公开(公告)号：US11639346B2

公开(公告)日：2023-05-02

申请号：US16616066

申请日：2018-05-24

申请人： Araxes Pharma LLC

发明人： Liansheng Li ,  Jun Feng ,  Tao Wu ,  Yuan Liu ,  Yi Wang ,  Pingda Ren ,  Yi Liu

IPC分类号： C07D403/14 ,  C07D403/04

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, stereoisomer, isotopic form or prodrug thereof, wherein R1, R2a, R2b, R2c, R3a, R3b, R4a, R4b, R5, L1, L2, E, m1 and m2 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：US11021470B2

公开(公告)日：2021-06-01

申请号：US16514675

申请日：2019-07-17

申请人： Araxes Pharma LLC

发明人： Liansheng Li ,  Jun Feng ,  Yun Oliver Long ,  Yuan Liu ,  Tao Wu ,  Pingda Ren ,  Yi Liu

IPC分类号： C07D403/14 ,  C07D401/14 ,  C07D403/04 ,  C07D405/14 ,  C07D413/14 ,  C07D471/04 ,  C07D487/10 ,  C07D491/10

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 or prodrug thereof, wherein R1, R2a, R2b, R2c, R3a, R3b, R4a, R4b, R5a, R5b, R6, A, G1, G2, L1, L2, m1, m2, n, X and E are as defined herein, and wherein at least one of R3a, R3b, R4a or R4b is not H. 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：US10689356B2

公开(公告)日：2020-06-23

申请号：US15764088

申请日：2016-09-28

申请人： Araxes Pharma LLC

发明人： Liansheng Li ,  Jun Feng ,  Yun Oliver Long ,  Yuan Liu ,  Pingda Ren ,  Yi Liu

IPC分类号： C07D401/04 ,  C07D471/04 ,  A61P35/00 ,  A61K9/00 ,  A61K31/4375 ,  A61K31/4725

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, R1, R3a, R3b, R4a, R4b, G2, G3, G4, m1, m2, m3, m4, L1, L2 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.

公开(公告)号：US09862701B2

公开(公告)日：2018-01-09

申请号：US14866147

申请日：2015-09-25

申请人： Araxes Pharma LLC

发明人： Liansheng Li ,  Jun Feng ,  Pingda Ren ,  Yi Liu

IPC分类号： C07D295/10 ,  C07D295/104 ,  C07D295/185 ,  A61K31/495 ,  C07D231/56 ,  C07D401/04 ,  C07D213/75 ,  C07D239/42

CPC分类号： C07D401/04 ,  C07D213/75 ,  C07D231/56 ,  C07D239/42 ,  C07D295/10 ,  C07D295/185

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 R1, R2, R3a, R3b, R4a, R4b, G1, G2, L, m1, m2 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.

公开(公告)号：US09227978B2

公开(公告)日：2016-01-05

申请号：US14212656

申请日：2014-03-14

申请人： Araxes Pharma LLC

发明人： Pingda Ren ,  Yi Liu ,  Liansheng Li ,  Jun Feng ,  Tao Wu

IPC分类号： A61K31/496 ,  C07D403/04 ,  C07D487/10 ,  C07D211/62 ,  C07D213/64 ,  C07D487/04 ,  C07D295/16 ,  C07D205/04 ,  C07D401/04 ,  C07D285/14 ,  G01N33/58 ,  C07D213/74 ,  C07D231/40 ,  C07D401/12 ,  C07D237/04 ,  C07D403/06 ,  C07D405/06 ,  C07D419/12 ,  C07D471/04 ,  C07D285/16 ,  C07D211/56 ,  C07D211/58 ,  C07D211/60

CPC分类号： C07D205/04 ,  C07D211/56 ,  C07D211/58 ,  C07D211/60 ,  C07D211/62 ,  C07D213/64 ,  C07D213/74 ,  C07D231/40 ,  C07D237/04 ,  C07D285/14 ,  C07D285/16 ,  C07D295/16 ,  C07D401/04 ,  C07D401/12 ,  C07D403/04 ,  C07D403/06 ,  C07D403/12 ,  C07D405/06 ,  C07D419/12 ,  C07D471/04 ,  C07D487/04 ,  C07D487/10 ,  G01N33/58

摘要： Irreversible inhibitors of G12C mutant K-Ras protein are provided. Also disclosed are methods to modulate the activity of G12C mutant K-Ras protein and methods of treatment of disorders mediated by G12C mutant K-Ras protein.

摘要翻译： 提供了G12C突变体K-Ras蛋白的不可逆抑制剂。 还公开了调节G12C突变体K-Ras蛋白的活性的方法和治疗由G12C突变体K-Ras蛋白介导的病症的方法。

公开(公告)号：US20230303586A1

公开(公告)日：2023-09-28

申请号：US18178452

申请日：2023-03-03

申请人： Araxes Pharma LLC

发明人： Liansheng LI ,  Jun FENG ,  Tao WU ,  Pingda REN ,  Yi LIU ,  Yuan Liu ,  Yun Oliver Long

IPC分类号： C07D495/04 ,  C07D239/94 ,  C07D401/12 ,  C07D217/22 ,  C07D215/46 ,  C07D215/54 ,  C07D239/84 ,  C07D487/04 ,  C07D239/95 ,  C07D403/04 ,  C07D241/44 ,  C07D401/04 ,  C07D409/04

CPC分类号： C07D495/04 ,  C07D215/46 ,  C07D215/54 ,  C07D217/22 ,  C07D239/84 ,  C07D239/94 ,  C07D239/95 ,  C07D241/44 ,  C07D401/04 ,  C07D401/12 ,  C07D403/04 ,  C07D409/04 ,  C07D487/04

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, prodrug or stereoisomer thereof, wherein R1, R2a, R3a, R3b, R4a, R4b, G1, G2, L1, L2, m1, m2, A, B, W, X, Y, Z 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.

公开(公告)号：US20230147053A1

公开(公告)日：2023-05-11

申请号：US17839232

申请日：2022-06-13

申请人： Araxes Pharma LLC

发明人： Liansheng Li ,  Jun Feng ,  Yuan Liu ,  Pingda Ren ,  Yi Liu

IPC分类号： C07D403/14 ,  A61P35/04 ,  C07D401/10

CPC分类号： C07D403/14 ,  A61P35/04 ,  C07D401/10

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 or prodrug thereof, wherein A, B, E, L1, Ra. Rb, Rc 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：US11279689B2

公开(公告)日：2022-03-22

申请号：US16480195

申请日：2018-01-24

申请人： Araxes Pharma LLC

发明人： Liansheng Li ,  Jun Feng ,  Yuan Liu ,  Pingda Ren ,  Yi Liu

IPC分类号： C07D405/04 ,  C07D403/04 ,  A61P35/04 ,  A61K9/00

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, L1, E, R1, R2b R2c 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. 1-(3-(6-(3-hydroxynaphthalen-1-yl)benzofuran-2-yl)azetidin-1yl)prop-2-en-1-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 (L1) 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 (R1).

公开(公告)号：US20210380595A1

公开(公告)日：2021-12-09

申请号：US17287473

申请日：2019-10-23

申请人： ARAXES PHARMA LLC

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

IPC分类号： C07D487/10

摘要： The present invention provides e.g. 2-(2-acryloyl-2, 6-diazaspiro[3.4]octan-6-yl)-6-(1H-indazol-4-yl)-benzonitrile and e.g. 2-(2-acryloyl-2,7-diazaspiro[3.5]nonan-7-yl)-6-(1H-indazol-4-yl)-benzonitrile derivatives and related compounds of formula (I) as inhibitors of G12C mutant KRAS protein for treating tumor metastasis. The present description discloses exemplary compounds (e.g. pages 53 to 90; table 1; compounds I-1 to I-141), pharmacological data (e.g. page 125 to 128; table 2; example 1) and synthesis thereof (e.g. pages 129 to 143; examples 2 to 7). Exemplary compounds are e.g. 2-(2-acryloyl-2,6-diazaspiro[3.4]octan-6-yl)-6-(5-methyl-1H-indazol-4-yl)-4-morpholinobenzonitrile (example 2; compound I-1) and 6-(2-acryloyl-2,7-diazaspiro[3.5]nonan-7-yl)-3-methoxy-2-(5-methyl-1H-indazol-4-yl)-4-morpholinobenzonitrile (example 7; compound I-84).

公开(公告)号：US11059819B2

公开(公告)日：2021-07-13

申请号：US16480874

申请日：2018-01-25

申请人： Araxes Pharma LLC

发明人： Liansheng Li ,  Jun Feng ,  Yuan Liu ,  Pingda Ren ,  Yi Liu

IPC分类号： C07D471/04 ,  C07D473/30 ,  C07D487/04 ,  A61P35/04 ,  A61K9/00

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.