ES2548135T3 - Heterociclos condensados que contienen nitrógeno y composiciones de los mismos como inhibidores de quinasa - Google Patents

Heterociclos condensados que contienen nitrógeno y composiciones de los mismos como inhibidores de quinasa Download PDF

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ES2548135T3
ES2548135T3 ES09747213.8T ES09747213T ES2548135T3 ES 2548135 T3 ES2548135 T3 ES 2548135T3 ES 09747213 T ES09747213 T ES 09747213T ES 2548135 T3 ES2548135 T3 ES 2548135T3
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imidazo
fluorophenyl
pyridazin
pyrrolidin
pyridin
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Pamela A. Albaugh
Ha-Soon Choi
Gregory Chopiuk
Yi Fan
Paul Vincent Rucker
Zhicheng Wang
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Abstract

Un compuesto de Fórmula (I), una sal farmacéuticamente aceptable, un solvato farmacéuticamente aceptable del mismo:**Fórmula** en donde: R1 es en donde, X1 y X2 son ambos N y X3 y X4 son ambos C k es 1, 2, o 3; cada R3 es fenilo opcionalmente sustituido con 1 a 3 sustituyentes independientemente seleccionados de halógeno, alquilo de 1 a 8 átomos de carbono y alquilo de 1 a 8 átomos de carbono sustituido con halógeno; R2 es arilo de 6 a 14 átomos de carbono, heteroarilo de 2 a 13 átomos de carbono o heterocicloalquilo de 2 a 14 átomos de carbono, en donde el arilo de 6 a 14 átomos de carbono, heteroarilo de 2 a 13 átomos de carbono o heterocicloalquilo de 2 a 14 átomos de carbono de R2 están opcionalmente sustituidos con 1 a 3 sustituyentes independientemente seleccionados de halógeno, heterocicloalquilo de 2 a 14 átomos de carbono, heteroarilo de 2 a 13 átomos de carbono, alquilo de 1 a 8 átomos de carbono, cicloalquilo de 3 a 8 átomos de carbono, -CN, -C(O)N(R4)2, - N(R4)C(O)OR4, -N(R4)C(O)R4, -C(O)R9, -OR9, -C(O)OR9, -N(R4)2, -R6, -OR6, -L1R5, -L1R6, -Y1R5,-Y1R6, -S(O)2R9, - S(O)2N(R4)2, -NR4S(O)2R4, -OC(O)R9 , alcoxi de 1 a 8 átomos de carbono, hidroxilalquilo de 1 a 8 átomos de carbono, alquilo de 1 a 8 átomos de carbono sustituido con halógeno y alcoxi de 1 a 8 átomos de carbono sustituido con halógeno; cada R4 es independientemente seleccionado de H, alquilo de 1 a 8 átomos de carbono, -L1R5, -L1R6, -L1R8, heteroarilo de 2 a 13 átomos de carbono, arilo de 6 a 14 átomos de carbono, heterocicloalquilo de 2 a 14 átomos de carbono y cicloalquilo de 3 a 8 átomos de carbono, en donde el alquilo de 1 a 8 átomos de carbono, heteroarilo de 2 a 13 átomos de carbono y cicloalquilo de 3 a 8 átomos de carbono están opcionalmente sustituidos con 1 a 3 sustituyentes independientemente seleccionados de halógeno, deuterio, -CD3, -S(O)2R9, -CN, alquilo de 1 a 8 átomos de carbono, - OR9, -N(R9)2 y -(CH2)pOR9; L1 es un enlace, alquileno de 1 a 8 átomos de carbono, alquenileno de 2 a 8 átomos de carbono, -O(CH2)p-, -C(O)-, - N(R9)-, (CH2)pC(O)-, -C(O)(CH2)pO(CH2)p- o -C(O)O-; Y1 es arileno de 6 a 14 átomos de carbono, heteroarileno de 2 a 13 átomos de carbono, cicloalquileno de 3 a 8 átomos de carbono, heterocicloalquileno de 2 a 14 átomos de carbono o alcoxileno de 1 a 8 átomos de carbono, cada uno de los cuales está opcionalmente sustituido con 1 a 3 sustituyentes independientemente seleccionados de halógeno, heterocicloalquilo de 2 a 14 átomos de carbono, heteroarilo de 2 a 13 átomos de carbono, alquilo de 1 a 8 átomos de carbono, cicloalquilo de 3 a 8 átomos de carbono, -CN, -C(O)N(R4)2, -N(R4)C(O)OR4, -N(R4)C(O)R4, -C(O)R9, -OR9 , - C(O)OR9, - N(R4)2, -R6, -OR6, -L1R5, -L1R6, -Y1R5, -Y1R6, -S(O)2R9, -S(O)2N(R4)2, - NR4S(O)2R4, -OC(O)R9, alcoxi de 1 a 8 átomos de carbono, hidroxilalquilo de 1 a 8 átomos de carbono, alquilo de 1 a 8 átomos de carbono sustituido con halógeno y alcoxi de 1 a 8 átomos de carbono sustituido con halógeno; R5 es arilo de 6 a 14 átomos de carbono, heteroarilo de 2 a 13 átomos de carbono, heterocicloalquilo de 2 a 14 átomos de carbono, -N(R9)2, -N(R9)C(O)R9, -C(O)N(R9)2, -(CH2)pOR9 o -OR9. R6 es arilo de 6 a 14 átomos de carbono, heteroarilo de 2 a 13 átomos de carbono, heterocicloalquilo de 2 a 14 átomos de carbono, -OCH(R7)2, -C(O)R7, alquilo de 1 a 8 átomos de carbono, o cicloalquilo de 3 a 8 átomos de carbono, en donde el alquilo de 1 a 8 átomos de carbono, cicloalquilo de 3 a 8 átomos de carbono, arilo de 6 a 14 átomos de carbono, heteroarilo de 2 a 13 átomos de carbono, y heterocicloalquilo de 2 a 14 átomos de carbono de R6 están opcionalmente sustituidos con 1 a 3 sustituyentes independientemente seleccionados de halógeno, -CN,-OR9, - (CH2)pOR9,-L1C(O)R8, -L1R8, -L1R5, -C(O)R9, -OC(O)R9, -C(O)OR9, -C(O)R8, OC(O)N(R4)2, -N(R9)2, -C(O)C(O)OR9, - (CH2)pN(R9)2, -N(R4)2, -C(O)N(R4)2, -N(R4)C(O)R4, N(R4)C(O)OR4, -(CH2)pS(O)2R9, -S(O)2R9, -S(O)2N(R4)2, - NR4S(O)2R4,-NR4S(O)2R9, heterocicloalquilo de 2 a 14 átomos de carbono, heteroarilo de 2 a 13 átomos de carbono, alquilo de 1 a 8 átomos de carbono, alqueno de 2 a 8 átomos de carbono, alcoxi de 1 a 8 átomos de carbono, alquilo de 1 a 8 átomos de carbono sustituido con hidroxilo, alquilo de 1 a 8 átomos de carbono sustituido con halógeno y alcoxi de 1 a 8 átomos de carbono sustituido con halógeno; o R6 es arilo de 6 a 14 átomos de carbono, heteroarilo de 1 a 13 átomos de carbono o, heterocicloalquilo de 2 a 14 átomos de carbono o cicloalquilo de 3 a 8 átomos de carbono que tiene un puente alquilo de 1 a 4 átomos de carbono; o R6 es a heterocicloalquilo de 2 a 14 átomos de carbono opcionalmente sustituido con 1 a 3 sustituyentes independientemente seleccionados de halógeno, >=O, -CN,-OR9, -(CH2)pOR9, -L1C(O)R8, -L1R8, -L1R5, -C(O)R9, - OC(O)R9, -C(O)OR9, -C(O)R8, OC(O)N(R4)2, -N(R9)2,-C(O)C(O)OR9, -(CH2)pN(R9)2, -N(R4)2, -C(O)N(R4)2, -N(R4)C(O)R4, -N(R4)C(O)OR4, -(CH2)pS(O)2R9, -S(O)2R9, -S(O)2N(R4)2, -NR4S(O)2R4, NR4S(O)2R9, heterocicloalquilo de 2 a 14 átomos de carbono, heteroarilo de 1 a 13 átomos de carbono, alquilo de 1 a 8 átomos de carbono, alqueno de 2 a 8 átomos de carbono, alcoxi de 1 a 8 átomos de carbono, alquilo de 1 a 8 átomos de carbono sustituido con hidroxilo, alquilo de 1 a 8 átomos de carbono sustituido con halógeno y alcoxi de 1 a 8 átomos de carbono sustituido con halógeno; cada R7 es independientemente seleccionado de H, alquilo de 1 a 8 átomos de carbono y -L1R8; R8 es H, -N(R9)2, -N(R4)2, -SR9, -CN, alquilo de 1 a 8 átomos de carbono, cicloalquilo de 3 a 8 átomos de carbono y heterocicloalquilo de 2 a 14 átomos de carbono, en donde el alquilo de 1 a 8 átomos de carbono, cicloalquilo de 3 a 8 átomos de carbono y heterocicloalquilo de 2 a 14 átomos de carbono de R8 están opcionalmente sustituidos con 1 a 3 sustituyentes independientemente seleccionados de halógeno, alquilo de 1 a 6 átomos de carbono, -CN, -OR9, - (CH2)pOR9, -L1C(O)R8, -C(O)R9, -OC(O)R9, -C(O)OR9, -N(R9)2, -N(R4)2, -C(O)N(R4)2,-N(R4)C(O)R4, -N(R4)C(O)OR4, - S(O)2R9, -S(O)2N(R4)2, y -NR4S(O)2; cada R9 es independientemente seleccionado de H, cicloalquilo de 3 a 8 átomos de carbono y alquilo de 1 a 8 átomos de carbono, y cada p es independientemente 1, 2, 3, 4, 5 o 6.

Description

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E09747213
23-09-2015
fluorofenil)morfolino)imidazo[1,2-b]piridazin-3-il)-2-((4-metilpiperazin-1-il)metil)benzonitrilo; 1-(6-(6-(2-(2,5-difluorofenil) pirrolidin-1-il)imidazo[1,2-b]piridazin-3-il)piridin-2-il)piperidin-4-ol; 3-(3-fluorofenil)-4-(3-(6-fluoropiridin-2-il)imidazo[1,2-b] piridazin-6-il)morfolina; (5-(6-(2-(3-fluorofenil)pirrolidin-1-il)imidazo[1,2-b]piridazin-3-il)piridin-2-il)(4-hidroxipiperidin-1-il) metanona; 3-(3-fluorofenil)-4-(3-(6-morfolinopiridin-2-il)imidazo[1,2-b]piridazin-6-il)morfolina; 3-(3-fluorofenil)-4-(3-(6(piperazin-1-il)piridin-2-il)imidazo[1,2-b]piridazin-6-il)morfolina; 4-(6-(2-(2-fluorofenil)pirrolidin-1-il)imidazo[1,2-b]piridazin3-il)benzonitrilo; 3-(6-(2-(2-fluorofenil)pirrolidin-1-il)imidazo[1,2-b]piridazin-3-il)benzonitrilo; 4-(4-(6-(2-(2-fluorofenil) pirrolidin-1-il)imidazo[1,2-b]piridazin-3-il)tiazol-2-il)morfolina; 5-(6-(3-(3-fluorofenil)morfolino)imidazo[1,2-b]piridazin-3-il)2-(4-metilpiperazin-1-il)benzonitrilo; 2-(4-acetilpiperazin-1-il)-5-(6-(3-(3-fluorofenil)morfolino)imidazo[1,2-b]piridazin-3-il) benzonitrilo; 5-(6-(2-(2-fluorofenil)pirrolidin-1-il)imidazo[1,2-b]piridazin-3-il)-2-(4-hidroxipiperidin-1-il)benzonitrilo; 1-(6-(6(3-(3-fluorofenil)morfolino)imidazo[1,2-b]piridazin-3-il)piridin-2-il)piperidin-4-ol; N-(5-(6-(2-(3-fluorofenil)pirrolidin-1-il) imidazo[1,2-b]piridazin-3-il)pirazin-2-il)ciclopropano-carboxamida; 4-(6-(2-(3-fluorofenil)pirrolidin-1-il)imidazo[1,2-b] piridazin-3-il)-2-((4-metilpiperazin-1-il)metil)benzonitrilo; (2S)-4-(6-(6-(2-(3-fluorofenil)pirrolidin-1-il)imidazo[1,2-b] piridazin-3-il)piridin-2-il)-2-metilmorfolina; ácido 1-(6-(6-(2-(3-fluorofenil)pirrolidin-1-il)imidazo[1,2-b]piridazin-3-il)piridin-2il)piperidin-4-carboxílico; 5-(6-(2-(3-fluorofenil)pirrolidin-1-il)imidazo[1,2-b]piridazin-3-il)-2-metoxitiazol; ácido 4-(6-(2-(3fluorofenil)pirrolidin-1-il)imidazo[1,2-b]piridazin-3-il)tiazol-2-carboxílico; (4-(6-(2-(3-fluorofenil)pirrolidin-1-il)imidazo[1,2b]piridazin-3-il)tiazol-2-il)metanol; 1-(6-(6-(2-(3-fluorofenil)pirrolidin-1-il)imidazo[1,2-b]piridazin-3-il)piridin-2-il)piperidin-3ol; (3R)-1-(6-(6-(2-(3-fluorofenil)pirrolidin-1-il)imidazo[1,2-b]piridazin-3-il)piridin-2-il)-N,Ndimetilpirrolidin-3-amina; 6-(2-(3fluorofenil)pirrolidin-1-il)-3-(1-metil-1H-imidazol-2-il)imidazo[1,2-b]piridazina; 5-(6-(3-(3-fluorofenil)morfolino)imidazo[1,2b]piridazin-3-il)-2-(piperazin-1-il)benzonitrilo; 4-(6-(6-(3-(3-fluorofenil)morfolino)imidazo[1,2-b]piridazin-3-il)piridin-2-il) piperazina-1-carboxilato de terc-butilo; 3-(3-fluorofenil)-4-(3-(6-(4-metilpiperazin-1-il)piridin-2-il)imidazo[1,2-b]piridazin-6il)morfolina; 4-(6-(6-(3-(3-fluorofenil)morfolino)imidazo[1,2-b]piridazin-3-il)piridin-2-il)-2,6-dimetilmorfolina; 3-(3fluorofenil)-4-(3-(6-(piperidin-4-iloxi)piridin-2-il)imidazo[1,2-b]piridazin-6-il)morfolina; 4-(6-(2-(3-fluorofenil)pirrolidin-1il)imidazo[1,2-b]piridazin-3-il)-2-(piperazin-1-ilmetil)tiazol; 2,2’-(6-(6-(2-(3-fluorofenil)pirrolidin-1-il)imidazo[1,2-b]piridazin3-il)piridin-2-ilazanediil)dietanol; 4-(2-(6-(6-(2-(3-fluorofenil)pirrolidin-1-il)imidazo[1,2-b]piridazin-3-il)piridin-2-iloxi)etil) morfolina; 6-(2-(3-fluorofenil)pirrolidin-1-il)-3-(6-(2-(pirrolidin-1-il)etoxi)piridin-2-il)imidazo[1,2-b]piridazina; 4-((6-(6-(2-(3fluorofenil)pirrolidin-1-il)imidazo[1,2-b]piridazin-3-il)piridin-2-il)metil)morfolina; 4-((6-(6-(2-(3-fluorofenil)pirrolidin-1-il) imidazo[1,2-b]piridazin-3-il)piridin-2-il)metil)-2,6-dimetilmorfolina; 1-((6-(6-(2-(3-fluorofenil)pirrolidin-1-il)imidazo[1,2-b] piridazin-3-il)piridin-2-il)metil)pirrolidin-3-ol; 4-(6-(2-(3-fluorofenil)pirrolidin-1-il)imidazo[1,2-b]piridazin-3-il)-2-metoxitiazol; 4-(5-(6-(3-(3-fluorofenil) morfolino) imidazo [1,2-b]piridazin-3-il)-2-oxo-2,3-dihidro-1H-benzo [d]imidazol-1-il) piperidin-1carboxilato de etilo; 6-(6-(2-(2,5-difluorofenil)pirrolidin-1-il)imidazo[1,2-b]piridazin-3-il)nicotinonitrilo; 5-(6-(3-(3-fluorofenil) morfolino)imidazo[1,2-b]piridazin-3-il)-1-(piperidin-4-il)-1H-benzo[d]imidazol-2(3H)-ona; 2-(4-(6-(6-(2-(3-fluorofenil) pirrolidin-1-il)imidazo[1,2-b]piridazin-3-il)piridin-2-il)piperazin-1-il)-N,N-dimetilacetamida; 6-(2-(3-fluorofenil)pirrolidin-l-il)3-(6-(4-isopropilpiperazin-l-il)piridin-2-il)imidazo[l,2-b]piridazina; 2-(1-(6-(6-(2-(3-fluorofenil)pirrolidin-1-il)imidazo[1,2-b] piridazin-3-il)piridin-2-il)piperidin-4-il)propan-2-ol; 4-(1-(6-(6-(2-(3-fluorofenil)pirrolidin-1-il)imidazo[1,2-b]piridazin-3-il) piridin-2-il)piperidin-4-il)morfolina; 3-(4-(6-(6-(2-(3-fluorofenil)pirrolidin-1-il)imidazo[1,2-b]piridazin-3-il)piridin-2-il) piperazin-1-il)propanonitrilo; 1-(6-(6-(2-(3-fluorofenil)piperidin-1-il)imidazo[1,2-b]piridazin-3-il)piridin-2-il)piperidin-4-ol; 2(4-(6-(6-(2-(3-fluorofenil)pirrolidin-1-il)imidazo[1,2-b]piridazin-3-il)piridin-2-il)piperazin-1-il)-N-isopropil-acetamida; (1-(6(6-(2-(3-fluorofenil)pirrolidin-1-il)imidazo[1,2-b]piridazin-3-il)piridin-2-il)piperidin-4-il)metanol; (1-(6-(6-(2-(3-fluorofenil) pirrolidin-1-il)imidazo[1,2-b]piridazin-3-il)piridin-2-il)piperidin-3-il)metanol; 1-(6-(6-(2-(3-fluorofenil)pirrolidin-1-il)imidazo [1,2-b]piridazin-3-il)piridin-2-il)piperidin-4-carbonitrilo; 2-(4-(6-(6-(2-(3-fluorofenil)pirrolidin-1-il)imidazo[1,2-b]piridazin-3-il) piridin-2-il)piperazin-1-il)etanol; (6-(6-(2-(3-fluorofenil)pirrolidin-1-il)imidazo[1,2-b]piridazin-3-il)piridin-2-il)metanol; 6-(2-(3fluorofenil)pirrolidin-1-il)-3-(6-(5-metil-1H-imidazol-2-il)piridin-2-il)imidazo[1,2-b]piridazina; 6-(6-(2-(3-fluorofenil)pirrolidin1-il)imidazo[1,2-b]piridazin-3-il)picolinamida; (R)-6-(2-(3-fluorofenil)pirrolidin-1-il)-3-(6-fluoropiridin-2-il)imidazo[1,2-b] piridazina; (R)-1-(6-(6-(2-(3-fluorofenil)pirrolidin-1-il)imidazo[1,2-b]piridazin-3-il)piridin-2-il)piperidin-4-ol; (1-(6-(6-(3-(3fluorofenil)morfolino)imidazo[1,2-b]piridazin-3-il)piridin-2-il)piperidin-4-il)metanol; 2-(1-(6-(6-(3-(3-fluorofenil)morfolino) imidazo[1,2-b]piridazin-3-il)piridin-2-il)piperidin-4-il)etanol; 1-(6-(6-(3-(3-fluorofenil)morfolino)imidazo[1,2-b]piridazin-3il)piridin-2-il)piperidin-3-carboxamida; 1-(6-(6-(3-(3-fluorofenil)morfolino)imidazo[1,2-b]piridazin-3-il)piridin-2-il)piperidin-4carboxamida; 6-(6-(2-(3-fluorofenil)pirrolidin-1-il)imidazo[1,2-b]piridazin-3-il)piridin-2-ol; ácido 6-(6-(2-(3fluorofenil)pirrolidin-1-il)imidazo[1,2-b]piridazin-3-il)picolínico; 2-fluoro-3-(6-(2-(3-fluorofenil)pirrolidin-1-il)imidazo[1,2-b] piridazin-3-il)quinolina; 3-(6-(2-(3-fluorofenil)pirrolidin-1-il)imidazo[1,2-b]piridazin-3-il)quinolin-2(1H)-ona; 5-(6-(2-(3fluorofenil)pirrolidin-1-il)imidazo[1,2-b]piridazin-3-il)quinolina; 6-(2-(3-fluorofenil)pirrolidin-1-il)-3-(4-(metilsulfonil)fenil) imidazo[1,2-b]piridazina; 6-(2-(3-fluorofenil)pirrolidin-1-il)-3-(6-(piperidin-4-iloxi)piridin-2-il)imidazo[1,2-b]piridazina; (1-(6(6-(2-(3-fluorofenil)pirrolidin-1-il)imidazo[1,2-b]piridazin-3-il)piridin-2-ilamino)ciclopentil)metanol; 3-(3-fluorofenil)-4-(3-(6(4-(1-metilpiperidin-4-il)piperazin-1-il)piridin-2-il)imidazo[1,2-b]piridazin-6-il)morfolina; 3-(6-(2-(3-fluorofenil)pirrolidin-1il)imidazo[1,2-b]piridazin-3-il)quinolina; (6-(6-(2-(3-fluorofenil)pirrolidin-1-il)imidazo[1,2-b]piridazin-3-il)piridin-2-il)(4hidroxipiperidin-1-il)metanona; 6-(2-(3-fluorofenil)pirrolidin-1-il)-3-(2-fluoropiridin-4-il)imidazo[1,2-b]piridazina; 1-(4-(6-(2(3-fluorofenil)pirrolidin-1-il)imidazo[1,2-b]piridazin-3-il)piridin-2-il)piperidin-4-ol; N1,N1-dietil-N2-(6-(6-(2-(3-fluorofenil) piperidin-1-il)imidazo[1,2-b]piridazin-3-il)piridin-2-il)etano-1,2-diamina; 6-(2-(3-fluorofenil)piperidin-1-il)-3-(6-(4-isopropilpiperazin-1-il)piridin-2-il)imidazo[1,2-b]piridazina; (3S)-1-(6-(6-(2-(3-fluorofenil)piperidin-1-il)imidazo[1,2-b]piridazin-3-il) piridin-2-il)-N,N-dimetilpirrolidin-3-amina; 4-(3-(6-(2,5-diazabiciclo[2.2.1]heptan-2-il)piridin-2-il)imidazo[1,2-b]piridazin-6il)-3-(3-fluorofenil)morfolina; 6-(6-(3-(3-fluorofenil)morfolino)imidazo[1,2-b]piridazin-3-il)-N-(2-(piperazin-1-il)etil)piridin-2amina; 6-(2-(3-fluorofenil)pirrolidin-1-il)-3-(6-(1-(metilsulfonil)piperidin-4-iloxi)piridin-2-il)imidazo[1,2-b]piridazina; 5-(6-(2(2,5-difluorofenil)pirrolidin-1-il)imidazo[1,2-a]piridin-3-il)-2-fluorobenzonitrilo; ácido 4-(6-(2-(3-fluorofenil)pirrolidin-1-il) imidazo[1,2-b]piridazin-3-il)picolínico; ácido 5-(6-(2-(3-fluorofenil)pirrolidin-1-il)imidazo[1,2-b]piridazin-3-il)picolínico; (2S,6R)-4-(6-(6-(2-(3-fluorofenil)pirrolidin-1-il)imidazo[1,2-b]piridazin-3-il)piridin-2-il)-2,6-dimetilmofolina; 6-(6-(2-(3fluorofenil)piperidin-1-il)imidazo[1,2-b]piridazin-3-il)-N-metilpiridin-2-amina; 6-(6-(2-(3-fluorofenil)piperidin-1-il)imidazo
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23-09-2015
il}piridin-2-il)amino]etan-1-ol; (3R)-1-[(6-{6-[2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)carbonil]N,N-dimetilpirrolidin-3-amina; 1-(5-{6-[2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}pirimidin-2-il)piperidin-4-ol; 6-{6-[2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}-N-metilpiridine-2-carboxamida; 4-[(6-{6-[2-(3-fluorofenil) pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)carbonil]morfolina; (3R)-1-(4-{6-[2-(3-fluorofenil)pirrolidin-1-il]imidazo [1,2-b]piridazin-3-il}piridin-2-il)pirrolidin-3-ol; (3S)-1-(4-{6-[2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin2-il)pirrolidin-3-ol; (3R,4R)-1-(4-{6-[2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)pirrolidine-3,4-diol; 1-(6-{6-[2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)-N,N-dimetilpiperidin-4-amina; 2-[(5-{6-[2-(3fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}pirimidin-2-il)amino]etan-1-ol; 5-{6-[2-(3-fluorofenil)pirrolidin-1-il] imidazo[1,2-b]piridazin-3-il}-N-metilpirimidin-2-amina; 5-{6-[2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}-N,Ndimetilpirimidin-2-amina; 1-(4-{6-[2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)-N,N-dimetilpiperidin4-amina; 2-cloro-5-{6-[2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}pirimidina; 4-[(5-{6-[2-(3-fluorofenil) pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}pirimidin-2-il)oxi]piperidin-1-carboxilato de terc-butilo; 5-{6-[2-(3-fluorofenil) pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}-2-(piperidin-4-iloxi)pirimidina; 1-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo [1,2-b]piridazin-3-il}piridin-2-il)-N,Ndimetilpiperidin-4-amina; 5-{6-[2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3il}pirimidina; 5-{6-[2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}-1,2-dihidropirimidina; 1-(6-{6-[(2R)-2-(3fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)piperidin-4-ona; 1-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il] imidazo[1,2-b]piridazin-3-il}piridin-2-il)piperazina; 6-{6-[2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}-N-[1(propan-2-il)piperidin-4-il]piridin-2-amina; [1-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2il)piperidin-4-il] carbamato; 1-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)piperidin-4-il N-metil-carbamato; 1-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)piperidin-4-il-N-tercbutil-carbamato; 1-[4-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)piperazin-1-il]etan-1ona; N,N-dietil-1-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)piperidin-4-amina; 2,2,2trifluoro-1-[4-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)piperazin-1-il]etan-1-ona; 1-(6{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)-4-metanosulfonilpiperazina; 2-(benciloxi)-1[4-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)piperazin-1-il]etan-1-ona; 1-[4-(6-{6-[(2R) -2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)piperazin-1-il]-2-hidroxietan-1-ona; 2-{[1-(6-{6-[(2R)-2(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)piperidin-4-il]amino}etan-1-ol; 2-{6-[(2R)-2-(3-fluorofenil) pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}-6-(1,2,3,6-tetrahidropiridin-1-il)piridina; N,N-dietil-1-(6-{6-[2-(3-fluorofenil) pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)pirrolidin-3-amina; N-ciclopropil-1-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)piperidin-4-amina; (3R)-1-(6-{6-[2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b] piridazin-3-il}piridin-2-il)-N-metilpirrolidin-3-amina; (3R)-1-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin3-il}piridin-2-il)-N-metilpirrolidin-3-amina; 1-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)N-metilpiperidin-4-amina; 2-fluoro-N-[1-(6-{6-[2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)pirrolidin3-il]-N,2-dimetilpropanamida; 2-fluoro-N-[1-(6-{6-[2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il) pirrolidin-3-il]-N-metil-propanamida; 1-terc-butil-4-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il} piridin-2-il)piperazina; ácido 1-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)azetidin-3carboxilico; 2-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}-6-[4-(pirrolidin-1-il)piperidin-1-il]piridina; 2fluoro-N-[1-(6-{6-[(2R)-2-(3-fluorofenil) pirrolidin-1-il]imidazo [1,2-b] piridazin-3-il} piridin-2-il) piperidin-4-il] -N,2-dimetilpropanamida; 2,2,2-trifluoro-N-[(3R)-1-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il) pirrolidin-3-il]-N-metil-acetamida; 6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}-N-metil-N-(piperidin4-il)piridin-2-amina; 2-fluoro-N-[(3R)-1-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il) pirrolidin-3-il]-N,2-dimetilpropanamida; [1-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il) azetidin-3-il]metanol; (3R)-N-(2-fluoro-2-metilpropil)-1-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il} piridin-2-il)-N-metilpirrolidin-3-amina; 1-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)-4(propano-2-sulfonil)piperazina; 1-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)-4-[(2metilpropano)sulfonil]piperazina; 1-(butano-2-sulfonil)-4-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin3-il}piridin-2-il)piperazina; 1-(etanosulfonil)-4-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2il)piperazina; (3S)-1-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)-N-metilpirrolidin-3amina; (3S)-N-etil-1-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)pirrolidin-3-amina; (3R) -1-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo [1,2-b]piridazin-3-il}piridin-2-il)-N-(2,2,2-trifluoroetil)pirrolidin-3-amina; acetato de 2-[4-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)piperazin-1-il]-2-oxoetilo; acetato de {[(3R)-1-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)pirrolidin-3-il]carbamoil} metilo; N-[(3R)-1-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)pirrolidin-3-il]-2-hidroxiacetamida; 4-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)-1-metilpiperazin-2-ona; 4-(6{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)-1-(2-hidroxietil)piperazin-2-ona; 2-{6-[(2R)-2(3-fluorofenil) pirrolidin-1-il] imidazo[1,2-b] piridazin-3-il} -6-[4-(piperidin-1-il) piperidin-1-il]piridina; {[1-(6-{6-[(2R)-2-(3fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)piperidin-4-il]metil}dimetilamina; 2-(4,4-dimetilpiperidin-1-il)6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridina; 2-(3,3-dimetilpiperidin-1-il)-6-{6-[(2R)-2-(3fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridina; ácido 4-[4-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo [1,2-b]piridazin-3-il}piridin-2-il)piperazin-1-il]benzoico; acetato de 1-[4-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il] imidazo[1,2-b]piridazin-3-il}piridin-2-il)piperazin-1-il]-2-metil-1-oxopropan-2-ilo; acetato de (2S)-1-[4-(6-{6-[(2R)-2-(3fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)piperazin-1-il]-1-oxopropan-2-ilo; 1-(6-{6-[(2R)-2-(3fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)-N,Ndimetilpiperidin-4-amina; N,N-dietil-4-(6-{6-[(2R)-2-(3fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)piperazina-1-sulfonamida; N-etil-1-(6-{6-[(2R)-2-(3fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)-N-metilpiperidin-4-amina; (2S)-1-[4-(6-{6-[(2R)-2-(3fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)piperazin-1-il]-2-hidroxipropan-1-ona; 1-[4-(6-{6-[(2R)-2-(3
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indol-2-ona; 3-(3-fluorofenil)-4-{3-[6-(piperazin-1-il)piridin-2-il]imidazo[1,2-b]piridazin-6-il}morfolina; 1-(6-{6-[(3S)-3fenilmorfolin-4-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)piperidin-4-ol; 1-(6-{6-[3-(3-fluorofenil)morfolin-4-il]imidazo[1,2b]piridazin-3-il}piridin-2-il)piperidin-4-carbaldehído; 3-(3-fluorofenil)-4-(3-{6-[4-(4-metil-1H-imidazol-2-il)piperidin-1-il] piridin-2-il}imidazo[1,2-b]piridazin-6-il)morfolina; 6-{6-[3-(3-fluorofenil)morfolin-4-il]imidazo[1,2-b]piridazin-3-il}-N,Ndimetilpiridin-2-amina; 3-(3-fluorofenil)-4-[3-(6-{4-[2-(metil-sulfanil)etil]piperazin-1-il}piridin-2-il)imidazo[1,2-b]piridazin-6il]morfolina; 3-(3-fluorofenil)-4-(3-{6-[4-(2-metanosulfoniletil)piperazin-1-il]piridin-2-il}imidazo[1,2-b]piridazin-6-il)morfolina; (N-ciclopropil-1-(6-(6-(2-(3-fluorofenil)pirrolidin-1-il)imidazo[1,2-b]piridazin-3-il)-2,4’-bipiridin-2’-il)piperidin-4-amina); 3-(3fluorofenil)-4-(3-{6-[4-(1H-1,2,4-triazol-5-il)piperidin-1-il]piridin-2-il}imidazo[1,2-b]piridazin-6-il)morfolina, y 3-(3-fluorofenil) -4-(3-{6-[4-(1,2,4-oxadiazol-5-il)piperidin-1-il]piridin-2-il}imidazo[1,2-b]piridazin-6-il)morfolina.
Otro aspecto proporcionado en la presente invención es el de las composiciones farmacéuticas que comprenden una cantidad terapéuticamente efectiva de un compuesto de la Fórmula (I), y un vehículo farmacéuticamente aceptable.
En ciertas realizaciones de estas composiciones farmacéuticas, las composiciones farmacéuticas se formulan para administración intravenosa, administración oral, administración rectal, inhalación, administración nasal, administración tópica, administración oftálmica, o administración ótica. En ciertas realizaciones de estas composiciones farmacéuticas, la composición farmacéutica es una tableta, una píldora, una cápsula, un líquido, un inhalador, una solución de aspersión nasal, un supositorio, una solución, una emulsión, un ungüento, gotas para los ojos, o gotas para los oídos.
Otro aspecto proporcionado en la presente invención es el de los medicamentos para el tratamiento de una enfermedad
o condición mediada por quinasa en un paciente, en donde el medicamento comprende una cantidad terapéuticamente efectiva de un compuesto de la Fórmula (l), en donde la quinasa se selecciona a partir de Ros, KDR, FMS, c-FMS, FLT3, c-Kit, JAK2, JAK3, Aurora, PDGFR, Lck, TrkA, TrkB, TrkC, IGF-1R, ALK4, ALK5 y ALK.
Otro aspecto proporcionado en la presente invención es el uso de un compuesto de la Fórmula (l) en la elaboración de un medicamento para el tratamiento de una enfermedad o condición mediada por quinasa, en donde la quinasa se selecciona a partir de Ros, KDR, FMS, c-FMS, FLT3, c-Kit, JAK2, JAK3, Aurora, PDGFR, Lck, TrkA, TrkB, TrkC, lGF1R, ALK4, ALK5 y ALK.
Otro aspecto proporcionado en la presente invención es un método para la elaboración de cualquiera de los compuestos anteriormente mencionados de la Fórmula (l), en donde X1 es N; X2 es N; X3 es C, y X4 es C. Este método comprende: mezclar un compuesto de la estructura:
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con un compuesto que tiene la estructura:
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en la presencia de KF, para proporcionar un compuesto que tiene la estructura:
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y mezclar, en presencia de un catalizador de paladio, el compuesto que tiene la estructura:
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con un compuesto que tiene ya sea la estructura: R2-B(OH)2,
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El término “opcionalmente sustituido“, como se utiliza en la presente invención, significa que el grupo referenciado puede o no estar sustituido con uno o más grupos adicionales individual e independientemente seleccionados a partir de alquilo, alquenilo, alquinilo, cicloalquilo, arilo, heteroarilo, heterocicloalquilo, hidroxilo, alcoxi, mercaptilo, ciano, halógeno, carbonilo, tiocarbonilo, isocianato, tiocianato, isotiocianato, nitro, perhaloalquilo, perfluoroalquilo, y amino, incluyendo los grupos amino mono y disustituidos, y los derivados protegidos de los mismos. Los ejemplos no limitantes de los sustituyentes opcionales incluyen halógeno, -CN, =O, -OR, -C(O)R, -C(O)OR, -OC(O)R, -OC(O)OR, -C(O)NHR, C(O)NR2, -OC(O)NHR, OC(O)NR2-, -SR-, -S(O)R, -S(O)2R, -NHR, -N(R)2, -NHC(O)R, -NRC(O)R, -NHC(O)OR, NRC(O)OR, S(O)2NHR, -S(O)2N(R)2, -NHS(O)2, -NRS(O)2, -NHS(O)2R, -NRS(O)2R, alquilo de 1 a 8 átomos de carbono, alcoxi de 1 a 8 átomos de carbono, arilo, heteroarilo, cicloalquilo, heterocicloalquilo, alquilo de 1 a 8 átomos de carbono sustituido por halógeno, alcoxi de 1 a 8 átomos de carbono sustituido por halógeno, en donde cada R se selecciona independientemente a partir de H, halógeno, alquilo de 1 a 8 átomos de carbono, alcoxi de 1 a 8 átomos de carbono, arilo, heteroarilo, cicloalquilo, heterocicloalquilo, alquilo de 1 a 8 átomos de carbono sustituido por halógeno, y alcoxi de 1 a 8 átomos de carbono sustituido por halógeno. La colocación y el número de estos grupos sustituyentes se hacen de acuerdo con las limitaciones de valencia bien entendidas de cada grupo, por ejemplo =O es un sustituyente adecuado para un grupo alquilo pero no para un grupo arilo.
El término “solvato”, como se utiliza en la presente invención, se refiere a un complejo de estequiometría variable formado por un soluto (a manera de ejemplo, un compuesto de la Fórmula (l), o una sal del mismo, como se describe en la presente invención), y un solvente. Los ejemplos no limitantes de un solvente son agua, acetona, metanol, etanol, y ácido acético.
El término “aceptable” con respecto a una formulación, composición o ingrediente, como se utiliza en la presente invención, significa que no tiene un efecto perjudicial persistente sobre la salud general del sujeto que se esté siendo tratado.
El término “administración" o "administrar” al sujeto el compuesto, significa proporcionar un compuesto de la invención y profármacos del mismo a un sujeto que necesite del tratamiento.
El término "enfermedad ósea", como se utiliza en la presente invención, se refiere a una enfermedad o condición de los huesos, incluyendo, pero no limitándose a, remodelación ósea inapropiada, pérdida o ganancia, osteopenia, osteomalacia, osteofibrosis, y enfermedad de Paget.
El término “enfermedad cardiovascular", como se utiliza en la presente invención, se refiere a enfermedades que afectan al corazón o a los vasos sanguíneos, o a ambos, incluyendo, pero no limitándose a: arritmia; ateroesclerosis y sus secuelas; angina; isquemia del miocardio; infarto del miocardio; aneurisma cardíaco o vascular; vasculitis, embolia; arteriopatía obstructiva periférica de una extremidad, un órgano, o un tejido; lesión por reperfusión después de isquemia del cerebro, corazón, u otro órgano o tejido; choque endotóxico, quirúrgico, o traumático; hipertensión, enfermedad cardíaca valvular, insuficiencia cardíaca, presión sanguínea anormal; choque; vasoconstricción (incluyendo aquella asociada con migrañas); anormalidad vascular, inflamación, insuficiencia limitada a un solo órgano o tejido.
El término “cáncer,", como se utiliza en la presente invención, se refiere a un crecimiento anormal de células que tienden a proliferar de una manera incontrolada, y, en algunos casos, a hacer metástasis (esparcirse). Los tipos de cáncer incluyen, pero no se limitan a, tumores sólidos (tales como aquéllos de la vejiga, intestino, cerebro, mama, endometrio, corazón, riñón, pulmón, tejido linfático (linfoma), ovario, páncreas, u otro órgano endocrino (tiroides), próstata, piel (melanoma), o tumores hematológicos (tales como las leucemias).
El término “vehículo", como se utiliza en la presente invención, se refiere a compuestos químicos o agentes que facilitan la incorporación de un compuesto descrito en la presente invención en las células o tejidos.
Los términos “coadministración" o “administración combinada", o similares, como se utilizan en la presente invención, pretenden abarcar la administración de los agentes terapéuticos seleccionados a un paciente particular, y se pretende que incluyan los regímenes de tratamiento en los que los agentes no necesariamente se administran por la misma vía de administración o al mismo tiempo.
El término “trastorno dermatológico", como se utiliza en la presente invención, se refiere a un trastorno de la piel. Estos trastornos dermatológicos incluyen, pero no se limitan a, trastornos proliferativos o inflamatorios de la piel, tales como dermatitis atópica, trastornos bullosos, colagenosos, dermatitis por contacto, eczema, Enfermedad de Kawasaki, rosácea, síndrome de Sjogren-Larsson, y urticaria.
El término “diluyente”, como se utiliza en la presente invención, se refiere a los compuestos químicos que se utilizan para diluir un compuesto descrito en la presente invención antes de su suministro. También se pueden utilizar diluyentes para estabilizar los compuestos descritos en la presente invención.
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Tabla 1
No. del compuesto
Estructura Datos físicos RMN 1 H 400 MHz (DMSO-d6) y/o MS (m/z)
1
RMN 1 H metanol-d4 δ (ppm) 8.86 (s, 1H), 8.28 (s, 1H), 7.98 (m, 1H), 7.89 (d, 1H), 7.78 (d, 1H), 7.63 (t, 1H), 7.33 (m, 1H), 7.09 (dm, 1H), 6.93(m, 2H), 6.70 (d, 1H), 5.18 (d, 1H), 3.94 (m, 1H), 3.68 (m, 1H), 2.48 (m, 1H), 2.11 (m, 2), 1.97 (m, 1H); m/z 384 (M+1)
2
imagen65 RMN 1 H metanol-d4 δ (ppm) 8.79 (s, 1H), 7.89 (m, 3H), 7.80 (m, 2H), 7.36 (m, 1H), 7.09 (d, 1H), 6.99 (m, 2H), 6.70 (d, 1H), 5.13 (dd, 1H), 3.94 (m, 1H), 3.69 (m, 1H), 2.49 (m, 1H), 2.11 (m, 2H), 1.97 (m, 1H); m/z 384 (M+1)
3
m/z 420 (M+1)
4
m/z 443 (M+1)
5
imagen66 m/z 443 (M+1)
6
MS m/z 402 (M+1)
No. del compuesto
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
7
MS m/z 402 (M+1)
8
MS m/z 402 (M+1)
9
MS m/z 402 (M+1)
10
MS m/z 402 (M+1)
11
MS m/z 402 (M+1)
12
imagen67 MS m/z 402 (M+1)
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carbonato de sodio 2.0 M, y se calentó a 150 ºC, y se agitó durante 20 horas. Se enfrió la solución a temperatura ambiente, y se purificó mediante HPLC para proporcionar la 6-(6-(3-(3-fluorofenil)morfolino)imidazo[1,2-b]piridazin-3il)indolin-2-ona (2-6) como un sólido de color blanco.
Mediante la repetición de los procedimientos descritos en los ejemplos anteriores, utilizando los materiales de partida apropiados, se obtuvieron los siguientes compuestos de la Fórmula I, como se definen en la Tabla 2.
Tabla 2
No. del compuesto
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
1
RMN 1H metanol-d4 δ (ppm) 7.97 (m, 3H), 7.72 (d, 2H), 7.66 (b, 1H), 7.45 (s, 1H), 2.24 (q, 1H), 7.11 (d, 1H), 7.07 (m, 1H), 6.89 (m, 1H), 5.17 (m, 1H), 1.46 (dd, 1H), 4.00 (m, 3H), 3.76 (m, 1H), 3.66 (m, 1H); m/z 400 (M+1)
2
imagen69 m/z 400 (M+1)
3
RMN 1H metanol-d4 δ (ppm) 7.97 (m, 3H), 7.72 (d, 2H), 7.66 (b, 1H), 7.45 (s, 1H), 2.24 (q, 1H), 7.11 (d, 1H), 7.07 (m, 1H), 6.89 (m, 1H), 5.17 (m, 1H), 1.46 (dd, 1H), 4.00 (m, 3H), 3.76 (m, 1H), 3.66 (m, 1H); m/z 400 (M+1)
4
RMN 1H CDCl3 δ (ppm) 8.72 (s, 1H), 8.49 (d, 1H), 8.30 (s, 1H), 8.08 (d, 1H), 7.84 (t, 1H), 7.39 (m, 1H), 7.26 (m, 2H), 7.03 (m, 2H), 6.91 (m, 1H), 5.08 (s, 1H), 4.22 (dd, 1H), 4.06 (m, 2H), 3.92 (m, 1H), 3.81 (m, 1H), 3.67 (m, 1H); m/z 376 (M+1)
5
m/z 401 (M+1)
6
m/z 418 (M+1)
No. del compuesto
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
7
m/z 499 (M+1)
8
imagen70 m/z 569 (M+1)
9
m/z 394 (M+1)
10
RMN 1H metanol-d4 δ (ppm) 8.43 (s, 1H), 8.12 (d, 1H), 7.69 (m, 3H), 7.34 (m, 1H), 7.25 (m, 2H), 7.00 (m, 1H), 6.88 (dd, 1H), 5.39 (m, 1H), 4.33 (dd, 1H), 4.15 (m, 3H), 3.82 (m, 6H), 3.58 (m, 4H); m/z 461 (M+1)
11
imagen71 RMN 1H metanol-d4 δ (ppm) 8.50 (s, 1H), 8.14 (d, 1H), 7.77 (m, 3H), 7.36 (m, 1H), 7.36 (m, 2H), 7.01 (m, 2H), 5.40 (m, 1H), 4.34 (dd, 1H), 4.14 (m, 3H), 3.91 (m, 6H), 3.77 (m, 1H), 3.34 (m, 5H); m/z 460 (M+1)
12
m/z 484 (M+1)
No. del compuesto
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
13
RMN 1H metanol-d4 δ (ppm) 8.31 (d, 1H), 8.22 (s, 1H), 8.12 (m, 2H), 7.72 (d, 1H), 7.34 (m, 2H), 7.23 (d, 1H), 7.16 (m, 1H), 6.97 (m, 1H), 5.29 (m, 1H), 4.27 (dd, 1H), 4.05 (m, 3H), 3.86 (m, 3H), 3.72 (m, 3H), 3.45 (m, 4H), 3.03 (s, 3H); m/z 498 (M+1)
14
m/z 526 (M+1)
15
m/z 475 (M+1)
16
m/z 560 (M+1)
17
RMN 1H DMSO-d6 δ (ppm) 8.12 (m, 1H), 7.95 (m,1H), 7.59 (d, 1H), 7.51 (t, 1H), 7.20 (m, 4H), 6.97 (td, 1H), 6.71 (d, 1H), 5.23 (m, 1H), 4.16 (m, 3H), 3.97 (m, 3H), 3.71 (td, 1H), 3.56 (m, 3H), 2.33 (m, 2H), 1.12 (s, 3H), 1.10 (s, 3H); m/z 489 (M+1)
18
m/z 475 (M+1)
No. del compuesto
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
19
RMN 1H metanol-d4 δ (ppm) 8.18 (s, 1H), 8.12 (d, 1H), 7.73 (m, 2H), 7.56 (dd, 1H), 7.34 (d, 1H), 7.28 (m,1H), 7.20 (m, 2H), 6.96 (m, 1H), 5.29 (m, 1H), 4.51 (m, 1H), 4.36 (m, 3H), 4.18 (q, 2H), 4.09 (m, 3H), 3.87 (td, 1H), 3.74 (m, 1H), 3.00 (m, 2H), 2.41 (m, 2H), 1.85 (m, 2H), 1.31 (t, 3H); m/z 586 (M+1)
20
MS m/z 475 (M+1)
21
MS m/z 512 (M+1)
22
MS m/z 489 (M+1)
23
MS m/z 503 (M+1)
24
MS m/z 502 (M+1)
imagen72
imagen73
imagen74
Tabla 3
No. del compuesto
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
1
\ m/z 414.2 (M+1)
2
m/z 395.2 (M+1)
3
m/z 398.2 (M+1)
4
m/z 412.2 (M+1)
5
m/z 398.2 (M+1)
6
m/z 449.2 (M+1)
No. del compuesto
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
7
m/z 459.2 (M+1)
8
m/z 430.2 (M+1)
9
imagen75 m/z 404.2 (M+1)
10
m/z 395.2 (M+1)
11
m/z 427.2 (M+1)
12
m/z 400.6 (M+1)
No. del compuesto
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
13
m/z 404.2 (M+1)
14
m/z 416.2 (M+1)
15
m/z 416.2 (M+1)
16
m/z 399.2 (M+1)
17
m/z 398.2 (M+1)
18
m/z 398.2 (M+1)
No. del compuesto
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
19
m/z 447.2 (M+1)
20
m/z 417.2 (M+1)
21
m/z 404.2 (M+1)
22
m/z 399.2 (M+1)
23
imagen76 m/z 417.2 (M+1)
No. del compuesto
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
24
m/z 444.5 (M+1)
25
m/z 462.2 (M+1)
26
m/z 487.3 (M+1)
27
m/z 396.2 (M+1)
28
m/z 410.2 (M+1)
No. del compuesto
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
29
m/z 396.2 (M+1)
30
m/z 464.2 (M+1)
31
m/z 414 (M+1)
32
RMN 1H DMSO-d6 (ppm) 10.64 (s, 1H), 8.31 (m, 1H), 8.05 (m, 1H), 7.64 (m, 1H), 7.35 (m, 2H), 7.13 (m, 5H), 5.23 (m 1H), 4.01 (m, 2H), 3.69 (m, 1H), 3.56 (s, 2H), 2.05 (m, 2H), 1.91 (m, 1H); m/z 414 (M+1)
33
m/z 491 (M+1)
34
MS m/z 399 (M+1)
No. del compuesto
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
35
MS m/z 469 (M+1)
36
imagen77 MS m/z 488 (M+1)
37
MS m/z 360 (M+1)
38
MS m/z 451 (M+1)
39
MS m/z 482 (M+1)
40
MS m/z 459 (M+1)
No. del compuesto
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
41
MS m/z 444 (M+1)
42
imagen78 MS m/z 496 (M+1)
43
MS m/z 459 (M+1)
44
MS m/z 487 (M+1)
45
MS m/z 459 (M+1)
46
MS m/z 389 (M+1)
No. del compuesto
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
47
MS m/z 440 (M+1)
48
m/z 404.2 (M+1)
49
m/z 404.2 (M+1)
50
RMN 1H (DMSO-d6): δ 8.02 (s, 1 H), 7.90 (s, 1 H), 7.88 (s, 1 H), 7.86 (s, 1 H), 7.37 -7.40 (m, 1 H), 7.14 (d, 2 H), 7.05 (t, 1 H), 6.95 (d, 1 H), 6.81 (d, 1 H), 5.18 (d, 1 H), 4.40 -4.45 (m, 1 H), 4.30 -4.40 (m, 1 H), 3.95 -3.99 (m, 1H), 3.62 -3.66 (m, 1H), ; 2.43 -2.49 (m, 1H), 1.95 -2.05 (m, 2H), 1.85 -1.90 (m, 1H) m/z 430.4 (M+1)
51
m/z 448.4 (M+1)
52
imagen79 RMN 1H (DMSO-d6): d 8.49 (s, 1 H), 8.18 -8.24 (m, 1 H), 8.16 (s, 1 H), 8.00 (d, 1 H), 7.73 (d, 1 H), 7.56 (t, 1 H), 7.49 (d, 2 H), 7.40 (t, 2 H), 7.32 (t, 1 H), 6.88 -6.96 (m, 1 H), 5.43 (d, 1 H), 4.37 (t, 1 H), 3.40 (t, 1H), 2.76 -2.94 (m, 1H), 1.17 (d, 3H) m/z 416.4 (M+1)
No. del compuesto
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
53
imagen80 RMN 1H (DMSO-d6): 8.55 (s, 1 H), 8.18 -8.25 (m, 1 H), 8.16 (s, 1 H), 8.00 (d, 1 H), 7.74 (d, 1 H), 7.55 (t, 1 H), 7.42 -7.49 (m, 1 H), 7.33 -7.39 (m, 2 H), 7.11 -7.19 (m, 1 H), 6.88 -6.98 (m, 1 H), 5.47 (d, 1 H), 4.38 (t, 1 H), 3.86 (t, 1H), 2.78 -2.94 (m, 1H), 1.17 (d, 3H) m/z 434.4 (M+1)
54
imagen81 RMN 1H (DMSO-d6) d 8.55 (s, 1 H), 8.20 -8.32 (bs, 1 H), 8.12 (s, 1H), 7.89 (d, 1 H), 7.71 (d, 1 H), 7.54 (t, 1 H), 7.26 -7.36 (m, 4 H), 7.18 -7.24 (m, 1 H), 6.76 -6.91 (bs, 1 H), 5.15 -5.21 (m, 1 H), 3.94 -4.02 (m, 1 H), 3.66 3.72 (m, 1 H), 2.45 -2.50 (m, 1 H), 2.01 -2.08 (m, 2 H), 1.82 -1.90 (m, 1 H) m/z 366.4 (M+1)
55
imagen82 m/z 412.5 (M+1)
56
m/z 384.4 (M+1)
57
imagen83 RMN 1H (DMSO-d6) 8.14 (s, 1 H), 7.91 (s, 1 H), 7.58 7.64 (m, 2 H), 7.53 -7.57 (m, 1 H), 7.35 -7.41 (m, 1 H), 7.15 -7.17 (m, 2 H), 7.01 -7.05 (m, 1 H), 6.68 (d, 1 H), 5.16 -5.19 (q, 1H), 3.98 -4.02 (m, 1 H), 3.91 (s, 3 H), 3.65 -3.71 (m, 1H), 2.44 -2.49 (m, 1 H), 2.01 -2.07 (m, 2 H), 1.85 -1.90 (m, 1 H) m/z 390.4 (M+1)
58
imagen84 RMN 1H (DMSO-d6, 400MHz) 8.725 (d, J = 0.005, 1H) 8.374 (s, 1H) 8.195 (d, J = 0.025, 1H) 8.074 (dd, J = 0.023, 0.006, 1H) 7.705 (d, J = 0.026, 1H) 7.406 (q, J = 0.02, 1H) 7.149 (s, 1H) 7.129 (s, 1H) 7.082 (dt, J = 0.015, 0.005, 1H) 6.973 (d, J = 0.023, 1H) 5.561 (t, J = 0.01, 1H) 4.270 (d, J = 0.033, 1H) 3.725 (t, J = 0.011, 4H) 3.561 (t, J = 0.013, 4H) 3.317 (dt, J = 0.035, 0.01, 1H) 2.265 (m, 1H) 20.39 (m, 1H) 1.782 (m, 1H) 1.649 (m, 2H) 1.455 (m, 1H) m/z 459.2 (M+1)
No. del compuesto
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
59
m/z 431.2 (M+1)
60
m/z 398.2 (M+1)
61
m/z 398.2 (M+1)
62
m/z 398.2 (M+1)
63
m/z 398.2 (M+1)
64
imagen85 m/z 398.2 (M+1)
65
m/z 398.2 (M+1)
No. del compuesto
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
66
imagen86 RMN 1H (DMSO-d6, 400 MHz) 9.198 (br.s, 1H) 8.790 (ds, J = 0.011, 1H) 8.504 (s, 1H) 8.102 (d, J = 0.025, 1H) 8.008 (br.s, 1H) 7.377 (q, J = 0.019, 1H) 7.166 (d, J = 0.019) 7.166 (m, 3H) 7.083 (dt, J = 0.019, 0.004, 1H) 5.192 (d, J = 0.017, 1H) 4.011 (m, 1H) 3.695 (q, J = 0.025, 1H) 2.868 (d, J = 0.012, 3H) 2.451 (m, 1H) 2.056 (m, 2H), 1.898 (m, 1H) m/z 417.5 (M+1)
67
m/z 384.4 (M+1)
68
m/z 431.5 (M+1)
69
imagen87 RMN 1H (DMSO-d6, 400MHz) 8.205 (br.s, 2H) 7.994 (d, J = 0.025, 1H) 7.815 (d, J = 0.019, 2H) 7.486 (q, J = 0.021, 1H) 7.222 (m, 2H) 7.108 (dt, J = 0.023, 0.006, 1H) 6.959 (br.s, 1H) 5.209 (dd, J = 0.021, 0.007, 1H) 4.048 (p, J = 0.014, 1H) 3.719 (q, J = 0.02, 1H) 2.513 (m, 1H), 2.092 (m, 2H) 1.919 (m, 1H) m/z 384.4 (M+1)
70
imagen88 RMN 1H (DMSO-d6, 400MHz) 8.084 (br.s, 2H) 7.875 (d, J = 0.024, 1H) 7.697 (d, J = 0.02, 2H) 7.364 (q, J = 0.02, 1H) 7.100 (m, 2H) 6.985 (dt, J = 0.023, 0.006, 2H) 6.841 (br.s, 1H) 5.091 (dd, J = 0.02, 0.006, 1H) 3.928 (p, J = 0.014 1H) 3.600 (q, J = 0.021, 1H) 2.370 (m, 1H) 1.971 (m, 2H) 1.797 (m, 1H) m/z 384.4 (M+1)
71
m/z 402.4 (M+1)
No. del compuesto
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
72
imagen89 RMN 1H (DMSO-d6, 400MHz) 8.572 (br.s, 1H) 7.739 (m, 3H) 7.306 (m, 1H) 7.056 (m, 1H) 7.056 (m, 1H) 6.954 (m, 1H) 6.739 (s, 1H) 6.638 (m, 1H) 5.203 (d, J = 0.016, 1H) 3.916 (m, 1H) 3.837 (m, 1H) 3.667 (m, 4H) 3.540 (m, 1H) 3.425 (m, 4H) 2.391 (m, 1H) 2.009 (m, 2H) 1.830 (m, 1H) m/z 463.5 (M+1)
73
imagen90 RMN 1H (DMSO-d6, 400MHz) 8.094 (s, 1H) 7.998 (br.s, 2H) 7.917 (d, J = 0.024, 1H) 7.660 (d, J = 0.021 2H) 7.423 (dq, J = 0.024, 0.011, 1H) 7.061 (m, 1H) 6.992 (m, 1H) 6.925 (br.s, 1H) 5.248 (d, J = 0.019, 1H) 3.962 (m, 1H) 3.561 (q, J = 0.018, 1H) 2.382 (m, 1H) 1.998 (m, 2H) 1.830 (m, 1H) m/z 402.4 (M+1)
74
imagen91 RMN 1H (DMSO-d6, 400MHz) 8.091 (s, (1H) 7.994 (br.s, 2H) 7.913 (d, J = 0.025, 1H) 7.655 (d, J = 0.02, 1 H) 7.421 (dq, J = 0.021, 0.011, 1H) 7.059 (m, 1H) 6.989 (m, 1H) 6.925 (br.s, 1H) 5.242 (d, J = 0.019, 1H) 3.959 (m, 1H) 3.556 (q, J = 0.018, 1H) 2.390 (m, 1H) 1.997 (m, 2H) 1.819 (m, 1H) m/z 402.4 (M+1)
75
m/z 403.4 (M+1)
76
imagen92 m/z 403.4 (M+1)
77
imagen93 RMN 1H (DMSO-d6, 400 MHz) 7.854 (d, J = 0.024, 1H) 7.710 (s, 1H) 7.248 (m, 1H) 7.072 (m, 1H) 6.979 (m, 1H) 6.801 (m, 1H), 6.694 (m, 1H) 5.274 (d, J = 0.019, 1H) 3.948 (dt, J = 0.025, 0.007, 1H) 3.658 (t, 0.011, 4H), 3.572 (q, J = 0.024, 1H) 3.359 (t, J = 0.012, 3H) 2.007 (m, 3H) 1.285 (s, 1H) 1.164 (s, 1H) m/z 469.5 (M+1)
No. del compuesto
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
78
m/z 398.4 (M+1)
79
m/z 398.4 (M+1)
80
m/z 398.4 (M+1)
81
m/z 398.4 (M+1)
82
m/z 398.4 (M+1)
83
m/z 398.4 (M+1)
84
m/z 403.4 (M+1)
85
m/z 403.4 (M+1)
No. del compuesto
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
86
m/z 384.4 (M+1)
87
m/z 384.4 (M+1)
88
m/z 451.5 (M+1)
89
m/z 363.4 (M+1)
90
imagen94 m/z 403.4 (M+1)
91
m/z 398.4 (M+1)
92
imagen95 8.166 (s, 1H) 8.019 (s, 1H) 7.998 (d, J = 0.01, 1H) 7.963 (s, 1H) 7.719 (d, J = 0.021, 2H) 7.514 (dq, J = 0.024, 0.011, 1H) 7.143 (m, 1H) 6.990 (m, 2H) 5.199 (t, J = 0.02, 1H) 4.338 (d sexteto, J = 0.017, 0.006, 1H) 2.550 (m, 1H) 2.223 (m, 1H) 1.944 (m, 1H) 1.768 (m, 1H) 1.497 (d, J = 0.016, 3H) m/z 416.4 (M+1)
93
8.327 (br s, 1H) 8.123 (s, 2H) 7.938 (d, J = 0.025, 1H) 7.678 (d, J = 0.020, 1H) 7.423 (t, J = 0.020, 1H) 7.272 (m, 1H) 7.045 (m, 1H) 6.964 (m, 2H) 5.275 (d, J = 0.019, 1H) 3.967 (dt, J = 0.024, 0.006, 1H) 3.564 (q, J = 0.023, 2H) 1.998 (m, 3H) m/z 402.4 (M+1)
imagen96
No. del compuesto
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
2
m/z 476.3 (M+1)
3
m/z 476.3 (M+1)
4
m/z 477.3 (M+1)
5
m/z 458.2 (M+1)
6
m/z 445.2 (M+1)
7
m/z 445.2 (M+1)
8
m/z 487.2 (M+1)
9
m/z 544.3 (M+1)
No. del compuesto
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
10
m/z 463.2 (M+1)
11
imagen97 RMN 1H (DMSO-d6) 8.04 (s, 1 H), 7.88 (d, 1 H), 7.40 7.60 (m, 2 H), 7.37 (q, 1 H), 7.13 -7.17 (m, 2 H), 7.00 7.05 (m, 1 H), 6.75 -6.85 (bs, 1 H), 6.73 (d, 1 H), 5.15 5.17 (m, 1 H), 4.67 (d, 1H), 4.04 -4.10 (m, 2 H), 3.96 4.01 (m, 1 H), 3.64 -3.71 (m, 2 H), 3.05 -3.11 (m, 2 H), 2.00 -2.06 (m, 2 H), 1.84 -1.89 (m, 1 H), 1.77 -1.82 (m, 2 H), 1.33 -1.40 (m, 2 H) m/z 473.2 (M+1)
12
imagen97 m/z 378.4 (M+1)
13
m/z 419.5 (M+1)
14
imagen98 m/z 474.6 (M+1)
15
imagen99 RMN 1H (DMSO-d6) 8.10 (s, 1 H), 7.88 (d, 1 H), 7.46 7.66 (m, 2 H), 7.36 -7.40 (m, 1 H), 7.12 -7.18 (m, 2 H), 7.00 -7.06 (m, 1 H), 6.80 -6.90 (m, 1 H), 6.78 (d, 1 H), 5.14 -5.18 (m, 1 H), 4.20 (d, 1 H), 4.11 (d, 1 H), 3.96 4.02 (m, 1 H), 3.50 -3.90 (m, 4 H), 3.64 -3.70 (m, 1 H), 3.32 (s, 3 H), 2.70 -3.00 (m, 4 H), 2.45 -2.50 (m, 1 H), 2.00 -2.08 (m, 2 H), 1.84 -1.91 (m, 1 H) m/z 45 8.5 (M+1)
16
imagen100 RMN 1H (DMSO-d6) 8.03 (s, 1 H), 7.88 (d, 1 H), 7.26 7.44 (m, 3 H), 7.12 -7.18 (m, 2 H), 7.01 -7.06 (m, 1 H), 6.75 -6.85 (m, 1 H), 6.50 -6.56 (m, 1 H), 6.43 (d, 1 H), 5.14 -5.18 (m, 1 H), 5.00 -5.06 (bs, 1 H), 4.58 -4.68 (m, 1 H), 3.95 -4.05 (m, 1 H), 3.62 -3.70 (m, 2 H), 3.42 -3.50 (m, 1 H), 3.36 -3.38 (m, 2 H), 3.18 -3.26 (m, 1 H), 2.45 -2.50 (m, 1 H), 2.00 -2.08 (m, 2 H), 1.82 -1.90 (m, 1 H) m/z 449.5 (M+1)
No. del compuesto
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
17
imagen101 RMN 1H (DMSO-d6) 8.10 (s, 1 H), 7.89 (d, 1 H), 7.42 7.60 (m, 2 H), 7.34 -7.42 (m, 1 H), 7.12 -7.18 (m, 2 H), 6.98 -7.06 (m, 1 H), 6.76 -6.86 (m, 1 H), 6.74 (d, 1 H), 5.14 -5.19 (m, 1 H), 4.21 (d, 2 H), 3.96 -4.02 (m, 1 H), 3.64 -3.70 (m, 3 H), 2.45 -2.50 (m, 1 H), 2.35 -2.43 (m, 2 H), 1.98 -2.08 (m, 2 H), 1.82 -1.90 (m, 1 H), 1.18 (m, 6 H)
m/z 473.6 (M+1)
18
imagen101 RMN 1H (DMSO-d6) 8.09 (s, 1 H), 7.89 (d, 1 H), 7.42 7.64 (m, 2 H), 7.33 -7.42 (m, 1 H), 7.12 -7.18 (m, 2 H), 6.98 -7.06 (m, 1 H), 6.76 -6.86 (m, 1 H), 6.73 (d, 1 H), 5.14 -5.18 (m, 1 H), 4.20 (d, 1 H), 4.11 (d, 1 H), 3.95 4.05 (m, 1 H), 3.62 -3.70 (m, 1 H), 3.50 -3.62 (m, 2 H), 3.36 -3.38 (m, 2 H), 2.74 -2.84 (m, 1 H), 2.45 -2.50 (m, 1 H), 1.98 -2.07 (m, 2 H), 1.82 -1.91 (m, 1 H),1.18 (m, 3 H) m/z 459.5 (M+1)
19
m/z 428.5 (M+1)
20
imagen102 RMN 1H (DMSO-d6) 8.57 (d, 1 H), 8.03 (s, 1 H), 7.87 (d, 1 H), 7.67 -7.71 (m, 1 H), 7.36 -7.48 (bs, 2 H), 7.29 (d, 1 H), 7.20 -7.23 (m, 1 H), 6.78 -6.88 (bs, 1 H), 6.71 (d, 1H), 5.16 -5.19 (q, 1 H), 4.65 -4.68 (d, 1 H), 4.04 4.09 (m, 2H), 3.94 -3.98 (m, 1 H), 3.65 -3.73 (m, 2 H), 3.04 -3.11 (m, 2 H), 2.45 -2.48 (m, 1 H), 2.03 -2.08 (m, 2 H), 1.95 -2.01 (m, 1 H), 1.76 -1.82 (m, 2 H), 1.33 -1.40 (m, 2 H) m/z 442.5 (M+1)
21
m/z 442.5 (M+1)
22
imagen103 RMN 1H (DMSO -d6) 8.06 (s, 1 H), 7.88 (d, 1 H), 7.40 7.50 (m, 2 H), 7.35 -7.40 (m, 1 H), 7.13 -7.17 (m, 2 H), 7.01 -7.05 (m, 1 H), 6.75 -6.85 (bs, 1 H), 6.69 (d, 1 H), 5.14 -5.18 (q, 1 H), 4.83 (t, 1 H), 4.24 -4.29 (m, 1H), 3.95 -4.05 (m, 2 H), 3.63 -3.70 (m, 1 H), 3.44 -3.53 (m, 1 H), 2.87 -2.93 (m,1 H), 2.67 -2.73 (q, 1 H), 2.45 2.50 (m, 1 H), 2.00 -2.06 (m, 2 H), 1.84 -1.94 (m, 2 H), 1.70 -1.76 (m, 1 H), 1.33 -1.40 (m, 2 H) m/z 459.5 (M+1)
No. del compuesto
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
23
imagen104 RMN 1H (DMSO -d6) 8.07 (s, 1 H), 7.87 (d, 1 H), 7.32 7.60 (m, 3 H), 7.11 -7.19 (m, 2 H), 7.00 -7.05 (m, 1 H), 6.75 -6.85 (bs, 1 H), 6.36 (d, 1 H), 5.15 -5.18 (m, 1 H), 3.96 -4.01 (m, 1 H), 3.60 -3.75 (m, 3 H), 3.33 -3.37 (m, 1 H), 3.10 -3.15 (m, 1 H), 2.73 -2.80 (m, 1 H), 2.45 -2.50 (m, 1 H), 2.11 -2.18 (m, 1 H), 2.00 -2.06 (m, 2 H), 1.84 -1.90 (m, 1 H), 1.76 -1.82 (m, 1 H)
m/z 472.6 (M+1)
24
imagen105 RMN 1H (DMSO -d6) 8.58 (d, 1 H), 8.41 -8.43 (q, 1H), 8.02 (s, 1 H), 7.89 (d, 1 H), 7.68 -7.71 (m, 1 H), 7.39 7.45 (m, 2 H), 7.32 -7.35 (q, 1 H), 6.82 -6.90 (bs, 1 H), 6.72 (d, 1H), 5.19 -5.23 (q, 1 H), 4.67 (d, 1 H), 4.03 4.09 (m, 2 H), 3.97 -4.02 (m, 1 H), 3.65 -3.71 (m, 2 H), 3.05 -3.10 (m, 2 H), 2.51 -2.53 (m, 1 H), 2.01 -2.09 (m, 2 H), 1.85 -1.91 (m, 1 H), 1.76 -1.82 (m, 2 H), 1.31 -1.40 (m, 2 H) m/z 463.5 (M+1)
25
imagen106 RMN 1H (DMSO -d6) 8.58 (d, 1 H), 8.41 -8.43 (q, 1H), 8.02 (s, 1 H), 7.89 (d, 1 H), 7.68 -7.71 (m, 1 H), 7.39 7.45 (m, 2 H), 7.32 -7.35 (q, 1 H), 6.82 -6.90 (bs, 1 H), 6.72 (d, 1H), 5.19 -5.23 (q, 1 H), 4.67 (d, 1 H), 4.03 4.09 (m, 2 H), 3.97 -4.02 (m, 1 H), 3.65 -3.71 (m, 2 H), 3.05 -3.10 (m, 2 H), 2.51 -2.53 (m, 1 H), 2.01 -2.09 (m, 2 H), 1.85 -1.91 (m, 1 H), 1.76 -1.82 (m, 2 H), 1.31 -1.40 (m, 2 H) m/z 489.6 (M+1)
26
imagen106 RMN 1H (DMSO -d6) 8.13 (s, 1 H), 7.92 (d, 1 H), 7.74 7.98 (bs, 1 H), 7.68 -7.66 (bs, 1 H), 7.36 -7.40 (m, 1 H), 7.14 -7.20 (m, 2 H), 7.00 -7.06 (m, 1 H), 6.80 -6.92 (bs, 1 H), 6.70 (d, 1H), 5.16 -5.20 (q, 1 H), 4.47 -4.56 (m, 2 H), 3.98 -4.03(m, 1 H), 3.65 -3.71 (m, 1 H), 3.03 -3.20 (m, 2 H), 2.70 -2.95 (m,4 H), 2.45 -2.50 (m, 1 H), 2.00 -2.08 (m, 2 H), 1.85 -1.90 (m, 1 H), 1.71 -1.83 (m, 4 H) m/z 473.6 (M+1)
27
imagen106 RMN 1H (DMSO -d6) 8.06 (s, 1 H), 7.88 (d, 1 H), 7.42 7.60 (m, 2 H), 7.34 -7.40 (m, 1 H), 7.13 -7.17 (m, 2 H), 7.00 -7.05 (m, 1 H), 6.75 -6.85 (bs, 1 H), 6.73 (d, 1H), 5.14 -5.19 (q, 1 H), 3.96 -4.01 (m, 1 H), 3.64 -3.70 (q, 1 H), 3.48 -3.58 (bs, 4 H), 3.15 -3.24 (bs, 2 H), 3.04 (s, 3H), 2.82 (s, 3 H), 2.50 -2.60 (bs, 4 H), 2.45 -2.50 (m, 1 H), 2.01 -2.06 (m, 2 H), 1.84 -1.89 (m, 1 H)
m/z 529.6 (M+1)
No. del compuesto
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
28
imagen106 RMN 1H (DMSO -d6) 8.05 (s, 1 H), 7.88 (d, 1 H), 7.42 7.60 (m, 2 H), 7.35 -7.40 (m, 1 H), 7.13 -7.17 (m, 2 H), 7.00 -7.05 (m, 1 H), 6.76 -6.86 (bs, 1 H), 6.71 (d, 1H), 5.15 -5.17 (q, 1 H), 3.96 -4.01 (m, 1 H), 3.64 -3.70 (q, 1 H), 3.46 -3.54 (bs, 4 H), 2.64 -2.71 (m, 1H), 2.50 2.56 (bs, 4 H), 2.45 -2.50 (m, 1 H), 2.00 -2.06 (m, 2 H), 1.84 -1.90 (m, 1 H), 1.00 (d, 6 H) m/z 486.6 (M+1)
29
imagen106 RMN 1H (DMSO -d6) 8.04 (s, 1 H), 7.88 (d, 1 H), 7.34 7.50 (m, 3 H), 7.12 -7.37 (m, 2 H), 7.00 -7.16 (m, 1 H), 6.76 -6.84 (bs, 1H), 6.72 (d, 1H), 5.15 -5.18 (q, 1 H), 4.45 (d, 1 H), 4.01 (s, 1 H), 3.96 -4.01 (m, 1 H), 3.64 3.68 (m, 1 H), 2.65 -2.71 (m, 2 H), 2.44 -2.48 (m, 1 H), 2.00 -2.06 (m, 2 H), 1.84 -1.89 (m, 1 H), 1.74 -1.79 (m, 2 H), 1.38 -1.45 (m, 1 H), 1.18 -1.28 (m, 2 H), 1.04 (s, 6 H), 0.82 -.088 (m, 1H) m/z 501.6 (M+1)
30
imagen106 RMN 1H (DMSO -d6) 8.04 (s, 1 H), 7.87 (d, 1 H), 7.40 7.52 (m, 2 H), 7.34 -7.40 (m, 1 H), 7.13 -7.17 (m, 2 H), 7.00 -7.05 (m, 1 H), 6.77 -6.85 (bs, 1H), 6.74 (d, 1H), 5.14 -5.18 (q, 1 H), 4.36 (d, 2 H), 3.96 -4.01 (m, 1 H), 3.63 -3.69 (q, 1 H), 3.55 (t, 4 H), 2.80 (t, 2 H), 2.42 2.50 (m, 5 H), 2.34 -2.40 (m, 1 H), 2.00 -2.05 (m, 2 H), 1.82 -1.89 (m, 3 H), 1.33 -1.41 (m, 2 H)
m/z 528.6 (M+1)
31
imagen106 RMN 1H (DMSO -d6) 8.06 (s, 1 H), 7.88 (d, 1 H), 7.41 7.60 (m, 2 H), 7.34 -7.40 (m, 1 H), 7.12 -7.18 (m, 2 H), 7.00 -7.15 (m, 1 H), 6.77 -6.85 (bs, 1H), 6.74 (d, 1H), 5.15 -5.18 (q, 1 H), 3.96 -4.01 (m, 1 H), 3.64 -3.70 (q, 1 H), 3.54 (t, 4 H), 2.72 (t, 2 H), 2.62 (t, 2 H), 2.51 -2.55 (m, 4 H), 2.45 -2.50 (m, 1 H), 2.00 -2.06 (m, 2 H), 1.84 -1.90 (m, 1 H)
m/z 497.6 (M+1)
32
imagen106 RMN 1H (DMSO -d6) 8.07 (s, 1 H), 7.88 (d, 1 H), 7.50 7.58 (bs, 1 H), 7.42 -7.48 (bs, 1 H), 7.35 -7.40 (m, 1 H), 7.13 -7.17 (m, 2 H), 7.01 -7.05 (m, 1 H), 6.78 -6.85 (bs, 1 H), 6.73 (d, 1H), 5.15 -5.18 (q, 1 H), 3.96 -4.01 (m, 1 H), 3.87 -3.94 (m, 1 H), 3.64 -3.70 (m, 1 H), 3.54 -360 (bs, 4 H), 2.91 -2.96 (bs, 2 H), 2.50 -2.60 (bs, 4 H), 2.45 -2.50 (m, 1 H), 2.00 -2.06 (m, 2 H), 1.84 -1.90 (m, 1 H), 1.08 (d, 6 H) m/z 543.7 (M+1)
No. del compuesto
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
33
imagen106 RMN 1H (DMSO -d6) 8.04 (s, 1 H), 7.87 (d, 1 H), 7.40 7.50 (m, 2 H), 7.35 -7.40 (m, 1 H), 7.13 -7.17 (m, 2 H), 7.01 -7.05 (m, 1 H), 6.76 -6.85 (bs, 1H), 6.72 (d, 1H), 5.14 -5.17 (q, 1 H), 4.46 (t, 1 H), 4.37 (d, 2 H), 3.96 4.01 (m, 1 H), 3.64 -3.69 (q, 1 H), 3.27 (t, 2 H), 2.74 2.81 (m, 2 H), 2.45 -2.50 (m, 1 H), 2.00 -2.06 (m, 2 H), 1.84 -1.89 (m, 1 H), 1.58 -1.64 (m, 1 H), 1.08 -1.17 (m, 2 H) m/z 473.6 (M+1)
34
imagen106 RMN 1H (DMSO -d6) 8.05 (s, 1 H), 7.88 (d, 1 H), 7.40 7.50 (m, 2 H), 7.34 -7.40 (m, 1 H), 7.13 -7.17 (m, 2 H), 7.00 -7.05 (m, 1 H), 6.76 -6.85 (bs, 1H), 6.69 (t, 1 H), 5.15 -5.18 (q, 1 H), 4.54 -4.57 (m, 1 H), 4.34 (d, 1 H), 4.22 (d, 1 H), 3.96 -4.02 (m, 1 H), 3.64 -3.70 (q, 1 H), 3.28 -3.37 (m, 2 H), 2.81 -2.88 (m, 1 H), 2.59 (t, 1 H), 2.45 -2.50 (m, 1 H), 2.00 -2.08 (m, 2 H), 1.84 -1.90 (m, 1 H), 1.72 -1.77 (m, 1 H), 1.66 -1.72 (m, 1 H), 1.58 -1.65 (m, 1 H), 1.40 -1.59 (m, 1 H), 1.14 -1.22 (m, 1 H) m/z 473.6 (M+1)
35
imagen106 RMN 1H (DMSO -d6) 8.07 (s, 1 H), 7.88 (d, 1 H), 7.41 7.60 (m, 2 H), 7.34 -7.40 (m, 1 H), 7.12 -7.18 (m, 2 H), 7.00 -7.15 (m, 1 H), 6.78 -6.85 (bs, 1H), 6.77 (d, 1H), 5.15 -5.18 (q, 1 H), 3.96 -4.01 (m, 1 H), 3.83 -3.89 (m, 2 H), 3.64 -3.70 (q, 1 H), 3.09 -3.14 (m, 1 H), 2.45 2.50 (m, 1 H), 2.00 -2.06 (m, 2 H), 1.94 -1.97 (m, 2 H), 1.84 -1.89 (m, 1 H), 1.71 -1.77 (m, 2 H) m/z 468.5 (M+1)
36
imagen106 RMN 1H (DMSO -d6) 8.05(s, 1 H), 7.88 (d, 1 H), 7.42 7.60 (m, 2 H), 7.35 -7.40 (m, 1 H), 7.13 -7.17 (m, 2 H), 7.00 -7.05 (m, 1 H), 6.75 -6.85 (bs, 1H), 6.72 (d, 1H), 5.14 -5.18 (q, 1 H), 4.43 (t, 1 H), 3.96 -4.01 (m, 1 H), 3.63 -3.70 (q, 1 H), 3.47 -3.57 (m, 6 H), 2.50 -2.55 (m, 4 H), 2.40 -2.50 (m, 3 H), 2.00 -2.06 (m, 2 H), 1.84 1.89 (m, 1 H)
m/z 488.6 (M+1)
37
imagen106 RMN 1H (DMSO -d6) 8.07 (s, 1 H), 7.88 (d, 1 H), 7.46 7.68 (m, 2 H), 7.36 -7.40 (q, 1 H), 7.12 -7.18 (m, 2 H), 7.00 -7.06 (m, 1 H), 6.78 -6.88 (bs, 1 H), 6.73 (d, 1 H), 5.15 -5.18 (q, 1 H), 3.96 -4.01 (m, 1 H), 3.70 -3.73 (m, 4 H), 3.64 -3.69 (q, 1 H), 3.46 -3.51 (m, 4 H), 2.45 2.50 (m, 1 H), 2.01 -2.06 (m, 2 H), 1.84 -1.89 (m, 1 H) m/z 445.5 (M+1)
No. del compuesto
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
38
m/z 488.3 (M+1)
39
m/z 500.3 (M+1)
40
imagen107 m/z 486.3 (M+1)
41
imagen108 RMN 1H (DMSO -d6): d 8.06 (s, 1 H), 7.75 (s, 1 H), 7.51 (d, 1 H), 7.32 -7.40 (m, 2 H), 7.22 (d, 1 H), 7.14 (d, 2 H), 6.99 -7.05 (m, 1 H), 6.45 -6.50 (m, 1 H), 6.35 9d, 1 H), 4.14 -4.21 (m, 1 H), 3.30 -3.39 (m, 2 H), 2.82 (d, 3 H), 2.17 -2.26 (m, 1 H), 2.00 -2.10 (m, 1 H), 1.56 1.83 (m, 3 H), 1.35 -1.50 (m, 1 H) m/z 403.2 (M+1)
42
imagen109 RMN 1H (DMSO -d6): d 8.02 (s, 1 H), 7.90 (d, 1 H), 7.46 (d, 1 H), 7.30 -7.40 (m, 2 H), 7.21 (d, 1 H), 7.13 (d, 2 H), 6.98 -7.06 (m, 1 H), 6.30 -6.36 (m, 2 H), 4.12 4.20 (m, 1 H), 4.02 -4.10 (m, 1 H), 3.30 -3.38 (m, 2 H), 2.18 -2.26 (m, 1 H), 2.00 -2.10 (m, 1 H), 1.56 -1.84 (m, 3 H), 1.36 -1.48 (m, 1 H), 1.17 (d, 6 H) m/z 431.2 (M+1)
43
imagen110 RMN 1H (DMSO -d6): d 10.63 (s, 1 H), 8.06 (s, 1 H), 7.97 (s, 1 H), 7.94 (d, 1 H), 7.72 (t, 1 H), 7.33 -7.40 (m, 1 H), 7.25 (d, 1 H), 7.12 -7.18 (m, 2 H), 6.99 -7.05 (m, 1 H), 6.80 (d, 1 H), 4.15 -4.22 (m, 1 H), 3.42 (s, 3 H), 3.35 -3.42 (m, 2 H), 2.17 -2.26 (m, 1 H), 2.01 -2.14 (m, 1 H), 1.57 -1.85 (m, 3 H), 1.36 -1.49 (m, 1 H) m/z 467.2 (M+1)
No. del compuesto
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
44
m/z 417.3 (M+1)
45
m/z 473.3 (M+1)
46
m/z 459.2 (M+1)
47
m/z 431.1 (M+1)
48
imagen111 m/z 461.5 (M+1)
Esquema 6A
imagen112
imagen113
imagen114
imagen115
imagen116
imagen117
No. del compuesto
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
2
487.5 (M+H)
3
487.5 (M+H)
4
imagen118 8.247 (s, 1H) 8.192 (br s, 1H) 8.071 (d, J = 0.024, 1H) 7.926 (br s, 1H) 7.341 (dt, J = 0.024, 0.011, 1H) 7.139 (m, 2H) 7.037 (m, 1H) 6.929 (m, 1H) 5.332 (d, J = 0.018, 1H) 4.033 (m, 1H) 3.652 (q, J = 0.023, 2H) 3.090 (s, 6H) 2.122 (m, 3H)
 445.5 (M+H)
5
imagen119 8.212 (br s, 1H) 8.019 (br s, 1H) 7.927 (s, 1H) 7.849 (d, J = 0.024, 1H) 7.274 (dt, J = 0.024, 0.012, 1H) 7.046 (m, 1H) 6.950 (m, 2H) 6.782 (m, 1H) 5.250 (d, J = 0.019, 1H) 3.933 (dt, J = 0.024, 0.006, 1H) 3.553 (q, 0.022, 1H) 3.132 (t, J = 0.012, 3H) 2.473 (m, 6H) 2.197 (s, 3H) 1.986 (m, 3H) 500.6 (M+H)
6
544.6 (M+H)
7
imagen120 530.6 (M+H)
8
445.5 (M+H)
No. del compuesto
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
9.935 (br s, 1H) 8.364 (s, 1H) 8.019 (d, J = 0.024,
1H) 7.626 (m, 2H) 7.430 (dt, J = 0.024, 0.011, 1H)
7.153 (m, 1H) 7.033 (m, 2H) 5.325 (d, J = 0.019,
9
1H) 4.035 (dt, J = 0.019, 0.006, 1H) 3.727 (d, J = 0.028, 2H) 3.603 (m, 3H) 3.241 (m, 4H) 2.926 (s,
3H) 2.090 (m, 4H)
500.6 (M+H)
9.840 (br s, 1H) 8.335 (s, 1H) 8.007 (d, J = 0.025,
1H) 7.622 (m, 2H) 7.429 (m, 1H) 7.153 (m, 1H)
7.033 (m, 2H)5.324 (d, J = 0.019, 1H) 4.035 (dt, J =
10
0.019, 0.007, 1H) 3.724 (m, 9H) 3.357 (s, 3H) 3.305
(m, 4H) 2.122 (m, 4H)
544.6 (M+H)
8.050 (s, 1H) 7.854 (d, 0.025, 1H) 7.434 (br s, 1H)
7.327 (dt, J = 0.023, 0.011, 1H) 7.262 (m, 1H)
7.173 (m, 1H) 7.070 (m, 1H) 6.937 (m, 1H) 6.747
(br s, 1H) 5.770 (t, J = 0.012, 1H) 5.244 (d, J =
11
0.019, 1H) 3.949 (dt, J = 0.017, 0.006, 1H) 3.575
(q, J = 0.023, 1H) 3.522 (t, J = 0.011, 4H) 3.268 (m,
4H) 2.536 (t, J = 0.016, 2H) 1.985 (m, 3H)
530.6 (M+H)
12
487.5 (M+H)
9.908 (br s, 1H) 8.362 (s, 1H) 8.046 (d, J = 0.025,
1H) 7.600 (br s, 2H) 7.437 (dt, J = 0.024, 0.011, 1H)
7.155 (m, 1H) 7.032 (m, 2H) 5.330 (d, J = 0.019,
1H) 4.035 (d, J = 0.024, 3H) 3.698 (m, 5H) 3.543
(d, J = 0.030, 2H) 3.409 (m, 2H) 3.182 (m, 2H)
13
2.898 (t, J = 0.030,
2H) 2.277 (d, J = 0.026, 2H) 1.950 (m, 5H)
570.6 (M+H)
8.230 (s, 1H) 7.910 (d, J = 0.025, 1H) 7.239 (m, 2H)
7.008 (m, 3H) 6.867 (m, 2H) 5.178 (d, J = 0.020,
14
1H) 3.883 (t, J = 0.019, 2H) 3.441 (m, 5H) 1.829 (m, 7H)
471.5 (M+H)
No. del compuesto
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
15
imagen121 9.934 (br s, 1H) 8.264 (s, 1H) 7.994 (d, J = 0.025, 1H) 7.419 (m, 3H) 7.154 (m, 1H) 7.024 (m, 2H) 5.310 (m, 1H) 3.799 (m, 12H) 2.904 (d, J = 0.019, 4H) 2.228 (m, 1H) 2.0677 (m, 2H) 514.6 (M+H)
16
515.6 (M+H)
17
531.6 (M+H)
18
515.6 (M+H)
19
515.6 (M+H)
20
imagen122 9.747 (br s, 1H) 8.280 (d, J = 0.009, 1H) 7.999 (m, 1H) 7.419 (m, 3H) 7.132 (m, 3H) 6.297 (br s, 1H) 5.313 (d, J = 0.019, 1H) 4.001 (m, 4H) 3.625 (m, 3H) 3.433 (m, 4H) 3.197 (m, 4H) 1.994 (m, 5H) 544.6 (M+H)
21
556.6 (M+H)
22
501.5 (M+H)
No. del compuesto
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
23
502.6 (M+H)
24
515.6 (M+H)
25
545.6 (M+H)
26
imagen123 9..321 (m, 1H) 8.935 (m, 1H) 8.365 (m,1H) 7.998 (m, 1H) 7.743 (m, 2H) 7.408 (m, 1H) 7.147 (m, 1H) 7.034 (m,1H) 5.321 (d, J = 0.019, 1H) 4.530 (m, 2H) 4.371 (m, 2H) 4.048 (m, 2H) 3.674 (m, 1H) 3.281 (m, 2H) 2.216 (m, 1H) 2.072 (m, 3H) 1.947 (m, 3H) 501.5 (M+H)
27
546.6 (M+H)
28
imagen124 9.774 (br s, 1H) 8.374 (s, 1H) 8.014 (m, 1H) 7.863 (m, 1H) 7.726 (m, 1H) 7.632 (m, 1H)7.453 (m, 1H) 7.152 (m, 1H) 7.047 (m, 1H) 5.327 (m, 2H) 5.203 (d, J = 0.02, 1H) 4.533 (m, 1H) 4.038 (m, 1H) 3.653 (m, 1H) 3.543 (m, 2H) 2.920 (m, 4H) 2.046 (m, 2H) 1.914 (m, 1H) 1.349 (d, J = 0.015, 2H) 503.6 (M+H)
29
imagen125 9.584 (br s, 1H) 8.324 (s, 1H) 7.988 (m, 1H) 7.697 (m, 1H) 7.608 (m, 1H) 7.428 (m, 2H) 7.145 (m, 1H) 7.033 (m, 1H) 5.337 (d, J = 0.019, 1H) 4.342 (m, 3H) 4.041 (m, 2H) 3.644 (m, 3H) 3.415 (m, 1H) 3.132 (m, 1H) 2.922 (d, J = 0.013, 2H) 2.334 (m, 1H) 2.036 (m, 6H) 1.829 (m, 1H) 529.6 (M+H)
No. del compuesto
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
30
519.6 (M+H)
31
imagen126 9.973 (br s, 1H) 8.358 (m, 1H) 7.994 (m, 2H) 7.764 (m, 1H), 7.667 (m, 1H) 7.410 (m, 1H) 7.147 (m, 1H) 7.034 (m, 2H) 5.343 (d, J = 0.02, 1H) 4.655 (m, 2H) 4.390 (m, 2H) 4.038 (m, 2H) 3.657 (m, 2H) 3.191 (m, 1H) 2.334 (m, 1H) 2.122 (m, 5H) 515.6 (M+H)
32
imagen127 8.367 (br d, 1H) 8.221 (d, J = 0.013, 1H) 7.952 (t, J = 0.024, 1H) 7.142 (m, 7H) 5.151 (dd, J = 0.016, 0.004, 1H) 3.930 (m, 2H) 3.738 (t, J = 0.011, 4H) 3.614 (t, J = 0.021, 2H) 3.174 (m, 3H) 1.977 (m, 2H) 1.826 (m, 1H) 469.5 (M+H)
33
imagen128 482.6 (M+H)
34
imagen129 526.6 (M+H)
35
512.6 (M+H)
36
imagen130 552.7 (M+H)
37
imagen131 497.6 (M+H)
38
511.6 (M+H)
No. del compuesto
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
39
482.6 (M+H)
40
497.6 (M+H)
41
imagen132 513.6 (M+H)
42
595.7 (M+H)
43
553.6 (M+H)
44
553.7 (M+H)
45
483.6 (M+H)
46
554.7 (M+H)
47
556.6 (M+H)
No. del compuesto
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
48
497.5 (M+H)
49
501.5 (M+H)
50
501.5 (M+H)
51
imagen133 483.6 (M+H)
52
imagen134 480.5 (M+H)
53
imagen135 452.5 (M+H)
imagen136
Tabla 6
No. del compuesto
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
1
419.1 (M+H)
2
427.2 (M+H)
3
409.2 (M+H)
Esquema 14
imagen137
5 Ejemplo 14
Se sintetizó (R)-1-(4-(6-(6-((R)-2-(3-fluorofenil)pirrolidin-1-il)imidazo[1,2-b]piridazin-3-il)piridin-2-il)pirimidin-2-il)pirrolidin3-ol (14-4) en tres etapas como se muestra en el esquema 14.
En la etapa 14-1, se agregaron 2-(metiltio)-4-(tributilestaniI)pirimidina (4.3 g, 13.2 mmol), y Pd(PPh3)4 (196 mg, 0.17 mmol) a una solución de (R)-3-(6-bromopiridin-2-il)-6-(2-(3-fluorofenil)pirrolidin-1-il)imidazo[1,2-b]piridazina (14-1) (1.5 g,
10 3.4 mmol) en tolueno (35 mL). Se desgasificó la mezcla utilizando N2 durante 15 minutos, y luego se calentó a 110ºC durante 2 horas. Se removieron todos los solventes. Se purificó la mezcla resultante mediante cromatografía en columna (gel de sílice, EtOAc/CH3OH, gradiente del 0 al 10 por ciento), para producir (R)-6-(2-(3-fluorofenil)pirrolidin-1il)-3-(6-(2-(metiltio)pirimidin-4-il)piridin-2-iI)imidazo[1,2-b]piridazina (14-2) como una espuma color amarillo claro. LC/MS:
484.2 (MH+).
imagen138
imagen139
imagen140
imagen141
Tabla 7
Compuesto número
Estructura Datos físicos RMN 1 H 400 MHz (DMSO-d6) y/o MS (m/z)
1
RMN 1H (400 MHz, MeOH-d4) d 7.99 (s, 1H), 7.71(d, 1H, J = 10.0 Hz), 7.46 (m, 2H), 7.19 (m, 1H), 7.11 (m, 3H), 6.83 (m, 1H), 6.65 (d, 1H, J = 8.0 Hz), 5.01 (t, 1H, J = 3.6 Hz), 4.10 (m, 3H), 4.00 (m, 2H), 3.77 (m, 3H), 3.59 (m ,1H), 3.03 (m, 1H), 1.91 (s, 1H), 1.84 (m, 2H), 1.44 (m, 2H) MS (m/z): 474.53
2
MS (m/z): 389.42
3
MS (m/z): 439.49
4
imagen142 RMN 1H (400 MHz, CHCl3-d3) d 8.54(d, 1H, J = 10.0 Hz), 8.23 (s, 1H), 7.46 (m, 2H), 7.23 (m, 1H), 7.12 (d, 1H, J = 10.4 Hz), 7.05 (m, 2H), 6.91 (m, 1H), 6.65 (m, 1H), 5.09 (t, 1H, J = 2.8 Hz), 4.34 (m ,2H), 4.24 (dd, 1H, J = 12.0, 2.0 Hz), 4.12 (dt, 1H, J = 11.2, 2.8 Hz), 4.05 (dd, 1H, J = 12.8, 3.6 Hz), 3.92 (dt, 1H, J = 12.8, 2.8 Hz), 3.82 (ddd, 1H, J = 11.2, 11.2, 3.2 Hz), 3.65 (m,2H), 3.48 (d, 2H, J = 6.0 Hz), 3.30 (brs, 1H), 2.82 (ddd, 1H, J = 12.4, 12.4, 1.6 Hz), 1.73 (m, 1H), 1.24 (m, 3H), 0.80 (m, 1H) MS (m/z): 488.56
5
imagen143 RMN 1H (400 MHz, CHCl3-d3) d 8.41(d, 1H, J = 10.0 Hz), 8.20 (s, 1H), 7.64 (d, 1H, J = 7.6 Hz), 7.58 (t, 1H, J = 8.0 Hz), 7.24 (m, 1H), 7.13 (d, 1H, J = 10.0 Hz), 7.05 (m, 1H), 6.91 (m, 1H), 6.67 (d,1H,J = 8.4Hz), 5.09 (t,1H,J = 2.8Hz), 4.23 (dd, 2H, J = 12.0, 2.4 Hz), 4.12 (dt, 2H, J = 12.8, 3.2 Hz), 4.05 (dd, 2H, J = 12.0, 4.0 Hz), 3.99 (m, 3H), 3.90 (dt, 2H, J = 13.2, 2.8 Hz), 3.82 (ddd, 2H, J = 10.4, 10.4, 3.2 Hz), 3.66 (m ,3H), 3.17(m, 3H) MS (m/z): 503.57
6
MS (m/z): 501.55
Compuesto número
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
7
MS (m/z): 501.55
8
MS (m/z): 556.68
9
imagen144 RMN 1H (400 MHz, MeOH-d4) d 8.19 (s, 1H), 7.74 (d, 1H, J = 10.0 Hz), 7.51 (t, 1H, J = 8.8 Hz), 7.42 (ddd, 1H, J = 8.0, 8.0, 2.8 Hz), 7.17 (m, 1H), 7.08 (m, 2H), 6.84 (ddd, 1H, J = 8.4, 8.4, 2.0 Hz), 6.76 (d,1H,J = 9.6Hz), 6.23 (d,1H, J = 8.0 Hz), 5.00 (m, 1H), 4.11 (dd, 1H, J = 13.2, 3.2 Hz), 4.03 (m, 2H), 3.80 (m, 3H), 3.59 (m, 2H), 3.28 (d ,1H, J = 9.6 Hz), 3.08 (s, 2H), 1.85 (m, 1H) MS (m/z): 471.53
10
MS (m/z): 502.59
11
imagen145 RMN 1H (400 MHz, MeOH-d4) d 8.10 (s, 1H), 7.82 (d, 1H, J = 10.0 Hz), 7.57 (m, 2H), 7.32 (m, 1H), 7.20 (m, 3H), 6.91 (m, 1H), 6.76 (d, 1H, J = 8.40 Hz), 5.22 (t, 1H, J = 3.2 Hz), 4.49 (d , 2H, J = 13.2 Hz), 4.20 (dd, 1H, J = 12.0, 3.2 Hz), 4.11 (m, 2H), 3.90 (m, 2H), 3.70 (m, 1H), 2.88 (ddd, 2H, J = 12.4, 12.4, 2.4 Hz), 2.72 (s, 3H), 2.72 (s, 1H), 1.84 (m, 2H), 1.74 (m, 2H) MS (m/z): 515.58
12
imagen146 RMN 1H (400 MHz, MeOH-d4) d 8.18 (s, 1H), 7.73 (d, 1H, J = 10.0 Hz), 7.53 (d, 1H, J = 7.6 Hz), 7.45 (t, 1H, J = 8.0 Hz), 7.17 (m, 1H), 7.07 (m, 2H), 6.84 (m, 1H), 6.76 (d, 1H, J = 8.0 Hz), 6.54 (d, 1H, J = 8.4 Hz), 6.16 (t, 1H, J = 4.2 Hz), 5.00 (t, 1H, J = 3.6 Hz), 4.38 (d ,2H, J = 12.4 Hz), 4.11 (dd, 1H, J = 12.0, 3.6 Hz), 4.03 (m, 2H), 3.80 (m, 2H), 3.66 (t, 2H, J = 4.8), 3.60 (m, 1H), 3.37 (m ,1H), 2.83 (m, 2H), 2.31 (m, 1H), 1.80 (m, 2H), 1.74 (m, 2H), 1.18 (m, 1H) MS (m/z): 545.61
Compuesto número
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
13
MS (m/z): 429.45
14
MS (m/z): 429.45
15
MS (m/z): 474.53
16
MS (m/z): 474.53
17
imagen147 MS (m/z): 530.59
18
MS (m/z): 431.46
Compuesto número
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
19
MS (m/z): 502.54
20
imagen148 MS (m/z): 426.45
21
MS (m/z): 568.64
22
imagen149 MS (m/z): 571.65
23
imagen150 RMN 1H (400 MHz, DMSO-d6) d 8.12 (s, 1H), 8.09 (d, 1H, J = 6.0 Hz), 7.67 (d, 1H, J = 7.6 Hz), 7.56 (m, 2H), 7.09 (m, 4H), 7.04 (ddd, 1H, J = 8.4, 8.4, 2.4 Hz), 6.78 (d, 1H, J = 8.0 Hz), 5.30 (s, 1H), 4.40 (d, 2H, J = 11.6 Hz), 4.19 (dd, 1H, J = 12.0, 2.0 Hz), 4.02 (m, 3H), 3.80 (m, 2H), 3.60 (m, 1H), 2.82 (t, 2H, J = 12.0 Hz), 2.34 (m, 1H), 1.70 (m, 2H), 1.56 (m, 2H), 1.03 (d, 6H, J = 6.4 Hz) MS (m/z): 543.64
24
MS (m/z): 541.62
Compuesto número
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
25
MS (m/z): 568.60
26
MS (m/z): 571.65
27
MS (m/z): 540.59
28
imagen151 MS (m/z): 502.58
29
imagen152 RMN 1H (400 MHz, MeOH-d4) d 8.33 (s, 1H), 8.03 (s br, 1H), 7.75 (d, 1H, J = 9.6 Hz), 7.60 (m, 2H), 7.46 (d, 1H, J = 7.6 Hz), 7.26 (m, 1H), 7.09 (d, 1H, J = 7.6 Hz), 6.91 (m, 2H), 6.73 (d, 1H, J = 2.0 Hz), 6.55 (d, 1H, J = 10.0 Hz), 5.03 (dd, 1H, J = 8.0, 2.4 Hz), 3.91 (m, 1H), 3.68 (q, 1H, J = 8.8 Hz), 2.44 (m, 1H), 2.06 (m,2H), 1.97 (m, 2H) MS (m/z): 425.46
30
RMN 1H (400 MHz, DMSO-d6) d 9.01 (d, 1H, J = 4.8 Hz), 8.99 (s, 1H), 8.82 (d, 1H, J = 8.0 Hz), 8.52 (s br, 1H), 8.23 (d, 1H, J = 8.4 Hz), 8.07 (m, 3H), 7.43 (m, 1H), 7.22 (m, 2H), 7.07 (m, 2H), 5.25 (dd, 1H, J = 8.0, 2.4 Hz), 4.07 (m, 1H), 3.74 (q, 1H, J = 8.0 Hz), 2.47 (m, 1H), 2.08 (m, 2H), 1.92 (m, 1H) MS (m/z): 501.52
31
imagen153 MS (m/z): 451.50
Compuesto número
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
32
imagen154 RMN 1H (400 MHz, DMSO-d6) d 8.42 (d, 1H, J = 4.8 Hz), 8.26 (s br, 1H), 8.31 (s, 1H), 8.15 (d, 1H, J = 8.0 Hz), 7.95 (d, 1H, J = 8.0 Hz), 7.89 (m, 1H), 7.64 (d, 1H, J = 4.8 Hz), 7.41 (ddd, 1H, J = 8.0, 6.4, 6.4 Hz), 7.20 (m, 2H), 7.05 (ddd, 1H, J = 8.4, 8.4, 2.4 Hz), 6.90 (s br, 1H), 6.76 (s, 2H), 5.22 (dd, 1H, J = 8.4, 2.8 Hz), 4.03 (m, 1H), 3.70 (q, 1H, J = 8.4 Hz), 2.47 (m, 1H), 2.06 (m, 2H), 1.89 (m, 1H) MS (m/z): 452.49
33
MS (m/z): 471.57
34
MS (m/z): 471.57
35
MS (m/z): 453.47
36
MS (m/z): 521.59
37
MS (m/z): 521.59
Compuesto número
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
38
MS (m/z): 508.59
39
imagen155 RMN 1H (400 MHz, DMSO-d6) 8.64 (d, 1H, J = 4.8 Hz), 8.40 (s, 1H), 8.35 (s br, 1H), 8.34 (d, 1H, J = 8.0 Hz), 8.01 (d, 1H, J = 10.0 Hz), 7.96 (m, 1H), 7.81 (d, 1H, J = 4.8 Hz), 7.46 (m, 1H), 7.26 (d, 1H, J = 7.6 Hz), 7.10 (m, 1H), 6.96 (s br, 1H), 5.27 (dd, 1H, J = 8.0, 2.8 Hz), 4.09 (m, 1H), 3.89 (t, 4H, J = 4.8 Hz), 3.78 (m, 5H), 2.53 (m, 1H), 2.12 (m, 2H), 1.95 (m, 1H) MS (m/z): 522.58
40
MS (m/z): 549.66
41
MS (m/z): 496.54
42
MS (m/z): 520.60
43
MS (m/z): 514.64
Compuesto número
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
44
imagen156 RMN 1H (400 MHz, DMSO-d6) 9.38 (d, 1H, J = 1.2 Hz), 9.05 (d, 1H, J = 5.2 Hz), 8.64 (dd, 1H, J = 9.2, 1.2 Hz), 8.46 (s, 1H), 8.36 (d, 1H, J = 8.0 Hz), 8.01 (d, 1H, J = 10.0 Hz), 7.96 (m, 1H), 7.47 (ddd, 1H, J = 8.0, 6.4, 6.4 Hz), 7.26 (m, 3H), 7.11 (ddd, 1H, J = 8.4, 8.4, 2.4 Hz), 6.98 (s br, 1H), 5.27 (dd, 1H, J = 8.0, 2.4 Hz), 4.09 (m, 1H), 3.76 (t, 4H, J = 9.2 Hz), 2.53 (m, 1H), 2.12 (m, 2H), 1.95 (m, 1H) MS (m/z): 437.47
45
MS (m/z): 513.61
46
MS (m/z): 547.65
47
MS (m/z): 501.55
48
RMN 1H (400 MHz, DMSO-d6) d 8.10 (s, 1H), 7.89 (d, 1H, J = 6.0 Hz), 7.54 (m, 2H), 7.39 (m, 1H), 7.17 (m, 2H), 7.04 (m, 1H), 6.81 (m, 2H), 6.40 (s, 1H), 5.18 (dd, 1H, J = 8.0, 2.4 Hz), 4.00 (m, 1H), 3.69 (m, 9H), 2.45 (m, 2H), 1.87 (m, 1H), 0.96 (m, 2H), 0.80 (m, 2H) MS (m/z): 527.59
49
MS (m/z): 451.50
Compuesto número
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
50
RMN 1H (400 MHz, DMSO-d6) d 8.09 (s, 1H), 7.90 (d, 1H, J = 10.0 Hz), 7.53 (m, 2H), 7.38 (m, 1H), 7.16 (m, 2H), 7.03 (m, 1h), 6.82 (s br, 1H), 6.77 (d, 1H, J = 8.4 Hz), 5.17 (dd, 1H, J = 8.4, 2.8 Hz), 4.00 (m, 1H), 3.86 (m, 2H), 3.59 (m, 8H), 3.40 (m, 3H), 2.94 (m, 1H), 2.45 (m, 1H), 2.04 (m, 2H), 1.87 (m, 1H), 1.58 (m, 4H) MS (m/z): 555.65
51
imagen157 RMN 1H (400 MHz, DMSO-d6) d 8.15 9s, 1H), 7.95 (d, 1H, J = 9.6 Hz), 7.65 (d, 2H), 7.44 (d, 1H), 7.22 (m, 2H), 7.09 (m, 1H), 6.84 (m, 2H), 5.23 (dd, 1H, J = 8.0, 2.4 Hz), 4.78 (dd, 1H, J = 8.0, 5.6 Hz), 4.05 (m, 1H), 3.70 (m, 11H), 2.50 (m, 1H), 2.09 (m, 4H), 1.91 (m, 3H) MS (m/z): 541.62
52
MS (m/z): 521.59
53
MS (m/z): 506.58
54
RMN 1H (400 MHz, DMSO-d6) d 9.17 (s, 1H), 8.31 (s, 1H), 8.11 (s br, 1H), 7.94 9d, 1H, J = 10.0 Hz), 7.78 (m, 2H), 7.41 (m, 2H), 7.20 (m, 2H), 7.05 (m, 1H), 6.88 (m, 1H), 5.21(dd, 1H, J = 8.0, 2.4 Hz), 4.00 (m, 1H), 3.80 (m, 4H), 3.69 (m, 5H), 2.57 (m, 1H), 2.06 (m, 2H), 1.89 (m, 1H) MS (m/z): 522.58
Compuesto número
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
55
MS (m/z): 536.61
56
imagen158 MS (m/z): 523.61
57
imagen159 MS (m/z): 536.60
58
MS (m/z): 480.54
59
MS (m/z): 475.52
60
MS (m/z): 495.55
Compuesto número
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
61
MS (m/z): 535.61
62
RMN 1H (400 MHz, DMSO-d6) d 8.46 (d, 1H, J = 4.8 Hz), 8.32 (s, 1H), 8.22 (s br, 1H), 7.95 (d, 1H, J = 6.0 Hz), 7.89 (m, 1H), 7.65 (d, 1H, J = 4.2 Hz), 7.42 (m,1H), 7.19 (m, 3H), 7.05 (ddd, 1H, J = 8.0, 8.0, 2.0 Hz), 6.90 (m, 1H), 5.20 (m, 1H), 4.74 (t, 1H, J = 5.6 Hz), 4.03 (m, 1H), 3.70 (q, 1H, J = 8.4 Hz), 3.60 (m, 2H), 3.47 (s br, 2H), 3.34 (s, 1H), 2.49 (m, 1H), 2.06 (m, 2H), 1.95 (m, 1H) MS (m/z): 496.54
63
imagen160 MS (m/z): 513.61
64
imagen161 MS (m/z): 541.66
65
imagen162 MS (m/z): 508.55
66
RMN 1H (400 MHz, DMSO-d6) d 8.53 (d, 1H, J = 4.4 Hz), 8.22 (s, 1H), 8.16 (s br, 1H), 8.07 (d, 1H, J = 7.6 Hz), 7.82 (m, 3H), 7.29 (m, 1H), 7.07 (m, 2H), 6.91(ddd, 1H, J = 8.4, 8.4, 2.4 Hz), 6.77 (s br, 1H), 5.08 (d, 1H, J = 8.0, Hz), 3.90 (m, 1H), 3.57 (q, 1H, J = 8.0 Hz), 3.15 (s, 3H), 3.10 (m, 1H), 2.33 (m, 1H), 1.92 (m, 2H), 1.76 (m, 1H) MS (m/z): 530.58
Compuesto número
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
67
MS (m/z): 527.64
68
RMN 1H (400 MHz, DMSO-d6) d 8.31 (s, 1H), 8.18 (s br, 1H), 8.08 (d, 1H, J = 5.2 Hz), 7.95 (d, 1H, J = 9.6 Hz), 7.79 (m, 2H), 7.40 (m ,2H), 7.19 (m, 3H), 7.05 (m, 1H), 6.90 (m, 1H), 6.68 (t, 1H, J = 5.6 Hz), 5.21 (dd, 1H, J = 8.4, 2.4 Hz), 4.78 (t, 1H, J = 5.2 Hz), 4.03 (m, 1H), 3.69 (q, 1H, J = 8.4 Hz), 3.58 (m, 2H), 3.39 (q, 1H, J = 6.0 Hz), 3.34 (s, 1H), 2.46 (m, 1H), 2.05 (m, 2H), 1.89 (m, 1H)
MS (m/z): 495.55
69
imagen163 RMN 1H (400 MHz, DMSO-d6) d 8.29 (s, 1H), 8.19 (d, 1H, J = 5.2 Hz), 7.96 (d, 1H, J = 9.6 Hz), 7.91 (d, 1H, J = 8.0 Hz), 7.83 (m, 1H), 7.40 (m, 2H), 7.20 (d, 2H, J = 7.6 Hz), 7.09 (s, 1H), 7.05 (m, 1H), 6.90 (s br, 1H), 5.67(d, 1H, J = 6.8 Hz), 5.20 (dd, 1H, J = 8.0, 2.4 Hz), 4.61 (m, 1H), 4.25 (t, 1H, J = 8.0 Hz), 4.03 (m, 1H), 3.76 (q, 1H, J = 4.0Hz), 3.70 (m, 1H), 3.34 (s, 4H), 2.49 (m, 1H), 2.06 (m, 2H), 1.89 (m, 1H)
MS (m/z): 507.56
70
imagen164 RMN 1H (400 MHz, DMSO-d6) d 8.28 (s, 1H), 8.24 (s br, 1H), 8.18 (d, 1H, J = 5.2 Hz), 7.95 (d, 1H, J = 9.6 Hz), 7.90 (d, 1H, J = 8.0 Hz), 7.82 (m, 1H), 7.40 (q, 1H, J = 8.4 Hz), 7.27 (m, 1Hz), 7.19 (d, 1H, J = 7.6 Hz) 7.14 (s, 1H), 7.05 (m, 1H), 6.89 (s br, 1H), 5.19 (dd, 1H, J = 8.0, 2.4 Hz), 4.99 (d, 1H, J = 3.2 Hz), 4.43 (s, 1H), 4.02 (m, 1H), 3.90 (q, 1H, J = 9.2Hz), 3.58 (m, 1H), 3.42 (d, 1H, J = 10.8 Hz), 2.46 (m, 1H), 2.05 (m, 3H), 1.91 (m, 2H) MS (m/z): 521.59
71
RMN 1H (400 MHz, DMSO-d6) d 8.31 (d, 1H, J = 5.6 Hz), 8.29 (s, 1H), 8.25 (s br, 1H), 7.96 (d, 1H, J = 10.0 Hz), 7.87 (m, 2H), 7.73 (s, 1H), 7.60 (dd, 1H, J = 5.6, 1.2 Hz), 7.41(m, 1H), 7.20 (d, 1H, J = 8.4 Hz), 7.05 (m, 1H), 6.91 (s br, 1H), 5.21 (dd, 1H, J = 8.4, 2.4 Hz), 4.03 (m, 1H), 3.71 (q, 1H, J = 8.0 Hz), 3.23 (s, 3H), 3.20 (m, 1H), 2.47 (m, 1H), 2.06 (m, 2H), 1.89 (m, 1H)
MS (m/z): 529.59
Compuesto número
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
72
imagen165 RMN 1H (400 MHz, DMSO-d6) d 8.65 (s br, 1H), 8.48 (d, 1H, J = 5.2 Hz), 8.44 (dd, 1H, J = 4.8, 1.6 Hz), 8.31 (s, 1H), 8.18 (d, 1H, J = 8.0 Hz), 7.95 (d, 2H, 9.6 Hz), 7.88 (m, 1H), 7.81 (m, 1H), 7.68 (d, 1H, J = 6.8 Hz), 7.39 (m, 2H), 7.19 (m, 2H), 7.05 (ddd, 1H, J = 8.0, 8.0, 2.0 Hz), 6.90 (s br, 1H), 5.21 (dd, 1H, J = 6.0, 1.6Hz), 4.63 (d, 2H, J = 5.6Hz), 4.03 (m 1H), 3.70 (q, 1H, J = 8.4 Hz), 3.34 (s, 1H), 2.46 (m, 1H), 2.05 (m, 2H), 1.88 (m, 1H) MS (m/z): 543.60
73
MS (m/z): 534.63
74
imagen166 RMN 1H (400 MHz, DMSO-d6) d 8.51 (d, 1H, J = 4.8 Hz), 8.33 (s, 1H), 8.26 (s br, 1H), 7.96 (d, 1H, J = 9.6 Hz), 7.90 (m, 1H), 7.73 (d, 1H, J = 4.8 Hz), 7.45(m, 2H), 7.20 (m, 2H), 7.05 (ddd, 1H, J = 8.4, 8.4, 2.0 Hz), 6.91 (s br, 1H), 5.21 (dd, 1H, J = 8.0, 2.8 Hz), 4.04 (m, 1H),3.81 (m, 2H), 3.71 (q, 1H, J = 8.0 Hz), 3.45 (t, 2H, J = 6.8 Hz), 3.34 (s, 1H), 3.07(s, 3H), 2.46 (m, 1H), 2.06 (m, 2H), 1.89 (m, 1H) MS (m/z): 558.63
75
imagen167 RMN 1H (400 MHz, DMSO-d6) d 8.98 (d, 1H, J = 6.0 Hz), 8.45 (dd, 1H, J = 8.8, 2.0 Hz), 8.31 (s, 1H), 8.10 (s br, 1H), 7.95 (d, 1H, J = 10.0 Hz), 7.80 (m, 2H), 7.41 (m, 1H), 7.07 (m, 2H), 6.91 (ddd, 1H, J = 8.4, 8.4, 2.4 Hz), 6.77 (s br, 1H), 5.08 (dd, 1H, J = 8.0, 2.4 Hz), 3.90 (m, 1H), 3.57 (q, 1H, J = 8.0 Hz), 3.15 (s, 3H), 3.10 (m, 1H), 2.33 (m, 1H), 1.92 (m, 2H), 1.76 (m, 1H) MS (m/z): 529.59
76
MS (m/z): 475.52
Compuesto número
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
77
imagen168 RMN 1H (400 MHz, DMSO-d6) d 8.30 (s, 1H), 8.23 (d, 1H, J = 5.6 Hz), 8.1 (s br, 1H), 7.95 (t, 2H, J = 8.8 Hz), 7.85 (s br, 1H), 7.39 (m, 2H), 7.21 (m, 3H), 7.05 (m, 1H), 6.90 (s br, 1H), 5.21 (dd, 1H, J = 8.0, 2.8 Hz), 4.03 (m, 1H), 3.80 (m, 2H), 3.67 (m, 3H), 2.61 (s, 3H), 2.47 (m, 1H), 2.35 (m, 1H), 2.20 (m, 1H), 2.06 (m, 2H), 1.89 (m, 1H), 1.18 (d, 1H, J = 6.8 Hz)
MS (m/z): 534.63
78
imagen169 RMN 1H (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.19 (d, 1H, J = 8.0 Hz), 7.94 (d, 1H, J = 9.6 Hz), 7.84 (m, 3H), 7.68 (t, 2H, J = 8.4 Hz), 7.41 (m, 1H), 7.19 (m, 2H), 7.05 (m, 1H), 6.93 (d, 1H, J = 8.4 Hz), 6.90 (s br), 5.21 (dd, 1H, J = 8.0, 2.8 Hz), 4.73 9d, 1H, J = 4.4 Hz), 4.16 (m ,2H), 4.03 (m, 1H), 3.73 (m, 2H), 3.17 (m, 2H), 2.47 (m, 1H), 2.06 (m, 2H), 1.87 (m, 3H), 1.44 (m, 2H)
MS (m/z): 535.61
79
imagen170 RMN 1H (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 8.14 (d, 1H, J = 8.0 Hz), 7.94 (d, 1H, 9.6 Hz), 7.82 (m, 1H), 7.68 (d, 1H, J = 7.2 Hz), 7.53 (t, 1H, J = 7.2 Hz), 7.41 (ddd, 1H, J = 8.0, 8.0, 6.4 Hz)), 7.19 (m, 2H), 7.05 (ddd, 1H, J = 8.4, 8.4, 2.0 Hz), 6.88 (s br, 1H), 6.665 (t, 1H, J = 5.6 Hz), 6.58 (d, 1H, J = 8.0 Hz), 5.21 (dd, 1H, J = 8.0, 2.4 Hz), 4.79 (t, 1H, J = 5.6 Hz), 4.03 (m, 1H), 3.66(m, 3H), 3.46 (m, 2H), 2.45 (m, 1H), 2.06 (m, 2H), 1.89 (m, 1H) MS (m/z): 495.55
80
MS (m/z): 534.63
81
imagen171 RMN 1H (400 MHz, DMSO-d6) δ 8.57 (s, 1H,J = 5.2 Hz), 8.39 (s, 1H), 8.36 (s br, 1H), 8.34(d, 1H, J = 7.6 Hz), 7.99 (m, 2H), 7.72 (d, 1H, J = 4.2 Hz), 7.47 (m, 1H), 7.26 (m, 2H), 7.11 (m, 1H), 6.96 (s br, 1H), 5.27 (dd, 1H, J = 8.0, 2.0 Hz), 4.09 (m, 1H), 3.58 (m, 4H), 3.49 (s br, 1H), 3.46 (m, 2H), 2.53 (m, 1H), 2.40 (s, 3H), 2.15 (m, 3H), 1.93 (m, 2H) MS (m/z): 535.62
Compuesto número
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
82
imagen172 RMN 1H (400 MHz, DMSO-d6) δ 8.54 (d, 1H, J = 4.2 Hz), 8.33 (s, 1H), 8.25 (d, 1H, J = 7.6 Hz), 8.28 (br s, 1H), 7.94 (d, 1H, J = 10.0 Hz), 7.89 (m, 1H), 7.68 (d, 1H, J = 4.8 Hz), 7.40 (m, 1H), 7.19 (m, 2H), 7.04 (m, 1H), 6.88 (br s, 1H), 5.20 (dd, 1H, J = 8.0, 2.8 Hz), 4.48 (br s, 1H), 4.02 (m, 1H), 3.85 (m, 4H), 3.69 (1, 1H, J = 9.2 Hz), 3.57 (t, 2H, J = 6.0 Hz), 2.50 (m, 7H), 2.05 (m, 2H), 1.89 (m, 1H)
MS (m/z): 565.64
83
imagen173 RMN 1H (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 8.30 (d, 1H, J = 4.2 Hz), 8.01 (m, 2H), 7.98 (br s, 1H), 7.89 (m, 1H), 7.59 (s, 1H), 7.46 (m, 2H), 7.26 (d, 2H, J = 7.6 Hz), 7.11 (m, 1H), 6.69 (br s, 1H), 5.27 (dd, 1H, J = 8.4, 2.4 Hz), 4.53 (m, 1H), 4.021(m, 1H), 3.76 (m, 1H), 3.64 (m, 6H), 2.61 (t, 4H, 4.8 Hz), 2.53 (m, 3H), 2.11 (m, 2H), 1.96 (m, 1H)
MS (m/z): 564.66
84
imagen174 MS (m/z): 529.61
85
imagen175 RMN 1H (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.23 (d, 1H, J = 7.6 Hz), 8.15 (br s, 1H), 7.93 (d, 1H, J = 10.0 Hz), 7.82 (m, 1H), ), 7.76 (d, 1H, J = 7.2 Hz), 7.65 (t, 1H, J = 8.0 Hz), 7.40 (ddd, 1H, J = 8.0, 8.0, 6.4 Hz), 7.18 (m, 2H), 7.04 (ddd, 1H, J = 8.8, 8.0, 2.4 Hz), 6.86 (br s, 1H), 6.52 (d, 1H, J = 8.0 Hz), 5.19 (dd, 1H, J = 8.4, 2.4 Hz), 5.00 (s br, 1H), 4.44 (m, 1H), 4.02 (m, 1H), 3.69 (q, 1H, J = 7.6 Hz), 3.58 (m, 3H), 3.37 (m, 1H), 2.48 (m, 3H), 1.96 (m, 2H) MS (m/z): 521.56
86
imagen176 RMN 1H (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 8.25 (d, 1H, J = 48.0 Hz), 8.20 (s br, 1H), 7.90 (d, 1H, J = 8.0 Hz), 7.81 (br s, 1H), 7.76 (t, 1H, J = 8.0 Hz), 7.46 (q, 1H, J = 8.0 Hz), 7.25 (m, 2H), 7.11 (m, 1H), 6.97 (d, 1H, J = 8.4 Hz), 6.92 (br s, 1H), 5.26 (d, 1H, J = 8.0 Hz), 4.54 (m, 1H), 4.08 (m, 1H), 3.67 (m, 7H), 2.63 (t, 4H, J = 4.2 Hz), 2.52 (t, 3H, J = 6.4 Hz), 2.11 (m, 2H), 1.96 (m, 1H)
MS (m/z): 564.66
Compuesto número
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
87
imagen177 RMN 1H (400 MHz, DMSO-d6) δ 8.44 (d, 1H, 8.0 Hz), 8.40 (s, 1H), 8.00(m, 3H), 7.91 (s br, 1H), 7.76 (m, 1H), 7.52 (s, 2H), 7.46 (m, 1H), 7.27 (d, 2H, J = 7.6 Hz), 7.11 (m, 1H), 6.97 (s br, 1H), 5.28 (dd, 1H, J = 8.4, 2.4 Hz), 4.20 (dd, 1H, J = 6.0, 3.2 Hz), 4.10 (m, 1H), 3.77 (1, 1H, J = 8.0 Hz), 2.60 (s, 1H), 2.53 (m, 1H), 2.12 (m, 2H), 1.95 (m, 1H) MS (m/z): 514.57
88
MS (m/z): 514.57
89
imagen178 RMN 1H (400 MHz, DMSO-d6) δ 8.40 (s, 1 H), 8.23 (d, 1H, θ = 7. 6 Hz), 8.19 (d, 1H, J = 7.6 Hz), 8.10 (d, 1H, J = 8.0 Hz), 7.95 (m, 2H), 7.48 (ddd, 1H, J = 8.0, 6.4, 6.4 Hz), 7.25 (m, 3H), 7.10 (ddd, 1H, J = 8.8, 8.8, 2.4 Hz), 7.03 (d, 1H, J = 8.0 Hz), 6.95 (s br, 1H), 5.26 (dd, 1H, J = 8.4, 2.4 Hz), 4.09 (m, 1H), 3.75 (q, 1H, J = 8.4 z), 3.51 (s, 3H), 2.55 (m, 1H), 2.11 (m, 2H), 1.91 (m, 1H) MS (m/z): 529.59
90
MS (m/z): 520.60
91
MS (m/z): 513.59
92
imagen179 RMN 1H (400 MHz, DMSO-d6) δ 8.49 (s, 1H), 8.33 (s, 1H), 8.14 (s, 1H), 8.05 (s br, 1H), 7.99 (d, 1H, J = 9.6 Hz), 7.77 (m, 1H), 7.56 (d, 1H, J = 7.6 Hz), 7.45 (m, 1H), 7.24 (m, 2H), 7.10 (m, 1H), 6.95 (s br, 1H), 5.26 (dd, 1H, J = 8.0, 2.8 Hz), 4.34 (t, 2H, J = 7.2 Hz), 4.08 (m, 1H), 3.75 (q, 1H, J = 8.4 z), 3.62 (t, 4H, J = 4.2 Hz), 2.83 (t, 2H, J = 6.8 Hz), 2.55 (m, 4H), 2.11 (m, 2H), 1.91 (m, 1H) MS (m/z): 538.62
Compuesto número
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
93
imagen180 RMN 1H (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 8.29 (d, 1H, J = 4.2 Hz), 8.20 (s br, 1H), 8.01 (m, 2H), 7.90 (m, 1H), 7.59 (s, 1H), 7.46 (m, 2H), 7.26 (d, 2H, J = 7.6 Hz), 7.11 (m, 1H), 6.96 (s br, 1H), 5.27 (dd, 1H, J = 8.0, 2.8 Hz), 4.09 (m, 1H), 3.76 (m, 1H), 3.64 (m, 3H), 3.40 (s, 2H), 2.76 (m, 1H), 2.64 (m, 3H), 2.53 (m, 1H), 2.12 (m, 2H), 1.95 (m, 1H), 1.08 (d, 6H, J = 6.4 Hz)
MS (m/z): 562.68
94
MS (m/z): 528.60
95
MS (m/z): 521.59
96
imagen181 RMN 1H (DMSO-d6) 8.07 (s, 1 H), 7.88 (d, 1 H), 7.50 7.58 (bs, 1 H), 7.42 -7.48 (bs, 1 H), 7.35 -7.40 (m, 1 H), 7.13 -7.17 (m, 2 H), 7.01 -7.05 (m, 1 H), 6.78 -6.85 (bs, 1 H), 6.73 (d, 1H), 5.15-5.18 (q, 1 H), 3.96 -4.01 (m, 1 H), 3.87 -3.94 (m, 1 H), 3.64 -3.70 (m, 1 H), 3.54 -360 (bs, 4 H), 2.91 -2.96 (bs, 2 H), 2.50 -2.60 (bs, 4 H), 2.45 -2.50 (m, 1 H), 2.00 -2.06 (m, 2 H), 1.84 -1.90 (m, 1 H), 1.08 (d, 6 H). MS (m/z): 543.7
97
imagen182 RMN 1H (DMSO -d6) 8.04 (s, 1 H), 7.87 (d, 1 H), 7.40 7.50 (m, 2 H), 7.35 -7.40 (m, 1 H), 7.13 -7.17 (m, 2 H), 7.01 -7.05 (m, 1H), 6.76 -6.85 (bs, 1H), 6.72 (d, 1H), 5.14 -5.17 (q, 1 H), 4.46 (t, 1 H), 4.37 (d, 2 H), 3.96 -4.01 (m, 1 H), 3.64 -3.69 (q, 1 H), 3.27 (t, 2 H), 2.74 -2.81 (m, 2 H), 2.45 -2.50 (m, 1 H), 2.00 -2.06 (m, 2 H), 1.84 -1.89 (m, 1 H), 1.58 -1.64 (m, 1 H), 1.08 -1.17 (m, 2 H).
MS (m/z): 473.6
98
imagen183 RMN 1H (DMSO -d6) 8.05 (s, 1 H), 7.88 (d, 1 H), 7.40 7.50 (m, 2 H), 7.34 -7.40 (m, 1 H), 7.13 -7.17 (m, 2 H), 7.00 -7.05 (m, 1 H), 6.76 -6.85 (bs, 1H), 6.69 (t, 1 H), 5.15 -5.18 (q, 1 H), 4.54 -4.57 (m, 1 H), 4.34 (d, 1 H), 4.22 (d, 1 H), 3.96 -4.02 (m, 1 H), 3.64 -3.70 (q, 1 H), 3.28 -3.37 (m, 2H), 2.81 -2.88 (m, 1 H), 2.59 (t, 1 H), 2.45 -2.50 (m, 1 H), 2.00 -2.08 (m, 2 H), 1.84 -1.90 (m, 1H), 1.72 -1.77 (m, 1 H), 1.66 -1.72 (m, 1 H), 1.58 -1.65 (m, 1 H), 1.40 -1.59 (m, 1H), 1.14 -1.22 (m, 1H).
MS (m/z): 473.6
Compuesto número
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
99
imagen184 RMN 1H (DMSO -d6) 8.07 (s, 1 H), 7.88 (d, 1 H), 7.41 7.60 (m, 2 H), 7.34 -7.40 (m, 1 H), 7.12 -7.18 (m, 2 H), 7.00 -7.15 (m, 1 H), 6.78 -6.85 (bs, 1H), 6.77 (d, 1H), 5.15 -5.18 (q, 1 H), 3.96 -4.01 (m, 1 H), 3.83 -3.89 (m, 2 H), 3.64 -3.70 (q, 1 H), 3.09 -3.14 (m, 1 H), 2.45 -2.50 (m, 1 H), 2.00 -2.06 (m, 2 H), 1.94 -1.97 (m, 2 H), 1.84 1.89 (m, 1 H), 1.71 -1.77 (m, 2 H). MS (m/z): 468.5
100
imagen185 RMN 1H (DMSO -d6) 8.05(s, 1 H), 7.88 (d, 1 H), 7.42 7.60 (m, 2 H), 7.35 -7.40 (m, 1 H), 7.13 -7.17 (m, 2 H), 7.00 -7.05 (m, 1 H), 6.75 -6.85 (bs, 1H), 6.72 (d, 1H), 5.14 -5.18 (q, 1 H), 4.43 (t, 1 H), 3.96 -4.01 (m, 1 H), 3.63 -3.70 (q, 1 H), 3.47 -3.57 (m, 6 H), 2.50 -2.55 (m, 4 H), 2.40 -2.50 (m, 3 H), 2.00 -2.06 (m, 2 H), 1.84 -1.89 (m, 1 H). MS (m/z): 488.6
101
imagen186 RMN 1H (CDCl3 -d6) d 8.24 (s, 1 H), 7.69 (d, 1 H, J = 9.6 Hz), 7.55 -7.63 (m, 1 H), 7.43 (t, 1 H), 7.25 -7.33 (m, 1 H), 7.05 (d, 1 H, J = 7.6 Hz), 6.90 -7.00 (m, 2 H), 6.59 (d, 1 H, J = 8.4 Hz), 6.51 (d, 1 H, j = 9.6 Hz), 5.04 -5.11 (m, 1 H), 4.13 -4.22 (m, 2 H), 3.90 -4.00 (m, 2 H), 3.69 -3.78 (m, 1 H), 3.13 -3.22 (m, 2H), 2.42 -2.54 (m, 1 H), 2.06 -2.20 (m, 2 H), 1.96 -2.05 (m, 3 H), 1.55 -1.62 (m, 2 H) MS (m/z): 459.5
102
MS (m/z): 378.4
103
MS (m/z): 378.4
104
MS (m/z): 488.6
Compuesto número
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
105
MS (m/z): 500.6
106
imagen187 MS (m/z): 486.6
107
imagen188 RMN 1H (DMSO -d6): d 8.06 (s, 1H), 7.75 (s, 1 H), 7.51 (d, 1 H), 7.32 -7.40 (m, 2 H), 7.22 (d, 1 H), 7.14 (d, 2 H), 6.99 -7.05 (m, 1 H), 6.45 -6.50 (m, 1 H), 6.35 9d, 1 H), 4.14 -4.21 (m, 1 H), 3.30 -3.39 (m, 2 H), 2.82 (d, 3 H), 2.17 -2.26 (m, 1 H), 2.00 -2.10 (m, 1 H), 1.56 -1.83 (m, 3 H), 1.35 -1.50 (m, 1 H). MS (m/z): 403.5
108
imagen189 RMN 1H (DMSO -d6): d 8.02 (s, 1 H), 7.90 (d, 1 H), 7.46 (d, 1 H), 7.30 -7.40 (m, 2 H), 7.21 (d, 1 H), 7.13 (d, 2 H), 6.98 -7.06 (m, 1 H), 6.30 -6.36 (m, 2 H), 4.12 -4.20 (m, 1 H), 4.02 -4.10 (m, 1 H), 3.30 -3.38 (m, 2 H), 2.18 -2.26 (m, 1 H), 2.00 -2.10 (m, 1 H), 1.56 -1.84 (m, 3 H), 1.36 1.48 (m, 1 H), 1.17 (d, 6 H). MS (m/z): 431.5
109
imagen190 RMN 1H (DMSO -d6): d 10.63 (s, 1 H), 8.06 (s, 1 H), 7.97 (s, 1 H), 7.94 (d, 1 H), 7.72 (t, 1 H), 7.33 -7.40 (m, 1 H), 7.25 (d, 1 H), 7.12 -7.18 (m, 2 H), 6.99 -7.05 (m, 1 H), 6.80 (d, 1 H), 4.15 -4.22 (m, 1 H), 3.42 (s, 3 H), 3.35 3.42 (m, 2 H), 2.17 -2.26 (m, 1 H), 2.01 -2.14 (m, 1 H), 1.57 -1.85 (m, 3 H), 1.36 -1.49 (m, 1 H). MS (m/z): 467.5
110
MS (m/z): 417.5
Compuesto número
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
111
MS (m/z): 473.6
112
MS (m/z): 431.5
113
MS (m/z): 472.6
114
imagen191 RMN 1H (DMSO -d6) 8.05 (s, 1 H), 7.88 (d, 1 H, J = 9.6 Hz), 7.81 (t, 1 H, J = 5.6 Hz), 7.34 7.58 (m, 3 H), 7.10 -7.18 (m, 2 H), 7.00 -7.06 (m, 1H), 6.76 -6.86 (bs, 1 H), 6.74 (d, 1 H, J = 8.8 Hz), 5.14 -5.19 (m, 1 H), 4.64 (t, 1 H, J = 5.6 Hz), 4.33 -4.42 (m, 2 H), 3.95 -4.02 (m, 1 H), 3.62 -3.71 (m, 1 H), 3.34 -3.42 (m, 2 H), 3.07 -3.13 (m, 2 H), 2.76 -2.86 (m, 2 H), 2.44 -2.50 (m, 1 H), 2.32 -2.44 (m, 1 H), 2.00 2.10 (m, 2 H), 1.84 -1.91 (m, 1 H), 1.67 -1.78 (m, 2 H), 1.46 -1.60 (m, 2 H). MS (m/z): 530.6
115
MS (m/z): 557.7
Compuesto número
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
116
MS (m/z): 459.5
117
MS (m/z): 525.6
118
imagen192 RMN 1H (DMSO -d6) 9.30 -9.60 (bs, 1 H), 8.63 -8.66 (m, 1H), 8.52 (d, 1 H, J = 12.4 Hz), 8.16 (s, 1 H), 7.95 (d, 1 H, J = 10 Hz), 7.32 -7.40 (m, 1 H), 7.11 -7.17 (m, 2 H), 6.98 -7.06 (m, 1H), 6.78 -6.92 (bs, 1 H), 5.19 5.24 (m, 1 H), 3.98 -4.05 (m, 1 H), 3.64 -3.74 (m, 1 H), 2.44 -2.50 (m, 1 H), 2.00 -2.10 (m, 2 H), 1.85 -1.93 (m, 1H). MS (m/z): 361.4
119
imagen193 RMN 1H (DMSO -d6) 8.16 (d, 1 H, J=6.8 Hz), 8.04 (s, 1 H), 7.87 (d, 1 H, J = 9.6 Hz), 7.44 -7.60 (bs, 1 H), 7.34 -7.44 (m, 2 H), 7.12 -7.20 (m, 2 H), 7.00 -7.06 (m, 1H), 6.72 -6.90 (bs, 1H), 6.36 (d, 1 H, J = 8.4 Hz), 5.14 -5.20 (m, 1 H), 4.30 -4.40 (m, 1 H), 3.96 -4.02 (m, 1 H), 3.61 -3.72 (m, 2 H), 3.42 -3.60 (m, 2 H), 3.24 -3.30 (m, 1 H), 2.42 -2.50 (m, 1 H), 2.10 -2.20 (m, 1 H), 2.00 -2.10 (m, 2 H), 1.82 -1.90 (m, 2 H), 1.81 (s, 3 H). MS (m/z): 486.6
120
MS (m/z): 349.4
121
MS (m/z): 460.5
Compuesto número
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
122
MS (m/z): 473.6
123
MS (m/z): 445.5
124
MS (m/z): 489.6
125
imagen194 RMN 1H (DMSO -d6) 8.70 -8.88 (bs, 1 H), 8.12 (s, 1 H), 7.86 -7.90 (m, 2 H), 7.34 -7.39 (m, 1 H), 7.04 7.15 (m, 2 H), 7.00 -7.06 (m, 1 H), 6.65 -6.82 (m, 1H), 5.17 -5.23 (m, 1 H), 3.95 -4.05 (m, 1 H), 3.75 -3.83 (m, 1 H), 3.64 -3.74 (m, 2 H), 3.36 -3.45 (m, 1 H), 3.15 -3.23 (m, 1 H), 2.75 -2.85 (m, 1 H), 2.42 -2.50 (m, 1 H), 2.24 (s, 6 H), 2.13 -2.22 (m, 1 H), 1.95 -2.08 (m, 2 H), 1.75 -1.92 (m, 2 H). MS (m/z): 473.6
126
MS (m/z): 472.5
127
imagen195 RMN 1H (DMSO -d6) 8.01 (s, 1 H), 7.88 (d, 1 H, J = 10 Hz), 7.46 -7.62 (bs, 1 H), 7.32 -7.44 (m, 2 H), 7.12 7.18 (m, 2 H), 7.00 -7.06 (m, 1H), 6.72 -6.90 (bs, 1H), 6.27 (d, 1 H, J = 8 Hz), 5.13 -5.20 (m, 1 H), 4.09 -4.16 (m, 2 H), 3.95 -4.03 (m, 1 H), 3.76 -3.85 (m, 1 H), 3.62 -3.71 (m, 1 H), 3.51 -3.57 (m, 2 H), 2.41 -2.50 (m, 1 H), 2.00 -2.10 (m, 2 H), 1.83 -1.90 (m, 1 H). MS (m/z): 430.5
Compuesto número
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
128
imagen196 RMN 1H (DMSO -d6) 8.03 (s, 1 H), 7.89 (d, 1 H, J = 10 Hz), 7.83 (d, 1 H, J = 8 Hz), 7.50 -7.62 (bs, 1 H), 7.41 7.50 (m, 1 H), 7.34 -7.42 (m, 1 H), 7.12 -7.18 (m, 2 H), 7.00 -7.06 (m, 1H), 6.78 -6.90 (bs, 1H), 6.32 (d, 1 H, J = 8.4 Hz), 5.04 -5.20 (m, 1 H), 4.24 -4.36 (m, 3 H), 3.95 4.02 (m, 1 H), 3.77 -3.85 (m, 2 H), 3.60 -3.71 (m, 1 H), 2.95 (s, 3 H), 2.42 -2.50 (m, 1 H), 2.00 -2.07 (m, 2 H), 1.82 -1.90 (m, 1 H). MS (m/z): 508.6
129
MS (m/z): 458.5
130
MS (m/z): 458.6
131
imagen197 MS (m/z): 348.4
132
MS (m/z): 488.5
133
imagen198 RMN 1H (DMSO -d6) 8.03 (s, 1 H), 7.88 (d, 1 H, J = 10 Hz), 7.52 -7.64 (bs, 1 H), 7.42 -7.50 (m, 1 H), 7.32 7.42 (m, 1 H), 7.12 -7.18 (m, 2 H), 7.00 -7.06 (m, 1H), 6.74 -6.90 (bs, 1H), 6.34 (d, 1 H, J = 8 Hz), 5.12 -5.2 (m, 1 H), 4.62 -4.70 (m, 1 H), 4.22 -4.32 (m, 2 H), 3.94 4.02 (m, 3 H), 3.62 -3.70 (m, 1 H), 3.30 -3.38 (m, 2 H), 2.95 (s, 3 H), 2.42 -2.50 (m, 1 H), 1.98 -2.08 (m, 2 H), 1.82 -1.90 (m, 1 H), 1.20 (t, 3H). MS (m/z): 536.6
Compuesto número
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
134
MS (m/z): 536.6
135
imagen199 RMN 1H (DMSO -d6) 8.02 (s, 1 H), 7.88 (d, 1 H, J = 10 Hz), 7.48 -7.62 (bs, 1 H), 7.40 -7.47 (m, 1 H), 7.33 7.40 (m, 1 H), 7.12 -7.17 (m, 2 H), 6.99 -7.06 (m, 1H), 6.75 -6.87 (bs, 1H), 6.29 (d, 1 H, J = 8.4 Hz), 5.13 -5.18 (q, 1 H), 4.72 (s, 4 H), 4.12 (s, 4 H), 3.94 -4.03 (m, 1 H), 3.60 -3.70 (m, 1 H), 2.40 -2.48 (m, 1 H), 1.98 -2.06 (m, 2 H), 1.82 -1.90 (m, 1 H). MS (m/z): 457.5
136
imagen200 RMN 1H (DMSO -d6) 8.52 (d, 1 H, J = 5.2 Hz), 8.32 (s, 1 H), 8.21 (d, 1 H, J = 7.6 Hz), 7.94 (d, 1 H, J = 10 Hz), 7.86 -7.92 (m, 1 H), 7.74 (d, 1 H, J = 4.8 Hz), 7.36 -7.44 (m, 1 H), 7.14 -7.22 (m, 2 H), 7.00 -7.08 (m, 1H), 6.82 -6.96 (bs, 1H), 5.17 -5.23 (q, 1 H), 4.76 (s, 4 H), 4.29 (s, 4 H), 3.98 -4.06 (m, 1 H), 3.64 -3.74 (m, 1 H), 2.43 -2.50 (m, 1H), 2.00 -2.10 (m, 2 H), 1.84 -1.92 (m, 1 H). MS (m/z): 535.6
137
MS (m/z): 414.4
138
RMN 1H metanol -d4, d (ppm) 8.05 (b, 2H), 7.65 (b, 1H), 7.46 (s, 1H), 7.38 (m, 1H), 7.28 (m, 1H), 7.18 (m, 1H), 7.10 (m, 2H), 6.87 (td, 1H), 5.20 (s, 1H), 4.18 (dd, 1H), 4.02 (m, 3H), 3.76 (td, 1H), 3.60 (m, 1H), 3.53 (s, 2H). MS (m/z): 430.4
139
MS (m/z): 460.5
Compuesto número
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
140
MS (m/z): 376.4
141
imagen201 RMN 1H metanol -d4, d (ppm) 7.98 (s, 1H), 7.68 (d, 1H), 7.52 (d, 1H), 7.44 (t, 1H), 7.31 (m, 2H), 7.19 (t, 2H), 7.09 (m, 2H), 6.64 (d, 1H), 5.09 (t, 1H), 4.11 (m, 3H), 4.01 (m, 2H), 3.74 (m, 3H), 3.63 (m, 1H), 3.03 (m, 2H), 1.83 (m, 2H), 1.41 (m, 2H) MS (m/z): 457.5
142
RMN 1H metanol -d4, d (ppm) 8.12 (s, 1H), 7.85 (m, 1H), 7.60 (m, 2H), 7.27 (m, 4H), 6.97 (m, 1H), 6.75 (m, 1H), 5.25 (t, 1H), 4.28 (m, 4H), 4.14 (m, 3H), 3.93 (m, 2H), 3.73 (m, 1H), 2.83 (m, 1H), 1.92 (m, 2H), 1.82 (m, 1H), 1.41 (m, 1H). MS (m/z): 487.5
143
RMN 1H metanol -d4, d (ppm) 8.45 (s, 1H), 8.17 (d, 1H), 7.79 (d, 1H), 7.67 (m, 2H), 7.36 (m, 1H), 7.26 (m, 2H), 7.13 (d, 1H), 6.98 (m, 2H), 5.40 (m, 1H), 4.63 (m, 2H), 4.34 (m, 1H), 4.15 (m 3H), 3.88 (m, 1H), 3.79 (m, 1H), 3.06 (td, 2H), 2.31 (s, 3H), 2.12 (m, 2H), 1.85 (m, 2H). MS (m/z): 539.6
144
MS (m/z): 419.5
145
imagen202 MS (m/z): 534.7
146
imagen203 RMN 1H metanol -d4, d (ppm) 8.52 (s, 1H), 8.15 (d, 1H), 7.81 (m, 3H), 7.36 (m, 1H), 7.25 (m, 2H), 7.00 (m, 2H), 5.40 (m, 1H), 4.34 (dd, 1H), 4.15 (m, 4H), 3.89 (td, 2H), 3.74 (m, 5H), 3.51 (m, 4H), 3.33 (m, 2H), 3.13 (s, 3H). MS (m/z): 566.7
Compuesto número
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
147
RMN 1H metanol -d4, d (ppm) 8.33 (s, 1H), 8.27 (s, 1H), 8.03 (d, 1H), 7.65 (d, 1H), 7.54 (m, 2H), 7.25 (m, 1H), 7.15 (m, 2H), 6.87 (m, 2H), 5.29 (m, 1H), 4.45 (m, 2H), 4.24 (dd, 1H), 4.04 (m, 3H), 3.77 (td, 1H), 3.66 (m, 1H), 3.20 (m, 1H), 3.00 (m, 2H), 1.99 (m, 2H), 1.75 (m, 2H). MS (m/z): 526.6
148
RMN 1H metanol -d4, d (ppm) 8.50 (s, 1H), 8.31 (s, 1H), 8.00 (d, 1H), 7.61 (d, 1H), 7.54 (m, 2H), 7.25 (m, 1H), 7.15 (m, 2H), 6.84 (m, 2H), 5.28 (m, 1H), 4.36 (m, 2H), 4.21 (dd, 1H), 4.04 (m, 3H), 3.77 (td, 1H), 3.66 (m, 1H), 3.03 (m, 3H), 2.08 (m, 2H), 1.81 (m, 2H). MS (m/z): 527.6
149
imagen204 RMN 1H (400 MHz, D6 acetona) ppm: 8.40 (br s 1H), 8.35 (d, J = 8.1 Hz, 1H), 7.85 (d, J = 7.0 Hz, 1H), 7.62(d, J = 6.2 Hz, 1H), 7.52 -7.40 (m, 1H), 7.38 -7.28 (m, 1H), 7.14 (d, J = 6.0 Hz, 1H),7.04 (app d, J = 8.0Hz,1H), 6.85 (app dt, J = 8.4, 3.5 Hz, 1H), 6.77 (d, J = 8.0 Hz, 1H), 5.58 (d, J = 6.7 Hz, 1H), 4.31 (app dt, J = 6.8, 2.5 Hz, 2H), 4.22 -4.04 (m, 2H), 3.52 -3.48 (m, 1H),3.28 -3.07 (m, 3H), 2.39 -2.31 (m, 1H), 2.22 -2.10 (m, 1H), 1.97 -1.77 (m, 4H), 1.67 1.42 (m, 4H). MS (m/z): 473.6
150
imagen205 RMN 1H (400 MHz, D3 acetonitrilo) ppm: 8.45 (br s, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.92 (d, J = 7.4 Hz, 1H), 7.81 7.77 (m. 2H), 7.42 -7.36 (m, 2H), 7.14 (app d, J = 8.0 Hz, 1H), 6.95 (d, J = 8.2 Hz, 1H), 6.81 (app t, J = 7.2 Hz, 1H), 6.18 (br s, 2H), 5.21 (d, J= 7.7 Hz, 1H), 3.95 (app q, J = 5.5 Hz, 1H), 3.67 (app q, J = 7.5 Hz, 1H), 2.62 -2.45 (m, 2H), 2.22 -2.02 (m, 1H), 1.95 (app t, J = 2.5 Hz,1H).
MS (m/z): 403.4
151
imagen206 RMN 1H (400 MHz, D3 acetonitrilo) ppm: 8.15 (br s 1H), 7.90 -7.83 (m, 1H), 7.58 -7.52 (m, 1H), 7.34(app q, J = 8.0 Hz, 1H), 7.10 (d, J = 7.2 Hz, 1H), 7.02 (d, J = 8.2 Hz, 1H), 6.89 (app t, J = 6.2 Hz, 2H), 6.82 (br s, 1H), 6.52 (app d, J = 4.6 Hz, 1.0 H), 5.19 (d, J= 7.7 Hz, 1H), 4.05 (app q, J = 6.2 Hz, 1H), 3.74 (app q, J = 8.5 Hz, 1H), 2.64 -2.40 (m, 2H), 2.20 -2.00 (m, 1H), 1.95 (app t, J = 2.5 Hz, 1H). MS (m/z): 376.4
Compuesto número
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
152
MS (m/z): 404.4
153
MS (m/z): 428.4
154
MS (m/z): 426.5
155
MS (m/z): 410.5
156
imagen207 RMN 1H (400 MHz, D3 acetonitrilo) ppm: 8.05 -7.98 (m, 2H), 7.83 (app d, J = 6.8 Hz, 2H), 7.28 ( app q, J = 6.2 Hz, 2H), 7.14 (br s, 1H), 6.98 (d, J = 7.0 Hz, 1H), 6.90 (d, J = 8.2 Hz, 1H), 6.85 (app t, J = 6.2 Hz, 2H), 5.02 (dd, J = 7.4, 2.2 Hz, 1H), 3.87 (app q, J = 5.5 Hz, 1H), 3.61 (app q, J = 8.5 Hz, 1H), 2.99 (s, 3H), 2.44 -2.38(m, 2H), 2.06 1.95(m, 2H). MS (m/z): 437.5
157
imagen208 RMN 1H (400 MHz, D3 acetonitrilo) ppm: 8.14 (app t, J = 5.6 Hz, 2H), 8.12 (br s, 1H), 8.02 (br s, 1H), 7.98 (app dt, J = 6.8, 1.2 Hz, 2H), 7.78 (app dt, J = 6.8, 1.2 Hz, 2H), 7.30 7.25 (m, 2H), 7.15 ( app d, J = 6.1 Hz, 1H), 7.04 (dd, J= 8.2, 1.9 Hz, 1H), 6.96 (t, J = 7.0 Hz, 1H), 5.22 (d, J= 7.94 Hz, 1H), 4.05 (m, 1H), 3.78 (app q, J = 7.5 Hz, 1H), 2.57 2.54 (m, 1H), 2.14 -1.99 (m, 3H). MS (m/z): 410.5
Compuesto número
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
158
imagen209 RMN 1H (400 MHz, D3 acetonitrilo) ppm: 8.30 (br s, 1H), 8.14 (app d, J = 2.6 Hz, 2H), 7.89 (br s, 1H), 7.54 (d, J = 6.8 Hz, 1H), 7.35 (q, J = 7.2 Hz, 1H), 7.25 (br s, 1H), 7.16 (d, J = 6.9 Hz, 1H), 7.08 (d, J = 8.2 Hz, 1H), 6.96 (t, J = 7.4 Hz, 1H), 5.23 (dd, J = 7.94, 1.9 Hz, 1H), 4.15 (br d, J = 7.8 Hz, 1H), 4.05 (app q, J = 6.8 Hz, 1H), 3.87 (app q, J = 6.7 Hz, 1H), 3.72 (q, J = 7.5 Hz, 1H), 3.67 -3.63 (m, 1H), 3.33 -3.12 (m, 4H), 2.57 -2.54 (m, 1H), 2.14 -1.99(m, 2H), 1.65 -1.59 (m 2H).
MS (m/z): 487.5
159
RMN 1H (400 MHz, D3 acetonitrilo) ppm: 8.28 (d, J = 6.2 Hz, 1H), 8.20 (br s, 1H), 8.04 (app d, J = 6.6 Hz, 1H), 7.74 (s, 1H), 7.67 (s, 1H), 7.34 (q, J = 6.8 Hz, 1H), 7.22 -7.14 (m, 2H), 7.03 (dd, J = 6.9, 1.2 Hz, 1H), 6.97 (dt, J = 6.4, 1.2 Hz, 1H), 5.18 (dd, J= 6.7, 1.9 Hz, 1H), 4.00 (app q, J = 5.8 Hz, 1H), 3.72 (app q, J = 6.4 Hz, 1H), 2.54 -2.47 (m, 1H), 2.13 -2.03 (m, 2H), 1.97 -1.87 (m, 1H).
MS (m/z): 378.4
160
imagen210 RMN 1H (400 MHz, D3 acetonitrilo) ppm: 8.18 (s, 1H), 8.04 (d, J = 6.9 Hz, 1H), 7.78 (s, 1H), 7.38 (q, J = 7.2 Hz, 1H), 7.28 -7.19 (m, 1H), 7.10 (dd, J = 6.2,1.2Hz,1H),6.94(app d, J = 6.8Hz, 2H), 6.82 -6.74 (m, 2H), 5.32 (app t, J= 2.9 Hz, 1H), 5.12 (dd, J= 7.4, 1.6 Hz, 1H), 4.01 -3.86 (m, 4H), 3.74 (app q, J = 6.8 Hz, 1H), 3.52 (app t, J = 6.0 Hz, 1H), 2.58 -2.50 (m, 1H), 2.20 -2.18 (m, 1H), 2.15 -1.98 (m, 6H), 1.67 -1.61 (m, 1H).
MS (m/z): 459.5
161
imagen211 RMN 1H (400 MHz, D3 acetonitrilo) ppm: 8.08 (d, J = 7.1 Hz, 1H), 7.92 (s, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.62 (s, 1H), 7.41 (q, J = 8.2 Hz, 1H), 7.18 (app t, J = 8.9 Hz, 2H), 7.08 (d, J = 6.8 Hz, 1H), 6.95 (t, J = 5.8 Hz, 1H), 6.68 (dd, J = 7.4, 1.8 Hz, 1H), 5.17 (d, J= 6.9 Hz, 1H), 3.98 (dd, J= 7.6, 2.6 Hz, 1H), 3.72 (app q, J = 7.8 Hz, 1H), 3.58 -3.51 (m, 4H), 2.46 -2.40 (m, 4H), 2.20 (s, 3H), 2.08 -2.03 (m, 1H).
MS (m/z): 458.5
162
MS (m/z): 419.5
Compuesto número
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
163
MS (m/z): 500.6
164
RMN 1H (400 MHz, D3 acetonitrilo) ppm: 8.82 (s, 1H), 7.73 (s, 1H), 7.72 -7.70 (m, 2H), 7.35 (q, J = 6.9 Hz, 1H), 7.09 (d, J = 6.9 Hz, 1H), 7.02 (d, J = 5.6 Hz, 1H), 6.89 (t, J = 5.8 Hz, 1H), 6.69 (dd, J = 6.9, 1.3 Hz, 1H), 5.07 (d, J = 7.9 Hz, 1H), 4.48 -4.42 (m, 2H), 3.92 -3.89 (m, 1H), 3.85 -3.80 (m, 1H), 3.66 (q, J= 7.1 Hz, 1H), 3.38 -3.32 (m, 2H), 2.48 2.42 (m, 1H), 2.13 -2.03 (m, 4H), 1.50 -1.45 (m, 2H). MS (m/z): 460.5
165
imagen212 RMN 1H (400 MHz, D3 acetonitrilo) ppm: 8.58 (s, 1H), 8.30 -8.16 (m, 2H), 8.08 (app d, J = 6.9 Hz, 1H), 7.91 (br s, 1H), 7.42 (q, J = 5.9 Hz, 1H), 7.22 (br s, 1H), 7.19 (dd, J = 6.9, 1.2 Hz, 1H), 7.02 (d, J = 7.2 Hz, 1H), 6.99 (dt, J = 6.8, 1.0 Hz, 1H), 5.24 (dd, J = 6.8, 1.9 Hz, 1H), 4.04 (app q, J = 6.4 Hz, 1H), 3.72 (app q, J = 5.4 Hz, 1H), 2.92 (d, J = 4.2 Hz, 3H), 2.54 -2.47 (m, 1H), 2.19 -2.10 (m, 2H), 2.03 1.95 (m, 1H). MS (m/z): 417.5
166
imagen213 MS (m/z): 473.5
167
imagen214 RMN 1H (600 MHz, D3 acetonitrilo) ppm: 8.08 (s, 1H), 8.04 (s, 1H), 7.72 (d, J = 7.2 Hz, 1H), 7.52 -7.45 (m, 2H), 7.41 (app d, J = 3.2 Hz, 1H), 7.18 (br s, 2H), 7.01 (t, J = 6.1 Hz, 1H), 6.72(d, J = 5.8 Hz, 1H), 5.27 (d, J= 6.9 Hz, 1H), 4.58 (br s, 1H), 4.11 (app t, J = 6.8 Hz, 1H), 4.04 (d, J = 4.5 Hz, 1H), 3.82 (q, J = 4.9 Hz, 1H), 3.77 -3.54 (m, 3H), 3.52 3.48 (m, 1H), 2.66 -2.60 (m, 1H), 2.20 -2.01 (m, 4H). MS (m/z): 445.5
Compuesto número
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
168
MS (m/z): 445.5
169
imagen215 RMN 1H (600 MHz, D3 acetonitrilo) ppm: 8.06 (br s, 2H), 7.74 (d, J = 7.2 Hz, 1H), 7.48 -7.42 (m, 2H), 7.28 (d, J = 7.2 Hz, 1H), 7.18 (br s, 2H), 7.01 (t, J = 6.8 Hz, 1H), 6.72 (d, J = 6.8 Hz, 1H), 5.23 (d, J = 6.4 Hz, 1H), 4.58 (br s, 1H), 4.31 (br s, 2H), 4.11 (app t, J = 6.8 Hz, 1H), 3.88 (d, J = 4.5 Hz, 1H), 3.82 (t, J = 5.9 Hz, 1H), 3.61 -3.59 (m, 2H), 3.21 (app d, J = 5.5 Hz, 1H), 2.63 -2.58 (m, 1H), 2.16 2.00 (m, 4H). MS (m/z): 461.5
170
imagen216 RMN 1H (400 MHz, D3 acetonitrilo) ppm: 8.26 (s, 1H), 8.04 (br d, J = 6.2 Hz, 1H), 7.48 (br s, 1H), 7.39 (q, J = 7.5 Hz, 1H), 7.20 (s, 1H), 7.10 -7.04 (m, 2H), 7.03 (d, J = 7.0 Hz, 1H), 6.99 (dt, J = 6.9,1.2Hz,1H), 6.82 (d, J = 6.8 Hz, 1H), 5.13 (dd, J = 6.4, 1.2 Hz, 1H), 4.58 (br s, 2H), 4.02 -4.00 (m, 1H), 3.62 (app q, J = 6.9 Hz, 1H), 3.22 (app t, 1H), 2.82 (app t, J = 6.5 Hz, 1H), 2.75 (br s, 6H), 2.62 -2.52 (m, 2H), 2.48 -2.38 (m, 3H), 2.11 -2.00 (m, 3H), 1.84 -1.80 (m, 1H). MS (m/z): 486.6
171
MS (m/z): 420.5
172
imagen217 RMN 1H (400 MHz, D3 acetonitrilo) ppm: 8.82 (s, 2H), 8.33 (d, 7.8 Hz, 1H), 8.18 (br s, 1H), 7.43 -7.32 (m, 2H), 7.15 (d, J = 6.9 Hz, 1H), 7.04 (dd, J = 6.9, 1.5 Hz, 1H), 6.92 (t, J = 7.0 Hz,1H), 5.27 (dd, J= 7.4, 2.2 Hz, 1H), 4.28 -4.22 (m, 1H), 3.89 (app q, J = 6.7 Hz, 1H), 3.05(s, 3H), 2.71 -2.62 (m, 1H), 2.23 -2.03 (m, 2H), 2.01 -1.99 (m, 1H). MS (m/z): 390.4
Compuesto número
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
173
imagen218 RMN 1H (400 MHz, D3 acetonitrilo) ppm: 8.62 (s, 2H), 8.06 (d, 7.9 Hz, 1H), 7.94 (br s, 1H), 7.23 (q, J = 6.4 Hz, 1H), 7.04 (app t, J = 6.5 Hz, 1H), 6.94 (d, J = 7.2 Hz, 1H), 6.82 (t, J = 6.1 Hz, 1H), 5.21 (dd, J= 7.0, 2.2 Hz, 1H), 3.92 (ddd, J = 6.6 Hz, 4.3 Hz, 1.9 Hz, 1H), 3.71 -3.65 (m, 1H), 3.10 (s, 6H), 2.51 -2.43 (m, 1H), 2.23 -2.03 (m, 2H), 2.01 1.99 (m, 1H). MS (m/z): 404.5
174
MS (m/z): 486.6
175
MS (m/z): 395.8
176
imagen219 RMN 1H (400 MHz, D6 acetona) ppm: 8.91 (s, 2H), 7.80 (s, 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.22 (q, J = 6.8 Hz, 1H), 6.98 (d, J = 7.5 Hz,1H), 6.92 (d, J = 7.4 Hz, 1H), 6.82 (t, J = 7.1 Hz, 1H), 6.67 (d, J = 7.2 Hz, 1H), 5.11 (t, J = 5.4 Hz, 1H), 5.02 (dd, J = 7.0, 2.2 Hz, 1H), 3.96 -3.87 (m, 1H), 3.74 -3.63 (m, 2H), 3.01 (app q, J = 5.2 Hz, 1H), 2.72 (s, 9H), 2.43 -2.38 (m, 1H), 2.13 -1.99 (m, 4H), 1.67 -1.58 (m, 3H), 1.54 -1.48 (m, 2H). MS (m/z): 560.6
177
MS (m/z): 460.5
178
MS (m/z): 486.6
Compuesto número
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
179
imagen220 RMN 1H (400 MHz, D6 DMSO) ppm: 9.30 (s, 2H), 9.06 (s, 1H), 8.20 (s, 1H), 7.93 (d, J =7.9 Hz, 1H), 7.35 (q, J = 6.4 Hz, 1H), 7.15 -7.05 (m, 2H), 7.03 (app t, J = 6.9 Hz,1H), 6.88 (d, J = 7.2 Hz, 1H), 5.19 (dd, J= 7.0, 2.2 Hz, 1H), 3.99 (app d, J = 6.9 Hz, 1H), 3.66 (m, 1H), 3.10 (s, 6H), 2.51 -2.43 (m, 1H), 2.23 -2.03 (m, 2H), 2.01 1.99 (m, 1H). MS (m/z): 361.4
180
MS (m/z): 363.4
181
imagen221 RMN 1H (400 MHz, D6 acetona) ppm: 8.45 (s, 1H), 8.28 (d, J = 6.7 Hz, 1H), 7.64 -7.58 (m, 2H), 7.38 (app q, J = 6.9 Hz, 1H), 7.29 (br s, 1H), 7.21 (d, J = 7.3 Hz, 1H), 7.19 (d, J = 6.9 Hz, 1H), 7.02 -6.97 (m, 2H), 5.34 (dd, J= 6.8, 2.49 Hz, 1H), 4.22 -4.17 (m, 1H), 4.08 (app t, J = 8.4 Hz, 4H), 3.82 (app q, J = 6.4 Hz, 1H), 2.62 -2.57 (m, 1H), 2.48 (app t, J = 8.4 Hz, 4H), 2.21 -2.10 (m, 2H), 2.03 -1.99 (m, 1H). MS (m/z): 457.5
182
imagen222 MS (m/z): 444.5
183
MS (m/z): 500.6
Compuesto número
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
184
RMN 1H (400 MHz, D6 acetona) ppm: 8.51 (s, 1H), 8.38 (d, J = 6.4 Hz, 1H), 7.54 (br s, 1H), 7.42 (app q, J = 6.3 Hz, 1H),7.28 (d, J = 6.9 Hz, 1H), 7.02 (dt, J = 6.7, 1.6 Hz, 1H), 6.92 (d, J = 6.9 Hz, 1H), 5.82 (br s, 2H), 5.37 (dd, J= 6.0, 1.5 Hz, 1H), 4.88 -4.77 (m, 1H), 4.32 -4.26 (m, 2H), 3.92 (app q, J = 7.4 Hz, 4H), 3.42 (app dt, J = 6.8, 1.9 Hz, 1H), 2.68 -2.63 (m, 1H), 2.38 -2.22 (m, 2H), 2.06 -2.02 (m, 1H), 2.00 -1.97 (m, 1H), 1.64 -1.55 (m, 2H). MS (m/z): 502.6
185
MS (m/z): 516.6
186
MS (m/z): 558.7
187
imagen223 RMN 1H (400 MHz, D3 acetonitrilo) ppm: 8.28 (s, 1H), 8.08 (s, 1H), 7.54 (br s, 1H), 7.38 (app q, J = 6.8 Hz, 1H), 7.35 7.26 (m, 2H), 7.18 (d, J = 6.9 Hz, 1H), 7.10 (d, J = 6.9 Hz, 1H), 7.00 (dt, J = 7.2, 1.9 Hz, 1H), 6.82 (d, J = 6.9 Hz, 1H), 5.22 (dd, J = 6.4, 1.7 Hz, 1H), 4.08 -4.02 (m, 1H), 3.76 (app q, J = 7.0 Hz, 1H), 3.68 -3.62 (m, 4H), 3.59 -3.54 (m, 4H), 2.60 -2.48 (m, 1H), 2.38 -2.22 (m, 2H), 2.14 -2.02 (m, 1H), 1.97 (s, 3H). MS (m/z): 486.6
188
MS (m/z): 514.7
189
MS (m/z): 540.5
Compuesto número
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
190
imagen224 RMN 1H (400 MHz, D6 DMSO) ppm: 8.38 (s, 1H), 8.04 (d, J = 7.5 Hz, 1H), 7.56 (br s, 1H), 7.39 (app q, J = 7.2 Hz, 1H), 7.23 (d, J = 7.7 Hz, 1H), 7.17 -7.11 (m, 2H), 7.05 (t, J = 7.9 Hz, 1H), 6.98 (d, J = 7.9 Hz, 1H), 6.90 (br d, J = 8.2 Hz, 1H), 5.22 (dd, J = 7.4, 2.2 Hz, 1H), 4.03 -4.01 (m, 1H), 3.71 (br s, 2H), 3.21 (app t, J = 5.6 Hz, 1H), 2.90 (s, 3H), 2.56 -2.42 (s, 6H), 2.28 -2.12 (m, 2H), 2.04 -1.90 (m, 2H). MS (m/z): 522.6
191
MS (m/z): 592.7
192
imagen225 RMN 1H (400 MHz, D3 acetonitrilo) ppm: 8.12 (s, 1H), 7.75 (d, J = 7.5 Hz, 1H), 7.60 (br s, 1H), 7.49 (t, J = 7.0 Hz, 1H), 7.36 (app q, J = 7.4 Hz, 1H), 7.18 (d, J = 7.2 Hz, 1H), 7.11 (d, J = 7.8 Hz, 1H), 6.98 (t, J = 7.7 Hz, 1H), 6.76 (dt, J = 7.2, 1.1 Hz, 1H), 6.67 (d, J = 6.9 Hz, 1H), 5.16 (dd, J=7.8, 2.2 Hz, 1H), 4.18 (br s, 2H), 3.93 (p, J = 3.8 Hz, 1H), 3.67 3.57 (m, 8H), 3.42 -3.38 (m, 1H), 2.52 -2.45 (m, 1H), 2.18 -2.06 (m, 2H), 1.92 -1.88 (m, 1H). MS (m/z): 502.6
193
MS (m/z): 502.6
194
MS (m/z): 441.5
195
imagen226 RMN 1H (400 MHz, D6 acetona) ppm: 8.32 (s, 1H), 8.14 (d, J = 7.6 Hz, 1H), 7.55 -7.46 (m, 1H), 7.41 (app q, J = 7.4 Hz, 1H), 7.41 (app q, J = 5.4 Hz, 1H), 7.21 -7.11 (m, 2H), 7.03 (d, J = 7.6 Hz, 1H), 6.88 (t, J = 7.7 Hz, 1H), 6.42 (d, J = 7.2 Hz, 1H), 5.18 (d, J = 5.6 Hz, 1H), 4.10 -4.00 (m, 2H), 3.70 -3.59 (m, 3H), 3.38 -3.04 (m, 8H), 2.50 -2.40 (m, 2H), 2.06 -1.99 (m, 2H), 2.18 -2.06 (m, 2H), 1.42 (t, J = 6.0 Hz, 4H). MS (m/z): 500.6
Compuesto número
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
196
MS (m/z): 498.6
197
MS (m/z): 458.5
198
imagen227 RMN 1H (400 MHz, D6 acetona) ppm: 8.28 (d, J = 7.1 Hz, 1H), 8.04 (s, 1H), 7.42 (app q, J = 7.8 Hz, 1H), 7.38 (br s, 1H), 7.28 (d, J = 7.4 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 6.94 (t, J = 7.7 Hz, 1H), 6.42 (d, J = 6.4 Hz, 1H), 5.28 (d, J = 6.6 Hz, 1H), 4.18 -4.04 (m, 2H), 3.98 (app d, J = 6.8 Hz, 1H), 3.88 -3.62 (m, 4H), 3.48 -3.42 (m, 1H), 2.92 (s, 3H), 2.77 -2.70 (m, 1H), 2.67 -2.56 (m, 1H), 2.32 -2.26 (m, 2H), 2.18 -2.09 (m, 1H). MS (m/z): 458.5
199
imagen228 RMN 1H (400 MHz, D6 acetona) ppm: 9.43 -9.02 (br s, 2H), 8.48 (br s, 1H), 8.35 (s, 1H), 8.56( s, 1H), 7.42 (app q, J = 7.8 Hz, 1H), 7.31 (d, J = 5.6 Hz, 1H), 7.20 (d, J = 7.4 Hz, 1H), 7.02 (dt, J = 8.4, 1.9 Hz, 1H), 6.92 (br d, J = 4.5 Hz, 1H), 5.35 (d, J = 4.6 Hz, 1H), 4.20 (app d, J = 4.9 Hz, 1H), 3.98 (app t, J = 6.8 Hz, 1H), 3.58 -3.52 (m, 1H), 3.08 -2.98 (m, 3H), 2.82 (s, 3H), 2.71 -2.60 (m, 1H), 2.38 (app d, J = 6.8 Hz, 2H), 2.27 -2.18 (m, 2H), 2.32 -2.26 (m, 2H), 1.88 -1.69 (m, 2H). MS (m/z): 472.6
200
MS (m/z): 546.6
Compuesto número
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
201
MS (m/z): 532.6
202
MS (m/z): 500.6
203
imagen229 RMN 1H (400 MHz, D6 acetona) ppm: 8.28 (br s, 1H), 8.15 (d, J = 7.8 Hz, 1H), 7.56 (br s, 2H), 7.46 (app q, J = 7.8 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.30 (br s, 1H),7.18 (d, J = 7.6 Hz, 1H), 7.04 (dt, J = 7.4, 1.9 Hz, 1H), 6.42 (br d, J = 6.5 Hz, 1H), 5.25 (d, J = 6.6 Hz, 1H), 4.20 (app d, J = 5.9 Hz, 2H), 4.12 -4.06 (m, 2H), 3.98 (p, J = 6.8 Hz, 1H), 3.78 (app q, J = 8.2 Hz, 1H), 3.52 -3.48 (m, 1H), 2.77 -2.68 (m, 1H), 2.28 -2.18 (m, 2H), 2.02 -1.97(m, 1H). MS (m/z): 459.5
204
imagen230 RMN 1H (400 MHz, D3 acetonitrilo) ppm: 8.29 (br s, 1H), 8.19 (d, J = 6.7 Hz, 1H), 7.52 (br s, 2H), 7.38 (app q, J = 7.3 Hz, 1H), 7.24 (br s, 1H), 7.19 (d, J = 7.2 Hz, 1H), 7.08 (d, J = 7.9 Hz, 1H), 6.94 (dt, J = 7.6, 1.9 Hz, 1H), 6.82 (d, J = 5.5 Hz, 1H), 5.23 (d, J = 6.9 Hz, 1H), 4.52 (app br d, J = 7.9 Hz, 2H), 4.04 -3.99 (m, 1H), 3.78 (q, J = 6.9 Hz, 1H), 3.69 -3.62 (m, 1H), 3.33 -3.21 (m, 2H), 3.09 -3.02 (m, 2H), 2.83 (app t, J = 8.0 Hz, 2H), 2.77 -2.50 (m, 6H), 2.28 -2.08 (m, 4H), 1.84 -1.74 (m, 2H). MS (m/z): 512.6
205
MS (m/z): 560.7
Compuesto número
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
206
MS (m/z): 554.6
207
imagen231 RMN 1H (400 MHz, D3 acetonitrilo) ppm: 8.32 (br s, 1H), 8.21 (s, 1H), 8.02 (d, J = 7.4 Hz, 1H), 7.76 (br s, 1H), 7.38 (app t, J = 2.3 Hz, 1H), 7.26 (app q, J = 7.2 Hz, 1H), 7.04 6.97 (m, 2H), 6.92 (d, J = 7.6 Hz, 1H), 6.52 (d, J = 6.5 Hz, 1H), 5.15 (d, J = 6.6 Hz, 1H), 4.78 (dt, J = 6.9, 1.9 Hz, 1H), 3.91 -3.79 (m, 1H), 3.58 (q, J = 6.8 Hz, 1H), 3.34 (app d, J = 8.2 Hz, 1H), 3.03 (br q, J = 4.5 Hz, 1H), 2.78 (s, 3H), 2.67 -2.48 (m, 4H), 2.28 -2.08 (m, 4H), 1.82 -1.73 (m, 2H). MS (m/z): 472.6
208
MS (m/z): 546.6
209
MS (m/z): 445.5
210
MS (m/z): 532.6
211
MS (m/z): 550.7
Compuesto número
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
212
MS (m/z): 564.7
213
MS (m/z): 564.7
214
imagen232 RMN 1H (400 MHz, D6 DMSO) ppm: 8.35 (s, 1H), 8.03 (d, J = 8.5 Hz, 1H), 7.54 (br s, 2H), 7.39 (q, J = 7.0 Hz, 1H), 7.21 -7.14 (m, 2H), 7.06 (d, J = 7.0 Hz, 1H), 7.00 (br s, 1H), 6.87 (d, J = 7.8 Hz, 1H), 5.20 (d, J = 6.8 Hz, 1H), 4.08 -4.00 (m, 1H), 3.78 -3.67 (m, 2H), 3.30 -3.26 (m, 1H), 2.67 (q, J = 7.0 Hz, 2H), 2.62 -2.54 (m, 6H), 2.42 -2.35 (m, 1H), 2.08 -2.00 (m, 2H), 1.92 -1.88 (m, 1H), 1.25 (t, J = 7.4 Hz, 3H). MS (m/z): 536.6
215
MS (m/z): 458.5
216
MS (m/z): 472.6
217
imagen233 RMN 1H (400 MHz, D6 DMSO) ppm: 8.20 (br s, 1H), 8.04 (d, J = 7.8 Hz, 1H), 7.48 (br s, 1H), 7.38(app q, J = 6.3 Hz, 1H), 7.22 (d, J = 7.2 Hz, 1H), 7.13 (d, J = 8.2 Hz,1H), 7.04 (d, J = 6.7 Hz, 1H), 6.92 (dt, J = 7.6, 1.9 Hz, 1H), 6.42 (d, J = 7.5 Hz, 1H), 5.25 (d, J = 6.1 Hz, 1H), 4.18 -4.04 (m, 3H), 3.92 (dd, 10.1, 6.7 Hz, 1H), 3.78 (q, J = 6.8 Hz, 1H), 3.72 (q, J = 5.8 Hz, 1H), 3.48 (app d, J = 7.2 Hz, 1H), 2.92 (s, 2H), 2.72 -2.64 (m, 1H), 2.58 -2.53 (m, 2H), 2.21 -2.17 (m, 2H), 2.05 -1.98 (m, 1H). MS (m/z): 526.5
Compuesto número
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
218
MS (m/z): 544.6
219
imagen234 MS (m/z): 544.6
220
imagen235 MS (m/z): 502.6
221
MS (m/z): 472.5
222
MS (m/z): 502.6
223
imagen236 MS (m/z): 526.7
Compuesto número
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
224
MS (m/z): 500.6
225
imagen237 RMN 1H (400 MHz, D6 DMSO) ppm: 8.34 (s, 1H), 8.04 (br d, J = 6.4 Hz, 1H), 7.46 (br s, 2H), 7.38 (q, J = 7.6 Hz, 1H), 7.24 (s, 1H), 7.18 -7.10 (m, 2H), 7.05 (t, J = 6.7 Hz, 1H), 6.82 (d, J = 6.8 Hz, 1H), 5.21 (d, J= 6.5 Hz, 1H), 4.05 4.02 (m, 2H), 3.70 (q, J = 5.6 Hz, 1H), 3.56 (app q, J = 6.2 Hz, 1H), 2.82 -2.72 (m, 2H), 2.54 -2.44 (m, 1H), 2.08 2.04 (m, 2H), 1.90 -1.82 (m, 1H), 1.38 -1.35 (m, 4H), 0.95 (s, 6H). MS (m/z): 471.6
226
MS (m/z): 471.6
227
MS (m/z): 564.6
228
MS (m/z): 572.6
229
MS (m/z): 558.6
Compuesto número
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
230
imagen238 RMN 1H (400 MHz, D3 acetonitrilo) ppm: 8.20 (s, 1H), 8.00 (br d, J = 6.4 Hz, 1H), 7.40 (br s, 2H), 7.30 (q, J = 7.6 Hz, 1H), 7.04 (d, J= 6.9 Hz, 1H), 6.95 (app d, J = 7.7 Hz, 2H), 6.92 (dt, J = 6.9, 1.2 Hz, 1H), 6.62 (d, J = 6.2 Hz, 1H), 5.03 (dd, J= 6.5, 1.2 Hz, 1H), 4.45 -4.40 (m, 2H), 3.98 -3.90 (m, 1H), 3.62 (app q, J = 6.9 Hz, 1H), 3.22 (app t, 1H), 2.80 (app t, J = 6.0 Hz, 1H), 2.62 -2.52 (m, 2H), 2.48 2.38 (m, 3H), 2.05 -1.99 (m, 3H), 1.69 -1.67 (m, 1H). MS (m/z): 492.6
231
MS (m/z): 579.7
232
MS (m/z): 500.6
233
MS (m/z): 516.6
234
MS (m/z): 530.6
235
MS (m/z): 501.6
Compuesto número
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
236
imagen239 RMN 1H (400 MHz, D3 acetonitrilo) ppm: 8.18 (s, 1H), 7.92 (br s, 2H), 7.38 (br s, 2H), 7.28 (app q, J = 7.0 Hz, 1H), 7.08 (s, 1H), 7.02 (d, J = 7.3 Hz, 1H), 6.83 (app t, J = 7.2 Hz, 1H), 6.72 (d, J = 7.6 Hz, 1H), 5.08 (d, J = 6.9 Hz, 1H), 3.95 -3.81 (m, 3H), 3.62 (app q, J = 6.2 Hz, 1H), 3.52 (t, J = 4.8 Hz, 1H), 3.22 (app t, J = 5.0 Hz, 2H), 2.55 -2.43 (m, 1H), 2.09 -1.99(m, 2H), 1.88 -1.80 (m, 1H), 1.67 (br s, 1H), 1.50 -1.45 (m, 2H), 1.38 (q, J = 5.9 Hz, 2H), 0.80 (t, J= 5.0 Hz, 3H). MS (m/z): 487.6
237
MS (m/z): 501.6
238
MS (m/z): 485.6
239
MS (m/z): 473.6
240
RMN 1H (400 MHz, D6 acetona) ppm: 8.51 (br s, 1H), 8.41 (d, J = 8.8 Hz, 1H), 7.68 -7.52 (m, 2H), 7.48 (br s, 1H), 7.38 (app q, J = 7.5 Hz, 1H), 7.20 (d, J = 7.2 Hz,1H), 7.14 (d, J = 7.8 Hz, 1H), 6.94 (app dt, J = 7.8, 1.9 Hz, 1H), 6.90 (d, J = 5.6 Hz, 1H), 5.38 (d, J = 6.4 Hz, 1H), 5.05 (dd, J = 5.4 Hz, 1.7 Hz, 1H), 4.72 (app t, J = 7.2 Hz, 1H), 4.22 (d, J = 4.2 Hz, 2H), 4.18 (app q, J = 6.0 Hz, 1H), 4.05 (br s, 1H), 3.98 -3.62 (m, 3H), 3.48 -3.40 (m, 2H), 3.28 -3.22 (m, 1H), 3.18 -3.00 (m, 1H), 2.65 -2.59 (m, 1H), 2.39 -1.99 (m, 5H). MS (m/z): 484.6
Compuesto número
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
241
MS (m/z): 541.6
242
MS (m/z): 558.6
243
imagen240 RMN 1H (400 MHz, D6 acetona) ppm: 8.21 (br s, 1H), 7.98 -7.82 (m, 2H), 7.45 (app q, J = 6.5 Hz, 2H), 7.40 (app q, J = 6.2 Hz, 1H), 7.22 (d, J = 6.8 Hz, 1H), 7.15 (app d, J = 7.8 Hz, 1H), 6.94 (dt, J = 8.6, 1.9 Hz, 1H), 6.90 (br s, 1H), 6.42 (d, J = 6.2 Hz, 1H), 5.22 (d, J = 6.4 Hz, 1H), 4.54 (app p, J = 6.2 Hz, 1H), 4.22 (app q, J = 5.6 Hz, 2H), 3.78 (q, J = 6.8 Hz, 1H), 3.68 -3.62 (m, 1H), 3.58 -3.53 (m, 1H), 3.42 (dd, J = 4.8, 1.6 Hz, 1H), 3.21 (app t, J = 7.2 Hz, 2H), 2.62 2.56 (m, 1H), 2.31 -2.25 (m, 1H), 2.18 -1.99 (m, 3H), 1.42 (d, J = 5.4 Hz, 3H). MS (m/z): 516.6
244
MS (m/z): 512.5
245
MS (m/z): 472.6
Compuesto número
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
246
imagen241 RMN 1H (400 MHz, D3 acetonitrilo) ppm: 8.56 (br s, 1H), 8.24 (d, J = 7.2 Hz, 1H), 8.18 (app d, J = 6.5 Hz, 2H), 7.95 (d, J = 6.2 Hz, 1H), 7.88 (br s, 1H), 7.78 (s, 1H), 7.52 (d, J = 6.4 Hz, 1H), 7.38 (app q, J = 6.8 Hz, 1H), 7.28 (br s, 1H), 7.22 (d, J = 7.2 Hz, 1H), 7.09 (d, J = 8.2 Hz, 1H), 6.92 (dt, J = 8.6, 1.9 Hz, 1H), 5.22 (dd, J = 6.9, 1.9 Hz, 1H), 4.51 (app d, J = 10 Hz, 2H), 4.02 (app q, J = 3.6 Hz, 1H), 3.78 (q, J = 6.8 Hz, 1H), 3.48 (t, J = 5.8 Hz, 1H), 3.21 (app t, J = 7.2 Hz, 2H), 2.82 (s, 6H), 2.37 -2.25 (m, 2H), 2.18 -2.03 (m, 2H), 1.97 -1.86 (m, 4H) MS (m/z): 563.7
247
MS (m/z): 612.6
248
MS (m/z): 570.6
249
MS (m/z): 549.7
250
imagen242 MS (m/z): 453.5
Compuesto número
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
251
imagen243 RMN 1H (400 MHz, D3 acetonitrilo) ppm: 8.61 (br s, 1H), 8.14 (d, J = 7.7 Hz, 1H), 7.62 (br s, 1H), 7.58 (s, 1H), 7.42 (app q, J = 7.8 Hz, 1H), 7.34 -7.29 (m, 1H), 7.26 (d, J = 7.4 Hz, 1H), 7.17 (d, J = 7.2 Hz, 1H), 7.02 (t, J = 8.2 Hz, 1H), 6.72 (d, J = 7.6 Hz, 1H), 5.27 (dd, J = 7.9,1.9 Hz, 1H), 4.54 (p, J = 7.6 Hz, 1H), 4.17 (app q, J = 6.6 Hz, 1H), 3.82 (q, J = 6.8 Hz, 1H), 2.77 -2.67 (m, 1H), 2.48 -2.35 (m, 2H), 2.38 -2.06 (m, 5H), 1.97 -1.82 (m, 2H) MS (m/z): 429.5
252
MS (m/z): 415.5
253
MS (m/z): 575.7
254
MS (m/z): 534.6
255
MS (m/z): 521.6
256
imagen244 RMN 1H (400 MHz, D3 acetonitrilo) ppm: 8.38 (br s, 2H), 7.58 (s, 1H), 7.42 (q, J = 7.7 Hz, 1H), 7.39 (d, J = 6.7 Hz, 1H), 7.39 -7.31 (m, 4H), 7.28 (br s, 1H), 7.22 (d, J = 6.2 Hz, 1H), 7.12 (d, J = 7.6 Hz, 1H), 6.98 (t, J = 7.2 Hz, 1H), 6.88 (d, J = 7.2 Hz, 1H), 5.27 (d, J = 7.2 Hz, 1H), 4.22 4.15 (m, 1H), 4.12 -4.00 (m, 4H), 3.82 (app q, J = 6.7 Hz, 1H), 3.71 -3.59 (m, 4H), 2.67 -2.59 (m, 1H), 2.28 -2.19 (m, 2H), 2.08 -2.00 (m, 1H). MS (m/z): 521.6
Compuesto número
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
257
MS (m/z): 538.6
258
imagen245 MS (m/z): 535.6
259
MS (m/z): 589.6
260
imagen246 RMN 1H (400 MHz, D3 acetonitrilo) ppm: 8.35 (br s, 1H), 8.18 (app t, J = 4.5 Hz, 1H), 7.80 -7.67 (m, 1H), 7.62 (app t, J = 6.7 Hz, 2H), 7.55 (q, J = 6.2 Hz, 1H), 7.35 (br s, 1H), 7.28 (d, J = 7.6 Hz, 1H), 7.22 (d, J = 7.5 Hz, 1H), 7.15 (app t, J = 8.2 Hz, 2H), 7.08 (dt, J = 7.2, 1.9 Hz, 1H), 6.95 (d, J = 6.9 Hz, 1H), 6.85 -6.78 (m, 1H), 5.37 (d, J = 6.2 Hz, 1H), 4.32 (br s, 2H), 4.25 -4.11 (m, 4H), 3.82 (s, 3H), 3.62 -3.43 (m, 4H), 2.62 -2.54 (m, 1H), 2.25 2.14 (m, 2H), 2.08 -2.00 (m, 1H). MS (m/z): 591.7
261
MS (m/z): 516.5
262
MS (m/z): 403.4
Compuesto número
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
263
MS (m/z): 403.4
264
MS (m/z): 473.6
265
imagen247 MS (m/z): 461.5
266
MS (m/z): 473.6
267
imagen248 RMN 1H 400 MHz (DMSO -d6) 7.983 (s, 1H) 7.822 (d, J = 0.024, 1H) 7.459 -7.281 (m, 3H) 7.101 -7.081 (m, 2H), 6.966 (dt, J = 0.021, 0.005, 1H), 6.726 (brs, 1H) 6.272 (d, J = 0.021, 1H) 5.118 -5.098 (m, 2H), 3.976 -3.901 (m, 2H) 3.591 (q, J = 0.021, 1H), 3.522 (dd, J = 0.027, 0.009, 2H), 2.380 (m, 1H) 1.969 -1.921 (m, 3H), 1.818 1.787 (m, 2H), 1.166 (m, 2H) MS (m/z): 461.5
268
imagen249 RMN 1H 400 MHz (DMSO -d6) 7.981 (s, 1H), 7.823 (d, J = 0.025, 1H), 7.461 -7.282 (m, 3H) 7.101 (m, 2H), 6.991 (dt, J = 0.022, 0.005, 1H), 6.725 (brs, 1H) 6.272 (d, J = 0.021, 1H), 5.119 (m, 2H), 3.977 -3.901(m, 2H), 3.614 (q, J = 0.021, 1H), 3.516 (dd, J = 0.028, 0.009, 2H), 2.380 (m, 1H), 2.001 -1.921 (m, 3H), 1.831 -1.792 (m, 2H), 1.167 (m, 2H) MS (m/z): 461.5
Compuesto número
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
269
MS (m/z): 432.5
270
imagen250 RMN 1H 400 MHz (DMSO -d6) 8.019 (s, 1H), 7.828 (d, J = 0.025, 1H), 7.507 -7.282 (m, 3H), 7.105 -7.081 (m, 2H), 6.988 -6.943 (m, 1H) 6.725 (brs, 1H) 6.356 (d, J = 0.021, 1H), 5.111 -5.091 (m, 1H), 4.483 (p, J = 0.019, 1H), 3.952 -3.900 (m, 1H), 3.649 -3.572(m,1H), 3.441 -3.400 (m, 1H), 3.359 -3.305 (m, 2H), 2.921 (s, 3H), 2.714 (s, 3H), 2.170 -2.041 (m, 2H) 2.002, 1.929(m, 2H), 1.832 -1.771 (m, 1H) MS (m/z): 536.6
271
MS (m/z): 461.5
272
MS (m/z): 500.6
273
MS (m/z): 516.6
274
imagen251 MS (m/z): 479.5
Compuesto número
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
275
MS (m/z): 514.6
276
MS (m/z): 530.6
277
MS (m/z): 522.6
278
MS (m/z): 550.7
279
RMN 1H 400 MHz (DMSO -d6) 7.981 (s, 1H), 7.829 (d, J = 0.024, 1H), 7.741 (d, J = 0.02, 1H), 7.475 -7.217 (m, 3H), 7.098 -7.078 (m, 2H), 6.990 (dt, J = 0.022, 0.005, 1H), MS (m/z): 500.6
280
imagen252 RMN 1H 400 MHz (DMSO -d6) 8.041 (s, 1H), 7.902 (d, J = 0.025, 1H), 7.476 -7.265 (m, 3H), 7.169 (d, J = 0.02, 2H), 7.055, (t, J = 0.02, 1H), 6.824 (brs, 1H), 6.763 (d, J = 0.022, 1H), 5.177 (d, J = 0.20, 1H), 4.341 (d, J = 0.033, 1H), 4.248 (d, J = 0.031, 1H), 4.018 -3.967 (m, 1H), 3.701 (q, J = 0.021, 1H), 3.207 -3.133 (m, 1H), 2.878 (t, J = 0.021, 1H), 2.070 -1.998 (m, 3H), 1.888 -1.830(m, 2H), 1.477 -1.292 (m, 3H), 0.988 (d, J = 0.016, 3H) MS (m/z): 473.6
Compuesto número
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
281
MS (m/z): 444.5
282
MS (m/z): 540.5
283
imagen253 RMN 1H 400 MHz (DMSO -d6) 8.061 (s, 1H), 7.871 d, J = 0.019, 1H), 7.386 -7.287 (m, 3H), 7.102 7.081 (m, 2H), 6.992 (dt, J = 0.019, 0.004, 1H), 6.831 (brs, 1H), 6.343 (d, J = 0.023, 1H), 5.122 (dd, J = 0.02, 0.006, 1H), 4.108 -3.908 (m, 2H), 3.713 (dd, J = 0.026, 0.010, 1H), 3.638 (q, J = 0.020, 1H), 3.536 -3.478 (m, 1H), 3.375 (q, J = 0.018, 1H), 3.313 (dd, J = 0.027, 0.014, 1H), 2.409 2.359 (m, 1H), 2.223 (sexteto, J = 0.015, 1H), 2.009 1.776 (m, 4H) MS (m/z): 522.6
284
imagen254 RMN 1H 400 MHz (DMSO -d6) 8.047 (d, J = 0.038, 1H), 7.893 (d, J = 0.025, 1H), 7.571 -7.355 (m, 3H), 7.170 7.149 (m, 2H), 7.059 (dt, J = 0.019, 0.004, 1H), 6.802 (brs, 1H), 6.413 (t, J = 0.022, 1H), 5.182 (dd, J = 0.02, 0.006, 1H), 4.879 (p, J = 0.020, 1H), 4.622 (p, J = 0.020, 1H), 4.059 -3.967 (m, 1H), 3.699 -3.636 (m, 3H), 3.392 -3.23 (m, 2H), 2.209 -1.994 (m, 7H), 1.90 -1.818 (m, 1H), 1.196 -1.135(m, 2H), 1.079 (t, J = 0.017, 2H) MS (m/z): 514.6
285
MS (m/z): 522.6
Compuesto número
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
286
imagen255 RMN 1H 400 MHz (DMSO -d6) 7.969 (s, 1H), 7.815 (d, J = 0.024, 1H), 7.397 -7.279(m, 3H), 7.096 7.069 (m, 2H), 6.984 (dt, J = 0.022, 0.006, 1H), 6.738 (brs, 1H), 6.256 (d, J = 0.022, 1H), 5.111 (dd, J = 0.020, 0.006, 1H), 3.946 -3.895 (m, 1H), 3.628 (q, J = 0.021, 1H), 3.515 -3.439 (m, 3H), 3.374 -3.314(m, 1H), 3.047 (q, J = 0.017, 1H), 2.405 -2.355(m, 1H), 2.018 -1.922 (m, 3H), 1.827 1.766 (m, 3H), 1.666 (sexteto, J = 0.016, 1H) MS (m/z): 444.5
287
MS (m/z): 529.6
288
MS (m/z): 458.5
289
MS (m/z): 558.6
290
MS (m/z): 516.6
291
MS (m/z): 501.6
Compuesto número
Estructura Datos físicos RMN 1H 400 MHz (DMSO-d6) y/o MS (m/z)
292
MS (m/z): 515.6
293
MS (m/z): 543.7
294
MS (m/z): 557.6
295
MS (m/z): 571.7
296
MS (m/z): 514.6
297
RMN 1H 400 MHz (DMSO -d6) 8.472 (s, 1H), 8.165 (d, J = 0.019, 1H), 8.003 -7.976 (m, 2H), 7.888 (brs, 1H), 7.630 7.600 (m, 2H), 7.376 (q, J = 0.019, 1H), 7.148 (d, J = 0.019, 2H), 7.010 (t, J = 0.019, 2H), 5.496 (brs, 2H), 5.160 (d, J = 0.017, 1H), 4.148 (d, J = 0.007, 2H), 7.007 -3.953 (m, 1H), 3.806 (d, J = 0.022, 3H), 3.674 -3.582 (m, 4H), 2.031 -1.958 (m, 2H), 1.854 -1.819 (m, 1H) MS (m/z): 538.6
Ensayos
imagen256
imagen257
imagen258
imagen259

Claims (5)

  1. imagen1
    imagen2
    imagen3
    imagen4
    imagen5
    imagen6
    imagen7
    imagen8
    imagen9
    imagen10
    1-(6-(6-(3-(3-fluorofenil)morfolino)imidazo[1,2-b]piridazin-3-il)piridin-2-il)piperidin-4-carboxamida; 6-(6-(2-(3-fluorofenil)pirrolidin-1-il)imidazo[1,2-b]piridazin-3-il)piridin-2-ol; ácido 6-(6-(2-(3-fluorofenil)pirrolidin-1-il)imidazo[1,2-b]piridazin-3-il)picolínico; 2-fluoro-3-(6-(2-(3-fluorofenil)pirrolidin-1-il)imidazo[1,2-b] piridazin-3-il)quinolina; 3-(6-(2-(3-fluorofenil)pirrolidin-1-il)imidazo[1,2-b]piridazin-3-il)quinolin-2(1H)-ona; 5-(6-(2-(3-fluorofenil)pirrolidin-1-il)imidazo[1,2-b]piridazin-3-il)quinolina; 6-(2-(3-fluorofenil)pirrolidin-1-il)-3-(4-(metilsulfonil)fenil) imidazo[1,2-b]piridazina; 6-(2-(3-fluorofenil)pirrolidin-1-il)-3-(6-(piperidin-4-iloxi)piridin-2-il)imidazo[1,2-b]piridazina; (1-(6-(6-(2-(3-fluorofenil)pirrolidin-1-il)imidazo[1,2-b]piridazin-3-il)piridin-2-ilamino)ciclopentil)metanol; 3-(3-fluorofenil)-4-(3-(6-(4-(1-metilpiperidin-4-il)piperazin-1-il)piridin-2-il)imidazo[1,2-b]piridazin-6-il)morfolina; 3-(6-(2-(3-fluorofenil)pirrolidin-1-il)imidazo[1,2-b]piridazin-3-il)quinolina; (6-(6-(2-(3-fluorofenil)pirrolidin-1-il)imidazo[1,2-b]piridazin-3-il)piridin-2-il)(4-hidroxipiperidin-1-il)metanona; 6-(2-(3-fluorofenil)pirrolidin-1-il)-3-(2-fluoropiridin-4-il)imidazo[1,2-b]piridazina; 1-(4-(6-(2-(3-fluorofenil)pirrolidin-1-il)imidazo[1,2-b]piridazin-3-il)piridin-2-il)piperidin-4-ol; N1,N1-dietil-N2-(6-(6-(2-(3-fluorofenil) piperidin-1-il)imidazo[1,2-b]piridazin-3-il)piridin-2-il)etano-1,2-diamina; 6-(2-(3-fluorofenil)piperidin-1-il)-3-(6-(4-isopropil-piperazin-1-il)piridin-2-il)imidazo[1,2-b]piridazina; (3S)-1-(6-(6-(2-(3-fluorofenil)piperidin-1-il)imidazo[1,2-b]piridazin-3-il) piridin-2-il)-N,N-dimetilpirrolidin-3-amina; 4-(3-(6-(2,5-diazabiciclo[2.2.1]heptan-2-il)piridin-2-il)imidazo[1,2-b]piridazin-6-il)-3-(3-fluorofenil)morfolina; 6-(6-(3-(3-fluorofenil)morfolino)imidazo[1,2-b]piridazin-3-il)-N-(2-(piperazin-1-il)etil)piridin-2-amina; 6-(2-(3-fluorofenil)pirrolidin-1-il)-3-(6-(1-(metilsulfonil)piperidin-4-iloxi)piridin-2-il)imidazo[1,2-b]piridazina; 5-(6-(2-(2,5-difluorofenil)pirrolidin-1-il)imidazo[1,2-a]piridin-3-il)-2-fluorobenzonitrilo; ácido 4-(6-(2-(3-fluorofenil)pirrolidin-1-il) imidazo[1,2-b]piridazin-3-il)picolínico; ácido 5-(6-(2-(3-fluorofenil)pirrolidin-1-il)imidazo[1,2-b]piridazin-3-il)picolínico; (2S,6R)-4-(6-(6-(2-(3-fluorofenil)pirrolidin-1-il)imidazo[1,2-b]piridazin-3-il)piridin-2-il)-2,6-dimetilmofolina; 6-(6-(2-(3-fluorofenil)piperidin-1-il)imidazo[1,2-b]piridazin-3-il)-N-metilpiridin-2-amina; 6-(6-(2-(3-fluorofenil)piperidin-1-il)imidazo [1,2-b]piridazin-3-il)-N-isopropilpiridin-2-amina; N-(6-(6-(2-(3-fluorofenil)piperidin-1-il)imidazo[1,2-b]piridazin-3-il)piridin-2-il)metanosulfonamida; 6-(6-(2-(3-fluorofenil)piperidin-1-il)imidazo[1,2-b]piridazin-3-il)-N,N-dimetilpiridin-2-amina; 6-(2-(3-fluorofenil)piperidin-1-il)-3-(6-(piperidin-4-iloxi)piridin-2-il)imidazo[1,2-b]piridazina; ácido 1-(6-(6-(2-(3-fluorofenil)pirrolidin-1-il)imidazo[1,2-b]piridazin-3-il)piridin-2-il)azetidin-3-carboxílico; 1-(6-(6-(2-(3-fluorofenil)pirrolidin-1-il)imidazo[1,2-b] piridazin-3-il)piridin-2-il)azetidin-3-ol;
    192
    imagen11
    imagen12
    imagen13
    imagen14
    (3R)-1-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)-3-metilpiperazina;
    2-[(2R)-4-(6-{6-[(2R)-2-(3-fluorofenil) pirrolidin-1-il] imidazo[1,2-b]piridazin-3-il}piridin-2-il)-2-metilpiperazin-1-il]-2-oxoetil
    acetato; 1-[(2R)-4-(6-{6-[(2R) -2-(3-fluorofenil) pirrolidin-1-il] imidazo[1,2-b]piridazin-3-il}piridin-2-il)-2-metilpiperazin-1-il]-2-hidroxietan-1-ona;
    2-amino-1-[4-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)piperazin-1-il]etan-1-ona;
    1-[4-(6-{6-[(2R) -2-(3-fluorofenil) pirrolidin-1-il] imidazo [1,2-b]piridazin-3-il}piridin-2-il)piperazin-1-il]-2-(metilamino)etan-1ona; 2-(dimetil-amino)-1-[(2R)-4-(6-{6-[(2R)-2-(3-fluorofenil) pirrolidin-1-il] imidazo [1,2-b] piridazin -3-il} piridin-2-il) -2-metil
    piperazin-1-il]etan-1-ona; (3R)-3-{[4-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)piperazin-1-il]carbonil} morfolina; (3R) -3-{[(2R)-4-(6-{6-[(2R)-2-(3-fluorofenil) pirrolidin-1-il] imidazo [1,2-b] piridazin-3-il} piridin-2-il) -2-metilpiperazin-1-il]
    carbonil}morfolina; 8-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)-octahidro-piperazin[2,1-c]morfolin-4-ona; (3R,4R)-1-[4-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)piridin-2-il]pirrolidin-3,4-diol; 1-(6-{6-[2-(3-fluorofenil)piperidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)piperidin-4-ol; 6-{6-[2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-carboxamida; 6-{6-[2-(3-fluorofenil)pirrolidin-1-il] imidazo[1,2-b]piridazin-3-il}piridin-2-ol; ácido 6-{6-[2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-carboxílico; 2-fluoro-3-{6-[2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}quinolina; 3-{6-[2-(3-fluorofenil) pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}-1,2-dihidroquinolin-2-ona; 5-{6-[2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b] piridazin-3-il}quinolina; 2-(3-fluorofenil)-1-[3-(4-metanosulfonilfenil)imidazo[1,2-b]piridazin-6-il]pirrolidina; 3-{6-[2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}quinolina; 1-[(6-{6-[2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin -3-il}piridin-2-il)carbonil]piperidin-4-ol; 2-fluoro-4-{6-[2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridina; 1-(4-{6-[2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)piperidin-4-ol; 1-(4-{6-[2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)-4-metilpiperazina; 2-[(4-{6-[2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)amino]etan-1-ol; (3R)-1-[(6-{6-[2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)carbonil]-N,N-dimetilpirrolidin-3-amina;
    1-(5-{6-[2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}pirimidin-2-il)piperidin-4-ol; 6-{6-[2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}-N-metilpiridine-2-carboxamida; 4-[(6-{6-[2-(3-fluorofenil) pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)carbonil]morfolina; (3R)-1-(4-{6-[2-(3-fluorofenil)pirrolidin-1-il]imidazo [1,2-b]piridazin-3-il}piridin-2-il)pirrolidin-3-ol;
    197
    imagen15
    (3R)-1-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)-N-metilpirrolidin-3-amina;
    1-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)-N-metilpiperidin-4-amina;
    2-fluoro-N-[1-(6-{6-[2-(3-fluorofenil) pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)pirrolidin-3-il]-N,2-dimetilpropanamida; 2-fluoro-N-[1-(6-{6-[2-(3-fluorofenil) pirrolidin-1-il] imidazo[1,2-b]piridazin-3-il}piridin-2-il)pirrolidin-3-il]-N-metil-propanami
    da; 1-terc-butil-4-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il} piridin-2-il)piperazina; ácido 1-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)azetidin-3-carboxilico; 2-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}-6-[4-(pirrolidin-1-il)piperidin-1-il]piridina; 2-fluoro-N-[1-(6-{6-[(2R)-2-(3-fluorofenil) pirrolidin-1-il]imidazo [1,2-b] piridazin-3-il} piridin-2-il) piperidin-4-il] -N,2-dimetil
    propanamida;
    2,2,2-trifluoro-N-[(3R)-1-(6-{6-[(2R)-2-(3-fluorofenil) pirrolidin-1-il]imidazo [1,2-b]piridazin-3-il}piridin-2-il) pirrolidin-3-il]-Nmetil-acetamida; 6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}-N-metil-N-(piperidin-4-il)piridin-2-amina; 2-fluoro-N-[(3R)-1-(6-{6-[(2R)-2-(3-fluorofenil) pirrolidin-1-il] imidazo [1,2-b]piridazin-3-il} piridin-2-il) pirrolidin-3-il] -N,2
    dimetilpropanamida; [1-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il) azetidin-3-il]metanol; (3R)-N-(2-fluoro-2-metilpropil)-1-(6-{6-[(2R)-2-(3-fluorofenil) pirrolidin-1-il]imidazo [1,2-b]piridazin-3-il} piridin-2-il)-N-metil
    pirrolidin-3-amina; 1-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)-4-(propano-2-sulfonil)piperazina; 1-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)-4-[(2-metilpropano)sulfonil]piperazina; 1-(butano-2-sulfonil)-4-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)piperazina; 1-(etanosulfonil)-4-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)piperazina; (3S)-1-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)-N-metilpirrolidin-3-amina; (3S)-N-etil-1-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)pirrolidin-3-amina; (3R)-1-(6-{6-[(2R)-2-(3-fluorofenil) pirrolidin-1-il] imidazo [1,2-b]piridazin-3-il} piridin-2-il) -N-(2,2,2-trifluoroetil)pirrolidin-3
    amina; acetato de 2-[4-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)piperazin-1-il]-2-oxoetilo; acetato de {[(3R)-1-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)pirrolidin-3-il]carbamoil}
    metilo;
    N-[(3R)-1-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)pirrolidin-3-il]-2-hidroxi-acetamida; 4-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)-1-metilpiperazin-2-ona; 4-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)-1-(2-hidroxietil)piperazin-2-ona; 2-{6-[(2R)-2-(3-fluorofenil) pirrolidin-1-il] imidazo[1,2-b] piridazin-3-il} -6-[4-(piperidin-1-il) piperidin-1-il]piridina; {[1-(6-{6-[(2R)-2-(3-fluorofenil)pirrolidin-1-il]imidazo[1,2-b]piridazin-3-il}piridin-2-il)piperidin-4-il]metil}dimetilamina;
    199
    imagen16
    imagen17
    imagen18
    3-(3-fluorofenil)-4-(3-{6-[4-(4-metil-1H-imidazol-2-il)piperidin-1-il] piridin-2-il}imidazo[1,2-b]piridazin-6-il)morfolina;
    6-{6-[3-(3-fluorofenil)morfolin-4-il]imidazo[1,2-b]piridazin-3-il}-N,N-dimetilpiridin-2-amina;
    3-(3-fluorofenil)-4-[3-(6-{4-[2-(metil-sulfanil)etil]piperazin-1-il}piridin-2-il)imidazo[1,2-b]piridazin-6-il]morfolina;
    3-(3-fluorofenil)-4-(3-{6-[4-(2-metanosulfoniletil)piperazin-1-il]piridin-2-il}imidazo[1,2-b]piridazin-6-il)morfolina;
    5 (N-ciclopropil-1-(6-(6-(2-(3-fluorofenil)pirrolidin-1-il)imidazo[1,2-b]piridazin-3-il)-2,4’-bipiridin-2’-il)piperidin-4-amina);
    3-(3-fluorofenil)-4-(3-{6-[4-(1H-1,2,4-triazol-5-il)piperidin-1-il]piridin-2-il}imidazo[1,2-b]piridazin-6-il)morfolina, y
    3-(3-fluorofenil) -4-(3-{6-[4-(1,2,4-oxadiazol-5-il)piperidin-1-il]piridin-2-il}imidazo[1,2-b]piridazin-6-il)morfolina.
  2. 11. Un compuesto de la reivindicación 10 que es (R)-1-(6-(6-(2-(3-fluorofenil)pirrolidin-1-il)imidazo[1,2-b]piridazin-3-il)-2, 4'-bipiridina-2 'il) piperidin-4-ol.
    10 12. Una composición farmacéutica que comprende una cantidad terapéuticamente eficaz de un compuesto de cualquiera de las reivindicaciones 1 -11 y un vehículo farmacéuticamente aceptable.
  3. 13.
    Una composición farmacéutica de acuerdo con la reivindicación 12, que comprende además un agente quimioterapéutico.
  4. 14.
    Un compuesto de una cualquiera de las reivindicaciones 1-13 para uso en el tratamiento de una enfermedad
    15 seleccionada de cáncer, enfermedades proliferativas, un trastorno de dolor, una enfermedad dermatológica, una enfermedad metabólica, una enfermedad muscular, un enfermedad neurodegenerativa, una enfermedad neurológica, una enfermedad de inmunodeficiencia, una enfermedad mediada inmunológicamente, una enfermedad autoinmune, una enfermedad mediada autoinmune, una enfermedad de los huesos, una enfermedad inflamatoria, fibrosis, una enfermedad oftálmica, una enfermedad infecciosa, una enfermedad viral, reparación de heridas, una enfermedad
    20 respiratoria, una enfermedad pulmonar, una enfermedad renal, una enfermedad del riñón, una enfermedad hepática, una enfermedad cardiovascular, una enfermedad vascular, una enfermedad cardíaca, muerte celular y enfermedad inflamatoria hiperplásica.
  5. 15. El compuesto de la reivindicación 14, en donde la enfermedad es asma, enfermedad pulmonar obstructiva crónica (EPOC), síndrome de insuficiencia respiratoria de adultos (ARDS), colitis ulcerativa, enfermedad de Crohn, bronquitis,
    25 dermatitis, rinitis alérgica, soriasis, esclerodermia, urticaria, artritis reumatoide, esclerosis múltiple, linfoma, metástasis, linfoma anaplásico de células grandes, osteosarcoma, fibrosarcoma, melanoma, cáncer de mama, cáncer renal, cáncer cerebral, cáncer de próstata, cáncer colorrectal, cáncer de tiroides, cáncer de ovario, cáncer pancreático, cáncer neuronal, neuroblastoma, cáncer de pulmón, cáncer uterino, cáncer gastrointestinal, VIH, o lupus, carcinoma papilar de tiroides, o caquexia.
    203
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