Modified proteins and protein binders and degraders

Abstract

Provided herein are compounds, pharmaceutical compositions, and methods for binding to or modulating DDB1- and CUL4-associated factor 1 (DCAF1) protein. In some embodiments, the compounds induce proteasomal degradation of target proteins.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of International Application PCT / CN2022 / 119083, filed September 15, 2022, which is incorporated herein by reference in its entirety.

[0002] Sequence Listing This application is accompanied by a Sequence Listing that has been submitted electronically in XML file format and is incorporated herein by reference in its entirety. A copy of this XML is titled 54922_712_602_SL.xml, created on September 11, 2023, and is 2,985 bytes in size. [Background technology]

[0003] The present invention relates to compounds, pharmaceutical compositions, modified proteins, and protein-ligand complexes, and methods for binding or degrading DDB1- and CUL4-associated factor 1 (DCAF1) protein, which are useful in biotechnology applications such as the selective degradation of target proteins, molecular glues, or antimicrobial drugs.

[0004] The ubiquitin pathway plays a key role in regulating most cellular processes through an enzyme cascade, with E1 and E2 enzymes catalyzing ubiquitin activation and conjugation, and E3s conferring reaction specificity through substrate recruitment (Hershko and Ciechanover, 1998; Pickart, 2004). The largest family of E3 ubiquitin ligases is the cullin-RING E3 ligase (CRL). In the CRL ligase complex, cullin functions as a scaffold, binding to the small RING finger proteins ROC1 or ROC2 (RBX1 or RBX2) through its C-terminal domain and directly to linker-substrate receptor dimers or substrate receptors through its 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 a linker. DDB1 bridges the interaction between CUL4 and a subset of DDB1-binding WD40 repeat proteins (DWD or DCAF for DDB1 cullin-associated factors). These DCAF proteins function as substrate receptors that target specific substrates to the CRL4 E3 complex (Jackson and Xiong, 2009). One of the most abundant DCAF proteins is DCAF1 (also known as VprBP).

[0005] DDB1- and CUL4-associated factor 1 (DCAF1) is evolutionarily conserved in mammals, Drosophila, Xenopus, C. elegans, and Arabidopsis, but no obvious homologues have been identified in yeast (Nakagawa et al., 2013; Schabla et al., 2019). It is ubiquitously expressed in all tissues and organs examined (Zhang et al., 2001). Genetic analysis has revealed essential functions for DCAF1 during embryonic development in plants, flies, and mammals, resulting in developmental delay at the globular stage in Arabidopsis (Zhan et al., 2008), late pupal stage in Drosophila (Tamori et al., 2010), and early embryonic lethality in mice. DCAF1 is an example of an E3 ubiquitin ligase.

[0006] DCAF1 was first identified as an HIV-1 accessory viral protein R (Vpr)-binding protein ( Zhang et al., 2001 , Zhao et al., 1994 ) and was subsequently found to associate with the DDB1-CUL4-ROC1 E3 ubiquitin ligase (CRL4) ( Angers et al., 2006 , He et al., 2006 , Jin et al., 2006 ). DCAF1 contains multiple functional domains, including a putative protein kinase-like domain (Kim et al., 2013), a chromodomain that functions as a monomethylation substrate recognition pocket (Lee et al., 2012), a putative LisH motif required for dimerization and interaction with the H3 tail (Ahn et al., 2011; Kim et al., 2012), a promiscuous α-helical H-box required for binding to DDB1 (Fischer et al., 2011; Li et al., 2010), a WD40 repeat region required for binding to DDB1, and an acidic domain that provides interactions with additional proteins (Huang and Chen, 2008; Wang et al., 2016). DCAF1 ligands have the potential to be used as antiviral drugs.

[0007] Many viral proteins exploit the ubiquitin ligase activity of CRL4 to degrade cellular proteins to create a favorable environment for the virus. The viral hijacking of DCAF1 is the most extensively studied. The HIV-1 accessory protein Vpr has been shown to induce G2 cell cycle arrest in host cells, and several studies have shown that CRL4 hijacks cellular substrates by targeting them for proteasome-mediated degradation. DCAF1 It has become clear that E3 ligase is required (Belzile et al., 2007; Hrecka et al., 2007; Le Rouzic et al., 2007; Tan et al., 2007; Wen et al., 2007). DCAF1 Substrates identified for Vpr-directed degradation through E3 ligases include the uracil DNA glycosylases UNG2 and SMUG1 (single-strand-selective monofunctional uracil DNA glycosylase 1) (Ahn et al., 2010; Schrofelbauer et al., 2005), the transcriptional regulators ZIP and sZIP (Maudet et al., 2013), the dsRNA endoribonuclease Dicer (Casey Klockow et al., 2013), the DNA endonuclease MUS81 (Laguette et al., 2014), the DNA deaminase APOBEC3G (Zhou et al., 2015), the DNA replication factor MCM10 (Romani et al., 2015), the HLTF (helicase-like transcription factor) (Zhou et al., 2017), and the methylcytosine dioxygenase TET2 (Lv et al., 2018). HIV-2 and the related SIV encode another accessory protein, Vpx, which shares a high degree of similarity with Vpr and binds to the DCAF1 E3 ligase (Srivastava et al., 2008). Vpx binds to the CRL4 DCAF1 It has been reported that DCAF1 reduces the degradation of dNTP triphosphohydrolase SAMHD1 through E3 ligase. Structural analysis revealed that the viral proteins Vpr and Vpx bind to the C-terminal WD40 motif of DCAF1 (Schwefel et al., 2014; Wu et al., 2016).

[0008] Small molecules that bind to DCAF1 have been reported recently, and interest in using DCAF1-binding agents for targeted protein degradation has been described.For example, International Publication WO2022 / 194087, published September 22, 2022; Cyclica / Structural Genomics Consortium (SGC), Designing chemical probes for DCAF1 using MatchMaker™ (N-(1-(3-fluorophenyl)piperidin-3-yl)-6-morpholinopyrimidin-4-amine (CYCA-117-70) and N-(1-(3-fluorophenyl)piperidin-3-yl)-4-morpholinopyrimidin-2-amine (CYCA-117-113), and human DCAF1 complexed with CYCA-117-70 (PDB code published December 15, 2021)). Co-crystal structure of the WDR domain is described); ASM Li et al., "Discovery of Nanomolar DCAF1 Small Molecule Ligands," J. Med. Chem. (2023), 66:5041-5060; M. Shroder et al., "Reinstating targeted protein degradation with DCAF1 PROTACs in CRBN PROTAC resistant settings," posted on April 9, 2023, bioRxiv, doi:https: / / doi.org / 10.1101 / 2023.04.09.536153; A. Vulpetti et al., "Discovery of New Binders of DCAF1, an Emerging Ligase Target in the Targeted Protein Degradation Field," ACS Med. Chem. Lett. (2023), 14:949-954; X. Han & Y. Sun, "PROTACS: A novel strategy for cancer discovery and development, MedComm(2020),2023 May 29;4:e290,doi:10.1002 / mco2.290

[0009] There is still a need to discover DCAF1 ligands for protein binding or modification. In the pharmaceutical field, there is a need for compounds and compositions that are capable of selectively regulating or targeting the degradation of proteins. Summary of the Invention

[0010] Described herein are modified proteins and protein-ligand complexes. The modified proteins and protein-ligand complexes of some embodiments are useful in biotechnology applications, such as the selective modulation of proteins.

[0011] Described herein are ligands capable of binding to DDB1- and CUL4-associated factor 1 (DCAF1). DCAF1-binding ligands are useful in biotechnology applications, such as selective modulation of DCAF1.

[0012] Further described herein are monofunctional and heterobifunctional compounds comprising DCAF1 binding ligands.Monofunctional compounds can be useful as synthetic intermediates in the preparation of heterobifunctional compounds comprising DCAF1 binding moieties conjugated to target protein binding moieties via linkers.Heterobifunctional compounds can be useful for targeted degradation of target proteins.

[0013] In one aspect herein, a compound of formula (I):

[0014] [ka] or a salt thereof, wherein A is X 1 C6-C, including 10 aryl or 5-10 membered heteroaryl; X 1 is C(R 5A ), N, N(R 5B ), O, or S; E 1 and E 2are independently a bond, -N(R 8 )-, -(C(R 9 )2) t N(R 8 )-, -N(R 8 )(C(R 9 )2) t -, -(C(R 9 )2) t N(R 8 )(C(R 9 )2) u -, -O-, -(C(R 9 )2) t O-, -O-(C(R 9 )2) t -, -(C(R 9 )2) t O(C(R 9 )2) u -, -(C(R 9 )2) u -, -C(O)-, -C(O)N(R 8 )-, -(C(R 9 )2) t C(O)N(R 8 )-, -C(O)N(R 8 )(C(R 9 )2) t -, -(C(R 9 )2) t C(O)N(R 8 )(C(R 9 )2) u -, -N(R 8 )C(O)-, -(C(R 9 )2) t N(R 8 )C(O)-, -N(R 8 )C(O)(C(R 9 )2) t - and -(C(R 9 )2) t N(R 8 )C(O)(C(R 9 )2) u - selected from the group consisting of Q 1 is C3-C 11 cycloalkyl or 3- to 11-membered heterocycle, each of which is one or more R 3and optionally substituted with one or more R 4 and optionally further substituted with Q 2 is hydrogen, halogen, CN, Z 1 , C3-C 11 cycloalkyl, and 3- to 11-membered heterocycle; 11 Each of the cycloalkyl and 3- to 11-membered heterocycles may be selected from one or more R 2 and optionally substituted with Z 1 and optionally further substituted with R 1 are each independently hydrogen, halogen, CN, OR 10 , S.R. 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 , C1-C6 alkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl, each C1-C6 alkyl being selected from the group consisting of one or more R 11 and each of the C-C cycloalkyl and 3- to 6-membered heterocyclyl is optionally substituted with one or more R 12 optionally substituted with R 2 are each independently hydrogen, fluoro, oxo, thioxo, OR 13 , S.R. 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 , C1-C6 alkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl, each C1-C6 alkyl being selected from the group consisting of one or more R 14and each of the C-C cycloalkyl and 3- to 6-membered heterocyclyl is optionally substituted with one or more R 15 optionally substituted with R 3 are each independently hydrogen, fluoro, oxo, thioxo, OR 16 , S.R. 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 , C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, each of the C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl moieties being selected from the group consisting of one or more R 17A optionally substituted with R 4 are each independently hydrogen, C(O)(C2-C6 alkenyl), N(R 16 )C(O)(C2-C6 alkenyl), (C1-C6 alkylene)-N(R 16 )C(O)(C2-C6 alkenyl), C(O)(C2-C6 alkynyl), N(R 16 )C(O)(C2-C6 alkynyl), (C1-C6 alkylene)-N(R 16 )C(O)(C2-C6 alkynyl), C6-C 10 Aryl, 5-10 membered heteroaryl, E 3 -C6-C 10 Aryl, E 3 -5-10 membered heteroaryl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, E 3 -C3-C6 cycloalkyl, and E 3 - 3- to 6-membered heterocyclyl, and each of C-C alkenyl and C-C alkynyl is selected from the group consisting of one or more R 17B and optionally substituted with C6-C 10 Each of the aryl and 5- to 10-membered heteroaryl may be selected from one or more R 18and each of the C-C cycloalkyl and 3- to 6-membered heterocyclyl is optionally substituted with one or more R 19 optionally substituted with E 3 are each independently -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 - selected from the group consisting of R 5A are independently hydrogen, halogen, CN, OR 22 , N(R 22 )2, C1-C6 alkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl, each C1-C6 alkyl being selected from the group consisting of one or more R d and each of the C-C cycloalkyl and 3- to 6-membered heterocyclyl is optionally substituted with one or more R e is optionally replaced by R 5B are independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl, each C1-C6 alkyl being selected from one or more R d and each of the C-C cycloalkyl and 3- to 6-membered heterocyclyl is optionally substituted with one or more R e optionally substituted with R 8 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl, and each C1-C6 alkyl is selected from one or more R dand each of the C-C cycloalkyl and 3- to 6-membered heterocyclyl is optionally substituted with one or more R e optionally substituted with R 9 are each independently selected from the group consisting of hydrogen, fluoro, C1-C6 alkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl, and each C1-C6 alkyl is selected from one or more R d and each of the C-C cycloalkyl and 3- to 6-membered heterocyclyl is optionally substituted with one or more R e or two R 9 are united as oxo, R 10 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl; R 11 are each independently fluoro, oxo, thioxo, OR a , S.R. 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-C cycloalkyl, and 3- to 6-membered heterocyclyl, each of which is selected from the group consisting of one or more R e optionally substituted with R 12 are each independently fluoro, oxo, thioxo, OR a , S.R. 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 C1-C6 alkyl, each of which is selected from the group consisting of one or more R d optionally substituted with R 13 are each independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl; R 14 are each independently fluoro, oxo, thioxo, OR b , S.R. 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 , C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl, each of which is selected from the group consisting of one or more R e optionally substituted with R 15 are each independently fluoro, oxo, thioxo, OR b , S.R. 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 C1-C6 alkyl, each of which is selected from the group consisting of one or more R d optionally substituted with R 16 are each independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl; R 17A and R 17B are each independently fluoro, oxo, thioxo, OR c , S.R.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 , C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl, each of which is selected from the group consisting of one or more R e optionally substituted with R 18 are each independently halogen, CN, OR c , S.R. 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 , C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl, each of the C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkenyl, and C2-C6 alkynyl being selected from the group consisting of one or more R d and each of the C-C cycloalkyl and 3- to 6-membered heterocyclyl is optionally substituted with one or more R e optionally substituted with R 19 are each independently fluoro, oxo, thioxo, OR c , S.R. 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 C1-C6 alkyl, each of which is selected from the group consisting of one or more R doptionally substituted with R 20 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl, and each C1-C6 alkyl is selected from one or more R d and each of the C-C cycloalkyl and 3- to 6-membered heterocyclyl is optionally substituted with one or more R e optionally substituted with R 21 are each independently selected from the group consisting of hydrogen, fluoro, C1-C6 alkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl, and each C1-C6 alkyl is selected from one or more R d and each of the C-C cycloalkyl and 3- to 6-membered heterocyclyl is optionally substituted with one or more R e or two R 21 are united as oxo, R 22 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl; R a , R b , and R c are each independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl; R d are each independently selected from the group consisting of fluoro, hydroxy, C1-C4 alkoxy, oxo, NH2, NH(C1-C4 alkyl), and N(C1-C4 alkyl)2; R e are each independently selected from the group consisting of fluoro, hydroxy, C-C alkyl, C-C fluoroalkyl, C-C alkoxy, oxo, NH, NH(C-C alkyl), and N(C-C alkyl); m is an integer from 0 to 6, t is an integer from 1 to 4, u is an integer from 1 to 5, y is an integer from 1 to 3, z is an integer from 1 to 4, Z 1 L 1 -P, L 1 -G, and Z 2 wherein: L 1 is selected from a bond and a bivalent chemical linker; P is a target protein binding moiety, G is a reactive functional group, Z 2 is selected from the group consisting of hydrogen, C1-C4 alkyl, and an amine protecting group; Provided is a compound, or a salt thereof, provided that 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.

[0015] In the compound of formula (I), Q 1 is C3-C 11 cycloalkyl or 3- to 11-membered heterocycle, each of which is one or more R 3 and optionally substituted with one or more R 4 Optionally further substituted with Q 1 are monocyclic, spirocyclic, fused, or bridged C3-C 11 cycloalkyl or 3- to 11-membered heterocycle, each of which is one or more R 3 and optionally substituted with one or more R 4 is optionally further substituted with

[0016] In some embodiments of Formula (I), Q 1 is Y 3 containing formula (IV)

[0017] [ka] C3-C 11 cycloalkyl or a 3- to 11-membered heterocycle, * indicates E 1 is the attachment point for Y 3 is N, C(R 3 ), or C(R 4 ) and r is an integer from 0 to 4, s is an integer of 0 to 2.

[0018] In some embodiments of Formula (I) or Formula (II), Q 1 Formula (IVa), Formula (IVb), and Formula (IVc)

[0019] [ka] C3-C 11 cycloalkyl or a 3- to 11-membered heterocycle, * indicates E 1 is the attachment point for Y 3 is N, C(R 3 ), or C(R 4 ) and Y 4 is N(R 3 ), N(R 4 ), C(R 3 )2, C(R 3 )(R 4 ), or C(R 4 )2, A 1 , B 1 , C 1 , and D 1 are independently null, O, C(O), S(O), S(O)2, N(R 3 ), N(R 4 ), C(R 3 )2, C(R 3 )(R 4 ), and C(R 4)2, r is an integer from 0 to 4, s is an integer from 0 to 2, v 1 , w 1 , v 2 , w 2 , v 3 , w 3 , v 4 , and w 4 are each independently an integer of 0 to 5.

[0020] In some embodiments of Formula (I) or Formula (II), Q 1 is a C3-C having the structure of formula (IVa) 11 In some embodiments of Formula (I) or Formula (II), Q is a cycloalkyl or a 3- to 11-membered heterocycle. 1 is a C3-C having the structure of formula (IVb) 11 In some embodiments of Formula (I) or Formula (II), Q is a cycloalkyl or a 3- to 11-membered heterocycle. 1 is a C3-C having the structure of formula (IVc) 11 It is a cycloalkyl or a 3- to 11-membered heterocycle.

[0021] In some embodiments of Formula (I) or Formula (II), compounds comprising a moiety of Formula (IVa), Formula (IVb), or Formula (IVc) have one, two, three, four, or more than four of the following selected characteristics, provided that these characteristics are not consistent. 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. In some embodiments, Y3 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 In some embodiments, Y 3 is C(R 3 ) or C(R 4 ) and Y 4 is C(R 3 )2, C(R 3 )(R 4 ), or C(R 4 )2. In some embodiments, A 1 , B 1 , C 1 , and D 1 are each independently C(R 3 )2, C(R 3 )(R 4 ), or C(R 4 )2. In some embodiments, A 1 , B 1 , C 1 , and D 1 one or more of may be independently selected from null, O, C(O), S(O), S(O), N(R 3 ), or N(R 4 In some embodiments, r is an integer from 0 to 1. In some embodiments, s is an integer from 0 to 1. In some embodiments, v 1 , w1 , v 2 , w 2 , v 3 , w 3 , v 4 , and w 4 are each independently an integer of 1 to 2. In some embodiments, v 1 is 1 and w 1 is 2. In some embodiments, v 1 is 1 and w 1 is 1. In some embodiments, v 1 is 2 and w 1 is 2. In some embodiments, v 2 is 1 and w 2 is 2. In some embodiments, v 2 is 1 and w 2 is 1. In some embodiments, v 2 is 2 and w 2 is 2. In some embodiments, v 1 and w 1 The sum of v and v is 2 to 4. 2 and w 2 The sum of v and v is 2 to 4. 2 is 1 and w 2 is 2. In some embodiments, v 2 is 1 and w 2 is 1. In some embodiments, v 3 is 0 and w 3 is 2. In some embodiments, v 4 is 1 and w 4 is 2. In some embodiments, v 4 is 1 and w 4 is 1. In some embodiments, v 4 is 0 and w 4 is 2. In some embodiments, v 4 is 2 and w 4 is 1. In some embodiments, v 4 is 2 and w 4 is 0.

[0022] In the compound of formula (I), Q 2is hydrogen, halogen, CN, Z 1 , C3-C 11 cycloalkyl, and 3- to 11-membered heterocycle; 11 Each of the cycloalkyl and 3- to 11-membered heterocycles may be selected from one or more R 2 and optionally substituted with Z 1 is optionally further substituted with

[0023] In some embodiments of Formula (I), Q 2 is C3-C 11 selected from the group consisting of cycloalkyl and 3- to 11-membered heterocycles; 11 Each of the cycloalkyl and 3- to 11-membered heterocycles may be selected from one or more R 2 and optionally substituted with Z 1 Optionally further substituted with Q 2 are monocyclic, spirocyclic, fused, or bridged C3-C 11 cycloalkyl or 3- to 11-membered heterocycle, each of which is one or more R 2 and optionally substituted with Z 1 In some embodiments, Q 2 is selected from the group consisting of C3-C8 cycloalkyl and 3- to 8-membered heterocycle, and each of the C3-C8 cycloalkyl and 3- to 8-membered heterocycle is selected from the group consisting of one or more R 2 and optionally substituted with Z 1 In some such embodiments, Z 1 L 1 In some such embodiments, Z 1 L 1 In other such embodiments, Z 1 is Z 2 is.

[0024] In some embodiments of Formula (I), Q 2 is C3-C 11cycloalkyl and 3- to 11-membered heterocycle, each of which is selected from the group consisting of one or more R 2 and optionally substituted with Z 1 is replaced by Z 1 L 1 In some embodiments of Formula (I), Q 2 is C3-C 11 cycloalkyl and 3- to 11-membered heterocycle, each of which is selected from the group consisting of one or more R 2 and optionally substituted with Z 1 is replaced by Z 1 L 1 In some embodiments of Formula (I), Q 2 is C3-C 11 cycloalkyl and 3- to 11-membered heterocycle, each of which is selected from the group consisting of one or more R 2 and optionally substituted with Z 1 is replaced by Z 1 is Z 2 is.

[0025] In some embodiments of Formula (I), Q 2 is the formula (Va), the formula (Vb), and the formula (Vc)

[0026] [ka] C3-C 11 is selected from the group consisting of cycloalkyl and 3- to 11-membered heterocycle, # is E 2 is the attachment point for Y 1 is C(R 6 ) or N, or Y 1 is O and Z 1 is null, Y 2 is C(R 7 ) or N, R 6 are independently hydrogen, fluoro, OR 23 , N(R23 )2, and C1-C6 alkyl, each of which is selected from the group consisting of one or more R d optionally substituted with R 7 are independently hydrogen, fluoro, OR 24 , N(R 24 )2, and C1-C6 alkyl, each of which is selected from the group consisting of one or more R d optionally substituted with R 23 and R 24 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl; R d are each independently selected from the group consisting of fluoro, hydroxy, C1-C4 alkoxy, oxo, NH2, NH(C1-C4 alkyl), and N(C1-C4 alkyl)2; A 2 , B 2 , C 2 , and D 2 are independently 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, v 5 , w 5 , v 6 , w 6 , v 7 , w 7 , v 8 , and w 8 are each independently an integer of 0 to 5.

[0027] In some embodiments of Formula (I) or Formula (II), a compound comprising a moiety of Formula (Va), Formula (Vb), or Formula (Vc) has one, two, three, four, or more than four of the following selected characteristics, provided that these characteristics are not consistent. 1 is N. In some embodiments, Y1 is C(R 6 In some embodiments, Y 1 is O. In some embodiments, Y 2 is N. In some embodiments, Y 2 is C(R 7 In some embodiments, Y 1 is N and Y 2 is N. In some embodiments, Y 1 is N and Y 2 is C(R 7 In some embodiments, Y 1 is C(R 6 ) and Y 2 is N. In some embodiments, Y 1 is C(R 6 ) and Y 2 is C(R 7 In some embodiments, Y 1 is O and Y 2 is C(R 7 In some embodiments, Y 1 is O and Y 2 is N. In some embodiments, A 2 , B 2 , C 2 , and D 2 are each independently C(R 2 )2. In some embodiments, A 2 , B 2 , C 2 , and D 2 one or more of are independently null, O, C(O), S(O), S(O)2, or N(R 2 In some embodiments, n is an integer from 0 to 1. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, v 5 , w 5 , v 6 , w 6 , v 7 , w 7 , v 8 , and w 8 are each independently an integer from 1 to 3. In some embodiments, v 5is 1 and w 5 is 1. In some embodiments, v 5 is 1 and w 5 is 2. In some embodiments, v 5 is 2 and w 5 is 1. In some embodiments, v 5 is 2 and w 5 is 2. In some embodiments, v 5 is 0 or 1, and w 5 is 3. In some embodiments, v 5 is 3 and w 5 is 0 or 1. In some embodiments, v 5 is 0 and w 5 is 4. In some embodiments, v 5 is 4 and w 5 is 0. In some embodiments, 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, v 5 and w 5 The sum of v and v is 2 to 4. 6 and w 6 The sum of v and v is 2 to 4. 7 is 1 and w 7 is 1. In some embodiments, v 7 is 1 and w 7is 2. In some embodiments, v 7 is 2 and w 7 is 1. In some embodiments, v 7 is 0 and w 7 is 2 or 3. In some embodiments, v 7 is 2 or 3, and w 7 is 0. In some embodiments, v 8 is 1 and w 8 is 1. In some embodiments, v 8 is 1 and w 8 is 2. In some embodiments, v 8 is 2 and w 8 is 1. In some embodiments, v 8 is 0 and w 8 is 2 or 3. In some embodiments, v 8 is 2 or 3, and w 8 is 0. In some embodiments, v 7 and w 7 The sum of v and v is 2 to 3. 8 and w 8 The total is 2 to 3.

[0028] In some embodiments of Formula (I), Q 2 is C3-C 11 selected from the group consisting of cycloalkyl and 3- to 11-membered heterocycles; 11 Each of the cycloalkyl and 3- to 11-membered heterocycles may be selected from one or more R 2 and optionally substituted with Z 1 In some embodiments of Formula (I), Q 2 is one or more R 2 and optionally substituted with Z 1 C-C optionally further substituted with 11 In some embodiments of Formula (I), Q is cycloalkyl. 2 is one or more R 2 and optionally substituted with Z 1In some such embodiments, Z is a 3- to 11-membered heterocycle optionally further substituted with 1 L 1 In some such embodiments, Z 1 L 1 In other such embodiments, Z 1 is Z 2 is.

[0029] In some embodiments of Formula (I), Q 2 is selected from the group consisting of hydrogen, halogen, and CN.

[0030] In some embodiments of Formula (I), Q 2 is Z 1 In some such embodiments, Z 1 L 1 In some such embodiments, Z 1 L 1 In other such embodiments, Z 1 is Z 2 is.

[0031] In another aspect herein, a compound of formula (II):

[0032] [ka] or a salt thereof, wherein A is X 1 C6-C, including 10 aryl or 5-10 membered heteroaryl; X 1 is C(R 5A ), N, N(R 5B ), O, or S; Y 1 is C(R 6 ) or N, or Y 1 is O and Z 1 is null, Y 2 is C(R 7) or N, E 1 and E 2 are independently a bond, -N(R 8 )-, -(C(R 9 )2) t N(R 8 )-, -N(R 8 )(C(R 9 )2) t -, -(C(R 9 )2) t N(R 8 )(C(R 9 )2) u -, -O-, -(C(R 9 )2) t O-, -O-(C(R 9 )2) t -, -(C(R 9 )2) t O(C(R 9 )2) u -, -(C(R 9 )2) u -, -C(O)-, -C(O)N(R 8 )-, -(C(R 9 )2) t C(O)N(R 8 )-, -C(O)N(R 8 )(C(R 9 )2) t -, -(C(R 9 )2) t C(O)N(R 8 )(C(R 9 )2) u -, -N(R 8 )C(O)-, -(C(R 9 )2) t N(R 8 )C(O)-, -N(R 8 )C(O)(C(R 9 )2) t - and -(C(R 9 )2) t N(R 8 )C(O)(C(R 9 )2) u - selected from the group consisting of Y 3 is N, C(R 3 ), or C(R4 ) and Q 1 is C3-C 11 cycloalkyl or 3- to 11-membered heterocycle, each of which is one or more R 3 and optionally substituted with one or more R 4 and optionally further substituted with Q 2 is C3-C 11 cycloalkyl or 3-11 membered heterocycle, C3-C 11 Each of the cycloalkyl and 3- to 11-membered heterocycles may be selected from one or more R 2 and optionally substituted with Z 1 and optionally further substituted with R 1 are each independently hydrogen, halogen, CN, OR 10 , S.R. 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 , C1-C6 alkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl, each C1-C6 alkyl being selected from the group consisting of one or more R 11 and each of the C-C cycloalkyl and 3- to 6-membered heterocyclyl is optionally substituted with one or more R 12 optionally substituted with R 2 are each independently fluoro, oxo, thioxo, OR 13 , S.R. 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, C1-C6 alkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl, each C1-C6 alkyl being selected from the group consisting of one or more R 14 and each of the C-C cycloalkyl and 3- to 6-membered heterocyclyl is optionally substituted with one or more R 15 optionally substituted with R 3 are each independently hydrogen, fluoro, oxo, thioxo, OR 16 , S.R. 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 , C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, each of the C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl moieties being selected from the group consisting of one or more R 17A optionally substituted with R 4 are each independently C(O)-(C2-C6 alkenyl), N(R 16 )C(O)(C2-C6 alkenyl), C(O)-(C2-C6 alkynyl), N(R 16 )C(O)(C2-C6 alkynyl), C6-C 10 Aryl, 5-10 membered heteroaryl, E 3 -C6-C 10 Aryl, E 3 -5-10 membered heteroaryl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, E 3 -C3-C6 cycloalkyl, and E 3 - 3- to 6-membered heterocyclyl, and each of C-C alkenyl and C-C alkynyl is selected from the group consisting of one or more R 17B and optionally substituted with C6-C 10 Each of the aryl and 5- to 10-membered heteroaryl may be selected from one or more R 18and each of the C-C cycloalkyl and 3- to 6-membered heterocyclyl is optionally substituted with one or more R 19 optionally substituted with E 3 are each independently -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 - selected from the group consisting of R 5A are independently hydrogen, halogen, CN, OR 22 , N(R 22 )2, C1-C6 alkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl, each C1-C6 alkyl being selected from the group consisting of one or more R d and each of the C-C cycloalkyl and 3- to 6-membered heterocyclyl is optionally substituted with one or more R e is optionally replaced by R 5B are independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl, each C1-C6 alkyl being selected from one or more R d and each of the C-C cycloalkyl and 3- to 6-membered heterocyclyl is optionally substituted with one or more R e optionally substituted with R 6 are independently hydrogen, fluoro, OR 23 , N(R 23 )2, and C1-C6 alkyl, each of which is selected from the group consisting of one or more R d optionally substituted with R 7are independently hydrogen, fluoro, OR 24 , N(R 24 )2, and C1-C6 alkyl, each of which is selected from the group consisting of one or more R d optionally substituted with R 8 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl, and each C1-C6 alkyl is selected from one or more R d and each of the C-C cycloalkyl and 3- to 6-membered heterocyclyl is optionally substituted with one or more R e optionally substituted with R 9 are each independently selected from the group consisting of hydrogen, fluoro, C1-C6 alkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl, and each C1-C6 alkyl is selected from one or more R d and each of the C-C cycloalkyl and 3- to 6-membered heterocyclyl is optionally substituted with one or more R e or two R 9 are united as oxo, R 10 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl; R 11 are each independently fluoro, oxo, thioxo, OR a , S.R. 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-C cycloalkyl, and 3- to 6-membered heterocyclyl, each of which is selected from the group consisting of one or more R e optionally substituted with R 12 are each independently fluoro, oxo, thioxo, OR a , S.R. 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 C1-C6 alkyl, each of which is selected from the group consisting of one or more R d optionally substituted with R 13 are each independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl; R 14 are each independently fluoro, oxo, thioxo, OR b , S.R. 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 , C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl, each of which is selected from the group consisting of one or more R e optionally substituted with R 15 are each independently fluoro, oxo, thioxo, OR b , S.R. 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 C1-C6 alkyl, each of which is selected from the group consisting of one or more R doptionally substituted with R 16 are each independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl; R 17A and R 17B are each independently fluoro, oxo, thioxo, OR c , S.R. 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 , C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl, each of which is selected from the group consisting of one or more R e optionally substituted with R 18 are each independently halogen, CN, OR c , S.R. 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 , C1-C6 alkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl, each C1-C6 alkyl being selected from the group consisting of one or more R d and each of the C-C cycloalkyl and 3- to 6-membered heterocyclyl is optionally substituted with one or more R e optionally substituted with R 19 are each independently fluoro, oxo, thioxo, OR c , S.R. c , N(R c )2, C(O)R c ,OC(O)R c , C(O)ORc , C(O)N(R c )2, N(R c )C(O)R c and C1-C6 alkyl, each of which is selected from the group consisting of one or more R d optionally substituted with R 20 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl, and each C1-C6 alkyl is selected from one or more R d and each of the C-C cycloalkyl and 3- to 6-membered heterocyclyl is optionally substituted with one or more R e optionally substituted with R 21 are each independently selected from the group consisting of hydrogen, fluoro, C1-C6 alkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl, and each C1-C6 alkyl is selected from one or more R d and each of the C-C cycloalkyl and 3- to 6-membered heterocyclyl is optionally substituted with one or more R e or two R 21 are united as oxo, R 22 , R 23 , and R 24 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl; R a , R b , and R c are each independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl; R dare each independently selected from the group consisting of fluoro, hydroxy, C1-C4 alkoxy, oxo, NH2, NH(C1-C4 alkyl), and N(C1-C4 alkyl)2; R e are each independently selected from the group consisting of fluoro, hydroxy, C-C alkyl, C-C fluoroalkyl, C-C alkoxy, oxo, NH, NH(C-C alkyl), and N(C-C alkyl); m 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, y is an integer from 1 to 3, z is an integer from 1 to 4, Z 1 L 1 -P, L 1 -G, and Z 2 wherein: L 1 is selected from a bond and a bivalent chemical linker; P is a target protein binding moiety, G is a reactive functional group, Z 2 is selected from the group consisting of hydrogen, C1-C4 alkyl, and an amine protecting group; or Y 1 When is O, Z 2 does not exist, Provided is a compound, or a salt thereof, provided that the compound of formula (II) 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.

[0033] In the compound of formula (I) or formula (II), A is X 1 C6-C, including 10 aryl or 5-10 membered heteroaryl. Ring A can be monocyclic or can be a fused C6-C 10 A may form part of an aryl or a 5- to 10-membered heteroaryl. In each case, A may be one or more R 1 In some embodiments of Formula (I) or Formula (II), A is optionally substituted with X 1 Contains one or more R 1 C-C optionally substituted with 10 In some embodiments of Formula (I) or Formula (II), A is X 1 Contains one or more R 1 In some embodiments of Formula (I) or Formula (II), A is a 5-6 membered heteroaryl optionally substituted with X 1 Contains one or more R 1 In some embodiments of Formula (I) or Formula (II), Ring A is a 6-membered heteroaryl optionally substituted with X 1 and one or more R are selected from pyridine, pyrimidine, pyrazine, pyridazine, or triazine. 1 In some such embodiments, A is a 6-membered heteroaryl optionally substituted with one or more R 1 is a pyridine or pyrimidine optionally substituted with

[0034] In the compound of formula (I) or formula (II), X 1 is C(R 5A ), N, N(R 5B ), O, or S. In some embodiments of Formula (I) or Formula (II), X 1 is C(R 5A ) or N. In some embodiments, X 1 is C(R 5A ) or N and X 1 In some embodiments, the ring containing X is a 6-membered heteroaryl.1 is C(R 5A ), N, N(R 5B ), O, or S, and X 1 A ring containing X is a 5-membered heteroaryl. 1 Each 5- or 6-membered heteroaryl containing A may be monocyclic (i.e., A is a 5- or 6-membered heteroaryl, respectively) or may form part of a fused 5- to 10-membered heteroaryl, in each case A may be one or more R 1 is optionally replaced by

[0035] In some embodiments of Formula (I) or Formula (II), X 1 is N and A is one or more R 1 In some such embodiments, X is a 6-membered heteroaryl optionally substituted with 1 is N, A is a 6-membered heteroaryl selected from pyridine, pyrimidine, pyrazine, or triazine, each of the 6-membered heteroaryls being selected from one or more R 1 In some such embodiments, X is optionally substituted with 1 is N, and A is one or more R 1 In some such embodiments, X is a 6-membered heteroaryl selected from pyridine or pyrimidine optionally substituted with 1 is N, and A is one or more R 1 In some such embodiments, X is a 6-membered heteroaryl selected from pyridine optionally substituted with 1 is N, and A is one or more R 1 In some embodiments of Formula (I) or Formula (II), X is a 6-membered heteroaryl selected from pyrimidine optionally substituted with 1 is C(R 5A ) and A is one or more R 1 In some such embodiments, X is a 6-membered heteroaryl optionally substituted with 1 is C(R 5A), wherein A is a 6-membered heteroaryl selected from pyridine, pyrimidine, pyridazine, or triazine, and each of the 6-membered heteroaryls is selected from one or more R 1 In some such embodiments, X is optionally substituted with 1 is C(R 5A ) and A is a 6-membered heteroaryl selected from pyridine, pyrimidine, or pyridazine. In some such embodiments, X 1 is C(R 5A ), each A is one or more R 1 In some such embodiments, X is a 6-membered heteroaryl selected from pyridine or pyrimidine optionally substituted with 1 is C(R 5A ), each A is one or more R 1 In some such embodiments, X is a 6-membered heteroaryl selected from pyridine optionally substituted with 1 is C(R 5A ), each A is one or more R 1 and a 6-membered heteroaryl selected from pyrimidine optionally substituted with

[0036] In some embodiments of Formula (I) or Formula (II), X 1 is C(R 5A ), N, N(R 5B ), O, or S, and A is one or more R 1 In some such embodiments, X is a 5-membered heteroaryl optionally substituted with 1 is C(R 5A ), N, N(R 5B ), O, or S; A is a 5-membered heteroaryl selected from pyrrole, pyrazole, imidazole, thiophene, thiazole, isothiazole, furan, oxazole, isoxazole, thiadiazole, and oxadiazole; each 5-membered heteroaryl is selected from one or more R 1 is optionally replaced by

[0037] In some embodiments of Formula (I) or Formula (II), A is

[0038] [ka] or a tautomeric form thereof. 10 aryl or 5-6 membered heteroaryl, wherein * indicates E 1 is the attachment point for # is E 2 is the attachment point for X 1 When the ring containing X 1 is C(R 5A ) or N, X 2 , X 3 , and X 4 are each independently C(R 5A ) or N, However, X 1 , X 2 , X 3 , or X 4 At least one of C(R 5A ), or X 1 When the ring containing X 1 is C(R 5A ), N, N(R 5B ), O, or S; X 2 and X 3 Each of the groups independently represents C(R 5A ), N, N(R 5B ), O, or S; However, X 1 , X 2 , or X 3 At least one of C(R 5A ), or X 1 The ring containing C6-C 10 When it is aryl, X 1 is C(R 5A ) and X 2 , X 3 , and X 4 are each independently C(R 5A ) and C6-C 10 Each aryl or 5- to 10-membered heteroaryl may be one or more R 1 is optionally replaced by

[0039] In some embodiments of Formula (I) or Formula (II), A is one or more R 1 In some such embodiments, A is a 9-10 membered heteroaryl optionally substituted with

[0040] [ka] or a tautomeric form thereof, wherein * indicates E 1 is the attachment point for # is E 2 is the attachment point for X 1 When the ring containing X 1 is C(R 5A ) or N, X 2 , X 3 , and X 4 are independently C, C(R 5A ), or N, X 5 are each independently C(R 5A ), N, N(R 5B ), O, or S; X 6 are each independently C(R 5A ) or N, but with at least one X 6 is C(R 5A ), X1 When the ring containing X 1 is C(R 5A ), N, N(R 5B ), O, or S; X 2 and X 3 are each independently C or N, X 6 are each independently C(R 5A ) or N, but with at least one X 6 is C(R 5A ), However, X 1 , X 2 , X 3 , X 4 , X 5 , or X 6 At least one of C(R 5A ) Each 9- to 10-membered heteroaryl may be selected from one or more R 1 is optionally replaced by

[0041] In some embodiments of Formula (I) or Formula (II), X 1 is C(R 5A In some embodiments of Formula (I) or Formula (II), X 1 is N. In some embodiments, X 1 is N(R 5B In some embodiments of Formula (I) or Formula (II), X 1 is O or S. In some embodiments of Formula (I) or Formula (II), X 1 , X 2 , X 3 , X 4 , X 5 , or X 6 One or more of the C(R 5A In some embodiments of Formula (I) or Formula (II), X 1 , X 2 , X 3 , X 4 , X 5 , or X6 One or more of X is N. 1 , X 2 , X 3 , X 4 , X 5 , or X 6 At least two of them are N.

[0042] In the compounds of formula (I) or (II), R 5A are independently hydrogen, halogen, CN, OR 22 , N(R 22 )2, C1-C6 alkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl, each C1-C6 alkyl being selected from the group consisting of one or more R d and each of the C-C cycloalkyl and 3- to 6-membered heterocyclyl is optionally substituted with one or more R e In some embodiments, R 5A is hydrogen. In some embodiments, R 22 is independently selected from the group consisting of hydrogen, C-C alkyl, and C-C fluoroalkyl. 22 is hydrogen.

[0043] In the compounds of formula (I) or (II), R 5B are independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl, each C1-C6 alkyl being selected from one or more R d and each of the C-C cycloalkyl and 3- to 6-membered heterocyclyl is optionally substituted with one or more R e In some embodiments, R 5B is hydrogen or C1-C6 alkyl. In some embodiments, R 5B is hydrogen or C1-C4 alkyl.

[0044] In some embodiments of Formula (I) or Formula (II), A is

[0045] [ka] or a tautomeric form thereof. 10 aryl or 5-10 membered heteroaryl, wherein * indicates E 1 is the attachment point for # is E 2 is the attachment point for C6-C 10 Each aryl or 5- to 10-membered heteroaryl may be one or more R 1 is optionally replaced by

[0046] In the compounds of formula (I) or (II), R a , R b , and R c are each independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, and 3-6 membered heterocyclyl. a , R b , and R c are each independently selected from the group consisting of hydrogen and C1-C4 alkyl.

[0047] In the compounds of formula (I) or (II), R d are each independently selected from the group consisting of fluoro, hydroxy, C1-C4 alkoxy, oxo, NH2, NH(C1-C4 alkyl), and N(C1-C4 alkyl)2.

[0048] In the compounds of formula (I) or (II), R e are each independently selected from the group consisting of fluoro, hydroxy, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, oxo, NH2, NH(C1-C4 alkyl), and N(C1-C4 alkyl)2.

[0049] In compounds of Formula (I) or Formula (II), m is an integer from 0 to 6. In some embodiments, m is an integer from 0 to 4. In some embodiments, m is an integer from 0 to 2. In some embodiments, m is an integer from 0 to 1. In frequent embodiments of Formula (I) or Formula (II), m is 0. In compounds of Formula (II), n is an integer from 0 to 4. In some embodiments, n is an integer from 0 to 2. In some embodiments, n is an integer from 0 to 1. In some embodiments of compounds of Formula (II), n is 0. In some embodiments of Formula (II), m is an integer from 0 to 1 and n is an integer from 0 to 1. In some embodiments of Formula (II), m is 0 and n is 0.

[0050] In the compounds of formula (I) or (II), R 1 are each independently hydrogen, halogen, CN, OR 10 , S.R. 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 , C1-C6 alkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl, each C1-C6 alkyl being selected from the group consisting of one or more R 11 and each of the C-C cycloalkyl and 3- to 6-membered heterocyclyl is optionally substituted with one or more R 12 In some embodiments, m is 0 (i.e., R 1 is absent). In some embodiments, R 1 are independently halogen, OR 10 , N(R 10 )2, and C1-C6 alkyl. In some embodiments, R 1 is halogen (preferably fluoro) or C1-C6 alkyl. In some embodiments, R 1 is C1-C6 alkyl. In some embodiments, R 1is halogen (preferably fluoro). In some embodiments, m is an integer from 0 to 1. In some such embodiments, m is 1. In some such embodiments, m is 1 and R 1 are independently halogen, OR 10 , N(R 10 )2, and C1-C6 alkyl.

[0051] In the compounds of formula (I) or (II), R 10 are each independently selected from the group consisting of hydrogen, C-C alkyl, C-C fluoroalkyl, C-C cycloalkyl, and 3- to 6-membered heterocyclyl. 10 are each independently selected from the group consisting of hydrogen and C1-C6 alkyl. 10 are each independently selected from the group consisting of hydrogen and C1-C4 alkyl.

[0052] In the compounds of formula (I) or (II), R 11 are each independently fluoro, oxo, thioxo, OR a , S.R. 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-C cycloalkyl, and 3- to 6-membered heterocyclyl, each of which is selected from the group consisting of one or more R e In some embodiments, R 11 are each independently fluoro, OR a , and N(R a In some such embodiments, R a are each independently selected from the group consisting of hydrogen and C1-C4 alkyl.

[0053] In the compounds of formula (I) or (II), R 12 are each independently fluoro, oxo, thioxo, OR a , S.R. 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 C1-C6 alkyl, each of which is selected from the group consisting of one or more R d In some embodiments, R 12 are each independently fluoro, OR a , N(R a )2, and C1-C6 alkyl. In some such embodiments, R a are each independently selected from the group consisting of hydrogen and C1-C4 alkyl.

[0054] In the compound of formula (II), Q 2 is C3-C 11 cycloalkyl or 3-11 membered heterocycle, C3-C 11 Each of the cycloalkyl and 3- to 11-membered heterocycles may be selected from one or more R 2 and optionally substituted with Z 1 In frequent embodiments of formula (II), Q 2 is a C3-C8 cycloalkyl or a 3- to 8-membered heterocycle, and each of the C3-C8 cycloalkyl and the 3- to 8-membered heterocycle is selected from one or more R 2 and optionally substituted with Z 1 In some embodiments, Z 1 L 1 In another embodiment, Z 1 L 1 In a further embodiment, Z 1 is Z 2 is.

[0055] Ring Q of formula (II) 2 is a ring atom Y as defined herein 1 and Y 2 In the compound of formula (II), Y 1 is C(R 6 ) or N, or Y 1 is O and Z 1 In the compound of formula (II), Y 2 is C(R 7 ) or N. In frequent embodiments of formula (II), Y 1 is C(R 6 ) or N. In some embodiments, Y 1 is N and Y 2 is N. In some embodiments, Y 1 and Y 2 One of them is N, and the other is C(R 6 ) or C(R 7 In some embodiments, Y 1 is C(R 6 ) and Y 2 is N. In some embodiments, Y 1 is N and Y 2 is C(R 7 In some embodiments, Y 1 is C(R 6 ) and Y 2 is C(R 7 )

[0056] In some embodiments of Formula (II), R 6 are independently hydrogen, fluoro, OR 23 , N(R 23 )2, and C1-C6 alkyl, each of which is selected from the group consisting of one or more R d In frequent embodiments, R 6 is hydrogen. In some embodiments of Formula (II), R 7 are independently hydrogen, fluoro, OR 24 , N(R 24)2, and C1-C6 alkyl, each of which is selected from the group consisting of one or more R d In frequent embodiments, R 7 is hydrogen. In some embodiments, R 6 and R 7 Each of R is hydrogen. 23 and R 24 are each independently selected from the group consisting of hydrogen, C-C alkyl, and C-C fluoroalkyl. 23 and R 24 are hydrogen atoms.

[0057] In some embodiments of Formula (II), Y 1 is O, provided 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. In an embodiment of formula (II), Y 1 When is O, Z 1 is Z 2 and Z 2 In some embodiments of the compound of Formula (II), Y 1 is not O.

[0058] In the compound of Formula (II), p is an integer from 0 to 3. In some embodiments, p is an integer from 0 to 2. In the compound of Formula (II), q is an integer from 1 to 3. In some embodiments, q is an integer from 1 to 2. In some embodiments of Formula (II), the sum of p and q is less than Y 1 and Y 2 The ring containing one or more R 2 In some such embodiments, n is an integer from 3 to 4, such as a C5-C6 cycloalkyl or 5-6 membered heterocyclyl ring optionally substituted with

[0059] In the compounds of formula (I), R 2are each independently hydrogen, fluoro, oxo, thioxo, OR 13 , S.R. 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 , C1-C6 alkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl, each C1-C6 alkyl being selected from the group consisting of one or more R 14 and each of the C-C cycloalkyl and 3- to 6-membered heterocyclyl is optionally substituted with one or more R 15 In some embodiments of Formula (I), R 2 are each independently hydrogen, fluoro, oxo, OR 13 , N(R 13 )2, and one or more R 14 C1-C6 alkyl optionally substituted with

[0060] In the compound of formula (II), R 2 are each independently hydrogen, fluoro, oxo, thioxo, OR 13 , S.R. 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 , C1-C6 alkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl, each C1-C6 alkyl being selected from the group consisting of one or more R 14 and each of the C-C cycloalkyl and 3- to 6-membered heterocyclyl is optionally substituted with one or more R 15 In some embodiments of Formula (II), R 2 are each independently fluoro, oxo, OR13 , N(R 13 )2, and one or more R 14 C1-C6 alkyl optionally substituted with

[0061] In some embodiments of compounds of Formula (II), n is 0. In some embodiments of Formula (II), n is 1 and R 2 are each independently fluoro, oxo, OR 13 , N(R 13 )2, and one or more R 14 In some such embodiments, R 13 are each independently selected from the group consisting of hydrogen and C1-C4 alkyl.

[0062] In the compounds of formula (I) or (II), R 13 are each independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl. 13 are each independently selected from the group consisting of hydrogen, C-C alkyl, and C-C fluoroalkyl. 13 are each independently selected from the group consisting of hydrogen and C1-C4 alkyl. 13 is hydrogen.

[0063] In the compounds of formula (I) or (II), R 14 are each independently fluoro, oxo, thioxo, OR b , S.R. 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, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl, each of which is selected from the group consisting of one or more R e In some embodiments, R 14 are each independently fluoro, OR b , and N(R b In some such embodiments, R b are each independently selected from the group consisting of hydrogen and C1-C4 alkyl.

[0064] In the compounds of formula (I) or (II), R 15 are each independently fluoro, oxo, thioxo, OR b , S.R. 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 C1-C6 alkyl, each of which is selected from the group consisting of one or more R d In some embodiments, R 15 are each independently fluoro, OR b , N(R b )2, and C1-C6 alkyl. In some such embodiments, R b are each independently selected from the group consisting of hydrogen and C1-C4 alkyl.

[0065] In the compound of formula (II), Q 1 As described, C3-C 11 cycloalkyl or 3- to 11-membered heterocycle, each of which is one or more R 3 and optionally substituted with one or more R 4 In the compound of formula (II), Q 1is Y 3 containing formula (IV)

[0066] [ka] wherein: * indicates E 1 is the attachment point for Y 3 is N, C(R 3 ), or C(R 4 ) and r is an integer from 0 to 4, s is an integer of 0 to 2.

[0067] In some embodiments of Formula (I) or Formula (II), Q 1 is Y 3 C3-C including 11 cycloalkyl or a 3- to 11-membered heterocycle; Y 3 is E 1 In some embodiments, Y is a ring atom that is bonded to 3 is N, C(R 3 ), or C(R 4 ) Q 1 each may be a monocyclic, spirocyclic, fused, or bridged C-C ring, as further described herein. 11 cycloalkyl or 3- to 11-membered heterocycle, each of which is one or more R 3 and optionally substituted with one or more R 4 In some embodiments, Y 3 is N. In some embodiments, Y 3 is C(R 3 In some embodiments, Y 3 is C(R 4 )

[0068] In the compound of formula (I) or formula (II), E 1 and E 2 are independently a bond, -N(R 8 )-, -(C(R 9 )2)t N(R 8 )-, -N(R 8 )(C(R 9 )2) t -, -(C(R 9 )2) t N(R 8 )(C(R 9 )2) u -, -O-, -(C(R 9 )2) t O-, -O-(C(R 9 )2) t -, -(C(R 9 )2) t O(C(R 9 )2) u -, -(C(R 9 )2) u -, -C(O)-, -C(O)N(R 8 )-, -(C(R 9 )2) t C(O)N(R 8 )-, -C(O)N(R 8 )(C(R 9 )2) t -, -(C(R 9 )2) t C(O)N(R 8 )(C(R 9 )2) u -, -N(R 8 )C(O)-, -(C(R 9 )2) t N(R 8 )C(O)-, -N(R 8 )C(O)(C(R 9 )2) t - and -(C(R 9 )2) t N(R 8 )C(O)(C(R 9 )2) u - is selected from the group consisting of

[0069] In some embodiments of Formula (I) or Formula (II), E 1 is a bond, -N(R 8 )-, -(C(R 9 )2) t N(R 8 )-, -N(R 8)(C(R 9 )2) t -, -(C(R 9 )2) t N(R 8 )(C(R 9 )2) u -, -O-, -(C(R 9 )2) t O-, -O-(C(R 9 )2) t -, -(C(R 9 )2) t O(C(R 9 )2) u - and -(C(R 9 )2) u In some embodiments, E 1 is a bond, -N(R 8 )-, -(C(R 9 )2) t N(R 8 )-, and -N(R 8 )(C(R 9 )2) t - is selected from the group consisting of

[0070] In compounds of Formula (I) or Formula (II), t is an integer from 1 to 4. In some embodiments, t is an integer from 1 to 2. In compounds of Formula (I) or Formula (II), u is an integer from 1 to 5. In some embodiments, u is an integer from 1 to 3. In some embodiments, t is an integer from 1 to 2 and u is an integer from 1 to 3. In compounds of Formula (I) or Formula (II), t and u(E 1 and / or E 2 ) are each independently selected.

[0071] In some embodiments of Formula (I) or Formula (II), E 1 is a bond. In some embodiments of Formula (I) or Formula (II), E 1 is a bond, -N(R 8 )-, -(C(R 9 )2) t N(R 8 )-, and -N(R 8 )(C(R9 )2) t In some embodiments of Formula (I) or Formula (II), E 1 is -N(R 8 )-, -(C(R 9 )2) t N(R 8 )-, and -N(R 8 )(C(R 9 )2) t In some embodiments, E 1 is -N(R 8 )-. In some embodiments, E 1 is -N(R 8 )(C(R 9 )2) t In some embodiments, E 1 is a bond, —NH—, —NHCH—, or —NH(CH)—. In some such embodiments, R 8 are each hydrogen. 9 are each hydrogen or two R 9 together is oxo. In some such embodiments, R 9 are each hydrogen. In some such embodiments, R 8 and R 9 are each hydrogen. In some embodiments of Formula (I) or Formula (II), E 1 is a bond, -NH-, -(CH2) t NH- and -NH(CH2) t -, and t is an integer from 1 to 4.

[0072] In some embodiments of Formula (I) or Formula (II), E 2 is a bond, -N(R 8 )-, -(C(R 9 )2) t N(R 8 )-, -N(R 8 )(C(R 9 )2) t -, -(C(R 9 )2) t N(R 8)(C(R 9 )2) u -, -O-, -(C(R 9 )2) t O-, -O-(C(R 9 )2) t -, -(C(R 9 )2) t O(C(R 9 )2) u - and -(C(R 9 )2) u In some embodiments, E 2 is a bond, -N(R 8 )-, -(C(R 9 )2) t N(R 8 )-, and -N(R 8 )(C(R 9 )2) t - is selected from the group consisting of

[0073] In some such embodiments, R 8 are each hydrogen. In some such embodiments, R 9 are each hydrogen. In some such embodiments, R 8 and R 9 are each hydrogen. In some embodiments of Formula (I) or Formula (II), E 2 is a bond, -NH-, -(CH2) t NH- and -NH(CH2) t -, and t is an integer from 1 to 4.

[0074] In other embodiments of Formula (I) or Formula (II), E 2 is 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)—. In some embodiments, E 2is a bond. 2 is -N(R 8 )-, -(C(R 9 )2) t N(R 8 )-, and -N(R 8 )(C(R 9 )2) t In other embodiments, E 2 is -C(O)N(R 8 )- and -N(R 8 )C(O)—. In some such embodiments, R 8 are each hydrogen. 9 are each hydrogen. In some embodiments, two R 9 together is oxo. In some such embodiments, R 8 and R 9 are each hydrogen. In some embodiments of Formula (I) or Formula (II), E 2 is a bond, -NH-, -(CH2) t NH-, -NH(CH2) t and t is an integer of 1 to 4.

[0075] In the compounds of formula (I) or (II), R 8 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl, and each C1-C6 alkyl is selected from one or more R d and each of the C-C cycloalkyl and 3- to 6-membered heterocyclyl is optionally substituted with one or more R e is optionally replaced by

[0076] In the compounds of formula (I) or (II), R 9 are each independently selected from the group consisting of hydrogen, fluoro, C1-C6 alkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl, and each C1-C6 alkyl is selected from one or more Rd and each of the C-C cycloalkyl and 3- to 6-membered heterocyclyl is optionally substituted with one or more R e or two R 9 together is oxo. In some such embodiments, R 8 are each hydrogen. In some such embodiments, R 9 are each hydrogen. In some such embodiments, R 8 and R 9 are hydrogen atoms.

[0077] In some embodiments of Formula (I) or Formula (II), E 1 is a bond and Q 1 is one or more R 3 and optionally substituted with one or more R 4 is a 3- to 11-membered heterocycle optionally further substituted with

[0078] In some embodiments of Formula (I) or Formula (II), E 1 is a bond, -N(R 8 )-, -(C(R 9 )2) t N(R 8 )-, and -N(R 8 )(C(R 9 )2) t -, and Q is selected from the group consisting of 1 is one or more R 3 and optionally substituted with one or more R 4 In some embodiments of Formula (I) or Formula (II), E 1 is -N(R 8 )-, -(C(R 9 )2) t N(R 8 )-, and -N(R 8 )(C(R 9 )2) t -, and Q is selected from the group consisting of 1 is one or more R 3and optionally substituted with one or more R 4 is a 3- to 11-membered heterocycle optionally further substituted with

[0079] In some embodiments of Formula (I) or Formula (II), Q 1 is R 4 and one or more R 3 In some embodiments of Formula (I) or Formula (II), Q is a 3- to 11-membered heterocycle optionally further substituted with 1 is R 3 and one or more R 4 is a 3- to 11-membered heterocycle optionally further substituted with

[0080] In some embodiments of Formula (I) or Formula (II), Q 1 is R 4 and one or more R 3 C3-C optionally further substituted with 11 In some embodiments of Formula (I) or Formula (II), Q is cycloalkyl. 1 is R 3 and one or more R 4 C3-C optionally further substituted with 11 It is cycloalkyl.

[0081] In some embodiments of Formula (I) or Formula (II), Q 1 is R 3 and R is a 3- to 11-membered heterocycle substituted with 3 is R 17A In some such embodiments, R 17A are each independently fluoro, OR c , and N(R c )2.

[0082] In some embodiments of Formula (I) or Formula (II), Q 1 is R 3 C3-C substituted with11 is cycloalkyl, and R 3 is R 17A In some such embodiments, R 17A are each independently fluoro, OR c , and N(R c )2.

[0083] In some embodiments of Formula (I) or Formula (II), Q 1 is R 4 and R is a 3- to 11-membered heterocycle substituted with 4 independently, C6-C 10 Aryl, 5-10 membered heteroaryl, E 3 -C6-C 10 Aryl, and E 3 - 5-10 membered heteroaryl, C6-C 10 Each of the aryl and 5- to 10-membered heteroaryl may be selected from one or more R 18 In some such embodiments, R 18 are each independently halogen, C1-C6 alkyl, C1-C6 heteroalkyl, OR c , and N(R c In some such embodiments, R 18 is halogen, preferably fluoro. In some such embodiments, R 18 is C1-C6 alkyl, preferably methyl. In some such embodiments, R 18 is C1-C6 heteroalkyl, preferably hydroxymethyl. In some such embodiments, E 3 are independently -NH-, -(CH2) y -NH-, -NH-(CH2) y , and -(CH2) z - is selected from the group consisting of

[0084] In some embodiments of Formula (I) or Formula (II), Q 1 is R4 and R is a 3- to 11-membered heterocycle substituted with 4 are independently C(O)(C2-C6 alkenyl), N(R 16 )C(O)(C2-C6 alkenyl), (C1-C6 alkylene)-N(R 16 )C(O)(C2-C6 alkenyl), C(O)(C2-C6 alkynyl), N(R 16 )C(O)(C2-C6 alkynyl), and (C1-C6 alkylene)-N(R 16 )C(O)(C2-C6 alkynyl), wherein each of the C2-C6 alkenyl and C2-C6 alkynyl is selected from the group consisting of one or more R 17B In some such embodiments, R 17B are each independently fluoro, OR c , and N(R c )2.

[0085] In some embodiments of Formula (I) or Formula (II), Q 1 is R 4 C3-C substituted with 11 is cycloalkyl, and R 4 are independently C(O)(C2-C6 alkenyl), N(R 16 )C(O)(C2-C6 alkenyl), (C1-C6 alkylene)-N(R 16 )C(O)(C2-C6 alkenyl), C(O)(C2-C6 alkynyl), N(R 16 )C(O)(C2-C6 alkynyl), and (C1-C6 alkylene)-N(R 16 )C(O)(C2-C6 alkynyl), wherein each of the C2-C6 alkenyl and C2-C6 alkynyl is selected from the group consisting of one or more R 17B is optionally replaced by

[0086] In some embodiments of Formula (I) or Formula (II), Q 1 is R 4 C3-C substituted with 11 is cycloalkyl, and R 4 independently, C6-C10 Aryl, 5-10 membered heteroaryl, E 3 -C6-C 10 Aryl, and E 3 - 5-10 membered heteroaryl, C6-C 10 Each of the aryl and 5- to 10-membered heteroaryl may be selected from one or more R 18 is optionally further substituted with

[0087] In the compounds of formula (I) or (II), R 17A and R 17B are each independently fluoro, oxo, thioxo, OR c , S.R. 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 , C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl, each of which is selected from the group consisting of one or more R e In some embodiments, R 17A are each independently fluoro, OR c , and N(R c In some such embodiments, R 17B are each independently fluoro, OR c , and N(R c )2.

[0088] In the compounds of formula (I) or (II), R 18 are each independently halogen, CN, OR c , S.R. c , N(R c )2, C(O)R c ,OC(O)R c , C(O)OR c , C(O)N(R c )2, N(Rc )C(O)R c , C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl, each of the C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkenyl, and C2-C6 alkynyl being selected from the group consisting of one or more R d and each of the C-C cycloalkyl and 3- to 6-membered heterocyclyl is optionally substituted with one or more R e In some embodiments, R 18 are each independently halogen, CN, OR c , N(R c )2, C1-C6 alkyl, and C1-C6 heteroalkyl. In some such embodiments, R 18 is halogen, preferably fluoro. In some embodiments, R 18 is C1-C6 alkyl. In some such embodiments, R 18 is C1-C6 heteroalkyl.

[0089] In some embodiments of Formula (I) or Formula (II), E 1 is a bond and Y 3 is N and Q 1 is Y 3 Contains one or more R 3 and optionally substituted with one or more R 4 is a 3- to 11-membered heterocycle optionally further substituted with

[0090] In some embodiments of Formula (I) or Formula (II), Q 1 teeth,

[0091] [ka] or a stereoisomer thereof, wherein * is selected from the group consisting of E 1 is the connection point for Q 1 is one or more R3 In some such embodiments, E 1 is a bond.

[0092] In some such embodiments of Formula (I) or Formula (II), Q 1 teeth,

[0093] [ka] or a stereoisomer thereof, wherein * is selected from the group consisting of E 1 is the connection point for Q 1 is one or more R 3 optionally further substituted with

[0094] In some embodiments of Formula (I) or Formula (II), E 1 -N(R 8 )- and Y 3 is C(R 3 ) and Q 1 is Y 3 Contains one or more R 3 and optionally substituted with one or more R 4 C3-C optionally further substituted with 11 cycloalkyl or a 3- to 11-membered heterocycle. In some such embodiments, R 8 is hydrogen and R 3 is hydrogen.

[0095] In some embodiments of Formula (I) or Formula (II), E 1 -N(R 8 )- and Q 1 is one or more R 3 and optionally substituted with one or more R 4 C3-C optionally further substituted with 11 It is a cycloalkyl or a 3- to 11-membered heterocycle.

[0096] In some such embodiments of Formula (I) or Formula (II), Q 1teeth,

[0097] [ka] or a stereoisomer thereof, wherein * is selected from the group consisting of E 1 is the connection point for Q 1 is one or more R 3 In some such embodiments, E 1 is -N(R 8 )-, preferably -NH-.

[0098] In some embodiments of Formula (I) or Formula (II), the moiety

[0099] [ka] teeth,

[0100] [ka] or a stereoisomer thereof, wherein

[0101] [ka] is the point of attachment to A, E 1 is a bond, -NH-, or -NHCH2-, Q 1 is R 4 and optionally substituted with one or more R 3 is a 3- to 11-membered heterocycle optionally further substituted with

[0102] In some embodiments of Formula (I) or Formula (II), the moiety

[0103] [ka] teeth,

[0104] [ka] or a stereoisomer thereof, wherein

[0105] [ka] is the point of attachment to A.

[0106] In compounds of Formula (II), r is an integer from 0 to 4. In some embodiments, r is an integer from 0 to 1. In compounds of Formula (II), s is an integer from 0 to 2. In some embodiments, s is an integer from 0 to 1. In some embodiments of Formula (II), r is 0 (i.e., R 3 In some embodiments of Formula (II), r is 1 (i.e., R 3 In some embodiments of Formula (II), s is 0 (i.e., R 4 In some embodiments of Formula (II), s is 1 (i.e., R 4 In some embodiments of Formula (II), r is 0 (i.e., R 3 does not exist), s is 1 (i.e., R 4 is present). In some embodiments of Formula (II), r is an integer of 1 and s is an integer from 0 to 1. In some embodiments of Formula (II), s is an integer of 1 and r is an integer from 0 to 1. In some embodiments of Formula (II), r is an integer of 1 and s is an integer of 0.

[0107] In the compounds of formula (I) or formula (II), R 3 are each independently hydrogen, fluoro, oxo, thioxo, OR 16 , S.R. 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, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, each of the C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl moieties being selected from the group consisting of one or more R 17A is optionally replaced by

[0108] In the compounds of formula (I) or (II), R 16 are each independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, and 3-6 membered heterocyclyl. 16 are each independently selected from the group consisting of hydrogen, C1-C4 alkyl, and C1-C4 fluoroalkyl.

[0109] In the compounds of formula (I) or (II), R 4 are each independently hydrogen, C(O)(C2-C6 alkenyl), N(R 16 )C(O)(C2-C6 alkenyl), (C1-C6 alkylene)-N(R 16 )C(O)(C2-C6 alkenyl), C(O)(C2-C6 alkynyl), N(R 16 )C(O)(C2-C6 alkynyl), (C1-C6 alkylene)-N(R 16 )C(O)(C2-C6 alkynyl), C6-C 10 Aryl, 5-10 membered heteroaryl, E 3 -C6-C 10 Aryl, E 3 -5-10 membered heteroaryl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, E 3 -C3-C6 cycloalkyl, and E 3 - 3- to 6-membered heterocyclyl, and each of C-C alkenyl and C-C alkynyl is selected from the group consisting of one or more R 17B and optionally substituted with C6-C 10 Each of the aryl and 5- to 10-membered heteroaryl may be selected from one or more R 18and each of the C-C cycloalkyl and 3- to 6-membered heterocyclyl is optionally substituted with one or more R 19 is optionally replaced by

[0110] In some embodiments of Formula (I) or Formula (II), R 4 are each independently C(O)(C2-C6 alkenyl), N(R 16 )C(O)(C2-C6 alkenyl), (C1-C6 alkylene)-N(R 16 )C(O)(C2-C6 alkenyl), C(O)(C2-C6 alkynyl), N(R 16 )C(O)(C2-C6 alkynyl), and -(C1-C6 alkylene)-N(R 16 )C(O)(C2-C6 alkynyl), wherein each of the C2-C6 alkenyl and C2-C6 alkynyl is selected from the group consisting of one or more R 17B In some such embodiments, R 17B are each independently fluoro, OR c , and N(R c In some embodiments, R 4 are each independently C(O)(C2-C6 alkenyl), N(R 16 )C(O)(C2-C6 alkenyl), C(O)(C2-C6 alkynyl), wherein each of the C2-C6 alkenyl and C2-C6 alkynyl is selected from the group consisting of one or more R 17B In some such embodiments, R 4 is C(O)(C-C alkenyl). In some such embodiments, R 4 is N(R 16 )C(O)(C2-C6 alkenyl).

[0111] In some embodiments of Formula (I) or Formula (II), R 4 are independently C6-C 10 Aryl, 5-10 membered heteroaryl, E 3 -C6-C 10 Aryl, and E3 - 5-10 membered heteroaryl, C6-C 10 Each of the aryl and 5- to 10-membered heteroaryl may be selected from one or more R 18 In some such embodiments, R 4 is C6-C 10 Aryl or E 3 -C6-C 10 Aryl, C6-C 10 Each aryl may be one or more R 18 In some such embodiments, R 4 is a 5- to 10-membered heteroaryl or E 3 - 5-10 membered heteroaryl, each 5-10 membered heteroaryl being selected from one or more R 18 In some such embodiments, R 18 are each independently halogen, C1-C6 alkyl, C1-C6 heteroalkyl, OR c , and N(R c In some such embodiments, R 18 is halogen or C1-C6 alkyl. In some such embodiments, R 18 is halogen, preferably fluoro. In some such embodiments, R 18 is C1-C6 alkyl, preferably methyl. In some such embodiments, R 18 is C1-C6 heteroalkyl, preferably hydroxymethyl.

[0112] In some embodiments of Formula (I) or Formula (II), R 4 are each independently C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, E 3 -C3-C6 cycloalkyl, and E 3 - 3- to 6-membered heterocyclyl, wherein each of the C-C cycloalkyl and the 3- to 6-membered heterocyclyl is selected from the group consisting of one or more R 19In some such embodiments, R 4 is C3-C6 cycloalkyl or E 3 -C3-C6 cycloalkyl, each C3-C6 cycloalkyl being one or more R 19 In some such embodiments, R 4 is a 3- to 6-membered heterocyclyl or E 3 -3- to 6-membered heterocyclyl, each 3- to 6-membered heterocyclyl being selected from one or more R 19 is optionally replaced by

[0113] In the compounds of formula (I) or (II), R 19 are each independently fluoro, oxo, thioxo, OR c , S.R. 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 C1-C6 alkyl, each of which is selected from the group consisting of one or more R d In some such embodiments, R 19 are each independently fluoro, OR c , and N(R c )2.

[0114] In the compounds of formula (I) or formula (II), if present, E 3 are each independently -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 In some such embodiments, E 3 are independently -NH-, -(CH2) y -NH-, -NH-(CH2) y , and -(CH2) z - is selected from the group consisting of

[0115] In some embodiments of Formula (I) or Formula (II), Z 1 L 1 -P, wherein L 1 is a bond or a bivalent chemical linker (e.g., of the formula -(J) x - or a linker of formula (III)), and P is a target protein binding moiety. 1 is a bond or formula -(J) x In some such embodiments, L 1 is a bond or a divalent chemical linker of formula (III).

[0116] In some embodiments of Formula (I) or Formula (II), Z 1 L 1 -G, wherein L 1 is a bond or a bivalent chemical linker (e.g., of the formula -(J) x - or a linker of formula (III)), and G is a reactive functional group. In some such embodiments, G is a reactive functional group selected from a protected or unprotected primary or secondary amine, a carboxylic acid, a carboxylic acid ester, a halogen, a hydroxy, or a sulfonate ester. In some such embodiments, G is a reactive functional group selected from NH, COOH, a halogen, a hydroxy, OMs, or OTs. In some such embodiments, L 1 is a bond or formula -(J) x In some such embodiments, L 1 is a bond or a divalent chemical linker of formula (III).

[0117] As used herein, the term "reactive functional group" refers to an atom or related group of atoms that is intended to undergo or can reasonably be expected to undergo a chemical reaction. Examples of reactive functional groups include, but are not limited to, moieties containing: α,β-unsaturated amides, α,β-unsaturated ketones, α,β-unsaturated acids, and α,β-unsaturated esters; α-haloamides, α-haloketones, α-haloacids, and α-haloesters; protected or unprotected primary or secondary amines; carboxylic acids or derivatives thereof (e.g., carboxylic acid esters, acyl halides, acid anhydrides, Weinreb amides, activated esters, etc.); aldehydes, ketones, imines, or acetals; alkyl moieties substituted with halo, hydroxy, alkoxy, amides, ketones, carboxylic acids, carboxylic esters, sulfonate esters, boronic acids, boronate esters, etc.; protected or unprotected thiols, thioethers, disulfides; halo-substituted heteroaryls; azides; nitriles; alkenes or alkynes; epoxides, aziridines, etc.

[0118] In the compounds of formula (I) or (II), 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 formula -(J) x In some such embodiments, L 1 is a bond or a divalent chemical linker of formula (III).

[0119] In some embodiments of Formula (I) or Formula (II), L 1 is a bond or formula -(J) x -, and each -J- is independently -N(R 25 )-, -C(R 26 )2-, -O-, -C(O)-, -C(=N(R 25))-, -C(S)-, -C(R 26 )=C(R 26 )-, -C≡C-, -S-, -S(O)-, -S(O)2-, R 27 C3-C optionally substituted with 11 cycloalkyl, and R 27 and R is selected from the group consisting of 3- to 11-membered heterocyclyl optionally substituted with, provided that no two -O- and / or -S- are adjacent; 25 are each independently hydrogen, C1-C6 alkyl, C3-C 11 cycloalkyl, and 3- to 11-membered heterocyclyl, each C1-C6 alkyl being selected from the group consisting of one or more R f and C3-C 11 Each of the cycloalkyl and 3- to 11-membered heterocyclyl groups may be selected from one or more R g optionally substituted with R 26 are each independently selected from the group consisting of hydrogen, fluoro, C1-C6 alkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl, and each C1-C6 alkyl is selected from one or more R f and each of the C-C cycloalkyl and 3- to 6-membered heterocyclyl is optionally substituted with one or more R g optionally substituted with R 27 are each independently selected from the group consisting of hydrogen, fluoro, C1-C6 alkyl, and oxo, each C1-C6 alkyl being selected from one or more R f and each of the C-C cycloalkyl and 3- to 6-membered heterocyclyl is optionally substituted with one or more R g optionally substituted with R f are each independently selected from the group consisting of fluoro, hydroxy, C-C alkoxy, oxo, NH, NH(C-C alkyl), and N(C-C alkyl), and R gare each independently selected from the group consisting of fluoro, hydroxy, C-C alkyl, C-C fluoroalkyl, C-C alkoxy, oxo, NH, NH(C-C alkyl), and N(C-C alkyl), where x is an integer from 1 to 30. In some embodiments, R 25 are each hydrogen. 26 are each hydrogen. In some such embodiments, R 25 and R 26 are each 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.

[0120] In some embodiments of Formula (I) or Formula (II), L 1 is a bond or formula -(J) x -, and each -J- is independently -N(R 25 )-, -C(R 26 )2-, and -O-; R 25 and R 26 are each hydrogen, and x is an integer from 1 to 20.

[0121] In some embodiments of Formula (I) or Formula (II), L 1 is a bond, or [-C(R 26 )2-] 1-12 or [-(C(R 26 )2)2O-] 1-6 Formula (J) selected from x In some such embodiments, R 26 and each are hydrogen. In some such embodiments, L 1 is a bond, or [-CH2-] 1-10 or [-(CH2)2O-] 1-6 Formula (J) selected from x - is a bivalent chemical linker.

[0122] In some embodiments of Formula (I) or Formula (II), L 1 is a bond or [-C(R 26 )2-] 1-10 , [-(C(R 26 )2)2O-] 1-6 , C3-C 11 Cycloalkyl, 3- to 11-membered heterocyclyl, [-C(R 26 )2-] 1-6 -C3-C 11 Cycloalkyl, [-C(R 26 )2-] 1-6 -3-11 membered heterocyclyl, C3-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 -C3-C 11 Cycloalkyl-[-C(R 26 )2-] 1-6 , or [-C(R 26 )2-] 1-6 -3 to 11-membered heterocyclyl-[-C(R 26 )2-] 1-6 Formula (J) selected from x - a bivalent chemical linker of C3-C 11 Each of the cycloalkyl and 3- to 11-membered heterocyclyl moieties is R 27 In some such embodiments, R 26 and each are hydrogen. In some such embodiments, L 1 is a bond or [-CH2-] 1-10 , [-(CH2)2O-] 1-6 , C3-C 11 Cycloalkyl, 3-11 membered heterocyclyl, [-CH2-] 1-6 -C3-C 11 Cycloalkyl, [-CH2-] 1-6 -3-11 membered heterocyclyl, C3-C 11 Cycloalkyl-[-CH2-] 1-6, 3 to 11-membered heterocyclyl-[-CH2-] 1-6 , [-CH2-] 1-6 -C3-C 11 Cycloalkyl-[-CH2-] 1-6 , or [-CH2-] 1-6 -3 to 11-membered heterocyclyl-[-CH2-] 1-6 Formula (J) selected from x - a bivalent chemical linker of C3-C 11 Each of the cycloalkyl and 3- to 11-membered heterocyclyl moieties is R 27 In some such embodiments, R 27 are each independently selected from the group consisting of hydrogen, fluoro, C1-C6 alkyl, C1-C6 fluoroalkyl, and oxo.

[0123] In some such embodiments of Formula (I) or Formula (II), L 1 is an optionally substituted C-C 20 an alkylene or 1-20 membered heteroalkylene linker (i.e., a C1-C4 alkyl group in which 1-5 carbon atoms are replaced with an O, NH, N(C1-C4 alkyl), S(O), S(O)2, or C(O) moiety); 20 In some embodiments of Formula (I) or Formula (II), L is an alkylene moiety, provided that the two O atoms are not adjacent. 1 is an optionally substituted C-C 12 In some embodiments of Formula (I) or Formula (II), L is an alkylene or 1-12 membered heteroalkylene linker. 1 is an optionally substituted C-C 10 In some embodiments of Formula (I) or Formula (II), L is an alkylene or 1-10 membered heteroalkylene linker. 1 is an optionally substituted C1-C8 alkylene or 1-8 membered heteroalkylene linker. In some embodiments of Formula (I) or Formula (II), L 1 is an optionally substituted C1-C6 alkylene or 1-6 membered heteroalkylene linker.

[0124] In some embodiments, -(J) x The one or more groups -J- are sequentially arranged in a repeating pattern of polyethylene glycol (PEG) units containing -(CH)(CH)(O)-. In some embodiments, the one or more groups -J- are -(O)-N(R 25 In some embodiments, the -(J)-containing carboxamide units are arranged consecutively in a repeating pattern. x The one or more groups -J- are selected from polyethylene glycol (PEG) units containing -(CH2)(CH2)(O)- and -(O)-N(R 25 )-containing carboxamide units are arranged consecutively in an alternating pattern.

[0125] In embodiments of Formula (I), Z 2 is selected from the group consisting of hydrogen, C1-C4 alkyl, and an amine protecting group. In some embodiments of Formula (II), Z 2 is selected from the group consisting of hydrogen, C1-C4 alkyl, and an amine protecting group; or Y 1 When is O, Z 2 does not exist.

[0126] In some embodiments of Formula (I), Z 1 is Z 2 and Z 2 is hydrogen or C1-C4 alkyl when attached to a ring carbon atom, or Z 2 is hydrogen, C1-C4 alkyl, or an amine protecting group when attached to a ring nitrogen atom.

[0127] In some embodiments of Formula (II), Z 1 is Z 2 and Z 2 is Y 1 is C(R 6 ) is hydrogen or C1-C4 alkyl, or Z 2 is Y 1 is N, then hydrogen, C1-C4 alkyl, or an amine protecting group, or Z2 is Y 1 is O, provided that the compound is neither N-(1-(3-fluorophenyl)piperidin-3-yl)-6-morpholinopyrimidin-4-amine nor N-(1-(3-fluorophenyl)piperidin-3-yl)-4-morpholinopyrimidin-2-amine.

[0128] In another aspect, there is provided a pharmaceutical composition comprising a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0129] In some embodiments, methods of treatment are provided that include administering a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, to a subject in need of treatment.

[0130] In some embodiments, there is provided a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in treating a disease or disorder in a subject in need of such treatment.

[0131] In some embodiments, there is provided a use of 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.

[0132] In some embodiments, there is provided the use of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or disorder.

[0133] Some embodiments relate to methods for degrading a target protein in a cell, such as a cancer cell, comprising administering a compound or composition to the cell. In some embodiments, 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. In some embodiments, the target protein comprises CDK4 or cyclin D. In some embodiments, the target protein comprises CDK4. In some embodiments, the target protein comprises cyclin D. In some embodiments, the target protein comprises cyclin D3. In some embodiments, administering the compound or composition to the cell comprises administering the compound or composition to a subject comprising the cell. Some embodiments relate to methods of treatment comprising administering an effective amount of the compound or composition to a subject in need of treatment. In some embodiments, the subject is a human.

[0134] In some embodiments, the subject has cancer, hi some such embodiments, the cancer is breast cancer, ovarian cancer, endometrial cancer, cervical cancer, uterine cancer, bladder cancer, bile duct cancer, prostate cancer, lung cancer (e.g., NSCLC, SCLC, squamous cell carcinoma or adenocarcinoma), osteosarcoma, central nervous system cancer, oral cancer, esophageal cancer, head and neck cancer, colorectal cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, thyroid cancer, melanoma, or a blood or lymphatic cancer (e.g., lymphoma, myeloma, or leukemia).

[0135] Some embodiments disclosed herein are in vivo modified or manipulated proteins. The in vivo modified or manipulated proteins may include a DDB1- and CUL4-associated factor 1 (DCAF1) protein that directly binds to a ligand at the binding region of the DCAF1 protein, where the ligand comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the binding region comprises WD40. In some embodiments, 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. In some embodiments, the ligand binds non-covalently to the DCAF1 protein. In some embodiments, the ligand binds covalently to the DCAF1 protein.

[0136] In some embodiments, the ligand binds to the DCAF1 protein with a Kd of 40 μM or less. In some embodiments, the ligand binds to the DCAF1 protein with a Kd of more than 40 μM and less than or equal to 70 μM. In some embodiments, the ligand binds to the DCAF1 protein with a Kd of more than 70 μM and less than or equal to 1000 μM. In some embodiments, the ligand binds to the DCAF1 protein with a Kd of less than or equal to 100 μM.

[0137] In vivo modified or engineered proteins can include DCAF1 proteins comprising non-naturally occurring covalent modifications at cysteines of DCAF1. In some embodiments, DCAF1 comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 1. In some embodiments, DCAF1 comprises the amino acid sequence of SEQ ID NO: 1. In some embodiments, the covalent modification is at cysteine ​​1227 relative to SEQ ID NO: 1. In some embodiments, the covalent modification is at cysteine ​​1113 relative to SEQ ID NO: 1. In some embodiments, the covalent modification is formed by a Michael addition reaction.

[0138] Any of the embodiments described herein may be combined with one or more other non-consistent embodiments.

[0139] All publications, patents, and patent applications mentioned herein are hereby incorporated by reference for the specific purposes identified herein. [Brief explanation of the drawings]

[0140] [Figure 1] FIG. 1 shows a docking model of an exemplary compound bound to the binding region of the DCAF1 protein. [Figure 2] FIG. 1 shows surface plasmon resonance (SPR) binding data for compounds B-072, B-124, and B-151 to purified DCAF1(1058-1396). [Figure 3] FIG. 1 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). [Figure 4] FIG. 1 shows example data confirming that CDK4 protein levels were reduced in MOLT-4 cells in a concentration-dependent manner by heterobifunctional compounds, according to some embodiments. [Figure 5A] FIG. 1 shows example data confirming that BRD4 protein levels were reduced in MV4;1 cells in a concentration- and time-dependent manner by heterobifunctional compounds, according to some embodiments. [Figure 5B] FIG. 1 shows example data confirming that BRD4 protein levels were reduced in MV4;1 cells in a concentration- and time-dependent manner by heterobifunctional compounds, according to some embodiments. [Figure 6] FIG. 1 shows example data confirming that cell viability of MV4;1 cells was inhibited in a concentration-dependent manner by heterobifunctional compounds targeting BRD4, according to some embodiments. [Figure 7A]FIG. 1 shows example data confirming that cyclin D1 and CDK4 protein levels were reduced in T47D cells in a concentration-dependent manner by heterobifunctional compounds, according to some embodiments. [Figure 7B] FIG. 1 shows example data confirming that cyclin D1 and CDK4 protein levels were reduced in Calu-1 cells in a concentration-dependent manner by heterobifunctional compounds, according to some embodiments. [Figure 8] FIG. 1 shows example data confirming that cyclin D1 and CDK4 protein levels were reduced in T47D cells in a concentration-dependent manner by heterobifunctional compounds, according to some embodiments. [Figure 9] FIG. 1 shows example data confirming that cyclin D1 and CDK4 protein levels were reduced in MDA-MB-157 cells in a concentration-dependent manner by heterobifunctional compounds, according to some embodiments. DETAILED DESCRIPTION OF THE INVENTION

[0141] Provided herein are compounds, pharmaceutical compositions, and methods for binding or modulating DDB1- and -CUL4-associated factor 1 (DCAF1) protein. Also provided herein are ligand-DCAF1 complexes or in vivo modified DCAF1 proteins.

[0142] The DCAF1 protein can be a mammalian DCAF1 protein. The DCAF1 protein can be a human DCAF1 protein. The DCAF1 protein can be encoded by a DCAF1 gene, such as NCBI Gene ID 9730 (revised January 29, 2021). The DCAF1 protein can comprise an amino acid sequence. An example of a DCAF1 amino acid sequence is contained in UniProt ref. Q9Y4B6 (sequence last modified May 15, 2007). In some embodiments, the DCAF1 protein contains 1507 amino acids or has a mass of 169 kDa.

[0143] In some embodiments, DCAF1 includes any aspect described at UniProt.org under accession number Q9Y4B6 (last modified on February 23, 2022). In some embodiments, DCAF1 comprises the following amino acid sequence: MTTVVVHVDS KAELTTLLEQ WEKEHGSGQD MVPILTRMSQ LIEKETEEYRKGDPDPFDDR HPGRADPECM LGHLLRILFK NDDFMNALVN AYVMTSREPPLNTAACRLLL DIMPGLETAV VFQEKEGIVE NLFKWAREAD QPLRTYSTGL LGGAMENQDI AANYRDENSQ LVAIVLRRLR ELQLQEVALR QENKRPSPRK LSSEPLLPLD EEAVDMDYGD MAVDVVDGDQ EEASGDMEIS FHLDSGHKTS SRVNSTTKPE DGGLKKNKSA KQGDRENFRK AKQKLGFSSS DPDRMFVELSNSSWSEMSPW VIGTNYTLYP MTPAIEQRLI LQYLTPLGEY QELLPIFMQLGSRELMMFYI DLKQTNDVLL TFEALKHLAS LLLHNKFATE FVAHGGVQKLLEIPRPSMAA TGVSMCLYYL SYNQDAMERV CMHPHNVLSD VVNYTLWLMECSHASGCCHA TMFFSICFSF RAVLELFDRY DGLRRLVNLI STLEILNLEDQGALLSDDEI FASRQTGKHT CMALRKYFEA HLAIKLEQVK QSLQRTEGGILVHPQPPYKA CSYTHEQIVE MMEFLIEYGP AQLYWEPAEV FLKLSCVQLL LQLISIACNW KTYYARNDTV RFALDVLAIL TVVPKIQLQL AESVDVLDEAGSTVSTVGIS IILGVAEGEF FIHDAEIQKS ALQIIINCVC GPDNRISSIGKFISGTPRRK LPQNPKSSEH TLAKMWNVVQ SNNGIKVLLS LLSIKMPITDADQIRALACK ALVGLSRSST VRQIISKLPL FSSCQIQQLM KEPVLQDKRS DHVKFCKYAAELIERVSGKP LLIGTDVSLA RLQKADVVAQ SRISFPEKEL LLLIRNHLIS KGLGETATVL TKEADLPMTA ASHSSAFTPV TAAASPVSLP RTPRIANGIA TRLGSHAAVG ASAPSAPTAH PQPRPPQGPL ALPGPSYAGN SPLIGRISFI RERPSPCNGR KIRVLRQKSD HGAYSQSPAI KKQLDRHLPS PPTLDSIITE YLREQHARCK NPVATCPPFS LFTPHQCPEP KQRRQAPINF TSRLNRRASF PKYGGVDGGC FDRHLIFSRF RPISVFREAN EDESGFTCCA FSARERFLML GTCTGQLKLY NVFSGQEEAS YNCHNSAITH LEPSRDGSLL LTSATWSQPL SALWGMKSVF DMKHSFTEDH YVEFSKHSQD RVIGTKGDIA HIYDIQTGNK LLTLFNPDLA NNYKRNCATF NPTDDLVLND GVLWDVRSAQ AIHKFDKFNM NISGVFHPNG LEVIINTEIW DLRTFHLLHT VPALDQCRVV FNHTGTVMYG AMLQADDEDD LMEERMKSPF GSSFRTFNAT DYKPIATIDV KRNIFDLCTD TKDCYLAVIE NQGSMDALNM DTVCRLYEVG RQRLAEDEDE EEDQEEEEQE EEDDDEDDDD TDDLDELDTD QLLEAELEED DNNENAGEDG DNDFSPSDEE LANLLEEGED GEDEDSDADE EVELILGDTD SSDNSDLEDD IILSLNE (SEQ ID NO: 1).

[0144] In some embodiments, the DCAF protein comprises an amino acid sequence at least 70% identical to SEQ ID NO: 1. In some embodiments, the DCAF protein comprises an amino acid sequence at least 80% identical to SEQ ID NO: 1. In some embodiments, the DCAF protein comprises an amino acid sequence at least 90% identical to SEQ ID NO: 1. In some embodiments, the DCAF protein comprises an amino acid sequence at least 91% identical to SEQ ID NO: 1. In some embodiments, the DCAF protein comprises an amino acid sequence at least 92% identical to SEQ ID NO: 1. In some embodiments, the DCAF protein comprises an amino acid sequence at least 93% identical to SEQ ID NO: 1. In some embodiments, the DCAF protein comprises an amino acid sequence at least 94% identical to SEQ ID NO: 1. In some embodiments, the DCAF protein comprises an amino acid sequence at least 95% identical to SEQ ID NO: 1. In some embodiments, the DCAF protein comprises an amino acid sequence at least 96% identical to SEQ ID NO: 1. In some embodiments, the DCAF protein comprises an amino acid sequence at least 97% identical to SEQ ID NO: 1. In some embodiments, the DCAF protein comprises an amino acid sequence at least 98% identical to SEQ ID NO: 1. In some embodiments, the DCAF protein comprises an amino acid sequence at least 99% identical to SEQ ID NO: 1. In some embodiments, the DCAF protein comprises an amino acid sequence at least 99.1% identical to SEQ ID NO: 1. In some embodiments, the DCAF protein comprises an amino acid sequence at least 99.2% identical to SEQ ID NO: 1. In some embodiments, the DCAF protein comprises an amino acid sequence at least 99.3% identical to SEQ ID NO: 1. In some embodiments, the DCAF protein comprises an amino acid sequence at least 99.4% identical to SEQ ID NO: 1. In some embodiments, the DCAF protein comprises an amino acid sequence at least 99.4% identical to SEQ ID NO: 1. In some embodiments, the DCAF protein comprises an amino acid sequence at least 99.5% identical to SEQ ID NO: 1. In some embodiments, the DCAF protein comprises an amino acid sequence at least 99.6% identical to SEQ ID NO: 1.In some embodiments, the DCAF protein comprises an amino acid sequence at least 99.7% identical to SEQ ID NO: 1. In some embodiments, the DCAF protein comprises an amino acid sequence at least 99.8% identical to SEQ ID NO: 1. In some embodiments, the DCAF protein comprises an amino acid sequence at least 99.9% identical to SEQ ID NO: 1. In some embodiments, the DCAF protein comprises an amino acid sequence that is at most 70% identical to SEQ ID NO: 1. In some embodiments, the DCAF protein comprises an amino acid sequence at most 80% identical to SEQ ID NO: 1. In some embodiments, the DCAF protein comprises an amino acid sequence at most 90% identical to SEQ ID NO: 1. In some embodiments, the DCAF protein comprises an amino acid sequence at most 91% identical to SEQ ID NO: 1. In some embodiments, the DCAF protein comprises an amino acid sequence at most 92% identical to SEQ ID NO: 1. In some embodiments, the DCAF protein comprises an amino acid sequence at most 93% identical to SEQ ID NO: 1. In some embodiments, the DCAF protein comprises an amino acid sequence at most 94% identical to SEQ ID NO: 1. In some embodiments, the DCAF protein comprises an amino acid sequence at most 95% identical to SEQ ID NO: 1. In some embodiments, the DCAF protein comprises an amino acid sequence that is at most 96% identical to SEQ ID NO: 1. In some embodiments, the DCAF protein comprises an amino acid sequence that is at most 97% identical to SEQ ID NO: 1. In some embodiments, the DCAF protein comprises an amino acid sequence that is at most 98% identical to SEQ ID NO: 1. In some embodiments, the DCAF protein comprises an amino acid sequence that is at most 99% identical to SEQ ID NO: 1. In some embodiments, the DCAF protein comprises an amino acid sequence that is at most 99.1% identical to SEQ ID NO: 1. In some embodiments, the DCAF protein comprises an amino acid sequence that is at most 99.2% identical to SEQ ID NO: 1. In some embodiments, the DCAF protein comprises an amino acid sequence that is at most 99.3% identical to SEQ ID NO: 1. In some embodiments, the DCAF protein comprises an amino acid sequence that is at most 99.4% identical to SEQ ID NO: 1.In some embodiments, the DCAF protein comprises an amino acid sequence that is at most 99.4% identical to SEQ ID NO: 1. In some embodiments, the DCAF protein comprises an amino acid sequence that is at most 99.5% identical to SEQ ID NO: 1. In some embodiments, the DCAF protein comprises an amino acid sequence that is at most 99.6% identical to SEQ ID NO: 1. In some embodiments, the DCAF protein comprises an amino acid sequence that is at most 99.7% identical to SEQ ID NO: 1. In some embodiments, the DCAF protein comprises an amino acid sequence that is at most 99.8% identical to SEQ ID NO: 1. In some embodiments, the DCAF protein comprises an amino acid sequence that is at most 99.9% identical to SEQ ID NO: 1.

[0145] Modified proteins and ligand-protein complexes In some embodiments, modified proteins are disclosed herein. In some embodiments, the modified protein comprises an in vivo modified protein. In some embodiments, the modified protein comprises an in vitro modified protein. In some embodiments, the modified protein comprises a DDB1- and CUL4-associated factor 1 (DCAF1) protein. In some embodiments, the modified protein comprises an in vivo modified DCAF1 protein. In some embodiments, the DCAF1 protein is conjugated to a compound described herein. In some embodiments, the DCAF1 protein is directly conjugated to a compound. In some embodiments, the DCAF1 protein is conjugated to a ligand. The ligand can be a compound described herein, e.g., a compound in any of Tables 1-5 or Formula (I) or Formula (II). In some embodiments, the bond between the DCAF1 protein and the compound is a non-covalent bond. In some embodiments, the bond between the DCAF1 protein and the compound is a covalent bond. In some embodiments, the modified protein can be used in the methods described herein. In some embodiments, the ligand is conjugated to a DCAF1 fragment. In some embodiments, the ligand is conjugated to a full-length DCAF1 protein.

[0146] In some embodiments, a ligand-protein complex is disclosed herein. In some embodiments, the ligand-protein complex comprises a DCAF1 protein. In some embodiments of the ligand-protein complex, the DCAF1 protein is bound to a ligand. The ligand can be a compound described herein, such as any compound in Tables 1-5 or Formula (I) or (II). In some embodiments, the DCAF1 protein is directly bound to the compound. In some embodiments, the bond between the DCAF1 protein and the compound is a non-covalent bond. In some embodiments, the bond between the DCAF1 protein and the compound is a covalent bond. The ligand-protein complex can be formed in vivo. The ligand-protein complex can be formed in vitro. The ligand-protein complex can be used in the methods 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.

[0147] In some embodiments, disclosed herein is a modified protein or ligand-protein complex comprising a compound described herein bound to a DCAF1 protein. In some embodiments, the DCAF1 protein comprises a binding region. In some embodiments, the compound is bound to the binding region of the DCAF1 protein. In some embodiments, the binding region comprises a WD40 domain. In some embodiments, the DCAF1 fragment comprises a WD40 domain.

[0148] In some embodiments, 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.

[0149] In some embodiments, 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.

[0150] In some embodiments, 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 region may comprise THR1097, ALA1137, THR1139, HIS1140, THR1155, HIS1180, TYR1181, ARG1225, CYS1227, ILE1262, VAL1265, ARG1298, VAL1299, VAL1300, LYS1327, PRO1329, or PHE1355. In some embodiments, the binding region of the DCAF1 protein comprises THR1097. In some embodiments, the binding region of the DCAF1 protein comprises ALA1137. In some embodiments, the binding region of the DCAF1 protein comprises THR1139. In some embodiments, the binding region of the DCAF1 protein comprises HIS1140. In some embodiments, the binding region of the DCAF1 protein comprises THR1155. In some embodiments, the binding region of the DCAF1 protein comprises HIS1180. In some embodiments, the binding region of the DCAF1 protein comprises TYR1181. In some embodiments, the binding region of the DCAF1 protein comprises ARG1225. In some embodiments, the binding region of the DCAF1 protein comprises CYS1227. In some embodiments, the binding region of the DCAF1 protein comprises ILE1262. In some embodiments, the binding region of the DCAF1 protein comprises VAL1265. In some embodiments, the binding region of the DCAF1 protein comprises ARG1298. In some embodiments, the binding region of the DCAF1 protein comprises VAL1299. In some embodiments, the binding region of the DCAF1 protein comprises VAL1300. In some embodiments, the binding region of the DCAF1 protein comprises LYS1327. In some embodiments, the binding region of the DCAF1 protein comprises PRO1329. In some embodiments, the binding region of the DCAF1 protein comprises PHE1355.

[0151] In some embodiments, the bond between the DCAF1 protein and the compound comprises one or more of a salt bridge, a hydrogen bond, a stereoelectronic interaction, and a dispersed contact. In some embodiments, the bond between the DCAF1 protein and the compound comprises a salt bridge. In some embodiments, the bond between the DCAF1 protein and the compound comprises one or more hydrogen bonds. In some embodiments, the bond between the DCAF1 protein and the compound comprises a stereoelectronic interaction. In some embodiments, the bond between the DCAF1 protein and the compound comprises a dispersed contact.

[0152] In some embodiments, the binding between the DCAF1 protein and the ligand has an equilibrium dissociation constant (K) of less than 1500 μM. d ), K<1250 μM d , K<1000 μM d , K<750 μM d , K<500 μM d , K<450 μM d , K<400 μM d , K<350 μM d , K<300 μM d , K<250 μM d , K<200 μM d , K<150 μM d , K<100 μM d , K<90 μM d , K<80 μM d , K<70 μM d , K<60 μM d , K<50 μM d , K<45 μM d , K<40 μM d , K<35 μM d , K<30 μM d , K<25 μM d , or a K less than 20 μM d In some embodiments, the binding affinity has a K d is 100 μM or less. d In some embodiments, the K dIn some embodiments, the K d is about 100 μM or less. d is about 70 μM or less. d is about 40 μM or less.

[0153] In some embodiments, the binding between the DCAF1 protein and the ligand has a K of greater than 1250 μM. d , K > 1000 μM d , K > 750 μM d , K > 500 μM d , K > 450 μM d , K > 400 μM d , K > 350 μM d , K > 300 μM d , K > 250 μM d , K > 200 μM d , K > 150 μM d , K > 100 μM d , K > 90 μM d , K > 80 μM d , K > 70 μM d , K > 60 μM d , K > 50 μM d , K > 45 μM d , K > 40 μM d , K > 35 μM d , K > 30 μM d , K > 25 μM d , K > 20 μM d , or a K > 15 μM d In some embodiments, the binding affinity has a K d is greater than 100. In some embodiments, K d is greater than 70. In some embodiments, K d is greater than 40. In some embodiments, K d is greater than about 100. In some embodiments, K d is greater than about 70. In some embodiments, K d is approximately over 40.

[0154] In some embodiments, the binding between the DCAF1 protein and the compound has a K d , K > 40 and ≤ 70 μM d , K > 70 and ≤ 100 μM d , or a K >100 μM d In some embodiments, the binding between the DCAF1 protein and the compound has a K of 40 μM or less. d In some embodiments, the binding between the DCAF1 protein and the compound has a K of greater than 40 and less than or equal to 70 μM. d K d In some embodiments, the binding between the DCAF1 protein and the compound has a K of greater than 70 and less than or equal to 100 μM. d In some embodiments, the binding between the DCAF1 protein and the compound has a K of greater than 100 μM. d The binding affinity of the β-glutamic acid esters is

[0155] Various embodiments of in vivo engineered proteins are described herein. In some embodiments, the in vivo engineered protein comprises a non-naturally occurring modification. In some embodiments, the in vivo engineered protein comprises a non-naturally occurring covalent modification. In some embodiments, the in vivo engineered protein is DCAF1. In some embodiments, the in vivo engineered protein comprises a non-naturally occurring covalent modification at a cysteine ​​of DCAF1. In some embodiments, the in vivo engineered protein comprises a non-naturally occurring covalent modification at an amino acid of DCAF1. In some embodiments, the in vivo engineered protein comprises a non-naturally occurring covalent modification at more than one amino acid of DCAF1. In some embodiments, the in vivo engineered protein comprises a non-naturally occurring covalent modification at a cysteine ​​(CYS) of DCAF1. In some embodiments, the in vivo engineered protein comprises a non-naturally occurring covalent modification at more than one CYS of DCAF1. In some embodiments, DCAF1 comprises the amino acid of SEQ ID NO: 1. In some embodiments, the covalent modification is formed by a Michael addition reaction of a compound with CYS1113 for SEQ ID NO: 1. In some embodiments, the covalent modification is formed by a Michael addition reaction of the compound with CYS1227 with respect to SEQ ID NO: 1. In some embodiments, the covalent modification is formed by a Michael addition reaction of the compound with CYS1227 or CYS1113 with respect to SEQ ID NO: 1. In some embodiments, the covalent modification is formed by a Michael addition reaction. In some embodiments, the covalent modification is formed by a Michael addition reaction of the compound with an amino acid of DCAF1. In some embodiments, the covalent modification is formed by a Michael addition reaction of the compound with more than one amino acid of DCAF1. In some embodiments, the covalent modification is formed by a Michael addition reaction of the compound with a CYS of DCAF1. In some embodiments, the covalent modification is formed by a Michael addition reaction of the compound with more than one CYS of DCAF1. In some embodiments, the covalent modification is formed by a Michael addition reaction of the compound with CYS1227 or CYS1113 with respect to SEQ ID NO: 1.In some embodiments, the sulfur atom of the CYS residue undergoes a Michael reaction with the double bond of the compound. In some embodiments, the sulfur atom of the CYS residue is a Michael donor. In some embodiments, the compound is a Michael acceptor. In some embodiments, the compound is an extrinsic Michael acceptor.

[0156] compound In some embodiments, compounds are disclosed herein. The compound may be or comprise a DCAF1 ligand. The compound may comprise a DCAF1 binding moiety. The compound may comprise a linker. The compound may comprise a target protein binding moiety. The ligand may be a heterobifunctional compound. The heterobifunctional compound may comprise a DCAF1 binding moiety covalently connected to the target protein binding moiety via a linker. The compound may comprise a ligand. The ligand may comprise a DCAF1 binding moiety. The ligand may comprise a linker. The ligand may comprise a target protein binding moiety. The DCAF1 binding moiety may be connected to the target protein binding moiety via a linker. The ligand may be a heterobifunctional compound. The heterobifunctional compound may comprise a DCAF1 binding moiety covalently connected to the target protein binding moiety via a linker.

[0157] In some embodiments, DCAF1 ligands are disclosed herein. The ligands can include small molecules. Examples of small molecules are organic compounds with a molecular weight of less than 900 daltons. The ligands can have a molecular weight of less than 2500 daltons, less than 2250 daltons, less than 2000 daltons, less than 1750 daltons, less than 1500 daltons, or less than 1250 daltons. The ligands can have a molecular weight of less than 1000 daltons, less than 900 daltons, less than 800 daltons, less than 700 daltons, less than 600 daltons, or less than 500 daltons. The ligands can have a molecular weight of more than 2500 daltons, more than 2250 daltons, more than 2000 daltons, more than 1750 daltons, more than 1500 daltons, or more 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.

[0158] In some embodiments herein, compounds are disclosed for use in methods such as treatment methods. Some embodiments include compounds for use in methods for degrading, inhibiting, or regulating proteins or target proteins. The compounds may be or include compounds described herein. Some embodiments include methods for making the compounds disclosed herein.

[0159] In some embodiments, administering a compound or composition to a cell, such as a cancer cell, comprises administering the compound or composition to a subject that includes the cell.

[0160] Some embodiments relate to methods of treatment comprising administering an effective amount of a compound or composition to a subject in need of treatment. In some embodiments, the subject is a human. In some embodiments, the subject is suffering from cancer.

[0161] DCAF1 binding part The present specification describes compounds that contain DCAF1 binding moieties. Some of these compounds can be useful as antiviral drugs, DCAF1 protein level or function modulators, as part of molecular glues, or as part of targeted protein degradation agents. In some embodiments, the DCAF1 binding moiety is included as part of a heterobifunctional compound.

[0162] Described herein are compounds comprising a DCAF1 binding moiety. In some embodiments, the DCAF1 binding moiety binds to the DCAF1 protein. In some embodiments, the DCAF1 binding moiety is bound to the DCAF1 protein. In some embodiments, the compound binds to the DCAF1 protein via the DCAF1 binding moiety. In some embodiments, the compound is bound to the DCAF1 protein via the DCAF1 binding moiety. In some instances, the DCAF binding moiety comprises a compound of formula (I) without including a linker or target protein binding moiety of formula (I). In some instances, the DCAF binding moiety is included in a compound of formula (I). In some embodiments, the compound or DCAF1 binding moiety does not inhibit DCAF1 function. In some embodiments, the DCAF1 binding moiety is a small molecule.

[0163] Described herein are compounds comprising a DCAF1-binding moiety. In some embodiments, the binding moiety comprises a compound of Table 1. A compound of Table 1 can be used by itself as a DCAF1-binding agent or can be included in another compound as a DCAF1-binding moiety. For example, a compound of Table 1 can be included as part of a heterobifunctional molecule comprising a DCAF1-binding moiety linked to a target protein-binding moiety. Also included herein are analogs of the DCAF1-binding moieties of Table 1 that allow for further modification, e.g., as a linker and / or point of attachment to the protein-binding moiety. Representative analogs of the DCAF1-binding agents of Table 1 include: (a) compounds in which the morpholino moiety is replaced with a piperazine (which can serve as a point of attachment for a linker) or another suitable cycloalkyl or heterocyclyl ring; (b) compounds in which the carboxamide moiety is modified to install a linker (e.g., C(O)NHMe is replaced with, e.g., C(O)NH-linker-); or (c) compounds in which the alkyl, halo, or OH moiety, in each case, is replaced with Z 1 (For example, L 1 -P or L 1 -G).

[0164]

Table 1-1

[0165]

Table 1-2

[0166]

Table 1-3

[0167]

Table 1-4

[0168]

Table 1-5

[0169]

Table 1-6

[0170]

Table 1-7

[0171]

Table 1-8

[0172]

Table 1-9

[0173]

Table 1-10

[0174]

Table 1-11

[0175]

Table 1-12

[0176]

Table 1-13

[0177]

Table 1-14

[0178]

Table 1-15

[0179]

Table 1-16

[0180]

Table 1-17

[0181]

Table 1-18

[0182]

Table 1-19

[0183]

Table 1-20

[0184]

Table 1-21

[0185] [Table 1-22]

[0186] [Table 1-23]

[0187] [Table 1-24]

[0188] [Table 1-25]

[0189] [Table 1-26]

[0190] [Table 1-27]

[0191] [Table 1-28]

[0192] In some embodiments herein, the DCAF1-binding moieties shown in Table 2 are provided. The compounds in Table 2 can be used as DCAF1-binding agents by themselves, or can be included in another compound as a DCAF1-binding moiety. For example, the compounds in Table 2 can be included as part of a heterobifunctional molecule that includes a DCAF1-binding moiety linked to a target protein-binding moiety.

[0193] [Table 2-1]

[0194]

Table 2-2

[0195]

Table 2-3

[0196]

Table 2-4

[0197]

Table 2-5

[0198]

Table 2-6

[0199]

Table 2-7

[0200]

Table 2-8

[0201]

Table 2-9

[0202]

Table 2-10

[0203]

Table 2-11

[0204]

Table 2-12

[0205]

Table 2-13

[0206]

Table 2-14

[0207]

Table 2-15

[0208] In some embodiments, the compounds of Table 2 are capped with a capping group to simulate a linker. In some examples, the capping group includes a substituted amino group. In some examples, the capping group includes an N-alkyl or N-dialkyl group, an acetamide, an alkyl or haloalkyl group, a lactam, an aminofuran, or an aminopyran group. Without being bound by theory, in some examples the capping group is used to approximate the effect on activity from a similar linker. The compounds of Table 1 may further include a capping group.

[0209] Also included herein are analogs of the DCAF1 binding moiety of Table 2 that permit further modification, for example, as attachment points for linkers and / or protein binding moieties. Representative analogs of the DCAF1 binders of Table 2 are (a) compounds in which a morpholino moiety is replaced with a piperazine analog (an additional nitrogen atom can function as an attachment point), (b) compounds in which a carboxamide moiety is modified to install a linker, or (c) compounds in which an alkyl, halo, or OH moiety is modified to install a linker that can function as an attachment site for L 1 -P or L 1 -G, respectively.

[0210] Disclosed herein in some embodiments are ligands that comprise a DCAF1 binding moiety that binds to or is bound by a DCAF1 protein. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity with an equilibrium dissociation constant (Kd) of less than 100 μM, a Kd of less than 90 μM, a Kd of less than 80 μM, a Kd of less than 70 μM, a Kd of less than 60 μM, a Kd of less than 50 μM, a Kd of less than 45 μM, a Kd of less than 40 μM, a Kd of less than 35 μM, a Kd of less than 30 μM, a Kd of less than 25 μM, a Kd of less than 20 μM, a Kd of less than 15 μM, a Kd of less than 14 μM, a Kd of less than 13 μM, a Kd of less than 12 μM, a Kd of less than 11 μM, a Kd of less than 10 μM, a Kd of less than 9 μM, a Kd of less than 8 μM, a Kd of less than 7 μM, a Kd of less than 6 μM, a Kd of less than 5 μM, a Kd of less than 4 μM, a Kd of less than 3 μM, a Kd of less than 2 μM, or a Kd of less than 1 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity having a Kd value of about 100 μM, about 90 μM, about 80 μM, about 70 μM, about 60 μM, about 50 μM, about 45 μM, about 40 μM, about 35 μM, about 30 μM, about 25 μM, about 20 μM, about 15 μM, about 14 μM, about 13 μM, about 12 μM, about 11 μM, about 10 μM, about 9 μM, about 8 μM, about 7 μM, about 6 μM, about 5 μM, about 4 μM, about 3 μM, about 2 μM, or 1 μM, or a Kd value range defined by any two of the aforesaid Kd values. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity having a Kd value of 100 μM, 90 μM, 80 μM, 70 μM, 60 μM, 50 μM, 45 μM, 40 μM, 35 μM, 30 μM, 25 μM, 20 μM, 15 μM, 14 μM, 13 μM, 12 μM, 11 μM, 10 μM, 9 μM, 8 μM, 7 μM, 6 μM, 5 μM, 4 μM, 3 μM, 2 μM, or 1 μM, or a Kd value range defined by any two of the aforesaid Kd values.

[0211] In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity having a Kd of less than 100 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity having a Kd of less than 90 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity having a Kd of less than 80 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity having a Kd of less than 70 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity having a Kd of less than 60 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity having a Kd of less than 50 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity having a Kd of less than 45 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity having a Kd of less than 40 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity having a Kd of less than 35 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity having a Kd of less than 30 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity having a Kd of less than 25 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity having a Kd of less than 20 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity having a Kd of less than 15 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity having a Kd of less than 14 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity having a Kd of less than 13 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity having a Kd of less than 12 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity having a Kd of less than 11 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity having a Kd of less than 10 μM.In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity having a Kd of less than 9 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity having a Kd of less than 8 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity having a Kd of less than 7 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity having a Kd of less than 6 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity having a Kd of less than 5 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity having a Kd of less than 4 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity having a Kd of less than 3 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity having a Kd of less than 2 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity having a Kd of less than 1 μM.

[0212] In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd of greater than 100 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd of greater than 90 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd of greater than 80 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd of greater than 70 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd of greater than 60 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd of greater than 50 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd of greater than 45 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd of greater than 40 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd of greater than 35 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd of greater than 30 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd of greater than 25 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd of greater than 20 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd of greater than 15 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd of greater than 14 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd of greater than 13 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd of greater than 12 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd of greater than 11 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd of greater than 10 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd of greater than 9 μM.In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd of greater than 8 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd of greater than 7 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd of greater than 6 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd of greater than 5 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd of greater than 4 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd of greater than 3 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd of greater than 2 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity with a Kd of greater than 1 μM.

[0213] In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity having a Kd of less than 20 μM, a Kd of 20-100 μM, or a Kd of greater than 100 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity having a Kd of less than 20 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity having a Kd of 20-100 μM. In some embodiments, the binding between the DCAF1 protein and the ligand comprises a binding affinity having a Kd of greater than 100 μM.

[0214] In some embodiments, the bond between the DCAF1-binding moiety and DCAF1 is a non-covalent bond. In some embodiments, the bond between the DCAF1-binding moiety and DCAF1 is a covalent bond.

[0215] Described herein are compounds in Table 3 that comprise a DCAF1-binding moiety and a linker. In frequent embodiments, the linker is terminated with a reactive functional group (e.g., NH, COOH, halogen, OH, OMs, OTs, etc.) that can serve as a point for further modification of the linker or attachment to a protein-binding moiety. In some embodiments, compounds that comprise molecular aspects shown in Table 3 are attached to DCAF1 via a DCAF1-binding moiety.

[0216] [Table 3-1]

[0217] [Table 3-2]

[0218] [Table 3-3]

[0219] [Table 3-4]

[0220] [Table 3-5]

[0221] [Table 3-6]

[0222] [Table 3-7]

[0223] [Table 3-8]

[0224] [Table 3-9]

[0225] [Table 3-10]

[0226] [Table 3-11]

[0227] [Table 3-12]

[0228] Linker Described herein are compounds comprising a bivalent chemical linker. In some embodiments, the linker is covalently connected to a DCAF1 binding moiety described herein. In some embodiments, the linker is covalently connected to a target protein binding moiety described herein. In some embodiments, the linker is covalently connected to a DCAF1 binding moiety and a target protein binding moiety. In some embodiments, the linker is incorporated into a ligand described herein. For example, each of the linkers described in this section can be represented by Formula (I) or Formula (II) (i.e., linker L 1 as a linker L 2 In some embodiments, the linker is a bond. In some embodiments, the linker includes more than one bond.

[0229] As used herein, DCAF1-binding moieties and linkers (e.g., L 1 or L 2In some embodiments, the linker comprises an optionally substituted polyethylene glycol (PEG). In some embodiments, the linker comprises an optionally substituted alkyl chain. In some embodiments, the linker is a straight chain alkane. In some embodiments, the linker is an optionally substituted C2-C 30 , C2-C 25 , C3-C 25 , C4-C 10 , C6-C 12 , C6-C 18 , or C4-C 20 In some embodiments, the linker comprises an alkyl unit. In some embodiments, the linker comprises an optionally substituted carbocycle. In some embodiments, the linker comprises an optionally substituted heterocycle. 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 C2-C 30 , C2-C 25 , C3-C 25 , C4-C 10 , C6-C 12 , C6-C 18 , or C4-C 20 In some embodiments, the PEG is an optionally substituted -(O-CH2CH2)- unit having a length of 1 to 5, 2 to 7, 2 to 10, 2 to 20, 5 to 25, or 4 to 30 units. In some embodiments, the linker comprises an amine. In some embodiments, the linker is a C2-C 30 , C2-C 25 , C3-C 25 , C4-C 10 , C6-C 12 , C6-C 18 , or C4-C 20In some embodiments, the linker comprises an alkylamino unit. In some embodiments, the linker comprises 1 to 5, 2 to 7, 2 to 10, 2 to 20, 5 to 25, or 4 to 30 optionally substituted -(NH-CHCH)- units. In some embodiments, the linker comprises an amide. In some embodiments, the linker comprises a sulfonamide. In some embodiments, the linker comprises a carbamide. In some embodiments, the linker comprises a carbamate. In some embodiments, the linker comprises a carbonate. In some embodiments, the compound comprises a DCAF1-binding moiety, a linker, and / or a target protein-binding moiety.

[0230] In some embodiments of Formula (I), Formula (II), or Formula (X), a linker (e.g., L 1 or L 2 ) is a compound of formula (III)

[0231] [ka] is the divalent part of

[0232] During the ceremony, U, W 1 , W 2 , and V, when each occurs, independently represent null, R'-R'', R'COR'', R'CO2R'', 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'SO2R'', R'SO2N(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)2R'', R'N(Rx )S(O)2N(R y )R'', optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 heteroalkenylene, optionally substituted C2-C8 heteroalkynylene, optionally substituted C1-C8 alkoxyC1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C3-C 13 a divalent moiety selected from the group consisting of cycloalkyl, optionally substituted 3- to 13-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R' and R'' at each occurrence are independently selected from null, optionally substituted (C-C alkylene)-R r (Preferably CH2-R r ), optionally substituted R r -(C1-C8 alkylene), optionally substituted (C1-C8 alkylene)-R r -(C1-C8 alkylene), or optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 heteroalkenylene, optionally substituted C2-C8 heteroalkynylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkoxyC1-C8 alkylene, optionally substituted C1-C8 alkylaminoC1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C3-C 13 is selected from a divalent moiety consisting of cycloalkyl, optionally substituted 3- to 13-membered heteroalkyl, optionally substituted aryl, and optionally substituted heteroaryl; R rEach occurrence is an optionally substituted C-C 13 selected from cycloalkyl, optionally substituted 3- to 13-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R x and R y are, at each occurrence, independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 heteroalkenyl, optionally substituted C2-C8 heteroalkynyl, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C3-C8 alkyl, optionally substituted C3-C8 alkylamino ... 13 selected from cycloalkyl, optionally substituted 3- to 13-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R' and R'', R x and R y , R' and R x , R' and R y , R'' and R x , or R'' and R y together with the atoms to which they are connected, optionally C3-C 20 forming a cycloalkyl or 3- to 20-membered heterocyclyl ring, j is an integer from 0 to 15.

[0233] The linker of formula (III) is a compound of formula (I) or formula (II) 1 The linker of formula (III) can be included in the compound of formula (X) as L 2 It can be included as:

[0234] In some embodiments of the linker of formula (III), U is (CH2) 0-12 and w 1is independently selected from C1-C8 alkylene at each occurrence; 2 is null and V is null. In some embodiments of the linker of formula (III), U is (CH2) 0-12 N(R x ) and w 1 is independently selected from C1-C8 alkylene at each occurrence; 2 is null and V is null. In some embodiments of the linker of formula (III), U is (CH2) 0-12 C(O) and w 1 is independently selected from C1-C8 alkylene at each occurrence; 2 is null and V is null. In some embodiments of the linker of formula (III), U is (CH2) 0-12 OC(O) and w 1 is independently selected from C1-C8 alkylene at each occurrence; 2 is null and V is null. In some embodiments of the linker of formula (III), U is (CH2) 0-12 N(R x )C(O) and w 1 is independently selected from C1-C8 alkylene at each occurrence; 2 is null and V is null. In some embodiments of the linker of formula (III), U is (CH2) 0-12 C(O)O, and w 1 is independently selected from C1-C8 alkylene at each occurrence; 2 is null and V is null. In some embodiments of the linker of formula (III), U is (CH2) 0-12 C(O)N(R x ) and w 1 is independently selected from C1-C8 alkylene at each occurrence; 2 is null and V is null. In some embodiments of a linker of Formula (III), j is an integer from 0 to 10. In some embodiments of a linker of Formula (III), j is an integer from 2 to 7. In some embodiments of a linker of Formula (III), j is an integer from 5 to 10.

[0235] In some embodiments of the linker of formula (III), U is (CH2) 0-12 and w 1 is independently selected from C1-C8 alkylene at each occurrence; 2 is O and V is C1-C8 alkylene. In some embodiments of the linker of formula (III), U is (CH2) 0-12 N(R x ) and w 1 is independently selected from C1-C8 alkylene at each occurrence; 2 is O and V is C1-C8 alkylene. In some embodiments of the linker of formula (III), U is (CH2) 0-12 C(O) and w 1 is independently selected from C1-C8 alkylene at each occurrence; 2 is O and V is C1-C8 alkylene. In some embodiments of the linker of formula (III), U is (CH2) 0-12 OC(O) and w 1 is independently selected from C1-C8 alkylene at each occurrence; 2 is O and V is C1-C8 alkylene. In some embodiments of the linker of formula (III), U is (CH2) 0-12 N(R x )C(O) and w 1 is independently selected from C1-C8 alkylene at each occurrence; 2 is O and V is C1-C8 alkylene. In some embodiments of the linker of formula (III), U is (CH2) 0-12 C(O)O, and w 1 is independently selected from C1-C8 alkylene at each occurrence; 2 is O and V is C1-C8 alkylene. In some embodiments of the linker of formula (III), U is (CH2) 0-12 C(O)N(R x ) and w 1 is independently selected from C1-C8 alkylene at each occurrence; 2is O and V is C1-C8 alkylene. In some embodiments of a linker of Formula (III), j is an integer from 0 to 12. In some embodiments of a linker of Formula (III), j is an integer from 2 to 7. In some embodiments of a linker of Formula (III), j is an integer from 5 to 12.

[0236] In some embodiments of the linker of formula (III), U is (CH2) 0-12 and w 1 is independently selected from C1-C8 alkylene at each occurrence; 2 is N(R y ) and V is C1-C8 alkylene. In some embodiments of the linker of formula (III), U is (CH2) 0-12 N(R x ) and w 1 is independently selected from C1-C8 alkylene at each occurrence; 2 is N(R y ) and V is C1-C8 alkylene. In some embodiments of the linker of formula (III), U is (CH2) 0-12 C(O) and w 1 is independently selected from C1-C8 alkylene at each occurrence; 2 is N(R y ) and V is C1-C8 alkylene. In some embodiments of the linker of formula (III), U is (CH2) 0-12 OC(O) and w 1 is independently selected from C1-C8 alkylene at each occurrence; 2 is N(R y ) and V is C1-C8 alkylene. In some embodiments of the linker of formula (III), U is (CH2) 0-12 N(R x )C(O) and w 1 is independently selected from C1-C8 alkylene at each occurrence; 2 is N(R y ) and V is C1-C8 alkylene. In some embodiments of the linker of formula (III), U is (CH2) 0-12 C(O)O, and w 1is independently selected from C1-C8 alkylene at each occurrence; 2 is N(R y ) and V is C1-C8 alkylene. In some embodiments of the linker of formula (III), U is (CH2) 0-12 C(O)N(R x ) and w 1 is independently selected from C1-C8 alkylene at each occurrence; 2 is N(R y ) and V is C1-C8 alkylene. In some embodiments of the linker of Formula (III), j is an integer from 0 to 12. In some embodiments of the linker of Formula (III), j is an integer from 2 to 7. In some embodiments of the linker of Formula (III), j is an integer from 5 to 12.

[0237] In some embodiments, the linker has formula (IIIa):

[0238] [ka] wherein: R s , R t , R u , and R vare, at each occurrence, independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 heteroalkenyl, optionally substituted C2-C8 heteroalkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1- selected from C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, and optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 10-membered cycloalkyl, optionally substituted 3- to 8-membered cycloalkoxy, optionally substituted 3- to 10-membered cycloalkylamino, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or R s and R t , or R u and R v optionally, taken together with the atoms to which they are attached, form a 3- to 20-membered cycloalkyl or 4- to 20-membered heterocyclyl ring; U, W, and V, each occurrence, independently, can be null or R'-R'', R'COR'', R'CO2R'', 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'SO2R'', R'SO2N(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)2R'', R'N(R x )S(O)2N(R y )R'', a divalent moiety selected from optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 heteroalkenylene, optionally substituted C2-C8 heteroalkynylene, optionally substituted C1-C8 alkoxyC1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted 3-10 membered cycloalkyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R' and R'' at each occurrence are independently selected from null, optionally substituted (C-C alkylene)-R r (Preferably CH2-R r ), optionally substituted Rr-(C1-C8 alkylene), optionally substituted (C1-C8 alkylene)-R r -(C1-C8 alkylene) or a divalent moiety consisting of optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 heteroalkenylene, optionally substituted C2-C8 heteroalkynylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkoxyC1-C8 alkylene, optionally substituted C1-C8 alkylaminoC1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted 3- to 10-membered cycloalkyl, optionally substituted 4- to 10-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R r is selected at each occurrence from optionally substituted 3- to 10-membered cycloalkyl, optionally substituted 4- to 10-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R x and R y is independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 heteroalkenyl, optionally substituted C2-C8 heteroalkynyl, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylaminoC1-C8 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 , or R'' and R 6 optionally, taken together with the atoms to which they are attached, form a 3- to 20-membered cycloalkyl or 4- to 20-membered heterocyclyl ring; k is 0 to 15; l is 0 to 15 at each occurrence, o is a number between 0 and 15.

[0239] In some embodiments, the linker has formula (IIIb):

[0240] [ka] wherein: R sand R t are, at each occurrence, independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, and optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 heteroalkenyl, optionally substituted C2-C8 heteroalkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 10-membered cycloalkyl, optionally substituted 3- to 8-membered cycloalkoxy, optionally substituted 3- to 10-membered cycloalkylamino, optionally substituted 4- to 10-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R s and R t optionally, taken together with the atoms to which they are attached, form a 3- to 20-membered cycloalkyl or 4- to 20-membered heterocyclyl ring; U and V, each occurrence, independently, are null or R'-R'', R'COR'', R'CO2R'', 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'SO2R'', R'SO2N(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)2R'', R'N(R x )S(O)2N(R y )R'', a divalent moiety selected from optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 heteroalkenylene, optionally substituted C2-C8 heteroalkynylene, optionally substituted C1-C8 alkoxyC1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted 3-10 membered cycloalkyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R' and R'' at each occurrence are independently selected from null, optionally substituted (C-C alkylene)-R r (Preferably CH2-R r ), optionally substituted Rr-(C1-C8 alkylene), optionally substituted (C1-C8 alkylene)-R r -(C1-C8 alkylene) or a divalent moiety consisting of optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 heteroalkenylene, optionally substituted C2-C8 heteroalkynylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkoxyC1-C8 alkylene, optionally substituted C1-C8 alkylaminoC1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted 3- to 10-membered cycloalkyl, optionally substituted 4- to 10-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R s and Rt is independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 heteroalkenyl, optionally substituted C2-C8 heteroalkynyl, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 10-membered cycloalkyl, optionally substituted 4- to 10-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R' and R'', R s and R t , R' and R s , R' and R t , R'' and R s , or R'' and R t optionally, taken together with the atoms to which they are attached, form a 3- to 20-membered cycloalkyl or 4- to 20-membered heterocyclyl ring; k is 0 to 15, o is a number between 0 and 15.

[0241] In some embodiments, the linker has formula (IIIc):

[0242] [ka] wherein: X, when present, is O, NH, and NR aa is selected from R s , R t , R u , R v , R w , and R zare, at each occurrence, independently represent hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 heteroalkenyl, optionally substituted C2-C8 heteroalkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 selected from alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 10-membered cycloalkyl, optionally substituted 3- to 8-membered cycloalkoxy, optionally substituted 4- to 10-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; U and V, each occurrence, independently, are null or R'-R'', R'COR'', R'CO2R'', 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'SO2R'', R'SO2N(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)2R'', R'N(R x )S(O)2N(R y)R'', a divalent moiety selected from optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 heteroalkenylene, optionally substituted C2-C8 heteroalkynylene, optionally substituted C1-C8 alkoxyC1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted 3-10 membered cycloalkyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R' and R'' at each occurrence are independently selected from null, optionally substituted (C-C alkylene)-R r (Preferably CH2-R r ), optionally substituted R r -(C1-C8 alkylene) or a divalent moiety consisting of optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 heteroalkenylene, optionally substituted C2-C8 heteroalkynylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkoxyC1-C8 alkylene, optionally substituted C1-C8 alkylaminoC1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted 3- to 10-membered cycloalkyl, optionally substituted 4- to 10-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R r is selected at each occurrence from optionally substituted 3- to 10-membered cycloalkyl, optionally substituted 4- to 10-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; Raa , R x , and R y is independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 heteroalkenyl, optionally substituted C2-C8 heteroalkynyl, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylaminoC1-C8 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 , or R'' and R y optionally, taken together with the atoms to which they are attached, form a 3- to 20-membered cycloalkyl or 4- to 20-membered heterocyclyl ring; k is 0 to 15 at each occurrence, i is 0 to 15 at each occurrence, l is 0 to 15, o is a number between 0 and 15.

[0243] In some embodiments, the linker has formula (IIId):

[0244] [ka] wherein: U, W 1 , W 2 , and V, when each occurs, independently represent null, R'-R'', R'COR'', R'CO2R'', 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'SO2R'', R'SO2N(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)2R'', R'N(R x )S(O)2N(R y )R'', optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 heteroalkenylene, optionally substituted C2-C8 heteroalkynylene, optionally substituted C1-C8 alkoxyC1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C3-C 13 a divalent moiety selected from the group consisting of cycloalkyl, optionally substituted 3- to 13-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R' and R'' at each occurrence are independently selected from null, optionally substituted (C-C alkylene)-R r (Preferably CH2-R r ), optionally substituted R r -(C1-C8 alkylene), optionally substituted (C1-C8 alkylene)-R r-(C1-C8 alkylene), or optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 heteroalkenylene, optionally substituted C2-C8 heteroalkynylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkoxyC1-C8 alkylene, optionally substituted C1-C8 alkylaminoC1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C3-C 13 is selected from a divalent moiety consisting of cycloalkyl, optionally substituted 3- to 13-membered, optionally substituted aryl, and optionally substituted heteroaryl; R r Each occurrence is an optionally substituted C-C 10 selected from cycloalkyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R x and R y are, at each occurrence, independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 heteroalkenyl, optionally substituted C2-C8 heteroalkynyl, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C3-C8 alkyl, optionally substituted C3-C8 alkylamino ... 10 selected from cycloalkyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R' and R'', R x and R y , R' and Rx , R' and R y , R'' and R x , or R'' and R y together with the atoms to which they are connected, optionally C3-C 20 It forms a cycloalkyl or 3- to 20-membered heterocyclyl ring, and o is 0-15.

[0245] The linker of formula (IIIa), (IIIb), (IIIc), or (IIId) is a compound of formula (I) or formula (II) linked to a bivalent chemical linker L 1 The linker of formula (IIIa), (IIIb), (IIIc), or (IIId) can be attached to a compound of formula (X) via a bivalent chemical linker, L 2 It can be included as:

[0246] In some embodiments, U and V, at each occurrence, are independently selected from null, CO, NH, NH—CO, CO—NH, CH—NH—CO, CH—CO—NH, NH—CO—CH, CO—NH—CH, CH—NH—CH—CO—NH, CH—NH—CH—NH—CO, —CO—NH, CO—NH—CH—NH—CH, CH—NH—CH. In some embodiments, o is 0 to 5. In some embodiments, the linker comprises a ring selected from the group consisting of a 3-13 membered ring, a 3-13 membered fused ring, a 3-13 membered bridged ring, and a 3-13 membered spiro ring.

[0247] In some embodiments, the linker is selected from the group consisting of formula (IIIC1a), formula (IIIC2a), formula (IIIC3a), formula (IIIC4a), and formula (IIIC5a):

[0248] [ka] wherein the ring comprises one or more rings selected from the group consisting of: X' and Y' are independently N, CR bb is selected from A 1 , B 1 , C 1 , and D1 are independently null, O, CO, SO, SO2, and NR when they occur. bb , and C.R. bb R cc is selected from A 2 , B 2 , C 2 , and D 2 are independently N and CR at each occurrence. bb is selected from A 3 , B 3 , C 3 , D 3 , and E 3 are independently N, O, S, and NR when they occur. bb , and C.R. bb is selected from R bb and R cc are, at each occurrence, independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 heteroalkenyl, optionally substituted C2-C8 heteroalkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C selected from 1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, and optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 10-membered cycloalkyl, optionally substituted 3- to 8-membered cycloalkoxy, optionally substituted 3- to 10-membered cycloalkylamino, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; m 1 , n 1 , o 1 , and p 1 is independently selected from 0, 1, 2, 3, 4, and 5.

[0249] In some embodiments, the linker is selected from the group consisting of formula (IIIC1), formula (IIIC2), formula (IIIC3), formula (IIIC4), and formula (IIIC5):

[0250] [ka] The rings comprise one or more rings selected from the group consisting of:

[0251] In some embodiments, the linker is

[0252] [ka] The compound includes one or more rings selected from:

[0253] The linkers of formula (IIIC1a), (IIIC2a), (IIIC3a), (IIIC4a), (IIIC5a) are the same as the linker L of formula (I). 1 The linkers of formula (IIIC1a), (IIIC2a), (IIIC3a), (IIIC4a), (IIIC5a) can be included as the linker L of formula (II). 1 The linkers of formula (IIIC1a), (IIIC2a), (IIIC3a), (IIIC4a), (IIIC5a) can be included as a linker L of formula (X). 2 It can be included as:

[0254] In a preferred embodiment, the linker of formula (I) or formula (II) is a bond or a linker of formula -(J) x -, and each -J- is independently -N(R 25 )-, -C(R 26 )2-, -O-, -C(O)-, -C(N(R 25 ))-, -C(S)-, -C(R 26 )=C(R 26 )-, -C≡C-, -S-, -S(O)-, -S(O)2-, R 27 C-C cycloalkyl optionally substituted with, and R 27and R is selected from the group consisting of 3- to 6-membered heterocyclyl optionally substituted with, provided that no two -O- and / or -S- are adjacent; 25 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl, and each C1-C6 alkyl is selected from one or more R f and each of the C-C cycloalkyl and 3- to 6-membered heterocyclyl is optionally substituted with one or more R g optionally substituted with R 26 are each independently selected from the group consisting of hydrogen, fluoro, C1-C6 alkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl, and each C1-C6 alkyl is selected from one or more R f and each of the C-C cycloalkyl and 3- to 6-membered heterocyclyl is optionally substituted with one or more R g optionally substituted with R 27 are each independently selected from the group consisting of hydrogen, fluoro, C1-C6 alkyl, and oxo, each C1-C6 alkyl being selected from one or more R f and each of the C-C cycloalkyl and 3- to 6-membered heterocyclyl is optionally substituted with one or more R g optionally substituted with R f are each independently selected from the group consisting of fluoro, hydroxy, C-C alkoxy, oxo, NH, NH(C-C alkyl), and N(C-C alkyl), and R g are each independently selected from the group consisting of fluoro, hydroxy, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, oxo, NH2, NH(C1-C4 alkyl), and N(C1-C4 alkyl)2, and x is an integer from 1 to 30;

[0255] In some embodiments, the linker has the structure -(CH) 1-12 -Has.

[0256] In some embodiments, the linker has the structure -(CH2)1-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, -(CH2)9-, -(CH2) 10 -, -(CH2) 11 - or -(CH2) 12 -Has.

[0257] In some embodiments, the linker has the structure -C(=O)(CH) 1-12 -Has.

[0258] In some embodiments, the linker has the structure -C(=O)(CH2)-, -C(=O)(CH2)2-, -C(=O)(CH2)3-, -C(=O)(CH2)4-, -C(=O)(CH2)5-, -C(=O)(CH2)6-, -C(=O)(CH2)7-, -C(=O)(CH2)8-, -C(=O(CH2)9-, -C(=O)(CH2) 10 -, -C(=O)(CH2) 11 - or -C(=O)(CH2) 12 -Has.

[0259] In some embodiments, the linker has the structure -(CH) 0-12 NH(CH2) 1-12 -Has.

[0260] In some embodiments, the linker has the structure -NH(CH2)-, -NH(CH2)2-, -NH(CH2)3-, -NH(CH2)4-, -NH(CH2)5-, -NH(CH2)6-, -NH(CH2)7-, -NH(CH2)8-, -NH(CH2)9-, -NH(CH2) 10 -, -NH(CH2) 11 - or -NH(CH2) 12 -Has.

[0261] In some embodiments, the linker has the structure -(CH) 0-12 NHC(=O)(CH2) 1-12 -Has.

[0262] In some embodiments, the linker has the structure -NHC(=O)(CH2)-, -NHC(=O)(CH2)2-, -NHC(=O)(CH2)3-, -NHC(=O)(CH2)4-, -NHC(=O)(CH2)5-, -NHC(=O)(CH2)6-, -NHC(=O)(CH2)7-, -NHC(=O)(CH2)8-, -NHC(=O)(CH2)9-, -NHC(=O)(CH2) 10 -, -NHC(=O)(CH2) 11 - or -NHC(=O)(CH2) 12 -Has.

[0263] In some embodiments, the linker has the structure -(CH2)2NHC(=O)(CH2)-, -(CH2)2NHC(=O)(CH2)2-, -(CH2)2NHC(=O)(CH2)3-, -(CH2)2NHC(=O)(CH2)4-, -(CH2)2NHC(=O)(CH2)5-, -(CH2)2NHC(=O)(CH2)6-, -(CH2)2NHC(=O)(CH2)7-, -(CH2)2NHC(=O)(CH2)8-, -(CH2)2NHC(=O)(CH2)9-, -(CH2)2NHC(=O)(CH2) 10 -, -(CH2)2NHC(=O)(CH2) 11 - or -(CH2)2NHC(=O)(CH2) 12 -Has.

[0264] In some embodiments, the linker has the structure -(CH) 0-12 C(=O)NH(CH2) 1-12 -Has.

[0265] In some embodiments, the linker has the structure -C(=O)NH(CH2)-, -C(=O)NH(CH2)2-, -C(=O)NH(CH2)3-, -C(=O)NH(CH2)4-, -C(=O)NH(CH2)5-, -C(=O)NH(CH2)6-, -C(=O)NH(CH2)7-, -C(=O)NH(CH2)8-, -C(=O)NH(CH2)9-, -C(=O)NH(CH2) 10 -, -C(=O)NH(CH2) 11 - or -C(=O)NH(CH2)12 -Has.

[0266] In some embodiments, the linker has the structure -(CH2)C(=O)NH-(CH2)-, -(CH2)C(=O)NH-(CH2)2-, -(CH2)C(=O)NH(CH2)3-, -(CH2)C(=O)NH(CH2)4-, -(CH2)C(=O)NH(CH2)5-, -(CH2)C(=O)NH(CH2)6-, -(CH2)C(=O)NH(CH2)7-, -(CH2)C(=O)NH(CH2)8-, -(CH2)C(=O)NH(CH2)9-, -(CH2)C(=O)NH(CH2) 10 -, -(CH2)C(=O)NH(CH2) 11 - or -(CH2)C(=O)NH(CH2) 12 -Has.

[0267] In some embodiments, the linker has the structure -(CH2)2C(=O)NH(CH2)-, -(CH2)2C(=O)NH(CH2)2-, -(CH2)2C(=O)NH(CH2)3-, -(CH2)2C(=O)NH(CH2)4-, -(CH2)2C(=O)NH(CH2)5-, -(CH2)2C(=O)NH(CH2)6-, -(CH2)2C(=O)NH(CH2)7-, -(CH2)2C(=O)NH(CH2)8-, -(CH2)2C(=O)NH(CH2)9-, -(CH2)2C(=O)NH(CH2) 10 -, -(CH2)2C(=O)NH(CH2) 11 - or -(CH2)2C(=O)NH(CH2) 12 -Has.

[0268] In some embodiments, the linker has the structure -(CH2)3C(=O)NH(CH2)-, -(CH2)3C(=O)NH(CH2)2-, -(CH2)3C(=O)NH(CH2)3-, -(CH2)3C(=O)NH(CH2)4-, -(CH2)3C(=O)NH(CH2)5-, -(CH2)3C(=O)NH(CH2)6-, -(CH2)3C(=O)NH(CH2)7-, -(CH2)3C(=O)NH(CH2)8-, -(CH2)3C(=O)NH(CH2)9-, -(CH2)3C(=O)NH(CH2) 10 -, -(CH2)3C(=O)NH(CH2) 11 - or -(CH2)3C(=O)NH(CH2) 12 -Has.

[0269] In some embodiments, the linker has the structure -(CH) 0-12 (CH2CH2O) 1-12 (CH2) 0-12 -Has.

[0270] In some embodiments, the linker has the structure -(CH2CH2O) 1-12 (CH2) 0-12 -Has.

[0271] In some embodiments, the linker has the structure -(CH2CH2O) 1-12 It has (CH2)2-.

[0272] In some embodiments, the linker has the structure -(CH2CHO)(CH2)2-, -(CH2CHO)2(CH2)2-, -(CH2CHO)3(CH2)2-, -(CH2CHO)4(CH2)2-, -(CH2CHO)5(CH2)2-, -(CH2CHO)6(CH2)2-, -(CH2CHO)7(CH2)2-, -(CH2CHO)8(CH2)2-, -(CH2CHO)9(CH2)2-, -(CH2CHO) 10 (CH2)2-, -(CH2CH2O) 11 (CH2)2-, or -(CH2CH2O) 12 It has (CH2)2-.

[0273] In some embodiments, the linker has the structure -(CH) 0-12 C(=O)(CH2CH2O) 1-12 (CH2) 0-12 -Has.

[0274] In some embodiments, the linker has the structure -C(=O)(CHCHO) 1-12 (CH2) 0-12 -Has.

[0275] In some embodiments, the linker has the structure -C(=O)(CHCHO) 1-12 It has (CH2)2-.

[0276] In some embodiments, the linker has the structure -C(=O)(CH2CHO)(CH2)2-, -C(=O)(CH2CHO)2(CH2)2-, -C(=O)(CH2CHO)3(CH2)2-, -C(=O)(CH2CHO)4(CH2)2-, -C(=O)(CH2CHO)5(CH2)2-, -C(=O)(CH2CHO)6(CH2)2-, -C(=O)(CH2CHO)7(CH2)2-, -C(=O)(CH2CHO)8(CH2)2-, -C(=O)(CH2CHO)9(CH2)2-, -C(=O)(CH2CHO) 10 (CH2)2-, -C(=O)(CH2CH2O) 11 (CH2)2-, or -C(=O)(CH2CH2O) 12 It has (CH2)2-.

[0277] In some embodiments, the linker has the structure -(CH) 0-12 NH(CH2CH2O) 1-12 It has (CH2)2-.

[0278] In some embodiments, the linker has the structure -NH(CH2CHO)(CH2)2-, -NH(CH2CHO)2(CH2)2-, -NH(CH2CHO)3(CH2)2-, -NH(CH2CHO)4(CH2)2-, -NH(CH2CHO)5(CH2)2-, -NH(CH2CHO)6(CH2)2-, -NH(CH2CHO)7(CH2)2-, -NH(CH2CHO)8(CH2)2-, -NH(CH2CHO)9(CH2)2-, -NH(CH2CHO) 10 (CH2)2-, -NH(CH2CH2O) 11 (CH2)2-, or -NH(CH2CH2O) 12 It has (CH2)2-.

[0279] In some embodiments, the linker has the structure -(CH) 0-12 NHC(=O)(CH2CH2O) 1-12 It has (CH2)2-.

[0280] In some embodiments, the linker has the structure -NHC(=O)(CH2CHO)(CH2)2-, -NHC(=O)(CH2CHO)2(CH2)2-, -NHC(=O)(CH2CHO)3(CH2)2-, -NHC(=O)(CH2CHO)4(CH2)2-, -NHC(=O)(CH2CHO)5(CH2)2-, -NHC(=O)(CH2CHO)6(CH2)2-, -NHC(=O)(CH2CHO)7(CH2)2-, -NHC(=O)(CH2CHO)8(CH2)2-, -NHC(=O)(CH2CHO)9(CH2)2-, -NHC(=O)(CH2CHO) 10 (CH2)2-, -NHC(=O)(CH2CH2O) 11 (CH2)2-, or -NHC(=O)(CH2CH2O) 12 It has (CH2)2-.

[0281] In some embodiments, the linker has the structure -(CH2)2NHC(=O)(CH2CH2O)(CH2)2-, -(CH2)2NHC(=O)(CH2CH2O)2(CH2)2-, -(CH2)2NHC(=O)(CH2CH2O)3(CH2)2-, -(CH2)2NHC(=O)(CH2CH2O)4(CH2)2-, -(CH2)2NHC(=O)(CH2C H2O)5(CH2)2-, -(CH2)2NHC(=O)(CH2CH2O)6(CH2)2-, -(CH2)2NHC(=O)(CH2CH2O)7(CH2)2-, -(CH2 )2NHC(=O)(CH2CH2O)8(CH2)2-, -(CH2)2NHC(=O)(CH2CH2O)9(CH2)2-, -(CH2)2NHC(=O)(CH2CH2O) 10 (CH2)2-, -(CH2)2NHC(=O)(CH2CH2O) 11 (CH2)2-, or -(CH2)2NHC(=O)(CH2CH2O) 12 It has (CH2)2-.

[0282] In some embodiments, the linker has the structure -(CH) 0-12 C(=O)NH(CH2CH2O) 1-12 It has (CH2)2-.

[0283] In some embodiments, the linker has the structure -(CH) 0-2 C(=O)NH(CH2CH2O) 1-12 It has (CH2)2-.

[0284] In some embodiments, the linker has the structure -C(=O)NH(CHCHO)(CH)-, -C(=O)NH(CHCHO)(CH)-, -C(=O)NH(CHCHO)(CH)-, -C(=O)NH(CHCHO)(CH)-, -C(=O)NH(CHCHO)(CH)-, -C(=O)NH(CHCHO)(CH)-, -C(=O)NH(CHCHO)(CH)-, -C(=O)NH(CHCHO)(CH)-, -C(=O)NH(CHCHO)(CH)-, -C(=O)NH(CHCHO)(CH)-, -C(=O)NH(CHCHO) 10(CH2)2-, -C(=O)NH(CH2CH2O) 11 (CH2)2-, or -C(=O)NH(CH2CH2O) 12 It has (CH2)2-.

[0285] In some embodiments, the linker has the structure -(CH2)C(=O)NH(CH2CHO)(CH2)2-, -(CH2)C(=O)NH(CH2CHO)2(CH2)2-, -(CH2)C(=O)NH(CH2CHO)3(CH2)2-, -(CH2)C(=O)NH(CH2CHO)4(CH2)2-, -(CH2)C(=O)NH(CH2CHO)4(CH2)2-, -(CH2)C(=O)NH(CH2C H2O)5(CH2)2-, -(CH2)C(=O)NH(CH2CH2O)6(CH2)2-, -(CH2)C(=O)NH(CH2CH2O)7(CH2)2-, -(CH 2)C(=O)NH(CH2CH2O)8(CH2)2-, -(CH2)C(=O)NH(CH2CH2O)9(CH2)2-, -(CH2)C(=O)NH(CH2CH2O) 10 (CH2)2-, -(CH2)C(=O)NH(CH2CH2O) 11 (CH2)2-, or -(CH2)C(=O)NH(CH2CH2O) 12 It has (CH2)2-.

[0286] In some embodiments, the linker has the structure -(CH2)2C(=O)NH(CH2CHO)(CH2)2-, -(CH2)2C(=O)NH(CH2CHO)2(CH2)2-, -(CH2)2C(=O)NH(CH2CHO)2(CH2)2-, -(CH2)2C(=O)NH(CH2CHO)3(CH2)2-, -(CH2)2C(=O)NH(CH2CHO)4(CH2)2-, -(CH2)2C(=O)NH(CH2C H2O)5(CH2)2-, -(CH2)2C(=O)NH(CH2CH2O)6(CH2)2-, -(CH2)2C(=O)NH(CH2CH2O)7(CH2)2-, -(CH2 )2C(=O)NH(CH2CH2O)8(CH2)2-, -(CH2)2C(=O)NH(CH2CH2O)9(CH2)2-, -(CH2)2C(=O)NH(CH2CH2O) 10 (CH2)2-, -(CH2)2C(=O)NH(CH2CH2O) 11(CH2)2-, or -(CH2)2C(=O)NH(CH2CH2O) 12 It has (CH2)2-.

[0287] In some embodiments, the linker has the structure -(CH2)3C(=O)NH(CH2CHO)(CH2)2-, -(CH2)3C(=O)NH(CH2CHO)2(CH2)2-, -(CH2)3C(=O)NH(CH2CHO)2(CH2)2-, -(CH2)3C(=O)NH(CH2CHO)3(CH2)2-, -(CH2)3C(=O)NH(CH2CHO)4(CH2)2-, -(CH2)3C(=O)NH(CH2C H2O)5(CH2)2-, -(CH2)3C(=O)NH(CH2CH2O)6(CH2)2-, -(CH2)3C(=O)NH(CH2CH2O)7(CH2)2-, -(CH2 )3C(=O)NH(CH2CH2O)8(CH2)2-, -(CH2)3C(=O)NH(CH2CH2O)9(CH2)2-, -(CH2)3C(=O)NH(CH2CH2O) 10 (CH2)2-, -(CH2)3C(=O)NH(CH2CH2O) 11 (CH2)2-, or -(CH2)3C(=O)NH(CH2CH2O) 12 It has (CH2)2-.

[0288] Target protein In some embodiments, a target protein is disclosed herein. In some embodiments, the target protein comprises a transcription factor. In some embodiments, the target protein comprises an epigenetic modulator. In some embodiments, the target protein comprises p300 or CBP (CREB binding protein). In some embodiments, the target protein comprises p300. In some embodiments, the target protein comprises CBP. In some embodiments, the target protein comprises a bromodomain-containing protein. In some embodiments, the target protein comprises bromodomain-containing protein 4 (BRD4).

[0289] In some embodiments, the target protein comprises a kinase. In some embodiments, the target protein comprises a cyclin-dependent kinase (CDK). In some embodiments, the target protein comprises cyclin-dependent kinase 4 (CDK4) or cyclin-dependent kinase 6 (CDK6). In some embodiments, the target protein comprises CDK4. In some embodiments, the target protein comprises CDK6. In some embodiments, the target protein comprises CDK9. In some embodiments, the target protein comprises a CDK, CDK1, CDK2, CDK3, CDK4, CDK6, CDK7, CDK8, CDK9, CDK10, CDK11, CDK12, or CDK13. In some embodiments, the target protein comprises a tyrosine receptor kinase. In some embodiments, the target protein comprises a tropomyosin receptor kinase (TrK). In some embodiments, the target protein comprises TrKA. In some embodiments, the target protein comprises TrKB. In some embodiments, the target protein comprises TrKC. In some embodiments, the target protein comprises a mitogen-activated protein kinase kinase (MKK or MEK). In some embodiments, the target protein comprises MEK1. In some embodiments, the target protein comprises MEK2. In some embodiments, the target protein may comprise a cyclin. In some embodiments, the cyclin is cyclin D. The cyclin D may comprise cyclin D1. The cyclin D may comprise cyclin D2. The cyclin D may comprise cyclin D3. In some embodiments, the heterobifunctional compound degrades a cyclin. Some examples of cyclins include cyclin A, cyclin B, cyclin C, cyclin D, cyclin D1, cyclin D2, cyclin D3, cyclin E, cyclin H, cyclin K, cyclin T, or cyclin T1. In some embodiments, the heterobifunctional compound degrades a target protein.

[0290] Some further non-limiting examples of target proteins include B7.1, B7, TINFRlm, TNFR2, NADPH oxidase, partners in the apoptosis pathway, BclIBax, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type, PDE IV phosphodiesterase type 4, PDE I, PDEII, PDEIII, squalene cyclase inhibitors, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclooxygenase 1, cyclooxygenase 2, receptor, 5HT receptor, dopamine receptor, G protein (e.g., Gq), histamine receptor, 5-lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside phosphorylase, GAPDH, trypanosome protein, glycogen phosphorylase, carbonic anhydrase, chemokine receptor, JAK, STAT, RXR, RAR, HIV 1 protease, HIV 1 integrase, influenza, neuraminidase, hepatitis B reverse transcriptase, sodium channel, multidrug resistance (MDR), protein P-glycoprotein, MRP, tyrosine kinase, CD23, CD124, tyrosine kinase p56 lck, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-alphaR, ICAM1, Ca+ channel, VCAM, integrin, VLA-4 integrin, selectin, CD40, CD40L, neurokinin, neurokinin receptor, inosine monophosphate dehydrogenase, p38 MAP kinase, Ras, Raf, Mek, Erk, interleukin-1 converting enzyme, caspase, HCV, NS3 protease, HCV NS3RNA helicase, glycinamide ribonucleotide formyltransferase, rhinovirus 3C protease, herpes simplex virus-1 (HSV-I) protease, cytomegalovirus (CMV) protease, poly(ADP-ribose) polymerase, cyclin-dependent kinase (CDK), vascular endothelial growth factor, oxytocin receptor, microsomal transfer protein inhibitor, bile acid transport inhibitor, 5-alpha-reductase inhibitor, angiotensin II, glycine receptor, norepinephrine reuptake Innervation receptors, endothelin receptors, neuropeptide Y, neuropeptide Y receptors, estrogen receptors, androgen receptors, adenosine receptors, adenosine kinase, AMP deaminase, purinergic receptors (e.g., P2Y1, P2Y2, P2Y4, P2Y6, or P2X1-7), farnesyltransferase, geranylgeranyltransferase, Trk, NGF receptor, beta-amyloid tyrosine kinase, Flk-II, KDR, vitronectin receptor, integrin receptor, Her2 neu, telomerase inhibition, cytosolic phospholipase A2, EGF receptor tyrosine kinase, ecdysone 20-monooxygenase, GABA-gated chloride channel ion channel, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel, chloride channel, acetyl-CoA carboxylase, adenylosuccinate synthase, protoporphyrinogen oxidase, enolpyruvylshikimate-phosphate synthase, HSP, Hsp90, kinase, MDM, MDM2, human BET bromodomain-containing protein, HDAC, lysine methyltransferase, angiogenic protein, immunomodulatory protein, AHR, VEGFR3, Alk, Abl, Janus kinase, JAK2, Met, B The target protein may include any one of Raf, phosphatase, FKBP, thyroid hormone receptor, acyl-protein thioesterase-1, acyl-protein thioesterase-2, HIV protein, HIV protease, HIV integrase, HCV protein, or HCV protease. The target protein may include p25 or p35.

[0291] In some embodiments, the target protein comprises a protein associated with a disease state. For example, the target protein may be present or upregulated in a disease state. In some embodiments, the target protein comprises a pathogenic protein. In some embodiments, the target protein comprises a viral protein. In some embodiments, the target protein comprises a bacterial protein.

[0292] The target protein is selected from proteins expressed in cells, such that at least a portion of the sequence is found in the cell and can bind to the target protein binding moiety. The term "protein" can include oligopeptide and polypeptide sequences of sufficient length that they can bind to the target protein binding moiety. As otherwise described herein, any protein in a eukaryotic or microbial system, including viruses, bacteria, or fungi, can be a target protein for ubiquitination mediated by the compounds disclosed herein. The target protein can be a eukaryotic protein.

[0293] Any protein that can bind to a protein target moiety and act on or be degraded by a ubiquitin ligase can be a target protein. In general, target proteins may include, for example, structural proteins, receptors, enzymes, cell surface proteins, proteins involved in the integral function of a cell including proteins involved in catalytic activity, aromatase activity, motility activity, helicase activity, metabolic processes (anabolic and catabolic), antioxidant activity, proteolysis, biosynthesis, proteins with kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulatory activity, signal transduction activity, structural molecule activity, binding activity (proteins, lipids carbohydrates), receptor activity, cell motility, membrane fusion, cell-to-cell communication, regulation of biological processes, development, cell differentiation, response to stimuli, behavioral proteins, cell adhesion proteins, proteins involved in cell death, proteins involved in transport (including protein transporter activity, nuclear transport, ion transporter activity, channel transporter activity, carrier activity, permease activity, secretion activity, electron transporter activity, pathogenesis, chaperone regulatory activity, nucleic acid binding activity, transcription regulatory activity, extracellular organization, and biogenesis activity, translation regulatory activity). Proteins of interest can include proteins from eukaryotic and prokaryotic organisms, including humans as targets for drug therapy, domestic animals and other animals, including microorganisms for targeting antibiotics and other antimicrobial agents, plants, and even viruses, among many others.

[0294] In some embodiments, the target protein comprises any of Hsp90, kinase, MDM2, human BET bromodomain-containing protein, HDAC, lysine methyltransferase, angiogenic protein, immune modifier protein, or aryl hydrocarbon receptor (AHR). In some embodiments, the target protein comprises a heat shock protein (HSP), such as HSP90. In some embodiments, the target protein comprises a kinase or phosphatase. In some embodiments, the target protein comprises a kinase. In some embodiments, the kinase is a tyrosine kinase. In some embodiments, the kinase is VEGFR3. In some embodiments, the kinase is 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, the target protein comprises a phosphatase. In some embodiments, the phosphatase is a protein tyrosine phosphatase. In some embodiments, the phosphatase comprises a SHP-2 domain. In some embodiments, the target protein comprises an MDM. In some embodiments, the MDM is MDM2. In some embodiments, the target protein comprises an HDAC. In some embodiments, the target protein comprises a methyltransferase, such as a lysine methyltransferase. In some embodiments, the target protein comprises angiogenesis. In some embodiments, the target protein comprises an immunomodulatory or immunosuppressive protein. In some embodiments, the target protein comprises an aryl carbohydrate receptor (AHR). In some embodiments, the target protein comprises a RAF receptor. In some embodiments, the target protein comprises an FKBP. In some embodiments, the target protein comprises an estrogen receptor or an androgen receptor. In some embodiments, the target protein comprises an androgen receptor. In some embodiments, the target protein comprises an estrogen receptor.In some embodiments, the target protein comprises a thyroid hormone receptor. In some embodiments, the target protein comprises an HIV protein, such as HIV protease or HIV integrase. In some embodiments, the target protein comprises an HCV protein, such as HCV protease. In some embodiments, the target protein comprises acyl-protein thioesterase-1 or -2.

[0295] Target protein binding moiety In some embodiments herein, a target protein binding moiety is disclosed. For example, the ligand described herein may comprise a target protein binding moiety. In some embodiments, the target protein binds to or is bound by the target protein binding moiety. In some embodiments, the target protein binding moiety binds to the target protein. In some embodiments, the binding of the ligand to the target protein in a cell results in degradation of the target protein. For example, the ligand may increase ubiquitin-mediated target protein degradation or proteasomal degradation of the target protein. The target protein binding moiety can be any molecule that binds to the target protein. For example, the target protein binding moiety can be any small molecule known to bind to the target protein.

[0296] In some embodiments, Z 1 is L 1 -P, wherein P comprises a target protein binding moiety that binds to CBP, p300, TrkA, TrkB, TrkC, CDK4, CDK6, CDK9, or cyclin D, or a combination thereof.

[0297] In some embodiments, disclosed herein is a compound comprising a DCAF1 binding moiety. In some embodiments, the DCAF1 binding moiety binds to DCAF1 protein. In some embodiments, the DCAF1 binding moiety is bound to DCAF1 protein. In some embodiments, the compound binds to DCAF1 protein via the DCAF1 binding moiety. In some embodiments, the compound is bound to DCAF1 protein via the DCAF1 binding moiety.

[0298] In some embodiments, the DCAF1 binding moiety is incorporated into a ligand described herein. In some embodiments, the DCAF1 binding moiety is part of a modified protein described herein. In some embodiments, the DCAF1 binding moiety is part of a ligand-protein complex described herein. In some embodiments, the DCAF1 binding moiety is attached to a linker, such as a linker described herein. In some embodiments, the DCAF1 binding moiety is covalently connected to a target protein binding moiety described herein by a linker. In some embodiments, the target protein binding moiety is incorporated into a molecular structure or formula disclosed herein. For example, the target protein binding moiety can be included in a compound of formula (I). The target protein binding moiety can be included in a compound of formula (II).

[0299] Non-limiting examples of small molecule target protein binding moieties include Hsp90 inhibitors, kinase inhibitors, MDM2 inhibitors, compounds targeting human BET bromodomain-containing proteins, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, immunosuppressive compounds, and compounds targeting the aryl hydrocarbon receptor (AHR), among many others. By attaching a DCAF1 binding moiety to the target protein binding moiety, the target protein can be ubiquitinated and / or degraded by the proteasome.

[0300] In certain embodiments, the protein binding moiety is a haloalkane (preferably a C-C 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). 10 alkyl group), which can be covalently attached to a dehalogenase enzyme in a patient or subject or in a diagnostic assay.

[0301] Target protein binding moieties according to the present disclosure can include any moiety that specifically binds to a protein (e.g., binds to a target protein) and can include the following non-limiting examples of small molecule target protein moieties: Hsp90 inhibitors, kinase inhibitors, MDM2 inhibitors, compounds targeting human BET bromodomain-containing proteins, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, immunosuppressive compounds, and compounds targeting the aryl hydrocarbon receptor (AHR), among many others. The compositions described herein exemplify some of these types of small molecule target protein binding moieties. Such small molecule target protein binding moieties also include pharmaceutically acceptable salts, enantiomers, solvates, and polymorphs of these compositions, as well as other small molecules that can target a protein of interest. These binding moieties can be linked to the DCAF1 binding moiety by a linker to present the target protein (which binds to the protein target moiety) in proximity to a ubiquitin ligase for ubiquitination and degradation.

[0302] In some embodiments, the target protein binding moiety comprises a haloalkyl group, which generally ranges in size from about 1 or 2 carbons to about 12 carbons in length, often about 2-10 carbons in length, often about 3 carbons to about 8 carbons in length, and more often about 4 carbons to about 6 carbons in length. Haloalkyl groups are generally linear alkyl groups (branched alkyl groups may also be used) that are end-capped with at least one halogen group, preferably a single halogen group, often a single chloride group. Haloalkyl target protein binding moieties for use in the present disclosure can be represented by the chemical structure -(CH)v-halo, where v is an integer between 2 and about 12, often between about 3 and about 8, and more often between about 4 and about 6. Halo can be any halogen, but is preferably Cl or Br, more often Cl.

[0303] In some embodiments, the target protein binding moiety comprises a group wherein w is 0 to 3, preferably 1 or 2.

[0304] [ka] This group can selectively bind to target proteins, including estrogen receptors, and can be useful in treating diseases regulated through estrogen receptors, particularly cancers such as breast, endometrial, ovarian, and uterine cancers.

[0305] Target protein binding moieties according to the present disclosure can include, for example, haloalkane halogenase inhibitors, Hsp90 inhibitors, kinase inhibitors, MDM2 inhibitors, compounds targeting human BET bromodomain-containing proteins, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, immunosuppressive compounds, and compounds targeting the aryl hydrocarbon receptor (AHR). Some of the compounds described below exemplify some of the members of these types of small molecule target protein binding moieties.

[0306] Such small molecule target protein binding moieties also include pharmaceutically acceptable salts, enantiomers, solvates, and polymorphs of these compositions, as well as other small molecules that can target a protein of interest.

[0307] In some embodiments, the target protein binding moiety comprises a heat shock protein (HSP, e.g., HSP90) binder or inhibitor. HSP90 inhibitors used herein include, but are not limited to, N-[4-(3H-imidazo[4,5-C]pyridin-2-yl)-9H-fluoren-9-yl]-succinamide, 8-[(2,4-dimethylphenyl)sulfanyl]-3-pent-4-yn-1-yl-3H-purin-6-amine, 5-[2,4-dihydroxy-5-(1-methylethyl)phenyl]-N-ethyl-4-[4-(morpholin-4-ylmethyl)phenyl]isoxidase, and the like. These include, but are not limited to, sazol-3-carboxamide, PU3, or (4E,6Z,8S,9S,10E,12S,13R,14S,16R)-13-hydroxy-8,14,19-trimethoxy-4,10,12,16-tetramethyl-3,20,22-trioxo-2-azabicyclo[16.3.1] or any of its derivatives (e.g., 17-alkylamino-17-desmethoxygeldanamycin).

[0308] In some embodiments, N-[4-(3H-imidazo[4,5-C]pyridin-2-yl)-9H-fluoren-9-yl]-succinamide is bonded to a linker described herein via its terminal amide group. In some embodiments, 8-[(2,4-dimethylphenyl)sulfanyl]-3-pent-4-yn-1-yl-3H-purin-6-amine is bonded to a linker described herein via its terminal amide group. In some embodiments, 5-[2,4-dihydroxy-5-(1-methylethyl)phenyl]-N-ethyl-4-[4-(morpholin-4-ylmethyl)phenyl]isoxazole-3-carboxamide is bonded to a linker described herein via its terminal amide group (e.g., at the amine or alkyl group on the amine). In some embodiments, PU3 is bonded to a linker described herein via its butyl group. In some embodiments, (4E,6Z,8S,9S,10E,12S,13R,14S,16R)-13-hydroxy-8,14,19-trimethoxy-4,10,12,16-tetramethyl-3,20,22-trioxo-2-azabicyclo[16.3.1] or any of its derivatives is attached to a linker described herein by an amide group.

[0309] In some embodiments, the target protein binding moiety comprises a kinase inhibitor or a phosphatase inhibitor. In some embodiments, the target protein binding moiety comprises a kinase inhibitor. In some embodiments, the kinase inhibitor is a tyrosine kinase inhibitor. In some embodiments, the kinase inhibitor is a VEGFR3 inhibitor. In some embodiments, the kinase inhibitor is an Aurora kinase inhibitor. In some embodiments, the kinase inhibitor is an ALK inhibitor. In some embodiments, the kinase inhibitor is a JAK2 inhibitor. In some embodiments, the kinase inhibitor is an Alk inhibitor. In some embodiments, the kinase inhibitor is a Met inhibitor. In some embodiments, the kinase inhibitor is an Abl inhibitor. In some embodiments, the kinase inhibitor is a B-Raf / Mek inhibitor.

[0310] Non-limiting examples of kinase inhibitors include erlotinib, sunitinib, sorafenib, dasatinib, lapatinib, U09-CX-5279, Y1W, Y1X, 1-ethyl-3-(2-{[3-(1-methylethyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]sulfanyl}benzyl)urea, 2,6-naphthyridine, 07U, YCF, XK9, NXP, N-{4-[(1E)-N- (N-hydroxycarbamimidoyl)ethane-hydrazonoyl]phenyl}-7-nitro-1H-indole-2-carboxamide, afatinib, fostamatinib, gefitinib, lenvatinib, vandetanib, vemurafenib, imatinib, pazopanib, AT-9283, TAE684, nilotinib, NVP-BSK805, crizotinib, JNJ FMX, or foretinib.

[0311] In some embodiments, erlotinib is coupled to a linker described herein through its ether group. In some embodiments, sunitinib is coupled to a linker described herein through its pyrrole moiety. In some embodiments, sorafenib is coupled to a linker described herein through its phenyl moiety. In some embodiments, dasatinib is coupled to a linker described herein through its pyrimidine. In some embodiments, lapatinib is coupled to a linker described herein through the terminal methyl of its sulfonylmethyl group. In some embodiments, U09-CX-5279 is coupled to a linker described herein through its amine (aniline), carboxylic acid, or amine alpha to a cyclopropyl group, or through a cyclopropyl group. In some embodiments, 1-ethyl-3-(2-{[3-(1-methylethyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]sulfanyl}benzyl)urea is coupled to a linker described herein through its propyl group. In some embodiments, Y1W is coupled to a linker described herein through its propyl or butyl group. In some embodiments, 6TP is coupled to a linker described herein through a terminal methyl group attached to an amide moiety. In some embodiments, 07U is coupled to a linker described herein through its secondary amine or terminal amino group. In some embodiments, YCF is coupled to a linker described herein through an ether of its terminal hydroxyl group. In some embodiments, XK9 is coupled to a linker described herein through its terminal hydroxyl group. In some embodiments, NXP is coupled to a linker described herein through its terminal hydrazone group (NXP). In some embodiments, afatinib is coupled to a linker described herein through its aliphatic amine group. In some embodiments, fostamatinib is coupled to a linker described herein through its methoxy group. In some embodiments, gefitinib is coupled to a linker described herein through its methoxy group or ether group. In some embodiments, lenvatinib is coupled to a linker described herein through its cyclopropyl group.In some embodiments, vandetanib is coupled to a linker described herein through its methoxy group or hydroxyl group. In some embodiments, vemurafenib is coupled to a linker described herein through its sulfonylpropyl group. In some embodiments, imatinib is coupled to a linker described herein through its amide group or aniline amine group. In some embodiments, pazopanib is coupled to a linker described herein through its phenyl group or aniline amine group. In some embodiments, AT-9283 is coupled to a linker described herein through its phenyl moiety. In some embodiments, TAE684 is coupled to a linker described herein through its phenyl moiety. In some embodiments, nilotinib is coupled to a linker described herein through its phenyl moiety or aniline amine group. In some embodiments, crizotinib is coupled to a linker described herein through its phenyl moiety or diazole group. In some embodiments, crizotinib is coupled to a linker described herein through its phenyl moiety or diazole group. In some embodiments, JNJ FMX is coupled to a linker described herein through its phenyl moiety.

[0312] In some embodiments, the target protein binding moiety comprises a phosphatase inhibitor. In some embodiments, the phosphatase inhibitor is a protein tyrosine phosphatase inhibitor. In some embodiments, the phosphatase inhibitor is an inhibitor of the SHP-2 domain of a tyrosine phosphatase. Non-limiting examples of phosphatase inhibitors include PTP1B. Non-limiting examples of phosphatase inhibitors are included in Table 4.

[0313] In some embodiments, the target protein binding moiety comprises an MDM inhibitor. In some embodiments, the MDM inhibitor is an MDM2 inhibitor. Non-limiting examples of MDM2 inhibitors include any one of Nutlin-3, Nutlin-2, Nutlin-1, or trans-4-iodo-4'-boranyl-chalcone. In some embodiments, Nutlin-3, Nutlin-2, or Nutlin-1 is bound to a linker described herein via a methoxy group or a hydroxyl group. In some embodiments, Trans-4-iodo-4'-boranyl-chalcone is bound to a linker described herein via its hydroxyl group. Non-limiting examples of MDM2 inhibitors are included in Table 4.

[0314] In some embodiments, the target protein binding moiety comprises a compound that targets a human BET bromodomain-containing protein. In some embodiments, the compound that targets a human BET bromodomain-containing protein is 3,5-dimethylisoxazole. Compounds that target a human BET bromodomain-containing protein are included in Table 4.

[0315] In some embodiments, the target protein binding moiety comprises a compound that inhibits HDAC. Non-limiting examples of compounds that inhibit HDAC are included in Table 4.

[0316] In some embodiments, the target protein binding moiety comprises a compound that inhibits a methyltransferase, such as a lysine methyltransferase. In some embodiments, the methyltransferase is human lysine methyltransferase. In some embodiments, the lysine methyltransferase inhibitor is azacytidine. In some embodiments, azacytidine is attached to a linker described herein via a hydroxy group or an amino group. In some embodiments, the lysine methyltransferase inhibitor is decitabine. In some embodiments, decitabine is attached to a linker described herein via a hydroxy group or an amino group. Non-limiting examples of lysine methyltransferase inhibitors are included in Table 4.

[0317] In some embodiments, the target protein binding moiety comprises an angiogenesis inhibitor. Non-limiting examples of angiogenesis inhibitors include GA-1, estradiol, testosterone, DHT, ovalicin, or fumagillin.

[0318] In some embodiments, the target protein binding moiety comprises an immunosuppressant compound. Non-limiting examples of immunosuppressant compounds include AP21998, glucocorticoids (e.g., hydrocortisone, prednisone, prednisolone, or methylprednisolone), beclomethasone dipropionate, methotrexate, cyclosporine, tacrolimus, rapamycin, or actinomycin. In some embodiments, the glucocorticoid is coupled to a linker described herein via a hydroxyl. In some embodiments, beclomethasone dipropionate is coupled to a linker described herein via a propionate. In some embodiments, methotrexate is coupled to a linker described herein via an ether of its terminal hydroxyl. In some embodiments, cyclosporine is coupled to a linker described herein via a butyl group. In some embodiments, tacrolimus is coupled to a linker described herein via a methoxy group. In some embodiments, rapamycin is coupled to a linker described herein via a methoxy group. In some embodiments, actinomycin is attached to a linker described herein via an isopropyl group.

[0319] In some embodiments, the target protein binding moiety comprises a compound that targets the aryl hydrocarbon receptor (AHR). Non-limiting examples of compounds that target the AHR include apigenin, SR1, or LGC006.

[0320] In some embodiments, the target protein binding moiety comprises a compound that targets the RAF receptor. Non-limiting examples of compounds that target the receptor for RAF are included in Table 4.

[0321] In some embodiments, the target protein binding moiety comprises a compound that targets FKBP. Non-limiting examples of compounds that target FKBP are included in Table 4.

[0322] In some embodiments, the target protein binding moiety comprises a compound that targets the androgen receptor. Non-limiting examples of compounds that target the androgen receptor include any one of RU59063, SARM, DHT, MDV3100, ARN-509, hexahydrobenzisoxazole, or tetramethylcyclobutane. Non-limiting examples of compounds that target the androgen receptor are included in Table 4. In some embodiments, the target protein binding moiety comprises a compound that targets the estrogen receptor. Non-limiting examples of compounds that target the estrogen receptor are included in Table 4.

[0323] In some embodiments, the target protein binding moiety comprises a compound that targets the thyroid hormone receptor. Non-limiting examples of compounds that target the thyroid hormone receptor are included in Table 4.

[0324] In some embodiments, the target protein binding moiety comprises a compound that inhibits HIV protease. Non-limiting examples of compounds that inhibit HIV protease are included in Table 4.

[0325] In some embodiments, the target protein binding moiety comprises a compound that inhibits HIV integrase. Non-limiting examples of compounds that inhibit HIV integrase are included in Table 4.

[0326] In some embodiments, the target protein binding moiety comprises a compound that targets HCV protease. Non-limiting examples of compounds that target HCV protease are included in Table 4.

[0327] In some embodiments, the target protein binding moiety comprises a compound that targets acyl-protein thioesterase-1 and / or -2. Non-limiting examples of compounds that target acyl-protein thioesterase-1 and / or -2 are included in Table 4.

[0328] In some embodiments, compounds comprising a target protein binding moiety are shown in Table 4. In this table, an "R" or wavy line indicates an optional point of attachment to a linker or other molecule, such as a DCAF1 binding moiety.

[0329] [Table 4-1]

[0330] [Table 4-2]

[0331] [Table 4-3]

[0332] [Table 4-4]

[0333] [Table 4-5]

[0334] [Table 4-6]

[0335] [Table 4-7]

[0336] [Table 4-8]

[0337] [Table 4-9]

[0338] [Table 4-10]

[0339] [Table 4-11]

[0340] [Table 4-12]

[0341] [Table 4-13]

[0342] [Table 4-14]

[0343] [Table 4-15]

[0344] Heterobifunctional Compounds Described herein are heterobifunctional compounds. Such compounds can be useful for a variety of purposes, including as molecular binders or targeted proteolytic agents for proteins of interest. The heterobifunctional compounds can be small molecules. The heterobifunctional compounds can be included in the methods of treatment or use described herein. For example, the heterobifunctional compounds can be administered to a subject in a pharmaceutical composition.

[0345] As used herein, "subject" refers to a human or non-human animal subject. Examples of subjects include humans and other mammals, such as dogs, cats, cows, mice, rats, monkeys, or other non-human primates. In some preferred embodiments, the subject is a human. A subject may include, for example, a human or veterinary patient, or a human or veterinary subject participating in a clinical trial.

[0346] As used herein, the term "treat" or "treating" means administering a compound, salt, or composition described herein to a subject having a disease or disorder, such as cancer, to achieve at least one positive therapeutic effect. Such therapeutic effect may include reversing, alleviating, reducing, or slowing the progression of the disease or disorder, or any damage associated with any symptom thereof. The term "treatment," as used herein, unless otherwise specified, refers to the act of treating as "treating," as defined above.

[0347] In some embodiments herein, Z 1 L 1 Heterobifunctional compounds of Formula (I) or Formula (II), or compounds of Formula (X), wherein -P, and pharmaceutically acceptable salts, as well as pharmaceutical compositions comprising the compounds and salts, are provided. In some embodiments, heterobifunctional compounds are provided comprising a DDB1- and CUL4-associated factor 1 (DCAF1) binding moiety described herein, a linker, and a target protein binding moiety. In some embodiments, the DCAF1 binding moiety is a natural product. In some embodiments, the DCAF1 binding moiety is a synthetic product. In some embodiments, the DCAF1 binding moiety covalently binds to DCAF1. In some embodiments, the DCAF1 binding moiety binds non-covalently to DCAF1. In some embodiments, the target protein binding moiety is configured to bind to a target protein.

[0348] Heterobifunctional compounds of Formula (I), Formula (II), or Formula (X) can include a DCAF1 binding moiety according to any of the embodiments described herein. Heterobifunctional compounds of Formula (I), Formula (II), or Formula (X) can include a linker according to any of the embodiments described herein.

[0349] In some embodiments, the compound of Formula (I) or Formula (II) is selected from the group consisting of a compound in Table 1, Table 3, or Table 5, or a salt thereof.

[0350] In some embodiments, the compound of Formula (I) or Formula (II) is a monofunctional intermediate comprising a compound of Table 1 or Table 3, or an analog or salt thereof. In some embodiments, the compound of Formula (I) or Formula (II) is a monofunctional intermediate selected from a compound of Table 1 or Table 3, or an analog or salt thereof.

[0351] In some embodiments, the compound of Formula (I) or Formula (II) is a heterobifunctional compound that includes a monofunctional intermediate comprising a compound of 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 that includes a monofunctional intermediate selected from a compound of Table 1 or Table 3, or an analog or salt thereof.

[0352] In some embodiments, the compound of Formula (I) or Formula (II) is a heterobifunctional compound, including a monofunctional intermediate comprising a compound of Table 2, or an analog or salt thereof.

[0353] In some embodiments, the compound of Formula (I) or Formula (II) is a heterobifunctional compound selected from the group consisting of the compounds of Table 5 or a pharmaceutically acceptable salt thereof.

[0354] In some embodiments, the compound of formula (I) or formula (II) includes 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.

[0355] In some embodiments, the compound of formula (I) or formula (II) includes 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. In a frequent embodiment, the analog is a compound in which (a) the morpholino moiety is replaced by a piperazine analog, (b) the carboxamide moiety is modified to have a linker installed, or (c) the halo or OH moiety is modified to have a linker installed that can function as a binding site for L 1 -P or L 1 -G, respectively, in each case.

[0356] In some embodiments, the compound of formula (I) or formula (II) is (R)-2-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)-N-(5-(4-(6-((1-(3-fluorophenyl)piperidin-3-yl)amino)pyrimidin-4-yl)piperazin-1-yl)pentyl)acetamide (D-003), (R)-1-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)-3-(2-(2-(2-(4-(6-((1-(3-fluorophenyl)piperidin-3-yl)amino)pyrimidin-4-yl)piperazin-1-yl)ethoxy)ethoxy)ethoxy)propan-1-one (D-006), (R)-2-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)-N-(2-(4-(6-((1-(3-fluorophenyl)piperidin-3-yl)amino)pyrimidin-4-yl)piperazin-1-yl)ethyl)acetamide (D-067), (R)-2-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)-N-(4-(4-(6-((1-(3-fluorophenyl)piperidin-3-yl)amino)pyrimidin-4-yl)piperazin-1-yl)butyl)acetamide (D-068), (R)-2-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)-N-(8-(4-(6-((1-(3-fluorophenyl)piperidin-3-yl)amino)pyrimidin-4-yl)piperazin-1-yl)octyl)acetamide (D-069), (R)-2-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)-N-(2-(2-(4-(6-((1-(3-fluorophenyl)piperidin-3-yl)amino)pyrimidin-4-yl)piperazin-1-yl)ethoxy)ethyl)acetamide (D-070), and (R)-1-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)-3-(2-(4-(6-((1-(3-fluorophenyl)piperidin-3-yl)amino)pyrimidin-4-yl)piperazin-1-yl)ethoxy)propan-1-one (D-076), or a pharmaceutically acceptable salt thereof.

[0357] In some embodiments, the compound of Formula (I) or Formula (II) is selected from the group consisting of D-079, D-080, D-081, or D-082, or a pharmaceutically acceptable salt thereof.

[0358] In some embodiments, 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.

[0359] In some embodiments, the compound of Formula (I) or Formula (II) is selected from the group consisting of D-201, D-202, D-203, or D-208, or a pharmaceutically acceptable salt thereof.

[0360] In a further aspect herein, a compound of formula (X) T 1 -L 2 -T 2 Formula (X) The compound is described, wherein T 1 is the target protein binding moiety, L2 is a divalent chemical linker, T 2 is the DCAF1 binding moiety,

[0361] The compound of formula (X) may include a compound of formula (I) or formula (II). The heterobifunctional compound may include a compound of formula (I) or formula (II). The heterobifunctional compound may include a compound of formula (X). The linker L in the compound of formula (I) or formula (II) 1 Each of the embodiments described herein for use as a linker, including use as 2 Each of the embodiments described herein for use as a target protein binding moiety, including use as a target protein binding moiety P in a compound of Formula (I) or Formula (II), may also be suitable for use as a target protein binding moiety T in a compound of Formula (X). 1 may also be suitable for use herein as

[0362] A heterobifunctional compound can include any embodiment of a compound shown in Table 5, such as a DCAF1-binding moiety, a linker, a target protein-binding moiety, or a combination thereof. In some examples, a heterobifunctional compound in Table 5 is referred to as a heterobifunctional compound. In some examples, a compound including a DCAF1-binding moiety, a linker, and a target protein-binding moiety is referred to as a heterobifunctional compound.

[0363] [Table 5-1]

[0364] [Table 5-2]

[0365] [Table 5-3]

[0366]

Table 5-4

[0367]

Table 5-5

[0368]

Table 5-6

[0369]

Table 5-7

[0370]

Table 5-8

[0371]

Table 5-9

[0372]

Table 5-10

[0373]

Table 5-11

[0374]

Table 5-12

[0375]

Table 5-13

[0376]

Table 5-14

[0377]

Table 5-15

[0378]

Table 5-16

[0379]

Table 5-17

[0380]

Table 5-18

[0381]

Table 5-19

[0382]

Table 5-20

[0383]

Table 5-21

[0384]

Table 5-22

[0385]

Table 5-23

[0386]

Table 5-24

[0387]

Table 5-25

[0388]

Table 5-26

[0389]

Table 5-27

[0390]

Table 5-28

[0391]

Table 5-29

[0392]

Table 5-30

[0393]

Table 5-31

[0394]

Table 5-32

[0395]

Table 5-33

[0396]

Table 5-34

[0397]

Table 5-35

[0398]

Table 5-36

[0399]

Table 5-37

[0400]

Table 5-38

[0401]

Table 5-39

[0402]

Table 5-40

[0403]

Table 5-41

[0404]

Table 5-42

[0405]

Table 5-43

[0406]

Table 5-44

[0407]

Table 5-45

[0408]

Table 5-46

[0409]

Table 5-47

[0410]

Table 5-48

[0411]

Table 5-49

[0412]

Table 5-50

[0413]

Table 5-51

[0414]

Table 5-52

[0415]

Table 5-53

[0416]

Table 5-54

[0417]

Table 5-55

[0418]

Table 5-56

[0419]

Table 5-57

[0420]

Table 5-58

[0421]

Table 5-59

[0422]

Table 5-60

[0423]

Table 5-61

[0424]

Table 5-62

[0425]

Table 5-63

[0426]

Table 5-64

[0427] [Table 5-65]

[0428] [Table 5-66]

[0429] [Table 5-67]

[0430] [Table 5-68]

[0431] [Table 5-69]

[0432] The compounds described herein may be useful for binding to DDB1- and CUL4-associated factor 1 (DCAF1) and / or binding to and / or degrading a target protein, subsequently inducing a cellular effect, and / or inhibiting a microorganism, such as a virus or bacteria. In some embodiments, the compounds are used as antiviral drugs. For example, compounds, such as compounds containing the ligands described herein, may compete with one or more viral proteins. In some embodiments, the compounds are used as antiparasitic drugs. In some embodiments, the compounds are used as molecular glues, holding two molecules together, such as DCAF1 protein and / or a target protein. In some embodiments, the compounds are used as degraders. For example, the heterobifunctional compounds described herein can be used as targeted protein degraders.

[0433] Preparation of compounds The compounds used in the chemical reactions described herein can be made according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and / or compounds described in the chemical literature. "Commercially available chemicals" include Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancarshire, UK), BDH Inc. (Toronto, Canada), Bionet (Cornwall, UK), Chemservice Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, UK), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, UK), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CT), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hannover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[0434] Suitable references and papers detailing the synthesis of reactants useful in preparing the compounds described herein or providing references to articles describing their preparation include, for example, "Synthetic Organic Chemistry," John Wiley & Sons, Inc., New York; "Organic Functional Group Preparations," by S.R. Sandler et al., 2nd ed., Academic Press, New York, 1983; "Modern Synthetic Reactions," by H.O. House, 2nd ed., W.A. Benjamin, Inc., Menlo Park, Calif., 1972; "Heterocyclic Chemistry," by T.L.G. Gilchrist, 2nd ed., John Wiley & Sons, New York, 1992; and "Advanced Organic Chemistry: Reactions, Mechanisms and Structure," by J. March, 4th ed., Wiley-Interscience, New York, 1992. Additional suitable references and papers that detail the synthesis of reactants useful in the preparation of the compounds described herein or provide references to articles describing their preparation include, for example, "Organic Synthesis: Concepts, Methods, Starting Materials" by Fuhrhop, J. and Penzlin G., 2nd Edition, Revised and Enlarged Edition (1994) John Wiley & Sons, ISBN: 3-527-29074-5; "Organic Chemistry, An Intermediate Text" by Hoffman, RV (1996) Oxford University Press, ISBN 0-19-509618-5; "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" by Larock, RC, 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4;"Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2, "Modern Carbonyl Chemistry" by Otera, J. (ed.) (2000) Wiley-VCH, ISBN: 3-527-29871-1, "Patai's 1992 Guide to the Chemistry of Functional Groups" by Patai, S. (1992) Interscience ISBN: 0-471-93022-9, "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0, "Intermediate Organic Chemistry" by Stowell, JC "Chemistry," 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2, "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes, "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes, and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes.

[0435] Alternatively, specific and similar reactants can be identified by an index of known chemicals and reactants prepared by the Chemical Abstract Service of the American Chemical Society, which is available through most public and university libraries as well as through online databases (for more information, contact the American Chemical Society in Washington, D.C.). Chemicals that are known but not commercially available in catalogs are optionally prepared by specialized chemical synthesis laboratories, where many of the standard chemical supply facilities (e.g., those listed above) offer specialized synthesis services. With regard to the preparation and selection of pharmaceutical salts of the compounds described herein, see "Handbook of Pharmaceutical Salts" by P.H. Stahl & C.G. Wermuth, Verlag Helvetica Chimica Acta, Zurich 2002.

[0436] The compounds described herein can be prepared using conventional methods in the art of organic synthesis, as described in the Examples section. Alternative synthetic methods can also be used to produce the compounds described herein.

[0437] Characterization of exemplary compounds DCAF1 functions as a substrate recruitment receptor for the DDB1-CUL4-ROC1 E3 ubiquitin ligase (CRL4). DCAF1 is often hijacked by viral proteins to degrade cellular proteins, creating favorable conditions for the virus. Structural analysis revealed the WD40 repeat region (1058-1396) of DCAF1 as a viral protein binding site and a highly druggable pocket for ligand development. The binding affinity of specific exemplary compounds to DCAF1(1058-1396), a fragment of the DCAF1 protein containing amino acid residues A1058 to E1396, was determined by surface plasmon resonance (SPR) assay. Briefly, biotinylated and avi-tagged DCAF1(1058-1396) protein was immobilized on a streptavidin (SA) sensor chip at a density of 9,000–10,000 resonance units (RU). Sensorgrams were recorded at different concentrations of compound in a multi-cycle fast kinetic format. Data were analyzed using a steady-state affinity model through Biacore Evaluation Software to determine the equivalent dissociation constant (K d The data show that exemplary compounds bind to DCAF1 in a concentration-dependent manner, with some binding affinity (K d ) ranged from 10 μM to 100 μM (Tables 6 and 7, Figure 2).

[0438] Some compounds are expected to covalently bind to DCAF1. Covalent binding can be achieved by Michael addition, where a cysteine ​​(CYS) residue in DCAF1, such as CYS1227 or CYS1113, serves as a Michael donor for a compound from Table 1 or Table 3, which can function as a Michael acceptor in the reaction. Covalent binding of compounds to DCAF1 was determined by intact mass spectrometry. Briefly, purified DCAF1(1058-1396) protein (5 μM) was incubated with a 40 molar excess of a putative DCAF1 ligand (200 μM) at room temperature for 8 hours. The resulting samples were separated using UPLC and analyzed using a built-in high-performance mass spectrometer. The molecular weight of DCAF1 protein incubated with solvent was tested as a control. The data indicate that some exemplary compounds could readily react covalently with DCAF1 (Table 8, Figure 3).

[0439] Certain exemplary heterobifunctional compounds are designed to target various target proteins by conjugating DCAF1 ligands with various substrate ligands (warheads), such as TL13-87 (a pan-kinase inhibitor targeting many CDKs, Huang et al., 2018), JQ-1 (a BRD4 inhibitor), PF-06873600 (a CDK2 / 4 / 6 inhibitor, Freeman-Cook, KD et al., J Med Chem 2021, 64(13), pp. 9056-9077), palbociclib (a selective CDK4 / 6 inhibitor), PF-07220060 (a selective CDK4 inhibitor, U.S. Patent Application No. 2019330196, 2019), and lasofoxifene (a selective estrogen receptor modulator (SERM)). Heterobifunctional compounds using TL13-87 as the warhead were characterized on MOLT-4 cells. Cells were treated with selected heterobifunctional compounds at the indicated concentrations for 8 hours. Cells were harvested, lysed, and subjected to immunoblotting using antibodies specific for CDK4 protein. GAPDH or tubulin were included as loading controls. DMSO treatment was used as a negative control. Following treatment with various heterobifunctional compounds, CDK4 protein levels in MOLT-4 cells were significantly reduced in a concentration-dependent manner, whereas the E3 ligand CYCA-117-70 (N-(1-(3-fluorophenyl)piperidin-3-yl)-6-morpholinopyrimidin-4-amine) and the warhead TL13-87 did not dramatically affect CDK4 protein levels (Figure 4, Table 9).

[0440] Exemplary heterobifunctional compounds using JQ-1 as a warhead were characterized in MV4;11 cells. After 8 hours of treatment with the heterobifunctional compounds, BRD4 protein levels were significantly reduced in samples treated at 10 μM (Figure 5A, Table 10). MV4;11 cells were also treated with 10 μM D-025 or D-028 for the indicated time periods. Significant degradation of BRD4 was readily detected as early as 4 hours after compound administration (Figure 5B). Targeting BRD4 to the bromodomain with ligands has been demonstrated to impair cancer cell proliferation and survival. MV4;11 AML cells plated in 96-well plates were treated with 10 μM of selected heterobifunctional compounds, followed by 11 three-fold serial dilutions. After 3 days of treatment, cell viability was determined using the CellTiter-Glo kit. Cell viability was normalized to the mean value of three replicates of untreated cells. Dose-dependent responses were analyzed using GraphPad Prism software according to least-squares nonlinear regression. The heterobifunctional compounds inhibited the viability of MV4;11 AML cells in a dose-dependent manner (Figure 6, Table 10).

[0441] An exemplary heterobifunctional compound using PF-06873600 as the warhead was characterized in ER+ breast cancer T47D cells and NSCLC Calu-1 cells. After 16 hours of treatment, the heterobifunctional compound significantly reduced cyclin D1 and CDK4 protein levels and inhibited downstream Rb phosphorylation in a concentration-dependent manner (Figures 7A-7B, Table 11). The warhead PF-06873600 did not affect cyclin D1 and CDK4 protein levels at the indicated concentrations.

[0442] An exemplary heterobifunctional compound using palbociclib as a warhead was characterized in ER+ breast cancer T47D cells. After 16 hours of treatment with the heterobifunctional compound at the indicated concentrations, cyclin D1 protein levels were significantly reduced in samples treated with 5 μM, while downstream Rb phosphorylation and cyclin A2 protein levels were also inhibited in a concentration-dependent manner (Figure 8). The warhead palbociclib did not dramatically affect cyclin D1 protein levels.

[0443] An exemplary heterobifunctional compound using PF-07220060 as the warhead was characterized against breast cancer MDA-MB-157 cells. After 16 hours of treatment with the heterobifunctional compound, cyclin D1 protein levels were significantly reduced in samples treated with 5 μM, whereas the warhead PF-07220060 did not dramatically affect cyclin D1 protein levels (Figure 9).

[0444] Exemplary heterobifunctional compounds using lasofoxifene as a warhead were characterized against ER+ breast cancer T47D cells. After 24 hours of treatment with the representative heterobifunctional compounds under serum-free conditions, ERα protein levels were significantly reduced in samples treated at 1 μM, whereas the warhead lasofoxifene had no significant effect on ERα protein levels at 1 μM (Table 12).

[0445] As described herein, DCAF1 ligands conjugated with different target protein binding moieties can regulate cellular target protein levels of proteins of interest, including, for example, CDK4, cyclin D1, BRD4, and ERα. These results support the use of DCAF1 ligands in targeted protein degradation technology.

[0446] Methods for binding or regulating DCAF1 In some embodiments, the compounds described herein are used to bind to DCAF1 protein. The compounds may include compounds in Tables 1, 2, 3, or 5. In some embodiments, the compounds described herein are used to modulate DCAF1 protein. In some embodiments, the compounds described herein are used to inhibit DCAF1 protein. Some embodiments include contacting DCAF1 protein with a compound described herein. The contacting may include administering the compound to a subject containing DCAF1 protein. The contacting may include administering the compound to a cell containing DCAF1 protein. The contacting may include administering the compound to a sample containing DCAF1 protein. The contacting may include administering the compound to a solution containing DCAF1 protein. The contacting may occur in vivo. The contacting may occur in vitro. The compound may bind to DCAF1 protein with a binding affinity described herein.

[0447] In some embodiments, contacting the compound with the DCAF1 protein comprises contacting the compound with a binding region on the DCAF1 protein, i.e., a binding region comprising a WD40 domain. In some embodiments, 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.

[0448] In some embodiments, the compounds described herein bind to DCAF1 proteins, such as full-length DCAF1 proteins. In some embodiments, the compounds described herein bind to DCAF1 fragments.

[0449] Treatment methods and pharmaceutical compositions In certain embodiments, the compounds described herein are used to treat a subject. Some embodiments include administering a compound described herein to a subject, e.g., a compound included in any of Tables 1-5 or Formula (I) or Formula (II). Some embodiments include administering a compound comprising a DCAF1-binding moiety to a subject. Some embodiments include administering a heterobifunctional compound comprising a DCAF1-binding moiety to a subject. Some embodiments include administering a compound comprising a structure in Table 1. Some embodiments include administering a compound in Table 1. Some embodiments include administering a compound comprising a structure in Table 2. Some embodiments include administering a compound in Table 2. Some embodiments include administering a compound comprising a structure in Table 3. Some embodiments include administering a compound in Table 3. Some embodiments include administering a compound comprising a structure in Table 4. Some embodiments include administering a compound comprising a structure in Table 5. Some embodiments include administering a compound in Table 5. Some embodiments include administering a compound comprising an aspect, such as the 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 of treatment. 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.

[0450] In some embodiments, the modified proteins disclosed herein are formed in vivo after administration of a compound or pharmaceutical composition to a subject. In some embodiments, the ligand-protein complexes disclosed herein are formed by administration of a compound or pharmaceutical composition to a subject.

[0451] In certain embodiments, the compounds described herein are administered as pure chemicals. In other embodiments, the compounds described herein are combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient, or a physiologically suitable (or acceptable) carrier) selected based on the chosen route of administration and standard pharmaceutical practice, as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)). One embodiment provides a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0452] Provided herein are pharmaceutical compositions comprising at least one compound described herein, or its stereoisomer, pharmaceutically acceptable salt, or N-oxide, together with one or more pharmaceutically acceptable carriers. A carrier (or excipient) is acceptable or suitable if it is compatible with the other components of the composition and not harmful to the recipient (i.e., subject or patient) of the composition. In some embodiments, the excipient comprises a buffer or solution. In some embodiments, the pharmaceutical composition is sterile.

[0453] In certain embodiments, the compounds described herein are substantially pure in that they contain less than about 5%, or less than about 1%, or less than about 0.1% of other small organic molecules, such as unreacted intermediates or synthetic by-products arising from one or more of the steps of the synthetic method.

[0454] Some embodiments include the use of a compound described herein, a ligand-DCAF1 complex, or an in vivo modified DCAF1 protein. The use may include use as an antiviral drug. The use may include use as a molecular glue. The use may include use as a targeted proteolytic agent. In some embodiments, the use includes administering the compound to a subject. In some embodiments, the use includes contacting a sample with the compound.

[0455] Some embodiments herein provide a method for degrading a target protein in a subject. Some embodiments include administering a ligand described herein to the subject. Some embodiments include administering to the subject a ligand comprising a DNA damage binding protein 1 (DCAF1) binding moiety covalently linked to the target protein binding moiety by a linker. In some embodiments, the subject is a subject in need of administration of a ligand or in need of treatment with a ligand. Some embodiments include a method for modulating a target protein, comprising administering a therapeutically effective amount of a compound described herein (e.g., a heterobifunctional compound) to a subject in need thereof. In some embodiments, the target protein is reduced in the subject compared to a baseline measurement. After administering a heterobifunctional compound described herein to a subject, the measurement of the target protein may be reduced in a tissue or fluid sample from the subject compared to a baseline target protein measurement in a first tissue or fluid sample from the subject. Some embodiments include measuring the reduction of CDK after administration.

[0456] Some embodiments include obtaining a baseline measurement of the target protein. The baseline measurement may be obtained in a first sample obtained before administering a compound described herein to a subject. The first sample may include a fluid sample. The first sample may include a tissue sample. The baseline measurement may be obtained directly from the subject. The baseline measurement may include a concentration. The baseline measurement may be normalized to, for example, sample weight, sample volume, total sample protein measurement, or housekeeping protein measurement.

[0457] Some embodiments include obtaining a measurement of a target protein. The measurement may be obtained in a second sample obtained after administering a compound described herein to a subject. The measurement may be obtained in a second sample obtained during administration of a compound described herein to a subject. The second sample may include a fluid sample. The second sample may include a tissue sample. The measurement may be obtained directly from the subject. The measurement may be normalized to, for example, sample weight, sample volume, total sample protein measurement, or housekeeping protein measurement.

[0458] The measurement or baseline measurement of the target protein may include any method known in the art. For example, the measurement or baseline measurement may be obtained using an assay such as an immunoassay, a colorimetric assay, a lateral flow assay, a fluorescent assay, a proteomics assay, or a cell-based assay. The immunoassay may include an immunoblot such as a Western blot or a dot blot, an enzyme-linked immunosorbent assay, or immunostaining. The proteomics assay may include mass spectrometry. The measurement or baseline measurement may be obtained using flow cytometry. The measurement or baseline measurement may be obtained using chromatography, for example, high-performance liquid chromatography.

[0459] The target protein may be or include any of the target proteins included herein, as well as other target proteins not specified. Some embodiments include methods of degrading cyclin-dependent kinases (CDKs). Some embodiments include methods of degrading target proteins including CDKs. Some examples of such cyclin-dependent kinases include, but are not limited to, CDK4 or CDK6. Some embodiments include methods of modulating CDKs, comprising administering a therapeutically effective amount of a compound (e.g., a heterobifunctional compound) described herein to a subject in need thereof. In some embodiments, CDK is decreased in the subject compared to baseline measurements. Some embodiments include measuring the decrease in CDK after administration.

[0460] Some embodiments include methods of degrading a cyclin. Some embodiments include methods of degrading a target protein that includes a cyclin. Some examples of such cyclins include cyclin D, such as cyclin D1, cyclin D2, cyclin D3, or cyclin E. Some embodiments include methods of modulating a cyclin, comprising administering a therapeutically effective amount of a compound described herein (e.g., a heterobifunctional compound) to a subject in need thereof. Some embodiments include methods of modulating cyclin D, comprising administering a therapeutically effective amount of a compound described herein (e.g., a heterobifunctional compound) to a subject in need thereof. In some embodiments, the cyclin is decreased in the subject compared to a baseline measurement. Some embodiments include measuring the decrease in the cyclin after administration.

[0461] Some embodiments include methods of degrading a transcription factor. Non-limiting examples of transcription factors include CBP and P300. Some embodiments include methods of degrading a target protein comprising CBP or P300. Some embodiments include methods of degrading a target protein comprising CBP. Some embodiments include methods of degrading a target protein comprising P300. Some embodiments include methods of modulating a transcription factor, comprising administering a therapeutically effective amount of a compound described herein (e.g., a heterobifunctional compound) to a subject in need thereof. In some embodiments, the transcription factor is decreased in the subject compared to a baseline measurement. Some embodiments include measuring the decrease in the transcription factor after administration. Additional examples of target proteins are included herein.

[0462] Examples of subjects include vertebrates, animals, mammals, dogs, cats, cows, rodents, mice, rats, primates, monkeys, and humans. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0463] In some embodiments, administering the ligand to the subject comprises administering an effective amount of the ligand sufficient to degrade the target protein. In some embodiments, after administering the ligand to the subject, the target protein is ubiquitinated to form a ubiquitinated target protein. In some embodiments, the administration is intravenous. In some embodiments, the administration comprises injection. In some embodiments, the administration comprises dermal administration. In some embodiments, the administration comprises subcutaneous administration. In some embodiments, the administration comprises intraperitoneal administration. In some embodiments, the administration comprises oral administration. In some embodiments, the route of administration is intravenous, oral, subcutaneous, intraperitoneal, ocular, intraocular, intramuscular, intrainterstitial, intraarterial, intracranial, intraventricular, intrasynovial, transepithelial, transdermal, inhalation, ophthalmic, sublingual, buccal, topical, cutaneous, rectal, nasal, insufflation, or nebulization. In some embodiments, the administration is intramuscular. In some embodiments, the administration is intrathecal. In some embodiments, the administration is subcutaneous. In some embodiments, the administration is oral. In some embodiments, the administration is sublingual. In some embodiments, administration is buccal. In some embodiments, administration is rectal. In some embodiments, administration is vaginal. In some embodiments, administration is ocular. In some embodiments, administration is otic. In some embodiments, administration is nasal. In some embodiments, administration is by inhalation. In some embodiments, administration is by nebulization. In some embodiments, administration is dermal. In some embodiments, administration is topical. In some embodiments, administration is transdermal. In some embodiments, administration is systemic.

[0464] In some embodiments herein, a method for degrading target protein in a sample is provided.Some embodiments comprise contacting target protein with the ligand described herein.Some embodiments comprise contacting target protein with the ligand comprising DNA damage binding protein 1 (DCAF1) binding moiety, which is covalently connected to target protein binding moiety by a linker.

[0465] In some embodiments, the sample is a biological sample. In some embodiments, the biological sample comprises tissue, cells, or bodily fluid. In some embodiments, the contacting occurs in vitro. In some embodiments, the contacting occurs in vivo. In some embodiments, the target protein is ubiquitinated after contact with the ligand to form a ubiquitinated target protein.

[0466] In some embodiments, after administration or contact, the ubiquitinated target protein is degraded. In some embodiments, the ubiquitinated target protein is degraded. In some embodiments, the degradation of the target protein is specific to the target protein. In some embodiments, the target protein undergoes proteasomal degradation. In some embodiments, the target protein is degraded by the proteasome.

[0467] In some embodiments, after administration or contact, the ligand binds to the DCAF1 protein to form a ligand-DCAF1 complex. In some embodiments, the ligand binds directly to the DCAF1 protein via the DCAF1-binding moiety of the ligand. In some embodiments, the bond between the DCAF1-binding moiety and the DCAF1 protein is non-covalent. In some embodiments, the bond between the DCAF1-binding moiety and the DCAF1 protein is covalent. In some embodiments, the target protein is ubiquitinated by a ubiquitin E3 ligase complex comprising the DCAF1 protein. In some embodiments, the ligand (e.g., a DCAF1 ligand) recruits the ubiquitin E3 ligase complex to the target protein via the DCAF1-binding moiety. In some embodiments, the ligand is a small molecule. In some embodiments, the ligand comprises a targeted protein degradation agent. In some embodiments, the ligand is synthetic. In some embodiments, the ligand comprises a ligand described herein.

[0468] The target protein to be degraded using the methods described herein can be or include any of the target proteins described herein. In some embodiments, the target protein includes any one of transcription factors, CBP, p300, kinases, receptors, TRK, TrkA, TrkB, TrkC, cyclin-dependent kinases, CDK4, or CDK6. Some embodiments include multiple target proteins, such as a combination of any two or more of the target proteins disclosed herein.

[0469] The compounds described herein (e.g., compounds comprising a DCAF1-binding moiety) may be useful for: 1) antiviral agents; 2) DCAF1 protein level modulators (e.g., increasing or decreasing DCAF1 protein levels); 3) DCAF1 function modulators (e.g., activating or inhibiting DCAF1); 4) molecular binding (e.g., increasing protein-protein interaction between DCAF1 and another protein); 6) affecting the activity or protein level of a second protein via molecular binding function; 7) decreasing the protein level of a second protein via molecular binding function; 8) decreasing the activity of a second protein via molecular binding function; or 9) increasing the activity of a second protein via molecular binding function.

[0470] The compounds described herein can be useful for treating disease or disorder. For example, the compounds can be administered to a subject with disease or disorder. Administration can reduce the severity of the subject's disease or disorder compared to baseline measurements. The compounds can bind to target proteins involved in disease or disorder, leading to the inhibition or degradation of the target protein. The compounds can be heterobifunctional compounds and can include a DCAF1 binding portion and a target protein binding portion, where the target protein is involved in disease or disorder. The target protein can exacerbate disease or disorder. The target protein can prevent or reduce the inhibition of disease or disorder.

[0471] In some embodiments, the compounds described herein are used as antibacterial agents. For example, the compounds can be administered to a subject with a microbial infection. Administration can reduce the severity of the subject's microbial infection from baseline measurements. The compounds can bind to a target protein involved in the microbial infection, resulting in the inhibition or degradation of the target protein. The microbial infection can include a viral infection. The microbial infection can include a bacterial infection. The compounds can be heterobifunctional compounds and can include a DCAF1-binding moiety and a target protein-binding moiety, where the target protein is a microbial protein. The microbial protein can include a viral protein. The microbial protein can include a bacterial protein. The target protein can be a non-microbial protein that exacerbates the microbial infection. The target protein can be a non-microbial protein that prevents or reduces the inhibition of the microbial infection. In some embodiments, the compounds enter a subject's cells, bind to a cellular microbial protein via its target protein-binding moiety, bind to DCAF1 via its DCAF1-binding moiety, and induce ubiquitin-mediated degradation of the microbial protein. Such an effect can be useful against microorganisms, such as bacteria or viruses, that infect or reside within cells.

[0472] The compounds described herein may be useful for regulating DCAF1 protein levels. For example, the compounds may be used to increase or decrease DCAF1 protein levels. In some embodiments, compounds comprising a DCAF1-binding moiety described herein are used to increase DCAF1 protein levels. For example, the compounds may bind to DCAF1 and prevent its degradation. In some embodiments, compounds comprising a DCAF1-binding moiety described herein are used to decrease DCAF1 protein levels. For example, the compounds may bind to DCAF1 and increase its degradation. The compounds may be heterobifunctional compounds and may include a DCAF1-binding moiety linked (directly or via a linker) to a second moiety that increases DCAF1 protein degradation or decreases DCAF1 protein degradation. The second moiety may accomplish this by binding to a target protein. In some such embodiments, the target protein may include an E3 ubiquitin ligase protein that enhances DCAF1 protein degradation. In some embodiments, the compounds are not heterobifunctional compounds. In some embodiments, the compounds include or consist of a DCAF1-binding moiety. In some embodiments, the compound comprises, consists essentially of, or consists of the structure of Formula (I) or Formula (II), an aspect thereof, such as a DCAF1-binding moiety, or a compound provided in Table 1, Table 2, or a derivative or salt thereof. In some embodiments, the compound is administered to a subject to increase the subject's DCAF1 protein level. The administration may increase the subject's DCAF1 activity above baseline measurements. In some embodiments, the compound is administered to a subject to decrease the subject's DCAF1 protein level. The administration may decrease the subject's DCAF1 activity below baseline measurements.

[0473] The compounds described herein can be useful for modulating DCAF1 function. For example, the compounds can be used to activate or inhibit DCAF1. In some embodiments, compounds comprising a DCAF1-binding moiety described herein are used to increase DCAF1 activity. For example, the compounds can bind to DCAF1 and activate it. The compounds can allosterically activate DCAF1. The compounds can activate DCAF1 by binding to a protein binding site on DCAF1. In some embodiments, compounds comprising a DCAF1-binding moiety described herein are used to decrease DCAF1 activity. For example, the compounds can bind to DCAF1 and inhibit it. The compounds can allosterically inhibit DCAF1. The compounds can inhibit DCAF1 by binding to the active site of DCAF1. The compounds can inhibit DCAF1 by binding to a protein binding site on DCAF1. The compound may be a heterobifunctional compound and may include a DCAF1 binding moiety linked (directly or via a linker) to a second moiety that increases the activity of DCAF1 protein or decreases the activity of DCAF1 protein. The second moiety may accomplish this by binding to the target protein. In some embodiments, the compound is administered to a subject to increase the subject's DCAF1 activity. The administration may increase the subject's DCAF1 activity above baseline measurements. In some embodiments, the compound is administered to a subject to decrease the subject's DCAF1 activity. The administration may decrease the subject's DCAF1 activity below baseline measurements.

[0474] The compounds described herein can be useful as molecular glues. For example, the compounds can bind to multiple molecules and hold them together. In some embodiments, the molecular glue binds to DCAF1 and a target protein. The compounds can accomplish this as heterobifunctional compounds containing a DCAF1-binding portion and a target protein-binding portion. The compounds can increase protein-protein interactions between DCAF1 and the target protein. The compounds can function as molecular glues to regulate the activity or amount of the target protein. As a molecular glue, the compounds can decrease the amount of the target protein. As a molecular glue, the compounds can increase the amount of the target protein. As a molecular glue, the compounds can decrease the activity of the target protein. As a molecular glue, the compounds can increase the activity of the target protein.

[0475] Some embodiments disclosed herein are methods for degrading a target protein in a cell. 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 is sometimes referred to as cross-link 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 to 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 degrading the target protein by administering to a subject a binding molecule that binds to a first protein that interacts with the target protein, where the target protein is degraded before the first protein or 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, 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 includes a cyclin. In some embodiments, the target protein includes cyclin D. In some embodiments, the cyclin D includes 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. In some embodiments, the first protein includes a cyclin-dependent kinase (CDK). The CDK may include CDK4. The CDK may include CDK6. In some embodiments, the first protein includes CDK4 or CDK6.

[0476] In some embodiments, the binding molecule reduces cell viability. In some embodiments, the cell is a eukaryotic cell. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell is a human cell. In some embodiments, the cell is a cancer cell. In some embodiments, administering the binding molecule to the cell comprises administering the binding molecule to a subject comprising the cell. In some embodiments, the binding molecule recruits a ubiquitin E3 ligase that ubiquitinates a target protein. In some embodiments, the E3 ubiquitin ligase comprises DNA damage-binding protein 1 (DCAF1) or von Hippel-Lindau tumor suppressor (VHL). The E3 ubiquitin ligase may comprise DCAF1. The E3 ubiquitin ligase may comprise VHL. In some embodiments, the binding molecule comprises a heterobifunctional compound comprising an E3 ubiquitin ligase binding moiety covalently connected to a first protein binding moiety by a linker. The first protein binding moiety may comprise a target protein binding moiety disclosed herein. In some embodiments, the binding molecule comprises a structure disclosed herein.

[0477] In some embodiments, the binding molecule comprises a heterobifunctional compound including an E3 ubiquitin ligase binding moiety covalently connected to a CDK binding moiety by a linker. In some embodiments, the E3 ubiquitin ligase binding moiety comprises a chemical structure disclosed herein. In some embodiments, the CDK binding moiety comprises a target protein binding moiety disclosed herein. In some embodiments, the binding molecule comprises a ligand disclosed herein.

[0478] Examples of subjects include vertebrates, animals, mammals, dogs, cats, cows, rodents, mice, rats, primates, monkeys, and humans. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0479] In some embodiments, administering a compound to a subject comprises administering an effective amount of the compound. In some embodiments, the administration is intravenous. In some embodiments, the administration comprises injection. In some embodiments, the administration is local. In some embodiments, the administration is systemic.

[0480] In some embodiments, the sample is a biological sample. In some embodiments, the biological sample comprises tissue, cells, or bodily fluid. In some embodiments, the contacting occurs in vitro. In some embodiments, the contacting occurs in vivo.

[0481] definition As used in this specification and the appended claims, the singular forms "a," "and," and "the" include the plural forms unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, reference to "the cell" includes a reference to one or more cells (or cells) and equivalents thereof known to those skilled in the art, and so forth.

[0482] When ranges relating to physical properties, such as molecular weight, or chemical properties, such as chemical formula, are used herein, all combinations and subcombinations of ranges and specific embodiments therein are intended to be encompassed.

[0483] The term "about," when referring to a number or numerical range, means that the referenced number or numerical range is approximate within experimental variation (or within statistical experimental error), and thus the number or numerical range may vary, in some cases, by between 1% and 15% of the stated number or numerical range.

[0484] The term "comprising" (and related terms such as "comprise," "comprises," "having," or "including") is not intended to exclude that in other particular embodiments, embodiments such as, for example, any composition of matter, composition of matter, method, or process described herein, "consist of" or "consist essentially of" the recited features.

[0485] As used in this specification and the appended claims, the following terms have the meanings indicated below, unless expressly stated to the contrary.

[0486] "Amino" refers to the -NH2 radical.

[0487] "Cyano" refers to the -CN radical.

[0488] "Nitro" refers to the -NO2 radical.

[0489] "Oxa" refers to the -O- radical.

[0490] "Oxo" refers to the =O radical.

[0491] "Thioxo" refers to the =S radical.

[0492] "Imino" refers to the =NH radical.

[0493] "Oximo" refers to the =N-OH radical.

[0494] "Hydrazino" refers to the =N-NH2 radical.

[0495] "Alkyl" refers to a group consisting solely of carbon and hydrogen atoms, without unsaturation, having from 1 to 15 carbon atoms (e.g., C1-C 15Alkyl) refers to a straight or branched hydrocarbon chain radical. In certain embodiments, alkyl contains 1 to 13 carbon atoms (e.g., C1-C 13 In some embodiments, an alkyl contains 1 to 8 carbon atoms (e.g., a C1-C8 alkyl). In other embodiments, an alkyl contains 1 to 5 carbon atoms (e.g., a C1-C5 alkyl). In other embodiments, an alkyl contains 1 to 4 carbon atoms (e.g., a C1-C4 alkyl). In other embodiments, an alkyl contains 1 to 3 carbon atoms (e.g., a C1-C3 alkyl). In other embodiments, an alkyl contains 1 to 2 carbon atoms (e.g., a C1-C2 alkyl). In other embodiments, an alkyl contains 1 carbon atom (e.g., a C1 alkyl). In other embodiments, an alkyl contains 5 to 15 carbon atoms (e.g., a C5-C 15 In other embodiments, an alkyl group contains 5 to 8 carbon atoms (e.g., a C5-C8 alkyl). In other embodiments, an alkyl group contains 2 to 5 carbon atoms (e.g., a C2-C5 alkyl). In other embodiments, an alkyl group contains 3 to 5 carbon atoms (e.g., a C3-C5 alkyl). In other embodiments, an 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), and 1-pentyl (n-pentyl). An alkyl group is attached to the remainder of the molecule by a single bond. Unless otherwise specified in the specification, an alkyl group may contain any 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 (t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t R a (t is 1 or 2), and S(O) t N(R a )2 (t is 1 or 2), optionally substituted with one or more of R a are each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0496] "Alkoxy" refers to a radical attached through an oxygen atom of the formula --O-alkyl, where alkyl is an alkyl chain as defined above.

[0497] "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.

[0498] "Heteroalkyl," "heteroalkenyl," and "heteroalkynyl" refer to substituted or unsubstituted alkyl, alkenyl, and alkynyl groups, respectively, having one or more skeletal atoms selected from atoms other than carbon. Exemplary skeletal atoms selected from atoms other than carbon include, for example, O, N, P, Si, S, or combinations thereof, where the nitrogen, phosphorus, and sulfur atoms can be optionally oxidized and the nitrogen heteroatom can be optionally quaternized. When given, numerical ranges refer to the total chain length. For example, a 3-8-membered heteroalkyl has a chain length of 3 to 8 atoms. Connection to the remainder of the molecule can be through either a heteroatom or a carbon in the heteroalkyl, heteroalkenyl, or heteroalkynyl chain. Unless otherwise specified herein, a heteroalkyl, heteroalkenyl, or heteroalkynyl group can be optionally substituted with one or more substituents, such as those described herein.

[0499] "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 2 to 12 carbon atoms. In certain embodiments, an alkenyl contains from 2 to 8 carbon atoms. In other embodiments, an alkenyl contains from 2 to 4 carbon atoms. An alkenyl is attached to the remainder of the molecule by a single bond and is, 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. Unless otherwise specified in the specification, an alkenyl group may contain the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, R a , -OR a , -SRa , -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 (t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t R a (t is 1 or 2), and -S(O) t N(R a )2 (t is 1 or 2), optionally substituted with one or more of R a are each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0500] "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, and having from 2 to 12 carbon atoms. In certain embodiments, an alkynyl contains from 2 to 8 carbon atoms. In other embodiments, an alkynyl contains from 2 to 6 carbon atoms. In other embodiments, an alkynyl contains from 2 to 4 carbon atoms. An alkynyl is attached to the remainder of the molecule by a single bond and is, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless otherwise specified in the specification, an alkynyl group may contain any 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 (t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t R a (t is 1 or 2), and S(O) t N(R a )2 (t is 1 or 2), optionally substituted with one or more of R aare each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0501] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain that connects the rest of the molecule, consists solely of carbon and hydrogen, contains no unsaturation, and has 1 to 12 carbon atoms, e.g., methylene, ethylene, propylene, n-butylene, and the like, linking the radical group to the rest of the molecule. 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 a carbon atom in the alkylene chain or any two carbon atoms within the chain. In certain embodiments, alkylene contains 1 to 8 carbon atoms (e.g., C1-C8 alkylene). In other embodiments, alkylene contains 1 to 5 carbon atoms (e.g., C1-C5 alkylene). In other embodiments, alkylene contains 1 to 4 carbon atoms (e.g., C1-C4 alkylene). In other embodiments, alkylene contains 1 to 3 carbon atoms (e.g., C1-C3 alkylene). In other embodiments, alkylene contains 1 to 2 carbon atoms (e.g., C1-C2 alkylene). In other embodiments, alkylene contains 1 carbon atom (e.g., C1 alkylene). In other embodiments, alkylene contains 5 to 8 carbon atoms (e.g., C5-C8 alkylene). In other embodiments, alkylene contains 2 to 5 carbon atoms (e.g., C2-C5 alkylene). In other embodiments, alkylene contains 3 to 5 carbon atoms (e.g., C3-C5 alkylene). Unless otherwise specified in the specification, an alkylene chain may contain any 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(t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t R a (t is 1 or 2), and -S(O) t N(R a )2 (t is 1 or 2), optionally substituted with one or more of R a are each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0502] "Aryl" refers to a radical derived from a monocyclic or polycyclic aromatic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The monocyclic or polycyclic aromatic hydrocarbon ring system contains only hydrogen and carbon atoms of 5 to 18 carbon atoms, and at least one ring in the ring system is fully unsaturated, i.e., contains a cyclic delocalized (4n+2) π-electron system according to Hückel's theory. Ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene. Unless otherwise defined in this specification, the term “aryl” or the prefix “ar” (such as in “aralkyl”) means any of 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 -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -O-Rc-C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -Rb -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), and -R b -S(O) t N(R a )2, where t is 1 or 2; a are each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl); and R b are each independently a direct bond or a straight or branched alkylene or alkenylene chain; R c is a straight or branched alkylene or alkenylene chain, and unless otherwise specified, each of the above substituents is unsubstituted.

[0503] "Aralkyl" is a group of the formula -R c -aryl radicals, such as methylene and ethylene, where R c is an alkylene chain as defined above. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0504] "Cycloalkyl" refers to a stable, non-aromatic, monocyclic or polycyclic radical, consisting solely of carbon and hydrogen atoms, including fused or bridged ring links, having 3 to 15 carbon atoms. In certain embodiments, cycloalkyls contain 3 to 10 carbon atoms. In other embodiments, cycloalkyls contain 5 to 7 carbon atoms. A cycloalkyl is attached to the remainder of the molecule by a single bond. A cycloalkyl can be saturated (i.e., contains only one C-C bond) or unsaturated (i.e., contains one or more double or triple bonds). A fully saturated cycloalkyl radical is also referred to as a "carbocyclyl." Examples of monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unsaturated cycloalkyls are also referred to as "cycloalkenyls." Examples of monocyclic cycloalkenyls include, for example, 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. Unless otherwise defined in this specification, the term "cycloalkyl" includes alkyl, alkenyl, alkynyl, halo, fluoroalkyl, 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 , -R b -OC(O)-OR a , -R b -OC(O)-N(Ra )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), and -R b -S(O) t N(R a )2, where t is 1 or 2; aare each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl); and R b are each independently a direct bond or a straight or branched alkylene or alkenylene chain; R c is a straight or branched alkylene or alkenylene chain, and unless otherwise specified, each of the above substituents is unsubstituted.

[0505] "Carbocyclylalkyl" and "cycloalkylalkyl" refer to groups of the formula -R c -refers to the cycloalkyl radical, R c is an alkylene chain as defined above. The alkylene chain and the cycloalkyl radical are optionally substituted as defined above.

[0506] "Halo" or "halogen" refers to a bromo, chloro, fluoro, or iodo substituent.

[0507] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted with one or more fluoro radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.

[0508] "Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring radical containing 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specified specifically in the specification, a heterocyclyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, optionally including 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 by any atom of the ring. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless otherwise defined in this specification, the term "heterocyclyl" includes any of the following: alkyl, alkenyl, alkynyl, halo, fluoroalkyl, 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 , -R b -OC(O)-OR a, -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), and -R b -S(O) t N(R a )2 (t is 1 or 2), and R aare each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl); and R b are each independently a direct bond or a straight or branched alkylene or alkenylene chain; R c is a straight or branched alkylene or alkenylene chain, and unless otherwise specified, each of the above substituents is unsubstituted.

[0509] "N-heterocyclyl" or "N-linked heterocyclyl" refers to a heterocyclyl radical, as defined above, containing at least one nitrogen, and the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. The N-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such N-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

[0510] "C-heterocyclyl" or "C-linked heterocyclyl" refers to a heterocyclyl radical, as defined above, containing at least one heteroatom, and the point of attachment of the heterocyclyl radical to the rest of the molecule is through a carbon atom in the heterocyclyl radical. The 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-, 3-, or 4-piperidinyl, 2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.

[0511] "Heteroaryl" refers to a radical derived from a 3- to 18-membered aromatic ring radical containing 2 to 17 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system in which at least one ring in the ring system is fully unsaturated, i.e., contains a cyclic delocalized (4n+2) π-electron system according to Hückel theory. Heteroaryl includes fused or bridged ring systems. Heteroatoms in a heteroaryl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. A heteroaryl is attached to the remainder of the molecule through any atom of the ring. Examples of heteroaryls include azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, 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 (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1, 2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno-[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydro-cycloocta[d]pyridazinyl, 5,6,7,8,9,10-Hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl idinonyl), oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, p Purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydroquinazolinyl Hydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno-[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-d]pyridinyl, and thiophenyl (i.e., thienyl). Unless otherwise specified herein, the term "heteroaryl" includes 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 , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a(t is 1 or 2), and -R b -S(O) t N(R a )2 (t is 1 or 2), and R a are each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl); and R b are each independently a direct bond or a straight or branched alkylene or alkenylene chain; R c is a straight or branched alkylene or alkenylene chain, and unless otherwise specified, each of the above substituents is unsubstituted.

[0512] "N-heteroaryl" refers to a heteroaryl radical, as defined above, containing at least one nitrogen, and the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. The N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0513] "C-heteroaryl" refers to a heteroaryl radical as defined above, where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. The C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0514] In some embodiments, the compounds disclosed herein contain one or more asymmetric centers, thus giving rise to enantiomers, diastereomers, and other stereoisomeric forms defined in terms of absolute stereochemical configuration as (R) or (S). Unless otherwise specified, all stereoisomeric forms of the compounds disclosed herein are intended to be contemplated by the present disclosure. When a compound described herein contains an alkene double bond, and unless otherwise specified, the present disclosure is intended to include both E and Z geometric isomers (e.g., cis or trans). Similarly, all possible isomers, as well as racemic and optically pure forms thereof, and all tautomers, are intended to be included. The term "geometric isomer" refers to E or Z geometric isomers (e.g., cis or trans) of the alkene double bond. The term "positional isomer" refers to structural isomers around a central ring, such as ortho-, meta-, and para-isomers around a benzene ring.

[0515] "Tautomer" refers to a molecule capable of transferring a proton from one atom of the molecule to another atom of the same molecule. The compounds presented herein exist as tautomers in certain embodiments. In situations where tautomerization is possible, a chemical equilibrium of tautomers will exist. The exact ratio of tautomers will depend on various factors, including physical conditions, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

[0516] [ka] Examples include:

[0517] In some embodiments, the compounds disclosed herein are used in various enriched isotopic forms, e.g., 2 H, 3 H, 11 C. 13 C, and / or 14 In one embodiment, the compound is deuterated at at least one position. Such deuterated forms can be prepared by the procedures described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can increase the duration of action of a drug by improving metabolic stability or efficacy.

[0518] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of a hydrogen by deuterium or tritium, or 13 C or 14 Compounds having this structure, except for the replacement of a carbon with a C-rich carbon, are within the scope of this disclosure.

[0519] The compounds of the present disclosure may optionally contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain unnatural proportions of atomic isotopes, such as deuterium ( 2 H), tritium ( 3 H), iodine-125( 125 I), or carbon-14 ( 14 It may be labeled with an isotope such as C. 2 H, 11 C. 13 C. 14 C. 15 C. 12 N, 13 N, 15 N, 16 N, 16 O. 17 O. 14 F, 15 F, 16 F, 17 F,18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, 125 All isotopic substitutions at I are contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0520] In certain embodiments, the compounds disclosed herein are 2 exchanged with H atoms 1 Some or all of the H atoms are present. Methods for synthesizing deuterium-containing compounds are known in the art, and non-limiting examples include the following synthesis methods:

[0521] Deuterium-substituted compounds are synthesized using a variety of methods, including those described in: Dean, Dennis C., ed., Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000;6(10)] 2000, p. 110; 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.

[0522] Deuterated starting materials are readily available and amenable to the synthetic methods described herein to synthesize deuterated compounds. Many deuterated reagents and building blocks are commercially available from chemical suppliers such as Aldrich Chemical Co.

[0523] Unless otherwise specified, all references to compounds herein include references to salts (including pharmaceutically acceptable salts), solvates (including hydrates), and complexes thereof, as well as solvates and complexes of salts thereof, and isotopically labeled variations thereof.

[0524] "Salts" includes both acid addition and base addition salts of the compounds described herein, and encompasses both pharmaceutically acceptable and non-pharmaceutically acceptable salts. Pharmaceutically acceptable salts are utilized for therapeutic or medicinal purposes, while non-pharmaceutically acceptable salts may be useful as synthetic intermediates or for purification, isolation, chiral resolution, solubilization, handling, and the like.

[0525] A "pharmaceutically acceptable salt" is a salt that retains the biological effectiveness and properties of the free base compound and is suitable for administration to a subject. Reference to a "pharmaceutically acceptable salt" includes both acid addition salts 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.

[0526] "Pharmaceutically acceptable acid addition salts" refer to salts that retain the biological effectiveness and properties of the free base, which are not biologically or otherwise undesirable, and 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 formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic acids, and aromatic sulfonic acids, including, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Thus, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Additionally, salts of amino acids such as arginate, gluconate, galacturonate, and the like are contemplated (see, e.g., Berge SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt according to methods and techniques familiar to those skilled in the art.

[0527] A "pharmaceutically acceptable base addition salt" refers to a salt that retains the biological effectiveness and properties of the free acid, which salt is not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals, or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. See Berge et al., supra.

[0528] Where an "optionally substituted" embodiment is described, it is contemplated that the embodiment may be included without optional substituents, i.e., may be substituted or unsubstituted.

[0529] In some embodiments, the compound of Formula (I) or Formula (II) comprises one, two, three, four, or more than four of the following selected features: Z 1 L 1 -P, where L 1 is a bond, or a group of formula -(J), as further defined herein. x - a bivalent chemical linker, P is a target protein binding moiety; E1 is -N(R 8 )-, -(C(R 9 )2) t N(R 8 )-, and -N(R 8 )(C(R 9 )2) t - selected from the group consisting of E 2 is -N(R 8 )-, -(C(R 9 )2) t N(R 8 )-, and -N(R 8 )(C(R 9 )2) t - selected from the group consisting of R 8 are hydrogen; R 9 are each hydrogen or two R 9 are united as oxo; R 1 does not exist (m is 0); R 2 is absent; in formula (I), Q 1 is Y 3 and having the structure of formula (IV): 11 cycloalkyl or a 3- to 11-membered heterocycle; Q 2 is C3-C 11 cycloalkyl or 3- to 11-membered heterocycle, each of which is one or more R 2 and optionally substituted with Z 1 is replaced by Z 1 is L 1 -P; in formula (II), s is 1 and R 4 is present; in formula (II), r is 0 and R 3 is absent; and in formula (II), Y 1 is N or C(R 6 )

[0530] In some preferred embodiments, the compounds of Formula (I) or Formula (II) include one, two, three, four, or more than four of the following selected features, provided that these features are not consistent: A is X 1 Contains one or more R 1A is a 5-6 membered heteroaryl optionally substituted with X 1 and one or more R are selected from pyridine or pyrimidine. 1 X is a 6-membered heteroaryl optionally substituted with 1 is C(R 5A ) or N;Z 1 L 1 -P; P is a target protein binding moiety; Z 1 L 1 -G or Z 2 Z 1 L 1 -G;Z 1 is Z 2 L 1 is a bond or a group of formula -(J) x - is a divalent chemical linker of formula (I); G is a reactive functional group; G is a reactive functional group selected from a protected or unprotected primary or secondary amine, a carboxylic acid, a carboxylic acid ester, a halogen, a hydroxy, or a sulfonate ester; G is a reactive functional group selected from NH, COOH, a halogen, a hydroxy, OMs, or OTs; Z 2 is selected from the group consisting of hydrogen, C1-C4 alkyl, and an amine protecting group; Z 2 is hydrogen; E 1 is a bond, -N(R 8 )-, -(C(R 9 )2) t N(R 8 )-, and -N(R 8 )(C(R 9 )2) t - selected from the group consisting of E 1 is -N(R 8 )-, -(C(R 9 )2) t N(R 8 )-, and -N(R 8 )(C(R 9 )2) t - selected from the group consisting of E 1 is a bond;E 2 is a bond, -N(R8 )-, -(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)—; E 2 is a bond, -NH-, -(CH2) t NH-, -NH(CH2) t -, -C(O)NH-, and -NHC(O)-; E 2 is a bond;E 1 is -NH-, and E 2 is a bond;E 1 is a bond and E 2 is a bond, -NH-, -(CH2) t NH-, -NH(CH2) t -, -C(O)NH-, and -NHC(O)-; R 8 are hydrogen; R 9 are each hydrogen or two R 9 together form oxo; t is an integer of 1 to 4; t is an integer of 1 to 2; m is 0; Q 1 is Y 3 and having the structure of formula (IV): 11 cycloalkyl or a 3- to 11-membered heterocycle; Q 1 is a C3-C aryl group having the structure of formula (IVa), (IVb), or (IVc): 11 cycloalkyl or a 3- to 11-membered heterocycle; Q 1 is a 3- to 11-membered heterocycle having the structure of formula (IVa), (IVb), or (IVc); Q 2 is C3-C 11 cycloalkyl or 3- to 11-membered heterocycle, each of which is one or more R 2 and optionally substituted with Z 1 Replaced by ;Q 2 is one or more R 2 and optionally substituted with Z1 In formula (I), Q is a 3- to 11-membered heterocycle substituted with 2 is Z 1 In formula (II), s is 1; in formula (II), r is 0; in formula (II), Y 1 is N or C(R 6 ) is; A is X 1 Contains one or more R 1 A is a 5-6 membered heteroaryl optionally substituted with X 1 and one or more R are selected from pyridine or pyrimidine. 1 X is a 6-membered heteroaryl optionally substituted with 1 is C(R 5A ) or N.

[0531] In some preferred embodiments, the compounds of Formula (I) or Formula (II) include one, two, three, four, or more than four of the following preferred features, provided that these features are not consistent: 1 L 1 -P; P is a target protein binding moiety; Z 1 L 1 -G or Z 2 L 1 is a bond or a group of formula -(J) x - is a divalent chemical linker of formula (I); G is a reactive functional group; G is a reactive functional group selected from a protected or unprotected primary or secondary amine, a carboxylic acid, a carboxylic acid ester, a halogen, a hydroxy, or a sulfonate ester; G is a reactive functional group selected from NH, COOH, a halogen, a hydroxy, OMs, or OTs; Z 2 is selected from the group consisting of hydrogen, C1-C4 alkyl, and an amine protecting group; Z 2 is hydrogen; E 1 is a bond;E 2 is a bond, -N(R 8 )-, -(C(R 9 )2) t N(R8 )-, -N(R 8 )(C(R 9 )2) t -, -C(O)N(R 8 )-, and -N(R 8 )C(O)—; E 2 is a bond, -NH-, -(CH2) t NH-, -NH(CH2) t -, -C(O)NH-, and -NHC(O)-; R 8 are hydrogen; R 9 are each hydrogen or two R 9 together form oxo; t is an integer of 1 to 4; or t is an integer of 1 to 2.

[0532] Selected Embodiments Preferred embodiments include embodiments E1 to E45, in each case including salts thereof (including pharmaceutically acceptable salts).

[0533] E1. Formula (I)

[0534] [ka] or a salt thereof, wherein A is X 1 C6-C, including 10 aryl or 5-10 membered heteroaryl; X 1 is C(R 5A ), N, N(R 5B ), O, or S; E 1 and E 2 are independently a bond, -N(R 8 )-, -(C(R 9 )2) t N(R 8 )-, -N(R 8 )(C(R 9 )2) t -, -(C(R 9 )2) t N(R8 )(C(R 9 )2) u -, -O-, -(C(R 9 )2) t O-, -O-(C(R 9 )2) t -, -(C(R 9 )2) t O(C(R 9 )2) u -, -(C(R 9 )2) u -, -C(O)-, -C(O)N(R 8 )-, -(C(R 9 )2) t C(O)N(R 8 )-, -C(O)N(R 8 )(C(R 9 )2) t -, -(C(R 9 )2) t C(O)N(R 8 )(C(R 9 )2) u -, -N(R 8 )C(O)-, -(C(R 9 )2) t N(R 8 )C(O)-, -N(R 8 )C(O)(C(R 9 )2) t - and -(C(R 9 )2) t N(R 8 )C(O)(C(R 9 )2) u - selected from the group consisting of Q 1 is C3-C 11 cycloalkyl or 3- to 11-membered heterocycle, each of which is one or more R 3 and optionally substituted with one or more R 4 and optionally further substituted with Q 2 is hydrogen, halogen, CN, Z 1 , C3-C 11 cycloalkyl, and 3- to 11-membered heterocycle; 11Each of the cycloalkyl and 3- to 11-membered heterocycles may be selected from one or more R 2 and optionally substituted with Z 1 and optionally further substituted with R 1 are each independently hydrogen, halogen, CN, OR 10 , S.R. 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 , C1-C6 alkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl, each C1-C6 alkyl being selected from the group consisting of one or more R 11 and each of the C-C cycloalkyl and 3- to 6-membered heterocyclyl is optionally substituted with one or more R 12 optionally substituted with R 2 are each independently hydrogen, fluoro, oxo, thioxo, OR 13 , S.R. 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 , C1-C6 alkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl, each C1-C6 alkyl being selected from the group consisting of one or more R 14 and each of the C-C cycloalkyl and 3- to 6-membered heterocyclyl is optionally substituted with one or more R 15 optionally substituted with R 3 are each independently hydrogen, fluoro, oxo, thioxo, OR 16 , S.R. 16 , N(R 16 )2, C(O)R 16 ,OC(O)R16 , C(O)OR 16 , C(O)N(R 16 )2, N(R 16 )C(O)R 16 , C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, each of the C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl moieties being selected from the group consisting of one or more R 17A optionally substituted with R 4 are each independently hydrogen, C(O)(C2-C6 alkenyl), N(R 16 )C(O)(C2-C6 alkenyl), (C1-C6 alkylene)-N(R 16 )C(O)(C2-C6 alkenyl), C(O)(C2-C6 alkynyl), N(R 16 )C(O)(C2-C6 alkynyl), (C1-C6 alkylene)-N(R 16 )C(O)(C2-C6 alkynyl), C6-C 10 Aryl, 5-10 membered heteroaryl, E 3 -C6-C 10 Aryl, E 3 -5-10 membered heteroaryl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, E 3 -C3-C6 cycloalkyl, and E 3 - 3- to 6-membered heterocyclyl, and each of C-C alkenyl and C-C alkynyl is selected from the group consisting of one or more R 17B and optionally substituted with C6-C 10 Each of the aryl and 5- to 10-membered heteroaryl may be selected from one or more R 18 and each of the C-C cycloalkyl and 3- to 6-membered heterocyclyl is optionally substituted with one or more R 19 optionally substituted with E 3 are each independently -N(R 20 )-, -(C(R 21 )2) y -N(R 20 )-, -N(R 20 )-(C(R21 )2) y -, -O-, -(C(R 21 )2) y -O-, -O-(C(R 21 )2) y - and -(C(R 21 )2) z - selected from the group consisting of R 5A are independently hydrogen, halogen, CN, OR 22 , N(R 22 )2, C1-C6 alkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl, each C1-C6 alkyl being selected from the group consisting of one or more R d and each of the C-C cycloalkyl and 3- to 6-membered heterocyclyl is optionally substituted with one or more R e is optionally replaced by R 5B are independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl, each C1-C6 alkyl being selected from one or more R d and each of the C-C cycloalkyl and 3- to 6-membered heterocyclyl is optionally substituted with one or more R e optionally substituted with R 8 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl, and each C1-C6 alkyl is selected from one or more R d and each of the C-C cycloalkyl and 3- to 6-membered heterocyclyl is optionally substituted with one or more R e optionally substituted with R 9 are each independently selected from the group consisting of hydrogen, fluoro, C1-C6 alkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl, and each C1-C6 alkyl is selected from one or more R dand each of the C-C cycloalkyl and 3- to 6-membered heterocyclyl is optionally substituted with one or more R e or two R 9 are united as oxo, R 10 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl; R 11 are each independently fluoro, oxo, thioxo, OR a , S.R. 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-C cycloalkyl, and 3- to 6-membered heterocyclyl, each of which is selected from the group consisting of one or more R e optionally substituted with R 12 are each independently fluoro, oxo, thioxo, OR a , S.R. 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 C1-C6 alkyl, each of which is selected from the group consisting of one or more R d optionally substituted with R 13 are each independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl; R 14 are each independently fluoro, oxo, thioxo, OR b , S.R. 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 , C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl, each of which is selected from the group consisting of one or more R e optionally substituted with R 15 are each independently fluoro, oxo, thioxo, OR b , S.R. 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 C1-C6 alkyl, each of which is selected from the group consisting of one or more R d optionally substituted with R 16 are each independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl; R 17A and R 17B are each independe...

Claims

1. Formula (I) 【Chemical 1】 or a salt thereof, wherein A is X １ C including ６ -C １０ aryl or 5-10 membered heteroaryl; X １ is C(R ５Ａ ), N, N(R ５Ｂ ), O, or S; E １ and E ２ are independently a bond, —N(R ８ ) -, -(C(R ９ ) ２ ) ｔ N (R ８ ) -, -N(R ８ ) (C (R ９ ) ２ ) ｔ -, -(C(R ９ ) ２ ) ｔ N (R ８ ) (C (R ９ ) ２ ) ｕ -, -O-, -(C(R ９ ) ２ ) ｔ O-, -O-(C(R ９ ) ２ ) ｔ -, -(C(R ９ ) ２ ) ｔ O(C(R ９ ) ２ ) ｕ -, -(C(R ９ ) ２ ) ｕ -, -C(O)-, -C(O)N(R ８ ) -, -(C(R ９ ) ２ ) ｔ C(O)N(R ８ )-, -C(O)N(R ８ ) (C (R ９ ) ２ ) ｔ -, -(C(R ９ ) ２ ) ｔ C(O)N(R ８ ) (C (R ９ ) ２ ) ｕ -, -N(R ８ )C(O)-,-(C(R ９ ) ２ ) ｔ N (R ８ )C(O)-,-N(R ８ )C(O)(C(R ９ ) ２ ) ｔ -, and -(C(R ９ ) ２ ) ｔ N (R ８ )C(O)(C(R ９ ) ２ ) ｕ - selected from the group consisting of Q １ is C ３ -C １１ cycloalkyl or 3- to 11-membered heterocycle, each of which is one or more R ３ and optionally substituted with one or more R ４ and optionally further substituted with Q ２ is hydrogen, halogen, CN, Z １ , C ３ -C １１ cycloalkyl, and 3- to 11-membered heterocycle, ３ -C １１ Each of the cycloalkyl and the 3- to 11-membered heterocycles may be selected from one or more R ２ and optionally substituted with Z １ and optionally further substituted with R １ are each independently hydrogen, halogen, CN, OR １０ , S.R. １０ , N(R １０ ) ２ , C(O)R １０ , O.C.(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, １ -C ６ Each alkyl may be one or more R １１ and wherein said C ３ -C ６ Each of the cycloalkyl and the 3- to 6-membered heterocyclyl may be selected from one or more R １２ optionally substituted with R ２ are each independently hydrogen, fluoro, oxo, thioxo, OR １３ , S.R. １３ , N(R １３ ) ２ , C(O)R １３ , O.C.(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, １ -C ６ Each alkyl may be one or more R １４ and wherein said C ３ -C ６ Each of the cycloalkyl and 3- to 6-membered heterocyclyl may be one or more R １５ optionally substituted with R ３ are each independently hydrogen, fluoro, oxo, thioxo, OR １６ , S.R. １６ , N(R １６ ) ２ , C(O)R １６ , O.C.(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, １ -C ６ alkyl, the C ２ -C ６ alkenyl, and the C ２ -C ６ Each alkynyl moiety may be one or more R １７Ａ optionally substituted with R ４ are each independently hydrogen, 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), (C １ -C ６ alkylene)-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 C ２ -C ６ Alkenyl and the C ２ -C ６ Each alkynyl may be one or more R １７Ｂ and wherein said C ６ -C １０ Each of the aryl and the 5- to 10-membered heteroaryl may be one or more R １８ and wherein said C ３ -C ６ Each of the cycloalkyl and the 3- to 6-membered heterocyclyl may be selected from one or more R １９ optionally substituted with E ３ are each independently -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 - and R ５Ａ are independently 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, １ -C ６ Each alkyl may be one or more R ｄ and wherein said C ３ -C ６ Each of the cycloalkyl and 3- to 6-membered heterocyclyl may be one or more R ｅ is optionally replaced by R ５Ｂ are independently hydrogen, C １ -C ６ Alkyl, C ３ -C ６ cycloalkyl, and 3- to 6-membered heterocyclyl, １ -C ６ Each alkyl may be one or more R ｄ and wherein said C ３ -C ６ Each of the cycloalkyl and 3- to 6-membered heterocyclyl may be one or more R ｅ optionally substituted with R ８ are each independently hydrogen, C １ -C ６ Alkyl, C ３ -C ６ cycloalkyl, and 3- to 6-membered heterocyclyl, １ -C ６ Each alkyl may be one or more R ｄ and wherein said C ３ -C ６ Each of the cycloalkyl and the 3- to 6-membered heterocyclyl may be selected from one or more R ｅ optionally substituted with R ９ are each independently hydrogen, fluoro, C １ -C ６ Alkyl, C ３ -C ６ cycloalkyl, and 3- to 6-membered heterocyclyl, １ -C ６ Each alkyl may be one or more R ｄ and wherein said C ３ -C ６ Each of the cycloalkyl and the 3- to 6-membered heterocyclyl may be selected from one or more R ｅ or two R ９ are united as oxo, R １０ are each independently hydrogen, C １ -C ６ Alkyl, C １ -C ６ Fluoroalkyl, C ３ -C ６ cycloalkyl, and 3- to 6-membered heterocyclyl; R １１ are each independently fluoro, oxo, thioxo, OR ａ , S.R. ａ , N(R ａ ) ２ , C(O)R ａ , O.C.(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, ３ -C ６ Each of the cycloalkyl and the 3- to 6-membered heterocyclyl may be selected from one or more R ｅ optionally substituted with R １２ are each independently fluoro, oxo, thioxo, OR ａ , S.R. ａ , N(R ａ ) ２ , C(O)R ａ , O.C.(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 C １ -C ６ Each alkyl may be one or more R ｄ optionally substituted with R １３ are each independently hydrogen, C １ -C ４ Alkyl, C １ -C ４ Fluoroalkyl, C ３ -C ６ cycloalkyl, and 3- to 6-membered heterocyclyl; R １４ are each independently fluoro, oxo, thioxo, OR ｂ , S.R. ｂ , N(R ｂ ) ２ , C(O)R ｂ , O.C.(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, ３ -C ６ Each of the cycloalkyl and the 3- to 6-membered heterocyclyl may be selected from one or more R ｅ optionally substituted with R １５ are each independently fluoro, oxo, thioxo, OR ｂ , S.R. ｂ , N(R ｂ ) ２ , C(O)R ｂ , O.C.(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 C １ -C ６ Each alkyl may be one or more R ｄ optionally substituted with R １６ are each independently hydrogen, C １ -C ４ Alkyl, C １ -C ４ Fluoroalkyl, C ３ -C ６ cycloalkyl, and 3- to 6-membered heterocyclyl; R １７Ａ and R １７Ｂ are each independently fluoro, oxo, thioxo, OR ｃ , S.R. ｃ , N(R ｃ ) ２ , C(O)R ｃ , O.C.(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, ３ -C ６ Each of the cycloalkyl and the 3- to 6-membered heterocyclyl may be selected from one or more R ｅ optionally substituted with R １８ are each independently a halogen, CN, OR ｃ , S.R. ｃ , N(R ｃ ) ２ , C(O)R ｃ , O.C.(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, １ -C ６ alkyl, the C １ -C ６ Heteroalkyl, the C １ -C ６ alkenyl, and the C ２ -C ６ Each alkynyl may be one or more R ｄ and wherein said C ３ -C ６ Each of the cycloalkyl and the 3- to 6-membered heterocyclyl may be selected from one or more R ｅ optionally substituted with R １９ are each independently fluoro, oxo, thioxo, OR ｃ , S.R. ｃ , N(R ｃ ) ２ , C(O)R ｃ , O.C.(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 C １ -C ６ Each alkyl may be one or more R ｄ optionally substituted with R ２０ are each independently hydrogen, C １ -C ６ Alkyl, C ３ -C ６ cycloalkyl, and 3- to 6-membered heterocyclyl, １ -C ６ Each alkyl may be one or more R ｄ and wherein said C ３ -C ６ Each of the cycloalkyl and the 3- to 6-membered heterocyclyl is optionally substituted with one or more R ｅ optionally substituted with R ２１ are each independently hydrogen, fluoro, C １ -C ６ Alkyl, C ３ -C ６ cycloalkyl, and 3- to 6-membered heterocyclyl, １ -C ６ Each alkyl may be one or more R ｄ and wherein said C ３ -C ６ Each of the cycloalkyl and the 3- to 6-membered heterocyclyl may be selected from one or more R ｅ or two R ２１ are united as oxo, R ２２ are independently hydrogen, C １ -C ６ Alkyl, C １ -C ６ Fluoroalkyl, C ３ -C ６ cycloalkyl, and 3- to 6-membered heterocyclyl; R ａ , R ｂ , and R ｃ are each independently hydrogen, C １ -C ４ Alkyl, C １ -C ４ Fluoroalkyl, C ３ -C ６ cycloalkyl, and 3- to 6-membered heterocyclyl; R ｄ are each independently fluoro, hydroxy, C １ -C ４ Alkoxy, oxo, NH ２ , NH(C １ -C ４ alkyl), and N(C １ -C ４ alkyl) ２ is selected from the group consisting of R ｅ are each independently 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 is selected from the group consisting of m is an integer from 0 to 6; t is an integer from 1 to 4, u is an integer from 1 to 5; y is an integer from 1 to 3, z is an integer from 1 to 4, Z １ Is, L １ -P, L １ -G, and Z ２ wherein: L １ is selected from a bond and a bivalent chemical linker; P is a target protein binding moiety; G is a reactive functional group; Z ２ is hydrogen, C １ -C ４ alkyl, and amine protecting groups; A compound or a salt thereof, provided that the compound of formula (I) is neither N-(1-(3-fluorophenyl)piperidin-3-yl)-6-morpholinopyrimidin-4-amine nor N-(1-(3-fluorophenyl)piperidin-3-yl)-4-morpholinopyrimidin-2-amine.

2. Formula (II) 【Chemistry 2】 or a salt thereof, wherein A is X １ C including ６ -C １０ aryl or 5-10 membered heteroaryl; X １ is C(R ５Ａ ), N, N(R ５Ｂ ), O, or S; Y １ is C(R ６ ) or N, or Y １ is O and Z １ is null, Y ２ is C(R ７ ) or N, E １ and E ２ are independently a bond, —N(R ８ ) -, -(C(R ９ ) ２ ) ｔ N (R ８ ) -, -N(R ８ ) (C (R ９ ) ２ ) ｔ -, -(C(R ９ ) ２ ) ｔ N (R ８ ) (C (R ９ ) ２ ) ｕ -, -O-, -(C(R ９ ) ２ ) ｔ O-, -O-(C(R ９ ) ２ ) ｔ -, -(C(R ９ ) ２ ) ｔ O(C(R ９ ) ２ ) ｕ -, -(C(R ９ ) ２ ) ｕ -, -C(O)-, -C(O)N(R ８ ) -, -(C(R ９ ) ２ ) ｔ C(O)N(R ８ )-, -C(O)N(R ８ ) (C (R ９ ) ２ ) ｔ -, -(C(R ９ ) ２ ) ｔ C(O)N(R ８ ) (C (R ９ ) ２ ) ｕ -, -N(R ８ )C(O)-,-(C(R ９ ) ２ ) ｔ N (R ８ )C(O)-,-N(R ８ )C(O)(C(R ９ ) ２ ) ｔ -, and -(C(R ９ ) ２ ) ｔ N (R ８ )C(O)(C(R ９ ) ２ ) ｕ - selected from the group consisting of Y ３ is N, C(R ３ ), or C(R ４ ) and Q １ is C ３ -C １１ cycloalkyl or 3- to 11-membered heterocycle, each of which is one or more R ３ and optionally substituted with one or more R ４ and optionally further substituted with Q ２ is C ３ -C １１ cycloalkyl or 3- to 11-membered heterocycle, ３ -C １１ Each of the cycloalkyl and the 3- to 11-membered heterocycles may be selected from one or more R ２ and optionally substituted with Z １ and optionally further substituted with R １ are each independently hydrogen, halogen, CN, OR １０ , S.R. １０ , N(R １０ ) ２ , C(O)R １０ , O.C.(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, １ -C ６ Each alkyl may be one or more R １１ and wherein said C ３ -C ６ Each of the cycloalkyl and the 3- to 6-membered heterocyclyl may be selected from one or more R １２ optionally substituted with R ２ are each independently fluoro, oxo, thioxo, OR １３ , S.R. １３ , N(R １３ ) ２ , C(O)R １３ , O.C.(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, １ -C ６ Each alkyl may be one or more R １４ and wherein said C ３ -C ６ Each of the cycloalkyl and 3- to 6-membered heterocyclyl may be one or more R １５ optionally substituted with R ３ are each independently hydrogen, fluoro, oxo, thioxo, OR １６ , S.R. １６ , N(R １６ ) ２ , C(O)R １６ , O.C.(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, １ -C ６ alkyl, the C ２ -C ６ alkenyl, and the C ２ -C ６ Each alkynyl moiety may be one or more R １７Ａ optionally substituted with R ４ are each independently 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 C ２ -C ６ Alkenyl and the C ２ -C ６ Each alkynyl may be one or more R １７Ｂ and wherein said C ６ -C １０ Each of the aryl and the 5- to 10-membered heteroaryl may be one or more R １８ and wherein said C ３ -C ６ Each of the cycloalkyl and the 3- to 6-membered heterocyclyl may be selected from one or more R １９ optionally substituted with E ３ are each independently -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 - selected from the group consisting of R ５Ａ are independently 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, １ -C ６ Each alkyl may be one or more R ｄ and wherein said C ３ -C ６ Each of the cycloalkyl and the 3- to 6-membered heterocyclyl may be selected from one or more R ｅ is optionally replaced by R ５Ｂ are independently hydrogen, C １ -C ６ Alkyl, C ３ -C ６ cycloalkyl, and 3- to 6-membered heterocyclyl, １ -C ６ Each alkyl may be one or more R ｄ and wherein said C ３ -C ６ Each of the cycloalkyl and the 3- to 6-membered heterocyclyl may be selected from one or more R ｅ optionally substituted with R ６ are independently hydrogen, fluoro, OR ２３ , N(R ２３ ) ２ , and C １ -C ６ alkyl, wherein C １ -C ６ Each alkyl may be one or more R ｄ optionally substituted with R ７ are independently hydrogen, fluoro, OR ２４ , N(R ２４ ) ２ , and C １ -C ６ alkyl, wherein C １ -C ６ Each alkyl may be one or more R ｄ optionally substituted with R ８ are each independently hydrogen, C １ -C ６ Alkyl, C ３ -C ６ cycloalkyl, and 3- to 6-membered heterocyclyl, １ -C ６ Each alkyl may be one or more R ｄ and wherein said C ３ -C ６ Each of the cycloalkyl and the 3- to 6-membered heterocyclyl may be selected from one or more R ｅ optionally substituted with R ９ are each independently hydrogen, fluoro, C １ -C ６ Alkyl, C ３ -C ６ cycloalkyl, and 3- to 6-membered heterocyclyl, １ -C ６ Each alkyl may be one or more R ｄ and wherein said C ３ -C ６ Each of the cycloalkyl and the 3- to 6-membered heterocyclyl may be selected from one or more R ｅ or two R ９ are united as oxo, R １０ are each independently hydrogen, C １ -C ６ Alkyl, C １ -C ６ Fluoroalkyl, C ３ -C ６ cycloalkyl, and 3- to 6-membered heterocyclyl; R １１ are each independently fluoro, oxo, thioxo, OR ａ , S.R. ａ , N(R ａ ) ２ , C(O)R ａ , O.C.(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, ３ -C ６ Each of the cycloalkyl and the 3- to 6-membered heterocyclyl may be selected from one or more R ｅ optionally substituted with R １２ are each independently fluoro, oxo, thioxo, OR ａ , S.R. ａ , N(R ａ ) ２ , C(O)R ａ , O.C.(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 C １ -C ６ Each alkyl may be one or more R ｄ optionally substituted with R １３ are each independently hydrogen, C １ -C ４ Alkyl, C １ -C ４ Fluoroalkyl, C ３ -C ６ cycloalkyl, and 3- to 6-membered heterocyclyl; R １４ are each independently fluoro, oxo, thioxo, OR ｂ , S.R. ｂ , N(R ｂ ) ２ , C(O)R ｂ , O.C.(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, ３ -C ６ Each of the cycloalkyl and the 3- to 6-membered heterocyclyl may be selected from one or more R ｅ optionally substituted with R １５ are each independently fluoro, oxo, thioxo, OR ｂ , S.R. ｂ , N(R ｂ ) ２ , C(O)R ｂ , O.C.(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 C １ -C ６ Each alkyl may be one or more R ｄ optionally substituted with R １６ are each independently hydrogen, C １ -C ４ Alkyl, C １ -C ４ Fluoroalkyl, C ３ -C ６ cycloalkyl, and 3- to 6-membered heterocyclyl; R １７Ａ and R １７Ｂ are each independently fluoro, oxo, thioxo, OR ｃ , S.R. ｃ , N(R ｃ ) ２ , C(O)R ｃ , O.C.(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, ３ -C ６ Each of the cycloalkyl and the 3- to 6-membered heterocyclyl may be selected from one or more R ｅ optionally substituted with R １８ are each independently a halogen, CN, OR ｃ , S.R. ｃ , N(R ｃ ) ２ , C(O)R ｃ , O.C.(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 ３ -C ６ cycloalkyl, and 3- to 6-membered heterocyclyl, １ -C ６ Each alkyl may be one or more R ｄ and wherein said C ３ -C ６ Each of the cycloalkyl and the 3- to 6-membered heterocyclyl may be selected from one or more R ｅ optionally substituted with R １９ are each independently fluoro, oxo, thioxo, OR ｃ , S.R. ｃ , N(R ｃ ) ２ , C(O)R ｃ , O.C.(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 C １ -C ６ Each alkyl may be one or more R ｄ optionally substituted with R ２０ are each independently hydrogen, C １ -C ６ Alkyl, C ３ -C ６ cycloalkyl, and 3- to 6-membered heterocyclyl, １ -C ６ Each alkyl may be one or more R ｄ and wherein said C ３ -C ６ Each of the cycloalkyl and the 3- to 6-membered heterocyclyl is optionally substituted with one or more R ｅ optionally substituted with R ２１ are each independently hydrogen, fluoro, C １ -C ６ Alkyl, C ３ -C ６ cycloalkyl, and 3- to 6-membered heterocyclyl, １ -C ６ Each alkyl may be one or more R ｄ and wherein said C ３ -C ６ Each of the cycloalkyl and the 3- to 6-membered heterocyclyl may be selected from one or more R ｅ or two R ２１ are united as oxo, R ２２ , R ２３ , and R ２４ are each independently hydrogen, C １ -C ６ Alkyl, C １ -C ６ Fluoroalkyl, C ３ -C ６ cycloalkyl, and 3- to 6-membered heterocyclyl; R ａ , R ｂ , and R ｃ are each independently hydrogen, C １ -C ４ Alkyl, C １ -C ４ Fluoroalkyl, C ３ -C ６ cycloalkyl, and 3- to 6-membered heterocyclyl; R ｄ are each independently fluoro, hydroxy, C １ -C ４ Alkoxy, oxo, NH ２ , NH(C １ -C ４ alkyl), and N(C １ -C ４ alkyl) ２ is selected from the group consisting of R ｅ are each independently 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 is selected from the group consisting of m 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; y is an integer from 1 to 3, z is an integer from 1 to 4, Z １ Is, L １ -P, L １ -G, and Z ２ wherein: L １ is selected from a bond and a bivalent chemical linker; P is a target protein binding moiety; G is a reactive functional group; Z ２ is hydrogen, C １ -C ４ alkyl, and amine protecting groups; or Y １ When is O, Z ２ does not exist, A compound or a salt thereof, provided that the compound of formula (II) is neither N-(1-(3-fluorophenyl)piperidin-3-yl)-6-morpholinopyrimidin-4-amine nor N-(1-(3-fluorophenyl)piperidin-3-yl)-4-morpholinopyrimidin-2-amine.

3. A is X １ and one or more R １ 3. The compound according to claim 1 or 2, wherein R is a 5- to 6-membered heteroaryl optionally substituted with R, or a salt thereof.

4. A is selected from pyridine and pyrimidine １ and one or more R １ 4. The compound according to any one of claims 1 to 3, wherein R is a 6-membered heteroaryl optionally substituted with R, or a salt thereof.

5. X １ is C(R ５Ａ 5. The compound according to claim 1, wherein R is 1 or N, or a salt thereof.

6. A is, 【Chemistry 3】 or a tautomeric form thereof, wherein: * is E １ is the attachment point for # is E ２ is the attachment point for Each of the 6-membered aryl or the 5- to 10-membered heteroaryl may be one or more R １ 4. The compound according to any one of claims 1 to 3, or a salt thereof, optionally substituted with:

7. Y １ The compound according to any one of claims 2 to 6, or a salt thereof, wherein is N.

8. Y １ is C(R ６ 7. The compound according to claim 2, or a salt thereof, wherein

9. Y ２ The compound according to any one of claims 2 to 8, or a salt thereof, wherein is N.

10. Y ２ is C(R ７ 9. The compound according to claim 2, or a salt thereof, wherein

11. E １ is a bond, -N(R ８ ) -, -(C(R ９ ) ２ ) ｔ N (R ８ )-, and -N(R ８ ) (C (R ９ ) ２ ) ｔ The compound according to any one of claims 1 to 10, or a salt thereof, selected from the group consisting of:

12. E １ is a bond, -NH-, -(CH ２ ) ｔ NH-, and -NH(CH ２ ) ｔ 12. The compound of claim 11, or a salt thereof, selected from the group consisting of:

13. Q １ But Y ３ and formula (IV) 【Chemistry 4】 C having the structure ３ -C １１ cycloalkyl or a 3- to 11-membered heterocycle, wherein * is E １ is the attachment point for Y ３ is N, C(R ３ ), or C(R ４ ) and r is an integer from 0 to 4; 13. The compound according to any one of claims 1 or 3 to 12, or a salt thereof, wherein s is an integer of 0 to 2.

14. Q １ Formula (IVa), Formula (IVb), and Formula (IVc) 【Chemistry 5】 C having the structure ３ -C １１ cycloalkyl or a 3- to 11-membered heterocycle, wherein * is E １ is the attachment point for Y ３ is N, C(R ３ ), or C(R ４ ) and Y ４ is N(R ３ ), N(R ４ ), C(R ３ ) ２ , C(R ３ ) (R ４ ), or C(R ４ ) ２ and A １ , B １ , C １ , and D １ are each independently null, O, C(O), S(O), S(O) ２ , N(R ３ ), N(R ４ ), C(R ３ ) ２ , C(R ３ ) (R ４ ), and C(R ４ ) ２ is selected from the group consisting of r is an integer from 0 to 4; s is an integer from 0 to 2; v １ , w １ , v ２ , w ２ , v ３ , w ３ , v ４ , and w ４ are each independently an integer of 0 to 5, or a salt thereof.

15. Q １ but, 【Chemistry 6】 or a stereoisomer thereof, wherein * is E １ is the attachment point for Q １ is one or more R ３ 15. The compound of any one of claims 1 to 14, optionally substituted by: or a salt thereof.

16. Q １ but, 【Chemistry 7】 or a stereoisomer thereof, wherein * is E １ is the attachment point for Q １ is one or more R ３ 15. The compound of any one of claims 1 to 14, optionally substituted by: or a salt thereof.

17. Q ２ But C ３ -C １１ cycloalkyl or 3- to 11-membered heterocycle, each of which is one or more R ２ and optionally substituted with Z １ 17. The compound according to any one of claims 1 to 16, or a salt thereof, substituted with:

18. Q ２ Formula (Va), Formula (Vb), and Formula (Vc) 【Chemistry 8】 C having the structure ３ -C １１ is selected from the group consisting of cycloalkyl and 3- to 11-membered heterocycle, # is E ２ is the attachment point for Y １ is C(R ６ ) or N, or Y １ is O and Z １ is null, Y ２ is C(R ７ ) or N, R ６ are independently hydrogen, fluoro, OR ２３ , N(R ２３ ) ２ , and C １ -C ６ alkyl, wherein C １ -C ６ Each alkyl may be one or more R ｄ optionally substituted with R ７ are independently hydrogen, fluoro, OR ２４ , N(R ２４ ) ２ , and C １ -C ６ alkyl, wherein C １ -C ６ Each alkyl may be one or more R ｄ optionally substituted with R ２３ and R ２４ are independently hydrogen, C １ -C ６ Alkyl, C １ -C ６ Fluoroalkyl, C ３ -C ６ cycloalkyl, and 3- to 6-membered heterocyclyl; R ｄ are each independently fluoro, hydroxy, C １ -C ４ Alkoxy, oxo, NH ２ , NH(C １ -C ４ alkyl), and N(C １ -C ４ alkyl) ２ is selected from the group consisting of A ２ , B ２ , C ２ , and D ２ are each independently null, O, C(O), S(O), S(O) ２ , N(R ２ ), and C(R ２ ) ２ is selected from the group consisting of n is an integer from 0 to 4, v ５ , w ５ , v ６ , w ６ , v ７ , w ７ , v ８ , and w ８ are each independently an integer of 0 to 5, or a salt thereof.

19. Q ２ Z １ 17. The compound according to claim 1, or any one of claims 3 to 16, or a salt thereof, wherein:

20. R ４ But independently, 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, wherein said C ６ -C １０ Each of the aryl and the 5- to 10-membered heteroaryl may be one or more R １８ 20. The compound of any one of claims 1 to 19, optionally further substituted by: or a salt thereof.

21. R ４ are independently 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), (C １ -C ６ alkylene)-N(R １６ )C(O)(C ２ -C ６ alkynyl), wherein C ２ -C ６ Alkenyl and the C ２ -C ６ Each alkynyl may be one or more R １７Ｂ 20. The compound of any one of claims 1 to 19, optionally substituted by: or a salt thereof.

22. E ２ is 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 22. The compound according to any one of claims 1 to 21, or a salt thereof, selected from the group consisting of: )C(O)-;

23. E ２ is a bond, -NH-, -(CH ２ ) ｔ NH-, -NH(CH ２ ) ｔ 23. The compound according to any one of claims 1 to 22, or a salt thereof, selected from the group consisting of -, -C(O)NH-, and -NHC(O)-.

24. R ８ The compound according to any one of claims 1 to 23, or a salt thereof, wherein each is hydrogen.

25. R ９ are each hydrogen, or two R ９ The compound according to any one of claims 1 to 24, or a salt thereof, wherein together are oxo.

26. Z １ But, L １ -G or Z ２ 26. The compound according to any one of claims 1 to 25, or a salt thereof,

27. 27. The compound according to any one of claims 1 to 26, or a salt thereof, wherein G is a reactive functional group selected from a protected or unprotected primary or secondary amine, a carboxylic acid, a carboxylic acid ester, a halogen, a hydroxy, or a sulfonate ester.

28. Z ２ 28. The compound of any one of claims 1 to 27, or a salt thereof, wherein is selected from the group consisting of hydrogen and an amine protecting group.

29. 29. The compound or salt according to any one of claims 1 to 28, wherein the salt is a pharmaceutically acceptable salt.

30. Z １ L １ 29. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein:

31. L １ is a bond or a group represented by the formula -(J) ｘ - a divalent chemical linker of the formula Each -J- is independently -N(R ２５ ) -, -C(R ２６ ) ２ -, -O-, -C(O)-, -C(=N(R ２５ ))-, -C(S)-, -C(R ２６ ) = C(R ２６ )-, -C≡C-, -S-, -S(O)-, -S(O) ２ -, R ２７ C optionally substituted with ３ -C １１ cycloalkyl, and R ２７ and 3- to 11-membered heterocyclyl optionally substituted with, provided that no two —O— and / or —S— are adjacent; R ２５ are each independently hydrogen, C １ -C ６ Alkyl, C ３ -C １１ cycloalkyl, and 3- to 11-membered heterocyclyl, １ -C ６ Each alkyl may be one or more R ｆ and wherein said C ３ -C １１ Each of the cycloalkyl and the 3- to 11-membered heterocyclyl may be selected from one or more R ｇ optionally substituted with R ２６ are each independently hydrogen, fluoro, C １ -C ６ Alkyl, C ３ -C ６ cycloalkyl, and 3- to 6-membered heterocyclyl, １ -C ６ Each alkyl may be one or more R ｆ and wherein said C ３ -C ６ Each of the cycloalkyl and the 3- to 6-membered heterocyclyl may be selected from one or more R ｇ optionally substituted with R ２７ are each independently hydrogen, fluoro, C １ -C ６ alkyl, and oxo, １ -C ６ Each alkyl may be one or more R ｆ and wherein said C ３ -C ６ Each of the cycloalkyl and the 3- to 6-membered heterocyclyl may be selected from one or more R ｇ optionally substituted with R ｆ are each independently fluoro, hydroxy, C １ -C ４ Alkoxy, oxo, NH ２ , NH(C １ -C ４ alkyl), and N(C １ -C ４ alkyl) ２ is selected from the group consisting of R ｇ are each independently 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 is selected from the group consisting of 31. The compound or salt according to any one of claims 1 to 30, wherein x is an integer from 1 to 30.

32. A pharmaceutical composition comprising a compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

33. A method of treatment, comprising the step of administering to a subject in need thereof an effective amount of a compound or salt according to any one of claims 1 to 31, or a pharmaceutical composition according to claim 32.

34. 34. The method of claim 33, wherein the subject has cancer.

35. 35. The method of treatment of claim 34, wherein the subject is a human.

36. 33. A method for degrading, inhibiting, or regulating a protein in a cell, comprising contacting the cell with an effective amount of a compound or salt of any one of claims 1 to 31, or a pharmaceutical composition of claim 32.

37. 37. The method of claim 36, wherein the cell is a cancer cell.

38. A compound or salt according to any one of claims 1 to 31, or a pharmaceutical composition according to claim 32, for use in a method of treatment.

39. A compound or salt according to any one of claims 1 to 31, or a pharmaceutical composition according to claim 32, for use in a method for degrading, inhibiting or regulating a protein in a cell.

40. Z １ L １ A method for preparing heterobifunctional compounds of formula (I) or (II) according to claim 1 or 2, wherein Z １ L １ -G or Z ２ The compound or salt according to any one of claims 1 to 29 or 31, １ conjugating the target protein binding moiety P to the target protein binding moiety P via

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