Modulators of p97 aaa atpase activity

Abstract

The present invention is directed to methods of inhibiting or modulating p97 and compounds and compositions useful in such methods. Diseases and conditions that can be treated with the compounds and compositions of the invention include, but are not limited to, cancer and neurodegenerative disorders susceptible to treatment by modulation or inhibition of p97.

1 . A method of modulating p97 in a subject in need thereof,
 comprising administering to the subject a therapeutically effective amount of a compound having a structure of formula (I):   
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate or prodrug thereof, 
       
       wherein:
 Z is O, SO 0-2 , NR, C(R 7 ) 2 , alkenyl or alkynyl; 
 R 2  and R 3  are independently an optionally substituted C 1-9  cyclic, C 3-9  heterocyclic, or halogen, or R 2  and R 3  together form an optionally substituted C 3-9  cyclic or 3- to 9-membered heterocyclic ring; 
 R 1  is optionally substituted phenyl or an optionally substituted 5- or 6-membered heteroaryl; 
 R 4  is H, aryl, or heteroaryl; 
 X is O or SO 0-2 ; 
 Y is an optionally substituted alkyl, alkenyl, aryl, heteroaryl, cycloalkyl, or heterocycle; 
 R 5  is H, nitrile, an optionally substituted aryl, an optionally substituted heterocycle, optionally substituted C 1 -C 6  alkyl, optionally substituted C 3 -C 9  cycloalkyl, or 
 
       
         
           
           
               
               
           
         
          where 
         R′ and R″ are each independently selected from H, optionally substituted alkyl, —OR, halogen, —N(R) 2 , and optionally substituted cycloalkyl or heterocycle; 
         or R′ and R″ may together form a 3- to 6-membered cycloalkyl or heterocycle that is optionally substituted; 
         D′ is selected from the group consisting of —O—, —NR—, —OCONR—, —NRSO 2 —, —NRCO—, —NRSO 2 NR—, —NRCOO—, —NRCONR—, and —NRC(NR)NR—; 
         E′ is selected from a bond or an optionally substituted C 1 -C 6  alkyl or cycloalkyl; 
         F′ is selected from the group consisting of H, an optionally substituted cycloalkyl, an optionally substituted heterocycle, an optionally substituted aryl, and an optionally substituted heteroaryl; 
         R is selected from the group consisting of H, optionally substituted alkyl, and optionally substituted cycloalkyl; and 
         R 7  is selected from the group consisting of H, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, —OR, and —N(R) 2 . 
       
     
     
         2 . The method of  claim 1 , wherein X is O or S. 
     
     
         3 . The method of  claim 1 , wherein Y is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The method of  claim 1 , wherein Z is selected from O, S and CH 2 . 
     
     
         5 . The method of  claim 1 , wherein R 5  is a phenyl, optionally substituted with one or more alkyl, —OR, —CN, —CO 2 R, halogen, —SR, —SOR, —SO 2 R, —SF 5  or —NR 2 . 
     
     
         6 . The method of  claim 1 , wherein R 5  is a heterocycle optionally substituted with one or more alkyl, —OR, —CN, —CO 2 R, halogen, —SR, —SOR, —SO 2 R, —SF 5  or —NR 2 . 
     
     
         7 . The method of  claim 1 , wherein R 5  is 
       
         
           
           
               
               
           
         
       
     
     
         8 . A method of modulating p97 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound having a structure of formula (II): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: 
         X is O, SO 0-2 , or NR; 
         Y is optionally substituted alkyl, optionally substituted alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted non-aromatic heterocyclic; 
         Y′ is alkynyl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted non-aromatic heterocyclic; 
         R 2  and R 3  are independently optionally substituted C 1-6  alkyl, optionally substituted C 1-9  cyclic, optionally substituted C 3-9  heterocyclic, or halogen, or R 2  and R 3  together form an optionally substituted C 3-9  cyclic or optionally substituted 3- to 9-membered heterocyclic ring; 
         Z is O, SO 0-2 , NR, C(R 7 ) 2 , alkenyl or alkynyl; 
         R 1  is optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted non-aromatic heterocyclic; 
         R 4  is H, C(R 7 ) 2 , aryl, or heteroaryl; 
         R 5  is H, nitrile, an optionally substituted aryl, an optionally substituted heterocycle, optionally substituted C 1 -C 6  alkyl, optionally substituted C 3 -C 9  cycloalkyl, or 
       
       
         
           
           
               
               
           
         
          wherein 
         R′ and R″ are each independently selected from the group consisting of H, optionally substituted alkyl, —OR, halogen, —N(R) 2 , optionally substituted cycloalkyl, and optionally substituted heterocycle; 
         or R′ and R″ may together form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 6-membered heterocycle; 
         D′ is selected from the group consisting of —O—, —NR—, —OCONR—, —OCO—, —NRSO 2 —, —NRCO—, —NRSO 2 NR—, —NRCOO—, —NRCONR—, and —NRC(NR)NR—; 
         E′ is selected from the group consisting of a bond, an optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  alkenyl, and optionally substituted cycloalkyl; and 
         F′ is selected from the group consisting of H, an optionally substituted cycloalkyl, an optionally substituted non-aromatic heterocycle, an optionally substituted aryl, and an optionally substituted heteroaryl; 
         R is independently selected from the group consisting of H, optionally substituted alkyl, and optionally substituted cycloalkyl; and 
         R 7  is independently selected from the group consisting of H, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, —OR, and —N(R) 2 . 
       
     
     
         9 .- 22 . (canceled) 
     
     
         23 . A method of treating cancer or a neurodegenerative disease susceptible to treatment by p97 modulation in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound having a structure of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: 
         Z is O, SO 0-2 , NR, C(R 7 ) 2 , alkenyl or alkynyl; 
         R 2  and R 3  are independently an optionally substituted C 1-9  cyclic, C 3-9  heterocyclic, or halogen, or R 2  and R 3  together form an optionally substituted C 3-9  cyclic or 3- to 9-membered heterocyclic ring; 
         R 1  is optionally substituted phenyl or an optionally substituted 5- or 6-membered heteroaryl; 
         R 4  is H, aryl, or heteroaryl; 
         X is O or SO 0-2 ; 
         Y is an optionally substituted alkyl, alkenyl, aryl, heteroaryl, cycloalkyl, or heterocycle; 
         R 5  is H, nitrile, an optionally substituted aryl, an optionally substituted heterocycle, optionally substituted C 1 -C 6  alkyl, optionally substituted C 3 -C 9  cycloalkyl, or 
       
       
         
           
           
               
               
           
         
          where 
         R′ and R″ are each independently selected from H, optionally substituted alkyl, —OR, halogen, —N(R) 2 , and optionally substituted cycloalkyl or heterocycle; 
         or R′ and R″ may together form a 3- to 6-membered cycloalkyl or heterocycle that is optionally substituted; 
         D′ is selected from the group consisting of —O—, —NR—, —OCONR—, —NRSO 2 —, —NRCO—, —NRSO 2 NR—, —NRCOO—, —NRCONR—, and —NRC(NR)NR—; 
         E′ is selected from a bond or an optionally substituted C 1 -C 6  alkyl or cycloalkyl; 
         F′ is selected from the group consisting of H, an optionally substituted cycloalkyl, an optionally substituted heterocycle, an optionally substituted aryl, and an optionally substituted heteroaryl; 
         R is selected from the group consisting of H, optionally substituted alkyl, and optionally substituted cycloalkyl; and 
         R 7  is selected from the group consisting of H, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, —OR, and —N(R) 2 . 
       
     
     
         24 . The method of  claim 23 , which is a method of treating cancer susceptible to treatment by p97 inhibition, and wherein the cancer is selected from the group consisting of a solid tumor, non-small cell lung carcinoma, multiple myeloma, and mantle cell lymphoma. 
     
     
         25 . The method of  claim 23 , which is a method of treating a neurodegenerative disease susceptible to treatment, and wherein the neurodegenerative disease is selected from the group consisting of inclusion body myopathy (IBM), Paget's disease of the bone (PDB), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). 
     
     
         26 . The method of  claim 23 , wherein X is O or S. 
     
     
         27 . The method of  claim 23 , wherein Y is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         28 . The method of  claim 23 , wherein Z is selected from O, S and CH 2 . 
     
     
         29 . The method of  claim 23 , wherein R 5  is a phenyl, optionally substituted with one or more alkyl, —OR, —CN, —CO 2 R, halogen, —SR, —SOR, —SO 2 R, —SF 5  or —NR 2 . 
     
     
         30 . The method of  claim 23 , wherein R 5  is a heterocycle optionally substituted with one or more alkyl, —OR, —CN, —CO 2 R, halogen, —SR, —SOR, —SO 2 R, —SF 5  or —NR 2 . 
     
     
         31 . The method of  claim 23 , wherein R 5  is 
       
         
           
           
               
               
           
         
       
     
     
         32 . The method of  claim 31 , wherein R′ and R″ together form a 3- to 6-membered cycloalkyl or heterocycle. 
     
     
         33 . The method of  claim 31 , wherein R′ and R″ are each H, or at least one of R′ and R″ is methyl and any remaining R′ or R″ is H. 
     
     
         34 . A method of treating cancer or a neurodegenerative disease susceptible to treatment by p97 modulation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound having a structure of formula (II): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: 
         X is O, SO 0-2 , or NR; 
         Y is optionally substituted alkyl, optionally substituted alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted non-aromatic heterocyclic; 
         Y′ is alkynyl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted non-aromatic heterocyclic; 
         R 2  and R 3  are independently optionally substituted C 1-6  alkyl, optionally substituted C 1-9  cyclic, optionally substituted C 3-9  heterocyclic, or halogen, or R 2  and R 3  together form an optionally substituted C 3-9  cyclic or optionally substituted 3- to 9-membered heterocyclic ring; 
         Z is O, SO 0-2 , NR, C(R 7 ) 2 , alkenyl or alkynyl; 
         R 1  is optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted non-aromatic heterocyclic; 
         R 4  is H, C(R 7 ) 2 , aryl, or heteroaryl; 
         R 5  is H, nitrile, an optionally substituted aryl, an optionally substituted heterocycle, optionally substituted C 1 -C 6  alkyl, optionally substituted C 3 -C 9  cycloalkyl, or 
       
       
         
           
           
               
               
           
         
          wherein 
         R′ and R″ are each independently selected from the group consisting of H, optionally substituted alkyl, —OR, halogen, —N(R) 2 , optionally substituted cycloalkyl, and optionally substituted heterocycle; 
         or R′ and R″ may together form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 6-membered heterocycle; 
         D′ is selected from the group consisting of —O—, —NR—, —OCONR—, —OCO—, —NRSO 2 —, —NRCO—, —NRSO 2 NR—, —NRCOO—, —NRCONR—, and —NRC(NR)NR—; 
         E′ is selected from the group consisting of a bond, an optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  alkenyl, and optionally substituted cycloalkyl; and 
         F′ is selected from the group consisting of H, an optionally substituted cycloalkyl, an optionally substituted non-aromatic heterocycle, an optionally substituted aryl, and an optionally substituted heteroaryl; 
         R is independently selected from the group consisting of H, optionally substituted alkyl, and optionally substituted cycloalkyl; and 
         R 7  is independently selected from the group consisting of H, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, —OR, and —N(R) 2 .