Cereblon ligands and bifunctional compounds comprising the same

Abstract

The description relates to cereblon E3 ligase binding compounds, including bifunctional compounds comprising the same, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds according to the present disclosure. In particular, the description provides compounds, which contain on one end a ligand which binds to the cereblon E3 ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. Compounds can be synthesized that exhibit a broad range of pharmacological activities consistent with the degradation/inhibition of targeted polypeptides of nearly any type.

What is claimed is: 
     
         1 . A cereblon E3 ubiquitin ligase binding compound having a chemical structure selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein:
 W is independently selected from CH 2 , CHR, C═O, SO 2 , NH, and N-alkyl; 
 Q 1 , Q 2 , Q 3 , Q 4 , Qs are each independently represent a carbon C or N substituted with a group independently selected from R′, N or N-oxide; 
 R 1  is selected from absent, H, OH, CN, C1-C3 alkyl, C═O; 
 R 2  is selected from the group absent, H, OH, CN, C1-C3 alkyl, CHF 2 , CF 3 , CHO, C(═O)NH 2 ; 
 R 3  is selected from absent, H, alkyl (e.g., C1-C6 or C1-C3 alkyl), substituted alkyl (e.g., substituted C1-C6 or C1-C3 alkyl), alkoxy (e.g., C1-C6 or C1-C3 alkoxyl), substituted alkoxy (e.g., substituted C1-C6 or C1-C3 alkoxyl); 
 R 4  is selected from H, alkyl, substituted alkyl; 
 R 5  and R 6  are each independently H, halogen, C(═O)R′; CN, OH, CF 3 ; 
 X is C, CH, C═O, or N; 
 X 1  is C═O, N, CH, or CH 2 ; 
 R′ is selected from H, halogen, amine, alkyl (e.g., C1-C3 alkyl), substituted alkyl (e.g., substituted C1-C3 alkyl), alkoxy (e.g., C1-C3 alkoxyl), substituted alkoxy (e.g., substituted C1-C3 alkoxyl), NR 2 R 3 , C(═O)OR 2 , optionally substituted phenyl; 
 n is 0-4; and 
    is a single or double bond. 
 
     
     
         2 . A bifunctional compound having the chemical structure:
   CLM-L-PTM,   or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or prodrug thereof,   wherein:
 the PTM is a small molecule comprising a protein targeting moiety; 
 the L is a bond or a chemical linking moiety covalently coupling the CLM and the PTM; and 
 the CLM is a small molecule cereblon E3 ubiquitin ligase binding moiety that binds or targets an cereblon E3 ubiquitin ligase and has a chemical structure selected from the group consisting of: 
   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein:
 W is independently selected from CH 2 , CHR, C═O, SO 2 , NH, and N-alkyl; 
 Q 1 , Q 2 , Q 3 , Q 4 , Qs are each independently represent a carbon C or N substituted with a group independently selected from R′, N or N-oxide; 
 R 1  is selected from absent, H, OH, CN, C1-C3 alkyl, C═O; 
 R 2  is selected from the group absent, H, OH, CN, C1-3 alkyl, CHF 2 , CF 3 , CHO, C(═O)NH 2 ; 
 R 3  is selected from absent, H, alkyl (e.g., C1-C6 or C1-C3 alkyl), substituted alkyl (e.g., substituted C1-C6 or C1-C3 alkyl), alkoxy (e.g., C1-C6 or C1-C3 alkoxyl), substituted alkoxy (e.g., substituted C1-C6 or C1-C3 alkoxyl); 
 R 4  is selected from H, alkyl, substituted alkyl; 
 R 5  and R 6  are each independently H, halogen, C(═O)R′; CN, OH, CF 3 ; 
 X is C, CH, C═O, or N; 
 X 1  is C═O, N, CH, or CH 2 ; 
 R′ is selected from H, halogen, amine, alkyl (e.g., C1-C3 alkyl), substituted alkyl (e.g., substituted C1-C3 alkyl), alkoxy (e.g., C1-C3 alkoxyl), substituted alkoxy (e.g., substituted C1-C3 alkoxyl), NR 2 R 3 , C(═O)OR 2 , optionally substituted phenyl; 
 n is 0-4; and 
    is a single or double bond 
 
     
     
         3 . The bifunctional compound of  claim 2 , wherein the CLM is linked to the PTM, the chemical linker group (L), or a combination thereof via W, X, R 1 , R 2 , R 3 , R 4 , R′, Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 . 
     
     
         4 . The bifunctional compound of  claim 2 , wherein the PTM is a moiety that binds Brd4, Tau Protein, Estrogen Receptor (ER), or Androgen Receptor (AR). 
     
     
         5 . The bifunctional compound of  claim 2 , wherein the compound further comprises a second E3 ubiquitin ligase binding moiety coupled through a linker group. 
     
     
         6 . The bifunctional compound of  claim 5 , wherein the second E3 ubiquitin ligase binding moiety binds or targets an E3 ubiquitin ligase selected from the group consisting of Von Hippel-Lindau (VLM), cereblon (CLM), mouse double-minute homolog2 (MLM), and inhibitors of apoptosis proteins (ILM). 
     
     
         7 . The bifunctional compound of  claim 2 , wherein the CLM is represented by a chemical structure selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein Rn comprises a functional group or an atom. 
     
     
         8 . The bifunctional compound of  claim 2 , wherein the CLM is represented by a chemical structure selected by: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         9 . The compound of  claim 2 , wherein the linker (L) comprises a chemical structural unit represented by the formula:
   -(A L )q-   
       wherein:
 (A L ) q  is a group which is connected to at least one of the CLM, the PTM, or a combination thereof; 
 q is an integer greater than or equal to 1; 
 each A L  is independently selected from the group consisting of, a bond, CR L1 R L2 , O, S, SO, SO 2 , NR L3 , SO 2 NR L3 , SONR L3 , CONR L3 , NR L3 CONR L4 , NR L3 SO 2 NR L4 , CO, CR L1 ═CR L2 , C≡C, SiR L1 R L2 , P(O)R L1 , P(O)OR L1 , NR L3 C(═NCN)NR L4 , NR L3 C(═NCN), NR L3 C(═CNO 2 )NR L4 , C 3-11 cycloalkyl optionally substituted with 0-6 R L1  and/or R L2  groups, C 3-11 heterocyclyl optionally substituted with 0-6 R L1  and/or R L2  groups, aryl optionally substituted with 0-6 R L1  and/or R L2  groups, heteroaryl optionally substituted with 0-6 R L1  and/or R L2  groups, where R L1  or R L2 , each independently are optionally linked to other groups to form cycloalkyl and/or heterocyclyl moiety, optionally substituted with 0-4 R L5  groups; and 
 R L1 , R L2 , R L3 , R L4  and R L5  are, each independently, H, halo, C 1-8 alkyl, OC 1-8 alkyl, SC 1-8 alkyl, NHC 1-8 alkyl, N(C 1-8 alkyl) 2 , C 3-11 cycloalkyl, aryl, heteroaryl, C 3-11 heterocyclyl, OC 1-8 cycloalkyl, SC 1-8 cycloalkyl, NHC 1-8 cycloalkyl, N(C 1-8 cycloalkyl) 2 , N(C 1-8 cycloalkyl)(C 1-8 alkyl), OH, NH 2 , SH, SO 2 C 1-8 alkyl, P(O)(OC 1-8 alkyl)(C 1-8 alkyl), P(O)(OC 1-8 alkyl) 2 , CC—C 1-8 alkyl, C≡CH, CH═CH(C 1-8 alkyl), C(C 1-8 alkyl)═CH(C 1-8 alkyl), C(C 1-8 alkyl)═C(C 1-8 alkyl) 2 , Si(OH) 3 , Si(C 1-8 alkyl) 3 , Si(OH)(C 1-8 alkyl) 2 , COC 1-8 alkyl, CO 2 H, halogen, CN, CF 3 , CHF 2 , CH 2 F, NO 2 , SF 5 , SO 2 NHC 1-8 alkyl, SO 2 N(C 1-8 alkyl) 2 , SONHC 1-8 alkyl, SON(C 1-8 alkyl) 2 , CONHC 1-8 alkyl, CON(C 1-8 alkyl) 2 , N(C 1-8 alkyl)CONH(C 1-8 alkyl), N(C 1-8 alkyl)CON(C 1-8 alkyl) 2 , NHCONH(C 1-8 alkyl), NHCON(C 1-8 alkyl) 2 , NHCONH 2 , N(C 1-8 alkyl)SO 2 NH(C 1-8 alkyl), N(C 1-8 alkyl) SO 2 N(C 1-8 alkyl) 2 , NH SO 2 NH(C 1-8 alkyl), NH SO 2 N(C 1-8 alkyl) 2 , NH SO 2 NH 2 . 
 
     
     
         10 . The bifunctional compound of  claim 9 , wherein L is selected from the group consisting of:
 —N(R)—(CH2) m —O(CH2) n —O(CH2) o —O(CH2) p —O(CH2) q —O(CH2) r -OCH2-,   —O—(CH2) m —O(CH2) n —O(CH2) o —O(CH2) p —O(CH2) q —O(CH2) r -OCH2-,   —O—(CH2) m —O(CH2) n —O(CH2) o —O(CH2) p —O(CH2) q —O(CH2) r —O—;   —N(R)—(CH2) m —O(CH2) n —O(CH2) o —O(CH2) p —O(CH2) q —O(CH2) r —O—;   —(CH2) m —O(CH2) n —O(CH2) o —O(CH2) p —O(CH2) q —O(CH2) r —O—;   —(CH2) m —O(CH2) n —O(CH2) o —O(CH2) p —O(CH2) q —O(CH2) r -OCH2-;   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein
 m, n, o, p, q, and r of the linker are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20; 
 when the number is zero, there is no N—O or O—O bond 
 R of the linker is H, methyl and ethyl; 
 X of the linker is H and F 
 
       
         
           
           
               
               
           
         
         where m of the linker can be 2, 3, 4, 5 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         where each n and m of the linker can independently be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20. 
       
     
     
         11 . The bifunctional compound of 9, wherein L is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein each m and n is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20. 
     
     
         12 . The bifunctional compound of  claim 9 , wherein the linker (L) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein each m, n, o, p, q, and r is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. 
     
     
         13 . The bifunctional compound of  claim 9 , wherein the linker (L) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         14 . The bifunctional compound of  claim 9 , wherein the linker (L) is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein:
 “X” in above structures can be linear chain with atoms ranging from 2 to 14, and the mentioned chain can contain heteroatoms such as oxygen; and 
 “Y” in above structures can be O, N, S(O) n  (n=0, 1, 2). 
 
     
     
         15 . The bifunctional compound of  claim 2 , wherein the linker (L) comprises a structure selected from: 
       
         
           
           
               
               
           
         
       
       wherein:
 W L1  and W L2  are each independently a 4-8 membered ring with 0-4 heteroatoms, optionally substituted with R Q , each R Q  is independently a H, halo, OH, CN, CF 3 , C 1 -C 6  alkyl (linear, branched, optionally substituted), C 1 -C 6  alkoxy (linear, branched, optionally substituted), or 2 R Q  groups taken together with the atom they are attached to, form a 4-8 membered ring system containing 0-4 heteroatoms; 
 Y L1  is each independently a bond, C 1 -C 6  alkyl (linear, branched, optionally substituted) and optionally one or more C atoms are replaced with O; or C 1 -C 6  alkoxy (linear, branched, optionally substituted); 
 n is 0-10; and 
 a dashed line indicates the attachment point to the PTM or CLM moieties. 
 
     
     
         16 . The bifunctional compound of  claim 2 , wherein the linker comprises a structure selected from: 
       
         
           
           
               
               
           
         
       
       wherein:
 W L1  and W L2  are each independently aryl, heteroaryl, cyclic, heterocyclic, C 1-6  alkyl, bicyclic, biaryl, biheteroaryl, or biheterocyclic, each optionally substituted with R Q , each R Q  is independently a H, halo, OH, CN, CF 3 , hydroxyl, nitro, C≡CH, C 2-6  alkenyl, C 2-6  alkynyl, C 1 -C 6  alkyl (linear, branched, optionally substituted), C 1 -C 6  alkoxy (linear, branched, optionally substituted), OC 1-3 alkyl (optionally substituted by 1 or more —F), OH, NH 2 , NR Y1 R Y2 , CN, or 2 R Q  groups taken together with the atom they are attached to, form a 4-8 membered ring system containing 0-4 heteroatoms; 
 Y L1  is each independently a bond, NR YL1 , O, S, NR YL2 , CR YL1 R YL2 , C═O, C═S, SO, SO 2 , C 1 -C 6  alkyl (linear, branched, optionally substituted) and optionally one or more C atoms are replaced with O; C 1 -C 6  alkoxy (linear, branched, optionally substituted); 
 Q L  is a 3-6 membered alicyclic or aromatic ring with 0-4 heteroatoms, optionally bridged, optionally substituted with 0-6 R Q , each R Q  is independently H, C 1-6  alkyl (linear, branched, optionally substituted by 1 or more halo, C 1-6  alkoxyl), or 2 R Q  groups taken together with the atom they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms); 
 R YL1 , R YL2  are each independently H, OH, C 1-6  alkyl (linear, branched, optionally substituted by 1 or more halo, C 1-6  alkoxyl), or R 1 , R 2  together with the atom they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms); 
 n is 0-10; and 
 a dashed line indicates the attachment point to the PTM or CLM moieties. 
 
     
     
         17 . The bifunctional compound of  claim 9 , wherein the linker (L) is a polyethylenoxy group optionally substituted with aryl or phenyl comprising from 1 to 10 ethylene glycol units. 
     
     
         18 . The bifunctional compound of  claim 2 , wherein the PTM a chemical structure that includes at least one of (A), (B), (C), (D), (E), or a combination thereof:
 (A) an estrogen receptor binding moiety (EBM) comprising PTM-I or PTM-II:   
       
         
           
           
               
               
           
         
         
           wherein:
 X PTM  is O or C═O; 
 each of X PTM1  and X PTM2  is independently selected from N or CH; 
 R PTM1  is independently selected from OH, O(CO)R PTM , O-lower alkyl, wherein R PTM  is an alkyl or aryl group in the ester; 
 R PTM2  and R PTM4  are independently selected from H, OH, halogen, CN, CF 3 , SO 2 -alkyl, O-lower alkyl; 
 R PTM3  and R PTM5  are independently selected from H, halogen; 
 PTM-I has at least one R PTM2  and at least one R PTM3  on each respective rings; and the 
 
         
       
       
         
           
           
               
               
           
         
       
       indicates the site of attachment of at least one of the linker, the CLM, a CLM′, or a combination thereof;
 (B) an estrogen receptor protein targeting moiety represented by the chemical structure: 
 
       
         
           
           
               
               
           
         
         
           wherein:
 each X PTM  is independently CH, N; 
    indicates the site of attachment of at least one of the linker, the CLM, a CLM′, or a combination thereof; 
 each R PTM1  is independently OH, halogen, alkoxy, methoxy, ethoxy, O(CO)R PTM , wherein the substitution can be a mono-, di- or tri-substitution and the R PTM  is alkyl or cycloalkyl group with 1 to 6 carbons or aryl groups; 
 each R PTM2  is independently H, halogen, CN, CF 3 , liner or branched alkyl, alkoxy, methoxy, ethoxy, wherein the substitution can be mono- or di-substitution; 
 each R PTM3  is independently H, halogen, wherein the substitution can be mono- or di-substitution; and 
 R PTM4  is a H, alkyl, methyl, ethyl. 
 
         
         (C) an androgen receptor (AR) binding moiety (ABM) comprises a structure selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         
           wherein:
 W 1  is aryl, heteroaryl, bicyclic, or biheterocyclic, each independently substituted by 1 or more H, halo, hydroxyl, nitro, CN, C≡CH, C 1-6  alkyl (linear, branched, optionally substituted; for example, optionally substituted by 1 or more halo, C 1-6  alkoxyl), C 1-6  alkoxyl (linear, branched, optionally substituted; for example, optionally substituted by 1 or more halo), C 2-6  alkenyl, C 2-6  alkynyl, or CF 3 ; 
 Y 1 , Y 2  are each independently NR Y1 , O, S, SO2, heteroaryl, or aryl; 
 Y 3 , Y 4 , Y 5  are each independently a bond, O, NR Y2 , CR Y1 R Y2 , C═O, C═S, SO, SO 2 , heteroaryl, or aryl; 
 Q is a 3-6 membered ring with 0-4 heteroatoms, optionally substituted with 0-6 R Q , each R Q , is independently H, C 1-6  alkyl (linear, branched, optionally substituted, for example, optionally substituted by 1 or more halo, C 1-6  alkoxyl), halogen, C 1-6  alkoxy, or 2 R Q  groups taken together with the atom they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms); 
 R 1 , R 2 , R a , R b , R Y1 , R Y2  are each independently H, C 1-6  alkyl (linear, branched, optionally substituted; for example, optionally substituted by 1 or more halo, C 1-6  alkoxyl), halogen, C 1-6  alkoxy, cyclic, heterocyclic or R 1 , R 2  together with the atom they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms); 
 W 2  is a bond, C 1-6  alkyl, C 1-6  heteroalkyl, O, aryl, heteroaryl, alicyclic, heterocyclic, biheterocyclic, biaryl, or biheteroaryl, each optionally substituted by 1-10 R W2 ; 
 each R W2  is independently H, halo, C 1-6  alkyl (linear or branched optionally substituted; for example, optionally substituted by 1 or more F), —OR W2A , C 3-6  cycloalkyl, C 4-6  cycloheteroalkyl, C 1-6  alkyl (optionally substituted), heterocyclic (optionally substituted), aryl (optionally substituted), or heteroaryl (optionally substituted), bicyclic heteroaryl or aryl, OC 1-3 alkyl (optionally substituted; for example, optionally substituted by 1 or more —F), OH, NH 2 , NR Y1 R Y2 , CN; 
 R W2A  is H, C 1-6  alkyl (linear, branched), or C 1-6  heteroalkyl (linear, branched), each optionally substituted by a cycloalkyl, cycloheteroalkyl, aryl, heterocyclic, heteroaryl, halo, or OC 1-3 alkyl; and 
 the dashed line indicates the site of attachment of at least one of the linker, the CLM, a CLM′, or a combination thereof; 
 
         
         (D) a Tau protein targeting moiety that is represented by at least one of Formula I-XI: 
       
       
         
           
           
               
               
           
         
         
           wherein:
 A, B, C, D, E, and F are independently selected from an optionally substituted 5- or 6-membered aryl or heteroaryl ring, an optionally substituted 4- to 7-membered cycloalkyl or a heterocycloalkyl, where contact between circles indicates ring fusion; 
 L PTM  is selected from a bond, an alkyl, an alkenyl or an alkynyl, optionally interrupted by one or more rings (i.e., cycloalkyl, heterocycloalkyl, aryl or heteroaryl), or one or more functional groups selected from the groups —O—, —S—, —NR 1   PTM —, —N═N—, —S(O)—, —SO 2 —, —C(O)—, —NHC(O)—, —C(O)NH—, —NHSO 2 —, —NHC(O)NH—, —NHC(O)O—, or —OC(O)NH—, wherein the said functional group is optionally located at either end of the linker; and 
 R 1   PTM  is selected from H or alkyl. 
 
         
         (E) a tricyclic diazepine or azepine BET/BRD4 binding ligand comprising a group according to the chemical structure PTM-a: 
       
       
         
           
           
               
               
           
         
         
           wherein:
 Y 1 , Y 2  and Y 3  are independently selected from the group of carbon, nitrogen or oxygen and together with the atoms to form an aromatic fused ring. 
 A and B are independently selected from the group of a 5-membered aromatic ring, a 6-membered aromatic ring, a heteroaromatic ring, a carbocyclic, a thiophene a pyrrole ring, a pyridine, a pyrimidine, a pyrazine, a pyrazole ring each optionally substituted with alkyl, alkoxy, halogen, an aromatic and a heteroaromatic ring; wherein ring A is fused to the central azepine (Y1=C) or diazepine (Y1=N) moiety; and 
 Z1 is selected from the group of methyl or analkyl group, and 
 wherein the dashed line indicates the site of attachment of at least one of the linker, the CLM, a CLM′, or a combination thereof. 
 
         
       
     
     
         19 . The bifunctional compound of  claim 2 , wherein the PTM has a structure selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein R or Linker is a bond or a chemical linker moiety coupling the CLM to the PTM, including pharmaceutically acceptable salt forms thereof. 
       
     
     
         20 . The bifunctional compound of  claim 2 , wherein the compound is selected from the group consisting of PROTAC-1 through PROTAC-112. 
     
     
         21 . A composition comprising an effective amount of a bifunctional compound of any of  claim 2 , and a pharmaceutically acceptable carrier. 
     
     
         22 . The composition of  claim 21 , wherein the composition further comprises at least one of additional bioactive agent or another bifunctional compound of  claim 2 . 
     
     
         23 . The composition of  claim 22 , wherein the additional bioactive agent is anti-cancer agent, an anti-neurodegenerative agent, an antimicrobial agent, an antiviral agent, an anti-HIV agent, or an antifungal agent. 
     
     
         24 . A method of treating a disease or disorder in a subject, the method comprising administering a composition comprising an effective amount of at least one compound of  claim 2  and a pharmaceutically acceptable carrier, additive, and/or excipient to a subject in need thereof, wherein the compound is effective in treating or ameliorating at least one symptom of the disease or disorder. 
     
     
         25 . The method of  claim 24 , wherein the disease or disorder is associated with the accumulation and/or aggregation of the target protein. 
     
     
         26 . The method of  claim 24 , wherein the disease or disorder is selected from the group consisting of asthma, autoimmune diseases such as multiple sclerosis, various cancers, ciliopathies, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, mental retardation, mood disorder, obesity, refractive error, infertility, Angelman syndrome, Canavan disease, Coeliac disease, Charcot-Marie-Tooth disease, Cystic fibrosis, Duchenne muscular dystrophy, Haemochromatosis, Haemophilia, Klinefelter's syndrome, Neurofibromatosis, Phenylketonuria, Polycystic kidney disease, (PKD1) or 4 (PKD2) Prader-Willi syndrome, Sickle-cell disease, Tay-Sachs disease, Turner syndrome. 
     
     
         27 . The method of  claim 24 , wherein the disease or disorder is selected from the group consisting of Alzheimer's disease, Amyotrophic lateral sclerosis (Lou Gehrig's disease), Anorexia nervosa, Anxiety disorder, Atherosclerosis, Attention deficit hyperactivity disorder, Autism, Bipolar disorder, Chronic fatigue syndrome, Chronic obstructive pulmonary disease, Crohn's disease, Coronary heart disease, Dementia, Depression, Diabetes mellitus type 1, Diabetes mellitus type 2, Epilepsy, Guillain-Barré syndrome, Irritable bowel syndrome, Lupus, Metabolic syndrome, Multiple sclerosis, Myocardial infarction, Obesity, Obsessive-compulsive disorder, Panic disorder, Parkinson's disease, Psoriasis, Rheumatoid arthritis, Sarcoidosis, Schizophrenia, Stroke, Thromboangiitis obliterans, Tourette syndrome, Vasculitis. 
     
     
         28 . The method of  claim 24 , wherein the disease or disorder is selected from the group consisting of aceruloplasminemia, Achondrogenesis type II, achondroplasia, Acrocephaly, Gaucher disease type 2, acute intermittent porphyria, Canavan disease, Adenomatous Polyposis Coli, ALA dehydratase deficiency, adenylosuccinate lyase deficiency, Adrenogenital syndrome, Adrenoleukodystrophy, ALA-D porphyria, ALA dehydratase deficiency, Alkaptonuria, Alexander disease, Alkaptonuric ochronosis, alpha 1-antitrypsin deficiency, alpha-1 proteinase inhibitor, emphysema, amyotrophic lateral sclerosis Alström syndrome, Alexander disease, Amelogenesis imperfecta, ALA dehydratase deficiency, Anderson-Fabry disease, androgen insensitivity syndrome, Anemia Angiokeratoma Corporis Diffusum, Angiomatosis retinae (von Hippel-Lindau disease) Apert syndrome, Arachnodactyly (Marfan syndrome), Stickler syndrome, Arthrochalasis multiplex congenital (Ehlers-Danlos syndrome#arthrochalasia type) ataxia telangiectasia, Rett syndrome, primary pulmonary hypertension, Sandhoff disease, neurofibromatosis type II, Beare-Stevenson cutis gyrata syndrome, Mediterranean fever, familial, Benjamin syndrome, beta-thalassemia, Bilateral Acoustic Neurofibromatosis (neurofibromatosis type II), factor V Leiden thrombophilia, Bloch-Sulzberger syndrome (incontinentia pigmenti), Bloom syndrome, X-linked sideroblastic anemia, Bonnevie-Ullrich syndrome (Turner syndrome), Bourneville disease (tuberous sclerosis), prion disease, Birt-Hogg-Dubé syndrome, Brittle bone disease (osteogenesis imperfecta), Broad Thumb-Hallux syndrome (Rubinstein-Taybi syndrome), Bronze Diabetes/Bronzed Cirrhosis (hemochromatosis), Bulbospinal muscular atrophy (Kennedy's disease), Burger-Grutz syndrome (lipoprotein lipase deficiency), CGD Chronic granulomatous disorder, Campomelic dysplasia, biotinidase deficiency, Cardiomyopathy (Noonan syndrome), Cri du chat, CAVD (congenital absence of the vas deferens), Caylor cardiofacial syndrome (CBAVD), CEP (congenital erythropoietic porphyria), cystic fibrosis, congenital hypothyroidism, Chondrodystrophy syndrome (achondroplasia), otospondylomegaepiphyseal dysplasia, Lesch-Nyhan syndrome, galactosemia, Ehlers-Danlos syndrome, Thanatophoric dysplasia, Coffin-Lowry syndrome, Cockayne syndrome, (familial adenomatous polyposis), Congenital erythropoietic porphyria, Congenital heart disease, Methemoglobinemia/Congenital methaemoglobinaemia, achondroplasia, X-linked sideroblastic anemia, Connective tissue disease, Conotruncal anomaly face syndrome, Cooley's Anemia (beta-thalassemia), Copper storage disease (Wilson's disease), Copper transport disease (Menkes disease), hereditary coproporphyria, Cowden syndrome, Craniofacial dysarthrosis (Crouzon syndrome), Creutzfeldt-Jakob disease (prion disease), Cockayne syndrome, Cowden syndrome, Curschmann-Batten-Steinert syndrome (myotonic dystrophy), Beare-Stevenson cutis gyrata syndrome, primary hyperoxaluria, spondyloepimetaphyseal dysplasia (Strudwick type), muscular dystrophy, Duchenne and Becker types (DBMD), Usher syndrome, Degenerative nerve diseases including de Grouchy syndrome and Dejerine-Sottas syndrome, developmental disabilities, distal spinal muscular atrophy, type V, androgen insensitivity syndrome, Diffuse Globoid Body Sclerosis (Krabbe disease), Di George's syndrome, Dihydrotestosterone receptor deficiency, androgen insensitivity syndrome, Down syndrome, Dwarfism, erythropoietic protoporphyria Erythroid 5-aminolevulinate synthetase deficiency, Erythropoietic porphyria, erythropoietic protoporphyria, erythropoietic uroporphyria, Friedreich's ataxia, familial paroxysmal polyserositis, porphyria cutanea tarda, familial pressure sensitive neuropathy, primary pulmonary hypertension (PPH), Fibrocystic disease of the pancreas, fragile X syndrome, galactosemia, genetic brain disorders, Giant cell hepatitis (Neonatal hemochromatosis), Gronblad-Strandberg syndrome (pseudoxanthoma elasticum), Gunther disease (congenital erythropoietic porphyria), haemochromatosis, Hallgren syndrome, sickle cell anemia, hemophilia, hepatoerythropoietic porphyria (HEP), Hippel-Lindau disease (von Hippel-Lindau disease), Huntington's disease, Hutchinson-Gilford progeria syndrome (progeria), Hyperandrogenism, Hypochondroplasia, Hypochromic anemia, Immune system disorders, including X-linked severe combined immunodeficiency, Insley-Astley syndrome, Kennedy's syndrome, Jackson-Weiss syndrome, Joubert syndrome, Lesch-Nyhan syndrome, Jackson-Weiss syndrome, Kidney diseases, including hyperoxaluria, Klinefelter's syndrome, Kniest dysplasia, Lacunar dementia, Langer-Saldino achondrogenesis, ataxia telangiectasia, Lynch syndrome, Lysyl-hydroxylase deficiency, Machado-Joseph disease, Metabolic disorders, including Kniest dysplasia, Marfan syndrome, Movement disorders, Mowat-Wilson syndrome, cystic fibrosis, Muenke syndrome, Multiple neurofibromatosis, Nance-Insley syndrome, Nance-Sweeney chondrodysplasia, Niemann-Pick disease, Noack syndrome (Pfeiffer syndrome), Osler-Weber-Rendu disease, Peutz-Jeghers syndrome, Polycystic kidney disease, polyostotic fibrous dysplasia (McCune-Albright syndrome), Peutz-Jeghers syndrome, Prader-Labhart-Willi syndrome, hemochromatosis, primary hyperuricemia syndrome (Lesch-Nyhan syndrome), primary pulmonary hypertension, primary senile degenerative dementia, prion disease, progeria (Hutchinson Gilford Progeria Syndrome), progressive chorea, chronic hereditary (Huntington) (Huntington's disease), progressive muscular atrophy, spinal muscular atrophy, propionic acidemia, protoporphyria, proximal myotonic dystrophy, pulmonary arterial hypertension, PXE (pseudoxanthoma elasticum), Rb (retinoblastoma), Recklinghausen disease (neurofibromatosis type I), Recurrent polyserositis, Retinal disorders, Retinoblastoma, Rett syndrome, RFALS type 3, Ricker syndrome, Riley-Day syndrome, Roussy-Levy syndrome, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Li-Fraumeni syndrome, sarcoma, breast, leukemia, and adrenal gland (SBLA) syndrome, sclerosis tuberose (tuberous sclerosis), SDAT, SED congenital (spondyloepiphyseal dysplasia congenita), SED Strudwick (spondyloepimetaphyseal dysplasia, Strudwick type), SEDc (spondyloepiphyseal dysplasia congenita) SEMD, Strudwick type (spondyloepimetaphyseal dysplasia, Strudwick type), Shprintzen syndrome, Skin pigmentation disorders, Smith-Lemli-Opitz syndrome, South-African genetic porphyria (variegate porphyria), infantile-onset ascending hereditary spastic paralysis, Speech and communication disorders, sphingolipidosis, Tay-Sachs disease, spinocerebellar ataxia, Stickler syndrome, stroke, androgen insensitivity syndrome, tetrahydrobiopterin deficiency, beta-thalassemia, Thyroid disease, Tomaculous neuropathy (hereditary neuropathy with liability to pressure palsies), Treacher Collins syndrome, Triplo X syndrome (triple X syndrome), Trisomy 21 (Down syndrome), Trisomy X, VHL syndrome (von Hippel-Lindau disease), Vision impairment and blindness (Alström syndrome), Vrolik disease, Waardenburg syndrome, Warburg Sjo Fledelius Syndrome, Weissenbacher-Zweymüller syndrome, Wolf-Hirschhorn syndrome, Wolff Periodic disease, Weissenbacher-Zweymüller syndrome and Xeroderma pigmentosum. 
     
     
         29 . The method of  claim 24 , further comprising an additional bioactive agent. 
     
     
         30 . The method of  claim 29 , wherein the additional bioactive agent is at least one of an anti-cancer agent, an anti-neurodegenerative agent, an antimicrobial agent, an antiviral agent, an anti-HIV agent, an antifungal agent, or a combination thereof. 
     
     
         31 . The method of  claim 30 , wherein said anticancer agent is selected from the group consisting of everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, a FLT-3 inhibitor, a VEGFR inhibitor, an EGFR TK inhibitor, an aurora kinase inhibitor, a PIK-1 modulator, a Bcl-2 inhibitor, an HDAC inhibitor, a c-MET inhibitor, a PARP inhibitor, a Cdk inhibitor, an EGFR TK inhibitor, an IGFR-TK inhibitor, an anti-HGF antibody, a PI3 kinase inhibitors, an AKT inhibitor, an mTORC1/2 inhibitor, a JAK/STAT inhibitor, a checkpoint-1 or 2 inhibitor, a focal adhesion kinase inhibitor, a Map kinase kinase (mek) inhibitor, a VEGF trap antibody, pemetrexed, erlotinib, dasatanib, nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, batabulin, ofatumumab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR 1  KRX-0402, lucanthone, LY 317615, neuradiab, vitespan, Rta 744, Sdx 102, talampanel, atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, liposomal doxorubicin, 5′-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib; PD0325901, AZD-6244, capecitabine, L-Glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole, DES(diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258,); 3-[5-(methylsulfonylpiperadinemethyl)-indolylj-quinolone, vatalanib, AG-013736, AVE-0005, the acetate salt of [D-Ser(Bu t) 6, Azgly 10] (pyro-Glu-His-Trp-Ser-Tyr-D-Ser(Bu t)-Leu-Arg-Pro-Azgly-NH 2  acetate [C 59 H 84 N 18 Oi 4 -(C 2 H 4 O 2 ) X  where x=1 to 2.4], goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF antibody, erbitux, EKB-569, PKI-166, GW-572016, Ionafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoyl analide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrine, anagrelide, L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, adriamycin, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gleevac, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deooxyuridine, cytosine arabinoside, 6-mecaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat, COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin diftitox, gefitinib, bortezimib, paclitaxel, cremophor-free paclitaxel, docetaxel, epithilone B, BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, topotecan, PTK787/ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating factor, zolendronate, prednisone, cetuximab, granulocyte macrophage colony-stimulating factor, histrelin, pegylated interferon alfa-2a, interferon alfa-2a, pegylated interferon alfa-2b, interferon alfa-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-transretinoic acid, ketoconazole, interleukin-2, megestrol, immune globulin, nitrogen mustard, methylprednisolone, ibritgumomab tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium 89, casopitant, netupitant, an NK-1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa, darbepoetin alfa and mixtures thereof. 
     
     
         32 . A method for inducing degradation of a target protein in a cell comprising administering an effective amount of a compound of  claim 2  to the cell, wherein the compound effectuates degradation of the target protein. 
     
     
         33 . A method for treating cancer, said method comprising administering a composition comprising an effective amount of a compound of  claim 2  to a patient in need thereof, wherein the composition is effectuates for the treatment or alleviation of at least one symptom of cancer in the patient. 
     
     
         34 . The method of  claim 33 , wherein the cancer is squamous-cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas, cancer of the bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemias; benign and malignant lymphomas, particularly Burkitt's lymphoma and Non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative diseases; multiple myeloma, sarcomas, including Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor or teratocarcinomas, T-lineage Acute lymphoblastic Leukemia (T-ALL), T-lineage lymphoblastic Lymphoma (T-LL), Peripheral T-cell lymphoma, Adult T-cell Leukemia, Pre-B ALL, Pre-B Lymphomas, Large B-cell Lymphoma, Burkitts Lymphoma, B-cell ALL, Philadelphia chromosome positive ALL and Philadelphia chromosome positive CML.