ES2693718T3 - Derivados de piridina sustituidos útiles como inhibidores de GSK-3 - Google Patents

Derivados de piridina sustituidos útiles como inhibidores de GSK-3 Download PDF

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ES2693718T3
ES2693718T3 ES14802989.5T ES14802989T ES2693718T3 ES 2693718 T3 ES2693718 T3 ES 2693718T3 ES 14802989 T ES14802989 T ES 14802989T ES 2693718 T3 ES2693718 T3 ES 2693718T3
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esi
isonicotinamide
mhz
nmr
alkyl
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Guanglin Luo
Ling Chen
Gene M. Dubowchik
Swanee E. Jacutin-Porte
Prasanna SIVAPRAKASAM
John E. Macor
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Bristol Myers Squibb Co
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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Abstract

Un compuesto de formula I**Fórmula** donde: R1 es alquilo, haloalquilo, cicloalquilo, halocicloalquilo alquilcicloalquilo, dialquilcicloalquilo, fenilcicloalquilo, hidroxicicloalquilo o cetocicloalquilo; R2 es hidrogeno o alquilo; R3 es hidrogeno o alquilo; o N(R2)(R3) tomado conjuntamente es azetidinilo, pirrolidinilo, piperidinilo, piperazinilo, morfolinilo o azabicicloheptano, y esta sustituido con 0-4 sustituyentes halo o alquilo; Ar1 es 3-piridinilo y esta sustituido con 0-3 sustituyentes seleccionados entre ciano, halo, alquilo, haloalquilo, hidroxialquilo, (hidroxil)haloalquilo, alcoxialquilo, alquilo (N(R2)(R3)), bencilo, alquenilo, cicloalquilo, hidroxi, alcoxi, haloalcoxi, (hidroxil)alcoxi, (alcoxi)alcoxi, (cicloalquil)alcoxi, fenoxi, alquilcarbonilo, (haloalquil)carbonilo, fenilcarbonilo, alcoxicarbonilo, carboxi, aminocarbonilo, acetamido, N(R2)(R3) y Ar2; y Ar2 es fenilo, naftalenilo, pirrolilo, furanilo, tienilo, pirrazolilo, isoxazolilo, isotiazolilo, imidazolilo, oxazolilo, tiazolilo, piridinilo, pirimidinilo, pirazinilo, piridazinilo, indolilo, benzofuranilo, benzotiofenilo o quinolinilo, y esta sustituido con 0-3 sustituyentes seleccionados entre el grupo que consiste en ciano, halo, alquilo, haloalquilo, alcoxi, haloalcoxi, alquilcarbonilo y N(R2)(R3); en donde "alquilo" significa un grupo alquilo lineal o ramificado compuesto por de 1 a 6 atomos de carbono; "alquenilo" significa un grupo alquilo lineal o ramificado compuesto por de 2 a 6 atomos de carbono con al menos un doble enlace; "cicloalquilo" significa un sistema de anillo monociclico compuesto por de 3 a 7 atomos de carbono; o una sal farmaceuticamente aceptable del mismo.

Description

imagen1
imagen2
imagen3
imagen4
imagen5
y se evaluaron a once concentraciones. Los valores de la CI50 se derivaron mediante análisis por regresión no lineal.
imagen6
Ejemplos
R1 R2 GSK3β/α (nM) pTau (nM)
1
H H 60/9,0 1000
2
H 4-OMe 2,8/4,5 240
3
H 4-OCH2CF3 4,6/2,2 260
4
H 6-NHC(O)CH3 370/180 7200
5*
H 5,6-Benzo 570/230 10000
6*
H 4,5-Benzo 7,2/2,7 190
7
H 6-OMe 2000/1000 10000
8
H 5-Me-6-F 48/24 1800
9
H 4-Me 30/22 1200
10
H 6-Ph 16/64 1800
11
H 6-Me 30/15 2200
12
H 5-F 33/16 1400
13
H 5-OMe 13/7,3 550
14
H 4-C(O)Me 0,85/0,54 76
15
H 5-Br 16/11 610
16
H 4-C(OH)Me2 0,11/0,20 2,8
17
H 4-C(OH)Me 0,25/1,4 35
18
H 4-Ph 11/5,6 360
19
H 4-I 1,4/0,96 35
20
H 4-CF3 15/6,3 960
21*
H 4,5-(CH2)4 13/3,3 -
22
H 5-Ciclopropil 7,1/2,4 250
23
H 4-C(OH)CF3 5,8/2,4 48
24
H 4-C(O)CF3 0,95/1,2 110
25
H 4-OEt 6,3/2,6 170
26
H 4-OiPr 2,6/1,4 -
27
H 4-O(CH2)2OH 6,2/3,2 270
28
H 4-OCH2-Ciclopropil 4,7/1,8 65
29
H 4-Cl 12/4,3 260
30
H 4-(N-morfolina) 1,0/0,54 23
31
H 4-(3-tiofeno) 4,4/ 200
32
H 4-(3-piridina) 160/ 3200
33
H 4-(4-piridina) 28/ 670
34
H 4-(4-F-Ph) 6,5/1,7 180
35
H 4-(3-F-Ph) 42/ 480
36
H 4-ciclopentil 41/ 800
37
H 4-ciclohexil 120/ 1200
38
H 4-isopropenil 4,4/ 80
39
H 4-isopropil 23/ 470
40
H 4-OPh 4,3/1,9 200
41
H 4-ciclobutil 7,5/3,0 380
42
H 4-(2-F-Ph) 10/3,2 290
43
H 4-(5-Me-3-tiofeno) 2,8/0,85 49
44
H 4-OCH2tBu 0,94/0,74 36
45
H 4-(4,4-F2-1-piperidina) 0,22/0,19 5,1
46
H 4-(2-Me-4-morfolina) 0,54/0,37 57
47
H 4-(4-OMe-Ph) 1,3/0,49 77
48
H 4-(4-Me-Ph) 3,4/1,1 120
49
H 4-(4-CN-Ph) 6,2/1,9 96
50
H 4-(N-piperidina) 0,99/0,35 23
51
H 4-(4-Cl-Ph) 7,1/2,0 200
52
H 4-(3 (R)-Me-4-morfolina) 0,49/0,21 12
53
H 4-(N-azepan-1-il) 37/14 1200
54
H 4-(3(S)-Me-4-morfolina) 0,06/0,07 2,0
55
H 4-(4-OCF3-Ph) 15/6,9 270
56
H 4-(4-CF3-Ph) 13/8,4 230
57
H 2-OH 500/210 10000
58
H 2-F 35/34 1600
59
H 2-Cl-4-Ph 78/70 8200
60
H imagen7 16/5,7 620
61
H 2-CN 65/43 -
62
H 2-Ph-4-OMe 2,6/4,8 310
63*
H 2-Ph-4,5-Benzo 12/56 4100
64
H 4-(5-pirimidina) 97/76 10000
65
H 4-(2,4-(CF3)2-Ph) 29/25 -
66
H 4-(2,4-Cl2-Ph) 3,6/2,1 -
67
H 4-(2-CF3-Ph) 1,4/0,66 28
68
H 4-(2-Cl-Ph) 2,3/0,88 61
69
H 4-(2-Cl-4-F-Ph) 0,70/0,28 29
70
H 4-(2-Cl-4-CF3-Ph) 7,0/4,5 280
71
H 4-(2-CF3-4-F-Ph) 0,33/0,17 14
72
H 4-(4-nPr-Ph) 3,1/6,4 250
73
H 4-(2,4-F2-Ph) 1,0/0,34 62
74
H 4-(4-tBu-Ph) 5,4/19 800
75
H 4-(4-iPr-Ph) 30/7,4 460
76
H 4-(2-F-4-Cl-Ph) 4,9/1,2 75
77
H 4-(2(R)-Me-4-morfolina) 8,8/2,7 220
78
H 4-(2(S)-Me-4-morfolina) 0,99/0,35 18
79
H 4-(2,6(cis)-Me2-4-morfolina) 14/5,5 190
80
H 4-(3,3-F2-1-piperidina) 1,5/0,46 34
81
H 4 -(2-F-4-OMe-Ph) 1,3/0,58 31
82
H 4-(2-F-4-CF3-Ph) 9,6/4,0 200
83
H 4-(3,3-F2-1-pirrolidina) 71/49 4400
84
H 4-(2,5-F2-Ph) 28/15 770
85
H 4-(2-F-4-CN-Ph) 2,9/0,94 33
86
H 4-(2-F-5-Cl-Ph) 54/26 630
87
H 4-(2,2-Me2-4-morfolina) 0,79/0,39 25
88
H 2-F-4-(4-morfolina) 9,1/3,9 170
89
H 4-(2-CN-4-F-Ph) 470/190 -
90
H 4-(3,3-Me2-4-morfolina) 0,15/0,10 0,40
91
H 4-(2,3-F2-Ph) 19/6,4 230
92
H 4-(2-F-4-C(O)NMe2-Ph) 24/11 460
93
H 4-(4-OCHF2-Ph) 7,8/3,1 180
94
H 4-(2-F-4-OCF3-Ph) 13/5,0 120
95
H imagen7 1,9/1,4 100
96
H imagen7 4,1/1,7 66
97
2,2-Me2 4-Ph 1,1/8,5 870
98
2,2-F2 4-Ph 11/17 1400
99
2(trans)-Ph 4-Ph 1,8/24 4500
100
2(trans)-Me 4-Ph 26/7,5 350
101
H 5-COOMe 30/13 3100
102
H 5-Me 9,5/5,4 740
103
H 5-COOH 197/121 10000
104
H 5-Ph 5/2 270
105
H 5-CONH2 6,5/3,6 6900
106
H 5-(4-Py) 4,8/2,5 320
107
H 5-(OPh) 19/9,1 3300
108
H 5-(N-piperidina) 130/23 5400
109
H 5-(N-Morfolina) 73/17 2000
110
H 5-(CH2Ph) 73/11 5600
111
H 5-(4-F-Ph) 6,4/0,95 570
112
H 5-(3,4-diF-Ph) BMT 041729
113
H 5-ciclobutil 1,0/1,75 330
114
H 5-(2,4-diF-Ph) 1,6/1,3 990
115
H 5-(4-CN-Ph) 4,1/4,3 780
116
H 5-(2-F-Ph) 0,35/0,28 180
117
H 5-(3-tiofeno) 1,2/1,9 -
118
H 5-(1-pirazol) 1,5/0,74 330
119
H 5-(1-imidazol) 2,4/1,0 410
120
H 5-(4-OCF3-Ph) 11/8,0 5400
121
H 5-(3-furan) 2,4/0,99 -
122
H 5-(2-Me-Ph) 7,3/3,3 -
123
H 5-(2-OMe-Ph) 3,7/1,4 200
124
H 5-(2-CF3-Ph) 12/6,1 510
125
H 5-(3-piridina) 2,0/0,86 -
126
H 5-(3-F-Ph) 2,5/1,1 -
127
H 5-(2-Cl-Ph) 1,3/0,54 -
128
H 5-(2-piridina) 0,5/2,6 -
129
H 5-(3-benzo[b] tiofeno) 5,1/7,0 -
130
H 5 -(4-Me-3 -tiofeno) 2,5/0,41 -
131
H 5-(4-CN-3-tiofeno) 0,41/0,76 -
132
H 5-ciclopentil 4,1/8,0 -
133
H 5-(4-Cl-Ph) 3,3/4,4 -
134
H 5-(2-iPr-Ph) 2,7/ -
135
H 5-(2,5 diMe 3-tiofeno) 2,7/ -
136
H 5-(2-OiPr-Ph) 19/5,4 -
137
H 5-(2,3-diF-Ph) 3,4/0,74 -
138
H 5-(2,3-diCl-Ph) 10,5/1,8 -
139
H 5-(2-F,3-OMe-Ph) 3,7/0,81 -
140
H 5-(2-F,3-Cl-Ph) 13/2,8 -
141
H 5-(2,6-diF-Ph) 21/4,3 -
142
H 5-(2,5-diF-Ph) 1,5/0,76 100
143
H 5-(8-quinolina) 190/35 -
144
H 5-(2-COCH3-Ph) 55/15 -
145
H 5-(2-CH2N(Me)2) 780/170 1400
146
H 5-(2-OPr-Ph) 4,5/3,4 -
147
H 5-(8-1H-indol) 27/5,9 950
148
H 5-(2,4-diCl-Ph) 9,7/2,4 620
149
H 5-(2-OCF3-Ph) 8,5/1,75 -
150
H 5-CF3 88/17 -
151
H 5-(1-metil-1H-pirrol-3-il) 8,8/3,1 240
152
H 5-(1-metil-1H-pirazol-4-il) 4,9/1,4 -
153
H 5-(2-F,5-Cl-Ph) 5,3/1,6 -
154
H 5-(2-NMe2-Ph) 40/18 -
155
H 5-(3-Cl-Ph) 9,1/3,3 770
156
H 5-(3-morfolino-Ph) 11/3,6 420
157
H 5-(3-OCHF2-Ph) 7,9/3,3 670
158
H 5-(2-Cl,3-OEt-Ph) 7,7/2,5 425
159
H 5-(2-Me,5-il-tiazol) 4,7/1,9 -
160
H 5-(3-Cl, piridina-5-il) 3,9/1,6 150
161
H 5-(3-F, piridina-5-il) 1,7/0,6 175
162
H 5-(2-Me, piridina-5-il) 2,5/1,1 115
163
H 5-(2-F, piridina-5-il) 6,0/1,7 130
164
H 5-(2-OMe,piridina-6-il) 6,0/1,4 270
165
H 5-(2-F, piridina-6-il) 3,8/1,3 125
166
H 5-(2,3-diF, piridina-4-il) 44/11 360
167
H 4-(2,5 diBr-Ph) 20/9,3 5500
168
H 4-(4-Br-Ph) 6,8/2,2 240
169
H 4-(4-I-Ph) 2,8/1,5 170
* Ejemplo de referencia
imagen8
Ejemplos de referencia
R GSK3β/α (nM) pTau (nM)
170
imagen7 8,1/2,9 570
171
imagen7 370/170 4000
172
35/14 700
173
imagen7 18/14 2500
174
imagen7 2000/1200 10000
175
imagen7 68/33 3700
176
imagen9 650/ 5500
177
imagen7 61/ 3900
178
imagen7 14/12 1200
179
imagen10 160/40 3000
180
6,2/1,2 190
181
imagen11 2000/ 5500
182
1300/470 10000
183
imagen12 530/200 10000
184
imagen7 800/170 10000
imagen13
Ejemplo
R GSK3β/α (nM) pTau (nM)
185
4-Ph 1,4/4,2 180
186
4-(4-Cl-Ph) 20/6,5 360
187
4-OCH2CHF2-6-F 2,7/1,2 210
188
imagen14 39/19 2200
189
imagen15 2,3/1,1 99
190
imagen16 3,3/1,4 19
191
imagen17 0,08/0,12 12
192
5-(2,5 diF-Ph) 4,6/1,4 94
193
5-(2 F-Ph) 5,6/2,2 85
194
5-(2,3 diF-Ph) 3,8/1,4 140
195
5-(2 Cl-Ph) 10/1,5 107
196
4-(COPh) 13/5,9 520
197
4-(CHOHPh) 19/12 320
198
4-(CF2Ph) 390/230 9900
199
4-(CHFPh) 10/12 720
200
4-(CH2=CPh) 6,1/4,7 510
201
imagen18 1,1/0,4 26
202
4-OCH2CF2CH3 1,0/0,46 50
203
4-OCH2CF3 0,72/0,35 70
204
4-OCH2CF2H 1,8/0,97 41
imagen19
Ejemplo
R GSK3β/α (nM) pTau (nM)
205
Ph 49/52 5100
imagen20
Ejemplo
R GSK3β/α (nM) pTau (nM)
206
4-(4,4-F2-piperidina) 3,0/2,1 190
imagen21
Ejemplo de referencia
GSK3β/α (nM) pTau (nM)
207
2,5/1,1 160
imagen22
Ejemplo
R1 R GSK3β/α (nM) pTau (nM)
208
4-(4,4-F2-piperidina) 4,2/3,1 120
209
5-(2,3 diF Ph) 24/14 2100
210
imagen7 3,6/1,3 250
imagen23
Ejemplo
R1 R2 GSK3β/α (nM) pTau (nM)
211
H 4-OEt 2,2/0,90 72
212
H 4-Ph 4,3/4,4 96
213
H 5-Ph -/2,8 1600
214
3,3-F2 5-Ph 4,1/2,9 490
215
3-Cl 4-Ph 0,40/0,25 -
216
3,3-F2 4-Ph 1,9/3,4 120
217
3,3-Me2 4-Ph 1,7/3,2 170
218
3-Ceto 4-Ph 3,9/ -
219
3-OH(trans) 4-Ph 17/6,4 450
220
3-Cl(trans)* 4-(4,4-F2-1-piperidina) 0,37/0,22 1,7
221
3-Cl(cis)* 4-(4,4-F2-1-piperidina) 0,16/0,09 1,9
222
3-F(trans)* 4-(4-Cl-Ph) 1,7/1,3 37
223
3-F(cis)* 4-(4-Cl-Ph) 6,9/3,1 150
224
3-Cl(trans)* 4-(4-Cl-Ph) -/- 15
225
3-Cl(cis)* 4-(4-Cl-Ph) -/- 43
*: Asignado arbitrariamente.
imagen24
Ejemplo
R1 R2 GSK3β/α (nM) pTau (nM)
226
H 4-OEt 0,62/0,41 31
227
H 4-Ph 1,6/1,4 47
228*
H 4,5-Benzo 1,6/1,1 130
229
3-Ceto 4-Ph 1,6/ -
230
3-OH(trans) 4-Ph 2,5/0,68 73
231
3,3-F2 4-(4-Cl-Ph) 0,46/0,90 30
232
H 5-Ph 1,2/0,51 330
233
3,3-F2 5-Ph 1,0/0,33 340
234
3,3-F2 5-(2F-Ph) 1,4/0,9 160
235
3,3-F2 5-(2,3 diF-Ph) 1,4/0,6 130
236
3,3-F2 5-(2,5 diF-Ph) 4,3/2,1 180
237
3,3-F2 5-(2Cl-Ph) 4,1/0,78 94
238
3,3-F2 imagen25 0,11/0,07 8,3
* Ejemplo de referencia
Composiciones farmacéuticas y métodos de tratamiento
5 Los compuestos de la invención pueden ser útil en el tratamiento de trastornos neurológicos o psiquiátricos. Por lo tanto, otro aspecto de la invención es una composición que comprende un compuesto de la invención, o una sal farmacéuticamente aceptable del mismo, y un vehículo farmacéuticamente aceptable.
Otro aspecto de la invención es un compuesto de la invención para su uso en un método para el tratamiento de
10 depresión, enfermedad de Alzheimer, enfermedad de Parkinson, o dolor neuropático, que comprende administrar a un paciente una cantidad terapéuticamente eficaz de un compuesto de la invención.
Otro aspecto de la invención es un compuesto de la invención para su uso en un método para el tratamiento de la enfermedad de Alzheimer que comprende administrar a un paciente una cantidad terapéuticamente eficaz de un
15 compuesto de la invención.
Otro aspecto de la invención es el uso de un compuesto de la invención en la fabricación de un medicamento para el tratamiento de trastornos neurológicos o psiquiátricos.
20 Otro aspecto de la invención es el uso de un compuesto de la invención en la fabricación de un medicamento para el tratamiento de depresión, enfermedad de Alzheimer, enfermedad de Parkinson, dolor neuropático, o enfermedad de Parkinson.
Otro aspecto de la invención es el uso de un compuesto de la invención en la fabricación de un medicamento para el 25 tratamiento de la enfermedad de Alzheimer.
"Paciente" significa una persona adecuada para terapia tal como lo entienden los médicos en el campo de los trastornos afectivos y los trastornos neurodegenerativos.
imagen26
imagen27
imagen28
2CloroN(4(2hidroxipropan2il)piridin3il)isonicotinamida: EM (IEN) (m/z): 292 (M+H)+; RMN 1H (400 MHz, MeOD) δ 9,58 (s, 1H), 8,62 (dd, J = 5,2, 0,6 Hz, 1H), 8,32 (d, J = 5,3 Hz, 1H), 7,92 (dd, J = 1,5, 0,6 Hz, 1H), 7,83 (dd, J = 5,2, 1,5 Hz, 1H), 7,46 (d, J = 5,2 Hz, 1H), 1,69 (s, 6H).
imagen29
2CloroN(5,6,7,8tetrahidroisoquinolin4il)isonicotinamida: EM (IEN) (m/z): 288 (M+H)+ .
imagen7
2CloroN(4(2,2,2trifluoroacetil)piridin3il)isonicotinamida: EM (IEN) (m/z): 330 (M+H)+ .
imagen30
2CloroN(4(2hidroxietoxi)piridin3il)isonicotinamida: EM (IEN) (m/z): 294 (M+H)+; RMN 1H (400 MHz, MeOD) δ 9,06 (s, 1H), 8,57 (dd, J = 5,1, 0,6 Hz, 1H), 8,29 (d, J = 5,8 Hz, 1H), 7,95 (d, J = 0,7 Hz, 1H), 7,84 (dd, J = 5,2, 1,5 Hz, 1H), 7,15 (d, J = 5,8 Hz, 1H), 4,30 -4,24 (m, 2H), 4,01 - 3,94 (m, 2H).
imagen31
2CloroN(4(ciclopropilmetoxi)piridin3il)isonicotinamida: EM (IEN) (m/z): 304 (M+H)+; RMN 1H (400 MHz, CDCl3) δ = 9,39 (s, 1H), 8,65 (s, 1H), 8,51 (dd, J = 5,1, 0,5 Hz, 1H), 8,24 (d, J = 5,6 Hz, 1H), 7,74 (d, J = 0,7 Hz, 1H), 25 7,60 (dd, J = 5,1, 1,5 Hz, 1H), 6,80 (d, J = 5,6 Hz, 1H), 3,96 (d, J = 7,1 Hz, 2H), 1,38 -1,23 (m, 1H), 0,72 - 0,63 (m, 2H), 0,40 - 0,33 (m, 2H).
imagen32
Ejemplo 2
imagen33
5 2(Ciclopropanocarboxamido)N(4metoxipiridin3il)isonicotinamida: EM (IEN) (m/z): 313 (M+H)+; RMN 1H (500 MHz, DMSO) δ 11,02 (s, 1H), 10,07 (s, 1H), 8,57 (s, 1H), 8,54 (s, 1H), 8,50 (d, J = 5,0 Hz, 1H), 8,38 (d, J = 5,6 Hz, 1H), 7,57 (d, J = 4,5 Hz, 1H), 7,19 (d, J = 5,7 Hz, 1H), 3,90 (s, 3H), 2,05 (tt, J = 6,9, 5,5 Hz, 1H), 0,92 - 0,80 (m, 4H).
10 Ejemplo 3
imagen34
2(Ciclopropanocarboxamido)N(4(2,2,2trifluoroetoxi)piridin3il)isonicotinamida: EM (IEN) (m/z): 381
15 (M+H)+; RMN 1H (500 MHz, MeOD) δ 11,83 (s, 1H), 11,01 (s, 1H), 9,34 (s, 2H), 9,32 (d, J = 5,2 Hz, 1H), 9,25 (d, J = 5,7 Hz, 1H), 8,33 (d, J = 4,3 Hz, 1H), 8,13 (d, J = 5,7 Hz, 1H), 5,76 (c, J = 8,7 Hz, 2H), 2,85 (dc, J = 6,6, 5,7 Hz, 1H), 1,69 - 1,64 (m, 4H).
Ejemplo 4
20
imagen35
N(6Acetamidopiridin3il)2(ciclopropanocarboxamido)isonicotinamida: EM (IEN) (m/z): 340 (M+H)+ . 25 Ejemplo de referencia 5
imagen36
2(Ciclopropanocarboxamido)N(quinolin3il)isonicotinamida: EM (IEN) (m/z): 333 (M+H)+ .
Ejemplo 7
imagen37
2(Ciclopropanocarboxamido)N(6metoxipiridin3il)isonicotinamida: EM (IEN) (m/z): 313 (M+H)+ . Ejemplo 8
imagen38
2(Ciclopropanocarboxamido)N(6fluoro5metilpiridin3il)isonicotinamida: EM (IEN) (m/z): 315 (M+H)+ . Ejemplo 9
imagen39
2(Ciclopropanocarboxamido)N(4 metilpiridin3il)isonicotinamida: EM (IEN) (m/z): 297 (M+H)+ . Ejemplo 10
imagen40
2(Ciclopropanocarboxamido)N(6fenilpiridin3il)isonicotinamida: EM (IEN) (m/z): 359 (M+H)+ .
imagen41
Ejemplo 14
imagen42
5 N(4acetilpiridin3il)2(cycIopropanocarboxamido)isonicotinamida: EM (IEN) (m/z): 325 (M+H)+; RMN 1H (400 MHz, CDCl3) δ = 12,29 (s, 1H), 10,25 (s, 1H), 8,87 (s, 1H), 8,60 (d, J = 5,1 Hz, 2H), 8,48 (dd, J = 5,2, 0,7 Hz, 1H), 7,79 - 7,70 (m, 1H), 7,64 (dd, J = 5,2, 1,6 Hz, 1H), 2,78 (s, 3H), 1,69 - 1,59 (m, 1H), 1,25 - 1,18 (m, 2H), 0,99 0,92 (m, 2H).
10 Ejemplo 16
imagen43
2(Ciclopropanocarboxamido)N(4(2hidroxipropan2il)piridin3il)isonicotinamida: EM (IEN) (m/z): 341
15 (M+H)+; RMN 1H (400 MHz, CDCl3) δ = 11,29 (s, 1H), 9,72 (s, 1H), 8,73 (s, 1H), 8,54 (s, 1H), 8,46 (d, J = 5,1 Hz, 1H), 8,35 (d, J = 5,2 Hz, 1H), 7,67 (dd, J = 5,1, 1,4 Hz, 1H), 7,17 (d, J = 5,3 Hz, 1H), 3,87 -3,71 (m, 1H), 1,74 (s, 6H), 1,65 - 1,60 (m, 1H), 1,16 - 1,09 (m, 2H), 0,98 - 0,92 (m, 2H).
Ejemplo 18
20
imagen44
2(Ciclopropanocarboxamido)N(4fenilpiridin3il)isonicotinamida: EM (IEN) (m/z): 359 (M+H)+; RMN 1H (500 MHz, DMSO) δ 11,00 (s, 1H), 10,46 (s, 1H), 8,63 (s, 1H), 8,58 (d, J = 5,0 Hz, 1H), 8,46 (d, J = 4,5 Hz, 2H), 7,55 25 - 7,48 (m, 3H), 7,48 - 7,43 (m, 2H), 7,40 (tt, J = 6,2, 1,4 Hz, 2H), 2,04 (tt, J = 7,1, 5,3 Hz, 1H), 0,90 - 0,80 (m, 4H).
Ejemplo de referencia 21
imagen45
30
2(Ciclopropanocarboxamido)N(5,6,7,8tetrahidroisoquinolin4il)isonicotinamida: EM (IEN) (m/z): 337 (M+H)+; RMN 1H (500 MHz, DMSO) δ 11,04 (s, 1H), 10,25 (s, 1H), 8,57 (s, 1H), 8,51 (d, J = 5,1 Hz, 1H), 8,28 (s, 1H),
imagen46
1,23 (m, 1H), 0,86 (d, J = 6,1 Hz, 4H), 0,59 - 0,51 (m, 2H), 0,42 - 0,32 (m, 2H).
Ejemplo 26
imagen47
5
2(Ciclopropanocarboxamido)N(4isopropoxipiridin3il)isonicotinamida: EM (IEN) (m/z): 341 (M+H)+; RMN 1H (500 MHz, DMSO) δ 11,03 (s, 1H), 9,86 (s, 1H), 8,60 (s, 1H), 8,55 (s, 1H), 8,51 (d, J = 5,1 Hz, 1H), 8,32 (d, J = 5,6 Hz, 1H), 7,54 (s, 1H), 7,18 (d, J = 5,8 Hz, 1H), 4,80 (dt, J = 12,1, 6,0 Hz, 1H), 2,10 -2,01 (m, 1H), 1,31 (d, J =
10 6,0 Hz, 6H), 0,90 - 0,84 (m, 4H).
Ejemplo 29
imagen48
15 N(4cloropiridin3il)2(ciclopropanocarboxamido)isonicotinamida: EM (IEN) (m/z): 317 (M+H)+; RMN 1H (400 MHz, CDCI3) δ = 9,60 (s, 1H), 8,76 (s, 1H), 8,71 (d, J = 0,7 Hz, 1H), 8,49 (dd, J = 5,1, 0,7 Hz, 1H), 8,42 (s, 1H), 8,38 (d, J = 5,3 Hz, 1H), 7,59 (dd, J = 5,1, 1,6 Hz, 1H), 7,42 (d, J = 5,2 Hz, 1H), 1,69-1,58 (m, 1H), 1,20 - 1,13 (m, 2H), 1,00 - 0,93 (m, 2H).
20
Ejemplo 25
imagen49
25 2(Ciclopropanocarboxamido)N(4etoxipiridin3il)isonicotinamida: EM (IEN) (m/z): 327 (M+H)+; RMN 1H (400 MHz, CLOROFORMO-d) δ 9,58 (s, 1H), 8,70 (s, 1H), 8,50 - 8,41 (m, 3H), 8,35 (d, J= 5,5 Hz, 1H), 7,59 (dd, J = 5,0, 1,5 Hz, 1H), 6,87 (d, J= 5,5 Hz, 1H), 4,24 (c, J=7,0 Hz, 2H), 1,67 - 1,60 (m, 1H), 1,59 - 1,54 (m, 3H), 1,17 -1,12 (m, 2H), 0,99 - 0,94 (m, 2H).
30 Ejemplo 226
imagen50
2(Ciclopentanocarboxamido)N(4etoxipiridin3il)isonicotinamida: EM (IEN) (m/z): 355 (M+H); RMN 1H (400 MHz, DMSOd6) δ 10,66 -10,61 (m, 1H), 9,97 - 9,91 (m, 1H), 8,63 - 8,60 (m, 1H), 8,60 - 8,56 (m, 1H), 8,52 - 8,48 (m, 1H), 8,38 - 8,33 (m, 1H), 7,56 - 7,52 (m, 1H), 7,19 - 7,15 (m, 1H), 4,24 - 4,17 (m, 2H), 3,04 - 2,94 (m, 1H), 1,94-1,51 (m, 9H), 1,36 (s, 3H).
Ejemplo 211
imagen51
10 2(Ciclobutanocarboxamido)N(4etoxipiridin3il)isonicotinamida: EM (IEN) (m/z): 341 (M+H)+; RMN 1H (400 MHz, DMSOd6) δ 10,53 - 10,48 (s, 1H), 9,97 - 9,90 (s, 1H), 8,61 (d, J= 10,3 Hz, 2H), 8,51 - 8,47 (m, 1H), 8,35 (d, J = 5,5 Hz, 1H), 7,57 - 7,52 (m, 1H), 7,18 (m, 1H), 4,21 (d, J= 7,0 Hz, 2H), 3,47 - 3,37 (m, 1H), 2,31 - 2,09 (m, 4H), 2,03 - 1,76 (m, 2H), 1,37 (t, J=7,0 Hz, 3H)
15 Ejemplo 17
imagen52
2(Ciclopropanocarboxamido)N(4(1hidroxietil)piridin3il)isonicotinamida. En un matraz de fondo redondo de
20 100 ml se disolvió N-(4-acetilpiridin-3-il)-2-(ciclopropanocarboxamido)isonicotinamida (5,7 mg, 0,018 mmol) en metanol (1 ml) para dar a solución incolora. Se añadió borohidruro sódico (3,32 mg, 0,088 mmol) (exceso), y la mezcla se agitó a ta durante 1 h. La CLEM mostró conversión completa. El disolvente se retiró al vacío. El residuo se repartió entre solución saturada de NaHCO3 y acetato de etilo. Las capas se separaron. La capa orgánica se lavó con salmuera, se secó y se concentró. El residuo se purificó por cromatografía en columna ultrarrápida sobre gel de
25 sílice, eluyendo con metanol al 10 % en cloruro de metileno para proporcionar el producto deseado (6.1 mg, 100 %) en forma de un sólido de color blanco: EM (IEN) (m/z): 327 (M+H)+; RMN 1H (400 MHz, CDCl3) δ = 10,64 (s, 1H), 9,58 (s, 1H), 8,73 (s, 1H), 8,68 (s, 1H), 8,45 (d, J = 5,0 Hz, 1H), 8,34 (d, J = 4,9 Hz, 1H), 7,64 (dd, J = 5,1, 1,6 Hz, 1H), 7,09 (d, J = 5,0 Hz, 1H), 5,14 (t, J = 6,6 Hz, 1H), 4,44 (s, 1H), 1,68 - 1,59 (m, 4H), 1,15 -1,08 (m, 2H), 0,99 - 0,90 (m, 2H).
30
Ejemplo 23
imagen53
35 2(Ciclopropanocarboxamido)N(4(2,2,2trifluoro1hidroxietil)piridin3il)isonicotinamida. Un matraz de fondo redondo de 100 ml se cargó con 2-(ciclopropanocarboxamido)-N-(4-(2,2,2-trifluoroacetil)piridin-3il)isonicotinamida (14 mg, 0,037 mmol) en metanol (2 ml) para dar una suspensión de color blanco, Se añadió borohidruro sódico (7,00 mg, 0,185 mmol) (exceso), y la mezcla se agitó a ta durante 30 min. El material en bruto se purificó por HPLC prep. para proporcionar el producto deseado (10,3 mg, 73 %): EM (IEN) (m/z): 381 (M+H)+; RMN
40 1H (500 MHz, DMSO) δ 11,07 (s, 1H), 10,57 (s, 1H), 8,74 (s, 1H), 8,57 (d, J = 5,0 Hz, 2H), 8,54 (d, J = 5,1 Hz, 1H),
imagen54
imagen55
imagen56
Ejemplo 40
imagen57
5 2(Ciclopropanocarboxamido)N(4fenoxipiridin3il)isonicotinamida: EM (IEN) (m/z): 375 (M+H)+; RMN 1H (500 MHz, DMSO) δ 11,02 (s, 1H), 10,41 (s, 1H), 8,71 (s, 1H), 8,55 (s, 1H), 8,52 - 8,43 (m, 1H), 8,34 (d, J = 5,6 Hz, 1H), 7,54 - 7,50 (m, 1H), 7,50 - 7,45 (m, 2H), 7,31 - 7,25 (m, 1H), 7,20 -7,15 (m, 2H), 6,79 (d, J = 5,6 Hz, 1H), 2,09 1,99 (m, 1H), 0,88 - 0,79 (m, 4H).
10 Ejemplo 59
imagen58
N(2cIoro4fenilpiridin3il)2(ciclopropanocarboxamido)isonicotinamida: EM (IEN) (m/z): 393 (M+H)+; RMN 15 1H (500 MHz, DMSO) δ 10,99 (s, 1H), 10,59 (s, 1H), 8,46 (s, 3H), 7,56 - 7,50 (m, 3H), 7,46 - 7,37 (m, 4H), 2,07 -1,99 (m, 1H), 0,88 - 0,81 (m, 4H).
Ejemplo 19
imagen59
2(Ciclopropanocarboxamido)N(4yodopiridin3il)isonicotinamida. Un matraz de fondo redondo de 250 ml se cargó con ácido 2-(ciclopropanocarboxamido)isonicotínico (776,5 mg, 3,77 mmol) en cloruro de metileno (30 ml) para dar una suspensión de color blanco. Después de enfriar a 0 °C, se añadieron dimetilformamida (0,029 ml, 25 0,377 mmol) y cloruro de oxalilo (0,363 ml, 4,14 mmol). La mezcla se agitó a 0 °C durante 2 h. Se añadió 4yodopiridin-3-amina (829 mg, 3,77 mmol) a 0 °C, seguido de trietilamina (2,1 ml, 15,06 mmol). La mezcla se volvió homogénea. A continuación se concentró para dar un aceite de color castaño. El residuo se purificó por cromatografía en columna ultrarrápida sobre gel de sílice, eluyendo con metanol al 0-10 % en cloruro de metileno (que contenía ácido acético al 1 %), dando un sólido de color castaño (1,00 %) que se usó sin caracterización
30 adicional.
Ejemplo 31
imagen60
5 2(Ciclopropanocarboxamido)N(4(tiofen3il)piridin3il)isonicotinamida. En un tubo de microondas de 5 ml en una atmósfera de nitrógeno se añadió 2-(ciclopropanocarboxamido)-N-(4-yodopiridin-3-il)isonicotinamida (40 mg, 0,098 mmol), ácido tiofen-3-ilborónico (18,81 mg, 0,147 mmol), y Na2CO3 (0,196 ml, 0,392 mmol, 2,0 M en agua) en dioxano (1 ml) para dar una suspensión de color castaño. Se añadió Pd(PPh3)4(1,132 mg, 0,980 µmol) en una atmósfera de nitrógeno. El vial se cerró herméticamente y se calentó a 110 °C usando microondas durante 30 min.
10 Los volátiles se retiraron al vacío y el residuo se disolvió en 1,5 ml de dimetilformamida y se purificó por HPLC prep. para proporcionar el producto deseado (7,6 mg, 21 %): EM (IEN) (m/z): 365 (M+H)+; RMN 1H (400 MHz, DMSO) δ 10,97 (s, 1H), 10,45 (s, 1H), 8,62 (s, 1H), 8,57 - 8,46 (m, 3H), 7,93 (dd, J = 2,9, 1,3 Hz, 1H), 7,65 (dd, J = 5,0, 2,9 Hz, 1H), 7,60 (d, J = 5,1 Hz, 1H), 7,52 (d, J = 4,4 Hz, 1H), 7,44 (dd, J = 5,0, 1,3 Hz, 1H), 2,12 -1,97 (m, 1H), 0,85 (dd, J = 11,1, 3,5Hz, 4H).
15
Ejemplo 32
imagen61
20 N([3,4'bipiridin]3'il)2(cycIopropanocarboxamido)isonicotinamida: EM (IEN) (m/z): 360 (M+H)+; RMN 1H (400 MHz, DMSO) δ 10,95 (s, 1H), 10,50 (s, 1H), 8,69 (d, J = 2,7 Hz, 2H), 8,61 (d, J = 5,0 Hz, 1H), 8,58 (dd, J = 4,8, 1,6 Hz, 1H), 8,49 - 8,41 (m, 2H), 7,96 - 7,90 (m, 1H), 7,56 (d, J = 5,0 Hz, 1H), 7,47 (ddd, J = 7,9, 4,8, 0,7 Hz, 1H), 7,39 (d, J = 5,1 Hz, 1H), 2,09 -1,99 (m, 1H), 0,85 (dd, J = 6,2, 3,8 Hz, 4H).
25 Ejemplo 33
imagen62
N([4,4'bipiridin]3il)2(ciclopropanocarboxamido)isonicotinamida: EM (IEN) (m/z): 360 (M+H)+; RMN 30 (400 MHz, DMSO) δ 10,97 (s, 1H), 10,52 (s, 1H), 8,71 (s, 1H), 8,68 - 8,58 (m, 3H), 8,51 -8,40 (m, 2H), 7,60 -7,46 (m, 3H), 7,40 (dd, J = 5,1, 1,3 Hz, 1H), 2,04 (dc, J = 7,3, 5,4 Hz, 1H), 0,90 - 0,82 (m, 4H).
imagen63
imagen64
imagen65
5,1 Hz, 1H), 8,43 (s, 1H), 7,85 (d, J = 8,2 Hz, 2H), 7,74 (d, J = 8,1 Hz, 2H), 7,55 (d, J = 5,0 Hz, 1H), 7,39 (d, J = 3,9 Hz, 1H), 2,10 -1,95 (m, 1H), 0,91 - 0,81 (m, 4H).
Ejemplo 64
imagen66
2(Ciclopropanocarboxamido)N(4(pirimidin5il)piridin3il)isonicotinamida: EM (IEN) (m/z): 361 (M+H)+; RMN 1H (500 MHz, DMSO-d6) δ 10,99 (s, 1H), 9,19 (s, 1H), 8,94 (s, 2H), 8,74 (s, 1H), 8,63 (d, J= 4,9 Hz, 1H), 8,46 10 (d, J= 5,2 Hz, 1H), 8,43 (s, 1H), 7,63 (d, J= 5,2 Hz, 1H), 7,41 (d, J= 4,9 Hz, 1H), 2,03 (t, J=6,1 Hz, 1H), 0,87 - 0,81 (m, 4H).
Ejemplo 65
imagen67
N(4(2,4bis(trifluorometil)fenil)piridin3il)2(ciclopropanocarboxamido)isonicotinamida: EM (IEN) (m/z): 495 (M+H)+. RMN 1H (500 MHz, DMSO-d6) δ 10,95 (s, 1H), 8,84 (s, 1H), 8,40 (d, J= 4,9 Hz, 1H), 8,23 (s, 1H), 8,18 - 8,12 (m, 2H), 7,67 (d, J= 7,9 Hz, 1H), 7,41 (d, J= 5,2 Hz, 1H), 7,24 (dd, J=5,0, 1,4 Hz, 1H), 2,01 (t, J=5,8 Hz, 1H), 0,86
20 0,81 (m, 4H).
Ejemplo 66
imagen68
25 2(Ciclopropanocarboxamido)N(4(2,4diclorofenil)piridin3il)isonicotinamida: EM (IEN) (m/z): 427 (M+H)+; RMN 1H (500 MHz, DMSO-d6) δ 10,98 (s, 1H), 10,34 (s a, 1H), 8,77 (s, 1H), 8,58 (d, J= 5,2 Hz, 1H), 8,44 (d, J= 4,9 Hz, 1H), 8,35 (s, 1H), 7,73 (d, J= 1,8 Hz, 1H), 7,51 (dd, J = 8,2, 2,1 Hz, 1H), 7,43 (d, J= 5,2 Hz, 1H), 7,39 (d, J= 8,2 Hz, 1H), 7,31 (d, J= 4,0 Hz, 1H), 2,06 -1,99 (m, 1H), 0,89 - 0,82 (m, 4H).
30
Ejemplo 67
imagen69
5 2(Ciclopropanocarboxamido)N(4(2(trifluorometil)fenil)piridin3il)isonicotinamida: EM (IEN) (m/z): 427 (M+H)+; RMN 1H (500 MHz, DMSO-d6) δ 10,95 (s, 1H), 10,19 (s, 1H), 8,72 (s, 1H), 8,56 (d, J= 4,9 Hz, 1H), 8,39 (d, J = 5,2 Hz, 1H), 8,31 (s, 1H), 7,83 (d, J= 7,6 Hz, 1H), 7,73 -7,67 (m, 1H), 7,65 -7,59 (m, 1H), 7,40 (d, J = 7,6 Hz, 1H), 7,36 (d, J= 5,2 Hz, 1H), 7,20 (dd, J=5,0, 1,4 Hz, 1H), 2,05 -1,98 (m, 1H), 0,86 -0,81 (m, 4H).
10 Ejemplo 68
imagen70
2(Ciclopropanocarboxamido)N(4(2clorofenil)piridin3il)isonicotinamida: EM (IEN) (m/z): 393 (M+H)+; RMN
15 1H (500 MHz, DMSO-d6) δ 11,02 (s, 1H), 10,58 (s, 1H), 8,94 (s, 1H), 8,72 (d, J= 5,2 Hz, 1H), 8,44 (d, J= 5,2 Hz, 1H), 8,37 (s, 1H), 7,71 (d, J= 5,5 Hz, 1H), 7,60 -7,56 (m, 1H), 7,48 -7,40 (m, 3H), 7,30 (dd, J= 5,2, 1,2 Hz, 1H), 2,03 (quin, J=6,2 Hz, 1H), 0,86 -0,83 (m, 4H).
Ejemplo 69
20
imagen71
N(4(2cloro4fluorofenil)piridin3il)2(ciclopropanocarboxamido)isonicotinamida: EM (IEN) (m/z): 393 (M+H)+; RMN 1H (500 MHz, DMSO-d6) δ 10,98 (s, 1H), 10,32 (s a, 1H), 8,75 (s, 1H), 8,57 (d, J= 4,9 Hz, 1H), 8,43 (d, 25 J= 5,2 Hz, 1H), 8,35 (s, 1H), 7,55 (dd, J=9,0, 2,6 Hz, 1H), 7,45 - 7,39 (m, 2H), 7,34 - 7,27 (m, 2H), 2,05 - 1,99 (m, 1H), 0,87 - 0,83 (m, 4H).
Ejemplo 70
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N(4(2chIoro4(trifluorometil)fenil)piridin3il)2(ciclopropanocarboxamido)isonicotinamida: EM (IEN) (m/z):
imagen73
imagen74
imagen75
Ejemplo 86
imagen76
5 2(Ciclopropanocarboxamido)N(4(2fluoro5clorofenil)piridin3il)isonicotinamida: EM (IEN) (m/z): 411 (M+H)+; RMN 1H (500 MHz, DMSO-d6) δ 10,99 (s, 1H), 10,47 (s a, 1H), 8,72 (s, 1H), 8,59 (d, J= 4,9 Hz, 1H), 8,45 (d, J= 5,2 Hz, 1H), 8,40 (s, 1H), 7,51 (dd, J=12,2, 4,9 Hz, 3H), 7,38 - 7,29 (m, 2H), 2,03 (t, J=5,2 Hz, 1H), 0,87 - 0,81 (m, 4H).
10 Ejemplo 89
imagen77
N(4 (2ciano4fluorofenil)piridin3il)2(ciclopropanocarboxamido)isonicotinamida: EM (IEN) (m/z): 402
15 (M+H)+; RMN 1H (500 MHz, DMSOd6) δ 11,02 (s, 1H), 9,28 (s, 1H), 9,05 (dd, J=9,0, 5,3 Hz, 1H), 8,76 (d, J= 5,5 Hz, 1H), 8,72 - 8,67 (m, 2H), 8,53 (d, J= 4,9 Hz, 1H), 8,13 (d, J= 7,9 Hz, 1H), 8,03 - 7,95 (m, 1H), 7,76 (d, J= 4,6 Hz, 1H), 2,12 - 2,03 (m, 1H), 0,89 - 0,84 (m, 4H).
Ejemplo 91
20
imagen78
2(Ciclopropanocarboxamido)N(4(2,3difluorofenil)piridin3il)isonicotinamida: EM (IEN) (m/z): 395 (M+H)+; RMN 1H (500 MHz, DMSOd6) δ 10,97 (s, 1H), 8,75 (s, 1H), 8,57 (d, J= 4,9 Hz, 1H), 8,43 (d, J= 5,2 Hz, 1H), 8,39 (s, 25 1H), 7,51 (d, J= 4,9 Hz, 1H), 7,46 (c, J=8,5 Hz, 1H), 7,34 (d, J= 4,6 Hz, 1H), 7,30 -7,19 (m, 2H), 2,07 - 1,99 (m, 1H), 0,87 - 0,81 (m, 4H).
Ejemplo 92
imagen79
2(Ciclopropanocarboxamido)N(4(4(dimetilcarbamoil)2fluorofenil)piridin3il)isonicotinamida: EM (IEN)
(m/z): 448 (M+H)+; RMN 1H (500 MHz, DMSOd6) δ 10,98 (s, 1H), 10,48 (s, 1H), 8,80 (s, 1H), 8,63 (d, J= 5,2 Hz, 1H), 8,44 (d, J= 4,9 Hz, 1H), 8,37 (s, 1H), 7,59 (d, J= 5,2 Hz, 1H), 7,48 (t, J=7,6 Hz, 1H), 7,37 (d, J= 10,4 Hz, 1H), 7,35 - 7,28 (m, 2H), 2,99 (s, 3H), 2,87 (s, 3H), 2,02 (quin, J=6,2 Hz, 1H), 0,84 (d, J=6,1 Hz, 4H).
Ejemplo 93
imagen80
2(Ciclopropanocarboxamido)N(4(4(difluorometoxi)fenil)piridin3il)isonicotinamida: EM (IEN) (m/z): 425
10 (M+H)+; RMN 1H (500 MHz, DMSO-d6) δ 11,00 (s, 1H), 10,42 (s, 1H), 8,66 (s, 1H), 8,57 (d, J = 4,9 Hz, 1H), 8,46 (d, J = 5,2 Hz, 1H), 8,43 (s, 1H), 7,59 (d, J= 8,5 Hz, 2H), 7,49 (d, J= 4,9 Hz, 1H), 7,41 (d, J= 5,2 Hz, 1H), 7,31 - 7,25 (m, 3H), 2,08 - 1,99 (m, 1H), 0,88 - 0,82 (m, 4H).
Ejemplo 94
15
imagen81
2(Ciclopropanocarboxamido)N(4(2fluoro4(trifluorometoxi)fenil)piridin3il)isonicotinamida: EM (IEN) (m/z): 461 (M+H)+; RMN 1H (500 MHz, DMSO-d6) δ 10,99 (s, 1H), 10,44 (s, 1H), 8,78 (s, 1H), 8,60 (d, J= 4,9 Hz, 20 1H), 8,44 (d, J= 4,9 Hz, 1H), 8,37 (s, 1H), 7,61 - 7,47 (m, 3H), 7,37 - 7,29 (m, 2H), 2,07 -1,99 (m, 1H), 0,88 - 0,79 (m, 4H).
Ejemplo 95
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N(4(benzofuran2il)piridin3il)2(ciclopropanocarboxamido)isonicotinamida: EM (IEN) (m/z): 399 (M+H)+; RMN 1H (500 MHz, DMSOd6) δ 11,09 (s, 1H), 10,74 (s a, 1H), 8,77 (s, 1H), 8,69 (s, 1H), 8,61 (d, J= 5,2 Hz, 1H), 8,57 (d, J= 5,2 Hz, 1H), 7,95 (d, J= 5.2 Hz, 1H), 7,75 (d, J = 7,6 Hz, 1H), 7,66 -7,60 (m, 2H), 7,56 (s, 1H), 7,39 (t,
30 J=7,8 Hz, 1H), 7,34 - 7,28 (m, 1H), 2,12 - 2,04 (m, 1H), 0,92 - 0,83 (m, 4H).
imagen83
imagen84
imagen85
imagen86
Ejemplo de referencia 6
imagen87
5 2(Ciclopropanocarboxamido)N(isoquinolin4il)isonicotinamida: EM (IEN) (m/z): 333 (M+H)+; RMN 1H (500 MHz, DMSO) δ 11,06 (s, 1H), 10,81 (s, 1H), 9,28 (s, 1H), 8,67 (s, 1H), 8,62 (s, 1H), 8,56 (d, J = 5,1 Hz, 1H), 8,22 (d, J = 8,1 Hz, 1H), 7,99 (d, J = 7,9 Hz, 1H), 7,87 - 7,82 (m, 1H), 7,76 (ddd, J = 8,0, 7,0, 1,0 Hz, 1H), 7,71 (d, J = 4,6 Hz, 1H), 2,14 - 2,01 (m, 1H), 0,91 -0,82 (m, 4H).
10 Ejemplo 44
imagen88
2(Ciclopropanocarboxamido)N(4(neopentiloxi)piridin3il)isonicotinamida: EM (IEN) (m/z): 369 (M+H)+; RMN
15 1H (400 MHz, DMSO) δ 10,98 (s, 1H), 9,97 (s, 1H), 8,56 (s, 1H), 8,51 (dd, J = 5,1, 0,6 Hz, 1H), 8,49 (s, 1H), 8,36 (d, J = 5,6 Hz, 1H), 7,53 (dd, J = 5,1, 1,4 Hz, 1H), 7,16 (d, J = 5,7 Hz, 1H), 3,77 (s, 2H), 2,12 -1,99 (m, 1H), 0,96 (s, 9H), 0,90 - 0,83 (m, 4H).
Ejemplo 45
20
imagen89
2(Ciclopropanocarboxamido)N(4(4,4difluoropiperidin1il)piridin3il)isonicotinamida: EM (IEN) (m/z): 402 (M+H)+; RMN 1H (500 MHz, DMSO) δ 11,07 (s, 1H), 10,05 (s, 1H), 8,58 (d, J = 10,6 Hz, 2H), 8,53 (d, J = 5,1 Hz, 1H), 25 8,29 (d, J = 5,5 Hz, 1H), 7,57 (d, J = 4,7 Hz, 1H), 7,12 (d, J = 5,5 Hz, 1H), 3,26 - 3,16 (m, 4H), 2,18 - 2,00 (m, 5H), 0,91 - 0,81 (m, 4H).
Ejemplo 46
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imagen91
imagen92
imagen93
imagen94
1H), 8,26 (d, J = 5,6 Hz, 1H), 7,52 (d, J = 4,4 Hz, 1H), 7,01 (d, J = 5,6 Hz, 1H), 3,76 - 3,63 (m, 2H), 3,41 - 3,37 (m, 2H), 2,50 - 2,40 (m, 2H), 2,05 (dd, J = 12,4, 6,2 Hz, 1H), 1,06 (s, 3H), 1,05 (s, 3H), 0,86 (d, J = 6,2 Hz, 4H).
Ejemplo 80
imagen95
2(Ciclopropanocarboxamido)N(4(3,3difluoropiperidin1il)pyiridin3il)isonicotinamida: EM (IEN) (m/z): 402 (M+H)+; RMN 1H (500 MHz, DMSO) δ 11,02 (s, 1H), 10,09 (s, 1H), 8,57 (s, 1H), 8,52 (d, J = 5,0 Hz, 1H), 8,38 (s, 1H), 10 8,29 (d, J = 5,5 Hz, 1H), 7,58 (d, J = 5,0 Hz, 1H), 7,08 (d, J = 5,6 Hz, 1H), 3,42 (t, J = 11,7 Hz, 2H), 3,19 (s, 2H), 2,12
-1,97 (m, 3H), 1,77 (s, 2H), 0,91 - 0,79 (m, 4H).
Ejemplo 83
imagen96
2(Ciclopropanocarboxamido)N(4(3,3difluoropirroIidin1il)piridin3il)isonicotinamida: EM (IEN) (m/z): 388 (M+H)+; RMN 1H (500 MHz, DMSO) δ 11,03 (s, 1H), 10,30 (s, 1H), 8,58 (s, 1H), 8,52 (d, J = 5,1 Hz, 1H), 8,15 (d, J = 5,8 Hz, 1H), 8,04 (s, 1H), 7,58 (dd, J = 5,1, 1,5 Hz, 1H), 6,71 (d, J = 5,9 Hz, 1H), 3,82 (t, J = 13,2 Hz, 2H), 3,65 (t, J =
20 7,3 Hz, 2H), 2,46 (dt, J = 21,5, 7,3 Hz, 2H), 2,05 (t, J = 6,1 Hz, 1H), 0,92 -0,80 (m, 4H).
Ejemplo 87
imagen97
25 2(Ciclopropanocarboxamido)N(4(2,2dimetilmorfolino)piridin3il)isonicotinamida: EM (IEN) (m/z): 396 (M+H)+; RMN 1H (500 MHz, DMSO) δ 11,03 (s, 1H), 10,10 (s, 1H), 8,58 (s, 1H), 8,51 (d, J = 5,1 Hz, 1H), 8,31 (s, 1H), 8,29 (d, J = 5,5 Hz, 1H), 7,58 (d, J = 4,8 Hz, 1H), 7,01 (d, J = 5,6 Hz, 1H), 3,73 - 3,64 (m, 2H), 3,07 - 3,02 (m, 2H), 2,91 (s, 2H), 2,10 - 2,00 (m, 1H), 1,13 (s, 6H), 0,86 (d, J = 5,3 Hz, 4H).
30
imagen98
imagen99
Ejemplo 189
imagen100
5 2IsobutiramidoN(4(2morfolinoetoxi)piridin3il)isonicotinamida: EM (IEN) (m/z): 414 (M+H)+; RMN 1H (500 MHz, DMSO-d6) δ 10,64 (s, 1H), 10,04 (s, 1H), 8,60 (s, 1H), 8,56 (s, 1H), 8,49 (d, J = 5,3 Hz, 1H), 8,35 (d, J = 5,8 Hz, 1H), 7,52 (d, J = 5,5 Hz, 1H), 7,19 (d, J = 5,8 Hz, 1H), 4,23 (t, J = 5,5 Hz, 2H), 2,83 - 2,73 (m, 1H), 2,72 (t, J = 5,5 Hz, 2H), 2,51 (s, 4H), 2,47 - 2,35 (m, 4H), 1,11 (d, J = 6,9 Hz, 6H).
10 Ejemplo 190
imagen101
N(4(3hidroxi3metilbutoxi)piridin3il)2isobutiramidoisonicotinamida: EM (IEN) (m/z): 387 (M+H)+; RMN 1H
15 (500 MHz, DMSO-d6) δ 10,64 (s, 1H), 9,92 (s, 1H), 8,61 (s, 1H), 8,56 (s, 1H), 8,49 (d, J = 5,2 Hz, 1H), 8,35 (d, J = 5,8 Hz, 1H), 7,52 (s, 1H), 7,19 (d, J = 5,7 Hz, 1H), 4,23 (t, J = 7,1 Hz, 2H), 2,78 (c, J = 7,2 Hz, 1H), 1,87 (d, J = 7,0 Hz, 2H), 1,14 (s, 6H), 1,11 (d, J = 7,6 Hz, 6H).
Ejemplo 191
20
imagen102
N(6cloro4(2etil1,3dioxolan2il)piridin3il)2isobutiramidoisonicotinamida: EM (IEN) (m/z): 419 (M+H)+; RMN 1H (500 MHz, DMSO-d6) δ 10,70 (s, 1H), 10,15 (s, 1H), 8,98 (s, 1H), 8,63 (s, 1H), 8,55 (d, J= 5,2 Hz, 1H), 7,50 25 (d, J= 5,2 Hz, 1H), 7,47 (s, 1H), 4,14 -4,05 (m, 2H), 3,92 -3,84 (m, 2H), 2,80 (dt, J= 13,4, 6,6 Hz, 1H), 1,89 (c, J=7,1 Hz, 2H), 1,12 (d, J= 6,7 Hz, 6H), 0,82 (t, J=7,3 Hz,3H).
imagen103
N(6cloro4(2etil1,3dioxolan2il)piridin3il)2pivalamidoisonicotinamida: EM (IEN) (m/z): 433 (M+H)+; RMN 1H (500 MHz, DMSOd6) δ 10,16 (s a, 1H), 10,11 (s, 1H), 8,99 (s, 1H), 8,61 - 8,55 (m, 2H), 7,53 (d, J= 5,2 Hz, 1H), 7,48 (s, 1H), 4,13 - 4,06 (m, 2H), 3,92 -3,84 (m, 2H), 1,90 (c, J= 7,1 Hz, 2H), 1,28 (s, 9H), 0,83 (t, J = 7,3 Hz, 3H).
Ejemplo 238
imagen104
N(6cIoro4(2etil1,3dioxolan2il)piridin3il)2(3,3difluorociclopentanocarboxamido)isonicotinamida: EM
10 (IEN) (m/z): 481 (M+H)+; RMN 1H (500 MHz, DMSOd6) δ 10,92 - 10,85 (m, 1H), 10,15 (s a, 1H), 8,98 (s, 1H), 8,63 (s, 1H), 8,57 (d, J= 4,9 Hz, 1H), 7,53 (d, J= 4,3 Hz, 1H), 7,47 (s, 1H), 4,14 -4,03 (m, 2H), 3,93 - 3,83 (m, 2H), 2,39 (dd, J=17,1, 8,9 Hz, 2H), 2,29 - 2,03 (m, 3H), 2,00 - 1,83 (m, 3H), 0,82 (t, J=7,3 Hz, 3H).
imagen105
15 (4((4Fenilpiridin3il)carbamoil)piridin2il)carbamato de bencilo. Un matraz de fondo redondo de 100 ml se cargó con 2-cloro-N-(4-fenilpiridin-3-il)isonicotinamida (200 mg, 0,646 mmol), carbamato de bencilo (137 mg, 0,904 mmol), y Cs2CO3 (337 mg, 1,033 mmol) en dioxano (6 ml) para dar una suspensión de color castaño en una atmósfera de nitrógeno. Se añadieron Pd(OAc)2 (7,25 mg, 0,032 mmol) y XANTPHOS (28,0 mg, 0,048 mmol), y la
20 mezcla se calentó a 110 °C en una atmósfera de nitrógeno durante la noche durante 22 h. La mezcla se repartió entre acetato de etilo y agua. Las capas se separaron. La capa orgánica se lavó con salmuera, se secó y se concentró. El residuo se purificó por cromatografía ultrarrápida sobre gel de sílice, eluyendo con metanol 0-8 % en cloruro de metileno para proporcionar el producto (110 mg, 20 %, 50 % de pureza). Se purificó adicionalmente una pequeña cantidad mediante HPLC prep para obtener la RMN 1H: EM (IEN) (m/z): 425 (M+H)+; RMN 1H (500 MHz,
25 MeOD) δ 11,29 (s, 2H), 9,44 (s, 1H), 9,34 (d, J = 5,0 Hz, 1H), 9,19 (d, J = 5,1 Hz, 1H), 9,02 (s, 1H), 8,37 - 8,31 (m, 2H), 8,29 -8,21 (m, 5H), 8,21 -8,12 (m, 5H), 6,01 (s, 2H).
imagen106
30 2AminoN(4fenilpiridin3il)isonicotinamida. Un matraz de fondo redondo de 250 ml se cargó con (4-((4fenilpiridin-3-il)carbamoil)piridin-2-il)carbamato de bencilo (100 mg, 0,236 mmol) en metanol (4 ml) para dar una suspensión de color castaño. Se añadió Pd/C (25,07 mg, 0,024 mmol), y la mezcla se agitó bajo atmósfera de hidrógeno (1 atm.) durante 6 h. La mezcla se filtró, se lavó, y se concentró para dar un sólido de color castaño claro, que se purificó usando cromatografía ultrarrápida sobre gel de sílice, eluyendo con metanol al 0-10 % en cloruro de
35 metileno para proporcionar el producto deseado (25 mg, 36 %) en forma de un sólido de color blanco: EM (IEN) (m/z): 291 (M+H)+; RMN 1H (400 MHz, CDCl3) δ = 9,60 (s, 1H), 8,51 (d, J = 4,9 Hz, 1H), 8,11 (d, J = 5,3 Hz, 1H), 7,95 (s, 1H), 7,63 - 7,52 (m, 3H), 7,48 - 7,41 (m, 2H), 7,27 (d, J = 5,0 Hz, 1H), 6,85 (s, 1H), 6,60 (dd, J = 5,3, 1,5 Hz, 1H), 4,70 (s, 2H).
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Ejemplo 219
imagen111
5 2((1,3Trans)3hidroxiciclobutanocarboxamido)N(4fenilpiridin3il)isonicotinamida: EM (IEN) (m/z): 389 (M+H)+; RMN 1H (500 MHz, DMSO) δ 10,59 (s, 1H), 10,46 (s, 1H), 8,64 (s, 1H), 8,58 (d, J = 5,0 Hz, 1H), 8,49 (s, 1H), 8,44 (d, J = 5,0 Hz, 1H), 7,54 (d, J = 7,2 Hz, 2H), 7,51 - 7,44 (m, 3H), 7,41 (t, J = 6,7 Hz, 2H), 5,21 (s, 1H), 3,99 (s, 1H), 2,77 (dd, J = 16,1, 8,5 Hz, 1H), 2,37 (dt, J = 9,9, 7,4 Hz, 2H), 2,04 (td, J = 10,9, 2,6 Hz, 2H).
10 Ejemplo 220
imagen112
2((1,3Trans)3clorociclobutanocarboxamido)N(4fenilpiridin3il)isonicotinamida: EM (IEN) (m/z): 450
15 (M+H)+; RMN 1H (500 MHz, DMSO) δ 10,80 (s, 1H), 10,09 (s, 1H), 8,63 (s, 1H), 8,57 (s, 1H), 8,53 (d, J = 5,1 Hz, 1H), 8,30 (d, J = 5,5 Hz, 1H), 7,60 (d, J = 4,4 Hz, 1H), 7,13 (d, J = 5,5 Hz, 1H), 4,65 - 4,52 (m, 1H), 3,27 -3,17 (m, 5H), 2,79 - 2,72 (m, 2H), 2,47 (ddd, J = 18,3, 9,2, 2,8 Hz, 2H), 2,18-2,04 (m, 4H).
Ejemplo 221
20
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2((1,3Cis)3clorociclobutanocarboxamido)N(4fenilpiridin3il)isonicotinamida: EM (IEN) (m/z): 450 (M+H)+; RMN 1H (500 MHz, DMSO) δ 10,78 (s, 1H), 10,08 (s, 1H), 8,64 (s, 1H), 8,59 (s, 1H), 8,53 (d, J = 5,0 Hz, 1H), 8,30 (d,
25 J = 5,5 Hz, 1H), 7,60 (d, J = 4,7 Hz, 1H), 7,14 (d, J = 5,5 Hz, 1H), 4,71 (p, J = 6,8 Hz, 1H), 3,62 (tt, J = 9,7, 4,8 Hz, 1H), 3,24 - 3,20 (m, 4H), 2,81 (ddd, J = 12,3, 7,5, 4,7 Hz, 2H), 2,58 - 2,52 (m, 2H), 2,13 (ddd, J = 19,8, 14,0, 5,5 Hz, 4H).
Ejemplo 229
30
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2(3OxocycIopentanocarboxamido)N(4fenilpiridin3il)isonicotinamida: EM (IEN) (m/z): 401 (M+H)+; RMN 1H (400 MHz, MeOD/CDCl3) δ 8,86 (s, 1H), 8,51 (d, J = 5,1 Hz, 1H), 8,46 - 8,37 (m, 2H), 7,48 (dd, J = 9,8, 5,0 Hz, 5H), 35 7,43 (dd, J = 6,1, 2,7 Hz, 1H), 7,37 (d, J = 5,1 Hz, 1H), 2,67 -2,13 (m, 7H).
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2CloroN(4(4,4difluoropiperidin1il)piridin3il)3fluoroisonicotinamida. En un vial de 15 ml se disolvió 4(4,4-difluoropiperidin-1-il)piridin-3-amina (139 mg, 0,650 mmol) y ácido 2-cloro-3-fluoroisonicotínico (103,8 mg, 5 0,591 mmol) en dimetilformamida (4 ml) para dar una solución de color castaño. Se añadieron HATU (450 mg, 1,183 mmol) y base de Hunig (0.207 ml, 1,183 mmol), y la mezcla se agitó a ta durante 22 h. Se diluyó con agua y se extrajo con acetato de etilo. La capa orgánica se lavó con salmuera, se secó y se concentró. El residuo se purificó usando gel de sílice cromatografía ultrarrápida, eluyendo con acetato de etilo al 50 % en hexano para proporcionar el producto deseado (31,8 mg, 14,5 %) en forma de una aceite de color castaño: EM (IEN) (m/z): 371 (M+H)+; RMN 1H
10 (400 MHz, MeOD) δ 9,14 (s, 1H), 8,37 (d, J = 5,0 Hz, 1H), 8,30 (dd, J = 4,6, 3,7 Hz, 1H), 7,81 (t, J = 4,9 Hz, 1H), 7,39 (dd, J = 8,4, 4,4 Hz, 1H), 7,19 (d, J = 5,8 Hz, 1H), 3,38 - 3,31 (m, 2H), 3,25 - 3,18 (m, 2H), 2,16 - 2,02 (m, 2H), 2,01 1,91 (m, 2H); RMN 19F (376 MHz, MeOD) δ -73,28 (s), -75,17 (s).
Ejemplo 206
15
imagen120
N(4(4,4difluoropiperidin1il)piridin3il)5fluoro2isobutiramidoisonicotinamida. En un tubo de microondas de 5 ml se añadieron 2-cloro-N-(4-(4,4-difluoropiperidin-1-il)piridin-3-il)-5-fluoroisonicotinamida (24 mg, 0,065 mmol), 20 isobutiramida (11,28 mg, 0,129 mmol) y K2CO3 (13,42 mg, 0,097 mmol) en dioxano (0,5 ml) (desgasificado) para dar una suspensión incolora en una atmósfera de nitrógeno. Se añadieron Pd(OAc)2 (1,453 mg, 6,47 µmol) y XANTPHOS (7,49 mg, 0,013 mmol). El vial se cerró herméticamente y se calentó a 150 °C durante 2 h. La mezcla se repartió entre agua y acetato de etilo. La solución orgánica se secó y se concentró. El residuo se disolvió en dimetilformamida, y se purificó por HPLC prep. para proporcionar el producto deseado (3,7 mg, 13 %): EM (IEN)
25 (m/z): 422 (M+H)+; RMN 1H (500 MHz, DMSO) δ 10,73 (s, 1H), 10,06 (s, 1H), 8,56 (s, 1H), 8,52 (s, 1H), 8,47 (d, J = 5,2 Hz, 1H), 8,30 (d, J = 5,5 Hz, 1H), 7,11 (d, J = 5,5 Hz, 1H), 3,45 (t, J = 11,6 Hz, 2H), 3,19 (s, 2H), 2,78 (dt, J 13,4, 6.8 Hz, 1H), 2,05 (dt, J - 20,4, 7.0 Hz, 2H), 1,83 (s, 2H), 1,12 (d, J = 6,8 Hz, 6H).
Ejemplo de referencia 228
30
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2(Ciclopentanocarboxamido)N(isoquinolin4il)isonicotinamida. En matraz de fondo redondo de 5 ml se disolvió ácido 2-(ciclopentanocarboxamido)isonicotínico (36 mg, 0,154 mmol) e isoquinolin-4-amina (26,6 mg, 35 0,184 mmol) en dimetilformamida (0,8 ml) para dar una solución de color castaño. Se añadieron HATU (117 mg, 0,307 mmol) y base de Hunig (0,054 ml, 0,307 mmol), y la mezcla se agitó a ta durante la noche durante 19 h. El producto deseado se obtuvo mediante HPLC prep (5,9 mg, 10 %): EM (IEN) (m/z): 361 (M+H)+; RMN 1H (400 MHz, DMSO) δ 10,81 (s, 1H), 10,67 (s, 1H), 9,32 (s, 1H), 8,69 (s, 1H), 8,65 (s, 1H), 8,59 -8,51 (m, 1H), 8,30 - 8,20 (m, 1H), 8,07 - 7,99 (m, 1H), 7,91 - 7,84 (m, 1H), 7,82 - 7,74 (m, 1H), 7,73 - 7,66 (m, 1H), 3,05 - 2,98 (m, 1H), 1,95 - 1,85
imagen122
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M, (0,054 ml, 0,108 mmol) se añadió gota a gota. El matraz se desgasificó y se lavó abundantemente con nitrógeno y después recipiente de reacción se cerró herméticamente y después se calentó a 80 °C durante 2,5 h. La reacción se diluyó con acetato de etilo y cloruro de amonio saturado. La capa orgánica se lavó con agua, salmuera y se secó con sulfato de sodio. El material en bruto se purificó por CL preparativa. RMN 1H (500 MHz, DMSO-d6) δ ppm 11,08
5 (s, 1 H) 10,83 (s a, 1 H) 8,95 (d, J=2,14 Hz, 1 H) 8,68 (d, J=1,83 Hz, 1 H) 8,58 (d, J=0,61 Hz, 1 H) 8,55 (dd, J = 5,04, 0,76 Hz, 1 H) 8,46 (t, J=2,29 Hz, 1 H) 7,73 (dd, J=8,24, 1,22 Hz, 2 H) 7,60 (dd, J=5,19, 1,53 Hz, 1 H) 7,55 (t, J=7,63 Hz, 2 H) 7,45 - 7,50 (m, 1 H) 2,03 - 2,10 (m, 1 H) 0,84 - 0,89 (m, 4 H). EM (IEN) (m/z): 359,1 (M+H)+ .
Ejemplo 106
10
imagen126
N([3,4'bipiridin]5il)2(cycIopropanocarboxamido)isonicotinamida. RMN 1H (500 MHz, DMSOd6) δ ppm 11,08 (s, 1 H) 10,89 (s, 1 H) 9,02 (d, J=2,14 Hz, 1 H) 8,81 (d, J=1,83 Hz, 1 H) 8,69 - 8,75 (m, 2 H) 8,59 (s, 1 H) 8,58 15 (t, J=2,14 Hz, 1 H) 8,56 (dd, J=5,04, 0,76 Hz, 1 H) 7,77 - 7,80 (m, 2 H) 7,60 (dd, J= 5,19,1,53 Hz, 1 H) 2,03 - 2,10 (m, 1 H) 0,83 - 0,89 (m, 4 H). EM (IEN) (m/z): 360,1 (M+H)+ .
Ejemplo 111
imagen127
20
2(ciclopropanocarboxamido)N(5(4fluorofenil)piridin3il)isonicotinamida. RMN 1H (400 MHz, DMSO-d6) δ ppm 11,04 (s, 1 H) 10,80 (s a, 1 H) 8,93 (d, J=2,20 Hz, 1 H) 8,66 (d, J=1,96 Hz, 1 H) 8,57 (s, 1 H) 8,54 (d, J=5,14 Hz, 1 H) 8,43 (t, J=2,20 Hz, 1 H) 7,77 (dd, J=8,80, 5,38 Hz, 2 H) 7,59 (dd, J=5,14, 1,22 Hz, 1 H) 7,37 (t, J=8,80 Hz, 2 H)
25 2,02 - 2,10 (m, 1 H) 0,84 - 0,89 (m, 4 H). EM (IEN) (m/z): 377,2 (M+H)+ .
Ejemplo 112
imagen128
30 2(ciclopropanocarboxamido)N(5(3,4difluorofenil)piridin3il)isonicotinamida. RMN 1H (400 MHz, DMSO-d6) δ ppm 11,05 (s, 1 H) 10,81 (s a, 1 H) 8,94 (d, J=2,20 Hz, 1 H) 8,69 (d, J=1,96 Hz, 1 H) 8,57 (s, 1 H) 8,54 (d, J=5,14 Hz, 1 H) 8,45 (t, J=2,08 Hz, 1 H) 7,83 - 7,90 (m, 1 H) 7,56 - 7,64 (m, 3 H) 2,02 - 2,10 (m, 1 H) 0,84 - 0,89 (m, 4 H). EM (IEN) (m/z): 395,1 (M+H)+ .
35
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Ejemplo 128
imagen133
5 N([2,3'bipiridin]5'il)2(ciclopropanocarboxamido)isonicotinamida. RMN 1H (500 MHz, DMSO-d6) δ ppm 11,07 (s a, 1 H) 10,90 (s a, 1 H) 9,00 -9,08 (m, 2 H) 8,90 (s,1H) 8,75 (d, J=3,97 Hz, 1 H) 8,59 (s, 1 H) 8,54 (d, J=5,19 Hz, 1 H) 8,08 (d, J=7,93 Hz, 1 H) 7,97 (t, J= 7,78 Hz, 1 H) 7,62 (d, J=4,88 Hz, 1 H) 7,46 (dd, J=6,71, 5,49 Hz, 1 H) 2,00 - 2,11 (m, 1 H) 0,82 - 0,91 (m, 4 H). EM (IEN) (m/z): 360,2 (M+H)+ .
10 Ejemplo 129
imagen134
N([2,3'bipiridin]5'il)2(ciclopropanocarboxamido)isonicotinamida. RMN 1H (500 MHz, DMSO-d6) δ ppm
15 11,08 (s, 1 H) 10,88 (s, 1 H) 9,02 (d, J=2,14 Hz, 1 H) 8,63 (d, J=1,83 Hz, 1 H) 8,59 (s, 1 H) 8,55 (d, J=5,19 Hz, 1 H) 8,49 (s, 1 H) 8,15 (d, J=7,32 Hz, 1 H) 8,07 (s, 1 H) 7,99 (d, J=7,63 Hz, 1 H) 7,61 (dd, J = 5,04, 1,37 Hz, 1 H) 7,47 7,56 (m, 2 H) 2,02 - 2,10 (m, 1 H) 0,82 -0,90 (m, 4 H). EM (IEN) (m/z): 415,2 (M+H)+ .
Ejemplo 130
20
imagen135
2(ciclopropanocarboxamido)N(5(4metiltiofen3il)piridin3il)isonicotinamida. RMN 1H (500 MHz, DMSO-d6) δ ppm 11,07 (s, 1 H) 10,80 (s, 1 H) 8,92 (d, J=2,14 Hz, 1 H) 8,56 (s, 1 H) 8,52 - 8,55 (m, 1 H) 8,45 (d, J= 1,83 Hz, 1 25 H) 8,27 (t, J=2,14 Hz, 1 H) 7,68 (d, J=3,36 Hz, 1 H) 7,58 (dd, J=5,19, 1,53 Hz, 1 H) 7,38 (dd, J=3,20, 1,07 Hz, 1 H) 2,30 (s, 3 H) 2,02 - 2,09 (m, 1 H) 0,83 - 0,89 (m, 4 H). EM (IEN) (m/z): 379,2 (M+H)+ .
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Ejemplo 144
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5 N(5(2acetilfenil)piridin3il)2(ciclopropanocarboxamido)isonicotinamida. RMN 1H (500 MHz, DMSO-d6) δ ppm 11,07 (s, 1 H) 10,83 (s a, 1 H) 8,94 (d, J=2,44 Hz, 1 H) 8,56 (s, 1 H) 8,53 (d, J=5,19 Hz, 1 H) 8,28 (d, J=2,14 Hz, 1 H) 8,14 (t, J=2,14 Hz, 1 H) 7,82 (dd, J = 7,63, 1,22 Hz, 1 H) 7,65 - 7,70 (m, 1 H) 7,56 - 7,61 (m, 2 H) 7,46 - 7,51 (m, 1 H) 2,40 (s, 3 H) 2,02 - 2,09 (m, 1 H) 0,84 - 0,88 (m, 4 H). EM (IEN) (m/z): 401,2 (M+H)+ .
10 Ejemplo 145
imagen141
2(ciclopropanocarboxamido)N(5(2((dimetilamino)metil)fenil)piridin3il)isonicotinamida. RMN 1H
15 (500 MHz, DMSO-d6) δ ppm 11,06 (s, 1 H) 10,80 (s a, 1 H) 8,93 (d, J=2,14 Hz, 1 H) 8,56 (s, 1 H) 8,53 (d, J=4,88 Hz, 1 H) 8,40 (d, J = 1,83 Hz, 1 H) 8,22 (s, 1 H) 7,58 (d, J=5,19 Hz, 1 H) 7,54 (d, J= 7,63 Hz, 1 H) 7,38 - 7,47 (m, 2 H) 7,31 (d, J=7,32 Hz, 1 H) 2,08 (s, 6 H) 2,05 (d, J=6,41 Hz, 1 H) 1,90 (s, 2 H) 0,79 -0,92 (m, 4 H). EM (IEN) (m/z): 416,2 (M+H)+ .
20 Ejemplo 146
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2(ciclopropanocarboxamido)N(5(2propoxifenil)piridin3il)isonicotinamida. RMN 1H (500 MHz, DMSOd6) δ
25 ppm 11,06 (s, 1 H) 10,76 (s, 1 H) 8,86 (d, J=2,44 Hz, 1 H) 8,56 (s, 1 H) 8,53 (d, J=5,19 Hz, 1 H) 8,50 (d, J=2,14 Hz, 1 H) 8,37 (t, J=2,14 Hz, 1 H) 7,57 (dd, J=5,19,1,53 Hz, 1 H) 7,37 - 7,44 (m, 2 H) 7,17 (d, J=7,93 Hz, 1 H) 7,06 - 7,11 (m, 1 H) 4,00 (t, J=6,41 Hz, 2 H) 2,02 - 2,10 (m, 1 H) 1,65 -1,75 (m, 2 H) 0,92 (t, J=7,32 Hz, 3 H) 0,83 - 0,88 (m, 4 H). EM (IEN) (m/z): 417,3 (M+H)+ .
30
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Ejemplo 160
imagen147
5 N(5(2cloro3etoxifenil)piridin3il)2(ciclopropanocarboxamido)isonicotinamida. RMN 1H (500 MHz, DMSOd6) δ ppm 11,07 (s, 1 H) 10,89 (s a, 1 H) 9,00 (d, J=2,44 Hz, 1 H) 8,92 (d, 7H, 83 Hz, 1 H) 8,78 (d, J=2,14 Hz, 1 H) 8,73 (d, J = 2,44 Hz, 1 H) 8,55 (d, J=5,19 Hz, 1 H) 8,53 (t, J=2,14 Hz, 1 H) 8,34 (t, J=2,14 Hz, 1 H) 7,97 (s, 1 H) 7,60 (dd, J=5,04, 1,37 Hz, 1 H) 2,02 - 2,11 (m, 1 H) 0,83 - 0,91 (m, 4 H). EM (IEN) (m/z): 394,2 (M+H)+ .
10 Ejemplo 161
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2(ciclopropanocarboxamido)N(5'fluoro[3,3'bipiridin]5il)isonicotinamida. RMN 1H (500 MHz, DMSOd6) δ
15 ppm 11,07 (s, 1 H) 10,88 (a, s., 1 H) 9,00 (d, J=2,14 Hz, 1 H) 8,82 - 8,87 (m, 1 H) 8,78 (d, J=2,14 Hz, 1 H) 8,69 (d, J=2,44 Hz, 1 H) 8,59 (s, 1 H) 8,55 (d, J=4,88 Hz, 1 H) 8,53 (t, J=2,14 Hz, 1 H) 8,18 (dt, J=10,07, 2,29 Hz, 1 H) 7,60 (dd, J=5,19, 1,53 Hz, 1 H) 2,04 - 2,10 (m, 1 H) 0,85 - 0,89 (m, 4 H). EM (IEN) (m/z): 378,2 (M+H)+ .
Ejemplo 162
20
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2(cicIopropanocarboxamido)N(6'metil[3,3'bipiridin]5il)isonicotinamida. RMN 1H (500 MHz, DMSO-d6) δ ppm 11,07 (s, 1 H) 10,85 (s a, 1 H) 8,97 (d, J=2,44 Hz, 1 H) 8,81 (d, J=2,44 Hz, 1 H) 8,71 (d, J=2,14 Hz, 1 H) 8,59 (s, 25 1 H) 8,55 (d, J=4,88 Hz, 1 H) 8,47 (t, J = 2,14 Hz, 1 H) 8,04 (dd, J= 7,93, 2,44 Hz, 1 H) 7,60 (dd, J=5,19, 1,53 Hz, 1 H) 7,43 (d, J=7,93 Hz, 1 H) 2,55 (s, 3 H) 2,02 -2,12 (m, 1 H) 0,82 - 0,90 (m, 4 H). EM (IEN) (m/z): 374,2 (M+H)+ .
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