Pyrrolopyrimidine and pyrrolopyridine derivatives substituted with cyclic amino group
Abstract
A pyrrolopyrimidine or pyrrolopyridine derivative substituted with a cyclic amino group represented by the following formula [I]: ** see formula ** (where the cyclic amino group is represented by the following formula [II]: ** see formula ** in which the cyclic amino group is a 3 to 8 membered saturated cyclic amine or a 3 to 8 membered saturated cyclic amine linked by C 1 -C 5 alkylene bridge or alkylene (C 1-C 4) -O-C 1 -C 4 alkylene between any two different carbon atoms of the cyclic amine, whose cyclic amine is substituted with a group represented by - (CR 1 R 2) m- (CHR 3) aX, R 4 and R 5 independently at the same or different carbon atoms of the cyclic amine; X is cyano, hydroxy or -OR 9; Y is No. CR 10; R 1 is hydrogen, hydroxy, C 1 -C 5 alkyl, C 1 -C 5 alkoxy C 1 -C 5 alkyl or C 1 -C 5 hydroxyalkyl; R 2 is hydrogen or C 1 -C 5 alkyl; R 3 is hydrogen, cyano, C 1 -C 5 alkyl, C 1 -C 5 alkoxy C 1 -C 5 alkyl or C 1 -C 5 hydroxyalkyl; m is an integer selected from 0, 1, 2, 3, 4 and 5; n is 0 or 1; with the proviso that when X is hydroxy or OR 9, and n is 0, m is an integer selected from 1, 2, 3, 4 and 5; R 4 is hydrogen, hydroxy, C1-C5 hydroxyalkyl, cyano, C1-C5 cyanoalkyl or C1-C5 alkyl; R 5 is hydrogen or C 1 -C 5 alkyl; R 6 is hydrogen, C1-C5 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl C1-C5 alkyl, hydroxy, C1-C5 alkoxy, cycloalkyl (C3-C8) oxy or -N (R 11) R 12; R 7 and R 8 are the same or different, and are independently hydrogen, halogen, C 1 -C 5 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl, C 1 -C 5 alkyl, hydroxy, C 1 -C alkoxy 5, cycloalkyl (C 3-C 8) oxy, -N (R 11a) R 12a, -CO 2R 13, cyano, nitro, (C 1-C 5) alkyl thio, trifluoromethyl or trifluoromethoxy; or R 7 and R 8 are taken together to form -CH 2-CH 2-CH 2- CH2- or -CH = CH-CH = CH-; R 9 is C1-C24 acyl, (C1-C10) alkoxycarbonyl, aryl (C1-C5) oxycarbonyl, -CO-O-CHR 14 -O-CO-R 15, -P (= O) (OR 14a) OR 15a, -CO- (CH 2) p- (CHR 16) q-NR 17 R 18, arylcarbonyl or heteroarylcarbonyl, where each of said acyl, aryl and heteroaryl is not substituted or is substituted with C 1 -C 5 alkoxy, and C 1 -C 24 acyl optionally includes one to six double bonds; R 10 is hydrogen, C1-C5 alkyl, halogen, cyano or-CO2R 19; Ar is aryl or heteroaryl whose aryl or heteroaryl is not substituted or substituted with 1 or more substituents, which are the same or different, selected from the group consisting of halogen, C 1 -C 5 alkyl, C 3- C8 cycloalkyl, C 2 alkenyl -C5, C2-C5 alkynyl, C1-C5 alkoxy, (C1-C5) alkyl thio, (C1-C5) alkyl sulfinyl, (C1-C5) alkyl sulfonyl, cyano, nitro, hydroxy, -CO2R 19a, -C ( = O) R 19a, -CONR 11b R 12b, -OC (= O) R 19a, -NR 11b CO2R 19a, -S (O) rNR 11b R 12b, hydroxyalkyl (C2-C5) aminoalkoxy C2-C5, trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoromethoxy, methylenedioxy, ethylenedioxy and -N (R 20) R 21; with the proviso that when X is hydroxy, Y is N, and the cyclic amino group is a 5-membered ring, Ar is aryl or heteroaryl whose aryl or heteroaryl is substituted with at least one of the substituents selected from halogen and trifluoromethyl; with the proviso that the compounds in which X is hydroxy; Y is N; the cyclic amino group is a 6-membered saturated cyclic amine; m is an integer selected from 1, 2 and 3; n is 0; R 1, R 2, R 4 and R 5 are hydrogen; R 6 is methyl; R 7 and R 8 are the same or different, and are independently hydrogen or methyl; Ar is phenyl whose phenyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of chlorine, bromine, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3) alkyl thio, trifluoromethyl, trifluoromethoxy and dimethylamino; They are excluded; R 11 and R 12 are the same or different, and are independently hydrogen, C 1 -C 5 alkyl, C 3 -C 8 cycloalkyl or (C 3-C 8 cycloalkyl) C 1 -C 5 alkyl; R 11a and R 12a are the same or different, and are independently hydrogen, C 1 -C 5 alkyl, C 3-C 8 cycloalkyl or (C3-C8 cycloalkyl) C1-C5 alkyl; R 11b and R 12b are the same or different, and are independently hydrogen, C1-C5 alkyl, C3-C8 cycloalkyl or (C 3-C 8 cycloalkyl) C 1 -C 5 alkyl; R 13 is hydrogen, C 1 -C 5 alkyl, C 3-C 8 cycloalkyl, C 3-C 8 cycloalkyl, C 1-C 5 alkyl, C 1 -C 5 alkoxy, C 1-C 5 alkyl, cycloalkyl (C3-C8) C1-C5 oxyalkyl or phenyl; R 14 and R 15 are the same or different, and are independently hydrogen, C1-C5 alkyl or C1-C5 arylalkyl; R 14a and R 15a are the same or different, and are independently hydrogen, C 1 -C 5 alkyl or C 1 -C 5 arylalkyl; R 16 is hydrogen, C1-C5 alkyl, aryl, heteroaryl, C1-C5 arylalkyl, C1-C5 heteroarylalkyl, C1-C5 hydroxyalkyl, C1-C5 hydroxycarbonylalkyl, C1-C5 hydroxyphenylalkyl, C1-C5 alkoxy, C1-C5 alkyl C 1 -C 5 aminoalkyl, C 1 -C 5 guanidinoalkyl, C 1-C 5 mercaptoalkyl, C 1 -C 5 alkyl, C 1-C 5 thioalkyl or C 1-C 5 aminocarbonylalkyl; R 17 and R 18 are the same or different, and are independently hydrogen, C 1 -C 5 alkyl, C 3-C 8 cycloalkyl, C3-C8 cycloalkyl, C1-C5 alkyl, C1-C10 acyl, (C1-C10 alkoxy) ) carbonyl or arylalkyl (C1-C5) oxycarbonyl; or R 16 and R 17 are taken together to form -CH2-, -CH2CH2-, -CH2CH2CH2- or -CH2CH2CH2CH2-; p is an integer selected from 0, 1, 2, 3, 4 and 5; q is 0 or 1; R 19 is hydrogen or C1-C5 alkyl; R 19a is hydrogen or C 1 -C 5 alkyl; r is 1 or 2; R 20 and R 21 are the same or different, and are independently hydrogen or C 1 -C 5 alkyl), one of their individual isomers, their mixtures of racemic or non-racemic isomers or one of their N-oxides, or their salts and hydrates pharmaceutically acceptable.

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Projected expiry passed 24 December 2023, 2.8 years ago.
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48 claims: 2 independent, 46 dependent
- 1ES 2 325 596 T3 REIVINDICACIONES 1. Un derivado de pirrolopirimidina o pirrolopiridina sustituido con un grupo amino cíclico representado por la siguiente fórmula [I]:(donde el grupo amino cíclico está representado por la siguiente fórmula [II]: en la que el grupo amino cíclico es una amina cíclica saturada de 3 a 8 miembros o una amina cíclica saturada de 3 a 8 miembros unida mediante puente de alquileno C 1 -C 5 o alquilen(Ci -C 4 )-O-alquileno C 1 -C 4 entre dos átomos de carbono diferentes cualesquiera de la amina cíclica, cuya amina cíclica está sustituida con un grupo representado por -(CR 1 R 2 )m-(CHR 3 )a-X, R 4 y R 5 independientemente en el mismo o diferentes átomos de carbono de la amina cíclica;X es ciano, hidroxi o -OR 9 ;Y es N o CR 10 ;R 1 es hidrógeno, hidroxi, alquilo C 1 -C 5 , alcoxi(C 1 -C 5 )alquilo C 1 -C 5 o hidroxialquilo C 1 -C 5 ;R 2 es hidrógeno o alquilo Ci-C5;R 3 es hidrógeno, ciano, alquilo C 1 -C 5 , alcoxi(C 1 -C 5 )alquilo C 1 -C 5 o hidroxialquilo C 1 -C 5 ;m es un entero seleccionado entre 0, 1, 2, 3, 4 y 5;n es 0 o 1;con la condición de que cuando X es hidroxi o OR 9 , y n es 0, m es un entero seleccionado entre 1, 2, 3,4 y 5;R 4 es hidrógeno, hidroxi, hidroxialquilo C 1 -C 5 , ciano, cianoalquilo C 1 -C 5 o alquilo C 1 -C 5 ;R 5 es hidrógeno o alquilo C1-C5;R 6 es hidrógeno, alquilo C 1 -C 5 , cicloalquilo C 3 -C 8 , cicloalquil(C 3 -C 8 )alquilo C 1 -C 5 , hidroxi, alcoxi C 1 -C 5 , cicloalquil(C3-C 8 )oxi o -N(R 11 )R 12 ;R 7 y R 8 son iguales o diferentes, y son independientemente hidrógeno, halógeno, alquilo C1-C5, cicloalquilo C3C8, cicloalquil(C3-C8)alquilo Q-C5, hidroxi, alcoxi Q-C5, cicloaíquil(C3-C8)oxi, -N(R 11a )R 12a , -CO2R 13 , ciano, nitro, alquil(C1-C5)tio, trifluorometilo o trifluorometoxi;o R 7 y R 8 se toman juntos para formar -CH2-CH 2 -CH 2 CH 2 - o -CH=CH-CH=CH-;R 9 es acilo C1 -C24, alcoxi(C1 -C10)carbonilo, arilalquil(C1 -C5)oxicarbonilo, -CO-O-CHR 14 -O-CO-R 15 , -P(=O)(OR 14a )OR 15a , -CO-(CH2) p -(CHR 16 )q-NR 17 R 18 , arilcarbonilo o heteroarilcarbonilo, donde cada uno de dichos acilo, arilo y heteroarilo no está sustituido o está sustituido con alcoxi C1-C 5 , y acilo C 1 -C 2 4 incluye opcionalmente de uno a seis enlaces dobles;R 10 es hidrógeno, alquilo C 1 -C 5 , halógeno, ciano o-CO 2 R 19 ;174 ES 2 325 596 T3 Ar es arilo o heteroarilo cuyo arilo o heteroarilo no está sustituido o está sustituido con 1 o más sustituyentes, que son iguales o diferentes, seleccionados del grupo que consiste en halógeno, alquilo C1-C5, cicloalquilo C 3 C 8 , alquenilo C 2 -C 5 , alquinilo C 2 -C 5 , alcoxi C 1 -C 5 , alquil(C 1 -C 5 )tio, alquil(C 1 -C 5 )sulfinilo, alquil(C 1 -C 5 )sulfonilo, ciano, nitro, hidroxi, -CO 2 R 19a , -C(=O)R 19a , -CONR 11b R 12b , -OC(=O)R 19a , -NR 11b CO2R 19a , -S(O)rNR 11b R 12b , hidroxialquil(C 2 -C 5 )aminoalcoxi C 2 -C 5 , trifluorometilo, trifluorometoxi, difluorometoxi, fluorometoxi, metilendioxi, etilendioxi y -N(R 20 )R 21 ;con la condición de que cuando X es hidroxi, Y es N, y el grupo amino cíclico es un anillo de 5 miembros, Ar es arilo o heteroarilo cuyo arilo o heteroarilo está sustituido con al menos uno de los sustituyentes que se seleccionan entre halógeno y trifluorometilo;con la condición de que los compuestos en los que X es hidroxi;Y es N;el grupo amino cíclico es una amina cíclica saturada de 6 miembros;m es un entero seleccionado entre 1, 2 y 3;n es 0;R 1 , R 2 , R 4 y R 5 son hidrógeno;R 6 es metilo;R 7 y R 8 son iguales o diferentes, y son independientemente hidrógeno o metilo;Ar es fenilo cuyo fenilo está sustituido con dos o tres sustituyentes, que son iguales o diferentes, seleccionados del grupo que consiste en cloro, bromo, alquilo C 1 -C 3 , alcoxi C 1 -C 3 , alquil(C 1 -C 3 )tio, trifluorometilo, trifluorometoxi y dimetilamino;están excluidos;R 11 y R 12 son iguales o diferentes, y son independientemente hidrógeno, alquilo C 1 -C 5 , cicloalquilo C 3 -C 8 o cicloalquil(C 3 -C 8 )alquilo C 1 -C 5 ;R 11a y R 12a son iguales o diferentes, y son independientemente hidrógeno, alquilo C 1 -C 5 , cicloalquilo C 3 -C 8 o cicloalquil(C 3 -C 8 )alquilo C 1 -C 5 ;R 11b y R 12b son iguales o diferentes, y son independientemente hidrógeno, alquilo C 1 -C 5 , cicloalquilo C 3 -C 8 o cicloalquil(C 3 -C 8 )alquilo C 1 -C 5 ;R 13 es hidrógeno, alquilo C 1 -C 5 , cicloalquilo C 3 -C 8 , cicloalquil(C 3 -C 8 )alquilo C 1 -C 5 , alcoxi(C 1 -C 5 )alquilo C 1 -C 5 , cicloalquil(C 3 -C 8 )oxialquilo C 1 -C 5 o fenilo;R 14 y R 15 son iguales o diferentes, y son independientemente hidrógeno, alquilo C 1 -C 5 o arilalquilo C 1 -C 5 ;R 14a y R 15a son iguales o diferentes, y son independientemente hidrógeno, alquilo C 1 -C 5 o arilalquilo C 1 -C 5 ;R 16 es hidrógeno, alquilo C 1 -C 5 , arilo, heteroarilo, arilalquilo C 1 -C 5 , heteroarilalquilo C 1 -C 5 , hidroxialquilo C 1 -C 5 , hidroxicarbonilalquilo C 1 -C 5 , hidroxifenilalquilo C 1 -C 5 , alcoxi(C 1 -C 5 )alquilo C 1 -C 5 , aminoalquilo C 1 -C 5 , guanidinoalquilo C 1 -C 5 , mercaptoalquilo C 1 -C 5 , alquil(C 1 -C 5 )tioalquilo C 1 -C 5 o aminocarbonilalquilo C 1 -C 5 ;R 17 y R 18 son iguales o diferentes, y son independientemente hidrógeno, alquilo C 1 -C 5 , cicloalquilo C 3 -C 8 , cicloalquil(C 3 -C 8 )alquilo C 1 -C 5 , acilo C 1 -C 10 , alcoxi(C 1 -C 10 )carbonilo o arilalquil(C 1 -C 5 )oxicarbonilo;o R 16 y R 17 se toman juntos para formar -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 - o -CH 2 CH 2 CH 2 CH 2 -;p es un entero seleccionado entre 0, 1, 2, 3, 4 y 5;q es 0 o 1;R 19 es hidrógeno o alquilo C1-C5;R 19a es hidrógeno o alquilo C 1 -C 5 ;r es 1 o 2;r 20 y r 21 son iguales o diferentes, y son independientemente hidrógeno o alquilo C 1 -C 5 ), uno de sus isómeros individuales, sus mezclas de isómeros racémicas o no racémicas o uno de sus N-oxidos, o sus sales e hidratos farmacéuticamente aceptables.
- 2El derivado de pirrolopirimidina o pirrolopiridina sustituido con el grupo amino cíclico de acuerdo con la reivindicación 1, que es un compuesto representado por la siguiente fórmula [III]:175 ES 2 325 596 T3 (donde el grupo amino cíclico está representado por la siguiente fórmula [IV]: en la que el grupo amino cíclico es una amina cíclica saturada de 3 a 8 miembros o una amina cíclica saturada de 3 a 8 miembros unida mediante puente de alquileno C 1 -C 5 o alquilen(Ci -C 4 )-O-alquileno C, -C 4 entre dos átomos de carbono diferentes cualesquiera de la amina cíclica, cuya amina cíclica está sustituida con un grupo representado por -(CR 1 R 2 )m-(CHR 3 )n-CN, R 4 y R 5 independientemente en el mismo o diferentes átomos de carbono de la amina cíclica;Y es N o CR 10 ;R 1 es hidrógeno, hidroxi, alquilo C 1 -C 5 , alcoxi(C 1 -C 5 )-C 1-5 a1kilo o hidroxialquilo C 1 -C 5 ;R 2 es hidrógeno o alquilo C 1 -C 5 ;R 3 es hidrógeno, ciano, C 1-5 allcilo, alcoxi(C 1 -C 5 )alquilo C 1 -C 5 o hidroxialquilo C 1 -C 5 ;m es un entero seleccionado entre 0, 1, 2, 3, 4 y 5;n es 0 o 1;R 4 es hidrógeno, hidroxi, hidroxialquilo C 1 -C 5 , ciano, cianoalquilo C 1 -C 5 o alquilo C 1 -C 5 ;R 5 es hidrógeno o alquilo C1-C5;R 6 es hidrógeno, alquilo C 1 -C 5 , cicloalquilo C 3 -C 8 , cicloalquil(C 3 -C 8 )alquilo C 1 -C 5 , hidroxi, alcoxi C 1 -C 5 , cicloalquil(C3-C 8 )oxi o -N(R 11 )R 12 ;R 7 y R 8 son iguales o diferentes, y son independientemente hidrógeno, halógeno, alquilo C1-C5, cicloalquilo C3C8, cicloalquil(C3-C8)alquilo Q-C5, hidroxi, alcoxi C1-C5, cicloalquil(C3-C8)oxi, -N(R 11a )R 12a , -CO2R 13 , ciano, nitro, alquil(C1-C5)tio, trifluorometilo o trifluorometoxi;o R 7 y R 8 se toman juntos para formar -CH2-CH 2 -CH 2 CH 2 - o -CH=CH-CH=CH-;R 10 es hidrógeno, alquilo C 1 -C 5 , halógeno, ciano o-CO 2 R 19 ;Ar es arilo o heteroarilo cuyo arilo o heteroarilo no está sustituido o está sustituido con 1 o más sustituyentes, que son iguales o diferentes, seleccionados del grupo que consiste en halógeno, alquilo C 1 -C 5 , cicloalquilo C 3 C 8 , alquenilo C 2 -C 5 , alquinilo C 2 -C 5 , alcoxi C 1 -C 5 , alquil(C 1 -C 5 )tio, alquil(C 1 -C 5 )sulfinilo alquil(C 1 -C 5 )sulfonilo, ciano, nitro, hidroxi, -CO 2 R 19a , -C(=O)R 19a , -CONR 11b R 12b , -OC(=O)R 19a , -NR 11b COZR 19a , -S(O), -NR 11b R 11b , hidroxialquil(C 2 -C 5 )aminoalcoxi C 2 -C 5 , trifluorometilo, trifluorometoxi, difluorometoxi, fluorometoxi, metilendioxi, etilendioxi y -N(R 20 )R 21 ;R 11 y R 12 son iguales o diferentes, y son independientemente hidrógeno, alquilo C 1 -C 5 , cicloalquilo C 3 -C 8 o cicloalquil(C 3 -C 8 )alquilo C 1 -C 5 ;R 11a y R 12a son iguales o diferentes, y son independientemente hidrógeno, alquilo C 1 -C 5 , cicloalquilo C 3 -C 8 o cicloalquil(C 3 -C 8 )alquilo C 1 -C 5 ;R 11b y R 12b son iguales o diferentes, y son independientemente hidrógeno, alquilo C 1 -C 5 , cicloalquilo C 3 -C 8 o cicloalquil(C 3 -C 8 )alquilo C 1 -C 5 ;R 13 es hidrógeno, alquilo C 1 -C 5 , cicloalquilo C 3 -C 8 , cicloalquil(C 3 -C 8 )alquilo C 1 -C 5 , alcoxi(C 1 -C 5 )alquilo C 1 -C 5 , cicloalquil(C 3 -C 8 )oxialquilo C 1 -C 5 o fenilo;R 19 es hidrógeno o alquilo C 1 -C 5 ;R 19a es hidrógeno o alquilo C 1 -C 5 ;r es 1 o 2;r 20 y r 21 son iguales o diferentes, y son independientemente hidrógeno o alquilo C 1 -C 5 ), uno de sus isómeros individuales o sus mezclas de isómeros racémicas o no racémicas, o sus sales e hidratos farmacéuticamente aceptables. 176 ES 2 325 596 T3
- 3El derivado de pirrolopirimidina sustituido con el grupo amino cíclico de acuerdo con la reivindicación 2 representado por la fórmula [III], donde Y es N;el grupo amino cíclico, m, n, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 y Ar se definen como en la reivindicación 2;uno de sus isómeros individuales o sus mezclas de isómeros racémicas o no racémicas, o sus sales e hidratos farmacéuticamente aceptables.
- 4El derivado de pirrolopirimidina sustituido con el grupo amino cíclico de acuerdo con la reivindicación 2 representado por la fórmula [III], donde Y es N;n es 0;R 1 , R 2 , R 4 y R 5 son hidrógeno;el grupo amino cíclico, m, R 6 , R 7 , R 8 y Ar se definen como en la reivindicación 2;uno de sus isómeros individuales o sus mezclas de isómeros racémicas o no racémicas, o sus sales e hidratos farmacéuticamente aceptables.
- 5El derivado de pirrolopirimidina sustituido con el grupo amino cíclico de acuerdo con la reivindicación 2 representado por la fórmula [III], donde Y es N;el grupo amino cíclico es una amina cíclica saturada de 4 a 7 miembros;m es un entero seleccionado entre 0, 1, 2 y 3;n es 0;R 1 , R 2 , R 4 y R 5 son hidrógeno;R 6 es metilo;R 7 y R 8 son iguales o diferentes, y son independientemente hidrógeno o alquilo C1-C5;Ar es fenilo o piridilo cuyo fenilo o piridilo está sustituido con dos o tres sustituyentes, que son iguales o diferentes, seleccionados del grupo que consiste en halógeno, alquilo C1-C3, alcoxi C1-C3, alquil(C1-C3)tio, trifluorometilo, trifluorometoxi y -N(R 20 )R 21 (donde R 20 y R 21 son iguales o diferentes, y son independientemente hidrógeno o alquilo C1-C 3 );uno de sus isómeros individuales o sus mezclas de isómeros racémicas o no racémicas, o sus sales e hidratos farmacéuticamente aceptables.
- 6El derivado de pirrolopirimidina sustituido con el grupo amino cíclico de acuerdo con la reivindicación 2 representado por la fórmula [III], donde Y es N;el grupo amino cíclico es una amina cíclica saturada de 6 miembros;m es 0 o 1;n es 0;R 1 , R 2 , R 4 y R 5 son hidrógeno;R 6 es metilo;R 7 y R 8 son iguales o diferentes, y son independientemente hidrógeno o metilo;Ar es fenilo cuyo fenilo está sustituido con dos o tres sustituyentes, que son iguales o diferentes, seleccionados del grupo que consiste en cloro, bromo, alquilo C 1 -C 3 , alcoxi C 1 -C 3 , alquil(C 1 -C 3 )tio, trifluorometilo, trifluorometoxi y dimetilamino;uno de sus isómeros individuales o sus mezclas de isómeros racémicas o no racémicas, o sus sales e hidratos farmacéuticamente aceptables.
- 7El derivado de pirrolopiridina sustituido con el grupo amino cíclico de acuerdo con la reivindicación 2 representado por la fórmula [III], donde Y es CR 10 ;el grupo amino cíclico, m, n, R 1 , R 2 , R 3 , R 4 R 5 , R 6 , R 7 , R 8 , R 10 y Ar se definen como en la reivindicación 2;uno de sus isómeros individuales o sus mezclas de isómeros racémicas o no racémicas, o sus sales e hidratos farmacéuticamente aceptables.
- 8El derivado de pirrolopiridina sustituido con el grupo amino cíclico de acuerdo con la reivindicación 2 representado por la fórmula [III], donde Y es CR 10 ;n es 0;R 1 , R 2 , R 4 y R 5 son hidrógeno;R 10 es hidrógeno o halógeno;el grupo amino cíclico, m, R 6 , R 7 , R 8 y Ar se definen como en la reivindicación 2;uno de sus isómeros individuales o sus mezclas de isómeros racémicas o no racémicas, o sus sales e hidratos farmacéuticamente aceptables.
- 9El derivado de pirrolopiridina sustituido con el grupo amino cíclico de acuerdo con la reivindicación 2 representado por la fórmula [III], donde Y es CR 10 ;el grupo amino cíclico es una amina cíclica saturada de 4 a 7 miembros;m es un entero seleccionado entre 0, 1, 2 y 3;n es 0;R 1 , R 2 , R 4 y R 5 son hidrógeno;R 6 es metilo;R 7 y R 8 son iguales o diferentes, y son independientemente hidrógeno o alquilo C1-C5;R 10 es hidrógeno o halógeno;Ar es fenilo o piridilo cuyo fenilo o piridilo está sustituido con dos o tres sustituyentes, que son iguales o diferentes, seleccionados del grupo que consiste en halógeno, alquilo C1-C 3 , alcoxi C 1 -C 3 , alquil(C 1 -C 3 )tio, trifluorometilo, trifluorometoxi y -N(R 20 )R 21 (donde R 20 y R 21 son iguales o diferentes, y son independientemente hidrógeno o alquilo C 1 -C 3 );uno de sus isómeros individuales o sus mezclas de isómeros racémicas o no racémicas, o sus sales e hidratos farmacéuticamente aceptables.
- 10El derivado de pirrolopiridina sustituido con el grupo amino cíclico de acuerdo con la reivindicación 2 representado por la fórmula [III], donde Y es CR 10 ;el grupo amino cíclico es una amina cíclica saturada de 6 miembros;m es 0 o 1;n es 0;R 1 , R 2 , R 4 y R 5 son hidrógeno;R 6 es metilo;R 7 y R 8 son iguales o diferentes, y son independientemente hidrógeno o metilo;R 10 es hidrógeno;Ar es fenilo cuyo fenilo está sustituido con dos o tres sustituyentes, que son iguales o diferentes, seleccionados del grupo que consiste en cloro, bromo, alquilo C 1 -C 3 , alcoxi C 1 -C 3 , alquil(C 1 C3)tio, trifluorometilo, trifluorometoxi y dimetilamino;uno de sus isómeros individuales o sus mezclas de isómeros racémicas o no racémicas, o sus sales e hidratos farmacéuticamente aceptables.
- 11El derivado de pirrolopirimidina o pirrolopiridina sustituido con el grupo amino cíclico de acuerdo con la reivindicación 1, que es un compuesto representado por la siguiente fórmula [V]:177 ES 2 325 596 T3 (donde el grupo amino cíclico está representado por la siguiente fórmula [VI]: en la que el grupo amino cíclico es una amina cíclica saturada de 3 a 8 miembros o una amina cíclica saturada de 3 a 8 miembros unida mediante puente de alquileno C 1 -C 5 o alquilen(C 1 -C 4 )-O-alquileno C 1 -C 4 entre dos átomos de carbono diferentes cualesquiera de la amina cíclica, cuya amina cíclica está sustituida con un grupo representado por -(CR 1 R 2 )m-(CHR 3 )n-OH, R 4 y R 5 independientemente en el mismo o diferentes átomos de carbono de la amina cíclica;Y es N o CR 10 ;R 1 es hidrógeno, hidroxi, alquilo C 1 -C 5 , alcoxi(C 1 -C 5 )alquilo C 1 -C 5 o hidroxialquilo C 1 -C 5 ;R 2 es hidrógeno o alquilo C1-C5;R 3 es hidrógeno, ciano, alquilo C 1 -C 5 , alcoxi(C 1 -C 5 )alquilo C 1 -C 5 o hidroxialquilo C 1 -C 5 ;m es un entero seleccionado entre 0, 1, 2, 3, 4 y 5;n es 0 o 1;con la condición de que cuando n es 0, m es un entero seleccionado entre 1, 2, 3, 4 y 5;R 4 es hidrógeno, hidroxi, hidroxialquilo C 1 -C 5 , ciano, cianoalquilo C 1 -C 5 o alquilo C 1 -C 5 ;R 5 es hidrógeno o alquilo C1-C5;R 6 es hidrógeno, alquilo C 1 -C 5 , cicloalquilo C 3 -C 8 , cicloalquil(C 3 -C 8 )alquilo C 1 -C 5 , hidroxi, alcoxi C 1 -C 5 , cicloalquil(C 3 -C 8 )oxi o -N(R 11 )R 12 ;R 7 y R 8 son iguales o diferentes, y son independientemente hidrógeno, halógeno, alquilo C1-C5, cicloalquilo C3C8, cicloalquil(C3-C8)alquilo C1-C5, hidroxi, alcoxi C1-C5, cicloalquil(C3-C8)oxi, -N(R 11a )R 12a , -CO2R 13 , ciano, nitro, alquil(C1-C5)tio, trifluorometilo o trifluorometoxi;o R 7 y R 8 se toman juntos para formar -CH2-CH 2 -CH 2 CH2- o -CH=CH-CH=CH-;R 10 es hidrógeno, alquilo C 1 -C 5 , halógeno, ciano o-CO 2 R 19 ;Ar es arilo o heteroarilo cuyo arilo o heteroarilo no está sustituido o está sustituido con 1 o más sustituyentes, que son iguales o diferentes, seleccionados del grupo que consiste en halógeno, alquilo C 1 -C 5 , cicloalquilo C 3 C 8 , alquenilo C 2 -C 5 , alquinilo C 2 -C 5 , alcoxi C 1 -C 5 , alquil(C 1 -C 5 )tio, alquil(C 1 -C 5 )sulfinilo, alquil(C 1 -C 5 )sulfonilo, ciano, nitro, hidroxi, -CO 2 R 19a , -C(=O)R 19a , -CONR 11b R 12b , -OC(=O)R 19a , -NR 11b CO2R 19a , -S(O)rNR 11b R 12b , hidroxialquil(C2-C5)aminoalcoxi C2-C5, trifluorometilo, trifluorometoxi, difluorometoxi, fluorometoxi, metilendioxi, etilendioxi y -N(R 20 )R 21 ;con la condición de que cuando Y es N, y el grupo amino cíclico es un anillo de 5 miembros, Ar es arilo o heteroarilo cuyo arilo o heteroarilo está sustituido con al menos uno de los sustituyentes que se seleccionan entre halógeno y trifluorometilo;con la condición de que los compuestos en los que Y es N;el grupo amino cíclico es una amina cíclica saturada de 6 miembros;m es un entero seleccionado entre 1, 2 y 3;n es 0;R 1 , R 2 , R 4 y R 5 son hidrógeno;R 6 es metilo;R 7 y R 8 son iguales o diferentes, y son independientemente hidrógeno o metilo;Ar es fenilo cuyo fenilo está sustituido con dos o tres sustituyentes, que son iguales o diferentes, seleccionados del grupo que consiste en cloro, bromo, alquilo C 1 -C 3 , alcoxi C 1 -C 3 , alquil(C 1 -C 3 )tio, trifluorometilo, trifluorometoxi y dimetilamino;están excluidos;R 11 y R 12 son iguales o diferentes, y son independientemente hidrógeno, alquilo C 1 -C 5 , cicloalquilo C 3 -C 8 o cicloalquil(C 3 -C 8 )alquilo C 1 -C 5 ;R 11a y R 12a son iguales o diferentes, y son independientemente hidrógeno, alquilo C 1 -C 5 , cicloalquilo C 3 -C 8 o cicloalquil(C 3 -C 8 )alquilo C 1 -C 5 ;R 11b y R 12b son iguales o diferentes, y son independientemente hidrógeno, alquilo C 1 -C 5 , cicloalquilo C 3 -C 8 o cicloalquil(C 3 -C 8 )alquilo C 1 -C 5 ;178 ES 2 325 596 T3 R 13 es hidrógeno, alquilo C 1 -C 5 , cicloalquilo C 3 -C 8 , cicloalquil(C 3 -C 8 )alquilo C 1 -C 5 , alcoxi(C 1 -C 5 )alquilo C 1 -C 5 , cicloalquil(C 3 -C 8 )oxialquilo C 1 -C 5 o fenilo;R 19 es hidrógeno o alquilo C 1 -C 5 ;R 19a es hidrógeno o alquilo C 1 -C 5 ;r es 1 o 2;r 20 y r 21 son iguales o diferentes, y son independientemente hidrógeno o alquilo C 1 -C 5 ), uno de sus isómeros individuales o sus mezclas de isómeros racémicas o no racémicas, o sus sales e hidratos farmacéuticamente aceptables.
- 12El derivado de pirrolopirimidina sustituido con el grupo amino cíclico de acuerdo con la reivindicación 11 representado por la fórmula [V], donde Y es N;el grupo amino cíclico, m, n, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 y Ar se definen como en la reivindicación 11;uno de sus isómeros individuales o sus mezclas de isómeros racémicas o no racémicas, o sus sales e hidratos farmacéuticamente aceptables.
- 13El derivado de pirrolopirimidina sustituido con el grupo amino cíclico de acuerdo con la reivindicación 11 representado por la fórmula [V], donde Y es N;m es un entero seleccionado entre 1, 2, 3, 4 y 5;n es 0;R 1 , R 2 , R 4 y R 5 son hidrógeno;el grupo amino cíclico, R 6 , R 7 , R 8 y Ar se definen como en la reivindicación 11;sus isómeros individuales o sus mezclas de isómeros racémicas o no racémicas, o sus sales e hidratos farmacéuticamente aceptables.
- 14El derivado de pirrolopirimidina sustituido con el grupo amino cíclico de acuerdo con la reivindicación 11 representado por la fórmula [V], donde Y es N;el grupo amino cíclico es una amina cíclica saturada de 4 a 7 miembros;m es un entero seleccionado entre 1, 2 y 3;n es 0;R 1 , R 2 , R 4 y R 5 son hidrógeno;R 6 es metilo;R 7 y R 8 son iguales o diferentes, y son independientemente hidrógeno o alquilo C1-C5;Ar es fenilo o piridilo cuyo fenilo o piridilo está sustituido con dos o tres sustituyentes, que son iguales o diferentes, seleccionados del grupo que consiste en halógeno, alquilo C1-C3, alcoxi C1-C3, alquil(C1-C3)tio, trifluorometilo, trifluorometoxi y -N(R 20 )R 21 (donde R 20 y R 21 son iguales o diferentes, y son independientemente hidrógeno o alquilo C1-C 3 );con la condición de que cuando el grupo amino cíclico es un anillo de 5 miembros, Ar es fenilo o piridilo cuyo fenilo o piridilo está sustituido con al menos uno de los sustituyentes que se seleccionan entre halógeno y trifluorometilo;sus isómeros individuales o sus mezclas de isómeros racémicas o no racémicas, o sus sales e hidratos farmacéuticamente aceptables.
- 15Los derivados de pirrolopirimidina sustituidos con el grupo amino cíclico de acuerdo con la reivindicación 11 representados por la fórmula [V], donde Y es N;m es 1;n es 0;R 1 es alquilo C 1 -C 5 o hidroxialquilo C 1 -C 5 ;R 2 , R 4 y R 5 son hidrógeno;el grupo amino cíclico, R 6 , R 7 , R 8 y Ar se definen como en la reivindicación 11;uno de sus isómeros individuales o sus mezclas de isómeros racémicas o no racémicas, o sus sales e hidratos farmacéuticamente aceptables.
- 16Los derivados de pirrolopirimidina sustituidos con el grupo amino cíclico de acuerdo con la reivindicación 11 representados por la fórmula [V], donde Y es N;m es 1;n es 0;el grupo amino cíclico es una amina cíclica saturada de 4 a 7 miembros;R 1 es alquilo C1-C5 o hidroxialquilo C1-C5;R 2 , R 4 y R 5 son hidrógeno;R 6 es metilo;R 7 y R 8 son iguales o diferentes, y son independientemente hidrógeno o alquilo C1-C 5 ;Ar es fenilo o piridilo cuyo fenilo o piridilo está sustituido con dos o tres sustituyentes, que son iguales o diferentes, seleccionados del grupo que consiste en halógeno, alquilo C 1 -C 3 , alcoxi C 1 -C 3 , alquil(C 1 -C 3 )tio, trifluorometilo, trifluorometoxi y -N(R 20 )R 21 (donde R 20 y R 21 son iguales o diferentes, y son independientemente hidrógeno o alquilo C 1 -C 3 );uno de sus isómeros individuales o sus mezclas de isómeros racémicas o no racémicas, o sus sales e hidratos farmacéuticamente aceptables.
- 17Los derivados de pirrolopirimidina sustituidos con el grupo amino cíclico de acuerdo con la reivindicación 11 representados por la fórmula [V], donde Y es N;m es 1;n es 0;el grupo amino cíclico es una amina cíclica saturada de 6 miembros;R 1 es alquilo C1 -C5 o hidroxialquilo C1-C5;R 2 , R 4 y R 5 son hidrógeno;R 6 es metilo;R 7 y R 8 son iguales o diferentes, y son independientemente hidrógeno o metilo;Ar es fenilo cuyo fenilo está sustituido con dos o tres sustituyentes, que son iguales o diferentes, seleccionados del grupo que consiste en cloro, bromo, alquilo C1 -C 3 , alcoxi C 1 -C 3 , alquil(C 1 -C 3 )tio, trifluorometilo, trifluorometoxi y dimetilamino;uno de sus isómeros individuales o sus mezclas de isómeros racémicas o no racémicas, o sus sales e hidratos farmacéuticamente aceptables.
- 18El derivado de pirrolopirimidina sustituido con el grupo amino cíclico de acuerdo con la reivindicación 11 representado por la fórmula [V], donde Y es N;m es un entero seleccionado entre 1, 2, 3, 4 y 5;n es 0;R 1 , R 2 y R 5 son hidrógeno;R 4 es ciano;el grupo amino cíclico, R 6 , R 7 , R 8 y Ar se definen como en la reivindicación 11, donde un grupo representado por -(CR 1 R 2 )m-(CHR 3 )n-OH y R 4 están sustituidos en el mismo átomo de carbono de la amina cíclica;uno de sus isómeros individuales o sus mezclas de isómeros racémicas o no racémicas, o sus sales e hidratos farmacéuticamente aceptables.
- 19El derivado de pirrolopirimidina sustituido con el grupo amino cíclico de acuerdo con la reivindicación 11 representado por la fórmula [V], donde Y es N;el grupo amino cíclico es una amina cíclica saturada de 4 a 7 miembros;m es un entero seleccionado entre 1, 2 y 3;n es 0;R 1 , R 2 y R 5 son hidrógeno;R 4 es ciano;R 6 es metilo;R 7 y R 8 son iguales o diferentes, y son independientemente hidrógeno o alquilo C 1 -C 5 ;Ar es fenilo o piridilo cuyo fenilo o piridilo 179 ES 2 325 596 T3 está sustituido con dos o tres sustituyentes, que son iguales o diferentes, seleccionados del grupo que consiste en halógeno, alquilo C 1 -C 3 , alcoxi C 1 -C 3 , alquil(C 1 -C 3 )tio, trifluorometilo, trifluorometoxi y -N(R 20 )R 21 (donde R 20 y R 21 son iguales o diferentes, y son independientemente hidrógeno o alquilo C 1 -C 3 ), donde un grupo representado por -(CR 1 R 2 )m-(CHR 3 )n-OH y R 4 están sustituidos en el mismo átomo de carbono de la amina cíclica;uno de sus isómeros individuales o sus mezclas de isómeros racémicas o no racémicas, o sus sales e hidratos farmacéuticamente aceptables.
- 20El derivado de pirrolopirimidina sustituido con el grupo amino cíclico de acuerdo con la reivindicación 11 representado por la fórmula [V], donde Y es N;el grupo amino cíclico es una amina cíclica saturada de 6 miembros;m es un entero seleccionado entre 1, 2 y 3;n es 0;R r , R 2 y R 5 son hidrógeno;R 4 es ciano;R 6 es metilo;R 7 y R 8 son iguales o diferentes, y son independientemente hidrógeno o metilo;Ar es fenilo cuyo fenilo está sustituido con dos o tres sustituyentes, que son iguales o diferentes, seleccionados del grupo que consiste en cloro, bromo, alquilo C1 -C3, alcoxi C1 -C3, alquil(C1-C3)tio, trifluorometilo, trifluorometoxi y dimetilamino, donde un grupo representado por -(CR 1 R 2 )m-(OiR 3 ) n -OH y R 4 están sustituidos en el mismo átomo de carbono de la amina cíclica;sus isómeros individuales, o sus mezclas de isómeros racémicas o no racémicas, o sus sales e hidratos farmacéuticamente aceptables.
- 21El derivado de pirrolopiridina sustituido con el grupo amino cíclico de acuerdo con la reivindicación 11 representado por la fórmula [V], donde Y es CR 10 ;el grupo amino cíclico, m, n, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 10 y Ar se definen como en la reivindicación 11;uno de sus isómeros individuales o sus mezclas de isómeros racémicas o no racémicas, o sus sales e hidratos farmacéuticamente aceptables.
- 22El derivado de pirrolopiridina sustituido con el grupo amino cíclico de acuerdo con la reivindicación 11 representado por la fórmula [V], donde Y es CR 10 ;m es un entero seleccionado entre 1, 2, 3, 4 y 5;n es 0;R 1 , R 2 , R 4 y R 5 son hidrógeno;R 10 es hidrógeno o halógeno;el grupo amino cíclico, R 6 , R 7 , R 8 y Ar se definen como en la reivindicación 11;uno de sus isómeros individuales o sus mezclas de isómeros racémicas o no racémicas, o sus sales e hidratos farmacéuticamente aceptables.
- 23El derivado de pirrolopiridina sustituido con el grupo amino cíclico de acuerdo con la reivindicación 11 representado por la fórmula [V], donde Y es CR 10 ;el grupo amino cíclico es una amina cíclica saturada de 4 a 7 miembros;m es un entero seleccionado entre 1, 2 y 3;n es 0;R 1 , R 2 , R 4 y R 5 son hidrógeno;R 6 es metilo;R 7 y R 8 son iguales o diferentes, y son independientemente hidrógeno o alquilo C1-C5;R 10 es hidrógeno o halógeno;Ar es fenilo o piridilo cuyo fenilo o piridilo está sustituido con dos o tres sustituyentes, que son iguales o diferentes, seleccionados del grupo que consiste en halógeno, alquilo C1-C 3 , alcoxi C 1 -C 3 , alquil(C 1 -C 3 )tio, trifluorometilo, trifluorometoxi y -N(R 20 )R 21 (donde R 20 y R 21 son iguales o diferentes, y son independientemente hidrógeno o alquilo C 1 -C 3 );uno de sus isómeros individuales o sus mezclas de isómeros racémicas o no racémicas, o sus sales e hidratos farmacéuticamente aceptables.
- 24El derivado de pirrolopiridina sustituido con el grupo amino cíclico de acuerdo con la reivindicación 11 representado por la fórmula [V], donde Y es CR 10 ;el grupo amino cíclico es una amina cíclica saturada de 6 miembros;m es un entero seleccionado entre 1, 2 y 3;n es 0;R 1 , R 2 , R 4 y R 5 son hidrógeno;R 6 es metilo;R 7 y R 8 son iguales o diferentes, y son independientemente hidrógeno o metilo;R 10 es hidrógeno;Ar es fenilo cuyo fenilo está sustituido con dos o tres sustituyentes, que son iguales o diferentes, seleccionados del grupo que consiste en cloro, bromo, alquilo C 1 C 3 , alcoxi C 1 -C 3 , alquil(C 1 -C 3 )tio, trifluorometilo, trifluorometoxi y dimetilamino;uno de sus isómeros individuales o sus mezclas de isómeros racémicas o no racémicas, o sus sales e hidratos farmacéuticamente aceptables.
- 25Los derivados de pirrolopiridina sustituidos con el grupo amino cíclico de acuerdo con la reivindicación 11 representados por la fórmula [V], donde Y es CR 10 ;m es 1;n es 0;R 1 es alquilo C 1 -C 5 o hidroxialquilo C 1 -C 5 ;R 2 , R 4 y R 5 son hidrógeno;R 10 es hidrógeno o halógeno;el grupo amino cíclico, R 6 , R 7 , R 8 y Ar se definen como en la reivindicación 11;uno de sus isómeros individuales o sus mezclas de isómeros racémicas o no racémicas, o sus sales e hidratos farmacéuticamente aceptables.
- 26Los derivados de pirrolopiridina sustituidos con el grupo amino cíclico de acuerdo con la reivindicación 11 representados por la fórmula [V], donde Y es CR 10 ;m es 1;n es 0;el grupo amino cíclico es una amina cíclica saturada de 4 a 7 miembros;R 1 es alquilo C1-C5 o hidroxialquilo C1-C5;R 2 , R 4 y R 5 son hidrógeno;R 6 es metilo;R 7 y R 8 son iguales o diferentes, y son independientemente hidrógeno o alquilo C1-C 5 ;R 10 es hidrógeno o halógeno;Ar es fenilo o piridilo cuyo fenilo o piridilo está sustituido con dos o tres sustituyentes, que son iguales o diferentes, seleccionados del grupo que consiste en halógeno, alquilo C1-C3, alcoxi C1-C3, alquil(C1-C3)tio, trifluorometilo, trifluorometoxi y-N (R 20 )R 21 (donde R 20 y R 21 son iguales o diferentes, y son independientemente hidrógeno o alquilo C1 -C 3 );uno de sus isómeros individuales o sus mezclas de isómeros racémicas o no racémicas, o sus sales e hidratos farmacéuticamente aceptables.
- 27Los derivados de pirrolopiridina sustituidos con el grupo amino cíclico de acuerdo con la reivindicación 11 representados por la fórmula [V], donde Y es CR 10 ;m es 1;n es 0;el grupo amino cíclico es una amina cíclica saturada de 6 miembros;R 1 es alquilo C1-C5 o hidroxialquilo C1 -C5;R 2 , R 4 y R 5 son hidrógeno;R 6 es metilo;R 7 y R 8 son iguales o diferentes, y son independientemente hidrógeno o metilo;R 10 es hidrógeno;Ar es fenilo cuyo fenilo está sustituido con dos o tres sustituyentes, que son iguales o diferentes, seleccionados del grupo que consiste en cloro, bromo, alquilo C1-C 3 , alcoxi C 1 -C 3 , alquil(C 1 -C 3 )tio, trifluorometilo, trifluorometoxi y dimetilamino;uno de sus isómeros individuales o sus mezclas de isómeros racémicas o no racémicas, o sus sales e hidratos farmacéuticamente aceptables. 180 ES 2 325 596 T3
- 28El derivado de pirrolopiridina sustituido con el grupo amino cíclico de acuerdo con la reivindicación 11 representado por la fórmula [V], donde Y es CR 10 ;m es un entero seleccionado entre 1, 2, 3, 4 y 5;n es 0;R 1 , R 2 y R 5 son hidrógeno;R 4 es ciano;R 10 es hidrógeno o halógeno;el grupo amino cíclico, R 6 , R 7 , R 8 y Ar se definen como en la reivindicación 11, donde un grupo representado por -(CR 1 R 2 )m-(CHR 3 )n-OH y R 4 están sustituidos en el mismo átomo de carbono de la amina cíclica;uno de sus isómeros individuales o sus mezclas de isómeros racémicas o no racémicas, o sus sales e hidratos farmacéuticamente aceptables.
- 29El derivado de pirrolopiridina sustituido con el grupo amino cíclico de acuerdo con la reivindicación 11 representado por la fórmula [V], donde Y es CR 10 ;el grupo amino cíclico es una amina cíclica saturada de 4 a 7 miembros;m es un entero seleccionado entre 1, 2 y 3;n es 0;R 1 , R 2 y R 5 son hidrógeno;R 4 es ciano;R 6 es metilo;R 7 y R 8 son iguales o diferentes, y son independientemente hidrógeno o alquilo C1-C5;R 10 es hidrógeno o halógeno;Ar es fenilo o piridilo cuyo fenilo o piridilo está sustituido con dos o tres sustituyentes, que son iguales o diferentes, seleccionados del grupo que consiste en halógeno, alquilo C1-C 3 , alcoxi C 1 -C 3 , alquil(C 1 -C 3 )tio, trifluorometilo, trifluorometoxi y -N(R 20 )R 21 (donde R 20 y R 21 son iguales o diferentes, y son independientemente hidrógeno o alquilo C 1 -C 3 ), donde un grupo representado por -(CR 1 R 2 )m-(CHR 3 )n-OH y R 4 están sustituidos en el mismo átomo de carbono de la amina cíclica;uno de sus isómeros individuales o sus mezclas de isómeros racémicas o no racémicas, o sus sales e hidratos farmacéuticamente aceptables.
- 30El derivado de pirrolopiridina sustituido con el grupo amino cíclico de acuerdo con la reivindicación 11 representado por la fórmula [V], donde Y es CR 10 ;el grupo amino cíclico es una amina cíclica saturada de 6 miembros;m es un entero seleccionado entre 1, 2 y 3;n es 0;R 1 , R 2 y R 5 son hidrógeno;R 4 es ciano;R 6 es metilo;R 7 y R 8 son iguales o diferentes, y son independientemente hidrógeno o metilo;R 10 es hidrógeno;Ar es fenilo cuyo fenilo está sustituido con dos o tres sustituyentes, que son iguales o diferentes, seleccionados del grupo que consiste en cloro, bromo, alquilo C 1 -C 3 , alcoxi C 1 -C 3 , alquil(C 1 -C 3 )tio, trifluorometilo, trifluorometoxi y dimetilamino, donde un grupo representado por -(CR 1 R 2 )m-(CHR 3 )n-OH y R 4 están sustituidos en el mismo átomo de carbono de la amina cíclica;uno de sus isómeros individuales o sus mezclas de isómeros racémicas o no racémicas, o sus sales e hidratos farmacéuticamente aceptables.
- 31El derivado de pirrolopirimidina o pirrolopiridina sustituido con el grupo amino cíclico de acuerdo con la reivindicación 1, que es un compuesto representado por la siguiente fórmula [VII]:(donde el grupo amino cíclico está representado por la siguiente fórmula [VIII]: [V111] en la que el grupo amino cíclico es una amina cíclica saturada de 3 a 8 miembros o una amina cíclica saturada de 3 a 8 miembros unida mediante puente de alquileno C 1 -C 5 o -alquilen(C 1 -C 4 )-O-alquileno C 1 -C 4 entre dos átomos de carbono diferentes cualesquiera de la amina cíclica, cuya amina cíclica está sustituida con un grupo representado por -(CR 1 R 2 )m-CHR 3 )n-OR 9 : R 4 y R 5 independientemente en el mismo o diferentes átomos de carbono de la amina cíclica;Y es N o CR 10 ;R 1 es hidrógeno, hidroxi, alquilo C 1 -C 5 , alcoxi(C 1 -C 5 )alquilo C 1 -C 5 o hidroxialquilo C 1 -C 5 ;R 2 es hidrógeno o alquilo C1-C5;R 3 es hidrógeno, ciano, alquilo C 1 -C 5 , alcoxi(C 1 -C 5 )alquilo C 1 -C 5 o hidroxialquilo C 1 -C 5 ;m es un entero seleccionado entre 0, 1, 2, 3, 4 y 5;n es 0 o 1;con la condición de que cuando n es 0, m es un entero seleccionado entre 1, 2, 3, 4 y 5;181 ES 2 325 596 T3 R 4 es hidrógeno, hidroxi, hidroxialquilo C 1 -C 5 , ciano, cianoalquilo C 1 -C 5 o alquilo C 1 -C 5 ;R 5 es hidrógeno o alquilo C1-C5;R 6 es hidrógeno, alquilo C 1 -C 5 , cicloalquilo C 3 -C 8 , cicloalquil(C 3 -C 8 )alquilo C 1 -C 5 , hidroxi, alcoxi C 1 -C 5 , cicloalquil(C3-C8)oxi o -N(R 11 )R 12 ;R 7 y R 8 son iguales o diferentes, y son independientemente hidrógeno, halógeno, alquilo C1-C5, cicloalquilo C3C8, cicloalquil(C3-C8)alquilo C1-C5, hidroxi, alcoxi C1-C5, cicloalquil(C3-C8)oxi, -N(R 11a )R 12a , -CO2R 13 , ciano, nitro, alquil(C1-C5)tio, trifluorometilo o trifluorometoxi;o R 7 y R 8 se toman juntos para formar -CH2-CH 2 -CH 2 CH2- o -CH=CH-CH=CH-;R 9 es acilo C1 -C24, alcoxi(C1 -C10)carbonilo arilalquil(C1 -C5)oxicarbonilo, -CO-O-CHR 14 -O-CO-R 15 , P(=O)(OR 14a )OR 15a , -CO-(CH2) p -(CHR 16 ) q -NR 17 R 18 , arilcarbonilo o heteroarilcarbonilo, donde cada uno de dichos acilo, arilo y heteroarilo no está sustituido o está sustituido con alcoxi C1-C5, y acilo C1-C24 incluye opcionalmente de uno a seis enlaces dobles;R 10 es hidrógeno, alquilo C 1 -C 3 , halógeno, ciano o-CO 2 R 19 ;Ar es arilo o heteroarilo cuyo arilo o heteroarilo no está sustituido o está sustituido con 1 o más sustituyentes, que son iguales o diferentes, seleccionados del grupo que consiste en halógeno, alquilo C 1 -C 5 , cicloalquilo C 3 C 8 , alquenilo C 2 -C 5 , alquinilo C 2 -C 5 , alcoxi C 1 -C 5 , alquil(C 1 -C 5 )tio, alquil(C 1 -C 5 )sulfinilo, alquil(C 1 -C 5 )sulfonilo, ciano, nitro, hidroxi, -CO 2 R 19a , -C(=O)R 19a , -CONR 11b R 12b , -OC(=O)R 19a , -NR 11b CO2R 19a , -S(O)rNR 11b R 12b , hidroxialquil(C 2 -C 5 )aminoalcoxi C 2 -C 5 , trifluorometilo, trifluorometoxi, difluorometoxi, fluorometoxi, metilendioxi, etilendioxi y -N(R 20 )R 21 ;R 11 y R 12 son iguales o diferentes, y son independientemente hidrógeno, alquilo C 1 -C 5 , cicloalquilo C 3 -C 8 o cicloalquil(C 3 -C 8 )alquilo C 1 -C 5 ;R 11a y R 12a son iguales o diferentes, y son independientemente hidrógeno, alquilo C 1 -C 5 , cicloalquilo C 3 -C 8 o cicloalquil(C 3 -C 8 )alquilo C 1 -C 5 ;R 11b y R 12b son iguales o diferentes, y son independientemente hidrógeno, alquilo C 1 -C 5 , cicloalquilo C 3 -C 8 o cicloalquil(C 3 -C 8 )alquilo C 1 -C 5 ;R 13 es hidrógeno, alquilo C 1 -C 5 , cicloalquilo C 3 -C 8 , cicloalquil(C 3 -C 8 )alquilo C 1 -C 5 , alcoxi(C 1 -C 5 )alquilo C 1 -C 5 , cicloalquil(C 3 -C 8 )oxialquilo C 1 -C 5 o fenilo;R 14 y R 15 son iguales o diferentes, y son independientemente hidrógeno, alquilo C 1 -C 5 o arilalquilo C 1 -C 5 ;R 14a y R 15a son iguales o diferentes, y son independientemente hidrógeno, alquilo C 1 -C 5 o arilalquilo C 1 -C 5 ;R 16 es hidrógeno, alquilo C 1 -C 5 , arilo, heteroarilo, arilalquilo C 1 -C 5 , heteroarilalquilo C 1 -C 5 , hidroxialquilo C 1 -C 5 , hidroxicarbonilalquilo C 1 -C 5 , hidroxifenilalquilo C 1 -C 5 , alcoxi(C 1 -C 5 )alquilo C 1 -C 5 , aminoalquilo C 1 -C 5 , guanidinoalquilo C 1 -C 5 , mercaptoalquilo C 1 -C 5 , alquil(C 1 -C 5 )tioalquilo C 1 -C 5 o aminocarbonilalquilo C 1 -C 5 ;R 17 y R 18 son iguales o diferentes, y son independientemente hidrógeno, alquilo C 1 -C 5 , cicloalquilo C 3 -C 8 , cicloalquil(C 3 -C 8 )alquilo C 1 -C 5 , acilo C 1 -C 10 , alcoxi(C 1 -C 10 )carbonilo y arilalquil(C 1 -C 5 )oxicarbonilo, o R 16 y R 17 se toman juntos para formar -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 - o -CH 2 CH 2 CH 2 CH 2 -;p es un entero seleccionado entre 0, 1, 2, 3, 4 y 5;q es 0 o 1;R 19 es hidrógeno o alquilo C 1 -C 5 ;R 19a es hidrógeno o alquilo C 1 -C 5 ;r es 1 o 2;r 20 y r 21 son iguales o diferentes, y son independientemente hidrógeno o alquilo C 1 -C 5 ), uno de sus isómeros individuales o sus mezclas de isómeros racémicas o no racémicas, o sus sales e hidratos farmacéuticamente aceptables.
- 32El derivado de pirrolopirimidina sustituido con el grupo amino cíclico de acuerdo con la reivindicación 31 representado mediante la fórmula [VII], donde Y es N;el grupo amino cíclico, m, n, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 y Ar se definen como en la reivindicación 31;uno de sus isómeros individuales o sus mezclas de isómeros racémicas o no racémicas, o sus sales e hidratos farmacéuticamente aceptables. 182 ES 2 325 596 T3
- 33El derivado de pirrolopirimidina sustituido con el grupo amino cíclico de acuerdo con la reivindicación 31 representado por la fórmula [VlI], donde Y es N;m es un entero seleccionado entre 1, 2, 3, 4 y 5;n es 0;R 1 , R 2 , R 4 y R 5 son hidrógeno;el grupo amino cíclico, R 6 , R 7 , R 8 , R 9 y Ar se definen como en la reivindicación 31;uno de sus isómeros individuales o sus mezclas de isómeros racémicas o no racémicas, o sus sales e hidratos farmacéuticamente aceptables.
- 34El derivado de pirrolopirimidina sustituido con el grupo amino cíclico de acuerdo con la reivindicación 31 representado mediante la fórmula [VII], donde el grupo amino cíclico es una amina cíclica saturada de 4 a 7 miembros;m es un entero seleccionado entre 1, 2, 3,4 y 5;n es 0;Y es N;R 1 , R 2 , R 4 y R 5 son hidrógeno;R 6 es metilo;R 7 y R 8 son iguales o diferentes, y son independientemente hidrógeno o alquilo C1-C5;Ar es fenilo o piridilo cuyo fenilo o piridilo está sustituido con dos o tres sustituyentes, que son iguales o diferentes, seleccionados del grupo que consiste en halógeno, alquilo C1-C3, alcoxi C1-C3, alquil(C1-C3)tio, trifluorometilo, trifluorometoxi y -N(R 20 )R 21 (donde R 20 y R 21 son iguales o diferentes, y son independientemente hidrógeno o alquilo C1 -C 3 );R 9 se define como en la reivindicación 31;uno de sus isómeros individuales o sus mezclas de isómeros racémicas o no racémicas, o sus sales e hidratos farmacéuticamente aceptables.
- 35El derivado de pirrolopirimidina sustituido con el grupo amino cíclico de acuerdo con la reivindicación 31 representado mediante la fórmula [VII], donde el grupo amino cíclico es una amina cíclica saturada de 6 miembros;m es un entero seleccionado entre 1, 2 y 3;n es 0;Y es N;R 1 , R 2 , R 4 y R 5 son hidrógeno;R 6 es metilo;R 7 y R 8 son iguales o diferentes, y son independientemente hidrógeno o metilo;Ar es fenilo cuyo fenilo está sustituido con dos o tres sustituyentes, que son iguales o diferentes, seleccionados del grupo que consiste en cloro, bromo, alquilo C 1 -C 3 , alcoxi C 1 -C 3 , alquil(C 1 -C 3 )tio, trifluorometilo, trifluorometoxi y dimetilamino;R 9 se define como en la reivindicación 31;uno de sus isómeros individuales o sus mezclas de isómeros racémicas o no racémicas, o sus sales e hidratos farmacéuticamente aceptables.
- 36El derivado de pirrolopiridina sustituido con el grupo amino cíclico de acuerdo con la reivindicación 31 representado por la fórmula [VII], donde Y es CR 10 ;el grupo amino cíclico, m, n, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 y Ar se definen como en la reivindicación 31;uno de sus isómeros individuales o sus mezclas de isómeros racémicas o no racémicas, o sus sales e hidratos farmacéuticamente aceptables.
- 37El derivado de pirrolopiridina sustituido con el grupo amino cíclico de acuerdo con la reivindicación 31 representado por la fórmula [VII], donde Y es CR 10 ;m es un entero seleccionado entre 1, 2, 3, 4 y 5;n es 0;R 1 , R 2 , R 4 y R 5 son hidrógeno;el grupo amino cíclico, R 6 , R 7 , R 8 , R 9 , R 10 y Ar se definen como en la reivindicación 31;uno de sus isómeros individuales o sus mezclas de isómeros racémicas o no racémicas, o sus sales e hidratos farmacéuticamente aceptables.
- 38El derivado de pirrolopiridina sustituido con el grupo amino cíclico de acuerdo con la reivindicación 31 representado por la fórmula [VII], donde Y es CR 10 ;el grupo amino cíclico es una amina cíclica saturada de 4 a 7 miembros;m es un entero seleccionado entre 1, 2 y 3;n es 0;R 1 , R 2 , R 4 y R 5 son hidrógeno;R 6 es metilo;R 7 y R 8 son iguales o diferentes, y son independientemente hidrógeno o alquilo C1-C5;R 10 es hidrógeno o halógeno;Ar es fenilo o piridilo cuyo fenilo o piridilo está sustituido con dos o tres sustituyentes, que son iguales o diferentes, seleccionados del grupo que consiste en halógeno, alquilo C1-C 3 , alcoxi C 1 -C 3 , alquil(C 1 -C 3 )tio, trifluorometilo, trifluorometoxi y -N(R 20 )R 21 (donde R 20 y R 21 son iguales o diferentes, y son independientemente hidrógeno o alquilo C 1 -C 3 );R 9 se define como en la reivindicación 31;uno de sus isómeros individuales o sus mezclas de isómeros racémicas o no racémicas, o sus sales e hidratos farmacéuticamente aceptables.
- 39El derivado de pirrolopiridina sustituido con el grupo amino cíclico de acuerdo con la reivindicación 31 representado por la fórmula [VII], donde Y es CR 10 ;el grupo amino cíclico es una amina cíclica saturada de 6 miembros;m es un entero seleccionado entre 1, 2 y 3;n es 0;R 1 , R 2 , R 4 y R 5 son hidrógeno;R 6 es metilo;R 7 y R 8 son iguales o diferentes, y son independientemente hidrógeno o metilo;R 10 es hidrógeno;Ar es fenilo cuyo fenilo está sustituido con dos o tres sustituyentes, que son iguales o diferentes, seleccionados del grupo que consiste en cloro, bromo, alquilo C 1 -C 3 , alcoxi C 1 -C 3 , alquil(C 1 -C 3 )tio, trifluorometilo, trifluorometoxi y dimetilamino;R 9 se define como en la reivindicación 31;uno de sus isómeros individuales o sus mezclas de isómeros racémicas o no racémicas, o sus sales e hidratos farmacéuticamente aceptables.
- 40Los compuestos representados mediante la fórmula [I] de acuerdo con la reivindicación 1, cuyos compuestos se seleccionan del grupo que consiste en {1-[2-metil-9-(2,4,6-trimetil-fenil)-9H-1,3,9-triaza-fluoren-4-il]-piperidin-4-il}-metanol, {1-[7-(2,6-dibromo-4-trifluorometil-fenil)-2,5,6-trimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-3-metil-piperidin-3-il}metanol, {1-[7-(4-bromo-2,6-dimetil-fenil)-2,5,6-trimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-3-metil-piperidin-3-il}-metanol, {1-[7-(4-bromo-2,6-dimetil-fenil)-2,5-dimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-3-metil-piperidin-3-il}-metanol, 1-{1-[7-(4-bromo-2,6-dimetil-fenil)-2,5,6-trimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidin-4-il}-etano-1,2-diol, 183 ES 2 325 596 T3 {1-[7-(4-bromo-2,6-dimetil-fenil)-2,5,6-trimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-pirrolidin-2-il}-metanol, {1-[7-(4-bromo-2,6-dimetil-fenil)-2,5-dimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-pirrolidin-2-il}-metanol, 2- {1-[7-(4-bromo-2,6-dimetil-fenil)-2,5-dimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-pirrolidin-3-il}-etanol, {1-[7-(4-bromo-2,6-dimetil-fenil)-2,5,6-trimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-azepan-4-il}-metanol, {1-[7-(4-bromo-2,6-dimetil-fenil)-2,5-dimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-azepan-4-il}-metanol, {1-[7-(4-bromo-2,6-dimetil-fenil)-2,5,6-trimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidin-2-il}-acetonitrilo, 1-[2,5,6-trimetil-7-(2,4,6-trimetil-fenil)-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidino-3-carbonitrilo, 1-[2,5-dimetil-7-(2,4,6-trimetil-fenil)-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidino-3-carbonitrilo, 1-[7-(2,4-dibromo-6-metilsulfanil-fenil)-2,5-dimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidino-3-carbonitrilo, 1-[7-(2,6-dibromo-4-trifluorometil-fenil)-2,5,6-trimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidino-3-carbonitrilo, 1-[7-(4-bromo-2,6-dimetil-1-fenil)-2,5,6-trimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidino-3-carbonitrilo, 1-[7-(4-bromo-2,6-dimetil-fenil)-2,5-dimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidino-3-carbonitrilo, 1-[7-(4-isopropil-2-metilsulfanil-fenil)-2,5,6-trimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidino-3-carbonitrilo, 1-[7-(4-isopropil-2-metilsulfanil-fenil)-2,5-dimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidino-3-carbonitrilo, 1-[7-(2-bromo-4-trifluorometil-fenil)-2,5,6-trimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidino-3-carbonitrilo, 1-[7-(4-bromo-2,6-dietil-fenil)-2,5,6-trimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidino-3-carbonitrilo, 1-[7-(4-bromo-2,6-dietil-fenil)-2,5-dimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidino-3-carbonitrilo, {1-[7-(2,6-dibromo-4-trifluorometil-fenil)-2,5,6-trimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidin-3-il}-acetoni- trilo, {1-[7-(4-bromo-2,6-dimetil-fenil)-2,5,6-trimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidin-3-il}-acetonitrilo, {1-[7-(4-bromo-2,6-dimetil-fenil)-2,5-dimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidin-3-il}-acetonitrilo, 3- {1-[7-(4-bromo-2,6-dimetil-fenil)-2,5,6-trimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidin-3-il}-propionitrilo, 3-{1-[7-(4-bromo-2,6-dimetil-fenil)-2,5-dimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidin-3-il}-propionitrilo, 1-[7-(4-bromo-2,6-dimetil-fenil)-2,5,6-trimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidino-4-carbonitrilo, 1-[7-(4-bromo-2,6-dimetil-fenil)-2,5-dimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidino-4-carbonitrilo, {1-[2,5,6-trimetil-7-(2,4,6-trimetil-fenil)-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidin-4-il}-acetonitrilo, {1-[7-(2,6-dibromo-4-trifluorometil-fenil)-2,5,6-trimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidin-4-il}-acetonitrilo, {1-[7-(4-bromo-2,6-dimetil-fenil)-2,5,6-trimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidin-4-il}-acetonitrilo, {1-[7-(4-bromo-2,6-dimetil-fenil)-2,5-dimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidin-4-il}-acetonitrilo, {1-[7-(4-bromo-2,6-dietil-fenil)-2,5,6-trimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidin-4-il}-acetonitrilo, {1-[7-(4-bromo-2,6-dietil-fenil)-2,5-dimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidin-4-il}-acetonitrilo, {1-[2,5,6-trimetil-7-(2,4,6-tribromo-fenil)-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidin-4-il}-acetonitrilo, {1-[2,5-dimetil-7-(2,4,6-tribromo-fenil)-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidin-4-il}-acetonitrilo, {1-[7-(4-bromo-2,6-dicloro-fenil)-2,5,6-trimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidin-4-il}-acetonitrilo, 184 ES 2 325 596 T3 {1-[7-(4-bromo-2,6-dicloro-fenil)-2,5-dimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidin-4-il}-acetonitrilo, {1-[7-(2,6-dibromo-4-isopropil-fenil)-2,5,6-trimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidin-4-il}-acetonitrilo, {1-[7-(2,6-dibromo-4-isopropil-fenil)-2,5-dimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidin-4-il}-acetonitrilo, {1-[7-(4-metoxi-2,6-dimetil-fenil)-2,5,6-trimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidin-4-il}-acetonitrilo, {1-[7-(4-metoxi-2,6-dimetil-fenil)-2,5-dimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidin-4-il}-acetonitrilo, {1-[7-(4-cloro-2,6-dimetil-fenil)-2,5,6-trimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidin-4-il}-acetonitrilo, {1-[7-(4-cloro-2,6-dimetil-fenil)-2,5-dimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidin-4-il}-acetonitrilo, 8-[7-(4-bromo-2,6-dimetil-fenil)-2,5,6-trimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-8-aza-biciclo[3,2,1]octano-3-carbonitrilo, 8-[7-(4-bromo-2,6-dimetil-fenil)-2,5-dimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-8-aza-biciclo[3,2,1]octano-3-carbonitrilo, 1-[7-(4-bromo-2,6-dimetil-fenil)-2,5,6-trimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-pirrolidino-3-carbonitrilo, 1-[7-(4-bromo-2,6-dimetil-fenil)-2,5-dimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-pirrolidino-3-carbonitrilo, 1-[7-(4-bromo-2,6-dimetil-fenil)-2,5,6-trimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-azepano-4-carbonitrilo, 1-[7-(4-bromo-2,6-dimetil-fenil)-2,5-dimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-azepano-4-carbonitrilo, 1-[7-(4-bromo-2,6-dimetil-fenil)-2,5,6-trimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-3-hidroximetil-piperidino-3-carbonitrilo, 1-{1-[7-(4-bromo-2,6-dimetil-fenil)-2,5,6-trimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidin-4-il}-propano-1,3diol, {1-[7-(2,6-dibromo-4-cloro-fenil)-2,5-dimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidin-4-il}-acetonitrilo, {1-[7-(4-bromo-2,6-dimetil-fenil)-2,5,6-trimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-pirrolidin-3-il}-acetonitrilo, 1-[7-(4-bromo-2,6-dimetil-fenil)-2,5-dimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-pirrolidin-3-il}-acetonitrilo, 1-[7-(4-cloro-2,6-dimetil-fenil)-2,5,6-trimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidino-4-carbonitrilo, {1-[7-(2,6-Dicloro-4-trifluorometil-fenil)-2,5-dimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidin-4-il}-acetonitrilo, 1-[7-(4-bromo-2,6-dimetil-fenil)-2,5,6-trimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-azetidino-3-carbonitrilo, 1-{1-[7-(4-bromo-2,6-dimetil-fenil)-2,5,6-trimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidin-4-il}-etanol, 1-{1-[7-(4-isopropil-2-metilsulfanil-fenil)-2,5-dimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidin-4-il}-etanol, 1-{1-[7-(4-cloro-2,6-dimetil-fenil)-2,5,6-trimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidin-4-il}-etanol, 1-{1-[7-(4-cloro-2,6-dimetil-fenil)-2,5-dimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidin-4-il}-etanol, {1-[7-(4-bromo-2,6-dimetil-fenil)-2,5,6-trimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-3-metil-piperidin-4-il}-metanol, {1-[7-(4-bromo-2,6-dimetil-fenil)-2,5-dimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-3-metil-piperidin-4-il}-metanol, {8-[7-(4-bromo-2,6-dimetil-fenil)-2,5,6-trimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-8-aza-biciclo[3,2,1]oct-3-il}metanol, {8-[7-(4-bromo-2,6-dimetil-fenil)-2,5-dimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-8-aza-biciclo[3,2,1]oct-3-il}-metanol, {8-[7-(4-bromo-2,6-dimetil-fenil)-2,5,6-trimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-8-aza-biciclo[3,2,1]oct-3-il}acetonitrilo, 185 ES 2 325 596 T3 {8-[7-(4-bromo-2,6-dimetil-fenil)-2,5-dimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-8-aza-biciclo[3,2,1]oct-3-il}-acetonitrilo, 2-{1-[7-(4-bromo-2,6-dimetil-fenil)-2,5,6-trimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidin-4-il}-malononitrilo, 2-{1-[7-(4-bromo-2,6-dimetil-fenil)-2,5-dimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidin-4-il}-malononitrilo, 2-{1-[1-(2,4-dicloro-fenil)-2,3,6-trimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-3-il}-etanol, 2-{1-[1-(4-bromo-2,6-dimetil-fenil)-3,6-dimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-3-il}-etanol, {1-[1-(2,4-dicloro-fenil)-2,3,6-trimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-metanol, {1-[1-(4-bromo-2,6-dimetil-fenil)-3,6-dimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-metanol, 2-{1-[1-(2,4-dicloro-fenil)-2,3,6-trimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-etanol, 2- {1-[1-(4-bromo-2,6-dimetil-fenil)-3,6-dimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-etanol, 3- {1-[1-(2,4-dicloro-fenil)-2,3,6-trimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-propan-1-ol, 3-{1-[1-(4-bromo-2,6-dimetil-fenil)-3,6-dimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-propan-1-ol, 1-[1-(2,4-dicloro-fenil)-2,3,6-trimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidino-3-carbonitrilo, 1-[1-(4-bromo-2,6-dimetil-fenil)-3,6-dimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidino-3-carbonitrilo, {1-[1-(2,4-dicloro-fenil)-2,3,6-trimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-3-il}-acetonitrilo, 1-[1-(2,4-dicloro-fenil)-2,3,6-trimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidino-4-carbonitrilo, 1- [1-(4-bromo-2,6-dimetil-fenil)-3,6-dimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidino-4-carbonitrilo, {1-[1-(2,4-dicloro-fenil)-2,3,6-trimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-acetonitrilo, 2- {1-[1-(4-bromo-2,6-dimetil-fenil)-2,3,6-trimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-3-il}-etanol, {1-[1-(4-bromo-2,6-dimetil-fenil)-2,3,6-trimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-metanol, {1-[1-(4-cloro-2,6-dimetil-fenil)-2,3,6-trimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-metanol, {1-[1-(4-cloro-2,6-dimetil-fenil)-3,6-dimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-metanol, 2-{1-[1-(4-bromo-2,6-dimetil-fenil)-2,3,6-trimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-etanol, 2-{1-[1-(4-cloro-2,6-dimetil-fenil)-2,3,6-trimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-etanol, 2- {1-[1-(4-cloro-2,6-dimetil-fenil)-3,6-dimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-etanol, 3- {1-[1-(4-bromo-2,6-dimetil-fenil)-2,3,6-trimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-propan-1-ol, 3-{1-[1-(4-cloro-2,6-dimetil-fenil)-2,3,6-trimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-propan-1-ol, 3-{1-[1-(4-cloro-2,6-dimetil-fenil)-3,6-dimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-propan-1-ol, 1-[1-(4-bromo-2,6-dimetil-fenil)-2,3,6-trimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidino-3-carbonitrilo, 1-[1-(4-bromo-2,6-dimetil-fenil)-2,3,6-trimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidino-4-carbonitrilo, 1-[1-(4-cloro-2,6-dimetil-fenil)-2,3,6-trimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidino-4-carbonitrilo, 1-[1-(4-cloro-2,6-dimetil-fenil)-3,6-dimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidino-4-carbonitrilo, {1-[1-(4-bromo-2,6-dimetil-fenil)-2,3,6-trimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-acetonitrilo, {1-[1-(4-bromo-2,6-dimetil-fenil)-3,6-dimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-acetonitrilo, {1-[1-(4-cloro-2,6-dimetil-fenil)-3,6-dimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-acetonitrilo, 186 ES 2 325 596 T3 {1-[1-(2,6-dibromo-4-isopropil-fenil)-2,3,6-trimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-metanol, {1-[1-(2,6-dibromo-4-isopropil-fenil)-3,6-dimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-metanol, {1-[2,3,6-trimetil-1-(2,4,6-tribromo-fenil)-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-metanol, {1-[3,6-dimetil-1-(2,4,6-tribromo-fenil)-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-metanol, {1-[1-(4-bromo-2,6-dicloro-fenil)-2,3,6-trimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-metanol, {1-[1-(4-bromo-2,6-dicloro-fenil)-3,6-dimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-metanol, {1-[2,3,6-trimetil-1-(2,4,6-tricloro-fenil)-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-metanol, {1-[3,6-dimetil-1-(2,4,6-tricloro-fenil)-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-metanol, {1-[1-(2,6-dibromo-4-cloro-fenil)-2,3,6-trimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-metanol, {1-[1-(2,6-dibromo-4-cloro-fenil)-3,6-dimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-metanol, {1-[1-(4-metoxi-2,6-dimetil-fenil)-2,3,6-trimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-metanol, {1-[1-(4-metoxi-2,6-dimetil-fenil)-3,6-dimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-metanol, {1-[1-(2-bromo-4-isopropil-fenil)-3,6-dimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-metanol, {1-[1-(4-isopropil-2-metilsulfanil-fenil)-3,6-dimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-metanol, {1-[1-(2,4-dibromo-fenil)-3,6-dimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-metanol, {1-[1-(2-bromo-4-trifluorometil-fenil)-3,6-dimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-metanol, {1-[2,3,6-trimetil-1-(2,4,5-tribromo-fenil)-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-metanol, {1-[3,6-dimetil-1-(2,4,5-tribromo-fenil)-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-metanol, 2-{1-[1-(2,6-dibromo-4-isopropil-fenil)-2,3,6-trimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-etanol, 2-{1-[1-(2,6-dibromo-4-isopropil-fenil)-3,6-dimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-etanol, 2-{1-[2,3,6-trimetil-1-(2,4,6-tribromo-fenil)-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-etanol, 2-{1-[3,6-dimetil-1-(2,4,6-tribromo-fenil)-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il} -etanol, 2-{1-[1-(4-bromo-2,6-dicloro-fenil)-2,3,6-trimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-etanol, 2-{1-[1-(4-bromo-2,6-dicloro-fenil)-3,6-dimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-etanol, 2-{1-[2,3,6-trimetil-1-(2,4,6-tricloro-fenil)-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-etanol, 2-{1-[3,6-dimetil-1-(2,4,6-tricloro-fenil)-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il} -etanol, 2-{1-[1-(2,6-dibromo-4-cloro-fenil)-2,3,6-trimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-etanol, 2-{1-[1-(2,6-dibromo-4-cloro-fenil)-3,6-dimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-etanol, 2-{1-[1-(4-metoxi-2,6-dimetil-fenil)-2,3,6-trimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-etanol, 2-{1-[1-(4-metoxi-2,6-dimetil-fenil)-3,6-dimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-etanol, 2-{1-[1-(2-bromo-4-isopropil-fenil)-3,6-dimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-etanol, 2-{1-[1-(4-isopropil-2-metilsulfanil-fenil)-3,6-dimetil-1H-pirrolo[2,3-b]piridin-4-il] -piperidin-4-il}-etanol, 2-{1-[1-(2,4-dibromo-fenil)-3,6-dimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-etanol, 2-{1-[2,3,6-trimetil-1-(2,4,5-tribromo-fenil)-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-etanol, 187 ES 2 325 596 T3 2-{1-[3,6-dimetil-1-(2,4,5-tribromo-fenil)-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-etanol, 2- {1-[5-bromo-1-(4-cloro-2,6-dimetil-fenil)-3,6-dimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-etanol, 3- {1-[1-(2,6-dibromo-4-isopropil-fenil)-2,3,6-trimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-propan-1-ol, 3-{1-[1-(2,6-dibromo-4-isopropil-fenil)-3,6-dimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-propan-1-ol, 3-{1-[2,3,6-trimetil-1-(2,4,6-tribromo-fenil)-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-propan-1-ol, 3-{1-[3,6-dimetil-1-(2,4,6-tribromo-fenil)-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-propan-1-ol, 3-{1-[1-(4-bromo-2,6-dicloro-fenil)-2,3,6-trimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-propan-1-ol, 3-{1-[1-(4-bromo-2,6-dicloro-fenil)-3,6-dimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-propan-1-ol, 3-{1-[2,3,6-trimetil-1-(2,4,6-tricloro-fenil)-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-propan-1-ol, 3-{1-[3,6-dimetil-1-(2,4,6-tricloro-fenil)-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il }-propan-1-ol, 3-{1-[1-(2,6-dibromo-4-cloro-fenil)-2,3,6-trimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-propan-1-ol, 3-{1-[1-(2,6-dibromo-4-cloro-fenil)-3,6-dimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-propan-1-ol, 3-{1-[1-(4-metoxi-2,6-dimetil-fenil)-2,3,6-trimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-propan-1-ol, 3-{1-[1-(4-metoxi-2,6-dimetil-fenil)-3,6-dimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-propan-1-ol, 3-{1-[1-(4-isopropil-2-metilsulfanil-fenil)-3,6-dimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-propan-1-ol, 3-{1-[2,3,6-trimetil-1-(2,4,5-tribromo-fenil)-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-propan-1-ol, 3-{1-[3,6-dimetil-1-(2,4,5-tribromo-fenil)-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-propan-1-ol, 1-{1-[1-(4-bromo-2,6-dimetil-fenil)-2,3,6-trimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-etano-1,2-diol, 1-{1-[1-(4-bromo-2,6-dimetil-fenil)-3,6-dimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-etano-1,2-diol, 1-{1-[1-(4-bromo-2,6-dimetil-fenil)-2,3,6-trimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-propano-1,3-diol, 1-{1-[1-(4-bromo-2,6-dimetil-fenil)-3,6-dimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-propano-1,3-diol, 1-[1-(2,6-dibromo-4-isopropil-fenil)-2,3,6-trimetil-1H-pirrolo[1,3-b]piridin-4-il]-piperidino-4-carbonitrilo, 1-[1-(2,6-dibromo-4-isopropil-fenil)-3,6-dimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidino-4-carbonitrilo, 1-[2,3,6-trimetil-1-(2,4,6-tribromo-fenil)-1H-pirrolo[2,3-b]piridin-4-il]-piperidino-4-carbonitrilo, 1-[3,6-dimetil-1-(2,4,6-tribromo-fenil)-1H-pirrolo[2,3-b]piridin-4-il]-piperidino-4-carbonitrilo, 1-[1-(4-bromo-2,6-dicloro-fenil)-2,3,6-trimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidino-4-carbonitrilo, 1-[1-(4-bromo-2,6-dicloro-fenil)-3,6-dimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidino-4-carbonitrilo, 1-[2,3,6-trimetil-1-(2,4,6-tricloro-fenil)-1H-pirrolo[2,3-b]piridin-4-il]-piperidino-4-carbonitrilo, 1-[3,6-dimetil-1-(2,4,6-tricloro-fenil)-1H-pirrolo[2,3-b]piridin-4-il]-piperidino-4-carbonitrilo, 1-[1-(2,6-dibromo-4-cloro-fenil)-2,3,6-trimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidino-4-carbonitrilo, 1-[1-(2,6-dibromo-4-cloro-fenil)-3,6-dimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidino-4-carbonitrilo, 1-[1-(4-metoxi-2,6-dimetil-fenil)-2,3,6-trimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidino-4-carbonitrilo, 1-[1-(4-metoxi-2,6-dimetil-fenil)-3,6-dimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidino-4-carbonitrilo, 1-[1-(2-bromo-4-isopropil-fenil)-3,6-dimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidino-4-carbonitrilo, 188 ES 2 325 596 T3 1-[1-(4-isopropil-2-metilsulfanil-fenil)-3,6-dimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidino-4-carbonitrilo, 1-[1-(2,4-dibromo-fenil)-3,6-dimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidino-4-carbonitrilo, 1-[1-(2-bromo-4-trifluorometil-fenil)-3,6-dimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidino-4-carbonitrilo, 1-[2,3,6-trimetil-1-(2,4,5-tribromo-fenil)-1H-pirrolo[2,3-b]piridin-4-il]-piperidino-4-carbonitrilo, 1-[3,6-dimetil-1-(2,4,5-tribromo-fenil)-1H-pirrolo[2,3-b]piridin-4-il]-piperidino-4-carbonitrilo, {1-[1-(4-cloro-2,6-dimetil-fenil)-2,3,6-trimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-acetonitrilo, {1-[1-(2,6-dibromo-4-isopropil-fenil)-2,3,6-trimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-acetonitrilo, {1-[1-(2,6-dibromo-4-isopropil-fenil)-3,6-dimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-acetonitrilo, {1-[2,3,6-trimetil-1-(2,4,6-tribromo-fenil)-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-acetonitrilo, {1-[3,6-dimetil-1-(2,4,6-tribromo-fenil)-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-acetonitrilo, {1-[1-(4-bromo-2,6-dicloro-fenil)-2,3,6-trimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-acetonitrilo, {1-[1-(4-bromo-2,6-dicloro-fenil)-3,6-dimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-acetonitrilo, {1-[2,3,6-trimetil-1-(2,4,6-tricloro-fenil)-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-acetonitrilo, {1-[3,6-dimetil-1-(2,4,6-tricloro-fenil)-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-acetonitrilo, {1-[1-(2,6-dibromo-4-cloro-fenil)-2,3,6-trimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-acetonitrilo, {1-[1-(2,6-dibromo-4-cloro-fenil)-3,6-dimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-acetonitrilo, {1-[1-(4-metoxi-2,6-dimetil-fenil)-2,3,6-trimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-acetonitrilo, {1-[1-(4-metoxi-2,6-dimetil-fenil)-3,6-dimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-acetonitrilo, {1-[1-(2-bromo-4-isopropil-fenil)-3,6-dimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-acetonitrilo, {1-[1-(4-isopropil-2-metilsulfanil-fenil)-3,6-dimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-acetonitrilo, {1-[1-(2,4-dibromo-fenil)-3,6-dimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-acetonitrilo, {1-[1-(2-bromo-4-trifluorometil-fenil)-3,6-dimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-acetonitrilo, {1-[3,6-dimetil-1-(2,4,5-tribromo-fenil)-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-il}-acetonitrilo, éster etílico de éster 1-[7-(4-bromo-2,6-dimetil-fenil)-2,5-dimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidin-4-ilmetílico de ácido carbónico, éster 1-[7-(4-bromo-2,6-dimetil-fenil)-2,5-dimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidin-4-ilmetílico de ácido piridino-2-carboxílico, éster 1-[7-(4-bromo-2,6-dimetil-fenil)-2,5-dimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidin-4-ilmetílico de ácido metoxi-acético, éster 1-[1-(4-bromo-2,6-dimetil-fenil)-3,6-dimetil-1H-pirrolo[2,3-b]piridin-4-il]-piperidin-4-ilmetílico de ácido metoxi-acético, éster bencílico de éster 1-[7-(4-bromo-2,6-dimetil-fenil)-2,5-dimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidin-4ilmetílico de ácido carbónico, éster 1-[7-(4-bromo-2,6-dimetil-fenil)-2,5-dimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidin-4-ilmetílico de ácido decanoico, éster 1-[7-(4-bromo-2,6-dimetil-fenil)-2,5-dimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidin-4-ilmetílico de ácido 3-dietilamino-propiónico 189 ES 2 325 596 T3 y éster mono-{1-[7-(4-bromo-2,6-dimetil-fenil)-2,5-dimetil-7H-pirrolo[2,3-d]pirimidin-4-il]-piperidin-4-ilmetílico} de ácido fosfórico, uno de sus isómeros individuales o sus mezclas de isómeros racémicas o no racémicas, o sus sales e hidratos farmacéuticamente aceptables.
- 41Una composición farmacéutica que comprende el derivado de pirrolopirimidina o pirrolopiridina sustituido con un grupo amino cíclico, una de sus sales farmacéuticamente aceptables o su hidrato de acuerdo con una cualquiera de las reivindicaciones 1 a 40;como ingrediente activo.
- 42El derivado de pirrolopirimidina o pirrolopiridina sustituido con un grupo amino cíclico como se ha definido en cualquiera de las reivindicaciones 1 a 40 para su uso en un método para tratar las enfermedades relacionadas con el CRF.
- 43El derivado de pirrolopirimidina o pirrolopiridina sustituido con un grupo amino cíclico de acuerdo con la reivindicación 42, donde el método es para tratar la depresión, la ansiedad, la enfermedad de Alzheimer, la enfermedad de Parkinson, el corea de Huntington, los trastornos de la ingesta, la hipertensión, las enfermedades gástricas, la dependencia de fármacos, la epilepsia, el infarto cerebral, la isquemia cerebral, el edema cerebral, las heridas externas cefálicas, la inflamación, las enfermedades relacionadas con la inmunidad, la alopecia, el síndrome del intestino irritable, los trastornos del sueño, las dermatitis y la esquizofrenia.
- 44El derivado de pirrolopirimidina o pirrolopiridina sustituido con un grupo amino cíclico de acuerdo con la reivindicación 42, donde el método es para tratar la depresión, la ansiedad o el síndrome del intestino irritable.
- 45El derivado de pirrolopirimidina o pirrolopiridina sustituido con un grupo amino cíclico de acuerdo con la reivindicación 42, donde el método es para tratar la depresión.
- 46El derivado de pirrolopirimidina o pirrolopiridina sustituido con un grupo amino cíclico de acuerdo con la reivindicación 42, donde el método es para tratar la ansiedad.
- 47El uso del derivado de pirrolopirimidina o pirrolopiridina sustituido con un grupo amino cíclico de acuerdo con cualquiera de las reivindicaciones 1 a 40 para la fabricación de un medicamento para el tratamiento de las enfermedades relacionadas con el CRF.
- 48El uso del derivado de pirrolopirimidina o del derivado de pirrolopiridina sustituido con un grupo amino cíclico de acuerdo con la reivindicación 47 para la fabricación de un medicamento para el tratamiento de la depresión, la ansiedad, la enfermedad de Alzheimer, la enfermedad de Parkinson, el corea de Huntington, los trastornos de la ingesta, la hipertensión, las enfermedades gástricas, la dependencia de fármacos, la epilepsia, el infarto cerebral, la isquemia cerebral, el edema cerebral, las heridas externas cefálicas, la inflamación, las enfermedades relacionadas con la inmunidad, la alopecia, el síndrome del intestino irritable, los trastornos del sueño, las dermatitis y la esquizofrenia. 190
Independent claims48
1,599 paragraphs in 133 sections, as filed
ES 2 325 596 T3
DESCRIPTION
Derivatives of pyrrolopyrimidine and pyrrolopyridine substituted with a cyclic amino group.
Detailed description of the invention
Technical field
The present invention relates to a therapeutic agent for diseases in which corticotropin releasing factor (CRF) is considered to be involved, such as depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea , eating disorders, hypertension, gastric diseases, drug dependence, cerebral infarction, cerebral ischemia, cerebral edema, external head injuries, inflammatory diseases related to immunity, alopecia, irritable bowel syndrome, sleep disorders, epilepsy, dermatitis, schizophrenia, etc.
Description of the prior art
CRF is a hormone comprising 41 amino acids (Science, 213, 1394-1397, 1981; and J. Neurosci., 7, 88100, 1987), and it is suggested that CRF plays a central role in biological reactions against stress (Cell. Mol. Neurobiol., 14, 579-588, 1994; Endocrinol., 132,723-728,1994; and Neuroendocrinol. 61,445-452,1995). For CRF, there are the following two pathways: a pathway in which CRF acts on the peripheral immune system or the sympathetic nervous system via the hypothalamic-pituitary-adrenal system, and a pathway in which CRF functions as a neurotransmitter in the central nervous system (in Corticotropin Releasing Factor: Basic and Clinical Studies of a Neuropeptide, pp. 29-52, 1990). Intraventricular administration of CRF to hypophysectomized rats and normal rats causes an anxiety-like symptom in both types of rats (Pharmacol. Rev., 43, 425-473, 1991; and Brain Res. Rev., 15, 71-100, 1990 ). That is, the involvement of CRF in the hypothalamic-adrenal system and the pathway through which CRF functions as a neurotransmitter in the central nervous system is suggested.
The study by Owens and Nemeroff in 1991 summarizes the diseases in which CRF is implicated (Pharmacol. Rev., 43, 425-474, 1991). That is, CRF is implicated in depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorders, hypertension, gastrointestinal diseases, drug dependence, inflammation, diseases related to immunity, etc. CRF has recently been reported to also be implicated in epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, and external head injuries (Brain Res. 545, 339-342, 1991; Ann. Neurol. 31, 48-498, 1992; Dev. Brain Res. 91, 245-251, 1996; and Brain Res. 744, 166-170, 1997). Therefore, CRF receptor antagonists are useful as therapeutic agents for the diseases described above.
In WO02 / 002549 and WO00 / 053604 derivatives of pyrrolopyridine and pyrrolopyrimidine are described respectively as receptor antagonists of CRF. Pyrrolopyrimidine derivatives are also described in Bioorganic & Medicinal Chemistry 10 (2002) 175-183. However, none describe the compounds provided in the present invention.
Problems to be solved by the invention
An object of the present invention is to provide an antagonist against CRF receptors that is effective as a therapeutic or prophylactic agent for diseases in which CRF is considered to be involved, such as depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorders, hypertension, gastric diseases, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, brain edema, external head injuries, inflammation, immunity-related diseases, alopecia, irritable bowel syndrome, sleep disorders, epilepsy, dermatitis, schizophrenia, etc.
Means to solve the problem
The present inventors carefully investigated cyclic amino substituted pyrrolopyrimidine and pyrrolopyridine derivatives having high affinity for CRF receptors, thus completing the present invention.
The present invention consists of the pyrrolopyrimidine and pyrrolopyridine derivatives substituted with a cyclic amino group explained below.
ES 2 325 596 T3
A pyrrolopyrimidine or pyrrolopyridine derivative substituted with a cyclic amino group represented by the following formula [I]:
<img file="ES2325596T3_D0001.tif" />
(where the cyclic amino group is represented by the following formula [II]:
<img file="ES2325596T3_D0002.tif" />
wherein the cyclic amino group is a 3- to 8-membered saturated cyclic amine or a 3- to 8-membered saturated cyclic amine bridged by alkylene C<sub>1</sub> -C<sub>5</sub> or alkylene (Ci -C<sub>4</sub>) -O-Ci -C alkylene<sub>4</sub> between any two different carbon atoms of the cyclic amine, the cyclic amine of which is substituted with a group represented by - (CR<sup>1</sup>R<sup>2</sup>) m- (CHR<sup>3</sup>) nX, R<sup>4</sup> and R<sup>5</sup> independently on the same or different carbon atoms of the cyclic amine;
X is cyano, hydroxy, or -OR<sup>9</sup>;
Y is N or CR<sup>10</sup>;
R<sup>1</sup> is hydrogen, hydroxy, C alkyl<sub>1</sub>-C<sub>5</sub>, alkoxy (C<sub>1</sub>-C<sub>5</sub>) C alkyl<sub>1</sub>-C<sub>5</sub> or hydroxyalkyl C<sub>i</sub>-C<sub>5</sub>;
R<sup>2</sup> is hydrogen or C1-C5 alkyl;
R<sup>3</sup> is hydrogen, cyano, C alkyl<sub>1</sub>-C<sub>5</sub>, alkoxy (C<sub>1</sub>-C<sub>5</sub>) C alkyl<sub>1</sub>-C<sub>5</sub> or hydroxyalkyl C<sub>1</sub> -C<sub>5</sub>;
m is an integer selected from 0, 1, 2, 3, 4 and 5;
n is 0 or 1;
provided that when X is hydroxy or OR<sup>9</sup>, and n is 0, m is an integer selected from 1, 2, 3, 4 and 5;
R<sup>4</sup> is hydrogen, hydroxy, hydroxyalkyl C<sub>1</sub>-C<sub>5</sub>, cyano, cyanoalkyl C<sub>1</sub>-C<sub>5</sub> or C alkyl<sub>1</sub>-C<sub>5</sub>;
R<sup>5</sup> is hydrogen or C1-C5 alkyl;
R<sup>6</sup> is hydrogen, C alkyl<sub>1</sub>-C<sub>5</sub>, cycloalkyl C<sub>3</sub>-C<sub>8</sub>, cycloalkyl (C<sub>3</sub>-C<sub>8</sub>) C alkyl<sub>1</sub>-C<sub>5</sub>, hydroxy, C alkoxy<sub>1</sub>-C<sub>5</sub>, cycloalkyl (C3-C8) oxy or -N (R<sup>11</sup>) R<sup>12</sup>;
R<sup>7</sup> and R<sup>8</sup> are the same or different, and are independently hydrogen, halogen, C1-C5 alkyl, C3-C8 cycloalkyl, (C3-C8 cycloalkyl) C1-Cs alkyl, hydroxy, C1-C5 alkoxy, (C3-C8) cycloalkyl, -N (R<sup>11a</sup>) R<sup>12a</sup>, -CO2R<sup>13</sup>, cyano, nitro, (C1-C5) alkylthio, trifluoromethyl, or trifluoromethoxy; or R<sup>7</sup> and R<sup>8</sup> are taken together to form -CH2-CH<sub>2</sub>-CH<sub>2</sub>CH2- or -CH = CH-CH = CH-;
R<sup>9</sup> is C1 -C24 acyl, (C1-C10) alkoxy carbonyl, arylalkyl (C1-C5) oxycarbonyl, -CO-O-CHR<sup>14</sup>-O-CO-R<sup>15</sup>, -P (= O) (OR<sup>14 to</sup>OR<sup>15th</sup>, -CO- (CH2)<sub>p</sub>- (CHR<sup>16</sup>) q-NR<sup>17</sup>R<sup>18</sup>, arylcarbonyl or heteroarylcarbonyl, where each of said acyl, aryl and heteroaryl is unsubstituted or substituted with C1-C alkoxy<sub>5</sub>, and acyl C<sub>1</sub>-C<sub>2</sub>4 optionally includes one to six double bonds;
R<sup>10</sup> is hydrogen, C alkyl<sub>1</sub>-C<sub>5</sub>, halogen, cyano or-CO<sub>2</sub>R<sup>19</sup>;
Ar is aryl or heteroaryl whose aryl or heteroaryl is unsubstituted or is substituted with 1 or more substituents, which are the same or different, selected from the group consisting of halogen, C alkyl<sub>1</sub>-C<sub>5</sub>, cycloalkyl C<sub>3</sub>C<sub>8</sub>, alkenyl C<sub>2</sub> -C<sub>5</sub>, C alkynyl<sub>1</sub>-C<sub>5</sub>, C alkoxy<sub>1</sub>-C<sub>5</sub>, alkyl (C<sub>1</sub>-C<sub>5</sub>) thio, alkyl (C<sub>1</sub>-C<sub>5</sub>) sulfinyl, alkyl (C<sub>1</sub>-C<sub>5</sub>) sulfonyl, cyano, nitro, hydroxy, -CO<sub>2</sub>R<sup>19th</sup>, -C (= O) R<sup>19th</sup>, -CONR<sup>11b</sup>R<sup>12b</sup>, -OC (= O) R<sup>19th</sup>, -NR<sup>11b</sup>CO2R<sup>19th</sup>, -S (O) rNR<sup>11b</sup>R<sup>12b</sup>, hydroxyalkyl (C<sub>2</sub>-C<sub>5</sub>) aminoalkoxy C<sub>2</sub>-C<sub>5</sub>, trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoromethoxy, methylenedioxy, ethylenedioxy and -N (R<sup>20</sup>) R<sup>21</sup>;
ES 2 325 596 T3 with the proviso that when X is hydroxy, Y is N, and the cyclic amino group is a 5-membered ring, Ar is aryl or heteroaryl whose aryl or heteroaryl is substituted with at least one of the substituents that they are selected from halogen and trifluoromethyl;
provided that the compounds in which X is hydroxy; Y is N; the cyclic amino group is a 6-membered saturated cyclic amine; m is an integer selected from 1, 2 and 3; n is 0; R<sup>1</sup>, R<sup>2</sup>, R<sup>4</sup> and R<sup>5</sup> they are hydrogen; R<sup>6</sup> is methyl; R<sup>7</sup> and R<sup>8</sup> they are the same or different, and are independently hydrogen or methyl; Ar is phenyl whose phenyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of chlorine, bromine, C alkyl<sub>1</sub>-C<sub>3</sub>, C alkoxy<sub>1</sub>-C<sub>3</sub>, alkyl (C<sub>1</sub>-C<sub>3</sub>) thio, trifluoromethyl, trifluoromethoxy and dimethylamino; They are excluded;
R<sup>11</sup> and R<sup>12</sup> are the same or different, and are independently hydrogen, C alkyl<sub>1</sub> -C<sub>5</sub>, cycloalkyl C<sub>3</sub>-C<sub>8</sub> or cycloalkyl (C<sub>3</sub>-C<sub>8</sub>) C alkyl<sub>1</sub>-C<sub>5</sub>;
R<sup>11a</sup> and R<sup>12a</sup> are the same or different, and are independently hydrogen, C alkyl<sub>1</sub>-C<sub>5</sub>, cycloalkyl C<sub>3</sub>-C<sub>8</sub> or cycloalkyl (C<sub>3</sub>-C<sub>8</sub>) C alkyl<sub>1</sub>-C<sub>5</sub>;
R<sup>11b</sup> and R<sup>12b</sup> are the same or different, and are independently hydrogen, C alkyl<sub>1</sub>-C<sub>5</sub>, cycloalkyl C<sub>3</sub>-C<sub>8</sub> or cycloalkyl (C<sub>3</sub>-C<sub>8</sub>) C alkyl<sub>1</sub>-C<sub>5</sub>;
R<sup>13</sup> is hydrogen, C alkyl<sub>1</sub>-C<sub>5</sub>, cycloalkyl C<sub>3</sub>-C<sub>8</sub>, cycloalkyl (C<sub>3</sub>-C<sub>8</sub>) C alkyl<sub>1</sub>-C<sub>5</sub>, alkoxy (C<sub>1</sub>-C<sub>5</sub>) C alkyl<sub>1</sub>-C<sub>5</sub>, cycloalkyl (C<sub>3</sub>-C<sub>8</sub>) oxyalkyl C<sub>1</sub>-C<sub>5</sub> or phenyl;
R<sup>14</sup> and R<sup>15</sup> are the same or different, and are independently hydrogen, C alkyl<sub>1</sub> -C<sub>5</sub> or arylalkyl C<sub>1</sub>-C<sub>5</sub>;
R<sup>14 to</sup> and R<sup>15th</sup> are the same or different, and are independently hydrogen, C alkyl<sub>1</sub>-C<sub>5</sub> or arylalkyl C<sub>1</sub>-C<sub>5</sub>;
R<sup>16</sup> is hydrogen, C alkyl<sub>1</sub>-C<sub>5</sub>, aryl, heteroaryl, arylalkyl C<sub>1</sub>-C<sub>5</sub>, heteroarylalkyl C<sub>1</sub>-C<sub>5</sub>, hydroxyalkyl C<sub>1</sub>-C<sub>5</sub>, hydroxycarbonylalkyl C<sub>1</sub>-C<sub>5</sub>, hydroxyphenylalkyl C<sub>1</sub>-C<sub>5</sub>, alkoxy (C<sub>1</sub>-C<sub>5</sub>) C alkyl<sub>1</sub>-C<sub>5</sub>, C aminoalkyl<sub>1</sub>-C<sub>5</sub>, guanidinoalkyl C<sub>1</sub>-C<sub>5</sub>, C mercaptoalkyl<sub>1</sub>-C<sub>5</sub>, alkyl (C<sub>1</sub>-C<sub>5</sub>) thioalkyl C<sub>1</sub>-C<sub>5</sub> or aminocarbonylalkyl C<sub>1</sub>-C<sub>5</sub>;
R<sup>17</sup> and R<sup>18</sup> are the same or different, and are independently hydrogen, C alkyl<sub>1</sub>-C<sub>5</sub>, cycloalkyl C<sub>3</sub>-C<sub>8</sub>, cycloalkyl (C<sub>3</sub>-C<sub>8</sub>) C alkyl<sub>1</sub>-C<sub>5</sub>, acyl C<sub>1</sub>-C<sub>10</sub>, alkoxy (C<sub>1</sub>-C<sub>10</sub>) carbonyl or arylalkyl (C<sub>1</sub>-C<sub>5</sub>) oxycarbonyl; or
R<sup>16</sup> and R<sup>17</sup> are taken together to form -CH<sub>2</sub>-, -CH<sub>2</sub>CH<sub>2</sub>-, -CH<sub>2</sub>CH<sub>2</sub>CH<sub>2</sub>- or -CH<sub>2</sub>CH<sub>2</sub>CH<sub>2</sub>CH<sub>2</sub>-;
p is an integer selected from 0, 1, 2, 3, 4 and 5;
q is 0 or 1;
R<sup>19</sup> is hydrogen or C alkyl<sub>1</sub>-C<sub>5</sub>;
R<sup>19th</sup> is hydrogen or C alkyl<sub>1</sub>-C<sub>5</sub>;
r is 1 or 2;
R<sup>20</sup> and R<sup>21</sup> are the same or different, and are independently hydrogen or C-alkyl<sub>1</sub> -C<sub>5</sub>), one of its individual isomers, its racemic or non-racemic isomer mixtures or one of its N-oxides, or its pharmaceutically acceptable salts and hydrates.
The terms used herein have the following meanings.
The term "a 3- to 8-membered saturated cyclic amine" means aziridine, azetidine, pyrrolidine, piperidine, azepane, or azocane.
The term "C alkylene<sub>1</sub>-C<sub>5</sub>"Means a straight or branched chain alkylene of 1 to 5 carbon atoms, such as methylene, ethylene, propylene, trimethylene, tetramethylene, pentamethylene or the like.
The term "a saturated 3- to 8-membered cyclic amine" linked by C alkylene bridge<sub>1</sub> -C<sub>5</sub> or alkylene (C<sub>1</sub> C<sub>4</sub>) -O-alkylene C<sub>1</sub> -C<sub>4</sub> between any two different carbon atoms of the cyclic amine includes, for example, 8azabicyclo [3,2,1] oct-8-yl, 9-azabicyclo [3,3,1] non-9-yl, 7-azabicyclo [ 2,2.1] hept-7-yl, 3-oxa-7-azabicyclo [3.3.1] non7-yl and 3-oxa-9-azabicyclo [3.3.1] non-9-yl.
The term "C alkyl<sub>1</sub> -C<sub>5</sub>"Means a straight chain or branched chain alkyl group of 1 to 5 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, sec-butyl, pentyl, isopentyl or the like.
The term "C alkoxy<sub>1</sub> -C<sub>5</sub>"Means a straight chain or branched chain alkoxy group of 1 to 5 carbon atoms, such as methoxy, ethoxy, propoxy, isopropyloxy, butoxy, isobutyloxy, pentyloxy, isopentyloxy or the like.
ES 2 325 596 T3
The term "alkoxy (Ci -C<sub>5</sub>) C1-C5 alkyl "means a C alkyl group<sub>i</sub>-C<sub>5</sub> substituted having the C alkoxy group<sub>i</sub>C<sub>5</sub> aforementioned as a substituent, such as methoxymethyl, 2-methoxyethyl, 2-ethoxyethyl or the like.
The term "hydroxyalkyl C<sub>1</sub> -C<sub>5</sub>"Means a C alkyl group<sub>i</sub>-C<sub>5</sub> substituted having a hydroxy group, such as hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl or the like.
The term "cyanoalkyl C<sub>1</sub> -C<sub>5</sub>"Means a C alkyl group<sub>1</sub> -C<sub>5</sub> substituted having a cyano group, such as cyanomethyl, 1-cyanoethyl, 2-cyanoethyl, 3-cyanopropyl, 4-cyanobutyl, 5-cyanopentyl or the like.
The term "C cycloalkyl<sub>3</sub>-C<sub>8</sub>"Means a cyclic alkyl group of 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or the like.
The term "cycloalkyl (C<sub>3</sub>-C<sub>8</sub>) C alkyl<sub>i</sub>-C<sub>5</sub>"Means a C alkyl group<sub>i</sub>-C<sub>5</sub> substituted having cycloalkyl C<sub>3</sub>-C<sub>8</sub> aforementioned as a substituent, such as cyclopropylmethyl, cyclopropylethyl, cyclopentylethyl or the like.
The term "(C3-C8) cycloalkyl oxy" means a cyclic alkoxy group of 3 to 8 carbon atoms, such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or the like.
The term "halogen" means a fluorine, chlorine, bromine or iodine atom.
The term "cycloalkyl (C<sub>3</sub>-C<sub>8</sub>) oxyalkyl C<sub>1</sub>-C<sub>5</sub> "Means a C alkyl group<sub>1</sub>-C<sub>5</sub> substituted having the above-mentioned (C3-C8) cycloalkyl oxy as a substituent, such as cyclopropyloxymethyl, 2-cyclopropyloxyethyl or the like.
The term "alkyl (C<sub>1</sub>-C<sub>5</sub>) thio "means a straight chain or branched chain alkylthio group of 1 to 5 carbon atoms, such as methylthio, ethylthio, propylthio or the like.
The term "acyl C<sub>1</sub>-C<sub>24</sub>"Means a saturated or unsaturated, straight chain or branched chain acyl group of 1 to 24 carbon atoms, such as acetyl, propionyl, butyryl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, isobutyryl, 2,2- dimethylpropionyl, octadeca-9,12-dienoyl, eicosa-5,8,11,14-tetraenoyl, docosa4,7,10,13,16,19-hexaenoyl, eicosa-5,8,11,14,17-pentaenoyl or Similar.
The term "alkoxy (C<sub>1</sub>-C<sub>10</sub>) carbonyl "means a straight chain or branched chain alkoxycarbonyl group of 2 to 11 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, heptyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, or the like decyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, or the like .
The term "aryl" means a monocyclic or bicyclic group of 6 to 12 ring carbon atoms having at least one aromatic ring, such as phenyl, naphthyl or the like.
The term "arylalkyl (C<sub>1</sub>-C<sub>5</sub>) oxycarbonyl "means a (C<sub>1</sub>-C<sub>5</sub>) substituted oxycarbonyl having the aforementioned aryl as a substituent, such as benzyloxycarbonyl, phenethyloxycarbonyl or the like.
The term "arylcarbonyl" means a substituted carbonyl group having the aforementioned aryl as a substituent, such as benzoyl, naphthalene-1-carbonyl, naphthalene-2-carbonyl or the like.
The term "heteroaryl" means a monocyclic or bicyclic group of 5 to 12 ring atoms that has at least one aromatic ring that has in its ring of 1 to 4 atoms that can be the same or different and are selected from nitrogen, oxygen and sulfur, such as pyridyl, pyrimidinyl, imidazolyl, quinolyl, indolyl, benzofuranyl, quinoxalinyl, benzo [1,2,5] thiadiazolyl, benzo [1,2,5] oxadiazolyl or the like.
The term "heteroarylcarbonyl" means a substituted carbonyl group having the aforementioned heteroaryl as a substituent, such as pyridine-2-carbonyl, pyridine-3-carbonyl, pyridine-4-carbonyl, pyrimidine-2-carbonyl, pyrimidine-4-carbonyl, pyrimidine -5-carbonyl or the like.
The term "C alkenyl<sub>2</sub>-C<sub>5</sub>"Means a straight chain or branched chain alkenyl group of 2 to 5 carbon atoms, such as vinyl, isopropenyl, allyl or the like.
The term "C alkynyl<sub>2</sub>-C<sub>5</sub>"Means a straight chain or branched chain alkynyl group of 2 to 5 carbon atoms, such as ethynyl, prop-1-ynyl, prop-2-ynyl or the like.
The term "alkyl (C<sub>1</sub>-C<sub>5</sub>) sulfinyl "means a straight chain or branched chain alkylsulfinyl group of 1 to 5 carbon atoms, such as methanesulfinyl, ethanesulfinyl or the like.
The term "alkyl (C<sub>1</sub>-C<sub>5</sub>) sulfonyl "means a straight chain or branched chain alkylsulfonyl group of 1 to 5 carbon atoms, such as methanesulfonyl, ethanesulfonyl or the like.
ES 2 325 596 T3
The term "hydroxyalkyl (C2-C<sub>5</sub>) aminoalkoxy C<sub>2</sub>-C<sub>5</sub>"Means a C alkoxy group<sub>2</sub>-C<sub>5</sub> substituted having a hydroxyalkyl group (C<sub>2</sub>-C<sub>5</sub>) amino as a substituent such as 2- (2-hydroxyethylamino) ethoxy or the like.
The term "arylalkyl C<sub>1</sub>-C<sub>5</sub>"Means a C alkyl group<sub>1</sub>-C<sub>5</sub> substituted having the aforementioned aryl as a substituent, such as benzyl, phenethyl, 3-phenylpropyl, naphthalen-1-ylmethyl, naphthalen-2-ylmethyl or the like.
The term "heteroarylalkyl C<sub>1</sub>-C<sub>5</sub>"Means a C alkyl group<sub>1</sub>-C<sub>5</sub> substituted having the aforementioned heteroaryl as a substituent, such as 1H-indol-3-ylmethyl, 1H-imidazol-4-ylmethyl or the like.
The term "hydroxycarbonylalkyl C<sub>1</sub>-C<sub>5</sub>"Means a C alkyl group<sub>1</sub>-C<sub>5</sub> substituted having a hydroxycarbonyl group as a substituent, such as hydroxycarbonylmethyl, 2-hydroxycarbonylethyl, 3-hydroxycarbonylpropyl, 4-hydroxycarbonylbutyl, or the like.
The term "hydroxyphenylalkyl C<sub>1</sub>-C<sub>5</sub>"Means a C alkyl group<sub>1</sub>-C<sub>5</sub> substituted having a hydroxyphenyl group as a substituent, such as 4-hydroxybenzyl, 3-hydroxybenzyl, 2-hydroxybenzyl, 2- (4-hydroxyphenyl) ethyl or the like.
The term "C aminoalkyl<sub>1</sub>-C<sub>5</sub>"Means a C alkyl group<sub>1</sub> -C<sub>5</sub> substituted having an amino group as a substituent, such as aminomethyl, 1-aminoethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl or the like.
The term "C-guanidinoalkyl<sub>1</sub> -C<sub>5</sub>"Means a C alkyl group<sub>1</sub> -C<sub>5</sub> substituted having a guanidino group as a substituent, such as guanidinomethyl, 1-guanidinoethyl, 2-guanidinoethyl, 3-guanidinopropyl, 4-guanidinobutyl, 5-guanidinopentyl or the like.
The term "C mercaptoalkyl<sub>1</sub>-C<sub>5</sub>"Means a C alkyl group<sub>1</sub>-C<sub>5</sub> substituted having a mercapto group as a substituent, such as mercaptomethyl, 1-mercaptoethyl, 2-mercaptoethyl, 3-mercaptopropyl, 4-mercaptobutyl, 5-mercaptopentyl or the like.
The term "alkyl (C<sub>1</sub>-C<sub>5</sub>) thioalkyl C<sub>1</sub> -C<sub>5</sub>"Means a C alkyl group<sub>1</sub>-C<sub>5</sub> substituted having the alkyl group (C<sub>1</sub>-C<sub>5</sub>) above-mentioned thio as a substituent, such as methylthiomethyl, 1-methylthioethyl, 2-methylthioethyl, 3-methylthiopropyl, 4-methylthiobutyl, 5-methylthiopentyl or the like.
The term "aminocarbonylalkyl C<sub>1</sub>-C<sub>5</sub>"Means a C alkyl group<sub>1</sub>-C<sub>5</sub> substituted having an aminocarbonyl group as a substituent, such as aminocarbonylmethyl, 2-aminocarbonylethyl, 3-aminocarbonylpropyl, 4-aminocarbonylbutyl or the like.
The phrase "aryl or heteroaryl" whose aryl or heteroaryl is unsubstituted or is substituted with 1 or more substituents, which are the same or different, selected from the group consisting of halogen, C-alkyl<sub>1</sub>-C<sub>5</sub>, cycloalkyl C<sub>3</sub>-C<sub>8</sub>, alkenyl C<sub>2</sub>-C<sub>5</sub>, C alkynyl<sub>2</sub>-C<sub>5</sub>, C alkoxy<sub>1</sub>-C<sub>5</sub>, alkyl (C<sub>1</sub>-C<sub>5</sub>) thio, alkyl (C<sub>1</sub>-C<sub>5</sub>) sulfinyl, alkyl (C<sub>1</sub>-C<sub>5</sub>) sulfonyl, cyano, nitro, hydroxy, -CO<sub>2</sub>R<sup>19th</sup>, -C (= O) R<sup>19th</sup>, -CONR<sup>11b</sup>R<sup>12b</sup>, -OC (= O) R<sup>19th</sup>, -NR<sup>11b</sup>CO2R<sup>19th</sup>, -S (O) rNR<sup>11b</sup>R<sup>12b</sup>, hydroxyalkyl (C<sub>2</sub>-C<sub>5</sub>) aminoalkoxy C<sub>2</sub>-C<sub>5</sub>, trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoromethoxy, methylenedioxy, ethylenedioxy and -N (R<sup>20</sup>) R<sup>21</sup>"Includes, for example, 2,4-dimethylphenyl, 2,6-dimethylphenyl, 2,4-dibromophenyl, 2-bromo-4-isopropylphenyl, 2,4-dichlorophenyl, 2,6-dichlorophenyl, 2-chloro-4- trifluoromethylphenyl, 4-methoxy-2-methylphenyl, 2-chloro-4-trifluoromethoxyphenyl, 4-isopropyl-2-methylthio-phenyl, 2,4,6-trimethylphenyl, 4-bromo-2,6-dimethylphenyl, 4-bromo- 2,6-diethylphenyl, 4-chloro-2,6-dimethylphenyl, 2,4,6-tribromophenyl, 2,4,5-tribromophenyl, 2,4,6-trichlorophenyl, 2,4,5-trichlorophenyl, 4-bromo- 2,6-dichlorophenyl, 6-chloro-2,4-dibromophenyl, 2,4-dibromo-6-fluorophenyl, 2,4-dibromo-6-methylphenyl, 2,4-dibromo-6-methoxyphenyl, 2,4-dibromo-6-methylthiophenyl, 2,6-dibromo-4-isopropylphenyl, 2,6-dibromo-4-trifluoromethylphenyl, 2-bromo-4-trifluoromethylphenyl, 4-bromo-2-chlorophenyl, 2-bromo-4-chlorophenyl, 4-bromo-2- methylphenyl, 4-chloro2-methylphenyl, 2,4-dimethoxyphenyl, 2,6-dimethyl-4-methoxyphenyl, 4-chloro-2,6-dibromophenyl, 4-bromo-2,6-difluorophenyl,
2.6- dichloro-4-trifluoromethylphenyl, 2,6-dichloro-4-trifluoromethoxyphenyl, 2,6-dibromo-4-trifluoro-methoxyphenyl, 2-chloro-
4.6- dimethylphenyl, 2-bromo-4,6-dimethoxyphenyl, 2-bromo-4-isopropyl-6-methoxyphenyl, 2,4-dimethoxy-6-methylphenyl, 2,6-dimethyl-4- [2- (2-hydroxyethyl- amino) ethoxy] phenyl, 6-dimethylamino-4-methylpyridin-3-yl, 2-chloro-6-trifluoromethylpyridin-3-yl, 2-chloro-6-trifluoromethoxypyridin-3-yl, 2-chloro-6-methoxypyridin-3- yl, 6-methoxy-2-trifluoromethylpyridin-3-yl, 2-chloro-6-difluoromethylpyridin-3-yl, 6-methoxy-2-methylpyridin-3-yl, 2,6-dimethoxypyridin-3-yl, 4, 6-dimethyl-2-trifluoro-methylpyrimidin-5-yl, 2-dimethylamino-6-methylpyridin-3-yl, 6-dimethylamino-2-methylpyridin-3-yl, 2,3-dihydro-benzo [1,4] dioxin-5-yl and benzo [1,3] dioxol- 4-yl, 5,7-dimethylbenzo [1,2,5] thiadiazol-4-yl, 5,7-dimethylbenzo- [1,2,5] oxadiazol-4-yl, 2-isopropoxy-6-trifluoromethyl-pyridin-3 -yl, 2-methoxy-6-methylpyridin-3-yl, 2,6-dimethylpyridin-3-yl, 2-bromo-6-methoxypyridin-3-yl, 2-chloro-6-dimethylaminopyridin-3-yl, 2 , 6-dichloropyridin-3-yl, 2,4-dimethyl-6-dimethylaminopyridin-3-yl,
2.4.6- trimethylpyridin-3-yl, 2,4,6-trimethylpyrimidin-5-yl, 4,6-dimethyl-2-dimethylaminopyrimidin-5-yl, 5-iodo-3-methylpyridin-2-yl, 3- methyl-5-methylaminopyridin-2-yl, 3-dimethylamino-5-methylpyridin-2-yl, 5-methyl-3-methylamino-pyridin-2-yl, 3-chloro-5-methylpyridin-2-yl, 3-amino- 5-methylpyridin-2-yl, 5-methyl-3-nitropyridin-2-yl, 5-diethylamino-3-methylpyridin-2-yl, 5-fluoro-3-methyl-pyridin-2-yl, 5-chloro- 3-methylpyridin-2-yl, 5-dimethylamino-3-methylpyridin-2-yl, 5-amino-3methyl-pyridin-2-yl, 3-methyl-5-nitropyridin-2-yl, 3-bromo-5-methylpyridin-2-yl, 4-chloro-2,5-dimethoxyphenyl, 4,5-dimethyl-2-methoxyphenyl, 5-fluoro-2, 4-dimethylphenyl, 2,4-dimethoxy-5-methylphenyl, 2-chloro-4-methoxy-5-methyl-phenyl, 2-chloro-5-fluoro-4-methylphenyl, 2-bromo-4,5-dimethoxy-phenyl, 2-bromo-5-fluoro-4-methoxyphenyl, 2-chloro-4,5-dimethoxyphenyl,
2.5- dichloro-4-methoxyphenyl, 2,4-dichloro-5-fluorophenyl, 2-chloro-5-fluoro-4-methoxyphenyl, 2,4,5-trichlorophenyl, 2-chloro5-fluoro-4-methylphenyl, 5- fluoro-4-methoxy-2-methylphenyl, 4,5-dimethoxy-2-methylphenyl, 5-chloro-4-methoxy-2-methylphenyl,
2.4.5- trimethylphenyl, 6-methoxy-4-methylpyridin-3-yl, 4-methoxy-6-methylpyridin-3-yl, 4,6-dimethylpyridin-3-yl, 2-chloro
ES 2 325 596 T3
4-isopropyl-phenyl, 2-chloro-4-methylphenyl, 4-amino-2-chlorophenyl, 2-chloro-4-dimethylcarbamoylphenyl, 2-chloro-4-methylcarbamoylphenyl, 4-carbamoyl-2-chlorophenyl, 2-chloro- 4-methylsulfonylphenyl, 4-carboxy-2-chlorophenyl, 2-chloro-4-iodophenyl, 2-bromo-4-methylthiophenyl, 2-bromo-4-methylsulfinylphenyl, 2-bromo-4-dimethylaminophenyl, 2-bromo-4- methylsulfonylphenyl, 2-bromo-4-cyclopentylphenyl, 2-bromo-4-tert-butylphenyl, 2-bromo-4-propylphenyl, 2-bromo-4-methylphenyl, 2-bromo-4-trifluoromethoxyphenyl, 2-bromo-4-methoxyphenyl, 2-bromo-4-ethoxyphenyl, 4-isopropyl-2-methylsulfonylphenyl, 4-cyclopentyl-2-methylthiophenyl, 4-butyl-2-methylthiophenyl, 4-methoxy-2-methylthiophenyl, 2- methylthio-4-propylphenyl, 2-dimethylamino-4-isopropyl-phenyl, 2-iodo-4-isopropylphenyl, 2-fluoro-4-methylphenyl, 2,4-difluorophenyl, 2-chloro-4-methoxyphenyl, 2-chloro- 4-hydroxyphenyl, 4-cyano-2-methoxyphenyl, 4-bromo-2-methoxyphenyl, 2-methoxy-4-methylphenyl, 4-chloro-2-methoxyphenyl, 2-hydroxy-4-methylphenyl, 4-fluoro-2- methoxyphenyl, 2-hydroxy-4-methylphenyl, 4-cyano-2-methoxyphenyl, 2-chloro-4-methylthiophenyl, 2-methoxy-4-trifluoromethylphenyl, 4-isopropyl-2-methoxyphenyl, 2-chloro-4-cyanophenyl, 2- chloro-4-ethoxycarbonylphenyl, 2-chloro-4-methylaminophenyl, 4-cyano-2-trifluoromethylphenyl, 4-cyano-2-methylphenyl, 2-methyl-4-trifluoromethoxyphenyl, 2-cyano-4-trifluoromethylphenyl, 4-carboxyamino- 2-trifluoromethylphenyl, 4-methoxy-2-trifluoromethylphenyl, 4-fluoro-2-methylphenyl, 4-hydroxy-2-methylphenyl, 4-methoxy-2-methoxycarbonylphenyl, 2-ethyl-4-methoxyphenyl, 2-formyl4-methoxyphenyl, 4-chloro-2-trifluoromethylphenyl, 4-dimethylamino-2-trifluoromethylphenyl, 4-difluoromethoxy-2-methylphenyl, 2-cyano-4-methoxyphenyl, 4-hydroxy- 2-trifluoromethylphenyl, 4-isopropyl-2-trifluoromethylphenyl, 4-diethylamino-2-methylphenyl, 4-fluoro-2-trifluoromethyl-phenyl, 4-propoxy-2-trifluoromethylphenyl, 4-dimethylamino-2-methylthiophenyl, 4-isopropyl- 2-isopropylthiophenyl, 2-ethylthio-4-isopropylphenyl, 4-methylamino-2-methylthiophenyl, 2-methylthio-4-propionylphenyl, 4-acetyl-2-methylthiophenyl, 4-cyano-2-methylthiophenyl, 4-methoxy-2-methylthiophenyl, 4-ethyl-2-methylthiophenyl, 4-bromo-2-methylthiophenyl, 4-isopropyl-2-methylsulfinylphenyl, 2,4- dimethylthiophenyl, 4,6-dimethyl-2-isopropylphenyl, 4,6-dimethyl-2-isopropenyl-phenyl, 2-acetyl-4,6-dimethylphenyl, 2,6-dimethyl-4-trifluoromethylphenyl, 2,6-dimethyl- 4-isopropenylphenyl, 4-ac ethyl-2,6-dimethylphenyl, 2,4,6-triethylphenyl, 4,6-dimethyl-2-methylthiophenyl, 4,6-dimethyl-2-iodophenyl, 2-fluoromethoxy-4,6 -dimethylphenyl, 4,6-dimethyl-2-isopropoxy-phenyl, 4,6-dimethyl-2-ethoxyphenyl, 2,6-dichloro-4-ethoxyphenyl, 2-bromo-4,6-dimethoxyphenyl, 2-bromo6-hydroxy-4- methoxyphenyl, 2,6-dibromo-4-ethoxyphenyl, 4-bromo-2-methoxy-6-methylphenyl, 2,6-dibromo-4-methoxyphenyl,
4,6-dibromo-2-trifluoromethoxyphenyl, 2,4-dibromo-6-trifluoromethylphenyl, 4-bromo-2-chloro-6-methylphenyl, 4-chloro-2,6-dimethoxyphenyl, 2,4-dichloro-6-methoxyphenyl, 4,6-dichloro-2-methylthiophenyl, 4,6-dichloro-2-trifluoromethylphenyl, 2,6-dimethoxy-4-ethylphenyl, 4,6-dimethyl-2-methoxyphenyl, 2,6-dimethoxy-4- methylphenyl, 2-chloro-6-methoxy-4-methylphenyl, 4,6-dimethyl-2-ethoxyphenyl, 6-hydroxy-2,4-dimethylphenyl, 4-cyano-2-methoxy-6-methyl-phenyl, 6-fluoro- 2-methoxy-4-methylphenyl, 4-acetyl-2-methoxy-6-methylphenyl, 2-chloro-4,6-dimethoxyphenyl, 2,6-dimethoxy-4-ethoxyphenyl, 2,4,6-trimethoxyphenyl, 4,6-dibromo-2-trifluoromethoxyphenyl, 2-bromo-4-dimethylamino-6-methoxyphenyl, 4- bromo-2-methoxy-6-methylphenyl, 4,6-dimethoxy-2-propoxyphenyl, 4,6-dichloro-2-propoxyphenyl, 2-bromo-6-hydroxy-4-methoxyphenyl, 2,4,6-trifluorophenyl, 2-bromo-6-fluoro-4-methylphenyl, 4-difluoromethoxy-2,6-dimethylphenyl, 2,6-dimethyl-4-ethoxyphenyl, 2,6-dimethyl-4-isopropoxyphenyl, 2,6-dimethyl-4-methylthiophenyl, 2, 6-dimethyl-4-methylsulfonylphenyl, 2,6-dimethyl-4-methyl-sulfinylphenyl, 2,3-dichlorophenyl, 4-methoxy-2,3-dimethylphenyl, 2-chloro-3-fluoro-4-methoxyphenyl, 2,3,4-trichlorophenyl and 4-methoxy 2,5-dimethylphenyl.
The "pharmaceutically acceptable salts" in the present invention include, for example, salts with an inorganic acid such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid or the like; salts with an organic acid such as acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, citric acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzoic acid, camphorsulfonic acid, ethanesulfonic acid, glucoheptonic acid , gluconic acid, glutamic acid, glycolic acid, malic acid, malonic acid, mandelic acid, galactaric acid, naphthalene-2-sulfonic acid or the like; salts with one or more metal ions such as lithium ion, sodium ion, potassium ion, calcium ion, magnesium ion, zinc ion, aluminum ion, or the like; salts with amines such as ammonia, arginine, lysine, piperazine, choline, diethylamine, 4-phenylcyclohexylamine, 2-aminoethanol, benzathine or the like.
A compound of the present invention includes any isomers such as diastereomers, enantiomers, geometric isomers, and tautomeric forms. In a compound represented by formula [I], if the cyclic amino group has one or more chiral carbons and / or if there is axial chirality between Ar and the pyrrolopyrimidine (or pyrrolopyridine) ring, there may be several stereoisomers (diastereomers or enantiomers). The compound of the present invention includes the individual isomers and racemic and non-racemic mixtures of the isomers.
Preferable examples of the compound of the present invention are as follows.
That is, the compounds represented by the following formula [III] are preferable
<img file="ES2325596T3_D0003.tif" />
ES 2 325 596 T3 (where the cyclic amino group is represented by the following formula [IV]:
NC- (CHR<sup>3</sup>) - (CR<sup>1</sup>
[IV] wherein the cyclic amino group is a 3- to 8-membered saturated cyclic amine or a 3- to 8-membered saturated cyclic amine linked by C alkylene bridge<sub>1</sub> -C<sub>5</sub> or alkylene ^ -C<sub>4</sub>) -O-Ci -C alkylene<sub>4</sub> between any two different carbon atoms of the cyclic amine, the cyclic amine of which is substituted with a group represented by - (CR<sup>1</sup>R<sup>2</sup>) m- (CHR<sup>3</sup>) n-CN, R<sup>4</sup> and R<sup>5</sup> independently on the same or different carbon atoms of the cyclic amine;
Y is N or CR<sup>10</sup>;
R<sup>1</sup> is hydrogen, hydroxy, C alkyl<sub>1</sub>-C<sub>5</sub>, alkoxy (C<sub>1</sub>-C<sub>5</sub>) C alkyl<sub>1</sub>-C<sub>5</sub> or hydroxyalkyl C<sub>1</sub> -C<sub>5</sub>;
R<sup>2</sup> is hydrogen or Ci-C5 alkyl;
R<sup>3</sup> is hydrogen, cyano, C alkyl<sub>1</sub>-C<sub>5</sub>, alkoxy (C<sub>1</sub>-C<sub>5</sub>) C alkyl<sub>1</sub>-C<sub>5</sub> or hydroxyalkyl C<sub>1</sub> -C<sub>5</sub>;
m is an integer selected from 0, 1, 2, 3, 4 and 5;
n is 0 or 1;
R<sup>4</sup> is hydrogen, hydroxy, hydroxyalkyl C<sub>1</sub>-C<sub>5</sub>, cyano, cyanoalkyl C<sub>1</sub>-C<sub>5</sub> or C alkyl<sub>1</sub>-C<sub>5</sub>;
R<sup>5</sup> is hydrogen or C1-C5 alkyl;
R<sup>6</sup> is hydrogen, C alkyl<sub>1</sub>-C<sub>5</sub>, cycloalkyl C<sub>3</sub>-C<sub>8</sub>, cycloalkyl (C<sub>3</sub>-C<sub>8</sub>) C alkyl<sub>1</sub>-C<sub>5</sub>, hydroxy, C alkoxy<sub>1</sub>-C<sub>5</sub>, cycloalkyl (C3-C<sub>8</sub>) oxy or -N (R<sup>11</sup>) R<sup>12</sup>;
R<sup>7</sup> and R<sup>8</sup> are the same or different, and are independently hydrogen, halogen, C1-C5 alkyl, C3-C8 cycloalkyl, (C3-C8 cycloalkyl) -C1-C5 alkyl, hydroxy, C1-C5 alkoxy, (C3-C8) cycloalkyl oxy, -N ( R<sup>11a</sup>) R<sup>12a</sup>, -CO2R<sup>13</sup>, cyano, nitro, (C1-C5) alkylthio, trifluoromethyl, or trifluoromethoxy; or R<sup>7</sup> and R<sup>8</sup> are taken together to form -CH2-CH<sub>2</sub>-CH<sub>2</sub>CH2- or -CH = CH-CH = CH-;
R<sup>10</sup> is hydrogen, C alkyl<sub>1</sub>-C<sub>5</sub>, halogen, cyano or-CO<sub>2</sub>R<sup>19</sup>;
Ar is aryl or heteroaryl whose aryl or heteroaryl is unsubstituted or is substituted with 1 or more substituents, which are the same or different, selected from the group consisting of halogen, C alkyl<sub>1</sub>-C<sub>5</sub>, cycloalkyl C<sub>3</sub>C<sub>8</sub>, alkenyl C<sub>2</sub> -C<sub>5</sub>, C alkynyl<sub>2</sub>-C<sub>5</sub>, C alkoxy<sub>1</sub> -C<sub>5</sub>, alkyl (C<sub>1</sub>-C<sub>5</sub>) thio, alkyl (C<sub>1</sub> -C<sub>5</sub>) sulfinyl, alkyl (C<sub>1</sub>-C<sub>5</sub>) sulfonyl, cyano, nitro, hydroxy, -CO<sub>2</sub>R<sup>19th</sup>, -C (= O) R<sup>19th</sup>, -CONR<sup>11b</sup>R<sup>12b</sup>, -OC (= O) R<sup>19th</sup>, -NR<sup>11b</sup>CO2R<sup>19th</sup>, -S (O) rNR<sup>11b</sup>R<sup>12b</sup>, hydroxyalkyl (C<sub>2</sub>-C<sub>5</sub>) aminoalkoxy C<sub>2</sub>-C<sub>5</sub>, trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoromethoxy, methylenedioxy, ethylenedioxy and -N (R<sup>20</sup>) R<sup>21</sup> ;
R<sup>11</sup> and R<sup>12</sup> are the same or different, and are independently hydrogen, C alkyl<sub>1</sub> -C<sub>5</sub>, cycloalkyl C<sub>3</sub>-C<sub>8</sub> or cycloalkyl (C<sub>3</sub>-C<sub>8</sub>) C alkyl<sub>1</sub>-C<sub>5</sub>;
R<sup>11a</sup> and R<sup>12a</sup> are the same or different, and are independently hydrogen, C alkyl<sub>1</sub>-C<sub>5</sub>, cycloalkyl C<sub>3</sub>-C<sub>8</sub> or cycloalkyl (C<sub>3</sub>-C<sub>8</sub>) C alkyl<sub>1</sub>-C<sub>5</sub>;
R<sup>11b</sup> and R<sup>12b</sup> are the same or different, and are independently hydrogen, C alkyl<sub>1</sub>-C<sub>5</sub>, cycloalkyl C<sub>3</sub>-C<sub>8</sub> or cycloalkyl (C<sub>3</sub>-C<sub>8</sub>) C alkyl<sub>1</sub>-C<sub>5</sub>;
R<sup>13</sup> is hydrogen, C alkyl<sub>1</sub>-C<sub>5</sub>, cycloalkyl C<sub>3</sub>-C<sub>8</sub>, cycloalkyl (C<sub>3</sub>-C<sub>8</sub>) C alkyl<sub>1</sub>-C<sub>5</sub>, alkoxy (C<sub>1</sub>-C<sub>5</sub>) C alkyl<sub>1</sub>-C<sub>5</sub>, cycloalkyl (C<sub>3</sub>-C<sub>8</sub>) oxyalkyl C<sub>1</sub>-C<sub>5</sub> or phenyl;
R<sup>19</sup> is hydrogen or C alkyl<sub>1</sub>-C<sub>5</sub>;
R<sup>19th</sup> is hydrogen or C alkyl<sub>1</sub>-C<sub>5</sub>;
r is 1 or 2;
r<sup>20</sup> yr<sup>21</sup> are the same or different, and are independently hydrogen or C-alkyl<sub>1</sub>-C<sub>5</sub>). More preferable are compounds represented by formula [III] in which Y is N. More preferable are compounds represented by formula [III] in which Y is N; n is 0; R<sup>1</sup>, R<sup>2</sup>, R<sup>4</sup> and R<sup>5</sup> they are hydrogen. More preferable are compounds represented by formula [III] wherein Y is N; the cyclic amino group is an amine
ES 2 325 596 T3 4-7 membered saturated cyclic; m is an integer selected from 0, 1, 2, and 3; n is 0; R<sup>1</sup>, R<sup>2</sup>, R<sup>4</sup> and R<sup>5</sup> they are hydrogen; R<sup>6</sup> is methyl; R<sup>7</sup> and R<sup>8</sup> are the same or different, and are independently hydrogen or C1-C5 alkyl; Ar is phenyl or pyridyl whose phenyl or pyridyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3) alkylthio, trifluoromethyl , trifluoromethoxy and -N (R<sup>20</sup>) R<sup>21</sup> (where R<sup>20</sup> and R<sup>21</sup> are the same or different, and are independently hydrogen or C1-C alkyl<sub>3</sub>). More preferable are compounds represented by formula [III] wherein where Y is N; the cyclic amino group is a 6-membered saturated cyclic amine; m is 0 or 1; n is 0; R<sup>1</sup>, R<sup>2</sup>, R<sup>4</sup> and R<sup>5 </sup>they are hydrogen; R<sup>6</sup> is methyl; R<sup>7</sup> and R<sup>8</sup> they are the same or different, and are independently hydrogen or methyl; Ar is phenyl whose phenyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of chlorine, bromine, C alkyl<sub>1</sub>-C<sub>3</sub>, C alkoxy<sub>1</sub>-C<sub>3</sub>, alkyl (C<sub>1</sub> -C<sub>3</sub>) thio, trifluoromethyl, trifluoromethoxy and dimethylamino.
Other preferable ones are the compounds represented by the formula [III] wherein Y is CR<sup>10,</sup> More preferable are compounds represented by formula [III] wherein Y is CR<sup>10</sup>; n is 0; R<sup>1</sup>, R<sup>2</sup>, R<sup>4</sup> and R<sup>5</sup> they are hydrogen; R<sup>10</sup> it is hydrogen or halogen. More preferable are compounds represented by formula [III] wherein Y is CR<sup>10</sup>; the cyclic amino group is a 4- to 7-membered saturated cyclic amine; m is an integer selected from 0, 1.2 and 3; n is 0; R<sup>1</sup>, R<sup>2</sup>, R<sup>4</sup> and R<sup>5</sup> they are hydrogen; R<sup>6</sup> is methyl; R<sup>7</sup> and R<sup>8</sup> are the same or different, and are independently hydrogen or C1-C5 alkyl; R<sup>10</sup> is hydrogen or halogen; Ar is phenyl or pyridyl whose phenyl or pyridyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of halogen, C1-C alkyl<sub>3</sub>, C alkoxy<sub>1</sub> -C<sub>3</sub>, alkyl (C<sub>1</sub>-C<sub>3</sub>) thio, trifluoromethyl, trifluoromethoxy and -N (R<sup>20</sup>) R<sup>21</sup> (where R<sup>20</sup> and R<sup>21</sup> they are the same or different, and are independently hydrogen or C1-C3 alkyl. More preferable are compounds represented by formula [III] wherein Y is CR<sup>10</sup>; the cyclic amino group is a 6-membered saturated cyclic amine; m is 0 or 1; n is 0; R<sup>1</sup>, R<sup>2</sup>, R<sup>4</sup> and R<sup>5</sup> they are hydrogen; R<sup>6</sup> is methyl; R<sup>7</sup> and R<sup>8</sup> they are the same or different, and are independently hydrogen or methyl; R<sup>10</sup> is hydrogen; Ar is phenyl whose phenyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of chlorine, bromine, C1-C alkyl<sub>3</sub>, C alkoxy<sub>1</sub>-C<sub>3</sub>, alkyl (C<sub>1</sub>C3) thio, trifluoromethyl, trifluoromethoxy, and dimethylamino.
Other preferable ones are the compounds represented by the following formula [V]:
<img file="ES2325596T3_D0004.tif" />
(where the cyclic amino group is represented by the following formula [VI]:
<img file="ES2325596T3_D0005.tif" />
wherein the cyclic amino group is a 3- to 8-membered saturated cyclic amine or a 3- to 8-membered saturated cyclic amine bridged by alkylene C<sub>1</sub>-C<sub>5</sub> or C alkylene<sub>1</sub>-C<sub>5</sub>-O-alkylene C<sub>1</sub>-C<sub>4</sub> between any two different carbon atoms of the cyclic amine, the cyclic amine of which is substituted with a group represented by - (CR<sup>1</sup> R<sup>2</sup>) m- (CHR<sup>3</sup>) n-OH, R<sup>4</sup> and R<sup>5</sup> independently on the same or different carbon atoms of the cyclic amine;
Y is N or CR<sup>10</sup>;
R<sup>1</sup> is hydrogen, hydroxy, C alkyl<sub>1</sub>-C<sub>5</sub>, alkoxy (C<sub>1</sub>-C<sub>5</sub>) C alkyl<sub>1</sub>-C<sub>5</sub> or hydroxyalkyl C<sub>1</sub>-C<sub>5</sub>;
R<sup>2</sup> is hydrogen or C1-C5 alkyl;
R<sup>3</sup> is hydrogen, cyano, C alkyl<sub>1</sub>-C<sub>5</sub>, alkoxy (C<sub>1</sub>-C<sub>5</sub>) C alkyl<sub>1</sub>-C<sub>5</sub> or hydroxyalkyl C<sub>1</sub> -C<sub>5</sub>;
m is an integer selected from 0, 1, 2, 3, 4 and 5;
n is 0 or 1;
ES 2 325 596 T3 with the proviso that when n is 0, m is an integer selected from 1, 2, 3, 4 and 5;
R<sup>4</sup> is hydrogen, hydroxy, C 1 -C 5 hydroxyalkyl, cyano, C cyanoalkyl<sub>1</sub>-C<sub>5</sub> or C alkyl<sub>1</sub>-C<sub>5</sub>;
R<sup>5</sup> is hydrogen or C alkyl<sub>1</sub>-C<sub>5</sub>;
R<sup>6</sup> is hydrogen, C alkyl<sub>1</sub>-C<sub>5</sub>, cycloalkyl C<sub>3</sub>-C<sub>8</sub>, cycloalkyl (C<sub>3</sub>-C<sub>8</sub>) C alkyl<sub>1</sub>-C<sub>5</sub>, hydroxy, C alkoxy<sub>1</sub>-C<sub>5</sub>, cycloalkyl (C<sub>3</sub>-C<sub>8</sub>) oxy or -N (R<sup>11</sup>) R<sup>12</sup>;
R<sup>7</sup> and R<sup>8</sup> are the same or different, and are independently hydrogen, halogen, C1-C5 alkyl, (C3C8) cycloalkyl or; (C3-C8) cycloalkyl C1-C5 alkyl, hydroxy, C1-C5 alkoxy, (C3-C8) cycloalkyl oxy, -N (R<sup>11a</sup>) R<sup>12a</sup>, -CO2R<sup>13</sup>, cyano, nitro, (C1-C5) alkylthio, trifluoromethyl, or trifluoromethoxy; or R<sup>7</sup> and R<sup>8</sup> are taken together to form -CH2-CH<sub>2</sub>-CH<sub>2</sub>CH2- or -CH = CH-CH = CH-;
R<sup>10</sup> is hydrogen, C alkyl<sub>1</sub>-C<sub>5</sub>, halogen, cyano or -CO<sub>2</sub>R<sup>19</sup>;
Ar is aryl or heteroaryl whose aryl or heteroaryl is unsubstituted or is substituted with 1 or more substituents, which are the same or different, selected from the group consisting of halogen, C alkyl<sub>1</sub>-C<sub>5</sub>, cycloalkyl C<sub>3</sub>C<sub>8</sub>, alkenyl C<sub>2</sub> -C<sub>5</sub>, C alkynyl<sub>2</sub>-C<sub>5</sub>, C alkoxy<sub>1</sub> -C<sub>5</sub>, alkyl (C<sub>1</sub>-C<sub>5</sub>) thio, alkyl (C<sub>1</sub> -C<sub>5</sub>) sulfinyl, alkyl (C<sub>1</sub>-C<sub>5</sub>) sulfonyl, cyano, nitro, hydroxy, -CO<sub>2</sub>R<sup>19th</sup>, -C (= O) R<sup>19th</sup>, -CONR<sup>11b</sup>R<sup>12b</sup>, -OC (= O) R<sup>19th</sup>, -NR<sup>11b</sup>CO2R<sup>19th</sup>, -S (O) rNR<sup>11b</sup>R<sup>12b</sup>, hydroxyalkyl (C2-C5) amino C2-C5 alkoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoromethoxy, methylenedioxy, ethylenedioxy and -N (R<sup>20</sup>) R<sup>21</sup>;
provided that when Y is N, and the cyclic amino group is a 5-membered ring, Ar is aryl or heteroaryl whose aryl or heteroaryl is substituted with at least one of the substituents selected from halogen and trifluoromethyl;
provided that the compounds in which Y is N; the cyclic amino group is a 6-membered saturated cyclic amine; m is an integer selected from 1, 2 and 3; n is 0; R<sup>1</sup>, R<sup>2</sup>, R<sup>4</sup> and R<sup>5</sup> they are hydrogen; R<sup>6</sup> is methyl; R<sup>7</sup> and R<sup>8</sup> they are the same or different, and are independently hydrogen or methyl; Ar is phenyl whose phenyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of chlorine, bromine, C alkyl<sub>1</sub>-C<sub>3</sub>, C alkoxy<sub>1</sub>-C<sub>3</sub>, alkyl (C<sub>1</sub>-C<sub>3</sub>) thio, trifluoromethyl, trifluoromethoxy and dimethylamino; They are excluded;
R<sup>11</sup> and R<sup>12</sup> are the same or different, and are independently hydrogen, C alkyl<sub>1</sub> -C<sub>5</sub>, cycloalkyl C<sub>3</sub>-C<sub>8</sub> or cycloalkyl (C<sub>3</sub>-C<sub>8</sub>) C alkyl<sub>1</sub>-C<sub>5</sub>;
R<sup>11a</sup> and R<sup>12a</sup> are the same or different, and are independently hydrogen, C alkyl<sub>1</sub>-C<sub>5</sub>, cycloalkyl C<sub>3</sub>-C<sub>8</sub> or cycloalkyl (C<sub>3</sub>-C<sub>8</sub>) C alkyl<sub>1</sub>-C<sub>5</sub>;
R<sup>11b</sup> and R<sup>12b</sup> are the same or different, and are independently hydrogen, C alkyl<sub>1</sub>-C<sub>5</sub>, cycloalkyl C<sub>3</sub>-C<sub>8</sub> or cycloalkyl (C<sub>3</sub>-C<sub>8</sub>) C alkyl<sub>1</sub>-C<sub>5</sub>;
R<sup>13</sup> is hydrogen, C alkyl<sub>1</sub>-C<sub>5</sub>, cycloalkyl C<sub>3</sub>-C<sub>8</sub>, cycloalkyl (C<sub>3</sub>-C<sub>8</sub>) C alkyl<sub>1</sub>-C<sub>5</sub>, alkoxy (C<sub>1</sub>-C<sub>5</sub>) C alkyl<sub>1</sub>-C<sub>5</sub>, cycloalkyl (C<sub>3</sub>-C<sub>8</sub>) oxyalkyl C<sub>1</sub>-C<sub>5</sub> or phenyl;
R<sup>19</sup> is hydrogen or C1-C5 alkyl;
R<sup>19th</sup> is hydrogen or C alkyl<sub>1</sub>-C<sub>5</sub>;
r is 1 or 2;
r<sup>20</sup> yr<sup>21</sup> are the same or different, and are independently hydrogen or C1-C5 alkyl). More preferable are compounds represented by formula [V] in which Y is N. More preferable are compounds represented by formula [V] in which Y is N; m is an integer selected from 1, 2, 3, 4 and 5; n is 0; R<sup>1</sup>, R<sup>2</sup>, R<sup>4</sup> and R<sup>5</sup> they are hydrogen. More preferable are compounds represented by formula [V] wherein Y is N; the cyclic amino group is a 4- to 7-membered saturated cyclic amine; m is an integer selected from 1, 2 and 3; n is 0; R<sup>1</sup>, R<sup>2</sup>, R<sup>4</sup> and R<sup>5</sup> they are hydrogen; R<sup>6</sup> is methyl; R<sup>7</sup> and R<sup>8</sup> are the same or different, and are independently hydrogen or C1-C alkyl<sub>5</sub>; Ar is phenyl or pyridyl whose phenyl or pyridyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of halogen, C alkyl<sub>1</sub>-C<sub>3</sub>, C alkoxy<sub>1</sub>-C<sub>3</sub>, alkyl (C<sub>1</sub>-C<sub>3</sub>) thio, trifluoromethyl, trifluoromethoxy and -N (R<sup>20</sup>) R<sup>21</sup> (where R<sup>20</sup> and R<sup>21</sup> are the same or different, and are independently hydrogen or C1-C3 alkyl); with the proviso that when the cyclic amino group is a 5-membered ring, Ar is phenyl or pyridyl whose phenyl or pyridyl is substituted with at least one of the substituents selected from halogen and trifluoromethyl. Compounds represented by formula [V] wherein Y is N; the cyclic amino group is a 6-membered saturated cyclic amine; m is an integer selected from 1, 2 and 3; n is 0; R<sup>1</sup>, R<sup>2</sup>, R<sup>4</sup> and R<sup>5</sup> they are hydrogen; R<sup>6</sup> is methyl; R<sup>7</sup> and R<sup>8</sup> they are the same or different, and are independently hydrogen or methyl; Ar is phenyl whose phenyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of chlorine, bromine, C1-C alkyl<sub>3</sub>, C alkoxy<sub>1</sub> -C<sub>3</sub>, alkyl (C<sub>1</sub>-C<sub>3</sub>) thio, trifluoromethyl, trifluoromethoxy and dimethylamino are excluded from the present invention.
ES 2 325 596 T3
Other preferable ones are the compounds represented by the formula [V] wherein Y is N; m is 1; n is 0; R<sup>1</sup> is C1-C5 alkyl or C1-C5 hydroxyalkyl; R<sup>2</sup>, R<sup>4</sup> and R<sup>5</sup> they are hydrogen. More preferable are compounds represented by formula [V] wherein Y is N; m is 1; n is 0; the cyclic amino group is a 4- to 7-membered saturated cyclic amine; R<sup>1</sup> is C1-C alkyl<sub>5</sub> or hydroxyalkyl C<sub>1</sub>-C<sub>5</sub>; R<sup>2</sup>, R<sup>4</sup> and R<sup>5</sup> they are hydrogen; R<sup>6</sup> is methyl; R<sup>7</sup> and R<sup>8</sup> are the same or different, and are independently hydrogen or C1-C5 alkyl; Ar is phenyl or pyridyl whose phenyl or pyridyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3) alkylthio, trifluoromethyl , trifluoromethoxy and -N (R<sup>20</sup>) R<sup>21</sup> (where R<sup>20</sup> and R<sup>21 </sup>are the same or different, and are independently hydrogen or C1-C alkyl<sub>3</sub>). More preferable are compounds represented by formula [V] wherein Y is N; m is 1; n is 0; the cyclic amino group is a 6-membered saturated cyclic amine; R<sup>1</sup> is C1-C5 alkyl or C1-C5 hydroxyalkyl; R<sup>2</sup>, R<sup>4</sup> and R<sup>5</sup> they are hydrogen; R<sup>6</sup> is methyl; R<sup>7</sup> and R<sup>8</sup> they are the same or different, and are independently hydrogen or methyl; Ar is phenyl whose phenyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of chlorine, bromine, C1-C alkyl<sub>3</sub>, C alkoxy<sub>1</sub>-C<sub>3</sub>, alkyl (C<sub>1</sub>-C<sub>3</sub>) thio, trifluoromethyl, trifluoromethoxy and dimethylamino.
Other preferable ones are the compounds represented by the formula [V] wherein Y is N; m is an integer selected from 1, 2, 3, 4 and 5; n is 0; R<sup>1</sup>, R<sup>2</sup> and R<sup>5</sup> they are hydrogen; R<sup>4</sup> is cyano, where a group represented by - (CR<sup>1</sup>R<sup>2</sup>) m- (CHR<sup>3</sup>) n-OH and R<sup>4</sup> they are substituted on the same carbon atom of the cyclic amine. More preferable are compounds represented by formula [V] wherein Y is N; the cyclic amino group is a 4- to 7-membered saturated cyclic amine; m is an integer selected from 1, 2 and 3; n is 0; R<sup>1</sup>, R<sup>2</sup> and R<sup>5</sup> they are hydrogen; R<sup>4</sup> is cyano; R<sup>6</sup> is methyl; R<sup>7</sup> and R<sup>8</sup> are the same or different, and are independently hydrogen or C1-C5 alkyl; Ar is phenyl or pyridyl whose phenyl or pyridyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3) alkylthio, trifluoromethyl , trifluoromethoxy and N (R<sup>20</sup>) R<sup>21</sup> (where R<sup>20</sup> and R<sup>21</sup> are the same or different, and are independently hydrogen or C1-C alkyl<sub>3</sub>), where a group represented by - (CR<sup>1</sup>R<sup>2</sup>) m- (CHR<sup>3</sup>) n-OH and R<sup>4</sup> they are substituted on the same carbon atom of the cyclic amine. More preferable are compounds represented by formula [V] wherein Y is N; the cyclic amino group is a 6-membered saturated cyclic amine; m is an integer selected from 1, 2 and 3; n is 0; R<sup>1</sup>, R<sup>2</sup> and R<sup>5</sup> they are hydrogen; R<sup>4</sup> is cyano; R<sup>6</sup> is methyl; R<sup>7</sup> and R<sup>8</sup> they are the same or different, and are independently hydrogen or methyl; Ar is phenyl whose phenyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of chlorine, bromine, C alkyl<sub>1</sub> -C<sub>3</sub>, C alkoxy<sub>1</sub>-C<sub>3</sub>, alkyl (C<sub>1</sub>-C<sub>3</sub>) thio, trifluoromethyl, trifluoromethoxy, and dimethylamino, where a group represented by - (CR<sup>1</sup>R<sup>2</sup>) m- (CHR<sup>3</sup>) n-OH and R<sup>4</sup> they are substituted on the same carbon atom of the cyclic amine.
Other preferable ones are the compounds represented by the formula [V] wherein Y is CR<sup>10</sup>. More preferable are compounds represented by formula [V] wherein Y is CR<sup>10</sup>; m is an integer selected from 1, 2, 3, 4 and 5; n is 0; R<sup>1</sup>, R<sup>2</sup>, R<sup>4</sup> and R<sup>5</sup> they are hydrogen; R<sup>10</sup> it is hydrogen or halogen. More preferable are compounds represented by formula [V] wherein Y is CR<sup>10</sup>; the cyclic amino group is a 4- to 7-membered saturated cyclic amine; m is an integer selected from 1, 2 and 3; n is 0; R<sup>1</sup>, R<sup>2</sup>, R<sup>4</sup> and R<sup>5</sup> they are hydrogen; R<sup>6</sup> is methyl; R<sup>7</sup> and R<sup>8</sup> are the same or different, and are independently hydrogen or C1-C5 alkyl; R<sup>10</sup> is hydrogen or halogen; Ar is phenyl or pyridyl whose phenyl or pyridyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of halogen, C1-C alkyl<sub>3</sub>, C alkoxy<sub>1</sub> -C<sub>3</sub>, alkyl (C<sub>1</sub> -C<sub>3</sub>) thio, trifluoromethyl, trifluoromethoxy and -N (R<sup>20</sup>) R<sup>21</sup> (where R<sup>20</sup> and R<sup>21</sup> are the same or different, and are independently hydrogen or C1-C3 alkyl). More preferable are compounds represented by formula [V] wherein Y is CR<sup>10</sup>; the cyclic amino group is a 6-membered saturated cyclic amine; m is an integer selected from 1, 2 and 3; n is 0; R<sup>1</sup>, R<sup>2</sup>, R<sup>4</sup> and R<sup>5</sup> they are hydrogen; R<sup>6</sup> is methyl; R<sup>7</sup> and R<sup>8</sup> they are the same or different, and are independently hydrogen or methyl; R<sup>10</sup> is hydrogen; Ar is phenyl whose phenyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of chlorine, bromine, C1-C alkyl<sub>3</sub>, C alkoxy<sub>1</sub>-C<sub>3</sub>, alkyl (C<sub>1</sub>-C<sub>3</sub>) thio, trifluoromethyl, trifluoromethoxy and dimethylamino.
Other preferable ones are the compounds represented by the formula [V] wherein Y is CR<sup>10</sup>; m is 1; n is 0; R<sup>1</sup> is C1-C5 alkyl or C1-C5 hydroxyalkyl; R<sup>2</sup>, R<sup>4</sup> and R<sup>5</sup> they are hydrogen; R<sup>10</sup> it is hydrogen or halogen. More preferable are compounds represented by formula [V] wherein Y is CR<sup>10</sup>; m is 1; n is 0; the cyclic amino group is a 4- to 7-membered saturated cyclic amine; R<sup>1</sup> is C1-C alkyl<sub>5</sub> or hydroxyalkyl C<sub>1</sub>-C<sub>5</sub>; R<sup>2</sup>, R<sup>4</sup> and R<sup>5</sup> they are hydrogen; R<sup>6</sup> is methyl; R<sup>7</sup> and R<sup>8</sup> are the same or different, and are independently hydrogen or C1-C5 alkyl; R<sup>10 </sup>is hydrogen or halogen; Ar is phenyl or pyridyl whose phenyl or pyridyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of halogen, C1-C alkyl<sub>3</sub>, C alkoxy<sub>1</sub>-C<sub>3</sub>, alkyl (C<sub>1</sub>-C<sub>3</sub>) thio, trifluoromethyl, trifluoromethoxy and -N (R<sup>20</sup>) R<sup>21</sup> (where R<sup>20</sup> and R<sup>21</sup> are the same or different, and are independently hydrogen or C1-C3 alkyl). More preferable are compounds represented by formula [V] wherein Y is CR<sup>10</sup>; m is 1; n is 0; the cyclic amino group is a 6-membered saturated cyclic amine; R<sup>1</sup> is C1-C alkyl<sub>5</sub> or hydroxyalkyl C<sub>1</sub>-C<sub>5</sub>; R<sup>2</sup>, R<sup>4</sup> and R<sup>5</sup> they are hydrogen; R<sup>6</sup> is methyl; R<sup>7</sup> and R<sup>8</sup> they are the same or different, and are independently hydrogen or methyl; R<sup>10</sup> is hydrogen; Ar is phenyl whose phenyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of chlorine, bromine, C alkyl<sub>1</sub>-C<sub>3</sub>, C alkoxy<sub>1</sub>-C<sub>3</sub>, alkyl (C<sub>1</sub>C3) thio, trifluoromethyl, trifluoromethoxy, and dimethylamino.
Other preferable ones are the compounds represented by the formula [V] wherein Y is CR<sup>10</sup>; m is an integer selected from 1, 2, 3, 4 and 5; n is 0; R<sup>1</sup>, R<sup>2</sup> and R<sup>5</sup> they are hydrogen; R<sup>4</sup> is cyano; R<sup>10</sup> is hydrogen or halogen, where a group represented by - (CR<sup>1</sup>R<sup>2</sup>) m- (CHR<sup>3</sup>) n-OH and R<sup>4</sup> they are substituted on the same carbon atom of the cyclic amine. More preferable are compounds represented by formula [V] wherein Y is CR<sup>10</sup>; the cyclic amino group is a 4- to 7-membered saturated cyclic amine; m is an integer selected from 1, 2 and 3; n is 0; R<sup>1</sup>, R<sup>2</sup> Y
ES 2 325 596 T3
R<sup>5</sup> they are hydrogen; R<sup>4</sup> is cyano; R<sup>6</sup> is methyl; R<sup>7</sup> and R<sup>8</sup> are the same or different, and are independently hydrogen or C1-C5 alkyl; R<sup>10</sup> is hydrogen or halogen; Ar is phenyl or pyridyl whose phenyl or pyridyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3) alkylthio, trifluoromethyl , trifluoromethoxy and -N (R<sup>20</sup>) R<sup>21</sup> (where R<sup>20</sup> and R<sup>21</sup> are the same or different, and are independently hydrogen or C1-C alkyl<sub>3</sub>), where a group represented by - (CR<sup>1</sup>R<sup>2</sup>) m- (CHR<sup>3</sup>) n-OH and R<sup>4 </sup>they are substituted on the same carbon atom of the cyclic amine. More preferable are compounds represented by formula [V] wherein Y is CR<sup>10</sup>; the cyclic amino group is a 6-membered saturated cyclic amine; m is an integer selected from 1, 2 and 3; n is 0; R<sup>1</sup>, R<sup>2</sup> and R<sup>5</sup> they are hydrogen; R<sup>4</sup> is cyano; R<sup>6</sup> is methyl; R<sup>7</sup> and R<sup>8</sup> they are the same or different, and are independently hydrogen or methyl; R<sup>10</sup> is hydrogen; Ar is phenyl whose phenyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of chlorine, bromine, C alkyl<sub>1</sub>-C<sub>3</sub>, C alkoxy<sub>1</sub>-C<sub>3</sub>, alkyl (C<sub>1</sub>-C<sub>3</sub>) thio, trifluoromethyl, trifluoromethoxy, and dimethylamino, where a group represented by - (CR<sup>1</sup>R<sup>2</sup>) m- (CHR<sup>3</sup>) n-OH and R<sup>4</sup> they are substituted on the same carbon atom of the cyclic amine.
Other preferable ones are the compounds represented by the following formula [VII]:
<img file="ES2325596T3_D0006.tif" />
(where the cyclic amino group is represented by the following formula [VIII]:
<img file="ES2325596T3_D0007.tif" />
wherein the cyclic amino group is a 3- to 8-membered saturated cyclic amine or a 3- to 8-membered saturated cyclic amine bridged by alkylene C<sub>1</sub> -C<sub>5</sub> or alkylene (C<sub>1</sub> -C<sub>4</sub>) -O-alkylene C<sub>1</sub> -C<sub>4</sub> between any two different carbon atoms of the cyclic amine, the cyclic amine of which is substituted with a group represented by - (CR<sup>1</sup>R<sup>2</sup>) m- (CHR<sup>3</sup>) n-OR<sup>9</sup>, R<sup>4</sup> and R<sup>5</sup> independently on the same or different carbon atoms of the cyclic amine;
Y is N or CR<sup>10</sup>;
R<sup>1</sup> is hydrogen, hydroxy, C alkyl<sub>1</sub>-C<sub>5</sub>, alkoxy (C<sub>1</sub>-C<sub>5</sub>) C alkyl<sub>1</sub>-C<sub>5</sub> or hydroxyalkyl C<sub>1</sub> -C<sub>5</sub>;
R<sup>2</sup> is hydrogen or C1-C5 alkyl;
R<sup>3</sup> is hydrogen, cyano, C alkyl<sub>1</sub>-C<sub>5</sub>, alkoxy (C<sub>1</sub>-C<sub>5</sub>) C alkyl<sub>1</sub>-C<sub>5</sub> or hydroxyalkyl C<sub>1</sub> -C<sub>5</sub>;
m is an integer selected from 0, 1, 2, 3, 4 and 5;
n is 0 or 1;
provided that when n is 0, m is an integer selected from 1, 2, 3, 4 and 5;
R<sup>4</sup> is hydrogen, hydroxy, hydroxyalkyl C<sub>1</sub>-C<sub>5</sub>, cyano, cyanoalkyl C<sub>1</sub>-C<sub>5</sub> or C alkyl<sub>1</sub>-C<sub>5</sub>;
R<sup>5</sup> is hydrogen or C1-C5 alkyl;
R<sup>6</sup> is hydrogen, C alkyl<sub>1</sub>-C<sub>5</sub>, cycloalkyl C<sub>3</sub>-C<sub>8</sub>, cycloalkyl (C<sub>3</sub>-C<sub>8</sub>) C alkyl<sub>1</sub>-C<sub>5</sub>, hydroxy, C alkoxy<sub>1</sub>-C<sub>5</sub>, cycloalkyl (C3-C8) oxy or -N (R<sup>11</sup>) R<sup>12</sup>;
R<sup>7</sup> and R<sup>8</sup> are the same or different, and are independently hydrogen, halogen, C1-C5 alkyl, C3-C8 cycloalkyl, (C3-C8 cycloalkyl), Q-C5 alkyl, hydroxy, C1-C5 alkoxy, (C3-C8) cycloalkyl, -N (R<sup>11a</sup>) R<sup>12a</sup>, -CO2R<sup>13</sup>, cyano, nitro, (C1-C5) alkylthio, trifluoromethyl, or trifluoromethoxy; or R<sup>7</sup> and R<sup>8</sup> taken together to form -CH2-CH2-CH2CH2- or -CH = CH-CH = CH-;
R<sup>9</sup> is C1 -C24 acyl, (C1-C10) alkoxy carbonyl, arylalkyl (C1-C5) oxycarbonyl, -CO-O-CHR<sup>14</sup>-O-CO-R<sup>15</sup>, -P (= O) (OR<sup>14 to</sup>) OR<sup>15th</sup>, -CO- (CH2)<sub>p</sub>- (CHR<sup>16</sup>) q-NR<sup>17</sup>R<sup>18</sup>, arylcarbonyl or heteroarylcarbonyl, where each of said acyl, aryl and heteroaryl is unsubstituted or substituted with C1-C alkoxy<sub>5</sub>, and acyl C<sub>1</sub>-C<sub>2</sub>4 optionally includes one to six double bonds;
ES 2 325 596 T3
R<sup>10</sup> is hydrogen, C alkyl<sub>1</sub>-C<sub>5</sub>, halogen, cyano or-CO<sub>2</sub>R<sup>19</sup>;
Ar is aryl or heteroaryl whose aryl or heteroaryl is unsubstituted or is substituted with 1 or more substituents, which are the same or different, selected from the group consisting of halogen, C alkyl<sub>1</sub>-C<sub>5</sub>, cycloalkyl C<sub>3</sub>C<sub>8</sub>, alkenyl C<sub>2</sub>-C<sub>5</sub>, C alkynyl<sub>2</sub>-C<sub>5</sub>, C alkoxy<sub>1</sub>-C<sub>5</sub>, alkyl (C<sub>1</sub>-C<sub>5</sub>) thio, alkyl (C<sub>1</sub> -C<sub>5</sub>) sulfinyl, alkyl (C<sub>1</sub> -C<sub>5</sub>) sulfonyl, cyano, nitro, hydroxy, -CO = R<sup>19th</sup>, -C (= O) R<sup>19th</sup>, -CONR<sup>11b</sup>R<sup>12b</sup>, -OC (= O) R<sup>19th</sup>, -NR<sup>11b</sup>CO2R<sup>19th</sup>, -S (O) rNR<sup>11b</sup>R<sup>12b</sup>, hydroxyalkyl (C<sub>2</sub>-C<sub>5</sub>) aminoalkoxy C<sub>2</sub>-C<sub>5</sub>, trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoromethoxy, methylenedioxy, ethylenedioxy and -N (R<sup>20</sup>) R<sup>2i</sup>;
R<sup>11</sup> and R<sup>12</sup> are the same or different, and are independently hydrogen, C alkyl<sub>1</sub> -C<sub>5</sub>, cycloalkyl C<sub>3</sub>-C<sub>8</sub> or cycloalkyl (C<sub>3</sub>-C<sub>8</sub>) C alkyl<sub>1</sub>-C<sub>5</sub>;
R<sup>11a</sup> and R<sup>12a</sup> are the same or different, and are independently hydrogen, C alkyl<sub>1</sub>-C<sub>5</sub>, cycloalkyl C<sub>3</sub>-C<sub>8</sub> or cycloalkyl (C<sub>3</sub>-C<sub>8</sub>) C alkyl<sub>1</sub>-C<sub>5</sub>;
R<sup>11b</sup> and R<sup>12b</sup> are the same or different, and are independently hydrogen, C alkyl<sub>1</sub>-C<sub>5</sub>, cycloalkyl C<sub>3</sub>-C<sub>8</sub> or cycloalkyl (C<sub>3</sub>-C<sub>8</sub>) C alkyl<sub>1</sub>-C<sub>5</sub>;
R<sup>13</sup> is hydrogen, C alkyl<sub>1</sub>-C<sub>5</sub>, cycloalkyl C<sub>3</sub>-C<sub>8</sub>, cycloalkyl (C<sub>3</sub>-C<sub>8</sub>) C alkyl<sub>1</sub>-C<sub>5</sub>, alkoxy (C<sub>1</sub> -C<sub>5</sub>) C alkyl<sub>1</sub>-C<sub>5</sub>, cycloalkyl (C<sub>3</sub>-C<sub>8</sub>) oxyalkyl C<sub>1</sub>-C<sub>5</sub> or phenyl;
R<sup>14</sup> and R<sup>15</sup> are the same or different, and are independently hydrogen, C alkyl<sub>1</sub>-C<sub>5</sub> or arylalkyl C<sub>1</sub>-C<sub>5</sub>;
R<sup>14 to</sup> and R<sup>15th</sup> are the same or different, and are independently hydrogen, C alkyl<sub>1</sub>-C<sub>5</sub> or arylalkyl C<sub>1</sub> -C<sub>5</sub>;
R<sup>16</sup> is hydrogen, C alkyl<sub>1</sub> -C<sub>5</sub>, aryl, heteroaryl, arylalkyl C<sub>1</sub>-C<sub>5</sub>, heteroarylalkyl C<sub>1</sub>-C<sub>5</sub>, hydroxyalkyl C<sub>1</sub>-C<sub>5</sub>, hydroxycarbonylalkyl C<sub>1</sub>-C<sub>5</sub>, hydroxyphenylalkyl C<sub>1</sub>-C<sub>5</sub>, alkoxy (C<sub>1</sub>-C<sub>5</sub>) C alkyl<sub>1</sub>-C<sub>5</sub>, C aminoalkyl<sub>1</sub>-C<sub>5</sub>, guanidinoalkyl C<sub>r</sub>C<sub>5</sub>, C mercaptoalkyl<sub>1</sub>-C<sub>5</sub>, alkyl (C<sub>1</sub>-C<sub>5</sub>) thioalkyl C<sub>1</sub>-C<sub>5</sub> or aminocarbonylalkyl C<sub>1</sub> -C<sub>5</sub>;
R<sup>17</sup> and R<sup>18</sup> are the same or different, and are independently hydrogen, C alkyl<sub>1</sub>-C<sub>5</sub>, cycloalkyl C<sub>3</sub>-C<sub>8</sub>, cycloalkyl (C<sub>3</sub>-C<sub>8</sub>) C alkyl<sub>1</sub>-C<sub>5</sub>, acyl C<sub>1</sub>-C<sub>10</sub>, alkoxy (C<sub>1</sub>-C<sub>10</sub>) carbonyl and arylalkyl (C<sub>1</sub>-C<sub>5</sub>) oxycarbonyl, or
R<sup>16</sup> and R<sup>17</sup> are taken together to form -CH<sub>2</sub>-, -CH<sub>2</sub>CH<sub>2</sub>-, -CH<sub>2</sub>CH<sub>2</sub>CH<sub>2</sub>- or -CH<sub>2</sub>CH<sub>2</sub>CH<sub>2</sub>CH<sub>2</sub>-;
p is an integer selected from 0, 1, 2, 3, 4 and 5;
q is 0 or 1;
R<sup>19</sup> is hydrogen or C1-C5 alkyl;
R<sup>19th</sup> is hydrogen or C alkyl<sub>1</sub>-C<sub>5</sub>;
r is 1 or 2;
R<sup>20</sup> yr<sup>21</sup> are the same or different, and are independently hydrogen or C1-C5 alkyl). More preferable are compounds represented by formula [VII] in which Y is N. More preferable are compounds represented by formula [VII] in which Y is N; m is an integer selected from 1, 2, 3, 4 and 5; n is 0; R<sup>1</sup>, R<sup>2</sup>, R<sup>4</sup> and R<sup>5</sup> they are hydrogen. More preferable are compounds represented by formula [VII] wherein the cyclic amino group is a saturated 4- to 7-membered cyclic amine; m is an integer selected from 1, 2, 3, 4 and 5; n is 0; Y is N; R<sup>1</sup>, R<sup>2</sup>, R<sup>4</sup> and R<sup>5</sup> they are hydrogen; R<sup>6</sup> is methyl; R<sup>7</sup> and R<sup>8</sup> are the same or different, and are independently hydrogen or C1-C alkyl<sub>5</sub>; Ar is phenyl or pyridyl whose phenyl or pyridyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of halogen, C alkyl<sub>1</sub>-C<sub>3</sub>, C alkoxy<sub>1</sub>-C<sub>3</sub>, alkyl (C<sub>1</sub>-C<sub>3</sub>) thio, trifluoromethyl, trifluoromethoxy and -N (r<sup>20</sup>) r<sup>21</sup> (where R<sup>20</sup> and R<sup>21</sup> are the same or different, and are independently hydrogen or C1-C3 alkyl). More preferable are compounds represented by formula [VII] wherein the cyclic amino group is a 6-membered saturated cyclic amine; m is an integer selected from 1, 2 and 3; n is 0; Y is N; R<sup>1</sup>, R<sup>2</sup>, R<sup>4</sup> and R<sup>5</sup> they are hydrogen; R<sup>6</sup> is methyl; R<sup>7</sup> and R<sup>8</sup> they are the same or different, and are independently hydrogen or methyl; Ar is phenyl whose phenyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of chlorine, bromine, C1-C alkyl<sub>3</sub>, C alkoxy<sub>1</sub>-C<sub>3</sub>, alkyl (C<sub>1</sub>-C<sub>3</sub>) thio, trifluoromethyl, trifluoromethoxy and dimethylamino.
Other preferable ones are the compounds represented by formula [VII] wherein Y is CR<sup>10</sup>. More preferable are compounds represented by formula [VII] wherein Y is CR<sup>10</sup>; m is an integer selected from 1, 2, 3, 4 and 5; n is 0; R<sup>1</sup>, R<sup>2</sup>, R<sup>4</sup> and R<sup>5</sup> they are hydrogen. More preferable are compounds represented by formula [VII] wherein Y is CR<sup>10</sup>; the cyclic amino group is a 4- to 7-membered saturated cyclic amine; m is an integer selected from 1.2 to 3; n is 0; R<sup>1</sup>, R<sup>2</sup>, R<sup>4</sup> and R<sup>5</sup> they are hydrogen; R<sup>6</sup> is methyl; R<sup>7</sup> and R<sup>8</sup> are the same or different, and are independently hydrogen or C1-C5 alkyl; R<sup>10</sup> is hydrogen or halogen; Ar is phenyl or pyridyl whose phenyl or pyridyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of halogen, C1-C alkyl<sub>3</sub>, C alkoxy<sub>1</sub>-C<sub>3</sub>, alkyl (C<sub>1</sub>-C<sub>3</sub>) thio, trifluoromethyl, trifluoromethoxy and N (R<sup>20</sup>) R<sup>21</sup> (where R<sup>20</sup> and R<sup>21</sup> are the same or different, and are independently hydrogen or C-alkyl<sub>1</sub> -C<sub>3</sub>). Compounds are more preferable
ES 2 325 596 T3 represented by formula [VII] wherein Y is CR<sup>10</sup>; the cyclic amino group is a 6-membered saturated cyclic amine; m is an integer selected from 1, 2 and 3; n is 0; R<sup>1</sup>, R<sup>2</sup>, R<sup>3</sup> and R<sup>5</sup> they are hydrogen; R<sup>6</sup> is methyl; R<sup>7</sup> and R<sup>8 </sup>they are the same or different, and are independently hydrogen or methyl; R<sup>10</sup> is hydrogen; Ar is phenyl whose phenyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of chlorine, bromine, C alkyl<sub>1</sub>-C<sub>3</sub>, C alkoxy<sub>1</sub>-C<sub>3</sub>, alkyl (C<sub>1</sub> -C<sub>3</sub>) thio, trifluoromethyl, trifluoromethoxy and dimethylamino.
The especially preferred compounds of the present invention are listed below. Compounds marked with "#" are excluded from the invention.
2- {1- [7- (2,6-dibromo-4-trifluoromethyl-phenyl) -2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-2 -il} -ethanol,
<img file="ES2325596T3_D0008.tif" />
2- {1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-2 -il} -ethanol,
<img file="ES2325596T3_D0009.tif" />
2- {1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-2-yl }-ethanol,
<img file="ES2325596T3_D0010.tif" />
2- {1- [7- (4-bromo-2,6-diethyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-2-yl }-ethanol,
<img file="ES2325596T3_D0011.tif" />
ES 2 325 596 T3
2- {1- [2,5-dimellihil-7- (2,4,6-tribromo-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-2-yl} - ethanol,
<img file="ES2325596T3_D0012.tif" />
3- {1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-2 -il} -propan-1-ol,
<img file="ES2325596T3_D0013.tif" />
3- {1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-2-yl } -propan-1-ol,
<img file="ES2325596T3_D0014.tif" />
{1- [7- (2,4-dibromo-6-methoxy-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-3-yl} - methanol,
<img file="ES2325596T3_D0015.tif" />
{1- [7- (2,4-dibromo-6-methylsulfanyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-3-yl} - methanol,
<img file="ES2325596T3_D0016.tif" />
ES 2 325 596 T3 {1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5,6-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] - piperidin-3-yl} -methanol,
<img file="ES2325596T3_D0017.tif" />
{1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-3-yl} - methanol,
<img file="ES2325596T3_D0018.tif" />
{1- [2,5-dimethyl-7- (2,4,6-tribromo-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-3-yl} -methanol,
<img file="ES2325596T3_D0019.tif" />
2- {1- [7- (2,6-dibromo-4-trifluoromethyl-phenyl) -2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-3 -il} -ethanol,
<img file="ES2325596T3_D0020.tif" />
2- {1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-3 -il} -ethanol,
<img file="ES2325596T3_D0021.tif" />
ES 2 325 596 T3
2- {1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-3-yl }-ethanol,
<img file="ES2325596T3_D0022.tif" />
2- {1- [2,5-dimethyl-7- (2,4,6-tribromo-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-3-yl} - ethanol,
<img file="ES2325596T3_D0023.tif" />
{1- [2,5,6-trimethyl-7- (2,4,6-trimethyl-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4-yl} - methanol,
<img file="ES2325596T3_D0024.tif" />
{1- [2,5-dimethyl-7- (2,4,6-trimethyl-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4-yl} -methanol,
<img file="ES2325596T3_D0025.tif" />
{1- [7- (2,6-dibromo-4-trifluoromethyl-phenyl) -2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4-yl } -methanol,
<img file="ES2325596T3_D0026.tif" />
ES 2 325 596 T3 {1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] - piperidin-4-yl} -methanol,
<img file="ES2325596T3_D0027.tif" />
{1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4-yl} - methanol,
<img file="ES2325596T3_D0028.tif" />
{1- [2-methyl-9- (2,4,6-trimethyl-phenyl) -9H-1,3,9-triaza-fluoren-4-yl] -piperidin-4-yl} -methanol,
<img file="ES2325596T3_D0029.tif" />
{1- [7- (4-bromo-2,6-diethyl-phenyl) -2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4-yl } -methanol,
<img file="ES2325596T3_D0030.tif" />
{1- [7- (4-bromo-2,6-diethyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4-yl} - methanol,
<img file="ES2325596T3_D0031.tif" />
ES 2 325 596 T3 {1- [2,5,6-trimethyl-7- (2,4,6-tribromo-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin- 4-yl} -methanol,
<img file="ES2325596T3_D0032.tif" />
{1- [2,5-dimethyl-7- (2,4,6-tribromo-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4-yl} -methanol,
<img file="ES2325596T3_D0033.tif" />
{1- [7- (4-bromo-2,6-dichloro-phenyl) -2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4-yl } -methanol,
<img file="ES2325596T3_D0034.tif" />
{1- [7- (4-bromo-2,6-dichloro-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4-yl} - methanol,
<img file="ES2325596T3_D0035.tif" />
{1- [7- (2,6-dibromo-4-isopropyl-phenyl) -2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4-yl } -methanol,
<img file="ES2325596T3_D0036.tif" />
ES 2 325 596 T3 {1- [7- (2,6-dibromo-4-isopropyl-phenyl) -2,5-dimethyl-7H-pyrolo [2,3-d] pyrimidin-4-yl] -piperidin- 4-yl} -methanol,
<img file="ES2325596T3_D0037.tif" />
{1- [7- (4-Chloro-2,6-dimethyl-phenyl) -2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4-yl } -methanol,
<img file="ES2325596T3_D0038.tif" />
<img file="ES2325596T3_D0039.tif" />
{1- [7- (4-chloro-2,6-dimethyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4-yl} - methanol,
<img file="ES2325596T3_D0040.tif" />
2- {1- [7- (2,6-dibromo-4-trifluoromethyl-phenyl) -2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4 -il} -ethanol,
<img file="ES2325596T3_D0041.tif" />
<img file="ES2325596T3_D0042.tif" />
2- {1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4 -il} -ethanol,
<img file="ES2325596T3_D0043.tif" />
ES 2 325 596 T3
2- {1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4-yl }-ethanol,
<img file="ES2325596T3_D0044.tif" />
2- {1- [2,5,6-trimethyl-7- (2,4,6-tribromo-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4-yl }-ethanol,
<img file="ES2325596T3_D0045.tif" />
2- {1- [2,5-dimethyl-7- (2,4,6-tribromo-phenyl) -7H-pyrolo [2,3-d] pyrimin-4-yl] -piperidin-4-yl} - ethanol,
<img file="ES2325596T3_D0046.tif" />
3- {1- [2,5,6-trimethyl-7- (2,4,6-trimethyl-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4-yl } -propan-1-ol,
<img file="ES2325596T3_D0047.tif" />
3- {1- [2,5-dimethyl-7- (2,4,6-trimethyl-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4-yl} - propan-1-ol,
<img file="ES2325596T3_D0048.tif" />
ES 2 325 596 T3
3- {1- [7- (2,6-dibromo-4-trifluoromethyl-phenyl) -2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4 -il} -propan-1-ol,
<img file="ES2325596T3_D0049.tif" />
3- {1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4 -il} -propan-1-ol,
<img file="ES2325596T3_D0050.tif" />
3- {1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4-yl } -propan-1-ol,
<img file="ES2325596T3_D0051.tif" />
3- {1- [2,5-dimethyl-1-7- (2,4,6-tribromo-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4-yl } -propan-1-ol,
<img file="ES2325596T3_D0052.tif" />
3- {1- [7- (4-bromo-2,6-dichloro-phenyl) -2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4 -il} -propan-1-ol,
<img file="ES2325596T3_D0053.tif" />
ES 2 325 596 T3
3- {1- [7- (4-bromo-2,6-dichloro-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4-yl } -propan-1-ol,
<img file="ES2325596T3_D0054.tif" />
{1- [7- (2,6-dibromo-4-trifluoromethyl-phenyl) -2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -3-methyl-piperidin -3-yl} methanol,
<img file="ES2325596T3_D0055.tif" />
{1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -3-methyl-piperidin -3-yl} -methanol,
<img file="ES2325596T3_D0056.tif" />
{1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -3-methyl-piperidin-3 -il} -methanol,
<img file="ES2325596T3_D0057.tif" />
1- {1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4 -yl} -ethane-1,2-diol,
<img file="ES2325596T3_D0058.tif" />
ES 2 325 596 T3 {1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] - pyrrolidin-2-yl} -methanol,
<img file="ES2325596T3_D0059.tif" />
{1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -pyrrolidin-2-yl} - methanol,
<img file="ES2325596T3_D0060.tif" />
2- {1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -pyrrolidin-3-yl }-ethanol,
<img file="ES2325596T3_D0061.tif" />
{1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -azepan-4-yl } -methanol,
<img file="ES2325596T3_D0062.tif" />
{1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -azepan-4-yl} - methanol,
<img file="ES2325596T3_D0063.tif" />
ES 2 325 596 T3 {1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] - piperidin-2-yl} -acetonitrile,
<img file="ES2325596T3_D0064.tif" />
1- [2,5,6-trimethyl-7- (2,4,6-trimethyl-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidine-3-carbonitrile,
<img file="ES2325596T3_D0065.tif" />
1- [2,5-dimethyl-7- (2,4,6-trimethyl-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidine-3-carbonitrile,
<img file="ES2325596T3_D0066.tif" />
1- [7- (2,4-dibromo-6-methylsulfanyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidine-3-carbonitrile,
<img file="ES2325596T3_D0067.tif" />
1- [7- (2,6-dibromo-4-trifluoromethyl-phenyl) -2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidine-3-carbonitrile,
<img file="ES2325596T3_D0068.tif" />
ES 2 325 596 T3
1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidine-3-carbonitrile,
<img file="ES2325596T3_D0069.tif" />
1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidine-3-carbonitrile,
<img file="ES2325596T3_D0070.tif" />
1- [7- (4-isopropyl-2-methylsulfanyl-phenyl) -2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidine-3-carbonitrile,
<img file="ES2325596T3_D0071.tif" />
1- [7- (4-isopropyl-2-methylsulfanyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidine-3-carbonitrile,
<img file="ES2325596T3_D0072.tif" />
1- [7- (2-bromo-4-trifluoromethyl-phenyl) -2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidine-3-carbonitrile,
<img file="ES2325596T3_D0073.tif" />
ES 2 325 596 T3
1- [7- (4-bromo-2,6-diethyl-phenyl) -2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidine-3-carbonitrile,
<img file="ES2325596T3_D0074.tif" />
1- [7- (4-bromo-2,6-diethyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidine-3-carbonitrile,
<img file="ES2325596T3_D0075.tif" />
{1- [7- (2,6-dibromo-4-trifluoromethyl-phenyl) -2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-3-yl } -acetonitrile,
<img file="ES2325596T3_D0076.tif" />
{1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-3-yl } -acetonitrile,
<img file="ES2325596T3_D0077.tif" />
{1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-3-yl} - acetonitrile,
<img file="ES2325596T3_D0078.tif" />
ES 2 325 596 T3
3- {1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-3 -il} -propionitrile,
<img file="ES2325596T3_D0079.tif" />
3- {1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-3-yl } -propionitrile,
<img file="ES2325596T3_D0080.tif" />
1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidine-4-carbonitrile,
<img file="ES2325596T3_D0081.tif" />
1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidine-4-carbonitrile,
<img file="ES2325596T3_D0082.tif" />
{1- [2,5,6-trimethyl-7- (2,4,6-trimethyl-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4-yl} - acetonitrile,
<img file="ES2325596T3_D0083.tif" />
ES 2 325 596 T3 {1- [7- (2,6-dibromo-4-trifluoromethyl-phenyl) -2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] - piperidin-4-yl} -acetonitrile,
<img file="ES2325596T3_D0084.tif" />
F {1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4- yl} -acetonitrile,
<img file="ES2325596T3_D0085.tif" />
{1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4-yl} - acetonitrile,
<img file="ES2325596T3_D0086.tif" />
{1- [7- (4-bromo-2,6-diethyl-phenyl) -2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4-yl } -acetonitrile,
<img file="ES2325596T3_D0087.tif" />
{1- [7- (4-bromo-2,6-diethyl-pheny) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4-yl} - acetonitrile,
<img file="ES2325596T3_D0088.tif" />
ES 2 325 596 T3 {1- [2,5,6-trimethyl-7- (2,4,6-tribromo-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin- 4-yl} -acetonitrile,
<img file="ES2325596T3_D0089.tif" />
{1- [2,5-dimethyl-7- (2,4,6-tribromo-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4-yl} -acetonitrile,
<img file="ES2325596T3_D0090.tif" />
{1- [7- (4-bromo-2,6-dichloro-phenyl) -2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4-yl } -acetonitrile,
<img file="ES2325596T3_D0091.tif" />
{1- [7- (4-bromo-2,6-dichloro-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4-yl} - acetonitrile,
Cl
<img file="ES2325596T3_D0092.tif" />
{1- [7- (2,6-dibromo-4-isopropyl-phenyl) -2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4-yl } -acetonitrile,
<img file="ES2325596T3_D0093.tif" />
ES 2 325 596 T3 {1- [7- (2,6-dibromo-4-isopropyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin- 4-yl} -acetonitrile,
<img file="ES2325596T3_D0094.tif" />
{1- [7- (4-methoxy-2,6-dimethyl-phenyl) -2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4-yl } -acetonitrile,
<img file="ES2325596T3_D0095.tif" />
{1- [7- (4-methoxy-2,6-dimethyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4-yl} - acetonitrile,
<img file="ES2325596T3_D0096.tif" />
{1- [7- (4-chloro-2,6-dimethyl-phenyl) -2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4-yl } -acetonitrile,
<img file="ES2325596T3_D0097.tif" />
{1- [7- (4-Chloro-2,6-dimethyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4-yl} - acetonitrile,
<img file="ES2325596T3_D0098.tif" />
ES 2 325 596 T3
8- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -8-aza-bicyclo [ 3,2,1] octane-3-carbonitrile,
<img file="ES2325596T3_D0099.tif" />
8- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -8-aza-bicyclo [3, 2,1] octane-3-carbonitrile,
<img file="ES2325596T3_D0100.tif" />
1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -pyrrolidine-3-carbonitrile,
<img file="ES2325596T3_D0101.tif" />
1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -pyrrolidine-3-carbonitrile,
<img file="ES2325596T3_D0102.tif" />
1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimdin-4-yl] -azepane-4-carbonitrile,
<img file="ES2325596T3_D0103.tif" />
ES 2 325 596 T3
1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -azepane-4-carbonitrile,
<img file="ES2325596T3_D0104.tif" />
1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -3-hydroxymethyl-piperidino- 3-carbonitrile,
<img file="ES2325596T3_D0105.tif" />
{1- [7- (4-isopropyl-2-methylsulfanyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4-yl} -methanol,
<img file="ES2325596T3_D0106.tif" />
{1- [7- (2-bromo-4-isopropyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4-yl} -methanal,
<img file="ES2325596T3_D0107.tif" />
{1- [7- (2,4-dibromo-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4-yl} -methanol,
<img file="ES2325596T3_D0108.tif" />
ES 2 325 596 T3 {1- [7- (2,6-dibromo-4-chloro-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin- 4-yl} -methanol,
<img file="ES2325596T3_D0109.tif" />
2- {1- [7- (2,6-dibromo-4-chloro-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4-yl }-ethanol,
<img file="ES2325596T3_D0110.tif" />
1- {1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5,6-trimethyl-7H-1-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin -4-yl} -propane-
1,3-diol,
<img file="ES2325596T3_D0111.tif" />
{1- [7- (2,6-dibromo-4-chloro-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4-yl} - acetonitrile,
<img file="ES2325596T3_D0112.tif" />
{1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5,6-trimethyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl] -pyrrolidin-3- yl} -acetonitrile,
<img file="ES2325596T3_D0113.tif" />
ES 2 325 596 T3 {1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -pyrrolidin- 3-yl} -acetonitrile,
<img file="ES2325596T3_D0114.tif" />
{1- [2,5-dimethyl-7- (2,4,6-trichloro-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4-yl} -methanol,
<img file="ES2325596T3_D0115.tif" />
{1- [7- (2,6-dichloro-4-trifluoromethyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4-yl} - methanol,
<img file="ES2325596T3_D0116.tif" />
3- {1- [7- (4-chloro-2,6-dimethyl-phenyl) -2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4 -il} -propan-1-ol,
<img file="ES2325596T3_D0117.tif" />
1- [7- (4-chloro-2,6-dimethyl-phenyl) -2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidine-4-carbonitrile,
<img file="ES2325596T3_D0118.tif" />
ES 2 325 596 T3 {1- [7- (2,6-Dichloro-4-trifluoromethyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin- 4-yl} -acetonitrile,
<img file="ES2325596T3_D0119.tif" />
1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -azetidine-3-carbonitrile,
<img file="ES2325596T3_D0120.tif" />
1- {1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4 -il} -ethanol,
<img file="ES2325596T3_D0121.tif" />
1- {1- [7- (4-isopropyl-2-methylsulfanyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4-yl} - ethanol,
<img file="ES2325596T3_D0122.tif" />
1- {1- [7- (4-chloro-2,6-dimethyl-phenyl) -2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4 -il} -ethanol,
<img file="ES2325596T3_D0123.tif" />
ES 2 325 596 T3
1- {1- [7- (4-chloro-2,6-dimethyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4-yl }-ethanol,
<img file="ES2325596T3_D0124.tif" />
{1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -3-methyl-piperidin -4-yl} -methanol,
<img file="ES2325596T3_D0125.tif" />
{1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -3-methyl-piperidin-4 -il} -methanol,
<img file="ES2325596T3_D0126.tif" />
{8- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -8-aza-bicyclo [3,2,1] oct-3-yl} methanol,
<img file="ES2325596T3_D0127.tif" />
{8- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -8-aza-bicyclo [3 , 2.1] oct-3-yl} -methanol,
<img file="ES2325596T3_D0128.tif" />
ES 2 325 596 T3 {8- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] - 8-aza-bicyclo [1,2,1] oct-3-yl} acetonitrile,
<img file="ES2325596T3_D0129.tif" />
{8- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -8-aza-bicyclo [3 , 2,1] oct-3-yl} -acetonitrile,
<img file="ES2325596T3_D0130.tif" />
2- {1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4 -il} -malononitrile,
<img file="ES2325596T3_D0131.tif" />
2- {1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4-yl } -malononitrile,
<img file="ES2325596T3_D0132.tif" />
2- {1- [1- (2,4-dichloro-phenyl) -2,3,6-trimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-3-yl} - ethanol,
<img file="ES2325596T3_D0133.tif" />
ES 2 325 596 T3
2- {1- [1- (4-bromo-2,6-dimethyl-phenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-3-yl }-ethanol,
<img file="ES2325596T3_D0134.tif" />
{1- [1- (2,4-dichloro-phenyl) -2,3,6-timethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl} -methanol,
<img file="ES2325596T3_D0135.tif" />
{1- [1- (4-bromo-2,6-dimethyl-phenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl} - methanol,
<img file="ES2325596T3_D0136.tif" />
2- {1- [1- (2,4-dichloro-phenyl) -2,3,6-trimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl} - ethanol,
<img file="ES2325596T3_D0137.tif" />
2- {1- [1- (4-bromo-2,6-dimethyl-phenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl }-ethanol,
<img file="ES2325596T3_D0138.tif" />
ES 2 325 596 T3
3- {1- [1- (2,4-dichloro-phenyl) -2,3,6-trimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl} - propan-1-ol,
<img file="ES2325596T3_D0139.tif" />
3- {1- [1- (4-bromo-2,6-dimethyl-phenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl } -propan-1-ol,
<img file="ES2325596T3_D0140.tif" />
1- [1- (2,4-dichloro-phenyl) -2,3,6-trimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidine-3-carbonitrile,
<img file="ES2325596T3_D0141.tif" />
1- [1- (4-bromo-2,6-dimethyl-phenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidine-3-carbonitrile,
<img file="ES2325596T3_D0142.tif" />
{1- [1- (2,4-dichloro-phenyl) -2,3,6-trimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-3-yl} -acetonitrile,
<img file="ES2325596T3_D0143.tif" />
ES 2 325 596 T3
1- [1- (2,4-dichloro-phenyl) -2,3,6-trimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidine-4-carbonitrile,
<img file="ES2325596T3_D0144.tif" />
1- [1- (4-bromo-2,6-dimethyl-phenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidine-4-carbonitrile,
<img file="ES2325596T3_D0145.tif" />
Br {1- [1- (2,4-dichloro-phenyl) -2,3,6-trimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl} -acetonitrile ,
<img file="ES2325596T3_D0146.tif" />
2- {1- [1- (4-bromo-2,6-dimethyl-phenyl) -2,3,6-trimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-3 -il} -ethanol,
<img file="ES2325596T3_D0147.tif" />
{1- [1- (4-bromo-2,6-dimethyl-phenyl) -2,3,6-trimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl } -methanol,
<img file="ES2325596T3_D0148.tif" />
ES 2 325 596 T3 {1- [1- (4-chloro-2,6-dimethyl-phenyl) -2,3,6-trimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] - piperidin-4-yl} -methanol,
<img file="ES2325596T3_D0149.tif" />
{1- [1- (4-Chloro-2,6-dimethyl-phenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl} - methanol,
<img file="ES2325596T3_D0150.tif" />
2- {1- [1- (4-bromo-2,6-dimethyl-phenyl) -2,3,6-trimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4 -il} -ethanol,
<img file="ES2325596T3_D0151.tif" />
2- {1- [1- (4-chloro-2,6-dimethyl-phenyl) -2,3,6-trimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4 -il} -ethanol,
<img file="ES2325596T3_D0152.tif" />
2- {1- [1- (4-Chloro-2,6-dimethyl-phenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl }-ethanol,
<img file="ES2325596T3_D0153.tif" />
ES 2 325 596 T3
3- {1- [1- (4-bromo-2,6-dimethyl-phenyl) -2,3,6-trimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4 -il} -propan-1-ol,
<img file="ES2325596T3_D0154.tif" />
3- {1- [1- (4-chloro-2,6-dimethyl-phenyl) -2,3,6-trimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4 -il} -propan-1-ol,
<img file="ES2325596T3_D0155.tif" />
3- {1- [1- (4-Chloro-2,6-dimethyl-phenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl } -propan-1-ol,
<img file="ES2325596T3_D0156.tif" />
1- [1- (4-bromo-2,6-dimethyl-phenyl) -2,3,6-trimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidine-3-carbonitrile,
<img file="ES2325596T3_D0157.tif" />
1- [1- (4-bromo-2,6-dimethyl-phenyl) -2,3,6-trimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidine-4-carbonitrile,
<img file="ES2325596T3_D0158.tif" />
ES 2 325 596 T3
1- [1- (4-chloro-2,6-dimethyl-phenyl) -2,3,6-trimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidine-4-carbonitrile,
<img file="ES2325596T3_D0159.tif" />
1- [1- (4-Chloro-2,6-dimethyl-phenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidine-4-carbonitrile,
<img file="ES2325596T3_D0160.tif" />
{1- [1- (4-bromo-2,6-dimethyl-phenyl) -2,3,6-trimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl } -acetonitrile,
<img file="ES2325596T3_D0161.tif" />
{1- [1- (4-bromo-2,6-dimethyl-phenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl} - acetonitrile,
<img file="ES2325596T3_D0162.tif" />
{1- [1- (4-Chloro-2,6-dimethyl-phenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl} - acetonitrile,
<img file="ES2325596T3_D0163.tif" />
ES 2 325 596 T3 {1- [1- (2,6-dibromo-4-isopropyl-phenyl) -2,3,6-timethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] - piperidin-4-yl} -methanol,
<img file="ES2325596T3_D0164.tif" />
{1- [1- (2,6-dibromo-4-isopropyl-phenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl} - methanol,
<img file="ES2325596T3_D0165.tif" />
{1- [2,3,6-trimethyl-1- (2,4,6-tribromo-phenyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl} - methanol,
<img file="ES2325596T3_D0166.tif" />
{1- [3,6-dimethyl-1- (2,4,6-tribromo-phenyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl} -methanol,
<img file="ES2325596T3_D0167.tif" />
{1- [1- (4-bromo-2,6-dichloro-phenyl) -2,3,6-trimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl } -methanol,
<img file="ES2325596T3_D0168.tif" />
ES 2 325 596 T3 {1- [1- (4-bromo-2,6-dichloro-phenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin- 4-yl} -methanol,
<img file="ES2325596T3_D0169.tif" />
{1- [2,3,6-trimethyl-1- (2,4,6-trichloro-phenyl) -1H-pyrrolo [2,3-b] pirdin-4-yl] -piperidin-4-yl} - methanol,
<img file="ES2325596T3_D0170.tif" />
{1- [3,6-dimethyl-1- (2,4,6-trichloro-phenyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl} -methanol,
<img file="ES2325596T3_D0171.tif" />
{1- [1- (2,6-dibromo-4-chloro-phenyl) -2,3,6-trimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl } -methanol,
<img file="ES2325596T3_D0172.tif" />
{1- [1- (2,6-dibromo-4-chloro-phenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl} - methanol,
<img file="ES2325596T3_D0173.tif" />
ES 2 325 596 T3 {1- [1- (4-methoxy-2,6-dimethyl-phenyl) -2,3,6-trimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] - piperidin-4-yl} -methanol,
<img file="ES2325596T3_D0174.tif" />
{1- [1- (4-methoxy-2,6-dimethyl-phenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl} - methanol,
<img file="ES2325596T3_D0175.tif" />
{1- [1- (2-bromo-4-isopropyl-phenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl} -methanol,
<img file="ES2325596T3_D0176.tif" />
{1- [1- (4-isopropyl-2-methylsulfanyl-phenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl} -methanol,
<img file="ES2325596T3_D0177.tif" />
{1- [1- (2,4-dibromo-phenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl} -methanol,
<img file="ES2325596T3_D0178.tif" />
ES 2 325 596 T3 {1- [1- (2-bromo-4-trifluoromethyl-phenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4- yl} -methanol,
<img file="ES2325596T3_D0179.tif" />
{1- [2,3,6-trimethyl-1- (2,4,5-tribromo-phenyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl} - methanol,
<img file="ES2325596T3_D0180.tif" />
{1- [3,6-dimethyl-1- (2,4,5-tribromo-phenyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl} -methanol,
<img file="ES2325596T3_D0181.tif" />
2- {1- [1- (2,6-dibromo-4-isopropyl-phenyl) -2,3,6-trimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4 -il} -ethanol,
<img file="ES2325596T3_D0182.tif" />
2- {1- [1- (2,6-dibromo-4-isopropyl-phenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl }-ethanol,
<img file="ES2325596T3_D0183.tif" />
ES 2 325 596 T3
2- {1- [2,3,6-trimethyl-1- (2,4,6-tribromo-phenyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl }-ethanol,
<img file="ES2325596T3_D0184.tif" />
2- {1- [3,6-dimethyl-1- (2,4,6-tribromo-phenyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl} - ethanol,
<img file="ES2325596T3_D0185.tif" />
2- {1- [1- (4-bromo-2,6-dichloro-phenyl) -2,3,6-trimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4 -il} -ethanol,
<img file="ES2325596T3_D0186.tif" />
2- {1- [1- (4-bromo-2,6-dichloro-phenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl }-ethanol,
<img file="ES2325596T3_D0187.tif" />
2- {1- [2,3,6-trimethyl-1- (2,4,6-trichloro-phenyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl }-ethanol,
<img file="ES2325596T3_D0188.tif" />
ES 2 325 596 T3
2- {1- [3,6-dimethyl-1- (2,4,6-trichloro-phenyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl} - ethanol,
<img file="ES2325596T3_D0189.tif" />
2- {1- [1- (2,6-dibromo-4-chloro-phenyl) -2,3,6-trimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4 -il} -ethanol,
<img file="ES2325596T3_D0190.tif" />
2- {1- [1- (2,6-dibromo-4-chloro-phenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl }-ethanol,
<img file="ES2325596T3_D0191.tif" />
2- {1- [1- (4-methoxy-2,6-dimethyl-phenyl) -2,3,6-trimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4 -il} -ethanol,
<img file="ES2325596T3_D0192.tif" />
2- {1- [1- (4-methoxy-2,6-dimethyl-phenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl }-ethanol,
<img file="ES2325596T3_D0193.tif" />
ES 2 325 596 T3
2- {1- [1- (2-bromo-4-isopropyl-phenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl} - ethanol,
<img file="ES2325596T3_D0194.tif" />
2- {1- [1- (4-isopropyl-2-methylsulfanyl-phenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl} - ethanol,
<img file="ES2325596T3_D0195.tif" />
2- {1- [1- (2,4-dibromo-phenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl} -ethanol,
<img file="ES2325596T3_D0196.tif" />
2- {1- [2,3,6-trimethyl-1- (2,4,5-tribromo-phenyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl }-ethanol,
<img file="ES2325596T3_D0197.tif" />
2- {1- [3,6-dimethyl-1- (2,4,5-tribromo-phenyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl} - ethanol,
<img file="ES2325596T3_D0198.tif" />
ES 2 325 596 T3
2- {1- [5-bromo-1- (4-chloro-2,6-dimethyl-phenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin -4-yl} -ethanol,
<img file="ES2325596T3_D0199.tif" />
3- {1- [1- (2,6-dibromo-4-isopropyl-phenyl) -2,3,6-trimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4 -il} -propan-1-ol,
<img file="ES2325596T3_D0200.tif" />
3- {1- [1- (2,6-dibromo-4-isopropyl-phenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl } -propan-1-ol,
<img file="ES2325596T3_D0201.tif" />
3- {1- [2,3,6-trimethyl-1- (2,4,6-tribromo-phenyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl } -propan-1-ol,
<img file="ES2325596T3_D0202.tif" />
3- {1- [3,6-dimethyl-1- (2,4,6-tribromo-phenyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl} - propan-1-ol,
<img file="ES2325596T3_D0203.tif" />
ES 2 325 596 T3
3- {1- [1- (4-bromo-2,6-dichloro-phenyl) -2,3,6-trimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4 -il} -propan-1-ol,
<img file="ES2325596T3_D0204.tif" />
3- {1- [1- (4-bromo-2,6-dichloro-phenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl } -propan-1-ol,
<img file="ES2325596T3_D0205.tif" />
3- {1- [2,3,6-trimethyl-1- (2,4,6-trichloro-phenyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl } -propan-1-ol,
<img file="ES2325596T3_D0206.tif" />
3- {1- [3,6-dimethyl-1- (2,4,6-trichloro-phenyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl} - propan-1-ol,
<img file="ES2325596T3_D0207.tif" />
3- {1- [1- (2,6-dibromo-4-chloro-phenyl) -2,3,6-trimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4 -il} -propan-1-ol,
<img file="ES2325596T3_D0208.tif" />
ES 2 325 596 T3
3- {1- [1- (2,6-dibromo-4-chloro-phenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl } -propan-1-ol,
<img file="ES2325596T3_D0209.tif" />
3- {1- [1- (4-methoxy-2,6-dimethyl-phenyl) -2,3,6-trimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4 -il} -propan-1-ol,
<img file="ES2325596T3_D0210.tif" />
3- {1- [1- (4-methoxy-2,6-dimethyl-phenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl } -propan-1-ol,
<img file="ES2325596T3_D0211.tif" />
3- {1- [1- (4-isopropyl-2-methylsulfanyl-phenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl} - propan-1-ol,
<img file="ES2325596T3_D0212.tif" />
3- {1- [2,3,6-trimethyl-1- (2,4,5-tribromo-phenyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl } -propan-1-ol,
<img file="ES2325596T3_D0213.tif" />
ES 2 325 596 T3
3- {1- [3,6-dimethyl-1- (2,4,5-tribromo-phenyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl} - propan-1-ol,
<img file="ES2325596T3_D0214.tif" />
1- {1- [1- (4-bromo-2,6-dimethyl-phenyl) -2,3,6-trimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4 -yl} -ethane-1,2-diol,
<img file="ES2325596T3_D0215.tif" />
1- {1- [1- (4-bromo-2,6-dimethyl-phenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl } -ethane-1,2-diol,
<img file="ES2325596T3_D0216.tif" />
1- {1- [1- (4-bromo-2,6-dimethyl-phenyl) -2,3,6-trimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4 -yl} -propane-1,3-diol,
<img file="ES2325596T3_D0217.tif" />
1- {1- [1- (4-bromo-2,6-dimethyl-phenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl } -propane-1,3-diol,
<img file="ES2325596T3_D0218.tif" />
ES 2 325 596 T3
1- [1- (2,6-dibromo-4-isopropyl-phenyl) -2,3,6-trimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidine-4-carbonitrile,
<img file="ES2325596T3_D0219.tif" />
1- [1- (2,6-dibromo-4-isopropyl-phenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidine-4-carbonitrile,
<img file="ES2325596T3_D0220.tif" />
1- [2,3,6-trimethyl-1- (2,4,6-tribromo-phenyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidine-4-carbonitrile,
<img file="ES2325596T3_D0221.tif" />
1- [3,6-dimethyl-1- (2,4,6-tribromo-phenyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidine-4-carbonitrile,
<img file="ES2325596T3_D0222.tif" />
1- [1- (4-bromo-2,6-dichloro-phenyl) -2,3,6-trimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidine-4-carbonitrile,
<img file="ES2325596T3_D0223.tif" />
ES 2 325 596 T3
1- [1- (4-bromo-2,6-dichloro-phenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidine-4-carbonitrile,
<img file="ES2325596T3_D0224.tif" />
1- [2,3,6-trimethyl-1- (2,4,6-trichloro-phenyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidine-4-carbonitrile,
<img file="ES2325596T3_D0225.tif" />
1- [3,6-dimethyl-1- (2,4,6-trichloro-phenyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidine-4-carbonitrile,
<img file="ES2325596T3_D0226.tif" />
1- [1- (2,6-dibromo-4-chloro-phenyl) -2,3,6-trimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidine-4-carbonitrile,
<img file="ES2325596T3_D0227.tif" />
1- [1- (2,6-dibromo-4-chloro-phenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidine-4-carbonitrile,
<img file="ES2325596T3_D0228.tif" />
ES 2 325 596 T3
1- [1- (4-methoxy-2,6-dimethyl-phenyl) -2,3,6-trimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidine-4-carbonitrile,
<img file="ES2325596T3_D0229.tif" />
1- [1- (4-methoxy-2,6-dimethyl-phenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidine-4-carbonitrile,
<img file="ES2325596T3_D0230.tif" />
1- [1- (2-bromo-4-isopropyl-phenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidine-4-carbonitrile,
<img file="ES2325596T3_D0231.tif" />
1- [1- (4-isopropyl-2-methylsulfanyl-phenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidine-4-carbonitrile,
<img file="ES2325596T3_D0232.tif" />
1- [1- (2,4-dibromo-phenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidine-4-carbonitrile,
<img file="ES2325596T3_D0233.tif" />
ES 2 325 596 T3
1- [1- (2-bromo-4-trifluoromethyl-phenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidine-4-carbonitrile,
<img file="ES2325596T3_D0234.tif" />
1- [2,3,6-trimethyl-1- (2,4,5-tribromo-phenyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidine-4-carbonitrile,
<img file="ES2325596T3_D0235.tif" />
1- [3,6-dimethyl-1- (2,4,5-tribromo-phenyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidine-4-carbonitrile,
<img file="ES2325596T3_D0236.tif" />
{1- [1- (4-chloro-2,6-dimethyl-phenyl) -2,3,6-trimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl } -acetonitrile,
<img file="ES2325596T3_D0237.tif" />
{1- [1- (2,6-dibromo-4-isopropyl-phenyl) -2,3,6-trimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl } -acetonitrile,
<img file="ES2325596T3_D0238.tif" />
ES 2 325 596 T3 {1- [1- (2,6-dibromo-4-isopropyl-phenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin- 4-yl} -acetonitrile,
<img file="ES2325596T3_D0239.tif" />
{1- [2,3,6-trimethyl-1- (2,4,6-tribromo-phenyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl} - acetonitrile,
<img file="ES2325596T3_D0240.tif" />
{1- [3,6-dimethyl-1- (2,4,6-tribromo-phenyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl} -acetonitrile,
<img file="ES2325596T3_D0241.tif" />
{1- [1- (4-bromo-2,6-dichloro-phenyl) -2,3,6-trimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl } -acetonitrile,
<img file="ES2325596T3_D0242.tif" />
{1- [1- (4-bromo-2,6-dichloro-phenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl} - acetonitrile,
<img file="ES2325596T3_D0243.tif" />
ES 2 325 596 T3 {1- [2,3,6-trimethyl-1- (2,4,6-trichloro-phenyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin- 4-yl} -acetonitrile,
<img file="ES2325596T3_D0244.tif" />
{1- [3,6-dimethyl-1- (2,4,6-trichloro-phenyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl} -acetonitrile,
<img file="ES2325596T3_D0245.tif" />
{1- [1- (2,6-dibromo-4-chloro-phenyl) -2,3,6-trimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl } -acetonitrile,
<img file="ES2325596T3_D0246.tif" />
{1- [1- (2,6-dibromo-4-chloro-phenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl} - acetonitrile,
<img file="ES2325596T3_D0247.tif" />
{1- [1- (4-methoxy-2,6-dimethyl-phenyl) -2,3,6-trimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl } -acetonitrile,
<img file="ES2325596T3_D0248.tif" />
ES 2 325 596 T3 {1- [1- (4-methoxy-2,6-dimethyl-phenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin- 4-yl} -acetonitrile,
<img file="ES2325596T3_D0249.tif" />
{1- [1- (2-bromo-4-isopropyl-phenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl} -acetonitrile,
<img file="ES2325596T3_D0250.tif" />
{1- [1- (4-isopropyl-2-methylsulfanyl-phenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl} -acetonitrile,
<img file="ES2325596T3_D0251.tif" />
{1- [1- (2,4-dibromo-phenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl} -acetonitrile,
<img file="ES2325596T3_D0252.tif" />
{1- [1- (2-bromo-4-trifluoromethyl-phenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-yl} -acetonitrile,
<img file="ES2325596T3_D0253.tif" />
ES 2 325 596 T3 {1- [3,6-dimethyl-1- (2,4,5-tribromo-phenyl) -1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4- yl} -acetonitrile,
<img file="ES2325596T3_D0254.tif" />
1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4- ester ethyl ester carbonic acid ylmethyl,
<img file="ES2325596T3_D0255.tif" />
1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4-ylmethyl acid ester pyridine-2-carboxylic,
<img file="ES2325596T3_D0256.tif" />
1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4-ylmethyl acid ester methoxy-acetic,
<img file="ES2325596T3_D0257.tif" />
1- [1- (4-bromo-2,6-dimethyl-phenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] -piperidin-4-ylmethyl acid ester methoxy-acetic,
<img file="ES2325596T3_D0258.tif" />
ES 2 325 596 T3 1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] ester benzyl ester -piperidin-4-
<img file="ES2325596T3_D0259.tif" />
1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4-ylmethyl acid ester decanoic,
<img file="ES2325596T3_D0260.tif" />
1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4-ylmethyl acid ester
3-diethylamino-propionic,
<img file="ES2325596T3_D0261.tif" />
and mono- {1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4 ester -ylmethyl} of phosphoric acid.
<img file="ES2325596T3_D0262.tif" />
The compound represented by the formula [I] can be produced, for example, by the procedure shown in the following reaction scheme 1-4 [in the following reaction scheme, R<sup>1</sup>, R<sup>2</sup>, R<sup>3</sup>, R<sup>4</sup>, R<sup>5</sup>, R<sup>6</sup>, R<sup>7</sup>, R<sup>8</sup>, m, n, X, Y and Ar are defined as before; LG is a chloro, bromine, iodo, methanesulfonyloxy, benzenesulfonyloxy, 4-toluenesulfonyloxy or trifluoromethanesulfonyloxy group; Z<sup>1</sup> and Z<sup>2</sup> they are the same or different, and are independently chloride or bromide; R<sup>to</sup> and R<sup>b</sup> are the same or different, and are independently hydrogen, C1-C5 alkyl, C3-C8 cycloalkyl or (C3-C8 cycloalkyl) C1-C5 alkyl; and X<sup>to</sup> is - (CHR<sup>3</sup>) n-OH, - (CHR<sup>3</sup>)<sub>n</sub>-CN or -CO<sub>2</sub>- (C<sub>1</sub>-C<sub>5</sub>)].
ES 2 325 596 T3
Reaction scheme 1
<img file="ES2325596T3_D0263.tif" />
Stage 1
Compound (3), a compound of the present invention, can be obtained by reacting Compound (1) with Compound (2) in an inert solvent in the presence or absence of a base. As used herein, the base includes, for example, amines such as triethylamine, N, N-diisopropylethylamine, pyridine, and the like; inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium hydride, and the like; metal alcoholates such as sodium methoxide, sodium ethoxide, potassium t-butoxide, and the like; metal amides such as sodium amide, lithium diisopropylamide, and the like; and Grignard reagents such as methyl magnesium bromide and the like. The inert solvent includes, for example, alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol, and the like; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and the like; hydrocarbons such as benzene, toluene, xylene, and the like; amides such as N, N-dimethylformamide, N-methylpyrrolidone, N, N-dimethylacetamide, and the like; acetonitrile; dimethylsulfoxide; pyridine; Water; and mixtures of solvents selected from these inert solvents.
The compound of the present invention can be converted to a salt in an inert solvent with an inorganic acid such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid or the like, with an organic acid such as acetic acid, oxalic acid. , lactic acid, tartaric acid, fumaric acid, maleic acid, citric acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzoic acid, camphorsulfonic acid, ethanesulfonic acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, malic acid, malonic acid, mandelic acid, galactaric acid, naphthalene-2-sulfonic acid or the like, with an inorganic base such as lithium hydroxide, sodium hydroxide, potassium hydroxide , calcium hydroxide, magnesium hydroxide, zinc hydroxide, aluminum hydroxide or the like or with an organic base such as ammonia, arginine, lysine, piperazine, choline, diethylamine, 4-phenylcyclohexylamine, 2-aminoethanol, benzathine or the like. The inert solvent includes, for example, alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol, and the like; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and the like; hydrocarbons such as benzene, toluene, and the like; esters such as ethyl acetate, ethyl formate, and the like; ketones such as acetone, methyl ethyl ketone, and the like; amides such as N, N-dimethylformamide, N-methylpyrrolidone, N, N-dimethylacetamide, and the like; acetonitrile; dichloromethane; chloroform; dimethylsulfoxide; pyridine; Water; and mixtures of solvents selected from these inert solvents.
ES 2 325 596 T3
Reaction Scheme 2
<img file="ES2325596T3_D0264.tif" />
Stage 2
Compound (4) can be converted to Compound (6) by reacting Compound (4) with Compound (5) in an inert solvent in the presence or absence of a base. As used herein, the base includes, for example, amines such as triethylamine, N, N-diisopropylethylamine, pyridine, and the like; inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium hydride, and the like; metal alcoholates such as sodium methoxide, sodium ethoxide, potassium t-butoxide, and the like; metal amides such as sodium amide, lithium diisopropylamide, and the like; and Grignard reagents such as methyl magnesium bromide and the like. The inert solvent includes, for example, alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol, and the like; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and the like; hydrocarbons such as benzene, toluene, xylene, and the like; amides such as N, N-dimethylformamide, N-methylpyrrolidone, N, N-dimethylacetamide, and the like; acetonitrile; dimethylsulfoxide; pyridine; Water; and mixtures of solvents selected from these inert solvents.
Stage 3
Compound (6) can be converted to Compound (7) by reacting Compound (6) with malononitrile in an inert solvent in the presence or absence of a base. As used herein, the base includes, for example, amines such as triethylamine, N, N-diisopropylethylamine, pyridine, and the like; inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium hydride, potassium hydride and the like; metal alcoholates such as sodium methoxide, sodium ethoxide, potassium t-butoxide, and the like; metal amides such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazanide, sodium hexamethyldisilazanide, potassium hexamethyldisilazanide and the like; alkyl lithiums such as methyl lithium, n-butyl lithium, sec-butyl lithium, t-butyl lithium, and phenyl lithium; and Grignard reagents such as methyl magnesium bromide and the like. The inert solvent includes, for example, alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol, and the like; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and the like; hydrocarbons such as benzene, toluene, and the like; amides such as N, N-dimethylformamide, N-methylpyrrolidone, N, N-dimethylacetamide, and the like; acetonitrile; dimethylsulfoxide; pyridine; Water; and mixtures of solvents selected from these inert solvents.
ES 2 325 596 T3
Stage 4
Compound (7) can be converted to Compound (8) by acylation of the amino group in Compound (7) and followed by formation of the pyrimidine ring. Acylation and pyrimidine ring formation can occur continuously in a vessel. Acylation can be achieved by reacting Compound (7) with an acylating reagent in an inert solvent in the presence or absence of a base or an acid. The following pyrimidine ring formation can be carried out by heating the acylated compound in an inert solvent in the presence or absence of an acid. Herein, the acylating reagent includes, for example, halogenated acyls such as acetyl chloride, acetyl bromide, propionyl chloride, propionyl bromide, butyryl chloride, cyclopropanecarbonyl chloride, benzoyl chloride, and the like; acid anhydrides such as acetic anhydride, propionic anhydride, butyric anhydride, benzoic anhydride, and the like. The base includes, for example, amines such as triethylamine, N, N-diisopropylethylamine, pyridine, and the like; inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium hydride, potassium hydride and the like; metal alcoholates such as sodium methoxide, sodium ethoxide, potassium t-butoxide, and the like; metal amides such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazanide, sodium hexamethyldisilazanide, potassium hexamethyldisilazanide and the like; and Grignard reagents such as methyl magnesium bromide and the like. The acid includes, for example, organic acids such as formic acid, acetic acid, trifluoroacetic acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzoic acid, trifluoromethanesulfonic acid, and the like; inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, poly (phosphoric acid), nitric acid or the like. The inert solvent includes, for example, alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol, and the like; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and the like; hydrocarbons such as benzene, toluene, xylene, and the like; amides such as N, N-dimethylformamide, N-methylpyrrolidone, N, N-dimethyl-acetamide, and the like; acetonitrile; dimethylsulfoxide; pyridine; acetic acid; Water; and mixtures of solvents selected from these inert solvents.
Stage 5
Compound (8) can be converted to Compound (9) by reacting (8) with a halogenating reagent or a sulfonating reagent in the presence or absence of a base in an inert solvent or without a solvent. As used herein, the halogenating reagent includes, for example, phosphoryl chloride, phosphoryl bromide, phosphorous pentachloride, phosphorous trichloride, phosphorous pentabromide, phosphorous tribromide, chloride chloride, thionyl bromide, oxalyl chloride, oxalyl bromide, and the like. . The sulfonating reagent includes, for example, p-toluenesulfonyl chloride, methanesulfonyl chloride, p-toluenesulfonic anhydride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, N-phenylbis (trifluoromethanesulfonimide), and the like. The base includes, for example, amines such as triethylamine, N, N-diisopropylethylamine, pyridine, N, N-dimethylaniline, N, N-diethylaniline, and the like; inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium hydride, and the like; metal alcoholates such as sodium methoxide, sodium ethoxide, potassium t-butoxide, and the like; metal amides such as sodium amide, lithium diisopropylamide, and the like; and Grignard reagents such as methyl magnesium bromide and the like. The inert solvent includes, for example, alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol, and the like; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and the like; hydrocarbons such as benzene, toluene, and the like; amides such as N, N-dimethylformamide, N-methylpyrrolidone, N, N-dimethylacetamide, and the like; dichloromethane; chloroform; acetonitrile; dimethylsulfoxide; pyridine; Water; and mixtures of solvents selected from these inert solvents.
Stage 6
Compound (9) can be converted to Compound (11) by reacting Compound (9) with Compound (10) in the same method as in step 1.
Stage 7
Compound (11) can be converted to Compound (12) by reducing compound (11) with a conventional reducing agent in an inert solvent. Or if necessary, treatment with an acid in the presence or absence of an inert solvent after reduction can provide compound (12). When X<sup>to</sup> is -CO<sub>2</sub>- (C<sub>1</sub>C5), the ester group can be converted to a hydroxymethyl group at the same time. Herein, the reducing agent includes, for example, lithium borohydride, sodium borohydride, calcium borohydride, lithium triethylborohydride, lithium tri-sec-butylborohydride, potassium tri-sec-butylborohydride, zinc borohydride, borane , lithium trimethoxyborohydride, lithium triacetoxyborohydride, tetramethylammonium borohydride, lithium aluminum hydride, sodium aluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, isobutylaluminum hydride, trichlorosilane and the like. The reduction can also be carried out by hydrogenation using a catalyst including palladium, platinum dioxide, Raney nickel, or the like. The acid includes, for example, organic acids such as acetic acid, trifluoroacetic acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzoic acid, and the like; inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, po
ES 2 325 596 T3 li (phosphoric acid), nitric acid or the like. The inert solvent includes, for example, alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol, and the like; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and the like; hydrocarbons such as benzene, toluene, and the like; amides such as N, N-dimethylformamide, N-methylpyrrolidone, N, N-dimethylacetamide, and the like; acetonitrile; dimethylsulfoxide; pyridine; Water; and mixtures of solvents selected from these inert solvents.
Reaction Scheme 3
<img file="ES2325596T3_D0265.tif" />
Stage 8
Compound (7) can be converted to Compound (13) by reacting Compound (7) with ketones such as acetone and the like; vinyl ethers such as isopropenylmethyl ether and the like in an inert solvent in the presence or absence of an acid, and the following conversion of Compound (13) to Compound (14) can be carried out in the presence of a base in an inert solvent. As used herein, the acid includes, for example, organic acids such as acetic acid, trifluoroacetic acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzoic acid, and the like. The base includes, for example, amines such as triethylamine, N, N-diisopropylethylamine, pyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene, and the like; inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium hydride, and the like; metal alcoholates such as sodium methoxide, sodium ethoxide, potassium t-butoxide, and the like; metal amides such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazanide, sodium hexamethyldisilazanide, potassium hexamethyldisilazanide and the like; alkyl lithiums such as n-butyl lithium, sec-butyl lithium, t-butyl lithium, methyl lithium, and the like; and Grignard reagents such as methyl magnesium bromide and the like. The inert solvent includes, for example, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and the like; hydrocarbons such as benzene, toluene, and the like; amides such as N, N-dimethylformamide, N-methylpyrrolidone, N, N-dimethylacetamide, and the like; acetonitrile; dimethylsulfoxide; pyridine; and mixtures of solvents selected from these inert solvents.
ES 2 325 596 T3
Stage 9
Compound (14) can be converted to Compound (15) in the same way as in step 7.
Stage 10
Compound (15) can be converted to Compound (16) through the corresponding diazonium compound. Conversion to the diazonium compound can be carried out using, for example, sodium nitrite, potassium nitrite, butyl nitrite, tert-butyl nitrite, isobutyl nitrite or the like in the presence or absence of an acid in a solvent. inert. The acid includes, for example, inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, nitric acid, or the like. The inert solvent includes, for example, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and the like; hydrocarbons such as benzene, toluene, and the like; amides such as N, N-dimethylformamide, N-methylpyrrolidone, N, N-dimethylacetamide, and the like; acetonitrile; dimethylsulfoxide; pyridine; Water; and mixtures of solvents selected from these inert solvents.
Stage 11
Compound (16) can be converted to Compound (17) in the same way as in step 5.
Stage 12
When LG is chloride, bromide or iodide, Compound (17) can be obtained from Compound (15) directly by forming the diazonium compound in the presence of one or more metal salts in an inert solvent. The formation of the diazonium compound can be carried out in the same way as in step 1. Metal salts include, for example, potassium iodide, potassium bromide, sodium iodide, sodium bromide, sodium chloride, copper (I) chloride, copper (II) chloride, copper (I) bromide, bromide copper (II), copper (I) iodide and the like. The inert solvent includes, for example, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and the like; hydrocarbons such as benzene, toluene, and the like; amides such as N, N-dimethylformamide, N-methylpyrrolidone, N, N-dimethylacetamide, and the like; acetonitrile; dimethylsulfoxide; pyridine; Water; and mixtures of solvents selected from these inert solvents.
Stage 13
Compound (17) can be converted to Compound (18) in the same way as in step 1.
Stage 14
When X<sup>to</sup> is -CO<sub>2</sub>- (Ci-C alkyl<sub>5</sub>), the ester group can be converted to a hydroxymethyl group in the same way as in step 7.
Reaction Scheme 4
<img file="ES2325596T3_D0266.tif" />
Stage 15
Compound (20) can be converted to Compound (21) by coupling compound (20) to the corresponding carboxylic acid using a conventional coupling reagent in the presence or absence of an additive or base in an inert solvent or by coupling compound (20 ) to the corresponding acyl halide in the presence or absence of a base in an inert solvent. When R<sup>9</sup> has protecting groups of an amino group, a hydroxy group, a mercapto group, a carboxy group, a guanidine group or a phosphoric acid group, those protecting groups can be
ES 2 325 596 T3 separate by conventional methods for deprotection (ref. Theodora W. Greene and Peter GM Wuts "Protective Groups in Organic Synthesis"; Wiley-Interscience) after the above coupling. Herein, the coupling reagent includes, for example, N, N'-dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDC), 1,1'-carbonyldiimidazole (CDI), diphenylphosphorylazide (DPPA ), diethyl cyanophosphate and the like. The additive includes, for example, 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide, 4-dimethylaminopyridine, and the like. The base includes amines such as triethylamine, N, N-diisopropylethylamine, pyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene, and the like; inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium hydride, and the like; metal alcoholates such as sodium methoxide, sodium ethoxide, potassium t-butoxide, and the like; metal amides such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazanide, sodium hexamethyldisilazanide, potassium hexamethyldisilazanide and the like; alkyl lithiums such as n-butyl lithium, sec-butyl lithium, t-butyl lithium, methyl lithium, and the like; and Grignard reagents such as methyl magnesium bromide and the like. The inert solvent includes, for example, alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol, and the like; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and the like; hydrocarbons such as benzene, toluene, and the like; amides such as N, N-dimethylformamide, N-methylpyrrolidone, N, N-dimethylacetamide, and the like; acetonitrile; dimethylsulfoxide; pyridine; chloroform; dichloromethane; Water; and mixtures of solvents selected from these inert solvents.
The compound of the present invention is useful as a therapeutic or prophylactic agent for diseases in which CRF is believed to be involved. For this purpose, the compound of the present invention can be formulated into tablets, pills, capsules, granules, powders, solutions, emulsions, suspensions, injectables and the like by a conventional preparation technique by adding fillers, binders, disintegrators, adjusting agents. pH, solvents, etc. conventional.
The compound of the present invention can be administered to an adult patient at a dose of 0.1 to 500 mg per day in one or several portions orally or parenterally. The dose can be appropriately increased or decreased depending on the kind of disease and the age, body weight and symptoms of the patient.
Embodiments of the invention
The present invention is explained concretely with reference to the following examples and test examples, but is not limited thereto.
Reference Example 1
Synthesis of 2- {1- [7- (4-bromo-2,6-dimethylphenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] piperidin4-yl} hydrochloride ethanol (compound 1-074)
<img file="ES2325596T3_D0267.tif" />
1. (1) A mixture of 7- (4-bromo-2,6-dimethylphenyl) -4-chloro-2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidine (6.0 g), 4- (2-hydroxyethyl) piperidine (3.2 g), N, N-diisopropylethylamine (3.2 g) in ethanol (15 mL) was heated under reflux for 5.5 hours. The reaction mixture was cooled to room temperature, poured into saturated aqueous sodium hydrogen carbonate, and then extracted with ethyl acetate three times. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (silica gel: Wako Gel (C<sub>2</sub>00), eluent: hexane / ethyl acetate = 2: 1) to obtain 2- {1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5-dimethyl-7Hpyrrolo [2,3 -d] pyrimidin-4-yl] -piperidin-4-yl} -ethanol as a white solid (6.41 g).
2. (2) To a suspension of 2- {1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl ] -piperidin-4-yl} -ethanol (6.41 g) in ethanol (51 mL) was added 4M HCl in ethyl acetate (4.2 mL) under ice-cooling. After removing the solvent, ethyl acetate (26 mL) was added to the residue. The mixture was stirred overnight to provide a white crystal. The crystal was collected by filtration to give the title compound (6.1 g).
mp 187-189 ° C.
Table 1 and Table 2 list the compound obtained in Example 1 and the compounds obtained by the procedure similar to that of Example 1.
ES 2 325 596 T3
Example 2
Synthesis of 1- [7- (2-bromo-4-trifluoromethylphenyl) -2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidino-4-yl] piperidine-3-carbonitrile optically active (compound 1-134, 1-135, 1-136 and 1-137)
<img file="ES2325596T3_D0268.tif" />
A mixture of 7- (2-bromo-4-trifluoromethylphenyl) -4-chloro-2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidine (400 mg), piperidine-3-carbonitrile (290 mg), N, N-diisopropylethylamine (309 mg) in ethanol (2 mL) was heated under reflux for 6 days. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel: Wako Gel (C<sub>2</sub>00), eluent: hexane / ethyl acetate = 5: 1) to obtain two diastereoisomers (less polar diastereoisomer: 62 mg and more polar diastereoisomer: 36 mg) of 1- [7- (2-bromo-4-trifluoromethylphenyl) - 2,5,6-trimethyl-7H-pyrrolo [2,3-d] pyrimidino-4-yl] piperidine-3-carbonitrile.
Least polar diastereoisomer:
Rf value 0.64 (developing solvent: hexane / ethyl acetate = 1: 1, Silica Gel 60 F TLC Plate<sub>254 </sub>(Merck))
H NMR<sup>1</sup> (300 MHz) δ 1.68-1.83 (1H, m), 1.85-2.07 (3H, m), 2.08 (3H, s), 2.40 (3H, s ), 2.51 (3H, s), 3.04-
3.16 (1H, m), 3.26-3.62 (3H, m), 3.81-3.95 (1H, m), 7.43 (1H, d, J = 8 , 2Hz), 7.74 (1H, d, J = 8.2Hz), 8.02 (1H, s)
Most polar diastereoisomer:
Rf value 0.56 (developing solvent: hexane / ethyl acetate = 1: 1, Silica Gel 60 F TLC plate<sub>254 </sub>(Merck))
H NMR<sup>1</sup> (300 MHz) δ 1.65-1.83 (1H, m), 1.82-2.16 (6H, m), 2.40 (3H, s), 2.51 (3H, s), 3 , 04-3.17 (1H, m),
3.28-3.63 (3H, m), 3.85-3.98 (1H, m), 7.47 (1H, d, J = 8.6 Hz), 7.74 (1H, d, J = 8.6 Hz), 8.02 (1H, s)
The less polar diastereoisomer was optically resolved by high performance liquid chromatography to yield each enantiomer.
Compound 1-134:
H NMR<sup>1</sup> (300 MHz) δ 1.68-1.83 (1H, m), 1.85-2.07 (3H, m), 2.08 (3H, s), 2.40 (3H, s ), 2.51 (3H, s), 3.04-
3.16 (1H, m), 3.26-3.62 (3H, m), 3.81-3.95 (1H, m), 7.43 (1H, d, J = 8 , 2Hz), 7.74 (1H, d, J = 8.2Hz), 8.02 (1H, s)
HPLC retention time: 20.0 min. (CHIRAL PAK AD (DAICEL CHEMICAL INDUSTRIES, LTD), 2.0 cm ID x 25 cm, mobile phase: hexane - IPA = 4: 1, flow rate: 5.0 mL / min.)
Compound 1-135:
H NMR<sup>1</sup> (300 MHz) δ 1.68-1.83 (1H, m), 1.85-2.07 (3H, m), 2.08 (3H, s), 2.40 (3H, s ), 2.51 (3H, s), 3.04-
3.16 (1H, m), 3.26-3.62 (3H, m), 3.81-3.95 (1H, m), 7.43 (1H, d, J = 8 , 2Hz), 7.74 (1H, d, J = 8.2Hz), 8.02 (1H, s)
HPLC retention time: 23.0 min. (CHIRAL PAK AD (DAICEL CHEMICAL INDUSTRIES, LTD), 2.0 cm ID x 25 cm, mobile phase: hexane - IPA = 4: 1, flow rate: 5.0 mL / min.)
The more polar diastereoisomer was also optically resolved by high performance liquid chromatography to yield each enantiomer.
ES 2 325 596 T3
Compound 1-136:
H NMR<sup>1</sup> (300 MHz) δ 1.65-1.83 (1H, m), 1.82-2.16 (6H, m), 2.40 (3H, s), 2.51 (3H, s), 3 , 04-3.17 (1H, m),
3.28-3.63 (3H, m), 3.85-3.98 (1H, m), 7.47 (1H, d, J = 8.6 Hz), 7.74 (1H, d, J = 8.6 Hz), 8.02 (1H, s)
HPLC retention time: 21.4 min. (CHIRAL PAK AD (DAICEL CHEMICAL INDUSTRIES, LTD), 2.0 cm ID x 25 cm, mobile phase: hexane - IPA = 4: 1, flow rate: 5.0 mL / min.)
Composite 1-137:
H NMR<sup>1</sup> (300 MHz) δ 1.65-1.83 (1H, m), 1.82-2.16 (6H, m), 2.40 (3H, s), 2.51 (3H, s), 3 , 04-3.17 (1H, m),
3.28-3.63 (3H, m), 3.85-3.98 (1H, m), 7.47 (1H, d, J = 8.6 Hz), 7.74 (1H, d, J = 8.6 Hz), 8.02 (1H, s)
HPLC retention time: 32.8 min. (CHIRAL PAK AD (DAICEL CHEMICAL INDUSTRIES, LTD), 2.0 cm ID x 25 cm, mobile phase: hexane - IPA = 4: 1, flow rate: 5.0 mL / min.)
Table 1 lists the compounds obtained in Example 2.
Reference Example 3
Synthesis of {1- [7- (4-bromo-2,6-dimethylphenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] piperidin-4yl} methanol hydrochloride ( 1-054)
<img file="ES2325596T3_D0269.tif" />
1. (1) To a solution of 4-bromo-2,6-dimethylaniline (100.0 g) in tetrahydrofuran (400 mL) was added triethylamine (60.7 g) and 2-bromopropionyl bromide (129.5 g) cooling with ice. The mixture was stirred at room temperature for 1 hour and cooled in a cooling ice bath. Aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The precipitate was collected by filtration, washed with water and diethyl ether, and dried to yield 2-bromo-N- (4-bromo-2,6-dimethylphenyl) propionamide (151.2 g).
mp 187-189 ° C
<img file="ES2325596T3_D0270.tif" />
2. (2) To a suspension of NaH (17.2 g) in tetrahydrofuran (500 mL) was added a solution of malononitrile (28.4 g) in tetrahydrofuran (100 mL) under ice-cooling and the mixture was stirred at room temperature for 1 hour. 2-Bromo-N- (4-bromo-2,6-dimethylphenyl) propionamide (120 g) was added and the mixture heated under reflux for 1 hour. Cooling with ice, an aqueous ammonium chloride solution was added and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to produce a solid. The solid was washed with a mixture of diisopropyl ether and ethyl acetate and filtered, dried to yield 2-amino-1- (4-bromo2,6-dimethylphenyl) -4-methyl-5-oxo-4,5- dihydro-1H-pyrrolo-3-carbonitrile (110.1 g).
<img file="ES2325596T3_D0271.tif" />
ES 2 325 596 T3
3. (3) To a suspension of 2-amino-1- (4-bromo-2,6-dimethylphenyl) -4-methyl-5-oxo-4,5-dihydro-1H-pyrrolo-3-carbonitrile (100 g) Acetic anhydride (38.3 g) was added in acetic acid (100 mL) and the mixture was refluxed for 8 hours. After cooling to room temperature, the solvent was concentrated under reduced pressure, and water was added and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the residue was crystallized from a mixture of ethyl acetate and diisopropyl ether to yield 7- (4-bromo-2,6-dimethylphenyl) -4-hydroxy-2,5-dimethyl-5.7 -dihydropyrrolo [2,3-d] pyrimidin-6-one (56.6 g).
<img file="ES2325596T3_D0272.tif" />
Four. (4) To a suspension of 7- (4-bromo-2,6-dimethylphenyl) -4-hydroxy-2,5-dimethyl-5,7-dihydropyrrolo [2,3-d] pyrimidin-6-one (10 , 0 g) in phosphoryl chloride (25.7 mL) was added N, N-dimethylaniline (2.6 mL) and the mixture was heated at 120 ° C for 6 hours. After cooling to room temperature the mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to produce a solid. The solid was washed with diisopropyl ether to provide 7- (4-bromo-2,6-dimethylphenyl) -4-chloro-2,5-dimethyl-5,7-dihydropyrrolo [2,3-d] pyrimidin6-one (8 , 0 g).
mp 148-150 ° C
<img file="ES2325596T3_D0273.tif" />
5. (5) A suspension of 7- (4-bromo-2,6-dimethylphenyl) -4-chloro-2,5-dimethyl-5,7-dihydropyrrolo [2,3-d] pyrimidin-6one (7.5 g ), ethyl isonipecotate (4.7 g), N, N-diisopropylethylamine (3.8 g) in ethanol (35 mL) was heated under reflux for 12 hours. The reaction mixture was stirred at room temperature to provide a solid. The solid was collected by filtration and washed with cold ethanol to yield 1- [7- (4-bromo-2,6-dimethylphenyl) -2,5-dimethyl-6-oxo-6,7-dihydro ethyl ester. -5H-pyrrolo [2,3-d] pyrimidin-4-yl] piperidine4-carboxylic acid (7.7 g).
mp 159-161 ° C
<img file="ES2325596T3_D0274.tif" />
6. (6) To a solution of lithium borohydride (2.61 g) in tetrahydrofuran (60 mL) was added a solution of 1- [7- (4-bromo-2,6-dimethylphenyl) -2 acid ethyl ester , 5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-4-yl] piperidine-4-carboxylic acid (6.0 g) in a mixture of tetrahydrofuran (60 mL ) and methanol (3 mL) dropwise over 10 minutes under ice-cooling. The reaction mixture was warmed to room temperature and stirred for 3 hours. After cooling with an ice bath, a 6M HCl aqueous solution (30 mL) was added and stirred at room temperature for 1 hour. The solution was made alkaline (pH = 9) with a 6M NaOH aqueous solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (silica gel: Wako Gel (C<sub>2</sub>00), eluent: hexane / ethyl acetate = 1: 1) to yield {1- [7- (4-bromo-2,6-dimethylphenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidine -4-yl] piperidin-4-yl} methanol (4.6 g).
ES 2 325 596 T3
7. (7) To a suspension of {1- [7- (4-bromo-2,6-dimethylphenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] piperidin-4 -il} methanol (0.71 g) in water (7 mL) was added an aqueous solution of concentrated HCl (0.15 mL) under ice-cooling. The mixture was stirred at room temperature for 5 minutes, cooled with an ice bath again, and stirred for 15 minutes in a cooling ice bath. The precipitate was collected by filtration; washed with water and dried to give the title compound (0.73 g).
Example 4
Synthesis of {1- [1- (4-chloro-2,6-dimethylphenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] piperidin-4yl} methanol hydrochloride ( 2-019)
<img file="ES2325596T3_D0275.tif" />
1. (1) To a solution of 2-amino-1- (4-chloro-2,6-dimethylphenyl) -4-methyl-5-oxo-4,5-dihydro-1H-pyrrolo-3-carbonitrile (44.1 g), which was obtained by the same method as in example 3, in tetrahydrofuran (220 mL) isopropenyl-methylether (46.2 g) and p-toluenesulfonic acid (608 mg) were added. The mixture was refluxed for 1 hour. After removing the solvent under reduced pressure, the residue was dissolved in tetrahydrofuran (500 mL) and cooled in an ice-NaCl bath. A solution of lithium diisopropylamide in tetrahydrofuran (generated from 2.64 M n-butyl lithium in hexane (127 mL), diisopropylamine (40.5 g) and tetrahydrofuran (300 mL)) was added dropwise throughout 30 minutes, and stirred at room temperature for 1 hour. A saturated aqueous NH solution was added to the reaction mixture.<sub>4</sub>Cl and separated. The aqueous layer was extracted with CHCl<sub>3</sub>. The organic layer was washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (silica gel: Wako Gel (C200), eluent: hexane / ethyl acetate = 1: 1) to yield 4-amino- 1- (4-chloro-2,6-dimethylphenyl) -3,6-dimethyl-1,3-dihydropyrrolo [2,3-b] pyridin-2-one (35.8 g) in amorphous form.
MS (ES, Pos.): 316 (M + 1)<sup>+</sup>, 318 (M + 3)<sup>+</sup>, 338 (M + Na)<sup>+</sup>.340 (M + Na + 2)<sup>+</sup>
<img file="ES2325596T3_D0276.tif" />
2. (2) To a suspension of lithium borohydride (11.6 g) in tetrahydrofuran (50 mL) was added a solution of 4-amino-1- (4-chloro-2,6-dimethylphenyl) -3,6- dimethyl-1,3-dihydropyrrolo [2,3-b] pyridin-2-one (33.7 g) in tetrahydrofuran (100 mL). The mixture was stirred under reflux for 1 hour. After cooling with an ice cooling bath, a 6M aqueous HCl solution was slowly added. The solution was made alkaline (pH = 9) with a 4M NaOH aqueous solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (silica gel: Wako Gel (C200), eluent: hexane / ethyl acetate = 3: 1) to yield 1- (4 -chloro-2,6-dimethylphenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-ylamine (17.9 g) as a solid.
mp 190-192 ° C
<img file="ES2325596T3_D0277.tif" />
ES 2 325 596 T3
3. (3) Cooling with ice, to a suspension of 1- (4-chloro-2,6-dimethylphenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin4-ylamine (17.9 g) In a mixture of 1,4-dioxane (45 mL) and water (45 mL), a mixture of H<sub>2</sub>SW<sub>4</sub> concentrate (17.8 mL) and water (90 mL) and then a NaNO solution<sub>2</sub> (6.2 g) in water (62 mL). The mixture was stirred at room temperature for 20 minutes, and heated at 100 ° C for 1.5 hours. After cooling in an ice cooling bath, the reaction mixture was poured into a saturated aqueous NaHCO solution.<sub>3</sub> and extracted with CHCl<sub>3</sub>. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to produce a solid. The solid was washed with a mixture of ethyl acetate and diisopropyl ether (1: 5) to yield 1- (4-chloro-2,6-dimethylphenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridine -4-ol (14.4 g).
mp 260 ° C (decomp.)
<img file="ES2325596T3_D0278.tif" />
Four. (4) To a mixture of 1- (4-chloro-2,6-dimethylphenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-ol (14.4 g) and triethylamine (9.7 g) in CHCl3 (100 mL) was added trifluoromethanesulfonic anhydride (9.7 mL) in a cooling ice bath. After stirring for 10 minutes, water was added and extracted with CHCl3. The organic layer was washed with water and brine successively, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to yield crude trifluoromethanesulfonic acid 1- (4-chloro-2,6-dimethylphenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-folic ester (20.7 g).
A mixture of crude trifluoromethanesulfonic acid 1- (4-chloro-2,6-dimethylphenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl ester (20.5 g), Ethyl isonipecotate (74.4 g) and N, N-diisopropylethylamine (12.2 g) were heated at 150-170 ° C for 1 hour. To the reaction mixture, water was added and extracted with ethyl acetate. The organic layer was washed with water, and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (silica gel: Wako Gel (C200), eluent: hexane / ethyl acetate = 5: 1) to yield acid ethyl ester 1- [1- (4-chloro-2,6-dimethylphenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] piperidine-4-carboxylic form (16.6 g) as colorless yellow solid.
mp 140-142 ° C
<img file="ES2325596T3_D0279.tif" />
5. (5) To a suspension of lithium borohydride (4.11 g) in tetrahydrofuran (50 mL) was added a solution of 1- [1- (4-chloro-2,6-dimethylphenyl) -3 , 6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] piperidine-4-carboxylic acid (16.6 g) in a mixture of tetrahydrofuran (80 mL) and methanol (7.7 mL) in a bath coolant with ice. The mixture was stirred at room temperature for 2 hours. After cooling with an ice cooling bath, water was added and the mixture was slowly poured into a 3M HCl aqueous solution. The solution was made alkaline (pH = 8) with a 4M NaOH aqueous solution to produce a solid. The solid was collected by filtration and washed with water and diethyl ether. The solid was recrystallized from a mixture of ethanol and ethyl acetate to yield {1- [1- (4-chloro-2,6-dimethylphenyl) -3,6-dimethyl-1H-pyrrolo [2,3-b] pyridine -4-yl] piperidin-4-yl} methanol (9.1 g).
6. (6) By the same method as Example 1- (2), the title compound (8.0 g) was obtained from {1- [1- (4-chloro-2,6-dimethylphenyl) - 3,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl] piperidin-4-yl} methanol (9.1 g).
ES 2 325 596 T3
Example 5
Ethyl ester synthesis of 1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin- 4-ylmethyl carbonic acid (3-001)
<img file="ES2325596T3_D0280.tif" />
{1- [7- (4-bromo-2,6-dimethylphenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] piperidin-4-yl} methanol (1 , 15 g) synthesized in a similar manner to example 1 in tetrahydrofuran (25 mL) was stirred, then NaH (60% in paraffin, 0.10 g) was added and the mixture was heated under reflux for 3 hours. After cooling to 0 ° C, ethyl chloroformate (0.28 g) in a small amount of tetrahydrofuran was added and the reaction mixture was allowed to reach room temperature and evaporated. The residue was purified on silica gel on a glass filter (eluent: CH<sub>2</sub>Cl<sub>2</sub>/ CH<sub>3</sub>CN = 95: 5 then 90:10) to yield the title product (366 mg).
Table 3 lists the compound obtained in Example 5 and the compounds obtained by the procedure similar to that of Example 5.
Example 6
Synthesis of 1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4-ylmethyl ester decanoic acid (3-009)
<img file="ES2325596T3_D0281.tif" />
Under nitrogen atmosphere, {1- [7- (4-bromo-2,6-dimethylphenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] piperidin-4- yl} methanol (1.15 g) synthesized in a similar manner to example 1 in tetrahydrofuran (25 mL) was stirred, then NaH (60% in paraffin, 0.10 g) was added and the mixture was heated to reflux overnight, providing mixture (I). Decanoic acid (0.45 g) was stirred in tetrahydrofuran (25 mL), then 1,1'-carbonyldiimidazole (0.42 g) was added and the mixture was stirred overnight at room temperature to provide mixture (II) . The mixture (II) was added dropwise to the mixture (I) at 0-5 ° C and the reaction mixture was allowed to reach room temperature. The solvent was evaporated and the residue was purified on silica gel on a glass filter (eluent: CH<sub>2</sub>Cl<sub>2</sub>/ CH<sub>3</sub>CN = 100: 0, 95: 5 then 90:10) to yield the title product (888 mg).
Table 3 lists the compound obtained in Example 6 and the compounds obtained by the procedure similar to that of Example 6.
Example 7
Synthesis of 1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4-ylmethyl ester eicosa-5,8,11,14-tetraenoic acid (3-020)
<img file="ES2325596T3_D0282.tif" />
ES 2 325 596 T3
Under nitrogen atmosphere, to a solution of 1- [7- (4-bromo-2,6-dimethylphenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] piperidin- 4-yl} methanol (606 mg) in CH2Cl2 (20 ml) was added arachidonic acid (500 mg), 4-dimethylaminopyridine (33 mg) and N, N'-dicyclohexylcarbodiimide (565 mg). The mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel: Wako Gel (C200), eluent: hexane / ethyl acetate = 7: 1) to yield the title compound (990 mg) as an oil .
Table 3 lists the compound obtained in Example 7 and the compounds obtained by the procedure similar to that of Example 7.
Example 8
Synthesis of 1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4-ylmethyl ester of (S) -2-tert-butoxycarbonylamino-3- (1H-indol-3-yl) -propionic acid (3-014) and 1- [7- (4-bromo-2,6-dimethylphenyl) -2 ester (S) -2-amino-3- (1H-indol-3-yl) -propionic acid, 5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin-4-ylmethyl (3-016)
<img file="ES2325596T3_D0283.tif" />
1. (1) A solution of N- (tert-butoxycarbonyl) -L-tryptophan (510 mg) and 1,1'-carbonyldiimidazole (330 mg) in acetonitrile (10 mL) was stirred at room temperature overnight. The solvent was evaporated and the residue was redissolved in toluene (5 mL). {1- (7- (4-bromo-2,6-dimethylphenyl) -2,5-dimethyl7H-pyrrolo [2,3-d] pyrimidin-4-yl] piperidin-4-yl} methanol (594 mg) and 1,8-diazabicyclo [5.4.0] undec-7-ene (40 juL) and stirred at room temperature for 2 days. After evaporation of the solvent, the residue was extracted with ethyl acetate and a dilute NaHCO solution.<sub>3</sub>. After the usual work-up, the extract residue was purified on silica gel (eluent: CH<sub>2</sub>Cl<sub>2</sub>/ MeOH = 95: 5) to yield the title product 3-014 (578 mg).
<img file="ES2325596T3_D0284.tif" />
2. (2) To a solution of 3-014 (1.16 g) in CH<sub>2</sub>Cl<sub>2</sub> (200 mL) a 6M solution of HCl in isopropanol (2.7 mL) was added and it was stirred at room temperature for 2 days. After evaporation, the residue was purified by reverse phase chromatography (BDS RP18, 8 μm particle size, 200 g, 5 cm ID column, eluent: (NH gradient<sub>4</sub>Ac 0.5% / CH<sub>3</sub>CN: 9: 1 (v / v)) / CH<sub>3</sub>CN 85/15 to 1/9). After partial evaporation of the aqueous fractions, a fine precipitate of pure Compound is formed and recovered, yielding the title Compound 3-016 (139 mg). The aqueous filtrate was extracted with CH2Cl2 and the organic extract was washed with dilute ammonia. After the usual treatment of the organic extract, slightly more product 3-016 (304 mg) was recovered.
ES 2 325 596 T3
Example 9
Diethyl ester synthesis of 1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin- 4-ylmethyl phosphoric acid (3-017)
<img file="ES2325596T3_D0285.tif" />
Under nitrogen atmosphere, to a solution of {1- [7- (4-bromo-2,6-dimethylphenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] piperidin -4-yl} methanol (0.50 g) and 4-dimethylaminopyridine (0.55 g) in CH2Cl2 (50 mL) at 0 ° C diethyl chlorophosphate (0.38 g) was added dropwise and the reaction slowly warmed to room temperature. The reaction mixture was poured into ice water and extracted with CH2Cl2. After the usual work-up, the residue was purified on silica gel on a glass filter (eluent: CH<sub>2</sub>Cl<sub>2</sub>/ MeOH = 98: 2) yielding product 3-017 (0.31 g).
Example 10
Mono- {1- [7- (4-bromo-2,6-dimethyl-phenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] -piperidin- ester synthesis 4-ylmethyl} phosphoric acid (3-018)
<img file="ES2325596T3_D0286.tif" />
The diphenoxyphosphate ester of {1- [7- (4-bromo-2,6-dimethylphenyl) -2,5-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl] piperidin-4-yl} Methyl (1.8 g), which was produced in a similar manner to Example 9, was dissolved in 50% NaOH (1 mL) and dioxane (50 mL) and stirred at 60 ° C for several hours until hydrolysis was complete. The solution was treated with water (25 mL), acidified with HCl until pH = 2 and extracted five times with CH2Cl2 in portions, using NaCl to improve phase separation. After the usual work-up, the residue was purified on silica gel on a glass filter (eluent: CH<sub>2</sub>Cl<sub>2</sub>/ MeOH = 9: 1 to neat MeOH) yielding the title product 3-0 18 (0.38 g).
(Table goes to next page)
ES 2 325 596 T3
<img file="ES2325596T3_D0287.tif" />
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<td>1 l</td><td>p- HO</td><td>λ</td><td colspan="2"> 7* ‘</td><td colspan="2"></td><td colspan="2">HO</td><td></td><td> 8</td><td colspan="2"> -</td>
<td colspan="2">r ~ d i !</td><td>r4</td><td colspan="2">vH</td><td colspan="2">vH</td><td colspan="2">Rh</td><td> 5—1</td><td></td><td colspan="2">γΉ</td>
<td>Cñ m</td><td></td><td>OR</td><td>t — 1</td><td></td><td>CM ^ -H</td><td></td><td>CO</td><td></td><td></td><td></td><td>IT</td><td></td>
<td>Or |</td><td></td><td>or</td><td>I heard</td><td></td><td>or i</td><td></td><td>XJ 'O i</td><td></td><td>or</td><td></td><td>'sT o</td><td></td>
<td>Rh</td><td></td><td>r4</td><td>l! —1</td><td></td><td>I rH</td><td></td><td>1 t — 1</td><td></td><td>i — 1</td><td></td><td>i — 1</td><td></td>
ES 2 325 596 T3
<img file="ES2325596T3_D0293.tif" />
ES 2 325 596 T3
<img file="ES2325596T3_D0294.tif" />
ES 2 325 596 T3
<img file="ES2325596T3_D0295.tif" />
ES 2 325 596 T3
<img file="ES2325596T3_D0296.tif" />
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<img file="ES2325596T3_D0297.tif" />
ES 2 325 596 T3
<img file="ES2325596T3_D0298.tif" />
ES 2 325 596 T3
<img file="ES2325596T3_D0299.tif" />
ES 2 325 596 T3
<img file="ES2325596T3_D0300.tif" />
ES 2 325 596 T3
<img file="ES2325596T3_D0301.tif" />
<td>OR</td><td>or</td><td>or</td><td>OR</td><td>i ! or</td><td>io</td><td>i 0</td><td colspan="2">00 í o</td>
<td>Rh</td><td></td><td> 4-1</td><td> 4-1</td><td>i 4-4</td><td>Ϊ 4-1</td><td>i 4-4</td><td>i C \ J</td><td></td>
<td>I</td><td>or</td><td> <1</td><td>M</td><td>1 M</td><td>'M</td><td></td><td>i 1</td><td>ω</td>
<td>CO</td><td>+ J</td><td>OR</td><td>. OR</td><td>i °</td><td>! OR</td><td>: O</td><td>; <O</td><td>Oj</td>
<td>ΙΩ</td><td>ω</td><td> £</td><td> £</td><td> ! £</td><td> ! £</td><td> 1 £</td><td>i O</td><td>M</td>
<td>τ — 1</td><td> —</td><td> 05</td><td>u</td><td></td><td> ?</td><td>i ru</td><td>i OJ</td><td></td>
<img file="ES2325596T3_D0302.tif" />
<img file="ES2325596T3_D0303.tif" />
<img file="ES2325596T3_D0304.tif" />
<img file="ES2325596T3_D0305.tif" />
<img file="ES2325596T3_D0306.tif" />
<img file="ES2325596T3_D0307.tif" />
<img file="ES2325596T3_D0308.tif" />
ES 2 325 596 T3
<img file="ES2325596T3_D0309.tif" />
ES 2 325 596 T3
<img file="ES2325596T3_D0310.tif" />
ES 2 325 596 T3
<img file="ES2325596T3_D0311.tif" />
ES 2 325 596 T3
<img file="ES2325596T3_D0312.tif" />
-130 | 1 I CH, CH. CH. I amorphous
<td>or</td><td>í O</td><td>io</td><td>! OR</td><td>i O</td><td>* : O</td>
<td> 4-1</td><td>i</td><td>i 4-4</td><td>i 4-1</td><td>i 4-1</td><td>i 4-1</td>
<td> 5-1</td><td>1 M</td><td>i 5-4</td><td> ! 5-4</td><td>i 5-4</td><td>I 5-4</td>
<td>OR</td><td>io</td><td>io</td><td>1 O</td><td>IO</td><td> OR</td>
<td>g</td><td>! g</td><td>ig</td><td>1 g</td><td>1 g</td><td>í ε</td>
<td>(you</td><td>1 (you</td><td>¡(Β</td><td>i <e</td><td>; (you</td><td>i</td>
<td></td><td>to<sub>s</sub></td>
<td>CM</td><td>CM</td>
<td>IT</td><td>CO</td>
<td>CO</td><td>CO</td>
<td>vH</td><td><sup>1</sup></td>
<td>1 r ™ 1</td><td>1 <-l</td>
ES 2 325 596 T3
<img file="ES2325596T3_D0313.tif" />
ES 2 325 596 T3
<img file="ES2325596T3_D0314.tif" />
100
ES 2 325 596 T3
<img file="ES2325596T3_D0315.tif" />
101
ES 2 325 596 T3
<img file="ES2325596T3_D0316.tif" />
102
ES 2 325 596 T3
<img file="ES2325596T3_D0317.tif" />
103
ES 2 325 596 T3
OR
CM i CM ¡ΓΣ j CM * i * wi *
<td colspan="2">or</td><td colspan="2">! oo</td><td colspan="3">i! oo</td><td>in</td><td></td><td>í Γ</td><td></td><td>i</td><td></td>
<td>r- ~</td><td></td><td>í CO</td><td></td><td>I 0</td><td>'CH</td><td></td><td>m</td><td>or</td><td>Ϊ or</td><td>OR</td><td>i CO</td><td>OR</td>
<td>CN</td><td></td><td>i OJ</td><td></td><td>i <M</td><td> ; ?—1</td><td></td><td>ΐ — i</td><td> <</td><td>1 CX1</td><td> <</td><td>| <—Yes</td><td> <</td>
<td> 1</td><td>ω</td><td>í J</td><td>ω</td><td>: S-4</td><td>í 1</td><td>ω</td><td> 1</td><td>or</td><td>1 i</td><td>or</td><td>í 1</td><td>or</td>
<td></td><td>CM</td><td>Í kD</td><td>I heard</td><td> ' 0</td><td>k £></td><td> £14</td><td>in</td><td> 4-></td><td>1 LO</td><td>-P</td><td>í CN</td><td>+ j</td>
<td>kO</td><td>F — 1</td><td>i</td><td>M</td><td>i £</td><td>i</td><td>M</td><td>it</td><td>ω</td><td>í o</td><td>ω</td><td> !<sup>00</sup></td><td>w</td>
<td>Cx]</td><td></td><td>! cm</td><td> '—</td><td></td><td>| t — 1</td><td> --'</td><td>ϊ — i</td><td> —</td><td>i Csl</td><td> —</td><td>1 rl</td><td> '—</td>
<img file="ES2325596T3_D0318.tif" />
<td><n 1st</td><td>X</td><td>m X OR</td><td>re</td><td>m 32 O</td><td> 32</td><td>m 32 OR</td>
<td>i m</td><td>ro</td><td></td><td>co</td><td>CO</td><td>CO</td><td>CO</td>
<td>! X</td><td>X</td><td>EC</td><td> 32</td><td> 32</td><td>X</td><td> 32</td>
<td> 1 °</td><td>or</td><td>or</td><td>or</td><td>OR</td><td>or</td><td>OR</td>
<td></td><td>C0</td><td>co</td><td>CO</td><td>CO</td><td>CO</td><td>C0</td>
<td>l X</td><td>X</td><td>π</td><td> 32</td><td> 32</td><td> 32</td><td> 32</td>
<td>1 O</td><td>or</td><td>or</td><td>OR</td><td><J</td><td>OR</td><td>OR</td>
<td>Φ</td><td>Φ</td><td>Φ</td><td>Φ</td><td></td><td>ή</td><td>Φ.</td>
<td></td><td></td><td></td><td> ¥</td><td>Y</td><td></td><td>z</td>
<td>Γ — 1</td><td> !----1</td><td>r-í</td><td>Rh</td><td>ϊ — 1</td><td>r-4</td><td>t — 1 </td>
<td>Cx]</td><td>in</td><td></td><td>IT</td><td>IT</td><td>r-</td><td>co</td>
<td>r ~</td><td>or-</td><td>r-</td><td>r-</td><td>r-</td><td>Γ- <sup>5</sup></td><td>r- i</td>
<td> ?—1</td><td>i — 1</td><td> ?—1</td><td>ϊ — 1</td><td>r ~ -1</td><td>ri</td><td>r — 1</td>
<td>t — 1</td><td>t — 1</td><td>t — 1</td><td>r — 1</td><td>t — 1</td><td>r-4</td><td>v — 1</td>
104
ES 2 325 596 T3
-179] 1 í I CH<sub>3</sub> I CH'3 IH j amorphous
<img file="ES2325596T3_D0319.tif" />
105
ES 2 325 596 T3
<img file="ES2325596T3_D0320.tif" />
106
ES 2 325 596 T3
<img file="ES2325596T3_D0321.tif" />
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<img file="ES2325596T3_D0322.tif" />
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ES 2 325 596 T3 i
<td colspan="6">4E í</td><td colspan="6" rowspan="2">(HO</td>
<td colspan="2"></td><td colspan="4">1 xi i OR <sup>1</sup></td>
<td>CN *</td><td> =«=</td><td>• CN</td><td>-P ω</td><td></td><td></td><td>CN</td><td></td><td>i CN</td><td>P ω</td><td></td><td></td>
<td></td><td></td><td></td><td></td><td></td><td></td><td>IT</td><td></td><td></td><td></td><td> “0</td><td></td>
<td>CO</td><td>or</td><td>r-</td><td>or</td><td> 0</td><td>or</td><td>ΟΊ</td><td>OR</td><td>; <O</td><td>or</td><td>[<or</td><td></td>
<td> <—1</td><td> <</td><td>; t -------- 1</td><td> <</td><td>i 4-1</td><td> ¡ 4-1</td><td>r — 1</td><td> <</td><td>it — 1</td><td> <</td><td>Item<sup>-</sup>1</td><td> .______________________________.</td>
<td> 1</td><td>or</td><td> 1</td><td>or</td><td>: P</td><td>s P</td><td> 1</td><td>or</td><td>i 1</td><td>or</td><td><sup>!</sup> 1</td><td>ω</td>
<td></td><td> 4-)</td><td>i CN</td><td>P</td><td>1 O</td><td>i O</td><td>co</td><td>P</td><td></td><td>P</td><td>Í CO</td><td>CL,</td>
<td>co</td><td>ω</td><td>go-</td><td>ω</td><td>E</td><td>g</td><td>σ></td><td>ω</td><td><or</td><td>ω</td><td>í <o</td><td> 1—1</td>
<td> <—1</td><td></td><td>: t<sup>-</sup>1</td><td> '</td><td></td><td>' (OR</td><td> !—1</td><td> —'</td><td>i '—1</td><td> -—</td><td>ΐ —1</td><td></td>
<img file="ES2325596T3_D0323.tif" />
<td> )</td><td>x</td><td>m 2C O</td><td>1 ' '' x:</td><td>co XO</td><td>X</td><td>in X or</td>
<td></td><td></td><td></td><td></td><td></td><td></td><td></td>
<td>co</td><td>í CO</td><td>co</td><td>co</td><td>'CO</td><td>co</td><td>co</td>
<td>x</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td>
<td>ω</td><td>or</td><td>or</td><td>or</td><td>ω</td><td>or</td><td>or</td>
<td> —..............................................-</td><td> —.......-..............................-................·</td><td> —....................—..........—</td><td></td><td> ----------------</td><td> ..—----------------........</td><td> ............................</td>
<td>CO</td><td>CO</td><td>co</td><td>co</td><td>co</td><td>co</td><td></td>
<td>x</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td>
<td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td>ω</td>
<td></td><td></td><td>X</td><td></td><td>$ X</td><td>X</td><td>X</td>
<td>t — 1</td><td>i — 1</td><td>c — 1</td><td>i — 1</td><td>t — 1</td><td>i — 1</td><td> <—1</td>
<td>r-</td><td>co</td><td>in</td><td>OR</td><td>t — 1</td><td>CN</td><td>co</td>
<td>or</td><td>or</td><td>or</td><td>t — 1</td><td>i — 1</td><td>Rh</td><td>Rh</td>
<td>CN</td><td>CN</td><td>CN</td><td>CN</td><td>CN</td><td>CN</td><td>CN</td>
<td>t — 1</td><td>t — 1</td><td>t — 1</td><td>t—!</td><td>t — 1</td><td>τ — 1</td><td> !—1</td>
109
ES 2 325 596 T3
<img file="ES2325596T3_D0324.tif" />
110
ES 2 325 596 T3
<img file="ES2325596T3_D0325.tif" />
111
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<img file="ES2325596T3_D0326.tif" />
112
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<img file="ES2325596T3_D0327.tif" />
113
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<img file="ES2325596T3_D0328.tif" />
114
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<img file="ES2325596T3_D0329.tif" />
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<img file="ES2325596T3_D0330.tif" />
116
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<img file="ES2325596T3_D0331.tif" />
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<img file="ES2325596T3_D0332.tif" />
118
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<img file="ES2325596T3_D0333.tif" />
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<img file="ES2325596T3_D0334.tif" />
120
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<img file="ES2325596T3_D0335.tif" />
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<img file="ES2325596T3_D0336.tif" />
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<img file="ES2325596T3_D0337.tif" />
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<img file="ES2325596T3_D0338.tif" />
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<img file="ES2325596T3_D0339.tif" />
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<img file="ES2325596T3_D0340.tif" />
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<img file="ES2325596T3_D0341.tif" />
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-339 11! I CH? i CH? Η! -.amorphous
<img file="ES2325596T3_D0342.tif" />
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<img file="ES2325596T3_D0343.tif" />
129
ES 2 325 596 T3 * 1: Comp. = Compound number, Ex. No. = Example number, crystallization solvent; EtOAc = ethyl acetate, EtOH = ethanol, IPE = diisopropyl ether, THF = tetrahydrofuran, IPA = isopropyl alcohol, ACE = acetone, CH<sub>3</sub>CN = acetonitrile. Analytical data for non-crystalline compounds, diastereoisomers, and optically active compounds are described below, where "#" means "not according to the invention".
1-003: #
MS (ES, Pos.): 589 (M + 1)<sup>+</sup>, 591 (M + 3)<sup>+</sup>, 593 (M + 5)<sup>+</sup>, 611 (M + Na)<sup>+</sup>, 613 (M + Na + 2)<sup>+</sup>, 615 (M + Na + 4)<sup>+</sup>; HPLC retention time: 4.84 min. (Capcell Pak UG120, 4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / aqueous solution of ammonium acetate 0.05 M (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-005: #
MS (ES, Pos.): 457 (M + 1)<sup>+</sup>, 459 (M + 3)<sup>+</sup>, 479 (M + Na)<sup>+</sup>, 481 (M + Na + 2)<sup>+</sup>; HPLC retention time: 9.47 min. (Capcell Pak UG120, 4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-011: #
MS (ES, Pos.): 393 (M + 1)<sup>+</sup>, 415 (M + Na)<sup>+</sup>; HPLC retention time: 4.16 min. (Capcell Pak UG120,
4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-012: #
MS (ES, Pos.): 379 (M + 1)<sup>+</sup>, 401 (M + Na)<sup>+</sup>; HPLC retention time: 3.8 min. (Capcell Pak UG120,
4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-013: #
MS (ES, Pos.): 523 (M + 1)<sup>+</sup>, 525 (M + 3)<sup>+</sup>, 527 (M + 5)<sup>+</sup>, 545 (M + Na)<sup>+</sup>, 547 (M + Na + 2)<sup>+</sup>, 549 (M + Na + 4)<sup>+</sup>; HPLC retention time: 3.14 and 3.27 min. (Capcell Pak uG120, 4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-014: #
MS (ES, Pos.): 539 (M + 1)<sup>+</sup>, 541 (M + 3)<sup>+</sup>, 543 (M + 5)<sup>+</sup>, 561 (M + Na)<sup>+</sup>, 563 (M + Na + 2)<sup>+</sup>, 565 (M + Na + 4)<sup>+</sup>; HPLC retention time: 3.57 and 3.69 min. (Capcell Pak UG120.4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-015: #
MS (ES, Pos.): 575 (M + 1)<sup>+</sup>, 577 (M + 3)<sup>+</sup>.579 (M + 5)<sup>+</sup>; HPLC retention time: 4.05 min. (Capcell Pak UG120, 4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-016: #
MS (ES, Pos.): 457 (M + 1)<sup>+</sup>, 459 (M + 3)<sup>+</sup>, 479 (M + Na)<sup>+</sup>, 481 (M + Na + 2)<sup>+</sup>; HPLC retention time: 4.60 min. (Capcell Pak UG120, 4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-017 (the enantiomer of 1-018): #
HPLC retention time: 10.0 min. (CHIRAL PAK AD (DAICEL CHEMICAL INDUSTRIES, LTD), 0.46 cm ID x 25 cm, mobile phase: hexane / IPA = 20: 1, flow rate: 1.0 mL / min.)
1-018 (the enantiomer of 1-017): #
HPLC retention time: 11.4 min. (CHIRAL PAK AD (DAICEL CHEMICAL INDUSTRIES, LTD), 0.46 cm ID x 25 cm, mobile phase: hexane / IPA = 20: 1, flow rate: 1.0 mL / min.)
130
ES 2 325 596 T3
1-019:#
MS (ES, Pos.): 443 (M + 1)<sup>+</sup>, 466 (M + Na)<sup>+</sup>; HPLC retention time: 4.27 min. (Capcell Pak UG120,
4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-020 (the enantiomer of 1-021): #
HPLC retention time: 9.1 min. (CHIRAL PAK AD (DAICEL CHEMICAL INDUSTRIES, LTD), 0.46 cm ID x 25 cm, mobile phase: hexane / IPA = 20: 1, flow rate: 1.0 mL / min.)
1-021 (the enantiomer of 1-020): #
HPLC retention time: 11.0 min. (CHIRAL PAK AD (DAICEL CHEMICAL INDUSTRIES, LTD), 0.46 cm ID x 25 cm, mobile phase: hexane / IPA = 20: 1, flow rate: 1.0 mL / min.)
1-022:
MS (ES, Pos.): 439 (M + 1)<sup>+</sup>, 461 (M + Na)<sup>+</sup>; HPLC retention time: 4.27 and 4.56 min. (Capcell Pak UG120, 4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-023: #
MS (ES, Pos.): 425 (M + 1)<sup>+</sup>, 447 (M + Na)<sup>+</sup>; HPLC retention time: 4.16 min. (Capcell Pak UG120,
4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-024: #
MS (ES, Pos.): 497 (M + 1)<sup>+</sup>, 499 (M + 3)<sup>+</sup>, 519 (M + Na)<sup>+</sup>, 521 (M + Na + 2)<sup>+</sup>; HPLC retention time: 3.72 min. (Capcell Pak UG120, 4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-025: #
MS (ES, Pos.): 483 (M + 1)<sup>+</sup>, 485 (M + 3)<sup>+</sup>, 505 (M + Na)<sup>+</sup>, 507 (M + Na + 2)<sup>+</sup>; HPLC retention time: 3.66 min. (Capcell Pak UG120, 4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / aqueous solution of ammonium acetate 0.05 M (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-026:
MS (ES, Pos.): 421 (M + 1)<sup>+</sup>; HPLC retention time: 5.20 min. (Capcell Pak UG120, 4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-027:
MS (ES, Pos.): 409 (M + 1)<sup>+</sup>, 431 (M + Na)<sup>+</sup>; HPLC retention time: 2.70 min. (Capcell Pak UG120,
4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-028:
MS (ES, Pos.): 419 (M + 1)<sup>+</sup>; HPLC retention time: 5.45 min. (Capcell Pak UG120, 4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-029:
MS (ES, Pos.): 415 (M + 1)<sup>+</sup>; HPLC retention time: 5.27 min. (Capcell Pak UG120, 4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
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ES 2 325 596 T3
1-030: #
MS (ES, Pos.): 485 (M + 1)<sup>+</sup>, 487 (M + 3)<sup>+</sup>, 507 (M + Na)<sup>+</sup>, 509 (M + Na + 2)<sup>+</sup>; HPLC retention time: 8.57 min. (Capcell Pak UG120, 4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-031: #
MS (ES, Pos.): 471 (M + 1)<sup>+</sup>, 473 (M + 3)<sup>+</sup>, 493 (M + Na)<sup>+</sup>, 495 (M + Na + 2)<sup>+</sup>; HPLC retention time: 7.71 min. (Capcell Pak UG120, 4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-036: #
MS (ES, Pos.): 407 (M + 1)<sup>+</sup>, 429 (M + Na)<sup>+</sup>; HPLC retention time: 4.32 min. (Capcell Pak UG120,
4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-037: #
MS (ES, Pos.): 415 (M + Na)<sup>+</sup>; HPLC retention time: 3.98 min. (Capcell Pak UG120, 4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-039: #
MS (ES, Pos.): 471 (M + 1)<sup>+</sup>, 473 (M + 3)<sup>+</sup>, 493 (M + Na)<sup>+</sup>, 495 (M + Na + 2)<sup>+</sup>; HPLC retention time: 4.91 min. (Capcell Pak UG120, 4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-040: #
MS (ES, Pos.): 479 (M + Na)<sup>+</sup>, 481 (M + Na + 2)<sup>+</sup>; HPLC retention time: 4.46 min. (Capcell Pak UG120, 4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-041:
MS (ES, Pos.): 435 (M + 1)<sup>+</sup>; HPLC retention time: 5.56 min. (Capcell Pak UG120, 4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-043:
MS (ES, Pos.): 429 (M + 1)<sup>+</sup>; HPLC retention time: 5.47 min. (Capcell Pak UG120, 4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-044: #
MS (ES, Pos.): 499 (M + 1)<sup>+</sup>, 501 (M + 3)<sup>+</sup>; HPLC retention time: 6.66 min. (Capcell Pak UG120,
4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-045: #
MS (ES, Pos.): 485 (M + 1)<sup>+</sup>, 487 (M + 3)<sup>+</sup>, 507 (M + Na)<sup>+</sup>, 509 (M + Na + 2)<sup>+</sup>; HPLC retention time: 6.89 min. (Capcell Pak UG120, 4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-056:
MS (ES, Pos.): 415 (M + 1)<sup>+</sup>; HPLC retention time: 4.45 min. (Capcell Pak UG120, 4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
132
ES 2 325 596 T3
1-057: #
MS (ES, Pos.): 485 (M + 1)<sup>+</sup>, 487 (M + 3)<sup>+</sup>; HPLC retention time: 7.54 min. (Capcell Pak UG120,
4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-063: #
MS (ES, Pos.): 571 (M + Na)<sup>+</sup>.573 (M + Na + 2)<sup>+</sup>.575 (M + Na + 4)<sup>+</sup>; HPLC retention time: 5.20 min. (Capcell Pak UG120, 4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-092:
MS (ES, Pos.): 449 (M + 1)<sup>+</sup>; HPLC retention time: 6.24 min. (Capcell Pak UG120, 4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / aqueous solution of ammonium acetate 0.05 M (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-094:
MS (ES, Pos.): 443 (M + 1)<sup>+</sup>; HPLC retention time: 6.22 min. (Capcell Pak UG120, 4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-103:
MS (ES, Pos.): 589 (M + 1)<sup>+</sup>, 591 (M + 3)<sup>+</sup>, 593 (M + 5), 611 (M + Na)<sup>+</sup>, 613 (M + Na + 2)<sup>+</sup>, 615 (M + Na + 4)<sup>+</sup>; HPLC retention time: 5.01 min. (Capcell Pak UG120, 4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-104:
MS (ES, Pos.): 471 (M + 1)<sup>+</sup>, 473 (M + 3)<sup>+</sup>, 493 (M + Na)<sup>+</sup>, 495 (M + Na + 2)<sup>+</sup>; HPLC retention time: 6.69 min. (Capcell Pak UG120, 4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-105:
MS (ES, Pos.): 457 (M + 1)<sup>+</sup>, 459 (M + 3)<sup>+</sup>, 479 (M + Na)<sup>+</sup>, 481 (M + Na + 2)<sup>+</sup>; HPLC retention time: 6.01 min. (Capcell Pak UG120, 4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / aqueous solution of ammonium acetate 0.05 M (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-106:
MS (ES, Pos.): 499 (M + 1)<sup>+</sup>, 501 (M + 3)<sup>+</sup>, 521 (M + Na)<sup>+</sup>, 523 (M + Na + 2)<sup>+</sup>; HPLC retention time: 8.06 min. (Capcell Pak UG120, 4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-107:
MS (ES, Pos.): 485 (M + 1)<sup>+</sup>, 487 (M + 3)<sup>+</sup>, 507 (M + Na)<sup>+</sup>, 509 (M + Na + 2)<sup>+</sup>; HPLC retention time: 10.24 min. (Capcell Pak UG120, 4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-110:
MS (ES, Pos.): 501 (M + 1)<sup>+</sup>, 503 (M + 3)<sup>+</sup>, 523 (M + Na)<sup>+</sup>, 525 (M + Na + 2)<sup>+</sup>; Retention time
HPLC: 4.61 min. (Capcell Pak UG120, 4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase:
acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
133
ES 2 325 596 T3
1-114:
MS (ES, Pos.): 613 (M + Na)<sup>+</sup>, 615 (M + Na + 2)<sup>+</sup>, 617 (M + Na + 4)<sup>+</sup>; HPLC retention time: 2.57 min. (Capcell Pak UG120, 4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-115:
HPLC retention time: 10.6 min. (CHIRAL PAK AD (DAICEL CHEMICAL INDUSTRIES, LTD), 0.46 cm ID x 25 cm, mobile phase: hexane / IPA = 20: 1, flow rate: 1.0 mL / min.)
1-116:
MS (ES, Pos.): 451 (M + Na)<sup>+</sup>, 453 (M + Na + 2)<sup>+</sup>; HPLC retention time: 11.5 min. (CHIRAL PAK AD (DAICEL CHEMICAL INDUSTRIES, LTD), 0.46 cm ID x 25 cm, mobile phase: hexane / IPA = 20: 1, flow rate: 1.0 mL / min.)
1-117:
HPLC retention time: 9.3 min. (CHIRAL PAK AD (DAICEL CHEMICAL INDUSTRIES, LTD), 0.46 cm ID x 25 cm, mobile phase: hexane / IPA = 20: 1, flow rate: 1.0 mL / min.)
1-118:
MS (ES, Pos.): 429 (M + 1)<sup>+</sup>, 431 (M + 3)<sup>+</sup>; HPLC retention time: 12.1 min. (CHIRAL PAK AD (DAICEL CHEMICAL INDUSTRIES, LTD), 0.46 cm ID x 25 cm, mobile phase: hexane / IPA = 20: 1, flow rate: 1.0 mL / min.)
1-125:
MS (ES, Pos.): 388 (M + 1)<sup>+</sup>, 410 (M + Na)<sup>+</sup>; HPLC retention time: 4.20 min. (Capcell Pak UG120,
4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-126:
MS (ES, Pos.): 396 (M + Na)<sup>+</sup>; HPLC retention time: 4.40 min. (Capcell Pak UG120, 4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-127 (to diastereoisomer of 1-128):
Rf value 0.55 (developing solvent: hexane / EtOAc = 1: 1, Silica Gel 60 F TLC plate <sub>254</sub> (Merck)); H NMR<sup>1</sup> (300 MHz, CDCl3) δ 1.64-1.82 (1H, m), 1.83-2.03 (2H, m), 2.05-2.18 (1H, m), 2 , 34 (3H, s), 2.46 (3H, m), 2.53 (3H, s), 2.99-3.12 (1H, m), 3.31-3.70 (3H, m), 3.90-4.02 (1H, m), 6.63 (1H, s), 7.30 (1H, d, J = 2.0Hz), 7.62 (1H, d, J = 2.0Hz); MS (ES, Pos.): 556 (M + Na)<sup>+</sup>, 558 (M + Na + 2), 560 (M + Na + 4)<sup>+</sup>
1-128 (to diastereoisomer of 1-127):
Rf value 0.48 (developing solvent: hexane / EtOAc = 1: 1, Silica Gel 60 F TLC plate <sub>254</sub> (Merck)); H NMR<sup>1</sup> (300 MHz, CDCl3) δ 1.62-1.81 (1H, m), 1.89-2.03 (2H, m), 2.05-2.19 (1H, m), 2 , 35 (3H, s), 2.46 (3H, d, J = 1.2Hz), 2.53 (3H, s), 3.01-3.13 (1H, m), 3.34-3.70 (3H, m), 3.91-4.02 (1H, m), 6.63 (1H, s), 7.30 (1H, d, J = 2, 0Hz), 7.62 (1H, d, J = 2.0Hz); MS (ES, Pos.): 534 (M + 1)<sup>+</sup>, 536 (M + 3)<sup>+</sup>, 538 (M + 5)<sup>+</sup>, 556 (M + Na)<sup>+</sup>, 558 (M + Na + 2), 560 (M + Na + 4)<sup>+</sup>
1-129:
MS (ES, Pos.): 570 (M + 1)<sup>+</sup>, 572 (M + 3)<sup>+</sup>.574 (M + 5)<sup>+</sup>; HPLC retention time: 4.46 min. (Capcell Pak UG120, 4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-130:
MS (ES, Pos.): 452 (M + 1)<sup>+</sup>, 454 (M + 3)<sup>+</sup>, 474 (M + Na)<sup>+</sup>, 476 (M + Na + 2)<sup>+</sup>; HPLC retention time:
5.36 min. (Capcell Pak UG120, 4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
134
ES 2 325 596 T3
1-131:
MS (ES, Pos.): 460 (M + Na)<sup>+</sup>, 462 (M + Na + 2)<sup>+</sup>; HPLC retention time: 4.87 min. (Capcell Pak UG120, 4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-132:
MS (ES, Pos.): 456 (M + Na)<sup>+</sup>; HPLC retention time: 5.12 min. (Capcell Pak UG120, 4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-133:
MS (ES, Pos.): 442 (M + Na)<sup>+</sup>; HPLC retention time: 4.64 min. (Capcell Pak UG120, 4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-138:
MS (ES, Pos.): 500 (M + Na)<sup>+</sup>, 502 (M + Na + 2)<sup>+</sup>; HPLC retention time: 4.05 min. (Capcell Pak UG120, 4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-140:
MS (ES, Pos.): 410 (M + 1)<sup>+</sup>; HPLC retention time: 5.85 min. (Capcell Pak UG120, 4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-141:
MS (ES, Pos.): 480 (M + 1)<sup>+</sup>, 482 (M + 3)<sup>+</sup>, 502 (M + Na)<sup>+</sup>, 504 (M + Na + 2)<sup>+</sup>; HPLC retention time: 7.51 min. (Capcell Pak UG120, 4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-142:
MS (ES, Pos.): 466 (M + 1)<sup>+</sup>, 468 (M + 3)<sup>+</sup>, 488 (M + Na)<sup>+</sup>, 490 (M + Na + 2)<sup>+</sup>; HPLC retention time: 9.01 min. (Capcell Pak UG120, 4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-143:
MS (ES, Pos.): 584 (M + 1)<sup>+</sup>, 586 (M + 3)<sup>+</sup>, 588 (M + 5)<sup>+</sup>, 606 (M + Na)<sup>+</sup>.608 (M + Na + 2)<sup>+</sup>, 610 (M + Na + 4)<sup>+</sup>; HPLC retention time: 4.48 min. (Capcell Pak UG120, 4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-144:
MS (ES, Pos.): 466 (M + 1)<sup>+</sup>, 468 (M + 3)<sup>+</sup>, 488 (M + Na)<sup>+</sup>, 490 (M + Na + 2)<sup>+</sup>; HPLC retention time: 5.92 min. (Capcell Pak UG120, 4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-146:
MS (ES, Pos.): 516 (M + Na)<sup>+</sup>, 518 (M + Na + 2)<sup>+</sup>; HPLC retention time: 8.63 min. (Capcell Pak UG120, 4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-147:
MS (ES, Pos.): 480 (M + 1)<sup>+</sup>, 482 (M + 3)<sup>+</sup>, 502 (M + Na)<sup>+</sup>, 504 (M + Na + 2)<sup>+</sup>; HPLC retention time: 3.44 min. (Capcell Pak UG120, 4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase:
135
ES 2 325 596 T3 acetonitrile / aqueous ammonium acetate solution 0.05 M (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-149:
MS (ES, Pos.): 466 (M + 1)<sup>+</sup>, 468 (M + 3)<sup>+</sup>, 488 (M + Na)<sup>+</sup>, 490 (M + Na + 2)<sup>+</sup>
1-168:
MS (ES, Pos.): 444 (M + 1)<sup>+</sup>, 466 (M + Na)<sup>+</sup>; HPLC retention time: 4.11 min. (Capcell Pak UG120,
4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-171:
MS (ES, Pos.): 596 (M + 1)<sup>+</sup>, 598 (M + 3)<sup>+</sup>.600 (M + 5)<sup>+</sup>, 618 (M + Na)<sup>+</sup>, 620 (M + Na + 2)<sup>+</sup>, 622 (M + Na + 4)<sup>+</sup>; HPLC retention time: 5.87 min. (Capcell Pak UG120, 4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-174:
MS (ES, Pos.): 506 (M + 1)<sup>+</sup>, 508 (M + 3)<sup>+</sup>, 528 (M + Na)<sup>+</sup>, 530 (M + Na + 2)<sup>+</sup>; HPLC retention time: 5.83 min. (Capcell Pak UG120, 4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-179:
MS (ES, Pos.): 474 (M + Na)<sup>+</sup>, 476 (M + Na + 2)<sup>+</sup>; HPLC retention time: 5.74 min. (Capcell Pak UG120, 4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-194:
MS (ES, Pos.): 421 (M + 1)<sup>+</sup>; HPLC retention time: 5.08 min. (Capcell Pak UG120, 4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-209:
MS (ES, Pos.): 496 (M + 1)<sup>+</sup>
1-210:
MS (ES, Pos.): 482 (M + 1)<sup>+</sup>
1-222:
MS (ES, Pos.): 421 (M + 1)<sup>+</sup>; HPLC retention time: 7.13 min. (Capcell Pak UG120, 4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-238: #
MS (ES, Pos.): 575 (M + 1)<sup>+</sup>, 577 (M + 3)<sup>+</sup>.579 (M + 5)<sup>+</sup>
HPLC retention time: 8.6 min. (CHIRAL PAK AD (DAICEL CHEMICAL INDUSTRIES, LTD), 0.46 cm ID x 25 cm, mobile phase: hexane / IPA = 20: 1, flow rate: 1.0 mL / min.)
1-239: ##
MS (ES, Pos.): 575 (M + 1)<sup>+</sup>, 577 (M + 3)<sup>+</sup>.579 (M + 5)<sup>+</sup>
HPLC retention time: 9.6 min. (CHIRAL PAK AD (DAICEL CHEMICAL INDUSTRIES, LTD), 0.46 cm ID x 25 cm, mobile phase: hexane / IPA = 20: 1, flow rate: 1.0 mL / min.)
136
ES 2 325 596 T3
1-240:
MS (ES, Pos.): 570 (M + 1)<sup>+</sup>, 572 (M + 3)<sup>+</sup>.574 (M + 5)<sup>+</sup>
HPLC retention time: 13.0 min. (CHIRAL PAK AD (DAICEL CHEMICAL INDUSTRIES, LTD), 0.46 cm ID x 25 cm, mobile phase: hexane / IPA = 100: 1, flow rate: 1.0 mL / min.)
1-241:
MS (ES, Pos.): 570 (M + 1)<sup>+</sup>, 572 (M + 3)<sup>+</sup>.574 (M + 5)<sup>+</sup>
HPLC retention time: 11.9 min. (CHIRAL PAK AD (DAICEL CHEMICAL INDUSTRIES, LTD), 0.46 cm ID x 25 cm, mobile phase: hexane / IPA = 100: 1, flow rate: 1.0 mL / min.)
1-267:
MS (ES, Pos.): 438 (M + 1)<sup>+</sup>, 440 (M + 3)<sup>+</sup>, 460 (M + Na)<sup>+</sup>, 462 (M + Na + 2)<sup>+</sup>; HPLC retention time: 4.43 min. (Capcell Pak UG120, 4.6mm x 150mm, Shiseido); Flow rate: 1.0 ml / min; Mobile phase: acetonitrile / 0.05M aqueous ammonium acetate solution (80:20), the pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
1-276 (the enantiomer of 1-278):
[to]<sub>D</sub><sup>29</sup> = +7.41 (c 1.00, CH3OH)
1-277 (the enantiomer of 1-279):
HPLC retention time: 6.0 min. (CHIRAL PAK AD (DAICEL CHEMICAL INDUSTRIES, LTD), 0.46 cm ID x 25 cm, mobile phase: hexane / IPA = 8: 1, flow rate: 1.0 mL / min.)
1-278 (the enantiomer of 1-276):
[to]<sub>D</sub><sup>29</sup> = -5.90 (c 1.01, CH<sub>3</sub>OH)
1-279 (the enantiomer of 1-277):
HPLC retention time: 5.5 min. (CHIRAL PAK AD (DAICEL CHEMICAL INDUSTRIES, LTD), 0.46 cm ID x 25 cm, mobile phase: hexane / IPA = 8: 1, flow rate: 1.0 mL / min.)
1-280:
[a] D<sup>29</sup> = -9.30 (c 0.41, CH3OH)
1-281:
[a] D<sup>28</sup> = -11.2 (c 0.41, CH3OH)
1-282:
[to]<sub>D</sub><sup>28</sup> = -18.0 (c 0.41, CH<sub>3</sub>OH)
1-283:
[a] D<sup>22</sup> = -6.6 (c 0.40, CH3OH)
1-284:
[a] D<sup>28</sup> = -5.5 (c 0.40, CH3OH)
1-302 (the enantiomer of 1-304):
HPLC retention time: 8.4 min. (CHIRAL PAK AD (DAICEL CHEMICAL INDUSTRIES, LTD), 0.46 cm ID x 25 cm, mobile phase: hexane / IPA = 8: 1, flow rate: 1.0 mL / min.)
1-303 (the enantiomer of 1-305):
HPLC retention time: 9.2 min. (CHIRAL PAK AD (DAICEL CHEMICAL INDUSTRIES, LTD), 0.46 cm ID x 25 cm, mobile phase: hexane / IPA = 8: 1, flow rate: 1.0 mL / min.)
137
ES 2 325 596 T3
1-304 (the enantiomer of 1-302):
HPLC retention time: 8.9 min. (CHIRAL PAK AD (DAICEL CHEMICAL INDUSTRIES, LTD), 0.46 cm ID x 25 cm, mobile phase: hexane / IPA = 8: 1, flow rate: 1.0 mL / min.)
1-305 (the enantiomer of 1-303):
HPLC retention time: 10.6 min. (CHIRAL PAK AD (DAICEL CHEMICAL INDUSTRIES, LTD), 0.46 cm ID x 25 cm, mobile phase: hexane / IPA = 8: 1, flow rate: 1.0 mL / min.)
1-306 (the enantiomer of 1-308):
[to]<sub>D</sub><sup>28</sup> = +5.38 (c 0.81, CH3OH)
1-307 (the enantiomer of 1-309):
HPLC retention time: 16.6 min. (CHIRAL PAKAD (DAICEL CHEMICAL INDUSTRIES, LTD), (0.46 cm ID x 25 cm) x 2, mobile phase: hexane / IPA = 8: 1, flow rate: 1.0 mL / min.)
1-308 (the enantiomer of 1-306):
[a] D<sup>29</sup> = -7.69 (c 0.80, CH3OH)
1-309 (the enantiomer of 1-307):
HPLC retention time: 17.4 min. (CHIRAL PAK AD (DAICEL CHEMICAL INDUSTRIES, LTD), (0.46 cm ID x 25 cm) x 2, mobile phase: hexane / IPA = 8: 1, flow rate: 1.0 mL / min.)
1-316:
MS (ES, Pos.): 451 (M + 1)<sup>+</sup>; HPLC retention time: 6.26 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 jum, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
1-325:
MS (ES, Pos.): 449 (M + 1)<sup>+</sup>; HPLC retention time: 5.78 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 jum, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
1-338:
MS (ES, Pos.): 360 (M + 1)<sup>+</sup>; HPLC retention time: 6.19 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 jum, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
1-339:
MS (ES, Pos.): 424 (M + 1)<sup>+</sup>, 426 (M + 3)<sup>+</sup>; HPLC retention time: 5.93 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 pm, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min) * 2: HCl salt * 3: A mixture of diastereomers * 4: Optically active compound * 5: Crystallized on standing from the purified compound (silica gel column chromatography ) and drying.
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Table
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<img file="ES2325596T3_D0348.tif" />
143
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<img file="ES2325596T3_D0349.tif" />
144
ES 2 325 596 T3
<img file="ES2325596T3_D0350.tif" />
145
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<td>or</td><td>'or</td><td>i. — 1</td><td>z</td><td>or</td><td>io</td><td>i O</td><td>OR</td>
<td> 4-1</td><td> : 44</td><td>! CM</td><td>or</td><td> 44</td><td> : 44</td><td> ! 44</td><td> 44</td>
<td> 54</td><td>M</td><td>i 1</td><td>n</td><td>i 54</td><td>ΐ Í4</td><td> ! 54</td><td> : 54</td>
<td>OR</td><td>i O</td><td> !</td><td>X</td><td>! OR</td><td>Ϊ O</td><td>io</td><td>1st</td>
<td>g</td><td>ig</td><td> : <sup>1</sup>—*</td><td>or</td><td>1 ε</td><td>ig</td><td>ig</td><td>ig</td>
<td> 05</td><td> 05</td><td>| CM</td><td> —'</td><td> \ <sup>75</sup></td><td>i 05</td><td> ! <sup>í! 3</sup></td><td>i 05</td>
<td>in</td><td>in</td><td>; in</td>
<td>X</td><td>X</td><td>i X</td>
<td>or</td><td>or</td><td>j O</td>
<td>X</td><td>X</td><td>i X</td>
<td>X</td><td>X</td><td>1 X</td>
<td></td><td>or</td><td>í .....</td>
<td>in</td><td>in</td><td>; m</td>
<td>X</td><td>X</td><td> 1 ®</td>
<td>or</td><td>or</td><td>i °</td>
<td>in</td><td>in</td><td>? in</td>
<td>X</td><td>X</td><td> 1</td>
<td>or</td><td>or</td><td> 1 <sup>or</sup></td>
147
ES 2 325 596 T3
<img file="ES2325596T3_D0353.tif" />
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<td></td><td></td><td> |</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>
<td></td><td></td><td></td><td></td><td></td><td>X</td><td></td><td></td><td></td><td></td><td></td><td></td>
<td></td><td></td><td></td><td></td><td></td><td>or</td><td></td><td></td><td></td><td></td><td></td><td></td>
<td>CN</td><td></td><td></td><td></td><td>: CN</td><td> 4-></td><td></td><td>i CN</td><td></td><td></td><td></td><td></td>
<td>* IT</td><td></td><td>i CN i *</td><td>CN *</td><td>; * i 00</td><td>w</td><td></td><td>i + i ΟΊ</td><td></td><td>CN *</td><td></td><td>: cn! +</td>
<td>i — 1</td><td></td><td>or</td><td>OR</td><td> r — 1</td><td>or</td><td></td><td>i ™</td><td> .—</td><td>OR</td><td></td><td> OR</td>
<td>τ — 1</td><td></td><td>í 4-1</td><td> 4-1</td><td>CN</td><td> <</td><td></td><td>: I<sup>-</sup>1</td><td>X</td><td> 4-1</td><td></td><td> : 4-4</td>
<td></td><td>ω</td><td>i P</td><td>P</td><td> 1</td><td>or</td><td></td><td> 1</td><td>or</td><td>P</td><td></td><td>: P</td>
<td>co</td><td>cu</td><td>: O</td><td>OR</td><td></td><td>4J</td><td></td><td>: r-</td><td> 05</td><td>OR</td><td></td><td>or</td>
<td>r — 1</td><td>H H</td><td>'e</td><td>g</td><td>: 1 — I</td><td>ω</td><td></td><td> 1</td><td>s</td><td>g</td><td></td><td>ί ε</td>
<td>t — 1</td><td> *·—'</td><td>j 0)</td><td> 05</td><td>I oj</td><td></td><td></td><td>, '"I</td><td> •—</td><td> 05</td><td></td><td>i OS</td>
<img file="ES2325596T3_D0354.tif" />
<img file="ES2325596T3_D0355.tif" />
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<td>or</td><td>i O</td><td>i O</td><td>OR</td><td>io</td><td>OR</td><td>i <—1</td>
<td> 44</td><td>im</td><td> : 44</td><td> 44</td><td> ! 4-1</td><td> 44</td><td>CXI</td>
<td>Μ</td><td>Ϊ M</td><td>i M</td><td>M</td><td></td><td>M</td><td>i 1</td>
<td>OR</td><td>io</td><td>i O</td><td>OR</td><td>! OR</td><td>> OR</td><td>; Γ-</td>
<td>g</td><td>G</td><td>G</td><td>g</td><td>ΐ g</td><td>g</td><td>it — 1</td>
<td>(you</td><td> (you</td><td>j (you</td><td>(you</td><td>! (you</td><td>(you</td><td>i C \!</td>
<img file="ES2325596T3_D0362.tif" />
<img file="ES2325596T3_D0363.tif" />
<img file="ES2325596T3_D0364.tif" />
<img file="ES2325596T3_D0365.tif" />
<img file="ES2325596T3_D0366.tif" />
<img file="ES2325596T3_D0367.tif" />
<img file="ES2325596T3_D0368.tif" />
<img file="ES2325596T3_D0369.tif" />
<img file="ES2325596T3_D0370.tif" />
<img file="ES2325596T3_D0371.tif" />
<img file="ES2325596T3_D0372.tif" />
<img file="ES2325596T3_D0373.tif" />
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ES 2 325 596 T3 * 1: Comp. = Compound number, Ex. No. = Example number, crystallization solvent; ACE = acetone, EtOAc = ethyl acetate, EtOH = ethanol, Et<sub>2</sub>O = diethyl ether, IPA = isopropyl alcohol, IPE = diisopropyl ether, MeOH = methanol, CH3CN = acetonitrile.
Analytical data for non-crystalline compounds are described below.
2-001:
MS (ES, Pos.): 418 (M + 1)<sup>+</sup>, 420 (M + 3)<sup>+</sup>, 422 (M + 5)<sup>+</sup>
2-002:
MS (ES, Pos.): 432 (M + 1)<sup>+</sup>, 434 (M + 3)<sup>+</sup>, 436 (M + 5)<sup>+</sup>
2-012:
MS (ES, Pos.): 427 (M + 1)<sup>+</sup>
2-034:
MS (ES, Pos.): 534 (M + 1)<sup>+</sup>, 536 (M + 3)<sup>+</sup>, 538 (M + 5)<sup>+</sup>; HPLC retention time: 6.55 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 pm, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-041:
MS (ES, Pos.): 540 (M + 1)<sup>+</sup>, 542 (M + 3)<sup>+</sup>, 544 (M + 5)<sup>+</sup>; HPLC retention time: 6.60 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 pm, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-045:
MS (ES, Pos.): 456 (M + 1)<sup>+</sup>, 458 (M + 3)<sup>+</sup>; HPLC retention time: 6.72 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 pm, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-046:
MS (ES, Pos.): 424 (M + 1)<sup>+</sup>; HPLC retention time: 6.61 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 pm, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-048:
MS (ES, Pos.): 482 (M + 1)<sup>+</sup>, 484 (M + 3)<sup>+</sup>; HPLC retention time: 5.67 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 pm, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-049:
MS (ES, Pos.): 584 (M + 1)<sup>+</sup>, 586 (M + 3)<sup>+</sup>, 588 (M + 5)<sup>+</sup>; HPLC retention time: 6.73 min. (Xterra MS
C18 (Waters, Milford, MA) 3.5 pm, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min,
100% B for 1 min. and rebalance with 100% A for 1.5 min)
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ES 2 325 596 T3
2-050:
MS (ES, Pos.): 570 (M + 1)<sup>+</sup>, 572 (M + 3)<sup>+</sup>.574 (M + 5)<sup>+</sup>; HPLC retention time: 6.90 min. (Xterra MS
C18 (Waters, Milford, MA) 3.5 jum, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min,
100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-052:
MS (ES, Pos.): 562 (M + 1)<sup>+</sup>, 564 (M + 3)<sup>+</sup>, 562 (M + 5)<sup>+</sup>; HPLC retention time: 6.81 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 jum, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-053:
MS (ES, Pos.): 548 (M + 1)<sup>+</sup>, 550 (M + 3)<sup>+</sup>, 552 (M + 5)<sup>+</sup>; HPLC retention time: 6.72 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 jum, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-054:
MS (ES, Pos.): 598 (M + 1)<sup>+</sup>, 600 (M + 3)<sup>+</sup>, 602 (M + 5)<sup>+</sup>; HPLC retention time: 6.47 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 jum, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-056:
MS (ES, Pos.): 510 (M + 1)<sup>+</sup>, 512 (M + 3)<sup>+</sup>.514 (M + 5)<sup>+</sup>; HPLC retention time: 6.42 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 jum, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-057:
MS (ES, Pos.): 496 (M +1)<sup>+</sup>, 498 (M + 3)<sup>+</sup>.500 (M + 5)<sup>+</sup>; HPLC retention time: 6.55 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 jum, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-058:
MS (ES, Pos.): 466 (M + 1)<sup>+</sup>, 468 (M + 3)<sup>+</sup>, 470 (M + 5)<sup>+</sup>; HPLC retention time: 6.82 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 jum, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-059:
MS (ES, Pos.): 452 (M + 1)<sup>+</sup>, 454 (M + 3)<sup>+</sup>, 456 (M + 5)<sup>+</sup>; HPLC retention time: 6.23 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 jum, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-060:
MS (ES, Pos.): 554 (M + 1)<sup>+</sup>, 556 (M + 3)<sup>+</sup>.558 (M + 5)<sup>+</sup>; HPLC retention time: 6.43 min. (Xterra MS
C18 (Waters, Milford, MA) 3.5 jum, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases were used
159
ES 2 325 596 T3 (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min,
100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-062:
MS (ES, Pos.): 422 (M + 1)<sup>+</sup>; HPLC retention time: 6.29 min. (Xterra MS C18 (Waters, Milford, MA) 3.5m, 4.6 x 100mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-063:
MS (ES, Pos.): 408 (M + 1)<sup>+</sup>; HPLC retention time: 5.94 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 pm, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-064:
MS (ES, Pos.): 470 (M + 1)<sup>+</sup>, 472 (M + 3)<sup>+</sup>, HPLC retention time: 6.92 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 pm, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-065:
MS (ES, Pos.): 438 (M + 1)<sup>+</sup>; HPLC retention time: 6.40 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 pm, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-066:
MS (ES, Pos.): 506 (M + 1)<sup>+</sup>, 508 (M + 3)<sup>+</sup>, 510 (M + 5)<sup>+</sup>; HPLC retention time: 6.31 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 pm, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-068:
MS (ES, Pos.): 598 (M + 1)<sup>+</sup>, 600 (M + 3)<sup>+</sup>, 602 (M + 5)<sup>+</sup>; HPLC retention time: 7.11 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 pm, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-069:
MS (ES, Pos.): 584 (M + 1)<sup>+</sup>, 586 (M + 3)<sup>+</sup>, 588 (M + 5)<sup>+</sup>; HPLC retention time: 7.11 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 pm, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-072:
MS (ES, Pos.): 562 (M + 1)<sup>+</sup>, 564 (M + 3)<sup>+</sup>, 566 (M + 5)<sup>+</sup>; HPLC retention time: 6.63 min. (Xterra MS
C18 (Waters, Milford, MA) 3.5 pm, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min,
100% B for 1 min. and rebalance with 100% A for 1.5 min)
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ES 2 325 596 T3
2-073:
MS (ES, Pos.): 612 (M + 1)<sup>+</sup>, 614 (M + 3)<sup>+</sup>, 616 (M + 5)<sup>+</sup>; HPLC retention time: 6.61 min. (Xterra MS
C18 (Waters, Milford, MA) 3.5 pm, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min,
100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-077:
MS (ES, Pos.): 480 (M + 1)<sup>+</sup>, 482 (M + 3)<sup>+</sup>, 484 (M + 5)<sup>+</sup>; HPLC retention time: 6.54 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 pm, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-078:
MS (ES, Pos.): 466 (M + 1)<sup>+</sup>, 468 (M + 3)<sup>+</sup>, 470 (M + 5)<sup>+</sup>; HPLC retention time: 5.95 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 pm, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-079:
MS (ES, Pos.): 568 (M + 1)<sup>+</sup>, 570 (M + 3)<sup>+</sup>, 572 (M + 5)<sup>+</sup>; HPLC retention time: 6.97 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 pm, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-081:
MS (ES, Pos.): 436 (M + 1)<sup>+</sup>; HPLC retention time: 6.49 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 pm, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-083:
MS (ES, Pos.): 484 (M + 1)<sup>+</sup>, 486 (M + 3)<sup>+</sup>; HPLC retention time: 7.09 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 pm, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-084:
MS (ES, Pos.): 452 (M + 1)<sup>+</sup>; HPLC retention time: 6.55 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 pm, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-087:
MS (ES, Pos.): 612 (M + 1)<sup>+</sup>, 614 (M + 3)<sup>+</sup>, 616 (M + 5)<sup>+</sup>; HPLC retention time: 7.24 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 pm, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-088:
MS (ES, Pos.): 598 (M + 1)<sup>+</sup>, 600 (M + 3)<sup>+</sup>, 602 (M + 5)<sup>+</sup>; HPLC retention time: 7.21 min. (Xterra MS
C18 (Waters, Milford, MA) 3.5 pm, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases were used
161
ES 2 325 596 T3 (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min,
100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-094:
MS (ES, Pos.): 529 (M + 1)<sup>+</sup>, 531 (M + 3)<sup>+</sup>, 533 (M + 5)<sup>+</sup>; HPLC retention time: 6.40 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 pm, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-097:
MS (ES, Pos.): 491 (M + 1)<sup>+</sup>, 493 (M + 3)<sup>+</sup>, 495 (M + 5)<sup>+</sup>; HPLC retention time: 6.78 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 pm, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-099:
MS (ES, Pos.): 447 (M + 1)<sup>+</sup>, 449 (M + 3)<sup>+</sup>, 451 (M + 5)<sup>+</sup>; HPLC retention time: 6.73 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 pm, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-100:
MS (ES, Pos.): 433 (M + 1)<sup>+</sup>, 435 (M + 3)<sup>+</sup>, 437 (M + 5)<sup>+</sup>; HPLC retention time: 5.70 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 pm, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-101:
MS (ES, Pos.): 535 (M + 1)<sup>+</sup>, 537 (M + 3)<sup>+</sup>, 539 (M + 5)<sup>+</sup>; HPLC retention time: 6.72 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 pm, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-102:
MS (ES, Pos.): 521 (M + 1)<sup>+</sup>, 523 (M + 3)<sup>+</sup>, 525 (M + 5)<sup>+</sup>; HPLC retention time: 6.27 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 pm, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-103:
MS (ES, Pos.): 403 (M + 1); HPLC retention time: 6.24 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 pm, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-104:
MS (ES, Pos.): 389 (M + 1)<sup>+</sup>; HPLC retention time: 5.89 min. (Xterra MS C18 (Waters, Milford,
MA) 3.5 µm, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
162
ES 2 325 596 T3
2-105:
MS (ES, Pos.): 451 (M + 1)<sup>+</sup>, 453 (M + 3)<sup>+</sup>, HPLC retention time: 6.87 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 pm, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-106:
MS (ES, Pos.): 419 (M + 1)<sup>+</sup>; HPLC retention time: 6.33 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 pm, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-107:
MS (ES, Pos.): 487 (M + 1)<sup>+</sup>, 489 (M + 3)<sup>+</sup>, 491 (M + 5)<sup>+</sup>; HPLC retention time: 6.20 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 pm, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-108:
MS (ES, Pos.): 477 (M + 1)<sup>+</sup>, 479 (M + 3)<sup>+</sup>, 481 (M + 5)<sup>+</sup>; HPLC retention time: 6.21 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 pm, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-109:
MS (ES, Pos.): 579 (M + 1)<sup>+</sup>, 581 (M + 3)<sup>+</sup>, 583 (M + 5)<sup>+</sup>; HPLC retention time: 7.00 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 pm, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-110:
MS (ES, Pos.): 565 (M + 1)<sup>+</sup>, 567 (M + 3)<sup>+</sup>, 569 (M + 5)<sup>+</sup>; HPLC retention time: 7.00 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 pm, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-111:
MS (ES, Pos.): 421 (M + 1)<sup>+</sup>, 423 (M + 3)<sup>+</sup>; HPLC retention time: 6.84 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 pm, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-112:
MS (ES, Pos.): 557 (M + 1)<sup>+</sup>, 559 (M + 3)<sup>+</sup>, 561 (M + 5)<sup>+</sup>; HPLC retention time: 6.54 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 pm, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-113:
MS (ES, Pos.): 543 (M + 1)<sup>+</sup>, 545 (M + 3)<sup>+</sup>, 547 (M + 5)<sup>+</sup>; HPLC retention time: 6.69 min. (Xterra MS
C18 (Waters, Milford, MA) 3.5 pm, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases were used
163
ES 2 325 596 T3 (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min,
100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-114:
MS (ES, Pos.): 593 (M + 1)<sup>+</sup>, 595 (M + 3)<sup>+</sup>, 597 (M + 5)<sup>+</sup>; HPLC retention time: 6.84 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 pm, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-116:
MS (ES, Pos.): 505 (M + 1)<sup>+</sup>, 507 (M + 3)<sup>+</sup>, 509 (M + 5)<sup>+</sup>; HPLC retention time: 6.37 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 pm, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-117:
MS (ES, Pos.): 491 (M + 1)<sup>+</sup>, 493 (M + 3)<sup>+</sup>, 495 (M + 5)<sup>+</sup>; HPLC retention time: 6.52 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 pm, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-118:
MS (ES, Pos.): 461 (M + 1)<sup>+</sup>, 463 (M + 3)<sup>+</sup>, 465 (M + 5)<sup>+</sup>; HPLC retention time: 6.34 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 pm, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-119:
MS (ES, Pos.): 447 (M + 1)<sup>+</sup>, 449 (M + 3)<sup>+</sup>, 451 (M + 5)<sup>+</sup>; HPLC retention time: 5.79 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 pm, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-120:
MS (ES, Pos.): 549 (M + 1)<sup>+</sup>, 551 (M + 3)<sup>+</sup>, 553 (M + 5)<sup>+</sup>; HPLC retention time: 6.77 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 pm, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-121:
MS (ES, Pos.): 535 (M + 1)<sup>+</sup>, 537 (M + 3)<sup>+</sup>, 539 (M + 5)<sup>+</sup>; HPLC retention time: 5.83 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 pm, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-122:
MS (ES, Pos.): 417 (M + 1)<sup>+</sup>; HPLC retention time: 6.49 min. (Xterra MS C18 (Waters, Milford,
MA) 3.5 µm, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
164
ES 2 325 596 T3
2-123:
MS (ES, Pos.): 403 (M + 1)<sup>+</sup>; HPLC retention time: 5.96 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 jum, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-124:
MS (ES, Pos.): 465 (M + 1)<sup>+</sup>, 467 (M + 3)<sup>+</sup>, HPLC retention time: 6.87 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 jum, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-125:
MS (ES, Pos.): 433 (M + 1)<sup>+</sup>; HPLC retention time: 6.38 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 jum, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-126:
MS (ES, Pos.): 501 (M + 1)<sup>+</sup>, 503 (M + 3)<sup>+</sup>, 505 (M + 5)<sup>+</sup>; HPLC retention time: 6.26 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 jum, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
2-128:
MS (ES, Pos.): 579 (M + 1)<sup>+</sup>, 581 (M + 3)<sup>+</sup>, 583 (M + 5)<sup>+</sup>; HPLC retention time: 6.10 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 jum, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min) * 2: HCl salt (Table goes to next page)
165
ES 2 325 596 T3
Table
<img file="ES2325596T3_D0379.tif" />
166
ES 2 325 596 T3
<img file="ES2325596T3_D0380.tif" />
167
ES 2 325 596 T3
-010 J 6 I | CH | CH<sub>3</sub>ÍCH3¡CH<sub>3</sub>j -oil
<img file="ES2325596T3_D0381.tif" />
168
ES 2 325 596 T3
<img file="ES2325596T3_D0382.tif" />
169
ES 2 325 596 T3
-020, 7 ί I Ν) CH<sub>3</sub> | CH<sub>3</sub> ί Η! amorphous
<img file="ES2325596T3_D0383.tif" />
170
ES 2 325 596 T3 * 1: Comp. = Compound number, Ex. No. = Example number, crystallization solvent; IPE = diisopropyl ether
Analytical data for non-crystalline compounds are described below.
3-002:
MS (ES, Pos.): 514 (M + 1)<sup>+</sup>, 516 (M + 3)<sup>+</sup>; HPLC retention time: 6.77 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 jum, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
3-005:
MS (ES, Pos.): 547 (M + 1)<sup>+</sup>, 549 (M + 3)<sup>+</sup>; HPLC retention time: 7.06 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 jum, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
3-007:
MS (ES, Pos.): 514 (M + 1)<sup>+</sup>, 516 (M + 3)<sup>+</sup>; HPLC retention time: 7.01 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 jum, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
3-008:
MS (ES, Pos.): 577 (M + 1)<sup>+</sup>, 579 (M + 3)<sup>+</sup>; HPLC retention time: 10.89 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 jum, 4.6 x 100 mm); Flow rate 1.2 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions of 30% A, 50% B and 20% C to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
3-009:
MS (ES, Pos.): 597 (M + 1)<sup>+</sup>, 599 (M + 3)<sup>+</sup>; HPLC retention time: 13.94 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 jum, 4.6 x 100 mm); Flow rate 1.2 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions of 30% A, 50% B and 20% C to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
3-010:
MS No spectrum (decomposition in LC-MS); H NMR<sup>1</sup> (360 MHz, DMSO-D6) δ ppm 0.83 (3 H, t, J = 6.4 Hz), 1.24 (12 H, broad s), 1.52 (4 H, m), 1, 79 (9H, m), 1.93 (3H, s), 2.29 (3H, s), 2.32 (2H, t, J = 7.1Hz), 2.39 (3 H, s), 2.68 (2H, t, J = 11.3Hz), 3.46 (2H, d, J = 11.7Hz,), 4.00 (2H, d, J = 5.9 Hz), 6.45 (1H, s), 7.47 (2H, s)
3-011:
MS (ES, Pos.): 596 (M + 1)<sup>+</sup>, 598 (M + 3)<sup>+</sup>; HPLC retention time: 6.45 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 jum, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
3-013:
MS (ES, Pos.): 617 (M + 1)<sup>+</sup>, 619 (M + 3)<sup>+</sup>, 621 (M + 5)<sup>+</sup>; HPLC retention time: 6.65 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 jum, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (95% 25 mM ammonium acetate mobile phase + 5% acetonitrile; B mobile phase: acetonitrile; C mobile phase: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., To 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
171
ES 2 325 596 T3
3-015:
MS (ES, Pos.): 570 (M + 1)<sup>+</sup>, 572 (M + 3)<sup>+</sup>; HPLC retention time: 7.05 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 pm, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
3-016:
MS (ES, Pos.): 629 (M + 1)<sup>+</sup>, 631 (M + 3)<sup>+</sup>; HPLC retention time: 6.86 min. (Xterra MS C18 (Waters, Milford, MA) 3.5 pm, 4.6 x 100 mm); Flow rate 1.6 ml / min. Three mobile phases (mobile phase A 95% ammonium acetate 25 mM + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were used to prepare gradient conditions from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and rebalance with 100% A for 1.5 min)
3-019:
MS (ES, Pos.): 705 (M + 1)<sup>+</sup>, 707 (M + 3)<sup>+</sup>; H NMR<sup>1</sup> (300 MHz, CDCl<sub>3</sub>) δ ppm 0.89 (3 H, t, J = 6.7 Hz), 1.17-
1.40 (14H, m), 1.42-1.72 (4H, m), 1.81-1.93 (3H, m), 1.92 (6H, s), 2, 00-2.07 (4H, m), 2.34 (2H, t, J = 7.5Hz), 2.44 (3H, d, J = 1.1Hz), 2.51 (3 H, s), 2.74-2.81 (2H, m), 2.90-3.04 (2H, m), 4.03 (2H, d, J = 6.4 Hz,) , 4.10-4.19 (2H, m), 5.28-5.42 (4H, m), 6.57 (1H, m), 7.30 (2H, s)
3-020:
MS (ES, Pos.): 729 (M + 1)<sup>+</sup>, 731 (M + 3)<sup>+</sup>; H NMR<sup>1</sup> (300 MHz, CDCl<sub>3</sub>) δ ppm 0.89 (3 H, t, J = 6.7 Hz), 1.20-
1.40 (6H, m), 1.41-1.53 (2H, m), 1.65-1.80 (2H, m), 1.81-2.00 (3H, m ), 1.92 (6H, s), 2.02-2.19 (4H, m), 2.36 (2H, t, J = 7.5Hz), 2.44 (3H, d , J = 1.0 Hz), 2.51 (3H, s), 2.77-2.90 (6H, m), 2.92-3.05 (2H, m), 4.03 (2H, d, J = 6.4Hz,), 4.05-4.19 (2H, m), 5.28-5.47 (8H, m), 6.57 (1H, m), 7.30 (2H, s)
3-021:
MS (ES, Pos.): 753 (M + 1)<sup>+</sup>, 754 (M + 3)<sup>+</sup>; H NMR<sup>1</sup> (500 MHz, CDCl<sub>3</sub>) δ ppm 0.97 (3 H, t, J = 7.3 Hz), 1.15-
1.40 (1H, m), 1.45-1.55 (2H, m), 1.84-2.00 (3H, m), 1.92 (6H, s), 2, 04-2.11 (2H, m), 2.38-2.44 (4H, m), 2.43 (3H, d, J = 1.2Hz), 2.50 (3H, s ), 2.77-2.90 (10H, m), 2.94-3.02 (2H, m), 4.04 (2H, d, J = 6.7Hz,), 4, 09-4.16 (2H, m), 5.27-5.46 (12H, m), 6.57 (1H, m), 7.30 (2H, s)
3-022:
MS (ES, Pos.): 727 (M + 1)<sup>+</sup>, 729 (M + 3)<sup>+</sup>; H NMR<sup>1</sup> (500 MHz, CDCl<sub>3</sub>) δ ppm 0.97 (3 H, t, J = 7.3 Hz), 1.15-
1.40 (1H, m), 1.45-1.55 (2H, m), 1.65-1.80 (2H, m), 1.84-1.98 (2H, m ), 1.92 (6H, s), 2.03-2.17 (4H, m), 2.36 (2H, t, J = 7.3Hz), 2.43 (3H, d, J = 1.2 Hz), 2.50 (3H, s), 2.77-2.91 (8H, m), 2.94-3.02 (2H, m), 4, 04 (2H, d, J = 6.7Hz,), 4.09-4.16 (2H, m), 5.28-5.44 (10H, m), 6.57 (1H , m), 7.30 (2 H, s) * 2: Optically active compound * 3: 1 Na salt
Assay Example [CRF receptor binding assay]
Monkey tonsil membranes were used as receptor preparation.
CRF-I was used<sup>125</sup> as I-labeled ligand<sup>125</sup>.
The binding reaction was carried out using the ligand labeled with I<sup>125</sup> by the following method described in The Journal of Neuroscience, 7, 88 (1987).
Preparation of receptor membranes:
Monkey tonsil was homogenized in 50 mM Tris-HCl buffer (pH 7.0) containing MgCl<sub>2</sub> 10 mM, 2 mM EDTA and centrifuged at 48,000 xg for 20 min, and the precipitate was washed once with Tris-HCl buffer. The washed precipitate was suspended in 50 mM Tris-HCl buffer (pH 7.0) containing MgCl<sub>2</sub> 10 mM, 2 mM EDTA, 0.1% bovine serum albumin and 100 kallikrein units / ml of aprotinin, to obtain a membrane preparation.
172
ES 2 325 596 T3
CRF receptor binding assay:
Membrane preparation (0.3 mg protein / ml), CRF-I<sup>125</sup> (0.2 nM) and a test drug were reacted at 25 ° C for 2 hours. After completion of the reaction, the reaction mixture was filtered by suction through a glass filter (GF / C) treated with 0.3% polyethyleneimine, and the glass filter was washed three times with phosphate buffered saline. containing 0.01% Triton X-100. After washing, the radioactivity of the filter paper was measured in a gamma counter.
The amount of CRF-I<sup>125</sup> bound when the reaction was carried out in the presence of 1 pM CRF, the degree of non-specific binding of CRF-I was considered<sup>125</sup>, and the difference between the total degree of CRF-I binding<sup>125</sup> and the degree of binding of CRF-I<sup>125</sup> non-specific, the degree of CRF-I binding was considered<sup>125</sup> specific. An inhibition curve was obtained by reacting a defined concentration (0.2 nM) of CRF-I<sup>125</sup> with different concentrations of each test drug under the conditions described above. The concentration of test drug at which CRF-I binding is inhibited<sup>125</sup> by 50% (CI<sub>50</sub>) was determined from the inhibition curve.
As a result, it was found that the compounds 1-003,1-004,1-005,1-007,1-008,1-009,1-010,1-013,1-014, 1016, 1-018, 1-019, 1-021, 1-032 #, 1-038 #, 1-039 #, 1-040 #, 1-046 #, 1-050 #, 1-051 #, 1-052 #, 1- 053 #, 1-054 #, 1-056 #, 1-057 #, 1-058 #, 1-059 #, 1-060 #, 1-061 #, 1-062 #, 1-063 #, 1- 064 #, 1-067 #, 1-068 #, 1-072 #, 1-073 #, 1-074 #, 1-077 #, 1-078 #, 1-087 #, 1-088 #, 1- 089 #, 1-090 #, 1-091 #, 1-097 #, 1-098 #, 1-099 #, 1-103, 1-104, 1-105, 1-112, 1-117, 1- 118, 1-120, 1-121, 1-122, 1-123, 1-125, 1-126, 1-127, 1-128, 1-129, 1-130, 1-131, 1-132, 1-133, 1-135, 1-141, 1-142, 1143, 1-144, 1-145, 1-148, 1-149, 1-150, 1-151, 1-152, 1-153, 1-154, 1-155, 1-156, 1-157, 1-158, 1-159, 1-160, 1-161, 1- 162, 1-163, 1-164, 1-165, 1-166, 1-167, 1-172, 1-173, 1-176, 1-177, 1-178, 1-179, 1-181, 1-183 #, 1-184 #, 1-188 #,
1- 195#, 1-208#, 1-213, 1-235, 1-236, 1-237, 1-243#, 1-245#, 1-251#, 1-257, 1-262, 1-264, 1-278, 1-280, 1-283, 1284, 1-285, 1-286, 1-287, 1-288, 1-302, 1-304, 1-306, 1-308, 1-319, 1-320, 1-332, 1-333, 1-336, 1-337, 2-002, 2-003,
2- 004, 2-005, 2-006, 2-007, 2-008, 2-009, 2-010, 2-011, 2-012, 2-013, 2-014, 2-015, 2- 016, 2-017, 2-018, 2-019, 2020, 2-021, 2-022, 2-023, 2-024, 2-025, 2-026, 2-027, 2-028, 2- 029, 2-030, 2-031, 2-032, 2-033, 2-034, 2-035, 2-036, 2-037, 2-038, 2-039, 2-040, 2-041, 2-042, 2-043, 2-044, 2-045, 2-046, 2-047, 2-048, 2-049, 2-050, 2-052, 2-053, 2054, 2-055, 2-056, 2-057, 2-058, 2-059, 2-060, 2-061, 2-062, 2-063, 2-064, 2-065, 2-066, 2-068, 2- 069, 2-070, 2-071, 2-072, 2-073, 2-074, 2-075, 2-076, 2-077, 2-078, 2-079, 2-080, 2-081, 2-082, 2-084, 2-087, 2-088, 2-089, 2-090, 2091, 2-092, 2-093, 2-094, 2-095, 2-096, 2-097, 2-098, 2-099, 2-100, 2-101, 2-102, 2-103, 2-104, 2- 105, 2-106, 2-107, 2-108, 2-109, 2-110, 2-111, 2-112, 2-113, 2-114, 2-115, 2-116, 2-117, 2-118, 2-119, 2-120, 2-121, 2-122, 2-123, 2124, 2-125, 2-126, 2-127, 2-128, 3-001, 3-004, 3-006, 3-007, 3-008, 3-009, 3-015 and 3-018 can be illustrated as typical compounds that have a CI value<sub>50</sub> 50 nM or less (# means "not according to the invention").
Effect of the invention
In accordance with the present invention, compounds having a high affinity for CRF receptors have been provided. These compounds are effective against diseases in which CRF is considered to be involved, such as depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorders, hypertension, gastric diseases, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, external head injuries, inflammation, immunity-related diseases, alopecia, irritable bowel syndrome, sleep disorders, epilepsy, dermatitis, schizophrenia, etc.
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Contents133
383 sheets
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45 members in 23 offices
Priority claims5
| Document | Office | Kind | Date |
|---|---|---|---|
| 20020383667 | Japan | – | |
| 2002383667 | Japan | A | |
| 2002383667 | Japan | A | |
| 200238366706019987 | – | – | – |
| JP20020383667 | – | – | – |
Members45
| Document | Office | Kind | |
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| CA2485556A1 | Canada | A1 | |
| WO2004058767A1 | World Intellectual Property Organization (WIPO) | A1 | |
| AU2003292550A1 | Australia | A1 | |
| NO20043508L | Norway | L | |
| EP1467997A1 | European Patent Office (EPO) | A1 | |
| HRP20040724A2 | Croatia | A2 | |
| MXPA04008081A | Mexico | A | |
| KR20040111369A | Republic of Korea | A | |
| BR0307587A | Brazil | A | |
| TW200505921A | Taiwan Province of China | A | |
| EA200401060A1 | Eurasian Patent Organization (EAPO) | A1 | |
| CL2003002762A1 | Chile | A1 | |
| PL371810A1 | Poland | A1 | |
| AR042667A1 | Argentina | A1 | |
| ZA200405982B | South Africa | B | |
| US2005209253A1 | United States of America | A1 | |
| CN1692115A | China | A | |
| JP2005539090A | Japan | A | |
| CA2485556C | Canada | C | |
| AU2003292550B2 | Australia | B2 | |
| AU2003292550B8 | Australia | B8 | |
| UA77265C2 | Ukraine | C2 | |
| KR20060128063A | Republic of Korea | A | |
| TWI270549B | Taiwan Province of China | B | |
| KR100688395B1 | Republic of Korea | B1 | |
| EP1787992A1 | European Patent Office (EPO) | A1 | |
| KR100808756B1 | Republic of Korea | B1 | |
| EP1467997B1 | European Patent Office (EPO) | B1 | |
| AT390426T | Austria | T | |
| ATE390426T1 | Austria | T1 | |
| DE60319951D1 | Germany | D1 | |
| ES2302949T3 | Spain | T3 | |
| EP1467997B8 | European Patent Office (EPO) | B8 | |
| JP4181126B2 | Japan | B2 | |
| US2008287397A1 | United States of America | A1 | |
| EP1787992B1 | European Patent Office (EPO) | B1 | |
| AT430151T | Austria | T | |
| ATE430151T1 | Austria | T1 | |
| DE60319951T2 | Germany | T2 | |
| DE60327477D1 | Germany | D1 | |
| ES2325596T3This record | Spain | T3 | |
| MY141200A | Malaysia | A | |
| US7932259B2 | United States of America | B2 | |
| US2011130364A1 | United States of America | A1 | |
| US8455511B2 | United States of America | B2 |
Numbers
- Publication
- 2325596
- Publication, DOCDB
- 2325596
- Publication, EPODOC
- ES2325596T
- Application
- 6019987
- Application, DOCDB
- 06019987
- Application, EPODOC
- ES20060019987T
Titles2
- Spanish
- DERIVADOS DE PIRROLOPIRIMIDINA Y PIRROLOPIRIDINA SUSTITUIDOS CON UN GRUPO AMINO CICLICO.
- English
- PIRROLOPIRIMIDINE AND PIRROLOPIRIDINE DERIVATIVES REPLACED WITH A CYCLIC AMINO GROUP.
Classification
- CPC, 23
- C07D471/04
- C07D487/04
- C07F9/6561
- A61P1/00
- A61P1/04
- A61P1/14
- A61P17/00
- A61P17/14
- A61P25/00
- A61P25/08
- A61P25/14
- A61P25/16
- A61P25/18
- A61P25/22
- A61P25/24
- A61P25/28
- A61P25/36
- A61P29/00
- A61P37/00
- A61P43/00
- A61P9/00
- A61P9/10
- A61P9/12
- IPC, 38
- C07D487 04
- A61K31 436
- A61K31 437
- A61K31 4375
- A61K31 439
- A61K31 519
- A61K31 661
- A61P1 00
- A61P1 04
- A61P9 10
- A61P9 12
- A61P17 00
- A61P17 14
- A61P25 00
- A61P25 08
- A61P25 14
- A61P25 16
- A61P25 18
- A61P25 22
- A61P25 24
- A61P25 28
- A61P25 36
- A61P29 00
- A61P37 00
- A61P43 00
- C07D209 00
- C07D221 00
- C07D239 00
- C07D451 00
- C07D471 00
- C07D471 04
- C07D471 08
- C07D487 00
- C07D491 00
- C07D491 08
- C07D519 00
- C07F9 59
- C07F9 6561