Inhibitors of the unfolded protein response and methods for their use

Abstract

Compounds that are inhibitors of the unfolded protein response and endonuclease IRE1 are provided, together with compositions comprising such compounds, and methods for their use in the treatment of various disorders, such as cancer, autoimmune disorders, and diabetes. Also provided are packaged pharmaceuticals comprising these compositions. The compositions may be administered in combination with another therapeutic agent.

What is claimed is: 
     
         1 . A method for inhibiting an unfolded protein response in a mammalian host, comprising administering to the mammalian host in need thereof a therapeutically-effective amount of a pharmaceutical composition comprising a compound represented by structural formula (I): 
       
         
           
           
               
               
           
         
         or a pharmacuetically acceptable salt thereof, wherein: 
         X is S; 
         Y is O or S; 
         Z 1 , Z 2 , Z 3 , and Z 4  are each C(R 6 )(R 6 ′); 
         n is 0; 
         R 1 , R 1 ′, R 6 , and R 6 ′ are independently hydrogen, alkyl, halo, or cyano; 
         R 2  is alkyl or cyano; 
         R 3  is alkyl or haloalkyl and is optionally substituted with 1-3 J groups; 
         R 4  is hydrogen; 
         R 4 ′ is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
         
           and J is one of alkyl or halo 
         
         and a pharmaceutically acceptable carrier. 
       
     
     
         2 . A method for inhibiting IRE1 in a mammalian host, comprising administering to the mammalian host in need thereof a therapeutically-effective amount of the pharmaceutical composition comprising a compound represented by structural formula (I) as set forth in  claim 1 . 
     
     
         3 . A method for treating or preventing a disorder associated with the unfolded protein response in a mammalian host, comprising administering to the mammalian host in need thereof a therapeutically-effective amount of the pharmaceutical composition comprising a compound represented by structural formula (I) as set forth in  claim 1 . 
     
     
         4 . The method of  claim 3 , wherein the disorder is characterized by uncontrolled cell growth under conditions of hypoxia or ER stress. 
     
     
         5 . The method of  claim 3 , wherein the disorder is selected from the group consisting of cancer, autoimmune disorders, and diabetes. 
     
     
         6 . The method of  claim 5 , wherein the cancer is selected from the group consisting of multiple myeloma, cervical cancer, brain cancer, pancreatic cancer, head and neck cancers, prostate cancer, breast cancer, soft tissue sarcomas, primary and metastatic liver cancer, primary and metastatic lung cancer, esophageal cancer, colorectal cancer, lymphoma, and leukemia. 
     
     
         7 . The method of  claim 5 , wherein the cancer is a solid tumor. 
     
     
         8 . The method of  claim 7 , wherein the solid tumor is a sarcoma, a carcinoma, or a lymphoma. 
     
     
         9 . The method of  claim 5 , wherein the autoimmune disorder is selected from the group consisting of: diabetes, lupus, rheumatoid arthritis, psoriasis, multiple sclerosis, and inflammatory bowel disease. 
     
     
         10 . The method of  claim 9 , wherein the inflammatory bowel disease is selected from the group consisting of: ulcerative colitis and Crohn's disease. 
     
     
         11 . The method of  claim 9 , wherein the autoimmune disorder is rheumatoid arthritis. 
     
     
         12 . The method of  claim 5 , wherein the disorder is cancer and wherein the method further comprises administration of a chemotherapeutic agent. 
     
     
         13 . The method of  claim 12 , wherein the chemotherapeutic agent is selected from the group consisting of bevacizumab, bortezomib, cetuximab, erlotinib, gemcitabine, cisplatin, oxaliplatin, etoposide, adriamycin, taxol, and thalidomide. 
     
     
         14 . A packaged pharmaceutical comprising a pharmaceutical composition of a compound of Formula I and instructions for using the composition to inhibit the unfolded protein response in a mammalian host, wherein Formula I is as follows: 
       
         
           
           
               
               
           
         
       
       or a pharmacuetically acceptable derivative or prodrug thereof, wherein:
 X is O, S, or N—R 4 ″; 
 Y is O or S; 
 Z 1 , Z 2 , Z 3 , and Z 4  are independently C(R 6 )(R 6 ′) or NR 4 ″, provided that only one of Z 1 , Z 2 , Z 3 , and Z 4  at a time is N—R 4 ″; 
 n is 0-2; 
 R 1 , R 1 ′, R 6 , and R 6 ′ are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkoxy, heterocyclyl, heterocyclyloxy, heterocyclylalkyl, heteroaryl, heteroaralkyl, hydroxy, thio, amino, alkylamino, alkanoylamino, aroylamino, aralkanoylamino, carboxy, carbonate, carbamate, guanidinyl, urea, halo, cyano, nitro, formyl, acyl, phosphoryl, sulfonyl, or sulfonamido and are optionally substituted with 1-3 J groups; 
 R 2  is alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkoxy, heterocyclyl, heterocyclyloxy, heterocyclylalkyl, heteroaryl, heteroaralkyl, hydroxy, thio, amino, alkylamino, alkanoylamino, aroylamino, aralkanoylamino, carboxy, carbonate, carbamate, guanidinyl, urea, halo, cyano, nitro, formyl, acyl, phosphoryl, sulfonyl, or sulfonamido and is optionally substituted with 1-3 J groups; 
 R 3  is alkyl, alkenyl, alkynyl, aralkyl, alkoxy, aryloxy, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkoxy, haloalkyl, heterocyclyl, heterocyclyloxy, heterocyclylalkyl, heteroaryl, heteroaralkyl, hydroxy, thio, amino, alkylamino, alkanoylamino, aroylamino, aralkanoylamino, carboxy, carbonate, carbamate, guanidinyl, urea, halo, cyano, nitro, formyl, acyl, phosphoryl, sulfonyl, or sulfonamido and is optionally substituted with 1-3 J groups; 
 R 1 , R 1 ′, and R 2  taken together may form 
 
       
         
           
           
               
               
           
         
       
       wherein R 5  is hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkoxy, heterocyclyl, heterocyclyloxy, heterocyclylalkyl, heteroaryl, heteroaralkyl, hydroxy, thio, amino, alkylamino, alkanoylamino, aroylamino, aralkanoylamino, carboxy, carbonate, carbamate, guanidinyl, urea, halo, cyano, nitro, formyl, acyl, phosphoryl, sulfonyl, or sulfonamido and is optionally substituted with 1-3 J groups;
 R 4 , R 4 ′, and R 4 ″ are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkenyl, cycloalkoxy, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, formate, formamide, acyl, phosphoryl, sulfonyl, or sulfonamido and are optionally substituted with 1-3 J groups, wherein R 4  and R 4 ′ taken together with the N atom to which they are attached complete a cyclic structure having from 4 to 8 atoms in the ring; 
 J is alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, cycloalkyl, cycloalkoxy, heterocyclyl, heterocyclyloxy, heterocyclylalkyl, heteroaryl, heteroaralkyl, keto, hydroxy, thio, amino, alkylamino, alkanoylamino, aroylamino, aralkanoylamino, carboxy, carbonate, carbamate, guanidinyl, urea, halo, cyano, nitro, formyl, acyl, phosphoryl, sulfonyl, or sulfonamido and is optionally substituted with 1-3 J′ groups; and 
 J′ is alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy, aryloxy, heterocyclyl, heterocyclyloxy, keto, hydroxy, thio, amino, alkanoylamino, aroylamino, carboxy, carbonate, carbamate, guanidinyl, urea, halo, cyano, nitro, formyl, acyl, phosphoryl, sulfonyl, or sulfonamido; 
 
       and a pharmaceutically acceptable carrier.