WO2022068933A1

WO2022068933A1 - Compounds and methods of treating diseases

Info

Publication number: WO2022068933A1
Application number: PCT/CN2021/122279
Authority: WO
Inventors: Michael Bruno Plewe; Jialiang Wang; Xiaoran HAN; Liqun Chen; Ting Yang; Chengwei Zhang
Original assignee: Cullgen (Shanghai) , Inc.
Priority date: 2020-09-30
Filing date: 2021-09-30
Publication date: 2022-04-07
Also published as: CN116323570A

Abstract

Provided are heterobifunctional compounds (e.g., bi-functional small molecule compounds), compositions comprising one or more of the heterobifunctional compounds, methods of use the heterobifunctional compounds for the treatment of certain disease in a subject in need thereof, and methods for identifying such heterobifunctional compounds.

Description

COMPOUNDS AND METHODS OF TREATING DISEASES

TECHNICAL FEILD

The present disclosure belongs to the field of medicine, and specifically relates to compounds and methods of treating diseases such as cancers.

BACKGROUND OF THE INVENTION

The human Janus kinase (JAK) family comprises four nonreceptor tyrosine kinases, JAK1, JAK2, JAK3 and TYK2. JAK kinases play a central role in the hematopoietic system through transducing cytokine-mediated signals. These intracellular kinases bound to type I and II cytokine receptors, which lack catalytic domains and reply on the kinase activities of JAKs for transducing signals to downstream molecules. Cytokine binding triggers conformational changes of their respective receptors and subsequently induces autophosphorylation and activation of JAK kinases bound to the receptors. JAK kinases then recruit and phosphorylate downstream signaling molecules, most importantly the signal transducer and activator of transcription (STAT) family transcription factors. Phosphorylated STATs are subsequently translocated into nucleus and activate transcription of genes implicated in hematopoiesis and immune response. Different cytokine receptors recruit distinct combinations of JAK kinases, which transduce signals to a wide range of downstream targets, modulating complex and lineage-dependent signaling networks.

Acting downstream of a variety of cytokine receptors, JAK kinases are crucially implicated in proliferation, survival, activation, and differentiation of hematopoietic cells. Furthermore, there is no known pathways that may adequately compensate the JAK/STAT signaling in the hematopoietic system. Hence, the activities of JAK kinases are essential to hematopoiesis and immunity. As a consequence, aberrations of JAK kinases are known to drive the pathogenesis of many diseases, most significantly inflammation, autoimmune diseases, and cancer. For many of these indications, JAK family kinases are well documented as important therapeutic targets. Therefore, there is an urgent need for new drugs targeting JAK kinases in the art.

SUMMARY OF THE INVENTION

This disclosure relates to heterobifunctional compounds (e.g., bi-functional small molecule compounds) , compositions comprising one or more of the heterobifunctional compounds, and to methods of use of the heterobifunctional compounds for the treatment of certain diseases in a subject in need thereof. The disclosure also relates to methods for identifying such heterobifunctional compounds.

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

In one embodiment, JAK ligand is capable of binding to a JAK protein comprising JAK1, JAK2, JAK3, and Tyrosine Kinase 2 (TYK2) , a JAK mutant, JAK deletion, or a JAK fusion protein. In one embodiment, the JAK ligand is a JAK inhibitor or a portion of JAK inhibitor. In another embodiment, the JAK ligand is selected from the group consisting of BSK805 (NVP-BSK805) , 1-amino- [1, 2, 4] triazolo [1, 5-a] pyridines (Cmpd 12) , TG101209, CEP-33799, Ruxolitinib, Tofacitinib (CP-690550) , Baricitinib, Oclacitinib, Cerdulatinib (PRT-062070) , Decernotinib (VX509) , Delgocitinib (JTE-052) , Fedratinib, Filgotinib (GLP0634) , Gandotinib (LY2784544) , Ilginatinib (NS-018) , Itacitinib (INCB03911) , Lestauritinib, Momelotinib (CYT387) , Pacritinib (SB1578) , Peficitinib, 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-amido pyrrolopyrazine (Cmpd 3q) , pyridone containing tetracycle (Cmpd 6) , triazolo-pyrrolopyridines (Cmpd 7) , pyrazolopyrimidines (Cmpd 7j) , imidazolopyridines (Cmpd 19) , 1-methyl-1H-imidazole derivatives (Cmpd 19a) , C-2 methyl imidazopyrrolopyridines (Cmpd 20) , pyrazolopyridinone (Cmpd 20a) , 9H-carbazole-1-carboxamides (Cmpd 21) , thianopyridines (Cmpd 23) , pyrazole-4-carboxamide (Cmpd 28) , imidazopyridine (Cmpd 30) , hydroxyethyl imidazo-pyrrolopyridines (Cmpd 31) , pyrrolopyridazines (Cmpd 35) , 6-oxopyridopyrimidines (Compound 36) , 2-aminopyrazolo [1, 5-a] pyrimidines (Cmpd 45) , cyclopropyl amides (Cmpd 46) , imidazo-pyrrolopyridines (Cmpd 49) , 1-amino-5H-pyrido [4, 3-b] indol-4-carboxamides (Cmpd 65) , Cmpd 3, Cmpd 13a, Cmpd 45a, and analogs thereof.

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

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.

In another embodiment, the JAK ligand is conjugated to the degradation tag via a linker moiety.

In another embodiment, the JAK ligand comprises a moiety of FORMULA 1:

wherein the linker moiety of the heterobifunctional compound is attached to R ¹; and A, B, C, D, E. F, G, X, Y, V, W, R ¹, R ², R ³ and n are as defined hereinafter.

In another embodiment, the JAK ligand comprises a moiety of FORMULA 2:

wherein the linker moiety of the heterobifunctional compound is attached to R ¹; and A, B, D, X, Y, V, W, R ¹, and R ² are as defined hereinafter.

In another embodiment, the JAK ligand comprises a moiety of FORMULA 1. In another embodiment, the JAK ligand is derived from NVP-BSK805. In another embodiment, the JAK ligand is FORMULA 3A.

In another embodiment, the degradation tag is a moiety of FORMULA 5, and the degradation tag is connected to the linker moiety of the heterobifunctional compound via Z _E;

wherein Z _E. R _E ¹. L _E. and Ring A _E are as defined hereinafter.

In some embodiments, the linker moiety is of FORMULA 9:

wherein A _L, W _L, B _L, and m _L, are as defined hereinafter.

In one embodiment, the linker moiety is of FORMULA 9A:

wherein R _L ¹, R _L ², R _L ³, R _L ⁴, A _L, W _L, B _L, m _L, n _L, and o _L are as defined hereinafter.

In another embodiment, the linker moiety is of FORMULA 9B:

wherein R _L ¹, R _L ², A _L, B _L, m _L and n _L. are as defined hereinafter.

In another embodiment, the linker moiety is of FORMULA 9C:

wherein 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 are as defined hereinafter.

In one embodiment, the linker moiety is of FORMULA 9D:

-A _L- (W _L) _qL-B _L-

(FORMULA 9D)

wherein W _L, A _L , B _L, and q _L are as defined hereinafter.

According to the 2nd aspect of the present disclosure, a composition disclosed herein comprises the heterobifunctional compound or a pharmaceutically acceptable salt or analog thereof.

In one embodiment, the composition further comprises one or more additional therapeutic agents.

In one embodiment, the additional therapeutic agent is selected from the group consisting of anti-cancer or anti-tumor agents, or the combination thereof.

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

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

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

In one embodiment, the composition comprises the heterobifunctional compound, wherein the JAK ligand is a moiety of FORMULA 1.

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

In one embodiment, the additional therapeutic agent is an inhibitor of PI3K/AKT/mTOR pathway.

In one embodiment, the additional therapeutic agent is an inhibitor of RAS/RAF/MEK/ERK pathway.

In one embodiment, the additional therapeutic agent is an inhibitor of FLT3 pathway.

In one embodiment, the additional therapeutic agent is an inhibitor of MAPK pathway.

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

In one embodiment, the additional therapeutic agent is selected from the group consisnting of FLT3 inhibitor, PI3K inhibitor, AKT inhibitor, mTOR inhibitor, RAS inhibitor, RAF inhibitor, MEK inhibitor, ERK. inhibitor, and the combinations thereof.

In one embodiment, the additional therapeutic agent is FLT3 inhibitor and/or AKT inhibitor.

According to the 3rd aspect of the present disclosure, a method of treating a JAK-mediated disease disclosed herein comprises administering to a subject with a JAK-mediated disease the heterobifunctional compound or a pharmaceutically acceptable salt or analog thereof.

In one embodiment, the JAK-mediated disease results from JAK expression, mutation, deletion, or fusion.

In one embodiment, the subject with the JAK-mediated disease has an elevated JAK function relative to a healthy subject without the JAK-mediated disease.

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

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

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

In one embodiment, the method further comprises administering to the subject an additional therapeutic regimen for treating cancer, inflammatory disorders, or autoimmune diseases.

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

In one embodiment, the JAK-mediated cancer is selected from the group consisting of brain cancer, stomach cancer, gastrointestinal tract cancer, liver cancer, biliary passage cancer, breast cancer, ovary cancer, cervix cancer, prostate cancer, testis cancer, penile cancer, genitourinary tract cancer, esophagus cancer, larynx cancer, skin cancer, lung cancer, pancreas cancer, thyroid cancer, gland cancer, bladder cancer, kidney cancer, muscle cancer, bone cancer, cancers of the hematopoietic system, myeloproliferative neoplasms, essential thrombocythemia, polycythemia vera, primary myelofibrosis, chronic neutrophilic leukemia, acute lymphoblastic leukemia, Hodgkin’s 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 disorders are selected from the group consisting of ankylosing spondylitis, Crohn’s disease, inflammatory bowel disease, ulcerative colitis, and ischemia reperfusion injuries.

In one embodiment, the JAK-mediated auto-immune diseases are 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 disorders, alopecia areata, and bullous pemphigoid.

In one embodiment, the JAK-mediated dermatological disorders are selected from the group consisting of atopic dermatitis, pruritus, alopecia areata, psoriasis, skin rash, skin irritation, skin sensitization, chronic mucocutaneous candidiasis, dermatomyositis, erythema multiforme, palmoplantar pustulosis, vitiligo, polyarteritis nodosa, and STING vasculopathy.

In one embodiment, the JAK-mediated viral infections are selected from the group consisting of infections of Hepatitis B, Hepatitis C, Human Immunodeficiency Virus (HIV) , Human T-lymphotropic Virus (HTLV1) , Epstein Barr Virus (EBV) , Varicella-Zoster Virus (VZV) and Human Papilloma Virus (HPV) .

In one embodiment, the JAK-mediated dry eye disorders are selected from the group consisting of dry eye syndrome (DES) and keratoconjunctivitis sicca (KCS) .

In one embodiment, the JAK-mediated bone remodeling disorders are selected from the group consisting of osteoporosis and osteoarthritis.

In one embodiment, the JAK-mediated organ transplant associated immunological complications are selected from the group consisting of graft-versus-host diseases.

In one embodiment, the JAK-mediated disease is a relapsed cancer.

In one embodiment, the JAK-mediated disease is refractory to one or more previous treatments.

According to the 4 ^th aspect of the present disclosure, a method for identifying a heterobifunctional compound which mediates degradation or reduction of JAK is disclosed. The method comprises:

providing a heterobifunctional test compound comprising an JAK ligand conjugated to a degradation tag through a linker;

contacting the heterobifunctional test compound with a cell comprising a ubiquitin ligase and JAK;

determining whether JAK level is decreased in the cell; and

identifying the heterobifunctional test compound as a heterobifunctional compound which mediates degradation or reduction of JAK.

In one embodiment, the cell is a cancer cell.

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

According to 5th aspect of the present disclosure, a method of treating a GSTP1-mediated disease disclosed herein comprises administering to a subject with a GSTP1-mediated disease the heterobifunctional compound or a pharmaceutically acceptable salt or analog thereof.

According to the 6th aspect of the present disclosure, a method of treating a JAK-and GSTP1-mediated disease disclosed herein comprises administering to a subject with a JAK-and GSTP1-mediated disease the heterobifunctional compound or a pharmaceutically acceptable salt or analog thereof.

According to the 7th aspect of the present disclosure, a use of the heterobifunctional compound, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or analog thereof, is provided in combination with a second therapeutic agent.

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

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 as in the first aspect.

In one embodiment, the second therapeutic agent is selected from the group consisting of anti-cancer or anti-tumor agents, anti-proliferative agent, immunomodulatory agent, kinase inhibitor, kinase activator, signaling pathway inhibitor, or the combination thereof.

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

In one embodiment, the second therapeutic agent is an inhibitor of PI3K/AKT/mTOR pathway.

In one embodiment, the second therapeutic agent is an inhibitor of RAS/RAF/MEK/ERK pathway.

In one embodiment, the second therapeutic agent t is an inhibitor of FLT3 pathway.

In one embodiment, the second therapeutic agent t is an inhibitor of MAPK pathway.

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

In one embodiment, the second therapeutic agent is selected from the group consisnting of FLT3 inhibitor, PI3K inhibitor, AKT inhibitor, mTOR inhibitor, RAS inhibitor, RAF inhibitor, MEK inhibitor, ERK. inhibitor, and the combinations thereof.

In one embodiment, the second therapeutic agent is FLT3 inhibitor, AKT inhibitor, and/or MEK inhibitor.

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

According to the 8 ^th of aspect of the present disclosure, a method for treating or preventing diseases is provided, the method comprises administering the heterobifunctional compound, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or analog thereof and the second therapeutic agent to the subject in need.

In one embodiment, the diseases is JAK-mediated disease or GSTP1-mediated disease described herein, or the disease selected from cancer, inflammatory disorders, or autoimmune diseases.

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

In one embodiment, the heterobifunctional compound and the second therapeutic agent may be administered simultaneiously, separately or over a period of time.

According to the 9 ^th of aspect of the present disclosure, a pharmaceutical combination is provided, comprising

(i) the heterobifunctional compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or analog thereof; and

(ii) the second therapeutic agent.

In one embodiment, the pharmaceutical combination is used for treating the diseases as defined above (such as JAK-mediated disease or GSTP1-mediated disease) .

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

According to the 10 ^th of aspect of the present disclosure, a use of the pharmaceutical combination in treating or preventing diseases is provided. In one embodiment, the diseases is JAK-mediated disease or GSTP1-mediated disease described herein, or the disease selected from cancer, inflammatory disorders, or autoimmune diseases.

INCORPORATION BY REFERENCE

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.

BRIEF DESCRIPTION OF THE DRAWINGS

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

FIG. 1 shows an immunoblot of JAK1/2/3 proteins expressed in HEL cells after treatment with a dose range of heterobifunctional compounds JA-189 or JA-213 or a single dose of NVP-BSK805.

FIG. 2 shows an immunoblot of JAK1/3 proteins expressed in RS4; 11 cells after treatment with a dose range of compounds JA-189, JA-213, NVP-BSK805 or TG101209.

FIG. 3 shows graphs of MV4; 11, RS4; 11, Kasumi-1 and HEL cell viability vs. concentration of JA-189, JA-213, NVP-BSK805 and TG101209.

FIG. 4 shows graphs of MV4; 11, RS4; 11, Kasumi-1 and HEL cell viability vs. concentration of JA-189, JA-213, NVP-BSK805 and TG101209 in the presence or absence of pomalidomide at 10μM.

FIG. 5 shows an immunoblot of GSPT1 and tubulin expressed in RS4: 11 cells treated with JA-189, JA-213, or CC-885 at indicated concentrations for 16 hours.

FIG. 6 shows graphs of immortalized human lung fibroblast IMR-90 and keratinocyte HACAT cell viability vs. concentration of JA-189, and JA-213.

FIG. 7 shows inhibition of FLT3 in FLT3-mutant AML cells, remarkably increases sensitivity to GSPT1 degraders, JA-189, JA-263, JA-322, and JA-324.

FIG. 8 shows inhibition of FLT3 in FLT3-wild type AML cells does not affect sensitivity to GSPT1 degraders JA-189 and JA-263.

FIG. 9 shows GSPT1 degraders, JA-189, JA-263, JA-322, JA-323, and JA-324, reduce GSPT1 protein levels.

FIG. 10 shows inhibition of MAPK or PI3K/AKT signaling increases sensitivity to GSPT1 degraders, JA-189 and JA-263.

DETAILED DESCRIPTION OF THE INVENTION

The human Janus kinase (JAK) family comprises four nonreceptor tyrosine kinases, JAK1, JAK2, JAK3 and TYK2. JAK kinases play a central role in the hematopoietic system through transducing cytokine-mediated signals (O'Shea, Schwartz et al. 2015) . These intracellular kinases bound to type I and II cytokine receptors, which lack catalytic domains and reply on the kinase activities of JAKs for transducing signals to downstream molecules. Cytokine binding triggers conformational changes of their respective receptors and subsequently induces autophosphorylation and activation of JAK kinases bound to the receptors. JAK kinases then recruit and phosphorylate downstream signaling molecules, most importantly the signal transducer and activator of transcription (STAT) family transcription factors. Phosphorylated STATs are subsequently translocated into nucleus and activate transcription of genes implicated in hematopoiesis and immune response. Different cytokine receptors recruit distinct combinations of JAK kinases, which transduce signals to a wide range of downstream targets, modulating complex and lineage-dependent signaling networks (Schwartz, Kanno et al. 2017) .

Acting downstream of a variety of cytokine receptors, JAK kinases are crucially implicated in proliferation, survival, activation, and differentiation of hematopoietic cells (Villarino, Kanno et al. 2015) . Furthermore, there is no known pathways that may adequately compensate the JAK/STAT signaling in the hematopoietic system. Hence, the activities of JAK kinases are essential to hematopoiesis and immunity. As a consequence, aberrations of JAK kinases are known to drive the pathogenesis of many diseases, most significantly inflammation, autoimmune diseases, and cancer (O'Shea, Schwartz et al. 2015) . For many of these indications, JAK family kinases are well documented as important therapeutic targets.

Mutations leading to constitutive JAK2 activation are found in the majority of BCR-ABL-negative myeloproliferative neoplasms (MPNs) , including essential thrombocythemia (ET) , polycythemia vera (PV) , and primary myelofibrosis (PMF) (Levine, Wadleigh et al. 2005, Griesshammer and Sadjadian 2017) . Within these indications, JAK2-V617F is the most common mutation. JAK2 mutations have also been described in chronic neutrophilic leukemia, acute lymphoblastic leukemia, Hodgkin’s lymphoma, and other hematologic malignancies. In addition to JAK2 point mutations, fusions of JAK2, and mutations of JAK1 and JAK3 have also been identified as mechanisms activating the JAK pathway, albeit to less extent (O'Shea, Holland et al. 2013) . Alternative mechanisms to activate JAK kinases include mutations of JAK regulators, such as CSFR3 (Maxson, Gotlib et al. 2013) , MPL (Kilpivaara and Levine 2008) , and CALR (Rumi, Pietra et al. 2014) . Activation of JAK2 is also implicated in non-malignant hematopoietic indications, such as hereditary thrombocythemia (Langabeer 2014) . Importantly, a wide range of immunological disorders involves aberrant activation of JAK kinases, 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) .

Three JAK inhibitors have been approved for use in human for treatment of rheumatoid arthritis including Ruxolitinib (Mesa, et al., 2012) , Tofacitinib (CP-690550) (Traynor, 2012; Lee, et al., 2014; Dhillon, 2017; Strand, et al., 2019) , and Baricitinib (Taylor, et al., 2017; Markham, 2017) , and the JAK inhibitor Oclacitinib (Gonzales, et al., 2014) has been approved for treatment of canine allergic dermatitis. Multiple JAK kinase inhibitors are currently undergoing clinical or pre-clinical development, including but are not limited to Cerdulatinib (PRT-062070) (Hamlin, et al., 2019) , Decernotinib (VX509) (Farmer, et al., 2015) , Delgocitinib (JTE-052) (Nakagawa, et al., 2018) , Fedratinib (Wernig, et al., 2008; Harrison, et al., 2017) , Filgotinib (GLP0634) (Menet, et al., 2014; Van Rompaey, et al., 2013) , Gandotinib (LY2784544) (Berdeja, et al., 2018) , Ilginatinib (NS-018) (Nakaya, et al., 2011; Verstovsek, et al., 2016) , Itacitinib (INCB03911) (Beatty, et al., 2018) , Lestauritinib (Mascarenhas, et al., 2019; Pinto, et al., 2018) , Momelotinib (CYT387) (Pardanani, et al., 2018) , Pacritinib (SB1578) (Tremblay, et al., 2018; William, et al., 2012) , Peficitinib (Takeuchi, et al., 2016; Hamaguchi, et al., 2018) , Solcitinib (GSK2586184, GLG0778) (Kahl, et al., 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-031301 (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-amido pyrrolopyrazine (Cmpd 3q) (Soth, et al., 2013) , pyridone containing tetracycle (Cmpd 6) (Thompson, et al., 2001; Williams, et al., 2009) , triazolo-pyrrolopyridines (Cmpd 7) (Hurley, et al., 2013) , pyrazolopyrimidines (Cmpd 7j) (Hanan, et al., 2012) , 1-amino- [1, 2, 4] triazolo [1, 5-a] pyridines (Cmpd 12) (Siu, et al., 2013) , imidazolopyridines (Cmpd 19) (Simov, et al., 2016) , 1-methyl-1H-imidazole derivatives (Cmpd 19a) (Su, et al., 2014) , C-2 methyl imidazopyrrolopyridines (Cmpd 20) (Zak, et al., 2012) , pyrazolopyridinone (Cmpd 20a) (Yogo, et al., 2016) , 9H-carbazole-1-carboxamides (Cmpd 21) (Zimmermann, et al., 2015) , thianopyridines (Cmpd 23) (Schenkel, et al., 2011) , pyrazole-4-carboxamide (Cmpd 28) (Siu, et al., 2017) , imidazopyridine (Cmpd 30) (Liang, et al., 2017) , hydroxyethyl imidazo-pyrrolopyridines (Cmpd 31) (Zak, et al., 2013) , pyrrolopyridazines (Cmpd 35) (Hynes, et al., 2017) , 6-oxopyridopyrimidines (Compound 36) (Labadie, et al., 2013) , 2-aminopyrazolo [1, 5-a] pyrimidines (Cmpd 45) (Ledeboer, et al., 2009) , cyclopropyl amides (Cmpd 46) (Liang, et al., 2013; Liang, et al., 2013) , imidazo-pyrrolopyridines (Cmpd 49) (Kulagowski, et al., 2012) , 1-amino-5H-pyrido [4, 3-b] indol-4-carboxamides (Cmpd 65) (Lim, et al., 2011) , and covalent selective inhibitors of JAK3 (Cmpd 3) (Goedken, et al., 2015) , (Cmpd 13a) (Kempson, et al., 2017) , and (Cmpd 45a) (Tan, et al., 2015) .

Despite the approval of JAK2 kinase inhibitors 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 functions of JAK2. Knockout of JAK2 in mouse models results in embryonic lethality due to a complete loss of EpoR signaling and a lack of erythropoiesis (Neubauer, Cumano et al. 1998) . JAK2-knockout mice also show deficient interferon γ signaling. The tyrosine residues 1007/1008 of JAK2 within the kinase activation loop are essential for its kinase activity. Using a genetically engineered mouse model that expresses a kinase-dead mutant (YY1007/1008FF) of JAK2, Keil and colleagues demonstrate that kinase-dead JAK2 partially sustains the interferon γ signaling, possibly through acting as a scaffolding protein at the heteromeric interferon γ receptor (Keil, Finkenstadt et al. 2014) . It is also well documented that JAK2 kinase inhibitors stimulate the activation loop phosphorylation, leading to reactivation of JAK signaling through dimerization of JAK2 with other JAK kinases, and consequently promoting resistance to JAK2 kinase inhibitors in MPNs (Koppikar, Bhagwat et al. 2012) . Most importantly, cells resistant to JAK2 kinase inhibitors remain sensitive to depletion of JAK2 expressions (Koppikar, Bhagwat et al. 2012) . Therefore, depleting JAK2 protein is an appealing strategy to improve outcomes of patients with JAK2-driven MPNs.

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 which degrade JAK (e.g. JAK1, JAK2, JAK3, and TYK2) , JAK fusion proteins, JAK deletion proteins, and/or JAK mutant proteins are useful in the treatment of JAK-mediated diseases: such as cancer (e.g. cancers of brain, stomach, gastrointestinal tracts, liver, biliary passage, breast, ovary, cervix, prostate, testis, penile, genitourinary tract, esophagus, larynx, skin, lung, pancreas, thyroid, glands, bladder, kidney, muscle, bone, and cancers of the hematopoietic system, such as myeloproliferative neoplasms, including essential thrombocythemia, polycythemia vera, primary myelofibrosis, chronic neutrophilic leukemia, acute lymphoblastic leukemia, Hodgkin’s lymphoma, chronic myelomonocytic leukemia, systemic mast cell disease, hypereosinophilic syndrome, cutaneous T-cell lymphoma, B-cell lymphoma, myeloma, and other hematologic malignancies, particularly cancers that involve inflammation, mutations or other aberrations that activate the JAK pathway) (LaFave and Levine 2012, O'Shea, Holland et al. 2013) ; inflammation (e.g. ankylosing spondylitis, Crohn’s disease, inflammatory bowel disease, ulcerative colitis, and ischemia reperfusion injuries, which are conditions related to inflammatory ischemic events such as stroke or cardiac arrest) (Schwartz, Kanno et al. 2017) ; auto-immune diseases (e.g. multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, psoriasis, myasthenia gravis, type I diabetes, systemic lupus erythematosus, IgA nephropathy, autoimmune thyroid disorders, alopecia areata, and bullous pemphigoid) (O'Shea, Kontzias et al. 2013) ; dermatological disorders (e.g. atopic dermatitis, pruritus, alopecia areata, psoriasis, skin rash, skin irritation, skin sensitization, 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 consequent complications, such as infections of Hepatitis B, Hepatitis C, Human Immunodeficiency Virus (HIV) , Human T-lymphotropic Virus (HTLV1) , Epstein Barr Virus (EBV) , Varicella-Zoster Virus (VZV) and Human Papilloma Virus (HPV) ) (Fleming 2016) ; dry eye disorder, also known as dry eye syndrome (DES) or keratoconjunctivitis sicca (KCS) (Colligris, Alkozi et al. 2014) ; bone remodeling disorders (e.g. osteoporosis and osteoarthritis) (Li 2013) ; organ transplant associated immunological complications (e.g. graft-versus-host diseases) (Moore, Iasella et al. 2017) .

Termination of translation is a GTP-dependent process that is regulated by two key proteins eRF1 and eRF3. The translation termination factor eRF3a (also known as GSPT1) is a GTPase that interacts with eRF1 to promote stop codon recognition and release of nascent peptide from ribosome (Chauvin, Salhi et al. 2005) . GSPT1 activates eRF1 in a GTP-dependent manner and its GTPase activity requires complexing with eRF1 and ribosomes (Frolova, Le Goff et al. 1996) . The GTP-bound GSPT1 and eRF1 together with ribosomes form the functional translation termination complexes (Zhouravleva, Frolova et al. 1995) . Through regulation of translation, GSPT1 has diverse and important roles in cell physiology. Increased expression of GSPT1 has been reported in human malignancies, including lung cancer and gastric cancer (Malta-Vacas, Aires et al. 2005, Tian, Tian et al. 2018, Sun, Zhang et al. 2019, Zhang, Zou et al. 2019) . Hence, GSPT1 is thought to be a novel cancer target through which may compromise active translation that contributes to malignant phenotypes of cancer cells. Recently, Matyskiela and colleagues have reported that a phthalimide-derived molecule CC-885 led 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 was degraded by a subset of heterobiofunctional compounds derived from phthalimide (Ishoey, Chorn et al. 2018) . CC-885 induced significant toxicity in the vast majority of tested cell lines, presumably due to degrading GSTP1 and many other proteins (Matyskiela, Lu et al. 2016) . Therefore, despite the broad and potent anti-cancer activity, CC-885 exhibits unacceptable toxicity that prevents further development (Hansen, Correa et al. 2020) .

Selective degradation of a target protein induced by a small molecule may be achieved by recruiting an E3 ubiquitin ligase and mimicking protein misfolding with a hydrophobic tag (Buckley and Crews 2014) . Additionally, protein degraders are heterobifunctional compounds having one moiety that binds to an E3 ubiquitin ligase and another moiety that binds the protein target of interest (Buckley and Crews 2014) . The induced proximity leads to ubiquitination of the target followed by its degradation via proteasome-mediated proteolysis. 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 cereblon (CRBN or CRL4CRBN) , a component of a 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, which binds van Hippel-Lindau protein (VHL or CRL2VHL) , a component of another 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 KEAP1, a component of a CRL3 complex (Davies, Wixted et al. 2016) ; (4) AMG232, which selectively binds MDM2, a heterodimeric RING E3 ligase (Sun, Li et al. 2014) ; and (5) LCL161, which selectively binds IAP, a homodimeric RING E3 ligase (Okuhira, Ohoka et al. 2011, Ohoka, Okuhira et al. 2017, Shibata, Miyamoto et al. 2017) . The PROTAC technology has been applied to degradation of several 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 approach, which utilizes a bulky and hydrophobic adamantyl group, has been developed to mimic protein misfolding, leading to the degradation of the target protein (Buckley and Crews 2014) . This approach has been applied to selective degradation of the pseudokinase HER3 (Xie, Lim et al. 2014) . The inventors have not yet seen any efforts applying any of these approaches to degradation of JAK (e.g. JAK1, JAK2, JAK3, and TYK2) , JAK mutant, JAK deletion, or JAK fusion proteins.

Currently available small molecules targeting JAK (e.g. JAK1, JAK2, JAK3, and TYK2) focus on inhibition of JAK kinase activities.

In the present disclosure, a novel approach is taken: to develop compounds that directly and selectively modulate not only the kianse activity of JAK (e.g. JAK1, JAK2, JAK3, and TYK2) , but also their protein level. Strategies for inducing protein degradation include recruiting E3 ubiquitin ligases, mimicking protein misfolding with hydrophobic tags, and inhibiting chaperones. Such an approach, based on the use of heterobifunctional small molecule compounds, permits more flexible regulation of protein levels in vitro and in vivo compared with techniques such as genetic knockout or knockdown. Unlike genetic knockout or knockdown, a small molecule approach further provides an opportunity to study dose and time dependency in a disease model through modulating the administration routes, concentrations and frequencies of administration of the corresponding small molecule.

This disclosure includes all stereoisomers, geometric isomers, tautomers and isotopes of the structures depicted and compounds named herein. This disclosure also includes compounds described herein, regardless of how they are prepared, e.g., synthetically, through biological process (e.g., metabolism or enzyme conversion) , or a combination thereof.

This disclosure includes pharmaceutically acceptable salts of the structures depicted and compounds named herein.

One or more constituent atoms of the compounds presented herein can be replaced or substituted with isotopes of the atoms in natural 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 of the hydrogen atoms in a 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 of the hydrogen atoms in a compound can be replaced or substituted by fluorine atoms.

Heterobifunctional Compounds

As used herein, the term “heterobifunctional compound (s) ” and “bivalnt compound (s) ” can be used interchangeably.

In some aspects, the present disclosure provides heterobifunctional compounds including a JAK ligand conjugated to a degradation tag, or a pharmaceutically acceptable salt or analog thereof. The JAK ligand may be conjugated to the degradation tag directly or via a linker moiety. In certain embodiments, the JAK ligand may be conjugated to the degradation tag directly. In certain embodiments, the JAK ligand may be conjugated to the degradation tag via a linker moiety.

As used herein, the terms “Janus kinase liagnd” and “JAK ligand” , or “JAK targeting moiety” are to be construed to encompass any molecules ranging from small molecules to large proteins that associate with or bind to any of JAK1, JAK2, JAK3, or TYK2 proteins. In certain embodiments, the JAK ligand is capable of binding to a JAK protein comprising JAK (e.g. 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 JAK inhibitor. The JAK ligand can be, for example but not limited to, a small molecule compound (i.e., a molecule of molecular weight less than about 1.5 kilodaltons (kDa) ) , a peptide or polypeptide, nucleic acid or oligonucleotide, carbohydrate such as oligosaccharides, or an antibody or fragment thereof.

JAK Ligand

The JAK ligand or targeting moiety can be a JAK inhibitor or a portion of JAK inhibitor. In certain embodiments, the JAK inhibitor comprises one or more of (e.g., Ruxolitinib, Tofacitinib (CP-690550) , Baricitinib, Oclacitinib, Cerdulatinib (PRT-062070) , Decernotinib (VX509) , Delgocitinib (JTE-052) , Fedratinib, Filgotinib (GLP0634) , Gandotinib (LY2784544) , Ilginatinib (NS-018) , Itacitinib (INCB03911) , Lestauritinib, Momelotinib (CYT387) , Pacritinib (SB1578) , Peficitinib, Solcitinib (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, 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-amido pyrrolopyrazine (Cmpd 3q) , pyridone containing tetracycle (Cmpd 6) , triazolo-pyrrolopyridines (Cmpd 7) , pyrazolopyrimidines (Cmpd 7j) , 1-amino- [1, 2, 4] triazolo [1, 5-a] pyridines (Cmpd 12) , imidazolopyridines (Cmpd 19) , 1-methyl-1H-imidazole derivatives (Cmpd 19a) , C-2 methyl imidazopyrrolopyridines (Cmpd 20) , pyrazolopyridinone (Cmpd 20a) , 9H-carbazole-1-carboxamides (Cmpd 21) , thianopyridines (Cmpd 23) , pyrazole-4-carboxamide (Cmpd 28) , imidazopyridine (Cmpd 30) , hydroxyethyl imidazo-pyrrolopyridines (Cmpd 31) , pyrrolopyridazines (Cmpd 35) , 6-oxopyridopyrimidines (Compound 36) , 2-aminopyrazolo [1, 5-a] pyrimidines (Cmpd 45) , cyclopropyl amides (Cmpd 46) , imidazo-pyrrolopyridines (Cmpd 49) , 1-amino-5H-pyrido [4, 3-b] indol-4-carboxamides (Cmpd 65) , Cmpd 3, Cmpd 13a, Cmpd 45a, and analogs thereof) , which is capable of inhibiting the protein-protein interaction or acetyltransferase activity of JAK. As used herein, a “JAK inhibitor” refers to an agent that restrains, retards, or otherwise causes inhibition of a physiological, chemical or enzymatic action or function and causes a decrease in binding of at least 5%. An inhibitor can also or alternately refer to a drug, compound, or agent that prevents or reduces the expression, transcription, or translation of a gene or protein. An inhibitor can reduce or prevent the function of a protein, e.g., by binding to or activating/inactivating another protein or receptor.

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

In certain embodiments, the JAK ligand include, but are not limited to Ruxolitinib, Tofacitinib (CP- 690550) , Baricitinib, Oclacitinib, Cerdulatinib (PRT-062070) , Decernotinib (VX509) , Delgocitinib (JTE-052) , Fedratinib, Filgotinib (GLP0634) , Gandotinib (LY2784544) , Ilginatinib (NS-018) , Itacitinib (INCB03911) , Lestauritinib, Momelotinib (CYT387) , Pacritinib (SB1578) , Peficitinib, Solcitinib (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, 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-amido pyrrolopyrazine (Cmpd 3q) , pyridone containing tetracycle (Cmpd 6) , triazolo-pyrrolopyridines (Cmpd 7) , pyrazolopyrimidines (Cmpd 7j) , 1-amino- [1, 2, 4] triazolo [1, 5-a] pyridines (Cmpd 12) , imidazolopyridines (Cmpd 19) , 1-methyl-1H-imidazole derivatives (Cmpd 19a) , C-2 methyl imidazopyrrolopyridines (Cmpd 20) , pyrazolopyridinone (Cmpd 20a) , 9H-carbazole-1-carboxamides (Cmpd 21) , thianopyridines (Cmpd 23) , pyrazole-4-carboxamide (Cmpd 28) , imidazopyridine (Cmpd 30) , hydroxyethyl imidazo-pyrrolopyridines (Cmpd 31) , pyrrolopyridazines (Cmpd 35) , 6-oxopyridopyrimidines (Compound 36) , 2-aminopyrazolo [1, 5-a] pyrimidines (Cmpd 45) , cyclopropyl amides (Cmpd 46) , imidazo-pyrrolopyridines (Cmpd 49) , 1-amino-5H-pyrido [4, 3-b] indol-4-carboxamides (Cmpd 65) , Cmpd 3, Cmpd 13a, and Cmpd 45a.

In one embodiment, the JAK ligand comprises a moiety of FORMULA 1:

wherein

the linker moiety of the heterobifunctional compound is attached to R ¹;

A and D are independently selected from CR ⁴ and N, wherein

R ⁴ is selected from H, halogen, optionally substituted C ₁-C ₈ alkyl, and optionally substituted 3-10 membered carbocyclyl;

B, C, and G are independently selected from C and N; with the proviso that at most only one of B, C, and G is N;

E and F are independently selected from null, CR ⁵ and N, wherein

R ⁵ is selected from H, halogen, optionally substituted C ₁-C ₈ alkyl, and optionally substituted 3-10 membered carbocyclyl;

X and Y are independently selected from null, or a bivalent moiety selected from null, CR ⁶R ⁷, CO, CO ₂, CONR ⁶, NR ⁶, NR ⁶CO, NR ⁶CO ₂, NR ⁶C (O) NR ⁷, NR ⁶SO, NR ⁶SO ₂, NR ⁶SO ₂NR ⁷, O, OC (O) , OCO ₂, OCONR ⁶, S, SO, SO ₂, and SO ₂NR ⁶, wherein

R ⁶ and R ⁷ are independently selected from H, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C ₁-C ₈ alkyl, optionally substituted C ₂-C ₈ alkenyl, optionally substituted C ₂-C ₈ alkynyl, optionally substituted C ₁-C ₈ alkoxy, optionally substituted C ₁-C ₈ alkylamino, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

R ⁶ and R ⁷ together with the atom or atoms to which they are connected form a 3-20 membered carbocyclyl ring or 3-20 membered heterocyclyl ring;

V and W are independently selected from null, carbocyclyl, heterocyclyl, aryl, and heteroaryl, which are optionally substituted with one or more R ¹⁶;

R ¹ is connected to the “linker” moiety of the heterobifunctional compound, and is selected from null,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'SO ₂N (R ¹¹) R" , R'NR ¹²C (O) OR" , R'NR ¹²C (O) R" , R'NR ¹²C (O) N (R ¹¹) R" , R'NR ¹²S (O) R" , R'NR ¹²S (O) ₂R" , and R'NR ¹²S (O) ₂N (R ¹¹) R" , wherein

R'and R" are divalent groups independently selected from null, optionally substituted C ₁-C ₈ alkylene, optionally substituted C ₂-C ₈ alkenylene, optionally substituted C ₂-C ₈ alkynylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C ₄-C ₁₃ fused carbocyclyl, optionally substituted C ₅-C ₁₃ fused heterocyclyl, optionally substituted C ₅-C ₁₃ bridged carbocyclyl, optionally substituted C ₅-C ₁₃ bridged heterocyclyl, optionally substituted C ₅-C ₁₃ spiro carbocyclyl, optionally substituted C ₅-C ₁₃ spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R ¹¹ and R ¹² are independently selected from optionally substituted C ₁-C ₈ alkyl, optionally substituted C ₂-C ₈ alkenyl, optionally substituted C ₂-C ₈ alkynyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

R'and R" , R ¹¹ and R ¹², R'and R ¹¹, R'and R ¹², R" and R ¹¹ or R" and R ¹², together with the atom to which they are connected, form a 3-20 membered carbocyclyl or 3-20 membered heterocyclyl ring;

R ² is selected from H, halogen, OH, -O-C ₁-C ₈ alkyl, CN, NO ₂, C ₁-C ₈ alkyl, C ₂-C ₈ alkenyl, C ₂-C ₈ alkynyl, 3-10 membered carbocyclyl, 3-10 membered heterocyclyl, aryl, and heteroaryl; each of which are optionally substituted with one or more R ¹⁷;

R ¹⁶ and R ¹⁷ are each independently selected from H, halogen, oxo, CN, NO ₂, OR ⁸, SR ⁸, NR ⁸R ⁹, OCOR ⁸, OCO ₂R ⁸, OCON (R ⁸) R ⁹, COR ⁸, CO ₂R ⁸, CONR ⁸R ⁹, SOR ⁸, SO ₂R ⁸, SO ₂N (R ⁸) R ⁹, NR ¹⁰CO ₂R ⁸, NR ¹⁰COR ⁸, NR ¹⁰C (O) N (R ⁸) R ⁹, NR ¹⁰SOR ⁸, NR ¹⁰SO ₂R ⁸, NR ¹⁰SO ₂N (R ⁸) R ⁹, optionally substituted C ₁-C ₈ alkyl, optionally substituted C ₂-C ₈ alkenyl, optionally substituted C ₂-C ₈ alkynyl, optionally substituted C ₁-C ₈alkoxyC ₁-C ₈alkyl, optionally substituted C ₁-C ₈alkylaminoC ₁-C ₈alkyl, optionally substituted 3-10 membered heterocyclylC ₁-C ₈alkyl, optionally substituted 3-10 membered carbocyclylC ₁-C ₈alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein

R ⁸, R ⁹, and R ¹⁰ are independently selected from hydrogen, optionally substituted C ₁-C ₈ alkyl, optionally substituted C ₂-C ₈ alkenyl, optionally substituted C ₂-C ₈ alkynyl, optionally substituted C ₁-C ₈ alkoxy, optionally substituted C ₁-C ₈alkoxyC ₁-C ₈alkyl, optionally substituted C ₁-C ₈alkylaminoC ₁-C ₈alkyl, optionally substituted 3-10 membered carbocyclylC ₁-C ₈alkyl, optionally substituted 3-10 membered heterocyclylC ₁-C ₈alkyl, 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 together with the atom to which they are connected form a 3-20 membered heterocyclyl ring;

R ³, at each occurance, is selected from hydrogen, halogen, optionally substituted C ₁-C ₈ alkyl, and optionally substituted 3-10 membered carbocyclyl; and

n is selected from 1 or 2.

In one refinement, V is Ar ² _.

In one refinement, at least one of E and F is null. In one refinement, both of E and F are not null.

In one refinement, V is Ar ²; and Ar ² is selected from null, aryl and heteroaryl (preferably Ar ² is selected from null, monocyclic aryl, monocyclic heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl, and tricyclic heteroaryl) , each of which is optionally substituted with one or more R ¹⁶.

In one refinement, the JAK ligand comprises a moiety of FORMULA 1A:

wherein

the linker moiety of the heterobifunctional compound is attached to R ¹;

Ar ² is selected from null, aryl, and heteroaryl, each of which is optionally substituted with one or more R ¹⁶,

A, B, C, D, E, F, G, X, Y, W, R ¹, R ², R ³, R ¹⁶ and n are defined as in FORMULA 1.

In another refinement, V is Ar ²; and W is Ar ¹.

In another refinement, V is Ar ² and W is Ar ¹; and Ar ¹ and Ar ² are independently selected from null, aryl, and heteroaryl (preferably selected from null, monocyclic aryl, monocyclic heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl, and tricyclic heteroaryl) , each of which is optionally substituted with one or more R ¹⁶.

In another refinement, the JAK ligand comprises a moiety of FORMULA 1B:

wherein

the linker moiety of the heterobifunctional compound is attached to R ¹;

Ar ¹ and Ar ² are independently selected from null, aryl, and heteroaryl, each of which is optionally substituted with one or more R ¹⁶;

A, B, C, D, E, F, G, X, Y, R ¹, R ², R ³, and n are defined as in FORMULA 1.

In another refinement, A is N.

In another refinement, the JAK ligand comprises a moiety of FORMULA 1C:

wherein

the linker moiety of the heterobifunctional compound is attached to R ¹; and

B, C, D, E, F, G, V, W, X, Y, R ¹, R ², R ³, and n are defined as in FORMULA 1.

In another refinement, A is N; and V is Ar ²; and Ar ² is defined as above..

In another refinement, the JAK ligand comprises a moiety of FORMULA 1D:

wherein

the linker moiety of the heterobifunctional compound is attached to R ¹;

B, C, D, E, F, G, W, X, Y, R ¹, R ², R ³, and n are defined as in FORMULA 1; and

Ar ² is defined as in FORMULA 1A.

In another refinement, A is N; V is Ar ²; and W is Ar ¹; and Ar ¹ and Ar ² is defined as above..

In another refinement, the JAK ligand comprises a moiety of FORMULA 1E:

wherein

the linker moiety of the heterobifunctional compound is attached to R ¹;

B, C, D, E, F, G, X, Y, R ¹, R ², R ³, and n are defined as in FORMULA 1, and

Ar ¹ and Ar ² are defined as in FORMULA 1B.

In another refinement, the JAK ligand comprises a moiety of FORMULAE 1F, 1G, 1H, or 1I:

wherein

the linker moiety of the heterobifunctional compound is attached to R ¹;

R ¹³ and R ¹⁴ are defined as R ³; preferably, selected from hydrogen, halogen, optionally substituted C ₁-C ₈ alkyl, and optionally substituted 3-10 membered carbocyclyl;

V, W, X, Y, R ¹, R ², R ³, and n are defined as in FORMULA 1.

In another refinement, R ¹³ and R ¹⁴ are indenpently selected from H, halogen, optionally substituted C ₁-C ₈ alkyl, and optionally substituted 3-10 membered carbocyclyl.

In another refinement, the JAK ligand comprises a moiety of FORMULAE 1J, 1K, 1L, or 1M:

wherein

the linker moiety of the heterobifunctional compound is attached to R ¹;

R ¹³ and R ¹⁴ are defined as R ³ (preferably, defined as in FORMULAE 1F, 1G, 1H or 1I) ;

W, X, Y, R ¹, R ², R ³, and n are defined as in FORMULA 1;

Ar ² is defined as in FORMULA 1A.

In another refinement, the JAK ligand comprises a moiety of FORMULAE 1N, 1O, 1P, and 1Q:

wherein

the linker moiety of the heterobifunctional compound is attached to R ¹;

X, Y, R ¹, R ², R ³, and n are defined as in FORMULA 1;

Ar ¹ and Ar ² are defined as in FORMULA 1B.

In another refinement, the JAK ligand comprises a moiety of FORMULAE 1N.

In another refinement, X is selected from null, O, and NR ⁶, wherein R ⁶ is selected from H, optionally substituted C ₁-C ₈ alkyl, and optionally substituted 3-10 membered carbocyclyl.

In another refinement, X is selected from null and NH.

In another refinement, Y is selected from null, CR ⁶R ⁷, CO, CO ₂, O, SO, SO ₂, and NR ⁶, wherein

R ⁶ and R ⁷ are independently selected from H, optionally substituted C ₁-C ₈ alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 3-10 membered heterocyclyl.

In another refinement, Y is selected from CR ⁶R ⁷, CO, CO ₂, O, SO, SO ₂, and NR ⁶ (preferably, Y is CR ⁶R ⁷) , wherein R ⁶ and R ⁷ are independently selected from H, optionally substituted C ₁-C ₈ 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 C ₁-C ₈ alkyl) .

In another refinement, Y is selected from null, CH ₂, CO, and SO ₂. In another refinement, Y is selected from CH ₂, CO, and SO ₂. In another refinement, Y is CH ₂.

In another refinement, W and V are independently selected from null, monocyclic aryl, monocyclic heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl, and tricyclic heteroaryl, each of which is optionally substituted with one or more R ¹⁶. In another refinement, W and V are independently selected from null, monocyclic aryl (such as phenyl) , and monocyclic heteroaryl (such as 5, 6 or 7 membered heteroaryl) , each of which is optionally substituted with one or more R ¹⁶.

In another refinement, Ar ¹ and Ar ² are independently selected from null, monocyclic aryl, monocyclic heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl, and tricyclic heteroaryl, each of which is optionally substituted with one or more R ¹⁶. In another refinement, Ar ¹ and Ar ² are independently selected from null, monocyclic aryl (such as phenyl) , and monocyclic heteroaryl (such as 5, 6 or 7 membered heteroaryl) , each of which is optionally substituted with one or more R ¹⁶. In another refinement, Ar ¹ and Ar ² are 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 with one or more R ¹⁶.

In another refinement, each R ¹⁶ is independently selected from H, halogen, oxo, CN, NO ₂, OR ⁸, SR ⁸, N (R ⁸) R ⁹, COR ⁸, CO ₂R ⁸, CON (R ⁸) R ⁹, SOR ⁸, SO ₂R ⁸, SO ₂N (R ⁸) R ⁹, NR ¹⁰COR ⁸, NR ¹⁰SOR ⁸, NR ¹⁰SO ₂R ⁸, optionally substituted C ₁-C ₈ alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 3-10 membered heterocyclyl, wherein

R ⁸, R ⁹, and R ¹⁰ are independently selected from H, optionally substituted C ₁-C ₈ 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 together with the atom to which they are connected form a 3-10 membered heterocyclyl ring.

In another refinement, R ¹⁶ is each independently selected from H, halogen, oxo, CN, NO ₂, OR ⁸, NR ⁸R ⁹, NR ¹⁰COR ⁸, optionally substituted C ₁-C ₈ alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 3-10 membered heterocyclyl, wherein

In another refinement, R ¹⁶ is each independently selected from H, halogen, oxo, CN, NO ₂, OR ⁸, NR ⁸R ⁹, NR ¹⁰COR ⁸, and optionally substituted C ₁-C ₈ alkyl, wherein R ⁸, R ⁹, and R ¹⁰ are independently selected from H, and optionally substituted C ₁-C ₈ alkyl, or R ⁸ and R ⁹ together with the atom to which they are connected form a 3-10 membered heterocyclyl ring.

In another refinement, R ¹⁶ is each independently selected from H, CH ₃, CF ₃, iPr, cPr, OCH ₃, OCF ₃, OiPr, OcPr, F, Cl, and Br. In another refinement, R ¹⁶ is each independently selected from H and F.

In another refinement, V (or Ar ²) is monocyclic aryl (such as phenyl) , or monocyclic heteroaryl (such as 5, 6 or 7 membered heteroaryl) , preferably, V (or Ar ²) is phenyl, or 5, 6 or 7 membered heteroaryl containing 1, 2 or 3 N atoms as ring member, more preferably, V (or Ar ²) is phenyl; each of which is optionally substituted with one or more R ¹⁶

In another refinement, W (or Ar ¹) is monocyclic aryl (such as phenyl) , or monocyclic heteroaryl (such as 5, 6 or 7 membered heteroaryl) , preferably, W (or Ar ¹) is phenyl, or 5, 6 or 7 membered heteroaryl containing 1, 2 or 3 N atoms as ring member, more preferably, W (or Ar ¹) is 5 membered heteroaryl containing 1 or 2 N atoms; each of which is optionally substituted with one or more R ¹⁶.

In another refinement, Ar ¹ and Ar ² are independently selected from null, 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 substituted with R ² and optionally substituted with one or more R ¹⁶, and R ¹⁶ is each independently selected from hydrogen, halogen, oxo, CN, NO ₂, OR ⁸, SR ⁸, NR ⁸R ⁹, COR ⁸, CO ₂R ⁸, CONR ⁸R ⁹, SOR ⁸, SO ₂R ⁸, SO ₂NR ⁸R ⁹, NR ¹⁰COR ⁸, NR ¹⁰SOR ⁸, NR ¹⁰SO ₂R ⁸, optionally substituted C ₁-C ₈ alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 3-10 membered heterocyclyl, wherein

R ⁸, R ⁹, and R ¹⁰ are independently selected from hydrogen, optionally substituted C ₁-C ₈ 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 together with the atom to which they are connected form a 3-10 membered heterocyclyl ring.

In another refinement, Ar ¹ and Ar ² are independently selected from null, 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 substituted with R ² and optionally substituted with one or more R ¹⁶, and R ¹⁶ is each independently selected from hydrogen, halogen, oxo, CN, NO ₂, OR ⁸, NR ⁸R ⁹, NR ¹⁰COR ⁸, optionally substituted C ₁-C ₈ alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 3-10 membered heterocyclyl, wherein

In another refinement, Ar ¹ and Ar ² are independently selected from null, monocyclic aryl, monocyclic heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl, and tricyclic heteroaryl , each of which is substituted with R ² and optionally substituted with one or more R ¹⁶, and R ¹⁶ is each independently selected from hydrogen, CH ₃, CF ₃, iPr, cPr, OCH ₃, OCF ₃, OiPr, OcPr, F, Cl, and Br.

In another refinement, Ar ¹ and Ar ² are are independently selected from null, monocyclic aryl, monocyclic heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl, and tricyclic heteroaryl , each of which is substituted with R ² and optionally substituted with one or more R ¹⁶, and R ¹⁶ is each independently selected from H and F.

In another refinement, R ¹ is selected from null, O, NH, CO, CONH, optionally substituted C ₁-C ₈ alkylene, optionally substituted C ₂-C ₈ alkenylene, optionally substituted C ₂-C ₈ alkynylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.

In another refinement, R ¹ is selected from null, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 3-10 membered heterocyclyl.

In another refinement, R ¹ is selected from null and optionally substituted 3-10 membered heterocyclyl, which contains at least one of O or N.

In another refinement, R ¹ is selected from null, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted morpholinyl, optionally substituted pyrrolidinyl, optionally substituted tetrahydrofuranyl, optionally substituted azetidinyl, and optionally substituted oxetanyl.

In another refinement, R ² is selected from hydrogen, halogen, C ₁-C ₈ alkyl, C ₂-C ₈ alkenyl, C ₂-C ₈ alkenyl, 3-10 membered carbocyclyl, and 3-10 membered heterocyclyl, each of which are optionally substituted with one or more R ¹⁷.

In another refinement, R ² is selected from H, OH, -O-C ₁-C ₈ alkyl, halogen, C ₁-C ₈ alkyl, C ₂-C ₈ alkenyl, C ₂-C ₈ alkenyl, 3-10 membered carbocyclyl, and 3-10 membered heterocyclyl; each of which are optionally substituted with one or more R ¹⁷.

In another refinement, R ² is selected from H, OH, -O-C ₁-C ₈ alkyl, halogen, C ₁-C ₈ alkyl, 3-10 membered carbocyclyl, and 3-10 membered heterocyclyl; each of which are optionally substituted with one or more R ¹⁷.

In another refinement, R ² is selected from hydrogen, halogen, C ₁-C ₈ alkyl, 3-10 membered carbocyclyl, and 3-10 membered heterocyclyl, each of which are optionally substituted with one or more R ¹⁷.

In another refinement, R ² is selected from OH, CH ₃, CF ₃, iPr, cPr, F, Cl, Br, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl, and oxetanyl; each of which are optionally substituted with one or more R ¹⁷.

In another refinement, R ² is selected from CH ₃, CF ₃, iPr, cPr, F, Cl, Br, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl, and oxetanyl, each of which are optionally substituted with one or more R ¹⁷.

In another refinement, R ² is 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 are optionally substituted with one or more R ¹⁷. In another refinement, R ² is selected from piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl, and oxetanyl; each of which are optionally substituted with one or more R ¹⁷.

In another refinement, R ¹⁷ is each independently selected from H, halogen, oxo, CN, NO ₂, OR ⁸, SR ⁸, N (R ⁸) R ⁹, COR ⁸, CO ₂R ⁸, CON (R ⁸) R ⁹, SOR ⁸, SO ₂R ⁸, SO ₂N (R ⁸) R ⁹, NR ¹⁰COR ⁸, NR ¹⁰SOR ⁸, NR ¹⁰SO ₂R ⁸, optionally substituted C ₁-C ₈ alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 3-10 membered heterocyclyl, wherein

In another refinement, R ¹⁷ is each independently selected from H, halogen, oxo, CN, NO ₂, R ⁸, OR ⁸, SR ⁸, N (R ⁸) R ⁹, COR ⁸, CO ₂R ⁸, CON (R ⁸) R ⁹, SOR ⁸, SO ₂R ⁸, wherein R ⁸, and R ⁹ are independently selected from H, C ₁-C ₃ alkyl, C ₃-C ₆ alkyl, C ₁- ₃ haloalkyl, and C ₁- ₃ hydroxyalky.

In another refinement, R ¹⁷ is each independently selected from H, oxo, CH ₃, iPr, cPr, and OH.

In another refinement, R ³, at ech ocurrance, R ¹³ and R ¹⁴ are independently selected from hydrogen, CH ₃, CF ₃, iPr, cPr, tBu, CNCH ₂, F, Cl, Br, OH, NH ₂, CN, CH ₃, and CONH ₂.

In another embodiment, the JAK ligand comprises a moiety of FORMULA 2:

wherein

the linker moiety of the heterobifunctional compound is attached to R ¹;

A, B, and D are independently selected from CR ³ and N, with the proviso that not all of A, B, and D are N, wherein

R ³ is selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, CONR ⁴R ⁵, optionally substituted C ₁-C ₈ alkyl, and optionally substituted 3-10 membered carbocyclyl, wherein

R ⁴ and R ⁵ are independently selected from hydrogen, optionally substituted C ₁-C ₈ alkyl, optionally substituted C ₂-C ₈ alkenyl, optionally substituted C ₂-C ₈ alkynyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 3-10 membered heterocyclyl, or

R ⁴ and R ⁵ together with the atom or atoms to which they are connected form a 3-20 membered carbocyclyl ring or 3-20 membered heterocyclyl ring;

X and Y are independently selected from null, or a bivalent moiety selected from null, C (R ⁶) R ⁷, CO, CO ₂, CONR ⁶, NR ⁶, NR ⁶CO, NR ⁶CO ₂, NR ⁶C (O) NR ⁷, NR ⁶SO, NR ⁶SO ₂, NR ⁶SO ₂NR ⁷, O, OC (O) , OCO ₂, OCONR ⁶, S, SO, SO ₂, and SO ₂NR ⁶, wherein

R ⁶ and R ⁷ are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C ₁-C ₈ alkyl, optionally substituted C ₂-C ₈ alkenyl, optionally substituted C ₂-C ₈ alkynyl, optionally substituted C ₁-C ₈ alkoxy, optionally substituted C ₁-C ₈ alkylamino, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

R ¹⁶; is each independently selected from hydrogen, halogen, oxo, CN, NO ₂, OR ⁸, SR ⁸, N (R ⁸) R ⁹, OCOR ⁸, OCO ₂R ⁸, OCONR ⁸R ⁹, COR ⁸, CO ₂R ⁸, CON (R ⁸) R ⁹, SOR ⁸, SO ₂R ⁸, SO ₂N (R ⁸) R ⁹, NR ¹⁰CO ₂R ⁸, NR ¹⁰COR ⁸, NR ¹⁰C (O) N (R ⁸) R ⁹, NR ¹⁰SOR ⁸, NR ¹⁰SO ₂R ⁸, NR ¹⁰SO ₂N (R ⁸) R ⁹, optionally substituted C ₁-C ₈ alkyl, optionally substituted C ₂-C ₈ alkenyl, optionally substituted C ₂-C ₈ alkynyl, optionally substituted C ₁-C ₈alkoxyC ₁-C ₈alkyl, optionally substituted C ₁-C ₈alkylaminoC ₁-C ₈alkyl, optionally substituted 3-10 membered heterocyclylC ₁-C ₈alkyl, optionally substituted 3-10 membered carbocyclylC ₁-C ₈alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein

R ¹ is connected to the “linker” moiety of the heterobifunctional compound, and is selected from null, R'-R" , R'OR" , R'SR" , R'NR ¹¹R" , 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'SO ₂N (R ¹¹) R" , R'NR ¹²C (O) OR" , R'NR ¹²C (O) R" , R'NR ¹²C (O) N (R ¹¹) R" , R'NR ¹²S (O) R" , R'NR ¹²S (O) ₂R" , and R'NR ¹²S (O) ₂N (R ¹¹) R" , wherein

R'and R"are independently selected from null, optionally substituted C ₁-C ₈ alkyl, optionally substituted C ₂-C ₈ alkenyl, optionally substituted C ₂-C ₈ alkynyl, optionally substituted C ₁-C ₈ alkylene, optionally substituted C ₂-C ₈ alkenylene, optionally substituted C ₂-C ₈ alkynylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C ₄-C ₁₃ fused carbocyclyl, optionally substituted C ₅-C ₁₃ fused heterocyclyl, optionally substituted C ₅-C ₁₃ bridged carbocyclyl, optionally substituted C ₅-C ₁₃ bridged heterocyclyl, optionally substituted C ₅-C ₁₃ spiro carbocyclyl, optionally substituted C ₅-C ₁₃ spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R'and R" , R ¹¹ and R ¹², R'and R ¹¹, R'and R ¹², R" and R ¹¹, or R" and R ¹², together with the atom to which they are connected, form a 3-20 membered carbocyclyl or 3-20 membered heterocyclyl ring; and

R ² is selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C ₁-C ₈ alkyl, optionally substituted C ₂-C ₈ alkenyl, optionally substituted C ₂-C ₈ alkenyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

or when neither of V and W is null, V and W together with the substituents to which they are connected optionally form a 10-30 membered macrocyclic ring; when W is null and V is not null, V and R ¹ together with the substituents to which they are connected optionally form a 10-30 membered macrocyclic ring; when V is null and W is not null, W and R ² together with the substituents to which they are connected optionally form a 10-30 membered macrocyclic ring; or when W and V are null, R ¹ and R ² together with the substituents to which they are connected optionally form a 10-30 membered macrocyclic ring.

In another refinement, V is Ar ². In another refinement, V is Ar ²; and Ar ² is selected from null, aryl, and heteroaryl (preferably selected from null, monocyclic aryl, monocyclic heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl, and tricyclic heteroaryl) , each of which is optionally substituted with one or more R ¹⁶.

In another refinement, the JAK ligand comprises a moiety of FORMULA 2A:

wherein

the linker moiety of the heterobifunctional compound is attached to R ¹;

Ar ² is selected from null, aryl, and heteroaryl, each of which is optionally substituted with one or more R ¹⁶;

A, B, D, X, Y, W, R ¹, R ² and R ¹⁶ are defined as in FORMULA 2;

or when neither of W and Ar ² is null, W and Ar ² together with the substituents to which they are connected optionally form a 10-30 membered macrocyclic ring; When W is null and Ar ² is not null, Ar ² and R ¹ together with the substituents to which they are connected optionally form a 10-30 membered macrocyclic ring; When Ar ² is null and W is not null, W and R ² together with the substituents to which they are connected optionally form a 10-30 membered macrocyclic ring; or When W and Ar ² are null, R ¹ and R ² together with the substituents to which they are connected optionally form a 10-30 membered macrocyclic ring.

In another refinement, V is Ar ²; and W is Ar ¹. In another refinement, V is Ar ²; and W is Ar ¹; and Ar ¹ and Ar ² are independently selected from null, aryl, and heteroaryl (preferably selected from null, monocyclic aryl, monocyclic heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl, and tricyclic heteroaryl) , each of which is optionally substituted with one or more R ¹⁶.

In another refinement, the JAK ligand comprises a moiety of FORMULA 2B:

wherein

the linker moiety of the heterobifunctional compound is attached to R ¹;

Ar ¹ and Ar ² are independently selected from null, aryl, and heteroaryl (preferably selected from null, monocyclic aryl, monocyclic heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl, and tricyclic heteroaryl) , each of which is optionally substituted with one or more R ¹⁶;

A, B, D, X, Y, R ¹, R ² and R ¹⁶ are defined as in FORMULA 2;

or when neither of Ar ¹ and Ar ² is null, Ar ¹ and Ar ² together with the substituents to which they are connected optionally form a 10-30 membered macrocyclic ring; when Ar ¹ is null and Ar ² is not null, Ar ² and R ¹ together with the substituents to which they are connected optionally form a 10-30 membered macrocyclic ring; when Ar ² is null and Ar ¹ is not null, Ar ¹ and R ² together with the substituents to which they are connected optionally form a 10-30 membered macrocyclic ring; or when Ar ¹ and Ar ² are null, R ¹ and R ² together with the substituents to which they are connected optionally form a 10-30 membered macrocyclic ring.

In another refinement, the JAK ligand comprises a moiety of FORMULAE 2C, 2D, 2E or 2F:

wherein

the linker moiety of the heterobifunctional compound is attached to R ¹;

R ¹³, R ¹⁴ and R ¹⁵ are defined as R ³;

X, Y, Ar ¹, Ar ², R ¹, R ² and R ³ are defined as in FORMULA 2.

In another refinement, R ¹³, R ¹⁴ and R ¹⁵ are selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, CONR ⁴R ⁵, optionally substituted C ₁-C ₈ alkyl, and optionally substituted 3-10 membered carbocyclyl, wherein R ⁴ and R ⁵ are independently selected from hydrogen, optionally substituted C ₁-C ₈ alkyl, optionally substituted C ₂-C ₈ alkenyl, optionally substituted C ₂-C ₈ alkynyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 3-10 membered heterocyclyl, or R ⁴ and R ⁵ together with the atom or atoms to which they are connected form a 3-20 membered carbocyclyl ring or 3-20 membered heterocyclyl ring.

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

wherein

the linker moiety of the heterobifunctional compound is attached to R ¹;

R ¹³, R ¹⁴ and R ¹⁵ are defined as R ³;;

Y, R ¹, R ² and R ³ are defined as in FORMULA 2;

Ar ¹ and Ar ² are defined as above such as in FORMULA 2B.

In another refinement, R ¹³, R ¹⁴ and R ¹⁵ are defined as in FORMULAE 2C, 2D, 2E or 2F.

In another refinement, Y is selected from null, CR ⁶R ⁷, CO, CO ₂, CONR ⁶, NR ⁶CO, NR ⁶C (O) NR ⁷, O, SO, SO ₂, SO ₂NR ⁶ and NR ⁶, wherein

R ⁶ and R ⁷ are independently selected from hydrogen, optionally substituted C ₁-C ₈ alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 3-10 membered heterocyclyl.

In another refinement, Y is selected from null, CH ₂, CO, CONH, NR ⁶C (O) , NR ⁶C (O) NR ⁷, SO ₂ and SO ₂NH.

In another refinement, Ar ¹ and Ar ² are independently selected from null, monocyclic aryl, monocyclic heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl, and tricyclic heteroaryl , each of which is optionally substituted with one or more R ¹⁶.

In another refinement, R ¹⁶ is each independently selected from hydrogen, halogen, oxo, CN, NO ₂, OR ⁸, SR ⁸, NR ⁸R ⁹, COR ⁸, CO ₂R ⁸, CONR ⁸R ⁹, SOR ⁸, SO ₂R ⁸, SO ₂NR ⁸R ⁹, NR ¹⁰COR ⁸, NR ¹⁰SOR ⁸, NR ¹⁰SO ₂R ⁸, optionally substituted C ₁-C ₈ alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 3-10 membered heterocyclyl, wherein

R ⁸, R ⁹, and R ¹⁰ are independently selected from hydrogen, optionally substituted C ₁-C ₈ 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 together with the atom to which they are connected form a 3-10 membered heterocyclyl ring.

In another refinement, R ¹⁶ is each independently selected from hydrogen, halogen, oxo, CN, NO ₂, OR ⁸, NR ⁸R ⁹, NR ¹⁰COR ⁸, optionally substituted C ₁-C ₈ alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 3-10 membered heterocyclyl, wherein

In another refinement, R ¹⁶ is each independently selected from hydrogen, CH ₃, CF ₃, iPr, cPr, OCH ₃, OCF ₃, OiPr, OcPr, F, Cl, and Br.

In another refinement, R ¹⁶ is each independently selected from H and F.

In another refinement, Ar ¹ and Ar ² are independently selected from null, monocyclic aryl, monocyclic heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl, and tricyclic heteroaryl, each of which is substituted with R ² and optionally substituted with one or more R ¹⁶; and R ¹⁶ is each independently selected from hydrogen, halogen, oxo, CN, NO ₂, OR ⁸, SR ⁸, NR ⁸R ⁹, COR ⁸, CO ₂R ⁸, CONR ⁸R ⁹, SOR ⁸, SO ₂R ⁸, SO ₂NR ⁸R ⁹, NR ¹⁰COR ⁸, NR ¹⁰SOR ⁸, NR ¹⁰SO ₂R ⁸, optionally substituted C ₁-C ₈ alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 3-10 membered heterocyclyl, wherein

In another refinement, Ar ¹ and Ar ² are independently selected from null, monocyclic aryl, monocyclic heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl, and tricyclic heteroaryl, each of which is substituted with R ² and optionally substituted with one or more R ¹⁶; and R ¹⁶ is each independently selected from hydrogen, halogen, oxo, CN, NO ₂, OR ⁸, NR ⁸R ⁹, NR ¹⁰COR ⁸, optionally substituted C ₁-C ₈ alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 3-10 membered heterocyclyl, wherein

In another refinement, Ar ¹ and Ar ² are independently selected from null, monocyclic aryl, monocyclic heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl, and tricyclic heteroaryl, each of which is substituted with R ² and optionally substituted with one or more R ¹⁶; and R ¹⁶ is each independently selected from H, CH ₃, CF ₃, iPr, cPr, OCH ₃, OCF ₃, OiPr, OcPr, F, Cl, and Br.

In another refinement, Ar ¹ and Ar ² are are independently selected from null, monocyclic aryl, monocyclic heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl, and tricyclic heteroaryl, each of which is substituted with R ² and optionally substituted with one or more R ¹⁶; and R ¹⁶ is each independently selected from H and F.

In another refinement, R ¹ is selected from null, O, NH, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 3-10 membered heterocyclyl.

In another refinement, R ¹ is selected from null, O, NH, and optionally substituted 3-10 membered heterocyclyl, which contains at least one of O or N.

In another refinement, R ¹ is selected from null, O, NH, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted morpholinyl, optionally substituted pyrrolidinyl, optionally substituted tetrahydrofuranyl, optionally substituted azetidinyl, and optionally substituted oxetanyl.

In another refinement, R ² is selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C ₁-C ₈ alkyl, optionally substituted C ₂-C ₈ alkenyl, optionally substituted C ₂-C ₈ alkenyl, optionally substituted C ₁-C ₈ alkoxy, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.

In another refinement, R ² is selected from hydrogen, halogen, optionally substituted C ₁-C ₈ alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.

In another refinement, R ² is selected from hydrogen, CH ₃, CF ₃, iPr, cPr, tBu, CNCH ₂, F, Cl, Br, optionally substituted piperidinyl, optionally substituted optionally substituted piperazinyl, optionally substituted morpholinyl, optionally substituted pyrrolidinyl, optionally substituted tetrahydrofuranyl, optionally substituted azetidinyl, and optionally substituted oxetanyl, optionally substituted phenyl, optionally substituted triazolyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted triazinyl, optionally substituted fruranyl, optionally substituted oxazolyl, optionally substituted pyrrolyl, optionally substituted imidazolyl, optionally substituted triazolyl, optionally substituted oxadiazolyl, optionally substituted thiophenyl, optionally substituted thiazolyl, and optionally substituted thiadiazolyl.

In another refinement, R ¹³, R ¹⁴ and R ¹⁵ are independently selected from hydrogen, CH ₃, CF ₃, iPr, cPr, tBu, CNCH ₂, F, Cl, Br, OH, NH ₂, CN, CH ₃, and CONH ₂.

In another embodiment, the JAK ligand is derived from any of the following:

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

In another embodiment, the JAK ligand is derived from the following JAK inhibitors: NDI-031301, NDI-31232, VR588, R333 and R348.

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

In another embodiment, the JAK ligand is selected from FORMULA 3A, FORMULA 3C, FORMULA 3D, FORMULA 3I, and 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.

Degradation Tag

As used herein, the term “degradation tag” refers to a compound, which associates with or binds to an ubiquitin ligase for recruitment of the corresponding ubiquitination machinery to JAK or is a hydrophobic group or a tag that leads to misfolding of the JAK protein and subsequent degradation at the proteasome or loss of function.

wherein

Z _E is a divalent group of - (R _E ^z) _nE-; wherein subscript n _E = 0、1、2、3、4、5 or 6; wherein R _E ^Z, at each occurrence, is independently R _E ^r, or R _E ^w; wherein R _E ^w, at each occurrence, is a bond or selected from the group consisting of -CO-, -CR _E ⁵R _E ⁶-, -NR _E ⁵-, -O-, optionally substituted C ₁-C ₁₀ alkylene, optionally substituted C ₁-C ₁₀ alkenylene, optionally substituted C ₁-C ₁₀ alkynylene; and R _E ^r, at each occurrence, is a bond, or selected from the group consisting of optionally substituted 3-10 membered carbocyclyl such as 3-8 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl such as 3-8 membered heterocyclyl, optionally substituted C ₄-C ₁₃ fused cycloalkyl, optionally substituted C ₅-C ₁₃ fused heterocyclyl, optionally substituted C ₅-C ₁₃ bridged cycloalkyl, optionally substituted C ₅-C ₁₃ bridged heterocyclyl, optionally substituted C ₅-C ₁₃ spiro cycloalkyl, optionally substituted C ₅-C ₁₃ spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; with the proviso that -R _E ^z -R _E ^z-is not -O-O-; R _E ⁵ and R _E ⁶ at each occurrence are independently selected from the group consisting of hydrogen, halogen, oxo, hydroxy, amino, cyano, nitro, optionally substituted C ₁-C ₆ 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 atom (s) to which they are connected form an optionally substituted 3-8 membered cycloalkyl or heterocyclyl ring;

R _E ¹ is selected from the group consisting of hydrogen, halogen, cyano, nitro, optionally substituted C ₁-C ₆ alkyl, optionally substituted 3-8 membered carbocyclyl, and optionally substituted 3-8 membered heterocyclyl;

L _E is a divalent group selected from the group consisting of null, -L _E ¹-, and -L _E ¹-L _E ²-; wherein L _E ¹ and L _E ² are independently selected from the group consisting of -CO-, -O-, -CR _E ¹⁰R _E ¹¹-and -NR _E ¹⁰-, with the proviso that -L _E ¹-L _E ²-is not –O-O-; wherein R _E ¹⁰ and R _E ¹¹ are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, amino, optionally substituted C ₁-C ₆ alkyl, optionally substituted C ₁-C ₆ alkoxy, and optionally substituted C ₁-C ₆ alkylamino;

Ring A _E is a divalent group selected from the group consisting of FORMULA A _E1, A _E2, A _E3, A _E4 and A _E5:

wherein

*indicates the attachment to L _E, and Z _E is attached to any possible position on the Ring A _E;

indicates a single bond or a double bond;

V _E ¹, V _E ², V _E ³, V _E ⁴ and V _E ⁵, at each occurrence, are each independently selected from the group consisting of a bond (null) , C, CR _E ², S, N, and NR _E ²; or V _E ¹ and V _E ², V _E ² and V _E ³, V _E ³ and V _E ⁴, or V _E ⁴ and V _E ⁵ are combined together to optionally form 6 membered aryl ring or a 5, 6 or 7 membered heteroaryl ring;

R _E ², at each occurrence, is independently selected from the group consisting of absent, hydrogen, halogen, cyano, nitro, hydroxy, amino, optionally substituted C ₁-C ₆ alkyl, optionally substituted C ₁-C ₆ alkenyl, optionally substituted C ₁-C ₆ alkynyl, optionally substituted C ₁-C ₆ alkoxy, optionally substituted C ₁-C ₆ 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 atom (s) to which they are connected form optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-8 membered heterocyclyl ring, optionally substituted aryl, and optionally substituted heteroaryl;

W _E ¹, W _E ², W _E ³ and W _E ⁴ are each independently selected from the group consisting of -N=, -C≡, -CR _E ³=, -CO-, -O-, -CR _E ³R _E ⁴-, -NR _E ³-, -CR _E ³=CR _E ⁴-, -N=CR _E ³-, and -N=N-; or W _E ¹ and W _E ², W _E ² and W _E ³, or W _E ³ and W _E ⁴ are combined together to optionally form 6 membered aryl ring or a 5, 6 or 7 membered heteroaryl ring;

R _E ³ and R _E ⁴, at each occurrence, are independently selected from the group consisting of absent, hydrogen, halogen, cyano, nitro, hydroxy, amino, optionally substituted C ₁-C ₆ alkyl, optionally substituted 3 to 8 membered carbocyclyl, and optionally substituted 3 to 8 membered heterocyclyl; or R _E ³ and R _E ⁴, on the same atom or on the adjent atoms, together with the atom (s) to which they are connected form an optionally substituted 3-8 membered cycloalkyl or heterocyclyl ring.

In another embodiment, R _E ² at each occurrence, is independently selected from the group consisting of absent, hydrogen, halogen, cyano, nitro, hydroxy, amino, optionally substituted C ₁-C ₆ alkyl, optionally substituted C ₁-C ₆ alkenyl, optionally substituted C ₁-C ₆ alkynyl, optionally substituted C ₁-C ₆ alkoxy, optionally substituted C ₁-C ₆ alkylamino, optionally substituted 3-8 membered carbocyclyl, and optionally substituted 3-8 membered heterocyclyl.

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 each independently selected from the group consisting of C, CR _E ², S, N, and NR _E ²; or V _E ¹ and V _E ², V _E ² and V _E ³, V _E ³ and V _E ⁴, or V _E ⁴ and V _E ⁵ are combined to optionally form 6 membered aryl ring or a 5, 6 or 7 membered heteroaryl ring.

In another embodiment, the degradation tag is a moiety of FORMULA 5, and wherein Ring A _E is a group consisting of FORMULA A _E1, and wherein V _E ¹, V _E ², V _E ³, and V _E ⁴ are each independently selected from the group consisting of C, CR _E ², S, N, and NR _E ².

In another embodiment, the degradation tag is a moiety of FORMULA 5, and wherein Ring A _E is a group consisting of FORMULA A _E2, and wherein V _E ¹, V _E ², V _E ³, V _E ⁴ and V _E ⁵, at each occurrence, are each independently selected from the group consisting of C, CR _E ², S, N, and NR _E ².

In another embodiment, the degradation tag is a moiety of FORMULA 5, and wherein Ring A _E is a group consisting of FORMULA A _E3, and wherein V _E ¹, V _E ², V _E ³, V _E ⁴ and V _E ⁵ are each independently selected from the group consisting of C, CR _E ², S, N, and NR _E ²; or V _E ¹ and V _E ², V _E ² and V _E ³, V _E ³ and V _E ⁴, or V _E ⁴ and V _E ⁵ are combined together to optionally form 6 membered aryl ring or a 5, 6 or 7 membered heteroaryl ring.

In another embodiment, the degradation tag is a moiety of FORMULA 5, and wherein Ring A _E is a group consisting of FORMULA A _E4, and wherein

is a single bond and W _E ¹, W _E ², W _E ³ and W _E ⁴ are each independently selected from the group consisting of -N=, -CR _E ³=, -CO-, -O-, -CR _E ³R _E ⁴-, and -NR _E ³-.

In another embodiment, the degradation tag is a moiety of FORMULA 5, and wherein Ring A _E is a group consisting of FORMULA A _E5, and wherein V _E ¹, V _E ², and V _E ³ are each independently selected from the group consisting of CR _E ², S, N, with the proviso that at least one of V _E ¹, V _E ², and V _E ³ is S, N or NR _E ²; or V _E ¹ and V _E ², V _E ² and V _E ³ are combined together to optionally form 5 membered heteroaryl ring.

In another embodiment, the degradation tag is a moiety of FORMULA 5, and wherein R _E ¹ is selected from hydrogen, halogen, cyano, nitro, optionally substituted C ₁-C ₆ alkyl, optionally substituted 3 -8 membered carbocyclyl, and optionally substituted 3 -8 membered heterocyclyl; preferably, R _E ¹ is selected from hydrogen, halogen, cyano, nitro, and C ₁-C ₅ alkyl; more preferably, R _E ¹ is selected from H, CH ₃, or F.

In another embodiment, the degradation tag is a moiety of FORMULA 5, and wherein R _E ² is selected from hydrogen, halogen, cyano, nitro, hydroxy, amino, optionally substituted C ₁-C ₆ alkyl, optionally substituted C ₁-C ₆ alkyl, optionally substituted C ₁-C ₆ alkoxyl, optionally substituted C ₁-C ₆ alkylamino, optionally substituted 3 to 8 membered carbocyclyl, and optionally substituted 3 to 8 membered heterocyclyl; preferably, R _E ² is selected from hydrogen, halogen, cyano, nitro, and C ₁-C ₆ alkyl, optionally substituted C ₁-C ₆ alkoxyl, optionally substituted 3 to 8 membered carbocyclyl, and optionally substituted 3 to 8 membered heterocyclyl; more preferably, R _E ² is selected from H, F, OMe, O-iPr, or O-cPr.

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 C ₁-C ₆ 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 atom (s) to which they are connected form a 3-8 membered carbocyclyl, or 3-8 membered heterocyclyl.

In another embodiment, R _E ^r, at each occurrence, is selected from Group R _E, and Group R _E consists of

In another embodiment, the degradation tag is a moiety of FORMULA 5, and wherein in the group of Z _E, at most one R _E ^Z is R _E ^r.

In another embodiment, the degradation tag is a moiety of FORMULA 5, and wherein n _E = 0, 1, 2 or 3.

In another embodiment, 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-.

In another embodiment, the degradation tag is a moiety of FORMULA 5, and wherein R _E ⁵ and R _E ⁶ at each occurrence are independently selected from a bond, hydrogen, halogen, oxo, hydroxyl, amino, cyano, nitro, optionally substituted C ₁-C ₆ 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 atom (s) to which they are connected form a 3-8 membered cycloalkyl or heterocyclyl ring.

In another embodiment, the degradation tag is a moiety of FORMULA 5, and wherein R _E ^Z is selected from -CO-, -CR _E ⁵R _E ⁶-, -NR _E ⁵-, -O-, optionally substituted C ₁-C ₁₀ alkylene, optionally substituted C ₁-C ₁₀ alkenylene, optionally substituted C ₁-C ₁₀ alkynylene, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl.

In another embodiment, the degradation tag is a moiety of FORMULA 5, and wherein Z _E is selected from a bond, CH ₂, CH=CH, C≡C, NH, and O.

In another embodiment, the degradation tag is a moiety of FORMULA 5, and wherein Ring A _E is of FORMULA A _E4 and L _E is not null.

In another embodiment, the degradation tag is a moiety of FORMULA 5, and wherein Ring A _E is of FORMULA A _E4 and L _E is selected from the group consisting of -NH-, -N (C ₁-C ₄ alkyl) -, -CO-, -NH-CO-, -N (C ₁-C ₄ alkyl) -CO-, -CO-NH-, and -CO-N (C ₁-C ₄ alkyl) -.

In another embodiment, the degradation tag is a moiety selected from the group consisting of FORMULA 5-1, 5-2, 5-3, 5-4, 5-5 and 5-6, and the degradation tag is connected to the linker moiety of the heterobifunctional compound via a divalent group of Z _E;

wherein

Z _E, R _E ¹. L _E,

V _E ¹, V _E ², V _E ³, V _E ⁴, V _E ⁵, W _E ¹, W _E ², W _E ³ and W _E ⁴ are defined as in FORMULA 5.

In another embodiment, the degradation tag is a moiety selected from the group consisting of FORMULAE 5A, 5B, 5C, 5D, 5E, 5F, 5G, 5H, 5I, 5J, 5K, 5L and 5M:

wherein,

V _E ⁶, V _E ⁷, V _E ⁸, and V _E ⁹ are each independently selected from a bond, C, CR _E ¹² and N; or V _E ¹ and V _E ², V _E ² and V _E ³, V _E ³ and V _E ⁴, or V _E ⁴ and V _E ⁵ are combined together to optionally form 6 membered aryl ring or a 5, 6 or 7 membered heteroaryl ring;

R _E ¹², at each occurrence, is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, amino, optionally substituted C ₁-C ₆ alkyl, optionally substituted C ₁-C ₆ alkenyl, optionally substituted C ₁-C ₆ alkynyl, optionally substituted C ₁-C ₆ alkoxy, optionally substituted C ₁-C ₆ alkylamino, optionally substituted 3-8 membered carbocyclyl, and optionally substituted 3-8 membered heterocyclyl;

W _E ⁶ and W _E ⁷ are each independently seleted from -CR _E ²= and -N=;

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 are defined as in FORMULA 5.

In another embodiment, W _E ¹ is selected from -CO-, -O-, -CR _E ³R _E ⁴-, -NR _E ³-, -CR _E ³=CR _E ⁴-, -N=CR _E ³-, and -N=N-.

In another embodiment, Ring A _E is a divalent group of FORMULA A _E1 or A _E5; and Ring A _E is attached to L _E via W _E ².

In another embodiment, Ring A _E is a divalent group of FORMULA A _E1 or A _E5, wherein W _E ¹and W _E ³ are each independently selected from the group consisting of CO, O, CR _E ³R _E ⁴, NR _E ³; and W _E ² is N.

In another embodiment, the degradation tag is a moiety of FORMULA 5-1or 5-6, and the degradation tag is connected to the linker moiety of the heterobifunctional compound via a divalent group of Z _E; wherein

W _E ¹and W _E ³ are each independently selected from the group consisting of -CO-, -O-, -CR _E ³R _E ⁴-, -NR _E ³-;

W _E ² is N, and connected to

Z _E, R _E ¹. R _E ³. R _E ⁴L _E,

V _E ¹, V _E ², V _E ³, V _E ⁴, and V _E ⁵, are defined as in FORMULA 5.

In another embodiment, the degradation tag is a moiety of FORMULAE 5A or 5M; wherein W _E ¹ is independently selected from the group consisting of -CO-, -O-, -CR _E ³R _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 are defined as in FORMULA 5.

In another embodiment, R _E ³ and R _E ⁴, at each occurrence, are independently selected from the group consisting of absent, hydrogen, halogen, cyano, nitro, hydroxy, amino, optionally substituted C ₁-C ₆ alkyl.

In another embodiment, the degradation tag is a moiety of FORMULA 5-1, or FORMULA 5-3,

wherein

V _E ¹, V _E ², V _E ³, and V _E ⁴ are each independently selected from a bond, C, CR _E ², and N; or V _E ¹ and V _E ², V _E ² and V _E ³, or V _E ³ and V _E ⁴ are combined together to optionally form 6 memberedaryl ring or 5, 6 or 7 membered heteroaryl ring;

indicates a single bond or a double bond; wherein (i) when there is a single bond between W _E ¹ and W _E ² (i.e. the

between W _E ¹ and W _E ² indicates single bond) , W _E ¹, W _E ² and W _E ³ are each independently selected from the group consisting of –N=, -CR _E ³=, -CO-, -O-, -CR _E ³R _E ⁴-, -NR _E ³-, - CR _E ³=CR _E ⁴-, -N=CR _E ³-, and -N=N-; or (ii) when there is a double bond between W _E ¹ and W _E ² (i.e. the

between W _E ¹ and W _E ² indicates a double bond) , W _E ¹ and W _E ² are each independently selected from the group consisting of -N=, -C≡ and -CR _E ³=; W _E ³ is selected from the group consisting of -CR _E ³R _E ⁴-, -O-, -N=, -NR _E ³-, -C (O) NR _E ³-, -CR _E ³=CR _E ⁴-, and -CR _E ³=N-;

Z _E, R _E ², R _E ³, R _E ⁴ and R _E ¹ are defined as in FORMULA 5.

In another embodiment, 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 are each independently selected from C, N, and CR _E ².

In another embodiment, the degradation tag is a moiety of FORMULA 5-1, and wherein V _E ² is C (i.e. the attachment to Z _E) , and V _E ¹, V _E ³, and V _E ⁴ are each independently selected from N, and CR _E ² (preferably, N or CH) ; or V _E ³is C (i.e. the attachment to Z _E) , and V _E ¹, V _E ², and V _E ⁴ are each independently selected from N, and CR _E ² (preferably, N or CH) .

In another embodiment, the degradation tag FORMULA 5-1 is moiety of FORMULA 5A, 5B, 5E, 5F or 5G

wherein W _E ⁶ and W _E ⁷ are each independently seleted from -CR _E ²= and -N=; and V _E ¹, V _E ², V _E ³, V _E ⁴, W _E ¹, W _E ³, Z _E, R _E ³ and R _E ¹ are defined as in FORMULA 5-1.

In another embodiment, the degradation tag is a moiety of FORMULA 5A, 5B, 5E, 5F or 5G, and whereinV _E ¹, V _E ², V _E ³, and V _E ⁴ are each independently selected from a bond, C, CR _E ² and N (preferably, C, CR _E ² and N) .

In another embodiment, the degradation tag is a moiety of FORMULA 5A, 5B, 5E, 5F or 5G, and whereinW _E ¹ and W _E ³ are each independently selected from -CO-, -O-, -CR _E ³R _E ⁴--NR _E ³-, -CR _E ³=CR _E ⁴-, - N=CR _E ³-, and -N=N-; preferably, W _E ¹ and W _E ³ are each independently selected from -CO-, -O-, -CR _E ³R _E ⁴-, and -NR _E ³-.

In another embodiment, the degradation tag is a moiety of FORMULA 5A, and wherein V _E ² is C (i.e. the attachment to Z _E) , and V _E ¹, V _E ³, and V _E ⁴ are each independently selected from N, and CR _E ² (preferably, N or CH) ; or V _E ³is C (i.e. the attachment to Z _E) , and V _E ¹, V _E ², and V _E ⁴ are each independently selected from N, and CR _E ² (preferably, N or CH) .

In another embodiment, the degradation tag FORMULA 5-3 is moiety of FORMULA 5C

wherein W _E ³ is N or CR _E ³; and V _E ¹, V _E ², V _E ³, V _E ⁴, Z _E, and R _E ¹ are defined as 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 are each independently selected from a bond, CR _E ² and N.

In another embodiment, the degradation tag is a moiety of FORMULA 5-2,

V _E ¹, V _E ², V _E ³, V _E ⁴ and V _E ⁵ are each independently selected from a bond, C, CR _E ², and N; 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 combined together to optionally form 6 membered aryl ring or 5, 6, or 7 heteroaryl ring;

indicates a single bond or a double bond; (i) when there is a single bond between W _E ¹ and W _E ² (i.e. the

between W _E ¹ and W _E ² indicates single bond) , W _E ¹ and W _E ⁴ are each independently selected from -N=, -CR _E ³=, -CO-, -O-, -CR _E ³R _E ⁴-, -NR _E ³-, -CR _E ³=CR _E ⁴-, -N=CR _E ³-, and -N=N-, and W _E ² and W _E ³ are each independently selected from -N=, -CR _E ³=, -CO-, -O-, -CR _E ³R _E ⁴-, and -NR _E ³-; or (ii) when there is a double bond between W _E ¹ and W _E ² (i.e. the

between W _E ¹ and W _E ² indicates a double bond) , W _E ¹ and W _E ² are each independently selected from -N=, C and -CR _E ²=; W _E ³ is selected from -N=, -CR _E ³=, -CO-, -O-, - CR _E ³R _E ⁴-, and -NR _E ³-; and W _E ⁴ is selected from -N=, -CR _E ³=, -CO-, -O-, -CR _E ³R _E ⁴-, -NR _E ³-, -CR _E ³=CR _E ⁴-, -N=CR _E ³-, and -N=N-;

Z _E, R _E ², R _E ³, R _E ⁴ and R _E ¹ are defined as in FORMULA 5.

In another embodiment, the degradation tag is a moiety of FORMULA 5-2, wherein V _E ¹, V _E ², V _E ³, V _E ⁴ and V _E ⁵ are each independently selected from a bond, C, CR _E ², and N.

In another embodiment, the degradation tag is a moiety of FORMULA 5-2, wherein

indicates a single bond.

In another embodiment, the degradation tag is a moiety of FORMULA 5-2, wherein

indicates a single bond, W _E ¹ and W _E ⁴ are each independently selected from -CO-, -O-, -CR _E ³R _E ⁴-, and -NR _E ³-, and W _E ² and W _E ³ are each independently selected from -N=, -CR _E ³=, -CO-, -O-, -CR _E ³R _E ⁴-, and -NR _E ³-.

In another embodiment, the degradation tag FORMULA 5-2 is moiety of FORMULA 5D.

wherein V _E ¹, V _E ², V _E ³, V _E ⁴, V _E ⁵, W _E ¹, Z _E, and R _E ¹ are defined as in FORMULA 5-2.

In another embodiment, the degradation tag is a moiety of FORMULA 5D, wherein W _E ¹ is selected from -CO-, -O-, -CR _E ³R _E ⁴-, -NR _E ³-, -CR _E ³=CR _E ⁴-, -N=CR _E ³-, and -N=N-; preferably, W _E ¹ is seleted from -CO-, -O-, -CR _E ³R _E ⁴-, and -NR _E ³-.

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 are each independently selected from a bond, C, CR _E ² and N; or V _E ¹ and V _E ², V _E ² and V _E ³, V _E ³ and V _E ⁴, or V _E ⁴ and V _E ⁵ are combined together to optionally form a 6 membered aryl ring or 5, 6 or 7 heteroaryl ring; preferably, V _E ¹, V _E ², V _E ³, V _E ⁴, and V _E ⁵ are each independently selected from a bond, C, CR _E ² and N.

In another embodiment, the degradation tag is a moiety of FORMULA 5-4,

wherein V _E ¹, V _E ², V _E ³, V _E ⁴, V _E ⁵. L _E, Z _E, and R _E ¹ are defined as in FORMULA 5.

In another embodiment, the degradation tag is a moiety of FORMULA 5-4, and wherein L _E is not null.

In another embodiment, the degradation tag is a moiety of FORMULA 5-4, and wherein L _E is selected from the group consisting of -NH-, -N (C ₁-C ₄ alkyl) -, -CO-, -NH-CO-, -N (C ₁-C ₄ alkyl) -CO-, -CO-NH-, and -CO-N (C ₁-C ₄ alkyl) -.

In another embodiment, the degradation tag is a moiety of FORMULA 5-4, and wherein

V _E ¹, V _E ², V _E ³, V _E ⁴ and V _E ⁵, at each occurrence, are each independently selected from the group consisting of 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 combined together to optionally form a ring of

wherein V _E ⁶, V _E ⁷, V _E ⁸, and V _E ⁹ are each independently selected from the group consisting of C, CR _E ¹² and N;

R _E ¹², at each occurrence, is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, amino, optionally substituted C ₁-C ₆ alkyl, optionally substituted C ₁-C ₆ alkenyl, optionally substituted C ₁-C ₆ alkynyl, optionally substituted C ₁-C ₆ alkoxy, optionally substituted C ₁-C ₆ alkylamino, optionally substituted 3-8 membered carbocyclyl, and optionally substituted 3-8 membered heterocyclyl.

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 are each independently selected from the group consisting of CR _E ¹² and N.

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, optionally substituted C ₁-C ₆ alkyl.

is selected from the group consisting of

wherein

V _E ¹, V _E ², V _E ³, V _E ⁴ and V _E ⁵ are each independently selected from the group consisting of C, CR _E ² and N; and V _E ⁶, V _E ⁷, V _E ⁸, and V _E ⁹ are each independently selected from the group consisting of CR _E ¹² and N.

In another embodiment, the degradation tag is a moiety of FORMULA 5-4, and wherein Z _E is null, -CH ₂-, -O-, or -NH-.

In another embodiment, the degradation tag FORMULA 5-4 is moiety of FORMULA 5H, or 5I;

wherein V _E ¹, V _E ², V _E ³, V _E ⁴, V _E ⁵, V _E ⁶, V _E ⁷, V _E ⁸, and V _E ⁹ are each independently selected from a bond, C, CR _E ² and N; and Z _E and R _E ¹ are defined as in FORMULA 5-4.

In another embodiment, the degradation tag is a moiety of FORMULA 5-5,

wherein

W _E ¹, W _E ², W _E ³, W _E ⁴, Z _E and R _E ¹ are defined as in FORMULA 5.

In another embodiment, the degradation tag is a moiety of FORMULA 5-5, and whereinW _E ¹, W _E ², W _E ³ and W _E ⁴ are each independently selected from the group consisting of -N=, -C≡, -CR _E ³=, -CO-, -O-, -CR _E ³R _E ⁴-, and -NR _E ³-.

In another embodiment, the degradation tag is a moiety of FORMULA 5-5, and whereinW _E ¹, W _E ², W _E ³ and W _E ⁴ are each independently selected from the group consisting of -N=, -C≡, -CH=, -CO-, -O-, -N-, -CH ₂-, and -NH-.

In another embodiment, the degradation tag FORMULA 5-5 is moiety of FORMULA 5J, 5K or 5L;

wherein W _E ¹, W _E ², W _E ³, W _E ⁴, Z _E, R _E ³ and R _E ¹ are defined as in FORMULA 5-5.

In another embodiment, the degradation tag is a moiety of FORMULA 5-6,

wherein

V _E ¹, V _E ², and V _E ³ are each independently selected from C, CR _E ², S, N, and NR _E ²; or V _E ¹ and V _E ², or V _E ² and V _E ³ are combined together to optionally form 5 membered heteroaryl ring;

between W _E ¹ and W _E ² indicates single bond) , W _E ¹, W _E ² and W _E ³ are each independently selected from the group consisting of –N=, -CR _E ³=, -CO-, -O-, -CR _E ³R _E ⁴-, -NR _E ³-, -CR _E ³=CR _E ⁴-, -N=CR _E ³-, and -N=N-; or (ii) when there is a double bond between W _E ¹ and W _E ² (i.e. the

between W _E ¹ and W _E ² indicates a double bond) , W _E ¹ and W _E ² are each independently selected from the group consisting of -N-, -C≡ and -CR _E ³=; W _E ³ is selected from the group consisting of -O-, -N=, -NR _E ³-, -C (O) NR _E ³-, -CR _E ³R _E ⁴-, -CR _E ³=CR _E ⁴-, and -CR _E ³=N-;

Z _E, R _E ², R _E ³, R _E ⁴ and R _E ¹ are defined as in FORMULA 5.

In another embodiment, 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 are each independently selected from C, CR _E ², S, N, and NR _E ².

In another embodiment, the degradation tag FORMULA 5-6 is moiety of FORMULA 5M:

wherein V _E ¹, V _E ², V _E ³, W _E ¹, Z _E and R _E ¹ are defined as in FORMULA 5-6.

In another embodiment, the degradation tag is a moiety of FORMULA 5M, and wherein V _E ¹, V _E ², and V _E ³ are each independently selected from C, CR _E ², S, N, and NR _E ² (preferably, one of V _E ¹, V _E ², and V _E ³ is S) .

In another embodiment, the degradation tag is a moiety of FORMULA 5M, and whereinW _E ¹ is selected from -CO-, -O-, -CR _E ³R _E ⁴-, -NR _E ³-, -CR _E ³=CR _E ⁴-, -N=CR _E ³-, and -N=N-; preferably, W _E ¹ is selected from -CO-, -O-, -CR _E ³R _E ⁴-, and -NR _E ³-.

In another embodiment, the degradation tag is a moiety of FORMULAE 6A, 6B, and 6C:

wherein

R _E ¹ and R _E ² are independently selected from hydrogen, hydroxyl, amino, cyano, nitro, optionally substituted C ₁-C ₈ alkyl, optionally substituted C ₂-C ₈ alkenyl, optionally substituted C ₂-C ₈ alkynyl; optionally substituted C ₁-C ₈alkoxyC ₁-C ₈alkyl, optionally substituted C ₁-C ₈ haloalkyl, optionally substituted C ₁-C ₈ hydroxyalkyl, optionally substituted C ₁-C ₈ aminoalkyl, optionally substituted C ₁-C ₈alkylaminoC ₁-C ₈alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 3-10 membered heterocyclyl;

R _E ³ is selected from hydrogen, optionally substituted C (O) C ₁-C ₈ alkyl, optionally substituted C (O) C ₁-C ₈alkoxyC ₁-C ₈alkyl, optionally substituted C (O) C ₁-C ₈ haloalkyl, optionally substituted C (O) C ₁-C ₈ hydroxyalkyl, optionally substituted C (O) C ₁-C ₈ aminoalkyl, optionally substituted C (O) C ₁-C ₈alkylaminoC ₁-C ₈alkyl, optionally substituted C (O) (3-10 membered carbocyclyl) , optionally substituted C (O) (3-10 membered heterocyclyl) , optionally substituted C (O) C ₂-C ₈ alkenyl, optionally substituted C (O) C ₂-C ₈ alkynyl, optionally substituted C (O) OC ₁-C ₈alkoxyC ₁-C ₈alkyl, optionally substituted C (O) OC ₁-C ₈ haloalkyl, optionally substituted C (O) OC ₁-C ₈ hydroxyalkyl, optionally substituted C (O) OC ₁-C ₈ aminoalkyl, optionally substituted C (O) OC ₁-C ₈alkylaminoC ₁-C ₈alkyl, optionally substituted C (O) O (3-10 membered carbocyclyl) , optionally substituted C (O) O (3-10 membered heterocyclyl) , optionally substituted C (O) OC ₂-C ₈ alkenyl, optionally substituted C (O) OC ₂-C ₈ alkynyl, optionally substituted C (O) NC ₁-C ₈alkoxyC ₁-C ₈alkyl, optionally substituted C (O) NC ₁-C ₈ haloalkyl, optionally substituted C (O) NC ₁-C ₈ hydroxyalkyl, optionally substituted C (O) NC ₁-C ₈ aminoalkyl, optionally substituted C (O) NC ₁-C ₈alkylaminoC ₁-C ₈alkyl, optionally substituted C (O) N (3-10 membered carbocyclyl) , optionally substituted C (O) N (3-10 membered heterocyclyl) , optionally substituted C (O) NC ₂-C ₈ alkenyl, optionally substituted C (O) NC ₂-C ₈ alkynyl, optionally substituted P (O) (OH) ₂, optionally substituted P (O) (OC ₁-C ₈ alkyl) ₂, and optionally substituted P (O) (OC ₁-C ₈ aryl) ₂, and

R _E ⁴ is selected from NR _E ⁷R _E ⁸,

optionally substituted C ₁-C ₈alkoxy, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteraryl, in which

R _E ⁷ is selected from hydrogen, optionally substituted C ₁-C ₈alkyl, optionally substituted C ₁-C ₈cycloalkyl, optionally substituted C ₁-C ₈alkyl-CO, optionally substituted C ₁-C ₈cycloalkyl-CO, optionally substituted C ₁-C ₈cycloalkyl-C ₁-C ₈alkyl-CO, optionally substituted 3-10 membered heterocyclyl-CO, optionally substituted 3-10 membered heterocyclyl-C ₁-C ₈alkyl-CO, optionally substituted aryl-CO, optionally substituted aryl-C ₁-C ₈alkyl-CO, optionally substituted heteroaryl-CO, optionally substituted heteroaryl-C ₁-C ₈alkyl-CO, optionally substituted aryl, and optionally substituted heteroaryl;

R _E ⁸ is selected from hydrogen, optionally substituted C ₁-C ₈alkyl, and optionally substituted C ₁-C ₈cycloalkyl;

R _E ⁹, at each occurance, is independently selected from hydrogen, halogen, cyano, optionally substituted C ₁-C ₈alkyl, optionally substituted C ₁-C ₈cycloalkyl, optionally substituted C ₁-C ₈heterocycloalkyl, optionally substituted C ₁-C ₈alkoxy, optionally substituted C ₁-C ₈cycloalkoxy, halo substituted C ₁-C ₈alkyl, halo substituted C ₁-C ₈cycloalkyl, halo substituted C ₁-C ₈alkoxl, halo substituted C ₁-C ₈cycloalkoxy, and halo substituted C ₁-C ₈heterocycloalkyl;

X _E is selected from CH and N; and

n _E is 0, 1, 2, 3, or 4;

R _E ⁵ is selected from hydrogen and halogen, preferably, H and F.

R _E ⁶ is selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C ₁-C ₈alkyl, optionally substituted C ₁-C ₈cycloalkyl, optionally substituted C ₁-C ₈alkoxy, and optionally substituted C ₁-C ₈cycloalkoxy, optionally substituted C ₁-C ₈heterocycloalkyl, 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 group.

In another embodiment, the degradation tag is a moiety of FORMULA 7A:

wherein

V _E ¹, V _E ², V _E ³, V _E ⁴, and V _E ⁵, are independently selected from CR _E ⁴ and N; and

R _E ¹, R _E ², R _E ³, and R _E ⁴ are independently selected from hydrogen, halogen, cyano, nitro, optionally substituted C ₁-C ₈ alkyl, optionally substituted C ₂-C ₈ alkenyl, and optionally substituted C ₂-C ₈ alkynyl; optionally substituted C ₁-C ₈alkoxyC ₁-C ₈alkyl, optionally substituted C ₁-C ₈ haloalkyl, optionally substituted C ₁-C ₈ hydroxyalkyl, optionally substituted C ₁-C ₈alkoxy, optionally substituted C ₁-C ₈alkylamino, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 3-10 membered heterocyclyl.

In another embodiment, the degradation tag is a moiety of FORMULA 7B:

wherein

R _E ¹, R _E ², and R _E ³ are independently selected from hydrogen, halogene, optionally substituted C ₁-C ₈ alkyl, optionally substituted C ₁-C ₈alkoxyC ₁-C ₈alkyl, optionally substituted C ₁-C ₈ haloalkyl, optionally substituted C ₁-C ₈ hydroxyalkyl, optionally substituted C ₃-C ₇ cycloalkyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted C ₂-C ₈ alkenyl, and optionally substituted C ₂-C ₈ alkynyl;

R _E ⁴ and R _E ⁵ are independently selected from hydrogen, COR _E ⁶, CO ₂R _E ⁶, CONR _E ⁶R _E ⁷, SOR _E ⁶, SO ₂R _E ⁶, SO ₂NR _E ⁶R _E ⁷, optionally substituted C ₁-C ₈ alkyl, optionally substituted C ₁-C ₈alkoxyC ₁-C ₈alkyl, optionally substituted C ₁-C ₈alkylaminoC ₁-C ₈alkyl, optionally substituted aryl-C ₁-C ₈alkyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein

R _E ⁶ and R _E ⁷ are independently selected from hydrogen, optionally substituted C ₁-C ₈ alkyl, optionally substituted C ₁-C ₈alkoxyC ₁-C ₈alkyl, optionally substituted C ₁-C ₈alkylaminoC ₁-C ₈alkyl, 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 together with the atom (s) to which they are connected form a 3-8 membered cycloalkyl or heterocyclyl ring.

In another embodiment, the degradation tag is a moiety of FORMULA 5-1 or 5-2 or 5-3.

In another embodiment, the degradation tag is a moiety of FORMULA 5-4.

In another embodiment, the degradation tag is a moiety of FORMULA 5A, 5B, 5C, 5D, 5E, 5F, 5G, 5H, 5I, 5J, 5K, or 5L.

In another embodiment, the degradation tag is a moiety of FORMULA 5A, 5B, 5C, 5H, or 5I.

In another embodiment, the degradation tag is derived from any of the following:

In another embodiment, the degradation tag is derived from any of the follows: 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.

In another embodiment, the degradation tag is selected from the group consisting of:

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, and 8BN, 8BO, 8BP, 8BQ, 8BR, 8BS, 8CB, 8CC, 8CD, 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, 8HC, 8HD, 8HE, 8HF, 8HG, 8HH, 8HI, 8HJ, 8HK, 8HL, 8HM, 8HN, 8HO, 8HP, 8HQ, 8HR, 8HS, 8HT, 8HU, 8HV, 8HW, 8HX, 8HY, 8HZ, 8IA, 8IB, 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.

Linker Moiety

As used herein, a “linker” or “linker moiety” is a bond, molecule, or group of molecules that binds two separate entities to one another. Linkers provide for optimal spacing of the two entities. The term “linker” in some aspects refers to any agent or molecule that bridges the JAK ligand to the degradation tag. One of ordinary skill in the art recognizes that sites on the JAK ligand or the degradation tag, which are not necessary for the function of the bifunctional degraders of the present disclosure, are ideal sites for attaching a linker, provided that the linker, once attached to the conjugate of the present disclosures, does not interfere with the function of the JAK ligand, i.e., its ability to bind JAK, or the function of the degradation tag, i.e., its ability to recruit a ubiquitin ligase.

The length of the linker of the heterobifunctional compound can be adjusted to minimize the molecular weight of the heterobifunctional compounds, avoid the clash of the JAK ligand or targeting moiety with the ubiquitin ligase and/or induce JAK misfolding by the hydrophobic tag. In certain embodiments, the linker comprises acyclic or cyclic saturated or unsaturated carbon, ethylene glycol, amide, amino, ether, urea, carbamate, aromatic, heteroaromatic, heterocyclic or carbonyl groups. In certain 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.

In some embodiments, the linker moiety is of FORMULA 9:

FORMULA 9,

wherein

A _L, W _L and B _L, at each occurrence, are independently selected from null, or bivalent moiety selected from R _L ^d-R _L ^e, R _L ^dCOR _L ^e, R _L ^dCO ₂R _L ^e, R _L ^dC (O) N (R _L ¹) R _L ^e, R _L ^dC (S) N (R _L ¹) R _L ^e, R _L ^dOR _L ^e, R _L ^dSR _L ^e, R _L ^dSOR _L ^e, R _L ^dSO ₂R _L ^e, R _L ^dSO ₂N (R _L ¹) R _L ^e, R _L ^dN (R _L ¹) R _L ^e, R _L ^dN (R _L ¹) COR _L ^e, R _L ^dN (R _L ¹) CON (R _L ²) R _L ^e, R _L ^dN (R _L ¹) C (S) R _L ^e, optionally substituted C ₁-C ₈ alkylene, optionally substituted C ₂-C ₈ alkenylene, optionally substituted C ₂-C ₈ alkynylene, optionally substituted C ₁-C ₈alkoxyC ₁-C ₈alkylene, optionally substituted C ₁-C ₈ haloalkylene, optionally substituted C ₁-C ₈ 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 spiro cycloalkyl, optionally substituted 5-13 membered spiro heterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein

R _L ^d and R _L ^e , at each occurrence, are independently selected from null, optionally substituted (C ₁-C ₈ alkylene) -R _L ^r (preferably, CH ₂-R _L ^r) , optionally substituted R _L ^r- (C ₁-C ₈ alkylene) , optionally substituted (C ₁-C ₈ alkylene) -R _L ^r- (C ₁-C ₈ alkylene) , or a moiety comprising of optionally substituted C ₁-C ₈ alkyl, optionally substituted C ₂-C ₈ alkenyl, optionally substituted C ₂-C ₈ alkynyl, optionally substituted C ₁-C ₈ hydroxyalkyl, optionally substituted C ₁-C ₈alkoxyC ₁-C ₈alkyl, optionally substituted C ₁-C ₈alkylaminoC ₁-C ₈alkyl, optionally substituted C ₁-C ₈ haloalkyl, optionally substituted C ₁-C ₈ alkylene, optionally substituted C ₂-C ₈ alkenylene, optionally substituted C ₂-C ₈ alkynylene, optionally substituted C ₁-C ₈ hydroxyalkylene, optionally substituted C ₁-C ₈alkoxyC ₁-C ₈alkylene, optionally substituted C ₁-C ₈alkylaminoC ₁-C ₈alkylene, optionally substituted C ₁-C ₈ 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 spiro cycloalkyl, optionally substituted 5-13 membered spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R _L ^r, at each occurrence, is selected from 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 spiro cycloalkyl, optionally substituted 5-13 membered spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R _L ¹ and R _L ² , at each occurrence, are independently selected from hydrogen, optionally substituted C ₁-C ₈ alkyl, optionally substituted C ₂-C ₈ alkenyl, optionally substituted C ₂-C ₈ alkynyl, optionally substituted C ₁-C ₈ alkoxyalkyl, optionally substituted C ₁-C ₈ haloalkyl, optionally substituted C ₁-C ₈ hydroxyalkyl, optionally substituted C ₁-C ₈alkylaminoC ₁-C ₈alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

or R _L ^dand R _L ^e, R _L ¹ and R _L ², R _L ^dand R _L ¹, R _L ^dand R _L ², R _L ^e and R _L ¹, R _L ^e and R _L ² together with the atom (s) to which they are connected optionally form a 3-20 membered cycloalkyl or 3-20 membered heterocyclyl ring; and

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

In another embodiment, W _L and m are defined as above; and A _L and B _L, at each occurrence, are independently selected from null, CO, NH, NH-CO, CO-NH, - (CH ₂) _0-8-, - (CH ₂) _0-3-CO- (CH ₂) _0-8-, (CH ₂) _0-8-NH-CO, (CH ₂) _0-8-CO-NH, NH-CO- (CH ₂) _0-8, CO-NH- (CH ₂) _0-8, (CH ₂) _1-3-NH- (CH ₂) _1-3-CO-NH, (CH ₂) _1-3-NH- (CH ₂) _1-3-NH-CO, -CO-NH, CO-NH- (CH ₂) _1-3-NH- (CH ₂) _1-3, (CH ₂) _1-3-NH- (CH ₂) _1-3, - (CH ₂) _0-3-R _L ^r- (CH ₂) _0-3, - (CH ₂) _0-3- (CO) - (CH ₂) _0-3-R _L ^r- (CH ₂) _0-3-, - (CH ₂) _0-3- (CO-NH) - (CH ₂) _0-3-R _L ^r- (CH ₂) _0-3-, - (CH ₂) _0-3- (NH-CO) - (CH ₂) _0-3-R _L ^r- (CH ₂) _0-3-, and - (CH ₂) _0-3- (NH) - (CH ₂) _0-3-R _L ^r- (CH ₂) _0-3-. In another embodiment, R _L ^r, at each occurrence, is selected from FORMULAE C1, C2, C3, C4, and C5

wherein

A _L ¹, B _L ¹, C _L ¹ and D _L ¹, at each occurrence, are independently selected from null, O, CO, SO, SO ₂, NR _L ^b, CR _L ^bR _L ^c; R _L ^b

A _L ², B _L ², C _L ², D _L ² and E _L ², at each occurrence, are independently selected from N, CR _L ^b;

A _L ³, B _L ³, C _L ³, D _L ³, and E _L ³, at each occurrence, are independently selected from N, O, S, NR _L ^b, CR _L ^b;

R _L ^b and R _L ^c, at each occurrence, are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C ₁-C ₈ alkyl, optionally substituted C ₂-C ₈ alkenyl, optionally substituted C ₂-C ₈ alkynyl, optionally substituted C ₁-C ₈ alkoxy, optionally substituted C ₁-C ₈ alkoxyalkyl, optionally substituted C ₁-C ₈ haloalkyl, optionally substituted C ₁-C ₈ hydroxyalkyl, optionally substituted C ₁-C ₈ alkylamino, and optionally substituted C ₁-C ₈ alkylaminoC ₁-C ₈ alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 3-8 membered membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; and

m _L ¹, n _L ¹, o _L ¹ and p _L ¹ are independently selected from 0, 1, 2, 3, 4 and 5.

In another embodiment, R _L ^r, at each occurrence, is selected from Group R _L ^r1 or Group R _L ^r2, and

Group R _L ^r1 consists of the following optionally substituted groups

Group R _L ^r2 consists of the following optionally substituted groups

In one embodiment, the linker moiety is of FORMULA 9A:

wherein

R _L ¹, R _L ², R _L ³ and R _L ⁴, at each occurrence, are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C ₁-C ₈ alkyl, optionally substituted C ₂-C ₈ alkenyl, optionally substituted C ₂-C ₈ alkynyl, optionally substituted C ₁-C ₈ alkoxy, optionally substituted C ₁-C ₈ alkoxyalkyl, optionally substituted C ₁-C ₈ haloalkyl, optionally substituted C ₁-C ₈ hydroxyalkyl, optionally substituted C ₁-C ₈ alkylamino, and optionally substituted C ₁-C ₈ alkylaminoC ₁-C ₈ alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 3-8 membered membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

R _L ¹ and R _L ², R _L ³ and R _L ⁴ together with the atom (s) to which they are connected form a 3-20 membered cycloalkyl or 3-20 membered heterocyclyl ring;

A _L, W _L and B _L, at each occurrence, are independently selected from null, or bivalent moiety selected from R _L ^d-R _L ^e, R _L ^dCOR _L ^e, R _L ^dCO ₂R _L ^e, R _L ^dC (O) N (R _L ⁵) R _L ^e, R _L ^dC (S) N (R _L ⁵) R _L ^e, R _L ^dOR _L ^e, R _L ^dSR _L ^e, R _L ^dSOR _L ^e, R _L ^dSO ₂R _L ^e, R _L ^dSO ₂N (R _L ⁵) R _L ^e, R _L ^dN (R _L ⁵) R _L ^e, R _L ^dN (R _L ⁵) COR _L ^e, R _L ^dN (R _L ⁵) CON (R _L ⁶) R _L ^e, R _L ^dN (R _L ⁵) C (S) R _L ^e, optionally substituted C ₁-C ₈ alkylene, optionally substituted C ₂-C ₈ alkenylene, optionally substituted C ₂-C ₈ alkynylene, optionally substituted C ₁-C ₈alkoxyC ₁-C ₈alkylene, optionally substituted C ₁-C ₈ haloalkylene, optionally substituted C ₁-C ₈ 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 spiro cycloalkyl, optionally substituted 5-13 membered spiro heterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein

R _L ^d and R _L ^e, at each occurrence, are independently selected from null, optionally substituted (C ₁-C ₈ alkyl) -R _L ^r (preferably, CH ₂-R _L ^r) , optionally substituted R _L ^r- (C ₁-C ₈ alkylene) , optionally substituted (C ₁-C ₈ alkylene) -R _L ^r- (C ₁-C ₈ alkylene) , or a moiety comprising of optionally substituted C ₁-C ₈ alkyl, optionally substituted C ₂-C ₈ alkenyl, optionally substituted C ₂-C ₈ alkynyl, optionally substituted C ₁-C ₈ hydroxyalkyl, optionally substituted C ₁-C ₈alkoxyC ₁-C ₈alkyl, optionally substituted C ₁-C ₈alkylaminoC ₁-C ₈alkyl, optionally substituted C ₁-C ₈ haloalkyl, optionally substituted C ₁-C ₈ alkylene, optionally substituted C ₂-C ₈ alkenylene, optionally substituted C ₂-C ₈ alkynylene, optionally substituted C ₁-C ₈ hydroxyalkylene, optionally substituted C ₁-C ₈alkoxyC ₁-C ₈alkylene, optionally substituted C ₁-C ₈alkylaminoC ₁-C ₈alkylene, optionally substituted C ₁-C ₈ 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 spiro cycloalkyl, optionally substituted 5-13 membered spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R _L ^r, at each occurrence, is selected from 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 spiro cycloalkyl, optionally substituted 5-13 membered spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R _L ⁵ and R _L ⁶, at each occurrence, are independently selected from hydrogen, optionally substituted C ₁-C ₈ alkyl, optionally substituted C ₂-C ₈ alkenyl, optionally substituted C ₂-C ₈ alkynyl, optionally substituted C ₁-C ₈ alkoxyalkyl, optionally substituted C ₁-C ₈ haloalkyl, optionally substituted C ₁-C ₈ hydroxyalkyl, optionally substituted C ₁-C ₈alkylaminoC ₁-C ₈alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

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 atom (s) to which they are connected optionally form a 3-20 membered cycloalkyl or 3-20 membered heterocyclyl ring;

m _L is 0 to 15;

n _L, at each occurrence, is 0 to 15; and

o _L is 0 to 15.

In another embodiment, A _L, W _L and B _L, at each occurrence, are independently selected from null, CO, NH, NH-CO, CO-NH, - (CH ₂) _0-8-, - (CH ₂) _0-3-CO- (CH ₂) _0-8-, (CH ₂) _0-8-NH-CO, (CH ₂) _0-8-CO-NH, NH-CO- (CH ₂) _0-8, CO-NH- (CH ₂) _0-8, (CH ₂) _1-3-NH- (CH ₂) _1-3-CO-NH, (CH ₂) _1-3-NH- (CH ₂) _1-3-NH-CO, -CO-NH, CO-NH- (CH ₂) _1-3-NH- (CH ₂) _1-3, (CH ₂) _1-3-NH- (CH ₂) _1-3, - (CH ₂) _0-3-R _L ^r- (CH ₂) _0-3, - (CH ₂) _0-3- (CO) - (CH ₂) _0-3-R _L ^r- (CH ₂) _0-3-, - (CH ₂) _0-3- (CO-NH) - (CH ₂) _0-3-R _L ^r- (CH ₂) _0-3-, - (CH ₂) _0-3- (NH-CO) - (CH ₂) _0-3-R _L ^r- (CH ₂) _0-3-, and - (CH ₂) _0-3- (NH) - (CH ₂) _0-3-R _L ^r- (CH ₂) _0-3-.

In another embodiment, R _L ^r, at each occurrence, is selected from Group R _L ^r1 or Group R _L ^r2, and Group R _L ^r1 and Group R _L ^r2 are defined as before.

In one embodiment, the JAK ligand of the heterobifunctional compound is attached to A _L in FORMULA `9A.

In another embodiment, A _L (when A _L is attached to the JAK ligand) is selected from null, CO, NH, NH-CO, CO-NH, - (CH ₂) _0-8-, - (CH ₂) _0-3-CO- (CH ₂) _0-8-, (CH ₂) _0-8-NH-CO, (CH ₂) _0-8-CO-NH, NH-CO- (CH ₂) _0-8, CO-NH- (CH ₂) _0-8, (CH ₂) _0-8-NH- (CH ₂) _0-8-CO-NH, (CH ₂) _1-3-NH- (CH ₂) _1-3-NH-CO, CO-NH- (CH ₂) _1-3-NH- (CH ₂) _1-3, (CH ₂) _1-3-NH- (CH ₂) _1-3, - (CH ₂) _0-3-R _L ^r- (CH ₂) _0-3, - (CH ₂) _0-3- (CO) - (CH ₂) _0-3-R _L ^r- (CH ₂) _0-3-, - (CH ₂) _0-3- (CO-NH) - (CH ₂) _0-3-R _L ^r- (CH ₂) _0-3-, - (CH ₂) _0-3- (NH-CO) - (CH ₂) _0-3-R _L ^r- (CH ₂) _0-3-, - (CH ₂) _0-3- (NH) - (CH ₂) _0-3-R _L ^r- (CH ₂) _0-3-., wherein

R _L ^r, at each occurrence, is selected from Group R _L ^r1 or Group R _L ^r2, and Group R _L ^r1 and Group R _L ^r2 are defined above; and

W _L and B _L is null.

In one embodiment, the linker moiety is of FORMULA 9A:

wherein

R _L ¹, R _L ², R _L ³ and R _L ⁴, at each occurrence, are independently selected from hydrogen, optionally substituted C ₁-C ₈ alkyl (preperably, C ₁-C ₄ alkyl) , optionally substituted C ₃-C ₈ cycloalkyl (preperably, C ₃-C ₆ cycloalkyl) , or

R _L ¹ and R _L ², R _L ³ and R _L ⁴ together with the atom (s) to which they are connected form a 3-20 membered cycloalkyl (preferably, 3-5 membered cycloalkyl) or 3-20 membered heterocyclyl ring;

A _L is defined as before; and W and B are null;

m _L is 0 to 15 (preferably, m is 0, 1, or 2) ;

n _L, at each occurrence, is 1 to 15 (preferably, n is 1) ; and

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

In another embodiment, A _L is independently selected from null, or bivalent moiety selected from R _L ^d-R _L ^e, R _L ^dCOR _L ^e, R _L ^dCO ₂R _L ^e, R _L ^dC (O) N (R _L ⁵) R _L ^e, R _L ^dC (S) N (R _L ⁵) R _L ^e, R _L ^dOR _L ^e, R _L ^dSR _L ^e, R _L ^dSOR _L ^e, R _L ^dSO ₂R _L ^e, R _L ^dSO ₂N (R _L ⁵) R _L ^e, R _L ^dN (R _L ⁵) R _L ^e, R _L ^dN (R _L ⁵) COR _L ^e, R _L ^dN (R _L ⁵) CON (R _L ⁶) R _L ^e, R _L ^dN (R _L ⁵) C (S) R _L ^e; R _L ^dand R _L ^eare defined as above.

In another embodiment, R _L ^d and R _L ^e, at each occurrence, are independently selected from null, optionally substituted (C ₁-C ₈ alkyl) -R _L ^r (preferably, CH ₂-R _L ^r) , or optionally substituted C ₁-C ₈ alkyl (preferably, optionally substituted C ₁-C ₂ alkyl) .

In another embodiment, the linker moiety is of FORMULA 9B:

wherein

R _L ¹ and R _L ², at each occurrence, are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, and optionally substituted C ₁-C ₈ alkyl, optionally substituted C ₁-C ₈ alkoxy, optionally substituted C ₁-C ₈ alkoxy C ₁-C ₈ alkyl, optionally substituted C ₁-C ₈ haloalkyl, optionally substituted C ₁-C ₈ hydroxyalkyl, optionally substituted C ₁-C ₈ alkylamino, C ₁-C ₈alkylaminoC ₁-C ₈alkyl, 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

R _L ¹ and R _L ² together with the atom (s) to which they are connected form a 3-20 membered cycloalkyl or 3-20 membered heterocyclyl ring;

A _L and B _L, at each occurrence, are independently selected from null, or bivalent moiety selected from R _L ^d-R _L ^e, R _L ^dCOR _L ^e, R _L ^dCO ₂R _L ^e, R _L ^dC (O) N (R _L ³) R _L ^e, R _L ^dC (S) N (R _L ³) R _L ^e, R _L ^dOR _L ^e, R _L ^dSR _L ^e, R _L ^dSOR _L ^e, R _L ^dSO ₂R _L ^e, R _L ^dSO ₂N (R _L ³) R _L ^e, R _L ^dN (R _L ³) R _L ^e, R _L ^dN (R _L ³) COR _L ^e, R _L ^dN (R _L ³) CON (R _L ⁴) R _L ^e, R _L ^dN (R _L ³) C (S) R _L ^e, optionally substituted C ₁-C ₈ alkylene, optionally substituted C ₂-C ₈ alkenylene, optionally substituted C ₂-C ₈ alkynylene, optionally substituted C ₁-C ₈alkoxyC ₁-C ₈alkylene, optionally substituted C ₁-C ₈ haloalkylene, optionally substituted C ₁-C ₈ 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 spiro cycloalkyl, optionally substituted 5-13 membered spiro heterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein

R _L ^d and R _L ^e, at each occurrence, are independently selected from null, optionally substituted (C ₁-C ₈ alkylene) -R _L ^r (preferably, CH ₂-R _L ^r) , optionally substituted R _L ^r- (C ₁-C ₈ alkylene) , optionally substituted (C ₁-C ₈ alkylene) -R _L ^r- (C ₁-C ₈ alkylene) , or a moiety comprising of optionally substituted C ₁-C ₈ alkyl, optionally substituted C ₂-C ₈ alkenyl, optionally substituted C ₂-C ₈ alkynyl, optionally substituted C ₁-C ₈ hydroxyalkyl, optionally substituted C ₁-C ₈alkoxyC ₁-C ₈alkyl, optionally substituted C ₁-C ₈alkylaminoC ₁-C ₈alkyl, optionally substituted C ₁-C ₈ haloalkyl, optionally substituted C ₁-C ₈ alkylene, optionally substituted C ₂-C ₈ alkenylene, optionally substituted C ₂-C ₈ alkynylene, optionally substituted C ₁-C ₈ hydroxyalkylene, optionally substituted C ₁-C ₈alkoxyC ₁-C ₈alkylene, optionally substituted C ₁-C ₈alkylaminoC ₁-C ₈alkylene, optionally substituted C ₁-C ₈ 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 spiro cycloalkyl, optionally substituted 5-13 membered spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R _L ³ and R _L ⁴, at each occurrence, are independently selected from hydrogen, optionally substituted C ₁-C ₈ alkyl, optionally substituted C ₂-C ₈ alkenyl, optionally substituted C ₂-C ₈ alkynyl, optionally substituted C ₁-C ₈ alkoxyalkyl, optionally substituted C ₁-C ₈ haloalkyl, optionally substituted C ₁-C ₈ hydroxyalkyl, optionally substituted C ₁-C ₈alkylaminoC ₁-C ₈alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

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 atom (s) to which they are connected form a 3-20 membered cycloalkyl or 3-20 membered heterocyclyl ring;

each m _L is 0 to 15 (such as 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15) ; and

n _L is 0 to 15 (such as 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15) .

In another embodiment, A _L and B _L, at each occurrence, are independently selected from null, CO, NH, NH-CO, CO-NH, - (CH ₂) _0-8-, - (CH ₂) _0-3-CO- (CH ₂) _0-8-, (CH ₂) _0-8-NH-CO, (CH ₂) _0-8-CO-NH, NH-CO- (CH ₂) _0-8, CO-NH- (CH ₂) _0-8, (CH ₂) _1-3-NH- (CH ₂) _1-3-CO-NH, (CH ₂) _1-3-NH- (CH ₂) _1-3-NH-CO, CO-NH- (CH ₂) _1-3-NH- (CH ₂) _1-3, (CH ₂) _1-3-NH- (CH ₂) _1-3, - (CH ₂) _0-3-R _L ^r- (CH ₂) _0-3, - (CH ₂) _0-3- (CO) - (CH ₂) _0-3-R _L ^r- (CH ₂) _0-3-, - (CH ₂) _0-3- (CO-NH) - (CH ₂) _0-3-R _L ^r- (CH ₂) _0-3-, - (CH ₂) _0-3- (NH-CO) - (CH ₂) _0-3-R _L ^r- (CH ₂) _0-3-, - (CH ₂) _0-3- (NH) - (CH ₂) _0-3-R _L ^r- (CH ₂) _0-3-.

In another embodiment, R _L ^r, at each occurrence, is selected from Group R _L ^r1 or Group R _L ^r2, , and Group R _L ^r1 and Group R _L ^r2 are defined as in FORMULA 9.

In another embodiment, the linker moiety is of FORMULA 9C:

wherein

X _L, at each occurrence, is selected from O and NR _L ⁷;

R _L ¹, R _L ², R _L ³, R _L ⁴, R _L ⁵, and R _L ⁶, at each occurrence, are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C ₁-C ₈ alkyl, optionally substituted C ₂-C ₈ alkenyl, optionally substituted C ₂-C ₈ alkynyl, optionally substituted C ₁-C ₈ alkoxy, optionally substituted C ₁-C ₈ alkoxy C ₁-C ₈ alkyl, optionally substituted C ₁-C ₈ haloalkyl, optionally substituted C ₁-C ₈ hydroxyalkyl, optionally substituted C ₁-C ₈ alkylamino, optionally substituted C ₁-C ₈ alkylaminoC ₁-C ₈ 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;

A _L and B _L, at each occurrence, are independently selected from null, or bivalent moiety selected from R _L ^d-R _L ^e, R _L ^dCOR _L ^e, R _L ^dCO ₂R _L ^e, R _L ^dC (O) N (R _L ⁸) R _L ^e, R _L ^dC (S) N (R _L ⁸) R _L ^e, R _L ^dOR _L ^e, R _L ^dSR _L ^e, R _L ^dSOR _L ^e, R _L ^dSO ₂R _L ^e, R _L ^dSO ₂N (R _L ⁸) R _L ^e, R _L ^dN (R _L ⁸) R _L ^e, R _L ^dN (R _L ⁸) COR _L ^e, R _L ^dN (R _L ⁸) CON (R _L ⁹) R _L ^e, R _L ^dN (R _L ⁸) C (S) R _L ^e, optionally substituted C ₁-C ₈ alkylene, optionally substituted C ₂-C ₈ alkenylene, optionally substituted C ₂-C ₈ alkynylene, optionally substituted C ₁-C ₈alkoxyC ₁-C ₈alkylene, optionally substituted C ₁-C ₈ haloalkylene, optionally substituted C ₁-C ₈ 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 spiro cycloalkyl, optionally substituted 5-13 membered spiro heterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein

R _L ⁷, R _L ⁸ and R _L ⁹, at each occurrence, are independently selected from hydrogen, optionally substituted C ₁-C ₈ alkyl, optionally substituted C ₂-C ₈ alkenyl, optionally substituted C ₂-C ₈ alkynyl, optionally substituted C ₁-C ₈ alkoxyalkyl, optionally substituted C ₁-C ₈ haloalkyl, optionally substituted C ₁-C ₈ hydroxyalkyl, optionally substituted C ₁-C ₈alkylaminoC ₁-C ₈alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

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 atom (s) to which they are connected form a 3-20 membered cycloalkyl or 3-20 membered heterocyclyl ring;

m _L, at each occurrence, is 0 to 15 (such as 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15) ;

n _L, at each occurrence, is 0 to 15 (such as 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15) ;

o _L is 0 to 15 (such as 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15) ; and

p _L is 0 to 15 (such as 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15) .

In one embodiment, the linker moiety is of FORMULA 9D:

-A _L- (W _L) _qL-B _L- (FORMULA 9D)

wherein

W _L, at each occurrence, is each independently selected from null, R _L ^d-R _L ^e, R _L ^dCOR _L ^e, R _L ^dCO ₂R _L ^e, R _L ^dC (O) N (R _L ¹) R _L ^e, R _L ^dC (S) N (R _L ¹) R _L ^e, R _L ^dOR _L ^e, R _L ^dSR _L ^e, R _L ^dSOR _L ^e, R _L ^dSO ₂R _L ^e, R _L ^dSO ₂N (R _L ¹) R _L ^e, R _L ^dN (R _L ¹) R _L ^e, R _L ^dN (R _L ¹) COR _L ^e, R _L ^dN (R _L ¹) CON (R _L ²) R _L ^e, R _L ^dN (R _L ¹) C (S) R _L ^e, optionally substituted C ₁-C ₈ alkylene, optionally substituted C ₂-C ₈ alkenylene, optionally substituted C ₂-C ₈ alkynylene, optionally substituted C ₁-C ₈alkoxyC ₁-C ₈alkylene, optionally substituted C ₁-C ₈ haloalkylene, optionally substituted C ₁-C ₈ 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 spiro cycloalkyl, optionally substituted 5-13 membered spiro heterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl,

q _L = 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

R _L ¹, R _L ², R _L ^d, R _L ^e, A _L and B _L are defined as in FORMULA 9.

In another embodiment, at least one W _L is not null.

In another embodiment, W _L is not null.

In another embodiment, A _L and B _L are independently selected from null, R _L ^r _, CH ₂-R _L ^r, R _L ^dCOR _L ^e, R _L ^dC (O) N (R _L ¹) R _L ^e, R _L ^dOR _L ^e, R _L ^dSR _L ^e, R _L ^dSOR _L ^e, R _L ^dSO ₂R _L ^e, R _L ^dSO ₂N (R _L ¹) R _L ^e, R _L ^dN (R _L ¹) R _L ^e, R _L ^dN (R _L ¹) COR _L ^e, R _L ^dN (R _L ¹) CON (R _L ²) R _L ^e, R _L ^dN (R _L ¹) C (S) R _L ^e, optionally substituted C ₁-C ₂ alkylene, optionally substituted C ₂ alkenylene, and optionally substituted C ₂ alkynylene; and

R _L ^d and R _L ^e, at each occurrence, is independently selected from null, C ₁-C ₂ alkylene optionally substituted with one or more C ₁-C ₃ alkyl, halogen, and C ₁-C ₃ haloalkyl;

R _L ¹ and R _L ², at each occurrence, are independently selected from H, C ₁-C ₃ alkyl, C ₁-C ₃ haloalkyl, C ₃-C ₆ cycloalkyl, and C ₃-C ₆ halocycloalkyl.

In another embodiment, the linker moiety is attached to the the JAK ligand via A _L; wherein

A _L is selected from null, R _L ^r _, CH ₂-R _L ^r, CO, and CH ₂-CO;

B _L is independently selected from null, N (R _L ¹) , N (R _L ¹) -CH ₂, O, CH ₂, R _L ^r, R _L ^r-N (R _L ¹) , R _L ^r-CH ₂, and R _L ^r-O;

W _L, at each occurrence, is selected from CO, N (R _L ¹) , C (S) , SO, SO ₂, C (O) N (R _L ¹) , N (R _L ²) C (O) N (R _L ¹) , S (O) ₂N (R _L ¹) , optionally substituted C ₁-C ₂ alkylene, optionally substituted C ₂ alkenylene, optionally substituted C ₂ alkynylene, and R _L ^r;

R _L ¹ and R _L ², at each occurrence, are independently selected from H, C ₁-C ₃ alkyl, C ₁-C ₃ haloalkyl, C ₃-C ₆ cycloalkyl, and C ₃-C ₆ halocycloalkyl;

q _L = 1, 2, 3, 4, or 5.

In another embodiment, in A _L, R _L ^r, at each occurrence, is of FORMULAE C4, or C5.

In another embodiment, in A _L, R _L ^r, at each occurrence, is selected from Group R _L ^r2 as defined in FORMULA 9.

In another embodiment, R _L ^r, at each occurrence, is of FORMULAE C4, or C5; preferably, selected from Group R _L ^r2 as defined in FORMULA 9.

In another embodiment, 2 or 3 of W _L that are adjacent optionally combined to form a segment selected from optionally substituted C ₁ alkylene -CO-N (R _L ¹) -, (such as -CF ₂-CO-NH-) , or -N (R _L ¹) -CO-N (R _L ¹) , (such as-NH-CO-NH-) -; and the other W _L are optionally substituted C ₁-C ₂ alkylene; preferably, independently are unsubstituted C ₁-C ₂ alkylene, or C ₁-C ₂ alkylene substituted with one or more C ₁-C ₃ alkyl, halogen, and C ₁-C ₃ haloalkyl.

In another embodiment, 2 or 3 of W _L that are adjacent optionally combined to form a segment selected from -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 -) ; wherein R _L ^r, at each occurrence, is of FORMULAE C4, or C5; preferably, selected from Group R _L ^r2 as defined in FORMULA 9 and the other W _L are optionally substituted C ₁-C ₂ alkylene; preferably, independently are unsubstituted C ₁-C ₂ alkylene, or C ₁-C ₂ alkylene substituted with one or more C ₁-C ₃ alkyl, halogen, and C ₁-C ₃ haloalkyl.

In another embodiment, adjacent W _L are combined to form a segment selected from -optionally substituted C ₁ alkylene -CO-N (R _L ¹) - (such as -CF ₂-CO-NH-) , or -N (R _L ¹) -CO-N (R _L ¹) - (such as-NH-CO-NH-) -.

In another embodiment, adjacent W _L are combined to form a segment selected from -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 -) ; wherein R _L ^r, at each occurrence, is of FORMULAE C4, or C5; preferably, selected from Group R _L ^r2 as defined in FORMULA 9.

In another embodiment, W _L, at each occurrence, are selected from N (R _L ¹) and optionally substituted C ₁-C ₂ alkylene.

In another embodiment, optionally substituted C ₁-C ₂ alkylene are each independently unsubstituted C ₁-C ₂ alkylene, or C ₁-C ₂ alkylene substituted with one or more C ₁-C ₃ alkyl, halogen, and C ₁-C ₃ haloalkyl.

In another embodiment, W _L, at each occurrence, are optionally substituted C ₁-C ₂ alkylene; preferably, independently are unsubstituted C ₁-C ₂ alkylene, or C ₁-C ₂ alkylene substituted with one or more C ₁-C ₃ alkyl, halogen, and C ₁-C ₃ haloalkyl.

In another embodiment, optionally substituted C ₁-C ₂ alkylene means unsubstituted C ₁-C ₂ alkylene or C ₁-C ₂ alkylene with one or more C ₁-C ₃ alkyl, halogen (such as F, Cl, Br or I) , and C ₁-C ₃ haloalkyl; preferably, optionally substituted C ₁-C ₂ alkylene means C ₁-C ₂ alkylene with one or more (1, 2, 3 or 4) halogen (such as F, Cl, Br or I) .

In another embodiment, the linker is selected from - (CH ₂) _0-1-R _L ^r- (CH ₂) _0-2-NH-R _L ^r-NH- (CH ₂) _0-3-, - (CH ₂) _0-3- (CF ₂) -CO-NH- (CH ₂) _0-3-, - (CH ₂) _0-1-CO- (CH ₂) _0-3- (CF ₂) -CO-NH- (CH ₂) _0-3-,

In another embodiment, the linker is - (CH ₂) _0-1-R _L ^r- (CH ₂) _0-2-NH-R _L ^r- (CH ₂) _0-3-; wherein R _L ^r, at each occurrence, is of FORMULAE C4, or C5; preferably, selected from Group R _L ^r2 as defined in FORMULA 9.

In another embodiment, the linker is selected from - (CH ₂) _0-1-R _L ^r- (CH ₂) _0-3- (CF ₂) -CO-NH- (CH ₂) _0-3-, - (CH ₂) _0-3- (CF ₂) -CO-NH- (CH ₂) _0-3-, - (CH ₂) _0-1-CO- (CH ₂) _0-3- (CF ₂) -CO-NH- (CH ₂) _0-3-, - (CH ₂) _0-1-R _L ^r- (CH ₂) _0-3-NH-CO-NH- (CH ₂) _0-3-, - (CH ₂) _0-3-NH-CO-NH- (CH ₂) _0-3-, - (CH ₂) _0-1-CO- (CH ₂) _0-3-NH-CO-NH- (CH ₂) _0-3-.

In another refinement, the length of the linker is 0 to 40 chain atoms.

In another refinement, the length of the linker is 1 to 20 chain atoms.

In another refinement, the length of the linker is 2 to 12 chain atoms.

In another refinement, the linker is selected from - (CO) - (CH ₂) _1-8-, - (CH ₂) _1-9-, - (CH ₂) _1-2- (CO) -NH- (CH ₂) _2-9-, - (CH ₂) _1-2- (CO) -NH- (CH ₂) _1-3- (OCH ₂CH ₂) _1-7, and - (CH ₂) _0-1- (CO) - (CH ₂ ) _1-3- (OCH ₂CH ₂) _1-7.

In another refinement, the linker is - (CO) - (CH ₂) _1-8-, - (CH ₂) _1-9-, - (CH ₂) _1-2 (CO) -NH- (CH ₂) _2-9-, or - (CH ₂) _1- ₂- (CO) -NH- (CH ₂) _1-3- (OCH ₂CH ₂) _1-7.

In another refinement, (preferably when the degradation tag is a moiety of FORMULA 6) the linker is - (CO) - (CH ₂) _1-10- (CO) -, or - (CO) - (CH ₂) _1-9- (CO) -.

In another refinement, (preferably when the degradation tag is a moiety of FORMULA 6) the linker is - (CO) - (CH ₂) _1-3-O- (CH ₂CH ₂O) _0-5- (CH ₂) _1-3- (CO) -, or - (CO) - (CH ₂) -O- (CH ₂CH ₂O) _0-4- (CH ₂) - (CO) -, or - (CO) - (CH ₂) ₂-O- (CH ₂CH ₂O) _0-4- (CH ₂) ₂- (CO) -.

In another refinement, (preferably when the degradation tag is a moiety of FORMULA 6) the linker is - (CH ₂) _0-3- (CO) -NH- (CH ₂) _1-10- (CO) -, - (CH ₂) _1-2- (CO) -NH- (CH ₂) _1-10- (CO) -, or - (CH ₂) - (CO) -NH- (CH ₂) _1-10- (CO) -.

In another refinement, (preferably when the degradation tag is a moiety of FORMULA 6) the linker is - (CH ₂) _0-3- (CO) -NH- (CH ₂) _2-3-O- (CH ₂CH ₂O) _0-5- (CH ₂) _1-3- (CO) -, - (CH ₂) _1-2- (CO) -NH- (CH ₂) _2-3-O- (CH ₂CH ₂O) _0-5- (CH ₂) _1-3- (CO) -, or - (CH ₂) - (CO) -NH- (CH ₂) ₂-O- (CH ₂CH ₂O) _0-4- (CH ₂) _1-2- (CO) -.

In another refinement, (preferably when the degradation tag selected from FORMULAE 5A, 5B, 5C, 5D, 5E, and 5F) the linker is - (CO) - (CH ₂) _1-8-, - (CO) - (CH ₂) _1-7-, - (CH ₂) _1-9-, or - (CH ₂) _1-8-.

In another refinement, (preferably when the degradation tag selected from FORMULAE 5A, 5B, 5C, 5D, 5E, and 5F) the linker is - (CH ₂) _1-2 (CO) -NH- (CH ₂) _4-9-, or - (CH ₂) _1-2 (CO) -NH- (CH ₂) _2-9-, or - (CH ₂) _1-2 (CO) -NH- (CH ₂) _2-8-.

In another refinement, (preferably when the degradation tag selected from FORMULAE 5A, 5B, 5C, 5D, 5E, and 5F) the linker is - (CH ₂) _1-2- (CO) -NH- (CH ₂) _1, 2 or 3- (OCH ₂CH ₂) _1-7-, or - (CH ₂) _1-2- (CO) -NH- (CH ₂) _1, 2 _or 3- (OCH ₂CH ₂) _5-7-, or - (CH ₂) _1-2- (CO) -NH- (CH ₂) _1, ₂ _or ₃- (OCH ₂CH ₂) _1-5-.

In another refinement, (preferably when the degradation tag selected from FORMULAE 5A, 5B, 5C, 5D, 5E, and 5F) the linker is - (CH ₂) _0-1- (CO) - (CH ₂) _1, 2 or 3- (OCH ₂CH ₂) _1-7-, - (CH ₂) _0-1- (CO) - (CH ₂) _1, 2 or 3- (OCH ₂CH ₂) _5-7-, - (CH ₂) _0-1- (CO) - (CH ₂) _1, 2 or 3- (OCH ₂CH ₂) _1-5-.

In another refinement, when the JAK ligand derived from NVP-BSK805 (and preferably the degradation tag is selected from FORMULAE 5A, 5B, 5C, 5D, 5E, and 5F) , the linker is - (CO) - (CH ₂) _3-8- (preferably, - (CO) - (CH ₂) _4-7-; more preferably, - (CO) - (CH ₂) _4-5-) .

In another refinement, when the JAK ligand is FORMULA 3A (and preferably the degradation tag is selected from FORMULAE 5A, 5B, 5C, 5D, 5E, and 5F) , the linker is - (CO) - (CH ₂) _3-8- (preferably, - (CO) - (CH ₂) _4-7-; more preferably, - (CO) - (CH ₂) _4-5-) .

In another refinement, when the JAK ligand derived from Cmpd 12 (and preferably the degradation tag is selected from FORMULAE 5A, 5B, 5C, 5D, 5E, and 5F) , the linker is - (CO) - (CH ₂) _3-8- (preferably, - (CO) - (CH ₂) _4-7-; more preferably, - (CO) - (CH ₂) _5-7-) ; or the linker is - (CH ₂) _1-2- (CO) -NH- (CH ₂) _5-9- (preferably, -(CH ₂) _1-2- (CO) -NH- (CH ₂) _7-8-) .

In another refinement, when the JAK ligand is FORMULA 3C and 3D (and preferably the degradation tag is selected from FORMULAE 5A, 5B, 5C, 5D, 5E, and 5F) , the linker is - (CO) - (CH ₂) _3-8- (preferably, - (CO) - (CH ₂) _4-7-; more preferably, - (CO) - (CH ₂) _5-7-) ; or the linker is - (CH ₂) _1-2- (CO) -NH- (CH ₂) _5-9- (preferably, - (CH ₂) _1-2- (CO) -NH- (CH ₂) _7-8-) .

In another refinement, when the JAK ligand derived from TG101209 (and preferably the degradation tag is selected from FORMULAE 5A, 5B, 5C, 5D, 5E, and 5F) , the linker r is - (CO) - (CH ₂) _1-7- (preferably, - (CO) - (CH ₂) _1-2-or - (CO) - (CH ₂) _6-7-) ; or the linker is - (CH ₂) _1-2- (CO) -NH- (CH ₂) _4-7- (preferably, - (CH ₂) _1-2- (CO) -NH- (CH ₂) _5-6-) ; or the linker is - (CH ₂) _1-2- (CO) -NH- (CH ₂) _1, 2 or 3- (OCH ₂CH ₂) _1-7 (preferably, - (CH ₂) _1-2- (CO) - NH- (CH ₂) _1, 2 or 3- (OCH ₂CH ₂) _4-7-; more preferably, - (CH ₂) _1-2- (CO) -NH- (CH ₂) _1, 2 or 3- (OCH ₂CH ₂) ₅-) .

In another refinement, when the JAK ligand is FORMULA 3I (and preferably the degradation tag is selected from FORMULAE 5A, 5B, 5C, 5D, 5E, and 5F) , the linker is - (CO) - (CH ₂) _1-7- (preferably, - (CO) - (CH ₂) _1-2-or - (CO) - (CH ₂) _6-7-) ; or the linker is - (CH ₂) _1-2- (CO) -NH- (CH ₂) _4-7- (preferably, - (CH ₂) _1-2- (CO) -NH- (CH ₂) _5-6-) ; or the linker is - (CH ₂) _1-2- (CO) -NH- (CH ₂) _1, 2 or 3- (OCH ₂CH ₂) _1-7 (preferably, - (CH ₂) _1-2- (CO) -NH- (CH ₂) _1, 2 or 3- (OCH ₂CH ₂) _4-7-; more preferably, - (CH ₂) _1-2- (CO) -NH- (CH ₂) _1, 2 or 3- (OCH ₂CH ₂) ₅-) .

In another embodiment, R ^r, at each occurrence, is selected from FORMULA C1, C2, C3, C4, and C5 as defined above.

In another embodiment, R ^r, at each occurrence, is selected from Group R _L ^r1 or Group R _L ^r2.

In some embodiments, the heterobifunctional compound is selected from the group consisting of JA-001 to JA-295 or a pharmaceutically acceptable salt or analog thereof.

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 a pharmaceutically acceptable salt or analog thereof.

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) .

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-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) hexyl) acetamide (JA-094) .

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) .

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) .

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) isoindoline-1, 3-dione (JA-182) .

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) isoindoline-1, 3-dione (JA-187) .

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) isoindoline-1, 3-dione (JA-188) .

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) isoindoline-1, 3-dione (JA-189) .

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) isoindoline-1, 3-dione (JA-196) .

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) isoindoline-1, 3-dione (JA-198) .

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) isoindoline-1, 3-dione (JA-199) .

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) isoindoline-1, 3-dione (JA-202) .

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) isoindoline-1, 3-dione (JA-203) .

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) .

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) .

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-pentaoxaheptadecyl) acetamide (JA-224) .

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) .

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) .

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) .

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) .

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) .

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) .

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) .

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) .

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) .

In some embodiments, the heterobifunctional compound is selected from the group consisting of JA-296 to JA-350 or a pharmaceutically acceptable salt or analog thereof.

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 a pharmaceutically acceptable salt or analog thereof.

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) .

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) .

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) .

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-oxopentanamide (JA-315) .

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) .

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) .

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) .

In one embodiment, the heterobifunctional compound is 5- ( (6- (4- (4- (8- (3, 5-difluoro-4- ( (4-hydroxypiperidin-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) .

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) .

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) methyl) urea (JA-325) .

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) .

In one embodiment, the heterobifunctional compound is 3- (4- ( (2- ( (4- (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) .

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) .

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) .

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) .

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) .

In one embodiment, the heterobifunctional compound is 5- ( (6- (4- (4- (8- (3, 5-difluoro-4- ( (4- hydroxypiperidin-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) .

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) .

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

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

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

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

Synthesis and Testing of Heterobifunctional Compounds

The binding affinity of novel synthesized heterobifunctional compounds can be assessed using standard biophysical assays known in the art (e.g., isothermal titration calorimetry (ITC) , surface plasmon resonance (SPR) ) . Cellular assays can then be used to assess the heterobifunctional compound’s ability to induce JAK (e.g. JAK1, JAK2, JAK3, and TYK2) degradation and inhibit cancer cell proliferation. Besides evaluating a heterobifunctional compound’s induced changes in the protein levels of JAK, JAK mutants, JAK deletions, or JAK fusion proteins, protein-protein interaction or acteryltransferase enzymatic activity can also be assessed. Assays suitable for use in any or all of these steps are known in the art, and include, e.g., western blotting, quantitative mass spectrometry (MS) analysis, flow cytometry, enzymatic activity assay, ITC, SPR, cell growth inhibition, xenograft, orthotopic, and patient-derived xenograft models. Suitable cell lines for use in 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 use in 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.

By way of non-limiting example, detailed synthesis protocols are described in the Examples for specific exemplary heterobifunctional compounds.

Pharmaceutically acceptable isotopic variations 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 variations of those reagents) . Specifically, an isotopic variation 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 thus include, e.g., ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl.

Isotopic variations (e.g., isotopic variations containing ²H) can provide therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements. In addition, certain isotopic variations (particularly those containing a radioactive isotope) can be used in drug or substrate tissue distribution studies. The radioactive isotopes tritium ( ³H) and carbon-14 ( ¹⁴C) are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

Pharmaceutically acceptable solvates of the compounds disclosed herein are contemplated. A solvate can be generated, e.g., by substituting a solvent used to crystallize a compound disclosed herein with an isotopic variation (e.g., D ₂O in place of H ₂O, d ₆-acetone in place of acetone, or d ₆-DMSO in place of DMSO) .

Pharmaceutically acceptable fluorinated variations 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 fluorinated variations of those reagents) . Specifically, a fluorinated variation is a compound in which at least one hydrogen atom is replaced by a fluoro atom. Fluorinated variations can provide therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements.

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 hydroxyl groups or carboxylic acid groups to ester groups) . As used herein, a "prodrug" refers to a compound that can be converted via some chemical or physiological process (e.g., enzymatic processes and metabolic hydrolysis) to a therapeutic agent. Thus, the term "prodrug" also refers to a precursor of a biologically active compound that is pharmaceutically acceptable. A prodrug may be inactive when administered to a subject, i.e. an ester, but is converted in vivo to an active compound, for example, by hydrolysis to the free carboxylic acid or free hydroxyl. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in an organism. The term "prodrug" is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a subject. Prodrugs of an active compound may be prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of an alcohol or acetamide, formamide and benzamide derivatives of an amine functional group in the active compound and the like.

Characterization of Exemplary Heterobifunctional Compounds

Specific exemplary heterobifunctional compounds were first characterized using cell viability assays. RS4; 11 ALL cells were treated with bifunctional degraders for three days. The IC ₅₀ values ranged from 2 nM to over 10 uM. 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, JA-231 showed significant cell viability inhibition activity with IC ₅₀ values below 100 nM (Table 2) . JA-189 and JA-213 were further characterized in a varity of additional cell lines shown in Table 2. Compared to 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 cell lines (Table 3) . The anti-proliferative activities of compounds JA-296 to JA-340 were 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 activities.

To confirm JA-189 and JA-213 are true JAK degraders, HEL cell were treated with these two compounds at various compounds concentrations. Comparing with NVP-BSK805 and DMSO control, JA-189 and JA-213 were able to reduce JAK1, JAK2 and JAK3 protein levels, as well as down stream signaling as demonstrated by the weaker bands of p-STAT3 and p-STAT5 (Figure 1) . In RS4; 11 cells, JA-189 and JA-213 showed even better activity in reducing the JAK1 and JAK3 protein levels (Figure 2) .

Comparing with NVP-BSK805 and G101209, JA-189 and JA-213 showed significant improvement at inhibiting the viability of MV4; 11, MS4; 11, Kasumi-1, and HEL cell lines (Figure 3) . We further demonstrated that pomalidomide (POM) and degrader (JA-189 or JA-213) combination treatment greatly reduce the potencies of the degraders in MV4; 11, MS4; 11, Kasumi-1, and HEL cells (Figure 4) . Since pomalidomide competes with the degraders at the CRBN binding site, pomalidomide combination will reduce the CRBN binding of the degraders, thus diminishing the JAK protein degradation. This experiment demonstrated that CRBN binding is required for the observed cell viability inhibition activities of degraders, JA-189 and JA-213.

Our results further showed that some of the heterobifunctional molecules, as exemplified by JA-189 and JA-213, also induced degradation of GSPT1 in a dose dependent manner (Figure 5) .

In addition, immortalized human lung fibroblast IMR-90 and keratinocyte HACAT cells were not sensitive to JA-189 and JA-213 (Figure 6) . These non-cancerous human cell growth inhibition data indicate potential therapeutic windows of these degraders.

Moreover, JA-189, JA-263, JA-322, and JA-324 showed significant synergic effect when they were combined with FLT3 inhibitor, gilteritinib in the treatment of FLT3-mutant AML cells, such as MV4; 11 and MOLM-13 cells (Figure 7) . For wild type FLT3 cells, such as NOMO-1 cells, gilteritinib did not potentiate the anti-proliferation effect of JA-189 and JA-263 (Figure 8) . This experiment demonstrated that GSPT1 degraders and FLT3 inhibtior are synergic at the inhibition of the growth of cells expressing FLT3-mutantion.

We further confirmed that JA-189, JA-263, JA-322, JA-323 and JA-324 were able to reduce GSPT1 protein levels in MV4; 11 cells (Figure 9) .

Furthermore, AKT inhibitor MK-2206 (Figure 10A) and MEK inhibitor trametinib (Figure 10B) also significantly potentiated the anti-proliferation activities of GSPT1 degarders JA-189 and JA-263, indicating poteintial combination therapeutic applications of GSPT1 degraders with either PI3K/AKT/mTOR pathway inhibitors or MAPK pathway inhibitors.

Definition of Terms

As used herein, the terms “comprising” and “including” are used in their open, non-limiting sense.

"Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation. An alkyl may comprise one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or sixteen carbon atoms. In certain embodiments, an alkyl comprises one to fifteen carbon atoms (e.g., C ₁-C ₁₅ alkyl) . In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C ₁-C ₁₃ alkyl) . In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., C ₁-C ₈ alkyl) . In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C ₅-C ₁₅ alkyl) . In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C ₅-C ₈ alkyl) . The alkyl is attached to the rest of the molecule by a single bond, for example, methyl (Me) , ethyl (Et) , n-propyl, 1-methylethyl (iso-propyl) , n-butyl, n-pentyl, 1, 1-dimethylethyl (t-butyl) , pentyl, 3-methylhexyl, 2-methylhexyl, and the like.

"Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond. An alkenyl may comprise two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or sixteen carbon atoms. In certain embodiments, an alkenyl comprises two to twelve carbon atoms (e.g., C ₂-C ₁₂ alkenyl) . In certain embodiments, an alkenyl comprises two to eight carbon atoms (e.g., C ₂-C ₈ alkenyl) . In certain embodiments, an alkenyl comprises two to six carbon atoms (e.g., C ₂-C ₆ alkenyl) . In other embodiments, an alkenyl comprises two to four carbon atoms (e.g., C ₂-C ₄ alkenyl) . The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl) , prop-1-enyl (i.e., allyl) , but-1-enyl, pent-1-enyl, penta-1, 4-dienyl, and the like.

The term “allyl, ” as used herein, means a –CH ₂CH=CH ₂ group.

As used herein, the term "alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond. An alkynyl may comprise two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or sixteen carbon atoms. In certain embodiments, an alkynyl comprises two to twelve carbon atoms (e.g., C ₂-C ₁₂ alkynyl) . In certain embodiments, an alkynyl comprises two to eight carbon atoms (e.g., C ₂-C ₈ alkynyl) . In other embodiments, an alkynyl has two to six carbon atoms (e.g., C ₂-C ₆ alkynyl) . In other embodiments, an alkynyl has two to four carbon atoms (e.g., C ₂-C ₄ alkynyl) . The alkynyl is attached 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, and the like.

The term "alkoxy" , as used herein, means an alkyl group as defined herein witch is attached to the rest of the molecule via an oxygen atom. Examples of such groups include, but are not limited to, methoxy, ethoxy, n-propyloxy, iso-propyloxy, n-butoxy, iso-butoxy, tert-butoxy, pentyloxy, hexyloxy, and the like.

The term “aryl” , as used herein, "refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon atoms. An aryl may comprise from six to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) π–electron system in accordance with the Hückel theory. In certain embodiments, an aryl comprises six to fourteen carbon atoms (C ₆-C ₁₄ aryl or 6-14 membered aryl) . In certain embodiments, an aryl comprises six to ten carbon atoms (C ₆-C ₁₀ aryl or 6-10 membered aryl) . Examples of such groups include, but are not limited to, phenyl, fluorenyl and naphthyl. The terms “Ph” and “phenyl, ” as used herein, mean a -C ₆H ₅ group.

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

The term “heterocyclyl” , as used herein, means a non-aromatic, monocyclic, bicyclic, tricyclic, or tetracyclic radical having a total of from 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 atoms in its ring system, and containing from 3 to 12 (such as 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms and from 1 to 4 (such as 1, 2.3 or 4) heteroatoms each independently selected from O, S and N, and with the proviso that the ring of said group does not contain two adjacent O atoms or two adjacent S atoms. A heterocyclyl group may include fused, bridged or spirocyclic ring systems. In certain embodiments, a hetercyclyl group comprises 3 to 10 ring atoms (3-10 membered heterocyclyl) . In certain embodiments, a hetercyclyl group comprises 3 to 8 ring atoms (3-8 membered heterocyclyl) . In certain embodiments, a hetercyclyl group comprises 3 to 10 ring atoms (3-10 membered heterocyclyl) . In certain embodiments, a hetercyclyl group comprises 3 to 8 ring atoms (3-8 membered heterocyclyl) . A heterocyclyl group may contain an oxo substituent at any available atom that will result in a stable compound. For example, such a group may contain an oxo atom at an available carbon or nitrogen atom. Such a group may contain more than one oxo substituent if chemically feasible. In addition, it is to be understood that when such a heterocyclyl group contains a sulfur atom, said sulfur atom may be oxidized with one or two oxygen atoms to afford either a sulfoxide or sulfone. An example of a 4 membered heterocyclyl 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-quinolizinyl. Further examples of such heterocyclyl groups include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1, 2, 3, 6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1, 3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo [3.1.0] hexanyl, 3-azabicyclo [4.1.0] heptanyl, 3H-indolyl, quinolizinyl, 3-oxopiperazinyl, 4-methylpiperazinyl, 4-ethylpiperazinyl, and 1-oxo-2, 8, diazaspiro [4.5] dec-8-yl. A heteroaryl group may be attached to the rest of molecular via a carbon atom (C-attached) or a nitrogen atom (N-attached) . For instance, a group derived from piperazine may be piperazin-1-yl (N-attached) or piperazin-2-yl (C-attached) .

The term "cycloalkyl" or "carbocyclyl" means a saturated, monocyclic, bicyclic, tricyclic, or tetracyclic radical having a total of from 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms in its ring system. A cycloalkyl may be fused, bridged or spirocyclic. In certain embodiments, a cycloalkyl comprises 3 to 8 carbon ring atoms (3-8 membered carbocyclyl) . In certain embodiments, a cycloalkyl comprises 3 to 10 carbon ring atoms (3-10 membered cycloalkyl) . Examples of such groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptyl, adamantyl, and the like.

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

The term "spirocyclic" as used herein has its conventional meaning, that is, any ring system containing two or more rings wherein two of the rings have one ring carbon in common. Each ring of the spirocyclic ring system, as herein defined, independently comprises 3 to 20 ring atoms. Preferably, they have 3 to 10 ring atoms. Non-limiting examples of a spirocyclic system include spiro [3.3] heptane, spiro [3.4] octane, and spiro [4.5] decane.

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

An "aldehyde" group refers to a –C (O) H group.

An "alkoxy" group refers to both an –O-alkyl, as defined herein.

An "alkoxycarbonyl" refers to a -C (O) -alkoxy, as defined herein.

An "alkylaminoalkyl" group refers to an -alkyl-NR-alkyl group, as defined herein.

An "alkylsulfonyl" group refer to a -SO ₂alkyl, as defined herein.

An "amino" group refers to an optionally substituted -NH ₂.

An "aminoalkyl" group refers to an –alky-amino group, as defined herein.

An "aminocarbonyl" refers to a -C (O) -amino, as defined herein.

An "arylalkyl" group refers to -alkylaryl, where alkyl and aryl are defined herein.

An "aryloxy" group refers to both an –O-aryl and an –O-heteroaryl group, as defined herein.

An "aryloxycarbonyl" refers to -C (O) -aryloxy, as defined herein.

An "arylsulfonyl" group refers to a -SO ₂aryl, as defined herein.

A "carbonyl" group refers to a -C (O) -group, as defined herein.

A "carboxylic acid" group refers to a –C (O) OH group.

A “cycloalkoxy” refers to a –O-cycloalkyl group, as defined herein.

A "halo" or "halogen" group refers to fluorine, chlorine, bromine or iodine.

A "haloalkyl" group refers to an alkyl group substituted with one or more halogen atoms.

A "hydroxy" group refers to an -OH group.

A "nitro" group refers to a -NO ₂ group.

An “oxo” group refers to the =O substituent.

A "trihalomethyl" group refers to a methyl substituted with three halogen atoms.

The term “length” when refers to a moiety means the smallest number of carbon and/or hetero atoms from one end to the other end of the moiety. When it refers to the linker, it means the smallest number of atoms from the end connects to the TRK ligand and the end connects to the degradation tag. It applies to both situations where the linker is linear or branched, and where the linker comprises a ring system.

The term “substituted, ” means that the specified group or moiety bears one or more substituents independently selected from C ₁-C ₄ alkyl, aryl, heteroaryl, aryl-C ₁-C ₄ alkyl-, heteroaryl-C ₁-C ₄ alkyl-, C ₁-C ₄ haloalkyl, -OC ₁-C ₄ alkyl, -OC ₁-C ₄ alkylphenyl, -C ₁-C ₄ alkyl-OH, -OC ₁-C ₄ haloalkyl, halo, -OH, -NH ₂, -C ₁-C ₄ alkyl-NH ₂, -N (C ₁-C ₄ alkyl) (C ₁-C ₄ alkyl) , -NH (C ₁-C ₄ alkyl) , -N (C ₁-C ₄ alkyl) (C ₁-C ₄ alkylphenyl) , -NH (C ₁-C ₄ alkylphenyl) , cyano, nitro, oxo, -CO ₂H, -C (O) OC ₁-C ₄ alkyl, -CON (C ₁-C ₄ alkyl) (C ₁-C ₄ alkyl) , -CONH (C ₁-C ₄ alkyl) , -CONH ₂, -NHC (O) (C ₁-C ₄ alkyl) , -NHC (O) (phenyl) , -N (C ₁-C ₄ alkyl) C (O) (C ₁-C ₄ alkyl) , -N (C ₁-C ₄ alkyl) C (O) (phenyl) , -C (O) C ₁-C ₄ alkyl, -C (O) C ₁-C ₄ alkylphenyl, -C (O) C ₁-C ₄ haloalkyl, -OC (O) C ₁-C ₄ alkyl, -SO ₂ (C ₁-C ₄ alkyl) , -SO ₂ (phenyl) , -SO ₂ (C ₁-C ₄ haloalkyl) , -SO ₂NH ₂, -SO ₂NH (C ₁-C ₄ alkyl) , -SO ₂NH (phenyl) , -NHSO ₂ (C ₁-C ₄ alkyl) , -NHSO ₂ (phenyl) , and -NHSO ₂ (C ₁-C ₄ haloalkyl) .

The term “null” means the absence of an atom or moiety, and there is a bond between adjacent atoms in the structure.

The term “optionally substituted” means that the specified group may be either unsubstituted or substituted by one or more substituents as defined herein. It is to be understood that in the compounds of the present invention when a group is said to be “unsubstituted, ” or is “substituted” with fewer groups than would fill the valencies of all the atoms in the compound, the remaining valencies on such a group are filled by hydrogen. For example, if a C ₆ aryl group, also called “phenyl” herein, is substituted with one additional substituent, one of ordinary skill in the art would understand that such a group has 4 open positions left on carbon atoms of the C ₆ aryl ring (6 initial positions, minus one at which the remainder of the compound of the present invention is attached to and an additional substituent, remaining 4 positions open) . In such cases, the remaining 4 carbon atoms are each bound to one hydrogen atom to fill their valencies. Similarly, if a C ₆ aryl group in the present compounds is said to be “disubstituted, ” one of ordinary skill in the art would understand it to mean that the C ₆ aryl has 3 carbon atoms remaining that are unsubstituted. Those three unsubstituted carbon atoms are each bound to one hydrogen atom to fill their valencies. Unless otherwise specified, an optionally substituted radical may be a radical unsubstituted or substituted with one or more substituents selected from halogen, CN, NO ₂, OR ^m, SR ^m, NR ⁿR ^o, COR ^m, CO ₂R ^m, CONR ⁿR ^o, SOR ^m, SO ₂R ^m, SO ₂NR ⁿR ^o, NR ⁿCOR ^o, NR ^mC (O) NR ⁿR ^o, NR ⁿSOR ^o, NR ⁿSO ₂R ^o, C ₁-C ₈ alkyl, C ₁-C ₈alkoxyC ₁-C ₈alkyl, C ₁-C ₈ haloalkyl, C ₁-C ₈ hydroxyalkyl, C ₁-C ₈alkylaminoC ₁-C ₈ alkyl, C ₃-C ₇ cycloalkyl, 3-7 membered heterocyclyl, C ₂-C ₈ alkenyl, C ₂-C ₈ alkynyl, aryl, and heteroaryl, wherein R ^m, R ⁿ, and R ^o are independently selected from null, hydrogen, C ₁-C ₈ alkyl, C ₂-C ₈ alkenyl, C ₂-C ₈ alkynyl, C ₃-C ₇ cycloalkyl, 3-7 membered heterocyclyl, aryl, and heteroaryl, or R ⁿ and R ^o together with the atom to which they are connected form a 3-8 membered cycloalkyl or heterocyclyl ring.

As used herein, the same symbol in different FORMULA means different definition, for example, the definition of R1 in FORMULA 1 is as defined with respect to FORMULA 1 and the definition of R1 in FORMULA 6 is as defined with respect to FORMULA 6.

As used herein, each unit in the linker moiety (e.g.,

) can be the same as or different from each other. In certain embodiments, each unit in the linker moiety is the same as each other.

As used herein, when m (or n or o or p) is definited by a range, for example, “m is 0 to 15” or “m = 0-3” mean 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 is any integer in the defined range.

"Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the heterobifunctional compounds described herein is intended to encompass 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.

"Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono-and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc. and include, 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. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S. M. et al., "Pharmaceutical Salts, " Journal of Pharmaceutical Science, 66: 1-19 (1997) , which is hereby incorporated by reference in its entirety) . Acid addition salts of basic compounds may be prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.

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

Pharmaceutical Compositions

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

In some aspects, the compositions disclosed herein can include other compounds, drugs, or agents used for the treatment of cancer. For example, in some instances, pharmaceutical compositions disclosed herein can be combined with one or more (e.g., one, two, three, four, five, or less than ten) compounds. Such additional compounds can include, e.g., conventional chemotherapeutic agents or any other cancer treatment known in the art. When co-administered, heterobifunctional compounds disclosed herein can operate in conjunction with conventional chemotherapeutic agents or any other cancer treatment known in the art to produce mechanistically additive or synergistic therapeutic effects.

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.

Pharmaceutical compositions typically include a pharmaceutically acceptable excipient, adjuvant, or vehicle. As used herein, the phrase “pharmaceutically acceptable” refers to molecular entities and compositions that are generally believed to be physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as gastric upset, dizziness and the like, when administered to a human. A pharmaceutically acceptable excipient, adjuvant, or vehicle is a substance that can be administered to a patient, together with a compound of the invention, and which does not compromise the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound. Exemplary conventional nontoxic pharmaceutically acceptable excipients, adjuvants, and vehicles include, but not limited to, saline, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration.

In particular, pharmaceutically acceptable excipients, adjuvants, and vehicles that can be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric 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, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. Cyclodextrins such as α-, β-, and γ-cyclodextrin, may also be advantageously used to enhance delivery of compounds of the formulae described herein.

Depending on the dosage form selected to deliver the heterobifunctional compounds disclosed herein, different pharmaceutically acceptable excipients, adjuvants, and vehicles may be used. In the case of tablets for oral use, pharmaceutically acceptable excipients, adjuvants, and vehicles may be used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oily phase is combined with emulsifying or suspending agents. If desired, certain sweetening, flavoring, or coloring agents can be added.

As used herein, the heterobifunctional compounds disclosed herein are defined to include pharmaceutically acceptable derivatives or prodrugs thereof. A “pharmaceutically acceptable derivative” means any pharmaceutically acceptable salt, solvate, or prodrug, e.g., carbamate, ester, phosphate ester, salt of an ester, or other derivative of a compound or agent disclosed herein, which upon administration to a recipient is capable of providing (directly or indirectly) a compound described herein, or an active metabolite or residue thereof. Particularly favored derivatives and prodrugs are those that increase the bioavailability of the compounds disclosed herein when such compounds are administered to a subject (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species. Preferred prodrugs include derivatives where a group that enhances aqueous solubility or active transport through the gut membrane is appended to the structure of formulae described herein. Such derivatives are recognizable to those skilled in the art without undue experimentation. Nevertheless, reference is made to the teaching of Burger's Medicinal Chemistry and Drug Discovery, 5 ^th Edition, Vol. 1: Principles and Practice, which is incorporated herein by reference to the extent of teaching such derivatives.

The heterobifunctional compounds disclosed herein include pure enantiomers, mixtures of enantiomers, pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixtures of diastereoisomeric racemates and the meso-form and pharmaceutically acceptable salts, solvent complexes, morphological forms, or deuterated derivatives thereof.

In some aspects, the pharmaceutical compositions disclosed herein can include an effective amount of one or more heterobifunctional compounds. The terms “effective amount” and “effective to treat, ” as used herein, refer to an amount or a concentration of one or more compounds or a pharmaceutical composition described herein utilized for a period of time (including acute or chronic administration and periodic or continuous administration) that is effective within the context of its administration for causing an intended effect or physiological outcome (e.g., treatment or prevention of cell growth, cell proliferation, or cancer) . In some aspects, pharmaceutical compositions can further include one or more additional compounds, drugs, or agents used for the treatment of cancer (e.g., conventional chemotherapeutic agents) in amounts effective for causing an intended effect or physiological outcome (e.g., treatment or prevention of cell growth, cell proliferation, or cancer) .

In some aspects, the pharmaceutical compositions disclosed herein can be formulated for sale in the United States, import into the United States, or export from the United States.

Administration of Pharmaceutical Compositions

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

For example, the pharmaceutical compositions disclosed herein can be administered, e.g., topically, rectally, nasally (e.g., by inhalation spray or nebulizer) , buccally, vaginally, subdermally (e.g., by injection or via an implanted reservoir) , or ophthalmically.

For example, pharmaceutical compositions of this 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.

For example, the pharmaceutical compositions of this invention can be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycols.

For example, the pharmaceutical compositions of this 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 solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, or other solubilizing or dispersing agents known in the art.

For example, the pharmaceutical compositions of this 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 dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, e.g., as a solution in 1, 3-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringers solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed, including synthetic mono-or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, e.g., olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions can also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions. Other commonly used surfactants such as Tweens, Spans, or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms can also be used for the purposes of formulation.

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

When the pharmaceutical compositions disclosed herein include a combination of the heterobifunctional compounds described herein and one or more additional compounds (e.g., one or more additional compounds, drugs, or agents used for the treatment of cancer or any other condition or disease, including conditions or diseases known to be associated with or caused by cancer) , both the heterobifunctional compounds and the additional compounds may be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95%of the dosage normally administered in a monotherapy regimen. The additional agents can be administered separately, as part of a multiple dose regimen, from the compounds of this invention. Alternatively, those agents can be part of a single dosage form, mixed together with the compounds of this invention in a single composition. Such additional compounds may preberably be a kinase inhibitor, in particular, FLT3 pathway inhibitor (e.g. Gilteritinib, Midostaurin, Sorafenib, Sunitinib, Lestaurtinib) , MAPK pathway inhibitor, RAS-RAF-MEK-ERK pathway inhibitor (e.g. Vemurafenib, Dabrafenib; Encorafenib, SB590885, PLX4720, XL281, RAF265, Trametinib, Binimetinib, Cobimetinib, Selumetinib, CI-1040, PD0325901) , and PI3K-AKT-mTOR pathway inhibitor or activators (e.g. Apitolisib, 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, and AZD2014, Wortmannin, LY294002, hibiscone C, Taselisib, Perifosine, Buparlisib, Umbralisib, PX-866, Dactolisib, CUDC-907, Voxtalisib, bisper oxovanadium, Sarcopoterium) .

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

Methods of Treatment

The methods disclosed herein contemplate administration of an effective amount of a compound or composition to achieve the desired or stated effect. Typically, the compounds or compositions of the invention will be administered from about 1 to about 6 times per day or, alternately or in addition, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. A typical preparation will contain from about 5%to about 95%active compound (w/w) . Alternatively, such preparations can contain from about 20%to about 80%active compound.

In some aspects, provided herein are a heterobifunctional compound described herein for preventing or treating a disease or condition.

In some aspects, provided herein are a heterobifunctional compound described herein for 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 resulted from JAK expression, mutation, deletion, or fusion. In certain embodiments, the diseases or conditions are cancer, inflammation, auto-immune disease, viral infections, and immunological diseases. In one embodiment, the JAK-mediated cancer is selected from the group consisting of brain cancer, stomach cancer, gastrointestinal tract cancer, liver cancer, biliary passage cancer, breast cancer, ovary cancer, cervix cancer, prostate cancer, testis cancer, penile cancer, genitourinary tract cancer, esophagus cancer, larynx cancer, skin cancer, lung cancer, pancreas cancer, thyroid cancer, gland cancer, bladder cancer, kidney cancer, muscle cancer, bone cancer, cancers of the hematopoietic system, myeloproliferative neoplasms, essential thrombocythemia, polycythemia vera, primary myelofibrosis, chronic neutrophilic leukemia, acute lymphoblastic leukemia, Hodgkin’s 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 disorders are selected from the group consisting of ankylosing spondylitis, Crohn’s disease, inflammatory bowel disease, ulcerative colitis, and ischemia reperfusion injuries. In one embodiment, the JAK-mediated auto-immune diseases are 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 disorders, alopecia areata, and bullous pemphigoid. In one embodiment, the JAK-mediated dermatological disorders are selected from the group consisting of atopic dermatitis, pruritus, alopecia areata, psoriasis, skin rash, skin irritation, skin sensitization, chronic mucocutaneous candidiasis, dermatomyositis, erythema multiforme, palmoplantar pustulosis, vitiligo, polyarteritis nodosa, and STING-associated vasculopathy. In one embodiment, the JAK-mediated viral infections are selected from the group consisting of infections of Hepatitis B, Hepatitis C, Human Immunodeficiency Virus (HIV) , Human T-lymphotropic Virus (HTLV1) , Epstein Barr Virus (EBV) , Varicella-Zoster Virus (VZV) and Human Papilloma Virus (HPV) . In one embodiment, the JAK-mediated dry eye disorders are selected from the group consisting of dry eye syndrome (DES) and keratoconjunctivitis sicca (KCS) . In one embodiment, the JAK-mediated bone remodeling disorders are selected from the group consisting of osteoporosis and osteoarthritis. In one embodiment, the JAK-mediated organ transplant associated immunological complications are selected from the group consisting of graft-versus-host diseases.

In some aspects, provided herein are use of a heterobifunctional compound in manufacture of a medicament for preventing or treating one or more diseases or conditions disclosed herein.

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

In some aspects, subject selection can include obtaining a sample from a subject (e.g., a candidate subject) and testing the sample for an indication that the subject is suitable for selection. In some aspects, the subject can be confirmed or identified, e.g. by a health care professional, as having had, having an elevated risk to have, or having a condition or disease. In some aspects, suitable subjects include, for example, subjects who have or had a condition or disease but that resolved the disease or an aspect thereof, present reduced symptoms of disease (e.g., relative to other subjects (e.g., the majority of subjects) with the same condition or disease) , or that survive for extended periods of time with the condition or disease (e.g., relative to other subjects (e.g., the majority of subjects) with the same condition or disease) , e.g., in an asymptomatic state (e.g., relative to other subjects (e.g., the majority of subjects) with the same condition or disease) . In some aspects, exhibition of a positive immune response towards a condition or disease can be made from patient records, family history, or detecting an indication of a positive immune response. In some aspects, multiple parties can be included in subject selection. For example, a first party can obtain a sample from a candidate subject and a second party can test the sample. In some aspects, subjects can be selected or referred by a medical practitioner (e.g., a general practitioner) . In some aspects, subject selection can include obtaining a sample from a selected subject and storing the sample or using the in the methods disclosed herein. Samples can include, e.g., cells or populations of cells.

In some aspects, methods of treatment can include a single administration, multiple administrations, and repeating administration of one or more compounds disclosed herein as required for the prevention or treatment of the disease or condition disclosed herein (e.g., an JAK-mediated disease) . In some aspects, methods of treatment can include assessing a level of disease in the subject prior to treatment, during treatment, or after treatment. In some aspects, treatment can continue until a decrease in the level of disease in the subject is detected.

The term “subject, ” as used herein, refers to any animal. In some instances, the subject is a mammal. In some instances, the term “subject, ” as used herein, refers to a human (e.g., a man, a woman, or a child) .

The terms “administer, ” “administering, ” or “administration, ” as used herein, refer to implanting, ingesting, injecting, inhaling, or otherwise absorbing a compound or composition, regardless of form. For example, the methods disclosed herein include administration of an effective amount of a compound or composition to achieve the desired or stated effect.

The terms “treat” , “treating, ” or “treatment, ” as used herein, refer to partially or completely alleviating, inhibiting, ameliorating, or relieving the disease or condition from which the subject is suffering. This means any manner in which one or more of the symptoms of a disease or disorder (e.g., cancer) are ameliorated or otherwise beneficially altered. As used herein, amelioration of the symptoms of a particular disorder (e.g., cancer) refers to any lessening, whether permanent or temporary, lasting or transient that can be attributed to or associated with treatment by the heterobifunctional compounds, compositions and methods of the present 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 prior to treatment; a decrease in the viability (e.g., the average/mean viability) of tumor cells (e.g., in a subject) relative to the viability of tumor cells prior to treatment; a decrease in the rate of growth of tumor cells; a decrease in the rate of local or distant tumor metastasis; or reductions in one or more symptoms associated with one or more tumors in a subject relative to the subject’s symptoms prior to treatment.

The terms “prevent, ” “preventing, ” and “prevention, ” as used herein, shall refer to a decrease in the occurrence of a disease or decrease in the risk of acquiring a disease or its associated symptoms in a subject. The prevention may be complete, e.g., the total absence of disease or pathological cells in a subject. The prevention may also be partial, such that the occurrence of the disease or pathological cells in a subject is less than, occurs later than, or develops more slowly than that which would have occurred without the present invention. In certain embodiments, the subject has an elevated risk of developing one or more JAK-mediated diseases. Exemplary JAK-mediated diseases that can be treated with heterobifunctional compounds include, for example, cancer (e.g. cancers of brain, stomach, gastrointestinal tracts, liver, biliary passage, breast, ovary, cervix, prostate, testis, penile, genitourinary tract, esophagus, larynx, skin, lung, pancreas, thyroid, glands, bladder, kidney, muscle, bone, and cancers of the hematopoietic system, such as myeloproliferative neoplasms, including essential thrombocythemia, polycythemia vera, primary myelofibrosis, chronic neutrophilic leukemia, acute lymphoblastic leukemia, Hodgkin’s lymphoma, chronic myelomonocytic leukemia, systemic mast cell disease, hypereosinophilic syndrome, cutaneous T-cell lymphoma, B-cell lymphoma, myeloma, and other hematologic malignancies, particularly cancers that involve inflammation, mutations or other aberrations that activate the JAK pathway) ; inflammation (e.g. ankylosing spondylitis, Crohn’s disease, inflammatory bowel disease, ulcerative colitis, and ischemia reperfusion injuries, which are conditions related to inflammatory ischemic events such as stroke or cardiac arrest) ; auto-immune diseases (e.g. multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, psoriasis, myasthenia gravis, type I diabetes, systemic lupus erythematosus, IgA nephropathy, autoimmune thyroid disorders, alopecia areata, and bullous pemphigoid) ; dermatological disorders (e.g. atopic dermatitis, pruritus, alopecia areata, psoriasis, skin rash, skin irritation, skin sensitization, chronic mucocutaneous candidiasis, dermatomyositis, erythema multiforme, palmoplantar pustulosis, vitiligo, polyarteritis nodosa, and STING-associated vasculopathy) ; viral infections (e.g. viral infections and consequent complications, such as infections of Hepatitis B, Hepatitis C, Human Immunodeficiency Virus (HIV) , Human T-lymphotropic Virus (HTLV1) , Epstein Barr Virus (EBV) , Varicella-Zoster Virus (VZV) and Human Papilloma Virus (HPV) ) ; dry eye disorder, also known as dry eye syndrome (DES) or keratoconjunctivitis sicca (KCS) ; bone remodeling disorders (e.g. osteoporosis and osteoarthritis) ; organ transplant associated immunological complications (e.g. graft-versus-host diseases) .

Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the patient’s disposition to the disease, condition or symptoms, and the judgment of the treating physician.

An effective amount can be administered in one or more administrations, applications or dosages. A therapeutically effective amount of a therapeutic compound (i.e., an effective dosage) depends on the therapeutic compounds selected. Moreover, treatment of a subject with a therapeutically effective amount of the compounds or compositions described herein can include a single treatment or a series of treatments. For example, effective amounts can be administered at least once. The compositions can be administered from one or more times per day to one or more times per week; including once every other day. The skilled artisan will appreciate that certain factors can influence the dosage and timing required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health or age of the subject, and other diseases present.

Following administration, the subject can be evaluated to detect, assess, or determine their level of disease. In some instances, treatment can continue until a change (e.g., reduction) in the level of disease in the subject is detected. Upon improvement of a patient’s condition (e.g., a change (e.g., decrease) in the level of disease in the subject) , a maintenance dose of a compound, or composition disclosed herein can be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, can be reduced, e.g., as a function of the symptoms, to a level at which the improved condition is retained. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.

The present disclosure is also described and demonstrated by way of 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 invention or of any exemplified term. Likewise, the invention is not limited to any particular preferred embodiment or aspect described herein. Indeed, many modifications and variations may be apparent to those skilled in the art upon reading this specification, and such variations can be made without departing from the invention in spirit or in scope. The invention is therefore to be limited only by the terms of the appended claims along with the full scope of equivalents to which those claims are entitled.

Combination Therapy

The present invention contemplates the use of the heterobifunctional compound disclosed herein in combination with one or more additional therapeutic agents (or second therapeutic agent) (such as those described above) or other prophylactic or therapeutic modalities (e.g., radiation) . In such combination therapy, the various additional agents frequently have different, complementary mechanisms of action. Such combination therapy may be especially advantageous by allowing a dose reduction of one or more of the agents, thereby reducing or eliminating the adverse effects associated with one or more of the agents. Furthermore, such combination therapy may have a synergistic therapeutic or prophylactic effect on the underlying disease, disorder, or condition. [0002] As used herein, “combination” is meant to include therapies that can be administered separately, for example, formulated separately for separate administration (e.g., as may be provided in a kit) , and therapies that can be administered together in a single formulation (i.e., a “co-formulation” ) .

In certain embodiments, the heterobifunctional compound disclosed herein are administered or applied sequentially, e.g., where one agent is administered prior to one or more other agents. In other embodiments, the heterobifunctional compound are administered simultaneously, e.g., where two or more agents are administered at or about the same time; the two or more agents may be present in 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 purposes of the present invention.

The heterobifunctional compound disclosed herein may be used in combination with at least one o additional agents in any manner appropriate under the circumstances. In one embodiment, treatment with the at least one additional agent and at least one heterobifunctional compound disclosed herein is maintained over a period of time. In another 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 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 reduced (e.g., lower dose, less frequent dosing or shorter treatment regimen) . In yet another embodiment, treatment with the at least one additional agent is reduced or discontinued (e.g., when the subject is stable) , and 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 the 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 the at least one active agent and treatment with the heterobifunctional compound disclosed herein are reduced or discontinued (e.g., lower dose, less frequent dosing or shorter treatment regimen) .

Kits

The present invention also contemplates kits comprising a the heterobifunctional compound described herein, and pharmaceutical compositions thereof. The kits are generally in the form of a physical structure housing various components, as described below, and may be utilized, for example, in practicing the methods described above.

A kit can include one or more of the heterobifunctional compound described herein (provided in, e.g., a sterile container) , which may be in the form of a pharmaceutical composition suitable for administration to a subject. The heterobifunctional compound described herein can be provided in a form that is ready for use (e.g., a tablet or capsule) or in a form requiring, for example, reconstitution or dilution (e.g., a powder) prior to administration. When the the heterobifunctional compound described herein are in a form that needs to be reconstituted or diluted by a user, the kit may also include diluents (e.g., sterile water) , buffers, pharmaceutically acceptable excipients, and the like, packaged with or separately from the heterobifunctional compound described herein. When combination therapy is contemplated, the kit may contain the several agents separately or they may already be combined in the kit. Each component of the kit may be enclosed within an individual container, and all of the various containers may be within a single package. A kit of the present invention may be designed for conditions necessary to properly maintain the components housed therein (e.g., refrigeration or freezing) . The Kit may be include one or more additional therapeutic agents as discirbed herein.

A kit may contain a label or packaging insert including identifying information for the components therein and instructions for their use (e.g., dosing parameters, clinical pharmacology of the active ingredient (s) , including mechanism of action, pharmacokinetics and pharmacodynamics, adverse effects, contraindications, etc. ) . Labels or inserts can include manufacturer information such as lot numbers and expiration dates. The label or packaging insert may be, e.g., integrated into the physical structure housing the components, contained separately within the physical structure, or affixed to a component of the kit (e.g., an ampule, tube or vial) .

Labels or inserts can additionally include, or be incorporated into, a computer readable medium, such as a disk (e.g., hard disk, card, memory disk) , optical disk such as CD-or DVD-ROM/RAM, DVD, MP3, magnetic tape, or an electrical storage media such as RAM and ROM or hybrids of these such as magnetic/optical storage media, FLASH media or memory-type cards. In some embodiments, the actual instructions are not present in the kit, but means for obtaining the instructions from a remote source, e.g., via the internet, are provided.

EXAMPLES

Example 1: 4- ( (2-Aminoethyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (Linker 1)

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 (2.32g, 18 mmmol) in DMF (12 mL) was heated to 85 ℃ in a microwave reactor for 50 min. 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 (hexanes : EtOAc = 1 : 1) to give tert-butyl (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethyl) carbamate (1.3 g, yield: 16%) as 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 rt 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) isoindoline-1, 3-dione as yellow solid (Linker 1) (1.3 g, yield: 98%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 11.14 (s, 1 H) , 7.85 (s, 3H) , 7.45 (t, J = 7.2 Hz, 1H) , 7.19 (d, J = 7.2 Hz, 1H) , 7.10 (d, J = 7.2 Hz, 1H) , 6.84 (t, J = 6.4 Hz, 1H) , 5.07 (dd, J = 5.2, 12.8 Hz, 1H) , 3.58 (q, J = 6.4 Hz, 2H) , 3.00 (s, 2H) , 2.94 –2.85 (m, 1H) , 2.62 –2.50 (m, 2H) , 2.05 –2.00 (m, 1H) . MS (ESI) m/z = 317.1 [M+H] ⁺.

Example 2: 4- ( (3-Aminopropyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (Linker 2)

Linker 2 was synthesized following the same procedures as Linker 1 as described for Example 1. (1.2 g, yield: 89%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 11.11 (s, 1H) , 7.74 (s, 3H) , 7.62 –7.58 (m, 1H) , 7.15 (d, J =8.4 Hz, 1H) , 7.05 (d, J = 7.2 Hz, 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] ⁺.

Example 3: 4- ( (4-Aminobutyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (Linker 3)

Linker 3 was synthesized following the same procedures as Linker 1 as described for Example 1. (1.4 g, yield: 93%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 11.11 (s, 1 H) , 7.84 (s, 3H) , 7.62 –7.57 (m, 1H) , 7.13 (d, J =8.4 Hz, 1H) , 7.04 (d, J = 6.8 Hz, 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] ⁺.

Example 4: 4- ( (5-Aminopentyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (Linker 4)

Linker 4 was synthesized following the same procedures as Linker 1 as described for Example 1. (2.3 g, yield: 85%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 11.14 (s, 1H) , 7.72 (s, 3H) , 7.61 –7.57 (m, 1H) , 7.10 (d, J =8.4 Hz, 1H) , 7.03 (d, J = 7.2 Hz, 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] ⁺.

Example 5: 4- ( (6-Aminohexyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (Linker 5)

Linker 5 was synthesized following the same procedures as Linker 1 as described for Example 1. (1.8 g, yield: 67%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 11.10 (s, 1 H) , 7.76 (s, 3H) , 7.58 (t, J = 7.2 Hz, 1H) , 7.10 (d, J = 8.4 Hz, 1H) , 7.03 (d, J = 7.2 Hz, 1H) , 6.54 (t, J = 6.0 Hz, 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] ⁺.

Example 6: 4- ( (7-Aminoheptyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (Linker 6)

Linker 6 was synthesized following the same procedures as Linker 1 as described for Example 1. (2.0 g, yield: 94%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 11.05 (br, 1H) , 7.94 –7.56 (m, 4H) , 7.10 –7.02 (m, 2H) , 6.52 (t, J = 6.0 Hz, 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] ⁺.

Example 7: 4- ( (8-Aminooctyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (Linker 7)

Linker 7 was synthesized following the same procedures as Linker 1 as described for Example 1. (1.1 g, yield: 61%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 11.10 (s, 1 H) , 7.69 –7.56 (m, 4H) , 7.09 (d, J = 8.4 Hz, 1H) , 7.03 (d, J = 6.8 Hz, 1H) , 6.52 (t, J = 6.0 Hz, 1H) , 5.07 –5.03 (m, 1H) , 3.34 –3.26 (m, 2H) , 2.89 –2.85 (m, 1H) , 2.76 (s, 2H) , 2.61 –2.56 (m, 2 H) , 2.04 –2.00 (m, 1H) , 1.59 –1.49 (m, 4 H) , 1.35 –1.27 (m, 8H) . MS (ESI) m/z = 401.2 [M+H] ⁺.

Example 8: 4- ( (2- (2-Aminoethoxy) ethyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (Linker 8)

Linker 8 was synthesized following the same procedures as Linker 1 as described for Example 1. (2.0 g, yield: 94%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 10.10 (s, 1 H) , 7.88 (s, 3H) , 7.60 (t, J = 8.0 Hz, 1H) , 7.17 (d, J = 8.4 Hz, 1H) , 7.06 (d, J = 6.8 Hz, 1H) , 6.40 (d, J = 5.6 Hz, 1H) , 5.05 (dd, J = 5.2, 12.8 Hz, 1 H) , 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 = 7.6 Hz, 1H) . MS (ESI) m/z = 361.1 [M+H] ⁺.

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

Linker 9 was synthesized following the same procedures as Linker 1 as described for Example 1. (1.1 g, yield: 82%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 11.11 (s, 1 H) , 7.84 (s, 3H) , 7.62 –7.58 (m, 1H) , 7.15 (d, J =8.8 Hz, 1H) , 7.05 (d, J = 6.8 Hz, 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] ⁺.

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

Linker 10 was synthesized following the same procedures as Linker 1 as described for Example 1. (1.3 g, yield: 70%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 11.11 (s, 1 H) , 7.83 (s, 3H) , 7.61 –7.57 (m, 1H) , 7.15 (d, J = 8.8 Hz, 1H) , 7.05 (d, J = 6.8 Hz, 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] ⁺.

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

Linker 11 was synthesized following the same procedures as Linker 1 as described for Example 1. (1.2 g, yield: 89%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 11.11 (s, 1H) , 7.84 (s, 3H) , 7.61 –7.57 (m, 1H) , 7.15 (d, J = 8.8 Hz, 1H) , 7.05 (d, J = 6.8 Hz, 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] ⁺.

Example 12: 4- ( (17-Amino-3, 6, 9, 12, 15-pentaoxaheptadecyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (Linker 12)

Linker 12 was synthesized following the same procedures as Linker 1 as described for Example 1. (1.2 g, yield: 86%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 11.11 (s, 1 H) , 7.82 (s, 3H) , 7.61 –7.57 (m, 1H) , 7.15 (d, J = 8.4 Hz, 1H) , 7.05 (d, J = 7.2 Hz, 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] ⁺.

Example 13: (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) glycine (Linker 13)

Linker 13 was synthesized following the same procedures as Linker 1 as described for Example 1. (840 mg, yield: 98%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 11.07 (s, 1 H) , 7.52 (t, J = 7.6 Hz, 1H) , 6.99 –6.88 (m, 3H) , 5.04 (dd, J = 5.2, 12.8 Hz, 1 H) , 3.73 (s, 2H) , 2.93 –2.83 (m, 1H) , 2.61 –2.50 (m, 2H) , 2.02 (t, J = 5.6 Hz, 1H) . MS (ESI) m/z = 330.1 [M-H] ^-.

Example 14: 3- ( (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) propanoic acid (Linker 14)

Linker 14 was synthesized following the same procedures as Linker 1 as described for Example 1. (1.42 g, yield: 88%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 11.61 (br, 1H) , 11.08 (s, 1H) , 7.58 (dd, J = 7.2, 8.8 Hz, 1H) , 7.15 (d, J = 8.8 Hz, 1H) , 7.04 (d, J = 7.2 Hz, 1H) , 6.64 (s, 1H) , 5.05 (dd, J = 5.2, 12.8 Hz, 1H) , 3.53 (t, J = 6.4 Hz, 2H) , 2.92 –2.83 (m, 1H) , 2.61 –2.50 (m, 4H) , 2.05 –2.00 (m, 1H) . MS (ESI) m/z = 346.1 [M+H] ⁺.

Example 15: 4- ( (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) butanoic acid (Linker 15)

Linker 15 was synthesized following the same procedures as Linker 1 as described for Example 1. (1.27 g, yield: 53%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 12.12 (br, 1H) , 11.08 (s, 1 H) , 7.58 (dd, J = 7.2, 8.8 Hz, 1H) , 7.13 (d, J = 8.8 Hz, 1H) , 7.03 (d, J = 7.2 Hz, 1H) , 6.64 (t, J = 6.0 Hz, 1H) , 5.05 (dd, J = 5.6, 12.8 Hz, 1H) , 3.33 (q, J = 6.8 Hz, 2H) , 2.93 –2.83 (m, 1H) , 2.61 –2.50 (m, 2H) , 2.31 (t, J = 6.8 Hz, 2H) , 2.07 –2.00 (m, 1H) , 1.83 –1.75 (m, 2H) . MS (ESI) m/z = 360.1 [M+H] ⁺.

Example 16: 5- ( (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) pentanoic acid (Linker 16)

Linker 16 was synthesized following the same procedures as Linker 1 as described for Example 1. (1.4 g, yield: 85%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 12.02 (br, 1H) , 11.08 (s, 1H) , 7.58 (dd, J = 8.8, 7.2 Hz, 1H) , 7.10 (d, J = 8.4 Hz, 1H) , 7.02 (d, J = 7.2 Hz, 1H) , 6.64 (t, J = 5.6 Hz, 1 H) , 5.07 –5.03 (m, 1H) , 3.32 –3.02 (m, 2H) , 2.93 –2.84 (m, 1H) , 2.61 –2.54 (m, 2H) , 2.28 –2.25 (m, 2H) , 2.05 –2.01 (m, 1H) , 1.60 –1.51 (m, 4H) . MS (ESI) m/z = 374.1 [M+H] ⁺.

Example 17: 6- ( (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) hexanoic acid (Linker 17)

Linker 17 was synthesized following the same procedures as Linker 1 as described for Example 1. (1.43 g, yield: 91%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 11.97 (s, 1 H) , 11.08 (s, 1 H) , 7.57 (dd, J = 7.2, 8.8 Hz, 1H) , 7.08 (d, J = 8.8 Hz, 1H) , 7.02 (d, J = 7.2 Hz, 1H) , 6.52 (t, J = 6.0 Hz, 1H) , 5.05 (dd, J = 5.6, 12.8 Hz, 1H) , 3.30 (q, J = 6.8 Hz, 2H) , 2.93 –2.83 (m, 1H) , 2.61 –2.50 (m, 2H) , 2.32 (t, J = 7.2 Hz, 2H) , 2.07 –2.00 (m, 1H) , 1.61 –1.50 (m, 4H) , 1.39 –1.33 (m, 2H) . MS (ESI) m/z = 388.1 [M+H] ⁺.

Example 18: 7- ( (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) heptanoic acid (Linker 18)

Linker 18 was synthesized following the same procedures as Linker 1 as described for Example 1. (2.3 g, yield: 86%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 11.92 (br, 1 H) , 11.08 (s, 1 H) , 7.57 (t, J = 8.0 Hz, 1 H) , 7.13 (d, J = 8.8 Hz, 1 H) , 7.03 (d, J = 6.8 Hz, 1 H) , 6.52 (t, J = 5.6 Hz, 1 H) , 5.05 (dd, J = 5.6, 12.8 Hz, 1 H) , 3.30 (q, J = 6.4 Hz, 2H) , 2.93 –2.83 (m, 1H) , 2.61 –2.50 (m, 2H) , 2.31 (t, J = 7.2 Hz, 2H) , 2.07 –2.00 (m, 1H) , 1.58 –1.48 (m, 4H) , 1.34 –1.31 (m, 4H) . MS (ESI) m/z =402.1 [M+H] ⁺.

Example 19: 8- ( (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) octanoic acid (Linker 19)

Linker 19 was synthesized following the same procedures as Linker 1 as described for Example 1. (1.14 g, yield: 77%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 11.94 (s, 1H) , 11.08 (s, 1H) , 7.57 (t, J = 8.0 Hz, 1H) , 7.08 (d, J = 8.4Hz, 1H) , 7.02 (d, J = 6.8 Hz, 1H) , 6.52 (t, J = 5.6 Hz, 1H) , 5.05 (dd, J = 5.6, 12.8 Hz, 1H) , 3.31 –3.26 (m, 2H) , 2.93 –2.83 (m, 1H) , 2.61 –2.50 (m, 2H) , 2.19 (t, J = 7.2 Hz, 2 H) , 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] ⁺.

Example 20: 3- (2- ( (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethoxy) propanoic acid (Linker 20)

Linker 20 was synthesized following the same procedures as Linker 1 as described for Example 1. (3.5 g, yield: 80%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 12.18 (s, 1H) , 11.08 (s, 1 H) , 7.58 (dd, J = 7.2 Hz, 8.8 Hz, 1H) , 7.13 (d, J = 8.4 Hz, 1H) , 7.04 (d, J = 7.2 Hz, 1H) , 6.58 (t, J = 5.6 Hz 1H) , 5.05 (dd, J = 6.4 Hz, 12.8 Hz, 1H) , 3.67 –3.58 (m, 4H) , 3.47 –3.43 (m, 2H) , 2.93 –2.84 (m, 1H) , 2.61 –2.45 (m, 4H) , 2.07 –2.01 (m, 1H) . MS (ESI) m/z = 390.1 [M+H] ⁺.

Example 21: 3- (2- (2- ( (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethoxy) ethoxy) propanoic acid (Linker 21)

Linker 21 was synthesized following the same procedures as Linker 1 as described for Example 1. (2.0 g, yield: 58%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 12.13 (s, 1H) , 11.08 (s, 1 H) , 7.58 (dd, J = 7.2 Hz, 8.4 Hz, 1H) , 7.14 (d, J = 8.4 Hz, 1H) , 7.04 (d, J = 6.8 Hz, 1H) , 6.60 (t, J = 6.0 Hz 1H) , 5.05 (dd, J = 5.2 Hz, 12.4 Hz, 1H) , 3.63 –3.44 (m, 10H) , 2.88 –2.85 (m, 1H) , 2.61 –2.49 (m, 2H) , 2.44 –2.41 (m, 2H) , 2.04 –2.01 (m, 1H) . MS (ESI) m/z = 434.1 [M+H] ⁺.

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)

Linker 22 was synthesized following the same procedures as Linker 1 as described for Example 1. (3.2 g, yield: 93%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 12.14 (s, 1H) , 11.08 (s, 1H) , 7.58 (dd, J = 7.2 Hz, 8.4 Hz, 1H) , 7.14 (d, J = 8.8 Hz, 1H) , 7.04 (d, J = 6.8 Hz, 1H) , 6.60 (t, J = 6.0 Hz, 1H) , 5.05 (dd, J = 5.2 Hz, 12.8 Hz, 1H) , 3.63 –3.45 (m, 14H) , 2.88 –2.85 (m, 1H) , 2.61 –2.49 (m, 2H) , 2.44 –2.40 (m, 2H) , 2.04 –2.01 (m, 1H) . MS (ESI) m/z = 478.2 [M+H] ⁺.

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)

Linker 23 was synthesized following the same procedures as Linker 1 as described for Example 1. (2.3 g, yield: 59%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 12.14 (s, 1H) , 11.08 (s, 1H) , 7.58 (dd, J = 7.2 Hz, 8.8 Hz, 1H) , 7.14 (d, J = 8.4 Hz, 1H) , 7.04 (d, J = 7.2 Hz, 1H) , 6.60 (t, J = 6.0 Hz, 1H) , 5.05 (dd, J = 5.2 Hz, 12.8 Hz, 1H) , 3.63 –3.48 (m, 18H) , 2.898 –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] ⁺.

Example 24: 1- ( (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) -3, 6, 9, 12, 15-pentaoxaoctadecan-18-oic acid (Linker 24)

Linker 24 was synthesized following the same procedures as Linker 1 as described for Example 1. (2.4 g, yield: 66%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 11.09 (s, 1 H) , 7.58 (dd, J = 7.2, 8.4 Hz, 1 H) , 7.13 (d, J = 8.4 Hz, 1 H) , 7.04 (d, J = 7.2 Hz, 1 H) , 6.60 (t, J = 5.6 Hz, 1 H) , 5.05 (dd, J = 5.6, 12.8 Hz, 1H) , 3.64 –3.46 (m, 22H) , 2.93 –2.83 (m, 1H) , 2.61 –2.50 (m, 2H) , 2.44 –2.40 (m, 2H) , 2.02 (t, J = 6.4 Hz, 1H) . MS (ESI) m/z = 566.2 [M+H] ⁺.

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)

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) , HOBt (756 mg, 5.60 mmol) at 0 ℃. The mixture was stirred at room temperature for 16 h, before 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] ⁺.

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 ethylacetate (EtOAc) (30 mL) was added HCl/EtOAc (100 mL, 4 M) . The mixture was stirred at room temperature for 3 h and filtered to give 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 (400 MHz, DMSO-d ₆) δ 9.29 (s, 1H) , 8.72 (s, 1H) , 8.56 (d, J = 9.2 Hz, 1H) , 8.26 (s, 3H) , 7.38 –7.47 (m, 4H) , 4.61 (d, J = 9.2 Hz, 1H) , 4.36 –4.47 (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] ⁺.

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

Linker 26 was synthesized following the same procedures as Linker 25 as described for Example 25. (1.38 g, yield: 88%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 9.36 (s, 1H) , 8.68 (s, 1H) , 8.26 (d, J = 9.2 Hz, 1H) , 8.16 (s, 3H) , 7.49 –7.39 (m, 4H) , 4.53 (d, J = 9.2 Hz, 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 = 7.2 Hz, 2H) , 2.48 (s, 3H) , 2.06 –2.01 (m, 1H) , 1.92 –1.85 (m, 1H) , 0.95 (s, 9H) . MS (ESI) m/z = 502.3 [M+H] ⁺.

Example 27: (2S, 4R) -1- ( (S) -2- (4-Aminobutanamido) -3, 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (Linker 27)

Linker 27 was synthesized following the same procedures as Linker 25 as described for Example 25. (1.38 g, yield: 88%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 9.66 (s, 1H) , 8.74 (t, J = 6.0, 1H) , 8.25 (s, 3H) , 8.03 (d, J = 9.2 Hz, 1H) , 7.49 –7.41 (m, 4H) , 4.53 (d, J = 9.2 Hz, 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] ⁺.

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

Linker 28 was synthesized following the same procedures as Linker 25 as described for Example 25. (1.50 g, yield: 79%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 9.52 (s, 1H) , 8.73 (t, J = 11.6 Hz, 1H) , 8.20 (s, 3H) , 7.95 (d, J = 9.6 Hz, 1H) , 7.43 –7.50 (m, 4H) , 4.55 (d, J = 9.2 Hz, 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 = 4.4 Hz, 4H) , 0.96 (s, 9H) . MS (ESI) m/z = 530.1 [M+H] ⁺.

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

Linker 29 was synthesized following the same procedures as Linker 25 as described for Example 25. (2.70 g, yield: 98%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 9.36 (s, 1H) , 8.69 (t, J = 6.4 Hz, 1H) , 8.12 (brs, 3H) , 7.92 (d, J = 9.6 Hz, 1H) , 7.44 (dd, J = 13.6, 8.4 Hz, 4H) , 4.54 (d, J = 9.6 Hz, 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] ⁺.

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

Linker 30 was synthesized following the same procedures as Linker 25 as described for Example 25. (2.13 g, yield: 86%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 9.45 (s, 1H) , 8.70 (t, J = 6.0 Hz, 1H) , 8.14 (brs, 3H) , 7.86 (d, J = 9.2 Hz, 1H) , 7.44 (dd, J = 12.8, 8.4 Hz, 4H) , 4.54 (d, J = 9.2 Hz, 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] ⁺.

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)

Linker 31 was synthesized following the same procedures as Linker 25 as described for Example 25. (1.81 g, yield: 72%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 9.35 (s, 1H) , 8.69 (t, J = 6.0 Hz, 1H) , 8.11 (brs, 3H) , 7.88 (d, J = 9.2 Hz, 1H) , 7.44 (dd, J = 14.0, 8.4 Hz, 4H) , 4.54 (d, J = 9.6 Hz, 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] ⁺.

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

Linker 32 was synthesized following the same procedures as Linker 25 as described for Example 25. (2.32 g, yield: 89%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 9.30 (s, 1H) , 8.67 (t, J = 6.4 Hz, 1H) , 8.10 (brs, 3H) , 7.88 (d, J = 9.2 Hz, 1H) , 7.43 (dd, J = 14.0, 8.8 Hz, 4H) , 4.55 (d, J = 9.2 Hz, 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] ⁺.

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

Linker 33 was synthesized following the same procedures as Linker 25 as described for Example 25. (2.29 g, yield: 90%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 9.41 (s, 1H) , 8.67 (t, J = 6.0 Hz, 1H) , 8.14 (brs, 3H) , 7.85 (d, J = 8.8 Hz, 1H) , 7.44 (dd, J = 13.6, 8.8 Hz, 4H) , 4.54 (d, J = 8.8 Hz, 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] ⁺.

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

Linker 34 was synthesized following the same procedures as Linker 25 as described for Example 25. (1.10 g, yield: 44%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 8.99 (s, 1H) , 8.61 (t, J = 6.4 Hz, 1H) , 7.87 (d, J = 8.8 Hz, 1H) , 7.41 (dd, J = 17.6, 8.0 Hz, 4H) , 4.55 (d, J = 9.6 Hz, 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] ⁺.

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

Linker 35 was synthesized following the same procedures as Linker 25 as described for Example 25.

(1.35 g, 2.38 mmol, yield: 79%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 9.23 (s, 1H) , 8.70 (t, J = 6.0 Hz, 1H) , 8.35 –8.14 (m, 3H) , 7.78 (d, J = 9.6 Hz, 1H) , 7.47 –7.38 (m, 4H) , 4.61 (d, J = 9.6 Hz, 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] ⁺.

Example 36: (2S, 4R) -1- ( (S) -2- (3- (2-Aminoethoxy) propanamido) -3, 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (Linker 36)

Linker 36 was synthesized following the same procedures as Linker 25 as described for Example 25. (1.32 g, 2.01 mmol, yield: 65%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 8.99 (s, 1H) , 8.57 (t, J = 6.0 Hz, 1H) , 8.03 (d, J = 8 Hz, 1H) , 7.85 (s, 3H) , 7.43 –7.37 (m, 4H) , 4.57 (d, J = 9.2 Hz, 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] ⁺.

Example 37: (2S, 4R) -1- ( (S) -2- (2- (2- (2-Aminoethoxy) ethoxy) acetamido) -3, 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (Linker 37)

Linker 37 was synthesized following the same procedures as Linker 25 as described for Example 25. (1.2 g, yield: 94%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 9.38 (s, 1H) , 8.78 (t, J = 6.0 Hz, 1H) , 8.18 (s, 3H) , 7.59 –7.37 (m, 5H) , 4.58 (d, J = 9.6 Hz, 1H) , 4.49 (t, J = 8.2 Hz, 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] ⁺.

Example 38: (2S, 4R) -1- ( (S) -2- (3- (2- (2-Aminoethoxy) ethoxy) propanamido) -3, 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (Linker 38)

Linker 38 was synthesized following the same procedures as Linker 25 as described for Example 25. (1.34 g, 1.94 mmol, yield: 65%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 9.02 (s, 1H) , 8.58 (t, J = 6.0 Hz, 1H) , 7.94 (d, J = 8 Hz, 1H) , 7.82 (s, 3H) , 7.42 –7.30 (m, 4H) , 4.58 (d, J = 9.2 Hz, 1H) , 4.60 –4.37 (m, 3H) , 4.25 –4.31 (m, 1H) , 3.70 –3.50 (m, 10H) , 3.00 –2.96 (m, 2H) , 2.57 –2.55 (m, 1H) , 2.45 (s, 3H) , 2.41 –2.38 (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] ⁺.

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)

Linker 39 was synthesized following the same procedures as Linker 25 as described for Example 25. (1.53 g, yield: 77%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 9.01 (s, 1H) , 8.59 (t, J = 6.0 Hz, 1H) , 7.81 (s, 3H) , 7.48 –7.41 (m, 5H) , 4.58 (d, J = 9.6 Hz, 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] ⁺.

Example 40: (2S, 4R) -1- ( (S) -1-Amino-14- (tert-butyl) -12-oxo-3, 6, 9-trioxa-13-azapentadecan-15-oyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (Linker 40)

Linker 40 was synthesized following the same procedures as Linker 25 as described for Example 25. (1.52 g, yield: 64%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 9.01 (s, 1H) , 8.57 (t, J = 6.0 Hz, 1H) , 7.91 (d, J = 9.2 Hz, 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, 1H) , 3.70 –3.48 (m, 14H) , 3.00 –2.97 (m, 2H) , 2.59 –2.52 (m, 1H) , 2.46 (s, 3H) , 2.39 –2.34 (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] ⁺.

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

Linker 41 was synthesized following the same procedures as Linker 25 as described for Example 25. (1.12 g, yield: 52%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 8.98 (s, 1H) , 8.58 (t, J = 5.6 Hz, 1H) , 7.92 (d, J = 9.2 Hz, 1H) , 7.44 –7.38 (m, 4H) , 4.56 (d, J = 9.2 Hz, 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 = 5.6 Hz, 2H) , 2.64 (t, J = 5.6 Hz, 2H) , 2.58 –2.50 (m, 1H) , 2.45 (s, 3H) , 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] ⁺.

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

Linker 42 was synthesized following the same procedures as Linker 25 as described for Example 25. (1.1 g, yield: 42%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 9.38 (s, 1H) , 8.67 (t, J = 16 Hz, 1H) , 8.14 (br, 3H) , 7.91 (d, J = 9.2 Hz, 1H) , 7.39 –7.48 (m, 4H) , 4.53 (d, J = 9.2 Hz, 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] ⁺.

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)

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 rt for overnight. The mixture was concentrated. The resulting residue was purified by flash chromatography (reversed-phase, MeCN/H ₂O) to give the title compound Linker 43 (1.05 g, yield: 86%) . ¹H NMR (400 MHz, DMSO-d ₆) : δ 12.02 (s, 1H) , 8.99 (s, 1H) , 8.58 (t, J = 6.0 Hz, 1H) , 7.96 (d, J = 9.2 Hz, 1H) , 7.43 –7.37 (m, 4H) , 5.13 (d, J = 3.6 Hz, 1H) , 4.53 (d, J = 9.2 Hz, 1H) , 4.46 –4.40 (m, 2H) , 4.34 (s, 1H) , 4.21 (dd, J = 16.0, 5.2 Hz, 1H) , 3.69 –3.60 (m, 2H) , 2.45 (s, 3H) , 2.44 –2.33 (m, 4H) , 2.06 – 2.01 (m, 1H) , 1.93 –1.87 (m, 1H) , 0.93 (s, 9H) . ¹³C NMR (100 MHz, DMSO-d6) : δ 173.83, 171.92, 170.86, 169.56, 151.41, 147.70, 139.48, 131.15, 129.63, 128.62, 127.41, 68.87, 58.70, 56.44, 56.34, 41.65, 37.91, 35.35, 29.74, 29.25, 26.35, 15.92. MS (ESI) m/z = 531.2 [M+H] ⁺.

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)

Linker 44 was synthesized following the same procedures as Linker 43 as described for Example 43. (1.5 g, yield: 79%) . ¹H NMR (400 MHz, DMSO-d ₆) : δ 8.99 (s, 1H) , 8.59 (t, J = 6.0 Hz, 1H) , 7.91 (d, J = 9.2 Hz, 1H) , 7.44 –7.37 (m, 4H) , 5.16 (brs, 1H) , 4.54 (d, J = 9.2 Hz, 1H) , 4.47 –4.42 (m, 2H) , 4.36 (s, 1H) , 4.21 (dd, J = 16.0, 5.2 Hz, 1H) , 3.7 –3.64 (m, 2H) , 2.45 (s, 3H) , 2.31 –2.14 (m, 4H) , 2.07 –2.02 (m, 1H) , 1.94 –1.81 (m, 1H) , 1.74 –1.68 (m, 2H) , 0.94 (s, 9H) .

¹³C NMR (100 MHz, DMSO-d ₆) : δ 174.18, 171.94, 171.63, 169.66, 151.41, 147.70, 139.46, 131.15, 129.61, 128.62, 127.41, 68.86, 58.69, 56.38, 41.65, 37.91, 35.16, 34.03, 33.10, 26.35, 20.89, 15.92. MS (ESI) m/z = 543.2 [M+H] ⁺.

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)

Linker 45 was synthesized following the same procedures as Linker 25 as described for Example 25. (1.198 g, yield: 74%) . ¹H NMR (400 MHz, CDCl ₃) δ 8.68 (s, 1H) , 7.75 (s, 1H) , 7.32 –7.27 (m, 5H) , 4.64 –4.57 (m, 3H) , 4.56 –4.50 (m, 1H) , 4.28 –4.25 (m, 1H) , 4.02 –3.99 (m, 1H) , 3.71 –3.68 (m, 1H) , 2.47 (s, 3H) , 2.24 –2.18 (m, 6H) , 1.59 –1.48 (m, 4H) , 0.96 (s, 9H) . MS (ESI) m/z = 559.3 [M+H] ⁺.

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)

Linker 46 was synthesized following the same procedures as Linker 45 as described for Example 45. (1.099 g, yield: 50%) . ¹H NMR (400 MHz, CDCl ₃) δ 8.67 (s, 1H) , 7.56 –7.55 (m, 1H) , 7.34 –7.30 (m, 5H) , 4.68 –4.59 (m, 3H) , 4.59 –4.51 (m, 1H) , 4.25 (dd, J = 4.8 Hz, 15.2 Hz, 1H) , 4.06 –4.03 (m, 1H) , 3.70 – 3.68 (m, 1H) , 2.46 (s, 3H) , 2.31 –2.11 (m, 6H) , 1.55 –1.51 (m, 4H) , 1.29 –1.24 (m, 2H) , 0.94 (s, 9H) . MS (ESI) m/z = 573.1 [M+H] ⁺.

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)

Linker 47 was synthesized following the same procedures as Linker 45 as described for Example 45. (1.08 g, yield: 60%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 8.99 (s, 1H) , 8.55 (t, J = 2.4 Hz, 1H) , 7.83 (d, J = 9.2 Hz, 1H) , 7.44 –7.38 (m, 4H) , 4.55 (d, J = 9.6 Hz, 1H) , 4.52 –4.41 (m, 2H) , 4.36 (s, 1H) , 4.25 –4.21 (m, 1H) , 3.67 –3.66 (m, 2H) , 2.45 (s, 3H) , 2.30 –1.91 (m, 6H) , 1.49 –1.47 (m, 4H) , 1.26 –1.24 (m, 4H) , 0.92 (s, 9H) . MS (ESI) m/z = 587.3 [M+H] ⁺.

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)

Linker 48 was synthesized following the same procedures as Linker 45 as described for Example 45. (1.155 g, yield: 56%) . ¹H NMR (400 MHz, CDCl ₃) δ 8.70 (s, 1H) , 7.55 (s, 1H) , 7.33 –7.27 (m, 4H) , 7.08 (d, J = 8.0 Hz, 1H) , 4.68 –4.52 (m, 4H) , 4.31 –4.27 (m, 1H) , 4.08 –4.05 (m, 1H) , 3.69 –3.67 (m, 1H) , 2.48 (s, 3H) , 2.33 –2.11 (m, 6H) , 1.60 –1.47 (m, 4H) , 1.29 –1.20 (m, 6H) , 0.96 (s, 9H) . MS (ESI) m/z = 601.1 [M+H] ⁺.

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)

Linker 49 was synthesized following the same procedure as Linker 45 as described for Example 45. (1.1 g, yield: 35.5%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 8.99 (s, 1H) , 8.58 (t, J = 6.0 Hz, 1H) , 7.85 (d, J = 9.2 Hz, 1H) , 7.43 –7.37 (m, 4H) , 4.54 (d, J = 9.2 Hz, 1H) , 4.47 –4.41 (m, 2H) , 4.35 (s, 1H) , 4.21 (dd, J = 16.0, 5.6 Hz, 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) .

¹³C NMR (100 MHz, DMSO-d ₆) : δ 172.07, 171.92, 169.69, 151.41, 147.70, 139.48, 131.14, 129.62, 128.61, 127.40, 68.84, 58.67, 56.32, 56.26, 41.64, 37.93, 35.18, 34.85, 28.62, 26.36, 25.39, 15.93. MS (ESI) m/z = 615.3 [M+H] ⁺.

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)

Linker 50 was synthesized following the same procedure as Linker 45 as described for Example 45. (1.1 g, yield: 50%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 8.99 (s, 1H) , 8.58 (t, J = 6.0 Hz, 1H) , 7.85 (t, J = 9.2 Hz, 1H) , 7.37 –7.43 (m, 4H) , 4.56 –4.19 (m, 5H) , 3.70 –3.60 (m, 2H) , 2.45 (s, 3H) , 2.27 –1.90 (m, 6H) , 1.49 –1.45 (m, 4H) , 1.23 (m, 10H) , 0.93 (s, 9H) .

¹³C NMR (100 MHz, DMSO-d ₆) : δ 174.59, 172.07, 171.92, 169.69, 151.42, 147.70, 139.49, 131.14, 129.62, 128.61, 127.41, 68.84, 58.67, 56.32, 56.25, 41.64, 37.93, 35.19, 34.85, 33.80, 28.82, 28.70, 28.68, 28.62, 28.55, 26.37, 25.42, 24.55, 15.93. MS (ESI) m/z = 629.4 [M+H] ⁺.

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)

Linker 51 was synthesized following the same procedure as Linker 45 as described for Example 45. (1.1 g, yield: 42%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 8.98 (s, 1H) , 8.55 (t, J = 6.0 Hz, 1H) , 7.91 (d, J = 9.2 Hz, 1H) , 7.43 –7.37 (m, 4H) , 4.55 –4.53 (m, 1H) , 4.45 –4.40 (m, 2H) , 4.35 (s, 1H) , 4.24 –4.19 (m, 1H) , 3.68 –3.52 (m, 6H) , 2.54 –2.56 (m, 1H) , 2.45 –2.37 (m, 5H) , 2.34 –2.30 (m, 1H) , 2.05 –2.00 (m, 1H) , 1.93 –1.86 (m, 1H) , 0.93 (s, 9H) . MS (ESI) m/z = 575 [M+H] ⁺.

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)

Linker 52 was synthesized following the same procedure as Linker 43 as described for Example 43. (1.2 g, yield: 63%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 12.81 (br s, 1H) , 8.98 (s, 1H) , 8.58 (t, J = 6.0 Hz, 1H) , 7.60 (d, J = 9.6 Hz, 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] ⁺.

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)

Linker 53 was synthesized following the same procedures as Linker 45 as described for Example 45. (1.4 g, yield 41%) . ¹H NMR (400 MHz, DMSO-d ₆) : δ 8.98 (s, 1H) , 8.56 (t, J = 6.0 Hz, 1H) , 7.91 (d, J = 9.2 Hz, 1H) , 7.43 –7.37 (m, 4H) , 4.55 (d, J = 9.6 Hz, 1H) , 4.46 –4.41 (m, 2H) , 4.35 (s, 1H) , 4.29 –4.20 (m,

1H) , 3.70 –3.57 (m, 7H) , 3.50 –3.45 (m, 5H) , 2.57 –2.55 (m, 1H) , 2.45 (s, 3H) , 2.43 –2.41 (m, 1H) , 2.37 –2.32 (m, 1H) , 2.09 –2.01 (m, 1H) , 1.94 –1.87 (m, 1H) , 0.94 (s, 9H) . MS (ESI) m/z = 619.3 [M+H] ⁺.

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)

Linker 54 was synthesized following the same procedures as Linker 53 as described for Example 53. (1.126 g, yield 30%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 8.98 (s, 1H) , 8.60 (t, J = 6.0 Hz, 1H) , 7.49 (d, J = 9.2 Hz, 1H) , 7.40 (s, 4H) , 4.57 (d, J = 9.2 Hz, 1H) , 4.47 –4.36 (m, 3H) , 4.28 –4.23 (m, 1H) , 4.05 –3.93 (m, 4H) , 3.69 –3.61 (m, 6H) , 2.45 (s, 3H) , 2.08 –2.03 (m, 1H) , 1.94 –1.87 (m, 1H) , 0.94 (s, 9H) . MS (ESI) m/z = 591.2 [M+H] ⁺.

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)

Linker 55 was synthesized following the same procedure as Linker 45 as described for Example 45. (1.7 g, yield 37%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 8.99 (s, 1H) , 8.56 (t, J = 6.0 Hz, 1H) , 7.91 (d, J = 9.6 Hz, 1H) , 7.44 –7.38 (m, 4H) , 4.56 (d, J = 9.2 Hz, 1H) , 4.47 –4.42 (m, 2H) , 4.36 (s, 1H) , 4.25 –4.20 (m, 1H) , 3.70 –3.55 (m, 6H) , 3.50 –3.46 (m, 8H) , 2.58 –2.51 (m, 3H) , 2.45 –2.42 (m, 5H) , 2.40 –2.33 (m, 1H) , 2.07 –2.02 (m, 1H) , 1.94 –1.88 (m, 1H) , 0.94 (s, 9H) . LCMS (ESI) m/z = 661.0 [M-H] ^-.

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)

Linker 56 was synthesized following the same procedures as Linker 45 as described for Example 45. (1.21 g, yield 42%) . ¹H NMR (400 MHz, CDCl ₃) δ 8.68 (s, 1H) , 7.80 –7.71 (m, 11H) , 7.41 –7.33 (m, 5H) , 4.71 –7.65 (m, 1H) , 4.61 –4.50 (m, 3H) , 4.37 –4.33 (m, 1H) , 4.07 –3.94 (m, 5H) , 3.77 –3.58 (m, 10H) , 2.51 (s, 3H) , 2.38 –2.30 (m, 1H) , 2.24 –2.19 (m, 1H) , 0.98 (s, 9H) . LCMS (ESI) m/z = 635.0 [M+H] ⁺.

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-azaicosanoic acid (Linker 57)

Linker 57 was synthesized following the same procedure as Linker 45 as described for Example 45. (1.6 g, yield 43%) . ¹H NMR (400 MHz, CDCl ₃) δ 8.69 (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] ⁺.

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)

Linker 58 was synthesized following the same procedure as Linker 45as described for Example 45. (1.2 g, yield: 23%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 8.98 (s, 1H) , 8.57 (t, J = 6.0 Hz, 1H) , 7.91 (d, J = 9.6 Hz, 1H) , 7.43 –7.31 (m, 4H) , 4.56 –4.53 (m, 1H) , 4.45 –4.35 (m, 3H) , 4.24 –4.19 (m, 1H) , 3.69 –3.55 (m, 6H) , 3.49 –3.47 (m, 16H) , 2.57 –2.53 (m, 1H) , 2.45 (s, 3H) , 2.39 –2.32 (m, 3H) , 2.06 –2.01 (m, 1H) , 1.93 – 1.86 (m, 1H) , 0.95 (s, 9H) . MS (ESI) m/z = 751 [M+H] ⁺.

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-azahenicosanoic acid (Linker 59)

Linker 59 was synthesized following the same procedure as Linker 45 as described for Example 45. (1.3 g, yield: 39%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 8.98 (s, 1H) , 8.69 (t, J = 6.0 Hz, 1H) , 7.45 (d, J = 9.6 Hz, 1H) , 7.43 –7.37 (m, 4H) , 4.57 –4.55 (m, 1H) , 4.47 –4.34 (m, 3H) , 4.27 –4.22 (m, 1H) , 3.97 (s, 2H) , 3.68 –3.65 (m, 2H) , 3.61 –3.48 (m, 18H) , 2.45 (s, 3H) , 2.09 –2.04 (m, 1H) , 1.92 –1.86 (m, 1H) , 0.94 (s, 9H) . MS (ESI) m/z = 723 [M+H] ⁺.

Example 60: 5- ( (2- (2-Aminoethoxy) ethyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (Linker 60)

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 ℃ overnight. After cooling down 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 afford a solid which was dried in vacuum to give 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (120 g, yield: 83%) as yellow solid. MS (ESI) m/z = 277.1 [M+H] ⁺.

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 at 130 ℃ in microwave reactor for 50 min. After cooling down to room temperature, the mixture was poured into EtOAc (200 mL) , and washed with water (200 mL x 2) followed by brine (200 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated to give a crude product which was purified by chromatography on silica gel (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 yellow oil. MS (ESI) m/z = 361.1 [M+H] ⁺.

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. The reaction mixture was stirred at room temperature for 2 h. After concentration, the resulting residue was dissolved in water (20 mL) , washed with EtOAc (40 mL) and MTBE (40 mL) . The aqueous phase was lyophilized to afford TFA salt of 5- ( (2- (2-aminoethoxy) ethyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (1.9 g, yield: 77%) as yellow solid. ¹H NMR (400 MHz, DMSO-d ₆) δ 11.06 (s, 1H) , 8.01 (s, 3H) , 7.58 (d, J = 8.4 Hz, 1H) , 7.12 (br, s, 1H) , 7.02 (d, J = 2.0 Hz, 1H) , 6.91 (dd, J = 2.0 Hz, 8.8 Hz, 1H) , 5.04 (dd, J = 5.6 Hz, 13.2 Hz, 1H) , 3.64 (t, J = 5.6 Hz, 4H) , 3.40 (t, J = 5.2 Hz, 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] ⁺.

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

Linker 61 was synthesized following the same procedure as Linker 60 as described for Example 60. (1.4 g, yield: 71%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 11.05 (s, 1H) , 7.94 (br, 3H) , 7.56 (d, J = 8.4 Hz, 1H) , 7.01 (s, 1H) , 6.90 (d, J = 8.0 Hz, 1H) , 5.03 (dd, J = 5.2 Hz, 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] ⁺.

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

Linker 62 was synthesized following the same procedure as Linker 60 as described for Example 60. (1.19 g, yield: 59%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 11.05 (s, 1H) , 7.79 (br, 3H) , 7.57 (d, J = 8.4 Hz, 1H) , 7.15 (br, s, 1H) , 7.00 (d, J = 2.0 Hz, 1H) , 6.90 (dd, J = 2.0 Hz, 8.4 Hz, 1H) , 5.03 (dd, J = 5.6 Hz, 12.8 Hz, 1H) , 3.61 –3.55 (m, 12H) , 3.36 (t, J = 5.6 Hz, 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] ⁺.

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

Linker 63 was synthesized following the same procedure as Linker 60 as described for Example 60. (1.2 g, yield: 73%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 11.05 (s, 1H) , 7.79 (br, J = 1.6 Hz, 3H) , 7.56 (d, J = 8.4 Hz, 1H) , 7.14 (br, s, 1H) , 7.01 (d, J = 2.0 Hz, 1H) , 6.90 (dd, J = 2.0 Hz, 8.4 Hz, 1H) , 5.03 (dd, J = 5.6 Hz, 13.2 Hz, 1H) , 3.61 –3.56 (m, 16H) , 3.36 (t, J = 5.2 Hz, 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] ⁺.

Example 64: 5- ( (17-Amino-3, 6, 9, 12, 15-pentaoxaheptadecyl) amino) -2- (2, 6-dioxopiperidin-3- yl) isoindoline-1, 3-dione (Linker 64)

Linker 64 was synthesized following the same procedure as Linker 60 as described for Example 60. (1.73 g, yield: 88%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 11.05 (s, 1H) , 7.79 (s, 3H) , 7.55 (d, J = 8.4 Hz, 1H) , 7.18 (br, s, 1H) , 7.01 (s, 1H) , 6.90 (d, J = 8.4 Hz, 1H) , 5.03 (dd, J = 5.2 Hz, 12.8 Hz, 1H) , 3.61 –3.54 (m, 20H) , 3.35 (s, 2H) , 2.98 (s, 2H) , 2.92 –2.83 (m, 1H) , 2.61 –2.54 (m, 2H) , 2.02 –1.98 (m, 1H) . MS (ESI) m/z = 537.2 [M+H] ⁺.

Example 65: (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) glycine (Linker 65)

Linker 65 was synthesized following the same procedure as Linker 60 as described for Example 60. (1.0 g, yield: 84%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 12.80 (br, 1H) , 11.06 (s, 1H) , 7.59 (d, J = 8.4 Hz, 1H) , 7.32 (br, s, 1H) , 6.98 (d, J = 1.2 Hz, 1H) , 6.89 (dd, J = 2.0 Hz, 8.4 Hz, 1H) , 5.04 (dd, J = 5.6 Hz, 13.2 Hz, 1H) , 4.03 (s, 2H) , 2.92 –2.83 (m, 1H) , 2.60 –2.52 (m, 2H) , 2.03 –1.98 (m, 1H) . MS (ESI) m/z = 332.0 [M+H] ⁺.

Example 66: 3- ( (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) propanoic acid (Linker 66)

Linker 66 was synthesized following the same procedure as Linker 60 as described for Example 60. (1.24 g, yield: 60%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 11.05 (s, 1H) , 7.57 (d, J = 8.4 Hz, 1H) , 6.97 (d, J = 2.0 Hz, 1H) , 6.87 (dd, J = 2.0 Hz, 8.4 Hz, 1H) , 5.02 (dd, J = 5.2 Hz, 12.8 Hz, 1H) , 3.41 (t, J = 6.8 Hz, 2H) , 2.89 –2.83 (m, 1H) , 2.60 –2.52 (m, 4H) , 2.02 –1.97 (m, 1H) . MS (ESI) m/z = 346.0 [M+H] ⁺.

Example 67: 4- ( (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) butanoic acid (Linker 67)

Linker 67 was synthesized following the same procedure as Linker 60 as described for Example 60. (0.52 g, yield: 25%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 12.12 (s, 1H) , 11.05 (s, 1H) , 7.55 (d, J = 8.4 Hz, 1H) , 7.14 (t, J = 4.8 Hz, 1H) , 6.95 (d, J = 2.0 Hz, 1H) , 6.85 (dd, J = 2.0 Hz, 8.4 Hz, 1H) , 5.02 (dd, J = 5.6 Hz, 12.8 Hz, 1H) , 3.21 –3.16 (m, 2H) , 2.91 –2.83 (m, 1H) , 2.60 –2.51 (m, 2H) , 2.34 (t, J = 7.2 Hz, 2H) , 2.01 –1.97 (m, 1H) , 1.82 –1.75 (m, 2H) . MS (ESI) m/z = 360.1 [M+H] ⁺.

Example 68: 5- ( (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) pentanoic acid (Linker 68)

Linker 68 was synthesized following the same procedure as Linker 60 as described for Example 60. (0.66 g, yield: 51%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 12.03 (br, 1H) , 11.05 (s, 1H) , 7.55 (d, J = 8.4 Hz, 1H) , 7.10 (t, J = 5.2 Hz, 1H) , 6.94 (s, 1H) , 6.83 (dd, J = 1.6 Hz, 8.4 Hz, 1H) , 5.02 (dd, J = 5.6 Hz, 12.8 Hz, 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] ⁺.

Example 69: 6- ( (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) hexanoic acid (Linker 69)

Linker 69 was synthesized following the same procedure as Linker 60 as described for Example 60. (1.33 g, yield: 66%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 11.98 (s, 1H) , 11.05 (s, 1H) , 7.55 (d, J = 8.4 Hz, 1H) , 7.08 (t, J = 5.2 Hz, 1H) , 6.95 (s, 1H) , 6.83 (dd, J = 1.2 Hz, 8.4 Hz, 1H) , 5.03 (dd, J = 5.2 Hz, 12.8 Hz, 1H) , 3.17 –3.12 (m, 2H) , 2.92 –2.83 (m, 1H) , 2.60 –2.53 (m, 2H) , 2.22 (t, J = 7.2 Hz, 2H) , 2.01 –1.98 (m, 1H) , 1.61 –1.51 (m, 4H) , 1.41 –1.33 (m, 2H) . MS (ESI) m/z = 388.1 [M+H] ⁺.

Example 70: 7- ( (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) heptanoic acid (Linker 70)

Linker 70 was synthesized following the same procedure as Linker 60 as described for Example 60. (1.06 g, yield: 39%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 11.94 (s, 1H) , 11.04 (s, 1H) , 7.55 (d, J = 8.4 Hz, 1H) , 7.09 (t, J = 5.6 Hz, 1H) , 6.94 (d, J = 2.0 Hz, 1H) , 6.84 (dd, J = 2.0 Hz, 8.4 Hz, 1H) , 5.02 (dd, J = 5.6 Hz, 13.2 Hz, 1H) , 3.17 –3.12 (m, 2H) , 2.88 –2.83 (m, 1H) , 2.60 –2.53 (m, 2H) , 2.21 (t, J = 7.2 Hz, 2H) , 2.01 – 1.97 (m, 1H) , 1.58 –1.48 (m, 4H) , 1.39 –1.29 (m, 4H) . MS (ESI) m/z = 402.1 [M+H] ⁺.

Example 71: 8- ( (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) octanoic acid (Linker 71)

Linker 71 was synthesized following the same procedure as Linker 60 as described for Example 60. (1.66 g, yield: 51%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 11.95 (s, 1H) , 11.05 (s, 1H) , 7.55 (d, J = 8.4 Hz, 1H) , 7.09 (t, J = 5.6 Hz, 1H) , 6.94 (d, J = 2.0 Hz, 1H) , 6.84 (dd, J = 2.0 Hz, 8.4 Hz, 1H) , 5.02 (dd, J = 5.6 Hz, 13.2 Hz, 1H) , 3.17 –3.12 (m, 2H) , 2.88 –2.83 (m, 1H) , 2.60 –2.53 (m, 2H) , 2.19 (t, J = 7.2 Hz, 2H) , 2.02 –1.98 (m, 1H) , 1.58 –1.47 (m, 4H) , 1.36 –1.29 (m, 6H) . MS (ESI) m/z = 416.1 [M+H] ⁺.

Example 72: 5- ( (2-Aminoethyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (Linker 72)

Linker 72 was synthesized following the same procedure as Linker 60 as described for Example 60. (1.74 g, yield: 80%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 11.08 (s, 1H) , 8.10 (s, 3H) , 7.62 (d, J = 8.4 Hz, 1H) , 7.33 (t, J = 5.2 Hz, 1H) , 7.05 (s, 1H) , 6.94 (d, J = 8.0 Hz, 1H) , 5.07 (dd, J = 5.2 Hz, 12.8 Hz, 1H) , 3.50 –3.49 (m, 2H) , 3.03 (t, J = 6.0 Hz, 2H) , 2.95 –2.86 (m, 1H) , 2.63 –2.57 (m, 2H) , 2.05 –2.02 (m, 1H) . MS (ESI) m/z = 317.1 [M+H] ⁺.

Example 73: 5- ( (3-Aminopropyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (Linker 73)

Linker 73 was synthesized following the same procedure as Linker 60 as described for Example 60. (1.3 g, yield: 57%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 11.07 (s, 1H) , 7.85 (br, 3H) , 7.59 (d, J = 8.4 Hz, 1H) , 7.22 (t, J = 5.2 Hz, 1H) , 6.98 (d, J = 2.0 Hz, 1H) , 6.88 (dd, J = 2.0 Hz, 8.4 Hz, 1H) , 5.04 (dd, J = 5.6 Hz, 13.2 Hz, 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] ⁺.

Example 74: 5- ( (4-Aminobutyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (Linker 74)

Linker 74 was synthesized following the same procedure as Linker 60 as described for Example 60. (2.9 g, yield: 85%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 11.08 (s, 1H) , 7.97 (br, 3H) , 7.58 (d, J = 8.4 Hz, 1H) , 7.22 (br, s, 1H) , 6.99 (s, 1H) , 6.89 (d, J = 8.0 Hz, 1H) , 5.05 (dd, J = 5.2 Hz, 12.8 Hz, 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] ⁺.

Example 75: 5- ( (5-Aminopentyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (Linker 75)

Linker 75 was synthesized following the same procedure as Linker 60 as described for Example 60. (1.8 g, yield: 78%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 11.09 (s, 1H) , 7.89 (br, 3H) , 7.57 (d, J = 6.8 Hz, 1H) , 7.17 (br, s, 1H) , 6.96 (s, 1H) , 6.86 (d, J = 6.0 Hz, 1H) , 5.05 (d, J = 7.2 Hz, 1H) , 3.19-3.15 (m, 2H) , 2.89-2.70 (m, 3H) , 2.61-2.51 (m, 2H) , 2.01-1.90 (m, 1H) , 1.62-1.56 (m, 4H) , 1.45-1.40 (m, 2H) . MS (ESI) m/z = 359.1 [M+H] ⁺.

Example 76: 5- ( (6-Aminohexyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (Linker 76)

Linker 76 was synthesized following the same procedure as Linker 60 as described for Example 60. (1.8 g, yield: 62%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 11.05 (s, 1H) , 7.71 (br, 3H) , 7.57 (d, J = 8.4 Hz, 1H) , 7.12 (t, J = 5.2 Hz, 1H) , 6.94 (d, J = 2.0 Hz, 1H) , 6.85 (dd, J = 2.0 Hz, 8.4 Hz, 1H) , 5.03 (dd, J = 5.2 Hz, 12.8 Hz, 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] ⁺.

Example 77: 5- ( (7-Aminoheptyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (Linker 77)

Linker 77 was synthesized following the same procedure as Linker 60 as described for Example 60. (1.3 g, yield: 70%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 11.05 (s, 1H) , 7.72 (br, 3H) , 7.56 (d, J = 8.4 Hz, 1H) , 7.12 (t, J = 5.6 Hz, 1H) , 6.94 (d, J = 2.0 Hz, 1H) , 6.85 (dd, J = 2.4 Hz, 8.8 Hz, 1H) , 5.03 (dd, J = 5.6 Hz, 12.8 Hz, 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] ⁺.

Example 78: 5- ( (8-Aminooctyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (Linker 78)

Linker 78 was synthesized following the same procedure as Linker 60 as described for Example 60. (1.6 g, yield: 62%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 11.05 (s, 1H) , 7.73 (br, 3H) , 7.56 (d, J = 8.4 Hz, 1H) , 7.14 (br, 1H) , 6.94 (d, J = 1.6 Hz, 1H) , 6.85 (dd, J = 2.0 Hz, 8.8 Hz, 1H) , 5.03 (dd, J = 5.6 Hz, 12.8 Hz, 1H) , 3.15 (t, J = 7.2 Hz, 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] ⁺.

Example 79: 3- (2- ( (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) ethoxy) propanoic acid (Linker 79)

Linker 79 was synthesized following the same procedure as Linker 60 as described for Example 60. (1.7 g, yield: 60%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 12.19 (br, 1H) , 11.06 (s, 1H) , 7.57 (d, J = 8.4 Hz, 1H) , 7.09 (br, 1H) , 7.01 (d, J = 2.0 Hz, 1H) , 6.90 (dd, J = 2.0 Hz, 8.4 Hz, 1H) , 5.04 (dd, J = 5.6 Hz, 13.2 Hz, 1H) , 3.66 (t, J = 6.4 Hz, 2H) , 3.59 (t, J = 5.6 Hz, 2H) , 3.35 (t, J = 5.2 Hz, 2H) , 2.93 –2.84 (m, 1H) , 2.62 –2.56 (m, 2H) , 2.52 –2.47 (m, 2H) , 2.03 –1.99 (m, 1H) . MS (ESI) m/z = 390.1 [M+H] ⁺.

Example 80: 3- (2- (2- ( (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) ethoxy) ethoxy) propanoic acid (Linker 80)

Linker 80 was synthesized following the same procedure as Linker 60 as described for Example 60. (2.3 g, yield: 78%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 11.06 (s, 1H) , 7.57 (d, J = 8.4 Hz, 1H) , 7.02 (d, J = 2.0 Hz, 1H) , 6.90 (dd, J = 2.0 Hz, 8.4 Hz, 1H) , 5.04 (dd, J = 5.6 Hz, 13.2 Hz, 1H) , 3.63 –3.59 (m, 4H) , 3.57 –3.51 (m, 4H) , 3.36 (t, J = 5.6 Hz, 2H) , 2.90 –2.84 (m, 1H) , 2.61 –2.55 (m, 2H) , 2.44 (t, J = 6.4 Hz, 2H) , 2.04 –1.99 (m, 1H) . MS (ESI) m/z = 434.1 [M+H] ⁺.

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)

Linker 81 was synthesized following the same procedure as Linker 60 as described for Example 60. (1.2 g, yield: 52%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 7.59 (d, J = 11.2 Hz, 1H) , 7.23 (t, J = 6.8 Hz, 1H) , 7.04 (d, J = 1.6 Hz, 1H) , 7.04 (dd, J = 2.4 Hz, 11.2 Hz, 1H) , 5.06 (dd, J = 7.2 Hz, 16.8 Hz, 1H) , 3.64 –3.57 (m, 8H) , 3.54 –3.48 (m, 4H) , 3.40 –3.38 (m, 2H) , 2.92 –2.89 (m, 1H) , 2.64 –2.54 (m, 2H) , 2.42 –2.38 (m, 2H) , 2.05 –2.01 (m, 1H) . MS (ESI) m/z = 478.1 [M+H] ⁺.

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)

Linker 82 was synthesized following the same procedure as Linker 60 as described for Example 60. (1.3 g, yield: 55%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 12.17 (br, 1H) , 11.07 (s, 1H) , 7.56 (d, J = 8.4 Hz, 1H) , 7.17 (t, J = 5.6 Hz, 1H) , 7.01 (d, J = 1.2 Hz, 1H) , 6.90 (dd, J = 1.6 Hz, 8.4 Hz, 1H) , 5.03 (dd, J = 5.6 Hz, 12.8 Hz, 1H) , 3.61 –3.48 (m, 18H) , 2.92 –2.83 (m, 1H) , 2.60 –2.54 (m, 2H) , 2.43 (t, J = 6.4 Hz, 2H) , 2.03 –1.98 (m, 1H) . MS (ESI) m/z = 522.1 [M+H] ⁺.

Example 83: 1- ( (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) -3, 6, 9, 12, 15-pentaoxaoctadecan-18-oic acid (Linker 83)

Linker 83 was synthesized following the same procedure as Linker 60 as described for Example 60. (1.0 g, yield: 50%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 12.17 (br, s, 1H) , 11.07 (s, 1H) , 7.56 (d, J = 8.0 Hz, 1H) , 7.17 (t, J = 5.6 Hz, 1H) , 7.01 (s, 1H) , 6.90 (dd, J = 1.6 Hz, 8.4 Hz, 1H) , 5.03 (dd, J = 5.6 Hz, 13.2 Hz, 1H) , 3.60 –3.48 (m, 22H) , 2.89 –2.83 (m, 1H) , 2.60 –2.54 (m, 2H) , 2.43 (t, J = 6.4 Hz, 2H) , 2.01 –1.98 (m, 1H) . MS (ESI) m/z = 566.1 [M+H] ⁺.

Example 84. N- (tert-Butyl) -3- ( (5-methyl-2- ( (4- (piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) benzenesulfonamide

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

To a solution of N- (tert-butyl) -3- ( (2-chloro-5-methylpyrimidin-4-yl) amino) benzenesulfonamide (1.1 g, 3.1 mmol ) , tert-butyl 4- (4-aminophenyl) piperazine-1-carboxylate (1.03 g, 3.7 mmol ) in 1, 4-dioxane (20 mL) was added palladium acetate (70 mg, 0.31 mmol) , (+/-) -2, 2'-bis (diphenylphosphino) -1, 1'-binaphthyl (386 mg, 0.62 mmol ) , cesium carbonate (2.0 g, 6.2 mmol ) . The resulting mixture was stirred at 100 ℃ for 12 h under nitrogen atmosphere. LCMS showed that the reaction was completed. The mixture was diluted with ethyl acetate, washed with water. The organic layer was dried over anhydrous sodium sulphate and concentrated. The residue was purified by column chromatography (hexanes : ethyl acetate = 1 : 1 ) to give tert-butyl 4- (4- ( (4- ( (3- (N- (tert-butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) piperazine-1-carboxylate (1.2 g, yield: 65%) as brown solid. MS (ESI) m/z 596.0 [M+H] ⁺.

Step 2: Synthesis of N- (tert-Butyl) -3- ( (5-methyl-2- ( (4- (piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) benzenesulfonamide

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 completed. The mixture was concentrated, triturated with methanol and ethyl acetate to give N- (tert-butyl) -3- ( (5-methyl-2- ( (4- (piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) benzenesulfonamide (1.002 g, yield: 94%) as white solid. ¹H NMR (400 MHz, DMSO-d ₆) δ 10.59 (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 = 8.0 Hz, 1H) , 7.64 (s, 1H) , 7.58 (t, J = 8.0 Hz, 1H) , 7.27 (d, J = 9.2 Hz, 2H) , 6.94 (d, J = 8.8 Hz, 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] ⁺.

Example 85. 2- (4- (4- ( (4- ( (3- (N- (tert-Butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) piperazin-1-yl) acetic acid

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

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 Et ₃N (208.8 mg, 2.07 mmol) at room temperature. The reaction was stirred at room temperature for 10 min. After addition of methyl 2-chloroacetate (168.26 mg, 1.55 mmol) for over 2 min, the resulting mixture was stirred at room temperature for 2 h, at which time TLC showed the starting material was consumed. The mixture was diluted with H ₂O (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 solvent (petroleum ether : EtOAc = 10 : 1) to get pure methyl 2- [4- [4- [ [4- [3- (tert-butylsulfamoyl) anilino] -5-methyl-pyrimidin-2- yl] amino] phenyl] piperazin-1-yl] acetate (240 mg, 82%yield) as white solid which was used directly in the next step.

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

To a solution of methyl 2- [4- [4- [ [4- [3- (tert-butylsulfamoyl) anilino] -5-methyl-pyrimidin-2-yl] amino] phenyl] piperazin-1-yl] acetate (240 mg, 0.42 mmol) in THF (10 mL) was added LiOH (67.64 mg, 1.69 mmol) and H ₂O (2 mL) at room temperature. The reaction was stirred for 12 h, at which time TLC showed the starting material was consumed. The mixture was acidified by 0.1 N HCl to pH = 6, and concentrated to remove THF. The resulting solid was collected by filtration and dried in vacuum to get 2- [4- [4- [ [4- [3- (tert-butylsulfamoyl) anilino] -5-methyl-pyrimidin-2-yl] amino] phenyl] piperazin-1-yl] acetic acid (200 mg, 85%yield) as white solid. MS (ESI) m/z: 554.5 [M-H] ^-.

Example 86. 5- (4- (Methylsulfonyl) phenyl) -N- (4- (piperazin-1-yl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-amine

Step 1: Synthesis of 5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-amine

A solution of (4-methylsulfonylphenyl) boronic acid (12g, 60 mmol) , 5-bromo- [l, 2, 4] triazolo [l, 5-a] pyridine-2-amine (6.39g, 30mmol) , 1, 1'-bis (diphenylphosphino) ferrocenepalladium (II) chloride (2.2 g, 3 mmol) , and potassium carbonate (12.4 g, 90 mmol) in 4: 1 dioxane/water (30mL) was heated at 150 ℃ under microwave radiation for 1 h. After the reaction mixture was diluted with dichloromethane (100 mL) , the resulting suspension was filtered through celite. The filtrate was concentrated, and the resulting residue was purified by flash column chromatography (dichloromethane : methanol = 20 : 1) to provide 5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-amine (4.0 g, yield: 46%) as white solid. ¹H NMR (400 MHz, DMSO-d ₆) δ 8.21 (d, J = 8.4 Hz, 2H) , 8.08 (d, J = 8.4 Hz, 2H) , 7.58 –7.54 (m, 1H) , 7.45 (dd, J =8.8 Hz, 0.8 Hz, 1H) , 7.13 (dd, J = 7.6Hz, 0.8Hz, 1H) , 6.12 (brs, 2H) 3.32 (s, 3H) . MS (ESI) m/z 289.1 [M+H] ⁺.

Step 2: Synthesis of tert-butyl 4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazine-1-carboxylate

To an oven-dried flask was added 5- (4-methanesulfonyl-phenyl) - [1, 2, 4] triazolo [1, 5-a] -pyridin-2-ylamine (3.79g, 13.16mmol) , tert-butyl 4- (4-bromophenyl) piperazine-1-carboxylate (4.92g, 14.48mmol) , palladium acetate (295mg, 1.32mmol) , 2- (dicyclohexylphosphino) -2', 4', 6'-tri-i-propyl-1, 1'-biphenyl (X-phos, 1.25g, 2.63mmol) , cesium carbonate (8.58 g, 26.32 mmol) , and dry toluene (100 mL) under nitrogen. The resulting mixture was vacuumed and purged with nitrogen three times before being heated at 100 ℃ for 3 d, at which time the reaction mixture was cooled to room temperature and filtered. After the solid was washed with toluene followed by water, it was dried under vacuo and purified by column chromatography (amine dichloromethane : methane = 20 : 1) to give tert-butyl 4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazine-1-carboxylate (3.9 g, yield: 54%) as yellow solid. ¹H NMR (400 MHz, DMSO-d ₆) δ 9.43 (s, 1H) , 8.33 (d, J = 8.4 Hz, 2H) , 8.14 (d, J = 8.4 Hz, 2H) , 7.67 – 7.62 (m, 2H) , 7.55 (d, J = 8.8 Hz, 2H) , 7.27 (dd, J = 6.4 Hz, 1.6 Hz, 1H) , 6.92 (d, J = 9.2 Hz, 2H) , 3.46 (t, J =4.8 Hz, 4H) , 3.35 (s, 3H) , 2.97 (d, J = 4.8Hz, 4H) . MS (ESI) m/z 549.1 [M+H] ⁺.

Step 3: Synthesis of 5- (4- (methylsulfonyl) phenyl) -N- (4- (piperazin-1-yl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-amine

To a solution tert-butyl 4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazine-1-carboxylate (2.0g, 3.65mmol) indichloromethane (50 mL) and methanol (10 mL) was added saturated HCl/EtOAc solution (20 mL, 4 M) . After the mixture was stirred at room temperature for 2 h, the precipitate was filtered and dried under vacuo to give 5- (4- (methylsulfonyl) phenyl) -N- (4- (piperazin-1-yl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-amine hydrochloride (1.7 g, yield: 96%) as white solid. ¹H NMR (400 MHz, DMSO-d ₆) : δ 9.78 (br, 1H) , 9.54 (br, 2H) , 8.35 (d, J =11.2 Hz, 2H) , 8.17 (d, J=11.2 Hz , 2H) , 7.78 –7.65 (m, 4H) , 7.36 (d, J = 9.2 Hz, 1H) , 7.19 (d, J = 8.0 Hz, 1H) , 3.46 –3.38 (m, 11H) . MS (ESI) m/z 449.1 [M+H] ⁺.

Example 87. 2- (4- (4- ( (5- (4- (Methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) acetic acid

Step1: Synthesis of tert-butyl 2- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) acetate

5- (4- (Methylsulfonyl) phenyl) -N- (4- (piperazin-1-yl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-amine (500 mg, 1.11 mmol, HCl salt) in DMF (5 mL) was added DIPEA (289 mg, 2.22 mmol) at room temperature. The reaction was stirred at room temperature for 10 min. After addition of tert-butyl 2-bromoacetate (238 mg, 1.22 mmol) for over 2 min, the resulting mixture was stirred at room temperature for 2 h, at which time TLC showed the starting material was consumed. The mixture was diluted with H ₂O (15 mL) , and extracted with EtOAc (10 mL x 3) . The combined organic layers were dried and concentrated to give 430 mg of crude product which was triturated with 10 mL solvent (petroleum ether : EtOAc =10 : 1) to get pure compound as yellow solid. (430 mg, 70%yield) MS (ESI) m/z: 564.0 [M+H] ⁺.

Step2: Synthesis of 2- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) acetic acid

To a solution of methyl 2- [4- [4- [ [4- [3- (tert-butylsulfamoyl) anilino] -5-methyl-pyrimidin-2-yl] amino] phenyl] piperazin-1-yl] acetate (240 mg, 0.42 mmol) in DCM (10 mL) was added TFA (10 mL) at room temperature. The reaction was stirred for 12 h, at which time TLC showed the starting material was consumed. The mixture was concentrated to remove DCM and TFA. The resulting solid was collected by filtration and dried in vacuum to afford 2- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) acetic acid (183 mg, 85%yield) as yellow solid. MS (ESI) m/z: 507.1 [M+H] ⁺.

Example 88. 2- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) acetic acid

Step 1: Synthesis of tert-butyl 2- (4- (4- (8- (3, 5-difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) acetate

To a solution of 4- [ [2, 6-difluoro-4- [3- [1- (4-piperidyl) pyrazol-4-yl] quinoxalin-5-yl] phenyl] methyl] morpholine (109.37 mg, 211.80 umol) in DMF (3 mL) was added K ₂CO ₃ (73.18 mg, 529.50 umol) , followed by tert-Butyl 2-bromoacetate (47.84 mg, 232.98 umol) over 5 min. The resulting mixture was stirred at 25 ℃ for 3 h. After the amine was totally consumed, the reaction was poured into water (300 mL) and extracted with ethyl acetate (50 mL x 3) . The combined organic layers were washed with saturated brine (100 mL) , dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford the desired product tert-butyl 2- [4- [4- [8- [3, 5-difluoro-4- (morpholinomethyl) phenyl] quinoxalin-2-yl] pyrazol-1-yl] -1-piperidyl] acetate (112 mg, 87.4%yield) as light yellow solid. MS (ESI) m/z: 605.3 [M+H] ⁺.

Step 2: Synthesis of 2- (4- (4- (8- (3, 5-difluoro-4- (morpholinomethyl) phenyl) quinoxalin -2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) acetic acid

To a solution of tert-butyl 2- [4- [4- [8- [3, 5-difluoro-4- (morpholinomethyl) phenyl] quinoxalin-2-yl] pyrazol-1-yl] -1-piperidyl] acetate (110 mg, 181.91 umol) in DCM (2 mL) was added TFA (8 g, 70.16 mmol) . The resulting mixture was stirred at 25 ℃ for 3 h. After the starting material was totally consumed, the reaction was evaporated under reduced pressure. The resulting residue was purified by reverse -phase chromatography to yield the desired product 2- [4- [4- [8- [3, 5-difluoro-4- (morpholino methyl) phenyl] quinoxalin-2-yl] pyrazol-1-yl] -1-piperidyl] acetic acid (86 mg, 86.2%yield) as light yellow solid. MS (ESI) m/z: 547.2 [M-H] ^-.

Example 89. 4- [ [6- [4- [4- [8- [3, 5-Difluoro-4- (morpholinomethyl) phenyl] quinoxalin-2-yl] pyrazol-1-yl] -1-piperidyl] -6-oxo-hexyl] amino] -2- (2, 6-dioxo-3-piperidyl) isoindoline-1, 3-dione (JA-001)

To a solution of 6- [ [2- (2, 6-dioxo-3-piperidyl) -1, 3-dioxo-isoindolin-4-yl] amino] hexanoic acid (6.32 mg, 16.31 umol) in DMSO (1 mL) was added HOAt (2.22 mg, 16.31 umol) , EDCI (3.13 mg, 16.31 umol) , NMM (8.25 mg, 81.54 umol) and 4- [ [2, 6-difluoro-4- [3- [1- (4-piperidyl) pyrazol-4-yl] quinoxalin-5-yl] phenyl] methyl] morpholine (8 mg, 16.31 umol) sequentially. The resulting solution was stirred at 25 ℃for 16 h, before the reaction was poured into water (200 mL) and extracted with ethyl acetate (50 mL x 3) . The combined organic layers were washed with saturated brine (100 mL) , dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by reverse-phase chromatography to yield the desired product 4- [ [6- [4- [4- [8- [3, 5-difluoro-4- (morpholinomethyl) phenyl] quinoxalin-2-yl] pyrazol-1-yl] -1-piperidyl] -6-oxo-hexyl] amino] -2- (2, 6-dioxo-3-piperidyl) isoindoline-1, 3-dione (6.3 mg, 44.9%yield) as light yellow solid. MS (ESI) m/z: 860.4 [M+H] ⁺.

Example 90. 4- [ [2- [4- [4- [8- [3, 5-Difluoro-4- (morpholinomethyl) phenyl] quinoxalin-2-yl] pyrazol-1-yl] -1-piperidyl] -2-oxo-ethyl] amino] -2- (2, 6-dioxo-3-piperidyl) isoindoline-1, 3-dione (JA-002)

JA-002 was synthesized following the standard procedure for preparing JA-001 (6.9 mg, 52.6%yield) . MS (ESI) m/z: 804.3 [M+H] ⁺.

Example 91. 4- [ [5- [4- [4- [8- [3, 5-Difluoro-4- (morpholinomethyl) phenyl] quinoxalin-2-yl] pyrazol-1-yl] -1-piperidyl] -5-oxo-pentyl] amino] -2- (2, 6-dioxo-3-piperidyl) isoindoline-1, 3-dione (JA-003)

JA-003 was synthesized following the standard procedure for preparing JA-001 (7.6 mg, 55.1%yield) . MS (ESI) m/z: 846.3 [M+H] ⁺.

Example 92. 4- [ [3- [4- [4- [8- [3, 5-Difluoro-4- (morpholinomethyl) phenyl] quinoxalin-2-yl] pyrazol-1-yl] -1-piperidyl] -3-oxo-propyl] amino] -2- (2, 6-dioxo-3-piperidyl) isoindoline-1, 3-dione (JA-004)

JA-004 was synthesized following the standard procedure for preparing JA-001 (7.9 mg, 59.2%yield) . MS (ESI) m/z: 818.3 [M+H] ⁺.

Example 93. 4- [ [4- [4- [4- [8- [3, 5-Difluoro-4- (morpholinomethyl) phenyl] quinoxalin-2-yl] pyrazol-1-yl] -1-piperidyl] -4-oxo-butyl] amino] -2- (2, 6-dioxo-3-piperidyl) isoindoline-1, 3-dione (JA-005)

JA-005 was synthesized following the standard procedure for preparing JA-001 (8.1 mg, 59.7%yield) . MS (ESI) m/z: 832.3 [M+H] ⁺.

Example 94. N- (tert-Butyl) -3- ( (2- ( (4- (4- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) glycyl) piperazin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide (JA-006)

JA-006 was synthesized following the standard procedure for preparing JA-015 (7.7 mg, 55.1%yield) . MS (ESI) m/z: 809.3 [M+H] ⁺.

Example 95. N- (tert-Butyl) -3- ( (2- ( (4- (4- (6- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) hexanoyl) piperazin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide (JA-007)

JA-007 was synthesized following the standard procedure for preparing JA-015 (7.1 mg, 53.6%yield) . MS (ESI) m/z: 865.4 [M+H] ⁺.

Example 96. N- (tert-Butyl) -3- ( (2- ( (4- (4- (4- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) butanoyl) piperazin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide (JA-008)

JA-008 was synthesized following the standard procedure for preparing JA-015 (7.4 mg, 54.5%yield) . MS (ESI) m/z: 837.3 [M+H] ⁺.

Example 97. N- (tert-Butyl) -3- ( (2- ( (4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) propanoyl) piperazin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide (JA-009)

JA-009 was synthesized following the standard procedure for preparing JA-015 (7.5 mg, 56.2%yield) . MS (ESI) m/z: 823.3 [M+H] ⁺.

Example 98. 2- (2, 6-Dioxopiperidin-3-yl) -4- ( (4- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) -4-oxobutyl) amino) isoindoline-1, 3-dione (JA-010)

To a solution of 4- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) butanoic acid (7.90 mg, 0.022 mmol) was added HOAt (2.72 mg, 0.020 mmol) , EDCI (3.87 mg, 0.020 mmol) and NMM (2.04 mg, 0.020 mmol) . The resulting mixture was stirred at room temperature for 2 min, before [5- (4-methanesulfonyl-phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl] - (4-piperazin-1-yl-phenyl) -amine (8.9 mg, 0.020 mmol) was added. After the reaction was stirred at 25 ℃ for 12 h, TLC showed the reaction was completed. The mixture was purified by reverse phase flash chromatography, followed by prep-TLC to give 2- (2, 6-dioxopiperidin-3-yl) -4- ( (4- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) -4-oxobutyl) amino) isoindoline-1, 3-dione (11.9 mg, 76%yield) . MS (ESI) m/z: 790.6 [M+H] ⁺.

Example 99. 2- (2, 6-Dioxo-piperidin-3-yl) -4- [5- (4- {4- [5- (4-methanesulfonyl-phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-ylamino] -phenyl} -piperazin-1-yl) -5-oxo-pentylamino] -isoindole-1, 3-dione (JA-011)

JA-011 was synthesized following the standard procedure for preparing JA-010 (10 mg, 77%yield) . MS (ESI) m/z: 804.37 [M+H] ⁺.

Example 100. 2- (2, 6-Dioxo-piperidin-3-yl) -4- [3- (4- {4- [5- (4-methanesulfonyl-phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-ylamino] -phenyl} -piperazin-1-yl) -3-oxo-propylamino] -isoindole-1, 3-dione (JA-012)

JA-012 was synthesized following the standard procedure for preparing JA-010 (9 mg, 75%yield) . MS (ESI) m/z: 776.3 [M+H] ⁺.

Example 101. 2- (2, 6-Dioxo-piperidin-3-yl) -4- [6- (4- {4- [5- (4-methanesulfonyl-phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-ylamino] -phenyl} -piperazin-1-yl) -6-oxo-hexylamino] -isoindole-1, 3-dione (JA-013)

JA-013 was synthesized following the standard procedure for preparing JA-010 (11 mg, 77%yield) . MS (ESI) m/z: 817.3 [M+H] ⁺.

Example 102. 2- (2, 6-Dioxo-piperidin-3-yl) -4- [2- (4- {4- [5- (4-methanesulfonyl-phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-ylamino] -phenyl} -piperazin-1-yl) -2-oxo-ethylamino] -isoindole-1, 3-dione (JA-014)

JA-014 was synthesized following the standard procedure for preparing JA-010 (8 mg, 76%yield) . MS (ESI) m/z: 762.2 [M+H] ⁺.

Example 103. N- (tert-Butyl) -3- ( (2- ( (4- (4- (7- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) heptanoyl) piperazin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide (JA-015)

To a solution of 7- [ [2- (2, 6-dioxo-3-piperidyl) -1, 3-dioxo-isoindolin-4-yl] amino] heptanoic acid (8.91 mg, 0.022 mmol) was added HOAt (2.72 mg, 0.020 mmol) , EDCI (3.87 mg, 0.020 mmol) and NMM (2.04 mg, 0.020 mmol) . The mixture was stirred at room temperature for 2 min, before N-tert-butyl-3- [ [5-methyl-2- (4-piperazin-1-ylanilino) pyrimidin-4-yl] amino] benzenesulfonamide (10 mg, 0.020 mmol) was added. After the reaction mixture was stirred at 25 ℃ for 12 h, TLC showed the reaction was completed. The mixture was purified by reverse phase flash chromatography, followed by prep-TLC to give N-tert-butyl-3- [ [2- [4- [4- [7-[ [2- (2, 6-dioxo-3-piperidyl) -1, 3-dioxo-isoindolin-4-yl] amino] heptanoyl] piperazin-1-yl] anilino] -5-methyl-pyrimidin-4-yl] amino] benzenesulfonamide (13.5 mg, 76%yield) . MS (ESI) m/z: 879.6 [M-H] ^-.

Example 104. N- (tert-Butyl) -3- ( (2- ( (4- (4- (8- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) octanoyl) piperazin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide (JA-016)

JA-016 was synthesized following the standard procedure for preparing JA-015 (17 mg, 94%yield) . MS (ESI) m/z: 894.7 [M+H] ⁺.

Example 105. N- (tert-Butyl) -3- ( (2- ( (4- (4- (3- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethoxy) propanoyl) piperazin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide (JA-017)

JA-017 was synthesized following the standard procedure for preparing JA-015 (16 mg, 98%yield) . MS (ESI) m/z: 867.6 [M+H] ⁺.

Example 106. N- (tert-Butyl) -3- ( (2- ( (4- (4- (3- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethoxy) ethoxy) propanoyl) piperazin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide (JA-018)

JA-018 was synthesized following the standard procedure for preparing JA-015 (15.8 mg, 92%yield) . MS (ESI) m/z: 911.6 [M+H] ⁺.

Example 107. N- (tert-Butyl) -3- ( (2- ( (4- (4- (3- (2- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethoxy) ethoxy) ethoxy) propanoyl) piperazin-1-yl) phenyl) amino) -5- methylpyrimidin-4-yl) amino) benzenesulfonamide (JA-019)

JA-019 was synthesized following the standard procedure for preparing JA-015 (16.3 mg, 91%yield) . MS (ESI) m/z: 956.9 [M+H] ⁺.

Example 108. N- (tert-Butyl) -3- ( (2- ( (4- (4- (1- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) -3, 6, 9, 12-tetraoxapentadecan-15-oyl) piperazin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide (JA-020)

JA-020 was synthesized following the standard procedure for preparing JA-015 (15.4 mg, 82%yield) . MS (ESI) m/z: 1000.8 [M+H] ⁺.

Example 109. N- (tert-Butyl) -3- ( (2- ( (4- (4- (1- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) -3, 6, 9, 12, 15-pentaoxaoctadecan-18-oyl) piperazin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide (JA-021)

JA-021 was synthesized following the standard procedure for preparing JA-015 (13.8 mg, 70%yield) . MS (ESI) m/z: 1043.5 [M+H] ⁺.

Example 110. (2S, 4R) -1- ( (S) -2- (4- (4- (4- ( (4- ( (3- (N- (tert-Butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) piperazin-1-yl) -4-oxobutanamido) -3, 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-022)

JA-022 was synthesized following the standard procedure for preparing JA-015 (17.7 mg, 93%yield) . MS (ESI) m/z: 1009.8 [M+H] ⁺.

Example 111. (2S, 4R) -1- ( (S) -2- (5- (4- (4- ( (4- ( (3- (N- (tert-Butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) piperazin-1-yl) -5-oxopentanamido) -3, 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-023)

JA-023 was synthesized following the standard procedure for preparing JA-015 (6.3 mg, 33%yield) . MS (ESI) m/z: 1023.6 [M+H] ⁺.

Example 112. (2S, 4R) -1- ( (S) -2- (6- (4- (4- ( (4- ( (3- (N- (tert-Butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) piperazin-1-yl) -6-oxohexanamido) -3, 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-024)

JA-024 was synthesized following the standard procedure for preparing JA-015 (19 mg, 97%yield) . MS (ESI) m/z: 1036.7 [M+H] ⁺.

Example 113. (2S, 4R) -1- ( (S) -2- (7- (4- (4- ( (4- ( (3- (N- (tert-Butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) piperazin-1-yl) -7-oxoheptanamido) -3, 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-025)

JA-025 was synthesized following the standard procedure for preparing JA-015 (18.9 mg, 96%yield) . MS (ESI) m/z: 1050.6 [M+H] ⁺.

Example 114. (2S, 4R) -1- ( (S) -2- (8- (4- (4- ( (4- ( (3- (N- (tert-Butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) piperazin-1-yl) -8-oxooctanamido) -3, 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-026)

JA-026 was synthesized following the standard procedure for preparing JA-015 (19.2 mg, 96%yield) . MS (ESI) m/z: 1065.9 [M+H] ⁺.

Example 115. (2S, 4R) -1- ( (S) -2- (9- (4- (4- ( (4- ( (3- (N- (tert-Butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) piperazin-1-yl) -9-oxononanamido) -3, 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-027)

JA-027 was synthesized following the standard procedure for preparing JA-015 (18.3 mg, 90%yield) . MS (ESI) m/z: 1078.7 [M+H] ⁺.

Example 116. (2S, 4R) -1- ( (S) -2- (10- (4- (4- ( (4- ( (3- (N- (tert-Butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) piperazin-1-yl) -10-oxodecanamido) -3, 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-028)

JA-028 was synthesized following the standard procedure for preparing JA-015 (18.5 mg, 90%yield) . MS (ESI) m/z: 1093.9 [M+H] ⁺.

Example 117. (2S, 4R) -1- ( (S) -2- (11- (4- (4- ( (4- ( (3- (N- (tert-Butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) piperazin-1-yl) -11-oxoundecanamido) -3, 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-029)

JA-029 was synthesized following the standard procedure for preparing JA-015 (18.6 mg, 89%yield) . MS (ESI) m/z: 1107.6 [M+H] ⁺.

Example 118. (2S, 4R) -1- ( (S) -2- (2- (2- (4- (4- ( (4- ( (3- (N- (tert-Butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) piperazin-1-yl) -2-oxoethoxy) acetamido) -3, 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-030)

JA-030 was synthesized following the standard procedure for preparing JA-015 (6 mg, 29%yield) . MS (ESI) m/z: 1025.7 [M+H] ⁺.

Example 119. (2S, 4R) -1- ( (S) -2- (3- (3- (4- (4- ( (4- ( (3- (N- (tert-Butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) piperazin-1-yl) -3-oxopropoxy) propanamido) -3, 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-031)

JA-031 was synthesized following the standard procedure for preparing JA-015 (7 mg, 33%yield) . MS (ESI) m/z: 1053.9 [M+H] ⁺.

Example 120. (2S, 4R) -1- ( (S) -2- (2- (2- (2- (4- (4- ( (4- ( (3- (N- (tert-Butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) piperazin-1-yl) -2-oxoethoxy) ethoxy) acetamido) -3, 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-032)

JA-032 was synthesized following the standard procedure for preparing JA-015 (7 mg, 32%yield) . MS (ESI) m/z: 1069.8 [M+H] ⁺.

Example 121. (2S, 4R) -1- ( (S) -2- (3- (2- (3- (4- (4- ( (4- ( (3- (N- (tert-Butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) piperazin-1-yl) -3-oxopropoxy) ethoxy) propanamido) -3, 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-033)

JA-033 was synthesized following the standard procedure for preparing JA-015 (5 mg, 23%yield) . MS (ESI) m/z: 1097.6 [M+H] ⁺.

Example 122. (2S, 4R) -1- ( (S) -2- (tert-Butyl) -16- (4- (4- ( (4- ( (3- (N- (tert-butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) piperazin-1-yl) -4, 16-dioxo-7, 10, 13-trioxa-3-azahexadecanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-034)

JA-034 was synthesized following the standard procedure for preparing JA-015 (6 mg, 26%yield) . MS (ESI) m/z: 1141.1 [M+H] ⁺.

Example 123. (2S, 4R) -1- ( (S) -2- (tert-Butyl) -19- (4- (4- ( (4- ( (3- (N- (tert-butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) piperazin-1-yl) -4, 19-dioxo-7, 10, 13, 16-tetraoxa-3-azanonadecanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-035)

JA-035 was synthesized following the standard procedure for preparing JA-015 (7 mg, 29%yield) . MS (ESI) m/z: 1185.1 [M+H] ⁺.

Example 124. (2S, 4R) -1- ( (S) -2- (tert-Butyl) -20- (4- (4- ( (4- ( (3- (N- (tert-butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) piperazin-1-yl) -4, 20-dioxo-6, 9, 12, 15, 18-pentaoxa-3-azaicosanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-036)

JA-036 was synthesized following the standard procedure for preparing JA-015 (7 mg, 29%yield) . MS (ESI) m/z: 1201.9 [M+H] ⁺.

Example 125. (2S, 4R) -1- ( (S) -2- (tert-Butyl) -22- (4- (4- ( (4- ( (3- (N- (tert-butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) piperazin-1-yl) -4, 22-dioxo-7, 10, 13, 16, 19-pentaoxa-3-azadocosanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-037)

JA-037 was synthesized following the standard procedure for preparing JA-015 (7 mg, 28%yield) . MS (ESI) m/z: 1229.1 [M+H] ⁺.

Example 126. 4- [ [8- [4- [4- [8- [3, 5-Difluoro-4- (morpholinomethyl) phenyl] quinoxalin-2-yl] pyrazol-1-yl] -1-piperidyl] -8-oxo-octyl] amino] -2- (2, 6-dioxo-3-piperidyl) isoindoline-1, 3-dione (JA-038)

JA-038 was synthesized following the standard procedure for preparing JA-001 (6.8 mg, 46.9%yield) . MS (ESI) m/z: 888.4 [M+H] ⁺.

Example 127. 4- [2- [2- [3- [4- [4- [8- [3, 5-Difluoro-4- (morpholinomethyl) phenyl] quinoxalin-2-yl] pyrazol-1-yl] -1-piperidyl] -3-oxo-propoxy] ethoxy] ethylamino] -2- (2, 6-dioxo-3-piperidyl) isoindoline-1, 3-dione (JA-039)

JA-039 was synthesized following the standard procedure for preparing JA-001 (7.2 mg, 48.7%yield) . MS (ESI) m/z: 906.4 [M+H] ⁺.

Example 128. 4- [ [7- [4- [4- [8- [3, 5-Difluoro-4- (morpholinomethyl) phenyl] quinoxalin-2-yl] pyrazol-1-yl] -1-piperidyl] -7-oxo-heptyl] amino] -2- (2, 6-dioxo-3-piperidyl) isoindoline-1, 3-dione (JA-040)

JA-040 was synthesized following the standard procedure for preparing JA-001 (8.1 mg, 56.8%yield) . MS (ESI) m/z: 874.4 [M+H] ⁺.

Example 129. (2S, 4R) -1- [ (2S) -2- [ [6- [4- [4- [8- [3, 5-Difluoro-4- (morpholinomethyl) phenyl] quinoxalin-2-yl] pyrazol-1-yl] -1-piperidyl] -6-oxo-hexanoyl] amino] -3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ [4- (4-methylthiazol-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide (JA-041)

JA-041 was synthesized following the standard procedure for preparing JA-001 (6.7 mg, 39.8%yield) . MS (ESI) m/z: 1031.5 [M+H] ⁺.

Example 130. (2S, 4R) -1- [ (2S) -2- [ [10- [4- [4- [8- [3, 5-Difluoro-4- (morpholinomethyl) phenyl] quinoxalin-2-yl] pyrazol-1-yl] -1-piperidyl] -10-oxo-decanoyl] amino] -3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ [4- (4-methylthiazol-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide (JA-042)

JA-042 was synthesized following the standard procedure for preparing JA-001 (5.9 mg, 33.2%yield) . MS (ESI) m/z: 1087.5 [M+H] ⁺.

Example 131.4- [2- [2- [2- [2- [2- [3- [4- [4- [8- [3, 5-Difluoro-4- (morpholinomethyl) phenyl] quinoxalin-2-yl] pyrazol-1-yl] -1-piperidyl] -3-oxo-propoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethylamino] -2- (2, 6-dioxo-3-piperidyl) isoindoline-1, 3-dione (JA-043)

JA-043 was synthesized following the standard procedure for preparing JA-001 (7.8 mg, 46.1%yield) . MS (ESI) m/z: 1038.4 [M+H] ⁺.

Example 132. (2S, 4R) -1- [ (2S) -2- [3- [2- [2- [2- [2- [3- [4- [4- [8- [3, 5-Difluoro-4- (morpholinomethyl) phenyl] quinoxalin-2-yl] pyrazol-1-yl] -1-piperidyl] -3-oxo-propoxy] ethoxy] ethoxy] ethoxy] ethoxy] propanoylamino] -3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ [4- (4-methylthiazol-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide (JA-044)

JA-044 was synthesized following the standard procedure for preparing JA-001 (9.1 mg, 45.6%yield) . MS (ESI) m/z: 1223.6 [M+H] ⁺.

Example 133. 4- [2- [3- [4- [4- [8- [3, 5-Difluoro-4- (morpholinomethyl) phenyl] quinoxalin-2-yl] pyrazol-1-yl] -1-piperidyl] -3-oxo-propoxy] ethylamino] -2- (2, 6-dioxo-3-piperidyl) isoindoline-1, 3-dione (JA-045)

JA-045 was synthesized following the standard procedure for preparing JA-001 (6.8 mg, 48.4%yield) . MS (ESI) m/z: 862.3 [M+H] ⁺.

Example 134. (2S, 4R) -1- [ (2S) -2- [ [5- [4- [4- [8- [3, 5-Difluoro-4- (morpholinomethyl) phenyl] quinoxalin-2-yl] pyrazol-1-yl] -1-piperidyl] -5-oxo-pentanoyl] amino] -3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ [4- (4-methylthiazol-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide (JA-046)

JA-046 was synthesized following the standard procedure for preparing JA-001 (7.6 mg, 45.8%yield) . MS (ESI) m/z: 1017.5 [M+H] ⁺.

Example 135. 4- [2- [2- [2- [2- [3- [4- [4- [8- [3, 5-Difluoro-4- (morpholinomethyl) phenyl] quinoxalin-2-yl] pyrazol-1-yl] -1-piperidyl] -3-oxo-propoxy] ethoxy] ethoxy] ethoxy] ethylamino] -2- (2, 6-dioxo-3-piperidyl) isoindoline-1, 3-dione (JA-047)

JA-047 was synthesized following the standard procedure for preparing JA-001 (8.2 mg, 50.5%yield) . MS (ESI) m/z: 994.4 [M+H] ⁺.

Example 136. (2S, 4R) -1- [ (2S) -2- [ [7- [4- [4- [8- [3, 5-Difluoro-4- (morpholinomethyl) phenyl] quinoxalin-2-yl] pyrazol-1-yl] -1-piperidyl] -7-oxo-heptanoyl] amino] -3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ [4- (4-methylthiazol-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide (JA-048)

JA-048 was synthesized following the standard procedure for preparing JA-001 (9.0 mg, 52.8%yield) . MS (ESI) m/z: 1045.5 [M+H] ⁺.

Example 137. 4- [2- [2- [2- [3- [4- [4- [8- [3, 5-Difluoro-4- (morpholinomethyl) phenyl] quinoxalin-2-yl] pyrazol-1-yl] -1-piperidyl] -3-oxo-propoxy] ethoxy] ethoxy] ethylamino] -2- (2, 6-dioxo-3-piperidyl) isoindoline-1, 3-dione (JA-049)

JA-049 was synthesized following the standard procedure for preparing JA-001 (7.8 mg, 50.3%yield) . MS (ESI) m/z: 950.4 [M+H] ⁺.

Example 138. (2S, 4R) -1- [ (2S) -2- [3- [2- [2- [3- [4- [4- [8- [3, 5-Difluoro-4- (morpholinomethyl) phenyl] quinoxalin-2-yl] pyrazol-1-yl] -1-piperidyl] -3-oxo-propoxy] ethoxy] ethoxy] propanoylamino] -3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ [4- (4-methylthiazol-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide (JA-050)

JA-050 was synthesized following the standard procedure for preparing JA-001 (8.3 mg, 44.8%yield) . MS (ESI) m/z: 1135.5 [M+H] ⁺.

Example 139. (2S, 4R) -1- [ (2S) -2- [ [9- [4- [4- [8- [3, 5-Difluoro-4- (morpholinomethyl) phenyl] quinoxalin-2-yl] pyrazol-1-yl] -1-piperidyl] -9-oxo-nonanoyl] amino] -3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ [4- (4-methylthiazol-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide (JA-051)

JA-051 was synthesized following the standard procedure for preparing JA-001 (8.0 mg, 45.7%yield) . MS (ESI) m/z: 1073.5 [M+H] ⁺.

Example 140. (2S, 4R) -1- [ (2S) -2- [ [8- [4- [4- [8- [3, 5-Difluoro-4- (morpholinomethyl) phenyl] quinoxalin-2-yl] pyrazol-1-yl] -1-piperidyl] -8-oxo-octanoyl] amino] -3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ [4- (4-methylthiazol-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide (JA-052)

JA-052 was synthesized following the standard procedure for preparing JA-001 (7.3 mg, 42.2%yield) . MS (ESI) m/z: 1059.5 [M+H] ⁺.

Example 141. (2S, 4R) -1- [ (2S) -2- [ [2- [2- [2- [2- [4- [4- [8- [3, 5-Difluoro-4- (morpholinomethyl) phenyl] quinoxalin-2-yl] pyrazol-1-yl] -1-piperidyl] -2-oxo-ethoxy] ethoxy] ethoxy] acetyl] amino] -3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ [4- (4-methylthiazol-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide (JA-053)

JA-053 was synthesized following the standard procedure for preparing JA-001 (8.9 mg, 49.3%yield) . MS (ESI) m/z: 1107.5 [M+H] ⁺.

Example 142. (2S, 4R) -1- [ (2S) -2- [ [2- [2- [2- [4- [4- [8- [3, 5-Difluoro-4- (morpholinomethyl) phenyl] quinoxalin-2-yl] pyrazol-1-yl] -1-piperidyl] -2-oxo-ethoxy] ethoxy] acetyl] amino] -3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ [4- (4-methylthiazol-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide (JA-054)

JA-054 was synthesized following the standard procedure for preparing JA-001 (8.3 mg, 47.8%yield) . MS (ESI) m/z: 1063.5 [M+H] ⁺.

Example 143. (2S, 4R) -1- [ (2S) -2- [ [2- [2- [2- [2- [2- [2- [4- [4- [8- [3, 5-Difluoro-4- (morpholinomethyl) phenyl] quinoxalin-2-yl] pyrazol-1-yl] -1-piperidyl] -2-oxo-ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] acetyl] amino] -3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ [4- (4-methylthiazol-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide (JA-055)

JA-055 was synthesized following the standard procedure for preparing JA-001 (6.9 mg, 35.4%yield) . MS (ESI) m/z: 1195.5 [M+H] ⁺.

Example 144. (2S, 4R) -1- [ (2S) -2- [3- [2- [3- [4- [4- [8- [3, 5-Difluoro-4- (morpholinomethyl) phenyl] quinoxalin-2-yl] pyrazol-1-yl] -1-piperidyl] -3-oxo-propoxy] ethoxy] propanoylamino] -3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ [4- (4-methylthiazol-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide (JA-056)

JA-056 was synthesized following the standard procedure for preparing JA-001 (6.9 mg, 38.7%yield) . MS (ESI) m/z: 1091.5 [M+H] ⁺.

Example 145. (2S, 4R) -1- [ (2S) -2- [ [2- [2- [4- [4- [8- [3, 5-Difluoro-4- (morpholinomethyl) phenyl] quinoxalin-2-yl] pyrazol-1-yl] -1-piperidyl] -2-oxo-ethoxy] acetyl] amino] -3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ [4- (4-methylthiazol-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide (JA-057)

JA-057 was synthesized following the standard procedure for preparing JA-001 (9.1 mg, 54.7%yield) . MS (ESI) m/z: 1019.4 [M+H] ⁺.

Example 146. (2S, 4R) -1- [ (2S) -2- [3- [3- [4- [4- [8- [3, 5-Difluoro-4- (morpholinomethyl) phenyl] quinoxalin-2-yl] pyrazol-1-yl] -1-piperidyl] -3-oxo-propoxy] propanoylamino] -3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ [4- (4-methylthiazol-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide (JA-058)

JA-058 was synthesized following the standard procedure for preparing JA-001 (9.7 mg, 56.8%yield) . MS (ESI) m/z: 1047.5 [M+H] ⁺.

Example 147. (2S, 4R) -1- [ (2S) -2- [ [11- [4- [4- [8- [3, 5-Difluoro-4- (morpholinomethyl) phenyl] quinoxalin-2-yl] pyrazol-1-yl] -1-piperidyl] -11-oxo-undecanoyl] amino] -3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ [4- (4-methylthiazol-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide (JA-059)

JA-059 was synthesized following the standard procedure for preparing JA-001 (9.0 mg, 50.1%yield) . MS (ESI) m/z: 1101.5 [M+H] ⁺.

Example 148. (2S, 4R) -1- [ (2S) -2- [ [4- [4- [4- [8- [3, 5-Difluoro-4- (morpholinomethyl) phenyl] quinoxalin-2-yl] pyrazol-1-yl] -1-piperidyl] -4-oxo-butanoyl] amino] -3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ [4- (4-methylthiazol-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide (JA-060)

JA-060 was synthesized following the standard procedure for preparing JA-001 (8.9 mg, 54.4%yield) . MS (ESI) m/z: 1003.4 [M+H] ⁺.

Example 149. (2S, 4R) -1- [ (2S) -2- [3- [2- [2- [2- [3- [4- [4- [8- [3, 5-Difluoro-4- (morpholinomethyl) phenyl] quinoxalin-2-yl] pyrazol-1-yl] -1-piperidyl] -3-oxo-propoxy] ethoxy] ethoxy] ethoxy] propanoylamino] -3, 3-dimethyl-butanoyl] -4-hydroxy-N- [ [4- (4-methylthiazol-5-yl) phenyl] methyl] pyrrolidine-2-carboxamide (JA-061)

JA-061 was synthesized following the standard procedure for preparing JA-001 (10.8 mg, 56.1%yield) . MS (ESI) m/z: 1179.5 [M+H] ⁺.

Example 150. (2S, 4R) -1- ( (S) -3, 3-Dimethyl-2- (8- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) -8-oxooctanamido) butanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-062)

JA-062 was synthesized following the standard procedure for preparing JA-010 (7 mg, 60%yield) . MS (ESI) m/z: 1017.4 [M+H] ⁺.

Example 151. (2S, 4R) -1- ( (S) -2- (tert-Butyl) -19- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) -4, 19-dioxo-7, 10, 13, 16-tetraoxa-3-azanonadecanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-063)

JA-063 was synthesized following the standard procedure for preparing JA-010 (6.9mg, 61%yield) . MS (ESI) m/z: 1137.5 [M+H] ⁺.

Example 152. (2S, 4R) -1- ( (S) -2- (tert-Butyl) -14- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) -4, 14-dioxo-6, 9, 12-trioxa-3-azatetradecanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-064)

JA-064 was synthesized following the standard procedure for preparing JA-010 (7.2mg, 70%yield) . MS (ESI) m/z: 1065.4 [M+H] ⁺.

Example 153. (2S, 4R) -1- ( (S) -3, 3-Dimethyl-2- (9- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) -9-oxononanamido) butanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-065)

JA-065 was synthesized following the standard procedure for preparing JA-010 (8.1mg, 78%yield) . MS (ESI) m/z: 1031.5 [M+H] ⁺.

Example 154. (2S, 4R) -1- ( (S) -3, 3-Dimethyl-2- (5- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) -5-oxopentanamido) butanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-066)

JA-066 was synthesized following the standard procedure for preparing JA-010 (6 mg, 70%yield) . MS (ESI) m/z: 975.4 [M+H] ⁺.

Example 155. (2S, 4R) -1- ( (S) -3, 3-Dimethyl-2- (10- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) -10-oxodecanamido) butanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-067)

JA-067 was synthesized following the standard procedure for preparing JA-010 (7.2 mg, 66%yield) . MS (ESI) m/z: 1045.4 [M+H] ⁺.

Example 156. (2S, 4R) -1- ( (S) -2- (tert-Butyl) -16- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) -4, 16-dioxo-7, 10, 13-trioxa-3-azahexadecanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-068)

JA-068 was synthesized following the standard procedure for preparing JA-010 (7.3 mg, 65%yield) . MS (ESI) m/z: 1093.5 [M+H] ⁺.

Example 157. (2S, 4R) -1- ( (S) -3, 3-Dimethyl-2- (4- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) -4-oxobutanamido) butanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-069)

JA-069 was synthesized following the standard procedure for preparing JA-010 (6.3 mg, 61%yield) . MS (ESI) m/z: 961.4 [M+H] ⁺.

Example 158. (2S, 4R) -1- ( (S) -3, 3-Dimethyl-2- (3- (2- (3- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) -3-oxopropoxy) ethoxy) propanamido) butanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-070)

JA-070 was synthesized following the standard procedure for preparing JA-010 (6.3 mg, 61%yield) . MS (ESI) m/z: 1049.4 [M+H] ⁺.

Example 159. (2S, 4R) -1- ( (S) -2- (tert-Butyl) -22- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) -4, 22-dioxo-7, 10, 13, 16, 19-pentaoxa-3-azadocosanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-071)

JA-071 was synthesized following the standard procedure for preparing JA-010 (7.5 mg, 63%yield) . MS (ESI) m/z: 1181.5 [M+H] ⁺.

Example 160. (2S, 4R) -1- ( (S) -3, 3-Dimethyl-2- (2- (2- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) -2-oxoethoxy) acetamido) butanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-072)

JA-072 was synthesized following the standard procedure for preparing JA-010 (6.2 mg, 60%yield) . MS (ESI) m/z: 977.4 [M+H] ⁺.

Example 161. (2S, 4R) -1- ( (S) -3, 3-Dimethyl-2- (2- (2- (2- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) -2-oxoethoxy) ethoxy) acetamido) butanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-073)

JA-073 was synthesized following the standard procedure for preparing JA-010 (4.5 mg, 50%yield) . MS (ESI) m/z: 1021.4 [M+H] ⁺.

Example 162. (2S, 4R) -1- ( (S) -3, 3-Dimethyl-2- (6- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) -6-oxohexanamido) butanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-074)

JA-074 was synthesized following the standard procedure for preparing JA-010 (5.5 mg, 55%yield) . MS (ESI) m/z: 989.4 [M+H] ⁺.

Example 163. 2- (2, 6-Dioxopiperidin-3-yl) -4- ( (2- (2- (3- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) -3-oxopropoxy) ethoxy) ethyl) amino) isoindoline-1, 3-dione (JA-075)

JA-075 was synthesized following the standard procedure for preparing JA-010 (5.6 mg, 56%yield) . MS (ESI) m/z: 864.3 [M+H] ⁺.

Example 164. (2S, 4R) -1- ( (S) -3, 3-Dimethyl-2- (7- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) -7-oxoheptanamido) butanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-076)

JA-076 was synthesized following the standard procedure for preparing JA-010 (6.3 mg, 65%yield) . MS (ESI) m/z: 1003.4 [M+H] ⁺.

Example 165. 2- (2, 6-Dioxo-piperidin-3-yl) -4- (2- {2- [2- (2- {2- [3- (4- {4- [5- (4-methanesulfonyl-phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-ylamino] -phenyl} -piperazin-1-yl) -3-oxo-propoxy] -ethoxy} -ethoxy) -ethoxy] -ethoxy} -ethylamino) -isoindole-1, 3-dione (JA-077)

JA-077 was synthesized following the standard procedure for preparing JA-010 (12 mg, 76%yield) . MS (ESI) m/z: 996.4 [M+H] ⁺.

Example 166. 2- (2, 6-Dioxo-piperidin-3-yl) -4- [7- (4- {4- [5- (4-methanesulfonyl-phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-ylamino] -phenyl} -piperazin-1-yl) -7-oxo-heptylamino] -isoindole-1, 3-dione (JA-078)

JA-078 was synthesized following the standard procedure for preparing JA-010 (11 mg, 70%yield) . MS (ESI) m/z: 832.3 [M+H] ⁺.

Example 167. 2- (2, 6-Dioxo-piperidin-3-yl) -4- {2- [3- (4- {4- [5- (4-methanesulfonyl-phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-ylamino] -phenyl} -piperazin-1-yl) -3-oxo-propoxy] -ethylamino} -isoindole-1, 3-dione (JA-079)

JA-079 was synthesized following the standard procedure for preparing JA-010 (11 mg, 70%yield) . MS (ESI) m/z: 820.3 [M+H] ⁺.

Example 168. 2- (2, 6-Dioxo-piperidin-3-yl) -4- {2- [2- (2- {2- [3- (4- {4- [5- (4-methanesulfonyl-phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-ylamino] -phenyl} -piperazin-1-yl) -3-oxo-propoxy] -ethoxy} -ethoxy) -ethoxy] -ethylamino} -isoindole-1, 3-dione (JA-080)

JA-080 was synthesized following the standard procedure for preparing JA-010 (12 mg, 71%yield) . MS (ESI) m/z: 952.3 [M+H] ⁺.

Example 169. 4-Hydroxy-1- {2- [11- (4- {4- [5- (4-methanesulfonyl-phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-ylamino] -phenyl} -piperazin-1-yl) -11-oxo-undecanoylamino] -3, 3-dimethyl-butyryl} -pyrrolidine-2-carboxylic acid 4- (4-methyl-thiazol-5-yl) -benzylamide (JA-081)

JA-081 was synthesized following the standard procedure for preparing JA-010 (5.2 mg, 51%yield) . MS (ESI) m/z: 1059.5 [M+H] ⁺.

Example 170. 4-Hydroxy-1- (2- {3- [3- (4- {4- [5- (4-methanesulfonyl-phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-ylamino] -phenyl} -piperazin-1-yl) -3-oxo-propoxy] -propionylamino} -3, 3-dimethyl-butyryl) -pyrrolidine-2-carboxylic acid 4- (4-methyl-thiazol-5-yl) -benzylamide (JA-082)

JA-082 was synthesized following the standard procedure for preparing JA-010 (5.5 mg, 50%yield) . MS (ESI) m/z: 1005.4 [M+H] ⁺.

Example 171. (2S, 4R) -1- ( (S) -2- (tert-Butyl) -20- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) -4, 20-dioxo-6, 9, 12, 15, 18-pentaoxa-3-azaicosanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-083)

JA-083 was synthesized following the standard procedure for preparing JA-010 (5.7 mg, 51%yield) . MS (ESI) m/z: 1153.5 [M+H] ⁺.

Example 172. 2- (2, 6-Dioxo-piperidin-3-yl) -4- [8- (4- {4- [5- (4-methanesulfonyl-phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-ylamino] -phenyl} -piperazin-1-yl) -8-oxo-octylamino] -isoindole-1, 3-dione (JA-084)

JA-084 was synthesized following the standard procedure for preparing JA-010 (10 mg, 71%yield) . MS (ESI) m/z: 846.3 [M+H] ⁺.

Example 173. 2- (2, 6-Dioxo-piperidin-3-yl) -4- [2- (2- {2- [3- (4- {4- [5- (4-methanesulfonyl-phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-ylamino] -phenyl} -piperazin-1-yl) -3-oxo-propoxy] -ethoxy} -ethoxy) - ethylamino] -isoindole-1, 3-dione (JA-085)

JA-085 was synthesized following the standard procedure for preparing JA-010 (10 mg, 72%yield) . MS (ESI) m/z: 908.3 [M+H] ⁺.

Example 174. 2- (4- (4- ( (4- ( (3- (N- (tert-Butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) piperazin-1-yl) -N- (2- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethoxy) ethoxy) ethyl) acetamide (JA-086)

JA-086 was synthesized following the standard procedure for preparing JA-015 (17.6 mg, 99%yield) . MS (ESI) m/z: 940.8 [M+H] ⁺.

Example 175. 2- (4- (4- ( (4- ( (3- (N- (tert-Butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) piperazin-1-yl) -N- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethoxy) ethyl) acetamide (JA-087)

JA-087 was synthesized following the standard procedure for preparing JA-015 (9.5 mg, 59%yield) . MS (ESI) m/z: 896.5 [M+H] ⁺.

Example 176. 2- (4- (4- ( (4- ( (3- (N- (tert-Butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) piperazin-1-yl) -N- (2- (2- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethoxy) ethoxy) ethoxy) ethyl) acetamide (JA-088)

JA-088 was synthesized following the standard procedure for preparing JA-015 (11 mg, 62%yield) . MS (ESI) m/z: 984.8 [M+H] ⁺.

Example 177. 2- (4- (4- ( (4- ( (3- (N- (tert-Butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) piperazin-1-yl) -N- (14- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) -3, 6, 9, 12-tetraoxatetradecyl) acetamide (JA-089)

JA-089 was synthesized following the standard procedure for preparing JA-015 (5.6 mg, 30%yield) . MS (ESI) m/z: 1050.8 [M+H] ⁺.

Example 178. 2- (4- (4- ( (4- ( (3- (N- (tert-Butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) piperazin-1-yl) -N- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethyl) acetamide (JA-090)

JA-090 was synthesized following the standard procedure for preparing JA-015 (4 mg, 26%yield) . MS (ESI) m/z: 852.7 [M+H] ⁺.

Example 179. 2- (4- (4- ( (4- ( (3- (N- (tert-Butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) piperazin-1-yl) -N- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) propyl) acetamide (JA-091)

JA-091 was synthesized following the standard procedure for preparing JA-015 (11.7 mg, 75%yield) . MS (ESI) m/z: 866.6 [M+H] ⁺.

Example 180. 2- (4- (4- ( (4- ( (3- (N- (tert-Butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) piperazin-1-yl) -N- (4- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) butyl) acetamide (JA-092)

JA-092 was synthesized following the standard procedure for preparing JA-015 (12.4 mg, 78%yield) . MS (ESI) m/z: 880.8 [M+H] ⁺.

Example 181. 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)

JA-093 was synthesized following the standard procedure for preparing JA-015 (5.9 mg, 37%yield) . MS (ESI) m/z: 894.8 [M+H] ⁺.

Example 182. 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-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) hexyl) acetamide (JA-094)

JA-094 was synthesized following the standard procedure for preparing JA-015 (7.0 mg, 43%yield) . MS (ESI) m/z: 909.1 [M+H] ⁺.

Example 183. 2- (4- (4- ( (4- ( (3- (N- (tert-Butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2- yl) amino) phenyl) piperazin-1-yl) -N- (7- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) heptyl) acetamide (JA-095)

JA-095 was synthesized following the standard procedure for preparing JA-015 (12 mg, 72%yield) . MS (ESI) m/z: 922.9 [M+H] ⁺.

Example 184. 2- (4- (4- ( (4- ( (3- (N- (tert-Butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) piperazin-1-yl) -N- (8- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) octyl) acetamide (JA-096)

JA-096 was synthesized following the standard procedure for preparing JA-015 (9.5 mg, 56%yield) . MS (ESI) m/z: 936.5 [M+H] ⁺.

Example 185. (2S, 4R) -1- ( (S) -2- (2- (2- (4- (4- ( (4- ( (3- (N- (tert-Butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) piperazin-1-yl) acetamido) acetamido) -3, 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-097)

JA-097 was synthesized following the standard procedure for preparing JA-015 (9 mg, 49%yield) . MS (ESI) m/z: 1024.3 [M+H] ⁺.

Example 186. (2S, 4R) -1- ( (S) -2- (3- (2- (4- (4- ( (4- ( (3- (N- (tert-Butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) piperazin-1-yl) acetamido) propanamido) -3, 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-098)

JA-098 was synthesized following the standard procedure for preparing JA-015 (2.7 mg, 14%yield) . MS (ESI) m/z: 1038.7 [M+H] ⁺.

Example 187. (2S, 4R) -1- ( (S) -2- (4- (2- (4- (4- ( (4- ( (3- (N- (tert-Butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) piperazin-1-yl) acetamido) butanamido) -3, 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-099)

JA-099 was synthesized following the standard procedure for preparing JA-015 (3.2 mg, 17%yield) . MS (ESI) m/z: 1051.5 [M+H] ⁺.

Example 188. (2S, 4R) -1- ( (S) -2- (5- (2- (4- (4- ( (4- ( (3- (N- (tert-Butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) piperazin-1-yl) acetamido) pentanamido) -3, 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-100)

JA-100 was synthesized following the standard procedure for preparing JA-015 (4.2 mg, 22%yield) . MS (ESI) m/z: 1066.9 [M+H] ⁺.

Example 189. (2S, 4R) -1- ( (S) -2- (6- (2- (4- (4- ( (4- ( (3- (N- (tert-Butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) piperazin-1-yl) acetamido) hexanamido) -3, 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-101)

JA-101 was synthesized following the standard procedure for preparing JA-015 (8 mg, 41%yield) . MS (ESI) m/z: 1079.8 [M+H] ⁺.

Example 190. (2S, 4R) -1- ( (S) -2- (7- (2- (4- (4- ( (4- ( (3- (N- (tert-Butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) piperazin-1-yl) acetamido) heptanamido) -3, 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-102)

JA-102 was synthesized following the standard procedure for preparing JA-015 (1.04 mg, 5%yield) . MS (ESI) m/z: 1094.2 [M+H] ⁺.

Example 191. (2S, 4R) -1- ( (S) -2- (8- (2- (4- (4- ( (4- ( (3- (N- (tert-Butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) piperazin-1-yl) acetamido) octanamido) -3, 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-103)

JA-103 was synthesized following the standard procedure for preparing JA-015 (3.7 mg, 19%yield) . MS (ESI) m/z: 1108.1 [M+H] ⁺.

Example 192. (2S, 4R) -1- ( (S) -2- (9- (2- (4- (4- ( (4- ( (3- (N- (tert-Butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) piperazin-1-yl) acetamido) nonanamido) -3, 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-104)

JA-104 was synthesized following the standard procedure for preparing JA-015 (6 mg, 30%yield) . MS (ESI) m/z: 1122.4 [M+H] ⁺.

Example 193. (2S, 4R) -1- ( (S) -2- (10- (2- (4- (4- ( (4- ( (3- (N- (tert-Butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) piperazin-1-yl) acetamido) decanamido) -3, 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-105)

JA-105 was synthesized following the standard procedure for preparing JA-015 (9 mg, 44%yield) . MS (ESI) m/z: 1136.2 [M+H] ⁺.

Example 194. (2S, 4R) -1- ( (S) -2- (11- (2- (4- (4- ( (4- ( (3- (N- (tert-Butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) piperazin-1-yl) acetamido) undecanamido) -3, 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-106)

JA-106 was synthesized following the standard procedure for preparing JA-015 (11.4 mg, 55%yield) . MS (ESI) m/z: 1150.8 [M+H] ⁺.

Example 195. N- (tert-Butyl) -3- ( (2- ( (4- (4- (5- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) pentanoyl) piperazin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide (JA-107)

JA-107 was synthesized following the standard procedure for preparing JA-015 (6 mg, 35%yield) . MS (ESI) m/z: 851.9 [M+H] ⁺.

Example 196. (2S, 4R) -1- ( (S) -2- (tert-Butyl) -14- (4- (4- ( (4- ( (3- (N- (tert-butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) piperazin-1-yl) -4, 14-dioxo-6, 9, 12-trioxa-3-azatetradecanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-108)

JA-108 was synthesized following the standard procedure for preparing JA-015 (6 mg, 27%yield) . MS (ESI) m/z: 1113.0 [M+H] ⁺.

Example 197. N- (4- ( (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) butyl) -2- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) acetamide (JA-109)

JA-109 was synthesized following the standard procedure for preparing JA-010 (7.2 mg, 61%yield) . MS (ESI) m/z: 833.3 [M+H] ⁺.

Example 198. N- (2- (2- ( (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethoxy) ethyl) -2- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) acetamide (JA-110)

JA-110 was synthesized following the standard procedure for preparing JA-010 (6.7 mg, 62%yield) . MS (ESI) m/z: 849.3 [M+H] ⁺.

Example 199. N- (3- ( (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) propyl) -2- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) acetamide (JA-111)

JA-111 was synthesized following the standard procedure for preparing JA-010 (7.0 mg, 70%yield) . MS (ESI) m/z: 819.3 [M+H] ⁺.

Example 200. N- (6- ( (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) hexyl) -2- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) acetamid e (JA-112)

JA-112 was synthesized following the standard procedure for preparing JA-010 (7.1 mg, 71%yield) . MS (ESI) m/z: 861.3 [M+H] ⁺.

Example 201. N- (5- ( (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) pentyl) -2- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) acetamide (JA- 113)

JA-113 was synthesized following the standard procedure for preparing JA-010 (6.7 mg, 72%yield) . MS (ESI) m/z: 847.3 [M+H] ⁺.

Example 202. N- (14- ( (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) -3, 6, 9, 12-tetraoxatetradecyl) -2- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) acetamide (JA-114)

JA-114 was synthesized following the standard procedure for preparing JA-010 (7.5 mg, 71%yield) . MS (ESI) m/z: 982.4 [M+H] ⁺.

Example 203. N- (2- (2- (2- ( (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethoxy) ethoxy) ethyl) -2- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) acetamide (JA-115)

JA-115 was synthesized following the standard procedure for preparing JA-010 (6.5 mg, 72%yield) . MS (ESI) m/z: 893.3 [M+H] ⁺.

Example 204. N- (7- ( (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) heptyl) -2- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) acetamide (JA-116)

JA-116 was synthesized following the standard procedure for preparing JA-010 (6.5 mg, 71%yield) . MS (ESI) m/z: 875.4 [M+H] ⁺.

Example 205. N- (2- ( (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethyl) -2- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) acetamide (JA-117)

JA-117 was synthesized following the standard procedure for preparing JA-010 (6.3 mg, 75%yield) . MS (ESI) m/z: 805.3 [M+H] ⁺.

Example 206. N- (8- ( (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) octyl) -2- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) acetamide (JA-118)

JA-118 was synthesized following the standard procedure for preparing JA-010 (7.5 mg, 76%yield) . MS (ESI) m/z: 889.4 [M+H] ⁺.

Example 207. (2S, 4R) -1- ( (S) -3, 3-Dimethyl-2- (3- (2- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) acetamido) propanamido) butanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-119)

JA-119 was synthesized following the standard procedure for preparing JA-010 (6.3 mg, 60%yield) . MS (ESI) m/z: 989.4 [M+H] ⁺.

Example 208. (2S, 4R) -1- ( (S) -3, 3-Dimethyl-2- (10- (2- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) acetamido) decanamido) butanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-120)

JA-120 was synthesized following the standard procedure for preparing JA-010 (5.3 mg, 61%yield) . MS (ESI) m/z: 1088.5 [M+H] ⁺.

Example 209. (2S, 4R) -1- ( (S) -3, 3-Dimethyl-2- (9- (2- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) acetamido) nonanamido) butanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-121)

JA-121 was synthesized following the standard procedure for preparing JA-010 (5.3 mg, 62%yield) . MS (ESI) m/z: 1074.5 [M+H] ⁺.

Example 210. (2S, 4R) -1- ( (S) -3, 3-Dimethyl-2- (6- (2- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) acetamido) hexanamido) butanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-122)

JA-122 was synthesized following the standard procedure for preparing JA-010 (6.1 mg, 60%yield) . MS (ESI) m/z: 1032.5 [M+H] ⁺.

Example 211. (2S, 4R) -1- ( (S) -3, 3-Dimethyl-2- (7- (2- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) acetamido) heptanamido) butanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-123)

JA-123 was synthesized following the standard procedure for preparing JA-010 (5.6 mg, 50%yield) . MS (ESI) m/z: 1046.5 [M+H] ⁺.

Example 212. (2S, 4R) -1- ( (S) -3, 3-Dimethyl-2- (8- (2- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) acetamido) octanamido) butanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-124)

JA-124 was synthesized following the standard procedure for preparing JA-010 (5.4 mg, 55%yield) . MS (ESI) m/z: 1060.5 [M+H] ⁺.

Example 213. (2S, 4R) -1- ( (S) -3, 3-Dimethyl-2- (4- (2- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) acetamido) butanamido) butanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-125)

JA-125 was synthesized following the standard procedure for preparing JA-010 (5.3 mg, 52%yield) . MS (ESI) m/z: 1004.4 [M+H] ⁺.

Example 214. (2S, 4R) -1- ( (S) -3, 3-Dimethyl-2- (2- (2- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) acetamido) acetamido) butanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-126)

JA-126 was synthesized following the standard procedure for preparing JA-010 (5.7 mg, 55%yield) . MS (ESI) m/z: 976.4 [M+H] ⁺.

Example 215. N- (2- (2- (2- (2- ( (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethoxy) ethoxy) ethoxy) ethyl) -2- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) acetamide (JA-127)

JA-127 was synthesized following the standard procedure for preparing JA-010 (7.3 mg, 65%yield) . MS (ESI) m/z: 937.4 [M+H] ⁺.

Example 216. (2S, 4R) -1- ( (S) -3, 3-Dimethyl-2- (11- (2- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) acetamido) undecanamido) butanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-128)

JA-128 was synthesized following the standard procedure for preparing JA-010 (5.3 mg, 55%yield) . MS (ESI) m/z: 1102.5 [M+H] ⁺.

Example 217. N- (17- ( (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) -3, 6, 9, 12, 15-pentaoxaheptadecyl) -2- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) acetamide (JA-129)

JA-129 was synthesized following the standard procedure for preparing JA-010 (6.3 mg, 58%yield) . MS (ESI) m/z: 1025.4 [M+H] ⁺.

Example 218. (2S, 4R) -1- ( (S) -3, 3-Dimethyl-2- (5- (2- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) acetamido) pentanamido) butanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-130)

JA-130 was synthesized following the standard procedure for preparing JA-010 (6.5 mg, 58%yield) . MS (ESI) m/z: 1018.4 [M+H] ⁺.

Example 219. (2S, 4R) -1- ( (S) -2- (tert-Butyl) -17- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) -4, 16-dioxo-6, 9, 12-trioxa-3, 15-diazaheptadecanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-131)

JA-131 was synthesized following the standard procedure for preparing JA-010 (6.3 mg, 55%yield) . MS (ESI) m/z: 1108.5 [M+H] ⁺.

Example 220. (2S, 4R) -1- ( (S) -3, 3-Dimethyl-2- (2- (2- (2- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) acetamido) ethoxy) acetamido) butanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-132)

JA-132 was synthesized following the standard procedure for preparing JA-010 (6.1 mg, 50%yield) . MS (ESI) m/z: 1020.4 [M+H] ⁺.

Example 221. (2S, 4R) -1- ( (S) -20- (tert-Butyl) -1- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) -2, 18-dioxo-6, 9, 12, 15-tetraoxa-3, 19-diazahenicosan-21-oyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-133)

JA-133 was synthesized following the standard procedure for preparing JA-010 (6.1 mg, 52%yield) . MS (ESI) m/z: 1166.5 [M+H] ⁺.

Example 222. (2S, 4R) -1- ( (S) -2- (tert-Butyl) -14- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) -4, 13-dioxo-6, 9-dioxa-3, 12-diazatetradecanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-134)

JA-134 was synthesized following the standard procedure for preparing JA-010 (5.7 mg, 55%yield) . MS (ESI) m/z: 1064.5 [M+H] ⁺.

Example 223. (2S, 4R) -1- ( (S) -14- (tert-Butyl) -1- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) -2, 12-dioxo-6, 9-dioxa-3, 13-diazapentadecan-15-oyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-135)

JA-135 was synthesized following the standard procedure for preparing JA-010 (6.7 mg, 60%yield) . MS (ESI) m/z: 1078.5 [M+H] ⁺.

Example 224. (2S, 4R) -1- ( (S) -3, 3-Dimethyl-2- (3- (2- (2- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) acetamido) ethoxy) propanamido) butanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-136)

JA-136 was synthesized following the standard procedure for preparing JA-010 (6.0 mg, 60%yield) . MS (ESI) m/z: 1034.4 [M+H] ⁺.

Example 225. (2S, 4R) -1- ( (S) -17- (tert-Butyl) -1- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) -2, 15-dioxo-6, 9, 12-trioxa-3, 16-diazaoctadecan-18-oyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-137)

JA-137 was synthesized following the standard procedure for preparing JA-010 (5.0 mg, 61%yield) . MS (ESI) m/z: 1122.5 [M+H] ⁺.

Example 226. (2S, 4R) -1- ( (S) -23- (tert-Butyl) -1- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) -2, 21-dioxo-6, 9, 12, 15, 18-pentaoxa-3, 22-diazatetracosan-24-oyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-138)

JA-138 was synthesized following the standard procedure for preparing JA-010 (6.5 mg, 62%yield) . MS (ESI) m/z: 1210.5 [M+H] ⁺.

Example 227. 2- [4- [4- [8- [3, 5-Difluoro-4- (morpholinomethyl) phenyl] quinoxalin-2-yl] pyrazol-1-yl] -1-piperidyl] -N- [2- [2- [ [2- (2, 6-dioxo-3-piperidyl) -1, 3-dioxo-isoindolin-4-yl] amino] ethoxy] ethyl] acetamide (JA-139)

JA-139 was synthesized following the standard procedure for preparing JA-001 (7.9 mg, 47.4%yield) . MS (ESI) m/z: 891.4 [M+H] ⁺.

Example 228. 2- [4- [4- [8- [3, 5-Difluoro-4- (morpholinomethyl) phenyl] quinoxalin-2-yl] pyrazol-1-yl] -1-piperidyl] -N- [2- [2- [2- [ [2- (2, 6-dioxo-3-piperidyl) -1, 3-dioxo-isoindolin-4-yl] amino] ethoxy] ethoxy] ethyl] acetamide (JA-140)

JA-140 was synthesized following the standard procedure for preparing JA-001 (8.6 mg, 49.1%yield) . MS (ESI) m/z: 935.4 [M+H] ⁺.

Example 229. 2- [4- [4- [8- [3, 5-Difluoro-4- (morpholinomethyl) phenyl] quinoxalin-2-yl] pyrazol-1-yl] -1-piperidyl] -N- [2- [2- [2- [2- [ [2- (2, 6-dioxo-3-piperidyl) -1, 3-dioxo-isoindolin-4-yl] amino] ethoxy] ethoxy] ethoxy] ethyl] acetamide (JA-141)

JA-141 was synthesized following the standard procedure for preparing JA-001 (9.8 mg, 53.5%yield) . MS (ESI) m/z: 979.4 [M+H] ⁺.

Example 230. 2- [4- [4- [8- [3, 5-Difluoro-4- (morpholinomethyl) phenyl] quinoxalin-2-yl] pyrazol-1-yl] -1-piperidyl] -N- [2- [2- [2- [2- [2- [ [2- (2, 6-dioxo-3-piperidyl) -1, 3-dioxo-isoindolin-4-yl] amino] ethoxy] ethoxy] ethoxy] ethoxy] ethyl] acetamide (JA-142)

JA-142 was synthesized following the standard procedure for preparing JA-001 (10.9 mg, 56.9%yield) . MS (ESI) m/z: 1023.4 [M+H] ⁺.

Example 231. 2- [4- [4- [8- [3, 5-Difluoro-4- (morpholinomethyl) phenyl] quinoxalin-2-yl] pyrazol-1-yl] -1-piperidyl] -N- [2- [2- [2- [2- [2- [2- [ [2- (2, 6-dioxo-3-piperidyl) -1, 3-dioxo-isoindolin-4-yl] amino] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethyl] acetamide (JA-143)

JA-143 was synthesized following the standard procedure for preparing JA-001 (9.8 mg, 49.1%yiel) . MS (ESI) m/z: 1067.5 [M+H] ⁺.

Example 232. 2- [4- [4- [8- [3, 5-Difluoro-4- (morpholinomethyl) phenyl] quinoxalin-2-yl] pyrazol-1-yl] -1-piperidyl] -N- [2- [ [2- (2, 6-dioxo-3-piperidyl) -1, 3-dioxo-isoindolin-4-yl] amino] ethyl] acetamide (JA-144)

JA-144 was synthesized following the standard procedure for preparing JA-001 (7.9 mg, 49.8%yield) . MS (ESI) m/z: 847.3 [M+H] ⁺.

Example 233. 2- [4- [4- [8- [3, 5-Difluoro-4- (morpholinomethyl) phenyl] quinoxalin-2-yl] pyrazol-1-yl] -1-piperidyl] -N- [3- [ [2- (2, 6-dioxo-3-piperidyl) -1, 3-dioxo-isoindolin-4-yl] amino] propyl] acetamide (JA-145)

JA-145 was synthesized following the standard procedure for preparing JA-001 (8.1 mg, 50.29%yield) . MS (ESI) m/z: 889.4 [M+H] ⁺.

Example 234. 2- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -N- (4- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) butyl) acetamide (JA-146)

JA-146 was synthesized following the standard procedure for preparing JA-001 (8.0 mg, 48.8%yield) . MS (ESI) m/z: 875.4 [M+H] ⁺.

Example 235. 2- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -N- (6- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) hexyl) acetamide (JA-147)

JA-147 was synthesized following the standard procedure for preparing JA-001 (9.5 mg, 56.2%yield) . MS (ESI) m/z: 903.4 [M+H] ⁺.

Example 236.

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-4-yl) amino) heptyl) acetamide (JA-148)

JA-148 was synthesized following the standard procedure for preparing JA-001 (8.5 mg, 49.5%yield) . MS (ESI) m/z: 917.4 [M+H] ⁺.

Example 237.2- (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-4-yl) amino) octyl) acetamide (JA- 149)

JA-149 was synthesized following the standard procedure for preparing JA-001 (8.9 mg, 51.1%yield) . MS (ESI) m/z: 931.4 [M+H] ⁺.

Example 238. (2S, 4R) -1- ( (S) -2- (11- (2- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) acetamido) undecanamido) -3, 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-150)

JA-150 was synthesized following the standard procedure for preparing JA-001 (10.9 mg, 50.9%yield) . MS (ESI) m/z: 1144.6 [M+H] ⁺.

Example 239. (2S, 4R) -1- ( (S) -17- (tert-Butyl) -1- (4- (4- (8- (3, 5-difluoro-4-

(morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -2, 15-dioxo-6, 9, 12-trioxa-3, 16- diazaoctadecan-18-oyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-151)

JA-151 was synthesized following the standard procedure for preparing JA-001 (10.2 mg, 46.8%yield) . MS (ESI) m/z: 1164.5 [M+H] ⁺.

Example 240. (2S, 4R) -1- ( (S) -2- (4- (2- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) acetamido) butanamido) -3, 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-152)

JA-152 was synthesized following the standard procedure for preparing JA-001 (9.4 mg, 48.0%yield) . MS (ESI) m/z: 1046.5 [M+H] ⁺.

Example 241. (2S, 4R) -1- ( (S) -2- (2- (2- (2- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) acetamido) ethoxy) acetamido) -3, 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-153)

JA-153 was synthesized following the standard procedure for preparing JA-001 (10.3 mg, 51.8%yield) . MS (ESI) m/z: 1062.5 [M+H] ⁺.

Example 242.2- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -N- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) propyl) acetamide (JA- 154)

JA-154 was synthesized following the standard procedure for preparing JA-001 (8.9 mg, 55.2%yield) . MS (ESI) m/z: 861.4 [M+H] ⁺.

Example 243. (2S, 4R) -1- ( (S) -2- (3- (2- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) acetamido) propanamido) -3, 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-155)

JA-155 was synthesized following the standard procedure for preparing JA-001 (8.5 mg, 44.0%yield) . MS (ESI) m/z: 1032.5 [M+H] ⁺.

Example 244. (2S, 4R) -1- ( (S) -2- (8- (2- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) acetamido) octanamido) -3, 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-156)

JA-156 was synthesized following the standard procedure for preparing JA-001 (10.6 mg, 51.4%yield) . MS (ESI) m/z: 1102.5 [M+H] ⁺.

Example 245. (2S, 4R) -1- ( (S) -2- (tert-Butyl) -17- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -4, 16-dioxo-6, 9, 12-trioxa-3, 15-diazaheptadecanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-157)

JA-157 was synthesized following the standard procedure for preparing JA-001 (10.8 mg, 50.2%yield) . MS (ESI) m/z: 1150.5 [M+H] ⁺.

Example 246. (2S, 4R) -1- ( (S) -2- (2- (2- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) acetamido) acetamido) -3, 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-158)

JA-158 was synthesized following the standard procedure for preparing JA-001 (9.2 mg, 48.3%yield) . MS (ESI) m/z: 1018.4 [M+H] ⁺.

Example 247. (2S, 4R) -1- ( (S) -23- (tert-Butyl) -1- (4- (4- (8- (3, 5-difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -2, 21-dioxo-6, 9, 12, 15, 18-pentaoxa-3, 22-diazatetracosan-24-oyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2- carboxamide (JA-159)

JA-159 was synthesized following the standard procedure for preparing JA-001 (10.6 mg, 45.2%yield) . MS (ESI) m/z: 1252.6 [M+H] ⁺.

Example 248. (2S, 4R) -1- ( (S) -2- (3- (2- (2- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) acetamido) ethoxy) propanamido) -3, 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-160)

JA-160 was synthesized following the standard procedure for preparing JA-001 (8.4 mg, 41.7%yield) . MS (ESI) m/z: 1076.5 [M+H] ⁺.

Example 249. (2S, 4R) -1- ( (S) -2- (9- (2- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) acetamido) nonanamido) -3, 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-161)

JA-161 was synthesized following the standard procedure for preparing JA-001 (9.4 mg, 45.0%yield) . MS (ESI) m/z: 1116.6 [M+H] ⁺.

Example 250. (2S, 4R) -1- ( (S) -14- (tert-Butyl) -1- (4- (4- (8- (3, 5-difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -2, 12-dioxo-6, 9-dioxa-3, 13-diazapentadecan-15-oyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-162)

JA-162 was synthesized following the standard procedure for preparing JA-001 (10.6 mg, 50.6%yield) . MS (ESI) m/z: 1120.5 [M+H] ⁺.

Example 251. (2S, 4R) -1- ( (S) -2- (tert-Butyl) -14- (4- (4- (8- (3, 5-difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -4, 13-dioxo-6, 9-dioxa-3, 12-diazatetradecanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-163)

JA-163 was synthesized following the standard procedure for preparing JA-001 (10.8 mg, 52.2%yield) . MS (ESI) m/z: 1106.5 [M+H] ⁺.

Example 252. (2S, 4R) -1- ( (S) -2- (6- (2- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) acetamido) hexanamido) -3, 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-164)

JA-164 was synthesized following the standard procedure for preparing JA-001 (9.8 mg, 48.7%yield) . MS (ESI) m/z: 1074.5 [M+H] ⁺.

Example 253. (2S, 4R) -1- ( (S) -2- (7- (2- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) acetamido) heptanamido) -3, 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-165)

JA-165 was synthesized following the standard procedure for preparing JA-001 (9.5 mg, 46.6%yield) . MS (ESI) m/z: 1088.5 [M+H] ⁺.

Example 254. (2S, 4R) -1- ( (S) -2- (10- (2- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) acetamido) decanamido) -3, 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-166)

JA-166 was synthesized following the standard procedure for preparing JA-001 (9.6 mg, 45.4%yield) . MS (ESI) m/z: 1130.6 [M+H] ⁺.

Example 255. (2S, 4R) -1- ( (S) -20- (tert-Butyl) -1- (4- (4- (8- (3, 5-difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -2, 18-dioxo-6, 9, 12, 15-tetraoxa-3, 19-diazahenicosan-21-oyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-167)

JA-167was synthesized following the standard procedure for preparing JA-001 (9.5 mg, 42.0%yield) . MS (ESI) m/z: 1208.6 [M+H] ⁺.

Example 256. (2S, 4R) -1- ( (S) -2- (5- (2- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) acetamido) pentanamido) -3, 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-168)

JA-168 was synthesized following the standard procedure for preparing JA-001 (9.8 mg, 49.4%yield) . MS (ESI) m/z: 1060.5 [M+H] ⁺.

Example 257. 2- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -N- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) ethoxy) ethyl) acetamide (JA-169)

JA-169 was synthesized following the standard procedure for preparing JA-001 (6.3 mg, 34.1%yield) . MS (ESI) m/z: 891.4 [M+H] ⁺.

Example 258. 2- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -N- (2- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) ethoxy) ethoxy) ethyl) acetamide (JA-170)

JA-170 was synthesized following the standard procedure for preparing JA-001 (7.1 mg, 37.6%yield) . MS (ESI) m/z: 935.4 [M+H] ⁺.

Example 259. 2- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -N- (2- (2- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) ethoxy) ethoxy) ethoxy) ethyl) acetamide (JA-171)

JA-171 was synthesized following the standard procedure for preparing JA-001 (5.6 mg, 30%yield) . MS (ESI) m/z: 979.4 [M+H] ⁺.

Example 260. 2- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -N- (14- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) -3, 6, 9, 12-tetraoxatetradecyl) acetamide (JA-172)

JA-172 was synthesized following the standard procedure for preparing JA-001 (5.1 mg, 27.2%yield) . MS (ESI) m/z: 1023.4 [M+H] ⁺.

Example 261. 2- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -N- (17- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) -3, 6, 9, 12, 15-pentaoxaheptadecyl) acetamide (JA-173)

JA-173 was synthesized following the standard procedure for preparing JA-001 (6.9 mg, 37.7%yield) . MS (ESI) m/z: 1067.5 [M+H] ⁺.

Example 262. 2- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -N- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) ethyl) acetamide (JA-174)

JA-174 was synthesized following the standard procedure for preparing JA-001 (7.1 mg, 40.4%yield) . MS (ESI) m/z: 847.3 [M+H] ⁺.

Example 263. 2- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -N- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) propyl) acetamide (JA-175)

JA-175 was synthesized following the standard procedure for preparing JA-001 (5.9 mg, 38.4%yield) . MS (ESI) m/z: 861.4 [M+H] ⁺.

Example 264. 2- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -N- (4- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) butyl) acetamide (JA-176)

JA-176 was synthesized following the standard procedure for preparing JA-001 (6.9 mg, 40.3%yield) . MS (ESI) m/z: 875.4 [M+H] ⁺.

Example 265. 2- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -N- (5- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) pentyl) acetamide (JA-177)

JA-177 was synthesized following the standard procedure for preparing JA-001 (5.8 mg, 34.6%yield) . MS (ESI) m/z: 889.4 [M+H] ⁺.

Example 266. 2- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -N- (6- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) hexyl) acetamide (JA-178)

JA-178 was synthesized following the standard procedure for preparing JA-001 (6.1 mg, 39.5%yield) . MS (ESI) m/z: 903.4 [M+H] ⁺.

Example 267. 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)

JA-179 was synthesized following the standard procedure for preparing JA-001 (5.4 mg, 35.9%yield) . MS (ESI) m/z: 917.4 [M+H] ⁺.

Example 268. 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)

JA-180 was synthesized following the standard procedure for preparing JA-001 (4.7 mg, 32.3%yield) . MS (ESI) m/z: 931.4 [M+H] ⁺.

Example 269. 5- ( (2- (3- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -3-oxopropoxy) ethyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (JA-181)

JA-181 was synthesized following the standard procedure for preparing JA-001 (5.1 mg, 33.2%yield) . MS (ESI) m/z: 862.3 [M+H] ⁺.

Example 270. 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) isoindoline-1, 3-dione (JA-182)

JA-182 was synthesized following the standard procedure for preparing JA-001 (5.5 mg, 35.1%yield) . MS (ESI) m/z: 846.3 [M+H] ⁺.

Example 271. 5- ( (2- (2- (3- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -3-oxopropoxy) ethoxy) ethyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (JA-183)

JA-183 was synthesized following the standard procedure for preparing JA-001 (5.8 mg, 36.3%yield) . MS (ESI) m/z: 906.4 [M+H] ⁺.

Example 272. 5- ( (2- (2- (2- (3- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -3-oxopropoxy) ethoxy) ethoxy) ethyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (JA-184)

JA-184 was synthesized following the standard procedure for preparing JA-001 (5.9 mg, 37.8%yield) . MS (ESI) m/z: 950.4 [M+H] ⁺.

Example 273. 5- ( (15- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -15-oxo-3, 6, 9, 12-tetraoxapentadecyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (JA-185)

JA-185 was synthesized following the standard procedure for preparing JA-001 (5.2 mg, 33.9%yield) . MS (ESI) m/z: 994.4 [M+H] ⁺.

Example 274. 5- ( (18- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -18-oxo-3, 6, 9, 12, 15-pentaoxaoctadecyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (JA-186)

JA-186 was synthesized following the standard procedure for preparing JA-001 (6.3 mg, 36.4%yield) . MS (ESI) m/z: 1038.4 [M+H] ⁺.

Example 275. 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) isoindoline-1, 3-dione (JA-187)

JA-187 was synthesized following the standard procedure for preparing JA-001 (7.2 mg, 44.1%yield) . MS (ESI) m/z: 888.4 [M+H] ⁺.

Example 276. 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) isoindoline-1, 3-dione (JA-188)

JA-188 was synthesized following the standard procedure for preparing JA-001 (7.6 mg, 45.1%yield) . MS (ESI) m/z: 874.4 [M+H] ⁺.

Example 277. 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) isoindoline-1, 3-dione (JA-189)

JA-189 was synthesized following the standard procedure for preparing JA-001 (6.3 mg, 38.1%yield) . MS (ESI) m/z: 860.4 [M+H] ⁺.

Example 278. 5- ( (3- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -3-oxopropyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (JA-190)

JA-190 was synthesized following the standard procedure for preparing JA-001 (5.7 mg, 40.1%yield) . MS (ESI) m/z: 818.3 [M+H] ⁺.

Example 279. 5- ( (2- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -2-oxoethyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (JA-191)

JA-191was synthesized following the standard procedure for preparing JA-001 (5.7 mg, 34.9%yield) . MS (ESI) m/z: 804.3 [M+H] ⁺.

Example 280. 5- ( (4- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -4-oxobutyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (JA-192)

JA-192 was synthesized following the standard procedure for preparing JA-001 (6.3 mg, 37.9%yield) . MS (ESI) m/z: 832.3 [M+H] ⁺.

Example 281. 2- (2, 6-Dioxopiperidin-3-yl) -5- ( (18- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) -18-oxo-3, 6, 9, 12, 15-pentaoxaoctadecyl) amino) isoindoline-1, 3-dione (JA-193)

JA-193 was synthesized following the standard procedure for preparing JA-010 (6.9 mg, 56%yield) . MS (ESI) m/z: 996.4 [M+H] ⁺.

Example 282. 2- (2, 6-Dioxopiperidin-3-yl) -5- ( (2- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) -2-oxoethyl) amino) isoindoline-1, 3-dione (JA-194)

JA-194 was synthesized following the standard procedure for preparing JA-010 (7.2 mg, 60%yield) . MS (ESI) m/z: 762.2 [M+H] ⁺.

Example 283. 2- (2, 6-Dioxopiperidin-3-yl) -5- ( (2- (3- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) -3-oxopropoxy) ethyl) amino) isoindoline-1, 3-dione (JA-195)

JA-195 was synthesized following the standard procedure for preparing JA-010 (7.0 mg, 61%yield) . MS (ESI) m/z: 820.3 [M+H] ⁺.

Example 284. 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) isoindoline-1, 3-dione (JA-196)

JA-196 was synthesized following the standard procedure for preparing JA-010 (7.2 mg, 62%yield) . MS (ESI) m/z: 804.3 [M+H] ⁺.

Example 285. 2- (2, 6-Dioxopiperidin-3-yl) -5- ( (15- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) -15-oxo-3, 6, 9, 12-tetraoxapentadecyl) amino) isoindoline-1, 3-dione (JA-197)

JA-197 was synthesized following the standard procedure for preparing JA-010 (7.6 mg, 65%yield) . MS (ESI) m/z: 952.4 [M+H] ⁺.

Example 286. 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) isoindoline-1, 3-dione (JA-198)

JA-198 was synthesized following the standard procedure for preparing JA-010 (7.1 mg, 64%yield) . MS (ESI) m/z: 818.3 [M+H] ⁺.

Example 287. 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) isoindoline-1, 3-dione (JA-199)

JA-199 was synthesized following the standard procedure for preparing JA-010 (7.1 mg, 64%yield) . MS (ESI) m/z: 832.3 [M+H] ⁺.

Example 288. 2- (2, 6-Dioxopiperidin-3-yl) -5- ( (2- (2- (2- (3- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) -3-oxopropoxy) ethoxy) ethoxy) ethyl) amino) isoindoline-1, 3-dione (JA-200)

JA-200 was synthesized following the standard procedure for preparing JA-010 (8.3 mg, 65%yield) . MS (ESI) m/z: 908.4 [M+H] ⁺.

Example 289. 2- (2, 6-Dioxopiperidin-3-yl) -5- ( (2- (2- (3- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) -3-oxopropoxy) ethoxy) ethyl) amino) isoindoline-1, 3-dione (JA-201)

JA-201 was synthesized following the standard procedure for preparing JA-010 (7.3 mg, 66%yield) . MS (ESI) m/z: 864.3 [M+H] ⁺.

Example 290. 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) piperazin-1-yl) -3-oxopropyl) amino) isoindoline-1, 3-dione (JA-202)

JA-202 was synthesized following the standard procedure for preparing JA-010 (7.6 mg, 68%yield) . MS (ESI) m/z: 776.3 [M+H] ⁺.

Example 291. 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) piperazin-1-yl) -8-oxooctyl) amino) isoindoline-1, 3-dione (JA-203)

JA-203 was synthesized following the standard procedure for preparing JA-010 (7.1 mg, 65%yield) . MS (ESI) m/z: 846.4 [M+H] ⁺.

Example 292. N- (5- ( (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) pentyl) -2- (4- (4- ( (5-(4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) acetamide (JA-204)

JA-204 was synthesized following the standard procedure for preparing JA-010 (8.1 mg, 67%yield) . MS (ESI) m/z: 847.3 [M+H] ⁺.

Example 293. N- (4- ( (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) butyl) -2- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) acetamide (JA-205)

JA-205 was synthesized following the standard procedure for preparing JA-010 (8.2 mg, 64%yield) . MS (ESI) m/z: 833.3 [M+H] ⁺.

Example 294. N- (14- ( (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) -3, 6, 9, 12- tetraoxatetradecyl) -2- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) acetamide (JA-206)

JA-206 was synthesized following the standard procedure for preparing JA-010 (6.8 mg, 68%yield) . MS (ESI) m/z: 981.4 [M+H] ⁺.

Example 295. N- (2- ( (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) ethyl) -2- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) acetamide (JA-207)

JA-207 was synthesized following the standard procedure for preparing JA-010 (6.8 mg, 68%yield) . MS (ESI) m/z: 805.3 [M+H] ⁺.

Example 296. N- (2- (2- (2- ( (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) ethoxy) ethoxy) ethyl) -2- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) acetamide (JA-208)

JA-208 was synthesized following the standard procedure for preparing JA-010 (7.7 mg, 69%yield) . MS (ESI) m/z: 893.4 [M+H] ⁺.

Example 297. N- (2- (2- (2- (2- ( (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) ethoxy) ethoxy) ethoxy) ethyl) -2- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) acetamide (JA-209)

JA-209 was synthesized following the standard procedure for preparing JA-010 (7.7 mg, 64%yield) . MS (ESI) m/z: 937.4 [M+H] ⁺.

Example 298. N- (3- ( (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) propyl) -2- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) acetamide (JA- 210)

JA-210 was synthesized following the standard procedure for preparing JA-010 (6.9 mg, 71%yield) . MS (ESI) m/z: 819.3 [M+H] ⁺.

Example 299. N- (17- ( (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) -3, 6, 9, 12, 15-pentaoxaheptadecyl) -2- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) acetamide (JA-211)

JA-211 was synthesized following the standard procedure for preparing JA-010 (7.2 mg, 72%yield) . MS (ESI) m/z: 1025.3 [M+H] ⁺.

Example 300. N- (2- (2- ( (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) ethoxy) ethyl) -2- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) acetamide (JA-212)

JA-212 was synthesized following the standard procedure for preparing JA-010 (6.2 mg, 72%yield) . MS (ESI) m/z: 849.3 [M+H] ⁺.

Example 301. 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) piperazin-1-yl) acetamide (JA-213)

JA-213 was synthesized following the standard procedure for preparing JA-010 (7.3 mg, 62%yield) . MS (ESI) m/z: 889.3 [M+H] ⁺.

Example 302. 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) piperazin-1-yl) acetamide (JA-214)

JA-214 was synthesized following the standard procedure for preparing JA-010 (7.1 mg, 66%yield) . MS (ESI) m/z: 875.4 [M+H] ⁺.

Example 303. N- (6- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) hexyl) -2- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) acetamide (JA-215)

JA-215 was synthesized following the standard procedure for preparing JA-010 (7.3 mg, 67%yield) . MS (ESI) m/z: 861.4 [M+H] ⁺.

Example 304. 2- (2, 6-Dioxopiperidin-3-yl) -5- ( (4- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) -4-oxobutyl) amino) isoindoline-1, 3-dione (JA-216)

JA-216 was synthesized following the standard procedure for preparing JA-010 (8.4 mg, 69%yield) . MS (ESI) m/z: 790.3 [M+H] ⁺.

Example 305. (2S, 4R) -1- ( (S) -2- (2- (2- (2- (4- (4- ( (4- ( (3- (N- (tert-butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) piperazin-1-yl) acetamido) ethoxy) acetamido) -3, 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-217)

JA-217 was synthesized following the standard procedure for preparing JA-015 (4 mg, 31%yield) . MS (ESI) m/z: 1067.9 [M+H] ⁺.

Example 306. (2S, 4R) -1- ( (S) -2- (3- (2- (2- (4- (4- ( (4- ( (3- (N- (tert-butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) piperazin-1-yl) acetamido) ethoxy) propanamido) -3, 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-218)

JA-218 was synthesized following the standard procedure for preparing JA-015 (5 mg, 38%yield) . MS (ESI) m/z: 1082.0 [M+H] ⁺.

Example 307. (2S, 4R) -1- ( (S) -14- (tert-butyl) -1- (4- (4- ( (4- ( (3- (N- (tert-butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) piperazin-1-yl) -2, 12-dioxo-6, 9-dioxa-3, 13-diazapentadecan-15-oyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-219)

JA-219 was synthesized following the standard procedure for preparing JA-015 (3 mg, 21%yield) . MS (ESI) m/z: 1126.2 [M+H] ⁺.

Example 308. (2S, 4R) -1- ( (S) -2- (tert-butyl) -17- (4- (4- ( (4- ( (3- (N- (tert-butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) piperazin-1-yl) -4, 16-dioxo-6, 9, 12-trioxa-3, 15-diazaheptadecanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-220)

JA-220 was synthesized following the standard procedure for preparing JA-015 (3 mg, 22%yield) . MS (ESI) m/z: 1156.3 [M+H] ⁺.

Example 309. (2S, 4R) -1- ( (S) -17- (tert-butyl) -1- (4- (4- ( (4- ( (3- (N- (tert-butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) piperazin-1-yl) -2, 15-dioxo-6, 9, 12-trioxa-3, 16-diazaoctadecan-18-oyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-221)

JA-221 was synthesized following the standard procedure for preparing JA-015 (6 mg, 43%yield) . MS (ESI) m/z: 1170.1 [M+H] ⁺.

Example 310. (2S, 4R) -1- ( (S) -20- (tert-butyl) -1- (4- (4- ( (4- ( (3- (N- (tert-butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) piperazin-1-yl) -2, 18-dioxo-6, 9, 12, 15-tetraoxa-3, 19-diazahenicosan-21-oyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-222)

JA-222 was synthesized following the standard procedure for preparing JA-015 (4 mg, 28%yield) . MS (ESI) m/z: 1214.3 [M+H] ⁺.

Example 311. (2S, 4R) -1- ( (S) -23- (tert-butyl) -1- (4- (4- ( (4- ( (3- (N- (tert-butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) piperazin-1-yl) -2, 21-dioxo-6, 9, 12, 15, 18-pentaoxa-3, 22-diazatetracosan-24-oyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (JA-223)

JA-223 was synthesized following the standard procedure for preparing JA-015 (6 mg, 40%yield) . MS (ESI) m/z: 1258.4 [M+H] ⁺.

Example 312. 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-pentaoxaheptadecyl) acetamide (JA-224)

JA-224 was synthesized following the standard procedure for preparing JA-015 (1.3 mg, 6%yield) . MS (ESI) m/z: 1073.0 [M+H] ⁺.

Example 313. 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)

JA-225 was synthesized following the standard procedure for preparing JA-015 (9 mg, 59%yield) . MS (ESI) m/z: 809.7 [M+H] ⁺.

Example 314. N- (tert-butyl) -3- ( (2- ( (4- (4- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) propanoyl) piperazin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide (JA-226)

JA-226 was synthesized following the standard procedure for preparing JA-015 (9 mg, 58%yield) . MS (ESI) m/z: 823.7 [M+H] ⁺.

Example 315. N- (tert-butyl) -3- ( (2- ( (4- (4- (4- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) butanoyl) piperazin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide (JA-227)

JA-227 was synthesized following the standard procedure for preparing JA-015 (9.6 mg, 61%yield) . MS (ESI) m/z: 837.7 [M+H] ⁺.

Example 316. N- (tert-butyl) -3- ( (2- ( (4- (4- (5- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) pentanoyl) piperazin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide (JA-228)

JA-228 was synthesized following the standard procedure for preparing JA-015 (9.5 mg, 59%yield) . MS (ESI) m/z: 851.8 [M+H] ⁺.

Example 317. N- (tert-butyl) -3- ( (2- ( (4- (4- (6- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) hexanoyl) piperazin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide (JA-229)

JA-229 was synthesized following the standard procedure for preparing JA-015 (9 mg, 55%yield) . MS (ESI) m/z: 865.7 [M+H] ⁺.

Example 318. N- (tert-butyl) -3- ( (2- ( (4- (4- (7- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) heptanoyl) piperazin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide (JA-230)

JA-230 was synthesized following the standard procedure for preparing JA-015 (9 mg, 54%yield) . MS (ESI) m/z: 879.8 [M+H] ⁺.

Example 319. 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)

JA-231 was synthesized following the standard procedure for preparing JA-015 (9.6 mg, 57%yield) . MS (ESI) m/z: 893.8 [M+H] ⁺.

Example 320. N- (tert-butyl) -3- ( (2- ( (4- (4- (3- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) ethoxy) propanoyl) piperazin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide (JA-232)

JA-232 was synthesized following the standard procedure for preparing JA-015 (9.9 mg, 61%yield) . MS (ESI) m/z: 867.9 [M+H] ⁺.

Example 321. N- (tert-butyl) -3- ( (2- ( (4- (4- (3- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) ethoxy) ethoxy) propanoyl) piperazin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide (JA-233)

JA-233 was synthesized following the standard procedure for preparing JA-015 (10.2 mg, 60%yield) . MS (ESI) m/z: 911.8 [M+H] ⁺.

Example 322. N- (tert-butyl) -3- ( (2- ( (4- (4- (3- (2- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) ethoxy) ethoxy) ethoxy) propanoyl) piperazin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide (JA-234)

JA-234 was synthesized following the standard procedure for preparing JA-015 (11 mg, 61%yield) . MS (ESI) m/z: 955.8 [M+H] ⁺.

Example 323. N- (tert-butyl) -3- ( (2- ( (4- (4- (1- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) -3, 6, 9, 12-tetraoxapentadecan-15-oyl) piperazin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide (JA-235)

JA-235 was synthesized following the standard procedure for preparing JA-015 (11.5 mg, 61%yield) . MS (ESI) m/z: 999.9 [M+H] ⁺.

Example 324. N- (tert-butyl) -3- ( (2- ( (4- (4- (1- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) -3, 6, 9, 12, 15-pentaoxaoctadecan-18-oyl) piperazin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide (JA-236)

JA-236 was synthesized following the standard procedure for preparing JA-015 (10.5 mg, 54%yield) . MS (ESI) m/z: 1043.9 [M+H] ⁺.

Example 325. 2- (4- (4- ( (4- ( (3- (N- (tert-butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) piperazin-1-yl) -N- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) ethoxy) ethyl) acetamide (JA-237)

JA-237 was synthesized following the standard procedure for preparing JA-015 (7.6 mg, 47%yield) . MS (ESI) m/z: 896.6 [M+H] ⁺.

Example 326. 2- (4- (4- ( (4- ( (3- (N- (tert-butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) piperazin-1-yl) -N- (2- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) ethoxy) ethoxy) ethyl) acetamide (JA-238)

JA-238 was synthesized following the standard procedure for preparing JA-015 (9.7 mg, 57%yield) . MS (ESI) m/z: 940.8 [M+H] ⁺.

Example 327. 2- (4- (4- ( (4- ( (3- (N- (tert-butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) piperazin-1-yl) -N- (2- (2- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) ethoxy) ethoxy) ethoxy) ethyl) acetamide (JA-239)

JA-239 was synthesized following the standard procedure for preparing JA-015 (9.2 mg, 52%yield) . MS (ESI) m/z: 984.8 [M+H] ⁺.

Example 328. 2- (4- (4- ( (4- ( (3- (N- (tert-butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) piperazin-1-yl) -N- (14- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) -3, 6, 9, 12-tetraoxatetradecyl) acetamide (JA-240)

JA-240 was synthesized following the standard procedure for preparing JA-015 (9.2 mg, 50%yield) . MS (ESI) m/z: 1028.8 [M+H] ⁺.

Example 329. 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-5-yl) amino) -3, 6, 9, 12, 15-pentaoxaheptadecyl) acetamide (JA-241)

JA-241 was synthesized following the standard procedure for preparing JA-015 (9.2 mg, 48%yield) . MS (ESI) m/z: 1072.9 [M+H] ⁺.

Example 330. 2- (4- (4- ( (4- ( (3- (N- (tert-butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) piperazin-1-yl) -N- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) ethyl) acetamide (JA-242)

JA-242 was synthesized following the standard procedure for preparing JA-015 (9.2 mg, 60%yield) . MS (ESI) m/z: 852.6 [M+H] ⁺.

Example 331. 2- (4- (4- ( (4- ( (3- (N- (tert-butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) piperazin-1-yl) -N- (4- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) butyl) acetamide (JA-243)

JA-243 was synthesized following the standard procedure for preparing JA-015 (8.8 mg, 55%yield) . MS (ESI) m/z: 880.7 [M+H] ⁺.

Example 332. 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-5-yl) amino) pentyl) acetamide (JA-244)

JA-244 was synthesized following the standard procedure for preparing JA-015 (9.3 mg, 58%yield) . MS (ESI) m/z: 894.6 [M+H] ⁺.

Example 333. 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-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) hexyl) acetamide (JA-245)

JA-245 was synthesized following the standard procedure for preparing JA-015 (11 mg, 67%yield) . MS (ESI) m/z: 908.6 [M+H] ⁺.

Example 334. 2- (4- (4- ( (4- ( (3- (N- (tert-butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) piperazin-1-yl) -N- (7- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) heptyl) acetamide (JA-246)

JA-246 was synthesized following the standard procedure for preparing JA-015 (9.5 mg, 57%yield) . MS (ESI) m/z: 922.7 [M+H] ⁺.

Example 335. 2- (4- (4- ( (4- ( (3- (N- (tert-butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) piperazin-1-yl) -N- (8- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) octyl) acetamide (JA-247)

JA-247 was synthesized following the standard procedure for preparing JA-015 (7.8 mg, 46%yield) . MS (ESI) m/z: 936.7 [M+H] ⁺.

Example 336. 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-oxohept-1-yn-1-yl) isoindoline-1, 3-dione (JA-248)

Step 1: Synthesis of 7- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) hept-6-ynoic acid

A mixture of 5-bromo-2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (100 mg, 298 umol) , Pd (dppf) Cl ₂ (22 mg, 29.8 umol) , hept-6-ynoic acid (56 mg, 447 umol) , CuI (6 mg, 29.8 umol) and DIPEA (116 mg, 894 umol) in DMSO (6 mL) was stirred at 80 ℃ for 16 h. The reaction mixture was purified by reverse-phase chromatography to give the desired product (45 mg, 39%yield) as a light yellow solid. MS (ESI) m/z: 381.1 [M-H] ^-.

Step 2: Synthesis of 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-oxohept-1-yn-1-yl) isoindoline-1, 3-dione

JA-248 was synthesized following the standard procedure for preparing JA-001 (8 mg, 38%yield) as a light yellow solid. MS (ESI) m/z: 813.3 [M+H] ⁺.

Example 337. 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) isoindoline-1, 3-dione (JA-249)

Step 1: Synthesis of 7- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) heptanoic acid

To a solution of 7- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) hept-6-ynoic acid (100 mg, 261 umol) in MeOH (10 mL) was added Pd/C (5.5 mg, 2.6 umol) . The mixture was stirred at 25 ℃ for 16 h under hydrogen atmosphere. The reaction mixture was purified by reverse-phase chromatography to give the desired product (83 mg, 82%yield) as a light yellow solid. MS (ESI) m/z: 385.1 [M-H] ^-.

Step 2: Synthesis of 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) isoindoline-1, 3-dione

JA-249 was synthesized following the standard procedure for preparing JA-001 (10.2 mg, 40 %yield) as a light yellow solid. MS (ESI) m/z: 817.3 [M+H] ⁺.

Example 338. 3- (5- (7- (4- (4- ( (5- (4- (Methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) -7-oxohept-1-yn-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (JA-250)

Step 1: Synthesis of 7- (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) hept-6-ynoic acid

A mixture of 3- (5-bromo-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (100 mg, 311 umol) , Pd (dppf) Cl ₂ (23 mg, 31.1 umol) , hept-6-ynoic acid (59 mg, 467 umol) , CuI (6 mg, 31.1 umol) and DIPEA (120 mg, 931 umol) in DMSO (6 mL) was stirred at 80 ℃ for 16 h. The reaction mixture was purified by reverse-phase chromatography to give the desired product (51 mg, 45%yield) as a light yellow solid. MS (ESI) m/z: 367.1 [M-H] ^-.

Step 2: Synthesis of 3- (5- (7- (4- (4- ( (5- (4- (methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) -7-oxohept-1-yn-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione

JA-250 was synthesized following the standard procedure for preparing JA-001 (8.6 mg, 35%yield) as a light yellow solid. MS (ESI) m/z: 799.3 [M+H] ⁺.

Example 339. 3- (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) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (JA-251)

Step 1: Synthesis of 7- (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) heptanoic acid

A mixture of 7- (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) hept-6-ynoic acid (100 mg, 261 umol) and Pd/C (5.5 mg, 2.6 umol) in MeOH (10 mL) was stirred at 25 ℃ for 16 h. The reaction mixture was purified by reverse-phase chromatography to give the desired product (67 mg, 68%yield) as a light yellow solid. MS (ESI) m/z: 371.2 [M-H] ^-.

Step 2: Synthesis of 3- (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) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione

JA-251 was synthesized following the standard procedure for preparing JA-001 (7.3 mg, 34%yield) as a light yellow solid. MS (ESI) m/z: 803.3 [M+H] ⁺.

Example 340. 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)

Step 1: Synthesis of 2- (2, 6-dioxopiperidin-3-yl) -5- (7-hydroxyhept-1-yn-1-yl) isoindoline-1, 3-dione

A mixture of 5-bromo-2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (100 mg, 298 umol) , Pd (dppf) Cl2 (22 mg, 29.8 umol) , hept-6-yn-1-ol (56 mg, 447 umol) , CuI (6 mg, 29.8 umol) and DIPEA (116 mg, 894 umol) in DMSO (6 mL) was stirred at 80 ℃ for 16 h. The reaction mixture was purified by reverse-phase chromatography to give the desired product (61 mg, 48%yield) as a light yellow solid. MS (ESI) m/z: 369.1 [M+H] ⁺.

Step 2: Synthesis of 7- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) hept-6-yn-1-yl 4-methylbenzenesulfonate

To a solution of 2- (2, 6-dioxopiperidin-3-yl) -5- (7-hydroxyhept-1-yn-1-yl) isoindoline-1, 3-dione (50 mg, 136 umol) and TEA (27 mg, 272 umol) in DCM (5 mL) was added TsCl (39 mg, 204 umol) at room temperature. After the reaction was stirred at room temperature for 16 h, the mixture was concentrated and purified by reverse-phase chromatography to give the desired product (21 mg, 30%yield) as a light yellow solid. MS (ESI) m/z: 523.1 [M+H] ⁺.

Step 3: Synthesis of 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

A mixture of 7- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) hept-6-yn-1-yl 4-methylbenzenesulfonate (10 mg, 12.5 umol) , K ₂CO ₃ (27 mg, 272 umol) , 5- (4- (methylsulfonyl) phenyl) -N- (4-(piperazin-1-yl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-amine (39 mg, 204 umol) and NaI (27 mg, 272 umol) in CH ₃CN (4 mL) was stirred at 80 ℃ for 16 h. The mixture was concentrated and purified by reverse-phase chromatography to give the desired product (6 mg, 30%yield) as a light yellow solid. MS (ESI) m/z: 799.3 [M+H] ⁺.

Example 341. 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) heptyl) isoindoline-1, 3-dione (JA-253)

Step 1: Synthesis of 2- (2, 6-dioxopiperidin-3-yl) -5- (7-hydroxyheptyl) isoindoline-1, 3-dione

A mixture of 2- (2, 6-dioxopiperidin-3-yl) -5- (7-hydroxyhept-1-yn-1-yl) isoindoline-1, 3-dione (100 mg, 261 umol) and Pd/C (5.5 mg, 2.6 umol) in MeOH (10 mL) was stirred at 25 ℃ for 16 h, under hydrogen atmosphere. The reaction mixture was purified by reverse-phase chromatography to give the desired product (76 mg, 80%yield) as a light yellow solid. MS (ESI) m/z: 373.2 [M+H] ⁺.

Step 2: Synthesis of 7- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) heptyl 4-methylbenzenesulfonate

To a solution of 2- (2, 6-dioxopiperidin-3-yl) -5- (7-hydroxyheptyl) isoindoline-1, 3-dione (50 mg, 136 umol) and TEA (27 mg, 272 umol) in DCM (5 mL) was added TsCl (39 mg, 204 umol) at room temperature. After the reaction was stirred at room temperature for 16 h, the mixture was concentrated and purified by reverse-phase chromatography to give the desired product (24 mg, 32%yield) as a light yellow solid. MS (ESI) m/z: 527.2 [M+H] ⁺.

Step 3: Synthesis of 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) heptyl) isoindoline-1, 3-dione

JA-253 was synthesized following the standard procedure for preparing JA-252 (7.5 mg, 36%yield) as a light yellow solid. MS (ESI) m/z: 803.3 [M+H] ⁺.

Example 342. 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) hexyl) amino) isoindoline-1, 3-dione (JA-254)

Step 1: Synthesis of 2- (2, 6-dioxopiperidin-3-yl) -5- ( (6-hydroxyhexyl) amino) isoindoline-1, 3-dione

A mixture of 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (100 mg, 0.36 mmol) , KF (61 mg, 1.08 mmol) and 6-aminohexan-1-ol (64 mg, 0.54 mmol) in DMSO (10 mL) was stirred at 130 ℃ for 16 h. The reaction mixture was purified by reverse-phase chromatography to give the desired product (58 mg, 43%yield) as a little yellow solid. MS (ESI) m/z: 374.2 [M+H] ⁺.

Step 2: Synthesis of 6- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) hexyl 4-methylbenzenesulfonate

To a solution of 2- (2, 6-dioxopiperidin-3-yl) -5- ( (6-hydroxyhexyl) amino) isoindoline-1, 3-dione (50 mg, 136 umol) and TEA (27 mg, 272 umol) in DCM (5 mL) was added TsCl (39 mg, 204 umol) at room temperature. After the reaction was stirred at room temperature for 16 h, the mixture was concentrated and purified by reverse-phase chromatography to give the desired product (31 mg, 46%yield) as a light yellow solid. MS (ESI) m/z: 528.2 [M+H] ⁺.

Step 3: Synthesis 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) hexyl) amino) isoindoline-1, 3-dione

JA-254 was synthesized following the standard procedure for preparing JA-252 (8.9 mg, 39%yield) as a light yellow solid. MS (ESI) m/z: 804.3 [M+H] ⁺.

Example 343. 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) oxy) isoindoline-1, 3-dione (JA-255)

Step 1: Synthesis of 6- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxy) hexanoic acid

A mixture of 2- (2, 6-dioxopiperidin-3-yl) -5-hydroxyisoindoline-1, 3-dione (100 mg, 385 umol) , NaHCO ₃ (81 mg, 769 umol) , 6-bromohexanoic acid (74 mg, 769 umol) and KI (64 mg, 385 umol) in DMSO (10 mL) was stirred at 110 ℃ for 16 h. The reaction mixture was purified by reverse-phase chromatography to give the desired product (65 mg, 44%yield) as a light yellow solid. MS (ESI) m/z: 387.1 [M-H] ^-.

Step 2: Synthesis of 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) oxy) isoindoline-1, 3-dione

JA-255 was synthesized following the standard procedure for preparing JA-252 (7.5 mg, 35%yield) as a light yellow solid. MS (ESI) m/z: 819.3 [M+H] ⁺.

Example 344. 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) hexyl) oxy) isoindoline-1, 3-dione (JA-256)

Step 1: Synthesis of 2- (2, 6-dioxopiperidin-3-yl) -5- ( (6-hydroxyhexyl) oxy) isoindoline-1, 3-dione

A mixture of 2- (2, 6-dioxopiperidin-3-yl) -5-hydroxyisoindoline-1, 3-dione (100 mg, 385 umol) , NaHCO3 (81 mg, 769 umol) , 6-bromohexan-1-ol (74 mg, 769 umol) and KI (64 mg, 385 umol) in DMSO (10 mL) was stirred at 110 ℃ for 16 h. The reaction mixture was purified by reverse-phase chromatography to give the desired product (52 mg, 40%yield) as a light yellow solid. MS (ESI) m/z: 375.1 [M+H] ⁺.

Step 2: Synthesis of 6- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxy) hexyl 4-methylbenzenesulfonate

To a solution of 2- (2, 6-dioxopiperidin-3-yl) -5- ( (6-hydroxyhexyl) oxy) isoindoline-1, 3-dione (50 mg, 136 umol) and TEA (27 mg, 272 umol) in DCM (5 mL) was added TsCl (39 mg, 204 umol) at room temperature. After the reaction was stirred at room temperature for 16 h, the mixture was concentrated and purified by reverse-phase chromatography to give the desired product (31 mg, 46%yield) as a light yellow solid. MS (ESI) m/z: 529.2 [M+H] ⁺.

Step 3: Synthesis of 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) hexyl) oxy) isoindoline-1, 3-dione

JA-256 was synthesized following the standard procedure for preparing JA-252 (10.5 mg, 43%yield) as a light yellow solid. MS (ESI) m/z: 805.3 [M+H] ⁺.

Example 345. 5- (7- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -7-oxoheptyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (JA-257)

JA-257 was synthesized following the standard procedure for preparing JA-001 (7.4 mg, 34%yield) as a light yellow solid. MS (ESI) m/z: 859.4 [M+H] ⁺.

Example 346. 5- (7- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -7-oxohept-1-yn-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (JA-258)

JA-258 was synthesized following the standard procedure for preparing JA-001 (7.9 mg, 37%yield) as a light yellow solid. MS (ESI) m/z: 855.3 [M+H] ⁺.

Example 347. 3- (6- (7- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -7-oxohept-1-yn-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (JA-259)

JA-259 was synthesized following the standard procedure for preparing JA-001 (8.3 mg, 37%yield) as a light yellow solid. MS (ESI) m/z: 841.4 [M+H] ⁺.

Example 348. 5- ( (6- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -6-oxohexyl) oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (JA-260)

JA-260 was synthesized following the standard procedure for preparing JA-001 (9.2 mg, 41%yield) as a light yellow solid. MS (ESI) m/z: 861.3 [M+H] ⁺.

Example 349. 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)

Step 1: Synthesis of tert-butyl 6- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) oxy) hexanoate

A mixture of 3- (5-hydroxy-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (100 mg, 385 umol) , K ₂CO ₃ (106 mg, 769 umol) , NaI (22 mg, 385 umol) and tert-butyl 6- (tosyloxy) hexanoate (263 mg, 769 umol) in DMF (10 mL) was stirred at 80 ℃ for 16 h. The mixture was concentrated and purified by reverse-phase chromatography to give the desired product (32 mg, 22%yield) as a light yellow solid. MS (ESI) m/z: 431.2 [M+H] ⁺.

Step 2: Synthesis of 6- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) oxy) hexanoic acid

To a solution of tert-butyl 6- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) oxy) hexanoate (30 mg, 69.7 umol) in DCM (5 mL) was added TFA (4 mL) . After the reaction was stirred at room temperature for 2 h, the mixture was concentrated and purified by reverse-phase chromatography to give the desired product (24 mg, 92%yield) as a light yellow solid. MS (ESI) m/z: 372.1 [M-H] ^-.

Step 3: Synthesis of 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 was synthesized following the standard procedure for preparing JA-001 (11 mg, 42%yield) as a light yellow solid. MS (ESI) m/z: 805.3 [M+H] ⁺.

Example 350. 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-oxohept-1-yn-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (JA-262)

Step 1: Synthesis of 7- (2- (2, 6-dioxopiperidin-3-yl) -3-oxoisoindolin-5-yl) hept-6-ynoic acid

A mixture of 3- (6-bromo-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (100 mg, 298 umol) , Pd (dppf) Cl ₂ (22 mg, 29.8 umol) , hept-6-ynoic acid (56 mg, 447 umol) , DIPEA (116 mg, 894 umol) and CuI (6 mg, 29.8 umol) in DMSO (6 mL) was stirred at 80 ℃ for 16 h. The reaction mixture was purified by reverse-phase chromatography to give the desired product (49 mg, 45%yield) as a light yellow solid. MS (ESI) m/z: 367.1 [M-H] ^-.

Step 2: Synthesis of 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-oxohept-1-yn-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione

JA-262 was synthesized following the standard procedure for preparing JA-001 (10 mg, 40 %yield) as a light yellow solid. MS (ESI) m/z: 799.3 [M+H] ⁺.

Example 351. 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)

JA-263 was synthesized following the standard procedure for preparing JA-001 (13 mg, 38%yield) as a light yellow solid. MS (ESI) m/z: 847.4 [M+H] ⁺.

Example 352. 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)

A mixture of 7- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) hept-6-yn-1-yl 4-methylbenzenesulfonate (15 mg, 28 umol) , K ₂CO ₃ (12 mg, 84 umol) , NaI (4 mg, 28 umol) and 4- (2, 6-difluoro-4- (3- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) quinoxalin-5-yl) benzyl) morpholine (14 mg, 28 umol) in DMF (10 mL) was stirred at 80 ℃ for 16 h. The mixture was concentrated and purified by reverse-phase chromatography to give the desired product (7.6 mg, 32%yield) as a light yellow solid. MS (ESI) m/z: 841.4 [M+H] ⁺.

Example 353. 5- (7- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) heptyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (JA-265)

JA-265 was synthesized following the standard procedure for preparing JA-264 (8.3 mg, 38%yield) as a light yellow solid. MS (ESI) m/z: 845.4 [M+H] ⁺.

Example 354. 5- ( (6- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) hexyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (JA-266)

JA-266 was synthesized following the standard procedure for preparing JA-264 (6.8 mg, 32%yield) as a light yellow solid. MS (ESI) m/z: 846.4 [M+H] ⁺.

Example 355. 5- ( (6- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) hexyl) oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (JA-267)

JA-267 was synthesized following the standard procedure for preparing JA-264 (9.2 mg, 38%yield) as a light yellow solid. MS (ESI) m/z: 847.4 [M+H] ⁺.

Example 356. 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)

Step 1: Synthesis of 7- (2- (2, 6-dioxopiperidin-3-yl) -3-oxoisoindolin-5-yl) heptanoic acid

To a solution of 7- (2- (2, 6-dioxopiperidin-3-yl) -3-oxoisoindolin-5-yl) hept-6-ynoic acid (100 mg, 261 umol) in MeOH (10 mL) was added Pd/C (5.5 mg, 2.6 umol) . After the reaction was stirred at 25 ℃ for 16 h, the reaction mixture was purified by reverse-phase chromatography to give the desired product (77 mg, 78.4%yield) as a light yellow solid. MS (ESI) m/z: 371.2 [M-H] ^-.

Step 2: Synthesis of 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 was synthesized following the standard procedure for preparing JA-001 (11 mg, 42%yield) as a light yellow solid. MS (ESI) m/z: 803.3 [M+H] ⁺.

Example 357. 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)

JA-269 was synthesized following the standard procedure for preparing JA-001 (7.2 mg, 35%yield) as a light yellow solid. MS (ESI) m/z: 845.4 [M+H] ⁺.

Example 358. 3- (5- (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-270)

JA-270 was synthesized following the standard procedure for preparing JA-001 (8.7 mg, 37%yield) as a light yellow solid. MS (ESI) m/z: 845.4 [M+H] ⁺.

Example 359. 3- (5- (7- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -7-oxohept-1-yn-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (JA-271)

JA-271 was synthesized following the standard procedure for preparing JA-001 (9.3 mg, 39%yield) as a light yellow solid. MS (ESI) m/z: 841.4 [M+H] ⁺.

Example 360 .3- (6- ( (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-272)

JA-272 was synthesized following the standard procedure for preparing JA-001 (7.8 mg, 34%yield) as a light yellow solid. MS (ESI) m/z: 846.4 [M+H] ⁺.

Example 361.3- (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)

JA-273 was synthesized following the standard procedure for preparing JA-001 (9.1 mg, 37%yield) as a light yellow solid. MS (ESI) m/z: 846.4 [M+H] ⁺.

Example 362. 3- (6- ( (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-274)

JA-274 was synthesized following the standard procedure for preparing JA-001 (8.5 mg, 35%yield) as a light yellow solid. MS (ESI) m/z: 847.4 [M+H] ⁺.

Example 363. 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) amino) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (JA-275)

Step 1: Synthesis of 6- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) amino) hexanoic acid

To a solution of 6-oxohexanoic acid (75 mg, 0.58 mmol) and 3- (5-amino-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (100 mg, 0.38 mmol) in DMF (6 mL) was added TMSCl (83 mg, 0.77 mmol) at 0 ℃. After the reaction was stirred at 0 ℃ for 30 min, NaBH ₄ (44 mg, 1.16 mmol) was added to the mixture in two portions. After the reaction was stirred at 0 ℃ for 4 h, the reaction was poured into water (50 mL) and extracted with ethyl acetate (3 × 20 mL) . The combined organic layers were washed with saturated brine (50 mL) , dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The resulting residue was concentrated and purified by reverse-phase chromatography to give the desired product (23 mg, 10%yield) as a light yellow solid. MS (ESI) m/z: 372.2 [M-H] ^-.

Step 2: Synthesis of 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) amino) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione

JA-275 was synthesized following the standard procedure for preparing JA-001 (9.8 mg, 38%yield) as a light yellow solid. MS (ESI) m/z: 804.3 [M+H] ⁺.

Example 364. 3- (6- ( (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) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (JA-276)

Step 1: Synthesis of 6-oxohexanoic acid

To a solution of 6-hydroxyhexanoic acid (500 mg, 3.8 mmol) in DMSO (10 mL) was added IBX (2.1 g, 7.6 mmol) . After the reaction was stirred at room temperature for 16 h, the reaction was poured into water (50 mL) and extracted with ethyl acetate (3 × 20 mL) . The combined organic layers were washed with saturated brine (50 mL) , dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude product (486 mg, 98%yield) was used directly in the next step. MS (ESI) m/z: 129.1 [M-H] ^-.

Step 2: Synthesis of 6- ( (2- (2, 6-dioxopiperidin-3-yl) -3-oxoisoindolin-5-yl) amino) hexanoic acid

To a solution of 6-oxohexanoic acid (75 mg, 0.58 mmol) and 3- (6-amino-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (100 mg, 0.38 mmol) in DMF (6 mL) was added TMSCl (83 mg, 0.77 mmol) at 0 ℃. After the reaction was stirred at 0 ℃ for 30 min, NaBH ₄ (44 mg, 1.16 mmol) was added to the mixture. After the resulting reaction mixture was stirred at 0 ℃ for 4 h, the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (3 × 20 mL) . The combined organic layers were washed with saturated brine (50 mL) , dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by reverse-phase chromatography to give the desired product (18 mg, 8%yield) as a light yellow solid. MS (ESI) m/z: 372.2 [M-H] ^-.

Step 3: Synthesis of 3- (6- ( (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) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione

JA-276 was synthesized following the standard procedure for preparing JA-001 (11 mg, 42%yield) as a light yellow solid. MS (ESI) m/z: 804.3 [M+H] ⁺.

Example 365. 3- (6- ( (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-277)

Step 1: Synthesis of tert-butyl 6- ( (2- (2, 6-dioxopiperidin-3-yl) -3-oxoisoindolin-5-yl) oxy) hexanoate

A mixture of 3- (6-hydroxy-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (100 mg, 385 umol) , K ₂CO ₃ (106 mg, 769 umol) , NaI (22 mg, 385 umol) , tert-butyl 6- (tosyloxy) hexanoate (263 mg, 769 umol) and DMF (10 mL) was stirred at 80 ℃ for 16 h. The reaction mixture was purified by reverse-phase chromatography to give the desired product (35 mg, 23%yield) as a light yellow solid. MS (ESI) m/z: 431.2 [M+H] ⁺.

Step 2: Synthesis of 6- ( (2- (2, 6-dioxopiperidin-3-yl) -3-oxoisoindolin-5-yl) oxy) hexanoic acid

To a solution of tert-butyl 6- ( (2- (2, 6-dioxopiperidin-3-yl) -3-oxoisoindolin-5-yl) oxy) hexanoate (30 mg, 69.7 umol) in DCM (5 mL) was added TFA (4 mL) , before it was stirred at room temperature for 2 h. The mixture was concentrated and purified by reverse-phase chromatography to give the desired product (25 mg, 90%yield) as a light yellow solid. MS (ESI) m/z: 373.1 [M-H] ^-.

Step 3: Synthesis of 3- (6- ( (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-277 was synthesized following the standard procedure for preparing JA-001 (11 mg, 42%yield) as a light yellow solid. MS (ESI) m/z: 805.3 [M+H] ⁺.

Example 366. 3- (3- (6- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -6-oxohexyl) -2-oxo-2, 3-dihydro-1H-benzo [d] imidazol-1-yl) piperidine-2, 6-dione (JA-278)

Step 1: Synthesis of tert-butyl 6- ( (2-nitrophenyl) amino) hexanoate

A mixture of 1-fluoro-2-nitrobenzene (528 mg, 3.74 mmol) , tert-butyl 6-aminohexanoate (841 mg, 4.49 mmol) and TEA (1.14 g, 11.23 mmol) in EtOH (10 mL) was stirred at 85 ℃ overnight. The reaction mixture was concentrated to afford the crude product which was used directly in the next step without further purification.

Step 2: Synthesis of tert-butyl 6- ( (2-aminophenyl) amino) hexanoate

The mixture of tert-butyl 6- ( (2-nitrophenyl) amino) hexanoate (1.2 g, 3.89 mmol) , Pd/C (100 mg) in EtOH (30 mL) was stirred under H ₂ at room temperature for 1.5 h. After the reaction mixture was filtered, the filtrate was concentrated and the residue was purified by silica gel column chromatography (petroleum ether/EtOAc = 8: 1 to 5: 1) to give desired product (690 mg, yield 64%) . (ESI) m/z: 279.7 [M+H] ⁺.

Step 3: Synthesis of tert-butyl 6- (2-oxo-2, 3-dihydro-1H-benzo [d] imidazol-1-yl) hexanoate

To a solution of tert-butyl 6- ( (2-aminophenyl) amino) hexanoate (592 mg, 2.13 mmol) in THF (40 mL) was added CDI (517 mg, 3.19 mmol) . After the resulting mixture was stirred at room temperature for 16 h, the reaction mixture was concentrated and diluted with EtOAc, washed with water. The organic layer was dried over Na ₂SO ₄, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc = 3: 1 to 2: 1) to give desired product (579 mg, yield 89%) . (ESI) m/z: 305.5 [M+H] ⁺.

Step 4: Synthesis of tert-butyl 6- (3- (2, 6-dioxopiperidin-3-yl) -2-oxo-2, 3-dihydro-1H-benzo [d] imidazol-1-yl) hexanoate

To a solution of tert-butyl 6- (2-oxo-2, 3-dihydro-1H-benzo [d] imidazol-1-yl) hexanoate (550 mg, 1.81 mmol) in anhydrous DMF (2.2 ml) was added NaH (56 mg, 2.35 mmol) at 0 ℃ under N ₂. The resulting mixrure was stirred at 0 ℃ for 15 min, before it was added dropwise a solution of 3-bromopiperidine-2, 6-dione (173 mg, 0.90 mmol) in anhydrous DMF (2.2 mL) over 10 min. The reaction mixture was stirred at room temperature overnight, before it was quenched with water and extracted with EtOAc. The aquous phase was adjusted to pH= 5～6 with citric acid and extracted with EtOAc. The combined organic layers were dried over Na ₂SO ₄, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc = 2: 1 to 1: 1) to give desired product (170 mg, yield 23%) . (ESI) m/z: 416.6 [M+H] ⁺.

Step 5: Synthesis of 6- (3- (2, 6-dioxopiperidin-3-yl) -2-oxo-2, 3-dihydro-1H-benzo [d] imidazol-1-yl) hexanoic acid

A mixrue of tert-butyl 6- (3- (2, 6-dioxopiperidin-3-yl) -2-oxo-2, 3-dihydro-1H-benzo [d] imidazol-1-yl) hexanoate (170 mg, 0.41 mmol) in DCM (3 mL) and TFA (3 mL) was stirred at room temperature for 0.5 h. The solvent was removed to afford the desired product (147 mg, yield 99%) . (ESI) m/z: 360.6 [M+H] ⁺.

Step 6: Synthesis of 3- (3- (6- (4- (4- (8- (3, 5-difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H- pyrazol-1-yl) piperidin-1-yl) -6-oxohexyl) -2-oxo-2, 3-dihydro-1H-benzo [d] imidazol-1-yl) piperidine-2, 6-dione (JA-278)

JA-278 was synthesized following the standard procedure for preparing JA-001 (7.4 mg, yield 38%) . MS (ESI) m/z: 833.1 [M+H] ⁺.

Example 367. 3- (3- (7- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -7-oxoheptyl) -2-oxo-2, 3-dihydro-1H-benzo [d] imidazol-1-yl) piperidine-2, 6-dione (JA-279)

JA-279 was synthesized following the standard procedure for preparing JA-278 (9.3 mg, 48%yield) . MS (ESI) m/z: 847.1 [M+H] ⁺.

Example 368. 3- (3- (6- (4- (4- ( (5- (4- (Methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) -6-oxohexyl) -2-oxo-2, 3-dihydro-1H-benzo [d] imidazol-1-yl) piperidine-2, 6-dione (JA-280)

JA-280 was synthesized following the standard procedure for preparing JA-278 (16 mg, 79%yield) . MS (ESI) m/z: 791.0 [M+H] ⁺.

Example 369. 3- (3- (7- (4- (4- ( (5- (4- (Methylsulfonyl) phenyl) - [1, 2, 4] triazolo [1, 5-a] pyridin-2-yl) amino) phenyl) piperazin-1-yl) -7-oxoheptyl) -2-oxo-2, 3-dihydro-1H-benzo [d] imidazol-1-yl) piperidine-2, 6-dione (JA-281)

JA-281 was synthesized following the standard procedure for preparing JA-278 (13 mg, 64%yield) . MS (ESI) m/z: 805.1 [M+H] ⁺.

Example 370. 3- (4- ( (6- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H- pyrazol-1-yl) piperidin-1-yl) -6-oxohexyl) amino) -3-methyl-2-oxo-2, 3-dihydro-1H-benzo [d] imidazol-1-yl) piperidine-2, 6-dione (JA-282)

Step 1: Synthesis of 2- (methylamino) -3-nitrobenzoic acid

A mixture of 2-fluoro-3-nitrobenzoic acid (20 g, 108 mmol) , methylamine hydrochloride (36.47 g, 540 mmol) and DIEA (167.25 g, 1.30 mol) in EtOH (300 mL) was stirred at 80 ℃ for 2 h. After the reaction was concentrated, the residue was poured into ice water, and the pH was adjusted to ～3 with aq. HCl. The aquoes phase was extracted with EtOAc. And the combined organic layers were washed with brine, dried over Na ₂SO ₄, filtered and concentrated to give the desired product (24 g, 99%yield) as a yellow solid which was used directly in the next step.

Step 2: Synthesis of 1-methyl-7-nitro-1, 3-dihydro-2H-benzo [d] imidazol-2-one

A solution of 2- (methylamino) -3-nitrobenzoic acid (24 g, 122.35 mmol) , DPPA (35.71 g, 146.82 mmol) and DIEA (31.63 g, 244.70 mmol) in ^tBuOH (250 mL) was stirred at 90 ℃ overnight. After concentration, the residue was poured into ice water. The precipitate was collected by filtration, washed with water and EtOAc, dried under vacuum to give the desired product (22 g, yield 93%) as a yellow solid. (ESI) m/z: 194.1 [M+H] ⁺.

Step 3: Synthesis of 3- (3-methyl-4-nitro-2-oxo-2, 3-dihydro-1H-benzo [d] imidazol-1-yl) piperidine-2, 6-dione

To a suspension of NaH (48 mg, 1.20 mmol) in DMF (5 mL) was added 3-methyl-5-nitro-1H-benzimidazol-2-one (193 mg, 999.18 umol) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 0.5 h, before a slolution of 3-bromopiperidine-2, 6-dione (383.70 mg, 2.00 mmol) in DMF (5 mL) was added dropwise. After the completion of addition, the reaction mixture was stirred at 80 ℃ for 2 h. After concentration, the resulting residue was purified by prep-HPLC to give the desired product (80 mg, yield 26%) as a black solid. MS (ESI) m/z: 305.3 [M+H] ⁺.

Step 4: Synthesis of 3- (4-amino-3-methyl-2-oxo-2, 3-dihydro-1H-benzo [d] imidazol-1-yl) piperidine-2, 6-dione

To a solution of 3- (3-methyl-4-nitro-2-oxo-benzimidazol-1-yl) piperidine-2, 6-dione (80 mg, 262.93 umol) in MeOH (10 mL) and THF (10 mL) was added Pd/C (20 mg) at room temperature. After the reaction mixture was stirred at room temperature for 1 h under hydrogen atmosphere, the reaction was filtered and concentrated to give the desired product (70 mg, yield 97%) as a brown solid, which was used in the next step directly without further purification. MS (ESI) m/z: 275.3 [M+H] ⁺.

Step 5: Synthesis of 6- ( (1- (2, 6-dioxopiperidin-3-yl) -3-methyl-2-oxo-2, 3-dihydro-1H-benzo [d] imidazol-4-yl) amino) hexanoic acid

A mixture of 3- (4-amino-3-methyl-2-oxo-2, 3-dihydro-1H-benzo [d] imidazol-1-yl) piperidine-2, 6-dione (5 mg, 0.018 mmol) and 6-oxohexanoic acid (4.74 mg, 0.036 mmol) in ⁱPrOH (2 mL) and AcOH (2 mL) was stirred at 90 ℃ for 4 h. After the reaction was cooled to room temperature, NaBH ₃CN (2.3 mg, 0.036 mmol) was added. The reaction mixture was stirred at room temperature for another 2 h, before it was purified by prep-TLC (DCM/MeOH = 10: 1) to give the desired product (3 mg, yield 42%) as a white solid. MS (ESI) m/z: 389.7 [M+H] ⁺.

Step 6: Synthesis of 3- (4- ( (6- (4- (4- (8- (3, 5-difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -6-oxohexyl) amino) -3-methyl-2-oxo-2, 3-dihydro-1H-benzo [d] imidazol-1-yl) piperidine-2, 6-dione (JA-282)

JA-282 was synthesized following the standard procedure for preparing JA-001 (2.0 mg, 23%yield) . MS (ESI) m/z: 862.1 [M+H] ⁺.

Example 371. 3- (4- ( (7- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -7-oxoheptyl) amino) -3-methyl-2-oxo-2, 3-dihydro-1H-benzo [d] imidazol-1-yl) piperidine-2, 6-dione (JA-283)

JA-283 was synthesized following the standard procedure for preparing JA-282 (2.0 mg, 15%yield) . MS (ESI) m/z: 876.2 [M+H] ⁺.

Example 372. 3- (3-Methyl-4- ( (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) -2-oxo-2, 3-dihydro-1H-benzo [d] imidazol-1-yl) piperidine-2, 6-dione (JA-284)

JA-284 was synthesized following the standard procedure for preparing JA-282 (2.0 mg, 24%yield) . MS (ESI) m/z: 820.0 [M+H] ⁺.

Example 373. 3- (3-Methyl-4- ( (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) -2-oxo-2, 3-dihydro-1H-benzo [d] imidazol-1-yl) piperidine-2, 6-dione (JA-285)

JA-285 was synthesized following the standard procedure for preparing JA-282 (2.0 mg, 16%yield) . MS (ESI) m/z: 834.1 [M+H] ⁺.

Example 374. 3- (4- ( (5- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -5-oxopentyl) amino) -3-methyl-2-oxo-2, 3-dihydro-1H-benzo [d] imidazol-1-yl) piperidine-2, 6-dione (JA-286)

JA-286 was synthesized following the standard procedure for preparing JA-282 (4.3 mg, 19%yield) . MS (ESI) m/z: 848.0 [M+H] ⁺.

Example 375. 3- (5- ( (5- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -5-oxopentyl) amino) -3-methyl-2-oxo-2, 3-dihydro-1H-benzo [d] imidazol-1-yl) piperidine-2, 6-dione (JA-287)

JA-287 was synthesized following the standard procedure for preparing JA-282 (2.4 mg, 11%yield) . MS (ESI) m/z: 848.0 [M+H] ⁺.

Example 376. 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) -3-methyl-2-oxo-2, 3-dihydro-1H-benzo [d] imidazol-1-yl) piperidine-2, 6-dione (JA-288)

JA-288 was synthesized following the standard procedure for preparing JA-282 (5.1 mg, 26%yield) . MS (ESI) m/z: 861.9 [M+H] ⁺.

Example 377. 3- (5- ( (7- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -7-oxoheptyl) amino) -3-methyl-2-oxo-2, 3-dihydro-1H-benzo [d] imidazol-1-yl) piperidine-2, 6-dione (JA-289)

JA-289 was synthesized following the standard procedure for preparing JA-282 (3.9 mg, 36%yield) . MS (ESI) m/z: 876.1 [M+H] ⁺.

Example 378. 3- (3-Methyl-4- ( (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) -2-oxo-2, 3-dihydro-1H-benzo [d] imidazol-1-yl) piperidine-2, 6-dione (JA-290)

JA-290 was synthesized following the standard procedure for preparing JA-282 (2.1 mg, 10%yield) . MS (ESI) m/z: 805.9 [M+H] ⁺.

Example 379. 3- (3-Methyl-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) -2-oxo-2, 3-dihydro-1H-benzo [d] imidazol-1-yl) piperidine-2, 6-dione (JA-291)

JA-291 was synthesized following the standard procedure for preparing JA-282 (1.8 mg, 8%yield) . MS (ESI) m/z: 805.8 [M+H] ⁺.

Example 380. 3- (3-Methyl-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) -2-oxo-2, 3-dihydro-1H-benzo [d] imidazol-1-yl) piperidine-2, 6-dione (JA-292)

JA-292 was synthesized following the standard procedure for preparing JA-282 (4.7 mg, 25%yield) . MS (ESI) m/z: 819.9 [M+H] ⁺.

Example 381. 3- (3-Methyl-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) -2-oxo-2, 3-dihydro-1H-benzo [d] imidazol-1-yl) piperidine-2, 6-dione (JA-293)

JA-293 was synthesized following the standard procedure for preparing JA-282 (4.6 mg, 44%yield) . MS (ESI) m/z: 833.9 [M+H] ⁺.

Certain compounds disclosed herein have the structures shown in Table 1B.

Table 1B

Example 382. 5- ( (2- (3- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidine-1-carbonyl) azetidin-1-yl) ethyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (JA-296)

Step 1: Synthesis of tert-butyl 3- (4- (4- (8- (3, 5-difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidine-1-carbonyl) azetidine-1-carboxylate

A mixture of 1- (tert-butoxycarbonyl) azetidine-3-carboxylic acid (30 mg, 0.061 mmol) , 4- (2, 6-difluoro-4- (3- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) quinoxalin-5-yl) benzyl) morpholine (18.46 mg, 0.092 mmol) , HOAT (16.47 mg, 0.122 mmol) , EDCI (23.42 mg, 0.122 mmol) and 4-Methylmorpholine (30.81 mg, 0.305 mmol) in DMSO (2 mL) was stirred at room temperature for 12 h. Then the mixture was purified by C18 flash chromatography to yeild the title compound (40 mg, yield: 97.4%) as yellow solid. MS (ESI) m/z: 674.8 [M+H] ⁺.

Step 2: Synthesis of azetidin-3-yl (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) methanone

To a solution of tert-butyl 3- (4- (4- (8- (3, 5-difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidine-1-carbonyl) azetidine-1-carboxylate (40 mg, 0.059 mmol) in DCM (1 mL) was added TFA (1 mL) . Then it was stirred at room temperature for 2 h. The resulting mixture was concentrated in vacuum to get crude product (38 mg, yield: 100%) as white solid which was used directly in the next step without further purification. MS (ESI) m/z = 574.8 [M+H] ⁺.

Step 3: Synthesis of 5- ( (2- (3- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidine-1-carbonyl) azetidin-1-yl) ethyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione

A mixture of azetidin-3-yl (4- (4- (8- (3, 5-difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) methanone (20 mg, 0.035 mmol) , 2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) ethyl 4-methylbenzenesulfonate (16.49 mg, 0.035 mmol) , sodium iodide (7.9 mg, 0.053 mmol) and DIEA (13.57 mg, 0.106 mmol) in DMSO (1 mL) was heated at 90 ℃. Then it was stirred at the same temperature for 3 h. After addition of water, the solution was extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂SO ₄, and filtered. After the filtrate was concentrated, the residue was purified by Prep-TLC to get the title compound (4.9 mg, yield: 15%) as yellow solid. MS (ESI) m/z = 873.8 [M+H] ⁺.

Example 383. 5- ( (2- (4- (2- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -2-oxoethyl) piperazin-1-yl) ethyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (JA-297)

JA-297 was synthesized following the standard procedure for preparing JA-296 (7.9 mg, yield: 8.3%) . MS (ESI) m/z = 916.5 [M+H] ⁺.

Example 384. 5- ( ( (5- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -5-oxopentyl) (4-methoxybenzyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (JA-298)

Step 1: Synthesis of 5- ( (4-methoxybenzyl) amino) pentanoic acid

To a solution of 5-aminopentanoic acid (1.17 g, 9.99 mmol) and 4-methoxybenzaldehyde (1.36 g, 9.99 mmol) in EtOH (100 mL) was added MgSO ₄ (100 mg, 9.99 mmol) . After the mixture was stirred at 85 ℃for 4 h, it was cooled to rt. To the reaction was added NaBH ₄ (379.53 mg, 9.99 mmol) . The resulting mixture was fitrated, the filtrate was concentrated and purified by prep-HPLC to give the title compound (1.0 g, 42%yield) as a white solid. MS (ESI) m/z = 238.3 [M+H] ⁺.

Step 2: Synthesis of 5- ( ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) (4-methoxybenzyl) amino) pentanoic acid

To a solution of 5- ( (4-methoxybenzyl) amino) pentanoic acid (100 mg, 421.42 umol) in DMSO (5 mL) were added NaI (126.33 mg, 842.84 umol) , DIPEA (217.86 mg, 1.69 mmol) and 5- (bromomethyl) -2-(2, 6-dioxo-3-piperidyl) isoindoline-1, 3-dione (147.98 mg, 421.42 umol) . After the reaction mixture was stirred at rt for 2 h, it was purified by prep-HPLC to give the title compoundd (80 mg, 37%yield) as a white solid. MS (ESI) m/z = 508.4 [M+H] ⁺.

Step 3: Synthesis of 5- ( ( (5- (4- (4- (8- (3, 5-difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -5-oxopentyl) (4-methoxybenzyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione

To a solution of 5- ( ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) (4-methoxybenzyl) amino) pentanoic acid (40 mg, 78.81 umol) and 4- (2, 6-difluoro-4- (3- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) quinoxalin-5-yl) benzyl) morpholine (38.66 mg, 78.81 umol) in DMSO (5 mL) were added HOAT (21.44 mg, 157.62 umol) , EDCI (30.11 mg, 157.62 umol) and TEA (47.85 mg, 472.87 umol) . The resulting mixture was stirred at rt for 16 h, before it was purified by prep-HPLC to give a crude product which was further purified by prep-TLC (DCM/MeOH = 10/1) to give the title compound (50 mg, yield: 65%) as a white solid. MS (ESI) m/z = 980.9 [M+H] ⁺.

Example 385. 5- ( (3- (2- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -2-oxoethoxy) azetidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (JA-299)

JA-299 was synthesized following the standard procedure for preparing JA-298 (35.2 mg, yield: 48%) . MS (ESI) m/z = 874.8 [M+H] ⁺.

Example 386. 5- ( (1- (2- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -2-oxoethyl) piperidin-4-yl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (JA-300)

JA-300 was synthesized following the standard procedure for preparing JA-298 (25 mg, yield: 75%) . MS (ESI) m/z = 887.8 [M+H] ⁺.

Example 387. 5- ( (1- (3- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -3-oxopropyl) piperidin-4-yl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (JA-301)

JA-301 was synthesized following the standard procedure for preparing JA-298 (30 mg, yield: 71%) . MS (ESI) m/z = 901.6 [M+H] ⁺.

Example 388. 5- ( ( (5- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -5-oxopentyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (JA-302)

Step 1: Synthesis of tert-butyl (5- (4- (4- (8- (3, 5-difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -5-oxopentyl) carbamate

To a solution of 5- (tert-butoxycarbonylamino) pentanoic acid (22 mg, 101.26 umol) and 4- [ [2, 6-difluoro-4- [3- [1- (4-piperidyl) pyrazol-4-yl] quinoxalin-5-yl] phenyl] methyl] morpholine (49.67 mg, 101.26 umol) in DMSO (5 mL) were added HOAt (27.54 mg, 202.52 umol) , EDCI (38.68 mg, 202.52 umol) and TEA (40.99 mg, 405.04 umol) at rt. After the mixture was stirred at rt for 16 h, it was purified by prep-HPLC to give the title compound (70 mg, 86%yield) . MS (ESI) m/z = 690.9 [M+H] ⁺.

Step 2: Synthesis of 5-amino-1- (4- (4- (8- (3, 5-difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) pentan-1-one

To a solution of tert-butyl (5- (4- (4- (8- (3, 5-difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -5-oxopentyl) carbamate (70 mg, 87.08 umol) in DCM (2 mL) was added TFA (1 mL) . After the mixture was stirred at rt for 3 h, it was concentrated to give the crude title compound which was used directly in the next step without further purification.

Step 3: Synthesis of 5- ( ( (5- (4- (4- (8- (3, 5-difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -5-oxopentyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione

To a solution of 5-amino-1- (4- (4- (8- (3, 5-difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) pentan-1-one in DMSO (10 mL) was added NaI (26.11 mg, 174.17 umol) , DIPEA (45.02 mg, 348.34 umol) and 5- (bromomethyl) -2- (2, 6-dioxo-3-piperidyl) isoindoline-1, 3-dione (30.58 mg, 87.08 umol) at rt. After completion of addition, the reaction mixture was stirred at rt for 1 h. The reaction solution was purified by prep-HPLC to give crude product 50 mg which was further purified by prep-TLC (DCM/MeOH = 10: 1) to give the title product (18 mg, 24%yield) . MS (ESI) m/z = 860.8 [M+H] ⁺.

Example 389. 5- ( (2- (1- (2- (4- (4- (8- (3, 5-difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -2-oxoethyl) piperidin-4-yl) ethyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (JA-303)

JA-303 was synthesized following the standard procedure for preparing JA-298 (8.4 mg, yield: 20%) . MS (ESI) m/z = 915.7 [M+H] ⁺.

Example 390. 5- ( ( (1- (2- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -2-oxoethyl) piperidin-4-yl) methyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (JA-304)

JA-304 was synthesized following the standard procedure for preparing JA-298 (3.3 mg, yield: 11%) . MS (ESI) m/z = 901.7 [M+H] ⁺.

Example 391. 5- ( ( (1- (3- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -3-oxopropyl) piperidin-4-yl) methyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (JA-305)

JA-305 was synthesized following the standard procedure for preparing JA-298 (3.5 mg, yield: 13%) . MS (ESI) m/z = 915.8 [M+H] ⁺.

Example 392. 5- (3- (3- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -3-oxopropoxy) azetidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (JA-306)

JA-306 was synthesized following the standard procedure for preparing JA-298 (60.2 mg, yield: 51%) . MS (ESI) m/z = 874.9 [M+H] ⁺.

Example 393. 5- ( ( (4- (2- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -2-oxoethyl) morpholin-2-yl) methyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (JA-307)

JA-307 was synthesized following the standard procedure for preparing JA-298 (17 mg, yield: 82%) . MS (ESI) m/z = 903.8 [M+H] ⁺.

Example 394. 5- ( ( (1- (3- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -3-oxopropyl) piperidin-4-yl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (JA-308)

JA-308 was synthesized following the standard procedure for preparing JA-302 (21 mg, yield: 35%) . MS (ESI) m/z = 915.8 [M+H] ⁺.

Example 395. 5- (3- (3- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidine-1-carbonyl) azetidin-1-yl) propyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (JA-309)

JA-309 was synthesized following the standard procedure for preparing JA-296 (1.08 mg, yield: 5%) . MS (ESI) m/z = 872.9 [M+H] ⁺.

Example 396. 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)

Step 1: Synthesis of tert-butyl (3- (4- (4- (8- (3, 5-difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) phenyl) carbamate

To a solution of 4- (2, 6-difluoro-4- (3- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) quinoxalin-5-yl) benzyl) morpholine (520 mg, 1.06 mmol) in dioxane (10 mL) were added tert-butyl (3-bromophenyl) carbamate (573 mg, 2.12 mmol) , Pd ₂ (dba) ₃ (194 mg, 0.21 mmol) , XantPhos (184 mg, 0.32 mmol) and ^tBuONa (305 mg, 3.18 mmol) under Ar atmosphere. After the mixture was stirred at 110 ℃overnight, the mixture was purified by silica gel column chromatography to give the title compound (117 mg, yield: 24%) as white solid. MS (ESI) m/z = 682.7 [M+H] ⁺.

Step 2: Synthesis of 3- (4- (4- (8- (3, 5-difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) aniline

A mixture of (3- (4- (4- (8- (3, 5-difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) phenyl) carbamate (117 mg, 0.17 mmol) and TFA (2 mL) in DCM (4 mL) was stirred at rt for 1 h. After the solvent was removed, the residue was dissolved with DCM. The resulting solution was washed with saturated aqueous NaHCO ₃. The organic layer was dried over Na ₂SO ₄, filtered and concentrated to give the title compound (77 mg, yield: 77%) as white solid. MS (ESI) m/z = 582.6 [M+H] ⁺.

Step 3: Synthesis 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

The mixture of CDI (16.2 mg, 0.1 mmol) and DIEA (46 mg, 0.36 mmpl) in anhydrous DMF (1.5 mL) was stirred at rt for 10 min, before 5- (aminomethyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (26 mg, 0.09 mmol) was added to above mixture. After the reaction mixture was stirred at rt for 2 h, 3- (4- (4- (8- (3, 5-difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) aniline (52 mg, 0.09 mmol) was added. The reaction was stirred at 60 ℃ for 16 h, before the mixture was purified by prep-TLC (MeOH: DCM = 1: 13) to give the title compound (20.3 mg, yield: 25%) as white solid. MS (ESI) m/z = 895.8 [M+H] ⁺.

Example 397. 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)

JA-311 was synthesized following the standard procedure for preparing JA-298 (80 mg, yield: 49%) . MS (ESI) m/z = 875.9 [M+H] ⁺.

Example 398. 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, 3-dioxoisoindolin-5-yl) methyl) -5-oxopentanamide (JA-312)

Step 1: Synthesis of 5- (4- (4- (8- (3, 5-difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -5-oxopentanoic acid

To a solution of 4- [ [2, 6-difluoro-4- [3- [1- (4-piperidyl) pyrazol-4-yl] quinoxalin-5-yl] phenyl] methyl] morpholine (56 mg, 99.38 umol) and tetrahydropyran-2, 6-dione (11.34 mg, 99.38 umol) in DMSO (5 mL) was added DIPEA (51.38 mg, 397.54 umol) at rt. After the mixture was stirred at 80 ℃for 0.5 h, it was purified by prep-HPLC to give the title compound (65 mg, 79%yield) as yellow solid. MS (ESI) m/z = 605.7 [M+H] ⁺.

Step 2: Synthesis of 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, 3-dioxoisoindolin-5-yl) methyl) -5-oxopentanamide

To a solution of 5- [4- [4- [8- [3, 5-difluoro-4- (morpholinomethyl) phenyl] quinoxalin-2-yl] pyrazol-1-yl] -1-piperidyl] -5-oxo-pentanoic acid (60 mg, 83.49 umol) and 5- (aminomethyl) -2- (2, 6-dioxo-3-piperidyl) isoindoline-1, 3-dione (23.98 mg, 59.77 umol) in DMSO (5 mL) was added HOAt (22.71 mg, 166.98 umol) , EDCI (31.89 mg, 166.98 umol) and TEA (84.48 mg, 834.88 umol) at rt. After the mixture was stirred at rt for 16 h, it was purified by prep-HPLC to give a crude product which was further purified by prep-TLC (DCM/MeOH = 10: 1) to give the title compound (60 mg, 82%yield) . MS (ESI) m/z = 874.9 [M+H] ⁺.

Example 399. 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)

JA-313 was synthesized following the standard procedure for preparing JA-317 (2.02 mg, yield: 10%) . MS (ESI) m/z = 916.8 [M+H] ⁺.

Example 400. 5- (2- (3- (2- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -2-oxoethyl) azetidin-1-yl) ethyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (JA-314)

JA-314 was synthesized following the standard procedure for preparing JA-298 (12.2 mg, yield: 28%) . MS (ESI) m/z = 873.0 [M+H] ⁺.

Example 401. 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-oxopentanamide (JA-315)

JA-315 was synthesized following the standard procedure for preparing JA-298 (89 mg, yield: 60%) . MS (ESI) m/z = 896.8 [M+H] ⁺.

Example 402. 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-oxopentanamide (JA-316)

JA-316 was synthesized following the standard procedure for preparing JA-298 (69 mg, yield: 49%) . MS (ESI) m/z = 911.0 [M+H] ⁺.

Example 403. 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)

Step 1: Synthesis of ethyl 2- (3- (4- (4- (8- (3, 5-difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) phenyl) -2, 2-difluoroacetate

A mixture of 4- (2, 6-difluoro-4- (3- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) quinoxalin-5-yl) benzyl) morpholine hydrochloride (50 mg, 0.1 mmol) in 1, 4-dioxane (3 mL) was added ethyl 2- (3-bromophenyl) -2, 2-difluoroacetate (28 mg, 0.1 mmol) , Cs ₂CO ₃ (98 mg, 0.3 mmol) , Xantphos (11.5 mg, 0.02 mmol) and Pd ₂ (dba) ₃ (9 mg, 0.01 mmol) . The resulting mixture was heated to 100 ℃ and stirred for 16 h under N ₂ atmosphere. The mixture was diluted with water and extracted with EtOAc (3 x) . The combined organic layers were washed with brine, dried over Na ₂SO ₄, concentrated in vacuum. The resulting residue was purified by revere phase chromatography to afford the title compound (47 mg, 72%yield) as light brown solid. MS (ESI) m/z = 689.7 [M+H] ⁺.

Step 2: Synthesis of 2- (3- (4- (4- (8- (3, 5-difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) phenyl) -2, 2-difluoroacetic acid

To a mixture of ethyl 2- (3- (4- (4- (8- (3, 5-difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) phenyl) -2, 2-difluoroacetate (47 mg, 0.068 mmol) in MeOH (5 mL) and H ₂O (5 mL) was added NaOH (27 mg, 0.68 mmol) . The reaction mixture was stirred at rt for 3 h, before the solvent was removed in vacuum. The residue was dissolved in H ₂O and the pH was adjusted to 3. The mixture was diluted DCM and extracted with DCM (3x) . The combined organic layers were washed with brine, dried over Na ₂SO ₄ and concentrated in vacuum to give the title compound (28 mg, yield: 62%) as light brown solid. MS (ESI) m/z = 661.7 [M+H] ⁺.

Step 3: Synthesis of 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

To a mixture of 2- (3- (4- (4- (8- (3, 5-difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) phenyl) -2, 2-difluoroacetic acid (14 mg, 0.02 mmol) and HOAt (5 mg, 0.04 mmol) , EDCI (8 mg, 0.04 mmol) in DMSO (1 mL) were added NMM (10 mg, 0.1 mmol) and 5- (aminomethyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (6 mg, 0.02 mmol) . After the mixture was stirred at 25 ℃ for 16 h, the mixture was purified by prep-TLC to give the title compound (2.05 mg, yield: 10%) as light yellow solid. MS (ESI) m/z = 930.9 [M+H] ⁺.

Example 404. 5- (3- (4- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -4-oxobutyl) azetidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (JA-318)

JA-318 was synthesized following the standard procedure for preparing JA-298 (1.46 mg, yield: 16%) . MS (ESI) m/z = 872.9 [M+H] ⁺.

Example 405. 5- ( (2- (4- (2- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -2-oxoethyl) morpholin-2-yl) ethyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (JA-319)

JA-319 was synthesized following the standard procedure for preparing JA-298 (28 mg, yield: 75%) . MS (ESI) m/z = 917.9 [M+H] ⁺.

Example 406. 5- ( (3- (3- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -3-oxopropyl) azetidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (JA-320)

JA-320 was synthesized following the standard procedure for preparing JA-298 (18 mg, yield: 65%) . MS (ESI) m/z = 873.0 [M+H] ⁺.

Example 407. 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)

Step 1: Synthesis of tert-butyl 4- (4-bromo-2, 6-difluorobenzyl) piperazine-1-carboxylate

To a mixture of 4-bromo-3, 5-difluoro-benzaldehyde (2.0 g, 9.1 mmol) and tert-butyl piperazine-1-carboxylate (2.53 g, 13.6 mmol) in DCE (25 mL) were added NaBH (OAc) ₃ (2.30 g, 10.9 mmol) and AcOH (54.3 mg, 0.9 mmol) . The reaction was degassed three times and stirred at rt overnight. The reaction was quenched with water, and extracted with DCM. The organic layer was washed with brine, dried over Na ₂SO ₄, filtered and concentrated. The residue was purified by silica gel chromatography (0-20%EtOAc in petroleum ether) to afford the title compound (3.2 g, yield: 90%) as white solid. MS (ESI) m/z = 391.3 [M+H] ⁺.

Step 2: Synthesis of (4- ( (4- (tert-butoxycarbonyl) piperazin-1-yl) methyl) -3, 5-difluorophenyl) boronic acid

To a mixture of tert-butyl 4- [ (4-bromo-3, 5-difluoro-phenyl) methyl] piperazine-1-carboxylate (2.7 g, 6.9 mmol) and 4, 4, 5, 5-tetramethyl-2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 3, 2-dioxaborolane (2.63 g, 10.4 mmol) in dioxane (30 mL) were added KOAc (1.69 g, 17.3 mmol) and Pd (dppf) Cl ₂ (504 mg, 690 umol) . The reaction was degassed three times and stirred at 90 ℃ for 2 h. The solution was quenched with water, and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂SO ₄, filtered and concentrated. The residue was purified by silica gel chromatography (0-30%EtOAc in petroleum ether) to afford the title compound (2.4 g, yield: 98%) as light yellow solid. MS (ESI) m/z = 357.2 [M+H] ⁺.

Step 3: Synthesis of 8-bromo-2- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) quinoxaline

To a solution of tert-butyl 4- [4- (8-bromoquinoxalin-2-yl) pyrazol-1-yl] piperidine-1-carboxylate (1.0 g, 2.2 mmol) in DCM (10 mL) was added TFA (2 mL) . After the reaction was stirred at rt for 4 h, the mixture was concentrated and quenched with aqueous Na ₂CO ₃. The mixture was extracted with DCM. The organic layer was washed with brine, dried over Na ₂SO ₄, filtered and concentrated. The crude residue was purified by silica gel chromatography (0-70%EtOAc in petroleum ether) to afford the title compound (690 mg, yield: 88%) as white solid. MS (ESI) m/z = 358.2 [M+H] ⁺.

Step 4: Synthesis of (9H-fluoren-9-yl) methyl 4- (4- (8-bromoquinoxalin-2-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate

To a solution of 8-bromo-2- [1- (4-piperidyl) pyrazol-4-yl] quinoxaline (100 mg, 279.15 umol) in dioxane (2 mL) were added FmocCl (135 mg, 419 umol) and Na ₂CO ₃ (59 mg, 558 umol) . After the reaction was stirred at rt for 3 h, the mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂SO ₄, filtered and concentrated. The crude residue was purified by silica gel chromatography (0-70%EtOAc in petroleum ether) to afford the title compound (130 mg, yield: 80%) as white solid. MS (ESI) m/z = 580.4 [M+H] ⁺.

Step 5: Synthesis of tert-butyl 4- (4- (3- (1- (1- ( ( (9H-fluoren-9-yl) methoxy) carbonyl) piperidin-4-yl) -1H-pyrazol-4-yl) quinoxalin-5-yl) -2, 6-difluorobenzyl) piperazine-1-carboxylate

To a mixture of 9H-fluoren-9-ylmethyl 4- [4- (8-bromoquinoxalin-2-yl) pyrazol-1-yl] piperidine-1-carboxylate (610 mg, 1.1 mmol) and [4- [ (4-tert-butoxycarbonylpiperazin-1-yl) methyl] -3, 5-difluoro-phenyl] boronic acid (748 mg, 2.10 mmol) in water (2 mL) and dioxane (8 mL) were added K ₂CO ₃ (290 mg, 2.1 mmol) and Pd (dppf) Cl ₂ (76.82 mg, 105 umol) . After the reaction mixture was stirred at 90 ℃ for 1 h, the reaction was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂SO ₄, filtered and concentrated. The crude residue was purified by silica gel chromatography (0-70%EtOAc in petroleum ether) to afford the title compound (200 mg, yield: 23%) as white solid. MS (ESI) m/z = 813.0 [M+H] ⁺.

Step 6: Synthesis of tert-butyl 4- (2, 6-difluoro-4- (3- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) quinoxalin-5-yl) benzyl) piperazine-1-carboxylate

A solution of tert-butyl 4- [ [4- [3- [1- [1- (9H-fluoren-9-ylmethoxycarbonyl) -4-piperidyl] pyrazol-4-yl] quinoxalin-5-yl] -2, 6-difluoro-phenyl] methyl] piperazine-1-carboxylate (200 mg, 246 umol) in DMF (2 mL) and piperidine (0.4 mL) was stirred at rt for 1 h. After the mixture was quenched with water and extracted with EtOAc, the organic layer was washed with brine, dried over Na ₂SO ₄, filtered and concentrated. The crude residue was purified by silica gel chromatography (0-70%EtOAc in petroleum ether) to afford the title compound (100 mg, yield: 69%) as white solid. MS (ESI) m/z = 590.7 [M+H] ⁺.

Step 7: Synthesis of tert-butyl 4- (4- (3- (1- (1- (6- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) hexanoyl) piperidin-4-yl) -1H-pyrazol-4-yl) quinoxalin-5-yl) -2, 6-difluorobenzyl) piperazine-1-carboxylate

To a mixture of 6- [ [2- (2, 6-dioxo-3-piperidyl) -1, 3-dioxo-isoindolin-5-yl] amino] hexanoic acid (20 mg, 52 umol) and tert-butyl 4- [ [2, 6-difluoro-4- [3- [1- (4-piperidyl) pyrazol-4-yl] quinoxalin-5-yl] phenyl] methyl] piperazine-1-carboxylate (36 mg, 62 umol) in DMSO (1 mL) were added EDCI (16 mg, 103 umol) , HOAT (14 mg, 103 umol) and NMM (16 mg, 155 umol) . The reaction was stirred at rt overnight. The solution was purified by C18 chromatography (0-70%MeCN in H ₂O) to give the title compound (40 mg, yield: 81%) as yellow solid. MS (ESI) m/z = 960.1 [M+H] ⁺.

Step 8: Synthesis of 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

To a solution of tert-butyl 4- [ [4- [3- [1- [1- [6- [ [2- (2, 6-dioxo-3-piperidyl) -1, 3-dioxo-isoindolin-5-yl] amino] hexanoyl] -4-piperidyl] pyrazol-4-yl] quinoxalin-5-yl] -2, 6-difluoro-phenyl] methyl] piperazine-1-carboxylate (40 mg, 42 umol) in methanol (0.5 mL) was added HCl solution (4 M in dioxane, 0.5 mL) . After the reaction was stirred at rt for 30 min, the solution was purified by C18 chromatography (0-70%MeCN in H ₂O) to give the title compound (30.7 mg, yield: 86%) as yellow solid. MS (ESI) m/z = 859.8 [M+H] ⁺.

Example 408. 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)

JA-322 was synthesized following the standard procedure for preparing JA-321 (71.3 mg, yield: 70%) . MS (ESI) m/z = 791.8 [M+H] ⁺.

Example 409. 5- ( (6- (4- (4- (8- (3, 5-Difluoro-4- ( (4-hydroxypiperidin-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)

JA-323 was synthesized following the standard procedure for preparing JA-321 (45.7 mg, yield: 41%) . MS (ESI) m/z = 874.9 [M+H] ⁺.

Example 410. 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)

JA-324 was synthesized following the standard procedure for preparing JA-321 (46.6 mg, yield: 41%) . MS (ESI) m/z = 873.9 [M+H] ⁺.

Example 411. 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 (JA-325)

JA-325 was synthesized following the standard procedure for preparing JA-310 (12 mg, yield: 40%) . MS (ESI) m/z = 881.9 [M+H] ⁺.

Example 412. 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-oxoisoindolin-5-yl) methyl) urea (JA-326)

JA-326 was synthesized following the standard procedure for preparing JA-311 (49 mg, yield: 64%) . MS (ESI) m/z = 861.9 [M+H] ⁺.

Example 413. 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-difluoropentanamide (JA-327)

JA-327 was synthesized following the standard procedure for preparing JA-313 (18 mg, yield: 93%) . MS (ESI) m/z = 882.8 [M+H] ⁺.

Example 414. 4- (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) butane-1-sulfonamide (JA-331)

Step 1: Synthesis of 4- (4- (4- (8- (3, 5-difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) butane-1-sulfonic acid

To a solution of 4- [ [2, 6-difluoro-4- [3- [1- (4-piperidyl) pyrazol-4-yl] quinoxalin-5-yl] phenyl] methyl] morpholine (200 mg, 379.50 umol) and oxathiane 2, 2-dioxide (77.51 mg, 569.25 umol) in DMSO (20 mL) was added DIPEA (196.19 mg, 1.52 mmol) . After the reaction mixture was stirred at rt for 16 h, it was purified by prep-HPLC to give the title compound (200 mg, 84%yield) . MS (ESI) m/z = 627.8 [M+H] ⁺.

Step 2: Synthesis of 4- (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) butane-1-sulfonamide

A suspension of 4- [4- [4- [8- [3, 5-difluoro-4- (morpholinomethyl) phenyl] quinoxalin-2-yl] pyrazol-1-yl] -1-piperidyl] butane-1-sulfonic acid (60 mg, 95.74 umol) in DCM (10 mL) was added (COCl) ₂ (95.74 umol) and DMF (7.00 mg, 95.74 umol) at 0 ℃. After completion of addition, the reaction mixture was stirred at 0 ℃ for another 2 h. Then, the reaction was concentrated to give the crude product which was dissolved in DCM (10 mL) . To the resulting mixture was added DIPEA (123.73 mg, 957.37 umol) , followed by a solution of 3- [5- (aminomethyl) -1-oxo-isoindolin-2-yl] piperidine-2, 6-dione (29.65 mg, 95.74 umol) in DMF (2 mL) at 0 ℃. After the reaction was stirred at 0 ℃ for 0.5 h, it was concentrated and purified by prep- HPLC to give 15 mg crude product which was further purified by prep-TLC (DCM/MeOH = 10/1) to give the title compound (6.5 mg, 8%yield) as a white solid. MS (ESI) m/z = 882.9 [M+H] ⁺.

Example 415. 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)

JA-334 was synthesized following the similar procedure for preparing JA-336 (18 mg, yield: 57%) . MS (ESI) m/z = 917.9 [M+H] ⁺.

Example 416. 3- (4- ( (2- ( (4- (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)

JA-335 was synthesized following the similar procedure for preparing JA-336 (1.1 mg, yield: 6%) . MS (ESI) m/z = 917.8 [M+H] ⁺.

Example 417. 3- (4- ( (2- ( (3- ( (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) methyl) phenyl) amino) pyrimidin-4-yl) amino) -1-oxoisoindolin-2-yl) piperidine- 2, 6-dione (JA-336)

Step 1: Synthesis of 3- (4- ( (2-chloropyrimidin-4-yl) amino) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione

To a solution of 3- (4-amino-1-oxo-isoindolin-2-yl) piperidine-2, 6-dione (2.0 g, 7.71 mmol) and 2, 4-dichloropyrimidine (2.30 g, 15.42 mmol) in DMF (50 mL) was added DIPEA (5.98 g, 46.26 mmol) at rt. After the reaction mixture was stirred at 120 ℃ for 16 h, it was concentrated and purified by silica gel chromatography (DCM/MeOH = 20/1) to give the title compound (1.5 g, 52%yield) . MS (ESI) m/z = 372.3 [M+H] ⁺.

Step 2: Synthesis of tert-butyl (3- (hydroxymethyl) phenyl) carbamate

To a solution of (3-aminophenyl) methanol (2.0 g, 16.24 mmol) in THF (50 mL) was added Na ₂CO ₃ (3.44 g, 32.48 mmol) and Boc ₂O (3.91 g, 17.86 mmol) at rt. After the mixture was stirred at rt for 4 h, it was concentrated and purified by silica gel chromatography (petroleum ether /EtOAc = 10/1 to 5/1) to give the title compound (3.4 g, 94%yield) which was used directly in the next step without further characterization.

Step 3: Synthesis of tert-butyl (3- (bromomethyl) phenyl) carbamate

To a solution of tert-butyl N- [3- (hydroxymethyl) phenyl] carbamate (2.90 g, 12.99 mmol) in DCM (80 mL) were added CBr ₄ (6.45 g, 19.48 mmol) and PPh ₃ (5.10 g, 19.48 mmol) at 0 ℃. After the mixture was slowly warmed to rt, it was concentrated and purified by silica gel chromatography (petroleum ether /EtOAc = 10/1) to give the title compound (1.5 g, 41%yield) as a white solid.

Step 4: Synthesis of tert-butyl (3- ( (4- (4- (8- (3, 5-difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) methyl) phenyl) carbamate

To a solution of tert-butyl N- [3- (bromomethyl) phenyl] carbamate (50.00 mg, 174.72 umol) and 4- [ [2, 6-difluoro-4- [3- [1- (4-piperidyl) pyrazol-4-yl] quinoxalin-5-yl] phenyl] methyl] morpholine (85.71 mg, 174.72 umol) in DMSO (5 mL) were added DIPEA (67.74 mg, 524.17 umol) and NaI (26.19 mg, 174.72 umol) at rt. After the mixture was stirred at rt for 16 h, it was purified by prep-HPLC to give the title compound (90 mg, 74%yield) as a yellow solid. MS (ESI) m/z = 696.8 [M+H] ⁺.

Step 5: Synthesis of 3- ( (4- (4- (8- (3, 5-difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) methyl) aniline

To a solution of tert-butyl N- [3- [ [4- [4- [8- [3, 5-difluoro-4- (morpholinomethyl) phenyl] quinoxalin-2-yl] pyrazol-1-yl] -1-piperidyl] methyl] phenyl] carbamate (100 mg, 143.72 umol) in DCM (10 mL) was added TFA (2 mL) at rt. After the mixture was stirred at rt for 2 h, it was concentrated to give the crude product which was used directly in the next step.

Step 6: Synthesis of 3- (4- ( (2- ( (3- ( (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) methyl) phenyl) amino) pyrimidin-4-yl) amino) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione

The crude 3- ( (4- (4- (8- (3, 5-difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) methyl) aniline was dissolved in t-BuOH (10 mL) and DMSO (2 mL) . Then TFA (0.5 mL) was added. After the mixture was stirred at 100 ℃ for 3 h, it was concentrated and purified by prep-HPLC to give crude product which was further purified by prep-TLC (DCM/MeOH = 10/1) to give the title compound (72 mg, 54%yield) . MS (ESI) m/z = 931.8 [M+H] ⁺.

Example 418. 3- (4- ( (2- ( (4- ( (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) methyl) phenyl) amino) pyrimidin-4-yl) amino) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (JA-337)

JA-337 was synthesized following the similar procedure for preparing JA-336 (42 mg, yield: 31%) . MS (ESI) m/z = 931.8 [M+H] ⁺.

Example 419. 3- (5- ( (2- ( (2- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -2, 3-dihydro-1H-inden-5-yl) amino) pyrimidin-4-yl) amino) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (JA-338)

JA-338 was synthesized following the similar procedure for preparing JA-336 (3.2 mg, yield: 21%) . MS (ESI) m/z = 957.9 [M+H] ⁺.

Example 420. 2- (3- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) cyclobutyl) -N- ( (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) acetamide (JA-341)

JA-341 was synthesized following the similar procedure for preparing JA-312 (4.2 mg, yield: 73%) . MS (ESI) m/z = 858.8 [M+H] ⁺.

Example 421. 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)

Step 1: Synthesis of tert-butyldimethyl (2- (2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclopropyl) ethoxy) silane

To a solution of tert-butyl-dimethyl- [ (E) -4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) but-3-enoxy] silane (2.0 g, 6.40 mmol) in DCM (30 mL) was added Et ₂Zn (32.02 mmol, 32 mL) at 0 ℃. After the mixture was stirred at 0 ℃ for 0.5 h, CH ₂I ₂ (8.58 g, 32.02 mmol) and TFA (3.65 g, 32.02 mmol) was added at 0 ℃. The mixture was stirred at 0 ℃ for 1 h, before it was warmed to rt and stirred for another 2 h. The reaction was quenched with aq. NH ₄Cl, and extracted with DCM. The organic phase was concentrated and purified by silica gel chromatography (petroleum ether /EtOAc = 10/1) to give the title compound (2.0 g, 96%yield) as a colorless oil which was used directly in the next step without further characterization.

Step 2: Synthesis of 2- (2- ( (tert-butyldimethylsilyl) oxy) ethyl) cyclopropan-1-ol

To a solution of tert-butyl-dimethyl- [2- [2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclopropyl] ethoxy] silane (2.0 g, 6.13 mmol) in THF (50 mL) was added NaHCO ₃ (6.13 mmol, 30 mL) and H ₂O ₂ (6.13 mmol, 20 mL) at 0 ℃. After the reaction mixture was stirred at 0 ℃ for 1 h, it was extracted with DCM, concentrated and purified by silica gel chromatography (petroleum ether /EtOAc = 3/1) to give the title compound (1.2 g, 91%yield) as a colorless oil which was used directly in the next step without further characterization.

Step 3: Synthesis of 4- (4- (3- (1- (1- (2- (2- ( (tert-butyldimethylsilyl) oxy) ethyl) cyclopropyl) piperidin-4-yl) -1H-pyrazol-4-yl) quinoxalin-5-yl) -2, 6-difluorobenzyl) morpholine

To a solution of 4- [ [2, 6-difluoro-4- [3- [1- (4-piperidyl) pyrazol-4-yl] quinoxalin-5-yl] phenyl] methyl] morpholine (340 mg, 693.10 umol) and 2- [2- [tert-butyl (dimethyl) silyl] oxyethyl] cyclopropanol (277.55 mg, 1.28 mmol) in dioxane (20 mL) was added Zn (Et) ₂ (693.10 umol, 2.76 mL) at rt. After the reaction mixture was stirred at 110 ℃ for 16 h, it was quenched with aq. NH ₄Cl, extracted with DCM, concentrated, and purified by silica gel chromatography (DCM/MeOH =15/1) to give the title compound (250 mg, 52%yield) . MS (ESI) m/z = 689.8 [M+H] ⁺.

Step 4: Synthesis of 2- (2- (4- (4- (8- (3, 5-difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) cyclopropyl) ethan-1-ol

To a solution of tert-butyl- [2- [2- [4- [4- [8- [3, 5-difluoro-4- (morpholinomethyl) phenyl] quinoxalin-2-yl] pyrazol-1-yl] -1-piperidyl] cyclopropyl] ethoxy] -dimethyl-silane (250 mg, 362.89 umol) in THF (10 mL) was added TBAF (94.88 mg, 362.89 umol, 3.6 mL) at rt. After the mixture was stirred at rt for 0.5 h, it was concentrated and purified by silica gel chromatography (DCM/MeOH = 15/1 to 10/1) to give the title compound (150 mg, 72%yield) as a yellow solid. MS (ESI) m/z = 575.2 [M+H] ⁺.

Step 5: Synthesis of 2- (2- (4- (4- (8- (3, 5-difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) cyclopropyl) acetic acid

To a solution of 2- [2- [4- [4- [8- [3, 5-difluoro-4- (morpholinomethyl) phenyl] quinoxalin-2-yl] pyrazol-1-yl] -1-piperidyl] cyclopropyl] ethanol (140 mg, 243.62 umol) in acetone (20 mL) and DMF (5 mL) was added Jones reagent (1 mL) at 0 ℃. After the reaction mixture was stirred at 0 ℃ for 3 h. it was purified by prep-HPLC to give the title compound (130 mg, 91%yield) . MS (ESI) m/z = 589.5 [M+H] ⁺.

Step 6: Synthesis of 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

To a solution of 2- [2- [4- [4- [8- [3, 5-difluoro-4- (morpholinomethyl) phenyl] quinoxalin-2-yl] pyrazol-1-yl] -1-piperidyl] cyclopropyl] acetic acid (100 mg, 142.31 umol) and 3- [5- (aminomethyl) -1-oxo-isoindolin-2-yl] piperidine-2, 6-dione (38.89 mg, 125.56 umol) in DMSO (5 mL) were added HOAt (38.42 mg, 284.63 umol) , EDCI (54.65 mg, 284.63 umol) and DIPEA (110.36 mg, 853.89 umol) at rt. After the reaction mixture was stirred at rt for 16 h, it was purified by prep-HPLC to give 150 mg crude product which was further purified by prep-TLC (DCM/MeOH = 8/1) to give the title compound (75 mg, 63%yield) as a white solid. MS (ESI) m/z = 844.7 [M+H] ⁺.

Example 422. 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)

To a solution of 4- (2, 6-difluoro-4- (3- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) quinoxalin-5-yl) benzyl) morpholine (49 mg, 0.10 mmol) and 3- (5- (4-aminobutoxy) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (33 mg, 0.10 mmol ) in DMF (3 mL) were added CDI (16 mg, 0.10 mmol) and DIEA (13 mg, 0.10 mmol) at room temperature. Then the reaction mixture was stirred at 80 ℃ for 1 h. The mixture was purified by reverse-phase chromatography to give the desired product (40 mg, 46%yield) as a light yellow solid. MS (ESI) m/z: 848.4 [M+H] ⁺.

Example 423. 3- (5- ( (6- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -5, 5-dimethyl-6-oxohexyl) oxy) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (JA- 344)

Step 1. Synthesis of methyl 6- (benzyloxy) -2, 2-dimethylhexanoate

To a solution of methyl isobutyrate (200 mg, 2.0 mmol) in THF (10 mL) was added LDA (1M, 2.1 mL) at -78

2, 2-dimethylhexanoate (569 mg, 2.3 mmol) was added. The reaction mixture was warmed to 0 ℃ for 1 h, before it was poured into water (50 mL) and extracted with ethyl acetate (20 mL×3) . The combined organic layers were washed with saturated brine (50 mL) , dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel chromatography to give the desired product (300 mg, 58%yield) as a light yellow solid. MS (ESI) m/z: 265.2 [M+H] ⁺.

Step 2. Synthesis of 6- (benzyloxy) -2, 2-dimethylhexanoic acid

To a solution of methyl 6- (benzyloxy) -2, 2-dimethylhexanoate (150 mg, 0.62 mmol) in THF (5 mL) and H ₂O (2 mL) was added LiOH (59.5 mg, 2.5 mmol) at room temperature. Then the mixture was stirred at reflux under inert atmosphere for 1 h. The mixture was concentrated and purified by reverse-phase chromatography to give the desired product (96 mg, 67%yield) as a light yellow solid. MS (ESI) m/z: 251.2 [M+H] ⁺.

Step 3. Synthesis of 6-hydroxy-2, 2-dimethylhexanoic acid

To a solution of 6- (benzyloxy) -2, 2-dimethylhexanoic acid (100 mg, 0.4 mmol) in THF (10 mL) was added Pd/C (10%, 10 mg) . After the reaction mixture was stirred at room temperature under hydrogen balloon for 4 h, it was filtered and the filtrate was concentrated. The resulting residue was used directly in the next step without further purification.

Step 4. Synthesis of 1- (4- (4- (8- (3, 5-difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -6-hydroxy-2, 2-dimethylhexan-1-one

To a solution of 6-hydroxy-2, 2-dimethylhexanoic acid (50 mg, 0.31 mmol) in DMSO (2 mL) were added 4- (2, 6-difluoro-4- (3- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) quinoxalin-5-yl) benzyl) morpholine (153 mg, 0.31 mmol) , HATU (178 mg, 0.47 mmol) and DIPEA (121 mg, 0.94 mmol) . After the reaction mixture was stirred at room temperature for 4 h, it was purified by reverse-phase chromatography to give the desired product (60.2 mg, 30%yield) as a light yellow solid. MS (ESI) m/z: 633.5 [M+H] ⁺.

Step 5. Synthesis of 6- (4- (4- (8- (3, 5-difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -5, 5-dimethyl-6-oxohexyl 4-methylbenzenesulfonate

To a solution of 1- (4- (4- (8- (3, 5-difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -6-hydroxy-2, 2-dimethylhexan-1-one (60.2 mg, 0.09 mmol) in DCM (5 mL) were added TsCl (27.1 mg, 0.14 mmol) and TEA (28.8 mg, 0.29 mmol) . After the reaction mixture was stirred room temperature for 4 h, it was concentrated and purified by reverse-phase chromatography to give the desired product (30.8 mg, 41%yield) as a light yellow solid. MS (ESI) m/z: 787.5 [M+H] ⁺

Step 6. Synthesis of 3- (5- ( (6- (4- (4- (8- (3, 5-difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -5, 5-dimethyl-6-oxohexyl) oxy) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione

To a solution of 6- (4- (4- (8- (3, 5-difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -5, 5-dimethyl-6-oxohexyl 4-methylbenzenesulfonate (30.8 mg, 0.04 mmol) in DMF (2 mL) were added 3- (5-hydroxy-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (15.2 mg, 0.06 mmol) and K ₂CO ₃ (16.2 mg, 0.12 mmol) at room temperature. After the reaction mixture was stirred at 80 ℃ under i ne for 1 h, it was filtered and purified by reverse-phase chromatography to give the desired product (8.1 mg, 24%yield) as a light yellow solid. MS (ESI) m/z: 875.5 [M+H] ⁺

Example 424. 3- (5- ( (5- ( (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) sulfonyl) pentyl) oxy) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (JA-345)

Step 1. Synthesis of 5-hydroxypentane-1-sulfonic acid

To a solution of 5-bromopentan-1-ol (166 mg, 1.00 mmol) in EtOH (10 mL) was added Na ₂SO ₃ (216 mg, 2.00 mmol) and H ₂O (1 ml) at room temperature. Then the mixture was stirred at 90

mixture was evaporated under reduced pressure and purified by reverse-phase chromatography to give the desired product (34 mg, 20%yield) as a light yellow solid. MS (ESI) m/z: 169.0 [M+H] ⁺.

Step 2. Synthesis of 4- (4- (3- (1- (1- ( (5-chloropentyl) sulfonyl) piperidin-4-yl) -1H-pyrazol-4-yl) quinoxalin-5-yl) -2, 6-difluorobenzyl) morpholine

A solution of 5-hydroxypentane-1-sulfonic acid (34 mg, 0.20 mmol) in SOCl ₂ (5 mL) was stirred at reflux for 1 h. Then the mixture was evaporated under reduced pressure. The resulting residue was dissolved in DCM (5 mL) and added into a mixture of 4- (2, 6-difluoro-4- (3- (1- (piperidin-4-yl) -1H-pyrazol-4-yl)quinoxalin-5-yl) benzyl) morpholine (98 mg, 0.20 mmol) and TEA (60 mg, 0.6 mmol) in DMF (5 mL) at 0 ℃. After the mi and purified by reverse-phase chromatography to give the desired product (26 mg, 20%yield) as a light yellow solid. MS (ESI) m/z: 659.2 [M+H] ⁺.

Step 3. Synthesis of 3- (5- ( (5- ( (4- (4- (8- (3, 5-difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) sulfonyl) pentyl) oxy) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione

To a solution of 4- (4- (3- (1- (1- ( (5-chloropentyl) sulfonyl) piperidin-4-yl) -1H-pyrazol-4-yl) quinoxalin-5-yl) -2, 6-difluorobenzyl) morpholine (13 mg, 0.02 mmol) and 5-hydroxy-2- (6-oxopiperidin-3-yl) isoindolin-1-one (6 mg, 0.02 mmol ) in DMSO (2 mL) was added Na ₂CO ₃ (6 mg, 0.06 mmol) at room temperature. After the reaction mixture was stirred at 90

by reverse-phase chromatography to give the desired product (3 mg, 19%yield) as a light yellow solid. MS (ESI) m/z: 883.4 [M+H] ⁺.

Example 425. 3- (5- ( (6- (4- (4- (8- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -5, 5-difluoro-6-oxohexyl) oxy) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (JA-346)

Step 1. Synthesis of 6- (benzyloxy) -2, 2-difluorohexanoic acid

To a solution of tert-butyl 6- (benzyloxy) -2, 2-difluorohexanoate (100 mg, 0.32 mmol) in DCM (4 mL) was added TFA (2 mL) . After the reaction mixture was stirred at room temperature for 4 h, it was concentrated and purified by reverse-phase chromatography to give the desired product (73.5 mg, 89%yield) as a light yellow solid. MS (ESI) m/z: 259.3 [M+H] ⁺

JA-346 (2.7 mg, 30%yield) was then synthesized as a light yellow solid following the standard procedure for preparing JA-344. MS (ESI) m/z: 883.5 [M+H] ⁺.

Example 426. 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)

Step 1. Synthesis of tert-butyl 4- (4-bromo-2, 6-difluorobenzyl) piperazine-1-carboxylate

To a mixture of 4-bromo-3, 5-difluoro-benzaldehyde (2.0 g, 9.1 mmol) and tert-butyl piperazine-1-carboxylate (2.53 g, 13.6 mmol) in DCE (25 mL) were added NaBH (OAc) ₃ (2.30 g, 10.9 mmol) and AcOH (54.3 mg, 0.9 mmol) . The reaction mixture was degassed and recharged with N ₂ for three times. The mixture was then stirred at rt overnight, and quenched with water. The obtained mixture was extracted with DCM. The organic layer was washed with brine, dried over Na ₂SO ₄, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether: EtOAc = 1: 0 to 4: 1) to afford the title compound (3.2 g, 90%yield) as white solid. MS (ESI) m/z: 391.3 [M+H] ⁺.

Step 2. Synthesis of (4- ( (4- (tert-butoxycarbonyl) piperazin-1-yl) methyl) -3, 5-difluorophenyl) boronic acid

To a mixture of tert-butyl 4- (4-bromo-2, 6-difluorobenzyl) piperazine-1-carboxylate (2.7 g, 6.9 mmol) and 4, 4, 5, 5-tetramethyl-2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 3, 2-dioxaborolane (2.63 g, 10.4 mmol) in dioxane (30 mL) were added KOAc (1.69 g, 17.3 mmol) and Pd (dppf) Cl ₂ (504 mg, 690 umol) . After the reaction mixture was degassed and recharged with N ₂ for three times, it was stirred at 90 ℃ for 2 h. The reaction solution was quenched with water, and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂SO ₄, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether: EtOAc = 1: 0 to 7: 3) to afford the title compound (2.4 g, 98%yield) as light yellow solid. MS (ESI) m/z: 357.2 [M+H] ⁺.

Step 3. Synthesis of 8-bromo-2- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) quinoxaline

To a solution of tert-butyl 4- (4- (8-bromoquinoxalin-2-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate (1.0 g, 2.2 mmol) in DCM (10 mL) was added TFA (2 mL) . The reaction mixture was stirred at rt for 4 h. The mixture was concentrated, quenched with aqueous Na ₂CO ₃ solution, and then extracted with DCM. The organic layer was washed with brine, dried over Na ₂SO ₄, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether: EtOAc = 1: 0 to 3: 7) to afford the title compound (690 mg, 88%yield) as white solid. MS (ESI) m/z: 358.2 [M+H] ⁺.

Step 4. Synthesis of (9H-fluoren-9-yl) methyl 4- (4- (8-bromoquinoxalin-2-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate

To a solution of 8-bromo-2- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) quinoxaline (100 mg, 279.15 umol) in dioxane (2 mL) were added FmocCl (135 mg, 419 umol) and Na ₂CO ₃ (59 mg, 558 umol) . The reaction mixture was stirred at rt for 3 h, and then quenched with water. The mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂SO ₄, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether: EtOAc = 1: 0 to 3: 7) to afford the title compound (130 mg, 80%yield) as white solid. MS (ESI) m/z: 580.4 [M+H] ⁺.

Step 5. Synthesis of tert-butyl 4- (4- (3- (1- (1- ( ( (9H-fluoren-9-yl) methoxy) carbonyl) piperidin-4-yl) -1H-pyrazol-4-yl) quinoxalin-5-yl) -2, 6-difluorobenzyl) piperazine-1-carboxylate

To a mixture of (9H-fluoren-9-yl) methyl 4- (4- (8-bromoquinoxalin-2-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate (610 mg, 1.1 mmol) and (4- ( (4- (tert-butoxycarbonyl) piperazin-1-yl) methyl) -3, 5-difluorophenyl) boronic acid (748 mg, 2.10 mmol) in water (2 mL) and dioxane (8 mL) were added K ₂CO ₃ (290 mg, 2.1 mmol) and Pd (dppf) Cl ₂ (76.82 mg, 105 umol) . The reaction mixture was stirred at 90 ℃ for 1 h, and then quenched with water. The mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂SO ₄, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether: EtOAc = 1: 0 to 3: 7) to afford the title compound (200 mg, 23%yield) as white solid. MS (ESI) m/z: 813.0 [M+H] ⁺.

Step 6. Synthesis of tert-butyl 4- (2, 6-difluoro-4- (3- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) quinoxalin-5-yl) benzyl) piperazine-1-carboxylate

A solution of tert-butyl 4- (4- (3- (1- (1- ( ( (9H-fluoren-9-yl) methoxy) carbonyl) piperidin-4-yl) -1H-pyrazol-4-yl) quinoxalin-5-yl) -2, 6-difluorobenzyl) piperazine-1-carboxylate (200 mg, 246 umol) in DMF (2 mL) and piperidine (0.4 mL) was stirred at rt for 1 h. The mixture was quenched with water, and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂SO ₄, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether: EtOAc = 1: 0 to 3: 7) to afford the title compound (100 mg, 69%yield) as white solid. MS (ESI) m/z: 590.7 [M+H] ⁺.

Step 7. Synthesis of tert-butyl 4- (4- (3- (1- (1- (6- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) hexanoyl) piperidin-4-yl) -1H-pyrazol-4-yl) quinoxalin-5-yl) -2, 6-difluorobenzyl) piperazine-1-carboxylate

To a mixture of 6- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) hexanoic acid (20 mg, 52 umol) and tert-butyl 4- (2, 6-difluoro-4- (3- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) quinoxalin-5-yl) benzyl) piperazine-1-carboxylate (36 mg, 62 umol) in DMSO (1 mL) were added EDCI (16 mg, 103 umol) , HOAT (14 mg, 103 umol) and NMM (16 mg, 155 umol) . The reaction mixture was stirred at rt overnight. The solution was purified by reverse phase chromatography (0-70%MeCN in H ₂O) to afford the title compound (40 mg, 81%yield) as yellow solid. MS (ESI) m/z: 960.1 [M+H] ⁺.

Step 8. Synthesis of 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

To a solution of tert-butyl 4- (4- (3- (1- (1- (6- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) hexanoyl) piperidin-4-yl) -1H-pyrazol-4-yl) quinoxalin-5-yl) -2, 6-difluorobenzyl) piperazine-1-carboxylate (40 mg, 42 umol) in methanol (0.5 mL) was added HCl solution (4 M in dioxane, 0.5 mL) . The reaction mixture was stirred at rt for 30 min. The solution was purified by reverse phase chromatography (0-70%MeCN in H ₂O) to afford the title compound (30.7 mg, 86%yield) as yellow solid. MS (ESI) m/z: 859.8 [M+H] ⁺.

Example 427. 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)

JA-348 was synthesized following the similar procedures as described for

step

2, 5, 8 and 7 of JA-347 (71.3 mg) . MS (ESI) m/z: 791.8 [M+H] ⁺.

Example 428. 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-349)

Step 1. Synthesis of 4- ( (tert-butyldimethylsilyl) oxy) piperidine

To a solution of piperidin-4-ol (2 g, 19.77 mmol) and imidazole (4.04 g, 59.32 mmol) in DCM (20 mL) was added tert-butyl-chloro-dimethyl-silane (4.47 g, 29.66 mmol) at 0

was stirred at rt overnight before being quenched with H ₂O. The organic phase was separated, and then concentrated. The residue was purified by silica gel chromatography (DCM: MeOH = 10: 1) to afford the title compound (3.7 g, 87%yield) .

Step 2 to 6. Synthesis of 1- (4-bromo-2, 6-difluorobenzyl) -4- ( (tert-butyldimethylsilyl) oxy) piperidine

JA-349 was synthesized following the similar procedures as described for JA-347 (45.7 mg) . MS (ESI) m/z = 874.9 [M+H] ⁺.

Example 429. 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)

JA-350 was synthesized following the similar procedures as described for JA-347 (46.6 mg) . MS (ESI) m/z = 873.9 [M+H] ⁺.

Certain compounds disclosed herein have the structures shown in Table 1A.

Table 1A

As used herein, in case of discrepancy between the structure and chemical name provided for a particular compound, the structure shall control.

Example 430. Selected JAK degraders concentration-dependently reduced JAK2 and JAK1 protein levels in HEL cells (Fig. 1) .

HEL cells harboring JAK2-V617F mutation were treated with compounds at indicated concentrations for 24 hours. Data showed that JAK2-V617F and JAK1 proteins levels were reduced in a concentration-dependent manner. The concentrations required to reduce JAK2-V617 by 50% (DC ₅₀) were below 60 nM for compound JA-213.

Example 431. Selected JAK degraders concentration-dependently reduced JAK1 protein levels in RS4; 11 cells (Fig. 2) .

RS4; 11 cells were treated with compounds at indicated concentrations for 24 hours. Data showed that JAK1 proteins levels were reduced in a concentration-dependent manner. The concentrations required to reduce JAK1 by 50% (DC ₅₀) were below 5 nM and 35 nM for compound JA-189 and JA213, respectively.

Example 432. Selected JAK degraders suppressed viability of some leukemia cells (Fig. 3 &Table. 3) .

MV4; 11, RS4; 11, Kasumi-1, HEL and other cells were treated with NVP-BSK805, TG101209 or selected degraders for 3 days at indicated concentrations following a 3-fold serial dilution. Data indicated that JAK degraders significantly and selectively suppressed viability of some leukemia cells while their warhead, NVP-BSK805 or TG101209 has none or less effect.

Example 433. Selected JAK degraders caused cell viability inhibition is CRBN dependent (Fig. 4) .

MV4; 11, RS4; 11, Kasumi-1 and HEL were treated with NVP-BSK805, TG101209 or selected degraders for 3 days at indicated concentrations in the presence or absence of pomalidomide at 10 μM. Data showed that JAK degraders caused cell viability inhibition was completely compromised by high concentration of pomalidomide, which competes JAK degraders off from Cereblon (CRBN) E3 ligase. Taking together, data indicated that JAK degraders caused cell viability inhibition is CRBN dependent.

Example 434. Selected JAK degraders concentration-dependently reduced GSPT1 protein levels in RS4; 11 cells (Fig. 5) .

RS4; 11 cells were treated with compounds at indicated concentrations for 16 hours. Data showed that GSPT1 proteins levels were reduced in a concentration-dependent manner. The concentrations required to reduce GSPT1 by 50% (DC ₅₀) were below 2 nM for compound JA-189 and 10 nM JA213.

Example 435. Non-cancerous human cells are resistant to selected JAK degraders (Fig. 6) .

Immortalized human lung fibroblast IMR-90 and keratinocyte HACAT cells were treated with JA-189 or JA-213 for 3 days at indicated concentrations following a 3-fold serial dilution. Data indicate that these non-cancerous human cells were not sensitive to these compounds, suggesting potential therapeutic windows.

Example 436. Inhibition of FLT3 in FLT3-mutant AML cells remarkably increases sensitivity to GSPT1 degraders (Table 6) .

MV4; 11 cells (A) and MOLM13 cells (B) were treated with GSPT1 degraders at indicated concentrations with or without 10 nM (A) or 20 nM (B) gilteritinib for 3 days, respectively. Cell viability and dose response curves were determined as described in the method section.

Example 437. Inhibition of FLT3 in FLT3-wild type AML cells does not affect sensitivity to GSPT1 degraders.

NOMO-1 cells were treated with GSPT1 degraders at indicated concentrations with or without 20 nM gilteritinib for 3 days.

Example 438. GSPT1 degraders reduce GSPT1 protein levels.

MV4; 11 cells were treated with GSPT1 degraders at indicated concentrations for 16 hours prior to sampling for immunoblotting.

Example 439. Inhibition of MAPK or PI3K/AKT signaling increases sensitivity to GSPT1 degraders.

L-363 cells (A) and NOMO-1 cells (B) were treated with GSPT1 degraders at indicated concentrations with or without (A) 100 nM MK-2206, an AKT inhibitor, or (B) 20 nM trametinib, a MEK inhibitor, for 3 days, respectively.

Materials and Methods:

General Chemistry Methods:

All chemicals and reagents were purchased from commercial suppliers and used without further purification. LCMS spectra for all compounds were acquired using a Shimadzu LC-MS 2020 system or a Waters UPLC-MS H class system. The Shimadzu LC-MS 2020 system comprising a pump (LC-20AD) with degasser (DGU-20A3) , an autosampler (SIL-20AHT) , a column oven (CTO-20A) (set at 40 ℃, unless otherwise indicated) , a photo-diode array (PDA) (SPD-M20A) detector, an evaporative light-scattering (ELSD) (Alltech 3300ELSD) detector. Chromatography was performed on a Shimadzu SunFire C18 (5μm 50 *4.6mm) with water containing 0.1%formic acid as solvent A and acetonitrile containing 0.1%formic acid as solvent B at a flow rate of 2.0 ml/min. Flow from the column was split to a MS spectrometer. The MS detector was configured with an electrospray ionization source. Nitrogen was used as the nebulizer gas. Data acquisition was performed with a Labsolution data system. The Waters UPLC-MS H class system comprising a pump (Quaternary Solvent Manager) with degasser, an autosampler (FTN) , a column oven (set at 40℃, unless otherwise indicated) , a photo-diode array PDA detector. Chromatography was performed on a AcQuity UPLC BEH C18 (1.7μm 50 *2.1mm) with water containing 0.1%formic acid as solvent A and acetonitrile containing 0.1%formic acid as solvent B at a flow rate of 0.6 mL/min. Flow from the column was split to a MS spectrometer. The MS detector was configured with an electrospray ionization source. Nitrogen was used as the nebulizer gas. Data acquisition was performed with a MassLynx data system. Proton Nuclear Magnetic Resonance ( ¹H-NMR) spectra were recorded on a Bruker Avance Ⅲ400 spectrometer. Chemical shifts are expressed in parts per million (ppm) and reported as δ value (chemical shift δ) . Coupling constants are reported in units of hertz (J value, Hz; Integration and splitting patterns: where s = singlet, d = double, t = triplet, q = quartet, brs = broad singlet, m = multiple) . Preparative HPLC was performed on Agilent Prep 1260 series with UV detector set to 254 nm or 220 nm. Samples were injected onto a Phenomenex Luna 75 x 30 mm, 5 μm, C18 column at room temperature. The flow rate was 40 mL/min. A linear gradient was used with 10% (or 50%) of MeOH (A) in H ₂O (with 0.1 %TFA) (B) to 100%of MeOH (A) . All compounds showed > 90%purity using the LCMS methods described above.

Cell Culture

HEL, RS4; 11, MV4; 11, Kasumi-1, MV4; 11, MOLM-13, NOMO-1, L-363, and other cells were cultured at 37℃ with 5%CO ₂ in RPMI 1640 or DMEM Medium supplemented with 10%fetal bovine serum. Cells were authenticated using the short tandem repeat (STR) assays. Mycoplasma test results were negative.

Antibodies and reagents

Rabbit anti-JAK1 antibody (3344S) , anti-JAK2 antibody (3230S) , anti-JAK3 antibody (8827S) , anti-TYK2 antibody (14193S) , anti-FLT3 antibody (3462S) , anti-RET antibody (14556S) , anti-phospho-STAT3 (Tyr705) antibody (9145S) and anti-phospho-STAT5 (Tyr694) antibody (4322S) were purchased from Cell Signaling Technology. Rabbit anti-GSPT1 antibody (ab126090) was purchased from Abcam. HRP-conjugated anti-α-tubulin antibody was produced in house. Media and other cell culture reagents were purchased from Thermo Fisher. The CellTiter-Glo Luminescent Assay kit was purchased from Promega.

Immunoblotting

Cultured cells were washed with cold PBS once and lysed in cold RIPA buffer supplemented with protease inhibitors and phosphatase inhibitors (Beyotime Biotechnology) . The solutions were then incubated at 4 ℃ for 30 minutes with gentle agitation to fully lyse cells. Cell lysates were centrifuged at 13, 000 rpm for 10 minutes at 4 ℃ and pellets were discarded. Total protein concentrations in the lysates were determined by BCA assays (Beyotime Biotechnology) . Cell lysates were mixed with Laemmli loading buffer to 1 × and heated at 99 ℃ for 5 min. Proteins were resolved on SDS-PAGE and visualized by chemiluminescence. Images were taken by a ChemiDoc MP Imaging system (Bio-Rad) . Protein bands were quantitated using the accompanied software provided by Bio-Rad.

Cell viability assays

Cells were seeded at a density of 5000 cells per well in 96-well assay plates and treated with test compounds following a 8-point or 12-point 3-fold serial dilution. Three days later, cell viability was determined using the CellTiter-Glo assay kit according to the manufacturers instructions. The dose-response curves were determined and IC ₅₀ values were calculated using the GraphPad Prism software following a nonlinear regression (least squares fit) method.

The cell viability inhibition results of selected heterobifunctional compounds are set forth in Table 2, Table 3, Table 4 and Table 5 below.

Table 2.

The IC ₅₀ value (nM) of each compound was determined in RS4; 11 cells as described in Methods and calculated using the GraphPad Prism 5.0 software.

Table 3.

Cell line	Disease	JA-189	JA-213	NVP-BSK805	TG101209
HEL	erythroleukemia	177.4	82.12	1045	1195
RS4; 11	B-ALL	2.03	8.45	>10000	1839
MOLT-4	T-ALL	6.36	16.5	>10000	2504
CCRF-CEM	T-ALL	3.84	19.05	>10000	3959
Jurkat	T-ALL	34.2	62.7	2515	550
MV4; 11	AML	7.93	19.55	390.5	193.6
Kasumi-1	AML	86.34	69.14	757.6	529.3
NOMO-1	AML	53.16	81.68	6275	1303
MOLM-13	AML	20.8	27.4	201.1	48.2
HL-60	APL	2.54	19.2	>10000	>10000
MM. 1S	Multiple Myeloma	2.27	23.05	>10000	6110
AMO-1	Multiple Myeloma	612.2	721.8	>10000	4775
NCI-H929	Multiple Myeloma	105.8	123.7	>10000	>10000
MEG-01	CML	89.25	74.04	8871	7116
WSU-DLCL2	DLBCL	106.1	167.9	>10000	1068
Pfeiffer	DLBCL	320.2	266.3	>10000	>10000
SU-DHL-1	large cell lymphoma	221.9	318.6	>10000	>10000
KM12	colorectal carcinoma	2370	678.6	2863

The IC ₅₀ values (nM) of selected compounds were determined in indicated cells as described in Methods and calculated using the GraphPad Prism 5.0 software.

Table 4.

The IC ₅₀ values (nM) of each compound were determined in MV4; 11 and MOLM-13 cells as described in Methods and calculated using the GraphPad Prism 5.0 software.

Table 5

ID	MV4; 11 IC ₅₀	MOLM-13 IC ₅₀	ID	MV4; 11 IC ₅₀	MOLM-13 IC ₅₀
NVP-BS K805	C	C	JA-319	D	D
CC-90009	B	C	JA-320	D	D
JA-296	D	D	JA-321	C	C
JA-297	D	D	JA-322	C	D
JA-298	D	D	JA-323	B	B
JA-299	D	D	JA-324	C	C
JA-300	C	C	JA-325	A	A
JA-301	C	C	JA-326	D	D
JA-302	D	D	JA-327	D	D
JA-303	C	C	JA-331	D	D
JA-304	D	D	JA-334	B	B
JA-305	D	D	JA-335	B	C
JA-306	D	D	JA-336	C	C
JA-307	D	D	JA-337	C	C
JA-308	D	D	JA-338	D	C
JA-309	D	D	JA-341	D	D
JA-310	A	A	JA-342	B	C
JA-311	B	C	JA-343	C	D
JA-312	D	D	JA-344	D	D
JA-313	A	A	JA-345	D	D
JA-314	D	C	JA-346	D	C
JA-315	B	C	JA-347	C	C
JA-316	D	D	JA-348	C	D
JA-317	B	B	JA-349	B	B
JA-318	D	C	JA-350	C	C

The IC ₅₀ values (nM) of each compound were determined in MV4; 11 and MOLM-13 cells with or without gilteritinib (10 nM for MV4; 11; and 20 nM for MOML-13) as described in Methods. A: < 10 nM; 100 nM > B >= 10 nM; 1 uM > C >= 100 nM; D >= 1 uM.

References

Bondeson, D.P., A. Mares, I.E. Smith, E. Ko, S. Campos, A.H. Miah, K.E. Mulholland, N. Routly, D.L. Buckley, J.L. Gustafson, N. Zinn, P. Grandi, S. Shimamura, G. Bergamini, M. Faelth-Savitski, M. Bantscheff, C. Cox, D.A. Gordon, R.R. Willard, J.J. Flanagan, L.N. Casillas, B.J. Votta, W. den Besten, K. Famm, L. Kruidenier, P.S. Carter, J.D. Harling, I. Churcher and C.M. Crews (2015) . "Catalytic in vivo protein knockdown by small-molecule PROTACs. " Nat Chem Biol 11 (8) : 611-617.

Buckley, D.L. and C.M. Crews (2014) . "Small-molecule control of intracellular protein levels through modulation of the ubiquitin proteasome system. " Angew Chem Int Ed Engl 53 (9) : 2312-2330.

Buckley, D.L., J.L. Gustafson, I. Van Molle, A.G. Roth, H.S. Tae, P.C. Gareiss, W.L. Jorgensen, A. Ciulli and C.M. Crews (2012) . "Small-molecule inhibitors of the interaction between the E3 ligase VHL and HIF1alpha. " Angew Chem Int Ed Engl 51 (46) : 11463-11467.

Buckley, D.L., K. Raina, N. Darricarrere, J. Hines, J.L. Gustafson, I.E. Smith, A.H. Miah, J.D. Harling and C.M. Crews (2015) . "HaloPROTACS: Use of Small Molecule PROTACs to Induce Degradation of HaloTag Fusion Proteins. " ACS Chem Biol 10 (8) : 1831-1837.

Buckley, D.L., I. Van Molle, P.C. Gareiss, H.S. Tae, J. Michel, D.J. Noblin, W.L. Jorgensen, A. Ciulli and C.M. Crews (2012) . "Targeting the von Hippel-Lindau E3 ubiquitin ligase using small molecules to disrupt the VHL/HIF-1alpha interaction. " J Am Chem Soc 134 (10) : 4465-4468.

Chamberlain, P.P., A. Lopez-Girona, K. Miller, G. Carmel, B. Pagarigan, B. Chie-Leon, E. Rychak, L.G. Corral, Y.J. Ren, M. Wang, M. Riley, S.L. Delker, T. Ito, H. Ando, T. Mori, Y. Hirano, H. Handa, T. Hakoshima, T.O. Daniel and B.E. Cathers (2014) . "Structure of the human Cereblon-DDB1-lenalidomide complex reveals basis for responsiveness to thalidomide analogs. " Nat Struct Mol Biol 21 (9) : 803-809.

Chauvin, C., S. Salhi, C. Le Goff, W. Viranaicken, D. Diop and O. Jean-Jean (2005) . "Involvement of human release factors eRF3a and eRF3b in translation termination and regulation of the termination complex formation. " Mol Cell Biol 25 (14) : 5801-5811.

Colligris, B., H.A. Alkozi and J. Pintor (2014) . "Recent developments on dry eye disease treatment compounds. " Saudi J Ophthalmol 28 (1) : 19-30.

Damsky, W. and B.A. King (2017) . "JAK inhibitors in dermatology: The promise of a new drug class. " J Am Acad Dermatol 76 (4) : 736-744.

Davies, T.G., W.E. Wixted, J.E. Coyle, C. Griffiths-Jones, K. Hearn, R. McMenamin, D. Norton, S.J. Rich, C. Richardson, G. Saxty, H.M. Willems, A.J. Woolford, J.E. Cottom, J.P. Kou, J. G. Yonchuk, H.G. Feldser, Y. Sanchez, J.P. Foley, B.J. Bolognese, G. Logan, P.L. Podolin, H. Yan, J.F. Callahan, T.D. Heightman and J.K. Kerns (2016) . "Monoacidic Inhibitors of the Kelch-like ECH-Associated Protein 1: Nuclear Factor Erythroid 2-Related Factor 2 (KEAP1: NRF2) Protein-Protein Interaction with High Cell Potency Identified by Fragment-Based Discovery. " J Med Chem 59 (8) : 3991-4006.

Fischer, E.S., K. Bohm, J.R. Lydeard, H. Yang, M.B. Stadler, S. Cavadini, J. Nagel, F. Serluca, V. Acker, G.M. Lingaraju, R.B. Tichkule, M. Schebesta, W.C. Forrester, M. Schirle, U. Hassiepen, J. Ottl, M. Hild, R.E. Beckwith, J.W. Harper, J.L. Jenkins and N.H. Thoma (2014) . "Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide. " Nature 512 (7512) : 49-53.

Fleming, S.B. (2016) . "Viral Inhibition of the IFN-Induced JAK/STAT Signalling Pathway: Development of Live Attenuated Vaccines by Mutation of Viral-Encoded IFN-Antagonists. " Vaccines (Basel) 4 (3) .

Frolova, L., X. Le Goff, G. Zhouravleva, E. Davydova, M. Philippe and L. Kisselev (1996) . "Eukaryotic polypeptide chain release factor eRF3 is an eRF1-and ribosome-dependent guanosine triphosphatase. " RNA 2 (4) : 334-341.

Galdeano, C., M.S. Gadd, P. Soares, S. Scaffidi, I. Van Molle, I. Birced, S. Hewitt, D. M.Dias and A. Ciulli (2014) . "Structure-guided design and optimization of small molecules targeting the protein-protein interaction between the von Hippel-Lindau (VHL) E3 ubiquitin ligase and the hypoxia inducible factor (HIF) alpha subunit with in vitro nanomolar affinities. " J Med Chem 57 (20) : 8657-8663.

Griesshammer, M. and P. Sadjadian (2017) . "The BCR-ABL1-negative myeloproliferative neoplasms: a review of JAK inhibitors in the therapeutic armamentarium. " Expert Opin Pharmacother 18 (18) : 1929-1938.

Hansen, J.D., M. Correa, M.A. Nagy, M. Alexander, V. Plantevin, V. Grant, B. Whitefield, D. Huang, T. Kercher, R. Harris, R.K. Narla, J. Leisten, Y. Tang, M. Moghaddam, K. Ebinger, J. Piccotti, C.G. Havens, B. Cathers, J. Carmichael, T. Daniel, R. Vessey, L.G. Hamann, K. Leftheris, D. Mendy, F. Baculi, L.A. LeBrun, G. Khambatta and A. Lopez-Girona (2020) . "Discovery of CRBN E3 Ligase Modulator CC-92480 for the Treatment of Relapsed and Refractory Multiple Myeloma. " J Med Chem.

Ishoey, M., S. Chorn, N. Singh, M.G. Jaeger, M. Brand, J. Paulk, S. Bauer, M.A. Erb, K. Parapatics, A.C. Muller, K.L. Bennett, G.F. Ecker, J.E. Bradner and G.E. Winter (2018) . "Translation Termination Factor GSPT1 Is a Phenotypically Relevant Off-Target of Heterobifunctional Phthalimide Degraders. " ACS Chem Biol 13 (3) : 553-560.

Ito, T., H. Ando, T. Suzuki, T. Ogura, K. Hotta, Y. Imamura, Y. Yamaguchi and H. Handa (2010) . "Identification of a primary target of thalidomide teratogenicity. " Science 327 (5971) : 1345-1350.

Keil, E., D. Finkenstadt, C. Wufka, M. Trilling, P. Liebfried, B. Strobl, M. Muller and K. Pfeffer (2014) . "Important scaffold function of the Janus kinase 2 uncovered by a novel mouse model harboring a Jak2 activation-loop mutation. " Blood 123 (4) : 520-529.

Kilpivaara, O. and R.L. Levine (2008) . "JAK2 and MPL mutations in myeloproliferative neoplasms: discovery and science. " Leukemia 22 (10) : 1813-1817.

Koppikar, P., N. Bhagwat, O. Kilpivaara, T. Manshouri, M. Adli, T. Hricik, F. Liu, L.M. Saunders, A. Mullally, O. Abdel-Wahab, L. Leung, A. Weinstein, S. Marubayashi, A. Goel, M. Gonen, Z. Estrov, B.L. Ebert, G. Chiosis, S.D. Nimer, B.E. Bernstein, S. Verstovsek and R.L. Levine (2012) . "Heterodimeric JAK-STAT activation as a mechanism of persistence to JAK2 inhibitor therapy. " Nature 489 (7414) : 155-159.

LaFave, L.M. and R.L. Levine (2012) . "JAK2 the future: therapeutic strategies for JAK-dependent malignancies. " Trends Pharmacol Sci 33 (11) : 574-582.

Lai, A.C., M. Toure, D. Hellerschmied, J. Salami, S. Jaime-Figueroa, E. Ko, J. Hines and C.M. Crews (2016) . "Modular PROTAC Design for the Degradation of Oncogenic BCR-ABL. " Angew Chem Int Ed Engl 55 (2) : 807-810.

Langabeer, S.E. (2014) . "JAK2 mutations to the fore in hereditary thrombocythemia. " JAKSTAT 3 (3) : e957618.

Levine, R.L., M. Wadleigh, J. Cools, B.L. Ebert, G. Wernig, B.J. Huntly, T.J. Boggon, I. Wlodarska, J.J. Clark, S. Moore, J. Adelsperger, S. Koo, J.C. Lee, S. Gabriel, T. Mercher, A. D'Andrea, S. Frohling, K. Dohner, P. Marynen, P. Vandenberghe, R.A. Mesa, A. Tefferi, J.D. Griffin, M.J. Eck, W.R. Sellers, M. Meyerson, T.R. Golub, S.J. Lee and D. G. Gilliland (2005) . "Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. " Cancer Cell 7 (4) : 387-397.

Li, J. (2013) . "JAK-STAT and bone metabolism. " JAKSTAT 2 (3) : e23930.

Lu, J., Y. Qian, M. Altieri, H. Dong, J. Wang, K. Raina, J. Hines, J.D. Winkler, A.P. Crew, K. Coleman and C.M. Crews (2015) . "Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4. " Chem Biol 22 (6) : 755-763.

Malta-Vacas, J., C. Aires, P. Costa, A.R. Conde, S. Ramos, A.P. Martins, C. Monteiro and M. Brito (2005) . "Differential expression of the eukaryotic release factor 3 (eRF3/GSPT1) according to gastric cancer histological types. " J Clin Pathol 58 (6) : 621-625.

Matyskiela, M.E., G. Lu, T. Ito, B. Pagarigan, C.C. Lu, K. Miller, W. Fang, N.Y. Wang, D. Nguyen, J. Houston, G. Carmel, T. Tran, M. Riley, L. Nosaka, G.C. Lander, S. Gaidarova, S. Xu, A.L. Ruchelman, H. Handa, J. Carmichael, T.O. Daniel, B. E. Cathers, A. Lopez-Girona and P. P. Chamberlain (2016) . "A novel cereblon modulator recruits GSPT1 to the CRL4 (CRBN) ubiquitin ligase. " Nature 535 (7611) : 252-257.

Maxson, J.E., J. Gotlib, D.A. Pollyea, A.G. Fleischman, A. Agarwal, C.A. Eide, D. Bottomly, B. Wilmot, S.K. McWeeney, C.E. Tognon, J.B. Pond, R.H. Collins, B. Goueli, S.T. Oh, M.W. Deininger, B. H. Chang, M.M. Loriaux, B.J. Druker and J.W. Tyner (2013) . "Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML. " N Engl J Med 368 (19) : 1781-1790.

Moore, C.A., C.J. Iasella, R. Venkataramanan, F.G. Lakkis, R.B. Smith, J.F. McDyer, A. Zeevi and C.R. Ensor (2017) . "Janus kinase inhibition for immunosuppression in solid organ transplantation: Is there a role in complex immunologic challenges? " Hum Immunol 78 (2) : 64-71.

Neubauer, H., A. Cumano, M. Muller, H. Wu, U. Huffstadt and K. Pfeffer (1998) . "Jak2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis. " Cell 93 (3) : 397-409.

O'Shea, J.J., S.M. Holland and L.M. Staudt (2013) . "JAKs and STATs in immunity, immunodeficiency, and cancer. " N Engl J Med 368 (2) : 161-170.

O'Shea, J.J., A. Kontzias, K. Yamaoka, Y. Tanaka and A. Laurence (2013) . "Janus kinase inhibitors in autoimmune diseases. " Ann Rheum Dis 72 Suppl 2: ii111-115.

O'Shea, J.J., D.M. Schwartz, A.V. Villarino, M. Gadina, I.B. McInnes and A. Laurence (2015) . "The JAK-STAT pathway: impact on human disease and therapeutic intervention. " Annu Rev Med 66: 311-328.

Ohoka, N., K. Okuhira, M. Ito, K. Nagai, N. Shibata, T. Hattori, O. Ujikawa, K. Shimokawa, O. Sano, R. Koyama, H. Fujita, M. Teratani, H. Matsumoto, Y. Imaeda, H. Nara, N. Cho and M. Naito (2017) . "In Vivo Knockdown of Pathogenic Proteins via Specific and Nongenetic Inhibitor of Apoptosis Protein (IAP) -dependent Protein Erasers (SNIPERs) . " J Biol Chem 292 (11) : 4556-4570.

Okuhira, K., N. Ohoka, K. Sai, T. Nishimaki-Mogami, Y. Itoh, M. Ishikawa, Y. Hashimoto and M. Naito (2011) . "Specific degradation of CRABP-II via cIAP1-mediated ubiquitylation induced by hybrid molecules that crosslink cIAP1 and the target protein. " FEBS Lett 585 (8) : 1147-1152.

Rumi, E., D. Pietra, C. Pascutto, P. Guglielmelli, A. Martinez-Trillos, I. Casetti, D. Colomer, L. Pieri, M. Pratcorona, G. Rotunno, E. Sant'A ntonio, M. Bellini, C. Cavalloni, C. Mannarelli, C. Milanesi, E. Boveri, V. Ferretti, C. Astori, V. Rosti, F. Cervantes, G. Barosi, A.M. Vannucchi, M. Cazzola and I. Associazione Italiana per la Ricerca sul Cancro Gruppo Italiano Malattie Mieloproliferative (2014) . "Clinical effect of driver mutations of JAK2, CALR, or MPL in primary myelofibrosis. " Blood 124 (7) : 1062-1069.

Schwartz, D.M., Y. Kanno, A. Villarino, M. Ward, M. Gadina and J.J. O'Shea (2017) . "JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. " Nat Rev Drug Discov 16 (12) : 843-862.

Shibata, N., N. Miyamoto, K. Nagai, K. Shimokawa, T. Sameshima, N. Ohoka, T. Hattori, Y. Imaeda, H.Nara, N. Cho and M. Naito (2017) . "Development of protein degradation inducers of oncogenic BCR-ABL protein by conjugation of ABL kinase inhibitors and IAP ligands. " Cancer Sci 108 (8) : 1657-1666.

Sun, D., Z. Li, Y. Rew, M. Gribble, M.D. Bartberger, H.P. Beck, J. Canon, A. Chen, X. Chen, D. Chow, J. Deignan, J. Duquette, J. Eksterowicz, B. Fisher, B.M. Fox, J. Fu, A.Z. Gonzalez, F. Gonzalez-Lopez De Turiso, J.B. Houze, X. Huang, M. Jiang, L. Jin, F. Kayser, J.J. Liu, M.C. Lo, A.M. Long, B. Lucas, L.R. McGee, J. McIntosh, J. Mihalic, J.D. Oliner, T. Osgood, M.L. Peterson, P. Roveto, A.Y. Saiki, P. Shaffer, M. Toteva, Y. Wang, Y.C. Wang, S. Wortman, P. Yakowec, X. Yan, Q. Ye, D. Yu, M. Yu, X. Zhao, J. Zhou, J. Zhu, S.H. Olson and J.C. Medina (2014) . "Discovery of AMG 232, a potent, selective, and orally bioavailable MDM2-p53 inhibitor in clinical development. " J Med Chem 57 (4) : 1454-1472.

Sun, W., L. Zhang, R. Yan, Y. Yang and X. Meng (2019) . "LncRNA DLX6-AS1 promotes the proliferation, invasion, and migration of non-small cell lung cancer cells by targeting the miR-27b-3p/GSPT1 axis. " Onco Targets Ther 12: 3945-3954.

Tefferi, A. (2012) . "JAK inhibitors for myeloproliferative neoplasms: clarifying facts from myths. " Blood 119 (12) : 2721-2730.

Tian, Q.G., R.C. Tian, Y. Liu, A.Y. Niu, J. Zhang and W.F. Gao (2018) . "The role of miR-144/GSPT1 axis in gastric cancer. " Eur Rev Med Pharmacol Sci 22 (13) : 4138-4145.

Villarino, A.V., Y. Kanno, J.R. Ferdinand and J.J. O'Shea (2015) . "Mechanisms of Jak/STAT signaling in immunity and disease. " J Immunol 194 (1) : 21-27.

Winter, G.E., D.L. Buckley, J. Paulk, J. M. Roberts, A. Souza, S. Dhe-Paganon and J. E. Bradner (2015) . "Phthalimide conjugation as a strategy for in vivo target protein degradation. " Science 348 (6241) : 1376-1381.

Xie, T., S.M. Lim, K.D. Westover, M.E. Dodge, D. Ercan, S.B. Ficarro, D. Udayakumar, D. Gurbani, H.S. Tae, S.M. Riddle, T. Sim, J.A. Marto, P.A. Janne, C.M. Crews and N.S. Gray (2014) . "Pharmacological targeting of the pseudokinase Her3. " Nat Chem Biol 10 (12) : 1006-1012.

Zengerle, M., K.H. Chan and A. Ciulli (2015) . "Selective Small Molecule Induced Degradation of the BET Bromodomain Protein BRD4. " ACS Chem Biol 10 (8) : 1770-1777.

Zhang, C., Y. Zou and D. Q. Dai (2019) . "Downregulation of microRNA-27b-3p via aberrant DNA methylation contributes to malignant behavior of gastric cancer cells by targeting GSPT1. " Biomed Pharmacother 119: 109417.

Zhouravleva, G., L. Frolova, X. Le Goff, R. Le Guellec, S. Inge-Vechtomov, L. Kisselev and M. Philippe (1995) . "Termination of translation in eukaryotes is governed by two interacting polypeptide chain release factors, eRF1 and eRF3. " EMBO J 14 (16) : 4065-4072.

OTHER EMBODIMENTS

It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

A heterobifunctional compound comprising a Janus kinase ligand (JAK ligand) conjugated to a degradation tag via a linker moiety (JAK ligand-linker-degradation tag) , or a pharmaceutically acceptable salt or analog thereof,

wherein

I) the JAK ligand comprises a comprises a moiety of FORMULA 1;

wherein

the linker moiety of the heterobifunctional compound is attached to R ¹;

A and D are independently selected from CR ⁴ and N, wherein

R ⁴ is selected from H, halogen, optionally substituted C ₁-C ₈ alkyl, and optionally substituted 3-10 membered carbocyclyl;

B, C and G are independently selected from C and N; with the proviso that at most only one of B, C and G is N;

E and F are independently selected from null, CR ⁵ and N, wherein

R ⁵ is selected from H, halogen, optionally substituted C ₁-C ₈ alkyl, and optionally substituted 3-10 membered carbocyclyl;

X and Y are independently selected from null, or a bivalent moiety selected from null, CR ⁶R ⁷, CO, CO ₂, CONR ⁶, NR ⁶, NR ⁶CO, NR ⁶CO ₂, NR ⁶C (O) NR ⁷, NR ⁶SO, NR ⁶SO ₂, NR ⁶SO ₂NR ⁷, O, OC (O) , OCO ₂, OCONR ⁶, S, SO, SO ₂, and SO ₂NR ⁶, wherein

R ⁶ and R ⁷ are independently selected from H, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C ₁-C ₈ alkyl, optionally substituted C ₂-C ₈ alkenyl, optionally substituted C ₂-C ₈ alkynyl, optionally substituted C ₁-C ₈ alkoxy, optionally substituted C ₁-C ₈ alkylamino, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or R ⁶ and R ⁷ together with the atom or atoms to which they are connected form a 3-20 membered carbocyclyl ring or 3-20 membered heterocyclyl ring;

V and W are independently selected from null, carbocyclyl, heterocyclyl, aryl, and heteroaryl, which are optionally substituted with one or more R ¹⁶;

R ¹ is connected to the “linker” moiety of the heterobifunctional compound, and is selected from null, 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'SO ₂N (R ¹¹) R", R'NR ¹²C (O) OR", R'NR ¹²C (O) R", R'NR ¹²C (O) N (R ¹¹) R", R'NR ¹²S (O) R", R'NR ¹²S (O) ₂R", and R'NR ¹²S (O) ₂NR ¹¹R", wherein

R' and R" are divalent groups independently selected from null, optionally substituted C ₁-C ₈ alkylene, optionally substituted C ₂-C ₈ alkenylene, optionally substituted C ₂-C ₈ alkynylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C ₄-C ₁₃ fused carbocyclyl, optionally substituted C ₅-C ₁₃ fused heterocyclyl, optionally substituted C ₅-C ₁₃ bridged carbocyclyl, optionally substituted C ₅-C ₁₃ bridged heterocyclyl, optionally substituted C ₅-C ₁₃ spiro carbocyclyl, optionally substituted C ₅-C ₁₃ spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R ¹¹ and R ¹² are independently selected from optionally substituted C ₁-C ₈ alkyl, optionally substituted C ₂-C ₈ alkenyl, optionally substituted C ₂-C ₈ alkynyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

R' and R", R ¹¹ and R ¹², R' and R ¹¹, R' and R ¹², R" and R ¹¹ or R" and R ¹², together with the atom to which they are connected, form a 3-20 membered carbocyclyl or 3-20 membered heterocyclyl ring;

R ² is selected from H, halogen, OH, O-C ₁-C ₈ alkyl, CN, NO ₂, C ₁-C ₈ alkyl, C ₂-C ₈ alkenyl, C ₂-C ₈ alkynyl, 3-10 membered carbocyclyl, 3-10 membered heterocyclyl, aryl, and heteroaryl; each of which are optionally substituted with one or more R ¹⁷;

R ¹⁶ and R ¹⁷ are each independently selected from hydrogen, halogen, oxo, CN, NO ₂, OR ⁸, SR ⁸, NR ⁸R ⁹, OCOR ⁸, OCO ₂R ⁸, OCON (R ⁸) R ⁹, COR ⁸, CO ₂R ⁸, CON (R ⁸) R ⁹, SOR ⁸, SO ₂R ⁸, SO ₂N (R ⁸) R ⁹, NR ¹⁰CO ₂R ⁸, NR ¹⁰COR ⁸, NR ¹⁰C (O) N (R ⁸) R ⁹, NR ¹⁰SOR ⁸, NR ¹⁰SO ₂R ⁸, NR ¹⁰SO ₂N (R ⁸) R ⁹, optionally substituted C ₁-C ₈ alkyl, optionally substituted C ₂-C ₈ alkenyl, optionally substituted C ₂-C ₈ alkynyl, optionally substituted C ₁-C ₈alkoxyC ₁-C ₈alkyl, optionally substituted C ₁-C ₈alkylaminoC ₁-C ₈alkyl, optionally substituted 3-10 membered heterocyclylC ₁-C ₈alkyl, optionally substituted 3-10 membered carbocyclylC ₁-C ₈alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein

R ⁸, R ⁹, and R ¹⁰ are independently selected from hydrogen, optionally substituted C ₁-C ₈ alkyl, optionally substituted C ₂-C ₈ alkenyl, optionally substituted C ₂-C ₈ alkynyl, optionally substituted C ₁-C ₈ alkoxy, optionally substituted C ₁-C ₈alkoxyC ₁-C ₈alkyl, optionally substituted C ₁-C ₈alkylaminoC ₁-C ₈alkyl, optionally substituted 3-10 membered carbocyclylC ₁-C ₈alkyl, optionally substituted 3-10 membered heterocyclylC ₁-C ₈alkyl, 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 together with the atom to which they are connected form a 3-20 membered heterocyclyl ring;

R ³, at each occurance, is selected from H, halogen, optionally substituted C ₁-C ₈ alkyl, and optionally substituted 3-10 membered carbocyclyl; and

n is selected from 1 or 2;

II) the degradation tag is a moiety of FORMULA 5, and the degradation tag is connected to the linker moiety of the heterobifunctional compound via Z _E;

wherein

Z _E is a divalent group of - (R _E ^z) _nE-; wherein subscript n _E = 0、 1、 2、 3、 4、 5 or 6; wherein R _E ^Z, at each occurrence, is independently R _E ^r, or R _E ^w; wherein R _E ^w, at each occurrence, is a bond or selected from the group consisting of -CO-, -CR _E ⁵R _E ⁶-, -NR _E ⁵-, -O-, optionally substituted C ₁-C ₁₀ alkylene, optionally substituted C ₁-C ₁₀ alkenylene, optionally substituted C ₁-C ₁₀ alkynylene; and R _E ^r, at each occurrence, is a bond, or selected from the group consisting of optionally substituted 3-10 membered carbocyclyl such as 3-8 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl such as 3-8 membered heterocyclyl, optionally substituted C ₄-C ₁₃ fused cycloalkyl, optionally substituted C ₄-C ₁₃ fused heterocyclyl, optionally substituted C ₅-C ₁₃ bridged cycloalkyl, optionally substituted C ₅-C ₁₃ bridged heterocyclyl, optionally substituted C ₅-C ₁₃ spiro cycloalkyl, optionally substituted C ₅-C ₁₃ spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; with the proviso that -R _E ^z -R _E ^z-is not -O-O-; R _E ⁵ and R _E ⁶ at each occurrence are independently selected from the group consisting of hydrogen, halogen, oxo, hydroxy, amino, cyano, nitro, optionally substituted C ₁-C ₆ 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 atom (s) to which they are connected form an optionally substituted 3-8 membered cycloalkyl or heterocyclyl ring;

R _E ¹ is selected from the group consisting of hydrogen, halogen, cyano, nitro, optionally substituted C ₁-C ₆ alkyl, optionally substituted 3-8 membered carbocyclyl, and optionally substituted 3-8 membered heterocyclyl;

L _E is a divalent group selected from the group consisting of null, -L _E ¹-, and -L _E ¹-L _E ²-; wherein L _E ¹ and L _E ² are independently selected from the group consisting of -CO-, -O-, -CR _E ¹⁰R _E ¹¹-and -NR _E ¹⁰-, with the proviso that -L _E ¹-L _E ²-is not –O-O-; wherein R _E ¹⁰ and R _E ¹¹ are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, amino, optionally substituted C ₁-C ₆ alkyl, optionally substituted C ₁-C ₆ alkoxy, and optionally substituted C ₁-C ₆ alkylamino;

Ring A _E is a divalent group selected from the group consisting of FORMULA A _E1, A _E2, A _E3, A _E4 and A _E5:

wherein

* indicates the attachment to L _E, and Z _E is attached to any possible position on the Ring A _E;

indicates a single bond or a double bond;

V _E ¹, V _E ², V _E ³, V _E ⁴ and V _E ⁵, at each occurrence, are each independently selected from the group consisting of a bond, C, CR _E ², S, N, and NR _E ²; or V _E ¹ and V _E ², V _E ² and V _E ³, V _E ³ and V _E ⁴, or V _E ⁴ and V _E ⁵ are combined together to optionally form 6 membered aryl ring or a 5, 6 or 7 membered heteroaryl ring;

R _E ², at each occurrence, is independently selected from the group consisting of absent, hydrogen, halogen, cyano, nitro, hydroxy, amino, optionally substituted C ₁-C ₆ alkyl, optionally substituted C ₁-C ₆ alkenyl, optionally substituted C ₁-C ₆ alkynyl, optionally substituted C ₁-C ₆ alkoxy, optionally substituted C ₁-C ₆ 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 atom (s) to which they are connected form optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-8 membered heterocyclyl ring, optionally substituted aryl, and optionally substituted heteroaryl;

W _E ¹, W _E ², W _E ³ and W _E ⁴ are each independently selected from the group consisting of -N=, -C≡, -CR _E ³=, -CO-, -O-, -CR _E ³R _E ⁴-, -NR _E ³-, -CR _E ³=CR _E ⁴-, -N=CR _E ³-, and -N=N-; or W _E ¹ and W _E ², W _E ² and W _E ³, or W _E ³ and W _E ⁴ are combined together to optionally form 6 membered aryl ring or a 5, 6 or 7 membered heteroaryl ring;

R _E ³ and R _E ⁴, at each occurrence, are independently selected from the group consisting of absent, hydrogen, halogen, cyano, nitro, hydroxy, amino, optionally substituted C ₁-C ₆ alkyl, optionally substituted 3 to 8 membered carbocyclyl, and optionally substituted 3 to 8 membered heterocyclyl; or R _E ³ and R _E ⁴, on the same atom or on the adjent atoms, together with the atom (s) to which they are connected form an optionally substituted 3-8 membered cycloalkyl or heterocyclyl ring;

III) the linker moiety is of FORMULA 9:

wherein

A _L, W _L and B _L, at each occurrence, are independently selected from null, or bivalent moiety selected from R _L ^d-R _L ^e, R _L ^dCOR _L ^e, R _L ^dCO ₂R _L ^e, R _L ^dC (O) N (R _L ¹) R _L ^e, R _L ^dC (S) N (R _L ¹) R _L ^e, R _L ^dOR _L ^e, R _L ^dSR _L ^e, R _L ^dSOR _L ^e, R _L ^dSO ₂R _L ^e, R _L ^dSO ₂N (R _L ¹) R _L ^e, R _L ^dN (R _L ¹) R _L ^e, R _L ^dN (R _L ¹) COR _L ^e, R _L ^dN (R _L ¹) CON (R _L ²) R _L ^e, R _L ^dN (R _L ¹) C (S) R _L ^e, optionally substituted C ₁-C ₈ alkylene, optionally substituted C ₂-C ₈ alkenylene, optionally substituted C ₂-C ₈ alkynylene, optionally substituted C ₁-C ₈alkoxyC ₁-C ₈alkylene, optionally substituted C ₁-C ₈ haloalkylene, optionally substituted C ₁-C ₈ 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 spiro cycloalkyl, optionally substituted 5-13 membered spiro heterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein

R _L ^d and R _L ^e, at each occurrence, are independently selected from null, optionally substituted (C ₁-C ₈ alkylene) -R _L ^r (preferably, CH ₂-R _L ^r) , optionally substituted R _L ^r- (C ₁-C ₈ alkylene) , optionally substituted (C ₁-C ₈ alkylene) -R _L ^r- (C ₁-C ₈ alkylene) , or a moiety comprising of optionally substituted C ₁-C ₈ alkyl, optionally substituted C ₂-C ₈ alkenyl, optionally substituted C ₂-C ₈ alkynyl, optionally substituted C ₁-C ₈ hydroxyalkyl, optionally substituted C ₁-C ₈alkoxyC ₁-C ₈alkyl, optionally substituted C ₁-C ₈alkylaminoC ₁-C ₈alkyl, optionally substituted C ₁-C ₈ haloalkyl, optionally substituted C ₁-C ₈ alkylene, optionally substituted C ₂-C ₈ alkenylene, optionally substituted C ₂-C ₈ alkynylene, optionally substituted C ₁-C ₈ hydroxyalkylene, optionally substituted C ₁-C ₈alkoxyC ₁-C ₈alkylene, optionally substituted C ₁-C ₈alkylaminoC ₁-C ₈alkylene, optionally substituted C ₁-C ₈ 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 spiro cycloalkyl, optionally substituted 5-13 membered spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R _L ^r, at each occurrence, is selected from 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 spiro cycloalkyl, optionally substituted 5-13 membered spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R _L ¹ and R _L ², at each occurrence, are independently selected from hydrogen, optionally substituted C ₁-C ₈ alkyl, optionally substituted C ₂-C ₈ alkenyl, optionally substituted C ₂-C ₈ alkynyl, optionally substituted C ₁-C ₈ alkoxyalkyl, optionally substituted C ₁-C ₈ haloalkyl, optionally substituted C ₁-C ₈ hydroxyalkyl, optionally substituted C ₁-C ₈alkylaminoC ₁-C ₈alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R _L ^dand R _L ^e, R _L ¹ and R _L ², R _L ^dand R _L ¹, R _L ^dand R _L ², R _L ^e and R _L ¹, R _L ^e and R _L ² together with the atom (s) to which they are connected form a 3-20 membered cycloalkyl or 3-20 membered heterocyclyl ring; and

m _L is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.
The heterobifunctional compound of claim 1, wherein the heterobifunctional compound is not any compound selected from Table 1B.
The heterobifunctional compound of claim 1 or 2, wherein Ring A _E is a divalent group selected of FORMULA A _E1, or A _E5; and Ring A _E is attached to L _E via W _E ².
The heterobifunctional compound of claim 3, wherein W _E ¹ and W _E ³ are each independently selected from the group consisting of CO, O, CR _E ³R _E ⁴, NR _E ³; and W _E ² is N.
The heterobifunctional compound of claim 1 or 2, wherein the degradation tag is a moiety of FORMULA 5-1 or 5-6, and the degradation tag is connected to the linker moiety of the heterobifunctional compound via a divalent group of Z _E;

wherein

W _E ¹and W _E ³ are each independently selected from the group consisting of CO, O, CR _E ³R _E ⁴, and NR _E ³;

W _E ² is N, and connected to

Z _E, R _E ¹. R _E ³. R _E ⁴L _E,
V _E ¹, V _E ², V _E ³, V _E ⁴, and V _E ⁵, are defined as in FORMULA 5.
The heterobifunctional compound of claim 1 or 2, wherein the degradation tag is a moiety of FORMULAE 5A or 5M

wherein,

W _E ¹ is independently selected from the group consisting of CO, O, CR _E ³R _E ⁴, and NR _E ³;

V _E ¹, V _E ², V _E ³, V _E ⁴, R _E ¹, R _E ³, R _E ⁴ and Z _E are defined as in FORMULA 5.
The heterobifunctional compound of claim 1 or 2, wherein R _E ³ and R _E ⁴, at each occurrence, are independently selected from the group consisting of absent, hydrogen, halogen, cyano, nitro, hydroxy, amino, optionally substituted C ₁-C ₆ alkyl.
The heterobifunctional compound of claim 1 or 2, wherein the degradation tag is moiety selected from the group consisting of:
The heterobifunctional compound of claim 1 or 2, wherein the JAK ligand is a moiey of FORMULA 1A, 1B, 1C, 1D or 1E

wherein

the linker moiety of the heterobifunctional compound is attached to R ¹;

Ar ¹ and Ar ² are independently selected from null, aryl, and heteroaryl, each of which is optionally substituted with one or more R ¹⁶;

A, B, C, D, E, F, G, X, Y, R ¹, R ², R ³, R ¹⁶ and n are defined as in FORMULA 1.
The heterobifunctional compound of claim 1 or 2, wherein the JAK ligand is a moiey of FORMULA 1F, 1G, 1H, 1J, 1I, 1K, 1L, 1M:

wherein

the linker moiety of the heterobifunctional compound is attached to R ¹;

R ¹³ and R ¹⁴ are defined as R ³;

Ar ¹ and Ar ² are independently selected from null, aryl, and heteroaryl, each of which is optionally substituted with one or more R ¹⁶;

X, Y, R ¹, R ², R ³, R ¹⁶ and n are defined as in FORMULA 1.
The heterobifunctional compound of claim 1, 2, 9 or 10, wherein X is selected from null, O, and NR ⁶, wherein R ⁶ is selected from H, optionally substituted C ₁-C ₈ alkyl, and optionally substituted 3-10 membered carbocyclyl.
The heterobifunctional compound of claim 1, 2, 9 or 10, wherein Y is selected from null, CR ⁶R ⁷, CO, CO ₂, O, SO, SO ₂, and NR ⁶, wherein R ⁶ and R ⁷ are independently selected from H, optionally substituted C ₁-C ₈ alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 3-10 membered heterocyclyl.
The heterobifunctional compound of claim 1, 2, 9 or 10, wherein W, V, Ar ¹ or Ar ², at each occurrence, are independently selected from null, monocyclic aryl (such as phenyl) , and monocyclic heteroaryl (such as 5, 6 or 7 membered heteroaryl) , each of which is optionally substituted with one or more R ¹⁶; wherein

each R ¹⁶ is independently selected from H, halogen, oxo, CN, NO ₂, OR ⁸, SR ⁸, N (R ⁸) R ⁹, COR ⁸, CO ₂R ⁸, CON(R ⁸) R ⁹, SOR ⁸, SO ₂R ⁸, SO ₂N (R ⁸) R ⁹, NR ¹⁰COR ⁸, NR ¹⁰SOR ⁸, NR ¹⁰SO ₂R ⁸, optionally substituted C ₁-C ₈ alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 3-10 membered heterocyclyl, wherein

R ⁸, R ⁹, and R ¹⁰ are independently selected from H, optionally substituted C ₁-C ₈ 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 together with the atom to which they are connected form a 3-10 membered heterocyclyl ring.
The heterobifunctional compound of claims 1, 2, 9 or 10, wherein each R ¹⁶ is independently selected from H, halogen, oxo, CN, NO ₂, OR ⁸, NR ⁸R ⁹, NR ¹⁰COR ⁸, optionally substituted C ₁-C ₈ alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 3-10 membered heterocyclyl, wherein

R ⁸, R ⁹, and R ¹⁰ are independently selected from H, optionally substituted C ₁-C ₈ 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 together with the atom to which they are connected form a 3-10 membered heterocyclyl ring.
The heterobifunctional compound of claims 1, 8 -13, wherein R ¹⁶ is each independently selected from H, CH ₃, CF ₃, iPr, cPr, OCH ₃, OCF ₃, OiPr, OcPr, F, Cl, and Br.
The heterobifunctional compound of claim 1, 2, 9 or 10, wherein R ¹ is selected from null and optionally substituted 3-10 membered heterocyclyl, which contains at least one of O or N.
The heterobifunctional compound of claim 1, 2, 9 or 10, wherein R ¹ is selected from null, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted morpholinyl, optionally substituted pyrrolidinyl, optionally substituted tetrahydrofuranyl, optionally substituted azetidinyl, and optionally substituted oxetanyl.
The heterobifunctional compound of claim 1, 2, 9 or 10, wherein R ² is selected from H, OH, -O-C ₁-C ₈ alkyl, halogen, C ₁-C ₈ alkyl, 3-10 membered carbocyclyl, and 3-10 membered heterocyclyl; each of which are optionally substituted with one or more R ¹⁷.
The heterobifunctional compound of claim 1, 2, 9 or 10, wherein R ² is selected from OH, CH ₃, CF ₃, iPr, cPr, F, Cl, Br, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl, and oxetanyl; each of which are optionally substituted with one or more R ¹⁷.
The heterobifunctional compound of claim 18, or 19, wherein R ¹⁷ is each independently selected from H, halogen, oxo, CN, NO ₂, R ⁸, OR8, SR ⁸, N (R ⁸) R ⁹, COR ⁸, CO ₂R ⁸, CON (R ⁸) R ⁹, SOR ⁸, SO ₂R ⁸, wherein R ⁸ and R ⁹ are independently selected from H, C ₁-C ₃ alkyl, C ₃-C ₆ cycloalkyl, C _1-3 haloalkyl, and C _1-3 hydroxyalky.
The heterobifunctional compound of claim 1 or 2, wherein R _L ^r is selected from FORMULAE C1, C2, C3, C4, and C5

wherein

A _L ¹, B _L ¹, C _L ¹ and D _L ¹, at each occurrence, are independently selected from null, O, CO, SO, SO ₂, NR _L ^b, CR _L ^bR _L ^c; R _L ^b

A _L ², B _L ², C _L ², D _L ² and E _L ², at each occurrence, are independently selected from N, CR _L ^b;

A _L ³, B _L ³, C _L ³, D _L ³, and E _L ³, at each occurrence, are independently selected from N, O, S, NR _L ^b, CR _L ^b;

R _L ^b and R _L ^c, at each occurrence, are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C ₁-C ₈ alkyl, optionally substituted C ₂-C ₈ alkenyl, optionally substituted C ₂-C ₈ alkynyl, optionally substituted C ₁-C ₈ alkoxy, optionally substituted C ₁-C ₈ alkoxyalkyl, optionally substituted C ₁-C ₈ haloalkyl, optionally substituted C ₁-C ₈ hydroxyalkyl, optionally substituted C ₁-C ₈ alkylamino, and optionally substituted C ₁-C ₈ alkylaminoC ₁-C ₈ alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 3-8 membered membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; and

m _L ¹, n _L ¹, o _L ¹ and p _L ¹ are independently selected from 0, 1, 2, 3, 4 and 5.
The heterobifunctional compound of claim 1 or 2, wherein R _L ^r is selected from Group R _L ^r1 or Group R _L ^r2, and

Group R _L ^r1 consists of

Group R _L ^r2 consists of
The heterobifunctional compound of claim 1 or 2, wherein the linker moiety is of FORMULA 9D:

-A _L- (W _L) _qL-B _L- (FORMULA 9D)

wherein

W _L is each independently selected from null, R _L ^d-R _L ^e, R _L ^dCOR _L ^e, R _L ^dCO ₂R _L ^e, R _L ^dC (O) N (R _L ¹) R _L ^e, R _L ^dC (S) N (R _L ¹) R _L ^e, R _L ^dOR _L ^e, R _L ^dSR _L ^e, R _L ^dSOR _L ^e, R _L ^dSO ₂R _L ^e, R _L ^dSO ₂N (R _L ¹) R _L ^e, R _L ^dN (R _L ¹) R _L ^e, R _L ^dN (R _L ¹) COR _L ^e, R _L ^dN (R _L ¹) CON (R _L ²) R _L ^e, R _L ^dN (R _L ¹) C (S) R _L ^e, optionally substituted C ₁-C ₈ alkylene, optionally substituted C ₂-C ₈ alkenylene, optionally substituted C ₂-C ₈ alkynylene, optionally substituted C ₁-C ₈alkoxyC ₁-C ₈alkylene, optionally substituted C ₁-C ₈ haloalkylene, optionally substituted C ₁-C ₈ 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 spiro cycloalkyl, optionally substituted 5-13 membered spiro heterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl,

q _L = 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

R _L ¹, R _L ², R _L ^d, R _L ^e, A _L and B _L are defined as in FORMULA 9.
The heterobifunctional compound of claim 22, wherein

A _L and B _L are independently selected from null, R _L ^r, CH ₂-R _L ^r, R _L ^dCOR _L ^e, R _L ^dC (O) N (R _L ¹) R _L ^e, R _L ^dOR _L ^e, R _L ^dSR _L ^e, R _L ^dSOR _L ^e, R _L ^dSO ₂R _L ^e, R _L ^dSO ₂N (R _L ¹) R _L ^e, R _L ^dN (R _L ¹) R _L ^e, R _L ^dN (R _L ¹) COR _L ^e, R _L ^dN (R _L ¹) CON (R _L ²) R _L ^e, R _L ^dN (R _L ¹) C (S) R _L ^e, optionally substituted C ₁-C ₂ alkylene, optionally substituted C ₂ alkenylene, and optionally substituted C ₂ alkynylene; wherein

R _L ^d and R _L ^e is independently selected from null, C ₁-C ₂ alkylene optionally substituted with one or more C ₁-C ₃ alkyl, halogen, and C ₁-C ₃ haloalkyl;

R _L ¹ and R _L ² are independently selected from H, C ₁-C ₃ alkyl, C ₃-C ₆ cycloalkyl, and C ₁-C ₃ haloalkyl.
The heterobifunctional compound of claim 22, wherein the linker moiety is attached to the the JAK ligand via A _L; wherein

A _L is selected from null, R _L ^r, CH ₂-R _L ^r, CO, and CH ₂-CO;

B _L are independently selected from null, N (R _L ¹) , N (R _L ¹) -CH ₂, O, CH ₂, R _L ^r, R _L ^r-N (R _L ¹) , R _L ^r-CH ₂, and R _L ^r-O;

W _L is each selected from CO, N (R _L ¹) , C (S) , SO, SO ₂, C (O) N (R _L ¹) , N (R _L ²) C (O) N (R _L ¹) , S (O) ₂N (R _L ¹) , R _L ^r, optionally substituted C ₁-C ₂ alkylene, optionally substituted C ₂ alkenylene, and optionally substituted C ₂ alkynylene;

R _L ¹ and R _L ² are independently selected from H, C ₁-C ₃ alkyl, and C ₁-C ₃ haloalkyl;

q _L = 1, 2, 3, 4, or 5.
The heterobifunctional compound any one of claims 23 -25, wherein in A _L, R _L ^r is of FORMULAE C4, or C5; preferably in A _L, R _L ^r is selected from Group R _L ^r2 as defined inFORMULA 9.
The heterobifunctional compound any one of claims 23 -26, wherein

2 or 3 of W _L that are adjacent optionally combined to form a segment selected from -optionally substituted C ₁ alkylene -CO-N (R _L ¹) -, (preferably, -CF ₂-CO-NH-) , -N (R _L ¹) -CO-N (R _L ¹) , (preferably, -NH-CO-NH-) -, -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 -) ; and/or

W _L, at each occurrence, is optionally substituted C ₁-C ₂ alkylene.
The heterobifunctional compound of claim 1 or 2, wherein

the JAK ligand comprises a moiety of FORMULAE 1N; wherein Ar ¹ and Ar ² are 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 with one or more R ¹⁶,

the degradation tag is a moiety of FORMULA 5-1, and wherein V _E ² is C, and V _E ¹, V _E ³, and V _E ⁴ are each independently selected from N, and CR _E ²; or V _E ³is C, and V _E ¹, V _E ², and V _E ⁴ are each independently selected from N, and CR _E ²; and

the linker moiety is of FORMULA 9D.
The heterobifunctional compound of claim 1 or 2, wherein the heterobifunctional compound is selected from the group consisting of JA-296 to JA-350 or a pharmaceutically acceptable salt or analog thereof.
The heterobifunctional compound of claim 1 or 2, wherein 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 (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 (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 (JA-313) ;

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-oxopentanamide (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 (JA-317) ;

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) ;

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) ;

5- ( (6- (4- (4- (8- (3, 5-difluoro-4- ( (4-hydroxypiperidin-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) ;

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) ;

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 (JA-325) ;

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) ;

3- (4- ( (2- ( (4- (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) ;

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) ;

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) ;

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) ;

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) ;

5- ( (6- (4- (4- (8- (3, 5-difluoro-4- ( (4-hydroxypiperidin-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) ; and

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) ;

or a pharmaceutically acceptable salt or analog thereof.
A composition comprising a heterobifunctional compound according to any of claims 1 to 30 or a pharmaceutically acceptable salt or analog thereof.
A method of treating or preventing a disease, comprising administering to a subject in need a heterobifunctional compound or a pharmaceutically acceptable salt or analog thereof according to any one of claims 1 to 30.
The method of claim 32, wherein the disease is JAK-mediated disease, GSTP1-mediated disease, or the combination thereof.
The method of claim 33, wherein the JAK-mediated disease results from JAK expression, mutation, deletion, or fusion.
The method of claim 33 or 34, wherein the subject in need is a subject with the JAK-mediated disease, and the subject has an elevated JAK function relative to a healthy subject without the JAK-mediated disease.
The method of any one of claims 33 to 35, wherein the JAK-mediated cancer is selected from the group consisting of brain cancer, stomach cancer, gastrointestinal tract cancer, liver cancer, biliary passage cancer, breast cancer, ovary cancer, cervix cancer, prostate cancer, testis cancer, penile cancer, genitourinary tract cancer, esophagus cancer, larynx cancer, skin cancer, lung cancer, pancreas cancer, thyroid cancer, gland cancer, bladder cancer, kidney cancer, muscle cancer, bone cancer, cancers of the hematopoietic system, myeloproliferative neoplasms, essential thrombocythemia, polycythemia vera, primary myelofibrosis, chronic neutrophilic leukemia, acute lymphoblastic leukemia, Hodgkin’s lymphoma, chronic myelomonocytic leukemia, systemic mast cell disease, hypereosinophilic syndrome, cutaneous T-cell lymphoma, B-cell lymphoma, and myeloma.
The method of any one of claims 33 to 35, wherein

the JAK-mediated inflammatory disorders are selected from the group consisting of ankylosing spondylitis, Crohn’s disease, inflammatory bowel disease, ulcerative colitis, and ischemia reperfusion injuries; and/or

the JAK-mediated auto-immune diseases are 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 disorders, alopecia areata, and bullous pemphigoid; and/or

the JAK-mediated dermatological disorders are selected from the group consisting of atopic dermatitis, pruritus, alopecia areata, psoriasis, skin rash, skin irritation, skin sensitization, chronic mucocutaneous candidiasis, dermatomyositis, erythema multiforme, palmoplantar pustulosis, vitiligo, polyarteritis nodosa, and STING-associated vasculopathy; and/or

the JAK-mediated viral infections are selected from the group consisting of infections of Hepatitis B, Hepatitis C, Human Immunodeficiency Virus (HIV) , Human T-lymphotropic Virus (HTLV1) , Epstein Barr Virus (EBV) , Varicella-Zoster Virus (VZV) and Human Papilloma Virus (HPV) ; and/or

the JAK-mediated dry eye disorders are selected from the group consisting of dry eye syndrome (DES) and keratoconjunctivitis sicca (KCS) ; and/or

the JAK-mediated bone remodeling disorders are selected from the group consisting of osteoporosis and osteoarthritis; and/or

the JAK-mediated organ transplant associated immunological complications are selected from the group consisting of graft-versus-host diseases.
The method of any one of claims 33 to 37, wherein the JAK-mediated disease is a relapsed disease.
The method of any one of claims 33 to 38, wherein the JAK-mediated disease is refractory to one or more previous treatments.
The method of any one of claims 33 to 39, wherein the heterobifunctional compound is selected from the group consisting of JA-296 to JA-340, or analogs thereof.
The method of any one of claims 33 to 40, wherein the heterobifunctional compound is administered to the subject orally, parenterally, intradermally, subcutaneously, topically, or rectally.
The method of any one of claims 33 to 41, further comprising administering to the subject an additional therapeutic regimen for treating cancer, inflammatory disorders, autoimmune diseases, dermatological disorders, viral infections, dry eye disorders, bone remodeling disorder, and organ transplant associated immunological complications.
The method of claim 42, wherein the additional therapeutic regimen is selected from the group consisting of surgery, chemotherapy, radiation therapy, hormone therapy, targeted therapy, and immunotherapy.
A method for identifying a heterobifunctional compound which mediates degradation or reduction of JAK, the method comprising:

providing a heterobifunctional test compound comprising an JAK ligand conjugated to a degradation tag through a linker;

contacting the heterobifunctional test compound with a cell comprising a ubiquitin ligase and JAK;

determining whether JAK level is decreased in the cell; and

identifying the heterobifunctional test compound as a heterobifunctional compound which mediates degradation or reduction of JAK.
The method of claim 44, wherein the cell is a cancer cell.
The method of claim 45, wherein the cancer cell is a JAK-mediated cancer cell.
A method of treating a JAK-mediated disease disclosed herein comprises administering to a subject with a GSTP1-mediated disease the heterobifunctional compound according to any of claims 1 to 30 or a pharmaceutically acceptable salt or analog thereof.
A method of treating a GSTP1-mediated disease disclosed herein comprises administering to a subject with a GSTP1-mediated disease the heterobifunctional compound according to any of claims 1 to 30 or a pharmaceutically acceptable salt or analog thereof.
A method of treating a JAK-and GSTP1-mediated disease disclosed herein comprises administering to a subject with a JAK-and GSTP1-mediated disease the heterobifunctional compound according to any of claims 1 to 30 or a pharmaceutically acceptable salt or analog thereof.
A pharmaceutical combination comprising

(i) the heterobifunctional compound according to claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or analog thereof; and

(ii) the second therapeutic agent, wherein the second therapeutic agent a signaling pathway inhibitor, wherein the signaling pathway is selected from the group consisting of PI3K/AKT/mTOR pathway, RAS/RAF/MEK/ERK pathway, FLT3 pathway, MAPK pathway and the combinations thereof.
The pharmaceutical combination of claim 50, wherein the second therapeutic agent is FLT3 inhibitor, AKT inhibitor, and/or MEK inhibitor;
The pharmaceutical combination of claim 50, wherein the second therapeutic agent is gilteritinib, MK-2206; and/or trametinib;
The pharmaceutical combination of claim 50, wherein the heterobifunctional compound is selected from the group consisting of

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) isoindoline-1, 3-dione (JA-189) ;

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) ;

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) ;

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) ;

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-oxopentanamide (JA-315) ;

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) ;

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) ;

5- ( (6- (4- (4- (8- (3, 5-difluoro-4- ( (4-hydroxypiperidin-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) ;

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) ;

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 (JA-325) ;

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) ;

3- (4- ( (2- ( (4- (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) ;

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) ;

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) ;

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) ;

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) ;

5- ( (6- (4- (4- (8- (3, 5-difluoro-4- ( (4-hydroxypiperidin-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) ; and

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) ;

or a pharmaceutically acceptable salt or analog thereof.