Compounds and methods for treating diseases

Abstract

Provided are heterobifunctional compounds (e.g., bifunctional small molecule compounds), compositions containing one or more of the heterobifunctional compounds, methods of using the heterobifunctional compounds to treat certain diseases in subjects in need thereof, and methods of identifying such heterobifunctional compounds.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and in particular relates to compounds and methods for treating diseases such as cancer. Background of the Invention

[0003] The human Janus kinase (JAK) family includes four non-receptor tyrosine kinases, JAK1, JAK2, JAK3, and TYK2. JAK kinases play a central role in the hematopoietic system by transmitting cytokine-mediated signals. These intracellular kinases bind to type I and type II cytokine receptors, which lack catalytic domains and transduce signals to downstream molecules in response to the kinase activity of JAKs. Cytokine binding triggers conformational changes in the respective receptors, which in turn induce autophosphorylation and activation of the receptor-bound JAK kinases. JAK kinases then recruit and phosphorylate downstream signaling molecules, most importantly transcription factors of the signal transducer and activator of transcription (STAT) family. Phosphorylated STATs then translocate to the nucleus and activate transcription of genes related to hematopoiesis and immune responses. Different cytokine receptors recruit different combinations of JAK kinases, which transduce signals to a wide range of downstream targets and regulate complex, lineage-dependent signaling networks.

[0004] JAK kinases act downstream of multiple cytokine receptors and are closely associated with the proliferation, survival, activation, and differentiation of hematopoietic cells. Furthermore, no known pathways can fully compensate for JAK / STAT signaling in the hematopoietic system. Therefore, the activity of JAK kinases is crucial for hematopoiesis and immunity. Consequently, aberrations in JAK kinases are known to drive the pathogenesis of many diseases, most notably inflammation, autoimmune diseases, and cancer. For many of these indications, the JAK family kinases are well-documented as important therapeutic targets. Therefore, there is an urgent need in the art for new drugs targeting JAK kinases. Summary of the Invention

[0005] The present invention relates to heterobifunctional compounds (e.g., bifunctional small molecule compounds), compositions containing one or more heterobifunctional compounds, and methods of using the compositions to treat certain diseases in subjects in need thereof. The present invention also relates to methods of identifying such heterobifunctional compounds.

[0006] According to a first aspect of the present invention, the heterobifunctional compound disclosed herein includes a Janus kinase (JAK) ligand bound to a degradation tag, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, isomer or analog thereof. In another embodiment, the heterobifunctional compound is not a compound disclosed in PCT / CN2020 / 083041 (such as JA-001-JA-295) or is selected from Table 1B.

[0007] In one embodiment, the JAK ligand is capable of binding to a JAK protein, including JAK1, JAK2, JAK3, tyrosine kinase 2 (TYK2), a JAK mutant, a JAK deletion, or a JAK fusion protein. In one embodiment, the JAK ligand is a JAK inhibitor or part of a JAK inhibitor. In another embodiment, the JAK ligand is selected from the group consisting of BSK805 (NVP-BSK805), 1-amino-[1,2,4]thiazolo[1,5-a]pyridine (Compound 12), TG101209, CEP-33799, Ruxolitinib, Tofacitinib (CP-690550), Baricitinib, Oclacitinib, Cerdulatinib (PRT-062070), Decernotinib (Decernotinib), and 1-amino-[1,2,4]thiazolo[1,5-a]pyridine (Compound 12). ib)(VX509), Delgocitinib(JTE-052), Fedratinib, Filgotinib(GLP0634), Gandotinib(LY2784544), Ilginatinib(NS-018), Itacitinib(INCB03911), Lestauritinib, Momelotinib(CYT387), Pacritinib( inib)(SB1578), Pefitinib, Solcitinib(GSK2586184, GLG0778), Upadacitinib(ABT-494), AT9283, AZ-3, AZ960, AZD1480, BMS-986165, BMS-911543, BVB808(NVP-BVB808), BBT594(NVP-BBT594), CHZ868, FM381, PF-04965842, PF-06263276, PF-06651600, PF-06700841, SAR-20347, NDI-031301, NDI-31232, NVP-P830, SHR-0302, VR588, XL019, R333 and R348, 3-aminopyrrolopyrazine (compound (Cmpd) 3q), tetracyclic pyridone (compound 6), triazole-pyrrolopyridines (compound (Cmpd) 7), pyrazolopyrimidines (compound (Cmpd) 7j), imidazopyridines (compound (Cmpd) 19), 1-methyl-1H-imidazole derivatives (compound (Cmpd) 19a),C-2 methyl imidazopyrrolopyridines (compound (Cmpd) 20), pyrazolopyridones (compound 20a), 9H-carbazole-1-carboxamides (compound (Cmpd) 21), thienopyridines (compound (Cmpd) 23), pyrazole-4-carboxamides (compound (Cmpd) 28), imidazopyridines (compound (Cmpd) 30), hydroxyethyl imidazopyrrolopyridines (compound (Cmpd) 31), pyrrolopyridazines (compound (Cmpd) 35), 6- Oxopyridopyrimidines (compound (Cmpd) 36), 2-aminopyrazolo[1,5-a]pyrimidines (compound (Cmpd) 45), cyclopropylamides (compound (Cmpd) 46), imidazole-pyrrolopyridines (compound (Cmpd) 49), 1-amino-5H-pyrido[4,3-b]indole-4-carboxamides (compound (Cmpd) 65), compound (Cmpd) 3, compound (Cmpd) 13a, compound (Cmpd) 45a and analogs thereof.

[0008] In another embodiment, the degradation tag is bound to a ubiquitin ligase or is a hydrophobic group or tag that causes JAK protein misfolding. In another embodiment, the ubiquitin ligase is an E3 ligase. In another embodiment, the E3 ligase is selected from the group consisting of cereblon E3 ligase, VHL E3 ligase, IAP ligase, MDM2 ligase, TRIM24 ligase, TRIM21 ligase, KEAP1 ligase, DCAF16 ligase, RNF4 ligase, RNF114 ligase, and AhR ligase.

[0009] In another embodiment, the degradation tag is selected from the group consisting of pomalidomide, thalidomide, lenalidomide, VHL-1, 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 and analogs thereof.

[0010] In additional embodiments, the JAK ligand is conjugated to the degradation tag via a linker moiety.

[0011] In other embodiments, the JAK ligand comprises a moiety of Formula 1:

[0012]

[0013] Wherein, the linker portion of the heterobifunctional compound is connected to R 1 ;and,A,B,C,D,E,F,G,X,Y,V,W,R 1 、R 2 、R 3 and n are defined below.

[0014] In other embodiments, the JAK ligand comprises a moiety of Formula 2:

[0015]

[0016] Wherein, the linker portion of the heterobifunctional compound is connected to R 1 ;and,A,B,D,X,Y,V,W,R 1 and R 2 As defined below.

[0017] In another embodiment, the JAK ligand comprises a moiety of Formula 1. In another embodiment, the JAK ligand is derivatized with NVP-BSK805. In another embodiment, the JAK ligand is of Formula 3A.

[0018] In another embodiment, the degradation tag is a moiety of formula 5, and the degradation tag is represented by Z E a linker moiety connected to the heterobifunctional compound;

[0019]

[0020] Among them, Z E 、R E 1 、L E and Ring A E As defined below.

[0021] In some embodiments, the connector portion is as shown in Formula 9:

[0022]

[0023] Among them, A L 、W L 、B L and m L As defined below.

[0024] In one embodiment, the linker portion is as shown in Formula 9A:

[0025]

[0026] Among them, R L1 、R L 2 、R L 3 、R L 4 、A L 、W L 、B L 、m L 、n L and o L As defined below.

[0027] In another embodiment, the linker portion is as shown in Formula 9B:

[0028]

[0029] Among them, R L 1 、R L 2 、A L 、B L 、m L and n L As defined below.

[0030] In another embodiment, the linker portion is as shown in Formula 9C:

[0031]

[0032] Among them, R L 1 、R L 2 、R L 3 、R L 4 、R L 5 、R L 6 、A L 、B L 、X L 、m L 、n L 、o L and p L As defined below.

[0033] In one embodiment, the linker portion is as shown in Formula 9D:

[0034] -A L -(W L ) qL -B L -

[0035] (Formula 9D)

[0036] Among them, W L 、A L 、B L and q L As defined below.

[0037] According to the second aspect of the present invention, the composition of the present invention comprises the heterobifunctional compound or a pharmaceutically acceptable salt or analog thereof.

[0038] In one embodiment, the pharmaceutical composition further comprises one or more additional therapeutic agents.

[0039] In one embodiment, the additional therapeutic agent is selected from the group consisting of anticancer or antitumor drugs, or a combination thereof.

[0040] In one embodiment, the additional therapeutic agent is selected from the group consisting of an anti-proliferative agent, an immunomodulatory agent, or a combination thereof.

[0041] In one embodiment, the additional therapeutic agent is selected from the group consisting of a signaling pathway inhibitor, a signaling pathway activator, or a combination thereof.

[0042] In one embodiment, the additional therapeutic agent is selected from the group consisting of a kinase inhibitor, a kinase activator, or a combination thereof.

[0043] In one embodiment, the composition comprises a heterobifunctional compound wherein the JAK ligand is a moiety of Formula 1.

[0044] In one embodiment, the additional therapeutic agent is a signaling pathway inhibitor, wherein the signaling pathway is selected from the group consisting of a PI3K / AKT / mTOR pathway, a RAS / RAF / MEK / ERK pathway, a FLT3 pathway, a MAPK pathway, and combinations thereof.

[0045] In one embodiment, the additional therapeutic agent is a PI3K / AKT / mTOR pathway inhibitor.

[0046] In one embodiment, the additional therapeutic agent is a RAS / RAF / MEK / ERK pathway inhibitor.

[0047] In one embodiment, the additional therapeutic agent is a FLT3 pathway inhibitor.

[0048] In one embodiment, the additional therapeutic agent is a MAPK pathway inhibitor.

[0049] In one embodiment, the additional therapeutic agent is a kinase inhibitor.

[0050] In one embodiment, the additional therapeutic agent is selected from the group consisting of a FLT3 inhibitor, a PI3K inhibitor, an AKT inhibitor, an mTOR inhibitor, a RAS inhibitor, a RAF inhibitor, a MEK inhibitor, an ERK inhibitor, and combinations thereof.

[0051] In one embodiment, the additional therapeutic agent is a FLT3 inhibitor and / or an AKT inhibitor.

[0052] According to a third aspect of the present invention, the method for treating a JAK-mediated disease disclosed herein comprises administering the heterobifunctional compound or a pharmaceutically acceptable salt or analog thereof to a subject suffering from a JAK-mediated disease.

[0053] In one embodiment, the JAK-mediated disease is caused by JAK expression, mutation, deletion or fusion.

[0054] In one embodiment, a subject suffering from a JAK-mediated disease has elevated JAK function relative to a healthy subject not suffering from the JAK-mediated disease.

[0055] In one embodiment, the heterobifunctional compound is selected from the group consisting of JA-001 to JA-295, or analogs thereof.

[0056] In one embodiment, the heterobifunctional compound is selected from the group consisting of JA-296 to JA-350, or analogs thereof.

[0057] In one embodiment, the heterobifunctional compound is administered to a subject orally, parenterally, intradermally, subcutaneously, topically, or rectally.

[0058] In one embodiment, the method further comprises administering to the subject an additional therapeutic regimen for treating cancer, an inflammatory disorder, or an autoimmune disease.

[0059] In one embodiment, the additional treatment regimen is selected from the group consisting of surgery, chemotherapy, radiation therapy, hormone therapy, targeted therapy, and immunotherapy.

[0060] In one embodiment, the JAK-mediated cancer is selected from the group consisting of brain cancer, stomach cancer, gastrointestinal cancer, liver cancer, biliary tract cancer, breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, penile cancer, genitourinary tract 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 neoplasms, essential thrombocythemia, polycythemia vera, primary myelofibrosis, chronic neutrophilic leukemia, acute lymphocytic leukemia, Hodgkin lymphoma, chronic myelomonocytic leukemia, systemic mast cell disease, hypereosinophilic syndrome, cutaneous T-cell lymphoma, B-cell lymphoma, and myeloma.

[0061] In one embodiment, the JAK-mediated inflammatory disorder is selected from the group consisting of ankylosing spondylitis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, and reperfusion injury.

[0062] In one embodiment, the JAK-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.

[0063] In one embodiment, the JAK-mediated skin disorder 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.

[0064] In one embodiment, the JAK-mediated viral infection is selected from the group consisting of infection 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).

[0065] In one embodiment, the JAK-mediated dry eye disease is selected from the group consisting of dry eye syndrome (DES) and keratoconjunctivitis sicca (KCS).

[0066] In one embodiment, the JAK-mediated bone remodeling disorder is selected from the group consisting of osteoporosis and osteoarthritis.

[0067] In one embodiment, the JAK-mediated immune complication associated with organ transplantation is selected from the group consisting of graft-versus-host disease.

[0068] In one embodiment, the JAK-mediated disease is recurrent cancer.

[0069] In one embodiment, the JAK-mediated disease is refractory to one or more prior therapies.

[0070] According to a fourth aspect of the present invention, a method for identifying a heterobifunctional compound that mediates degradation or reduction of JAK is disclosed. The method comprises:

[0071] providing a heterobifunctional test compound comprising a JAK ligand conjugated to a degradation tag via a linker;

[0072] contacting the heterobifunctional test compound with cells comprising a ubiquitin ligase and a JAK;

[0073] Determining whether JAK levels are reduced in the cells; and

[0074] Heterobifunctional test compounds that mediate degradation or reduction of JAK are identified as heterobifunctional compounds.

[0075] In one embodiment, the cell is a cancer cell.

[0076] In one embodiment, the cancer cell is a JAK-mediated cancer cell.

[0077] According to a fifth aspect of the present invention, the method for treating a GSTP1-mediated disease disclosed herein comprises administering the heterobifunctional compound or a pharmaceutically acceptable salt or analog thereof to a subject suffering from a GSTP1-mediated disease.

[0078] According to a sixth aspect of the present invention, the method for treating JAK-mediated and GSTP1-mediated diseases disclosed herein comprises administering the heterobifunctional compound or a pharmaceutically acceptable salt or analog thereof to a subject suffering from the JAK-mediated and GSTP1-mediated disease.

[0079] According to a seventh aspect of the present disclosure, there is provided use of a heterobifunctional compound or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, isomer or analog thereof in combination with a second therapeutic agent.

[0080] In one embodiment, the JAK ligand of the heterobifunctional compound is a moiety of formula 1 as defined in the first aspect.

[0081] In one embodiment, the JAK ligand of the heterobifunctional compound is a moiety of formula 1A, 1B, 1C, 1D, 1F, 1E, 1F, 1G, 1H, 1I, 1J, 1K, 1L, 1M, 1N, 1O, 1P or 1Q as defined in the first aspect.

[0082] In one embodiment, the second therapeutic agent is selected from the group consisting of an anticancer or antitumor agent, an antiproliferative agent, an immunomodulatory agent, a kinase inhibitor, a kinase activator, a signaling pathway inhibitor, or a combination thereof.

[0083] In one embodiment, the second therapeutic agent is a signaling pathway inhibitor, wherein the signaling pathway is selected from the group consisting of a PI3K / AKT / mTOR pathway, a RAS / RAF / MEK / ERK pathway, a FLT3 pathway, a MAPK pathway, and combinations thereof.

[0084] In one embodiment, the second therapeutic agent is a PI3K / AKT / mTOR pathway inhibitor.

[0085] In one embodiment, the second therapeutic agent is a RAS / RAF / MEK / ERK pathway inhibitor.

[0086] In one embodiment, the second therapeutic agent is a FLT3 pathway inhibitor.

[0087] In one embodiment, the second therapeutic agent is a MAPK pathway inhibitor.

[0088] In one embodiment, the second therapeutic agent is a kinase inhibitor.

[0089] In one embodiment, the second therapeutic agent is selected from the group consisting of a FLT3 inhibitor, a PI3K inhibitor, an AKT inhibitor, an mTOR inhibitor, a RAS inhibitor, a RAF inhibitor, a MEK inhibitor, an ERK inhibitor, and combinations thereof.

[0090] In one embodiment, the second therapeutic agent is a FLT3 inhibitor, an AKT inhibitor, and / or a MEK inhibitor.

[0091] In one embodiment, the second therapeutic agent is gilteritinib, MK-2206 and / or trametinib.

[0092] According to an eighth aspect of the present disclosure, there is provided a method for treating or preventing a disease, the method comprising administering a heterobifunctional compound or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, isomer or analog thereof and a second therapeutic agent to a subject in need thereof.

[0093] In one embodiment, the disease is a JAK-mediated disease or a GSTP1-mediated disease as described herein, or the disease is selected from cancer, an inflammatory disorder, or an autoimmune disease.

[0094] In one embodiment, the second therapeutic agent and the heterobifunctional compound are as defined in the seventh aspect.

[0095] In one embodiment, the heterobifunctional compound and the second therapeutic agent may be administered simultaneously, separately, or within a period of time.

[0096] According to a ninth aspect of the present disclosure, there is provided a pharmaceutical combination comprising

[0097] (i) a heterobifunctional compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, isomer, or analog thereof; and

[0098] (ii) a second therapeutic agent.

[0099] In one embodiment, the pharmaceutical combination is used to treat the above-defined diseases (such as JAK-mediated diseases or GSTP1-mediated diseases).

[0100] In another embodiment, the second therapeutic agent and the heterobifunctional compound are as defined in the seventh aspect.

[0101] According to a tenth aspect of the present disclosure, a use of a drug combination for treating or preventing a disease is provided. In one embodiment, the disease is a JAK-mediated disease or a GSTP1-mediated disease as described herein, or the disease is selected from cancer, inflammatory disorders, or autoimmune diseases.

[0102] Incorporation by reference

[0103] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0104] BRIEF DESCRIPTION OF THE DRAWINGS

[0105] The novel features of the present invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention may be obtained by reference to the following detailed description, which sets forth illustrative embodiments in which the principles of the present invention are utilized, and the accompanying drawings:

[0106] Figure 1 Shown are immunoblots of JAK1 / 2 / 3 proteins expressed in HEL cells following treatment with a dose range of heterobifunctional compounds JA-189 or JA-213 or a single dose of NVP-BSK805.

[0107] Figure 2Shown are immunoblots of JAK1 / 3 protein expressed in RS4;11 cells following treatment with a dose range of the heterobifunctional compounds JA-189, JA-213, NVP-BSK805, or TG101209.

[0108] Figure 3 Shown are graphs of MV4;11, RS4;11, Kasumi-1, and HEL cell viability versus JA-189, JA-213, NVP-BSK805, and TG101209 concentrations.

[0109] Figure 4 Shown are graphs of MV4;11, RS4;11, Kasumi-1, and HEL cell viability versus JA-189, JA-213, NVP-BSK805, and TG101209 concentrations in the presence or absence of 10 μM pomalidomide.

[0110] Figure 5 Shown are immunoblots of GSPT1 and tubulin expressed in RS4:11 cells after treatment with JA-189, JA-213, or CC-885 at the indicated concentrations for 16 hours.

[0111] Figure 6 Graph showing the relationship between cell viability of immortalized human lung fibroblasts IMR-90 and keratinocytes HACAT versus JA-189 and JA-213 concentrations.

[0112] Figure 7 showed that in FLT3 mutant AML cells, inhibition of FLT3 significantly increased sensitivity to the GSPT1 degraders JA-189, JA-263, JA-322, and JA-324.

[0113] Figure 8 We show that in FLT3 wild-type AML cells, inhibition of FLT3 does not affect sensitivity to the GSPT1 degraders JA-189 and JA-263.

[0114] Figure 9 It was shown that GSPT1 degraders JA-189, JA-263, JA-322, JA-323 and JA-324 reduced GSPT1 protein levels.

[0115] Figure 10 We show that inhibition of MAPK or PI3K / AKT signaling increases sensitivity to the GSPT1 degraders JA-189 and JA-263. Detailed Description of the Invention

[0117] The human Janus kinase (JAK) family includes four non-receptor tyrosine kinases: JAK1, JAK2, JAK3, and TYK2. JAK kinases play a central role in the hematopoietic system by transducing cytokine-mediated signals (O'Shea, Schwartz et al. 2015). These intracellular kinases bind to type I and type II cytokine receptors, which lack catalytic domains and respond to the kinase activity of JAKs, transducing signals to downstream molecules. Cytokine binding triggers conformational changes in the respective receptors, inducing autophosphorylation and activation of the receptor-bound JAK kinases. JAK kinases then recruit and phosphorylate downstream signaling molecules, most importantly transcription factors of the signal transducer and activator of transcription (STAT) family. Phosphorylated STATs subsequently translocate to the nucleus and activate transcription of genes involved in hematopoiesis and immune responses. Different cytokine receptors recruit distinct combinations of JAK kinases, which transduce signals to a wide range of downstream targets, regulating complex, lineage-dependent signaling networks (Schwartz, Kanno et al. 2017).

[0118] JAK kinases act downstream of multiple cytokine receptors and are closely related to the proliferation, survival, activation, and differentiation of hematopoietic cells (Villarino, Kanno et al. 2015). In addition, there is no known pathway that can fully compensate for JAK / STAT signaling in the hematopoietic system. Therefore, the activity of JAK kinases is crucial for hematopoiesis and immunity. Therefore, aberrations in JAK kinases are known to drive the pathogenesis of many diseases, most notably inflammation, autoimmune diseases, and cancer (O'Shea, Schwartz et al. 2015). For many of these indications, JAK family kinases are well-established as important therapeutic targets.

[0119] Mutations leading to constitutive JAK2 activation are found in most BCR-ABL-negative myeloproliferative neoplasms, including essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF) (Levine, Wadleigh et al. 2005, Griesshammer and Sadjadian 2017). Among these, JAK2-V617F is the most common mutation. JAK2 mutations have also been reported in chronic neutrophilic leukemia, acute lymphoblastic leukemia, Hodgkin lymphoma, and other hematological malignancies. In addition to JAK2 point mutations, JAK2 fusions and mutations in JAK1 and JAK3 are also considered mechanisms for activating the JAK pathway, although to a lesser extent (O'Shea, Holland et al. 2013). Alternative mechanisms for activating JAK kinases include mutations in JAK regulatory factors such as CSFR3 (Maxson, Gotlib et al. 2013), MPL (Kilpivaara and Levine 2008), and CALR (Rumi, Pietra et al. 2014). Activation of JAK2 has also been associated with non-malignant hematopoietic indications, such as hereditary thrombocythaemia (Langabeer 2014). Importantly, aberrant activation of JAK kinases has been implicated in a wide variety of immunological diseases, such as rheumatoid arthritis, atopic dermatitis, psoriasis, pruritus, inflammatory bowel disease, Crohn's disease, ulcerative colitis, psoriatic arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, alopecia areata, systemic lupus erythematosus, and graft-versus-host disease (Schwartz, Kanno et al. 2017).

[0120] Three JAK inhibitors have been approved for the treatment of rheumatoid arthritis in humans, including ruxolitinib (Mesa et al., 2012), tofacitinib (CP-690550) (Traynor, 2012; Lee et al., 2014; Dhillon, 2017; Strand et al., 2019), and decinitib (Taylor et al., 2017; Markham, 2017), and the JAK inhibitor oclacitinib (Gonzales et al., 2014) has been approved for the treatment of canine atopic dermatitis. Several JAK kinase inhibitors are currently in clinical or preclinical development, including but not limited to: seletinib (PRT-062070) ( Hamlin et al., 2019 ), decitatinib (VX509) ( Farmer et al., 2015 ), dicartinib (JTE-052) ( Nakagawa et al., 2018 ), filgotinib ( Wernig et al., 2008 ; Harrison et al., 2017 ), filgotinib (GLP0634) ( Menet et al., 2014 ; Van Rompaey et al., 2013), tucatinib (LY2784544) (Berdeja et al., 2018), igitinib (NS-018) (Nakaya et al., 2011; Verstovsek et al., 2016), itatinib (INCB03911) (Beatty et al., 2018), lestaurtinib (Mascarenhas et al., 2019; Pinto et al., 2018), molotinib (CYT387) (Pardanani et al., 2018), paritinib (SB1578) (Tremblay et al., 2018; William et al., 2012), pegfitinib (Takeuchi et al., 2016; Hamaguchi et al., 2018), societinib (GSK2586184, GLG0778) (Kahl et al., 2018), and suturing agent (CNS-018) (Beatty et al., 2018). 2016), upadacitinib (ABT-494) (Serhal et al., 2018; Genovese et al., 2018), AT9283 (Howard et al., 2009), AZ-3 (Grimster et al., 2018), AZ960 (Gozgit et al., 2008), AZD1480 (Verstovsek et al., 2015; Ioannidis et al., 2011), BMS-986165 (Papp et al., 2018), BMS-911543 (Wan et al., 2015), BSK805 (NVP-BSK805) and BVB808 (NVP-BVB808) (Ringel et al., 2014; Andraos et al., 2012), BBT594 (NVP-BBT594) (Koppikar et al., 2012;Andraos et al., 2012), CEP-33799 (Dugan et al., 2012), CHZ868 (Wu et al., 2015), FM381 (Forster et al., 2016; Forster et al., 2018), PF-04965842 (Vazquez et al., 2018), PF-06263276 (Jones et al., 2017), PF-06651600 (Thorarensen et al., 2017; Telliez et al., 2016), PF-06700841 (Fensome et al., 2018), SAR-20347 (Works et al., 2014), NDI-03130 1 (Akahane et al., 2017), NDI-31232 (Masse et al., 2015), NVP-P830 (Brasca et al., 2015), SHR-0302 (Wu et al., 2016), VR588 (Wiegman et al., 2015), XL019 (Forsyth et al., 2012), TG101209 (Demyanets et al., 2018; Pardanani et al., 2007), R333 and R348 (Deuse et al., 2008), 3-aminopyrrolopyrazine (compound 3q) (Soth et al., 2013), tetracyclic pyridone (compound 6) (Thompson et al., 2001;Williams et al., 2009), triazole-pyrrolopyridines (compound 7) (Hurley et al., 2013), pyrazolopyrimidines (compound 7j) (Hanan et al., 2012), 1-amino-[1,2,4]triazolo[1,5-a]pyridines (compound 12) (Siu et al., 2013), imidazopyridines (compound 19) (Simov et al., 2016), 1-methyl-1H-imidazole derivatives (compound 19a) (Su et al., 2012) 014), C-2-methylimidazopyrrolopyridines (Compound 20) (Zak et al., 2012), pyrazolopyridones (Compound 20a) (Yogo et al., 2016), 9H-carbazole-1-carboxamides (Compound 21) (Zimmermann et al., 2015), thienopyridines (Compound 23) (Schenkel et al., 2011), pyrazole-4-carboxamides (Compound 28) (Siu et al., 2017), imidazopyridines (Compound 30) ( Liang et al., 2017), hydroxyethylimidazole-pyrrolopyridines (Compound 31) (Zak et al., 2013), pyrrolopyridazines (Compound 35) (Hynes et al., 2017), 6-oxopyridopyrimidines (Compound 36) (Labadie et al., 2013), 2-aminopyrazolo[1,5-a]pyrimidines (Compound 45) (Ledeboer et al., 2009), cyclopropylamides (Compound 46) (Liang et al., 2013; L iang et al., 2013), imidazole-pyrrolopyridines (compound 49) (Kulagowski et al., 2012), 1-amino-5H-pyrido[4,3-b]indole-4-carboxamides (compound 65) (Lim et al., 2011), covalent selective inhibitors of JAK3 (compound 3) (Goedken et al., 2015), (compound 13a) (Kempson et al., 2017), and (compound 45a) (Tan et al., 2015).

[0121] Although JAK2 kinase inhibitors are approved for the treatment of MPNs, the efficacy of these drugs is generally modest and short-lived (Tefferi 2012). A key mechanism of resistance to JAK2 kinase inhibitors is the kinase-independent function of JAK2. JAK2 knockout in mouse models leads to embryonic lethality due to complete loss of EpoR signaling and deficient erythropoiesis (Neubauer, Cumano et al. 1998). JAK2 knockout mice also exhibit defective interferon-γ signaling. Tyrosine residues 1007 / 1008 of JAK2 within the kinase activation loop are essential for its kinase activity. Using a genetically engineered mouse model expressing a kinase-dead mutant (YY1007 / 1008FF) of JAK2, Keil and colleagues demonstrated that kinase-dead JAK2 partially maintains interferon-γ signaling, likely by acting as a scaffold protein on the heteromorphic interferon-γ receptor (Keil, Finkenstadt et al. 2014). It is also well documented that JAK2 kinase inhibitors stimulate activation loop phosphorylation, leading to reactivation of JAK signaling through dimerization of JAK2 with other JAK kinases, thereby promoting resistance to JAK2 kinase inhibitors in MPNs (Koppikar, Bhagwat et al. 2012). Crucially, cells resistant to JAK2 kinase inhibitors remain sensitive to loss of JAK2 expression (Koppikar, Bhagwat et al. 2012). Therefore, JAK2 protein depletion is an attractive strategy to improve the prognosis of patients with JAK2-driven MPNs.

[0122] Without wishing to be bound by any theory, the present disclosure is believed to be based, at least in part, on the discovery that novel heterobifunctional small molecules that degrade JAKs (e.g., JAK1, JAK2, JAK3, and TYK2), JAK fusion proteins, JAK deletion proteins, and / or JAK mutant proteins can be used to treat JAK-mediated diseases such as cancer (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 tract cancer, esophageal cancer, laryngeal cancer, skin cancer, lung cancer, , pancreatic cancer, thyroid cancer, adenocarcinoma, bladder cancer, kidney cancer, muscle cancer, bone cancer, and hematopoietic cancers such as myeloproliferative neoplasms, including essential thrombocythemia, polycythemia vera, primary myelofibrosis, chronic neutrophilic leukemia, acute lymphoblastic leukemia, Hodgkin lymphoma, chronic myelomonocytic leukemia, systemic mast cell disease, hypereosinophilic syndrome, cutaneous T-cell lymphoma, B-cell lymphoma, myeloma, and other hematologic malignancies, particularly those involving other activated JAKs inflammatory diseases (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) (Schwartz, Kanno et al. 2017); autoimmune diseases (e.g., multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, psoriasis, myasthenia gravis, type I diabetes mellitus, systemic lupus erythematosus, IgA nephropathy, autoimmune thyroid disease, alopecia areata, and bullous pemphigoid (O'Shea, Kontzias et al. 2013); 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) (Damsky and King 2017); viral infections (e.g., viral infections and their attendant complications, such as 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)) (Fleming 2016); dry eye diseases (e.g., dry eye syndrome (DES) and keratoconjunctivitis sicca (KCS)) (Colligris, Alkozi et al. 2014); bone remodeling disorders (e.g., osteoporosis and osteoarthritis) (Li 2013); and immune complications associated with organ transplantation (e.g., graft-versus-host disease) (Moore, Iasella et al. 2017).

[0123] Translation termination is a GTP-dependent process regulated by two key proteins, eRF1 and eRF3. Translation termination factor eRF3a (also known as GSPT1) is a GTPase that interacts with eRF1 to promote stop codon recognition and release of the nascent peptide from the ribosome (Chauvin, Salhi et al. 2005). GSPT1 activates eRF1 in a GTP-dependent manner, and its GTPase activity requires complexing with eRF1 and the ribosome (Frolova, Le Goff et al. 1996). GTP-bound GSPT1 and eRF1, together with the ribosome, form a functional translation termination complex (Zhouravleva, Frolova et al. 1995). Through translational regulation, GSPT1 plays a variety of important roles in cellular physiology. GSPT1 expression is increased in human malignancies, including lung and gastric cancer (Malta-Vacas, Aires et al. 2005, Tian, ​​Tian et al. 2018, Sun, Zhang et al. 2019, Zhang, Zou et al. 2019). GSPT1 is therefore considered a novel tumor target through which active translation, which contributes to the malignant phenotype of cancer cells, may be disrupted. Recently, Matyskiela and colleagues reported that a phthalimide-derived molecule, CC-885, leads to cereblon-dependent degradation of GSPT1 and other targets, such as IKZF1 and IKZF3 (Matyskiela, Lu et al. 2016). Ishoey et al. also reported that GSPT1 is degraded by a series of heterobifunctional compounds derived from phthalimide (Ishoey, Chorn et al. 2018). CC-885 induced significant toxicity in the vast majority of cell lines tested, likely due to degradation of GSTP1 and numerous other proteins (Matyskiela, Lu et al. 2016). Therefore, despite its broad and potent anticancer activity, CC-885 exhibits unacceptable toxicity, which has prevented further development (Hansen, Correa et al. 2020).

[0124] Selective degradation of target proteins induced by small molecules can be achieved by recruiting E3 ubiquitin ligases and mimicking protein misfolding with hydrophobic tags (Buckley and Crews 2014). In addition, protein degraders are heterobifunctional compounds that have one portion that binds to the E3 ubiquitin ligase and another portion that binds to the target protein (Buckley and Crews 2014). The induced proximity leads to ubiquitination of the target, followed by proteolytic degradation mediated by the proteasome. Several types of high-affinity small molecule E3 ligase ligands have been identified or developed. They include (1) immunomodulatory drugs (IMiDs), such as thalidomide and pomalidomide, which bind to cereblon (CRBN or CRL4CRBN), a component of the cullin-RING ubiquitin ligase (CRL) complex (Ito, Ando et al. 2010, Chamberlain, Lopez-Girona et al. 2014, Fischer, Bohm et al. 2014, Bondeson, Mares et al. 2015, Winter, Buckley et al. 2015); (2) VHL-1, a hydroxyproline-containing ligand that binds to the van Hippel-Lindau protein (VHL or CRL2VHL), another component of the CRL complex (Buckley, Gustafson et al. 2012, Buckley, Van Molle et al. 2012, Galdeano, Gadd et al. 2014, Bondeson, Mares et al. 2015, Zengerle, Chan et al. 2015); (3) compound 7, which selectively binds to KEAP1 (a component of the CRL3 complex) (Davies, Wixted et al. 2016); (4) AMG232, which selectively binds to MDM2 (a heterodimeric RING E3 ligase) (Sun, Li et al. 2014); (5) LCL161, which selectively binds to IAP (a homodimeric RING E3 ligase) (Okuhira, Ohoka et al. 2011, Ohoka, Okuhira et al. 2017, Shibata, Miyamoto et al. 2017). PROTAC technology has been applied to degrade a variety of protein targets (Bondeson, Mares et al. 2015, Buckley, Raina et al. 2015, Lu, Qian et al. 2015, Winter, Buckley et al. 2015, Zengerle, Chan et al. 2015, Lai, Toure et al. 2016).In addition, a hydrophobic tagging method using bulky and hydrophobic adamantyl groups has been developed to mimic protein misfolding, thereby degrading the target protein (Buckley and Crews 2014). This method has been applied to the selective degradation of the pseudokinase HER3 (Xie, Lim et al. 2014). The present inventors are not aware of any efforts to apply any of these methods to the degradation of JAKs (e.g., JAK1, JAK2, JAK3, and TYK2), JAK mutants, JAK deletions, or JAK fusion proteins.

[0125] Currently available small molecules targeting JAKs (such as JAK1, JAK2, JAK3, and TYK2) mainly inhibit the activity of JAK kinases.

[0126] In the present disclosure, a new approach is adopted: developing compounds that not only directly and selectively regulate the kinase activity of JAKs (such as JAK1, JAK2, JAK3 and TYK2), but also regulate their protein levels. Strategies for inducing protein degradation include recruiting E3 ubiquitin ligases, simulating protein misfolding with hydrophobic tags, and inhibiting molecular chaperones. Compared with techniques such as gene knockout or silencing, this method based on the use of heterobifunctional small molecule compounds allows for more flexible regulation of protein levels in vitro and in vivo. Unlike gene knockout or silencing, small molecule methods further provide opportunities for studying dose and time dependence in disease models by adjusting the route of administration, concentration, and frequency of administration of the corresponding small molecules.

[0127] The present disclosure includes all stereoisomers, geometric isomers, tautomers and isotopes of the described structures and compounds named herein. The present disclosure also includes compounds described herein, no matter how they are prepared, for example, synthetically, by biological processes (e.g., metabolic or enzymatic conversion) or a combination thereof.

[0128] The present disclosure includes pharmaceutically acceptable salts of the compounds depicted in the structures and named herein.

[0129] One or more constituent atoms of the exothermic compounds provided herein can be replaced or substituted by atomic isotopes of natural abundance or non-natural abundance. In some embodiments, the compound includes at least one deuterium atom. In some embodiments, the compound includes two or more deuterium atoms. In some embodiments, the compound includes 1-2, 1-3, 1-4, 1-5, or 1-6 deuterium atoms. In some embodiments, all hydrogen atoms in the compound can be replaced or substituted by deuterium atoms. In some embodiments, the compound includes at least one fluorine atom. In some embodiments, the compound includes two or more fluorine atoms. In some embodiments, the compound includes 1-2, 1-3, 1-4, 1-5, or 1-6 fluorine atoms. In some embodiments, all hydrogen atoms in the compound can be replaced or substituted by fluorine atoms.

[0130] Heterobifunctional compounds

[0131] As used herein, the terms "heterobifunctional compound" and "divalent compound" are used interchangeably.

[0132] In some aspects, the present disclosure provides heterobifunctional compounds comprising a JAK ligand conjugated to a degradation tag, or a pharmaceutically acceptable salt or analog thereof. The JAK ligand can be bound to the degradation tag directly or through a linker portion. In certain embodiments, the JAK ligand can be bound directly to the degradation tag. In certain embodiments, the JAK ligand can be bound to the degradation tag through a linker portion.

[0133] As used herein, the terms "Janus kinase ligand" and "JAK ligand" or "JAK targeting moiety" should be interpreted to include any molecule ranging from small molecules to large proteins that is associated with or bound to any of the JAK1, JAK2, JAK3 or TYK2 proteins. In certain embodiments, the JAK ligand is capable of binding to a JAK protein, including (such as JAK1, JAK2, JAK3 and TYK2), a JAK mutant, a JAK deletion or a JAK fusion protein. In one embodiment, the JAK ligand is a JAK inhibitor or a portion of a JAK inhibitor. A JAK ligand can be, for example, but not limited to, a small molecule compound (i.e., a molecule having a molecular weight of 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 fragment thereof.

[0134] JAK ligands

[0135] The JAK ligand or targeting moiety can be a JAK inhibitor or a portion of a JAK inhibitor. In certain embodiments, the JAK inhibitor comprises one of the following (e.g., ruxolitinib, tofacitinib (CP-690550), baricitinib, oclacitinib, seletinib (PRT-062070), dectinib (VX509), digatinib (JTE-052), fizotinib, filgotinib (GLP0634), tucatinib (LY2784544), ijitinib (NS-018), itatinib (INCB03911), lestaurtinib, molotinib (CYT387), paritinib (SB1578), pegfitinib, societinib (GSK2586184, GLG0778), upa ABT-494, AT9283, AZ-3, AZ960, AZD1480, BMS-986165, BMS-911543, BSK805 (NVP-BSK805) and BVB808 (NVP-BVB808), BBT594 (NVP-BBT594), CEP-33799, CHZ868, FM381, PF-04965842, PF-06263276, PF-06651600, PF-06700841, SAR-20347, NDI-031301 (Akahane, Li, & Etchin, 2017), NDI-31232 (Masse, Miao, Greenwood, Shelley, & Kapeller, 2015), NVP-P830, SHR-0302, VR588 (Wiegman, Adcock, Rothaul, Main, & Morgan, 2015), XL019, TG101209, R333 and R348 (Deuse et al., 2008), 3-aminopyrrolopyrazine (compound 3q), tetracyclic pyridone (compound 6), triazole-pyrrolopyridines (compound 7), pyrazolopyrimidines (compound 7j), 1- Amino-[1,2,4]triazolo[1,5-a]pyridines (Compound 12), imidazopyridines (Compound 19), 1-methyl-1H-imidazole derivatives (Compound 19a), C-2-methylimidazopyrrolopyridines (Compound 20), pyrazolopyridones (Compound 20a), 9H-carbazole-1-carboxamides (Compound 21), thienopyridines (Compound 23), pyrazole-4-carboxamides (Compound 28), imidazopyridines (Compound 30), hydroxyethylimidazopyrrolopyridines (Compound 31), pyrrolopyridazines (Compound 35), 6-oxopyridopyrimidines (Compound 36), 2-aminopyrazolo[1,5-a] pyrimidines (Compound 45), cyclopropylamides (Compound 46), imidazole-pyrrolopyridines (Compound 49), 1-amino-5H-pyrido[4,3-b]indole-4-carboxamides (Compound 65), Compound 3, Compound 13a, Compound 45a and analogs thereof), which can inhibit the protein-protein interaction or acetyltransferase activity of JAK. As used herein, "JAK inhibitor" refers to an agent that inhibits, hinders or otherwise causes the inhibition of physiological, chemical or enzymatic action or function and causes at least 5% reduction in binding. Inhibitors may also or alternatively refer to drugs, compounds or agents that prevent or reduce the expression, transcription or translation of a gene or protein. Inhibitors can reduce or prevent the function of a protein, for example by binding to or activating / inactivating another protein or receptor. ,

[0136] In certain embodiments, the JAK ligand is derived from a JAK inhibitor comprising:

[0137]

[0138]

[0139] In certain embodiments, JAK ligands include but are not limited to ruxolitinib, tofacitinib (CP-690550), baricitinib, oclacitinib, seletinib (PRT-062070), dectinib (VX509), digotinib (JTE-052), filzotinib, filgotinib (GLP0634), tucatinib (LY2784544), ijitinib (NS-018), itatinib (INCB03911), lestaurtinib, molotinib (CYT387), paritinib (SB1578), pegfitinib, societinib (GSK2586184, GLG0778), upadacitinib (ABT-494), AT9283, AZ-3, AZ960, AZD1480, BMS-986165, BMS-911543, BSK805 (NVP-BSK805) and BVB808 (NVP-BVB808), BBT594 (NVP-BBT594), CEP-33799, CHZ868, FM381, PF-04965842, PF-06263276, PF-06651600, PF-06700841, SAR-20347, NDI-031301 (Akahane, Li, & Etchin, 2017), NDI-31232 (Masse, Miao, Greenw Wood, Shelley, & Kapeller, 2015), NVP-P830, SHR-0302, VR588 (Wiegman, Adcock, Rothaul, Main, & Morgan, 2015), XL019, TG101209, R333 and R348 (Deuse et al., 2008), 3-aminopyrrolopyrazine (compound 3q), tetracyclic pyridone (compound 6), triazole-pyrrolopyridines (compound 7), pyrazolopyrimidines (compound 7j), 1-amino-[1,2,4]triazolo[1,5-a]pyridines (compound 12), imidazopyridines (compound 19), 1- Methyl-1H-imidazole derivatives (Compound 19a), C-2-methylimidazopyrrolopyridines (Compound 20), pyrazolopyridones (Compound 20a), 9H-carbazole-1-carboxamides (Compound 21), thienopyridines (Compound 23), pyrazole-4-carboxamides (Compound 28), imidazopyridines (Compound 30), hydroxyethylimidazopyrrolopyridines (Compound 31), pyrrolopyridazines (Compound 35), 6-oxopyridopyrimidines (Compound 36), 2-aminopyrazolo[1,5-a]pyrimidines (Compound 45), cyclopropylamides (Compound 46), imidazole-pyrrolopyridines (Compound 49), 1-amino-5H-pyrido[4,3-b] indole-4-carboxamides (Compound 65), Compound 3, Compound 13a and Compound 45a.

[0140] In one refinement, the JAK ligand comprises a moiety of formula 1:

[0141]

[0142] in,

[0143] The linker portion of the heterobifunctional compound is bound to R 1 ;

[0144] A and D are independently selected from: CR 4 and N; among them,

[0145] R 4 is selected from the group consisting of: H, halogen, optionally substituted C1-C8 alkyl and optionally substituted 3-10 membered carbocyclyl;

[0146] B, C and G are independently selected from: C and N; provided that at most only one of B, C and G is N;

[0147] E and F are independently selected from: none, CR 5 and N; among them,

[0148] R 5 is selected from the group consisting of: H, halogen, optionally substituted C1-C8 alkyl and optionally substituted 3-10 membered carbocyclyl;

[0149] X and Y are independently selected from: none, or a divalent moiety selected from: none, CR 6 R 7 、CO、CO2、CONR 6 NR 6 NR 6 CO、NR 6 CO2、NR 6 C(O)NR 7 NR 6 SO、NR 6 SO2、NR 6 SO2NR 7 、O、OC(O、OCO2、OCONR 6 , S, SO, SO2 and SO2NR 6 ,in,

[0150] R 6 and R 7is independently selected from: 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 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0151] R 6 and R 7 Together with the atoms to which they are attached, they form a 3-20 membered carbocyclyl ring or a 3-20 membered heterocyclyl ring;

[0152] V and W are independently selected from: none, carbocyclyl, heterocyclyl, aryl and heteroaryl, optionally replaced by one or more R 16 replaced by;

[0153] R 1 is a "linker" moiety attached to the heterobifunctional compound and is selected from: none, R'-R", R'OR", R'SR", R'N(R 11 )R", R'OC(O)R", R'OC(O)OR", R'OCON(R 11 )R", R'C(O)R", R'C(O)OR", R'CON(R 11 )R", R'S(O)R", R'S(O)2R", R'SO2N(R 11 )R", R'NR 12 C(O)OR", R'NR 12 C(O)R", R'NR 12 C(O)N(R 11 )R", R'NR 12 S(O)R", R'NR 12 S(O)2R" and R'NR 12 S(O)2N(R 11 )R", where

[0154] R' and R" are independently a divalent group selected from the group consisting of none, an optionally substituted C1-C8 alkylene group, an optionally substituted C2-C8 alkenylene group, an optionally substituted C2-C8 alkynylene group, an optionally substituted 3-10 membered carbocyclyl group, an optionally substituted 3-10 membered heterocyclyl group, an optionally substituted C4-C8 alkyl ...alkylene group, an optionally substituted C2-C8 alkynylene group, an optionally substituted C2-C8 alkylene group, an optionally substituted C2-C8 alkylene group, an optionally substituted C2-C8 alkylene group, an optionally substituted C2-C8 13 Fused carbocyclyl, optionally substituted C5-C 13 Fused heterocyclic group, optionally substituted C5-C 13 Bridged carbocyclyl, optionally substituted C5-C 13 Bridged heterocyclic group, optionally substituted C5-C 13 Spirocarbocyclyl, optionally substituted C5-C13 spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0155] R 11 and R 12 is independently selected from: optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0156] R' and R", R 11 and R 12 , R' and R 11 , R' and R 12 , R" and R 11 , R" and R 12 Together with the atoms to which they are attached, they form a 3-20 membered carbocyclyl or 3-20 membered heterocyclyl ring;

[0157] R 2 is selected from the group consisting of: H, halogen, OH, -O-C1-C8 alkyl, CN, NO2, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, 3-10 membered carbocyclyl, 3-10 membered heterocyclyl, aryl and heteroaryl; each of which is optionally replaced by one or more R 17 replaced by;

[0158] R 16 and R 17 Each independently selected from: H, halogen, oxo, CN, NO2, OR 8 SR 8 NR 8 R 9 , OCOR 8 、OCO2R 8 、OCON(R 8 )R 9 、COR 8 、CO2R 8 、CONR 8 R 9 、SOR 8 、SO2R 8 、SO2N(R 8 )R 9 NR 10 CO2R 8 NR 10 COR 8 NR 10 C(O)N(R 8 )R 9 NR 10 SOR 8 NR10 SO2R 8 NR 10 SO2N(R 8 )R 9 , 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 heterocyclyl C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, wherein,

[0159] R 8 、R 9 and R 10 R is 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, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclylC1-C8 alkyl, optionally substituted 3-10 membered heterocyclylC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or R 8 and R 9 、R 8 and R 10 and together with the atoms to which they are attached form a 3-20 membered heterocyclyl ring;

[0160] R 3 , at each occurrence, is selected from the group consisting of: hydrogen, halogen, optionally substituted C1-C8 alkyl, and optionally substituted 3-10 membered carbocyclyl; and

[0161] n is selected from 1 or 2.

[0162] In a refinement, V is Ar 2 .

[0163] In a refinement, at least one of E and F is absent. In a refinement, both E and F are absent.

[0164] In a refinement, V is Ar 2 ; and Ar 2 Selected from: none, aryl and heteroaryl (preferably, Ar 2 selected from none, monocyclic aryl, monocyclic heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl and tricyclic heteroaryl), each of which is optionally replaced by one or more R 16 replaced.

[0165] In one refinement, the JAK ligand comprises a moiety of Formula 1A:

[0166]

[0167] in,

[0168] The linker portion of the heterobifunctional compound is bound to R 1 ;

[0169] Ar 2 Selected from: none, aryl and heteroaryl, each optionally substituted by one or more R 16 replaced by

[0170] A, B, C, D, E, F, G, X, Y, W, R 1 、R 2 、R 3 、R 16 and n are defined as in Equation 1.

[0171] In another improved embodiment, V is Ar 2 ; and W is Ar 1 .

[0172] In another improved embodiment, V is Ar 2 And W is Ar 1 ; and Ar 1 and Ar 2 Independently selected from: none, aryl and heteroaryl (preferably, selected from none, monocyclic aryl, monocyclic heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl and tricyclic heteroaryl), each of which is optionally replaced by one or more R 16 replaced.

[0173] In another refinement, the JAK ligand comprises a moiety of Formula 1B:

[0174]

[0175] in,

[0176] The linker portion of the heterobifunctional compound is bound to R 1 ;

[0177] Ar 1 and Ar 2 independently selected from: none, aryl and heteroaryl, each optionally substituted by one or more R 16 replaced by;

[0178] A, B, C, D, E, F, G, X, Y, R 1 、R 2 、R 3and n are defined as in Equation 1.

[0179] In another refinement, A is N.

[0180] In another refinement, the JAK ligand comprises a moiety of Formula 1C:

[0181]

[0182] in,

[0183] The linker portion of the heterobifunctional compound is bound to R 1 ;as well as

[0184] B,C,D,E,F,G,V,W,X,Y,R 1 、R 2 、R 3 and n are defined as in Equation 1.

[0185] In another improved embodiment, A is N; V is Ar 2 ; and Ar 2 As defined above.

[0186] In another refinement, the JAK ligand comprises a moiety of formula 1D:

[0187]

[0188] in,

[0189] The linker portion of the heterobifunctional compound is bound to R 1 ;

[0190] B,C,D,E,F,G,W,X,Y,R 1 、R 2 、R 3 and n are as defined in Formula 1; and

[0191] Ar 2 As defined in Formula 1A.

[0192] In another improved embodiment, A is N; V is Ar 2 ; and W is Ar 1 ; and Ar 1 and Ar 2 As defined above.

[0193] In another refinement, the JAK ligand comprises a moiety of formula 1E:

[0194]

[0195] in,

[0196] The linker portion of the heterobifunctional compound is bound to R 1 ;

[0197] B,C,D,E,F,G,X,Y,R 1 、R 2 、R 3 and n are defined as in Equation 1, and

[0198] Ar 1 and Ar 2 As defined in Formula 1B.

[0199] In another refinement, the JAK ligand comprises a moiety of Formula 1F, 1G, 1H, or 1I:

[0200]

[0201] in,

[0202] The linker portion of the heterobifunctional compound is bound to R 1 ;

[0203] R 13 and R 14 Such as R 3 Definition; preferably, selected from: hydrogen, halogen, optionally substituted C1-C8 alkyl and optionally substituted 3-10 membered carbocyclic group;

[0204] V, W, X, Y, R 1 、R 2 、R 3 and n are defined as in Equation 1.

[0205] In another improved method, R 13 and R 14 Independently selected from: H, halogen, optionally substituted C1-C8 alkyl and optionally substituted 3-10 membered carbocyclyl.

[0206] In another refinement, the JAK ligand comprises a moiety of Formula 1J, 1K, 1L, or 1M:

[0207]

[0208] in,

[0209] The linker portion of the heterobifunctional compound is bound to R 1 ;

[0210] R 13 and R 14 Such as R 3 Definition (preferably, as defined in Formula 1F, 1G, 1H or 1I);

[0211] W, X, Y, R1 、R 2 、R 3 and n are defined as in Equation 1;

[0212] Ar 2 As defined in Formula 1A.

[0213] In another refinement, the JAK ligand comprises moieties 1N, 1O, 1P, and 1Q of formula:

[0214]

[0215] in,

[0216] The linker portion of the heterobifunctional compound is bound to R 1 ;

[0217] R 13 and R 14 Such as R 3 Definition (preferably, as defined in Formula 1F, 1G, 1H or 1I);

[0218] X, Y, R 1 、R 2 、R 3 and n are defined as in Equation 1;

[0219] Ar 1 and Ar 2 As defined in Formula 1B.

[0220] In another refinement, the JAK ligand comprises a moiety of formula 1N.

[0221] In another refinement, X is selected from the group consisting of: none, O, and NR 6 , where R 6 is selected from the group consisting of: H, optionally substituted C1-C8 alkyl and optionally substituted 3-10 membered carbocyclyl.

[0222] In another refinement, X is selected from none and NH.

[0223] In another refinement, Y is selected from: none, CR 6 R 7 , CO, CO2, O, S, SO, SO2 and NR 6 ,in

[0224] R 6 and R 7 Independently selected from: H, optionally substituted C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl and optionally substituted 3-10 membered heterocyclyl.

[0225] In another refinement, Y is selected from: CR 6 R7 , CO, CO2, O, SO, SO2 and NR 6 (Preferably, Y is CR 6 R 7 ), where R 6 and R 7 are independently selected from: H, optionally substituted C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl and optionally substituted 3-10 membered heterocyclyl (preferably, R 6 and R 7 are independently selected from: H, optionally substituted C1-C8 alkyl).

[0226] In another refinement, Y is selected from the group consisting of: none, CH2, CO, and SO2. In another refinement, Y is selected from the group consisting of: CH2, CO, and SO2. In another refinement, Y is CH2.

[0227] In another refinement, W and V are independently selected from none, monocyclic aryl, monocyclic heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl, and tricyclic heteroaryl, each of which is optionally replaced by one or more R 16 In another refinement, W and V are independently selected from: none, monocyclic aromatic groups (such as phenyl) and monocyclic heteroaromatic groups (such as 5-, 6- or 7-membered heteroaromatic groups), each of which is optionally substituted by one or more R 16 replaced.

[0228] In another improved embodiment, Ar 1 and Ar 2 independently selected from: none, monocyclic aryl, monocyclic heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl and tricyclic heteroaryl, each of which is optionally replaced by one or more R 16 In another improved embodiment, Ar 1 and Ar 2 independently selected from: none, monocyclic aryl (such as phenyl) and monocyclic heteroaryl (such as 5-, 6- or 7-membered heteroaryl), each of which is optionally substituted by one or more R 16 In another improved embodiment, Ar 1 and Ar 2 Independently selected from: monocyclic aryl (such as phenyl) and monocyclic heteroaryl (such as 5, 6 or 7 membered heteroaryl), each of which is optionally substituted by one or more R 16 replaced.

[0229] In another improved embodiment, each R 16 Independently selected from: H, halogen, oxo, CN, NO2, OR 8 SR 8 、N(R 8 )R 9 、COR8 、CO2R 8 、CON(R 8 )R 9 、SOR 8 、SO2R 8 、SO2N(R 8 )R 9 NR 10 COR 8 NR 10 SOR 8 NR 10 SO2R 8 , optionally substituted C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl and optionally substituted 3-10 membered heterocyclyl, wherein,

[0230] R 8 、R 9 and R 10 are independently selected from: H, optionally substituted C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl and optionally substituted 3-10 membered heterocyclyl, or, R 8 and R 9 、R 8 and R 10 and together with the atoms to which they are attached form a 3-10 membered heterocyclyl ring.

[0231] In another improved method, R 16 Each independently selected from: H, halogen, oxo, CN, NO2, OR 8 NR 8 R 9 NR 10 COR 8 , optionally substituted C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl and optionally substituted 3-10 membered heterocyclyl, wherein,

[0232] R 8 、R 9 and R 10 are independently selected from: H, optionally substituted C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl and optionally substituted 3-10 membered heterocyclyl, or, R 8 and R 9 、R 8 and R 10 and together with the atoms to which they are attached form a 3-10 membered heterocyclyl ring.

[0233] In another improved method, R 16 Each independently selected from: H, halogen, oxo, CN, NO2, OR 8 NR 8 R 9NR 10 COR 8 and optionally substituted C1-C8 alkyl, wherein R 8 、R 9 and R 10 are independently selected from: H and optionally substituted C1-C8 alkyl, or, R 8 and R 9 and together with the atoms to which they are attached form a 3-10 membered heterocyclyl ring.

[0234] In another improved method, R 16 are each independently selected from the group consisting of: H, CH3, CF3, iPr, cPr, OCH3, OCF3, OiPr, OcPr, F, Cl, and Br. In another refinement, R 16 Each independently selected from: H and F.

[0235] In another refinement, V (or Ar 2 ) is a monocyclic aromatic group (such as phenyl) or a monocyclic heteroaromatic group (such as a 5-, 6- or 7-membered heteroaromatic group), preferably, V (or Ar 2 ) is phenyl or a 5-, 6- or 7-membered heteroaryl group containing 1, 2 or 3 N atoms as ring members, more preferably, V (or Ar 2 ) is phenyl; each of which is optionally substituted by one or more R 16 replaced.

[0236] In another refinement, W (or Ar 1 ) is a monocyclic aromatic group (such as phenyl) or a monocyclic heteroaromatic group (such as a 5-, 6- or 7-membered heteroaromatic group), preferably, W (or Ar 1 ) is phenyl or a 5-, 6- or 7-membered heteroaryl group containing 1, 2 or 3 N atoms as ring members, more preferably, W (or Ar 1 ) is a 5-membered heteroaryl group containing 1 or 2 N atoms; each of which is optionally substituted by one or more R 16 replaced.

[0237] In another improved embodiment, Ar 1 and Ar 2 independently selected from: none, monocyclic aryl (such as phenyl), monocyclic heteroaryl (such as 5-, 6- or 7-membered heteroaryl), bicyclic aryl, bicyclic heteroaryl, tricyclic aryl and tricyclic heteroaryl, each of which is replaced by R 2 substituted and optionally substituted by one or more R 16 replaced, and R 16 Each independently selected from: hydrogen, halogen, oxo, CN, NO2, OR 8 SR 8 NR 8 R 9 、COR 8、CO2R 8 、CONR 8 R 9 、SOR 8 、SO2R 8 、SO2NR 8 R 9 NR 10 COR 8 NR 10 SOR 8 NR 10 SO2R 8 , optionally substituted C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl and optionally substituted 3-10 membered heterocyclyl, wherein

[0238] R 8 、R 9 and R 10 are independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl and optionally substituted 3-10 membered heterocyclyl, or, R 8 and R 9 、R 8 and R 10 and together with the atoms to which they are attached form a 3-10 membered heterocyclyl ring.

[0239] In another improved embodiment, Ar 1 and Ar 2 independently selected from: none, monocyclic aryl (such as phenyl), monocyclic heteroaryl (such as 5-, 6- or 7-membered heteroaryl), bicyclic aryl, bicyclic heteroaryl, tricyclic aryl and tricyclic heteroaryl, each of which is replaced by R 2 substituted and optionally substituted by one or more R 16 replaced, and R 16 Each independently selected from: hydrogen, halogen, oxo, CN, NO2, OR 8 NR 8 R 9 NR 10 COR 8 , optionally substituted C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, wherein

[0240] R 8 、R 9 and R 10 are independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl and optionally substituted 3-10 membered heterocyclyl, or, R 8 and R 9 、R 8 and R 10and together with the atoms to which they are attached form a 3-10 membered heterocyclyl ring.

[0241] In another improved embodiment, Ar 1 and Ar 2 are independently selected from: none, monocyclic aryl, monocyclic heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl, and tricyclic heteroaryl, each of which is replaced by R 2 substituted and optionally substituted by one or more R 16 replaced, and R 16 Each is independently selected from the group consisting of hydrogen, CH3, CF3, iPr, cPr, OCH3, OCF3, OiPr, OcPr, F, Cl and Br.

[0242] In another improved embodiment, Ar 1 and Ar 2 are independently selected from: none, monocyclic aryl, monocyclic heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl, and tricyclic heteroaryl, each of which is replaced by R 2 substituted and optionally substituted by one or more R 16 replaced, and R 16 Each independently selected from: H and F.

[0243] In another improved method, R 1 is selected from the group consisting of: none, O, NH, CO, CONH, optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.

[0244] In another improved method, R 1 is selected from the group consisting of: none, optionally substituted 3-10 membered carbocyclyl and optionally substituted 3-10 membered heterocyclyl.

[0245] In another improved method, R 1 Selected from: unsubstituted and optionally substituted 3-10 membered carbocyclyl containing at least one O or N.

[0246] In another improved method, R 1 is selected from the group consisting of: none, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted morpholinyl, optionally substituted pyrrolidinyl, optionally substituted tetrahydrofuranyl, optionally substituted azetidinyl, and optionally substituted oxetanyl.

[0247] In another improved method, R 2 Selected from: hydrogen, halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, 3-10 membered carbocyclyl and 3-10 membered heterocyclyl, each of which is optionally substituted by one or more R17 replaced.

[0248] In another improved method, R 2 is selected from the group consisting of: H, OH, -O-C1-C8 alkyl, halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkenyl, 3-10 membered carbocyclyl and 3-10 membered heterocyclyl; each of which is optionally replaced by one or more R 17 replaced.

[0249] In another improved method, R 2 Selected from: H, OH, -O-C1-C8 alkyl, halogen, C1-C8 alkyl, 3-10 membered carbocyclyl and 3-10 membered heterocyclyl; each of which is optionally replaced by one or more R 17 replaced.

[0250] In another improved method, R 2 Selected from: hydrogen, halogen, C1-C8 alkyl, 3-10 membered carbocyclyl and 3-10 membered heterocyclyl, each of which is optionally substituted by one or more R 17 replaced.

[0251] In another improved method, R 2 is selected from the group consisting of: OH, CH3, CF3, iPr, cPr, F, Cl, Br, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl; each of which is optionally replaced by one or more R 17 replaced.

[0252] In another improved method, R 2 is selected from the group consisting of: CH3, CF3, iPr, cPr, F, Cl, Br, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl; each of which is optionally replaced by one or more R 17 replaced.

[0253] In another improved method, R 2 Selected from: 3-10 membered carbocyclyl (preferably, 4, 5, 6 or 7 membered heterocyclyl) and 3-10 membered heterocyclyl (preferably, 5, 6 or 7 membered heterocyclyl); each of which is optionally replaced by one or more R 17 In another improved embodiment, R 2 Selected from: piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl; each of which is optionally substituted by one or more R 17 replaced.

[0254] In another improved method, R 17 Each independently selected from: H, halogen, oxo, CN, NO2, OR8 SR 8 、N(R 8 )R 9 、COR 8 、CO2R 8 、CON(R 8 )R 9 、SOR 8 、SO2R 8 、SO2N(R 8 )R 9 NR 10 COR 8 NR 10 SOR 8 NR 10 SO2R 8 , optionally substituted C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl and optionally substituted 3-10 membered heterocyclyl, wherein,

[0255] R 8 、R 9 and R 10 are independently selected from: H, optionally substituted C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl and optionally substituted 3-10 membered heterocyclyl, or, R 8 and R 9 、R 8 and R 10 and together with the atoms to which they are attached form a 3-10 membered heterocyclyl ring.

[0256] In another improved method, R 17 Each independently selected from: H, halogen, oxo, CN, NO2, R 8 , OR 8 SR 8 、N(R 8 )R 9 、COR 8 、CO2R 8 、CON(R 8 )R 9 、SOR 8 、SO2R 8 , where R 8 and R 9 Each independently selected from: H, C1-C3 alkyl, C3-C6 alkyl, C 1-3 Haloalkyl and C 1-3 Hydroxyalkyl.

[0257] In another improved method, R 17 Each is independently selected from the group consisting of: H, oxo, CH3, iPr, cPr and OH.

[0258] In another improved method, R 3 , at each occurrence, R 13 and R 14 Independently selected from the group consisting of hydrogen, CH3, CF3, iPr, cPr, tBu, CNCH2, F, Cl, Br, OH, NH2, CN, CH3 and CONH2.

[0259] In other embodiments, the JAK ligand comprises a moiety of Formula 2:

[0260]

[0261] in,

[0262] The linker portion of the heterobifunctional compound is bound to R 1 ;

[0263] A, B and D are independently selected from: CR 3 and N, with the restriction that A, B and D are not all N, where

[0264] R 3 Selected from: hydrogen, halogen, hydroxy, amino, cyano, nitro, CONR 4 R 5 , optionally substituted C1-C8 alkyl and optionally substituted 3-10 membered carbocyclyl, wherein

[0265] R 4 and R 5 is independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted 3-10 membered carbocyclyl and optionally substituted 3-10 membered heterocyclyl, or

[0266] R 4 and R 5 Together with the atoms to which they are attached, they form a 3-20 membered carbocyclyl ring or a 3-20 membered heterocyclyl ring;

[0267] X and Y are independently selected from: none, or a divalent moiety selected from: none, C(R 6 )R 7 、CO、CO2、CONR 6 NR 6 NR 6 CO、NR 6 CO2、NR 6 C(O)NR 7 NR 6 SO、NR 6 SO2、NR 6 SO2NR 7 、O、OC(O、OCO2、OCONR6 , S, SO, SO2 and SO2NR 6 ,in,

[0268] R 6 and R 7 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 alkylamino, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

[0269] R 6 and R 7 Together with the atoms to which they are attached, they form a 3-20 membered carbocyclyl ring or a 3-20 membered heterocyclyl ring;

[0270] V and W are independently selected from: none, carbocyclyl, heterocyclyl, aryl and heteroaryl, optionally replaced by one or more R 16 replaced by;

[0271] R 16 Each independently selected from: hydrogen, halogen, oxo, CN, NO2, OR 8 SR 8 、N(R 8 )R 9 , OCOR 8 、OCO2R 8 、OCONR 8 R 9 、COR 8 、CO2R 8 、CON(R 8 )R 9 、SOR 8 、SO2R 8 、SO2N(R 8 )R 9 NR 10 CO2R 8 NR 10 COR 8 NR 10 C(O)N(R 8 )R 9 NR 10 SOR 8 NR 10 SO2R 8 NR 10 SO2N(R 8 )R 9, 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 heterocyclyl C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, wherein,

[0272] R 8 、R 9 and R 10 R is 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, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclylC1-C8 alkyl, optionally substituted 3-10 membered heterocyclylC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or R 8 and R 9 、R 8 and R 10 and together with the atoms to which they are attached form a 3-20 membered heterocyclyl ring;

[0273] R 1 is the "linker" portion attached to the heterobifunctional compound and is selected from: none, R'-R", R'OR", R'SR", R'NR 11 R"、R'OC(O)R"、R'OC(O)OR"、R'OCON(R 11 )R", R'C(O)R", R'C(O)OR", R'CON(R 11 )R", R'S(O)R", R'S(O)2R", R'SO2N(R 11 )R", R'NR 12 C(O)OR", R'NR 12 C(O)R", R'NR 12 C(O)N(R 11 )R", R'NR 12 S(O)R", R'NR 12 S(O)2R" and R'NR 12 S(O)2N(R 11 )R", where

[0274] R' and R" are independently selected from the group consisting of: none, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C4-C 13 Fused carbocyclyl, optionally substituted C5-C 13 Fused heterocyclic group, optionally substituted C5-C 13 Bridged carbocyclyl, optionally substituted C5-C 13 Bridged heterocyclic group, optionally substituted C5-C 13 Spirocarbocyclyl, optionally substituted C5-C 13 spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0275] R 11 and R 12 is independently selected from: optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0276] R' and R", R 11 and R 12 , R' and R 11 , R' and R 12 , R” and R 11 , R” and R 12 Together with the atoms to which they are attached, they form a 3-20 membered carbocyclyl or 3-20 membered heterocyclyl ring; and

[0277] R 2 is 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 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0278] Alternatively, when both V and W are not null, V and W together with the substituents to which they are attached optionally form a 10-30 membered macrocyclic ring; when W is null and V is not null, V and R 1 and optionally form a 10-30 membered macrocyclic ring together with the substituents to which they are attached; when V is absent and W is not absent, W and R 2 and optionally form a 10-30 membered macrocyclic ring together with the substituents to which they are attached; or when W and V are absent, R 1 and R 2and together with the substituents to which they are attached, optionally form a 10-30 membered macrocyclic ring;

[0279] In another improved embodiment, V is Ar 2 In another improved embodiment, V is Ar 2 ; and Ar 2 Selected from: none, aryl and heteroaryl (preferably, selected from none, monocyclic aryl, monocyclic heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl and tricyclic heteroaryl), each of which is optionally replaced by one or more R 16 replaced.

[0280] In another refinement, the JAK ligand comprises a moiety of formula 2A:

[0281]

[0282] in,

[0283] The linker portion of the heterobifunctional compound is bound to R 1 ;

[0284] Ar 2 Selected from: none, aryl and heteroaryl, each optionally substituted by one or more R 16 replaced by;

[0285] A, B, D, X, Y, W, R 1 、R 2 and R 16 As defined in Equation 2;

[0286] Or when W and Ar 2 Neither is for nothing, W and Ar 2 and together with the substituents to which they are attached, optionally form a 10-30 membered macrocyclic ring; when W is absent and Ar 2 Not for nothing, Ar 2 and R 1 and together with the substituents to which they are attached, optionally form a 10-30 membered macrocyclic ring; when Ar 2 is nothing and W is not nothing, W and R 2 and optionally form a 10-30 membered macrocyclic ring together with the substituents to which they are attached; or when W and Ar 2 For none, R 1 and R 2 and together with the substituents to which they are attached, optionally form a 10-30 membered macrocyclic ring.

[0287] In another improved embodiment, V is Ar 2 ; and W is Ar 1 In another improved embodiment, V is Ar 2 ; and W is Ar 1; and Ar 1 and Ar 2 Independently selected from: none, aryl and heteroaryl (preferably, selected from none, monocyclic aryl, monocyclic heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl and tricyclic heteroaryl), each of which is optionally replaced by one or more R 16 replaced.

[0288] In another refinement, the JAK ligand comprises a moiety of formula 2B:

[0289]

[0290] in,

[0291] The linker portion of the heterobifunctional compound is bound to R 1 ;

[0292] Ar 1 and Ar 2 Independently selected from: none, aryl and heteroaryl (preferably, selected from none, monocyclic aryl, monocyclic heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl and tricyclic heteroaryl), each of which is optionally replaced by one or more R 16 replaced by;

[0293] A, B, D, X, Y, R 1 、R 2 and R 16 As defined in Equation 2;

[0294] Or when Ar 1 and Ar 2 It's not all time, Ar 1 and Ar 2 and together with the substituents to which they are attached, optionally form a 10-30 membered macrocyclic ring; when Ar 1 is none and Ar 2 Not for nothing, Ar 2 and R 1 and together with the substituents to which they are attached, optionally form a 10-30 membered macrocyclic ring; when Ar 2 is none and Ar 1 Not for nothing, Ar 1 and R 2 and together with the substituents to which they are attached, optionally form a 10-30 membered macrocyclic ring; or when Ar 1 and Ar 2 For none, R 1 and R 2 and together with the substituents to which they are attached, optionally form a 10-30 membered macrocyclic ring.

[0295] In another refinement, the JAK ligand comprises a moiety of Formula 2C, 2D, 2E, or 2F:

[0296]

[0297] in,

[0298] The linker portion of the heterobifunctional compound is bound to R 1 ;

[0299] R 13 、R 14 and R 15 Such as R 3 definition;

[0300] X, Y, Ar 1 、Ar 2 、R 1 、R 2 and R 3 As defined in Equation 2.

[0301] In another improved method, R 13 、R 14 and R 15 Selected from: hydrogen, halogen, hydroxy, amino, cyano, nitro, CONR 4 R 5 , an optionally substituted C1-C8 alkyl group and an optionally substituted 3-10 membered carbocyclic group, wherein R 4 and R 5 is independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted 3-10 membered carbocyclyl and optionally substituted 3-10 membered heterocyclyl, or, R 4 and R 5 and together with the atoms to which they are attached form a 3-20 membered carbocyclyl ring or a 3-20 membered heterocyclyl ring.

[0302] In another refinement, the JAK ligand comprises a moiety of formula 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q, 2R, or 2S:

[0303]

[0304]

[0305] in,

[0306] The linker portion of the heterobifunctional compound is bound to R 1 ;

[0307] R 13 、R 14 and R 15 Such as R 3 definition;

[0308] Y, R 1 、R 2 and R 3 As defined in Equation 2;

[0309] Ar 1 and Ar 2 As defined above, as defined in Formula 2B.

[0310] In another improved method, R 13 、R 14 and R 15 As defined in Formula 2C, 2D, 2E or 2F.

[0311] In another refinement, Y is selected from: none, CR 6 R 7 、CO、CO2、CONR 6 NR 6 CO、NR 6 C(O)NR 7 、O、SO、SO2、SO2NR 6 and NR 6 ,in

[0312] R 6 and R 7 are independently selected from the group consisting of hydrogen, optionally substituted C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 3-10 membered heterocyclyl.

[0313] In another refinement, Y is selected from the group consisting of: none, CH2, CO, CONH, NR 6 C(O), NR 6 C(O)NR 7 , SO2 and SO2NH.

[0314] In another improved embodiment, Ar 1 and Ar 2 independently selected from: none, monocyclic aryl, monocyclic heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl and tricyclic heteroaryl, each of which is optionally replaced by one or more R 16 replaced.

[0315] In another improved method, R 16 Each independently selected from: hydrogen, halogen, oxo, CN, NO2, OR 8 SR 8 NR 8 R 9 、COR 8 、CO2R 8 、CONR 8 R 9、SOR 8 、SO2R 8 、SO2NR 8 R 9 NR 10 COR 8 NR 10 SOR 8 NR 10 SO2R 8 , optionally substituted C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl and optionally substituted 3-10 membered heterocyclyl, wherein,

[0316] R 8 、R 9 and R 10 are independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl and optionally substituted 3-10 membered heterocyclyl, or

[0317] R 8 and R 9 、R 8 and R 10 Together with the atoms to which they are attached, they form a 3-10 membered heterocyclyl ring.

[0318] In another improved method, R 16 Each independently selected from: hydrogen, halogen, oxo, CN, NO2, OR 8 NR 8 R 9 NR 10 COR 8 , optionally substituted C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl and optionally substituted 3-10 membered heterocyclyl, wherein,

[0319] R 8 、R 9 and R 10 are independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl and optionally substituted 3-10 membered heterocyclyl, or R 8 and R 9 、R 8 and R 10 and together with the atoms to which they are attached form a 3-10 membered heterocyclyl ring.

[0320] In another improved method, R 16 Each is independently selected from the group consisting of hydrogen, CH3, CF3, iPr, cPr, OCH3, OCF3, OiPr, OcPr, F, Cl and Br.

[0321] In another improved method, R 16Each independently selected from: H and F.

[0322] In another improved embodiment, Ar 1 and Ar 2 are independently selected from: none, monocyclic aryl, monocyclic heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl, and tricyclic heteroaryl, each of which is replaced by R 2 substituted and optionally substituted by one or more R 16 replaced, and R 16 Each independently selected from: hydrogen, halogen, oxo, CN, NO2, OR 8 SR 8 NR 8 R 9 、COR 8 、CO2R 8 、CONR 8 R 9 、SOR 8 、SO2R 8 、SO2NR 8 R 9 NR 10 COR 8 NR 10 SOR 8 NR 10 SO2R 8 , optionally substituted C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl and optionally substituted 3-10 membered heterocyclyl, wherein

[0323] R 8 、R 9 and R 10 are independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl and optionally substituted 3-10 membered heterocyclyl, or, R 8 and R 9 、R 8 and R 10 and together with the atoms to which they are attached form a 3-10 membered heterocyclyl ring.

[0324] In another improved embodiment, Ar 1 and Ar 2 are independently selected from: none, monocyclic aryl, monocyclic heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl, and tricyclic heteroaryl, each of which is replaced by R 2 substituted and optionally substituted by one or more R 16 replaced by; and R 16 Each independently selected from: hydrogen, halogen, oxo, CN, NO2, OR 8 NR 8 R 9 NR10 COR 8 , optionally substituted C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl and optionally substituted 3-10 membered heterocyclyl, wherein

[0325] R 8 、R 9 and R 10 are independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl and optionally substituted 3-10 membered heterocyclyl, or, R 8 and R 9 、R 8 and R 10 and together with the atoms to which they are attached form a 3-10 membered heterocyclyl ring.

[0326] In another improved embodiment, Ar 1 and Ar 2 are independently selected from: none, monocyclic aryl, monocyclic heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl, and tricyclic heteroaryl, each of which is replaced by R 2 substituted and optionally substituted by one or more R 16 replaced, and R 16 Each is independently selected from the group consisting of: H, CH3, CF3, iPr, cPr, OCH3, OCF3, OiPr, OcPr, F, Cl and Br.

[0327] In another improved embodiment, Ar 1 and Ar 2 are independently selected from: none, monocyclic aryl, monocyclic heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl, and tricyclic heteroaryl, each of which is replaced by R 2 substituted and optionally substituted by one or more R 16 replaced by; and R 16 Each independently selected from: H and F.

[0328] In another improved method, R 1 is selected from the group consisting of: none, O, NH, CO, CONH, optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.

[0329] In another improved method, R 1 is selected from the group consisting of: none, O, NH, optionally substituted 3-10 membered carbocyclyl and optionally substituted 3-10 membered heterocyclyl.

[0330] In another improved method, R 1is selected from the group consisting of: none, O, NH, and an optionally substituted 3-10 membered heterocyclyl containing at least one O or N.

[0331] In another improved method, R 1 is selected from the group consisting of: none, O, NH, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted morpholinyl, optionally substituted pyrrolidinyl, optionally substituted tetrahydrofuranyl, optionally substituted azetidinyl, and optionally substituted oxetanyl.

[0332] In another improved method, R 2 is 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 alkenyl, optionally substituted C1-C8 alkoxy, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl.

[0333] In another improved method, R 2 is selected from the group consisting of hydrogen, halogen, optionally substituted C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl.

[0334] In another improved method, R 2 is selected from the group consisting of: hydrogen, CH3, CF3, iPr, cPr, tBu, CNCH2, F, Cl, Br, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted morpholinyl, optionally substituted pyrrolidinyl, optionally substituted tetrahydrofuranyl, optionally substituted azetidinyl, optionally substituted oxetanyl, optionally substituted phenyl, optionally substituted triazolyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted triazinyl, optionally substituted furanyl, optionally substituted oxazolyl, optionally substituted pyrrolyl, optionally substituted imidazolyl, optionally substituted triazolyl, optionally substituted oxadiazolyl, optionally substituted thiophene, optionally substituted thiazolyl, and optionally substituted thiadiazolyl.

[0335] In another improved method, R 13 、R 14 and R 15 Independently selected from: H, CH3, CF3, iPr, cPr, tBu, CNCH2, F, Cl, Br, OH, NH2, CN, CH3 and CONH2.

[0336] In other embodiments, the JAK ligand is derived from any of the following:

[0337]

[0338]

[0339] In another embodiment, the JAK ligand is derived from any one of the following: NVP-BSK805, Compound (Cmpd) 12, and TG101209 (preferably, NVP-BSK805 and Compound 12; more preferably, NVP-BSK805).

[0340] In other embodiments, the JAK ligand is derived from the following JAK inhibitors: NDI-031301, NDI-31232, VR588, R333, and R348.

[0341] In another embodiment, the JAK ligand is selected from the group consisting of:

[0342]

[0343]

[0344] In another embodiment, the JAK ligand is selected from: Formula 3A, Formula 3C, Formula 3D, Formula 3I, Formula 3BW, Formula 3BX, Formula 3BY and Formula 3BZ; preferably, selected from: Formula 3A, Formula 3C, Formula 3D, Formula 3BW, Formula 3BX, Formula 3BY and Formula 3BZ.

[0345] Degradable labels

[0346] As used herein, the term "degradation tag" refers to a compound that associates with or binds to a ubiquitin ligase to recruit the corresponding ubiquitination machinery to JAK, or a hydrophobic group or tag that causes JAK protein misfolding and subsequent proteasomal degradation or loss of function.

[0347] In another embodiment, the degradation tag is a moiety of formula 5, and the degradation tag is represented by Z E a linker moiety connected to the heterobifunctional compound;

[0348]

[0349] in,

[0350] Z E For example-(R E z ) nE - shown as a divalent group; wherein the subscript n E =0, 1, 2, 3, 4, 5 or 6; where R E Z , at each occurrence, independently R E r or R Ew ; Among them, R E w , at each occurrence, is a bond or is 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 C1-C 10 Alkenylene, optionally substituted C1-C 10 Alkynylene; and R E r , at each occurrence, is a bond, or is selected from the group consisting of optionally substituted 3-10 membered carbocyclyl (e.g., 3-8 membered carbocyclyl), optionally substituted 3-10 membered heterocyclyl (e.g., 3-8 membered heterocyclyl), optionally substituted C4-C 13 Fused cycloalkyl, optionally substituted C5-C 13 Fused heterocyclic group, optionally substituted C5-C 13 Bridged cycloalkyl, optionally substituted C5-C 13 Bridged heterocyclic group, optionally substituted C5-C 13 Spirocycloalkyl, optionally substituted C5-C 13 spiroheterocyclyl, optionally substituted aryl and optionally substituted heteroaryl; provided that -R E z -R E z -Not-OO-;R E 5 and R E 6 , at each occurrence, 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 carbocyclyl, and optionally substituted 3 to 8 membered heterocyclyl; or, R E 5 and R E 6 Together with the atoms to which they are attached, they form an optionally substituted 3-8 membered cycloalkyl or heterocyclyl ring;

[0351] R E 1 Selected from the group consisting of hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3-8 membered carbocyclyl, and optionally substituted 3-8 membered heterocyclyl;

[0352] L E is a divalent group selected from the group consisting of: none, -L E 1 -and-LE 1 -L E 2 -; among them, L E 1 and L E 2 Independently selected from the group consisting of: -CO-, -O-, -CR E 10 R E 11 -and-NR E 10 -, the limiting condition is -L E 1 -L E 2 - is not –OO-; where R E 10 and R E 11 independently 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;

[0353] Ring A E is a divalent group selected from the following group: E 1. A E 2. A E 3. A E 4 and A E 5:

[0354]

[0355] in,

[0356] *Indicates the same as L E The connection of Z E Connect to Ring A E Any possible position;

[0357] is a single bond or a double bond;

[0358] V E 1 、V E 2 、V E 3 、V E 4 and V E 5 , at each occurrence, are independently selected from the group consisting of: bond (none), C, CR E 2 , S, N and NRE 2 ; or, VE 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 are optionally joined together to form a 6-membered aromatic ring or a 5-, 6-, or 7-membered heteroaromatic ring;

[0359] R E 2 , at each occurrence, is independently selected from the group consisting of absence, 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 carbocyclyl, and optionally substituted 3-8 membered heterocyclyl; or, R E 2 and another R E 2 Together with the atoms to which they are attached, they form an optionally substituted 3-8 membered cycloalkyl, an optionally substituted 3-8 membered heterocyclyl ring, an optionally substituted aryl, and an optionally substituted heteroaryl;

[0360] W E 1 、W E 2 、W E 3 and W E 4 Each 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 E2 and W E 3 or W E 3 and W E 4 are optionally joined together to form a 6-membered aromatic ring or a 5-, 6-, or 7-membered heteroaromatic ring;

[0361] R E 3 and R E 4 , at each occurrence, is independently selected from the group consisting of absence, hydrogen, halogen, cyano, nitro, hydroxy, amino, optionally substituted C1-C6 alkyl, optionally substituted 3 to 8 membered carbocyclyl, and optionally substituted 3 to 8 membered heterocyclyl; or, R on the same atom or on adjacent atoms E 3 and R E 4 Together with the atoms to which they are attached, they form an optionally substituted 3-8 membered cycloalkyl or heterocyclyl ring.

[0362] In another embodiment, R E 2 , at each occurrence, is independently selected from the group consisting of absence, 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 carbocyclyl, and optionally substituted 3-8 membered heterocyclyl.

[0363] In another embodiment, the degradation tag is a moiety of formula 5, and wherein V E 1 、V E 2 、V E 3 、V E 4 and V E 5 , at each occurrence, are 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 VE 4 , or V E 4 and V E 5 Taken together they are optionally formed into a 6-membered aromatic ring or a 5-, 6- or 7-membered heteroaromatic ring.

[0364] In another embodiment, the degradation tag is a moiety of formula 5, and wherein Ring A E A group consisting of: E 1, and where V E 1 、V E 2 、V E 3 and V E 4 Each independently selected from the following group: C, CR E 2 , S, N and NR E 2 .

[0365] In another embodiment, the degradation tag is a moiety of formula 5, and wherein Ring A E A group consisting of: E 2, and where V E 1 、V E 2 、V E 3 、V E 4 and V E 5 , at each occurrence, are independently selected from the group consisting of: C, CR E 2 , S, N and NR E 2 .

[0366] In another embodiment, the degradation tag is a moiety of formula 5, and wherein Ring A E A group consisting of: E 3, and among them, V E 1 、V E 2 、V E 3 、V E 4 and V E 5 Each independently selected from the following group: C, CR E 2 , S, N and NRE 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 Taken together they are optionally formed into a 6-membered aromatic ring or a 5-, 6- or 7-membered heteroaromatic ring.

[0367] In another embodiment, the degradation tag is a moiety of formula 5, and wherein Ring A E A group consisting of: E 4, and among them, For single bond and W E 1 、W E 2 、W E 3 and W E 4 Each independently selected from the following group: -N=, -CR E 3 =, -CO-, -O-, -CR E 3 R E 4 -and-NR E 3 -.

[0368] In another embodiment, the degradation tag is a moiety of formula 5, and wherein Ring A E A group consisting of: E 5, and among them, V E 1 、V E 2 and V E 3 Each independently selected from the group consisting of: CR E 2 , S, N, additional condition is V E 1 、V E 2 and V E 3 At least one of them is S, N or NR E 2; or, V E 1 and V E2 、V E2 and V E 3 Taken together they are optionally formed into a 5-membered heteroaryl ring.

[0369] In another embodiment, the degradation tag is a moiety of formula 5, and wherein R E 1 is selected from the group consisting of: hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3-8 membered carbocyclyl and optionally substituted 3-8 membered heterocyclyl; preferably R E 1 is selected from the group consisting of: hydrogen, halogen, cyano, nitro and C1-C5 alkyl; more preferably R E 1 Selected from: H, CH3 or F.

[0370] In another embodiment, the degradation tag is a moiety of formula 5, and wherein R E 2 is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, amino, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkylamino, optionally substituted 3 to 8-membered carbocyclyl and optionally substituted 3 to 8-membered heterocyclyl; preferably R E 2 is selected from the group consisting of: hydrogen, halogen, cyano, nitro, 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 Selected from: H, F, OMe, O-iPr or O-cPr.

[0371] In another embodiment, the degradation tag is a moiety of formula 5, and wherein R E 3 and R E 4 are independently selected from hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3 to 8-membered carbocyclyl and optionally substituted 3 to 8-membered heterocyclyl; or, R E 3 and R E 4 Together with the atoms to which they are attached, they form a 3-8 membered carbocyclic group or a 3-8 membered heterocyclic group.

[0372] In another embodiment, R E r , at each occurrence, selected from the group R E and group RE , which consists of:

[0373]

[0374] In another embodiment, the degradation tag is a moiety of Formula 5, and wherein, in Z E In a group, at most one R E Z R E r .

[0375] In another embodiment, the degradation tag is a moiety of formula 5, and wherein n E =0, 1, 2 or 3.

[0376] In other embodiments, the degradation tag is a 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-.

[0377] In another embodiment, the degradation tag is a moiety of formula 5, and wherein R E 5 and R E 6 , at each occurrence, is independently selected from: a bond, hydrogen, halogen, oxo, hydroxy, amino, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3 to 8 membered carbocyclyl, and optionally substituted 3 to 8 membered heterocyclyl; or, R E 5 and R E 6 Together with the atoms to which they are attached, they form a 3-8 membered cycloalkyl ring or heterocyclyl ring.

[0378] In another embodiment, the degradation tag is a 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 alkylene, an optionally substituted 3- to 8-membered carbocyclyl, or an optionally substituted 3- to 8-membered heterocyclyl.

[0379] In other embodiments, the degradation tag is a moiety of Formula 5, and wherein Z E Selected from: a bond, CH2, CH=CH, C≡C, NH and O.

[0380] In another embodiment, the degradation tag is a moiety of formula 5, and wherein ring A E Formula A E 4 and L E Not for nothing.

[0381] In another embodiment, the degradation tag is a moiety of formula 5, and wherein Ring A E Formula A E 4 and L E 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)-.

[0382] In another embodiment, the degradation tag is a moiety selected from the group consisting of Formulas 5-1, 5-2, 5-3, 5-4, 5-5, and 5-6, and the degradation tag is linked to the divalent group Z. E a linker moiety attached to the heterobifunctional compound;

[0383]

[0384] in,

[0385] Z E 、R E 1 、L E 、 V E 1 、V E 2 、V E 3 、V E 4 、VE 5 、W E 1 、W E 2 、W E 3 and W E 4 As defined in Equation 5.

[0386] In additional embodiments, the degradation tag is a moiety selected from the group consisting of Formulas 5A, 5B, 5C, 5D, 5E, 5F, 5G, 5H, 5I, 5J, 5K, 5L, and 5M;

[0387]

[0388]

[0389] in,

[0390] V E 6 、V E 7 、V E 8 and V E 9 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 are optionally joined together to form a 6-membered aromatic ring or a 5-, 6-, or 7-membered heteroaromatic ring;

[0391] R E 12 , at 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 carbocyclyl, and optionally substituted 3-8 membered heterocyclyl;

[0392] W E6 and W E 7 Each independently selected from: -CR E 2 = and -N =;

[0393] 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 Equation 5.

[0394] In another embodiment, W E 1 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-.

[0395] In another embodiment, Ring A E As shown in formula A E 1 or A E 5; and ring A E By W E 2 Connect to L E .

[0396] In another embodiment, Ring A E As shown in formula A E 1 or A E 5, wherein W E 1 and W E3 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.

[0397] In another embodiment, the degradation tag is a moiety of formula 5-1 or 5-6, and the degradation tag is formed by Z E The divalent group shown is connected to the linker portion of the heterobifunctional compound; wherein,

[0398] W E 1 and W E 3 Each independently selected from the following group: -CO-, -O-, -CR E 3 R E 4 -、-NR E 3 -;

[0399] W E 2 is N and connected to

[0400] 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 Equation 5.

[0401] In another embodiment, the degradation tag is a moiety of formula 5A or 5M; wherein W E 1 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 Equation 5.

[0402] In another embodiment, R E 3 and R E 4 , at each occurrence, is independently selected from the group consisting of absent, hydrogen, halogen, cyano, nitro, hydroxy, amino, optionally substituted C1-C6 alkyl.

[0403] In other embodiments, the degradation tag is a moiety of Formula 5-1 or Formula 5-3.

[0404]

[0405] in,

[0406] V E 1 、V E 2 、V E 3 and V E 4 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 or V E 3 and V E 4 are optionally joined together to form a 6-membered aromatic ring or a 5-, 6-, or 7-membered heteroaromatic ring;

[0407] represents a single bond or a double bond; wherein, (i) when W E 1 and W E 2 When there is a single bond between E1 and W E 2 between represents a single bond), W E 1 、W E 2 and W E 3 Each independently selected from the group consisting of: -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 When there is a double bond between E 1 and W E 2 between represents a double bond), W E 1 and W E 2 Each independently selected from the group consisting of: -N=, -C≡, and -CR E 3 =;W E 3 Selected from the following group: -CR E 3 R E 4 -、-O-、-N=、-NR E 3 -、-C(O)NR E 3 -、-CR E 3 =CR E 4 -and-CR E 3 =N-;

[0408] Z E 、R E 2 、R E 3 、RE 4 and R E 1 As defined in Equation 5.

[0409] In other embodiments, the degradation tag is a moiety of formula 5-1 or 5-3, and wherein V E 1 、V E 2 、V E 3 and V E 4 Each independently selected from: C, N and CR E 2 .

[0410] In another embodiment, the degradation tag is a moiety of formula 5-1, and wherein V E 2 C (that is, with Z E connection location), and V E 1 、V E 3 and V E 4 Each independently selected from: N and CR E 2 (preferably, N or CH); or, V E 3 C (ie, with Z E connection location), and V E 1 、V E 2 and V E 4 Independently selected from: N and CR E 2 (Preferably, N or CH).

[0411] In another embodiment, the degradation tag of formula 5-1 is a moiety of formula 5A, 5B, 5E, 5F or 5G

[0412]

[0413] Among them, W E 6 and W E 7 Each independently selected from: -CR E 2 = and -N =; and V E 1 、V E 2 、V E3 、V E 4 、W E 1 、W E 3 , Z E 、R E 3 and R E 1 As defined in Equation 5-1.

[0414] In other embodiments, 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 Each independently selected from: a bond, C, CR E 2 and N (preferably C, CR E 2 and N).

[0415] In other embodiments, the degradation tag is of Formula 5A, 5B, 5E, 5F or 5G, and wherein W E 1 - and W E 3 Each 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 Each independently selected from: -CO-, -O-, -CR E 3 R E 4 -and-NR E 3 -.

[0416] In another embodiment, the degradation tag is a moiety of formula 5A, and wherein V E 2C (that is, with Z E connection location), and V E 1 、V E 3 and V E 4 Each independently selected from: N and CR E 2 (preferably, N or CH); or, V E 3 C (ie, with Z E connection location), and V E 1 、V E 2 and V E 4 Independently selected from: N and CR E 2 (Preferably, N or CH).

[0417] In another embodiment, the degradation tag of formula 5-3 is a moiety of formula 5C

[0418]

[0419] Among them, W E 3 N or CR E 3 ; and V E 1 、V E 2 、V E 3 、V E 4 , Z E and R E 1 As defined in Formula 5-3. In another embodiment, the degradation tag is a moiety of Formula 5C, wherein V E 1 、V E 2 、V E 3 and V E 4 Independently selected from: bond, CR E 2 and N.

[0420] In another embodiment, the degradation tag is a moiety of formula 5-2:

[0421]

[0422] V E1 、V E 2 、V E 3 、V E 4 and V E 5 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 are optionally joined together to form a 6-membered aromatic ring or a 5-, 6-, or 7-membered heteroaromatic ring;

[0423] represents a single bond or a double bond; (i) when W E 1 and W E 2 When there is a single bond between E 1 and W E 2 between represents a single bond), W E 1 and W E 4 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 Each independently selected from: N=, -CR E 3=, -CO-, -O-, -CR E 3 R E 4 -and-NR E 3 -; or, (ii) W E 1 and W E 2 When there is a double bond between E 1 and W E 2 between represents a double bond), W E 1 and W E 2 Each independently selected from: -N=, C and -CR E 2 =;W E 3 Selected from: -N=, -CR E 3 =, -CO-, -O-, -CR E 3 R E 4 -and-NR E 3 -; and W E 4 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-;

[0424] Z E 、R E 2 、R E 3 、R E 4 and R E 1 As defined in Equation 5.

[0425] In another embodiment, the degradation tag is a moiety of formula 5-2, wherein V E1 、V E 2 、V E 3 、V E 4 and V E 5 Independently selected from: a bond, C, CR E 2 and N.

[0426] In another embodiment, the degradation tag is a moiety of formula 5-2, wherein, Represents a single bond.

[0427] In another embodiment, the degradation tag is a moiety of formula 5-2, wherein, Represents a single bond, W E 1 and W E 4 Each independently selected from: -CO-, -O-, -CR E 3 R E 4 -and-NR E 3 -, and W E 2 and W E 3 Independently selected from: -N=, -CR E 3 =, -CO-, -O-, -CR E 3 R E 4 -and-NR E 3 -.

[0428] In another embodiment, the degradation tag of formula 5-2 is a moiety of formula 5D

[0429]

[0430] Among them, V E 1 、V E 2 、V E 3 、V E 4 、V E 5 、W E 1 , Z E and R E 1 As defined in Equation 5-2.

[0431] In another embodiment, the degradation tag is a moiety of formula 5D, wherein W E 1 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 Selected from: -CO-, -O-, -CR E 3 R E 4 -and-NR E 3 -.

[0432] In another embodiment, the degradation tag is a moiety of formula 5D, wherein V E 1 、V E 2 、V E 3 、V E 4 and V E 5 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 Taken together, optionally form a 6-membered aromatic ring or a 5-, 6-, or 7-membered heteroaromatic ring; preferably V E 1 、V E 2 、V E 3 、V E4 and V E 5 Independently selected from: a bond, C, CR E 2 and N.

[0433] In another embodiment, the degradation tag is a moiety of formula 5-4:

[0434]

[0435]

[0436] Among them, 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 Equation 5.

[0437] In another embodiment, the degradation tag is a moiety of formula 5-4, and wherein L E Not for nothing.

[0438] In another embodiment, the degradation tag is a moiety of formula 5-4, and wherein L E 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)-.

[0439] In another embodiment, the degradation tag is a moiety of formula 5-4, and wherein,

[0440] V E 1 、V E 2 、V E 3 、V E 4 and V E 5 , at each occurrence, are independently selected from the group consisting of: C, CR E 2 and N; or,

[0441] V E 1 and V E2 、V E 2 and V E 3 、V E 3 and V E 4 ; or V E 4 and V E 5 Combined together optionally to form The ring shown; where V E 6 、V E 7 、V E 8 and V E 9 Each independently selected from the following group: C, CR E 12 and N;

[0442] R E 12 , at 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 carbocyclyl, and optionally substituted 3-8 membered heterocyclyl.

[0443] In another embodiment, the degradation tag is a moiety of formula 5-4, and wherein V E 6 、V E 7 、V E 8 and V E 9 Each independently selected from the group consisting of: CR E 12 and N.

[0444] In another embodiment, the degradation tag is a moiety of formula 5-4, and wherein R E 12 , at each occurrence, is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, amino, and optionally substituted C1-C6 alkyl.

[0445] In another embodiment, the degradation tag is a moiety of formula 5-4, and wherein,

[0446] Select from the following groups:

[0447]

[0448] in,

[0449] V E 1 、V E 2 、V E 3 、V E 4 and V E 5 Each independently selected from the following group: C, CR E 2 and N; and V E 6 、V E 7 、V E 8 and V E 9 Each independently selected from the group consisting of: CR E 12 and N.

[0450] In another embodiment, the degradation tag is a moiety of formula 5-4, and wherein Z E is none, -CH2-, -O- or -NH-.

[0451] In other embodiments, the degradation tag of formula 5-4 is a moiety of formula 5H or 5I;

[0452]

[0453] Among them, 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 Each independently selected from: a bond, C, CR E 2 and N; and Z E and R E 1 As defined in Equation 5-4.

[0454] In another embodiment, the degradation tag is a moiety of formula 5-5:

[0455]

[0456] in, W E 1 、W E 2 、W E 3 、W E 4 、Z E and R E 1 As defined in Equation 5.

[0457] In another embodiment, the degradation tag is a moiety of formula 5-5, and wherein W E 1 、W E 2 、W E 3 and W E 4 Each independently selected from the following group: -N=, -C≡, -CR E 3 =, -CO-, -O-, -CR E 3 R E 4 -and-NR E 3 -.

[0458] In another embodiment, the degradation tag is a moiety of formula 5-5, and wherein W E 1 、W E 2 、W E 3 and W E 4 Each is independently selected from the group consisting of -N=, -C≡, -CH=, -CO-, -O-, -N-, -CH2- and -NH-.

[0459] In other embodiments, the degradation tag of formula 5-5 is a moiety of formula 5J, 5K, or 5L;

[0460]

[0461] Among them, 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.

[0462] In another embodiment, the degradation tag is a moiety of formula 5-6:

[0463]

[0464] in,

[0465] V E 1 、V E 2 and V E 3 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 are optionally taken together to form a 5-membered heteroaryl ring;

[0466] represents a single bond or a double bond; wherein, (i) when W E 1 and W E 2 When there is a single bond between E 1 and W E 2 between represents a single bond), W E 1 、W E 2 and W E 3 Each independently selected from the following group: -N=, -CR E 3 =, -CO-, -O-, -CR E 3 R E 4 -、-NR E 3 -、-CR E 3 =CR E4 -、-N=CR E 3 - and -N=N-; or, (ii) when W E 1 and W E 2 When there is a double bond between E 1 and W E 2 between represents a double bond), W E 1 and W E 2 Each independently selected from the group consisting of -N-, -C≡ and -CR E 3 =;W E 3 Selected from the following group: -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-;

[0467] Z E 、R E 2 、R E 3 、R E 4 and R E 1 As defined in Equation 5.

[0468] In other embodiments, the degradation tag is a moiety of Formula 5-6, and wherein V E 1 、V E 2 、V E 3 and V E 4 Each independently selected from: C, CR E 2 , S, N and NR E 2 .

[0469] In another embodiment, the degradation tag of formula 5-6 is a moiety of formula 5M;

[0470]

[0471] Among them, V E 1 、V E 2 、V E 3 、W E 1 、Z E and R E 1 As defined in Equation 5-6.

[0472] In another embodiment, the degradation tag is a moiety of formula 5M, and wherein V E 1 、V E 2 and V E 3 Each independently selected from: C, CR E 2 , S, N and NR E 2 (Preferably, V E 1 、V E 2 and V E 3 One of them is S).

[0473] In another embodiment, the degradation tag is a moiety of formula 5M, wherein W E 1 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 Selected from: -CO-, -O-, -CR E 3 R E 4 -and-NR E 3 -.

[0474] In other embodiments, the degradation tag is a moiety of Formula 6A, 6B, and 6C:

[0475]

[0476] in,

[0477] R E 1 and R E 2 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 alkoxyC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 aminoalkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 3-10 membered heterocyclyl;

[0478] R E 3Selected from: hydrogen, optionally substituted C(O)C1-C8 alkyl, optionally substituted C(O)C1-C8 alkoxy C1-C8 alkyl, optionally substituted C(O)C1-C8 haloalkyl, optionally substituted C(O)C1-C8 hydroxyalkyl, optionally substituted C(O)C1-C8 aminoalkyl, optionally substituted C(O)C1-C8 alkylamino C1-C8 alkyl, optionally substituted C(O) (3-10 membered carbocyclyl), optionally substituted C(O) (3 -10 membered heterocyclyl), optionally substituted C(O)C2-C8 alkenyl, optionally substituted C(O)C2-C8 alkynyl, optionally substituted C(O)OC1-C8 alkoxy C1-C8 alkyl, optionally substituted C(O)OC1-C8 haloalkyl, optionally substituted C(O)OC1-C8 hydroxyalkyl, optionally substituted C(O)OC1-C8 aminoalkyl, optionally substituted C(O)OC1-C8 alkylamino C1-C8 alkyl, optionally substituted C(O)O(3-10 membered carbocyclyl), optionally substituted C(O)O(3-10 membered heterocyclyl), optionally substituted C(O)OC2-C8 alkenyl, optionally substituted C(O)OC2-C8 alkynyl, optionally substituted C(O)NC1-C8 alkoxy C1-C8 alkyl, optionally substituted C(O)NC1-C8 haloalkyl, optionally substituted C(O)NC1-C8 hydroxyalkyl, optionally substituted C(O)NC1-C8 aminoalkyl, optionally substituted Substituted C(O)NC1-C8 alkylaminoC1-C8 alkyl, optionally substituted C(O)N(3-10 membered carbocyclyl), optionally substituted C(O)N(3-10 membered heterocyclyl), optionally substituted C(O)NC2-C8 alkenyl, optionally substituted C(O)NC2-C8 alkynyl, optionally substituted P(O)(OH)2, optionally substituted P(O)(OC1-C8 alkyl)2, and optionally substituted P(O)(OC1-C8 aryl)2; and

[0479] R E 4 Selected from: NR E 7 R E 8 、 optionally substituted C1-C8 alkoxy, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0480] R E 7is selected from the group consisting of hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 cycloalkyl, optionally substituted C1-C8 alkyl-CO, optionally substituted C1-C8 cycloalkyl-CO, optionally substituted C1-C8 cycloalkyl-C1-C8 alkyl-CO, optionally substituted 3-10 membered heterocyclyl-CO, optionally substituted 3-10 membered heterocyclyl-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;

[0481] R E 8 is selected from the group consisting of: hydrogen, optionally substituted C1-C8 alkyl, and optionally substituted C1-C8 cycloalkyl;

[0482] R E 9 , at each occurrence, is independently selected from the group consisting of hydrogen, halogen, cyano, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 cycloalkyl, optionally substituted C1-C8 heterocycloalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 cycloalkoxy, halosubstituted C1-C8 alkyl, halosubstituted C1-C8 cycloalkyl, halosubstituted C1-C8 alkoxy, halosubstituted C1-C8 cycloalkoxy, and halosubstituted C1-C8 heterocycloalkyl;

[0483] X E Selected from: CH and N; and

[0484] n E is 0, 1, 2, 3, or 4;

[0485] R E 5 Selected from: hydrogen and halogen, preferably, H and F.

[0486] R E 6 is selected from the group consisting of: hydrogen, halogen, hydroxy, amino, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 cycloalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 cycloalkyloxy, optionally substituted C1-C8 heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, preferably, halogen, cyano, optionally substituted imidazole, optionally substituted pyrazole, optionally substituted oxadiazole, optionally substituted triazole, 4-methylthiazol-5-yl or oxazol-5-yl.

[0487] In another embodiment, the degradation tag is a moiety of formula 7A:

[0488]

[0489] in,

[0490] V E 1 、V E 2 、V E 3 、V E 4 and V E 5 Independently selected from: CR E 4 and N; and

[0491] R E 1 、R E 2 、R E 3 and R E 4 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 3-10 membered carbocyclyl and optionally substituted 3-10 membered heterocyclyl.

[0492] In another embodiment, the degradation tag is a moiety of formula 7B:

[0493]

[0494] in,

[0495] R E 1 、R E 2 and R E 3 each independently selected from hydrogen, halogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted C2-C8 alkenyl and optionally substituted C2-C8 alkynyl;

[0496] R E 4 and R E 5 Independently selected from: hydrogen, COR E 6 、CO2RE 6 、CONR E 6 R E 7 、SOR E 6 、SO2R E 6 、SO2NR E 6 R E 7 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted aryl-C1-C8 alkyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, wherein,

[0497] R E 6 and R E 7 are independently 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 heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, or, R E 6 and R E 7 and together with the atoms to which they are attached form a 3-8 membered cycloalkyl or heterocycloalkyl ring.

[0498] In other embodiments, the degradation tag is a moiety of Formula 5-1, 5-2, or 5-3.

[0499] In another embodiment, the degradation tag is a moiety of formula 5-4:

[0500] In additional embodiments, the degradation tag is a moiety of Formula 5A, 5B, 5C, 5D, 5E, 5F, 5G, 5H, 5I, 5J, 5K, or 5L.

[0501] In additional embodiments, the degradation tag is a moiety of Formula 5A, 5B, 5C, 5H, or 5I.

[0502] In other embodiments, the degradation tag is derived from any of the following:

[0503]

[0504]

[0505] In other embodiments, the degradation tag is derived from any one of the following: thalidomide, pomalidomide, lenalidomide, 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 and CRBN-16.

[0506] In other embodiments, the degradation tag is selected from the group consisting of:

[0507]

[0508]

[0509]

[0510]

[0511]

[0512]

[0513]

[0514] In another embodiment, the degradation tag is selected from the group consisting of Formula 8A, 8B, 8C, 8D, 8E, 8F, 8G, 8H, 8I, 8J, 8K, 8L, 8M, 8O, 8P, 8Q, 8R, 8AQ, 8AR, 8AS, 8AT, 8AU, 8AV, 8AW, 8AX, 8AY, 8AZ, 8BA, 8BB, 8BC, 8BD, 8BE, 8BF, 8BG, 8BH, 8BI, 8BJ, 8BK, 8BL, 8BM, 8BN, 8BO, 8BP, 8BQ, 8BR, 8BS, 8CB, 8CC, 8 CD, 8CE, 8CF, 8CG, 8CH, 8CI, 8CJ, 8CK, 8CL, 8CM, 8CN, 8CO, 8CP, 8CQ, 8CR, 8CS, 8CT, 8CU, 8CV, 8CW, 8CX, 8CY, 8CZ, 8DA, 8DB, 8DC, 8DD, 8DE, 8DF, 8DG, 8DH, 8DI, 8DJ, 8DK, 8DL, 8DM, 8DN, 8DO, 8DP, 8DQ, 8DR, 8DS, 8DT, 8DU, 8DV, 8DW, 8DX, 8DY, 8DZ, 8EA , 8EB, 8EC, 8ED, 8EE, 8EF, 8EG, 8EH, 8EI, 8EJ, 8EK, 8EL, 8EM, 8EN, 8EO, 8EP, 8EO, 8GU, 8GV, 8GW, 8GX, 8GY, 8GZ, 8HA, 8HB, 8H C, 8HD, 8HE, 8HF, 8HG, 8HH, 8HI, 8HJ, 8HK, 8HL, 8HM, 8HN, 8HO, 8HP, 8HQ, 8HR, 8HS, 8HT, 8HU, 8HV, 8HW, 8HX, 8HY, 8HZ, 8IA, 8 IB, 8IC, 8ID, 8IE, 8IF, ​​8IG, 8IH, 8II, 8IJ, 8IK, 8IL, 8IM, 8IN, 8IO, 8IP, 8IQ, 8IR, 8IS, 8IT, 8IU, 8IV, 8IW, 8IX, 8IY, 8IZ, 8JA, 8JB, 8JC, 8JD, 8JE, 8JF, 8JG, 8JH, 8JI, 8JJ, 8JK, 8JL, 8JM, 8JN, 8JO, 8JP, 8JQ, 8JR, 8JS, 8JT, 8JU, 8JV, 8JY, 8KE and 8KM.

[0515] Connector part

[0516] As used herein, a "linker" or "linker moiety" is a bond, molecule, or group of molecules that binds two separate entities to each other. A linker provides an optimal spacing between two entities. In some aspects, the term "linker" refers to any agent or molecule that bridges a JAK ligand to a degradation tag. One of ordinary skill in the art recognizes that sites on a JAK ligand or degradation tag that are not essential for the function of the bifunctional degradation head of the present disclosure are ideal sites for attachment of a linker, provided that the linker, once attached to the conjugate of the present disclosure, does not interfere with the function of the JAK ligand (i.e., its ability to bind to JAK), or the function of the degradation tag (i.e., its ability to recruit ubiquitin ligase).

[0517] The length of the linker of the heterobifunctional compound can be adjusted to minimize the molecular weight of the heterobifunctional compound, avoid collision of the JAK ligand or targeting moiety with the ubiquitin ligase and / or induce JAK misfolding through the hydrophobic tag. In certain embodiments, the linker comprises an acyclic or cyclic saturated or unsaturated carbon, glycol, amide, ammonia, ether, urea, carbamate, aromatic, heteroaromatic, heterocyclic or carbonyl group. 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.

[0518] In some embodiments, the connector portion is as shown in Formula 9:

[0519]

[0520] in,

[0521] A L 、W L and B L , at each occurrence, is independently selected from: none, or a divalent moiety selected from: 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 1 )R L e 、R L d C(S)N(R L 1 )R Le 、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 4-13 membered fused cycloalkyl, optionally substituted 5-13 membered fused heterocyclyl, optionally substituted 5-13 membered bridged cycloalkyl, optionally substituted 5-13 membered bridged heterocyclyl, optionally substituted 5-13 membered spirocycloalkyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein

[0522] R L d and RL e , at each occurrence, 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 consisting of optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, 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 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted 4-13 membered fused cycloalkyl, optionally substituted 5-13 membered fused heterocyclyl, optionally substituted 5-13 membered bridged cycloalkyl, optionally substituted 5-13 membered bridged heterocyclyl, optionally substituted 5-13 membered spirocycloalkyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0523] R L r , at each occurrence, is selected from the group consisting of optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted 4-13 membered fused cycloalkyl, optionally substituted 5-13 membered fused heterocyclyl, optionally substituted 5-13 membered bridged cycloalkyl, optionally substituted 5-13 membered bridged heterocyclyl, optionally substituted 5-13 membered spirocycloalkyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0524] R L 1 and R L 2, is independently selected at each occurrence 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 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0525] Or, R L d and R L e 、R L 1 and R L 2 、R L d and R L 1 、R L d and R L 2 、R L e and R L 1 、R L e and R L 2 Together with the atoms to which they are attached, they form a 3-20 membered cycloalkyl ring or a 3-20 membered heterocyclyl ring; and

[0526] m L is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

[0527] In another embodiment, W L and m are as defined above; and A L and B L , at each occurrence, is independently selected from: none, CO, NH, NH-CO, CO-NH, -(CH2) 0-8 -、-(CH2) 0-3 -CO-(CH2) 0-8 -、(CH2) 0-8 -NH-CO, (CH2) 0-8 -CO-NH, NH-CO-(CH2) 0-8 、CO-NH-(CH2) 0-8 、(CH2) 1-3 -NH-(CH2) 1-3 -CO-NH, (CH2) 1-3-NH-(CH2) 1-3 -NH-CO, -CO-NH, CO-NH-(CH2) 1-3 -NH-(CH2) 1-3 、(CH2) 1-3 -NH-(CH2) 1-3 、-(CH2) 0-3 -R L r -(CH2) 0-3 、-(CH2) 0-3 -(CO)-(CH2) 0-3 -R L r -(CH2) 0-3 -、-(CH2) 0-3 -(CO-NH)-(CH2) 0-3 -R L r -(CH2) 0-3 -、-(CH2) 0-3 -(NH-CO)-(CH2) 0-3 -R L r -(CH2) 0-3 - and -(CH2) 0-3 -(NH)-(CH2) 0-3 -R L r -(CH2) 0-3 -. In another embodiment, R L r , at each occurrence, is selected from the group consisting of: Formulas C1, C2, C3, C4, and C5

[0528]

[0529] in,

[0530] A L 1 、B L 1 、C L 1 and D L 1 , at each occurrence, is independently selected from: none, O, CO, SO, SO2, NR L b , CR L b R L c 、R L b ;

[0531] AL 2 、B L 2 、C L 2 、D L 2 and E L 2 , at each occurrence, is independently selected from: N, CR L b ;

[0532] A L 3 、B L 3 、C L 3 、D L 3 and E L 3 , at each occurrence, is independently selected from: N, O, S, NR L b , CR L b ;

[0533] R L b and R L c , is independently selected at each occurrence 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, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; and

[0534] m L 1 、n L 1 、o L 1 and p L 1 Independently selected from: 0, 1, 2, 3, 4 and 5.

[0535] In another embodiment, R L r , at each occurrence, selected from the group R L r1or Group R L r2 ,and

[0536] Group R L r1 Composed of the following optionally substituted groups:

[0537]

[0538] Group R L r2 Composed of the following optionally substituted groups:

[0539]

[0540] In one embodiment, the linker portion is as shown in Formula 9A:

[0541]

[0542] in,

[0543] R L 1 、R L 2 、R L 3 and R L 4 , is independently selected at each occurrence 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, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or,

[0544] R L 1 and R L 2 、R L 3 and R L 4 and together with the atoms to which they are attached form a 3-20 membered cycloalkyl ring or a 3-20 membered heterocyclyl ring.

[0545] A L 、W L and B L, at each occurrence, is independently selected from: none, or a divalent moiety selected from: 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 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 alkoxyC1-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 heterocyclyl, optionally substituted 5-13 membered bridged cycloalkyl, optionally substituted 5-13 membered bridged heterocyclyl, optionally substituted 5-13 membered spirocycloalkyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein

[0546] R L d and R L e , at each occurrence, is independently selected from: none, 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 consisting of optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, 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 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted 4-13 membered fused cycloalkyl, optionally substituted 5-13 membered fused heterocyclyl, optionally substituted 5-13 membered bridged cycloalkyl, optionally substituted 5-13 membered bridged heterocyclyl, optionally substituted 5-13 membered spirocycloalkyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0547] RL r , at each occurrence, is selected from the group consisting of optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted 4-13 membered fused cycloalkyl, optionally substituted 5-13 membered fused heterocyclyl, optionally substituted 4-13 membered bridged cycloalkyl, optionally substituted 5-13 membered bridged heterocyclyl, optionally substituted 5-13 membered spirocycloalkyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0548] R L 5 and R L 6 , is independently selected at each occurrence 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 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0549] Or, 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 Together with the atoms to which they are attached, they form a 3-20 membered cycloalkyl ring or a 3-20 membered heterocyclyl ring;

[0550] m L 0 to 15;

[0551] n L , at each occurrence, from 0 to 15; and

[0552] o L 0 to 15.

[0553] In another embodiment, A L 、W L and B L , at each occurrence, is independently selected from: none, CO, NH, NH-CO, CO-NH, -(CH2) 0-8 -、-(CH2) 0-3 -CO-(CH2) 0-8 -、(CH2) 0-8 -NH-CO, (CH2) 0-8 -CO-NH, NH-CO-(CH2) 0-8 、CO-NH-(CH2) 0-8 、(CH2) 1-3 -NH-(CH2) 1-3 -CO-NH, (CH2) 1-3 -NH-(CH2) 1-3 -NH-CO, -CO-NH, CO-NH-(CH2) 1-3 -NH-(CH2) 1-3 、(CH2) 1-3 -NH-(CH2) 1-3 、-(CH2) 0-3 -R L r -(CH2) 0-3 、-(CH2) 0-3 -(CO)-(CH2) 0-3 -R L r -(CH2) 0-3 -、-(CH2) 0-3 -(CO-NH)-(CH2) 0-3 -R L r -(CH2) 0-3 -、-(CH2) 0-3 -(NH-CO)-(CH2) 0-3 -R L r -(CH2) 0-3 - and -(CH2) 0-3 -(NH)-(CH2) 0-3 -R L r -(CH2) 0-3 -.

[0554] In another embodiment, R L r , at each occurrence, selected from the group R L r1 or Group R Lr2 , and group R L r1 and group R L r2 As defined above.

[0555] In one embodiment, the JAK ligand of the heterobifunctional compound is bound to A in Formula 9A. L .

[0556] In another embodiment, A L (When A L When attached to a JAK ligand) is selected from: none, CO, NH, NH-CO, CO-NH, -(CH2) 0-8 -、-(CH2) 0-3 -CO-(CH2) 0-8 -、(CH2) 0-8 -NH-CO, (CH2) 0-8 -CO-NH, NH-CO-(CH2) 0-8 、CO-NH-(CH2) 0-8 、(CH2) 0-8 -NH-(CH2) 0-8 -CO-NH, (CH2) 1-3 -NH-(CH2) 1-3 -NH-CO, CO-NH-(CH2) 1-3 -NH-(CH2) 1-3 、(CH2) 1-3 -NH-(CH2) 1-3 、-(CH2) 0-3 -R L r -(CH2) 0-3 、-(CH2) 0-3 -(CO)-(CH2) 0-3 -R L r -(CH2) 0-3 -、-(CH2) 0-3 -(CO-NH)-(CH2) 0-3 -R L r -(CH2) 0-3 -、-(CH2) 0-3 -(NH-CO)-(CH2) 0-3 -R L r -(CH2) 0-3 -、-(CH2) 0-3 -(NH)-(CH2) 0-3 -R Lr -(CH2) 0-3 -,in

[0557] R L r , at each occurrence, selected from the group R L r1 or Group R L r2 , and group R L r1 and group R L r2 As defined above; and

[0558] W L and B L For nothing.

[0559] In one embodiment, the linker portion is as shown in Formula 9A:

[0560] in,

[0561] R L 1 、R L 2 、R L 3 and R L 4 , at each occurrence, is independently selected from: hydrogen, optionally substituted C1-C8 alkyl (preferably C1-C4 alkyl), optionally substituted C3-C8 cycloalkyl (preferably C3-C6 cycloalkyl), or,

[0562] R L 1 and R L 2 、R L 3 and R L 4 and together with the atoms to which they are attached form a 3-20 membered cycloalkyl (preferably, a 3-5 membered cycloalkyl) ring or a 3-20 membered heterocyclyl ring.

[0563] A L As defined above; and W and B are none;

[0564] m L is 0 to 15 (preferably, m is 0, 1 or 2);

[0565] n L , at each occurrence, is from 1 to 15 (preferably, n is 1); and

[0566] o Lis 1 to 15 (preferably, o is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13).

[0567] In another embodiment, A L 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 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 L d N(R L 5 )C(S)R L e ; R L d and R L e As defined above.

[0568] In another embodiment, R L d and R L e , at each occurrence, is independently selected from: none, optionally (C1-C8 alkyl)-R r (Preferably, CH2-R L r ), or an optionally substituted C1-C8 alkyl group (preferably, an optionally substituted C1-C2 alkyl group).

[0569] In another embodiment, the linker portion is as shown in Formula 9B:

[0570]

[0571] in,

[0572] R L 1 and R L 2 , is independently selected at each occurrence from the group consisting of hydrogen, halogen, hydroxy, amino, cyano, nitro, 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 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

[0573] R L 1 and R L 2 Together with the atoms to which they are attached, they form a 3-20 membered cycloalkyl ring or a 3-20 membered heterocyclyl ring;

[0574] A L and B L, at each occurrence, is independently selected from: none, or a divalent moiety selected from: 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 L e 、R L d N(R L 3 )CON(R L 4 )R L e 、R Ld 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 alkoxyC1-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 heterocyclyl, optionally substituted 5-13 membered bridged cycloalkyl, optionally substituted 5-13 membered bridged heterocyclyl, optionally substituted 5-13 membered spirocycloalkyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein,

[0575] R L d and R L e , at each occurrence, 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 consisting of optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, 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 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted 4-13 membered fused cycloalkyl, optionally substituted 5-13 membered fused heterocyclyl, optionally substituted 5-13 membered bridged cycloalkyl, optionally substituted 5-13 membered bridged heterocyclyl, optionally substituted 5-13 membered spirocycloalkyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0576] RL r , at each occurrence, is selected from the group consisting of optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted 4-13 membered fused cycloalkyl, optionally substituted 5-13 membered fused heterocyclyl, optionally substituted 5-13 membered bridged cycloalkyl, optionally substituted 5-13 membered bridged heterocyclyl, optionally substituted 5-13 membered spirocycloalkyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0577] R L 3 and R L 4 , is independently selected at each occurrence 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 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0578] 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 Together with the atoms to which they are attached, they form a 3-20 membered cycloalkyl ring or a 3-20 membered heterocyclyl ring;

[0579] Each m L is 0 to 15 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15); and

[0580] n L is 0 to 15 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15).

[0581] In another embodiment, A L and B L , at each occurrence, is independently selected from: none, CO, NH, NH-CO, CO-NH, -(CH2) 0-8 -、-(CH2) 0-3 -CO-(CH2) 0-8 -、(CH2) 0-8 -NH-CO, (CH2) 0-8 -CO-NH, NH-CO-(CH2) 0-8 、CO-NH-(CH2) 0-8 、(CH2) 1-3 -NH-(CH2) 1-3 -CO-NH, (CH2) 1-3 -NH-(CH2) 1-3 -NH-CO, CO-NH-(CH2) 1-3 -NH-(CH2) 1-3 、(CH2) 1-3 -NH-(CH2) 1-3 、-(CH2) 0-3 -R L r -(CH2) 0-3 、-(CH2) 0-3 -(CO)-(CH2) 0-3 -R L r -(CH2) 0-3 -、-(CH2) 0-3 -(CO-NH)-(CH2) 0-3 -R L r -(CH2) 0-3 -、-(CH2) 0-3 -(NH-CO)-(CH2) 0-3 -R L r -(CH2) 0-3 -、-(CH2) 0-3 -(NH)-(CH2) 0-3 -R L r -(CH2) 0-3 -.

[0582] In another embodiment, R L r , at each occurrence, selected from the group R L r1 or Group R L r2, and group R L r1 and group R L r2 As defined in Equation 9.

[0583] In another embodiment, the linker portion is as shown in Formula 9C:

[0584]

[0585] in,

[0586] X L , at each occurrence, selected from: O and NR L 7 ;

[0587] R L 1 、R L 2 、R L 3 、R L 4 、R L 5 and R L 6 , is independently selected at each occurrence 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 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0588] A L and B L , at each occurrence, is independently selected from: none, or a divalent moiety selected from: 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 alkoxyC1-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 heterocyclyl, optionally substituted 5-13 membered bridged cycloalkyl, optionally substituted 5-13 membered bridged heterocyclyl, optionally substituted 5-13 membered spirocycloalkyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein,

[0589] R L d and R L e , at each occurrence, 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 consisting of optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, 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 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted 4-13 membered fused cycloalkyl, optionally substituted 5-13 membered fused heterocyclyl, optionally substituted 5-13 membered bridged cycloalkyl, optionally substituted 5-13 membered bridged heterocyclyl, optionally substituted 5-13 membered spirocycloalkyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0590] R L r, at each occurrence, is selected from the group consisting of optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted 4-13 membered fused cycloalkyl, optionally substituted 5-13 membered fused heterocyclyl, optionally substituted 5-13 membered bridged cycloalkyl, optionally substituted 5-13 membered bridged heterocyclyl, optionally substituted 5-13 membered spirocycloalkyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0591] R L 7 、R L 8 and R L 9 , is independently selected at each occurrence 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 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0592] 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 、R L e and R L 9 Together with the atoms to which they are attached, they form a 3-20 membered cycloalkyl ring or a 3-20 membered heterocyclyl ring;

[0593] At each occurrence, m L is 0 to 15 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15);

[0594] At each occurrence, n Lis 0 to 15 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15);

[0595] o L is 0 to 15 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15); and

[0596] p L is 0 to 15 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15).

[0597] In one embodiment, the linker portion is as shown in Formula 9D:

[0598] -A L -(W L ) qL -B L -(Formula 9D)

[0599] in,

[0600] W L , at each occurrence, is independently selected from: none, 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 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 SO2RL 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 4-13 membered fused cycloalkyl, optionally substituted 5-13 membered fused heterocyclyl, optionally substituted 5-13 membered bridged cycloalkyl, optionally substituted 5-13 membered bridged heterocyclyl, optionally substituted 5-13 membered spirocycloalkyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl,

[0601] q L =1, 2, 3, 4, 5, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0602] R L 1 、R L 2 、R L d 、R L e 、A L and B L As defined in Equation 9.

[0603] In another embodiment, at least one W L Not for nothing.

[0604] In another embodiment, W L Not for nothing.

[0605] In another embodiment, A L and B L Independently selected from: none, R L r 、CH2-R L r 、R L d COR 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 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(RL 1 )C(S)R L e , optionally substituted C1-C2 alkylene, optionally substituted C2 alkenylene, and optionally substituted C2 alkynylene;

[0606] R L d and R L e , at each occurrence, is independently selected from: none, C1-C2 alkylene substituted with one or more C1-C3 alkyl, halogen, and C1-C3 haloalkyl;

[0607] R L 1 and R L 2 , at each occurrence, is independently selected from the group consisting of: H, C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, and C3-C6 halocycloalkyl.

[0608] In another embodiment, the connector portion is L connected to the JAK ligand; wherein,

[0609] A L Selected from: None, R L r 、 CH2-R L r , CO and CH2-CO;

[0610] B L Independently selected from: None, N(R L 1 )、N(R L 1 )-CH2、O、CH2、R L r 、R L r -N(R L 1 ), R L r -CH2 and R L r -O;

[0611] W L , at each occurrence, selected from: CO, N(R L 1 )、C(S)、SO、SO2、C(O)N(R L 1 )、N(R L 2)C(O)N(R L 1 )、S(O)2N(R L 1 ), optionally substituted C1-C2 alkylene, optionally substituted C2 alkenylene, optionally substituted C2 alkynylene, and R L r ;

[0612] R L 1 and R L 2 , at each occurrence, is independently selected from: H, C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, and C3-C6 halocycloalkyl;

[0613] q L =1, 2, 3, 4 or 5.

[0614] In another embodiment, A L In, R L r , at each occurrence, as shown in formula C4 or C5.

[0615] In another embodiment, A L In, R L r , at each occurrence, is selected from the group R defined in Equation 9 L r2 .

[0616] In another embodiment, R L r , at each occurrence, as shown in formula C4 or C5; preferably, selected from the group R defined in formula 9 L r2 .

[0617] In another embodiment, adjacent 2 or 3 W L optionally combined to form a moiety selected from the group consisting of: optionally substituted C1 alkylene-CO-N(R L 1 )-(such as -CF2-CO-NH-) or -N(R L 1 )-CO-N(R L 1 )(such as -NH-CO-NH-)-; and other W L is an optionally substituted C1-C2 alkylene group; preferably, independently an unsubstituted C1-C2 alkylene group or a C1-C2 alkylene group substituted by one or more C1-C3 alkyl groups, halogen groups and C1-C3 haloalkyl groups.

[0618] In another embodiment, adjacent 2 or 3 W L optionally combined to form a moiety selected from the group consisting of: optionally substituted -N(R L 1 )-R L r -N(R L 1 )-(such as -NH-R L r -NH-) or -N(R L 1 )-R L r -(such as -NH-R L r -); where R L r , in each occurrence of formula, as shown in formula C4 or C5; preferably, selected from: group R defined in formula 9 L r2 , and other W L is an optionally substituted C1-C2 alkylene group; preferably, independently an unsubstituted C1-C2 alkylene group or a C1-C2 alkylene group substituted by one or more C1-C3 alkyl groups, halogen groups and C1-C3 haloalkyl groups.

[0619] In another embodiment, adjacent W L Combined to form a moiety selected from the group consisting of: optionally substituted C1 alkylene-CO-N(R L 1 )-(such as -CF2-CO-NH-) or -N(R L 1 )-CO-N(R L 1 )-(such as -NH-CO-NH-)-.

[0620] In another embodiment, adjacent W L Combined to form a moiety selected from the group consisting of: optionally substituted -N(R L 1 )-R L r -N(R L 1 )-(such as -NH-R L r -NH-)- or -N(R L 1 )-R L r -(such as -NH-R L r -); where R L r, at each occurrence, as shown in formula C4 or C5; preferably, selected from: group R defined in formula 9 L r2 .

[0621] In another embodiment, W L , at each occurrence, selected from: N(R L 1 ) and optionally substituted C1-C2 alkylene.

[0622] In other embodiments, the optionally substituted C1-C2 alkylene groups are each independently unsubstituted C1-C2 alkylene groups or C1-C2 alkylene groups substituted with one or more of C1-C3 alkyl, halogen, and C1-C3 haloalkyl.

[0623] In another embodiment, W L , at each occurrence, is optionally substituted C1-C2 alkylene; preferably, is independently unsubstituted C1-C2 alkylene or C1-C2 alkylene substituted with one or more C1-C3 alkyl, halogen and C1-C3 haloalkyl.

[0624] In another embodiment, the optionally substituted C1-C2 alkylene represents an unsubstituted C1-C2 alkylene or a C1-C2 alkylene substituted by one or more C1-C3 alkyl, halogen (such as F, Cl, Br or I) and C1-C3 haloalkyl; preferably, the optionally substituted C1-C2 alkylene represents a C1-C2 alkylene substituted by one or more (1, 2, 3 or 4) halogen (such as F, Cl, Br or I).

[0625] In another embodiment, the linker is selected from: -(CH2) 0-1 -R L r -(CH2) 0-2 -NH-R L r -NH-(CH2) 0-3 -、-(CH2) 0-3 -(CF2)-CO-NH-(CH2) 0-3 -、-(CH2) 0-1 -CO-(CH2) 0-3 -(CF2)-CO-NH-(CH2) 0-3 -.

[0626] In another embodiment, the linker is -(CH2) 0-1 -R L r -(CH2) 0-2 -NH-R Lr -(CH2) 0-3 -; among them, R L r , at each occurrence, as shown in formula C4 or C5; preferably, selected from the group R defined in formula 9 L r2 .

[0627] In another embodiment, the linker is selected from: -(CH2) 0-1 -R L r -(CH2) 0-3 -(CF2)-CO-NH-(CH2) 0-3 -、-(CH2) 0-3 -(CF2)-CO-NH-(CH2) 0-3 -、-(CH2) 0-1 -CO-(CH2) 0-3 -(CF2)-CO-NH-(CH2) 0-3 -、-(CH2) 0-1 -R L r -(CH2) 0-3 -NH-CO-NH-(CH2) 0-3 -、-(CH2) 0-3 -NH-CO-NH-(CH2) 0-3 -、-(CH2) 0-1 -CO-(CH2) 0-3 -NH-CO-NH-(CH2) 0-3 -.

[0628] In another refinement, the linker has a length of 0 to 40 chain atoms.

[0629] In another refinement, the linker has a length of 1 to 20 chain atoms.

[0630] In another refinement, the linker is 2 to 12 chain atoms in length.

[0631] In another improved embodiment, the linker is selected from: -(CO)-(CH2) 1-8 -、-(CH2) 1-9 -、-(CH2) 1-2 -(CO)-NH-(CH2) 2-9 -、-(CH2) 1-2 -(CO)-NH-(CH2) 1-3 -(OCH2CH2) 1-7 and -(CH2) 0-1-(CO)-(CH2) 1-3 -(OCH2CH2) 1-7 .

[0632] In another improved embodiment, the linker is -(CO)-(CH2) 1-8 -、-(CH2) 1-9 -、-(CH2) 1-2 (CO)-NH-(CH2) 2-9 -or-(CH2) 1-2 -(CO)-NH-(CH2) 1-3 -(OCH2CH2) 1-7 -.

[0633] In another improved embodiment, (preferably, when the degradation tag is a moiety of formula 6) the linker is -(CO)-(CH2) 1-10 -(CO)- or -(CO)-(CH2) 1-9 -(CO)-.

[0634] In another improved embodiment, (preferably, when the degradation tag is a moiety of formula 6) the linker is -(CO)-(CH2) 1-3 -O-(CH2CH2O) 0-5 -(CH2) 1-3 -(CO)-、-(CO)-(CH2)-O-(CH2CH2O) 0-4 -(CH2)-(CO)- or -(CO)-(CH2)2-O-(CH2CH2O) 0-4 -(CH2)2-(CO)-.

[0635] In another improved embodiment, (preferably, when the degradation tag is a moiety of formula 6) the linker is -(CH2) 0-3 -(CO)-NH-(CH2) 1-10 -(CO)-, -(CH2) 1-2 -(CO)-NH-(CH2) 1-10 -(CO)- or -(CH2)-(CO)-NH-(CH2) 1-10 -(CO)-.

[0636] In another improved embodiment, (preferably, when the degradation tag is a moiety of formula 6) the linker is -(CH2) 0-3 -(CO)-NH-(CH2) 2-3 -O-(CH2CH2O) 0-5 -(CH2) 1-3 -(CO)-, -(CH2) 1-2-(CO)-NH-(CH2) 2-3 -O-(CH2CH2O) 0-5 -(CH2) 1-3 -(CO)- or -(CH2)-(CO)-NH-(CH2)2-O-(CH2CH2O) 0-4 -(CH2) 1-2 -(CO)-.

[0637] In another improved embodiment, (preferably, when the degradation tag is selected from the group consisting of Formula 5A, 5B, 5C, 5D, 5E and 5F) the linker is -(CO)-(CH2) 1-8 -、-(CO)-(CH2) 1-7 -、-(CH2) 1-9 -or-(CH2) 1-8 -.

[0638] In another improved embodiment, (preferably, when the degradation tag is selected from Formula 5A, 5B, 5C, 5D, 5E and 5F) the linker is -(CH2) 1-2 (CO)-NH-(CH2) 4-9 -、-(CH2) 1-2 (CO)-NH-(CH2) 2-9 -or-(CH2) 1-2 (CO)-NH-(CH2) 2-8 -.

[0639] In another improved embodiment, (preferably, when the degradation tag is selected from Formula 5A, 5B, 5C, 5D, 5E and 5F) the linker is -(CH2) 1-2 -(CO)-NH-(CH2) 1、2或3 -(OCH2CH2) 1-7 -、-(CH2) 1-2 -(CO)-NH-(CH2) 1、2或3 -(OCH2CH2) 5-7 -or-(CH2) 1-2 -(CO)-NH-(CH2) 1、2或3 -(OCH2CH2) 1-5 -.

[0640] In another improved embodiment, (preferably, when the degradation tag is selected from Formula 5A, 5B, 5C, 5D, 5E and 5F) the linker is -(CH2) 0-1 -(CO)-(CH2) 1、2或3 -(OCH2CH2) 1-7 -、-(CH2) 0-1 -(CO)-(CH2)1、2或3 -(OCH2CH2) 5-7 -、-(CH2) 0-1 -(CO)-(CH2) 1、2或3 -(OCH2CH2) 1-5 -.

[0641] In another improved embodiment, when the JAK ligand is derived from NVP-BSK805 (and preferably, the degradation tag is selected from Formula 5A, 5B, 5C, 5D, 5E and 5F), the linker is -(CO)-(CH2) 3-8 -(preferably -(CO)-(CH2) 4-7 -; more preferably -(CO)-(CH2) 4-5 -).

[0642] In another improved embodiment, when the JAK ligand is of formula 3A (and preferably, the degradation tag is selected from formulas 5A, 5B, 5C, 5D, 5E and 5F), the linker is -(CO)-(CH2) 3-8 -(preferably -(CO)-(CH2) 4-7 -; more preferably -(CO)-(CH2) 4-5 -).

[0643] In another improved embodiment, when the JAK ligand is derived from Cmpd 12 (and preferably, the degradation tag is selected from Formula 5A, 5B, 5C, 5D, 5E and 5F), the linker is -(CO)-(CH2) 3-8 -(preferably -(CO)-(CH2) 4-7 -; more preferably -(CO)-(CH2) 5-7 -); or the connector is -(CH2) 1-2 -(CO)-NH-(CH2) 5-9 -(Preferably -(CH2) 1-2 -(CO)-NH-(CH2) 7-8 -).

[0644] In another improved embodiment, when the JAK ligand is of formula 3C and 3D (and preferably, the degradation tag is selected from formula 5A, 5B, 5C, 5D, 5E and 5F), the linker is -(CO)-(CH2) 3-8 -(preferably -(CO)-(CH2) 4-7 -; more preferably -(CO)-(CH2) 5-7 -); or the connector is -(CH2) 1-2 -(CO)-NH-(CH2) 5-9 -(Preferably -(CH2) 1-2-(CO)-NH-(CH2) 7-8 -).

[0645] In another improved embodiment, when the JAK ligand is derived from TG101209 (and preferably, the degradation tag is selected from Formula 5A, 5B, 5C, 5D, 5E and 5F), the linker is -(CO)-(CH2) 1-7 -(Preferably, -(CO)-(CH2) 1-2 -or-(CO)-(CH2) 6-7 -); or, the linker is -(CH2) 1-2 -(CO)-NH-(CH2) 4-7 -(Preferably, -(CH2) 1-2 -(CO)-NH-(CH2) 5-6 -); or, the linker is -(CH2) 1-2 -(CO)-NH-(CH2) 1、2或3 -(OCH2CH2) 1-7 (Preferably, -(CH2) 1-2 -(CO)-NH-(CH2) 1、2或3 -(OCH2CH2) 4-7 -; more preferably, -(CH2) 1-2 -(CO)-NH-(CH2)1, 2或3 -(OCH2CH2)5-).

[0646] In another improved embodiment, when the JAK ligand is of formula 3I (and preferably, the degradation tag is selected from formulas 5A, 5B, 5C, 5D, 5E and 5F), the linker is -(CO)-(CH2) 1-7 -(Preferably, -(CO)-(CH2) 1-2 -or-(CO)-(CH2) 6-7 -); or the connector is -(CH2) 1-2 -(CO)-NH-(CH2) 4-7 -(Preferably, -(CH2) 1-2 -(CO)-NH-(CH2) 5-6 -); or the connector is -(CH2) 1-2 -(CO)-NH-(CH2) 1、2或3 -(OCH2CH2) 1-7 (Preferably, -(CH2) 1-2 -(CO)-NH-(CH2) 1、2或3 -(OCH2CH2) 4-7 -; more preferably, -(CH2) 1-2-(CO)-NH-(CH2) 1、2或3 -(OCH2CH2)5-).

[0647] In another embodiment, R r , at each occurrence, is selected from the group consisting of formulae C1, C2, C3, C4 and C5 as defined above.

[0648] In another embodiment, R r , at each occurrence, selected from the group R L r1 or Group R L r2 .

[0649] In some embodiments, the heterobifunctional compound is selected from the group consisting of JA-001 to JA-295 or pharmaceutically acceptable salts or analogs thereof.

[0650] In some embodiments, the heterobifunctional compound is selected from the group consisting of JA-093, JA-094, JA-179, JA-180, JA-182, JA-187, JA-188, JA-189, JA-196, JA-198, JA-199, JA-202, JA-203, JA-213, JA-214, JA-224, JA-225, JA-231, JA-252, JA-261, JA-263, JA-264, JA-268, JA-269, JA-273, and pharmaceutically acceptable salts or analogs thereof.

[0651] In one embodiment, the heterobifunctional compound is 2-(4-(4-((4-((3-(N-(tert-butyl)sulfamoyl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)phenyl)piperazin-1-yl)-N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentyl)acetamide (JA-093).

[0652] In one embodiment, the heterobifunctional compound is 2-(4-(4-((4-((3-(N-(tert-butyl)sulfamoyl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)phenyl)piperazin-1-yl)-N-(6-((2-(2,6-dioxapiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)acetamide (JA-094).

[0653] In one embodiment, the heterobifunctional compound is 2-(4-(4-(8-(3,5-difluoro-4-(morpholinomethyl)phenyl)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-N-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)heptyl)acetamide (JA-179).

[0654] In one embodiment, the heterobifunctional compound is 2-(4-(4-(8-(3,5-difluoro-4-(morpholinomethyl)phenyl)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-N-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)octyl)acetamide (JA-180).

[0655] In one embodiment, the heterobifunctional compound is 5-((5-(4-(4-(8-(3,5-difluoro-4-(morpholinomethyl)phenyl)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-5-oxopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoquinoline-1,3-dione (JA-182).

[0656] In one embodiment, the heterobifunctional compound is 5-((8-(4-(4-(8-(3,5-difluoro-4-(morpholinomethyl)phenyl)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-8-oxooctyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoquinoline-1,3-dione (JA-187).

[0657] In one embodiment, the heterobifunctional compound is 5-((7-(4-(4-(8-(3,5-difluoro-4-(morpholinomethyl)phenyl)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-7-oxoheptyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoquinoline-1,3-dione (JA-188).

[0658] In one embodiment, the heterobifunctional compound is 5-((6-(4-(4-(8-(3,5-difluoro-4-(morpholinomethyl)phenyl)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-6-oxohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoquinoline-1,3-dione (JA-189).

[0659] In one embodiment, the heterobifunctional compound is 2-(2,6-dioxopiperidin-3-yl)-5-((5-(4-(4-((5-(4-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)phenyl)piperazin-1-yl)-5-oxopentyl)amino)isoquinoline-1,3-dione (JA-196).

[0660] In one embodiment, the heterobifunctional compound is 2-(2,6-dioxopiperidin-3-yl)-5-((6-(4-(4-((5-(4-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)phenyl)piperazin-1-yl)-6-oxohexyl)amino)isoquinoline-1,3-dione (JA-198).

[0661] In one embodiment, the heterobifunctional compound is 2-(2,6-dioxopiperidin-3-yl)-5-((7-(4-(4-((5-(4-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)phenyl)piperazin-1-yl)-7-oxoheptyl)amino)isoquinoline-1,3-dione (JA-199).

[0662] In one embodiment, the heterobifunctional compound is 2-(2,6-dioxopiperidin-3-yl)-5-((3-(4-(4-((5-(4-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)phenyl)piperidin-1-yl)-3-oxopropyl)amino)isoquinoline-1,3-dione (JA-202).

[0663] In one embodiment, the heterobifunctional compound is 2-(2,6-dioxopiperidin-3-yl)-5-((8-(4-(4-((5-(4-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)phenyl)piperidin-1-yl)-8-oxooctyl)amino)isoquinoline-1,3-dione (JA-203).

[0664] In one embodiment, the heterobifunctional compound is N-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)octyl)-2-(4-(4-((5-(4-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)phenyl)piperidin-1-yl)acetamide (JA-213).

[0665] In one embodiment, the heterobifunctional compound is N-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)heptyl)-2-(4-(4-((5-(4-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)phenyl)piperidin-1-yl)acetamide (JA-214).

[0666] In one embodiment, the heterobifunctional compound is 2-(4-(4-((4-((3-(N-(tert-butyl)sulfamoyl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)phenyl)piperazin-1-yl)-N-(17-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12,15-pentaoxaheptadecanyl)acetamide (JA-224).

[0667] In one embodiment, the heterobifunctional compound is N-(tert-butyl)-3-((2-((4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycyl)piperazin-1-yl)phenyl)amino)-5-methylpyrimidin-4-yl)amino)benzenesulfonamide (JA-225).

[0668] In one embodiment, the heterobifunctional compound is N-(tert-butyl)-3-((2-((4-(4-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)octanoyl)piperazin-1-yl)phenyl)amino)-5-methylpyrimidin-4-yl)amino)benzenesulfonamide (JA-231).

[0669] In one embodiment, the heterobifunctional compound is 2-(2,6-dioxopiperidin-3-yl)-5-(7-(4-(4-((5-(4-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)phenyl)piperazin-1-yl)hept-1-yn-1-yl)isoindoline-1,3-dione (JA-252).

[0670] In one embodiment, the heterobifunctional compound is 3-(5-((6-(4-(4-((5-(4-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)phenyl)piperazin-1-yl)-6-oxohexyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (JA-261).

[0671] In one embodiment, the heterobifunctional compound is 3-(5-((6-(4-(4-(8-(3,5-difluoro-4-(morpholinomethyl)phenyl)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-6-oxohexyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (JA-263).

[0672] In one embodiment, the heterobifunctional compound is 5-(7-(4-(4-(8-(3,5-difluoro-4-(morpholinomethyl)phenyl)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)hept-1-yn-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (JA-264).

[0673] In one embodiment, the heterobifunctional compound is 3-(6-(7-(4-(4-((5-(4-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)phenyl)piperazin-1-yl)-7-oxoheptyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (JA-268).

[0674] In one embodiment, the heterobifunctional compound is 3-(6-(7-(4-(4-(8-(3,5-difluoro-4-(morpholinomethyl)phenyl)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-7-oxoheptyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (JA-269).

[0675] In one embodiment, the heterobifunctional compound is 3-(5-((6-(4-(4-(8-(3,5-difluoro-4-(morpholinomethyl)phenyl)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-6-oxohexyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (JA-273).

[0676] In some embodiments, the heterobifunctional compound is selected from the group consisting of JA-296 to JA-350 or pharmaceutically acceptable salts or analogs thereof.

[0677] In some embodiments, the heterobifunctional compound is selected from the group consisting of JA-310, JA-311, JA-313, JA-315, JA-317, JA-321, JA-322, JA-323, JA-324, JA-325, JA-334, JA-335, JA-342, JA-343, JA-347, JA-348, JA-349, JA-350 and or a pharmaceutically acceptable salt or analog thereof.

[0678] In one embodiment, the heterobifunctional compound is 1-(3-(4-(4-(8-(3,5-difluoro-4-(morpholinomethyl)phenyl)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)phenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)urea (JA-310).

[0679] In one embodiment, the heterobifunctional compound is 1-(3-(4-(4-(8-(3,5-difluoro-4-(morpholinomethyl)phenyl)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-3-oxopropyl)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)urea (JA-311).

[0680] In one embodiment, the heterobifunctional compound is 2-(3-(4-(4-(8-(3,5-difluoro-4-(morpholinomethyl)phenyl)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)2,2-difluoroacetamide (JA-313).

[0681] In one embodiment, the heterobifunctional compound is 5-(4-(4-(8-(3,5-difluoro-4-(morpholinomethyl)phenyl)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-5-oxopentamide (JA-315).

[0682] In one embodiment, the heterobifunctional compound is 2-(3-(4-(4-(8-(3,5-difluoro-4-(morpholinomethyl)phenyl)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide (JA-317).

[0683] In one embodiment, the heterobifunctional compound is 5-((6-(4-(4-(8-(3,5-difluoro-4-(piperazin-1-ylmethyl)phenyl)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-6-oxohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (JA-321).

[0684] In one embodiment, the heterobifunctional compound is 5-((6-(4-(4-(8-(3,5-difluoro-4-(hydroxymethyl)phenyl)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-6-oxohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (JA-322).

[0685] In one embodiment, the heterobifunctional compound is 5-((6-(4-(4-(8-(3,5-difluoro-4-((4-hydroxypiperazin-1-yl)methyl)phenyl)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-6-oxohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (JA-323).

[0686] In one embodiment, the heterobifunctional compound is 5-((6-(4-(4-(8-(3,5-difluoro-4-((3-oxopiperazin-1-yl)methyl)phenyl)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-6-oxohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (JA-324).

[0687] In one embodiment, the heterobifunctional compound is 1-(3-(4-(4-(8-(3,5-difluoro-4-(morpholinomethyl)phenyl)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)phenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)amino)methyl)urea (JA-325).

[0688] In one embodiment, the heterobifunctional compound is 3-(4-((2-((3-(4-(4-(8-(3,5-difluoro-4-(morpholinomethyl)phenyl)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (JA-334).

[0689] In one embodiment, the heterobifunctional compound is 3-(4-((2-((4-(4-(8-(3,5-difluoro-4-(morpholinomethyl)phenyl)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (JA-335).

[0690] In one embodiment, the heterobifunctional compound is 2-(2-(4-(4-(8-(3,5-difluoro-4-(morpholinomethyl)phenyl)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)cyclopropyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)acetamide (JA-342).

[0691] In one embodiment, the heterobifunctional compound is 4-(4-(8-(3,5-difluoro-4-(morpholinomethyl)phenyl)quinoxalin-2-yl)-1H-pyrazol-1-yl)-N-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)butyl)piperidine-1-carboxamide (JA-343).

[0692] In one embodiment, the heterobifunctional compound is 5-((6-(4-(4-(8-(3,5-difluoro-4-(piperazin-1-ylmethyl)phenyl)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-6-oxohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (JA-347).

[0693] In one embodiment, the heterobifunctional compound is 5-((6-(4-(4-(8-(3,5-difluoro-4-(hydroxymethyl)phenyl)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-6-oxohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (JA-348).

[0694] In one embodiment, the heterobifunctional compound is 5-((6-(4-(4-(8-(3,5-difluoro-4-((4-hydroxypiperazin-1-yl)methyl)phenyl)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-6-oxohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (JA-349).

[0695] In one embodiment, the heterobifunctional compound is 5-((6-(4-(4-(8-(3,5-difluoro-4-((3-oxopiperazin-1-yl)methyl)phenyl)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-6-oxohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (JA-350).

[0696] In one embodiment, the heterobifunctional compound is not a compound disclosed in PCT / CN2020 / 083041 (such as JA-001-JA-295).

[0697] Without wishing to be bound by any particular theory, it is contemplated herein that, in some embodiments, attachment of pomalidomide or VHL-1 to either portion of the molecule can recruit cereblon E3 ligase or VHL E3 ligase to the JAK.

[0698] The heterobifunctional compounds disclosed herein can selectively affect JAK-mediated disease cells compared to WT (wild-type) cells (i.e., the heterobifunctional compounds can kill or inhibit the growth of JAK-mediated disease cells while also having relatively low ability to lyse or inhibit the growth of WT cells), for example, having a GI of 1.5-fold or more, 2-fold or more, 2.5-fold or more, 3-fold or more, 4-fold or more, 5-fold or more, 6-fold or more, 7-fold or more, 8-fold or more, 9-fold or more, 10-fold or more, 15-fold or more, or 20-fold or more to one or more JAK-mediated disease cells. 50 , compared to the GI of one or more WT cells (e.g., WT cells of the same species and tissue type as the JAK-mediated disease cells) 50 .

[0699] In some aspects, provided herein is a method for identifying a heterobifunctional compound that mediates JAK degradation or reduction, the method comprising: providing a heterobifunctional test compound comprising a JAK ligand conjugated to a degradation tag via a linker; contacting the heterobifunctional test compound with a cell comprising a ubiquitin ligase and a JAK; determining whether the JAK level in the cell is reduced; and identifying the heterobifunctional test compound that mediates JAK degradation or reduction as a heterobifunctional compound. In certain embodiments, the cell is a cancer cell. In certain embodiments, the cancer cell is a JAK-mediated cancer cell.

[0700] Synthesis and testing of heterobifunctional compounds

[0701] The binding affinity of the newly synthesized heterobifunctional compound can be assessed using standard biophysical assays known in the art (e.g., isothermal titration calorimetry (ITC), surface plasmon resonance (SPR)). Cellular analysis can then be used to assess the ability of heterobifunctional compound to induce JAK (e.g., JAK1, JAK2, JAK3, and TYK2) degradation and to inhibit cancer cell proliferation. In addition to assessing the induction changes of the protein levels of the heterobifunctional compound to JAK, JAK mutants, JAK deletions, or JAK fusion proteins, the enzymatic activity of protein-protein interactions or acetyltransferases can also be assessed. Applicable assays for any or all of these steps are known in the art, including, for example, western blotting, quantitative mass spectrometry (MS) analysis, flow cytometry, enzyme activity assays, ITC, SPR, cell growth inhibition, xenotransplantation, orthotopic and patient-derived xenograft models. Cell lines suitable for any or all of these steps are known in the art and include HEL, RS4; 11, MV4; 11, MOLT-4, CCRF-CEM, Kasumi-1, MM.1S, HL-60, WSU-DLCL2, Pfeiffer, and SU-DHL-1 cancer cell lines. Suitable mouse models for 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.

[0702] As non-limiting examples, detailed synthetic schemes are described in the Examples for specific exemplary heterobifunctional compounds.

[0703] Pharmaceutically acceptable isotopic 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 (substituting appropriate reagents with appropriate isotopic variants of those reagents). Specifically, an isotopic variant is a compound in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Useful isotopes are known in the art and 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.

[0704] Isotopic variants (e.g., containing 2Isotopic variants of H may offer therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In addition, certain isotopic variants (particularly those containing radioactive isotopes) are useful in drug or substrate tissue distribution studies. In particular, the radioactive isotope tritium ( 3 H) and carbon 14 ( 14 C), can be used for this purpose given their ease of binding and existing detection methods.

[0705] 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 isotopic variant (e.g., D2O instead of H2O, d6-acetone instead of acetone, or d6-DMSO instead of DMSO).

[0706] Pharmaceutically acceptable fluorinated 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 fluorinated variants of those reagents). Specifically, fluorinated variants are compounds in which at least one hydrogen atom is replaced by a fluorine atom. Fluorinated variants can provide therapeutic advantages due to greater metabolic stability (e.g., increasing half-life in vivo or reducing dosage requirements).

[0707] 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 into an ester group). As used herein, "prodrug" refers to a compound that can be converted into a therapeutic agent by some chemical or physiological process (e.g., enzymatic process and metabolic hydrolysis). Therefore, the term "prodrug" also refers to a precursor of a pharmaceutically acceptable biologically active compound. The prodrug may be inactive when administered to a subject, i.e., an ester, but is converted into an active compound in vivo, for example, by hydrolysis to a free carboxylic acid or a free hydroxyl group. Prodrug compounds generally provide 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 the active compound in vivo when such a prodrug is administered to a subject. Prodrugs of active compounds can be prepared by modifying functional groups present in the active compound in a manner that is cleaved into the parent active compound in conventional operations or in vivo. Prodrugs include compounds in which a hydroxyl, amino, or sulfhydryl group is bound to any group that, when the prodrug of the active compound is administered to a subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohols, or acetamide, formamide, and benzamide derivatives of amine functional groups in the active compound.

[0708] Characterization of exemplary heterobifunctional compounds

[0709] First, a cell viability assay was used to characterize specific exemplary heterobifunctional compounds. RS4;11ALL cells were treated with bifunctional degraders for 3 days. 50 The values ​​ranged from 2nM to 10uM. Compounds JA-093, JA-094, JA-179, JA-180, JA-182, JA-187, JA-188, JA-189, JA-196, JA-198, JA-199, JA-202, JA-203, JA-213, JA-214, JA-224, JA-225, and JA-231 showed significant cell viability inhibitory activity, IC 50 The values ​​were less than 100 nM (Table 2). JA-189 and JA-213 were further characterized in the additional cell lines shown in Table 2. Compared with JAK inhibitors (NVP-BSK805 and TG101209), JA-189 and JA-213 showed significant cell viability inhibition activity in RS4; 11, HEL, MOLT-4, CCRF-CEM, MV4; 11, Kasumi-1, MM.1S, HL-60, WSU-DLCL2, Pfeiffer and SU-DHL-1 cells (Table 3). The antiproliferative activity of compounds JA-296 to JA-340 was characterized in MV4; 11 and MOLM-13 cells (Table 4). Among them, JA-310, JA-311, JA-313, JA-315, JA-317, JA-323 and JA-325 showed significant cell viability inhibition activity.

[0710] To confirm that JA-189 and JA-213 are true JAK degraders, HEL cells were treated with these two compounds at different compound concentrations. Compared with NVP-BSK805 and DMSO controls, JA-189 and JA-213 were able to reduce JAK1, JAK2, and JAK3 protein levels and reduce downstream signaling, as evidenced by weak bands for p-STAT3 and p-STAT5 ( Figure 1 In RS4;11 cells, JA-189 and JA-213 showed better activity in reducing JAK1 and JAK3 protein levels ( Figure 2 ).

[0711] Compared with NVP-BSK805 and G101209, JA-189 and JA-213 showed significant improvement in inhibiting the viability of MV4;11, MS4;11, Kasumi-1 and HEL cell lines ( Figure 3We further demonstrated that combined treatment with pomalidomide (POM) and a degrader (JA-189 or JA-213) significantly reduced the potency of the degrader in MV4;1, MS4;11, Kasumi-1, and HEL cells ( Figure 4 Because pomalidomide competes with degraders at the CRBN binding site, its combined use with pomalidomide reduces the binding of degraders to CRBN, thereby reducing JAK protein degradation. This experiment demonstrates that the cell viability inhibition activity of the degraders JA-189 and JA-213 requires binding to CRBN.

[0712] Our results further showed that some heterobifunctional molecules, such as JA-189 and JA-213, also induced GSPT1 degradation in a dose-dependent manner ( Figure 5 ).

[0713] Furthermore, immortalized human lung fibroblasts IMR-90 and keratinocytes HACAT cells were insensitive to JA-189 and JA-213 ( Figure 6 These non-cancerous human cell growth inhibition data suggest a potential therapeutic window for these degraders.

[0714] Furthermore, JA-189, JA-263, JA-322, and JA-324 showed significant synergistic effects when combined with the FLT3 inhibitor gilteritinib to treat FLT3 mutant AML cells, such as MV4;11 and MOLM-13 cells ( Figure 7 Gilteritinib did not enhance the antiproliferative effects of JA-189 and JA-263 in wild-type FLT3 cells, such as NOMO-1 cells ( Figure 8 ). This experiment demonstrated that a GSPT1 degrader and a FLT3 inhibitor act synergistically in inhibiting the growth of cells expressing a FLT3-mutation.

[0715] We further confirmed that JA-189, JA-263, JA-322, JA-323, and JA-324 could reduce the GSPT1 protein level in MV4;11 cells ( Figure 9 ).

[0716] In addition, the AKT inhibitor MK-2206 ( Figure 10 A) and the MEK inhibitor trametinib ( Figure 10 B) It also significantly enhanced the anti-proliferative activity of GSPT1 degraders JA-189 and JA-263, indicating the potential for combined therapeutic applications of GSPT1 degraders with PI3K / AKT / mTOR pathway inhibitors or MAPK pathway inhibitors.

[0717] Definition of terms

[0718] As used herein, the terms "including" and "comprising" are used in their open, non-limiting sense.

[0719] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation. An 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, an alkyl group contains from one to fifteen carbon atoms (e.g., C1-C 15 In certain embodiments, the alkyl group contains from one to thirteen carbon atoms (e.g., C1-C 13 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 attached to the rest of the molecule by a single bond, for example, methyl (Me), ethyl (Et), n-propyl, 1-methylethyl (i-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), pentyl, 3-methylhexyl, 2-methylhexyl, and the like.

[0720] "Alkenyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one double bond. An 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, an alkenyl group contains two to twelve carbon atoms (e.g., C2-C 12 In some embodiments, the alkenyl group comprises two to eight carbon atoms (e.g., C2-C8 alkenyl). In some embodiments, the alkenyl group comprises two to six carbon atoms (e.g., C2-C6 alkenyl). In some embodiments, the alkenyl group comprises 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, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, pent-1,4-dienyl, and the like.

[0721] As used herein, the term "allyl" refers to a -CH2CH=CH2 group.

[0722] As used herein, "alkynyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one triple bond. An 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, an alkynyl group contains two to twelve carbon atoms (e.g., C2-C 12In some embodiments, the alkynyl group comprises two to eight carbon atoms (e.g., C2-C8 alkynyl). In some embodiments, the alkynyl group comprises two to six carbon atoms (e.g., C2-C6 alkynyl). In some embodiments, the alkynyl group comprises two to four carbon atoms (e.g., C2-C4 alkynyl). The alkynyl group is connected to the rest 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, etc.

[0723] As used herein, the term "alkoxy" refers to an alkyl group, as defined herein, attached to the remainder of the molecule via 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.

[0724] As used herein, the term "aryl" refers to a radical derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing hydrogen atoms from ring carbon atoms. The aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon atoms. The aryl group may 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 group contains six to fourteen carbon atoms (e.g., C6-C 14 In certain embodiments, the aryl group contains six to ten carbon atoms (e.g., C6-C 10 Examples of such groups include, but are not limited to, phenyl, fluorenyl, and naphthyl. As used herein, the terms "Ph" and "phenyl" refer to a -C6H5 group.

[0725] 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., a 3- to 18-membered heteroaryl group). As used herein, a heteroaryl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring 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 the Hückel theory. In certain embodiments, a heteroaryl group refers to a group derived from a 3- to 10-membered aromatic ring group (a 3- to 10-membered heteroaryl group). In certain embodiments, a heteroaryl group refers to a group derived from a 5- to 7-membered aromatic ring (a 5- to 7-membered heteroaryl group). Heteroaryls include fused or bridged ring systems. The heteroatoms in the heteroaryl group are optionally oxidized. One or more nitrogen atoms (if present) are optionally quaternized. The heteroaryl group is connected to the rest 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, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, etc. In certain embodiments, heteroaryl is connected to the rest of the molecule via a ring carbon atom. In certain embodiments, heteroaryl is connected to the rest of the molecule via a nitrogen atom (N- connected) or a carbon atom (C- connected). For example, a group derived from pyrrole can be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). For example, a group derived from imidazole can be imidazol-1-yl (N-attached) or imidazol-3-yl (C-attached).

[0726] As used herein, the term "heterocyclyl" refers to a non-aromatic, monocyclic, bicyclic, tricyclic or tetracyclic group having a total of 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 atoms in its ring system and containing 3 to 12 (such as 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms and 1 to 4 (such as 1, 2, 3 or 4) heteroatoms independently selected from O, S and N, with the proviso that the ring of the group does not contain two adjacent O atoms or two adjacent S atoms. The heterocyclyl group may include a fused ring, a bridged ring or a spiro ring system. In certain embodiments, the heterocyclyl group includes 3 to 10 ring atoms (3-10 membered heterocyclyl). In certain embodiments, the heterocyclyl group includes 3 to 8 ring atoms (3-8 membered heterocyclyl). In certain embodiments, the heterocyclyl group includes 3 to 10 ring atoms (3-10 membered heterocyclyl). In certain embodiments, the heterocyclic group includes 3 to 8 ring atoms (3-8 membered heterocyclic groups). The heterocyclic group can include an oxo substituent on any available atom that can produce a stable compound. For example, such a group can include an oxo group at an available carbon atom or nitrogen atom. If chemically feasible, such a group can include more than one oxo group. In addition, it should be understood that when such a heterocyclic group contains a sulfur atom, the sulfur atom can be oxidized by one or two oxygen atoms to provide a sulfoxide or sulfone. An example of a 4-membered heterocyclic group is azetidinyl (derived from azetidine). An example of a 5-membered cycloheteroalkyl group is pyrrolidinyl. An example of a 6-membered cycloheteroalkyl group is piperidinyl. An example of a 9-membered cycloheteroalkyl group is indolinyl. An example of a 10-membered cycloheteroalkyl group is 4H-quinolinyl. Other examples of such heterocyclic groups include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidine, morpholine, thiomorpholine, oxathianyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl ] heptyl, 3H-indolyl, quinolyl, 3-oxopiperazinyl, 4-methylpiperazinyl, 4-ethylpiperazinyl and 1-oxo-2,8, diazaspiro [4.5] ten-decane-8-yl. Heteroaryl can be connected to the rest of the molecule by a carbon atom (C-connection) or a nitrogen atom (N-connection). For example, the group derived from piperazine can be piperazine-1-yl (N-connection) or piperazine-2-yl (C-connection).

[0727] The term "cycloalkyl" or "carbocyclyl" 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 spirocyclic. In certain embodiments, cycloalkyl includes 3 to 8 carbon ring atoms (3-8 membered carbocyclyl). In certain embodiments, cycloalkyl includes 3 to 10 carbon ring atoms (3-10 membered carbocyclyl). Examples of such groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptyl, adamantyl, etc.

[0728] The term "cycloalkylene" is a bidentate group obtained by removing a hydrogen atom from a cycloalkyl group as defined above. Examples of such groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclopentenylene, cyclohexylene, cycloheptylene, and the like.

[0729] As used herein, the term "spirocyclic" has its conventional meaning, i.e., any ring system comprising two or more rings, wherein both rings have one common ring carbon. As defined herein, each ring of a spirocyclic system independently comprises from 3 to 20 ring atoms. Preferably, it has from 3 to 10 ring atoms. Non-limiting examples of spirocyclic systems include spiro[3.3]heptane, spiro[3.4]octane, and spiro[4.5]decane.

[0730] The term "cyano" refers to a -C≡N group.

[0731] An "aldehyde" group refers to a -C(O)H group.

[0732] "Alkoxy" refers to an -O-alkyl group, as defined herein.

[0733] "Alkoxycarbonyl" refers to a -C(O)-alkoxy group, as defined herein.

[0734] "Alkylaminoalkyl" refers to an -alkyl-NR-alkyl group, as defined herein.

[0735] "Alkylsulfonyl" refers to a -SO2 alkyl group, as defined herein.

[0736] "Amino" refers to an optionally substituted -NH2.

[0737] "Aminoalkyl" means an -alkyl-amino group, as defined herein.

[0738] "Aminocarbonyl" refers to a -C(O)-amino group, as defined herein.

[0739] "Arylalkyl" means an -alkylaryl group in which alkyl and aryl are as defined herein.

[0740] An "aryloxy" group refers to both -O-aryl and -O-heteroaryl groups, as defined herein.

[0741] "Aryloxycarbonyl" means a -C(O)-aryloxy group, as defined herein.

[0742] "Arylsulfonyl" means a -SO2 aryl group, as defined herein.

[0743] "Carbonyl" means a -C(O)- group, as defined herein.

[0744] A "carboxylic acid" group refers to a -C(O)OH group.

[0745] "Cycloalkoxy" refers to an -O-cycloalkyl group, as defined herein.

[0746] A "halo" or "halogen" group refers to fluoro, chloro, bromo, or iodo.

[0747] "Haloalkyl" refers to an alkyl group substituted with one or more halogen atoms.

[0748] "Hydroxy" refers to an -OH group.

[0749] A "nitro" group refers to a -NO2 group.

[0750] An "oxo" group refers to a =0 substituent.

[0751] "Trihalomethyl" refers to a methyl group substituted with three halogen atoms.

[0752] When referring to a moiety, the term "length" refers to the minimum number of carbon and / or heteroatoms from one end of the moiety to its 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. This applies whether the linker is linear or branched, as well as when the linker contains a ring system.

[0753] The term "substituted" means that the designated group or moiety bears one or more substituents independently selected from the group consisting of C1-C4 alkyl, aryl, heteroaryl, arylC1-C4 alkyl-, heteroarylC1-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 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).

[0754] The term "absent" refers to the absence of an atom or moiety and the presence of bonds between adjacent atoms in the structure.

[0755] The term "optionally substituted" means that the specified 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 "substituted" with a group that is less than the valence of all atoms in the compound, the remaining valences of the group are filled with hydrogen. For example, if a C6 aryl group, 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 and one additional substituent to which the rest of the compounds of the present invention are attached, leaving 4 positions open). In this case, each of the remaining 4 carbon atoms is combined with a hydrogen atom to fill their valences. Similarly, if a C6 aryl group in a compound 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 group has 3 unsubstituted remaining carbon atoms. Each of these three unsubstituted carbon atoms is combined with a hydrogen atom to fill their valences. Unless otherwise indicated, an optionally substituted group may be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, CN, NO2, OR m 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 heterocyclyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl and heteroaryl, wherein R m 、R n and R o are independently selected from: none, hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloalkyl, 3-7 membered heterocyclyl, aryl and heteroaryl, or R n and R oTogether with the atoms to which they are attached, they form a 3-8 membered cycloalkyl ring or heterocyclyl ring.

[0756] As used herein, the same symbols in different formulas represent different definitions. For example, in Formula 1, R 1 The definition of is the same as that of formula 1. In formula 6, R 6 The definition of corresponds to the definition of formula 6.

[0757] As used herein, each unit in the linker portion (e.g., They may be identical to or different from one another. In certain embodiments, each unit in the linker portion is identical to one another.

[0758] As used herein, when m (or n or o or p) is defined by a range, for example, "m is 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.

[0759] "Pharmaceutically acceptable salts" include both 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.

[0760] "Pharmaceutically acceptable acid addition salts" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like, as well as salts including, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Thus, exemplary salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, toluate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, malate, tartrate, methanesulfonate, and the like. Also contemplated are salts of amino acids such as arginate, gluconate, and galacturonate (see, e.g., Berge SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66: 1-19 (1997), which is incorporated herein 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 to produce the salt according to methods and techniques familiar to the skilled artisan.

[0761] "Pharmaceutically acceptable base addition salts" refer to those salts that retain the biological effectiveness and properties of the free acids and are not biologically or otherwise undesirable. These salts are prepared by the addition of inorganic or organic bases to the free acids. 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, and the like. 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, ethylenediphenylamine, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. See Berge et al., supra.

[0762] Pharmaceutical composition

[0763] In some aspects, the compositions and methods described herein include the manufacture and use of pharmaceutical compositions and medicaments comprising one or more heterobifunctional compounds disclosed herein. Also included are the pharmaceutical compositions themselves.

[0764] 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 may be combined with one or more (e.g., one, two, three, four, five or less than ten) compounds. Such additional compounds may include, for example, conventional chemotherapeutic agents or any other cancer treatment known in the art. When co-administered, the heterobifunctional compounds disclosed herein may act in conjunction with conventional chemotherapeutic agents or any other cancer treatment known in the art to produce a mechanical additive or synergistic therapeutic effect.

[0765] In some aspects, the pH of the compositions disclosed herein can be adjusted with pharmaceutically acceptable acids, bases, or buffers to enhance the stability of the heterobifunctional compound or its delivery form.

[0766] Pharmaceutical compositions typically include a pharmaceutically acceptable excipient, adjuvant, or carrier. As used herein, the phrase "pharmaceutically acceptable" refers to molecular entities and compositions that are generally considered to be physiologically tolerable and that generally do not produce allergic or similar adverse reactions, such as stomach upset, dizziness, etc., when administered to humans. Pharmaceutically acceptable excipients, adjuvants, or carriers are substances that can be administered to patients together with the compounds of the present invention and do not impair their pharmacological activity and are non-toxic when administered in a dose sufficient to deliver a therapeutic 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 agents, and absorption delaying agents that are compatible with drug administration.

[0767] In particular, pharmaceutically acceptable excipients, adjuvants and carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopheryl polyethylene glycol 1000 succinate, surfactants for pharmaceutical dosage forms such as Tween or other similar polymer delivery matrices, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and lanolin. Cyclodextrins such as α-, β- and γ-cyclodextrins can also be advantageously used to enhance the delivery of compounds of the formula described herein.

[0768] 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 also typically added. For oral administration in capsule form, useful diluents include lactose and dry corn starch. When an aqueous suspension or emulsion is administered orally, the active ingredient can be suspended or dissolved in an oil phase and mixed with an emulsifier or suspending agent. If desired, certain sweeteners, flavorings, or coloring agents can be added.

[0769] As used herein, heterobifunctional compounds disclosed herein are defined as including pharmaceutically acceptable derivatives or prodrugs thereof. "Pharmaceutically acceptable derivatives" refers to any pharmaceutically acceptable salt, solvate or prodrug of a compound or medicament disclosed herein, such as a carbamate, ester, phosphate, salt or other derivative of an ester, which can provide (directly or indirectly) a compound as described herein or its active metabolite or residue after being administered to a recipient. Particularly preferred derivatives and prodrugs are compounds disclosed herein that increase the bioavailability of the compound disclosed herein when administered to a subject (e.g., by making the orally administered compound more readily absorbed into the blood) or enhance the delivery of the parent compound to a biological compartment (e.g., brain or lymphatic system) relative to the parent species. Preferred prodrugs include derivatives that are groups that enhance water solubility or active transport through the intestinal membrane attached to the formula structure described herein. Those skilled in the art can identify such derivatives without excessive experimentation. Nevertheless, reference is made to Burger's Medicinal Chemistry and Drug Discovery, 5th edition, Volume 1: Principles and Practices, which is incorporated herein by reference within the scope of teaching such derivatives.

[0770] The heterobifunctional compounds disclosed herein include pure enantiomers, mixtures of enantiomers, pure diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates and meso forms, and pharmaceutically acceptable salts, solvate complexes, morphological forms, or deuterated derivatives thereof.

[0771] In some aspects, the pharmaceutical compositions disclosed herein may comprise an effective amount of one or more heterobifunctional compounds. As used herein, the terms "effective amount" and "effective treatment" refer to the amount or concentration of one or more compounds or pharmaceutical compositions described herein that effectively causes a desired effect or physiological result (e.g., treatment or prevention of cell growth, cell proliferation, or cancer) within the scope of its administration over a period of time (including acute or chronic administration and regular or continuous administration). In some aspects, the pharmaceutical composition may further comprise one or more additional compounds, drugs, or agents (e.g., conventional chemotherapeutics) for the treatment of cancer in an amount effective to cause a desired effect or physiological result (e.g., treatment or prevention of cell growth, cell proliferation, or cancer).

[0772] In some aspects, the pharmaceutical compositions disclosed herein can be formulated for sale in, imported into, or exported from the United States.

[0773] Administration of the pharmaceutical composition

[0774] Pharmaceutical compositions disclosed herein can be formulated or adjusted for administration to a subject by any approach such as that 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, pharmaceutical compositions can be formulated for oral, parenteral or transdermal delivery. As used herein, the term "parenteral" includes subcutaneous, intradermal, intravenous, intramuscular, intraperitoneal, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.

[0775] 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 via an implanted reservoir), or ophthalmically.

[0776] For example, the pharmaceutical compositions of the present invention can be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions, and solutions.

[0777] For example, the pharmaceutical compositions of the present invention can be administered in the form of suppositories for rectal administration. 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 therefore melt in the rectum to release the active ingredient. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

[0778] 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 formulation and can be prepared as saline solutions, using benzyl alcohol or other suitable preservatives, absorption enhancers to increase bioavailability, fluorocarbons or other solubilizing or dispersing agents known in the art.

[0779] For example, the pharmaceutical compositions of the present invention can be administered by injection (e.g., as a solution or powder). Such compositions can be formulated according to techniques known in the art using suitable dispersants or wetting agents (e.g., Tween 80) and suspending agents. Sterile injectable preparations can also be sterile injectable solutions or suspensions in a nontoxic, parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Among acceptable carriers and solvents, mannitol, water, Ringer's solution, and isotonic sodium chloride solution can be used. In addition, sterile, fixed oils are commonly used as solvents or suspending media. For this purpose, any bland fixed oil can be used, including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives, can be used to prepare injectable preparations, as can natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially their polyoxyethylated forms. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, or carboxymethylcellulose or similar dispersants, 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 that are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

[0780] In some aspects, 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 0.5, 1.5, 2.5, 3.5, 4.5, 5.0, 6.5, 7.5, 8.5, 9.5, 10.0, 15.0, 20.0, 30.0, 40.0, 50.0, 60.0, 70.0, 80.0, 90.0, 100.0, 200.0, 300.0, 400.0, 500.0, 600.0, 700.0, 800.0, 900.0, 1000.0, 2500.0, 5000, or 10000 mg / kg / day, or as required for a particular pharmaceutical composition.

[0781] When the pharmaceutical compositions disclosed herein comprise a heterobifunctional compound described herein and one or more additional compounds (e.g., one or more additional compounds, drugs, or agents that are useful in treating cancer or any other condition or disease, including conditions or diseases known to be associated with or caused by cancer), the dosage levels of both the heterobifunctional compound and the additional compound can be between about 1% and 100%, more preferably between about 5% and 95% of the dose typically administered as a single-drug treatment regimen. The additional agent can be administered separately from the compounds of the invention as part of a multiple-dose regimen. Alternatively, these agents can be part of a single dosage form, mixed with the compounds of the invention in a single composition.Such additional compounds may preferably be kinase inhibitors, specifically, FLT3 pathway inhibitors (such as Gilteritinib, Midostaurin, Sorafenib, Sunitinib, Lestaurtinib), MAPK pathway inhibitors, RAS-RAF-MEK-ERK pathway inhibitors (e.g., Vemurafenib), Dabrafenib, ); Encorafenib, SB590885, PLX4720, XL281, RAF265, Trametinib, Binimetinib, Cobimetinib, Selumetinib, CI-1040, PD0325901, and PI3K-AKT-mTOR pathway inhibitors or agonists (e.g., Apitolisib, Idralixib, Idelalisib, Copanlisib, Duvelisib, MK-2206, ARQ-092, Gedatolisib, Apitolisib, VQD-002, Perifosine, AZD5363, Ipatasertib, Rapamycin, Temsirolimus, Everolimus, ridaforolimus, Rapalogs, sirolimus, dactolisib, BGT226, SF1126, PKI-587, NVPBE235, sapanisertib, AZD8055, AZD2014, wortmannin, LY294002, hibiscone C, taselisib, perifosine, buparlisib, umbralisib, PX-866, dactolisib, CUDC-907, voxtalisib, bisper oxovanadium, sarcopoterium.

[0782] In some aspects, a pharmaceutical composition disclosed herein may be included in a container, pack, or dispenser together with instructions for administration.

[0783] Treatment

[0784] Method disclosed herein contemplates administering an effective amount of a compound or composition to achieve the desired or prescribed effect. Typically, the compound or composition of the present invention is administered daily for approximately 1 to approximately 6 times, or, or, or in addition, as a continuous infusion. This administration can be used as a chronic or acute treatment. The amount of the active ingredient that can be combined with a carrier material to produce a single dosage form will vary according to the host being treated and a specific mode of administration. Typical preparations will contain approximately 5% to approximately 95% active compound (w / w). Alternatively, such preparations can include approximately 20% to approximately 80% active compound.

[0785] In some aspects, provided herein are heterobifunctional compounds described herein for use in preventing or treating a disease or disorder.

[0786] In some aspects, provided herein are heterobifunctional compounds as described herein for use in treating or preventing one or more diseases or conditions disclosed herein in a subject in need thereof. In certain embodiments, the disease or condition is a JAK-mediated disease or condition. In certain embodiments, the disease or condition is caused by JAK 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 JAK-mediated cancer is selected from the group consisting of brain cancer, stomach cancer, gastrointestinal cancer, liver cancer, biliary tract cancer, breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, penile cancer, genitourinary tract 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 neoplasms, essential thrombocythemia, polycythemia vera, primary myelofibrosis, chronic neutrophilic leukemia, acute lymphocytic leukemia, Hodgkin lymphoma, chronic myelomonocytic leukemia, systemic mast cell disease, hypereosinophilic syndrome, cutaneous T-cell lymphoma, B-cell lymphoma, and myeloma. In one embodiment, the JAK-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 JAK-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 JAK-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 JAK-mediated viral infection is selected from the group consisting of infection 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). In one embodiment, the JAK-mediated dry eye disease is selected from the group consisting of dry eye syndrome (DES) and keratoconjunctivitis sicca (KCS). In one embodiment, the JAK-mediated bone remodeling disorder is selected from the group consisting of osteoporosis and osteoarthritis. In one embodiment, the JAK-mediated organ transplant-related immune complication is selected from the group consisting of graft-versus-host disease.

[0787] In some aspects, provided herein is the use of a heterobifunctional compound in the preparation of a medicament for preventing or treating one or more diseases or conditions disclosed herein.

[0788] In some aspects, the disclosed methods include administering a therapeutically effective amount of one or more compounds or compositions described herein to a subject (e.g., a mammalian subject, such as a human subject) who is in need 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 compounds or compositions described herein, and optionally repeating the administration as needed to prevent or treat cancer.

[0789] In some respects, the selection of subject can include obtaining sample from subject (such as candidate subject) and being suitable for the indication test sample of selecting for subject.In some respects, can, for example, by health care professional, confirm or identify subject as having suffered from, having elevated risk and will suffer from or suffering from certain illness or disease.In some respects, suitable subject includes, for example, suffers from or once suffered from illness or disease but solved the subject of this disease or its aspect, presents the subject of disease symptom alleviation (for example relative to other subjects (such as most subjects) suffering from same illness or disease), or survives long time in illness or disease (for example, relative to other subjects (such as, most subjects) suffering from same illness or disease), for example, is in asymptomatic state (for example, relative to other subjects (such as, most subjects) suffering from same illness or disease).In some respects, the demonstration for the positive immune response of illness or disease can be made by patient record, family history or the indication of detecting positive immune response.In some respects, subject selection can be multi-party participation.For example, the first party can obtain sample from candidate subject, and the second party can test this sample.In some respects, subject can be selected or mentioned by medical practitioner (for example, general practitioner). In some aspects, 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, for example, a cell or a cell population.

[0790] In some aspects, methods of treatment may include the need for preventing or treating a disease or condition disclosed herein (e.g., a JAK-mediated disease), single administration, multiple administration, and repeated administration of one or more compounds disclosed herein. In some aspects, methods of treatment may include assessing the disease level of a subject before, during, or after treatment. In some aspects, treatment may continue until a reduction in the disease level of the subject is detected.

[0791] 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).

[0792] As used herein, the terms "administer," "apply," or "administering" 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 prescribed effect.

[0793] As used herein, the terms "treat," "treated," or "therapy" refer to partial or complete alleviation, inhibition, amelioration, or alleviation of a disease or condition suffered by a subject. This means any manner in which one or more symptoms of a disease or condition (e.g., cancer) are ameliorated or otherwise beneficially altered. As used herein, improvement of the symptoms of a particular condition (e.g., cancer) refers to any alleviation, whether permanent or temporary, long-lasting or transient, attributable to or associated with treatment with the heterobifunctional compounds, compositions, and methods of the invention. 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 before 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 before treatment; a decrease in the growth rate of tumor cells; a decrease in the rate of local or distant tumor metastasis; or a reduction in one or more symptoms associated with one or more tumors compared to the subject's symptoms before treatment.

[0794] As used herein, the terms "prevent," "preventing," and "prophylaxis" shall refer to a reduction in the occurrence of a disease in a subject or a reduction in the risk of developing a disease or its associated symptoms. Prevention can be complete, e.g., the complete absence of disease or pathological cells in the subject. Prevention can also be partial, such that the occurrence of disease or pathological cells in the subject is less, occurs later, or progresses more slowly than would occur in the absence of the present invention. In certain embodiments, the subject is at increased risk for one or more JAK-mediated diseases. Exemplary JAK-mediated diseases that can be treated with heterobifunctional compounds include, for example, cancer (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 tract cancer, esophageal cancer, laryngeal cancer, skin cancer, lung cancer, pancreatic cancer, thyroid cancer, adenocarcinoma, bladder cancer, kidney cancer, muscle cancer, bone cancer, and hematopoietic cancers such as myeloproliferative neoplasms, including essential thrombocythemia, polycythemia vera, primary myelofibrosis, chronic neutrophilic leukemia , acute lymphoblastic leukemia, Hodgkin lymphoma, chronic myelomonocytic leukemia, systemic mast cell disease, hypereosinophilic syndrome, cutaneous T-cell lymphoma, B-cell lymphoma, myeloma, and other hematologic malignancies, particularly those involving inflammation, mutations, or aberrations that activate the JAK pathway); inflammatory (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 mellitus, 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 infections (e.g., viral infections and their attendant complications, such as 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 (e.g., osteoporosis and osteoarthritis); and immune complications associated with organ transplantation (e.g., graft-versus-host disease).

[0795] 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, the age, weight, general health, sex, diet, time of administration, rate of excretion, drug combinations, the severity and course of the disease, disorder or symptom, the patient's predisposition to the disease, disorder or symptom, and the judgment of the treating physician.

[0796] The effective amount can be administered in one or more administrations, one or more applications, or one or more doses. The therapeutically effective amount (i.e., effective dose) of the therapeutic compound depends on the selected therapeutic compound. In addition, treating a subject with a therapeutically effective amount of a compound or composition as described herein can include a single treatment or a series of treatments. For example, an 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. It will be understood by those skilled in the art that certain factors may affect the dosage and time required to effectively treat the subject, including but not limited to the severity of the disease or condition, previous treatment, the general health or age of the subject, and other diseases present.

[0797] After administration, the subject can be assessed to detect, evaluate or determine their disease level. In some cases, treatment can continue until a change (such as a reduction) in the subject's disease level is detected. After the patient's condition improves (for example, the subject's disease level changes (for example, decreases)), if necessary, a maintenance dose of a compound or composition disclosed herein can be administered. Subsequently, the dosage or frequency of administration or both can be reduced (for example, as a function of symptoms) to a level that maintains the improved condition. However, once any disease symptoms recur, the patient may need long-term intermittent treatment.

[0798] The present disclosure is further described and demonstrated by the following examples. However, the use of these and other examples anywhere in the specification is illustrative only and in no way limits the scope and meaning of the present invention or any exemplary term. Likewise, the present invention is not limited to any particular preferred embodiment or aspect described herein. Indeed, many modifications and variations will be apparent to those skilled in the art upon reading this specification, and such changes may be made without departing from the spirit or scope of the present invention. Therefore, the present invention is limited only by the terms of the appended claims and the full scope of equivalents to which those claims are entitled.

[0799] Combination therapy

[0800] The present invention contemplates the use of the heterobifunctional compounds disclosed herein in combination with one or more additional therapeutic agents (or second therapeutic agents) such as those described above, or other prophylactic or therapeutic modalities such as radiation. In such combination therapies, the various additional agents typically have different, complementary mechanisms of action. Such combination therapies are particularly advantageous in that they can reduce or eliminate side effects associated with one or more agents by allowing the dosage of one or more agents to be reduced. In addition, such combination therapies may have a synergistic therapeutic or prophylactic effect on the underlying disease, disorder, or condition.

[0801] As used herein, "combination" is meant to include therapies that can be administered separately, e.g., separately formulated for separate administration (e.g., as may be provided in a kit) as well as therapies that can be administered together in a single formulation (i.e., a "co-formulation").

[0802] In certain embodiments, the heterobifunctional compounds disclosed herein are administered or used sequentially, e.g., one agent is administered prior to one or more other agents. In other embodiments, the heterobifunctional compounds are administered simultaneously, e.g., two or more drugs are administered simultaneously or approximately simultaneously; the two or more agents may be present as two or more separate formulations or combined into a single formulation (i.e., a co-formulation). Regardless of whether the two or more agents are administered sequentially or simultaneously, they are considered to be administered in combination for the purposes of the present invention.

[0803] In this case, the heterobifunctional compounds disclosed herein can be used in combination with at least one additional agent in any suitable manner. In one embodiment, treatment with at least one additional agent and at least one heterobifunctional compound disclosed herein is maintained over a period of time. In a further embodiment, treatment with the at least one additional agent is reduced or discontinued (e.g., when the subject is stable), while treatment with the heterobifunctional compound disclosed herein is maintained at a constant dosing regimen. In a further embodiment, treatment with at least one additional agent is reduced or discontinued (e.g., when the subject is stable), while treatment with the heterobifunctional compound disclosed herein is reduced (e.g., lower dose, less frequent dosing, or shorter treatment regimen). In another embodiment, treatment with at least one additional agent is reduced or discontinued (e.g., when the subject is stable), while treatment with the heterobifunctional compound disclosed herein is increased (e.g., higher dose, more frequent dosing, or longer treatment regimen). In yet another embodiment, treatment with at least one additional agent is maintained, and treatment with the heterobifunctional compound disclosed herein is reduced or discontinued (e.g., lower dose, less frequent dosing, or shorter treatment regimen). In yet another embodiment, treatment with at least one active agent and treatment with the heterobifunctional compound disclosed herein is reduced or discontinued (eg, lower dose, less frequent dosing, or shorter treatment regimen).

[0804] Reagent test kit

[0805] The present invention also contemplates kits and pharmaceutical compositions comprising the heterobifunctional compounds disclosed herein. As described below, a kit is generally in the form of a physical structure that houses the various components and can be used, for example, to perform the methods described above.

[0806] The kit may include one or more heterobifunctional compounds described herein (e.g., provided in a sterile container), which may be in the form of a pharmaceutical composition suitable for administration to a subject. The heterobifunctional compounds described herein may be provided in a ready-to-use form (e.g., tablets or capsules) or in a form that requires, for example, reconstitution or dilution prior to administration (e.g., powder). When the heterobifunctional compounds described herein are in a form that requires reconstitution or dilution by the user, the kit may further include a diluent (e.g., sterile water), a buffer, a pharmaceutically acceptable excipient, etc., packaged together with or separately from the heterobifunctional compounds described herein. When combination therapy is contemplated, the kit may contain several agents individually, or they may already be combined in the kit. Each component of the kit may be contained in a separate container, and all of the various containers may be in a single package. The kits of the present invention may be designed to appropriately maintain the conditions required for the components contained therein (e.g., refrigeration or freezing). The kit may include one or more additional agents described herein.

[0807] The kit may include a label or package insert that includes identifying information about the components and instructions for their use (e.g., dosage parameters, clinical pharmacology of the active ingredient, including mechanism of action, pharmacokinetics and pharmacodynamics, adverse effects, contraindications, etc.). The label or package insert may include manufacturer information, such as batch number and date of manufacture. The label or package insert may, for example, be integrated into the physical structure that houses the components, be contained separately within the physical structure, or be attached to a component of the kit (e.g., an ampoule, tube, or vial).

[0808] The label or insert may additionally be included or incorporated into a computer-readable medium such as a magnetic disk (e.g., hard disk, card, memory disk), an optical disk (e.g., CD or DVD-ROM / RAM), a DVD, an MP3, a magnetic tape, or a combination of these, an electronic storage medium such as RAM and ROM, or a magnetic / optical storage medium, a FLASH medium, or a memory-type storage card. In some embodiments, the actual instructions are not included in the kit, but a means for obtaining instructions from a remote source, e.g., via the Internet, is provided. Example

[0809] Example 1: 4-((2-aminoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 1)

[0810]

[0811] In a microwave reactor, a solution of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (1.66 g, 6.0 mmol), tert-butyl (2-aminoethyl)carbamate (1.25 g, 6.6 mmol), and N,N-diisopropylethylamine (2.32 g, 18 mmol) in DMF (12 mL) was heated to 85°C for 50 min. The three batches were combined and diluted with EtOAc (200 mL). The reaction was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane / EtOAc = 1:1) to give tert-butyl (2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)ethyl)carbamate (1.3 g, 16% yield) as a yellow solid. MS (ESI) m / z = 317.1 [M-100 + H] +A solution of tert-butyl (2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)carbamate (2.0 g, 4.5 mmol) in DCM (10 mL) and TFA (5 mL) was stirred at room temperature for 2 h. The reaction was concentrated and triturated with EtOAc. The solid precipitate was filtered, washed with MTBE, and dried to give 4-((2-aminoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione as a yellow solid (Linker 1) (1.3 g, 98% yield). 1 H NMR (400MHz, DMSO-d6) δ11.14(s,1H),7.85(s,3H),7.45(t,J=7.2Hz,1H),7.19(d,J=7.2Hz,1H),7.10(d,J=7.2Hz,1H),6.84(t,J=6.4Hz,1H),5. 07(dd,J=5.2,12.8Hz,1H),3.58(q,J=6.4Hz,2H),3.00(s,2H),2.94–2.8 5(m,1H),2.62–2.50(m,2H),2.05–2.00(m,1H).MS(ESI)m / z=317.1[M+H] + .

[0812] Example 2: 4-((3-aminopropyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 2)

[0813]

[0814] Linker 2 was synthesized according to the same procedure as Linker 1 described in Example 1 (1.2 g, yield: 89%). 1 H NMR (400MHz, DMSO-d6) δ11.11(s,1H),7.74(s,3H),7.62–7.58(m,1H),7.15(d,J=8.4Hz,1H),7.05(d,J=7.2Hz,1H),6.78–6.75(m,1H),5. 08–5.04(m,1H),3.43–3.36(m,2H),2.90–2.86(m,3H),2.62–2.51(m,2H),2.08–2.01(m,1H),1.86–1.80(m,2H).MS(ESI)m / z=331.1[M+H] + .

[0815] Example 3: 4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 3)

[0816]

[0817] Linker 3 was synthesized according to the same procedure as Linker 1 described in Example 1 (1.4 g, yield: 93%). 1 H NMR (400MHz, DMSO-d6) δ11.11(s,1H),7.84(s,3H),7.62–7.57(m,1H),7.13(d,J=8.4Hz,1H),7.04(d,J=6.8Hz,1H),6.62(s,1H),5. 08–5.04(m,1H),3.34(s,2H),2.90–2.83(m,3H),2.62–2.51(m,2H),2.06–2.01(m,1H),1.65–1.60(m,4H).MS(ESI)m / z=345.1[M+H] + .

[0818] Example 4: 4-((5-aminopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 4)

[0819]

[0820] Linker 4 was synthesized according to the same procedure as Linker 1 described in Example 1 (2.3 g, yield: 85%). 1 H NMR (400MHz, DMSO-d6) δ11.14(s,1H),7.72(s,3H),7.61–7.57(m,1H),7.10(d,J=8.4Hz,1H),7.03(d,J=7.2Hz,1H),6.56–6.53(m,1H),5.07–5.03( m,1H),3.32–3.28(m,2H),2.90–2.78(m,3H),2.62–2.51(m,2H),2.05–1. 90(m,1H),1.62–1.54(m,4H),1.41–1.37(m,2H).MS(ESI)m / z=359.1[M+H] + .

[0821] Example 5: 4-((6-aminohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 5)

[0822]

[0823] Linker 5 was synthesized according to the same procedure as Linker 1 described in Example 1 (1.8 g, yield: 67%).1 H NMR(400MHz,DMSO-d6)δ11.10(s,1H),7.76(s,3H),7.58(t,J=7.2Hz,1H),7 .10(d,J=8.4Hz,1H),7.03(d,J=7.2Hz,1H),6.54(t,J=6.0Hz,1H),5.07–5. 03(m,1H),3.37–3.27(m,2H),2.88–2.78(m,3H),2.61–2.50(m,2H),2.04–2 .01(m,1H),1.57–1.52(m,4H),1.40–1.30(m,4H).MS(ESI)m / z=373.1[M+H] + .

[0824] Example 6: 4-((7-aminoheptyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 6)

[0825]

[0826] Linker 6 was synthesized according to the same procedure as Linker 1 described in Example 1 (2.0 g, yield: 94%). 1 H NMR(400MHz, DMSO-d6)δ11.05(br,1H),7.94–7.56(m,4H),7.10–7.02(m,2H),6.52(t,J=6.0Hz,1H),5.07–5.02(m,1H),3.32–3.27(m,2H), 2.88–2.77(m,1H),2.75–2.61(m,2H),2.60–2.50(m,2H),2.04–2.02(m,1H),1.59–1.50(m,4H),1.35–1.30(m,6H).MS(ESI)m / z=387.2[M+H] + .

[0827] Example 7: 4-((8-aminooctyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 7)

[0828]

[0829] Linker 7 was synthesized according to the same procedure as that of Linker 1 described in Example 1 (1.1 g, yield: 61%). 1H NMR (400MHz, DMSO-d6) δ11.10(s,1H),7.69–7.56(m,4H),7.09(d,J=8.4Hz,1H),7.03(d,J=6.8Hz,1H),6.52(t,J=6.0Hz,1H),5.07–5.03(m,1H),3.3 4–3.26(m,2H),2.89–2.85(m,1H),2.76(s,2H),2.61–2.56(m,2H),2.04–2 .00(m,1H),1.59–1.49(m,4H),1.35–1.27(m,8H).MS(ESI)m / z=401.2[M+H] + .

[0830] Example 8: 4-((2-(2-aminoethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 8)

[0831]

[0832] Linker 8 was synthesized according to the same procedure as Linker 1 described in Example 1 (2.0 g, yield: 94%). 1 H NMR (400MHz, DMSO-d6) δ10.10(s,1H),7.88(s,3H),7.60(t,J=8.0Hz,1H),7. 17(d,J=8.4Hz,1H),7.06(d,J=6.8Hz,1H),6.40(d,J=5.6Hz,1H),5.05(dd,J= 5.2,12.8Hz,1H),3.67–3.62(m,4H),3.54–3.50(m,2H),3.00(s,2H),2.90–2. 85(m,1H),2.62–2.50(m,2H),2.03(t,J=7.6Hz,1H).MS(ESI)m / z=361.1[M+H] + .

[0833] Example 9: 4-((2-(2-(2-aminoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 9)

[0834]

[0835] Linker 9 was synthesized according to the same procedure as that of Linker 1 described in Example 1 (1.1 g, yield: 82%). 1H NMR (400MHz, DMSO-d6) δ11.11(s,1H),7.84(s,3H),7.62–7.58(m,1H),7.15(d,J=8.8Hz,1H),7.05(d,J=6.8Hz,1H),6.62–6.59(m,1H),5. 08–5.04(m,1H),3.65–3.59(m,8H),3.50–3.46(m,2H),2.97–2.86(m,3H),2.62–2.51(m,2H),2.05–1.99(m,1H).MS(ESI)m / z=405.2[M+H] + .

[0836] Example 10: 4-((2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 10)

[0837]

[0838] The same procedure as described for connector 1 in Example 1 was followed to synthesize connector 10 (1.3 g, yield: 70%). 1 HNMR (400MHz, DMSO-d6) δ11.11(s,1H),7.83(s,3H),7.61–7.57(m,1H),7.15(d,J=8.8Hz,1H),7.05(d,J=6.8Hz,1H),6.62–6.59( m,1H),5.08–5.04(m,1H),3.64–3.45(m,14H),2.97–2.86(m,3H),2.62–2.51(m,2H),2.08–2.01(m,1H).MS(ESI)m / z=449.2[M+H] + .

[0839] Example 11: 4-((14-amino-3,6,9,12-tetraoxatetradecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 11)

[0840]

[0841] Linker 11 was synthesized according to the same procedure as that of linker 1 described in Example 1 (1.2 g, yield: 89%). 1HNMR (400MHz, DMSO-d6) δ11.11(s,1H),7.84(s,3H),7.61–7.57(m,1H),7.15(d,J=8.8Hz,1H),7.05(d,J=6.8Hz,1H),6.61(s, 1H),5.08–5.04(m,1H),3.64–3.47(m,18H),2.99–2.86(m,3H),2.62–2.51(m,2H),2.08–2.01(m,1H).MS(ESI)m / z=493.2[M+H] + .

[0842] Example 12: 4-((17-amino-3,6,9,12,15-pentaoxaheptadecanyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 12)

[0843]

[0844] Linker 12 was synthesized according to the same procedure as that of Linker 1 described in Example 1 (1.2 g, yield: 86%). 1 HNMR (400MHz, DMSO-d6) δ11.11(s,1H),7.82(s,3H),7.61–7.57(m,1H),7.15(d,J=8.4Hz,1H),7.05(d,J=7.2Hz,1H),6.61–6.59( m,1H),5.08–5.03(m,1H),3.64–3.47(m,22H),3.00–2.86(m,3H),2.62–2.51(m,2H),2.05–2.02(m,1H).MS(ESI)m / z=537.2[M+H] + .

[0845] Example 13: (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycine (Linker 13)

[0846]

[0847] Linker 13 was synthesized according to the same procedure as that of linker 1 described in Example 1 (840 mg, yield: 98%). 1HNMR(400MHz,DMSO-d6)δ11.07(s,1H),7.52(t,J=7.6Hz,1H),6.99–6.88(m,3H),5.04(dd,J=5.2,12.8H z,1H),3.73(s,2H),2.93–2.83(m,1H),2.61–2.50(m,2H),2.02(t,J=5.6Hz,1H).MS(ESI)m / z=330.1[MH] - .

[0848] Example 14: 3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propanoic acid (Linker 14)

[0849]

[0850] Linker 14 was synthesized according to the same procedure as that of Linker 1 described in Example 1 (1.42 g, yield: 88%). 1 HNMR (400MHz, DMSO-d6) δ11.61(br,1H),11.08(s,1H),7.58(dd,J=7.2,8.8Hz,1H),7.15(d,J=8.8Hz,1H),7.04(d,J=7.2Hz,1H),6.64(s,1 H),5.05(dd,J=5.2,12.8Hz,1H),3.53(t,J=6.4Hz,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] + .

[0851] Example 15: 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butanoic acid (Linker 15)

[0852]

[0853] Linker 15 was synthesized according to the same procedure as that of Linker 1 described in Example 1 (1.27 g, yield: 53%). 1HNMR(400MHz,DMSO-d6)δ12.12(br,1H),11.08(s,1H),7.58(dd,J=7.2,8.8Hz,1H ),7.13(d,J=8.8Hz,1H),7.03(d,J=7.2Hz,1H),6.64(t,J=6.0Hz,1H),5.05(dd,J= 5.6,12.8Hz,1H),3.33(q,J=6.8Hz,2H),2.93–2.83(m,1H),2.61–2.50(m,2H),2.3 1(t,J=6.8Hz,2H),2.07–2.00(m,1H),1.83–1.75(m,2H).MS(ESI)m / z=360.1[M+H] + .

[0854] Example 16: 5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentanoic acid (Linker 16)

[0855]

[0856] Linker 16 was synthesized according to the same procedure as that of linker 1 described in Example 1 (1.4 g, yield: 85%). 1 HNMR(400MHz,DMSO-d6)δ12.02(br,1H),11.08(s,1H),7.58(dd,J=8.8,7.2Hz ,1H),7.10(d,J=8.4Hz,1H),7.02(d,J=7.2Hz,1H),6.64(t,J=5.6Hz,1H),5.0 7–5.03(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] + .

[0857] Example 17: 6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexanoic acid (Linker 17)

[0858]

[0859] Linker 17 was synthesized according to the same procedure as that of Linker 1 described in Example 1 (1.43 g, yield: 91%). 1HNMR(400MHz,DMSO-d6)δ11.97(s,1H),11.08(s,1H),7.57(dd,J=7.2,8.8Hz,1H),7.0 8(d,J=8.8Hz,1H),7.02(d,J=7.2Hz,1H),6.52(t,J=6.0Hz,1H),5.05(dd,J=5.6,12.8H z,1H),3.30(q,J=6.8Hz,2H),2.93–2.83(m,1H),2.61–2.50(m,2H),2.32(t,J=7.2Hz, 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] + .

[0860] Example 18: 7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptanoic acid (Linker 18)

[0861]

[0862] Linker 18 was synthesized according to the same procedure as that of Linker 1 described in Example 1 (2.3 g, yield: 86%). 1 HNMR(400MHz,DMSO-d6)δ11.92(br,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,2 H),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] + .

[0863] Example 19: 8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octanoic acid (Linker 19)

[0864]

[0865] Linker 19 was synthesized according to the same procedure as that of Linker 1 described in Example 1 (1.14 g, yield: 77%).1 HNMR (400MHz, DMSO-d6) δ11.94(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] + .

[0866] Example 20: 3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)propanoic acid (Linker 20)

[0867]

[0868] The same procedure as described for connector 1 in Example 1 was followed to synthesize connector 20 (3.5 g, yield: 80%). 1 HNMR (400MHz, DMSO-d6) δ12.18(s,1H),11.08(s,1H),7.58(dd,J=7.2Hz,8.8Hz,1H),7.13(d,J=8.4Hz,1H),7.04(d,J=7.2Hz,1H),6.58(t,J=5.6Hz 1H),5.05(dd,J=6.4Hz,12.8Hz,1H),3.67–3.58(m,4H),3.47–3.43(m,2H),2.9 3–2.84(m,1H),2.61–2.45(m,4H),2.07–2.01(m,1H).MS(ESI)m / z=390.1[M+H] + .

[0869] Example 21: 3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanoic acid (Linker 21)

[0870]

[0871] Linker 21 was synthesized according to the same procedure as that of Linker 1 described in Example 1 (2.0 g, yield: 58%). 1HNMR (400MHz, DMSO-d6) δ12.13(s,1H),11.08(s,1H),7.58(dd,J=7.2Hz,8.4Hz,1H),7.14(d,J=8.4Hz,1H),7.04(d,J=6.8Hz,1H),6.60(t,J=6.0Hz 1H),5.05(dd,J=5.2Hz,12.4Hz,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] + .

[0872] Example 22: 3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propanoic acid (Linker 22)

[0873]

[0874] Linker 22 was synthesized according to the same procedure as that of Linker 1 described in Example 1 (3.2 g, yield: 93%). 1 HNMR(400MHz,DMSO-d6)δ12.14(s,1H),11.08(s,1H),7.58(dd,J=7.2Hz,8.4 Hz,1H),7.14(d,J=8.8Hz,1H),7.04(d,J=6.8Hz,1H),6.60(t,J=6.0Hz,1H), 5.05(dd,J=5.2Hz,12.8Hz,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] + .

[0875] Example 23: 1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)3,6,9,12-tetraoxapentadecan-15-oic acid (Linker 23)

[0876]

[0877] Linker 23 was synthesized according to the same procedure as that of Linker 1 described in Example 1 (2.3 g, yield: 59%). 1HNMR(400MHz,DMSO-d6)δ12.14(s,1H),11.08(s,1H),7.58(dd,J=7.2Hz,8.8 Hz,1H),7.14(d,J=8.4Hz,1H),7.04(d,J=7.2Hz,1H),6.60(t,J=6.0Hz,1H),5 .05(dd,J=5.2Hz,12.8Hz,1H),3.63–3.48(m,18H),2.898–2.85(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] + .

[0878] Example 24: 1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12,15-pentaoxaoctadecane-18-oic acid (Linker 24)

[0879]

[0880] Linker 24 was synthesized according to the same procedure as that of Linker 1 described in Example 1 (2.4 g, yield: 66%). 1 HNMR (400MHz, DMSO-d6) δ11.09(s,1H),7.58(dd,J=7.2,8.4Hz,1H),7.13(d,J=8.4Hz,1H),7.04(d,J=7.2Hz,1H),6.60(t,J=5.6Hz,1H),5.05(dd, J=5.6,12.8Hz,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=6.4Hz,1H).MS(ESI)m / z=566.2[M+H] + .

[0881] Example 25: (2S,4R)-1-((S)-2-(2-aminoacetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 25)

[0882]

[0883] Step 1: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, 4.67 mmol), 2-((tert-butoxycarbonyl)amino)acetic acid (900 mg, 5.14 mmol) and triethylamine (TEA) (3.2 mL, 23.35 mmol) in DCM / DMF (225 mL / 11 mL) was added EDCI (1.07 g, 5.60 mmol) and HOBt (756 mg, 5.60 mmol) at 0° C. The mixture was stirred at room temperature for 16 h, after which the reaction mixture was poured into water and extracted with DCM. The combined organic layers were concentrated, and the resulting residue was purified by chromatography on a silica gel column (DCM / MeOH=20 / 1, v / v) to give the desired product, tert-butyl (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-oxoethyl)carbamate (1.5 g, yield: 55%). MS (ESI) m / z=588.2 [M+H] + .

[0884] Step 2: To a solution of tert-butyl (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-oxoethyl)carbamate (1.50 g, 2.56 mmol) in ethyl acetate (EtOAc) (30 mL) was added HCl / EtOAc (100 mL, 4 M). The mixture was stirred at room temperature for 3 hours and filtered to obtain the desired product, which was dissolved in water (100 mL) and lyophilized to give (2S,4R)-1-((S)-2-(2-aminoacetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride (Linker 25) (1.07 g, yield: 80%). 1H NMR(400MHz, DMSO-d6)δ9.29(s,1H),8.72(s,1H),8.56(d,J=9.2Hz,1H),8.26(s,3H),7.38–7.47(m,4H),4.61(d,J=9.2Hz,1H),4.36–4.4 7(m,3H),4.20–4.25(m,1H),3.60–3.70(m,4H),2.46(s,3H),2.10–2.05(m,1H),1.97–1.89(m,1H),0.95(s,9H).MS(ESI)m / z=488.3[M+H] + .

[0885] Example 26: (2S,4R)-1-((S)-2-(3-aminopropionylamino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 26)

[0886]

[0887] Linker 26 was synthesized according to the same procedure as linker 25 described in Example 25 (1.38 g, yield: 88%). 1 HNMR(400MHz,DMSO-d6)δ9.36(s,1H),8.68(s,1H),8.26(d,J=9.2Hz,1H),8.16 (s,3H),7.49–7.39(m,4H),4.53(d,J=9.2Hz,1H),4.47–4.35(m,3H),4.24–4.19 (m,1H),3.69–3.60(m,2H),2.94–2.93(m,2H),2.64(t,J=7.2Hz,2H),2.48(s,3 H),2.06–2.01(m,1H),1.92–1.85(m,1H),0.95(s,9H).MS(ESI)m / z=502.3[M+H] + .

[0888] Example 27: (2S,4R)-1-((S)-2-(4-aminobutyrylamino)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 27)

[0889]

[0890] Linker 27 was synthesized according to the same procedure as linker 25 described in Example 25 (1.38 g, yield: 88%). 1HNMR(400MHz,DMSO-d6)δ9.66(s,1H),8.74(t,J=6.0,1H),8.25(s,3H),8.03(d, J=9.2Hz,1H),7.49–7.41(m,4H),4.53(d,J=9.2Hz,1H),4.51–4.35(m,3H),4.29 –4.24(m,1H),3.71–3.65(m,2H),2.79–2.77(m,2H),2.52(s,3H),2.45–2.27(m, 2H),2.12–2.07(m,1H),1.94–1.80(m,3H),0.94(s,9H).MS(ESI)m / z=516.0[M+H] + .

[0891] Example 28: (2S,4R)-1-((S)-2-(5-aminopentanoylamino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 28)

[0892]

[0893] Linker 28 was synthesized according to the same procedure as linker 25 described in Example 25 (1.50 g, yield: 79%). 1 HNMR(400MHz,DMSO-d6)δ9.52(s,1H),8.73(t,J=11.6Hz,1H),8.20(s,3H),7.95(d,J=9.6H z,1H),7.43–7.50(m,4H),4.55(d,J=9.2Hz,1H),4.38–4.50(m,3H),4.23–4.29(m,1H),3.64 –3.71(m,2H),2.74–2.78(m,2H),2.51(s,3H),2.30–2.35(m,1H),2.18–2.23(m,1H),2.07–2 .12(m,1H),1.88–1.95(m,1H),1.58(d,J=4.4Hz,4H),0.96(s,9H).MS(ESI)m / z=530.1[M+H] + .

[0894] Example 29: (2S,4R)-1-((S)-2-(6-aminohexanoylamino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 29)

[0895]

[0896] Linker 29 was synthesized according to the same procedure as linker 25 described in Example 25 (2.70 g, yield: 98%). 1 HNMR(400MHz,DMSO-d6)δ9.36(s,1H),8.69(t,J=6.4Hz,1H),8.12(brs,3H),7.92(d,J=9.6Hz,1H),7.44(d d,J=13.6,8.4Hz,4H),4.54(d,J=9.6Hz,1H),4.48–4.39(m,2H),4.36(brs,1H),4.28–4.19(m,1H),3.72–3. 60(m,2H),2.79–2.67(m,2H),2.49(s,3H),2.31–2.21(m,1H),2.20–2.12(m,1H),2.10–2.01(m,1H),1.94–1 .85(m,1H),1.62–1.54(m,2H),1.53–1.44(m,2H),1.34–1.22(m,2H),0.94(s,9H).MS(ESI)m / z=544.3[M+H] + .

[0897] Example 30: (2S,4R)-1-((S)-2-(7-aminoheptanoylamino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 30)

[0898]

[0899] Linker 30 was synthesized according to the same procedure as linker 25 described in Example 25 (2.13 g, yield: 86%). 1HNMR(400MHz,DMSO-d6)δ9.45(s,1H),8.70(t,J=6.0Hz,1H),8.14(brs,3H),7.86(d,J=9.2Hz,1H),7. 44(dd,J=12.8,8.4Hz,4H),4.54(d,J=9.2Hz,1H),4.49–4.40(m,2H),4.36(brs,1H),4.29–4.20(m,1H) ,3.71–3.61(m,2H),2.78–2.67(m,2H),2.50(s,3H),2.31–2.22(m,1H),2.21–2.13(m,1H),2.11–2.03( m,1H),1.95–1.85(m,1H),1.60–1.44(m,4H),1.35–1.18(m,4H),0.94(s,9H).MS(ESI)m / z=558.3[M+H] + .

[0900] Example 31: (2S,4R)-1-((S)-2-(8-aminooctanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 31)

[0901]

[0902] Linker 31 was synthesized according to the same procedure as linker 25 described in Example 25 (1.81 g, yield: 72%). 1 HNMR(400MHz,DMSO-d6)δ9.35(s,1H),8.69(t,J=6.0Hz,1H),8.11(brs,3H),7.88(d,J=9.2Hz,1H),7. 44(dd,J=14.0,8.4Hz,4H),4.54(d,J=9.6Hz,1H),4.48–4.39(m,2H),4.36(brs,1H),4.27–4.20(m,1H) ,3.71–3.60(m,2H),2.78–2.68(m,2H),2.49(s,3H),2.31–2.22(m,1H),2.18–2.11(m,1H),2.09–2.01( m,1H),1.94–1.85(m,1H),1.58–1.44(m,4H),1.32–1.19(m,6H),0.94(s,9H).MS(ESI)m / z=572.3[M+H] + .

[0903] Example 32: (2S,4R)-1-((S)-2-(9-aminononanoylamino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 32)

[0904]

[0905] Linker 32 was synthesized according to the same procedure as linker 25 described in Example 25 (2.32 g, yield: 89%). 1 HNMR(400MHz,DMSO-d6)δ9.30(s,1H),8.67(t,J=6.4Hz,1H),8.10(brs,3H),7.88(d,J=9.2Hz,1H),7 .43(dd,J=14.0,8.8Hz,4H),4.55(d,J=9.2Hz,1H),4.48–4.39(m,2H),4.35(brs,1H),4.28–4.19(m, 1H),3.71–3.60(m,2H),2.77–2.67(m,2H),2.48(s,3H),2.31–2.22(m,1H),2.17–2.10(m,1H),2.09– 2.01(m,1H),1.94–1.85(m,1H),1.60–1.40(m,4H),1.33–1.19(m,8H),0.94(s,9H).m / z=586.3[M+H] + .

[0906] Example 33: (2S,4R)-1-((S)-2-(10-aminodecanoylamino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 33)

[0907]

[0908] Linker 33 was synthesized according to the same procedure as linker 25 described in Example 25 (2.29 g, yield: 90%). 1HNMR(400MHz,DMSO-d6)δ9.41(s,1H),8.67(t,J=6.0Hz,1H),8.14(brs,3H),7.85(d,J=8.8Hz,1H),7.4 4(dd,J=13.6,8.8Hz,4H),4.54(d,J=8.8Hz,1H),4.48–4.39(m,2H),4.36(brs,1H),4.29–4.20(m,1H), 3.71–3.60(m,2H),2.78–2.67(m,2H),2.49(s,3H),2.32–2.22(m,1H),2.17–2.11(m,1H),2.10–2.01(m ,1H),1.95–1.86(m,1H),1.62–1.40(m,4H),1.34–1.16(m,10H),0.94(s,9H).MS(ESI)m / z=600.4[M+H] + .

[0909] Example 34: (2S,4R)-1-((S)-2-(11-aminoundecanoylamino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 34)

[0910]

[0911] Linker 34 was synthesized according to the same procedure as linker 25 described in Example 25 (1.10 g, yield: 44%). 1 HNMR(400MHz,DMSO-d6)δ8.99(s,1H),8.61(t,J=6.4Hz,1H),7.87(d,J=8.8Hz,1H),7.41(dd,J=17.6,8 .0Hz,4H),4.55(d,J=9.6Hz,1H),4.49–4.40(m,2H),4.36(brs,1H),4.26–4.17(m,1H),3.70–3.64(m,2H ),2.59–2.52(m,2H),2.45(s,3H),2.31–2.22(m,1H),2.16–2.08(m,1H),2.06–1.99(m,1H),1.96–1.86( m,1H),1.56–1.42(m,2H),1.39–1.30(m,2H),1.28–1.19(m,12H),0.94(s,9H).MS(ESI)m / z=614.4[M+H] + .

[0912] Example 35: (2S,4R)-1-((S)-2-(2-aminoethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 35)

[0913]

[0914] Linker 35 was synthesized according to the same procedure as linker 25 described in Example 25 (1.35 g, 2.38 mmol, yield: 79%). 1 H NMR (400MHz, DMSO-d6) δ9.23 (s, 1H), 8.70 (t, J = 6.0Hz, 1H), 8.35–8.14 (m, 3H), 7. 78(d,J=9.6Hz,1H),7.47–7.38(m,4H),4.61(d,J=9.6Hz,1H),4.49–4.34(m,3H),4 .30–4.21(m,1H),4.09–3.99(m,2H),3.75–3.58(m,4H),3.06–2.94(m,2H),2.48(s ,3H),2.13–2.03(m,1H),1.95–1.85(m,1H),0.95(s,9H).MS(ESI)m / z=532.0[M+H] +

[0915] Example 36: (2S,4R)-1-((S)-2-(3-(2-aminoethoxy)propionylamino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 36)

[0916]

[0917] Linker 36 was synthesized according to the same procedure as linker 25 described in Example 25 (1.32 g, 2.01 mmol, yield: 65%). 1H NMR(400MHz,DMSO-d6)δ8.99(s,1H),8.57(t,J=6.0Hz,1H),8.03(d,J=8Hz,1H),7 .85(s,3H),7.43–7.37(m,4H),4.57(d,J=9.2Hz,1H),4.46–4.31(m,3H),4.26–4. 20(m,1H),3.69–3.55(m,6H),3.99–2.95(m,2H),2.60–2.56(m,1H),2.46–2.42(m ,4H),2.05–2.03(m,1H),1.93–1.92(m,1H),0.95(s,9H).MS(ESI)m / z=546.0[M+H] + .

[0918] Example 37: (2S,4R)-1-((S)-2-(2-(2-(2-aminoethoxy)ethoxy)acetylamino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 37)

[0919]

[0920] Linker 37 was synthesized according to the same procedure as linker 25 described in Example 25 (1.2 g, yield: 94%). 1 HNMR(400MHz,DMSO-d6)δ9.38(s,1H),8.78(t,J=6.0Hz,1H),8.18(s,3H),7 .59–7.37(m,5H),4.58(d,J=9.6Hz,1H),4.49(t,J=8.2Hz,1H),4.42–4.26(m ,3H),4.09–3.95(m,2H),3.72–3.55(m,8H),2.99–2.92(m,2H),2.49(s,3H), 2.15–2.04(m,1H),1.95–1.85(m,1H),0.95(s,9H).MS(ESI)m / z=576.1[M+H] + .

[0921] Example 38: (2S,4R)-1-((S)-2-(3-(2-aminoethoxy)propionylamino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 38)

[0922]

[0923] Linker 38 was synthesized according to the same procedure as linker 25 described in Example 25 (1.34 g, 1.94 mmol, yield: 65%). 1 H NMR (400MHz, DMSO-d6) δ9.02 (s, 1H), 8.58 (t, J = 6.0Hz, 1H), 7.94 (d, J = 8Hz, 1H), 7.82 (s,3H),7.42–7.30(m,4H),4.58(d,J=9.2Hz,1H),4.60–4.37(m,3H),4.25–4.31(m,1 H),3.70–3.50(m,10H),3.00–2.96(m,2H),2.57–2.55(m,1H),2.45(s,3H),2.41–2.3 8(m,1H),2.06–2.04(m,1H),1.95–1.93(m,1H),0.95(s,9H).MS(ESI)m / z=590.1[M+H] + .

[0924] Example 39: (2S,4R)-1-((S)-14-amino-2-(tert-butyl)-4-oxo-6,9,12-trioxa-3-azatetradecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 39)

[0925]

[0926] Linker 39 was synthesized according to the same procedure as linker 25 described in Example 25 (1.53 g, yield: 77%). 1 HNMR (400MHz, DMSO-d6) δ9.01(s,1H),8.59(t,J=6.0Hz,1H),7.81(s,3H),7.48–7.41(m,5H),4.58(d,J=9.6Hz,1H),4.47–4.26(m,4H),3. 99(s,2H),3.70–3.58(m,12H),3.0–2.96(m,2H),2.46(s,3H),2.11–2.06(m,1H),1.95–1.88(m,1H),0.96(s,9H).MS(ESI)m / z=621.1[M+H] + .

[0927] Example 40: (2S,4R)-1-((S)-1-amino-14-(tert-butyl)-12-oxo-3,6,9-trioxa-13-azapentadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 40)

[0928]

[0929] Linker 40 was synthesized according to the same procedure as linker 25 described in Example 25 (1.52 g, yield: 64%). 1 HNMR(400MHz,DMSO-d6)δ9.01(s,1H),8.57(t,J=6.0Hz,1H),7.91(d,J=9.2Hz,1H),7 .81(s,3H),7.44–7.38(m,4H),4.58–4.55(m,1H),4.45–4.36(m,3H),4.25–4.21(m,1 H),3.70–3.48(m,14H),3.00–2.97(m,2H),2.59–2.52(m,1H),2.46(s,3H),2.39–2.3 4(m,1H),2.08–2.03(m,1H),1.95–1.88(m,1H),0.94(s,9H).MS(ESI)m / z=633.8[M+H] + .

[0930] Example 41: (2S,4R)-1-((S)-1-amino-17-(tert-butyl)-15-oxo-3,6,9,12-tetraoxa-16-azaoctadecane-18-yl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 41)

[0931]

[0932] Linker 41 was synthesized according to the same procedure as linker 25 described in Example 25 (1.12 g, yield: 52%). 1HNMR(400MHz, DMSO-d6)δ8.98(s,1H),8.58(t,J=5.6Hz,1H),7.92(d,J=9.2Hz,1H),7.44–7.38(m, 4H),4.56(d,J=9.2Hz,1H),4.47–4.41(m,2H),4.38–4.34(m,1H),4.26–4.19(m,1H),3.70–3.55(m, 5H),3.53–3.45(m,14H),3.35(t,J=5.6Hz,2H),2.64(t,J=5.6Hz,2H),2.58–2.50(m,1H),2.45(s,3 H),2.40–2.35(m,1H),2.08–2.00(m,1H),1.94–1.91(m,1H),0.94(s,9H).MS(ESI)m / z=678.1[M+H] + .

[0933] Example 42: (2S,4R)-1-((S)-1-amino-20-(tert-butyl)-18-oxo-3,6,9,12,15-pentaoxa-19-azaicos-21-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 42)

[0934]

[0935] Linker 42 was synthesized according to the same procedure as linker 25 described in Example 25 (1.1 g, yield: 42%). 1 HNMR(400MHz,DMSO-d6)δ9.38(s,1H),8.67(t,J=16Hz,1H),8.14(br,3H),7.91(d,J=9.2Hz ,1H),7.39–7.48(m,4H),4.53(d,J=9.2Hz,1H),4.39–4.46(m,2H),4.36–4.34(m,1H),4.20 –4.25(m,1H),3.45–3.68(m,22H),2.91–2.95(m,2H),2.52–2.58(m,1H),2.47(s,3H),2.32 –2.39(m,1H),2.03–2.08(m,1H),1.85–1.92(m,1H),0.92(s,9H).MS(ESI)m / z=722.4[M+H] + .

[0936] Example 43: 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 (Linker 43)

[0937]

[0938] 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 at room temperature overnight. The mixture was concentrated. The resulting residue was purified by flash chromatography (reverse phase, MeCN / HO) to give the title compound, connector 43 (1.05 g, 86% yield). 1 H NMR (400MHz, DMSO-d6): δ12.02(s,1H),8.99(s,1H),8.58(t,J=6.0Hz,1H),7.96( d,J=9.2Hz,1H),7.43–7.37(m,4H),5.13(d,J=3.6Hz,1H),4.53(d,J=9.2Hz,1H),4 .46–4.40(m,2H),4.34(s,1H),4.21(dd,J=16.0,5.2Hz,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). 13 C NMR (100MHz, DMSO-d6): δ173.83,171.92,170.86,169.56,151.41,147.70,139.48,131.15,129.63,128.62,1 27.41,68.87,58.70,56.44,56.34,41.65,37.91,35.35,29.74,29.25,26.35,15.92.MS(ESI)m / z=531.2[M+H] + .

[0939] Example 44: 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 (Linker 44)

[0940]

[0941] Linker 44 was synthesized according to the same procedure as linker 43 described in Example 43 (1.5 g, yield: 79%). 1 HNMR (400MHz, DMSO-d6): δ8.99(s,1H),8.59(t,J=6.0Hz,1H),7.91(d,J=9.2Hz,1 H),7.44–7.37(m,4H),5.16(brs,1H),4.54(d,J=9.2Hz,1H),4.47–4.42(m,2H),4 .36(s,1H),4.21(dd,J=16.0,5.2Hz,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).

[0942] 13 C NMR (100MHz, DMSO-d6): δ174.18,171.94,171.63,169.66,151.41,147.70,139.46,131.15,129.61,128.62,1 27.41,68.86,58.69,56.38,41.65,37.91,35.16,34.03,33.10,26.35,20.89,15.92.MS(ESI)m / z=543.2[M+H] + .

[0943] Example 45: 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 (Linker 45)

[0944]

[0945] Linker 45 was synthesized according to the same procedure as linker 25 described in Example 25 (1.198 g, yield: 74%). 1H NMR(400MHz, CDCl3)δ8.68(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] + .

[0946] Example 46: 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 (Linker 46)

[0947]

[0948] Linker 46 was synthesized according to the same procedure as linker 45 described in Example 45 (1.099 g, yield: 50%). 1 H NMR(400MHz, CDCl3)δ8.67(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=4.8Hz,15.2Hz,1H),4 .06–4.03(m,1H),3.70–3.68(m,1H),2.46(s,3H),2.31–2.11(m,6H),1.5 5–1.51(m,4H),1.29–1.24(m,2H),0.94(s,9H).MS(ESI)m / z=573.1[M+H] + .

[0949] Example 47: 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 (Linker 47)

[0950]

[0951] Linker 47 was synthesized according to the same procedure as linker 45 described in Example 45 (1.08 g, yield: 60%). 1HNMR (400MHz, DMSO-d6) δ8.99 (s, 1H), 8.55 (t, J = 2.4Hz, 1H), 7.83 (d, J = 9.2 Hz,1H),7.44–7.38(m,4H),4.55(d,J=9.6Hz,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] + .

[0952] Example 48: 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 (Linker 48)

[0953]

[0954] Linker 48 was synthesized according to the same procedure as linker 45 described in Example 45 (1.155 g, yield: 56%). 1 H NMR(400MHz, CDCl3)δ8.70(s,1H),7.55(s,1H),7.33–7.27(m,4H),7.08(d,J=8.0Hz,1H),4.68–4.52(m,4H),4.31–4.27(m,1H),4.08–4.0 5(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] + .

[0955] Example 49: 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 (Linker 49)

[0956]

[0957] Linker 49 was synthesized according to the same procedure as linker 45 described in Example 45 (1.1 g, yield: 35.5%). 1 H NMR (400MHz, DMSO-d6) δ8.99(s,1H),8.58(t,J=6.0Hz,1H),7.85(d,J=9.2Hz,1 H),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(b,8H),0.94(s,9H).

[0958] 13 C NMR (100MHz, DMSO-d6): δ172.07,171.92,169.69,151.41,147.70,139.48,131.14,129.62,128.61,127.40,6 8.84,58.67,56.32,56.26,41.64,37.93,35.18,34.85,28.62,26.36,25.39,15.93.MS(ESI)m / z=615.3[M+H] + .

[0959] Example 50: 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 (Linker 50)

[0960]

[0961] Linker 50 was synthesized according to the same procedure as linker 45 described in Example 45 (1.1 g, yield: 50%). 1 HNMR(400MHz, DMSO-d6)δ8.99(s,1H),8.58(t,J=6.0Hz,1H),7.85(t,J=9.2Hz,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).

[0962] 13 C NMR (100MHz, DMSO-d6): δ174.59,172.07,171.92,169.69,151.42,147.70,139.49,131.14,129.62,128.61,127.41,68.84,58.67,56. 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] + .

[0963] Example 51: 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 (Linker 51)

[0964]

[0965] Linker 51 was synthesized according to the same procedure as linker 45 described in Example 45 (1.1 g, yield: 42%). 1 HNMR(400MHz,DMSO-d6)δ8.98(s,1H),8.55(t,J=6.0Hz,1H),7.91(d,J=9.2Hz,1 H),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] + .

[0966] Example 52: 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 (Linker 52)

[0967]

[0968] Linker 52 was synthesized according to the same procedure as linker 43 described in Example 43 (1.2 g, yield: 63%). 1 HNMR(400MHz,DMSO-d6)δ12.81(br s,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(br,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] + .

[0969] Example 53: 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 (Linker 53)

[0970]

[0971] Linker 53 was synthesized following the same procedure as described for linker 45 in Example 45 (1.4 g, 41% yield). 1 HNMR (400MHz, DMSO-d6): δ8.98(s,1H),8.56(t,J=6.0Hz,1H),7.91(d,J=9.2Hz,1H),7.43– 7.37(m,4H),4.55(d,J=9.6Hz,1H),4.46–4.41(m,2H),4.35(s,1H),4.29–4.20(m,1H),3.7 0–3.57(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] + .

[0972] Example 54: 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 (Linker 54)

[0973]

[0974] Linker 54 was synthesized following the same procedure as described for Linker 53 in Example 53 (1.126 g, 30% yield). 1 HNMR(400MHz, DMSO-d6)δ8.98(s,1H),8.60(t,J=6.0Hz,1H),7.49(d,J=9.2Hz,1H),7.40(s,4H),4.57(d,J=9.2Hz,1H),4.47–4.36(m,3H),4.2 8–4.23(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] + .

[0975] Example 55: (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-azaheptadecanoic acid (Linker 55)

[0976]

[0977] Linker 55 was synthesized following the same procedure as described for linker 45 in Example 45 (1.7 g, 37% yield). 1HNMR(400MHz,DMSO-d6)δ8.99(s,1H),8.56(t,J=6.0Hz,1H),7.91(d,J=9.6Hz,1H),7.4 4–7.38(m,4H),4.56(d,J=9.2Hz,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[MH] - .

[0978] Example 56: (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 (Linker 56)

[0979]

[0980] Linker 56 was synthesized following the same procedure as described for linker 45 in Example 45 (1.21 g, 42% yield). 1 HNMR(400MHz, CDCl3)δ8.68(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] + .

[0981] Example 57: (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-azaeicosanoic acid (Linker 57)

[0982]

[0983] Linker 57 was synthesized by following the same procedure as described for linker 45 in Example 45 (1.6 g, 43% yield). 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] + .

[0984] Example 58: (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 (Linker 58)

[0985]

[0986] Linker 58 was synthesized according to the same procedure as linker 45 described in Example 45 (1.2 g, yield: 23%). 1 HNMR(400MHz,DMSO-d6)δ8.98(s,1H),8.57(t,J=6.0Hz,1H),7.91(d,J=9.6Hz,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] + .

[0987] Example 59: (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 (Linker 59)

[0988]

[0989] Linker 59 was synthesized by the same procedure as linker 45 described in Example 45 (1.3 g, yield: 39%). 1 HNMR (400MHz, DMSO-d6) δ8.98 (s, 1H), 8.69 (t, J = 6.0 Hz, 1H), 7.45 (d, J = 9. 6Hz,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] + .

[0990] Example 60: 5-((2-(2-aminoethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 60)

[0991]

[0992] A mixture of 5-fluoroisobenzofuran-1,3-dione (87 g, 524 mmol), 3-aminopiperidine-2,6-dione (85.7 g, 524 mmol) and NaOAc (85.9 g, 1050 mmol) in acetic acid (500 mL) was stirred at 130 ° C overnight. After cooling to room temperature, the mixture was concentrated. The resulting residue was poured into ice water and filtered. The filter cake was washed with water (500 mL x 2), EtOH (500 mL x 2), MeOH (500 mL) and DCM (500 mL) to obtain a solid, which was dried in vacuo to obtain 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (120 g, yield: 83%) as a yellow solid. MS (ESI) m / z = 277.1 [M+H] + .

[0993] A mixture of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (6.9 g, 25.0 mmol), tert-butyl (2-(2-aminoethoxy)ethyl)carbamate (5.6 g, 27.5 mmol) and DIEA (9.7 g, 75 mmol) in NMP (75 mL) was stirred in a microwave reactor at 130° C. for 50 min. After cooling to room temperature, the mixture was poured into EtOAc (200 mL) and washed with water (200 mL×2) followed by brine (200 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product, which was chromatographed on silica (petroleum ether / EtOAc = 2:1 to 1:2) to give tert-butyl (2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethyl)carbamate (2.4 g, yield: 21%) as a yellow oil. MS (ESI) m / z = 361.1 [M+H] + .

[0994] To a solution of tert-butyl (2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethyl)carbamate (2.4 g, 5.2 mmol) in DCM (10 mL) was added TFA (5 mL) in one portion. After concentration, the resulting residue was dissolved in water (20 mL) and washed with EtOAc (40 mL) and MTBE (40 mL). The aqueous phase was lyophilized to afford 5-((2-(2-aminoethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (1.9 g, yield: 77%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ11.06 (s, 1H), 8.01 (s, 3H), 7.58 (d, J = 8.4Hz, 1H), 7.12 (br,s,1H),7.02(d,J=2.0Hz,1H),6.91(dd,J=2.0Hz,8.8Hz,1H),5.04(dd,J=5. 6Hz,13.2Hz,1H),3.64(t,J=5.6Hz,4H),3.40(t,J=5.2Hz,2H),3.01(br,2H),2. 89–2.83(m,1H),2.60–2.50(m,2H),2.03–1.97(m,1H).MS(ESI)m / z=361.1[M+H] + .

[0995] Example 61: 5-((2-(2-(2-aminoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 61)

[0996]

[0997] Linker 61 was synthesized according to the same procedure as linker 60 described in Example 60 (1.4 g, yield: 71%). 1 HNMR (400MHz, DMSO-d6) δ11.05(s,1H),7.94(br,3H),7.56(d,J=8.4Hz,1H),7.01(s,1H),6.90(d,J=8.0Hz,1H),5.03(dd,J=5.2Hz,12.8 Hz,1H),3.58(br,8H),3.36(s,2H),2.97–2.92(m,2H),2.91–2.83(m,1H),2.60–2.50(m,2H),2.01–1.99(m,1H).MS(ESI)m / z=405.1[M+H] + .

[0998] Example 62: 5-((2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 62)

[0999]

[1000] Linker 62 was synthesized according to the same procedure as linker 60 described in Example 60 (1.19 g, yield: 59%). 1 HNMR(400MHz,DMSO-d6)δ11.05(s,1H),7.79(br,3H),7.57(d,J=8.4Hz,1H),7.1 5(br,s,1H),7.00(d,J=2.0Hz,1H),6.90(dd,J=2.0Hz,8.4Hz,1H),5.03(dd,J=5. 6Hz,12.8Hz,1H),3.61–3.55(m,12H),3.36(t,J=5.6Hz,2H),2.99–2.94(m,2H), 2.88–2.84(m,1H),2.60–2.52(m,2H)2.01–1.98(m,1H).MS(ESI)m / z=449.1[M+H] + .

[1001] Example 63: 5-((14-amino-3,6,9,12-tetraoxatetradecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 63)

[1002]

[1003] Linker 63 was synthesized according to the same procedure as linker 60 described in Example 60 (1.2 g, yield: 73%). 1 HNMR(400MHz,DMSO-d6)δ11.05(s,1H),7.79(br,J=1.6Hz,3H),7.56(d,J=8.4Hz,1 H),7.14(br,s,1H),7.01(d,J=2.0Hz,1H),6.90(dd,J=2.0Hz,8.4Hz,1H),5.03(dd, J=5.6Hz,13.2Hz,1H),3.61–3.56(m,16H),3.36(t,J=5.2Hz,2H),2.99–2.95(m,2H ),2.89–2.83(m,1H),2.60–2.53(m,2H)2.01–1.97(m,1H).MS(ESI)m / z=493.1[M+H] + .

[1004] Example 64: 5-((17-amino-3,6,9,12,15-pentaoxaheptadecanyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 64)

[1005]

[1006] Linker 64 was synthesized according to the same procedure as linker 60 described in Example 60 (1.73 g, yield: 88%). 1 HNMR(400MHz,DMSO-d6)δ11.05(s,1H),7.79(s,3H),7.55(d,J=8.4Hz,1H),7.18(br,s,1H),7.01(s,1H),6.90(d,J=8.4Hz,1H),5.03(dd,J=5.2H z,12.8Hz,1H),3.61–3.54(m,20H),3.35(s,2H),2.98(s,2H),2.92–2.8 3(m,1H),2.61–2.54(m,2H),2.02–1.98(m,1H).MS(ESI)m / z=537.2[M+H] + .

[1007] Example 65: (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycine (Linker 65)

[1008]

[1009] Linker 65 was synthesized according to the same procedure as linker 60 described in Example 60 (1.0 g, yield: 84%). 1 HNMR (400MHz, DMSO-d6) δ12.80(br,1H),11.06(s,1H),7.59(d,J=8.4Hz,1H),7.32(br,s,1H),6.98(d,J=1.2Hz,1H),6.89(dd,J=2.0Hz,8 .4Hz,1H),5.04(dd,J=5.6Hz,13.2Hz,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] + .

[1010] Example 66: 3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)propanoic acid (Linker 66)

[1011]

[1012] Linker 66 was synthesized according to the same procedure as linker 60 described in Example 60 (1.24 g, yield: 60%). 1 HNMR (400MHz, DMSO-d6) δ11.05(s,1H),7.57(d,J=8.4Hz,1H),6.97(d,J=2.0Hz,1H),6.87(dd,J=2.0Hz,8.4Hz,1H),5.02(dd,J =5.2Hz,12.8Hz,1H),3.41(t,J=6.8Hz,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[M+H] + .

[1013] Example 67: 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butanoic acid (Linker 67)

[1014]

[1015] Linker 67 was synthesized according to the same procedure as linker 60 described in Example 60 (0.52 g, yield: 25%). 1 HNMR(400MHz,DMSO-d6)δ12.12(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=2.0Hz,8.4Hz,1H),5.02(dd,J =5.6Hz,12.8Hz,1H),3.21–3.16(m,2H),2.91–2.83(m,1H),2.60–2.51(m,2H),2.3 4(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] + .

[1016] Example 68: 5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)pentanoic acid (Linker 68)

[1017]

[1018] Linker 68 was synthesized according to the same procedure as linker 60 described in Example 60 (0.66 g, yield: 51%). 1 HNMR(400MHz,DMSO-d6)δ12.03(br,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=1.6Hz,8.4Hz,1H),5.02(dd,J=5 .6Hz,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] + .

[1019] Example 69: 6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)hexanoic acid (Linker 69)

[1020]

[1021] Linker 69 was synthesized according to the same procedure as linker 60 described in Example 60 (1.33 g, yield: 66%). 1 HNMR(400MHz,DMSO-d6)δ11.98(s,1H),11.05(s,1H),7.55(d,J=8.4Hz,1H),7.08(t ,J=5.2Hz,1H),6.95(s,1H),6.83(dd,J=1.2Hz,8.4Hz,1H),5.03(dd,J=5.2Hz,12.8H z,1H),3.17–3.12(m,2H),2.92–2.83(m,1H),2.60–2.53(m,2H),2.22(t,J=7.2Hz,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] + .

[1022] Example 70: 7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)heptanoic acid (Linker 70)

[1023]

[1024] Linker 70 was synthesized according to the same procedure as linker 60 described in Example 60 (1.06 g, yield: 39%). 1 HNMR(400MHz,DMSO-d6)δ11.94(s,1H),11.04(s,1H),7.55(d,J=8.4Hz,1H),7.09(t,J =5.6Hz,1H),6.94(d,J=2.0Hz,1H),6.84(dd,J=2.0Hz,8.4Hz,1H),5.02(dd,J=5.6Hz,1 3.2Hz,1H),3.17–3.12(m,2H),2.88–2.83(m,1H),2.60–2.53(m,2H),2.21(t,J=7.2Hz, 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] + .

[1025] Example 71: 8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)octanoic acid (Linker 71)

[1026]

[1027] Linker 71 was synthesized according to the same procedure as linker 60 described in Example 60 (1.66 g, yield: 51%). 1 HNMR(400MHz,DMSO-d6)δ11.95(s,1H),11.05(s,1H),7.55(d,J=8.4Hz,1H),7.09(t,J =5.6Hz,1H),6.94(d,J=2.0Hz,1H),6.84(dd,J=2.0Hz,8.4Hz,1H),5.02(dd,J=5.6Hz,1 3.2Hz,1H),3.17–3.12(m,2H),2.88–2.83(m,1H),2.60–2.53(m,2H),2.19(t,J=7.2Hz, 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] + .

[1028] Example 72: 5-((2-aminoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 72)

[1029]

[1030] Linker 72 was synthesized according to the same procedure as linker 60 described in Example 60 (1.74 g, yield: 80%). 1 HNMR (400MHz, DMSO-d6) δ11.08(s,1H),8.10(s,3H),7.62(d,J=8.4Hz,1H),7.33(t,J=5.2Hz,1H),7.05(s,1H),6.94(d,J=8.0Hz,1H),5.07(dd,J =5.2Hz,12.8Hz,1H),3.50–3.49(m,2H),3.03(t,J=6.0Hz,2H),2.95–2.8 6(m,1H),2.63–2.57(m,2H),2.05–2.02(m,1H).MS(ESI)m / z=317.1[M+H] + .

[1031] Example 73: 5-((3-aminopropyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 73)

[1032]

[1033] Linker 73 was synthesized according to the same procedure as linker 60 described in Example 60 (1.3 g, yield: 57%). 1 HNMR(400MHz,DMSO-d6)δ11.07(s,1H),7.85(br,3H),7.59(d,J=8.4Hz,1H),7.22(t,J=5.2Hz,1H),6.98(d,J=2.0Hz,1H),6.88(dd,J=2.0Hz,8.4Hz,1H), 5.04(dd,J=5.6Hz,13.2Hz,1H),3.29–3.25(m,2H),2.91–2.85(m,3H),2.60– 2.53(m,2H),2.02–1.98(m,1H),1.87–1.81(m,2H).MS(ESI)m / z=331.1[M+H] + .

[1034] Example 74: 5-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 74)

[1035]

[1036] Linker 74 was synthesized according to the same procedure as linker 60 described in Example 60 (2.9 g, yield: 85%). 1 HNMR(400MHz,DMSO-d6)δ11.08(s,1H),7.97(br,3H),7.58(d,J=8.4Hz,1H),7.22(br,s,1H),6.99(s,1H),6.89(d,J=8.0Hz,1H),5.05( dd,J=5.2Hz,12.8Hz,1H),3.22(s,2H),2.93-2.84(m,3H),2.63–2.53(m,2H),2.04–2.00(m,1H),1.66(s,4H).MS(ESI)m / z=345.1[M+H] + .

[1037] Example 75: 5-((5-aminopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 75)

[1038]

[1039] Linker 75 was synthesized according to the same procedure as linker 60 described in Example 60 (1.8 g, yield: 78%). 1HNMR(400MHz,DMSO-d6)δ11.09(s,1H),7.89(br,3H),7.57(d,J=6.8Hz,1H),7.17(br,s,1H),6.96(s,1H),6.86(d,J=6.0Hz,1H),5.05(d,J=7.2Hz ,1H),3.19-3.15(m,2H),2.89-2.70(m,3H),2.61-2.51(m,2H),2.01-1.9 0(m,1H),1.62-1.56(m,4H),1.45-1.40(m,2H).MS(ESI)m / z=359.1[M+H] + .

[1040] Example 76: 5-((6-aminohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 76)

[1041]

[1042] Linker 76 was synthesized according to the same procedure as linker 60 described in Example 60 (1.8 g, yield: 62%). 1 HNMR(400MHz,DMSO-d6)δ11.05(s,1H),7.71(br,3H),7.57(d,J=8.4Hz,1H),7.12 (t,J=5.2Hz,1H),6.94(d,J=2.0Hz,1H),6.85(dd,J=2.0Hz,8.4Hz,1H),5.03(dd, J=5.2Hz,12.8Hz,1H),3.17–3.16(m,2H),2.88–2.77(m,3H),2.60–2.53(m,2H),2 .01–1.98(m,1H),1.59–1.51(m,4H),1.37–1.36(m,4H).MS(ESI)m / z=373.1[M+H] + .

[1043] Example 77: 5-((7-aminoheptyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 77)

[1044]

[1045] Linker 77 was synthesized according to the same procedure as linker 60 described in Example 60 (1.3 g, yield: 70%). 1HNMR(400MHz,DMSO-d6)δ11.05(s,1H),7.72(br,3H),7.56(d,J=8.4Hz,1H),7.12 (t,J=5.6Hz,1H),6.94(d,J=2.0Hz,1H),6.85(dd,J=2.4Hz,8.8Hz,1H),5.03(dd, J=5.6Hz,12.8Hz,1H),3.18–3.14(m,2H),2.92–2.76(m,3H),2.60–2.51(m,2H),2 .01–1.98(m,1H),1.59–1.51(m,4H),1.36–1.32(m,6H).MS(ESI)m / z=387.1[M+H] + .

[1046] Example 78: 5-((8-aminooctyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 78)

[1047]

[1048] Linker 78 was synthesized according to the same procedure as linker 60 described in Example 60 (1.6 g, yield: 62%). 1 HNMR(400MHz,DMSO-d6)δ11.05(s,1H),7.73(br,3H),7.56(d,J=8.4Hz,1H),7.14(br ,1H),6.94(d,J=1.6Hz,1H),6.85(dd,J=2.0Hz,8.8Hz,1H),5.03(dd,J=5.6Hz,12.8H z,1H),3.15(t,J=7.2Hz,2H),2.89–2.83(m,1H),2.80–2.75(m,2H),2.60–2.54(m,2H ),2.02–1.98(m,1H),1.59–1.51(m,4H),1.37–1.30(m,8H).MS(ESI)m / z=401.1[M+H] + .

[1049] Example 79: 3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)propanoic acid (Linker 79)

[1050]

[1051] Linker 79 was synthesized according to the same procedure as linker 60 described in Example 60 (1.7 g, yield: 60%). 1HNMR(400MHz,DMSO-d6)δ12.19(br,1H),11.06(s,1H),7.57(d,J=8.4Hz,1H),7.09(br ,1H),7.01(d,J=2.0Hz,1H),6.90(dd,J=2.0Hz,8.4Hz,1H),5.04(dd,J=5.6Hz,13.2Hz, 1H),3.66(t,J=6.4Hz,2H),3.59(t,J=5.6Hz,2H),3.35(t,J=5.2Hz,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] + .

[1052] Example 80: 3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)propanoic acid (Linker 80)

[1053]

[1054] Linker 80 was synthesized according to the same procedure as linker 60 described in Example 60 (2.3 g, yield: 78%). 1 HNMR(400MHz,DMSO-d6)δ11.06(s,1H),7.57(d,J=8.4Hz,1H),7.02(d,J=2.0H z,1H),6.90(dd,J=2.0Hz,8.4Hz,1H),5.04(dd,J=5.6Hz,13.2Hz,1H),3.63–3. 59(m,4H),3.57–3.51(m,4H),3.36(t,J=5.6Hz,2H),2.90–2.84(m,1H),2.61–2 .55(m,2H),2.44(t,J=6.4Hz,2H),2.04–1.99(m,1H).MS(ESI)m / z=434.1[M+H] + .

[1055] Example 81: 3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)ethoxy)propanoic acid (Linker 81)

[1056]

[1057] Linker 81 was synthesized according to the same procedure as linker 60 described in Example 60 (1.2 g, yield: 52%). 1 HNMR(400MHz,DMSO-d6)δ7.59(d,J=11.2Hz,1H),7.23(t,J=6.8Hz,1H),7.04(d ,J=1.6Hz,1H),7.04(dd,J=2.4Hz,11.2Hz,1H),5.06(dd,J=7.2Hz,16.8Hz,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] + .

[1058] Example 82: 1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)-3,6,9,12-tetraoxapentadecan-15-oic acid (Linker 82)

[1059]

[1060] Linker 82 was synthesized according to the same procedure as linker 60 described in Example 60 (1.3 g, yield: 55%). 1 HNMR(400MHz,DMSO-d6)δ12.17(br,1H),11.07(s,1H),7.56(d,J=8.4Hz,1H), 7.17(t,J=5.6Hz,1H),7.01(d,J=1.2Hz,1H),6.90(dd,J=1.6Hz,8.4Hz,1H),5 .03(dd,J=5.6Hz,12.8Hz,1H),3.61–3.48(m,18H),2.92–2.83(m,1H),2.60–2 .54(m,2H),2.43(t,J=6.4Hz,2H),2.03–1.98(m,1H).MS(ESI)m / z=522.1[M+H] + .

[1061] Example 83: 1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)-3,6,9,12,15-pentaoxaoctadecane-18-oic acid (Linker 83)

[1062]

[1063] Linker 83 was synthesized according to the same procedure as linker 60 described in Example 60 (1.0 g, yield: 50%). 1 HNMR (400MHz, DMSO-d6) δ12.17(br,s,1H),11.07(s,1H),7.56(d,J=8.0Hz,1H),7.17(t,J=5.6Hz,1H),7.01(s,1H),6.90(dd,J=1.6Hz,8.4Hz,1H),5.03 (dd,J=5.6Hz,13.2Hz,1H),3.60–3.48(m,22H),2.89–2.83(m,1H),2.60–2.5 4(m,2H),2.43(t,J=6.4Hz,2H),2.01–1.98(m,1H).MS(ESI)m / z=566.1[M+H] + .

[1064] Example 84. N-(tert-Butyl)-3-((5-methyl-2-((4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)benzenesulfonamide

[1065]

[1066] Step 1: Synthesis of tert-butyl 4-(4-((4-((3-(N-(tert-butyl)sulfamoyl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate

[1067]

[1068] To a solution of N-(tert-butyl)-3-((2-chloro-5-methylpyrimidin-4-yl)amino)benzenesulfonamide (1.1 g, 3.1 mmol) and tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate (1.03 g, 3.7 mmol) in 1,4-dioxane (20 mL) were added palladium acetate (70 mg, 0.31 mmol), (+ / -)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (386 mg, 0.62 mmol), and cesium carbonate (2.0 g, 6.2 mmol). The resulting mixture was stirred at 100°C for 12 h under a nitrogen atmosphere. LCMS indicated the reaction was complete. The mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (hexane:ethyl acetate = 1:1) to give tert-butyl 4-(4-((4-((3-(N-(tert-butyl))sulfamoyl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)phenyl)piperazin-1-yl-1-carboxylate (1.2 g, yield: 65%) as a brown solid. MS (ESI) m / z 596.0 [M+H] + .

[1069] Step 2: Synthesis of N-(tert-butyl)-3-((5-methyl-2-((4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)benzenesulfonamide

[1070]

[1071] To a solution of tert-butyl 4-(4-((4-((3-(N-(tert-butyl)sulfamoyl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (1.2 g, 2.02 mmol) in methanol (250 mL) was added HCl / EtOAc (100 mL, 4 M). The resulting mixture was stirred at room temperature for 3 h. LCMS showed the reaction was complete. The mixture was concentrated and triturated with methanol and ethyl acetate to afford N-(tert-butyl)-3-((5-methyl-2-((4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)benzenesulfonamide (1.002 g, yield: 94%) as a white solid. 1H NMR (400MHz, DMSO-d6) δ10.59(s,1H),10.02(s,1H),9.50(s,2H),7.96–7.95(m,2H),7.89–7.88(m,1H),7.73(d,J=8.0Hz,1H),7.64(s,1H),7. 58(t,J=8.0Hz,1H),7.27(d,J=9.2Hz,2H),6.94(d,J=8.8Hz,2H),3.36–3.35(m,4H),3.21–3.20(m,4H),2.19(s,3H),1.10(s,9H).MS(ESI)m / z 496.2[M+H] + .

[1072] Example 85. 2-(4-(4-((4-((3-(N-(tert-butyl)sulfamoyl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)phenyl)piperazin-1-yl)acetic acid

[1073]

[1074] Step 1: Synthesis of methyl 2-(4-(4-((4-((3-(N-(tert-butyl)sulfamoyl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)phenyl)piperazin-1-yl)acetate

[1075]

[1076] To a solution of N-tert-butyl-3-[[5-methyl-2-(4-piperazin-1-ylanilino)pyrimidin-4-yl]amino]benzenesulfonamide (275 mg, 0.52 mmol, HCl) in DMF (5 mL) was added EtN (208.8 mg, 2.07 mmol) at room temperature. The reaction was stirred at room temperature for 10 min. Methyl 2-chloroacetate (168.26 mg, 1.55 mmol) was added and the resulting mixture was stirred at room temperature for 2 h, at which time TLC indicated that the starting material had been consumed. The mixture was diluted with H O (15 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried and concentrated to give 280 mg of crude product, which was triturated with 10 mL of solvent (petroleum ether: EtOAc = 10: 1) to give pure 2-[4-[4-[[4-[3-(tert-butylsulfamoyl)anilino]-5-methyl-pyrimidin-2-yl]amino]phenyl]piperazin-1-yl]acetic acid methyl ester (240 mg, yield 82%) as a white solid, which was used directly in the next step.

[1077] Step 2:Synthesis of 2-(4-(4-((4-((3-(N-(tert-butyl)sulfamoyl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)phenyl)piperazin-1-yl)acetic acid

[1078]

[1079] To a solution of methyl 2-[4-[4-[[4-[3-(tert-butyl)sulfamoyl]-5-methyl-pyrimidin-2-yl]amino]phenyl]piperazin-1-yl]acetate (240 mg, 0.42 mmol) in THF (10 mL) at room temperature were added LiOH (67.64 mg, 1.69 mmol) and H2O (2...

Claims

1. A heterobifunctional compound or a pharmaceutically acceptable salt thereof, characterized in that: The heterobifunctional compound is selected from the group consisting of: 1-(3-(4-(4-(8-(3,5-difluoro-4-(morpholinomethyl)phenyl)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)phenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)urea, i.e. JA-310; 1-(3-(4-(4-(8-(3,5-difluoro-4-(morpholinomethyl)phenyl)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)3-oxopropyl)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)urea i.e. JA-311 2-(3-(4-(4-(8-(3,5-difluoro-4-(morpholinomethyl)phenyl)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide, i.e. JA-313; 5-(4-(4-(8-(3,5-difluoro-4-(morpholinomethyl)phenyl)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl JA-315; 2-(3-(4-(4-(8-(3,5-difluoro-4-(morpholinomethyl)phenyl)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide, i.e. JA-317; 1-(3-(4-(4-(8-(3,5-difluoro-4-(morpholinomethyl)phenyl)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)phenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)urea, i.e., JA-325; and 2-(2-(4-(4-(8-(3,5-difluoro-4-(morpholinomethyl)phenyl)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)cyclopropyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)acetamide is JA-342.

2. The heterobifunctional compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The heterobifunctional compound is selected from the group consisting of: 1-(3-(4-(4-(8-(3,5-difluoro-4-(morpholinomethyl)phenyl)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)phenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)urea, i.e. JA-310; 2-(3-(4-(4-(8-(3,5-difluoro-4-(morpholinomethyl)phenyl)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide, i.e. JA-313; and 1-(3-(4-(4-(8-(3,5-difluoro-4-(morpholinomethyl)phenyl)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)phenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)urea, namely JA-325.

3. A composition comprising the heterobifunctional compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

4. Use of the heterobifunctional compound or a pharmaceutically acceptable salt thereof as claimed in claim 1 or 2 or the composition as claimed in claim 3 in the preparation of a medicament for treating or preventing a disease, wherein the disease is AML (acute myeloid leukemia).

5. A drug combination comprising (i) a heterobifunctional compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof; and (Ii) a second therapeutic agent, wherein The second therapeutic agent is a FLT3 inhibitor.

6. The pharmaceutical combination according to claim 5, characterized in that The second therapeutic agent is gilteritinib.

7. Use of the drug combination according to claim 5 or 6 in the preparation of a drug for treating or preventing a disease, wherein the disease is AML (acute myeloid leukemia).

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