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Definitions

• Breast cancer is the most common malignancy to affect women and worldwide, the incidence of the disease is increasing.
• Estrogens in particular, act as endocrine growth factors for at least one-third of breast cancers, and depriving the tumor of this stimulus is a recognized therapy for advanced disease in premenopausal women, this is achieved by the ablation of ovarian function through surgical, radio therapeutics, or medical means and, in postmenopausal women, by the use of aromatase inhibitors.
• Cereblon is a protein that in humans is encoded by the CRBN gene. CRBN orthologs are highly conserved from plants to humans, which underscores its physiological importance. Cereblon forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB 1), Cullin-4A (CUL4A), and regulator of cullins 1 (ROC1). This complex ubiquitinates a number of other proteins. Through a mechanism which has not been completely elucidated, cereblon ubquitination of target proteins results in increased levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10). FGF8 in turn regulates a number of developmental processes, such as limb and auditory vesicle formation. The net result is that this ubiquitin ligase complex is important for limb outgrowth in embryos. In the absence of cereblon, DDB 1 forms a complex with DDB2 that functions as a DNA damage-binding protein.
• DDB1 forms a complex
• the present disclosure describes bifunctional compounds which function to recruit endogenous proteins to an E3 ubiquitin ligase for degradation, and methods of using the same.
• the present disclosure provides bifunctional or proteolysis targeting chimeric (PROTAC) compounds, which find utility as modulators of targeted ubiquitination of a variety of polypeptides and other proteins, such as estrogen receptor, which are then degraded and/or otherwise inhibited by the bifunctional compounds as described herein.
• An advantage of the compounds provided herein is that a broad range of pharmacological activities is possible, consistent with the degradation/inhibition of targeted polypeptides from virtually any protein class or family.
• the description provides methods of using an effective amount of the compounds as described herein for the treatment or amelioration of a disease condition, such as cancer, e.g., breast cancer.
• the ubiquitin ligase is involved in polyubiquitination such that a second ubiquitin is attached to the first; a third is attached to the second, and so forth.
• Polyubiquitination marks proteins for degradation by the proteasome.
• Mono- ubiquitinated proteins are not targeted to the proteasome for degradation, but may instead be altered in their cellular location or function, for example, via binding other proteins that have domains capable of binding ubiquitin.
• different lysines on ubiquitin can be targeted by an E3 to make chains. The most common lysine is Lys48 on the ubiquitin chain. This is the lysine used to make polyubiquitin, which is recognized by the proteasome.
• the bifunctional compound further comprises a chemical linker ("L").
• L a chemical linker
• the ULM (e.g., a ILM, a CLM, a VLM, or a MLM) shows activity or binds to the E3 ubiquitin ligase (e.g., IAP E3 ubiquitin ligase, cereblon E3 ubiquitin ligase, VHL, or MDM2 E3 ubiquitin ligase) with an IC 50 of less than about 200 ⁇ .
• the IC 50 can be determined according to any method known in the art, e.g., a fluorescent polarization assay.
• R for Formulas (I), (II), (III), (IV), and (V) is selected from cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, each one further optionally substituted with 1-3 substituents selected from halogen, alkyl, haloalkyl, hydroxyl, alkoxy, cyano, (hetero)cycloalkyl or (hetero)aryl, or R is -
• Rio of Formula (VI) is selected from H, -CH 3 . -CF 3 , -CH 2 OH, or -CH 2 C1;
• X of Formula (VII) is selected from the group -CH and N;
• R e of Formula (VII) is selected from the group Ci-g-alkyl and alkylidene, and each Re is either unsubstituted or substituted;
• Q is selected from the group N, O, S, S(O), and S(0) 2 ;
• R f and R g of Formula (VII) are independently selected from H, -Cl-10-alkyl, Ct-jo-alkylaryl, -OH, -O-Ci -io-alkyl, - (CH 2 )o-6-C 3-7 -cycloalky, -0-(CH 2 )o-6-aryl, phenyl, aryl, phenyl - phenyl, -(CH 2 )i-6-het, -0-(CH 2 )i-6-het, -OR13, -C(Q)-R B .
• R is selected from the group H, unsubstituted or substituted Ci -7 -alkyl, aryl, unsubstituted or substituted -0-(C 1-7 -cycloalkyl), -C(0)-C 1-1 o-aIkyl, - C(0)-Co-io-alkyl-aryI, -C-O-Coi- 10-alkyl, -C-O-Co-io-alkyl-aryl, -S0 2 -C 1-1 o-alkyL or -SQ 2 -iCo-io- alkylaryl);
• Re and R 14 of Formula (VII) are independently selected from the group H, Cj-io-alkyl, - (CH 2 )o-6-C 3 -7-cycIoalkyl, -(CH 2 ) 0 . 6 - (Ci ! ),, ; -i ar> i ) ; , -C(O)-Ci..
• the compound further comprises an independently selected second ILM attached to the ILM of Formula (VI), or an unnatural mimetic thereof, by way of at least one additional independently selected linker group.
• the second ILM is a derivative of Formula (VI), or an unnatural mimetic thereof.
• the at least one additional independently selected linker group comprises two additional independently selected linker groups chemically linking the ILM and the second ILM.
• the at least one additional linker group for an ILM of the Formula (VI) , or an unnatural mimetic thereof chemically links groups selected from R 4 and R5.
• an ILM of Formula (VI) and a second ILM of Formula (VI) can be linked as shown below:
• the ILM can have the structure of Formula (IX), which is derived from the chemotypes cross-referenced in Mannhold, R., et al. IAP antagonists: promising candidates for cancer therapy, Drug Discov. Today, 15 (5-6), 210-9 ( 2010), or an unnatural mimetic thereof:
• R 1 of Formula (XII) is selected from:
• R 1 of Formula (XIII) is selected from:
• the ILM can have the structure of Formula (XVI), which is based on the IAP ligand described in WO Pub. No. 2006/069063, or an unnatural mimetic thereof:
• R of Formula (XVI) is selected from alkyl, cycloalkyl and heterocycloalkyl; more preferably, from isopropyl, tert-butyl, cyclohexyl and tetrahydropyranyl, most preferably from cyclohexyl;
• X of Formula (XVII) is selected from the group O or CH2.
• the ILM can have the structure of Formula (XVIII), which is based on the IAP ligands described in Cohen, F. et al., Antogonists of inhibitors of apoptosis proteins based on thiazole amide isosteres, Bioorg. Med. Chem. Lett., 20(7), 2229-33 (2010), or an unnatural mimetic thereof: (xviii),
• the ILM of the composition is selected from the group consistin of:
• the ILM of the composition is selected from the group consisting of:
• R of Formula (XXI) is selected from: b and ;
• the ILM of the compound is selected from the group consisting of:
• v is an integer from 1-3;
• R 21 of -CH 2 CHR 21 COR 2 is selected from the group NR 24 R 25 ;
• R 23 of -CH 2 R 23 is sleeted from optionally substituted aryl or optionally substituted heterocyclyl, where the optional substituents include alkyl and halogen;
• R 24 of NR 24 R 25 is selected from hydrogen or optionally substituted alkyl
• R 26 of OR 26 is selected from optionally substituted alkyl, wherein the optional substituents are OH, halogen or NH 2 ;
• n is an integer from 1-8;
• R 3 and R 4 of Formula (XXII) or (XXIII) are independently selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heteroarylalkyl or optionally substituted heterocycloalkyl, wherein the substituents are alkyl, halogen or OH;
• R 5 , R 6 , R 7 and R 8 of Formula (XXII) or (XXIII) are independently selected from hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl;
• X is a bond or is selected from the group consisting of:
• the ILM can have the structure of Formula (XXIV) or (XXVI), which are derived from the IAP ligands described in WO Pub. No. 2015/006524 and Perez HL, Discovery of potent heterodimeric antagonists of inhibitor of apoptosis proteins (IAPs) with sustained antitumor activity. J. Med. Chem. 58(3), 1556-62 (2015), or an unnatural mimetic thereof, and the chemical linker to linker group L as shown: r
• n is an integer from 1-8;
• R 5 and R 6 are selected from the group comprising:
• R" of Formula (XXVII) and (XXVIII) is selected from H or an optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted arylalkyl or optionally substituted aryl; or alternatively,
• R 23 of -CH 2 R 23 is selected from an optionally substituted aryl or optionally substituted heterocyclyl, where the optional substituents include alkyl and halogen;
• X of Formulas (XXVII) and (XXVIII) is selected from -(CR sl R s ) m -, optionally substituted heteroaryl or heterocyclyl,
• R of Formula (XXIX) through (XXXII) is selected from H, an optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted arylalkyl or optionally substituted aryl; or alternatively;
• v is an integer from 1-3;
• R 21 of -CH 2 CHR 21 COR 22 is selected from NR 24 R 25 ;
• R 25 of NR 24 R 25 is selected from hydrogen, optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted arylalkyl, optionally substituted heterocyclyl, - CH 2 CH 2 (OCH 2 CH 2 ) m CH 3 , or a polyamine chain
• R 26 of OR 26 is an optionally substituted alkyl, wherein the optional substituents are OH, halogen or NH 2; m is an integer from 1-8;
• R 6 and R 8 of Formula (XXIX) through (XXXII) are independently selected from hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl;
• the ILM of the compound is:
• the ILM can have the structure of Formula (XXXIII), which are derived from the IAP ligands described in WO Pub. No. 2014/074658 and WO Pub. No. 2013 71035, or an unnatural mimetic thereof:
• R of Formula (XXXIII) is selected from H, an optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted arylalkyl or optionally substituted aryl;
• R 6 and R 8 of Formula (XXXIII) are independently selected from hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl;
• R 32 of Formula (XXXIII) is selected from (C1-C4 alkylene)-R 33 wherein R 33 is selected from hydrogen, aryl, heteroaryl or cycloalkyl optionally further substituted;
• Y of Formula (XXXIII) is selected from:
• X is selected from:
• n is an integer from 1-3;
• R 12 and R 13 taken together with the nitrogen atom to which they are commonly bound to form a saturated heterocyclyl optionally comprising one additional heteroatom selected from N, O and S, and wherein the saturated heterocycle is optionally substituted with methyl.
• the ILM can have the structure of Formula (XXXIV) or (XXXV), which are derived from the IAP ligands described in WO Pub. No. 2014/047024, or an unnatural mimetic thereof:
• R 21 of -CH 2 CHR 21 COR 22 is selected from NR 24 R 25 ;
• R 24 of NR 24 R 25 is selected from hydrogen or optionally substituted alkyl
• R 26 is an optionally substituted alkyl, wherein the optional substituents are OH, halogen or NH 2 ;
• R 14 and are independently selected from hydrogen, halogen, optionally substituted alkyl or OR 19 ;
• R 19 of OR 19 is selected from hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl;
• n and n of -(CR 10 R n ) m - are independently 0, 1, 2, 3, or 4;
• q of -(CR 10 R n ) m - is 0, 1, 2, 3, or 4; r is 0 or 1;
• the ILM can have the structure of
• a of Formula (XXXVI) is selected from: or where the dotted line represents an optional double bond;
• X of Formula (XXXVI) is selected from: -(CR M R zz ) m -,
• Y and Z of Formula (XXXVI) are independently selected from -0-, -NR - or are absent;
• W of Formula (XXXVI) is selected from -CH- or -N-;
• R 3 and R 4 of Formula (XXXVI) are independently selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl or optionally substituted heterocycloalkyl;
• R 5 , R 6 , R 7 and R 8 of Formula (XXIV), (XXV) or (XXVI) are independently selected from hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl, or preferably methyl;
• R y and R 1U are independently selected from hydrogen, halogen or optionally substituted alkyl, or 9 and R 10 can be taken together to form a ring;
• R 15 of OR 15 is selected from hydrogen, optionally substituted alkyl or optionally substituted cycloalk l;
• n and n of -(CR) are independently selected from 0, 1, 2, 3, or 4;
• r of is selected from 0 or 1, and/or or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.
• the ILM can have the structure of
• R 3 and R 4 of Formula (XXXVII) and (XXXVIII) are independently selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted arylalkyl or optionally substituted aryl;
• R 5 and R 6 of Formula (XXXVII) and (XXXVIII) are independently selected from optionally substituted alkyl or optionally substituted cycloalkyl; 7 8
• R 15 of OR 15 is selected from hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl;
• R and R of -(CR R ) m - are independently selected from hydrogen, halogen or optionally substituted alkyl;
• R 50 and R 51 of Formula (XXXVII) and (XXXVIII) are independently selected from optionally substituted alkyl, or R 50 and R 51 are taken together to form a ring;
• o and of are inde endently an integer from 0-3;
• R 1 and R 2 of the ILM of Formula (XXXVII) or (XXXVIII) are t-butyl and R 3 and R 4 of the ILM of Formula (XXXVII) or (XXXVIII) are tetrahydronaphtalene.
• the ILM can have the structure of
• R and R of Formulas (XXXIX) and (XL) are independently selected from hydrogen, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl further optionally substituted, and
• R 6 and R 8 of Formula (XXXIX) and (XL) are independently selected from hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl.
• each X of Formulas (XXXIX) and (XL) is independently selected from: e Z of Formulas (XXXIX) and (XL) is selected from wherein each represents a point of attachment to the compound; and
• each Y is selected from:
• ⁇ represents a second point of attachment to Z
• R 3 of -C(0)R 3 is selected from OH, NHCN, NHS0 2 R 10 , NHOR 11 or N(R 12 )(R 13 );
• R 10 and R 11 of NHS0 2 R 10 and NHOR 11 are independently selected from -C C 4 alkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, any of which are optionally substituted, and hydrogen;
• each of R and R of N(R )(R ) are independently selected from hydrogen, -Ci-C 4 alkyl, -
• the ILM can have the structure of
• W 1 of Formula (XLI) is selected from O, S, N-R A , or C(R 8a )(R 8b );
• R 1 of Formula (XLI) is selected from H, Ci-C 6 alkyl, C 3 -C 6 cycloalkyl, -Ci-C 6 alkyl-
• X 1 and X 2 of Formula (XLI) are independently selected from C and N, and are members of a fused substituted or unsubstituted saturated or partially saturated 3-10 membered cycloalkyl ring, a fused substituted or unsubstituted saturated or partially saturated 3-10 membered heterocycloalkyl ring, a fused substituted or unsubstituted 5-10 membered aryl ring, or a fused substituted or unsubstituted 5-10 membered heteroaryl ring;
• R 2a , R 2b , R 2c , R 2d of CR 2c R 2d and CR 2a R 2b are independently selected from H, substituted or unsubstituted C l-C6alkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3-C 6 cycloalkyl, substituted or unsubstituted Ci-Csheterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-C 6 alkyl- (substituted or unsubstituted C 3 - Cecycloalkyl), -Ci-C 6 alkyl-(substituted or unsubstituted C 2 -C 5 heterocycloalkyl), -Ci-C 6 alkyl- (substituted or unsubstituted aryl), -Ci-C
• R" and R of NR R are independently selected from H, substituted or unsubstituted Q- C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 - Csheterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-C 6 aLkyl- (substituted or unsubstituted C 3 -C 6 cycloalkyl), -Ci-C 6 aLkyl- (substituted or unsubstituted C 2 - Csheterocycloalkyl), -Ci-C 6 alkyl-(substituted or unsubstituted aryl), or -Ci-C 6 alkyl- (substituted or unsubstituted heteroaryl);
• R of Formula (XLI) is selected from Ci-C 3 alkyl, or Ci-C 3 fluoroalkyl;
• R 4 of Formula (XLI) is selected from -NHR 5 , -N(R 5 )2, -N+(R 5 )3 or -OR 5 ;
• each R 5 of -NHR 5 , -N(R 5 )2, -N+(R 5 )3 and -OR 5 is independently selected from H, Ci-C 3 alkyl,
• R 8a and R 8d are as defined above, and R 8b and R 8c together form a bond; or:
• R 8a and R 8d are as defined above, and R 8b and R 8c together with the atoms to which they are attached form a substituted or unsubstituted fused 5-7 membered saturated, or partially saturated carbocyclic ring or heterocyclic ring comprising 1 -3 heteroatoms selected from S, O and N, a substituted or unsubstituted fused 5-10 membered aryl ring, or a substituted or unsubstituted fused 5-10 membered heteroaryl ring comprising 1 -3 heteroatoms selected from S, O and N;
• R 8c and R 8d are as defined above, and R 8a and R 8b together with the atoms to which they are attached form a substituted or unsubstituted saturated, or partially saturated 3 -7 membered spirocycle or heterospirocycle comprising 1 -3 heteroatoms selected from S, O and N;
• the ILM can have the structure of
• W 1 of Formula (XLII) is O, S, N-R A , or C(R 8a )(R 8b );
• W 2 of Formula (XLII) is O, S, N-R A , or C(R 8c )(R 8d ); provided that W 1 and W 2 are not both O, or both S;
• X 1 of Formula (XLII) is CH 3
• X 2 is selected from O, N-R A , S, S(O), or S(0) 2
• X 3 is CR 2a R 2b ;
• each R c is independently selected from H, -CN, -OH, alkoxy, substituted or unsubstituted Cl-C6alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-C 6 alkyl-(substituted or unsubstituted C 3 -C 6 cycloalkyl), -Ci- C 6 alkyl-(substituted or unsubstituted C 2 - Csheterocycloalkyl), -Ci-C 6 alkyl-(substituted or unsubstituted aryl), or -Ci-C 6 alkyl- (substituted or unsubstituted heteroaryl); or:
• R D" and R E of NR D R E are independently selected from H, substituted or unsubstituted Ci- C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 - Csheterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-C 6 alkyl- (substituted or unsubstituted C 3 -C 6 cycloalkyl), -Ci-C 6 alkyl- (substituted or unsubstituted C 2 - Csheterocycloalkyl), -Ci-C 6 alkyl-(substituted or unsubstituted aryl), or -Ci-C 6 alkyl- (substituted or unsubstituted heteroaryl);
• n 1 or 2;
• R 4 of Formula (XLII) is selected from -NHR 5 , -N(R 5 ) 2 , -N+(R 5 ) 3 or -OR 5 ;
• R of Formula (XLII) is bonded to a nitrogen atom of U to form a substituted or unsubstituted 5-7 membered ring;
• p of R is selected from 0, 1 or 2;
• R 8a , R 8b , R 8c , and R 8d of C(R 8a )(R 8b ) and C(R 8c )(R 8d ) are independently selected from H, C Cealkyl, Ci-Cefluoroalkyl, Ci-C 6 alkoxy, Ci-Ceheteroalkyl, and substituted or unsubstituted aryl;
• R 8a and R 8d are as defined above, and R 8b and R 8c together form a bond;
• R 8a and R 8d are as defined above, and R 8b and R 8c together with the atoms to which they are attached form a substituted or unsubstituted fused 5-7 membered saturated, or partially saturated carbocyclic ring or heterocyclic ring comprising 1 -3 heteroatoms selected from S, O and N, a substituted or unsubstituted fused 5-10 membered aryl ring, or a substituted or unsubstituted fused 5-10 membered heteroaryl ring comprising 1 -3 heteroatoms selected from S, O and N;
• R 8a and R 8b are as defined above, and R 8c and R 8d together with the atoms to which they are attached form a substituted or unsubstituted saturated, or partially saturated 3 -7 membered spirocycle or heterospirocycle comprising 1 -3 heteroatoms selected from S, O and N;
• the ILM can have the structure of
• W 1 of Formula (XLIII) is selected from O, S, N-R A , or C(R 8a )(R 8b );
• W 2 of Formula (XLIII) is selected from O, S, N-R A , or C(R 8c )(R 8d ); provided that W 1 and W 2 are not both O, or both S;
• R 1 of Formula (XLIII) is selected from H, Ci-C 6 alkyl, C 3 -C 6 cycloalkyl, -Ci-C 6 alkyl-
• X 1 of Formula (XLIII) is O
• X 2 of Formula (XLIII) is selected from O, N-R A , S, S(O), or S(0) 2
• X 3 of Formula (XLIII) is CR 2a R 2b ;
• X 1 and X 2 of Formula (XLIII) are independently selected from C and N, and are members of a fused substituted or unsubstituted saturated or partially saturated 3-10 membered cycloalkyl ring, a fused substituted or unsubstituted saturated or partially saturated 3-10 membered heterocycloalkyl ring, a fused substituted or unsubstituted 5-10 membered aryl ring, or a fused substituted or unsubstituted 5-10 membered heteroaryl ring, and X of Formula (XLIII) is CR 2a R 2b ;
• X 2 and X 3 of Formula (XLIII) are independently selected from C and N, and are members of a fused substituted or unsubstituted saturated or partially saturated 3-10 membered cycloalkyl ring, a fused substituted or unsubstituted saturated or partially saturated 3-10 membered heterocycloalkyl ring, a fused substituted or unsubstituted 5-10 membered aryl ring, or a fused substituted or unsubstituted 5- 10 membered heteroaryl ring, and X 1 of Formula (VLII) is CR 2e R 2f ;
• R 2a , R 2b , R 2c , R 2d , R 2e , and R 2f of CR 2c R 2d , CR 2a R 2b and CR 2e R 2f are independently selected from H, substituted or unsubstituted C Cealkyl, substituted or unsubstituted Q- Ceheteroalkyl, substituted or unsubstituted C3-C 6 cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-C 6 alkyl-(substituted or unsubstituted C 3 - Cecycloalkyl), -Q-CeaLkyl- (substituted or unsubstituted C 2 -Csheterocycloalkyl), -Ci-C 6 alkyl-(substituted
• n of Formula (XLIII) is 0, 1 or 2;
• R 3 of Formula (XLIII) is d-C 3 alkyl, or Ci-C 3 fluoroalkyl
• R 4 of Formula (XLIII) is -NHR 5 , -N(R 5 ) 2 , -N+(R 5 ) 3 or -OR 5 ;
• each R 5 of -NHR 5 , -N(R 5 ) 2 , -N+(R 5 ) 3 and -OR 5 is independently selected from H, Ci-C 3 alkyl, Ci-C haloalkyl, Ci-C heteroalkyl and -Ci-C alkyl-(C -C 5 cycloalkyl);
• R of Formula (XLIII) is bonded to a nitrogen atom of U to form a substituted or unsubstituted 5-7 membered ring;
• R 7 is 0, 1 or 2;
• R 8a , R 8b , R 8c , and R 8d of C(R 8a )(R 8b ) and C(R 8c )(R 8d ) are independently selected from H, C Cealkyl, Ci-Cefluoroalkyl, Ci-C 6 alkoxy, Ci-Ceheteroalkyl, and substituted or unsubstituted aryl;
• R 8a and R 8d are as defined above, and R 8b and R 8c together with the atoms to which they are attached form a substituted or unsubstituted fused 5-7 membered saturated, or partially saturated carbocyclic ring or heterocyclic ring comprising 1 -3 heteroatoms selected from S, O and N, a substituted or unsubstituted fused 5-10 membered aryl ring, or a substituted or unsubstituted fused 5-10 membered heteroaryl ring comprising 1 -3 heteroatoms selected from S, O and N;
• R 8a and R 8b are as defined above, and R 8c and R 8d together with the atoms to which they are attached form a substituted or unsubstituted saturated, or partially saturated 3 -7 membered spirocycle or heterospirocycle comprising 1 -3 heteroatoms selected from S, O and N;
• the ILM can have the structure of
• W 1 of Formula (XLIV) is selected from O, S, N-R A , or C(R 8a )(R 8b );
• W 2 of Formula (XLIV) is selected from O, S, N-R A , or C(R 8c )(R 8d ); provided that W 1 and W 2 are not both O, or both S;
• W 3 of Formula (XLIV) is selected from O, S, N-R A , or C(R 8e )(R 8f ), providing that the ring comprising W 1 , W2 , and W 3 does not comprise two adjacent oxygen atoms or sulfer atoms;
• X 1 of Formula (XLIV) is O
• X 2 of Formula (XLIV) is selected from CR 2c R 2d and N-R A
• X 3 of Formula (XLIV) is CR 2a R 2b ;
• X 1 of Formula (XLIV) is CH 2
• X 2 of Formula (XLIV) is selected from O, N-R A , S, S(O), or S(0) 2
• X 3 of Formula (XLIV) is CR 2a R 2b ; or:
• each R c is independently selected from H, -CN, -OH, alkoxy, substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-C 6 alkyl-(substituted or unsubstituted C 3 -C 6 cycloalkyl), -Ci- C 6 alkyl-(substituted or unsubstituted C 2 - Csheterocycloalkyl), -Ci-C 6 alkyl-(substituted or unsubstituted aryl), or -Ci-C 6 alkyl- (substituted or unsubstituted heteroaryl);
• X 1 and X 2 of Formula (XLIV) are independently selected from C and N, and are members of a fused substituted or unsubstituted saturated or partially saturated 3-10 membered cycloalkyl ring, a fused substituted or unsubstituted saturated or partially saturated 3-10 membered heterocycloalkyl ring, a fused substituted or unsubstituted 5-10 membered aryl ring, or a fused substituted or unsubstituted 5-10 membered heteroaryl ring, and X of Formula (XLIV) is CR 2a R 2b ;
• X 3 of Formula (XLIV) are independently selected from C and N, and are members of a fused substituted or unsubstituted saturated or partially saturated 3-10 membered cycloalkyl ring, a fused substituted or unsubstituted saturated or partially saturated 3-10 membered heterocycloalkyl ring, a fused substituted or unsubstituted 5-10 membered aryl ring, or a fused substituted or unsubstituted 5-10 membered heteroaryl ring, and X 1 of Formula (VLIV) is CR 2e R 2f ;
• R 2a , R 2b , R 2c , R 2d , R 2e , and R 2f of CR 2c R 2d , CR 2a R 2b and CR 2e R 2f are independently selected from H, substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted Q- Ceheteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-C 6 alkyl-(substituted or unsubstituted C 3 - Cecycloalkyl), -Ci-C 6 alkyl- (substituted or unsubstituted C 2 -C 5 heterocycloalkyl), -Ci-C 6 alkyl-(substitute
• R D" and R E of NR D R E are independently selected from H, substituted or unsubstituted Ci- C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 - Csheterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-C 6 aLkyl- (substituted or unsubstituted C 3 -C 6 cycloalkyl), -Ci-C 6 aLkyl- (substituted or unsubstituted C 2 - Csheterocycloalkyl), -Ci-C 6 alkyl-(substituted or unsubstituted aryl), or -Q-Cealkyl- (substituted or unsubstituted heteroaryl);
• n 1 or 2;
• R of Formula (XLIV) is selected from Ci-C 3 alkyl, or Ci-C 3 fluoroalkyl;
• R 4 of Formula (XLIV) is selected from -NHR 5 , -N(R 5 ) 2 , -N+(R 5 ) 3 or -OR 5 ;
• each R 5 of -NHR 5 , -N(R 5 ) 2 , -N+(R 5 ) 3 and -OR 5 is independently selected from H, Ci-C 3 alkyl,
• R of Formula (XLIII) is bonded to a nitrogen atom of U to form a substituted or unsubstituted 5-7 membered ring;
• R 8a , R 8b , R 8c , R 8d , R 8e , and R 8f of C(R 8a )(R 8b ), C(R 8c )(R 8d ) and C(R 8e )(R 8f ) are independently selected from H, Ci-C 6 alkyl, Ci-Cefluoroalkyl, Ci-C 6 alkoxy, Ci-Ceheteroalkyl, and substituted or unsubstituted aryl;
• R 8a , R 8d , R 8e , and R 8f of C(R 8a )(R 8b ), C(R 8c )(R 8d ) and C(R 8e )(R 8f ) are as defined above, and R 8b and R 8c together form a bond;
• R 8a , R 8b , R 8d , and R 8f of C(R 8a )(R 8b ), C(R 8c )(R 8d ) and C(R 8e )(R 8f ) are as defined above, and R 8c and R 8e together form a bond;
• R 8a , R 8b , R 8d , and R 8f of C(R 8a )(R 8b ), C(R 8c )(R 8d ) and C(R 8e )(R 8f ) are as defined above, and R 8c and R 8e together with the atoms to which they are attached form a substituted or unsubstituted fused 5-7 membered saturated, or partially saturated carbocyclic ring or heterocyclic ring comprising 1 -3 heteroatoms selected from S, O and N, a substituted or unsubstituted fused 5-10 membered aryl ring, or a substituted or unsubstituted fused 5-10 membered heteroaryl ring comprising 1 -3 heteroatoms selected from S, O and N;
• R 8c , R 8d , R 8e , and R 8f of C(R 8c )(R 8d ) and C(R 8e )(R 8f ) are as defined above, and R 8a and R 8b together with the atoms to which they are attached form a substituted or unsubstituted saturated, or partially saturated 3-7 membered spirocycle or heterospirocycle comprising 1 -3 heteroatoms selected from S, O and N;
• R 8a , R 8b , R 8e , and R 8f of C(R 8a )(R 8b ) and C(R 8e )(R 8f ) are as defined above, and R 8c and R 8d together with the atoms to which they are attached form a substituted or unsubstituted saturated, or partially saturated 3-7 membered spirocycle or heterospirocycle comprising 1-3 heteroatoms selected from S, O and N;
• the ILM can have the structure of
• R 2 , R 3 and R 4 of Formula (XLV) are independently selected from H or ME;
• X of Formula (XLV) is independently selected from O or S;
• R 1 of Formula (XLV) is selected from:
• the ILM has a structure according to Formula XLVIII):
• R 3 and R 4 of Formula (XLVIII) are independently selected from H or ME;
• the ILM has a structure and attached to a linker group
• R 3 of Formula (XLIX), (L) or (LI) are independently selected from H or ME;
• L of Formula (XLIX), (L) or (LI) is selected from:
• the ILM according to Formula (LII) is chemically linked to the linker group L in the area denoted with , and as shown below
• the ILM can have the structure of
• R 1 of Formulas (LIII) and (LIV) is selected from:
• R of Formulas (LIII) and (LIV) is selected from:
• X of is selected from H, halogen, methyl, methoxy, hydroxy, nitro or trifluoromethyl.
• the ILM can have the structure of
• Rl of Formulas (LVII) is selected from:
• the ILM is represented by the following structure:
• the ILM is selected from the group consisting of the structures below, which are based on the IAP ligands described in Asano, M, et al., Design, sterioselective synthesis, and biological evaluation of novel tri-cyclic compounds as inhibitor of apoptosis proteins (IAP) antagonists, Bioorg. Med. Chem., 21(18): 5725-37 (2013), or an unnatural mimetic thereof:
• the ILM is selected from the group consisting of, and which the chemical link between the ILM and linker group L is shown:
• the ILM can have the structure of
• Formula (LVIII) which is based on the IAP ligands described in Asano, M, et al., Design, sterioselective synthesis, and biological evaluation of novel tri-cyclic compounds as inhibitor of apoptosis proteins (IAP) antagonists, Bioorg. Med. Chem., 21(18): 5725-37 (2013), or an unnatural mimetic thereof:
• X of Formula (LVIII) is one or two substituents independently selected from H, halogen or cyano.
• the ILM can have the structure of and be chemically linked to the linker group L as shown in Formula (LIX) or (LX), or an unnatural mimetic thereof:
• X of Formula (LIX) and (LX) is one or two substituents independently selected from H, halogen or cyano, and ; and L of Formulas (LIX) and (LX) is a linker group as described herein.
• the ILM can have the structure of
• R 1 of Formula (LXI) is ;
• R of Formula (LXI) is selected from:
• the ILM can have the structure of and be chemically linked to the linker group L as shown in Formula (LXII) or (LLXIII), or an unnatural mimetic thereof:
• Formula (LXI) is a natural or unnatural amino acid
• L of Formula (LXI) is a linker group as described herein.
• the ILM can have the structure selected from the group consisting of, which is based on the IAP ligands described in Wang, J, et al., Discovery of novel second mitochondrial-derived activator of caspase mimetics as selective inhibitor or apoptosis protein inhibitors, J. Pharmacol. Exp. Ther., 349(2): 319-29 (2014), or an unnatural mimetic thereof:
• Formula (LXIX) which is based on the IAP ligands described in Hird, AW, et al., Structure- based design and synthesis of tricyclic IAP (Inhibitors of Apoptosis Proteins) inhibitors, Bioorg.
• R of Formula LIX is selected from the group consisting of:
• Rl of is selected from H or Me
• HET of * ⁇ is mono- or fused bicyclic heteroaryl
• — of Formula (LIX) is an optional double bond.
• the ILM of the compound has a chemical structure as re resented by:
• alkyl shall mean within its context a linear, branch-chained or cyclic fully saturated hydrocarbon radical or alkyl group, preferably a Ci-Cio, more preferably a Ci-C 6 , alternatively a C1-C3 alkyl group, which may be optionally substituted.
• alkyl groups are methyl, ethyl, n-butyl, sec-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl, 2-methylpropyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopen- tylethyl, cyclohexylethyl and cyclohexyl, among others.
• the alkyl group is end-capped with a halogen group (At, Br, CI, F, or I).
• compounds according to the present disclosure which may be used to covalently bind to dehalogenase enzymes.
• These compounds generally contain a side chain (often linked through a polyethylene glycol group) which terminates in an alkyl group which has a halogen substituent (often chlorine or bromine) on its distal end which results in covalent binding of the compound containing such a moiety to the protein.
• alkenyl refers to linear, branch-chained or cyclic C 2 -C 10 (preferably
• Alkynyl refers to linear, branch-chained or cyclic C 2 -C 10 (preferably
• alkylene when used, refers to a -(CH 2 ) n - group (n is an integer generally from 0-6), which may be optionally substituted.
• the alkylene group When substituted, the alkylene group preferably is substituted on one or more of the methylene groups with a Ci-C 6 alkyl group (including a cyclopropyl group or a t-butyl group), but may also be substituted with one or more halo groups, preferably from 1 to 3 halo groups or one or two hydroxyl groups, 0-(Ci-C 6 alkyl) groups or amino acid sidechains as otherwise disclosed herein.
• the alkylene (often, a methylene) group may be substituted with an amino acid sidechain group such as a sidechain group of a natural or unnatural amino acid, for example, alanine, ⁇ -alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline, serine, threonine, valine, tryptophan or tyrosine.
• an amino acid sidechain group such as a sidechain group of a natural or unnatural amino acid, for example, alanine, ⁇ -alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methion
• the term "unsubstituted” shall mean substituted only with hydrogen atoms.
• a range of carbon atoms which includes Co means that carbon is absent and is replaced with H.
• a range of carbon atoms which is Co-C 6 includes carbons atoms of 1, 2, 3, 4, 5 and 6 and for Co, H stands in place of carbon.
• substituted or “optionally substituted” shall mean independently (i.e., where more than substituent occurs, each substituent is independent of another substituent) one or more substituents (independently up to five sub stitu tents, preferably up to three substituents, often 1 or 2 substituents on a moiety in a compound according to the present disclosure and may include substituents which themselves may be further substituted) at a carbon (or nitrogen) position anywhere on a molecule within context, and includes as substituents hydroxyl, thiol, carboxyl, cyano (C ⁇ N), nitro (N0 2 ), halogen (preferably, 1, 2 or 3 halogens, especially on an alkyl, especially a methyl group such as a trifluoromethyl), an alkyl group (preferably, Ci-Cio , more preferably, Ci-C 6 ), aryl (especially phenyl and substituted phenyl for example benzyl or benzoyl),
• Substituents according to the present disclosure may include, for example - SiRiR 2 R 3 groups where each of Ri and R 2 is as otherwise described herein and R 3 is H or a Q- C 6 alkyl group, preferably Ri, R 2 , R 3 in this context is a Ci-C 3 alkyl group (including an isopropyl or t-butyl group).
• Each of the above-described groups may be linked directly to the substituted moiety or alternatively, the substituent may be linked to the substituted moiety (preferably in the case of an aryl or heteraryl moiety) through an optionally substituted -(CH 2 ) m - or alternatively an optionally substituted -(OCH 2 ) m -, -(OCH 2 CH 2 ) m - or -(CH 2 CH 2 0) m - group, which may be substituted with any one or more of the above-described substituents.
• the alkylene group (often a single methylene group) is substituted with one or two optionally substituted Ci-C 6 alkyl groups, preferably Ci-C 4 alkyl group, most often methyl or O-methyl groups or a sidechain of an amino acid as otherwise described herein.
• a moiety in a molecule may be optionally substituted with up to five substituents, preferably up to three substituents. Most often, in the present disclosure moieties which are substituted are substituted with one or two substituents.
• Ri and R 2 are each, within context, H or a Ci-C 6 alkyl group (which may be optionally substituted with one or two hydroxyl groups or up to three halogen groups, preferably fluorine).
• substituted shall also mean, within the chemical context of the compound defined and substituent used, an optionally substituted aryl or heteroaryl group or an optionally substituted heterocyclic group as otherwise described herein.
• aryl or "aromatic”, in context, refers to a substituted (as otherwise described herein) or unsubstituted monovalent aromatic radical having a single ring (e.g., benzene, phenyl, benzyl) or condensed rings (e.g., naphthyl, anthracenyl, phenanthrenyl, etc.) and can be bound to the compound according to the present disclosure at any available stable position on the ring(s) or as otherwise indicated in the chemical structure presented.
• aryl groups in context, may include heterocyclic aromatic ring systems, "heteroaryl” groups having one or more nitrogen, oxygen, or sulfur atoms in the ring (moncyclic) such as imidazole, furyl, pyrrole, furanyl, thiene, thiazole, pyridine, pyrimidine, pyrazine, triazole, oxazole or fused ring systems such as indole, quinoline, indolizine, azaindolizine, benzofurazan, etc., among others, which may be optionally substituted as described above.
• heteroaryl groups having one or more nitrogen, oxygen, or sulfur atoms in the ring (moncyclic) such as imidazole, furyl, pyrrole, furanyl, thiene, thiazole, pyridine, pyrimidine, pyrazine, triazole, oxazole or fused ring systems such as indole, quinoline, indolizin
• substituted aryl refers to an aromatic carbocyclic group comprised of at least one aromatic ring or of multiple condensed rings at least one of which being aromatic, wherein the ring(s) are substituted with one or more substituents.
• an aryl group can comprise a substituent(s) selected from: -(CH 2 ) n OH, -(CH 2 ) n -0-(Ci-C 6 )alkyl, -(CH 2 ) n -0-(CH 2 ) n - (d-Q kyl, -(CH 2 ) compassion-C(0)(Co-C 6 ) alkyl, -(CH 2 ) n -C(O)O(C 0 -C 6 )alkyl, -(CH 2 ) n -OC(O)(C 0 - C 6 )alkyl, amine, mono- or di-(Ci-C 6 alkyl) amine wherein the alkyl group on the amine is optionally substituted with 1 or 2 hydroxyl groups or up to three halo (preferably F, CI) groups, OH, COOH, Ci-C 6 alkyl, preferably CH 3 , CF 3 , OMe,
• Carboxyl denotes the group— C(0)OR, where R is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl , whereas these generic substituents have meanings which are identical with definitions of the corresponding groups defined herein.
• S c is CHR , NR , or O;
• RTM 1 is H, CN, N0 2 , halo (preferably CI or F), optionally substituted Ci-C 6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g. CF 3 ), optionally substituted 0(Ci-C 6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or an optionally substituted acetylenic group -C ⁇ C-R a where R a is H or a Ci-C 6 alkyl group (preferably C 1 -C 3 alkyl);
• R ss is H, CN, N0 2 , halo (preferably F or CI), optionally substituted Ci-C 6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted 0-(Ci-C 6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or an optionally substituted -C(0)(Ci-C 6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups);
• R URE is H, a Ci-C 6 alkyl (preferably H or C 1 -C 3 alkyl) or a -C(0)(Ci-C 6 alkyl), each of which groups is optionally substituted with one or two hydroxyl groups or up to three halogen, preferably fluorine groups, or an optionally substituted heterocycle, for example piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted, and
• arylaikyi refers to an aryl group as defined above appended to an alkyl group defined above.
• the arylaikyi group is attached to the parent moiety through an alkyl group wherein the alkyl group is one to six carbon atoms.
• the aryl group in the arylaikyi group may be substituted as defined above.
• Heterocycle refers to a cyclic group which contains at least one heteroatom, e.g., N, O or S, and may be aromatic (heteroaryl) or non-aromatic. Thus, the heteroaryl moieties are subsumed under the definition of heterocycle, depending on the context of its use. Exemplary heteroaryl groups are described hereinabove. [00159] Exemplary heterocyclics include: azetidinyl, benzimidazolyl, 1,4- benzodioxanyl,
• Heterocyclic groups can be optionally substituted with a member selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxy, carboxyalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, — SO-alkyl, — SO-substituted alkyl,
• heterocyclic groups can have a single ring or multiple condensed rings.
• nitrogen heterocycles and heteroaryls include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, morpholino, piperidinyl, tetrahydrofur
• heterocyclic also includes bicyciic groups in which any of the heterocyclic rings is fused to a benzene ring or a cyclohexane ring or another heterocyclic ring (for example, indolyl, quinolyl, isoquinoiyl, tetrahydroquinolyl, and the like).
• cycloalkyl can mean but is in no way limited to univalent groups derived from monocyclic or polycyclic alkyl groups or cycloalkanes, as defnied herein, e.g., saturated monocyclic hydrocarbon groups having from three to twenty carbon atoms in the ring, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
• substituted cycloalkyl can mean but is in no way limited to a monocyclic or polycyclic alkyl group and being substituted by one or more substituents, for example, amino, halogen, alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto or sulfo, whereas these generic substituent groups have meanings which are identical with definitions of the corresponding groups as defined in this legend.
• Heterocycloalkyl refers to a monocyclic or polycyclic alkyl group in which at least one ring carbon atom of its cyclic structure being replaced with a heteroatom selected from the group consisting of N, O, S or P.
• Substituted heterocycloalkyl refers to a monocyclic or polycyclic alkyl group in which at least one ring carbon atom of its cyclic structure being replaced with a heteroatom selected from the group consisting of N, O, S or P and the group is containing one or more substituents selected from the group consisting of halogen, alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto or sulfo, whereas these generic substituent group have meanings which are identical with definitions of the corresponding groups as defined in this legend.
• hydrocarbyl shall mean a compound which contains carbon and hydrogen and which may be fully saturated, partially unsaturated or aromatic and includes aryl groups, alkyl groups, alkenyl groups and alkynyl groups.
• lower alkyl refers to methyl, ethyl or propyl
• lower alkoxy refers to methoxy, ethoxy or propoxy.
• Q1-Q4, A, and Rn can independently be covalently coupled to a linker and/or a linker to which is attached one or more PTM, ULM, ILM or ILM' groups.
• the MLM of the bifunctional compound comprises chemical moieties such as substituted imidazolines, substituted spiro-indolinones, substituted pyrrolidines, substituted piperidinones, substituted morpholinones, substituted pyrrolopyrimidines, substituted imidazolopyridines, substituted thiazoloimidazoline, substituted pyrrolopyrrolidinones, and substituted isoquinolinones.
• chemical moieties such as substituted imidazolines, substituted spiro-indolinones, substituted pyrrolidines, substituted piperidinones, substituted morpholinones, substituted pyrrolopyrimidines, substituted imidazolopyridines, substituted thiazoloimidazoline, substituted pyrrolopyrrolidinones, and substituted isoquinolinones.
• the MLM comprises the core structures mentioned above with adjacent bis-aryl substitutions positioned as cis- or trans-configurations.
• the MLM comprises part of structural features as in RG7112, RG7388, SAR405838, AMG-232, AM-7209, DS-5272, MK-8242, and NVP-CGM- 097, and analogs or derivatives thereof.
• MLM is a derivative of substituted imidazoline represented as Formula (A-1), or thiazoloimidazoline represented as Formula (A-2), or spiro indolinone represented as Formula (A-3), or pyrollidine represented as Formula (A-4), or piperidinone / morphlinone represented as Formula (A-5), or isoquinolinone represented as Formula (A-6), or pyrollopyrimidine / imidazolopyridine represented as Formula (A-7), or pyrrolopyrrolidinone / imidazolopyrrolidinone represented as Formula (A-8).
• X of Formula (A-1) through Formula (A-8) 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;
• A, A' and A" of Formula (A-1) through Formula (A-8) are independently selected from C, N, O or S, can also be one or two atoms forming a fused bicyclic ring, or a 6,5- and 5,5-fused aromatic bicyclic group;
• R 2 of Formula (A-1) through Formula (A-8) 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:
• R5 of Formula (A-1) through Formula (A-8) 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, CI 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 b of Formula (A-1) through Formula (A-8) is selected from the group consisting of alkyl, cycloalkyl, mono-, di- or tri-substituted aryl or heteroaryl, 4-morpholinyl, l-(3-oxopiperazunyl),
• R c of Formula (A-1) through Formula (A-8) 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 7 of Formula (A-1) through Formula (A-8) is selected from the group consisting of H, CI 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 e of Formula (A-1) through Formula (A-8) is an alkylene with 1 to 6 carbons, or a bond;
• R of Formula (A-1) through Formula (A-8) is a substituted 4- to 7-membered
• R g of Formula (A-l) through Formula (A-8) is selected from the group consisting of aryl, hetero aryl, substituted aryl or heteroaryl, and 4- to 7-membered heterocycle;
• R9 of Formula (A-l) through Formula (A-8) 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 CI or F;
• Rio of Formula (A-l) through Formula (A-8) 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, CI, -CN, alkene, alkyne, CI to C6 alkyl group, CI 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;
• substituents including a halogen, F, CI, -CN, alkene, alkyne, CI to C6 alkyl group, CI to C
• R11 of Formula (A-l) through Formula (A-8) is -C(0)-N(R h )(R i ), wherein R h and R ⁇ are selected from groups consisting of the following:
• R h and R 1 of Formula (A-l) through Formula (A-8) 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;
• R12 and Ri 3 of Formula (A-l) through Formula (A-8) are independently selected from H, lower alkyl (CI 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;
• Ri 4 of Formula (A-l) through Formula (A-8) 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;
• Ri 5 of Formula (A-l) through Formula (A-8) is CN;
• 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, Cl-6 alkyl groups, hydroxylated Cl-6 alkyl, Cl-6 alkyl containing thioether, ether, sulfone, sulfoxide, fluorine substituted ether or cyano group;
• Ri 7 of Formula (A-l) through Formula (A-8) is selected from the group consisting of
• Ri 8 of Formula (A-l) through Formula (A-8) is selected from the group consisting of substituted aryl, heteroaryl, alkyl, cycloalkyl, the substitution is preferably -N(Cl-4 alkyl)(cycloalkyl), - N(Cl-4 alkyl)alkyl-cycloalkyl, and -N(Cl-4 alkyl)[(alkyl)-(heterocycle-substituted)-cycloalkyl];
• Ri9 of Formula (A-l) through Formula (A-8) is selected from the group consisting of aryl, heteroaryl, bicyclic heteroaryl, and these aryl or hetroaryl groups can be substituted with halogen, Cl-6 alkyl, Cl-6 cycloalkyl, CF 3 , F, CN, alkyne, alkyl sulfone, the halogen substitution can be mon- bis- or tri-substituted; R20 and R21 of Formula
• R23 of Formula (A-l) through Formula (A-8) 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, Cl-6 alkyl, hydoxylated Cl-6 alkyl, cycloalkyl, fluorine-substituted Cl-6 alkyl, CN, alkoxy, alkyl sulfone, amide and sulfonamide;
• R 24 of Formula (A-l) through Formula (A-8) 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 cycloalkyl;
• R25 of Formula (A-l) through Formula (A-8) is selected from the group consisting of Cl-6 alkyl, Cl-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 Cl-6 alkyl, fluorine-substituted Cl-6 alkyl, alkoxy, aryl and heteroaryl group;
• R 2 6 of Formula (A-l) through Formula (A-8) is selected from the group consisting of Cl-6 alkyl, C3-6 cycloalkyl, the alkyl or cycloalkyl can be substituted with -OH, alkoxy, fluorine- substituted alkoxy, fluorine-substituted alkyl, -NH 2 ,
• R27 of Formula (A-l) through Formula (A-8) is selected from the group consisting of aryl, heteroaryl, bicyclic heteroaryl, wherein the aryl or heteroaryl groups can be substituted with Cl- 6 alkyl, alkoxy, NH2, NH-alkyl, halogen, or -CN, and the substitution can be independently mono-, bis- and tri-substitution;
• R 2 8 of Formula (A-l) through Formula (A-8) 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 substitute
• Ri" of Formula (A-l) through Formula (A-8) is selected from the group consisting of alkyl, aryl substitituted alkyl, alkoxy substituted alkyl, cycloalkyl, aryl- substituted cycloalkyl, and alkoxy substituted cycloalkyl.
• Formula (A-8) are substituted pyrrolidine, substituted piperidine, substituted piperizine.
• MLMs include those shown below as well as those 'hybrid' molecules that arise from the combination of 1 or more of the different features shown in the molecules below.
• PROTACs can be prepared to target a particular protein for degradation, where 'L" is a connector (i.e. a linker group), and "PTM” is a ligand binding to a target protein.
• the description provides a bifunctional molecule comprising a structure selected from the roup consisting of:
• R4' of Formulas A-l-1 throught A-l-4 is 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(0)CH 3 , -C(CH 3 ) 2 C(0)NHCH 3 , -C(CH 3 ) 2 C(0)N(CH 3 ) 2 , -SCH 3 , - SCH 2
• R4' can also serve as the linker attachment position.
• linker will be connected to the terminal atom of R4' groups shown above.
• the linker connection position of Formulas A-l-1 throught A-l-4 is at least one of R4' or R6' or both.
• R6' of Formulas A-l-1 throught A-l-4 is independently selected from the roup consisting of H,
• the linker of Formula A-4-1 through A-4-6 is attached to at least one of Rl ⁇ R2', R3', R4', R5', R6', or a combination thereof.
• the description provides bifunctional or chimeric molecules with the structure: PTM-L-MLM, wherein PTM is a protein target binding moiety coupled to an MLM by L, wherein L is a bond (i.e., absent) or a chemical linker.
• the MLM has a structure selected from the group consisting of A-4-1, A-4-2, A-4- 3, A-4-4, A-4-5, and A-4-6:
• R7' of Formula A-4-1 through A-4-6 is a member selected from the group consisting of halogen, mono-, and di- or tri-substituted halogen;
• R8' of Formula A-4-1 through A-4-6 is selected from the group consisting of H, -F, -CI, -Br, -I, - CN, -NO 2 , ethylnyl, cyclopropyl, methyl, ethyl, isopropyl, vinyl, methoxy, ethoxy, isopropoxy, - OH, other Cl-6 alkyl, other Cl-6 alkenyl, and Cl-6 alkynyl, mono-, di- or tri-substituted;
• R9' of Formula A-4-1 through A-4-6 is selected from the group consisting 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 of Formula A-4-1 through A-4-6 is selected from the group consistin of H, -OCH 3 , -OCH 2 CH 3 , and halogen;
• RIO' and Rl l' of Formula A-4-1 through A-4-6 are each independently selected from the group consisting of H, (CH 2 ) compassion-R', (CH 2 ) compassion-NR'R", (CH 2 ) complicat-NR'COR", (CH 2 ) admir-NR'S0 2 R", (CH 2 ) admir-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 -S0 2 R ⁇ (CH 2 ) n -SONR'R", (CH 2 ) n -S0 2 NR'R", (CH 2 CH 2 0) m -(CH 2 ) n -R', (CH 2 CH 2
• n, and p are independently 0 to 6;
• R12' of Formula A-4-1 through A-4-6 is selected from the group consisting of -O-(alkyl), -O- (alkyl)-akoxy, -C(0)-(alkyl), -C(OH)-alkyl-alkoxy, -C(0)-NH-(alkyl), -C(0)-N-(alkyl) 2 , -S(O)- (alkyl), S(0) 2 -(alkyl), -C(0)-(cyclic amine), and -O-aryl-(alkyl), -O-aryl-(alkoxy);
• Rl" of Formula A-4-1 through A-4-6 is selected from the group consisting of alkyl, aryl substitituted alkyl, aloxy substituted alkyl, cycloalkyl, ary- substituted cycloalkyl, and alkoxy substituted cycloalkyl.
• the alkyl, alkoxy or the like can be a lower alkyl or lower alkoxy.
• A-4-6 is at least one of Z, R8', R9', R10', Rl l", R12", or Rl".
• A-4-1 through A-4-6 can be applied to MLM with formula A-2, A-3, A-5, A-6, A-7 and A-8, wherein the solvent exposed area in the MLM can be connected to linker "L” which will be attached to target protein ligand "PTM", to construct PROTACs.
• Exemplary MDM2 binding moieties include, but not limited, the following: [00186] 1. The HDM2/MDM2 inhibitors identified in Vassilev, et al, In vivo activation of the p53 pathway by small-molecule antagonists of MDM2, SCIENCE vol:303, pag:844-848 (2004), and Schneekloth, et al, Targeted intracellular protein degradation induced by a small molecule: En route to chemical proteomics, Bioorg. Med. Chem. Lett. 18 (2008) 5904-5908, including (or additionally) the compounds nutlin-3, nutlin-2, and nutlin-1 (derivatized) as described below, as well as all derivatives and analogs thereof:
• the description provides compounds useful for binding and/or inhibiting cereblon.
• the compound is selected from the group consisting of chemical structures:
• X of Formulas (a) through (f) is independently selected from the group O, S and H 2;
• Z of Formulas (a) through (f) is independently selected from the group O, and S or H 2 except that both X and Z cannot be H 2;
• G and G' of Formulas (a) through (f) are independently selected from the group H, alkyl
• Ql - Q4 of Formulas (a) through (f) represent a carbon C substituted with a group independently selected from R', N or N-oxide;
• a of Formulas (a) through (f) is independently selected from the group H, alkyl (linear, branched, optionally substituted), cycloalkyl, CI and F;
• R of Formulas (a) through (f) comprises, but is not limited to: -CONR'R", -OR', -NR'R", -SR', -S0 2 R', -S0 2 NR'R", -CR'R"-, -CR'NR'R”-, (-CR'0) n R", -aryl, -hetaryl, -alkyl (linear, branched, optionally substituted), -cycloalkyl, -heterocyclyl, -P(0)(OR')R", - P(0)R'R", -OP(0)(OR')R", -OP(0)R'R", -CI, -F, -Br, -I, -CF 3 , -CN, -NR'S0 2
• n of Formulas (a) through (f) is an integer from 1-10 (e.g., 1-4, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10); of Formulas (a) through (f) represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific; and
• R n of Formulas (a) through (f) comprises 1-4 independent functional groups or atoms.
• the CLM comprises a chemical structure selected from the roup:
• X of Formulas (a) through (f) is independently selected from the group O, S and H2;
• G and G' of Formulas (a) through (f) are independently selected from the group H, alkyl
• Ql - Q4 of Formulas (a) through (f) represent a carbon C substituted with a group independently selected from R', N or N-oxide;
• a of Formulas (a) through (f) is independently selected from the group H, alkyl (linear, branched, optionally substituted), cycloalkyl, CI and F;
• the CLM or ULM comprises a chemical structure selected from the
• Formula (g) represents a bond that may be stereospecific ((R) or (S)) or non- stereospecific;
• Q1-Q4, A, and Rn of Formulas (a) through (g) can independently be covalently coupled to a linker and/or a linker to which is attached one or more PTM, ULM, CLM or CLM' groups.
• Qi, Q2, Q3, Q4, Q5 of Formulas (h) through (ab) are independently represent a carbon C substituted with a group independently selected from R', N or N-oxide;
• R 1 of Formulas (h) through (ab) is selected from H, CN, C1-C3 alkyl;
• R 5 of Formulas (h) through (ab) is H or lower alkyl
• X of Formulas (h) through (ab) is C, CH or N;
• R' of Formulas (h) through (ab) is selected from H, halogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy;
• R of Formulas (h) through (ab) is H, OH, lower alkyl, lower alkoxy, cyano, halogenated lower alkoxy, or halogenated lower alkyl
• the CLM is covalently joined to a PTM, a chemical linker group (L), a ULM, CLM (or CLM') or combination thereof.
• the CLM or CLM' is covalently joined to a PTM, a chemical linker group (L), a ULM, a CLM, a CLM', or a combination thereof via an R group (such as, R, R 1 , R2 , R 3 , R 4 or R'), W, X, or a Q group (such as, Qi, Q 2 , Q 3 , Q 4 , or Q5) of Formulas (h) through (ab).
• R group such as, R, R 1 , R2 , R 3 , R 4 or R'
• W X
• Q group such as, Qi, Q 2 , Q 3 , Q 4 , or Q5
• the CLM or CLM' is covalently joined to a PTM, a chemical linker group (L), a ULM, a CLM, a CLM', or a combination thereof via W, X, R, R 1 , R 2 , R 3 , R 4 , R 5 , R', Qi, Q 2 , Q 3 , Q 4 , and Q 5 of Formulas (h) through (ab).

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