Isothiazolopyrimidinones, pyrazolopyrimidinones, and pyrrolopyrimidinones as ubiquitin-specific protease 7 inhibitors

Abstract

The disclosure relates to inhibitors of USP7 inhibitors useful in the treatment of cancers, neurodegenerative diseases, immunological disorders, inflammatory disorders, cardiovascular diseases, ischemic diseases, viral infections and diseases, and bacterial infections and diseases, having the Formula:where R1, R2, R3, R4, R5, R5′, X1, X2, X3, n, and m are described herein.

1 - 16 . (canceled) 
     
     
         17 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         X 1  is C, S, or S(O); 
         X 2  is S or NR 6 ; 
         X 3  is N or CR 7 , wherein, one of X 2  or X 3  is N; 
         R 1  is H, OH, SH, NH 2 , or F; 
         R 2  is (C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, heterocycloalkyl, —NR 10 R 11 , or —OR 10 , wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 8 ; 
         each R 3  is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 18 ; or 
         two R 3  together when on adjacent carbons form a (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 18 ; or two R 3  together when attached to the same carbon atom form a (C 3 -C 8 ) spirocycloalkyl optionally substituted with one or more R 18 ; or two R 3  together when attached to the same carbon atom form a spiroheterocycloalkyl optionally substituted with one or more R 18 ; or two R 3  together when on adjacent carbons form an aryl ring optionally substituted with one or more R 18 ; or two R 3  together when on adjacent carbons form an heteroaryl ring optionally substituted with one or more R 18 ; 
         R 4  is H, (C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 12 ; 
         R 5  and R 5′  are independently H, D, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, or CN; 
         R 6  is H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, or (C 1 -C 6 ) haloalkyl; 
         R 7  is H, D, (C 1 -C 6 ) alkyl, halogen, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 14 ; 
         each R 8  is independently D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, CN, —(C 1 -C 3 )-alkylene-O—(C 1 -C 6 ) alkyl, —(C 0 -C4)-alkylene-aryl, —(C 0 -C 4 )-alkylene-heteroaryl, (C 3 -C 10 ) cycloalkyl, heterocycloalkyl, —(C 0 -C 4 )-alkylene-O-aryl, —(C 0 -C 4 )-alkylene-O-heteroaryl, —O—(C 3 -C 8 )cycloalkyl, —S-heteroaryl, —CN, —C(O)R 19 , —CO(O)R 19 , —C(O)NR 19 R 20 , —S(O) q R 19 , —S(O) q NR 19 R 20 , —NR19S(O) q R 20 , —(C 0 -C 3 )-alkylene-NR 19 R 20 , —NR 19 C(O)R 20 , —NR 19 C(O)C(O)R 20 , —NR 19 C(O)NR 19 R 20 , —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , —SF 5 , or —OR 19 , wherein the alkyl, alkylene, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 9 ; or 
         two R 8  together when on adjacent atoms form a (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 9 ; or two R 8  together when on adjacent atoms form a heterocycloalkyl ring optionally substituted with one or more R 9 ; or two R 8  together when on adjacent atoms form an aryl ring optionally substituted with one or more R 9 ; or two R 8  together when on adjacent atoms form an heteroaryl ring optionally substituted with one or more R 9 ; 
         each R 9  is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, (C 3 -C 8 ) cycloalkyl, heterocycloalkyl, (C 6 -C 14 ) aryl, heteroaryl, —NH 2 , —OH, CN, —C(O)R 21 , —C(O)NR 21 R 22 , —NR 21 C(O)R 22 , —NR 21 R 22 , —S(O) q R 21 , —S(O) q NR 21 R 22 , —NR 21 S(O) q R 22 , oxo, —P(O)((C 1 -C 6 )alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , —SF 5 , —O-aryl, CN, or —O-heteroaryl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 24 ; 
         R 10  and R 11  are independently H, (C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 16 ; or 
         R 10  and R 11  together with the nitrogen to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R 16 ; 
         each R 12  is independently D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, CN, —OH, —NH 2 , —C(O)(C 1 -C 6 ) alkyl, —S(O) q (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, (C 6 -C 14 ) aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, heterocycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C 3 -C 8 )cycloalkyl, —C(O)O(C 1 -C 6 ) alkyl, —C(O)NR 25 R 26 , —S(O) q NR 25 R 26 , —NR 25 R 26 , —NR 25 C(O)NR 25 R 26 , —NR 25 C(O)OR 26 , —NR 25 S(O) q R 26 , —NR 25 C(O)R 26 , halogen, —P(O)((C 1 -C 6 ) alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , or —SF 5 , wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 13 ; or 
         two R 12  together when on adjacent atoms form a (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 13 ; or two R 12  together when on adjacent atoms form a heterocycloalkyl ring optionally substituted with one or more R 13 ; or two R 12  together when on adjacent atoms form an aryl ring optionally substituted with one or more R 13 ; or two R 12  together when on adjacent atoms form an heteroaryl ring optionally substituted with one or more R 13 ; 
         each R 13  is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —C(O)(C 1 -C 6 ) alkyl, —S(O) q (C1-C 6 ) alkyl, —NH 2 , (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, (C 6 -C 14 ) aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, heterocycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C 3 -C 8 )cycloalkyl, —OH, or CN, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 27 ; 
         each R 14  is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, CN, —C(O)(C 1 -C 6 ) alkyl, —S(O) q (C 1 -C 6 ) alkyl, —NH 2 , —OH, (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 15 ; 
         each R 15  is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —C(O)(C 1 -C 6 ) alkyl, —S(O) q (C 1 -C 6 ) alkyl, —NH 2 , (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, OH, or CN; 
         each R 16  is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, (C 1 -C 6 ) hydroxyalkyl, —OH, CN, —C(O)(C 1 -C 6 ) alkyl, —S(O) q (C 1 -C 6 ) alkyl, —NH 2 , (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 17 ; 
         each R 17  is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —C(O)(C 1 -C 6 ) alkyl, —S(O) q (C 1 -C 6 ) alkyl, —NH 2 , (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, —OH, or CN; 
         each R 18  is independently at each occurrence (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —OH, —NH 2 , or CN; 
         each R 19  and R 20  is independently H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R 23 ; 
         each R 21  and R 22  is independently H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R 23 ; 
         each R 23  is independently at each occurrence (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —OH, or CN; 
         each R 24  is independently at each occurrence (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —NR 25 C(O)R 26 , —NR 25 S(O) q R 26 , —C(O)R 25 , —C(O)NR 25 R 26 , —NR 25 R 26 , —S(O) q R 25 , —S(O) q NR 25 R 26 , —P(O)((C 1 -C 6 ) alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , —SF 5 , —OH, or CN; 
         each R 25  and R 26  is independently at each occurrence H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, or heterocycloalkyl; 
         each R 27  is independently at each occurrence (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —C(O)(C 1 -C 6 ) alkyl, —S(O) q (C 1 -C 6 ) alkyl, —NH 2 , (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, —OH, or CN; 
         m is 0, 1, 2, 3, or 4; 
         n is 0, 1, 2, or 3; and 
         q is independently at each occurrence 0, 1, or 2. 
       
     
     
         18 . The compound of  claim 17 , having Formula (Ia): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         19 . The compound of  claim 17 , having Formula (Ib): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         20 . The compound of  claim 17 , having Formula (Ic): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         21 . The compound of  claim 17 , having Formula (Id): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         22 . The compound of  claim 17 , having Formula (Ie): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         23 . The compound of  claim 17 , having Formula (If): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         24 . The compound of  claim 17 , having Formula (Ig): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         25 . The compound of  claim 17 , having Formula (Ih): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         26 . The compound of  claim 17 , having Formula (Ii): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         27 . A pharmaceutical composition comprising a compound of  claim 17  and a pharmaceutically acceptable carrier. 
     
     
         28 . A method of treating a disease or disorder associated with modulation of USP7, the method comprising administering to a patient in need thereof an effective amount of a compound of  claim 17 . 
     
     
         29 . A method of inhibiting USP7 comprising administering to a patient in need thereof an effective amount of a compound of  claim 17 . 
     
     
         30 . A method of treating cancer, the method comprising administering to a patient in need thereof an effective amount of a compound of  claim 17 . 
     
     
         31 . A method of treating a neurodegenerative disease, the method comprising administering to a patient in need thereof an effective amount of a compound of  claim 17 . 
     
     
         32 . A method of treating a viral infection and disease, the method comprising administering to a patient in need thereof an effective amount of a compound of  claim 17 . 
     
     
         33 . A method of inducing cell cycle arrest, apoptosis in tumor cells, and/or enhanced tumor specific T-cell immunity, comprising contacting the cells with an effective amount of  claim 17 .