US2016083327A1PendingUtilityA1
GPBP inhibition using Q2 peptidomimetics

Assignee: FIBROSTATIN S LPriority: Nov 5, 2009Filed: Nov 18, 2015Published: Mar 24, 2016
Est. expiryNov 5, 2029(~3.3 yrs left)· nominal 20-yr term from priority
Inventors:Juan Saus Santos Fustero Juan F. Sanz-Cervera Enrique Perez-Paya Raül Blasco Francisco Revert-Ros Fernando Revert
A61P 35/00A61P 37/00A61P 37/06A61P 37/02A61P 29/00A61P 17/00C07C 59/70C07D 213/48C07C 59/52C07C 309/65C07C 67/313C07C 45/68C07C 69/732C07D 213/55C07D 213/58C07C 69/738C07D 213/26C07C 59/56C07D 213/34C07C 47/565C07C 69/734C07C 59/64
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Claims
Abstract

Disclosed are compounds of formula: that inhibiting GPBP activity, making them useful as therapeutics in antibody-mediated disorders, drug-resistant cancer, inflammation, protein misfolding and ER stress-mediated disorders, and aberrant apoptosis.
Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A compound of formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 5  is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, halo(C 1 -C 6  alkyl), C 1 -C 6  alkoxy, halo(C 1 -C 6  alkoxy), amino, (C 1 -C 6  alkyl)amino, di(C 1 -C 6  alkyl)amino, hydroxy(C 1 -C 6  alkyl), (C 1 -C 6  alkoxy)C 1 -C 6  alkyl, amino(C 1 -C 6  alkyl), sulfanyl(C 1 -C 6  alkyl), (C 1 -C 6  alkyl)sulfanyl(C 1 -C 6  alkyl), —(CH 2 ) 1-5 —C(O)(C 1 -C 6  alkoxy), —(CH 2 ) 1-5 —C(O)NH 2 , (aryl)C 2 -C 6  alkyl, and (heteroaryl)C 1 -C 6  alkyl; 
         R 1  is hydrogen, halogen, hydroxy, C 1 -C 6  alkyl, halo(C 1 -C 6  alkyl), C 1 -C 6  alkoxy, halo(C 1 -C 6  alkoxy), hydroxy(C 1 -C 6  alkyl), (C 1 -C 6  alkoxy)C 1 -C 6  alkyl, amino(C 1 -C 6  alkyl), sulfanyl(C 1 -C 6  alkyl), or (C 1 -C 6  alkyl)sulfanyl(C 1 -C 6  alkyl); 
         R 2  is C 1 -C 6  alkyl, halo(C 1 -C 6  alkyl), C 1 -C 6  alkoxy, halo(C 1 -C 6  alkoxy), hydroxy(C 1 -C 6  alkyl), (C 1 -C 6  alkoxy)C 1 -C 6  alkyl, formyl(C 0 -C 6  alkyl), amino(C 1 -C 6  alkyl), sulfanyl(C 1 -C 6  alkyl), (C 1 -C 6  alkyl)sulfanyl(C 1 -C 6  alkyl), —(CH 2 ) 1-5 —C(O)OH, —(CH 2 ) 1-5 —C(O)(C 1 -C 6  alkoxy), —(CH 2 ) 1-5 —C(O)NH 2 , (aryl)C 1 -C 6  alkyl, or (heteroaryl)C 1 -C 6  alkyl; 
         R 3  is C 1 -C 6  alkyl, halo(C 1 -C 6  alkyl), C 1 -C 6  alkoxy, halo(C 1 -C 6  alkoxy), hydroxy(C 1 -C 6  alkyl), (C 1 -C 6  alkoxy)C 1 -C 6  alkyl, formyl(C 1 -C 6  alkyl), amino(C 1 -C 6  alkyl), sulfanyl(C 1 -C 6  alkyl), (C 1 -C 6  alkyl)sulfanyl(C 1 -C 6  alkyl), —(CH 2 ) 1-5 —C(O)(C 1 -C 6  alkoxy), —(CH 2 ) 1-5 —C(O)NH 2 , —(CH 2 ) 1-5 —C(O)NH(C 1 -C 6  alkyl), —(CH 2 ) 1-5 —C(O)N(C 1 -C 6  alkyl) 2 , —CH═CH—C(O)OH, —CH═CH—C(O)(C 1 -C 6  alkoxy), (aryl)C 1 -C 6  alkyl, or (heteroaryl)C 1 -C 6  alkyl; and 
         R 4  is hydroxy, halogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halo(C 1 -C 6  alkoxy), benzyloxy, —(CH 2 ) 1-5 —C(O)OH, —(CH 2 ) 1-5 —C(O)(C 1 -C 6  alkoxy), —(CH 2 ) 1-5 —C(O)NH 2 , —(CH 2 ) 1-5 —C(O)NH(C 1 -C 6  alkyl), —(CH 2 ) 1-5 —C(O)N(C 1 -C 6  alkyl) 2 , —CH═CH—C(O)OH, —CH═CH—C(O)(C 1 -C 6  alkoxy), —O(CH 2 ) 1-5 —C(O)(C 1 -C 6  alkoxy), (aryl)C 1 -C 6  alkyl, or (heteroaryl)C 1 -C 6  alkyl. 
       
     
     
         2 . A compound according to  claim 1 , wherein:
 R 5  is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, halo(C 1 -C 6  alkyl), C 1 -C 6  alkoxy, halo(C 1 -C 6  alkoxy), amino, (C 1 -C 6  alkyl)amino, di(C 1 -C 6  alkyl)amino, hydroxy(C 1 -C 6  alkyl), (C 1 -C 6  alkoxy)C 1 -C 6  alkyl, amino(C 1 -C 6  alkyl), sulfanyl(C 1 -C 6  alkyl), (C 1 -C 6  alkyl)sulfanyl(C 1 -C 6  alkyl), —(CH 2 ) 1-5 —C(O)(C 1 -C 6  alkoxy), and —(CH 2 ) 1-5 —C(O)NH 2 ;   R 1  is hydrogen, halogen, hydroxy, C 1 -C 6  alkyl, halo(C 1 -C 6  alkyl), C 1 -C 6  alkoxy, halo(C 1 -C 6  alkoxy), hydroxy(C 1 -C 6  alkyl), (C 1 -C 6  alkoxy)C 1 -C 6  alkyl, amino(C 1 -C 6  alkyl), sulfanyl(C 1 -C 6  alkyl), or (C 1 -C 6  alkyl)sulfanyl(C 1 -C 6  alkyl);   R 2  is C 1 -C 6  alkyl, halo(C 1 -C 6  alkyl), C 1 -C 6  alkoxy, halo(C 1 -C 6  alkoxy), hydroxy(C 1 -C 6  alkyl), (C 1 -C 6  alkoxy)C 1 -C 6  alkyl, formyl(C 0 -C 6  alkyl), amino(C 1 -C 6  alkyl), sulfanyl(C 1 -C 6  alkyl), (C 1 -C 6  alkyl)sulfanyl(C 1 -C 6  alkyl), —(CH 2 ) 1-5 —C(O)OH, —(CH 2 ) 1-5 —C(O)(C 1 -C 6  alkoxy), or —(CH 2 ) 1-5 —C(O)NH 2 ;   R 3  is C 1 -C 6  alkyl, halo(C 1 -C 6  alkyl), C 1 -C 6  alkoxy, halo(C 1 -C 6  alkoxy), hydroxy(C 1 -C 6  alkyl), (C 1 -C 6  alkoxy)C 1 -C 6  alkyl, formyl(C 1 -C 6  alkyl), amino(C 1 -C 6  alkyl), sulfanyl(C 1 -C 6  alkyl), (C 1 -C 6  alkyl)sulfanyl(C 1 -C 6  alkyl), —(CH 2 ) 1-5 —C(O)(C 1 -C 6  alkoxy), —(CH 2 ) 1-5 —C(O)NH 2 , —(CH 2 ) 1-5 —C(O)NH(C 1 -C 6  alkyl), —(CH 2 ) 1-5 —C(O)N(C 1 -C 6  alkyl) 2 , —CH═CH—C(O)OH, or —CH═CH—C(O)(C 1 -C 6  alkoxy); and   R 4  is hydroxy, halogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halo(C 1 -C 6  alkoxy), benzyloxy, —(CH 2 ) 1-5 —C(O)OH, —(CH 2 ) 1-5 —C(O)(C 1 -C 6  alkoxy), —(CH 2 ) 1-5 —C(O)NH 2 , —(CH 2 ) 1-5 —C(O)NH(C 1 -C 6  alkyl), —(CH 2 ) 1-5 —C(O)N(C 1 -C 6  alkyl) 2 , —CH═CH—C(O)OH, —CH═CH—C(O)(C 1 -C 6  alkoxy), or —O(CH 2 ) 1-5 —C(O)(C 1 -C 6  alkoxy).   
     
     
         3 . A compound according to  claim 1 , wherein
 R 5  is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, halo(C 1 -C 6  alkyl), C 1 -C 6  alkoxy, halo(C 1 -C 6  alkoxy), amino, (C 1 -C 6  alkyl)amino, di(C 1 -C 6  alkyl)amino, hydroxy(C 1 -C 6  alkyl), (C 1 -C 6  alkoxy)C 1 -C 6  alkyl, and amino(C 1 -C 6  alkyl);   R 1  is hydrogen, halogen, hydroxy, C 1 -C 6  alkyl, halo(C 1 -C 6  alkyl), C 1 -C 6  alkoxy, or halo(C 1 -C 6  alkoxy);   R 2  is C 1 -C 6  alkyl, halo(C 1 -C 6  alkyl), hydroxy(C 1 -C 6  alkyl), (C 1 -C 6  alkoxy)C 1 -C 6  alkyl, formyl(C 0 -C 6  alkyl), amino(C 1 -C 6  alkyl), sulfanyl(C 1 -C 6  alkyl), or (C 1 -C 6  alkyl)sulfanyl(C 1 -C 6  alkyl);   R 3  is C 1 -C 6  alkyl, —(CH 2 ) 1-5 —C(O)(C 1 -C 6  alkoxy), —(CH 2 ) 1-5 —C(O)NH 2 , —(CH 2 ) 1-5 —C(O)NH(C 1 -C 6  alkyl), —(CH 2 ) 1-5 —C(O)N(C 1 -C 6  alkyl) 2 , —CH═CH—C(O)OH, or —CH═CH—C(O)(C 1 -C 6  alkoxy); and   R 4  is hydroxy, halogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halo(C 1 -C 6  alkoxy), benzyloxy, —(CH 2 ) 1-5 —C(O)OH, —(CH 2 ) 1-5 —C(O)(C 1 -C 6  alkoxy), —(CH 2 ) 1-5 —C(O)NH 2 , —(CH 2 ) 1-5 —C(O)NH(C 1 -C 6  alkyl), —(CH 2 ) 1-5 —C(O)N(C 1 -C 6  alkyl) 2 , —CH═CH—C(O)OH, —CH═CH—C(O)(C 1 -C 6  alkoxy), or —O(CH 2 ) 1-5 —C(O)(C 1 -C 6  alkoxy).   
     
     
         4 . A compound according to  claim 1 , wherein
 R 1  is hydrogen.   
     
     
         5 . A compound according to  claim 1 , wherein
 R 2  is C 1 -C 6  alkyl, halo(C 1 -C 6  alkyl), hydroxy(C 1 -C 6  alkyl), formyl(C 0 -C 6  alkyl), amino(C 1 -C 6  alkyl), or sulfanyl(C 1 -C 6  alkyl).   
     
     
         6 . A compound according to  claim 5 , wherein R 2  is C 1 -C 6  alkyl, halo(C 1 -C 6  alkyl), or hydroxy(C 1 -C 6  alkyl). 
     
     
         7 . A compound according to  claim 1 , wherein
 R 3  is —CH═CH—C(O)OH or —CH═CH—C(O)(C 1 -C 6  alkoxy).   
     
     
         8 . A compound according to  claim 1 , wherein
 R 4  is hydroxy, halogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halo(C 1 -C 6  alkoxy), or benzyloxy.   
     
     
         9 . A compound according to  claim 8 , wherein R 4  is hydroxy or C 1 -C 6  alkoxy. 
     
     
         10 . A compound according to  claim 1 , wherein
 R 5  is C 1 -C 6  alkyl, halo(C 1 -C 6  alkyl), C 1 -C 6  alkoxy, or halo(C 1 -C 6  alkoxy).   
     
     
         11 . A compound according to  claim 1 , wherein
 R 5  is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, halo(C 1 -C 6  alkyl), C 1 -C 6  alkoxy, halo(C 1 -C 6  alkoxy), amino, (C 1 -C 6  alkyl)amino, di(C 1 -C 6  alkyl)amino, hydroxy(C 1 -C 6  alkyl), (C 1 -C 6  alkoxy)C 1 -C 6  alkyl, and amino(C 1 -C 6  alkyl);   R 1  is hydrogen, halogen, hydroxy, C 1 -C 6  alkyl, halo(C 1 -C 6  alkyl), C 1 -C 6  alkoxy, or halo(C 1 -C 6  alkoxy);   R 2  is C 1 -C 6  alkyl, halo(C 1 -C 6  alkyl), hydroxy(C 1 -C 6  alkyl), (C 1 -C 6  alkoxy)C 1 -C 6  alkyl, formyl(C 0 -C 6  alkyl), amino(C 1 -C 6  alkyl), sulfanyl(C 1 -C 6  alkyl), or (C 1 -C 6  alkyl)thio(C 1 -C 6  alkyl);   R 3  is —CH═CH—C(O)OH or —CH═CH—C(O)(C 1 -C 6  alkoxy); and   R 4  is hydroxy, C 1 -C 6  alkoxy, halo(C 1 -C 6  alkoxy), or benzyloxy.   
     
     
         12 . A compound according to  claim 1 , wherein
 R 1  is hydrogen;   R 2  is C 1 -C 6  alkyl, halo(C 1 -C 6  alkyl), hydroxy(C 1 -C 6  alkyl), or formyl(C 1 -C 6  alkyl);   R 3  is —CH═CH—C(O)OH or —CH═CH—C(O)(C 1 -C 6  alkoxy), or —(CH 2 ) 1-2 —C(O)NH 2 ,   R 4  is hydroxy or C 1 -C 6  alkoxy; and   R 5  is C 1 -C 6  alkyl, halo(C 1 -C 6  alkyl), C 1 -C 6  alkoxy, or halo(C 1 -C 6  alkoxy).   
     
     
         13 . A pharmaceutical composition comprising a compound according to  claim 1  and at least one pharmaceutically acceptable carrier, solvent, adjuvant or diluent. 
     
     
         14 . A method for treating antibody-mediated disorders, drug-resistant cancer, inflammation, protein misfolding, ER stress-mediated disorders, or aberrant apoptosis comprising administering to a subject a compound according to  claim 1 . 
     
     
         15 . A process for preparing a compound of formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         comprising reacting a compound of formula: 
       
       
         
           
           
               
               
           
         
         with a compound of formula: 
       
       
         
           
           
               
               
           
         
         wherein 
         R is selected from N and CR 5 ;
 R 5  is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, halo(C 1 -C 6  alkyl), C 1 -C 6  alkoxy, halo(C 1 -C 6  alkoxy), amino, (C 1 -C 6  alkyl)amino, di(C 1 -C 6  alkyl)amino, hydroxy(C 1 -C 6  alkyl), (C 1 -C 6  alkoxy)C 1 -C 6  alkyl, amino(C 1 -C 6  alkyl), sulfanyl(C 1 -C 6  alkyl), (C 1 -C 6  alkyl)sulfanyl(C 1 -C 6  alkyl), —(CH 2 ) 1-5 —C(O)OH, —(CH 2 ) 1-5 —C(O)(C 1 -C 6  alkoxy), —(CH 2 ) 1-5 —C(O)NH 2 , (aryl)C 1 -C 6  alkyl, and (heteroaryl)C 1 -C 6  alkyl; 
 
         R 1  is hydrogen, halogen, hydroxy, C 1 -C 6  alkyl, halo(C 1 -C 6  alkyl), C 1 -C 6  alkoxy, halo(C 1 -C 6  alkoxy), hydroxy(C 1 -C 6  alkyl), (C 1 -C 6  alkoxy)C 1 -C 6  alkyl, amino(C 1 -C 6  alkyl), sulfanyl(C 1 -C 6  alkyl), or (C 1 -C 6  alkyl)sulfanyl(C 1 -C 6  alkyl); 
         R 2  is C 1 -C 6  alkyl, halo(C 1 -C 6  alkyl), C 1 -C 6  alkoxy, halo(C 1 -C 6  alkoxy), hydroxy(C 1 -C 6  alkyl), (C 1 -C 6  alkoxy)C 1 -C 6  alkyl, formyl(C 0 -C 6  alkyl), amino(C 1 -C 6  alkyl), sulfanyl(C 1 -C 6  alkyl), (C 1 -C 6  alkyl)sulfanyl(C 1 -C 6  alkyl), —(CH 2 ) 1-5 —C(O)OH, —(CH 2 ) 1-5 —C(O)(C 1 -C 6  alkoxy), —(CH 2 ) 1-5 —C(O)NH 2 , (aryl)C 1 -C 6  alkyl, or (heteroaryl)C 1 -C 6  alkyl; 
         R 3  is C 1 -C 6  alkyl, halo(C 1 -C 6  alkyl), C 1 -C 6  alkoxy, halo(C 1 -C 6  alkoxy), hydroxy(C 1 -C 6  alkyl), (C 1 -C 6  alkoxy)C 1 -C 6  alkyl, formyl(C 1 -C 6  alkyl), amino(C 1 -C 6  alkyl), sulfanyl(C 1 -C 6  alkyl), (C 1 -C 6  alkyl)sulfanyl(C 1 -C 6  alkyl), —(CH 2 ) 1-5 —C(O)OH, —(CH 2 ) 1-5 —C(O)(C 1 -C 6  alkoxy), —(CH 2 ) 1-5 —C(O)*NH 2 , —(CH 2 ) 1-5 —C(O)NH(C 1 -C 6  alkyl), —(CH 2 ) 1-5 —C(O)N(C 1 -C 6  alkyl) 2 , —CH═CH—C(O)OH, —CH═CH—C(O)(C 1 -C 6  alkoxy), (aryl)C 1 -C 6  alkyl, or (heteroaryl)C 1 -C 6  alkyl; and 
         R 4  is hydroxy, halogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halo(C 1 -C 6  alkoxy), benzyloxy, —(CH 2 ) 1-5 —C(O)OH, —(CH 2 ) 1-5 —C(O)(C 1 -C 6  alkoxy), —(CH 2 ) 1-5 —C(O)NH 2 , —(CH 2 ) 1-5 —C(O)NH(C 1 -C 6  alkyl), —(CH 2 ) 1-5 —C(O)N(C 1 -C 6  alkyl) 2 , —CH═CH—C(O)OH, —CH═CH—C(O)(C 1 -C 6  alkoxy), —O(CH 2 ) 1-5 —C(O)OH, —O(CH 2 ) 1-5 —C(O)(C 1 -C 6  alkoxy), (aryl)C 1 -C 6  alkyl, or (heteroaryl)C 1 -C 6  alkyl; and 
         each R″ is independently hydrogen, or C 1 -C 6  alkyl, or two R″ together with the atoms to which they are attached form a dioxaborolanyl or dioxaborinanyl ring, each optionally substituted with C 1 -C 6  alkyl.
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