Mdm2-based modulators of proteolysis and associated methods of use

Abstract

The description relates to MDM2 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 invention. In particular, the description provides compounds, which contain on one end a ligand which binds to the MDM2 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.

1 . A compound having a chemical structure comprising of:
   PTM-L-MLM   wherein MLM is a MDM2 E3 ubiquitin ligase binding moiety, PTM is a protein targeting moiety, and L is a linker coupling the MLM to the PTM, and wherein the PTM binds to a targeted protein having a function or activity selected from the group consisting of: structural protein, regulatory, growth factor, receptor, cytoskeletal, hormonal, enzymatic, nucleic acid binding, immunological, contractile, storage, transportation, signal transduction, catalytic activity, protein binding, aromatase activity, lipase, protease, nuclease, motor activity, helicase activity, metabolism, antioxidant activity, proteolysis, biosynthesis, kinase, oxidoreductase, transferase, hydrolase, lyase, isomerase, ligase, enzyme regulator, signal transducer, protein or lipid binding, cell motility, membrane fusion, cell communication, cell growth or differentiation, cell division, response to stimulus, cell adhesion, apoptosis, transport, secretion, electron transport, ion channel, chaperone or chaperone regulator, nucleic acid binding activity, transcription regulator, extracellular organization and biogenesis, and translation regulator, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or prodrug thereof.   
     
     
         2 . The compound of  claim 1 , wherein the PTM binds to a protein selected from the group consisting of B7.1, B7, TINFR1m, TNFR2, NADPH oxidase, Bcl, Bax, apotosis pathway proteins, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase, PDE IV phosphodiesterase, PDE I, PDEII, PDEIII, squalene cyclase inhibitor, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclo-oxygenase 1, cyclo-oxygenase 2, 5HT receptor, dopamine receptor, G Protein, Gq, histamine receptor, 5-lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside phosphorylase, GAPDH trypanosomal, glycogen phosphorylase, carbonic anhydrase, chemokine receptor, JAK, STAT, RXR, HIV 1 protease, HIV 1 integrase, influenza, neuramimidase, hepatitis B reverse transcriptase, sodium channel, multi drug resistance (MDR), protein P-glycoprotein (and MRP), tyrosine kinase, CD23, CD124, tyrosine kinase p56 lck, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-alphaR, ICAM1, Cat+ channel, VCAM, VLA-4 integrin, selectin, CD40/CD40L, receptor, inosine monophosphate dehydrogenase, p38 MAP Kinase, JNK, Ras, Raf, ERK, FLT-3, KSR1, SMARCA, SMARCA2, interleukin-1 converting enzyme, caspase, HCV, NS3 protease, HCV NS3 RNA helicase, glycinamide ribonucleotide formyl transferase, rhinovirus 3C protease, herpes simplex virus-1 (HSV-I), protease, cytomegalovirus (CMV) protease, poly (ADP-ribose) polymerase, cyclin dependent kinase, growth factor, growth factor receptor, receptor tyrosine kinase, cytokine, GPCR, vascular endothelial growth factor, EGF, EGFR, HGF, HGFR, VEGF, VEGFR, Wnt, TNF-α, TPO, TCGF, PGF, NT-3, NT-4, TGF, TGF-β, oxytocin receptor, microsomal transfer protein inhibitor, bile acid transport inhibitor, 5 alpha reductase, angiotensin 11, glycine receptor, noradrenaline reuptake receptor, endothelin receptor, neuropeptide Y and receptor, estrogen receptor, androgen receptor, adenosine receptor, adenosine kinase and AMP deaminase, purinergic receptor, P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7, an E1, E2 or E3 ubiquitin ligase, VHL, cereblon, p53, farnesyltransferase, geranylgeranyl transferase, TrkA a receptor for NGF, beta-amyloid, tyrosine kinase Flk-IIKDR, vitronectin receptor, integrin receptor, Her-21 neu, telomerase, cytosolic phospholipaseA2 and EGF receptor tyrosine kinase, ecdysone 20-monooxygenase, GABA gated chloride channel, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel, chloride channel, Acetyl-CoA carboxylase, adenylosuccinate synthetase, protoporphyrinogen oxidase, enolpyruvylshikimate-phosphate synthase, haloalkane halogenase inhibitors, Hsp90, kinase, MDM2, human BET Bromodomain-containing protein, HDAC, EZH2, human lysine methyltransferase, and aryl hydrocarbon receptor (AHR). 
     
     
         3 . The compound of  claim 1 , wherein the PTM binds to a protein selected from the group consisting of a kinases, enzymes, transporters, nuclear hormone receptors, non-nuclear hormone receptors, G-protein coupled receptors (GPCRs), transcription factors, and epigenetic targets particularly, a human BET Bromodomain-containing protein (BRD), Brd4, Ras, Raf, MDM2, androgen receptor (AR) and estrogen receptor (ER), EZH2 and JNK. 
     
     
         4 . A compound having a structure selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein,
 PTM is a protein targeting moiety that binds a target protein, and L is a linker coupling the PTM to the molecule shown; 
 X is selected from the group consisting of carbon, oxygen, sulfur, sulfoxide, sulfone, and N—R a ; 
 R a  is independently H or an alkyl group with carbon number 1 to 6; 
 Y and Z are independently carbon or nitrogen; 
 A, A′ and A″ are independently selected from C, N, O or S, can also be one or two atoms forming a fused bycyclic ring, or a 6,5- and 5,5-fused aromatic bicyclic group; 
 R 1 , R 2  are independently selected from the group consisting of an aryl or heteroaryl group, a heteroaryl group having one or two heteroatoms independently selected from sulfur or nitrogen, wherein the aryl or heteroaryl group can be mono-cyclic or bi-cyclic, or unsubstituted or substituted with one to three substituents independently selected from the group consisting of: halogen, —CN, C1 to C6 alkyl group, C3 to C6 cycloalkyl, —OH, alkoxy with 1 to 6 carbons, fluorine substituted alkoxy with 1 to 6 carbons, sulfoxide with 1 to 6 carbons, sulfone with 1 to 6 carbons, ketone with 2 to 6 carbons, amides with 2 to 6 carbons, and dialkyl amine with 2 to 6 carbons; 
 R 3 , R 4  are independently selected from the group consisting of H, methyl and C1 to C6 alkyl; 
 R 5  is selected from the group consisting of an aryl or heteroaryl group, a heteroaryl group having one or two heteroatoms independently selected from sulfur or nitrogen, wherein the aryl or heteroaryl group can be mono-cyclic or bi-cyclic, or unsubstituted or substituted with one to three substituents independently selected from the group consisting of: halogen, —CN, C1 to C6 alkyl group, C3 to C6 cycloalkyl, —OH, alkoxy with 1 to 6 carbons, fluorine substituted alkoxy with 1 to 6 carbons, sulfoxide with 1 to 6 carbons, sulfone with 1 to 6 carbons, ketone with 2 to 6 carbons, amides with 2 to 6 carbons, dialkyl amine with 2 to 6 carbons, alkyl ether (C2 to C6), alkyl ketone (C3 to C6), morpholinyl, alkyl ester (C3 to C6), alkyl cyanide (C3 to C6); 
 R 6  is H or —C(═O)R b , wherein 
 R b  is selected from the group consisting of alkyl, cycloalkyl, mono-, di- or tri-substituted aryl or heteroaryl, 4-morpholinyl, 1-(3-oxopiperazunyl), 1-piperidinyl, 4-N—R c -morpholinyl, 4-R c -1-piperidinyl, and 3-R c -1-piperidinyl, wherein 
 R c  is selected from the group consisting of alkyl, fluorine substituted alkyl, cyano alkyl, hydroxyl-substituted alkyl, cycloalkyl, alkoxyalkyl, amide alkyl, alkyl sulfone, alkyl sulfoxide, alkyl amide, aryl, heteroaryl, mono-, bis- and tri-substituted aryl or heteroaryl, CH2CH2R d , and CH2CH2CH2R d , wherein 
 R d  is selected from the group consisting of alkoxy, alkyl sulfone, alkyl sulfoxide, N-substituted carboxamide, —NHC(O)-alkyl, —NH—SO 2 -alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl; 
 R 7  is selected from the group consisting of H, C1 to C6 alkyl, cyclic alkyl, fluorine substituted alkyl, cyano substituted alkyl, 5- or 6-membered hetero aryl or aryl, substituted 5- or 6-membered hetero aryl or aryl; 
 R 8  is selected from the group consisting of —R e —C(O)—R f , —R e -alkoxy, —R e -aryl, —R e -heteroaryl, and —R e —C(O)—R f —C(O)—R g , wherein: 
 R e  is an alkylene with 1 to 6 carbons, or a bond; 
 R f  is a substituted 4- to 7-membered heterocycle; 
 R g  is selected from the group consisting of aryl, hetero aryl, substituted aryl or heteroaryl, and 4- to 7-membered heterocycle; 
 R 9  is selected from the group consisting of a mono-, bis- or tri-substituent on the fused bicyclic aromatic ring in Formula (A-3), wherein the substitutents are independently selected from the group consistin of halogen, alkene, alkyne, alkyl, unsubstituted or substituted with Cl or F; 
 R 10  is selected from the group consistin of an aryl or heteroaryl group, wherein the heteroaryl group can contain one or two heteroatoms as sulfur or nitrogen, aryl or heteroaryl group can be mono-cyclic or bi-cyclic, the aryl or heteroaryl group can be unsubstituted or substituted with one to three substituents, including a halogen, F, Cl, —CN, alkene, alkyne, C1 to C6 alkyl group, C1 to C6 cycloalkyl, —OH, alkoxy with 1 to 6 carbons, fluorine substituted alkoxy with 1 to 6 carbons, sulfoxide with 1 to 6 carbons, sulfone with 1 to 6 carbons, ketone with 2 to 6 carbons; 
 R 11  is —C(O)—N(R h )(R i ), wherein R h  and R i  are selected from groups consisting of the following: H, C1 to C6 alkyl, alkoxy substituted alkyl, sulfone substituted alkyl, aryl, heterol aryl, mono-, bis- or tri-substituted aryl or hetero aryl, alkyl carboxylic acid, heteroaryl carboxylic acid, alkyl carboxylic acid, fluorine substituted alkyl carboxylic acid, aryl substituted cycloalkyl, hetero aryl substituted cycloalkyl; wherein 
 R h  and R i  are independently selected from the group consisting of H, connected to form a ring, 4-hydroxycyclohehexane; mono- and di-hydroxy substituted alkyl (C3 to C6); 3-hydroxycyclobutane; phenyl-4-carboxylic acid, and substituted phenyl-4-carboxylic acid; 
 R 12  and R 13  are independently selected from H, lower alkyl (C1 to C6), lower alkenyl (C2 to C6), lower alkynyl (C2 to C6), cycloalkyl (4, 5 and 6-membered ring), substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, 5- and 6-membered aryl and heteroaryl, R12 and R13 can be connected to form a 5- and 6-membered ring with or without substitution on the ring; 
 R 14  is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl; 
 R 15  is CN; 
 R 16  is selected from the group consisting of C1-6 alkyl, C1-6 cycloalkyl, C2-6 alkenyl, C1-6 alkyl or C3-6 cycloalkyl with one or multiple hydrogens replaced by fluorine, alkyl or cycloalkyl with one CH 2  replaced by S(═O), —S, or —S(═O) 2 , alkyl or cycloalkyl with terminal CH 3  replaced by S(═O) 2 N(alkyl)(alkyl), —C(═O)N(alkyl)(alkyl), —N(alkyl)S(═O) 2 (alkyl), —C(═O)2(allkyl), —O(alkyl), C1-6 alkyl or alkyl-cycloalkyl with hydron replaced by hydroxyl group, a 3 to 7 membered cycloalkyl or heterocycloalkyl, optionally containing a —(C=0)-group, or a 5 to 6 membered aryl or heteroaryl group, which heterocycloalkyl or heteroaryl group can contain from one to three heteroatoms independently selected from O, N or S, and the cycloalkyl, heterocycloalkyl, aryl or heteroaryl group can be unsubstituted or substituted with from one to three substituents independently selected from halogen, C1-6 alkyl groups, hydroxylated C1-6 alkyl, C1-6 alkyl containing thioether, ether, sulfone, sulfoxide, fluorine substituted ether or cyano group; 
 R 17  is selected from the group consisting of (CH 2 )nC(O)NR k R l , wherein R k  and R l  are independently selected from H, C1-6 alkyl, hydrxylated C1-6 alkyl, C1-6 alkoxy alkyl, C1-6 alkyl with one or multiple hydrogens replaced by fluorine, C1-6 alkyl with one carbon replaced by S(O), S(O)(O), C1-6 alkoxyalkyl with one or multiple hydrogens replaced by fluorine, C1-6 alkyl with hydrogen replaced by a cyano group, 5 and 6 membered aryl or heteroaryl, aklyl aryl with alkyl group containing 1-6 carbons, and alkyl heteroaryl with alkyl group containing 1-6 carbons, wherein the aryl or heteroaryl group can be further substituted; 
 R 18  is selected from the group consisting of substituted aryl, heteroaryl, alkyl, cycloalkyl, the substitution is preferably —N(C1-4 alkyl)(cycloalkyl), —N(C1-4 alkyl)alkyl-cycloalkyl, and —N(C1-4 alkyl)[(alkyl)-(heterocycle-substituted)-cycloalkyl]; 
 R 19  is selected from the group consisting of aryl, heteroaryl, bicyclic heteroaryl, and these aryl or hetroaryl groups can be substituted with halogen, C1-6 alkyl, C1-6 cycloalkyl, CF 3 , F, CN, alkyne, alkyl sulfone, the halogen substitution can be mon- bis- or tri-substituted; 
 R 20  and R 21  are independently selected from C1-6 alkyl, C1-6 cycloalkyl, C1-6 alkoxy, hydoxylated C1-6 alkoxy, and fluorine substituted C1-6 alkoxy, wherein R 20  and R 21  can further be connected to form a 5, 6 and 7-membered cyclic or heterocyclic ring, which can further be substituted; 
 R 22  is selected from the group consisting of H, C1-6 alkyl, C1-6 cycloalkyl, carboxylic acid, carboxylic acid ester, amide, reverse amide, sulfonamide, reverse sulfonamide, N-acyl urea, nitrogen-containing 5-membered heterocycle, the 5-membered heterocycles can be further substituted with C1-6 alkyl, alkoxy, fluorine-substituted alkyl, CN, and alkylsulfone; 
 R 23  is selected from aryl, heteroaryl, —O-aryl, —O-heteroaryl, —O-alkyl, —O-alkyl-cycloalkyl, —NH-alkyl, —NH-alkyl-cycloalkyl, —N(H)-aryl, —N(H)-heteroaryl, —N(alkyl)-aryl, —N(alkyl)-heteroaryl, the aryl or heteroaryl groups can be substituted with halogen, C1-6 alkyl, hydoxylated C1-6 alkyl, cycloalkyl, fluorine-substituted C1-6 alkyl, CN, alkoxy, alkyl sulfone, amide and sulfonamide; 
 R 24  is selected from the group consisting of —CH2-(C1-6 alkyl), —CH2-cycloalkyl, —CH2-aryl, CH2-heteroaryl, where alkyl, cycloalkyl, aryl and heteroaryl can be substituted with halogen, alkoxy, hydoxylated alkyl, cyano-substituted alkyl, cycloalyl and substituted cycloalky; 
 R 25  is selected from the group consisting of C1-6 alkyl, C1-6 alkyl-cycloalkyl, alkoxy-substituted alkyl, hydroxylated alkyl, aryl, heteroaryl, substituted aryl or heteroaryl, 5,6, and 7-membered nitrogen-containing saturated heterocycles, 5,6-fused and 6,6-fused nitrogen-containing saturated heterocycles and these saturated heterocycles can be substituted with C1-6 alkyl, fluorine-substituted C1-6 alkyl, alkoxy, aryl and heteroaryl group; 
 R 26  is selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, the alkyl or cycloalkyl can be substituted with —OH, alkoxy, fluorine-substituted alkoxy, fluorine-substituted alkyl, —NH 2 , —NH-alkyl, NH—C(O)alkyl, —NH—S(O) 2 -alkyl, and —S(O) 2 -alkyl; 
 R 27  is selected from the group consisting of aryl, heteroaryl, bicyclic heteroaryl, wherein the aryl or heteroaryl groups can be substituted with C1-6 alkyl, alkoxy, NH2, NH-alkyl, halogen, or —CN, and the substitution can be independently mono-, bis- and tri-substitution; 
 R 28  is selected from the group consisting of aryl, 5 and 6-membered heteroaryl, bicyclic heteroaryl, cycloalkyl, saturated heterocycle such as piperidine, piperidinone, tetrahydropyran, N-acyl-piperidine, wherein the cycloalkyl, saturated heterocycle, aryl or heteroaryl can be further substituted with —OH, alkoxy, mono-, bis- or tri-substitution including halogen, —CN, alkyl sulfone, and fluorine substituted alkyl groups; and 
 R 1″  is selected from the group consisting of alkyl, aryl substituted alkyl, alkoxy substituted alkyl, cycloalkyl, aryl-substituted cycloalkyl, and alkoxy substituted cycloalkyl, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or prodrug thereof. 
 
     
     
         5 . The compound of  claim 4 , wherein the heterocycles in R f  and R g  are independently selected from the group consisting of substituted pyrrolidine, substituted piperidine, and substituted piperizine. 
     
     
         6 . The compound of  claim 4 , wherein the R 9  substituents are selected from Cl and F. 
     
     
         7 . The compound of  claim 4 , wherein the R 10  substituents are selected from H, F and Cl. 
     
     
         8 . The compound of  claim 4 , wherein R h  and R i  are selected from the group consisting of:
 (i) R h  is H, and R i  is 4-hydroxycyclohehexane;   (ii) R h  is H, and R i  is mono- and di-hydroxy substituted lower alkyl (C3 to C6);   (iii) R h  is H, and R i  is 3-hydroxycyclobutane; and   (iv) R h  is H, and R i  is phenyl-4-carboxylic acid, substituted phenyl-4-carboxylic acid.   
     
     
         9 . The compound of  claim 4 , wherein the R 18  substitution is selected from the group consisting of —N(C1-4 alkyl)(cycloalkyl), —N(C1-4 alkyl)alkyl-cycloalkyl, and —N(C1-4 alkyl) [(alkyl)-(heterocycle-substituted)-cycloalkyl]. 
     
     
         10 . The compound of  claim 4 , wherein the R 28  saturated heterocycle is selected from piperidine, piperidinone, tetrahydropyran, and N-acyl-piperidine. 
     
     
         11 . The compound of  claim 4 , wherein the compound has a structure selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein R1′ and R2′ are independently selected from the group consisting of F, Cl, Br, I, acetylene, CN, CF 3  and NO 2 ; 
         R3′ is selected from the group consisting of —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 F, —OCH 2 CH 2 OCH 3 , and —OCH(CH 3 ) 2 ; 
         R4′ and R6′ are independently selected from the group consisting of H, halogen, —CH 3 , —CF 3 , —OCH 3 , —C(CH 3 ) 3 , —CH(CH 3 ) 2 , -cyclopropyl, —CN, —C(CH 3 ) 2 OH, —C(CH 3 ) 2 OCH 2 CH 3 , —C(CH 3 ) 2 CH 2 OH, —C(CH 3 ) 2 CH 2 OCH 2 CH 3 , —C(CH 3 ) 2 CH 2 OCH 2 CH 2 OH, —C(CH 3 ) 2 CH 2 OCH 2 CH 3 , —C(CH 3 ) 2 CN, —C(CH 3 ) 2 C(O)CH 3 , —C(CH 3 ) 2 C(O)NHCH 3 , —C(CH 3 ) 2 C(O)N(CH 3 ) 2 , —SCH 3 , —SCH 2 CH 3 , —S(O) 2 CH 3 , —S(O 2 )CH 2 CH 3 , —NHC(CH 3 ) 3 , —N(CH 3 ) 2 , pyrrolidinyl, and 4-morpholinyl; and 
         R5′ is selected from the group consisting of halogen, -cyclopropyl, —S(O) 2 CH 3 , —S(O) 2 CH 2 CH 3 , 1-pyrrolidinyl, —NH 2 , —N(CH 3 ) 2 , and —NHC(CH 3 ) 3 , or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or prodrug thereof. 
       
     
     
         12 . The compound of  claim 11 , wherein the linker is attached to at least one of R1′, R2′, R3′, R4′, R5′, R6′, or a combination thereof. 
     
     
         13 . The compound of  claim 11 , wherein R6′ is independently selected from the group consisting of H, 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein * indicates the point of attachment of the linker. 
     
     
         14 . The compound of  claim 4 , wherein the compound has a structure selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein
 R 7′  is a member selected from the group consisting of halogen, mono-, and di- or tri-substituted halogen; 
 R 8′  is selected from the group consisting of H, —F, —Cl, —Br, —I, —CN, —NO 2 , ethylnyl, cyclopropyl, methyl, ethyl, isopropyl, vinyl, methoxy, ethoxy, isopropoxy, —OH, other C1-6 alkyl, other C1-6 alkenyl, and C1-6 alkynyl, mono-, di- or tri-substituted; 
 R 9′  is selected from the group consistin of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, hetero aryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted cycloalkenyl; 
 Z is selected from the group consistin of H, —OCH 3 , —OCH 2 CH 3 , and halogen; 
 R 10′  and R 11′  are each independently selected from the group consisting of H, (CH 2 ) n —R′, (CH 2 ) n —NR′R″, (CH 2 ) n —NR′COR″, (CH 2 ) n —NR′SO 2 R″, (CH 2 ) n —COOH, (CH 2 ) n —COOR′, (CH) n —CONR′R″, (CH 2 ) n —OR′, (CH 2 ) n —SR′, (CH 2 ) n —SOR′, (CH 2 ) n —CH(OH)—R′, (CH 2 ) n —COR′, (CH 2 ) n —SO 2 R′, (CH 2 ) n —SONR′R″, (CH 2 ) n —SO 2 NR′R″, (CH 2 CH 2 O) m —(CH 2 ) n —R′, (CH 2 CH 2 O) m —(CH 2 ) n —OH, (CH 2 CH 2 O) m —(CH 2 ) n —OR′, (CH 2 CH 2 O) m —(CH 2 ) n —NR′R″, (CH 2 CH 2 O) m —(CH 2 ) n —NR′COR″, (CH 2 CH 2 O) m (CH 2 ) n —NR′SO 2 R″, (CH 2 CH 2 O) m (CH 2 ) n —COOH, (CH 2 CH 2 O) m (CH 2 ) n —COOR′, (CH 2 CH 2 O) m —(CH2) n —CONR′R″, (CH 2 CH 2 O) m —(CH 2 ) n —SO 2 R′, (CH 2 CH 2 O) m —(CH 2 ) n —COR′, (CH 2 CH 2 O) m —(CH 2 ) n —SONR′R″, (CH 2 CH 2 O) m —(CH 2 ) n —SO 2 NR′R″, (CH 2 ) p —(CH 2 CH 2 O) m —(CH 2 ) n R′, (CH 2 )p-(CH 2 CH 2 O) m —(CH 2 ) n —OH, (CH 2 ) p —(CH 2 CH 2 O) m —(CH 2 )n-OR′, (CH 2 ) p —(CH 2 CH 2 O) m —(CH 2 ) n —NR′R″, (CH 2 ) p —(CH 2 CH 2 O) m —(CH 2 ) n —NR′COR″, (CH 2 ) p —(CH 2 CH 2 O)m- (CH 2 ) n —NR′SO 2 R″, (CH 2 ) p —(CH 2 CH 2 O) m —(CH 2 ) n —COOH, (CH 2 ) p —(CH 2 CH 2 O) m —(CH 2 ) n —COOR′, (CH 2 ) p —(CH 2 CH 2 O) m —(CH 2 ) n —CONR′R″, (CH 2 )p-(CH 2 CH 2 O) m —(CH 2 ) n —SO 2 R′, (CH2) p —(CH 2 CH 2 O) m —(CH 2 ) n —COR′, (CH 2 ) p —(CH 2 CH 2 O) m —(CH 2 ) n —SONR′R″, (CH 2 ) p —(CH 2 CH 2 O) m —(CH 2 ) n —SO 2 NR′R″, Aryl-(CH 2 ) n —COOH, and heteroaryl-alkyl-CO-alkyl-NR′R″m, wherein the alkyl may be substituted with OR′, and heteroaryl-(CH 2 ) n -heterocycle wherein the heterocycle may optionally be substituted with alkyl, hydroxyl, COOR′ and COR′; wherein R′ and R″ are selected from H, alkyl, alkyl substituted with halogen, hydroxyl, NH2, NH(alkyl), N(alkyl) 2 , oxo, carboxy, clcloalkyl and heteroaryl; 
 m, n, and p are independently 0 to 6; 
 R 12′  is selected from the group consisting of —O-(alkyl), —O-(alkyl)-akoxy, —C(O)-(alkyl), —C(OH)-alkyl-alkoxy, —C(O)—NH-(alkyl), —C(O)—N-(alkyl) 2 , —S(O)-(alkyl), S(O) 2 -(alkyl), —C(O)-(cyclic amine), and —O-aryl-(alkyl), —O-aryl-(alkoxy); and 
 R 1″  is selected from the group consisting of alkyl, aryl substituted alkyl, aloxy substituted alkyl, cycloalkyl, ary-substituted cycloalkyl, and alkoxy substituted cycloalkyl, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or prodrug thereof. 
 
     
     
         15 . The compound of  claim 14 , wherein the linker is attached to at least one of Z, R 8′ , R 9′ , R 10′ , R 11′ , R 12′ , R 1″ , or a combination thereof. 
     
     
         16 . The compound of any of  claim 4 ,  11  or  14 , wherein the linker group (L) comprises a chemical structural unit represented by the formula:
   -Aq- 
 
       wherein:
 q is an integer greater than 1; and 
 A is independently selected from the group consisting of a bond, CRL1RL2, O, S, SO, SO2, NRL3, SO2NRL3, SONRL3, CONRL3, NRL3CONRL4, NRL3SO2NRL4, CO, CRL1=CRL2, C≡C, SiRL1RL2, P(O)RL1, P(O)ORL1, NRL3C(═NCN)NRL4, NRL3C(═NCN), NRL3C(═CNO2)NRL4, C3-11cycloalkyl optionally substituted with 0-6 RL1 and/or RL2 groups, C3-11heteocyclyl optionally substituted with 0-6 RL1 and/or RL2 groups, aryl optionally substituted with 0-6 RL1 and/or RL2 groups, heteroaryl optionally substituted with 0-6 RL1 and/or RL2 groups; wherein 
 RL1, RL2, RL3, RL4 and RL5 are each, independently, selected from the group consisting of H, halo, C1-8alkyl, OC1-8alkyl, SC1-8alkyl, NHC1-8alkyl, N(C1-8alkyl)2, C3-11cycloalkyl, aryl, heteroaryl, C3-11heterocyclyl, OC1-8cycloalkyl, SC1-8cycloalkyl, NHC1-8cycloalkyl, N(C1-8cycloalkyl)2, N(C1-8cycloalkyl)(C1-8alkyl), OH, NH2, SH, SO2C1-8alkyl, P(O)(OC1-8alkyl)(C1-8alkyl), P(O)(OC1-8alkyl)2, CC—C1-8alkyl, CCH, CH═CH(C1-8alkyl), C(C1-8alkyl)═CH(C1-8alkyl), C(C1-8alkyl)═C(C1-8alkyl)2, Si(OH)3, Si(C1-8alkyl)3, Si(OH)(C1-8alkyl)2, COC1-8alkyl, CO2H, halogen, CN, CF3, CHF2, CH2F, NO2, SF5, SO2NHC1-8alkyl, SO2N(C1-8alkyl)2, SONHC1-8alkyl, SON(C1-8alkyl)2, CONHC1-8alkyl, CON(C1-8alkyl)2, N(C1-8alkyl)CONH(C1-8alkyl), N(C1-8alkyl)CON(C1-8alkyl)2, NHCONH(C1-8alkyl), NHCON(C1-8alkyl)2, NHCONH2, N(C1-8alkyl)SO2NH(C1-8alkyl), N(C1-8alkyl) SO2N(C1-8alkyl)2, NH SO2NH(C1-8alkyl), NH SO2N(C1-8alkyl)2, and NH SO2NH2; and wherein: 
 when q is greater than 1, RL1 or RL2 each, independently, can be linked to another A group to form cycloalkyl and/or heterocyclyl moeity that can be further substituted with 0-4 RL5 groups. 
 
     
     
         17 . The compound of  claim 16  wherein the linker group (L) is selected from the structure consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein: 
         “X” is a linear chain with atoms ranging from 2 to 14 with heteroatoms optionally; and 
         “Y” is O, N and S(O) n  wherein, (n=0, 1, 2). 
       
     
     
         18 . The compound of  claim 1 , wherein the PTM group is a protein target moiety that binds to bromodomain-containing protein 4 (BRD4). 
     
     
         19 . The compound of  claim 18 , wherein the PTM is a protein target moiety that binds to a human BET Bromodomain-containing protein is selected from the structure consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein * indicates the point of attachment of the linker. 
       
     
     
         20 . The compound of  claim 1 , wherein the PTM is a protein target moiety selected from the structure consisting of: 
       
         
           
           
               
               
           
         
         wherein * indicates the point of attachment of the linker. 
       
     
     
         21 . The compound according to  claim 1 , wherein the MLM comprises part of structural feature as in at least one of RG7112, RG7388, SAR405838, AMG-232, AM-7209, DS-5272, MK-8242, or NVP-CGM-097, and analogs or derivatives thereof. 
     
     
         22 . A compound is selected from the group consisting of chemical formula:
 4-(3-{4-[2-(2-{4-[2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole-1-carbonyl]piperazin-1-yl}ethoxy)ethoxy]phenyl}-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile;   4-(3-{4-[(17-{4-[2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis (4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole-1-carbonyl]piperazin-1-yl}-3,6,9,12,15-pentaoxaheptadecan-1-yl)oxy]phenyl}-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile;   N-(17-{[3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)pyrrolidin-2-yl]formamido}-3,6,9,12,15-pentaoxaheptadecan-1-yl)-2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2,6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamide;   N-(2-{2-[2-(2-{[3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)pyrrolidin-2-yl]formamido}ethoxy)ethoxy]ethoxy}ethyl)-2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2,6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamide;   N-(14-{[3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)pyrrolidin-2-yl]formamido}-3,6,9,12-tetraoxatetradecan-1-yl)-2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2,6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamide;   3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-{2-[2-(4-{[(1,3-trans)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamoyl}phenoxy)ethoxy]ethyl}pyrrolidine-2-carboxamide;   3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-[1-(4-{[(1,3-trans)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamoyl}phenyl)-1,4,7,10-tetraoxadodecan-12-yl]pyrrolidine-2-carboxamide;   3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-(2-{2-[2-(4-{[(1,3-trans)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamoyl}phenoxy)ethoxy]ethoxy}ethyl)pyrrolidine-2-carboxamide;   3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-[1-(4-{[(1,3-trans)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]-carbamoyl}phenyl)-1,4,7,10,13,16-hexaoxaoctadecan-18-yl]pyrrolidine-2-carboxamide;   3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-[1-(4-{[(1,3-trans)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamoyl}phenyl)-1,4,7,10,13-pentaoxapentadecan-15-yl]pyrrolidine-2-carboxamide;   (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-[1-(4-{[(1,3-trans)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamoyl}phenyl)-1,4,7,10,13-pentaoxapentadecan-15-yl]pyrrolidine-2-carboxamide;   (2S,3R,4S,5R)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-[1-(4-{[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamoyl}phenyl)-1,4,7,10,13-pentaoxapentadecan-15-yl]pyrrolidine-2-carboxamide;   3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-N-{4-[(2-{2-[2-(2-{2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2,6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamido}ethoxy)ethoxy]ethoxy}ethyl)carbamoyl]-2-methoxyphenyl}-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxamide;   3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-N-[4-({2-[2-(2-{2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2,6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamido}ethoxy)ethoxy]ethyl}carbamoyl)-2-methoxyphenyl]-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxamide;   (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-N-[4-({2-[2-(2-{2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2,6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamido}ethoxy)ethoxy]ethyl}carbamoyl)-2-methoxyphenyl]-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxamide;   (2S,3R,4S,5R)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-N-[4-({2-[2-(2-{2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2,6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamido}ethoxy)ethoxy]ethyl}carbamoyl)-2-methoxyphenyl]-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxamide;   (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-N-{4-[(2-{2-[2-(2-{2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo [8.3.0.0 2,6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamido}ethoxy)ethoxy]ethoxy}ethyl) carbamoyl]-2-methoxyphenyl}-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxamide;   (2S,3R,4S,5R)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-N-{4-[(2-{2-[2-(2-{2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2,6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamido}ethoxy) ethoxy]ethoxy}ethyl)carbamoyl]-2-methoxyphenyl}-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxamide;   3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-N-{4-[(14-{2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2,6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamido}-3,6,9,12-tetraoxatetradecan-1-yl)carbamoyl]-2-methoxyphenyl}-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxamide;   3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-[4-({2-[2-({[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}methoxy)ethoxy]ethyl}carbamoyl)-2-methoxyphenyl]pyrrolidine-2-carboxamide;   3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-N-(4-{[2-(2-{2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2,6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamido}ethoxy)ethyl]carbamoyl}-2-methoxyphenyl)-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxamide;   (2S,3R,4S,5R)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-N-(4-{[2-(2-{2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo [8.3.0.0 2,6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamido}ethoxy)ethyl]carbamoyl}-2-methoxyphenyl)-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxamide;   (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-N-(4-{[2-(2-{2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo [8.3.0.0 2,6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamido}ethoxy)ethyl]carbamoyl}-2-methoxyphenyl)-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxamide;   (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-N-{4-[(14-{2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo [8.3.0.0 2,6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamido}-3,6,9,12-tetraoxatetradecan-1-yl)carbamoyl]-2-methoxyphenyl}-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxamide;   (2S,3R,4S,5R)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-N-{4-[(14-{2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo [8.3.0.0 2,6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamido}-3,6,9,12-tetraoxatetradecan-1-yl)carbamoyl]-2-methoxyphenyl}-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxamide;   3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-{4-[(1-{[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}-2,5,8,11-tetraoxatridecan-13-yl)carbamoyl]-2-methoxyphenyl} pyrrolidine-2-carboxamide;   (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-{4-[(1-{[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}-2,5,8,11-tetraoxatridecan-13-yl)carbamoyl]-2-methoxyphenyl} pyrrolidine-2-carboxamide;   (2S,3R,4S,5R)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-{4-[(1-{[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}-2,5,8,11-tetraoxatridecan-13-yl)carbamoyl]-2-methoxyphenyl} pyrrolidine-2-carboxamide;   (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-[4-({2-[2-({[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}methoxy)ethoxy]ethyl}carbamoyl)-2-methoxyphenyl]pyrrolidine-2-carboxamide;   (2S,3R,4S,5R)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-[4-({2-[2-({[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}methoxy)ethoxy]ethyl}carbamoyl)-2-methoxyphenyl]pyrrolidine-2-carboxamide;   3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-{4-[(2-{2-[2-({[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}methoxy)ethoxy]ethoxy}ethyl)carbamoyl]-2-ethoxyphenyl}pyrrolidine-2-carboxamide;   (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-{4-[(2-{2-[2-({[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}methoxy)ethoxy]ethoxy}ethyl)carbamoyl]-2-methoxyphenyl}pyrrolidine-2-carboxamide;   (2S,3R,4S,5R)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-{4-[(2-{2-[2-({[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}methoxy)ethoxy]ethoxy}ethyl)carbamoyl]-2-methoxyphenyl}pyrrolidine-2-carboxamide;   3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-N-(3-{[5-(4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl}phenoxy)pentyl]oxy}propyl)-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxamide 3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-N-{4-[(3-{[5-(4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl}phenoxy)pentyl]oxy}propyl)carbamoyl]-2-methoxyphenyl}-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxamide;   3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-(2-methoxy-4-{[2-(2-{[(1,4-trans)-4-({4-[1-benzyl-5-(dimethylamino)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)cyclohexyl]oxy} ethoxy)ethyl]carbamoyl}phenyl)pyrrolidine-2-carboxamide;   3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-[2-methoxy-5-({2-[2-(2-{[(1,4-trans)-4-({4-[1-benzyl-5-(dimethylamino)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)cyclohexyl]oxy} ethoxy)ethoxy]ethyl}carbamoyl)phenyl]pyrrolidine-2-carboxamide;   3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-N-[4-({1-[4-(3-{[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]carbamoyl}-5-[ethyl(oxan-4-yl)amino]-4-methylphenyl)phenyl]-1,4,7,10-tetraoxadodecan-12-yl}carbamoyl)-2-methoxyphenyl]-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxamide;   3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-[2-methoxy-4-({1-[(1,4-trans)-4-({4-[1-benzyl-5-(dimethylamino)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)cyclohexyl]-1,4,7,10-tetraoxadodecan-12-yl}carbamoyl)phenyl]pyrrolidine-2-carboxamide;   3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-[2-methoxy-5-({1-[(1,4-trans)-4-({4-[1-benzyl-5-(dimethylamino)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)cyclohexyl]-1,4,7,10,13-pentaoxapentadecan-15-yl}carbamoyl)phenyl]pyrrolidine-2-carboxamide; and   3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-N-[4-({1-[4-(3-{[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]carbamoyl}-5-[ethyl(oxan-4-yl)amino]-4-methylphenyl)phenyl]-1,4,7,10,13,16-hexaoxaoctadecan-18-yl}carbamoyl)-2-methoxyphenyl]-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxamide, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or prodrug thereof.   
     
     
         23 . A composition comprising an effective amount of the compound of  claim 1 . 
     
     
         24 . A pharmaceutical composition comprising an effective amount of a compound of 1 and a pharmaceutically acceptable carrier, additive, and/or excipient. 
     
     
         25 . The pharmaceutical composition of 24, further comprising an additional bioactive agent, wherein the additional bioactive agent is an anticancer agent. 
     
     
         26 . The composition according to 25, 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 inhbitor, 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, arnsacrine, 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. 
     
     
         27 . A method for inducing degradation of a target protein in a cell comprising administering an effective amount of the compound of 1 to the cell. 
     
     
         28 . A method for treating a disease state or condition in a patient wherein dysregulated protein activity is responsible for said disease state or condition, said method comprising administering an effective amount of a compound according to  claim 1 , wherein the disease state or condition is cancer. 
     
     
         29 . The method of 28, 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.