Tyrosine Kinase 2 (TYK2) Degrading Compounds and Methods of Use

Abstract

The present invention relates to heterobifunctional compounds (such as bifunctional small molecule compounds), compositions containing one or more heterobifunctional compounds, and methods of use for treating certain diseases in a subject in need thereof. The present invention also relates to methods for identifying such heterobifunctional compounds.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceuticals, and particularly relates to tyrosine kinase 2 (TYK2) degrading compounds and methods of using the same. Background of the Invention

[0003] Janus kinases (JAKs) are key signal transduction molecules that coordinate cytokine-induced signal networks. JAKs are non-receptor tyrosine kinases that include four members, JAK1 / 2 / 3, and TYK2. Upon cytokine binding, JAKs are recruited to the cytoplasmic tail regions of cytokine receptors and induce phosphorylation of each other as well as these receptors. Subsequently, the activated JAKs phosphorylate signal transducer and activator of transcription (STAT1-6) family transcription factors, dimerize them, and cause nuclear translocation, and thus lead to transcriptional activation of many genes related to cell proliferation, survival, differentiation, immune response, and other important biological processes. Due to the central role of JAKs in innate and adaptive immunity, the pharmaceutical industry has actively sought to use them for treating immune system diseases and cancers. In recent years, an increasing number of JAK kinase inhibitors have entered the market, including ruxolitinib, a JAK1 / 2 dual inhibitor for treating myelofibrosis and polycythemia vera, and fedratinib, also for myelofibrosis. Baricitinib is another JAK1 / 2 dual inhibitor that is used to treat rheumatoid arthritis (RA), atopic dermatitis, and systemic lupus erythematosus. Tofacitinib is a pan-JAK inhibitor that is used to treat patients with moderate to severe RA, psoriatic arthritis, and ulcerative colitis. However, despite the significant therapeutic effects in some autoimmune diseases and cancers, the broad immunosuppressive effects of JAK kinase inhibitors are remarkable.

[0004] TYK2 was the first JAK kinase to be identified but has only recently been extensively studied like other JAKs. TYK2 shares seven Janus homology domains (JH1 - 7) with other family members. The carboxyl - terminal JH1 domain contains the catalytic center. The adjacent JH2 domain is a pseudokinase domain that functions as a self - inhibitory domain. Once recruited to heterodimeric cytokine receptors, TYK2 typically cooperates with JAK1 or JAK2 to activate downstream STAT proteins. A growing number of studies have identified an important role of TYK2 in signal transduction induced by several key interleukins and interferons (notably IL - 12, IL - 23, and type I interferons). TYK2 may also be involved in the signal transduction of IL - 6 and IL - 10. The link between TYK2 and these cytokines makes it a potential therapeutic target for a variety of immune diseases, including rheumatoid arthritis, psoriasis, type I diabetes, systemic lupus erythematosus, ankylosing spondylitis, Crohn's disease, ulcerative colitis, multiple sclerosis, juvenile idiopathic arthritis, primary biliary cirrhosis, and inflammatory bowel disease (IBD). Aberrant activation of TYK2 has also been found in cancer.

[0005] Pan - JAK kinase inhibitors have the potential to block TYK2 signal transduction. However, blocking all JAK kinases severely impairs the immune response, leading to serious adverse events such as infections and cancer. Genetic engineering models in rodents and genetic diseases in humans have revealed very different consequences of individual JAK kinase deficiencies. Deletion of JAK1 or JAK2 in mice is embryonically lethal, while deletion of JAK3 results in severe combined immunodeficiency. In contrast, mice lacking TYK2 can survive with impaired immune responses but are difficult to cure when autoimmune diseases develop. Therefore, selectively targeting TYK2 has significant potential in autoimmune and inflammatory diseases and may not induce widespread immunosuppression as pan - JAK inhibition does.

[0006] Due to the favorable benefit - risk ratio, targeting TYK2 has increasingly attracted the interest of the academic and pharmaceutical industries. Neutralizing antibodies against IL - 12 and IL - 23 (the major cytokines that signal through TYK2) have been approved for the treatment of psoriasis, psoriatic arthritis, and Crohn's disease. Over the past decade, a variety of TYK2 kinase inhibitors have been reported and patented, with varying degrees of selectivity for other JAK family members. Some of these TYK2 inhibitors have entered different clinical phases.

[0007] Although TYK2 and other JAK kinase inhibitors hold promise for treating a variety of immune and malignant diseases, small molecule inhibitors primarily modulate the catalytic activity of these kinases. However, TYK2 can promote cytokine signaling through its scaffolding function. Kinase-dead TYK2 mutants retain the ability to regulate the stability of type I interferon receptors. The catalytic function of TYK2 is also essential for the activation of PI3K signaling. Therefore, eliminating the effects of TYK2 on cytokine responses using small molecule degraders may have a more profound impact than using kinase inhibitors.

[0008] Currently available small molecules targeting TYK2 primarily focus on inhibiting TYK2 kinase activity.

[0009] There is a need in the art for compounds, compositions, and methods of using such compounds for treating diseases in subjects in need thereof. SUMMARY OF THE INVENTION

[0010] The present invention relates to heterobifunctional compounds (such as bifunctional small molecule compounds), compositions comprising one or more heterobifunctional compounds, and methods of using heterobifunctional compounds for treating certain diseases in subjects in need thereof. The present invention also relates to methods of identifying such heterobifunctional compounds.

[0011] According to a first aspect of the present invention, the heterobifunctional compounds disclosed herein comprise a tyrosine kinase 2 (TYK2) ligand conjugated to a degron, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or analog thereof.

[0012] In one embodiment, the TYK2 ligand binds to the Janus homology 2 (JH2) domain of TYK2.

[0013] In another embodiment, the degron binds to a ubiquitin ligase or is a hydrophobic group or tag that causes misfolding of the TYK2 protein. In another embodiment, the ubiquitin ligase is an E3 ligase. In another embodiment, the E3 ligase is selected from the group consisting of: VHLE3 ligase, cereblon E3 ligase, IAP ligase, MDM2 ligase, TRIM24 ligase, TRIM21 ligase, KEAP1 ligase, DCAF16 ligase, RNF4 ligase, RNF114 ligase, and AhR ligase.

[0014] In another embodiment, the degrading tag is selected from the group consisting of: VHL-1, pomalidomide, thalidomide, lenalidomide, adamantane, 1-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonane, nutlin-3a, RG7112, RG7338, AMG232, AA-115, bestatin, MV-1, LCL161, CPD36, GDC-0152, CRBN-1, CRBN-2, CRBN-3, CRBN-4, CRBN-5, CRBN-6, CRBN-7, CRBN-8, CRBN-9, CRBN-10, CRBN-11, CRBN-12, CRBN-13, CRBN-14, CRBN-15, CRBN-16, and analogs thereof.

[0015] In a further embodiment, the TYK2 ligand is conjugated to the degrading tag via a linker moiety.

[0016] In a further embodiment, the heterobifunctional compounds described herein include a moiety of Formula 1;

[0017]

[0018] or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or analog thereof; wherein,

[0019] i) the TYK2 ligand includes a moiety of Formula 1 or Formula 2:

[0020]

[0021] wherein *, Ring A, R 1 , R 1 ’, R 2 , R 2 ’, R 3 , X, Y, Z 1 , Z 2 are as defined below;

[0022] ii) the degrading tag is a moiety represented by Formula 6A, 6B, and 6C:

[0023]

[0024] wherein *, R EV 1 , R EV 2 , R EV 2 ’, R EV 3 , R EV4 , R EV 4’, R EV 3 , R EV 4 , R EV 4 ’, R EV 5 and R EV 6 L are defined as follows;

[0025] Or, the degradation tag is the moiety shown in Formula 5, and the degradation tag is connected to the linker moiety of the heterobifunctional compound via Z E connected to the linker moiety of the heterobifunctional compound;

[0026]

[0027] wherein ring A E , L E , Z E and R E 1 are defined as follows;

[0028] and iii) the linker moiety is as shown in Formula 9:

[0029]

[0030]

[0031] wherein m L , A L , W L 1 , W L 2 and B L are defined as follows.

[0032] In some embodiments, the hetero-bifunctional compound is selected from the group consisting of CPD-001 to CPD-199, or a pharmaceutically acceptable salt or analogue thereof. In some embodiments, the hetero-bifunctional compound is selected from the group consisting of CPD-038, CPD-039, CPD-040, CPD-047, CPD-084, CPD-085, CPD-099, CPD-100, CPD-110, CPD-112, CPD-114, CPD-115, CPD-121, CPD-124, CPD-125, CPD-126, CPD-127, CPD-131, CPD-133, CPD-134, CPD-143, CPD-144, CPD-148, CPD-150, CPD-151, CPD-155, CPD-157, CPD-158, CPD-159, CPD-164, CPD-167, CPD-175, and a pharmaceutically acceptable salt or analogue thereof.

[0033] According to a second aspect of the present invention, there is provided a pharmaceutical composition herein comprising a compound according to the first aspect of the present invention, and one or more pharmaceutically acceptable carriers. In one embodiment, the pharmaceutical composition further comprises one or more additional therapeutic agents.

[0034] According to a third aspect of the present invention, a method of treating and / or preventing a TYK2-mediated disease provided herein comprises administering to a subject in need thereof the hetero-bifunctional compound or a pharmaceutically acceptable salt or analogue thereof.

[0035] In one embodiment, the subject in need thereof refers to a subject suffering from one or more TYK2-mediated diseases and / or a subject with elevated TYK2 function.

[0036] In one embodiment, the TYK2-mediated disease is caused by TYK2 expression, mutation, deletion or fusion.

[0037] In one embodiment, the TYK2 function of a subject suffering from a TYK2-mediated disease is increased relative to a healthy subject not suffering from a TYK2-mediated disease.

[0038] In one example, the subject is a mammal, preferably a human.

[0039] In one embodiment, the hetero-bifunctional compound is selected from the group consisting of CPD-001 to CPD-199, or an analogue thereof.

[0040] In one embodiment, the hetero-bifunctional compound is administered to the subject orally, parenterally, intradermally, subcutaneously, topically or rectally.

[0041] In one embodiment, the method further comprises administering to the subject an additional treatment regimen for treating cancer, an inflammatory disorder, or an autoimmune disease.

[0042] In one embodiment, the additional treatment regimen is selected from the group consisting of surgery, chemotherapy, radiotherapy, hormone therapy, targeted therapy, and immunotherapy.

[0043] In one embodiment, the TYK2-mediated disease is selected from the group consisting of cancer, inflammatory diseases, autoimmune diseases, skin diseases, viral infections, dry eye disease, bone remodeling disorders, immune complications associated with organ transplantation, recurrent cancer, or a combination thereof.

[0044] In one embodiment, the TYK2-mediated cancer is selected from the group consisting of brain cancer, gastric cancer, gastrointestinal cancer, liver cancer, biliary tract cancer, breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, penile cancer, urogenital cancer, esophageal cancer, laryngeal cancer, skin cancer, lung cancer, pancreatic cancer, thyroid cancer, adenocarcinoma, bladder cancer, kidney cancer, muscle cancer, bone cancer, hematopoietic system cancer, myeloproliferative neoplasm, essential thrombocythemia, polycythemia vera, primary myelofibrosis, chronic neutrophilic leukemia, acute lymphoblastic leukemia, Hodgkin lymphoma, chronic myelomonocytic leukemia, systemic mastocytosis, hypereosinophilic syndrome, cutaneous T-cell lymphoma, B-cell lymphoma, and myeloma.

[0045] In one embodiment, the TYK2-mediated inflammatory disorder is selected from the group consisting of ankylosing spondylitis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, and reperfusion injury.

[0046] In one embodiment, the TYK2-mediated autoimmune disease is selected from the group consisting of multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, psoriasis, myasthenia gravis, type I diabetes, systemic lupus erythematosus, IgA nephropathy, autoimmune thyroid disease, alopecia areata, and bullous pemphigoid.

[0047] In one embodiment, the TYK2-mediated skin disease is selected from the group consisting of atopic dermatitis, pruritus, alopecia areata, psoriasis, rash, skin irritation, skin allergy, chronic mucocutaneous candidiasis, dermatomyositis, erythema multiforme, palmoplantar pustulosis, vitiligo, polyarteritis nodosa, and STING vasculopathy.

[0048] In one embodiment, the TYK2-mediated viral infections are selected from the group consisting of: hepatitis B, hepatitis C, human immunodeficiency virus (HIV), human T-lymphotropic virus (HTLV1), Epstein-Barr virus (EBV), varicella-zoster virus (VZV), and human papillomavirus (HPV) infections.

[0049] In one embodiment, the TYK2-mediated dry eye diseases are selected from the group consisting of: dry eye syndrome (DES) and keratoconjunctivitis sicca (KCS).

[0050] In one embodiment, the TYK2-mediated bone remodeling disorders are selected from the group consisting of: osteoporosis and osteoarthritis.

[0051] In one embodiment, the TYK2-mediated immune complications associated with organ transplantation are selected from the group consisting of: graft-versus-host disease.

[0052] In one embodiment, the TYK2-mediated disease is recurrent cancer.

[0053] In one embodiment, the TYK2-mediated disease is refractory to one or more previous treatment methods.

[0054] According to a fourth aspect of the present invention, there is provided the use of a compound according to the first aspect of the present invention or a pharmaceutically acceptable salt or analogue thereof, or a pharmaceutical composition according to the second aspect of the present invention, in the preparation of a medicament for the treatment and / or prevention of a TYK2-mediated disease.

[0055] In one embodiment, the TYK2-mediated disease is as defined above.

[0056] According to a fifth aspect of the present invention, a method for identifying a heterobifunctional compound that mediates the degradation or reduction of TYK2 is disclosed. The method comprises:

[0057] providing a heterobifunctional test compound comprising a degradation tag coupled to a TYK2 ligand via a linker;

[0058] contacting the heterobifunctional test compound with a cell comprising a ubiquitin ligase and TYK2;

[0059] determining whether the level of TYK2 in the cell is reduced; and

[0060] identifying the heterobifunctional test compound as a heterobifunctional compound that mediates the degradation or reduction of TYK2.

[0061] In one embodiment, the cell is a cancer cell. In one embodiment, the cancer cell is a TYK2-mediated cancer cell.

[0062] According to a sixth aspect of the present invention, there is provided a method for selectively degrading or reducing TYK2, comprising contacting a cell with a compound according to the first aspect of the present invention or a pharmaceutically acceptable salt or analogue thereof, or a pharmaceutical composition according to the second aspect of the present disclosure.

[0063] In one embodiment, the cell is a cancer cell. In one embodiment, the cancer cell is a TYK2-mediated cancer cell (such as MOLT-4 cells).

[0064] In one embodiment, the method reduces the level of TYK2 protein in the cell.

[0065] In one embodiment, the method is an in vitro non-therapeutic method.

[0066] According to a seventh aspect of the present disclosure, there is provided the use of a heterobifunctional compound or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or analogue thereof in combination with one or more additional therapeutic agents.

[0067] In one embodiment, the heterobifunctional compound is as shown in Formula I.

[0068] In one embodiment, the TYK2 ligand of the heterobifunctional compound is a moiety as shown in Formula 1 or Formula 2 as defined in the first aspect.

[0069] Incorporation by reference

[0070] All publications, patents and patent applications mentioned in this specification are incorporated herein by reference to the extent that each individual publication, patent or patent application is specifically and individually indicated and incorporated by reference.

[0071] Brief description of the drawings

[0072] The novel features of the present invention are particularly set forth in the appended claims. The features and advantages of the present invention may be better understood by reference to the following detailed description, which sets forth illustrative embodiments that utilize the principles of the present invention, and the corresponding drawings:

[0073] Figure 1 Shows immunoblots of TYK2 and JAK1 / 2 / 3 proteins in MOLT-4 cells after treatment with the heterobifunctional compounds CPD-038, CPD-039 and CPD-040 within the indicated dose ranges.

[0074] Figure 2Shows immunoblots of TYK2 and β-actin in NOMO-1 cells after treatment with the heterobifunctional compounds CPD-155, CPD-157, and CPD-158 within the indicated dose ranges.

[0075] Figure 3 Shows immunoblots of TYK2, STAT1 / 3, pY705STAT3, pY701STAT1, and α-tubulin levels in Jurkat cells after treatment with the heterobifunctional compounds CPD-155, CPD-158, and CPD-164 within the indicated dose ranges in the presence or absence of interferon α (IFNα) as indicated. DETAILED DESCRIPTION OF THE INVENTION

[0077] In the present disclosure, a new approach is adopted: developing compounds that not only directly and selectively modulate the kinase activity of TYK2 but also modulate its protein level.

[0078] In some embodiments, heterobifunctional compounds are disclosed herein. In some embodiments, the heterobifunctional compounds comprise the chemical structures or general formulas disclosed herein. The heterobifunctional compounds can be or include TYK2 degraders. The TYK2 degraders can be characterized by the ability to degrade or reduce the cellular protein level of TYK2. Some embodiments relate to compositions comprising heterobifunctional compounds. Some embodiments relate to methods of preparing heterobifunctional compounds. Some embodiments relate to methods of using heterobifunctional compounds or pharmaceutical compositions containing heterobifunctional compounds. For example, the heterobifunctional compounds can be used to treat disorders or diseases. In certain cases, the compounds are used to treat autoimmune diseases. In certain cases, the compounds are used to treat inflammatory diseases. In certain cases, the compounds are used to treat cancer.

[0079] The present disclosure includes all stereoisomers, geometric isomers, tautomers, and isotopes of the compounds with the structures and names described herein. The present disclosure also includes the compounds described herein regardless of how they are prepared, e.g., synthesized, by biological processes (e.g., metabolism or enzymatic conversion), or a combination thereof.

[0080] The present disclosure includes pharmaceutically acceptable salts of the compounds with the structures and names described herein.

[0081] One or more constituent atoms of the compounds provided herein may be replaced or substituted with atomic isotopes of natural or non-natural abundances. In some embodiments, the compounds do not include any deuterium atoms. In some embodiments, the compounds include at least one deuterium atom. In some embodiments, the compounds include two or more deuterium atoms. In some embodiments, the compounds include 1-2, 1-3, 1-4, 1-5, or 1-6 deuterium atoms. In some embodiments, all hydrogen atoms in the compounds may be replaced or substituted with deuterium atoms. In some embodiments, the compounds do not include any fluorine atoms. In some embodiments, the compounds include at least one fluorine atom. In some embodiments, the compounds include two or more fluorine atoms. In some embodiments, the compounds include 1-2, 1-3, 1-4, 1-5, or 1-6 fluorine atoms. In some embodiments, all hydrogen atoms in the compounds may be replaced or substituted with fluorine atoms.

[0082] Heterobifunctional compound

[0083] In some embodiments, compounds are disclosed herein. In some embodiments, the compounds comprise a TYK2 binding moiety disclosed herein. In some embodiments, the compounds comprise a TYK2 JH2 domain binding moiety disclosed herein. In some embodiments, the compounds comprise a degron disclosed herein. In some embodiments, the compounds include a VHL binding moiety. In some embodiments, the compounds include a TYK2 degrader. For example, the compounds may cause TYK2 degradation. Due to truncation of the VHL ligase function, the compounds may degrade TYK2. The compounds may bind to or modulate TYK2 or VHL. In some embodiments, the compounds include heterobifunctional compounds. In some embodiments, the compounds include a linker.

[0084] According to one aspect of the present disclosure, the heterobifunctional compounds disclosed herein include a moiety represented by Formula I

[0085]

[0086] or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or analogue thereof;

[0087] Wherein,

[0088] 1) The TYK2 ligand includes a moiety represented by Formula 1 or Formula 2:

[0089]

[0090] Wherein,

[0091] * represents a connection to the linker portion of the hetero-bifunctional compound;

[0092] L is selected from: nothing, CR 4 R 5 、CO、CO2、CONR 4 、NR 4 、NR 4 CO、NR 4 CO2、NR 4 C(O)NR 5 、NR 4 SO、NR 4 SO2、NR 4 SO2NR 5 、O、OC(O)、OCO2、OCONR 4 、S、SO、SO2 and SO2NR 4 , where

[0093] R 4 and R 5 are independently selected from the group consisting of: H, halogen, hydroxy, amino, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkylamino, optionally substituted C3-C 10 carbocyclic group, optionally substituted 3-10 membered heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl, or, R 4 and R 5 together with one or more atoms to which they are attached form a C3-C 20 carbocyclic ring or 3-20 membered heterocyclic ring;

[0094] X, Y, Z 1 and Z 2 are independently selected from the group consisting of: CR 6 and N, where

[0095] R 6 , each time it appears, is independently selected from the group consisting of: nothing, hydrogen, halogen, CN, NO2, OR 7 、SR 7 、NR 7 R 8 、OCOR 7 、OCO2R 7 、OCON(R 7 )R 8 、COR 7 、CO2R 7 、CON(R 7 )R 8 、SOR 7, SO2R 7 , SO2N(R 7 )R 8 , NR 9 CO2R 7 , NR 9 COR 7 , NR 9 C(O)N(R 7 )R 8 , NR 9 SOR 7 , NR 9 SO2R 7 and NR 9 SO2N(R 7 )R 8 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-10 membered heterocyclic C1-C8 alkyl, optionally substituted C3-C 10 carbocyclic C1-C8 alkyl, optionally substituted C3-C 10 carbocyclic, optionally substituted 3-10 membered heterocyclic, optionally substituted aryl and optionally substituted heteroaryl; or, two R 6 groups together with the atom(s) to which they are attached optionally form: optionally substituted C5-C6 carbocyclic, optionally substituted 5-6 membered heterocyclic, optionally substituted C6 aryl and optionally substituted 5-6 membered heteroaryl, wherein,

[0096] R 7 , R 8 and R 9 are independently selected from the group consisting of: nothing, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 carbocyclic C1-C8 alkyl, optionally substituted 3-10 membered heterocyclic C1-C8 alkyl, optionally substituted C3-C 10 carbocyclic, optionally substituted 3-10 membered heterocyclic, optionally substituted aryl and optionally substituted heteroaryl, or, R 7 and R 8 , R 7 and R 9 and the atoms to which they are attached together form: a 3-20 membered heterocyclic ring;

[0097] R 2 (in formula 1) and R1 (in formula 2) selected from the group consisting of: none, hydrogen, halogen, CN, NO2, OR 10 、SR 10 、NR 10 R 11 、OCOR 10 、OCO2R 10 、OCONR 10 R 11 、COR 10 、CO2R 10 、CONR 10 R 11 、SOR 10 、SO2R 10 、SO2NR 10 R 11 、NR 12 CO2R 10 、NR 12 COR 10 、NR 12 C(O)NR 10 R 11 、NR 12 SOR 10 、NR 12 SO2R 10 、NR 12 SO2NR 10 R 11 、optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino, optionally substituted C3-C8 cycloalkylamino, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 carbocyclic group, optionally substituted C3-C 10 cycloalkoxy, optionally substituted C3-C 10 carbocyclic group amino, optionally substituted 3-10 membered heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl, wherein,

[0098] R 10 、R 11 and R 12 are independently selected from the group consisting of: hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 carbocyclic group, optionally substituted 3-10 membered heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl; or, R10 and R 11 , or R 10 and R 12 and together with the (one or more) atoms attached thereto form: C3-C 20 carbocyclic group or 3- to 20-membered heterocyclic group ring;

[0099] R 1 '(in formula 1) and R 2 '(in formula 2) are independently divalent groups selected from the group consisting of: none, R'-R", R'OR", R'SR", R'N(R 13 )R", R'OC(O)R", R'OC(O)OR", R'OCON(R 13 )R", R'C(O)R", R'C(O)OR", R'CON(R 13 )R", R'S(O)R", R'S(O)2R", R'SO2N(R 13 )R", R'N(R 14 )C(O)OR", R'N(R 14 )C(O)R", R'N(R 14 )C(O)N(R 13 )R", R'N(R 14 )S(O)R", R'N(R 14 )S(O)2R" and R'N(R 14 )S(O)2N(R 13 )R", optionally substituted C3-C 13 carbocyclic group, optionally substituted 3- to 13-membered heterocyclic group, optionally substituted aryl group, and optionally substituted heteroaryl group, wherein,

[0100] R' and R" are independently divalent groups selected from the group consisting of: none, optionally substituted C1-C8 alkylene group, optionally substituted C2-C8 alkenylene group, optionally substituted C2-C8 alkynylene group, optionally substituted C3-C 10 carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted aryl group, and optionally substituted heteroaryl group;

[0101] R 13 and R 14 are independently selected from the group consisting of: H, optionally substituted C1-C8 alkyl group, optionally substituted C2-C8 alkenyl group, optionally substituted C2-C8 alkynyl group, optionally substituted C3-C 10 carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted aryl group, and optionally substituted heteroaryl group; or,

[0102] R' and R", R 13 and R 14 , R' and R13 , R', and R 14 , R", and R 13 , or R" and R 14 and, together with the atoms to which they are attached, form a C3-C 20 carbocyclic group or a 3- to 20-membered heterocyclic group ring;

[0103] Ring A is selected from the group consisting of: optionally substituted C3-C 13 carbocyclic group, optionally substituted 3- to 13-membered heterocyclic group, optionally substituted aryl, and optionally substituted heteroaryl;

[0104] R 3 represents one or more substituents selected from the group consisting of: none, hydrogen, halogen, CN, NO2, OR 15 , SR 15 , NR 15 R 16 , OCOR 15 , OCO2R 15 , OCON(R 15 )R 16 , COR 15 , CO2R 15 , CON(R 15 )R 16 , SOR 15 , SO2R 15 , SO2N(R 15 )R 16 , NR 17 CO2R 15 , NR 17 , COR 15 , NR 17 , C(O)N(R 15 )R 16 , NR 17 , SOR 15 , NR 17 , SO2R 15 , NR 17 , SO2N(R 15 )R 16 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3- to 10-membered heterocyclic group C1-C8 alkyl, optionally substituted C3-C 10 carbocyclic group C1-C8 alkyl, optionally substituted C3-C 10 carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted aryl, and optionally substituted heteroaryl; or, two R 3The group, together with multiple atoms attached thereto, optionally forms: an optionally substituted C5-C6 carbocyclic group, an optionally substituted 5-6 membered heterocyclic group, an optionally substituted C6 aryl group, and an optionally substituted 5-6 membered heteroaryl group, wherein,

[0105] R 15 , R 16 and R 17 are independently selected from the group consisting of: none, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 carbocyclic group C1-C8 alkyl, optionally substituted 3-10 membered heterocyclic group C1-C8 alkyl, optionally substituted C3-C 10 carbocyclic group, optionally substituted 3-10 membered heterocyclic group, optionally substituted aryl, and optionally substituted heteroaryl, or, R 15 and R 16 , R 15 and R 17 together with the atoms attached thereto form a 3-20 membered heterocyclic group ring;

[0106] 2) The degradation tag is a moiety represented by Formulae 6A, 6B and 6C:

[0107]

[0108] wherein,

[0109] * represents the connection to the linker moiety of the heterobifunctional compound;

[0110] R EV 1 and R EV 2 are each independently selected from the group consisting of: hydrogen, hydroxy, amino, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 aminoalkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 carbocyclic group, optionally substituted 3-10 membered heterocyclic group;

[0111] R EV 2' is a divalent group selected from the group consisting of: none, O, NH, optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene; optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 aminoalkylene, optionally substituted C1-C8 alkylamino C1-C8 alkylene, optionally substituted C3-C 10 carbocyclic group and optionally substituted 3-10 membered heterocyclic group;

[0112] R EV 3 is selected from the group consisting of: hydrogen, optionally substituted -C(O)R EV 7 、-C(O)OR EV 7 、-C(O)NR EV 7 R EV 8 、-P(O)(OR EV 7 )2 and -CR EV 7 R EV 8 -OP(O)(OR EV 9 )2, wherein,

[0113] R EV 7 、R EV 8 and R EV 9 are each independently selected from the group consisting of: hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 aminoalkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 carbocyclic group, optionally substituted 3-10 membered heterocyclic group, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl and optionally substituted heteroaryl;

[0114] R EV 4 is selected from the group consisting of: -N(R EV 10 )R EV 11 、-OR EV 10 、-N(R EV 10)C(O)R EV 11 and optionally substituted C3-C 10 carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted aryl group, and optionally substituted heteroaryl group;

[0115] R EV 4 ' is a divalent group selected from the group consisting of: -N(R EV 10 )-, -O-, -N(R EV 10 )C(O)R EV 11 '- and optionally substituted C3-C 10 carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted aryl group, and optionally substituted heteroaryl group;

[0116] R EV 10 is selected from the group consisting of: hydrogen, optionally substituted C1-C8 alkyl group, optionally substituted C3-C8 cycloalkyl group, optionally substituted C1-C8 alkyl-CO, optionally substituted C1-C8 cycloalkyl-CO, optionally substituted C3-C8 cycloalkyl-C1-C8 alkyl-CO, optionally substituted 3- to 10-membered heterocyclic group-CO, optionally substituted 3- to 10-membered heterocyclic group-C1-C8 alkyl-CO, optionally substituted aryl group-CO, optionally substituted aryl group-C1-C8 alkyl-CO, optionally substituted heteroaryl group-CO, optionally substituted heteroaryl group-C1-C8 alkyl-CO, optionally substituted aryl group, and optionally substituted heteroaryl group;

[0117] R EV 11 is selected from the group consisting of: hydrogen, optionally substituted C1-C8 alkyl group, optionally substituted C3-C8 cycloalkyl group, optionally substituted 3- to 8-membered heterocycloalkyl group, optionally substituted C3-C8 carbocyclic group, and optionally substituted C3-C8 heterocyclic group;

[0118] R EV 11 ', each occurrence of which is independently a divalent group selected from the group consisting of: none, O, optionally substituted C1-C8 alkylene group, optionally substituted C3-C8 cycloalkylene group, optionally substituted 3- to 8-membered heterocycloalkylene group, optionally substituted C3-C8 carbocyclic group, and optionally substituted C3-C8 heterocyclic group;

[0119] R EV 5 is selected from the group consisting of: hydrogen and halogen (such as F); and

[0120] R EV 6Selected from: hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 cycloalkyl, optionally substituted C1-C8 alkoxy and optionally substituted C1-C8 cycloalkoxy, optionally substituted C1-C8 heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;

[0121] Alternatively, the degradation tag is the moiety shown in Formula 5, and the degradation tag is attached to the linker moiety of the heterobifunctional compound via Z E ;

[0122]

[0123] wherein ring A E , L E , Z E and R E 1 are as defined below;

[0124] and 3) the linker moiety is as shown in Formula 9:

[0125]

[0126] wherein,

[0127] A L , W L 1 , W L 2 and B L , each time they appear, are each independently a divalent moiety selected from the group consisting of: none, R L d -R L e , R L d COR L e , R L d C(O)OR L e , R L d C(O)N(R L 1 )R L e , R L d C(S)N(R L 1 )R L e , R L d OR L e , RL d SR L e , R L d SOR L e , R L d S02R L e , R L d SO2N(R L 1 )R L e , R L d N(R L 1 )R L e , R L d N(R L 1 )COR L e , R L d N(R L 1 )CON(R L 2 )R L e , R L d N(R L 1 )C(S)R L e , optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 heteroalkenylene, optionally substituted C2-C8 heteroalkynylene, optionally substituted C1-C8 alkoxyC1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C3-C 13 cycloalkyl, optionally substituted 3-13 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl (preferably, A L , W L 1 , W L 2 and B L , at each occurrence, is independently a divalent moiety selected from the group consisting of: none, R L d -R L e, R L d COR L e , R L d C(O)OR L e , R L d C(O)N(R L 1 )R L e , R L d C(S)N(R L 1 )R L e , R L d OR L e , R L d SR L e , R L d SOR L e , R L d SO2R L e , R L d SO2N(R L 1 )R L e , R L d N(R L 1 )R L e , R L d N(R L 1 )COR L e , R L d N(R L 1 )CON(R L 2 )R L e , R L d N(R L 1 )C(S)R L e, optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C3-C 13 cycloalkyl, optionally substituted 3-13 membered heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl); wherein,

[0128] R L d and R L e , each independently selected from: nothing, R L r , optionally substituted (C1-C8 alkylene)-R L r (preferably, CH2-R L r ), optionally substituted R L r -(C1-C8 alkylene), optionally substituted (C1-C8 alkylene)-R L r -(C1-C8 alkylene), or a divalent moiety comprising: optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 heteroalkenylene, optionally substituted C2-C8 heteroalkynylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 alkylamino C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C3-C 13 cycloalkyl, optionally substituted 3-13 membered heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl (preferably, R L d and R L e , each independently selected from: nothing, R L r , optionally substituted (C1-C8 alkylene)-R L r (preferably, CH2-R L r ), optionally substituted R L r -(C1-C8 alkylene), optionally substituted (C1-C8 alkylene)-R L r-(C1-C8 alkylene), or a divalent moiety comprising: optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkoxyC1-C8 alkylene, optionally substituted C1-C8 alkylaminoC1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C3-C 13 cycloalkyl, optionally substituted 3- to 13-membered heterocyclic group, optionally substituted aryl, and optionally substituted heteroaryl);

[0129] R L r , and in each occurrence, is selected from: optionally substituted C3-C 10 carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted aryl, and optionally substituted heteroaryl;

[0130] R L 1 and R L 2 , and in each occurrence, are each independently selected from the group consisting of: hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 heteroalkenyl, optionally substituted C2-C8 heteroalkynyl, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C3-C 10 carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted aryl, and optionally substituted heteroaryl (preferably, R L 1 and R L 2 , and in each occurrence, are each independently selected from the group consisting of: hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C3-C 10 carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted aryl, and optionally substituted heteroaryl);

[0131] R L d and R L e 、R L 1 and R L2 , R L d and R L 1 , R L d and R L 2 , R L e and R L 1 , or R L e and R L 2 optionally form, together with (one or more) atoms connected thereto, a C3-C 20 carbocyclic group or a 3- to 20-membered heterocyclic group ring; and

[0132] m L is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.

[0133] In some embodiments, the cycloalkyl group includes a monocyclic carbocyclic group, a fused cycloalkyl group, a bridged cycloalkyl group or a spirocycloalkyl group.

[0134] In some embodiments, the carbocyclic group includes a monocyclic carbocyclic group, a fused carbocyclic group, a spirocarbocyclic group or a bridged carbocyclic group.

[0135] In some embodiments, the heterocyclic group includes a monocyclic heterocyclic group, a bridged heterocyclic group, a fused heterocyclic group or a spiroheterocyclic group.

[0136] In some embodiments, the aryl group includes a monocyclic aryl group, a bicyclic fused aryl group or a tricyclic fused aryl group.

[0137] In some embodiments, the heteroaryl group includes a monocyclic heteroaryl group, a bicyclic fused heteroaryl group or a tricyclic fused heteroaryl group.

[0138] In some embodiments, each C3-C 13 cycloalkyl group, each time it appears, is independently selected from: C3-C 10 monocyclic carbocyclic group, C4-C 13 fused cycloalkyl group, C5-C 13 bridged cycloalkyl group or C5-C 13 spirocycloalkyl group.

[0139] In some embodiments, the C3-C 13 carbocyclic group, each time it appears, is independently selected from: C3-C 10 monocyclic carbocyclic group, C4-C 13 fused carbocyclic group, C5-C 13 spirocarbocyclic group or C5-C13 Bridged carbocyclic group.

[0140] In some embodiments, the 3- to 13-membered heterocyclic group, each occurrence of which is independently selected from: a 3- to 10-membered monocyclic heterocyclic group, a 5- to 13-membered bridged heterocyclic group, a 5- to 13-membered fused heterocyclic group, or a 5- to 13-membered spiro heterocyclic group.

[0141] In some embodiments, the aryl group, each occurrence of which is independently selected from: a monocyclic aryl group, a bicyclic fused aryl group, or a tricyclic fused aryl group.

[0142] In some embodiments, the heteroaryl group, each occurrence of which is independently selected from: a monocyclic heteroaryl group, a bicyclic fused heteroaryl group, or a tricyclic fused heteroaryl group.

[0143] In some preferred embodiments, the TYK2 ligand is the moiety shown in Formula 1.

[0144] In some embodiments, the TYK2 ligand is the moiety shown in Formula 1-1, 1-2, 2-1, or 2-2:

[0145]

[0146] Wherein,

[0147] X, Y, Z 1 and Z 2 are each independently selected from the group consisting of: CR 6 and N, wherein,

[0148] R 6 , each occurrence of which is independently selected from the group consisting of: none, hydrogen, halogen, CN, NO2, OR 7 , SR 7 , NR 7 R 8 , OCOR 7 , OCO2R 7 , OCON(R 7 )R 8 , COR 7 , CO2R 7 , CON(R 7 )R 8 , SOR 7 , SO2R 7 , SO2N(R 7 )R 8 , NR 9 CO2R 7 , NR 9 , COR 7 , NR 9 , C(O)N(R 7 )R8 , NR 9 SOR 7 , NR 9 SO2R 7 , NR 9 SO2N(R 7 )R 8 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-10 membered heterocyclic C1-C8 alkyl, optionally substituted C3-C 10 carbocyclic C1-C8 alkyl, optionally substituted C3-C 10 carbocyclic, optionally substituted 3-10 membered heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;

[0149] L, ring A, R 1 , R 2 , R 1 ', R 2 ', R 3 , R 7 , R 8 and R 9 as defined in Formula 1 or 2:

[0150] Ring B is selected from: optionally substituted 5-6 membered carbocyclic, optionally substituted 5-6 membered heterocyclic, optionally substituted aryl, optionally substituted heteroaryl; and

[0151] R 18 represents one or more groups each independently selected from the group consisting of: nothing, hydrogen, halogen, CN, NO2, OR 19 , SR 19 , NR 19 R 20 , OCOR 19 , OCO2R 19 , OCON(R 19 )R 20 , COR 19 , CO2R 19 , CON(R 19 )R 20 , SOR 19 , SO2R 19 , SO2N(R 19 )R 20 , NR 21 CO2R 19 , NR 21 , COR 19 , NR 21 , C(O)N(R 19)R 20 、NR 21 SOR 19 、NR 21 SO2R 19 、NR 21 SO2N(R 19 )R 20 、 optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-10 membered heterocyclic C1-C8 alkyl, optionally substituted C3-C 10 carbocyclic C1-C8 alkyl, optionally substituted C3-C 10 carbocyclic, optionally substituted 3-10 membered heterocyclic, optionally substituted aryl and optionally substituted heteroaryl; or, two R 5 groups and the atoms attached to them together optionally form: optionally substituted 5-6 membered carbocyclic, optionally substituted 5-6 membered heterocyclic, optionally substituted C6 aryl and optionally substituted 5-6 membered heteroaryl, wherein,

[0152] R 19 、R 20 and R 21 each independently selected from: none, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 carbocyclic C1-C8 alkyl, optionally substituted 3-10 membered heterocyclic C1-C8 alkyl, optionally substituted C3-C 10 carbocyclic, optionally substituted 3-10 membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl, or, R 19 and R 20 、R 19 and R 21 and the atoms attached to them together form a 3-20 membered heterocyclic ring.

[0153] In some embodiments, the TYK2 ligand is the moiety shown in Formula 1-1.

[0154] In some embodiments, the TYK2 ligand is the moiety shown in Formula 1-1A, 1-1B, 1-2A, 1-2B, 1-2C, 2-1A, 2-1B, 2-2A, 2-2B or 2-2C:

[0155]

[0156] wherein, L, ring A, R 1 , R 2 , R 1 ', R 2 ' and R 3 are defined as in Formulas 1 and 2; and ring B, X, Y, and R 18 are defined as in Formulas 1-1, 1-2, 2-1, and 2-2.

[0157] In some embodiments, the TYK2 ligand is the moiety shown in Formula 1-1A.

[0158] In some embodiments, ring B is selected from: optionally substituted 5- to 6-membered heterocyclic groups and optionally substituted 5- to 6-membered heteroaryl groups.

[0159] In some embodiments, ring B is selected from: optionally substituted 5-membered heteroaryl groups.

[0160] In some embodiments, the TYK2 ligand is the moiety shown in Formula 1-2D, 1-2E, 1-2F, 2-2D, 2-2E, or 2-2F:

[0161]

[0162]

[0163] wherein,

[0164] L, ring A, R 1 , R 2 , R 1 ', R 2 ' and R 3 are defined as in Formula 1 or 2;

[0165] V 1 and V 2 each independently selected from: CH and N; and

[0166] X, Y, R 18 are defined as in Formulas 1-1, 1-2, 2-1, or 2-2.

[0167] In some embodiments, the TYK2 ligand is the moiety shown in Formula 1-2G or 2-2G.

[0168]

[0169] wherein,

[0170] L, ring A, R 1 , R 2 , R 1 ', R 2 ' and R 3As defined in Formula 1 or 2;

[0171] X, Y, and R 18 As defined in Formulas 1-1, 1-2, 2-1, and 2-2.

[0172] In some embodiments, the TYK2 ligand is a moiety represented by Formula 1-1C, 1-1D, 1-2H, 2-1C, 2-1D, or 2-2H:

[0173]

[0174]

[0175] wherein,

[0176] L, Ring A, R 1 , R 2 , R 1 ', R 2 ', and R 3 As defined in Formula 1 or 2; and

[0177] R 6 and R 18 As defined in Formulas 1-1, 1-2, 2-1, and 2-2.

[0178] In some preferred embodiments, the TYK2 ligand is a moiety represented by Formula 1-1C.

[0179] In some embodiments, Ring A is selected from: optionally substituted 5-6-membered carbocyclic group, optionally substituted 5-6-membered heterocyclic group, optionally substituted C6 aryl group, and optionally substituted 5-6-membered heteroaryl group.

[0180] In some embodiments, Ring A is selected from: optionally substituted phenyl or pyridone.

[0181] In some embodiments, the TYK2 ligand is a moiety represented by Formula 1-1E, 1-1F, 1-2I, 2-1E, 2-1F, or 2-2I:

[0182]

[0183] wherein,

[0184] L, R 1 , R 2 , R 1 ', R 2 ', and R 3 As defined in Formula 1 or 2; and

[0185] R 6 and R 18 As defined in Formulas 1-1, 1-2, 2-1, and 2-2.

[0186] In some preferred embodiments, the TYK2 ligand is the moiety shown in Formula 1-1E.

[0187] In some embodiments, L is selected from: CR 4 R 5 、NR 4 and O.

[0188] In some embodiments, R 4 and R 5 are each independently selected from: H, halogen, hydroxy, amino, cyano, nitro, optionally substituted C1-C6 alkyl, and optionally substituted C3-C6 cycloalkyl. In some embodiments, R 4 and R 5 are independently selected from: H, halogen, optionally substituted C1-C6 alkyl, and optionally substituted C3-C6 cycloalkyl. In some embodiments, R 4 and R 5 are independently selected from: H, F, Me, Et, iPr, and cPr.

[0189] In some embodiments, L is selected from: NH and N(CH3). In some embodiments, L is NH.

[0190] In some embodiments, the TYK2 ligand is the moiety shown in Formula 1-1G, 1-1H, 1-2J, 2-1G, 2-1H, or 2-2J:

[0191]

[0192] wherein,

[0193] R 1 、R 2 、R 1 ', R 2 ' and R 3 are as defined in Formula 1 or 2; and

[0194] R 6 and R 18 are as defined in Formula 1-1, 1-2, 2-1, and 2-2.

[0195] In some embodiments, the TYK2 ligand is the moiety shown in Formula 1-1G.

[0196] In some embodiments, R 6 , upon each occurrence, is independently selected from the group consisting of: hydrogen, halogen, CN, NO2, COR 7 , CON(R 7 )R 8, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C3-C 10 carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, wherein,

[0197] R 7 and R 8 are independently selected from the group consisting of: nothing, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 carbocyclic group C1-C8 alkyl, optionally substituted 3- to 10-membered heterocyclic group C1-C8 alkyl, optionally substituted C3-C 10 carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl, or, R 7 and R 8 together with the atoms to which they are attached form: a 3- to 20-membered heterocyclic ring.

[0198] In some embodiments, the TYK2 ligand is a moiety represented by Formula 1-1I, 1-1J, 1-2K, 2-1I, 2-1J or 2-2K:

[0199]

[0200] wherein,

[0201] R 22 is R 7 or NHR 7 ;

[0202] R 23 is as defined for R 3 ;

[0203] L, R 1 、R 2 、R 1 ', R 2 ', R 3 、R 7 and R 8 are as defined in Formulas 1 and 2; and, R 6 is as defined in Formulas 1-1, 1-2, 2-1 and 2-2.

[0204] In some embodiments, the TYK2 ligand comprises Formulas 1-1I and 2-1I.

[0205] In some embodiments, the TYK2 ligand comprises Formula 1-1I.

[0206] In some embodiments, R 1 and R 2 are independently selected from the group consisting of: none, hydrogen, halogen, CN, NO2, OR 10 、NR 10 R 11 、COR 10 、CONR 10 R 11 、optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C 10 carbocyclic group, optionally substituted 3-10 membered heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl, wherein,

[0207] R 10 and R 11 are independently selected from the group consisting of: none, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C 10 carbocyclic group, optionally substituted 3-10 membered heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl, or, R 10 and R 11 together with the atom(s) to which they are attached optionally form: a 3-20 membered heterocyclic ring.

[0208] In some embodiments, R 1 is selected from: COR 10 、optionally substituted C1-C8 alkyl, optionally substituted C3-C 10 carbocyclic group, optionally substituted 3-10 membered heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl, wherein, R 10 is selected from: none, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C3-C 10 carbocyclic group, optionally substituted 3-10 membered heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl.

[0209] In some embodiments, R 1 is selected from: optionally substituted C(O)-cPr, optionally substituted methyl, optionally substituted pyridyl, optionally substituted phenyl, optionally substituted pyrazinyl, optionally substituted pyrimidinyl, optionally substituted pyridazinyl, optionally substituted triazinyl, optionally substituted pyrrolyl, optionally substituted furyl, optionally substituted thienyl, optionally substituted imidazolyl, optionally substituted pyrazolyl, optionally substituted oxazolyl, optionally substituted isoxazolyl, optionally substituted thiazolyl, optionally substituted isothiazolyl, optionally substituted triazolyl, optionally substituted oxadiazolyl, optionally substituted thiadiazolyl and optionally substituted tetrazolyl.

[0210] In some embodiments, R1 Selected from: optionally substituted C(O)-cPr, optionally substituted pyridyl, and optionally substituted methyl.

[0211] In some embodiments, R 2 is selected from: H, CN, halogen, CO2R 10 , CONR 10 R 11 , optionally substituted aryl, and optionally substituted heteroaryl. In some embodiments, R 2 is selected from: optionally substituted aryl and optionally substituted heteroaryl.

[0212] In some embodiments, R 2 is selected from the group consisting of: H, CN, F, Cl, Br, CO2H, CONH2, CONHCH3, optionally substituted triazolyl, optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrazinyl, optionally substituted pyrimidinyl, optionally substituted pyridazinyl, triazinyl, optionally substituted pyrrolyl, furyl, optionally substituted thienyl, optionally substituted imidazolyl, optionally substituted pyrazolyl, optionally substituted oxazolyl, optionally substituted isoxazolyl, optionally substituted thiazolyl, optionally substituted isothiazolyl, optionally substituted oxadiazolyl, optionally substituted thiadiazolyl, and optionally substituted tetrazolyl.

[0213] In some embodiments, R 2 is selected from the group consisting of: optionally substituted triazolyl, optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrazinyl, optionally substituted pyrimidinyl, optionally substituted pyridazinyl, triazinyl, optionally substituted pyrrolyl, furyl, optionally substituted thienyl, optionally substituted imidazolyl, optionally substituted pyrazolyl, optionally substituted oxazolyl, optionally substituted isoxazolyl, optionally substituted thiazolyl, optionally substituted isothiazolyl, optionally substituted oxadiazolyl, optionally substituted thiadiazolyl, and optionally substituted tetrazolyl.

[0214] In some embodiments, R 2 is selected from: H, CN, F, Cl, Br, CO2H, CONH2, CONHCH3, optionally substituted triazolyl, and optionally substituted phenyl. In some embodiments, R 2 is selected from: optionally substituted triazolyl and optionally substituted phenyl.

[0215] In some embodiments, the substituent(s) for R 2 are each independently an optionally substituted group selected from the following: CN, F, Cl, Br, C1-C8 alkyl (such as C1-C4 alkyl), C3-C8 carbocyclic group (such as cyclopropyl), and C1-C8 haloalkyl (such as C1-C4 haloalkyl).

[0216] In some embodiments, R 1 ' and R2 2 ' are selected from the group consisting of: none, R'-R", R'OR", R'SR", R'N(R 13 )R", R'OC(O)R", R'OC(O)OR", R'OCON(R 13 )R", R'C(O)R", R'C(O)OR", R'CON(R 13 )R", R'S(O)R", R'S(O)2R", R'SO2N(R 13 )R", R'NR 14 C(O)OR", R'NR 14 C(O)R", R'NR 14 C(O)N(R 13 )R", R'NR 14 S(O)R", R'NR 14 S(O)2R" and R'NR 14 S(O)2NR 13 R", optionally substituted C1-C8 alkylene, optionally substituted C3-C 13 carbocyclic group, optionally substituted 3-13 membered heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl, wherein R' and R" are divalent groups independently selected from the group consisting of: none, optionally substituted C1-C8 alkylene (such as CH2).

[0217] In some embodiments, R 1 ' (in formula 1) is a divalent group selected from the group consisting of: none, R'-R", R'C(O)R", optionally substituted C3-C 13 carbocyclic group, optionally substituted 3-13 membered heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl; and wherein,

[0218] R' and R" are divalent groups independently selected from the group consisting of: none, optionally substituted C2-C8 alkynylene, optionally substituted C3-C 10 carbocyclic group, optionally substituted 3-10 membered heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl. In some embodiments, R 1 ' is selected from the group consisting of: C(O), optionally substituted C(O)-CH2, optionally substituted pyridyl, (optionally substituted pyridyl)-(C2 alkynylene) and (optionally substituted pyridyl)-(optionally substituted piperazinyl)-. In further embodiments, R 1 ' is selected from the group consisting of: C(O), C(O)-CH2,

[0219] In some embodiments, R 1' is a divalent group selected from the following: optionally substituted C1-C8 alkylene, optionally substituted C3-C 13 carbocyclic group, optionally substituted 3-13 membered heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl.

[0220] In some embodiments, R 1 ' is selected from: C(O), optionally substituted C(O)-CH2 and optionally substituted pyridyl.

[0221] In some embodiments, R 2 ' is a divalent group selected from the following: none, CO, CON(R 13 ), optionally substituted aryl and optionally substituted heteroaryl. In some embodiments, R 2 ' is a divalent group selected from the following: optionally substituted aryl and optionally substituted heteroaryl.

[0222] In some embodiments, R 2 ' is a divalent group selected from the group consisting of: none, CO, CONH, optionally substituted triazolyl, optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrazinyl, optionally substituted pyrimidinyl, optionally substituted pyridazinyl, triazinyl, optionally substituted pyrrolyl, furyl, optionally substituted thienyl, optionally substituted imidazolyl, optionally substituted pyrazolyl, optionally substituted oxazolyl, optionally substituted isoxazolyl, optionally substituted thiazolyl, optionally substituted isothiazolyl, optionally substituted oxadiazolyl, optionally substituted thiadiazolyl and optionally substituted tetrazolyl.

[0223] In some embodiments, R 2 ' is a divalent group selected from the group consisting of: optionally substituted triazolyl, optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrazinyl, optionally substituted pyrimidinyl, optionally substituted pyridazinyl, triazinyl, optionally substituted pyrrolyl, furyl, optionally substituted thienyl, optionally substituted imidazolyl, optionally substituted pyrazolyl, optionally substituted oxazolyl, optionally substituted isoxazolyl, optionally substituted thiazolyl, optionally substituted isothiazolyl, optionally substituted oxadiazolyl, optionally substituted thiadiazolyl and optionally substituted tetrazolyl.

[0224] In some embodiments, R 2 ' is a divalent group selected from the following: none, CO, CONH, optionally substituted triazolyl and optionally substituted phenyl. In some embodiments, R 2 ' is a divalent group selected from the following: optionally substituted triazolyl and optionally substituted phenyl.

[0225] In some embodiments, for R 2The substituent(s) of 'is / are' independently an optionally substituted group selected from the following: CN, F, Cl, Br, C1-C8 alkyl (such as C1-C4 alkyl), C3-C8 carbocyclic group (such as cyclopropyl), and C1-C8 haloalkyl (such as C1-C4 haloalkyl).

[0226] In some embodiments, R 3 and R 6 each independently selected from the group consisting of: H, CN, halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, (optionally substituted C1-C6 alkyl)-S(O)2-, (optionally substituted C1-C6 alkyl)-C(O)-, (optionally substituted C1-C6 alkyl)-NH-C(O)-, optionally substituted 3-6 membered carbocyclic group, and optionally substituted 3-6 membered heterocyclic group.

[0227] In some embodiments, the TYK2 ligand is a moiety represented by Formula 1-1I, 1-1J, 1-2K, 2-1I, 2-1J, or 2-2K; and R 3 and R 6 are independently selected from the group consisting of: H, halogen, optionally substituted C1-C6 alkyl, optionally substituted 3-6 membered carbocyclic group, and optionally substituted 3-6 membered heterocyclic group.

[0228] In some embodiments, the TYK2 ligand is a moiety represented by Formula 1-1I, 1-1J, 1-2K, 2-1I, 2-1J, or 2-2K; and R 3 and R 6 are independently selected from the group consisting of: H, F, Cl, Me, Et, iPr, and cPr.

[0229] In some embodiments, the TYK2 ligand is a moiety represented by Formula 1-1I, 1-1J, 1-2K, 2-1I, 2-1J, or 2-2K; and R 22 is selected from: optionally substituted NH2, optionally substituted C1-C6 alkylamino, optionally substituted C3-C6 cycloalkylamino, optionally substituted C1-C6 alkyl, and optionally substituted 3-6 membered carbocyclic group.

[0230] In some embodiments, the TYK2 ligand is a moiety represented by Formula 1-1I, 1-1J, 1-2K, 2-1I, 2-1J, or 2-2K; and R 22 is selected from: NH2, NHMe, NHCD3, Me, Et, CD3, CH2CD3, iPr, and cPr.

[0231] In some embodiments, the TYK2 ligand is a moiety represented by Formula 1-1I, 1-1J, 1-2K, 2-1I, 2-1J, or 2-2K; and R 22Selected from: NH2, NHMe, NHCD3, Me, Et, iPr and cPr.

[0232] In some embodiments, the TYK2 ligand is a moiety represented by Formula 1-1I, 1-1J, 1-2K, 2-1I, 2-1J or 2-2K; and R 23 is selected from: hydrogen, halogen, CN, NO2, OR 15 , SR 15 , NR 15 R 16 , COR 15 , CON(R 15 )R 16 , SOR 15 , SO2R 15 , SO2N(R 15 )R 16 , optionally substituted C1-C8 alkyl, optionally substituted C3-C 10 carbocyclic group, optionally substituted 3-10 membered heterocyclic group, wherein,

[0233] R 15 and R 16 are independently selected from: hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C3-C 10 carbocyclic group, optionally substituted 3-10 membered heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl.

[0234] In some embodiments, the TYK2 ligand is a moiety represented by Formula 1-1I, 1-1J, 1-2K, 2-1I, 2-1J or 2-2K; and R 23 is selected from: H, F, OMe, CONH2, CONHMe, SMe, SOMe, SO2Me, OCD3, CONHCD3, SCD3, SOCD3 and SO2CD3.

[0235] In some embodiments, the degradation tag is a moiety represented by Formula 6A, 6B or 6C; and, R EV 1 is selected from isopropyl and tert-butyl.

[0236] In some embodiments, the degradation tag is a moiety represented by Formula 6A-1, 6B-1, 6C-1, 6A-2, 6B-2 or 6C-2:

[0237]

[0238] wherein, R EV 2 , R EV 2 ', R EV3 , R EV 4 , R EV 4 ', R EV 5 and R EV 6 as defined in Formulas 6A, 6B, and 6C.

[0239] In some embodiments, R EV 2 is an optionally substituted C1-C8 alkyl; preferably, an optionally substituted C1-C4 alkyl; more preferably, R EV 2 is Me.

[0240] In some embodiments, R EV 2 is H or Me. In some embodiments, R EV 2 is Me.

[0241] In some embodiments, R EV 2 ' is none or CH2.

[0242] In some embodiments, the degradation tag is a moiety represented by Formula 6A-3, 6B-3, 6C-3, 6A-4, 6B-4, or 6C-4:

[0243]

[0244] wherein R EV 1 , R EV 3 , R EV 4 , R EV 4 ', R EV 5 and R EV 6 are as defined in Formulas 6A, 6B, and 6C.

[0245] In some embodiments, R EV 3 is H.

[0246] In some embodiments, the degradation tag is a moiety represented by Formula 6A-5, 6B-5, or 6C-5:

[0247]

[0248] wherein,

[0249] REV 1 and R EV 2 ', R EV 2 ', R EV 4 and R EV 4 ', R EV 5 and R EV 6 as defined in Formulas 6A, 6B, and 6C.

[0250] In some embodiments, R EV 5 is H or F; preferably, it is H.

[0251] In some embodiments, the degradation tag is a moiety represented by Formulas 6A-6, 6B-6, 6C-6, 6A-7, 6B-7, or 6C-7:

[0252]

[0253] wherein

[0254] R EV 1 and R EV 2 and R EV 2 ', R EV 3 and R EV 4 and R EV 4 ', and R EV 6 are as defined in Formulas 6A, 6B, and 6C.

[0255] In some embodiments, R EV 6 is selected from: hydrogen, halogen, cyano, optionally substituted aryl, and optionally substituted heteroaryl,

[0256] In some embodiments, R EV 6 is selected from the group consisting of: halogen, cyano, optionally substituted thiazole, optionally substituted oxazole, optionally substituted imidazole, optionally substituted pyrazole, optionally substituted oxadiazole, optionally substituted triazole, and optionally substituted isoxazole.

[0257] In some embodiments, R EV 6 is methylthiazole. In some embodiments, R EV 6 is

[0258] In some embodiments, the degradation tag is a moiety represented by Formula 6A-8, 6B-8 or 6C-8:

[0259]

[0260] wherein,

[0261] R EV 1 、R EV 2 、R EV 2 '、R EV 3 、R EV 4 、R EV 4 ' and R EV 5 are as defined in Formulas 6A, 6B and 6C.

[0262] In some embodiments, R EV 4 is selected from: -N(R EV 10 )R EV 11 、-N(R EV 10 )C(O)R EV 11 、 and / or, R EV 4 ' is selected from: -N(R EV 10 )-、-N(R EV 10 )C(O)R EV 11 '-、 wherein,

[0263] * represents the attachment to the linker moiety of the heterobifunctional compound;

[0264] R EV 10Selected from: none, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 cycloalkyl, optionally substituted C1-C8 alkyl-CO, optionally substituted C3-C8 cycloalkyl-CO, optionally substituted C3-C8 cycloalkyl-C1-C8 alkyl-CO, optionally substituted 3-10 membered heterocyclic group-CO, optionally substituted 3-10 membered heterocyclic group-C1-C8 alkyl-CO, optionally substituted aryl-CO, optionally substituted aryl-C1-C8 alkyl-CO, optionally substituted heteroaryl-CO, optionally substituted heteroaryl-C1-C8 alkyl-CO, optionally substituted aryl, and optionally substituted heteroaryl;

[0265] R EV 11 Selected from: none, hydrogen, optionally substituted C1-C8 alkyl, and optionally substituted C3-C8 cycloalkyl, and optionally substituted 3-8 membered heterocycloalkyl, optionally substituted C3-C8 carbocyclic group, and optionally substituted C3-C8 heterocyclic group;

[0266] R EV 11 ', each occurrence of which is independently a divalent group selected from: none, O, optionally substituted C1-C8 alkylene, optionally substituted C3-C8 cycloalkylene, optionally substituted C3-C8 heterocycloalkylene, optionally substituted C3-C8 carbocyclic group and optionally substituted C3-C8 heterocyclic group;

[0267] R EV 12 , each occurrence of which is independently selected from: hydrogen, halogen, cyano, optionally substituted C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3-8 membered heterocycloalkyl, optionally substituted C1-C8 alkoxy and optionally substituted C3-C8 cycloalkoxy;

[0268] X EV Selected from: CH and N; and

[0269] n EV is 0, 1, 2, 3 or 4.

[0270] In some embodiments, for R EV 11 and R EV 11 ', the substituent(s) is / are independently an optionally substituted group selected from: C1-C4 alkyl, C1-C4 haloalkyl, halogen and CN.

[0271] In some embodiments, R EV 4 is selected from: NH2, NHC(O)Me,

[0272] In some embodiments, R EV 4 ' is selected from: NH, C(O)NH, CH2C(O)NH,

[0273] In some embodiments, the degradation tag is a moiety represented by Formula 6A-9, 6A-10, 6A-11, 6A-12, 6A-13, 6B-9, 6B-10, 6B-11, 6B-12, 6B-13, 6B-14, 6B-15, 6C-9, 6C-10, 6C-11, 6C-12, 6C-13, 6C-14 or 6C-15:

[0274]

[0275] wherein R EV 1 , R EV 2 , R EV 2 ', R EV 3 , R EV 5 and R EV 6 are as defined in Formulas 6A, 6B and 6C.

[0276] In some embodiments, the degradation tag is a moiety represented by any one of Formulas 7A to 7BJ:

[0277]

[0278]

[0279] In a further embodiment, the degradation tag is a moiety represented by Formula 5, and the degradation tag is attached to the linker moiety of the heterobifunctional compound via Z E ;

[0280]

[0281] wherein,

[0282] Z E is a divalent group represented by -(R E z ) nE -; wherein the subscript n E = 0, 1, 2, 3, 4, 5 or 6; wherein R E Z , each occurrence, is independently R Er or R E w ; wherein, R E w , each time it appears, is a bond or selected from the group consisting of: -CO-, -CR E 5 R E 6 -, -NR E 5 -, -O-, -S-, -S(O)-, -S(O)2-, -C≡C-, optionally substituted C1-C 10 alkylene, optionally substituted C2-C 10 alkenylene, optionally substituted C2-C 10 alkynylene; and R E r , each time it appears, is a bond or selected from the group consisting of: optionally substituted C3-C 10 carbocyclic group such as 3- to 13-membered carbocyclic group, optionally substituted 3- to 13-membered heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl (preferably, R E w , each time it appears, is a bond or selected from the group consisting of: -CO-, -CR E 5 R E 6 -, -NR E 5 -, -O-, optionally substituted C1-C 10 alkylene, optionally substituted C2-C 10 alkenylene, optionally substituted C2-C 10 alkynylene; and R E r , each time it appears, is a bond or selected from the group consisting of: optionally substituted C3-C 10 carbocyclic group such as 3- to 13-membered carbocyclic group, optionally substituted 3- to 13-membered heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl); provided that -R E z -R E z - is not -O-O-;

[0283] R E 5 and R E 6 , each time it appears, is independently selected from the group consisting of: hydrogen, halogen, oxo group, hydroxy group, amino group, cyano group, nitro group, optionally substituted C1-C6 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkylamino, optionally substituted 3- to 8-membered carbocyclic group and optionally substituted 3- to 8-membered heterocyclic group; or, RE 5 and R E 6 , together with the atom(s) to which they are attached, optionally form: an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 8-membered heterocyclic group (preferably, R E 5 and R E 6 , each time it appears, is independently selected from the group consisting of: hydrogen, halogen, oxo, hydroxy, amino, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3- to 8-membered carbocyclic group, and optionally substituted 3- to 8-membered heterocyclic group; or, R E 5 and R E 6 , together with the atom(s) to which they are attached, optionally form: an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 8-membered heterocyclic group):

[0284] R E 1 is selected from the group consisting of: hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted 3- to 8-membered carbocyclic group, and optionally substituted 3- to 8-membered heterocyclic group (preferably, R E 1 is selected from the group consisting of: hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3- to 8-membered carbocyclic group, and optionally substituted 3- to 8-membered heterocyclic group);

[0285] L E is a divalent group selected from the group consisting of: none, -L E 1 -, and -L E 1 -L E 2 -; wherein, L E 1 and L E 2 are independently selected from the group consisting of: -CO-, -O-, -CR E 10 R E 11 -, and -NR E 10 -, provided that -L E 1 -L E 2 - is not –O-O-; wherein, R E 10 and R E 11independently selected from the group consisting of: hydrogen, halogen, cyano, nitro, hydroxy, amino, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy and optionally substituted C1-C6 alkylamino;

[0286] Ring A E is a divalent group selected from the group consisting of: Formula A E 1, A E 2, A E 3, A E 4, A E 5, A E 6 and A E 7 (preferably, Ring A E is a divalent group selected from the group consisting of: Formula A E 1, A E 2, A E 3, A E 4 and A E 5):

[0287]

[0288] wherein,

[0289] * represents the connection to L E and Z E is connected to any possible position on Ring A E ;

[0290] is a single bond or a double bond;

[0291] V E 1 、V E 2 、V E 3 、V E 4 and V E 5 , each time it appears, is independently selected from the group consisting of: a bond, C, CR E 2 、S, N and NR E 2 ; or, V E 1 and V E 2 、V E 2 and V E 3 、V E 3 and V E 4 , or V E 4 and VE 5 Combined together, optionally forming a C6 aromatic ring or a 5-, 6- or 7-membered heteroaromatic ring;

[0292] R E 2 , at each occurrence, is independently selected from the group consisting of none, hydrogen, halogen, cyano, nitro, hydroxy, amino, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkylamino, optionally substituted 3-8 membered carbocyclyl, and optionally substituted 3-8 membered heterocyclyl; or, R E 2 and another R E 2 and together with the atoms to which they are attached form: optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl (preferably, R E 2 , at each occurrence, is independently selected from the group consisting of none, hydrogen, halogen, cyano, nitro, hydroxy, amino, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkylamino, optionally substituted 3-8 membered carbocyclyl, and optionally substituted 3-8 membered heterocyclyl; or, R E 2 and another R E 2 and together with the atom(s) to which they are attached form: optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl);

[0293] W E 1 , W E 2 , W E 3 and W E 4 Each is independently selected from the following group: -N=, -C≡, -CR E 3 =, -CO-, -O-, -CR E 3 R E 4 -、-NR E 3 -、-CR E 3=CR E 4 -, -N=CR E 3 -, and -N=N-; or, W E 1 and W E 2 , W E 2 and W E 3 , or W E 3 and W E 4 optionally combine to form a C6 aryl ring or a 5-, 6- or 7-membered heteroaryl ring;

[0294] R E 3 and R E 4 , each occurrence independently selected from the group consisting of: none, hydrogen, halogen, cyano, nitro, hydroxy, amino, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkylamino, optionally substituted arylamino, optionally substituted heteroarylamino, optionally substituted 3- to 8-membered carbocyclic group and optionally substituted 3- to 8-membered heterocyclic group (preferably, R E 3 and R E 4 , each occurrence independently selected from the group consisting of: none, hydrogen, halogen, cyano, nitro, hydroxy, amino, optionally substituted C1-C6 alkyl, optionally substituted 3- to 8-membered carbocyclic group and optionally substituted 3- to 8-membered heterocyclic group); or, R E 3 and R E 4 together with the atom(s) to which they are attached form: an optionally substituted 3-8 membered cycloalkyl group, an optionally substituted 3-8 membered heterocyclic group ring, an optionally substituted aryl group and an optionally substituted heteroaryl group (preferably, R E 3 and R E 4 together with the atom(s) to which they are attached form: an optionally substituted 3-8 membered cycloalkyl or heterocyclic group ring).

[0295] In a further embodiment, R E 2, each occurrence independently selected from the group consisting of: none, hydrogen, halogen, cyano, nitro, hydroxy, amino, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkylamino, optionally substituted 3-8 membered carbocyclic group, and optionally substituted 3-8 membered heterocyclic group.

[0296] In a further embodiment, R E 2 , each occurrence independently selected from the group consisting of: none, hydrogen, halogen, cyano, nitro, hydroxy, amino, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkylamino, optionally substituted 3-8 membered carbocyclic group, and optionally substituted 3-8 membered heterocyclic group.

[0297] In a further embodiment, the degradation tag is the moiety shown in Formula 5, and wherein, V E 1 、V E 2 、V E 3 、V E 4 and V E 5 , each occurrence independently selected from the group consisting of: C, CR E 2 、S、N and NR E 2 ; or, V E 1 and V E 2 、V E 2 and V E 3 、V E 3 and V E 4 , or V E 4 and V E 5 optionally combine together to form a C6 aryl ring or a 5-, 6- or 7-membered heteroaryl ring.

[0298] In a further embodiment, the degradation tag is the moiety shown in Formula 5, and wherein, ring A E is a group consisting of: Formula A E 1, and wherein, V E 1 、VE 2 , V E 3 , and V E 4 are each independently selected from the group consisting of: C, CR E 2 , S, N, and NR E 2 .

[0299] In another embodiment, the degradation tag is the moiety shown in Formula 5, and wherein Ring A E is a group consisting of: Formula A E 2, and wherein V E 1 , V E 2 , V E 3 , V E 4 and V E 5 , in each occurrence, are each independently selected from the group consisting of: C, CR E 2 , S, N, and NR E 2 .

[0300] In another embodiment, the degradation tag is the moiety shown in Formula 5, and wherein Ring A E is a group consisting of: Formula A E 3, and wherein V E 1 , V E 2 , V E 3 , V E 4 and V E 5 are each independently selected from the group consisting of: C, CR E 2 , S, N, and NR E 2 ; or, V E 1 and V E 2 , V E 2 and V E 3 , V E 3 and V E 4 , or V E 4 and VE 5 Optionally combine to form a C6 aryl ring or a 5-, 6- or 7-membered heteroaryl ring.

[0301] In a further embodiment, the degradation tag is the moiety shown in Formula 5, and wherein Ring A E is a group consisting of: Formula A E 4, and wherein is a single bond and W E 1 、W E 2 、W E 3 and W E 4 each independently selected from the group consisting of: -N=, -CR E 3 =, -CO-, -O-, -CR E 3 R E 4 -, and -NR E 3 -.

[0302] In a further embodiment, the degradation tag is the moiety shown in Formula 5, and wherein Ring A E is a group consisting of: Formula A E 5, and wherein V E 1 、V E 2 and V E 3 each independently selected from the group consisting of: CR E 2 、S、N and NR E 2 , provided that at least one of V E 1 、V E 2 and V E 3 is S, N or NR E 2 ; or, V E 1 、V E 2 and V E 3 optionally combine to form a 5-membered heteroaryl ring.

[0303] In a further embodiment, the degradation tag is the moiety shown in Formula 5, and wherein Ring A E is a group consisting of: Formula AE 1. A E 2 and A E 5, and wherein, W E 1 ), W E 2 ), W E 3 and W E 4 each independently selected from the group: -N=, -CR E 3 =, -CO-, -O-, -S-, -CR E 3 R E 4 -, and -NR E 3 -.

[0304] In a further embodiment, the degradation tag is the moiety shown in formula 5, and wherein, ring A E is a group consisting of: formula A E 6, and wherein, is a double bond and W E 1 ), W E 2 ), W E 3 and W E 4 each independently selected from the group: -N=, -CR E 3 =.

[0305] In a further embodiment, the degradation tag is the moiety shown in formula 5, and wherein, ring A E is a group consisting of: formula A E 7, and wherein, is a double bond and W E 1 and W E 4 independently selected from: -CO- and CR E 3 R E 4 -; and, W E 2 and W E 3 each independently selected from the group: -N= and -CR E 3 =.

[0306] In a further embodiment, the degradation tag is the moiety shown in formula 5, and wherein, ring A EA group consisting of the following: Formula A E 7, and wherein is a single bond and W E 1 、W E 2 、W E 3 and W E 4 are each independently selected from the group consisting of: -CO-, -O-, -CR E 3 R E 4 - and -NR E 3 -.

[0307] In another embodiment, the degradation tag is the moiety shown in Formula 5, and wherein R E 1 is selected from: hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3-8 membered carbocyclic group and optionally substituted 3-8 membered heterocyclic group; preferably R E 1 is selected from: hydrogen, halogen, cyano, nitro and C1-C5 alkyl; more preferably R E 1 is selected from: H, CH3 or F.

[0308] In another embodiment, the degradation tag is the moiety shown in Formula 5, and wherein R E 2 is selected from: hydrogen, halogen, cyano, nitro, hydroxy, amino, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkylamino, optionally substituted 3 to 8 membered carbocyclic group and optionally substituted 3 to 8 membered heterocyclic group; preferably, R E 2 is selected from: hydrogen, halogen, cyano, nitro, and C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted 3 to 8 membered carbocyclic group, and optionally substituted 3 to 8 membered heterocyclic group; more preferably, R E 2 is selected from: H, F, Cl, Me, OMe, OCF3, O-iPr or O-cPr (more preferably, R E 2 is selected from: H, F, Cl, Me, OMe, OCF3, O-iPr, or O-cPr).

[0309] In another embodiment, the degradation tag is the moiety shown in Formula 5, and wherein two adjacent R E 2and, together with the atom(s) to which they are attached, optionally form: an optionally substituted 3- to 8-membered cycloalkyl, an optionally substituted 3- to 8-membered heterocyclic group, an optionally substituted aryl, and an optionally substituted heteroaryl.

[0310] In a further embodiment, the degradation tag is the moiety of formula 5, and wherein R E 3 and R E 4 , each time it appears, is independently selected from: hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted arylamino, optionally substituted 3- to 8-membered carbocyclic group, and optionally substituted 3- to 8-membered heterocyclic group; or two independent R E 3 , two independent R E 4 , or R E 3 and R E 4 together with the atom(s) to which they are attached form: a 3- to 8-membered carbocyclic group or a 3- to 8-membered heterocyclic group.

[0311] In a further embodiment, the degradation tag is the moiety of formula 5, and wherein R E 3 and R E 4 , each time it appears, is independently selected from: hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3- to 8-membered carbocyclic group, and optionally substituted 3- to 8-membered heterocyclic group; or, R E 3 and R E 4 together with the atom(s) to which they are attached form a 3- to 8-membered carbocyclic group, or a 3- to 8-membered heterocyclic group.

[0312] In some embodiments, R E 3 and R E 4 , each time it appears, is independently selected from: H, F or Me.

[0313] In a further embodiment, R E r , each time it appears, is selected from the group of R E ; and

[0314] the group of R E consists of optionally substituted cyclic groups as follows:

[0315]

[0316]

[0317] In additional embodiments, the degradation tag is the moiety of formula 5, and wherein, in the Z E group, at most one R E Z is R E r .

[0318] In additional embodiments, the degradation tag is the moiety of formula 5, and wherein, n E = 0, 1, 2 or 3.

[0319] In additional embodiments, the degradation tag is the moiety of formula 5, and wherein, Z E is a divalent group selected from the group consisting of: -R E w -, -(R E w )2-, -(R E w )3-, -R E r -, -R E w -R E r -R E w -, -R E r -R E w - and -R E r -(R E w )2-.

[0320] In additional embodiments, the degradation tag is the moiety of formula 5, and wherein, R E 5 and R E 6 , each time they appear, are independently selected from: a bond, hydrogen, halogen, oxo group, hydroxyl group, amino group, cyano group, nitro group, optionally substituted C1-C6 alkyl, optionally substituted 3- to 8-membered carbocyclic group, and optionally substituted 3- to 8-membered heterocyclic group; or, R E 5 and R E 6 and the atom(s) to which they are attached together form a 3- to 8-membered cycloalkyl ring or heterocyclic ring.

[0321] In additional embodiments, the degradation tag is the moiety of formula 5, and wherein, RE Z Selected from: -CO-, -CR E 5 R E 6 -, -NR E 5 -, -O-, optionally substituted C1-C 10 alkylene, optionally substituted C1-C 10 alkenylene, optionally substituted C1-C 10 alkynylene, optionally substituted 3-8 membered carbocyclic group, optionally substituted 3-8 membered heterocyclic group.

[0322] In a further embodiment, the degradation tag is the moiety shown in Formula 5, and wherein Z E is selected from: a bond, CH2, CH=CH, C≡C, NH and O.

[0323] In a further embodiment, the degradation tag is the moiety shown in Formula 5, and wherein Ring A E is as shown in Formula A E 1, A E 2, A E 3, A E 4, A E 5, A E 6 as shown; and L E is none.

[0324] In a further embodiment, the degradation tag is the moiety shown in Formula 5, and wherein Ring A E is Formula A E 3 and L E is not none.

[0325] In a further embodiment, the degradation tag is the moiety shown in Formula 5, and wherein Ring A E is Formula A E 3 and L E is selected from the group consisting of: -NH-, -N(C1-C4 alkyl)-, -CO-, -NH-CO-, -N(C1-C4 alkyl)-CO-, -CO-NH-, and -CO-N(C1-C4 alkyl)-.

[0326] In a further embodiment, the degradation tag is a moiety selected from the group consisting of: Formula 5-1, 5-2, 5-3, 5-4, 5-5, 5-6, 5-7, 5-8 and 5-9, and the degradation tag is connected to the linker moiety of the heterobifunctional compound via a divalent group Z E ;

[0327]

[0328] Among them,

[0329] Z E 、R E 1 、L E 、 V E 1 、V E 2 、V E 3 、V E 4 、V E 5 、W E 1 、W E 2 、W E 3 and W E 4 are defined in Formula 5.

[0330] In another embodiment, the degradation tag is a moiety selected from the group consisting of Formulas 5A, 5B, 5C, 5D, 5E, F, 5G, 5H, 5I, 5J, 5K, 5L, 5M, 5N, 5O, and 5P;

[0331]

[0332]

[0333] Among them,

[0334] V E 6 、V E 7 、V E 8 、and V E 9 are each independently selected from: a bond, C, CR E 12 and N; or, V E 1 and V E 2 、V E 2 and V E 3 、V E 3 and V E 4 ,or V E 4 and V E 5 optionally combine together to form a C6 aryl ring or a 5-, 6-, or 7-membered heteroaryl ring;

[0335] R E 12 , upon each occurrence, is independently selected from the group consisting of: hydrogen, halogen, cyano, nitro, hydroxy, amino, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkylamino, optionally substituted 3-8 membered carbocyclic group, and optionally substituted 3-8 membered heterocyclic group;

[0336] W E 6 and W E 7 each independently selected from: -CR E 2 = and -N=;

[0337] W E 1 、W E 2 、W E 3 、W E 4 、V E 1 、V E 2 、V E 3 、V E 4 、V E 5 、R E 1 、R E 3 and Z E as defined in formula 5.

[0338] In another embodiment, W E 1 is selected from: -CO-, -O-, -CR E 3 R E 4 -, -NR E 3 -, -CR E 3 =CR E 4 -, -N=CR E 3 -, and -N=N-.

[0339] In another embodiment, ring A E is as formula A E 1 or AE the divalent group shown in 5; and ring A E is connected to L through W E 2 E .

[0340] In another embodiment, ring A E is a divalent group such as formula A E 1 or A E shown in 5, wherein W E 1 and W E 3 are each independently selected from the group consisting of: CO, O, CR E 3 R E 4 , NR E 3 ; and W E 2 is N.

[0341] In another embodiment, the degradation tag is the moiety shown in formula 5-1 or 5-6, and the degradation tag is connected to the linker portion of the heterobifunctional compound through a divalent group such as Z E shown; wherein

[0342] W E 1 and W E 3 are each independently selected from the group consisting of: -CO-, -O-, -CR E 3 R E 4 -, -NR E 3 -;

[0343] W E 2 is N, and is connected to

[0344] Z E , R E 1 , R E 3 , R E 4 , L E , V E 1 , V E 2 , V E 3 , V E ​4 and V E 5 as defined in Formula 5.

[0345] In another embodiment, the degradation tag is the moiety shown in Formula 5A or 5M; wherein, W E 1 are independently selected from the group consisting of: -CO-, -O-, -CR E 3 R E 4 -, -NR E 3 -; and, V E 1 、V E 2 、V E 3 、V E 4 、R E 1 、R E 3 、R E 4 and Z E as defined in Formula 5.

[0346] In another embodiment, R E 3 and R E 4 , each time it appears, is independently selected from the group consisting of: none, hydrogen, halogen, cyano, nitro, hydroxy, amino, optionally substituted C1-C6 alkyl.

[0347] In another embodiment, the degradation tag is the moiety shown in Formula 5-1 or Formula 5-3.

[0348]

[0349] wherein,

[0350] V E 1 、V E 2 、V E 3 、and V E 4 are each independently selected from: a bond, C, CR E 2 and N; or, V E 1 and V E 2 、V E 2 and VE 3 、 or V E 3 and V E 4 Optionally combined together to form a 6 - aryl ring or a 5, 6 or 7 - membered heteroaryl ring;

[0351] represents a single bond or a double bond; wherein, (i) when W E 1 and W E 2 is a single bond (i.e., the E 1 between W E 2 and W represents a single bond), W E 1 、W E 2 and W E 3 are each independently selected from the group: –N=, -CR E 3 =, -CO-, -O-, -CR E 3 R E 4 -, -NR E 3 -, -CR E 3 =CR E 4 -, -N=CR E 3 -, and -N=N-; or, (ii) when W E 1 and W E 2 is a double bond (i.e., the E 1 between W E 2 and W represents a double bond), W E 1 and W E 2 are each independently selected from the group: -N=, -C≡, and -CR E 3 =; W E 3 is selected from the group: -CR E 3 R E 4 -, -O-, -N=, -NR E3 -,-C(O)NR E 3 -,-CR E 3 =CR E 4 -、and -CR E 3 =N-;

[0352] Z E 、R E 2 、R E 3 、R E 4 and R E 1 as defined in formula 5.

[0353] In a further embodiment, the degradation tag is the moiety shown in formula 5-1 or 5-3, and wherein, V E 1 、V E 2 、V E 3 and V E 4 are each independently selected from: C, N, and CR E 2 .

[0354] In a further embodiment, the degradation tag of formula 5-1 is the moiety shown in formula 5A, 5B, 5E, 5F or 5G

[0355]

[0356] wherein, W E 6 and W E 7 are each independently selected from: -CR E 2 = and -N=; and V E 1 、V E 2 、V E 3 、V E 4 、W E 1 、W E 3 、Z E 、R E 3 and R E 1 as defined in formula 5-1.

[0357] In a further embodiment, the degradation tag is a moiety of Formula 5A, 5B, 5E, 5F or 5G, and wherein, V E 1 , V E 2 , V E 3 and V E 4 are each independently selected from: a bond, C, CR E 2 and N (preferably C, CR E 2 and N).

[0358] In a further embodiment, the degradation tag is a moiety of Formula 5A, 5B, 5E, 5F or 5G, and wherein, W E 1 and W E 3 are independently selected from: -CO-, -O-, -CR E 3 R E 4 -, -NR E 3 -, -CR E 3 =CR E 4 -, -N=CR E 3 -, and -N=N-; preferably W E 1 and W E 3 are each independently selected from: -CO-, -O-, -CR E 3 R E 4 - and -NR E 3 -.

[0359] In a further embodiment, the degradation tag of Formula 5-3 is a moiety of Formula 5C

[0360]

[0361] wherein, W E 3 is N or CR E 3 ; and, V E 1 , V E 2 , V E3 and V E 4 and Z E and R E 1 as defined in Formula 5-3. In an alternative embodiment, the degradation tag is the moiety shown in Formula 5C, wherein V E 1 and V E 2 and V E 3 and V E 4 are each independently selected from: CR E 2 and N.

[0362] In an alternative embodiment, the degradation tag is the moiety shown in Formula 5-2:

[0363]

[0364] V E 1 and V E 2 and V E 3 and V E 4 and V E 5 are each independently selected from: a bond, C, CR E 2 , and N; or, V E 1 and V E 2 and V E 2 and V E 3 and V E 3 and V E 4 , or V E 4 and V E 5 optionally combine together to form a C6 aryl ring or a 5-, 6- or 7-membered heteroaryl ring;

[0365] represents a single bond or a double bond; (i) when the bond between W E 1 and W E 2 is a single bond (i.e., the bond between W E 1 and W E 2 is (representing a single bond), W E 1 and W E 4 are each independently selected from: -N=, -CR E 3 =, -CO-, -O-, -CR E 3 R E 4 -, -NR E 3 -, -CR E 3 =CR E 4 -, -N=CR E 3 - and -N=N-, and W E 2 and W E 3 are each independently selected from: -N=, -CR E 3 =, -CO-, -O-, -CR E 3 R E 4 - and -NR E 3 -; or, (ii) when W E 1 and W E 2 are connected by a double bond (i.e., the bond between W E 1 and W E 2 represents a double bond), W (representing a double bond), W E 1 and W E 2 are each independently selected from: -N=, C and -CR E 2 =; W E 3 is selected from: -N=, -CR E 3 =, -CO-, -O-, -CR E 3 R E 4 - and -NR E 3 -; and W E 4 is selected from: -N=, -CR E 3 =, -CO-, -O-, -CRE 3 R E 4 -, -NR E 3 -, -CR E 3 =CR E 4 -, -N=CR E 3 - and -N=N-;

[0366] Z E , R E 2 , R E 3 , R E 4 and R E 1 as defined in formula 5.

[0367] In another embodiment, the degradation tag is the moiety shown in formula 5-2, wherein V E 1 , V E 2 , V E 3 , V E 4 and V E 5 are independently selected from: a bond, C, CR E 2 , and N.

[0368] In another embodiment, the degradation tag is the moiety shown in formula 5-2, wherein represents a single bond.

[0369] In another embodiment, the degradation tag is the moiety shown in formula 5-2, wherein represents a single bond, W E 1 and W E 4 are each independently selected from: -CO-, -O-, -CR E 3 R E 4 -, and -NR E 3 -, and W E 2 and W E 3 are each independently selected from: -N=, -CR E 3 =, -CO-, -O-, -CRE 3 R E 4 -, and -NR E 3 -.

[0370] In another embodiment, the degradation tag 5-2 is the moiety shown in Formula 5D.

[0371]

[0372] wherein V E 1 , V E 2 , V E 3 , V E 4 , V E 5 , W E 1 , Z E and R E 1 are as defined in Formula 5-2.

[0373] In another embodiment, the degradation tag is the moiety shown in Formula 5D, wherein W E 1 is selected from: -CO-, -O-, -CR E 3 R E 4 -, -NR E 3 -, -CR E 3 =CR E 4 -, -N=CR E 3 - and -N=N-; preferably, W E 1 is selected from: -CO-, -O-, -CR E 3 R E 4 - and -NR E 3 -.

[0374] In another embodiment, the degradation tag is the moiety shown in Formula 5D, wherein V E 1 , V E 2 , V E 3 , V E4 and V E 5 are each independently selected from: a bond, C, CR E 2 and N; or, V E 1 and V E 2 , V E 2 and V E 3 , V E 3 and V E 4 , or V E 4 and V E 5 optionally combine together to form a C6 aryl ring or a 5-, 6- or 7-membered heteroaryl ring; preferably V E 1 , V E 2 , V E 3 , V E 4 and V E 5 are each independently selected from: a bond, C, CR E 2 and N.

[0375] In a further embodiment, the degradation tag is the moiety shown in Formula 5-4:

[0376]

[0377] wherein, V E 1 , V E 2 , V E 3 , V E 4 , V E 5 , L E , Z E and R E 1 as defined in Formula 5.

[0378] In a further embodiment, the degradation tag is the moiety shown in Formula 5-4, and wherein, L E is not nil.

[0379] In a further embodiment, the degradation tag is the moiety shown in Formula 5-4, and wherein, L ESelected from the group consisting of: -NH-, -N(C1-C4 alkyl)-, -CO-, -NH-CO-, -N(C1-C4 alkyl)-CO-, -CO-NH-, and -CO-N(C1-C4 alkyl)-.

[0380] In a further embodiment, the degradation tag is the moiety shown in Formula 5-4, and wherein,

[0381] V E 1 、V E 2 、V E 3 、V E 4 and V E 5 , each independently selected from the group consisting of: C, CR E 2 and N; or,

[0382] V E 1 and V E 2 、V E 2 and V E 3 、V E 3 and V E 4 ; or V E 4 and V E 5 optionally combine to form a ring as shown in ; wherein, V E 6 、V E 7 、V E 8 and V E 9 each independently selected from the group consisting of: C, CR E 12 and N;

[0383] R E 12 , each independently selected from the group consisting of: hydrogen, halogen, cyano, nitro, hydroxy, amino, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkylamino, optionally substituted 3-8 membered carbocyclic group, and optionally substituted 3-8 membered heterocyclic group;

[0384] In another embodiment, the degradation tag is the moiety shown in Formula 5-4, and wherein V E 6 、V E 7 、V E 8 、and V E 9 are each independently selected from the group consisting of: CR E 12 and N.

[0385] In another embodiment, the degradation tag is the moiety shown in Formula 5-4, and wherein R E 12 , each occurrence independently, is selected from the group consisting of: hydrogen, halogen, cyano, nitro, hydroxy, amino, optionally substituted C1-C6 alkyl.

[0386] In another embodiment, the degradation tag is the moiety shown in Formula 5-4, and wherein

[0387] is selected from the group consisting of:

[0388]

[0389] wherein

[0390] V E 1 、V E 2 、V E 3 、V E 4 and V E 5 are each independently selected from the group consisting of: C, CR E 2 and N; and V E 6 、V E 7 、V E 8 、and V E 9 are each independently selected from the group consisting of: CR E 12 and N.

[0391] In another embodiment, the degradation tag is the moiety shown in Formula 5-4, and wherein Z E is none, -CH2-, -O-, or -NH-.

[0392] In another embodiment, the degradation tag of Formula 5-4 is the moiety shown in Formula 5H or 5I:

[0393]

[0394] wherein, V E 1 and V E 2 and V E 3 and V E 4 and V E 5 and V E 6 and V E 7 and V E 8 and V E 9 are each independently selected from: a bond, C, CR E 2 and N; and Z E and R E 1 are defined as in Formula 5-4.

[0395] In another embodiment, the degradation tag is the moiety shown in Formula 5-4, and wherein, L E is none.

[0396] In another embodiment, the degradation tag Formula 5-4 is the 5N moiety;

[0397]

[0398] wherein, V E 1 and V E 2 and V E 3 and V E 4 and V E 5 are each independently selected from: a bond, C, CR E 2 and N; and Z E and R E 1 are defined as in Formula 5-4.

[0399] In another embodiment, the degradation tag is the moiety shown in Formula 5-5:

[0400]

[0401] wherein, W E1 , W E 2 , W E 3 , W E 4 , Z E and R E 1 as defined in Formula 5.

[0402] In another embodiment, the degradation tag is the moiety shown in Formula 5-5, and wherein W E 1 , W E 2 , W E 3 and W E 4 are each independently selected from the group consisting of: -N=, -C≡, -CR E 3 =, -CO-, -O-, -CR E 3 R E 4 -, and -NR E 3 -.

[0403] In another embodiment, the degradation tag is the moiety shown in Formula 5-5, and wherein W E 1 , W E 2 , W E 3 and W E 4 are each independently selected from the group consisting of: -N=, -C≡, -CH=, -CO-, -O-, -N-, -CH2-, and -NH-.

[0404] In another embodiment, the degradation tag Formula 5-5 is the moiety of Formula 5J, 5K, or 5L;

[0405]

[0406] wherein W E 1 , W E 2 , W E 3 , W E 4 , Z E , R E 3 and R E 1 as defined in Formula 5-5.

[0407] In another embodiment, the degradation tag is the moiety shown in Formula 5-6:

[0408]

[0409] Wherein,

[0410] V E 1 、V E 2 and V E 3 are each independently selected from: C, CR E 2 、S, N and NR E 2 ; or, V E 1 and V E 2 、or V E 2 and V E 3 optionally combine to form a 5-membered heteroaryl ring;

[0411] represents a single bond or a double bond; wherein, (i) when W E 1 and W E 2 are a single bond between (i.e., W E 1 and W E 2 between the represents a single bond), W E 1 、W E 2 and W E 3 are each independently selected from the group: -N=, -CR E 3 =, -CO-, -O-, -CR E 3 R E 4 -, -NR E 3 -, -CR E 3 =CR E 4 -, -N=CR E 3 -, and -N=N-; or, (ii) when W E 1 and W E2 when the bond is a double bond (i.e., W E 1 and W E 2 therebetween represents a double bond), W E 1 and W E 2 are each independently selected from the group consisting of: -N-, -C≡, and -CR E 3 =; W E 3 is selected from the group consisting of: -O-, -N=, -NR E 3 -, -C(O)NR E 3 -, -CR E 3 R E 4 -, -CR E 3 =CR E 4 -, and -CR E 3 =N-;

[0412] Z E 、R E 2 、R E 3 、R E 4 and R E 1 are as defined in Formula 5.

[0413] In another embodiment, the degradation tag is the moiety shown in Formulas 5-6, and wherein V E 1 、V E 2 、V E 3 and V E 4 are each independently selected from: C, CR E 2 、S, N, and NR E 2 .

[0414] In another embodiment, the degradation tag of Formulas 5-6 is the moiety shown in Formula 5M;

[0415]

[0416] wherein V E1 , V E 2 , V E 3 , W E 1 , Z E and R E 1 as defined in Formula 5-6.

[0417] In another embodiment, the degradation tag is the moiety shown in Formula 5M, and wherein V E 1 , V E 2 and V E 3 are each independently selected from: C, CR E 2 , S, N, and NR E 2 (preferably, one of V E 1 , V E 2 and V E 3 is S).

[0418] In another embodiment, the degradation tag is the moiety shown in Formula 5M, and wherein W E 1 is selected from: -CO-, -O-, -CR E 3 R E 4 -, -NR E 3 -, -CR E 3 =CR E 4 -, -N=CR E 3 -, and -N=N-; preferably, W E 1 is selected from: -CO-, -O-, -CR E 3 R E 4 -, and -NR E 3 -.

[0419] In another embodiment, the degradation tag is the moiety shown in Formula 5-7:

[0420]

[0421] wherein, W E1 and W E 2 and W E 3 and W E 4 and Z E and R E 1 as defined in Formula 5.

[0422] In another embodiment, the degradation tag is the moiety shown in Formulas 5-7, and wherein

[0423] is a double bond;

[0424] W E 1 and W E 2 optionally combine to form a ring as shown in wherein V E 1 、V E 2 、V E 3 and V E 4 each independently selected from the group: C, CR E 12 and N;

[0425] W E 3 and W E 4 optionally combine to form a ring as shown in wherein V E 6 、V E 7 、V E 8 and V E 9 each independently selected from the group: C, CR E 12 and N; and

[0426] R E 12 , each occurrence independently selected from the group: hydrogen, halogen, cyano, nitro, hydroxy, amino, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkylamino, optionally substituted 3-8 membered carbocyclic group, and optionally substituted 3-8 membered heterocyclic group;

[0427] In another embodiment, the degradation tag is the moiety shown in Formulae 5-7, and wherein, R E 12 , each occurrence independently selected from the group consisting of: hydrogen, halogen, cyano, nitro, hydroxy, amino, optionally substituted C1-C6 alkyl.

[0428] In another embodiment, the degradation tag of Formulae 5-7 is the moiety of Formula 5O;

[0429]

[0430] wherein, V E 1 、V E 2 、V E 3 、V E 4 、V E 5 、V E 6 、V E 7 、V E 8 and V E 9 are each independently selected from: C, CR E 2 and N; and Z E and R E 1 are as defined in Formulae 5-7.

[0431] In another embodiment, the degradation tag is the moiety shown in Formulae 5-8:

[0432]

[0433] wherein, W E 1 、W E 2 、W E 3 、W E 4 、Z E and R E 1 are as defined in Formula 5.

[0434] In another embodiment, the degradation tag is the moiety shown in Formulae 5-8, wherein, represents a double bond.

[0435] In another embodiment, the degradation tag is the moiety shown in Formulae 5-8, and, W E1 and W E 4 are each independently selected from the group consisting of: -CO-, -O- or -CR E 3 R E 4 -.

[0436] In a further embodiment, the degradation tag is the moiety shown in Formula 5-8, and wherein, W E 2 is arylamino or heteroarylamino.

[0437] In a further embodiment, the degradation tag is the moiety shown in Formula 5-8, and wherein, W E 3 is CR E 3 or N.

[0438] In a further embodiment, the degradation tag Formula 5-8 is the moiety shown in Formula 5P;

[0439]

[0440] wherein, V E 1 、V E 2 、V E 3 、V E 4 and V E 5 are each independently selected from: C, CR E 2 and N; W E 1 is selected from: CO, CH2 and O; and Z E and R E 1 are as defined in Formula 5.

[0441] In a further preferred embodiment, the degradation tag is the moiety shown in Formula 5A.

[0442] In a further embodiment, the degradation tag is the moiety shown in Formula 5A, and Z E is connected to V E 1 or V E 4 .

[0443] In a further embodiment, the degradation tag is the moiety shown in Formulas 8A-8HT:

[0444]

[0445]

[0446]

[0447]

[0448]

[0449] In another embodiment, the degradation tag is a moiety represented by Formula 8A, 8B, 8G or 8H.

[0450] In another embodiment, the degradation tag is a moiety represented by Formula 8A, 8B, 8C, 8D, 8E, 8F, 8S, 8U, 8W, 8Y, 8AA or 8AC.

[0451] In another embodiment, the degradation tag is a moiety represented by Formula 8A or 8G (preferably a moiety represented by 8A).

[0452] In another embodiment, the degradation tag is a moiety represented by Formula 4A:

[0453]

[0454] Wherein,

[0455] V E 1 、V E 2 、V E 3 、V E 4 、and V E 5 are independently selected from: CR E 4 and N; and

[0456] R E 1 、R E 2 、R E 3 、and R E 4 are independently selected from: hydrogen, halogen, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, and optionally substituted C2-C8 alkynyl; optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkylamino, optionally substituted C3-C 10a carbocyclic group, and an optionally substituted 3- to 10-membered heterocyclic group.

[0457] In a further embodiment, the degrading tag is the moiety shown in Formula 4B:

[0458]

[0459] wherein,

[0460] R E 1 、R E 2 and R E 3 are each independently selected from: hydrogen, halogen, an optionally substituted C1-C8 alkyl, an optionally substituted C1-C8 alkoxy C1-C8 alkyl, an optionally substituted C1-C8 haloalkyl, an optionally substituted C1-C8 hydroxyalkyl, an optionally substituted C3-C7 cycloalkyl, an optionally substituted 3- to 7-membered heterocyclic group, an optionally substituted C2-C8 alkenyl, and an optionally substituted C2-C8 alkynyl;

[0461] R E 4 and R E 5 are independently selected from: hydrogen, COR E 6 、CO2R E 6 、CONR E 6 R E 7 、SOR E 6 、SO2R E 6 、SO2NR E 6 R E 7 、an optionally substituted C1-C8 alkyl, an optionally substituted C1-C8 alkoxy C1-C8 alkyl, an optionally substituted C1-C8 alkylamino C1-C8 alkyl, an optionally substituted aryl-C1-C8 alkyl, an optionally substituted 3- to 8-membered cycloalkyl, an optionally substituted 3- to 8-membered heterocyclic group, an optionally substituted aryl, and an optionally substituted heteroaryl, wherein,

[0462] R E 6 and R E 7Independently selected from: hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-8 membered heterocyclic group, optionally substituted aryl, and optionally substituted heteroaryl, or, R E 6 and R E 7 and together with the atom(s) to which they are attached form a 3-8 membered cycloalkyl or heterocyclic ring.

[0463] In a further embodiment, the degradation tag is selected from: the moieties shown in Formulas 6A, 6B and 6C.

[0464] In a further embodiment, the degradation tag is the moiety shown in Formula 6A.

[0465] In a further embodiment, the degradation tag is selected from: the moieties shown in Formulas 6A-1 to 6A-13.

[0466] In a further embodiment, the degradation tag is selected from: the moieties shown in Formulas 7A to 7T.

[0467] In a further embodiment, the degradation tag is selected from: the moieties shown in Formulas 7A, 7B, 7F, 7G, 7K, 7L, 7P and 7Q.

[0468] In a further embodiment, the degradation tag is the moiety shown in Formula 5.

[0469] In a further embodiment, the degradation tag is selected from: the moieties shown in Formulas 5-1, 5A and 5B.

[0470] In some embodiments, the linker comprises acyclic or cyclic saturated or unsaturated carbon, ethylene glycol, amide, ammonia, ether, urea, carbamate, aromatic, heteroaromatic, heterocyclic or carbonyl.

[0471] In some embodiments, the length of the linker is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more atoms.

[0472] In a further embodiment, A L and B L , each occurrence independently selected from the group consisting of: nothing, R L d -R L e , R L d COR L e, R L d C(O)OR L e , R L d C(O)N(R L 1 )R L e , R L d OR L e , R L d SR L e , R L d N(R L 1 )R L e , R L d N(R L 1 )COR L e ; wherein, R L d and R L e , each time it appears, is independently selected from the group consisting of: none, optionally substituted C1, C2 or C3 alkylene, R L r , R L r -(C1, C2 or C3 alkylene), (C1, C2 or C3 alkylene)-R L r , and (C1, C2 or C3 alkylene)-R L r -(C1, C2 or C3 alkylene).

[0473] In a further embodiment, A L and B L , each time it appears, is independently selected from the group consisting of: none, R L d -R L e , R L d COR L e , R L d C(O)OR L e , R L d C(O)N(R L1 )R L e 、R L d OR L e 、R L d SR L e 、R L d N(R L 1 )R L e 、R L d N(R L 1 )COR L e ; wherein, R L d and R L e , each time it appears, is independently selected from the group consisting of: none, R L r and optionally substituted C1, C2 or C3 alkylene groups.

[0474] In another embodiment, W L 1 and W L 2 , each time it appears, is independently selected from: none, O, S, NH, R L r , optionally substituted C1-C3 alkylene groups, provided that at least one of W L 1 and W L 2 is not none.

[0475] In another embodiment, W L 1 -W L 2 、A L -W L 1 and W L 2 -B L are not the moiety represented by -O-O-.

[0476] In another embodiment, W L 2 , each time it appears, is independently none, O or NH; and W L 1 , each time it appears, is independently selected from: R Lr and optionally substituted C1, C2 or C3 alkylene.

[0477] In a further embodiment, W L 1 , each occurrence independently being none, O or NH; and W L 2 , each occurrence independently being selected from: R L r and optionally substituted C1, C2 or C3 alkylene.

[0478] In a further embodiment, A L is the point of attachment to the TYK2 ligand;

[0479] A L is selected from: R L d -R L e 、R L d C(O)R L e 、R L d C(O)NHR L e 、R L d NHC(O)R L e 、R d C(O)NHR L e and R d NHC(O)R L e ;

[0480] B L is selected from the group consisting of: none, R L d C(O)NHR L e 、R L d C(O)R L e 、R L d NHC(O)R L e 、R L d NHR L e ;

[0481] R L d and R Le , upon each occurrence, is independently selected from the group consisting of: none, optionally substituted C1, C2 or C3 alkylene, R L r 、R L r -(C1, C2 or C3 alkylene), (C1, C2 or C3 alkylene)-R L r and (C1, C2 or C3 alkylene)-R L r -(C1, C2 or C3 alkylene);

[0482] W L 2 , upon each occurrence, is independently selected from: none, O or NH; and W L 1 , upon each occurrence, is independently selected from: R L r and optionally substituted C1, C2 or C3 alkylene.

[0483] In a further embodiment, A L is the point of attachment to the TYK2 ligand;

[0484] A L is selected from the group consisting of: R L d -R L e 、R L d C(O)R L e 、R L d C(O)NHR L e 、R L d NHC(O)R L e 、R d C(O)NHR L e and R d NHC(O)R L e ;

[0485] B L is selected from the group consisting of: none, R L d C(O)NHR L e 、R L d C(O)R L e 、R Ld NHC(O)R L e and R L d NHR L e ;

[0486] R L d and R L e and, each time it appears, is independently selected from the group consisting of: nothing, optionally substituted C1, C2 or C3 alkylene, R L r , R L r -(C1, C2 or C3 alkylene), (C1, C2 or C3 alkylene)-R L r and (C1, C2 or C3 alkylene)-R L r -(C1, C2 or C3 alkylene);

[0487] W L 2 and, each time it appears, is independently selected from: nothing, O or NH, and W L 1 and, each time it appears, is independently selected from: R L r and optionally substituted C1, C2 or C3 alkylene.

[0488] In a further embodiment, A L is the attachment position to the TYK2 ligand;

[0489] A L is selected from the group consisting of: R L d -R L e , R L d C(O)R L e , R L d C(O)NHR L e , R L d NHC(O)R L e , R d C(O)NHR L e and R d NHC(O)R L e ;

[0490] B L is selected from the group consisting of: none, R L d C(O)NHR L e 、R L d C(O)R L e 、R L d NHC(O)R L e 、R L d NHR L e ;

[0491] R L d and R L e each, independently of one another, is selected from the group consisting of: none, R L r 、optionally substituted C1, C2 or C3 alkylene;

[0492] W L 2 is none; and W L 1 each, independently of one another, is optionally selected from: R L r 、optionally substituted C1, C2 or C3 alkylene;

[0493] m L = 4, 5, 6, 7, 8, 9 or 10 (preferably 5, 6, 7 or 8).

[0494] In a further embodiment, the linker has a length of from 3 to 30 chain atoms.

[0495] In a further embodiment, the linker has a length of from 2 to 24 chain atoms.

[0496] In a further embodiment, the linker has a length of from 2 to 12 chain atoms.

[0497] In a further embodiment, R L r each, independently of one another, is selected from: formula C1, C2, C3, C4, and C5

[0498]

[0499] wherein,

[0500] A L 1, B L 1 , C L 1 and D L 1 , each time it appears, is independently selected from the group consisting of: none, O, CO, SO, SO2, NR L b , CR L b R L c ;

[0501] X L ’, Y L ’, A L 2 , B L 2 , C L 2 , D L 2 and E L 2 , each time it appears, is independently selected from: N, CR L b ;

[0502] A L 3 , B L 3 , C L 3 , D L 3 , and E L 3 , each time it appears, is independently selected from: N, O, S, NR L b , CR L b ;

[0503] R L b and R L c , each time it appears, is independently selected from: hydrogen, halogen, hydroxy, amino, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, and optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C3-C 10 carbocyclic group, optionally substituted C3-C 10 cycloalkoxy, optionally substituted C3-C10 carbocyclic amino, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted aryl group, and optionally substituted heteroaryl group; and

[0504] m L 1 、n L 1 、o L 1 and p L 1 are independently selected from: 0, 1, 2, 3, 4, and 5.

[0505] In a further embodiment, R L r , upon each occurrence, is selected from group R L r1 and group R L r2 , and

[0506] group R L r1 consists of optionally substituted cyclic groups as follows:

[0507]

[0508] group R L r2 consists of optionally substituted cyclic groups as follows:

[0509]

[0510] In one embodiment, the linker moiety is as shown in Formula 9A:

[0511]

[0512] wherein,

[0513] R L 1 、R L 2 、R L 3 and R L 4, each occurrence independently selected from: hydrogen, halogen, hydroxy, amino, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 heteroalkenyl, optionally substituted C2-C8 heteroalkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, and optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C3-C 10 carbocyclic group, optionally substituted C3-C 10 cycloalkoxy, optionally substituted C3-C 10 carbocyclic group amino, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted aryl, and optionally substituted heteroaryl, (preferably, R L 1 、R L 2 、R L 3 and R L 4 , each occurrence independently selected from: hydrogen, halogen, hydroxy, amino, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, and optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C3-C 10 carbocyclic group, optionally substituted C3-C 10 cycloalkoxy, optionally substituted C3-C 10 carbocyclic group amino, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted aryl, and optionally substituted heteroaryl), or

[0514] R L 1 and R L 2 、R L 3 and R L 4 and together with the atom(s) to which they are attached form an optionally substituted 3- to 20-membered cycloalkyl ring or an optionally substituted 3- to 20-membered heterocyclic ring.

[0515] A L 、W L and B L, upon each occurrence, is a divalent moiety independently selected from the following: none, R L d -R L e 、R L d COR L e 、R L d C(O)OR L e 、R L d C(O)N(R L 5 )R L e 、R L d C(S)N(R L 5 )R L e 、R L d OR L e 、R L d SR L e 、R L d SOR L e 、R L d SO2R L e 、R L d SO2N(R L 5 )R L e 、R L d N(R L 5 )R L e 、R L d N(R L 5 )COR L e 、R L d N(R L 5 )CON(R L 6 )R L e 、R Ld N(R L 5 )C(S)R L e , optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 heteroalkenylene, optionally substituted C2-C8 heteroalkynylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C3-C 13 carbocyclic group, optionally substituted 3- to 13-membered heterocyclic group, optionally substituted aryl, and optionally substituted heteroaryl, (preferably, A L , W L and B L , each time it appears, is a divalent moiety independently selected from the following: none, R L d -R L e , R L d COR L e , R L d C(O)OR L e , R L d C(O)N(R L 5 )R L e , R L d C(S)N(R L 5 )R L e , R L d OR L e , R L d SR L e , R L d SOR L e , R L d SO2R L e , R L d SO2N(R L 5 )R Le , R L d N(R L 5 )R L e , R L d N(R L 5 )COR L e , R L d N(R L 5 )CON(R L 6 )R L e , R L d N(R L 5 )C(S)R L e , optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene,, optionally substituted C3-C 13 carbocyclic group, optionally substituted 3- to 13-membered heterocyclic group, optionally substituted aryl, and optionally substituted heteroaryl), wherein,

[0516] R L d and R L e , each time it appears, is independently selected from: nothing, optionally substituted (C1-C8 alkyl)-R L r (preferably, CH2-R L r ), optionally substituted R L r -(C1-C8 alkylene), optionally substituted (C1-C8 alkylene)-R L r-(C1-C8 alkylene), or a moiety comprising: optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 heteroalkenylene, optionally substituted C2-C8 heteroalkynylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 alkylamino C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C3-C 13 carbocyclic group, optionally substituted 3- to 13-membered heterocyclic group, optionally substituted aryl, and optionally substituted heteroaryl (preferably, R L d and R L e , each occurrence independently selected from: nothing, optionally substituted (C1-C8 alkyl)-R L r (preferably, CH2-R L r ), optionally substituted R L r -(C1-C8 alkylene), optionally substituted (C1-C8 alkylene)-R L r -(C1-C8 alkylene), or a moiety comprising: optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 alkylamino C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C3-C 13 carbocyclic group, optionally substituted 3- to 13-membered heterocyclic group, optionally substituted aryl, and optionally substituted heteroaryl);

[0517] R L r as defined in Formula 9.

[0518] R L 5 and R L 6, each occurrence of which is independently selected from: hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 heteroalkenyl, optionally substituted C2-C8 heteroalkynyl, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted aryl, and optionally substituted heteroaryl ((preferably, R L 5 and R L 6 , each occurrence of which is independently selected from: hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 carbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted aryl, and optionally substituted heteroaryl);

[0519] R L d and R L e , R L 5 and R L 6 , R L d and R L 5 , R L d and R L 6 , R L e and R L 5 , R L e and R L 6 and together with the atom(s) to which they are attached optionally form a 3- to 20-membered cycloalkyl ring or a 3- to 20-membered heterocyclic ring;

[0520] m L is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15;

[0521] n L, at each occurrence, is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15; and

[0522] o L is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.

[0523] In another embodiment, the linker portion is as shown in Formula 9B:

[0524]

[0525] wherein,

[0526] R L 1 and R L 2 , at each occurrence, is independently selected from: hydrogen, halogen, hydroxyl, amino, cyano, nitro, and optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 heteroalkenyl, optionally substituted C2-C8 heteroalkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C3-C 10 carbocyclic group, optionally substituted C3-C 10 cycloalkoxy, optionally substituted C3-C 10 carbocyclic group amino, optionally substituted 3-10 membered heterocyclic group, optionally substituted aryl, and optionally substituted heteroaryl, ((preferably, R L 1 and R L 2 , at each occurrence, is independently selected from: hydrogen, halogen, hydroxyl, amino, cyano, nitro, and optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C3-C 10 carbocyclic group, optionally substituted C3-C 10 cycloalkoxy, optionally substituted C3-C 10 carbocyclic group amino, optionally substituted 3-10 membered heterocyclic group, optionally substituted aryl, and optionally substituted heteroaryl), or,

[0527] RL 1 and R L 2 optionally form, together with (one or more) atoms to which they are attached, a 3- to 20-membered cycloalkyl or 3- to 20-membered heterocyclic ring;

[0528] A L and B L , each occurrence independently being selected from: nothing, or a divalent moiety selected from the following: R L d -R L e 、R L d COR L e 、R L d CO2R L e 、R L d C(O)N(R L 3 )R L e 、R L d C(S)N(R L 3 )R L e 、R L d OR L e 、R L d SR L e 、R L d SOR L e 、R L d SO2R L e 、R L d SO2N(R L 3 )R L e 、R L d N(R L 3 )R L e 、R L d N(R L 3 )COR Le , R L d N(R L 3 )CON(R L 4 )R L e , R L d N(R L 3 )C(S)R L e , optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 heteroalkenylene, optionally substituted C2-C8 heteroalkynylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C3-C 13 carbocyclic group, optionally substituted 3- to 13-membered heterocyclic group, optionally substituted aryl, and optionally substituted heteroaryl (preferably, A L and B L , each occurrence independently selected from: nothing, or a divalent moiety selected from the following: R L d -R L e , R L d COR L e , R L d CO2R L e , R L d C(O)N(R L 3 )R L e , R L d C(S)N(R L 3 )R L e , R L d OR L e , R L d SR L e , R L d SOR L e , RL d SO2R L e 、R L d SO2N(R L 3 )R L e 、R L d N(R L 3 )R L e 、R L d N(R L 3 )COR L e 、R L d N(R L 3 )CON(R L 4 )R L e 、R L d N(R L 3 )C(S)R L e 、optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C3-C 13 carbocyclic group, optionally substituted 3- to 13-membered heterocyclic group, optionally substituted aryl, and optionally substituted heteroaryl), wherein,

[0529] R L d and R L e , each time it appears, is independently selected from: none, optionally substituted (C1-C8 alkylene)-R L r (preferably, CH2-R L r ), optionally substituted R L r -(C1-C8 alkylene), optionally substituted (C1-C8 alkylene)-R L r-(C1-C8 alkylene), or a moiety comprising: optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 heteroalkenylene, optionally substituted C2-C8 heteroalkynylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkoxyC1-C8 alkylene, optionally substituted C1-C8 alkylaminoC1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C3-C 13 carbocyclic group, optionally substituted 3- to 13-membered heterocyclic group, optionally substituted aryl, and optionally substituted heteroaryl (preferably, R L d and R L e , each occurrence independently selected from: nothing, optionally substituted (C1-C8 alkylene)-R L r (preferably, CH2-R L r ), optionally substituted R L r -(C1-C8 alkylene), optionally substituted (C1-C8 alkylene)-R L r -(C1-C8 alkylene), or a moiety comprising: optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkoxyC1-C8 alkylene, optionally substituted C1-C8 alkylaminoC1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C3-C 13 carbocyclic group, optionally substituted 3- to 13-membered heterocyclic group, optionally substituted aryl, and optionally substituted heteroaryl);

[0530] R L r as defined in Formula 9;

[0531] R L 3 and R L 4, upon each occurrence, is independently selected from: hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 heteroalkenyl, optionally substituted C2-C8 heteroalkynyl, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 carbocyclic group, optionally substituted 3-10 membered heterocyclic group, optionally substituted aryl, and optionally substituted heteroaryl (preferably, R L 3 and R L 4 , upon each occurrence, is independently selected from: hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 carbocyclic group, optionally substituted 3-10 membered heterocyclic group, optionally substituted aryl, and optionally substituted heteroaryl);

[0532] R L d and R L e , R L 3 and R L 4 , R L d and R L 3 , R L d and R L 4 , R L e and R L 3 , R L e and R L 4 and together with the atom(s) to which they are attached optionally form a 3-20 membered cycloalkyl or 3-20 membered heterocyclic ring;

[0533] Each m L is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15; and

[0534] n Lis 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.

[0535] In another embodiment, the linker portion is as shown in Formula 9C:

[0536]

[0537] wherein,

[0538] X L , upon each occurrence, is selected from: O and NR L 7 ;

[0539] R L 1 , R L 2 , R L 3 , R L 4 , R L 5 and R L 6 , upon each occurrence, is independently selected from the group consisting of: hydrogen, halogen, hydroxy, amino, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 heteroalkenyl, optionally substituted C2-C8 heteroalkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C3-C 10 carbocyclic group, optionally substituted C3-C 10 cycloalkoxy, optionally substituted 3-10 membered heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl (preferably, R L 1 , R L 2 , R L 3 , R L 4 , R L 5 and R L 6, each occurrence independently selected from the group consisting of: hydrogen, halogen, hydroxy, amino, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C3-C 10 carbocyclic group, optionally substituted C3-C 10 cycloalkoxy, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl);

[0540] A L and B L , each occurrence independently selected from: nothing, or a divalent moiety selected from the following: R L d -R L e 、R L d COR L e 、R L d CO2R L e 、R L d C(O)N(R L 8 )R L e 、R L d C(S)N(R L 8 )R L e 、R L d OR L e 、R L d SR L e 、R L d SOR L e 、R L d SO2R L e 、R L d SO2N(R L 8 )R Le , R L d N(R L 8 )R L e , R L d N(R L 8 )COR L e , R L d N(R L 8 )CON(R L 9 )R L e , R L d N(R L 8 )C(S)R L e , Optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 heteroalkenylene, optionally substituted C2-C8 heteroalkynylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted 4-13 membered fused cycloalkyl, optionally substituted 5-13 membered fused heterocyclic group, optionally substituted 5-13 membered bridged cycloalkyl, optionally substituted 5-13 membered bridged heterocyclic group, optionally substituted 5-13 membered spirocycloalkyl, optionally substituted 5-13 membered spiroheterocyclic group, optionally substituted C3-C 10 carbocyclic group, optionally substituted 3-10 membered heterocyclic group, optionally substituted aryl, and optionally substituted heteroaryl (preferably, A L and B L , each time it appears, is independently selected from: none, or a divalent moiety selected from the following: R L d -R L e , R L d COR L e , R L d CO2R L e , R L d C(O)N(R L 8 )R L e, R L d C(S)N(R L 8 )R L e , R L d OR L e , R L d SR L e , R L d SOR L e , R L d SO2R L e , R L d SO2N(R L 8 )R L e , R L d N(R L 8 )R L e , R L d N(R L 8 )COR L e , R L d N(R L 8 )CON(R L 9 )R L e , R L d N(R L 8 )C(S)R L e , Optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted 4-13 membered fused cycloalkyl, optionally substituted 5-13 membered fused heterocyclic group, optionally substituted 5-13 membered bridged cycloalkyl, optionally substituted 5-13 membered bridged heterocyclic group, optionally substituted 5-13 membered spirocycloalkyl, optionally substituted 5-13 membered spiroheterocyclic group, optionally substituted C3-C 10a carbocyclic group, an optionally substituted 3- to 10-membered heterocyclic group, an optionally substituted aryl group, and an optionally substituted heteroaryl group), wherein,

[0541] R L d and R L e , each time it appears, is independently selected from: none, an optionally substituted (C1-C8 alkylene)-R L r (preferably, CH2-R L r ), an optionally substituted R L r -(C1-C8 alkylene), an optionally substituted (C1-C8 alkylene)-R L r -(C1-C8 alkylene), or a moiety comprising: an optionally substituted C1-C8 alkylene, an optionally substituted C2-C8 alkenylene, an optionally substituted C1-C8 heteroalkylene, an optionally substituted C2-C8 heteroalkenylene, an optionally substituted C2-C8 heteroalkynylene, an optionally substituted C2-C8 alkynylene, an optionally substituted C1-C8 hydroxyalkylene, an optionally substituted C1-C8 alkoxy C1-C8 alkylene, an optionally substituted C1-C8 alkylamino C1-C8 alkylene, an optionally substituted C1-C8 haloalkylene, an optionally substituted C3-C 13 a carbocyclic group, an optionally substituted 3- to 13-membered heterocyclic group, an optionally substituted aryl group, and an optionally substituted heteroaryl group; preferably, R L d and R L e , each time it appears, is independently selected from: none, an optionally substituted (C1-C8 alkylene)-R L r (preferably, CH2-R L r ), an optionally substituted R L r -(C1-C8 alkylene), an optionally substituted (C1-C8 alkylene)-R L r -(C1-C8 alkylene), or a moiety comprising: an optionally substituted C1-C8 alkylene, an optionally substituted C2-C8 alkenylene, an optionally substituted C1-C8 heteroalkylene, an optionally substituted C2-C8 heteroalkenylene, an optionally substituted C2-C8 heteroalkynylene, an optionally substituted C2-C8 alkynylene, an optionally substituted C1-C8 hydroxyalkylene, an optionally substituted C1-C8 alkoxy C1-C8 alkylene, an optionally substituted C1-C8 alkylamino C1-C8 alkylene, an optionally substituted C1-C8 haloalkylene, an optionally substituted C3-C 13A carbocyclic group, an optionally substituted 3- to 13-membered heterocyclic group, an optionally substituted aryl group, and an optionally substituted heteroaryl group

[0542] R L r As defined in Formula 9;

[0543] R L 7 、R L 8 and R L 9 , each occurrence independently selected from: hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 heteroalkenyl, optionally substituted C2-C8 heteroalkynyl, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C3-C 10 A carbocyclic group, an optionally substituted 3- to 10-membered heterocyclic group, an optionally substituted aryl group, and an optionally substituted heteroaryl group; preferably, R L 7 、R L 8 and R L 9 , each occurrence independently selected from: hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C3-C 10 A carbocyclic group, an optionally substituted 3- to 10-membered heterocyclic group, an optionally substituted aryl group, and an optionally substituted heteroaryl group;

[0544] R L d and R L e 、R L 8 and R L 9 、R L d and R L 8 、R L d and R L 9 、R L e and R L 8 、RL e and R L 9 optionally form, together with the (one or more) atoms to which they are attached, a 3- to 20-membered cycloalkyl or 3- to 20-membered heterocyclic group ring;

[0545] In each occurrence, m L is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15;

[0546] In each occurrence, n L is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15;

[0547] o L is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15; and

[0548] p L is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.

[0549] In a further embodiment, the linker has a length of 3 to 30 chain atoms. In a further embodiment, the linker has a length of 2 to 24 chain atoms. In a further embodiment, the linker has a length of 2 to 12 chain atoms.

[0550] In one embodiment,

[0551] 1) the TYK2 ligand comprises a moiety represented by Formula 1 or 2 (preferably, the moiety represented by Formula 1; more preferably, the moiety represented by Formula 1-1G; even more preferably, the moiety represented by Formula 1-1I);

[0552] and / or

[0553] 2) the degrading tag is a moiety represented by Formula 6A:

[0554] and / or

[0555] 3) the linker moiety is as represented by Formula 9, wherein,

[0556] A L and B L , in each occurrence, are independently selected from the group consisting of: nothing, R L d -R L e 、R L d COR L e 、RL d C(O)OR L e and R L d C(O)N(R L 1 )R L e and R L d C(S)N(R L 1 )R L e and R L d OR L e and R L d SR L e and R L d SOR L e and R L d SO2R L e and R L d SO2N(R L 1 )R L e and R L d N(R L 1 )R L e and R L d N(R L 1 )COR L e and R L d N(R L 1 )CON(R L 2 )R L e and R L d N(R L 1 )C(S)R L e, optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 heteroalkenylene, optionally substituted C2-C8 heteroalkynylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C3-C 13 cycloalkyl, optionally substituted 3- to 13-membered heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl; and / or

[0557] W L 1 and W L 2 , each occurrence being independently a divalent moiety selected from the group consisting of: none, optionally substituted C1-C8 alkylene; and / or

[0558] wherein R L d , R L e , R L r , R L 1 and R L 2 are as defined above; and / or

[0559] m L is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.

[0560] In one embodiment,

[0561] 1) the TYK2 ligand comprises the moiety shown in Formula 1 (preferably, the moiety shown in Formula 1-1G; more preferably, the moiety shown in Formula 1-1I); and preferably, R 1 ' is selected from the group consisting of: C(O), optionally substituted C(O)-CH2, optionally substituted pyridyl, (optionally substituted pyridyl)-(C2 alkynylene) and (optionally substituted pyridyl)-(optionally substituted piperazinyl); preferably, R 1 ' is selected from the group consisting of: C(O), C(O)-CH2,

[0562] and / or

[0563] 2) the degron is the moiety shown in Formula 6A (preferably, the moiety shown in Formula 6A-9 or 6A-10, more preferably, the moiety shown in Formula 7F or 7G);

[0564] and / or

[0565] 3) The connector part is as shown in Formula 9, where A L is the connection position with the TYK2 ligand;

[0566] A L is selected from the group consisting of: none, R L d COR L e 、R L d C(O)N(R L 1 )R L e 、R L d N(R L 1 )COR L e ; Preferably, A L is selected from the group consisting of: R L r 、R L r CO、CO、R L r NHCO、NHCO、R L r CH2NHCO and CH2NHCO、R L r CH2CONH and CH2CONH; More preferably, A L is selected from the group consisting of: CO、NHCO、CONH、CH2CONH、CH2NHCO、

[0567] and / or

[0568] B L is none or R L d C(O)R L e ; Preferably, B L is none or C(O); More preferably, B L is C(O); and / or

[0569] W L 2 is none and W L 1 are independently optionally substituted C1-alkylene; Preferably, W L 2 is none and W L 1 is C1-alkylene; and / or

[0570] m Lis 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15; preferably, m L is 1, 2, 3, 4, 5, 6, 7 or 8.

[0571] In one embodiment,

[0572] 1) The TYK2 ligand comprises a moiety represented by Formula 1 or 2 (preferably, the moiety represented by Formula 1; more preferably, the moiety represented by Formula 1-1G; still more preferably, the moiety represented by Formula 1-1I);

[0573] and / or

[0574] 2) The degradation tag is a moiety represented by Formula 6B or 6C (preferably, the moiety represented by Formula 6B-10 or 6C-10, more preferably, the moiety represented by Formula 7AC or 7AQ);

[0575] and / or

[0576] 3) The linker moiety is as shown in Formula 9, wherein,

[0577] A L and B L , each occurrence, is independently a divalent moiety selected from the group consisting of: none, R L d -R L e , R L d COR L e , R L d C(O)OR L e , R L d C(O)N(R L 1 )R L e , R L d C(S)N(R L 1 )R L e , R L d OR L e , R L d SR L e , R L d SOR L e , R Ld SO2R L e 、R L d SO2N(R L 1 )R L e 、R L d N(R L 1 )R L e 、R L d N(R L 1 )COR L e 、R L d N(R L 1 )CON(R L 2 )R L e 、R L d N(R L 1 )C(S)R L e 、 optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 heteroalkenylene, optionally substituted C2-C8 heteroalkynylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C3-C 13 cycloalkyl, optionally substituted 3-13 membered heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl (preferably, A L and B L , each time it appears, is a divalent moiety independently selected from the group consisting of: none, R L d -R L e 、R L d COR L e 、R L d C(O)OR L e 、R L d C(O)N(R L 1 )RL e , R L d C(S)N(R L 1 )R L e , R L d OR L e , R L d SR L e , R L d SOR L e , R L d SO2R L e , R L d SO2N(R L 1 )R L e , R L d N(R L 1 )R L e , R L d N(R L 1 )COR L e , R L d N(R L 1 )CON(R L 2 )R L e , R L d N(R L 1 )C(S)R L e , optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 alkoxyC1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C3-C 13 cycloalkyl, optionally substituted 3-13 membered heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl); and / or

[0578] WL 2 is absent, and W L 1 is independently an optionally substituted C1, C2 or C3 alkylene; preferably, W L 2 is absent, and W L 1 is a C1, C2 or C3 alkylene; and / or

[0579] wherein R L d , R L e , R L r , R L 1 and R L 2 are as defined above; and / or

[0580] m L is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 (preferably, m L is 8, 9, 10, 11, 12, 13, 14 or 15).

[0581] In one embodiment,

[0582] 1) the TYK2 ligand comprises the moiety shown in Formula 1 or 2 (preferably, the moiety shown in Formula 1; more preferably, the moiety shown in Formula 1-1G; even more preferably, the moiety shown in Formula 1-1I);

[0583] and / or

[0584] 2) the degron is the moiety shown in Formula 6B or 6C (preferably, the moiety shown in Formula 6B-10 or 6C-10, more preferably, the moiety shown in Formula 7AC or 7AQ); and preferably, R 1 ' is selected from the group consisting of: C(O);

[0585] and / or

[0586] 3) the linker moiety is as shown in Formula 9, wherein A L is the attachment position to the TYK2 ligand;

[0587] A L is selected from the group consisting of: absent, R L d COR L e , R L d C(O)N(R L 1 )RL e , R L d N(R L 1 )COR L e ; Preferably, A L is selected from the group: NHCO, CONH, CH2CONH, CH2NHCO; and / or

[0588] B L is none or R L d C(O)R L e ; Preferably, B L is none or C(O); More preferably, B L is C(O); and / or

[0589] W L 2 is none, and W L 1 is independently an optionally substituted C1 alkylene; Preferably, W L 2 is none, and W L 1 is C1 alkylene; and / or

[0590] m L is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 (Preferably, m L is 8, 9, 10, 11, 12, 13, 14 or 15; More preferably, m L is 8, 9, 10, 11, 12 or 13).

[0591] In one embodiment,

[0592] 1) the TYK2 ligand comprises a moiety shown in Formula 1 or 2 (Preferably, the moiety shown in Formula 1; More preferably, the moiety shown in Formula 1-1G; Even more preferably, the moiety shown in Formula 1-1I);

[0593] and / or

[0594] 2) the degron is a moiety shown in Formula 5-1 (Preferably, the moiety shown in Formula 5A; More preferably, the moiety shown in Formula 5A and Z E is linked to V E 1 or V E 4 );

[0595] and / or

[0596] 3) The connector part is as shown in Formula 9, where,

[0597] A L and B L , each time they appear, are independently divalent moieties selected from the group consisting of: none, R L d -R L e , R L d COR L e , R L d C(O)OR L e , R L d C(O)N(R L 1 )R L e , R L d C(S)N(R L 1 )R L e , R L d OR L e , R L d SR L e , R L d SOR L e , R L d SO2R L e , R L d SO2N(R L 1 )R L e , R L d N(R L 1 )R L e , R L d N(R L 1 )COR L e , R L d N(R L 1 )CON(RL 2 )R L e 、R L d N(R L 1 )C(S)R L e 、optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 heteroalkenylene, optionally substituted C2-C8 heteroalkynylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C3-C 13 cycloalkyl, optionally substituted 3- to 13-membered heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl; and / or

[0598] W L 1 are independently optionally substituted C1, C2 or C3 alkylene and W L 2 is absent or O; wherein, R L d 、R L e 、R L r 、R L 1 and R L 2 are as defined above; and / or

[0599] m L is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.

[0600] In one embodiment,

[0601] 1) the TYK2 ligand comprises a moiety represented by Formula 1 or 2 (preferably, the moiety represented by Formula 1; more preferably, the moiety represented by Formula 1-1G; even more preferably, the moiety represented by Formula 1-1I);

[0602] and / or

[0603] 2) the degradation tag is a moiety represented by Formula 5A (preferably, the moiety represented by Formula 5A and Z E is linked to V E 1 or V E 4 ; more preferably, the moiety represented by Formula 8A or 8G) and preferably, R 1’ is an optionally substituted aryl or an optionally substituted heteroaryl; preferably, an optionally substituted pyridyl;

[0604] and / or

[0605] 3) The linker moiety is as shown in Formula 9, wherein A L is the linking position to the TYK2 ligand;

[0606] A L is selected from the group consisting of: none, R L d N(R L 1 )COR L e , R L d CON(R L 1 )R L e ; preferably, A L is selected from the group consisting of: NHCO and CONH; and / or

[0607] B L is none; and / or

[0608] W L 1 is independently an optionally substituted C1, C2 or C3 alkylene and W L 2 is none or O; wherein, R L d , R L e , R L r , R L 1 and R L 2 are as defined above; and / or

[0609] m L is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 (preferably, 4, 5, 6, 7, 8, 9, 10, 11 or 12).

[0610] In one embodiment,

[0611] 1) The TYK2 ligand comprises the moiety shown in Formula 1 or 2 (preferably, the moiety shown in Formula 1; more preferably, the moiety shown in Formula 1-1G; even more preferably, the moiety shown in Formula 1-1I);

[0612] and / or

[0613] 2) The degrading tag is the moiety shown in Formula 5A and ZE Linked to V E 1 or V E 4 ; preferably, it is the moiety shown in Formula 8A) and preferably, R 1 ' is selected from the group consisting of: C(O), optionally substituted C(O)-CH2; preferably, R 1 ' is selected from the group consisting of: C(O), C(O)-CH2;

[0614] and / or

[0615] 3) The linker moiety is as shown in Formula 9, wherein A L is the linking position with the TYK2 ligand;

[0616] A L is selected from the group consisting of: none, R L d N(R L 1 )COR L e 、R L d CON(R L 1 )R L e ; preferably, A L is selected from the group consisting of: CH2NHCO and CH2CONH, NHCO and CONH; and / or

[0617] B L is none; and / or

[0618] W L 1 is independently an optionally substituted C1 alkylene and W L 2 is none; and / or

[0619] m L is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10).

[0620] In some embodiments, the compound comprises any one of the compounds in Table 1, Table 2 or Table 3.

[0621] In some embodiments, the heterobifunctional compound is selected from the group consisting of CPD-001 to CPD-199, or a pharmaceutically acceptable salt or analogue thereof. In some embodiments, the heterobifunctional compound is selected from the group consisting of CPD-038, CPD-039, CPD-040, CPD-047, CPD-084, CPD-085, CPD-099, CPD-100, CPD-110, CPD-112, CPD-114, CPD-115, CPD-121, CPD-124, CPD-125, CPD-126, CPD-127, CPD-131, CPD-133, CPD-134, CPD-143, CPD-144, CPD-148, CPD-150, CPD-151, CPD-155, CPD-157, CPD-158, CPD-159, CPD-164, CPD-167, CPD-175, and a pharmaceutically acceptable salt and analogue thereof.

[0622] In some embodiments, the compound comprises PD-038, CPD-039, CPD-040, CPD-047, CPD-084, CPD-085, CPD-099, CPD-100, CPD-110, CPD-112, CPD-114, CPD-115, CPD-121, CPD-124, CPD-125, CPD-126, CPD-127, CPD-131, CPD-133, CPD-134, CPD-143, CPD-144, CPD-148, CPD-150, CPD-151, CPD-155, CPD-157, CPD-158, CPD-159, CPD-164, CPD-167, CPD-175, or a pharmaceutically acceptable salt and analogue thereof.

[0623] In one embodiment, the heterobifunctional compound is N1-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N8-(2-((5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(methylcarbamoyl)pyridazin-3-yl)amino)-2-oxoethyl)octanediamide (CPD-038).

[0624] In one embodiment, the heterobifunctional compound is N1-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N9-(2-((5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(methylcarbamoyl)pyridazin-3-yl)amino)-2-oxoethyl)nonanediamide (CPD-039).

[0625] In one embodiment, the heterobifunctional compound is N1-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N10-(2-((5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(methylcarbamoyl)pyridazin-3-yl)amino)-2-oxoethyl)decanediamide (CPD-040).

[0626] In one embodiment, the heterobifunctional compound is 6-(2-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptanamido)acetamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-047).

[0627] In one embodiment, the heterobifunctional compound is N1-((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N9-(2-((5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(methylcarbamoyl)pyridazin-3-yl)amino)-2-oxoethyl)nonanediamide (CPD-084).

[0628] In one embodiment, the heterobifunctional compound is N1-((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N10-(2-((5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(methylcarbamoyl)pyridazin-3-yl)amino)-2-oxoethyl)decanediamide (CPD-085).

[0629] In one embodiment, the heterobifunctional compound is 6-((5-(4-(7-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoyl)piperazin-1-yl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-099).

[0630] In one embodiment, the heterobifunctional compound is 6-((5-(4-(8-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-8-oxooctanoyl)piperazin-1-yl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-100).

[0631] In one embodiment, the heterobifunctional compound is 6-(2-(11-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)undecanamide)acetamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-110).

[0632] In one embodiment, the heterobifunctional compound is 6-((5-(4-(8-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-8-oxooctanoyl)piperazin-1-yl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-112).

[0633] In one embodiment, the heterobifunctional compound is 6-((5-(4-(10-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-10-oxodecanoyl)piperazin-1-yl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-114).

[0634] In one embodiment, the heterobifunctional compound is 6-((5-(4-(9-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-9-oxononanoyl)piperazin-1-yl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-115).

[0635] In one embodiment, the heterobifunctional compound is 6-((5-((1-(10-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-10-oxodecanoyl)piperidin-4-yl)ethynyl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-121).

[0636] In one embodiment, the heterobifunctional compound is 6-((5-((1-(7-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoyl)azetidin-3-yl)ethynyl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-124).

[0637] In one embodiment, the heterobifunctional compound is 6-((5-((1-(8-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-8-oxooctanoyl)azetidin-3-yl)ethynyl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-125).

[0638] In one embodiment, the heterobifunctional compound is 6-((5-((1-(9-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-9-oxononanoyl)azetidin-3-yl)ethynyl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-126).

[0639] In one embodiment, the heterobifunctional compound is 6-((5-((1-(10-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-10-oxodecanoyl)azetidin-3-yl)ethynyl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-127).

[0640] In one embodiment, the heterobifunctional compound is N1-((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N8-((6-((5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(methylcarbamoyl)pyridazin-3-yl)amino)pyridin-3-yl)methyl)octanediamide (CPD-131).

[0641] In one embodiment, the heterobifunctional compound is N1-((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N10-((6-((5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(methylcarbamoyl)pyridazin-3-yl)amino)pyridin-3-yl)methyl)decanediamide (CPD-133).

[0642] In one embodiment, the heterobifunctional compound is 6-((5-((1-(5-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-5-oxopentanoyl)piperidin-4-yl)ethynyl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-134).

[0643] In one embodiment, the heterobifunctional compound is 6-((5-((8-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-8-oxooctyl)carbamoyl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-143).

[0644] In one embodiment, the heterobifunctional compound is 6-((5-((9-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-9-oxononyl)carbamoyl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-144).

[0645] In one embodiment, the heterobifunctional compound is 6-((5-(4-(1-(7-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoyl)piperidin-4-yl)piperazin-1-yl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-148).

[0646] In one embodiment, the heterobifunctional compound is 6-((5-(4-(1-(9-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-9-oxononanoyl)piperidin-4-yl)piperazin-1-yl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-150).

[0647] In one embodiment, the heterobifunctional compound is 6-((5-(4-(1-(10-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-10-oxodecanoyl)piperidin-4-yl)piperazin-1-yl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-151).

[0648] In one embodiment, the heterobifunctional compound is 6-((5-((5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentyl)carbamoyl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-155).

[0649] In one embodiment, the heterobifunctional compound is 6-((5-((7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptyl)carbamoyl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-157).

[0650] In one embodiment, the heterobifunctional compound is 6-((5-((8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)carbamoyl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-158).

[0651] In one embodiment, the heterobifunctional compound is 6-((5-((2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethyl)carbamoyl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-159).

[0652] In one embodiment, the heterobifunctional compound is 6-((5-((5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)pentyl)carbamoyl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-164).

[0653] In one embodiment, the heterobifunctional compound is 6-((5-((8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)octyl)carbamoyl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-167).

[0654] In one embodiment, the heterobifunctional compound is 6-((5-((3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)propyl)carbamoyl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-175).

[0655] Without being bound by any particular theory, it is believed herein that in some embodiments, linking VHL-1 or pomalidomide to either portion of the molecule recruits the VHL E3 ligase or the Cereblon E3 ligase to TYK2.

[0656] Compared to WT (wild-type) cells, the heterobifunctional compounds disclosed herein can selectively affect TYK2-mediated disease cells (i.e., the heterobifunctional compounds are capable of killing or inhibiting the growth of cells of a TYK2-mediated disease while also having a relatively low ability to lyse or inhibit the growth of WT cells), e.g., having a GI that is at least 1.5-fold lower, at least 2-fold lower, at least 2.5-fold lower, at least 3-fold lower, at least 4-fold lower, at least 5-fold lower, at least 6-fold lower, at least 7-fold lower, at least 8-fold lower, at least 9-fold lower, at least 10-fold lower, at least 15-fold lower, or at least 20-fold lower for one or more TYK2-mediated disease cells 50 compared to the GI for one or more WT cells (e.g., WT cells of the same species and tissue type as the TYK2-mediated disease cells). 50 .

[0657] In some aspects, provided herein is a method of identifying a heterobifunctional compound that mediates the degradation or reduction of TYK2, the method comprising: providing a heterobifunctional test compound comprising a TYK2 ligand conjugated to a degradation tag via a linker; contacting the heterobifunctional test compound with a cell comprising a ubiquitin ligase and TYK2; determining whether the level of TYK2 in the cell is reduced; and identifying the heterobifunctional test compound that mediates the degradation or reduction of TYK2 as a heterobifunctional compound. In certain embodiments, the cell is a cancer cell. In certain embodiments, the cancer cell is a TYK2-mediated cancer cell.

[0658] Synthesis and Testing of Heterobifunctional Compounds

[0659] The binding affinity of newly synthesized heterobifunctional compounds can be evaluated using standard biophysical assays known in the art (such as isothermal titration calorimetry (ITC), surface plasmon resonance (SPR)). Cellular assays can then be used to evaluate the ability of the heterobifunctional compounds to induce TYK2 degradation and inhibit cancer cell proliferation. In addition to evaluating the induced changes in the protein levels of TYK2, TYK2 mutants, TYK2 deletions, or TYK2 fusion proteins by the heterobifunctional compounds, protein-protein interactions or the enzymatic activities of kinases can also be evaluated. Assays applicable to any or all of these steps are known in the art and include, for example, Western blotting, quantitative mass spectrometry (MS) analysis, flow cytometry, enzymatic activity assays, ITC, SPR, cell growth inhibition, xenografting, orthotopic, and patient-derived xenograft models. Cell lines applicable to any or all of these steps are known in the art and include MOLT-4, NOMO-1, and PBMC cell lines. Suitable mouse models applicable to any or all of these steps are known in the art and include subcutaneous xenograft models, orthotopic models, patient-derived xenograft models, and patient-derived orthotopic models.

[0660] As a non-limiting example, detailed synthetic protocols are described in the examples of specific exemplary heterobifunctional compounds.

[0661] Pharmaceutically acceptable isotopic variants of the compounds disclosed herein are contemplated and can be synthesized using conventional methods known in the art or corresponding to those described in the examples (replacing the appropriate reagents with the appropriate isotopic variants of these reagents). Specifically, an isotopic variant is a compound in which at least one atom is replaced with an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Isotopes available in the art include, for example, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine. Exemplary isotopes include, for example 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 32 P, 35 S, 18 F, and 36 Cl.

[0662] Isotopic variants (e.g., containing 2Isotope variants of H can provide therapeutic advantages due to higher metabolic stability (e.g., increased in vivo half-life or reduced dose requirements). In addition, certain isotope variants (especially those containing radioactive isotopes) can be used for drug or substrate tissue distribution studies. In particular, the radioactive isotopes tritium ( 3 H) and carbon-14 ( 14 C), given their ease of incorporation and existing detection methods, can be used for this purpose.

[0663] Pharmaceutically acceptable solvates of the compounds disclosed herein are contemplated. Solvates can be produced, for example, by replacing the solvent used to crystallize the compounds disclosed herein with an isotope variant (e.g., D2O instead of H2O, d6-acetone instead of acetone, or d6-DMSO instead of DMSO).

[0664] Pharmaceutically acceptable fluoro variants of the compounds disclosed herein are contemplated and can be synthesized using conventional methods known in the art or methods corresponding to those described in the Examples (replacing appropriate reagents with appropriate fluoro variants of those reagents). Specifically, a fluoro variant is a compound in which at least one hydrogen atom is replaced by a fluorine atom. Fluoro variants can provide therapeutic advantages due to higher metabolic stability (e.g., increased in vivo half-life or reduced dose requirements).

[0665] Pharmaceutically acceptable prodrugs of the compounds disclosed herein are contemplated and can be synthesized using conventional methods known in the art or methods corresponding to those described in the Examples (e.g., converting a hydroxyl or carboxylic acid group to an ester group). As used herein, a "prodrug" refers to a compound that can be converted to a therapeutic agent by some chemical or physiological process (e.g., an enzymatic process and metabolic hydrolysis). Thus, the term "prodrug" also refers to a precursor of a pharmaceutically acceptable bioactive compound. A prodrug may be inactive, i.e., an ester, when administered to a subject, but is converted to an active compound in vivo, e.g., by hydrolysis to the free carboxylic acid or free hydroxyl. Prodrug compounds generally provide the advantages of solubility, tissue compatibility, or delayed release in an organism. The term "prodrug" is also intended to include any covalently bonded carrier that releases an active compound in vivo when such prodrug is administered to a subject. Prodrugs of an active compound can be prepared by modifying the functional groups present in the active compound in such a way that the modification cleaves in a conventional operation or in vivo to form the parent active compound. Prodrugs include compounds in which a hydroxyl, amino, or mercapto group is bonded to any group that cleaves to form a free hydroxyl, free amino, or free mercapto group, respectively, when the prodrug of the active compound is administered to a subject. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohols or acetamides in active compounds, and formamide and benzamide derivatives of amine functional groups.

[0666] Characterization of Exemplary Heterobifunctional Compounds

[0667] The synthesized heterobifunctional compounds were first characterized using immunoblot analysis. MOLT-4 cells were treated with bifunctional degraders at 0.5 and 5 μM concentrations for 24 hours. Compounds CPD-038, CPD-039, and CPD-040 were able to significantly reduce the TYK2 protein level (Table 2). We further confirmed that CPD-038, CPD-039, and CPD-040 were able to reduce the TYK2 protein level in MOLT-4 cells in a concentration-dependent manner. More importantly, CPD-038, CPD-039, and CPD-040 had higher selectivity for the degradation of TYK2 compared to JAK1 / 2 / 3 proteins( Figure 1 ). Our data further showed that CPD-155, CPD-157, and CPD-158 were very effective in reducing the TYK2 protein level in NOMO-1 cells( Figure 2 ; Table 3). In addition, treatment with heterobifunctional compounds CPD-155, CPD-158, and CPD-164 significantly reduced the phosphorylation of STAT1 / 3 downstream of IFNα stimulation, which was associated with the reduction of the TYK2 protein level in Jurkat cells( Figure 3 ), indicating a significant inhibition of type I IFN immune response through TYK2 downregulation. Therefore, these selective TYK2 degraders may provide a good therapeutic window clinically.

[0668] Term Definitions

[0669] As used herein, the terms "comprising" and "including" are used in their open, non-limiting sense.

[0670] As used herein, the terms "heterobifunctional compound" and "bivalent compound" may be used interchangeably.

[0671] As used herein, the terms "tyrosine kinase 2 ligand" and "TYK2 ligand" or "TYK2 targeting moiety" shall be interpreted to include any molecule, ranging from small molecules to large proteins, that associates or binds with the TYK2 protein. The TYK2 ligand is capable of binding to the TYK2 protein, including TYK2, TYK2 mutants, TYK2 deletions, or TYK2 fusion proteins. The TYK2 ligand can be, for example but not limited to, a small molecule compound (i.e., a molecule with a molecular weight less than about 1.5 kilodaltons (kDa)), a peptide or polypeptide, a nucleic acid or oligonucleotide, a carbohydrate such as an oligosaccharide, or an antibody or a fragment thereof.

[0672] "Alkyl" refers to a straight-chain or branched-chain hydrocarbon chain group consisting only of carbon and hydrogen atoms, without unsaturation. The alkyl group may contain one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen or sixteen carbon atoms. In certain embodiments, the alkyl group contains one to fifteen carbon atoms (e.g., C1-C 15 alkyl). In certain embodiments, the alkyl group contains one to thirteen carbon atoms (e.g., C1-C 13 alkyl). In certain embodiments, the alkyl group contains one to eight carbon atoms (e.g., C1-C8 alkyl). In certain embodiments, the alkyl group contains five to fifteen carbon atoms (e.g., C5-C 15 alkyl). In certain embodiments, the alkyl group contains five to eight carbon atoms (e.g., C5-C8 alkyl). The alkyl group is connected to the rest of the molecule by a single bond, such as methyl (Me), ethyl (Et), n-propyl (nPr), 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (tert-butyl), pentyl, 3-methylhexyl, 2-methylhexyl, etc.

[0673] "Alkenyl" refers to a straight-chain or branched-chain hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one double bond. The alkenyl group may contain two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen or sixteen carbon atoms. In certain embodiments, the alkenyl group contains two to twelve carbon atoms (e.g., C2-C 12 alkenyl). In certain embodiments, the alkenyl group contains two to eight carbon atoms (e.g., C2-C8 alkenyl). In certain embodiments, the alkenyl group contains two to six carbon atoms (e.g., C2-C6 alkenyl). In certain embodiments, the alkenyl group contains two to four carbon atoms (e.g., C2-C4 alkenyl). The alkenyl group is connected to the rest of the molecule by a single bond, such as ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, pent-1,4-dienyl, etc. As used herein, the term "allyl" refers to the –CH2CH=CH2 group.

[0674] As used herein, "alkynyl" refers to a straight-chain or branched-chain hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one triple bond. The alkynyl group may contain two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen or sixteen carbon atoms. In certain embodiments, the alkynyl group contains two to twelve carbon atoms (e.g., C2-C 12alkynyl). In certain embodiments, the alkynyl contains two to eight carbon atoms (e.g., C2-C8 alkynyl group). In certain embodiments, the alkynyl contains two to six carbon atoms (e.g., C2-C6 alkynyl). In certain embodiments, the alkynyl contains two to four carbon atoms (e.g., C2-C4 alkynyl). The alkynyl is attached to the remainder of the molecule by a single bond. Examples of such groups include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, and the like.

[0675] Unless otherwise specified, the term "heteroalkyl" by itself or in combination with another term means a stable straight or branched chain consisting of the stated number of carbon atoms and one to three heteroatoms selected from O, N, Si, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatoms O, N, and S can be located at any position within the heteroalkyl. The heteroatom Si can be located at any position within the heteroalkyl, including the position where the alkyl is attached to the remainder of the molecule. Examples include: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -Si(CH3)3, and -CH2-CH=N-OCH3. Up to two heteroatoms can be consecutive, such as -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. Similarly, unless otherwise specified, the terms "heteroalkenyl" and "heteroalkynyl" by themselves or in combination with another term mean an alkenyl or alkynyl, respectively, containing the stated number of carbons and having one to three heteroatoms selected from O, N, Si, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatoms O, N, and S can be located at any position within the heteroalkyl.

[0676] As used herein, the term "alkoxy" refers to an alkyl as defined herein attached to the remainder of the molecule through an oxygen atom. Examples of such groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, and the like.

[0677] As used herein, the term "aryl" refers to a group derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon atoms. The aryl can contain 6 to 18 carbon atoms, wherein at least one ring in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n + 2)π - electron system consistent with the Hückel theory. In certain embodiments, the aryl contains six to fourteen carbon atoms (e.g., C6-C 14aryl or 6-14 membered aryl). In certain embodiments, the aryl contains six to ten carbon atoms (e.g., C6-C 10 aryl or 6-10 membered aryl). Examples of such groups include, but are not limited to, phenyl, fluorenyl, and naphthyl. As used herein, the terms “Ph” and “phenyl” refer to the —C6H5 group.

[0678] The term “heteroaryl” refers to a group derived from a 3- to 18-membered aromatic group containing 2 to 17 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur (i.e., 3-18 membered heteroaryl). As used herein, the heteroaryl may be a monocyclic, bicyclic, tricyclic, or tetracyclic system, wherein at least one ring in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2)π-electron system consistent with Hückel's theory. In certain embodiments, heteroaryl refers to a group derived from a 3- to 10-membered aromatic ring group (3-10 membered heteroaryl). In certain embodiments, heteroaryl refers to a group derived from a 5- to 7-membered aromatic ring (5-7 membered heteroaryl). Heteroaryl includes fused ring or bridged ring systems. The heteroatoms in heteroaryl are optionally oxidized. One or more nitrogen atoms (if present) are optionally quaternized. Heteroaryl is attached to the remainder of the molecule through any atom of the ring. Examples of such groups include, but are not limited to, pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furanopyridyl, and the like. In certain embodiments, heteroaryl is attached to the remainder of the molecule through a ring carbon atom. In certain embodiments, heteroaryl is attached to the remainder of the molecule through a nitrogen atom (N-linked) or a carbon atom (C-linked). For example, a group derived from pyrrole can be pyrrol-1-yl (N-linked) or pyrrol-3-yl (C-linked). For example, a group derived from imidazole can be imidazol-1-yl (N-linked) or imidazol-3-yl (C-linked).

[0679] As used herein, the term "heterocyclic group" refers to a non-aromatic, monocyclic, bicyclic, tricyclic or tetracyclic group having a total of from 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 ring atoms in its ring system, and containing from 3 to 12 (such as 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms and from 1 to 4 heteroatoms each independently selected from O, S and N, with the proviso that the rings of said group do not contain two adjacent O atoms or two adjacent S atoms. The heterocyclic group may include fused ring, bridged ring or spiro ring systems. In certain embodiments, the heterocyclic group includes from 3 to 10 ring atoms (3-10 membered heterocyclic group). In certain embodiments, the heterocyclic group includes from 3 to 8 ring atoms (3-8 membered heterocyclic group). In certain embodiments, the heterocyclic group includes from 3 to 6 ring atoms (3-6 membered heterocyclic group). In certain embodiments, the heterocyclic group includes from 4 to 6 ring atoms (4-6 membered heterocyclic group). The heterocyclic group may contain an oxo substituent on any available atom that results in a stable compound. For example, such a group may contain an oxo group at an available carbon atom or nitrogen atom. If chemically feasible, such a group may contain more than one oxo group. Further, it should be understood that when such a heterocyclic group contains a sulfur atom, the sulfur atom may be oxidized by one or two oxygen atoms to provide a sulfoxide or a sulfone. An example of a 4-membered heterocyclic group is azetidinyl (derived from azetidine). An example of a 5-membered heterocyclic alkyl group is pyrrolidinyl. An example of a 6-membered heterocyclic alkyl group is piperidinyl. An example of a 9-membered heterocyclic alkyl group is indolinyl. An example of a 10-membered heterocyclic alkyl group is 4H-quinolyl. Other examples of such heterocyclic groups include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidine, morpholine, thiomorpholine, oxathianyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, thiepanyl, oxazepine, diazepine, thiazepine, 1,2,3,6-tetrahydropyridyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxolanyl, 1,3-dioxolanyl, pyrazolinyl, dithiolanyl, dithiolothionyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 3H-indolyl, quinolyl, 3-oxopiperazinyl, 4-methylpiperazinyl, 4-ethylpiperazinyl, and 1-oxo-2,8-diazaspiro[4.5]dec-8-yl. The heteroaryl may be attached to the remainder of the molecule through a carbon atom (C-linked) or a nitrogen atom (N-linked). For example, a group derived from piperazine may be piperazin-1-yl (N-linked) or piperazin-2-yl (C-linked).

[0680] The term "cycloalkyl" or "carbocyclic group" refers to a saturated, monocyclic, bicyclic, tricyclic or tetracyclic group having a total of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms in its ring system. Cycloalkyl can be fused, bridged or spiro. In certain embodiments, cycloalkyl includes 3 to 8 carbocyclic atoms (3-8 membered or C3-C8 carbocyclic group). In certain embodiments, cycloalkyl includes 3 to 10 carbocyclic atoms (C3-C 10 cycloalkyl). Examples of such groups include, but are not limited to, cyclopropyl (cPr), cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptyl, adamantyl, and the like.

[0681] As used herein, the term "spiro" has its conventional meaning, i.e., any ring system containing two or more rings, wherein two rings have a common ring carbon. As defined herein, each ring of a spiro system independently contains 3 to 20 ring atoms. Preferably, it has 3 to 10 ring atoms. Non-limiting examples of spiro systems include spiro[3.3]heptane, spiro[3.4]octane, and spiro[4.5]decane.

[0682] The term "cyano" refers to the -C≡N group.

[0683] The "aldehyde" group refers to the -C(O)H group.

[0684] "Alkoxy" refers to -O-alkyl as defined herein.

[0685] "Alkoxycarbonyl" refers to -C(O)-alkoxy as defined herein.

[0686] "Alkylaminoalkyl" refers to -alkyl-NR-alkyl as defined herein.

[0687] "Alkylsulfonyl" refers to -SO2alkyl as defined herein.

[0688] "Amino" refers to optionally substituted -NH2.

[0689] The "aminoalkyl" group refers to -alkyl-amino group (such as -CH2(NH2)) as defined herein.

[0690] The "alkylamino" group refers to -amino-alkyl group (such as -NH(CH3)) as defined herein.

[0691] The "cycloalkylamino" group refers to -amino-cycloalkyl group (such as ) as defined herein.

[0692] "Aminocarbonyl" refers to -C(O)-amino as defined herein.

[0693] "Arylalkyl" means -alkylaryl, where alkyl and aryl are as defined herein.

[0694] "Aryloxy" group means -O-aryl and -O-heteroaryl, as defined herein.

[0695] "Aryloxycarbonyl" means -C(O)-aryloxy, as defined herein.

[0696] "Arylsulfonyl" means -SO2aryl, as defined herein.

[0697] "Carbonyl" means -C(O)- group, as defined herein.

[0698] "Carboxylic acid" group means -C(O)OH group.

[0699] "Cyclalkyloxy" means -O-cycloalkyl, as defined herein.

[0700] "Halogenated" or "halogen" group means fluorine, chlorine, bromine or iodine.

[0701] "Haloalkyl" means an alkyl group substituted by one or more halogen atoms.

[0702] "Hydroxy" means -OH group.

[0703] "Nitro" group means -NO2 group.

[0704] "Oxo" group means =O substituent.

[0705] "Trihalomethyl" means a methyl group substituted by three halogen atoms.

[0706] The term "alkylene" is a bidentate group obtained by removing a hydrogen atom from an alkyl group as defined above. Examples of such groups include, but are not limited to, -CH2-, -CH2CH2-, etc. The term "cycloalkylene" or "carbocyclylene" is a divalent group obtained by removing a hydrogen atom from a cycloalkyl ring as defined above. Examples of such groups include, but are not limited to, cyclopropylidene, cyclobutylidene, cyclopentylidene, cyclopentenylidene, cyclohexylidene, cycloheptylidene, etc. Similarly, the terms "alkenylene", "alkynylene", "alkoxyalkylene", "haloalkylene", "hydroxyalkylene", "aminoalkylene", "alkylaminoalkylene" and "heterocyclylene" are divalent groups obtained by removing a hydrogen atom from an alkenyl, alkynyl, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl and alkylaminoalkyl group, respectively.

[0707] Unless otherwise specified, the term "heteroalkylene" by itself or in combination with another term refers to a straight-chain, branched-chain, or divalent group derived from a heteroalkyl composed of the stated number of carbon atoms and one to three heteroatoms selected from O, N, Si, and S, and in which the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatoms O, N, and S can be located at any position within the heteroalkyl. The heteroatom Si can be located at any position within the heteroalkyl, including the position where the alkyl is attached to the remainder of the molecule. Examples include: -CH2-CH2-O-CH2-, -CH2-CH2-NH-CH2-, -CH2-CH2-N(CH3)-CH2-, -CH2-S-CH2-CH2-, -CH2-CH2-S(O)-CH2-, -CH2-CH2-S(O)2-CH2-, -CH(Si(CH3)3)-CH2-, and -CH2-CH=N-OCH2-. Up to two heteroatoms can be consecutive, such as -CH2-NH-OCH2- and -CH(O-Si(CH3)3)-CH2-. Similarly, unless otherwise specified, the terms "heteroalkenylene" and "heteroalkynylene" by themselves or in combination with another term denote an alkenylene or alkynylene, respectively, containing the stated number of carbons and having one to three heteroatoms selected from O, N, Si, and S, and in which the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatoms O, N, and S can be located at any position within the heteroalkyl.

[0708] When referring to a moiety, the term "length" means the minimum number of carbons and / or heteroatoms from one end of the moiety to the other end. When referring to a linker, it means the minimum number of atoms from the end attached to the TRK ligand to the end attached to the degradation tag. It applies to cases where the linker is linear or branched, as well as cases where the linker contains a ring system.

[0709] Unless otherwise indicated, the term "substituted" means that the designated group or moiety bears one or more substituents independently selected from: C1-C4 alkyl, aryl, heteroaryl, aryl-C1-C4 alkyl-, heteroaryl-C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, OC1-C4 alkylphenyl, -C1-C4 alkylOH, OC1-C4 haloalkyl, halogen, OH, NH2, C1-C4 alkylNH2, N(C1-C4 alkyl)(C1-C4 alkyl), NH(C1-C4 alkyl), N(C1-C4 alkyl)(C1-C4 alkylphenyl), NH(C1-C4 alkylphenyl), cyano, nitro, oxo, CO2H, C(O)OC1-C4 alkyl, CON(C1-C4 alkyl)(C1-C4 alkyl), CONH(C1-C4 alkyl), CONH2, NHC(O)(C1-C4 alkyl), NHC(O)(phenyl), N(C1-C4 alkyl)C(O)(C1-C4 alkyl), N(C1-C4 alkyl)C(O)(phenyl), C(O)C1-C4 alkyl, C(O)C1-C4 alkylphenyl, C(O)C1-C4 haloalkyl, OC(O)C1-C4 alkyl, -SO2(C1-C4 alkyl), -SO2(phenyl), -SO2(C1-C4 haloalkyl), -SO2NH2, SO2NH(C1-C4 alkyl), SO2NH(phenyl), -NHSO2(C1-C4 alkyl), -NHSO2(phenyl), and NHSO2(C1-C4 haloalkyl).

[0710] The term "absent" means that an atom or moiety is not present and there is a bond between adjacent atoms in the structure.

[0711] The term "optionally substituted" means that the designated group may be unsubstituted or substituted with one or more substituents as defined herein. It should be understood that in the compounds of the present invention, when a group is referred to as "unsubstituted" or is "substituted" with a group having fewer valences than all the atoms in the compound to be substituted, the remaining valences of the group are filled with hydrogen. For example, if a C6 aryl, also referred to herein as "phenyl", is substituted with an additional substituent, one of ordinary skill in the art will understand that such a group has 4 open positions on the carbon atoms of the C6 aromatic ring (6 initial positions, minus one position to which the remainder of the compound of the present invention is attached and one additional substituent, leaving 4 positions open). In this case, each of the remaining 4 carbon atoms is bonded to a hydrogen atom to fill their valences. Similarly, if a C6 aryl in the compounds of the present invention is referred to as "disubstituted", one of ordinary skill in the art will understand that it means that the C6 aryl has 3 unsubstituted remaining carbon atoms. Each of these three unsubstituted carbon atoms is bonded to a hydrogen atom to fill their valences. Unless otherwise indicated, an optionally substituted group may be a group that is unsubstituted or substituted with one or more substituents selected from: halogen, CN, NO2, ORm , SR m , NR n R o , COR m , CO2R m , CONR n R o , SOR m , SO2R m , SO2NR n R o , NR n COR o , NR m C(O)NR n R o , NR n , SOR o , NR n , SO2R o , C1-C8 alkyl, C1-C8 alkoxy C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 hydroxyalkyl, C1-C8 alkylamino C1-C8 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocyclic group, C2-C8 alkenyl, C2-C8 alkynyl, aryl, and heteroaryl, wherein R m , R n and Ro are independently selected from: none, hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloalkyl, 3-7 membered heterocyclic group, aryl and heteroaryl, or R n and R o and the atoms to which they are attached together form a 3-8 membered cycloalkyl ring or heterocyclic ring.

[0712] As used herein, the same symbol in different formulas represents a different definition. For example, the definition of R 1 in Formula 1 is the definition for Formula 1, and the definition of R 6 in Formula 6 is the definition for Formula 6.

[0713] As used herein, each unit in the linker moiety (e.g., -(W L 1 -W L 2 )- ) can be the same as or different from each other. In certain embodiments, each unit in the linker moiety is the same as each other.

[0714] As used herein, when m (or n or o or p) is limited by a range, for example, "m is from 0 to 15" or "m = 0 - 3" means that m is an integer from 0 to 15 (i.e., m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15) or m is an integer from 0 to 3 (i.e., m is 0, 1, 2 or 3) or any integer within the defined range.

[0715] "Pharmaceutically acceptable salts" include acid and base addition salts. Pharmaceutically acceptable salts of any of the heterobifunctional compounds described herein are intended to include any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0716] "Pharmaceutically acceptable acid addition salts" are those salts that retain the biological effectiveness and properties of the free base, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, etc. Also included are salts formed with organic acids, such as aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc., and including, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. Thus, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, octanoates, isobutyrates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, toluates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, etc. Salts of amino acids are also contemplated, such as arginine salts, gluconates and galacturonates (see, e.g., Berge SM et al., "Pharmaceutical Salts" Journal of Pharmaceutical Science, 66:1 - 19 (1997), which is hereby incorporated by reference in its entirety). Acid addition salts of basic compounds can be prepared by contacting the free base form with a sufficient amount of the desired acid according to methods and techniques familiar to those skilled in the art to produce the salt.

[0717] "Pharmaceutically acceptable base addition salts" refer to those salts which retain the biological effectiveness and properties of the free acids and which are not biologically or otherwise undesirable. These salts are prepared by the addition of an inorganic or organic base to the free acid. Pharmaceutically acceptable base addition salts can be formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, etc. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, salts of substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucosamine, glucosamine, meglumine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. See Berge et al., supra.

[0718] Pharmaceutical composition

[0719] In some aspects, the compositions and methods described herein include the manufacture and use of pharmaceutical compositions and medicaments comprising one or more of the heterobifunctional compounds disclosed herein. The pharmaceutical compositions themselves are also included.

[0720] In some aspects, the compositions disclosed herein may include other compounds, drugs, or agents for treating cancer. For example, in some cases, the pharmaceutical compositions disclosed herein can be combined with one or more (e.g., one, two, three, four, five, or fewer than ten) compounds. Such additional compounds can include, for example, conventional chemotherapeutic agents or any other cancer treatment known in the art. When co-administered, the heterobifunctional compounds disclosed herein can act in combination with conventional chemotherapeutic agents or any other cancer treatment known in the art to produce a mechanistically additive or synergistic therapeutic effect.

[0721] In some aspects, the pH of the compositions disclosed herein can be adjusted with a pharmaceutically acceptable acid, base, or buffer to enhance the stability of the heterobifunctional compound or its delivery form.

[0722] A pharmaceutical composition generally comprises a pharmaceutically acceptable excipient, adjuvant or carrier. As used herein, the phrase "pharmaceutically acceptable" refers to molecular entities and compositions that are generally considered physiologically tolerable and that typically do not produce an allergic or similar untoward reaction when administered to a human, such as gastric upset, dizziness and the like. A pharmaceutically acceptable excipient, adjuvant or carrier is a substance that can be administered with the compounds of the invention to a patient and that does not impair the pharmacological activity thereof and is non-toxic when administered in a dose sufficient to deliver a therapeutically effective amount of the compound. Exemplary conventional non-toxic pharmaceutically acceptable excipients, adjuvants and carriers include, but are not limited to, saline, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like which are compatible with drug administration.

[0723] In particular, pharmaceutically acceptable excipients, adjuvants and carriers useful in the pharmaceutical compositions of the invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants for pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins such as human serum albumin, buffering substances such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polypropylene-block polymers, polyethylene glycol and lanolin. Cyclodextrins such as α-, β- and γ-cyclodextrins can also be advantageously used to enhance the delivery of the compounds of the formula described herein.

[0724] Depending on the dosage form selected for delivering the heterobifunctional compounds disclosed herein, different pharmaceutically acceptable excipients, adjuvants and carriers can be used. In the case of oral tablets, pharmaceutically acceptable excipients, adjuvants and carriers that can be used include lactose and corn starch. Lubricants such as magnesium stearate are generally also added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When an oral aqueous suspension or emulsion is administered, the active ingredient can be suspended or dissolved in the oil phase and mixed with an emulsifying or suspending agent. If desired, certain sweetening, flavoring or coloring agents can be added.

[0725] As used herein, the hetero-bifunctional compounds disclosed herein are defined to include their pharmaceutically acceptable derivatives or prodrugs. A "pharmaceutically acceptable derivative" means any pharmaceutically acceptable salt, solvate, or prodrug of a compound or agent disclosed herein, such as a carbamate, ester, phosphate, salt of an ester, or other derivative, which is capable of providing (directly or indirectly) a compound described herein or its active metabolite or residue upon administration to a recipient. Particularly preferred derivatives and prodrugs are those that increase the bioavailability of a compound disclosed herein (e.g., by making an orally administered compound more readily absorbed into the blood) or enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species when the compound disclosed herein is administered to a subject. Preferred prodrugs include derivatives in which a group that enhances water solubility or active transport across an intestinal membrane is attached to a formula structure described herein. Such derivatives can be identified by those of ordinary skill in the art without undue experimentation. Nevertheless, reference is made to Burger's Medicinal Chemistry and Drug Discovery, 5th Edition, Volume 1: Principles and Practice, which is incorporated herein by reference to the extent it teaches such derivatives.

[0726] The hetero-bifunctional compounds disclosed herein include pure enantiomers, mixtures of enantiomers, pure diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates and meso forms, and their pharmaceutically acceptable salts, solvate complexes, morphological forms, or deuterated derivatives.

[0727] In some aspects, the pharmaceutical compositions disclosed herein may comprise an effective amount of one or more hetero-bifunctional compounds. As used herein, the terms "effective amount" and "effective treatment" refer to an amount or concentration of one or more compounds or pharmaceutical compositions described herein that is effective, within its dosing range, over a period of time (including acute or chronic dosing and regular or continuous dosing), to cause a desired effect or physiological outcome (e.g., treating or preventing cell growth, cell proliferation, or cancer). In some aspects, the pharmaceutical composition may further comprise one or more additional compounds, drugs, or agents for treating cancer (e.g., conventional chemotherapeutic agents) in an amount effective to cause a desired effect or physiological outcome (e.g., treating or preventing cell growth, cell proliferation, or cancer).

[0728] In some aspects, the pharmaceutical compositions disclosed herein may be formulated for sale in the United States, imported into the United States, or exported from the United States.

[0729] Administration of the Pharmaceutical Composition

[0730] The pharmaceutical compositions disclosed herein can be formulated or adjusted for administration to a subject by any route, e.g., any route approved by the Food and Drug Administration (FDA). Exemplary methods are described in the FDA Data Standards Manual (DSM) (available at http: / / www.fda.gov / Drugs / DevelopmentApprovalProcess / FormsSubmissionRequirements / ElectronicSubmissions / DataStandardsManualmonographs). In particular, the pharmaceutical compositions can be formulated for oral, parenteral, or transdermal delivery and administered by oral, parenteral, or transdermal routes. As used herein, the term "parenteral" includes subcutaneous, intradermal, intravenous, intramuscular, intraperitoneal, intra-articular, intra-arterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques.

[0731] For example, the pharmaceutical compositions disclosed herein can be administered, for example, topically, rectally, nasally (e.g., by inhalation spray or nebulizer), orally, vaginally, subcutaneously (e.g., by injection or by an implanted reservoir), or ophthalmically.

[0732] For example, the pharmaceutical compositions of the present invention can be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, emulsions, and aqueous suspensions, dispersions, and solutions.

[0733] For example, the pharmaceutical compositions of the present invention can be used for rectal administration in the form of suppositories. These compositions can be prepared by mixing the compounds of the present invention with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and will thus melt in the rectum to release the active ingredient. Such materials include but are not limited to cocoa butter, beeswax, and polyethylene glycol.

[0734] For example, the pharmaceutical compositions of the present invention can be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulations and can be prepared as a saline solution, using benzyl alcohol or other suitable preservatives, absorption enhancers to increase bioavailability, fluorocarbons, or other solubilizing or dispersing agents known in the art.

[0735] For example, the pharmaceutical composition of the present invention can be administered by injection (such as as a solution or powder). Such compositions can be formulated using suitable dispersing or wetting agents (such as Tween 80) and suspending agents according to techniques known in the art. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Mannitol, water, Ringer's solution, and isotonic sodium chloride solution can be used in acceptable carriers and solvents. Additionally, a sterile, fixed oil is commonly used as a solvent or suspending medium. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives, can be used to prepare injectables, and natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially their polyoxylated forms, can also be used to prepare injectables. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersing agents, or carboxymethyl cellulose or similar dispersing agents, which are commonly used to formulate pharmaceutically acceptable dosage forms, such as emulsions and / or suspensions. Other commonly used surfactants, such as Tweens, Spans, or other similar emulsifying agents or bioavailability enhancers, which are commonly used to manufacture pharmaceutically acceptable solid, liquid, or other dosage forms, can also be used for formulation purposes.

[0736] In some aspects, the effective doses of the pharmaceutical compositions of the present invention include, but are not limited to: for example, about 0.00001, 0.0001, 0.001, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2500, 5000, or 10000 mg / kg / day, or according to the requirements of a specific pharmaceutical composition.

[0737] When the pharmaceutical compositions disclosed herein comprise the heterobifunctional compounds described herein and one or more additional compounds (e.g., one or more additional compounds, drugs, or agents that are useful in the treatment of cancer or any other disorder or disease, including disorders or diseases known to be associated with or caused by cancer, inflammation, and / or autoimmune diseases), the dosage levels of the heterobifunctional compounds and the additional compounds can both be between about 1% and 100%, more preferably between about 5% and 95% of the usual dosage administered in a single-drug treatment regimen. The additional agent(s) can be administered separately from the compounds of the invention as part of a multi-dose regimen. Alternatively, these agents can be part of a single dosage form, mixed with the compounds of the invention in a single composition.

[0738] In some aspects, the pharmaceutical compositions disclosed herein can be included in a container, package, or dispenser together with instructions for administration.

[0739] Methods of treatment

[0740] The methods disclosed herein contemplate administering an effective amount of a compound or composition to achieve a desired or specified effect. Generally, the compounds or compositions of the invention are administered from about 1 to about 6 times per day, or, alternatively or additionally, as a continuous infusion. Such administration can be used for chronic or acute treatment. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the particular mode of administration. Typical formulations will contain from about 5% to about 95% active compound (w / w). Alternatively, such formulations can contain from about 20% to about 80% active compound.

[0741] In some aspects, provided herein are the heterobifunctional compounds described herein for use in preventing or treating a disease or disorder.

[0742] In some aspects, the present disclosure provides the hetero-bifunctional compounds described herein for treating or preventing one or more diseases or disorders disclosed herein in a subject in need thereof. In certain embodiments, the disease or disorder is a TYK2-mediated disease or disorder. In certain embodiments, the disease or disorder is caused by TYK2 expression, mutation, deletion, or fusion. In certain embodiments, the disease or condition is cancer, inflammation, autoimmune disease, viral infection, and immune disease. In one embodiment, the TYK2-mediated cancer is selected from the group consisting of: brain cancer, gastric cancer, gastrointestinal cancer, liver cancer, biliary tract cancer, breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, penile cancer, genitourinary cancer, esophageal cancer, laryngeal cancer, skin cancer, lung cancer, pancreatic cancer, thyroid cancer, adenocarcinoma, bladder cancer, kidney cancer, muscle cancer, bone cancer, hematopoietic cancer, myeloproliferative neoplasm, essential thrombocythemia, polycythemia vera, primary myelofibrosis, chronic neutrophilic leukemia, acute lymphoblastic leukemia, Hodgkin lymphoma, chronic myelomonocytic leukemia, systemic mastocytosis, hypereosinophilic syndrome, cutaneous T-cell lymphoma, B-cell lymphoma, and myeloma. In one embodiment, the TYK2-mediated inflammatory disorder is selected from the group consisting of: ankylosing spondylitis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, and reperfusion injury. In one embodiment, the TYK2-mediated autoimmune disease is selected from the group consisting of: multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, psoriasis, myasthenia gravis, type I diabetes, systemic lupus erythematosus, IgA nephropathy, autoimmune thyroid disease, alopecia areata, and bullous pemphigoid. In one embodiment, the TYK2-mediated skin disease is selected from the group consisting of: atopic dermatitis, pruritus, alopecia areata, psoriasis, rash, skin irritation, skin allergy, chronic mucocutaneous candidiasis, dermatomyositis, erythema multiforme, palmoplantar pustulosis, vitiligo, polyarteritis nodosa, and STING-associated vasculopathy. In one embodiment, the TYK2-mediated viral infection is selected from the group consisting of: hepatitis B, hepatitis C, human immunodeficiency virus (HIV), human T-lymphotropic virus (HTLV1), Epstein-Barr virus (EBV), varicella-zoster virus (VZV), and human papillomavirus (HPV) infection. In one embodiment, the TYK2-mediated dry eye disease is selected from the group consisting of: dry eye syndrome (DES) and keratoconjunctivitis sicca (KCS). In one embodiment, the TYK2-mediated bone remodeling disorder is selected from the group consisting of: osteoporosis and osteoarthritis. In one embodiment, the TYK2-mediated immune complication related to organ transplantation is selected from the group consisting of: graft-versus-host disease.

[0743] In some aspects, the present disclosure provides the use of the hetero-bifunctional compounds in the preparation of a medicament for preventing or treating one or more diseases or disorders disclosed herein.

[0744] In some aspects, the disclosed methods include administering a therapeutically effective amount of one or more of the compounds or compositions described herein to a subject (e.g., a mammalian subject, such as a human subject) in need of or determined to be in need of such treatment. In some aspects, the disclosed methods include selecting a subject and administering to the subject an effective amount of one or more of the compounds or compositions described herein, and optionally repeating the administration as needed for the prevention or treatment of cancer.

[0745] In some aspects, the selection of a subject can include obtaining a sample from the subject (e.g., a candidate subject) and testing the sample to determine the subject's suitability for a selected indication. In some aspects, the subject can be confirmed or identified, e.g., by a healthcare professional, as having, being at elevated risk of having, or having had a particular condition or disease. In some aspects, suitable subjects include, e.g., subjects who have had or have had a condition or disease but have resolved the disease or an aspect thereof, subjects presenting with a reduction in disease symptoms (e.g., relative to other subjects having the same condition or disease (such as the majority of subjects)), or subjects who have survived longer in a condition or disease (e.g., relative to other subjects having the same condition or disease (such as the majority of subjects)), e.g., being in an asymptomatic state (e.g., relative to other subjects having the same condition or disease (such as the majority of subjects)). In some aspects, the manifestation of a positive immune response to a condition or disease can be made based on patient records, family history, or an indication of a positive immune response detected. In some aspects, multiple parties can be involved in subject selection. For example, a first party can obtain a sample from a candidate subject, while a second party can test the sample. In some aspects, the subject can be selected or referred to by a practicing physician (e.g., a general practitioner). In some aspects, the selection of a subject can include obtaining a sample from the selected subject and storing the sample or using the sample in the methods disclosed herein. The sample can include, e.g., cells or a population of cells.

[0746] In some aspects, the treatment methods can include single, multiple, and repeated administration of one or more of the compounds disclosed herein as needed for the prevention or treatment of a disease or condition disclosed herein (e.g., a TYK2-mediated disease). In some aspects, the treatment methods can include assessing the disease level of the subject before, during, or after treatment. In some aspects, treatment can continue until a reduction in the disease level of the subject is detected.

[0747] As used herein, the term "subject" refers to any animal. In some cases, the subject is a mammal. In some cases, the term "subject" as used herein refers to a human (e.g., a man, woman, or child).

[0748] As used herein, the terms "administer", "administering", or "administration" refer to implanting, ingesting, injecting, inhaling, or otherwise absorbing a compound or composition, regardless of its form. For example, the methods disclosed herein include administering an effective amount of a compound or composition to achieve a desired or specified effect.

[0749] As used herein, the terms "treat", "treating", or "treatment" refer to partially or completely alleviating, inhibiting, ameliorating, or relieving a disease or disorder suffered by a subject. This means any manner in which one or more symptoms of a disease or disorder (e.g., cancer) are improved or otherwise beneficially altered. As used herein, improvement of the symptoms of a particular disorder (e.g., cancer) refers to any alleviation that can be attributed to or is associated with treatment with the heterobifunctional compounds, compositions, and methods of the present invention, whether permanent or temporary, enduring or transient. In some embodiments, treatment can promote or result in, for example, a decrease in the number of tumor cells (e.g., in a subject) relative to the number of tumor cells prior to treatment; a decrease in the viability (e.g., average / mean viability) of tumor cells (e.g., in a subject) relative to the viability of tumor cells prior to treatment; a decrease in the rate of tumor cell growth; a decrease in the rate of local or distant tumor metastasis; a reduction in one or more symptoms associated with one or more tumors compared to the symptoms of the subject prior to treatment.

[0750] As used herein, the terms "prevent", "preventing", and "prevention" shall refer to a reduction in the occurrence of a disease in a subject or a decrease in the risk of developing the disease or its associated symptoms. Prevention can be complete, e.g., the complete absence of a disease or pathological cells in the subject. Prevention can also be partial, such that the occurrence of the disease or pathological cells in the subject is less than, later than, or progresses more slowly than would occur in the absence of the present invention. In certain embodiments, the subject has an increased risk of having one or more TYK2-mediated diseases. Exemplary TYK2-mediated diseases treatable with a heterobifunctional compound include, for example, cancers (e.g., brain cancer, gastric cancer, gastrointestinal cancer, liver cancer, biliary tract cancer, breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, penile cancer, genitourinary cancer, esophageal cancer, laryngeal cancer, skin cancer, lung cancer, pancreatic cancer, thyroid cancer, adenocarcinoma, bladder cancer, kidney cancer, muscle cancer, bone cancer, and hematopoietic system cancers such as myeloproliferative neoplasms, including essential thrombocythemia, polycythemia vera, primary myelofibrosis, chronic neutrophilic leukemia, acute lymphoblastic leukemia, Hodgkin lymphoma, chronic myelomonocytic leukemia, systemic mastocytosis, hypereosinophilic syndrome, cutaneous T-cell lymphoma, B-cell lymphoma, multiple myeloma, and other hematological malignancies, particularly cancers involving other inflammations, mutations, or aberrations that activate the TYK2 pathway); inflammations (e.g., ankylosing spondylitis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, and reperfusion injury, which are diseases associated with inflammatory ischemic events such as stroke or cardiac arrest); autoimmune diseases (e.g., multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, psoriasis, myasthenia gravis, type I diabetes, systemic lupus erythematosus, IgA nephropathy, autoimmune thyroid disease, alopecia areata, and bullous pemphigoid); skin diseases (e.g., atopic dermatitis, pruritus, alopecia areata, psoriasis, rash, skin irritation, skin allergy, chronic mucocutaneous candidiasis, dermatomyositis, erythema multiforme, palmoplantar pustulosis, vitiligo, polyarteritis nodosa, and STING-associated vasculopathy); viral infections (e.g., viral infections and subsequent complications such as infections with hepatitis B, hepatitis C, human immunodeficiency virus (HIV), human T-lymphotropic virus (HTLV1), Epstein-Barr virus (EBV), varicella-zoster virus (VZV), and human papillomavirus (HPV)); dry eye diseases (e.g., dry eye syndrome (DES) and keratoconjunctivitis sicca (KCS)); bone remodeling disorders (such as osteoporosis and osteoarthritis); and immune complications associated with organ transplantation (e.g., graft-versus-host disease).

[0751] The specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, disease, disorder or severity and course of symptoms, the patient's predisposition to the disease, disorder or symptoms, and the judgment of the treating physician.

[0752] The effective amount can be administered in one or more administrations, applications or doses. The therapeutically effective amount (i.e., effective dose) of the therapeutic compound depends on the therapeutic compound selected. In addition, treating a subject with a therapeutically effective amount of the compounds or compositions described herein may include a single treatment or a series of treatments. For example, the effective amount can be administered at least once. The composition can be administered once or more per day to once or more per week; including once every other day. Those skilled in the art will understand that certain factors can affect the dosage and time required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatment, the general health or age of the subject, and the presence of other diseases.

[0753] After administration, the subject can be evaluated to detect, assess or determine their disease level. In some cases, treatment can continue until a change (such as a decrease) in the disease level of the subject is detected. After the patient's condition improves (e.g., a change (e.g., a decrease) in the disease level of the subject occurs), if necessary, a maintenance dose of the compounds or compositions disclosed herein can be administered. Subsequently, the dosage or frequency of administration or both can be reduced (e.g., as a function of symptoms) to a level that maintains the improved condition. However, once any disease symptoms recur, the patient may require long-term intermittent treatment.

[0754] The present disclosure is also described and demonstrated by the following examples. However, the use of these and other examples anywhere in the specification is merely illustrative and in no way limits the scope and meaning of the invention or any exemplary terms. Similarly, the invention is not limited to any particular preferred embodiment or aspect described herein. In fact, many modifications and variations will be apparent to those skilled in the art after reading this specification, and such changes can be made without departing from the spirit or scope of the invention. Therefore, the invention is limited only by the terms of the appended claims and the full scope of the equivalents given by those claims. Examples

[0755] Example 1: (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycine (Processing Handle 1)

[0756]

[0757] Step 1. Synthesis of tert-butyl (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycinate

[0758]

[0759] In a microwave reactor, a solution of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (1.93 g, 7.0 mmol), tert-butyl 2-aminoacetate (1.01 g, 7.7 mmol) and N,N-diisopropylethylamine (2.72 g, 18 mmol) in NMP (14 mL) was heated to 85 °C for 50 min. The two batches were combined and diluted with EtOAc (100 mL), washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluting with hexane / EtOAc = 2:1) to give the title compound (1.0 g, yield 18%) as a yellow solid. MS (ESI) m / z = 332.0 [M - 55] + .

[0760] Step 2. Synthesis of (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycine

[0761]

[0762] A solution of tert-butyl 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetate (1.0 g, 2.58 mmol) in HCOOH (88%, 10 mL) was stirred at room temperature overnight. The reaction was concentrated and triturated with DCM, filtered, washed with DCM and MTBE, and dried to give the title compound (840 mg, yield 98%) as a yellow solid. 1 1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 7.52 (t, J = 7.6 Hz, 1H), 6.99–6.88 (m, 3H), 5.04 (dd, J = 5.2, 12.8 Hz, 1H), 3.73 (s, 2H), 2.93–2.83 (m, 1H), 2.61–2.50 (m, 2H), 2.02 (t, J = 5.6 Hz, 1H). MS (ESI) m / z = 330.1 [M - H] - .

[0763] Example 2: 3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propanoic acid (treatment handle 2)

[0764]

[0765] The handle 2 (1.42 g, two-step yield 24%) was synthesized according to the same steps as the handle 1 described in Example 1. 1 H NMR (400 MHz, DMSO-d6) δ 11.61 (br, 1H), 11.08 (s, 1H), 7.58 (dd, J = 7.2, 8.8 Hz, 1H), 7.15 (d, J = 8.8 Hz, 1H), 7.04 (d, J = 7.2 Hz, 1H), 6.64 (s, 1H), 5.05 (dd, J = 5.2, 12.8 Hz, 1H), 3.53 (t, J = 6.4 Hz, 2H), 2.92–2.83 (m, 1H), 2.61–2.50 (m, 4H), 2.05–2.00 (m, 1H). MS (ESI) m / z = 346.1 [M+H] + .

[0766] Example 3: 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyric acid (handle 3)

[0767]

[0768] The handle 3 (1.27 g, two-step yield 13%) was synthesized according to the same steps as the handle 1 described in Example 1. 1 H NMR (400 MHz, DMSO-d6) δ 12.12 (br, 1H), 11.08 (s, 1H), 7.58 (dd, J = 7.2, 8.8 Hz, 1H), 7.13 (d, J = 8.8 Hz, 1H), 7.03 (d, J = 7.2 Hz, 1H), 6.64 (t, J = 6.0 Hz, 1H), 5.05 (dd, J = 5.6, 12.8 Hz, 1H), 3.33 (q, J = 6.8 Hz, 2H), 2.93–2.83 (m, 1H), 2.61–2.50 (m, 2H), 2.31 (t, J = 6.8 Hz, 2H), 2.07–2.00 (m, 1H), 1.83–1.75 (m, 2H). MS (ESI) m / z = 360.1 [M+H] + .

[0769] Example 4: 5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)valeric acid (handle 4)

[0770]

[0771] The handle 4 (1.4 g, two-step yield 15%) was synthesized according to the same steps as the handle 1 described in Example 1.1 HNMR(400 MHz, DMSO-d6) δ 12.02 (brs, 1H), 11.08 (s, 1H), 7.58 (dd, J = 8.8, 7.2 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 7.2 Hz, 1H), 6.64 (t, J = 5.6 Hz, 1H), 5.07–5.03 (m, 1H), 3.32–3.02 (m, 2H), 2.93–2.84 (m, 1H), 2.61–2.54 (m, 2H), 2.28–2.25 (m, 2H), 2.05–2.01 (m, 1H), 1.60–1.51 (m, 4H). MS(ESI) m / z = 374.1 [M+H] + .

[0772] Example 5: 6 - ((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexanoic acid (handle 5)

[0773]

[0774] Handle 5 (1.43 g, two-step yield 18%) was synthesized according to the same steps as handle 1 described in Example 1. 1 H NMR(400 MHz, DMSO-d6) δ 11.97 (s, 1H), 11.08 (s, 1H), 7.57 (dd, J = 7.2, 8.8 Hz, 1H), 7.08 (d, J = 8.8 Hz, 1H), 7.02 (d, J = 7.2 Hz, 1H), 6.52 (t, J = 6.0 Hz, 1H), 5.05 (dd, J = 5.6, 12.8 Hz, 1H), 3.30 (q, J = 6.8 Hz, 2H), 2.93–2.83 (m, 1H), 2.61–2.50 (m, 2H), 2.32 (t, J = 7.2 Hz, 2H), 2.07–2.00 (m, 1H), 1.61–1.50 (m, 4H), 1.39–1.33 (m, 2H). MS(ESI) m / z = 388.1 [M+H] + .

[0775] Example 6: 7 - ((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptanoic acid (handle 6)

[0776]

[0777] Handle 6 (2.3 g, two-step yield 24%) was synthesized according to the same steps as handle 1 described in Example 1. 1HNMR(400MHz, DMSO-d6) δ 11.92 (brs, 1H), 11.08 (s, 1H), 7.57 (t, J = 8.0Hz, 1H), 7.13 (d, J = 8.8Hz, 1H), 7.03 (d, J = 6.8Hz, 1H), 6.52 (t, J = 5.6Hz, 1H), 5.05 (dd, J = 5.6, 12.8Hz, 1H), 3.30 (q, J = 6.4Hz, 2H), 2.93–2.83 (m, 1H), 2.61–2.50 (m, 2H), 2.31 (t, J = 7.2Hz, 2H), 2.07–2.00 (m, 1H), 1.58–1.48 (m, 4H), 1.34–1.31 (m, 4H). MS(ESI) m / z = 402.1 [M+H] + .

[0778] Example 7: 8 - ((2 - (2,6 - dioxopiperidin - 3 - yl)-1,3 - dioxoisoindolin - 4 - yl)amino)octanoic acid (handle 7)

[0779]

[0780] Handle 7 (1.14 g, two - step yield 35%) was synthesized according to the same steps of handle 1 described in Example 1. 1 H NMR(400MHz, DMSO - d6) δ 11.94 (s, 1H), 11.08 (s, 1H), 7.57 (t, J = 8.0Hz, 1H), 7.08 (d, J = 8.4Hz, 1H), 7.02 (d, J = 6.8Hz, 1H), 6.52 (t, J = 5.6Hz, 1H), 5.05 (dd, J = 5.6, 12.8Hz, 1H), 3.31–3.26 (m, 2H), 2.93–2.83 (m, 1H), 2.61–2.50 (m, 2H), 2.19 (t, J = 7.2Hz, 2H), 2.05–2.00 (m, 1H), 1.58–1.47 (m, 4H), 1.35–1.25 (s, 6H). MS(ESI) m / z = 416.1 [M+H] + .

[0781] Example 8: 3 - (2 - ((2 - (2,6 - dioxopiperidin - 3 - yl)-1,3 - dioxoisoindolin - 4 - yl)amino)ethoxy)propanoic acid (handle 8)

[0782]

[0783] Handle 8 (3.5 g, two - step yield 18%) was synthesized according to the same steps of handle 1 described in Example 1. 1HNMR(400MHz, DMSO-d6) δ 12.18 (s, 1H), 11.08 (s, 1H), 7.58 (dd, J = 7.2 Hz, 8.8 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 7.2 Hz, 1H), 6.58 (t, J = 5.6 Hz, 1H), 5.05 (dd, J = 6.4 Hz, 12.8 Hz, 1H), 3.67–3.58 (m, 4H), 3.47–3.43 (m, 2H), 2.93–2.84 (m, 1H), 2.61–2.45 (m, 4H), 2.07–2.01 (m, 1H). MS(ESI) m / z = 390.1 [M+H] + .

[0784] Example 9: 3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanoic acid (handle 9)

[0785]

[0786] Synthesize handle 9 (2.0 g, two-step yield 24%) according to the same procedure as handle 1 described in Example 1. 1 HNMR(400MHz, DMSO-d6) δ 12.13 (s, 1H), 11.08 (s, 1H), 7.58 (dd, J = 7.2 Hz, 8.4 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 6.8 Hz, 1H), 6.60 (t, J = 6.0 Hz, 1H), 5.05 (dd, J = 5.2 Hz, 12.4 Hz, 1H), 3.63–3.44 (m, 10H), 2.88–2.85 (m, 1H), 2.61–2.49 (m, 2H), 2.44–2.41 (m, 2H), 2.04–2.01 (m, 1H). MS(ESI) m / z = 434.1 [M+H] + .

[0787] Example 10: 3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propanoic acid (handle 10)

[0788]

[0789] Synthesize handle 10 (3.2 g, two-step yield 42%) according to the same procedure as handle 1 described in Example 1. 11H NMR (400 MHz, DMSO-d6) δ 12.14 (s, 1H), 11.08 (s, 1H), 7.58 (dd, J = 7.2 Hz, 8.4 Hz, 1H), 7.14 (d, J = 8.8 Hz, 1H), 7.04 (d, J = 6.8 Hz, 1H), 6.60 (t, J = 6.0 Hz, 1H), 5.05 (dd, J = 5.2 Hz, 12.8 Hz, 1H), 3.63–3.45 (m, 14H), 2.88–2.85 (m, 1H), 2.61–2.49 (m, 2H), 2.44–2.40 (m, 2H), 2.04–2.01 (m, 1H). MS (ESI) m / z = 478.2 [M+H] + .

[0790] Example 11: 1-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxapentadecan-15-oic acid (handle 11)

[0791]

[0792] Handle 11 (2.3 g, two-step yield 31%) was synthesized according to the same procedure as handle 1 described in Example 1. 1 1H NMR (400 MHz, DMSO-d6) δ 12.14 (s, 1H), 11.08 (s, 1H), 7.58 (dd, J = 7.2 Hz, 8.8 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 7.2 Hz, 1H), 6.60 (t, J = 6.0 Hz, 1H), 5.05 (dd, J = 5.2 Hz, 12.8 Hz, 1H), 3.63–3.48 (m, 18H), 2.89–2.85 (m, 1H), 2.61–2.49 (m, 2H), 2.44–2.41 (m, 2H), 2.04–2.01 (m, 1H). MS (ESI) m / z = 522.2 [M+H] + .

[0793] Example 12: 1-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12,15-pentaoxaoctadecan-18-oic acid (handle 12)

[0794]

[0795] Handle 12 (2.4 g, two-step yield 36%) was synthesized according to the same procedure as handle 1 described in Example 1. 11H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 7.58 (dd, J = 7.2, 8.4 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 7.2 Hz, 1H), 6.60 (t, J = 5.6 Hz, 1H), 5.05 (dd, J = 5.6, 12.8 Hz, 1H), 3.64–3.46 (m, 22H), 2.93–2.83 (m, 1H), 2.61–2.50 (m, 2H), 2.44–2.40 (m, 2H), 2.02 (t, J = 6.4 Hz, 1H). MS (ESI) m / z = 566.2 [M+H] + .

[0796] Example 13: 4-(((S)-1-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-4-oxobutanoic acid (Treatment Handle 13)

[0797]

[0798] A mixture of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (1.0 g, 2.3 mmol) and succinic anhydride (465 mg, 4.65 mmol) in pyridine (5 mL) was stirred overnight at room temperature. The mixture was concentrated. The residue was purified by reverse-phase flash chromatography (MeCN / H2O) to give the title compound (1.05 g, yield: 86%). 1 1H NMR (400 MHz, DMSO-d6) δ 12.02 (s, 1H), 8.99 (s, 1H), 8.58 (t, J = 6.0 Hz, 1H), 7.96 (d, J = 9.2 Hz, 1H), 7.43–7.37 (m, 4H), 5.13 (d, J = 3.6 Hz, 1H), 4.53 (d, J = 9.2 Hz, 1H), 4.46–4.40 (m, 2H), 4.34 (s, 1H), 4.21 (dd, J = 16.0, 5.2 Hz, 1H), 3.69–3.60 (m, 2H), 2.45 (s, 3H), 2.44–2.33 (m, 4H), 2.06–2.01 (m, 1H), 1.93–1.87 (m, 1H), 0.93 (s, 9H). 1313C NMR (100 MHz, DMSO-d6): δ 173.83, 171.92, 170.86, 169.56, 151.41, 147.70, 139.48, 131.15, 129.63, 128.62, 127.41, 68.87, 58.70, 56.44, 56.34, 41.65, 37.91, 35.35, 29.74, 29.25, 26.35, 15.92. MS (ESI) m / z: 531.2 [M+H] + .

[0799] Example 14: 5-(((S)-1-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-5-oxopentanoic acid (handle 14)

[0800]

[0801] Handle 14 (1.5 g, yield 79%) was synthesized according to the same procedure as handle 13 described in Example 13. 1 1H NMR (400 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.59 (t, J = 6.0 Hz, 1H), 7.91 (d, J = 9.2 Hz, 1H), 7.44 - 7.37 (m, 4H), 5.16 (brs, 1H), 4.54 (d, J = 9.2 Hz, 1H), 4.47–4.42 (m, 2H), 4.36 (s, 1H), 4.21 (dd, J = 16.0, 5.2 Hz, 1H), 3.7–3.64 (m, 2H), 2.45 (s, 3H), 2.31–2.14 (m, 4H), 2.07–2.02 (m, 1H), 1.94–1.81 (m, 1H), 1.74–1.68 (m, 2H), 0.94 (s, 9H). 13 13C NMR (100 MHz, DMSO-d6): δ 174.18, 171.94, 171.63, 169.66, 151.41, 147.70, 139.46, 131.15, 129.61, 128.62, 127.41, 68.86, 58.69, 56.38, 41.65, 37.91, 35.16, 34.03, 33.10, 26.35, 20.89, 15.92. MS (ESI) m / z = 543.2 [M-H] - .

[0802] Example 15: 6 - (((S)-1-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-6-oxohexanoic acid (Treatment Handle 15)

[0803]

[0804] Step 1. Synthesis of Ethyl 6 - (((S)-1-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-6-oxohexanoate

[0805]

[0806] At room temperature, to a solution of (2S,4R)-1-((S)-2-Amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (2.00 g, 4.65 mmol) and 6-Ethoxy-6-oxohexanoic acid (809 mg, 4.65 mmol) in DMF (20 mL) was added DIEA (3.03 g, 23.26 mmol) and HATU (3.53 g, 9.30 mmol). The mixture was stirred overnight at room temperature, then diluted with H2O (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash chromatography on silica gel (DCM / MeOH = 20:1) to give the title compound (1.70 g, yield 74%), as a yellow solid. MS(ESI) m / z = 587.3 [M + H] + .

[0807] Step 2. Synthesis of 6 - (((S)-1-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-6-oxohexanoic acid

[0808]

[0809] At room temperature, LiOH·H2O (294 mg, 7.00 mmol) was added to a solution of ethyl 6-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-6-oxohexanoate (1.70 g, 3.50 mmol) in THF (20 mL) and H2O (20 mL). The reaction mixture was stirred overnight at room temperature. THF was removed under reduced pressure and the residue was adjusted to pH 6 with hydrochloric acid (1 N). The precipitate was collected to give the title compound (1.198 g, yield: 74%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 7.75 (s, 1H), 7.32–7.27 (m, 5H), 4.64–4.57 (m, 3H), 4.56–4.50 (m, 1H), 4.28–4.25 (m, 1H), 4.02–3.99 (m, 1H), 3.71–3.68 (m, 1H), 2.47 (s, 3H), 2.24–2.18 (m, 6H), 1.59–1.48 (m, 4H), 0.96 (s, 9H). MS (ESI) m / z = 559.3 [M+H] + .

[0810] Example 16: 7-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoic acid (Treatment Handle 16)

[0811]

[0812] Treatment Handle 16 (1.1 g, two-step yield 33%) was synthesized according to the same procedure as Treatment Handle 15 described in Example 15. 1 H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 7.56–7.55 (m, 1H), 7.34–7.30 (m, 5H), 4.68–4.59 (m, 3H), 4.59–4.51 (m, 1H), 4.25 (dd, J = 4.8 Hz, 15.2 Hz, 1H), 4.06–4.03 (m, 1H), 3.70–3.68 (m, 1H), 2.46 (s, 3H), 2.31–2.11 (m, 6H), 1.55–1.51 (m, 4H), 1.29–1.24 (m, 2H), 0.94 (s, 9H). MS (ESI) m / z = 573.1 [M+H] + .

[0813] Example 17: 8 - (((S)-1-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-8-oxooctanoic acid (handle 17)

[0814]

[0815] Handle 17 (1.08 g, two-step yield 52%) was synthesized according to the same procedure as handle 15 described in Example 15. 1 H NMR (400 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.55 (t, J = 2.4 Hz, 1H), 7.83 (d, J = 9.2 Hz, 1H), 7.44–7.38 (m, 4H), 4.55 (d, J = 9.6 Hz, 1H), 4.52–4.41 (m, 2H), 4.36 (s, 1H), 4.25–4.21 (m, 1H), 3.67–3.66 (m, 2H), 2.45 (s, 3H), 2.30–1.91 (m, 6H), 1.49–1.47 (m, 4H), 1.26–1.24 (m, 4H), 0.92 (s, 9H). MS (ESI) m / z = 587.3 [M+H] + .

[0816] Example 18: 9 - (((S)-1-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-9-oxononanoic acid (handle 18)

[0817]

[0818] Handle 18 (1.16 g, two-step yield 44%) was synthesized according to the same procedure as handle 15 described in Example 15. 1 H NMR (400 MHz, CDCl3) δ 8.70 (s, 1H), 7.55 (s, 1H), 7.33–7.27 (m, 4H), 7.08 (d, J = 8.0 Hz, 1H), 4.68–4.52 (m, 4H), 4.31–4.27 (m, 1H), 4.08–4.05 (m, 1H), 3.69–3.67 (m, 1H), 2.48 (s, 3H), 2.33–2.11 (m, 6H), 1.60–1.47 (m, 4H), 1.29–1.20 (m, 6H), 0.96 (s, 9H). MS (ESI) m / z = 601.1 [M+H] + .

[0819] Example 19: 10-(((S)-1-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-10-oxodecanoic acid (Treatment Handle 19)

[0820]

[0821] Treatment Handle 19 (1.1 g, yield 35%) was synthesized according to the same procedure as Treatment Handle 15 described in Example 45. 1 HNMR(400MHz,DMSO-d6)δ8.99(s,1H),8.58(t,J=6.0Hz,1H),7.85(d,J=9.2Hz,1H),7.43–7.37(m,4H),4.54(d,J=9.2Hz,1H),4.47–4.41(m,2H),4.35(s,1H),4.21(dd,J=16.0,5.6Hz,1H),3.69–3.63(m,2H),2.45(s,3H),2.29–2.09(m,4H),2.03–2.01(m,1H),1.94–1.88(m,1H),1.47(m,4H),1.24(br,8H),0.94(s,9H). 13 C NMR(100MHz,DMSO-d6):δ172.07,171.92,169.69,151.41,147.70,139.48,131.14,129.62,128.61,127.40,68.84,58.67,56.32,56.26,41.64,37.93,35.18,34.85,28.62,26.36,25.39,15.93.MS(ESI)m / z=615.3[M+H] + .

[0822] Example 20: 11-(((S)-1-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-11-oxoundecanoic acid (Treatment Handle 20)

[0823]

[0824] Treatment Handle 20 (1.1 g, yield 50%) was synthesized according to the same procedure as Treatment Handle 15 described in Example 15. 1HNMR(400MHz, DMSO-d6) δ 8.99 (s, 1H), 8.58 (t, J = 6.0 Hz, 1H), 7.85 (t, J = 9.2 Hz, 1H), 7.37–7.43 (m, 4H), 4.56–4.19 (m, 5H), 3.70–3.60 (m, 2H), 2.45 (s, 3H), 2.27–1.90 (m, 6H), 1.49–1.45 (m, 4H), 1.23 (m, 10H), 0.93 (s, 9H). 13 C NMR(100MHz, DMSO-d6): δ 174.59, 172.07, 171.92, 169.69, 151.42, 147.70, 139.49, 131.14, 129.62, 128.61, 127.41, 68.84, 58.67, 56.32, 56.25, 41.64, 37.93, 35.19, 34.85, 33.80, 28.82, 28.70, 28.68, 28.62, 28.55, 26.37, 25.42, 24.55, 15.93. MS(ESI) m / z = 629.4 [M+H] + .

[0825] Example 21: 3-(3-(((S)-1-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-3-oxopropoxy)propanoic acid (Treatment Handle 21)

[0826]

[0827] Treatment Handle 21 (1.1 g, yield 42%) was synthesized according to the same procedure as Treatment Handle 15 described in Example 15. 1 HNMR(400MHz, DMSO-d6) δ 8.98 (s, 1H), 8.55 (t, J = 6.0 Hz, 1H), 7.91 (d, J = 9.2 Hz, 1H), 7.43–7.37 (m, 4H), 4.55–4.53 (m, 1H), 4.45–4.40 (m, 2H), 4.35 (s, 1H), 4.24–4.19 (m, 1H), 3.68–3.52 (m, 6H), 2.54–2.56 (m, 1H), 2.45–2.37 (m, 5H), 2.34–2.30 (m, 1H), 2.05–2.00 (m, 1H), 1.93–1.86 (m, 1H), 0.93 (s, 9H). MS(ESI) m / z = 575 [M+H] + .

[0828] Example 22: 2-(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)acetic acid (handle 22)

[0829]

[0830] Handle 22 (1.2 g, yield 63%) was synthesized in the same steps as handle 13 described in Example 13. 1 HNMR(400MHz,DMSO-d6)δ12.81(brs,1H),8.98(s,1H),8.58(t,J=6.0Hz,1H),7.60(d,J=9.6Hz,1H),7.45–7.35(m,4H),5.14(brs,1H),4.58–4.55(m,1H),4.46–4.36(m,3H),4.28–4.26(m,1H),4.14(s,2H),4.04(s,2H),3.69–3.60(m,2H),2.44(s,3H),2.08–2.03(m,1H),1.93–1.87(m,1H),0.95(s,9H).MS(ESI)m / z=547[M+H] + .

[0831] Example 23: 3-(2-(3-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-3-oxopropoxy)ethoxy)propanoic acid (handle 23)

[0832]

[0833] Handle 23 (1.4 g, two-step yield 23%) was synthesized in the same steps as handle 15 described in Example 15. 1HNMR(400MHz, DMSO-d6) δ 8.98 (s, 1H), 8.56 (t, J = 6.0 Hz, 1H), 7.91 (d, J = 9.2 Hz, 1H), 7.43–7.37 (m, 4H), 4.55 (d, J = 9.6 Hz, 1H), 4.46–4.41 (m, 2H), 4.35 (s, 1H), 4.29–4.20 (m, 1H), 3.70–3.57 (m, 7H), 3.50–3.45 (m, 5H), 2.57–2.55 (m, 1H), 2.45 (s, 3H), 2.43–2.41 (m, 1H), 2.37–2.32 (m, 1H), 2.09–2.01 (m, 1H), 1.94–1.87 (m, 1H), 0.94 (s, 9H). MS(ESI) m / z = 619.3 [M + H] + .

[0834] Example 24: 2-(2-(2-(((S)-1-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)ethoxy)acetic acid (handle 24)

[0835]

[0836] Handle 24 (1.13 g, 20% yield in two steps) was synthesized according to the same procedure as handle 15 described in Example 15. 1 H NMR(400MHz, DMSO-d6) δ 8.98 (s, 1H), 8.60 (t, J = 6.0 Hz, 1H), 7.49 (d, J = 9.2 Hz, 1H), 7.40 (s, 4H), 4.57 (d, J = 9.2 Hz, 1H), 4.47–4.36 (m, 3H), 4.28–4.23 (m, 1H), 4.05–3.93 (m, 4H), 3.69–3.61 (m, 6H), 2.45 (s, 3H), 2.08–2.03 (m, 1H), 1.94–1.87 (m, 1H), 0.94 (s, 9H). MS(ESI) m / z = 591.2 [M + H] + .

[0837] Example 25: (S)-15-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-16,16-dimethyl-13-oxo-4,7,10-trioxa-14-azapentadecanoic acid (handle 25)

[0838]

[0839] The handle 25 (1.7 g, yield 37%) was synthesized following the same steps as those for the handle 15 described in Example 15. 1 HNMR (400 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.56 (t, J = 6.0 Hz, 1H), 7.91 (d, J = 9.6 Hz, 1H), 7.44–7.38 (m, 4H), 4.56 (d, J = 9.2 Hz, 1H), 4.47–4.42 (m, 2H), 4.36 (s, 1H), 4.25–4.20 (m, 1H), 3.70–3.55 (m, 6H), 3.50–3.46 (m, 8H), 2.58–2.51 (m, 3H), 2.45–2.42 (m, 5H), 2.40–2.33 (m, 1H), 2.07–2.02 (m, 1H), 1.94–1.88 (m, 1H), 0.94 (s, 9H). LCMS (ESI) m / z = 661.0 [M-H] - .

[0840] Example 26: (S)-13-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-14,14-dimethyl-11-oxo-3,6,9-trioxa-12-azapentadecanoic acid (handle 26)

[0841]

[0842] The handle 26 (1.21 g, overall yield 31% for two steps) was synthesized following the same steps as those for the handle 15 described in Example 15. 1 H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 7.80–7.71 (m, 11H), 7.41–7.33 (m, 5H), 4.71–7.65 (m, 1H), 4.61–4.50 (m, 3H), 4.37–4.33 (m, 1H), 4.07–3.94 (m, 5H), 3.77–3.58 (m, 10H), 2.51 (s, 3H), 2.38–2.30 (m, 1H), 2.24–2.19 (m, 1H), 0.98 (s, 9H). LCMS (ESI) m / z = 635.0 [M+H] + .

[0843] (S)-18-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-19,19-dimethyl-16-oxo-4,7,10,13-tetraoxa-17-azadocosanoic acid (handle 27)

[0844]

[0845] The handle 27 (1.6 g, yield 43%) was synthesized according to the same procedure as the handle 15 described in Example 15. 1 HNMR(400MHz,CDCl3)δ8.69(s,1H),7.55–7.52(m,1H),7.47–7.45(m,1H),7.36(s,4H),4.70–4.66(m,1H),4.62–4.57(m,2H),4.50(s,1H),4.34–4.29(m,1H),4.12–4.09(m,1H),3.75–3.48(m,18H),2.56–2.47(m,7H),2.40–2.33(m,1H),2.23–2.18(m,1H),0.96(s,9H).MS(ESI)m / z=707.1[M+H] + .

[0846] (S)-21-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-22,22-dimethyl-19-oxo-4,7,10,13,16-pentaoxa-20-azatricosanoic acid (handle 28)

[0847]

[0848] The handle 28 (1.2 g, yield 23%) was synthesized according to the same procedure as the handle 15 described in Example 15. 1HNMR(400MHz, DMSO-d6) δ 8.98 (s, 1H), 8.57 (t, J = 6.0 Hz, 1H), 7.91 (d, J = 9.6 Hz, 1H), 7.43–7.31 (m, 4H), 4.56–4.53 (m, 1H), 4.45–4.35 (m, 3H), 4.24–4.19 (m, 1H), 3.69–3.55 (m, 6H), 3.49–3.47 (m, 16H), 2.57–2.53 (m, 1H), 2.45 (s, 3H), 2.39–2.32 (m, 3H), 2.06–2.01 (m, 1H), 1.93–1.86 (m, 1H), 0.95 (s, 9H). MS(ESI) m / z = 751 [M+H] + .

[0849] Example 29: (S)-19-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-20,20-dimethyl-17-oxo-3,6,9,12,15-pentaoxa-18-azaheneicosanoic acid (handle 29)

[0850]

[0851] Handle 29 (1.3 g, yield 39%) was synthesized according to the same procedure as handle 15 described in Example 15. 1 HNMR(400MHz, DMSO-d6) δ 8.98 (s, 1H), 8.69 (t, J = 6.0 Hz, 1H), 7.45 (d, J = 9.6 Hz, 1H), 7.43–7.37 (m, 4H), 4.57–4.55 (m, 1H), 4.47–4.34 (m, 3H), 4.27–4.22 (m, 1H), 3.97 (s, 2H), 3.68–3.65 (m, 2H), 3.61–3.48 (m, 18H), 2.45 (s, 3H), 2.09 - 2.04 (m, 1H), 1.92–1.86 (m, 1H), 0.94 (s, 9H). MS(ESI) m / z = 723 [M+H] + .

[0852] Example 30: (2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycine (handle 30)

[0853]

[0854] Handle 30 (1.0 g, yield 84%) was synthesized according to the same procedure as handle 1 described in Example 1. 1HNMR (400 MHz, DMSO-d6) δ 12.80 (brs, 1H), 11.06 (s, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.32 (brs, 1H), 6.98 (d, J = 1.2 Hz, 1H), 6.89 (dd, J = 2.0, 8.4 Hz, 1H), 5.04 (dd, J = 5.6, 13.2 Hz, 1H), 4.03 (s, 2H), 2.92–2.83 (m, 1H), 2.60–2.52 (m, 2H), 2.03–1.98 (m, 1H). MS (ESI) m / z = 332.0 [M+H] + .

[0855] Example 31: 3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)propanoic acid (handle 31)

[0856]

[0857] Handle 31 (1.24 g, yield 60%) was synthesized according to the same procedure as handle 1 described in Example 1. [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 7.57 (d, J = 8.4 Hz, 1H), 6.97 (d, J = 2.0 Hz, 1H), 6.87 (dd, J = 2.0, 8.4 Hz, 1H), 5.02 (dd, J = 5.2, 12.8 Hz, 1H), 3.41 (t, J = 6.8 Hz, 2H), 2.89–2.83 (m, 1H), 2.60–2.52 (m, 4H), 2.02–1.97 (m, 1H). MS (ESI) m / z = 346.0

[0858] Example 32: 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butanoic acid (handle 32)

[0859]

[0860] Handle 32 (0.52 g, yield 25%) was synthesized according to the same procedure as handle 1 described in Example 1. 1HNMR(400MHz, DMSO-d6) δ 12.12(s, 1H), 11.05(s, 1H), 7.55(d, J = 8.4Hz, 1H), 7.14(t, J = 4.8Hz, 1H), 6.95(d, J = 2.0Hz, 1H), 6.85(dd, J = 2.0, 8.4Hz, 1H), 5.02(dd, J = 5.6, 12.8Hz, 1H), 3.21–3.16(m, 2H), 2.91–2.83(m, 1H), 2.60–2.51(m, 2H), 2.34(t, J = 7.2Hz, 2H), 2.01–1.97(m, 1H), 1.82–1.75(m, 2H). MS(ESI) m / z = 360.1 [M+H] + .

[0861] Example 33: 5 - ((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)pentanoic acid (handle 33)

[0862]

[0863] Handle 33 (0.66 g, yield 51%) was synthesized according to the same procedure as handle 1 described in Example 1. 1 HNMR(400MHz, DMSO-d6) δ 12.03(brs, 1H), 11.05(s, 1H), 7.55(d, J = 8.4Hz, 1H), 7.10(t, J = 5.2Hz, 1H), 6.94(s, 1H), 6.83(dd, J = 1.6, 8.4Hz, 1H), 5.02(dd, J = 5.6, 12.8Hz, 1H), 3.17–3.16(m, 2H), 2.92–2.83(m, 1H), 2.60–2.53(m, 2H), 2.26–2.25(m, 2H), 2.01–1.98(m, 1H), 1.60–1.59(m, 4H). MS(ESI) m / z = 374.1 [M+H] + .

[0864] Example 34: 6 - ((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)hexanoic acid (handle 34)

[0865]

[0866] Handle 34 (1.33 g, yield 66%) was synthesized according to the same procedure as handle 1 described in Example 1. 1HNMR(400MHz, DMSO-d6) δ 11.98 (s, 1H), 11.05 (s, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.08 (t, J = 5.2 Hz, 1H), 6.95 (s, 1H), 6.83 (dd, J = 1.2, 8.4 Hz, 1H), 5.03 (dd, J = 5.2, 12.8 Hz, 1H), 3.17–3.12 (m, 2H), 2.92–2.83 (m, 1H), 2.60–2.53 (m, 2H), 2.22 (t, J = 7.2 Hz, 2H), 2.01–1.98 (m, 1H), 1.61–1.51 (m, 4H), 1.41–1.33 (m, 2H). MS(ESI) m / z = 388.1 [M+H] + .

[0867] Example 35: 7 - ((2-(2,6 - dioxopiperidin - 3 - yl)-1,3 - dioxoisoindolin - 5 - yl)amino)heptanoic acid (handle 35)

[0868]

[0869] Handle 35 (1.06 g, yield 39%) was synthesized according to the same steps as handle 1 described in Example 1. 1 HNMR(400MHz, DMSO-d6) δ 11.94 (s, 1H), 11.04 (s, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.09 (t, J = 5.6 Hz, 1H), 6.94 (d, J = 2.0 Hz, 1H), 6.84 (dd, J = 2.0, 8.4 Hz, 1H), 5.02 (dd, J = 5.6, 13.2 Hz, 1H), 3.17–3.12 (m, 2H), 2.88–2.83 (m, 1H), 2.60–2.53 (m, 2H), 2.21 (t, J = 7.2 Hz, 2H), 2.01–1.97 (m, 1H), 1.58–1.48 (m, 4H), 1.39–1.29 (m, 4H). MS(ESI) m / z = 402.1 [M+H] + .

[0870] Example 36: 8 - ((2-(2,6 - dioxopiperidin - 3 - yl)-1,3 - dioxoisoindolin - 5 - yl)amino)octanoic acid (handle 36)

[0871]

[0872] Handle 36 (1.66 g, yield 51%) was synthesized according to the same steps as handle 1 described in Example 1. 1HNMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H), 11.05 (s, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.09 (t, J = 5.6 Hz, 1H), 6.94 (d, J = 2.0 Hz, 1H), 6.84 (dd, J = 2.0, 8.4 Hz, 1H), 5.02 (dd, J = 5.6, 13.2 Hz, 1H), 3.17–3.12 (m, 2H), 2.88–2.83 (m, 1H), 2.60–2.53 (m, 2H), 2.19 (t, J = 7.2 Hz, 2H), 2.02–1.98 (m, 1H), 1.58–1.47 (m, 4H), 1.36–1.29 (m, 6H). MS (ESI) m / z = 416.1 [M+H] + .

[0873] Example 37: 3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)propanoic acid (handle 37)

[0874]

[0875] Handle 37 was synthesized according to the same procedure as handle 1 described in Example 1. (1.7 g, yield: 60%). 1 HNMR (400 MHz, DMSO-d6) δ 12.19 (brs, 1H), 11.06 (s, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.09 (brs, 1H), 7.01 (d, J = 2.0 Hz, 1H), 6.90 (dd, J = 2.0, 8.4 Hz, 1H), 5.04 (dd, J = 5.6, 13.2 Hz, 1H), 3.66 (t, J = 6.4 Hz, 2H), 3.59 (t, J = 5.6 Hz, 2H), 3.35 (t, J = 5.2 Hz, 2H), 2.93–2.84 (m, 1H), 2.62–2.56 (m, 2H), 2.52–2.47 (m, 2H), 2.03–1.99 (m, 1H). MS (ESI) m / z = 390.1 [M+H] + .

[0876] Example 38: 3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)propanoic acid (handle 38)

[0877]

[0878] The handle 38 (2.3 g, yield 78%) was synthesized according to the same steps of the handle 1 described in Example 1. 1 HNMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 2.0 Hz, 1H), 6.90 (dd, J = 2.0, 8.4 Hz, 1H), 5.04 (dd, J = 5.6, 13.2 Hz, 1H), 3.63–3.59 (m, 4H), 3.57–3.51 (m, 4H), 3.36 (t, J = 5.6 Hz, 2H), 2.90–2.84 (m, 1H), 2.61–2.55 (m, 2H), 2.44 (t, J = 6.4 Hz, 2H), 2.04–1.99 (m, 1H). MS (ESI) m / z = 434.1 [M+H] + .

[0879] Example 39: 3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)ethoxy)propanoic acid (handle 39)

[0880]

[0881] The handle 39 (1.2 g, yield 52%) was synthesized according to the same steps of the handle 1 described in Example 1. 1 HNMR (400 MHz, DMSO-d6) δ 7.59 (d, J = 11.2 Hz, 1H), 7.23 (t, J = 6.8 Hz, 1H), 7.04 (d, J = 1.6 Hz, 1H), 7.04 (dd, J = 2.4, 11.2 Hz, 1H), 5.06 (dd, J = 7.2, 16.8 Hz, 1H), 3.64–3.57 (m, 8H), 3.54–3.48 (m, 4H), 3.40–3.38 (m, 2H), 2.92–2.89 (m, 1H), 2.64–2.54 (m, 2H), 2.42–2.38 (m, 2H), 2.05–2.01 (m, 1H). MS (ESI) m / z = 478.1 [M+H] + .

[0882] Example 40: 1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)-3,6,9,12-tetraoxapentadecan-15-oic acid (handle 40)

[0883]

[0884] The handle 40 (1.3 g, yield 55%) was synthesized according to the same steps of the handle 1 described in Example 1. 1 HNMR (400 MHz, DMSO-d6) δ 12.17 (brs, 1H), 11.07 (s, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.17 (t, J = 5.6 Hz, 1H), 7.01 (d, J = 1.2 Hz, 1H), 6.90 (dd, J = 1.6, 8.4 Hz, 1H), 5.03 (dd, J = 5.6, 12.8 Hz, 1H), 3.61–3.48 (m, 18H), 2.92–2.83 (m, 1H), 2.60–2.54 (m, 2H), 2.43 (t, J = 6.4 Hz, 2H), 2.03–1.98 (m, 1H). MS (ESI) m / z = 522.1 [M+H] + .

[0885] Example 41: 1-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)-3,6,9,12,15-pentaoxaoctadec-18-oic acid (handle 41)

[0886]

[0887] The handle 41 (1.0 g, yield 50%) was synthesized according to the same steps of the handle 1 described in Example 1. 1 HNMR (400 MHz, DMSO-d6) δ 12.17 (brs, 1H), 11.07 (s, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.17 (t, J = 5.6 Hz, 1H), 7.01 (s, 1H), 6.90 (dd, J = 1.6, 8.4 Hz, 1H), 5.03 (dd, J = 5.6, 13.2 Hz, 1H), 3.60–3.48 (m, 22H), 2.89–2.83 (m, 1H), 2.60–2.54 (m, 2H), 2.43 (t, J = 6.4 Hz, 2H), 2.01–1.98 (m, 1H). MS (ESI) m / z = 566.1 [M+H] + .

[0888] Synthesis steps of the TYK2 binding moiety

[0889] Example 42: 4-((3-(1-(2-Aminoethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamido)-N-methylpyridazine-3-carboxamide

[0890]

[0891] Step 1. Synthesis of methyl 2-methoxy-3-nitrobenzoate

[0892]

[0893] At room temperature, potassium carbonate (224.2 g, 1624.4 mmol) and methyl iodide (230.6 g, 1624.4 mmol) were added to a solution of methyl 2-hydroxy-3-nitrobenzoate (160 g, 812.2 mmol) in DMF (2.5 L). The mixture was stirred at 60 °C for 1 h. After cooling to room temperature, the mixture was diluted with water (3.0 L) and extracted with EtOAc (0.6 L×5). The combined organic layers were washed with brine (1.0 L), dried over Na2SO4, filtered and concentrated to give the title compound (170 g, yield 99.4%), as a yellow solid, which was used in the next step without further purification. 1 1H NMR (400 MHz, DMSO-d6) δ 8.13 (dd, J = 1.6, 8.0 Hz, 1H), 8.04 (dd, J = 2.0, 8.0 Hz, 1H), 7.45 (t, J = 7.8 Hz, 1H), 3.90 (s, 3H), 3.88 (s, 3H).

[0894] Step 2. Synthesis of 2-methoxy-3-nitrobenzamide

[0895]

[0896] Methyl 2-methoxy-3-nitrobenzoate (170 g, 805.7 mmol) was dissolved in a cold solution of ammonia in methanol (7N, 3.0 L) and concentrated ammonium hydroxide (0.6 L). The mixture was stirred at room temperature for 16 h. The mixture was concentrated and the residue was diluted with water (0.8 L). The mixture was sonicated and filtered. The filter cake was washed with ice-cold water (1.0 L) to give the title compound (150 g, yield 94.9%), as a yellow solid. 1 1H NMR (400 MHz, DMSO-d6) δ 7.99–7.94 (m, 2H), 7.76 (dd, J = 7.6, 1.6 Hz, 2H), 7.37 (t, J = 8.0 Hz, 1H), 3.88 (s, 3H).

[0897] Step 3. Synthesis of 3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole

[0898]

[0899] A solution of 2-methoxy-3-nitrobenzamide (150 g, 765.3 mmol) in DMF-DMA (1.1 L) was stirred at 95 °C for 30 min. TLC (petroleum ether / EtOAc = 1 / 1) showed complete reaction. The mixture was concentrated and azeotroped with 1,2-dichloromethane (0.5 L) to ensure complete removal of any residual DMF-DMA. At 0 °C, the crude oil was dissolved in EtOH (0.5 L) and added to a solution of hydrazine hydrate (0.4 L) in EtOH (3.0 L) and CH3COOH (0.8 L). After addition, the mixture was warmed to room temperature and stirred for 4 h. The mixture was concentrated and the residue was sonicated with water (1.0 mL) and filtered. The filter cake was washed with ice water (1.0 L) to give the title compound (155 g, yield 91.9%) as a pale yellow solid, which was used for the next step without further purification. 1 1H NMR (400 MHz, DMSO-d6) δ 14.33 (brs, 1H), 8.71 (brs, 1H), 8.22 (d, J = 7.2 Hz, 1H), 7.98 (brs, 1H), 7.46 (t, J = 8.0 Hz, 1H), 3.80 (s, 3H).

[0900] Step 4. Synthesis of tert-butyl (2-(3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazol-1-yl)ethyl)carbamate

[0901]

[0902] At 0 °C, a solution of K2CO3 (24.4 g, 177.0 mmol) and (2-bromoethyl)carbamic acid tert-butyl ester (19.7 g, 88.5 mmol) in DMF (30 mL) was added dropwise to a solution of 3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (13 g, 59.0 mmol) in DMF (150 mL). After the mixture was stirred at room temperature for 16 h, it was diluted with water (200 mL) and extracted with EtOAc (150 mL × 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 10:1 to 1:3) to give the title compound (20 g, yield 93.2%) as a yellow solid. MS (ESI) m / z = 364.1 [M+H] + .

[0903] Step 5. Synthesis of tert-butyl (2-(3-(3-amino-2-methoxyphenyl)-1H-1,2,4-triazol-1-yl)ethyl)carbamate

[0904]

[0905] A mixture of tert-butyl (2-(3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazol-1-yl)ethyl)carbamate (20 g, 55.1 mmol) and Pd / C (5 g) in EtOH (200 mL) was stirred in H2 at room temperature for 5 h. The mixture was filtered through Celite. The filtrate was concentrated under reduced pressure to give the title compound (17 g, yield 92.9%) as a colorless oil, which was used in the next step without further purification. MS (ESI) m / z = 334.2 [M+H] + .

[0906] Step 6. Synthesis of methyl 4-((3-(1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-chloropyridazine-3-carboxylate

[0907]

[0908] A mixture of tert-butyl (2-(3-(3-amino-2-methoxyphenyl)-1H-1,2,4-triazol-1-yl)ethyl)carbamate (5.8 g, 17.4 mmol) and methyl 4,6-dichloropyridazine-3-carboxylate (4.30 g, 20.88 mmol) in DMF (5 mL) was stirred at 100 °C for 6 h. After cooling to room temperature, the mixture was diluted with water (80 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 200:1 to 60:1) to give the title compound (4.2 g, yield 48.0%) as a yellow solid. MS (ESI) m / z = 504.1 [M+H] + .

[0909] Step 7. Synthesis of tert-butyl (2-(3-(3-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-1H-1,2,4-triazol-1-yl)ethyl)carbamate

[0910]

[0911] To a solution of methyl 4-((3-(1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-chloropyridazine-3-carboxylate (4.2 g, 8.35 mmol) in THF (50 mL) was added magnesium chloride (398.0 mg, 4.18 mmol). After stirring the mixture at room temperature for 5 min, a solution of methylamine (2 M in THF, 10 mL) was added. The mixture was stirred at room temperature for 16 h. The mixture was diluted with water (30 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 200:1 to 60:1) to give the title compound (3.8 g, yield 90.6%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 9.40 (d, J = 4.8 Hz, 1H), 8.54 (s, 1H), 7.74 (d, J = 6.8 Hz, 1H), 7.61 (dd, J = 8.0, 1.2 Hz, 1H), 7.29 (t, J = 8.0 Hz, 1H), 7.20 (s, 1H), 7.05–6.98 (m, 1H), 4.28 (t, J = 6.0 Hz, 2H), 3.71 (s, 3H), 3.42–3.37 (m, 2H), 2.87 (d, J = 4.8 Hz, 3H), 1.35 (s, 9H).

[0912] Step 8. Synthesis of tert-butyl (2-(3-(3-((6-(cyclopropanecarboxamido)-3-(methylcarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-1H-1,2,4-triazol-1-yl)ethyl)carbamate

[0913]

[0914] A mixture of tert-butyl (2-(3-(3-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-1H-1,2,4-triazol-1-yl)ethyl)carbamate (3.8 g, 7.57 mmol), cyclopropanecarboxamide (1.29 g, 15.14 mmol), Pd2(dba)3 (351.5 mg, 0.38 mmol), XantPhos (440.8 mg, 0.76 mmol) and Cs2CO3 (4.92 g, 15.14 mmol) in dioxane (40 mL) was stirred at 100 °C in N2 for 72 h. LCMS showed about 50% conversion. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 200:1 to 40:1) to give the title compound (1.25 g, yield 29.9%) as a green solid. MS (ESI) m / z = 552.7 [M+H] + .

[0915] Step 9. Synthesis of 4-((3-(1-(2-aminoethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamido)-N-methylpyridazine-3-carboxamide

[0916]

[0917] A solution of HCl / EtOAc (10 mL, 3 M) of tert-butyl (2-(3-(3-((6-(cyclopropanecarboxamido)-3-(methylcarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-1H-1,2,4-triazol-1-yl)ethyl)carbamate (1.25 g, 2.26 mmol) was stirred at room temperature for 2 h. The mixture was concentrated and diluted with saturated aqueous sodium bicarbonate (100 mL). After stirring at room temperature for 3 h, the suspension was filtered. The filter cake was washed with water and dried to give the title compound (860 mg, yield 84.5%) as a pale yellow solid. 11H NMR (400 MHz, DMSO-d6) δ 11.33 (brs, 1H), 10.98 (s, 1H), 9.17 (d, J = 4.8 Hz, 1H), 8.58 (s, 1H), 8.16 (s, 1H), 7.68 (d, J = 6.4 Hz, 1H), 7.51 (d, J = 6.8 Hz, 1H), 7.27 (t, J = 8.0 Hz, 1H), 4.20 (t, J = 6.0 Hz, 2H), 3.72 (s, 3H), 2.98 (t, J = 6.0 Hz, 2H), 2.86 (d, J = 4.8 Hz, 3H), 2.10–2.07 (m, 1H), 1.58 (s, 1H), 0.82 (d, J = 5.2 Hz, 4H). MS (ESI) m / z = 452.2 [M+H] + .

[0918] Example 43: 6-(2-Aminoacetamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide

[0919]

[0920] Step 1. Synthesis of 3-(2-methoxy-3-nitrophenyl)-1-methyl-1H-1,2,4-triazole

[0921]

[0922] At 0 °C, a solution of K2CO3 (94.1 g, 681.9 mmol) and CH3I (48.4 g, 341.0 mmol) in DMF (50 mL) was added dropwise to a solution of 3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (50 g, 227.3 mmol) in DMF (600 mL). After the mixture was stirred at room temperature for 4 h, it was diluted with water (800 mL) and extracted with EtOAc (300 mL × 3). The combined organic layers were washed with brine (500 × 2 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 10:1 to 1:2) to give the title compound (29.4 g, yield 55.4%) as an off-white solid. 1 1H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.17 (dd, J = 8.0, 1.6 Hz, 1H), 7.94 (dd, J = 8.0, 1.6 Hz, 1H), 7.43 (t, J = 8.0 Hz, 1H), 3.97 (s, 3H), 3.83 (s, 3H).

[0923] Step 2. Synthesis of 2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline

[0924]

[0925] A solution of 3-(2-Methoxy-3-nitrophenyl)-1-methyl-1H-1,2,4-triazole (20 g, 85.5 mmol) and Pd / C (5.0 g) in EtOH (200 mL) was stirred in H2 at room temperature for 5 h. LCMS showed the reaction was complete. The mixture was filtered through diatomaceous earth. The filtrate was concentrated to give the title compound (17.2 g, yield 98.8%) as a white solid, which was used for the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 8.47 (s, 1H), 6.95 (dd, J = 7.6, 1.6 Hz, 1H), 6.86 (t, J = 7.8 Hz, 1H), 6.74 (dd, J = 7.6, 1.6 Hz, 1H), 4.98 (s, 2H), 3.91 (s, 3H), 3.66 (s, 3H).

[0926] Step 3. Synthesis of Ethyl 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxylate

[0927]

[0928] A mixture of 2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline (17.2 g, 84.3 mmol), ethyl 4,6-dichloropyridazine-3-carboxylate (18.5 g, 84.3 mmol) and DIPEA (21.7 g, 168.6 mmol) in DMF (300 mL) was stirred at 110 °C for 16 h. After cooling to room temperature, the mixture was diluted with water (500 mL) and extracted with EtOAc (300 mL × 5). The combined organic layers were washed with brine (500 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 100:1 to 10:1) to give the title compound (16.8 g, yield 51.4%) as a yellow solid.

[0929] Step 4. Synthesis of 6-Chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide

[0930]

[0931] To a solution of ethyl 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxylate (15.5 g, 40.1 mmol) in THF (600 mL) was added magnesium chloride (1.9 g, 20.1 mmol). After stirring at room temperature for 5 min, a solution of methylamine / THF (50 mL, 2 M) was added. The mixture was stirred at room temperature for 16 h. LCMS indicated the completion of the reaction. The mixture was quenched with 1 M HCl (30 mL), diluted with water (300 mL) and extracted with EtOAc (150 mL × 5). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 100:1 to 10:1) to give the title compound (13.7 g, yield 91.9%) as an off-white solid. 1 HNMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.39 (d, J = 5.2 Hz, 1H), 8.57 (s, 1H), 7.72 (dd, J = 7.6, 1.6 Hz, 1H), 7.60 (dd, J = 8.0, 1.6 Hz, 1H), 7.29 (t, J = 8.0 Hz, 1H), 7.20 (s, 1H), 3.95 (s, 3H), 3.72 (s, 3H), 2.87 (d, J = 4.8 Hz, 3H). MS (ESI) m / z = 374.1 [M+H] + .

[0932] Step 5. tert-Butyl (2-((5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(methylcarbamoyl)pyridazin-3-yl)amino)-2-oxoethyl)carbamate

[0933]

[0934] A mixture of 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (1.5 g, 4.02 mmol) and K3PO4 (2.56 g, 12.06 mmol) in dioxane (10 mL) was added to (2-amino-2-oxoethyl)carbamic acid tert-butyl ester (1.05 g, 6.03 mmol), Pd2(dba)3 (37 mg, 0.04 mmol) and dppf (44 mg, 0.08 mmol). The resulting mixture was degassed with N2 and stirred at 100 °C for 16 h. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc (40 mL × 3). The combined organic layers were washed with brine (40 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by reverse-phase chromatography to give the title compound (1.05 g, yield: 51.2%), as an off-white solid. MS (ESI) m / z = 512.6 [M+H] + .

[0935] Step 6. Synthesis of 6-(2-aminoacetamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide

[0936]

[0937] TFA (15 mL) was added to a solution of (2-((5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(methylaminocarbonyl)pyridazine-3-yl)amino)-2-oxoethyl)carbamic acid tert-butyl ester (1.05 g, 2.05 mmol) in DCM (15 mL). The resulting mixture was stirred at 25 °C for 16 h. The solvent was removed under reduced pressure. The resulting residue was purified by reverse-phase chromatography to give the title compound (822 mg, yield: 97.4%), as an off-white solid. MS (ESI) m / z =

[0938] 412.6 [M+H] + .

[0939] Synthesis steps of hetero-bifunctional compounds

[0940] Example 44: 6-(Cyclopropanecarboxamido)-4-((3-(1-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetamido)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-001)

[0941]

[0942] CPD-001 (2.8 mg, yield 33%) was synthesized according to the same procedure for preparing CPD-042. MS (ESI) m / z = 765.6 [M+H] + .

[0943] Example 45: 6-(Cyclopropanecarboxamido)-4-((3-(1-(2-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propanamido)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-002)

[0944] CPD-002 (2.33 mg, yield 27%) was synthesized according to the same procedure for preparing CPD-042. MS (ESI) m / z = 779.6 [M+H] + .

[0945] Example 46: 6-(Cyclopropanecarboxamido)-4-((3-(1-(2-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butanamido)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-003)

[0946]

[0947] CPD-003 (2.74 mg, yield 31%) was synthesized according to the same procedure for preparing CPD-042. MS (ESI) m / z = 793.7 [M+H] + .

[0948] Example 47: 6-(Cyclopropanecarboxamido)-4-((3-(1-(2-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentanamido)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-004)

[0949]

[0950] CPD-004 (2.13 mg, yield 24%) was synthesized according to the same procedure for preparing CPD-042. MS (ESI) m / z = 807.7 [M+H]+ .

[0951] Example 48: 6-(Cyclopropanecarboxamido)-4-((3-(1-(2-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexanamido)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-005)

[0952]

[0953] CPD-005 (2.44 mg, yield 27%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 821.8 [M+H] + .

[0954] Example 49: 6-(Cyclopropanecarboxamido)-4-((3-(1-(2-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptanamido)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-006)

[0955]

[0956] CPD-006 (2.82 mg, yield 31%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 835.8 [M+H] + .

[0957] Example 50: 6-(Cyclopropanecarboxamido)-4-((3-(1-(2-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octanamido)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-007)

[0958]

[0959] CPD-007 (2.91 mg, yield 31%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 849.8 [M+H] + .

[0960] Example 51: 6-(Cyclopropanecarboxamido)-4-((3-(1-(2-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)propanamido)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-008)

[0961]

[0962] CPD-008 (2.14 g, yield 24%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 823.7 [M+H] + .

[0963] Example 52: 6-(Cyclopropanecarboxamido)-4-((3-(1-(2-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanamido)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-009)

[0964]

[0965] CPD-009 (2.39 mg, yield 25%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 867.7 [M+H] + .

[0966] Example 53: 6-(Cyclopropanecarboxamido)-4-((3-(1-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-12-oxo-3,6,9-trioxa-13-azapentadec-15-yl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-010)

[0967]

[0968] CPD-010 (2.63 mg, yield 26%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 911.8 [M+H] + .

[0969] Example 54: 6-(Cyclopropanecarboxamido)-4-((3-(1-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-15-oxo-3,6,9,12-tetraoxa-16-azaoctadec-18-yl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-011)

[0970]

[0971] CPD-011 (1.36 mg, yield 13%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 955.8 [M+H] + .

[0972] Example 55: 6-(Cyclopropanecarboxamido)-4-((3-(1-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-18-oxo-3,6,9,12,15-pentaoxa-19-azaheneicosan-21-yl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-012)

[0973]

[0974] CPD-012 (2.53 mg, yield 23%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 999.7 [M+H] + .

[0975] Example 56: 6-(Cyclopropanecarboxamido)-4-((3-(1-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)acetamido)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-013)

[0976]

[0977] CPD-013 (2.2 mg, yield 43%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 765.6 [M+H] + .

[0978] Example 57: 6-(Cyclopropanecarboxamido)-4-((3-(1-(2-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)propanamido)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-014)

[0979]

[0980] CPD-014 (2.29 mg, yield 44%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 779.7 [M+H] + .

[0981] Example 58: 6-(Cyclopropanecarboxamido)-4-((3-(1-(2-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butanamido)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-015)

[0982]

[0983] CPD-015 (2.05 mg, yield 39%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 793.7 [M+H] + .

[0984] Example 59: 6-(Cyclopropanecarboxamido)-4-((3-(1-(2-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)pentanamido)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-016)

[0985]

[0986] CPD-016 (2.39 mg, yield 44%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 807.7 [M+H] + .

[0987] Example 60: 6-(Cyclopropanecarboxamido)-4-((3-(1-(2-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)heptanamido)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-017)

[0988]

[0989] CPD-017 (2.13 mg, yield 38%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 835.8 [M+H] + .

[0990] Example 61: 6-(Cyclopropanecarboxamido)-4-((3-(1-(2-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)propanamido)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-018)

[0991]

[0992] CPD-018 (2.15 mg, yield 39%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 823.7 [M+H] + .

[0993] Example 62: 6-(Cyclopropanecarboxamido)-4-((3-(1-(2-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)propanamido)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-019)

[0994]

[0995] CPD-019 (2.5 mg, yield 43%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 867.7 [M+H] + .

[0996] Example 63: 6-(Cyclopropanecarboxamido)-4-((3-(1-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)-12-oxo-3,6,9-trioxa-13-aza-pentadec-15-yl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-020)

[0997]

[0998] CPD-020 (3.23 mg, yield 53%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 911.8 [M+H] + .

[0999] Example 64: 6-(Cyclopropanecarboxamido)-4-((3-(1-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)-15-oxo-3,6,9,12-tetraoxa-16-aza-octadec-18-yl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-021)

[1000]

[1001] CPD-021 (3.24 mg, yield 51%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 955.8 [M+H] + .

[1002] Example 65: 6-(Cyclopropanecarboxamido)-4-((3-(1-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)-18-oxo-3,6,9,12,15-pentaoxa-19-aza-heneicos-21-yl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-022)

[1003]

[1004] CPD-022 (3.01 mg, yield 45%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 999.7 [M+H] + .

[1005] Example 66: 6-(Cyclopropanecarboxamido)-4-((3-(1-(2-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)hexanamido)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-023)

[1006]

[1007] CPD-023 (3.3 mg, yield 60%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 821.7 [M+H] + .

[1008] Example 67: 6-(Cyclopropanecarboxamido)-4-((3-(1-(2-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)octanamido)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-024)

[1009]

[1010] CPD-024 (2.26 mg, yield 40%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 849.8 [M+H] + .

[1011] Example 68: 6-(2-(2-(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)acetamido)acetamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-025)

[1012]

[1013] CPD-025 (3.22 mg, yield 17.6%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 940.7 [M+H] + .

[1014] Example 69: 6-(2-(3-(3-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-3-oxopropoxy)propanamido)acetamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-026)

[1015]

[1016] CPD-026 (2.52 mg, yield 13.2%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 968.8 [M+H] + .

[1017] Example 70: 6-((S)-13-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-carbonyl)-14,14-dimethyl-4,11-dioxo-6,9-dioxa-3,12-diazapentadecanamido)-4-((2-methoxy-3-(1-meth

[1018]

[1019] CPD-027 (2.38 mg, yield 11.9%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 984.8 [M+H] + .

[1020] Example 71: 6-((S)-15-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-carbonyl)-16,16-dimethyl-4,13-dioxo-7,10-dioxa-3,14-diazapentadecanamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-028)

[1021]

[1022] CPD-028 (4.52 mg, yield 20.9%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 1012.8 [M+H] + .

[1023] Example 72: 6-((S)-16-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-17,17-dimethyl-4,14-dioxo-6,9,12-trioxa-3,15-diazaoctadecanamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-029)

[1024]

[1025] CPD-029 (1.96 mg, yield 10.4%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 1028.7 [M+H] + .

[1026] Example 73: 6-((S)-18-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-19,19-dimethyl-4,16-dioxo-7,10,13-trioxa-3,17-diazadocosanamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-030)

[1027]

[1028] CPD-030 (2.28 mg, yield 11.6%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 1056.9 [M+H] + .

[1029] Example 74: N 1 -((S)-1-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 16 -(2-((5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(methylcarbamoyl)pyridazine-3-yl)amino)-2-oxoethyl)-4,7,10,13-tetraoxahexadecanediamide (CPD-031)

[1030] CPD-031 (2.63 mg, yield 12.8%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 1100.9 [M+H] + .

[1031] Example 75: N 1 -((S)-1-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 17 -(2-((5-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(methylcarbamoyl)pyridazin-3-yl)amino)-2-oxoethyl)-3,6,9,12,15-pentaoxaheptadecanediamide (CPD-032)

[1032]

[1033] CPD-032 (2.25 mg, yield 10.5%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 1116.8 [M+H] + .

[1034] Example 76: N 1 -((S)-1-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 19 -(2-((5-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(methylcarbamoyl)pyridazin-3-yl)amino)-2-oxoethyl)-4,7,10,13,16-pentaoxanonadecanediamide (CPD-033)

[1035]

[1036] CPD-033 (2.63 mg, yield 11.8%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 1144.9 [M+H] + .

[1037] Example 77: N 1 -((S)-1-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 4-(2-((5-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(methylcarbamoyl)pyridazin-3-yl)amino)-2-oxoethyl)succinamide (CPD-034)

[1038]

[1039] CPD-034 (1.10 mg, yield 6.1%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 924.7 [M+H] + .

[1040] Example 78: N 1 -((S)-1-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 5 -(2-((5-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(methylcarbamoyl)pyridazin-3-yl)amino)-2-oxoethyl)glutaramide (CPD-035)

[1041]

[1042] CPD-035 (1.14 g, yield 6.3%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 938.7 [M+H] + .

[1043] Example 79: N 1 -((S)-1-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 6 -(2-((5-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(methylcarbamoyl)pyridazin-3-yl)amino)-2-oxoethyl)adipamide (CPD-036)

[1044]

[1045] CPD-036 (1.46 mg, yield 7.9%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 952.7 [M+H] + .

[1046] Example 80: N1 -((S)-1-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 7 -(2-((5-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(methylcarbamoyl)pyridazin-3-yl)amino)-2-oxoethyl)heptanediamide (CPD-037)

[1047]

[1048] CPD-037 (1.56 mg, yield 8.3%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 966.8 [M+H] + .

[1049] Example 81: N 1 -((S)-1-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 8 -(2-((5-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(methylcarbamoyl)pyridazin-3-yl)amino)-2-oxoethyl)octanediamide (CPD-038)

[1050]

[1051] CPD-038 (2.10 mg, yield 11.1%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 980.8 [M+H] + .

[1052] Example 82: N 1 -((S)-1-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 9 -(2-((5-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(methylcarbamoyl)pyridazin-3-yl)amino)-2-oxoethyl)nonanediamide (CPD-039)

[1053]

[1054] CPD-039 (3.49 mg, yield 18.1%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 994.8 [M+H] + .

[1055] Example 83: N 1 -((S)-1-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 10 -(2-((5-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(methylcarbamoyl)pyridazin-3-yl)amino)-2-oxoethyl)decanediamide (CPD-040)

[1056]

[1057] CPD-040 (3.97 mg, yield 20.3%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 1008.7 [M+H] + .

[1058] Example 84: N 1 -((S)-1-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 11 -(2-((5-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(methylcarbamoyl)pyridazin-3-yl)amino)-2-oxoethyl)undecanediamide (CPD-041)

[1059]

[1060] CPD-041 (2.02 mg, yield 10.2%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 1022.8 [M+H] + .

[1061] Example 85: 6-(2-(2-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetamido)acetamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-042)

[1062]

[1063] To a mixture of 6-(2-aminoacetamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (8 mg, 0.019 mmol), HOAt (5 mg, 0.038 mmol), and EDCI (7 mg, 0.038 mmol) in DMSO (1 mL) was added N-methylmorpholine (10 mg, 0.095 mmol) and (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycine (6 mg, 0.019 mmol). After the mixture was stirred at 25 °C for 16 h, it was purified by reverse-phase chromatography to give the title compound (1.18 mg, yield 8.4%) as a yellow solid. MS (ESI) m / z = 725.5 [M+H] + .

[1064] Example 86: 6-(2-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propanamido)acetamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-043)

[1065]

[1066] CPD-043 (1.22 mg, yield 8.5%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 739.6 [M+H] + .

[1067] Example 87: 6-(2-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butanamido)acetamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-044)

[1068]

[1069] CPD-044 (2.09 mg, yield 11.7%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 753.5 [M+H] + .

[1070] Example 88: 6-(2-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentanamido)acetamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-045)

[1071]

[1072] CPD-045 (2.47 mg, yield 16.6%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 767.6 [M+H] + .

[1073] Example 89: 6-(2-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexanamido)acetamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-046)

[1074]

[1075] CPD-046 (1.73 mg, yield 11.4%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 781.6 [M+H] + .

[1076] Example 90: 6-(2-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptanamido)acetamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-047)

[1077]

[1078] CPD-047 (2.00 mg, yield 12.9%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 795.6 [M+H] + .

[1079] Example 91: 6-(2-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octanamido)acetamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-048)

[1080]

[1081] CPD-048 (3.13 mg, yield 19.9%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 809.7 [M+H] + .

[1082] Example 92: 6-(2-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)propanamido)acetamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-049)

[1083]

[1084] CPD-049 (2.78 mg, yield 18.3%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 783.6 [M+H] + .

[1085] Example 93: 6-(2-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanamido)acetamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-050)

[1086]

[1087] CPD-050 (3.10 mg, yield 19.3%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 827.6 [M+H] + .

[1088] Example 94: 6-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-12-oxo-3,6,9-trioxa-13-aza-pentadecane-15-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-051)

[1089]

[1090] CPD-051 (2.29 mg, yield 13.6%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 871.7 [M+H] + .

[1091] Example 95: 6-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-15-oxo-3,6,9,12-tetraoxa-16-aza-octadecane-18-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-052)

[1092]

[1093] CPD-052 (2.17 mg, yield 12.2%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 915.6 [M+H] + .

[1094] Example 96: 6-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-18-oxo-3,6,9,12,15-pentaoxa-19-azaheneicosane-21-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-053)

[1095]

[1096] CPD-053 (1.72 mg, yield 9.2%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 959.8 [M+H] + .

[1097] Example 97: 6-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)acetamido)acetamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-054)

[1098] CPD-054 (2.10 mg, yield 14.9%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 725.5 [M+H] + .

[1099] Example 98: 6-(2-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)propanamido)acetamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-055)

[1100]

[1101] CPD-055 (3.01 g, yield 20.9%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 739.5 [M+H] + .

[1102] Example 99: 6-(2-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butanamido)acetamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-056)

[1103]

[1104] CPD-056 (2.20 mg, yield 15.1%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 753.6 [M+H] + .

[1105] Example 100: 6-(2-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)pentanamido)acetamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-057)

[1106]

[1107] CPD-057 (1.50 mg, yield 10.1%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 767.5 [M+H] + .

[1108] Example 101: 6-(2-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)hexanamido)acetamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-058)

[1109]

[1110] CPD-058 (1.71 mg, yield 11.3%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 781.6 [M+H] + .

[1111] Example 102: 6-(2-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)heptanamido)acetamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-059)

[1112]

[1113] CPD-059 (1.47 mg, yield 9.5%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 795.6 [M+H] + .

[1114] Example 103: 6-(2-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)octanamido)acetamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-060)

[1115]

[1116] CPD-060 (1.64 mg, yield 10.4%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 809.7 [M+H] + .

[1117] Example 104: 6-(2-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)propanamido)acetamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-061)

[1118]

[1119] CPD-061 (2.46 mg, yield 16.2%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 783.6 [M+H] + .

[1120] Example 105: 6-(2-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)propanamido)acetamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-062)

[1121]

[1122] CPD-062 (2.79 mg, yield 17.4%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 827.6 [M+H] + .

[1123] Example 106: 6-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)-12-oxo-3,6,9-trioxa-13-azapentadecane-15-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-063)

[1124]

[1125] CPD-063 (2.04 mg, yield 12%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 871.7 [M+H]+ .

[1126] Example 107: 6-(1-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)-15-oxo-3,6,9,12-tetraoxa-16-azaoctadecane-18-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-064)

[1127]

[1128] CPD-064 (2.87 mg, yield 16.1%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 915.7 [M+H] + .

[1129] Example 108: 6-(1-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)-18-oxo-3,6,9,12,15-pentaoxa-19-azaeicosane-21-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-065)

[1130]

[1131] CPD-065 (3.17 mg, yield 17%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 959.8 [M+H] + .

[1132] Example 109: 6-(Cyclopropanecarboxamido)-4-((3-(1-(2-(2-(2-(((S)-1-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)acetamido)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-066)

[1133]

[1134] CPD-066 (3.95 mg, yield 36.4%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 980.8 [M+H]+ .

[1135] Example 110: 6-(Cyclopropanecarboxamido)-4-((3-(1-(2-(3-(3-(((S)-1-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-3-oxopropoxy)propanamido)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-067)

[1136]

[1137] CPD-067 (3.59 mg, yield 32.1%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 1008.7 [M+H] + .

[1138] Example 111: 6-(Cyclopropanecarboxamido)-4-((3-(1-((S)-13-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-carbonyl)-14,14-dimethyl-4,11-dioxo-6,9-dioxo-3,12-diazapentadecyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-068)

[1139]

[1140] CPD-068 (3.61 mg, yield 31.8%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 1024.7 [M+H] + .

[1141] Example 112: 6-(Cyclopropanecarboxamido)-4-((3-(1-((S)-15-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-carbonyl)-16,16-dimethyl-4,13-dioxo-7,10-dioxo-3,14-diazapentadecyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-069)

[1142]

[1143] CPD-069 (4.37 mg, yield 37.5%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 1052.7 [M+H] + .

[1144] Example 113: 6-(Cyclopropanecarboxamido)-4-((3-(1-((S)-16-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-17,17-dimethyl-4,14-dioxo-6,9,12-trioxa-3,15-diazaoctadecyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-070)

[1145]

[1146] CPD-070 (2.96 mg, yield 25%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 1068.7 [M+H] + .

[1147] Example 114: 6-(Cyclopropanecarboxamido)-4-((3-(1-((S)-18-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-19,19-dimethyl-4,16-dioxo-7,10,13-trioxa-3,17-diazadocosyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-071)

[1148]

[1149] CPD-071 (3.04 mg, yield 25.1%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 1096.8 [M+H] + .

[1150] Example 115: N 1-(2-(3-(3-((6-(Cyclopropanecarboxamido)-3-(methylcarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-1H-1,2,4-triazol-1-yl)ethyl)-N16-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4,7,10,13-tetraoxahexadecanediamide (CPD-072)

[1151]

[1152] CPD-072 (2.62 mg, yield 20.7%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 1140.8 [M+H] + .

[1153] Example 116: N 1 -(2-(3-(3-((6-(Cyclopropanecarboxamido)-3-(methylcarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-1H-1,2,4-triazol-1-yl)ethyl)-N17-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-3,6,9,12,15-pentaoxaheptadecanediamide (CPD-073)

[1154]

[1155] CPD-073 (2.48 mg, yield 19.4%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 1156.8 [M+H] + .

[1156] Example 117: N 1 -(2-(3-(3-((6-(Cyclopropanecarboxamido)-3-(methylcarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-1H-1,2,4-triazol-1-yl)ethyl)-N 19 -((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4,7,10,13,16-pentaoxanonadecanediamide (CPD-074)

[1157]

[1158] CPD-074 (2.92 mg, yield 22.3%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 1184.9 [M+H] + .

[1159] Example 118: N 1 -(2-(3-(3-((6-(Cyclopropanecarboxamido)-3-(methylcarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-1H-1,2,4-triazol-1-yl)ethyl)-N 4 -((S)-1-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)succinamide (CPD-075)

[1160]

[1161] CPD-075 (1.94 mg, yield 18.2%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 964.8 [M+H] + .

[1162] Example 119: N 1 -(2-(3-(3-((6-(Cyclopropanecarboxamido)-3-(methylcarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-1H-1,2,4-triazol-1-yl)ethyl)-N 5 -((S)-1-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)glutarimide (CPD-076)

[1163]

[1164] CPD-076 (2.05 mg, yield 18.9%) was synthesized according to the same procedure as for the preparation of CPD-042. MS (ESI) m / z = 978.8 [M+H] + .

[1165] Example 120: N 1 -(2-(3-(3-((6-(Cyclopropanecarboxamido)-3-(methylcarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-1H-1,2,4-triazol-1-yl)ethyl)-N 6-((S)-1-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-y...

Claims

1. A heterobifunctional compound of formula I or a pharmaceutically acceptable salt thereof, wherein, 1) the TYK2 ligand comprises a moiety of formula 1-1I: wherein, * represents the connection to the linker moiety of the heterobifunctional compound; L is selected from: NH and N(CH3); R 2 selected from the group consisting of: optionally substituted triazolyl and optionally substituted phenyl, wherein said optionally substituted means unsubstituted or substituted with one or more substituents, and each of said substituents is independently a group selected from the following: CN, F, Cl, Br, C1-C4 alkyl, cyclopropyl, and C1-C4 haloalkyl; R 6 is hydrogen; R 3 is hydrogen; R 22 Selected from: NH2, NHMe, NHCD3, Me, Et, CD3, CH2CD3, iPr and cPr; R 23 Selected from: H, F, OMe, CONH2, CONHMe, SMe, SOMe, SO2Me, OCD3, CONHCD3, SCD3, SOCD3, and SO2CD3; and R 1 'selected from: C(O), C(O)-CH2 and pyridyl; 2) the degron is a moiety of formula 6A: wherein, * represents the connection to the linker moiety of the heterobifunctional compound; R EV 1 and R EV 2 are independently selected from the group consisting of: hydrogen, and C1-C8 alkyl; R EV 3 is hydrogen R EV 4 'selected from the group consisting of: NH, C(O)NH, CH2C(O)NH, R EV 5 selected from the group consisting of hydrogen and F; and R EV 6 Selected from: halogen, cyano, optionally substituted thiazole, optionally substituted oxazole, optionally substituted imidazole, optionally substituted pyrazole, optionally substituted oxadiazole, optionally substituted triazole and optionally substituted isoxazole, wherein the optionally substituted means unsubstituted or substituted by one or more substituents, and each of the substituents is independently an alkyl group containing one, two, three or four carbon atoms; and, 3) the linker moiety is as shown in formula 9: wherein, A L is the connection position with the TYK2 ligand; A L selected from the group consisting of: CO, NHCO, CONH, CH2CONH, CH2NHCO, B L is absent or C(O); W L 2 is absent, and W L 1 is a C1 alkylene; and m L is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.

2. The hetero-bifunctional compound according to claim 1, wherein, the degron is a moiety of formula 6A-1 or 6A-2: wherein, R EV 2 , R EV 3 , R EV 4 ', R EV 5 and R EV 6 are defined in Formula 6A.

3. The hetero-bifunctional compound according to claim 1, wherein the degron is a moiety of formula 6A-3 or 6A-4: wherein, R EV 1 , R EV 3 , R EV 4 ', R EV 5 and R EV 6 are defined as in Formula 6A.

4. The hetero-bifunctional compound according to claim 1, wherein, the degron is a moiety of formula 6A-5: wherein, R EV 1 , R EV 2 , R EV 4 ', R EV 5 and R EV 6 are defined in Formula 6A.

5. The hetero-bifunctional compound according to claim 1, wherein, the degron is a moiety of formula 6A-6: Among them, R EV 1 , R EV 2 , R EV 3 , R EV 4 ', and R EV 6 are defined as in Formula 6A.

6. The hetero-bifunctional compound according to claim 1, wherein, R EV 6 is methylthiazole.

7. The hetero-bifunctional compound according to claim 1, wherein, the degron is a moiety of any one of formulas 7A to 7T:

8. A hetero-bifunctional compound or a pharmaceutically acceptable salt thereof, wherein, the compound is selected from the group consisting of: N1-((S)-1-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N8-(2-((5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(methylcarbamoyl)pyridazin-3-yl)amino)-2-oxoethyl)octanediamide (CPD-038); N1-((S)-1-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N9-(2-((5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(methylcarbamoyl)pyridazin-3-yl)amino)-2-oxoethyl)nonanediamide (CPD-039); and N1-((S)-1-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N10-(2-((5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(methylcarbamoyl)pyridazin-3-yl)amino)-2-oxoethyl)decanediamide (CPD-040); 6-(2-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptanamido)acetamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-047); N1-((S)-1-((2S,4R)-4-Hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N9-(2-((5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(methylcarbamoyl)pyridazin-3-yl)amino)-2-oxoethyl)nonanediamide (CPD-084); N1-((S)-1-((2S,4R)-4-Hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N10-(2-((5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(methylcarbamoyl)pyridazin-3-yl)amino)-2-oxoethyl)decanediamide (CPD-085); 6-((5-(4-(7-(((S)-1-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoyl)piperazin-1-yl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-099); 6-((5-(4-(8-(((S)-1-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-8-oxooctanoyl)piperazin-1-yl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-100); 6-(2-(11-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide)methyl)-5-(4-methylthiazol-5-yl)phenoxy)undecanamide)acetamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-110); 6-((5-(4-(8-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-8-oxooctanoyl)piperazin-1-yl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide ((CPD-112); 6-((5-(4-(10-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-10-oxodecanoyl)piperazin-1-yl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-114); 6-((5-(4-(9-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-9-oxononanoyl)piperazin-1-yl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-115); 6-((5-((1-(10-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-10-oxodecanoyl)piperidin-4-yl)ethynyl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-121); 6-((5-((1-(7-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoyl)azetidin-3-yl)ethynyl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-124); 6-((5-((1-(8-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-8-oxooctanoyl)azetidin-3-yl)ethynyl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-125); 6-((5-((1-(9-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-9-oxononanoyl)azetidin-3-yl)ethynyl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-126); 6-((5-((1-(10-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-10-oxodecanoyl)azetidin-3-yl)ethynyl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-127); N1-((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N8-((6-((5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(methylaminocarbonyl)pyridazine-3-yl)amino)pyridin-3-yl)methyl)octanediamide (CP D-131); N1-((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N10-((6-((5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(methylaminocarbonyl)pyridazine-3-yl)amino)pyridin-3-yl)methyl)decanediamide (CPD-133); 6 - ((5 - ((1 - (5 - (((S)-1 - ((2S,4R)-4 - hydroxy - 2 - (((S)-1 - (4 - (4 - methylthiazol - 5 - yl)phenyl)ethyl)carbamoyl)pyrrolidin - 1 - yl)-3,3 - dimethyl - 1 - oxobutan - 2 - yl)amino)-5 - oxopentanoyl)piperidin - 4 - yl)ethynyl)pyridin - 2 - yl)amino)-4 - ((2 - methoxy - 3 - (1 - methyl - 1H - 1,2,4 - triazol - 3 - yl)phenyl)amino)-N - methylpyridazine - 3 - carboxamide (CPD - 134); 6 - ((5 - ((8 - (((S)-1 - ((2S,4R)-4 - hydroxy - 2 - (((S)-1 - (4 - (4 - methylthiazol - 5 - yl)phenyl)ethyl)carbamoyl)pyrrolidin - 1 - yl)-3,3 - dimethyl - 1 - oxobutan - 2 - yl)amino)-8 - oxooctyl)carbamoyl)pyridin - 2 - yl)amino)-4 - ((2 - methoxy - 3 - (1 - methyl - 1H - 1,2,4 - triazol - 3 - yl)phenyl)amino)-N - methylpyridazine - 3 - carboxamide (CPD - 143); 6 - ((5 - ((9 - (((S)-1 - ((2S,4R)-4 - hydroxy - 2 - (((S)-1 - (4 - (4 - methylthiazol - 5 - yl)phenyl)ethyl)carbamoyl)pyrrolidin - 1 - yl)-3,3 - dimethyl - 1 - oxobutan - 2 - yl)amino)-9 - oxononyl)carbamoyl)pyridin - 2 - yl)amino)-4 - ((2 - methoxy - 3 - (1 - methyl - 1H - 1,2,4 - triazol - 3 - yl)phenyl)amino)-N - methylpyridazine - 3 - carboxamide (CPD - 144); 6 - ((5 - (4 - (1 - (7 - (((S)-1 - ((2S,4R)-4 - hydroxy - 2 - (((S)-1 - (4 - (4 - methylthiazol - 5 - yl)phenyl)ethyl)carbamoyl)pyrrolidin - 1 - yl)-3,3 - dimethyl - 1 - oxobutan - 2 - yl)amino)-7 - oxoheptanoyl)piperidin - 4 - yl)piperazin - 1 - yl)pyridin - 2 - yl)amino)-4 - ((2 - methoxy - 3 - (1 - methyl - 1H - 1,2,4 - triazol - 3 - yl)phenyl)amino)-N - methylpyridazine - 3 - carboxamide (CPD - 148); 6 - ((5 - (4 - (1 - (9 - (((S)-1 - ((2S,4R)-4 - hydroxy - 2 - (((S)-1 - (4 - (4 - methylthiazol - 5 - yl)phenyl)ethyl)carbamoyl)pyrrolidin - 1 - yl)-3,3 - dimethyl - 1 - oxobutan - 2 - yl)amino)-9 - oxononanoyl)piperidin - 4 - yl)piperazin - 1 - yl)pyridin - 2 - yl)amino)-4 - ((2 - methoxy - 3 - (1 - methyl - 1H - 1,2,4 - triazol - 3 - yl)phenyl)amino)-N - methylpyridazine - 3 - carboxamide (CPD - 150); 6-((5-(4-(1-(10-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-10-oxodecanoyl)piperidin-4-yl)piperazin-1-yl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-151); 6-((5-((5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentyl)carbamoyl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-155); 6-((5-((7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptyl)carbamoyl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-157); 6-((5-((8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)carbamoyl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-158); 6-((5-((2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethyl)carbamoyl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-159); 6-((5-((5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)pentyl)carbamoyl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-164); 6-((5-((8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)octyl)carbamoyl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-167); 6-((5-((3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)propyl)carbamoyl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (CPD-175).

9. A pharmaceutical composition comprising the heterobifunctional compound according to any one of claims 1-8 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.

10. Use of the heterobifunctional compound according to any one of claims 1-8 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 9 in the preparation of a medicament for treating a TYK2-mediated disease.

11. The use according to claim 10, wherein The TYK2-mediated disease is cancer.

12. The use according to claim 11, wherein the cancer is selected from the group consisting of: brain cancer, gastric cancer, gastrointestinal cancer, liver cancer, biliary tract cancer, breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, penile cancer, urogenital cancer, esophageal cancer, laryngeal cancer, skin cancer, lung cancer, pancreatic cancer, thyroid cancer, adenocarcinoma, bladder cancer, kidney cancer, muscle cancer, bone cancer, hematopoietic system cancer, myeloproliferative neoplasm, essential thrombocythemia, polycythemia vera, primary myelofibrosis, chronic neutrophilic leukemia, acute lymphoblastic leukemia, Hodgkin lymphoma, chronic myelomonocytic leukemia, systemic mastocytosis, hypereosinophilic syndrome, cutaneous T-cell lymphoma, B-cell lymphoma, and myeloma.

13. The use according to claim 10, wherein, The TYK2-mediated disease is selected from the group consisting of: ankylosing spondylitis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, and reperfusion injury.

14. The use according to claim 10, wherein, The TYK2-mediated disease is selected from the group consisting of: multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, psoriasis, myasthenia gravis, type I diabetes, systemic lupus erythematosus, IgA nephropathy, autoimmune thyroid disease, alopecia areata, and bullous pemphigoid.

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