RU2492166C2 - Соединения, подходящие для применения в качестве ингибиторов киназы raf - Google Patents

Соединения, подходящие для применения в качестве ингибиторов киназы raf Download PDF

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RU2492166C2
RU2492166C2 RU2009149214/04A RU2009149214A RU2492166C2 RU 2492166 C2 RU2492166 C2 RU 2492166C2 RU 2009149214/04 A RU2009149214/04 A RU 2009149214/04A RU 2009149214 A RU2009149214 A RU 2009149214A RU 2492166 C2 RU2492166 C2 RU 2492166C2
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Russia
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compound
formula
independently selected
nitrogen
oxygen
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RU2009149214/04A
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RU2009149214A (ru
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Вэйжун ЧЭНЬ
Дженнифер КОССРОУ
Ллойд Франклин
Бин ГУАНЬ
Джон Ховард ДЖОУНЗ
Гнанасамбандам Кумаравел
Бенджамин ЛЭЙН
Адам ЛИТТКЕ
Алексей Луговской
Хайжо ПЭН
Ноэль ПАУЭЛЛ
Брайан РАЙМУНДО
Хироко Танака
Джеффри ВЕССЕЛЗ
Томас УИНН
Чжили СИНЬ
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Санесис Фармасьютикалз, Инк.
Байоджен Айдек Ма Инк.
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    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom

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Abstract

Изобретение относится к соединению формулы I:
Figure 00000270
или к его фармацевтически приемлемым солям, где значения Cy1; Cy2; L1; L2, R; R1; Rx и Ry и R2 представлены в п.1 формулы изобретения. При этом указанные соединения подходят для применения в качестве ингибиторов протеинкиназы Raf. 7 н. и 29 з.п. ф-лы, 6 табл.

Description

Текст описания приведен в факсимильном виде.
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Claims (36)

  1. Соединение формулы I
    Figure 00000270

    или фармацевтически приемлемая соль указанного соединения,
    где Cy1 представляет собой фенил или 5-6-членное ароматическое кольцо, содержащее от 1 до 3 гетероатомов, независимо выбранных из азота, кислорода или серы;
    Cy2 представляет собой 5-14-членное насыщенное, частично ненасыщенное или ароматическое моноциклическое, бициклическое или трициклическое кольцо, содержащее от 0 до 4 гетероатомов, независимо выбранных из азота или кислорода, где указанное кольцо может быть моно- или дизамещенным группами, независимо выбранными из галогена, -СF3, С1-4алкила и 1-метилциклопропила;
    L1 представляет собой прямую связь или линейную или разветвленную алкиленовую цепь С1-6;
    L2 представляет собой прямую связь или линейную или разветвленную алкиленовую цепь С1-6, при этом один или два метиленовых звена в группе L2 могут быть независимо замещены на -N(R)-, -C(O)-, -C(O)N(R)- или -N(R)C(O)-;
    каждая группа R независимо представляет собой водород или алифатическую группу C1-6;
    R1 представляет собой водород или алифатическую группу C1-6;
    каждый из Rx и Ry независимо выбран из следующих групп: -R2, -галоген, -CN, -OR2, -SR2, -N(R2)2, -CO2R2, -C(O)N(R2)2, -N(R2)C(O)R2, -N(R2)N(R2)2, -N(R2)SO2N(R2)2, -NHСН2СН2СН2N(СН3)2 или -N(R2)SO2R2: и
    каждый R2 независимо представляет собой водород или группу, выбранную из следующих групп: алифатической C1-6, моноциклического или бициклического арильного кольца С6-10 или 5-10-членного насыщенного, частично ненасыщенного или ароматического моноциклического или бициклического кольца, содержащего от 1 до 4 гетероатомов, независимо выбранных из азота, кислорода или серы, или
    две группы R2 у одного и того же атома азота совместно с указанным атомом азота образуют 5-8-членное насыщенное, частично ненасыщенное или ароматическое кольцо, содержащее от 1 до 4 гетероатомов, независимо выбранных из азота, кислорода или серы.
  2. 2. Соединение по п.1, в котором каждый из Rx и Ry независимо выбран из следующих групп: R2, галоген, -OR2, -N(R2)2, -N(R2)C(O)R2, -N(R2)N(R2)2, -N(R2)SO2N(R2)2, или -N(R2)SO2R2.
  3. 3. Соединение по п.2, в котором Rx представляет собой водород, алифатическую группу C1-6 или галоген.
  4. 4. Соединение по п.2, в котором группа Ry выбрана из R2, -OR2 или -N(R2)2.
  5. 5. Соединение по п.4, в котором Ry представляет собой -NH2, -NНСH3, -NHCH2CH3, -NНСН2СН2СН3, -NHСН(СН3)2, -NH(C3H5), -NHCH2CH2CH2OH, -N(CH2CH2)2O или -NНСН2СН2СН2N(СН3)2.
  6. 6. Соединение по п.4, в котором Ry представляет собой алифатическую группу С1-6.
  7. 7. Соединение по п.6, в котором Ry представляет собой группу, выбранную из С2-6алкенильной или С2-6алкинильной группы.
  8. 8. Соединение по п.4, в котором Ry представляет собой 5-10-членное насыщенное моноциклическое или бициклическое кольцо, содержащее от 1 до 4 гетероатомов, независимо выбранных из азота, кислорода или серы.
  9. 9. Соединение по п.8, в котором Ry представляет собой группу, выбранную из:
    (a) 5-6-членного насыщенного моноциклического кольца, содержащего от 1 до 3 гетероатомов, независимо выбранных из азота, кислорода или серы;
    (b) 5-6-членного ароматического кольца, содержащего от 1 до 3 гетероатомов, независимо выбранных из азота, кислорода или серы; или
    (c) 8-10-членного насыщенного, частично ненасыщенного или ароматического бициклического кольца, содержащего от 1 до 4 гетероатомов, независимо выбранных из азота, кислорода или серы.
  10. 10. Соединение по п.8, в котором Ry представляет собой группу, выбранную из фенила, октагидроазоцинила, тиоциклопентанила, тиоциклогексанила, пирролидинила, пиперидинила, пиперазинила, тетрагидротиопиранила, тетрагидротиофенила, дитиоланила, тетрагидрофуранила, тетрагидропиранила, диоксанила, тиоксанила, морфолинила, оксатиоланила, имидазолидинила, пирролила, пиразолила, имидазолила, триазолила, тетразолила, тиофенила, фуранила, тиазолила, изотиазолила, тиадиазолила, оксазолила, изоксазолила, оксадиазолила, пиридинила, пиримидинила, пиразинида, пиридазинила, триазинила, тетразинила, тетрагидропиридинила, бензофуранила, тианафтенила, пиролизинила, индолила, хинолинила, изохинолинила, бензимидазолила, имидазопиридинила, пуринила, индазолила, пирролопиридинила, циннолинила, хиназолинила, фталазинила, нафтиридинила или хиноксалинила.
  11. 11. Соединение по п.1, в котором R1 представляет собой водород, a L1 представляет собой линейную или разветвленную алкиленовую цепь C1-4.
  12. 12. Соединение по п.11, в котором L1 представляет собой разветвленную алкиленовую цепь С1-4.
  13. 13. Соединение по п.1, в котором Cy1 представляет собой 5-членное ароматическое кольцо, содержащее от 1 до 3 гетероатомов, независимо выбранных из азота, кислорода или серы.
  14. 14. Соединение по п.13, в котором Cy1 представляет собой пирролильную, пиразолильную, имидазолильную, триазолильную, тетразолильную, тиофенильную, фуранильную, тиазолильную, изотиазолильную, тиадиазолильную, оксазолильную, изоксазолильную или оксадиазолильную группу.
  15. 15. Соединение по п.1, в котором L2 представляет собой прямую связь или линейную или разветвленную алкиленовую цепь С1-4, при этом один или два метиленовых звена в группе L2 замещены на -N(R)- или -C(O)N(R)-.
  16. 16. Соединение по п.15, в котором L2 представляет собой -C(O)N(R)-.
  17. 17. Соединение по п.16, в котором L2 представляет собой -C(O)N(H)-.
  18. 18. Соединение по п.1, в котором Cy2 представляет собой группу, выбранную из:
    (a) 5-членного насыщенного, частично ненасыщенного или ароматического моноциклического кольца, содержащего от 1 до 3 гетероатомов, независимо выбранных из азота или кислорода;
    (b) фенила или 6-членного насыщенного, частично ненасыщенного или ароматического моноциклического кольца, содержащего от 1 до 4 атомов азота; или
    (c) 5-10-членного насыщенного, частично ненасыщенного или ароматического бициклического кольца, содержащего от 1 до 4 атомов азота;
    где указанный циклический заместитель может быть моно- или дизамещенным группами, независимо выбранными из галогена, -СF3, С1-4 алкила и 1-метилциклопропила.
  19. 19. Соединение по п.18, в котором Cy2 представляет собой группу, выбранную из:
    (а) 5-членного гетероарильного кольца, содержащего от 1 до 3 гетероатомов, независимо выбранных из азота или кислорода;
    (b) фенила или 6-членного гетероарильного кольца, содержащего от 1 до 3 атомов азота; или
    (c) 5,6-конденсированного бициклического гетероарильного цикла, содержащего от 1 до 4 атомов азота,
    где указанный циклический заместитель может быть моно- или дизамещенным группами, независимо выбранными из галогена, -СF3, С1-4 алкила и 1-метилциклопропила.
  20. 20. Соединение по п.19, в котором Cy2 представляет собой группу, выбранную из фенила, пирролила, пиразолила, имидазолила, триазолила, тетразолила, фуранила, оксазолила, изоксазолила, оксадиазолила, пиридинила, пиримидинила, пиразинила, пиридазинила, триазинила, тетразинила, пиролизинила, индолила, хинолинила, изохинолинила, бензимидазолила, имидазопиридинила, индазолила, пуринила, циннолинила, хипазолинила, фталазинила, нафтридинила, хиноксалинила, тианафтенила или бензофуранила;
    где указанный циклический заместитель может быть моно- или дизамещенным группами, независимо выбранными из галогена, -СF3, С1-4 алкила и 1-метилциклопропила.
  21. 21. Соединение по п.1, отличающееся тем, что указанное соединение представляет собой соединение формулы II
    Figure 00000271

    или фармацевтически приемлемую соль указанного соединения.
  22. 22. Соединение по п.21, отличающееся тем, что указанное соединение представляет собой соединение формулы II-а или II-b
    Figure 00000272
    Figure 00000273
  23. 23. Соединение по п.22, в котором Cy1 представляет собой 5-членное гетероарильное кольцо, содержащее от 1 до 3 гетероатомов, независимо выбранных из азота, кислорода или серы.
  24. 24. Соединение, выбранное из нижеследующих соединений:
    Figure 00000274
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    Figure 00000276
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    Figure 00000280
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    Figure 00001099

    или из фармацевтически приемлемых солей указанных соединений.
  25. 25. Способ ингибирования активности киназы Raf у пациента или в биологическом образце, включающий введение указанному пациенту соединения по п.1 или фармацевтической композиции указанного соединения или приведение указанного биологического образца в контакт с соединением по п.1 или фармацевтической композицией указанного соединения.
  26. 26. Способ лечения или уменьшения тяжести нарушения, опосредуемого Raf, у млекопитающего, страдающего or такого нарушения, причем указанное нарушение выбрано из пролиферативного нарушения, нарушения сердечной деятельности, нейродегенеративного нарушения, аутоиммунного нарушения, состояния, связанного с трансплантацией органа, воспалительного нарушения, иммунологически опосредуемого нарушения, вирусного заболевания или поражения костей, при этом указанный способ включает этап введения указанному пациенту соединения по п.1 или фармацевтической композиции на основе указанного соединения.
  27. 27. Способ по п.26, в котором указанное нарушение выбрано из меланомы, лейкоза, paкa толстой кишки, рака молочной железы, рака желудочно-кишечного тракта, рака яичников, рака легкого, рака головного мозга, рака гортани, рака шейки матки, рака почки, рака лимфатической системы, рака мочеполового тракта (включая рак мочевого пузыря и рак предстательной железы), рака желудка, рака кости, лимфомы, меланомы, глиомы, папиллярного рака щитовидной железы, нейробластомы и рака поджелудочной железы.
  28. 28. Способ получения соединения формулы II-а'
    Figure 00001100

    или фармацевтически приемлемой соли указанного соединения,
    где Cy1 представляет собой 5-6-членное ароматическое кольцо, содержащее от 1 до 3 гетероатомов, независимо выбранных из азота, кислорода или серы;
    Cy2 представляет собой 5-10-членное насыщенное, частично ненасыщенное или ароматическое моноциклическое или бициклическое кольцо, содержащее от 0 до 4 гетероатомов, независимо выбранных из азота или кислорода, где указанное кольцо может быть моно- или дизамещенным группами, независимо выбранными из галогена, -СF3, С1-4алкила и 1-метилциклопропила;
    каждая из групп Rx и Ry независимо выбрана из -R2, -галогена, -CN, -OR2, -SR2, -N(R2)2, -CO2R2, -C(O)N(R2)2, -N(R2)C(O)R2, -N(R2)N(R2)2, -N(R2)SO2N(R2)2 или -N(R2)SO2R2;
    каждая группа R2 независимо представляет собой водород или группу, выбранную из следующих групп: алифатической группы C1-6, моноциклического или бициклического арильного кольца С6-10 или 5-10-членного насыщенного, частично ненасыщенного или ароматического моноциклического или бициклического кольца, содержащего от 1 до 4 гетероатомов, независимо выбранных из азота, кислорода или серы, или две группы R2 у одного и того же атома азота совместно с указанным атомом азота образуют 5-8-членное насыщенное, частично ненасыщенное или ароматическое кольцо, содержащее от 1 до 4 гетероатомов, независимо выбранных из азота, кислорода или серы, включающий стадию проведения реакции сочетания соединения формулы II-viii
    Figure 00001101

    с соединением формулы II-vii
    Figure 00001102

    с образованием соединения формулы II-а'.
  29. 29. Способ по п.28, в котором соединение формулы II-vii получают из соединения формулы II-vi-b
    Figure 00001103

    где А' представляет собой подходящий хиральный анион,
    включающий стадию обработки соединения формулы II-vi-b подходящим основанием с образованием соединения формулы II-vii.
  30. 30. Способ по п.29, в котором соединение формулы II-vi-b получают из соединения формулы II-v
    Figure 00001104

    включающий следующие стадии:
    (а) обработка соединения формулы II-v хиральным агентом с образованием соединения формулы II-vi-a
    Figure 00001105

    и
    (b) разделение полученных диастерсомсров с помощью подходящих физических способов
    с получением соединения формулы II-vi-b.
  31. 31. Способ по п.30, в котором соединение формулы II-v
    Figure 00001106

    получают из соединения формулы II-iv
    Figure 00001107

    включающий стадию превращения оксимного фрагмента формулы II-iv в аминогруппу формулы II-v.
  32. 32. Способ по п.31, в котором соединение формулы II-iv получают из соединения формулы II-iii
    Figure 00001108

    включающий стадию обработки соединения формулы II-iii гидроксиламином с образованием соединения формулы II-iv.
  33. 33. Способ по п.32, в котором соединение формулы II-iii получают путем осуществления сочетания соединения формулы II-i
    Figure 00001109

    с соединением формулы II-ii
    Figure 00001110
  34. 34. Соединение, выбранное из
    Figure 00001111

    Figure 00001112
    Figure 00001113
    и
    Figure 00001114
  35. 35. Соединение формулы II-iv
    Figure 00001115

    в котором Cy1 представляет собой 5-6-членное насыщенное, частично ненасыщенное или ароматическое кольцо, содержащее от 1 до 3 гетероатомов, независимо выбранных из азота, кислорода или серы; и
    Cy2 представляет собой 5-10-членное насыщенное, частично ненасыщенное или ароматическое моноцикличсское или бициклическое кольцо, содержащее от 0 до 4 гетероатомов, независимо выбранных из азота или кислорода, где указанное кольцо может быть моно- или дизамещенным группами, независимо выбранными из галогена, -СF3, С1-4 алкила и 1-метилциклопропила.
  36. 36. Соединение по п.1 следующей формулы:
    Figure 00001116

    или его фармацевтически приемлемая соль.
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