ES2560612T3 - Derivados bencilamina como inhibidores de la calicreina plasmática - Google Patents

Derivados bencilamina como inhibidores de la calicreina plasmática Download PDF

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ES2560612T3
ES2560612T3 ES12735610.3T ES12735610T ES2560612T3 ES 2560612 T3 ES2560612 T3 ES 2560612T3 ES 12735610 T ES12735610 T ES 12735610T ES 2560612 T3 ES2560612 T3 ES 2560612T3
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phenyl
aminomethyl
benzylcarbamoyl
ethyl
ethoxy
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ES2560612T7 (es
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David Michael Evans
Rebecca Louise DAVIE
Hannah Joy EDWARDS
David Philip Rooker
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Kalvista Pharmaceuticals Ltd
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Kalvista Pharmaceuticals Ltd
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    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
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    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
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    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
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Abstract

Compuesto de fórmula I**Fórmula** en el que: R1 está seleccionado de entre H, alquilo, -COalquilo, -COarilo, -COheteroarilo, -CO2alquilo, -(CH2)aOH, -(CH2)bCOOR10, -(CH2)cCONH2, -SO2alquilo, -SO2arilo, -SO2(CH2)hR13, -CO(CH2)iR14, -COcicloalquilo, -COCH>=CHR15, -CO(CH2)jNHCO(CH2)kR16 y -CONR17R18; R2 está seleccionado de entre H y alquilo; R3 está seleccionado de entre H, alquilo, -(CH2)darilo, -(CH2)eheteroarilo, -(CH2)fcicloalquilo, -(CH2)gheterocicloalquilo, -CH(cicloalquilo)2, -CH(heterocicloalquilo)2 y -(CH2)larilo-O-(CH2)m-arilo; R4 y R6 están seleccionados independientemente de entre H y alquilo; R5 está seleccionado de entre H, alquilo, alcoxi y OH; o R4 y R5, junto con los átomos a los que están fijados, pueden unirse para formar un estructura azacicloalquilo de 5 ó 6 miembros; R7 y R8 están seleccionados independientemente de entre H, alquilo, alcoxi, CN, halo y CF3; R9 es arilo o heteroarilo; R10 es H o alquilo; a, b, c, d, e, f, g, h, i, j, l y m son independientemente 1, 2 ó 3; k es 0, 1, 2 ó 3; *1 y *2 indican centros quirales; el alquilo es un hidrocarburo saturado lineal que tiene hasta 10 átomos de carbono (C1-C10) o un hidrocarburo saturado ramificado de entre 3 y 10 átomos de carbono (C3-C10); el alquilo puede estar opcionalmente sustituido con 1 ó 2 sustituyentes seleccionados independientemente de entre cicloalquilo(C3-C10), alcoxi(C1-C6), OH, CN, CF3, COOR11, fluoro y NR11R12; el cicloalquilo es un hidrocarburo saturado monocíclico o bicíclico de entre 3 y 10 átomos de carbono; el cicloalquilo puede estar opcionalmente condensado con un grupo arilo; o el cicloalquilo es adamantilo; el heterocicloalquilo es un anillo monocíclico o bicíclico saturado de 3 a 10 miembros unido a través del C o del N, en el que dicho anillo heterocicloalquilo contiene, cuando sea posible, 1, 2 ó 3 heteroátomos seleccionados independientemente de entre N, NR11 y O; el alcoxi es un hidrocarburo lineal unido a través del O de entre 1 y 6 átomos de carbono (C1-C6) o un hidrocarburo ramificado unido a través del O de entre 3 y 6 átomos de carbono (C3-C6); el alcoxi puede estar opcionalmente sustituido con 1 ó 2 sustituyentes seleccionados independientemente de entre cicloalquilo(C3-C10), OH, CN, CF3, COOR11, fluoro y NR11R12; el arilo es fenilo, bifenilo o naftilo; el arilo puede estar opcionalmente sustituido con hasta 5 sustituyentes seleccionados independientemente de entre alquilo, alcoxi, OH, halo, CN, COOR11, CF3 y NR11R12; el heteroarilo es un anillo aromático monocíclico o bicíclico de 5, 6, 9 ó 10 miembros, que contiene, cuando sea posible, 1, 2 ó 3 miembros del anillo seleccionados independientemente de entre N, NR11, S y O; el heteroarilo puede estar opcionalmente sustituido con 1, 2 ó 3 sustituyentes seleccionados independientemente de entre alquilo, alcoxi, OH, halo, CN, COOR11, CF3, NR11R12 y NHR19; R11 y R12 están seleccionados independientemente de entre H y alquilo; R13 es arilo o heteroarilo; R14 es arilo, heteroarilo, cicloalquilo o heterocicloalquilo; R15 es H, alquilo, arilo, heteroarilo, cicloalquilo o heterocicloalquilo; R16 es H, arilo o heteroarilo; R17 es H, alquilo, arilo, heteroarilo o heterocicloalquilo; R18 es -(CH2)mR21, en el que m es 0, 1, 2 ó 3 y R21 es H, arilo o heteroarilo; R19 es -COalquilo, -COarilo o -COheteroarilo; y tautómeros, estereoisómeros (incluidos enantiómeros, diastereoisómeros y mezclas racémicas y no racémicas del mismo), sales y solvatos farmacéuticamente aceptables del mismo.

Description

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[(R)-1-[(S)-]1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido tiofeno-2carboxílico; [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido ciclohexanocarboxílico; [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido isoxazol-5carboxílico; [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido piridina-2carboxílico; [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido benzo[b]tiofeno-2-carboxílico; (R)-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-2-(4-cloro-bencenosulfonilamino)-3-(4-etoxi-fenil)propionamida; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-3-cloro-benzamida; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-2-cloro-benzamida N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-3-trifluorometilbenzamida; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-4-metilbenzamida; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-3,4-dicloro-benzamida; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-4-metoxi-benzamida; (S)-N-(4-aminometil-bencil)-2-[(R)-3-(4-etoxi-fenil)-2-(2-fenilacetilamino-acetilamino)-propionilamino]-3-fenilpropionamida; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-4-fluoro-benzamida; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-6-metil-nicotinamida; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-2-metil-nicotinamida; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-2,6-dicloro-nicotinamida; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-5,6-dicloro-nicotinamida; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-2,3,6-trifluoroisonicotinamida; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-3,3,3-trifluoropropionamida; [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 2,4-dimetiltiazol-5-carboxílico; [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 2-metiltiazol-5-carboxílico; [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 3-clorotiofeno-2-carboxílico; [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 4-metiltiazol-5-carboxílico; [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido furan-2carboxílico; [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 3-metiltiofeno-2-carboxílico; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-2-metoxi-isonicotinamida; [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 3-metil-1Hpirrol-2-carboxílico; [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 3-aminotiofeno-2-carboxílico; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-propoxifenil)-etil]-benzamida; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-piridin-2-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-benzamida; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-(3,4-dicloro-fenil)-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-benzamida; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-(4-cloro-fenil)-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-benzamida; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-(4-fluoro-fenil)-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-benzamida; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-piridin-3-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-benzamida; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-(4-metoxi-fenil)-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-benzamida; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-piridin-4-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-benzamida; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-(3-fluoro-fenil)-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-benzamida; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-tiofen-2-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-benzamida; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-tiofen-3-il-etilcarbamoil-2-(4-etoxi-fenil)-etil]-benzamida; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-tiazol-4-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-benzamida; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-benzo[b]tiofen-3-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-benzamida; N-[(R)-1-[(S)-1-(4-aminometil-3-fluoro-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-benzamida; N-[(R)-1-[(S)-1-(4-aminometil-3-cloro-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-benzamida; [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-tiofen-2-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido piridina-2-carboxílico; N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-piridin-2-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-4-metoxibenzamida;
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citratos, lactatos, tartratos, mesilatos, succinatos, oxalatos, fosfatos, esilatos, tosilatos, bencenosulfonatos, naftalenodisulfonatos, maleatos, adipatos, fumaratos, hipuratos, canforatos, xinafoatos, p-acetamidobenzoatos, dihidroxibenzoatos, hidroxinaftoatos, succinatos, ascorbatos, oleatos, bisulfatos, y similares.
También pueden formarse hemisales de ácidos y bases, por ejemplo, sales de hemisulfato y hemicalcio.
Para una revisión de las sales adecuadas, véase "Handbook of Pharmaceutical Salts: Properties, Selection and Use" de Stahl y Wermuth (Wiley-VCH, Weinheim, Alemania, 2002).
"Profármaco" se refiere a un compuesto que puede convertirse in vivo mediante medios metabólicos (por ejemplo, mediante hidrólisis, reducción u oxidación) en un compuesto de la invención. Los grupos adecuados para formar profármacos se describen en "The Practice of Medicinal Chemistry, 2ª ed. págs. 561-585 (2003) y en F.J. Leinweber, Drug Metab. Res., 1987, 18, 379.
Los compuestos de la invención pueden existir en formas tanto solvatadas como no solvatadas. El término “solvato” se utiliza en el presente documento para describir un complejo molecular que comprende el compuesto de la invención y una cantidad estequiométrica de una o más moléculas de disolvente farmacéuticamente aceptables, por ejemplo, etanol. El término "hidrato" se emplea cuando el disolvente es agua.
Cuando los compuestos de la invención existan en una o más formas geométricas, ópticas, enantioméricas, diastereoméricas y tautoméricas, incluidas pero no limitadas a las formas cis y trans, las formas E y Z, las formas R, S y meso, las formas ceto y enol. A menos que se indique otra cosa, una referencia a un compuesto concreto incluye todas esas formas isoméricas, incluidas las racémica y otras mezclas de las mismas. Cuando proceda, tales isómeros pueden separarse de sus mezclas aplicando o adaptando métodos conocidos (por ejemplo, técnicas cromatográficas y técnicas de recristalización). Cuando proceda, tales isómeros pueden prepararse aplicando o adaptando métodos conocidos (por ejemplo, síntesis asimétrica).
En el contexto de la presente invención, las referencias en el presente documento a "tratamiento" incluyen referencias al tratamiento curativo, paliativo y profiláctico.
Métodos generales
Los compuestos de fórmula (I) deben evaluarse para determinar sus propiedades biofarmacéuticas, tales como la solubilidad y la estabilidad de la solución (a través del pH), la permeabilidad, etc., con el fin de seleccionar la forma farmacéutica y vía de administración más apropiadas para el tratamiento de la indicación propuesta. Pueden administrarse solos o en combinación con uno o más de otros compuestos de la invención o en combinación con uno o más de otros fármacos (o como cualquier combinación de los mismos). Generalmente, se administrarán como una formulación en asociación con uno o más excipientes farmacéuticamente aceptables. El término "excipiente" se utiliza en el presente documento para describir cualquier ingrediente distinto del compuesto o compuestos de la invención que puede conferir a las formulaciones una característica funcional (es decir, el control de la velocidad de liberación del fármaco) y/o una no funcional (es decir, aditivo de procesamiento o diluyente). La elección del excipiente dependerá en gran medida de factores tales como el modo concreto de administración, el efecto del excipiente sobre la solubilidad y la estabilidad, y la naturaleza de la forma farmacéutica.
Los compuestos de la invención destinados a uso farmacéutico pueden administrarse como sólido o líquido, tal como un comprimido, una cápsula o una solución. Las composiciones farmacéuticas adecuadas para la administración de los compuestos de la presente invención y los métodos para su preparación resultarán evidentes para los expertos en la materia. Tales composiciones y métodos para su preparación pueden encontrarse, por ejemplo, en Remington’s Pharmaceutical Sciences, 19a edición (Mack Publishing Company, 1995).
Por consiguiente, la presente invención proporciona una composición farmacéutica que comprende un compuesto de fórmula (I) y un vehículo, diluyente o excipiente farmacéuticamente aceptable.
Para el tratamiento de afecciones tales como la permeabilidad vascular retiniana asociada con la retinopatía diabética y el edema macular diabético, los compuestos de la invención pueden administrarse en una forma adecuada para la inyección en la región ocular de un paciente, en particular, en una forma adecuada para la inyección intravítrea. Se prevé que las formulaciones adecuadas para tal uso adopten la forma de soluciones estériles de un compuesto de la invención en un vehículo acuoso adecuado. Las composiciones pueden administrarse al paciente bajo la supervisión del médico a cargo.
Los compuestos de la invención también pueden administrarse directamente en el torrente sanguíneo, en el tejido subcutáneo, en el músculo o en un órgano interno. Los medios adecuados para la administración parenteral incluyen la intravenosa, intraarterial, intraperitoneal, intratecal, intraventricular, intrauretral, intraesternal, intracraneal, intramuscular, intrasinovial y subcutánea. Los dispositivos adecuados para la administración parenteral incluyen inyectores de aguja (incluidos inyectores de microaguja), inyectores sin aguja y técnicas de infusión.
imagen10
imagen11
puede conseguirse en una sola etapa, ya sea por reducción directa del nitrilo mediante hidrogenación en un disolvente adecuado tal como metanol en presencia de un catalizador adecuado tal como paladio sobre carbón en presencia de un ácido tal como ácido clorhídrico o por reducción con un borohidruro adecuado en presencia de un metal de transición adecuado tal como cloruro de níquel o cobalto en un disolvente adecuado tal como metanol a
5 temperatura ambiente. Como alternativa, puede aislarse la amina protegida con terc-butoxicarbonilo (Boc) 9 (utilizando, por ejemplo, el método que se describe en S. Caddick et al., Tetrahedron Lett., 2000, 41, 3513) y desprotegerse posteriormente mediante los métodos convencionales descritos anteriormente para dar la amina 10.
imagen12
Breve descripción de los dibujos
La Figura 1 muestra el efecto inhibidor del Ejemplo 3 y CH-3457 (control positivo; inhibidor de calicreína plasmática) sobre la PVR estimulada con CA-I en ratas Sprague Dawley. La Figura 2 muestra las concentraciones del Ejemplo 3 en los tejidos oculares después de la administración IVT de 4,2 µg/ml (210 ng/ojo).
Ejemplos
La invención se ilustra mediante los siguientes ejemplos no limitativos en los que se utilizan las siguientes abreviaturas y definiciones:
imagen13
15
25
DMF
N,N-dimetilformamida
DMSO
Dimetilsulfóxido
Et
Etilo
EtOAc
Acetato de etilo
hrs
Horas
HOBt
Hidroxibenzotriazol
LCMS
Cromatografía de líquidos -espectrometría de masas
Me
Metilo
MeCN
Acetonitrilo
MeOH
Metanol
min
Minutos
MS
Espectro de masas
m/z
Relación entre masa y carga (del ion precursor, MH+, a menos que se indique otra cosa)
RMN
Espectro de resonancia magnética nuclear -los espectros de RMN se registraron a una frecuencia de 400 MHz a menos que se indique otra cosa
Éter de pet.
Fracción de éter de petróleo en ebullición a 60°C-80°C
Ph
Fenilo
Phe
Fenilalanina
n-Pr
n-propilo
THF
Tetrahidrofurano
TFA
Ácido trifluoroacético
Todas las reacciones se llevaron a cabo en atmósfera de nitrógeno a menos que se especifique otra cosa.
Los espectros de 1H RMN se registraron en un espectrómetro Brucker Avance III (400 MHz) con respecto a un
disolvente de deuterio y a temperatura ambiente.
Los iones moleculares se obtuvieron utilizando LCMS que se llevó a cabo utilizando una columna Chromolith
35 SpeedROD RP-18e, 50 x 4,6 mm, con un gradiente lineal del 10% al 90%, HCO2H al 0,1%/MeCN en HCO2H al 0,1%/H2O, durante 11 minutos, caudal 1,5 ml/min. Los datos se recogieron utilizando un espectrómetro de masas Thermofinnigan Surveyor MSQ con ionización por electronebulización junto con un sistema Thermofinnigan Surveyor LC. Los nombres químicos se generaron utilizando el software Autonom proporcionado como parte del paquete ISIS/Draw de MDL Information Systems. Cuando los productos se purificaron mediante cromatografía ultrarrápida, "sílice" se refiere a gel de sílice para cromatografía, de 0,035 mm a 0,070 mm (de malla 220 a 440) (por ejemplo, Merck Silica Gel 60), y una elución en columna acelerada a presión de nitrógeno aplicada de hasta 10 p.s.i . Las purificaciones de HPLC preparativa de fase inversa se llevaron a cabo utilizando un sistema de bombeo de gradiente binario Waters 2525 a caudales de por
45 lo general 20 ml/minutos utilizando un detector de matriz de fotodiodos Waters 2996. Todos los disolventes y reactivos comerciales se utilizaron tal como se recibieron.
EJEMPLO 1
(S)-N-(4-aminometil-bencil)-2-[(R)-3-(4-etoxi-fenil)-2-propionilamino-propionilamino]-3-fenil-propionamida
imagen14
65 A. Éster metílico del ácido (S)-2-[(R)-2-terc-butoxicarbonilamino-3-(4-etoxi-fenil)-propionilamino]-3-fenilpropiónico
5
15
25
35
45
55
65
Se disolvió H-Phe-OMe.HCl (2,3 g, 10,7 mmol) en CH2Cl2 (100 ml) y DMF (10 ml). Esta solución se enfrió a 0°C. Se añadió ácido (R)-2-butoxiloxicarbonilamino-3-(4-etoxi-fenil)-propiónico (3,0 g, 9,7 mmol) seguido de HOBt (1,57 g, 11,6 mmol) y trietilamina (2,9 g, 29,0 mmol). A continuación, se añadió carbodiimida hidrosoluble (2,04 g, 10,6 mmol). Después de 18 horas a una temperatura de 0°C a temperatura ambiente, la mezcla de reacción se diluyó con cloroformo (100 ml) y se lavó con NaHCO3 (1x30 ml), agua (1x30 ml), salmuera (1x30 ml), se secó (Na2SO4) y se evaporó a vacío, lo que dio un aceite amarillo. El residuo se purificó mediante cromatografía ultrarrápida (sílice), eluyente éter de pet. al 20% (60°C-80°C), EtOAc al 80%, las fracciones se combinaron y evaporaron a vacío para dar un aceite incoloro identificado como éster metílico del ácido (S)-2-[(R)-2-tercbutoxicarbonilamino-3-(4-etoxi-fenil)-propionilamino]-3-fenil-propiónico (4,25 g, 9,03 mmol, 93%). [M+H]+ = 471,27.
B. Ácido (S)-2-[(R)-2-terc-butoxicarbonilamino-3-(4-etoxi-fenil)-propionilamino]-3-fenil-propiónico
Se disolvió éster metílico del ácido (S)-2-[(R)-2-terc-butoxicarbonilamino-3-(4-etoxi-fenil)-propionilamino]-3fenilpropiónico (2,5 g, 5,3 mmol) en THF (100 ml). Se añadió hidróxido de litio monohidrato (668 mg, 15,9 mmol) en agua (10 ml). La mezcla de reacción se agitó a temperatura ambiente durante 18 horas, después de lo cual la mezcla de reacción se diluyó con EtOAc (150 ml). Esta solución se lavó con KHSO4 0,3 M (1x50 ml), agua (1x30 ml), salmuera (1x30 ml), se secó (Na2SO4) y se evaporó a vacío para dar un sólido blanco identificado como ácido (S)-2[(R)-2-terc-butoxicarbonilamino-3-(4-etoxi-fenil)-propionilamino]-3-fenil-propiónico (2,095 g, 4,58 mmol, 86%). [M+H]+ = 457,25.
C. Éster terc-butílico del ácido [(R)-1-[(S)-1-(4-ciano-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)etil]-carbámico
Se disolvió clorhidrato de 4-(aminometil)benzonitrilo (303 mg, 1,80 mmol) en CH2Cl2 (50 ml) y DMF (5 ml). Esta solución se enfrió a 0°C. Se añadió ácido (S)-2-[(R)-2-terc-butoxicarbonilamino-3-(4-etoxi-fenil)-propionilamino]3-fenil-propiónico (745 mg, 1,63 mmol) seguido de HOBt (265 mg, 1,96 mmol) y trietilamina (495 mg, 4,9 mmol). A continuación, se añadió carbodiimida hidrosoluble (344 mg, 1,8 mmol). Después de 18 horas a una temperatura de 0°C a temperatura ambiente, la mezcla de reacción se diluyó con cloroformo (100 ml) y se lavó con NaHCO3 (1x30 ml), agua (1x30 ml), salmuera (1x30 ml), se secó (Na2SO4) y se evaporó a vacío, lo que dio un aceite amarillo. El residuo se purificó mediante cromatografía ultrarrápida (sílice), eluyente éter de pet. al 20% (60°C-80°C), EtOAc al 80%, las fracciones se combinaron y evaporaron a vacío para dar un aceite incoloro identificado como éster tercbutílico del ácido [(R)-1-[(S)-1-(4-ciano-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-carbámico (493 mg, 0,86 mmol, 53%). [M+H]+ = 571,29
D. Clorhidrato de (R)-2-amino-N-[(S)-1-(4-ciano-bencilcarbamoil)-2-fenil-etil]-3-(4-etoxi-fenil)-propionamida
Se trató éster terc-butílico del ácido [(R)-1-[(S)-1-(4-ciano-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxifenil)-etil]-carbámico (225 mg, 0,39 mmol) con HCl/dioxano 4M (50 ml). Después de una hora a temperatura ambiente, se eliminó el disolvente para dar un sólido blanco identificado como clorhidrato de (R)-2-amino-N-[(S)-1-(4ciano-bencilcarbamoil)-2-fenil-etil]-3-(4-etoxi-fenil)-propionamida (200 mg, 0,39 mmol, 100%).
[M+H]+ = 471,26
E.
(S)-N-(4-ciano bencil)-2-[(R)-3-(4-etoxi-fenil)-2-propionilamino-propionilamino]-3-fenil
propionamida
Se
disolvió clorhidrato de (R)-2-amino-N-[(S)-1-(4-ciano-bencilcarbamoil)-2-fenil-etil]-3-(4-etoxi-fenil)
propionamida (200 mg, 0,37 mol) en diclorometano (50 ml), esta solución se enfrió a 0°C. Se añadió trietilamina (111 g, 1,1 mmol) seguido de cloruro de propionilo (39 mg, 0,40 mmol). Después de 18 horas a una temperatura de 0°C a temperatura ambiente, la mezcla de reacción se diluyó con CHCl3 (50 ml), esta solución se lavó con una solución saturada de NaHCO3 (1x20 ml), agua (1x20 ml), salmuera (1x20 ml), se secó (Na2SO4) y se evaporó a vacío. El residuo se purificó mediante cromatografía ultrarrápida (sílice), eluyente MeOH al 2%, CHCl3 al 98%, las fracciones se combinaron y evaporaron a vacío para dar un aceite incoloro identificado como (S)-N-(4-ciano-bencil)2-[(R)-3-(4-etoxi-fenil)-2-propionilamino-propionilamino]-3-fenil-propionamida (189 mg, 0,36 mmol, 98%). [M+H]+ = 527,27
F. Éster terc-butílico del ácido [4-({(S)-2-[(R)-3-(4-etoxi-fenil)-2-propionilamino-propionilamino]-3-fenilpropionilamino}-metil)-bencil]-carbámico
Se disolvió (S)-N-(4-ciano-bencil)-2-[(R)-3-(4-etoxi-fenil)-2-propionilamino-propionilamino]-3-fenilpropionamida (100 mg, 0,19 mmol) en metanol (50 ml). Esta solución se enfrió a 0°C. Se añadieron cloruro de níquel
(II) hexahidrato (4,5 mg, 0,0192 mmol) y dicarbonato de di-terc-butilo (83 mg, 0,38 mmol) seguido de borohidruro sódico (50 mg, 1,33 mmol) en porciones. La mezcla de reacción se agitó a una temperatura de 0°C a temperatura ambiente durante 18 horas. El metanol se eliminó por evaporación. El residuo se disolvió en CHCl3 (70 ml), se lavó
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imagen32
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Tabla 2
5
15
25
Nº de ejemplo
* & R1 R2 R4 R5 m/z
60
separado pero no confirmado R H H H OH 491,2
61
R H H H OH 491,2
62
separado pero no confirmado R CH3CH2CO H H OH 547,2
63
R CH3CH2CO H H OH 547,3
64
separado pero no confirmado R CH3CH2CO H CH3CH2 H 559,3
65
R CH3CH2CO H CH3CH2 H 559,3
66
S S CH3CH2CO CH3 H H 545,3
Tabla 3
imagen34
imagen35
imagen36
imagen37
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5
15
25
35
45
55
15
(R)-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-2-bencenosulfonilamino-3-(4-etoxi-fenil)propionamida
16
(S)-N-(4-aminometil-bencil)-3-(3,4-dicloro-fenil)-2-[(R)-3-(4-etoxi-fenil)-2-propionilaminopropionilamino]-propionamida
17
Ácido [(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)etilamino]-acético
18
(R)-2-amino-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-(3,4-dicloro-fenil)-etil]-3-(4-trifluorometilfenil)-propionamida
19
((R)-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-(3,4-dicloro-fenil)-etil]-2-propionilamino-3-(4trifluorometil-fenil)-propionamida
20
(R)-2-amino-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-(3,4-dicloro-fenil)-etil]-3-ciclohexilpropionamida
21
(R)-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-(3,4-dicloro-fenil)-etil]-3-ciclohexil-2-propionilaminopropionamida
22
N-{(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-etil}-benzamida
23
(S)-N-(4-aminometil-3-cloro-bencil)-2-[(R)-3-(4-etoxi-fenil)-2-propionilamino-propionilamino]-3fenil-propionamida
24
(S)-N-(4-aminometil-bencil)-2-[(R)-3-(4-etoxi-fenil)-2-propionilamino-propionilamino]-N-metil-3fenil-propionamida
25
(R)-2-amino-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-3-(4-etoxi-fenil)-N-metilpropionamida
26
(S)-N-(4-aminometil-bencil)-2-{[(R)-3-(4-etoxi-fenil)-2-propionilamino-propionil]-metilamino}-3fenil-propionamida
27
(R)-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-3-(4-etoxi-fenil)-2-metilaminopropionamida
28
Ácido {(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-3-metilbutilamino}-acético
29
Ácido ({(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-ciclohexil-etil}-metilamino)-acético
30
Ácido ((R)-1-{[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-metil-carbamoil}-2-ciclohexiletilamino)-acético
31
(S)-N-(4-aminometil-bencil)-2-[(R)-3-(4-etoxi-fenil)-2-(metil-propionilamino)-propionilamino]-3fenil-propionamida
32
(S)-N-(4-aminometil-3-fluoro-bencil)-2-{[(R)-3-(4-etoxi-fenil)-2-propionilamino-propionil]-metilamino}-3-fenil-propionamida
33
(R)-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-3-ciclohexil-2-metilamino-propionamida
34
Ácido ((R)-1-{[(S)-1-(4-aminometil-3-fluoro-bencilcarbamoil)-2-fenil-etil]-metil-carbamoil}-2ciclohexil-etilamino)-acético
35
(R)-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-3-(4-etoxi-fenil)-N-metil-2-propilaminopropionamida
36
Ácido ((R)-1-{(S)-1-[(4-aminometil-bencil)-metil-carbamoil]-2-fenil-etilcarbamoil}-2-ciclohexiletilamino)-acético
37
(R)-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-3-ciclohexil-2-propilamino-propionamida
38
N-[(R)-1-{[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-metil-carbamoil}-2-(4-etoxi-fenil)-etil]benzamida
39
(R)-2-acetilamino-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-3-(4-etoxi-fenil)-N-metilpropionamida
40
(R)-N-[(S)-1-(4-aminometil-3-fluoro-bencilcarbamoil)-2-fenil-etil]-3-ciclohexil-2-metilaminopropionamida
41
(R)-N-[(S)-1-(4-aminometil-3-fluoro-bencilcarbamoil)-2-(3,4-dicloro-fenil)-etil]-3-ciclohexil-2metilamino-propionamida
42
Ácido ({(R)-1-[(S)-1-(4-aminometil-3-fluoro-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-ciclohexil-etil}metil-amino)-acético
43
Ácido ({(R)-1-[(S)-1-(4-aminometil-3-fluoro-bencilcarbamoil)-2-(3,4-diclorofenil)-etilcarbamoil]-2ciclohexil-etil}-metil-amino)-acético
44
N-[(R)-1-{[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-metil-carbamoil}-2-(4-etoxi-fenil)-etil]isobutiramida
45
(R)-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-3-ciclohexil-2-(metil-propilamino)propionamida
46
Éster metílico del ácido {(R)-1-[(S)-1-(-4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2ciclohexil-etilamino}-acético
15
25
35
45
55
47
Éster metílico del ácido {(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2ciclohexil-etilamino}-acético
48
(R)-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-2-(carbamoilmetil-metilamino)-3ciclohexil-propionamida
49
(R)-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-3-ciclohexil-2-[(2-hidroxietil)-metil-amino]propionamida
50
(R)-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-2-(carbamoilmetil-amino)-3-ciclohexilpropionamida
51
(R)-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-3-ciclohexil-2-(2-hidroxietilamino)propionamida
52
(R)-2-amino-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-3,3-diciclohexil-propionamida
53
(R)-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-3-ciclohexil-2-dipropilamino-propionamida
54
[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido naftaleno-1-carboxílico
55
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-4-clorobenzamida
56
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-4trifluorometil-benzamida
57
[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido bifenil-4-carboxílico
58
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil)-2-(4-etoxi-fenil)-etil]-2,4dicloro-benzamida
59
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-3,4difluoro-benzamida
60
(R)-2-amino-N-[(1R,2S)-1-(4-aminometil-bencilcarbamoil)-2-hidroxi-2-fenil-etil]-3-(4-etoxi-fenil)propionamida
61
(R)-2-amino-N-[(1S,2S)-1-(4-aminometil-bencilcarbamoil)-2-hidroxi-2-fenil-etil]-3-(4-etoxi-fenil)propionamida
62
(2R,3S)-N-(4-aminometil-bencil)-2-[(R)-3-(4-etoxi-fenil)-2-propionilamino-propionilamino]-3hidroxi-3-fenil-propionamida
63
(2S,3S)-N-(4-aminometil-bencil)-2-[(R)-3-(4-etoxi-fenil)-2-propionilamino-propionilamino]-3hidroxi-3-fenil-propionamida
64
(R)-N-(4-aminometil-bencil)-2-{[(R)-3-(4-etoxi-fenil)-2-propionilamino-propionil]-etilamino}-3-fenilpropionamida
65
(S)-N-(4-aminometil-bencil)-2-{[(R)-3-(4-etoxi-fenil)-2-propionilamino-propionil]-etilamino}-3-fenilpropionamida
66
(S)-N-(4-aminometil-bencil)-2-[(S)-3-(4-etoxi-fenil)-2-(metil-propionilamino)-propionilamino]-3fenil-propionamida
67
4-aminometil-bencilamida del ácido (2S,3R)-1-[(R)-3-(4-etoxi-fenil)-2-propionilamino-propionil]-3fenil-pirrolidina-2-carboxílico
68
(R)-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-2-(3-bencil-ureido)-3-(4-etoxi-fenil)propionamida
69
(R)-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-3-(4-etoxi-fenil)-2-(3-fenil-ureido)propionamida
70
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]nicotinamida
71
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]isonicotinamida
72
[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido tiofeno-3-carboxílico
73
[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido tiofeno-2-carboxílico
74
[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido ciclopropanocarboxílico
75
[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido ciclohexanocarboxílico
76
[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido hexanoico
77
(R)-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-3-(4-etoxi-fenil)-2-(3-isopropil-ureido)propionamida
78
(R)-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-3-(4-etoxi-fenil)-2-(3-hexil-ureido)propionamida
15
25
35
45
55
79
[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido isoxazol-5-carboxílico
80
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-4trifluorometoxi-benzamida
81
[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido piridina-2-carboxílico
82
[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil] -2-(4-etoxi-fenil)-etil]-amida del ácido 2,5-dimetil-2H-pirazol-3-carboxílico
83
[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido benzo[b]tiofeno-2-carboxílico
84
(R)-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-2-(4-clorobencenosulfonilamino)-3-(4etoxi-fenil)-propionamida
85
(S)-N-(4-aminometil-bencil)-2-[(R)-3-(4-etoxi-fenil)-2-fenilacetilamino-propionilamino]-3-fenilpropionamida
86
(S)-N-(4-aminometil-bencil)-2-[(R)-3-(4-etoxi-fenil)-2-(3-fenilpropionilamino)-propionilamino]-3fenil-propionamida
87
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-4-fenilbutiramida
88
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-3-clorobenzamida
89
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-2-clorobenzamida
90
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-3trifluorometil-benzamida
91
[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido adamantano-1-carboxílico
92
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-4-metilbenzamida
93
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-3,4dicloro-benzamida
94
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoi]-2-(4-etoxi-fenil)-etil]-3,5dicloro-benzamida
95
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-4-metoxibenzamida
96
(E)-N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-3fenil-acrilamida
97
(S)-N-(4-aminometil-bencil)-2-[(R)-3-(4-etoxi-fenil)-2-(2-fenilacetilamino-acetilamino)propionilamino]-3-fenil-propionamida
98
N-{[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)etilcarbamoil]-metil}-benzamida
99
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-4-fluorobenzamida
100
(R)-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-3-(4-etoxi-fenil)-2fenilmetanosulfonilamino-propionamida
101
(S)-N-(4-aminometil-bencil)-2-{(R)-3-(4-etoxi-fenil)-2-[2-(tolueno-4-sulfonilamino)-acetilamino]propionilamino}-3-fenil-propionamida
102
(R)-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-2-[3-(4-cloro-fenil)-ureido]-3-(4-etoxifenil)-propionamida
103
(R)-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-2-(3-bencil-3-etil-ureido)-3-(4-etoxi-fenil)propionamida
104
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-6-metilnicotinamida
105
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-2-metilnicotinamida
106
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-2,6dicloro-nicotinamida
107
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-5,6dicloro-nicotinamida
108
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-2,3,6trifluoro-isonicotinamida
109
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-3,3,3trifluoro-propionamida
5
15
25
35
45
55
110
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-2-cloro6-metil-isonicotinamida
111
[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 2,4-dimetil-tiazol-5-carboxílico
112
[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 2-metil-tiazol-5-carboxílico
113
[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 2,5-dimetil-oxazol-4-carboxílico
114
[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 2-metil-quinolina-6-carboxílico
115
[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 7-cloro-quinolina-3-carboxílico
116
[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 3-cloro-tiofeno-2-carboxílico
117
[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 4-metil-tiazol-5-carboxílico
118
[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido furan-2-carboxílico
119
[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 3-metil-tiofeno-2-carboxílico
120
[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 6-metoxi-piridina-2-carboxílico
121
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-5-metoxinicotinamida
122
[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 3-metoxi-tiofeno-2-carboxílico
123
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-2-metoxiisonicotinamida
124
[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 3-metil-1H-pirrol-2-carboxílico
125
[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 3-amino-tiofeno-2-carboxílico
126
N-{(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-ciclohexil-etil}-benzamida
127
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-cloro-fenil)-etil]benzamida
128
N-{(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-[4-(4-cloro-benciloxi)-fenil]etil}-benzamida
129
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-hidroxifenil)-etil]benzamida
130
N-{(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-[4-(4-fluoro-benciloxi)-fenil]etil}-benzamida
131
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-propoxi-fenil)-etil]benzamida
132
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-benciloxi-fenil)-etil]benzamida
133
N-{(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-3-metil-butil}-benzamida
134
N-{(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-[4-(2,6-dicloro-benciloxi)fenil]-etil}-benzamida
135
N-{(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-p-tolil-etil}-benzamida
136
N-{(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-[4-(3-fluoro-benciloxi)-fenil]etil}-benzamida
137
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(6-metoxi-piridin-3-il)-etil]benzamida
138
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-metoxi-fenil)-etil]benzamida
139
N-{(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-fenil-etil}-benzamida
140
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-piridin-2-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]benzamida
141
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-(3,4-dicloro-fenil)-etilcarbamoil]-2-(4-etoxi-fenil)etil]-benzamida
142
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-(4-cloro-fenil)-etilcarbamoil]-2-(4-etoxi-fenil)-etil]benzamida
15
25
35
45
55
143
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-(4-fluoro-fenil)-etilcarbamoil]-2-(4-etoxi-fenil)etil]-benzamida
144
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-(3-trifluorometil-fenil)-etilcarbamoil]-2-(4-etoxifenil)-etil]-benzamida
145
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-piridin-3-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]benzamida
146
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-(4-metoxi-fenil)-etilcarbamoil]-2-(4-etoxi-fenil)etil]-benzamida
147
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-piridin-4-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]benzamida
148
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-(4-trifluorometil-fenil)-etilcarbamoil]-2-(4-etoxifenil)-etil]-benzamida
149
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-(3-fluoro-fenil)-etilcarbamoil]-2-(4-etoxi-fenil)etil]-benzamida
150
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-tiofen-2-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]benzamida
151
N-[(R)-1-[(S)-l-(4-aminometil-bencilcarbamoil)-2-tiofen-3-il-etilcarbamoil-2-(4-etoxi-fenil)-etil]benzamida
152
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-tiazol-4-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]benzamida
153
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-benzo[b]tiofen-3-il-etilcarbamoil]-2-(4-etoxi-fenil)etil]-benzamida
154
N-[(R)-1-[(S)-1-(4-aminometil-3-fluoro-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]benzamida
155
N-[(R)-1-[(S)-1-(4-aminometil-3-cloro-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]benzamida
156
N-[(R)-1-[(S)-1-(4-aminometil-3-trifluorometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxifenil)-etil]-benzamida
157
[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-tiofen-2-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido piridina-2-carboxílico
158
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-piridin-2-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-4metoxi-benzamida
159
[(R)-1-[(S)-1-(4-aminometil-3-cloro-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]amida del ácido piridina-2-carboxílico
160
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-piridin-3-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-4metoxi-benzamida
161
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-(3,4-difluoro-fenil)-etilcarbamoil]-2-(4-etoxi-fenil)etil]-isonicotinamida
162
[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-piridin-3-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido tiofeno-2-carboxílico
163
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-piridin-2-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-4cloro-benzamida
164
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-piridin-2-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-4metil-benzamida
165
[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-(3,4-diclorofenil)-etilcarbamoil]-2-(4-etoxi-fenil)etil]-amida del ácido piridina-2-carboxílico
166
(R)-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-piridin-2-il-etil]-3-(4-etoxi-fenil)-2-propionilaminopropionamida
167
N-[(R)-1-[(S)-1-(4-aminometil-3-fluoro-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]isonicotinamida
168
[(R)-1-[(S)-1-(4-aminometil-3-fluoro-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]amida del ácido piridina-2-carboxílico
169
[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-(3,4-diclorofenil)-etilcarbamoil]-2-(4-etoxi-fenil)etil]-amida del ácido tiofeno-2-carboxílico
170
(R)-N-[(S)-1-(4-aminometil-bencilcarbamoil)-2-piridin-3-il-etil]-3-(4-etoxi-fenil)-2-propionilaminopropionamida
171
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-(3,4-dicloro-fenil)-etilcarbamoil]-2-(4-etoxi-fenil)etil]-isonicotinamida
172
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-(3,4-dicloro-fenil)-etilcarbamoil]-2-(4-etoxi-fenil)etil]-3,3,3-trifluoro-propionamida
173
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-piridin-3-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-4cloro-benzamida
5
15
25
35
45
55
174
[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-piridin-3-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido isoxazol-5-carboxílico
175
[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-piridin-3-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 3-cloro-tiofeno-2-carboxílico
176
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-(1H-indol-3-il)-etilcarbamoil]-2-(4-etoxi-fenil)-etil]benzamida
177
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-(1H-imidazol-4-il)-etilcarbamoil]-2-(4-etoxi-fenil)etil]-benzamida
178
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-benzo[b]tiofen-3-il-etilcarbamoil]-2-(4-etoxi-fenil)etil]-isonicotinamida
179
[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 3-acetilamino-tiofeno-2-carboxílico
180
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-(2-fluoro-fenil)-etilcarbamoil]-2-(4-etoxi-fenil)etil]-benzamida
181
[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-piridin-3-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 3-metil-tiofeno-2-carboxílico
182
N-[(R)-1-[(S)-1-(4-aminometil-3-metil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]benzamida
183
[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-tiazol-4-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 3-amino-tiofeno-2-carboxílico
184
[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-tiazol-4-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 3-cloro-tiofeno-2-carboxílico
185
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-tiazol-4-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-4metil-benzamida
186
[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-benzo[b]tiofen-3-il-etilcarbamoil]-2-(4-etoxi-fenil)etil]-amida del ácido 3-metil-1H-pirrol-2-carboxílico
187
[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-tiazol-4-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 3-amino-tiofeno-2-carboxílico
188
[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-benzo[b]tiofen-3-il-etilcarbamoil]-2-(4-etoxi-fenil)etil]-amida del ácido 3-acetilamino-tiofeno-2-carboxílico
189
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-piridin-3-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-3metil-benzamida
190
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-piridin-3-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-2metil-benzamida
191
[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 3,5-dimetil-1H-pirrol-2-carboxílico
192
N-[(R)-1-[(S)-1-(4-aminometil-3-metil-bencilcarbamoil)-2-piridin-3-il-etilcarbamoil]-2-(4-etoxi-fenil)etil]-benzamida
193
[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-tiofen-3-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-amida del ácido 3-acetilamino-tiofeno-2-carboxílico
194
[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-benzo[b]tiofen-3-il-etilcarbamoil]-2-(4-etoxi-fenil)etil]-amida del ácido 3-amino-tiofeno-2-carboxílico
195
[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-benzo[b]tiofen-3-il-etilcarbamoil]-2-(4-etoxi-fenil)etil]-amida del ácido3-acetilamino-tiofeno-2-carboxílico
196
[(R)-1-{[(S)-1-(4-aminometil-bencilcarbamoil)-2-fenil-etil]-metil-carbamoil]-2-(4-etoxi-fenil)-etil]amida del ácido3-cloro-tiofeno-2-carboxílico
197
N-[(R)-1-[(1S,2R)-1-(4-aminometil-bencilcarbamoil)-2-hidroxi-2-fenil-etilcarbamoil]-2-(4-etoxifenil)-etil]-benzamida
198
[(R)-1-[(1S,2R)-1-(4-aminometil-bencilcarbamoil)-2-hidroxi-2-fenil-etilcarbamoil]-2-(4-etoxi-fenil)etil]-amida del ácido 3-cloro-tiofeno-2-carboxílico
imagen48
15
25
35
45
55
6
CD3OD δ1,42 (3H, t, J=7,0Hz), 2,80-2,89 (2H, m), 2,95-3,00 (1H, m), 3,08-3,13 (1H, m), 4,03-4,13 (3H, m), 4,21 (2H, s), 4,32-4,38 (1H, m), 4,46-4,51 (1H, m), 4,65-4,69 (1H, m), 6,88 (2H, d, J=8,6Hz), 7,03 (2H, d, J= 8,6Hz), 7,05-7,09 (2H, m), 7,267,37 (5H, m), 7,41-7,47 (1H, m), 8,78-8,80 (1H, m).
7
CD3OD δ 1,02 (3H, t, J=7,7Hz), 1,42 (3H, t, J=7,0Hz), 2,13-2,21 (2H, m), 2,71-2,77 (1H, m), 2,81-2,92 (3H, m), 3,12-3,16 (1H, m), 4,05 (2H, q, J=6,9Hz), 4,13 (2H, s), 4,374,50 (3H, m), 4,57-4,69 (1H, m), 6,82 (2H, d, J=8,6Hz), 7,05 (2H, d, J= 8,6Hz), 7,17-7,27 (4H, m), 7,30-7,35 (3H, m), 7,46-7,49 (1H, m).
8
CD3OD δ 0,82-0,94 (2H, m), 1,19-1,28 (4H, m), 1,42-1,48 (2H, m), 1,64-1,71 (5H, m), 2,922,98 (1H, m), 3,23-3,28 (1H, m), 3,88 (1H, q, J=7,6Hz), 4,15 (2H, s), 4,39 (1H, d, J=15,3Hz), 4,52 (1H, d, J=15,3Hz), 4,76-4,79 (1H, m), 7,33-7,37 (7H, m), 7,44 (2H, d, J= 8,1Hz).
9
CD3OD δ 0,84-1,03 (4H, m), 1,13-1,23 (2H, m), 1,52-1,77 (7H, m), 2,93 (6H, s), 2,96-3,02 (1H, m), 3,20-3,30 (1H, m), 3,81 (1H, q, J=3,9Hz), 4,15 (2H, s), 4,47 (2H, q, J=15,4Hz), 4,76 (1H, dd, J=5,3, 10,5Hz), 7,29-7,40 (7H, m), 7,45 (2H, d, J= 8,2Hz).
10
CD3OD δ 0,84-0,92 (2H, m), 1,03 (3H, t, J=7,7Hz), 1,11-1,20 (4H, m), 1,35-1,39 (2H, m), 1,64-1,67 (5H, m), 2,15-2,26 (2H, m), 2,87-2,93 (1H, m), 3,39-3,42 (1H, m), 4,14 (2H, s), 4,21-4,26 (1H, m), 4,41-4,42 (1H, m), 4,44-4,57 (1H, m), 4,69-4,75 (1H, m), 7,27-7,44 (9H, m), 8,08(1H, d, J=5,8Hz), 8,49 (1H, d, J= 8,3Hz), 8,63-8,70 (1H, m).
11
CD3OD δ 0,85-0,95 (2H, m), 1,21-1,40 (6H, m), 1,70-1,79 (5H, m), 2,85 (3H, s), 2,95 (1H, dd, J=10,0, 14,0Hz), 3,29 (1H, dd, J=5,5, 14,0Hz), 3,98 (1H, dd, J= 5,6, 8,8Hz), 4,14 (2H, s), 4,43 (2H, s), 4,71 (1H, dd, J=5,4, 10,0Hz), 7,27-7,35 (7H, m), 7,42 (2H, d, J= 8,1Hz).
12
CD3OD δ 1,04 (3H, t, J=7,5Hz), 1,40 (3H, t, J=7,0Hz), 2,15-2,23 (2H, m), 2,74-2,90 (3H, m), 2,97-3,21(2H, m), 3,98-4,13 (2H, m), 4,14 (2H, s), 4,35-4,58 (3H, m), 4,61-4,68 (1H, m), 6,82 (2H, d, J=8,6Hz), 7,04-7,08 (1H, m), 7,12-7,42 (9H, m), 7,55 (1H, d, J= 1,6Hz).
13
CD3OD δ 1,42 (3H, t, J=7,0Hz), 2,61-2,66 (1H, m), 2,83-2,88 (1H, m), 3,00 (6H, s), 3,023,08 (1H, m), 3,29 (1H, dd, J= 12,9, 4,9Hz), 3,98-4,06 (3H, m), 4,14 (2H, s), 4,194,21 (1H, m), 4,33-4,45 (2H, m), 6,87 (2H, d, J=8,6Hz), 6,89-7,05 (2H, m), 7,12 (2H, d, J= 8,6Hz), 7,22-7,27 (5H, m), 7,40 (2H, d, J= 8,2Hz), 8,61-8,64 (1H, m).
14
CD3OD δ 1,42 (3H, t, J=7,0Hz), 2,82-2,92 (2H, m), 3,03-3,09 (2H, m), 4,04-4,13 (3H, m), 4,15 (2H, s), 4,30-4,35 (1H, m), 4,48-4,53 (1H, m), 4,65-4,69 (1H, m), 6,87-6,91 (2H, m), 7,02-7,06 (2H, m), 7,15 (1H, dd, J=8,3, 2,0Hz), 7,29 (2H, d, J= 8,1Hz), 7,43-7,46 (4H, m), 8,74 (1H, t, J= 5,8Hz).
15
CD3OD δ 1,42 (3H, t, J=7,0Hz), 2,54-2,60 (1H, m), 2,67-2,72 (1H, m), 2,78-2,83 (1H, m), 3,06-3,11 (1H, m), 3,91-3,95 (1H, m), 3,98-4,04 (2H, m), 4,14 (2H, s), 4,36-4,49 (2H, m), 4,54-4,58 (1H, m), 6,69-6,72 (2H, m), 6,91 (2H, d, J= 8,6Hz), 7,19-7,21 (2H, m), 7,24-7,32 (5H, m), 7,41-7,45 (4H, m), 7,55-7,59 (1H, m), 7,64-7,66 (2H, m).
16
CD3OD δ 1,03 (3H, t, J=7,6Hz), 1,42 (3H, t, J=7,0Hz), 2,14-2,24 (2H, m), 2,75-2,94 (3H, m), 3,07-3,12 (1H, m), 4,04 (2H, q, J=7,0Hz), 4,14 (2H, s), 4,36-4,51 (3H, m), 4,614,65 (1H, m), 6,81-6,84 (2H, m), 7,03-7,09 (3H, m), 7,33 (2H, d, J= 8,1Hz), 7,387,43 (4H, m).
17
CD3OD δ 1,17 (3H, t, J=7,0Hz), 2,49-2,54 (1H, m), 2,74-2,83 (3H, m), 3,32 (2H, s), 3,81 (2H, q, J=7,0Hz), 3,88 (2H, s), 3,90-3,94 (1H, m), 4,08-4,21 (2H, m), 4,30-4,34 (1H, m), 6,60-6,65 (2H, m), 6,77-6,82 (2H, m), 6,94-6,96 (2H, m), 7,01-7,11 (5H, m), 7,17 (2H, d, J= 8,2Hz), 8,43 (1H, t, J= 6,0Hz).
18
CD3OD δ 2,82-2,88 (1H, m), 3,02-3,09 (2H, m), 3,20-3,26 (1H, m), 4,15 (2H, s), 4,21-4,34 (2H, m), 4,49-4,54 (1H, m), 4,68-4,72 (1H, m), 7,19 (1H, dd, J=8,2, 2,0Hz), 7,29 (2H, d, J=8,1Hz), 7,34 (2H, d, J=8,0Hz), 7,43-7,48 (4H, m), 7,68 (2H, d, J=8,2Hz), 8,76 (1H, t, J=5,8Hz).
19
CD3OD δ 1,02 (3H, t, J=7,6Hz), 2,19 (2H, q, J=7,6Hz), 2,86-2,94 (2H, m), 3,06-3,16 (2H, m), 4,14 (2H, s), 4,37-4,50 (2H, m), 4,61-4,70 (2H, m), 7,13 (1H, dd, J= 8,3, 2,0Hz), 7,32-7,37 (4H, m), 7,42-7,45 (4H, m), 7,60 (2H, d, J=8,2Hz).
20
CD3OD δ 0,82-0,99 (2H, m), 1,15-1,30 (4H, m), 1,44-1,54 (2H, m), 1,62-1,73 (5H, m), 2,912,97 (1H, m), 3,22-3,27 (1H, m), 3,90 (1H, t, J=7,1Hz), 4,16 (2H, s), 4,38-4,55 (2H, m), 4,77-4,81 (1H, m), 7,26 (1H, dd, J=8,2, 2,0Hz), 7,37 (2H, d, J=8,1Hz), 7,437,52 (4H, m).
21
CD3OD δ 0,85-0,94 (2H, m), 1,02-1,22 (7H, m), 1,34-1,42 (2H, m), 1,62-1,69 (5H, m), 2,162,27 (2H, m), 2,85-2,92 (1H, m), 3,39-3,44 (1H, m), 4,14 (2H, s), 4,18-4,24 (1H, m), 4,40-4,45 (1H, m), 4,53-4,58 (1H, m), 4,73-4,79 (1H, m), 7,24 (1H, dd, J=8,2, 2,0Hz), 7,38-7,51 (6H, m), 8,11 (1H, d, J=5,6Hz), 8,59 (1H, d, J=8,5Hz), 8,69 (1H, t, J=6,0Hz).
15
25
35
45
55
22
CD3OD δ 1,30 (3H, d, J=7,1 Hz), 2,92-2,98 (1 H, m), 3,40 (1H, d, J=4,9Hz), 4,09 (2H, s), 4,41-4,48 (2H, m), 4,54-4,60 (1H, m), 4,68-4,74 (1H, m), 7,24-7,34 (5H, m), 7,38 (4H, s), 7,43-7,49 (2H, m), 7,56-7,60 (1H, m), 7,80-7,82 (2H, m), 8,51 (1H, d, J=8,2Hz), 8,56 (1H, d, J=5,3Hz), 8,66 (1H, t, J=6,0Hz).
23
CD3OD δ 1,03 (3H, t, J=7,6Hz), 1,42 (3H, t, J=7,0Hz), 2,16-2,22 (2H, m), 2,73-2,93 (3H, m), 3,11-3,16 (1H, m), 4,05 (2H, q, J=6,9Hz),), 4,28 (2H, s), 4,37-4,48 (3H, m), 4,60-4,64 (1H, m), 6,82 (2H, d, J=8,6Hz), 7,05 (2H, d, J= 8,7Hz), 7,17 (2H, t, J=6,6Hz), 7,297,33 (4H, m), 7,46 (2H, dd, J=9,6,1,4Hz).
24
CD3OD δ 1,08 (3H, t, J=7,7Hz), 1,38-1,42 (3H, m), 2,18-2,25 (2H, m), 2,71-3,07 (7H, m), 4,00-4,07 (2H, m), 4,14 (2H, s), 4,54-4,58 (2H, m), 4,62-4,66 (1H, m), 5,09-5,15 (1H, m), 6,83-6,88 (2H, m), 7,08-7,21 (4H, m), 7,26-7,38 (4H, m), 7,42 (2H, d, J= 8,1Hz), 8,29 (1H, d, J=7,8Hz), 8,35 (1H, d, J= 8,3Hz).
25
CD3OD δ 1,41 (3H, t, J= 7,0Hz), 2,56-2,68 (2H, m), 2,94-2,98 (1H, m), 3,01 (3H, s), 3,39-3,41 (1H, m), 4,05 (2H, q, J= 7,0Hz), 4,14 (2H, s), 4,33-4,38 (1H, m), 4,49-4,55 (2H, m), 5,52-5,56 (1H, m), 6,86-6,89 (2H, m), 7,02 (2H, d, J= 8,6Hz), 7,28-7,39 (7H, m), 7,43 (2H, d, J=8,1Hz), 8,53 (1H, t, J= 5,8Hz).
26
CD3OD δ 1,05 (3H, t, J= 7,6Hz), 1,39 (3H, t, J= 7,0Hz), 2,15-2,23 (2H, m), 2,51-2,63 (2H, m), 2,83-2,90 (1H, m), 2,96 (3H, s), 3,39-3,41 (1H, m), 4,01 (2H, q, J= 7,0Hz), 4,13 (2H, s), 4,38-4,50 (2H, m), 4,83-4,87 (1H, m), 5,47-5,51 (1H, m), 6,78-6,82 (2H, m), 7,01 (2H, d, J= 8,6Hz), 7,22-7,40 (7H, m), 7,43 (2H, d, J= 8,1 Hz), 8,19 (1H, d, J= 6,8Hz), 8,34 (1H, t, J= 6,0Hz).
27
CD3OD δ 1,42 (3H, t, J= 7,0Hz), 2,66 (3H, s), 2,78-2,90 (1H, m), 3,01-3,15 (3H, m), 4,02-4,10 (3H, m), 4,14 (2H, s), 4,34-4,47 (2H, m), 4,59-4,70 (1H, m), 6,83-6,88 (2H, m), 6,977,02 (2H, m), 7,20-7,22 (2H, m), 7,26-7,34 (5H, m), 7,42 (2H, d, J= 8,1Hz), 8,69 (1H, t, J= 5,8Hz).
28
CD3OD δ 0,81-0,83 (6H, m), 1,10-1,18 (1H, m), 1,48-1,55 (1H, m), 1,58-1,65 (1H, m), 2,922,98 (1H, m), 3,25-3,30 (1H, m), 3,75 (2H, s), 3,92-3,96 (1H, m), 4,15 (2H, s), 4,484,53 (2H, m), 4,75-4,79 (1H, m), 7,27-7,40 (7H, m), 7,46 (2H, d, J= 8,2Hz), 8,83 (1H, t, J= 5,9Hz).
29
CD3OD δ 0,70-1,03 (6H, m), 1,37-1,69 (7H, m), 2,81-2,87 (4H, m), 3,06-3,11 (1H, m), 3,723,96 (3H, m), 3,99 (2H, s), 4,26-4,37 (2H, m), 4,58-4,62 (1H, m), 7,13-7,24 (7H, m), 7,30 (2H, d, J= 8,1Hz), 8,72 (1H, t, J= 5,9Hz).
30
CD3OD δ 0,75-0,93 (3H, m), 1,20-1,31 (5H, m), 1,54-1,81 (5H, m), 3,02 (3H, s), 3,08-3,17 (1H, m), 3,43-3,48 (1H, m), 3,81 (2H, s), 4,15 (2H, s), 4,45-4,53 (3H, m), 5,65-5,71 (1H, m), 7,27-7,39 (5H, m), 7,41 (2H, d, J= 8,1Hz), 7,48 (2H, d, J= 8,2Hz), 8,67 (1H, t, J= 5,9Hz).
31
CD3OD δ 0,67-0,71 y 0,77-0,80 (3H, m), 1,19-1,24 (3H, m), 1,99-2,11 (2H, m), 2,65-2,83 (5H, m), 2,91-3,09 (2H, m), 3,81-3,88 (2H, m), 3,95 (2H, s), 4,17-4,32 (2H, m), 4,43-4,54 (1H, m), 4,77-4,82 (1H, m), 6,62-6,69 (2H, m), 6,90-6,94 (2H, m), 6,98-7,20 (7H, m), 7,21-7,26 (2H, m), 7,69 (1H, d, J= 7,9Hz), 8,26-8,29 y 8,40-8,43 (1H, m).
32
CD3OD δ 1,02-1,10 (3H, m), 1,40 (3H, t, J= 7,0Hz), 2,11-2,24 (2H, m), 2,51-2,63 (2H, m), 2,82-2,90 (1H, m), 2,95 (3H, s), 3,36-3,41 (1H, m), 3,98-4,03 (2H, m), 4,20 (2H, s), 4,38-4,51 (2H, m), 4,85 (1H, t, J= 7,3Hz), 5,46-5,50 (1H, m), 6,77-6,85 (2H, m), 7,007,08 (2H, m), 7,11-7,18 (2H, m), 7,21-7,36 (5H, m), 7,42-7,48 (1H, m), 8,43 (1H, t, J= 6,1Hz).
33
CD3OD δ 0,63-0,80 (2H, m), 0,87-1,08 (4H, m), 1,32-1,54 (7H, m), 2,50 (3H, s), 2,79-2,85 (1H, m), 3,08-3,13 (1H, m), 3,66-3,70 (1H, m), 3,99 (2H, s), 4,27-4,36 (2H, m), 4,594,65 (1H, m), 7,13-7,24 (7H, m), 7,30 (2H, d, J= 8,2Hz), 8,71 (1H, t, J= 5,9Hz), 8,80 (1H, d, J= 7,6Hz).
34
CD3OD δ 0,75-0,91 (3H, m), 1,20-1,33 (5H, m), 1,55 (1H, d, J= 12,3Hz), 1,62-1,71 (3H, m), 1,80 (1H, d, J= 12,5Hz), 3,02 (3H, s), 3,08-3,18 (1H, m), 3,45-3,50 (1H, m), 3,83-3,87 (2H, m), 4,23 (2H, s), 4,46-4,52 (3H, m), 5,66-5,72 (1H, m), 7,21-7,41 (7H, m), 7,52 (1H, t, J=7,8Hz), 8,77 (1H, t, J= 6,0Hz).
35
CD3OD δ 0,83 (3H, t, J= 7,4Hz), 1,24-1,30 (3H, m), 1,51-1,62 (2H, m), 2,64 (3H, s), 2,65-2,89 (5H, m), 3,09-3,14 (1H, m), 3,85-3,96 (2H, m), 3,98 (2H, s), 4,16-4,22 (1H, m), 4,284,37 (1H, m), 4,47-4,50 (1H, m), 5,29 (1H, t, J= 8,1Hz), 6,67-6,75 (2H, m), 6,87-6,90 (2H, m), 7,09 (2H, d, J= 8,2Hz), 7,15-7,29 (7H, m), 8,42 (1H, t, J= 6,0Hz).
36
CD3OD δ 1,15-1,30 (6H, m), 1,52-1,76 (7H, m), 2,89-3,02 (4H, m), 3,10-3,19 (1H, m), 3,733,80 (2H, m), 3,99-4,05 (1H, m), 4,12-4,14 (2H, m), 4,48-4,59 (1H, m), 4,71-4,80 (1H, m), 5,08-5,16 (1H, m), 7,19-7,49 (9H, m).
38
CD3OD δ 1,39 (3H, t, J= 7,0Hz), 2,66-2,71 (1H, m), 2,79-2,94 (2H, m), 3,01 (3H, s), 3,38-3,43 (1H, m), 3,97-4,03 (2H, m), 4,07-4,14 (2H, m), 4,40-4,50 (2H, m), 5,03-5,09 (1H, m), 5,52-5,56 (1H, m), 6,78-6,86 (2H, m), 7,05-7,18 (2H, m), 7,20-7,71 (12H, m), 7,737,81 (2H, m), 8,37 (1H, t, J= 6,0Hz), 8,58 (1H, d, J= 6,7Hz).
5
15
25
35
45
55
39
CD3OD δ 1,39 (3H, t, J= 7,0Hz), 1,93 (3H, s), 2,50-2,63 (2H, m), 2,81-2,90 (1H, m), 2,95 (3H, s), 3,34-3,41 (1H, m), 3,95-4,05 (2H, m), 4,13 (2H, s), 4,33-4,51 (2H, m), 4,824,89( 1H, m), 5,46-5,50 (1H, m), 6,78-6,85 (2H, m), 7,00-7,05 (2H, m), 7,09-7,36 (7H, m), 7,39-7,43 (2H, m), 8,29 (1H, t, J= 6,0Hz).
40
CD3OD δ 0,61-0,81 (2H, m), 0,88-1,05 (4H, m), 1,34-1,54 (7H, m), 2,51 (3H, s), 2,80-2,86 (1H, m), 3,08-3,13 (1H, m), 3,67-3,70 (1H, m), 4,07 (2H, s), 4,27-4,37 (2H, m), 4,59-4,63 (1H, m), 6,99-7,04 (2H, m), 7,13-7,24 (5H, m), 7,34 (1H, t, J= 7,9Hz), 8,73 (1H, t, J= 6,0Hz).
41
CD3OD δ 0,73-1,25 (6H, m), 1,50-1,69 (7H, m), 2,67 (3H, s), 2,94-3,00 (1H, m), 3,24-3,29 (1H, m), 3,81-3,85 (1H, m), 4,23 (2H, s), 4,44-4,54 (2H, m), 4,76-4,80 (1H, m), 7,18-7,23 (2H, m), 7,31 (1H, dd, J= 8,3, 2,0 Hz), 7,45-7,56 (3H, m), 8,91 (1H, t, J= 5,9Hz), 8,97 (1H, d, J= 7,7Hz).
42
CD3OD δ 0,83-1,19 (6H, m), 1,53-1,85 (7H, m), 2,94-3,08 (4H, m), 3,21-3,26 (1H, m), 3,874,08 (3H, m), 4,22 (2H, s), 4,38-4,55 (2H, m), 4,72-4,76 (1H, m), 7,18-7,22 (2H, m), 7,28-7,39 (5H, m), 7,47-7,51 (1H, m), 8,93 (1H, t, J= 6,0Hz), 9,05 (1H, d, J= 7,2Hz).
43
CD3OD δ 0,78-0,97 (4H, m), 1,03-1,20 (2H, m), 1,47-1,50 (1H, m), 1,54-1,63 (5H, m), 1,751,82 (1H, m), 2,92-2,95 (1H, m), 2,98 (3H, s), 3,19-3,24 (1H, m), 3,98-4,13 (3H, m), 4,19 (2H, s), 4,38-4,52 (2H, m), 4,70-4,74 (1H, m), 7,17-7,20 (2H, m), 7,27 (1H, dd, J= 8,3, 2,0 Hz), 7,37-7,52 (3H, m), 8,92 (1H, t, J= 5,9Hz), 9,08 (1H, d, J= 7,3Hz).
44
CD3OD δ 1,01-1,05 (6H, m), 1,40 (3H, t, J=7,0Hz), 2,36-2,62 (3H, m), 2,85-2,91 (1H, m), 2,96 (3H, s), 3,37-3,42 (1H, ,m), 3,98-4,04 (2H, m), 4,13 (2H, s), 4,39-4,50 (2H, m), 4,82-4,86 (1H, ,m), 5,48-5,52 (1H, m), 6,77-6,85 (2H, m), 6,99-7,04 (2H, m), 7,227,36 (7H, m), 7,39-7,44 (2H, m), 8,37 (1H, t, J= 6,0Hz).
45
CD3OD δ 0,71-1,03 (9H, m), 1,36-1,63 (9H, m), 2,75 (3H, s), 2,81-3,11 (4H, m), 3,71-3,74 (1H, m), 4,00 (2H, s), 4,31-4,33 (2H, m), 4,59-4,63 (1H, m), 7,14-7,24 (7H, m), 7,30 (2H, d, J=8,2Hz), 8,71 (1H, t, J= 5,8Hz).
46
CD3OD δ 0,78-0,97 (2H, m), 1,09-1,25 (4H, m), 1,54-1,69 (7H, m), 2,93-2,99 (1H, m), 3,243,29 (1H, m), 3,87 (3H, s), 3,94 (2H, d, J= 2,5Hz), 3,99-4,04 (1H, m), 4,15 (2H, s), 4,43-4,53 (2H, m), 4,73-4,77 (1H, m), 7,25-7,38 (7H, m), 7,46 (2H, d, J= 8,1Hz), 8,83 (1H, t, J= 5,9Hz).
47
CD3OD δ 0,72-1,14 (6H, m), 1,40-1,73 (7H, m), 2,85-2,91 (4H, m), 3,11-3,16 (1H, m), 3,77 (3H, s), 3,93-3,96 (1H, m), 4,04 (2H, s), 4,07-4,18 (2H, m), 4,36 (2H, s), 4,63-4,67 (1H, m), 7,17-7,27 (7H, m), 7,35 (2H, d, J= 8,1Hz), 8,73 (1H, t, J= 5,9Hz), 8,92 (1H, d, J=7,3Hz).
48
CD3OD δ 0,87-1,17 (6H, m), 1,54-1,79 (7H, m), 2,89 (3H, s), 2,95-3,02 (1H, m), 3,21-3,27 (1H, m), 3,79-3,99 (3H, m), 4,15 (2H, s), 4,47 (2H, s), 4,74-4,78 (1H, m), 7,29-7,39 (7H, m), 7,46 (2H, d, J= 8,1Hz), 8,84 (1H, t, J= 5,8Hz).
49
CD3OD δ 0,75-1,08 (6H, m), 1,41-1,76 (7H, m), 2,85-2,91 (4H, m), 3,11-3,36 (3H, m), 3,783,90 (3H, m), 4,04 (2H, s), 4,31-4,41 (2H, m), 4,63-4,67 (1H, m), 7,18-7,29 (7H, m), 7,35 (2H, d, J= 8,2Hz), 8,76(1H, t, J= 5,9Hz).
52
CD3OD δ, 0,74-0,88 (4H 0,78-2,10 (23H, m), 2,92-3,08 (1H, m), 3,12-3,30 (1H, m), 4,07 (1H, d, 4,2Hz), 4,15 (2H, s), 4,42 (1H, dd, J=15,3, 5,5Hz), 4,52 (1H, dd, J=15,3, 6,0Hz), 4,66 (1H, dd, J=10,2, 5,2Hz), 7,20-7,48 (9H, m), 8,87 (1H, t, J=6,0Hz).
53
CD3OD δ 0,83-1,19 (12H, m), 1,50 (1H, d, J=12,2 Hz), 1,60-1,79 (10H, m), 2,98 (1H, dd, J=10,6, 14,2 Hz), 3,14-3,28 (5H, m), 3,91 (1H, dd, J=3,4, 11,7 Hz), 4,15 (2H, s), 4,47-4,49 (2H, m), 4,77 (1H, dd, J=5,2, 10,5 Hz), H, s7,36-7,41(6H (7H, m), 7,45 (2H, d, J=8,1 Hz), 8,89-8,92 (1H, m).
54
CD3OD δ 1,44 (3H, t, J= 7,0 Hz), 2,81-2,87 (1H, m), 2,95-3,02 (2H, m), 3,19-3,24 (1H, m), 4,03-4,09 (4H, m), 4,46 (2H, d, J = 6,0 Hz), 4,84-4,89 (1H, m), 6,88 (2H, d, J = 8,5 Hz), 7,04 (2H, d, J = 8,5 Hz), 7,17-7,51 (13H, m), 7,85 (1H, d, J= 8,5 Hz), 7,93 (1H, d, J= 8,5 Hz), 7,90 y 8,00 (1H total, cada uno dd, J= cada uno 7,2 Hz), 8,43 (1H, d, J= 8,1 Hz), 8,63 (1H, t, J= 5,9 Hz), 8,75 (1H, t, J= 7,0 Hz).
55
CD3OD δ 1,25 (3H, t, J= 7,0 Hz), 2,77-2,83 (H3H, m), 2,96-3,02 (1H, m), 3,85-3,97 (4H, m), 4,22-4,26 (1H, m), 4,27-4,39 (1H, m), 4,48-4,54 (2H, m), 6,66-6,68 (2H, m), 6,94 (2H, d, J = 8,6 Hz), 7,01-7,03 (2H, m), 7,11-7,29 (9H, m), 7,31 (1H, d, J= 1,8 Hz), 7,53 (1H,d, J=8,6 Hz), 8,22 (1H, d, J= 8,0 Hz), 8,36-8,44 (2H, m).
56
CD3OD δ 1,25 (3H, t, J= 7,0 Hz), 2,75-2,83 (4H, m), 2,87-2,99 (1H, m), 3,85-3,89 (2H, m), 3,97 (2H, s), 4,22-4,39 (2H, m), 4,53-4,57 (H1H, m), 6,67 (2H, d, J = 8,5 Hz), 6,95 (2H, d, J =8,5 Hz), 7,02-7,04 (2H, m), 7,11-7,22 (7H, m), 7,60 (2H, d, J= 8,3 Hz), 7,71 (2H, d, J= 8,2 Hz), 8,25 (1H, d, J= 8,0 Hz), 8,42 (1H, t, J= 5,8 Hz).
15
25
35
45
55
57
CD3OD δ 1,41 (3H, t, J= 7,0 Hz), 2,91-3,04 (4H, m), 3,15-3,20 (1H, m), 4,01-4,07 (4H, m), 4,40 (1H, d, J= 15,4 Hz), 4,53 (1H, d, J= 15,4 Hz), 4,67-4,71 (2H, m), 6,84 (2H, d, J = 8,7 Hz), 7,11 (2H, d, J = 8,6 Hz), 7,19-7,24 (2H, m), 7,27-7,37 (9H, m), 7,44-7,54 (2H, m), 7,70-7,73 (4H, m), 7,80-7,82 (1H, m).
58
CD3OD δ 1,42 (3H, t, J= 7,0 Hz), 2,80-2,98 (4H, m), 3,02-3,06 (1H, m), 4,05 (2H, d, J = 7,0 Hz), 4,12 (2H, s), 4,39-4,46 (2H, m), 4,68-4,76 (2H, m), 6,85 (2H, d, J = 8,6 Hz), 7,12 (2H, d, J = 8,6 Hz), 7,20-7,22 (2H, m), 7,26-7,32 (6H, m), 7,39-7,41 (3H, m), 7,54 (1H, d, J = 1,9 Hz), 8,54 (1H, t, J = 5,9 Hz).
59
CD3OD δ 1,25 (3H, t, J= 7,0 Hz), 2,77-2,81 (4H, m), 2,97-3,02 (1H, m), 3,87 (2H, q, J = 7,0 Hz), 3,93 (2H, s), 4,26-4,30 (1H, m), 4,35-4,40 (1H, m), 4,48-4,55 (2H, m), 6,68 (2H, d, J = 8,6 Hz), 6,94 (2H, d, J = 8,6 Hz), 7,01-7,03 (2H, m), 7,09-7,22 (8H, m), 7,42-7,45 (2H, m), 8,22 (1H, d, J= 8,1 Hz), 8,41 (1H, t, J= 5,8 Hz).
60
CD3OD δ 1,23 (3H, t, J= 7,0Hz), 2,81-2,87 (1H, m), 3,01-3,06 (1H, m), 3,85-3,91 (2H, m), 3,94 (2H, s), 3,96-4,04 (2H, m), 4,18-4,24 (1H, m), 4,53 (1H, d, J= 7,0Hz), 4,84 (1H, d, J=7,1Hz), 6,70-6,74 (2H, m), 6,88 (2H, d, J= 8,0Hz), 7,01-7,04 (2H, m), 7,13-7,23 (5H, m), 7,27-7,31 (2H, m).
61
CD3OD δ 1,43 (3H, t, J= 7,0Hz), 2,68-2,74 (1H, m), 2,98-3,03 (1H, m), 4,06 (2H, q, J= 7,0Hz), 4,14 (2H, s), 4,21-4,24 (1H, m), 4,42-4,50 (2H, m), 4,75 (1H, d, J= 4,4Hz), 5,28 (1H, d, J=4,4Hz), 6,85-6,89 (2H, m), 6,97-7,00 (2H, m), 7,30-7,35 (4H, m), 7,38-7,43 (3H, m), 7,5 (2H, d, J= 7,3Hz).
62
CD3OD δ 0,93 (3H, t, J= 7,7Hz), 1,25 (3H, t, J= 7,0Hz), 2,01-2,11 (2H, m), 2,60-2,66 (1H, m), 2,79-2,84 (1H, m), 3,86 (2H, q, J= 7,0Hz), 3,99 (2H, s), 4,22-4,32 (2H, m), 4,41-4,43 (1H, m), 4,46 (1H, d, J= 4,0Hz), 5,13 (1H, d, J= 4,0Hz), 6,64-6,67 (2H, m), 6,91-6,95 (2H, m), 7,14-7,33 (9H, m).
63
CD3OD δ 1,00 (3H, t, J= 7,6Hz), 1,43 (3H, t, J= 7,0Hz), 2,13-2,19 (2H, ,m), 2,61-2,66 (1H, m), 2,78-2,83 (1H, m), 4,04 (2H, q, J=7,0Hz), 4,14 (2H, s), 4,45-4,65 (4H, m), 5,37 (1H, d, J=3,0Hz), 6,77-6,81 (2H, m), 7,01 (2H, d, J= 8,6Hz), 7,28-7,45 (9H, ,m), 8,00 (1H, d, J=6,9Hz), 8,23 (1H, d, J= 8,4Hz), 8,51 (1H, t, J= 6,0Hz).
64
CD3OD δ 0,98 (3H, t, J= 7,2Hz), 1,06-1,13 (3H, m), 1,40 (3H, t, J= 7,0Hz), 2,19-2,24 (2H, m), 2,71-2,82 (2H, ,m), 2,98-3,05 (1H, m), 3,14-3,22 (1H, m), 3,29-3,35 (1H, ,m), 3,51-3,60 (1H, m), 3,98-4,04 (2H, m), 4,13 (2H, s), 4,35-4,48 (2H, m), 4,78-4,89 (1H, m), 5,125,21 (1H, m), 6,79-6,83 (2H, m), 7,07-7,16 (2H, m), 7,26-7,38 (7H, m), 7,41 (2H, d, J= 8,1Hz), 8,21 (1H, t, J= 6,1 Hz).
65
CD3OD δ 0,96-1,10 (6H, m), 1,33-1,44 (3H, m), 2,10-2,27 y 2,41-2,46 (3H total, m), 2,74-2,97 (2H, m), 3,12-3,23 (1H, m), 3,28-3,34 (1H, m), 3,41-3,50 (1H, m), 3,92-4,08 (2H, m), 4,12 (2H, s), 4,34-4,50 (2H, m), 4,60-4,64 y 4,78-4,82 (1H, m), 4,94-4,98 y 5,08-5,12(1H total, m), 6,80-6,89 (2H, m), 7,09-7,42 (11H, m), 8,11 (1H, t, J=6,0 Hz), 8,20 (1H, d, J=6,5 Hz), 8,45 (1H, d, J=7,2 Hz), 8,77 (1H, t, J=5,8 Hz).
66
CD3OD δ 0,82-0,86 y 0,96-1,00 (3H total, m), 1,38-1,43 (3H, m), 2,18-2,30 (2H, m), 2,63 (3H, s), 2,84-3,02 (2H, m), 3,11-3,28 (2H, m), 3,99-4,06 (2H, m), 4,15 (2H, s), 4,39-4,51 (2H, m), 4,64-4,79 (1H, m), 5,22-5,26 (1H, m), 6,81-6,87 (2H, m), 7,09-7,13 (2H, m), 7,22-7,37 (7H, m), 7,42-7,46 (2H, m), 7,76 (1H, d, J= 7,9Hz), 8,45-8,47 y 8,59-8,62 (1H total, m).
67
CD3OD δ 1,00 (3H, t, J=7,7Hz), 1,44 (3H, t, J=7,0Hz), 1,64-1,72 (1H, m), 2,08-2,31 (3H, m), 2,98-3,09 (2H, m), 3,30-3,36 (1H, m), 3,39-3,44 (1H, m), 3,91-3,97 (1H, m), 4,03-4,07 (2H, m), 4,14 (2H, s), 4,10-4,16 (1H, m), 4,31-4,34 (1H, m), 4,37 (1H, d, J=4,9Hz), 4,51-4,57 (1H, m), 4,82-4,86 (1H, m), H, s6,91-6,97 (4H, m), 7,25-7,36 (7H, m), 7,42 (2H, d, J=8,2Hz), 8,35-8,50 (1H, m).
68
d6-DMSO δ: 1,29 (3H, t, J = 7,0Hz), 2,43 (1H, dd, J = 13,7, 8,0Hz), 2,63 (1H, dd, J = 13,8, 4,7Hz), 2,77 (1H, dd, J = 13,6, 10,4Hz), 3,06 (1H, dd, J = 13,7, 4,4Hz), 3,91-3,96 (4H, m), 4,07 (1H, dd, J = 15,4, 5,8Hz), 4,15 (1H, dd, J = 15,4, 6,0Hz), 4,23-4,26 (2H, m), 4,32-4,37 (1H, m), 4,44-4,50 (1H, m), 6,09 (1H, d, J = 7,7Hz), 6,58 (1H, t, J = 6,0Hz)), 6,67 (2H, d, J =8,7Hz), 6,76 (2H, d, J = 8,6Hz), 7,08-7,38 (11H, m), 7,45 (2H, d, J = 7,5Hz), 8,28 (3H, br s), 8,48 (1H, d, J = 8,5Hz), 8,62 (1H, t, J = 6,0Hz).
69
d6-DMSO δ: 1,28 (3H, t, J = 7,0Hz), 2,47-2,50 (1H, m), 2,67 (1H, dd, J = 13,9, 4,6Hz), 2,79 (1H, dd, J = 13,6, 10,5Hz), 3,07 (1H, dd, J = 13,7, 4,3Hz), 3,90-3,97 (4H, m), 4,23-4,33 (2H, m), 4,43-4,53 (2H, m), 6,24 (1H, d, J = 7,7Hz), 6,66 (2H, d, J = 8,7Hz), 6,72 (2H, d, J = 8,7Hz), 6,86 (1H, t, J = 7,4Hz), 7,13-7,32 (11H, m), 7,36 (2H, d, J = 8,1Hz), 8,23 (2H, br s), 8,58-8,63 (2H, m), 8,77 (1H, s),
70
d6-DMSO δ: 1,26 (3H, t, J = 7,0Hz), 2,66 (1H, dd, J = 13,5, 10,6Hz), 2,73 (1H, dd, J = 13,8, 4,0Hz), 2,82 (1H, dd, J = 13,5, 10,2Hz), 3,05 (1H, dd, J = 13,6, 4,9Hz), 3,89-4,01 (4H, m), 4,27 (1H, dd, J = 15,4, 5,8Hz), 4,34 (1H, dd, J = 15,4, 6,1Hz), 4,55-4,68 (2H, m), 6,75 (2H, d, J = 8,6Hz), 7,07-7,32 (8H, m), 7,39 (2H, d, J = 8,1Hz), 7,73 (1H, dd, J = 7,9, 5,2Hz), 8,13-8,59 (4H, m), 8,63 (2H, m), 8,81 (1H, dd, J = 5,1, 1,3Hz), 8,99-9,01 (2H, m).
71
d6-DMSO δ: 1,26 (3H, t, J = 6,9Hz), 2,64 (1H, dd, J = 13,5, 10,8Hz), 2,72 (1H, dd, J = 13,6, 3,8Hz), 2,82 (1H, dd, J = 13,5, 10,2Hz), 3,05 (1H, dd, J = 13,6, 4,7Hz), 3,80-4,01 (4H, m), 4,27 (1H, dd, J = 15,4, 5,8Hz), 4,34 (1H, dd, J = 15,4, 6,0Hz), 4,58-4,68 (2H, m), 6,75 (2H, d, J = 8,6Hz), 7,14 (2H, d, J = 8,7Hz), 7,17-7,27 (6H, m), 7,38 (2H, d, J = 8,1Hz), 7,85 (2H, d, J = 5,9Hz), 8,14-8,50 (3H, m), 8,64 (1H, d, J = 6,2Hz), 8,67 (1H, d, J = 8,6Hz), 8,80 (2H, d, J = 6,0Hz), 9,03 (1H, d, J = 8,3Hz).
72
d6-DMSO δ: 1,26 (3H, t, J = 7,0Hz), 2,62-2,64 (2H, m), 2,81 (1H, dd, J = 13,6, 10,0Hz), 3,03 (1H, dd, J = 13,4, 4,5Hz), 3,92 (2H, q, J = 7,0Hz), 3,96 (2H, s), 4,25-4,35 (2H, m), 4,54-4,61 (2H, m), 6,74 (2H, d, J = 8,6Hz), 7,13 (2H, d, J = 8,7Hz), 7,16-7,25 (7H, m), 7,35 (2H, d, J = 8,1Hz), 7,43 (1H, dd, J = 5,0, 1,3Hz), 7,53 (1H, dd, J = 5,0, 3,0Hz), 8,11 (1H, dd, J =2,8, 1,0), 8,20 (2H, br s), 8,33 (1H, d, J = 8,2Hz), 8,54 (1H, d, J = 8,7Hz), 8,60 (1H, t, J =6,0Hz).
73
d6-DMSO δ: 1,26 (3H, t, J = 7,0Hz), 2,48-2,68 (2H, m), 2,81 (1H, dd, J = 13,6, 10,1Hz), 3,03 (1H, dd, J = 13,6, 4,7Hz), 3,89-3,96 (4H, m), 4,24-4,34 (2H, m), 4,53-4,62 (2H, m), 6,74 (2H, d, J = 8,6Hz), 7,10-7,27 (9H, m), 7,37 (2H, d, J = 8,1Hz)), 7,71 (1H, dd, J = 4,9, 0,9Hz), 7,82 (1H, dd, J = 3,6, 2,8Hz),8,20 (3H, br s), 8,56 (2H, dd, J = 10,5, 9,1Hz), 8,62 (1H, t, J = 6,0Hz).
74
d6-DMSO δ: 0,48-0,57(4H,m), 1,29(3H,t,J= 7,0Hz), 1,56-1,62(1H,m), 2,43-2,49(1H,m), 2,542,59(1H,m), 2,73-2,79(1H,m), 3,00-3,05(1H,m), 3,92-3,97(4H,m), 4,20-4,33(2H,m), 4,38-4,43(1H,m), 4,47-4,53(1H,m), 6,73(2H,d,J= 8,6Hz), 6,98(2H,d,J= 8,6Hz), 7,16-7,26(7H,m), 7,38(2H,d,J= 8,1Hz), 8,23(1H,d,J= 7,7Hz), 8,28(2H,s), 8,48(1H,d,J=8,6Hz), 8,54(1H,t,J =6,0Hz).
75
d6-DMSO δ: 0,96-1,15(5H,m), 1,20(3H,t,J= 7,0Hz), 1,36-1,55(5H,m), 1,96-2,01(1H,m), 2,342,41(1H,m), 2,51-2,56(1H,m), 2,67-2,73(1H,m), 2,92-2,97(1H,m), 3,86(2H,q,J=7,0Hz), 3,90(2H,s), 4,15-4,24(2H,m), 4,27-4,32(1H,m), 4,414,47(1H,m), 6,64(2H,d,J=8,6Hz), 6,88(2H,d,J= 8,6Hz), 7,08-7,18(7H,m), 7,30(2H,d,J= 8,1Hz), 7,66(1H,d,J= 8,0Hz), 8,17(2H,s), 8,29(1H,d,J= 8,5Hz), 8,51(1H,t,J =6,0Hz).
76
d6-DMSO δ: 0,78(3H,t,J= 7,3Hz), 0,99-1,05(2H,m), 1,12-1,21(2H,m), 1,26-1,36(5H,m), 1,912,03(2H,m), 2,38-2,44(1H,m), 2,56-2,61(1H,m), 2,74-2,80(1H,m), 2,99-3,04(1H,m), 3,93(2H,q,J= 7,0Hz), 3,97(2H,s), 4,23-4,33(2H,m), 4,39-4,44(1H,m), 4,504,56(1H,m), 6,72(2H,d,J= 8,6Hz), 6,98(2H,d,J= 8,6Hz), 7,15-7,26(7H,m), 7,38(2H,d,J= 8,1Hz), 7,88(1H,d,J= 8,0Hz), 8,22(2H,s), 8,42(1H,d,J= 8,6Hz), 8,58(1H,t,J =6,0Hz).
77
d6-DMSO δ: 0,93 (3H, d, J = 4,2Hz), 0,95 (3H, d, J = 4,1Hz), 1,28 (3H, t, J = 7,0Hz), 2,41 (1H, dd, J = 13,7, 8,0Hz), 2,58 (1H, dd, J = 13,8, 4,7Hz), 2,77 (1H, dd, J = 13,6, 10,5Hz)), 3,06 (1H, dd, J = 13,7, 4,2Hz), 3,50-3,58 (1H, m), 3,70-4,01 (4H, m), 4,25-4,30 (3H, m), 4,41-4,47 (1H, m), 5,82 (1H, d, J = 7,6Hz), 5,99 (1H, d, J = 7,6Hz), 6,67 (2H, d, J = 8,6Hz), 6,76 (2H, d, J = 8,6Hz), 7,16-7,26 (7H, m), 7,39 (2H, d, J = 8,1 Hz), 8,37 (2H, br s), 8,46 (1H, d, J = 8,5Hz), 8,65 (1H, t, J = 6,0Hz).
78
d6-DMSO δ: 0,83 (3H, t, J = 7,0Hz), 1,16-1,30 (11H, m), 2,41 (1H, dd, J = 13,8, 8,0Hz), 2,59 (1H, dd, J = 13,6, 4,6Hz), 2,77 (1H, dd, J = 13,7, 10,5Hz), 2,83-2,90 (2H, m), 3,05 (1H, dd, J = 13,7, 4,2Hz), 3,93 (2H, q, J = 7,0Hz), 3,95 (2H, m), 4,26-4,32 (3H, m), 4,42-4,46 (1H, m), 5,91 (1H, d, J = 7,6Hz), 6,09 (1H, t, J = 5,6Hz), 6,67 (2H, d, J = 8,7Hz), 6,76 (2H, d, J = 8,6Hz), 7,16-7,26 (7H, m), 7,39 (2H, d, J = 8,1Hz), 8,35 (2H, br s), 8,45 (1H, d, J =8,5Hz), 8,65 (1H, t, J = 6,0Hz).
79
d6-DMSO δ: 1,34(3H,t,J= 7,0Hz), 2,65-2,79(2H,m), 2,85-2,91 (1H,m), 3,09-3,13(1H,m), 3,99(2H,q,J= 7,0Hz), 4,04(2H,s), 4,32-4,42(2H,m), 4,65-4,73(2H,m), 6,80(2H,d,J= 8,6Hz), 7,15(2H,d,J= 1,9Hz)), 7,16(1H,s), 7,22-7,34(7H,m), 7,44(2H,d,J= 8,1Hz), 8,29(2H,s), 8,68-8,72(2H,m), 8,77(1H,d,J= 1,8Hz), 8,96(1H,d,J = 8,6Hz).
80
d6-DMSO δ: 1,26(3H,t,J= 7,0Hz), 2,61-2,72(2H,m), 2,79-2,84(1H,m), 3,02-3,07(1H,m), 3,92(2H,q,J=7,0Hz), 3,96(2H,s), 4,25-4,37(2H,m), 4,56-4,63(2H,m), 6,75(2H,d,J= 8,6Hz), 7,14(2H,d,J=8,6Hz), 7,16-7,25(7H,m), 7,37(2H,d,J= 8,1Hz), 7,42(2H,d,J= 8,2Hz), 7,85-7,88(2H,m), 8,21(2H,s), 8,56-8,64(3H,m).
81
d6-DMSO δ: 1,25 (3H, t, J = 7,0Hz), 2,68 (1H, m), 2,78-2,85 (2H, m), 3,06 (1H, dd, J = 13,6, 4,4Hz), 3,86-4,01 (4H, m), 4,28 (2H, d, J = 6,0Hz), 4,50-4,56 (1H, m), 4,74-4,79 (1H, m), 6,59 (2H, d, J = 8,7Hz), 6,65 (2H, d, J = 8,8Hz), 7,17-7,38 (8H, m), 7,597,61 (1H, m), 7,96-7,99 (2H, m), 8,33 (3H, br s), 8,48 (1H, d, J = 8,2Hz), 8,61 (1H, dt, J = 4,7, 1,2Hz), 8,66 (1H, t, J = 6,0Hz), 8,71 (1H, d, J = 8,5Hz).
82
d6-DMSO δ: 1,27 (3H, t, J = 6,9Hz), 2,13 (3H, s), 2,57-2,69 (2H, m), 2,82 (1H, dd, J = 13,6, 10,0Hz), 3,05 (1H, dd, J = 13,6, 4,7Hz), 3,78 (3H, s), 3,91 (2H, q, J = 7,0Hz), 3,923,99 (2H, m), 4,25-4,36 (2H, m), 4,50-4,62 (2H, m), 6,63 (1H, s), 6,74 (2H, d, J = 8,6Hz), 7,11 (2H, d, J = 8,7Hz), 7,17-7,25 (7H, m), 7,37 (2H, d, J = 8,2Hz), 8,25 (2H, br s), 8,35 (1H, d, J =8,4Hz), 8,55 (1H, d, J = 8,6Hz), 8,60 (1H, t, J = 6,0Hz).
83
d6-DMSO δ: 1,25 (3H, t, J = 7,0Hz), 2,61-2,70 (2H, m), 2,82 (1H, dd, J = 13,5, 10,1Hz), 3,05 (1H, dd, J = 13,6, 4,7Hz), 3,91 (2H, q, J = 7,0Hz), 3,94 (2H, s), 4,25-4,35 (2H, m), 4,58-4,64 (2H, m), 6,75 (2H, d, J = 8,6Hz), 7,14-7,25 (9H, m), 7,38 (2H, d, J = 8,2Hz), 7,42-7,45 (2H, m), 7,93-7,99 (2H, m), 8,18 (1H, s), 8,27 (2H, br s), 8,63-8,67 (2H, m), 8,84 (1H, d, J =8,4Hz).
84
d6-DMSO δ: 1,31(3H,t,J= 7,0Hz), 2,21-2,27(1H,m), 2,35-2,39(1H,m), 2,67-2,72(1H,m), 2,902,95(1H,m), 3,94(2H,q,J= 7,0Hz), 3,99(3H,s), 4,22-4,27(1H,m), 4,38-4,44(1H,m), 4,49-4,55(1H,m), 6,63(2H,d,J= 8,6Hz), 6,93(2H,d,J= 8,6Hz), 7,13-7,25(7H,m), 7,317,34(2H,m), 7,38-7,42(4H,m), 8,10(1H,s), 8,20(2H,s), 8,48(1H,d,J= 8,8Hz), 8,56(1H,t,J = 6,0Hz).
85
d6-DMSO δ: 1,30 (3H, t, J= 6,96Hz), 2,38-2,42 (1H, m), 2,58-2,62 (1H, m), 2,73-2,79 (1H,m), 2,99-3,03 (1H,m), 3,91-3,95 (4H, m), 4,24-4,25 (2H, m), 4,41-4,46 (1H,m), 4,51-4,57 (1H,m), 6,67 (2H, d, J= 8,69Hz), 6,89 (2H, d, J= 8,64Hz), 7,07 (2H, d, J= 1,8Hz), 7,17-7,25 (10H,m), 7,37 (2H, t, J= 8,08Hz), 8,14 (1H, t, J= 8,12Hz), 8,26 (3H,s, br), 8,49 (1H, d, J =8,57Hz), 8,56-8,59 (1H, m).
86
d6-DMSO δ: 1,28 (3H, t, J= 6,92Hz), 2,26-2,35 (2H, m), 2,39-2,45 (1H, m), 2,49 (2H, s), 2,562,65 (2H,m), 2,74-2,80 (1H, m), 3,00-3,05 (1H, m), 3,93-3,96 (3H, m), 4,25-4,32 (2H, m), 4,41-4,46 (1H,m), 4,49-4,55 (1H, m), 6,70 (2H, d, J= 8,48Hz), 6,92 (2H, d, J= 8,48Hz), 7,08 (2H, d, J= 7,16Hz), 7,18-7,24 (10H, m), 7,38 (2H, t, J= 8,0Hz), 8,00 (1H, d, J= 8,00Hz), 8,28 (3H,s, br), 8,46 (1H, d, J = 8,48Hz), 8,57 (1H, t, J= 5,92Hz).
87
d6-DMSO δ: 1,28 (3H, t, J= 6,92Hz), 1,51-1,58 (2H, m), 1,73-1,86 (2H, m), 2,39-2,45 (2H, m), 2,49 (2H, s), 2,56-2,65 (2H, m), 2,95-3,03 (1H, m), 3,86-3,97 (4H, m), 4,29-4,34 (3H, m), 4,47-4,53 (1H, m), 6,66 (2H, d, J= 8,21Hz), 6,96 (2H, d, J= 8,17Hz), 7,17-7,34 (10H, m), 7,36-7,40 (2H, m), 8,02-8,11 (1H, m), 8,26 (3H,s, br), 8,34-8,56 (2H, m).
88
d6-DMSO δ: 1,33 (3H,t,J= 6,93Hz), 2,71-2,75 (2H, m), 2,86-2,92 (1H, m), 3,09-3,14 (1H,m), 3,98-4,03 (4H, m), 4,32-4,43 (2H, m), 4,63-4,69 (2H,m), 6,82 (2H, d, J= 8,52Hz), 7,21 (2H, d, J=8,68Hz), 7,27-7,31 (7H,m), 7,44 (2H, d, J = 8,07Hz), 7,51-7,54 (1H,m), 7,63-7,65 (1H,m), 7,77 (1H, d, J= 7,84Hz), 7,86 (1H, d, J= 1,68Hz), 8,35 (3H,s, br), 8,63-8,74 (3H, m).
89
d6-DMSO δ: 1,29 (3H, t, J= 6,88Hz), 2,52-2,58 (1H, m), 2,71-2,79 (1H, m), 2,81-2,84 (1H, m), 3,02-3,07 (1H,m), 3,95-3,98 (4H, m), 4,24-4,36 (2H, m), 4,58-4,63 (2H,m), 6,76 (2H, d, J=8,56Hz), 7,08 (2H, d, J= 8,56Hz), 7,14-7,25 (9H, m), 7,33-7,43 (4H,m), 8,285 (3H,s, br), 8,47 (2H, t, J= 7,84Hz), 8,62 (1H, t, J= 5,764Hz).
90
d6-DMSO δ: 1,26 (3H,t,J= 6,89Hz), 2,61-2,74 (2H, m), 2,79-2,85 (1H, m), 3,02-3,07 (1H, m), 3,91-3,96 (4H, m), 4,25-4,36 (2H, m), 4,58-4,67 (2H,m), 6,74 (2H, d, J= 8,56Hz), 7,15-7,24 (9H, m), 7,37 (2H, d, J= 8,12Hz), 7,68 (1H, t, J= 7,80Hz), 7,87 (1H, d, J= 7,89Hz), 8,03 (1H, d, J=7,89Hz), 8,09 (1H, s) 8,28 (3H,s, br), 8,48=8,65 (2H, m), 8,82 (1H, d, J= 8,28Hz).
91
d6-DMSO δ: 1,27 (3H, t, J= 6,88Hz), 1,55-1,61 (11H, m), 1,89 (2H, s), 2,49 (2H, s), 2,62-2,72 (2H, m), 2,79-2,84 (1H, m), 3,01-3,05 (1H,m), 3,91-3,96 (4H, m), 4,23-4,39 (3H, m), 4,49-4,54 (1H,m), 6,69 (2H, d, J= 8,36Hz), 6,88 (2H, d, J= 8,37Hz), 7,19-7,25 (8H, m), 7,39 (2H, d, J = 7,84Hz), 8,32-8,38 (3H,m), 8,65-8,68 (1H, m).
92
d6-DMSO δ: 1,26 (3H, t, J= 6,93Hz), 2,32 (3H, s), 2,67 (2H,d, J = 7,20Hz), 2,78-2,84 (1H,m), 3,02-3,07 (1H,m), 3,91-3,97 (4H, m), 4,27-4,36 (2H, m), 4,57-4,60 (2H,m), 6,73 (2H, d, J= 8,57Hz), 7,12 (2H, d, J= 8,57Hz), 7,21-7,24 (9H,m), 7,36 (2H, t, J= 8,08Hz), 7,65 (2H, t, J= 8,17Hz), 8,25 (3H,s, br), 8,37 (1H, d, J = 8,08Hz), 8,54 (1H, d, J= 8,60Hz), 8,59-8,62 (1H, m).
93
d6-DMSO δ: 1,33 (3H,t,J= 6,97Hz), 2,67-2,79 (2H,m), 2,86-2,91 (1H,m), 3,093-3,14 (1H, m), 3,98-4,04 (4H, m), 4,32-4,44 (2H, m), 4,63-4,70 (2H, m), 6,81 (2H, d, J= 8,57Hz), 7,21 (2H, d, J= 8,60Hz), 7,27-7,32 (8H,m), 7,44 (2H, t, J= 8,08Hz), 7,79 (2H, s), 8,06 (1H, s), 8,38 (3H,s, br), 8,63-8,70 (1H, m), 8,83 (1H, d, J= 8,28Hz).
94
d6-DMSO δ: 1,26 (3H, t, J= 6,93Hz), 2,61-2,71 (2H, m), 2,71-2,84 (1H, m), 3,02-3,06 (1H, m), 3,92-3,96 (4H, m), 4,25-4,35 (2H, m), 4,57-4,64 (2H, m), 6,75 (2H, d, J= 8,64Hz), 7,14 (2H, d, J= 8,56Hz), 7,21-7,25 (8H,m), 7,36 (2H, d, J = 8,08Hz), 7,76-7,79 (3H,m), 8,24 (3H,s, br), 8,59 (1H, t, J = 6,32Hz), 8,78 (1H, d, J= 8,24Hz).
95
d6-DMSO δ: 1,26 (3H, t, J= 6,97Hz), 2,65-2,69 (2H, m), 2,79-2,84 (1H, m), 3,03-3,07 (1H, m), 3,797 (3H, s), 3,91-3,95 (4H, m), 4,25-4,34 (2H, m), 4,53-4,59 (2H,m), 6,73 (2H, d, J= 8,57Hz), 6,95 (2H, d, J= 8,88Hz), 7,13 (2H, d, J= 8,64Hz), 7,18-7,24 (7H,m), 7,37 (2H, d, J= 8,12H), 7,74 (2H, t, J= 8,85Hz), 8,29 (3H,s, br), 8,34 (1H, d, J = 8,60Hz), 8,54 (1H, d, J= 8,60Hz), 8,61 (1H, t, J= 5,96Hz).
96
d6-DMSO δ: 1,27 (3H, t, J= 6,92Hz), 2,61-2,66 (2H, m), 2,76-2,82 (1H, m), 3,01-3,06 (1H, m), 3,90-3,95 (4H, m), 4,28-4,31 (2H, m), 4,52-4,62 (2H, m), 6,67-6,73 (3H, m), 6,97 (2H, d, J= 8,53Hz), 7,18-7,27 (10H, m), 7,35-7,41 (3H, m), 7,50 (2H, d, J= 6,73Hz), 8,21 (4H, d, J= 8,00Hz), 8,59 (2H, t, J = 7,24Hz).
97
d6-DMSO δ: 1,28 (3H, t, J= 6,88Hz), 2,40-2,46 (1H, m), 2,59-2,64 (1H, m), 2,73-2,79 (1H,m), 2,98-3,03 (1H,m), 3,43 (2H, s), 3,51-3,57 (1H,m), 3,67-3,73 (1H, m), 3,92-3,97 (4H, m), 4,24-4,33 (2H, m), 4,43-4,54 (2H,m), 6,68 (2H, d, J= 8,56Hz), 6,88 (2H, d, J= 8,57Hz), 7,20-7,26 (12H, m), 7,37 (2H, d, J = 8,08Hz), 7,96 (1H, d, J= 8,21Hz), 8,20-8,27 (4H, m), 8,47 (1H, d, J = 8,50Hz), 8,57 (1H, t, J= 5,97Hz).
98
d6-DMSO δ: 1,27 (3H, t, J= 6,93Hz), 2,47-2,49 (1H, m), 2,62-2,66 (1H, m), 2,76-2,82 (1H, m), 3,01-3,06 (1H, m), 3,72-3,77 (1H, m), 3,85-3,91 (3H, m), 3,94-3,98 (2H, m), 4,264,30 (2H, m), 4,44-4,54 (2H,m), 6,61 (2H, d, J= 8,64Hz), 6,83 (2H, d, J= 8,60Hz), 7,18 (2H, d, J=8,05Hz), 7,26-7,27 (5H,m), 7,36 (2H, d, J= 8,12Hz), 7,46 (2H, d, J= 7,68Hz), 7,51-7,55 (1H,m), 7,84 (2H, t, J= 7,126Hz), 7,92 (1H, d, J= 8,08Hz), 8,30 (3H,s, br), 8,50 (1H, d, J = 8,53Hz), 8,57 (1H, t, J= 5,93Hz), 8,73 (1H, t, J = 5,84),
99
d6-DMSO δ: 1,26 (3H, t, J= 6,93Hz), 2,65-2,67 (2H, m), 2,78-2,84 (1H, m), 3,03-3,07 (1H, m), 3,91-3,96 (4H, m), 4,25-4,36 (2H, m), 4,55-4,61 (2H, m), 6,74 (2H, d, J= 8,60Hz), 7,14 (2H, d, J= 8,64Hz), 7,21-7,28 (9H,m), 7,36 (2H, d, J = 8,12Hz), 7,80-7,83 (2H, m), 8,23 (3H,s, br), 8,53-8,583 (3H, m).
100
d6-DMSO δ: 1,36(3H,t,J= 7,0Hz), 2,50-2,56(1H,m), 2,59-2,63(1H,m), 2,82-2,88(1H,m), 3,023,07(1H,m), 3,79-3,85(1H,m), 3,97(2H,s), 4,03(2H,q,J= 7,0Hz), 4,16-4,21(2H,m), 4,32(2H,d,J= 5,8Hz), 4,63-4,69(1H,m), 6,87(2H,d,J= 8,6Hz), 7,15(2H,d,J= 8,6Hz), 7,20-7,35(14H,m), 7,47-7,57(1H,m), 7,73-7,81(2H,m), 8,61-8,66(2H,m).
101
d6-DMSO δ: 1,28 (3H, t, J= 6,92Hz), 2,36 (3H, s), 2,38-2,42 (1H, m), 2,56-2,60 (1H, m), 2,732,78 (1H, m), 2,98-3,03 (1H, m), 3,23-3,28 (1H, m), 3,92-3,98 (4H, m), 4,27-4,32 (2H, m), 4,41-4,46 (1H, m), 4,49-4,55 (1H, m), 6,66 (2H, d, J= 8,61 Hz), 6,79 (2H, d, J= 8,60Hz), 7,20 (2H, d, J= 6,21 Hz), 7,26-7,29 (6H,m), 7,32-7,40 (4H,m), 7,62 (2H, d, J= 8,28Hz), 7,80-7,88 (2H, m), 8,29 (3H,s, br), 8,52 (1H, d, J = 8,52Hz), 8,59-8,62 (1H, m).
102
d6-DMSO δ: 1,27(3H,t,J= 7,0Hz), 2,42-2,47(1H,m), 2,64-2,69(1H,m), 2,75-2,81(1H,m), 3,043,08(1H,m), 3,92(2H,q,J= 7,0Hz), 3,96(2H,s), 4,28(2H,d,J= 5,8Hz), 4,434,53(2H,m), 6,23(1H,d,J= 7,7Hz), 6,65(4H,s), 7,17-7,23(5H,m), 7,26-7,36(8H,m), 8,19(2H,s), 8,63-8,65(2H,m), 8,91(1H,s),
103
d6-DMSO δ: 1,26 (3H, t, J= 6,93Hz), 1,31-1,43 (7H, m), 2,68 (2H, d, J= 7,47Hz), 2,79-2,84 (1H, m), 3,02-3,07 (1H, m), 3,90-3,95 (2H, m), 4,06 (2H, d, J= 6,40Hz), 4,25-4,32 (2H, m), 4,56-4,63 (2H,m), 6,75 (2H, d, J= 8,52Hz), 7,13-7,22 (12H, m), 7,32-7,35 (1H, m), 7,40-7,43 (2H, m), 7,59-7,63 (1H, m), 7,74 (2H, d, J = 7,90Hz), 8,45-8,52 (3H, m).
104
d6-DMSO δ:1,26 (3H,t,J= 6,93Hz), 2,65-2,75 (2H, m + 3H, s), 2,82-2,86 (1H, m), 3,04-3,08 (1H,m), 3,91-3,96 (4H, m), 4,24-4,36 (2H, m), 4,57-4,69 (2H,m), 6,73 (2H, d, J= 8,52Hz), 7,14 (2H, d, J= 8,68Hz), 7,17-7,24 (6H,m), 7,39 (2H, d, J = 8,07Hz), 7,79 (1H, d, J= 7,84Hz), 8,44 (3H,s, br), 8,49-8,52 (1H, m), 8,65-8,69 (2H, m), 9,00 (1H, d, J= 1,68Hz), 9,14 (1H, d, J=1,68Hz).
105
d6-DMSO δ: 1,29 (3H,t,J= 6,93Hz), 2,42 (3H, s), 2,75-2,86 (3H, m), 3,05-3,09 (1H,m), 3,953,97 (4H, m), 4,25-4,37 (2H, m), 4,61-4,74 (2H,m), 6,78 (2H, d, J= 8,52Hz), 7,09 (2H, d, J= 8,68Hz), 7,21-7,27 (6H,m), 7,40 (2H, d, J = 8,07Hz), 7,76-7,80 (1H, m), 8,07-8,13 (1H, m), 8,42 (3H,s, br), 8,67-8,73 (3H, m), 8,94 (1H, d, J= 1,68Hz).
106
d6-DMSO δ: 1,13 (3H,t,J= 6,93Hz), 2,70-2,84 (3H, m), 3,01-3,06 (1H,m), 3,95-3,98 (4H, m), 4,24-4,36 (2H, m), 4,59-4,69 (2H,m), 6,76 (2H, d, J= 8,52Hz), 7,04 (2H, d, J= 8,68Hz), 7,16-7,26 (6H,m), 7,38 (2H, d, J = 8,07Hz), 7,61 (2H, s), 8,33 (3H,s, br), 8,58-8,60 (1H, m), 8,64-8,67 (1H, m), 8,78 (1H, d, J= 1,68Hz).
107
d6-DMSO δ: 1,24 (3H,t,J= 6,93Hz), 2,56-2,62 (1H, m), 2,69-2,73 (1H, m), 2,78-2,84 (1H, m), 3,02-3,07 (1H,m), 3,89-3,95 (4H, m), 4,24-4,37 (2H, m), 4,58-4,67 (2H,m), 6,75 (2H, d, J= 8,52Hz), 7,13 (2H, d, J= 8,68Hz), 7,16-7,25 (8H, m), 7,36 (2H, d, J = 8,07Hz), 8,26 (3H,s, br), 8,59-8,64 (1H, m), 8,65 (1H, d, J= 1,68Hz), 8,94 (1H, d, J= 1,68Hz).
108
d6-DMSO δ: 1,28 (3H,t,J= 6,93Hz), 2,69-2,82 (2H, m), 3,02-3,09 (2H,m), 3,92-3,98 (4H, m), 4,26-4,33 (2H, m), 4,59-4,62 (2H,m), 6,74 (2H, d, J= 8,52Hz), 6,98 (2H, d, J= 8,68Hz), 7,23-7,29 (7H, m), 7,37-7,40 (2H, m), 8,05 (1H,s, br), 8,23 (3H,s, br), 8,658,69 (1H, m), 8,85 (1H,d,J=1,68Hz).
109
d6-DMSO δ: 1,28 (3H,t,J= 6,93Hz), 2,36-2,40 (1H, m), 2,59-2,63 (1H, m), 2,73-2,79 (1H, m), 3,00-3,03 (1H, m), 3,19-3,27 (1H, m), 3,91-3,97 (4H, m), 4,28-4,36 (2H, m), 4,524,54 (2H,m), 6,68 (2H, d, J= 8,52Hz), 6,84 (2H, d, J= 8,68Hz), 7,19-7,24 (7H,m), 7,38 (2H, d, J = 8,07Hz), 8,35 (3H,s, br), 8,59-8,63 (2H, m).
110
d6-DMSO δ: 1,26 (3H, t, J= 6,93Hz), 2,47 (3H, s), 2,49-2,50 (1H, m), 2,59-2,63 (1H, m), 2,692,74 (1H, m), 3,02-3 ,07 (1H,m), 3,91-3,95 (4H, m), 4,28-4,37 (2H, m), 4,57-4,66 (2H,m), 4,79-4,80 (2H,m), 6,74 (2H, d, J= 8,52Hz), 7,14 (2H, d, J= 8,68Hz), 7,167,23 (6H, m), 7,38 (2H, d, J = 8,07Hz), 7,55 (2H, d, J= 7,84Hz), 8,40 (2H,s, br), 8,638,67 (1H, m), 8,91 (1H, d, J= 1,68Hz).
111
d6-DMSO δ: 1,27 (3H, t, J= 6,93Hz), 2,30 (3H, s), 2,59 (3H, s), 2,61-2,72 (2H, m), 2,79-2,84 (1H, m), 3,04-3,09 (1H,m), 3,91-3,96 (4H, m), 4,29-4,35 (2H, m), 4,50-4,60 (2H, m), 6,73 (2H, d, J= 8,52Hz), 7,03 (2H, d, J= 8,68Hz), 7,15-7,27 (7H, m), 7,39 (2H, d, J = 8,07Hz), 8,07 (1H, d, J= 7,84Hz), 8,42 (2H,s, br), 8,62-8,66 (2H, m).
112
d6-DMSO δ: 1,26 (3H, t, J= 6,93Hz), 2,66 (3H, s), 2,77-2,84 (3H, m), 3,03-3,08 (1H, m), 3,873,97 (4H, m), 4,28 (2H, d), 4,49-4,55 (1H, m), 4,70-4,75 (1H, m), 6,61 (2H, d, J= 8,52Hz), 6,67 (2H, d, J= 8,68Hz), 7,19-7,30 (7H, m), 7,38 (2H, d, J = 8,07Hz), 7,89 (1H, d, J= 7,84Hz), 8,06 (1H, s), 8,41 (2H,s, br), 8,65-8,70 (2H, m).
113
d6-DMSO δ: 1,27 (3H, t, J= 6,93Hz), 2,36 (3H, s), 2,45 (3H, s), 2,63-2,68 (1H, m), 2,75-2,84 (2H, m), 3,04-3,08 (1H,m), 3,88-3,96 (4H, m), 4,29 (2H, d), 4,48-4,54 (1H, m), 4,644,69 (1H, m), 6,62 (2H, d, J= 8,52Hz), 6,65 (2H, d, J= 8,68Hz), 7,17-7,24 (6H, m), 7,39 (2H, d, J =8,07Hz), 7,54 (1H, d, J= 7,84Hz), 8,40 (3H,s, br), 8,64-8,66 (2H, m).
114
d6-DMSO δ: 1,26 (3H, t, J= 7,07Hz), 2,09 (3H, s), 2,67-2,77 (2H, m), 2,78-2,88 (1H, m), 3,053,09 (1H, m), 3,92-3,97 (4H, m), 4,31-4,40 (2H, m), 4,59-4,63 (1H, m), 4,64-4,74 (1H, m), 6,77 (2H, d, J= 8,34Hz), 7,17-7,29 (10H, m), 7,39 (2H, d, J = 8,36Hz), 7,87 (1H, d, J= 8,55Hz), 8,26-8,36 (4H, m), 8,62 (1H, s), 8,68-8,71 (2H, m), 8,88-8,95 (1H, m).
115
d6-DMSO δ: 1,26 (3H, t, J= 6,36Hz), 2,66-2,87 (3H, m), 3,05-3,10 (1H,m), 3,92-3,97 (4H, m), 4,31-4,38 (2H, m), 4,38-4,40 (2H, m), 4,59-4,63 (1H,m), 4,69-4,75 (1H,m), 6,77 (2H, d, J=7,95Hz), 7,14 (2H, d, J= 7,95Hz), 7,16-7,23 (6H, m), 7,38 (2H, d, J = 7,82Hz), 7,55 (2H, d, J= 7,95Hz), 7,74 (1H, d, J= 11,13Hz), 8,40 (3H,s, br), 8,63-8,67 (1H, m), 8,91 (1H, d, J= 2,69Hz), 9,05 (1H, J = 8,68Hz), 9,20 (1H, d, J = 2,2Hz).
116
d6-DMSO δ: 1,28(3H, t, J= 6,57Hz), 2,61-2,67 (1H, m), 2,79-2,85 (2H, m), 3,08-3,12 (1H,m), 3,92-3,98 (4H, m), 4,31 (2H, d, J = 6,57Hz), 4,53-4,58 (1H,m), 4,67-4,71 (1H, m), 6,66 (2H, d, J=8,09Hz), 6,74 (2H, d, J= 8,23Hz), 7,14 (1H, d, J= 5,47Hz), 7,22-7,25 (2H, m), 7,30-7,35 (4H, m),7,39 (2H, d, J = 8,09Hz), 7,82 (1H, d, J= 7,66Hz), 7,86 (1H, d, J= 5,47Hz), 8,35 (3H,s, br), 8,69(1H, t, J = 6,57Hz), 8,76 (1H, d, J= 8,21 Hz).
117
d6-DMSO δ: 1,28 (3H, t, J = 7,0 Hz), 2,38 (3H, s), 2,62 (1H, d, J = 10,3 Hz), 2,70 (1H, dd, J = 14,3 Hz, 4,2 Hz), 2,82 (1H, dd, J = 13,5 Hz, 10,1 Hz), 3,07 (1H, dd, J = 13,6 Hz, 4,5 Hz), 3,95 (2H, q, J = 7,0 Hz), 3,98 (2H, d, J = 4,8 Hz), 4,26 -4,37 (2H, m), 4,52 -4,62 (2H, m), 6,75 (2H, d, J = 8,7 Hz), 7,07 (2H, d, J = 8,6 Hz), 7,18 -7,12 (1H, m), 7,23 7,28 (6H, m), 7,38 (2H, d, J = 8,1 Hz), 8,21 (1H, d, J = 8,3 Hz), 8,26 (2H, br,s), 8,62 (2H, d, J = 7,6 Hz), 9,01 (1H, s)
118
d6-DMSO δ: 1,27 (3H, t, J = 7,0 Hz), 2,64 -2,67 (2H, m), 2,81 (1H, dd, J = 13,5 Hz, 10,1 Hz), 3,04 (1H, dd, J = 13,5, 4,6 Hz), 3,93 (2H, q, J = 7,0 Hz), 3,97 (2H, d, J = 5,4 Hz), 4,30 (2H, dd, J = 5,5 Hz, 3,5 Hz), 4,54 -4,63 (2H, m), 6,60 (1H, dd, J = 3,5 Hz, 1,9 Hz), 6,7 (2H, d, J =8,6 Hz), 7,01 (2H, d, J = 8,6 Hz), 7,11 (1H, d, J = 3,5 Hz), 7,16 7,28 (7H, m), 7,38 (2H, d, J = 8,1 Hz), 7,81 (1H, d, J = 1,1 Hz), 8,18 (1H, d, J = 8,4 Hz), 8,28 (2H, br,s), 8,60 (1H, d, J = 8,6 Hz), 8,64 (1H, t, J = 6,0 Hz).
119
d6-DMSO δ: 1,28 (3H, t, J = 6,9 Hz), 2,22 (3H, s), 2,65 (1H, dd, J = 13,6 Hz, 9,3 Hz), 2,72 (1H, dd, J = 13,8 Hz, 4,2 Hz), 2,82 (1H, dd, J = 13,5 Hz, 10,2 Hz), 3,08 (1H, dd, J = 13,5 Hz, 4,5 Hz), 3,94 (2H, q, J = 7,0 Hz), 3,98 (2H, br,s), 4,31 (2H, d, J = 5,8 Hz), 4,52 4,59 (2H, m), 6,73 (2H, d, J = 8,6 Hz), 6,91 (1H, d, J = 5,0 Hz), 6,98 (2H, d, J = 8,6 Hz), 7,18 -7,21 (1H, m), 7,23 -7,30 (6H, m), 7,38 (2H, d, J = 7,9 Hz), 7,55 (1H, d, J = 5,0 Hz), 7,72 (1H, d, J = 7,8 Hz), 8,23 (2H, br,s), 8,62 (2H, d, J = 9,6 Hz).
120
d6-DMSO δ: 1,27(3H,t,J= 7,0Hz), 2,70-2,75(1H,m), 2,80-2,86(2H,m), 3,07-3,11(1H,m), 3,88(3H,s), 3,92(2H,q,J= 6,9Hz), 3,97(2H,q,J= 5,7Hz), 4,31(2H,d,J= 6,1Hz), 4,524,58(1H,m), 4,67-4,72(1H,m), 6,65(2H,d,J= 8,6Hz), 6,76(2H,d,J= 8,4Hz), 7,027,04(1H,m), 7,21-7,34(7H,m), 7,37(2H,d,J= 8,1Hz), 7,53-7,55(1H,m), 7,857,88(1H,m), 8,23(2H,s), 8,27(1H,d,J= 8,1Hz), 8,67(1H,t,J= 5,9Hz), 8,71(1H,d,J= 8,4Hz).
121
d6-DMSO δ: 1,28(3H,t,J= 6,9Hz), 2,66-2,75(2H,m), 2,80-2,86(1H,m), 3,03-3,08(1H,m), 3,87(3H,s), 3,91-4,00(4H,m), 4,30-4,38(2H,m), 4,59-4,68(2H,m), 6,77(2H,d,J= 8,6Hz), 7,16(1H,s), 7,18-7,21(2H,m), 7,23-7,27(6H,m), 7,38(2H,d,J= 8,2Hz), 7,70(1H,t,J= 4,2Hz), 8,24(2H,s), 8,44(1H,d,J= 2,9Hz), 8,51(1H,d,J= 1,6Hz), 8,628,64(2H,m), 8,79(1H,d,J=8,4Hz).
122
d6-DMSO δ: 1,29(3H,t,J= 7,0Hz), 2,56-2,62(1H,m), 2,73-2,84(2H,m), 3,07-3,11(1H,m), 3,89(3H,s), 3,94(2H,q,J= 7,0Hz), 3,98(2H,s), 4,30(2H,d,J= 6,0Hz), 4,494,55(1H,m), 4,65-4,70(1H,m), 6,67(4H,s), 7,11(1H,d,J= 5,4Hz), 7,20-7,25(3H,m), 7,29-7,35(4H,m), 7,37(2H,d,J= 8,1Hz), 7,47(1H,d,J= 7,4Hz), 7,72(1H,d,J= 5,5Hz), 8,18(2H,s), 8,63(1H,t,J=6,0Hz), 8,67(1H,d,J= 8,5Hz).
123
d6-DMSO δ: 1,28(3H,t,J= 7,0Hz), 2,58-2,70(2H,m), 2,79-2,85(1H,m), 3,03-3,08(1H,m), 3,87(3H,s), 3,93(2H,q,J= 7,0Hz), 3,99(2H,q,J= 5,5Hz), 4,26-4,38(2H,m), 4,594,65(2H,m), 6,76(2H,d,J= 8,6Hz), 7,08(1H,s), 7,15(2H,d,J= 8,3Hz), 7,187,27(8H,m), 7,36(2H,d,J=8,0Hz), 8,19(2H,s), 8,25(1H,d,J= 5,2Hz), 8,598,62(2H,m), 8,72(1H,d,J= 8,1Hz).
124
d6-DMSO δ: 1,28(3H, t, J= 6,84Hz), 2,13 (3H, s), 2,56-2,59 (1H, m), 2,69-2,74 (1H, m), 2,782,84 (1H, m), 3,05-3,10 (1H,m), 3,91-4,00 (4H, m), 4,30 (2H, d, J = 5,82Hz), 4,524,64 (2H,m), 5,91 (1H, s) 6,71 (2H, d, J= 8,66Hz), 6,77 (1H, t, J= 2,36Hz), 6,92 (2H, d, J= 7,78Hz), 7,18-7,28 (8H, m), 7,34 (2H, d, J = 8,49Hz), 8,09 (3H,s, br), 8,60-8,64(2H, m).
125
d6-DMSO δ: 1,28 (3H, t, J = 7,0 Hz), 2,67 -2,69 (2H, m), 2,82 (1H, dd, J = 13,5 Hz, 10,0 Hz), 3,05 (1H, dd, J = 13,6 Hz, 6,4 Hz), 3,93 (2H, q, J = 7,0 Hz), 3,97 (2H, d, J = 5,6 Hz), 4,31 (2H, d, J = 5,8 Hz), 4,47 -4,57 (2H, m), 6,57 (1H, d, J = 5,4 Hz), 6,71 (2H, d, J = 8,6 Hz), 6,97 (2H, d, J = 8,6 Hz), 7,18 -7,27 (10H m), 7,38 (2H, d, J = 6,0 Hz), 7,40 (1H, d, J = 3,1 Hz), 8,28 (2H, br,s), 8,51 (1H, d, J = 8,5 Hz), 8,61 (1H, t, J = 6,0 Hz).
126
d6-DMSO δ: 0,80-0,85(2H,m), 1,02-1,12(4H,m), 1,22-1,32(1H,m), 1,41-1,48(1H,m), 1,531,62(5H,m), 2,76-2,82(1H,m), 3,09-3,13(1H,m), 3,95(2H,s), 4,28-4,35(2H,m), 4,374,43(1H,m), 4,46-4,52(1H,m), 7,15-7,27(7H,m), 7,34-7,37(2H,m), 7,39-7,46(2H,m), 7,48-7,54(1H,m), 7,80-7,83(2H,m), 8,21(2H,s), 8,51(2H,d,J= 7,8Hz), 8,59(1H,t,J= 6,1 Hz).
127
d6-DMSO δ: 2,62-2,69 (2H, m), 2,71-2,77 (1H, m), 2,96-3,01(1H, m), 3,87 (2H, d, J= 4,56Hz), 4,22-4,25 (2H, m), 4,49-4,61 (2H,m), 7,10-7,22 (10H, m), 7,30-7,36 (4H, m), 7,407,48 (1H, m), 7,67 (2H, d, J = 6,61Hz), 8,30 (3H,s, br), 8,47 (1H, d, J= 8,82Hz), 8,56-8,62 (2H, m).
128
d6-DMSO δ: 2,70 (2H, d, J = 7,21Hz), 2,78-2,85 (1H, m), 3,03-3,07 (1H, m), 3,95 (2H, d, J= 8,78Hz), 4,27-4,36 (2H, m), 4,55-4,63 (2H,m), 6,84 (2H, d, J=8,52Hz), 7,05-7,29 (12H, m), 7,37-7,44 (6H, m), 7,74 (2H, d, J= 7,52Hz), 8,34 (3H,s, br), 8,50 (1H, d, J= 7,57Hz), 8,58 (1H, d, J=8,77Hz), 8,63-8,66 (2H, m).
129
d6-DMSO δ: 2,61-2,63 (2H, m), 2,70-2,77 (1H, m), 2,95-3,00 (1H, m), 3,88 (2H, d, J= 6,26Hz), 4,18-4,29 (2H, m), 4,47-4,54 (2H,m), 4,91 (1H, s), 6,76 (2H, d, J= 8,18Hz), 7,07-7,18 (9H, m), 7,26-7,36 (4H, m), 7,66-7,68 (2H, m), 8,24 (3H,s, br), 8,42 (1H, d, J= 8,17Hz), 8,50 (1H, d, J= 8,02Hz), 8,53-8,58 (1H, m).
130
d6-DMSO δ: 2,65 (2H, d, J = 5,97Hz), 2,79-2,85 (1H, m), 3,03-3,06 (1H, m), 3,95 (2H, s), 4,31 (2H, s), 4,55 (2H, s, br), 6,58 (2H, d, J= 7,55Hz), 7,01 (2H, d, J= 7,12Hz), 7,18-7,24 (10H, m), 7,37-7,50 (7H, m), 7,74 (2H, d, J= 7,10Hz), 8,32 (3H,s, br), 8,46 (1H, d, J= 9,60Hz), 8,53 (1H, d, J= 9,60Hz), 8,61 (1H, s),
131
d6-DMSO δ: 1,43 (3H, t, J= 6,97Hz), 2,88 (2H, d, J= 6,67Hz), 2,95-3,06 (2H, m), 3,14-3,23 (2H, m), 4,06-4,12 (2H, m), 4,39-4,49 (2H, m), 4,75-4,78 (2H, m), 6,91 (2H, d, J= 8,95Hz), 7,31 (2H, m), 7,37-7,46 (9H, m), 7,54-7,67 (5H, m), 7,89-7,98 (2H, m), 8,46 (2H, s, br), 8,65-8,81 (3H, m).
132
d6-DMSO δ: 2,68 (2H, d, J = 7,36Hz), 2,79-2,98 (1H, m), 3,03-3,06 (1H, m), 3,96 (2H, s), 4,21-4,32 (2H, m), 4,59-4,61 (2H,m), 5,00 (2H, s), 6,84 (2H, d, J= 8,15Hz), 7,147,24 (12H, m), 7,35-7,40 (5H, m), 7,67-7,76 (2H, m), 7,82-7,88 (2H, m), 8,24(1H,s, br), 8,47-8,64 (4H, m).
133
d6-DMSO δ: 0,81(3H,d,J= 6,3Hz), 0,87(3H,d,J= 6,3Hz), 1,27-1,39(2H,m), 1,45-1,52(1H,m), 2,81-2,87(1H,m), 3,20-3,24(1H,m), 4,02(2H,s), 4,35-4,44(3H,m), 4,52-4,58(1H,m), 7,22-7,35(7H,m), 7,43(2H,d,J= 8,1Hz), 7,48-7,52(2H,m), 7,58-7,64(1H,m), 7,877,89(2H,m), 8,30(2H,s), 8,59-8,69(3H,m).
134
d6-DMSO δ: 2,70 (2H, d, J = 7,36Hz), 2,78-2,84 (1H, m), 3,03-3,06 (1H, m), 3,97 (2H, s), 4,11-4,34 (2H, m), 4,59-4,63 (2H,m), 5:14 (2H, s), 6,90 (2H, d, J= 8,21Hz), 7,117,30 (11H, m), 7,36-7,54 (5H, m), 7,67-7,75 (2H, m), 7,80-7,88 (2H, m), 8,47-8,58 (4H, m).
135
d6-DMSO δ: 2,20 (3H, s), 2,71 (2H, d, J = 7,81Hz), 2,79-2,85 (1H, m), 3,03-3,07(1H,m), 3,933,96 (2H, m), 4,25-4,36 (2H, m), 4,55-4,65 (2H,m), 7,00 (2H, d, J= 9,01Hz), 7,12 (2H, d, J=7,78Hz), 7,18 (2H, d, J= 7,79Hz), 7,22-7,24 (4H, m), 7,38 (2H, d, J= 6,49Hz), 7,42 (2H, d, J= 7,79Hz), 7,48-7,50 (1H, m), 7,74-7,76 (2H,m), 8,33 (3H,s, br), 8,51 (1H, d, J= 7,79Hz), 8,58 (1H, d, J= 7,79Hz), 8,62-8,65 (1H, m).
136
d6-DMSO δ: 2,70 (2H, d, J = 7,28Hz), 2,74-2,85 (1H, m), 3,04-3,08 (1H, m), 3,95 (2H, s), 4,274,36 (2H, m), 4,58-4,62 (2H,m), 5,03 (2H, s), 6,85 (2H, d, J= 8,21Hz), 7,15-7,24 (11H, m), 7,37-7,52 (5H, m), 7,56-7,61 (1H, m), 7,75 (2H, d, J = 8,22Hz), 8,34 (3H, s, br), 8,50(1H, d, J= 7,02Hz), 8,58(1H, d, J= 9,38Hz), 8,62-8,65 (1H, m).
137
d6-DMSO δ: 2,66-2,69 (2H, m), 2,81 (1H, dd, J = 13,5, 10,0Hz), 3,05 (1H, dd, J = 13,6, 4,7Hz), 3,69 (2H, s), 3,77 (3H, s), 4,23-4,33 (2H, m), 4,58-4,67 (2H, m), 6,68 (1H, d, J = 8,5Hz), 7,07-7,25 (11H, m), 7,43 (2H, t, J = 7,3Hz), 7,49-7,55 (2H, m), 7,75 (2H, d, J = 7,2Hz), 8,00 (1H, d, J = 1,8Hz),8,49-8,57 (3H, m).
138
d6-DMSO δ: 2,69-2,71 (1H, m), 2,79-2,85 (1H, m), 3,03-3,07(1H,m), 3,67 (3H, s), 3,96 (2H, s), 4,26-4,32 (2H, m), 4,55-4,63 (2H,m), 6,76 (2H, d, J= 8,52Hz), 7,14-7,25 (9H, m), 7,36-7,44 (4H, m), 7,48-7,52 (1H,m), 7,74-7,76 (2H,m), 8,29 (3H,s, br), 8,56 (1H, d, J= 1,68Hz), 8,613-8,64 (2H, m).
139
d6-DMSO δ: 2,82-2,85 (3H, m), 3,03-3,08 (1H,m), 3,93-3,98 (2H, m), 4,26-4,31 (2H, m), 4,564,69 (2H,m), 7,11-7,26 (12H, m), 7,37-7,43 (4H, m), 7,48-7,51 (1H,m), 7,73-7,75 (2H,m), 8,32 (3H,s, br), 8,53-8,65 (2H, m).
140
d6-DMSO δ: 1,09 (3H, t, J = 7,0Hz), 2,50-2,66 (2H, m), 3,05 (1H, dd, J = 13,4, 10,4Hz), 3,263,32 (1H, m), 3,45-3,54 (2H, m), 3,74 (2H, q, J = 7,0Hz), 4,09-4,15 (2H, m), 4,334,38 (1H, m), 4,65-4,71 (1H, m), 6,57 (2H, d, J = 8,6Hz), 7,00 (2H, d, J = 8,5Hz), 7,09 (2H, d, J = 8,0Hz), 7,16-7,35 (5H, m), 7,53-7,58 (4H, m), 7,95-8,20 (3H, br m), 8,48-8,56 (3H, m), 8,64 (1H, d, J = 8,5Hz).
141
d6-DMSO δ: 1,26(3H,t,J= 7,0Hz), 2,65-2,84(3H,m), 3,03-3,08(1H,m), 3,92(2H,q,J= 7,0Hz), 3,96(2H,s), 4,27-4,35(2H,m), 4,57-4,63(2H,m), 6,75(2H,d,J= 8,7Hz), 7,16(2H,d,J= 8,6Hz), 7,23(1H,dd,J= 8,3,1,7Hz), 7,27(2H,d,J= 8,1Hz), 7,37-7,51(6H,m), 7,55(1H,d,J=1,8Hz), 7,73-7,75(2H,m), 8,24(2H,s), 8,50(1H,d,J= 8,1Hz), 8,67-8,71 (2H,m).
142
d6-DMSO δ: 1,26(3H,t,J= 6,9Hz), 2,67-2,83(3H,m), 3,01-3,05(1H,m), 3,89-3,95(4H,m), 4,274,35(2H,m), 4,53-4,63(2H,m), 6,75(2H,d,J= 8,5Hz), 7,14(2H,d,J= 8,5Hz), 7,207,26(5H,m), 7,37-7,44(4H,m), 7,50(1H,t,J= 7,3Hz), 7,66-7,72(1H,m), 7,75(2H,d,J=7,4Hz), 8,31(2H,s), 8,53(1H,d,J= 8,1Hz), 8,62(1H,d,J= 8,7Hz), 8,69(1H,t,J= 5,9Hz).
143
d6-DMSO δ: 1,26 (3H, t, J= 6,93Hz), 2,70 (2H, d, J= 7,52Hz), 2,89-2,95 (1H, m), 3,12-3,17 (1H, m), 3,89-3,94 (2H, m), 3,95 (2H, s), 4,31 (2H, d, , J= 5,38Hz), 4,56-4,66 (2H,m), 6,74 (2H, d, J= 8,52Hz), 7,12 (2H, d, J= 6,93Hz), 7,26 (2H, d, J= 9,72Hz), 7,38-7,44 (5H, m), 7,50-7,54 (3H, m), 7,75 (2H, d, J = 8,31Hz), 8,34 (3H, s, br), 8,51 (1H, d, J= 8,32Hz), 8,62 (1H, d, J= 8,32Hz), 8,68-8,71 (1H, m).
144
d6-DMSO δ: 1,26 (3H, t, J= 6,93Hz), 2,65 (2H, d, J= 6,98Hz), 2,89-2,95 (1H, m), 3,16-3,21 (1H, m), 3,91-3,96 (2H, m), 4,32 (2H, J= 5,82Hz), 4,57-4,66 (2H, m), 6,73 (2H, d, J= 8,54Hz), 7,13 (2H, d, J= 9,08Hz), 7,27 (2H, d, J= 8,01Hz), 7,39-7,44 (8H, m), 7,507,57 (1H, m), 7,68-7,71 (1H, m), 7,73-7,75 (2H, m), 8,44-8,50 (4H, m), 8,72-8,76 (2H, m).
145
d6-DMSO δ: 1,26 (3H, t, J = 7,0Hz), 2,64 (2H, d, J = 7,2Hz), 2,82 (1H, dd, J = 13,5, 10,3Hz), 3,07 (1H, dd, J = 13,6, 4,2Hz), 3,81 (2H, s), 3,92 (2H, q, J = 7,0Hz), 4,26-4,35 (2H, m), 4,55-4,65 (2H, m), 5,70-6,60 (2H, br s), 6,75 (2H, d, J = 8,6Hz), 7,14-7,34 (7H, m), 7,39-7,51 (3H, m), 7,62 (1H, d, J = 7,7Hz), 7,73 (2H, d, J = 7,2Hz), 8,39 (1H, dd, J = 4,8, 1,4Hz), 8,46 (1H, d, J = 1,6Hz), 8,52 (1H, d, J = 8,0Hz), 8,62 (1H, t, J = 6,0Hz), 8,68 (1H, d, J = 8,8Hz).
146
d6-DMSO δ: 1,26(3H,t,J= 7,0Hz), 2,69-2,77(3H,m), 2,94-2,99(1H,m), 3,65(3H,s), 3,92(2H,q,J=7,0Hz), 3,96(2H,s), 4,25-4,35(2H,m), 4,49-4,54(1H,m), 4,57-4,63(1H,m), 6,75(4H,dd,J=8,6,1,7Hz), 7,13-7,18(4H,m), 7,25(2H,d,J= 8,1Hz), 7,36(2H,d,J= 8,1Hz), 7,40-7,44(2H,m),7,48-7,52(1H,m), 7,72-7,75(2H,m), 8,19(2H,s), 8,488,53(2H,m), 8,62(1H,t,J= 6,0Hz).
147
d6-DMSO δ: 1,26 (3H, t, J = 7,0 Hz), 2,69 (2H, d, J = 7,2 Hz), 2,83 (1H, dd J = 13,6, 10,0 Hz), 3,06 (1H, dd, J = 13,7,4,5 Hz), 3,87 (2H,s), 3,92 (2H, q, J = 7,0 Hz), 4,26-4,31(2H, m), 4,55-4,60 (1H, m), 4,62-4,67 (1H, m), 6,51-6,79 (1H, m), 6,75 (2H, d, J = 8,6Hz), 7,13-7,19 (3H, m), 7,20-7,22 (4H, m), 7,31 (1H, d, J = 8,1Hz), 7,40-7,44 (3H, m), 7,45-7,52 (1H, m), 7,71-7,75 (2H, m), 8,36-8,39 (2H, m), 8,50-8,61 (3H, m).
148
d6-DMSO δ: 1,26 (3H, t, J= 6,93Hz), 2,70 (2H, d, J= 7,09Hz), 2,89-2,95 (1H, m), 3,12-3,17 (1H, m), 3,89-3,94 (2H, m), 3,95 (2H, s), 4,31-4,32 (2H, m), 4,56-4,66 (2H,m), 6,74 (2H, d, J=7,19Hz), 7,12 (2H, d, J= 8,40Hz), 7,26 (2H, d, J= 8,40Hz), 7,38-7,44 (5H, m), 7,50-7,54 (3H, m), 7,74-7,76 (2H, m), 8,35 (3H, s, br), 8,51 (1H, d, J= 7,2Hz), 8,62 (1H, d, J= 8,40Hz), 8,68-8,71 (1H, m).
149
d6-DMSO δ: 1,26 (3H, t, J= 6,93Hz), 2,67-2,69 (2H, m), 2,81-2,87 (1H, m), 3,06-3,10 (1H,m), 3,59 (2H, s, br), 3,89-3,98 (4H, m), 4,22-4,33 (2H, m), 4,57-4,62 (2H,m), 6,74 (2H, d, J= 8,52Hz), 7,13-7,16 (7H, m), 7,22-7,27 (2H,m), 7,35-7,41 (3H,m), 7,43-7,51 (1H, m), 7,72-7,81 (2H,m), 8,29-8,32 (1H,m), 8,48-8,53 (1H, m), 8,54-8,64 (1H, m).
150
d6-DMSO δ: 1,28 (3H, t, J = 7,0 Hz), 2,80 -2,87 (2H, m), 3,07 (1H, dd, J = 14,7, 9,4 Hz), 3,27 (2H, dd, J = 14,8, 4,3 Hz), 3,32 (2H, br,s), 3,69 (1H, s), 3,94 (2H, q, J = 6,9 Hz), 4,27 -4,30 (2H, m), 4,53 -4,58 (1H, m), 4,60 -4,66 (1H, m), 6,78 (2H, d, J = 8,6 Hz), 6,86 -6,90 (2H, m), 7,12 -7,24 (6H, m), 7,31 (1H, d, J = 5,0 Hz), 7,42 (2H, t, J = 7,4 Hz), 7,50 (1H, q, J =7,3 Hz), 7,73 (2H, d, J = 7,1 Hz), 8,51 (1H, t, J = 5,5 Hz), 8,57 (2H, m).
151
d6-DMSO δ: 1,28 (3H, t, J = 6,9 Hz), 2,77 (2H, br,s), 2,89 (1H, dd, J = 14,1, 9,8 Hz), 3,07 (1H, dd, J = 14,1, 4,4 Hz), 3,33 (3H, br,s), 3,65 (1H, br,s), 3,94 (2H, q, J = 6,9 Hz), 4,28 (2H, t, J =5,8 Hz), 4,52 -4,58 (1H, m), 4,60 -4,65 (1H, m), 6,78 (2H, d, J = 8,5 Hz), 6,98 (1H, d, J = 4,6 Hz), 7,15 (3H, br,s), 7,18 -7,23 (4H, m), 7,38 -7,41 (1H, m), 7,44 (2H, d, J = 7,6 Hz), 7,51 (1H, t, J = 7,2 Hz), 7,75 (2H, d, J = 7,2 Hz), 8,50 (1H, br,s), 8,57 (2H, d, J = 6,2 Hz).
152
d6-DMSO δ: 1,28 (3H, t, J = 7,0 Hz), 2,67 (1H, t, J = 1,6 Hz), 2,77 (1H, d, J = 7,3 Hz), 3,06 (1H, dd, J = 14,5 Hz, 9,7 Hz), 3,23 (1H, dd, J = 14,6 Hz, 4,7 Hz), 3,94 (2H, q, J = 7,0 Hz), 3,96 -3,99 (2H, m), 4,31 (2H, t, J = 5,7 Hz), 4,58 (1H, q, J = 7,5 Hz), 4,70 (1H, td, J = 9,1 Hz, 4,6 Hz), 6,77 (2H, d, J = 8,6 Hz), 7,16 (2H, d, J = 8,6 Hz), 7,23 (2H, d, J = 8,1 Hz), 7,26 (1H, d, J = 1,5 Hz), 7,33 (2H, d, J = 8,2 Hz), 7,43 (2H, t, J = 7,5 Hz), 7,52 (1H, t, J = 7,4 Hz), 7,42 (2H, d, J = 7,1 Hz), 8,05 (2H, br,s), 8,55 (2H, d, J = 7,6 Hz), 8,59 (1H, d, J = 8,6 Hz), 8,95 (1H, d, J = 1,8 Hz).
153
d6-DMSO δ: 1,27 (3H, t, J = 7,0 Hz), 2,66 -2,72 (3H, m), 3,10 (1H, dd, J = 14,4 Hz, 9,8 Hz), 3,91 (2H, q, J = 7,0 Hz), 3,98 (2H, d, J = 5,2 Hz), 4,33 (2H, qd, J = 14,5 Hz, 6,0 Hz), 4,61 (1H, td, J = 8,7 Hz, 4,9 Hz), 4,72 (1H, td, J = 9,1 Hz, 4,7 Hz), 6,71 (2H, d, J = 8,6 Hz), 7,12 (2H, d, J = 8,6 Hz), 7,26 (2H, d, J = 8,2 Hz), 7,35 (3H, d, J = 7,7 Hz), 7,38 -7,40 (2H, m), 7,42 (2H, d, J = 7,8 Hz), 7,49 (1H, d, J = 7,4 Hz), 7,73 (2H, d, J = 7,2 Hz), 7,97 (2H, d, J = 8,0 Hz), 8,06 (2H, br,s), 8,45 (1H, d, J = 7,8 Hz), 8,66 -8,72 (2H, m).
154
d6-DMSO δ: 1,26(3H,t,J= 7,0Hz), 2,70(2H,d,J= 7,3Hz), 2,79-2,85(1H,m), 3,03-3,08(1H,m), 3,94(2H,q,J= 7,0Hz), 4,00(2H,s), 4,27-4,39(2H,m), 4,54-4,62(2H,m), 6,75(2H,d,J= 8,6Hz), 7,07-7,25(9H,m), 7,41-7,52(4H,m), 7,70-7,74(2H,m), 8,26(2H,s), 8,49(1H,d,J= 8,1Hz), 8,58(1H,d,J= 8,6Hz), 8,66(1H,t,J=6,0Hz).
155
d6-DMSO δ: 1,26(3H,t,J= 6,9Hz), 2,72(2H,d,J= 7,2Hz), 2,80-2,86(1H,m), 3,03-3,08(1H,m), 3,92(2H,q,J= 6,9Hz), 4,06(2H,s), 4,26-4,37(2H,m), 4,53-4,62(2H,m), 6,74(2H,d,J= 8,5Hz), 7,13(2H,d,J= 8,5Hz), 7,15-7,23(6H,m), 7,38-7,43(3H,m), 7,48-7,53(2H,m), 7,75(2H,d,J=7,3Hz), 8,49(2H,s), 8,52(1H,d,J= 8,2Hz), 8,59(1H,d,J= 8,5Hz), 8,71 (1H,t,J= 5,9Hz).
156
d6-DMSO δ: 1,26(3H,t,J= 7,0Hz), 2,70(2H,d,J= 7,2Hz), 2,79-2,85(1H,m), 3,03-3,07(1H,m), 3,92(2H,q,J= 7,0Hz), 4,11(2H,s), 4,33-4,46(2H,m), 4,54-4,62(2H,m), 6,74(2H,d,J= 8,6Hz), 7,12(2H,d,J= 8,6Hz), 7,16-7,25(7H,m), 7,39-7,43(2H,m), 7,47-7,56(2H,m), 7,67-7,74(4H,m), 8,48(1H,d,J= 8,0Hz), 8,59(1H,d,J= 8,5Hz), 8,75(1H,t,J= 6,0Hz).
157
d6-DMSO δ: 1,27(3H,t,J= 7,0Hz), 2,81-2,86(1H,m), 2,93-2,97(1H,m), 3,06-3,12(1H,m), 3,243,29(1H,m), 3,90-3,99(4H,m), 4,30(2H,d,J= 5,8Hz), 4,50-4,56(2H,m), 4,784,83(2H,m), 6,69(2H,d,J= 8,6Hz), 6,86(2H,d,J= 8,6Hz), 6,91-6,94(2H,m), 7,23(2H,d,J= 8,1Hz), 7,35-7,38(3H,m), 7,60-7,63(1H,m), 7,96-8,00(2H,m), 8,20(2H,s), 8,56(1H,d,J= 8,3Hz), 8,63(1H,d,J= 4,8Hz), 8,67(1 H,d,J= 6,0Hz), 8,74(1H,d,J= 8,3Hz).
158
d6-DMSO δ: 1,28 (3H, t, J = 6,9 Hz), 2,74 (2H, d, J = 7,2 Hz), 3,02 (2H, dd, J = 13,9 Hz, 9,4 Hz), 3,18 (1H, d, J = 13,9 Hz, 4,6 Hz), 3,66 (1H, s), 3,80 (3H, s), 3,93 (2H, q, J = 6,9 Hz), 4,27 (2H, d, J = 6,0 Hz), 4,52 (1H, q, J = 7,4 Hz), 4,73 -4,79 (1H, m), 6,74 (2H, d, J = 8,6 Hz), 6,96 (2H, d, J = 8,8 Hz), 7,09 (2H, d, J = 8,2 Hz), 7,13 (2H, d, J =8,6 Hz), 7,17 -7,21 (3H, m), 7,34 (1H, d, J = 7,8 Hz), 7,63 (1H, td, J = 7,6 Hz, 1,7 Hz), 7,7 (2H, d, J = 8,8 Hz), 8:36 (1H, d, J = 4,0 Hz), 8,41 (2H, d, J = 6,6 Hz), 8,60(1H,d,J=8,4Hz).
159
d6-DMSO δ: 1,27(3H,t,J= 7,0Hz), 2,68-2,74(1H,m), 2,82-2,88(2H,m), 3,05-3,10(1H,m), 3,90(2H,q,J=7,0Hz), 4,06(2H,q,J= 5,7Hz), 4,31(2H,d,J= 5,9Hz), 4,50-4,55(1H,m), 4,76-4,81(1H,m), 6,59-6,65(4H,m), 7,19-7,23(2H,m), 7,28(2H,t,J= 7,4Hz), 7,33(2H,d,J= 7,2Hz), 7,37(1H,d,J= 1,0Hz), 7,50(1H,d,J= 8,0Hz), 7,59-7,63(1H,m), 7,98-8,02(2H,m), 8,38(2H,s), 8,51(1H,d,J= 8,2Hz), 8,61(1H,d,J= 4,7Hz), 8,718,74(2H,m).
160
d6-DMSO δ: 1,28 (3H, t, J = 7,66Hz), 2,70 (2H, d, J = 7,60Hz), 2,94-3,00 (1H, m), 3,21-3,24 (1H, m), 3,80 (3H, s), 3,92-4,00 (4H, m), 4,33 (2H, d, J= 6,69Hz), 4,52 (1H, q, J = 7,45Hz), 4,66-4,69 (2H, m), 6,75 (2H, d, J = 7,79Hz), 6,96 (2H, d, J = 8,68Hz), 7,17 (2H, d, J = 8,45Hz), 7,27 (2H, d, J = 7,82Hz), 7,38 (2H, d, J = 7,82Hz), 7,67 (1H, s, br), 7,74 (1H, d, J = 9,03Hz), 8,11 (1H, s, br), 8,22 (2H, s, br), 8,45 (1H, d, J = 8,34Hz), 8,68-8,69 (4H, m).
161
d6-DMSO δ: 1,28 (3H, t, J= 6,94Hz), 2,62-2,84 (3H, m), 2,96-3,07 (1H, m), 3,90-4,02 (4H, m), 4,32 (2H, d, J= 5,8Hz), 4,60-4,67 (2H, m), 6,77(2H, d, J = 8,88Hz), 7,16 -7,22 (1H, m), 7,26 (2H, d, J= 8,32Hz), 7,29-7,35(5H, m), 7,36 (2H, d, J= 8,32Hz), 7,64 (1H, d, J= 6,53Hz), 8,08 (3H,s, br), 8,58-8,71(3H, m), 8,82 (1H, d, J= 7,71Hz).
162
d6-DMSO δ: 1,27 (3H, t, J = 7,0 Hz), 2,61 (2H, dd, J = 14,0 Hz, 4,3 Hz), 2,86 (1H, dd, J = 13,7 Hz, 10,3 Hz), 3,10 (1H, dd, J = 13,7 Hz, 4,5 Hz), 3,93 (2H, q, J = 7,0 Hz), 3,98 -4,00 (2H, m), 4,3 (2H, d, J = 5,8 Hz), 4,56 (1H, td, J = 9,0 Hz, 5,0 Hz), 4,66 (1H, td, J = 9,0 Hz, 4,8 Hz), 6,75 (2H, d, J = 8,6 Hz), 7,12 (1H, dd J = 4,9, 3,7 Hz), 7,16 (2H, d, J = 8,6 Hz), 7,26 (2H, d, J = 8,3 Hz), 7,36 (3H, d, J = 8,1 Hz), 7,72 (1H, dd, J = 5,0 Hz, 0,7 Hz), 7,76 (1H, br,s), 7,81 (1H, d, J = 3,2 Hz), 8,07 (2H, br,s), 8,47 -8,55 (3H, m), 8,64 (2H, t, J = 9,0 Hz).
163
d6-DMSO δ: 1,28 (3H, t, J = 7,0 Hz), 2,67 -2,75 (2H, m), 3,03 (2H, dd, J = 13,8 Hz, 9,5 Hz), 3,21 (2H, dd, J = 14,0 Hz, 4,7 Hz), 3,93 (2H, q, J = 7,0 Hz), 3,99 (2H, q, J = 5,8 Hz), 4,20 -4,40 (3H, m), 4,53 -4,58 (1H, m), 4,77 -4,83 (1H, m), 6,75 (2H, d, J = 8,6 Hz), 7,14 (2H, d, J = 8,6 Hz), 7,23 (2H, d, J = 8,1Hz), 7,34 (2H, d, J = 8,2 Hz), 7,52 (2H, d, J =8,6 Hz), 7,76 (2H, d, J = 8,6 Hz), 8,07 (2H, br,s), 8,44 (1H, d, J = 4,5 Hz), 8,53 (1H, br,s), 8,66 (2H, d, J = 7,6 Hz).
164
d6-DMSO δ: 1,28 (3H, t, J = 7,0 Hz), 2,34 (3H, s), 2,74 (2H, d, J = 8,2 Hz), 3,05 (1H, dd, J = 13,9, 9,5 Hz), 3,23 (1H, dd, J = 14,0, 4,7 Hz), 3,93 (2H, q, J = 7,0 Hz), 3,99 (2H, q, J = 5,8 Hz), 4,26 -4,36 (2H, m), 4,54 (1H, dd, J = 14,5, 7,7 Hz), 4,79 (1H, td, J = 8,9 Hz, 4,8 Hz), 6,75 (2H, d, J = 8,6 Hz), 7,13 (2H, d, J = 8,6 Hz), 7,24 (4H, d, J = 8,0 Hz), 7,30 (1H, br,s), 7,34 (3H, d, J = 8,0 Hz), 7,66 (2H, d, J = 8,1 Hz), 7,76 (1H, br,s), 8,09 (2H, br,s), 8,45 (2H, t, J = 6,0 Hz), 8,54 (1H, t, J = 6,0 Hz), 8,64 (1H, d, J = 8,3 Hz).
165
d6-DMSO δ: 1,28(3H,t,J= 6,9Hz), 2,71-2,92(3H,m), 3,06-3,10(1H,m), 3,92(2H,q,J= 6,9Hz), 3,96-4,01 (2H,m), 4,31(2H,d,J= 5,8Hz), 4,53-4,59(1H,m), 4,75-4,80(1H,m), 6,576,72(4H,m), 7,27(2H,d,J= 8,0Hz), 7,30-7,33(1H,m), 7,37(2H,d,J= 8,0Hz), 7,55(1H,d,J= 8,2Hz), 7,59-7,63(1H,m), 7,64(1H,s), 7,98-8,01(2H,m), 8,13(2H,s), 8,47(1H,d,J= 8,2Hz), 8,62(1H,d,J=4,7Hz), 8,65-8,67(1H,m), 8,77(1H,d,J= 8,2Hz).
166
d6-DMSO δ: 0,85 (3H, t, J = 7,6 Hz), 1,30 (3H, t, J = 7,0 Hz), 2,02 (2H, q, J = 7,6 Hz), 2,63 2,68 (1H, m), 2,99 (2H, dd, J = 14,0 Hz, 9,6 Hz), 3,20 (1H, dd, J = 13,9, 4,8 Hz), 3,95 (2H, q, J = 7,0 Hz), 4,00 (2H, q, J = 6,0 Hz), 4,28 (2H, t, J = 7,2 Hz), 4,32 -4,35 (1H, m), 4,74 (1H, td, J = 8,9 Hz, 4,8 Hz), 6,73 (2H, d, J = 8,6 Hz), 7,00 (2H, d, J = 8,6 Hz), 7,23 (2H, d, J = 8,1 Hz), 7,29 (2H, d, J = 7,24 Hz), 7,36 (2H, d, J = 8,12 Hz), 7,74 (1H, br,s), 7,97 (1H, d, J = 5,2 Hz), 8,08 (2H, br,s), 8,51 (3H, d, J = 4,2 Hz).
167
d6-DMSO δ: 1,27(3H,t,J= 6,9Hz), 2,65-2,89(3H,m), 3,05-3,10(1H,m), 3,93(2H,q,J= 6,9Hz), 4,00(2H,q,J= 5,4Hz), 4,27-4,40(2H,m), 4,58-4,70(2H,m), 6,76(2H,d,J= 8,5Hz), 7,08(1H,s), 7,11(1H,d,J= 2,8Hz), 7,16-7,29(7H,m), 7,51(1H,t,J= 8,0Hz), 7,95(2H,s), 8,47(2H,s), 8,72-8,78(2H,m), 8,87(2H,s), 9,19(1H,d,J= 7,7Hz).
168
d6-DMSO δ: 1,27(3H,t,J= 7,0Hz), 2,69-2,74(1H,m), 2,82-2,93(2H,m), 3,05-3,10(1H,m), 3,90(2H,q,J=7,0Hz), 4,01(2H,q,J= 5,7Hz), 4,32(2H,d,J= 6,0Hz), 4,51-4,56(1H,m), 4,76-4,79(1H,m), 6,60-6,67(3H,m), 7,06-7,09(2H,m), 7,18-7,22(2H,m), 7,28(2H,t,J= 7,4Hz), 7,33(2H,d,J=3,8Hz), 7,46(1H,t,J= 7,8Hz), 7,59-7,63(1H,m), 7,96-7,99(2H,m), 8,31(2H,s), 8,50(1H,d,J=8,2Hz), 8,60-8,62(1H,m), 8,71-8,74(2H,m).
169
d6-DMSO δ: 1,26-1,30(3H,m), 2,60-2,84(3H,m), 3,03-3,07(1H,m), 3,93(2H,q,J= 7,0Hz), 4,00(2H,q,J= 5,4Hz), 4,32(2H,d,J= 5,8Hz), 4,56-4,66(2H,m), 6,76(2H,d,J= 8,6Hz), 7,11-7,13(1H,m), 7,16(2H,d,J= 8,5Hz), 7,23(1H,dd,J= 8,3,1,8Hz), 7,28(2H,d,J= 8,0Hz), 7,38(2H,d,J= 8,0Hz), 7,48(1H,d,J= 8,2Hz) 7,55(1H,d,J=1,7Hz), 7,73(1H,dd,J= 5,0,0,7Hz), 7,81(1H,d,J= 3,2Hz), 8,17(2H,s), 8,53(1H,d,J= 8,3Hz), 8,63-8,66(2H,m).
170
d6-DMSO δ: 0,84 (3H, t, J = 7,6 Hz), 1,30 (3H, t, J = 7,0 Hz), 2,00 (2H, q, J = 7,6 Hz), 2,43 2,47 (1H, m), 2,61 (1H, dd, J = 13,7 Hz, 4,8 Hz), 2,94 (1H, dd, J = 13,6 Hz, 10,2 Hz), 3,20 (1H, dd, J = 13,8 Hz, 4,4 Hz), 3,97 (2H, q, J = 7,0 Hz), 3,99 (2H, q, J = 5,5 Hz), 4,30 (2H, d, J = 5,6 Hz), 4,35 (1H, td, J = 8,4, 5,2 Hz), 4,62 (1H, td, J = 9,3, 4,6 Hz), 6,73 (2H, d, J = 8,6 Hz), 7,02 (2H, d, J = 8,6 Hz), 7,26 (2H, d, J = 8,0 Hz), 7,40 (2H, d, J = 8,1 Hz), 7,71 (1H, br,s), 8,00 (1H, d, J = 7,6 Hz), 8,12 (1H, d, J = 6,4 Hz), 8,27 (2H, br,s), 8,58 (1H, d, J =8,4 Hz), 8,65 (1H, br,s), 8,66 (2H, br,s).
171
d6-DMSO δ: 1,28(3H,t,J= 7,0Hz), 2,62-2,68(1H,m), 2,75-2,85(2H,m), 3,03-3,08(1H,m), 3,94(2H,q,J=7,0Hz), 3,97-4,02(2H,m), 4,28-4,38(2H,m), 4,63-4,67(2H,m), 6,77(2H,d,J= 8,6Hz), 7,17(2H,d,J= 8,5Hz), 7,22-7,25(1H,m), 7,28(2H,d,J= 8,1Hz), 7,38(2H,d,J= 8,0Hz), 7,50(1H,d,J= 8,2Hz), 7,55(1H,d,J= 1,4Hz)), 7,65(2H,d,J= 5,8Hz), 7,71-7,78(1H,m), 8,12(2H,s), 8,62-8,73(3H,m), 8,81(1H,d,J= 8,4Hz).
173
d6-DMSO δ: 1,28 (3H, t, J = 6,82Hz), 2,61-2,71 (2H, m), 2,85-2,91 (1H, m), 3,02-3,14 (1H, m), 3,93-4,01 (4H, m), 4,32-4,34 (2H, m), 4,56-4,69 (2H, m), 6,76 (2H, d, J = 8,67Hz), 7,16 (2H, d, J = 8,67Hz), 7,26 (2H, d, J = 8,67Hz), 7,36 (2H, d, J = 7,51Hz), 7,40-7,47 (1H, m), 7,51 (2H, d, J = 8,48Hz), 7,56 (1H, d, J = 7,51Hz), 7,76 (2H, d, J = 8,09Hz), 8,12 (2H, s, br), 8,48-8,58 (2H, m), 8,62-8,68(3H, m).
174
d6-DMSO δ: 1,28(3H, t, J= 7,05Hz), 2,65-2,71 (1H, m), 2,79-2,82 (1H, m), 3,04-3,07 (1H, m), 3,28-3,31 (1H,m), 3,91-3,99 (4H, m), 4,31 (2H, s), 4,58-4,60 (1H,m), 4,74-4,75 (1H,m), 6,75 (2H, d, J= 8,13Hz), 7,14 (2H, d, J= 9,73Hz), 7,27 (2H, d, J= 8,41Hz), 7,41 (2H, d, J = 8,41Hz), 7,85-7,88 (1H, m),8,34-8,42 (4H, m), 8,72-8,83 (5H, m), 9,08 (1H, d, J= 8,41Hz).
175
d6-DMSO δ: 1,29 (3H, t, J = 6,75 Hz), 2,61-2,64 (1H, m), 2,78-2,83 (1H, m), 2,87-2,93 (1H, m), 3,14-3,19 (1H, m), 3,92-4,00 (4H, m), 4,32 (2H, d, J = 5,78Hz), 4,60-4,65 (2H, m), 6,71 (2H, d, J = 8,18 Hz), 6,87 (2H, d J = 8,56 Hz), 7,14 (1H, d, J = 5,45 Hz), 7,26 (2H, d, J =8,56 Hz), 7,37 (2H, d, J = 7,78 Hz), 7,49-7,52 (1H, m), 7,83-7,90 (2H, m), 8,10 (3H, s, br), 8,54 (1H, d, J = 4,69Hz), 8,60 -8,66 (2H, m), 8,77 (1H, d, J = 8,63 Hz).
176
d6-DMSO δ: 1,27 (3H, t, J = 7,0 Hz), 2,66 -2,77 (2H, m), 2,98 (1H, dd, J = 14,5 Hz, 9,6 Hz), 3,19 (1H, dd, J = 14,5 Hz, 4,6 Hz), 3,91 (2H, q, J = 7,0 Hz), 3,98 (2H, q, J = 5,7 Hz), 4,32 (2H, d, J = 5,9 Hz), 4,62 (2H, qd, J = 9,3 Hz, 4,6 Hz), 6,69 (2H, d, J = 8,6 Hz), 6,99 (1H, t, J =6,9 Hz), 7,08 (3H, d, J = 8,7 Hz), 7,16 (1H, d, J = 2,1 Hz), 7,26 (2H, d, J = 8,0 Hz), 7,33 (3H, dd, J = 8,0 Hz, 6,1 Hz), 7,42 (2H, t, J = 7,5 Hz), 7,51 (1H, t, J = 7,4 Hz), 7,66 (1H, d, J = 7,8 Hz), 7,73 (2H, d, J = 7,2 Hz), 8,06 (2H, br,s), 8,39 (1H, d, J = 7,8 Hz), 8,52 (1H, d, J = 6,5 Hz), 8,61 (1H, t, J = 4,9 Hz), 10,82 (1H, br,s).
177
d6-DMSO δ: 1,28 (3H, t, J = 7,0 Hz), 2,32 -2,34 (1H, m), 2,66 (2H, t, J = 1,7 Hz), 2,85 (1H, d, J =7,44 Hz), 2,91 -3,03 (1H, m), 3,17 (1H, dd, J = 15,2 Hz, 5,0 Hz), 3,94 (2H, q, J = 7,0 Hz), 3,98 -4,00 (1H, br,m), 4,20 (1H, d, J = 6,2 Hz), 4,55 (1H, q, J = 7,4 Hz), 4,62 -4,68 (1H, m), 6,78 (2H, d, J = 8,5 Hz), 7,19 (2H, d, J = 8,5 Hz), 7,28 (2H, d, J = 8,4 Hz), 7,34-7,38 (2H, m), 7,44 (2H, q, J = 8,0 Hz), 7,51 -7,56 (1H, m), 7,72 7,78 (2H, m), 8,08 (2H, br,s), 8,52 (1H, t, J = 6,6 Hz), 8,59 -8,66 (2H, m), 8,97 (1H, br,s), 14,02 (1H, br,s), 14,18 (1H, br,s).
178
d6-DMSO δ: 1,28 (3H, t, J = 7,0 Hz), 2,66 (1H, d, J = 11,0 Hz), 2,73 (1H, dd, J = 13,5, 3,6 Hz), 3,10 (1H, dd, J = 14,4, 9,8 Hz), 3,29 (1H, d, J = 4,9 Hz), 3,66 (2H, s), 3,92 (2H, q, J = 7,0 Hz), 4,30 (2H, qd, J = 15,2, 5,7 Hz), 4,66 (1H, td, J = 9,1, 4,4 Hz), 4,75 (1H, td, J = 9,0, 5,0 Hz), 6,73 (2H, d, J = 8,6 Hz), 7,14 (5H, dd, J = 8,3, 5,1 Hz), 7,22 (2H, d, J = 8,1 Hz), 7,35 -7,44 (4H, m), 7,61 (2H, dd, J = 4,5, 1,5 Hz), 7,97 (2H, t, J = 9,4 Hz), 8,62 (1H, br, s), 8,67 (2H, dd, J = 4,5, 1,5 Hz), 8,71 (1H, br,s), 8,80 (1H, br,s).
179
d6-DMSO δ: 1,28 (3H, t, J = 7,0 Hz), 2,02 (3H, s), 2,68 -2,74 (2H, m), 2,83 (1H, dd, J = 13,6, 10,0 Hz), 3,05 (1H, dd, J = 13,5, 4,6 Hz), 3,93 (2H, q, J = 7,0 Hz), 3,98 (2H, d, J = 5,8 Hz), 4,32 (2H, qd, J = 15,3, 6,0 Hz), 4,55-4,64 (2H, m), 6,73 (2H, d, J = 8,5 Hz), 7,06 (2H, d, J = 8,5 Hz), 7,19-7,27 (7H, m), 7,38 (2H, d, J = 8,1 Hz), 7,69 (1H, d, J = 5,4 Hz), 7,85 (1H, d, J =5,4 Hz), 8,11 (1H, d, J = 8,1 Hz), 8,22 (2H, br,s), 8,58 (1H, d, J = 8,5 Hz), 8,65 (1H, t, J =5,7 Hz), 10,70 (1H, s)
180
d6-DMSO δ: 1,27 (3H, t, J= 7,09Hz), 2,72-2,74 (2H, m), 2,84-2,90 (1H, m), 3,09-3,16 (1H,m), 3,59 (2H, s, br), 3,91-3,98 (4H, m), 4,29-4,33 (2H, m), 4,57-4,67 (2H,m), 6,76 (2H, d, J= 8,79Hz), 7,01-7,16 (7H, m), 7,22-7,27 (2H,m), 7,35-7,41 (3H,m), 7,43-7,51 (1H, m), 7,76 (2H, d, J = 7,19Hz), 8,37 (3H, s, br), 8,57 (1H, d, J = 7,97Hz), 8,648,69 (1H, m).
181
d6-DMSO δ: 1,30 (3H, t, J = 7,21 Hz), 2,22 (3H, s), 2,56-2,78 (2H, m), 2,96-3,08 (1H, m), 3,233,28 (1H, m), 3,95-4,00 (4H, m), 4,32 (2H, d, J = 5,60Hz), 4,49-4,54 (1H, m), 4,664,72 (1H, m), 6,76 (2H, d, J = 8,32 Hz), 6,91 (1H, d J = 5,14 Hz), 7,05 (2H, d, J = 8,69Hz), 7,27 (2H, d, J = 7,90 Hz), 7,39 (2H, d, J = 8,30 Hz), 7,56 (1H, d, J = 5,14Hz), 7,72 (1H, s, br), 7,88 (1H, d, J = 7,61?Hz), 8,16 (1H, d, J = 7,61Hz), 8,27 (3H, s, br), 8,67 -8,74 (3H, m).
182
d6-DMSO δ: 1,28(3H,t,J= 7,0Hz), 2,29(3H,s), 2,69(2H,d,J= 7,2Hz), 2,80-2,86(1H,m), 3,043,09(1H,m), 3,91-3,97(4H,m), 4,24-4,34(2H,m), 4,56-4,63(2H,m), 6,76(2H,d,J=8,7Hz), 7,08-7,31(10H,m), 7,41-7,45(2H,m), 7,50-7,53(1H,m), 7,747,76(2H,m), 8,15(2H,s), 8,48(1H,d,J= 8,0Hz), 8,57-8,61(2H,m).
183
d6-DMSO δ: 1,28 (3H, t, J = 7,0 Hz), 2,76 (2H, d, J = 5,8 Hz), 3,06 (2H, dd, J = 14,5, 9,5 Hz), 3,22 (1H, dd, J = 14,5, 4,5 Hz), 3,94 (2H, q, J = 7,0 Hz), 3,98 (1H, d, J = 5,7 Hz), 4,29 (2H, d, J = 6,0 Hz), 4,44 -4,50 (1H, m), 4,65 (1H, td, J = 8,8, 4,9 Hz), 6,33 (2H, br,s), 6,55 (1H, d, J = 5,3 Hz), 6,74 (2H, d, J = 8,6 Hz), 7,04 (2H, d, J = 8,5 Hz), 7,22 (2H, d, J = 8,0 Hz), 7,27 (1H, d, J = 1,4 Hz), 7,29 (1H, s), 7,34 (2H, d, J = 8,0 Hz), 7,39 (1H, d, J = 5,4 Hz), 8,07 (2H, br,s), 8,52 (1H, s), 8,53 (1H, s), 8,97 (1H, d, J = 1,8 Hz).
184
d6-DMSO δ: 1,28 (3H, t, J = 7,0 Hz), 1,35 (1H, s), 1,89 (3H, s), 2,72 (1H, dd, J = 14,7, 7,9 Hz), 2,86 (1H, dd, J = 13,7, 4,7 Hz), 3,05 (1H, dd, J = 14,4, 9,8 Hz), 3,24 (1H, dd, J = 14,7, 4,6 Hz), 3,67 (2H, s), 3,94 (2H, q, J = 7,0 Hz), 4,25 (2H, d, J = 5,2 Hz), 4,654,70 (2H, m), 6,72 (2H, d, J = 8,6 Hz), 6,88 (2H, d, J = 8,7 Hz), 7,11 (2H, d, J = 7,9 Hz), 7,14 (1H, d, J = 5,2 Hz), 7,22 (2H, d, J = 7,8 Hz), 7,34 (1H, d, J = 1,7 Hz), 7,85 (1H, d, J = 5,2 Hz), 7,89 (2H, d, J = 7,5 Hz), 8,51 (1H, t, J = 6,0 Hz), 8,68 (1H, d, J = 8,6 Hz), 9,04 (1H, d, J = 1,9 Hz).
185
d6-DMSO δ:1,28(3H,t,J= 6,9Hz), 2,34(3H,s), 2,77(2H,d,J= 7,3Hz), 3,05(1H,dd,J=14,6,9,6Hz), 3,22(1H,dd,J=14,6,4,7Hz), 3,93(2H,q,J=7,0Hz), 3,97(2H,m), 4,3(2H,dd,J=5,0,4,9Hz), 4,56(1H,dd,J=14,8,7,6), 4,66-4,71(1H,m), 6,76(2H,d,J= 8,7Hz), 7,15(2H,d,J=8,6Hz), 7,22-7,26(4H,m), 7,34(2H,d,J=8,2Hz), 7,66(2H,d,J=8,2Hz), 8,08(3H,br s), 8,47(1H,d,J=7,8Hz), 8,54(1H,d,J=6,0), 8,58(1H,d,J= 8,3Hz), 8,95(1H,d,J=2,0Hz).
186
d6-DMSO δ: 1,26 (3H, t, J = 7,0 Hz), 2,12 (3H, s), 2,26-2,67 (1H, m), 2,74 (1H, dd, J = 13,7, 4,7 Hz), 3,09 (1H, dd, J = 14,5, 10,1 Hz), 3,35 (1H, d, J = 5,6 Hz), 3,65 (2H, s), 3,89 (2H, q, J =7,0 Hz), 4,27 (2H, d, J = 6,0 Hz), 4,64 (2H, dd, J = 7,5, 4,7 Hz), 5,90 (1H, br,s), 6,59 (2H, d, J = 8,6 Hz), 6,76 (1H, t, J = 2,5 Hz), 6,86 (2H, d, J = 8,5 Hz), 7,13 (2H, d, J = 7,3 Hz), 7,20 (2H, d, J = 8,1 Hz), 7,24 (1H, br,s), 7,36-7,45 (3H, m), 7,97 (2H, d, J = 8,2 Hz), 8,64 (1H, br,s), 8,68 (1H, d, J = 7,2 Hz), 11,12 (1H, br,s).
187
d6-DMSO δ: 1,29 (3H, t, J = 7,0 Hz), 2,14 (3H, s), 2,66 (1H, dd, J = 13,1, 9,0 Hz), 2,78 (1H, dd, J =13,7, 4,5 Hz), 2,86 (1H, dd, J = 14,2, 10,0 Hz), 3,07 (1H, dd, J = 14,2, 4,4 Hz), 3,66 (2H, s), 3,95 (2H, q, J = 7,0 Hz), 4,26 (2H, d, J = 4,6 Hz), 4,51 (1H, td, J = 9,0, 4,8 Hz), 4,61-4,67 (1H, m), 5,91 (1H, s), 6,75 (2H, d, J = 8,6 Hz), 6,77 (1H, d, J = 2,7 Hz), 7,02 (3H, d, J =8,5 Hz), 7,12 (2H, d, J = 7,6 Hz), 7,15 (2H, br,s), 7,21 (2H, d, J = 8,3 Hz), 7,29 (1H, d, J = 7,4 Hz), 7,42 (1H, dd, J = 4,8, 2,9 Hz), 8,32 (1H, s), 8,49 (1H, br,s), 8,57 (1H, d, J = 7,0 Hz), 11,11 (1H, s)
188
d6-DMSO δ: 1,26 (3H, t, J = 7,0 Hz), 2,01 (3H, s), 2,08 (1H, s), 2,66-2,72 (1H, m), 2,76-2,80 (1H, m), 3,12 (1H, dd, J = 14,4, 9,6), 3,67 (1H, s), 3,90 (2H, q, J = 7,0 Hz), 4,10 (1H, dd, J =17,3, 6,1 Hz), 4,28-4,31 (2H, m), 4,35 (1H, dd, J = 13,5, 6,8 Hz), 4,59 (1H, br,s), 4,71-4,76 (1H, m), 6,66 (2H, d, J = 8,6 Hz), 7,02 (2H, d, J = 8,5 Hz), 7,14 (3H, d, J = 7,6 Hz), 7,22 (1H, d, J = 8,2 Hz), 7,31-7,42 (4H, m), 7,67 (1H, d, J = 5,2 Hz), 7,84 (1H, d, J = 5,4 Hz), 7,97 (2H, dd, J = 12,2, 8,0 Hz), 8,05 (br,s, 1H), 8,60 (2H, br,d, J = 7,1 Hz), 10,66 (1H, br,s).
189
d6-DMSO δ: 1,28 (3H, t, J = 6,70Hz), 2,33 (3H, s), 2,69 (2H, d, J = 7,51Hz), 2,91-2,99 (1H, m), 3,13-3,18 (1H, m), 3,92-4,00 (4H, m), 4,33 (2H, d, J = 5,94Hz), 4,52-4,61 (1H, m), 4,63-4,69 (1H, m), 6,76 (2H, d, J = 8,67Hz), 7,15 (2H, d, J = 7,86Hz), 7,27 (2H, d, J = 8,096Hz), 7,31 (2H, d, J= 6,36Hz), 7,36 (2H, d, J = 7,51Hz), 7,47-7,53 (1H, m), 7,56 (1H, d, J = 7,51Hz), 7,87 (1H, d, J = 7,341Hz), 8,11 (3H, s, br), 8,45 (1H, d, J = 7,86Hz), 8,53 (2H, d, J =4,72Hz), 8,57-8,65(2H, m).
190
d6-DMSO δ: 1,31 (3H, t, J = 6,88Hz), 2,08 (3H, s), 2,70-2,71 (1H, m), 2,74-2,75 (1H, m), 2,882,94 (1H, m), 3,13-3,18 (1H, m), 3,90-4,01 (4H, m), 4,33 (2H, d, J = 6,21?Hz), 4,574,62 (1H, m), 4,66-4,71 (1H, m), 6,80 (2H, d, J = 8,06Hz), 7,09-7,11 (5H, m), 7,147,31 (2H, m), 7,36 (2H, d, J = 8,056Hz), 7,45-7,48 (1H, m), 7,84 (1H, d, J = 7,051Hz), 8,11 (3H, s, br), 8,34 (1H, d, J = 8,06Hz), 8,52-8,53(1H, m), 8,56 (1H, d, J = 5,021Hz), 8,63-8,65(2H, m).
191
d6-DMSO δ: 1,29 (3H, t, J= 6,84Hz), 2,07 (3H, s), 2,14 (3H, s), 2,53-2,59 (1H, m), 2,69-2,74 (1H, m), 2,77-2,83 (1H, m), 3,05-3,09 (1H,m), 3,91-4,01 (4H, m), 4,30 (2H, d, J = 5,98Hz), 4,51-4,65 (2H, m), 5,63 (1H, d, J = 1,50Hz) 6,71 (2H, d, J= 8,88Hz), 6,90 (2H, t, J= 8,88Hz), 7,04 (1H, d, J= 8,17Hz), 7,18-7,28 (8H, m), 7,34 (2H, d, J = 7,35Hz), 8,10 (2H, s, br), 8,57-8,64(2H, m).
192
d6-DMSO δ: 1,28 (3H, t, J= 6,82Hz), 2,30 (3H,s), 2,71-2,74 (2H, m), 2,80-2,86(1H,m), 3,043,09(1H,m), 3,91-3,95 (4H,m), 4,25-4,30 (2H,m), 4,54-4,59(1H,m), 4,69-4,74 (1H,m), 6,76 (2H, d, J= 7,887Hz), 7,08-7,31(10H, m), 7,41-7,45(2H,m), 7,50-7,53(1H,m), 7,74-7,76(2H,m), 8,31-8,39 (3H, m), 8,63(1H, d, J= 7,88Hz), 8,75-8,78 (3H,m).
193
d6-DMSO δ: 1,27 (3H, t, J = 7,0 Hz), 2,01 (3H, s), 2,32-2,34 (1H, m), 2,67 (1H, t, J = 1,7 Hz), 2,76-2,78 (2H, m), 2,88 (2H, dd, J = 14,1, 9,6 Hz), 3,04 (2H, dd, J = 14,2, 4,6 Hz), 3,67 (1H, s), 3,93 (2H, q, J = 7,0 Hz), 4,28 (2H, t, J = 6,4 Hz), 4,56-4,62 (2H, m), 6,75 (2H, d, J = 8,6 Hz), 6,99 (1H, d, J = 5,8 Hz), 7,12 (3H, t, J = 8,3Hz), 7,15 (1H, d, J = 3,5 Hz), 7,22 (2H, d, J =8,0 Hz), 7,39 (1H, dd, J = 4,8, 3,0 Hz), 7,69 (1H, d, J = 5,4 Hz), 7,85 (1H, d, J = 5,4 Hz), 8,15 (1H, d, J = 8,3 Hz), 8,50 (2H, t, J = 8,0 Hz), 10,69 (1H, br,s).
194
d6-DMSO (DMSO) δ: 1,27 (3H, t, J = 7,0 Hz), 7,00 (2H, d, J = 7,0 Hz), 3,10 (2H, dd, J = 14,5, 10,0 Hz), 3,90 (2H, q, J= 7,0 Hz), 4,00 (2H, q, J = 5,5 Hz), 4,33 (2H, d, J = 6,1 Hz), 4,52 (1H, q, J = 6,6 Hz), 4,67 (1H, td, J = 9,6 Hz, 4,1 Hz), 6,35 (1H, br,s), 6,56 (1H, d, J = 5,4 Hz), 6,61 (2H, d, J = 8,6 Hz), 6,91 (2H, d, J = 8,6 Hz), 7,14 (1H, d, J = 7,7 Hz), 7,26 (2H, d, J = 7,5 Hz), 7,36 (2H, d, J = 8,1 Hz), 7,38 (2H, d, J = 5,3 Hz), 7,467,41 (3H, m), 7,98 (2H, d, J = 8,8 Hz), 8,06 (2H, br,s), 8,60 (1H, d, J = 8,12 Hz), 8,70 (1H, br,s).
195
d6-DMSO δ: 1,28 (3H, t, J = 7,0 Hz), 2,76 (2H, d, J = 5,8 Hz), 3,06 (2H, dd, J = 14,5, 9,5 Hz), 3,22 (1H, dd, J = 14,5, 4,5 Hz), 3,94 (2H, q, J = 7,0 Hz), 3,98 (1H, d, J = 5,7 Hz), 4,29 (2H, d, J = 6,0 Hz), 4,44 -4,50 (1H, m), 4,65 (1H, td, J = 8,8, 4,9 Hz), 6,33 (2H, br,s), 6,55 (1H, d, J = 5,3 Hz), 6,74 (2H, d, J = 8,6 Hz), 7,04 (2H, d, J = 8,5 Hz), 7,22 (2H, d, J = 8,0 Hz), 7,27 (1H, d, J = 1,4 Hz), 7,29 (1H, s), 7,34 (2H, d, J = 8,0 Hz), 7,39 (1H, d, J = 5,4 Hz), 8,07 (2H, br,s), 8,52 (1H, s), 8,53 (1H, s), 8,97 (1H,d,J=1,8Hz).
196
d6-DMSO δ: 1,29(3H, t, J= 6,91 Hz), 2,42-2,46 (1H, m), 2,76-3,00 (3H, m), 3,05 (3H, s), 3,273,31 (1H,m), 3,93-4,00 (4H, m), 4,29 (2H, d, J = 6,28Hz), 4,89-4,99 (1H, m), 5,345,38 (1H, m), 6,67 (2H, d, J= 8,78Hz), 6,74 (2H, d, J= 8,21Hz), 6,98-7,01 (1H, m), 7,14 (1H, d, J= 5,67Hz), 7,19-7,38 (7H, m), 7,86 (1H, d, J= 5,67Hz), 7,88 (1H, d, J= 7,09Hz), 8,09 (3H,s, br), 8,41-8,48 (1H, m).
197
d6-DMSO δ: 1,28 (3H, t, J= 7,15Hz), 2,72-2,74 (2H, m), 3,92-3,99 (4H, m), 4,36 (2H, d, J = 6,40Hz), 4,47-4,50 (1 H, m), 4,67-4,73 (1H, m), 5,22 (1H, s, br), 5,83 (1H, s, br), 6,76 (2H, d, J=8,51Hz), 7,17-7,30 (6H, m), 7,37-7,45 (5H, m), 7,52-7,53 (1H, m), 8,30 (4H,s, br), 8,38-8,44 (2H, m), 8,60 (1H, d, J = 7,64Hz).
198
d6-DMSO δ: 1,28(3H, t, J= 6,70Hz), 2,61-2,64 (1H, m), 2,79-2,83 (1H, m), , 3,91-4,00 (4H, m), 4,34-4,36 (2H, m), 4,45-4,48 (1H, m), 4,82-4,85 (1H, m), 5,26-5,28 (1H, m), 5,855,86 (1H, m), 6,54 (1H,s, br), 6,65 (2H, d, J= 8,21Hz), 6,71 (2H, d, J= 8,213Hz), 7,13 (1H, d, J=5,47Hz), 7,23-7,36 (4H, m), 7,49 (2H, d, J = 7,11Hz), 7,82-7,86 (3H, m), 8,07 (3H,s, br), 8,36(1H, t, J = 5,81Hz), 8,53 (1H, d, J= 8,92Hz).
EJEMPLO 199
N-[(R)-1-[(S)-1-(4-aminometil-bencilcarbamoil)-2-piridin-3-il-etilcarbamoil]-2-(4-etoxi-fenil)-etil]-4-metilbenzamida
imagen49
imagen50
imagen51
imagen52
imagen53
imagen54
Tabla 9
Nº de ejemplo
Solubilidad en tampón PO4 (µ/ml)
3
10
38
14,55
54
0,8
55
1,5
56
0,9
58
4,1
59
7,7
70
11,53
71
22,1
72
6,9
73
5,1
75
1,06
79
2,4
81
1,3
84
0,5
88
0,2
92
0,2
93
0,01
95
2,05
99
2,88
116
1,39
119
1,61
124
64,45
125
43,60
131
0,56
140
79,63
141
0,15
143
2,86
145
68,91
150
0,12
151
4,31
152
122,19
153
0,19
154
3,14
155
0,44
157
4,77
158
70,56
159
1,15
160
20,4
162
69,69
173
2,38
174
232,69
175
23,4
176
2,28
178
1,54
179
17,72
181
61,65
199
15,88
200
0,22
Métodos biológicos
La capacidad de los compuestos de fórmula (I) para inhibir la calicreína plasmática puede determinarse utilizando el siguiente ensayo biológico: Determinación de la CI50 para la calicreína plasmática
La actividad inhibidora de calicreína plasmática in vitro se determinó utilizando métodos convencionales publicados (véase, por ejemplo, Johansen et al., Int. J. Tiss. Reac. 1986, 8, 185; Shori et al., Biochem. Pharmacol., 1992, 43, 1209; Sturzebecher et al., Biol. Chem. Hoppe-Seyler, 1992, 373, 1025). Se incubó calicreína plasmática humana (Protogen) a 37°C con el sustrato fluorogénico H-DPro-Phe-Arg-AFC y diversas concentraciones del compuesto de ensayo. La actividad enzimática residual (velocidad de reacción inicial) se determinó midiendo el cambio en la absorbancia óptica a 410 nm y se determinó el valor de CI50 para el compuesto de ensayo.
Los datos obtenidos a partir de este ensayo se muestran en las siguientes Tablas 10 y 11:
Tabla 10
Nº de ejemplo
CI50 (PKal humana) µM Nº de ejemplo CI50 (PKal humana) µM Nº de ejemplo CI50 (PKal humana) µM
1
0,089 24 0,45 47 2,1
2
0,82 25 0,34 48 4,7
3
0,022 26 0,081 49 2,2
4
0,23 27 1,3 50 4,3
5
0,46 28 8,9 51 1,0
6
1,0 29 0,30 52 0,86
7
0,074 30 0,58 53 0,65
8
0,74 31 4,3 54 0,083
9
2,0 32 0,20 55 0,031
10
7,2 33 1,1 56 0,50
11
1,7 34 1,4 57 10
12
0,29 35 2,0 58 0,17
13
10 36 8,2 59 0,078
14
0,40 37 0,91 60 10
15
0,47 38 0,047 61 0,22
16
0,053 39 0,31 62 10
17
5,8 40 1,8 63 0,052
18
8,8 41 1,3 64 3,4
19
10 42 0,53 65 10
20
0,73 43 1,3 66 10
21
5,1 44 0,18 67 1,6
22
10 45 0,79
23
0,031 46 1,2
Tabla 11
Nº de ejemplo
CI50 (PKal humana) (µM)
68
0,861
69
0,621
70
0,126
71
0,077
72
0,046
73
0,025
74
0,545
75
0,270
76
0,452
77
1,959
78
10,000
79
0,038
80
0,398
81
0,040
82
0,539
83
0,254
84
0,219
85
0,485
86
0,423
87
0,755
88
0,090
89
0,099
90
0,276
91
2,083
92
0,032
93
0,175
94
1,080
95
0,046
96
0,764
97
0,241
98
0,576
99
0,095
100
0,474
101
1,113
102
10,000
103
10,000
104
0,159
105
0,185
106
0,256
107
0,133
108
0,232
109
0,155
110
0,598
111
0,058
112
0,298
113
0,455
114
0,427
115
0,417
116
0,018
117
0,048
118
0,061
119
0,015
120
0,540
121
0,310
122
0,519
123
0,214
124
0,020
125
0,010
126
4,013
127
0,521
128
2,009
129
10,000
130
2,491
131
0,040
132
1,209
133
10,000
134
10,000
135
0,424
136
1,017
137
7,540
138
0,310
139
1,141
140
0,045
141
0,055
142
0,096
143
0,083
144
0,340
145
0,025
146
0,232
147
0,284
148
0,934
149
0,091
150
0,051
imagen55
imagen56
101
>10
102
9,0
103
>10
104
>10
105
>10
106
8,4
107
7,5
108
>10
109
>10
110
>10
111
>10
112
>10
113
>10
114
>10
115
9,0
116
6,3
117
6,1
118
>10
119
6,1
120
>10
121
>10
122
4,8
123
>10
124
8,4
125
7,0
126
>10
127
>10
128
>10
129
>10
130
>10
131
9,5
132
>10
133
>10
134
>10
135
>10
136
>10
137
>10
138
>10
139
>10
140
>10
141
>10
142
>10
143
>10
144
>10
145
>10
146
>10
147
>10
148
>10
149
>10
150
>10
151
>10
152
>10
153
>10
154
>10
155
>10
156
>10
157
>10
158
>10
159
>10
160
>10
imagen57
imagen58

Claims (1)

  1. imagen1
    imagen2
    imagen3
    imagen4
    imagen5
    imagen6
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