University of Illinois

Massachusetts Institute of Technology

Karen C Morrison

Paul Joseph Hergenrother

Nicolas Cedric Boyer

Mohammad Movassaghi

Justin Kim

Robert W Huigens, Iii

Timothy A Flood, Jr

Robert W Hicklin, Ii

The synthesis of various pyrazino[1',2&#x2032;:1,5]pyrrolo[2,3-B]-indole-1,4-dione analogs has been successfully implemented in the present application. From these efforts, compounds having the structure of Formula I-a or Formula I-b: or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, are provided herein. These biologically active derivatives have been used to effectively treat various diseases including cancer.

Substituted pyrazino[1',2&#x2032;:1,5]pyrrolo[2,3-b]indole-1,4-diones for cancer treatment

The invention provides a novel, general, and facile strategy for the creation of small molecules with high structural and stereochemical complexity. Aspects of the methods include ring system distortion reactions that are systematically applied to rapidly convert readily available natural products to structurally complex compounds with diverse molecular architectures. Through evaluation of chemical properties including fraction of spcarbons, ClogP, and the number of stereogenic centers, these compounds are shown to be significantly more complex and diverse than those in standard screening collections. This approach is demonstrated with natural products (gibberellic acid, adrenosterone, and quinine) from three different structural classes, and methods are described for the application of this strategy to any suitable natural product.

Complex and structurally diverse compounds

The synthesis of various pyrazino[1',2&#x2032;:1,5]pyrrolo[2,3-b]-indole-1,4-dione analogs has been successfully implemented in the present application. From these efforts, compounds having the structure of Formula I-c: or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R, R, R-R, R, R, and n are as defined herein, are provided. These biologically active derivatives have been further used to prepare cell-specific drug conjugates effective in treating various diseases including cancer.

Substituted pyrazino[1',2&#x2032;:1 ,5]pyrrolo[2,3-b]indole-1,4-diones for cancer treatment

The invention a novel, general, and facile strategy for the creation of small molecules with high structural and stereochemical complexity. Aspects of the methods include ring system distortion reactions that are systematically applied to rapidly convert readily available natural products to structurally complex compounds with diverse molecular architectures. Through evaluation of chemical properties including fraction of spcarbons, ClogP, and the number of stereogenic centers, these compounds are shown to be significantly more complex and diverse than those in standard screening collections. This approach is demonstrated with natural products (gibberellic acid, adrenosterone, and quinine) from three different structural classes, and methods are described for the application of this strategy to any suitable natural product.

The present application provides, among other things, a compound of Formula I-a and/or I-b, or a pharmaceutically acceptable salt thereof, wherein the variables are defined in the specification. The compounds of the invention are useful for treating various diseases including cancer.

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Champaign, IL, United States of America

Karen C Morrison