US2021002289A1PendingUtilityA1
Monofunctional intermediates for ligand-dependent target protein degradation

Assignee: UNIV MICHIGAN REGENTSPriority: Apr 6, 2016Filed: Aug 31, 2020Published: Jan 7, 2021
Est. expiryApr 6, 2036(~9.7 yrs left)· nominal 20-yr term from priority
Inventors:Yangbing Li Angelo Aguilar Bing Zhou Jiantao Hu Fuming Xu Chong Qin Yang Hu Weiguo Xiang Rohan Rej Jiuling Yang Xin Han Longchuan Bai Chao-Yie Yang
C07D 401/04C07D 487/04C07D 495/14C07D 487/10C07D 401/14A61P 35/00
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References
Claims
Abstract

and the salts or solvates thereof, wherein X, L, Y, and B are as defined in the specification. Compounds having Formula I are immunomodulators and/or monofunctional synthetic intermediates that can be used to prepare small-molecule drug conjugates.
Claims

exact text as granted — not AI-modified
1 . A compound having Formula I: 
       
         
           
           
               
               
           
         
         and the salts or solvates thereof, 
         wherein: 
       
       X is selected from the group consisting of —C≡C—, —O—, —N(R 2a )—, —OC(═O)—, 
       
         
           
           
               
               
           
         
       
       wherein the —N(R 2b )— of 
       
         
           
           
               
               
           
         
       
       is attached to L; the —O— of 
       
         
           
           
               
               
           
         
       
       is attached to L; the —C(═O)— of —OC(═O)— is attached to L; 
       and the carbon atom of 
       
         
           
           
               
               
           
         
       
       is attached to L;
 L is selected from the group consisting of heteroalkylenyl, -A-(CH 2 ) m —W—(CH 2 ) n —, and —(CH 2 ) r —W—(CH 2 ) u —O—(CH 2 ) v —; 
 A is absent; or 
 A is heteroarylenyl; 
 W is selected from the group consisting of phenylenyl, heteroarylenyl, heterocyclenyl, and cycloalkylenyl; 
 m is 0, 1, 2, 3, 4, 5, 6, or 7; 
 n is 0, 1, 2, 3, 4, 5, 6, 7, or 8; 
 r is 0, 1, 2 or 3; 
 u is 0, 1, 2, or 3; 
 v is 1, 2, 3, or 4; 
 Y is selected from the group consisting of —C≡C—, —CH═CH—, —CH 2 —, —O—, —N(R 2c )—, —C(═O)N(R 2d )—, —N(R 2e )C(═O)CH 2 O—, and —N(R 2e )C(═O)CH 2 N(R 2f )—; or 
 Y is absent; 
 wherein the carboxamide nitrogen atom of —N(R 2e )C(═O)CH 2 O— and —N(R 2e )C(═O)CH 2 N(R 2f )—, and the carbon atom of —C(═O)N(R 2d )— is attached to L; 
 R 2a , R 2b , R 2c , R 2d , R 2e , and R 2f  are each independently selected from the group consisting of hydrogen and C 1-4  alkyl; 
 B is selected from the group consisting of: 
 
       
         
           
           
               
               
           
         
         A 1  is selected from the group consisting of —C(R 16a )═ and —N═; 
         A 2  is selected from the group consisting of —C(R 16b )═ and —N═; 
         A 3  is selected from the group consisting of —C(R 16c )═ and —N═; 
         G is selected from the group consisting of —C(R 16d )═ and —N═; 
         Z is selected from the group consisting of —CH 2  and —C(═O)—; 
         R 5  is selected from the group consisting of hydrogen, methyl, and fluoro; 
         R 16a  is selected from the group consisting of hydrogen, halo, and C 1-4  alkyl; 
         R 16b  is selected from the group consisting of hydrogen, halo, and C 1-4  alkyl; 
         R 16c  is selected from the group consisting of hydrogen, halo, and C 1-4  alkyl; and 
         R 16d  is selected from the group consisting of hydrogen, halo, and C 1-4  alkyl, 
         with the proviso the compound is not any one of the compounds of Table 6. 
       
     
     
         2 . The compound of  claim 1 , and the salts or solvates thereof, wherein;
 X is selected from the group consisting of —C≡C—, —O—, —N(R 2a )—,   
       
         
           
           
               
               
           
         
       
       wherein the —N(R 2b )— of 
       
         
           
           
               
               
           
         
       
       is attached to L; the —O— of 
       
         
           
           
               
               
           
         
       
       is attached to L; and
 B is selected from the group consisting of B-1a, B-2, and B-3. 
 
     
     
         3 . The compound of  claim 1 , wherein X is —C≡C—. 
     
     
         4 . The compound of  claim 1 , wherein X is —N(H)—. 
     
     
         5 . The compound of  claim 1 , wherein X is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
       wherein the carbon atom of 
       
         
           
           
               
               
           
         
       
       is attached to L. 
     
     
         6 . (canceled) 
     
     
         7 . (canceled) 
     
     
         8 . The compound of  claim 1 , wherein L is 3- to 12-membered heteroalkylenyl. 
     
     
         9 . The compound of  claim 8 , or a pharmaceutically acceptable salt or solvate thereof, wherein;
 L is —(CH 2 ) o O—(CH 2 CH 2 O) p —(CH 2 ) q —;   o is 1, 2, or 3;   p is 0, 1, 2, 3, 4, or 5; and   q is 1, 2, or 3.   
     
     
         10 . (canceled) 
     
     
         11 . The compound of  claim 1 , wherein;
 L is -A-(CH 2 ) m —W—(CH 2 ) n —; and   A is absent.   
     
     
         12 . (canceled) 
     
     
         13 . (canceled) 
     
     
         14 . The compound of  claim 11 , wherein W is 5-membered heteroarylenyl. 
     
     
         15 . (canceled) 
     
     
         16 . The compound of  claim 11 , wherein W is 6-membered heteroarylenyl. 
     
     
         17 . (canceled) 
     
     
         18 . The compound of  claim 11 , wherein W is heterocyclenyl. 
     
     
         19 - 21 . (canceled) 
     
     
         22 . The compound of  claim 1 , wherein;
 L is -A-(CH 2 ) m —W—(CH 2 ) n —; and   A is selected from the group consisting of 5-membered heteroarylenyl and 6-membered heteroarylenyl.   
     
     
         23 - 40 . (canceled) 
     
     
         41 . The compound of  claim 1 , wherein Y is selected from the group consisting of —C≡C—, —CH 2 —, —O—, and —N(R 2c )—. 
     
     
         42 - 45 . (canceled) 
     
     
         46 . The compound of  claim 1 , wherein B is B-1a. 
     
     
         47 - 54 . (canceled) 
     
     
         55 . The compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, having Formula II: 
       
         
           
           
               
               
           
         
       
     
     
         56 - 65 . (canceled) 
     
     
         66 . The compound of  claim 55 , or a pharmaceutically acceptable salt or solvate thereof, wherein L is 3- to 20-membered heteroalkylenyl. 
     
     
         67 . (canceled) 
     
     
         68 . (canceled) 
     
     
         69 . The compound of  claim 55 , or a pharmaceutically acceptable salt or solvate thereof, wherein L is —(CH 2 ) m —W—(CH 2 ) n —. 
     
     
         70 - 73 . (canceled) 
     
     
         74 . The compound of  claim 69 , or a pharmaceutically acceptable salt or solvate thereof, wherein;
 L is selected from the group consisting of:   
       
         
           
           
               
               
           
         
         Q 3  is selected from the group consisting of —O—, —S—, and —N(R 6 )—; and 
         R 6  is selected from the group consisting of hydrogen and C 1-4  alkyl. 
       
     
     
         75 . (canceled) 
     
     
         76 . The compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, selected from the group consisting of;
 2-(2,6-dioxopiperidin-3-yl)-4-((3-(2-(2-(3-(piperidin-4-ylamino)propoxy)ethoxy)ethoxy)propyl)amino)isoindoline-1,3-dione;   4-((2-(2-(2-(2-(4-aminophenoxy)ethoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;   4-((7-aminoheptyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;   5-amino-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pentanamide;   N-(3-(2-(2-(3-aminopropoxy)ethoxy)ethoxy)propyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide;   N-(3-(2-(2-(3-aminopropoxy)ethoxy)ethoxy)propyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetamide;   4-((3-(2-(2-(3-aminopropoxy)ethoxy)ethoxy)propyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;   4-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;   3-(4-(5-aminopentyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(5-aminopentyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   4-((3-aminopropyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;   4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;   4-((5-aminopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;   4-((6-aminohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;   4-((2-(2-aminoethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;   4-((2-(2-(2-aminoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;   4-((2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;   4-((3-(4-(3-aminopropoxy)butoxy)propyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;   4-((23-amino-3,6,9,12,15,18,21-heptaoxatricosyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;   3-(4-((2-(2-aminoethoxy)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-((2-(2-(2-aminoethoxy)ethoxy)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-((2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-((14-amino-3,6,9,12-tetraoxatetradecyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-((3-(2-(2-(3-aminopropoxy)ethoxy)ethoxy)propyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   4-((3-(2-(2-(3-aminopropoxy)ethoxy)ethoxy)propyl)amino)-2-(3-fluoro-2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;   3-(4-(3-(2-aminoethoxy)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(3-(2-(2-aminoethoxy)ethoxy)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   4-((4-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)butyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;   3-(4-((4-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)butyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-((3-(4-amino-1H-imidazol-1-yl)propyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(4-(4-amino-1H-imidazol-1-yl)butyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-((2-(4-(aminomethyl)-1H-imidazol-1-yl)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(3-(4-(aminomethyl)-1H-imidazol-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-((3-(1-(2-aminoethyl)-1H-imidazol-4-yl)propyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-((3-(1-(3-aminopropyl)-1H-imidazol-4-yl)propyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-((3-(4-(3-aminopropyl)-1H-imidazol-1-yl)propyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(4-(4-(3-aminopropyl)-1H-imidazol-1-yl)butyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-((3-(5-(2-aminoethyl)-1H-imidazol-2-yl)propyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(4-(5-(2-aminoethyl)-1H-imidazol-2-yl)butyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(4-(4-(aminomethyl)-1H-imidazol-1-yl)butyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   4-(4-(4-(aminomethyl)-1H-imidazol-1-yl)butyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;   3-(4-((3-(4-(2-aminoethyl)-1H-imidazol-1-yl)propyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-((3-(4-(aminomethyl)-1H-imidazol-1-yl)propyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(4-(4-(2-aminoethyl)-1H-imidazol-1-yl)butyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   4-(4-(4-(2-aminoethyl)-1H-imidazol-1-yl)butyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;   3-(4-(((1-(3-aminopropyl)-1H-imidazol-4-yl)methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-((2-(4-(3-aminopropyl)-1H-imidazol-2-yl)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(2-(1-(3-aminopropyl)-1H-imidazol-4-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   4-(2-(1-(3-aminopropyl)-1H-imidazol-4-yl)ethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;   3-(4-(3-((1-(3-aminopropyl)-1H-imidazol-4-yl)methoxy)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   4-(3-((1-(3-aminopropyl)-1H-imidazol-4-yl)methoxy)propyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;   3-(4-(3-(4-(3-aminopropyl)-1H-imidazol-2-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   4-(3-(4-(3-aminopropyl)-1H-imidazol-2-yl)propyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;   4-(5-aminopentyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;   4-(3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;   4-(3-(2-aminoethoxy)propyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;   3-(2-(2-aminoethoxy)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)propanamide;   3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)propanamide;   4-((2-(2-(2-aminoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;   3-(4-((4-aminobutyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-((3-(2-(2-(3-aminopropoxy)ethoxy)ethoxy)propyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-((2-(2-(2-(3-aminopropoxy)ethoxy)ethoxy)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-((2-(2-(3-aminopropoxy)ethoxy)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(1-amino-3,6,9,12-tetraoxapentadecan-15-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(3-(2-(2-(3-aminopropoxy)ethoxy)ethoxy)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(3-(2-(2-(3-aminopropoxy)ethoxy)ethoxy)prop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   4-(3-(2-(2-aminoethoxy)ethoxy)propyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;   4-(((1-(3-aminopropyl)-1H-imidazol-4-yl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;   (2S,4R)-1-((S)-2-(5-aminopentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;   (2S,4R)-1-((S)-2-(3-(2-(2-aminoethoxy)ethoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;   N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide;   2-(2,6-dioxopiperidin-3-yl)-4-((2-(prop-2-yn-1-yloxy)ethyl)amino)isoindoline-1,3-dione;   2-(2,6-dioxopiperidin-3-yl)-4-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)isoindoline-1,3-dione;   2-(2,6-dioxopiperidin-3-yl)-4-((2-(2-(prop-2-yn-1-yloxy)ethoxy)ethyl)amino)isoindoline-1,3-dione;   2-(2,6-dioxopiperidin-3-yl)-4-((2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)amino)isoindoline-1,3-dione;   4-((3,6,9,12-tetraoxapentadec-14-yn-1-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;   2-(2,6-dioxopiperidin-3-yl)-4-((2-(4-ethynyl-1H-pyrazol-1-yl)ethyl)amino)isoindoline-1,3-dione;   2-(2,6-dioxopiperidin-3-yl)-4-((4-(4-ethynyl-1H-pyrazol-1-yl)butyl)amino)isoindoline-1,3-dione;   2-(2,6-dioxonineridin-3-yl)-4-(((5-ethynylpyridin-2-yl)methyl)amino)isoindoline-1,3-dione;   2-(2,6-dioxopiperidin-3-yl)-4-((2-(2-(4-ethynyl-1H-pyrazol-1-yl)ethoxy)ethyl)amino)isoindoline-1,3-dione;   2-(2,6-dioxopiperidin-3-yl)-4-((3-(4-ethynyl-1H-pyrazol-1-yl)propyl)amino)isoindoline-1,3-dione;   3-(4-((4-(4-ethynyl-1H-pyrazol-1-yl)butyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   2-(2,6-dioxopiperidin-3-yl)-4-(5-(5-ethynyl-1H-imidazol-2-yl)pent-1-yn-1-yl)isoindoline-1,3-dione;   3-(4-((4-(4-ethynyl-1H-imidazol-1-yl)butyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   2-(2,6-dioxopiperidin-3-yl)-4-(5-(4-ethynyl-1H-pyrazol-1-yl)pent-1-yn-1-yl)isoindoline-1,3-dione;   3-(4-(5-(5-ethynyl-1-methyl-1H-imidazol-2-yl)pent-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   2-(2,6-dioxopiperidin-3-yl)-4-((4-(4-ethynyl-1H-pyrazol-1-yl)butyl)amino)isoindoline-1,3-dione;   3-(4-((4-(4-ethynyl-1H-pyrazol-1-yl)butyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(5-(4-ethynyl-1H-pyrazol-1-yl)pent-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(5-(4-ethynyl-1H-pyrazol-1-yl)pentyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(5-(4-ethynyl-1H-imidazol-1-yl)pent-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   2-(2,6-dioxopiperidin-3-yl)-4-(5-(4-ethynyl-1H-imidazol-1-yl)pent-1-yn-1-yl)isoindoline-1,3-dione;   2-(2,6-dioxopiperidin-3-yl)-4-(5-(4-ethynyl-1H-imidazol-1-yl)pent-1-yn-1-yl)isoindoline-1,3-dione;   2-(2,6-dioxonineridin-3-yl)-4-(4-(4-ethynyl-1H-pyrazol-1-yl) butoxy)isoindoline-1,3-dione;   3-(4-(5-(4-ethynyl-1H-1,2,3-triazol-1-yl)pent-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(5-(4-ethynyl-1H-1,2,3-triazol-1-yl)pentyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-((4-(4-ethynyl-1H-1,2,3-triazol-1-yl)butyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4(4-((6-ethynylpyridin-3-yl)butyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   2-(2,6-dioxopiperidin-3-yl)-4-(4-(6-ethynylpyridin-3-yl)butoxy)isoindoline-1,3-dione;   3-(4-(4-((6-ethynylpyridin-3-yl)oxy)butyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(5-(6-ethynylpyridin-3-yl)pent-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(4-(6-ethynylpyridin-3-yl)oxy)but-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-((4-(5-ethynylpyridin-2-yl)butyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(5-(5-ethynylpyridin-2-yl)pent-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(5-(5-ethynyl-1H-imidazol-1-yl)pent-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(4-(3-(4-ethynyl-1H-pyrazol-1-yl)propyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   2-(2,6-dioxopiperidin-3-yl)-4-(4-(3-(4-ethynyl-1H-pyrazol-1-yl)propyl)piperazin-1-yl)isoindoline-1,3-dione;   3-(4-(4-(3-(4-ethynyl-1H-pyrazol-1-yl)propyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   2-(2,6-dioxopiperidin-3-yl)-4-(4-(3-(4-ethynyl-1H-pyrazol-1-yl)propyl)piperazin-1-yl)isoindoline-1,3-dione;   3-(4-((1-((6-ethynylpyridin-3-yl)methyl)azetidin-3-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(((1-((6-ethynylpyridin-3-yl)methyl)azetidin-3-yl)methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(2-(1-((6-ethynylpyridin-3-yl)methyl)azetidin-3-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   2-(2,6-dioxopiperidin-3-yl)-4-((1-((6-ethynylpyridin-3-yl)methyl)azetidin-3-yl)methoxy)isoindoline-1,3-dione;   2-(2,6-dioxopiperidin-3-yl)-4-(((1-((6-ethynylpyridin-3-yl)methyl)azetidin-3-yl)methyl)amino)isoindoline-1,3-dione;   2-(2,6-dioxopiperidin-3-yl)-4-(2-(1-((6-ethynylpyridin-3-yl)methyl)azetidin-3-yl)ethyl)isoindoline-1,3-dione;   3-(4-((1-((6-ethynylpyridin-3-yl)methyl)azetidin-3-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(((1-((6-ethynylpyridin-3-yl)methyl)azetidin-3-yl)methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(2-(1-((6-ethynylpyridin-3-yl)methyl)azetidin-3-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   2-(2,6-dioxopiperidin-3-yl)-4-((1-((6-ethynylpyridin-3-yl)methyl)azetidin-3-yl)methoxy)isoindoline-1,3-dione;   2-(2,6-dioxopiperidin-3-yl)-4-(((1-((6-ethynylpyridin-3-yl)methyl)azetidin-3-yl)methyl)amino)isoindoline-1,3-dione;   2-(2,6-dioxopiperidin-3-yl)-4-(2-(1-((6-ethynylpyridin-3-yl)methyl)azetidin-3-yl)ethyl)isoindoline-1,3-dione;   3-(4-((1-((6-ethynylpyridin-3-yl)methyl)piperidin-4-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(((1-((6-ethynylpyridin-3-yl)methyl)piperidin-4-yl)methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(2-(1-((6-ethynylpyridin-3-yl)methyl)piperidin-4-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   2-(2,6-dioxopiperidin-3-yl)-4-((1-((6-ethynylpyridin-3-yl)methyl)piperidin-4-yl)methoxy)isoindoline-1,3-dione;   2-(2,6-dioxopiperidin-3-yl)-4-(((1-((6-ethynylpyridin-3-yl)methyl)piperidin-4-yl)methyl)amino)isoindoline-1,3-dione;   2-(2,6-dioxopiperidin-3-yl)-4-(2-(1-((6-ethynylpyridin-3-yl)methyl)piperidin-4-yl)ethyl)isoindoline-1,3-dione;   3-(4-((1-((6-ethynylpyridin-3-yl)methyl)piperidin-4-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(((1-((6-ethynylpyridin-3-yl)methyl)piperidin-4-yl)methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(2-(1-((6-ethynylpyridin-3-yl)methyl)piperidin-4-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   2-(2,6-dioxopiperidin-3-yl)-4-((1-((6-ethynylpyridin-3-yl)methyl)piperidin-4-yl)methoxy)isoindoline-1,3-dione;   2-(2,6-dioxopiperidin-3-yl)-4-(((1-((6-ethynylpyridin-3-yl)methyl)piperidin-4-yl)methyl)amino)isoindoline-1,3-dione;   2-(2,6-dioxopiperidin-3-yl)-4-(2-(1-((6-ethynylpyridin-3-yl)methyl)piperidin-4-yl)ethyl)isoindoline-1,3-dione;   3-(4-((4-(2-(4-ethynyl-1H-pyrazol-1-yl)ethyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   2-(2,6-dioxopiperidin-3-yl)-4-((4-(2-(4-ethynyl-1H-pyrazol-1-yl)ethyl)piperazin-1-yl)methyl)isoindoline-1,3-dione;   3-(4-((4-(2-(4-ethynyl-1H-pyrazol-1-yl)ethyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   2-(2,6-dioxopiperidin-3-yl)-4-((4-(2-(4-ethynyl-1H-pyrazol-1-yl)ethyl)piperazin-1-yl)methyl)isoindoline-1,3-dione;   3-(4-((1-(2-(4-ethynyl-1H-pyrazol-1-yl)ethyl)piperidin-4-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-((1-(2-(4-ethynyl-1H-pyrazol-1-yl)ethyl)piperidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-((1-(2-(4-ethynyl-1H-pyrazol-1-yl)ethyl)piperidin-4-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   2-(2,6-dioxopiperidin-3-yl)-4-((1-(2-(4-ethynyl-1H-pyrazol-1-yl)ethyl)piperidin-4-yl)oxy)isoindoline-1,3-dione;   2-(2,6-dioxopiperidin-3-yl)-4-((1-(2-(4-ethynyl-1H-pyrazol-1-yl)ethyl)piperidin-4-yl)amino)isoindoline-1,3-dione;   2-(2,6-dioxopiperidin-3-yl)-4-((1-(2-(4-ethynyl-1H-pyrazol-1-yl)ethyl)piperidin-4-yl)methyl)isoindoline-1,3-dione;   3-(4-((1-(2-(4-ethynyl-1H-pyrazol-1-yl)ethyl)piperidin-4-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-((1-(2-(4-ethynyl-1H-pyrazol-1-yl)ethyl)piperidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-((1-(2-(4-ethynyl-1H-pyrazol-1-yl)ethyl)piperidin-4-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   2-(2,6-dioxopiperidin-3-yl)-4-((1-(2-(4-ethynyl-1H-pyrazol-1-yl)ethyl)piperidin-4-yl)oxy)isoindoline-1,3-dione;   2-(2,6-dioxopiperidin-3-yl)-4-((1-(2-(4-ethynyl-1H-pyrazol-1-yl)ethyl)piperidin-4-yl)amino)isoindoline-1,3-dione;   2-(2,6-dioxopiperidin-3-yl)-4-((1-(2-(4-ethynyl-1H-pyrazol-1-yl)ethyl)piperidin-4-yl)methyl)isoindoline-1,3-dione;   3-(4-(5-(4-ethynyl-1H-pyrazol-1-yl)pentyl)-5-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(5-(4-ethynyl-1H-pyrazol-1-yl)pentyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(5-(4-ethynyl-1H-pyrazol-1-yl)pentyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(4-(4-ethynyl-1H-pyrazol-1-yl)butoxy)-5-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(4-(4-ethynyl-1H-pyrazol-1-yl)butoxy)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(4-(4-ethynyl-1H-pyrazol-1-yl)butoxy)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-((4-(4-ethynyl-1H-pyrazol-1-yl)butyl)amino)-5-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-((4-(4-ethynyl-1H-pyrazol-1-yl)butyl)amino)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-((4-(4-ethynyl-1H-pyrazol-1l-yl)buyl)amino)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-((1-(2-(4-ethynyl-1H-pyrazol-1-yl)ethyl)piperidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   2-(2,6-dioxopiperidin-3-yl)-4-((1-(2-(4-ethynyl-1H-pyrazol-1-yl)ethyl)piperidin-4-yl)amino)isoindoline-1,3-dione;   3-(4-((1-(2-(4-ethynyl-1H-pyrazol-1-yl)ethyl)piperidin-4-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   2-(2,6-dioxopiperidin-3-yl)-4-((1-(2-(4-ethynyl-1H-pyrazol-1-yl)ethyl)piperidin-4-yl)oxy)isoindoline-1,3-dione;   3-(4-((1-(2-(4-ethynyl-1H-pyrazol-1-yl)ethyl)-1H-imidazol-4-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(((1-(2-(4-ethynyl-1H-pyrazol-1-yl)ethyl)-1H-imidazol-4-yl)methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   2-(2,6-dioxopiperidin-3-yl)-4-((1-(2-(4-ethynyl-1H-pyrazol-1-yl)ethyl)-1H-imidazol-4-yl)methoxy)isoindoline-1,3-dione;   2-(2,6-dioxopiperidin-3-yl)-4-(((1-(2-(4-ethynyl-1H-pyrazol-1-yl)ethyl)-1H-imidazol-4-yl)methyl)amino)isoindoline-1,3-dione;   3-(4-((4-((4-ethynyl-1H-pyrazol-1-yl)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-((4-((4-ethynyl-1H-pyrazol-1-yl)methyl)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   2-(2,6-dioxopiperidin-3-yl)-4-((4-((4-ethynyl-1H-pyrazol-1-yl)methyl)benzyl)oxy)isoindoline-1,3-dione;   2-(2,6-dioxopiperidin-3-yl)-4-((4-((4-ethynyl-1H-pyrazol-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione;   3-(4-(4-(4-ethynyl-1H-pyrazol-1-yl)butoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(5-((4-(4-ethynyl-1H-pyrazol-1-yl)butyl)amino)-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione;   2-(2,6-dioxopiperidin-3-yl)-4-((1-(3-(4-ethynyl-1H-pyrazol-1-yl)propyl)piperidin-4-yl)amino)isoindoline-1,3-dione;   2-(2,6-dioxopiperidin-3-yl)-4-((1-(2-(4-ethynyl-1H-pyrazol-1-yl)ethyl)piperidin-4-yl)amino)isoindoline-1,3-dione;   2-(2,6-dioxopiperidin-3-yl)-4-(4-(2-(4-ethynyl-1H-pyrazol-1-yl)ethyl)piperazin-1-yl)isoindoline-1,3-dione;   3-(4-(((1-(2-(4-ethynyl-1H-pyrazol-1-yl)ethyl)-1H-imidazol-4-yl)methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   2-(2,6-dioxopiperidin-3-yl)-4-(4-(3-(4-ethynyl-1H-pyrazol-1-yl)propyl)piperazin-1-yl)isoindoline-1,3-dione;   3-(4-((4-((4-ethynyl-1H-pyrazol-1-yl)methyl)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(((1-(2-(4-ethynyl-1H-pyrazol-1-yl)ethyl)-1H-imidazol-5-yl)methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   2-(2,6-dioxopiperidin-3-yl)-4-(4-(4-(4-ethynyl-1H-pyrazol-1-yl)butyl)piperazin-1-yl)isoindoline-1,3-dione;   3-(4-(((1-(3-(4-ethynyl-1H-pyrazol-1-yl)propyl)-1H-imidazol-4-yl)methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(((1-((5-ethynylpyridin-2-yl)methyl)piperidin-4-yl)methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(((1-((6-ethynylpyridin-3-yl)methyl)azetidin-3-yl)methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   2-(2,6-dioxopiperidin-3-yl)-4-((1-(2-(4-ethynyl-1H-pyrazol-1-yl)ethyl)piperidin-4-yl)oxy)isoindoline-1,3-dione;   3-(4-((1-(2-(4-ethynyl-1H-pyrazol-1-yl)ethyl)-1H-imidazol-4-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-((1-(3-(4-ethynyl-1H-pyrazol-1-yl)propyl)piperidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   2-(2,6-dioxopiperidin-3-yl)-4-((1-(3-(4-ethynyl-1H-pyrazol-1-yl)propyl)piperidin-4-yl)oxy)isoindoline-1,3-dione;   3-(4-((1-(3-(4-ethynyl-1H-pyrazol-1-yl)propyl)-1H-imidazol-4-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-((1-(4-(4-ethynyl-1H-pyrazol-1-yl)butyl)piperidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   2-(2,6-dioxopiperidin-3-yl)-4-((1-(4-(4-ethynyl-1H-pyrazol-1-yl)butyl)piperidin-4-yl)oxy)isoindoline-1,3-dione;   3-(4-(((1-(2-(4-ethynyl-1H-pyrazol-1-yl)ethyl)-1H-imidazol-4-yl)methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(((1-(3-(4-ethynyl-1H-pyrazol-1-yl)propyl)-1H-imidazol-4-yl)methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(((1-(4-(4-ethynyl-1H-pyrazol-1-yl)butyl)-1H-imidazol-4-yl)methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-((4-((4-ethynyl-1H-pyrazol-1-yl)methyl)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-((3-((4-ethynyl-1H-pyrazol-1-yl)methyl)cyclobutyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(((1-(2-(4-ethynyl-1H-pyrazol-1-yl)ethyl)piperidin-4-yl)methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(((1-(2-(4-ethynyl-1H-pyrazol-1-yl)ethyl)azetidin-3-yl)methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-((1-(2-(4-ethynyl-1H-pyrazol-1-yl)ethyl)azetidin-3-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-((1-(3-(4-ethynyl-1H-pyrazol-1-yl)propyl)azetidin-3-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(4-(3-(4-ethynyl-1H-pyrazol-1-yl)propyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(3-aminopropyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(4-aminobutyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(1-oxo-4-(piperidin-4-ylamino)isoindolin-2-yl)piperidine-2,6-dione;   3-(4-(azetidin-3-ylamino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(1-oxo-4-((piperidin-4-ylmethyl)amino)isoindolin-2-yl)piperidine-2,6-dione;   3-(4-((azetidin-3-ylmethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-((1-(2-aminoethyl)piperidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-((1-(2-aminoethyl)azetidin-3-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(((1-(2-aminoethyl)piperidin-4-yl)methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(((1-(2-aminoethyl)azetidin-3-yl)methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(2-(4-aminocyclohexyl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(1-oxo-4-(2-(piperidin-4-yl)ethyl)isoindolin-2-yl)piperidine-2,6-dione;   4-(4-(2-aminoethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;   (2S,4R)-1-((S)-2-(5-aminopentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;   (2S,4R)-1-((S)-2-(3-(2-(2-aminoethoxy)ethoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;   (2S,4R)-1-((S)-1-amino-14-(tert-butyl)-12-oxo-3,6,9-trioxa-13-azapentadecan-15-oyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;   3-(5-(5-aminopent-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(6-(5-aminopent-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-26-dione;   3-(5-(5-aminopentyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(6-(5-aminopentyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(((1r,4r)-4-aminocyclohexyl)ethynyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-((Z)-2-((1r,4r)-4-aminocyclohexyl)vinyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(2-((1r,4s)-4-aminocyclohexyl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(6-(4-aminopiperidin-1-yl)-6-oxohex-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(5-(4-aminopiperidin-1-yl)-5-oxopent-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   N-((1r,4r)-4-aminocyclohexyl)-6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)hex-5-ynamide;   N-((1r,4r)-4-aminocyclohexyl)-5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pent-4-ynamide;   3-(4-(3-(2-(2-aminoethoxy)ethoxy)prop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)prop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(4-aminobutoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-((1-(3-aminopropyl)-1H-pyrazol-4-yl)ethynyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(2-(1-(3-aminopropyl)-1H-pyrazol-4-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-((1-(3-aminopropyl)-1H-imidazol-5-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(2-(1-(3-aminopropyl)-1H-imidazol-5-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-((1-(3-aminopropyl)piperidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-(7-(4-aminopiperidin-1-yl)hept-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   3-(4-((17-amino-3,6,9,12,15-pentaoxaheptadecyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;   1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12,15,18,21,24-octaoxaheptacosan-27-oic acid;   14-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxatetradecanoic acid;   2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide;   1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxapentadecan-15-oic acid;   3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propanoic acid;   (2S,4R)-1-((S)-1-amino-17-(tert-butyl)-15-oxo-3,6,9,12-tetraoxa-16-azaoctadecan-18-oyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-2-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; and 1-amino-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-3,6,9,12-tetraoxapentadecan-15-amide.   
     
     
         77 . (canceled) 
     
     
         78 . A method of preparing a compound having Formula IX: 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt or solvate thereof, 
         the method comprising: 
         (1) condensing a compound having Formula I: 
       
       
         
           
           
               
               
           
         
         wherein; 
         B is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         X is selected from the group consisting of —C≡C—, —O—, —N(R 2a )—, 
       
       
         
           
           
               
               
           
         
         wherein the —N(R 2b )— of 
       
       
         
           
           
               
               
           
         
       
       is attached to L and the —O— of 
       
         
           
           
               
               
           
         
       
       is attached to L
 L is selected from the group consisting of alkylenyl, heteroalkylenyl, -A-(CH 2 ) m —W—(CH 2 ) n —, and —(CH 2 ) r —W—(CH 2 ) u —O—(CH 2 ) v —; 
 A is absent; or 
 A is heteroarylenyl; 
 W is selected from the group consisting of phenylenyl, heteroarylenyl, heterocyclenyl, and cycloalkylenyl; 
 m is 0, 1, 2, 3, 4, 5, 6, or 7; 
 n is 0, 1, 2, 3, 4, 5, 6, 7, or 8; 
 r is 0, 1, 2 or 3; 
 u is 0, 1, 2, or 3; 
 v is 1, 2, 3, or 4; 
 Y is selected from the group consisting of —C≡C—, —CH 2 —, —O—, —N(R 2c )—, —C(═O)N(R 2d )—, —N(R 2e )C(═O)CH 2 O—, and —N(R 2e )C(═O)CH 2 N(R 2f )—; or 
 Y is absent; 
 wherein the carboxamide nitrogen atom of —N(R 2e )C(═O)CH 2 O— and —N(R 2e )C(═O)CH 2 N(R 2f )—, and the carbon atom of —C(═O)N(R 2d )— is attached to L; 
 R 2a , R 2b , R 2c , R 2d , R 2e , and R 2f  are each independently selected from the group consisting of hydrogen and C 1-4  alkyl; 
 B is selected from the group consisting of: 
 
       
         
           
           
               
               
           
         
         A is selected from the group consisting of —C(R 16a )═ and —N═; 
         A 2  is selected from the group consisting of —C(R 16b )═ and —N═; 
         A 3  is selected from the group consisting of —C(R 16c )═ and —N═; 
         Z is selected from the group consisting of —CH 2  and —C(═O)—; 
         R 5  is selected from the group consisting of hydrogen, methyl, and fluoro; 
         R 16a  is selected from the group consisting of hydrogen, halo, and C 1-4  alkyl; 
         R 16b  is selected from the group consisting of hydrogen, halo, and C 1-4  alkyl; and 
         R 16c  is selected from the group consisting of hydrogen, halo, and C 1-4  alkyl, with proviso that the compound having Formula I is not any of the compounds of Table 6, 
         with compound having Formula X;
   T-X 3 X 
 
         wherein; 
         T is a monovalent radical of a target protein inhibitor; 
         X 3  is selected from the group consisting of —C(═O)OH and -LG; and 
         LG is a leaving group, 
         (2) isolating the compound having Formula IX. 
       
     
     
         79 - 81 . (canceled)
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