ES2675022T3 - Inhibidores de indolamina 2,3-dioxigenasa (IDO) - Google Patents

Inhibidores de indolamina 2,3-dioxigenasa (IDO) Download PDF

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Publication number
ES2675022T3
ES2675022T3 ES14729491.2T ES14729491T ES2675022T3 ES 2675022 T3 ES2675022 T3 ES 2675022T3 ES 14729491 T ES14729491 T ES 14729491T ES 2675022 T3 ES2675022 T3 ES 2675022T3
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phenyl
ureido
cyclopropancarboxylic acid
diisobutylamino
acid
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James Aaron Balog
Audris Huang
Bin Chen
Libing Chen
Steven P. Seitz
Amy C. HART
Jay A. Markwalder
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Bristol Myers Squibb Co
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Bristol Myers Squibb Co
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    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
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Abstract

Un compuesto de la Fórmula (I)**Fórmula** caracterizado por que X es**Fórmula** E es NH o CH2; W es CR10; Y es CR11; V es CR12;**Fórmula** es cicloalquilo C3-C8; R1 es arilo, aril-alquilo C1-C10 o alquilo C1-C10; R2 es COOH, heteroarilo o -CONHSO2R14; R3 es H, alquilo C1-C10 o halo; R4 es H, alquilo C1-C10 o halo; R6 es H; R7 y R8 se seleccionan independientemente entre**Fórmula** R10 es H o halo; R11 es H o halo; y R12 es H, alquilo C1-C10 o alquenilo C2-C10; y R14 es CF3, cicloalquilo C3-C8 o alquilo C1-C10; y/o un estereoisómero, un tautómero o una sal del mismo farmacéuticamente aceptable.

Description

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DESCRIPCION
Inhibidores de indolamina 2,3-dioxigenasa (IDO)
Esta solicitud reivindica el beneficio de la Solicitud Provisional de los Estados Unidos No. 61/791,224, presentada el 15 de marzo de 2013.
Campo de la Invención
La invención se refiere en general a compuestos que modulan o inhiben la actividad enzimática de indolamina 2,3- dioxigenasa (IDO), composiciones farmacéuticas que contienen tales compuestos y el udos de tales compuestos en métodos para tratar trastornos proliferativos, tales como cáncer, infecciones virales y/o enfermedades autoinmunes.
Antecedentes de la Invención
El triptofano es un aminoácido el cual es esencial para la proliferación y supervivencia celular. La indolamina-2,3- dioxigenasa es una enzima intracelular que contiene hematina que cataliza la primera etapa y determinante de la velocidad en la degradación del aminoácido esencial L-triptofano a N-formil-cinurenina. La N-formil-cinurenina es entonces metabolizada por etapas múltiples para producir eventualmente nicotinamida adenina dinucleótido (NAD+). Los catabolitos de triptofano producidos a partir de N-formil-cinurenina, tales como cinurenina, se conocen por ser preferencialmente citotóxicos a células-T. De este modo, una sobreexpresión de IDO puede conducir a tolerancia incrementada en el microambiente tumoral. La sobre expresión de IDO ha sido mostrada por ser un factor pronóstico independiente para supervivencia disminuida en pacientes con melanoma, cánceres pancreáticos, colorrectal y endometrial entre otros. Sin embargo, el IDO se ha encontrado por estar implicado en los trastornos neurológicos y psiquiátricos que incluyen trastornos de humor así como también otras enfermedades crónicas caracterizadas por la activación de IDO y supresión de triptofano, tales como infecciones virales, por ejemplo SIDA, enfermedad de Alzheimer, cánceres que incluyen leucemia de células T y cáncer de colon, enfermedades autoinmunes, enfermedades de los ojos tales como cataratas, infecciones bacterianas tales como enfermedad de Lyme, e infecciones estreptocócicas.
Por consiguiente, un agente el cual es seguro y efectivo en la inhibición de la producción de IDO podría ser una adición muy bienvenida al arsenal del especialista.
Los moduladores IDO destinados a usarse en el tratamiento del cáncer y otras enfermedades se describen en los documentos WO 2008/058178 A1 y WO 2007/075598 A2. Las consideraciones con respecto al diseño de inhibidores de IDO se encuentran en Lancellotti et al. (Curr Med Chem 2011, 18 (15): 2205-14).
Breve Descripción de la Invención
La presente invención proporciona compuestos y/o sales de los mismos farmacéuticamente aceptables, estereoisómeros de los mismos o tautómeros de los mismos, como se define en las reivindicaciones. Además, se describen en el presente documento métodos para modular o inhibir la actividad enzimática de IDO, y métodos para tratar varias condiciones médicas usando tales compuestos.
También se descroben en el presente documento procesos e intermediarios para elaborar los compuestos de la presente invención y/o sales de los mismos farmacéuticamente aceptables o estereoisómeros de los mismos o tautómeros de los mismos.
La presente invención también proporciona composiciones farmacéuticas que comprenden un portador farmacéuticamente aceptable y uno o más de los compuestos de la presente invención y/o sales de los mismos farmacéuticamente aceptables o estereoisómeros de los mismos o tautómeros de los mismos.
Los compuestos de la invención y/o sales de los mismos farmacéuticamente aceptables o estereoisómeros de los mismos o tautómeros de los mismos pueden ser usados en el tratamiento y/o profilaxis de trastornos o enfermedades múltiples asociados con la actividad enzimática de la inhibición de IDO, tales como cáncer, infecciones virales, enfermedades autoinmunes, y otros males.
Los compuestos de la invención y/o sales de los mismos farmacéuticamente aceptables o estereoisómeros de los mismos o tautómeros de los mismos pueden ser usados en terapia.
Los compuestos de la invención y/o sales de los mismos farmacéuticamente aceptables o estereoisómeros de los mismos o tautómeros de los mismos pueden ser usados para la manufactura de un medicamento para el tratamiento y/o profilaxis de trastornos o enfermedades múltiples asociados con la actividad enzimática de IDO.
Los compuestos de la invención y/o sales de los mismos farmacéuticamente aceptables o estereoisómeros de los mismos o tautómeros de los mismos pueden ser usados solos, en combinación con otros compuestos de la presente
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invención y/o sales de los mismos farmacéuticamente aceptables o estereoisómeros de los mismos o tautómeros de los mismos, o en combinación con uno o más de otro(s) agente(s).
Otras características y ventajas de la invención serán aparentes a partir de la siguiente descripción detallada y reivindicaciones.
Descripción Detallada de la Invención
I. COMPUESTOS DE LA INVENCIÓN
En un primer aspecto, la presente invención proporciona compuestos de Formula (I)
imagen1
donde
X es
E es NH o CH2; W es N o CR10;
Y es N o CR11;
V es N o CR12;
imagen2
imagen3
imagen4
es un cicloalquilo C3-C8;
R1 es arilo, aril-alquilo C1-C10, o alquilo C1-C10;
R2 es COOH, heteroarilo o -CONHSO2R14;
R es H, alquilo C1-C10 o halo;
R4 es H, alquilo C1-C10, o halo;
R6 es H;
R7 y R8 se seleccionan independientemente entre
CH3,
5
CF3(CH2)2-
10
o
R9 es
imagen5
imagen6
CF3CH2“~CH—ch2 ch3
imagen7

Claims (11)

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    REIVINDICACIONES
    1. Un compuesto de la Fórmula (I)
    caracterizado por que X es
    imagen1
    imagen2
    imagen3
    E es NH o CH2; W es CR10;
    Y es CR11;
    V es CR12;
    imagen4
    es cicloalquilo C3-C8;
    R1 es arilo, aril-alquilo C1-C10 o alquilo C1-C10;
    R2 es COOH, heteroarilo o -CONHSO2R14;
    R es H, alquilo C1-C10 o halo;
    R4 es H, alquilo C1-C10 o halo;
    R6 es H;
    R7 y R8 se seleccionan independientemente entre
    imagen5
    imagen6
    CH3,
    5
    imagen7
    CF3(CH2)2-,
    10
    o
    imagen8
    imagen9
    15 R9es
    imagen10
    imagen11
    imagen12
    imagen13
    imagen14
    o
    5
    imagen15
    R10 es H o halo;
    R11 es H o halo; y
    R es H, alquilo C1-C10 o alquenilo C2-C10; y 10 R14 es CF3, cicloalquilo C3-C8 o alquilo C1-C10;
    y/o un estereoisómero, un tautómero o una sal del mismo farmacéuticamente aceptable.
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    imagen16
    en donde X, E
    imagen17
    R2 , R3, R4, R6 R9 ,
    10 11 12
    R , R y R son como se definen en la reivindicación 1;
    y/o un estereoisómero, un tautómero o una sal del mismo farmacéuticamente aceptable.
  2. 3. El compuesto de conformidad con la Reivindicación 2 caracterizado porque
    imagen18
    X es NR7R8; E es NH;
    R2 es COOH,
    imagen19
    o -CONHSO2R14;
    R3 es H o alquilo C1-C6;
    R4 es H, alquilo C1-C6 o halo;
    R6 es como se define en la reivindicación 1; R10 es H;
    R12 es H; y
    R es CF3, cicloalquilo C3-C6 o alquilo C1-C6;
    y/o un estereoisómero, un tautómero o una sal del mismo farmacéuticamente aceptable.
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    imagen20
    E es NH;
    X es
    imagen21
    imagen22
    R2 es COOH;
    R3, R4, R5 y R6 son H; y
    R7 y R8 son como se definen en la reivindicación 1;
    y/o un estereoisómero, un tautómero o una sal del mismo farmacéuticamente aceptable.
  3. 5. El compuesto de conformidad con la Reivindicación 4, caracterizado porque R7 y R8 son cada uno
    imagen23
    R9 es
    imagen24
    y/o un estereoisómero, un tautómero o una sal del mismo farmacéuticamente aceptable.
  4. 6. El compuesto de conformidad con la Reivindicación 2, caracterizado porque
    imagen25
    X es OR1;
    E es NH;
    R2 es COOH,
    ^/VTU-V/'
    imagen26
    N=N
    o -CONHSO2R14; R3, R4 y R6 son H;
    R1 es arilo, aril-alquilo C1-C6 o alquilo C1-C6;
    R9 es arilo o alquil arilo C1-C6;
    R es H, alquilo C1-C6, alquenilo C2-C6 o halo; y R14 es como se define en la reivindicación 1;
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    y/o un estereoisómero, un tautómero o una sal del mismo farmacéuticamente aceptable.
    10
  5. 7. El compuesto de conformidad con la Reivindicación 2, caracterizado porque E es CH2;
    imagen27
    X es -NR7R8;
    R2 es COOH; y
    15 R3, R4, R6, R7 y R8 son como se definen en la Reivindicación 1;
    y/o un estereoisómero, un tautómero o una sal del mismo farmacéuticamente aceptable.
    20
  6. 8. El compuesto de conformidad con la Reivindicación 7, caracterizado porque R7 y R8 son cada uno
    h3cx
    JcH—CH2 h3c
    25
    Y
    R9 es
    imagen28
    y/o un estereoisómero, un tautómero o una sal del mismo farmacéuticamente aceptable.
    30 9. El compuesto de conformidad con la Reivindicación 1 seleccionado entre el grupo que consiste en:
    ácido 2-(4-(diisobutilamino)-3-(3-(p-tolil)ureido)fenil)ciclopropancarboxílico,
    ácido 2-(3-(3-(4-clorofenil)ureido)-4-(diisobutilamino)fenil)ciclopropancarboxílico,
    ácido 2-(4-(diisobutilamino)-3-(3-(4-(trifluorometil)fenil)ureido)fenil)ciclopropancarboxílico,
    35 ácido 2-(4-(diisobutilamino)-3-(3-(4-fluorofenil)ureido)fenil)ciclopropancarboxílico,
    ácido 2-(3-(3-(2,4-difluorofenil)ureido)-4-(diisobutilamino)fenil)ciclopropancarboxílico, ácido 2-(4-(diisobutilamino)-3-(3-(2-fluorofenil)ureido)fenil)ciclopropancarboxílico, ácido 2-(3-(3-(4-ciclopropilfenil)ureido)-4-(diisobutilamino)fenil)ciclopropancarboxílico, ácido 2-(4-(diisobutilamino)-2-fluoro-5-(3-(p-tolil)ureido)fenil)ciclopropancarboxílico,
    40 ácido 2-(4-(diisobutilamino)-2-fluoro-5-(3-(6-metilpiridin-3-il)ureido)fenil)ciclopropancarboxílico,
    ácido 2-(4-(diisobutilamino)-2-fluoro-5-(3-(3-metilisoxazol-5-il)ureido)fenil)ciclopropancarboxílico, ácido 2-(4-(diisobutilamino)-3-(3-(3-metilisoxazol-5-il)ureido)fenil)ciclopropancarboxílico, ácido 2-(4-(diisobutilamino)-3-(3-(6-(trifluorometil)piridin-3-il)ureido)fenil)ciclopropancarboxílico, ácido 2-(4-(diisobutilamino)-3-(3-(6-fluoropiridin-3-il)ureido)fenil)ciclopropancarboxílico,
    45 ácido 2-(3-(3-(3-ciclopropilisoxazol-5-il)ureido)-4-(diisobutilamino)fenil)ciclopropancarboxílico,
    ácido 2-(4-(diisobutilamino)-3-(3-(3-(trifluorometil)isoxazol-5-il)ureido)fenil)ciclopropancarboxílico, ácido 2-(5-(3-(4-cloro-2-fluorofenil)urcido)-4-(diisobutilamino)-2-fluorofenil)ciclopropancarboxílico, ácido 2-(4-(diisobutilamino)-2-fluoro-5-(3-(2-fluorofenil)ureido)fenil)ciclopropancarboxílico, ácido 2-(4-(diisobutilamino)-3-(3-(6-metilpiridin-3-il)ureido)fenil)ciclopropancarboxílico,
    50 ácido 2-(4-((4-clorobencil)(2-metoxietil)amino)-3-(3-(p-tolil)ureido)fenil)ciclopropancarboxílico,
    ácido 2-(4-((4-clorobencil)(2-metoxietil)amino)-3-(3-(2-fluorofenil)ureido)fenil)ciclopropancarboxílico,
    ácido 2-(4-(ciclohexil(isobutil)amino)-3-(3-(p-tolil)ureido)fenil)ciclopropancarboxílico,
    ácido 2-(4-(ciclohexil(isobutil)amino)-3-(3-(3-metilisoxazol-5-il)ureido)fenil)ciclopropancarboxílico,
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    ácido 2-(4-(diisobutilamino)-3-(3-(p-tolil)ureido)fenil)-1-metilciclopropancarboxílico,
    ácido 3-(4-(diisobutilamino)-3-(3-(p-tolil)ureido)fenil)-2,2-difluorociclopropancarboxílico,
    2-(1H-tetrazol-5-il)ciclopropil)-2-(diisobutilamino)fenil)-3-(p-tolil)urea,
    ácido 3-(4-(diisobutilamino)-3-(3-(p-tolil)ureido)fenil)-2,2-dimetilciclopropancarboxílico,
    ácido 3-(4-(diisobutilamino)-3-(3-(2-fluorofenil)ureido)fenil)-2,2-dimetilciclopropancarboxílico,
    ácido 2-(3-butil-5-(3-(2-fluorofenil)ureido)-4-propoxifenil) ciclopropancarboxílico,
    2-(1H-tetrazol-5-il)ciclopropil)-3-butil-2-propoxifenil)-3-(p-tolil)urea,
    2-(1H-tetrazol-5-il)ciclopropil)-3-butil-2-propoxifenil)-3-(2-fluorofenil)urea,
    ácido 2-(4-(ciclohexil(4,4,4-trifluoro-2-metilbutil)amino)-3-(3-(p-tolil)ureido)fenil)ciclopropancarboxílico, ácido 2-(4-(ciclohexil(4,4,4-trifluoro-2-metilbutil)amino)-3-(3-(pirimidin-5-il)ureido)fenil)ciclopropancarboxílico, ácido 2-(4-(ciclohexil(4,4,4-trifluoro-2-metilbutil)amino)-3-(3-(5-metilisoxazol-3-
    il)ureido)fenil)ciclopropancarboxílico,
    ácido 2-(4-(ciclohexil(4,4,4-trifluoro-2-metilbutil)amino)-3-(3-(p-tolil)ureido)fenil)ciclopropancarboxílico, ácido 2-(4-(ciclohexil(4,4,4-trifluoro-2-metilbutil)amino)-3-(3-(pirimidin-5-il)ureido)fenil)ciclopropancarboxílico, ácido 2-(4-(ciclohexil(4,4,4-trifluoro-2-metilbutil)amino)-3-(3-(5-metilisoxazol-3-
    il)ureido)fenil)ciclopropancarboxílico,
    ácido 2-(4-(ciclohexil(4,4,4-trifluoro-2-metilbutil)amino)-3-(2-(p-tolil)acetamido)fenil)ciclopropancarboxílico, ácido 2-(4-(ciclohexil(4,4,4-trifluoro-2-metilbutil)amino)-3-(2-(p-tolil)acetamido)fenil)ciclopropancarboxílico, ácido 2-(4-(diisobutilamino)-3-(3-o-tolilureido)fenil) ciclopropancarboxílico, ácido and 2-(4-(diisobutilamino)-3-(3-p-tolilureido)fenil)ciclopentancarboxílico,
    y los enantiómeros (1S, 2R) y (1R, 2S) de los mismos; o un compuesto seleccionado entre el grupo que consiste en:
    ácido (1R,2S)-2-(4-(diisobutilamino)-3-(3-(3-fenilisoxazol-5-il)ureido)fenil)ciclopropancarboxílico,
    ácido (1R,2S)-2-(4-(diisobutilamino)-3-(3-(3,4-dimetilisoxazol-5-il)ureido)fenil)ciclopropancarboxílico,
    ácido (1R,2S)-2-(4-(diisobutilamino)-3-(2-(p-tolil)acetamido)fenil)ciclopropancarboxílico,
    ácido (1R,2S)-2-(4-(diisobutilamino)-3-(2-(3-metilisoxazol-5il)acetamido)fenil) ciclopropancarboxílico,
    ácido (1S,2R)-2-(4-(diisobutilamino)-3-(2-(p-tolil)acetamido)fenil)ciclopropancarboxílico,
    ácido (1S,2R)-2-(4-(diisobutilamino)-3-(2-(3-metilisoxazol-5-il)acetamido)fenil)ciclopropancarboxílico,
    ácido (1R,2S)-2-(4-(diisobutilamino)-3-(3-(pirimidin-5-il)ureido)fenil) ciclopropancarboxílico,
    ácido (1S,2R)-2-(4-(diisobutilamino)-3-(3-(pirimidin-5-il)ureido)fenil)ciclopropancarboxílico,
    ácido (1S,2R)-2-(4-(diisobutilamino)-3-(3-(quinoxalin-6-il)ureido)fenil)ciclopropancarboxílico,
    ácido (1S,2R)-2-(4-(diisobutilamino)-3-(3-(5-metilisoxazol-3-il)ureido)fenil)ciclopropancarboxílico,
    ácido (1R,2S)-2-(4-(diisobutilamino)-3-(3-(5-metilisoxazol-3-il)ureido)fenil)ciclopropancarboxílico,
    ácido (1S,2R)-2-(3-(3-(6-cianopiridin-3-il)ureido)-4-(diisobutilamino)fenil)ciclopropancarboxílico,
    ácido (1S,2R)-2-(3-(3-(benzo[c][1,2,5]oxadiazol-5-il)ureido)-4-(diisobutilamino)fenil)ciclopropancarboxílico,
    ácido (1S,2R)-2-(4-(diisobutilamino)-3-(3-(4-((etoxicarbonil)amino)fenil)ureido)fenil)ciclopropancarboxílico,
    ácido (1S,2R)-2-(4-(diisobutilamino)-3-(3-(4-(2,2,2-trifluoroetoxi)fenil)ureido)fenil)ciclopropancarboxílico,
    ácido (1R,2S)-2-(4-(ciclohexil(4,4,4-trifluorobutil)amino)-3-(3-(p-tolil)ureido)fenil)ciclopropancarboxílico,
    ácido (1R,2S)-2-(4-(ciclohexil(4,4,4-trifluorobutil)amino)-3-(3-(5-metilisoxazol-3-
    il)ureido)fenil)ciclopropancarboxílico,
    ácido (1R,2S)-2-(4-(ciclohexil(4,4,4-trifluorobutil)amino)-3-(3-pirimidina-5-il)ureido)fenil)ciclopropancarboxílico,
    ácido (1S,2R)-2-(4-(ciclohexil(4,4,4-trifluorobutil)amino)-3-(3-(p-tolil)ureido)fenil)ciclopropancarboxílico,
    ácido (1 S,2R)-2-(4-(diisobutilamino)-3-(3-(2-metilpirimidin-5-il)ureido)fenil)ciclopropancarboxílico,
    ácido (1S,2R)-2-(3-(3-(2-cianopirimidin-5-il)ureido)-4-(diisobutilamino)fenil)ciclopropancarboxílico,
    ácido (1R,2S)-2-(3-(3-(2-cianopirimidin-5-il)ureido)-4-(diisobutilamino)fenil)ciclopropancarboxílico,
    ácido (1R,2S)-2-(4-(ciclohexil(isobutil)amino)-3-(3-(5-metilisoxazol-3-il)ureido)fenil)ciclopropancarboxílico,
    ácido (1S,2R)-2-(4-(ciclohexil(isobutil)amino)-3-(3-(5-metilisoxazol-3-il)ureido)fenil)ciclopropancarboxílico,
    ácido (1R,2S)-2-(4-(ciclohexyl(isobutil)amino)-3-(3-(pirimidin-5-il)ureido)fenil)ciclopropancarboxílico,
    ácido (1S,2R)-2-(4-(ciclohexil(isobutil)amino)-3-(3-(pirimidin-5-il)ureido)fenil)ciclopropancarboxílico,
    ácido (1R,2S)-2-(4-((1R,2R,4S)-biciclo[2.2.1]heptan-2-il(isobutil)amino)-3-(3-(p-
    tolil)ureido)fenil)ciclopropancarboxílico,
    ácido (1R,2S)-2-(4-((1R,2R,4S)-biciclo[2.2.1]heptan-2-il(isobutil)amino)-3-(3-(pirimidin-5-
    il)ureido)fenil)ciclopropancarboxílico,
    (1R,2S)-2-(4-((1R,2R,4S)-biciclo[2.2.1]heptan-2-il(isobutil)amino)-3-(3-(5-metilisoxazol-3-
    il)ureido)fenil)ciclopropancarboxílico,
    ácido (1R,2S)-2-(4-(ciclohexil(3,3,3-trifluoropropil)amino)-3-(3-(pirimidin-5-il)ureido)fenil)ciclopropancarboxílico, ácido (1R,2S)-2-(4-(ciclohexil(3,3,3-trifluoropropil)amino)-3-(3-(p-tolil)ureido)fenil)ciclopropancarboxílico, ácido (1R,2S)-2-(3-(3-(2-cianopirimidin-5-il)ureido)-4-(ciclohexil(3,3,3-
    trifluoropropil)amino)fenil)ciclopropancarboxílico,
    ácido (1R,2S)-2-(4-(ciclohexil(3,3,3-trifluoropropil)amino)-3-(3-(5-metilisoxazol-3-
    il)ureido)fenil)ciclopropancarboxílico,
    ácido (1S,2R)-2-(4-(ciclohexil(3,3,3-trifluoropropil)amino)-3-(3-(p-tolil)ureido)fenil)ciclopropancarboxílico,
    ácido (1S,2R)-2-(4-(ciclohexil(3,3,3-trifluoropropil)amino)-3-(3-(5-metilisoxazol-3-
    il)ureido)fenil)ciclopropancarboxílico,
    ácido (1 R,2S)-2-(3-(3-(2-cianopirimidin-5-il)ureido)-4-(ciclohexil(isobutil)amino)fenil)ciclopropancarboxílico,
    5
    10
    15
    20
    25
    30
    35
    40
    45
    50
    55
    60
    65
    ácido (1R,2S)-2-(4-(ciclohexil(isobutil)amino)-3-(3-(p-tolil)ureido)fenil)ciclopropancarboxílico, ácido (1S,2R)-2-(3-(3-(2-cianopirimidin-5-il)ureido)-4-(ciclohexil(isobutil)amino)fenil)ciclopropancarboxílico, ácido (1R,2S)-2-(4-(ciclohexil(isobutil)amino)-2-fluoro-5-(3-(5-metilisoxazol-3-il)ureido)fenil)ciclopropancarboxílico, ácido (1R,2S)-2-(4-(ciclohexil(isobutil)amino)-2-fluoro-5-(3-(3-metilisoxazol-5-il)ureido)fenil)ciclopropancarboxílico, ácido (1R,2S)-2-(4-(ciclohexil(isobutil)amino)-2-fluoro-5-(3-(pirimidin-5-il)ureido)fenil) ciclopropancarboxílico, ácido (1R,2S)-2-(4-(ciclohexil(isobutil)amino)-2-fluoro-5-(3-(p-tolil)ureido)fenil)ciclopropancarboxílico, ácido (1R,2S)-2-(4-(ciclohexil(isobutil)amino)-5-(3-(4-etoxifenil)ureido)-2-fluorofenil)ciclopropancarboxílico, ácido (1R,2S)-2-(5-(3-(benzo[d][1,3]dioxol-5-il)ureido)-4-(ciclohexil-(isobutil)amino)-2-
    fluorofenil)ciclopropancarboxílico,
    ácido (1S,2R)-2-(4-(ciclohexil(isobutil)amino)-2-fluoro-5-(3-(5-metilisoxazol-3-il)ureido)fenil)ciclopropancarboxílico, ácido (1S,2R)-2-(4-(ciclohexil(isobutil)amino)-2-fluoro-5-(3-(pirimidin-5-il)ureido)fenil)ciclopropancarboxílico, ácido (1S,2R)-2-(4-(ciclohexil(isobutil)amino)-2-fluoro-5-(3-(p-tolil)ureido)fenil)ciclopropancarboxílico, ácido (1S,2R)-2-(4-(ciclohexil(isobutil)amino)-5-(3-(4-etoxifenil)ureido)-2-fluorofenil)ciclopropancarboxílico, ácido (1S,2R)-2-(5-(3-(benzo[d][1,3]dioxol-5-il)ureido)-4-(ciclohexil(isobutil)amino)-2-
    fluorofenil)ciclopropancarboxílico,
    ácido (1R,2S)-2-(3-(2-(4-cianofenil)acetamido)-4-(ciclohexil(3,3,3-
    trifluoropropil)amino)fenil)ciclopropancarboxílico,
    ácido (1S,2R)-2-(3-(2-(4-cianofenil)acetamido)-4-(ciclohexil(3,3,3-
    trifluoropropil)amino)fenil)ciclopropancarboxílico,
    ácido (1R,2S)-2-(3-(2-(4-cianofenil)acetamido)-4-(ciclohexil(isobutil)amino)fenil)ciclopropancarboxílico,
    ácido (1S,2R)-2-(3-(2-(4-cianofenil)acetamido)-4-(ciclohexil(isobutil)amino)fenil)ciclopropancarboxílico,
    ácido (1R,2S)-2-(4-(diisobutilamino)-3-(2-(4-fluorofenil)acetamido)fenil)ciclopropancarboxílico,
    ácido (1R,2S)-2-(4-(diisobutilamino)-3-(2-(6-metilpiridin-3-il)acetamido)fenil)ciclopropancarboxílico,
    ácido (1R,2S)-2-(3-(2-(4-clorofenil)acetamido)-4-(diisobutilamino)fenil)ciclopropancarboxílico,
    ácido (1R,2S)-2-(3-(2-(4-cianofenil)acetamido)-4-(diisobutilamino)fenil)ciclopropancarboxílico,
    ácido (1R,2S)-2-(4-(diisobutilamino)-3-(2-(4-metoxifenil) acetamido)fenil)ciclopropancarboxílico,
    (1S,2R)-2-(4-(diisobutilamino)-3-(3-(p-tolil)ureido)fenil)-N-(metilsulfonil)ciclopropancarboxamida,
    (1S,2R)-N-(ciclopropilsulfonil)-2-(4-(diisobutilamino)-3-(3-(p-tolil)ureido)fenil)ciclopropancarboxamida,
    ácido (1R,2S)-2-(4-(ciclohexil(isobutil)amino)-3-(3-(3-metilisoxazol-5-il)ureido)fenil)ciclopropancarboxílico,
    ácido (1R,2S)-2-(4-(diisobutilamino)-3-(3-(2-(trifluorometil)fenil)ureido)fenil)ciclopropancarboxílico,
    ácido (1R,2S)-2-(3-(3-(2,4-diclorofenil)ureido)-4-(diisobutilamino)fenil)ciclopropancarboxílico,
    ácido (1R,2S)-2-(3-(3-(3,4-diclorofenil)ureido)-4-(diisobutilamino)fenil)ciclopropancarboxílico,
    ácido (1R,2S)-2-(3-(3-(4-(difluorometoxi)fenil)ureido)-4-(diisobutilamino)fenil)ciclopropancarboxílico,
    ácido (1R,2S)-2-(3-(3-(2-clorofenil)ureido)-4-(diisobutilamino)fenil)ciclopropancarboxílico,
    ácido (1R,2S)-2-(3-(3-(4-cloro-2,6-difluorofenil)ureido)-4-(diisobutilamino)fenil)ciclopropancarboxílico,
    ácido (1R,2S)-2-(3-(3-(4-bromofenil)ureido)-4-(diisobutilamino)fenil)ciclopropancarboxílico,
    ácido (1R,2S)-2-(3-(3-(2-cloro-4-metilfenil)ureido)-4-(diisobutilamino)fenil)ciclopropancarboxílico,
    ácido (1R,2S)-2-(3-(3-(4-(cianometil)fenil)ureido)-4-(diisobutilamino)fenil)ciclopropancarboxílico,
    ácido (1S,2R)-2-(4-(diisobutilamino)-3-(3-(m-tolil)ureido)fenil)ciclopropancarboxílico,
    ácido (1S,2R)-2-(4-(diisobutilamino)-3-(3-fenilureido)fenil)ciclopropancarboxílico,
    ácido (1S,2R)-2-(4-(diisobutilamino)-3-(3-(4-etoxifenil)ureido)fenil)ciclopropancarboxílico, y
    ácido (1S,2R)-2-(3-(3-(4-cloro-2-fluorofenil)ureido)-4-(diisobutilamino)fenil)ciclopropancarboxílico.
  7. 10. Un compuesto seleccionado entre el grupo que consiste en:
    ácido 2-(4-(1-fenilpropoxi)-3-(3-(p-tolil)ureido)fenil)ciclopropancarboxílico,
    ácido 2-(4-(1-(4-clorofenil)butoxi)-3-(3-(p-tolil)ureido)fenil)ciclopropancarboxílico,
    ácido 2-(4-(1-fenilbutoxi)-3-(3-(p-tolil)ureido)fenil)ciclopropancarboxílico,
    ácido 2-(3-butil-5-(3-(p-tolil)ureido)-4-(4,4,4-trifluorobutoxi)fenil)ciclopropancarboxílico,
    ácido 2-(3-butil-5-(3-(2-fluorofenil)ureido)-4-(4,4,4-trifluorobutoxi) fenil)ciclopropancarboxílico
    y los enantiómeros (1S, 2R) y (1R, 2S) de los mismos; o un compuesto selecionado entre el grupo que consiste en:
    ácido (1S,2R)-2-(4-((S)-1-fenilpropoxi)-3-(3-(p-tolil)ureido)fenil)ciclopropancarboxílico y ácido (1R,2S)-2-(4-((R)-1- fenilpropoxi)-3-(3-(p-tolil)ureido)fenil)ciclopropancarboxílico.
  8. 11. El compuesto de conformidad con la Reivindicación 1, caracterizado porque el IC50 en el ensayo IDO-1 humano de HEK es < 10 nM.
  9. 12. Una composición farmacéutica caracterizada porque comprende uno o más compuestos y/o un estereoisómero, un tautómero o una sal del mismo farmacéuticamente aceptable de conformidad con cualquiera de las reivindicaciones 1-11, y un portador o un diluyente farmacéuticamente aceptables.
  10. 13. Un compuesto y/o un estereoisómero, un tautómero o una sal del mismo farmacéuticamente aceptable de conformidad con cualquiera de las reivindicaciones 1-11, para uso en terapia.
  11. 14. Un compuesto y/o un estereoisómero, un tautómero o una sal del mismo farmacéuticamente aceptable de conformidad con cualquiera de las reivindicaciones 1-11, para su uso en el tratamiento de cáncer, infecciones virales, depresión, rechazo al transplante de órgano o una enfermedad autoinmune.
    5 15. El compuesto y/o un estereoisómero, un tautómero o una sal del mismo farmacéuticamente aceptable para su
    buso en el tratamiento de la reivindicación 14, en donde tal cáncer se selecciona a partir de cáncer de colon, cáncer pancreático, cáncer de mama, cáncer de próstata, cáncer de pulmón, cáncer de ovario, cáncer cervical, cáncer renal, cáncer de cabeza y cuello, linfoma, leucemia y melanoma.
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