1H), 7,89 (d, J = 8,0 Hz,
1H), 7,66 (d, J = 8,5 Hz, 1H),
7,44 (s, 1H), 7,19 -7,14 (m, 3H),
II -36
509,2 0,0038 6,55 (s, 1H), 6,13 (s, 1H), 4,80 (s, 1H), 4,45 -4,37 (m, 1H), 4,18
4,04 (m, 2H), 3,90 (s, 3H), 3,82
(s, 3H), 3,78 -3,60 (m, 2H), 2,14
-2,04 (m, 1H), 1,89 -1,87 (m,
1H)
II -37
509,2 0,0036 (500 MHz, DMSO-d6): δ 9,64 (d, J = 8,0 Hz, 1H), 9,22 (s, 1H), 8,07 (s, 1H), 7,90 -7,84 (m, 2H), 7,67 (d, J = 8,0 Hz, 1H), 7,35 7,33 (m, 2H), 7,26 -7,17 (m, 2H), 6,49 (d, J = 8,0 Hz, 1H), 5,95 (s, 1H), 4,65 (s, 0,5H), 4,55 (s, 0,5H), 4,38 (s, 1H), 4,06 -4,02 (m, 1H), 3,86 -3,83 (m, 1H), 3,80 (s, 3H), 3,74 (s, 3H), 3,51 -3,42 (m, 2H), 2,08 -2,01 (m, 1H), 1,68 -1,61 (m, 1H)
II -38
487,3 0,0029 (500 MHz, DMSO-d6): δ 9,70 (s, 1H), 9,63(d, J = 8,5 Hz, 1H), 9,39 (s, 1H), 8,16 (s, 1H), 8,01 (d, J = 8,0 Hz, 1H), 7,80 (d, J = 8,5 Hz, 1H), 7,38 (d, J = 1,5, 1H) 7,34 7,30 (m, 2H), 7,26 -7,16 (m, 2H), 6,49 (d, J = 8,5 Hz, 1H), 6,39 (d, J = 1,5 Hz, 1H), 5,93 (d, J = 2,0 Hz, 1H), 3,83 (s, 3H), 3,73 (s, 3H), 3,71 (s, 3H)
II -39
495,3 0,151 (500 MHz, DMSO-d6): δ 9,68 (d, J = 8,0 Hz, 1H), 9,17 (s, 1H), 8,06 (s, 1H), 7,86 (d, J = 8,0 Hz, 1H), 7,65 -7,53 (m, 4H), 7,38 7,33 (m, 2H), 6,57 (d, J = 8,5 Hz, 1H), 5,89 (d, J = 1,5 Hz, 1H), 4,09 -4,05 (m, 1H), 3,89 (d, J = 11,0 Hz, 2H), 3,77 (s, 3H), 3,44 3,38 (m, 2H), 1,89 -1,86 (m, 2H), 1,61 -1,53 (m, 2H)
II -40
imagen35 502,1 0,026 (500 MHz, DMSO-d6): δ 9,73 (d, J = 8,0 Hz, 1H), 9,18 (s, 1H), 8,08 -8,02 (m, 2H), 7,88 -7,86 (m, 2H), 7,69 -7,60 (m, 3H), 7,34 (d, J = 1,5 Hz, 1H), 6,65 (d, J = 8,0 Hz, 1H), 5,85 (d, J = 2,0 Hz, 1H), 4,07 (s, 1H), 3,89 (d, J = 11,5 Hz, 2H), 3,80 (s, 3H), 3,44 3,41 (m, 2H), 1,91 -1,87 (m, 2H), 1,60 -1,53 (m, 2H)
II -41
529,3 0,0052
II -42
498,1 0,0346
II -43
509,3 0,0121
II -44
imagen36 548,2 0,216
II -45
550,3 0,0069
II -46
509,2 0,0011
II -47
496,2 0,0013
II -48
510,2 0,0014
II -49
509,3 0,0855
II -50
imagen37 495,2 0,0591
II -51
imagen38 509,2 0,164
II -52
509,2 0,0019
II -53
505,2 0,0015
II -54
505,2 0,0085
1. Ensayo enzimático de la ERK-2 (Ejemplo 9)
Los compuestos de la presente invención pueden ser elaborados mediante diversos métodos representados en los esquemas de reacción sintéticos ilustrativos mostrados y descritos a continuación. Los materiales y reactivos de partida usados en la preparación de estos compuestos generalmente están disponibles en proveedores comerciales, tales como Sigma Aldrich Chemical Co., o se preparan mediante métodos conocidos por los expertos en la materia. Los procedimientos sintéticos aplicables generalmente descritos en los tratados se establecen en referencias tales como Reagents for Organic Synthesis, de Fieser y Fieser; Wiley & Sons: Nueva York, Volúmenes 1 -21; R. C. LaRock, Comprehensive Organic Transformations, 2ª edición Wiley-VCH, Nueva York 1999; Comprehensive
imagen39
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imagen41
imagen42
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imagen47
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imagen49
imagen50
imagen51
imagen52
imagen53
imagen54
imagen55
imagen56
imagen57
imagen58
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Claims (1)

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