RU2012144751A - Гетероциклические соединения, эффективные для ингибирования киназы - Google Patents

Гетероциклические соединения, эффективные для ингибирования киназы Download PDF

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RU2012144751A
RU2012144751A RU2012144751/04A RU2012144751A RU2012144751A RU 2012144751 A RU2012144751 A RU 2012144751A RU 2012144751/04 A RU2012144751/04 A RU 2012144751/04A RU 2012144751 A RU2012144751 A RU 2012144751A RU 2012144751 A RU2012144751 A RU 2012144751A
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Ли Дэниел АРНОЛЬД
Эрик А. МЕРФИ
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Амитек Терапетикс Солюшинс, Инк.
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Abstract

1. Соединение формулы (I)или его N-оксид, N,N'-диоксид, N,N',N''-триоксид, или фармацевтически приемлемая соль:в которой:Q представляет собой O или S;W представляет собой C-Cарил или C-Cгетероарил, содержащий 1-3 гетероатома;каждый из Х и Y независимо отсутствует или представляет собой NH;каждый из Zи Zнезависимо выбран из группы, состоящей из CH, N, и NR, где Rпредставляет собой водород или низший алкил;Zпредставляет собой O, S, N, или NR, где Rпредставляет собой водород или низший алкил;Rпредставляет собой незамещенный или замещенный C-Cгетроарил, содержащий 1-3 гетероатома, или алкил, замещенный незамещенным или замещенным C-Cгетроарилом, содержащим 1-3 гетероатома;каждый из Rи Rнезависимо выбран из группы, состоящей из водорода, C-Cалкокси, необязательно замещенного C-Cаалкила, необязательно замещенного C-Cциклоалкила, необязательно замещенного C-Cгетероцикла, содержащего 1-3 гетероатома, необязательно замещенного C-Cарила, необязательно замещенного C-Cгетероарила, содержащего 1-3 гетероатома, CF, галогена, CN, CONHRи COR', где R' представляет собой водород или C-Cалкил; или, необязательно, Rи R, объединены вместе с образованием от пяти- до семичленного карбоцикла;Rнезависимо выбран из группы, состоящей из водорода, галогена, C-Cалкила, --OH, NO, -CN, C-Cалкокси, -NHSOR, -SONHR, -NHCOR, -NH, -NRR, -SR, -S(O)R, -S(O)R, -COR, -CONRR, где Rи Rнезависимо выбраны из группы, состоящей из водорода и необязательно замещенного C-Cалкила; p=0-4 и n равен 1 или 2.2. Соединение по п.1, в котором W представляет собой C-Cарил.3. Соединение по п.1, в котором Rпредставляет собой незамещенный или замещенный C-Cгетероарил, содержащий 1-3 гетероатома.4. Соединение по п.1, в котором Rпредставляет собой водород.5. Соединение по п.1, в котором

Claims (15)

1. Соединение формулы (I)
Figure 00000001
или его N-оксид, N,N'-диоксид, N,N',N''-триоксид, или фармацевтически приемлемая соль:
в которой:
Q представляет собой O или S;
W представляет собой C6-C12арил или C3-C12гетероарил, содержащий 1-3 гетероатома;
каждый из Х и Y независимо отсутствует или представляет собой NH;
каждый из Z1 и Z2 независимо выбран из группы, состоящей из CH, N, и NR5, где R5 представляет собой водород или низший алкил;
Z3 представляет собой O, S, N, или NR5, где R5 представляет собой водород или низший алкил;
R1 представляет собой незамещенный или замещенный C3-C12гетроарил, содержащий 1-3 гетероатома, или алкил, замещенный незамещенным или замещенным C3-C12гетроарилом, содержащим 1-3 гетероатома;
каждый из R2 и R3 независимо выбран из группы, состоящей из водорода, C1-C6алкокси, необязательно замещенного C1-C6аалкила, необязательно замещенного C3-C12циклоалкила, необязательно замещенного C3-C10гетероцикла, содержащего 1-3 гетероатома, необязательно замещенного C6-C12арила, необязательно замещенного C3-C12гетероарила, содержащего 1-3 гетероатома, CF3, галогена, CN, CONHR6 и CO2R', где R' представляет собой водород или C1-C6алкил; или, необязательно, R2 и R3, объединены вместе с образованием от пяти- до семичленного карбоцикла;
R4 независимо выбран из группы, состоящей из водорода, галогена, C1-C6алкила, --OH, NO2, -CN, C1-C6алкокси, -NHSO2R6, -SO2NHR6, -NHCOR6, -NH2, -NR6R7, -SR6, -S(O)R6, -S(O)2R6, -CO2R6, -CONR6R7, где R6 и R7 независимо выбраны из группы, состоящей из водорода и необязательно замещенного C1-C6алкила; p=0-4 и n равен 1 или 2.
2. Соединение по п.1, в котором W представляет собой C6-C12арил.
3. Соединение по п.1, в котором R1 представляет собой незамещенный или замещенный C3-C12гетероарил, содержащий 1-3 гетероатома.
4. Соединение по п.1, в котором R4 представляет собой водород.
5. Соединение по п.1, в котором каждый из R2 и R3 независимо выбран из группы, состоящей из C1-C6алкила, -CF3 и галогена, где p равен 0, или 1, или 2; или, необязательно, R2 и R3 объединены вместе с образованием от пяти- до семичленного карбоцикла.
6. Соединение по п.1, где соединение формулы (I) выбрано из группы, состоящей из:
Figure 00000002
,
Figure 00000003
,
Figure 00000004
,
Figure 00000005
,
Figure 00000006
,
Figure 00000007
,
Figure 00000008
,
Figure 00000009
,
Figure 00000010
,
Figure 00000011
,
Figure 00000012
,
Figure 00000013
,
Figure 00000014
,
Figure 00000015
,
Figure 00000016
,
Figure 00000017
,
Figure 00000018
,
Figure 00000019
,
Figure 00000020
,
Figure 00000021
,
Figure 00000022
,  
Figure 00000023
,
Figure 00000024
,
Figure 00000025
,  
Figure 00000026
,
Figure 00000027
,
Figure 00000028
,
Figure 00000029
,
Figure 00000030
,
Figure 00000031
,
Figure 00000032
,
Figure 00000033
,
Figure 00000034
,
Figure 00000035
,
Figure 00000036
,
Figure 00000037
, ,
Figure 00000038
,
Figure 00000039
,
Figure 00000040
,
Figure 00000041
,
Figure 00000042
,
Figure 00000043
,
Figure 00000044
,
Figure 00000045
,
Figure 00000046
,  
Figure 00000047
,
Figure 00000048
,
Figure 00000049
,
Figure 00000050
,
Figure 00000051
,
Figure 00000052
,
Figure 00000053
,
Figure 00000054
,
Figure 00000055
Figure 00000056
,
Figure 00000057
,
Figure 00000058
,
Figure 00000059
,
Figure 00000060
,
Figure 00000061
,
Figure 00000062
,
Figure 00000063
,
Figure 00000062
,
Figure 00000063
,
Figure 00000064
,
Figure 00000065
,
Figure 00000066
,
Figure 00000067
Figure 00000068
,
Figure 00000069
,  
Figure 00000070
,.
Figure 00000071
,
Figure 00000072
,
Figure 00000073
,
Figure 00000074
, и  
Figure 00000075
.
7. Соединение по п.1 формулы (II)
Figure 00000076
или его N-оксид, N,N'-диоксид, N,N',N''-триоксид, или фармацевтически приемлемая соль:
в которой:
R8 и R9 независимо выбраны из группы, состоящей из водорода, галогена, необязательно замещенного C1-C6алкила, -CF3, -OH, необязательно замещенного C1-C6алкокси, -NR10R11, и -SOmR12, где R10 и R11 независимо выбраны из группы, состоящей из водорода, необязательно замещенного C1-C6алкила, -SO2R12, -S(O)R12, и -COR12, и R12 представляет собой необязательно замещенный алкил или необязательно замещенный C3-C12гетероарил, содержащий 1-3 гетероатома и m равен 0-2.
8. Соединение по п.7, в котором R8 и R9 независимо выбраны из группы, состоящей из необязательно замещенного C1-C6алкокси, -NR10R11, и -SOmR12 и m равен 0-2.
9. Соединение по п.8, в котором каждый из R2 и R3 независимо выбраны из группы, состоящей из C1-C6алкилв, -CF3, и галогена, где p равен 0, или 1, или 2; или, необязательно, R2 и R3 объединены вместе с образованием от пяти- до семичленного карбоцикла.
10. Соединение по п.9, где соединение формулы (II) выбрано из группы, состоящей из:
Figure 00000077
,
Figure 00000078
,
Figure 00000079
,
Figure 00000080
,
Figure 00000081
,
Figure 00000082
,
Figure 00000083
,
Figure 00000084
,
Figure 00000085
,
Figure 00000086
,
Figure 00000087
,
Figure 00000088
,
Figure 00000089
,
Figure 00000090
,
Figure 00000091
,
Figure 00000092
,
Figure 00000093
,
Figure 00000094
,
Figure 00000094
,
Figure 00000095
,
Figure 00000096
,
Figure 00000097
,
Figure 00000098
,
Figure 00000099
,
Figure 00000100
,
Figure 00000101
,
Figure 00000102
,
Figure 00000103
,
Figure 00000104
,
Figure 00000105
,
Figure 00000106
,
Figure 00000107
,
Figure 00000108
,
Figure 00000109
,
Figure 00000110
,
Figure 00000111
,
Figure 00000112
,
Figure 00000113
,
Figure 00000114
,
Figure 00000115
,
Figure 00000116
,
Figure 00000117
,
Figure 00000118
,
Figure 00000119
,
Figure 00000120
,
Figure 00000121
,
Figure 00000122
,
Figure 00000123
,
Figure 00000124
,
Figure 00000125
,
Figure 00000126
,
Figure 00000127
,
Figure 00000128
,
Figure 00000129
,
Figure 00000130
,
Figure 00000131
,
Figure 00000132
,
Figure 00000133
,
Figure 00000134
,
Figure 00000135
,
Figure 00000136
,
Figure 00000137
,
Figure 00000138
,
Figure 00000139
,
Figure 00000140
,  
Figure 00000141
,
Figure 00000142
,
Figure 00000143
,
Figure 00000144
,
Figure 00000145
, и
Figure 00000146
.
11. Соединение по п.1, выбранное из группы, состоящей из:
Figure 00000147
,
Figure 00000148
,
Figure 00000149
,
Figure 00000150
,
Figure 00000151
,
Figure 00000152
,
Figure 00000153
,
Figure 00000154
,
Figure 00000155
,
Figure 00000156
,
Figure 00000157
,
Figure 00000158
,
Figure 00000159
,
Figure 00000160
,
Figure 00000161
,
Figure 00000162
,
Figure 00000163
,
Figure 00000164
,
Figure 00000165
,
Figure 00000166
,
Figure 00000167
,
Figure 00000168
,
Figure 00000169
,
Figure 00000170
,
Figure 00000171
,
Figure 00000172
,
Figure 00000173
,
Figure 00000174
,
Figure 00000175
,
Figure 00000176
,
Figure 00000177
,
Figure 00000178
,
Figure 00000179
,
Figure 00000180
,
Figure 00000181
,
Figure 00000182
,
Figure 00000183
,
Figure 00000184
,
Figure 00000185
,
Figure 00000186
,
Figure 00000187
,
Figure 00000188
,
Figure 00000189
,
Figure 00000190
,
Figure 00000191
,
Figure 00000192
,
Figure 00000191
,
Figure 00000192
,
Figure 00000193
,
Figure 00000194
,
Figure 00000195
,
Figure 00000196
,
Figure 00000197
,
Figure 00000198
,
Figure 00000199
,
Figure 00000200
,
Figure 00000201
,
Figure 00000202
,
Figure 00000203
,
Figure 00000204
,
Figure 00000205
,
Figure 00000206
,
Figure 00000207
,
Figure 00000208
,
Figure 00000209
,
Figure 00000210
,
Figure 00000211
,
Figure 00000212
,
Figure 00000213
,
Figure 00000214
,
Figure 00000215
,
Figure 00000216
,
Figure 00000217
,
Figure 00000218
,
Figure 00000219
, и
Figure 00000220
.
12. Соединение по п.1, выбранное из группы, состоящей из:
Figure 00000221
,
Figure 00000222
,
Figure 00000223
,
Figure 00000224
,
Figure 00000225
,
Figure 00000226
,
Figure 00000227
,
Figure 00000228
,
Figure 00000229
, и
Figure 00000230
.
13. Соединение формулы (V)
Figure 00000231
или его N-оксид, N,N'-диоксид, N,N',N''-триоксид, или фармацевтически приемлемая соль:
в которой:
R1 представляет собой незамещенный или замещенный C3-C12 гетероарил, содержащий 1-3 гетероатома, или алкил, замещенный незамещенным или замещенным C3-C12гетероарилом, содержащим 1-3 гетероатома;
R4 независимо выбран из группы, состоящей из водорода, галогена, C1-C6алкила, -OH, -NO2, -CN, C1-C6алкокси, -NHSO2R6, -SO2NHR6, -NHCOR6, -NH2, -NR6R7, -SR6, -S(O)R6, -S(O)2R6, -CO2R6, и -CONR6R7, где R6 и R7 независимо выбраны из группы, состоящей из водорода, и необязательно замещенного C1-C6алкила; n равен 1 или 2; и
R14 выбран из группы, состоящей из необязательно замещенного C1-C12алкила, необязательно замещенного C3-C12циклоалкила, необязательно замещенного C3-C10гетероцикла, содержащего 1-3 гетероатома, необязательно замещенного C6-C12арила, и необязательно замещенного C3-C12гетероарила, содержащего 1-3 гетероатома.
14. Фармацевтическая композиция, содержащая соединение по п.1 в фармацевтически приемлемом носителе.
15. Способ лечения рака, рестеноза, гиперплазии интимы, фиброзирующих заболеваний или расстройств, связанных с ангиогенезом, у пациента-человека, включающий введение соединения по п.1 пациенту, нуждающемуся в этом.
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