公开(公告)号：US08232273B2

公开(公告)日：2012-07-31

申请号：US12641141

申请日：2009-12-17

Applicant: Jonathan Bayldon Baell ,  Chinh Thien Bui ,  Peter Colman ,  Peter Czabotar ,  Danette A. Dudley ,  Wayne J. Fairbrother ,  John A. Flygare ,  Guillaume Laurent Lessene ,  Chudi Ndubaku ,  George Nikolakopoulos ,  Brad Edmund Sleebs ,  Brian John Smith ,  Keith Geoffrey Watson ,  Steven W. Elmore ,  Lisa A. Hasvold ,  Andrew M. Petros ,  Andrew J. Souers ,  Zhi-Fu Tao ,  Le Wang ,  Xilu Wang ,  Kurt Deshayes

Inventor： Jonathan Bayldon Baell ,  Chinh Thien Bui ,  Peter Colman ,  Peter Czabotar ,  Danette A. Dudley ,  Wayne J. Fairbrother ,  John A. Flygare ,  Guillaume Laurent Lessene ,  Chudi Ndubaku ,  George Nikolakopoulos ,  Brad Edmund Sleebs ,  Brian John Smith ,  Keith Geoffrey Watson ,  Steven W. Elmore ,  Lisa A. Hasvold ,  Andrew M. Petros ,  Andrew J. Souers ,  Zhi-Fu Tao ,  Le Wang ,  Xilu Wang ,  Kurt Deshayes

IPC: A61K31/5377 ,  C07D413/14

CPC classification number: C07D417/14 ,  C07D471/06 ,  C07D473/00 ,  C07D487/04 ,  C07D495/04 ,  C07D513/04 ,  C07D513/06

Abstract: In one aspect, the present invention provides for a compound of Formula I in which the variable X1a, X1b, X1c, X1d, Q, A, R1, B, L, E, and the subscripts m and n have the meanings as described herein. In another aspect, the present invention provides for pharmaceutical compositions comprising compounds of Formula I as well as methods for using compounds of Formula I for the treatment of diseases and conditions (e.g., cancer, thrombocythemia, etc) characterized by the expression or over-expression of Bcl-2 anti-apoptotic proteins, e.g., of anti-apoptotic Bcl-xL proteins.

Abstract translation: 一方面，本发明提供了其中变量X1a，X1b，X1c，X1d，Q，A，R1，B，L，E和下标m和n具有如本文所述的含义的式I化合物 。 另一方面，本发明提供包含式I化合物的药物组合物以及使用式I化合物治疗以表达或过表达为特征的疾病和病症（例如，癌症，血小板增多症等）的方法 的Bcl-2抗凋亡蛋白，例如抗凋亡Bcl-xL蛋白。

公开(公告)号：US08114893B2

公开(公告)日：2012-02-14

申请号：US12641063

申请日：2009-12-17

Applicant: Jonathan Bayldon Baell ,  Chinh Thien Bui ,  Peter Colman ,  Danette A. Dudley ,  Wayne J. Fairbrother ,  John A. Flygare ,  Guillaume Laurent Lessene ,  Chudi Ndubaku ,  George Nikolakopoulos ,  Carl Steven Rye ,  Brad Edmund Sleebs ,  Brian John Smith ,  Keith Geoffrey Watson ,  Steven W. Elmore ,  Andrew M. Petros ,  Andrew J. Souers ,  Peter Czabotar

Inventor： Jonathan Bayldon Baell ,  Chinh Thien Bui ,  Peter Colman ,  Danette A. Dudley ,  Wayne J. Fairbrother ,  John A. Flygare ,  Guillaume Laurent Lessene ,  Chudi Ndubaku ,  George Nikolakopoulos ,  Carl Steven Rye ,  Brad Edmund Sleebs ,  Brian John Smith ,  Keith Geoffrey Watson ,  Steven W. Elmore ,  Andrew M. Petros ,  Andrew J. Souers ,  Peter Czabotar

IPC: C07D417/14 ,  A61K31/5377 ,  A61K31/538 ,  A61K31/496 ,  A61K31/498 ,  A61K31/4709

CPC classification number: C07D417/14 ,  C07D417/12 ,  C07D487/04

Abstract: In one aspect, the present invention provides for a compound of Formula I in which in Formula I, the variables X1, X2a, X2b, X2c, R1, B, L, E, A and the subscript n are as defined herein. In another aspect, the present invention provides for pharmaceutical compositions comprising compounds of Formula I as well as methods for using compounds of Formula I for the treatment of diseases and conditions (e.g., cancer, thrombocythemia, etc) characterized by the expression or over-expression of Bcl-2 anti-apoptotic proteins, e.g., of anti-apoptotic Bcl-xL proteins.

Abstract translation: 一方面，本发明提供式I化合物，其中在式I中，变量X1，X2a，X2b，X2c，R1，B，L，E，A和下标n如本文所定义。 另一方面，本发明提供包含式I化合物的药物组合物以及使用式I化合物治疗以表达或过表达为特征的疾病和病症（例如，癌症，血小板增多症等）的方法 的Bcl-2抗凋亡蛋白，例如抗凋亡Bcl-xL蛋白。

公开(公告)号：US20110077265A1

公开(公告)日：2011-03-31

申请号：US12598027

申请日：2008-04-29

Applicant: John A. Flygare ,  Frederick Cohen ,  Kurt Deshayes ,  Michael F. T. Koehler ,  Lewis J. Gazzard ,  Lan Wang ,  Chudi Ndubaku

Inventor： John A. Flygare ,  Frederick Cohen ,  Kurt Deshayes ,  Michael F. T. Koehler ,  Lewis J. Gazzard ,  Lan Wang ,  Chudi Ndubaku

IPC: A61K31/437 ,  C07D417/14 ,  C07D513/04 ,  C07D403/12 ,  C12N5/071 ,  C07K2/00 ,  A61K31/4545 ,  A61K31/433 ,  A61K31/4025 ,  A61K31/427 ,  A61P35/00

CPC classification number: C07D417/14 ,  C07D207/16 ,  C07D519/00

Abstract: The invention provides novel inhibitors of IAP that are useful as therapeutic agents for treating malignancies where the compounds having the general formula U1-M-U2 wherein M is a linking group covalently joining R2, R3, R4 or R5 of U1 to an R2, R3, R4 or R5 group of U2; U1 and U2 have the general formula (I) and G, X1, X2, R2, R3, R3′, R4, R4′ and R5, are as described herein.

Abstract translation: 本发明提供了可用作治疗恶性肿瘤的治疗剂的新的IAP抑制剂，其中具有通式U1-M-U2的化合物，其中M是共价连接U1的R2，R3，R4或R5的连接基团与R2，R3 ，R4或R5组的U2; U1和U2具有通式（I），G，X 1，X 2，R 2，R 3，R 3'，R 4，R 4'和R 5如本文所述。

公开(公告)号：US20100256115A1

公开(公告)日：2010-10-07

申请号：US12727218

申请日：2010-03-18

Applicant: Frederick Cohen ,  Kurt Deshayes ,  Wayne J. Fairbrother ,  Bainian Feng ,  John A. Flygare ,  Lewis J. Gazzard ,  Vickie Hsiao-Wei Tsui

Inventor： Frederick Cohen ,  Kurt Deshayes ,  Wayne J. Fairbrother ,  Bainian Feng ,  John A. Flygare ,  Lewis J. Gazzard ,  Vickie Hsiao-Wei Tsui

IPC: A61K31/55 ,  C07D209/48 ,  A61K31/4035 ,  C07D277/06 ,  A61K31/427 ,  C07D487/04 ,  C07D231/40 ,  C07D285/06 ,  A61K31/4155 ,  A61K31/433 ,  C07D207/323 ,  A61K31/40 ,  C07D249/06 ,  A61K31/4192 ,  C07D261/14 ,  A61K31/42 ,  C07D257/06 ,  A61K31/41 ,  C07D271/04 ,  A61K31/4245 ,  C07D417/04 ,  A61K31/4439 ,  A61P35/00 ,  C12N5/071

CPC classification number: C07D417/14 ,  A61K31/55 ,  A61K38/177 ,  C07D403/12 ,  C07D413/12 ,  C07D417/04 ,  C07D417/12 ,  C07D495/04 ,  C07D513/04 ,  C07K5/06026 ,  C07K5/0806 ,  C07K5/0827 ,  C07K7/06 ,  C12N5/0693

Abstract: The invention provides novel inhibitors of IAP that are useful as therapeutic agents for treating malignancies where the compounds have the general formula I: wherein X, Y, A, R1, R2, R3, R4, R4′, R5, R5′, R6 and R6′ are as described herein.

Abstract translation: 本发明提供了可用作治疗恶性肿瘤的治疗剂的新的IAP抑制剂，其中化合物具有通式I：其中X，Y，A，R 1，R 2，R 3，R 4，R 4'，R 5，R 5'，R 6和 R6'如本文所述。

公开(公告)号：US06388131B2

公开(公告)日：2002-05-14

申请号：US09872463

申请日：2001-05-31

Applicant: Julio Cesar Medina ,  David Louis Clark ,  John A. Flygare ,  Terry J. Rosen ,  Bei Shan

Inventor： Julio Cesar Medina ,  David Louis Clark ,  John A. Flygare ,  Terry J. Rosen ,  Bei Shan

IPC: A61K3136

CPC classification number: C07C311/21

Abstract: The invention provides compounds, compositions and methods relating to novel electrophilic aromatic derivatives and their use as pharmacologically active agents. The compositions find particular use as pharmacological agents in the treatment of disease states, particularly cancer, psoriasis, vascular restenosis, infections, atherosclerosis and hypercholesterolemia, or as lead compounds for the development of such agents. The compositions include compounds of the general Formula I:

公开(公告)号：US08835393B2

公开(公告)日：2014-09-16

申请号：US13057176

申请日：2009-07-23

Applicant: Danette Dudley ,  John A. Flygare ,  Chudi Ndubaku

Inventor： Danette Dudley ,  John A. Flygare ,  Chudi Ndubaku

IPC: A61K38/06 ,  C07K5/08 ,  A61P35/00 ,  C07D403/12 ,  C07D513/04 ,  C07D207/16 ,  C07K5/083

CPC classification number: C07D403/12 ,  C07D207/16 ,  C07D513/04 ,  C07K5/0804

Abstract: The invention provides novel compounds that are inhibitors of IAPs having the general formula: wherein X1, X2, X3, Y, A, R1, R2, R3, R4, R4′, R5, R5′, R6 and R6′ are as described herein. The compouds of the invention may be used to induce apoptosis in cells (or sensitise cells to apoptosis) in which IAPs are overexpressed or otherwise implicated in resistance to normal apoptotic processes. Accordingly, the compounds may be provided in pharmaceutically acceptable compositions and used for the treatment cancers.

Abstract translation: 本发明提供了具有以下通式的IAP抑制剂的新化合物：其中X1，X2，X3，Y，A，R1，R2，R3，R4，R4'，R5，R5'，R6和R6'如本文所述 。 本发明的化合物可用于诱导细胞凋亡（或致敏细胞凋亡），其中IAP过表达或以其他方式涉及抗正常凋亡过程。 因此，化合物可以以药学上可接受的组合物提供，并用于治疗癌症。

公开(公告)号：US08518970B2

公开(公告)日：2013-08-27

申请号：US13347364

申请日：2012-01-10

Applicant: Jonathan Bayldon Baell ,  Chinh Thien Bui ,  Peter Colman ,  Danette A. Dudley ,  Wayne J. Fairbrother ,  John A. Flygare ,  Guillaume Laurent Lessene ,  Chudi Ndubaku ,  George Nikolakopoulos ,  Carl Steven Rye ,  Brad Edmund Sleebs ,  Brian John Smith ,  Keith Geoffrey Watson ,  Steven W. Elmore ,  Andrew M. Petros ,  Andrew J. Souers ,  Peter Czabotar

Inventor： Jonathan Bayldon Baell ,  Chinh Thien Bui ,  Peter Colman ,  Danette A. Dudley ,  Wayne J. Fairbrother ,  John A. Flygare ,  Guillaume Laurent Lessene ,  Chudi Ndubaku ,  George Nikolakopoulos ,  Carl Steven Rye ,  Brad Edmund Sleebs ,  Brian John Smith ,  Keith Geoffrey Watson ,  Steven W. Elmore ,  Andrew M. Petros ,  Andrew J. Souers ,  Peter Czabotar

IPC: C07D417/14 ,  A61K31/5377 ,  A61K31/538 ,  A61K31/496 ,  A61K31/498 ,  A61K31/4709

CPC classification number: C07D417/14 ,  C07D417/12 ,  C07D487/04

Abstract: In one aspect, the present invention provides for a compound of Formula I in which in Formula I, the variables X1, X2a, X2b, X2c, R1, B, L, E, A and the subscript n are as defined herein. In another aspect, the present invention provides for pharmaceutical compositions comprising compounds of Formula I as well as methods for using compounds of Formula I for the treatment of diseases and conditions (e.g., cancer, thrombocythemia, etc) characterized by the expression or over-expression of Bcl-2 anti-apoptotic proteins, e.g., of anti-apoptotic Bcl-xL proteins.

公开(公告)号：US20120202750A1

公开(公告)日：2012-08-09

申请号：US13356556

申请日：2012-01-23

Applicant: Frederick Cohen ,  Kurt Deshayes ,  Wayne J. Fairbrother ,  Bainian Feng ,  John A. Flygare ,  Lewis J. Gazzard ,  Vickie Hsiao-Wei Tsui

Inventor： Frederick Cohen ,  Kurt Deshayes ,  Wayne J. Fairbrother ,  Bainian Feng ,  John A. Flygare ,  Lewis J. Gazzard ,  Vickie Hsiao-Wei Tsui

IPC: C07D401/12 ,  A61K38/06 ,  A61K31/55 ,  C12N5/09 ,  A61K31/42 ,  A61K31/433 ,  A61K31/4436 ,  C07D285/10 ,  A61K31/426 ,  C07D261/14 ,  C07D271/08 ,  A61K31/415 ,  A61K31/381 ,  C07K5/08 ,  C07D513/04 ,  A61P35/04 ,  C07D417/04 ,  A61K31/4245 ,  C07D417/12 ,  C07D277/18 ,  C07D257/06 ,  A61K31/41 ,  C07D249/04 ,  C07D333/36 ,  A61K31/506

CPC classification number: C07D417/14 ,  A61K31/55 ,  A61K38/177 ,  C07D403/12 ,  C07D413/12 ,  C07D417/04 ,  C07D417/12 ,  C07D495/04 ,  C07D513/04 ,  C07K5/06026 ,  C07K5/0806 ,  C07K5/0827 ,  C07K7/06 ,  C12N5/0693

Abstract: The invention provides novel inhibitors of IAP that are useful as therapeutic agents for treating malignancies where the compounds have the general formula I: wherein X, Y, A, R1, R2, R3, R4, R4′, R5, R5′, R6 and R6′ are as described herein.

Abstract translation: 本发明提供了可用作治疗恶性肿瘤的治疗剂的新的IAP抑制剂，其中化合物具有通式I：其中X，Y，A，R 1，R 2，R 3，R 4，R 4'，R 5，R 5'，R 6和 R6'如本文所述。

公开(公告)号：US20120121615A1

公开(公告)日：2012-05-17

申请号：US13297408

申请日：2011-11-16

Applicant: John A. Flygare ,  Jagath R. Junutula ,  Thomas Harden Pillow

Inventor： John A. Flygare ,  Jagath R. Junutula ,  Thomas Harden Pillow

IPC: A61K39/395 ,  C07K16/00 ,  A61P35/00 ,  C07K16/30 ,  C07K16/32 ,  C07K16/40 ,  C07D498/18 ,  C07K16/28

CPC classification number: C07D491/12

Abstract: Linker-drug intermediates of Formula I are conjugated to antibodies to form antibody-drug conjugates where the drug moiety is an N-methylalaninyl-maytansinoid. L is E is n is 2, 3, 4, 5, or 6; m is 2, 3 or 4; and q is 0 or 1.

Abstract translation: 式I的接头 - 药物中间体与抗体缀合以形成抗体 - 药物偶联物，其中药物部分是N-甲基丙酰氨基 - 美登木素生物碱。 L是E是n是2,3,4,5或6; m为2,3或4; q为0或1。

公开(公告)号：US20110046066A1

公开(公告)日：2011-02-24

申请号：US12812292

申请日：2009-01-09

Applicant: Chudi Ndubaku ,  John A. Flygare ,  Frederick Cohen

Inventor： Chudi Ndubaku ,  John A. Flygare ,  Frederick Cohen

IPC: A61K38/06 ,  C07K5/083 ,  C07K5/062 ,  C12N5/071 ,  A61K38/05 ,  A61P35/00

CPC classification number: C07K5/06026 ,  A61K38/00 ,  C07K5/0806

Abstract: The invention provides novel inhibitors of IAP that are useful as therapeutic agents for treating malignancies where the compounds have the general formula (I), and G, X1, X2, R1, R2, R3, R4, R4′, R5, Ra, Rb, and Rc are as described herein.

Abstract translation: 本发明提供可用作治疗恶性肿瘤的治疗剂的新型IAP抑制剂，其中化合物具有通式（I），G，X1，X2，R1，R2，R3，R4，R4'，R5，Ra，Rb ，和Rc如本文所述。