ES2569665T3 - Derivados de imidazol condensados útiles como inhibidores de IDO - Google Patents

Derivados de imidazol condensados útiles como inhibidores de IDO Download PDF

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ES2569665T3
ES2569665T3 ES12715295.7T ES12715295T ES2569665T3 ES 2569665 T3 ES2569665 T3 ES 2569665T3 ES 12715295 T ES12715295 T ES 12715295T ES 2569665 T3 ES2569665 T3 ES 2569665T3
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imidazo
isoindole
ethanol
ethyl
hydroxy
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Mario Mautino
Sanjeev Kumar
Jesse Waldo
Firoz Jaipuri
Tanay Kesharwani
Xiaoxia Zhang
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Lumos Pharma Inc
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NewLink Genetics Corp
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Abstract

Un compuesto de la fórmula,**Fórmula** o sal del mismo farmacéuticamente aceptable, en donde el enlace ∞ es un enlace doble o sencillo; n es 0, 1, 2, 3, o 4; cada R1 es independientemente halógeno, ciano, nitro, alquilo C1-6, haloalquilo C1-6, -OR, -N(R)2, -SR, -C(O)OR, - C(O)N(R)2, -C(O)R, -S(O)R, -S(O)OR, -S(O)N(R)2, -S(O)2R, -S(O)2OR, -S(O)2N(R)2, -OC(O)R, -OC(O)OR, - OC(O)N(R)2, -N(R)C(O)R, -N(R)C(O)OR, o -N(R)C(O)N(R)2; R2 es -alquilo C1-4-RA o -alquenilo C2-4-R3 cuando el enlace α es un enlace sencillo; y R2 es >=C(H)RA cuando el enlace α es un enlace doble; en donde RA es -CN, -C(O)R3, -C(O)OR3, -C(O)N(R3)(RC), -C(ORB)(R3)(RC), -C(NHRB)(R3)(RC), o -C(>=N-ORC)R3, en donde RB es hidrógeno, alquilo C1-6, haloalquilo C1-6, -alquilo C1-6-RB1, -C(O)R3, -C(O)N(H)R3, o -S(O)2R3, -C(O)(CH2)1- 4COOR, -C(O)(CH2)1-4(NR)COOR, -C(O)CH(NH2)(RD), -S(O)2OR3, -S(O)2N(R3)2, -CH2-OP(O)2(OR)2, o -P(O)(OR3)2, en donde RB1 es ciano, nitro, alquilo C1-6, haloalquilo C1-6, -OR, -N(R)2, -SR, -C(O)OR, -C(O)N(R)2, -C(O)R, -S(O)R, -S(O)OR, -S(O)N(R)2, -S(O)2R, -S(O)2OR, -S(O)2N(R)2, -OC(O)R, -OC(O)OR, -OC(O)N(R)2, -N(R)C(O)R, -N(R)C(O)OR, o - N(R)C(O)N(R)2; RD es hidrógeno, metilo, -CH(CH3)2, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), bencilo, 4-hidroxibencilo, -CH2(3- indolil), - CH2SH, -CH2CH2SCH3, -CH2OH, -CH(CH3)OH, -(CH2)4-NH2, -(CH2)3-N(H)C(>=NH)NH2, -CH2(4-imidazolil), - CH2COOH, -CH2CH2COOH, -CH2CONH2, -CH2CH2CONH2; cada R3 es independientemente hidrógeno, alquilo C1-6, haloalquilo C1-6, arilo, heteroarilo, cicloalquilo C3-8, cicloalquenilo C3-8, heterociclilo de 3-10 miembros, arilalquilo C1-6-, heteroarilalquilo C1-6-, cicloalquilo C3-8-alquilo C1- 6-, cicloalquenilo C3-8 alquilo C1-6-, (heterociclilo de 3-10 miembros)alquilo C1-6-, o (heteroarilo)-(heterociclilo de 3-10 miembros)-, en donde el alquilo, cicloalquilo C3-8, cicloalquenilo C3-8, heterociclilo de 3-10 miembros, cicloalquilo C3-8 alquilo C1-6-, cicloalquenilo C3-8 alquilo C1-6-, (heterociclilo de 3-10 miembros)alquilo C1-6-, y (heteroarilo)-(heterociclilo de 3-10 miembros)-, son cada uno opcional e independientemente sustituidos por un grupo >=R32 y cada uno opcional e independientemente sustituidos por uno, dos, tres, o cuatro grupos R31; los grupos arilo, heteroarilo, arilalquilo C1-6-, y heteroarilalquilo C1-6-, son cada uno opcionalmente sustituido por uno, dos, tres, o cuatro grupos R31; en donde cada R31 es independientemente halógeno, ciano, nitro, alquilo C1-6, -alquilo C1-6-R33, haloalquilo C1-6, -OR, -N(R)2, - SR, -C(O)OR, -C(O)N(R)2, -C(O)N(OH)R, -C(O)R, -C(NR11)R, -C(NR11)N(R11)R, -S(O)R, -S(O)OR, -S(O)N(R)2, - S(O)2R, -S(O)2OR, -S(O)2N(R)2, -OC(O)R, -OC(O)OR, -OC(O)N(R)2, -N(R)C(O)R, -N(R)C(O)OR, -N(R)C(O)N(R)2, en donde R33 es ciano, -OR, -N(R)2, -SR, -C(O)OR, -C(O)N(R)2, -C(O)R, -S(O)R, -S(O)OR, -S(O)N(R)2, -S(O)2R, -S(O)2OR, -S(O)2N(R)2, -OC(O)R, -OC(O)OR, -OC(O)N(R)2, -N(R)C(O)R, -N(R)C(O)OR, o -N(R)C(O)N(R)2; R32 es >=O, >=S, >=N(R), >=N(OR), >=C(R34)2, >=(espiro-cicloalquilo C3-8), o >=(espiro-(heterociclilo de 3-10 miembros)), en donde cada R34 es independientemente hidrógeno, halógeno, ciano, alquilo C1-6, - alquilo C1-6-OR, haloalquilo C1-6, cicloalquilo C3-8, o heterociclilo de 3-10 miembros; o ambos R34 tomados junto con el átomo al que están unidos forman un cicloalquilo C3-8 monocíclico o heterociclilo monocíclico de 3-8 miembros; RC es hidrógeno o alquilo C1-6; y cada R es independientemente hidrógeno o R10, en donde R10 es alquilo C1-6, haloalquilo C1-6, arilo, heteroarilo, cicloalquilo C3-8, cicloalquenilo C3-8, heterociclilo de 3-10 miembros, arilalquilo C1-6, heteroarilalquilo C1-6-, cicloalquilo C3-8 alquilo C1-6-, cicloalquenilo C3-8 alquilo C1-6-, o (heterociclilo de 3-10 miembros) alquilo C1-6-, cada R10 opcionalmente sustituido por uno, dos, tres, o cuatro grupos que son cada uno independientemente halógeno, ciano, nitro, alquilo C1-6, haloalquilo C1-6, -OR11, -N(R11)2, -SR11, - C(O)OR11, -C(O)N(R11)2, -C(O)R11, -S(O)R11, -S(O)OR11, -S(O)N(R11)2, -S(O)2R11, -S(O)2OR11, -S(O)2N(R11)2, - OC(O)R11, -OC(O)OR11, -OC(O)N(R11)2, -N(R11)C(O)R11, -N(R11)C(O)OR11, -N(R11)C(O)N(R11)2, -N(R11)S(O)2R11, o - C(O)-(heterociclilo de 3-10 miembros), en donde cada R11 es independientemente hidrógeno o alquilo C1-6.

Description

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en donde
cada R31 es independientemente halógeno, ciano, nitro, alquilo C1–6, –alquilo C1–6–R33, haloalquilo C1–6, –OR, –N(R)2, – SR, –C(O)OR, –C(O)N(R)2, –C(O)R, –S(O)R, –S(O)OR, –S(O)N(R)2, –S(O)2R, –S(O)2OR, –S(O)2N(R)2, –OC(O)R, – OC(O)OR, –OC(O)N(R)2, –N(R)C(O)R, –N(R)C(O)OR, –N(R)C(O)N(R)2, en donde R33 es –OR, –N(R)2, o –SR;
y
R32 es oxo, =C(R34)2, =(espiro–cicloalquilo C3–8), o =(espiro–(heterociclilo de 3–10 miembros)), en donde cada R34 es independientemente hidrógeno, halógeno, alquilo C1–6, o cicloalquilo C3–8.
(6u) R3 es arilo, heteroarilo, cicloalquilo C3–8, cicloalquenilo C3–8, o heterociclilo de 3–10 miembros, en donde el cicloalquilo C3–8, cicloalquenilo C3–8, y heterociclilo de 3–10 miembros son cada uno opcionalmente sustituido por un grupo =R32 y uno, dos, tres, o cuatro grupos R31; y
el arilo y heteroarilo son cada uno opcionalmente sustituido por uno, dos, tres, o cuatro grupos R31.
(6v) R3 es fenilo, ciclopentilo, ciclohexilo, ciclohexenilo, furanilo, tetrahidropiranilo, piperidinilo, imidazolilo, tiazolilo, cada uno opcionalmente sustituido por uno, dos, tres, o cuatro grupos R31, y en donde los grupos ciclopentilo, ciclohexilo, ciclohexenilo, y piperidinilo son cada uno opcionalmente sustituido por un grupo =R32.
(6w) R3 es fenilo, ciclopentilo, ciclohexilo, ciclohex–1–en–1–ilo, ciclohex–3–en–1–ilo, furan–2–ilo, furan–3–ilo, tetrahidropiran– 3–ilo, tetrahidropiran–4–ilo, piperidin–3–ilo, piperidin–4–ilo, imidazol–2–ilo, imidazol–4–ilo, tiazol–2–ilo, tiazol–4–ilo, tiazol–5–ilo, cada uno opcionalmente sustituido por uno o dos grupos R31, y en donde los grupos ciclopentilo, ciclohexilo, ciclohexenilo, y piperidinilo son cada uno opcionalmente sustituido por un grupo =R32.
(6x) Uno cualquiera de los grupos (6a) – (6w), en donde cada R es independientemente hidrógeno, alquilo C1–6, haloalquilo C1–6, arilo, heteroarilo, cicloalquilo C3–8, cicloalquenilo C3–8, heterociclilo de 3–10 miembros, arilalquilo C1–6, heteroarilalquilo C1–6–, cicloalquilo C3–8– alquilo C1–6–, cicloalquenilo C3–8–alquilo C1–6–, o (heterociclilo de 3–10 miembros)alquilo C1–6–.
(6y) Uno cualquiera de los grupos (6a) – (6w), en donde cada R es independientemente hidrógeno, alquilo C1–6, haloalquilo C1–6, fenilo, heteroarilo de 5– o 6–miembros, cicloalquilo C3–8, cicloalquenilo C3–8, heterociclilo de 3–8 miembros, bencilo, (heteroarilo de 5– o 6–miembros)alquilo C1–6–, cicloalquilo C3–8 alquilo C1–6–, cicloalquenilo C3–8– alquilo C1–6–, o (heterociclilo de 3–6 miembros)alquilo C1–6–.
(6z) Uno cualquiera de los grupos (6a) – (6w), en donde cada R es independientemente hidrógeno o alquilo C1–6.
Las realizaciones particulares de este aspecto de la invención incluyen compuestos de una cualquiera de las fórmulas (I), (I'), y (Ia) – (Id), cada uno como se define en cada una de las siguientes filas, en donde cada entrada es un número de grupo como se definió anteriormente (por ejemplo, (1s) se refiere a n es 1 y cada R1 es halógeno), y un guion "–" indica que la variable es como se define para la fórmula (I) o (I’) o definido de acuerdo con una cualquiera de las definiciones de las variables pertinentes (1a) – (6z) [por ejemplo, cuando RC es un guion, que puede ser ya sea tal como se define para la Fórmula (I) o (I’) o una cualquiera de las definiciones (5a)–(5 g)]:
imagen11
imagen12
imagen13
imagen14
imagen15
En otro aspecto, la invención provee el compuesto de acuerdo con fórmula (II),
imagen16
o sal del mismo farmacéuticamente aceptable, en donde
5 n es 0 o 1;
cada R1 es independientemente halógeno, –OR, –N(R)2, o –SR;
cada R3 es independientemente hidrógeno, alquilo C1–6, arilo, heteroarilo, cicloalquilo C3–8, cicloalquenilo C3–8,
heterociclilo de 3–10 miembros, o cicloalquilo C3–8–alquilo C1–6–, en donde el alquilo C1–6, cicloalquilo C3–8, cicloalquenilo C3–8, heterociclilo de 3–10 miembros, y cicloalquilo C3–8–alquilo C1–6–, son cada uno opcional e independientemente 10 sustituidos por un grupo =R32 y cada uno opcional e independientemente sustituido por uno o dos grupos R31; los grupos arilo y heteroarilo, son cada uno opcionalmente sustituido por uno o dos grupos R31; en donde
imagen17
5
10
15
20
25
30
imagen18
(IIe): en donde la configuración estereoisomérica de carbono–1 (C–1) y carbono–3 (C–3) de fórmula (II) son respectivamente (R, R). (IIf): en donde la configuración estereoisomérica de carbono–1 y carbono–3 de fórmula (II) son respectivamente (R, S). (IIg): en donde la configuración estereoisomérica de carbono–1 y carbono–3 de fórmula (II) son respectivamente (S, R). (IIh): en donde la configuración estereoisomérica de carbono–1 y carbono–3 de fórmula (II) son respectivamente (S, S).
n y R1 se seleccionan de uno de los siguientes grupos (7a) – (7i): (7a) n es 0 o 1 y R1 es halógeno, –OR0, –N(R0)2, o –SR0; en donde cada R0 es independientemente hidrógeno o alquilo C1–6.
(7b) n es 0 o 1 y R1 es fluoro, cloro, hidroxi, o metoxi. (7c) n es 0 o 1 y R1 es halógeno. (7d) n es 0 o 1 y R1 es fluoro ocloro. (7e) n es 1 y R1 es halógeno, –OR0, –N(R0)2, o –SR0; en donde cada R0 es independientemente hidrógeno o alquilo C1–
6. (7f) n es 1 y R1 es fluoro, cloro, hidroxi, o metoxi. (7g) n es 1 y R1 es halógeno. (7h) n es 1 y R1 es fluoro o cloro. (7i) n es 0. RC se selecciona de uno de los siguientes grupos (8a) – (8g): (8a) RC es hidrógeno o alquilo C1–4. (8b) RC es hidrógeno o alquilo C1–2 . (8c) RC es hidrógeno o metilo. (8d) RC es hidrógeno. (8e) RC es alquilo C1–6. (8f) RC es alquilo C1–4. (8g) RC es metilo. R3 se selecciona de uno de los siguientes grupos (9a) – (9x): (9a) R3 es arilo, heteroarilo, cicloalquilo C3–8, cicloalquenilo C3–8, heterociclilo de 3–10 miembros, o cicloalquilo C3–8–
alquilo C1–6–, en donde el cicloalquilo C3–8, cicloalquenilo C3–8, heterociclilo de 3–10 miembros, y cicloalquilo C3–8–alquilo C1–6–, son cada uno opcional e independientemente sustituidos por un grupo =R32 y cada uno opcional e independientemente sustituido por uno o dos grupos R31; y los grupos arilo y heteroarilo, son cada uno opcionalmente sustituido por uno o dos grupos R31.
imagen19
imagen20
La realizaciones particulares de este aspecto de la invención incluyen compuestos de una cualquiera de las fórmulas (II), (II’), y (IIa) – (IId), cada una como se define en cada una de las siguientes filas, en donde cada entrada es un número de grupo como se define anteriormente y un guion "–" indica que la variable es como se define para la fórmula (II), o (II’), o definida de acuerdo con una cualquiera de las definiciones de las variables pertinentes (7a)–(9t) [por ejemplo, cuando RC es un guion, puede ser ya sea como se define para la Fórmula (II), o (II’), o cualquiera de las definiciones (8a)–(8g)]:
imagen21
imagen22
imagen23
imagen24
1256
etil 2–(5H–imidazo[5,1–a]isoindol–5–il)acetato
1258
ácido 2–(5H–imidazo[5,1–a]isoindol–5–il)acético
1259
2–(5H–imidazo[5,1–a]isoindol–5–il)–N–metilacetamida
1273
(E)–5–(2–bromostiril)–5H–imidazo[5,1–a]isoindol
1286
2–(6–cloro–5H–imidazo[5,1–a]isoindol–5–il)–1– ciclohexiletanol
1287
2–(6–cloro–5H–imidazo[5,1–a]isoindol–5–il)–1– ciclohexiletanona
1288
2–(5H–imidazo[5,1–a]isoindol–5–il)etil 2–(((1R,2R,5S)–2– isopropil–5–metilciclohexil)oxi)acetato
1300
tert–butil (4–(2–(5H–imidazo[5,1–a]isoindol–5– il)acetil)fenil)carbamato
1301
1–(4–aminofenil)–2–(5H–imidazo[5,1–a]isoindol–5–il)etanona
1302
tert–butil (4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5– il)etil)fenil)carbamato
1303
1–(4–aminofenil)–2–(5H–imidazo[5,1–a]isoindol–5–il)etanol
1304
1–ciclohexil–2–(5H–imidazo[5,1–a]isoindol–5–il)etanol
1306
imagen25 2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(3–nitrofenil)etanona
1307
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(3–nitrofenil)etanol
1326
imagen26 2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(2–nitrofenil)etanona
1327
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(2–nitrofenil)etanol
1328
tert–butil (2–(2–(5H–imidazo[5,1–a]isoindol–5– il)acetil)fenil)carbamato
1329
tert–butil (2–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5– il)etil)fenil)carbamato
1330
1–(2–aminofenil)–2–(5H–imidazo[5,1–a]isoindol–5–il)etanona
1331
1–(2–aminofenil)–2–(5H–imidazo[5,1–a]isoindol–5–il)etanol
1334
1–(2–clorofenil)–2–(5H–imidazo[5,1–a]isoindol–5–il)etanona
1335
1–(5H–imidazo[5,1–a]isoindol–5–il)–2–metilpropan–2–ol
1336
1–(2–clorofenil)–2–(5H–imidazo[5,1–a]isoindol–5–il)etanol
1343
imagen27 1–(3–clorofenil)–2–(5H–imidazo[5,1–a]isoindol–5–il)etanol
1348
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–feniletanona
1349
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–feniletanol
1352
1–(2,4–dimetilfuran–3–il)–2–(6–fluoro–5H–imidazo[5,1– a]isoindol–5–il)etanol;
1353
1–(3–clorofenil)–2–(5H–imidazo[5,1–a]isoindol–5–il)etanona
1356
1–ciclohexil–2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5– il)etanona
1357
1–ciclohexil–2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5– il)etanol
1358
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(tetrahidro–2Hpiran–4– il)etanol
1359
2–(7–cloro–5H–imidazo[5,1–a]isoindol–5–il)–1– ciclohexiletanol
1360
(Z)–1–ciclohexil–2–(5H–imidazo[5,1–a]isoindol–5–il)etanona oxima
1362
1–ciclopentil–2–(5H–imidazo[5,1–a]isoindol–5–il)etanol
1363
tert–butil 4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5– il)etil)piperidina–1–carboxilato
1364
1–ciclohexil–2–(5H–imidazo[5,1–a]isoindol–5–il)etanamina
1367
tert–butil (3–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5– il)etil)fenil)carbamato
1369
1–(3–aminofenil)–2–(5H–imidazo[5,1–a]isoindol–5–il)etanol
1370
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(piperidin–4–il)etanol
1371
4–(2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5–il)–1– hidroxietil)ciclohexanol;
1372
1–ciclohexil–2–(9–metoxi–5H–imidazo[5,1–a]isoindol–5– il)etanol
1373
5–(2–ciclohexil–2–hidroxietil)–5H–imidazo[5,1–a] isoindol–9– ol
1374
2–(8–cloro–5H–imidazo[5,1–a]isoindol–5–il)–1– ciclohexiletanol;
1375
1–(ciclohex–1–en–1–il)–2–(5H–imidazo[5,1–a]isoindol–5– il)etanol;
1376
1–ciclohexil–2–(8–fluoro–5H–imidazo[5,1–a]isoindol–5– il)etanol;
1378
2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5–il)–1–(1,4– dioxaspiro[4.5]decan–8–il)etanol;
1379
4–(2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5–il)–1– hidroxietil)ciclohexanona;
1381
2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5–il)–1–(4– metilenociclohexil)etanol;
1382
1–(ciclohex–3–en–1–il)–2–(5H–imidazo[5,1–a]isoindol–5– il)etanol;
1383
1–(4–(hidroximatil)ciclohexil)–2–(5H–imidazo[5,1–a] isoindol– 5–il)etanol;
1384
(4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5– il)etil)piperidin–1–il)(tiofen–2–il)metanona;
1385
1–(4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5– il)etil)piperidin–1–il)etanona;
1386
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(4– metilenociclohexil)etanol;
1387
2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5–il)–1–(4– metilciclohexil)etanol;
1389
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(1–metil–1Himidazol– 4–il)etanol;
1390
imagen28 2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(tiazol–4–il)etanol;
1391
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(tiazol–5–il)etanol;
1392
1–(4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5– il)etil)piperidin–1–il)–2,2–dimetilpropan–1–ona;
1393
2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5–il)–1–(furan–2– il)etanol;
1394
imagen29 2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5–il)–1–(1–metil–1H– imidazol–2–il)etanol;
1396
(1S)–1–ciclohexil–2–(5H–imidazo[5,1–a]isoindol–5–il)etanol;
1397
(1R)–1–ciclohexil–2–(5H–imidazo[5,1–a]isoindol–5–il)etanol;
1398
2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5–il)–1–(4– (yodometileno)ciclohexil)etanol;
1400
1–ciclohexil–2–(5H–imidazo[5,1–a]isoindol–5–il)propan–1–ol;
1402
2–(5H–imidazo[5,1–a]isoindol–5–il)acetonitrilo;
1403
imagen30 1–ciclohexil–3–(6–fluoro–5H–imidazo[5,1–a]isoindol–5– il)propan–2–ol;
1404
1–ciclohexil–3–(5H–imidazo[5,1–a]isoindol–5–il)propan–2–ol;
1405
1–(4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5– il)etil)piperidin–1–il)–2–feniletanona;
1406
1–(4,4–difluorociclohexil)–2–(6–fluoro–5H–imidazo[5,1– a]isoindol–5–il)etanol;
1407
1–(4,4–difluorociclohexil)–2–(5H–imidazo[5,1–a]isoindol–5– il)etanol;
1409
2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5–il)–1–(1–metil–1H– imidazol–5–il)etanol;
1410
1–(4–(ciclopropilmetileno)ciclohexil)–2–(6–fluoro– 5Himidazo[5,1–a]isoindol–5–il)etanol;
1411
2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5–il)–1–(4–(propan– 2–ilideno)ciclohexil)etanol;
1412
(E)–5–(2–ciclohexilvinil)–5H–imidazo[5,1–a]isoindol;
1413
2–(9–fluoro–5H–imidazo[5,1–a]isoindol–5–il)–1–(4– metilciclohexil)etanol;
1414
1–(ciclohex–3–en–1–il)–2–(6–fluoro–5H–imidazo[5,1– a]isoindol–5–il)etanol;
1415
(R)–1–ciclohexil–2–((R)–5H–imidazo[5,1–a]isoindol–5– il)etanol
1416
(S)–1–ciclohexil–2–((R)–5H–imidazo[5,1–a]isoindol–5– il)etanol
1417
imagen31 (S)–1–ciclohexil–2–((S)–5H–imidazo[5,1–a]isoindol–5– il)etanol
1418
(R)–1–ciclohexil–2–((S)–5H–imidazo[5,1–a]isoindol–5– il)etanol
1419
1–ciclohexil–2–(5H–imidazo[5,1–a]isoindol–5–ilideno)etanol
1420
imagen32 1–ciclohexil–2–(5H–imidazo[5,1–a]isoindol–5–il)etilacetato
1421
1–(4–(2–(benciloxi)etilideno)ciclohexil)–2–(5Himidazo[5,1– a]isoindol–5–il)etanol
1422
1–(1–(bencilsulfonil)piperidin–4–il)–2–(5H–imidazo[5,1– a]isoindol–5–il)etanol
1423
imagen33 1–(4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5– il)etil)piperidin–1–il)–2–(pirimidin–5–il)etanona
1424
2–(3,4–difluorofenil)–1–(4–(1–hidroxi–2–(5H–imidazo[5,1– a]isoindol–5–il)etil)piperidin–1–il)etanona
1425
ciclohexil(4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5– il)etil)piperidin–1–il)metanona
1426
metil 4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5– il)etil)ciclohexanocarboxilato
1427
1–ciclohexil–2–(5H–imidazo[5,1–a]isoindol–5–il)etil fenilcarbamato
1428
ácido 4–(1–ciclohexil–2–(5H–imidazo[5,1–a]isoindol–5– il)etoxi)–4–oxobutanoico
1429
imagen34 4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5– il)etil)ciclohexanol
1431
1–ciclohexil–2–(5H–imidazo[5,1–a]isoindol–5–il)etil benzoato
1432
4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5–il)etil)–N–(2– (metilsulfonamido)etil) ciclohexanocarboxamina
1433
(2S)–1–(1–ciclohexil–2–(5H–imidazo[5,1–a]isoindol–5– il)etoxi)–3–metil–1–oxobutan–2–aminio cloruro
1434
sodio 1–ciclohexil–2–(5H–imidazo[5,1–a]isoindol–5– il)etil fosfato
1436
ácido 4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5– il)etil)ciclohexanocarboxílico
1437
1–(4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5– il)etil)piperidin–1–il)–2–(piridin–4–il)etanona
1438
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(espiro[2.5]octan–6– il)etanol
1439
2–(4–fluorofenil)–1–(4–(1–hidroxi–2–(5H–imidazo[5,1–a] isoindol–5–il)etil)piperidin–1–il)etanona
1440
imagen35 (2S)–1–ciclohexil–2–(5H–imidazo[5,1–a]isoindol–5–il)etil 2– aminopropanoato
1441
1–(4–(2–hidroxietilideno)ciclohexil)–2–(5H–imidazo[5,1– a]isoindol–5–il)etanol
1442
imagen36 (2S)–1–ciclohexil–2–(5H–imidazo[5,1–a]isoindol–5–il)etil pirrolidina–2–carboxilato
1443
(2S)–5–(1–ciclohexil–2–(5H–imidazo[5,1–a]isoindol–5– il)etil) 1–metil 2–aminopentanodioato
1447
1–(4–((S)–1–hidroxi–2–((S)–5H–imidazo[5,1–a]isoindol–5– il)etil)piperidin–1–il)–2–feniletanona
1448
(3–fluoro–2–hidroxifenil)(4–(1–hidroxi–2–(5Himidazo[5,1– a]isoindol–5–il)etil)piperidin–1–il)metanona
1449
4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5–il)etil)– Nfenilpiperidina–1–carboxamina
1450
(4–fluorofenil)(4–(1–hidroxi–2–(5H–imidazo[5,1–a] isoindol–5– il)etil)piperidin–1–il)metanona
1451
(2S)–2–amino–1–(4–(1–hidroxi–2–(5H–imidazo[5,1–a] isoindol–5–il)etil)piperidin–1–il)–3–fenilpropan–1–ona
1454
(4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5– il)etil)piperidin–1–il)((S)–pirrolidin–2–il)metanona
1455
(1R,4s)–4–(2–((S)–6–fluoro–5H–imidazo[5,1–a]isoindol–5–il)– 1–hidroxietil)ciclohexil benzoato
1456
(1R,4s)–4–(2–((S)–6–fluoro–5H–imidazo[5,1–a]isoindol–5–il)– 1–hidroxietil)ciclohexanol
1458
imagen37 1–(3–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5– il)etil)azetidin–1–il)–2–feniletanona
1459
3–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5–il)etil)– Nfenilazetidina– 1–carboxamina
1460
tert–butil 3–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5– il)etil)azetidina–1–carboxilato
1461
1–(azetidin–3–il)–2–(5H–imidazo[5,1–a]isoindol–5–il)etanol
1469
tert–butil 4–((S)–1–hidroxi–2–((R)–5H–imidazo[5,1–a] isoindol–5–il)etil)piperidina–1–carboxilato
1470
tert–butil 4–((R)–1–hidroxi–2–((R)–5H–imidazo[5,1–a] isoindol–5–il)etil)piperidina–1–carboxilato
1471
tert–butil 4–((R)–1–hidroxi–2–((S)–5H–imidazo[5,1–a] isoindol–5–il)etil)piperidina–1–carboxilato
1472
imagen38 tert–butil 4–((S)–1–hidroxi–2–((S)–5H–imidazo[5,1–a] isoindol–5–il)etil)piperidina–1–carboxilato
1473
imagen39 1–((1s,4s)–4–(benciloxi)ciclohexil)–2–(6–fluoro– 5Himidazo[5,1–a]isoindol–5–il)etanol
1474
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(piridin–3–il)etanol
1475
imagen40 (1r,4r)–4–(2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5–il)–1– hidroxietil)ciclohexanol
1476
4–((S)–1–hidroxi–2–((R)–5H–imidazo[5,1–a]isoindol–5– il)etil)–N–fenilpiperidina–1–carboxamina
1477
4–((R)–1–hidroxi–2–((R)–5H–imidazo[5,1–a]isoindol–5– il)etil)–N–fenilpiperidina–1–carboxamina
1478
4–((R)–1–hidroxi–2–((S)–5H–imidazo[5,1–a]isoindol–5– il)etil)–N–fenilpiperidina–1–carboxamina
1479
4–((S)–1–hidroxi–2–((S)–5H–imidazo[5,1–a]isoindol–5–il)etil)– N–fenilpiperidina–1–carboxamina
1480
1–(4–((R)–1–hidroxi–2–((S)–5H–imidazo[5,1–a]isoindol–5– il)etil)piperidin–1–il)–2–feniletanona
1482
(1R,4s)–4–((S)–2–((R)–6–fluoro–5H–imidazo[5,1–a]isoindol– 5–il)–1–hidroxietil)ciclohexanol
1483
(1S,4s)–4–((R)–2–((R)–6–fluoro–5H–imidazo[5,1–a]isoindol– 5–il)–1–hidroxietil)ciclohexanol
1484
(1S,4s)–4–((R)–2–((S)–6–fluoro–5H–imidazo[5,1–a]isoindol– 5–il)–1–hidroxietil)ciclohexanol
1485
(1R,4s)–4–((S)–2–((S)–6–fluoro–5H–imidazo[5,1–a]isoindol– 5–il)–1–hidroxietil)ciclohexanol
1486
(1S,4r)–4–((S)–2–((S)–6–fluoro–5H–imidazo[5,1–a]isoindol– 5–il)–1–hidroxietil)ciclohexanol
1487
(1S,4r)–4–((S)–2–((R)–6–fluoro–5H–imidazo[5,1–a]isoindol– 5–il)–1–hidroxietil)ciclohexanol
1488
imagen41 (1R,4r)–4–((R)–2–((S)–6–fluoro–5H–imidazo[5,1–a]isoindol– 5–il)–1–hidroxietil)ciclohexanol
1489
(1R,4r)–4–((R)–2–((R)–6–fluoro–5H–imidazo[5,1–a]isoindol– 5–il)–1–hidroxietil)ciclohexanol
1490
1–(4–((S)–1–hidroxi–2–((S)–5H–imidazo[5,1–a]isoindol–5– il)etil)piperidin–1–il)–2–(tetrahidro–2H–piran–4–il)etanona
1491
1–(4–((R)–1–hidroxi–2–((R)–5H–imidazo[5,1–a]isoindol–5– il)etil)piperidin–1–il)–2–feniletanona
1492
N–((1s,4s)–4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5– il)etil)ciclohexil)benzamida
1493
1–(4–((S)–1–hidroxi–2–((R)–5H–imidazo[5,1–a]isoindol–5– il)etil)piperidin–1–il)–2–feniletanona
1494
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(1– (fenilcarbamoil)piperidin–4–il)etil fenilcarbamato
1495
4–((R)–1–hidroxi–2–((S)–5H–imidazo[5,1–a]isoindol–5– il)etil)–N–((1r,4R)–4–hidroxiciclohexil)piperidina–1– carboxamina
1496
4–((S)–1–hidroxi–2–((S)–5H–imidazo[5,1–a]isoindol–5–il)etil)– N–(tetrahidro–2H–piran–4–il)piperidina–1–carboxamina
1497
4–((S)–1–hidroxi–2–((S)–5H–imidazo[5,1–a]isoindol–5–il)etil)– N–((1r,4S)–4–hidroxiciclohexil)piperidina–1–carboxamina
1498
1–((1r,4r)–4–(benciloxi)ciclohexil)–2–(5H–imidazo[5,1–a] isoindol–5–il)etanol
1499
1–((1r,4r)–4–(benciloxi)ciclohexil)–2–(6–fluoro– 5Himidazo[5,1–a]isoindol–5–il)etanol
1500
1–(4–((R)–1–hidroxi–2–((S)–5H–imidazo[5,1–a]isoindol–5– il)etil)piperidin–1–il)–2–(tetrahidro–2H–piran–4–il)etanona
1501
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(piridin–4–il)etanol
1502
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(piridin–2–il)etanol
1503
4–((R)–1–hidroxi–2–((S)–5H–imidazo[5,1–a]isoindol–5– il)etil)–N–(tetrahidro–2H–piran–4–il)piperidina–1–carboxamina
1504
N–ciclohexil–4–((R)–1–hidroxi–2–((S)–5H–imidazo[5,1–a] isoindol–5–il)etil)piperidina–1–carboxamina
1505
N–((1r,4r)–4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5– il)etil)ciclohexil)benzamida
1507
N–ciclopentil–4–((R)–1–hidroxi–2–((S)–5H–imidazo[5,1–a] isoindol–5–il)etil)piperidina–1–carboxamina
1508
2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5–il)–1–(4– (trifluorometil)ciclohexil)etanol
1509
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(4– (trifluorometil)ciclohexil)etanol
1511
2–(4–fluorofenil)–1–(4–((R)–1–hidroxi–2–((S)–5Himidazo[5,1– a]isoindol–5–il)etil)piperidin–1–il)etanona
1512
4–((R)–1–hidroxi–2–((S)–5H–imidazo[5,1–a]isoindol–5– il)etil)–N–(4–(trifluorometil)fenil)piperidina–1–carboxamina
1513
(4–((R)–1–hidroxi–2–((S)–5H–imidazo[5,1–a]isoindol–5– il)etil)piperidin–1–il)(1H–imidazol–1–il)metanona
1–(5H–imidazo[5,1–a]isoindol–5–il)–3–metilbutan–2–ol
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(tetrahidro–2Hpiran– 3–il)etanol
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(piperidin–3– il)etanol
imagen42
1–ciclohexil–2–((R)–5H–imidazo[5,1–a]isoindol–5–il)etanol
1–ciclohexil–2–((S)–5H–imidazo[5,1–a]isoindol–5–il)etanol
1–ciclohexil–3–(5H–imidazo[5,1–a]isoindol–5–il)propan–1–ol
1–ciclohexil–2–(9–fluoro–5H–imidazo[5,1–a]isoindol–5– il)etanol
N–(4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5–il)etil)fenil)– 2–(tetrahidro–2H–piran–4–il)acetamida
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(1H–imidazol–2– il)etanol
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(1H–imidazol–4– il)etanol
2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5–il)–1–(tiazol–2– il)etanol
(5S)–5–(2–ciclohexil–2–hidroxietil)–5H–imidazo[5,1–a] isoindol–6–ol
1–(2–aminociclohexil)–2–(5H–imidazo[5,1–a]isoindol–5– il)etanol
N–(1–ciclohexil–2–(5H–imidazo[5,1–a]isoindol–5– il)etil)acetamida
N–(2–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5– il)etil)ciclohexil)acetamida
1–ciclohexil–2–(5H–imidazo[5,1–a]isoindol–5–il)– Nmetiletanamina
imagen43
2–(1–ciclohexil–2–((S)–5H–imidazo[5,1–a]isoindol–5– il)etil)amino)etanosulfonamida
2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5–il)–1–(1– metilpiperidin–4–il)etanol
1–(4–aminociclohexil)–2–(5H–imidazo[5,1–a]isoindol–5– il)etanol
N–(4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5– il)etil)ciclohexil)acetamida
1–(4–(aminometil)ciclohexil)–2–(5H–imidazo[5,1–a] isoindol– 5–il)etanol
4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5– il)etil)ciclohexanocarboxamina
1–(3–aminociclohexil)–2–(5H–imidazo[5,1–a]isoindol–5– il)etanol
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–((1r,4r)–4–(piridin–2– ilmetoxi)ciclohexil)etanol
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–((1r,4r)–4–(piridin–3– ilmetoxi)ciclohexil)etanol
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–((1r,4r)–4–(piridin–4– ilmetoxi)ciclohexil)etanol
imagen44
1–((1r,4r)–4–((2–aminopiridin–4–il)metoxi)ciclohexil)–2–(5H– imidazo[5,1–a]isoindol–5–il)etanol
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–((1r,4r)–4–(pyrazin–2– ilmetoxi)ciclohexil)etanol
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–((1r,4r)–4–(pirimidin– 5–ilmetoxi)ciclohexil)etanol
1–((1r,4r)–4–((6–aminopiridin–2–il)metoxi)ciclohexil)–2–(5H– imidazo[5,1–a]isoindol–5–il)etanol
1–((1r,4r)–4–((6–aminopiridin–3–il)metoxi)ciclohexil)–2–(5H– imidazo[5,1–a]isoindol–5–il)etanol
1–((1r,4r)–4–((3–aminopiridin–2–il)metoxi)ciclohexil)–2–(5H– imidazo[5,1–a]isoindol–5–il)etanol
1–((1r,4r)–4–((2–aminopirimidin–5–il)metoxi) ciclohexil)–2– (5H–imidazo[5,1–a]isoindol–5–il)etanol
imagen45
1–((1r,4r)–4–((4–aminopirimidin–5–il)metoxi) ciclohexil)–2– (5H–imidazo[5,1–a]isoindol–5–il)etanol
1–((1r,4r)–4–((5–aminopiridin–2–il)metoxi)ciclohexil)–2–(5H– imidazo[5,1–a]isoindol–5–il)etanol
imagen46
4–((((1r,4r)–4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5– il)etil)ciclohexil)oxi)metil)–N,N–dimetilbenzamida
3–((((1r,4r)–4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5– il)etil)ciclohexil)oxi)metil)–N,N–dimetilbenzamida
2–((((1r,4r)–4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5– il)etil)ciclohexil)oxi)metil)–N,N–dimetilbenzamida
imagen47
4–((((1r,4r)–4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5– il)etil)ciclohexil)oxi)metil) bencenosulfonamida
imagen48
3–((((1r,4r)–4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5– il)etil)ciclohexil)oxi)metil) bencenosulfonamida
2–((((1r,4r)–4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5– il)etil)ciclohexil)oxi)metil) bencenosulfonamida
4–((((1r,4r)–4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5– il)etil)ciclohexil)oxi)metil)benzamida
3–((((1r,4r)–4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5– il)etil)ciclohexil)oxi)metil)benzamida
2–((((1r,4r)–4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5– il)etil)ciclohexil)oxi)metil)benzamida
imagen49
metil 4–((((1r,4r)–4–(1–hidroxi–2–(5H–imidazo[5,1–a] isoindol–5–il)etil)ciclohexil)oxi)metil)benzoato
metil 3–((((1r,4r)–4–(1–hidroxi–2–(5H–imidazo[5,1–a] isoindol–5–il)etil)ciclohexil)oxi)metil)benzoato
metil 2–((((1r,4r)–4–(1–hidroxi–2–(5H–imidazo[5,1–a] isoindol–5–il)etil)ciclohexil)oxi)metil)benzoato
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–((1r,4r)–4– metoxiciclohexil)etanol
1–((1r,4r)–4–etoxiciclohexil)–2–(5H–imidazo[5,1–a] isoindol– 5–il)etanol
imagen50
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–((1r,4r)–4– isopropoxiciclohexil)etanol
1–((1r,4r)–4–(ciclopropilmetoxi)ciclohexil)–2–(5Himidazo[5,1– a]isoindol–5–il)etanol
imagen51
1–((1r,4r)–4–(ciclopentilmetoxi)ciclohexil)–2–(5Himidazo[5,1– a]isoindol–5–il)etanol
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–((1r,4r)–4–(tiofen–2– ilmetoxi)ciclohexil)etanol
1–((1r,4r)–4–((1H–indol–3–il)oxi)ciclohexil)–2– (5Himidazo[5,1–a]isoindol–5–il)etanol
1–((1r,4r)–4–((1H–indol–5–il)oxi)ciclohexil)–2– (5Himidazo[5,1–a]isoindol–5–il)etanol
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(4–((tetrahidro– 2Hpiran–4–il)metoxi)ciclohexil)etanol
imagen52
4–(((4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5– il)etil)ciclohexil)oxi)metil)bencenosulfonamida
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(4–(oxazol–2– ilmetoxi)ciclohexil)etanol
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(4–(tiazol–2– ilmetoxi)ciclohexil)etanol
imagen53
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(1–(1–imino–2– feniletil)piperidin–4–il)etanol
4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5–il)etil)– Nfenilpiperidina–1–carboximidamida
4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5–il)etil)–N– (piridin–4–il)piperidina–1–carboximidamida
4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5–il)etil)–N– (tetrahidro–2H–piran–4–il)piperidina–1–carboximidamida
N–(4–cianofenil)–4–(1–hidroxi–2–(5H–imidazo[5,1–a] isoindol–5–il)etil)piperidina–1–carboxamina
N–(tert–butil)–4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5– il)etil)piperidina–1–carboxamina
imagen54
N–(tert–butil)–4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5– il)etil)piperidina–1–sulfonamida
1–(4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5– il)etil)piperidin–1–il)–2–(3–hidroxifenil)etanona
2–(1–(azetidina–1–carbonil)piperidin–4–il)–2–hidroxi– 1–(4– (1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5–il)etil)piperidin–1– il)etanona
2–ciclopentil–1–(4–(1–hidroxi–2–(5H–imidazo[5,1–a] isoindol– 5–il)etil)piperidin–1–il)etanona
1–(4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5– il)etil)piperidin–1–il)–2–(2–metiltiazol–5–il)etanona
N–ciclohexil–N–hidroxi–4–(1–hidroxi–2–(5H–imidazo[5,1– a]isoindol–5–il)etil)piperidina–1–carboxamina
N–(4–(2–(4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5– il)etil)piperidin–1–il)–2–oxoetil)fenil) metanosulfonamida
N–ciclopropil–N–hidroxi–4–(1–hidroxi–2–(5Himidazo[5,1– a]isoindol–5–il)etil)piperidina–1–carboxamina
3,3–difluoro–1–(4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol– 5–il)etil)piperidin–1–il)butan–1–ona
1–(4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5– il)etil)piperidin–1–il)–2–(p–tolil)etanona
1–(11–(4–aminopirimidin–2–il)piperidin–4–il)–2– (5Himidazo[5,1–a]isoindol–5–il)etanol
1–(1–(2–aminopirimidin–4–il)piperidin–4–il)–2– (5Himidazo[5,1–a]isoindol–5–il)etanol
N–ciclopropil–4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5– il)etil)piperidina–1–carboxamina
2–ciclopropil–1–(4–(1–hidroxi–2–(5H–imidazo[5,1–a] isoindol– 5–il)etil)piperidin–1–il)etanona
2–(4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5– il)etil)ciclohexilideno)acetonitrilo
imagen55
4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5–il)etil)–N–(4– (trifluorometil)tiazol–2–il)piperidina–1–carboxamina
imagen56
4–(2–(4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5– il)etil)piperidin–1–il)–2–oxoetil)benzamida
1–(4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5– il)etil)piperidin–1–il)–2–(4–(metilsulfonil)fenil)etanona
4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5–il)etil)–N– ((1r,4r)–4–metilciclohexil)piperidina–1–carboxamina
1–(4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5– il)etil)piperidin–1–il)–3,3–dimetilbutan–1–ona
4–(2–(4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5– il)etil)piperidin–1–il)–2–oxoetil)bencenosulfonamida
N–(tert–butil)–4–(2–(4–(1–hidroxi–2–(5H–imidazo[5,1– a]isoindol–5–il)etil)piperidin–1–il)–2– oxoetil)bencenosulfonamida
ácido 4–(2–(4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5– il)etil)piperidin–1–il)–2–oxoetil)benzoico
1–(4–(difluorometileno)ciclohexil)–2–(5H–imidazo[5,1–a] isoindol–5–il)etanol
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(4–(2,2,2– trifluoroetilideno)ciclohexil)etanol
N–bencil–4–(2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5–il)–1– hidroxietil)ciclohexanocarboxamina
4–(2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5–il)–1– hidroxietil)–N–fenilciclohexanocarboxamina
N–(4–(2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5–il)–1– hidroxietil)ciclohexil)benzamida
1–(4–(2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5–il)–1– hidroxietil)ciclohexil)–3–fenilurea
N–(4–(2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5–il)–1– hidroxietil)ciclohexil)–2–fenilacetamida
y las sales farmacéuticamente aceptables de los mismos.
En otro aspecto, la presente divulgación provee compuestos y composiciones farmacéuticas que comprenden los compuestos de acuerdo con uno cualquiera de los aspectos precedentes de la invención o cualquier realización de la misma, junto con un excipiente, diluyente, o portador farmacéuticamente aceptable.
En otro aspecto de la divulgación, se describen los métodos para tratar inmunosupresión mediada por indolamina 2,3– dioxigenasa (IDO) en un sujeto en necesidad del mismo, que comprende la administración de una cantidad eficaz de
imagen57
imagen58
imagen59
imagen60
imagen61
imagen62
imagen63
imagen64
imagen65
imagen66
imagen67
imagen68
#
Compuesto Nombre Rendimiento (%)
1
(E)–3–(2–cloro–6–yodofenil)–1– ciclohexilprop–2–en–1–ona 63
1H RMN 1.22–1.45 (m, 5 H), 1.70–174 (m, 1H), 1.79–1.85 (m, 2H), 1.93–1.99 (m, 2H), 2.61–2.65 (m, 1H), 6.67 (d, 1H, J = 16 Hz), 6.93 (t, 1H, J = 8 Hz), 7.42 (d, 1H, J = 8 Hz), 7.48 (d, 1H, J = 16 Hz), 7.82 (d, 1H, J = 8 Hz)
2
imagen69 (E)–3–(2–yodofenil)–1–(3– nitrofenil)prop–2–en–1–ona 53
1H RMN 7.10–7.16 (m, 1H), 7.34 (d, 1H, J = 15.6 Hz), 7.41–7.46 (m, 1H), 7.71–7.76 (m, 2H), 7.94–7.97 (m, 1H), 8.05 (d, 1H, J = 15.6 Hz), 8.34–8.48 (m, 2H), 8.81 (s, 1H)
Ejemplo 2 Procedimiento general para la síntesis de 2–(5H–imidazo[5,1–a]isoindol–5–il)etanonas por acoplamiento cruzado Negishi catalizado con paladio de yoduro de arilos 1 y 2 con 4–yodo–1–tritil–1H–imidazol.
imagen70
5 A una solución agitada de 4–yodo–1–tritil–1H–imidazol (218 mg, 0.5 mmol) en THF anhidro (4 mL) a rt se le adicionó gota a gota EtMgBr (1.0 M en THF, 0.5 mmol, 0.5 mL), con una atmósfera de N2. La solución resultante se dejó agitar, durante 90 min y se le adicionó ZnCl2 anhidro (0.5 mmol, 68.2 mg). La suspensión de color blanco resultante se dejó agitar, durante 90 min y una solución del yoduro de arilo apropiado 1, 2 o 86 (0.5 mmol) en THF (1 mL) se le adicionó seguido de la adición inmediata de Pd(PPh3)4 (56 mg, 0.05 mmol). La mezcla de reacción se dejó agitar a 70 °C,
10 durante 12 h con una atmósfera de N2. Después de enfriar a temperatura ambiente, la solución se diluyó con CH2Cl2 (20 mL) y la capa orgánica se lavó con una solución reguladora EDTA (acuosa) (pH = 9) (2 x 5 mL) y salmuera. La capa orgánica se secó (Na2SO4) y se concentró a presión reducida. El residuo en bruto se utilizó en la siguiente etapa sin purificación adicional. A una solución del producto en bruto imidazol a partir de la etapa anterior se le adicionó ácido acético (1.0 mL) y MeOH (4.0 mL). La solución se agitó a 90 °C, durante 3 h. La mezcla de reacción se dejó enfriar a
15 temperatura ambiente y el pH se ajustó a 10 con K2CO3 saturado (acuoso). La fase acuosa se extrajo con EtOAc (3 x 20 mL). Las capas orgánicas combinadas se lavaron con agua, salmuera y se secaron. El solvente se eliminó a vacío para proporcionar el residuo en bruto, que se purificó por cromatografía en columna instantánea en sílica gel para proporcionar los siguientes compuestos.
20
#
Compuesto Nombre Rendimiento (%)
1287
2–(6–cloro–5H–imidazo[5,1–a]isoindol–5– il)–1–ciclohexiletanona 25
1H RMN 1.18–1.36 (m, 5H), 1.68–1.88 (m, 5H), 2.37–2.40 (m, 1H), 2.64 (dd, 1H, J = 20.0 Hz, 10.0 Hz), 3.79 (dd, 1H, J = 16.0 Hz, 4.0 Hz), 5.70 (d, 1H, J = 8.0 Hz), 7.17–7.20 (m, 2H), 7.32 (t, 1H, J = 8.0 Hz), 7.43 (d, 1H, J = 8.0 Hz), 7.61 (s, 1H)
1256
etil 2–(5H–imidazo[5,1–a]isoindol–5– il)acetato 23
1H RMN 1.31 (t, 3H, J = 7.5 Hz), 2.67 (dd, 1H, J = 20.0 Hz, 12.0 Hz), 3.07 (dd, 1H, J = 20.0 Hz, 4.0 Hz), 4.25 (q, 2H, J = 6.0 Hz), 5.53 (dd, 1H, J = 12.0 Hz, 4.0 Hz), 7.16 (s, 1H), 7.21–7.37 (m, 3H), 7.51 (d, 1H, J = 6.0 Hz), 7.75 (s, 1H)
1306
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(3– nitrofenil)etanona 15
1H RMN 3.49 (dd, 1H, J = 18.6 Hz, 9.6 Hz), 3.80 (dd, 2H, J = 18.3 Hz, 3.3 Hz), 5.84 (dd, 1H, J = 3 Hz, 9.3 Hz), 7.26–7.32 (m, 1H), 7.38–7.49 (m, 2H), 7.55–7.59 (m, 1H), 7.70–7.76 (m, 2H), 8.32 (d, 1H, J = 6 Hz), 8.46–8.50 (m, 1H), 8.78 (s, 1H)
Ejemplo 3 acoplamiento cruzado Suzuki de 4–yodo–1–tritil–1H–imidazol con ácidos fenilborónicos
imagen71
Una suspensión de 4–yodo–1–tritil–1H–imidazol (6.88 mmol), el derivado ácido 2–formil borónico apropiado (10.31 mmol) y K3PO4 (20.63 mmol) en N,N–dimetilformamida (30 mL) y agua (6 mL) se purgó con nitrógeno, durante 5 minutos, seguido por la adición de Pd(PPh3)4 y la mezcla se purgó con nitrógeno, durante otros 5 minutos. La mezcla de reacción se agitó a 90 °C, durante 16 h con una atmósfera de N2. La solución se dejó enfriar y se filtró a través de un tapón de celite. La mezcla se diluyó con agua (50 mL) y EtOAc (25 mL). La capa orgánica se recolectó y la capa acuosa se extrajo con EtOAc (2 x 25 mL). Los extractos orgánicos combinados se lavaron con agua (2 x 25 mL), salmuera y se secaron (Na2SO4). La solución se filtró y el solvente se eliminó a presión reducida para proporcionar el producto en bruto que se purificó por cromatografía en columna instantánea en sílica gel para proporcionar los siguientes compuestos.
#
Compuesto Nombre Rendimiento (%)
3
2–(1–tritil–1H–imidazol–4–il)benzaldehido 52
1H RMN 7.03 (s, 1H), 7.18–7.20 (m, 6 H), 7.36–7.39 (m, 10H), 7.53–7.58 (m, 3H), 7.64 (d, 1H, J = 7.78 Hz), 7.93 (d, 1H, J = 7.87 Hz)
4
2–fluoro–6–(1–tritil–1H–imidazol–4– il)benzaldehido 46
1H RMN 7.02–7.07 (m, 1H), 7.10 (d, 1H, J = 1.6 Hz), 7.16–7.18 (m, 6H), 7.36–7.39 (m, 9H), 7.46–7.52 (m, 2H), 7.57 (s, 1H), 10.27 (s, 1H)
5
5–cloro–2–(1–tritil–1H–imidazol–4– il)benzaldehido 48
1H RMN 7.04 (d, 1H, J = 1.2 Hz), 7.10–7.19 (m, 5H), 7.32–7.38 (m, 12H), 7.58 (dd, 1H, J = 2.4, 8.4 Hz), 7.57–7.59 (m, 2H), 7.89 (d, 1H, J = 2.0 Hz), 10.34 (s, 1H)
6
4–cloro–2–(1–tritil–1H–imidazol–4–il)benzaldehido 55
1H RMN 7.08–7.38 (m, 18 H), 7.60 (s, 1H), 7.88 (d, 1H, J = 8.4 Hz), 10.41 (s, 1H)
7
4–fluoro–2–(1–tritil–1H–imidazol–4– il)benzaldehido 89
1H RMN (MeOH–d4) 7.16–7.27 (m, 6H), 7.29–7.47 (m, 3H), 7.60–7.70 (m, 9H), 7.85–7.90 (m, 2H), 10.26 (s, 1H)
Ejemplo 4 3–Metoxi–2–(1–tritil–1H–imidazol–4–il)benzaldehido
77
imagen72
1H RMN 3.19 (dd, 1H, J = 20.0 Hz, 8.0 Hz), 3.65 (dd, 1H, J = 20.0 Hz, 4.0 Hz), 5.81 (dd, 1H, J = 8.0 Hz, 4.0 Hz), 7.19 (s, 1H), 7.22–7.28 (m, 1H), 7.36 (m, 3H), 7.54 (d, 1H, J = 8.0 Hz), 7.61–7.65 (m, 1H), 7.70–7.74 (m, 1H), 7.85 (s, 1H), 8.16 (d, 1H, J = 8.0 Hz).
1328
tert–butil (2–(2–(5H–imidazo[5,1–a] isoindol–5–il)acetil)fenil)carbamato 44
1H RMN 1.50 (s, 9H), 3.47 (dd, 1H, J = 18.0 Hz, 9.6 Hz), 3.77 (dd, 1H, 18.0 Hz, 3.3 Hz), 5.77–5.81 (m, 1H), 6.98 (t, 1H, J = 8.0 Hz), 7.19 (s, 1H), 7.28 (d, 1H, J = 7.6 Hz), 7.37 (d, 1H, J = 8.0 Hz), 7.41 (d, 1H, J = 8.0 Hz), 7.52–7.56 (m, 2H), 7.72 (d, 1H, J = 8.0 Hz), 7.77 (s, 1H), 8.54 (d, 1H, J = 8.4 Hz)
1300
tert–butil (4–(2–(5H–imidazo[5,1–a] isoindol–5– il)acetil)fenil)carbamato 39
1H RMN 1.52 (s, 9H), 3.39 (dd, 1H, J = 18.6 Hz, 9.6 Hz), 3.68 (dd, 1H, J = 18.3 Hz, 3.3 Hz), 5.83 (dd, 1H, J = 3 Hz, 9.3 Hz), 6.88 (s, 1H), 7.14–7.58 (m, 7H), 7.75 (s, 1H), 7.92 (d, 2H, J = 9 Hz)
1348
2–(5H–imidazo[5,1–a]isoindol–5–il)–1– feniletanona 45
1H RMN 3.44 (dd, 1H, J = 20.0 Hz, 8.0 Hz), 3.72 (dd, 1H, J = 20.0 Hz, 4.0 Hz), 5.83 (d, 1H, J = 8.0 Hz), 7.18 (s, 1H), 7.25–7.29 (m, 1H), 7.40 (t, 2H, J = 10 Hz), 7.47 (t, 2H, J = 8.0 Hz), 7.57 (d, 1H, J = 8.0 Hz), 7.61 (t, 1H, J = 6.0 Hz), 7.74 (s, 1H), 7.97 (d, 2H, J = 8 Hz)
9
tert–butil 4–(2–(5H–imidazo[5,1–a] isoindol–5–il)acetil)piperidina–1– carboxilato 19
1H RMN 1.44 (s, 9H), 1.50–1.82 (m, 4H), 2.72–2.76 (m, 2H), 2.90 (dd, 1H, J = 18.5 Hz, 9.4 Hz), 3.21 (dd, 1H, J = 18.57 Hz, 3.6 Hz), 5.63 (dd, 1H, J = 9.6 Hz, 3.6 Hz), 7.16 (s, 1H), 7.23 (m, 2H), 7.35–7.39 (m, 1H), 7.53 (d, 1H, J = 7.5 Hz), 7.59 (s, 1H)
10
imagen73 2–(6–fluoro–5H–imidazo[5,1–a] isoindol–5– il)–1–(1,4–dioxaspiro[4.5] decan–8– il)etanona 18
1H RMN (MeOH–d4) 1.50–1.90 (m, 6H), 2.35–2.60 (m, 2H), 2.98 (dd, 1H, J = 18.9 Hz, 10.2 Hz), 3.61 (dd, 1H, J = 18.9 Hz, 2.7 Hz), 5.78–5.82 (m, 1H), 7.01–7.07 (m, 1H), 7.16 (s, 1H), 7.42–7.45 (m, 2H), 7.66 (s, 1H)
11
2–(8–cloro–5H–imidazo[5,1–a] isoindol–5– il)–1–ciclohexiletanona 21
1H RMN (MeOH–d4) 1.10–1.90 (m, 10H), 2.42–2.48 (m, 1H), 2.99 (dd, 1H, J = 18.9 Hz, 9 Hz), 3.40 (dd, 1H, J = 18.9 Hz, 3.6 Hz), 5.58–5.62 (m, 1H), 6.95–7.08 (m, 1H), 7.16–7.88 (m, 4H)
12
2–(7–cloro–5H–imidazo[5,1–a] isoindol–5– il)–1–ciclohexiletanona 43
1H RMN 1.19–1.46 (m, 5H), 1.68–1.70 (m, 1H), 1.78–1.91 (m, 5H), 2.35–2.43 (m, 1H), 2.91 (dd, 1H, J = 10.0, 20.0 Hz), 3.18 (dd, 1H, J = 4.0, 20.0 Hz), 5.611 (dd, 1H, J = 4.0, 8.0 Hz), 7.15 (s, 1H), 7.28 (s, 1H), 7.35 (d, 1H, J = 8.0 Hz), 7.45 (d, 1H, J = 8.0 Hz), 7.60 (s, 1H)
13
1–ciclohexil–2–(6–fluoro–5Himidazo[5,1– a]isoindol–5–il)etanona 50
1H RMN 1.20–1.48 (m, 5H), 1.66–1.69 (m, 1H)1.78–1.92 (m, 5H), 2.36–2.44 (m, 1H), 2.79 (dd, J = 12.0, 20.0 Hz), 3.50 (dd, 1H, J = 4.0, 20.0 Hz), 5.77 (d, 1H, J = 8.0 Hz), 6.94 (t, 1H, J = 8.0 Hz), 7.18 (s, 1H), 7.31–7.37 (m, 2H), 7.62 (s, 1H)
14
1–ciclohexil–2–(9–metoxi–5H imidazo[5,1– a]isoindol–5–il)etanona 41
1H RMN 1.32–1.42 (m, 2H), 1.66–1.69 (m, 1H), 1.78–1.90 (m, 4H), 2.35–2.38 (m, 1H), 2.88 (dd, 1H, J = 18.4 Hz, 10 Hz), 3.17 (dd, 1H, J = 13.8 Hz, 3.2 Hz), 3.96 (s, 3H), 5.60–5.64 (m, 1H), 6.88 (d, 2H, J = 8 Hz), 7.15 (s, 1H), 7.21 (t, 1H, J = 8 Hz), 7.59 (s, 1H),
15
2–(5H–imidazo[5,1–a]isoindol–5–il)– 1– (tetrahidro–2H–piran–4– il)etanona 61
1H RMN 1.75–1.84 (m, 4H), 2.58–2.62 (m, 1H), 2.90 (dd, 1H, J = 18.4 Hz, 9.6 Hz), 3.21 (dd, 1H, J = 18.4 Hz, 3.6 Hz), 3.38–3.45 (m, 2H), 3.99–4.01 (m, 2H), 5.65 (dd, 1H, J = 9.6 Hz, 3.6 Hz), 7.17 (s, 1H), 7.22–7.30 (m, 2H), 7.38 (dt, 1H, J = 7.2 Hz, 0.8 Hz), 7.54 (d, 1H, J = 7.6 Hz), 7.61 (s, 1H)
16
1–ciclohexil–2–(8–fluoro–5Himidazo [5,1– a]isoindol–5–il)etanona 58
1H RMN a
17
tert–butil (3–(2–(5H–imidazo[5,1–a] isoindol–5– il)acetil)fenil)carbamato 80
1H RMN a
18
1–ciclopentil–2–(5H–imidazo[5,1–a] isoindol–5–il)etanona 11
1H RMN a
1334
1–(2–clorofenil)–2–(5Himidazo[5,1– a]isoindol–5–il)etanona 15
1H RMN 3.30–3.50 (m, 1H), 3.65–3.85 (m, 1H), 5.50–5.70 (m, 1H), 7.17 (s, 1H), 7.20–7.60 (m, 8H), 7.75 (s, 1H)
imagen74
imagen75
imagen76
imagen77
destilación y el producto en bruto se disolvió en EtOAc (40 mL) y la solución se lavó con solución saturada de NaHCO3 (25 mL). La capa orgánica se separó y la capa acuosa se extrajo con EtOAc (2 x 20 mL). Los extractos orgánicos combinados se secaron sobre Na2SO4 y se concentró a presión reducida para proporcionar 120 (4.90 g, 89%).1H RMN : 1.62–2.01 (m, 8H), 2.34–2.38 (m, 1H), 3.64 (s, 3H), 3.82–3.88 (m, 1H).
imagen78
A una solución de metil cis–4–hidroxiciclohexanocarboxilato (4.80 g, 30.3 mmol) en hexano/CHCl3 2:1 (60 mL) se le adicionó bencil tricloroacetimidato (9.19 g, 36.4 mmol) y ácido trifluorometanosulfónico (683 mg, 4.55 mmol) a 23 °C. La mezcla de reacción se agitó durante 18 h y se diluyó con EtOAc (300 mL). La mezcla se lavó con NaHCO3 saturado
10 acuoso, agua y salmuera. La capa orgánica se secó sobre Na2SO4 anhidro y se concentró a presión reducida. El residuo en bruto se purificó por cromatografía en columna en sílica gel para proporcionar 121 (4.60 g, 18.5 mmol).
Ejemplo 18 Procedimiento general para la reacción de metil piperidina–4–carboxilato clorhidrato con cloruros ácidos
imagen79
A una suspensión de metil piperidina–4–carboxilato clorhidrato (5.6 mmol) en CH2Cl2 (20 mL) a 0 °C se le adicionó
15 diisopropiletil amina (16.7 mmol) y la suspensión se agitó durante 10 minutos. Se le adicionó gota a gota cloruro ácido apropiado (8.4 mmol) y la solución se dejó calentar a rt y se agitó durante la noche. La reacción se diluyó con agua (15 mL) y CH2Cl2 (15 mL). La capa orgánica se recolectó y la capa acuosa se extrajo con CH2Cl2 (2 x 20 mL). Los extractos orgánicos combinados se secaron (Na2SO4) y se concentró bajo presión reducida para proporcionar los siguientes compuestos.
#
Compuesto Nombre Rendimiento (%)
24
metil 1–pivaloilpiperidina–4–carboxilato 77
1H RMN 1.21 (s, 9H) 1.65–1.53 (m, 2H), 1.87–1.92 (m, 2H), 2.48–2.52 (m, 1H), 2.89–2.93 (m, 2H), 3.63 (s, 3H), 4.18–4.22 (m, 1H), 4.24–4.27 (m, 1H)
25
metil 1–(tiofeno–2–carbonil)piperidina–4– carboxilato 91
1H RMN 1.69–1.79 (m, 2H), 1.89–1.95 (m, 2H), 2.56–2.63 (m, 1H), 3.12 (t, 2H, J= 12.0 Hz), 3.68 (s, 3H), 4.28– 4.31 (m, 2H), 7.0–7.02 (m, 1H), 7.24–7.26 (m, 1H), 7.40–7.42 (m, 1H)
imagen80
A una solución de metil 3–fluoro–2–(1–tritil–1H–imidazol–4–il)benzoato (62 mg, 0.134 mmol) en tolueno (4 mL) a –78 °C se le adicionó gota a gota una solución de DIBAH (1 M, 0.161 mL, 0.161 mmol). La agitación se continuó, durante 10 min. A esta temperatura, se adicionó metanol seco. La mezcla se vertió en NH4Cl acuoso saturado (5 mL), se diluyó con EtOAc (15 mL), se agitó vigorosamente, durante 3 min, se adicionó salmuera (5 mL), se agitó de nuevo, las fases se separaron y la capa orgánica se secó sobre Na2SO4, se filtró y evaporó para proporcionar el aldehído deseado que se utilizó sin purificación adicional.
Ejemplo 22 Procedimiento general para la síntesis de Dimetil (2–oxo)fosfonatos
imagen81
A una solución agitada de dimetil metilfosfonato (3.14 g, 25.3 mmol) en 20 mL de tetrahidrofurano anhidro a –78 °C se le
10 adicionó gota a gota una solución de n–butil litio (10.13 mL, 25.3 mmol, 2.5 M en hexanos) con una atmósfera de N2, y la mezcla se agitó durante 30 minutos. A esta mezcla de reacción se le adicionó gota a gota una solución del éter metílico o etílico apropiado disponible comercialmente o 19–26, 91 o 115–121 (12.7 mmol) como una solución en THF (5 mL). Después de ser agitado durante 30 minutos, la mezcla de reacción se dejó calentar a 0 °C, y se agitó durante 1
h. El solvente se separó por destilación y el producto en bruto se diluyó con NH4Cl saturada (10 mL) y 10 mL de agua.
15 La mezcla se extrajo con acetato de etilo (2 x 40 mL). Las capas de acetato de etilo combinadas se lavaron con agua (1 x 20 mL), salmuera (1 x 20 mL) y se secaron sobre sulfato de sodio anhidro. La solución se filtró y se concentró a presión reducida para proporcionar el producto en bruto. El producto en bruto se purificó por cromatografía en columna para proporcionar los siguientes compuestos.
#
Compuesto Nombre Rendimiento (%)
27
dimetil (2–(2,5–dimetilfuran–3–il)–2– oxoetil)fosfonato 52
1H RMN 2.23 (s, 3H), 2.53 (s, 3H), 3.31 (d, 2H, J = 22.5 Hz), 3.75 (s, 3H), 3.79 (s, 3H), 6.24 (s, 1H)
28
dimetil (2–(furan–2–il)–2–oxoetil)fosfonato 63
1H RMN 3.52 (d, 2H, J = 22.6 Hz), 3.75 (s, 3H), 3.78 (s, 3H), 6.56 (d, 1H, J = 1.6 Hz), 7.29 (s, 1H), 7.62 (s, 1H)
29
dimetil (2–(1–metil–1H–imidazol–2–il)–2– oxoetil)fosfonato 45
1H RMN 3.80 (s, 3H), 3.83 (s, 3H), 3.88 (d, 2H, J = 22.2 Hz), 4.01 (s, 3H), 7.07 (s, 1H), 7.18 (s, 1H)
30
dimetil (2–oxo–2–(tiazol–4–il)etil)fosfonato 91
1H RMN 3.76 (s, 3H), 3.79 (s, 3H), 3.90 (d, 2H, J = 22.8 Hz), 8.32 (s, 1H), 8.85 (s, 1H)
31
dimetil2–(4,4–difluorociclohexil)–2– oxoetilfosfonato 82
1H RMN 1.72–1.81 (m, 4H), 1.96–1.98 (m, 2H), 2.11–2.13 (m, 2H), 2.68–2.70 (m, 1H), 3.14 (d, 2H, J = 22.4 Hz), 3.79 (d, 6H, J = 11.2 Hz)
32
dimetil 2–(4–metilenociclohexil)–2– oxoetilfosfonato 67
1H RMN 1.43–1.53 (m, 2H), 1.95–2.13 (m, 4H), 2.37–2.41 (m, 2H), 2.72–2.78 (m, 1H), 3.18 (d, 2H, J = 22.5 Hz), 3.82 (d, 6H, J = 11.3 Hz), 4.68 (s, 2H)
33
dimetil 2–oxo–2–(1,4–dioxaspiro [4.5]decan– 8–il)etilfosfonato 72
1H RMN 1.31–1.39 (m, 2H), 1.70–1.85 (m, 5H), 1.85–1.98 (m, 2H), 3.15 (d, 2H, J = 11.2 Hz), 3.77 (d, J = 18 Hz, 6H), 3.92 (m, 4H)
34
dimetil 2–(4–metilciclohexil)–2– oxoetilfosfonato 60
1H RMN 0.88–0.90 (m, 3H), 1.20–1.50 (m, 2H), 1.50–1.65 (m, 5H), 1.80–1.95 (m, 2H), 2.62–2.71 (m, 2H), 3.13 (d, J = 22.8 Hz, 2H), 3.73 y 3.80 (dos s, 6H)
35
dimetil 2–(4–(yodometileno)ciclohexil)–2– oxoetilfosfonato 47
1H RMN 1.20–1.52 (m, 2H), 1.93–2.10 (m, 4H), 2.30–2.36 (m, 1H), 2.49–2.58 (m, 4H), 3.07–3.10 (m, 2H), 3.73– 3.76 (m, 6H), 4.60 (s, 1H)
36
dimetil (2–oxo–2–(4–(propan–2– ilideno)ciclohexil)etil)fosfonato 70
1H RMN 1.28–1.42 (m, 2H), 1.63 (s, 6H), 1.72–1.96 (m, 4H), 2.65–2.75 (m, 3H), 3.12 (d, 1H, J = 21.0 Hz), 3.75 (d, 6H, J = 12.0 Hz)
37
dimetil (2–(4–(ciclopropilmetileno)ciclohexil)– 2–oxoetil)fosfonato 68
1H RMN 0.24 (s, 2H), 0.67 (d, 2H, J = 7.8 Hz), 1.39–1.43 (m, 3H), 1.86–2.07 (m, 4H), 2.17–2.21 (m, 1H), 2.71– 2.79 (m, 2H), 3.13 (d, 2H, J = 22.5 Hz), 3.77 (d, 6H, J = 11.2 Hz), 4.50 (d, 1H, J = 9.3 Hz)
38
dimetil (2–oxo–2–(1–pivaloilpiperidin–4– il)etil)fosfonato 68
1H RMN 1.23 (s, 9H), 1.51 (m, 1H, 1.87 (m, 3H), 2.85 (m, 3H), 3.02 (s, 1H), 3.14 (s, 1H), 3.75 (d, 6H, J = 11.2 Hz), 4.34 (m, 1H), 4.37 (m, 1H)
39
dimetil (2–(1–metil–1H–imidazol–5–il)–2– oxoetil)fosfonato 36
1H RMN 3.35 (d, 2H, J = 22.8 Hz), 3.74 (d, 6H, J = 11.2 Hz), 3.86 (s, 3H), 7.54 (s, 1H), 7.78 (s, 1H)
40
dimetil (2–(1–metil–1H–imidazol–4–il)–2– oxoetil)fosfonato 29
1H RMN 3.66–3.74 (s, 3H condensado con d, 2H, J = 22.5 Hz), 3.78 (d, 6H, J = 11.2 Hz), 7.44 (s, 1H), 7.63 (s, 1H)
41
dimetil (2–oxo–2–(tiazol–5–il)etil)fosfonato 18
1H RMN 3.53 (s, 1H), 3.61 (s, 1H), 3.73 (d, 6H, J = 11.2 Hz), 8.52 (s, 1H), 9.04 (s, 1H)
42
dimetil (2–(1–acetilpiperidin–4–il)–2– oxoetil)fosfonato 64
1H RMN 1.44–1.69 (m, 2H), 1.83–1.89 (m, 2H), 2.07 (s, 3H), 2.66–2.73 (m, 1H), 2.79–2.85 (m, 1H), 3.03–3.22 (m, 3H), 3.72–3.83 (m, 1H superpuesto con d, 6H, J = 11.2 Hz), 4.53 (d, 1H, J = 13.4 Hz)
43
dimetil (2–oxo–2–(1–(tiofeno–2– carbonil)piperidin–4–il)etil)fosfonato 59
1H RMN 1.63 (m, 2H), 1.95 (m, 2H), 2.89 (s, 1H), 3.07 (m, 2H), 3.10 (s, 1H), 3.18 (s, 1H), 3.77 (d, 6H, J = 11.2 Hz), 4.38 (m, 2H), 7.02 (dd, 1H, J = 5.0 Hz, 3.7 Hz), 7.25 (dd, 1H, J = 3.7 Hz, 1.1 Hz), 7.42 (dd, 1H, J = 5.1 Hz,
1.2 Hz)
44
dimetil 2–oxo–2–(1–(2–fenilacetil)piperidin– 4–il)etilfosfonato 39
1H RMN 1.20–1.90 (m, 4H), 1.67 (d, 1H, J = 10.2 Hz), 1.84 (d, 1H, J = 9.6 Hz), 2.55–2.75 (m, 2H), 2.90–3.15 (m, 2H), 3.65(s, 2H), 3.70 (d, 6H, J = 11.2 Hz), 3.90 (d, 1H, J = 10.2 Hz), 4.48 (d, 1H, J = 9.9 Hz), 7.10–7.30 (m, 5H)
45
imagen82 dimetil 3–ciclohexil–2–oxopropilfosfonato 70
1H RMN 0.60–1.15 (m, 5H), 1.35–1.71 (m, 5H), 2.28 (d, 2H, J = 8.8 Hz), 2.83 (s, 1H), 2.91 (s, 1H), 3.55 (s, 3H), 3.59 (s, 1H)
46
dimetil (2–oxo–2–(4–(tritiloxi) ciclohexil)etil)fosfonato 79
1H RMN (mezcla de isómeros cis y trans) 1.08–1.36 (m, 5H), 1.59–1.91 (m, 3H), 2.41–2.52 (m, 1H), 3.03 y 3.13 (dos d, 2H, J = 20.0 Hz), 3.35–3.79 (m, 1H), 3.73–3.79 (m, 6H), 7.22–7.29 (m, 9H), 7.49–7.51 (m, 6H)
122
(trans)–metil 4–(2–(dimetoxifosforil) acetil)ciclo hexanocarboxilato 70
1H RMN 1.31–1.53 (m, 4H), 2.00–2.20 (m, 4H), 2.23–2.31 (m, 1H), 2.53–2.61 (m, 1H), 3.13 (d, 2H, J = 22.6 Hz), 3.67 (s, 3H), 3.79 (d, 6H, J = 11.2 Hz)
124
dimetil (2–oxo–2–(4–(propan–2– ilideno)ciclohexil)etil)fosfonato 70
1H RMN 1.28–1.42 (m, 2H), 1.63 (s, 6H), 1.72–1.96 (m, 4H), 2.65–2.75 (m, 3H), 3.12 (d, 1H, J = 21.0 Hz), 3.75 (d, 6H, J = 12.0 Hz)
125
dimetil (2–oxo–2–(espiro[2.5]octan–6– il)etil)fosfonato 77
1H RMN 0.13–0.27 (m, 4H), 0.91–0.95 (m, 2H), 1.40–2.06 (m, 6H), 2.52–2.58 (m, 1H), 3.11 (d, 2H, J = 24.0 Hz), 3.75 (d, 6H, J = 12.0 Hz)
126
dimetil (2–((trans)–4–((tertbutildimetilsilil) oxi)ciclohexil)–2–oxoetil) fosfonato 96
1H RMN 0.11 (s, 6H), 0.82 (s, 9H), 1.19–1.32 (m, 4H), 1.85–1.88 (m, 4H), 2.41–2.47 (m, 1H), 3.08 (d, 2H, J = 24.0 Hz), 3.72 (s, 3H), 3.74 (s, 3H)
127
dimetil (2–((trans)–4–(benciloxi) ciclohexil)– 2–oxoetil) fosfonato 16
1H RMN 1.13–1.41 (m, 4H), 1.93–2.02 (m, 2H), 2.12–2.15 (m, 2H), 2.51–2.56 (m, 1H), 3.11 (d, 2H, J = 24 Hz), 3.27–3.32 (m, 1H), 3.75 (d, 6H, J = 12 Hz), 7.22–7.32 (m, 5H)
128
dimetil (2–(cis–4–benzamidociclohexil) –2– oxoetil)fosfonato 83
1H RMN 1.76–1.85 (m, 8H), 2.78–2.79 (m, 1H), 3.18 (d, 2H, J = 22.8 Hz), 3.82 (d, 6H, J = 11.2 Hz), 4.21–4.25 (m, 1H), 7.40–7.52 (m, 3H), 7.76–7.78 (m, 2H)
129
dimetil (2–(trans–4–benzamidociclohexil) –2– oxoetil)fosfonato 54
1H RMN 1.29 (dq, 2H, J = 3.1, 12.1 Hz), 1.54 (dq, 2H, J = 3.0, 11.5 Hz), 2.04 (d, 2H, J = 12.9 Hz), 2.12 (dd, 2H, J = 3.0, 12.6 Hz), 2.60 (tt, 1H, J = 3.4, 12.0 Hz), 3.15 (d, 2H, J = 22.6 Hz), 3.79 (d, 6H, J = 11.2 Hz), 3.93–3.99 (m, 1H), 5.98 (d, 1H, J = 7.7 Hz), 7.41–7.45 (m, 2H), 7.48–7.52 (m, 2H), 7.74 (d, 2H, J = 7.1 Hz)
130
dimetil (2–oxo–2–(4–(2– (tritiloxi)etilideno)ciclohexil)etil) fosfonito 42
1H RMN 1.26–1.60 (m, 2H), 1.35–1.37 (m, 1H), 1.80–2.30 (m, 3H), 2.25–2.40 (m, 2H), 2.70–2.76 (m, 1H), 3.05 (d, J = 27 Hz, 2H), 3.57–3.61 (m, 2H), 3.71–3.75 (d, J = 12 Hz, 2H), 7.19–7.32 (m, 9H), 7.44–7.51 (m, 6H)
131
tert–butil 3–(2– (dimetoxifosforil)acetil)azetidina–1– carboxilato 99
1H RMN 1.43 (s, 9H), 3.11 (d, J = 24 Hz, 2H), 3.68–3.82 (m, 7H), 3.81–4.12 (m, 4H)
132
dimetil (2–oxo–2–(piridin–2–il)etil)fosfonato 56
1H RMN 3.69–3.77 (m, 6H), 3.96–4.04 (m, 2H), 7.45–7.48 (m, 1H), 7.80–7.85 (m, 1H), 8.03–8.09 (m, 1H), 8.66– 8.69 (m, 1H)
133
dimetil (2–oxo–2–(piridin–3–il)etil)fosfonato 65
1H RMN 3.60–3.80 (m, 8H), 7,41–7.45 (m, 1H), 8.26–8.29 (m, 1H), 8.78–8.79 (m, 1H), 9.18 (m, 1H)
134
dimetil (2–oxo–2–(4– (trifluorometil)ciclohexil)etil)fosfonato 30
1H RMN 1.55–1.64 (m, 4H), 1.75–1.77 (m, 2H), 204–2.16 (m, 3H), 2.83–2.84 (m, 1H), 3.14 (d, J = 22.4 Hz, 2H), 3.78 (d, J = 11.2 Hz, 6H)
135
dimetil (2–((1s,4s)–4–(benciloxi)ciclohexil)– 2–oxoetil)fosfonato 17
1H RMN 1.47–1.55 (m, 2H), 1.66–1.71 (m, 2H), 1.78–1.85 (m, 2H), 1.95–1.99 (m, 2H), 2.58–2.62 (m, 1H), 3.14 (d, 2H, J = 22.4 Hz), 3.60–3.63 (m, 1H), 3.78 (d, 6H, J = 11.2 Hz), 4.48 (s, 2H), 7.24–7.33 (m, 5H)

Ejemplo 23 Procedimiento general para la síntesis de 2–(5H–imidazo[5,1–a]isoindol–5–il)etanonas mediante reacción de Horner–Wadsworth– Emmons seguido por ciclación.
imagen83
A una suspensión de NaH al 95% (17.4 mg, 0.7 mmol) en THF (3 mL) a 0 °C se le adicionó el reactivo fosfonato apropiado 27–46, 89, 90 o 122–135 (0.75 mmol) como una solución en THF (2 mL) y la mezcla se agitó durante 40 min. El 2–(1–tritil–1H–imidazol–4–il)benzaldehido apropiado se le adicionó como una solución en THF (3 mL) gota a gota 5 durante un periodo de 3 min. La reacción se dejó calentar a rt y se agitó durante la noche. El solvente se eliminó a presión reducida y el producto en bruto se diluyó con NH4Cl saturada (10 mL) y agua (10 mL). La capa acuosa se extrajo con CH2Cl2 (2 x 20 mL) y las fracciones orgánicas combinadas se lavaron con salmuera (15 mL), se secaron sobre Na2SO4 y se concentraron a presión reducida para proporcionar el producto en bruto. Al residuo en bruto se le adicionó AcOH (1 mL) y MeOH (3 mL) y la solución se agitó a 90 °C, durante 2 h. Después de enfriar a rt, el solvente se
10 separó por destilación y el producto en bruto se agitó en una mezcla de K2CO3 saturada (5 mL) y EtOAc (5 mL). La capa orgánica se separó y la capa acuosa se extrajo con EtOAc (2 x 10 mL). Las capas orgánicas combinadas se lavaron con agua, salmuera y se secaron (Na2SO4) y el solvente se evaporó a presión reducida. El residuo en bruto se purificó por cromatografía en columna instantánea en sílica gel para proporcionar los siguientes compuestos.
#
Compuesto Nombre Rendimiento (%)
47
imagen84 1–(ciclohex–1–en–1–il)–2–(5H–imidazo[5,1– a] isoindol–5–il)etanona 54
1H RMN 1.64–1.68 (m, 4H), 2.23–2.33 (m, 4H), 3.12 (dd, 1H, J = 9.8, 17.8 Hz), 3.36 (dd, 1H, J = 3.2, 18.0 Hz), 5.72 (dd, 1H, J = 3.6, 7.6 Hz), 6.86–6.88 (m, 1H), 7.17 (s, 1H), 7.32 (d, 1H, J = 7.6 Hz), 7.38 (t, 1H, J = 7.4 Hz), 7.55 (d, 1H, J = 7.2 Hz), 7.65 (s, 1H)
48
imagen85 1–(2,5–dimetilfuran–3–il)–2–(6–fluoro–5H– imidazo[5,1–a]isoindol–5–il)etanona 93
1H RMN 2.22 (s, 3H), 2.60 (s, 3H), 2.97 (dd, 1H, J = 10.8, 18.4 Hz), 3.72 (d, 1H, J = 18.2Hz), 5.86 (d, 1H, J = 10.7 Hz), 6.11 (s, 1H), 6.93 (t, 1H, J = 8.5 Hz), 7.16 (s, 1H), 7.30–7.37 (m, 2H). 7.74 (s, 1H)
49
2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5– il)–1–(furan–2–il)etanona 65
1H RMN 3.16 (dd, 1H, J = 10.5, 18.4 Hz), 3.85 (d, 1H, J = 18.4 Hz), 5.86 (d, 1H, J = 10.5 Hz), 6.54 (s, 1H), 6.92 (t, 1H, J = 8.9 Hz), 7.14 (s, 1H), 7.24–7.35 (m, 3H), 7.57 (s, 1H), 7.74 (s, 1H)
50
2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5– il)–1–(1–metil–1H–imidazo 1–2–il)etanona 39
1H RMN 3.56 (dd, 1H, J = 12.0, 20.0 Hz), 4.07 (s, 3H), 4.13 (d, 1H, J= 20.0 Hz), 5.86 (d, 1H, J = 12.0 Hz), 6.92 (t, 1H, J = 8.0 Hz), 7.09 (d, 1H, J = 8.0 Hz), 7.15 (s, 1H), 7.31–7.34 (m, 3H), 7.71 (s, 1H)
51
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(tiazo 1–4–il)etanona 58
1H RMN 3.62 (dd, 1H, J = 9.7, 18.8 Hz), 3.92 (dd, 1H, J = 3.0, 18.9 Hz), 5.79 (d, 1H, 9.5 Hz), 7.18 (s, 1H), 7.26– 7.28 (m, 1H superpuesto con CHCl3), 7.36–7.40 (m, 2H), 7.55 (d, 1H, J = 7.4 Hz), 7.75 (s, 1H), 8.38 (s, 1H), 8.82 (s, 1H)
52
1–(4,4–difluorociclohexil)–2–(6–fluoro–5H– imidazo[5,1–a]isoindol–5–il)etanona 81
1H RMN 1.65–1.82 (m, 4H), 1.90–2.01 (m, 2H), 2.11–2.16 (m, 2H), 2.44–2.48 (m, 1H), 2.79 (dd, 1H, J = 10.4 Hz, 18.4 Hz), 3.52 (dd, 1H, J = 2 Hz, 18.4 Hz), 5.72 (d, 1H, J = 10.4 Hz), 6.92 (t, 1H, J = 8.8 Hz), 7.15 (s, 1H), 7.28–7.35 (m, 2H), 7.58 (s, 1H)
53
1–(4,4–difluorociclohexil)–2–(5H– imidazo[5,1–a] isoindol–5–il)etanona 96
1H RMN 1.73–1.80 (m, 4H), 1.91–1.95 (m, 2H), 2.10–2.14 (m, 2H), 2.41–2.47 (m, 1H), 2.90 (dd, 1H, J = 9.4 Hz, 18.8 Hz), 3.21 (dd, 1H, J = 3.6 Hz, 18.4 Hz), 5.60 (dd, 1H, J = 3.4 Hz, 9.4 Hz), 7.13 (s, 1H), 7.22–7.28 (m, 2H), 7.36 (t, 1H, J = 7.2 Hz), 7.51 (d, 1H, J = 7.6 Hz), 7.57 (s, 1H)
54
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(4– metilenociclohexil)etanona 93
1H RMN 1.30–1.50 (m, 2H), 1.80–2.05 (m, 3H), 2.20–2.32 (m, 2H), 2.40–2.50 (m, 1H), 2.58–2.67 (m, 1H), 2.78– 2.88 (m, 1H), 3.16–3.17 (m, 1H), 5.50–5.54 (m, 1H), 7.13–7.17 (m, 1H), 7.20–7.30 (m, 2H), 7.43–7.45 (m, 1H), 7.52 (s, 1H)
55
2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5– il)–1–(4–metilenociclohexil)etanona 64
1H RMN 1.30–1.60 (m, 2H), 1.90–2.10 (m, 3H), 2.32–2.35 (m, 2H), 2.50–2.60 (m, 1H), 2.60–2.72 (m, 1H), 2.76– 2.84 (m, 1H), 3.52 (d, J = 18.4 Hz, 1H), 4.63 (s, 2H), 5.73 (d, J = 10.4 Hz, 1H), 6.91–6.96 (m, 1H), 7.20–7.30 (m, 2H), 7.43–7.45 (m, 1H), 7.52 (s, 1H)
56
2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5– il)–1–(1,4–dioxaspiro [4.5]decan–8– il)etanona 84
1H RMN (CD3OD) 1.48–1.91 (m, 6H), 2.35–2.65 (m, 2H), 3.58–3.65 (m, 1H), 3.91 (s, 4H), 5.79–5.82 (m, 1H), 7.01–7.07 (m, 1H), 7.16 (m, 1H), 7.42–7.45 (m, 2H), 7.70 (s, 1H)
57
2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5– il)–1–(4–metilciclohexil)etanona 87
1H RMN 0.80–0.95 (m, 3H), 1.24–1.40 (m, 2H), 1.40–1.68 (m, 5H), 1.70–2.00 (m, 2H), 2.40–2.55 (m, 1H), 2.72– 2.84 (m, 1H), 3.48 (d, J = 18.4 Hz, 1H), 5.75 (d, J = 10.4 Hz, 1H), 6.89–6.95 (m, 1H), 7.15 (s, 1H), 7.26–7.38 (m, 2H), 7.62 (s, 1H)
58
2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5– il)– 1–(4–(yodometileno)ciclohexil)etanona 46
1H RMN (CD3OD) 1.20–1.52 (m, 2H), 1.80–2.20 (m, 4H), 2.30–2.36 (m, 1H), 2.45–2.80 (m, 3H), 2.90–3.02 (m, 1H), 3.59–3.64 (m, 1H), 4.63 (s, 1H), 5.75–5.80 (m, 1H), 7.02–7.08 (m, 1H), 7.15 (s, 1H), 7.42–7.47 (m, 2H), 7.65 (s, 1H).
59
2–(9–fluoro–5H–imidazo[5,1–a]isoindol–5– il)–1–(4–metilciclohexil)etanona 55
1H RMN (CD3OD) 0.80–0.95 (m, 3H), 1.24–1.40 (m, 2H), 1.40–1.68 (m, 5H), 1.70–2.00 (m, 2H), 2.40–2.55 (m, 1H), 2.72–2.84 (m, 1H), 3.48 (d, J = 18.4 Hz, 1H), 5.49–5.59 (m, 1H), 7.10–7.18 (m, 2H), 7.60–8.00 (m, 1H)
60
2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5– il)–1–(4–(propan–2– ilideno)ciclohexil)etanona 36
1H RMN 1.30–1.52 (m, 2H), 1.64 (s, 6H), 1.70–1.81 (m, 2H), 1.85–1.98 (m, 2H), 2.52–2.62 (m, 1H), 2.68–2.74 (m, 2H), 2.80 (dd, 1H, J = 18.5 Hz, 10.6 Hz), 3.50 (dd, 1H, J = 18.5 Hz, 2.2 Hz), 5.75 (d, 1H, J = 9.27 Hz), 6.90– 6.96 (m, 1H), 7.17 (s, 1H), 7.32–7.36 (m, 2H), 7.59 (s, 1H)
61
1–(4–(ciclopropilmetileno)ciclohexil)–2–(6– fluoro–5H–imidazo[5,1–a]iso indo 1–5– il)etanona 49
1H RMN 0.24 (s, 2H), 0.67 (d, 2H, J = 7.8 Hz), 1.43–1.49 (m, 3H), 1.82–2.15 (m, 3H), 2.12–2.28 (m, 1H), 2.50– 2.62 (m, 1H), 2.75–2.85 (m, 2H), 3.52 (d, 1H,J = 18.6 Hz), 4.52 (d, 1H, J = 9.3 Hz), 5.75 (d, 1H J = 10.2 Hz), 6.89–6.95 (m, 1H), 7.16 (s, 1H), 7.25–7.36 (m, 3H), 7.59 (s, 1H)
62
1–(4–(2–(5H–imidazo[5,1–a]isoindol–5– il)acetil)piperidin–1–il)–2,2–dimetilpropan–1– ona 42
1H RMN 1.26 (s, 9H), 1.60 (m, 2H), 1.88 (m, 2H), 2.61 (m, 1H), 2.84 (m, 2H), 2.89 (dd, 1H, J = 9.39 Hz, 18.6 Hz), 3.22 (dd, 1H, J = 3.6 Hz, 18.3 Hz), 4.41 (m, 2H), 5.62 (dd, 1H, J = 3.54 Hz, 9.45 Hz), 7.16 (s, 1H), 7.24 (m, 2H), 7.37 (m, 1H), 7.53 (d, 1H, J = 7.56 Hz), 7.59 (s, 1H)
63
2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5– il)–1–(1–metil–1H–imidazol–5–il)etanona 62
1H RMN 3.13–3.20 (m, 1H), 3.85–3.89 (m, 1H), 4.0 (s, 3H), 5.79 y 5.89 (dos d, 1H, J = 10.4 Hz), 6.96 (t, 1H, J = 8.8 Hz), 7.20 (s, 1H), 7.33–7.38 (m, 2H), 7.62 (s, 1H), 7.74 y 7.81 (dos s, 3H)
64
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(1– metil–1H–imidazol–4–il)etanona 24
1H RMN 3.42 (d, 1H, J = 9.9 Hz), 3.48 (d, 1H, J = 8.7 Hz), 3.75 (s, 3H), 5.75 (dd, 1H, J = 3.4 Hz, 9.8 Hz), 7.26– 7.19 (m, 1H), 7.14 (s, 1H), 7.35 (m, 2H), 7.41 (d, 1H, J = 1.0 Hz), 7.52 (dd, 1H, J = 1.2 Hz, 7.35 Hz), 7.71 (s,
1H), 7.67 (d, 1H, J = 1.2 Hz),
65
2–(5H–imidazo[5,1–a]isoindol–5–il)–1– (tiazol–5–il)etanona 30
1H RMN 3.40 (dd, 1H, J = 9.6 Hz, 18.4 Hz), 3.71 (dd, 1H, J = 3.2 Hz, 18.0 Hz), 5.80 (dd, 1H, J = 2.8 Hz, 9.2 Hz), 7.21 (s, 1H), 7.29 (d, 1H, J = 7.2 Hz), 7.36–7.41 (m, 2H), 7.57 (d, 1H, J = 8.0 Hz), 8.41 (s, 1H), 7.73 (s, 1H), 9.0 (s, 1H),
66
1–(1–acetilpiperidin–4–il)–2–(5H– imidazo[5,1–a] isoindol–5–il)etanona 74
1H RMN 1.57 (m, 2H), 1.90 (m, 2H), 2.09 (s, 3H), 2.60 (m, 2H), 2.91 (m, 1H), 3.07–3.26 (m, 2H), 3.82 (m, 1H), 4.58 (m, 1H), 5.62 (m, 1H), 7.16 (s, 1H) 7.29 (m, 2H), 7.37 (m, 1H), 7.53 (d, 1H, J= 10.4 Hz), 7.58 (d, 1H, J=4.8 Hz)
67
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(1– (tiofeno–2–carbonil)piperidin–4–il)etanona
1H RMN a
68
1–(4–(2–(5H–imidazo[5,1–a]isoindol–5– il)acetil)piperidin–1–il)–2–feniletanona 49
1H RMN 1.20–1.90 (m, 4H), 2.40–3.33(m, 5H), 3.73(s, 2H), 3.89 (d, 1H, J = 13.5 Hz), 4.59 (d, 1H, J = 13.5 Hz), 5.50–5.70 (m, 1H), 7.15–7.45 (m, 9H), 7.53 (d, 1H, J = 7.5 Hz), 7.68 (d, 1H, J = 7.8 Hz)
69
1–ciclohexil–3–(5H–imidazo[5,1–a]isoindol– 5–il)propan–2–ona 82
1H RMN 0.85–1.35 (m, 5H), 1.55–1.175 (m, 5H), 1.80–1.95 (m, 1H), 2.25–2.38 (m, 2H), 2.70–2.80 (m, 1H), 3.16 (dd, 1H, J = 2.4, 14.8 Hz), 5.50–5.60 (m, 1H), 7.16 (s, 1H), 7.20–7.30 (m, 3H), 7.35 (t, 1H, J = 5.4 Hz), 7.41 (d, 1H, J = 5.4 Hz), 7.73 (s, 1H)
70
1–ciclohexil–3–(6–fluoro–5H–imidazo [5,1–a] isoindol–5–il)propan–2–ona 78
1H RMN 0.80–1.40 (m, 5H), 1.45–2.00 (m, 6H), 2.32 (t, 2H, J = 9.3Hz), 2.80–2.60 (m, 1H), 3.46 (d, 1H, J = 18.6 Hz), 5.72 (d, 1H, J = 10.5 Hz), 6.92 (t, 1H, J = 9.3 Hz), 7.18 (s, 1H), 7.25–7.40 (m, 2H), 7.71 (s, 1H)
71
2–(6–fluoro–5H–imidazo[5,1–a]isoindol –5– il)–1–(4–hidroxiciclohexil)etanona 89
1H RMN (mezcla de isómeros cis y trans) 1.25–1.77 (m, 6H), 1.90–2.06 (m, 3H), 2.34–2.42 (m, 1H), 2.80 (dd, 1H, J = 10.8 Hz, 18.8 Hz), 3.51 (d, 1H, J = 18.8 Hz), 3.60–3.62 y 3.97–4.01 (m, 1H), 5.73–5.76 (m, 1H), 6.93 (t, 1H, J = 8.4 Hz), 7.17 (s, 1H), 7.30–7.37 (m, 2H), 7.59 y 7.62 (dos s, 1H)
72
1–ciclohexil–2–(5H–imidazo[5,1–a]iso indo 1–5–il)etanona 86
1H RMN 1.25 (m, 5H), 1.79 (m, 5H), 2.38 (m, 1H), 2.89 (dd, 1H, J = 18.0 Hz, 9.0 Hz), 3.18 (dd, 1H, J = 18 Hz, 3.0 Hz), 5.63 (m, 1H), 7.16 (s, 1H), 7.21–7.28 (m, 2H), 7.37 (t, 1H, J = 7.5 Hz), 7.53 (d, 1H, J = 6 Hz), 7.60 (s, 1H)
aEl compuesto no se caracterizó y se utilizó como tal para la siguiente etapa de síntesis
136
1–ciclohexil–2–(5H–imidazo[5,1–a]iso indo 1–5– ilideno)etanona 62
1H RMN indistinguible mezcla de isómeros E/Z 1.26–1.48 (m, 8.9H), 1.63–1.94 (m, 13.7H), 2.58–2.62 (m, 0.6H), 3.33–3.38 (m, 1H), 6.40 (s, 0.4H), 6.60 (s, 0.53H), 7.15 (d, 0.8 Hz, J = 6.0 Hz), 7.25–7.28 (m condensado con CHCl3, 0.8H), 7.43–7.49 (m, 3H), 7.63–7.67 (m, 2H), 7.74–7.77 (m, 3H), 7.93 (s, 1H), 8.06 (d, 1H, J = 8.0 Hz), 9.25 (s, 0.4H), 9.43 (s, 0.8 H)
137
(trans)–metil 4–(2–(5H–imidazo[5,1– a]isoindol–5–il)acetil)ciclohexanocarboxilato 90
1H RMN 1.38–1.49 (m, 4H), 1.95–2.11 (m, 4H), 2.27–2.32 (m, 1H), 2.27–2.42 (m, 1H), 2.91 (dd, J = 9.5, 18.5 Hz, 1H), 3.21 (dd, J = 3.5, 18.5 Hz, 1H), 3.67 (s, 3H), 5.63 (dd, J = 3.3, 9.5 Hz), 7.17 (s, 1H), 7.22–7.29 (m, 2H),
7.38 (t, 1H, J = 7.5 Hz), 7.54 (d, 1H, J = 7.6 Hz), 7.60 (s, 1H)
139
2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5– il)–1–(4–(propan–2– ilideno)ciclohexil)etanona 36
1H RMN 1.30–1.52 (m, 2H), 1.64 (s, 6H), 1.70–1.81 (m, 2H), 1.85–1.98 (m, 2H), 2.52–2.62 (m, 1H), 2.68–2.74 (m, 2H), 2.80 (dd, 1H, J = 18.5 Hz, 10.6), 3.50 (dd, 1H, J = 18.5 Hz, 2.2 Hz), 5.75 (d, 1H, J = 9.27 Hz), 6.90– 6.96 (m, 1H), 7.17 (s, 1H), 7.32–7.36 (m, 2H), 7.59 (s, 1H)
140
2–(5H–imidazo[5,1–a]isoindol–5–il)–1– (espiro[2.5] octan–6–il)etanona 59
1H RMN 0.18–0.30 (m, 4H), 0.90–0.98 (m, 2H), 1.52–1.87 (m, 6H), 2.38–2.53 (m, 1H), 2.91 (dd, 1H, J = 18.4, 9.60 Hz), 3.20 (dd, 1H, J = 18.47, 3.6 Hz), 5.58–5.65 (m, 1H), 7.15 (s, 1H), 7.21–7.27 (m, 2H), 7.36 (t, 1H, J = 7.60 Hz), 7.52 (d, 1H, J = 7.60 Hz), 7.61 (s, 1H)
141
1–((trans)–4– ((tertbutildimetilsilil)oxi)ciclohexil)–2–(6– fluoro–5H–imidazo[5,1–a]iso indo 1–5– il)etanona 79
1H RMN 0.028 (s, 6H), 0.88 (s, 9H), 11.27–1.96 (m, 8H), 2.32–2.38 (m, 1H), 2.80 (dd, 1H, J = 18.8, 10.6 Hz), 3.48–3.57 (m, 2H), 5.75 (d, J = 9.3 Hz), 6.91–6.95 (m, 1H), 7.17 (s, 1H), 7.23–7.39 (m, 2H), 7.59 y 7.64 (dos s, 1H)
142
1–((trans)–4–(benciloxi)ciclohexil)–2–(6– fluoro–5H–imidazo[5,1–a]iso indo 1–5– il)etanona 72
1H RMN 1.15–1.54 (m, 4H), 1.91–2.20 (m, 4H), 2.37–2.43 (m, 1H), 2.80 (dd, 1H, J = 18.5, 10.5 Hz), 3.31–3.36 (m, 1H), 3.51 (d, 1H, J = 18.6 Hz), 4.55 (s, 2H), 5.74 (d, 1H, J = 10.3 Hz), 6.93 (t, 1H, J = 8.0 Hz), 7.17 (s, 1H), 7.29–7.39 (m, 7H), 7.59 y 7.78 (dos s, 1H)
143
1–((trans)–4–(benciloxi)ciclohexil)–2–(5H– imidazo[5,1–a]isoindol–5–il)etanona 81
1H RMN 1.14–1.50 (m, 4H), 1.92–2.01 (m, 2H), 2.15–2.19 (m, 2H), 2.34–2.43 (m, 1H), 2.90 (dd, 1H, J = 18, 9 Hz), 3.19 (dd, 1H, J = 24, 6 Hz), 3.30–3.37 (m, 1H), 4.49 y 4.55 (dos s, 2H), 5.61 (dd, 1H, J = 10.5, 4.5 Hz), 7.16–7.39 (m, 9H), 7.53 (d, 1H, J = 9 Hz), 7.62 (s, 1H)
144
N–((cis)–4–(2–(5H–imidazo[5,1–a]isoindol– 5–il)acetil)ciclohexil)benzamida 53
1H RMN 1.25–1.34 (m, 2H), 1.53–1.63 (m, 2H), 1.98–2.08 (m, 2H), 2.20 (t, 2H, J = 11.6 Hz), 2.36 (t, 1H, J =12.2 Hz), 2.90 (dd, 1H, J = 9.4, 18.6 Hz), 3.25 (dd, 1H, J = 3.2, 18.4 Hz), 3.93–4.00 (m, 1H), 5.63 (dd, 1H, J = 3.2, 9.2 Hz), 6.32 (d, 1H, J = 6.8 Hz), 7.19 (s, 1H), 7.26–7.35 (m, 2H, condensado con cloroformo), 7.38–7.43 (m, 3H), 7.48 (d, 1H, J = 7.2 Hz), 7.55 (d, 1H, J = 7.6 Hz), 7.71 (s, 1H), 7.76 (d, 2H, J = 7.6 Hz)
145
N–((trans)–4–(2–(5H–imidazo[5,1– a]isoindol–5– il)acetil)ciclohexil)benzamida 69
1H RMN 1.19–1.36 (m, 2H), 1.48–1.65 (m, 2H), 1.93–2.07 (m, 2H), 2.18–2.23 (m, 2H), 2.35 (tt, 1H, J = 3.2, 12.2 Hz), 2.90 (dd, 1H, J = 9.5, 18.4 Hz), 3.22 (dd, 1H, J = 3.6, 18.4 Hz), 3.92–3.99 (m, 1H), 5.62 (dd, 1H, J = 3.4, 9.4 Hz), 6.23 (d, 1H, J = 7.6 Hz), 7.23–7.32 (m, 3H, condensado con cloroformo), 7.34–7.42 (m, 3H), 7.46–7.50 (m, 1H), 7.54 (d, 1H, J = 7.6 Hz), 7.63 (s, 1H), 7.76 (d, 2H, J = 7.6 Hz)
146
1–(4–(2–hidroxietilideno)ciclohexil)–2–(5H– imidazo[5,1–a]isoindol–5–il)etanona 85
1H RMN 1.26–1.50_(m, 2H), 1.70–2.30 (m, 4H), 2.31–2.40 (m, 1H), 2.41–2.75 (m, 2H), 2.76–2.90 (m, 1H), 3.15–3.25 (m, 1H), 4.08–4.13 (m, 1H), 5.25–5.40 (m, 1H), 5.51–5.60 (m, 1H), 7.12 (s, 1H), 7.13–7.40 (m, 2H), 7.48–7.60 (m, 3H)
147
tert–butil 3–(2–(5H–imidazo[5,1–a]isoindol– 5–il)acetil)azetidina–1–carboxilato 77
1H RMN 1.38 (s, 9H), 2.85–2.92 (m, 1H), 3.20–3.25 (m, 1H), 3.44–3.48 (m, 1H), 3.65–3.70 (m, 2H), 4.01–4.28 (m, 2H), 5.63–5.66 (m, 1H), 7.16 (s, 1H), 7.21–7.31 (m, 2H), 7.36–7.40 (m, 1H), 7.53–7.55 (m, 1H), 7.66 (s, 1H)
148
2–(5H–imidazo[5,1–a]isoindol–5–il)–1– (piridin–2–il)etanona 75
1H RMN 3.60 (dd, J = 10, 19.2Hz, 1H), 3.91 (dd, J = 3.2, 19.2Hz, 1H), 5.65 (dd, J = 3.2, 10 Hz, 1H), 7.08 (s, 1H), 7.13–7.17 (m, 1H), 7.25–7.30 (m, 2H), 7.38–7.45 (m, 2H), 7.66 (s, 1H), 7.78–7.80 (m, 1H), 8.05 (d, J = 8
Hz, 1H), 8.51–8.53 (m, 1H)
149
2–(5H–imidazo[5,1–a]isoindol–5–il)–1– (piridin–3–il)etanona 89
1H RMN 3.57–3.67 (m, 1H), 3.80–3.95 (m, 1H), 6.01–6.05 (m, 1H), 7.27–7.73 (m, 6H), 8.29–8.36 (m, 1H), 8.61(s, 1H), 8.86 (d, J = 3 Hz, 1H), 9.18 (s, 1H)
150
2–(5H–imidazo[5,1–a]isoindol–5–il)–1– (piridin–4–il)etanona 21
1H RMN 3.42–3.49 (dd, J = 9.2, 18.8 Hz, 1H), 3.76 (dd, J = 3.6, 18.8Hz, 1H), 5.83 (dd, J = 3.2, 9.2 Hz, 1H), 7.20 (s, 1H), 7.28–7.32 (m, 1H), 7.38–7.45 (m, 2H), 7.58–7.60 (m, 1H), 7.74–7.75(m, 2H), 7.81 (s, 1H), 8.84–8.86 (m, 2H)
151
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(4– (trifluorometil)ciclohexil)etanona 50
1H RMN 1.55–1.81 (m, 5H),_2.08–2.29 (m, 4H), 2.58–2.62 (m, 1H), 2.94 (dd, J = 9, 18 Hz, 1H), 3.22 (dd, J = 6, 18 Hz, 1H), 5.68 (dd, J = 6, 9 Hz, 1H), 7.18–7.57 (m, 5 H), 7.81 y 7.83 (dos s, 1H)
152
2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5– il)– 1–(4–(trifluorometil)ciclohexil)etanona 53
1H RMN 1.51–1.83 (m, 6H), 1.95–2.21 (m, 3H), 2.58–2.62 (m, 1H), 2.79 (dd, J = 9, 18 Hz, 1H), 3.46–3.55 (m, 1H), 5.73–5.79 (m, 1H), 6.89–6.98 (m, 1H), 7.20–7.38 (m, 4H), 7.71 (s, 1H)
153
1–((cis)–4–(benciloxi)ciclohexil)–2–(6–fluoro– 5H–imidazo[5,1–a]isoindol–5–il)etanona 77
1H RMN 1.67–2.04 (m, 8H), 2.39–2.45 (m, 1H), 2.79 (dd, 1H, J = 18.6, 10.6 Hz), 3.50 (dd, 1H, J = 16.4, 2.4 Hz), 3.60–3.65 (m, 1H), 4.49 y 4.55 (dos s , 1H), 5.76 (d, 1H, J = 8.8 Hz), 6.91–6.95 (m, 1H), 7.17 (s, 1H), 7.26–7.35 (m, 7H), 7.63 (s, 1H)
imagen86
1304
1–ciclohexil–2–(5H–imidazo[5,1–a]isoindo1– 5–il)etanol 79
1H RMN (una mezcla de diastereómeros) 1.10–1.37 (m, 6H), 1.66–1.80 (m, 5H), 2.05 (m, 2H), 2.15 (m, 1H), 3.72 (m, 1H), 5.36 y 5.46 (dos m, 1H), 7.16 (s, 1H), 7.25 (m,1H), 7.34 (m, 1H), 7.43 (d, 1H, J= 7.6 Hz), 7.54 (d, 1H, J= 7.6 Hz), 7.80 (s, 1H)
1327
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(2– nitrofenil)etanol 73
1H RMN (una mezcla de diastereómeros) 2.29 (m, 1H), 2.61 (m, 1H), 5.44 (m, 1H), 5.71 (dd, 1H, J = 9.0 Hz, 4.5 Hz), 7.08 (s, 1H), 7.27 (m, 2H), 7.34 (m,1H), 7.45–7.53 (m, 3H), 7.68 (m, 1H), 7.95 (m, 2H)
1307
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(3– nitrofenil)etanol 39
1H RMN (una mezcla de diastereómeros) 2.32–2.40 (m, 1H), 2.48–2.58 (m, 1H), 5.06–5.11 (m, 1H), 5.41 y 5.61 (dos m, 1H), 7.09 (s, 1H), 7.30–7.43 (m, 2H), 7.48–7.57 (m, 3H), 7.64–7.72 (m, 2H), 8.12–8.19 (m, 2H)
1329
tert–butil (2–(1–hidroxi–2–(5H–imidazo[5,1– a] isoindol–5–il)etil)fenil)carbamato 50
1H RMN (una mezcla de diastereómeros) 1.50 y 1.55 (dos s, 9H), 2.50 y 2.78 (dos m, 2H), 5.02 y 5.07 (dos m, 1H), 5.19 y 5.56 (dos m, 1H), 6.93–7.02 (m, 2H), 7.12 (d, 1H, J = 8.0 Hz), 7.24 (m, 2H), 7.36 (m, 2H), 7.49 (d, 1H, J = 7.6 Hz), 7.71 (br s, 1H), 7.80 y 7.85 (dos s, 1H, J = 8.0 Hz), 8.12 y 8.45 (dos s, 1H)
1302
tert–butil (4–(1–hidroxi–2–(5H –imidazo[5,1– a] isoindol–5–il)etil)fenil)carbamato 81
1H RMN (una mezcla de diastereómeros) 1.50 (s, 9H), 2.28–2.41 (m, 2H), 4.98–5.03 (m, 1H), 5.25 y 5.55 (dos m, 1H), 6.55 y 6.61 (dos s, 1H), 7.12–7.54 (m, 7H), 7.66 y 7.78 (dos s, 1H)
1367
tert–butil (3–(1–hidroxi–2–(5H–imidazo [5,1– a] isoindol–5–il)etil)fenil) carbamato 52
1H RMN (una mezcla de diastereómeros) (MeOH–d4) 1.51 (s, 9H), 2.33–2.57 (m, 2H), 4.93–4.96 (m, 1H), 5.36 y 5.49 (dos m, 1H), 7.00–7.06 (m, 2H), 7.19–7.40 (m, 4H), 7.48 (s, 1H), 7.53–7.57 (m, 2H), 7.72 (s, 1H)
1349
2–(5H–imidazo[5,1–a]isoindol–5–il)–1– feniletanol 73
1H RMN (una mezcla de diastereómeros) 2.30 (m, 1H), 2.41 (m, 1H), 5.08 (m, 1H), 5.31 (m, 1H), 7.08 (m, 1H), 7.20–7.51 (m, 9 H), 7.63 (s, 1H).
1363
tert–butil 4–(1–hidroxi–2–(5H–imidazo [5,1– a] isoindol–5–il)etil) piperidina–1–carboxilato 83
1H RMN (una mezcla de diastereómeros) 1.26 (m, 2H), 1.44 (s, 9 H), 1.47–1.59 (m, 2H), 1.76 (m, 1H), 206– 2.11 (m, 1H), 2.14–2.20 (m, 1H), 2.64 (m, 2H), 3.73 y 3.80 (dos m, 1H), 4.16 (m, 2H), 5.37 y 5.51 (dos m, 1H), 7.16 (s, 1H), 7.22 (m, 1H), 7.32–7.41 (m, 2H), 7.54 (d, 1H, J = 4.0 Hz), 7.79 y 7.81 (dos s, 1H)
1357
1–ciclohexil–2–(6–fluoro–5H–imidazo[5,1–a] isoindol–5–il)etanol 96
1H RMN (una mezcla de diastereómeros) 0.98–1.39 (m, 6H), 1.65–1.79 (m, 5H), 2.03–2.07 (m, 1H) 2.34– 2.50 (m, 2H), 3.54–3.73 (m, 1H), 5.46 y 5.67 (dos dd, 1H, J1 =, 3.0, 8.0 Hz, J2 =3.0, 10.4 Hz), 6.93 (t, 1H, J = 8.0 Hz), 7.17 (d, 1H, J = 7.17 Hz), 7.30–7.37 (m, 2H), 7.82, 7.88 (dos s, 1H)
1359
2–(7–cloro–5H–imidazo[5,1–a]isoindol–5–il)– 1–ciclohexiletanol 98
1H RMN (una mezcla de diastereómeros)1.00–1.28 (m, 5H), 1.37–1.40 (m, 1H), 1.66–2.01 (m, 5H), 1.91– 2.0 (m, 1H) 2.12–2.23 (m, 1H), 3.71–3.75 (m, 1H), 7.15 (s, 1H), 7.33 (d, 1H, J = 8.0 Hz), 7.45 (d, 1H, J = 8.0
Hz), 7.79, 7.82 (dos s, 1H)
1362
1–ciclopentil–2–(5H–imidazo[5,1 – a]isoindol–5–il)etanol 91
1H RMN (una mezcla de diastereómeros) 1.11–1.41 (m, 2H), 1.55–1.70 (m, 4H), 1.83–2.17 (m, 4H), 3.74– 3.79 (m, 1H), 5.38, 5.49 (una t y una d, 1H, J1 = 6.0 Hz, J2 = 6.0 Hz), 7.18 (s, 1H), 7.25 (d condensado con CHCl3, 1H), 7.38 (t, 1H, J = 7.2 Hz), 7.46 (d, 1H, J = 7.6 Hz), 7.55 (d, 1H, J= 7.6 Hz), 7.84 (s, 1H)
1375
1–(ciclohex–1–en–1–il)–2–(5H–imidazo[5,1– a] isoindol–5–il)etanol 92
1H RMN (una mezcla de diastereómeros) 1.47–1.68 (m, 3H), 1.73–1.82 (m, 1H), 1.93–2.14 (m, 4H), 2.18– 2.22 (m, 1H), 2.33–2.40 (m, 2H), 4.36 (t, 1H, J = 7.0 Hz), 5.26, 5.44 (una t y (una dd, 1H, J1 = 6.0 Hz, J2 = 10.0 Hz), 5.71, 5.72 (dos s, 1H), 7.15, 7.18 (dos, s, 1H), 7.2–7.26 (m, 1H), 7.34, 7.3 (dos d, 1H, J1 = 6.8 Hz, J2 =7.27 Hz), 7.43 (d, 1H, J = 7.6 Hz), 7.54 (d, 1H, J = 7.6 Hz), 7.81, 7.86 (dos s, 1H)
1343
1–(3–clorofenil)–2–(5H–imidazo[5,1–a]iso indo 1–5–il)etanol 59
1H RMN (una mezcla de diastereómeros) 2.18–2.52 (m, 2H), 5.25–5.40 (m, 1H), 5.46–5.60 (m, 1H), 7.07 (s, 1H), 7.15–7.55 (m, 7H), 7.69 (d, 1H, J= 8.0 Hz), 7.79 (s, 1H)
1336
1–(2–clorofenil)–2–(5H–imidazo[5,1–a]iso indo 1–5–il)etanol 45
1H RMN (una mezcla de diastereómeros) 2.20–2.50 (m, 2H), 5.0–5.08 (m, 1H), 5.26–5.38 (m, 1H), 7.05 (s, 1H), 7.20–7.45 (m, 7H), 7.45 (d, 1H, J = 7.6 Hz), 7.52 (d, 1H, J = 7.6 Hz) 7.68 (s, 1H)
1374
2–(8–cloro–5H–imidazo[5,1–a]isoindol–5–il)– 1–ciclohexiletanol 41
1H RMN (una mezcla de diastereómeros) (MeOH–d4) 1.00–2.30 (m, 13H), 3.60–3.70 (m, 1H), 5.35 y 5.50
(dos m, 1H), 6.95–7.08 (m, 1H), 7.16–7.88 (m, 4H)
1376
1–ciclohexil–2–(8–fluoro–5H–imidazo[5,1–a] isoindol–5–il)etanol 15
1H RMN (una mezcla de diastereómeros) (MeOH–d4) 1.00–2.30 (m, 13H), 3.50–3.57 (m, 1H), 5.35 y 5.50 (m, 1H), 7.18–7.50 (m, 3H), 7.60–7.65 (m, 1H), 7.92 y 7.98 (dos s, 1H)
1378
2–(6–fluoro–5H–imidazo[5,1–a]isoindo1–5– il)– 1–(1,4–dioxaspiro[4.5]decan–8–il)etanol 90
1H RMN (una mezcla de diastereómeros) (MeOH–d4) 1.31–1.52 (m, 5H), 1.60–1.63 (m, 1H), 1.71–1.78 (m, 3H), 1.86–2.07 (m, 1H), 2.43–2.48 (m, 1H), 3.48–3.64 (m, 1H), 3.90 (s, 4H), 5.57 y 5.69 (dos m, 1H), 7.00– 7.06 (m, 1H), 7.18 (d, 1H, J = 11.6 Hz), 7.41–7.44 (m, 2H), 7.94–8.00 (m, 2H)
1358
2–(5H–imidazo[5,1–a]isoindol–5–il)–1– (tetrahidro–2H–piran–4–il)etanol 92
1H RMN (una mezcla de diastereómeros)1.39–1.51 (m, 2H), 1.59–1.65 (m, 1H), 1.71–1.75 (m, 1H), 2.11– 2.17 (m, 1H), 3.32–3.39 (m, 3H), 3.69–3.73 (m, 1H), 3.96–4.05 (m, 3H), 5.39 y 5.49 (dos m, 1H), 7.17 (s, 1H), 7.23–7.28 (m, 1H), 7.33–7.44 (m, 2H), 7.55 (d, 1H, J = 8 Hz), 7.84 (s, 1H)
1372
1–ciclohexil–2–(9–metoxi–5H –imidazo[5,1– a] isoindol–5–il)etanol 83
1H RMN (una mezcla de diastereómeros) (CD3OD) 1.05–1.11 (m, 1H), 1.13–1.33 (m, 4H), 1.58–1.81 (m, 5H), 2.01–2.08 (m, 1H), 3.57 y 3.67 (dos m, 1H), 3.95 (s, 3H), 5.40 y 5.47 (dos m, 1H), 6.81 y 6.83 (dos d, 1H, J = 8 Hz), 6.90 y 6.97 (dos d, 1H, J = 7.6 Hz), 7.04 y 7.05 (dos s, 1H), 7.12–7.17 (m, 1H), 7.92 y 7.99 (dos s, 1H).
1352
1–(2,5–dimetilfuran–3–il)–2–(6–fluoro–5H– imidazo[5,1–a]isoindol–5–il)etanol 81
1H RMN (una mezcla de diastereómeros)1.89–1.96, 2.37–2.45, 2.53–2.59, 2.77–2.83 (cuatro m, 2H), 2.11, 2.17 (s, 3H), 2.20, 2.22 (dos s, 3H), 4.79–4.88 (m, 1H), 5.36–5.68, 5.63–5.64 (dos m, 1H), 5.94, 5.97 (dos s, 1H), 6.87–6.97 (m, 1H), 7.15, 7.21 (dos s, 1H), 7.32–7.38 (m, 2H), 7.74, 7.88 (dos s, 1H)
1393
2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5– il)– 1–(furan–2–il)etanol 88
1H RMN (una mezcla de diastereómeros 2.36–2.43 (dos m, 1H), 2.77–2.80, 2.92– 2.98 (dos m, 1H), 3.72 (d, 1H, J = 11.0 Hz), 5.02–5.08 (m, 1H), 5.39–5.40, 5.67–5.69 (dos m, 1H), 6.27 (t, 1H, J = 6.4 Hz), 6.31 (s, 1H), 6.93 (s, 1H, J = 9.2 Hz), 7.08 (d, 1H, J = 12.2 Hz), 7.26–7.36 (m, 2H), 7.77, 7.86 7.86 (dos s, 1H)
1394
2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5– il)–1–(1–metil–1H–imidazol–2–il)etanol 81
1H RMN (una mezcla de diastereómeros 2.81–2.85, 2.99–3.15 (tres m,2H), 3.69 (s, 3H), 5.00–5.08 (m, 1H), 5.38–5.40 5.67–5.69 (dos m, 1H), 6.77 (s, 1H), 6.79 (s, 1H), 6.91 (t, 1H, J = 8.9 Hz), 7.07 (s, 1H), 7.28–7.33 (m, 2H), 7.79 (s, 1H)
1390
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(tiazo 1–4–il)etanol 34
1H RMN (una mezcla de diastereómeros 2.49–2.58, 2.68–2.82 (m, 2H),5.23–5.53 (m, 2H), 7.11 (s, 1H), 7.21 (s, 1H), 7.25–7.28 (m, 1H, superpuesto con CHCl3), 7.37(t, 1H, J = 7.5 Hz), 7.47–7.54 (m, 2H), 7.74 (s, 1H), 8.79 (s, 1H)
1407
imagen87 1–(4,4–difluorociclohexil)–2–(5H– imidazo[5,1–a]isoindol–5–il)etanol 61
1H RMN (una mezcla de diastereómeros )1.26–1.36 (m, 3H), 1.63–1.97 (m, 5H), 2.02–2.08 (m, 3H), 3.69– 3.72 (m, 1H), 5.02 y 5.12 (dos d, 1H, J = 6.0 Hz), 5.34–5.53 y 5.41– 5.43 (dos m, 1H), 7.10 y 7.12 (dos s, 1H), 7.25 (t, 1H, J = 7.4 Hz), 7.36 (t, 1H, J = 7.4 Hz), 7.54–7.58 (m, 2H), 7.91 y 7.93 (dos s, 1H
1406
1–(4,4–difluorociclohexil)–2–(6–fluoro–5H– imidazo[5,1–a]isoindol–5–il)etanol 78
1H RMN (una mezcla de diastereómeros) (DMSO–d6): 1.21–1.29 (m, 3H), 1.56–1.72 (m, 4H), 1.88–1.96 (m, 3H), 2.28 y 2.32 (dos t, 1H, J = 5Hz), 3.41–3.44 y 3.62–3.65 (dos m, 1H), 4.73 y 5.17 (dos d, 1H, J = 8.2 Hz), 5.56–5.59 y 5.61–5.64 (dos m, 1H), 7.03–7.17 (m, 2H), 7.39–7.44 (m, 2H), 7.91 y 7.95 (dos s, 1H)
1414
1–(ciclohex–3–enil)–2–(6–fluoro– 5Himidazo[5,1–a]isoindol–5–il)etanol 74
1H RMN (una mezcla de diastereómeros)1.21–1.42 (m, 2H), 1.62–1.83 (m, 4H), 1.93–2.15 (m, 7H), 2.30– 2.44 (m, 1H), 2.6 (br s , 1H), 3.67–3.72 (m, 1H), 3.77–3.82 (m, 1H), 5.49 (q, 1H, J= 5.3 Hz), 5.64–5.70 (m, 3H), 6.92–6.96 (m, 2H), 7.16–7.19 (m, 2H), 7.31–7.38 (m, 3H), 7.77–7.79 (m, 1H), 7.88 (d, 1H, J = 3.6 Hz), 7.91 (s, 1H)
1386
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(4– metilenociclohexil)etanol 70
1H RMN (una mezcla de diastereómeros)1.11–1.20 (m, 2H), 1.49–1.55 (m, 1H), 1.74–1.78 (m, 1H), 1.90– 2.10 (m, 4H), 2.16–2.23 (m, 1H), 2.31–2.38 (m, 2H), 3.74–3.77 y 3.80–3.85 (dos m, 1H), 4.62 (d, 2H, J = 0.8 Hz), 5.37 y 5.48(t y dd, 1H, J = 6 Hz y J = 3 Hz, 10.4 Hz), 7.18 (s, 1H), 7.23 (dd, 1H, J= 1.2 Hz, 7.6 Hz), 7.37 (t, 1H, J = 7.6 Hz), 7.43 (d, 1H, J = 7.6 Hz), 7.55 (d, 1H, J = 7.6 Hz), 7.77 y 7.79 (dos s, 1H)
1381
2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5– il)–1–(1,4–dioxaspiro[4.5]decan–8–il)etanol 90
1H RMN (una mezcla de diastereómeros) (CD3OD) 1.20–2.00 (m, 2H), 1.38–1.60 (m, 1H), 1.70–1.80 (m, 1H), 1.87–2.09 (m, 6H), 3.30–3.34 y 3.53–3.78 (dos m, 1H), 5.56–5.58 y 5.69–5.71 (dos m, 1H), 7.00–7.04 (m, 1H), 7.42 y 7.62 (m y s, 2H), 7.93 y 8.00 (dos s, 1H)
1387
2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5– il)–1–(4–metilciclohexil)etanol 68
1H RMN (una mezcla de diastereómeros)0.81–0.95 (m, 3H), 1.20–1.83 (m, 10H), 1.85–2.03 (m, 1H), 2.35–
2.52 (m, 1H), 3.45–3.80 (m, 1H), 5.50–5.60 y 5.65–5.71 (dos m, 1H), 6.98–7.06 (m, 1H), 7.14 y 7.18 (dos s, 1H), 7.30–7.42 (m, 2H), 7.93 y 7.98 (dos s, 1H)
1398
2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5– il)–1–(4–(yodometileno)ciclohexil)etanol 77
1H RMN (una mezcla de diastereómeros)0.92–1.45 (m, 2H), 1.54–1.76 (m, 2H), 1.80–2.11 (m, 3H), 2.33– 3.10 (m, 4H), 3.59–3.90 (m, 1H), 4.60 (s, 1H), 5.45–5.81 (m, 1H), 6.91–6.95 (m, 1H), 7.16 (s, 1H), 7.26–7.31 (m, 2H), 7.81–7.83 (m, 1H)
1413
2–(9–fluoro–5H–imidazo[5,1–a]isoindol–5– il)– 1–(4–metilciclohexil)etanol 35
1H RMN (una mezcla de diastereómeros) (CD3OD) 0.75–0.96 (m, 3H), 1.00–1.25 (m, 1H), 1.28–1.74 (m, 9H), 2.01–2.14 (m, 2H), 3.67–3.80 (m, 1H), 5.49–5.59 (m, 1H), 7.10–7.18 (m, 2H), 7.60–8.00 (m, 1H)
1411
2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5– il)–1–(4–(propan–2–ilideno)ciclohexil )etanol 77
1H RMN (una mezcla de diastereómeros)1.01–1.06 (m, 2H), 1.46–1.57 (m, 2H), 1.63 (s, 6H), 1.68–1.75 (m, 2H), 1.82–1.96 (dos m, 1H), 2.03–2.11 (m, 1H), 2.32–2.39 (dos m , 1H), 2.45–2.51 y 2.66–2.75 (dos m, 2H), 3.65–3.75 (m, 1H), 5.44–5.65 (dos m, 1H), 6.91 (t, 1H, J = 8.7 Hz),7.16 y 7.17 (dos s, 1H), 7.28–7.36 (m, 2H), 7.80 y 7.87 (dos s, 1H)
1410
1–(4–(ciclopropilmetileno)ciclohexil)–2–(6– fluoro–5H–imidazo[5,1–a]isoindol–5–il)etanol 75
1H RMN (una mezcla de diastereómeros)0.24 (s, 2H), 0.65 (d, 2H, J = 7.4 Hz), 1.12–1.20 (m, 2H), 1.44–1.54 (m, 2H), 1.71–2.03 (m, 6H), 2.34–2.54 (dos m ,1H), 2.72–2.84 (m, 1H), 3.63–3.80 (m, 1H), 4.48 (d, 1H, J = 9.0 Hz), 5.43–5.67 (dos m, 1H), 6.81–6.94 (m, 1H), 7.15 (s, 1H), 7.15–7.30 (m, 3H), 7.80 y 7.88 (dos s, 1H)
1392
1–(4–(1–hidroxi–2–(5H–imidazo[5,1– a]isoindol–5–il)etil)piperidin–1–il)–2,2– dimetilpropan–1–ona 77
1H RMN (una mezcla de diastereómeros)1.24 (s, 9H), 1.28 (m, 2H), 1.60 (m, 2H), 2.13–1.86 (m, 3H), 2.70 (m, 2H), 3.78 (m, 1H), 4.46 (m, 2H), 5.53 y 5.38 (dos m, 1H), 7.12 (s, 1H), 7.21 (m, 1H), 7.33 (m, 1H), 7.42 (d, 1H, J = 7.5 Hz), 7.52 (d, 1H, J = 7.5 Hz), 7.81 y 7.79 (dos s, 1H),
1409
2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5– il)–1–(1–metil–1H–imidazo 1–5–il)etanol 44
1H RMN (una mezcla de diastereómeros)1.92–2.42 (tres m, 1H), 2.72–3.10 (tres m, 1H), 3.72 (s, 3H), 4.90– 5.10 (tres m, 1H), 5.42–5.76 (tres m, 1H), 6.77–6.92 (m, 2H), 7.07 y 7.13 (dos s, 1H), 7.25–7.37 (m, 3H), 7.82, 7.88 y 7.94 (tres s, 1H)
1389
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(1– metil–1H–imidazol–4–il)etanol 94
1H RMN (una mezcla de diastereómeros)2.01, 2.51, 2.67 (tres m, 2H), 3.61 (s, 3H), 5.09 y 5.00 (dos m, 1H), 5.53 y 5.33 (dos m, 1H), 6.75 y 6.70 (dos s , 1H), 7.11 (s, 1H), 7.25–7.16 (m, 2H), 7.32 (m, 1H), 7.37 (s, 1H), 7.49 (t, 1H, J = 7.80 Hz), 7.88 y 7.67 (dos s, 1H),
1391
imagen88 2–(5H–imidazo[5,1–a]isoindol–5–il)–1– (tiazol–5–il)etanol 75
1H RMN (una mezcla de diastereómeros)1.84, 2.03, 2.45, 2.51, 2.66, (cinco m, 2H), 5.29 5.41, 5.55 (tres m, 2H), 7.06–7.28 (m, 2H), 7.37 (t, 1H, J = 7.5 Hz), 7.41 (d, 1H, J = 7. 5Hz), 7.52 (d, 1H, J = 7.5 Hz), 7.71, 7.73 (dos s, 1H), 7.83 (s, 1H), 8.70, 8.71 (dos s, 1H),
1385
imagen89 1–(4–(1–hidroxi–2–(5H–imidazo[5,1– a]isoindol–5–il)etil)piperidin–1–il)etanona 93
1H RMN (una mezcla de diastereómeros) 1.28 (m, 2H), 1.62 (m, 2H), 1.83 (m, 1H), 2.04 y 2.06 (dos s, 3H), 2.19 (m, 1H), 2.47 (t, 1H, J = 12.4 Hz), 3.00 (t, 1H, J = 13.1 Hz), 3.74 (m, 1H), 3.84 (t, 1H, J = 15.5 Hz), 4.68
(d, 1H, J = 14.6 Hz), 5.37 y 5.51 (dos m, 1H), 7.15 (s, 1H), 7.23 (m, 1H), 7.39 (m, 2H), 7.54 (d, 1H, J = 7.5 Hz), 7.80 (s, 1H)
1384
(4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol– 5–il)etil)piperidin–1–il)(tiofen–2–il)metanona 72
1H RMN (una mezcla de diastereómeros)1.39 (m, 2H), 1.66 (m, 2H), 2.07 (m, 1H), 2.17 (m, 1H), 2.89 (m, 2H), 3.76 (m, 1H), 5.37 y 5.51 (m, 1H), 7.01 (t, 1H, J= 4.3 Hz), 7.16 (s, 1H), 7.24 (m, 2H), 7.31–7.40 (m, 3H), 7.54 (d, 1H, J = 7.6 Hz), 7.81 (s, 1H)
1405
1–(4–(1–hidroxi–2–(5H–imidazo[5,1–a] isoindo1–5–il)etil)piperidin–1–il)–2– feniletanona 68
1H RMN (una mezcla de diastereómeros)1.00–2.25 (m, 6H), 2.47 (t, 1H, J = 9.8 Hz), 2.47 (t, 1H, J = 9.8 Hz), 2.89 (t, 1H, J = 12.0 Hz), 3.70 (m, 3H), 3.90 (t, 1H, J = 12.6 Hz), 3.90 (t, 1H, J = 12.3 Hz), 5.25–5.50 (m, 1H), 7.10–7.30 (m, 9H), 7.36 (t, 1H, J = 9.6 Hz), 7.53 (d, 1H, J = 7.8 Hz)
1404
1–ciclohexil–3–(5H–imidazo[5,1–a]iso indo 1–5–il)propan–2–ol 85
1H RMN (una mezcla de diastereómeros)0.80–1–85 (m, 14H), 2.00–2.20 (m, 1H), 4.20–4.50 (m, 1H), 5.30– 5.60 (m, 1H), 7.14 (s, 1H), 7.20–7.39 (m, 2H), 7.43 (d, 1H, J = 7.2 Hz), 7.43 (d, 1H, J = 7.2 Hz), 7.91 (s, 1H)
1403
1–ciclohexil–3–(6–fluoro–5H–imidazo[5,1–a] isoindo1–5–il)propan–2–ol 55
1H RMN (una mezcla de diastereómeros)0.55–1.75 (m, 13H), 2.00–2.50 (m, 2H), 3.75–4.10 (m, 1H), 5.30– 5.75 (m, 1H), 6.85–7.00 (m, 1H), 7.10–7.25 (m, 2H), 7.25–7.40 (m, 2H), 7.93 (s, 1H)
1419
imagen90 1–ciclohexil–2–(5H–imidazo[5,1–a]isoindol– 5–ilideno)etanol 72
1H RMN mezcla de isómeros E/Z: 1.15–1.30 (m, 10H), 1.66–1.83 (m, 10H), 2.00–2.12 (m, 2H), 4.56 (t, 1H, J = 6.4 Hz), 4.66 (d, 1H, J = 7.4 Hz), 6.02 (d, 1H, J = 8.3 Hz), 6.76 (s, 1H), 7.07 (s, 1H), 7.33–7.48 (m, 4H),
7.56 (d, 2H, J = 7.8 Hz), 7.82 (s, 1H), 7.98 (d, 1H, J = 7.9 Hz), 8.04 (s, 1H), 8.42 (s, 1H).
1426
(trans)–metil 4–((1R)–1–hidroxi–2–(5H– imidazo[5,1–a]isoindol–5– il)etil)ciclohexanocarboxilato 87
1H RMN (una mezcla de diastereómeros) 1.05 – 1.20 (m, 2H), 1.42 (qt, J = 12.7, 4.0 Hz, 3H), 1.63 – 1.82 (m, 1H), 1.92 – 2.10 (m, 4H), 2.11 – 2.31 (m, 2H), 3.65 (s, 3H), 3.72 – 3.83 (m, 1H), 5.36 (t, J= 6.2 Hz, 0.7H), 5.52 (dd, J = 10.8, 3.1 Hz, 0.3H), 7.14 (s, 1H), 7.23 (t, J = 7.4 Hz, 1H), 7.31 – 7.40 (m, 1H), 7.42 (d, J = 7.7 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.83 (s, 1H)
1438
2–(5H–imidazo[5,1–a]isoindol–5–il)–1– (espiro[2.5]octan–6–il)etanol 46
1H RMN (una mezcla de diastereómeros) 0.14–0.28 (m, 4H), 0.89 (t, 2H, J = 12.0 Hz), 1.19–2.938(m, 9H), 2.81 (br s, 1H), 3.80–3.82 (m, 1H), 5.36–5.39 y 5.50–5.53 (dos m, 1H), 7.16 (s, 1H), 7.21–7.25 (m, 1H), 7.33 (t, 1H, J = 7.6 Hz), 7.44 (d, 1H, J = 7.6 Hz), 7.53 (d, 1H, J = 7.6 Hz), 7.80 y 7.81 (dos s, 1H)
1475
(trans)–4–(2–(6–fluoro–5H–imidazo[5,1–a] isoindol–5–il)–1–hidroxietil)ciclohexanol 92
1H RMN (una mezcla de diastereómeros) 1.07–2.52 (m, 11H), 3.48–3.68 (dos m, 2H), 5.45 (t, 1H, J = 6.0 Hz), 5.65 (dd, 1H, J = 9.0, 3.0 Hz), 6.89–6.96 (m, 1H), 7.16 (s, 1H), 7.29–7.38 (m, 2H), 7.80 y 7.88 (dos s, 1H)
1499
(1R)–1–((trans)–4–(benciloxi)ciclohexil)–2– (6–fluoro–5H–imidazo[5,1–a]isoindol–5– il)etanol 65
1H RMN (una mezcla de diastereómeros) 1.04–1.33 (m, 5H), 1.71–2.32 (m, 5H), 2.75–2.51 (dos m, 1H), 3.24–3.29 (m, 1H), 3.65–3.69 (m, 1H), 4.54 (s, 2H), 5.43 (t, 1H, J =4.7 Hz, isómero), 5.65 (dd, 1H, J = 10.4, 2.4 Hz, isómero), 6.92 (t, 1H, J = 8.8 Hz), 7.14 (s, 1H), 7.26–7.33 (m, 7H), 7.79 y 7.88 (dos s, 1H)
1498
(1R)–1–((trans)–4–(benciloxi)ciclohexil)–2– (5H–imidazo[5,1–a]isoindol–5–il)etanol 78
1H RMN (una mezcla de diastereómeros) 1.15–2.20 (m, 11H), 3.22–3.31 (m, 1H), 3.65–3.75 (m, 1H), 4.48 y 4.54 (dos s, 2H), 5.35 (t, 1H, J = 8.0 Hz, isómero), 5.48 (dd, 1H, J = 16.0, 4.0 Hz, isómero), 7.15–7.55 (m,
10H), 7.77 y 7.79 y 7.81 (tres s, 1H)
1492
N–((cis)–4–(1–hidroxi–2–(5H–imidazo[5,1–a] isoindol–5–il)etil)ciclohexil)benzamida 63
1H RMN (una mezcla de diastereómeros) (CD3OD) 1.27–1.46 (m, 5H), 1.79 (d, 1H, J = 12.0 Hz), 2.04–2.22 (m, 5H), 3.78–3.88 (m, 2H), 5.47–5.49 y 5.53–5.54 (dos m, 1H), 7.16 y 7.19 (dos s, 1H), 7.35 (t, 1H, J = 7.4 Hz), 7.42–7.49 (m, 3H), 7.53 (d, 1H, J = 7.2 Hz), 7.59 (d, 1H, J = 7.6 Hz), 7.64 (d, 1H, J = 7.6 Hz), 7.82 (d, 2H, J = 7.6 Hz), 7.97 y 8.01 (dos s, 1H)
1505
N–((trans)–4–(1–hidroxi–2–(5H–imidazo[5,1– a] isoindol–5–il)etil)ciclohexil)benzamida 57
1H RMN (una mezcla de diastereómeros) 1.14–1.45 (m, 4H), 1.74 (d, 1H, J = 10.6 Hz), 1.97 (d, 1H, J = 10.6 Hz), 2.09–2.20 (m, 4H), 3.71–3.82 (m, 1H), 3.85–3.95 (m, 1H), 5.3–5.40 y 5.48–5.59 (dos m, 1H), 6.03 (d, 1H, J = 7.6 Hz), 7.17 (s, 1H), 7.21–7.30 (m, 1H, condensado con cloroformo), 7.31–7.51 (m, 5H), 7.55 (d, 1H, J = 7.4 Hz), 7.74 (d, 2H, J = 7.6 Hz), 7.83 (s, 1H)
1441
1–(4–(2–hidroxietilideno)ciclohexil)–2– (5Himidazo[5,1–a]isoindol–5–il)etanol 59
1H RMN (una mezcla de diastereómeros) 1.00–1.30 (m, 2H), 1.40–1.60 (m, 1H), 1.62–1.81 (m, 2H), 1.82– 2.13 (m, 3H), 2.60–2.75 (m, 1H), 3.60–3.75 (m, 1H), 3.90–4.10 (m, 2H), 5.25–5.31 (m, 1H), 5.33–5.48 (m, 1H), 7.13 (s, 1H), 7.20–7.43 (m, 2H), 7.46–7.60 (m, 2H), 7.97 (s, 1H)
1460
tert–butil 3–(1–hidroxi–2–(5H–imidazo[5,1–a] isoindol–5–il)etil)azetidina–1–carboxilato 43
1H RMN (una mezcla de diastereómeros) 1.42 (s, 9H), 1.92–2.23 (m, 2H), 2.50–2.63 (m, 1H), 3.61–3.80 (m, 2H), 3.90–4.02 (m, 3H), 4.20–4.58 (br, 1H), 5.33–5.41 y 5.52–5.58 (dos m, 1H), 7.13 (s, 1H), 7.21–7.28 (m, 1.58H), 7.30–7.39 (m, 1.33H), 7.41–7.48 (m, 0.8H), 7.58 (d, J = 14.3 Hz, 1H), 7.93 y 7.99 (dos s, 1H)
1502
2–(5H–imidazo[5,1–a]isoindol–5–il)–1– (piridin–2–il)etanol 82
1H RMN (una mezcla de diastereómeros) 2.25–2.33 (m, 2H), 5.06–5.07 (m, 1H), 5.09 (br s, 1H), 5.35–5.38 y 5.46–5.49 (dos m, 1H), 7.02 (s, 1H), 7.13–7.24 (m, 4H), 7.44–7.48 (m, 2H), 7.57–7.62 (m, 2H), 8.46–8.47
(m, 1H)
1474
2–(5H–imidazo[5,1–a]isoindol–5–il)–1– (piridin–3–il)etanol 69
1H RMN (una mezcla de diastereómeros) 1.75–2.43 (m, 2H), 5.07–5.12 (m, 1H), 5.38–5.40 y 5.56–5.58 (dos m, 2H), 6.98 y 7.11 (dos s, 1H), 7.19–7.33 (m, 3H), 7.43–7.49 (m, 2H), 7.43–7.79 (m, 2H), 8.3–8.51 (m, 2H)
1501
2–(5H–imidazo[5,1–a]isoindol–5–il)–1– (piridin–4–il)etanol 30
1H RMN (una mezcla de diastereómeros) 1.98–2.32 (m, 2H), 3.59 (br, 1H), 5.03–5.06 (m, 1H), 5.42–5.45 y 5.56–5.58 (dos m, 1H), 7.20–7.23 (m, 1H), 7.24–7.25 (m, 4H), 7.34 (t, J = 7.0 Hz, 1H), 7.41 (d, J = 7.2 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 8.44–8.46 (m, 2H)
1509
2–(5H–imidazo[5,1–a]isoindol–5–il)– 1–(4– (trifluorometil)ciclohexil)etanol 69
1H RMN (una mezcla de diastereómeros) 1.53–2.22 (m, 12H), 3.92–3.98 (m, 1H), 4.12 (br s, 1H), 5.39–5.43 y 5.50–5.60 (dos m, 1H), 7.14 (s, 1H), 7.23–7.54 (m, 5H), 7.94 (s, 1H)
1508
2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5– il)– 1–(4–(trifluorometil)ciclohexil)etanol 61
1H RMN (una mezcla de diastereómeros) 1.40–1.70 (m, 7H), 1.70–1.90 (m, 2H), 1.91–2.04 (m, 1H), 2.09– 2.28 (m, 1H), 2.38–2.48 (m, 1H), 3.80–3.98 (br, 2H), 5.43–5.71 (dos m, 1H), 6.91–6.94 (m, 1H), 7.14 (s, 1H), 7.29–7.38 (m, 2H), 7.93 y 7.97 (dos s, 1H)
1473
1–((cis)–4–(benciloxi)ciclohexil)–2–(6–fluoro– 5H–imidazo[5,1–a]isoindol–5–il)etanol 87
1H RMN (una mezcla de diastereómeros) 1.39–2.42 (m, 12 H), 3.39–3.78 (m, 2H), 4.47 y 4.48 (dos s, 2H), 5.44 (t, 1H, J = 5.1 Hz), 5.67 (dd, 1H, J = 10.2, 2.8 Hz), 6.88–6.94 (m, 1H), 7.25–7.36 (m, 8H), 7.80, 7.82, 7.88 y 7.90 (cuatro s, 1H)
imagen91
imagen92
A un vial que contiene sal de amina apropiada obtenida del Ejemplo 27 (0.25 mmol) en DMF (4 mL) se le adicionó el correspondiente ácido carboxílico (0.26 mmol), DIPEA (1.5 mmol) y HATU (0.28 mmol). La mezcla de reacción se agitó a rt, durante 18 h y se vertió en agua (10 mL) y la capa acuosa se extrajo con diclorometano (2 x 20 mL). Las capas orgánicas combinadas se lavaron con agua (2 x 10 mL), se secaron sobre Na2SO4, y se concentró. El producto en bruto se purificó por cromatografía en columna instantánea para proporcionar 1423, 1424, 1425, 1437, 1439, 1448, 1450, 1458, 1480, 1481, 1490, 1493 o 1500.
imagen93
10 A un vial que contiene sal de amina apropiada obtenida del Ejemplo 19 (0.25 mmol) en diclorometano (4 mL) se le adicionó DIPEA (1.0 mmol) y fenilisocianato (0.25 mmol). La mezcla de reacción se agitó a rt, durante 30 min y se concentró. El residuo se disolvió en diclorometano (30 mL) y se lavó con agua (3 x 10 mL). La capa orgánica se secó sobre Na2SO4 y se concentró. El producto en bruto se purificó por cromatografía en columna instantánea para proporcionar ureas 1449, 1459, 1476, 1477, 1478 y 1479.
15 Ejemplo 30 Procedimiento general para la síntesis de 1495, 1496, 1497, 1503, 1504, 1507, 1512.
imagen94
A una solución de la amina (0.3 mmol) apropiada en CH2Cl2 (3 mL) se le adicionó carbonildiimidazol (0.35 mmol) y etil diisopropilamina (2.0 mmol) a 0 °C con una atmósfera de N2 y la mezcla se agitó durante 1 h. La sal de amina apropiada obtenida del Ejemplo 19 (0.25 mmol) se le adicionó y la mezcla se dejó agitar durante la noche. La solución se sometió
20 a partición con agua en un embudo de separación y la capa orgánica se recolectó. La capa acuosa se extrajo con diclorometano (3 x 10 mL) y las fracciones orgánicas combinadas se secaron (Na2SO4). El producto en bruto se purificó por cromatografía en columna instantánea para proporcionar 1495, 1496, 1497, 1503, 1504 o 1507.
imagen95
1423
1–(4–(1–hidroxi–2–(5H–imidazo[5,1– a]isoindol–5–il)etil)piperidin–1–il)–2– (pirimidin–5–il)etanona 76
1H RMN (una mezcla de diastereómeros) 1.30–1.41 (m, 3H), 1.63–1.72 (m, 2H), 1.87–2.22 (m, 2H), 2.56 (t, 1H, J = 12.4 Hz), 3.01–3.15 (m, 2H), 3.67 (d, 1H, J = 6.0 Hz), 3.83–3.85 (m, 1H), 3.96 (t, 1H, J = 14.6 Hz), 4.66 (t, 1H, J = 14.6 Hz), 5.44–5.46 y 5.62–5.65 (dos m, 1H), 7.17 y 7.19 (dos s, 1H), 7.26–7.30 (m, 1H, condensado con cloroformo), 7.39 (t, 1H, J = 7.4 Hz), 7.46 (d, 1H, J = 7.6 Hz), 7.56 (d, 1H, J = 7.2 Hz), 8.14 (d, 1H, J = 13.2 Hz), 8.63 (d, 2H, J = 4.4 Hz), 9.08–9.10 (m, 1H)
1424
2–(3,4–difluorofenil)–1–(4–(1–hidroxi–2–(5H– imidazo[5,1–a] isoindol–5–il)etil)piperidin–1– il)etanona 71
1H RMN (una mezcla de diastereómeros) 1.16–1.33 (m, 2H), 1.61–1.64 (m, 3H), 1.84–1.92 (m, 1H), 2.09– 2.15 (m, 1H), 2.53 (t, 1H, J = 12.8 Hz), 2.98 (t, 1H, J = 12.8 Hz), 3.67 (d, 2H, J = 4.0 Hz), 3.76–3.78 (m, 1H), 3.90 (t, 1H, J = 13.6 Hz), 4.19 (br s, 1H), 4.70 (t, 1H, J = 13.6 Hz), 5.32–5.36 y 5.49–5.53 (dos m, 1H), 6.94 (s, 1H), 7.06–7.13 (m, 2H), 7.14 (s, 1H), 7.24–7.30 (m, 1H), 7.34–7.42 (m, 2H), 7.56 (d, 1H, J = 6.8 Hz), 7.81–7.85 (m, 1H)
1425
ciclohexil(4–(1–hidroxi–2–(5H–imidazo[5,1– a]isoindol–5–il)etil)piperidin–1–il)metanona 44
1H RMN (una mezcla de diastereómeros) 1.20–1.34 (m, 6H), 1.49–1.77 (m, 10H), 1.87–1.97 (m, 1H), 2.03– 2.08 (m, 1H), 2.16–2.20 (m, 1H), 2.46 (t, 2H, J = 12.0 Hz), 3.76–3.79 (m, 1H), 3.97 (t, 1H, J = 16.2 Hz), 4.70 (t, 1H, J = 14.2 Hz), 5.38–5.41 y 5.51–5.56 (dos m, 1H), 7.15 (s, 1H), 7.23–7.27 (m, 1H, condensado con cloroformo), 7.37 (t, 1H, J = 7.8 Hz), 7.44 (d, 1H, J = 7.6 Hz), 7.54 (d, 1H, J = 7.6 Hz), 7.79 y 7.82 (dos s, 1H)
1437
1–(4–(1–hidroxi–2–(5H–imidazo[5,1– a]isoindol–5–il)etil)piperidin–1–il)–2– (136piridin–4–il)etanona 49
1H RMN (una mezcla de diastereómeros) 1.08–1.16 (m, 1H), 1.23–1.33 (m, 1H), 1.57–1.65 (m, 2H), 1.86 (t, 1H, J = 14.0 Hz), 1.99–2.17 (m, 2H), 2.52 (dt, 1H, J = 2.4, 12.8 Hz), 2.97 (dt, 1H, J = 4.0, 12.8 Hz), 3.70 (d, 2H, J = 7.2 Hz), 3.70–3.76 (m, 1H, condensado con doblete a 3.70), 3.83 (t, 1H, J = 13.8 Hz), 4.30 (br s, 1H), 4.69 (t, 1H, J = 14.0 Hz), 5.32–5.36 y 5.51–5.53 (dos m, 1H), 7.10 y 7.12 (dos s, 1H), 7.16–7.25 (m, 3H), 7.35–7.41 (m, 2H), 7.54 (d, 1H, J = 7.6 Hz), 7.76 (d, 1H, J = 4.4 Hz), 8.49–8.52 (m, 2H)
1439
imagen96 2–(4–fluorofenil)–1–(4–(1–hidroxi–2–(5H– imidazo[5,1–a] isoindol–5–il)etil)piperidin–1– il)etanona 80
1H RMN (una mezcla de diastereómeros) 1.08–1.13 (m, 1H), 1.23–1.30 (m, 1H), 1.54–1.63 (m, 2H), 1.78 y 1.86 (dos d, 1H, J = 13.0 Hz), 1.99–2.12 (m, 2H), 2.49 (dt, 1H, J = 2.4, 12.8 Hz), 2.93 (dt, 1H, J = 3.0, 12.8
Hz), 3.66 (d, 2H, J = 4.4 Hz), 3.71–3.73 (m, 2H, condensado con singlete amplio de OH), 3.90 (t, 1H, J = 15.2 Hz), 4.68 (t, 1H, J = 13.6 Hz), 5.30–5.37 y 5.47–5.50 (dos m, 1H), 6.94–7.00 (m, 2H), 7.13 (s, 1H), 7.15–7.20 (m, 2H), 7.22–7.31 (m, 1H, condensado con cloroformo), 7.35–7.41 (m, 2H), 7.54 (d, 1H, J = 7.6 Hz), 7.84 (d, 1H, J = 5.2 Hz)
1448
(3–fluoro–2–hidroxifenil)(4–(1–hidroxi–2– (5H–imidazo[5,1–a] isoindol–5– il)etil)piperidin–1–il)metanona 26
1H RMN 1.35–1.47 (m, 2H), 1.66–1.70 (m, 2H), 1.86–2.15 (m, 7H), 2.89 (m, 1H), 4.31 (br s, 1H), 5.43–5.47 y 5.53–5.59 (dos m, 1H), 6.78–6.84 (m, 1H), 6.99 (d, 1H, J = 7.6 Hz), 7.11 (t, 1H, J = 9.4 Hz), 7.19 (s, 1H), 7.33 (d, 1H, J = 7.2 Hz), 7.37–7.47 (m, 2H), 7.58 (d, 1H, J = 7.2 Hz), 8.03 y 8.13 (dos s, 1H)
1449
4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol– 5–il)etil)–Nfenilpiperidina–1–carboxamina 62
1H RMN (CD3OD) 1.33–1.43 (m, 2H), 1.59–1.71 (m, 2H), 1.92–1.95 (m, 1H), 2.10–2.22 (m, 2H), 2.87 (t, 2H, J = 11.8 Hz), 3.79–3.83 (m, 1H), 4.25 (t, 2H, J = 15.2 Hz), 5.48 y 5.52–5.55 (t, J = 6.0 Hz y m, 1H), 7.03 (t, 1H, J = 7.4 Hz), 7.16 y 7.19 (dos s, 1H), 7.28 (t, 2H, J = 8.0 Hz), 7.33–7.37 (m, 3H), 7.43 (t, 1H, J = 7.4 Hz), 7.62 (dd, 2H, J = 7.6, 21.6 Hz), 7.94 y 7.97 (dos s, 1H), 8.01 (s, 1H)
1450
(4–fluorofenil)(4–(1–hidroxi–2–(5H– imidazo[5,1–a]isoindol–5–il)etil)piperidin–1– il)metanona 29
1H RMN 1.29–1.37 (m, 3H), 1.57–1.87 (m, 3H), 2.18–2.36 (m, 2H), 3.73–3.86 (m, 4H), 4.74 (br s, 1H), 5.44–5.49 y 5.58–5.63 (dos m, 1H), 7.08 (t, 2H, J = 7.2 Hz), 7.23 (s, 1H), 7.31–7.48 (m, 5H), 7.59 (d, 1H, J = 7.2 Hz), 8.20 y 8.27 (dos s , 1H)
1458
1–(3–(1–hidroxi–2–(5H–imidazo[5,1– a]isoindol–5– il)etil)azetidin–1–il)–2– feniletanona 55
1H RMN (una mezcla de diastereómeros)1.79–2.13 (m, 2H), 2.44–2.48 (m, 1H), 3.33–3.42 (m, 2H), 3.67– 3.93 (m, 2H), 3.97–4.04 (m, 2H), 4.12–4.19 (m, 1H), 5.23–5.31 y 5.34–5.42 (dos m, 1H), 7.08–7.37 (m, 9H), 7.46–7.48 (m, 1 H), 7.93 y 8.07 (dos d, J = 7.6 Hz, 1H)
1459
3–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol– 5–il)etil)–Nfenilazetidina–1–carboxamina 19
1H RMN (una mezcla de diastereómeros) 1.95–2.20 (m, 2H), 2.64–2.68 (m, 1H), 3.76–3.81 (m, 1H), 3.98– 4.10 (m, 4H), 5.43–5.46 y 5.51–5.57 (dos m, 1H), 6.97–7.14 (m, 1H), 7.22 y 7.24 (dos s, 1H), 7.26–7.38 (m, 3.3H), 7.40–7.42 (m, 3H), 7.57–7.62 (m, 1.7H), 7.99 y 8.00 (dos s, 1H)
1476
4–((S)–1–hidroxi–2–((R)–5H–imidazo[5,1– a]isoindol–5–il)etil)–N–fenilpiperidina–1– carboxamina 67
1H RMN 1.32–1.41 (m, 2H), 1.51–1.57 (m, 1H), 1.61 (d, 1H, J = 12.4 Hz), 1.83 (d, 1H, J = 12.4 Hz), 2.00– 2.14 (m, 2H), 2.78 (t, 2H, J = 12.0 Hz), 3.74–3.76 (m, 1H), 4.15–4.18 (m, 2H), 4.42 (br s, 1H), 5.32 (t,1H, J = 6.0 Hz), 6.98 (t, 1H, J = 7.4 Hz), 7.15 (d, 2H, J = 14.4 Hz), 7.20–7.25 (m, 3H), 7.35–7.37 (m, 3H), 7.40 (d, 1H, J = 7.6 Hz), 7.52 (d, 1H, J = 7.6 Hz), 7.86 (s, 1H)
1477
4–((R)–1–hidroxi–2–((R)–5H–imidazo[5,1– a]isoindol–5– il)etil)–N–fenilpiperidina–1– carboxamina 78
1H RMN 1.15–1.61 (m, 6 H), 1.86 (d, 1H, J = 12.8 Hz), 2.17–2.22 (t, 1H, J = 11.2 Hz), 2.66–2.75 (m, 2H), 3.68–3.76 (m, 1H), 4.04–4.08 (m, 2H), 4.60 (br,2H), 5.47 (d, 1H, J = 8.8 Hz), 6.86–6.90 (t, 1H, J = 11.2 Hz), 6.94 (s, 1H), 7.09–7.31 (m, 7H), 7.45 (d, 1H, J = 7.2 Hz), 8.24 (s, 1H)
1478
imagen97 4–((R)–1–hidroxi–2–((S)–5H–imidazo[5,1– a]isoindol–5–il)etil)–N–fenilpiperidina–1– carboxamina 74
1H RMN 1.32–1.61 (m, 4H), 1.81 (d, 1H, J =12.5 Hz), 2.01–2.15 (m, 2H), 2.77 (t, 2H, J = 12.4 Hz), 3.68– 3.73 (m, 1H), 4.08–4.14 (m, 2H), 5.31 (t, 1H, J = 4.0 Hz), 6.92 (s, 1H), 6.97 (t, 1H, J = 6.0 Hz), 7.12 (s, 1H), 7.21–7.38 (m, 6H), 7.51 (d, 1H, J = 7.4 Hz), 7.87 (s, 1H)
1479
4–((S)–1–hidroxi–2–((S)–5H–imidazo[5,1– a]isoindol–5– il)etil)–N–fenilpiperidina–1– carboxamina 78
1H RMN 1.15–1.61 (m, 6 H), 1.86 (d, 1H, J = 12.8 Hz), 2.17–2.22 (t, 1H, J = 11.2 Hz), 2.66–2.75 (m, 2H), 3.68–3.76 (m, 1H), 4.04–4.08 (m, 2H), 4.60 (br,2H), 5.47 (d, 1H, J = 8.8 Hz), 6.86–6.90 (t, 1H, J = 11.2 Hz), 6.94 (s, 1H), 7.09–7.31 (m, 7H), 7.45 (d, 1H, J = 7.2 Hz), 8.24 (s, 1H)
1480
1–(4–((R)–1–hidroxi–2–((S)–5H– imidazo[5,1–a]isoindol–5–il)etil)piperidin–1– il)–2–feniletanona 82
1H RMN 1.0–2.14 (m, 8H), 2.46 (t, 1H, J = 12 Hz), 2.91 (t, 1H, J =12 Hz), 3.65–3.72 (m, 3H), 3.91 (t, 1H, J = 16 Hz), 4.71 (t, 1H, J = 12 Hz), 7.15–7.56 (m, 9H), 7.55 (d, 1H, J = 7.51 Hz), 7.91 (d, 1H, J = 7.7 Hz)
1481
1–(4–((S)–1–hidroxi–2–((S)–5H– imidazo[5,1–a]isoindol–5–il)etil)piperidin–1– il)–2–feniletanona 85
1H RMN 1.04–1.27 (m, 2H), 1.51–1.67 (m, 3H), 1.81–1.89 (m, 1H), 2.19–2.25 (m, 1H), 2.46–2.52 (m, 1H),
2.90 (t, 1H, J = 12.8 Hz), 3.66–3.74 (m, 3H), 3.90 (t, 1H, J = 16.0 Hz), 4.62–4.70 (m, 1H), 5.23 (br s, 1H), 5.49 (dd, 1H, J = 2.2, 10.2 Hz), 7.12 (s, 1H), 7.18–7.37 (m, 8H), 7.53 (d, 1H, J = 7.5 Hz), 7.92 (d, 1H, J = 3.0 Hz)
1490
1–(4–((S)–1–hidroxi–2–((S)–5H– imidazo[5,1–a]isoindol–5–il)etil)piperidin–1– il)–2–(tetrahidro–2H–piran–4–il)etanona 77
1H RMN (CD3OD) 1.06 –1.46 (m, 4H), 1.56 – 1.73 (m, 3H), 1.82 – 2.08 (m, 3H), 2.32 (t, J = 6.4 Hz, 2H), 2.39 (dd, J = 18.4, 7.2 Hz, 1H), 2.54 (t, J = 13.0 Hz, 1H), 3.03 (t, J = 12.9 Hz, 1H), 3.40 (t, J = 11.7 Hz, 2H), 3.48– 3.59 (m, 1H), 3.90 (d, J = 11.5 Hz, 2H), 3.94 – 4.06 (m, 1H), 4.57 (t, J = 14.8 Hz, 1H), 5.71 (d, J = 6.5 Hz, 1H), 7.41 –7.52 (m, 2H), 7.55 (d, J = 7.3 Hz, 1H), 7.73 (d, J = 7.1 Hz, 1H), 7.90 (s, 1H), 8.57 (s, 1H)
1493
1–(4–((S)–1–hidroxi–2–((R)–5H– imidazo[5,1–a]isoindol–5– il)etil)piperidin–1– il)–2–feniletanona 63
1H RMN 0.49–1.21 (m, 4H), 1.44–1.56 (m, 1H), 1.96–2.05 (m, 2H), 2.38–2.47 (m, 1H), 2.80–2.86 (m, 1H), 3.58–3.64 (m, 2H), 3.83 (t, J = 13.2 Hz, 1H), 4.62 (t, J = 13.2 Hz, 1H), 5.25–5.30 (m, 1H), 7.13–7.24 (m, 7H), 7.29–7.34 (m, 2H), 7.48 (d, J = 7.6 Hz, 1H), 7.94 (br s, 1H)
1495
4–((R)–1–hidroxi–2–((S)–5H–imidazo[5,1– a]isoindol–5–il)etil)–N–((trans)–4– hidroxiciclohexil)piperidina–1–carboxamina 56
1H RMN (CD3OD) 1.21–1.43 (m, 7H), 1.48–1.66 (m, 2H), 1.81–2.01 (m, 5H), 2.14 (ddd, 2H, J = 4.4, 8.4, 10.4 Hz), 2.71 (t, 2H, J = 11.7 Hz), 3.49–3.55 (m, 2H), 3.74–3.79 (m, 1H), 4.08 (t, 1H, J = 13.6 Hz), 5.46 (t, 1H, J = 6.2 Hz), 7.16 (s, 1H), 7.34 (t, 1H, J = 7.5 Hz), 7.43 (t, 1H, J = 7.3 Hz), 7.57 (d, 1H, J = 7.6 Hz), 7.64 (d, 1H, J = 7.6 Hz), 8.00 (s, 1H)
1496
4–((S)–1–hidroxi–2–((S)–5H–imidazo[5,1– a]isoindol–5– il)etil)–N–(tetrahidro–2H–piran– 4–il)piperidina–1– carboxamina 84
1H RMN 1.16–1.74 (m, 6H), 1.78– 2.00 (m, 2H), 2.18 – 2.37 (m, 1H), 2.70 (t, J = 12.7 Hz, 2H), 3.33 – 3.51 (m, 2H), 3.71– 4.13 (m, 5H), 4.76 (d, J = 7.4 Hz, 1H), 5.54 (dd condensado con br s, J = 10.6, 2.3 Hz, 3H), 7.13 (s, 1H), 7.20 – 7.38 (m, 3H), 7.51 (d, J = 7.5 Hz, 1H), 7.90 (s, 1H)
1497
4–((S)–1–hidroxi–2–((S)–5H–imidazo[5,1– a]isoindol–5–il)etil)–N–((trans)–4– hidroxiciclohexil)piperidina–1– carboxamina 65
1H RMN 1.08 – 1.44 (m, 6H), 1.57 (t, J = 12.5 Hz, 2H), 1.67 – 1.80 (m, 1H), 1.90 (dd, J = 24.8, 9.8 Hz, 4H), 2.29 (ddd, J = 14.3, 11.0, 3.1 Hz, 1H), 2.69 (t, J = 12.8 Hz, 2H), 3.35 (s, 1H), 3.49 (d, J = 4.4 Hz, 2H), 3.63– 3.77 (m, 1H), 3.95– 4.19 (m, 2H), 5.50 (dd, J = 9.7, 3.0 Hz, 1H), 6.05 (d, J = 7.8 Hz, 1H), 7.15 (s, 1H), 7.31 (td, J = 7.5, 1.0 Hz, 1H), 7.39 (t, J = 7.4 Hz, 1H), 7.46 (d, J = 7.2 Hz, 1H), 7.60 (d, J = 7.5 Hz, 1H), 7.91 (d, J = 8.5 Hz, 1H)
1500
1–(4–((R)–1–hidroxi–2–((S)–5H– imidazo[5,1–a]isoindol–5–il)etil)piperidin–1– il)–2–(tetrahidro–2H–piran–4–il)etanona 46
1H RMN 1.19–1.42 (m, 4H), 1.54–1.67 (m, 4H), 1.86–1.90 (m, 1H), 2.08–2.25 (m, 4H), 2.43–2.51 (m, 1H), 2.92–3.01 (m, 1H), 3.39 (t, 2H, J = 11.8 Hz), 3.72–3.76 (m, 1H), 3.90–3.99 (m, 3H), 4.70 (m, 1H, J = 9.75 Hz), 5.35–5.40 (m, 1H), 7.13 (s, 1H), 7.24–7.27 (m, 1H), 7.35–7.43 (m, 2H), 7.54 (d, 1H, J = 7.4 Hz), 7.80 (s, 1H)
1503
imagen98 4–((R)–1–hidroxi–2–((S)–5H–imidazo[5,1– a]isoindol–5– il)etil)–N–(tetrahidro–2H–piran– 4–il)piperidina–1– carboxamina 77
1H RMN 1.29–1.33 (m, 1H), 1.41–1.47 (m, 2H), 1.51–1.61 (m, 1H), 1.62 (d, 1H, J = 12.7 Hz), 1.83 (d, 1H, J = 12.4 Hz), 1.91 (d, 2H, J = 12.4 Hz), 2.07–2.26 (m, 2H), 2.73 (t, 2H, J = 12.2 Hz), 3.46 (t, 2H, J = 10.8 Hz), 3.73–3.78 (m, 1H), 3.81–3.89 (m, 1H), 3.93–4.05 (m, 4H), 4.40 (d, 1H, J = 7.5 Hz), 4.61 (br s, 2H), 5.41 (t, 1H, J = 5.9 Hz), 7.18 (s, 1H), 7.24–7.30 (m, 1H, condensado con cloroformo), 7.39 (t, 1H, J = 7.5 Hz), 7.44 (d, 1H, J = 7.6 Hz), 7.56 (d, 1H, J = 7.6 Hz), 7.92 (s, 1H)
1504
N–ciclohexil–4–((R)–1–hidroxi–2–((S)–5H– imidazo[5,1–a] isoindol–5–il)etil)piperidina– 1–carboxamina 77
1H RMN 0.97–1.23 (m, 3H), 1.26–1.36 (m, 4H), 1.48–1.70 (m, 5H), 1.82 (d, J = 13.1 Hz, 1H), 1.93 (d, J = 10.3 Hz, 2H), 2.07 (ddd, J = 14.3, 6.8, 2.7 Hz, 1H), 2.14 – 2.27 (m, 1H), 2.70 (td, J = 12.8, 2.5 Hz, 2H), 3.57– 3.65 (m, 1H), 3.71 – 3.81 (m, 1H), 3.97 (t, J = 13.2 Hz, 2H), 4.31 (d, J = 7.6 Hz, 1H), 5.39 (t, J = 6.0 Hz, 1H), 7.16 (s, 1H), 7.24 (dd, J = 7.6, 1.0 Hz, 1H), 7.37 (t, J = 7.4 Hz, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.80 (s, 1H)
1507
N–ciclopentil–4–((R)–1–hidroxi–2–((S)–5H– imidazo[5,1–a] isoindol–5–il)etil)piperidina– 1–carboxamina 87
1H RMN
1511
1–(4–((R)–1–hidroxi–2–((S)–5H– imidazo[5,1–a]isoindol–5–il)etil)piperidin–1– il)–2–(4–(trifluorometil)fenil)etanona 69
1H RMN 1.03 – 1.26 (m, 2H), 1.28 – 1.39 (m, 2H), 1.56 (q, J = 13.9, 13.1 Hz, 2H), 1.75 (d, J = 13.0 Hz, 1H), 1.91 – 2.10 (m, 2H), 2.45 (t, J = 13.4 Hz, 1H), 2.90 (t, J = 13.0 Hz, 1H), 3.68 (d, J = 6.5 Hz, 2H), 3.83 (t, J = 13.9 Hz, 1H), 4.59 (t, J = 11.5 Hz, 1H), 4.94 (br s, 1H), 5.35 (q, J = 6.6 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 7.21 – 7.40 (m, 5H), 7.42 – 7.56 (m, 3H), 8.16 (d, J = 17.3 Hz, 1H).
1512
4–((R)–1–hidroxi–2–((S)–5H–imidazo[5,1– a]isoindol–5– il)etil)–N–(4–(trifluorometil)fenil) piperidina–1– carboxamina 78
1H RMN 1.15–1.61 (m, 6 H), 1.86 (d, 1H,J = 12.8 Hz), 2.17–2.22 (t, 1H, J = 11.2 Hz), 2.66–2.75 (m, 2H), 3.68–3.76 (m, 1H), 4.04–4.08 (m, 2H), 4.60 (br,2H), 5.47 (d, 1H, J = 8.8 Hz), 6.86–6.90 (t, 1H, J = 11.2 Hz), 6.94 (s, 1H), 7.09–7.31 (m, 7H), 7.45 (d, 1H,J = 7.2 Hz), 8.24 (s, 1H)
1513
(4–((R)–1–hidroxi–2–((S)–5H–imidazo[5,1– a]isoindol–5–il)etil)piperidin–1–il)(1H– imidazol–1–il)metanona 50
1H RMN 1.44–1.54 (m, 2H), 1.65–1.68 (m, 1H), 1.73 (d, 1H, J = 12.8 Hz), 1.98 (d, 1H, J = 13.0 Hz), 2.05– 2.14 (m, 1H), 2.18–2.25 (m, 1H), 2.99 (t, 2H, J = 12.0 Hz), 3.82–3.87 (m, 1H), 4.16 (t, 2H, J = 10.7 Hz), 4.80 (br s, 1H), 5.41 (t, 1H, J = 5.9 Hz), 7.07 (s, 1H), 7.14 (s, 1H), 7.18 (s, 1H), 7.24–7.28 (m, 1H, condensado con cloroformo), 7.38 (t, 1H, J= 7.5 Hz), 7.43 (d, 1H, J = 7.6 Hz), 7.55 (d, 1H, J = 7.6 Hz), 7.84 (s, 1H), 7.86 (s, 1H).

Ejemplo 31 1–(1–(bencilsulfonil)piperidin–4–il)–2–(5H–imidazo[5,1–a]isoindol–5–il)etanol
imagen99
5 A un vial que contiene 2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(piperidin–4–il)etanol diclorhidrato (0.12 g, 0.34 mmol) en CH2Cl2 (3 mL) se le adicionó etil diisopropilamina (0.35 mL, 2.0 mmol) y bencil sulfonil cloruro (67 mg, 0.35 mmol). La mezcla de reacción se agitó a rt, durante 18 h y se concentró. El residuo se disolvió en diclorometano (30 mL) y se lavó con agua (3 x 10 mL). La capa orgánica se secó sobre Na2SO4 y se concentró. El producto en bruto se purificó por cromatografía en columna instantánea para proporcionar 1442 como un sólido de color blanco (85 mg, 58%).:1H RMN
10 (una mezcla de diastereómeros) 1.21–1.29 (m, 2H), 1.34–1.36 (m, 1H), 1.57–1.60 (m, 1H), 1.79–1.90 (m, 2H), 2.03–2.10 (m, 1H), 2.52–2.66 (m, 2H), 3.55–3.63 (m, 2H), 3.67–3.71(m, 1H), 4.38 (s, 2H), 5.03 y 5.14 (dos d, 1H, J = 6.0 Hz, OH),
5.39 (t, 1H, J = 6.8 Hz), 7.13 y 7.16 (dos s, 1H), 7.29 (t, 1H, J = 7.2 Hz), 7.37–7.42 (m, 6H), 7.60 (dd, 2H, J = 7.8, 14.2 Hz), 7.92 y 7.95 (dos s, 1H).
Ejemplo 32 ácido 2–(5H–imidazo[5,1–a]isoindol–5–il)acético
imagen100
imagen101
imagen102
imagen103
imagen104
A una solución de 86 (160 mg, 0.57 mmol) en EtOH (3 mL) a rt se le adicionó NH2OH acuoso al 50% (1.71 mmol) y la solución se agitó a 50 °C, durante la noche. Después de enfriar a rt, el solvente se eliminó a presión reducida y el producto en bruto se purificó por cromatografía en columna instantánea para proporcionar 1360 (120 mg, 71%). 1H RMN 0.99–1.15 (m, 5 H), 1.45–1.72 (m, 6 H), 2.43 y 2.58 (dos m, 1H), 2.70 y 2.91 (m, 1H), 4.69 (m, 1H), 7.23–7.29 (m, 3H),
7.40 y 7.46 (dos m, 1H), 7.53 y 7.58 (dos m, 1H), 7.75 y 7.76 (dos s, 1H), 10.34 y 10.41 (dos s, 1H).
imagen105
10 A una solución de 1360 (100 mg, 0.34 mmol) en EtOH/AcOH 1:1 (4 mL) se le adicionó polvo de zinc (67 mg, 1.0 mmol) y la mezcla se agitó durante la noche a rt. El solvente se eliminó a presión reducida y la mezcla se suspendió en MeOH/DCM 1:1 (10 mL) y se filtró. El filtrado se recolectó y se concentró a presión reducida. El producto en bruto se purificó por cromatografía de intercambio iónico utilizando agua y NH4OH como el eluyente para proporcionar 1364 (25 mg, 26%). 1H RMN (mezcla de diastereómeros) 0.89–1.75 (m, 11H), 2.24 y 2.42 (dos m, 1H), 2.62 (m, 1H), 4.52 (m,
15 1H), 7.09 (t, 1H, J = 9.2 Hz), 7.29 (m, 2H), 7.38 (m, 1H), 7.47 (m, 1H), 7.60 (d, 1H, J = 9.2 Hz).
Ejemplo 45 Procedimiento general para la eliminación del grupo protector BOC a partir de anilinas y aminas sustituidas
imagen106
A una solución de 17, 1300, 1328 o 1363 (66.0 mmol) en diclorometano (2 mL) se le adicionó ácido trifluoroacético (0.2 mL, 2.66 mmol) y la mezcla se agitó a rt, durante 2 h. Los solventes se separaron por destilación a presión reducida y la
20 solución se basificó con NaHCO3 saturado. La capa acuosa se extrajo con EtOAc (3 x 15 mL). Las capas orgánicas combinadas se lavaron con agua, salmuera y se secaron (Na2SO4). La solución se filtró y el solvente se eliminó a presión reducida. El residuo en bruto se purificó por cromatografía en columna para proporcionar los siguientes compuestos.
imagen107
1330
1–(2–aminofenil)–2–(5H imidazo[5,1– a]isoindol–5– il)etanona 76
1H RMN 3.40 (dd, 1H, J = 18.0 Hz, 9.6 Hz), 3.70 (dd, 1H, J = 18.0 Hz, 3.3 Hz), 5.81 (dd, 1H, J = 6.3 Hz, J = 3.3 Hz), 6.43 (br s, 2H), 6.60 (t, 1H, J = 7.5 Hz), 6.68 (d, 1H, J = 8.4 Hz), 7.18 (s, 1H), 7.29 (m, 2H), 7.36 (d, 2H, J = 7.8 Hz), 7.55 (d, 2H, J = 7.5 Hz), 7.74 (s, 1H)
1370
2–(5H–imidazo[5,1–a]isoindol–5–il)– 1– (piperidin–4–il)etanol 15
1H RMN (La mezcla de diastereómeros) 1.66–1.87 (m, 6 H), 2.20 (s, 1H), 2.75 (m, 2H), 3.40 (m, 2H), 3.84 (m, 2H), 5.27 y 5.34 (dos m, 1H), 7.05 (s, 1H), 7.19 (t, 1H, J = 4.0 Hz), 7.30 (t, 1H, J = 8.0 Hz), 7.38 (d, 1H, J = 8.0 Hz), 7.46 (d, 1H, J = 8.0 Hz), 8.06 y 8.12 (dos s, 1H)
1301
1–(4–aminofenil)–2–(5Himidazo[5,1– a]isoindol–5–il)etanona 87
1H RMN 3.35 (dd, 1H, J =18.6 Hz, 9.6 Hz), 3.61 (dd, 1H, J = 18.6 Hz, 9.6 Hz), 4.13 (br s, 2H), 5.84 (dd, 1H, J =18.6 Hz, 9.6 Hz), 6.65 (d, 2H, J = 8.7 Hz), 7.18 (s, 1H), 7.24–7.29 (m, 1H), 7.37–7.58 (m, 3H), 7.74–7.82 (m, 3H)
1369
1–(3–aminofenil)–2–(5Himidazo[5,1– a]isoindol–5–il)etanol 58
(MeOH–d4) 2.32 (t, 2H, J = 6.3 Hz), 4.89–4.94 (m, 1H), 5.30 y 5.38 (dos m, 1H), 6.64 (d, 1H, J = 7.8 Hz), 6.71–6.77 (m, 2H), 7.05–7.10 (m, 1H), 7.28–7.41 (m, 2H), 7.51–7.58 (m, 2H), 7.66 (s, 1H)

Ejemplo 46 5–(2–Ciclohexil–2–hidroxietil)–5H–imidazo[5,1–a]isoindol–9–ol
imagen108
imagen109
imagen110
imagen111
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A una solución de 1304 (40 mg, 0.14 mmol) en THF (5 mL) se le adicionó trietilamina (43 µL, 0.31 mmol) seguido por fenilisocianato (17 µL, 0.16 mmol). La mezcla de reacción se agitó a rt, durante 18 h y se concentró. El producto en bruto se purificó utilizando cromatografía en columna instantánea (EtOAc:MeOH 4:1) para proporcionar 1427 como gel
5 incoloro (19 mg, 34%). 1H RMN (una mezcla de diastereómeros): 1.02–1.04 (m, 5H), 1.56–1.70 (m, 6H), 2.10–2.14 (m, 1H), 2.31–2.40 (m, 1H), 5.02–5.10 (m, 1H), 5.18–5.24 (m, 1H), 7.04–7.08 (m, 1H), 7.18–7.35 (m, 6H), 7.39–7.41 (m, 2H), 7.50 (d, J = 4 Hz, 1H), 7.65 (d, J = 8 Hz, 1H), 7.74 (s, 1H).
Ejemplo 69 Procedimiento general para la síntesis de profármacos de 1304
A un vial que contiene 1304 (0.5 mmol) en diclorometano (5 mL) se le adicionó el apropiado ácido carboxílico (1.1
10 mmol), diisopropiletil amina (3.0 mmol) y HATU (1.3 mmol). La mezcla de reacción se agitó a rt, durante 48 h y se vertió en NaHCO3 saturado acuoso (10 mL) y la capa acuosa se extrajo con diclorometano (2 x 20 mL). Las capas orgánicas combinadas se secaron sobre Na2SO4, y se concentró. El producto en bruto se disolvió en diclorometano (6 mL) y TFA (2 mL) se le adicionó. La mezcla de reacción se agitó a temperatura ambiente durante 2 h y se concentró. El residuo se disolvió en agua y se le adicionó K2CO3 sólido hasta que la solución fue básica. La solución acuosa se extrajo con
15 diclorometano (2 x 20 mL). Las capas orgánicas combinadas se secaron sobre Na2SO4, se filtraron y concentraron para proporcionar 1433, 1440, 1442 y 1443.
#
Compuesto Nombre Rendimiento (%)
1440
(2S)–1–ciclohexil– 2–(5H–imidazo[5,1– a]isoindol1–5– il)etil 2–aminopropanoato 87
1H RMN (una mezcla de diastereómeros) 0.96–1.06 (m, 2H), 1.09–1.19 (m, 3H), 1.27 y 1.30 (dos d, 3H, J = 7.0 Hz), 1.41–1.53 (m, 3H), 1.63–1.77 (m, 5H), 2.10–2.16 y 2.23–2.26 (dos m, 1H), 2.37–2.45 (m, 1H), 3.21 y 3.50 (dos q, 1H, J = 7.0 Hz), 4.86–4.90, 5.06–5.09 y 5.15–5.17 (tres m, 2H), 7.19 (d, 1H, J = 3.2 Hz), 7.24– 7.27 (m, 1H, condensado con cloroformo), 7.37 (dt, 1H, J = 2.8, 7.6 Hz), 7.49–7.55 (m, 2H), 7.69 (s, 1H)
1442
(2S)–1–ciclohexil– 2–(5H–imidazo[5,1– a]isoindol–5– il)etil pirrolidina–2–carboxilato diclorhidrato 77
1H RMN (una mezcla de diastereómeros) (CD3OD) 0.90–1.17 (m, 5H), 1.4–1.75 (m, 10H), 2.11–2.18 (m, 2H), 2.36–2.42 (m, 1H), 2.82 (br s, 1H), 2.89–3.0 (m, 2H), 3.54–3.60 y 3.72–3.75 y 3.81–3.83 (tres m, 1H), 4.93–5.25 (cuatro m, 2H), 7.16 (s, 1H, J = 3.6 Hz), 7.22–7.16 (m, 1H), 7.35 (t, 1H, J = 7.40 Hz), 7.48–7.52 (m, 2H), 7.69 (d, 1H, J = 8.40 Hz)
1443
(2S)–5–(1–ciclohexil– 2–(5H–imidazo[5,1– a]isoindol–5–il)etil) 1–metil 2– aminopentanodioato diclorhidrato 73
1H RMN (una mezcla de diastereómeros) (DMOS–d6) 0.85–0.88 (m, 2H), 1.02–1.12 (m, 3H), 1.34–1.38 (m, 1H), 1.53–1.67 (m, 5H), 2.14–2.20 (m, 2H), 2.60–2.73 (m, 2H), 3.41–3.53 (m, 2H), 3.74 y 3.87 (dos s, 3H), 4.44–4.52 (m, 1H), 5.81–5.3 (m, 1H), 7.50–7.53 (m, 2H), 7.69–7.70 (m, 1H), 7.81–7.72 (m, 1H), 7.95 (d, 1H, J = 6.4 Hz), 8.66 (br s, 3H), 9.52 (s, 1H)
1433
(2S)–1–(1–ciclohexil–2–(5H–imidazo[5,1–a] isoindol–5– il)etoxi)–3–metil–1–oxobutan–2– aminio cloruro clorhidrato 40
1H RMN (una mezcla de diastereómeros) (DMOS–d6) 0.86–0.98 (m, 6H), 1.01–1.12 (m, 4H), 1.42 y 1.44 (dos s, 9H), 1.58–1.87 (m, 6H), 2.0–2.16 (m, 2H), 2.33–2.43 (m, 1H), 4.04–4.07 y 4.08–4.15 (dos m, 1H), 4.91–5.29 (tres m, 3H), 7.17 (s, 1H), 7.21–7.28 (m, 2H), 7.31–7.40 (m, 2H), 7.70 (s, 1H)
Ejemplo biológico 1 clonación, expresión y purificación de proteína IDO humana
Los vectores de expresión para la proteína humana indolamina–2,3–dioxigenasa (IDO) se prepararon por amplificación
5 de un fragmento de 1219 pb de la secuencia presente en el vector phID06His ADNc con los cebadores 5’– ggagcatgctaATGGCACACGCTATGGAAAAC– 3’ y 5’–gagagatctACCTTCCTTCAAAAGGGATTTC–3’ y clonación del fragmento BglII–SphI de 1213 pb en pQE70 (Qiagen), para producir vector pQE70–hIDO. Esta construcción adiciona 2 aminoácidos adicionales y una etiqueta de 6–histidina en el extremo C–terminal de la proteína IDO humana natural mientras se conserva intacto el codón de iniciación natural y la secuencia de aminoácidos N–terminal. El alelo
10 amplificado de IDO humana muestra dos polimorfismos con respecto a la secuencia depositada en el catálogo inventario P14902 de base de datos SwissProt. Estos polimorfismos resultan en un cambio de aminoácidos de P110S y E119G.
El plásmido pQE70–hIDO se transformó en células M15 (pREP4) (Qiagen) y los clones se seleccionaron en placas de agar LB suplementado con 50 g/mL de carbenicilina y 30 g/mL de kanamicina. La expresión de proteínas se llevó a 15 cabo por el crecimiento de un cultivo durante la noche del clon/pQE70–hIDO M15pRep4 en 100 µL de LB suplementado con 100 g/mL de carbenicilina, 50 g/mL de kanamicina y 50 g/mL de (medio LBCKT) de L–triptófano. 40 mL de este cultivo se inocularon en 750 mL de LBCKT durante 4 horas a 37 °C. Este cultivo se diluyó 1:10 en medio LBCKT y se cultivaron durante otras 2 horas a 37 °C hasta que OD600 fue mayor que 0.8. En este punto, se inocularon los cultivos con hemina a 7 M y L–triptófano a 75 g/mL y se incubaron a 37 ºC, durante 2 h. La inducción de la expresión de la
20 proteína se llevó a cabo complementando los cultivos con IPTG a 1 mM, PMSF a 200 M, EDTA a 1 mM y L–triptófano a 50 g/mL. La incubación se continuó durante otras 16 h a 25 ºC. Las células se recogieron por centrifugación y los sedimentos celulares se lavaron con solución reguladora de PBS suplementada con PMSF 200 M y EDTA 1 mM y se almacenaron a –80 ºC hasta la purificación de proteínas.
imagen119
control negativo del ensayo. Las células incubadas en medio de inducción y sin inhibidor sirven como el control positivo del ensayo. La incubación se lleva a cabo durante 16 horas a 37 ºC en una incubadora de cultivo celular. 200 L de medio se transfieren a placas de polipropileno de 96 pozos de fondo en U que contienen 25 L de TCA al 30%, se incubaron 30 minutos a 60 ºC y se centrifugaron a 3400 g durante 5 minutos. 150 L del sobrenadante claro se transfiere a un placa de poliestireno de 96 pozos que contenía 50 L de 4% (p/v) de p–dimetilaminobenzaldehído en ácido acético, se incubaron durante 10 min. La concentración de quinurenina se determina midiendo la absorbancia a 480 nm.
Para medir la toxicidad de cada compuesto después de 16 h de incubación con las células, la viabilidad celular se mide mediante un ensayo de WST– 1 (Roche) de acuerdo con las instrucciones del fabricante. En resumen, después de la incubación con cada compuesto, el medio se aspiró y se reemplazó con 100 mL de reactivo WST–1, y se incubó 30 min a 37 ºC. La absorbancia a 540 nm se correlaciona con el número de células viables. La determinación de IC50 (ensayo quinurenina) o LD50 (ensayo WST–1) se lleva a cabo a través de análisis de regresión no lineal utilizando el software GraphPad Prism.
Ejemplo biológico 4 Inversión de la represión mediada por IDO de la proliferación de células T por inhibidores de IDO.
Los monocitos humanos fueron recogidos a partir de células mononucleares periféricas de leucoaféresis y cultivadas durante la noche a 106 células/pozo en una placa de 96 pozos en medio RPMI 1640 suplementado con suero de ternera fetal al 10% y L–glutamina 2 mM. Las células adherentes se conservan y se cultivaron durante 7 días con 200 ng/mL de IL–4, 100 ng/mL de GM–CSF. Las células se maduraron durante 2 días con un cóctel de citoquinas que contiene TNF– , IL–1, IL–6 y PGE2 durante 2 días adicionales para inducir la maduración de células dendríticas. Al final de la maduración, las células débilmente adherentes se separaron por aspiración suave y se sembraron en placas de 96 pozos de fondo en V, a 5000 células/pozo. Estas células son > 80% de IDO + células dendríticas. Las células humanas alogénicas T (3x105) de donantes normales se resuspendieron en RPMI 1640 suplementado con 100 a 200 U/mL de IL– 2 y 100 ng/mL de anticuerpo anti–CD3 y se adicionaron a los pozos. Se adicionaron diluciones en serie de compuestos IDO disueltos en RPMI libre de rojo de fenol para producir una concentración final de inhibidores de IDO entre 500 nM y 1 M. Después de la incubación durante 2–4 días, la proliferación de células T se midió por ensayo de incorporación de BrdU después de un pulso durante la noche con mezcla de marcación BrdU (Roche Molecular Biochemicals). Al final del pulso, las células se fijaron y se incubaron con anticuerpo anti–BrdU–POD 100 L/pozo siguiendo las instrucciones del fabricante. Las placas se leyeron en un lector de microplacas.
Alternativamente, el ensayo de los inhibidores de IDO en un modelo de ratón in vitro en la supresión mediada por IDO de proliferación de células T se realiza mediante el siguiente procedimiento. Los ratones C57B16 se inoculan con 1x106 células tumorales B78H1–GMCSF en el flanco derecho. Después de 10–12 días, el drenaje del tumor de ganglios linfáticos se recogen y las células se tiñeron con anticuerpos monoclonales anti–CD11c y anti–B220. Las células están ordenadas por clasificación de células activadas por fluorescencia de alta velocidad y las células dendríticas plasmacitoides el CD11c +/B220 se recogen y se sembraron a 2000 células/pozo en placas de 96 pozos de fondo en V. Los esplenocitos se recogen de los ratones transgénicos BM3 (en el fondo CBA) y se recogieron por enriquecimiento de lana de nylon. Las células BM3 T (105 células/pozo) se adicionan a cada pozo en 200 L de RPMI, 10% de FCS, – mercaptoetanol 50 M. Alternativamente, las células T se obtienen a partir de bazos de ratones transgénicos OT–I y se adicionan al cultivo en combinación con el péptido OVA. Los inhibidores de IDO se adicionan disueltos en RPMI a concentraciones finales que van desde 1 mM a 10 nM. Después de 3 días de estimulación, las células se sometieron a un pulso por 16 h con BrdU o 3H–timidina. Las células se recogieron, se fijaron y se ensayaron para la incorporación de BrdU siguiendo las instrucciones del fabricante del kit de la marcación de BrdU (Roche Diagnostics). Si se utiliza 3H– timidina para medir la proliferación de células T, las células se recogen y el recuento de dpm se mide en un contador de centelleo siguiendo procedimientos ampliamente conocidos en la técnica. Las células CD11c+ de control tomadas desde el nodo linfático contralateral o células CD11c +/ B220– (población de IDO) de la TDLN se utilizan como control positivo de proliferación.
Ejemplo biológico 5 Valor farmacológico
Los valores farmacológicos probados en los compuestos ensayados de acuerdo con uno o más de los ejemplos anteriores en la siguiente tabla, incluyendo,
IC50 de IDO humana: esta es la concentración del compuesto a la que se observa el 50% de la actividad enzimática utilizando IDO humana recombinante en las condiciones de ensayo descritas en uno de los ejemplos;
Se reportan los valores de IC50 en rangos: A: <1 M, B: 1 –10 M, C: 10 –100 M; D: > 100 M.
imagen120
1254
2–(5H–imidazo[5,1–a]isoindol–5–il)etanol B
1256
etil 2–(5H–imidazo[5,1–a]isoindol–5–il)acetato B
1258
ácido 2–(5H–imidazo[5,1–a]isoindol–5– il)acético D
1259
2–(5H–imidazo[5,1–a]isoindol–5–il)–N– metilacetamida D
1273
imagen121 (E)–5–(2–bromostiril)–5H–imidazo[5,1– a]isoindol C
1286
2–(6–cloro–5H–imidazo[5,1–a]isoindol–5–il)– 1–ciclohexiletanol A
1287
2–(6–cloro–5H–imidazo[5,1–a]isoindol–5–il)– 1–ciclohexiletanona B
1288
2–(5H–imidazo[5,1–a]isoindol–5–il)etil 2– (((1R,2R,5S)–2–isopropil–5–metilciclohexil) oxi)acetato B
1299
2–(6–cloro–5H–imidazo[5,1–a]isoindol–5–il)– 1–ciclohexiletanol A
1300
tert–butil (4–(2–(5H–imidazo[5,1–a]isoindol–5– il)acetil)fenil)carbamato B
1301
imagen122 1–(4–aminofenil)–2–(5H–imidazo[5,1– a]isoindol–5–il)etanona C
1302
tert–butil (4–(1–hidroxi–2–(5H–imidazo[5,1– a]isoindol–5–il)etil)fenil)carbamato A
1303
1–(4–aminofenil)–2–(5H–imidazo[5,1– a]isoindol–5–il)etanol C
1304
1–ciclohexil–2–(5H–imidazo[5,1–a]isoindol–5– il)etanol A
1306
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(3– nitrofenil)etanona B
1307
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(3– nitrofenil)etanol A
1326
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(2– nitrofenil)etanona B
1327
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(2– nitrofenil)etanol A
1328
tert–butil (2–(2–(5H–imidazo[5,1–a]isoindol–5– il)acetil)fenil)carbamato B
1329
tert–butil (2–(1–hidroxi–2–(5H–imidazo[5,1– a]isoindol–5–il)etil)fenil)carbamato B
1330
1–(2–aminofenil)–2–(5H–imidazo[5,1– a]isoindol–5–il)etanona B
1331
imagen123 1–(2–aminofenil)–2–(5H–imidazo[5,1– a]isoindol–5–il)etanol A
1334
1–(2–clorofenil)–2–(5H–imidazo[5,1– a]isoindol–5–il)etanona B
1335
1–(5H–imidazo[5,1–a]isoindol–5–il)–2– metilpropan–2–ol B
1336
1–(2–clorofenil)–2–(5H–imidazo[5,1– a]isoindol–5–il)etanol A
1343
1–(3–clorofenil)–2–(5H–imidazo[5,1– a]isoindol–5–il)etanol A
1348
2–(5H–imidazo[5,1–a]isoindol–5–il)–1– feniletanona B
1349
2–(5H–imidazo[5,1–a]isoindol–5–il)–1– feniletanol A
1352
1–(2,4–dimetilfuran–3–il)–2–(6–fluoro–5H– imidazo[5,1–a]isoindol–5–il)etanol; B
1353
1–(3–clorofenil)–2–(5H–imidazo[5,1– a]isoindol–5–il)etanona B
1356
1–ciclohexil–2–(6–fluoro–5H–imidazo[5,1– a]isoindol–5–il)etanona B
1357
1–ciclohexil–2–(6–fluoro–5H–imidazo[5,1– a]isoindol–5–il)etanol A
1358
imagen124 2–(5H–imidazo[5,1–a]isoindol–5–il)–1– (tetrahidro–2H–piran–4–il)etanol A
1359
2–(7–cloro–5H–imidazo[5,1–a]isoindol–5–il)– 1–ciclohexiletanol A
1360
(Z)–1–ciclohexil–2–(5H–imidazo[5,1– a]isoindol–5–il)etanona oxima B
1362
1–ciclopentil–2–(5H–imidazo[5,1–a]isoindol– 5–il)etanol A
1363
tert–butil 4–(1–hidroxi–2–(5H–imidazo[5,1– a]isoindol–5–il)etil)piperidina–1–carboxilato A
1364
1–ciclohexil–2–(5H–imidazo[5,1–a]isoindol–5– il)etanamina B
1367
tert–butil (3–(1–hidroxi–2–(5H–imidazo[5,1– a]isoindol–5–il)etil)fenil)carbamato B
1369
imagen125 1–(3–aminofenil)–2–(5H–imidazo[5,1– a]isoindol–5–il)etanol B
1370
imagen126 2–(5H–imidazo[5,1–a]isoindol–5–il)–1– (piperidin–4–il)etanol D
1371
4–(2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5– il)–1–hidroxietil)ciclohexanol; A
1372
1–ciclohexil–2–(9–metoxi–5H–imidazo[5,1– a]isoindol–5–il)etanol C
1373
5–(2–ciclohexil–2–hidroxietil)–5H– imidazo[5,1–a]isoindol–9–ol C
1374
2–(8–cloro–5H–imidazo[5,1–a]isoindol–5–il)– 1–ciclohexiletanol; B
1375
1–(ciclohex–1–en–1–il)–2–(5H–imidazo[5,1– a]isoindol–5–il)etanol; B
1376
1–ciclohexil–2–(8–fluoro–5H–imidazo[5,1– a]isoindol–5–il)etanol; B
1378
2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5–il)– 1–(1,4–dioxaspiro[4.5]decan–8–il)etanol; B
1379
4–(2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5– il)–1–hidroxietil)ciclohexanona; A
1381
2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5–il)– 1–(4–metilenociclohexil)etanol; A
1382
1–(ciclohex–3–en–1–il)–2–(5H–imidazo[5,1– a]isoindol–5–il)etanol; A
1383
1–(4–(hidroximatil)ciclohexil)–2–(5H– imidazo[5,1–a]isoindol–5–il)etanol; A
1384
(4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol– 5–il)etil)piperidin–1–il)(tiofen–2–il)metanona; A
1385
1–(4–(1–hidroxi–2–(5H–imidazo[5,1– a]isoindol–5–il)etil)piperidin–1–il)etanona; B
1386
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(4– metilenociclohexil)etanol; A
1387
2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5–il)– 1–(4–metilciclohexil)etanol; A
1388
1–ciclohexil–2–(5H–imidazo[5,1–a]isoindol–5– il)etanamina B
1389
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(1– metil–1H–imidazol–4–il)etanol; D
1390
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(tiazol– 4–il)etanol; C
1391
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(tiazol– 5–il)etanol; B
1392
1–(4–(1–hidroxi–2–(5H–imidazo[5,1– a]isoindol–5–il)etil)piperidin–1–il)–2,2– dimetilpropan–1–ona; B
1393
2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5–il)– 1–(furan–2–il)etanol; B
1394
2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5–il)– 1–(1–metil–1H–imidazol–2–il)etanol; C
1398
imagen127 2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5–il)– 1–(4–(yodometileno)ciclohexil)etanol; A
1400
1–ciclohexil–2–(5H–imidazo[5,1–a]isoindol–5– il)propan–1–ol; B
1402
2–(5H–imidazo[5,1–a]isoindol–5–il)acetonitrilo; C
1403
1–ciclohexil–3–(6–fluoro–5H–imidazo[5,1– a]isoindol–5–il)propan–2–ol; A
1404
1–ciclohexil–3–(5H–imidazo[5,1–a]isoindol–5– il)propan–2–ol; A
1405
1–(4–(1–hidroxi–2–(5H–imidazo[5,1– a]isoindol–5–il)etil)piperidin–1–il)–2– feniletanona; A
1406
1–(4,4–difluorociclohexil)–2–(6–fluoro–5H– imidazo[5,1–a]isoindol–5–il)etanol; A
1407
1–(4,4–difluorociclohexil)–2–(5H–imidazo[5,1– a]isoindol–5–il)etanol; A
1409
2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5–il)– 1–(1–metil–1H–imidazol–5–il)etanol; C
1410
1–(4–(ciclopropilmetileno)ciclohexil)–2–(6– fluoro–5H–imidazo[5,1–a]isoindol–5–il)etanol; A
1411
2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5–il)– 1–(4–(propan–2–ilideno)ciclohexil)etanol; A
1412
(E)–5–(2–ciclohexilvinil)–5H–imidazo[5,1– a]isoindol; A
1413
2–(9–fluoro–5H–imidazo[5,1–a]isoindol–5–il)– 1–(4–metilciclohexil)etanol; A
1414
1–(ciclohex–3–en–1–il)–2–(6–fluoro–5H– imidazo[5,1–a]isoindol–5–il)etanol; A
1415
(R)–1–ciclohexil–2–((R)–5H–imidazo[5,1– a]isoindol–5–il)etanol B
1416
(S)–1–ciclohexil–2–((R)–5H–imidazo[5,1– a]isoindol–5–il)etanol B
1417
(S)–1–ciclohexil–2–((S)–5H–imidazo[5,1– a]isoindol–5–il)etanol A
1418
(R)–1–ciclohexil–2–((S)–5H–imidazo[5,1– a]isoindol–5–il)etanol A
1419
1–ciclohexil–2–(5H–imidazo[5,1–a]isoindol–5– ilideno)etanol B
1420
imagen128 1–ciclohexil–2–(5H–imidazo[5,1–a]isoindol–5– il)acetato de etilo C
1421
1–(4–(2–(benciloxi)etilideno)ciclohexil)–2– (5H–imidazo[5,1–a]isoindol–5–il)etanol A
1422
1–(1–(bencilsulfonil)piperidin–4–il)–2–(5H– imidazo[5,1–a]isoindol–5–il)etanol A
1423
1–(4–(1–hidroxi–2–(5H–imidazo[5,1– a]isoindol–5–il)etil)piperidin–1–il)–2– (pirimidin–5–il)etanona A
1424
2–(3,4–difluorofenil)–1–(4–(1–hidroxi–2–(5H– imidazo[5,1–a]isoindol–5–il)etil)piperidin–1– il)etanona A
1425
ciclohexil(4–(1–hidroxi–2–(5H–imidazo[5,1– a]isoindol–5–il)etil)piperidin–1–il)metanona A
1426
metil 4–(1–hidroxi–2–(5H–imidazo[5,1– a]isoindol–5–il)etil) ciclohexanocarboxilato A
1427
1–ciclohexil–2–(5H–imidazo[5,1–a]isoindol–5– il)etil fenilcarbamato B
1428
ácido 4–(1–ciclohexil–2–(5H–imidazo[5,1– a]isoindol–5–il)etoxi)–4–oxobutanoico B
1429
4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol– 5–il)etil)ciclohexanol A
1430
1–(4–(hidroximatil)ciclohexil)–2–(5H– imidazo[5,1–a]isoindol–5–il)etanol A
1431
1–ciclohexil–2–(5H–imidazo[5,1–a]isoindol–5– il)etil benzoato C
1432
imagen129 4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol– 5–il)etil)–N–(2– (metilsulfonamido)etil)ciclohexanocarboxamina B
1433
(2S)–1–(–ciclohexil–2–(5H–imidazo[5,1– a]isoindol–5–il)etoxi)–3–metil–1–oxobutan–2– aminio cloruro C
1434
sodio 1–ciclohexil–2–(5H–imidazo[5,1– a]isoindol–5–il)etil fosfato A
1436
4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol– 5–il)etil)ciclohexanoácido carboxílico B
1437
1–(4–(1–hidroxi–2–(5H–imidazo[5,1– a]isoindol–5–il)etil)piperidin–1–il)–2–(piridin– 4–il)etanona A
1438
2–(5H–imidazo[5,1–a]isoindol–5–il)–1– (espiro[2.5]octan–6–il)etanol C
1439
2–(4–fluorofenil)–1–(4–(1–hidroxi–2–(5H– imidazo[5,1–a]isoindol–5–il)etil)piperidin–1– il)etanona A
1440
(2S)–1–ciclohexil–2–(5H–imidazo[5,1– a]isoindol–5–il)etil 2–aminopropanoato C
1441
1–(4–(2–hidroxietilideno)ciclohexil)–2–(5H– imidazo[5,1–a]isoindol–5–il)etanol A
1442
(2S)–1–ciclohexil–2–(5H–imidazo[5,1– a]isoindol–5–il)etil pirrolidina–2–carboxilato B
1443
(2S)–5–(1–ciclohexil–2–(5H–imidazo[5,1– a]isoindol–5–il)etil) 1–metil 2– aminopentanodioato C
1447
1–(4–((S)–1–hidroxi–2–((S)–5H–imidazo[5,1– a]isoindol–5–il)etil)piperidin–1–il)–2– feniletanona A
1448
imagen130 (3–fluoro–2–hidroxifenil)(4–(1–hidroxi–2–(5H– imidazo[5,1–a]isoindol–5–il)etil)piperidin–1– il)metanona A
1449
imagen131 4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol– 5–il)etil)–N–fenilpiperidina–1–carboxamina A
1450
imagen132 (4–fluorofenil)(4–(1–hidroxi–2–(5H– imidazo[5,1–a]isoindol–5–il)etil)piperidin–1– il)metanona B
1451
(2S)–2–amino–1–(4–(1–hidroxi–2–(5H– imidazo[5,1–a]isoindol–5–il)etil)piperidin–1–il)– 3–fenilpropan–1–ona B
1454
(4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol– 5–il)etil)piperidin–1–il)((S)–pirrolidin–2– il)metanona D
1455
(1R,4s)–4–(2–((S)–6–fluoro–5H–imidazo[5,1– a]isoindol–5–il)–1–hidroxietil)ciclohexil benzoato A
1456
(1R,4s)–4–(2–((S)–6–fluoro–5H–imidazo[5,1– a]isoindol–5–il)–1–hidroxietil)ciclohexanol A
1458
1–(3–(1–hidroxi–2–(5H–imidazo[5,1– a]isoindol–5–il)etil)azetidin–1–il)–2– feniletanona A
1459
3–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol– 5–il)etil)–N–fenilazetidina–1–carboxamina A
1460
tert–butil 3–(1–hidroxi–2–(5H–imidazo[5,1– a]isoindol–5–il)etil)azetidina–1–carboxilato A
1461
1–(azetidin–3–il)–2–(5H–imidazo[5,1– a]isoindol–5–il)etanol C
1469
tert–butil 4–((S)–1–hidroxi–2–((R)–5H– imidazo[5,1–a]isoindol–5–il)etil)piperidina–1– carboxilato B
1470
tert–butil 4–((R)–1–hidroxi–2–((R)–5H– imidazo[5,1–a]isoindol–5–il)etil)piperidina–1– carboxilato B
1471
tert–butil 4–((R)–1–hidroxi–2–((S)–5H– imidazo[5,1–a]isoindol–5–il)etil)piperidina–1– carboxilato A
1472
tert–butil 4–((S)–1–hidroxi–2–((S)–5H– imidazo[5,1–a]isoindol–5–il)etil)piperidina–1– carboxilato A
1473
imagen133 1–((1s,4s)–4–(benciloxi)ciclohexil)–2–(6– fluoro–5H–imidazo[5,1–a]isoindol–5–il)etanol A
1474
2–(5H–imidazo[5,1–a]isoindol–5–il)–1– (piridin–3–il)etanol B
1475
(1r,4r)–4–(2–(6–fluoro–5H–imidazo[5,1– a]isoindol–5–il)–1–hidroxietil)ciclohexanol A
1476
4–((S)–1–hidroxi–2–((R)–5H–imidazo[5,1– a]isoindol–5–il)etil)–N–fenilpiperidina–1– carboxamina B
1477
4–((R)–1–hidroxi–2–((R)–5H–imidazo[5,1– a]isoindol–5–il)etil)–N–fenilpiperidina–1– carboxamina B
1478
4–((R)–1–hidroxi–2–((S)–5H–imidazo[5,1– a]isoindol–5–il)etil)–N–fenilpiperidina–1– carboxamina A
1479
4–((S)–1–hidroxi–2–((S)–5H–imidazo[5,1– a]isoindol–5–il)etil)–N–fenilpiperidina–1– carboxamina A
1480
1–(4–((R)–1–hidroxi–2–((S)–5H–imidazo[5,1– a]isoindol–5–il)etil)piperidin–1–il)–2– feniletanona A
1481
1–(4–((S)–1–hidroxi–2–((S)–5H–imidazo[5,1– a]isoindol–5–il)etil)piperidin–1–il)–2– feniletanona A
1482
(1R,4s)–4–((S)–2–((R)–6–fluoro–5H– imidazo[5,1–a]isoindol–5–il)–1– hidroxietil)ciclohexanol B
1483
(1S,4s)–4–((R)–2–((R)–6–fluoro–5H– imidazo[5,1–a]isoindol–5–il)–1– hidroxietil)ciclohexanol B
1484
(1S,4s)–4–((R)–2–((S)–6–fluoro–5H– imidazo[5,1–a]isoindol–5–il)–1– hidroxietil)ciclohexanol A
1485
(1R,4s)–4–((S)–2–((S)–6–fluoro–5H– imidazo[5,1–a]isoindol–5–il)–1– hidroxietil)ciclohexanol A
1486
(1S,4r)–4–((S)–2–((S)–6–fluoro–5H– imidazo[5,1–a]isoindol–5–il)–1– hidroxietil)ciclohexanol A
1487
(1S,4r)–4–((S)–2–((R)–6–fluoro–5H– imidazo[5,1–a]isoindol–5–il)–1– hidroxietil)ciclohexanol B
1488
(1R,4r)–4–((R)–2–((S)–6–fluoro–5H– imidazo[5,1–a]isoindol–5–il)–1– hidroxietil)ciclohexanol A
1489
imagen134 (1R,4r)–4–((R)–2–((R)–6–fluoro–5H– imidazo[5,1–a]isoindol–5–il)–1– hidroxietil)ciclohexanol B
1490
1–(4–((S)–1–hidroxi–2–((S)–5H–imidazo[5,1– a]isoindol–5–il)etil)piperidin–1–il)–2– (tetrahidro–2H–piran–4–il)etanona A
1491
1–(4–((R)–1–hidroxi–2–((R)–5H–imidazo[5,1– a]isoindol–5–il)etil)piperidin–1–il)–2– feniletanona B
1492
N–((1s,4s)–4–(1–hidroxi–2–(5H–imidazo[5,1– a]isoindol–5–il)etil)ciclohexil)benzamida A
1493
imagen135 1–(4–((S)–1–hidroxi–2–((R)–5H– imidazo[5,11–a]isoindol–5–il)etil)piperidin–1– il)–2–feniletanona B
1494
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(1– (fenilcarbamoil)piperidin–4–il)etil fenilcarbamato C
1495
4–((R)–1–hidroxi–2–((S)–5H–imidazo[5,1– a]isoindol–5–il)etil)–N–((1r,4R)–4– hidroxiciclohexil)piperidina–1–carboxamina A
1496
4–((S)–1–hidroxi–2–((S)–5H–imidazo[5,1– a]isoindol–5–il)etil)–N–(tetrahidro–2H–piran– 4–il)piperidina–1–carboxamina A
1497
4–((S)–1–hidroxi–2–((S)–5H–imidazo[5,1– a]isoindol–5–il)etil)–N–((1r,4S)–4– hidroxiciclohexil)piperidina–1–carboxamina A
1498
1–((1r,4r)–4–(benciloxi)ciclohexil)–2–(5H– imidazo[5,1–a]isoindol–5–il)etanol A
1499
imagen136 1–((1r,4r)–4–(benciloxi)ciclohexil)–2–(6– fluoro–5H–imidazo[5,1–a]isoindol–5–il)etanol A
1500
1–(4–((R)–1–hidroxi–2–((S)–5H–imidazo[5,1– a]isoindol–5–il)etil)piperidin–1–il)–2– (tetrahidro–2H–piran–4–il)etanona A
1501
2–(5H–imidazo[5,1–a]isoindol–5–il)–1– (piridin–4–il)etanol A
1502
2–(5H–imidazo[5,1–a]isoindol–5–il)–1– (piridin–2–il)etanol B
1503
4–((R)–1–hidroxi–2–((S)–5H–imidazo[5,1– a]isoindol–5–il)etil)–N–(tetrahidro–2H–piran– 4–il)piperidina–1–carboxamina A
1504
N–ciclohexil–4–((R)–1–hidroxi–2–((S)–5H– imidazo[5,1–a]isoindol–5–il)etil)piperidina–1– carboxamina A
1505
N–((1r,4r)–4–(1–hidroxi–2–(5H–imidazo[5,1– a]isoindol–5–il)etil)ciclohexil)benzamida A
1506
1–((1r,4r)–4–(benciloxi)ciclohexil)–2–(5H– imidazo[5,1–a]isoindol–5–il)etanol A
1507
N–ciclopentil–4–((R)–1–hidroxi–2–((S)–5H– imidazo[5,1–a]isoindol–5–il)etil)piperidina–1– carboxamina A
1508
2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5–il)– 1–(4–(trifluorometil)ciclohexil)etanol A
1509
2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(4– (trifluorometil)ciclohexil)etanol A
1511
1–(4–((R)–1–hidroxi–2–((S)–5H–imidazo[5,1– a]isoindol–5–il)etil)piperidin–1–il)–2–(4– (trifluorometil)fenil)etanona A
1512
4–((R)–1–hidroxi–2–((S)–5H–imidazo[5,1– a]isoindol–5–il)etil)–N–(4– (trifluorometil)fenil)piperidina–1–carboxamina A
1513
(4–((R)–1–hidroxi–2–((S)–5H–imidazo[5,1– a]isoindol–5–il)etil)piperidin–1–il)(1H– imidazol–1–il)metanona
Ejemplo biológico 6 Ensayo in vivo de los inhibidores de IDO para la actividad antitumoral en combinación con agentes quimioterapéuticos
5 La eficacia antitumoral in vivo se puede probar usando protocolos de aloinjertos tumorales modificadas. Por ejemplo, se ha descrito en la literatura que la inhibición de IDO puede actuar en sinergia con quimioterapia citotóxica en ratones inmunocompetentes. Debido a las diferentes susceptibilidades de diferentes líneas de células tumorales a fármacos quimioterapéuticos y a rechazo inmune mediado, cada inhibidor de IDO se prueba solo y en combinación con 2 fármacos quimioterapéuticos diferentes en 4 modelos en animales de tumores diferentes, representado por 4 líneas de
10 células tumorales de ratón diferentes, de diferente origen tisular (carcinoma colorrectal, de vejiga, de mama y de pulmón), implantado por vía subcutánea en cepas de ratones singénicos. Estas líneas celulares han sido seleccionadas en base a su susceptibilidad conocida a fármacos quimioterapéuticos, su respuesta parcial a los inhibidores de IDO como agentes individuales, su presunto patrón de expresión de IDO de acuerdo a su tejido de origen, y su capacidad para provocar una reacción inmune.
imagen137

Claims (2)

  1. imagen1
    imagen2
    imagen3
    imagen4
    imagen5
    imagen6
    2–(6–cloro–5H–imidazo[5,1–a]isoindol–5–il)–1–ciclohexiletanona;
    2–(5H–imidazo[5,1–a]isoindol–5–il)etil2–(((1R,2R,5S)–2–isopropil–5–metilciclohexil)oxi)acetato; tert–butil (4–(2–(5H–imidazo[5,1–a]isoindol–5–il)acetil)fenil)carbamato; 1–(4–aminofenil)–2–(5H–imidazo[5,1–a]isoindol–5–il)etanona; tert–butil (4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5–il)etil)fenil)carbamato; 1–(4–aminofenil)–2–(5H–imidazo[5,1–a]isoindol–5–il)etanol; 1–ciclohexil–2–(5H–imidazo[5,1–a]isoindol–5–il)etanol; 2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(3–nitrofenil)etanona; 2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(3–nitrofenil)etanol; 2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(2–nitrofenil)etanona; 2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(2–nitrofenil)etanol; tert–butil (2–(2–(5H–imidazo[5,1–a]isoindol–5–il)acetil)fenil)carbamato; tert–butil (2–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5–il)etil)fenil)carbamato; 1–(2–aminofenil)–2–(5H–imidazo[5,1–a]isoindol–5–il)etanona; 1–(2–aminofenil)–2–(5H–imidazo[5,1–a]isoindol–5–il)etanol; 1–(2–clorofenil)–2–(5H–imidazo[5,1–a]isoindol–5–il)etanona; 1–(5H–imidazo[5,1–a]isoindol–5–il)–2–metilpropan–2–ol; 1–(2–clorofenil)–2–(5H–imidazo[5,1–a]isoindol–5–il)etanol; 1–(3–clorofenil)–2–(5H–imidazo[5,1–a]isoindol–5–il)etanol; 2–(5H–imidazo[5,1–a]isoindol–5–il)–1–feniletanona; 2–(5H–imidazo[5,1–a]isoindol–5–il)–1–feniletanol; 1–(2,4–dimetilfuran–3–il)–2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5–il)etanol; 1–(3–clorofenil)–2–(5H–imidazo[5,1–a]isoindol–5–il)etanona; 1–ciclohexil–2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5–il)etanona; 1–ciclohexil–2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5–il)etanol; 2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(tetrahidro–2H–piran4–il)etanol; 2–(7–cloro–5H–imidazo[5,1–a]isoindol–5–il)–1–ciclohexiletanol; (Z)–1–ciclohexil–2–(5H–imidazo[5,1–a]isoindol–5–il)etanona oxima; 1–ciclopentil–2–(5H–imidazo[5,1–a]isoindol–5–il)etanol; tert–butil 4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5–il)etil)piperidina–1–carboxilato; 1–ciclohexil–2–(5H–imidazo[5,1–a]isoindol–5–il)etanamina; tert–butil (3–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5–il)etil)fenil)carbamato;
    177
    1–(3–aminofenil)–2–(5H–imidazo[5,1–a]isoindol–5–il)etanol;
    4–(2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5–il)–1–hidroxietil)ciclohexanol; 1–ciclohexil–2–(9–metoxi–5H–imidazo[5,1–a]isoindol–5–il)etanol; 5–(2–ciclohexil–2–hidroxietil)–5H–imidazo[5,1–a]isoindol–9–ol; 2–(8–cloro–5H–imidazo[5,1–a]isoindol–5–il)–1–ciclohexiletanol; 1–(ciclohex–1–en–1–il)–2–(5H–imidazo[5,1–a]isoindol–5–il)etanol; 1–ciclohexil–2–(8–fluoro–5H–imidazo[5,1–a]isoindol–5–il)etanol; 2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5–il)–1–(1,4–dioxaspiro[4.5]decan–8–il)etanol; 4–(2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5–il)–1–hidroxietil)ciclohexanona; 2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5–il)–1–(4–metilenociclohexil)etanol; 1–(ciclohex–3–en–1–il)–2–(5H–imidazo [5,1–a]isoindol–5–il)etanol; 1–(4–(hidroximatil)ciclohexil)–2–(5H–imidazo[5,1–a]isoindol–5–il)etanol; (4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5–il)etil)piperidin–1–il)(tiofen–2–il)metanona; 1–(4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5–il)etil)piperidin–1–il)etanona; 2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(4–metilenociclohexil)etanol; 2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5–il)–1–(4–metilciclohexil)etanol; 2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(tiazol–4–il)etanol; 2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(tiazol–5–il)etanol; 1–(4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5–il)etil)piperidin–1–il)–2,2–dimetilpropan–1–ona; 2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5–il)–1–(furan–2–il)etanol; (1S)–1–ciclohexil–2–(5H–imidazo[5,1–a]isoindol–5–il)etanol; (1R)–1–ciclohexi)–2–(5H–imidazo[5,1–a]isoindol–5–il)etanol; 2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5–il)–1–(4–(yodometileno)ciclohexil)etanol; 1–ciclohexil–2–(5H–imidazo[5,1–a]isoindol–5–il)propan–1–ol; 2–(5H–imidazo[5,1–a]isoindol–5–il)acetonitrilo; 1–ciclohexil–3–(6–fluoro–5H–imidazo[5,1–a]isoindol–5–il)propan–2–ol; 1–ciclohexil–3–(5H–imidazo[5,1–a]isoindol–5–il)propan–2–ol; 1–(4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5–il)etil)piperidin–1–il)–2–feniletanona; 1–(4,4–difluorociclohexil)–2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5–il)etanol; 1–(4,4–difluorociclohexil)–2–(5H–imidazo[5,1–a]isoindol–5–il)etanol; 2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5–il)–1–(1–metil–1H–imidazol–5–il)etanol; 1–(4–(ciclopropilmetileno)ciclohexil)–2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5–il)etanol;
    178
    imagen7
    imagen8
    imagen9
    imagen10
    2–((((1r,4r)–4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5–il)etil)ciclohexil)oxi)metil)benzamida;
    metil 4–((((1r,4r)–4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5–il)etil)ciclohexil)oxi)metil)benzoato; metil 3–((((1r,4r)–4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5–il)etil)ciclohexil)oxi)metil)benzoato; metil 2–((((1r,4r)–4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5–il)etil)ciclohexil)oxi)metil)benzoato; 2–(5H–imidazo[5,1–a]isoindol–5–il)–1–((1r,4r)–4–metoxiciclohexil)etanol; 1–((1 r,4r)–4–etoxiciclohexil)–2–(5H–imidazo[5,1–a]isoindol–5–il)etanol; 2–(5H–imidazo[5,1–a]isoindol–5–il)–1–((1r,4r)–4–isopropoxiciclohexil)etanol; 1–((1r,4r)–4–(ciclopropilmetoxi)ciclohexil)–2–(5H–imidazo[5,1–a]isoindol–5–il)etanol; 1–((1r,4r)–4–(ciclopentilmetoxi)ciclohexil)–2–(5H–imidazo[5,1–a]isoindol–5–il)etanol; 2–(5H–imidazo[5,1–a]isoindol–5–il)–1–((1r,4r)–4–(tiofen–2–ilmetoxi)ciclohexil)etanol; 1–((1r,4r)–4–((1H–indol–3–il)oxi)ciclohexil)–2–(5H–imidazo[5,1–a]isoindol–5–il)etanol; 1–((1r,4r)–4–((1H–indol–5–il)oxi)ciclohexil)–2–(5H–imidazo[5,1–a]isoindol–5–il)etanol; 2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(4–((tetrahidro–2H–piran–4–il)metoxi)ciclohexil)etanol; 4–(((4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5–il)etil)ciclohexil)oxi)metil)bencenosulfonamida; 2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(4–(oxazol–2–ilmetoxi)ciclohexil)etanol; 2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(4–(tiazol–2–ilmetoxi)ciclohoxil)etanol; 2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(1–(1–imino–2–feniletil)piperidin–4–il)etanol; 4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5–il)etil)–N–fenilpiperidina–1–carboximidamida; 4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5–il)etil)–N–(piridin–4–il)piperidina–1–carboximidamida; 4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5–il)etil)–N–(tetrahidro–2H–piran–4–il)piperidina–1–carboximidamida; N–(4–cianofenil)–4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5–il)etil)piperidina–1–carboxamina; N–(tert–butil)–4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5–il)etil)piperidina–1–carboxamina; N–(tert–butil)4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5–il)etil)piperidina–1–sulfonamida; 1–(4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5–il)etil)piperidin–1–il)–2–(3–hidroxifenil)etanona; 2–(1–(azetidina–1–carbonil)piperidin–4–il)–2–hidroxi–1–(4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5– il)etil)piperidin–
    1–il)etanona; 2–ciclopentil–1–(4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5–il)etil)piperidhe–1–il)etanona; 1–(4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5–il)etil)piperidin–1–il)–2–(2–metiltiazol–5–il)etanona; N–ciclohexil–N–hidroxi–4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5–il)etil)piperidina–1–carboxamina; N–(4–(2–(4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5–il)etil)piperidin–1–il)–2–oxoetil)fenil)metanosulfonamida; N–ciclopropil–N–hidroxi–4–(1–hidroxi–2–(3H–imidazo[5,1–a]isoindol–5–il)etil)piperidina–1–carboxamina; 3,3–difluoro–1–(4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5–il)etil)piperidin–1–il)butan–1–ona; 1–(4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindot–5–il)etil)pipendin–1–il)–2–(p–tolil)etanona;
    183
    1–(1–(4–aminopirimidin–2–il)piperidin4–il)–2–(5H–imidazo[5,1–a]isoindol–5–il)etanol; 1–(1–(2–aminopirimidin–4–il)piperidin–4–il)–2–(5H–imidazo[5,1–a]isoindol–5–il)etanol; N–ciclopropil–4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5–il)etil)piperidina–1–carboxamina; 2–ciclopropil–1–(4–(1–hidroxi–2–(5H–imidazo [5,1–a]isoindol–5–il)etil)piperidin–1–il)etanona;
    5 2–(4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5–il)etil)ciclohexilideno)acetonitrilo; 4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5–il)etil)–N–(4–(trifluorometil)tiazol–2–il)piperidina–1–carboxamina; 4–(2–(4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5–il)etil)piperidin–1–il)–2–oxoetil)benzamida; 1–(4–(1–hidroxi–2–(5H–imidazo[5,1–a]isomdol–5–il)etil)pipendin–1–il)–2–(4–(metilsulfonil)fenil)etanona; 4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5–il)etil)–N–((1r,4r)–4–metilciclohexil)piperidina–1–carboxamina;
    10 1–(4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5–il)etil)piperidin–1–il)–3,3–dimetilbutan–1–ona; 4–(2–(4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5–il)etil)piperidin–1–il)–2–oxoetil)bencenosulfonamida ; N–(tert–butil)–4–(2–(4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5–il)etil)piperidin–1–il)–2–oxoetil)bencenosulfonamida; ácido 4–(2–(4–(1–hidroxi–2–(5H–imidazo[5,1–a]isoindol–5–il)etil)piperidin–1–il)–2–oxoetil)benzoico; 1–(4–(difluorometileno)ciclohexil)–2–(5H–imidazo[5,1–a]isoindol–5–il)etanol;
    15 2–(5H–imidazo[5,1–a]isoindol–5–il)–1–(4–(2,2,2–trifluoroetilideno)ciclohexil)etanol; N–bencil–4–(2–(6–fiuoro–5H–imidazo[5,1–a]isoindol–5–il)–1–hidroxietil)ciclohexanocarboxamina; 4–(2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5–il–1–hidroxietil)–N–fenilciclohexanocarboxamina; N–(4–(2–(6–fluoro–5H–imidazo[5,1,a]isoindol–5–il)–1–hidroxietil)ciclohexil)benzamida; 1–(4–(2–(6–fluoro–5H–imidazo[5,1–a]isoindol–5–il)–1–hidroxietil)ciclohexil)–3–fenilurea;
    20 N–(4(2–6–fluoro–5H–imidazo[5,1–a]–isoindol–5–il)–1–hidroxietil)ciclohexil)–2–fenilacetamida;
    o una sal farmacéuticamente aceptable del mismo.
  2. 21. Una composición farmacéutica que comprende un compuesto de acuerdo con una cualquiera de las reivindicaciones 1 – 19 y un diluyente, excipiente, o portador farmacéuticamente aceptable.
    184
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