Polycyclic compounds and methods for targeted degradation of rapidly progressing fibrosarcoma polypeptides

Abstract

To provide compounds that find utility as modulators of RapidlyAcceleratedFibrosarcoma (RAF, such as c-RAF, A-RAF and / or B-RAF; target proteins).SOLUTION: The present invention is directed to bifunctional compounds that contain a von Hippel-Lindau, cereblon, Inhibitorsof Apoptosis Proteins, or mousedouble-RAF ligand that binds to the respective E3 ubiquitin ligase at one end and a moiety that binds to the target proteins RAF at the other end, such that the target proteins are placed in proximity to the ubiquitin ligase to effect degradation (and minutehomolog2) of the target proteins. The present disclosure presents a wide range of pharmacological activities related to degradation / inhibition of target proteins.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Cross-reference of related applications This disclosure claims priority to U.S. Provisional Patent Application No. 62 / 728,581 filed on September 7, 2018, and priority to U.S. Provisional Patent Application No. 62 / 438,803 filed on December 23, 2016, and U.S. Provisional Patent Application No. 62 / 582,698 filed on November 7, 2017, as of December 22, 2017. The U.S. patent application was filed as U.S. Patent Application No. 15 / 853,166 and published on June 28, 2018. This is a continuation-in-part application, Publication No. 2018 / 0179183A1. All of these patent applications are incorporated herein by reference in their entirety.

[0002] Reference U.S. Patent Application No. 15 / 230,354, filed on August 5, 2016, and filed on July 11, 2016. U.S. Patent Application No. 15 / 206,497, filed on July 13, 2016, U.S. Patent Application No. 15 / 209,648, filed on October 11, 2016, and U.S. Patent Application No. 62 / 406,888, filed on October 11, 2016, This U.S. patent application was filed on April 14, 2015, and published as U.S. Patent Application Publication No. 2015 / 0291562. U.S. Patent Application No. 14 / 686,640, and U.S. Patent Publication No. 2016 / 0058872, U.S. Patent Application No. 14 / 792,414, filed on July 6, 2015, and U.S. Patent Application No. 14 / 371,956, filed on July 11, 2014, and U.S. Patent Publication No. 2014 / 0356322, U.S. Patent Application No. 15 / 074,820, filed on March 18, 2016, and U.S. Patent Publication No. 2016 / 0272639, are incorporated herein by reference in their entirety. Furthermore, all references cited herein are incorporated herein by reference in their entirety.

[0003] Description of research funded by the federal government. This invention is based on grant number NIH R35CA197589 issued by the National Institutes of Health, United States. This was done with government support. The government has specific rights to this invention.

[0004] This specification provides a bifunctional compound comprising a target protein-binding moiety and an E3 ubiquitin ligase-binding moiety, and related methods of use. The bifunctional compound is useful as a regulator of targeted ubiquitination, particularly for RAF (Rapidly Accelerated Fibrosarcoma) proteins that are degraded and / or inhibited by other means by the bifunctional compound according to this disclosure. It is useful in that regard. [Background technology]

[0005] Most small molecule drugs bind tightly to enzymes or receptors in clearly defined pockets. On the other hand, small molecules are used to target protein-protein interactions. It is well known that this is difficult, because the protein contact surface is large and the interface involved is shallow groove-like or flat. E3 ubiquitin ligases (hundreds of which are known in humans) confer substrate specificity to ubiquitination. Therefore, they have specificity for specific protein substrates and are more attractive therapeutic targets than general-purpose proteasome inhibitors. The development of ligands for E3 ligases has proven to be difficult in part due to the fact that it is necessary to disrupt protein-protein interactions. However, recent developments have yielded specific ligands that bind to these ligases. For example, since the discovery of nathrin, the first small molecule E3 ligase inhibitor, further compounds targeting E3 ligases have been reported, but much of this field remains undeveloped. For example, since the discovery of nathrin, the first small molecule E3 ligase MDM2 (mouse double minute 2 homolog) inhibitor, MDM2 (i.e., Furthermore, more compounds targeting human double minute 2 (HDM2)E3 ligase have been reported. (J. Di, et al. Current Cancer Drug Targets (2011), 11(8) 987-994).

[0006] The tumor suppressor gene p53 plays a crucial role in the arrest of cell proliferation and apoptosis in response to DNA damage or stress ((A. Vazquez, et al. Nat. Rev. Drug. Dis. (2008), 7, 979-982), and p53 inactivation has been proposed as one of the important pathways for tumor cell survival (AJ Levine, et al. Nature (2000), 408, 307-310). In cancer patients, p53 mutations are It has been found in approximately 50% of cases (M. Hollstein, et al. Science (1991), 233, 49-53), while in patients with wild-type p53, downregulation of p53 by MDM2 through protein-protein interactions between p53 and MDM2 has been frequently observed (P. Chene, et al. Nat. Rev. Cancer (2003), 3, 102-109). In normal cells without oncogenic stress signals, MDM2 maintains p53 at low concentrations. In response to DNA damage and cellular stress, p53 levels increase, and further increases in MDM2 occur through a feedback loop from the p53 / MDM2 autoregulatory system. In other words, p53 regulates MDM2 at the transcriptional level, and MDM2 regulates p53 at its activity level (AJ Levine, et al. Genes Dev. (1993) 7, 1126-1132).

[0007] Several mechanisms can explain the downregulation of p53 by MDM2. First, MDM2 binds to the N-terminal domain of p53 and inhibits the expression of p53-responsive genes (J. Momand, et al. Cell (1992), 69, 1237-1245). Next, MDM2 causes p53 to travel back and forth from the nucleus to the cytoplasm, and It promotes the degradation of protein-soluble substances (J. Roth, et al. EMBO J. (1998), 17, 554-564). Finally, MDM2 has endogenous E3 ligase activity, binding ubiquitin to p53 and degrading it through the ubiquitin-dependent 26s proteasome system (UPS) (Y. Haupt, et al. Nature (1997) 387, 296-299). Since MDM2 functions as an E3 ligase, it is possible to use MDM2 to degrade disease-causing substances. Recruiting a drug into a protein and then utilizing its ubiquitination and degradation activity is a very interesting drug development technique.

[0008] One E3 ligase with intriguing therapeutic potential is von Hippel-Lindau (VHL) tumor suppressor, which is a substrate recognition subunit of the E3 ligase complex VCB. This complex further contains elongin B and C, Cul2, and Rbx1. The main substrate of VHL is hypoxia-inducible factor 1α (HIF-1α), a transcription factor that, in response to low levels of oxygen, upregulates genes such as the angiogenesis growth factor VEGF and the erythropoietin, a erythrocyte-induced cytokine. E3 rigger The first small molecule ligand for von Hippel-Lindou (VHL) against the substrate recognition subunit of ze has been constructed, its crystal structure has been obtained, and this compound is the major substrate of the transcription factor HIF, which is a key substrate of VHL. It was confirmed that it mimics the bonding mode of -1α.

[0009] Cereblon is a protein encoded by the CRBN gene in humans. CRBN orthologues are highly conserved from plants to humans, which clearly demonstrates their physiological importance. Cereblon is a DNA-binding protein (1) that binds to damaged DNA. It forms an E3 ubiquitin ligase complex with DDB1, Cullin-4A (CUL4A), and Cullins1 regulator (ROC1). This complex forms with numerous other proteins. It ubiquitinates the target protein. Through a mechanism that is not fully understood, cerebron ubiquitination of the target protein leads to increased levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10). FGF8 then plays a role in the formation of, for example, limbs and ear vesicles. It regulates numerous developmental processes, including those mentioned above. In embryos, this ubiquitin ligase complex has ultimately been concluded to be important for limb growth. In the absence of cereblon, DDB1 forms a complex with DDB2 and functions as a DNA damage binding protein.

[0010] Apoptosis inhibitors (IAPs) are a family of proteins involved in apoptosis, or cell death. The human IAP family includes eight types. Rarely, many other organisms also contain IAP homologs. IAP contains an E3 ligase-specific domain and a baculoviral IAP repeat (BIR) domain, which recognize substrates and promote their ubiquitination. IAP promotes ubiquitination, and then... Caspases can directly bind to and inhibit proteases. Caspases are proteases that carry out apoptosis (e.g., caspase-3, caspase-7, and caspase-9). In other words, IAP inhibits cell death through caspase binding. However, it promotes apoptosis. Stimulation of this gene induces the release of mitochondrial proteins DIABLO (second mitrochondria-derived activator of caspases, also known as SMAC) and HTRA2 (also known as Omi). The binding of DIABLO and HTRA2 is thought to inhibit IAP activity.

[0011] SMAC interacts with virtually all known IAPs, including XIAP, c-IAP1, c-IAP2, NIL-IAP, Bruce, and Survivin. The first four amino acids of mature SMAC (AVPI) bind to a portion of IAP. This is thought to be essential for inhibiting the anti-apoptotic effect of IAP.

[0012] Difunctional compounds, such as those described in U.S. Patent Publications 2015-0291562 and 2014-0356322 (incorporated herein by reference), function to recruit and degrade endogenous proteins into E3 ubiquitin ligases. In particular, these publications describe difunctional or proteolytic targeting chimeric (PROTAC) compounds, which have been found to be useful as regulators of targeted ubiquitination of various polypeptides and other proteins, which are degraded and / or inhibited by other means by these difunctional compounds.

[0013] Diseases associated with the overexpression or aggregation of RAF (Rapidly Accelerated Fibrosarcoma) There is a continuing need in the field of effective treatment or RAF hyperactivation (such as constitutively active RAF). For example, current BRaf inhibitors (such as vemurafenib and dabrafenib) can target V600 mutant BRaf. There is a need for drugs for diseases or disorders with different BRaf mutations that are insensitive to currently available drugs (such as melanoma, lung cancer, pancreatic cancer, and / or colorectal cancer). Furthermore, resistance mutations may emerge in response to BRaf / MEK inhibitor therapy. For example, the p61 splice variant has been observed in melanoma patients treated with BRaf / MEK inhibitor therapy. These patients may be left without clinical options. Currently available drugs also lead to and cause paradoxical activation of wild-type BRaf, resulting in clinical complications. Furthermore, a family of low-activity class III BRaf mutants, signaled through heterodimerization using CRaf, accounts for 40% of BRaf mutations in non-small cell lung cancer (NSCLC). These variants constitute a group of cancers and are found sporadically across other cancers, and cannot be targeted by any currently approved or clinically-staged BRaf inhibitors. Class I BRAF variants (V600E, V600K, V600D) have high kinase activity, are Ras and dimerization-independent, and are sensitive to vemuragenib. Class II BRAF variants have high to moderate kinase activity, are Ras-independent, dimerization-dependent, and are not sensitive to vemuragenib. Class III BRAF mutants have little to no kinase activity, and Ras and It is dimerization-dependent and shows no sensitivity to vemurafenib.

[0014] Therefore, the inability to target and modulate nonspecific effects and RAF remains. This is an obstacle to the development of effective treatments. Thus, small molecule therapeutics that effectively target RAF (e.g., effectively inhibit and / or degrade mutant BRaf while preserving wild-type BRaf) and utilize or enhance the substrate specificity of VHL, cereblon, MDM2, and IAP would be extremely useful. [Overview of the Initiative]

[0015] This disclosure describes how to recruit endogenous proteins to E3 ubiquitin ligase and degrade them. This disclosure describes functional bifunctional compounds and methods of use thereof. In particular, this disclosure provides bifunctional or proteolytic targeting chimeric (PROTAC) compounds, which have been found to be useful as regulators of targeted ubiquitination of various polypeptides and other proteins, and these polypeptides and other proteins are degraded and / or inhibited by other means by the bifunctional compounds described herein. The advantages of the compounds provided herein are that they may have broad pharmacological activity and are compatible with the degradation / inhibition of target polypeptides from virtually all protein species or families. Furthermore, this specification describes disease conditions such as cancer (e.g., renal cell carcinoma, pancreatic cancer, For the treatment or improvement of colorectal cancer, lung cancer, ovarian cancer, thyroid cancer, pilocytic astrocytoma, prostate cancer, gastric cancer, hepatocellular carcinoma, and melanoma, cardiac-facial-cutaneous syndrome, neurofibromatosis type 1, Costello syndrome, Noonan syndrome, and LEOPARD syndrome (moles, electrocardiogram abnormalities, bilateral eccentricity, pulmonary valve stenosis, genital abnormalities, growth retardation, hearing loss), use an effective amount of the compound described herein. To provide a method for using it.

[0016] Accordingly, in one embodiment, the present disclosure provides a bifunctional compound or PROTAC compound, the compound having an E3 ubiquitin ligase binding moiety (i.e., an E3 ubiquitin ligase) A ligand for the enzyme, or a "ULM" group, and a portion that binds to the target protein (i.e., a tag). The ULM (ubiquitination ligase regulator) comprises a protein / polypeptide targeting ligand (or "PTM" group), thereby positioning the target protein / polypeptide in close proximity to the ubiquitin ligase, thereby exerting a degradation (and inhibition) effect on the protein. In preferred embodiments, the ULM can be a von Hippel-Lindou E3 ubiquitin ligase (VHL) binding moiety (VLM), or a Cereblon E3 ubiquitin ligase binding moiety (CLM), or an MDM2 (mouse double minute 2 homolog) E3 ubiquitin ligase binding moiety (MLM), or an IAP E3 ubiquitin ligase binding moiety (i.e., "ILM"). For example, the structure of a bifunctional compound It can be shown as follows:

[0017] [ka]

[0018] The PTM and ULM portions exemplified herein (e.g., VLM, CLM, MLM) The positions and numbers of each ILM are provided for illustrative purposes only, and are not necessarily accurate. This method is not intended to limit the compounds. As will be understood by those skilled in the art, the bifunctional compounds described herein can be synthesized such that the number and position of each functional part can be varied as desired.

[0019] In certain embodiments, the bifunctional compound further comprises a chemical linker (L). In this embodiment, the structure of the bifunctional compound can be shown as follows:

[0020] [ka]

[0021] In the formula, PTM is the protein / polypeptide targeting portion, L is a linker, for example, a bond or chemical group that links PTM and ULM, and ULM is the IAP E3 ubiquitin ligase binding portion. , or von Hippel-Rindo E3 ubiquitin ligase (VHL) binding site (VLM) or cele This is either the Bron E3 ubiquitin ligase binding site (CLM) or the MDM2 (mouse double minute 2 homolog) E3 ubiquitin ligase binding site (MLM).

[0022] For example, the structure of a bifunctional compound can be shown as follows:

[0023] [ka]

[0024] In the formula, PTM is the protein / polypeptide targeting moiety; "L" is a linker that connects PTM to at least one of VLM, CLM, MLM, ILM, or a combination thereof (e.g. For example, a binding or chemical linker group; VLM is the von Hippel-Lindau E3 ubiquitin ligase binding site that binds to VHL E3 ligase; CLM is the cereblon E3 ubiquitin ligase binding site that binds to cereblon; MLM is the MDM2 E3 ubiquitin ligase binding site; and ILM is the IAP binding site that binds to IAP.

[0025] In a particular preferred embodiment, ILM is a four-peptide fragment of AVPI. In an additional embodiment, the ILM of the bifunctional compound is composed of the amino acids alanine (A) and valine (V). ), proline (P), and isoleucine (I) or their non-natural mimics, respectively. In additional embodiments, the amino acids of the AVPI tetrapeptide fragment are linked to each other via amide bonds (i.e., -C(O)NH- or -NHC(O)-).

[0026] In certain embodiments, the compounds described herein include ULM, multiple PTMs, and multiple chemical compounds. Includes multiple entries, or combinations thereof, selected independently.

[0027] In certain embodiments, ILM is a chemical part such as the chemical part described herein. Includes.

[0028] In additional embodiments, the VLM may be hydroxyproline or a derivative thereof. Furthermore, other anticipated VLMs include the VLM described in U.S. Patent Application Publication No. 2014 / 03022523, which is incorporated herein by reference in its entirety, as discussed above.

[0029] In one embodiment, CLM is derived from imides, thioimides, amides, or thioamides. It contains a derived chemical group. In certain embodiments, the chemical group is a phthalimide group, or an analog or derivative thereof. In certain embodiments, CLM is thalidomide, These include lenalidomide, pomalidomide, its analogues, its isosteres, or derivatives thereof. Other anticipated CLMs include the CLM described in U.S. Patent Application Publication No. 2015 / 0291562, which is incorporated herein by reference in its entirety.

[0030] In certain embodiments, MLM may be sodium or a derivative thereof. Furthermore, other expected An example of an MLM is the one described in U.S. Patent Application No. 15 / 206,497, filed on July 11, 2016, as discussed above, and the entire application is incorporated herein by reference. In a further embodiment, the MLM of the difunctional compound may be, for example, a substituted imidazoline or a substituted spi. It includes chemical parts such as low-indlinone, substituted pyrrolidine, substituted piperidinone, substituted substituted morpholinone, substituted pyrrolopyrimidine, substituted imidazolopyridine, substituted thiazoloimidazoline, substituted pyrrolopyrrolidinone, and substituted isoquinolinone.

[0031] In additional embodiments, the MLM is located adjacent to the adjacent MLM, positioned as either sys or trans configuration. This includes the aforementioned core structure with bis-aryl substitution.

[0032] In certain embodiments, "L" is a link. In additional embodiments, linker "L" is 1 This connector has a linear number of non-hydrogen atoms in the range of ~20. The "L" in the connector is The linker may, but is not limited to, functional groups such as ethers, amides, alkanes, alkenes, alkynes, ketones, hydroxyls, carboxylic acids, thioethers, sulfoxides, and sulfones. The linker may contain aromatic, aromatic heterocyclic, cyclic, bicyclic, and tricyclic parts. Substitutions with halogens such as Cl, F, Br, and I may be included in the linker. In the case of fluorine substitution, one or more fluorines may be included.

[0033] In certain embodiments, VLM is a derivative of trans-3-hydroxyproline, where both the nitrogen and carboxylic acid in trans-3-hydroxyproline are functionalized as an amide. It has a sex.

[0034] In certain embodiments, CLM is a derivative of piperidine-2,6-dione, which may be substituted at the 3-position, and the 3-position substitution is a CN bond or a CC bond. It may also be a bicyclic hetero-aromatic compound with a bond as such. An example of a CLM is, Examples include, but are not limited to, maridomide, lenalidomide, and thalidomide, as well as their derivatives.

[0035] In additional embodiments, this specification provides therapeutic compositions comprising an effective amount of a compound or a salt form thereof described herein and a pharmaceutically acceptable carrier. The therapeutic compositions can be used to modulate protein degradation in a patient or subject, such as an animal such as a human, and to treat or improve a disease or condition modulated by the degraded protein. In certain embodiments, the therapeutic compositions described herein may be used to induce degradation of a target protein for the purpose of treating or improving a disease, such as cancer. In yet another embodiment, this disclosure provides a method for ubiquitinating / degrading a target protein in a cell. In certain embodiments, the method comprises administering a bifunctional compound described herein, which preferably comprises ILM and PTM, PTM and VLM, or PTM and CLM, or PTM and MLM, linked via a linker moiety as otherwise described herein, where VLM / ILM / CLM / MLM is The PTM binds to the PTM via a linker, targeting and degrading the protein it binds to. Similarly, the PTM can be linked to the VLM, CLM, MLM, or ILM via a linker, targeting proteins or polypeptides for degradation. Degradation of the target protein occurs when the target protein is positioned in close proximity to the E3 ubiquitin ligase, resulting in degradation of the target protein / inhibition of the target protein's effects and regulation of protein levels. The regulation of protein levels brought about by this disclosure provides a therapeutic effect on a pathological condition or state, which is regulated via the target protein by reducing its level in patient cells.

[0036] In yet another embodiment, this specification provides a method for treating or improving a disease, disorder or its symptoms in a subject or patient, such as an animal or human, the method comprising administering a composition to the subject in need of such treatment or improvement, in which case the composition is effective in treating or improving a disease or disorder or its symptoms in the subject.

[0037] In another embodiment, this specification provides a method for identifying the degradation effect of a target protein in a biological system using the compounds of this disclosure.

[0038] The above general statements relating to usefulness are provided for illustrative purposes only and are not intended to limit the scope of this disclosure and the attached claims. Additional purposes and advantages relating to the compositions, methods, and processes of this disclosure will be apparent to those skilled in the art in view of the claims, detailed description, and examples. For example, various aspects and implementations of this disclosure The forms can be used in many combinations, all of which are expressly anticipated herein. These additional forms and embodiments are expressly included within the scope of this disclosure. Published documents and other materials used herein to explain the background of this disclosure and, in particular, to provide additional details relating to the implementation are incorporated by reference.

[0039] The accompanying drawings, incorporated into and forming part of this specification, illustrate several embodiments of the present disclosure and, together with the description in the specification, serve to illustrate the principles of the present disclosure. The drawings are for illustrative purposes only of the embodiments of the present disclosure and are not to be construed as limiting the present disclosure. Further objectives, features and advantages of the present disclosure will become apparent from the following detailed description, together with the accompanying drawings illustrating exemplary embodiments of the present disclosure. [Brief explanation of the drawing]

[0040] [Figure 1A]A diagram illustrating the general principles of the bifunctional compounds of this disclosure. (A) An exemplary bifunctional compound comprises a protein targeting moiety (PTM; dark shaded rectangle), a ubiquitin ligase binding moiety (ULM; light shaded triangle), and optionally a linker moiety (L; black line) that binds or connects the PTM to the ULM. (B) A diagram illustrating the functional applications of the bifunctional compounds described herein. Briefly, the ULM recognizes and binds to a specific E3 ubiquitin ligase, and the PTM binds to and recruits a target protein, bringing it into close proximity to the E3 ubiquitin ligase. Typically, the E3 ubiquitin ligase is complexed with an E2 ubiquitin-binding protein and, either alone or via the E2 protein, catalyzes ubiquitination via isopeptide bonds to lysine on the target protein (dark circle). The polyubiquitinated protein (far right) is then targeted for degradation by the cellular proteasomal mechanism. [Figure 1B] A diagram illustrating the general principles of the bifunctional compounds of this disclosure. (A) An exemplary bifunctional compound comprises a protein targeting moiety (PTM; dark shaded rectangle), a ubiquitin ligase binding moiety (ULM; light shaded triangle), and optionally a linker moiety (L; black line) that binds or connects the PTM to the ULM. (B) A diagram illustrating the functional applications of the bifunctional compounds described herein. Briefly, the ULM recognizes and binds to a specific E3 ubiquitin ligase, and the PTM binds to and recruits a target protein, bringing it into close proximity to the E3 ubiquitin ligase. Typically, the E3 ubiquitin ligase is complexed with an E2 ubiquitin-binding protein and, either alone or via the E2 protein, catalyzes ubiquitination via isopeptide bonds to lysine on the target protein (dark circle). The polyubiquitinated protein (far right) is then targeted for degradation by the cellular proteasomal mechanism. [Figure 2A] [Figure 2A-1] to [Figure 2A-88] Table 1A. Exemplary protein-targeting moieties and compounds of the present disclosure. [Figure 2B] [Figure 2B-1] to [Figure 2B-117] Table 1B. Exemplary protein-targeting moieties and compounds of the present disclosure. [Figure 2C][Figure 2C-1] to [Figure 2C-40] Table 1C. Exemplary protein-targeting moieties and compounds of the present disclosure. [Figure 2D] [Figure 2D-1] to [Figure 2D-6] Table 1D. Exemplary protein-targeting moieties and compounds of the present disclosure. [Figure 3A] [Figures 3A-1] to [Figures 3A-71] Table 2A. Data for exemplary protein targeting moieties and compounds of this disclosure. [Figure 3B] [Figures 3B-1] to [Figures 3B-63] Table 2B. Data for exemplary protein-targeting moieties and compounds of this disclosure. [Figure 3C] [Figure 3C-1] to [Figure 3C-20] Table 2C. Data for exemplary protein-targeting moieties and compounds of this disclosure. [Figure 3D] [Figure 3D-1] to [Figure 3D-4] Table 2D. Exemplary protein targeting moieties and compound data of the present disclosure. [Figure 4] A diagram illustrating the general principles of bifunctional compounds in this disclosure. [Figure 5] The exemplary bifunctional compounds of this disclosure induce mutant-selective degradation of BRAF. [Figure 6A] The exemplary bifunctional compounds of this disclosure induce mutant BRAF degradation, inhibit cell proliferation, and suppress MAPK signaling while preserving wild-type BRAF. [Figure 6B] The exemplary bifunctional compounds of this disclosure induce mutant BRAF degradation, inhibit cell proliferation, and suppress MAPK signaling while preserving wild-type BRAF. [Figure 6C] [Figure 6C-1]~[Figure 6C-2] Exemplary bifunctional compounds of this disclosure induce mutant BRAF degradation, inhibit cell proliferation, and suppress MAPK signaling while preserving wild-type BRAF. [Figure 7] The exemplary bifunctional compounds of this disclosure induce degradation of the vemurafenib-resistant mutant p61. [Figure 8A] The exemplary bifunctional compounds of this disclosure induce degradation of mutant BRAF in vivo (a) and reduce tumor volume (B). [Figure 8B] The exemplary bifunctional compounds of this disclosure induce degradation of mutant BRAF in vivo (a) and reduce tumor volume (B). [Figure 9A] The underlying mechanism of selectivity in exemplary bifunctional compounds. [Figure 9B] The underlying mechanism of selectivity in exemplary bifunctional compounds. [Figure 10] Wild-type BRAF is unable to recruit Cullin 2 (active E3 ligase). [Modes for carrying out the invention]

[0041] The following is a detailed description provided to assist those skilled in the art in implementing this disclosure. Those skilled in the art may modify and change the embodiments described herein without departing from the spirit or scope of this disclosure. All published documents, patent applications, patents, drawings and other references referenced herein are expressly incorporated in their entirety by reference.

[0042] A bifunctional or chimeric construct that binds an E3 ubiquitin ligase protein to a target protein can be used to target E3 ubiquitin ligase proteins (e.g., apoptosis inhibitor (IAP), von Hippel-Rindo E3 ubiquitin ligase (VHL), Cereblon E3 ubiquitin ligase, or mouse double minute 2 homolog (MDM2) E3 ubiquitin ligase). This disclosure describes compositions and methods relating to the surprising and unexpected discovery of ubiquitinating target proteins when they are positioned in close proximity. Accordingly, this disclosure provides compounds and compositions comprising an E3 ubiquitin ligase binding moiety (ULM) bound to a protein target binding moiety (PTM), thereby resulting in ubiquitination of a selected target protein, which in turn leads to proteasome degradation of the target protein (Figure 1). (See [reference]). This disclosure also provides a library of compositions and their uses.

[0043] In certain embodiments, this disclosure relates to ligands, for example, small molecule ligands (i.e., 2,000 (Having molecular weights of less than Dalton, 1,000 Dalton, 500 Dalton, or 200 Dalton) The invention provides a compound that can bind to a ubiquitin ligase, such as IAP, VHL, MDM2, or cereblon. The compound also includes a moiety that can bind to the target protein in such a way that it positions the target protein in close proximity to the ubiquitin ligase, causing the degradation (and / or inhibition) of the protein. In addition to the above, "small molecule" may mean that the molecule is non-peptidyl, i.e., 4, 3, or 2 molecules. They often contain fewer amino acids and are therefore not considered peptides. According to this specification, PTM, ULM, or PROTAC molecules may be small molecules.

[0044] Unless otherwise defined, all technical and scientific terms used herein are: The terms used herein have the same meaning as those generally understood by those skilled in the art to which this disclosure pertains. The technical terms used herein are for illustrative purposes only of describing specific embodiments and are not intended to limit this disclosure.

[0045] Where a range of values ​​is provided, unless otherwise explicitly stated by the context (for example, in the case of a group containing a certain number of carbon atoms, the number of carbon atoms that fall within that range is provided), it should be understood that each intervening value between that range and any other specified range, up to one-tenth of the lower limit unit, or intervening value within that specified range, is included within the scope of the invention. The upper and lower limits of these smaller ranges may independently be included within even smaller ranges, which are also included in this disclosure and constitute any specifically excluded boundary values ​​within a specified range. Where a specified range includes one or both of the boundary values, ranges excluding one or both of those included boundary values ​​are also included in this disclosure.

[0046] The following terms are used to describe this disclosure. If a term is not specifically defined herein, it shall be given the meaning that is known in the art to those skilled in the art to the extent that the term is used in describing this disclosure.

[0047] Where used herein, the articles "a" and "an" are used as more descriptively than the context would indicate. Unless otherwise indicated, the article is used herein to refer to one or more (i.e., at least one) of its grammatical objects. For example, “element” means one or more elements.

[0048] When used herein in this specification and in the claims, the phrase “and / or” should be understood to mean “either or both” of the elements that are thus combined. That is, in some examples the elements exist together, and in other examples they exist separately. Multiple elements listed using “and / or” should be interpreted similarly; that is, “one or more” of the elements are thus combined. Other elements other than those specifically identified by the “and / or” clause may exist, whether or not they are related to those specifically identified elements. Therefore, in a non-restrictive example, when used in conjunction with open-ended wording such as “including,” the reference “A and / or B” may, in one embodiment, refer only to A (and optionally, other than B). In another embodiment, it may refer only to B (optionally including elements other than A); in yet another embodiment, it may refer to both A and B (optionally including other elements); and so on.

[0049] As used herein and in the claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when separating items in a list, “or” or “and / or” should be interpreted as inclusive; that is, including many elements, or at least one of a list of elements, but also including multiple elements, and optionally additional items not listed. Only terms that clearly suggest the opposite, such as “exactly one of ~,” or “exactly one of ~,” or, as used in a claim, “consisting of ~,” refer to the inclusion of many elements, or exactly one of a list of elements. Generally as used herein, the term “or” should be interpreted as indicating an exclusive choice (i.e., “one or the other, but not both”) only when preceded by an exclusive term, such as “either,” “one of ~,” “only one of ~,” or “exactly one of ~.”

[0050] In the claims and the above description, the words "comprising," "containing," "carrying," "having," and "containing" are used. g) All transitional phrases such as "involving," "holding," and "composed of" should be understood as non-restrictive, meaning they include them but are not restricted. "consisting of" and "essentially consisting of" Only the transitional phrase "ru (consisting essentially of)" is either restrictive or semi-restrictive. This is a transitional clause, and this is described in Section 2111.03 of the U.S. Patent Examination Standards. It is.

[0051] Where used herein, in the specification and claims, the phrase “at least one” with respect to a list of one or more elements should be understood to mean at least one element selected from any one or more elements in the element list, but not necessarily including at least one of all elements specifically listed in the element list, nor excluding any combination of elements in the element list. Furthermore, this definition allows for the existence of elements other than those specifically identified in the element list to which the phrase “at least one” refers, regardless of whether those specifically identified elements are related or not. Thus, as a non-restrictive example, “at least one of A and B” (or equivalently, “at least one of A or B,” or equivalently, “at least one of A and / or B”) means that in one embodiment, B is absent. (and optionally include elements other than B), optionally include multiple A's, and refer to at least one Yes; in another embodiment, it may refer to at least one which does not have A (and optionally includes elements other than A), and optionally includes multiple B; in yet another embodiment, it may refer to at least one which optionally includes multiple A, and at least one which optionally includes multiple B (and optionally includes other elements). etc.

[0052] In any particular method described herein that includes multiple steps or operations, the order of the steps or operations of the method is not necessarily limited to the order in which the steps or operations of the method are listed, unless otherwise suggested by the context.

[0053] "Co-administration" and "administering simultaneously (co-administering)" The terms "combination therapy" or "simultaneous administration" refer to simultaneous administration (two or more treatments). This refers to both the simultaneous administration of drugs and the administration of therapeutic agents at different times while a certain amount, preferably an effective amount, of the therapeutic agents is simultaneously present in the patient's body (administering one or more therapeutic agents at different times than the administration of additional therapeutic agents). In a particular preferred embodiment, one or more of the compounds described herein are co-administered in combination with at least one additional bioactive agent, particularly an anticancer agent. In a particularly preferred embodiment, the co-administration of the compounds results in synergistic activity and / or therapeutic effects, including anticancer activity.

[0054] Where used herein, unless otherwise indicated, the term “compound” means any specific chemical compound disclosed herein, including tautomers, positional isomers, geometric isomers, and stereoisomers, including, where appropriate, optical isomers (enantiomers) and other stereoisomers (diastereomers), as well as pharmaceutically acceptable salts and derivatives, including, where appropriate in context, its prodrug and / or deuterated forms. An expected deuterated small molecule is a small molecule in which one or more hydrogen atoms contained in the drug molecule are substituted with deuterium.

[0055] In its contextual use, the term "compound" generally refers to a single compound, but may also include other compounds, such as stereoisomers, positional isomers, and / or optical isomers (including racemic mixtures) of the disclosed compound, as well as specific enantiomeric or enantiomeric-enriched mixtures. The term also, in context, refers to prodrug forms of compounds modified to facilitate administration and deliver the compound to the active site. Note that the description of the compound includes many substituents and, in particular, related variables. Those skilled in the art will understand that the molecules shown are stable compounds, as outlined below. Where bonds are shown, both double and single bonds are shown or understood in the context of the shown compounds and known rules regarding valency interactions.

[0056] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transport of ubiquitin to specific substrate proteins, thereby making those substrate proteins targets for degradation. For example, IAP E3 ubiquitin ligase proteins, either alone or in combination with E2 ubiquitin-conjugating enzymes, attach ubiquitin to lysine on a target protein, and then target that specific protein substrate for proteasomal degradation. Therefore, E3 ubiquitin ligases, either in complex with E2 ubiquitin-conjugating enzymes or alone, are involved in the transport of ubiquitin to the target protein. Generally, ubiquitin ligases are involved in polyubiquitination, where a second ubiquitin is attached to a first ubiquitin; and a third ubiquitin is attached to a second ubiquitin. Polyubiquitination marks proteins for proteasomal degradation. However, some ubiquitination events are limited to monoubiquitination, in which case only one ubiquitin molecule is attached to the substrate molecule by a ubiquitin ligase. Monoubiquitinated proteins are not targets for proteasome degradation, but instead may change their intracellular location and function through binding to other proteins that have domains capable of binding ubiquitin. Further complicating matters is the fact that other lysines on ubiquitin can be targeted by E3 and form chains. The most common lysine is Lys48 on the ubiquitin chain, which is recognized by the proteasome. This is lysine, which is used to produce polyubiquitin.

[0057] The terms “patient” or “subject” are used throughout this specification to describe animals, preferably humans or livestock, to which treatment, including prophylactic treatment with the compositions of this disclosure, is provided. In relation to the treatment of infections, conditions, or pathologies specific to certain animals, such as human patients, the term “patient” refers to certain animals, including, for example, domestic animals such as dogs or cats, or agricultural animals such as horses, cattle, or sheep. Generally, in this disclosure, the term “patient” refers to human patients unless otherwise suggested or implied by the context in which the term is used.

[0058] The term "effective," when used within the context of its intended use, is used to describe the amount of a compound, composition, or component that produces the intended result. The term "effective" includes all other terms for effective quantity or effective concentration, which are described or used separately in this application.

[0059] Compounds and compositions In one embodiment, this specification relates to the IAP E3 ubiquitin ligase binding moiety (ILM), cele Bron E3 ubiquitin ligase binding site (CLM), von Hippel-Rindo E3 ubiquitin The present invention provides a compound comprising an E3 ubiquitin ligase binding moiety (ULM), which is a ligase (VHL) binding moiety (VLM) and / or a mouse double minute 2 homologue (MDM2)E3 ubiquitin ligase binding moiety (MLM). In exemplary embodiments, the ULM is chemically ligase according to the following structure. It is linked to the target protein binding site (PTM) via a linker (L): (A) PTM-L-ULM In the formula, L is a bond or chemical linker group, and ULM is the E3 ubiquitin ligase binding site. The PTM is the target protein binding site. The number of parts in the compounds described herein, and / or their relative positions, are provided for illustrative purposes only. As will be understood by those skilled in the art, the compounds described herein can be synthesized using any desired number of functional group parts and / or at the relative positions of each functional group part.

[0060] The terms ULM, ILM, VLM, MLM, and CLM are used unless otherwise indicated by the context. It is used in an inclusive sense. For example, the term ULM encompasses all ULMs, including those that bind to IAP (i.e., ILM), MDM2 (i.e., MLM), cereblon (i.e., CLM), and VHL (i.e., VLM). Furthermore, the term ILM encompasses all possible IAP E3 ubiquitin ligase binding sites, the term MLM encompasses all possible MDM2 E3 ubiquitin ligase binding sites, and the term VLM encompasses all possible V The term CLM encompasses all cereblon-linked moieties, including the HL-linked moieties. .

[0061] In another embodiment, the present disclosure provides bifunctional or polyfunctional compounds (e.g., PROTACs) useful for controlling protein activity by inducing the degradation of target proteins. In certain embodiments, the compounds are directly or indirectly bound to a portion of the target protein that binds to it (i.e., a protein targeting portion or "PTM"), for example, by covalent bond. It includes ILM or VLM or CLM or MLM. In certain embodiments, ILM / VLM / CLM / MLM and PTM are linked or bonded via a chemical linker (L). ILM is bound to IAP E3 ubiquitin ligase, VLM is bound to VHL, and CLM is bound to cereblon E3 ubiquitin ligase. MLM binds to MDM2 E3 ubiquitin ligase, and PTM binds to the target protein. By recognizing and positioning the ubiquitin ligase protein in close proximity to the target protein, the interaction between each part and its target promotes the degradation of the target protein. Exemplary bifunctional compounds can be shown as follows: (B) PTM-ILM (C) PTM-CLM (D) PTM-VLM (E) PTM-MLM In certain embodiments, the bifunctional compound further comprises a chemical linker (L). For example, the bifunctional compound can be described as follows: (F) PTM-L-ILM (G) PTM-L-CLM (H) PTM-L-VLM (I) PTM-L-MLM In the formula, PTM is the protein / polypeptide targeting portion, L is the chemical linker, and ILM The IAP E3 ubiquitin ligase binding site is the Cereblon E3 ubiquitin ligase binding site, and CLM is the cereblon E3 ubiquitin ligase binding site. These are binding sites; VLM is the VHL binding site, and MLM is the MDM2 E3 ubiquitin ligase binding site.

[0062] In certain embodiments, ULM (e.g., ILM, CLM, VLM, or MLM) is less than approximately 200 μM. IC 50 IC exhibits activity towards or binds to E3 ubiquitin ligases (e.g., IAP E3 ubiquitin ligase, Cereblon E3 ubiquitin ligase, VHL, or MDM2 E3 ubiquitin ligase). 50 This can be determined, for example, by any method known in the art, such as a fluorescence polarization assay.

[0063] In certain additional embodiments, the difunctional compounds described herein are less than about 100, 50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 mM, or less than about 100, 50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 μM, or less than about 100, 50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 nM, or less than about 100, 50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 pM IC 50 It exhibits activity.

[0064] In certain embodiments, the compounds described herein include multiple PTMs (same or different proteins) This includes multiple ULMs (which target a chemical target), one or more ULMs (i.e., multiple / different E3 ubiquitin ligases, e.g., VHL, IAP, cereblon, and / or moieties that specifically bind to MDM2), or combinations thereof. In this configuration, the PTM and ULM (e.g., ILM, VLM, CLM, and / or MLM) can be linked directly or via one or more chemical linkers, or a combination thereof. In additional embodiments, if the compound has multiple ULMs, those ULMs may be for the same E3 ubiquitin ligase, or each ULM may be specific to a different E3 ubiquitin ligase. They may be bonded to each other. In further embodiments, the compound may have multiple PTMs. These PTMs may bind to the same target protein, or each PTM may specifically bind to a different target protein.

[0065] In certain embodiments, if a compound contains multiple ULMs, those ULMs are identical. In a typical embodiment, the compound is a multiple ULM (e.g., ULM, ULM'), directly or chemically phosphorus Includes at least one PTM that is coupled to the ULM via a Kerr(L) or both. In a further embodiment, the compound containing multiple ULMs further contains multiple PTMs. In a further embodiment, the PTMs are identical or optionally different. In a further embodiment, if the PTMs are different, each PTM may bind to the same protein target or may specifically bind to different protein targets.

[0066] In certain embodiments, the compound may contain multiple ULMs and / or multiple ULMs'. In further embodiments, the compound containing at least two different ULMs, multiple ULMs, and / or multiple ULMs' is transmitted directly, via a chemical linker, or both. The invention further comprises at least one PTM bonded to ULM or ULM'. In any of the embodiments, a compound containing at least two different ILMs may further contain multiple PTMs. In further additional embodiments, the PTMs may be identical or optionally different. In even further embodiments, if the PTMs are different, each PTM may bind to the same protein target or may bind specifically to different protein targets. In even further embodiments, the PTM itself may be an ULM (or ULM') such as ILM, VLM, CLM, MLM, ILM', VLM', CLM', and / or MLM'.

[0067] In additional embodiments, this specification provides compounds described herein, including their enantiomers, diastereomers, solvates, and polymorphs, and their pharmaceutically acceptable salt forms, such as acid salt forms and base salt forms.

[0068] In this specification, the term “independently” is used to indicate that variables applied independently change independently from one application to the next.

[0069] The term "alkyl" in this context should mean a linear, branched, or cyclic fully saturated hydrocarbon radical or alkyl group, preferably C1-C 10 , more preferably C1-C6 or C1-C3 alkyl groups, which may be optionally substituted. Examples of alkyl groups include, in particular, methyl, ethyl, n-butyl, sec-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl, 2-methylpropyl, and cyclo These include propyl, cyclopropyl-methyl, cyclobutyl, cyclopentyl, cyclopentylethyl, cyclohexylethyl, and cyclohexyl. In certain embodiments, the alkyl group is terminally capped with a halogen group (At, Br, Cl, F, or I). In certain preferred embodiments, the compounds according to the present disclosure may be used to covalently bond to a dehalogenase enzyme. These compounds generally include a side chain (often bonded via a polyethylene glycol group), the side chain terminated at its distal end with an alkyl group having a halogen substituent (often chlorine or bromine), thereby creating a covalent bond between the compound containing the portion and the protein.

[0070] The term "alkenyl" refers to a linear, branched chain containing at least one C=C bond. Or is a ring-shaped C2-C 10 This refers to (preferably C2-C6) hydrocarbon radicals.

[0071] The term "alkynyl" refers to a linear, branched, or cyclic C2-C bond containing at least one C≡C bond. 10 This refers to (preferably C2-C6) hydrocarbon radicals.

[0072] The term "alkylene" may be optionally substituted when used - (CH2) n - Refers to a group (n is generally an integer from 0 to 6). When substituted, the alkylene group is one of the methylene groups. Preferably, one or more C1-C6 alkyl groups (including cyclopropyl or t-butyl groups) are substituted, but one or more halo groups, preferably 1 to 3 halo groups, or one or two hydroxyl groups, O-(C1-C6 alkyl) groups, or as otherwise specified herein. The amino acid side chains may be substituted with the disclosed amino acid side chains. In certain embodiments, the alkylene group may be substituted with a urethane or alkoxy group (or other group), which may further be a polyethylene glycol chain (1 to 10, preferably 1 to 6, often 1 to 4 ethylene glycols). The alkyl chain is substituted with a glycol unit, which is substituted with an alkyl group (preferably on the distal end of the polyethylene glycol chain, but not limited to) and the alkyl chain is substituted with a halogen group, preferably a chlorine group. In yet another embodiment, the alkylene (often methylene) group is replaced with, for example, natural or unnatural amino acids, such as alanine, β-alanine, and argy It may be substituted with amino acid side chain groups such as nin, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline, serine, threonine, valine, tryptophan, or tyrosine.

[0073] The term "unsubstituted" shall mean that only hydrogen atoms are substituted. The range of carbon atoms including C0 means that there are no carbon atoms and they are replaced by H. Therefore, the range of carbon atoms C0-C6 includes 1, 2, 3, 4, 5, and 6 carbon atoms, with H instead of carbon in the case of C0.

[0074] The terms “substituted” or “optionally substituted” mean independently one or more substituents at any carbon (or nitrogen) position on the molecule in the context (up to five substituents independently on a portion of the compound in the present disclosure, preferably up to three substituents, often one or two substituents, which may include substituents that can be further substituted themselves) (i.e., if there are multiple substituents, each substituent is independent of the other substituents), and the substituents include hydroxyl, thiol, carboxyl, cyano (C≡N), and nitro (NO2). , halogens (especially alkyl groups, preferably 1, 2, or 3 halogens on a methyl group such as trifluoromethyl), alkyl groups (preferably C1-C 10 , more preferably C1-C6), aryl (particularly phenyl and substituted phenyl, e.g., benzyl or benzoyl), alkoxy group (preferably C1-C6 alkyl or aryl; phenyl and substituted phenyl) including) thioether (C1-C6 alkyl or aryl), acyl (preferably C1-C6 acyl kyl), ester or thioester (preferably C1-C6 alkyl or aryl), al chylene ester (the bond thereof is not an ester functional group but on an alkylene group and is preferably substituted with a C1-C6 alkyl or aryl group), preferably those containing C1-C6 alkyl or aryl, halogen (preferably F or Cl), amine (including 5- or 6-membered cyclic al kyleneamine and further including C1-C6 alkylamine or C1-C6 dialkylamine, and the alkyl group may be substituted with one or two hydroxyl groups), or optionally substituted -N(C0-C6 alkyl)C(O)(O-C1-C6 alkyl) group (which may be optionally substituted with a polyethylene glycol chain and to which an alkyl group containing one halogen, preferably a chlorine substituent, is further bonded), hydrazine, amide, which preferably contains one or two C1-C6 alkyl groups (including carboxamide optionally substituted with one or two C1-C6 alkyl groups), alkanol (preferably C1-C6 alkyl or aryl), or those substituted with alkanoic acid (preferably C1-C6 alkyl or aryl). The substituents according to the present disclosure may include, for example, -SiR1R2R3 group, wherein each of R1 and R2 is described separately herein, and R3 is H or a C1-C6 alkyl group, and preferably R1, R2, R3 are C1-C3 alkyl groups (including isopropyl or t-butyl group) in the present context. Each of the above groups may be directly bonded to the substituted moiety, or the substituent may be via an optionally substituted (CH2) m -, or via an optionally substituted -(OCH2) m -, -(OCH2CH2) m - or -(CH2CH2O) m-The substituted moieties (preferably aryl or heteroaryl moieties) may be bonded via the -(CH2) group, and these may be substituted with one or more of the substituents described above. m -or-(CH2) n - The group or other chains, such as the ethylene glycol chain specified above, may be substituted on any of the chains. Preferred substituents on the alkylene group include halogens or C1-C6 (preferably C1-C3) alkyl groups. This may optionally be substituted with one or two hydroxyl groups, one or two ether groups (O-C1-C6 groups), up to three halo groups (preferably F), or amino acid side chains as otherwise described herein, and optionally substituted with amides (preferably substituted carboxamides as described above) or urethane groups (often one or two C0-C6 groups). Examples include groups having alkyl substituents, which may also be further substituted. In certain embodiments, the alkylene group (often a single methylene group) is substituted with one or two optionally substituted C1-C6 alkyl groups, preferably C1-C4 alkyl groups, most often methyl or O-methyl groups, or amino acid side chains as otherwise described herein. The portion of the molecule in this disclosure may be substituted with up to five substituents, preferably up to three. In most cases, the portion substituted in this disclosure is substituted with one or two substituents.

[0075] The term "substituted" (each substituent being independent of any other substituent) in the context of its use refers to C1-C6 alkyl, C1-C6 alkoxy, halogen, amide, carboxamide, sulfonamide, sulfone, keto, carboxy, C1-C6 ester (oxy) Esters or carbonyl esters), C1-C6 keto, urethane-OC(O)-NR1R2 or -N(R1)-C(O)-O-R1, nitro, cyano, and amines (especially C1-C6 alkylene-NR1R2, mono or This also means di-C1-C6 alkyl-substituted amines, which may optionally be substituted with one or two hydroxyl groups. Each of these groups contains 1 to 6 carbon atoms in the context unless otherwise indicated. In some embodiments, preferred substituents may be, depending on the context of use of the substituent, e.g., -NH-, -NHC(O)-, -O-, =O, -(CH2) m - (where m and n are 1, 2, 3, 4, 5, or 6 in the context), -S-, -S(O)-, SO2- or -NH-C(O)-NH-, -(CH2) n OH, -(CH2) n SH, -(CH2) n COOH, C1-C6 alkyl, -(CH2) n O-(C1-C6 alkyl), -(CH2) n C(O)-(C1-C6 alkyl),-(CH2) n OC(O)-(C1-C6 alkyl),-(CH2) n C(O)O-(C1-C6 alkyl),-(CH2) n NHC(O)-R1, -(CH2) n C(O)-NR1R2, -(OCH2) n OH, -(CH2O) n COOH, C1-C6 alkyl, -(OCH2) n O-(C1-C6 alkyl), -(CH2O) n C(O)-(C1-C6 alkyl),-(OCH2) n NHC(O)-R1, -(CH2O) n C(O)-NR1R2, -S(O)2-R S ,-S(O)-R S (R S C1-C6 Alky Ru or -(CH2) m -NR1R2 group), NO2, CN, or halogen (F, Cl, Br, I, preferably) R1 and R2 are each H or C1-C6 alkyl groups (one or two hydroxyl groups, or up to three halogen groups, preferably optionally substituted with fluorine) in the context. The term “substituted” also means optionally substituted aryl or heteroaryl groups or optionally substituted heterocyclic groups as otherwise described herein, in the chemical background of the specified compounds and substituents used. The alkylene group may also be substituted as otherwise disclosed herein, preferably optionally substituted with C1-C6 alkyl groups (methyl, ethyl or hydroxyl). Xyxymethyl or hydroxyethyl is preferred, which in turn provides a chiral center; the side chain of an amino acid group as otherwise described herein; the amide group or urethane group described above; the OC(O)-NR1R2 group, where R1 and R2 are groups as otherwise described herein, may be substituted, but many other groups can also be used as substituents. Various optional substituted portions may have three or more substituents, preferably three or fewer substituents, and preferably one Alternatively, substitution may be performed with two substituents. In a compound, substitution is required at a specific position of the molecule. While this is required (primarily due to valency), it should be noted that if a substitution is not shown, the substituent is considered or understood to be H unless otherwise indicated in the context of that substitution. I want to.

[0076] The terms “aryl” or “aromatic” in context refer to a substituted (as otherwise specified herein) or unsubstituted monovalent aromatic radical having a single ring (e.g., benzene, phenyl, benzyl) or a fused ring (e.g., naphthyl, anthracenylphenyl, phenantrenyl, etc.), which can be attached to a compound at any available stable position on the ring or as otherwise specified in the presented chemical structure, in accordance with this disclosure. Other examples of aryl groups in context include heterocyclic aromatic ring systems, such as “heteroaryl” groups having one or more nitrogen, oxygen, or sulfur atoms in the ring, such as imidazole, furyl, pyrrole, furanyl, thiene, thiazole, pyridine, pyrimidine, pyrazine, triazole, oxazole, etc., or fused ring systems, such as indole, quinoline, indidine, azaindridine, benzofurazan, etc., which may be optionally substituted as described above.Examples of heteroaryl groups that may be mentioned include pyrrole, pyridine, pyridone, pyridazine, pyrimidine, pyrazine, pyrazole, imidazole, triazole, triazine, tetrazole, indole, isoindole, indidine, azaindidine, purine, indazole, quinoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, dihydroisoquinoline, tetrahydroisoquinoline, quinoridine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinolin, pteridine, imidazopyridine, imidazotriazine, pyrazinopyridazine, acridine, phenanthridine, carbazole, carbazoline, pyrimidine, phenanthroline, phenacene, oxadiazole, benzimidazole, pyrrolop Nitrogen-containing heteroaryl groups such as lysine, pyrrolopyrimidine, and pyridopyrimidine; sulfur-containing aromatic heterocycles such as thiophene and benzothiophene; oxygen-containing aromatic heterocycles such as furan, pyran, cyclopentapyran, benzofuran, and isobenzofuran; and aromatics containing two or more heteroatoms selected from nitrogen, sulfur, and oxygen, such as thiazole, thiadizol, isothiazole, benzoxazole, benzothiazole, benzothiadiazole, phenothiazine, isoxazole, furazan, phenoxazine, pyrazoloxazole, imidazothiazole, thienofuran, phlopyrrole, pyridoxazine, phlopyridine, phlopyrimidine, thienofyrimidine, and oxazole. Examples include complex algebras, all of which can be arbitrarily permuted.

[0077] The term "substituted aryl" refers to an aromatic carbon ring composed of at least one aromatic ring, or multiple fused rings, at least one of which are aromatic, where the ring is substituted with one or more substituents. For example, the aryl group may contain substituents selected from the following:-(CH2) n OH, -(CH2) n -O-(C1-C6)alkyl, -(CH2) n -O-(CH2) n -(C1-C6) alkyl, -(CH2) n-C(O)(C0-C6)alkyl, -(CH2) n -C(O)O(C0-C6)alkyl, -(CH2) n -OC(O)(C0-C6)alkyl, amine, mono or di-(C1-C6 alkyl)amine, The alkyl group on the amine may optionally consist of one or two hydroxyl groups or up to three halo (preferably F, Cl) groups, OH, COOH, C1-C6 alkyl groups, preferably CH3, CF3, OMe, OCF3, NO2, or CN groups (each of which is at the ortho, meta, and / or para positions of the phenyl ring). Substituted with an ortho, meta, and / or para (preferably para) position of the phenyl ring, optionally substituted with a phenyl group (preferably the phenyl group itself is substituted with a linker group attached to a PTM group containing a ULM group), and / or substituted with at least one of F, Cl, OH, COOH, CH3, CF3, OMe, OCF3, NO2, or CN group (ortho, meta, and / or para, preferably para) position of the phenyl ring, optionally substituted with a naphthyl group, optionally substituted with a heteroaryl group, optionally substituted with an isoxazole, preferably methyl-substituted with an isoxazole, optionally substituted with an oxazole, optionally substituted with an oxazole, optionally substituted with an oxazole, optionally substituted with an oxazole, optionally substituted with an oxazole, optionally substituted with an oxazole, optionally substituted with an isothiazole , optionally substituted pyrroles including methyl-substituted pyrroles, optionally substituted imidazoles including methylimidazole, optionally substituted benzimidazole or methoxybenzylimidazole, optionally substituted oxyimidazole or methyloxyimidazole, optionally substituted diazole groups including methyldiazole groups, optionally substituted triazole groups including methyl-substituted triazole groups, optionally substituted pyridine groups including halo-(preferably F) or methyl-substituted pyridine or oxapyridine groups (wherein the pyridine group is bonded to the phenyl group by oxygen), optionally substituted furan, optionally substituted benzofuran, optionally substituted dihydrobenzofuran, optionally substituted indole, indidine or azaindridine (2, 3, or 4-azandridine), optionally substituted quinoline, and combinations thereof.

[0078] "Carboxyl" means --C(O)OR, where R is hydrogen, alkyl, substituted alkyl, These are aryl, substituted aryl, heteroaryl, or substituted heteroaryl substituents, while these generic substituents have the same meaning as defined herein for the corresponding groups.

[0079] The terms "heteroaryl" or "hetaryl" are not limited to, but may include, optionally substituted quinolines (which may be added to the pharmacophore or substituted on any carbon atom within the quinoline ring), optionally substituted indoles (including dihydroindole), optionally substituted indidines, optionally substituted azaindidines (2, 3, or 4-azindidines), optionally substituted benzimidazoles, benzodiazoles, benzoxofrans, optionally substituted imidazoles, optionally substituted isoxazoles, optionally substituted oxazoles (preferably methyl-substituted), optionally substituted diazoles, optionally substituted triazoles, tetrazoles, optionally substituted benzofurans, optionally substituted thiophenes, optionally substituted thiazoles (preferably methyl-substituted and / or thiol-substituted), optionally substituted isothiazoles, optionally substituted triazoles (preferably methyl groups, triisopropylsilyl groups, optionally substituted -(CH2) m -O-C1-C6 alkyl group, or optionally substituted -(CH2) m -C(O)-O-C1-C6 alkyl group is substituted This can mean a group consisting of 1,2,3-triazole, optionally substituted pyridine (2,3, or 4-pyridine), or a group with the following chemical structure:

[0080] [ka]

[0081] During the ceremony: S c CHR SS , NR URE , or O; R HET This consists of H, CN, NO2, halo (preferably Cl or F), and optionally substituted C1-C6 alkyl ( Preferably one or two hydroxyl groups or up to three halo groups (e.g., CF3) O(C1-C6 alkyl) (preferably one or two) are optionally substituted. A hydroxyl group or an acetylene group (substituted with up to three halo groups), or optionally substituted with a -C≡CR group. a And in the formula R a is an acetylene group which is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl group); R SS This is H, CN, NO2, halo (preferably F or Cl), optionally substituted C1-C6 alkyl ( Preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted O-(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted -C(O)(C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups); R URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or -C(O)(C1-C6 alkyl), where each group is optionally substituted with one or two hydroxyl groups or up to three halo groups, preferably fluorine groups, or optionally substituted heterocycles, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, etc., each of which is optionally substituted, and Y C is N or CR YC And in the formula, R YC This can be H, OH, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted acetylene group-C≡CR a And in the formula, R a The group is an acetylene group which is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl group).

[0082] The terms "aralkyl" and "heteroarylalkyl" refer to groups that include aryl or heteroaryl, respectively, and alkyl, and / or heteroalkyl, and / or carbocyclic and / or heterocycloalkyl ring systems, as defined above.

[0083] As used herein, the term "arylalkyl" refers to the aryl group defined above that is attached to the alkyl group defined above. The arylalkyl group is attached to the parent part via an alkyl group, in this case having one to six carbon atoms. The aryl group in the arylalkyl group may be substituted as described above.

[0084] The term "heterocyclic" refers to a cyclic group containing at least one heteroatom, such as N, O, or S, which may be aromatic (heteroaryl) or non-aromatic. Therefore, heteroaryl moieties are included under the definition of heterocyclic, depending on their context of use. Exemplary heteroaryl groups are described above in this specification.

[0085] Exemplary heterocycles include, in particular, azetididine, benzimidazolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, benzoxazolyl, benzothiazolyl, benzothienyl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl, dioxanyl, dioxolanyl, ethyleneurea, 1,3-dioxolane, 1,3-dioxane, 1,4-dioxane, furyl, homopiperidinyl, imidazolyl, imidazolinyl, imidazolidinyl, indolinyl, indolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isoqui Examples include sazolidinil, isoxazolyl, morpholinil, naphthilidinil, oxazolidinil, oxazolyl, pyridone, 2-pyrrolidone, pyridine, piperazinil, N-methylpiperazinil, piperidinil, phthalimide, succinimide, pyrazinil, pyrazolinil, pyridyl, pyrimidinil, pyrrolidinil, pyrrolinil, pyrrolyl, quinolinil, tetrahydrofuranil, tetrahydropyranil, tetrahydroquinoline, thiazolidinil, thiazolyl, thienyl, tetrahydrothiophene, oxane, oxetanil, oxathiolanil, and thian.

[0086] The heterocyclic group may be optionally substituted with those selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxyl, keto, thioketo, carboxy, carboxyalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, oxo (=O), and -SO2-heteroaryl. Such a heterocyclic group may have a single ring or multiple fused rings. Examples of nitrogen heterocycles and heteroaryls include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indidine, isoindole, indole, indazole, purine, quinolidine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carborin, phenantholidine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, morpholino, piperidinyl, tetrahydrofuranyl, and N-alkoxy-nitrogen-containing heterocycles. The term "heterocyclic" also refers to any of the heterocycles. This also includes bicyclic groups that are condensed to a benzene ring, a cyclohexane ring, or another heterocycle (e.g., indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, etc.).

[0087] The term "cycloalkyl" includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, and consists of 3 to 20 carbon atoms. The term "substituted cycloalkyl" means, but is not limited to, monovalent groups derived from monocyclic or polycyclic alkyl groups or cycloalkanes as defined herein, such as saturated monocyclic hydrocarbon groups having a ring. The term "substituted cycloalkyl" means, but is not limited to, monocyclic or polycyclic alkyl groups substituted with one or more substituents such as amino, halogen, alkyl, substituted alkyl, carbyloxy, carbyl mercapto, aryl, nitro, mercapto, or sulfo, and these generic substituents have the same meaning as the definitions of the corresponding groups as defined herein.

[0088] "Heterocycloalkyl" refers to a monocyclic or polycyclic alkyl group in which at least one ring carbon atom of its cyclic structure is substituted with a heteroatom selected from the group consisting of N, O, S, or P. "Substitutive heterocycloalkyl" refers to a monocyclic or polycyclic alkyl group in which at least one ring carbon atom of its cyclic structure is substituted with a heteroatom selected from the group consisting of N, O, S, or P, and the group contains one or more substituents selected from the group consisting of halogen, alkyl, substituted alkyl, carbyloxy, carbyl mercapto, aryl, nitro, mercapto, or sulfo, but these generic substituents have the same meaning as the definition of the corresponding group as defined in this explanation.

[0089] The term "hydrocarbyl" means a compound containing carbon and hydrogen, which may be fully saturated, partially unsaturated, or aromatic, and which may include aryl, alkyl, alkenyl, and alkynyl groups.

[0090] In this specification, the term “independently” is used to indicate that variables applied independently change independently from one application to the next.

[0091] The term "lower alkyl" refers to methyl, ethyl, or propyl alkyl groups. The term "lower alkoxy" refers to methoxy, ethoxy, or propoxy compounds.

[0092] In any of the embodiments described herein, W, X, Y, Z, G, G', R, R', R'', Q1-Q4, and A can independently be covalently bonded to a linker and / or to one or more PTM, ULM, ILM, or ILM' groups.

[0093] Exemplary CLM Neo-imide compounds In one embodiment, this specification provides compounds useful for binding to and / or inhibiting cereblon. In a particular embodiment, the compound is selected from the group consisting of the following chemical structures:

[0094] [ka]

[0095] During the ceremony: In formulas (a) to (e) [e.g., (a1), (b), (c), (d1), (e), (f), (a2), (d2), (a3), and (a4)], W is independently CH2, O, CHR, C=O, SO2, NH, optionally substituted cycloalkyl (e.g., optionally substituted 3-6 membered cycloalkyl, optionally substituted cyclopropyl group, or optionally substituted cyclobutyl group), optionally substituted heterocycloalkyl, and Selected from the N-alkyl group; W3 is selected from C or N; In equations (a) to (e), X is either nonexistent or selected from the group O, S, and CH2; In equations (a) to (e), Y is independently CH2, -C=CR', NH, N-alkyl, N-aryl, or N-heta Selected from the group consisting of reels, N-cycloalkyls, N-heterocyclines, O, and S; In equations (a) to (e), Z is either nonexistent or selected from the group O, S, or CH2, provided that neither X nor Z is nonexistent or CH2; In equations (a) to (e), G and G' are independently H, and optionally substituted linear or branched A Lukil, OH, R'OCOOR, R'OCONRR”, -(CH2) n -OP(=O)(OC 1-6 Alkyl)(OH),-(CH2) n -OP(=O)(OC 1-6 Alkyl)2,-(CH2) n , -OP(=O)(OH)2, -CH2OCOO(CH2CH2O) n” CH3, Selected from the group of CH2-heterocyclyls optionally substituted with R', and benzyls optionally substituted with R'; n'' is an integer between 8 and 35 (for example, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35); Q1 to Q4 in equations (a) to (e) are each independently selected from H, R, N, or N-oxide. Represents the carbon C that is substituted with the group being substituted; In formulas (a) to (e), A is independently selected from the group consisting of H, optionally substituted linear or branched alkyl, cycloalkyl, Cl, and F; In equations (a) to (e), R is not limited but includes: H, -CONR'R”, -OR', -NR'R”, -SR', -SO2R', -SO2NR'R”, -CR'R”-, -CR'NR'R”-, (-CR'O) n’ R'', halogen , optionally substituted aryls (e.g., optionally substituted C5-C7 aryls), optionally substituted alkylaryls (e.g., alkylaryls containing at least one of optionally substituted C1-C6 alkyls, optionally substituted C5-C7 aryls, or combinations thereof), optionally substituted heteroaryls (e.g., optionally substituted C5-C7 heteroaryls) ), unsubstituted or substituted linear or branched alkyl (e.g., one or more halogens, cycloalkyl (e.g., C3-C6 cycloalkyl), or aryl (e.g., (e.g., C1-C6 linear or branched alkyl groups optionally substituted with C5-C7 aryl groups), optionally substituted alkoxy groups (e.g., methoxy, ethoxy, butoxy, propoxy, pentoxy or hexoxy; where alkoxy can be substituted with one or more halogens, alkyl, haloalkyl, fluoroalkyl, cycloalkyl (e.g., C3-C6 cycloalkyl) or aryl (e.g., C5-C7 aryl)), optionally substituted

[0096] [ka]

[0097] (For example, optionally substituted with one or more halogens, alkyls, haloalkyls, fluoroalkyls, cycloalkyls (e.g., C3-C6 cycloalkyls) or aryls (e.g., C5-C7 aryls), optionally substituted

[0098] [ka]

[0099] (For example, one or more halogens, alkyls, haloalkyls, fluoroalkyls, cycloalkyls (e.g., C3-C6 cycloalkyls) or aryls (e.g., C5-C7 aryls) as optional. ) which are substituted with, optionally substituted cycloalkyls (e.g., optionally substituted C3-C7 Cycloalkyls), optionally substituted heterocyclines (e.g., optionally substituted C3-C7 Heterocyclyl), -P(O)(OR')R'', -P(O)R'R'', -OP(O)(OR')R'', -OP(O)R'R'', -Cl, -F, -Br, -I, -CF3, -CN, -NR'SO2NR'R'', -NR'CONR'R'', -CONR'COR'', -NR'C(=N-CN)NR'R'', -C(=N-CN)NR'R'', -NR'C(=N-CN)R'', -NR'C(=C-NO2)NR'R'', -SO2NR'COR'', -NO2, -CO2R', -C(C=N-OR')R'', -CR'=CR'R'', -CCR', -S(C=O)(C=N-R')R'', -SF5 and -OCF3; Each of x, y, and z is independently 0, 1, 2, 3, 4, 5, or 6; In equations (a) to (e), R' and R'' are independently substituted with H, and can be linear or branched. alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic, -C(=O)R, optionally substituted heterocyclic Selected from krill; In equations (a) to (e), n and n' are each independently integers between 1 and 10 (for example, 1 to 4, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10);

[0100] [ka]

[0101] [ka]

[0102] Exemplary CLM In any of the compounds described herein, CLM is a chemical composition selected from the following group. Including construction:

[0103] [ka]

[0104] During the ceremony: In formulas (a) to (e) [e.g., (a1), (b), (c), (d1), (e), (f), (a2), (d2), (a3), and (a4)], W is independently selected from the group consisting of CH2, O, CHR, C=O, SO2, NH, optionally substituted cycloalkyls (e.g., optionally substituted 3-6 membered cycloalkyls, optionally substituted cyclopropyl groups, or optionally substituted cyclobutyl groups), optionally substituted heterocycloalkyls (e.g., optionally substituted 3-6 membered heterocycloalkyls), and N-alkyls. re; W3 is selected from C or N; In equations (a) to (e), X is either nonexistent or selected from the group O, S, and CH2; In equations (a) to (e), Y is independently CH2, -C=CR', NH, N-alkyl, N-aryl, or N-heta Selected from the group consisting of reels, N-cycloalkyls, N-heterocyclines, O, and S; In equations (a) to (e), Z is either nonexistent or selected from the group O, S, and CH2, provided that neither X nor Z is nonexistent or CH2; In equations (a) to (e), G and G' are independently H, and optionally substituted linear or branched A Lukil, OH, R'OCOOR, R'OCONRR”, -(CH2) n -OP(=O)(OC 1-6 Alkyl)(OH),-(CH2) n -OP(=O)(OC 1-6 Alkyl)2,-(CH2) n’ -OP(=O)(OH)2, -CH2OCOO(CH2CH2O) n” CH3, Selected from the group of CH2-heterocyclyls optionally substituted with R', and benzyls optionally substituted with R'; n'' is an integer between 8 and 35 (for example, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35); Q1 to Q4 in equations (a) to (e) are each independently selected from H, R, N, or N-oxide. Represents the carbon C that is substituted with the group being substituted; In formulas (a) to (e), A is independently selected from the group consisting of H, optionally substituted linear or branched alkyl, cycloalkyl, Cl, and F; In equations (a) to (e), R is not limited but includes: H, -CONR'R”, -OR', -NR'R”, -SR', -SO2R', -SO2NR'R”, -CR'R”-, -CR'NR'R”-, (-CR'O) n’ R'', halogen, optionally substituted heterocycline (e.g., optionally substituted C3-C7 heterocycline), Optionally substituted aryls (for example, optionally substituted C5-C7 aryls), optionally substituted alkylaryl (e.g., alkylaryl containing at least one of optionally substituted C1-C6 alkyls, optionally substituted C5-C7 aryls, or combinations thereof), optionally substituted heteroaryl (e.g., optionally substituted C5-C7 heteroaryls) (L), optionally substituted linear or branched alkyl (e.g., C1-C6 linear or branched alkyl optionally substituted with one or more halogens, cycloalkyl (e.g., C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)), optionally substituted The alkoxyl group (e.g., methoxy, ethoxy, butoxy, propoxy, pentoxy, or hexoxy; where the alkoxyl can be substituted with one or more halogens, alkyl, haloalkyl, fluoroalkyl, cycloalkyl (e.g., C3-C6 cycloalkyl) or aryl (e.g., C5-C7 aryl)), optionally substituted

[0105] [ka]

[0106] (For example, optionally substituted with one or more halogens, alkyls, haloalkyls, fluoroalkyls, cycloalkyls (e.g., C3-C6 cycloalkyls) or aryls (e.g., C5-C7 aryls), optionally substituted

[0107] [ka]

[0108] (For example, one or more halogens, alkyls, haloalkyls, fluoroalkyls, etc.) Substituted with cycloalkyl (e.g., C3-C6 cycloalkyl) or aryl (e.g., C5-C7 aryl), optionally substituted cycloalkyl (e.g., optionally substituted C3-C7 Cycloalkyl groups), optionally substituted cycloalkyl groups (e.g., optionally substituted C3-C7 groups) Cycloalkyls), optionally substituted heterocyclines (e.g., optionally substituted C3-C7 Heterocyclyl), -P(O)(OR')R'', -P(O)R'R'', -OP(O)(OR')R'', -OP(O)R'R'', -Cl, -F, -Br, -I, -CF3, -CN, -NR'SO2NR'R'', -NR'CONR'R'', -CONR'COR'', -NR'C(=N-CN)NR'R'', -C(=N-CN)NR'R'', -NR'C(=N-CN)R'', -NR'C(=C- NO2)NR'R'', -SO2NR'COR'', -NO2, -CO2R', -C(C=N-OR')R'', -CR'=CR'R'', -CCR', -S(C=O)(C=N-R')R'', -SF5 and -OCF3, where at least one R (e.g., O, OH, N, NH, NH2, C1-C6 alkyl, C1-C6 alkoxy, optionally substituted cycloalkyl (e.g., optionally substituted (C3-C7 cycloalkyl) or optionally substituted heterocycline (for example, optionally substituted (e.g., C3-C7 heterocyclyl, C4-C7 alkyl-aryl) A compound containing at least one of the following: an alkyl-aryl, aryl (e.g., C5-C7 aryl), heteroarylaryl (e.g., C5-C7 heteroaryl), amine, amide, or carboxyl (at least one of these), is a PTM, chemistry compound. Modified to covalently bond to a linker group (L), ULM, CLM' (for example, CLM' is an additional CLM having the same or different structure as the first CLM), or a combination thereof. . Each of x, y, and z is independently 0, 1, 2, 3, 4, 5, or 6; In formulas (a) to (e), R' and R'' are independently linked, H, and optionally substituted linear or fractional. Branched alkyl groups, optionally substituted cycloalkyl groups, optionally substituted aryl groups, optionally substituted heteroaryl groups, optionally substituted heterocyclic groups, -C(=O)R groups, optionally substituted heterocyclic groups. Selected from telosicryl; In equations (a) to (e), n and n' are each independently integers between 1 and 10 (for example, 1 to 4, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10); Equations (a) to (e)

[0109] [ka]

[0110] In the specific embodiments described herein, CLM or ULM comprises a chemical structure selected from the following group:

[0111] [ka]

[0112] During the ceremony: In formula (g), W is independently selected from the group CH2, C=O, NH, and N-alkyl; In formula (g), A is H, methyl, alkyl (e.g., C1-C6 alkyl (straight-chain, branched-chain, optionally substituted) Selected independently from ()), In formula (g), R is independently H, OH, NH2, halogen, methyl, or optionally substituted linear or branched alkyl (e.g., optionally substituted linear or branched C1-C6 alkyl). , optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl (for example, optional (C3-C7 cycloalkyls substituted with), heterocyclines optionally substituted (e.g., any (C3-C7 heterocyclyl substituted with), optionally substituted alkyl-aryl (e.g., containing at least one of C1-C6 alkyl, C4-C7 aryl or a combination thereof) Selected from alkyl-aryls, optionally substituted aryls (e.g., C5-C7 aryls), amines, amides, or carboxyls; In formula (g), n represents an integer between 1 and 4 (e.g., 1, 2, 3, or 4), and the formula contains at least one R (e.g., OH, NH2, halogen, C1-C6 alkyl, C1-C6 alkoxy, alkyl-aryl (e.g., alkyl-aryl containing at least one of C1-C6 alkyl, C4-C7 aryl, or a combination thereof), aryl (e.g., C5-C7 aryl), amine, amide). The group (or at least one of the carboxyls) is modified to be covalently bonded to a PTM, a chemical linker group (L), ULM, CLM (or CLM'), or a combination thereof; and Equation (g)

[0113] [ka]

[0114] In any embodiment described herein, W, X, Y, Z, G, G', R, R', R'', Q1-Q4, and A of formulas (a)-(g) [e.g., (a1), (b), (c), (d1), (e), (f), (a2), (d2), (a3), (a4), and (g)] are independently the linker, and / or It can be covalently bonded to one or more PTM, ULM, CLM, or CLM' bases in a linker.

[0115] In any of the embodiments or models described herein, the CLM comprises 1 to 4 R groups in Q1, Q2, Q3, Q4 or a combination thereof, where each R is, for example, an OH, halogen. , C1-C6 alkyl, C1-C6 alkoxy, optionally substituted cycloalkyl (e.g., optionally substituted C3-C7 cycloalkyl), optionally substituted heterocyclyl (e.g., optionally Substituting C3-C7 heterocyclyl, -alkyl-aryl (e.g., -alkyl-aryl containing at least one of C1-C6 alkyl, C4-C7 aryl, or a combination thereof) (L), aryl (e.g., C5-C7 aryl), amine, amide, cyano, or carboxy These are independently selected functional groups or atoms, such as C, and optionally one of them is shared with PTM, chemical linker group (L), ULM, CLM (or CLM'), or a combination thereof. It will be modified so that it can be combined.

[0116] In some embodiments, the CLM is represented by the following structure, where the dashed lines indicate linker joints:

[0117] [ka]

[0118] More specifically, non-limiting examples of CLMs include the following, as well as the following molecules. A "hybrid" molecule is a molecule that arises from a combination of one or more different properties shown in the given context. It can be done.

[0119] [ka]

[0120] [ka]

[0121] [ka]

[0122] [ka]

[0123] [ka]

[0124] [ka]

[0125] [ka]

[0126] [ka]

[0127] [ka]

[0128] [ka]

[0129] In any of the compounds described herein, CLM is a chemical composition selected from the following group. Including construction:

[0130] [ka]

[0131] [ka]

[0132] [ka]

[0133] [ka]

[0134] During the ceremony: W is independently selected from CH2, O, CHR, C=O, SO2, NH, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, and N-alkyl; Q1, Q2, Q3, Q4, and Q5 are each independently selected from H, R', N, or N-oxides. Represents a carbon C or N substituted with a group; R 1 It is either nonexistent or selected from H, OH, CN, C1-C3 alkyl, and C=O; R 2 It is either absent or selected from the group H, OH, CN, C1-C3 alkyl, CHF2, CF3, CHO, C(=O)NH2; R 3 H, alkyl (e.g., C1-C6 alkyl or C1-C3 alkyl), substituted alkyl (e.g.) (e.g., substituted C1-C6 alkyl or C1-C3 alkyl), alkoxy (e.g., C1-C6 alkoxy) Selected from syl or C1-C3 alkoxyls, or substituted alkoxyls (e.g., substituted C1-C6 alkoxyls or C1-C3 alkoxyls); R 4 is selected from H, alkyl, and substituted alkyl; R 5 and R 6 These are independently H, halogen, C(=O)R', CN, OH, and CF3; X is C, CH, C=O, or N; X1 is C=O, N, CH, or CH2; R' is H, OH, halogen, amine, cyano, alkyl (e.g., C1-C3 alkyl), substituted Lukyl (e.g., substituted C1-C3 alkyl), alkoxy (e.g., C1-C3 alkoxyl), substituted alkoxy (e.g., substituted C1-C3 alkoxyl), NR 2 R 3 , C(=O)OR 2 , optionally selected from substituted phenyl; n is between 0 and 4;

[0135] [ka]

[0136] In any aspect or embodiment described herein, CLM or CLM' is defined as formula (h )~R group of formula (ab) (for example, R, R 1 , R 2 , R 3 , R 4 or R'), W, X, or Q group (for example) , via Q1, Q2, Q3, Q4 or Q5) PTM, chemical linker group (L), ULM, CLM, CLM', or they are covalently bonded to each other in combination.

[0137] In any embodiment described herein, CLM or CLM' is defined as formula (h )~W, X, R, R in equation (ab)1 , R 2 , R 3 , R 4 , R 5 , R’, Q1, Q2, Q3, Q4, and Q5 are covalently attached via PTM, chemical linker group (L), ULM, CLM, CLM’, or combinations thereof .

[0138] In any of the embodiments described herein, W, X, R of formulas (h) to (ab) 1 , R 2 , R 3 , R 4 , R’, Q1, Q2, Q3, Q4, and Q5 may independently be covalently attached to the linker and / or to a linker covalently attached to one or more PTM, ULM, ULM’, CLM or CLM’ groups .

[0139] More specifically, non-limiting examples of CLM include those shown below, as well as “hybrid” molecules or compounds resulting from combinations of one or more properties of the following compounds :

[0140]

Chemical formula

[0141]

Chemical formula

[0142]

Chemical formula

[0143] wherein: W is independently selected from the group consisting of CH2, CHR, C=O, SO2, NH and N-alkyl; R 1 ​is absent or is selected from the group consisting of H, CH, CN, C1-C3 alkyl; R 2 is H or C1-C3 alkyl; R 3 is selected from H, alkyl, substituted alkyl, alkoxy, substituted alkoxy; R 4 is methyl or ethyl; R 5 is H or halo; R 6 is H or halo; R of CLM is H; R’ is H or is the bonding point of PTM, PTM’, chemical linker group (L), ULM, CLM CLM’, Q1 and Q2 are each independently C or N substituted with a group independently selected from H or C1-C3 alkyl;

[0144]

Chemical formula

[0145] is a single bond or a double bond; n is an integer from 1 to 4 (e.g., 1, 2, 3, or 4); and R includes the following: H, -CONR’R”, -OR’, -NR’R”, -SR’, -SO2R’, -SO2NR’R”, -CR’R”-,-CR’NR’R”-(-CR’O) n’ R”, halogen, optionally substituted heterocyclyl, optionally substituted aryl (e.g., optionally substituted C5-C7 aryl), optionally substituted alkyl-aryl (e.g., alkyl-aryl containing at least one of optionally substituted C1-C6 alkyl, optionally substituted C5-C7 aryl, or a combination thereof), optionally substituted heteroaryl (e.g., optionally substituted C5-C7 aryl) , optionally substituted linear or branched alkyl (e.g., C1-C6 linear or branched alkyl optionally substituted with one or more halogens, cycloalkyl (e.g., C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)), optionally substituted Alkoxyl groups (e.g., methoxy, ethoxy, butoxy, propoxy, pentoxy, or hexoxy; where alkoxyl can be substituted with one or more halogens, alkyl, haloalkyl, fluoroalkyl, cycloalkyl (e.g., C3-C6 cycloalkyl) or aryl (e.g., C5-C7 aryl)), optionally substituted

[0146] [ka]

[0147] (For example, optionally substituted with one or more halogens, alkyls, haloalkyls, fluoroalkyls, cycloalkyls (e.g., C3-C6 cycloalkyls) or aryls (e.g., C5-C7 aryls), optionally substituted

[0148] [ka]

[0149] (For example, optionally substituted with one or more halogens, alkyls, haloalkyls, fluoroalkyls, cycloalkyls (e.g., C3-C6 cycloalkyls) or aryls (e.g., C5-C7 aryls), optionally substituted cycloalkyls, optionally substituted heterocyclines, -P(O)(OR')R'', -P(O)R'R'', -OP(O)(OR')R'', -OP(O)R'R'', -Cl, -F, -Br, -I, -CF3, -CN, -NR'SO2NR'R", -NR'CONR'R", -CONR'COR", -NR'C(=N-CN)NR'R", -C(=N-CN)NR'R", -NR'C(=N-CN)R", -NR'C(=C -NO2)NR'R", -SO2NR'COR", -NO2, -CO2R', -C(C=N-OR')R", -CR'=CR'R", -CCR', -S(C=O)(C=N-R')R", -SF5 and -OCF3; In any of the embodiments or models described herein, at least one R (e.g., OH, NH2, C1-C6 alkyl) is selected from Q1, Q2, Q3, Q4, Q5 or any combination thereof. , C1-C6 alkoxy, C4-C7 aryl (for example, C1-C6 alkyl, C4-C7 aryl or It includes at least one of the following combinations: (-alkyl-aryl), aryl (e.g., C5-C7 aryl), amine, amide, or carboxyl. ) are PTM, chemical linker group (L), ULM, CLM' (for example, CLM' has the same structure as the first CLM). (or additional CLMs with different structures), or combinations thereof covalently bonded. It will be modified so that it can be modified.

[0150] In any of the embodiments described herein, W and R of formulas (ac) to (an) 1 , R 2 Q1, Q2, Q3, Q4, and R may be independently covalently bonded to a linker and / or covalently bonded to one or more PTM, ULM, ULM', CLM, or CLM' bases. It may also be used.

[0151] In any of the embodiments described herein, R of formulas (ac) to (an) 1 , R 2 Q1, Q2, Q3, Q4, and R may be independently covalently bonded to a linker and / or covalently bonded to one or more PTM, ULM, ULM', CLM or CLM' bases. That's fine.

[0152] In any of the embodiments described herein, Q1, Q2, Q3, Q4, and R of formulas (ac) to (an) may be independently covalently bonded to a linker and / or covalently bonded to one or more PTM, ULM, ULM', CLM, or CLM' bases of linkers. .

[0153] In any aspect or embodiment described herein, R in formulas (ac) to (an) is It is modified and covalently bonded to a linker group (L), a second CLM, CLM', a second linker, or any combination thereof, having the same chemical structure as PTM, ULM, or CLM.

[0154] In any aspect or embodiment described herein, the CLM is selected from the following: ru:

[0155] [ka]

[0156] [ka]

[0157] In the formula, R' is a halogen, and R 1 This refers to any aspect or embodiment described herein. It is as stated.

[0158] In certain cases, CLM may be an imide that binds to cereblon E3 ligase. These imide and linker bonds may, but are not limited to, have the following structures:

[0159] [ka]

[0160] Exemplary VLM In certain embodiments of the compounds described herein, ULM is VLM, and the following ULM-a It includes the chemical structure of,

[0161] [ka]

[0162] During the ceremony: The dashed line indicates at least one PTM, another ULM or VLM or MLM or ILM or CLM (i.e., ULM' or VLM' or CLM' or ILM' or MLM'), or a chemical linker — Indicates partial bonding, and at least one PTM, ULM' or VLM' or CLM' or ILM' Alternatively, attach the MLM' to the other end of the linker; Formula ULM-a X 1 , X 2 Each of these is independent of the bond, O, and NR. Y3 , CR Y3 R Y4 Selected from the groups C=O, C=S, SO, and SO2; Formula ULM-a's R Y3 , R Y4 Each of these is independently H, and optionally substituted linear or branched C 1-6 Alkyl (for example, optionally substituted with one or more halos), optionally substituted C 1-6 Al Coxyl (for example, 0 to 3 R P Selected from the group (which can be optionally substituted in the base); Formula ULM-a's R P These are 0, 1, 2, or 3 groups, each independently consisting of H, halo, -OH, and C. 1-3 Alki Lu, C=O is selected; W of formula ULM-a 3 T is optionally substituted, -TN(R) is optionally substituted. 1a R 1b) X 3 -TN(R) is optionally replaced. 1a R 1b ), optionally substituted -T-aryl, optionally substituted -T-heteroaryl, optionally substituted T-diheteroaryl, optionally substituted -T-heterocyclic, optionally substituted -T-diheterocyclic, optionally substituted -NR 1 -T-aryl, optionally replaced by -NR 1 -T-heteroaryl, or optionally substituted with -NR 1 -Selected from the group of T-heterogeneous algebras; Formula ULM-a X 3 C=O, R 1 , R 1a , R 1b and; R 1 , R 1a , R 1b Each of these is a linear chain optionally substituted with H, one or more halos, or -OH groups. or branched C1-C6 alkyl groups, R Y3 C=O, R Y3 C=S, R Y3 SO, R Y3 SO2, N(R Y3 R Y4 )C=O, N(R Y3 R Y4 )C=S, N(R Y3 R Y4 )SO, and N(R Y3 R Y4 )Independently selected from the group consisting of SO2; In formula ULM-a, T is an optionally substituted alkyl, -(CH2) n- group, or -OH group, or optionally placed Selected from the group of amino acid side chains to be replaced, in this case each methylene group can be optionally a halogen, methyl, optionally substituted alkoxy, or -(CH2) m’ C(=O)(CH2) m’ C(=O)(OH), (CH2) m’ OCOCH2(CH2) m’ OCH2(CH2) m’ CO(CH2) m’ OH, (CH2) m’ OCOCH2(CH2) m’ CO(CH2) m’ Linear or branched C1-C6 molecules optionally substituted with OH, one or more halogens, or OH groups. Alkyl alkyl group, C(O) NR 1 R 1a , or NR 1 R 1a With one or two substituents selected from the group Replaced, or R 1 and R 1a They combine to form a heterogeneous ring that can be optionally substituted; Each m' is an integer between 1 and 4 (for example, 1, 2, 3, or 4); W of formula ULM-a 4 -NR is optionally replaced 1- T-aryl, optionally replaced by -NR 1- T-heterozygous Reel group, or optionally substituted -NR 1- It is a T-heterocycle, and in this case, an aryl group may be optionally substituted with an optionally substituted 5-6 member heteroaryl, optionally substituted aryl, or optionally substituted alkoxy, in which case -NR 1 X 2 Covalently bonded to R 1 is H or CH 3 , preferably H; and n is between 0 and 6, and is often 0, 1, 2, or 3, preferably 0 or 1.

[0163] In any of the embodiments described herein, T is an optionally substituted alkyl group. ,-(CH2) n - A group selected from the group consisting of an - group, an -OH group, or an optionally substituted amino acid side chain, In this case, each methylene group can be any halogen, methyl, optionally substituted alkoxy, or -(CH2) m’ C(=O)(CH2) m’ C(=O)(OH), (CH2) m’ OCOCH2(CH2) m’ OCH2(CH2) m’ CO(CH 2) m’ OH, (CH2) m’ OCOCH2(CH2) m’ CO(CH2) m’ OH, linear or branched C1-C6 alkyl groups optionally substituted with one or more halogens, C(O)NR 1 R 1a , or NR 1 R 1a It is substituted with one or two substituents selected from the group, or R 1 and R 1a Combine and optionally replace It forms a complex ring; each m' is an integer from 1 to 4 (for example, 1, 2, 3, or 4) n is 0 to 6, often 0, 1, 2, or 3, and preferably 0 or 1.

[0164] In any aspect or embodiment described herein, W of formula ULM-a 4 teeth,

[0165] [ka]

[0166] W 5 is optionally substituted phenyl, optionally substituted naphthyl, or optionally substituted 5-10 member heteroaryl (e.g., W 5This is optional, and you can choose one or more [for example, 1, 2, 3, 4, Alternatively, a halo, CN, optionally substituted linear or branched C1-C12 alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, hydroxy, or optionally substituted haloalkoxy, having optionally one or more carbon atoms (e.g., 1, 2, 3, 4 or more) substituted with oxygen atoms; R 14a、 R 14b Each of these is independently H, a haloalkyl, an optionally substituted alkoxy, and optionally placed The hydroxyl alkyl group to be replaced is -(CH2) m’ C(=O)(CH2) m’ C(=O)(OH), (CH2) m’ OCOCH2(CH2) m’ OCH2(CH2) m’ CO(CH2) m’ OH, (CH2) m’ OCOCH2(CH2) m’ CO(CH2) m’ OH, or oxygen Selected from the group of optionally substituted linear or branched alkyls having one or more carbon atoms to be substituted; Each m' is an integer between 1 and 4 (for example, 1, 2, 3, or 4); R 1 This consists of H and linear or branched C, optionally substituted by one or more halos. 1- C6 alkyl group, or -OH group; W 6 is a biring complex ring of 8 to 14 members that can be arbitrarily substituted (for example,

[0167] [ka]

[0168] R 15 H, halogen, CN, OH, NO2, NR 14a R 14b , OR 14a CONR 14aR 14b , NR 14a COR 14b SO2NR 14a R 14b , NR 14a SO2R 14b , optionally substituted alkyl, optionally substituted haloalkyl The group consists of alkoxy, optionally substituted, haloalkoxy, optionally substituted, aryl, optionally substituted, heteroaryl, optionally substituted, cycloalkyl, or optionally substituted cycloheteralkyl.

[0169] In any aspect or embodiment described herein, W of formula ULM-a 5 This can be placed at will. The phenyl to be replaced, or optionally a 5-10 member heteroaryl (e.g., W 5 It is optional and can be substituted with one or more [e.g., 1, 2, 3, 4, or 5] halo, CN, or oxygen atoms. R of formula ULM-a 15 H, halogen, CN, OH, NO2, NR 14a R 14b , OR 14a CONR 14a R 14b , NR 14a COR 14b SO2NR 14a R 14b , NR 14a SO2R 14b , optionally substituted alkyl, optionally substituted ruha Selected from the group consisting of chloroalkyl, optionally substituted alkoxy, optionally substituted haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl; In the embodiments or aspects described herein, W for use in this disclosure 4 The substituent is further W present in the specific compound disclosed herein. 4 These W include specific substituents (but are not limited to the specific disclosed compound). 4 Each substituent is any number of W 3 It may also be used in conjunction with substituents, which are also disclosed herein.

[0170] In the embodiments or aspects described herein, ULM-a has 0 to 3 R in the pyrrolidine moiety. P It can be optionally substituted by each R. P These are independently H, halo, -OH, C1-3 alkyl, and C=O.

[0171] In the embodiments or models described herein, W of formula ULM-a 3 , W 4 It is independent, It may be covalently bonded to a linker that is bonded to one or more PTM groups. And in the formula, the dashed line represents at least one PTM, another ULM(ULM'), or at least one This shows the binding site of the chemical linker portion that binds PTM, ULM', or both to ULM. vinegar.

[0172] In a particular embodiment, ULM is VHL and is represented by the following structure:

[0173] [ka]

[0174] During the ceremony: W of formula ULM-b 3 is an optionally substituted aryl, optionally substituted heteroaryl, or

[0175] [ka]

[0176] R9 and R of formula ULM-b 10 R9, R9, R9 are independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl, or R9, 10 , and the carbon atoms to which they are bonded , forming optionally substituted cycloalkyl groups; R of formula ULM-b 11 This includes optionally substituted heterocyclic compounds, optionally substituted alkoxy compounds, optionally substituted heteroaryl compounds, optionally substituted aryl compounds,

[0177] [ka]

[0178] R of formula ULM-b 12 is selected from the group of H or optionally substituted alkyl groups; R of formula ULM-b 13 H, optionally substituted alkyl, optionally substituted alkylcarbonyl , selected from the group of optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl; R of formula ULM-b 14a、 R 14b Each of these is independently H, haloalkyl, optionally substituted alkoxy, optionally substituted hydroxylalkyl, -(CH2) m’ C(=O)(CH2) m’ C(=O)(OH), (CH2) m’ OCOCH2(CH2) m’ OCH2(CH2) m’ CO(CH2) m’ OH, (CH2) m’ OCOCH2(CH2) m’ CO(CH2) m’Oh, again is selected from the group of optionally substituted linear or branched alkyls having one or more carbon atoms optionally substituted with oxygen; R 1 This consists of H and linear or branched C, optionally substituted by one or more halos. 1- C6 alkyl group, or -OH group; Each m' is an integer between 1 and 4 (for example, 1, 2, 3, or 4); W of formula ULM-b 5 This is selected from the group of optionally substituted phenyl or optionally substituted 5- to 10-membered heteroaryls; R of formula ULM-b 15 H, halogen, CN, OH, NO2, NR 14a R 14b , OR 14a CONR 14a R 14b , NR 14a COR 14b SO2NR 14a R 14b , NR 14a SO2R 14b , selected from the group consisting of optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl; Each R in formula ULM-b 16 It independently contains one or more carbon atoms substituted with H, CN, halo, and oxygen atoms. Selected from the group of optionally substituted alkyl (e.g., optionally substituted with CN or OH), optionally substituted haloalkyl, hydroxy, or optionally substituted haloalkoxy; In formula ULM-b, o is 0, 1, 2, 3, or 4; R of formula ULM-b 18 H, halo, optionally substituted alkoxy, cyano, optionally substituted a Independently selected from the group consisting of lukyl, haloalkyl, haloalkoxy, or linker; and In formula ULM-b, p is 0, 1, 2, 3, or 4, and in the formula, the dashed line represents at least one PTM, another ULM (ULM'), or at least one PTM or ULM' or both of the same as ULM. This shows the bonding site of the chemical linker portion that forms the bond.

[0179] In certain embodiments, R of formula ULM-b 15 teeth,

[0180] [ka]

[0181] And in the formula, R 17 H, halo, and C which can be substituted as desired. 3-6 Cycloalkyl, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Alkenyl and C 1-6 It is a haloalkyl; and Xa is either S or O.

[0182] In certain embodiments, R of formula ULM-b 17 The compound is selected from the group consisting of methyl, ethyl, isopropyl, and cyclopropyl.

[0183] In certain additional embodiments, R of formula ULM-b 15 The following group is selected:

[0184] [ka]

[0185] In certain embodiments, R of formula ULM-b 11 The following group is selected:

[0186] [ka]

[0187] In a particular embodiment, the ULM has a chemical structure selected from the following group:

[0188] [ka]

[0189] During the ceremony: In formulas ULM-c, ULM-d, and ULM-e, R1 is H, ethyl, isopropyl, tert-butyl, sec-butyl. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; optionally substituted alkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl; Formulas ULM-c, ULM-d, and ULM-e 14a (CH2) m’ OCOCH2(CH2) m’ OCH2(CH2) m’ CO(CH2) m’ OH, (CH2) m’ OCOCH2(CH2) m’ CO(CH2) m’ OH, or cyclo It is propyl; Each m' is an integer between 1 and 4 (for example, 1, 2, 3, or 4); Formulas ULM-c, ULM-d, and ULM-e 15 This is selected from the group consisting of H, halogens, CN, OH, NO2, optionally substituted heteroaryls, optionally substituted aryls; optionally substituted alkyls, optionally substituted haloalkyls, optionally substituted haloalkoxys, cycloalkyls, or cycloheteralkyls; In formulas ULM-c, ULM-d, and ULM-e, X is C, CH2, or C=O. In formulas ULM-c, ULM-d, and ULM-e, R3 is a 5-membered or 6-membered heteroaryl that is absent, bonded, or optionally substituted; and In the formula, the dashed line indicates a chemical linker portion that binds at least one PTM, another ULM (ULM'), or at least one PTM or ULM' or both to ULM.

[0190] In certain embodiments, ULM comprises a group that conforms to the following chemical structure:

[0191] [ka]

[0192] During the ceremony: R of formula ULM-f 14a (CH2) m’ OCOCH2(CH2) m’ OCH2(CH2) m’ CO(CH2) m’ OH, (CH2) m’ OCOCH2(CH2) m’ CO(CH2) m’ It is OH, or cyclopropyl; Each m' is an integer between 1 and 4 (for example, 1, 2, 3, or 4); In formula ULM-f, R9 is H; R of formula ULM-f 10 These are H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; R of formula ULM-f 11 teeth,

[0193] [ka]

[0194] or a heteroaryl that can be optionally substituted; In formula ULM-f, p is 0, 1, 2, 3, or 4; Each R in formula ULM-f18 These are independently a halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy, or linker; R of formula ULM-f 12 H is C=O; R of formula ULM-f 13 H, optionally substituted alkyl, optionally substituted alkylcarbonyl , optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl; R of formula ULM-f 15 This includes H, halogens, Cl, CN, OH, NO2, optionally substituted heteroaryls, optionally substituted aryls, optionally substituted cycloheteralkyls,

[0195] [ka]

[0196] Selected from the group consisting of, The dashed lines in formula ULM-f indicate the binding sites of a chemical linker portion that binds at least one PTM, another ULM (ULM'), or at least one PTM or ULM' or both to ULM.

[0197] In a particular embodiment, the ULM is selected from the following structures:

[0198] [ka]

[0199] In a particular embodiment, the ULM is selected from the following structures:

[0200] [ka]

[0201] [ka]

[0202] [ka]

[0203] [ka]

[0204] Here, ULM-a1 to ULM-a15, ULM-b1 to ULM-b12, ULM-c1 to ULM-c15, and ULM-d1 The phenyl ring of ULM-d9 is optionally substituted with fluorine, lower alkyl, and alkoxy groups, where the dashed lines indicate the binding sites of a chemical linker moiety that binds at least one PTM, another ULM (ULM'), or at least one PTM or ULM' or both to ULM-a.

[0205] One possible progression is from ULM-a1 to ULM-a15, ULM-b1 to ULM-b12, ULM-c1 to ULM-c15, Furthermore, the phenyl rings from ULM-d1 to ULM-d9 can be functionalized as esters and used as part of a prodrug.

[0206] To achieve a specific version, ULM-a1 to ULM-a15, ULM-b1 to ULM-b12, ULM-c1 to ULM-c15, Furthermore, the hydroxyl groups on the pyrrolidine rings of ULM-d1 to ULM-d9 each contain an esterified prodrug moiety.

[0207] In any aspect or embodiment described herein, ULM and existing In some cases, ULM', or its pharmaceutically acceptable salts, stereoisomers, solvates, or polymorphs. Each body is an independent group that follows the following chemical structure:

[0208] [ka]

[0209] During the ceremony: ULM-g's R 1’ This is an optionally substituted C1-C6 alkyl group, and an optionally substituted -(CH2) n OH, optionally substituted -(CH2) n SH can be optionally replaced (CH2) n -O-(C1-C6) alkyl group, epoxide moiety (CH2) optionally substituted with WCOCW n -WCOCW-(C0-C6) alkyl group, where each W is independently H or C1-C3 alkyl group, optionally substituted with -(CH2) n COOH, optionally substituted rel-(CH2) n C(O)-(C1-C6 alkyl), optionally substituted with -(CH2) n NHC(O)-R1, optionally substituted rel-(CH2) n C(O)-NR1R2, optionally substituted with -(CH2) n OC(O)-NR1R2, -(CH2O) n H, optionally substituted -(CH2) n OC(O)-(C1-C6 alkyl), optionally substituted with -(CH2) n C(O)-O-(C1-C6 alkyl), optionally substituted with -(CH2O) n COOH, optionally substituted -(OCH2) n O-(C1-C6 alkyl), -(CH2O) is substituted by meaning. n C(O)-(C1-C6 alkyl), optionally substituted -(OCH2) n NHC(O)-R1, -(CH2O) can be optionally substituted. n C(O)-NR1R2, -(CH2CH2O) nH can be optionally substituted with -(CH2CH2O) n COOH can be optionally substituted with -(OCH2CH2) n O-(C1-C6 alkyl), optionally substituted -(CH2CH2O) n C(O)-(C1-C6 alkyl), optionally substituted -(OCH2CH2) n NHC(O)-R1, optionally substituted with -(CH2CH2O) n C(O)-NR1R2, optionally substituted with -SO2R S , optionally substituted S(O)R S NO2, CN or H It is a chlorogen (F, Cl, Br, I, preferably F or Cl); R1 and R2 of ULM-g are each C1-C6 alkyl groups that can be independently substituted with H, or optionally with one or two hydroxyl groups or up to three halogen groups (preferably fluorine). It is the basis; ULM-g's R S This is a C1-C6 alkyl group, optionally substituted aryl, heteroaryl or heterocyclic group, or -(CH2) m It has two NR1R groups; In ULM-g, X and X' are independently C=O, C=S, -S(O), and S(O)2 (preferably X is Both X' and C are C=O; ULM-g's R 2’ -(CH2) is optionally substituted. n -(C=O) u (NR1) v (SO2) w Alkyl alkyl group, optionally substituted. (CH2) n -(C=O) u (NR1) v (SO2) w NR 1N R 2N The base, optionally substituted -(CH2) n -(C=O) u (NR1) v (SO2) w -aryl, optionally substituted-(CH2)n -(C=O) u (NR1) v (SO2) w - Heteroaryl, optional -(CH2) is replaced by n -(C=O) v NR1(SO2) w - Complex algebra, optionally permutable -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -alkyl, optionally substituted with -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w - NR 1N R 2N -NR can be optionally replaced. 1 -(CH2) n -C(O) u (NR1) v (SO2) w -NR1C(O)R 1N -NR can be optionally replaced. 1 -(CH2) n -(C=O) u (NR1) v (SO2) w -aryl, optionally replaced by -NR 1 -(CH2) n -(C=O) u (NR1) v (SO2) w -heteroaryl, or optionally substituted -NR 1 -(CH2) n -(C=O) v NR1(SO2) w -A complex algebra, arbitrarily permutable -X R2’ -alkyl group; optionally substituted with -X R2’ -Aryl group; optionally substituted with -X R2’ -heteroaryl group; optionally substituted with -X R2’ -Hybrid algebra; arbitrarily permutable, and; R of ULM-g 3’ This is an optionally substituted alkyl group, and an optionally substituted -(CH2) group.n -(O) u (NR1) v (SO2) w -Alkyl, optionally substituted-(CH2) n -C(O) u (NR1) v (SO2) w -NR 1N R 2N , optionally substituted -(CH2) n -C(O) u (NR1) v (SO2) w -NR1C(O)R 1N , optionally substituted -(CH2) n -C(O) u (NR1) v (SO2) w -C(O)NR1R2, optionally substituted with -(CH2) n -C(O) u (NR1) v (SO2) w -aryl, optionally substituted-(CH2) n -C(O) u (NR1) v (SO2) w - Heteroaryl, optionally substituted - (CH2) n -C(O) u (NR1) v (SO2) w - Complex algebra, optionally permutable -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -alkyl, optionally substituted with -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w - NR 1N R 2N -NR can be optionally replaced. 1 -(CH2) n -C(O) u (NR1) v (SO2) w -NR1C(O)R1N -NR can be optionally replaced. 1 -(CH2) n -C(O) u (NR1) v (SO2) w -aryl, optionally replaced by -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -heteroaryl, optionally substituted with -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -A complex algebra, where any substitutions are possible -O-(CH2)n-(C=O) u (NR1) v (SO2) w -a Lukil, optionally substituted -O-(CH2)n-(C=O) u (NR1) v (SO2) w -NR 1N R 2N -O-(CH2)n-(C=O) which can be optionally substituted u (NR1) v (SO2) w -NR1C(O)R 1N -O-(CH2)n-(C=O) which can be optionally substituted u (NR1) v (SO2) w -aryl, optionally substituted -O-(CH2) n -(C=O) u (NR1) v (SO2) w -heteroaryl, also -O-(CH2) is optionally substituted. n -(C=O) u (NR1) v (SO2) w -Hybrid algebra;-(CH2) n -(V) n’ -(CH2) n -(V) n’ -Alkyl alkyl group, optionally substituted-(CH2) n -(V)n’ -(CH2) n -(V) n’ - Aryl group, optional Substituted -(CH2) n -(V) n’ -(CH2) n -(V) n’ - Heteroaryl group, optionally substituted - (CH2) n -(V) n’ -(CH2) n -(V) n’ -Heterocyclic group, optionally substituted-(CH2) n -N(R 1’ )(C=O) m’ -(V) n’ - Alkyl group, optionally substituted -(CH2) n -N(R 1’ )(C=O) m’ -(V) n’ - Aryl group, optionally placed (CH2) is replaced. n -N(R 1’ )(C=O) m’ -(V) n’ - Heteroaryl group, optionally substituted - (CH2) n -N(R 1’ )(C=O) m’ -(V) n’ -Heterogene group, optionally substituted with -X R3’ -Alkyl alkyl group; optionally substituted -X R3’ -Aryl group; optionally substituted with -X R3’ -heteroaryl group; optionally substituted with -X R3’ -A complex algebra; it is arbitrarily permutable, and; ULM-g's R 1N and R 2N Each of these is independently H, or one or two hydroxyl groups and three or fewer halogen groups or optionally substituted -(CH2) n -aryl group, -(CH2) n -heteroaryl group, or -(CH2) n -A C1-C6 alkyl group optionally substituted with a heterocyclic group; In ULM-g, V is O, S, or NR1; R1 of ULM-g is the same as above; ULM-g's R 1 and R 1’ Each of these is independently H or a C1-C3 alkyl group; ULM-g X R2’ and X R3’ Each of these can be substituted independently and arbitrarily (-CH2) n -, -CH2) n -CH(X v )=CH(X v )-(Sys or Trans), -CH2) n -CH≡CH-, -(CH2CH2O) n -, or a C3-C6 cycloalkyl group, where X v is H, halo, or optionally substituted C1-C3 alkyl group; Each m in ULM-g is independently 0, 1, 2, 3, 4, 5, or 6; Each m' in ULM-g is independently either 0 or 1; Each n in ULM-g is independently 0, 1, 2, 3, 4, 5, or 6; Each n' in ULM-g is independently either 0 or 1; Each u in ULM-g is independently either 0 or 1; Each v in ULM-g is independently either 0 or 1; Each w in ULM-g is independently either 0 or 1; and ULM-g's R 1’ , R 2’ , R 3’ If one or more of X and X' are optionally modified, and PTM is not ULM', it is covalently bonded to the PTM group via a linker group, and if PTM is ULM', the respective R of ULM and ULM' 1’ , R 2’ , R 3’ , either X or X' The above can be optionally modified and covalently bonded to each other directly or via linker groups.

[0210] In any aspect or embodiment described herein, ULM and existing In some cases, ULM', or its pharmaceutically acceptable salts, enantiomers, diastereomers, or solutions. Each mediator or polymorph is a group that independently follows the following chemical structure:

[0211] [ka]

[0212] During the ceremony: ULM-h's R 1’ , R 2 'and R 3 Each of the following is the same as described above, and X is C=O, C=S, -S(O) group , or S(O)2 group, more preferably C=O group, and ULM-h's R 1’ , R 2’ , and R 3’ If one or more of the following are optionally modified, and PTM is not ULM', a linker group is further covalently bonded to the PTM group, or if PTM is ULM', the respective R of ULM and ULM' 1’ , R 2’ , R 3’ One or more of the following These are optionally modified and covalently bonded to each other directly or via linker groups.

[0213] In any aspect or embodiment described herein, ULM and existing In some cases, ULM', or its pharmaceutically acceptable salts, enantiomers, diastereomers, or solutions. Each mediator or polymorph independently follows the following chemical structure:

[0214] [ka]

[0215] During the ceremony: ULM-I's R 1’ , R 2’ , and R 3’ If one or more of the following are optionally modified, and PTM is not ULM', a linker group is further covalently bonded to the PTM group, or if PTM is ULM', the respective R of ULM and ULM' 1’ , R 2’ , R 3’ One or more of the following These are optionally modified and covalently bonded to each other directly or via linker groups.

[0216] Further aspects of this disclosure refer to the R of ULM-g to ULM-i. 1’ Preferably, R is a hydroxyl group, or a group that can be metabolized to a hydroxyl group or a carboxylic acid group, thereby causing the compound to exhibit a prodrug form of the active compound. Preferred R 1’ An example of a base is -(CH2) n OH, (CH2) n -O-(C1-C6) alkyl group, -(CH2) n COOH, -(CH2O) n H, optionally substituted -(CH2) n OC(O)-(C1-C6 alkyl), or optionally substituted-(CH2) n Examples include C(O)-O-(C1-C6 alkyl), where n is 0 or 1. In the formula, R 1’ is a carboxylic acid group, a hydroxyl group or The group is an amine group or contains one, and the hydroxyl group, carboxylic acid group, or amine (each of which may be optionally substituted) may be further chemically modified to provide a covalent bond to a linker group bonded to a PTM group (including an ULM' group); In ULM-g and ULM-h, X and X', if present, are preferably C=O, C=S, -S(O) groups. It is an S(O)2 group, and more preferably a C=O group; ULM-g~ULM-i's R 2’ -NR is preferably optionally replaced. 1-T-aryl, optionally substituted rel-NR 1 -T-heteroaryl group, or optionally substituted -NR 1 -T- is a complex algebra, where R 1 is H or CH3, preferably H, and T is optionally substituted -(CH2) n - is a group, where each methylene group is preferably one or two substituents selected from halogens, amino acid side chains as otherwise described herein, or C1-C3 alkyl groups. , preferably optionally substituted with one or two methyl groups; and n is 0 to 6 (e.g., 0, 1, 2, or 3, e.g., 0 or 1). Alternatively, T is -(CH2O) n -group, -(OCH2) n - group, -(CH2CH2O) n - group, -(OCH2CH2) n -These may be groups, and all of them can be optionally substituted.

[0217] ULM-g~ULM-i's R 2’ A preferred aryl group for this is an optionally substituted phenyl Examples include a phenyl group or naphthyl group, preferably a linker group to which a PTM group (including a ULM' group) is attached, a halogen (preferably F or Cl), an amine, a monoalkylamine or dialkylamine (preferably dimethylamine). , F, Cl, OH, COOH, C1-C6 alkyl, preferably CH3, CF3, OMe, OCF3, NO2 or CN group (each of which may be substituted at the ortho-, meta-, and / or para-position of the phenyl ring, preferably the para-position), optionally substituted phenyl group (the phenyl group itself may optionally be attached to the PTM via a linker group (including an ULM' group)), and / or at least one of F, Cl, OH, COOH, CH3, CF3, OMe, OCF3, NO2 or CN group (located at the ortho-, meta-, and / or para-position of the phenyl ring, preferably the para-position), optionally substituted naphth A methyl group, optionally substituted heteroaryl, preferably an optionally substituted isoxazole including a methyl-substituted isoxazole, optionally substituted oxazole including a methyl-substituted oxazole, optionally substituted thiazole including a methyl-substituted thiazole, optionally substituted isothiazole including a methyl-substituted isothiazole, optionally substituted pyrrole including a methyl-substituted pyrrole, optionally substituted imidazole including methylimidazole, optionally substituted benzimidazole or methoxybenzylimidazole, optionally substituted oxyimidazole or methyloxyimidazole, methyl di Optionally substituted diazole groups containing an azole group, optionally substituted triazole groups containing a methyl-substituted triazole group, optionally substituted pyridine groups containing a halo-(preferably F) or methyl-substituted pyridine group or oxapyridine group (the pyridine group is bonded to the phenyl group by oxygen), optionally substituted furan, optionally substituted benzofuran, optionally substituted dihydrobenzofuran, optionally substituted indole, indidine or azaindridine (2,3 or 4-azandridine), optionally substituted quinoline, optionally bonded to the PTM group via an optionally substituted group according to the following chemical structure:

[0218] [ka]

[0219] During the ceremony: ULM-g~ULM-i's S c CHR SS , NR URE or O; ULM-g~ULM-i's R HET This can be H, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted acetylene group-C≡CR a And in the formula, R a is an acetylene group which is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl group); ULM-g~ULM-i's R SS This includes H, CN, NO2, halo (preferably F or Cl), and optionally substituted C1-C6 alkyl (preferably one or two hydroxyl groups or up to three halo groups). (substituted with), optionally substituted O-(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted -C(O)(C1-C6 alkyl) (preferably one or two hydroxyl groups or up to three (It is substituted with a halo group; ULM-g~ULM-i's R URE The group is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or -C(O)(C1-C6 alkyl), where each group is optionally substituted with one or two hydroxyl groups or up to three halo groups, preferably with a fluorine group, or optionally substituted with a phenyl group, optionally substituted with a heteroaryl group, or optionally substituted with a heterocycle, such as piperidine, morpholine, pyrrolidine, or tetrahydrofuran; ULM-g~ULM-i's R PROThe group is H, optionally substituted C1-C6 alkyl, or optionally substituted aryl (phenyl or naphthyl), heteroaryl, or heterocyclic group, and these groups are oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxyimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably a C1-C3 alkyl group, preferably a me A til group or a halo group (preferably substituted with F or Cl), benzofuran, India Selected from the group consisting of ol, indridine, and azaindridine; ULM-g~ULM-i's R PRO1 and R PRO2 Each is independently H, an optionally substituted C1-C3 alkyl group, or together forms a keto group; and Each n in ULM-g to ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1), or optionally substituted heterocycle, preferably tetrahydrofuran, tetrahydrotiene, piperidine, piperazine, or morpholine (each of these groups, if substituted, is preferably or are substituted with methyl or halo (F, Br, Cl), and each of these groups is a linker It can optionally be bonded to a PTM group (including an ULM' group) via a single group.

[0220] In a particular preferred embodiment,

[0221] [ka]

[0222] [ka]

[0223] ULM-g~ULM-i's R 2’Preferred heteroaryl groups for this include optionally substituted quinolines (which may be bonded to the pharmacophore or substituted on any carbon atom within the quinoline ring), optionally substituted indoles, optionally substituted indoridines, optionally substituted azaindidines, optionally substituted benzofurans including optionally substituted benzofurans, optionally substituted isoxazoles, optionally substituted thiazoles, optionally substituted isothiazoles, optionally substituted thiophenes, optionally substituted pyridines (2-, 3-, or 4-pyridines), optionally substituted imidazoles, optionally substituted pyrroles, optionally substituted diazoles, optionally substituted triazoles, tetrazoles, optionally substituted oxyimidazoles, or groups conforming to the following chemical structures:

[0224] [ka]

[0225] During the ceremony: ULM-g~ULM-i's S c CHR SS , NR URE or O; ULM-g~ULM-i's R HET This can be H, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted acetylene group-C≡CR a And in the formula, R of ULM-g ~ ULM-i a is an acetylene group which is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl group); ULM-g~ULM-i's R SS This includes H, CN, NO2, halo (preferably F or Cl), and optionally substituted C1-C6 alkyl (preferably one or two hydroxyl groups or up to three halo groups). (substituted with), optionally substituted O-(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted -C(O)(C1-C6 alkyl) (preferably one or two hydroxyl groups or up to three (It is substituted with a halo group; ULM-g~ULM-i's R URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or -C(O)(C1-C6 alkyl), where each group is optionally substituted with one or two hydroxyl groups or up to three halogens, preferably fluorine groups, or optionally substituted heterocycles, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, etc., each of which is optionally substituted, and ULM-g~ULM-i's Y C is N or CR YC And in the formula, R YC H, OH, CN, NO2, Halo (preferred) (or Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF3)), optionally substituted O(C1-C6 alkyl) (preferably one or two hydroxyl groups or up to three) Acetylene groups -C≡CR (substituted with halo groups) or optionally substituted. a And in the formula, R a This is an acetylene group which is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl group), Each of these groups may optionally be bonded to a PTM group (including an ULM' group) via a linker group.

[0226] ULM-g~ULM-i's R 2’Preferred heterocyclic groups for this include tetrahydrofuran, tetrahydrothien, tetrahydroquinoline, piperidine, piperazine, pyrrolidine, morpholine, oxane, or thian, each of which may be optionally substituted or may be a group conforming to the following chemical structure:

[0227] [ka]

[0228] [ka]

[0229] During the ceremony: ULM-g~ULM-i's R PRO is H, optionally substituted C1-C6 alkyl, or optionally substituted aryl, heteroaryl, or heterocyclic group; ULM-g~ULM-i's R PRO1 and R PRO2 Each of them independently is either H, an optionally substituted C1-C3 alkyl group, or together forms a keto group, and Each n in ULM-g to ULM-i can independently be 0, 1, 2, 3, 4, 5, or 6 (often 0 or 1), and each of these groups can optionally be bonded to a PTM group (including the ULM' group) via a linker group.

[0230] ULM-g~ULM-i preferred R 2' Substituents include specific compounds disclosed herein (honmei R found in (including specific compounds disclosed in the details and accompanying drawings of this specification) 2' Substituents can also be specifically mentioned (but are not limited to the specific compounds disclosed). These R 2' Each substituent can have any number of R 3’ It may also be used in conjunction with substituents, which are also disclosed herein.

[0231] ULM-g~ULM-i's R3’ Preferably, -T-aryl, -T-heteroaryl, -T-heterocyclic, or -NR are optionally substituted. 1 -T-aryl, optionally replaced by -NR 1 -T-heteroaryl, or optionally substituted with -NR 1 It is a -T-heterogenetic ring. In a preferred embodiment, R 1 is H or a C1-C3 alkyl group, preferably H or CH3, T is (CH2) can be optionally replaced. n - In the formula, one of the methylene groups is preferably a halogen, a C1-C6 alkyl group (linear, branched, or optionally substituted) or as otherwise specified herein. It may optionally be substituted with one or two substituents selected from the side chains of the amino acids, preferably methyl; and n is 0 to 6, e.g., 0, 1, 2, or 3 (e.g., 0 or 1). Alternatively, T is -(CH2O) n -group, -(OCH2) n - group, -(CH2CH2O) n - group, -(OCH2CH2) n -These may be groups, and each of these groups can be optionally substituted.

[0232] ULM-g~ULM-i's R 3’ Preferred aryl groups for this include optionally substituted phenyl or naphthyl groups, preferably phenyl groups, in which case the phenyl or naphthyl group is linked via a linker group and / or a halogen (preferably F Or Cl), amine, monoalkylamine or dialkylamine (preferably dimethylamine), amide group (preferably -(CH2) m -NR1C(O)R2 group (where m, R1 and R2 are the same as above), halo (often F or Cl), OH, CH3, CF3, OMe, OCF3, NO2, CN Or S(O)2R S Group(R SC1-C6 alkyl groups, optionally substituted aryls, heteroaryls, or heterocyclic group or -(CH2) m The PTM group (including the ULM' group) is optionally bonded via an NR1R2 group, and each of these can be substituted at the ortho, meta, and / or para positions of a phenyl ring (preferably at the para position), or an aryl (preferably phenyl), heteroaryl, or heterocyclic ring. The preferred substituent phenyl group is optionally substituted with a phenyl group (i.e., the substituent phenyl group itself is preferably substituted with at least one of F, Cl, OH, SH, COOH, CH3, CF3, OMe, OCF3, NO2, CN, or a linker group, and these groups are bonded to the PTM group (including the ULM' group), in which case the substitution is at the ortho, meta, or para positions of the phenyl ring. , and / or occurring at the para position, preferably at the para position), optionally substituted naphthyl groups including the above, optionally substituted heteroaryl groups (preferably methyl-substituted isoxazoles including optionally substituted isoxazoles, optionally substituted oxazoles including methyl-substituted oxazoles, optionally substituted thiazoles including methyl-substituted thiazoles, optionally substituted pyrroles including methyl-substituted pyrroles, optionally substituted imidazoles including methylimidazole, benzylimidazole or methoxybenzylimidazole, oxyimidazole or methyloxyimidazole, optionally substituted diazole groups including methyldiazole groups, optionally substituted triazole groups including methyl-substituted triazole groups, halo (preferably F) or methyl-substituted pyridyl Contains an oxypylene group or an oxapyridine group (the pyridine group is bonded to the phenyl group by oxygen). The group is a pyridine group, or optionally a substituted heterocycle (tetrahydrofuran, tetrahydrothiophene, pyrrolidine, piperidine, morpholine, piperazine, tetrahydroquinoline, oxane, or thian). Each aryl, heteroaryl, or heterocycle group may optionally be bonded to the PTM group (including the ULM' group) via a linker group.

[0233] ULM-g~ULM-i's R 3' Preferred heteroaryl groups for this include optionally substituted k Noline (which may be bonded to a pharmacophore or substituted on any carbon atom within the quinoline ring), optionally substituted indole (including dihydroindole), optionally substituted indidine, optionally substituted azaindidine (2, 3, or 4-azaidinidine), optionally substituted benzimidazole, benzodiazole, benzoxofran, optionally substituted imidazole, optionally substituted isoxazole, optionally substituted oxazole (preferably methyl-substituted), optionally substituted diazole, optionally substituted triazole, tetrazole, optionally substituted benzofuran, optionally substituted thiophene, optionally substituted thiazole (preferably methyl-substituted and / or thiol-substituted), optionally substituted isothiazole, optionally substituted triazole (preferably a methyl group, a triisopropylsilyl group, optionally substituted -(CH2) m -O-C1-C6 alkyl The base, or optionally substituted, -(CH2) m Examples include 1,2,3-triazoles substituted with C(O)-O-C1-C6 alkyl groups, optionally substituted pyridines (2,3, or 4-pyridines), or groups with the following chemical structures:

[0234] [ka]

[0235] During the ceremony: ULM-g~ULM-i's S c CHR SS , NR URE or O; ULM-g~ULM-i's R HETThis can be H, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted acetylene group-C≡CR a And in the formula, R a is an acetylene group which is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl group); ULM-g~ULM-i's R SS This includes H, CN, NO2, halo (preferably F or Cl), and optionally substituted C1-C6 alkyl (preferably one or two hydroxyl groups or up to three halo groups). (substituted with), optionally substituted O-(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted -C(O)(C1-C6 alkyl) (preferably one or two hydroxyl groups or up to three (It is substituted with a halo group; ULM-g~ULM-i's R URE The group is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or -C(O)(C1-C6 alkyl), and each group may optionally consist of one or two hydroxyl groups or the same group. A heterocycle having up to three halogens, preferably substituted with a fluorine group, or optionally substituted, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, and each of them optionally substituted, and ULM-g~ULM-i's Y C is N or CR YC And in the formula, R YC H, OH, CN, NO2, Halo (preferred) (or Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF3)), optionally substituted O(C1-C6 alkyl) (preferably one or two hydroxyl groups or up to three) Acetylene groups -C≡CR (substituted with halo groups) or optionally substituted. a And in the formula, R a The group is an acetylene group which is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl group). Each of these heteroaryl groups may optionally be bonded to a PTM group (including a ULM' group) via a linker group. ULM-g~ULM-i's R 3’ Preferred heterocyclic groups for this include tetrahydroquinoline, piperidine, piperazine, pyrrolidine, morpholine, tetrahydrofuran, tetrahydrothiophene, oxane, or thian, each of which may be optionally substituted or may be a group conforming to the following chemical structure:

[0236] [ka]

[0237] During the ceremony: ULM-g~ULM-i's R PRO The group is H, optionally substituted C1-C6 alkyl, or optionally substituted aryl (phenyl or naphthyl), heteroaryl, or heterocyclic group, and these groups are oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxyimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably a C1-C3 alkyl group, preferably a me A til group or a halo group (preferably substituted with F or Cl), benzofuran, India Selected from the group consisting of ol, indridine, and azaindridine; ULM-g~ULM-i's R PRO1 and R PRO2Each of them independently is either H, an optionally substituted C1-C3 alkyl group, or together forms a keto group, and Each n from ULM-g to ULM-i is 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1), and each of these heterocyclic groups can optionally be bonded to a PTM group (including the ULM' group) via a linker group.

[0238] ULM-g~ULM-i preferred R 3' Substituents include specific compounds disclosed herein (honmei R found in (including specific compounds disclosed in the details and accompanying drawings of this specification) 3' Substituents can also be specifically mentioned (but are not limited to the specific compounds disclosed). These R 3’ Each substituent can have any number of R 2’ It may also be used in conjunction with substituents, and these are also described in this specification. It is disclosed in the book.

[0239] In certain alternative preferred embodiments, R of ULM-g~ULM-i 2’ -NR1-X is optionally substituted. R2’ -alkyl group, -NR1-X R2’ -Aryl group; optionally substituted -NR1- X R2’ -HET, -NR1-X can be optionally replaced. R2’ -aryl-HET, or optionally replaced with -NR1-X R2’ -HET- It is Ariel, During the ceremony: R1 in ULM-g~ULM-i is H or a C1-C3 alkyl group (preferably H); ULM-g~ULM-i's X R2’ (This is optionally replaced by -CH2) n -, -CH2) n -CH(X v )=CH(X v )-(Sys or Trans),-(CH2) n -CH≡CH-, -(CH2CH2O) n-, or C3-C6 cycloalkyl groups; call ULM-g~ULM-i's X v is H, halo, or optionally one or two hydroxyl groups or It is a C1-C3 alkyl group substituted with up to three halogen groups; The alkyl group in ULM-g~ULM-i is optionally substituted with C1-C 10 Alkyl (preferably C1-C6 alkyl) It is a group (in certain preferred embodiments, the alkyl group is terminated with a halo group, often Cl or Br); The aryl group in ULM-g~ULM-i is optionally substituted with a phenyl group or a naphthyl group (preferably a phenyl group); and The HET in ULM-g to ULM-i can be optionally substituted with oxazole, isoxazole, thiazole, etc. Isothiazole, imidazole, diazole, oxyimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, benzofuran, indole, indidine, azaindidine, quinoline (if substituted, each preferably substituted with a C1-C3 alkyl group, preferably methyl, or halo group, preferably F or Cl), or a group following the following chemical structure:

[0240] [ka]

[0241] ULM-g~ULM-i's S c CHR SS , NR URE or O; ULM-g~ULM-i's R HETThis can be H, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted acetylene group-C≡CR a And in the formula, R a is an acetylene group which is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl group); ULM-g~ULM-i's R SS This includes H, CN, NO2, halo (preferably F or Cl), and optionally substituted C1-C6 alkyl (preferably one or two hydroxyl groups or up to three halo groups). (substituted with), optionally substituted O-(C1-C6 alkyl) (preferably one or two) A hydroxyl group or up to three halo groups (substituted), or optionally substituted -C(O)(C1-C6 alkyl) (preferably one or two hydroxyl groups or up to three (It is substituted with a halo group; ULM-g~ULM-i's R URE The group is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or -C(O)(C1-C6 alkyl), where each group is optionally substituted with one or two hydroxyl groups or up to three halo groups, preferably fluorine groups, or optionally substituted heterocycles, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, etc., each of which is optionally substituted; ULM-g~ULM-i's Y C is N or CR YC And in the formula, R YC H, OH, CN, NO2, Halo (preferred) (or Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF3)), optionally substituted O(C1-C6 alkyl) (preferably one or two hydroxyl groups or up to three) Acetylene groups -C≡CR (substituted with halo groups) or optionally substituted. a And in the formula , R a The acetylene group is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl group). ; ULM-g~ULM-i's R PRO The group is H, optionally substituted C1-C6 alkyl, or optionally substituted aryl (phenyl or naphthyl), heteroaryl, or heterocyclic group, and these groups are oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxyimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably a C1-C3 alkyl group, preferably a me A til group or a halo group (preferably substituted with F or Cl), benzofuran, India Selected from the group consisting of ol, indridine, and azaindridine; ULM-g~ULM-i's R PRO1 and R PRO2 Each of them independently is either H, an optionally substituted C1-C3 alkyl group, or together forms a keto group, and Each n from ULM-g to ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1).

[0242] Each of these groups may optionally be bonded to a PTM group (including an ULM' group) via a linker group.

[0243] In certain alternative embodiments of this disclosure, the R of ULM-g to ULM-i 3' -(CH2) is optionally substituted. n -(V) n’ -(CH2) n -(V) n’-R S3’ The base, optionally substituted -(CH2) n -N(R 1’ )(C=O) m’ -(V) n ’ -R S3’ The base, optionally substituted with -X R3’ -Alkyl alkyl group, optionally substituted with -X R3’ -Aryl group; optionally substituted with -X R3’ -HET group, optionally substituted with -X R3’ -aryl-HET base, or assignment -X is replaced by meaning R3’ -HET-aryl group, During the ceremony: R S3’ This is an optionally substituted alkyl group (C1-C 10 The group is preferably a C1-C6 alkyl group, optionally substituted with an aryl group or a HET group; R 1’ is H or a C1-C3 alkyl group (preferably H); V is O, S or NR 1’ and; X R3’ is, -(CH2) n -,-(CH2CH2O) n -, -CH2) n -CH(X v )=CH(X v )-(Sys or Trans), -CH2) n -CH≡CH- or C3-C6 cycloalkyl groups, all of which are optionally substituted; X v is H, halo, or any one or two hydroxyl groups or up to three hydroxyl groups It is a C1-C3 alkyl group substituted with a rogenic group; Alkyl is optionally substituted C1-C 10 It is an alkyl (preferably C1-C6 alkyl) group ( In certain preferred embodiments, the alkyl group is terminated with a halo group, often Cl or Br. The aryl group is optionally substituted with a phenyl group or a naphthyl group (preferably a phenyl group); and HET is an optional substitution of oxazole, isoxazole, thiazole, or isothiazole. Imidazole, diazole, oxyimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, benzofuran, indole, indidine, azaindidine, quinoline (if substituted, each preferably a C1-C3 alkyl group) Preferably substituted with methyl or halo groups, preferably with F or Cl), or the following It is a group that follows the chemical structure of:

[0244] [ka]

[0245] ULM-g~ULM-i's S c CHR SS , NR URE or O; ULM-g~ULM-i's R HET This can be H, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted acetylene group-C≡CR a And in the formula, R a is an acetylene group which is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl group); ULM-g~ULM-i's R SS This includes H, CN, NO2, halo (preferably F or Cl), and optionally substituted C1-C6 alkyl (preferably one or two hydroxyl groups or up to three halo groups). (substituted with), optionally substituted O-(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted -C(O)(C1-C6 alkyl) (preferably one or two hydroxyl groups or up to three (It is substituted with a halo group; ULM-g~ULM-i's R URE The group is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or -C(O)(C0-C6 alkyl), where each group is optionally substituted with one or two hydroxyl groups or up to three halo groups, preferably fluorine groups, or optionally substituted heterocycles, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, etc., each of which is optionally substituted; ULM-g~ULM-i's Y C is N or CR YC And in the formula, R YC H, OH, CN, NO2, Halo (preferred) (or Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF3)), optionally substituted O(C1-C6 alkyl) (preferably one or two hydroxyl groups or up to three) Acetylene groups -C≡CR (substituted with halo groups) or optionally substituted. a And in the formula , R a The acetylene group is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl group). ; ULM-g~ULM-i's R PROThe group is H, optionally substituted C1-C6 alkyl, or optionally substituted aryl (phenyl or naphthyl), heteroaryl, or heterocyclic group, and these groups are oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxyimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably a C1-C3 alkyl group, preferably a me A til group or a halo group (preferably substituted with F or Cl), benzofuran, India Selected from the group consisting of ol, indridine, and azaindridine; ULM-g~ULM-i's R PRO1 and R PRO2 Each of these is independently either H, an optionally substituted C1-C3 alkyl group, or together forms a keto group; Each n from ULM-g to ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1); Each m' in ULM-g~ULM-i is either 0 or 1; and Each n' in ULM-g ~ ULM-i is either 0 or 1; In the formula, each of the compounds preferably consisting of an alkyl group, an aryl group, or a Het group is optional. It is bonded to the PTM group (including the ULM' group) via a linker group.

[0246] In another embodiment, R of ULM-g~ULM-i 3’ is, -(CH2) n -aryl, -(CH2CH2O) n -Aryl, -(CH2) n -HET, or -(CH2CH2O) n -HET, During the ceremony: The aryl group in ULM-g to ULM-i is a phenyl group optionally substituted with one or two substituents, in which case the substituents are preferably -(CH2) n OH, that itself is CN, Hello (most Large three halo groups), OH, -(CH2) n O(C1-C6) alkyl, amine, mono- or di-(C1-C6 alkyl Selected from C1-C6 alkyl groups, which are further optionally substituted with lucylamine, in this case odor The alkyl group of the amine is optionally substituted with one or two hydroxyl groups or up to three halo (preferably F, Cl) groups, or The aryl group in ULM-g to ULM-i is -(CH2) n OH, -(CH2) n -O-(C1-C6)alkyl, -(CH2) n -O-(CH2) n -(C1-C6) alkyl, -(CH2) n -C(O)(C0-C6)alkyl, -(CH2) n -C(O)O(C0-C6)Alki Ru, -(CH2) n -OC(O)(C0-C6)alkyl, amine, mono- or di-(C1-C6alkyl)amine, in which case the alkyl group of the amine is substituted with one or two hydroxyl groups, or up to three halo (preferably F, Cl) groups, CN, NO2, or optionally -(CH2) n -(V) m’ -CH2) n -(V) m’ -(C1-C6) alkyl group, -(V) m’ -(CH2CH2O) n -R PEG The base is optionally substituted, where V is O, S or NR in the formula. 1’ And R 1’ is H or a C1-C3 alkyl group (preferably H) And R PEG is H or optionally substituted C1-C6 alkyl group (including those optionally substituted with a carboxyl group), or The aryl group in ULM-g to ULM-i is preferably C1-C3 aryl, and each is preferably C1-C3 aryl. A methyl group, preferably substituted with a methyl group, or a halo group, preferably substituted with F or Cl), The group is optionally substituted with a heterocyclic heterocycle selected from the group consisting of groups that follow the following chemical structure:

[0247] [ka]

[0248] ULM-g~ULM-i's S c CHR SS , NR URE or O; ULM-g~ULM-i's R HET This can be H, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted acetylene group-C≡CR a And in the formula, R a is an acetylene group which is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl group); ULM-g~ULM-i's R SS This includes H, CN, NO2, halo (preferably F or Cl), and optionally substituted C1-C6 alkyl (preferably one or two hydroxyl groups or up to three halo groups). (substituted with), optionally substituted O-(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted -C(O)(C1-C6 alkyl) (preferably one or two hydroxyl groups or up to three (It is substituted with a halo group; ULM-g~ULM-i's R URE The group is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or -C(O)(C0-C6 alkyl), where each group is optionally substituted with one or two hydroxyl groups or up to three halo groups, preferably fluorine groups, or optionally substituted heterocycles, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, etc., each of which is optionally substituted; ULM-g~ULM-i's Y C is N or CR YC And in the formula, R YC H, OH, CN, NO2, Halo (preferred) (or Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF3)), optionally substituted O(C1-C6 alkyl) (preferably one or two hydroxyl groups or up to three) Acetylene groups -C≡CR (substituted with halo groups) or optionally substituted. a And in the formula , R a The acetylene group is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl group). ; ULM-g~ULM-i's R PROThe group is H, optionally substituted C1-C6 alkyl, or optionally substituted aryl (phenyl or naphthyl), heteroaryl, or heterocyclic group, and these groups are oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxyimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably a C1-C3 alkyl group, preferably a me A til group or a halo group (preferably substituted with F or Cl), benzofuran, India Selected from the group consisting of ol, indridine, and azaindridine; ULM-g~ULM-i's R PRO1 and R PRO2 Each of these is independently either H, an optionally substituted C1-C3 alkyl group, or together forms a keto group; The HET in ULM-g to ULM-i is preferably an oxazole, isoxazole, thiazole, or iso Thiazole, imidazole, diazole, oxyimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted with a C1-C3 alkyl group, preferably methyl, or halo group, preferably F or Cl), benzofuran, indole, indidine, azaindidine, or a group following the following chemical structure:

[0249] [ka]

[0250] ULM-g~ULM-i's S c CHR SS , NR URE or O; ULM-g~ULM-i's R HETThis can be H, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted acetylene group-C≡CR a And in the formula, R a is an acetylene group which is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl group); ULM-g~ULM-i's R SS This includes H, CN, NO2, halo (preferably F or Cl), and optionally substituted C1-C6 alkyl (preferably one or two hydroxyl groups or up to three halo groups). (substituted with), optionally substituted O-(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted -C(O)(C1-C6 alkyl) (preferably one or two hydroxyl groups or up to three (It is substituted with a halo group; ULM-g~ULM-i's R URE The group is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or -C(O)(C0-C6 alkyl), where each group is optionally substituted with one or two hydroxyl groups or up to three halo groups, preferably fluorine groups, or optionally substituted heterocycles, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, etc., each of which is optionally substituted; ULM-g~ULM-i's Y C is N or CR YC And in the formula, R YC H, OH, CN, NO2, Halo (preferred) (or Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF3)), optionally substituted O(C1-C6 alkyl) (preferably one or two hydroxyl groups or up to three) Acetylene groups -C≡CR (substituted with halo groups) or optionally substituted. a And in the formula , R a The acetylene group is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl group). ; ULM-g~ULM-i's R PRO is H, optionally substituted C1-C6 alkyl, or optionally substituted aryl, heteroaryl, or heterocyclic group; ULM-g~ULM-i's R PRO1 and R PRO2 Each of these is independently either H, an optionally substituted C1-C3 alkyl group, or together forms a keto group; Each m' from ULM-g to ULM-i is independently either 0 or 1; and Each n from ULM-g to ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1). In the formula, each of the compounds preferably has a aryl group or HET group, optionally with It is bonded to the PTM group (including the ULM' group) via the NKER group.

[0251] In further embodiments, preferred compounds include those conforming to the following chemical structure, or pharmaceutically acceptable salts, stereoisomers, solvates, or polymorphs thereof:

[0252] [ka]

[0253] During the ceremony: ULM-i R 1’ It is a group that is metabolized to OH, or to OH in the patient or subject; ULM-i R 2’ This is directly -NH-CH2-aryl-HET (preferably methyl-substituted thiazole) It is a bonded phenyl; ULM-i R 3’ -CHR CR3’ -NH-C(O)-R 3P1 base or -CHR CR3’ -R 3P2 It is the basis; ULM-i R CR3’ This is a C1-C4 alkyl group, preferably methyl, isopropyl, or tert-propyl alkyl group. Chill; ULM-i R 3P1 This is a C1-C3 alkyl group (preferably methyl), and optionally substituted oxetane groups (preferably methyl-substituted -(CH2) n OCH3 group, where n is 1 or 2 (preferably 2) ), or

[0254] [ka]

[0255] [ka]

[0256] The aryl group in ULM-i is phenyl; The HET in ULM-i is optionally substituted with a thiazole or isothiazole; and ULM-i R HET is H or a halo group (preferably H); Each of these compounds can be optionally bonded to a PTM group (including ULM') via a linker group.

[0257] In a particular embodiment, a bifunctional compound containing a ubiquitin E3 ligase binding site (ULM), or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof, wherein the ULM is a group conforming to the following chemical structure:

[0258] [ka]

[0259] During the ceremony: Each R5 and R6 in ULM-j is independently an alkyl group that is substituted with OH, SH, or optionally substituted. Alternatively, R5, R6 and the carbon atoms to which they are bonded form a carbonyl group; R7 in ULM-j is H or optionally substituted alkyl; In ULM-j, E represents a bond, C=O, or C=S; The G in ULM-j is a bond, optionally substituted alkyl, -COOH, or C=J; The J in ULM-j is either O or N-R8; R8 of ULM-j is H, CN, optionally substituted alkyl, or optionally substituted alkoxy; In ULM-j, M is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic, or

[0260] [ka]

[0261] ULM-j R9 and R 10 H is independent of the alkyl group, which is optionally substituted, and which is optionally substituted. chloroalkyl, optionally substituted hydroxyalkyl, optionally substituted thioalkyl, disulfide-bonded ULM, optionally substituted heteroaryl, or haloalkyl Yes; or R9, R 10 The carbon atoms to which they are bonded are optionally substituted cycloal Form a kill; ULM-j's R 11 is an optionally substituted heterocyclic compound, an optionally substituted alkoxy, an optionally substituted heteroaryl, an optionally substituted aryl, or

[0262] [ka]

[0263] ULM-j's R 12 is an alkyl group that is H or optionally substituted; ULM-j's R 13 H, optionally substituted alkyl, optionally substituted alkylcarbonyl, Optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl; optionally substituted (oxoa Lukil is a carbamate salt. Each R of ULM-j 14 These are independently H, haloalkyl, optionally substituted cycloalkyl, and optionally A substituted alkyl, or optionally a substituted heterocycloalkyl; ULM-j's R 15 H, optionally substituted heteroaryl, haloalkyl, optionally substituted It is an aryl, optionally substituted alkoxy, or optionally substituted heterocyclyl; Each R of ULM-j 16 These are independently a halo, an optionally substituted alkyl, an optionally substituted haloalkyl, a CN, or an optionally substituted haloalkoxy; Each R of ULM-j 25 is independently H or optionally substituted alkyl; or R 25 Both groups may together form an oxo or optionally substituted cycloalkyl group; ULM-j's R 23 is either H or OH; Z1, Z2, Z3, and Z4 of ULM-j are independently C or N; and The 'o' in ULM-j can be 0, 1, 2, 3, or 4.

[0264] In a particular embodiment, G in ULM-j is C=J, J is O, R7 is H, and each R 14 is H, and o is 0.

[0265] In a particular embodiment, G in ULM-j is C=J, J is O, R7 is H, and each R 14 H is R 15 is a heteroaryl that can be optionally substituted, and o is 0. In another example, E is C=O and M is

[0266] [ka]

[0267] In certain embodiments, E in ULM-j is C=O, and R 11 is a complex algebra that can be optionally substituted or

[0268] [ka]

[0269] [ka]

[0270] In a particular embodiment, E in ULM-j is C=O, and M is

[0271] [ka]

[0272] [ka]

[0273] And each R 18 These are independently a halo, optionally substituted alkoxy, cyano, and optionally substituted It is an alkyl, haloalkyl, or haloalkoxy; and p is 0, 1, 2, 3, The answer is 4.

[0274] In certain embodiments, ULM, and ULM', if present, are groups that independently follow the following chemical structure:

[0275] [ka]

[0276] During the ceremony: In ULM-k, G is C=J, and J is O; R7 of ULM-k is H; Each R of ULM-k 14 is H; The value of o in ULM-k is 0; ULM-k R 15 teeth

[0277] [ka]

[0278] ULM-k R 17 H, halo, optionally substituted cycloalkyl, optionally substituted alkyl , optionally substituted alkenyls, and haloalkyls.

[0279] In another example, ULM-k's R 17 These are alkyl (e.g., methyl) or cycloalkyl (e.g., cyclopropyl).

[0280] In other embodiments, ULM, and ULM', if present, are groups that independently follow the following chemical structure:

[0281] [ka]

[0282] During the ceremony: In ULM-k, G is C=J, and J is O; R7 of ULM-k is H; Each R of ULM-k 14 is H; ULM-k's o is 0; and ULM-k R 15 The following group is selected:

[0283] [ka]

[0284] In other embodiments, ULM, and ULM', if present, are groups that independently follow the following chemical structure:

[0285] [ka]

[0286] [ka]

[0287] [ka]

[0288] In yet another embodiment, a compound having the following chemical structure,

[0289] [ka]

[0290] [ka]

[0291] [ka]

[0292] In ULM-k, q is either 1 or 2; ULM-k R 20 H, optionally substituted alkyl, optionally substituted cycloalkyl, optional The aryl that is replaced by, or

[0293] [ka]

[0294] ULM-k R 21 is an alkyl group that is H or optionally substituted; and ULM-k R 22 is H, optionally substituted alkyl, optionally substituted alkoxy, or H It is a rhalkyl compound.

[0295] In any embodiment described herein, the R of ULM-j or ULM-k 11 From the following Selected from the following group:

[0296] [ka]

[0297] [ka]

[0298] In certain embodiments, the R of ULM-j or ULM-k 11 The following group is selected:

[0299] [ka]

[0300] [ka]

[0301] In certain embodiments, ULM (or ULM', if present) is a group that follows the following chemical structure:

[0302] [ka]

[0303] During the ceremony: In ULM-l, X is either O or S; In ULM-l, Y is H, methyl, or ethyl; ULM-l's R 17 H is methyl, ethyl, hydroxymethyl, or cyclopropyl; M in ULM-l is optionally substituted aryl, optionally substituted heteroaryl, or

[0304] [ka]

[0305] R9 in ULM-1 is H; ULM-l's R 10 H, optionally substituted alkyl, optionally substituted haloalkyl, optionally The substituted heteroaryl, optionally substituted aryl, optionally substituted hydroxyalkyl, optionally substituted thioalkyl, or cycloalkyl; ULM-l's R 11 is an optionally substituted heteroaromatic, optionally substituted heterocyclic, optionally substituted aryl, or

[0306] [ka]

[0307] ULM-l's R 12 is an alkyl group that is H or optionally substituted; and ULM-l's R 13 H, optionally substituted alkyl, optionally substituted alkylcarbonyl, Optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl; optionally substituted (oxoa It is a carbamate salt (Luquil).

[0308] In some embodiments, ULM, and ULM', if present, are groups that independently follow the following chemical structure:

[0309] [ka]

[0310] During the ceremony: In ULM-m, Y stands for H, methyol, or ethyl. R9 of ULM-m is H; R 10 These are isopropyl, tert-butyl, sec-butyl, cyclopentyl, or cyclohexyl; ULM-m's R 11 is an optionally substituted amide, an optionally substituted isoindolinone, and optionally placed The isoxazole that is replaced is an optional heterocycle.

[0311] In other embodiments of this disclosure, ULM, and ULM', if present, are groups that independently conform to the following chemical structure:

[0312] [ka]

[0313] During the ceremony: ULM-n R 17 is methyl, ethyl, or cyclopropyl; and ULM-n R9, R 10 , and R 11 This is defined above. In other examples, R9 is H; and ULM-n R 10 The element is H, alkyl, or cycloalkyl (preferably isopropyl, tert-butyl, sec-butyl, cyclopentyl, or cyclohexyl).

[0314] In any of the embodiments or models described herein, the ULM (or ULM', if present) described herein may be a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, or polymorph thereof. Furthermore, in any of the embodiments or models described herein, the ULM (or ULM', if present) described herein may be bonded to the PTM directly via bonding or by a chemical linker.

[0315] In certain embodiments of this disclosure, the ULM portion is selected from the group consisting of:

[0316] [ka]

[0317] [ka]

[0318] [ka]

[0319] [ka]

[0320] [ka]

[0321]

change

[0322]

change

[0323]

change

[0324]

change

[0325]

change

[0326]

change

[0327]

change

[0328]

change

[0329]

change

[0330]

change

[0331]

change

[0332] [ka]

[0333] [ka]

[0334] [ka]

[0335] [ka]

[0336] [ka]

[0337] [ka]

[0338] In this case, the VLM may be bonded to the PTM via a linker as described herein, optionally via any suitable functional group such as an amine, ester, ether, alkyl, or alkoxy, at any suitable location including, for example, an aryl, heteroaryl, phenyl, or indole group.

[0339] Exemplary ILM AVPI Tetrapeptide Fragment In any of the compounds described herein, ILM is alanine-valine-proly It may contain n-isoleucine (AVPI) tetrapeptide fragments or non-natural mimics thereof. In certain embodiments, ILM is the following formulas (I), (II), (III), (IV), and Select from the group consisting of chemical structures represented by (V):

[0340] [ka]

[0341] During the ceremony: R in equations (I), (II), (III), (IV), and (V) 1 is selected from H or alkyl; R in equations (I), (II), (III), (IV), and (V) 2 is selected from H or alkyl; R in equations (I), (II), (III), (IV), and (V) 3 The element is selected from H, alkyl, cycloalkyl, and heterocycloalkyl; R5 and R6 in formulas (I), (II), (III), (IV), and (V) are independently selected from H, alkyl, cycloalkyl, heterocycloalkyl, or more preferably formula (I ), (II), (III), (IV), and (V) R 5 Furthermore, R 6 These together form a pyrrolidine ring or a piperidine ring, which can be further optionally condensed to one or two cycloalkyl, heterocycloalkyl, aryl, or heteroaryl rings, each of which can then be further condensed to another cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring; R in equations (I), (II), (III), (IV), and (V) 3 Furthermore, R 5 Both are groups of 5-8 members. This can form a ring which can be further optionally condensed with one or two cycloalkyl, heterocycloalkyl, aryl, or heteroaryl rings; R in equations (I), (II), (III), (IV), and (V) 7cycloalkyl, cycloalkylalkyl , heterocycloalkyl, heterocycloalkylalkyl, aryl, aryl-C(O)-R 4 arylalkyl, heteroaryl, heteroaryl-C(O)-R 4 , heteroaryl-R 4 , heteroaryl-naphthalene, heteroarylalkyl, or -C(O)NH-R 4 Select from Each of these can be further optionally halogenated, alkyl, haloalkyl, hydroxyl, alkoxy, cyano, (hetero)cycloalkyl, (hetero)aryl, or -C(O)NH-R 4 , or -C(O )-R 4 Substituted with 1 to 3 substituents selected from; and R 4 These are selected from alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, and they are further optionally substituted with 1 to 3 substituents as described above.

[0342] As described above, P1, P2, P3, and P4 in formula (II) correspond to A, V, P, and I of the AVPI tetrapeptide fragment or its unnatural mimetic, respectively. Similarly, each of formulas (I) and (III) to (V) has a portion that corresponds to A, V, P, and I of the AVPI tetrapeptide fragment or its unnatural mimetic.

[0343] In any of the compounds described herein, ILM is formula (VI), or its non-celestial properties. It can have the structure of a natural mimic, which is described in WO 2008 / 014236 IAP ANTA A derivative of a gonist, or a pharmaceutically acceptable salt or hydrate thereof:

[0344] [ka]

[0345] During the ceremony: In formula (VI), R1 is H, C1-C4-alkyl, C1-C4-alkenyl, C1-C4-alkynyl, or C3-C 10 -Independently selected from cycloalkyls, these are either unsubstituted or substituted; R2 in formula (VI) is H, C1-C4-alkyl, C1-C4-alkenyl, C1-C4-alkynyl, or C3-C 10 -Independently selected from cycloalkyls, these are either unsubstituted or substituted; R3 of formula (VI) is independently selected from H, -CF3, -C2H5, C1-C4-alkyl, C1-C4-alkenyl, C1-C4-alkynyl, -CH2-Z, or any R2 and R3 together form a heterocyclic ring. ; Each Z in equation (VI) is independently of H, -OH, F, Cl, -CH3, -CF3, -CH2Cl, -CH2F, or -CH2OH. and selected; R4 in equation (VI) is C1-C 16 Linear or branched alkyl, C1-C 16 -Alkenyl, C1-C 16 -Alkinyl, C3-C 10 -Cycloalkyl, -(CH2) 0-6 -Z1, -(CH2) 0-6 -aryl, and -(CH2) 0-6 - Selected independently from het, where alkyl, cycloalkyl and phenyl are either unsubstituted or substituted; R5 in equation (VI) is C 1-10 -alkyl, aryl, phenyl, C 3-7 -Cycloalkyl, -(CH2)1-6-C 3-7 -Cycloalkyl, -C 1-10 -Alkyl-aryl, -(CH2) 0-6 -C 3-7 -Cycloalkyl-(CH2) 0-6 -phenyl, -(CH2) 0-4 -CH[(CH2) 1-4 -phenyl]2, indanyl, -C(O)-C1-10 -a Lukil, -C(O)-(CH2) 1-6 -C 3-7 -Cycloalkyl, -C(O)-(CH2) 0-6 -phenyl,- (CH2) 0-6 -C(O)-phenyl, -(CH2) 0-6 -het, -C(O)-(CH2) 1-6 -het is selected independently, or R5 is selected from amino acid residues, where alkyl, cycloalkyl, phenyl, and aryl substituents are unsubstituted or substituted; In equation (VI), Z1 is -N(R 10 )-C(O)-C 1-10 -alkyl, -N(R 1O )-C(O)-(CH2) 0-6 -C 3-7 -cycloalkyl, -N(R 10 )-C(O)-(CH2) 0-6 -phenyl, -N(R) 10 )-C(O)(CH2) 1-6 -het, -C(O)-N(R 11 )(R 12 ), -C(O)-OC 1-10 -alkyl, -C(O)-O-(CH2) 1-6 -C 3-7 -Cycloalkyl, -C(O)-O-(CH2) 0-6 -phenyl, -C(O)-O- (CH2) 1-6 -het, -OC(O)-C 1-10 -alkyl, -OC(O)-(CH2) 1-6 -C3 -7 -Cycloalkyl, -OC(O)-(CH2) 0-6 -phenyl, -OC(O)-(CH2) 1-6 - Selected independently from -het, where alkyl, cycloalkyl, and phenyl are either unsubstituted or substituted; In formula (VI), het is independently selected from a 5-7 member heterocyclic ring containing 1-4 heteroatoms selected from N, O, and S, or from an 8-12 member fused ring system containing at least one 5-7 member heterocyclic ring containing 1, 2, or 3 heteroatoms selected from N, O, and S. Furthermore, the heterocyclic ring or fused ring system is either unsubstituted or substituted on a carbon or nitrogen atom; R in equation (VI) 10 This is selected from H, -CH3, -CF3, -CH2OH, or -CH2Cl; R in equation (VI) 11 and R 12 H, C 1-4 -alkyl, C 3-7 -Cycloalkyl, -(CH2) 1-6 -C 3-7 -Cycloalkyl, (CH2) 0-6 - Selected independently of phenyl, where alkyl, cyclo Lukil and phenyl are either unsubstituted or substituted; or R 11 and R 12 It forms het with nitrogen, and In equation (VI), U is independently as shown in equation (VII):

[0346] [ka]

[0347] During the ceremony: Each n in equation (VII) is independently selected from 0 to 5; In equation (VII), X is selected from the groups -CH and N; R in equation (VII) a and R b These are independently an O atom, an S atom, or an N atom or C 0-8 -alkyl Selected from the group, where one or more carbon atoms in the alkyl chain are substituted with a heteroatom selected from O, S, or N, where each alkyl is independently unsubstituted. or is substituted; R of formula (VII) d is Re-Q-(R f ) p (R g ) q and is selected from the group of Ar1-D-Ar2; R of formula (VII) c is selected from the H group, or any R c and R d together form cycloalkyl or het ; where, when R c and R d form cycloalkyl or het, R5 is bonded to the formed ring by a C atom or an N atom; p and q of formula (VII) are independently selected from 0 or 1; R of formula (VII) e is selected from the group of C 1-8 -alkyl and alkylidene, and each Re is unsubstituted or is substituted; Q is selected from the group of N, O, S, S(O) and S(O)2; Ar1 and Ar2 of formula (VII) are independently selected from the group of substituted or unsubstituted aryl and het; R of formula (VII) f and R<a g are independently H, -C 1-10 ]>-alkyl, C 1-10 -alkylaryl, -OH, -O-C 1-10 -alkyl, -(CH2) 0-6 -C 3-7 -cycloalkyl, -O-(CH2) 0-6 -aryl, phen yl, aryl, phenyl-phenyl, -(CH2) 1-6 -het, -O-(CH2) 1-6 -het, -OR 13 , -C(0)-R 13 , -C(O)-N(R 13 )(R 14 ), -N(R 13 )(R 14 ), -S-R 13,-S(O)-R 13 -S(O)2-R 13 -S(O)2- NR 13 R 14 , -NR 13 -S(O)2-R 14 , -SC t-10 -alkyl, aryl-C 1-4 -alkyl, or het-C 1-4 -Selected from alkyl, where alkyl, cycloalkyl, het and aryl are unsubstituted or substituted -SO2-C 1-2 -alkyl, -SO2-C 1-2 -alkylphenyl, -OC 1-4 -Alkyl is or any R g and R f Both form a ring selected from het or aryl. death; In equation (VII), D is -CO-, -C(O)-C 1-7 -alkylene or arrine, -CF 2- , -O-, -S(O) r of Selected from the group, where r is 0-2, 1,3-dioxalane, or C 1-7 -alkyl-OH; Alkyl, alkylene, or arylene is unsubstituted, or one or more halogens, OH, -OC 1-6 Alkyl, -SC 1-6 Substituted with alkyl or -CF3; or each D is N(R h Selected independently from; Rh is H, unsubstituted or substituted C 1-7 -alkyl, aryl, unsubstituted or substituted -O-(C 1-7 -Cycloalkyl), -C(O)-C 1-10 -alkyl, -C(O)-C 0-10 -alkyl-aryl, -COC 01-10 -alkyl, -COC 0-10 -alkyl-aryl, -SO2-C 1-10 -alkyl, also is -SO2-(C0-10 selected from the group of (-alkylaryl); R6, R7, R8, and R9 of formula (VII) are independently H, -C 1-10 -alkyl, -C 1-10 -alkoxy, aryl-C 1-10 -alkoxy, -OH, -O-C 1-10 -alkyl, -(CH2) 0-6 -C3-7-cycloalkyl, -O-(CH2) 0-6 -aryl, phenyl, -(CH2) 1-6 -het, -O-(CH2) 1-6 -het, -OR 13 , -C(O)-R 13 , -C(O)-N(R 13 )(R 14 ), -N(R 13 )(R 14 ), -S-R 13 , -S(O)-R 13 , -S(O)2-R 13 , -S(O)2-NR 13 R 14 , or -NR 13 -S(O)2-R 14 selected from the group of; wherein each alkyl, cycloalkyl, and aryl is unsubstituted or substituted; and any of R6, R7, R8, and R9 may optionally form a ring system together; R 13 and R 14 [[ID=5l]]are independently H, C 1-10 -alkyl, -(CH2) 0-6 -C 3-7 -cycloal kyl, -(CH2) 0-6 - (CH) 0-1 -(aryl) 1-2 , -C(O)-C 1-10 -alkyl, -C(O)-(CH2) 1-6 -C 3-7 -cycloalkyl, -C(O)-O-(CH2) 0-6 -aryl, - C(O)-(CH2) 0-6 -O-fluorenyl, -C(O)-NH-(CH2) 0-6 -aryl, -C(O)-(CH2)0-6 -aryl, -C(O)-(CH2) 0-6 -het, - C(S)-C 1-10 -alkyl, -C(S)-(CH2) 1-6 -C 3-7 -Cycloalkyl, -C(S)-O-(CH2) 0-6 -aryl, -C(S)-(CH2) 0-6 -O-Fluorenyl, -C(S)-NH-(CH2)O-6-aryl, -C(S)(CH2) 0-6 -aryl, or -C(S)-(CH2) 1-6 - Selected from the group het, where each alkyl, cycloalkyl, and aryl is either unsubstituted or substituted: or any R 13 and R 14 It forms het with nitrogen atoms; Here, R in equation (VII) 13 and R 14 The alkyl substituents are either unsubstituted or substituted. If replaced, C 1-10 -alkyl, halogen, OH, -OC 1-6 -alkyl, -SC 1-6 - Substituted with one or more substituents selected from alkyl and -CF3; and R 13 and R 14 Substituting phenyl or aryl atoms with halogens, hydroxyls, and C 1-4 Alkyl, C 1-4 Alkoxy, nitro, -CN, -OC(O)-C 1-4 Alkyl and -C(O)-OC 1-4 Selected from the alphabet It is substituted with one or more substituents.

[0348] In any of the compounds described herein, ILM is of formula (VIII), or its non-formula. It can have the structure of a native mimetic, which is based on the IAP ligand described in Ndubaku, C., et al. Antagonism of c-IAP and XIAP proteins is required for efficient induction of cell death by small-molecule IAP antagonists, ACS Chem. Biol., 557-566, 4 (7) (2009):

[0349] [ka]

[0350] Here, A1 and A2 in formula (VIII) are independently selected from optionally substituted monocyclic, fused, aryl, and heteroaryl rings; and In equation (VIII), R is selected from H or Me.

[0351] In certain embodiments, the linker group L is bonded to A1 of formula (VIII). In other embodiments, the linker group L is bonded to A2 of formula (VIII).

[0352] In a particular embodiment, the ILM is selected from the group consisting of:

[0353] [ka]

[0354] In any of the compounds described herein, ILM is the following formula (IX), or It can have the structure of a non-natural mimetic, which is derived from a chemical species cross-referenced in Mannhold, R., et al. IAP antagonists: promising candidates for cancer therapy, Drug Discov. Today, 15 (5-6), 210-9 (2010):

[0355] [ka]

[0356] In the formula, R 1 The alkyl group is selected from alkyl, cycloalkyl, and heterocycloalkyl groups, most preferably isopropyl, tert-butyl, cyclohexyl, and tetrahydropyrani. Selected from and R of formula (IX) 2 This is selected from -OPh or H.

[0357] In any of the compounds described herein, ILM may have the structure of formula (X) below, or a non-natural mimetic thereof, as described in Mannhold, R., et al. IAP antagonists: promising candidates for cancer therapy, Drug Discov. Today, 15 (5-6), 210-9 Derived from the chemical species cross-referenced in (2010):

[0358] [ka]

[0359] During the ceremony: R of equation (X) 1 It is selected from H, -CH2OH, --CH2CH2OH, --CH2NH2, --CH2CH2NH2; In equation (X), X is selected from S or CH2; R of equation (X) 2 The following can be selected:

[0360] [ka]

[0361] In any of the compounds described herein, ILM is the following formula (XI), or It can have the structure of a non-natural mimetic, which is derived from a chemical species cross-referenced in Mannhold, R., et al. IAP antagonists: promising candidates for cancer therapy, Drug Discov. Today, 15 (5-6), 210-9 (2010):

[0362] [ka]

[0363] [ka]

[0364] In any of the compounds described herein, ILM may have the structure of formula (XII) below, or a non-natural mimetic thereof, derived from the chemical species cross-referenced in Mannhold, R., et al. IAP antagonists: promising candidates for cancer therapy, Drug Discov. Today, 15 (5-6), 210-9 (2010):

[0365] [ka]

[0366] [ka]

[0367] In any of the compounds described herein, the IAP E3 ubiquitin ligase binding moiety is selected from the group consisting of:

[0368] [ka]

[0369] In any of the compounds described herein, ILM is formula (XIII), or its non-tenon. It can have the structure of a natural mimetic, which is based on IAP ligands summarized in Flygare, JA, et al. Small-molecule pan-IAP antagonists: a patent review, Expert Opin. Ther. Pat., 20 (2), 251-67 (2010):

[0370] [ka]

[0371] [ka]

[0372] [ka]

[0373] In any of the compounds described herein, ILM may have the structure of formula (XIV), as described in Flygare, JA, et al. Small-molecule pan-IAP antagonists: a patent IAP ligands summarized in review, Expert Opin. Ther. Pat., 20 (2), 251-67 (2010) Based on:

[0374] [ka]

[0375] During the ceremony: In equation (XIV), Z either does not exist or is O; R in equation (XIV) 3 and R 4It is independently selected from H or Me; R in equation (XIV) 1 The following can be selected:

[0376] [ka]

[0377] [ka]

[0378] In any of the compounds described herein, ILM is selected from the group consisting of the following: reru:

[0379] [ka]

[0380] This is disclosed in U.S. Patent Publication No. 2008 / 0269140 and U.S. Patent No. 7,244,851. It is a derivative of nd.

[0381] In any of the compounds described herein, ILM is formula (XV), or its non-celestial properties. It can have the structure of a natural mimetic, which is the IAP Rigan described in WO 2008 / 128171. It is a derivative of the drug:

[0382] [ka]

[0383] [ka]

[0384] [ka]

[0385] [ka]

[0386] In a particular embodiment, the ILM has the following structure:

[0387] [ka]

[0388] In any of the compounds described herein, ILM may have the structure of formula (XVI) or its non-natural mimetic, which is IAP-Rigan as described in WO 2006 / 069063. Derived from:

[0389] [ka]

[0390] During the ceremony: R in equation (XVI) 2 These are selected from alkyl, cycloalkyl, and heterocycloalkyl groups. More preferably isopropyl, tert-butyl, cyclohexyl, and tetrahydro From pyranyl, most preferably selected from cyclohexyl; Equation (XVI)

[0391] [ka]

[0392] is a 5-membered or 6-membered nitrogen-containing heteroaryl; more preferably a 5-membered nitrogen-containing heteroaryl It is a teroaryl, most preferably a thiazole; and In equation (XVI), Ar is either an aryl or heteroaryl.

[0393] In any of the compounds described herein, ILM is formula (XVII), or its non-tenon It can have the structure of a natural mimetic, based on the IAP ligand described in Cohen, F. et al., Antogonists of inhibitors of apoptosis proteins based on thiazole amide isosteres, Bioorg. Med. Chem. Lett., 20(7), 2229-33 (2010):

[0394] [ka]

[0395] [ka]

[0396] In any of the compounds described herein, ILM may have the structure of formula (XVIII) or its non-natural mimetic, which is based on the IAP ligand described in Cohen, F. et al., Antogonists of inhibitors of apoptosis proteins based on thiazole amide isosteres, Bioorg. Med. Chem. Lett., 20(7), 2229-33 (2010):

[0397] [ka]

[0398] In the formula, R in formula (XVIII) is selected from alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, or halogen (at a variable substitution position).

[0399] In any of the compounds described herein, ILM may have the structure of formula (XIX) or its non-natural mimetic, which is based on the IAP ligand described in Cohen, F. et al., Antogonists of inhibitors of apoptosis proteins based on thiazole amide isosteres, Bioorg. Med. Chem. Lett., 20(7), 2229-33 (2010):

[0400] [ka]

[0401] [ka]

[0402] In a particular embodiment, the ILM of the composition is selected from the group consisting of:

[0403] [ka]

[0404] In a particular embodiment, the ILM of the composition is selected from the group consisting of:

[0405] [ka]

[0406] In any of the compounds described herein, ILM is of formula (XX), or its non-celestial properties. It can have the structure of a natural mimic, which is the IAP Rigan described in WO 2007 / 101347. Based on:

[0407] [ka]

[0408] In any of the compounds described herein, ILM may have the structure of formula (XXI) or a non-natural mimetic thereof, which is the subject of U.S. Patent No. 7,345,081 and U.S. Patent Based on the IAP ligand described in No. 7,419,975

[0409] [ka]

[0410] [ka]

[0411] [ka]

[0412] [ka]

[0413] In a particular embodiment, the ILM of the compound is selected from the group consisting of:

[0414] [ka]

[0415] [ka]

[0416] In any of the compounds described herein, ILM may have the structure of formula (XXII) or formula (XXIV), or the structure of a non-natural mimetic thereof, and a chemical linker to the linker group L as shown below, the structure being derived from the IAP ligands described in WO 2015 / 006524 and Perez HL, Discovery of potent heterodimeric antagonists of inhibitor of apoptosis proteins (IAPs) with sustained antitumor activity. J. Med. Chem. 58(3), 1556-62 (2015):

[0417] [ka]

[0418] During the ceremony: R in equation (XXII), equation (XXIII), or equation (XXIV) 1 is an optionally substituted alkyl, optional Selected from cycloalkyls substituted with, optionally substituted cycloalkylalkyls, optionally substituted heterocyclyls, optionally substituted arylalkyls, or optionally substituted aryls; R in equation (XXII), equation (XXIII), or equation (XXIV) 2 is an optionally substituted alkyl, optionally Selected from substituted cycloalkyls, optionally substituted cycloalkylalkyls, optionally substituted heterocyclines, optionally substituted arylalkyls, or optionally substituted aryls; Or, R in equation (XXII), equation (XXIII), or equation (XXIV) 1 and R 2 These are independently and can be optionally replaced. A substituent is selected from thioalkyl groups, and the substituent bonded to the sulfur atom of the thioalkyl group is optional. Substitutable alkyl, optionally substituted branched alkyl, optionally substituted heterocyclyl, -(CH2) v COR 20 -CH2CHR 21 COR 22 or -CH2R 23 and; During the ceremony: v is an integer between 1 and 3; -(CH2) v COR 20 and -CH2R 23 R 20 Furthermore, R 22 These are independently OH, NR 24 R 25 OR 26 Selected from; -CH2CHR 21 COR 2 R 21 , NR 24 R 25 Selected from; -CH2R 23 R 23 This is selected from optionally substituted aryls or optionally substituted heterocyclines, where the optional substituents include alkyls and halogens; NR 24 R 25 R 24 is selected from hydrogen or optionally substituted alkyl; NR 24 R 25 R 25 This includes hydrogen, optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted arylalkyl, optionally substituted heterocycline, and -CH2(OCH2CH2O). m CH3, or selected from polyamine chains such as spermine or spermidine; OR 26 R 26 is selected from optionally substituted alkyl groups, where the optional substituent is OH, It is a halogen or NH2; and m is an integer between 1 and 8; R in equation (XXII), equation (XXIII), or equation (XXIV) 3 and R 4 These are independently and can be optionally replaced. Alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heteroarylalkyl, or optionally substituted heterocycloalkyl, where the substituent is alkyl, halogen, or OH; R in equation (XXII), equation (XXIII), or equation (XXIV) 5 , R 6 , R 7 and R 8 It is independent of hydrogen, It is an alkyl group that is optionally substituted, or a cycloalkyl group that is optionally substituted; In certain embodiments, the ILM follows formulas (XXII) to (XXIV): R 7 and R 8 It is selected from H or Me; R 5 and R 6 The group is selected from the following:

[0419] [ka]

[0420] [ka]

[0421] In any of the compounds described herein, ILM has the structure of formula (XXV), formula (XXVI), formula (XXVII), or formula (XXVIII), or the structure of its non-natural mimetic, as shown below. It may have a chemical linker to the linker group L, and this structure is derived from the IAP ligand described in WO 2014 / 055461 and Kim, KS, Discovery of tetrahydroisoquinoline-based bivalent heterodimeric IAP antagonists. Bioorg. Med. Chem. Lett. 24(21), 5022-9 (2014):

[0422] [ka]

[0423] During the ceremony: R in equations (XXV) to (XXVIII) 2 is selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted arylalkyl, or optionally substituted aryl; Or, R in equations (XXV) and (XXVIII) 1 Furthermore, R 2 These are independently H, and optionally substituted thiols. Kill-CR 60 R 61 SR 70 Selected from, in the formula, R 60 and R 61 is selected from H or methyl, and R 70 This includes optionally substituted alkyl groups, optionally substituted branched alkyl groups, optionally substituted heterocyclines, and -(CH2) v COR 20 -CH2CHR 21 COR 22 or -CH2R 23 and; During the ceremony: v is an integer between 1 and 3; -(CH2) v COR 20 and -CH2CHR 21 COR22 R 20 and R 22 These are independently OH, NR 24 R 25 OR 26 from Selected; -CH2CHR 21 COR 22 R 21 , NR 24 R 25 Selected from; -CH2R 23 R 23 This is selected from optionally substituted aryls or optionally substituted heterocyclines, where the optional substituents include alkyls and halogens; NR 24 R 25 R 24 is selected from hydrogen or optionally substituted alkyl; NR 24 R 25 R 25 This includes hydrogen, optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted arylalkyl, optionally substituted heterocycline, and CH2CH2(OCH2CH2). m CH3, or -[CH2CH2(CH2)] of a polyamine chain such as spermine or spermidine. δ NH] Ψ CH2CH2(CH2) ωr Selected from NH2, In the equation, δ = 0 to 2, Ψ = 1 to 3, and ω = 0 to 2; Ure 26 R 26 is an optionally substituted alkyl group, where the optional substituent is OH, halogen It is either n or NH2; m is an integer between 1 and 8; R in equations (XXV) to (XXVIII) 6 and R 8 These are independently hydrogen, optionally substituted alkyl, or optionally selected from substituted cycloalkyls; and R in equations (XXV) to (XXVIII) 31 The alkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl is optionally further substituted and is selected from the group consisting of the following:

[0424] [ka]

[0425] In any of the compounds described herein, the ILM may have the structure of formula (XXIX) or formula (XXX), or a non-natural mimetic thereof, which are derived from the IAP ligand described in WO 2013 / 071039:

[0426] [ka]

[0427] During the ceremony: R of equations (XXIX) and (XXX) 43 Furthermore, R 44 This is independently and optionally substituted with hydrogen. Selected from alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and cycloalkylalkyl, and R of equations (XXIX) and (XXX) 6 Furthermore, R 8 These are independently hydrogen, optionally substituted alkyl Selected from cycloalkyls, or optionally substituted cycloalkyls, Each X in equations (XXIX) and (XXX) is independently selected from the following:

[0428] [ka]

[0429] [ka]

[0430] [ka]

[0431] [ka]

[0432] [ka]

[0433] [ka]

[0434] [ka]

[0435] [ka]

[0436] [ka]

[0437] [ka]

[0438] Or selected from any of the aforementioned tautomers, in the formula: -C(O)R 3 R 3 OH, NHCN, NHS02R 10 NHOR 11 or N(R 12 )(R 13 ) selected from; NHS02R 10and NHOR 11 R 10 Furthermore, R 11 These are independently selected from C1-C4 alkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl groups, any of which may be optionally substituted, and hydrogen; N(R 12 )(R 13 ) of R 12 and R 13 Each of these is independently hydrogen, -C1-C4 alkyl, -(C1-C4 alkyl)-NH-(C1-C4 alkyl), benzyl, -(C1-C4 alkyl)-C(O)OH, -(C1-C4 alkylene)-C(O)CH3, -CH(benzyl)-COOH, -C1-C4 alkoxy, and -(C 1- C4 alkylene)-O-(C 1- Selected from C4 hydroxyalkyl; or N(R 12 )(R 13 ) of R 12 and R 13 These form a saturated heterocycline containing, along with a nitrogen atom to which they are commonly bonded, an optional additional heteroatom selected from N, O, and S, where the saturated heterocycle is optionally substituted with methyl.

[0439] In any of the compounds described herein, ILM is of formula (XXXI) or its non-tenon. They can have the structure of natural mimics, which are described in WO 2013 / 071039 IAP Rigan Derived from:

[0440] [ka]

[0441] During the ceremony: W in formula (XLI) 1 O, S, NR A , or C(R 8a )(R 8b ) selected from; W in formula (XLI) 2 O, S, NR A , or C(R 8c )(R 8d ) is selected from; however, W 1 and W 2 Both are not O, nor are both S; R in formula (XXXI) 1 H, C1-C6 alkyl, C3-C6 cycloalkyl, -C1-C6 alkyl- (substituted (or unsubstituted C3-C6 cycloalkyl), substituted or unsubstituted aryl, substituted or unsubstituted Selected from heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted aryl), or -C1-C6 alkyl-(substituted or unsubstituted heteroaryl); X 1 However, O, NR A If selected from S, S(O), or S(O)2, X 2 C(R 2a R 2b ) and; or: X in equation (XXXI) 1 CR 2c R 2d Selected from, X 2 CR 2a R 2b And R 2c and R 2a They form a bond together; or: X in equation (XXXI) 1 and X 2 The elements are independently selected from C and N, and are condensation-substituted or unsubstituted saturated or partially saturated 3-10 membered cycloalkyl rings, condensation-substituted or unsubstituted saturated or partially saturated rings. It is a component of a sum of 3-10 membered heterocycloalkyl rings, condensed-substituted or unsubstituted 5-10 membered aryl rings, or condensed-substituted or unsubstituted 5-10 membered heteroaryl rings; or: X in equation (XXXI) 1 It is selected from CH2, X 2 C=0, C=C(RC )2, or C=NR C and; each R C is German In addition, H, -CN, -OH, alkoxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl- (substituted or (Unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl- (substituted or unsubstituted C2-C5 heterocycloalkyl) Lukyl), -C1-C6 alkyl-(substituted or unsubstituted aryl), or -C1-C6 alkyl-(substituted Alternatively, selected from (or unsubstituted heteroaryl); NR A R A These include H, C1-C6 alkyl, -C(=O)C1-C2 alkyl, substituted or unsubstituted aryl, or selected from substituted or unsubstituted heteroaryls; CR 2c R 2d and CR 2a R 2b R 2a , R 2b , R 2c , R 2d These are independently H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or Unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocycloalkyl), -C1-C6 alkyl-(substituted (or unsubstituted aryls), -C1-C6 alkyl- (substituted or unsubstituted heteroaryls), and -C(=O)R B Selected from; -C(=O)R B R BThese include substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C3-C6 cycloalkyl groups, substituted or unsubstituted C2-C5 heterocycloalkyl groups, and substituted or unsubstituted aryl groups. , substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cyclo Alkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocycloalkyl), -C1-C6 Lukyl- (substituted or unsubstituted aryl), -C1-C6 alkyl- (substituted or unsubstituted heteroaryl), or -NR D R E Selected from; NR D R E R D and R E These are independently H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted Substituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocycloalkyl Kill), -C1-C6 alkyl- (substituted or unsubstituted aryl), -C1-C6 alkyl- (substituted or unsubstituted aryl) Selected from (substituted heteroaryl); In formula (XXXI), m is selected from 0, 1, or 2; In equation (XXXI), -U- is selected from -NHC(=O)-, -C(=O)NH-, -NHS(=O)2-, -S(=O)2NH-, -NHC(=O)NH-, -NH(C=O)O-, -O(C=O)NH-, or -NHS(=O)2NH-; R in formula (XXXI) 3 This is selected from C1-C3 alkyl or C1-C3 fluoroalkyl; R in formula (XXXI) 4 -NHR 5 , -N(R 5 )2, -N+(R 5 )3 or -OR 5Selected from; -NHR 5 , -N(R 5 )2, -N+(R 5 )3 and -OR 5 Each R 5 These are independently H, C1-C3 alkyl, and C1-C3 halo Selected from alkyl, C1-C3 heteroalkyl, and -C1-C3 alkyl-(C3-C5 cycloalkyl); or: R in formula (XXXI) 3 and R 5 They form substituted or unsubstituted 5-7 member rings with the atoms to which they are bonded; or: R in formula (XXXI) 3 It bonds to the nitrogen atom of U, forming a substituted or unsubstituted 5- to 7-membered ring; R in formula (XXXI) 6 is -NHC(=O)R 7 -C(=O)NHR 7 , -NHS(=O)2R 7 -S(=O)2NHR 7 ;-NHC(=O)NHR 7 , -NHS(=O)2NHR 7 ,-(C 1- C3 alkyl)-NHC(=O)R 7 ,-(C 1- C3 alkyl)-C(=O)NHR 7 ,-(C 1- C3 alkyl)-NHS(=O)2R 7 ,-(C 1- C3 alkyl)-S(O)2NHR 7 ;-(C 1- C3 alkyl)-NHC(=O)NHR 7 ,-(C 1- C3 alkyl)-NHS(=O)2NHR 7 , substitution or non-substitution of C 2- C 10 Heterocycloalkyl, also It is selected from substituted or unsubstituted heteroaryls; -NHC(=O)R 7 -C(=O)NHR 7, -NHS(=O)2R 7 -S(=O) 2 Each R of NHR7 7 is;-NHC(=O)NHR 7 , -NHS(=O) 2NHR 7 ,-(C 1- C3 alkyl)-NHC(=O)R 7 ,-(C 1- C3 alkyl)-C(=O)NHR 7 ,-(C 1- C3 alkyl)-NHS(=O)2R 7 ,-(C 1- C3 alkyl)-S(O)2NHR 7 ;-(C1-C3 alkyl)-NHC(=O)NHR 7 ,-(C1-C3A Lukil)-NHS(=O)2NHR 7 These are independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C2-C 10 hetero Cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C 10 Cycloalkyl), -C1-C6 alkyl- (substituted or These are unsubstituted C2-C10 heterocycloalkyl, -C1-C6 alkyl-(substituted or unsubstituted aryl), -C1-C6 alkyl-(substituted or unsubstituted heteroaryl), and -(CH2)p-CH(substituted or unsubstituted). Replacement aryl) 2, -(CH2) p -CH(substituted or unsubstituted heteroaryl)2, -(CH2) P -CH (substituted or unsubstituted aryl) (substituted or unsubstituted heteroaryl), - (substituted or unsubstituted aryl) Reel)-(substituted or non-substituted aryl),-(substituted or non-substituted aryl)-(substituted or (unsubstituted aryl), -(substituted or unsubstituted heteroaryl), -(substituted or unsubstituted aryl) (a heteroaryl), or -(substituted or unsubstituted heteroaryl)-(substituted or unsubstituted heteroaryl) Selected from (ru); R 7 p is selected from 0, 1, or 2; C(R 8a )(R 8b ) and C(R 8c )(R 8d ) of R 8a , R 8b , R 8c and R 8d H, C1-C6 alkyl, C1-C6 Selected from fluoroalkyls, C1-C6 alkoxys, C1-C6 heteroalkyls, and substituted or unsubstituted aryls; or: R 8a and R 8d As defined above, and R 8b and R 8c They form a bond together; or: R 8a and R 8d As defined above, and R 8b and R 8c These are substitutions that include 1 to 3 heteroatoms selected from S, O, and N, along with the atoms to which they are bonded. This forms an unsubstituted condensed 5-7 member saturated or partially saturated carbocyclic or heterocyclic ring, a substituted or unsubstituted condensed 5-10 member aryl ring, or a substituted or unsubstituted condensed 5-10 member heteroaryl ring containing 1-3 heteroatoms selected from S, O, and N; or: R 8c and R 8d As defined above, and R 8a and R 8b These are substitutions that include 1 to 3 heteroatoms selected from S, O, and N, along with the atoms to which they are bonded. It forms an unsubstituted, saturated or partially saturated 3- to 7-membered spiro ring or heterospiro ring; or: R8a and R 8b As defined above, and R 8c and R 8d These are substitutions that include 1 to 3 heteroatoms selected from S, O, and N, along with the atoms to which they are bonded. It forms an unsubstituted, saturated or partially saturated 3- to 7-membered spiro ring or heterospiro ring; Here, each substituted alkyl, heteroalkyl, fused ring, spiro ring, heterospiro ring, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl has 1 to 3 R 9 Replaced by; and R 8a , R 8b , R 8c and R 8d Each R 9 These are independently halogens, -OH, -SH, (C=O), CN, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, -NH2, -NH(C1-C4 alkyl), -NH(C1-C4 alkyl)2, -C(=O)OH, -C(=0)NH2, -C(=O)C1-C3 alkyl Selected from -S(=O)2CH3, -NH(C1-C4alkyl)-OH, -NH(C1-C4alkyl)-O-(C-C4alkyl), -O(C1-C4alkyl)-NH2; -O(C1-C4alkyl)-NH-(C1-C4alkyl) and -O(C1-C4alkyl)-N-(C1-C4alkyl)2, or two R 9 along with the atoms to which they are bonded They form a methylenedioxy ring or ethylenedioxy ring, which may be substituted with a halogen, -OH, or C1-C3 alkyl group, or be unsubstituted.

[0442] In any of the compounds described herein, ILM may have the structure of formula (XXXII) or its non-natural mimetic, which are IAP-ligans described in WO 2013 / 071039. Derived from:

[0443] [ka]

[0444] During the ceremony: W in formula (XXXII) 1 O, S, NR A , or C(R 8a )(R 8b ) and; W in formula (XXXII) 2 O, S, NR A , or C(R 8c )(R 8d ) and; however, W 1 and W 2 Both are not O, nor are both S; R in equation (XXXII) 1 This includes H, C1-C6 alkyl, C3-C6 cycloalkyl, -C1-C6 alkyl- (substituted or unsubstituted C3-C6 cycloalkyl), substituted or unsubstituted aryl, substituted or unsubstituted. Selected from heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted aryl), or -C1-C6 alkyl-(substituted or unsubstituted heteroaryl); X in equation (XXXII) 1 NR A If X 2 C=O or CR 2c R 2d And X 3 CR 2a R 2b and; or: X in equation (XXXII) 1 is selected from S, S(O), or S(O)2, and X 2 CR 2c R 2d And X 3 CR 2a R 2b and; or: X in equation (XXXII) 1 If X is O, 2 CR 2c R 2d And NRA and X 3 CR 2a R 2b and; or: X in equation (XXXII) 1 If it is CH3, then X 2 O, NR A Selected from S, S(O), or S(O)2 , and X 3 CR 2a R 2b and; X in equation (XXXII) 1 CR 2e R 2f X 2 CR 2c R 2d If R 2e and R 2c They are both connected Forms X of equation (XXXII) 3 CR 2a R 2b and; or: X in equation (XXXII) 1 and X 3 Both are CH2, and X in equation (XXXII) 2 C=0, C=C(R C )2, or C=NR C and; each R C These are independently H, -CN, -OH, alkoxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, and substituted or unsubstituted C2-C5 heteroalkyl. Rocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl- (substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl- (substituted Selected from (or unsubstituted C2-C5 heterocycloalkyl), -C1-C6 alkyl- (substituted or unsubstituted aryl), or -C1-C6 alkyl- (substituted or unsubstituted heteroaryl); or: X in equation (XXXII) 1 and X2 These are independently selected from C and N, and can be condensed, substituted, or unsubstituted in a saturated state. Or partially saturated 3-10 membered cycloalkyl rings, condensation-substituted or unsubstituted saturated or partially saturated rings. A component of a saturated 3-10 member heterocycloalkyl ring, a condensed-substituted or unsubstituted 5-10 member aryl ring, or a condensed-substituted or unsubstituted 5-10 member heteroaryl ring, and X 3 CR 2a R 2b and; or: X in equation (XXXII) 2 and X 3 These are independently selected from C and N, and can be condensed, substituted, or unsubstituted in a saturated state. Or partially saturated 3-10 membered cycloalkyl rings, condensation-substituted or unsubstituted saturated or partially saturated rings. A component of a saturated 3-10 member heterocycloalkyl ring, a condensed-substituted or unsubstituted 5-10 member aryl ring, or a condensed-substituted or unsubstituted 5-10 member heteroaryl ring, and formula (XXXII) X 1 CR 2e R 2f and; NR A R A These include H, C1-C6 alkyl, -C(=O)C1-C2 alkyl, substituted or unsubstituted aryl, or selected from substituted or unsubstituted heteroaryls; CR 2c R 2d CR 2a R 2b and CR 2e R 2f R 2a , R 2b , R 2c , R 2d , R 2e and R 2fThese are independently H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocycloalkyl) -C1-C6 alkyl-(substituted or unsubstituted aryl), -C1-C6 alkyl-(substituted or unsubstituted heteroaryl), and -C(=O)R B Selected from; -C(=O)R B R B These include substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C3-C6 cycloalkyl groups, substituted or unsubstituted C2-C5 heterocycloalkyl groups, and substituted or unsubstituted aryl groups. , substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocycloalkyl), -C1-C6 Lukyl- (substituted or unsubstituted aryl), -C1-C6 alkyl- (substituted or unsubstituted heteroaryl), or -NR D R E Selected from; NR D R E R D and R E These are independently H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted Substituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocycloalkyl Kill), -C1-C6 alkyl- (substituted or unsubstituted aryl), or -C1-C6 alkyl- (substituted (or unsubstituted heteroaryls) are selected; In equation (XXXII), m is selected from 0, 1, or 2; In equation (XXXII), -U- is selected from -NHC(=O)-, -C(=O)NH-, -NHS(=O)2-, -S(=O)2NH-, -NHC(=O)NH-, -NH(C=O)O-, -O(C=O)NH-, or -NHS(=O)2NH-; R in equation (XXXII) 3 This is selected from C1-C3 alkyl or C1-C3 fluoroalkyl; R in equation (XXXII) 4 -NHR 5 , -N(R 5 )2, -N+(R 5 )3 or -OR 5 Selected from; -NHR 5 , -N(R 5 )2, -N+(R 5 )3 and -OR 5 Each R 5 These are independently H, C1-C3 alkyl, and C1-C3 halo Selected from alkyl, C1-C3 heteroalkyl, and -C1-C3 alkyl-(C3-C5 cycloalkyl); or: R in equation (XXXII) 3 and R 5 These are substituted or unsubstituted 5-7 member rings along with the atoms to which they are bonded. form; or: R in equation (XXXII) 3 It bonds to the nitrogen atom of U, forming a substituted or unsubstituted 5- to 7-membered ring; R in equation (XXXII) 6 is -NHC(=O)R 7 -C(=O)NHR 7 , -NHS(=O)2R 7 -S(=O)2NHR 7 ;-NHC(=O)NHR 7 , -NHS(=O)2NHR 7 -(C1-C3 alkyl)-NHC(=O)R 7-(C1-C3 alkyl)-C(=O)NHR 7 -(C1-C3 alkyl)-NHS(=O)2R 7 -(C1-C3 alkyl)-S(=O)2NHR 7 -(C1-C3 alkyl)-NHC(=O)NHR 7 -(C1-C3 alkyl)-NHS(=O)2NHR 7 , substitute or non-substitute C2-C 10 Heterocycloalkyl, or selected from substituted or unsubstituted heteroaryls; -NHC(=O)R 7 -C(=O)NHR 7 , -NHS(=O)2R 7 -S(=O) 2 Each R of NHR7 7 is;-NHC(=O)NHR 7 , -NHS(=O)2NHR 7 ,-(C 1- C3 alkyl)-NHC(=O)R 7 ,-(C 1- C3 alkyl)-C(=O)NHR 7 ,-(C 1- C3 alkyl)-NHS(=O)2R 7 ,-(C 1- C3 alkyl)-S(O)2NHR 7 ;-(C1-C3 alkyl)-NHC(=O)NHR 7 ,-(C1-C3A Lukil)-NHS(=O)2NHR 7 These are independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C2-C 10 hetero Cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C 10 Cycloalkyl), -C1-C6 alkyl- (substituted or These are unsubstituted C2-C10 heterocycloalkyl, -C1-C6 alkyl-(substituted or unsubstituted aryl), -C1-C6 alkyl-(substituted or unsubstituted heteroaryl), and -(CH2)p-CH(substituted or unsubstituted). Replacement aryl) 2, -(CH2) p -CH(substituted or unsubstituted heteroaryl)2, -(CH2) P -CH (substituted or unsubstituted aryl) (substituted or unsubstituted heteroaryl), - (substituted or unsubstituted aryl) Reel)-(substituted or non-substituted aryl),-(substituted or non-substituted aryl)-(substituted or (unsubstituted aryl), -(substituted or unsubstituted heteroaryl), -(substituted or unsubstituted aryl) (a heteroaryl), or -(substituted or unsubstituted heteroaryl)-(substituted or unsubstituted heteroaryl) Selected from (ru); R 7 p is selected from 0, 1, or 2; C(R 8a )(R 8b ) and C(R 8c )(R 8d ) of R 8a , R 8b , R 8c and R 8d H, C1-C6 alkyl, C1-C6 Selected from fluoroalkyls, C1-C6 alkoxys, C1-C6 heteroalkyls, and substituted or unsubstituted aryls; or: R 8a and R 8d As defined above, and R 8b and R 8c They form a bond together; or: R 8a and R 8d As defined above, and R 8b and R 8c These are substitutions that include 1 to 3 heteroatoms selected from S, O, and N, along with the atoms to which they are bonded. This forms an unsubstituted condensed 5-7 member saturated or partially saturated carbocyclic or heterocyclic ring, a substituted or unsubstituted condensed 5-10 member aryl ring, or a substituted or unsubstituted condensed 5-10 member heteroaryl ring containing 1-3 heteroatoms selected from S, O, and N; or: R 8c and R 8d As defined above, and R 8a and R 8b These are substitutions that include 1 to 3 heteroatoms selected from S, O, and N, along with the atoms to which they are bonded. It forms an unsubstituted, saturated or partially saturated 3- to 7-membered spiro ring or heterospiro ring; or: R 8a and R 8b As defined above, and R 8c and R 8d These are substitutions that include 1 to 3 heteroatoms selected from S, O, and N, along with the atoms to which they are bonded. It forms an unsubstituted, saturated or partially saturated 3- to 7-membered spiro ring or heterospiro ring; Here, each substituted alkyl, heteroalkyl, fused ring, spiro ring, heterospiro ring, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl has 1 to 3 R 9 Replaced by; and R 8a , R 8b , R 8c and R 8d Each R 9 These are independently halogens, -OH, -SH, (C=O), CN, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, -NH2, -NH(C1-C4 alkyl), -NH(C1-C4 alkyl)2, -C(=O)OH, -C(=0)NH2, -C(=O)C1-C3 alkyl Selected from -S(=O)2CH3, -NH(C1-C4alkyl)-OH, -NH(C1-C4alkyl)-O-(C-C4alkyl), -O(C1-C4alkyl)-NH2; -O(C1-C4alkyl)-NH-(C1-C4alkyl) and -O(C1-C4alkyl)-N-(C1-C4alkyl)2, or two R 9 along with the atoms to which they are bonded They form a methylenedioxy ring or ethylenedioxy ring, which may be substituted with a halogen, -OH, or C1-C3 alkyl group, or be unsubstituted.

[0445] In any of the compounds described herein, ILM is formula (XXXIII), or They may have the structure of non-natural mimics, which are described in WO 2013 / 071039 as IAP-R Derived from Gand:

[0446] [ka]

[0447] During the ceremony: W in formula (XXXIII) 1 O, S, NR A , or C(R 8a )(R 8b ) selected from; W in formula (XXXIII) 2 O, S, NR A , or C(R 8c )(R 8d ) is selected from; however, W 1 and W 2 Both are not O, nor are both S; R in equation (XXXIII) 1 H, C1-C6 alkyl, C3-C6 cycloalkyl, -C1-C6 alkyl- (substitution) (or unsubstituted C3-C6 cycloalkyl), substituted or unsubstituted aryl, substituted or unsubstituted Selected from substituted heteroaryls, -C1-C6 alkyl-(substituted or unsubstituted aryls), or -C1-C6 alkyl-(substituted or unsubstituted heteroaryls); X in equation (XXXIII) 1 However, NR A If selected from S, S(O), or S(O)2, then X in formula (XXXIII) 2 CR 2c R 2d And X in equation (XXXIII) 3 CR 2a R 2b and; or: X in equation (XXXIII) 1 If it is O, then X in equation (XXXIII) 2 O, NR A Selected from S, S(O), or S(O)2, and X of formula (XXXIII) 3 CR 2a R 2b and; or: X in equation (XXXIII) 1 CR 2e R 2f And X in equation (XXXIII) 2 CR 2c R 2d If R 2e and R 2c They both form a bond, and X in equation (XXXIII) 3 CR 2a R 2b and; or: X in equation (XXXIII) 1 and X 2 The elements are independently selected from C and N, and are condensation-substituted or unsubstituted saturated or partially saturated 3-10 membered cycloalkyl rings, condensation-substituted or unsubstituted saturated or partially A component of a saturated 3-10 member heterocycloalkyl ring, a condensed-substituted or unsubstituted 5-10 member aryl ring, or a condensed-substituted or unsubstituted 5-10 member heteroaryl ring, and formula (XXXIII) X 3 CR 2aR 2b and; or: X in equation (XXXIII) 2 and X 3 The elements are independently selected from C and N, and are condensation-substituted or unsubstituted saturated or partially saturated 3-10 membered cycloalkyl rings, condensation-substituted or unsubstituted saturated or partially A component of a saturated 3-10 member heterocycloalkyl ring, a condensed-substituted or unsubstituted 5-10 member aryl ring, or a condensed-substituted or unsubstituted 5-10 member heteroaryl ring, and formula (VLII) X 1 CR 2e R 2f and; NR A R A These include H, C1-C6 alkyl, -C(=O)C1-C2 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryls; CR 2c R 2d CR 2a R 2b and CR 2e R 2f R 2a , R 2b , R 2c , R 2d , R 2e and R 2f These are independently H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted aryl), -C1-C6 alkyl-(substituted or unsubstituted hetero aryl), and - C(=O)R B Selected from; -C(=O)R B R BThis includes substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, and substituted... or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted aryl), -C1-C6 alkyl-(substituted or unsubstituted heteroaryl), or -NR D R E and; NR D R E R D and R E These are independently H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted Substituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocycloalkyl Kill), -C1-C6 alkyl- (substituted or unsubstituted aryl), or -C1-C6 alkyl- (substituted (or unsubstituted heteroaryls) are selected; In equation (XXXIII), m is 0, 1, or 2; -U- in formula (XXXIII) is -NHC(=O)-, -C(=O)NH-, -NHS(=O)2-, -S(=O)2NH-, -NHC(=O)NH-, -NH(C=O)O-, -O(C=O)NH-, or -NHS(=O)2NH-; R in equation (XXXIII) 3 These are C1-C3 alkyl or C1-C3 fluoroalkyl groups; R in equation (XXXIII) 4 -NHR 5 , -N(R 5 )2, -N+(R 5 )3 or -OR 5 and; -NHR 5 , -N(R 5 )2, -N+(R 5 )3 and -OR 5 Each R 5 These are independently H, C1-C3 alkyl, and C1-C3 halo Selected from alkyl, C1-C3 heteroalkyl, and -C1-C3 alkyl-(C3-C5 cycloalkyl); or: R in equation (XXXIII) 3 and R 5 They form substituted or unsubstituted 5-7 member rings with the atoms to which they are bonded; or: R in equation (XXXIII) 3 It bonds to the nitrogen atom of U, forming a substituted or unsubstituted 5- to 7-membered ring; R in equation (XXXIII) 6 is -NHC(=O)R 7 -C(=O)NHR 7 , -NHS(=O)2R 7 -S(=O)2NHR 7 ;-NHC(=O)NHR 7 , -NHS(=O)2NHR 7 -(C1-C3 alkyl)-NHC(=O)R 7 -(C1-C3 alkyl)-C(=O)NHR 7 -(C1-C3 alkyl)-NHS(=O)2R 7 -(C1-C3 alkyl)-S(=O)2NHR 7 -(C1-C3 alkyl)-NHC(=O)NHR 7 -(C1-C3 alkyl)-NHS(=O)2NHR 7 , substitute or non-substitute C2-C 10 Heterocycloalkyl, or selected from substituted or unsubstituted heteroaryls; -NHC(=O)R 7 -C(=O)NHR 7 , -NHS(=O)2R 7 -S(=O) 2 Each R of NHR7 7is;-NHC(=O)NHR 7 , -NHS(=O)2NHR 7 ,-(C 1- C3 alkyl)-NHC(=O)R 7 ,-(C 1- C3 alkyl)-C(=O)NHR 7 ,-(C 1- C3 alkyl)-NHS(=O)2R 7 ,-(C 1- C3 alkyl)-S(O)2NHR 7 ;-(C1-C3 alkyl)-NHC(=O)NHR 7 ,-(C1-C3A Lukil)-NHS(=O)2NHR 7 These are independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C2-C 10 hetero Cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C 10 Cycloalkyl), -C1-C6 alkyl- (substituted or These are unsubstituted C2-C10 heterocycloalkyl, -C1-C6 alkyl-(substituted or unsubstituted aryl), -C1-C6 alkyl-(substituted or unsubstituted heteroaryl), and -(CH2)p-CH(substituted or unsubstituted). Replacement aryl) 2, -(CH2) p -CH(substituted or unsubstituted heteroaryl)2, -(CH2) P -CH (substituted or unsubstituted aryl) (substituted or unsubstituted heteroaryl), - (substituted or unsubstituted aryl) Reel)-(substituted or non-substituted aryl),-(substituted or non-substituted aryl)-(substituted or (unsubstituted aryl), -(substituted or unsubstituted heteroaryl), -(substituted or unsubstituted aryl) (a heteroaryl), or -(substituted or unsubstituted heteroaryl)-(substituted or unsubstituted heteroaryl) Selected from (ru); R 7p is 0, 1, or 2; C(R 8a )(R 8b ) and C(R 8c )(R 8d ) of R 8a , R 8b , R 8c and R 8d H, C1-C6 alkyl, C1-C6 Selected from fluoroalkyls, C1-C6 alkoxys, C1-C6 heteroalkyls, and substituted or unsubstituted aryls; or: R 8a and R 8d As defined above, and R 8b and R 8c They form a bond together; or: R 8a and R 8d As defined above, and R 8b and R 8c These are substitutions that include 1 to 3 heteroatoms selected from S, O, and N, along with the atoms to which they are bonded. This forms an unsubstituted condensed 5-7 member saturated or partially saturated carbocyclic or heterocyclic ring, a substituted or unsubstituted condensed 5-10 member aryl ring, or a substituted or unsubstituted condensed 5-10 member heteroaryl ring containing 1-3 heteroatoms selected from S, O, and N; or: R 8c and R 8d As defined above, and R 8a and R 8b These are substitutions that include 1 to 3 heteroatoms selected from S, O, and N, along with the atoms to which they are bonded. It forms an unsubstituted, saturated or partially saturated 3- to 7-membered spiro ring or heterospiro ring; or: R 8a and R 8b As defined above, and R 8c and R 8d They are combined A substitution containing one to three heteroatoms selected from S, O, and N, along with the atom. It forms an unsubstituted, saturated or partially saturated 3- to 7-membered spiro ring or heterospiro ring; Here, each substituted alkyl, heteroalkyl, fused ring, spiro ring, heterospiro ring, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl has 1 to 3 R 9 Replaced by; and R 8a , R 8b , R 8c and R 8d Each R 9 These are independently halogens, -OH, -SH, (C=O), CN, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, -NH2, -NH(C1-C4 alkyl), -NH(C1-C4 alkyl)2, -C(=O)OH, -C(=0)NH2, -C(=O)C1-C3 alkyl Selected from -S(=O)2CH3, -NH(C1-C4alkyl)-OH, -NH(C1-C4alkyl)-O-(C-C4alkyl), -O(C1-C4alkyl)-NH2; -O(C1-C4alkyl)-NH-(C1-C4alkyl) and -O(C1-C4alkyl)-N-(C1-C4alkyl)2, or two R 9 along with the atoms to which they are bonded They form a methylenedioxy ring or ethylenedioxy ring, which may be substituted with a halogen, -OH, or C1-C3 alkyl group, or be unsubstituted.

[0448] In any of the compounds described herein, ILM may have the structure of formula (XXXIV) or its non-natural mimetic, which are IAP rigas described in WO 2013 / 071039. Derived from:

[0449] [ka]

[0450] During the ceremony: W in formula (XXXIV) 1 O, S, NR A , or C(R 8a )(R 8b ) selected from; W in formula (XXXIV) 2 O, S, NR A , or C(R 8c )(R 8d ) is selected from; however, W 1 and W 2 Both are not O, nor are both S; W in formula (XXXIV) 3 O, S, NR A , or C(R 8e )(R 8f ) is selected from, however W 1 , W 2 Oh biW 3 A ring containing does not contain two adjacent oxygen or sulfur atoms; R in formula (XXXIV) 1 This includes H, C1-C6 alkyl, C3-C6 cycloalkyl, -C1-C6 alkyl- (substituted or unsubstituted C3-C6 cycloalkyl), substituted or unsubstituted aryl, substituted or unsubstituted. Selected from heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted aryl), or -C1-C6 alkyl-(substituted or unsubstituted heteroaryl); X in equation (XXXIV) 1 If it is O, then X in equation (XXXIV) 2 CR 2c R 2d and NR A Selected from, W of formula (XXXIV) 3 CR 2a R 2b and; or: X in equation (XXXIV) 1 If it is CH2, then X in equation (XXXIV) 2 O, NR A Selected from S, S(O), or S(O)2, X in formula (XXXIV)3 CR 2a R 2b and; or: X in equation (XXXIV) 1 CR 2e R 2f And X in equation (XXXIV) 2 CR 2c R 2d If R 2e and R 2c They both form a bond, and X in equation (XXXIV) 3 CR 2a R 2b and; or: X in equation (XXXIV) 1 and X 3 Both are CH2, and X in equation (XXXIV) 2 C=0, C=C(R C )2, or C=NR C and; each R C These are independently H, -CN, -OH, alkoxy, substituted or unsubstituted C1-C6 Alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl- (substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl- (substituted or unsubstituted Substituted C2-C5 heterocycloalkyl, C1-C6 alkyl- (substituted or unsubstituted aryl), also It is selected from -C1-C6 alkyl- (substituted or unsubstituted heteroaryl); or: X in equation (XXXIV) 1 and X 2 These are independently selected from C and N, and can be condensed, substituted, or unsubstituted in a saturated state. Or partially saturated 3-10 membered cycloalkyl rings, condensation-substituted or unsubstituted saturated or partially saturated rings. A component of a saturated 3-10 member heterocycloalkyl ring, a condensed-substituted or unsubstituted 5-10 member aryl ring, or a condensed-substituted or unsubstituted 5-10 member heteroaryl ring, and formula (XXXIV) X 3 CR 2a R 2b and; or: X in equation (XXXIV) 2 and X 3 These are independently selected from C and N, and can be condensed, substituted, or unsubstituted in a saturated state. Or partially saturated 3-10 membered cycloalkyl rings, condensation-substituted or unsubstituted saturated or partially saturated rings. A component of a saturated 3-10 member heterocycloalkyl ring, a condensed-substituted or unsubstituted 5-10 member aryl ring, or a condensed-substituted or unsubstituted 5-10 member heteroaryl ring, and formula (VLIV) X 1 CR 2e R 2f and; NR A R A These include H, C1-C6 alkyl, -C(=O)C1-C2 alkyl, substituted or unsubstituted aryl, or selected from substituted or unsubstituted heteroaryls; CR 2c R 2d CR 2a R 2b and CR 2e R 2f R 2a , R 2b , R 2c , R 2d , R 2e and R 2fThese are independently H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted aryl), -C1-C6 alkyl-(substituted or unsubstituted hetero aryl), and - C(=O)R B Selected from; -C(=O)R B R B These include substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C3-C6 cycloalkyl groups, substituted or unsubstituted C2-C5 heterocycloalkyl groups, and substituted or unsubstituted aryl groups. , substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocycloalkyl), -C1-C6 Lukyl- (substituted or unsubstituted aryl), -C1-C6 alkyl- (substituted or unsubstituted heteroaryl), or -NR D R E Selected from; NR D R E R D and R E These are independently H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted Substituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocycloalkyl Kill), -C1-C6 alkyl- (substituted or unsubstituted aryl), or -C1-C6 alkyl- (substituted (or unsubstituted heteroaryls) are selected; In formula (XXXIV), m is selected from 0, 1, or 2; In formula (XXXIV), -U- is selected from -NHC(=O)-, -C(=O)NH-, -NHS(=O)2-, -S(=O)2NH-, -NHC(=O)NH-, -NH(C=O)O-, -O(C=O)NH-, or -NHS(=O)2NH-; R in formula (XXXIV) 3 This is selected from C1-C3 alkyl or C1-C3 fluoroalkyl; R in formula (XXXIV) 4 -NHR 5 , -N(R 5 )2, -N+(R 5 )3 or -OR 5 Selected from; -NHR 5 , -N(R 5 )2, -N+(R 5 )3 and -OR 5 Each R 5 These are independently H, C1-C3 alkyl, and C1-C3 halo Selected from alkyl, C1-C3 heteroalkyl, and -C1-C3 alkyl-(C3-C5 cycloalkyl); or: R in formula (XXXIV) 3 and R 5 These are substituted or unsubstituted 5-7 member rings along with the atoms to which they are bonded. form; or: R in formula (XXXIV) 3 It bonds to the nitrogen atom of U, forming a substituted or unsubstituted 5- to 7-membered ring; R in formula (XXXIV) 6 is -NHC(=O)R 7 -C(=O)NHR 7 , -NHS(=O)2R 7 -S(=O)2NHR 7 ;-NHC(=O)NHR 7 , -NHS(=O)2NHR 7 -(C1-C3 alkyl)-NHC(=O)R 7 -(C1-C3 alkyl)-C(=O)NHR7 ,-(C1-C3 Alkyl)-NHS(=O)2R 7 -(C1-C3 alkyl)-S(=O)2NHR 7 -(C1-C3 alkyl)-NHC(=O)NHR 7 -(C1-C3 alkyl)-NHS(=O)2NHR 7 , substitute or non-substitute C2-C 10 Heterocycloalkyl, or selected from substituted or unsubstituted heteroaryls; -NHC(=O)R 7 -C(=O)NHR 7 , -NHS(=O)2R 7 -S(=O) 2 Each R of NHR7 7 is;-NHC(=O)NHR 7 , -NHS(=O)2NHR 7 ,-(C 1- C3 alkyl)-NHC(=O)R 7 ,-(C 1- C3 alkyl)-C(=O)NHR 7 ,-(C 1- C3 alkyl)-NHS(=O)2R 7 ,-(C 1- C3 alkyl)-S(O)2NHR 7 ;-(C1-C3 alkyl)-NHC(=O)NHR 7 ,-(C1-C3A Lukil)-NHS(=O)2NHR 7 These are independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C2-C 10 hetero Cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C 10 Cycloalkyl), -C1-C6 alkyl- (substituted or These are unsubstituted C2-C10 heterocycloalkyl, -C1-C6 alkyl-(substituted or unsubstituted aryl), -C1-C6 alkyl-(substituted or unsubstituted heteroaryl), and -(CH2)p-CH(substituted or unsubstituted). Replacement aryl) 2, -(CH2) p -CH(substituted or unsubstituted heteroaryl)2, -(CH2) P -CH (substituted or unsubstituted aryl) (substituted or unsubstituted heteroaryl), - (substituted or unsubstituted aryl) Reel)-(substituted or non-substituted aryl),-(substituted or non-substituted aryl)-(substituted or (unsubstituted aryl), -(substituted or unsubstituted heteroaryl), -(substituted or unsubstituted aryl) (a heteroaryl), or -(substituted or unsubstituted heteroaryl)-(substituted or unsubstituted heteroaryl) Selected from (ru); R 7 p is selected from 0, 1, or 2; C(R 8a )(R 8b ), C(R 8c )(R 8d ) and C(R 8e )(R 8f ) of R 8a , R 8b , R 8c , R 8d , R 8e and R 8f is German In addition, H, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 alkoxy, C1-C6 heteroalkyl Luquill and selected from substituted or unsubstituted aryls; or: C(R 8a )(R 8b ), C(R 8c )(R 8d ) and C(R 8e )(R 8f ) of R 8a , R 8d , R 8e and R 8f is defined above As is the case, and R 8b and R 8c They form a bond together; or: C(R 8a )(R 8b ), C(R 8c )(R 8d ) and C(R 8e )(R 8f ) of R 8a , R 8b , R 8d and R 8f is defined above As is the case, and R 8c and R 8e They form a bond together; or: C(R 8a )(R 8b ), C(R 8c )(R 8d ) and C(R 8e )(R 8f ) of R 8a , R 8d , R 8e and R 8f is defined above As stated above, and R 8b and R 8c These are substituted or unsubstituted condensed 5-7 member saturated atoms containing 1-3 heteroatoms selected from S, O, and N, along with the atoms to which they are bonded. or partially saturated carbon rings or heterocyclic rings, substituted or unsubstituted condensed 5-10 membered aryl rings, Alternatively, a substituted or unsubstituted compound containing 1 to 3 heteroatoms selected from S, O, and N Condensation forms a 5-10 membered heteroaryl ring; or: C(R 8a )(R 8b ), C(R 8c )(R 8d ) and C(R 8e )(R 8f ) of R 8a , R 8b , R 8d and R 8f is defined above As stated above, and R 8c and R 8e These are substituted or unsubstituted condensed 5-7 member saturated atoms containing 1-3 heteroatoms selected from S, O, and N, along with the atoms to which they are bonded. or partially saturated carbon rings or heterocyclic rings, substituted or unsubstituted condensed 5-10 membered aryl rings, Alternatively, a substituted or unsubstituted compound containing 1 to 3 heteroatoms selected from S, O, and N Condensation forms a 5-10 membered heteroaryl ring; or: C(R 8c )(R 8d ) and C(R 8e )(R 8f ) of R 8c , R 8d , R 8e and R 8f As defined above, and R 8a and R 8b These, together with the atoms to which they are bonded, form substituted or unsubstituted saturated or partially saturated 3- to 7-membered spiro rings or heterospiro rings containing 1-3 heteroatoms selected from S, O, and N; or: C(R 8a )(R 8b ) and C(R 8e )(R 8f ) of R 8a , R 8b , R 8e and R 8f As defined above, and R 8c and R 8d These are selected from S, O, and N, along with the atoms to which they are bonded. Forming substituted or unsubstituted saturated or partially saturated 3-7 membered spiro rings or heterospiro rings containing 1-3 heteroatoms; or: C(R 8a )(R 8b ) and C(R 8c )(R 8d ) of R 8a , R 8b , R8c and R 8d As defined above, and R 8e and R 8f These, together with the atoms to which they are bonded, form substituted or unsubstituted saturated or partially saturated 3- to 7-membered spiro rings or heterospiro rings containing 1-3 heteroatoms selected from S, O, and N; or: Here, each substituted alkyl, heteroalkyl, fused ring, spiro ring, heterospiro ring, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl has 1 to 3 R 9 Replaced by; and R 8a , R 8b , R 8c , R 8d , R 8e , and R 8f Each R 9 These are independently halogen, -OH, -SH, (C=O), CN, and C. 1- C4 alkyl, C1-C4 fluoroalkyl, C 1- C4alkyl, C 1- C4 Fluoroalcoholic -NH2, -NH(C1-C4alkyl), -NH(C1-C4alkyl)2, -C(=O)OH, -C(=0)NH2, -C(=O)C1-C3alkyl, -S(=O)2CH3, -NH(C1-C4alkyl)-OH, -NH(C1-C4alkyl)-O-(C-C4alkyl) Selected from -O(C1-C4alkyl)-NH2; -O(C1-C4alkyl)-NH-(C1-C4alkyl) and -O(C1-C4alkyl)-N-(C1-C4alkyl)2, or two R 9 These, along with the atoms to which they are bonded, form a methylenedioxy ring or ethylenedioxy ring that is substituted with a halogen, -OH, or C1-C3 alkyl, or is unsubstituted.

[0451] In any of the compounds described herein, ILM may have the structure of formula (XXXV), formula (XXXVI), or formula (XXXVII), or a non-natural mimetic thereof, as described in Vamos, M., et al., Expedient synthesis of highly potent antagonists of inhibitor of apoptosis proteins (IAPs) with unique selectivity for ML-IAP, ACS Chem. Biol., Derived from the IAP ligand described in 8(4), 725-32 (2013):

[0452] [ka]

[0453] During the ceremony: R of equations (XXXV) and (XXXVII) 2 It is independently selected from H or ME; R in formula (XXXV) 3 and R 4 It is independently selected from H or ME; In formulas (XXXV) and (XXXVII), X is independently selected from O or S; and R of equations (XXXV) and (XXXVII) 1 The following can be selected:

[0454] [ka]

[0455] In a particular embodiment, the ILM has a structure that conforms to the following formula (XXXVIII):

[0456] [ka]

[0457] [ka]

[0458] [ka]

[0459] In a particular embodiment, the formula (XXXVIII)

[0460] [ka]

[0461] In a particular embodiment, the ILM has the structure shown below and is bonded to a linker group L:

[0462] [ka]

[0463] In any of the compounds described herein, ILM may have the structure of formula (XXXIX) or formula (XL), or a non-natural mimetic thereof, based on the IAP ligand described in Hennessy, EJ, et al., Discovery of aminopiperidine-based Smac mimetics as IAP antagonists, Bioorg. Med. Chem. Lett., 22(4), 1960-4 (2012):

[0464] [ka]

[0465] [ka]

[0466] R of formulas (XXXIX) and (XL) 2It is selected from H or Me; R of formulas (XXXIX) and (XL) 3 The following can be selected:

[0467] [ka]

[0468] X is selected from H, halogen, methyl, methoxy, hydroxy, nitro, or trifluoromethyl.

[0469] In any of the compounds described herein, ILM has a structure of formula (XLI) or formula (XLII) or its non-natural mimetic form, as shown in formula (XLI) or formula (XLII). It can have and can be chemically bonded to a linker:

[0470] [ka]

[0471] In any of the compounds described herein, ILM may have the structure of formula (XLIII) or its non-natural mimetic, which is based on the IAP ligand described in Cohen, F, et al., Orally bioavailable antagonists of inhibitor of apoptosis proteins based on an azabicyclooctane scaffold, J. Med. Chem., 52(6), 1723-30 (2009):

[0472] [ka]

[0473] [ka]

[0474] In a particular embodiment, the ILM is represented by the following structure:

[0475] [ka]

[0476] In a particular embodiment, the ILM is selected from the group consisting of the following, and between the ILM and the linker base L The chemical bond is shown:

[0477] [ka]

[0478] In any of the compounds described herein, ILM is the following, or its non-natural form The compounds were selected from a group consisting of mimetic structures, as described in Asano, M, et al., Design, sterioselective synthesis, and biological evaluation of novel tri-cyclic compounds as inhibitor of apoptosis proteins (IAP) antagonists, Bioorg. Med. Chem., 21(18): 5725-37. Based on the IAP ligand described in (2013):

[0479] [ka]

[0480] In a particular embodiment, the ILM is selected from the group consisting of the following, and between the ILM and the linker base L The chemical bond is shown:

[0481] [ka]

[0482] In any of the compounds described herein, ILM is of formula (XLIV), or its non-formula. It can have the structure of a native mimetic, based on the IAP ligand described in Asano, M, et al., Design, sterioselective synthesis, and biological evaluation of novel tri-cyclic compounds as inhibitor of apoptosis proteins (IAP) antagonists, Bioorg. Med. Chem., 21(18): 5725-37 (2013):

[0483] [ka]

[0484] In the formula, X in formula (XLIV) is one or two substituents independently selected from H, halogens, or cyano compounds.

[0485] In any of the compounds described herein, ILM has a structure of formula (XLV) or formula (XLVI) or its non-natural mimetic form, as shown in formula (XLV) or formula (XLVI). It can have and can be chemically bonded to a linker group L:

[0486] [ka]

[0487] In the formulas, X in formulas (XLV) and (XLVI) is independently selected from H, halogen, or cyanoacrylate. The substituents are one or two substituents, and L in formulas (XLV) and (XLVI) is a linker group as described herein.

[0488] In any of the compounds described herein, ILM may have the structure of formula (XLVII) or its unnatural mimetic, as described in Ardecky, RJ, et al., Design, sysnthesis and evaluation of inhibitor of apoptosis (IAP) antagonists that are highly selective for the BIR2 domain of XIAP, Bioorg. Med. Chem., 23(14): 4253-7 (2013). Based on the IAP ligands listed:

[0489] [ka]

[0490] [ka]

[0491] [ka]

[0492] In any of the compounds described herein, ILM is a non-natural mimetic of formula (XLVIII) or formula (XLIX) as shown in formula (XLVIII) or formula (XLIX). It can have a structure and can be chemically bonded to a linker group L:

[0493] [ka]

[0494] [ka]

[0495] are natural or unnatural amino acids; and In formulas (XLVIII) and (XLIX), L is a linker group as described herein.

[0496] In any of the compounds described herein, ILM is selected from the group consisting of the following: It can have a structure that is like that of a non-natural mimetic, which is described in Wang, J, et al., Discovery of novel second mitochondrial-derived activator of caspase mimetics Derived from IAP ligands as selected inhibitors or apoptosis protein inhibitors, J. Pharmacol. Exp. Ther., 349(2): 319-29 (2014):

[0497] [ka]

[0498] In any of the compounds described herein, ILM has a structure that conforms to formula (L) or its unnatural mimetic, which is based on the IAP ligand described in Hird, AW, et al., Structure-based design and synthesis of tricyclic IAP (Inhibitors of Apoptosis Proteins) inhibitors, Bioorg. Med. Chem. Lett., 24(7): 1820-4 (2014):

[0499] [ka]

[0500] [ka]

[0501] [ka]

[0502] [ka]

[0503] [ka]

[0504] [ka]

[0505] [ka]

[0506] HET is a monocyclic heteroaryl or fused bicyclic heteroaryl; and In equation (L), --- represents any double bond.

[0507] In certain embodiments, the ILM of the compound has a chemical structure selected from the group consisting of the following: ru:

[0508] [ka]

[0509] [ka]

[0510] An example of MLM In certain additional embodiments, the MLM of the difunctional compound is, for example, a substituted imidazoline, substituted It includes chemical parts such as spiro-indolinone, substituted pyrrolidine, substituted piperidinone, substituted substituted morpholinone, substituted pyrrolopyrimidine, substituted imidazolopyridine, substituted thiazoloidazoline, substituted pyrrolopyrrolidinone, and substituted isoquinolinone.

[0511] In additional embodiments, the MLM is located adjacent to the adjacent MLM, positioned as either sys or trans configuration. This includes the aforementioned core structure with bis-aryl substitution.

[0512] In further embodiments, the MLM includes structural feature portions such as those found in RG7112, RG7388, SAR405838, AMG-232, AM-7209, DS-5272, MK-8242, and NVP-CGM-097, as well as their analogs or derivatives.

[0513] In a particular preferred embodiment, the MLM is a substituted imidazoline represented by formula (A-1) Derivatives, or derivatives of thiazoloidazoline represented by formula (A-2), or derivatives of spiroindrinone represented by formula (A-3), or derivatives of pyrrolidine represented by formula (A-4). , or a derivative of piperidinone / morphurinone represented by formula (A-5), or a derivative of isoquinolinone represented by formula (A-6), or a derivative of pyrrolopyrimidine / imi represented by formula (A-7) Derivatives of dazolopyridine, or pyrrolopyrrolidinone / imidazolo represented by formula (A-8) It is a derivative of pyrrolidinone.

[0514] [ka]

[0515] In the above equations (A-1) to (A-8), In formulas (A-1) to (A-8), X is carbon, oxygen, sulfur, sulfoxide, sulfone, and NR. a Selected from the group consisting of; R a These are independently H or an alkyl group having 1 to 6 carbon atoms; In equations (A-1) to (A-8), Y and Z are independently carbon or nitrogen; In formulas (A-1) to (A-8), A, A', and A'' may be independently selected from C, N, O, or S, or may be one or two atoms that form a fused bicyclic ring or a 6,5- and 5,5-fused aromatic bicyclic group; In formulas (A-1) to (A-8), R1 and R2 are independently selected from the group consisting of aryl groups or heteroaryl groups, and the heteroaryl group has one or two heteroatoms independently selected from sulfur or nitrogen, and the aryl group or heteroaryl group may be monocyclic or bicyclic, or one to three substituents independently selected from the group consisting of the following. It may be replaced by, or it may not be replaced: Halogens, -CN, C1-C6 alkyl groups, C3-C6 cycloalkyl groups, -OH, alkoxys containing 1-6 carbon atoms, fluorine-substituted alkoxys containing 1-6 carbon atoms, sulfoxides containing 1-6 carbon atoms, sulfones containing 1-6 carbon atoms, ketones containing 2-6 carbon atoms, amides containing 2-6 carbon atoms, and dialkylamines containing 2-6 carbon atoms; In formulas (A-1) to (A-8), R3 and R4 are independently from the group consisting of H, methyl, and C1-C6 alkyl. Selected from; R5 in formulas (A-1) to (A-8) is selected from the group consisting of aryl groups or heteroaryl groups, the heteroaryl group having one or two heteroatoms independently selected from sulfur or nitrogen, the aryl group or heteroaryl group may be monocyclic or bicyclic, or may be substituted with one to three substituents independently selected from the group consisting of: Halogens, -CN, C1-C6 alkyl groups, C3-C6 cycloalkyl groups, -OH, alkoxys containing 1-6 carbon atoms, fluorine-substituted alkoxys containing 1-6 carbon atoms, sulfoxides containing 1-6 carbon atoms, sulfones containing 1-6 carbon atoms, ketones containing 2-6 carbon atoms, amides containing 2-6 carbon atoms, dialkylamines containing 2-6 carbon atoms, alkyl ethers (C2-C6), alkyl ketones (C3-C6), morpholinyl, alkyl esters (C3-C6), alkyl cyanides (C3-C6) ; In equations (A-1) to (A-8), R6 is either H or -C(=O)R. b And in the formula, R in equations (A-1) to (A-8) b These include alkyl, cycloalkyl, monosubstituted, disubstituted or trisubstituted aryl or heteroaryl, 4-morpholinyl, 1-(3-oxopiperazunil), 1-piperidinyl, and 4-NR. c -Molfolinyl, 4-R c -1-Piperidinyl, and 3-R c -1-Piperidinil Selected from the following groups, in the formula, R in equations (A-1) to (A-8) c This includes alkyl, fluorine-substituted alkyl, cyanoalkyl, hydroxyl-substituted alkyl, cycloalkyl, alkoxyalkyl, amidealkyl, alkylsulfone, alkylsulfoxide, alkylamide, aryl, heteroaryl, monosubstituted, disubstituted and trisubstituted aryl or heteroaryl, CH2CH2R d , and CH2CH2CH2R d Selected from the group consisting of, in the formula, R in equations (A-1) to (A-8) d These are alkoxy, alkyl sulfone, alkyl sulfoxide Selected from the group consisting of N-substituted carboxamide, -NHC(O)-alkyl, -NH-SO2-alkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; In formulas (A-1) to (A-8), R7 is H, C1-C6 alkyl, cyclic alkyl, or fluorine-substituted alkyl. Selected from the group consisting of cyanosubstituted alkyl groups, 5-membered or 6-membered heteroaryl or aryl groups, and 5-membered or 6-membered substituted heteroaryl or aryl groups; In equations (A-1) to (A-8), R8 is -R e -C(O)-R f , -R e -alkoxy, -R e -Aryl, -R e - Hete Royr, and -R e -C(O)-R f -C(O)-R g Selected from the group consisting of: R in equations (A-1) to (A-8) e This refers to an alkylene or bond containing 1 to 6 carbon atoms; R in equations (A-1) to (A-8) f is a 4- to 7-member permutation complex ring; R in equations (A-1) to (A-8) g This is selected from the group consisting of aryl, heteroaryl, substituted aryl or heteroaryl, and 4- to 7-membered heterorings; R in equations (A-1) to (A-8) 9 In formula (A-3), one substituent on the fused bicyclic aromatic ring, and two A group selected from the group consisting of substituents or trip substituents, where the substituents are independently substituted with Cl or F, or are unsubstituted halogens, alkenes, alkynes, or alkyl groups. Selected from; R in equations (A-1) to (A-8) 10 The group is selected from the group consisting of aryl groups or heteroaryl groups. Here, the heteroaryl group may contain one or two heteroatoms such as sulfur or nitrogen, and the aryl group or heteroaryl group may be monocyclic or bicyclic, and the aryl group or heteroaryl group may contain halogens, F, Cl, -CN, alkenes, alkynes, C1-C6 alkyl groups, C1-C6 cycloalkyl groups, -OH, and alcos containing 1-6 carbon atoms. Xy, fluorine-substituted alkoxy containing 1 to 6 carbon atoms, sulfoxide containing 1 to 6 carbon atoms, 1 Sulfones containing ~6 carbon atoms, ketones containing 2~6 carbon atoms, and ketones with one to three substituents. It may be replaced or remain unchanged; R in equations (A-1) to (A-8) 11 is -C(O)-N(R h )(R i ) and in the formula, R h and R i The group is selected from the following: H; optionally substituted linear or branched C1-C6 alkyl groups; alkoxy-substituted alkyl groups; mono-hydroxy-substituted alkyl groups and di-hydroxy-substituted alkyl groups (e.g., C3-C6), sulfone Hon-substituted alkyl; optionally substituted aryl; optionally substituted heteroaryl; mono-substituted, bis-substituted, or tri-substituted aryl or heteroaryl; phenyl-4-cal phenyl-4-carboxylic acid; substituted phenyl-4-carboxylic acid, alkylcarboxylic acid; optionally substituted heterocarboxylic acid Rheel carboxylic acids; alkyl carboxylic acids; fluorine-substituted alkyl carboxylic acids; optionally substituted cycloalkyls, 3-hydroxycyclobutane, 4-hydroxycyclohehexane, aryl-substituted cycloalkyls; heteroaryl-substituted cycloalkyls; or Rh and Ri together form a ring; R in equations (A-1) to (A-8) 12 and R 13 These are independently H, lower alkyl (C1-C6), and lower alkyl Lukenyl (C2-C6), lower alkynyl (C2-C6), cycloalkyl (4-membered, 5-membered, and 6-membered) R12 and R13 may be selected from a ring, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, 5-membered and 6-membered aryl and heteroaryl rings, and R12 and R13 may be bonded to form 5-membered and 6-membered rings with or without substitution on the ring; R in equations (A-1) to (A-8) 14 is alkyl, substituted alkyl, alkenyl, substituted alkenyl Selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkyl, substituted cycloalkyl, cycloalkenyl, and substituted cycloalkenyl; R in equations (A-1) to (A-8) 15 is CN; R in equations (A-1) to (A-8) 16 This includes C1-C6 alkyl, C1-6 cycloalkyl, C2-6 alkenyl, C1-6 alkyl or C3-6 cycloalkyl with one or more hydrogens substituted with fluorine, alkyl or cycloalkyl with one CH2 substituted with S(=O), -S, or -S(=O)2, and the end. Alkyl or cycloalkyl groups in which the terminal CH3 is substituted with S(=O)2N(alkyl)(alkyl), -C(=O)N(alkyl)(alkyl), -N(alkyl)S(=O)2(alkyl), -C(=O)2(alkyl), or -O(alkyl), or C1-6 alkyl or alkyl-cycloalkyl groups in which the hydrogen is substituted with a hydroxyl group. Roalkyl, optionally containing a -(C=O)- group, 3- to 7-membered cycloalkyl or heterocycloalkyl group Selected from the group consisting of alkyl groups, or 5- to 6-membered aryl or heteroaryl groups, the heterocycloalkyl or heteroaryl group is independently selected from O, N, or S. The cycloalkyl group, heterocycloalkyl group, aryl group, or heteroaryl group may be substituted with one to three substituents independently selected from halogens, C1-6 alkyl groups, hydroxylated C1-6 alkyl groups, thioether-containing C1-6 alkyl groups, ethers, sulfones, sulfoxides, fluorine-substituted ethers, or cyano groups, or may be unsubstituted; R in equations (A-1) to (A-8) 17 (CH2)nC(O)NR k R l Selected from the group consisting of, in the formula, R k and R l These are independently H, C1-6 alkyl, hydroxylated C1-6 alkyl, and C1-6 alkoxyal C1-6 alkyl groups with one or more hydrogens substituted with fluorine, C1-6 alkyl groups with one carbon substituted with S(O), S(O)(O), C1-6 alkyl groups with one or more hydrogens substituted with fluorine Selected from coxyalkyls, C1-6 alkyls in which hydrogen is substituted with a cyano group, 5-membered and 6-membered aryl or heteroaryls, alkylaryls having an alkyl group containing 1 to 6 carbon atoms, and alkylheteroaryls having an alkyl group containing 1 to 6 carbon atoms, wherein the aryl or heteroaryl group may be further substituted; R in equations (A-1) to (A-8) 18 These are substituted aryl, heteroaryl, alkyl, and cycloaryl Selected from the group consisting of Kil, the substitution is preferably -N(C1-4 alkyl)(cycloal These are Kil), -N(C1-4 alkyl)alkyl-cycloalkyl, and -N(C1-4 alkyl)[(alkyl)-(heterocyclic substituted)-cycloalkyl]; R in equations (A-1) to (A-8) 19 From aryl, heteroaryl, and bicyclic heteroaryl Selected from the group, these aryl and heteroaryl groups may be substituted with halogens, C1-6 alkyl groups, C1-6 cycloalkyl groups, CF3, F, CN, alkynes, or alkylsulfones, and such halogen substitution may be monosubstituted, disubstituted, or trisubstituted; R in equations (A-1) to (A-8) 20 and R 21 R is independently selected from C1-6 alkyl, C1-6 cycloalkyl, C1-6 alkoxy, hydroxylated C1-6 alkoxy, and fluorine-substituted C1-6 alkoxy, where R 20 and R 21 These are further joined to form 5, 6, and 7-membered rings or heterocycles. They may be formed, and they may be further replaced; R in equations (A-1) to (A-8) 22H, C1-6 alkyl, C1-6 cycloalkyl, carboxylic acid, carboxylic acid ester, amide, reverse amide, sulfonamide, riba Selected from the group consisting of reverse sulfonamide, N-acylurea, and nitrogen-containing 5-membered heterocycle, the 5-membered heterocycle is further composed of C1-6 alkyl, alkoxy, and fluorine-substituted elements. They may be substituted with lukyl, CN, and alkylsulfones; R in equations (A-1) to (A-8) 23 are aryl, heteroaryl, -O-aryl, -O-heteroaryl Selected from aryl, -O-alkyl, -O-alkyl-cycloalkyl, -NH-alkyl, -NH-alkyl-cycloalkyl, -N(H)-aryl, -N(H)-heteroaryl, -N(alkyl)-aryl, and -N(alkyl)-heteroaryl, the aryl or heteroaryl group may be substituted with halogen, C1-C6 alkyl, hydroxylated C1-6 alkyl, cycloalkyl, fluorine-substituted C1-6 alkyl, CN, alkoxy, alkylsulfone, amide, and sulfonamide; R in equations (A-1) to (A-8) 24 This is selected from the group consisting of -CH2-(C1-6 alkyl), -CH2-cycloalkyl, -CH2-aryl, and CH2-heteroaryl, and the alkyl, cycloalkyl, aryl, and heteroaryl may be substituted with halogens, alkoxy, hydroxylated alkyl, cyanosubstituted alkyl, cycloalkyl, and substituted cycloalkyl; R in equations (A-1) to (A-8) 25 This includes C1-6 alkyl, C1-6 alkyl-cycloalkyl, alkoxy-substituted alkyl, hydroxylated alkyl, aryl, heteroaryl, substituted aryl or heteroaryl, 5,6 and 7-membered nitrogen-containing saturated heterocycle, 5,6-condensed and 6,6-condensed nitrogen Selected from the group consisting of saturated heterocycles, these saturated heterocycles may be substituted with C1-6 alkyl, fluorine-substituted C1-6 alkyl, alkoxy, aryl, and heteroaryl groups; R in equations (A-1) to (A-8) 26 The group is selected from the group consisting of C1-6 alkyl and C3-6 cycloalkyl. Furthermore, the alkyl or cycloalkyl group is defined as -OH, alkoxy, or fluorine-substituted alkoxy. , fluorine-substituted alkyl, -NH2, -NH-alkyl, NH-C(O)alkyl, -NH-S(O)2-alkyl, And may be substituted with -S(O)2-alkyl; R in equations (A-1) to (A-8) 27 From aryl, heteroaryl, and bicyclic heteroaryl Selected from the group, the aryl group or heteroaryl group may be substituted with C1-6 alkyl, alkoxy, NH2, NH-alkyl, halogen or -CN, and such substitutions are independent of , may be one-substitution, two-substitution, or three-substitution; R in equations (A-1) to (A-8) 28 These include aryl, 5-membered and 6-membered heteroaryl, and bicyclic heteroaryl. Selected from the group consisting of loaryl, cycloalkyl, saturated heterocycle such as piperidine, piperidinone, tetrahydropyran, and N-acyl-piperidine, wherein the cycloalkyl, saturated heterocycle, aryl, or heteroaryl contains -OH, alkoxy, or halogen. Furthermore, substitution, disubstituted or trisubstituted, -CN, alkylsulfone, and fluorine-substituted alkyl groups It may be replaced with; and R in equations (A-1) to (A-8) 1” H, alkyl, aryl-substituted alkyl, alkoxy-substituted The group is selected from alkyl, cycloalkyl, aryl-substituted cycloalkyl, and alkoxy-substituted cycloalkyl.

[0516] In a particular embodiment, R in formulas (A-1) to (A-8) f and R g The heterocycles in this context are substituted pyrrolidines, substituted piperidines, and substituted piperidines.

[0517] More specifically, non-exclusive examples of MLM include the following, as well as the following molecules. A "hybrid" molecule is a molecule that arises from a combination of one or more different properties shown in the given context. It can be done.

[0518] Using the MLM formulas A-1 to A-8, the following PROTACs are used to degrade specific proteins. It can be fabricated to target, where "L" is the connector (i.e., the linker base). Therefore, "PTM" is a ligand that binds to the target protein.

[0519] In certain embodiments, this specification provides a bifunctional molecule comprising a structure selected from the group consisting of:

[0520] [ka]

[0521] In the formula, X, R a , Y, Z, A, A', A'', R1, R2, R3, R4, R5, R6, R b , R c , R d , R7, R e , R f , R g , R9, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R k , R l , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R28 , and R1 are defined in this specification as formulas (A-1) to (A-8) As defined with respect to ).

[0522] In certain embodiments, this specification describes a bifunctional molecule having the structure of PTM-L-MLM, or This provides a chimeric molecule, where PTM is a protein target binding site linked to MLM by L. In the formula, L is a bond (i.e., absent) or a chemical linker. In certain embodiments, The MLM has a structure selected from the group consisting of A-1-1, A-1-2, A-1-3, and A-1-4:

[0523] [ka]

[0524] During the ceremony: In formulas A-1-1 to A-1-4 (i.e., A-1-1, A-1-2, A-1-3, and A-1-4), R1' and R2' are independently selected from the group consisting of F, Cl, Br, I, acetylene, CN, CF3, and NO2; R3' is selected from the group consisting of -OCH3, -OCH2CH3, -OCH2CH2F, -OCH2CH2OCH3, and -OCH(CH3)2; In equations A-1-1 to A-1-4, R4' is H, halogen, -CH3, -CF3, -OCH3, -C(CH3)3. Selected from the group consisting of -CH(CH3)2, -cyclopropyl, -CN, -C(CH3)2OH, -C(CH3)2OCH2CH3, -C(CH3)2CH2OH, -C(CH3)2CH2OCH2CH3, -C(CH3)2CH2OCH2CH2OH, -C(CH3)2CH2OCH2CH3, -C(CH3)2CN, -C(CH3)2C(O)CH3, -C(CH3)2C(O)NHCH3, -C(CH3)2C(O)N(CH3)2, -SCH3, -SCH2CH3, -S(O)2CH3, -S(O2)CH2CH3, -NHC(CH3)3, -N(CH3)2, pyrrolidinyl, and 4-morpholinyl; R5' in formulas A-1-1 to A-1-4 is selected from the group consisting of halogen, -cyclopropyl, -S(O)2CH3, -S(O)2CH2CH3, 1-pyrrolidinyl, -NH2, -N(CH3)2, and -NHC(CH3)3; and In equations A-1-1 to A-1-4, R6' is selected from the structures shown below, where the linker joint is indicated by "*". Apart from R6' as a linker bonding site, R4' can also function as a linker bonding site. If R4' is the linker bonding site, the linker will be bonded to the terminal atom of the R4' group, as shown above.

[0525] In certain embodiments, the linker coupling points of formulas A-1-1 to A-1-4 are at least one of R4' or R6', or both.

[0526] In certain embodiments, R6' in formulas A-1-1 to A-1-4 is independently H,

[0527] [ka]

[0528] In certain embodiments, the linkers of formulas A-4-1 to A-4-6 are coupled to at least one of R1', R2', R3', R4', R5', R6', or a combination thereof.

[0529] In certain embodiments, this specification describes a bifunctional molecule having the structure of PTM-L-MLM, or This provides a chimeric molecule, where PTM is a protein target binding site linked to MLM by L. In the formula, L is a bond (i.e., absent) or a chemical linker. In certain embodiments, MLM is selected from the following group consisting of A-4-1, A-4-2, A-4-3, A-4-4, A-4-5, and A-4-6. Having a selected structure:

[0530] [ka]

[0531] During the ceremony: R7' in equations A-4-1 to A-4-6 (i.e., A-4-1, A-4-2, A-4-3, A-4-4, A-4-5, and A-4-6) is one or more (e.g., 1, 2, 3, or 4) halogens; R8' in formulas A-4-1 to A-4-6 is from the group consisting of H, -F, -Cl, -Br, -I, -CN, -NO2, ethylnyl, cyclopropyl, methyl, ethyl, isopropyl, vinyl, methoxy, ethoxy, isopropoxy, -OH, other C1-6 alkyls, other C1-6 alkenyls and C1-6 alkynyls. One or more groups (e.g., 1, 2, 3, or 4 groups) are selected and are monosubstituted, disubstituted, or trisubstituted; In formulas A-4-1 to A-4-6, R9' is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted cycloalkenyl; In formulas A-4-1 to A-4-6, Z is selected from the group consisting of H, -OCH3, -OCH2CH3, and halogens; In equations A-4-1 to A-4-6, R10' and R11' are independently H, (CH2) n -R', (CH2) n -NR'R'', (CH2) n -NR'COR'', (CH2) n -NR'SO2R'', (CH2) n -COOH, (CH2) n -COOR', (CH) n -CONR'R'', (CH2) n -OR', (CH2) n -SR', (CH2) n -SOR', (CH2) n-CH(OH)-R'、 (CH2) n -COR', (CH2) n -SO2R', (CH2) n -SONR'R''、 (CH2) n -SO2NR'R''、 (CH2CH2O) m -(CH2) n -R'、 (CH2CH2O) m -(CH2) n -OH、 (CH2CH2O) m -(CH2) n -OR'、 (CH2CH2O) m -(CH2) n -NR'R''、 (CH2CH2O) m -(CH2) n -NR'COR''、 (CH2CH2O) m (CH2) n -NR'SO2R''、 (CH2CH2O) m (CH2) n -COOH、 (CH2CH2O) m (CH2) n -COOR'、 (CH2CH2O) m -(CH2) n -CONR'R''、 (CH2CH2O) m -(CH2) n -SO2R'、 (CH2CH2O) m -(CH2) n -COR'、 (CH2CH2O) m -(CH2) n -SONR'R''、 (CH2CH2O) m -(CH2) n -SO2NR'R''、 (CH2) p -(CH2CH2O) m -(CH2) n R'、 (CH2)p-(CH2CH2O) m -(CH2) n -OH、 (CH2) p -(CH2CH2O) m -(CH2)n-OR'、 (CH2) p -(CH2CH2O) m -(CH2)n -NR'R'', (CH2) p -(CH2CH2O) m -(CH2) n -NR'COR'', (CH 2) p -(CH2CH2O)m-(CH2) n -NR'SO2R'', (CH2) p -(CH2CH2O) m -(CH2) n -COOH, (CH2) p -(CH2CH2O) m -(CH2) n -COOR', (CH2) p -(CH2CH2O) m -(CH2) n -CONR'R'', (CH2)p-(CH2CH2O) m -(CH2) n -SO2R', (CH2) p -(CH2CH2O) m -(CH2) n -COR', (CH2) p -(CH2CH2O) m -(CH2) n -SONR'R'', (CH2) p -(CH2CH2O) m -(CH2) n -SO2NR'R'', aryl-(CH2) n -COOH, and heteroaryl-al Kill-CO-alkyl-NR'R''m, and heteroaryl-(CH2) n -Selected from the group consisting of heterocycles, in which case alkyl may be substituted with OR', in which case heterocycle is The R' and R'' may optionally be substituted with alkyl, hydroxyl, COOR', and COR'; wherein the formula, R' and R'' are selected from H, alkyl, halogen-substituted alkyl, hydroxyl, NH2, NH(alkyl), N(alkyl)2, oxo, carboxy, chloroalkyl, and heteroaryl. Selected; m, n, and p are independently between 0 and 6; In formulas A-4-1 to A-4-6, R12' represents -O-(alkyl), -O-(alkyl)-alkoxy, and -C(O)-(alkyl Selected from the group consisting of -C(OH)-alkyl-alkoxy, -C(O)-NH-(alkyl), -C(O)-N-(alkyl)2, -S(O)-(alkyl), S(O)2-(alkyl), -C(O)-(cyclic amine), and -O-aryl-(alkyl), -O-aryl-(alkoxy); In formulas A-4-1 to A-4-6, R1'' represents H, alkyl, aryl-substituted alkyl, or alkoxy-substituted alkyl. Selected from the group consisting of cycloalkyl, aryl-substituted cycloalkyl, and alkoxy-substituted cycloalkyl.

[0532] In any of the embodiments or models described herein, alkyl, alkoxy or similar may be a lower alkyl or lower alkoxy.

[0533] In certain embodiments, the linker joint points of formulas A-4-1 to A-4-6 are at least one of Z, R8', R9', R10', R11”, R12”, or R1”.

[0534] The methods used to design the chimeric molecules presented in A-1-1 to A-1-4 and A-4-1 to A-4-6 can be applied to MLM using formulas A-2, A-3, A-5, A-6, A-7, and A-8, in which case the solvent-exposed region of MLM may be bound to linker "L", which will bind to the target protein ligand "PTM" to construct a PROTAC.

[0535] Examples of MDM2 coupling regions, though not limited to them, include the following: 1. Vassilev, et al., In vivo activation of the p53 pathway by small-molecule antagonists of MDM2, SCIENCE vol:303, pag:844-848 (2004), and Schneeekloth, et al. al., Targeted intracellular protein degradation induced by a small molecule: En route to chemical proteomics, Bioorg. Med. Chem. Lett. 18 (2008) 5904-5908 HDM2 / MDM2 inhibitors, including (or additionally), the following compounds identified by: nathrin-3, nathrin-2, and nathrin-1 (derivative), as well as all their derivatives and analogues:

[0536] [ka]

[0537] [ka]

[0538] [ka]

[0539] 2. Trans-4-iodo-4'-boranyl-chalcone

[0540] [ka]

[0541] Exemplary linker In certain embodiments, the compounds described herein are linked via a chemical linker (L) to one or more ULMs (e.g., at least one of CLM, VLM, MLM, ILM, or a combination thereof) It includes one or more PTMs that are chemically linked or bonded to it. In certain embodiments, The linker group L is a group that contains one or more covalently bonded structural units (for example, -A L 1… (A L ) q -or-(A L ) q -), in this case A1 is a group bonded to PTM, (A L ) q This is a group bonded to ULM.

[0542] In any aspect or embodiment described herein, linker(L) to ULM (for example) If the connection or bond is to VLM, ILM, CLM, or MLM, then the L-ULM connection is a stable L-ULM connection. For example, in any aspect or embodiment described herein, when the linker (L) and ULM are connected via a heteroatom, any subsequent heteroatom, if present, consists of at least one single carbon atom (e.g., -CH₂), such as an acetal group or an aminal group. 2- ) Therefore, separation occurs. As a further example, in any aspect or embodiment described herein, when the linker (L) and ULM are linked via a heteroatom, the heteroatom is not part of the ester.

[0543] In any aspect or embodiment described herein, the linker group L is a bond or of formula -(A L ) q - is a chemical linker group represented by the formula, where A is the chemical part. q is an integer from 1 to 100 (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100), and in the formula, L is covalently bonded to PTM and ULM, and the target Sufficient binding of PTM to the target protein and E3 ubiquitination are required to induce protein ubiquitination. It provides binding of ULM to biquitin ligase.

[0544] In any aspect or embodiment described herein, the linker group L is -(A L ) q - and in the formula, (A L ) q This consists of the ULM portion, the PTM portion (e.g., CLM or VLM), or a combination thereof. A group that is bonded to at least one of the members; The linker's q is an integer greater than or equal to 1 (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 5 (0, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100); Each A L They are independent, combined, and CR. L1 R L2 O, S, SO, SO2, NR L3 SO2NR L3 , SONR L3 CONR L3 , NR L3 CONR L4 , NR L3 SO2NR L4 CO, CR L1 =CR L2 , C≡C, SiR L1 R L2 P(O)R L1 , P(O)OR L1 , NR L3 C(=N CN)NR L4 , NR L3 C (=NCN), NR L3 C(=CNO2)NR L4 , optionally 0 to 6 R L1 and / or R L2 C substituted with the base 3-11 Cycloalkyl, optionally 0 to 9 R L1 and / or R L2 C substituted with the base 5-13 Spirocycloalkyl, optionally 0 to 6 R L1 and / or R L2 C substituted with the base 3-11 He Telosicryl, optionally 0 to 8 R L1 and / or R L2 C that is substituted with the group 5-13 Spirohetero Cycloalkyl, optionally 0 to 6 R L1 and / or R L2 The aryl group to be substituted, optionally 0 to 6 R L1 and / or R L2 Selected from the group consisting of heteroaryls substituted with the group, in this case R L1 or R L2 Each can be independently and arbitrarily bonded to other groups, with any 0 to 4 R groups. L5 Forms cycloalkyl and / or heterocyclyl moieties substituted with the group; and Beauty R L1 , R L2 , R L3 , R L4 and R L5 Each of these is independent of H, Halo, and C. 1-8 Alkyl, OC 1-8 Alki Lu, SC 1-8 Alkyl, NHC 1-8 Alkyl, N(C 1-8 Alkyl)2, C 3-11 Cycloalkyl, aryl, heteroaryl, C 3-11 Heterocycline, OC 3-8 Cycloalkyl, SC 3-8 Cycloalkyl Ru, NHC 3-8 Cycloalkyl, N(C 3-8 Cycloalkyl)2, N(C 3-8 Cycloalkyl)(C 1-8 Alkyl), OH, NH2, SH, SO2C 1-8 alkyl, P(O)(OC 1-8 Alkyl)(C 1-8 alkyl), P(O)(OC 1-8 Alkyl)2, CC-C 1-8 Alkyl, CCH, CH=CH(C 1-8 Alkyl), C(C 1-8 Alkyl)=CH(C 1-8 Alkyl), C(C 1-8 Alkyl) = C(C 1-8 Alkyl)2, Si(OH)3, Si(C 1-8 Alkyl)3,Si(OH)(C 1-8 Alkyl)2, COC 1-8 Alkyl, CO2H, Halogen, CN, CF3, CHF2, CH2F, NO2, SF5, SO2NHC 1-8 Alkyl, SO2N(C 1-8 Alkyl) 2, SONHC 1-8 Alkyl, SON(C 1-8 Alkyl)2, CONHC 1-8 Alkyl, CON(C 1-8 Alkyl)2, N(C 1-8 Alkyl)CONH(C 1-8 Alkyl), N(C1-8 Alkyl)CON(C 1-8 Alkyl)2, NHCONH(C 1-8 Alkyl), NHCON(C 1-8 Alkyl)2, NHCONH2, N(C 1-8 Alkyl)SO2NH(C 1-8 Alkyl), N(C 1-8 Alkyl) SO2N(C 1-8 Alkyl)2,NH₃SO₂NH₃(C 1-8 Alkyl), NH₃SO₂N(C 1-8 It is alkyl)2, NH₃SO₂NH₂.

[0545] In any aspect or embodiment described herein, the linker q is an integer greater than or equal to 0. In certain embodiments, q is an integer greater than or equal to 1.

[0546] In any aspect or embodiment described herein, for example, when the linker q is greater than 2, (A L ) q is, A L 1 and (A L ) q It is a base and unit A L This is the combination of PTM and ULM. That is the case.

[0547] In any aspect or embodiment described herein, for example, if the linker q is 2, (A L ) q is, A L It is a base that connects to 1 and ULM.

[0548] In any aspect or embodiment described herein, for example, when linker q is 1, the structure of linker group L is -A L 1- and A L 1 is a base that connects to the ULM portion and the PTM portion.

[0549] In any aspect or embodiment described herein, the linker (L) is derived from the following: It includes a group represented by a general structure selected from the group, -NR(CH2) n -(lower alkyl)-, -NR(CH2) n -(lower alkoxy)-, -NR(CH2) n -(Low-grade Arco Xyl)-OCH2-,-NR(CH2) n -(lower alkoxyl)-(lower alkyl)-OCH2-,-NR(CH2) n -( Chloalkyl)-(lower alkyl)-OCH2-,-NR(CH2) n -(heterocycloalkyl)-, -NR(CH2CH2O) n -(lower alkyl)-O-CH2-, -NR(CH2CH2O) n -(heterocycloalkyl)-O-CH2-, -NR(CH2CH2O) n -aryl-O-CH2-, -NR(CH2CH2O) n -(heteroaryl)-O-CH2-, -NR(CH2CH2O) n -(cycloalkyl)-O-(heteroaryl)-O-CH2-,-NR(CH2CH2O) n -(cycloalkyl)-O-aryl-O-CH2-,-NR(CH2CH2O) n -(lower alkyl)-NH-aryl-O-CH2-,-NR(CH2CH2O) n -(Low grade Alkyl)-O-aryl-CH2,-NR(CH2CH2O) n -Cycloalkyl-O-aryl-,-NR(CH2CH2O) n -Cycloalkyl-O-(heteroaryl)l-,-NR(CH2CH2) n -(cycloalkyl)-O-(heterocyclic)-CH 2、 -NR(CH2CH2) n -(heterogenetic ring)-(heterogenetic ring)-CH2, -N(R1R2)-(heterogenetic ring)-CH2; in the formula: The linker n can be anywhere from 0 to 10; The linker's R may be H, or a low alkyl group; Linkers R1 and R2 may form rings having N bonds.

[0550] In any aspect or embodiment described herein, the linker (L) is derived from the following: It includes a group represented by a general structure selected from the group, -N(R)-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -OCH2-, -O-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -OCH2-, -O-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -O-; -N(R)-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -O-; -(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -O-; -(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -OCH2-;

[0551] [ka]

[0552] [ka]

[0553] During the ceremony, Linker's m, n, o, p, q, and r are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20, respectively; If the number is zero, there are no NO or OO joins. The R in linker stands for H, methyl, and ethyl; The X in the linker is H and F,

[0554] [ka]

[0555] [ka]

[0556] [ka]

[0557] [ka]

[0558] [ka]

[0559] [ka]

[0560] [ka]

[0561] [ka]

[0562] [ka]

[0563] In any aspect or embodiment described herein, the linker (L) is as follows: Selected from the following groups:

[0564] [ka]

[0565] [ka]

[0566] [ka]

[0567] In any aspect or embodiment described herein, the linker (L) is as follows: Selected from the following groups:

[0568] [ka]

[0569] [ka]

[0570] [ka]

[0571] [ka]

[0572] [ka]

[0573] [ka]

[0574] [ka]

[0575] [ka]

[0576] [ka]

[0577] [ka]

[0578] In any aspect or embodiment described herein, the linker (L) is as follows: Selected from the following groups:

[0579] [ka]

[0580] [ka]

[0581] [ka]

[0582] In any aspect or embodiment described herein, the linker (L) is as follows: Selected from the following groups:

[0583] [ka]

[0584] [ka]

[0585] [ka]

[0586] [ka]

[0587] [ka]

[0588] [ka]

[0589] [ka]

[0590] [ka]

[0591] [ka]

[0592]

change

[0593]

change

[0594]

change

[0595]

change

[0596]

change

[0597]

change

[0598]

change

[0599]

change

[0600]

change

[0601]

change

[0602] [ka]

[0603] [ka]

[0604] [ka]

[0605] [ka]

[0606] [ka]

[0607] [ka]

[0608] In any aspect or embodiment described herein, the linker (L) is as follows: Selected from the following groups:

[0609] [ka]

[0610] [ka]

[0611] [ka]

[0612] [ka]

[0613] [ka]

[0614] [ka]

[0615] [ka]

[0616] [ka]

[0617] [ka]

[0618] In any aspect or embodiment described herein, the linker (L) is as follows: The structure is selected from, but is not limited to, structures including, where the dashed line represents the PTM portion. Or indicates the connection point to the ULM portion.

[0619] [ka]

[0620] During the ceremony: W L1 and W L2 Each is independent, either does not exist, or R Q A 4-8 member ring with 0-4 heteroatoms that can be optionally substituted, and each R Q These are independently H, halo, OH, CN, CF3, optionally substituted linear or branched C1-C6 alkyl, optionally substituted linear or branched It is either a chain-like C1-C6 alkoxy or two Rs. Q The groups, together with the atoms to which they are bonded, form a 4-8 membered ring system containing 0-4 heteroatoms; Y L1 Each is independently a linked or optionally substituted linear or branched C1-C6 alkyl, and optionally one or more C atoms are substituted with O; or optionally substituted linear or branched C1-C6 alkoxy; n is 0 to 10; and

[0621] [ka]

[0622] In any aspect or embodiment described herein, the linker (L) includes, but is not limited to, the structures shown below, where the dashed line indicates the PTM portion. Or indicates the connection point to the ULM portion.

[0623] [ka]

[0624] During the ceremony: W L1 and W L2 Each of these is independently either absent, or an aryl, heteroaryl, cyclic, heterocyclic, or C atom where one or more C atoms are substituted with O. 1-6 Alkyl, C in which one or more C atoms are optionally substituted with O 1-6 Alkenes, in which one or more C atoms are optionally replaced by O atoms. 1-6 They are alkynes, bicyclic, diaryl, diheteroaryl, or diheterocyclic, and each of them can be any R Q Replaced by each R Q These are independently H, halo, OH, CN, CF3, hydroxyl, nitro, and C. ≡CH, C 2-6 Alkenil, C 2-6Alkynyl, optionally substituted linear or branched C1-C6 alkyl, optionally substituted linear or branched C1-C6 alkoxy, optionally substituted OC 1-3 Alkyl (e.g., optionally substituted with one or more -F), OH, NH2, NR Y1 R Y2 , CN or two R Q The group, along with the atom to which they are bonded, has 0 to 4 heteroatoms. It contains a ring system of 4 to 8 members; Y L1 Each is independent, combined, NR YL1 , O, S, NR YL2 , C YL1 R YL2 C=O, C=S, SO, SO2, and optionally substituted linear or branched C 1- C6 alkyl, in which one or more C atoms are optionally substituted with O; optionally substituted linear or branched C1-C6 alkoxy; Q L A is a 3-6 membered alicyclic or aromatic ring with 0-4 heteroatoms, optionally bridged, and optionally 0-6 R Q Replaced by each R Q H is independently substituted, in a linear or modular fashion. Branched C 1-6 Alkyl (for example, one or more halos or C) 1-6 Substituted with alkoxyl (is done) or two R Q The group, along with the atom to which they are bonded, has 0 to 2 hete It forms a 3- to 8-membered ring system containing a 1x atom; R YL1 , R YL2 Each of these is independently H, OH, and optionally substituted linear or branched C 1-6 Alkyl (for example, one or more halos, or C) 1-6 (Optionally substituted with alkoxy) R, or R 1 , R 2It contains 0 to 2 heteroatoms along with the atoms to which they are bonded. Forms a ring system of ~8 members; n is 0 to 10; and

[0625] [ka]

[0626] In additional embodiments, the linker group consists of approximately 1 to approximately 100 ethylene glycol units (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 , 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 ethylene glycol units), approximately 1 to approximately 50 ethylene The linker is an optionally substituted (poly)ethylene glycol having ethylene glycol units, about 1 to about 25 ethylene glycol units, about 1 to about 10 ethylene glycol units, 1 to about 8 ethylene glycol units, and 1 to 6 ethylene glycol units, and about 2 to 4 ethylene glycol units, or an optionally substituted alkyl group with optionally substituted O, N, S, P or Si atoms. In certain embodiments, the linker is substituted with an aryl, phenyl, benzyl, alkyl, alkylene, or heterocyclic group. In certain embodiments, the linker may be asymmetric or symmetric.

[0627] In any embodiment of the compounds described herein, the linker group may be any suitable part described herein. In one embodiment, the linker is a substituted or unsubstituted polyethylene glycol group in the size range of about 1 to about 12 ethylene glycol units, 1 to about 10 ethylene glycol units, about 2 to 6 ethylene glycol units, about 2 to 5 ethylene glycol units, and about 2 to 4 ethylene glycol units.

[0628] In any aspect or embodiment described herein, linker (L) is optionally replaced by C1-C 100 Alkyl (for example, C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , C 22 , C 23 , C 24 , C 25 , C 26 , C 27 , C 28 , C 29 , C 30 , C 31 , C 32 , C 33 , C 34 , C 35 , C 36 , C 37 , C 38 , C 39 , C 40 , C 41 , C 42 , C 43 , C 44 , C 45 , C 46 , C 47 , C 48 , C 49 , C 50 , C 51 , C 52 , C 53 , C 54 , C 55 , C 56 , C 57 , C 58 , C 59 , C 60 , C 61 , C 62 , C 63 , C 64 , C 65 , C 66 , C 67 , C 68 , C 69 , C70 , C 71 , C 72 , C 73 , C 74 , C 75 , C 76 , C 77 , C 78 , C 79 , C 80 , C 81 , C 82 , C 83 , C 84 , C 85 , C 86 , C 87 , C 88 , C 89 , C 90 , C 91 , C 92 , C 93 , C 94 , C 95 , C 96 , C 97 , C 98 , C 99 , or C 100 alkyl), and in this case each carbon is optionally (1) having an appropriate number of hydrogens, substitutions, or both for its full valence, a heteroatom selected from N, S, P, or Si atoms, (2) an optionally substituted cycloalkyl or bicyclic cycloalkyl, (3) an optionally substituted heterocycloalkyl, or a bicyclic heterocycloalkyl, (4) an optionally substituted aryl or bicyclic aryl, or (5) an optionally substituted heteroaryl or bicyclic heteroaryl. In any aspect or embodiment described herein, the linker (L) has no heteroatom-heteroatom bonds (e.g., the heteroatoms are not covalent linkers or are not arranged adjacent to each other). In any aspect or embodiment described herein, the linker (L) is an optionally substituted C1-C and is substituted with a heteroatom selected from N, S, P, or Si atoms, (2) an optionally substituted cycloalkyl or bicyclic cycloalkyl, (3) an optionally substituted heterocycloalkyl, or a bicyclic heterocycloalkyl, (4) an optionally substituted aryl or bicyclic aryl, or (5) an optionally substituted heteroaryl or bicyclic heteroaryl. In any aspect or embodiment described herein, the linker (L) has no heteroatom-heteroatom bonds (e.g., the heteroatoms are not covalent linkers or are not arranged adjacent to each other). or a bicyclic heterocycloalkyl, (4) an optionally substituted aryl or bicyclic aryl, or (5) an optionally substituted heteroaryl or bicyclic heteroaryl. In any aspect or embodiment described herein, the linker (L) has no heteroatom-heteroatom bonds (e.g., the heteroatoms are not covalent linkers or are not arranged adjacent to each other). aryl, or (5) an optionally substituted heteroaryl or bicyclic heteroaryl. In any aspect or embodiment described herein, the linker (L) has no heteroatom-heteroatom bonds (e.g., the heteroatoms are not covalent linkers or are not arranged adjacent to each other). substituted. In any aspect or embodiment described herein, the linker (L) is, optionally substituted C1-C and has no heteroatom-heteroatom bonds (e.g., the heteroatoms are not covalent linkers or are not arranged adjacent to each other).

[0629] In any aspect or embodiment described herein, the linker (L) is an optionally substituted C1-C and is substituted with a heteroatom selected from N, S, P, or Si atoms, (2) an optionally substituted cycloalkyl or bicyclic cycloalkyl, (3) an optionally substituted heterocycloalkyl, or a bicyclic heterocycloalkyl, (4) an optionally substituted aryl or bicyclic aryl, or (5) an optionally substituted heteroaryl or bicyclic heteroaryl. In any aspect or embodiment described herein, the linker (L) has no heteroatom-heteroatom bonds (e.g., the heteroatoms are not covalent linkers or are not arranged adjacent to each other). 100Alkyl (e.g., C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 、C 12 、C 13 、C 14 、C 15 、C 16 、C 17 、C 18 、C 19 、C 20 、C 21 、C 22 、C 23 、C 24 、C 25 、C 26 、C 27 、C 28 、C​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​74 , C 75 , C 76 , C 77 , C 78 , C 79 , C 80 , C 81 , C 82 , C 83 , C 84 , C 85 , C 86 , C 87 , C 88 , C 89 , C 90 , C 91 , C 92 , C 93 , C 94 , C 95 , C 96 , C 97 , C 98 , C 99 , or C 100 Alkyl) is included in the formula, Each carbon is arbitrary, CR L1 R L2 O, S, SO, SO2, NR L3 SO2NR L3 , SONR L3 CONR L3 , NR L3 CONR L4 , NR L3 SO2NR L4 CO, CR L1 =CR L2 , C≡C, SiR L1 R L2 P(O)R L1 , P(O)OR L1 , NR L3 C(=NCN)NR L4 , NR L3 C (=NCN), NR L3 C(=CNO2)NR L4 , 0 to 6 R L1 and / or R L2 C is optionally substituted in the base. 3-11 Cycloalkyl, 0-9 R L1 and / or R L2 C is optionally substituted in the base. 5-13 Spirocycloalkyl, 0-6 R L1 and / or RL2 C is optionally substituted in the base. 3-11 Heterozy Krill, 0-8 R L1 and / or R L2 C is optionally substituted in the base. 5-13 Spiroheterocystriata R, 0 to 6 R L1 and / or R L2 Aryls that are optionally substituted by the base, 0 to 6 R L1 and / or R L2 Substituted with a heteroaryl that can be optionally substituted at the base, where R L1 or R L2 teeth, Each is independently bonded to other groups, and can optionally contain 0 to 4 R groups. L5 Cycloalkyl groups substituted with a group and / or form heterocycline moieties; and R L1 , R L2 , R L3 , R L4 and R L5 Each of these is independent of H, Halo, and C. 1-8 Alkyl, OC 1-8 Alki Lu, SC 1-8 Alkyl, NHC 1-8 Alkyl, N(C 1-8 Alkyl)2, C 3-11 Cycloalkyl, aryl, heteroaryl, C 3-11 Heterocycline, OC 3-8 Cycloalkyl, SC 3-8 Cycloalkyl Ru, NHC 3-8 Cycloalkyl, N(C 3-8 Cycloalkyl)2, N(C 3-8 Cycloalkyl)(C 1-8 Alkyl), OH, NH2, SH, SO2C 1-8 alkyl, P(O)(OC 1-8 Alkyl)(C 1-8 alkyl), P(O)(OC 1-8 Alkyl)2, CC-C 1-8 Alkyl, CCH, CH=CH(C 1-8Alkyl), C(C 1-8 Alkyl)=CH(C 1-8 Alkyl), C(C 1-8 Alkyl) = C(C 1-8 Alkyl)2, Si(OH)3, Si(C 1-8 Alkyl)3,Si(OH)(C 1-8 Alkyl)2, COC 1-8 Alkyl, CO2H, Halogen, CN, CF3, CHF2, CH2F, NO2, SF5, SO2NHC 1-8 Alkyl, SO2N(C 1-8 Alkyl) 2, SONHC 1-8 Alkyl, SON(C 1-8 Alkyl)2, CONHC 1-8 Alkyl, CON(C 1-8 Alkyl)2, N(C 1-8 Alkyl)CONH(C 1-8 Alkyl), N(C 1-8 Alkyl)CON(C 1-8 Alkyl)2, NHCONH(C 1-8 Alkyl), NHCON(C 1-8 Alkyl)2, NHCONH2, N(C 1-8 Alkyl)SO2NH(C 1-8 Alkyl), N(C 1-8 Alkyl) SO2N(C 1-8 Alkyl)2,NH₃SO₂NH₃(C 1-8 Alkyl), NH₃SO₂N(C 1-8 It is alkyl)2, NH₃SO₂NH₂.

[0630] In any aspect or embodiment described herein, the linker (L) is a heterogene It does not have a child-heteroatom bond (for example, the heteroatom is not a covalent linker, or is not located adjacent to it).

[0631] In any aspect or embodiment described herein, the linker (L) comprises about 1 to about 50 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50) optionally substituted alkylene glycol units, in which case carbon or oxygen may be substituted with heteroatoms selected from N, S, P, or Si atoms, accompanied by an appropriate number of hydrogen atoms relative to the full valency. In any aspect or embodiment described herein, the linker (L) has a chemical structure selected from the following:

[0632] [ka]

[0633] [ka]

[0634] In the formula, carbon or oxygen may be substituted with heteroatoms selected from N, S, P, or Si atoms, accompanied by an appropriate number of hydrogen atoms for the full valency, and m, n, o, p, q, r, and s are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

[0635] In any aspect or embodiment described herein, the disclosure relates to compounds comprising the PTM group described above, wherein the group is bound to a target protein or polypeptide (e.g., RAF), ubiquitinated by a ubiquitin ligase, and directly to a ULM group. It is either chemically bonded directly or through the linker moiety L. Alternatively, PTM is the ULM' group, which is also a ubiquitin ligase binding moiety, which may be the same as or different from the ULM group described above, and is bonded to the ULM group through the linker moiety or directly. And L is the linker moiety described above, which may or may not be present. This involves chemically bonding (covalently bonding) ULM and PTM, or their pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, or polymorphs.

[0636] In any aspect or embodiment described herein, the linker group L is derived from the following: A group containing one or more covalently bonded structural units independently selected from the group:

[0637] [ka]

[0638] X is selected from the group consisting of O, N, S, S(O), and SO2; n is an integer between 1 and 5, and R L1 is hydrogen or alkyl,

[0639] [ka]

[0640] is a monocyclic or bicyclic aryl or heteroaryl compound optionally substituted with 1 to 3 substituents selected from alkyl, halogen, haloalkyl, hydroxy, alkoxy, or cyano;

[0641] [ka]

[0642] is a monocyclic or bicyclic cycloalkyl or heterocycloalkyl that is optionally substituted with 1 to 3 substituents selected from alkyl, halogen, haloalkyl, hydroxy, alkoxy, or cyano; and the phenyl ring fragment is 1, 2, or 3 substituents selected from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, and cyano The substituents may be optionally substituted. In one embodiment, the linker group L is as described above. It contains up to 10 covalently bonded structural units.

[0643] The ULM and PTM groups may be covalently bonded to the linker group via any stable group suitable for the chemical properties of the linker, and in a preferred embodiment of this disclosure, the linker is independently covalently bonded to the ULM and PTM groups, preferably via an amide, ester, thioester, keto group, carbamate (urethane), carbon, or ether, and each of these groups is inserted onto either the ULM or PTM group, resulting in maximum bonding of the ULM group to the ubiquitin ligase and decomposition. It may provide maximum binding of PTM groups to the target protein. (Specifically, the PTM group is a ULM group.) Note that in this embodiment, the target protein to be degraded may be the ubiquitin ligase itself. In certain preferred embodiments, the linker may be bonded to an optionally substituted alkyl, alkylene, alkene or alkyne, aryl or heterocyclic group on the ULM group and / or PTM group.

[0644] Exemplary PTM In preferred embodiments of this disclosure, the PTM group is a group that binds to a target protein. The targets of the PTM group are diverse, and at least a portion of their sequences are present in cells and can bind to the PTM group. The target is selected from proteins expressed within cells. The term "protein" refers to an oligonucleotide sequence of sufficient length to bind to a PTM group in accordance with this disclosure. and polypeptide sequences. Any protein of a eukaryotic cell system or a microbial system including viruses, bacteria or fungi is a target of ubiquitination regulated by the disclosed compound, as otherwise described herein. The target protein is preferably a protein of a eukaryotic cell.

[0645] Examples of PTM groups conforming to this disclosure include those that specifically bind to proteins (target proteins). Any part of the small molecule target protein binding site can be mentioned, and non-limiting examples of small molecule target protein binding sites include: RAF inhibitors, Hsp90 inhibitors, kinase inhibitors, HDM2 and MDM2 inhibitors, compounds targeting human BET bromodomain-containing proteins, HDAC inhibitors, and human lycium. Methyltransferase inhibitors, angiogenesis inhibitors, nuclear hormone receptor compounds, immunosuppressive compounds, and compounds that specifically target aryl hydrocarbon receptors (AHRs). Compositions described below. The following exemplifies some of a series of small target protein binding sites. Such small target protein binding sites include pharmaceutically acceptable salts, enantiomers, solvates, and polymorphs of these compositions, as well as other small molecules that can target the protein of interest. These binding sites are preferably bound to a ubiquitin ligase binding site via a linker to present the target protein (to which the protein target site is bound) for the purpose of ubiquitination and degradation in close proximity to the ubiquitin ligase.

[0646] It can bind to protein target moieties or PTM groups and is transmitted by ubiquitin ligases. It can act on or be broken down by ubiquitin ligases (e.g., RAF). Any protein capable of this is a target protein according to this disclosure. Generally, target proteins include, for example, structural proteins, receptors, enzymes, cell surface proteins, as well as proteins with catalytic activity, aromatase activity, motor activity, helicase activity, metabolic processes (anabolic and catabolic), antioxidant activity, protein solubility, biosynthesis, kinase activity, redox activity, transferase activity, hydrolysis activity, lyase activity, isomerase activity, ligase activity, enzyme regulatory activity, signal transduction activity, structural molecular activity, binding activity (proteins, lipids, carbohydrates), receptor activity, cell motility, membrane fusion, cell transmission, regulation of biological processes, development, cell differentiation, stimulus response, behavioral proteins, cell adhesion proteins, proteins involved in cell death, and proteins involved in transport (protein transport activity, nuclear transport). (including ion transport activity, channel transport activity, carrier activity, permeability activity, secretory activity, electron transport activity), phagocytosis, chaperone regulatory activity, nucleic acid binding activity, transcriptional regulatory activity, extracellular integration These include proteins involved in the integrated function of cells, including proteins involved in biosynthetic activity and translational regulatory activity. Target proteins include those derived from eukaryotes (e.g., c-RAF, A-RAF, and / or B-RAF) and prokaryotes, including human and other animal proteins as targets for drug therapy. Among these, there are many others, such as livestock, microorganisms for determining targets for antibiotics and other antimicrobial agents, plants, and especially viruses (e.g., v-RAF and / or v-Mil).

[0647] Many pathological conditions and / or states may be treated using this disclosure, including any pathological conditions and / or states in which proteins are in a disregulated state and the patient would benefit from the degradation of proteins.

[0648] In additional embodiments, this specification provides therapeutic compositions comprising an effective amount of a compound or a salt form thereof described herein, and a pharmaceutically acceptable carrier, additive or excipient, and optionally additional bioactive agents. The therapeutic compositions can be used to modulate protein degradation in a patient or subject, such as an animal such as a human, and to treat or improve a disease or condition modulated via the degraded protein. In certain embodiments, the therapeutic compositions described herein may be used to induce degradation of a target protein for the purpose of treating or improving a disease, such as cancer, cardiac-facial-cutaneous syndrome, neurofibromatosis type 1, Costello syndrome, Noonan syndrome, and LEOPARD syndrome. In certain additional embodiments, the diseases are renal cell carcinoma, pancreatic cancer, colorectal cancer, lung cancer, ovarian cancer, thyroid cancer, pilocytic astrocytoma, prostate cancer, gastric cancer, hepatocellular carcinoma, and melanoma.

[0649] In another aspect, the present disclosure relates to a method for treating a pathological condition of a subject requiring such treatment, or a method for improving the symptoms of a disease or condition, by degrading a protein or polypeptide, wherein the pathological condition or condition is regulated via the protein or polypeptide, and the method comprises administering to the patient or subject an effective amount, e.g., a therapeutically effective amount, of at least one of the compounds described herein, in combination with optionally pharmaceutically acceptable carriers, additives or excipients, and optionally additional bioactive agents, wherein the composition is effective in treating or improving the disease or disorder or symptoms thereof of the subject. The method of the present disclosure involves administering an effective amount of at least one of the compounds described herein. This includes cancer, cardiac-facial-cutaneous syndrome, neurofibromatosis type 1, Costello syndrome, and Noonan syndrome. Many conditions or states, including syndromes and LEOPARD syndrome, can be treated. , microorganisms, or for example, viruses (e.g., mouse retrovirus or triretrovirus) It may also be a disease caused by exogenous factors such as viruses (e.g., triretrovirus MH2), bacteria, fungi, protozoa, or other microbial factors, or by the overexpression and / or constitutive activation of proteins that cause the pathological condition and / or state. It may be a condition caused by the presence of protein.

[0650] In another embodiment, this specification provides a method for identifying the degradation effect of a target protein in a biological system using the compounds of this disclosure.

[0651] The term “target protein” is used herein to describe a protein or polypeptide that is a target to which the disclosed compounds bind and which is degraded by a ubiquitin ligase. Such small target protein binding sites include pharmaceutically acceptable salts, enantiomers, solvates, and polymorphs of these compositions, as well as other small molecules that may target the protein of interest. These binding sites are bound to at least one ULM group (e.g., VLM, CLM, ILM, and / or MLM) via at least one linker group L.

[0652] Target proteins, which can be bound to a protein target moiety and to a ubiquitin ligase-binding moiety that can be degraded by ligase, include any protein or peptide, including fragments thereof, analogues thereof, and / or homologs thereof. Target proteins include any proteins and peptides having any biological function or activity, including structural, regulatory, hormonal, enzymatic, genetic, immunological, contractile, conservative, transport, and signaling. More specifically, many drug targets for human therapeutics are protein targets, to which a protein target moiety can be bound and incorporated into compounds according to this disclosure. These proteins include proteins that can be used for functional restoration in many polygenic diseases, such as B7.1 and B7, TINFRlm, TNFR2, NADPH oxidase, BclIBax and other partner factors of the apoptotic pathway, and the C5a receptor. HMG-CoA reductase, PDE V phosphodiesterase type, PDE IV phosphodiesterase type 4 PDE I, PDE II, PDE III, squalane cyclase inhibitors, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclo-oxygenase 1, cyclo-oxygenase 2, 5HT receptor, DOPA Histamine receptor, G protein, i.e., Gq, histamine receptor, 5-lipoxygenase, tri Butase serine protease, thymidylate synthase, purine nucleoside phosphorylase, GAPDH trypanosomal, glycogen phosphorylase, carbonic anhydrase, chemokine Receptors, JAW STAT, RXR and analogues, HIV 1 protease, HIV 1 integrase, Fluenza neuraminidase, hepatitis B virus reverse transcriptase, sodium channel, poly Drug resistance (MDR), protein P-glycoprotein (and MRP), tyrosine kinase, CD23, CD124, tyrosine kinase p56, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-αR, ICAM1, Cat+ channel, VCAM, VLA-4 integrin, selectin, CD40 / CD40L, neurokinin Receptors, inosine monophosphate dehydrogenase, p38 MAP kinase, Ras / Raf / MEK-ERK pathway, interleukin-1 converting enzyme, caspase, HCV, NS3 protease, HCV NS3 RNA Licase, glycinamide ribonucleotide formyltransferase, rhinovirus 3C protease, herpes simplex virus-1 (HSV-I) protease, cytomegalovirus (CMV) protease, poly(ADP-ribose) polymerase, cyclin-dependent kinase, Vascular endothelial growth factor, oxytocin receptor, microsomal transport protein inhibitor, bile acid transport inhibitor, 5α-reductase inhibitor, angiotensin 11, glycine receptor, norepinephrine Lenalin reuptake receptor, endothelin receptor, neuropeptide Y and receptor, Strogen receptors, androgen receptors, adenosine receptors, adenosine kinases and AMP deaminases, purinergic receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7), Farnesia Geryltransferase, geranylgeranyltransferase, TrkA NGF receptor, EGF receptors: TA-amyloid, tyrosine kinase Flk-IIKDR, vitronectin receptor, integrin receptor, Her-21 neu, telomerase inhibitor, cytoplasmic phospholipase A2, and EGF receptor. Tyrosine kinases are one example. Additional protein targets include, for example, ecdysone 20-monooxygenase, GABAergic chlorine channels, and acetylcholine. Examples of target proteins include telase, voltage-sensitive sodium channel proteins, calcium release channels, and chlorine channels. Further target proteins include acetyl-CoA-carbone. Examples include xylase, adenylosuccinate synthetase, protoporphyrinogen oxidase, and enolpyruvirshikimic acid-phosphate synthase.

[0653] These various protein targets may be used in screening to identify compound portions that bind to the protein, and by incorporating these portions into the disclosed compounds, the activity level of the protein can be altered for the final therapeutic outcome.

[0654] The term "protein targeting region" or "PTM" refers to the target protein or the other part of the target. This is used to describe small molecules that bind to a protein or polypeptide and position / present the protein or polypeptide in close proximity to the ubiquitin ligase so that degradation of the protein or polypeptide by the ubiquitin ligase may occur. Non-limiting examples of small molecule target protein binding sites include RAF inhibitors, Hsp90 inhibitors, kinase inhibitors, MDM2 inhibitors, compounds targeting human BET bromodomain-containing proteins, and HDAC inhibitors. Examples include agents, human lysine methyltransferase inhibitors, angiogenesis inhibitors, immunosuppressive compounds, and compounds that target aryl hydrocarbon receptors (AHRs) in particular. The compositions are as follows: The examples illustrate some of the components of small target proteins.

[0655] Exemplary protein targeting moieties in this disclosure include RAF inhibitors and haloalkanes. Transtransferase 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 aryl hydrocarbon receptors (AHRs) Items can be listed.

[0656] The compositions described below exemplify some of the components of these types of small target protein binding moieties. Such small target protein binding moieties include pharmaceutically acceptable salts, enantiomers, solvates, and polymorphs of these compositions, as well as other small molecules that can target the target protein. References cited herein below are incorporated herein by reference in their entirety.

[0657] In any aspect or embodiment described herein, the PTM is a small molecule containing a B-RAF protein targeting moiety.

[0658] In any aspect or embodiment described herein, the PTM targets and / or bond. For example, in any aspect or embodiment described herein, the PTM may include a chemical group selected from the following chemical structures consisting of PTM-Ia or PTM-Ib. ,

[0659] [ka]

[0660] During the ceremony: The double dashed line represents an aromatic bond. V PTM , W PTM , X PTM , Y PTM , Z PTM It is one of the following combinations: C, CH, N, N , C;C, N, N, CH, C; C, O, C, CH, C; C, S, C, CH, C; C, CH, C, O, C; C, CH, C, S, C; C, CH, N, CH, C; N, CH, C, CH, C; C, N, C, CH, N; C, N, C, N, C; and C, N, N, N, C; XPTM35 , X PTM36 , X PTM37 , and X PTM38 It is selected independently of CH and N; R PTM1 ULM, chemical linker group (L), CLM, ILM, VLM, MLM, ULM', CLM', ILM', VLM' Covalently bonded to MLM', or a combination thereof, R PTM2 is hydrogen, halogen, aryl, methyl, ethyl, OCH3, NHCH3, or M1-CH2-CH2-M2, where M1 is CH2, O and NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl It is a reel or a complex algebra; R PTM2a and...

Claims

1. 1. A bifunctional compound having the following chemical structure: or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, or prodrug thereof: ULM―L―PTM, During the ceremony: The ULM is a small molecule E3 ubiquitin ligase binding moiety that binds to E3 ubiquitin ligase. and the PTM is a small molecule that includes a rapidly accelerated fibrosarcoma (RAF) protein targeting moiety; and the L is a bifunctional linking or chemical linking moiety that connects the ULM and the PTM. sexual compound.

2. 2. The bifunctional compound of claim 1, wherein the E3 ubiquitin ligase binding moiety targets an E3 ubiquitin ligase selected from the group consisting of von Hippel-Lindau (VLM), cereblon (CLM), mouse double-minute homolog 2 (MLM), and IAP (ILM).

3. The PTM is represented by the following chemical structure PTM-Ia or PTM-Ib: 【Chemistry 1】 During the ceremony: The double-dashed bond is an aromatic bond, V PTM , W PTM , X PTM , Y PTM , Z PTM is one of the following combinations: C, CH, N, N, C; C, N, N, CH, C; C, O, C, CH, C; C, S, C, CH, C; C, CH, C, O, C; C, CH, C, S, C; C, CH, N, CH, C; N, CH, C, CH, C; C, CH, C, CH, N; N, N, C, CH, C; N, CH, C, N, C; C, CH, C, N, N; C, N, C, CH, N; C, N, C, N, C, CH, N; and C, N, N, N, N, C; X PTM35 , X PTM36 , X PTM37 , and X PTM38 is independently selected from CH and N; R PTM1 are ULM, chemical linker group (L), CLM, ILM, VLM, MLM, ULM', CLM', ILM', VLM ', MLM', or a combination thereof, R PTM2 is hydrogen, halogen, aryl, methyl, ethyl, OCH 3 , NHCH 3 , or M1-CH 2 -CH 2 -M2, where M1 is CH 2 , O and NH, M2 is hydrogen, alkyl, cyclic alkyl, is aryl or heterocyclic; R PTM2a and R PTM2b is hydrogen, OH, halogen; R PTM3 is absent or is selected from hydrogen, aryl, methyl, ethyl, other alkyl, ring alkyl, OCH 3 , NHCH 3 , or M1-CH 2 -CH 2 -M2, where M1 is CH 2 , O and NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle; R PTM4 is hydrogen, halogen, aryl, methyl, ethyl, OCH 3 , NHCH 3 , or M1-CH 2 -CH 2 -M2, where M1 is CH 2 , O and NH, M2 is hydrogen, alkyl, cyclic alkyl, is aryl or heterocyclic; and R PTM5 The bifunctional compound according to claim 1 or 2, wherein is selected from the group consisting of: 【Chemistry 2】

4. The PTM is represented by the following chemical structure PTM-IIa or PTM-IIb: 【Transformation 3】 During the ceremony: X PTM1 , X PTM2 , X PTM3 , X PTM4 , X PTM5 and X PTM6 are independently selected from CH or N ； R PTM5a is H, an optionally substituted amide (e.g., optionally substituted with an alkyl group, a methyl group, an ethyl group, a propyl group, or a butyl group), an optionally substituted amine, 【Chemistry 4】 【Transformation 5】 R PTM5b is hydrogen or linear or branched C1-C4 alkyl (e.g., methyl or ethyl); R PTM6a and R PTM6b are each independently hydrogen, halogen, or an optionally substituted linear or branched C 1 -C 6 alkyl; R PTM6 is one of the following groups: absent, hydrogen, halogen, aryl, methyl ethyl, OCH 3 , NHCH 3 , or M1-CH 2 -CH 2 -M2, where M1 is CH 2 , O and NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle; R PTM6c is hydrogen or linear or branched C1-C4 alkyl (e.g., methyl or ethyl); R PTM7 is absent or is selected from hydrogen, halogen, aryl, methyl, ethyl, OCH 3 , NHCH 3 , or M1-CH 2 -CH 2 -M2, where M1 is CH 2 , O and NH, and M2 is hydrogen, alkane alkyl, cyclic alkyl, aryl or heterocyclic; R PTM8 , R PTM9 or R PTM10 are independently absent or hydrogen, halogen, aryl, heteroaryl, alkyl, cycloalkyl, heterocycle, methyl, ethyl, OCH 3 , NHCH 3 or M1-CH 2 -CH 2 -M2, wherein M1 is CH 2 , O and NH, M2 is hydrogen, alkyl, cyclic alkyl, aryl, or heterocycle; and R PTM11 is absent or is hydrogen, halogen, methyl, ethyl, OCH 3 , NHCH 3 ,Ma or M1-CH 2 -CH 2 -M2, where M1 is CH 2 , O and NH, and M2 is hydrogen, alkyl, ring alkyl, aryl or heterocyclic; R PTM8 , R PTM9 , or R PTM10 At least one of is a ULM, a chemical linker group (L), a CLM, an ILM, a VLM, an MLM, a ULM', a CLM', an ILM', a VLM', an MLM', or a combination thereof. modified to covalently bond, or R PTM8 , R PTM9 , and R PTM10 wherein two of the groups are modified to form a polycyclic (e.g., bicyclic) fused ring with a chemical linker group.

2. A bifunctional compound according to claim 2.

5. R PTM9 is the covalent bond site, R PTM7 and R PTM8 is R PTM7 and R PTM8 Adheres to are linked together via a covalent bond in such a way as to form a bicyclic group having rings, or R PTM8 is the covalent bond site, R PTM9 and R PTM10 is R PTM9 and R PTM10 Adheres are linked together via a covalent bond in such a way as to form a bicyclic group having rings The bifunctional compound of claim 4, wherein when RPTM10 is the covalent bonding position, RPTM8 and RPTM9 are bonded to each other via a covalent bond in such a manner as to form a bicyclic group having a ring to which RPTM8 and RPTM9 are attached.

6. The PTM is represented by the following chemical structure: PTM-III: 【Transformation 6】 During the ceremony: X PTM7 , X PTM8 , X PTM9 , X PTM10 , X PTM11 , X PTM12 , X PTM13 , X PTM14 , X PTM15 , X PTM16 , X PTM17 , X PTM18 , X PTM19 , X PTM20 is independently CH or N; R PTM12 , R PTM13 , R PTM14 , R PTM15 , R PTM16 , R PTM17 , R PTM18 , R PTM19 are independently absent or hydrogen, halogen, aryl, heteroaryl, cycloalkyl, heterocycle, methyl, ethyl, other alkyl, OCH 3 , NHCH 3 or M1-CH 2 -CH 2 -M2, wherein M1 is CH 2 , O and NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle; R PTM20 is a small group containing less than four non-hydrogen atoms, R PTM21 is trifluoromethyl, chloro, bromo, fluoro, methyl, ethyl, propyl, isopropyl, tert-butyl, butyl, isobutyl, cyclopropyl, cyclobutyl , cyclopentyl, cyclohexyl, OCH 3 , NHCH 3 , dimethylamino or M1-CH 2 -CH 2 -M2, wherein M1 is CH 2 , O or NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle; and R PTM12 , R PTM13 and R PTM16 is modified to be covalently attached to a ULM, a chemical linker group (L), a CLM, an ILM, a VLM, an MLM, a ULM', a CLM', an ILM', a VLM', an MLM', or a combination thereof.

7. R PTM12 is the covalent bond site, R PTM13 and R PTM14 is R PTM13 and R PTM14 are bonded to each other via a covalent bond in such a way as to form a bicyclic group having a ring to which R is attached, and / or PTM15 and R PTM16 is R PTM15 and R PTM16 are linked together via a covalent bond in such a way as to form a bicyclic group having the ring to which is attached R PTM13 is the covalent bond site, R PTM12 and R PTM16 is R PTM12 and R PTM16 Adheres and / or R PTM15 and R PTM16 is R PTM15 and R PTM16 are linked together via a covalent bond in such a way as to form a bicyclic group having the ring to which is attached; or R PTM16 is the covalent bond site, R PTM12 and R PTM13 is R PTM12 and R PTM13 are bonded to each other via a covalent bond in such a way as to form a bicyclic group having a ring to which R is attached, and / or PTM13 and R PTM14 is R PTM13 and R PTM14 are attached to each other via a covalent bond in such a way as to form a bicyclic group having a ring to which compound.

8. The PTM is represented by the following chemical structure PTM-IVa or PTM-IVb: 【Transformation 7】 During the ceremony: X PTM21 , X PTM22 , X PTM23 , X PTM24 , X PTM25 , X PTM26 , X PTM27 , X PTM28 , X PTM29 , X PTM30 , X PTM31 , X PTM32 , X PTM33 , X PTM34 is independently CH or N; R PTM22 is selected from the group consisting of: 【Transformation 8】 R PTM25a and R PTM25b are each independently hydrogen, halogen, or C 1 -C 6 alkyl (straight chain, branched chain, optionally substituted); R PTM23 , R PTM24 , R PTM28 , R PTM29 , R PTM30 , R PTM31 , R PTM32 are independently absent or a bond, hydrogen, halogen, aryl (optionally substituted), heteroaryl (optionally substituted), cycloalkyl (optionally substituted), heterocycle (optionally substituted), methyl , ethyl (optionally substituted), other alkyl (straight chain, branched chain, optionally substituted), OCH 3 , NHCH 3 or M1-CH 2 -CH 2 -M2, wherein M1 is CH 2 , O and NH, and M2 is hydrogen, alkyl (linear, branched, optionally substituted), cyclic alkyl (optionally substituted), aryl (optionally substituted) or heterocycle (optionally substituted); and R PTM25 is absent or contains hydrogen, halogen, C 1 -C 6 Alkyl (straight chain, branched chain, optionally substituted), OCH 3 , NHCH 3 or SCH 3 Selected from: R PTM26 is absent or contains hydrogen, halogen, C 1 -C 6 Alkyl (straight chain, branched chain, optionally substituted), OCH3, NHCH 3 or SCH 3 Selected from: R PTM27 is absent or contains hydrogen, halogen, C 1 -C 6 Alkyl (straight chain, branched chain, optionally substituted), OCH3, NHCH 3 or SCH 3 selected from the group consisting of: R PTM24 , R PTM29 and R PTM32 At least one of the ULM, chemical linker group (L), and CLM , an ILM, a VLM, an MLM, a ULM', a CLM', an ILM', a VLM', an MLM', or a combination thereof.

9. R PTM24 is the covalent bond site, R PTM31 and R PTM32 is R PTM31 and R PTM32 are bonded to each other via a covalent bond in such a way as to form a bicyclic group having a ring to which R is attached, or PTM29 and R PTM30 is R PTM29 and R PTM30 are linked together via a covalent bond in such a way as to form a bicyclic group having the ring to which is attached; or R PTM29 is the covalent bond site, R PTM24 and R PTM32 is R PTM24 and R PTM32 are covalently bonded to each other in such a way as to form a bicyclic group having the ring to which is attached and / or R PTM31 and R PTM32 is R PTM31 and R PTM32 are linked together via a covalent bond in such a way as to form a bicyclic group having the ring to which is attached; or R PTM32 is the covalent bond site, R PTM24 and R PTM29 is R PTM24 and R PTM29 are bonded to each other via a covalent bond in such a way as to form a bicyclic group having a ring to which R is attached, and / or PTM29 and R PTM30 is R PTM29 and R PTM30 are attached to each other via a covalent bond in such a way as to form a bicyclic group having a ring to which Bifunctional compounds.

10. The PTM is represented by the following chemical structure: PTM-Va: 【Chemistry 9】 During the ceremony: X PTM35 , X PTM36 , X PTM37 , X PTM38 , and X PTM39 is independently CH or N; R PTM33 is halogen or linear or branched C1-C4 haloalkyl; R PTM34 , R PTM35 , R PTM36 , R PTM37 , and R PTM38 are each independently hydrogen, halogen, or a straight-chain or branched C 1- C 4 alkyl (e.g., methyl, ethyl, propyl, or butyl); R PTM39 is an optionally substituted C4-C7 heterocycloalkyl (e.g., an optionally substituted C5 or C6 heterocycloalkyl); and 【Chemistry 10】 are ULM, chemical linker group (L), CLM, ILM, VLM, MLM, ULM', CLM', ILM', VLM', MLM ', or a combination thereof.

11. The method of claim 1, wherein the PTM is selected from the group consisting of PTM-1, PTM-2, PTM-3, PTM-4, PTM-5, PTM-6, PTM-7, PTM-8, PTM-9, PTM-10, PTM-11, PTM-12, and PTM-13. Functional compounds. 【Chemistry 11-1】 【Chemistry 11-2】

12. The ULM is selected from the group consisting of: 【Chemistry 12】 In the formula, R 14a is methyl or hydroxymethyl. Functional compounds.

13. the ULM being a von Hippel-Lindau (VHL) ligase having the chemical structure represented by: binding moiety (VLM), 【Chemistry 13】 During the ceremony: X 1 , X 2 are each independently a bond, O, or NR Y3 , C.R. Y3 R Y4 , C=O, C=S, SO, and SO 2 group of Selected from: R Y3 , R Y4 are each independently H, straight or branched chain C 1-6 alkyl (optionally substituted with one or more halo), optionally substituted C 1-6 Alkoxyl (e.g., 0-3 R P and optionally substituted with a group; R P are 0, 1, 2 or 3 groups, each independently H, halo, —OH, C 1-3 alkyl, C=O; W 3 is an optionally substituted T, an optionally substituted -TN(R 1a R 1b )X 3 , optionally substituted -TN(R 1a R 1b ), optionally substituted -T-aryl, optionally substituted -T-heteroaryl, optionally Substituted T-diheteroaryl, optionally substituted -T-heterocycle, optionally substituted -T-diheterocycle, optionally substituted -NR 1 -T-aryl, optionally substituted -NR 1 -T-heteroaryl, or optionally substituted -NR 1 -T-heterocycle; X in the formula ULM-a 3 is C=O, R 1 , R 1a , R 1b and R 1 , R 1a , R 1b each is a direct alkyl group optionally substituted with H, one or more halo or -OH groups; Single or branched chain C 1 -C 6 Alkyl group, R Y3 C=O, R Y3 C=S, R Y3 SO, R Y3 SO 2 , N(R Y3 R Y4 )C=O, N(R Y3 R Y4 )C=S,N(R Y3 R Y4 )SO, and N(R Y3 R Y4 )SO 2 are independently selected from the group consisting of: T is optionally substituted alkyl, -(CH 2 ) n - groups, wherein the methylene group each one of halogen, methyl, optionally substituted alkoxy, one or more halogens , C(O)NR 1 R 1a , or NR 1 R 1a or R linked to form an optionally substituted heterocycle 1 and R 1a Straight or branched chain C optionally substituted with 1 -C 6 Alkyl group, or -OH optionally substituted with one or two substituents selected from the group: n is 0 to 6, W 4 teeth, 【Chemistry 14】 and R 14a、 R 14b are each independently H, haloalkyl, optionally substituted alkoxy, optionally Substituted hydroxyl alkyl, -(CH 2 ) m’ C(=O)(CH 2 ) m’ C(=O)(OH), (CH 2 ) m’ OCOCH 2 (CH 2 ) m’ OCH 2 (CH 2 ) m’ CO(CH 2 ) m’ OH, (CH 2 ) m’ OCOCH 2 (CH 2 ) m’ CO(CH 2 ) m’ OH, or oxygen is selected from the group of optionally substituted linear or branched alkyl, optionally having one or more carbons substituted with; R 1 is a straight or branched chain C optionally substituted with H, one or more halo 1- C 6 Alkyl group or an —OH group; each m' is an integer from 1 to 4 (e.g., 1, 2, 3, or 4); W 5 is selected from the group of optionally substituted phenyl, optionally substituted 5-10 membered heteroaryl; Selected from; W 6 is an optionally substituted 8-14 membered bicyclic heterocycle; R 15 H, halogen, CN, OH, NO 2 , N.R. 14a R 14b , OR 14a ,CONR 14a R 14b , N.R. 14a COR 14b , SO 2 NR 14a R 14b , N.R. 14a SO 2 R 14b , optionally substituted alkyl, optionally substituted haloal is selected from the group of alkyl, optionally substituted haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl; and The dashed lines indicate the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety linking at least one PTM or ULM', or both, to ULM.

12. The bifunctional compound according to any one of claims 1 to 11.

14. the ULM being a von Hippel-Lindau (VHL) ligase having the chemical structure represented by: binding moiety (VLM), 【Chemistry 15】 During the ceremony: W 3 is optionally substituted aryl, optionally substituted heteroaryl, or 【Chemistry 16】 selected from the group R 9 and R 10 are independently hydrogen, optionally substituted alkyl, optionally substituted cyclo alkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl, or R 9 , R 10 and the carbon atoms to which they are attached are any forming a cycloalkyl substituted with R 11 is an optionally substituted heterocyclic, an optionally substituted alkoxy, an optionally substituted heteroaryl, optionally substituted aryl; 【Chemistry 17】 selected from the group R 12 is selected from the group of H or optionally substituted alkyl; R 13 is selected from the group of H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl; R 1 is a straight or branched chain C optionally substituted with H, one or more halo 1- C 6 Alkyl group or an —OH group; R 14a、 R 14b are each independently H, haloalkyl, optionally substituted alkoxy, (CH 2 ) m ’ OCOCH 2 (CH 2 ) m’ OCH 2 (CH 2 ) m’ CO(CH 2 ) m’ OH, (CH 2 ) m’ OCOCH 2 (CH 2 ) m’ CO(CH 2 ) m’ OH, optionally substituted hydroxyl alkyl, -(CH 2 ) m’ C(=O)(CH 2 ) m’ C(=O)(OH), or oxygen is selected from the group of optionally substituted alkyl, optionally having one or more carbons substituted with; each m' is an integer from 1 to 4 (e.g., 1, 2, 3, or 4); W 5 is an optionally substituted phenyl or an optionally substituted 5- to 10-membered heteroaryl selected from the group R 15 H, halogen, CN, OH, NO 2 , N.R. 14a R 14b , OR 14a ,CONR 14a R 14b , N.R. 14a COR 14b , SO 2 NR 14a R 14b , N.R. 14a SO 2 R 14b , optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl; Each R 16 is independently selected from the group of H, CN, halo, optionally substituted alkyl optionally having one or more carbon atoms replaced with an oxygen atom, optionally substituted haloalkyl, hydroxy, or optionally substituted haloalkoxy; o is 0, 1, 2, 3, or 4; R 18 is independently selected from the group of H, halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy, or a linker; and p is 0, 1, 2, 3, or 4, and wherein the dashed line indicates a linkage between at least one PTM, another ULM (ULM'), or at least one PTM or ULM', or both, to a ULM.

12. The bifunctional compound according to claim 1, which exhibits a bonding site for a chemical linker moiety 。

15. The ULM has a chemical structure selected from the group consisting of: [Chemistry 18] During the ceremony: R 1 is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; optionally substituted alkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl; R 14a is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, Hydroxymethyl, ethyl, isopropyl, (CH 2 ) m’ OCOCH 2 (CH 2 ) m’ OCH 2 (CH 2 ) m’ CO(CH 2 ) m’ OH, (CH 2 ) m’ OCOCH 2 (CH 2 ) m’ CO(CH 2 ) m’ OH, or cyclopropyl; each m' is an integer from 1 to 4 (e.g., 1, 2, 3, or 4); R 15 H, halogen, CN, OH, NO 2 , optionally substituted heteroaryl, optionally substituted aryl, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl; X is C, CH 2 or C=O, R 3 is a bond or an optionally substituted 5- or 6-membered heteroaryl, and 12. The bifunctional compound of any of claims 1-11, wherein the dashed lines indicate the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety connecting at least one PTM or ULM', or both, to the ULM.

16. The ULM comprises a group according to the following chemical structure: 【Chemistry 19】 During the ceremony: R 14a is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, hydroxymethyl, ethyl, isopropyl, (CH 2 ) m’ OCOCH 2 (CH 2 ) m’ OCH 2 (CH 2 ) m’ CO(CH 2 ) m’ OH, (CH 2 ) m’ OCOCH 2 (CH 2 ) m’ CO(CH 2 ) m’ OH, or cyclopropyl; each m' is an integer from 1 to 4 (e.g., 1, 2, 3, or 4); R 9 is H; R 10 is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclo butyl, cyclopentyl, or cyclohexyl; R 11 teeth, 【Chemistry 20】 optionally substituted heteroaryl; 【Chemistry 21】 p is 0, 1, 2, 3, or 4; and Each R 18 are independently selected from halo, optionally substituted alkoxy, cyano, optionally substituted alkoxy, alkyl, haloalkyl, haloalkoxy or a linker; R 12 is H, C=O, R 13 is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl; R 15 H, halogens, Cl, CN, OH, NO 2 , optionally substituted heteroaryl, optionally substituted substituted aryl, optionally substituted cycloheteroalkyl, 【Chemistry 22】 【Chemistry 23】 The bifunctional compound of any one of claims 1-11, wherein dashed lines indicate attachment sites for at least one PTM, another ULM (ULM'), or a chemical linker moiety linking at least one PTM or ULM', or both, to the ULM.

17. The ULM is thalidomide, lenalidomide, pomalidomide, analogs thereof, isoforms thereof 12. The bifunctional compound of any one of claims 1 to 11, wherein the bifunctional compound is a cereblon E3 ligase binding moiety (CLM) selected from the group consisting of: cereblon E3 ligase-binding moiety (CLM), ...

18. The ULM is a CLM having the chemical structure represented by: 【Chemistry 24】 During the ceremony: W is CH 2 , O, CHR, C=O, SO 2 , NH, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, and N-alkyl; W 3 is selected from C or N; Each X is absent or selected from O, S and CH 2 are independently selected from the group consisting of: Y is CH2, -C=CR', NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl selected from the group consisting of aryl, N-heterocyclyl, O and S; Z is absent or selected from O, S and CH 2 selected from the group consisting of: G and G' are independently H, optionally substituted linear or branched alkyl, OH, -(CH 2 ) n’ -OP(=O)(OC 1-6 alkyl)(OH), -(CH 2 ) n’ -OP(=O)(OC 1-6 alkyl) 2 , -(CH 2 ) n’ -OP(=O)(OH) 2 , -CH 2 OCOO(CH 2 CH 2 O) n” CH 3 , R'OCOOR, R'OCONRR”, optionally replaced with R' CH to be exchanged 2 -heterocyclyl, and benzyl optionally substituted with R'. Selected; n" is an integer from 8 to 35 (e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35); Q 1 , Q 2 , Q 3 , and Q 4 are each independently selected from H, R, N, or N-oxide. represents a carbon C substituted with a group A is independently selected from the group of H, optionally substituted linear or branched alkyl, cycloalkyl, Cl, and F; R is halogen, -CONR'R", -OR', -NR'R", -SR', -SO 2 R', -SO 2 NR'R", -CR'R"-, -CR'NR'R"-, (-CR'O) n’ R″, optionally substituted aryl (e.g., optionally substituted optionally substituted C5-C7 aryl), optionally substituted alkyl-aryl (e.g., alkyl-aryl containing at least one of optionally substituted C1-C6 alkyl, optionally substituted C5-C7 aryl, or a combination thereof); optionally substituted heteroaryl (e.g., optionally substituted C5-C7 heteroaryl), optionally substituted straight or branched chain alkyl (e.g., one or more halogens), cycloalkyl (e.g., C3-C6 cycloalkyl C1-C6 straight or branched alkyl optionally substituted with aryl (e.g., C5-C7 aryl), optionally substituted alkoxyl groups (e.g., methoxy, ethoxy, butoxy, propoxy, pentoxy, or hexoxy; wherein the alkoxyl is substituted with one or more halogen, alkyl, haloalkyl, fluoroalkyl, cycloalkyl (e.g., C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl). ), optionally substituted 【Chemistry 25】 (e.g., optionally substituted with one or more halogen, alkyl, haloalkyl, fluoroalkyl, cycloalkyl (e.g., C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)), optionally substituted 【Chemistry 26】 (e.g., optionally substituted with one or more halogen, alkyl, haloalkyl, fluoroalkyl, cycloalkyl (e.g., C3-C6 cycloalkyl) or aryl (e.g., C5-C7 aryl)), optionally substituted cycloalkyl (e.g., optionally substituted C3-C7 cycloalkyl), optionally substituted heterocyclyl (e.g., optionally substituted C3-C7 ヘテロシクリル)、-P(O)(OR’)R”、-P(O)R’R”、-OP(O)(OR’)R”、-OP(O)R’R”、-Cl、-F、-Br、-I、-CF 3 、-CN、-NR’SO 2 NR’R”、-NR’CONR’R”、-CONR’COR”、-NR’C(=N-CN)NR’R”、-C(=N-CN)NR’R”、-NR’C(=N-CN)R”、-NR’C(=C-NO 2 )NR’R”、-SO 2 NR’COR”、-NO 2 、-CO 2 R’、-C(C=N-OR’)R”、-CR’=CR’R”、-CCR’、-S(C=O)(C=N-R’ )R”, -SF 5 and -OCF 3 wherein at least one R is selected from the group consisting of a PTM, a chemical linker group (L), a ULM, a CLM' (e.g., the CLM' can be an additional CLM having the same or different structure as the first CLM), ), or a combination thereof; each of x, y, and z is independently 0, 1, 2, 3, 4, 5, or 6; n' and n in formula (a) to formula (f) are each independently 1 to 10 (e.g., 1 to 4, 1, 2, 3, 4 , 5, 6, 7, 8, 9, or 10); R' and R" are independently H, optionally substituted straight or branched chain alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, -C(=O)R, optionally substituted heterocyclyl selected from the group consisting of: 【Chemistry 27】 【Chemistry 28】 12. The bifunctional compound according to any one of claims 1 to 11, wherein represents a bond which may be stereospecific ((R) or (S)) or non-stereospecific.

19. The ULM is a CLM having the chemical structure represented by: 【Chemistry 29】 During the ceremony: W is independently selected from the group: CH2, C=O, NH, and N-alkyl; A is independently selected from H, methyl, or optionally substituted alkyl (e.g., C1-C6 alkyl (optionally substituted straight or branched chain)); R in formula (g) is independently H, O, OH, N, NH, NH 2 , halogen, methyl, optionally substituted linear or branched alkyl (e.g., optionally substituted linear or branched C1-C6 alkyl), optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl (e.g., optionally substituted C3-C7 cycloalkyl), optionally substituted heterocyclyl (e.g., For example, optionally substituted C3-C7 heterocyclyl), optionally substituted alkyl-aryl (for example, alkyl-aryl containing at least one of C1-C6 alkyl, C4-C7 aryl, or a combination thereof), optionally substituted aryl (for example, C5-C7 aryl). , amine, amide, or carboxy; In formula (g), n represents an integer of 1 to 4 (e.g., 1, 2, 3, or 4), and in the formula, at least one R (e.g., O, OH, N, NH, NH 2 , C1-C6 alkyl, C1-C6 alkoxy, -alkyl-aryl (e.g., -alkyl-aryl including at least one of C1-C6 alkyl, C4-C7 aryl, or a combination thereof), aryl (e.g., C5-C7 aryl), amine, amino at least one of a C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C46, ​​C47, C48, C49, C51, C52, C53, C54, C55, C66, C67, C68, C79, C71, C72, C73, C74, C75, C76, C77, C78, ​​C79, C81, C82, C83, C94, C95, C96, C97, C98 【Transformation 30】 12. The bifunctional compound according to any one of claims 1 to 11, wherein represents a bond which may be stereospecific ((R) or (S)) or non-stereospecific.

20. The ULM is a CLM having the chemical structure represented by: 【Chemistry 31-1】 【Chemistry 31-2】 【Chemistry 31-3】 【Chemistry 31-4】 During the ceremony: W is independent, CH 2 , O, CHR, C=O, SO 2 , NH, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, and N-alkyl; Q 1 , Q 2 , Q 3 , Q 4 , Q 5 are each independently selected from H, R', N, or N-oxide; represents a carbon C or N substituted with a group R 1 is absent or selected from H, OH, CN, C1-C3 alkyl, C=O; R 2 is absent or is H, OH, CN, C1-C3 alkyl, CHF 2 , C.F. 3 , CHO, C(=O)NH 2 selected from the group R 3 is H, alkyl (e.g., C1-C6 alkyl or C1-C3 alkyl), substituted alkyl (e.g., substituted C1-C6 alkyl or C1-C3 alkyl), alkoxy (e.g., C1-C6 alkoxy), alkoxyl or C1-C3 alkoxyl), substituted alkoxy (e.g., substituted C1-C6 alkoxyl or C1-C3 alkoxyl); R 4 is selected from H, alkyl, and substituted alkyl; R 5 and R 6 are each independently H, halogen, C(=O)R', CN, OH, or CF 3 and X is C, CH, C═O or N; X 1 is C=O, N, CH or CH 2 and R' is H, OH, halogen, amine, cyano, alkyl (e.g., C1-C3 alkyl), substituted Alkyl (e.g., substituted C1-C3 alkyl), alkoxy (e.g., C1-C3 alkoxyl), substituted alkoxy (e.g., substituted C1-C3 alkoxyl), NR 2 R 3 , C(=O)OR 2 , optionally substituted phenyl; n is 0 to 4; 【Chemistry 32】 is a single or double bond; and 12. The bifunctional compound of any of claims 1-11, wherein the CLM is covalently attached to a PTM, a chemical linker group (L), a ULM, a CLM (or CLM'), or a combination thereof.

21. The ULMs include substituted imidazolines, substituted spiro-indolinones, substituted pyrrolidines, substituted pyridines, peridinones, substituted morpholinones, substituted pyrrolopyrimidines, substituted imidazolopyridines, substituted thiazoloimidazolines, substituted pyrrolopyrrolidinones, and substituted isoquinolinones. or The ULM is composed of the amino acids alanine (A), valine (V), proline (P), and isoleucine (I). IAP E3 ubiquitin ligase binding moieties (ILMs) containing ubiquitin (I) or non-natural mimetics thereof The bifunctional compound according to any one of claims 1 to 11.

22. the ULM comprising an IAP E3 ubiquitin ligator comprising an AVPI tetrapeptide fragment or a derivative thereof; 12. The bifunctional compound according to any one of claims 1 to 11, which is an enzyme-linking moiety (ILM).

23. 2. The bifunctional compound of claim 1, wherein at least one of: (i) the chemical linker group (L) is selected from the linkers in compounds 307-873; (ii) the ULM is selected from the ULMs in compounds 307-873; (iii) the PTM is selected from the PTMs in compounds 307-873; (iv) the compound further comprises a prodrug chemical moiety selected from the PTMs in compounds 796-873; or (v) a combination thereof.

24. The linker (L) comprises a chemical structural unit represented by the following formula: -(A L ) q -, During the ceremony: (A L ) q is linked to at least one of the ULM, the PTM, or a combination thereof. is a group q is an integer greater than or equal to 1; Each A L are independent, bond, CR L1 R L2 ,O,S,SO,SO 2 , N.R. L3 , SO 2 NR L3 ,SONR L3 ,CONR L3 , N.R. L3 CONR L4 , N.R. L3 SO 2 NR L4 , CO, CR L1 =CR L2 , C≡C, SiR L1 R L2 , P(O)R L1 , P(O)OR L1 , N.R. L3 C(=NCN)NR L4 , N.R. L3 C(=NCN), NR L3 C(=CNO 2 )NR L4 , optionally 0 to 6 R L1 Groups and / or R L2 C substituted with a group 3-11 cycloalkyl, optionally 0 to 6 R L1 Groups and / or R L2 Substituted with a group C 3-11 heterocyclyl, optionally 0 to 6 R L1 Groups and / or R L2 Aryl substituted with groups rule, optionally 0 to 6 R L1 Groups and / or R L2 heteroaryl substituted with a group; R L1 or R L2 are each independently optionally bonded to other groups and optionally have 0 to 4 R L5 forming cycloalkyl and / or heterocyclyl moieties substituted with groups; and Call R L1 , R L2 , R L3 , R L4 and R L5 each independently represents H, halo, C 1-8 Alkyl, OC 1-8 Al Kill, SC 1-8 Alkyl, NHC 1-8 Alkyl, N(C 1-8 alkyl) 2 , C 3-11 Cycloalkyl, aryl, heteroaryl, C 3-11 Heterocyclyl, OC 3-8 Cycloalkyl, SC 3-8 Cycloal Kill, NHC 3-8 Cycloalkyl, N(C 3-8 Cycloalkyl) 2 , N(C 3-8 Cycloalkyl)(C 1-8 alkyl), OH, NH 2 , SH, SO 2 C 1-8 Alkyl, P(O)(OC 1-8 Alkyl)(C 1-8 alkyl), P(O)(OC 1-8 alkyl) 2 , CC-C 1-8 Alkyl, CCH, CH=CH(C 1-8 alkyl), C(C 1-8 alkyl)=CH(C 1-8 alkyl), C(C 1-8 alkyl)=C(C 1-8 alkyl) 2 , Si(OH) 3 , Si(C 1-8 alkyl) 3 , Si(OH)(C 1-8 alkyl) 2 , COC 1-8 Alkyl, CO 2 H, halogen, CN, CF 3 , CHF 2 , C.H. 2 F, NO 2 ,SCIENCE FICTION 5 , SO 2 NHC 1-8 Alkyl, SO 2 N(C 1-8 alkyl) 2 ,SONHC 1-8 Alkyl, SON(C 1-8 alkyl) 2 , CONHC 1-8 Alkyl, CON(C 1-8 alkyl) 2 , N(C 1-8 alkyl)CONH(C 1-8 alkyl), N(C 1-8 alkyl)CON(C 1-8 alkyl) 2 , NHCONH(C 1-8 alkyl), NHCON(C 1-8 alkyl) 2 ,NHCONH 2 , N(C 1-8 alkyl)SO 2 NH(C 1-8 alkyl), N(C 1-8 alkyl) SO 2 N(C 1-8 alkyl) 2 , NHSO 2 NH(C 1-8 alkyl), NH SO 2 N(C 1-8 alkyl) 2 , NHSO 2 NH 2 The bifunctional compound according to any one of claims 1 to 23,

25. The linker (L) comprises a group represented by a general structure selected from the group consisting of: -N(R)-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -OCH2-, -O-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -OCH2-, -O-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -O-; -N(R)-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -O-; -(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -O-; -(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -OCH2-; 【Chemistry 33-1】 【Chemistry 33-2】 wherein m, n, o, p, q, and r are independently 0, 1, 2, 3, 4, 5, or 6, provided that 25. The bifunctional compound according to any one of claims 1 to 24, wherein when the number is zero and there are no N-O or O-O bonds, R is selected from the group of H, methyl and ethyl, and X is selected from the group of H and F. 【Chemistry 34-1】 【Chemistry 34-2】 【Chemistry 34-3】 【Chemistry 34-4】 【Chemistry 34-5】 【Chemistry 34-6】 【Chemistry 34-7】 【Chemistry 34-8】 【Chemistry 34-9】

26. The linker (L) is selected from the group consisting of: 【Chemistry 35-1】 【Chemistry 35-2】 【Chemistry 35-3】 【Chemistry 35-4】 【Transformation 35-5】 【Chemistry 35-6】 【Chemistry 35-7】 【Transformation 35-8】 【Chemistry 35-9】 【Chemistry 35-10】 【Chemistry 35-11】 【Chemistry 35-12】 【Chemistry 35-13】 【Chemistry 35-14】 【Chemistry 35-15】 [Chemistry 35-16] 【Chemistry 35-17】 【Chemistry 35-18】 【Chemistry 35-19】 【Chemistry 35-20】 【Chemistry 35-21】 【Chemistry 35-22】 [Chemistry 35-23] [Chemistry 35-24] [Chemistry 35-25]

27. The linker (L) is selected from the group consisting of: 【Chemistry 36-1】 【Chemistry 36-2】 【Chemistry 36-3】 【Chemistry 36-4】 【Chemistry 36-5】 【Chemistry 36-6】 [Chemistry 36-7] 【Transformation 36-8】 【Chemistry 36-9】 【Chemistry 36-10】 【Chemistry 36-11】 【Chemistry 36-12】 【Chemistry 36-13】 25. The bifunctional compound of any one of claims 1 to 24, wherein each m and n is independently 0, 1, 2, 3, 4, 5, or 6.

28. 25. The method according to claim 1, wherein the linker (L) is selected from the group consisting of: The bifunctional compounds described above. 【Chemistry 37-1】 【Chemistry 37-2】 【Chemistry 37-3】 【Chemistry 37-4】

29. The linker (L) comprises the following chemical structure: 【Transformation 38】 【Chemistry 39】 indicates the point of attachment to the PTM or ULM moiety. Functional compounds.

30. The linker (L) comprises the following chemical structure: 【Chemistry 40】 During the ceremony, W L1 and W L2 are each independently absent or an aryl, heteroaryl, cyclic, heterocyclic, or C in which one or more C atoms are optionally substituted by O; 1-6 Alkyl, optionally with one or more C atoms replaced by O 1-6 Alkenes, optionally with one or more C atoms replaced by O 1-6 alkyne, bicyclic, biaryl, biheteroaryl, or biheterocyclic, each of which is optionally R Q Each R is replaced by Q are independently H, halo, OH, CN, CF 3 , hydroxyl, nitro, C≡CH, C 2-6 Alkenyl, C 2-6 Alkynyl, optionally substituted straight or branched C 1 -C 6 Alkyl, optionally substituted straight or branched chain C 1 -C 6 Alkoxy, optionally substituted OC 1-3 Alkyl (e.g., optionally substituted with one or more —F), OH, NH 2 , N.R. Y1 R Y2 , CN or two R Q The groups, together with the atoms to which they are attached, may contain 0 to 4 heteroatoms. forming a 4- to 8-membered ring system containing; Y L1 are each independently a bond, NR YL1 ,O,S,NR YL2 , C YL1 R YL2 , C=O, C=S, SO, SO 2 , optionally substituted linear or branched C 1- C 6 alkyl, optionally with one or more C atoms substituted by O; optionally substituted linear or branched C 1 -C 6 Alkoxy; Q L is a 3-6 membered alicyclic or aromatic ring with 0-4 heteroatoms, optionally bridged, and optionally containing 0-6 R Q Each R is replaced by Q are independently H, optionally substituted linear or Branched C 1-6 Alkyl (e.g., optionally with one or more halo, or C 1-6 Alkoxylated or two R Q The groups, together with the atoms to which they are attached, may contain 0 to 2 hetero atoms. Forming a 3- to 8-membered ring system containing a heteroatom; R YL1 , R YL2 each independently represents H, OH, an optionally substituted straight or branched chain C 1-6 Alkyl (e.g., one or more halo, or C 1-6 optionally substituted with alkoxyl) or R 1 , R 2 3 containing 0-2 heteroatoms along with the atoms to which they are attached Forms an 8-membered ring system; n is 0 to 10; and 【Chemistry 41】 indicates the point of attachment to the PTM or ULM moiety. Functional compounds.

31. The linker (L) 【Chemistry 42-1】 【Chemistry 42-2】 【Chemistry 42-3】 31. The bifunctional compound of claim 29 or 30, selected from the group consisting of:

32. The linker (L) may be an optionally substituted C 1- C 100 alkyl, wherein Each carbon is optional, CR L1 R L2 ,O,S,SO,SO 2 , N.R. L3 , SO 2 NR L3 ,SONR L3 ,CONR L3 , N.R. L3 CONR L4 , N.R. L3 SO 2 NR L4 , CO, CR L1 =CR L2 , C≡C, SiR L1 R L2 , P(O)R L1 , P(O)OR L1 , N.R. L3 C(=NCN)NR L4 , N.R. L3 C(=NCN), NR L3 C(=CNO 2 )NR L4 , 0 to 6 R L1 and / or R L2 C optionally substituted with a group 3-11 Cycloalkyl, 0 to 9 R L1 and / or R L2 C optionally substituted with a group 5-13 Spirocycloalkyl, 0 to 6 R L1 and / or R L2 C optionally substituted with a group 3-11 Hetero Cyclyl, 0-8 R L1 and / or R L2 C optionally substituted with a group 5-13 Spiroheterocytic Rill, 0 to 6 R L1 and / or R L2 aryl optionally substituted with a group, 0 to 6 R L1 Oh and / or R L2 and substituted with heteroaryl optionally substituted with a group, wherein R L1 or R L2 teeth , each independently linked to other groups, optionally 0 to 4 R L5 cycloalkyl substituted with a group and / or forming a heterocyclyl moiety; and R L1 , R L2 , R L3 , R L4 and R L5 each independently represents H, halo, C 1-8 Alkyl, OC 1-8 Al Kill, SC 1-8 Alkyl, NHC 1-8 Alkyl, N(C 1-8 alkyl) 2 , C 3-11 Cycloalkyl, aryl, heteroaryl, C 3-11 Heterocyclyl, OC 3-8 Cycloalkyl, SC 3-8 Cycloal Kill, NHC 3-8 Cycloalkyl, N(C 3-8 Cycloalkyl) 2 , N(C 3-8 Cycloalkyl)(C 1-8 alkyl), OH, NH 2 , SH, SO 2 C 1-8 Alkyl, P(O)(OC 1-8 Alkyl)(C 1-8 alkyl), P(O)(OC 1-8 alkyl) 2 , CC-C 1-8 Alkyl, CCH, CH=CH(C 1-8 alkyl), C(C 1-8 alkyl)=CH(C 1-8 alkyl), C(C 1-8 alkyl)=C(C 1-8 alkyl) 2 , Si(OH) 3 , Si(C 1-8 alkyl) 3 , Si(OH)(C 1-8 alkyl) 2 , COC 1-8 Alkyl, CO 2 H, halogen, CN, CF 3 , CHF 2 , C.H. 2 F, NO 2 ,SCIENCE FICTION 5 , SO 2 NHC 1-8 Alkyl, SO 2 N(C 1-8 alkyl) 2 ,SONHC 1-8 Alkyl, SON(C 1-8 alkyl) 2 , CONHC 1-8 Alkyl, CON(C 1-8 alkyl) 2 , N(C 1-8 alkyl)CONH(C 1-8 alkyl), N(C 1-8 alkyl)CON(C 1-8 alkyl) 2 , NHCONH(C 1-8 alkyl), NHCON(C 1-8 alkyl) 2 ,NHCONH 2 , N(C 1-8 alkyl)SO 2 NH(C 1-8 alkyl), N(C 1-8 alkyl) SO 2 N(C 1-8 alkyl) 2 , NHSO 2 NH(C 1-8 alkyl), NH SO 2 N(C 1-8 alkyl) 2 , NHSO 2 NH 2 The bifunctional compound according to any one of claims 1 to 23,

33. The linker is 【Chemistry 43-1】 【Chemistry 43-2】 【Chemistry 43-3】 【Chemistry 43-4】 【Chemistry 43-5】 【Chemistry 43-6】 【Chemistry 43-7】 【Chemistry 43-8】 【Chemistry 43-9】 【Chemistry 43-10】 33. The bifunctional compound according to any one of claims 1 to 24 and 32, selected from the group consisting of:

34. 2. The bifunctional compound of claim 1, wherein the compound is selected from Tables 1A to 1C.

35. 35. The composition of claim 1, further comprising at least one polyethylene glycol chain. The bifunctional compound described above.

36. An effective amount of a bifunctional compound according to any one of claims 1 to 35 and a pharmaceutically acceptable carrier. A composition comprising:

37. The composition further comprises an additional bioactive agent or another bifunctional compound according to any of claims 1 to 34.

36. The composition of claim 35, further comprising at least one of a hydroxyl group-containing compound.

38. 37. The composition of claim 36, wherein the additional bioactive agent is an anti-cancer agent.

39. 1. A method for treating a disease or disorder in a subject, comprising administering to a subject a pharmaceutically acceptable carrier and a compound according to claim 1. A composition comprising an effective amount of at least one compound described in any one of claims 1 to 35, wherein the method comprises administering the composition to a subject in need thereof, and the compound is effective to treat or ameliorate at least one symptom of the disease or disorder.

40. 39. The composition of claim 38, wherein the disease or disorder is associated with accumulation and aggregation of BRaf.

41. The disease or disorder is cancer; cardio-faciocutaneous syndrome; neurological Fibromatosis type 1; Costello syndrome; Noonan syndrome; or lentigines, ECG abnormalities, hypertelorism 40. The composition of claim 38 or 39, wherein the condition is pulmonary valve stenosis, genital abnormalities, developmental delay, and hearing loss associated with accumulation and aggregation of RAF (LEOPARD) syndrome.

42. 40. The composition of claim 39, wherein the cancer is renal cell carcinoma; pancreatic cancer, colorectal cancer; lung cancer; ovarian cancer; thyroid cancer; pilocytic astrocytoma; prostate cancer; gastric cancer; hepatocellular carcinoma; or melanoma.

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