公开(公告)号：EP3800189A1

公开(公告)日：2021-04-07

申请号：EP20208218.6

申请日：2017-05-18

申请人： Loxo Oncology, Inc. ,  Array Biopharma, Inc.

发明人： REYNOLDS, Mark ,  EARY, Charles Todd ,  SPENCER, Stacey ,  JUENGST, Derrick ,  HACHE, Bruno ,  JIANG, Yutong ,  HAAS, Julia ,  ANDREWS, Steven W.

IPC分类号： C07D487/04 ,  A61K31/5025 ,  A61P35/00 ,  A61P43/00

摘要： Process for preparing (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a] pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide (formula I) or a salt thereof by reacting phenyl(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3,3a-dihydropyrazolo[1,5-a]pyrimidin-3-yl)carbamate or a similar derivative (formula 13) with (S)-pyrrolidin-3-ol (formula 14).
Process for preparing phenyl(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3,3a-dihydropyrazolo[1,5-a]pyrimidin-3-yl)carbamate (formula 13) or a similar derivative by reduction of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3-nitropyrazolo[1,5-a]pyrimidine (formula 11) to (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (formula 12).
Process for preparing (R)-2-(2,5-difluorophenyl)pyrrolidine(R)-2-hydroxysuccinate (formula 10) by treating (R)-N-((R)-1-(2,5-difluorophenyl)-3-(1,3-dioxan-2-yl)propyl)-2-methylpropane-2-sulfinamide (formula 19) with an acid and a reducing agent.
(S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-l-yl)-pyrazolo[l,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide, is a tyrosin kinase (TRK) inhibitor for trearing e.g. cancer.

公开(公告)号：EP3458456B1

公开(公告)日：2020-11-25

申请号：EP17726442.1

申请日：2017-05-18

申请人： Loxo Oncology, Inc. ,  Array Biopharma Inc.

发明人： REYNOLDS, Mark ,  EARY, Charles Todd ,  SPENCER, Stacey ,  JUENGST, Derrick ,  HACHE, Bruno ,  JIANG, Yutong ,  HAAS, Julia ,  ANDREWS, Steven W.

IPC分类号： C07D487/04 ,  A61K31/5025 ,  A61P35/00 ,  A61P43/00

公开(公告)号：EP3458456A1

公开(公告)日：2019-03-27

申请号：EP17726442.1

申请日：2017-05-18

申请人： Eary, Charles Todd ,  Loxo Oncology, Inc. ,  Array Biopharma Inc.

发明人： REYNOLDS, Mark ,  SPENCER, Stacey ,  JUENGST, Derrick ,  HACHE, Bruno ,  JIANG, Yutong ,  HAAS, Julia ,  ANDREWS, Steven W.

IPC分类号： C07D487/04 ,  A61K31/5025 ,  A61P35/00

公开(公告)号：EP2961744B1

公开(公告)日：2017-06-28

申请号：EP14710725.4

申请日：2014-02-27

申请人： Array Biopharma, Inc.

发明人： EARY, Todd C. ,  HACHE, Bruno P. ,  JUENGST, Derrick ,  SPENCER, Stacey Renee ,  STENGEL, Peter J. ,  WATSON, Daniel John

IPC分类号： C07D403/12 ,  C07D231/56 ,  A61K31/416 ,  A61P29/00

CPC分类号： C07D403/12 ,  C07D231/56

公开(公告)号：EP3699181A1

公开(公告)日：2020-08-26

申请号：EP20169707.5

申请日：2015-11-16

申请人： Array Biopharma, Inc.

发明人： ARRIGO, Alisha B. ,  JUENGST, Derrick ,  SHAH, Khalid

IPC分类号： C07D487/04 ,  A61K31/519 ,  A61P35/00

摘要： A novel crystalline form of (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide, pharmaceutical compositions containing said crystalline form and the use of said crystalline form in the treatment of pain, cancer, inflammation, neurodegenerative disease or Trypanosoma cruzi infection are disclosed. In some embodiments, the novel crystalline form comprises a stable polymorph of (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate.

公开(公告)号：EP3218380A1

公开(公告)日：2017-09-20

申请号：EP15808300.6

申请日：2015-11-16

申请人： Array Biopharma, Inc.

发明人： ARRIGO, Alisha B. ,  JUENGST, Derrick ,  SHAH, Khalid

IPC分类号： C07D487/04 ,  A61K31/519 ,  A61P35/00

CPC分类号： A61K31/519 ,  C07D487/04 ,  C12Q1/485 ,  C12Y207/10001 ,  G01N2333/91205 ,  G01N2800/52

摘要： A novel crystalline form of (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide, pharmaceutical compositions containing said crystalline form and the use of said crystalline form in the treatment of pain, cancer, inflammation, neurodegenerative disease or Trypanosoma cruzi infection are disclosed. In some embodiments, the novel crystalline form comprises a stable polymorph of (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate. The present invention is further directed to a process for the preparation of the novel crystalline form.

摘要翻译： （S）-N-（5 - （（R）-2-（2,5-二氟苯基）吡咯烷-1-基） - 吡唑并[1,5-a]嘧啶-3-基） - 3-羟基吡咯烷-1-甲酰胺，含有所述结晶形式的药物组合物和所述结晶形式在治疗疼痛，癌症，炎症，神经退行性疾病或克氏锥虫感染中的用途。 在一些实施方案中，新型结晶形式包含（S）-N-（5 - （（R）-2-（2,5-二氟苯基）吡咯烷-1-基） - 吡唑并[1,5-a ]嘧啶-3-基）-3-羟基吡咯烷-1-甲酰胺硫酸氢盐。 本发明还涉及制备新型结晶形式的方法。

公开(公告)号：EP2961744A1

公开(公告)日：2016-01-06

申请号：EP14710725.4

申请日：2014-02-27

申请人： Array Biopharma, Inc.

发明人： EARY, Todd C. ,  HACHE, Bruno P. ,  JUENGST, Derrick ,  SPENCER, Stacey Renee ,  STENGEL, Peter J. ,  WATSON, Daniel John

IPC分类号： C07D403/12 ,  C07D231/56 ,  A61K31/416 ,  A61P29/00

CPC分类号： C07D403/12 ,  C07D231/56

摘要： Provided herein are novel processes for preparing a compound of Formula (I) to the use of said compound as an intermediate in novel processes for the synthesis of indazole derivatives, and to indazole intermediates and derivatives prepared by the processes described herein.

摘要翻译： 本文提供了制备式（I）化合物以在所述化合物用作合成吲唑衍生物的新方法中作为中间体的新方法，以及通过本文所述方法制备的吲唑中间体和衍生物。