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  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/04—Ortho-condensed systems
  • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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Definitions

• the present invention relates to compounds, pharmaceutical compositions, modified proteins and protein-ligand complexes, and methods for binding or modulating a DDB1-and CUL4-associated factor 1 (DCAF1) protein, which may be useful for biotechnology applications such as selective degradation of a target protein, molecular glues, or anti-microbial drugs.
• DCAF1 DDB1-and CUL4-associated factor 1
• the ubiquitin pathway plays a critical role in the regulation of most cellular processes via an enzymatic cascade, where E1 and E2 enzymes catalyze the activation and conjugation of ubiquitin, and E3s confer reaction specificity through substrate recruitment (Hershko and Ciechanover, 1998; Pickart, 2004) .
• Cullin RING E3 ligases (CRLs) are the largest family of E3 ubiquitin ligases.
• cullin serves as a scaffold to bind small RING finger protein ROC1 or ROC2 (RBX1 or RBX2) through a C-terminal domain and a linker-substrate receptor dimer or a substrate receptor directly through an N-terminal domain.
• Mammalian cells express nine distinct cullins, including two cullin 4 (CUL4) proteins: CUL4A and CUL4B, which use DNA damage-binding protein 1 (DDB1) as the linker.
• DDB1 bridges the interaction between CUL4 and a subset of DDB1 binding WD40 repeat proteins (DWD or DCAFs for DDB1 cullin associated factors) .
• DWD or DCAFs for DDB1 cullin associated factors DDA1 binding WD40 repeat proteins
• DCAF proteins function as substrate receptors to target specific substrates to the CRL4 E3 complexes (Jackson and Xiong, 2009) .
• DCAF1 also known as VprBP
• DDB1-and CUL4-associated factor 1 (DCAF1) is evolutionarily conserved in mammals, Drosophila, Xenopus, C. elegans, and Arabidopsis, but has no apparent homolog in yeast (Nakagawa et al., 2013; Schabla et al., 2019) . It is ubiquitously expressed in all tissues and organs that have been examined (Zhang et al., 2001) .
• DCAF1 is an example of an E3 ubiquitin ligase.
• CRL4 DCAF1 E3 ligase is required by targeting cellular substrates for proteasome-mediated degradation (Belzile et al., 2007; Hrecka et al., 2007; Le Rouzic et al., 2007; Tan et al., 2007; Wen et al., 2007) .
• Monofunctional compounds may be useful as synthetic intermediates for the preparation of heterobifunctional compounds comprising a DCAF1 binding moiety conjugated to a target protein binding moiety via a linker.
• Heterobifunctional compounds may be useful for the targeted degradation of a protein of interest.
• each R 3 is independently selected from the group consisting of hydrogen, fluoro, oxo, thioxo, OR 16 , SR 16 , N (R 16 ) 2 , C (O) R 16 , OC (O) R 16 , C (O) OR 16 , C (O) N (R 16 ) 2 , N (R 16 ) C (O) R 16 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl, wherein each said C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl moiety is optionally substituted with one or more R 17A ;
• each R 8 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and 3-to 6-membered heterocyclyl, wherein each said C 1 -C 6 alkyl is optionally substituted with one or more R d , and each said C 3 -C 6 cycloalkyl and 3-to 6-membered heterocyclyl is optionally substituted with one or more R e ;
• each R 10 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 3 -C 6 cycloalkyl, and 3-to 6-membered heterocyclyl;
• each R 14 is independently selected from the group consisting of fluoro, oxo, thioxo, OR b , SR b , N (R b ) 2 , C (O) R b , OC (O) R b , C (O) OR b , C (O) N (R b ) 2 , N (R b ) C (O) R b , C 3 -C 6 cycloalkyl, and 3-to 6-membered heterocyclyl, wherein each said C 3 -C 6 cycloalkyl and 3-to 6-membered heterocyclyl is optionally substituted with one or more R e ;
• each R 17A and R 17B is independently selected from the group consisting of fluoro, oxo, thioxo, OR c , SR c , N (R c ) 2 , C (O) R c , OC (O) R c , C (O) OR c , C (O) N (R c ) 2 , N (R c ) C (O) R c , C 3 -C 6 cycloalkyl, and 3-to 6-membered heterocyclyl, wherein each said C 3 -C 6 cycloalkyl and 3-to 6-membered heterocyclyl is optionally substituted with one or more R e ;
• each R 20 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and 3-to 6-membered heterocyclyl, wherein each said C 1 -C 6 alkyl is optionally substituted with one or more R d , and each said C 3 -C 6 cycloalkyl and 3-to 6-membered heterocyclyl is optionally substituted with one or more is optionally substituted with one or more R e ;
• each R d is independently selected from the group consisting of fluoro, hydroxy, C 1 -C 4 alkoxy, oxo, NH 2 , NH (C 1 -C 4 alkyl) and N (C 1 -C 4 alkyl) 2 ;
• n is an integer from 0 to 6;
• t is an integer from 1 to 4.
• u is an integer from 1 to 5;
• z is an integer from 1 to 4.
• L 1 is selected from a bond and a bivalent chemical linker
• G is a reactive functional group
• Z 2 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and an amine protecting group
• r is an integer from 0 to 4.
• s is an integer from 0 to 2.
• each v 1 , w 1 , v 2 , w 2 , v 3 , w 3 , v 4 , and w 4 is independently an integer from 0 to 5.
• Y 3 is N. In some embodiments, Y 3 is C (R 3 ) or C (R 4 ) . In some embodiments, Y 4 is N (R 4 ) . In some embodiments, Y 4 is N (R 3 ) . In some embodiments, Y 4 is C (R 3 ) 2 , C (R 3 ) (R 4 ) or C (R 4 ) 2 .
• Y 3 is N and Y 4 is N (R 4 ) . In some embodiments, Y 3 is N and Y 4 is N (R 3 ) . In some embodiments, Y 3 is N and Y 4 is C (R 3 ) 2 , C (R 3 ) (R 4 ) or C (R 4 ) 2 . In some embodiments, Y 3 is C (R 3 ) or C (R 4 ) , and Y 4 is N (R 4 ) . In some embodiments, Y 3 is C (R 3 ) or C (R 4 ) , and Y 4 is N (R 3 ) .
• s is an integer from 0 to 1.
• each v 1 , w 1 , v 2 , w 2 , v 3 , w 3 , v 4 , and w 4 is independently an integer from 1 to 2.
• v 1 is 1 and w 1 is 2.
• v 1 is 1 and w 1 is 1.
• v 1 is 2 and w 1 is 2.
• v 2 is 1 and w 2 is 2.
• v 2 is 1 and w 2 is 1.
• v 2 is 2 and w 2 is 2.
• the sum of v 1 and w 1 is 2 to 4.
• the sum of v 2 and w 2 is 2 to 4.
• v 3 is 1 and w 3 is 2.
• v 3 is 1 and w 3 is 1.
• v 3 is 0 and w 3 is 2.
• v 4 is 1 and w 4 is 2.
• v 4 is 1 and w 4 is 1.
• v 4 is 0 and w 4 is 2.
• v 4 is 2 and w 4 is 1.
• v 4 is 2 and w 4 is 0.
• Q 2 is selected from the group consisting of hydrogen, halogen, CN, Z 1 , C 3 -C 11 cycloalkyl and 3-to 11-membered heterocycle, wherein each said C 3 -C 11 cycloalkyl and 3-to 11-membered heterocycle is optionally substituted with one or more R 2 andoptionally further substituted with Z 1 .
• Q 2 is selected from the group consisting of C 3 -C 11 cycloalkyl and 3-to 11-membered heterocycle, wherein each said C 3 -C 11 cycloalkyl and 3-to 11-membered heterocycle is optionally substituted with one or more R 2 andoptionally further substituted with Z 1 .
• Each Q 2 may be a monocyclic, spirocyclic, fused or bridged C 3 -C 11 cycloalkyl or 3-to 11-membered heterocycle, optionally substituted with one or more R 2 and optionally further substituted with Z 1 .
• Q 2 is selected from the group consisting of C 3 -C 8 cycloalkyl and 3-to 8-membered heterocycle, wherein each said C 3 -C 8 cycloalkyl and 3-to 8-membered heterocycle is optionally substituted with one or more R 2 andoptionally further substituted with Z 1 .
• Z 1 is L 1 -P.
• Z 1 is L 1 -G.
• Z 1 is Z 2 .
• Q 2 is selected from the group consisting of C 3 -C 11 cycloalkyl and 3-to 11-membered heterocycle having the structure of Formula (Va) , Formula (Vb) and Formula (Vc) :
• Y 1 is C (R 6 ) or N;
• Y 1 is O and Z 1 is null
• Y 2 is C (R 7 ) or N;
• R 6 is independently selected from the group consisting of hydrogen, fluoro, OR 23 , N (R 23 ) 2 , and C 1 -C 6 alkyl, wherein each said C 1 -C 6 alkyl is optionally substituted with one or more R d ;
• R 23 and R 24 are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 3 -C 6 cycloalkyl, and 3-to 6-membered heterocyclyl;
• each R d is independently selected from the group consisting of fluoro, hydroxy, C 1 -C 4 alkoxy, oxo, NH 2 , NH (C 1 -C 4 alkyl) and N (C 1 -C 4 alkyl) 2 ;
• each A 2 , B 2 , C 2 and D 2 is independently selected from the group consisting of null, O, C (O) , S (O) , S (O) 2 , N (R 2 ) , and C (R 2 ) 2 ;
• n is an integer from 0 to 4.
• each v 5 , w 5 , v 6 , w 6 , v 7 , w 7 , v 8 , and w 8 is independently an integer from 0 to 5.
• v 6 is 1 and w 6 is 1. In some embodiments, v 6 is 1 and w 6 is 2. In some embodiments, v 6 is 2 and w 6 is 1. In some embodiments, v 6 is 2 and w 6 is 2. In some embodiments, v 6 is 0 or 1 and w 6 is 3. In some embodiments, v 6 is 3 and w 6 is 0 or 1. In some embodiments, v 6 is 0 and w 6 is 4. In some embodiments, v 6 is 4 and w 6 is 0. In some embodiments, the sum of v 5 and w 5 is 2 to 4. In some embodiments, the sum of v 6 and w 6 is 2 to 4. In some embodiments, v 7 is 1 and w 7 is 1.
• Q 2 is selected from the group consisting of C 3 -C 11 cycloalkyl and 3-to 11-membered heterocycle, wherein each said C 3 -C 11 cycloalkyl and 3-to 11-membered heterocycle is optionally substituted with one or more R 2 andoptionally further substituted with Z 1 .
• Q 2 is C 3 -C 11 cycloalkyl optionally substituted with one or more R 2 and optionally further substituted with Z 1 .
• Q 2 is 3-to 11-membered heterocycle optionally substituted with one or more R 2 andoptionally further substituted with Z 1 .
• Z 1 is L 1 -P.
• Z 1 is L 1 -G.
• Z 1 is Z 2 .
• A is C 6 -C 10 aryl or 5-to 10-membered heteroaryl comprising X 1 ;
• X 1 is C (R 5A ) , N, N (R 5B ) , O or S;
• Q 1 is C 3 -C 11 cycloalkyl or 3-to 11-membered heterocycle, each optionally substituted with one or more R 3 andoptionally further substituted with one or more R 4 ;
• each R 1 is independently selected from the group consisting of hydrogen, halogen, CN, OR 10 , SR 10 , N (R 10 ) 2 , C (O) R 10 , OC (O) R 10 , C (O) OR 10 , C (O) N (R 10 ) 2 , N (R 10 ) C (O) R 10 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and 3-to 6-membered heterocyclyl, wherein each said C 1 -C 6 alkyl is optionally substituted with one or more R 11 , and each said C 3 -C 6 cycloalkyl and 3-to 6-membered heterocyclyl is optionally substituted with one or more R 12 ;
• each R 2 is independently selected from the group consisting of fluoro, oxo, thioxo, OR 13 , SR 13 , N (R 13 ) 2 , C (O) R 13 , OC (O) R 13 , C (O) OR 13 , C (O) N (R 13 ) 2 , N (R 13 ) C (O) R 13 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and 3-to 6-membered heterocyclyl, wherein each said C 1 -C 6 alkyl is optionally substituted with one or more R 14 , and each said C 3 -C 6 cycloalkyl and 3-to 6-membered heterocyclyl is optionally substituted with one or more R 15 ;
• each R 3 is independently selected from the group consisting of hydrogen, fluoro, oxo, thioxo, OR 16 , SR 16 , N (R 16 ) 2 , C (O) R 16 , OC (O) R 16 , C (O) OR 16 , C (O) N (R 16 ) 2 , N (R 16 ) C (O) R 16 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl, wherein each said C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl moiety is optionally substituted with one or more R 17A ;
• each R 4 is independently selected from the group consisting of C (O) - (C 2 -C 6 alkenyl) , N (R 16 ) C (O) (C 2 -C 6 alkenyl) , C (O) - (C 2 -C 6 alkynyl) , N (R 16 ) C (O) (C 2 -C 6 alkynyl) , C 6 -C 10 aryl, 5-to 10-membered heteroaryl, E 3 -C 6 -C 10 aryl, E 3 -5-to 10-membered heteroaryl, C 3 -C 6 cycloalkyl, 3-to 6-membered heterocyclyl, E 3 -C 3 -C 6 cycloalkyl, and E 3 -3-to 6-membered heterocyclyl, wherein each said C 2 -C 6 alkenyl and C 2 -C 6 alkynyl is optionally substituted with one or more R 17B , each said C 6 -C
• each E 3 is independently selected from the group consisting of -N (R 20 ) -, - (C (R 21 ) 2 ) y -N (R 20 ) -, -N (R 20 ) - (C (R 21 ) 2 ) y -, -O-, - (C (R 21 ) 2 ) y -O-, -O- (C (R 21 ) 2 ) y -, and - (C (R 21 ) 2 ) z -;
• R 5A is independently selected from the group consisting of hydrogen, halogen, CN, OR 22 , N (R 22 ) 2 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and 3-to 6-membered heterocyclyl, wherein each said C 1 -C 6 alkyl is optionally substituted with one or more R d , and each said C 3 -C 6 cycloalkyl, and 3-to 6-membered heterocyclyl is optionally substituted with one or more R e ;
• R 5B is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and 3-to 6-membered heterocyclyl, wherein each said C 1 -C 6 alkyl is optionally substituted with one or more R d , and each said C 3 -C 6 cycloalkyl, and 3-to 6-membered heterocyclyl is optionally substituted with one or more R e ;
• R 6 is independently selected from the group consisting of hydrogen, fluoro, OR 23 , N (R 23 ) 2 , and C 1 -C 6 alkyl, wherein each said C 1 -C 6 alkyl is optionally substituted with one or more R d ;
• R 7 is independently selected from the group consisting of hydrogen, fluoro, OR 24 , N (R 24 ) 2 , and C 1 -C 6 alkyl, wherein each said C 1 -C 6 alkyl is optionally substituted with one or more R d ;
• each R 8 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and 3-to 6-membered heterocyclyl, wherein each said C 1 -C 6 alkyl is optionally substituted with one or more R d , and each said C 3 -C 6 cycloalkyl and 3-to 6-membered heterocyclyl is optionally substituted with one or more R e ;
• each R 9 is independently selected from the group consisting of hydrogen, fluoro, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and 3-to 6-membered heterocyclyl, wherein each said C 1 -C 6 alkyl is optionally substituted with one or more R d , and each said C 3 -C 6 cycloalkyl and 3-to 6-membered heterocyclyl is optionally substituted with one or more R e , or two R 9 taken together are oxo;
• each R 10 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 3 -C 6 cycloalkyl, and 3-to 6-membered heterocyclyl;
• each R 11 is independently selected from the group consisting of fluoro, oxo, thioxo, OR a , SR a , N (R a ) 2 , C (O) R a , OC (O) R a , C (O) OR a , C (O) N (R a ) 2 , N (R a ) C (O) , C 3 -C 6 cycloalkyl, and 3-to 6-membered heterocyclyl, wherein each said C 3 -C 6 cycloalkyl and 3-to 6-membered heterocyclyl is optionally substituted with one or more R e ;
• each R 12 is independently selected from the group consisting of fluoro, oxo, thioxo, OR a , SR a , N (R a ) 2 , C (O) R a , OC (O) R a , C (O) OR a , C (O) N (R a ) 2 , N (R a ) C (O) , and C 1 -C 6 alkyl, wherein each said C 1 -C 6 alkyl is optionally substituted with one or more R d ;
• each R 13 is independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, C 3 -C 6 cycloalkyl, and 3-to 6-membered heterocyclyl;
• each R 15 is independently selected from the group consisting of fluoro, oxo, thioxo, OR b , SR b , N (R b ) 2 , C (O) R b , OC (O) R b , C (O) OR b , C (O) N (R b ) 2 , N (R b ) C (O) R b , and C 1 -C 6 alkyl, wherein each said C 1 -C 6 alkyl is optionally substituted with one or more R d ;
• each R 16 is independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, C 3 -C 6 cycloalkyl, and 3-to 6-membered heterocyclyl;
• each R 19 is independently selected from the group consisting of fluoro, oxo, thioxo, OR c , SR c , N (R c ) 2 , C (O) R c , OC (O) R c , C (O) OR c , C (O) N (R c ) 2 , N (R c ) C (O) R c , and C 1 -C 6 alkyl, wherein each said C 1 -C 6 alkyl is optionally substituted with one or more R d ;
• A is a 5-to 6-membered heteroaryl comprising X 1 , optionally substituted with one or more R 1 .
• A is a 6-membered heteroaryl comprising X 1 , optionally substituted with one or more R 1 .
• ring A is a 6- membered heteroaryl comprising X 1 , selected from pyridine, pyrimidine, pyrazine, pyridazine, or triazine, optionally substituted with one or more R 1 .
• A is pyridine or pyrimidine, optionally substituted with one or more R 1 .
• each of X 2 , X 3 , and X 4 is independently C (R 5A ) or N;
• X 1 , X 2 , X 3 , or X 4 is not C (R 5A ) ; or
• X 1 is C (R 5A ) , N, N (R 5B ) , O or S;
• each of X 2 and X 3 is independently C (R 5A ) , N, N (R 5B ) , O or S;
• X 1 is C (R 5A ) ;
• each said C 6 -C 10 aryl and 5-to 6-membered heteroaryl is optionally substituted with one or more R 1 .
• A is a 9-to 10-membered heteroaryl optionally substituted with one or more R 1 .
• A is a 9-to 10-membered heteroaryl selected from the group consisting of:
• X 1 is C (R 5A ) or N;
• X 2 , X 3 and X 4 are independently C, C (R 5A ) or N;
• each X 5 is independently C (R 5A ) , N, N (R 5B ) , O or S;
• each X 6 is independently C (R 5A ) or N, provided at least one X 6 is C (R 5A ) ;
• X 2 and X 3 are independently C or N;
• each X 6 is independently C (R 5A ) or N, provided at least one X 6 is C (R 5A ) ;
• X 1 , X 2 , X 3 , X 4 , X 5 , or X 6 is not C (R 5A ) ;
• one or more of X 1 , X 2 , X 3 , X 4 , X 5 , or X 6 is N. In some embodiments of Formula (I) or Formula (II) , two or more of X 1 , X 2 , X 3 , X 4 , X 5 , or X 6 is N.
• R 5A is independently selected from the group consisting of hydrogen, halogen, CN, OR 22 , N (R 22 ) 2 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and 3-to 6-membered heterocyclyl, wherein each said C 1 -C 6 alkyl is optionally substituted with one or more R d , and each said C 3 -C 6 cycloalkyl, and 3-to 6-membered heterocyclyl is optionally substituted with one or more R e .
• R 5A is hydrogen.
• R 22 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 fluoroalkyl. In some embodiments, R 22 is hydrogen.
• R 5B is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and 3-to 6-membered heterocyclyl, wherein each said C 1 -C 6 alkyl is optionally substituted with one or more R d , and each said C 3 -C 6 cycloalkyl, and 3-to 6- membered heterocyclyl is optionally substituted with one or more R e .
• R 5B is hydrogen or C 1 -C 6 alkyl.
• R 5B is hydrogen or C 1 -C 4 alkyl.
• A is a C 6 -C 10 aryl or 5-to 10-membered heteroaryl selected from the group consisting of:
• each said C 6 -C 10 aryl or 5-to 10-membered heteroaryl is optionally substituted with one or more R 1 .
• each R d is independently selected from the group consisting of fluoro, hydroxy, C 1 -C 4 alkoxy, oxo, NH 2 , NH (C 1 -C 4 alkyl) and N (C 1 -C 4 alkyl) 2 .
• each R e is independently selected from the group consisting of fluoro, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 alkoxy, oxo, NH 2 , NH (C 1 -C 4 alkyl) and N (C 1 -C 4 alkyl) 2 .
• each R 1 is independently selected from the group consisting of hydrogen, halogen, CN, OR 10 , SR 10 , N (R 10 ) 2 , C (O) R 10 , OC (O) R 10 , C (O) OR 10 , C (O) N (R 10 ) 2 , N (R 10 ) C (O) R 10 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and 3-to 6-membered heterocyclyl, wherein each said C 1 -C 6 alkyl is optionally substituted with one or more R 11 , and each said C 3 -C 6 cycloalkyl and 3-to 6-membered heterocyclyl is optionally substituted with one or more R 12 .
• each R 10 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 3 -C 6 cycloalkyl, and 3-to 6-membered heterocyclyl. In some embodiments, each R 10 is independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl. In some embodiments, each R 10 is independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl.
• each R 12 is independently selected from the group consisting of fluoro, oxo, thioxo, OR a , SR a , N (R a ) 2 , C (O) R a , OC (O) R a , C (O) OR a , C (O) N (R a ) 2 , N (R a ) C (O) , and C 1 -C 6 alkyl, wherein each said C 1 -C 6 alkyl is optionally substituted with one or more R d .
• each R 12 is independently selected from the group consisting of fluoro, OR a , N (R a ) 2 and C 1 -C 6 alkyl. In some such embodiments, each R a is independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl.
• each R 2 is independently selected from the group consisting of hydrogen, fluoro, oxo, OR 13 , N (R 13 ) 2 , and C 1 -C 6 alkyl optionally substituted with one or more R 14 .
• each R 2 is independently selected from the group consisting of fluoro, oxo, OR 13 , N (R 13 ) 2 , and C 1 -C 6 alkyl optionally substituted with one or more R 14 .
• n is 0. In some embodiments of Formula (II) , n is 1 and each R 2 is independently selected from the group consisting of fluoro, oxo, OR 13 , N (R 13 ) 2 , and C 1 -C 6 alkyl optionally substituted with one or more R 14 . In some such embodiments, each R 13 is independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl.
• each R 13 is independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, C 3 -C 6 cycloalkyl, and 3-to 6-membered heterocyclyl. In some embodiments, each R 13 is independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl and C 1 -C 4 fluoroalkyl. In some embodiments, each R 13 is independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl. In some embodiments, R 13 is hydrogen.
• each R 14 is independently selected from the group consisting of fluoro, oxo, thioxo, OR b , SR b , N (R b ) 2 , C (O) R b , OC (O) R b , C (O) OR b , C (O) N (R b ) 2 , N (R b ) C (O) R b , C 3 -C 6 cycloalkyl, and 3-to 6-membered heterocyclyl, wherein each said C 3 -C 6 cycloalkyl and 3-to 6-membered heterocyclyl is optionally substituted with one or more R e .
• each R 14 is independently selected from the group consisting of fluoro, OR b , and N (R b ) 2 .
• each R b is independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl.
• each R 15 is independently selected from the group consisting of fluoro, oxo, thioxo, OR b , SR b , N (R b ) 2 , C (O) R b , OC (O) R b , C (O) OR b , C (O) N (R b ) 2 , N (R b ) C (O) R b , and C 1 -C 6 alkyl, wherein each said C 1 -C 6 alkyl is optionally substituted with one or more R d .
• E 2 is selected from the group consisting of a bond, -NH-, - (CH 2 ) t NH-, -NH (CH 2 ) t -, -C (O) NH-and -NHC (O) -and t is an integer from 1 to 4.
• each R 8 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and 3-to 6-membered heterocyclyl, wherein each said C 1 -C 6 alkyl is optionally substituted with one or more R d , and each said C 3 -C 6 cycloalkyl and 3-to 6-membered heterocyclyl is optionally substituted with one or more R e .
• each R 9 is independently selected from the group consisting of hydrogen, fluoro, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and 3-to 6-membered heterocyclyl, wherein each said C 1 -C 6 alkyl is optionally substituted with one or more R d , and each said C 3 -C 6 cycloalkyl and 3-to 6-membered heterocyclyl is optionally substituted with one or more R e , or two R 9 taken together are oxo.
• each R 8 is hydrogen.
• each R 9 is hydrogen.
• each R 8 and R 9 is hydrogen.
• E 1 is a bond
• Q 1 is a 3-to 11-membered heterocycle optionally substituted by one or more R 3 , and optionally further substituted with one or more R 4 .
• E 1 is selected from the group consisting of a bond, -N (R 8 ) -, - (C (R 9 ) 2 ) t N (R 8 ) -and -N (R 8 ) (C (R 9 ) 2 ) t -, and Q 1 is a 3-to 11-membered heterocycle, optionally substituted by one or more R 3 , and optionally further substituted with one or more R 4 .
• E 1 is selected from the group consisting of -N (R 8 ) -, - (C (R 9 ) 2 ) t N (R 8 ) -and -N (R 8 ) (C (R 9 ) 2 ) t -, and Q 1 is a 3-to 11-membered heterocycle, optionally substituted by one or more R 3 , and optionally further substituted with one or more R 4 .
• Q 1 is a 3-to 11-membered heterocycle substituted with R 4 , and optionally further substituted with one or more R 3 . In some embodiments of Formula (I) or Formula (II) , Q 1 is a 3-to 11-membered heterocycle substituted with R 3 , and optionally further substituted with one or more R 4 .
• Q 1 is a C 3 -C 11 cycloalkyl substituted with R 4 , and optionally further substituted with one or more R 3 .
• Q 1 is a C 3 -C 11 cycloalkyl substituted with R 3 , and optionally further substituted with one or more R 4 .
• Q 1 is a 3-to 11-membered heterocycle substituted with R 3 , wherein R 3 is C 1 -C 6 alkyl optionally further substituted with R 17A .
• each R 17A is independently selected from the group consisting of fluoro, OR c , andN (R c ) 2 .
• Q 1 is a C 3 -C 11 cycloalkyl substituted with R 3 , wherein R 3 is C 1 -C 6 alkyl optionally further substituted with R 17A .
• each R 17A is independently selected from the group consisting of fluoro, OR c , andN (R c ) 2 .
• Q 1 is a C 3 -C 11 cycloalkyl substituted with R 4 , wherein R 4 is independently selected from the group consisting of C (O) (C 2 -C 6 alkenyl) , N (R 16 ) C (O) (C 2 -C 6 alkenyl) , (C 1 -C 6 alkylene) -N (R 16 ) C (O) (C 2 -C 6 alkenyl) , C (O) (C 2 -C 6 alkynyl) , N (R 16 ) C (O) (C 2 -C 6 alkynyl) , and (C 1 -C 6 alkylene) -N (R 16 ) C (O) (C 2 -C 6 alkynyl) , and each said C 2 -C 6 alkenyl and C 2 -C 6 alkynyl is optionally substituted with one or more R 17B .
• each R 17A and R 17B is independently selected from the group consisting of fluoro, oxo, thioxo, OR c , SR c , N (R c ) 2 , C (O) R c , OC (O) R c , C (O) OR c , C (O) N (R c ) 2 , N (R c ) C (O) R c , C 3 -C 6 cycloalkyl, and 3-to 6-membered heterocyclyl, wherein each said C 3 -C 6 cycloalkyl and 3-to 6-membered heterocyclyl is optionally substituted with one or more R e .
• each R 18 is independently selected from the group consisting of halogen, CN, OR c , SR c , N (R c ) 2 , C (O) R c , OC (O) R c , C (O) OR c , C (O) N (R c ) 2 , N (R c ) C (O) R c , C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, and 3-to 6-membered heterocyclyl, wherein each said C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 alkenyl, and C 2 -C 6 alkynyl is optionally substituted with one or more R d , and each said C 3 -C 6 cycl
• E 1 is a bond
• Y 3 is N
• Q 1 is a 3-to 11-membered heterocycle comprising Y 3 , optionally substituted with one or more R 3 and optionally further substituted with one or more R 4 .
• E 1 is a bond.
• E 1 is -N (R 8 ) -
• Y 3 is C (R 3 )
• Q 1 is a C 3 -C 11 cycloalkyl or 3-to 11-membered heterocycle comprising Y 3 , optionally substituted with one or more R 3 and optionally further substituted with one or more R 4 .
• R 8 is hydrogen and R 3 is hydrogen.
• E 1 is -N (R 8 ) -
• Q 1 is a C 3 -C 11 cycloalkyl or 3-to 11-membered heterocycle optionally substituted by one or more R 3 and optionally further substituted with one or more R 4 .
• aldehydes, ketones, imines, or acetals alkyl moieties substituted with halo, hydroxy, alkoxy, amide, ketone, carboxylic acid, carboxylic acid ester, sulfonate ester, boronic acid, boronate ester, etc.; protected or unprotected thiols thioethers, disulfides; halo substituted heteroaryls; azides; nitriles; alkenes or alkynes; epoxides, aziridines, and the like.
• L 1 is a bond or a bivalent chemical linker. In some embodiments, L 1 is a bond. In some embodiments, L 1 is a bivalent chemical linker. In some such embodiments, L 1 is a bond or a bivalent chemical linker of Formula - (J) x -. In some such embodiments, L 1 is a bond or a bivalent chemical linker of Formula (III) .
• each R 25 is hydrogen. In some embodiments, each R 26 is hydrogen. In some such embodiments, each R 25 and R 26 is hydrogen. In some embodiments, x is an integer from 1 to 20. In some embodiments, x is an integer from 1 to 12. In some embodiments, x is an integer from 1 to 10. In some embodiments, x is an integer from 1 to 8. In some embodiments, x is an integer from 1 to 6.
• L 1 is a bond or a bivalent chemical linker of formula - (J) x -, wherein each -J-is independently selected from the group consisting of -N (R 25 ) -, -C (R 26 ) 2 -, and -O-; each R 25 and R 26 is hydrogen; and x is an integer from 1 to 20.
• L 1 is a bond or a bivalent chemical linker of formula - (J) x -selected from [-C (R 26 ) 2 -] 1-12 or [- (C (R 26 ) 2 ) 2 O-] 1-6 .
• each R 26 is hydrogen.
• L 1 is a bond or a bivalent chemical linker of formula - (J) x -selected from [-CH 2 -] 1-10 or [- (CH 2 ) 2 O-] 1-6 .
• L 1 is a bond or a bivalent chemical linker of formula - (J) x -selected from [-C (R 26 ) 2 -] 1-10 , [- (C (R 26 ) 2 ) 2 O-] 1-6 , C 3 -C 11 cycloalkyl, 3-to 11-membered heterocyclyl, [-C (R 26 ) 2 -] 1-6 -C 3 -C 11 cycloalkyl, [-C (R 26 ) 2 -] 1-6 -3-to 11-membered heterocyclyl, C 3 -C 11 cycloalkyl- [-C (R 26 ) 2 -] 1-6 , 3-to 11-membered heterocyclyl- [-C (R 26 ) 2 -] 1-6 , [-C (R 26 ) 2 -] 1-6 -C 3 -C 11 cycloalkyl- [- C (R 26 )
• L 1 is an optionally substituted C 1 -C 10 alkylene or 1-to 10-membered heteroalkylene linker. In some embodiments of Formula (I) or Formula (II) , L 1 is an optionally substituted C 1 -C 8 alkylene or 1-to 8-membered heteroalkylene linker. In some embodiments of Formula (I) or Formula (II) , L 1 is an optionally substituted C 1 -C 6 alkylene or 1-to 6-membered heteroalkylene linker.
• one or more groups -J-of - (J) x - are sequentially arranged in a pattern of repeating polyethylene glycol (PEG) units comprising - (CH 2 ) (CH 2 ) (O) -.
• PEG polyethylene glycol
• one or more -J-of - (J) x - are sequentially arranged in a pattern of alternating polyethylene glycol (PEG) units comprising – (CH 2 ) (CH 2 ) (O) -and carboxamide units comprising -C (O) -N (R 25 ) -.
• PEG polyethylene glycol
• Z 2 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and an amine protecting group.
• Z 2 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and an amine protecting group; or Z 2 is absent when Y 1 is O.
• Z 1 is Z 2 , wherein: Z 2 is hydrogen or C 1 -C 4 alkyl when bound to a ring carbon atom; or Z 2 is hydrogen, C 1 -C 4 alkyl, or an amine protecting group when bound to a ring nitrogen atom.
• Z 1 is Z 2 , wherein: Z 2 is hydrogen or C 1 -C 4 alkyl when Y 1 is C (R 6 ) ; Z 2 is hydrogen, C 1 -C 4 alkyl, or an amine protecting group when Y 1 is N; or Z 2 is absent when Y 1 is O, with the proviso that the compound is not N- (1- (3-fluorophenyl) piperidin-3-yl) -6-morpholinopyrimidin-4-amine or N- (1- (3-fluorophenyl) piperidin-3-yl) -4-morpholinopyrimidin-2-amine.
• compositions comprising a compound of Formula (I) or Formula (II) , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
• methods of treatment comprising administering a compound of Formula (I) or Formula (II) , or a pharmaceutically acceptable salt or pharmaceutical composition thereof, to a subject in need thereof.
• compounds of Formula (I) or Formula (II) or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for use in treating a disease or disorder in a subject in need of such treatment.
• a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for treating a disease or disorder in a subject in need of such treatment.
• the target protein comprises a transcription factor, CBP, p300, a kinase, a receptor, a tyrosine receptor kinase, TrkA, TrkB, TrkC, a cyclin dependent kinase, CDK4, CDK6, CDK9, a cyclin, or cyclin D, or a combination thereof.
• the target protein comprises CDK4 or a cyclin D.
• the target protein comprises CDK4.
• the target protein comprises cyclin D.
• the target protein comprises cyclin D3.
• administering the compound or composition to the cell comprises administering the compound or composition to a subject comprising the cell.
• Some embodiments relate to a method of treatment, comprising administering an effective amount of the compound or composition to a subject in need thereof.
• the subject is a human.
• the in vivo modified or engineered protein may include a DDB1-and CUL4-associated factor 1 (DCAF1) protein directly bound to a ligand at a binding region of the DCAF1 protein, wherein the ligand comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
• the binding region comprises a WD40 domain.
• the binding region on the DCAF1 protein comprises one or more of the following DCAF1 residues: THR1097, ALA1137, THR1139, HIS1140, THR1155, HIS1180, TYR1181, ARG1225, CYS1227, ILE1262, VAL1265, ARG1298, VAL1299, VAL1300, LYS1327, PRO1329 or PHE1355.
• the ligand binds the DCAF1 protein non-covalently. In some embodiments, the ligand binds the DCAF1 protein covalently.
• the in vivo modified or engineered protein may include a DCAF1 protein comprising a non-naturally occurring covalent modification at a cysteine of the DCAF1.
• the DCAF1 comprises an amino acid sequence at least 80%identical to the amino acid sequence of SEQ ID NO: 1.
• the DCAF1 comprises the amino acid sequence of SEQ ID NO: 1.
• the covalent modification is at cysteine 1227 with regard to SEQ ID NO: 1.
• the covalent modification is at cysteine 1113 with regard to SEQ ID NO: 1.
• the covalent modification is formed by a Michael addition reaction.
• FIG. 1 shows a docking model of an exemplary compound bound to a binding region of a DCAF1 protein.
• FIG. 2 shows Surface Plasmon Resonance (SPR) binding data of compounds B-072, B-124 and B-151 to purified DCAF1 (1058-1396) .
• FIG. 3 shows mass spectroscopic analysis of covalent binders B-007, B-008, B-020, B-092, B-099 and B-103 to purified DCAF1 (1058-1396) .
• FIG. 4 shows example data confirming CDK4 protein levels were reduced in MOLT-4 cells in a concentration-dependent manner by heterobifunctional compounds, in accordance with some embodiments.
• the binding between the DCAF1 protein and the compound is non-covalent. In some embodiments, the binding between the DCAF1 protein and the compound is covalent. In some embodiments, the modified protein may be used in a method described herein. In some embodiments, the ligand is bound to a DCAF1 fragment. In some embodiments, the ligand is bound to a full-length DCAF1 protein.
• the ligand-protein complex comprises a DCAF1 protein.
• the DCAF1 protein is bound to a ligand.
• the ligand may be a compound described herein, for example a compound of Tables 1-5, or Formula (I) or Formula (II) .
• the DCAF1 protein is directly bound to the compound.
• the binding between the DCAF1 protein and the compound is non-covalent.
• the binding between the DCAF1 protein and the compound is covalent.
• the ligand-protein complex may be formed in vivo.
• the binding region of the DCAF1 protein comprises an alanine. In some embodiments, the binding region of the DCAF1 protein comprises an arginine. In some embodiments, the binding region of the DCAF1 protein comprises a cysteine. In some embodiments, the binding region of the DCAF1 protein comprises a histidine. In some embodiments, the binding region of the DCAF1 protein comprises a lysine. In some embodiments, the binding region of the DCAF1 protein comprises a proline. In some embodiments, the binding region of the DCAF1 protein comprises a threonine. In some embodiments, the binding region of the DCAF1 protein comprises a tyrosine. In some embodiments, the binding region of the DCAF1 protein comprises a valine.
• the binding region of the DCAF1 protein comprises one or more amino acids after amino acid position 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, or 1500 of the DCAF1 protein. In some embodiments, the binding region of the DCAF1 protein comprises one or more amino acids before amino acid position 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, or 1500 of the DCAF1 protein. In some embodiments, the binding region of the DCAF1 protein comprises one or more amino acids between amino acid positions 1095 and 1355 of the DCAF1 protein.
• the binding region of the DCAF1 protein comprises one or more of the following DCAF1 residues: THR1097, ALA1137, THR1139, HIS1140, THR1155, HIS1180, TYR1181, ARG1225, CYS1227, ILE1262, VAL1265, ARG1298, VAL1299, VAL1300, LYS1327, PRO1329 or PHE1355.
• the binding between the DCAF1 protein and the ligand comprises a binding affinity with an equilibrium dissociation constant (K d ) below 1500 ⁇ M, a K d below 1250 ⁇ M, a K d below 1000 ⁇ M, a K d below 750 ⁇ M, a K d below 500 ⁇ M, a K d below 450 ⁇ M, a K d below 400 ⁇ M, a K d below 350 ⁇ M, a K d below 300 ⁇ M, a K d below 250 ⁇ M, a K d below 200 ⁇ M, a K d below 150 ⁇ M, a K d below 100 ⁇ M, a K d below 90 ⁇ M, a K d below 80 ⁇ M, a K d below 70 ⁇ M, a K d below 60 ⁇ M, below 50 ⁇ M, a K d below 45 ⁇ M, a K d below 40 ⁇ M, a K d below
• the K d is 100 ⁇ M or less. In some embodiments, the K d is 70 ⁇ M or less. In some embodiments, the K d is 40 ⁇ M or less. In some embodiments, the K d is about 100 ⁇ M or less. In some embodiments, the K d is about 70 ⁇ M or less. In some embodiments, the K d is about 40 ⁇ M or less.
• the binding between the DCAF1 protein and the ligand comprises a binding affinity with a K d above 1250 ⁇ M, a K d above 1000 ⁇ M, a K d above 750 ⁇ M, a K d above 500 ⁇ M, a K d above 450 ⁇ M, a K d above 400 ⁇ M, a K d above 350 ⁇ M, a K d above 300 ⁇ M, a K d above 250 ⁇ M, a K d above 200 ⁇ M, a K d above 150 ⁇ M, a K d above 100 ⁇ M, a K d above 90 ⁇ M, a K d above 80 ⁇ M, a K d above 70 ⁇ M, a K d above 60 ⁇ M, above 50 ⁇ M, a K d above 45 ⁇ M, a K d above 40 ⁇ M, a K d above 35 ⁇ M, a K d above 30 ⁇ M, a binding affinity with
• the ligand may have a molecular weight greater than 2500 daltons, greater than 2250 daltons, greater than 2000 daltons, greater than 1750 daltons, greater than 1500 daltons, or greater than 1250 daltons.
• the ligand may have a molecular weight greater than 1000 daltons, greater than 900 daltons, greater than 800 daltons, greater than 700 daltons, greater than 600 daltons, or greater than 500 daltons.
• administering the compound or composition to a cell comprises administering the compound or composition to a subject comprising the cell.
• Some embodiments relate to a method of treatment, comprising administering an effective amount of the compound or composition to a subject in need thereof.
• the subject is a human.
• the subject has cancer.
• Representative analogs of the DCAF1 binders in Table 1 include compounds wherein (a) a morpholino moiety is replaced by a piperazine (which can serve as a point of attachment to a linker) , or another suitable cycloalkyl or heterocyclyl ring; (b) a carboxamide moiety is modified to install a linker (e.g., C (O) NHMe is replaced by (e.g., C (O) NH-linker-) ; or (c) an alkyl, halo or OH moiety is modified to install a linker; which in each case may serve as the site of attachment to Z 1 (e.g., L 1 -P or L 1 -G) .
• a linker e.g., C (O) NHMe is replaced by (e.g., C (O) NH-linker-)
• an alkyl, halo or OH moiety is modified to install a linker; which in each case may serve
• a DCAF1 binding moiety shown in Table 2 may be used as DCAF1 binders on their own or may be included in another compound as a DCAF1 binding moiety.
• the compounds in Table 2 may be included as part of a heterobifunctional molecule that includes a DCAF1 binding moiety linked to a target protein binding moiety.
• analogs of the DCAF1 binding moieties in Table 2 that permit further modification, e.g., as a point of attachment to a linker and/or a protein binding moiety.
• Representative analogs of the DCAF1 binders in Table 2 include compounds wherein (a) a morpholino moiety is replaced by a piperazine analog (wherein the additional nitrogen atom can serve as a point of attachment) ; (b) a carboxamide moiety is modified to install a linker; or (c) an alkyl, halo or OH moiety is modified to install a linker; which in each case may serve as the site of attachment to L 1 -P or L 1 -G.
• the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd value of 100 ⁇ M, 90 ⁇ M, 80 ⁇ M, 70 ⁇ M, 60 ⁇ M, 50 ⁇ M, 45 ⁇ M, 40 ⁇ M, 35 ⁇ M, 30 ⁇ M, 25 ⁇ M, 20 ⁇ M, 15 ⁇ M, 14 ⁇ M, 13 ⁇ M, 12 ⁇ M, 11 ⁇ M, 10 ⁇ M, 9 ⁇ M, 8 ⁇ M, 7 ⁇ M, 6 ⁇ M, 5 ⁇ M, 4 ⁇ M, 3 ⁇ M, 2 ⁇ M, or 1 ⁇ M, or a range of Kd values defined by any two of the aforementioned Kd values.
• the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd below 100 ⁇ M. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd below 90 ⁇ M. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd below 80 ⁇ M. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd below 70 ⁇ M. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd below 60 ⁇ M.
• the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd below 25 ⁇ M. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd below 20 ⁇ M. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd below 15 ⁇ M. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd below 14 ⁇ M. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd below 13 ⁇ M.
• the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd below 2 ⁇ M. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd below 1 ⁇ M.
• the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd above 100 ⁇ M. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd above 90 ⁇ M. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd above 80 ⁇ M. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd above 70 ⁇ M. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd above 60 ⁇ M.
• the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd above 12 ⁇ M. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd above 11 ⁇ M. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd above 10 ⁇ M. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd above 9 ⁇ M. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd above 8 ⁇ M.
• the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd above 7 ⁇ M. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd above 6 ⁇ M. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd above 5 ⁇ M. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd above 4 ⁇ M. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd above 3 ⁇ M.
• the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd ⁇ 20 ⁇ M, a Kd from 20-100 ⁇ M, or a Kd > 100 ⁇ M. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd ⁇ 20 ⁇ M. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd from 20-100 ⁇ M. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd > 100 ⁇ M.
• the binding between the DCAF1 binding moiety and DCAF1 is non-covalent. In some embodiments, the binding between the DCAF1 binding moiety and DCAF1 is covalent.
• the linker is terminated with a reactive functional group (e.g., NH 2 , COOH, halogen, OH, OMs, OTs, or the like) which can serve as a point for further modification of the linker or attachment to a protein binding moiety.
• a compound comprising an aspect of a molecule shown in Table 3 is bound to DCAF1 via the DCAF1 binding moiety.
• the linker is covalently connected to a DCAF1 binding moiety described herein.
• the linker is covalently connected to a target protein binding moiety described herein.
• the linker is covalently connected to a DCAF1 binding moiety and to a target protein binding moiety.
• the linker is incorporated into a ligand described herein.
• each of the linkers described in this section may be included in a compound of Formula (I) or Formula (II) (i.e., as the linker L 1 ) , or Formula (X) (i.e., as the linker L 2 ) .
• a linker is a bond.
• a linker includes more than a bond.
• the linker comprises optionally substituted polyethylene glycol (PEG) .
• the linker comprises an optionally substituted alkyl chain.
• the linker is a straight chain alkane.
• the linker comprises optionally substituted C 2 -C 30 , C 2 -C 25 , C 3 -C 25 , C 4 -C 10 , C 6 -C 12 , C 6 -C 18 , or C 4 -C 20 alkyl units.
• the linker comprises an optionally substituted carbocycle ring.
• the linker comprises an optionally substituted heterocycle ring. In some embodiments, the linker comprises an optionally substituted aryl ring. In some embodiments, the linker comprises an optionally substituted heteroaryl ring. In some embodiments, the linker comprises one or more ethers. In some embodiments, the linker comprises a C 2 -C 30 , C 2 -C 25 , C 3 -C 25 , C 4 -C 10 , C 6 -C 12 , C 6 -C 18 , or C 4 -C 20 alkylether units.
• the PEG is optionally substituted 1-5, 2-7, 2-10, 2-20, 5-25, or 4-30 - (O-CH 2 CH 2 ) -units in length.
• the linker comprises amines.
• the linker comprises a C 2 -C 30 , C 2 -C 25 , C 3 -C 25 , C 4 -C 10 , C 6 -C 12 , C 6 -C 18 , or C 4 -C 20 alkylamino units.
• the linker comprises optionally substituted 1-5, 2-7, 2-10, 2-20, 5-25, or 4-30 - (NH-CH 2 CH 2 ) -units.
• the linker comprises amides. In some embodiments, the linker comprises sulfonamides. In some embodiments, the linker comprises carbamides. In some embodiments, the linker comprises carbamates. In some embodiments, the linker comprises carbonates. In some embodiments, a compound comprises a DCAF1 binding moiety, a linker, and/or a target protein binding moiety.
• the linker e.g., L 1 or L 2
• the linker is a bivalent moiety of Formula (III) :
• R’and R are independently selected from null, R r , optionally substituted (C 1 -C 8 alkylene) -R r (preferably, CH 2 -R r ) , optionally substituted R r - (C 1 -C 8 alkylene) , optionally substituted (C 1 -C 8 alkylene) -R r - (C 1 -C 8 alkylene) , or a bivalent moiety comprising of optionally substituted C 1 -C 8 alkylene, optionally substituted C 2 -C 8 alkenylene, optionally substituted C 2 -C 8 alkynylene, optionally substituted C 1 -C 8 heteroalkylene, optionally substituted C 2 -C 8 heteroalkenylene, optionally substituted C 2 -C 8 heteroalkynylene, optionally substituted C 1 -C 8 hydroxyalkylene, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkylene,
• R x and R y are independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 2 -C 8 heteroalkenyl, optionally substituted C 2 -C 8 heteroalkynyl, optionally substituted C 1 -C 8 alkoxyalkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted C 3 -C 13 cycloalkyl, optionally substituted 3-13 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
• j is an integer from 0 to 15.
• the linker of Formula (III) may be included as L 1 in a compound of Formula (I) or Formula (II) .
• the linker of Formula (III) may be included as L 2 in a compound of Formula (X) .
• U is (CH 2 ) 0-12
• W 1 at each occurrence, is independently selected from C 1 -C 8 alkylene
• W 2 is null
• V is null.
• U is (CH 2 ) 0-12 N (R x )
• W 1 at each occurrence, is independently selected from C 1 -C 8 alkylene
• W 2 is null
• V is null .
• U is (CH 2 ) 0-12 C (O) , W 1 , at each occurrence, is independently selected from C 1 -C 8 alkylene, W 2 is null, and V is null.
• U is (CH 2 ) 0-12 OC (O) , W 1 , at each occurrence, is independently selected from C 1 -C 8 alkylene, W 2 is null, and V is null .
• U is (CH 2 ) 0- 12 N (R x ) C (O)
• W 1 at each occurrence, is independently selected from C 1 -C 8 alkylene
• W 2 is null
• V is null
• U is (CH 2 ) 0-12 C (O) O
• W 1 at each occurrence, is independently selected from C 1 -C 8 alkylene
• W 2 is null
• V is null.
• linker of Formula (III) U is (CH 2 ) 0-12 C (O) N (R x ) , W 1 , at each occurrence, is independently selected from C 1 -C 8 alkylene, W 2 is null, and V is null.
• j is an integer from 0 to 10. In some embodiments of linker of Formula (III) , j is an integer from 2 to 7. In some embodiments of linker of Formula (III) , j is an integer from 5 to10.
• U is (CH 2 ) 0- 12 C (O) , W 1 , at each occurrence, is independently selected from C 1 -C 8 alkylene, W 2 is O, and V is C 1 -C 8 alkylene.
• U is (CH 2 ) 0-12 OC (O) , W 1 , at each occurrence, is independently selected from C 1 -C 8 alkylene, W 2 is O, and V is C 1 -C 8 alkylene.
• U is (CH 2 ) 0-12 N (R x ) C (O)
• W 1 at each occurrence, is independently selected from C 1 -C 8 alkylene
• W 2 is O
• V is C 1 -C 8 alkylene.
• U is (CH 2 ) 0-12 C (O) O
• W 1 at each occurrence, is independently selected from C 1 -C 8 alkylene
• W 2 is O
• V is C 1 -C 8 alkylene.
• linker of Formula (III) U is (CH 2 ) 0-12 C (O) N (R x ) , W 1 , at each occurrence, is independently selected from C 1 -C 8 alkylene, W 2 is O, and V is C 1 -C 8 alkylene .
• j is an integer from 0 to 12. In some embodiments of linker of Formula (III) , j is an integer from 2 to 7. In some embodiments of linker of Formula (III) , j is an integer from 5 to 12.
• U is (CH 2 ) 0-12
• W 1 at each occurrence, is independently selected from C 1 -C 8 alkylene
• W 2 is N (R y )
• V is C 1 -C 8 alkylene.
• U is (CH 2 ) 0-12 N (R x )
• W 1 at each occurrence, is independently selected from C 1 -C 8 alkylene
• W 2 is N (R y )
• V is C 1 -C 8 alkylene .
• U is (CH 2 ) 0-12 C (O)
• W 1 at each occurrence, is independently selected from C 1 -C 8 alkylene
• W 2 is N (R y )
• V is C 1 -C 8 alkylene.
• U is (CH 2 ) 0-12 OC (O)
• W 1 at each occurrence, is independently selected from C 1 -C 8 alkylene
• W 2 is N (R y )
• V is C 1 -C 8 alkylene.
• U is (CH 2 ) 0-12 N (R x ) C (O)
• W 1 at each occurrence, is independently selected from C 1 -C 8 alkylene
• W 2 is N (R y )
• V is C 1 -C 8 alkylene.
• U is (CH 2 ) 0-12 C (O) O
• W 1 at each occurrence, is independently selected from C 1 -C 8 alkylene
• W 2 is N (R y )
• V is C 1 -C 8 alkylene.
• linker of Formula (III) U is (CH 2 ) 0- 12 C (O) N (R x ) , W 1 , at each occurrence, is independently selected from C 1 -C 8 alkylene, W 2 is N (R y ) , and V is C 1 -C 8 alkylene.
• j is an integer from 0 to 12. In some embodiments of linker of Formula (III) , j is an integer from 2 to 7. In some embodiments of linker of Formula (III) , j is an integer from 5 to 12.
• the linker is of Formula (IIIa) :
• R s , R t , R u and R v are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 2 -C 8 heteroalkenyl, optionally substituted C 2 -C 8 heteroalkynyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkoxyalkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 alkylamino, and optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted 3-10 membered
• U, W, and V at each occurrence, are independently selected from null, or bivalent moiety selected from R’-R”, R’COR”, R’CO 2 R”, R’C (O) N (R x ) R”, R’C (S) N (R x ) R”, R’OR”, R’OC (O) R”, R’OC (O) OR”, R’OCON (R x ) R”, R’SR”, R’SOR”, R’SO 2 R”, R’SO 2 N (R x ) R”, R’N (R x ) R”, R’N (R x ) COR”, R’N (R x ) C (O) OR”, R’N (R x ) CON (R y ) R”, R’N (R x ) C (S) R”, R’N (R x ) S (O) R”, R’N (R x ) S (O) 2 R”, R’N (R x ) S (O) 2 N (R y )
• R’and R are independently selected from null, optionally substituted (C 1 -C 8 alkylene) -R r (preferably, CH 2 -R r ) , optionally substituted R r - (C 1 -C 8 alkylene) , optionally substituted (C 1 -C 8 alkylene) -R r - (C 1 -C 8 alkylene) , or a bivalent moiety comprising of optionally substituted C 1 -C 8 alkylene, optionally substituted C 2 -C 8 alkenylene, optionally substituted C 2 -C 8 alkynylene, optionally substituted C 1 -C 8 heteroalkylene, optionally substituted C 2 -C 8 heteroalkenylene, optionally substituted C 2 -C 8 heteroalkynylene, optionally substituted C 1 -C 8 hydroxyalkylene, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkylene, optionally substituted C 1 -C 8
• R r at each occurrence, is selected from optionally substituted 3-10 membered cycloalkyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
• R x and R y are independently selected from hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 2 -C 8 heteroalkenyl, optionally substituted C 2 -C 8 heteroalkynyl, optionally substituted C 1 -C 8 alkoxyalkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted 3-10 membered cycloalkyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or
• R’and R”, R x and R y , R’and R x , R’and R y , R” and R x , R” and R 6 together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;
• l at each occurrence, is 0 to 15;
• the linker is of Formula (IIIb) :
• R s and R t are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, and optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 2 -C 8 heteroalkenyl, optionally substituted C 2 -C 8 heteroalkynyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkoxy C 1 -C 8 alkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 alkylamino, C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted 3-10 membered cycloalkyl, optionally substituted C 1
• R s and R t together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;
• R s and R t are independently selected from hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 2 -C 8 heteroalkenyl, optionally substituted C 2 -C 8 heteroalkynyl, optionally substituted C 1 -C 8 alkoxyalkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted 3-10 membered cycloalkyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or
• R’and R”, R s and R t , R’and R s , R’and R t , R” and R s , R” and R t together with the atom to which they are connected optionally form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;
• o 0 to 15.
• the linker is of Formula (IIIc) :
• X at each occurrence, is selected from O, NH, and NR aa ;
• U and V are independently selected from null, or bivalent moiety selected from R’-R”, R’COR”, R’CO 2 R”, R’C (O) N (R x ) R”, R’C (S) N (R x ) R”, R’OR”, R’OC (O) R”, R’OC (O) OR”, R’OCON (R x ) R”, R’SR”, R’SOR”, R’SO 2 R”, R’SO 2 N (R x ) R”, R’N (R x ) R”, R’N (R x ) COR”, R’N (R x ) C (O) OR”, R’N (R x ) CON (R y ) R”, R’N (R x ) C (S) R”, R’N (R x ) S (O) R”, R’N (R x ) S (O) 2 R”, R’N (R x ) S (O) 2 N (R y ) R”, optionally substituted C 1
• k at each occurrence, is 0 to 15;
• U, W 1 , W 2 , and V are bivalent moieties independently selected from the group consisting of null, R’ -R” , R’ COR” , R’ CO 2 R” , R’ C (O) N (R x ) R” , R’ C (S) N (R x ) R” , R’ OR” , R’ OC (O) R” , R’ OC (O) OR” , R’ OCON (R x ) R” , R’ SR” , R’ SOR” , R’ SO 2 R” , R’ SO 2 N (R x ) R” , R’ N (R x ) R” , R’ N (R x ) COR” , R’ N (R x ) C (O) OR” , R’ N (R x ) CON (R y ) R” , R’ N (R x ) C (S) R” , R’ N N (R x
• R x and R y are independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 2 -C 8 heteroalkenyl, optionally substituted C 2 -C 8 heteroalkynyl, optionally substituted C 1 -C 8 alkoxyalkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
• U and V are independently selected from null, CO, NH, NH-CO, CO-NH, CH 2 -NH-CO, CH 2 -CO-NH, NH-CO-CH 2 , CO-NH-CH 2 , CH 2 -NH-CH 2 -CO-NH, CH 2 -NH-CH 2 -NH-CO, -CO-NH, CO-NH-CH 2 -NH-CH 2 , CH 2 -NH-CH 2 .
• a 1 , B 1 , C 1 and D 1 are independently selected from null, O, CO, SO, SO 2 , NR bb , and CR bb R cc ;
• a 2 , B 2 , C 2 , and D 2 at each occurrence, are independently selected from N, and CR bb ;
• a linker has the structure - (CH 2 CH 2 O) 1-12 (CH 2 ) 0-12 -.
• a linker has the structure - (CH 2 CH 2 O) 1-12 (CH 2 ) 2 -.
• a linker has the structure - (CH 2 ) 0-12 NH (CH 2 CH 2 O) 1-12 (CH 2 ) 2 -.
• a linker has the structure -NH (CH 2 CH 2 O) (CH 2 ) 2 -, -NH (CH 2 CH 2 O) 2 (CH 2 ) 2 -, -NH (CH 2 CH 2 O) 3 (CH 2 ) 2 -, -NH (CH 2 CH 2 O) 4 (CH 2 ) 2 -, -NH (CH 2 CH 2 O) 5 (CH 2 ) 2 -, -NH (CH 2 CH 2 O) 6 (CH 2 ) 2 -, -NH (CH 2 CH 2 O) 7 (CH 2 ) 2 -, -NH (CH 2 CH 2 O) 8 (CH 2 ) 2 -, -NH (CH 2 CH 2 O) 9 (CH 2 ) 2 -, -NH (CH 2 CH 2 O) 10 (CH 2 ) 2 -, -NH (CH 2 CH 2 O) 11 (CH 2 ) 2 -, or -NH (CH 2 CH 2 O) 12 (CH 2 ) 2 -.
• a target protein comprises a kinase. In some embodiments, a target protein comprises a cyclin-dependent kinase (CDK) . In some embodiments, a target protein comprises cyclin-dependent kinase 4 (CDK4) or cyclin-dependent kinase 6 (CDK6) . In some embodiments, a target protein comprises CDK4. In some embodiments, a target protein comprises CDK6. In some embodiments, a target protein comprises CDK9. In some embodiments, a target protein comprises CDK, CDK1, CDK2, CDK3, CDK4, CDK6, CDK7, CDK8, CDK9, CDK10, CDK11, CDK12, or CDK13.
• Gq a histamine receptor, 5-lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside phosphorylase, GAPDH, a trypanosomal protein, glycogen phosphorylase, carbonic anhydrase, a chemokine receptor, JAK, STAT, RXR, RAR, HIV 1 protease, HIV 1 integrase, influenza, neuraminidase, hepatitis B reverse transcriptase, sodium channel, multi drug resistance (MDR) , protein P-glycoprotein, MRP, a tyrosine kinase, CD23, CD124, tyrosine kinase p56 lck, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-alphaR, ICAM1, a Ca+channel, VCAM, an integrin, a VLA-4 integrin, a selectin, CD40,
• P2Y1, P2Y2, P2Y4, P2Y6, or P2X1-7) a farnesyltransferase, geranylgeranyl transferase, a Trk, a receptor for NGF, beta-amyloid, tyrosine kinase, Flk-IIKDR, vitronectin receptor, an integrin receptor, Her2 neu, telomerase inhibition, cytosolic phospholipaseA2, EGF receptor tyrosine kinase, ecdysone 20-monooxygenase, ion channel of the GABA gated chloride channel, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel, a chloride channel, acetyl-CoA carboxylase, adenylosuccinate synthase, protoporphyrinogen oxidase, enolpyruvylshikimate-phosphate synthase, an HSP, Hs
• a target protein comprises a protein associated with a disease state.
• the target protein may be present or upregulated in the disease state.
• a target protein comprises a pathogen protein.
• a target protein comprises a viral protein.
• a target protein comprises a bacterial protein.
• Target proteins are numerous in kind and are selected from proteins that are expressed in a cell such that at least a portion of the sequences is found in the cell and may bind to a target protein binding moiety.
• the term “protein” may include oligopeptides and polypeptide sequences of sufficient length that they can bind to a target protein binding moiety. Any protein in a eukaryotic system or a microbial system, including a virus, bacteria, or fungus, as otherwise described herein, may be a target protein for ubiquitination mediated by the compounds according to the present disclosure.
• the target protein may be a eukaryotic protein.
• a target protein comprises any of Hsp90, a kinase, MDM2, a Human BET Bromodomain-containing protein, an HDAC, a lysine methyltransferase, an angiogenesis protein, an immunomodulatory protein, or aryl hydrocarbon receptor (AHR) .
• a target protein comprises a heat shock protein (HSP) such as HSP90.
• HSP heat shock protein
• a target protein comprises a kinase or a phosphatase.
• the target protein includes a kinase.
• the kinase is a tyrosine kinase.
• the kinase is VEGFR3. In some embodiments, the kinase is an aurora kinase. In some embodiments, the kinase is ALK. In some embodiments, the kinase is JAK2. In some embodiments, the kinase is Alk. In some embodiments, the kinase is Met. In some embodiments, the kinase is Abl. In some embodiments, the kinase is B-Raf or Mek. In some embodiments, a target protein comprises a phosphatase. In some embodiments, the phosphatase is a protein tyrosine phosphatase.
• the target protein comprises estrogen receptor or an androgen receptor. In some embodiments, a target protein comprises an androgen receptor. In some embodiments, a target protein comprises an estrogen receptor. In some embodiments, a target protein comprises a thyroid hormone receptor. In some embodiments, a target protein comprises an HIV protein such as an HIV protease or an HIV integrase. In some embodiments, a target protein comprises an HCV protein such as an HCV protease. In some embodiments, a target protein comprises acyl-protein thioesterase-1 or -2.
• DCAF1 binding moiety binds to a DCAF1 protein.
• the DCAF1 binding moiety is bound to a DCAF1 protein.
• the compound binds to a DCAF1 protein via the DCAF1 binding moiety.
• the compound is bound to a DCAF1 protein via the DCAF1 binding moiety.
• the protein binding moiety is a haloalkane (preferably a C 1 -C 10 alkyl group which is substituted with at least one halo group, preferably a halo group at the distal end of the alkyl group (i.e., away from the linker or DCAF1 binding moiety) , which may covalently bind to a dehalogenase enzyme in a patient or subject or in a diagnostic assay.
• a haloalkane preferably a C 1 -C 10 alkyl group which is substituted with at least one halo group, preferably a halo group at the distal end of the alkyl group (i.e., away from the linker or DCAF1 binding moiety) , which may covalently bind to a dehalogenase enzyme in a patient or subject or in a diagnostic assay.
• the target protein binding moiety includes a haloalkyl group, wherein said alkyl group generally ranges in size from about 1 or 2 carbons to about 12 carbons in length, often about 2 to 10 carbons in length, often about 3 carbons to about 8 carbons in length, more often about 4 carbons to about 6 carbons in length.
• the haloalkyl groups are generally linear alkyl groups (although branched-chain alkyl groups may also be used) and are end-capped with at least one halogen group, preferably a single halogen group, often a single chloride group.
• N- [4- (3H-imidazo [4, 5-C] pyridin-2-yl) -9H-fluoren-9-yl] -succinamide is attached via its terminal amide group to a linker described herein.
• 8- [ (2, 4-dimethylphenyl) sulfanyl] -3-pent-4-yn-1-yl-3H-purin-6-amine is attached via its terminal acetylene group to a linker described herein.
• 5- [2, 4-dihydroxy-5- (1-methylethyl) phenyl] -N-ethyl-4- [4- (morpholin-4-ylmethyl) phenyl] isoxazole-3-carboxamide is attached via its amide group (e.g. at the amine or at the alkyl group on the amine) to a linker described herein.
• PU3 is attached via its butyl group to a linker described herein.
• erlotinib is attached via its ether group to a linker described herein.
• sunitinib is attached via its pyrrole moiety to a linker described herein.
• sorafenib is attached via its phenyl moiety to a linker described herein.
• dasatinib is attached via its pyrimidine to a linker described herein.
• lapatinib is attached via its terminal methyl of its sulfonyl methyl group to a linker described herein.
• U09-CX-5279 is attached via its amine (aniline) , carboxylic acid or amine alpha to cyclopropyl group, or cyclopropyl group to a linker described herein.
• 1-ethyl-3- (2- ⁇ [3- (1-methylethyl) [1, 2, 4] triazolo [4, 3-a] pyridin-6-yl] sulfanyl ⁇ benzyl) urea is attached via its propyl group to a linker described herein.
• Y1W is attached via its propyl or butyl group to a linker described herein.
• fostamatinib is attached via its methoxy group to a linker described herein.
• gefitinib is attached via its methoxy group or its ether group to a linker described herein.
• lenvatinib is attached via its cyclopropyl group to a linker described herein.
• vandetanib is attached via its methoxy group or hydroxyl group to a linker described herein.
• vemurafenib is attached via its sulfonyl propyl group to a linker described herein.
• the target protein binding moiety includes a phosphatase inhibitor.
• the phosphatase inhibitor is a protein tyrosine phosphatase inhibitor.
• the phosphatase inhibitor is an inhibitor of a SHP-2 domain of a tyrosine phosphatase.
• a non-limiting example of a phosphatase inhibitors includes PTP1B.
• Non-limiting examples of phosphatase inhibitors are included in Table 4.
• the target protein binding moiety includes an MDM inhibitor.
• the MDM inhibitor is an MDM2 inhibitor.
• MDM2 inhibitors include any one of nutlin-3, nutlin-2, nutlin-1, or trans-4-iodo-4'-boranyl-chalcone.
• nutlin-3, nutlin-2, or nutlin-1 is attached via a methoxy group or hydroxyl group to a linker described herein.
• trans-4-iodo-4'-boranyl-chalcone is attached via its hydroxyl group to a linker described herein.
• MDM2 inhibitors are included in Table 4.
• the target protein binding moiety includes a compound that targets a human BET bromodomain-containing protein.
• the compound that targets a human BET bromodomain-containing protein is a 3, 5-dimethylisoxazole.
• Non-limiting examples of compounds that target a human BET bromodomain-containing protein are included in Table 4.
• the target protein binding moiety includes a compound that inhibits an HDAC.
• Non-limiting examples of compounds that inhibit an HDAC are included in Table 4.
• the target protein binding moiety includes an immunosuppressive compound.
• immunosuppressive compounds include AP21998, a glucocorticoid (e.g., hydrocortisone, prednisone, prednisolone, or methylprednisolone) , beclomethasone dipropionate, methotrexate, ciclosporin, tacrolimus, rapamycin, or actinomycin.
• the glucocorticoid is attached via a hydroxyl to a linker described herein.
• the beclomethasone dipropionate is attached via a propionate to a linker described herein.
• methotrexate is attached via either of its terminal hydroxyls to a linker described herein.
• ciclosporin is attached via a butyl group to a linker described herein.
• tacrolimus is attached via a methoxy group to a linker described herein.
• rapamycin is attached via a methoxy group to a linker described herein.
• actinomycin is attached via an isopropyl group to a linker described herein.
• the target protein binding moiety includes a compound that targets a RAF receptor.
• a compound that target a RAF receptor is included in Table 4.
• the target protein binding moiety includes a compound that targets FKBP.
• a compound that target FKBP is included in Table 4.
• the target protein binding moiety includes a compound that targets a thyroid hormone receptor.
• a compound that target a thyroid hormone receptor is included in Table 4.
• the target protein binding moiety includes a compound that inhibits an HIV protease.
• Non-limiting examples of compounds that inhibit an HIV protease are included in Table 4.
• the target protein binding moiety includes a compound that inhibits an HIV integrase.
• Non-limiting examples of compounds that inhibit an HIV integrase are included in Table 4.
• the target protein binding moiety includes a compound that targets an HCV protease.
• a compound that targets an HCV protease is included in Table 4.
• the target protein binding moiety includes a compound that targets acyl-protein thioesterase-1 and/or -2.
• a compound that targets acyl-protein thioesterase-1 and/or -2 is included in Table 4.
• compounds comprising a target protein binding moiety are shown in Table 4.
• “R” or a wavy line indicates an optional point of attachment to a linker or other molecule such as a DCAF1 binding moiety.
• heterobifunctional compounds Such compounds may be useful for a variety of purposes, including use as molecular glues or targeted protein degraders for a protein of interest.
• the heterobifunctional compound may be a small molecule.
• the heterobifunctional compound may be included in a method of treatment or use as described herein.
• the heterobifunctional compound may be included in a pharmaceutical composition and administered to a subject.
• treat means to administer a compound, salt or composition, as described herein, to a subject having a disease or disorder, such as cancer, to achieve at least one positive therapeutic effect. Such therapeutic effects may include reversing, relieving, alleviating, or slowing the progression of, or any damage associated with any symptoms of the disease or disorder.
• treatment refers to the act of treating as “treating” as defined above.
• Heterobifunctional compounds of Formula (I) , Formula (II) , or Formula (X) may comprise a DCAF1 binding moiety according to any of the embodiments described herein.
• Heterobifunctional compounds of Formula (I) , Formula (II) , or Formula (X) may comprise a linker according to any of the embodiments described herein.
• the compound of Formula (I) or Formula (II) is selected from the group consisting of the compounds in Table 1, Table 3 or Table 5, or a salt thereof.
• the compound of Formula (I) or Formula (II) is a heterobifunctional compound comprising a monofunctional intermediate comprising a compound in Table 1 or Table 3, or an analog or salt thereof. In some embodiments, the compound of Formula (I) or Formula (II) is a heterobifunctional compound comprising a monofunctional intermediate selected from the compounds in Table 1 or Table 3, or an analog or salt thereof.
• the compound of Formula (I) or Formula (II) is a heterobifunctional compound selected from the group consisting of the compounds in Table 5, or a pharmaceutically acceptable salt thereof.
• the compound of Formula (I) or Formula (II) comprises CPD-001, CPD-004, CDP-005, CPD-006, CPD-008, CPD-009, CPD-011, CPD-012, CPD-013, CPD-014, CPD-016, CPD-017, CPD-018, CPD-019, CPD-043, CPD-044, CPD-045, CPD-048, CPD-049, CPD-051, CPD-052, CPD-053, CPD-056, CPD-059, CPD-065, CPD-076, CPD-084, CPD-087, CPD-088, CPD-090, CPD-093, CPD-094, CPD-095, CPD-098, CPD-099, or CPD-105, or an analog or heterobifunctional derivative thereof.
• the compound of Formula (I) or Formula (II) comprises B-053, B-072, B-074, B-087, B-089, B-108, B-122, B-122, B-123, B-124, B-127, B-130, B-135, B-145, B-148, B-151, B-159, B-164, B-165, B-166, B-172, B-177, B-198, B-202, B-206, or B-210, or an analog or heterobifunctional derivative thereof.
• analogs are compounds wherein (a) a morpholino moiety has been replaced by a piperazine analog; (b) a carboxamide moiety has been modified to install a linker; or (c) a halo or OH moiety has been modified to install a linker; which in each case can act as the site of attachment to L 1 -P or L 1 -G.
• the compound of Formula (I) or Formula (II) is selected from the group consisting of: D-025, D-028, D-043, D-044, D-046, D-047, or D-048, or a pharmaceutically acceptable salt thereof.
• L 2 is a bivalent chemical linker
• the compounds described herein may be useful for binding DDB1-and CUL4-associated factor 1 (DCAF1) , binding and/or degrading target proteins, for inducing subsequent cellular effects, and/or for inhibiting microbes such as a virus or a bacteria.
• DCAF1 DDB1-and CUL4-associated factor 1
• the compound is used as an antiviral drug.
• a compound such as compound comprising a ligand described herein may compete with one or more viral proteins.
• the compound is used as an antiparasitic drug.
• the compound is used as a molecular glue, for example, to hold two molecules together such as DCAF1 proteins and/or target proteins.
• the compound is used as a degrader.
• a heterobifunctional compound described herein may be used as targeted protein degrader.
• heterobifunctional compounds using PF-06873600 as warhead were characterized in ER+ breast cancer T47D cells and NSCLC Calu-1 cells. Following a 16-hour treatment, heterobifunctional compounds significantly decrease cyclin D1 and CDK4 protein levels and inhibited downstream Rb phosphorylation in a concentration-dependent manner (FIG. 7A-7B, Table 11) . The warhead PF-06873600 didn’ t affect cyclin D1 and CDK4 protein levels at indicated concentrations.
• Exemplary heterobifunctional compounds using PF-07220060 as warhead were characterized in breast cancer MDA-MB-157 cells. Following a 16-hour treatment of heterobifunctional compounds, cyclin D1 protein levels were significantly decreased in 5 ⁇ M treated samples, while warhead PF-07220060 didn’ t affect cyclin D1 proteins levels dramatically (FIG. 9) .
• Exemplary heterobifunctional compounds using lasofoxifene as warhead were characterized in ER+ breast cancer T47D cells. Following a 24-hour treatment of representative heterobifunctional compounds in in serum-free condition, ER ⁇ protein levels were significantly decreased in 1 ⁇ M treated samples, while warhead lasofoxifene didn’ t affect ER ⁇ protein levels at 1 ⁇ M significantly (Table 12) .
• DCAF1 ligands conjugated with different target protein binding moieties can modulate the cellular target protein levels of proteins of interest, including for example, CDK4, cyclin D1, BRD4, and ER ⁇ .
• the results support the use of DCAF1 ligands in targeted protein degradation technology.
• a compound described herein is used to bind a DCAF1 protein.
• the compound may include a compound of Tables 1, 2, 3, or 5.
• a compound described herein is used to modulate a DCAF1 protein.
• a compound described herein is used to inhibit a DCAF1 protein.
• Some embodiments include contacting a DCAF1 protein with a compound described herein.
• the contact may include administration of the compound to a subject comprising the DCAF1 protein.
• the contact may include administration of the compound to a cell comprising the DCAF1 protein.
• the contact may include administration of the compound to a sample comprising the DCAF1 protein.
• the contact may include administration of the compound to a solution comprising the DCAF1 protein.
• the contact may be in vivo.
• the contact may be in vitro.
• the compound may bind to the DCAF1 protein with a binding affinity described herein.
• contacting the compound with the DCAF1 protein comprises contacting the compound with a binding region on the DCAF1 protein, the binding region comprising a WD40 domain.
• the binding region on the DCAF1 protein comprises one or more of the following DCAF1 residues: THR1097, ALA1137, THR1139, HIS1140, THR1155, HIS1180, TYR1181, ARG1225, CYS1227, ILE1262, VAL1265, ARG1298, VAL1299, VAL1300, LYS1327, PRO1329, or PHE1355.
• a compound described herein binds a DCAF1 protein such as a full-length DCAF1 protein. In some embodiments, a compound described herein binds a DCAF1 fragment.
• a compound described herein is used to treat a subject. Some embodiments include administering a compound described herein to a subject, for example administering a compound included in any of Tables 1-5 or Formula (I) or Formula (II) to a subject. Some embodiments include administering a compound that comprises a DCAF1 binding moiety to the subject. Some embodiments include administering a heterobifunctional compound that comprises a DCAF1 binding moiety to the subject. Some embodiments include administering a compound that comprise a structure in Table 1. Some embodiments include administering a compound of Table 1. Some embodiments include administering a compound that comprise a structure in Table 2. Some embodiments include administering a compound of Table 2. Some embodiments include administering a compound that comprise a structure in Table 3.
• Some embodiments include administering a compound of Table 3. Some embodiments include administering a compound that comprise a structure in Table 4. Some embodiments include administering a compound that comprise a structure in Table 5. Some embodiments include administering a compound of Table 5. Some embodiments include administering a compound that comprises an aspect such as a DCAF1 binding moiety of Formula (I) . Some embodiments include administering a compound of Formula (I) . Some embodiments include administering a compound of Formula (II) . Some embodiments include administering a compound described herein to a subject in need thereof. Some embodiments include administering a pharmaceutical composition comprising the compound to a subject. Some embodiments include providing a compound or pharmaceutical composition described herein for administration to a subject.
• the administration is vaginal. In some embodiments, the administration is ocular. In some embodiments, the administration is otic. In some embodiments, the administration is nasal. In some embodiments, the administration is inhalation. In some embodiments, the administration is nebulization. In some embodiments, the administration is cutaneous. In some embodiments, the administration is topical. In some embodiments, the administration is transdermal. In some embodiments, the administration is systemic.
• a compound described herein is used as an antimicrobial drug.
• the compound may be administered to a subject having a microbial infection.
• the administration may reduce the severity of the microbial infection in the subject, relative to a baseline measurement.
• the compound may bind a target protein involved in the microbial infection, resulting in inhibition or degradation of the target protein.
• the microbial infection may include a virus infection.
• the microbial infection may include a bacterial infection.
• the compound may be a heterobifunctional compound and comprise a DCAF1 binding moiety and a target protein binding moiety, wherein the target protein is a microbial protein.
• the microbial protein may include a viral protein.
• the microbial protein may include a bacterial protein.
• the compound may inhibit DCAF1 by binding to a protein binding site on DCAF1.
• the compound may be a heterobifunctional compound and include a DCAF1 binding moiety coupled to (directly or through a linker) a second moiety that increases activity of the DCAF1 protein, or that decreases activity of the DCAF1 protein.
• the second moiety may accomplish this by binding to a target protein.
• the compound is administered to a subject to increase DCAF1 activity in the subject.
• the administration may increase DCAF1 activity in the subject, relative to a baseline measurement.
• the compound is administered to a subject to decrease DCAF1 activity in the subject.
• the administration may decrease DCAF1 activity in the subject, relative to a baseline measurement.
• a compound described herein may be useful as a molecular glue.
• the compound may bind multiple molecules and hold them together.
• the molecular glue binds DCAF1 and a target protein.
• the compound may accomplish this as a heterobifunctional compound that comprises a DCAF1 binding moiety and a target protein binding moiety.
• the compound may increase a protein-protein interaction between DCAF1 and a target protein.
• the compound may act as a molecular glue to modulate an activity or amount of the target protein.
• the compound may decrease an amount of the target protein.
• the compound may increase an amount of the target protein.
• the compound may decrease activity of the target protein.
• the compound may increase activity of the target protein.
• the compound may increase activity of the target protein.
• the method may include degrading the target protein through direct binding of an intermediate protein (e.g., a first protein) that interacts with the target protein. This may be referred to as bridged degradation.
• Some embodiments include administering a binding molecule to a cell, such as a cancer cell.
• the binding molecule may include a ligand or compound disclosed herein.
• the ligand may be a heterobifunctional compound.
• the binding molecule may bind a first protein that interacts with the target protein.
• the target protein may be degraded before the first protein. In some embodiments, the first protein is not degraded.
• Some embodiments include administering, to the cell, a binding molecule that binds a first protein that interacts with the target protein, thereby degrading target protein, wherein the target protein is degraded before the first protein or wherein the first protein is not degraded. Some embodiments include measuring the target protein in the cell. Some embodiments include measuring the first protein in the cell. In some embodiments include measuring the first protein in the cell. In some embodiments, the interaction between the target protein and the first protein is binding. In some embodiments, the interaction between the target protein and the first protein is dimerization.
• the target protein may include a target protein described herein.
• the first protein may include another target protein described herein. In some embodiments, the target protein comprises a cyclin. In some embodiments, the target protein comprises Cyclin D.
• the Cyclin D comprises Cyclin D1, Cyclin D2, or Cyclin D3.
• the cyclin D may include Cyclin D1.
• the cyclin D may include Cyclin D2.
• the cyclin D may include Cyclin D3.
• the first protein comprises a cyclin-dependent kinase (CDK) .
• the CDK may include CDK4.
• the CDK may include CDK6.
• the first protein comprises CDK4 or CDK6.
• the binding molecule reduces viability of the cell.
• the cell is a eukaryotic cell.
• the cell is a mammalian cell.
• the cell is a human cell.
• the cell is a cancer cell.
• administering the binding molecule to the cell comprises administering the binding molecule to a subject comprising the cell.
• the binding molecule recruits a ubiquitin E3 ligase that ubiquitinates the target protein.
• the E3 ubiquitin ligase comprises DNA damage-binding protein 1 (DCAF1) or Von Hippel–Lindau tumor suppressor (VHL) .
• subjects include vertebrates, animals, mammals, dogs, cats, cattle, rodents, mice, rats, primates, monkeys, and humans.
• the subject is a mammal. In some embodiments, the subject is a human.
• administering the compound to a subject comprises administering an effective amount of the compound.
• the administration is intravenous.
• the administration comprises an injection.
• the administration is local.
• the administration is systemic.
• the sample is a biological sample.
• the biological sample comprises a tissue, a cell, or a biological fluid.
• the contact is in vitro. In some embodiments, the contact is in vivo.
• Amino refers to the —NH 2 radical.
• Niro refers to the -NO 2 radical.
• an alkyl comprises one to four carbon atoms (e.g., C 1 -C 4 alkyl) . In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C 1 -C 3 alkyl) . In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C 1 -C 2 alkyl) . In other embodiments, an alkyl comprises one carbon atom (e.g., C 1 alkyl) . In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C 5 -C 15 alkyl) .
• an alkyl comprises five to eight carbon atoms (e.g., C 5 -C 8 alkyl) . In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C 2 -C 5 alkyl) . In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C 3 -C 5 alkyl) .
• the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl) , 1-methylethyl (iso-propyl) , 1-butyl (n-butyl) , 1-methylpropyl (sec-butyl) , 2-methylpropyl (iso-butyl) , 1, 1-dimethylethyl (tert-butyl) , 1-pentyl (n-pentyl) .
• the alkyl is attached to the rest of the molecule by a single bond.
• an alkyl group is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, R a , -OR a , -SR a , -OC (O) -R a , -N (R a ) 2 , -C (O) R a , -C (O) OR a , -C (O) N (R a ) 2 , -N (R a ) C (O) OR a , -OC (O) -N (R a ) 2 , -N (R a ) C (O) R a , -N (R a ) S (O) t R a (where t is 1 or 2) , -S (O) t OR a (where t is 1 or 2) , -
• Alkoxy refers to a radical bonded through an oxygen atom of the formula –O-alkyl, where alkyl is an alkyl chain as defined above.
• Haloalkyl refers to an alkyl group that is substituted with one or more halogens.
• exemplary haloalkyl groups include trifluoromethyl, difluoromethyl, trichloromethyl, 2, 2, 2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, and 1, 2-dibromoethyl.
• Heteroalkyl refers to substituted or unsubstituted alkyl, alkenyl and alkynyl groups which respectively have one or more skeletal chain atoms selected from an atom other than carbon.
• Exemplary skeletal chain atoms selected from an atom other than carbon include, e.g., O, N, P, Si, S, or combinations thereof, wherein the nitrogen, phosphorus, and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. If given, a numerical range refers to the chain length in total.
• a 3-to 8-membered heteroalkyl has a chain length of 3 to 8 atoms. Connection to the rest of the molecule may be through either a heteroatom or a carbon in the heteroalkyl, heteroalkenyl or heteroalkynyl chain. Unless stated otherwise specifically in the specification, a heteroalkyl, heteroalkenyl, or heteroalkynyl group is optionally substituted with one or more substituents such as those substituents described herein.
• Alkenyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl) , prop-1-enyl (i.e., allyl) , but-1-enyl, pent-1-enyl, penta-1, 4-dienyl, and the like.
• ethenyl i.e., vinyl
• prop-1-enyl i.e., allyl
• pent-1-enyl penta-1, 4-dienyl, and the like.
• an alkenyl group is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, R a , -OR a , -SR a , -OC (O) -R a , -N (R a ) 2 , -C (O) R a , -C (O) OR a , -C (O) N (R a ) 2 , -N (R a ) C (O) OR a , -OC (O) -N (R a ) 2 , -N (R a ) C (O) R a , -N (R a ) S (O) t R a (where t is 1 or 2) , -S (O) t OR a (where t is 1 or 2) ,
• Alkynyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms.
• an alkynyl comprises two to eight carbon atoms.
• an alkynyl comprises two to six carbon atoms.
• an alkynyl comprises two to four carbon atoms.
• the alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
• an alkynyl group is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, R a , -OR a , -SR a , -OC (O) -R a , -N (R a ) 2 , -C (O) R a , -C (O) OR a , -C (O) N (R a ) 2 , -N (R a ) C (O) OR a , -OC (O) -N (R a ) 2 , -N (R a ) C (O) R a , -N (R a ) S (O) t R a (where t is 1 or 2) , -S (O) t OR a (where t is 1 or 2) ,
• Alkylene or "alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, n-butylene, and the like.
• the alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
• the points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain.
• an alkylene comprises one to eight carbon atoms (e.g., C 1 -C 8 alkylene) . In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C 1 -C 5 alkylene) . In other embodiments, an alkylene comprises one to four carbon atoms (e.g., C 1 -C 4 alkylene) . In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C 1 -C 3 alkylene) . In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C 1 -C 2 alkylene) .
• an alkylene comprises one carbon atom (e.g., C 1 alkylene) . In other embodiments, an alkylene comprises five to eight carbon atoms (e.g., C 5 -C 8 alkylene) . In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C 2 -C 5 alkylene) . In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C 3 -C 5 alkylene) .
• an alkylene chain is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, R a , -OR a , -SR a , -OC (O) -R a , -N (R a ) 2 , -C (O) R a , -C (O) OR a , -C (O) N (R a ) 2 , -N (R a ) C (O) OR a , -OC (O) -N (R a ) 2 , -N (R a ) C (O) R a , -N (R a ) S (O) t R a (where t is 1 or 2) , -S (O) t OR a (where t is 1 or 2) , -
• Aryl refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom.
• the aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ⁇ –electron system in accordance with the Hückel theory.
• the ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene.
• aryl or the prefix “ar-” (such as in “aralkyl” ) is meant to include aryl radicals optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, R a , -R b -OR a , -R b -OC (O) -R a , -R b -OC (O) -OR a , -R b
• Cycloalkyl refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, having from three to fifteen carbon atoms. In certain embodiments, a cycloalkyl comprises three to ten carbon atoms. In other embodiments, a cycloalkyl comprises five to seven carbon atoms. The cycloalkyl is attached to the rest of the molecule by a single bond. Cycloalkyl is saturated (i.e., containing single C-C bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds) .
• a fully saturated cycloalkyl radical is also referred to as "carbocyclyl.
• monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
• An unsaturated cycloalkyl is also referred to as “cycloalkenyl.
• Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
• Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo [2.2.1] heptanyl) , norbornenyl, decalinyl, 7, 7-dimethyl-bicyclo [2.2.1] heptanyl, and the like.
• Halo or halogen refers to bromo, chloro, fluoro or iodo substituents.
• Heterocyclyl refers to a stable 3-to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen, and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which optionally includes fused or bridged ring systems. The heteroatoms in the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl is attached to the rest of the molecule through any atom of the ring (s) .
• C-heterocyclyl or “C-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one heteroatom and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a carbon atom in the heterocyclyl radical.
• a C-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such C-heterocyclyl radicals include, but are not limited to, 2-morpholinyl, 2-or 3-or 4-piperidinyl, 2-piperazinyl, 2-or 3-pyrrolidinyl, and the like.
• heteroaryl is attached to the rest of the molecule through any atom of the ring (s) .
• heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1, 3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo [d] thiazolyl, benzothiadiazolyl, benzo [b] [1, 4] dioxepinyl, benzo [b] [1, 4] oxazinyl, 1, 4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzo
• heteroaryl is meant to include heteroaryl radicals as defined above which are optionally substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, R a , -R b -OR a , -R b -OC (O) -R a ,
• N-heteroaryl refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical.
• An N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
• geometric isomer refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond.
• positional isomer refers to structural isomers around a central ring, such as ortho-, meta-, and para-isomers around a benzene ring.
• Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6 (10) ] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45 (21) , 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64 (1-2) , 9-32.
• Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds.
• Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.
• references to compounds herein include references to salts (including pharmaceutically acceptable salts) , solvates (including hydrates) , and complexes thereof, as well as to solvates and complexes of the salts thereof, and isotopically labelled versions thereof.
• Salts include both acid and base addition salts of the compounds described herein and encompass both pharmaceutically acceptable salts and non-pharmaceutically acceptable salts. While pharmaceutically acceptable salts are utilized for therapeutic or medicinal uses, non-pharmaceutically acceptable salts may be useful as synthetic intermediates, or for purification, isolation, chiral resolution, solubility, handling and the like.
• “Pharmaceutically acceptable salts” are salts that retain the biological effectiveness and properties of the free base compound that are suitable for administration to a subject.
• Reference to “a pharmaceutically acceptable salt” includes both acid and base addition salts.
• a pharmaceutically acceptable salt of any one of the compounds described herein is intended to encompass all pharmaceutically suitable salt forms.
• Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
• “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono-and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc.
• R 22 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 3 -C 6 cycloalkyl, and 3-to 6-membered heterocyclyl;
• Z 1 is selected from the group consisting of L 1 -P, L 1 -G, and Z 2 , wherein:
• Z 2 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and an amine protecting group
• the compound of Formula (I) is not N- (1- (3-fluorophenyl) piperidin-3-yl) -6-morpholinopyrimidin-4-amine or N- (1- (3-fluorophenyl) piperidin-3-yl) -4-morpholinopyrimidin-2-amine.
• E8 The compound or salt of any one of embodiments E1 to E6, wherein: E 1 is -NH-.
• E9 The compound or salt of any one of embodiments E1 to E8, wherein: E 2 is selected from the group consisting of a bond, -N (R 8 ) -, - (C (R 9 ) 2 ) t N (R 8 ) -, -N (R 8 ) (C (R 9 ) 2 ) t -, -C (O) N (R 8 ) -, and -N (R 8 ) C (O) -.
• E10 The compound or salt of any one of embodiments E1 to E8, wherein: E 2 is selected from the group consisting of a bond, -NH-, - (CH 2 ) t NH-, -NH (CH 2 ) t -, -C (O) NH-and -NHC (O) -.
• R 4 is independently selected from the group consisting of C 6 -C 10 aryl, 5-to 10-membered heteroaryl, E 3 -C 6 -C 10 aryl, and E 3 -5-to 10-membered heteroaryl, and each said C 6 -C 10 aryl and 5-to 10-membered heteroaryl is optionally further substituted by one or more R 18 .
• each R 19 is independently selected from the group consisting of fluoro, oxo, thioxo, OR c , SR c , N (R c ) 2 , C (O) R c , OC (O) R c , C (O) OR c , C (O) N (R c ) 2 , N (R c ) C (O) R c , and C 1 -C 6 alkyl, wherein each said C 1 -C 6 alkyl is optionally substituted with one or more R d ;
• each R 21 is independently selected from the group consisting of hydrogen, fluoro, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and 3-to 6-membered heterocyclyl, wherein each said C 1 -C 6 alkyl is optionally substituted with one or more R d , and each said C 3 -C 6 cycloalkyl and 3-to 6-membered heterocyclyl is optionally substituted one or more R e , or two R 21 taken together are oxo;
• each R 22 , R 23 and R 24 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 3 -C 6 cycloalkyl, and 3-to 6-membered heterocyclyl;
• each R a , R b , and R c is independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, C 3 -C 6 cycloalkyl, and 3-to 6-membered heterocyclyl;
• each R d is independently selected from the group consisting of fluoro, hydroxy, C 1 -C 4 alkoxy, oxo, NH 2 , NH (C 1 -C 4 alkyl) and N (C 1 -C 4 alkyl) 2 ;
• each R e is independently selected from the group consisting of fluoro, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 alkoxy, oxo, NH 2 , NH (C 1 -C 4 alkyl) and N (C 1 -C 4 alkyl) 2 ;
• n is an integer from 0 to 6;
• n is an integer from 0 to 4.
• p is an integer from 0 to 3;
• q is an integer from 1 to 3;
• r is an integer from 0 to 4.
• s is an integer from 0 to 2;
• t is an integer from 1 to 4.
• u is an integer from 1 to 5;
• z is an integer from 1 to 4.
• Z 1 is selected from the group consisting of L 1 -P, L 1 -G, and Z 2 , wherein:
• P is a target protein binding moiety
• G is a reactive functional group
• R 4 is independently selected from the group consisting of C 6 -C 10 aryl, 5-to 10-membered heteroaryl, E 3 -C 6 -C 10 aryl, and E 3 -5-to 10-membered heteroaryl, and each said C 6 -C 10 aryl and 5-to 10-membered heteroaryl is optionally further substituted by one or more R 18 .
• each R 18 is independently selected from the group consisting of halogen, C 1 -C 6 alkyl, OR c , andN (R c ) 2 .
• F29 The compound or salt of any one of embodiments F1 to F28, wherein: E 3 is independently selected from the group consisting of -NH-, - (CH 2 ) y -NH-, -NH- (CH 2 ) y and – (CH 2 ) z -.
• each R 17B is independently selected from the group consisting of fluoro, OR c , andN (R c ) 2 .
• F31 The compound or salt of any one of embodiments F1 to F30, wherein: Z 1 is L 1 -G or Z 2 ; and G is a reactive functional group.
• G is a reactive functional group selected from a protected or unprotected primary or secondary amine, carboxylic acid, carboxylate ester, halogen, hydroxy or sulfonate ester; preferably G is a reactive functional group selected from NH 2 , COOH, halogen, hydroxy, Oms, or OTs.
• F35 The compound or salt of any one of embodiments F1 to F31 or F34, wherein: Z 2 is selected from the group consisting of hydrogen and an amine protecting group.
• F36 The compound or salt of any one of embodiments F1 to F31, F34 or F35, wherein: Z 2 is hydrogen.
• F38 The compound or salt of any one of embodiments F1 to F30 or F37, wherein: P is a target protein binding moiety that binds to CBP, p300, TrkA, TrkB, TrkC, CDK4, CDK6, CDK9, cyclin D, BRD4, ER ⁇ , or a combination thereof.
• a method of degrading, inhibiting, or modulating a protein in a cell comprising contacting the cell with an effective amount of the compound or salt of any one of embodiments F1 to F39, or the pharmaceutical composition of embodiment F40 to the cell (wherein the cell may be in a subject) .
• a method of making a heterobifunctional compound comprising conjugating a compound or salt of any one of embodiments F1 to F36 to a target protein binding moiety via a linker.
• Non-limiting examples of compound synthesis schemes are provided below.
• reaction mixture was stirred at 100 °C for 6 h under N 2 . After cooling down to rt, the reaction mixture was quenched with water (10 mL) and extracted with brine (10 mL ⁇ 3) . The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (29.3 mg, 14%yield) as a yellow oil in FA salt form.
• Example B6 1- (6- ( (6- (4-ethylpiperazin-1-yl) pyridin-2-yl) amino) -2-azaspiro [3.3] heptan-2-yl) prop-2-en-1-one (B-007)

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