ES2644758T3 - Moduladores de PKM2 y métodos para su uso - Google Patents

Moduladores de PKM2 y métodos para su uso Download PDF

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ES2644758T3
ES2644758T3 ES13847643.7T ES13847643T ES2644758T3 ES 2644758 T3 ES2644758 T3 ES 2644758T3 ES 13847643 T ES13847643 T ES 13847643T ES 2644758 T3 ES2644758 T3 ES 2644758T3
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nmr
mhz
cd3od
tfa
pkm2
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Koc-Kan Ho
Yong Xu
Micheal David SAUNDERS
Xiaohui Liu
Scott Albert Pearce
Kevin Bret WRIGHT
Jason Marc FOULKS
Kenneth Mark PARNELL
Steven Brian KANNER
David Lee VOLLMER
Jihua Liu
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Tolero Pharmaceuticals Inc
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    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/38—Nitrogen atoms
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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6503—Five-membered rings
    • C07F9/65031—Five-membered rings having the nitrogen atoms in the positions 1 and 2

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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Description

imagen1
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o un estereoisómero, sal farmacéuticamente aceptable, tautómero o profármaco del mismo, en donde: R7 y R8 son cada uno independientemente H, alquilo, alcoxi, halo, hidroxilo, hidroxialquilo, amino, aminoalquilo,
5 alquilaminoalquilo, nitrilo, nitro, -O(CH2)mP(=O)(OH)2, éster de aminoácido; y w es 1 o2. Por ejemplo, en algunas realizaciones del compuesto de estructura (I) tiene la siguiente estructura (la):
imagen16
10 o un estereoisómero, sal farmacéuticamente aceptable, tautómero o profármaco del mismo, en donde: R15 es halo; R16 es H oNH2; y w es 1 o2.
15 En algunas realizaciones de estructura (la), R15 es cloro. En otras realizaciones, R15 es flúor. En algunas otras realizaciones de estructura (la), R16 es H. En otras realizaciones, R16 es NH2. En aún otras realizaciones de estructura (la), w es 1. En otras realizaciones, w es 2. En otras realizaciones específicas de estructura (I), el compuesto tiene la siguiente estructura (Ib'):
imagen17
o un estereoisómero, sal farmacéuticamente aceptable, tautómero o profármaco del mismo, en dondee: Q es CH2 , O, NR13 , CF2 , o S(O)w;
5 R7 y R8 son cada uno independientemente H, alquilo, alcoxi, halo, hidroxilo, hidroxialquilo, amino, aminoalquilo, alquilaminoalquilo, nitrilo, nitro, -O (CH2)mP(=O)(OH)2, éster de aminoácido; R9, R11 y R13 son cada uno independientemente H o alquilo; R10 es H, hidroxilo, halo, alcoxi o alquilo; w es 0, 1o 2; y 10 tes1,2o3. Por ejemplo, en otras realizaciones específicas de estructura (I), el compuesto tiene la siguiente estructura (Ib):
imagen18
o un estereoisómero, sal farmacéuticamente aceptable, tautómero o profármaco del mismo,
15 en donde: R7 es halo; R18 es H oNH2; Z es CH2, O, NH, NR19, CHR20 o CF2; R19 es alquilo;
20 R20 es alcoxi, hidroxilo o halo; y xes 0, 1, 2 o3. Por ejemplo, en algunas realizaciones, R17 es cloro. En otras realizaciones, R18 es NH2. En todavía otras realizaciones de estructura (lb), Z es CHOH. En otras realizaciones, Z es CHOCH3. En más
realizaciones, Z es CHF, y en otras realizaciones Z es O.
imagen19
Tabla 1
Compuestos ilustrativos
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
1
imagen20 1H-RMN (CDCl3/400 MHz): 7,10 (m, 1H), 6,80 (m, 1H), 6,59 (d, J= 8,4 Hz, 1H), 6,52 (d, J = 12,0 Hz, 1H), 4,69 (s, 2H), 3,50 (s, 2H), 2,65 (m, 1H), 2,00-1,58 (m, 6H). 372,1 11/100 -
2
imagen21 1H-RMN (CD3OD/400 MHz): 7,31 (m, 1H), 7,00 (m, 3H), 4,80 (m, 2H), 3,56 (m, 2H), 2,66 (m, 1H), 2,00-1,59 (m, 6H). 410,1 3.788/39 -
3
imagen22 1H-RMN (CD3OD/400 MHz): 7,08 (m, 1H), 6,54 (m, 2H), 5,70 (m, 1H), 4,63 (m, 2H), 3,64 (m, 1H), 3,56 (m, 1H), 2,64 (m, 1H), 2,01-1,58 (m, 6H). 319,0 43.850/45 -
4
imagen23 1H-RMN (CD3OD/400 MHz): 7,34 (m, 5H), 6,60 (s, 1H), 5,60 (m, 1H), 4,80 (m, 1H), 3,40 (m, 2H), 2,40 (m, 1H), 2,01-1,58 (m, 6H). 361,9 1.482 /52 -
5
imagen24 1H-RMN (CD3OD/400 MHz): 7,40 (m, 5H), 6,80 (s, 1H), 5,48 (m, 2H), 3,50 (m, 2H), 2,34 (m, 1H), 2,01-1,58 (m, 6H). 352,0 4651/106 -
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
6
imagen25 1H-RMN (CDCl3/400 MHz; Se observaron rotámeros estables de amidas por RMN): 7,35 (m, 1H), 7,24 (br, 1H), 7,10 (m, 1H), 6,97 (m, 0,5H), 6,84 (m, 1H), 6,60 (m, 0,5H), 6,50 (m, 0,5H), 6,39 (m, 0,5H), 5,05 (s, 2H), 3,60 (s, 1H), 3,34 (s, 1H), 2,74 (m, 1H), 2,50-1,55 (m, 6H). 377,0 213/100 -
7
imagen26 1H-RMN (CD3OD/400 MHz): 7,31 (m, 1H), 7,04 (m, 3H), 5,04 (m, 1H), 5,04 (m, 1H), 3,70 (m, 1H), 3,50 (m, 1H), 2,56 (m, 1H), 2,00-1,56 (m, 6H). 368,0 3.446/87 -
8
imagen27 1H-RMN (CD3OD/400 MHz): 7,05 (m, 2H), 6,54 (m, 2H), 4,68 (m, 2H), 3,67 (m, 1H), 3,46 (m, 1H), 2,67 (m, 1H), 2,01-1,62 (m, 6H). 328,9 NA -
9
imagen28 1H-RMN (CD3OD/400 MHz): 7,30 (m, 1H), 7,10 (m, 2H), 6,50 (m, 1H), 4,77 (m, 2H), 3,53 (m, 2H), 2,66 (m, 1H), 2,00-1,59 (m, 6H). 377,0 15.400/80 -
10
imagen29 1H-RMN (CD3OD/400 MHz): 7,30 (m, 1H), 7,06 (m, 2H), 6,50 (m, 1H), 4,77 (m, 2H), 3,53 (m, 2H), 2,66 (m, 1H), 2,00-1,59 (m, 6H). 420,9 2.740/127 -
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
11
imagen30 1H-RMN (CD3OD/400 MHz): 7,06 (m, 1H), 6,60 (m, 3H), 4,80 (m, 2H), 4,00 (m, 4H), 3,75 (m, 2H), 3,10 (m, 1H). 382,9 10.400/61 -
12
imagen31 1H-RMN (CD3OD/400 MHz): 7,38 (m, 1H), 7,29 (m, 1H), 7,12 (m, 1H), 6,90 (m, 1H), 6,67 (m, 1H), 6,40 (m, 1H), 5,07 (m, 2H), 4,57 (m, 2H), 4,37 (m, 2H), 4,08 (m, 1H), 3,86 (m, 2H). 378,9 3.271/101 -
13
imagen32 1H-RMN (CD3OD/400 MHz): 7,33 (m, 1H), 7,27 (m, 1H), 7,07 (m, 1H), 6,73 (m, 2H), 6,36 (m, 1H), 6,40 (m, 1H), 5 ,17 (m, 2H), 3,42 (m, 2H), 1,02 (s, 9H). 379,0 49.110/33 -
14
imagen33 1H-RMN (CD3OD/400 MHz): 7,37 (m, 2H), 6,95 (m, 1H), 6,55 (m, 1H), 4,60 (m, 2H), 3,80 (m, 2H), 3,60 (m, 2H), 3,30 (m, 2H), 2,70 (m, 1H), 2,03-1,50 (m, 6H). 379,0 1.700/81 -
15
imagen34 1H-RMN (CD3OD/400 MHz): 7,01 (m, 1H), 6,82 (m, 1H), 6,60 (m, 1H), 6,54 (m, 1H), 4,88 (m, 2H), 4,67 (m, 4H), 4,44 (m, 2H), 3,78 (m, 1H). 373,9 150/102 -
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
16
imagen35 1H-RMN (CD3OD/400 MHz): 7,32 (m, 5H), 6,80 (m, 1H), 4,78 (m, 2H), 3,77 (m, 1H), 1,29 (m, 4H), 1,20 (m, 3H), 0,89 (m, 3H). 340,0 74.820/22 -
17
imagen36 1H-RMN (CD3OD/400 MHz): 7,25 (m, 4H), 6,83 (m, 1H), 4,80 (m, 2H), 3,40 (m, 2H), 1,62 (m, 2H), 1,29 (m, 4H), 0,87 (m, 3H). 350,7 138/83 -
18
imagen37 1H-RMN (CD3OD/400 MHz): 8,19 (m, 1H), 6,80 (m, 1H), 6,55 (m, 1H), 4,70 (m, 2H), 4,30 (m, 4H), 3,87 (m, 1H), 3,34 (m, 2H). 356,9 NA -
19
imagen38 1H-RMN (CD3OD/400 MHz): 7,34 (m, 5H), 6,80 (m, 1H), 4,77 (m, 2H), 3,47 (m, 2H), 1,62 (m, 2H), 1,23 (m, 4H), 0,89 (m, 3H). 340,0 920/76 -
20
imagen39 1H-RMN (CD3OD/400 MHz): 7,31 (m, 1H), 7,12 (m, 4H), 4,88 (m, 2H), 4,67 (m, 4H), 4,40 (m, 2H), 3,83 (m, 1H). 358,1 12.000/70 -
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
21
imagen40 1H-RMN (CD3OD/400 MHz): 7,28 (m, 1H), 7,14 (m, 2H), 6,56 (m, 1H), 3,93 (m, 3H), 3,80 (m, 2H), 3,40 (m, 2H), 2,77 (m, 1H), 1,89 (m, 2H), 1,44 (m, 2H). 388,5 >10.000 -
22
imagen41 1H-RMN (CD3OD/400 MHz): 7,38 (m, 2H), 7,14 (m, 3H), 3,95 (m, 2H), 3,40 (m, 2H), 3,40 (m, 3H), 1,95 (m, 2H), 1,86 (m, 2H), 1,10 (m, 2H). 388,5 1.516/99 -
23
imagen42 1H-RMN (CD3OD/400 MHz): 7,35 (m, 2H), 7,15 (m, 2H), 7,15 (m, 2H), 6,86 (m, 1H), 4,89 (s, 2H), 3,65 (m, 2H), 3,36 (m, 2H), 3,26 (m, 2H), 1,89 (m, 3H) 360,4 7.540/75 -
24
imagen43 1H-RMN (CD3OD/400 MHz): 7,11 (m, 2H), 6,55 (m, 2H), 4,76 (m, 2H), 3,67 (m, 4H), 3,31 (m, 2H), 1,16 (m, 3H). 376,4 210/100 -
25
imagen44 1H-RMN (CD3OD/400 MHz): 7,84 (m, 1H), 7,47 (m, 1H), 7,34 (m, 1H), 7,21 (m, 1H), 7,13 (m, 2H), 7,02 (m, 2H), 4,78 (m, 2H). 355,4 53.000/35 -
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
26
imagen45 1H-RMN (CD3OD/400 MHz): 7,40 (m, 2H), 7,15 (m, 2H), 7,84 (m, 1H), 4,90 (m, 2H), 3,78 (m, 4H), 3,32 (m, 2H), 2,07 (m, 2H), 1,69 (m, 2H), 1,50 (m, 1H). 386,4 377/99 -
27
imagen46 1H-RMN (DMSO-d6/400 MHz): 7,50 (m, 1H), 7,34 (m, 3H), 7,21 (m, 1H), 4,75 (m, 2H), 4,55 (m, 2H), 3,50 (m, 4H), 3,20 (m, 1H). 374,4 33.000/47 -
28
imagen47 1H-RMN (DMSO-d6/400 MHz): 7,92 (m, 1H), 7,72 (m, 2H), 7,60 (m, 1H), 7,51 (m, 2H), 5,00 (m, 2H), 4,65 (m, 2H), 4,40 (m, 4H), 3,20 (m, 1H). 365,4 NA -
29
imagen48 1H-RMN (CD3OD/400 MHz): 7,45 (m, 1H), 7,20 (m, 4H), 5,00 (m, 2H), 3,60 (m, 4H), 3,32 (m, 2H), 1,15 (m, 3H). 376,4 4.640/87 -
30
imagen49 1H-RMN (CD3OD/400 MHz): 7,38 (m, 2H), 7,13 (m, 3H), 4,85 (m, 2H), 3,76 (m, 2H), 3,47 (s, 2H), 3,43 (m, 2H), 1,49 (m, 3H). 360,4 9.770/72 -
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
31
imagen50 1H-RMN (CD3OD/400 MHz): 7,43 (m, 1H), 7,29 (m, 4H), 4,91 (m, 2H), 3,70 (m, 2H), 3,54 (m, 2H), 3,44 (m, 2H), 3,37 (m, 2H), 3,32 (s, 3H). 376,4 9.590/82 -
32
imagen51 1H-RMN (CD3OD/400 MHz): 7,03 (m, 4H), 6,50 (m, 1H), 4,63 (m, 2H), 3,57 (m, 2H), 3,10 (m, 2H), 3,02 (m, 2H), 1,30 (m, 4H), 1,15 (m, 3H). 416,4 1.002/107 -
33
imagen52 1H-RMN (CD3OD/400 MHz): 7,45 (m, 2H), 7,35 (m, 1H), 6,95 (m, 1H), 5,19 (m, 2H), 3,69 (m, 4H), 3,20 (m, 2H), 1,87 (m, 2H), 1,60 (m, 3H). 436,4 4.026/81 -
34
imagen53 1H-RMN (CD3OD/400 MHz): 7,15 (m, 1H), 7,02 (m, 1H), 6,58 (m, 1H), 6,52 (m, 1H), 4,74 (m, 2H), 3,77 (m, 4H), 3,44 (m, 2H), 2,14 (m, 2H), 1,64 (m, 3H). 402,4 77/109 -
35
imagen54 1H-RMN (CD3OD/400 MHz): 7,44 (m, 1H), 7,31 (m, 4H), 4,90 (m, 2H), 3,92 (m, 2H), 3,50 (m, 3H), 1,85 (m, 2H), 1,75 (m, 2H). 388,4 5.080/59 -
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
36
imagen55 1H-RMN (CD3OD/400 MHz): 7,44 (m, 1H), 7,32 (m, 3H), 6,80 (m, 1H), 4,91 (m, 2H), 3,68 (m, 2H), 3,47 (m, 2H), 3,11 (m, 2H), 1,45 (m, 7H). 416,4 1.218/88 -
37
imagen56 1H-RMN (DMSO-d6/400 MHz): 8,27 (m, 1H), 8,13 (m, 4H), 5,62 (m, 2H), 4,16 (m, 2H), 4,32 (m, 2H), 4,25 (m, 1H), 1,82 (d, 6H). 390,3 42.000/37 -
38
imagen57 1H-RMN (CD3OD/400 MHz): 7,42 (m, 1H), 7,29 (m, 4H), 4,89 (m, 2H), 3,50 (m, 2H), 3,41 (m, 4H), 1,92 (m, 2H), 1,12 (t, 6H). 300,3 33.000/47 -
39
imagen58 1H-RMN (CD3OD/400 MHz): 7,32 (m, 2H), 7,15 (m, 3H), 4,81 (m, 2H), 3,80 (m, 3H), 3,41 (m, 4H), 1,60 (m, 8H). 400,5 47.000/30 -
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
40
imagen59 1H-RMN (CD3OD/400 MHz): 7,41 (m, 1H), 7,00 (m, 3H), 4,88 (m, 2H), 3,70 (m, 4H), 3,40 (m, 2H), 2,05 (m, 2H), 1,62 (m, 2H), 1,40 (m, 1H). 404,4 1.171/114 -
41
imagen60 1H-RMN (CD3CN/400 MHz): 7,35 (m, 2H), 7,17 (m, 2H), 6,90 (m, 1H), 4,80 (d, 2H), 3,82 (m, 2H), 3,53 (m, 2H), 3,26 (m, 2H), 1,53(m, 5H), 1,16 (m, 2H). 400,4 1.258/118 -
42
imagen61 1H-RMN (CD3OD/400 MHz): 7,44 (d, 2H), 7,34 (t, 1H), 7,01 (m, 1H), 5,16 (m, 2H), 3,60 (m, 2H), 3,40 (m, 4H), 1,10 (m, 3H). 410,4 8.760/76 -
43
imagen62 1H-RMN (CD3OD/400 MHz): 7,46 (m, 1H), 7,20 (m, 3H), 6,88 (m, 1H), 4,85 (m, 2H), 3,80 (m, 2H), 3,60 (m, 1H), 3,48 (m, 2H), 3,25 (m, 1H), 2,01 (m, 2H), 1,70 (m, 2H), 1,45 (m, 1H). 402,4 1.330/110 -
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
44
imagen63 1H-RMN (CD3OD/400 MHz): 7,45 (m, 1H), 7,29 (m, 4H), 4,83 (m, 2H), 3,80 (m, 2H), 3,36 (m, 3H), 1,80 (m, 4H), 1,47 (m, 4H). 416,4 50.000/32 -
45
imagen64 1H-RMN (Acetona-d6/400 MHz): 7,40 (m, 2H), 7,28 (m, 3H), 4,98 (d, 2H), 3,84 (m, 2H), 3,61 (m, 1H), 3,40 (m, 1H), 3,28 (m, 2H), 2,08 (m, 1H), 1,63 (m, 2H), 1,30 (m, 2H). 386,4 25.150/52 -
46
imagen65 1H-RMN (CD3CN/400 MHz): 7,28 (m, 2H), 7,16 (m, 3H), 4,80 (d, 2H), 3,80 (m, 2H), 3,60 (m, 3H), 1,95 (m, 1H), 1,80 (m, 4H), 1,41 (m, 1H). 386,4 13.410/70 -
47
imagen66 1H-RMN (CD3OD/400 MHz): 7,33 (m, 2H), 7,12 (m, 2H), 6,90 (m, 1H), 4,81 (m, 2H), 4,20 (m, 1H), 3,14 (m, 1H), 2,09 (m, 2H), 1,82 (m, 2H), 1,66 (m, 2H), 1,21 (m, 2H). 400,4 435/89 -
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
48
imagen67 1H-RMN (CD3OD/400 MHz): 7,33 (m, 1H), 7,00 (m, 4H), 4,80 (m, 2H), 4,20 (m, 1H), 3,28 (s, 3H), 3,12 (m, 1H), 2,07 (m, 2H), 1,80 (m, 2H), 1,70 (m, 2H), 1,23 (m, 2H). 400,4 8.580/80 -
49
imagen68 1H-RMN (Acetona-d6/400 MHz): 7,40 (m, 1H), 7,00 (m, 3H), 4,92 (m, 2H), 3,24 (s, 3H), 3,00 (m, 2H), 1,76 (m, 4H), 1,15 (m, 4H). 418,4 914/122 -
50
imagen69 1H-RMN (Acetona-d6/400 MHz): 7,17 (m, 2H), 7,07 (m, 2H), 4,90 (m, 2H), 4,15 (m, 1H), 3,24 (s, 3H), 3,05 (m, 3H), 1,96 (m, 2H), 1,80 (m, 2H), 1,24 (m, 2H). 418,4 1.667/90 -
51
imagen70 1H-RMN (Acetona-d6/400 MHz): 7,03 (m, 3H), 6,89 (m, 1H), 4,80 (m, 2H), 4,32 (m, 1H), 3,25 (s, 3H), 3,05 (m, 3H), 1,96 (m, 2H), 1,80 (m, 2H), 1,20 (m, 2H). 418,4 50.380/31 -
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
52
imagen71 1H-RMN (CD3OD/400 MHz): 7,40 (m, 1H), 7,30 (m, 4H), 4,81 (m, 2H), 3,29 (s, 3H), 3,13 (m, 2H), 2,10 (m, 2H), 1,85 (m, 2H), 1,62 (m, 2H), 1,23 (m, 2H). 416,4 879/100 -
53
imagen72 1H-RMN (CD3OD/400 MHz): 7,40 (m, 1H), 7,30 (m, 4H), 4,79 (m, 2H), 3,79 (m, 2H), 2,00 (m, 2H), 1,85 (m, 2H), 1,63 (m, 2H), 1,22 (m, 2H), 1,10 (d, 6H). 444,4 2.287/63 -
54
imagen73 1H-RMN (CD3OD/400 MHz): 7,45 (m, 1H), 7,27 (m, 3H), 6,80 (m, 1H), 4,80 (m, 2H), 4,22 (m, 1H), 3,25 (s, 3H), 3,05 (m, 1H), 2,05 (m, 2H), 1,84 (m, 2H), 1,66 (m, 2H), 1,20 (m, 2H). 397,5 365/93 -
55
imagen74 1H-RMN (CD3OD/400 MHz): 7,30 (m, 2H), 7,08 (m, 3H), 4,78 (m, 2H), 4,20 (m, 1H), 3,50 (m, 2H), 3,20 (m, 1H), 2,05 (m, 2H), 1,80 (m, 2H), 1,70 (m, 2H), 1,20 (m, 2H), 1,12 (t, 3H). 414,4 469/101 -
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
56
imagen75 1H-RMN (Acetona-d6/400 MHz): 8,53 (m, 1H), 7,86 (m, 1H), 7,37 (m, 1H), 6,63 (m, 1H), 5,00 (m, 2H), 4,20 (m, 1H), 3,25 (s, 3H), 3,08 (m, 1H), 1,95 (m, 4H), 1,42 (m, 2H), 1,26 (m, 2H). 417,4 2.580/48 TFA
57
imagen76 1H-RMN (dmso-d6/400 MHz): 7,06 (m, 1H), 6,54 (m, 2H), 6,30 (m, 1H), 4,54 (m, 2H), 4,10 (m, 1H), 3,20 (s, 3H), 3,00 (m, 1H), 1,95 (m, 2H), 1,70 (m, 2H), 1,50 (m, 4H), 1,15 (m, 2H). 431,4 TBD TFA
58
imagen77 1H-RMN (CD3OD/400 MHz): 7,10 (m, 1H), 6,89 (m, 1H), 6,71 (m, 1H), 6,38 (m, 1H), 4,75 (m, 2H), 4,31 (m, 1H), 3,20 (s, 3H), 3,10 (m, 1H), 2,10 (m, 2H), 1,90 (m, 2H), 1,65 (m, 2H), 1,28 (m, 2H). 431,4 TBD TFA
59
imagen78 1H-RMN (CD3CN/400 MHz): 7,35 (m, 2H), 7,16 (m, 2H), 6,80 (m, 1H), 4,77 (m, 2H), 3,85 (m, 4H), 3,52 (m, 2H), 2,30 (m, 2H), 1,62 (m, 5H), 1,17 (m, 4H). 465,5 494/100 -
60
imagen79 1H-RMN (CDCl3/400 MHz): 7,35 (m, 1H), 7,18 (m, 3H), 6,70 (m, 1H), 4,87 (m, 2H), 3,59 (m, 2H), 2,28 (m, 4H), 2,04 (m, 2H), 1,70 (m, 3H), 1,44 (m, 2H). 412,5 101/105 -
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
61
imagen80 1H-RMN (DMSO-d6/400 MHz): 7,32 (m, 1H), 7,20 (m, 4H), 4,73 (m, 2H), 3,30 (m, 2H), 3,13 (m, 2H), 2,93 (s, 3H), 1,99 (m, 2H). 408,4 NA -
62
imagen81 1H-RMN (DMSO-d6/400 MHz): 7,46 (m, 1H), 7,35 (m, 3H), 6,85 (m, 1H), 4,91 (m, 2H), 3,60 (m, 2H), 3,10 (m, 2H), 2,72 (m, 1H), 2,41 (m, 2H), 1,85 (m, 2H). 450,4 273/105 -
63
imagen82 1H-RMN (CD3OD/400 MHz): 7,36 (m, 2H), 7,15 (m, 2H), 6,85 (m, 1H), 4,92 (m, 2H), 3,50 (m, 2H), 3,12 (m, 2H), 3,00 (m, 1H), 2,71 (m, 2H), 2,24 (m, 2H), 1,85 (m, 2H). 434,4 240/87 -
64
imagen83 1H-RMN (DMSO-d6/400 MHz): 7,52 (m, 2H), 7,35 (m, 1H), 7,38 (m, 1H), 5,03 (m, 2H), 3,50 (m, 2H), 3,12 (m, 2H), 2,92 (m, 3H), 2,16 (m, 2H), 1,65 (m, 2H). 484,3 3.780/71 -
65
imagen84 1H-RMN (CD3OD/400 MHz): 7,47 (m, 1H), 7,37 (m, 3H), 6,80 (m, 1H), 4,97 (m, 2H), 3,90 (m, 2H), 3,42 (m, 2H), 3,12 (m, 2H), 1,33 (m, 3H). 424,3 NA -
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
66
imagen85 1H-RMN (CD3OD/400 MHz): 7,41 (m, 1H), 7,00 (m, 3H), 5,01 (m, 2H), 3,58 (m, 2H), 3,10 (m, 2H), 2,65 (m, 1H), 2,35 (m, 2H), 1,77 (m, 4H). 452,4 375/102 -
67
imagen86 1H-RMN (CD3OD/400 MHz): 7,39 (m, 1H), 7,02 (m, 3H), 6,90 (m, 1H), 4,80 (m, 2H), 3,60 (m, 3H), 3,20 (m, 3H), 2,99 (m, 2H), 2,30 (m, 3H). 434,4 1.626/95 -
68
imagen87 1H-RMN (Acetona-d6/400 MHz): 7,20 (m, 4H), 4,98 (d, 2H), 3,61 (m, 2H), 3,20 (m, 2H), 3,00 (m, 2H), 2,60 (m, 1H), 2,45 (m, 2H), 1,80 (m, 2H). 452,4 766/103 -
69
imagen88 1H-RMN (Acetona-d6/400 MHz): 7,00 (m, 4H), 4,90 (d, 2H), 3,61 (m, 2H), 3,20 (m, 2H), 3,00 (m, 2H), 2,60 (m, 1H), 2,45 (m, 2H), 1,80 (m, 2H). 452,4 1.835/74 -
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
70
imagen89 1H-RMN (Acetona-d6/400 MHz): 7,20 (m, 4H), 4,90 (d, 2H), 3,61 (m, 2H), 3,20 (m, 2H), 3,00 (m, 2H), 2,60 (m, 1H), 2,45 (m, 2H), 1,80 (m, 2H). 452,4 884/91 -
71
imagen90 1H-RMN (Acetone-d6/400 MHz): 7,30 (m, 2H), 7,18 (m, 2H), 7,00 (m, 1H), 4,90 (d, 2H), 3,61 (m, 2H), 3,00 (m, 4H), 2,25 (m, 1H), 2,15 (m, 2H), 1,87 (m, 2H). 434,4 10.200/71 -
72
imagen91 1H-RMN (Acetona-d6/400 MHz): 7,36 (m, 4H), 7,00 (m, 1H), 4,95 (d, 2H), 3,61 (m, 2H), 3,00 (m, 4H), 2,25 (m, 1H), 2,15 (m, 2H), 1,87 (m, 2H). 450,4 19.660/22 -
73
imagen92 1H-RMN (Acetona-d6/400 MHz): 7,41 (m, 4H), 6,80 (m, 1H), 4,95 (d, 2H), 3,61 (d, 2H), 2,60 (m, 4H), 1,99 (m, 1H), 1,61 (m, 2H), 1,30 (m, 4H). 432,4 1.343/79 -
74
imagen93 1H-RMN (Acetona-d6/400 MHz): 7,41 (m, 4H), 6,90 (m, 1H), 4,95 (d, 2H), 3,61 (d, 2H), 3,16 (m, 2H), 2,81 (m, 1H), 2,53 (m, 2H), 2,08 (m, 2H), 1,73 (m, 4H). 448,4 640/95 -
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
75
imagen94 1H-RMN (CD3CN/400 MHz): 7,47 (m, 1H), 7,32 (m, 3H), 6,90 (m, 1H), 4,85 (m, 2H), 3,49 (m, 2H), 2,90 (m, 4H), 2,25 (m, 2H), 2,05 (m, 1H), 1,61 (m, 4H). 464,4 188/102 -
76
imagen95 1H-RMN (CD3CN/400 MHz): 7,15 (m, 1H), 6,80 (m, 1H), 6,60 (m, 2H), 4,72 (m, 2H), 3,50 (m, 2H), 3,19 (m, 2H), 2,95 (m, 1H), 2,55 (m, 1H), 2,35 (m, 2H), 1,80 (m, 3H). 450,4 54/93 -
77
imagen96 1H-RMN (CD3CN/400 MHz): 7,40 (m, 1H), 7,15 (m, 2H), 6,95 (m, 1H), 6,75 (m, 2H), 5,65 (s, 1H), 5,38 (s, 1H), 3,48 (m, 2H), 3,40 (m, 1H), 3,05 (m, 1H), 3,00 (m, 1H), 2,45 (m, 2H), 1,75 (m, 4H). 431,4 34.820/43 -
78
imagen97 1H-RMN (CD3CN/400 MHz): 7,47 (m, 2H), 7,18 (m, 2H), 6,90 (m, 1H), 4,85 (d, 2H), 3,59 (d, 2H), 2,90 (m, 4H), 2,05 (m, 1H), 2,70 (m, 6H). 448,4 485/102 -
79
imagen98 1H-RMN (Acetona-d6/400 MHz): 7,21 (m, 5H), 4,70 (d, 2H), 3,40 (d, 2H), 2,47 (m, 2H), 1,86 (m, 1H), 1,70 (m, 2H), 1,41 (m, 2H), 1,14 (m, 4H). 416,4 1.193/95 -
80
imagen99 1H-RMN (Acetonad6/400MHz): 7,35 (m, 1H), 7,18 (m, 2H), 4,70 (d, 2H), 3,60 (d, 2H), 2,60 (m, 2H), 2,50 (m, 2H), 2,00 (m, 2H), 1,61 (m, 2H), 1,27 (m, 3H). 382,4 1.301/46 -
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
81
imagen100 1H-RMN (CD3CN/400 MHz): 7,36 (m, 2H), 7,17 (m, 2H), 6,60 (m, 1H), 4,90 (d, 2H), 3,63 (d, 2H), 3,01 (m, 4H), 2,18 (m, 3H), 1,70 (m, 4H). 414,4 1.366/72 -
82
imagen101 1H-RMN (Acetona-d6/400 MHz): 7,35 (m, 2H), 7,15 (m, 2H), 6,55 (m, 1H), 4,90 (d, 2H), 3,60 (d, 2H), 2,60 (m, 4H), 2,00 (m, 2H), 1,60 (m, 2H), 1,25 (m, 3H). 426,4 1.372/74 -
83
imagen102 1H-RMN (CD3CN/400 MHz): 7,36 (m, 2H), 7,18 (m, 2H), 6,60 (m, 1H), 4,90 (d, 2H), 3,60 (d, 2H), 2,98 (m, 4H), 2,19 (m, 2H), 1,71 (m, 5H). 458,4 1.104/98 -
84
imagen103 1H-RMN (ACN-d3/400 MHz): 7,40 (m, 1H), 7,02 (m, 2H), 6,98 (m, 1H), 4,83 (m, 2H), 3,35 (m, 2H), 2,51 (m, 4H), 2,17 (m, 2H), 1,90 (m, 2H), 1,48 (m, 2H), 1,21 (m, 3H). 434,4 697/73 -
85
imagen104 1H-RMN (CD3CN/400 MHz): 7,36 (m, 2H), 7,05 (m, 3H), 5,00 (m, 2H), 3,60 (m, 2H), 2,99 (m, 4H), 2,90 (m, 2H), 1,68 (m, 5H), 2,98 (m, 4H). 466,4 64/100 -
86
imagen105 1H-RMN (Acetona-d6/400 MHz): 7,22 (m, 1H), 7,00 (m, 1H), 6,63 (m, 2H), 4,75 (m, 2H), 3,40 (m, 2H), 2,60 (m, 4H), 2,00 (m, 2H), 1,55 (m, 2H), 1,25 (m, 3H). 432,4 93/98 -
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
87
imagen106 1H-RMN (CD3CN/400 MHz): 7,15 (m, 1H), 6,84 (m, 1H), 6,63 (m, 2H), 4,72 (m, 2H), 3,44 (m, 2H), 2,92 (m, 4H), 2,04 (m, 2H), 1,60 (m, 5H). 464,4 64/100 -
88
imagen107 1H-RMN (CD3OD/400 MHz): 8,77 (m, 1H), 7,98 (m, 1H), 7,60 (m, 2H), 6,97 (m, 1H), 5,00 (m, 2H), 3,60 (m, 2H), 3,20 (m, 2H), 2,40 (m, 2H), 1,84 (m, 3H). 417,4 3.600/96 -
89
imagen108 1H-RMN (CD3OD/400 MHz): 8,80 (m, 1H), 7,90 (m, 3H), 6,97 (m, 1H), 5,10 (m, 2H), 3,85 (m, 2H), 3,20 (m, 2H), 2,80 (m, 2H), 2,40 (m, 2H), 1,90 (m, 3H). 417,4 58.000/35 TFA
90
imagen109 1H-RMN (CD3OD/400 MHz): 8,70 (m, 2H), 8,27 (m, 1H), 7,91 (m, 1H), 4,84 (m, 2H), 3,64 (m, 2H), 3,10 (m, 2H), 2,65 (m, 1H), 2,30 (m, 2H), 1,80 (m, 4H). 417,4 52.000/24 TFA
91
imagen110 1H-RMN (CD3OD/400 MHz): 7,09 (m, 1H), 6,90 (m, 1H), 6,52 (m, 1H), 6,41 (m, 1H), 4,84 (m, 2H), 3,50 (m, 4H), 2,80 (m, 5H), 1,55 (m, 4H). 463,4 58/78 TFA
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
92
imagen111 1H-RMN (Acetona-d6/400 MHz): 8,50 (m, 1H), 7,92 (m, 1H), 7,42 (m, 2H), 6,76 (m, 1H), 5,11 (m, 2H), 3,64 (m, 2H), 3,10 (m, 2H), 2,65 (m, 1H), 2,30 (m, 2H), 1,80 (m, 4H). 451,4 1.290/74 TFA
93
imagen112 1H-RMN (Acetona-d6/400 MHz): 8,94 (m, 1H), 7,90 (m, 1H), 7,05 (m, 1H), 5,10 (m, 2H), 3,75 (m, 2H), 3,20 (m, 2H), 2,90 (m, 1H), 2,70 (m, 1H), 2,40 (m, 2H), 1,80 (m, 3H). 423,6 49.000/26 -
94
imagen113 1H-RMN (CDCl3/400 MHz): 7,83 (m, 1H), 7,46 (m, 2H), 6,50 (m, 1H), 5,10 (m, 2H), 3,60 (m, 2H), 3,20 (m, 2H), 3,00 (m, 1H), 2,90 (m, 1H), 2,70 (m, 1H), 2,40 (m, 2H), 1,88 (m, 3H). 495,4 2.380/69 -
95
imagen114 1H-RMN (CD3CN/400 MHz): 7,17 (m, 1H), 6,64 (m, 2H), 6,52 (m, 1H), 4,62 (m, 2H), 3,49 (m, 1H), 3,30 (m, 1H), 3,10 (m, 2H), 2,90 (m, 1H), 2,70 (m, 1H), 2,20 (m, 2H), 1,73 (m, 3H). 465,4 TBD TFA
96
imagen115 1H-RMN (CD3CN/400 MHz): 7,06 (m, 1H), 6,80 (m, 1H), 6,56 (m, 1H), 6,47 (m, 1H), 4,77 (m, 2H), 3,50 (m, 2H), 3,10 (m, 2H), 2,90 (m, 1H), 2,80 (m, 1H), 2,60 (m, 1H), 2,30 (m, 2H), 1,80 (m, 3H). 465,4 TDB TFA
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
1H-RMN (CD3CN/400 MHz):
7,96 (m, 1H), 7,60 (m, 2H), 7,10
97
(m, 1H), 5,34 (m, 2H), 4,10 (m, 479,4 TDB TFA
2H), 3,59 (m, 4H), 2,50 (m, 2H),
2,17 (m, 5H).
1H-RMN (Acetona-d6/400
MHz): 7,37 (m, 2H), 7,13 (m,
98
2H), 7,00 (m, 1H), 5,00 (m, 2H), 399,4 2.050/56 TFA
3,62 (m, 4H), 3,00 (m, 2H), 1,55
(m, 7H).
1H-RMN (CDCl3/400 MHz):
7,35 (m, 2H), 7,16 (m, 2H), 6,66
99
(m, 1H), 4,87 (m, 2H), 3,77 (m, 2H), 3,53 (m, 2H), 2,74 (s, 3H), 477,5 110/100 -
2,61 (m, 2H), 1,60 (m, 4H), 1,36
(m, 3H).
1H-RMN (DMSO-d6/400 MHz):
9,32 (m, 1H), 7,43 (m, 1H), 7,20
100
(m, 3H), 6,94 (m, 1H), 4,80 (m, 399,5 101.000/29 TFA
2H), 3,40 (m, 4H), 2,90 (m, 5H),
1,90 (m, 3H), 1,40 (m, 2H).
1H-RMN (DMSO-d6/400 MHz):
7,92 (m, 1H), 7,72 (m, 2H), 7,60
101
(m, 1H), 7,51 (m, 2H), 5,00 (m, 365,4 1.856/96 TFA
2H), 4,65 (m, 2H), 4,40 (m, 4H),
3,20 (m, 1H).
102
imagen116 1H-RMN (CD3OD/400 MHz): 7,45 (m, 1H), 7,32 (m, 4H), 5,05 (m, 2H), 3,80 (m, 2H), 2,95 (m, 4H), 2,55 (m, 5H), 1,62 (m, 5H). 441,5 767/71 TFA
1H-RMN (CD3OD/400 MHz):
7,34 (m, 2H), 7,14 (m, 2H), 6,80
103
(m, 1H), 4,94 (m, 2H), 3,74 (m, 2H), 3,31 (m, 4H), 3,12 (m, 4H), 414,5 37.000/42 2TF A
2,85 (m, 5H).
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
104
imagen117 1H-RMN (CD3OD/400 MHz): 7,45 (m, 1H), 7,32 (m, 3H), 6,80 (m, 1H), 5,00 (m, 2H), 3,76 (m, 4H), 3,38 (m, 4H), 2,96 (m, 2H), 2,88 (m, 5H). 430,3 17.000/63 2TF A
105
imagen118 1H-RMN (CD3OD/400 MHz): 7,46 (d, 2H), 7,36 (t, 1H), 7,05 (m, 1H), 5,22 (m, 2H), 3,50 (m, 2H), 3,35 (m, 2H), 3,11 (m, 2H), 2,81 (m, 2H), 1,95 (m, 2H), 1,45 (m, 4H), 1,30 (m, 6H). 477,4 3268/71 TFA
106
imagen119 1H-RMN (Acetona-d6/400 MHz): 7,37 (m, 2H), 7,16 (m, 3H), 5,00 (m, 2H), 3,90 (m, 2H), 3,60 (m, 6H), 3,25 (m, 6H), 1,34 (m, 3H). 428,5 6.300/115 2TF A
107
imagen120 1H-RMN (CD3OD/400 MHz): 7,45 (m, 1H), 7,34 (m, 3H), 6,80 (m, 1H), 5,01 (m, 2H), 3,78 (m, 2H), 3,47 (m, 2H), 3,28 (m, 2H), 3,04 (m, 2H), 2,91 (m, 4H). 465,4 873/65 TFA
108
imagen121 1H-RMN (CD3OD/400 MHz): 7,40 (m, 2H), 7,20 (m, 3H), 5,00 (m, 2H), 3,65 (m, 2H), 3,50 (m, 2H), 3,40 (m, 2H), 3,25 (m, 2H), 3,00 (m, 4H). 449,4 7.800/92 TFA
109
imagen122 1H-RMN (CD3OD/400 MHz): 7,40 (m, 1H), 7,10 (m, 3H), 5,05 (m, 2H), 3,65 (m, 2H), 3,45 (m, 2H), 3,25 (m, 2H), 3,00 (m, 6H). 467,4 4.200/94 TFA
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
110
imagen123 1H-RMN (Acetona-d6/400 MHz): 7,52 (m, 2H), 7,43 (m, 1H), 7,20 (m, 1H), 5,20 (m, 2H), 3,60 (m, 2H), 3,00 (m, 10H). 499,3 1.644/84 TFA
111
imagen124 1H-RMN (Acetona-d6/400 MHz): 7,28 (m, 4H), 5,08 (m, 2H), 3,91 (m, 2H), 3,60 (m, 2H), 3,16 (m, 8H). 467,4 13.100/64 TFA
112
imagen125 1H-RMN (Acetona-d6/400 MHz): 7,58 (m, 1H), 7,40 (m, 2H), 6,78 (m, 1H), 5,04 (m, 2H), 3,90 (m, 2H), 3,71 (m, 2H), 3,47 (m, 4H), 3,14 (m, 4H). 446,4 1.066/91 2TF A
113
imagen126 1H-RMN (CD3OD/400 MHz): δ 7,30 (m, 1H), 7,02 (m, 2H), 6,95 (m, 1H), 4,78 (m, 2H), 3,57 (m, 2H), 2,65 (m, 1H), 2,02 (m, 2H), 1,78 (m, 4H). 418,0 77.000/21 -
114
imagen127 1H-RMN (CD3OD/400 MHz): δ 7,20 (m, 1H), 6,95 (m, 2H), 6,55 (m, 1H), 5,60 (d, 2H), 4,70 (m, 2H), 3,57 (m, 2H), 2,60 (m, 1H), 2,02-1,80 (m, 6H). 448,0 TBD -
115
imagen128 1H-RMN (CD3OD/400 MHz): δ 7,30 (m, 1H), 7,05 (m, 2H), 6,55 (m, 1H), 4,95 (d, 2H), 3,60 (m, 2H), 2,80 (m, 1H), 2,05 (m, 1H), 2,00 (m, 5H), 1,80 (m, 5H), 1,00 (t, 3H). 437,1 98/104 TFA
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
116
imagen129 1H-RMN (CD3OD/400 MHz): 8,50 (s, 1H), 8,38 (d, 1H), 7,43 (m, 1H), 6,55 (m, 1H), 4,88 (m, 2H), 3,60 (m, 2H), 2,66 (m, 1H), 2,10-1,20 (m, 6H). 323,4 38.000/NA TFA
117
imagen130 1H-RMN (CD3OD/400 MHz): 8,44 (d, 1H), 8,15 (d, 1H), 7,43 (m, 1H), 6,60 (m, 1H), 4,74 (m, 2H), 3,70 (m, 2H), 2,66 (m, 1H), 2,10-1,20 (m, 6H). 339,5 NA/NA TFA
118
imagen131 1H-RMN (CD3OD/400 MHz): 11,4(s, 1H), 7,57 (s, 1H), 7,43 (d, 1H), 7,21 (t, 1H), 6,60-7,13(m, 1H), 4,90 (m, 2H), 3,75 (m, 2H), 2,87 (s, 6H), 2,71 (m, 1H), 2,10-1,50 (m, 6H). 400,4 7.000/100 TFA
119
imagen132 1H-RMN (CD3OD/400 MHz): 8,20 (m, 1H), 7,55 (m, 1H), 7,26 (m, 1H), 7,10 (m, 1H), 6,32-6,58(m, 1H), 5,00 (s, 2H), 3,52 (m, 2H), 2,60 (m, 1H), 2,00-1,50 (m, 6H). 344,4 2.933/100 -
120
imagen133 1H-RMN (CD3OD/400 MHz): 8,20 (m, 1H), 7,56 (m, 1H), 7,28 (m, 1H), 7,11 (m, 1H), 6,43-6,67(m, 1H), 5,05 (s, 2H), 3,54 (m, 2H), 2,61 (m, 1H), 2,00-1,50 (m, 6H). 388,4/390,4 1.335/100 -
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
121
imagen134 1H-RMN (CD3OD/400 MHz): 11,2(s, 1H), 7,52 (nd, 1H), 7,41 (d, 1H), 7,21 (t, 1H), 6,60-7,13(m, 1H), 5,03 (bs, 2H), 3,80 (m, 2H), 2,73 (s, 6H), 2,71 (m, 1H), 2,10-1,50 (m, 6H). 23.000/NA TFA
122
imagen135 1H-RMN CD3OD/400 MHz): 7,96(m, 1H), 7,78 (m, 1H), 7,00 (m, 1H), 6,67-6,24 (m, 1H), 4,63 (m, 2H), 3,61 (m, 2H), 2,61 (m, 1H), 2,10-1,50 (m, 6H). NA/NA NA/NA -
123
imagen136 1H-RMN (CD3OD/400 MHz): 8,20 (m, 1H), 7,57 (m, 1H), 7,29 (m, 1H), 7,14 (m, 1H), 6,43-6,67(m, 1H), 5,03 (s, 2H), 3,54 (m, 2H), 2,61 (m, 1H), 2,00-1,50 (m, 6H). 828/100 -
124
imagen137 1H-RMN (CD3OD/400 MHz): 7,08 (m, 1H), 7,00 -6,60(m, 3H), 4,80 (m, 2H), 3,51 (m, 2H), 2,65 (m, 1H), 2,10-1,50 (m, 6H). 21/100 -
125
imagen138 1H-RMN (CD3OD/400 MHz): 7,08 (m, 1H), 6,83(m, 1H), 6,71(m, 1H), 6,63-6,36(m, 1H), 4,74 (m, 2H), 3,46 (m, 2H), 2,64 (m, 1H), 2,10-1,50 (m, 6H). 35/100 -
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
126
imagen139 1H-RMN (CD3OD/400 MHz): 9,00-8,40 (m, 1H), 7,75-7,35 (m, 2H), 6,98 (m, 1H), 5,18 (s, 2H), 3,56 (m, 2H), 2,65 (m, 1H), 2,10-1,50 (m, 6H). NA/NA -
127
imagen140 1H-RMN (CD3OD/400 MHz): 7,44 (m, 1H), 7,32 (m, 4H), 4,86 (m, 2H), 3,58 (m, 2H), 2,65 (m, 1H), 2,10-1,50 (m, 6H). 258/100 -
128
imagen141 1H-RMN (CD3OD/400 MHz): 8,56 (s, 1H), 8,45 (m, 1H), 7,32 (m, 1H), 7,04(m, 1H), 4,88 (m, 2H), 3,70 (m, 2H), 2,68 (m, 1H), 2,10-1,50 (m, 6H). 9.300/75 -
129
imagen142 1H-RMN (CD3OD/400 MHz): rotámeros 7,22+7,11 (t, 1H), 6,55(m, 2H), 6,31+6,27(s, 1H), 4,98+4,70 (s, 2H), 3,98+3,58 (m, 2H), 2,59+2,42 (m, 2H), 1,94(m, 1H), 0,99 (m, 2H), 0,73(m, 2H). 10.500/NA -
130
imagen143 1H-RMN (CD3OD/400 MHz): 7,08 (m, 2H), 6,61(d, 1H), 6,56(dd, 1H), 4,80 (m, 2H), 3,65 (m, 2H), 2,48 (m, 1H). 1000/100 -
131
imagen144 1H-RMN (CD3OD/400 MHz): 7,14 (m, 2H), 6,60(m, 1H), 6,54(d, 1H), 4,73 (m, 2H), 3,57 (m, 2H), 1,77 (m, 2H), 1,17(s, 3H), 1,13(s, 3H). 23.000/NA -
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
132
imagen145 1H-RMN (CD3OD/400 MHz): 7,07 (t, 1H), 6,59(d, 1H), 6,52(dd, 1H), 4,67(s, 2H), 4,54 (m, 1H), 2,00-1,50 (m, 8H). 213/100 -
133
imagen146 1H-RMN (CD3OD/400 MHz): 7.08 (m, 1H), 6.84(m, 1H), 6.63(d, 1H), 6.58(dd, 1H), 4.82 (m, 2H), 3.73 (m, 2H), 3.11 (m, 2H). 1.270/100 TFA
134
imagen147 1H-RMN (CD3OD/400 MHz): 7.15-6.55(m, 4H), 4.73 (m, 2H), 3.51 (m, 2H), 2.65 (m, 1H), 2.10-1.50 (m, 6H). 1.075/100 -
135
imagen148 1H-RMN (d6DMSO/400 MHz): 11.2(s, 1H), 7.33 (m, 3H), 7.06 (t, 1H), 6.88 (d, 1H), 6.52(m, 1H), 6.42(s, 1H), 5.05 (s, 1H), 4.84(d, 1H), 3.54 (m, 1H), 1.94 (m, 2H), 1.68 (m, 2H), 1.53 (m, 2H). 68/100 TFA
136
imagen149 1H-RMN (CD3OD/400 MHz): 7,10-6,55(m, 4H), 4,79 (s, 1H), 3,98(s, 1H), 3,59 (m, 1H), 2,65 (m, 2H), 2,10-1,50 (m, 6H). 380/100 -
137
imagen150 1H-RMN (CD3OD/400 MHz): 7,30-6,75 (m, 2H), 6,60(d, 1H), 6,53(d, 1H), 4,77 (s, 2H), 3,74 (m, 2H), 3,59 (m, 2H). 6.200/70 -
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
138
imagen151 1H-RMN (CD3OD/400 MHz): 7,30-6,75 (m, 2H), 6,60(d, 1H), 6,53(d, 1H), 4,90 (m, 2H), 3,74 (m, 2H), 1,23 (m, 6H). NA/NA -
139
imagen152 1H-RMN (CD3OD/400 MHz): 7,11 (m, 1H), 6,86(m, 1H), 6,57(d, 1H), 6,51(d, 1H), 4,70(s, 2H), 4,10 (m, 1H), 1,77(m, 5H), 1,58(m, 4H), 1,44-1,04(m, 4H). 152/100 -
140
imagen153 1H-RMN (CD3OD/400 MHz): rotámeros 7,24+7,04 (t, 1H), 6,94+6,81(s, 1H), 6,60(d, 1H), 6,53(dd, 1H), 4,76+4,72 (s, 2H), 3,59+3,50 (m, 2H), 1,48(q, 2), 0,67+0,53 (m, 2H), 0,41(m, 2H), 0,01(m, 2H). 32/100 -
141
imagen154 1H-RMN (CD3OD/400 MHz): 8,20-6,60(m, 4H), 4,81-4,45 (m, 2H), 3,61(m, 1H), 3,22 (m, 1H), 2,65 (m, 1H), 2,10-1,50 (m, 6H). 6.500/100 -
142
imagen155 1H-RMN (CD3OD/400 MHz): 7,30-6,75 (m, 2H), 6,59(d, 1H), 6,53(dd, 1H), 4,76 (s, 2H), 3,63 (m, 4H), 3,31 (s, 3H). 1.190/100 -
143
imagen156 1H-RMN (CD3OD/400 MHz): 7,15(nt, 1H), 6,97 (s, 1H), 6,65(d, 1H), 6,59(dd, 1H), 4,91 (s, 2H), 3,80(m, 2H), 3,25 (m, 6H), 1,30 (t, 6H). 108/100 TFA
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
144
imagen157 1H-RMN (CD3OD/400 MHz): 9,38(s, 1H), 7,78(d, 1H), 7,67(s, 1H), 7,60(t, 1H), 7,51 (m, 1H), 7,08(s, 1H), 6,32(s, 1H), 5,06(s, 2H). 25.000/NA TFA
145
imagen158 1H-RMN (CD3OD/400 MHz): 7,50-6,95(m, 4H), 4,81(s, 2H), 4,26(s, 2H), 3,82(m, 2H), 2,72(m, 1H), 2,10-1,50(m, 6H). 25.500/NA TFA
146
imagen159 1H-RMN (CD3OD/400 MHz): 9,48(m, 1H), 7,63(t, 1H), 7,40-7,00(m, 3H), 6,62(m, 1H), 4,49(m, 2H), 4,26(m, 2H). 385,5 NA/NA TFA
147
imagen160 1H-RMN (CD3OD/400 MHz): 7,00(m, 1H), 6,27(m, 2H), 4,69(s, 2H), 4,48(s, 2H), 3,56(m, 2H), 2,68(m, 1H), 2,10-1,50(m, 6H). 358,4 NA/NA -
148
imagen161 1H-RMN (CD3OD/400 MHz): 7,36(m, 2H), 7,19(m, 2H), 6,87(s, 1H), 4,99(m, 2H), 3,86(m, 2H), 3,30 (m, 6H), 1,31 (t, 6H). 387,5 505/100 TFA
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
149
imagen162 1H-RMN (CD3OD/400 MHz): 7,46-7,06(m, 4H), 7,00-6,73(m, 1H), 4,90(m, 2H), 3,65(m, 2H), 1,51(q, 2H), 0,62(m, 1H), 0,42(m, 2H), 0,02 (m, 2H). 356,5 1.995/100 -
150
imagen163 1H-RMN (CD3OD/400 MHz): 7,46-6,70(m, 5H), 4,92(m, 2H), 3,96-3,42(m, 6H), 2,68(m, 1H), 2,02(m, 1H), 1,62(m, 1H). 372,4 16.000/68 -
151
imagen164 1H-RMN (CD3OD/400 MHz): 7,39-7,09(m, 5H), 4,87(m, 2H), 4,00(m, 1H), 3,80(m, 2H), 3,67(m, 1H), 3,29(m, 1H), 2,30(m, 1H), 2,06(m, 1H). 358,4 NA/NA -
152
imagen165 1H-RMN (CD3OD/400 MHz): 7,39(m, 2H), 7,25(t, 1H), 7,17(t,1H), 6,92(m, 1H), 5,02(m, 2H), 4,34(m, 1H), 3,96(d, 1H), 3,86(t, 1H), 3,70-3,40(m, 1H), 3,28(m, 1H), 2,32(m, 2H), 1,36(t, 3H). 385,5 13.500/68 TFA
153
imagen166 1H-RMN (CD3OD/400 MHz): 7,32 (m, 2H), 7,10(m, 2H), 6,98-6,51(m, 1H), 4,81(s, 2H), 4,40-4,00 (m, 1H), 1,79(m, 4H), 1,70-1,04(m, 6H). 370,5 19.000/5,7 -
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
154
imagen167 1H-RMN (CD3OD/400 MHz): 7,54-6,72(m, 5H), 5,04(s, 2H), 3,86(m, 2H), 3,35 (m, 6H), 1,33 (t, 6H). 384,5 1.430/100 TFA
155
imagen168 1H-RMN (CD3OD/400 MHz): 7,35(m, 2H), 7,19(m, 2H), 6,81(s, 1H), 5,03(s, 2H), 3,81(m, 2H), 3,26 (m, 2H), 3,10(q, 2H), 1,32 (t, 3H). 359,4 2.150/100 TFA
156
imagen169 1H-RMN (CD3OD/400 MHz): 7,66(m, 1H), 7,53(m, 1H), 7,27(m, 2H), 6,93(s, 1H), 4,56(s, 2H), 3,92(m, 2H), 3,51(m, 4H), 3,27(m, 2H), 1,91(m, 2H), 1,65(m, 2H), 1,05(t, 3H), 0,89 (t, 3H). 415,5 NA/NA TFA
157
imagen170 1H-RMN (CD3OD/400 MHz): 7,41(m, 2H), 7,23(m, 2H), 6,96(s, 1H), 5,10(s, 2H), 3,78(m, 4H), 3,24 (t, 2H), 1,34 (s, 12H). 415,5 NA/NA TFA
158
imagen171 1H-RMN (CD3OD/400 MHz): 7,34(m, 2H), 7,19(m, 2H), 6,81(s, 1H), 5,03(s, 2H), 4,20-3,40(m, 6H), 3,15 (m, 2H), 2,10 (m, 4H). 385,4 265/100 TFA
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
159
imagen172 1H-RMN (CD3OD/400 MHz): 7,49(m, 1H), 7,39(m, 3H), 6,72(s, 1H), 5,07(s, 2H), 3,89(m, 2H), 3,31 (m, 6H), 1,32 (t, 6H). 403,4 73/100 TFA
160
imagen173 1H-RMN (CD3OD/400 MHz): 9,24(m, 1H), 7,80(d, 1H), 7,61(t, 1H), 7,47(m, 1H), 7,33-6,72(m, 1H), 5,39(m, 2H), 3,94(m, 2H), 3,41 (m, 6H), 1,33 (t, 6H). 409,5 825/100 TFA
161
imagen174 1H-RMN (CD3OD/400 MHz): 7,45(d, 1H), 7,33(nd, 1H), 7,17(t, 1H), 7,00(d, 1H), 6,94(s, 1H), 6,37(m, 1H), 5,24(m, 2H), 3,88(m, 2H), 3,20-2,90 (m, 6H), 1,18 (t, 6H). 408,5 76/100 TFA
162
imagen175 1H-RMN (CD3OD/400 MHz): 7,52-7,22(m, 5H), 5,03(s, 2H), 3,85(m, 4H), 3,45(m, 2H), 3,13 (m, 2H), 2,10 (m, 4H). 401,4 107/100 TFA
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
163
imagen176 1H-RMN (CD3OD/400 MHz): 9,34(s, 1H), 7,79(d, 1H), 7,60(t, 1H), 7,44(m, 1H), 7,33-6,72(m, 1H), 5,38(m, 2H), 4,30-3,40(m, 6H), 3,17 (m, 2H), 2,09 (m, 4H). 407,4 1.085/100 TFA
164
imagen177 1H-RMN (CD3OD/400 MHz): 7,41(d, 1H), 7,31(nd, 1H), 7,14(t, 1H), 6,92(d, 1H), 6,78(s, 1H), 6,39(m, 1H), 5,20(s, 2H), 3,86(m, 2H), 3,70(m, 2H), 3,29(m, 2H), 3,01 (m, 2H), 2,02(m, 4H). 406,4 113/100 TFA
165
imagen178 1H-RMN (CD3OD/400 MHz): 7,55(m, 1H), 7,37(m, 1H), 7,29(d, 1H), 5,02(s, 2H), 3,83(m, 4H), 3,46(m, 2H), 3,15 (m, 2H), 2,10 (m, 4H). 435,4+437,4 45.000/50 TFA
166
imagen179 1H-RMN (CD3OD/400 MHz): 7,56(s, 1H), 7,36(m, 2H), 7,29-6,60(m, 1H), 5,04(s, 2H), 3,84(m, 2H), 3,32(m, 6H), 1,32(t, 6H). 437,4+439,4 NA/NA TFA
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
167
imagen180 1H-RMN (CD3OD/400 MHz): 7,65-6,45(m, 4H), 4,96(m, 2H), 3,86(m, 2H), 3,30(m, 6H), 1,32(t, 6H). 437,4+439,4 186/100 TFA
168
imagen181 1H-RMN (CD3OD/400 MHz): 7,55-6,55(m, 4H), 4,92(m, 2H), 3,86(m, 2H), 3,30(m, 6H), 1,32(t, 6H). 437,4+439,4 97/100 TFA
169
imagen182 1H-RMN (CD3OD/400 MHz): 7.51(m, 2H), 7.41(m, 1H), 7.20(s, 1H), 5.32(s, 2H), 3.67(m, 2H), 3.21(m, 4H), 3.04(m, 2H), 1.24(t, 6H). 437,4+439,4 66/100 TFA
170
imagen183 1H-RMN (CD3OD/400 MHz): 7.36 (m, 2H), 7.21-6.68(m, 2H), 5.03(s,2H), 3.84(m, 2H), 3.32(m, 6H), 1.32(t, 6H). 421,4 505/100 TFA
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
171
imagen184 1H-RMN (CD3OD/400 MHz): 7,50(m, 1H), 7,28-6,50(m, 3H), 4,95(m, 2H), 3,87(m, 2H), 3,30(m, 6H), 1,33(t, 6H). 421,4 88/100 TFA
172
imagen185 1H-RMN (CD3OD/400 MHz): 7,43(m, 1H), 7,35(d, 1H), 7,20 (t, 1H), 7,16(s, 1H), 5,15(s, 2H), 3,71(m, 2H), 3,22(m, 4H), 3,12(m, 2H), 1,26(t, 6H). 421,4 94/100 TFA
173
imagen186 1H-RMN (CD3OD/400 MHz): 7.52-6.42(m, 5H), 4.97(s, 2H), 3.88(m, 2H), 3.68(m, 2H), 3.32(m, 2H), 2.97 (m, 2H), 1.96(m, 2H), 1.78(m, 3H), 1.54(m, 1H). 415,4 66/100 TFA
174
imagen187 1H-RMN (CD3OD/400 MHz): 7,52-6,42(m, 5H), 5,03(s, 2H), 4,20-3,45(m, 12H). 417,4 1.495/100 TFA
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
175
imagen188 1H-RMN (CD3OD/400 MHz): 7,45(m, 1H), 7,34(m, 3H), 6,87-6,44(m, 1H), 5,10(s, 2H), 3,82(m, 2H), 3,28 (m, 6H), 1,29 (t, 6H). 403,4+415,4 305/100 TFA
176
imagen189 1H-RMN (CD3OD/400 MHz): 7,47(m, 1H), 7,35(m, 3H), 6,80-6,32(m, 1H), 5,06(s, 2H), 3,83(m, 2H), 3,29 (m, 6H), 1,30 (t, 6H). 369,4 1.150/100 TFA
177
imagen190 1H-RMN (CD3OD/400 MHz): 7,41(m, 1H), 7,31 (m, 1H), 7,14(m, 2H), 5,19(s, 2H), 3,71(m, 4H), 3,33(m, 2H), 3,08(m, 2H), 2,08(m, 4H). 419,4 180/100 TFA
178
imagen191 1H-RMN (CD3OD/400 MHz): 7,48(m, 2H), 7,38(m, 1H), 7,18(s, 1H), 5,31(s, 2H), 3,64(m, 4H), 3,26(m, 2H), 3,25(m, 2H), 2,02(m, 4H). 435,4 126/100 TFA
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
179
imagen192 1H-RMN (CD3OD/400 MHz): 7,41(m, 1H), 7,32(m, 1H), 7,15(m,2H), 5,17(s, 2H), 3,73(m, 2H), 3,56(m, 2H), 3,18(m, 2H), 2,93(m, 2H), 1,92(m, 2H), 1,75(m, 3H), 1,48(m, 1H). 433,5 133/100 TFA
180
imagen193 1H-RMN (CD3OD/400 MHz): 7,48(m, 2H), 7,39(m, 1H), 7,18(s, 1H), 5,30(s, 2H), 3,68(m, 2H), 3,52(m, 2H), 3,10(m, 2H), 2,90(m, 2H), 1,90(m, 2H), 1,74(m, 3H), 1,48(m, 1H). 449,4 154/100 TFA
181
imagen194 1H-RMN (CD3OD/400 MHz): 7,46(m, 1H), 7,34(m, 2H), 7,27(m, 1H), 6,66(bs, 1H), 5,04(s, 2H), 4,04(m, 1H), 3,68(m, 4H), 3,24(m, 2H), 2,60 (m, 2H), 1,39 (d, 3H). 415,5 430/100 TFA
182
imagen195 1H-RMN (CD3OD/400 MHz): 7,39(m, 1H), 7,26(m, 1H), 7,17(d, 1H), 6,66(bs, 1H), 5,08(m, 2H), 3,86(m, 2H), 3,30(m, 6H), 1,32(t, 6H). 421,5 109/100 TFA
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
183
imagen196 1H-RMN (CD3OD/400 MHz): 7,34-6,66(m, 4H), 4,96(s, 2H), 3,85(m, 2H), 3,29(m, 6H), 1,31(t, 6H). 418,5 185/100 TFA
184
imagen197 1H-RMN (CD3OD/400 MHz): 7,41(m, 1H), 7,37(m, 1H), 7,24(m, 1H), 7,16(m, 1H), 6,54(bs, 1H), 5,01(s, 2H), 3,89(m, 2H), 3,31 (m, 6H), 2,99(m, 1H), 1,31 (t, 6H), 1,19(d, 6H). 411,5 1.950/85 TFA
185
imagen198 1H-RMN (CD3OD/400 MHz): 7,45(m, 1H), 7,33(m, 3H), 7,15-6,59(m, 1H), 4,99(s, 2H), 3,59(m, 2H), 3,18 (m, 6H), 2,01(m, 2H), 1,29 (t, 6H). 417,4 1750/53 TFA
186
imagen199 1H-RMN (CD3OD/400 MHz): 7,45(m, 1H), 7,33(m, 3H), 7,15-6,59(m, 1H), 4,97(s, 2H), 3,61(m, 2H), 3,16 (m, 6H), 2,88(s, 6H), 2,00 (m, 2H). 389,4 375/100 TFA
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
187
imagen200 1H-RMN (CD3OD/400 MHz): 7,47(m, 1H), 7,33(m, 3H), 6,61(bs, 1H), 5,04(bs, 2H), 3,87(t, 2H), 3,38 (t, 6H), 2,97(s, 6H). 375,4 295/100 TFA
188
imagen201 1H-RMN (CD3OD/400 MHz): 7,48(m, 1H), 7,33(m, 3H), 6,53(bs, 1H), 4,99(bs, 2H), 3,90(m, 2H), 3,59(m, 2H), 3,35(m, 2H), 2,52 (t, 2H), 1,88(m, 3H), 0,98(m, 7H). 443,5 46/60 TFA
189
imagen202 1H-RMN (CD3OD/400 MHz): 7,47(m, 1H), 7,34(m, 3H), 6,62(bs, 1H), 5,03(bs, 2H), 3,88(m, 2H), 3,56(m, 2H), 3,37(m, 2H), 3,25 (m, 2H), 1,93(m, 4H), 1,73(m, 4H). 429,4 24/100 TFA
190
imagen203 1H-RMN (CD3OD/400 MHz): 7,48(m, 1H), 7,33(m, 3H), 6,52(bs, 1H), 4,98(bs, 2H), 3,88(m, 2H), 3,71(m, 2H), 3,33(m, 2H), 2,97 (m, 2H), 1,93(m, 2H), 1,70(m, 1H), 1,44(m, 2H), 1,00 (d, 3H). 429,4 42/100 TFA
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
191
imagen204 1H-RMN (CD3OD/400 MHz): 7,48(m, 1H), 7,33(m, 3H), 6,50(bs, 1H), 4,97(bs, 2H), 3,90(m, 2H), 3,63(m, 2H), 3,33(m, 2H), 2,86 (t, 2H), 2,59 (t, 2H), 1,86 (m, 4H), 1,18(m, 1H), 1,00 (d, 3H). 429,4 29/100 TFA
192
imagen205 1H-RMN (CD3OD/400 MHz): 7,48(m, 1H), 7,33(m, 3H), 6,50(bs, 1H), 4,99(bs, 2H), 3,90(m, 2H), 3,62(m, 2H), 3,33(m, 2H), 2,05-1,20(m, 10H). 429,4 104/100 TFA
193
imagen206 1H-RMN (CD3OD/400 MHz): 7,40(m, 4H), 4,94(s, 2H), 3,76(m, 2H), 3,22(m, 6H), 1,26(t, 6H). 387,4 14.000/58 TFA
194
imagen207 1H-RMN (CD3OD/400 MHz): 7,18(m, 1H), 6,92-6,66(m, 3H), 4,87(bs, 2H), 3,81(m, 2H), 3,50(m, 2H), 3,28(m, 4H), 1,93(m, 4H), 1,73(s, 4H). 445,4 43/100 TFA
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
195
imagen208 1H-RMN (CD3OD/400 MHz): 7,10(m, 1H), 6,91(bs, 1H), 6,62(d, 1H), 6,57(d, 1H), 4,88(bs, 2H), 3,80(m, 2H), 3,51(m, 2H), 3,26(m, 4H), 1,91(m, 4H), 1,72(s, 4H). 429,5 95/100 TFA
196
imagen209 1H-RMN (CD3OD/400 MHz): 7,10(m, 1H), 6,73(m, 3H), 4,88(bs, 2H), 3,86(m, 2H), 3,54(m, 2H), 3,28(m, 4H), 1,92(m, 4H), 1,74(s, 4H). 444,4 99/100 TFA
197
imagen210 1H-RMN (CD3OD/400 MHz): 7,33(m, 2H), 7,18(m, 2H), 6,78(bs, 1H), 5,00 (bs, 2H), 3,85(m, 2H), 3,55(m, 2H), 3,37(m, 2H), 3,25(m, 2H), 1,91(m, 4H), 1,72(s, 4H). 413,4 63/100 TFA
198
imagen211 1H-RMN (CD3OD/400 MHz): 7,42(m, 1H), 7,10-6,95(m,32H), 5,09 (bs, 2H), 3,79(m, 2H), 3,51(m, 2H), 3,31(m, 2H), 3,21(m, 2H), 1,90(m, 4H), 1,72(s, 4H). 431,5 130/100 TFA
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
199
imagen212 1H-RMN (CD3OD/400 MHz): 7,49(m, 1H), 7,33(m, 3H), 6,50(bs, 1H), 4,97 (bs, 2H), 3,88(m, 2H), 3,70(m, 2H), 3,33(m, 2H), 2,97(m, 2H), 2,00(m, 2H), 1,38(m, 5H), 0,94(t, 3H). 443,5 100/100 TFA
200
imagen213 1H-RMN (CD3OD/400 MHz): 7,22(m, 1H), 6,74(m, 3H), 4,90 (bs, 2H), 3,88(m, 2H), 3,63(m, 2H), 3,31(m, 2H), 2,87(t, 1H), 2,59(t, 1H), 1,86(m, 4H), 1,18(m, 1H), 1,00(d, 3H). 444,5 130/100 TFA
201
imagen214 1H-RMN (CD3OD/400 MHz): 7,34(m, 2H), 7,18(m, 2H), 6,81(bs, 1H), 5,02 (bs, 2H), 3,86(m, 2H), 3,63(m, 2H), 3,31(m, 2H), 2,85(t, 1H), 2,58 (t, 1H), 1,85(m, 4H), 1,16(m, 1H), 0,98(d, 3H). 413,5 215/100 TFA
202
imagen215 1H-RMN (CD3OD/400 MHz): 7,23(m, 1H), 6,77(m, 3H), 4,94 (bs, 2H), 3,86(m, 2H), 3,76(m, 1H), 3,59(m, 1H), 3,39(m, 1H), 3,25(m, 2H), 3,05(t, 1H), 2,06-1,68(m, 5H), 1,57(m, 2H), 1,38(m, 3H). 444,4 395/100 TFA
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
203
imagen216 1H-RMN (CD3OD/400 MHz): 7,36(m, 2H), 7,18(m, 2H), 6,85(bs, 1H), 5,02 (bs, 2H), 3,86(m, 2H), 3,77(m, 1H), 3,59(m, 1H), 3,40(m, 1H), 3,26(m, 2H), 2,85(t, 1H), 2,58 (t, 1H), 2,22-1,68(m, 5H), 1,58(m, 2H), 1,36(m, 3H). 413,5 550/100 TFA
204
imagen217 1H-RMN (CD3OD/400 MHz): 7,48(m, 1H), 7,39(m, 3H), 6,74(bs, 1H), 5,07 (m, 2H), 3,86(m, 2H), 3,75(m, 1H), 3,25(m, 4H), 1,31(m, 9H). 417,4 880/53 TFA
205
imagen218 1H-RMN (CD3OD/400 MHz): 7,48(m, 1H), 7,32(m, 3H), 6,60(bs, 1H), 5,04(s, 2H), 3,92(m, 2H), 3,80-3,38(m, 6H), 2,38(m, 4H). 451,4 2.050/100 TFA
206
imagen219 1H-RMN (CD3OD/400 MHz): 7,32(m, 1H), 7,15(m, 2H), 6,92(m, 1H), 6,75(bs, 1H), 5,27(m, 2H), 3,88(t, 2H), 3,73(m, 2H), 3,33(t, 2H), 3,04 (m, 2H), 2,02(m, 4H). 424,4 136/100 TFA
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
207
imagen220 1H-RMN (CD3OD/400 MHz): 7,10(d, 1H), 6,84(m, 2H), 6,71(d, 1H), 4,89(s, 2H), 3,80(m, 2H), 3,49(m, 2H), 3,22(m, 4H), 1,90(m, 4H), 1,72(s, 4H). 444,4 170/75 TFA
208
imagen221 1H-RMN (CD3OD/400 MHz): 9,26(m, 1H), 7,77(m, 1H), 7,58(m, 1H), 7,44(bs, 1H), 7,32-6,78,(m, 1H), 5,45-5,07 (m, 2H), 4,35-3,82(m, 2H), 3,78-3,20(m, 6H), 1,92(s, 4H), 1,73(s, 4H). 435,5 125/100 TFA
209
imagen222 1H-RMN (CD3OD/400 MHz): 7,47(m, 1H), 7,37(m, 3H), 6,71(s, 1H), 5,05(s, 2H), 3,86(m, 2H), 3,50-3,20 (m, 4H), 3,13(m, 2H), 1,71(m, 2H), 1,30(t, 3H), 0,99 (t, 3H). 417,5 52/100 TFA
210
imagen223 1H-RMN (CD3OD/400 MHz): 7,83(m, 1H), 7,57(m, 3H), 7,28-6,40,(m, 1H), 5,45-4,90 (m, 2H), 3,90(m, 2H), 3,60(m, 2H), 3,46(m, 2H), 3,28(m,2H), 1,92(m, 4H), 1,74(s, 4H). 474,5 133/100 TFA
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
211
imagen224 1H-RMN (CD3OD/400 MHz): 7,89(m, 1H), 7,83(m, 1H), 7,63(m, 1H), 7,15(s, 1H), 5,24(bs, 2H), 3,75(m, 2H), 3,48(m, 2H), 3,27(m, 4H), 1,90(m, 4H), 1,73(s, 4H). 474,5 123/100 TFA
212
imagen225 1H-RMN (CD3OD/400 MHz): 7,49(m, 1H), 7,39(m, 3H), 6,76,(bs, 1H), 5,04(m, 2H), 3,75(m, 2H), 3,58-3,10 (m, 4H),2,01-1,25(m, 12H). 443,5 5.812/53 TFA
213
imagen226 1H-RMN (CD3OD/400 MHz): 7,10(t, 1H), 6,86(d, 1H), 6,67(bs, 1H), 6,60(d, 1H), 4,95(s, 2H), 3,86(t, 2H), 3,54(m, 2H), 3,31 (t, 2H), 3,22(m, 2H), 1,92(m, 4H), 1,73(m, 4H). 444,4 60/100 TFA
214
imagen227 1H-RMN (CD3OD/400 MHz): 7,40-6,70(m, 4H), 5,02(m, 2H), 3,86(m, 2H), 3,57(m, 2H), 3,40(m, 2H), 3,28(m, 2H), 1,92(m, 4H), 1,73(m, 4H). 428,5 153/100 TFA
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
215
imagen228 1H-RMN (CD3OD/400 MHz): 7,34(m, 1H), 7,18(m, 2H), 6,69(bs, 1H), 4,95(bs, 2H), 3,86(m, 5H), 3,56(m, 2H), 3,38(m, 2H), 3,28(m, 2H), 1,92(m, 4H), 1,73(bs, 4H). 440,5 1.185/100 TFA
216
imagen229 1H-RMN (CD3OD/400 MHz): 6,97(t, 1H), 6,89(m, 2H), 6,60(m, 1H), 4,97(s, 2H), 3,84(t, 2H), 3,52(m, 2H), 3,31(t, 2H), 3,22(m, 2H), 1,90(m, 4H), 1,72(m, 4H). 428,5 117/100 TFA
217
imagen230 1H-RMN (CD3OD/400 MHz): 7,04(t, 1H), 6,97 (d, 1H), 6,88(bs, 1H), 6,78(d, 1H), 4,96(s, 2H), 3,82(t, 2H), 3,62(s, 3H), 3,50(m, 2H), 3,23(m, 4H), 1,90(m, 4H), 1,72(m, 4H). 440,5 230/100 TFA
218
imagen231 1H-RMN (CD3OD/400 MHz): 7,52(d, 1H), 7,19(s, 1H), 7,09(t, 1H), 6,76 (d, 1H), 5,06(bs, 2H), 4,41-3,29(m, 6H), 3,06(m, 2H), 1,87(m, 4H), 1,72(m, 4H). 444,4 41/100 TFA
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
219
imagen232 1H-RMN (CD3OD/400 MHz): 7,47(m, 1H), 7,33(m, 3H), 6,60(bs, 1H), 5,03(bs, 2H), 4,12-3,81(m, 2H), 3,80-3,48(m, 2H), 3,36(m, 2H), 3,06 (m, 1H), 2,13(m, 1H), 1,94(m, 2H), 1,71 (m, 1H). 431,4 1.300/100 TFA
220
imagen233 1H-RMN (CD3OD/400 MHz): 7,47(m, 1H), 7,33(m, 3H), 6,61 (bs, 1H), 5,02(bs, 2H), 4,21-3,25(m, 7H), 3,19-2,62(m, 2H), 2,35-1,48 (m, 4H). 431,4 465/100 TFA
221
imagen234 1H-RMN (CD3OD/400 MHz): 7,43(m, 1H), 7,36(m, 2H), 7,13(m, 1H), 5,08(q, 2H), 4,40-4,00(m, 2H), 3,37(m, 3H), 2,04(m, 5H), 1,41 (d, 3H). 430,4 223/60 TFA
222
imagen235 1H-RMN (CD3OD/400 MHz): 7,50-6,68(m, 4H), 5,12(s, 2H), 4,20(t, 2H), 3,81(t, 2H), 3,43(m, 4H), 2,10(m, 4H). 416,5 56/100 TFA
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
223
imagen236 1H-RMN (CD3OD/400 MHz): 7,46-6,61(m, 4H), 5,08(m, 2H), 4,22-3,60(m, 2H), 3,14 (m, 2H), 2,98(m, 2H), 1,75(m, 1H), 1,58(m, 2H), 1,34(t, 1H), 1,22(t, 2H), 0,96 (m, 3H). 432,5 32/100 TFA
224
imagen237 1H-RMN (CD3OD/400 MHz): rotámeros 7,65-7,10(m, 4H), 5,16+4,41(s, 2H), 3,92+3,31(t, 2H), 3,16-3,01(m, 5H), 2,96(m, 4H), 2,88(t, 1H). 480,4 410/100 TFA
225
imagen238 1H-RMN (CD3OD/400 MHz): 7,49(m, 1H), 7,37(m, 2H), 7,14(m, 1H), 5,13(s, 2H), 4,22(m, 2H), 4,06(bs, 1H), 3,74(t, 2H), 3,25(m, 7H), 3,28(m, 4H), 2,14(m, 1H), 1,77 (m, 3H). 446,4 102/100 TFA
226
imagen239 1H-RMN (CD3OD/400 MHz): 7,50-7,12(m, 5H), 4,86 (m, 3H), 3,82 (m, 1H), 2,81 (m, 2H), 2,39 (m, 2H). 356,3 12.000/80 TFA
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
227
imagen240 1H-RMN (CD3OD/400 MHz): 7,61-7,22(m, 4H), 6,54(bs, 1H), 4,98 (m, 1H), 4,61(m, 1H), 4,45(m, 1H), 4,32(m, 1H), 4,00 (m, 1H), 3,83(m, 1H), 3,52(m, 1H), 3,07(m, 1H), 2,43 (m, 2H), 2,17 (m, 1H). 373,4 215/100 TFA
228
imagen241 1H-RMN (CD3OD/400 MHz): 7,42(m, 1H), 7,31(m, 3H), 7,15+6,59(bs, 1H), 4,89(m, 2H), 3,52(m, 5H), 2,74(m, 4H), 2,48(m, 1H), 1,60(m, 6H), 1,07 (m, 1H). 493,4 2.000/100 TFA
229
imagen242 1H-RMN (CD3OD/400 MHz): 7,50-6,90(m, 9H), 6,72-6,40(m, 1H), 4,87(s, 1H), 4,70(bs, 1H), 4,00-3,57(m, 2H), 2,89 (m, 2H). 408,4 NA/NA -
230
imagen243 1H-RMN (CD3OD/400 MHz): 7,42(m, 1H), 7,30(m, 3H), 6,99(d, 1H), 6,85(d, 1H), 6,78-6,42(m, 3H), 4,86(s, 1H), 4,74(bs, 1H), 3,72(m, 1H), 3,58(m, 1H), 2,78 (m, 2H). 424,4 12.000/100 -
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
231
imagen244 1H-RMN (CD3OD/400 MHz): 7,48(m, 1H), 7,33(m, 3H), 6,72(bs, 1H), 5,09 (m, 2H), 4,01(m, 1H), 3,71(m, 3H), 3,47(m, 1H), 3,22 (m, 1H), 3,10(m, 1H), 2,24(m, 1H), 2,07(m, 2H), 1,88 (m, 1H), 1,36 (t, 1H). 415,5 148/65 TFA
232
imagen245 1H-RMN (CD3OD/400 MHz): 7,56-7,20(m, 4H),, 6,49(bs, 1H), 4,99 (bs, 2H), 4,13(m, 1H), 3,76(m, 1H), 3,52(m, 1H), 3,40(m, 1H), 3,28 (m, 1H), 2,05(m, 3H), 1,73(m, 1H). 387,5 320/85 TFA
233
imagen246 1H-RMN (CD3OD/400 MHz): 7,53(m, 2H), 7,44(m, 1H), 7,37(m, 1H), 4,88 (m, 1H), 4,40(s, 2H), 4,10(m, 1H), 3,97(m, 1H), 3,77 (m, 1H), 3,57(m, 1H), 2,66(m, 1H), 2,52 (m, 1H). 388,4 930/75 TFA
234
imagen247 1H-RMN (CD3OD/400 MHz): 7,60-7,32(m, 3H), 7,20-6,66(m, 1H), 5,13+4,39(s, 2H), 5,05+4,94(bs, 1H), 4,56(m, 1H), 4,21+3,87(m, 1H), 3,64(m, 2H), 3,54 (m, 2H), 3,46(m, 2H), 2,26(m, 1H), 2,06 (m, 1H). 432,5 111/100 TFA
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
235
imagen248 1H-RMN (CD3OD/400 MHz): 7,60-7,32(m, 3H), 7,20-6,66(m, 1H), 5,12+4,37(s, 2H), 5,05+4,10(bs, 1H), 4,18(m, 1H), 4,20+3,84(m, 1H), 3,56(m, 2H), 3,50 (m, 2H), 3,41(m, 2H), 3,32(d, 3H), 2,06 (m, 2H). 446,5 133/100 TFA
236
imagen249 1H-RMN (CD3OD/400 MHz): 7,60-6,66(m, 4H), 5,20-4,45(m, 3H), 5,05+4,10(bs, 1H), 4,00-4,12(m, 1H), 3,80+3,52(m, 2H), 3,41(m, 2H), 3,23-2,78(m, 3H), 2,06(m, 2H), 1,82(m, 2H). 448,4 160,73 TFA
237
imagen250 1H-RMN (CD3OD/400 MHz): 7,60-6,66(m, 4H), 5,12+4,38(s, 2H), 5,00(m, 1H), 4,22(m, 1H), 3,80-2,80(m, 10H), 2,16-1,62 (m, 4H). 460,5 183/100 TFA
238
imagen251 1H-RMN (CD3OD/400 MHz): 7,60-6,66(m, 4H), 5,14+4,38(s, 2H), 5,07+3,10(bs, 1H), 4,24+3,92(m, 1H), 3,82(m, 4H), 3,51(m, 3H), 3,41(m, 1H), 3,36(m, 1H), 2,15(m, 2H). 446,5 116/100 TFA
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
239
imagen252 1H-RMN (CD3OD/400 MHz): 7,60-6,66(m, 4H), 5,13+4,39(s, 2H), 4,99(m, 1H), 4,25(m, 1H), 3,76(m, 1H), 3,56(m, 1H), 3,50-3,00(m, 6H), 2,14(m, 4H). 448,4 115/100 TFA
240
imagen253 1H-RMN (CD3OD/400 MHz): 7,58-6,35(m, 4H), 5,08(m, 2H), 4,22-3,60(m, 2H), 3,58-2,95(m, 6H), 1,69(m, 2H), 1,28(m, 3H), 0,97 (m, 3H). 416,5 68/100 TFA
241
imagen254 1H-RMN (CD3OD/400 MHz): 7,60-6,62(m, 4H), 5,55-4,97(m, 2H), 4,34(s, 1H), 4,19+3,80(m, 1H), 3,76-3,05(m, 7H), 2,30 (m, 2H). 434,4 125/100 TFA
242
imagen255 1H-RMN (CD3OD/400 MHz): 7,60-6,62(m, 4H), 5,55-4,97(m, 2H), 4,34(s, 1H), 4,19+3,80(m, 1H), 3,76-3,05(m, 7H), 2,30 (m, 2H). 434,4 465/100 TFA
EJ.
Estructura RMN ES-MS (M++1) PKM2 AC50 (nM)/Resp. máx.* (%) Nota†
243
imagen256 1H-RMN (CD3OD/400 MHz): 7,60-6,60(m, 4H), 5,16+4,24(s, 2H), 4,95(m, 1H), 4,19+3,85(m, 1H), 3,76-2,70(m, 7H), 2,08 (m, 6H). 462,4 106/100 TFA
244
imagen257 1H-RMN (CD3OD/400 MHz): 7,05 (m, 1H), 6,51 (m, 3H), 4,70 (m, 2H), 3,47 (m, 2H), 2,64 (s, 1H), 2,00 (s, 2H), 1,80 (m, 4H). 337,9 62/107 -
245
imagen258 1H-RMN (DMSO-d6/400 MHz): 13,84 (s, 1H), 9,87 (s, 1H), 7,05 (m, 1H), 6,58 (m, 3H), 4,56 (m, 2H), 3,46 (m, 2H), 2,55 (m, 1H), 1,90-1,54 (m, 6H). 382,1 35/100 -
246
imagen259 1H-RMN (CDCl3/400 MHz): 8,00 (s, 1H), 7,20 (m, 1H), 6,51 (m, 2H), 6,20 (m, 1H), 4,70 (m, 2H), 3,50 (m, 2H), 2,64 (m, 1H),1,99 (m, 2H), 1,85-1,79 (m, 5H), 0,93 (m, 2H), 0,70 (m, 2H) 344,2 92/85 -
* Resp. máx. (%) representa el % de respuesta máxima en un ensayo bioquímico en comparación con la fructosa 1,6bisfosfato. † Indica la forma salina si es aplicable. TFA = ácido trifluoroacético
Se entiende que cualquier forma de realización de los compuestos de estructura (I), incluidas las estructuras (Ia), (lb) e (Ic), como se ha indicado anteriormente, y cualquiera de los sustituyentes específicos expuestos en la presente memoria (p. ej., R1-R23) en los compuestos de estructuras (I), (la), (lb) y (Ic), como se ha indicado anteriormente, se 5 pueden combinar independientemente con otras realizaciones y/o sustituyentes de compuestos de estructuras (I), (la) , (Lb) y (Ic) para formar realizaciones de las invenciones no expuestas específicamente anteriormente. Además, en el caso de que una lista de sustituyentes se liste para cualquier grupo R determinado en una realización y/o reivindicación determinada, se entiende que cada uno de los sustituyentes puede ser eliminado de la realización y/o reivindicación determinada y que la lista restante de sustituyentes se considerará que están dentro del alcance de la 10 invención. Se entiende que en la presente descripción, las combinaciones de sustituyentes y/o variables de las
imagen260
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Indicación
Estirpe celular Sensibilidad a serina Sensibilidad al ejemplo 1
SW48
Sensible >30 μM
SW480
Insensible 100 nM
SW620
Sensible 200 nM
SW948
Insensible >30 μM
GIST
Gist882 Insensible 800 nM
Cabeza/Cuello
Detroit562 Sensible 3 μM
FaDu
Sensible >30 μM
Riñón
786-O Sensible >30 μM
A498
Insensible >30 μM
Caki-1
Insensible 80 nM
ACHN
Insensible 100 nM
Hígado
HepG2 Insensible >30 μM
Pulmón
A549 Sensible 100 nM
H1299
Insensible 600 nM
NCI-H460
Sensible 5 μM
NCI-H647
Sensible >30 μM
NCI-H23
Insensible N/A
NCI-H522
Insensible >30 μM
NCI-H1975
Sensible 90 nM
NCI-H441
Sensible N/A
Melanoma
Malme3M Insensible >30 μM
Ovario
OVCAR-3 Sensible 20 nM
Skov3
Sensible 8 μM
Pancreático
AsPC1 Sensible >30 μM
Capan1
Insensible >30 μM
Capan2
Sensible >30 μM
Panc-1
Insensible 14 nM
Hs766T
Insensible 300 nM
PSN-1
Sensible >30 μM
MiaPaCa2
Sensible 200 nM
PL45
Sensible >30 μM
Próstata
22RV1 Insensible >30 μM
Du145
Insensible >30 μM
LNCaP
Sensible >30 μM
PC3
Sensible 100 nM
Sarcoma
HT1080 Sensible 50 nM
imagen290
El porcentaje de viabilidad (CE50) de las células A549 y PC3 se ensayó frente a determinados compuestos ilustrativos según los procedimientos generales anteriores. Los resultados se presentan en la Tabla 5 y la figura 8.
Tabla 5. Viabilidad de las células A549 y PC3 en presencia de compuestos ilustrativos
imagen291
imagen292

Claims (4)

  1. imagen1
    imagen2
    imagen3
    imagen4
    imagen5
    R20 es alcoxi, hidroxilo o halo; y x es 0, 1, 2 o 3; o
    (Ic)
    imagen6
    o un estereoisómero, sal o tautómero farmacéuticamente aceptable del mismo,
    10
    en donde: R21 y R22 son cada uno independientemente H o halo; 15 R23 es H o alquilo; e
    imagen7
  2. 15. El compuesto de la reivindicación 1, en donde el compuesto se selecciona del grupo que consiste en:
    imagen8
    109
    imagen9
    imagen10
    imagen11
    imagen12
    imagen13
    114
    imagen14
    imagen15
    imagen16
    imagen17
    imagen18
    119
    imagen19
    imagen20
    imagen21
    imagen22
    imagen23
  3. 16. Una composición farmacéutica que comprende un compuesto de una cualquiera de las reivindicaciones 1-15, o
    un estereoisómero o sal farmacéuticamente aceptable del mismo, y un vehículo, diluyente o excipiente 5 farmacéuticamente aceptable.
  4. 17. El compuesto deuna cualquiera delas reivindicaciones 1-15 o la composición dela reivindicación 16 para uso en un método de tratamiento de cáncer en un mamífero que lo necesite, preferiblemente en donde el cáncer es cáncer pulmonar.
    124
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