公开(公告)号：WO2020028706A1

公开(公告)日：2020-02-06

申请号：PCT/US2019/044729

申请日：2019-08-01

申请人： ARAXES PHARMA LLC

发明人： LI, Liansheng ,  FENG, Jun ,  WU, Tao ,  LIU, Yuan ,  WANG, Yi ,  BORUM, Alana K. ,  REN, Pingda ,  LIU, Yi

IPC分类号： A61K31/4427 ,  A61K31/506 ,  A61P35/00 ,  C07D487/10

摘要： Compounds having activity as inhibitors of G12C mutant KRAS protein are provided. The compounds have the following structure (I): or a pharmaceutically acceptable salt, stereoisomer, isotopic form or prodrug thereof, wherein R 1 , L 1 , L 2 , L 3 , A 1 , A 2 , A 3 , A 4 , G 1 , G 2 , E, W, X, Y, Z, m, and n are as defined herein. Methods associated with preparation and use of such compounds, pharmaceutical compositions comprising such compounds and methods to modulate the activity of G12C mutant KRAS protein for treatment of disorders, such as cancer, are also provided.

公开(公告)号：WO2018218070A2

公开(公告)日：2018-11-29

申请号：PCT/US2018/034471

申请日：2018-05-24

申请人： ARAXES PHARMA LLC

发明人： LI, Liansheng ,  FENG, Jun ,  WU, Tao ,  LIU, Yuan ,  WANG, Yi ,  REN, Pingda ,  LIU, Yi

IPC分类号： C07D401/14 ,  C07D413/14 ,  C07D403/14 ,  C07D417/14 ,  A61P35/00 ,  A61K31/517

摘要： Compounds having activity as inhibitors of G12C mutant KRAS protein are provided. The compounds have the following structure (I): or a pharmaceutically acceptable salt, stereoisomer, isotopic form or prodrug thereof, wherein R 1 , R 2a , R 2b , R 2c , R 3a , R 3b , R 4a , R 4b , R 5 , L 1 , L 2 , L 3 , E, m 1 , m 2 and * are as defined herein. Methods associated with preparation and use of such compounds, pharmaceutical compositions comprising such compounds and methods to modulate the activity of G12C mutant KRAS protein for treatment of disorders, such as cancer, are also provided.

公开(公告)号：WO2018140513A1

公开(公告)日：2018-08-02

申请号：PCT/US2018/015071

申请日：2018-01-24

申请人： ARAXES PHARMA LLC

发明人： LI, Liansheng ,  FENG, Jun ,  LIU, Yuan ,  REN, Pingda ,  LIU, Yi

IPC分类号： C07D405/04 ,  C07D405/14 ,  C07D403/04 ,  C07D403/14 ,  C07D401/04 ,  C07D401/14 ,  C07D413/04 ,  C07D413/14 ,  C07D471/04 ,  C07D209/42 ,  A61K31/343 ,  A61K31/397 ,  A61K31/4184 ,  A61K31/416 ,  A61K31/403

摘要： Compounds having activity as inhibitors of G12C mutant KRAS protein are provided. The compounds have the following structure (I): or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof, wherein A is a five-membered heteroaryl comprising 1 or 2 non-adjacent heteroatoms, inclusive of X and Y; W, X, Y, Z, L, L 1 , E, R 1 , R 2b R 2c and the dotted circle are as defined herein. Methods associated with preparation and use of such compounds, pharmaceutical compositions comprising such compounds and compounds for use in methods to modulate the activity of G12C mutant KRAS protein for treatment of disorders, such as cancer, are also provided. Preferred compounds are e.g. l-(3-(6-(3-hydroxynaphthalen-l- yl)benzofuran-2-yl)azetidin-lyl)prop-2-en-l-one derivatives and related compounds such as e.g. the corresponding derivatives with e.g. a benzoimidazole, indole, benzooxazole, imidazopyridine or imidazole core structure, substituted on ring A by e.g. azetidine, pyrrolidine, azepane or bicyclopentane-amine (L 1 ) each substituted by e.g. propenone (E), and the core structure substituted on the six-membered ring with e.g. 3-hydroxynaphthalene or indazole or hydroxy-, alkoxy- and/or fluoro-substituted phenyl (R 1 ).

公开(公告)号：WO2017172979A1

公开(公告)日：2017-10-05

申请号：PCT/US2017/024839

申请日：2017-03-29

申请人： ARAXES PHARMA LLC

发明人： LI, Liansheng ,  FENG, Jun ,  REN, Pingda ,  LIU, Yi

IPC分类号： C11D3/50 ,  C07D239/74

CPC分类号： C07D239/95 ,  A61K31/517 ,  A61K45/06 ,  A61P35/00 ,  C07D401/14 ,  C07D403/04 ,  C07D403/12 ,  C07D403/14 ,  C11D3/50 ,  A61K2300/00

摘要： The present disclosure provides inhibitors of Ras protein. Also disclosed are methods to modulate the activity of Ras protein and methods of treatment of disorders mediated by Ras protein.

摘要翻译： 本披露提供了Ras蛋白的抑制剂。 还公开了调节Ras蛋白活性的方法和治疗Ras蛋白介导的病症的方法。

公开(公告)号：WO2017058915A1

公开(公告)日：2017-04-06

申请号：PCT/US2016/054179

申请日：2016-09-28

申请人： ARAXES PHARMA LLC

发明人： LI, Liansheng ,  FENG, Jun ,  LONG, Yun, Oliver ,  LIU, Yuan ,  REN, Pingda ,  LIU, Yi

IPC分类号： C07D403/04 ,  C07D403/14 ,  C07D413/04 ,  C07D417/04 ,  C07D243/14 ,  C07D471/04 ,  C07D307/82 ,  A61K31/4355 ,  A61K31/428 ,  A61P35/00

CPC分类号： C07D471/04 ,  C07D243/14 ,  C07D307/82 ,  C07D403/04 ,  C07D403/14 ,  C07D413/04 ,  C07D417/04

摘要： Compounds having activity as inhibitors of G12C mutant KRAS protein are provided. The compounds have the following structure (I): or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof, wherein A, B R 1 , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , G 1 , G 2 , m 1 , m 2 , L 1 , L 2 and E are as defined herein. Methods associated with preparation and use of such compounds, pharmaceutical compositions comprising such compounds and methods to modulate the activity of G12C mutant KRAS protein for treatment of disorders, such as cancer, are also provided.

摘要翻译： 提供具有作为G12C突变体KRAS蛋白质的抑制剂的活性的化合物。 该化合物具有以下结构（I）：或其药学上可接受的盐，互变异构体，立体异构体或前药，其中A，B R1，R2a，R2b，R3a，R3b，R4a，R4b，G1，G2，m1，m2，L1 ，L2和E如本文所定义。 还提供了与这种化合物的制备和使用相关的方法，包含这些化合物的药物组合物和调节G12C突变体KRAS蛋白质用于治疗疾病如癌症的活性的方法。

公开(公告)号：WO2017058807A1

公开(公告)日：2017-04-06

申请号：PCT/US2016/053990

申请日：2016-09-27

申请人： ARAXES PHARMA LLC

发明人： LI, Liansheng ,  FENG, Jun ,  LONG, Yun, Oliver ,  REN, Pingda ,  LIU, Yi

IPC分类号： C07D403/04 ,  C07D403/14 ,  A61K31/496 ,  A61K31/506 ,  A61P35/00

CPC分类号： C07D205/04 ,  C07D403/12

摘要： Compounds having activity as inhibitors of G12C mutant KRAS protein are provided. The compounds have the following structure (I) or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof, wherein R 1 , R 3a , R 3b , R 4a , R 4b , G 1 , G 2 , G 3 , G 4 , m 1 , m 2 , m 3 , m 4 , L 1 , L 2 and E are as defined herein. Methods associated with preparation and use of such compounds, pharmaceutical compositions comprising such compounds and methods to modulate the activity of G12C mutant KRAS protein for treatment of disorders, such as cancer, are also provided.

摘要翻译： 提供具有作为G12C突变体KRAS蛋白质的抑制剂的活性的化合物。 这些化合物具有以下结构（I）或其药学上可接受的盐，互变异构体，立体异构体或前药，其中R1，R3a，R3b，R4a，R4b，G1，G2，G3，G4，m1，m2，m3，m4，L1 ，L2和E如本文所定义。 还提供了与这种化合物的制备和使用相关的方法，包含这些化合物的药物组合物和调节G12C突变型KRAS蛋白质用于治疗疾病如癌症的活性的方法。

公开(公告)号：WO2020113071A1

公开(公告)日：2020-06-04

申请号：PCT/US2019/063702

申请日：2019-11-27

申请人： ARAXES PHARMA LLC

发明人： LIANSHENG, Li ,  LIU, Yuan ,  WU, Tao ,  REN, Pingda ,  LIU, Yi

IPC分类号： C07D471/10 ,  C07D487/10 ,  A61P35/00

摘要： Compounds having activity as inhibitors of G12C mutant KRAS protein are provided. The compounds have the following structure (I): (I) or a pharmaceutically acceptable salt, stereoisomer, isotopic form or prodrug thereof, wherein A, B, R 1 , R 3 , L 1 , L 2 , L 3 , E, A 1 , A 2 , A 3 , A 4 , G 1 , G 2 ,W, X, Y, Z, m1, m2, n1, and n2 are as defined herein. Methods associated with preparation and use of such compounds, pharmaceutical compositions comprising such compounds and methods to modulate the activity of G12C mutant KRAS protein for treatment of disorders, such as cancer, are also provided.

公开(公告)号：WO2018140600A1

公开(公告)日：2018-08-02

申请号：PCT/US2018/015233

申请日：2018-01-25

申请人： ARAXES PHARMA LLC

发明人： LI, Liansheng ,  FENG, Jun ,  LIU, Yuan ,  REN, Pingda ,  LIU, Yi

IPC分类号： C07D401/14 ,  C07D401/04 ,  C07D403/04 ,  C07D205/04 ,  A61P35/00 ,  A61K31/495 ,  A61K31/4035

摘要： Compounds having activity as inhibitors of G12C mutant KRAS protein are provided. The compounds have the following structure (I), or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein A, W, X, Y, Z, and are as defined herein. Methods associated with preparation and use of such compounds, pharmaceutical compositions comprising such compounds and methods to modulate the activity of G12C mutant KRAS protein for treatment of disorders, such as cancer, are also provided.

公开(公告)号：WO2017100546A1

公开(公告)日：2017-06-15

申请号：PCT/US2016/065786

申请日：2016-12-09

申请人： ARAXES PHARMA LLC

发明人： DENG, Xiaohu ,  LI, Liansheng ,  LONG, Yun Oliver ,  LIU, Yuan ,  REN, Pingda ,  MANI, Neelakandha S. ,  ALLISON, Brett D. ,  SALES, Zachary S. ,  LIANG, Jimmy T.

IPC分类号： C07D401/00 ,  C07D235/06 ,  C07D403/00 ,  C07D417/00 ,  C07D487/00 ,  C07F3/06

CPC分类号： C07D239/94 ,  C07D235/06 ,  C07D239/86 ,  C07D401/00 ,  C07D403/00 ,  C07D417/00 ,  C07D487/00 ,  C07F3/06

摘要： Methods for preparing compounds having the following structure (I): (Formula (I)) or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 1 , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b and R 4c , are as defined herein are provided. Related compounds and methods for making the same are also provided.

摘要翻译： 制备具有以下结构（I）的化合物的方法：（式（I））或其药学上可接受的盐，立体异构体或互变异构体，其中R 1，R R2a，R2a，R3a，R3b，R4a，R5，R5a，R5a，R5a，R5a， 4b和R 4c如本文所定义。 还提供了相关化合物及其制备方法。

公开(公告)号：WO2017070256A2

公开(公告)日：2017-04-27

申请号：PCT/US2016/057774

申请日：2016-10-19

申请人： ARAXES PHARMA LLC

发明人： PATRICELLI, Matthew, P. ,  PETERS, Ulf ,  LI, Liangsheng ,  REN, Pingda ,  LIU, Yi

IPC分类号： G01N33/573 ,  C12N9/14

CPC分类号： G01N33/573 ,  C12N9/14 ,  C12Y306/05002 ,  G01N2500/04 ,  G01N2500/20

摘要： Provided herein are compositions, reactions mixtures, mutant Ras proteins, kits, substrates, and systems for selecting a Ras antagonist, as well as methods of using the same.

摘要翻译： 本文提供了用于选择Ras拮抗剂的组合物，反应混合物，突变Ras蛋白，试剂盒，底物和系统，以及使用它们的方法。