TROPOMYOSIN RECEPTOR KINASE (TRK) DEGRADE COMPOUNDS AND TERMS OF USE

Description

BACKGROUND OF THE INVENTION

[0001] This disclosure relates to bivalent compounds (e.g., bi-functional small molecule compounds), compositions comprising one or more of the bivalent compounds, and to methods of use of the bivalent compounds for the treatment of certain diseases in a subject in need thereof. The disclosure also relates to methods for identifying such bivalent compounds.

[0002] WO 2015 / 160845 A2 discloses imide-based compounds, including bifunctional compounds comprising the same, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and / or otherwise inhibited by bifunctional compounds according to the present invention. In particular, the description provides compounds, which contain on one end a ligand which binds to the cereblon E3 ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. WO 2016 / 149668 A1 discloses bifunctional compounds, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and / or otherwise inhibited by bifunctional compounds. WO 2019 / 114770 A1 discloses a compounds having a degrading and inhibiting effect on an anaplastic lymphoma kinase (ALK)-targeted protein, and that is mainly composed of four parts: the first part, i.e., ALK-tyrosine kinase inhibitors (TKIs), is a compound having the activity of inhibiting an ALK tyrosine kinase; the second part, i.e., LIN, is a different linker; the third part, i.e., a ubiquitin ligase binding moiety (ULM), is a small molecule ligand of VHL, CRBN or other proteases having a ubiquitination function; and the fourth part, i.e., group A, is a carbonyl group or a default, which covalently binds the ALK-TKIs and the LIN, the LIN covalently binding to the ULM. The article "Tropomyosin receptor kinase inhibitors: an updated patent review for 2010-2016 - Part II" by J. Bailey et al. (Expert Opin Ther Pat. 2017 Jul; 27(7): 831-849) discloses tropomyosin receptor kinase inhibitors including entrectinib.Citation List:

[0003] PL 1: WO 2015 / 160845 A2 PL 2: WO 2016 / 149668 A1 PL 3: WO 2019 / 114770 A1 NPL 1: Justin J. Bailey, et al. Expert Opin Ther Pat. 2017 Jul; 27(7): 831-849 SUMMARY OF THE INVENTION

[0004] The references to methods of treatment in the subsequent paragraphs of this description are to be interpreted as references to compounds, pharmaceutical compositions and medicaments of the present invention for use in a method for treatment of the human body by therapy (or for diagnosis).

[0005] According to one aspect of the present disclosure, a bivalent compound disclosed herein is selected from the group consisting of: 2-(2,6-dioxopiperidin-3-yl)-5-((1-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)a0zetidin-3-yl)amino)isoindoline-1,3-dione (TR-175), 2-(2,6-dioxopiperidin-3-yl)-5-(((1-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)azetidin-3-yl)methyl)amino)isoindoline-1,3-dione (TR-179), 2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)azetidin-1-yl)isoindoline-1,3-dione (TR-184), 2-(2,6-dioxopiperidin-3-yl)-5-((2-((1-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)azetidin-3-yl)amino)ethyl)amino)isoindoline-1,3-dione (TR-192), 2-(2,6-dioxopiperidin-3-yl)-5-(3-((4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)methyl)azetidin-1-yl)isoindoline-1,3-dione (TR-198), 3-(5-(3-((4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)methyl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (TR-205), 3-(5-((1-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)azetidin-3-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (TR-206), 3-(5-(((1-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)azetidin-3-yl)methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (TR-210), 2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazine-1-carbonyl)azetidin-1-yl)isoindoline-1,3-dione (TR-211), 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)-N-(1-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)azetidin-3-yl)acetamide (TR-213), 3-(5-((1-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)azetidin-3-yl)ethynyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (TR-219), N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]azetidin-3-yl]methyl]piperazin-1-yl]-2-(tetrahydropyran-4-ylamino)benzamid (TR-231), 2-(2,6-dioxopiperidin-3-yl)-5-(3-((4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-yl)piperazin-1-yl)methyl)azetidin-1-yl)isoindoline-1,3-dione (TR-234), and 2-(2,6-dioxopiperidin-3-yl)-5-((3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)azetidin-1-yl)methyl)isoindoline-1,3-dione (TR-237), or a pharmaceutically acceptable salt thereof.

[0006] In one embodiment, the bivalent compound is selected from the group consisting of: 2-(2,6-dioxopiperidin-3-yl)-5-(3-((4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)methyl)azetidin-1-yl)isoindoline-1,3-dione (TR-198), 2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazine-1-carbonyl)azetidin-1-yl)isoindoline-1,3-dione (TR-211), and N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]azetidin-3-yl]methyl]piperazin-1-yl]-2-(tetrahydropyran-4-ylamino)benzamide (TR-231), or a pharmaceutically acceptable salt thereof.

[0007] According to another aspect of the present disclosure, a bivalent compound disclosed herein is 2-(2,6-dioxopiperidin-3-yl)-5-(3-((4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)methyl)azetidin-1-yl)isoindoline-1,3-dione (TR-198), or a pharmaceutically acceptable salt thereof.

[0008] According to another aspect of the present disclosure, a bivalent compound disclosed herein is 2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazine-1-carbonyl)azetidin-1-yl)isoindoline-1,3-dione (TR-211), or or a pharmaceutically acceptable salt thereof.

[0009] According to another aspect of the present disclosure, a bivalent compound disclosed herein is N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]azetidin-3-yl]methyl]piperazin-1-yl]-2-(tetrahydropyran-4-ylamino)benzamide (TR-231), or or a pharmaceutically acceptable salt thereof.

[0010] According to another aspect of the present disclosure, a bivalent compound disclosed herein is selected from the group consisting of: and

[0011] In one embodiment, a pharmaceutical composition disclosed herein comprises a bivalent compound as defined in the claims or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0012] In another embodiment, a pharmaceutical composition as defined in the claims is for use in a method of treating a tropomyosin receptor kinase (TRK)-mediated disease, the method comprising administering to a subject with a TRK-mediated disease the pharmaceutical composition, optionally wherein the TRK-mediated disease is cancer, inflammatory diseases, acute and chronic pain, pruritus, bone-related diseases, neurodegenerative diseases, infectious diseases, cachexia, anorexia, demyelination and dysmyelination.

[0013] In another embodiment of the pharmaceutical composition as defined in the claims, the TRK-mediated disease is cancer.

[0014] In another embodiment of the pharmaceutical composition as defined in the claims, the TRK-mediated disease is selected from the group consisting of non-small cell lung cancer, colorectal cancer, gastric cancer, liver cancer, invasive breast cancer, lung adenocarcinoma, uterine cancer, adrenal cancer, pancreatic cancer, ovarian cancer, esophageal cancer, urinary bladder cancer, endometrial cancer, prostate cancer, low-grade glioma, glioblastoma, Spitzoid cancer, soft tissue sarcoma, papillary thyroid carcinoma, head and neck squamous cell carcinoma, congenital fibrosarcoma, congenital mesoblastic nephroma, secretory breast carcinoma, mammary analogue secretory carcinoma, acute myeloid leukemia, ductal carcinoma, pulmonary neuroendocrine tumors, pheochromocytoma, and Wilms' tumor.

[0015] In another embodiment of the pharmaceutical composition as defined in the claims, the TRK-mediated disease is acute pain, chronic pain, cancer pain, surgical pain, inflammatory pain, neuropathic pain, nociceptive pain, pain of osteoarthritis, chronic low back pain, low back pain of osteoporosis, pain of bone fracture, pain of rheumatoid arthritis, postherpetic pain, pain of diabetic neuropathy, fibromyalgia, pain of pancreatitis, pain of interstitial cystitis, pain of endometriosis, pain of irritable bowel syndrome, migraine, pain of pulpitis, interstitial cystitis pain, painful bladder syndrome, central pain syndromes, postsurgical pain syndromes, bone and joint pain, repetitive motion pain, dental pain, myofascial pain, perioperative pain, dysmennorhea, myofascial pain, angina pain, headache, primary hyperalgesia, secondary hyperalgesia, primary allodynia, secondary allodynia, or other pain caused by central sensitization.

[0016] In another embodiment of the pharmaceutical composition as defined in the claims, the TRK-mediated disease is chronic pain.BRIEF DESCRIPTION OF THE DRAWINGS

[0017] The invention is defined in the appended claims and does not extend beyong the scope of the claims. A better understanding of the features and advantages of the present invention as defined in the claims will be obtained by reference to the following detailed description and the accompanying drawings of which: FIG. 1A shows an immunoblot of TPM3-TRKA fusion protein expressed by KM12 cells after treatment with comparative Entrectinib or comparative bivalent compounds CPD-001 - CPD-022. FIG. 1B shows an immunoblot of TPM3-TRKA fusion protein expressed by KM12 cells after treatment with comparative Entrectinib or comparative bivalent compounds CPD-023 - CPD-044. FIG. 1C shows an immunoblot of TPM3-TRKA fusion protein expressed by KM12 cells after treatment with comparative Entrectinib or comparative bivalent compounds CPD-045 - CPD-065. FIG. 2 shows an immunoblot of TPM3-TRKA fusion protein expressed by KM12 cells after treatment with comparative Entrectinib or comparative bivalent compounds CPD-027, CPD-053, and CPD-060 at various time points. FIG. 3 shows immunoblots of TPM3-TRKA fusion protein expressed by KM12 cells in subcutaneous xenograft tumors after treatment with a dose range of comparative bivalent compounds CPD-027, CPD-053, and CPD-060. FIG. 4A shows a graph of KM12 cell viability vs. concentration of comparative bivalent compounds CPD-010, CPD-053, and CPD-057. FIG. 4B shows KM12 and H358 cell viability vs. concentration of comparative bivalent compound CPD-053. FIG. 5A shows an immunoblot of TPM3-TRKA fusion protein expressed by KM12 cells after treatment with comparative GNF-8625, comparative LOXO101 or comparative bivalent compounds TR-104 - TR-129. FIG. 5B shows an immunoblot of TPM3-TRKA fusion protein expressed by KM12 cells after treatment with a dose range of comparative compouds TR-115, TR-116, TR-119, TR-123, TR-124, TR-127 or TR-129. FIG. 5C shows an immunoblot of TPM3-TRKA fusion protein expressed by KM12 cells after treatment with a dose range of comparative compouds TR-130, TR-131, TR-132, TR-140, TR-146, TR-150 or TR-168. FIG. 6A shows an immunoblot of TPM3-TRKA fusion protein expressed by KM12 cells after treatment with a dose range of comparative compouds TR-171, TR-172, TR-173 or TR-176. FIG. 6B shows an immunoblot of TPM3-TRKA fusion protein expressed by KM12 cells after treatment with a dose range of comparative compouds TR-177, TR-181, TR-182 or GNF-8625. FIG. 6C shows an immunoblot of TPM3-TRKA fusion protein expressed by KM12 cells after treatment with a dose range of comparative compouds TR-186, TR-188, TR-189 or TR-190. FIG. 6D shows an immunoblot of TPM3-TRKA fusion protein expressed by KM12 cells after treatment with a dose range of comparative compouds TR-191, TR-194, TR-196, and with compound TR198 which is according to the invention or comparative compoud GNF-8625. FIG. 7 shows immunoblots of overexpressed TPM3-TRKA, AGBL4-TRKB and ETV6-TRKC fusion protein in KM12 cells after treatment with a dose range of comparative compoud TR-123. FIG. 8A shows an immunoblot of TPM3-TRKA fusion protein expressed by KM12 cells after treatment with a dose range of comparative compound TR-123 or comparative compound TR-123-neg. FIG.8B shows an immunoblot of wild type TRKA protein expressed by HEL cells after treatment with a dose range of comparative compound TR-123 or comparative compound TR-123-neg. FIG. 9A shows an immunoblot of TPM3-TRKA fusion protein expressed by KM12 cells after treatment with a single dose of comparative compound TR-123 or combinations with comparative compound MG-132, comparative compound Bortezomib or comparative compound MLN4924. FIG. 9B shows an immunoblot of wild type TRKA protein expressed by HEL cells after treatment with a single dose of comparative compound TR-123 or combinations with comparative compound MG-132, comparative compound Bortezomib, comparative compound MLN4924 or comparative compound Pomalidomide. FIG. 10A shows an immunoblot of TPM3-TRKA fusion protein in subcutaneous KM12 xenograft tumors after treatment with a dose range of comparative compound TR-123. FIG. 10B shows an immunoblot of TPM3-TRKA fusion protein expressed in subcutaneous KM12 xenograft tumors after treatment with comparative compounds TR-171, TR-172, TR-173, TR-177 or TR-181. FIG. 11 shows a graph of plasma concentration of TR-123 vs. time points post dosing. FIG. 12A shows a graph of subcutaneous KM12 xenograft tumor volume vs. days after treatment with a dose range of comparative compound CPD-060. FIG. 12B shows a graph of body weight vs. days after treatment with a dose range of CPD-060. FIG. 13A shows an immunoblot of TPM3-TRKA fusion protein expressed by KM12 cells after treatment with a dose range of comparative compounds TR-202, TR-203 or TR-204. FIG. 13B shows an immunoblot of TPM3-TRKA fusion protein expressed by KM12 cells after treatment with a dose range of comparative compound TR-208, compound TR-210 which is according to the invention, compound TR-211 which is according to the invention or comparative compound TR-214. FIG. 13C shows an immunoblot of TPM3-TRKA fusion protein expressed by KM12 cells after treatment with a dose range of comparative compounds TR-215, TR216, TR-217, or TR218, compound TR-219 which is according to the invention or comparative compound TR-220. FIG. 13D shows an immunoblot of TPM3-TRKA fusion protein expressed by KM12 cells after treatment with a dose range of comparative compounds TR-221, TR-222, TR-223, TR-224, TR-225, TR-226 or TR-227. FIG. 13E shows an immunoblot of TPM3-TRKA fusion protein expressed by KM12 cells after treatment with a dose range of compound TR-231 which is according to the invention, comparative compound TR-232, comparative compound TR-233, compound TR-234 which is according to the invention or comparative compound TR-235. FIG. 14 shows a graph of plasma concentration of compound TR-198 which is according to the invention over time after dosing via intravenous injection or oral gavage. FIG. 15A shows a graph of subcutaneous KM12 xenograft tumor volume as a function of days after treatment with a dose range of comparative compound TR-181 or a single dose of compound TR-198 which is according to the invention. FIG. 15B shows a graph of body weight as a functional of days after treatment with a dose range of comparative compound TR-181 or a single dose of compound TR-198 which is according to the invention. FIG. 16A shows a graph of the percentage of weight born on the injured limb following treatment with a single dose of vehicle (Veh), comparative compound TR-181 or comparative compound ibuprofen (Ibu) in rats. FIG. 16B shows a graph of the percentage of weight born on the injured limb following treatment with a single dose of comparative compound TR-181 or comparative compound ibuprofen (Ibu) in guinea pigs. DETAILED DESCRIPTION OF THE INVENTION

[0018] It is recognized in the present disclosure that tropomyosin receptor kinase (TRK) receptor family comprises three members, TRKA, TRKB and TRKC that are encoded by the NTRK1, NTRK2 and NTRK3 genes, respectively (Khotskaya et al., 2017). TRKs are receptor tyrosine kinases primarily implicated in development and functions of the neuronal tissues. The main ligands of TRKs include nerve growth factor (NGF) for TRKA, brain-derived growth factor (BDGF) for TRKB, and neurotrophins for TRKC (Vaishnavi et al., 2015). The binding of ligands to the extracellular domains of TRKs induces dimerization and activation of the receptors, which activates downstream signal transduction pathways, such as PI3K / AKT, RAF / MEK / ERK, and PLCγ pathways. These pathways have well established roles to support cellular proliferation, survival, and promote oncogenesis (Hanahan and Weinberg, 2011).

[0019] It is further recognized herein that, like many other oncogenic receptor tyrosine kinases, TRKs are aberrantly activated in a variety of human malignancies. Interestingly, the primary molecular mechanism activating TRKs in cancer is not point mutations but in-frame fusions of NTRK genes (Vaishnavi et al., 2015). Typically, the 3' regions of the NTRK genes are joined with the 5' regions of a partner gene due to chromosomal rearrangement. The resulted chimeric proteins always retain the kinase domain of TRK proteins, indicating that the catalytic functions are crucial to the transforming activities. Loss of the 5' regions of the NTRK genes that encode the self-inhibitory domains renders these fusion kinases constitutively active. Additionally, expression of the chimeric proteins is driven by the promoters of the fusion partners, which often result in overexpression. The most common TRK fusions include LMNA-TRKA, TPM3-TRKA, and ETV6-TRKC (Amatu et al., 2016). Hence, genetic events lead to overexpressed and constitutively active TRK-fusion kinases. These fusions are oncogenic, as shown by their ability to transform mouse embryonic fibroblasts and normal epithelium (Russell et al., 2000; Vaishnavi et al., 2015).

[0020] TRK fusion was first reported in a human colon carcinoma, which was named as oncD at that time (Martin-Zanca et al., 1986). Recent advances in high-throughput RNA sequencing greatly promote the efficiency of identifying chromosomal rearrangement events in patient samples. Consequently, TRK fusions have been found across a wide range of human malignancies, including but are not limited to non-small cell lung cancer, colorectal cancer, gastric cancer, low-grade glioma glioblastoma, Spitzoid cancer, soft tissue sarcoma, papillary thyroid carcinoma, head and neck squamous cell carcinoma, congenital fibrosarcoma, congenital mesoblastic nephroma, secretory breast carcinoma, mammary analogue secretory carcinoma, acute myeloid leukemia, and ductal carcinoma (Amatu et al., 2016; Khotskaya et al., 2017) . The frequency of TRK fusions is relatively low. For example, approximately 0.5% to 2.7% colon cancers are affected by TRK fusions (Creancier et al., 2015; Lee et al., 2015). However, for certain cancer types, such as secretory breast carcinoma, TRK fusions can be found in the vast majority of cases (Tognon et al., 2002).

[0021] TRK mutations and deletions have been observed in additional human diseases, such as pulmonary neuroendocrine tumors, anhidrosis syndrome, obesity, congenital heart defects, and acute myeloid leukemia (Khotskaya et al., 2017). In addition, TRK amplification are associated with several human diseases, such as liver cancer, invasive breast cancer, lung adenocarcinoma, uterine cancer, adrenal cancer, pancreatic cancer, ovarian cancer, esophageal cancer, urinary bladder cancer, endometrial cancer, pheochromocytoma, Wilms' tumor, and prostate cancer (Khotskaya et al., 2017).

[0022] The never growth factor (NGF) and its main receptor, tropomyosin receptor kinase A (TRKA), have long been recognized for their roles in central and peripheral pain (Denk et al., 2017). Nociceptive neurons express TRKA and mediate pain sensation by transmitting pain signals to the central nervous system. Multiple NGF-neutralizing antibodies, such as tanezumab, are undergoing clinical assessment in patients with osteoarthritis, lower back pain, cancer pain, neuropathic pain, and other pain conditions (Miller et al., 2017). The efficacy of NGF antibodies in pain relief has been clearly documented in clinics. However, administration of NGF neutralizing antibodies has been shown to result in rapidly progressed joint destruction in some patients that leads to total joint replacement (Schnitzer and Marks, 2015). These adverse events may be related to sustained exposure to NGF antibodies. Targeting TRK represents another promising therapeutic strategy blocking the NGF / TRK signaling pathway for pain management. However, currently available pan-TRK kinase inhibitors may induce significant on-target adverse effects through modulating TRK family members in the central nervous system. Peripherally restricted TRK bifunctional degraders are expected to selective block the NGF / TRK pathway in peripheral nerves while spare these targets in the central nervous system.

[0023] TRK is associated with cancer, inflammatory diseases, acute and chronic pain, pruritus, bone-related diseases, neurodegenerative diseases, infectious diseases, and other diseases, including but no limited to neuroblastoma, prostate cancer, pancreatic cancer, melanoma, head and neck cancer, gastric carcinoma, lung carcinoma, liver cancer, uterine cancer, adrenal cancer, biliary tree cancer, intestinal cancer, colorectal cancer, ovarian cancer, lung carcinoma, small cell lung cancer, non-small cell lung cancer, gastric carcinoma, breast cancer, esophageal cancer, urinary bladder cancer, endometrial cancer, brain cancer, low-grade glioma, glioblastoma, medulloblastoma, secretory breast carcinoma, salivary gland cancer, papillary thyroid carcinoma, ductal carcinoma, acute myeloid leukemia, large cell neuroendocrine tumors, pulmonary neuroendocrine tumors, sarcomas, pheochromocytoma, fibrosarcoma, congenital fibrosarcoma, congenital mesoblastic nephroma, secretory breast carcinoma, malignant fibrous histiocytoma, embryonal rhabdomysocarcoma, leiomysosarcoma, neuro-fibrosarcoma, neoplasms of the central nervous systems, osteosarcoma, synovial sarcoma, liposarcoma, alveolar soft part sarcoma, , Spitzoid cancer, Wilms' tumor, lymphomas (e.g. including Hodgkin's lymphoma, lymphoplasmacytoid lymphoma, follicular lymphoma, mucosa-associated lymphoid tissue lymphoma, mantle cell lymphoma, B-lineage large cell lymphoma, Burkitt's lymphoma, and T-cell anaplastic large cell lymphoma), inflammatory lung diseases (e.g. asthma), inflammatory bowel diseases, (e.g. ulcerative colitis, Crohn's disease), inflammatory skin diseases (e.g. atopic dermatitis, eczema and psoriasis), interstitial cystitis, rhinitis, acute pain, chronic pain, cancer pain, surgical pain, inflammatory pain, neuropathic pain, nociceptive pain, pain of osteoarthritis, chronic low back pain, low back pain of osteoporosis, pain of bone fracture, pain of rheumatoid arthritis, postherpetic pain, pain of diabetic neuropathy, fibromyalgia, pain of pancreatitis, pain of interstitial cystitis, pain of endometriosis, pain of irritable bowel syndrome, migraine, pain of pulpitis, interstitial cystitis pain, painful bladder syndrome, central pain syndromes, postsurgical pain syndromes, bone and joint pain, repetitive motion pain, dental pain, myofascial pain, perioperative pain, dysmennorhea, myofascial pain, angina pain, headache, primary hyperalgesia, secondary hyperalgesia, primary allodynia, secondary allodynia, other pain caused by central sensitization, systemic cutaneous pruritus, localized cutaneous pruritus, senile cutaneous pruritus, gestational pruritus, pruritus ani, vulvar pruritus, metastatic bone disease, treatment-induce bone loss, osteoporosis, rheumatoid arthritis, bone metastases, ankylosing spondylitis, Paget's disease, periodontal disease, osteolytic disease, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Chagas disease, cachexia, anorexia, demyelination and dysmyelination.

[0024] TRK kinase inhibitors are currently undergoing clinical or pre-clinical development, including but are not limited to altiratinib (DCC2701, DCC-270, DP-5164) (Smith et al., 2015), sitravatinib (MGCD516) (Patwardhan et al., 2016), cabozantinib (XL-184, BMS-907351) (Fuse et al., 2017), dovitinib (TKI-258, CHIR-258) (Chong et al., 2017), entrectinib (RXDX-101) (Menichincheri et al., 2016), milciclib (PHA-848125AC) (Brasca et al., 2009), belizatinib (TSR-011) (Ricciuti et al., 2017), GZ389988 (Bailey et al., 2017a, b), pegcantratinib (Cranston et al., 2017), AZD7451 (Tatematsu et al., 2014), larotrectinib (LOXO-101; ARRY-470) (Drilon et al., 2018), TPX-0005 (Cui et al., 2016), LOXO-195 (Blake et al., 2016), regorafenib (Subbiah et al., 2017), DS-6051b (Fujiwara et al., 2018), F17752 (Amatu et al., 2016), PLX7486 (Amatu et al., 2016), AZD-6918 (Li et al., 2015), ASP7962 (Bailey et al., 2017a, b), VM902A (Bailey et al., 2017a, b), ONO-4474 (Bailey et al., 2017a, b), PF-06273340 (Skerratt et al., 2016) and GNF-8625 (Choi et al., 2015). The most advanced ones are entrectinib and larotrectinib (Khotskaya et al., 2017). These agents are tested in basket trials that recruit patients according to detection of TRK-fusions instead of histology. The phase 2 results of larotrectinib demonstrated that most patients (75%) responded to the therapy and that 55% patient remained progression-free at 1 year (Drilon et al., 2018). Phase 1 results of entrectinib also recorded marked and durable response in patients with TRK-fusion tumors (Drilon et al., 2017b). The remarkable efficacy of TRK inhibitors was independent of tumor types. These substantial results collectively highlight a role of TRK fusions as the sole oncogenic drivers in a subset of human malignancies, irrespective of tissue of origin.

[0025] Non-specific side effects and the development of resistance to TRK kinase inhibitors remain a challenge in development of effective treatments. Thus, new small-molecule targeting TRK's functions through inhibition and / or degradation will be very useful.

[0026] 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 heterobivalent small molecules which degrade TRK, TRK fusion proteins, and / or TRK mutant proteins are useful in the treatment of TRK-mediated diseases, particularly non-small cell lung cancer, colorectal cancer, gastric cancer, liver cancer, invasive breast cancer, lung adenocarcinoma, uterine cancer, adrenal cancer, pancreatic cancer, ovarian cancer, esophageal cancer, urinary bladder cancer, endometrial cancer, prostate cancer, low-grade glioma, glioblastoma, Spitzoid cancers, soft tissue sarcoma, papillary thyroid carcinoma, head and neck squamous cell carcinoma, congenital fibrosarcoma, congenital mesoblastic nephroma, secretory breast carcinoma, mammary analogue secretory carcinoma, acute myeloid leukemia, ductal carcinoma, pulmonary neuroendocrine tumors, pheochromocytoma, and Wilms' tumor (Amatu et al., 2016; Khotskaya et al., 2017). The disclosed noval bifunctional TRK degraders are useful in the treatment of TRK-mediated cancer, inflammatory diseases, acute and chronic pain, pruritus, bone-related diseases, neurodegenerative diseases, infectious diseases, and other diseases, including but not limited to neuroblastoma, prostate cancer, pancreatic cancer, melanoma, head and neck cancer, gastric carcinoma, lung carcinoma, liver cancer, uterine cancer, adrenal cancer, biliary tree cancer, intestinal cancer, colorectal cancer, ovarian cancer, lung carcinoma, small cell lung cancer, non-small cell lung cancer, gastric carcinoma, breast cancer, esophageal cancer, urinary bladder cancer, endometrial cancer, brain cancer, low-grade glioma, glioblastoma, medulloblastoma, secratory breast cancer, secretory breast carcinoma, salivary gland cancer, papillary thyroid carcinoma, ductal carcinoma, adult myeloid leukemia, acute myeloid leukemia, large cell neuroendocrine tumors , pulmonary neuroendocrine tumors, sarcomas, pheochromocytoma, fibrosarcoma, congenital fibrosarcoma, congenital mesoblastic nephroma, secretory breast carcinoma, malignant fibrous histiocytoma, embryonal rhabdomysocarcoma, leiomysosarcoma, neuro-fibrosarcoma, neoplasms of the central nervous systems, osteosarcoma, synovial sarcoma, liposarcoma, alveolar soft part sarcoma, , Spitzoid cancer, Wilms' tumor, lymphomas (e.g. including Hodgkin's lymphoma, lymphoplasmacytoid lymphoma, follicular lymphoma, mucosa-associated lymphoid tissue lymphoma, mantle cell lymphoma, B-lineage large cell lymphoma, Burkitt's lymphoma, and T-cell anaplastic large cell lymphoma), inflammatory lung diseases (e.g. asthma), inflammatory bowel diseases, (e.g. ulcerative colitis, Crohn's disease), inflammatory skin diseases (e.g. atopic dermatitis, eczema and psoriasis), interstitial cystitis, rhinitis, acute pain, chronic pain, cancer pain, surgical pain, inflammatory pain, neuropathic pain, nociceptive pain, pain of osteoarthritis, chronic low back pain, low back pain of osteoporosis, pain of bone fracture, pain of rheumatoid arthritis, postherpetic pain, pain of diabetic neuropathy, fibromyalgia, pain of pancreatitis, pain of interstitial cystitis, pain of endometriosis, pain of irritable bowel syndrome, migraine, pain of pulpitis, interstitial cystitis pain, painful bladder syndrome, central pain syndromes, postsurgical pain syndromes, bone and joint pain, repetitive motion pain, dental pain, myofascial pain, perioperative pain, dysmennorhea, myofascial pain, angina pain, headache, primary hyperalgesia, secondary hyperalgesia, primary allodynia, secondary allodynia, other pain caused by central sensitization, systemic cutaneous pruritus, localized cutaneous pruritus, senile cutaneous pruritus, gestational pruritus, pruritus ani, vulvar pruritus, metastatic bone disease, treatment-induce bone loss, osteoporosis, rheumatoid arthritis, bone metastases, ankylosing spondylitis, Paget's disease, periodontal disease, osteolytic disease, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Chagas disease, cachexia, anorexia, demyelination and dysmyelination.

[0027] 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, the small molecule has 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 (Bondeson et al., 2015; Chamberlain et al., 2014; Fischer et al., 2014; Ito et al., 2010; Winter 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 (Bondeson et al., 2015; Buckley et al., 2012a; Buckley et al., 2012b; Galdeano et al., 2014; Zengerle et al., 2015); (3) compound 7, which selectively binds KEAP1, a component of a CRL3 complex(Davies et al., 2016); (4) AMG232, which selectively binds MDM2, a heterodimeric RING E3 ligase(Sun et al., 2014); and (5) LCL161, which selectively binds IAP, a homodimeric RING E3 ligase (Ohoka et al., 2017; Okuhira et al., 2011; Shibata et al., 2017). The E3 ligase recruiting bifunctional degrader technology has been applied to degradation of several protein targets (Bondeson et al., 2015; Buckley et al., 2015; Lai et al., 2016; Lu et al., 2015; Winter et al., 2015; Zengerle et al., 2015). 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 by proteasome (Buckley and Crews, 2014). This approach has been applied to selective degradation of the pseudokinase HER3 (Xie et al., 2014). The inventors have not yet seen any efforts applying any of these approaches to degradation of TRK, TRK mutant, TRK deletion, or TRK fusion proteins.

[0028] Currently available small molecules targeting TRK focus on inhibition of the kinase activity of TRK. A number of selective small-molecule TRK kinase inhibitors, such as altiratinib (DCC2701, DCC-270, DP-5164) (Smith et al., 2015), sitravatinib (MGCD516) (Patwardhan et al., 2016), cabozantinib (XL-184, BMS-907351) (Fuse et al., 2017), dovitinib (TKI-258, CHIR-258) (Chong et al., 2017), entrectinib (RXDX-101) (Menichincheri et al., 2016), milciclib (PHA-848125AC) (Brasca et al., 2009), belizatinib (TSR-011) (Ricciuti et al., 2017), GZ389988 (Bailey et al., 2017a, b), pegcantratinib (Cranston et al., 2017), AZD7451 (Tatematsu et al., 2014), larotrectinib (LOXO-101; ARRY-470) (Drilon et al., 2018), TPX-0005 (Cui et al., 2016), LOXO-195 (Blake et al., 2016), regorafenib (Subbiah et al., 2017), DS-6051b (Fujiwara et al., 2018), F17752(Amatu et al., 2016), PLX7486 (Amatu et al., 2016), AZD-6918 (Li et al., 2015), ASP7962 (Bailey et al., 2017a, b), VM902A (Bailey et al., 2017a, b), ONO-4474 (Bailey et al., 2017a, b), PF-06273340 (Skerratt et al., 2016) and GNF-8625 (Choi et al., 2015) have been reported.

[0029] In the present disclosure, a novel approach is taken: to develop compounds that directly and selectively modulate not only the kinase activity of TRK, but also its 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 bivalent small molecule compounds, permits more flexible regulation of protein levels in vitro and in vivo compared with techniques such as gene knockout or short hairpin RNA-mediated (shRNA) knockdown. Unlike gene knockout or shRNA 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.Bivalent Compounds

[0030] The present disclosure provides bivalent compounds as defined in the claims.TRK Ligand

[0031] Generally, a TRK kinase inhibitor comprises one or more of (e.g., altiratinib (DCC2701, DCC-270, DP-5164) (Smith et al., 2015), sitravatinib (MGCD516) (Patwardhan et al., 2016), cabozantinib (XL-184, BMS-907351) (Fuse et al., 2017), dovitinib (TKI-258, CHIR-258) (Chong et al., 2017), entrectinib (RXDX-101) (Menichincheri et al., 2016), milciclib (PHA-848125AC) (Brasca et al., 2009), belizatinib (TSR-011) (Ricciuti et al., 2017), GZ389988 (Bailey et al., 2017a, b), pegcantratinib (Cranston et al., 2017), AZD7451 (Tatematsu et al., 2014), larotrectinib (LOXO-101; ARRY-470) (Drilon et al., 2018), TPX-0005 (Cui et al., 2016), LOXO-195 (Blake et al., 2016), regorafenib (Subbiah et al., 2017), DS-6051b (Fujiwara et al., 2018), F17752(Amatu et al., 2016), PLX7486 (Amatu et al., 2016), AZD-6918 (Li et al., 2015), ASP7962 (Bailey et al., 2017a, b), VM902A (Bailey et al., 2017a, b), ONO-4474 (Bailey et al., 2017a, b), PF-06273340 (Skerratt et al., 2016) and GNF-8625 (Choi et al., 2015), and analogs thereof), which is capable of inhibiting the kinase activity of TRK. As used herein, a "TRK kinase 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.

[0032] The invention is defined in the appended claims, but generally, a TRK ligand (not according to the invention) can be derived from a TRK kinase inhibitor comprising:

[0033] The invention is defined in the appended claims, but generally, a TRK ligand can include, DS-6051b (Fujiwara et al., 2018), F17752(Amatu et al., 2016), PLX7486 (Amatu et al., 2016), AZD-6918 (Li et al., 2015), ASP7962 (Bailey et al., 2017a, b), VM902A (Bailey et al., 2017a, b), PF-06273340 (Skerratt et al., 2016) and ONO-4474 (Bailey et al., 2017a, b). The invention is defined in the appended claims, but generally, a TRK ligand can be derived from any one or more of DS-6051b (Fujiwara et al., 2018), F17752(Amatu et al., 2016), PLX7486 (Amatu et al., 2016), AZD-6918 (Li et al., 2015), ASP7962 (Bailey et al., 2017a, b), VM902A (Bailey et al., 2017a, b), PF-06273340 (Skerratt et al., 2016) and ONO-4474 (Bailey et al., 2017a, b).

[0034] The invention is defined in the appended claims, but generally, a TRK ligand can comprise a moiety of Formula 1; Wherein, R 1< , R 2< , R 3< , R 4< , Ar, and X are defined as before.

[0035] The invention is defined in the appended claims, but generally, a TRK ligand can comprise a moiety of Formula 1 wherein X is selected from CR'R", CO, O, S, SO, SO 2 , and NR', wherein R' and R" are independently selected from hydrogen, halogen, OH, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1-8 alkoxy, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylamino, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 3 -C 10 cycloalkoxy, and optionally substituted 3-10 membered heterocyclyl; or R' and R" together with the atom to which they are connected form an optionally substituted 3-8 membered cycloalkyl or heterocyclyl ring; R is selected from optionally substituted C 1 -C 8 alkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R 1< , R 2< , and R 3< are independently selected from hydrogen, halogen, CN, NO 2 , OR 5< , SR 6< , NR 7< R 8< , COR 5< , CO 2 R 5< , C(O)NR 7< R 8< , SOR 5< , SO 2 R 5< , SO 2 NR 7< R 8< , NR 7< C(O)R 8< , NR 5< C(O)NR 7< R, NR 7< SOR 8< , NR 7< SO 2 R 8< , optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 3 -C 10 cycloalkoxy, optionally substituted 3-10 membered heterocyclyl, optionally substituted C 2 -C 8 alkenyl, and optionally substituted C 2 -C 8 alkynyl, wherein R 5< , R 6< , R 7< , and R 8< are independently selected from hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted aryl, or optionally substituted heteroaryl, or R 7< and R 8< together with the atom to which they are connected form an optionally substituted 4-8 membered heterocyclyl ring; R 4< is connected to the linker moiety of the bivalent compound, and is selected from a bond, OR 9< , SR 9< , NR 10< R 11< , COR 9< , CO 2 R 9< , CONR 10< R 11< , SOR 9< , SO 2 R 9< , SO 2 NR 10< R 11< , NR 10< COR 11< , NR 9< CONR 10< R 11< , NR 10< SOR 11< , NR 10< SO 2 R 11< , optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 3 -C 8 cycloalkoxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, aryl, and optionally substituted heteroaryl, wherein R 9< , R 10< , and R 11< are independently selected from null, a bond, hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 3 -C 8 cycloalkoxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or R 10< and R 11< together with the atom to which they are connected form a 4-8 membered cycloalkyl or heterocyclyl ring; and Ar is selected from aryl and heteroaryl group, each of which is optionally substituted with one or more substituents independently selected from hydrogen, halogen, CN, NO 2 , OR 12< , SR 12< , NR 13< R 14< , COR 12< , CO 2 R 12< , CONR 13< R 14< , SOR 12< , SO 2 R 12< , SO 2 NR 13< R 14< , NR 13< COR 14< , NR 15< C(O)NR 13< R 14< , NR 13< SOR 14< , NR 13< SO 2 R 14< , optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 3 -C 8 cycloalkoxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein R 12< , R 13< , R 14< , and R 15< are independently selected from hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 3 -C 8 cycloalkoxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or R 13< and R 14< together with the atom to which they are connected form a 4-8 membered cycloalkyl or heterocyclyl ring. X can be selected from CR'R", O, and NR', wherein R' and R" are independently selected from hydrogen, F, OH, optionally substituted C 1 -C 3 alkyl, and optionally substituted C 1 -C 3 alkoxy, or R' and R" together with the atom to which they are connected form an optionally substituted 3-6 membered cycloalkyl or heterocyclyl ring. X can be selected from CH 2 , cyclopropylene, CHF, CF 2 , O, NH, NCH 3 , NCH 2 CH 3 , and N-isopropyl. R can be selected from optionally substituted C 3 -C 8 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl. R can be selected from optionally substituted phenyl and optionally substituted heteroaryl. X can be CH 2 ; and R is 3,5-difluorophenyl. R 1< , R 2< , and R 3< can be independently selected from hydrogen, F, Cl, and OH. R 4< -Ar can be selected from a moiety of formulae A1, A2, A3, and A4: wherein * indicates the connection to the linker moiety of the bivalent compound; and R a< is selected from hydrogen, halogen, CN, NO 2 , OR 12< , SR 12< , NR 13< R 14< , COR 12< , CO 2 R 12< , CONR 13< R 14< , SOR 12< , SO 2 R 12< , SO 2 NR 13< R 14< , NR 13< COR 14< , NR 15< C(O)NR 13< R 14< , NR 13< SOR 14< , NR 13< SO 2 R 14< , optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 3 -C 8 cycloalkoxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein R 12< , R 13< , R 14< , and R 15< are independently selected from hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 3 -C 8 cycloalkoxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, aryl, and optionally substituted heteroaryl, or R 13< and R 14< together with the atom to which they are connected form a 4-8 membered cycloalkyl or heterocyclyl ring.

[0036] The invention is defined in the appended claims, but generally, R 4< -Ar can be selected from a moiety of formulae A1, A3, A3 and A4: wherein * indicates the connection to the linker moiety of the bivalent compound; and R a< is selected from hydrogen, halogen, NR 13< R 14< , and NR 13< COR 14< , wherein R 13< and R 14< are independently selected from hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 3 -C 8 cycloalkoxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, phenyl, and optionally substituted C 5 -C 6 heteroaryl, or R 13< and R 14< together with the atom to which they are connected form a 4-8 membered cycloalkyl or heterocyclyl ring.

[0037] The invention is defined in the appended claims, but generally, R a< can be (tetrahydro-2H-pyran-4-yl)amino.

[0038] The invention is defined in the appended claims, but generally, a TRK ligand can comprise a moiety of Formula 2; Wherein, R 1< , R 2< , R 3< , R 4< , Ar 1< , Ar 2< , X, X 1< , X 2< , X 3< , X 4< and n are defined as before.

[0039] The invention is defined in the appended claims, but generally, a TRK ligand can comprise a moiety of Formula 2: wherein X 1< , X 2< , X 3< , and X 4< are independently selected from C, CR', and N (preferly, X 1< is selected from CR' and N, X 2< , X 3< , and X 4< are independently selected from C and N), wherein R' is selected from hydrogen, halogen, CN, NO 2 , optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, and optionally substituted 3-6 membered heterocyclyl; X is selected from null, a bond, C(R 2< ) 2 , C(R 2< ) 2 C(R 2< ) 2 , CO, C(R 2< ) 2 CO, CONR 2< , C(R 2< ) 2 O, C(R 2< ) 2 NR 2< , and CH 2 NR 2< ; R 1< and R 2< , at each occurrence, are independently selected from hydrogen, halogen, OH, NH 2 , CN, NO 2 , optionally substituted C 1 -C 4 alkyl, optionally substituted C 1 -C 4 alkoxy, optionally substituted C 1 -C 4 alkylamino, optionally substituted C 1 -C 4 alkoxyalkyl, optionally substituted C 1 -C 4 haloalkyl, optionally substituted C 1 -C 4 hydroxyalkyl, optionally substituted C 1 -C 4 alkylaminoC 1 -C 4 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 3 -C 6 cycloalkoxy, and optionally substituted 3-6 membered heterocyclyl; n is 1 to 4; R 3< is connected to the linker moiety of the bivalent compound either directly or through R 4< ; R 3< and R 4< are independently selected from null, a bond, OR 5< , SR 5< , NR 6< R 7< , COR 5< , CO 2 R 5< , CONR 6< R 7< , SOR 5< , SO 2 R 5< , SO 2 NR 6< R 7< , NR 6< COR 7< , NR 5< C(O)NR 6< R 7< , NR 6< SOR 7< , NR 6< SO 2 R , optionally substituted C 1 -Cs alkyl, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 3 -C 8 cycloalkoxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein R 5< , R 6< and R 7< are independently selected from null, a bond, hydrogen, optionally substituted C 1 -Cs alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted aryl, and optionally substituted heteroaryl, or R 6< and R 7< together with the atom to which they are connected form a 3-8 membered cycloalkyl or 4-8 membered heterocyclyl ring; and Ar 1< and Ar 2< are independently selected from aryl and heteroaryl, each of which is optionally substituted with one or more substituents independently selected from halogen, CN, NO 2 , OR 10< , SR 10< , NR 11< R 12< , COR 10< , CO 2 R 10< , CONR 11< R 12< , SOR 10< , SO 2 R 10< , SO 2 NR 11< R 12< , NR 11< COR 12< , NR 10< C(O)NR 11< R 12< , NR 11< SOR 12< , NR 11< SO 2 R 12< , optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted C 3 -C 7 cycloalkyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein R 10< , R 11< , and R 12< are independently selected from null, 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 3 -C 7 cycloalkyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or R 11< and R 12< together with the atom to which they are connected form a 4-8 membered cycloalkyl or heterocyclyl ring.

[0040] The invention is defined in the appended claims, but generally, X 1< can be selected from CR' and N, wherein R' is selected from hydrogen, F, Cl, CH 3 , CF 3 , and cyclopropyl.

[0041] The invention is defined in the appended claims, but generally, X 2< , X 3< , and X 4< can be independently selected from C and N.

[0042] The invention is defined in the appended claims, but generally, X can be selected from a bond, CH 2 , CH 2 CH 2 , CO, CH 2 CO, CONH, CONCH 3 , CH 2 O, CH 2 NH, and CH 2 NCH 3 .

[0043] The invention is defined in the appended claims, but generally, R 1< and R 2< , at each occurrence, can be independently selected from hydrogen, F, Cl, OH, optionally substituted C 1 -C 4 alkyl, optionally substituted C 1 -C 4 alkoxy, optionally substituted C 1 -C 4 alkylamino, optionally substituted C 1 -C 4 haloalkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 3 -C 6 cycloalkoxy, and optionally substituted 3-6 membered heterocyclyl.

[0044] The invention is defined in the appended claims, but generally, X can be CH 2 ; and Ar 1< can be 3-fluorophenyl.

[0045] The invention is defined in the appended claims, but generally, R 3< can be connected to the linker moiety of the bivalent compound directly, and R 3< is selected from null, a bond, OR 5< , SR 5< , NR 6< R 7< , COR 5< , CO 2 R 5< , CONR 6< R 7< , SOR 5< , SO 2 R 5< , SO 2 NR 6< R 7< , NR 6< COR 7< , NR 5< C(O)NR 6< R 7< , NR 6< SOR 7< , NR 6< SO 2 R 7< optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein R 5< , R 6< and R 7< are independently selected from null, a bond, hydrogen, optionally substituted C 1 -Cs alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted aryl, and optionally substituted heteroaryl, or R 6< and R 7< together with the atom to which they are connected form a 4-8 membered cycloalkyl or heterocyclyl ring.

[0046] The invention is defined in the appended claims, but generally, R 3< can be connected to the linker moiety of the bivalent compound through R 4< , and R 3< and R 4< are independently selected from null, a bond, OR 5< , SR 5< , NR 6< R 7< , COR 5< , CO 2 R 5< , CONR 6< R 7< , SOR 5< , SO 2 R 5< , SO 2 NR 6< R 7< , NR 6< COR 7< , NR 5< C(O)NR 6< R 7< , NR 6< SOR 7< , NR 6< SO 2 R, optionally substituted C 1 -Cs alkyl, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein R 5< , R 6< and R 7< are independently selected from null, a bond, hydrogen, optionally substituted C 1 -Cs alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted aryl, and optionally substituted heteroaryl, or R 6< and R 7< together with the atom to which they are connected form a 4-8 membered cycloalkyl or heterocyclyl ring.

[0047] The invention is defined in the appended claims, but generally, Ar 1< can be selected from C 6 -C 10 aryl and C 5 -C 10 heteroaryl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, CN, NO 2 , OR 10< , NR 11< R 12< , COR 10< , CO 2 R 10< , CONR 11< R 12< , SOR 10< , SO 2 R 10< , SO 2 NR 11< R 12< , NR 11< COR 12< , NR 10< C(O)NR 11< R 12< , NR 11< SOR 12< , NR 11< SO 2 R 12< , optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxyalkyl, optionally substituted C 1 -C 6 haloalkyl, optionally substituted C 1 -C 6 hydroxyalkyl, optionally substituted C 1 -C 6 alkylaminoC 1 -C 6 alkyl, optionally substituted C 3 -C 7 cycloalkyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted aryl, and optionally substituted C 4 -C 5 heteroaryl, wherein R 10< , R 11< , and R 12< are independently selected from null, hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 7 cycloalkyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or R 11< and R 12< together with the atom to which they are connected form a 4-8 membered cycloalkyl or heterocyclyl ring.

[0048] The invention is defined in the appended claims, but generally, Ar 2< can be selected from C 6 -C 10 aryl and C 5 -C 10 heteroaryl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, CN, NO 2 , OR 10< , NR 11< R 12< , COR 10< , CO 2 R 10< , CONR 11< R 12< , SOR 10< , SO 2 R 10< , SO 2 NR 11< R 12< , NR 11< COR 12< , NR 10< C(O)NR 11< R 12< , NR 11< SOR 12< , NR 11< SO 2 R 12< , optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxyalkyl, optionally substituted C 1 -C 6 haloalkyl, optionally substituted C 1 -C 6 hydroxyalkyl, optionally substituted C 1 -C 6 alkylaminoC 1 -C 6 alkyl, optionally substituted C 3 -C 7 cycloalkyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted aryl, and optionally substituted C 4 -C 5 heteroaryl, wherein R 10< , R 11< , and R 12< are independently selected from null, hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 7 cycloalkyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or R 11< and R 12< together with the atom to which they are connected form a 4-8 membered cycloalkyl or heterocyclyl ring.

[0049] The invention is defined in the appended claims, but generally, R 3< -Ar 2< can be selected from a moiety of formulae B1 and B2: wherein * indicates the connection to the linker moiety of the bivalent compound; Y 1< , Y 2< , Y 3< , and Y 4< are independently selected from CH and N, with the proviso that up to 3 of Y 1< , Y 2< , Y 3< , and Y 4< are N; each R a< is independently selected from hydrogen, halogen, CN, NO 2 , OR 12< , SR 12< , NR 13< R 14< , COR 12< , CO 2 R 12< , CONR 13< R 14< , SOR 12< , SO 2 R 12< , SO 2 NR 13< R 14< , NR 13< COR 14< , NR 15< C(O)NR 13< R 14< , NR 13< SOR 14< , NR 13< SO 2 R 14< , optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 3 -C 8 cycloalkoxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein R 12< , R 13< , R 14< , and R 15< are independently selected from hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 3 -C 8 cycloalkoxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or R 13< and R 14< together with the atom to which they are connected form a 4-8 membered cycloalkyl or heterocyclyl ring; m is 0 to 4; and R 3< is the same as defined in Formula 2.

[0050] The invention is defined in the appended claims, but generally, R 3< -Ar 2< can be selected from a moiety of formula B3: wherein * indicates the connection to the linker moiety of the bivalent compound; Y 1< , Y 2< , Y 3< , and Y 4< are independently selected from CR a< , N, O, and S, with the proviso that up to 3 of Y 1< , Y 2< , Y 3< , and Y 4< are N; each R a< is independently selected from hydrogen, halogen, CN, NO 2 , OR 12< , SR 12< , NR 13< R 14< , COR 12< , CO 2 R 12< , CONR 13< R 14< , SOR 12< , SO 2 R 12< , SO 2 NR 13< R 14< , NR 13< COR 14< , NR 15< C(O)NR 13< R 14< , NR 13< SOR 14< , NR 13< SO 2 R 14< , optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 3 -C 8 cycloalkoxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein R 12< , R 13< , R 14< , and R 15< are independently selected from hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 3 -C 8 cycloalkoxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or R 13< and R 14< together with the atom to which they are connected form a 4-8 membered cycloalkyl or heterocyclyl ring; m is 0 to 4; and R 3< is the same as defined in Formula 2.

[0051] The invention is defined in the appended claims, but generally, X 1< can be N; X 2< is N; X 3< is C; X 4< is C; X is CH 2 ; Ar 1< is 3-fluorophenyl; and Ar 2< is 2-pyridyl.

[0052] The invention is defined in the appended claims, but generally, a TRK ligand can comprise a moiety of Formula 3; Wherein, R 1< , R 2< , R 3< , R 4< , Ar, X, X 1< , X 2< , X 3< , X 4< and n are defined as before.

[0053] The invention is defined in the appended claims, but generally, a TRK ligand can comprise a moiety of FORMULA 3: wherein X 1< , X 2< , X 3< , and X 4< are independently selected from C, CR', and N (preferably, X 1< and X 4< are independently selected from CR' and N; X 2< and X 3< are independently selected from C and N), wherein R' is selected from hydrogen, halogen, CN, NO 2 , and optionally substituted C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or 3-6 membered heterocyclyl; X is selected from null, a bond, C(R 2< ) 2 , C(R 2< ) 2 C(R 2< ) 2 , CO, C(R 2< ) 2 CO, NR 2< CO, OC(R 2< ) 2 , and NR 2< C(R 2< ) 2 ; R 1< and each R 2< are independently selected from hydrogen, halogen, OH, NH 2 , CN, NO 2 , optionally substituted C 1 -C 4 alkyl, optionally substituted C 1 -C 4 alkoxy, optionally substituted C 1 -C 4 alkylamino, optionally substituted C 1 -C 4 alkoxyalkyl, optionally substituted C 1 -C 4 haloalkyl, optionally substituted C 1 -C 4 hydroxyalkyl, optionally substituted C 1 -C 4 alkylaminoC 1 -C 4 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 3 -C 6 cycloalkoxy, and optionally substituted 3-6 membered heterocyclyl; n is 1 to 4; R 3< is selected from hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted 3-6 membered heterocyclyl, optionally substituted C 1 -C 6 alkoxyalkyl, optionally substituted C 1 -C 6 haloalkyl, optionally substituted C 1 -C 6 hydroxyalkyl, and optionally substituted C 1 -C 6 alkylaminoC 1 -C 6 alkyl; is connected to the linker moiety of the bivalent compound either directly or through R 5< , wherein R 4< and R 5< are independently selected from null, OR 6< , SR 6< , NR 7< R 8< , COR 6< , CO 2 R 6< , CONR 7< R 8< , SOR 6< , SO 2 R 6< , SO 2 NR 7< R 8< , NR 7< COR 8< , NR 9< C(O)NR 7< R', NR 7< SOR 8< , NR 7< SO 2 R 8< , optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein R 6< , R 7< , R 8< , and R 9< are independently selected from null, 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 3 -C 6 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted aryl, and optionally substituted heteroaryl, or R 7< and R 8< together with the atom to which they are connected form a 4-8 membered cycloalkyl or heterocyclyl ring; Ar is selected from aryl and heteroaryl, each of which is optionally substituted with one or more substituents independently selected from halogen, CN, NO 2 , OR 10< , SR 10< , NR 11< R 12< , COR 10< , CO 2 R 10< , CONR 11< R 12< , SOR 10< , SO 2 R 10< , SO 2 NR 11< R 12< , NR 11< COR 12< , NR 10< C(O)NR 11< R 12< , NR 11< SOR 12< , NR 11< SO 2 R 12< , optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted C 3 -C 7 cycloalkyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein R 10< , R 11< , and R 12< are independently selected from null, 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 3 -C 7 cycloalkyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or R 11< and R 12< together with the atom to which they are connected form a 4-8 membered cycloalkyl or heterocyclyl rings.

[0054] The invention is defined in the appended claims, but generally, X 1< and X 4< can be selected from CR' and N, and R' is selected from hydrogen, F, Cl, CH 3 , CF 3 , and cyclopropyl.

[0055] The invention is defined in the appended claims, but generally, X 2< and X 3< can be independently selected from C and N.

[0056] The invention is defined in the appended claims, but generally, X can be selected from a bond, CH 2 , CH 2 CH 2 , CO, CH 2 CO, CONH, CONCH 3 , CH 2 O, CH 2 NH, and CH 2 NCH 3 .

[0057] The invention is defined in the appended claims, but generally, R 1< and each R 2< can be independently selected from hydrogen, F, Cl, OH, optionally substituted C 1 -C 4 alkyl, optionally substituted C 1 -C 4 alkoxy, optionally substituted C 1 -C 4 alkylamino, optionally substituted C 1 -C 4 haloalkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 3 -C 6 cycloalkoxy, and optionally substituted 3-6 membered heterocyclyl.

[0058] The invention is defined in the appended claims, but generally, R 3< can be selected from hydrogen, CH 3 , CH 2 CH 3 , propyl, isopropyl, cyclopropyl, CH 2 F, CHF 2 , and CF 3 . R 4< can be connected to the linker moiety of the bivalent compound directly, and R 4< is selected from null, OR 6< , SR 6< , NR 7< R 8< , COR 6< , CO 2 R 6< , CONR 7< R 8< , SOR 6< , SO 2 R 6< , SO 2 NR 7< R 8< , NR 7< COR 8< , NR 9< C(O)NR 7< R 8< , NR 7< SOR 8< , NR 7< SO 2 R 8< , optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein R 6< , R 7< , R 8< , and R 9< are independently selected from null, 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 3 -C 6 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, heteroarylalkyl, optionally substituted aryl, and optionally substituted heteroaryl, or R 7< and R 8< together with the atom to which they are connected form a 4-8 membered cycloalkyl or heterocyclyl ring. R 4< can be connected to the linker moiety of the bivalent compound through R 5< , and R 4< and R 5< are independently selected from null, OR 6< , SR 6< , NR 7< R 8< , COR 6< , CO 2 R 6< , CONR 7< R 8< , SOR 6< , SO 2 R 6< , SO 2 NR 7< R 8< , NR 7< COR 8< , NR 9< C(O)NR 7< R 8< , NR 7< SOR 8< , NR 7< SO 2 R 8< , optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein R 6< , R 7< , R 8< , and R 9< are independently selected from null, 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 3 -C 6 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted aryl, and optionally substituted heteroaryl, or R 7< and R 8< together with the atom to which they are connected form a 4-8 membered cycloalkyl or heterocyclyl ring.

[0059] The invention is defined in the appended claims, but generally, Ar can be selected from aryl and heteroaryl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, CN, NO 2 , OR 10< , NR 11< R 12< , COR 10< , CO 2 R 10< , CONR 11< R 12< , SOR 10< , SO 2 R 10< , SO 2 NR 11< R 12< , NR 11< COR 12< , NR 10< C(O)NR 11< R 12< , NR 11< SOR 12< , NR 11< SO 2 R 12< , optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxyalkyl, optionally substituted C 1 -C 6 haloalkyl, optionally substituted C 1 -C 6 hydroxyalkyl, optionally substituted C 1 -C 6 alkylaminoC 1 -C 6 alkyl, optionally substituted C 3 -C 7 cycloalkyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted aryl, and optionally substituted C 4 -C 5 heteroaryl, wherein R 10< , R 11< , and R 12< are independently selected from null, hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 7 cycloalkyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or R 11< and R 12< together with the atom to which they are connected form a 4-8 membered cycloalkyl or heterocyclyl ring.

[0060] The invention is defined in the appended claims, but generally, a TRK ligand can be selected from the group consisting of: Degradation Tag

[0061] 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 TRK or is a hydrophobic group or a tag that leads to misfolding of the TRK protein and subsequent degradation at the proteasome or loss of function.

[0062] The invention is defined in the appended claims, but generally, a degradation tag can be a moiety selected from the group consisting of FORMULAE 5A, 5B, 5C, and 5D: wherein V, W, and X are independently selected from CR 2< and N; Y is selected from CO, CR 3< R 4< , and N=N; Z is selected from null, CO, CR 5< R 6< , NR 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 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C 3 -C 13 fused cycloalkyl, optionally substituted C 3 -C 13 fused heterocyclyl, optionally substituted C 3 -C 13 bridged cycloalkyl, optionally substituted C 3 -C 13 bridged heterocyclyl, optionally substituted C 3 -C 13 spiro cycloalkyl, optionally substituted C 3 -C 13 spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; preferly, Z is selected from null, CH 2 , CH=CH, C=C, NH and O; R 1< , and R 2< are independently selected from hydrogen, halogen, cyano, nitro, optionally substituted C 1 -C 6 alkyl, optionally substituted 3 to 6 membered carbocyclyl, and optionally substituted 4 to 6 membered heterocyclyl; R 3< , and R 4< are independently selected from hydrogen, halogen, cyano, nitro, optionally substituted C 1 -C 6 alkyl, optionally substituted 3 to 6 membered carbocyclyl, and optionally substituted 4 to 6 membered heterocyclyl; or R 3< and R 4< together with the atom to which they are connected form a 3-6 membered carbocyclyl, or 4-6 membered heterocyclyl; and R 5< and R 6< are independently selected from null, hydrogen, halogen, oxo, hydroxyl, amino, cyano, nitro, optionally substituted C 1 -C 6 alkyl, optionally substituted 3 to 6 membered carbocyclyl, and optionally substituted 4 to 6 membered heterocyclyl; or R 5< and R 6< together with the atom to which they are connected form a 3-6 membered carbocyclyl, or 4-6 membered heterocyclyl.

[0063] The invention is defined in the appended claims, but generally, a degradation tag can be a moiety selected from the group consisting of FORMULAE 5A, 5B, 5C, and 5D: wherein, V, W, and X are independently selected from CR 2< and N; Y is selected from CO and CH 2 ; Z is selected from CH 2 , NH and O; R 1< is selected from hydrogen, C 1 -C 8 alkyl and halogen; and R 2< is selected from hydrogen, halogen, and C 1 -C 8 alkyl.

[0064] A degradation tag can be a moiety selected from the group consisting of FORMULA 5B and FORMULA 5C.

[0065] A degradation tag can be a moiety selected from the group consisting of FORMULAE 5E, 5F, 5G, 5H, and 5I: wherein U, V, W, and X are independently selected from CR 2< and N; Y is selected from CR 3< R 4< , NR 3< and O; preferly, Y is selected from CH 2 , NH, NCH 3 and O; Z is selected from null, CO, CR 5< R 6< , NR 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 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C 3 -C 13 fused cycloalkyl, optionally substituted C 3 -C 13 fused heterocyclyl, optionally substituted C 3 -C 13 bridged cycloalkyl, optionally substituted C 3 -C 13 bridged heterocyclyl, optionally substituted C 3 -C 13 spiro cycloalkyl, optionally substituted C 3 -C 13 spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; preferly, Z is selected from null, CH 2 , CH=CH, C≡C, NH and O; R 1< , and R 2< are independently selected from hydrogen, halogen, cyano, nitro, optionally substituted C 1 -C 6 alkyl, optionally substituted 3 to 6 membered carbocyclyl, and optionally substituted 4 to 6 membered heterocyclyl; R 3< , and R 4< are independently selected from hydrogen, halogen, cyano, nitro, optionally substituted C 1 -C 6 alkyl, optionally substituted 3 to 6 membered carbocyclyl, and optionally substituted 4 to 6 membered heterocyclyl; or R 3< and R 4< together with the atom to which they are connected form a 3-6 membered carbocyclyl, or 4-6 membered heterocyclyl; and R 5< and R 6< are independently selected from null, hydrogen, halogen, oxo, hydroxyl, amino, cyano, nitro, optionally substituted C 1 -C 6 alkyl, optionally substituted 3 to 6 membered carbocyclyl, and optionally substituted 4 to 6 membered heterocyclyl; or R 5< and R 6< together with the atom to which they are connected form a 3-6 membered carbocyclyl, or 4-6 membered heterocyclyl.

[0066] The invention is defined in the appended claims, but generally, a degradation tag can be a moiety of FORMULA 6A: wherein R 1< and R 2< are independently selected from hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, 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 8 alkylaminoC 1 -C 8 alkyl, 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; and R 3< is hydrogen, optionally substituted C(O)C 1 -C 8 alkyl, optionally substituted C(O)C 1 -C 8 alkoxyC 1 -C 8 alkyl, 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 8 alkylaminoC 1 -C 8 alkyl, optionally substituted C(O)C 3 -C 7 cycloalkyl, optionally substituted C(O)(3-7 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 8 alkoxyC 1 -C 8 alkyl, 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 8 alkylaminoC 1 -C 8 alkyl, optionally substituted C(O)OC 3 -C 7 cycloalkyl, optionally substituted C(O)O(3-7 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 8 alkoxyC 1 -C 8 alkyl, 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 8 alkylaminoC 1 -C 8 alkyl, optionally substituted C(O)NC 3 -C 7 cycloalkyl, optionally substituted C(O)N(3-7 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 -Cs aryl) 2 .

[0067] The invention is defined in the appended claims, but generally, a degradation tag can be a moiety selected from the group consisting of FORMULAE 6B, 6C, 6D, 6E and 6F: wherein R 1< and R 2< are independently selected from hydrogen, halogen, OH, NH 2 , CN, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, 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 8 alkylaminoC 1 -C 8 alkyl, 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; (preferably, R 1< is selected from iso-propyl or tert-butyl; and R 2< is selected from hydrogen or methyl);. R 3< is hydrogen, optionally substituted C(O)C 1 -C 8 alkyl, optionally substituted C(O)C 1 -C 8 alkoxyC 1 -C 8 alkyl, 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 8 alkylaminoC 1 -C 8 alkyl, optionally substituted C(O)C 3 -C 7 cycloalkyl, optionally substituted C(O)(3-7 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 8 alkoxyC 1 -C 8 alkyl, 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 8 alkylaminoC 1 -C 8 alkyl, optionally substituted C(O)OC 3 -C 7 cycloalkyl, optionally substituted C(O)O(3-7 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 8 alkoxyC 1 -C 8 alkyl, 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 8 alkylaminoC 1 -C 8 alkyl, optionally substituted C(O)NC 3 -C 7 cycloalkyl, optionally substituted C(O)N(3-7 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 -Cs aryl) 2 ; and R 4< and R 5< are independently selected from hydrogen, COR 6< , CO 2 R 6< , CONR 6< R 7< , SOR 6< , SO 2 R 6< , SO 2 NR 6< R 7< , optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein R 6< and R 7< are independently selected from hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or R 4< and R 5< ; R 6< and R 7< together with the atom to which they are connected form a 4-8 membered cycloalkyl or heterocyclyl ring; Ar is selected from aryl and heteroaryl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, CN, NO 2 , OR 8< , NR 8< R 9< , COR s< , CO 2 R 8< , CONR 8< R 9< , SOR 8< , SO 2 R 8< , SO 2 NR 9< R 10< , NR 9< COR 10< , NR 8< C(O)NR 9< R 10< , NR 9< SOR 10< , NR 9< SO 2 R 10< , optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxyalkyl, optionally substituted C 1 -C 6 haloalkyl, optionally substituted C 1 -C 6 hydroxyalkyl, optionally substituted C 1 -C 6 alkylaminoC 1 -C 6 alkyl, optionally substituted C 3 -C 7 cycloalkyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted aryl, and optionally substituted C 4 -C 5 heteroaryl, wherein R 8< , R 9< , and R 1< ° are independently selected from null, hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 7 cycloalkyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or R 8< and R 9< ; R 9< and R 10< together with the atom to which they are connected form a 4-8 membered cycloalkyl or heterocyclyl ring.

[0068] The invention is defined in the appended claims, but generally, a degradation tag can be a moiety of FORMULA 7A: wherein V, W, X, and Z are independently selected from CR 4< and N. R 1< , R 2< , R 3< , and R 4< are independently selected from hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, 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.

[0069] The invention is defined in the appended claims, but generally, a degradation tag can be a moiety of FORMULA 7B: wherein R 1< , R 2< , and R 3< are independently selected from hydrogen, halogene, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, 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 4< and R 5< are independently selected from hydrogen, COR 6< , CO 2 R 6< , CONR 6< R 7< , SOR 6< , SO 2 R 6< , SO 2 NR 6< R 7< , optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted aryl-C 1 -C 8 alkyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein R 6< and R 7< are independently selected from hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or R 6< and R 7< together with the atom to which they are connected form a 4-8 membered cycloalkyl or heterocyclyl ring.

[0070] The invention is defined in the appended claims, but generally, a degradation tag can be derived from any of the following:

[0071] The invention is defined in the appended claims, but generally, a degradation tag can be an E3 ligase. A degradation tag can comprise one or more of cereblon E3 ligase, a VHL E3 ligase, a MDM2 ligase, a TRIM24 ligase, a TRIM21 ligase, a KEAP1 ligase, and an IAP ligase. The invention is defined in the appended claims, but generally, a degradation tag can include, e.g., pomalidomide (Fischer et al., 2014), thalidomide (Fischer et al., 2014), lenalidomide (Fischer et al., 2014), VH032 (Galdeano et al., 2014; Maniaci et al., 2017), adamantane (Xie et al., 2014), 1-((4,4,5,5,5-pentafluoropentyl)sulfmyl)nonane (E.Wakeling, 1995), nutlin-3a (Vassilev et al., 2004), RG7112 (Vu et al., 2013), RG7338, AMG 232 (Sun et al., 2014), AA-115 (Aguilar et al., 2017), bestatin (Hiroyuki Suda et al., 1976), MV1 (Varfolomeev et al., 2007), LCL161 (Weisberg et al., 2010), and / or analogs thereof. The invention is defined in the appended claims, but generally, a degradation tag can be derived from a compound comprising pomalidomide (Fischer et al., 2014), thalidomide (Fischer et al., 2014), lenalidomide (Fischer et al., 2014), VH032 (Galdeano et al., 2014; Maniaci et al., 2017), adamantane (Xie et al., 2014), 1-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonane (E.Wakeling, 1995), nutlin-3a (Vassilev et al., 2004), RG7112 (Vu et al., 2013), RG7338, AMG 232 (Sun et al., 2014), AA-115 (Aguilar et al., 2017), bestatin (Hiroyuki Suda et al., 1976), MV1 (Varfolomeev et al., 2007), LCL161 (Weisberg et al., 2010), and / or analogs thereof.

[0072] The invention is defined in the appended claims, but generally, a degradation tag can be selected from the group consisting of: Linker Moiety

[0073] 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" can generally refer to any agent or molecule that bridges the TRK ligand to the degradation tag. One of ordinary skill in the art recognizes that sites on the TRK ligand or the degradation tag, which are not necessary for the function of the 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 TRK ligand, i.e., its ability to bind TRK, or the function of the degradation tag, i.e., its ability to recruit a ubiquitin ligase.

[0074] The length of the linker of the bivalent compound can be adjusted to minimize the molecular weight of the bivalent compounds, avoid the clash of the TRK ligand or targeting moiety with the ubiquitin ligase and / or induce TRK misfolding by the hydrophobic tag. The invention is defined in the appended claims, but generally, a linker can comprise acyclic or cyclic saturated or unsaturated carbon, ethylene glycol, amide, amino, ether, urea, carbamate, aromatic, heteroaromatic, heterocyclic or carbonyl groups. The invention is defined in the appended claims, but generally, the length of a linker can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more atoms.

[0075] IThe invention is defined in the appended claims, but generally, a linker moiety can be of FORMULA 9: wherein A, W and B, at each occurrence, are independently selected from null, or bivalent moiety selected from R'-R", R'COR", R'CO 2 R", R'C(O)N(R 1< )R", R'C(S)N(R 1< )R", R'OR", R'OC(O)R", R'OC(O)OR", R'OCON(R 1< )R", R'SR", R'SOR", R'SO 2 R", R'SO 2 N(R 1< )R", R'N(R 1< )R", R'NR 1< COR", R'NR 1< C(O)OR", R'NR 1< CON(R 2< )R", R'NR 1< C(S)R", R'NR 1< S(O)R", R'NR 1< S(O) 2 R", and R'NR 1< S(O) 2 N(R 2< )R", wherein R' and R are independently selected from null, optionally substituted R r< -(C 1 -C 8 alkyl), 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 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, 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 8 alkoxyC 1 -C 8 alkylene, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkylene, optionally substituted C 1 -C 8 haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C 3 -C 13 fused cycloalkyl, optionally substituted C 3 -C 13 fused heterocyclyl, optionally substituted C 3 -C 13 bridged cycloalkyl, optionally substituted C 3 -C 13 bridged heterocyclyl, optionally substituted C 3 -C 13 spiro cycloalkyl, optionally substituted C 3 -C 13 spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R r< is selected from optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C 3 -C 13 fused cycloalkyl, optionally substituted C 3 -C 13 fused heterocyclyl, optionally substituted C 3 -C 13 bridged cycloalkyl, optionally substituted C 3 -C 13 bridged heterocyclyl, optionally substituted C 3 -C 13 spiro cycloalkyl, optionally substituted C 3 -C 13 spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R 1< and R 2< 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 8 alkylaminoC 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R' and R", R 1< and R 2< , R' and R 1< , R' and R 2< , R" and R 1< , R" and R 2< together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring; and m is 0 to 15.

[0076] The invention is defined in the appended claims, but generally, a linker moiety can be of FORMULA 9: wherein A, W, and B, at each occurrence, are independently selected from null, CO, CO 2 , C(O)NR 1< , C(S)NR 1< , O, S, SO, SO 2 , SO 2 NR 1< , NR 1< , NR 1< CO, NR 1< CONR 2< , NR 1< C(S), optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 3 -C 8 cycloalkoxy,optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 3 -C 13 fused cycloalkyl, optionally substituted C 3 -C 13 fused heterocyclyl, optionally substituted C 3 -C 13 bridged cycloalkyl, optionally substituted C 3 -C 13 bridged heterocyclyl, optionally substituted C 3 -C 13 spiro cycloalkyl, and optionally substituted C 3 -C 13 spiro heterocyclyl, wherein R 1< and R 2< are independently selected from hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 3 -C 6 cycloalkoxy, optionally substituted 3-6 membered heterocyclyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 1 -C 6 alkoxyalkyl, optionally substituted C 1 -C 6 haloalkyl, optionally substituted C 1 -C 6 hydroxyalkyl, optionally substituted C 1 -C 6 alkylamino, and optionally substituted C 1 -C 6 alkylaminoC 1 -C 6 alkyl; and m is 0 to 15.

[0077] The invention is defined in the appended claims, but generally, a linker moiety can be of FORMULA 9A:

[0078] WhereinR 1< , R 2< , R 3< and R 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 4-8 membered membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or R 1< and R 2< , R 3< and R 4< together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring; A, W and B, at each occurrence, are independently selected from null, or bivalent moiety selected from R'-R", R'COR", R'CO 2 R", R'C(O)N(R 5< )R", R'C(S)N(R 5< )R", R'OR", R'OC(O)R", R'OC(O)OR", R'OCONR 5< R", R'SR", R'SOR", R'SO 2 R", R'SO 2 N(R 5< )R", R'N(R 5< )R", R'NR 5< COR", R'NR 5< C(O)OR", R'NR 5< CON(R 6< )R", RNR5C(S)R", R'NR 5< S(O)R", R'NR 5< S(O 2 )R", and R'NR 5< S(O) 2 N(R 6< )R", wherein R' and R" are independently selected from null, optionally substituted R r< -(C 1 -C 8 alkyl), 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 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, 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 8 alkoxyC 1 -C 8 alkylene, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkylene, optionally substituted C 1 -C 8 haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C 3 -C 13 fused cycloalkyl, optionally substituted C 3 -C 13 fused heterocyclyl, optionally substituted C 3 -C 13 bridged cycloalkyl, optionally substituted C 3 -C 13 bridged heterocyclyl, optionally substituted C 3 -C 13 spiro cycloalkyl, optionally substituted C 3 -C 13 spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R r< is selected from optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C 3 -C 13 fused cycloalkyl, optionally substituted C 3 -C 13 fused heterocyclyl, optionally substituted C 3 -C 13 bridged cycloalkyl, optionally substituted C 3 -C 13 bridged heterocyclyl, optionally substituted C 3 -C 13 spiro cycloalkyl, optionally substituted C 3 -C 13 spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R 5< and R 6< 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 8 alkylaminoC 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R' and R", R 5< and R 6< , R' and R 5< , R' and R 6< , R" and R 5< , R" and R 6< together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring; m is 0 to 15; n, at each occurrence, is 0 to 15; and o is 0 to 15.

[0079] The invention is defined in the appended claims, but generally, a linker moiety can be of FORMULA 9A: wherein R 1< , R 2< , R 3< , and R 4< , at each occurrence, are independently selected from hydrogen, halogen, CN, OH, NH 2 , optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 3 -C 6 cycloalkoxy, optionally substituted 3-6 membered heterocyclyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 1 -C 6 alkoxyalkyl, optionally substituted C 1 -C 6 haloalkyl, optionally substituted C 1 -C 6 hydroxyalkyl, optionally substituted C 1 -C 6 alkylamino, and optionally substituted C 1 -C 6 alkylaminoC 1 -C 6 alkyl; A, W, and B, at each occurrence, are independently selected from null, CO, CO 2 , C(O)NR 5< , C(S)NR 5< , O, S, SO, SO 2 , SO 2 NR 5< , NR 5< , NR 5< CO, NR 5< CONR 6< , NR 5< C(S), optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 3 -C 8 cycloalkoxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 3 -C 13 fused cycloalkyl, optionally substituted C 3 -C 13 fused heterocyclyl, optionally substituted C 3 -C 13 bridged cycloalkyl, optionally substituted C 3 -C 13 bridged heterocyclyl, optionally substituted C 3 -C 13 spiro cycloalkyl, and optionally substituted C 3 -C 13 spiro heterocyclyl, wherein R 5< and R 6< are independently selected from hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 3 -C 6 cycloalkoxy, optionally substituted 3-6 membered heterocyclyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 1 -C 6 alkoxyalkyl, optionally substituted C 1 -C 6 haloalkyl, optionally substituted C 1 -C 6 hydroxyalkyl, optionally substituted C 1 -C 6 alkylamino, and optionally substituted C 1 -C 6 alkylaminoC 1 -C 6 alkyl; m is 0 to 15; each n is 0 to 15; and o is 0 to 15.

[0080] The invention is defined in the appended claims, but generally, a linker moiety can be of FORMULA 9B: wherein R 1< and R 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 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 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or R 1< and R 2< together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring; A and B, at each occurrence, are independently selected from null, or bivalent moiety selected from R'-R", R'COR", R'CO 2 R", R'C(O)NR 3< R", R'C(S)NR 3< R", R'OR", R'OC(O)R", R'OC(O)OR", R'OCON(R 3< )R", R'SR", R'SOR", R'SO 2 R", R'SO 2 N(R 3< )R", R'N(R 3< )R", R'NR 3< COR", R'NR 3< C(O)OR", R'NR 3< CON(R 4< )R', R'NR 3< C(S)R", R'NR 3< S(O)R", R'NR 1< S(O) 2 R", and R'NR 3< S(O) 2 N(R 4< )R", wherein R' and R" are independently selected from null, optionally substituted R r< -(C 1 -C 8 alkyl), 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 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, 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 8 alkoxyC 1 -C 8 alkylene, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkylene, optionally substituted C 1 -C 8 haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C 3 -C 13 fused cycloalkyl, optionally substituted C 3 -C 13 fused heterocyclyl, optionally substituted C 3 -C 13 bridged cycloalkyl, optionally substituted C 3 -C 13 bridged heterocyclyl, optionally substituted C 3 -C 13 spiro cycloalkyl, optionally substituted C 3 -C 13 spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R r< is selected from optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C 3 -C 13 fused cycloalkyl, optionally substituted C 3 -C 13 fused heterocyclyl, optionally substituted C 3 -C 13 bridged cycloalkyl, optionally substituted C 3 -C 13 bridged heterocyclyl, optionally substituted C 3 -C 13 spiro cycloalkyl, optionally substituted C 3 -C 13 spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R 3< and R 4< 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 8 alkylaminoC 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R' and R", R 3< and R 4< , R' and R 3< , R' and R 4< , R" and R 3< , R" and R 4< together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring; each m is 0 to 15; and n is 0 to 15.

[0081] The invention is defined in the appended claims, but generally, a linker moiety can be of FORMULA 9B: wherein each R 1< , and each R 2< are independently selected from hydrogen, halogen, CN, OH, NH 2 , and optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 3 -C 6 cycloalkoxy, optionally substituted 3-6 membered heterocyclyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 1 -C 6 alkoxyalkyl, optionally substituted C 1 -C 6 haloalkyl, optionally substituted C 1 -C 6 hydroxyalkyl, optionally substituted C 1 -C 6 alkylamino, or C 1 -C 6 alkylaminoC 1 -C 6 alkyl; each A and each B are independently selected from null, CO, CO 2 , C(O)NR 3< , C(S)NR 3< , O, S, SO, SO 2 , SO 2 NR 3< , NR 3< , NR 3< CO, NR 3< CONR 4< , NR 3< C(S), and optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 3 -C 8 cycloalkoxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 3 -C 13 fused cycloalkyl, optionally substituted C 3 -C 13 fused heterocyclyl, optionally substituted C 3 -C 13 bridged cycloalkyl, optionally substituted C 3 -C 13 bridged heterocyclyl, optionally substituted C 3 -C 13 spiro cycloalkyl, or C 3 -C 13 spiro heterocyclyl, wherein R 3< and R 4< are independently selected from hydrogen, and optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 3 -C 6 cycloalkoxy, optionally substituted 3-6 membered heterocyclyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 1 -C 6 alkoxyalkyl, optionally substituted C 1 -C 6 haloalkyl, optionally substituted C 1 -C 6 hydroxyalkyl, optionally substituted C 1 -C 6 alkylamino, or C 1 -C 6 alkylaminoC 1 -C 6 alkyl; each m is 0 to 15; and n is 0 to 15.

[0082] The invention is defined in the appended claims, but generally, in FORMULA 9B, m can be 1 to 15.

[0083] The invention is defined in the appended claims, but generally, in FORMULA 9B, n can be 1.

[0084] The invention is defined in the appended claims, but generally, in FORMULA 9B, R 1< and R 2< can be independently selected from hydrogen,and optionally substituted C 1 -C 8 alkyl.

[0085] The invention is defined in the appended claims, but generally, a linker moiety can be of FORMULA 9C: wherein X is selected from O, NH, and NR 7< ; R 1< , R 2< , R 3< , R 4< , R 5< , and R 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 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; A and B are independently selected from null, or bivalent moiety selected from R'-R", R'COR", R'CO 2 R", R'C(O)N(R 8< )R", R'C(S)N(R 8< )R", R'OR", R'OC(O)R", R'OC(O)OR", R'OCON(R 8< )R", R'SR", R'SOR", R'SO 2 R", R'SO 2 N(R 8< )R", R'N(R 8< )R", R'NR 8< COR", R'NR 8< C(O)OR", R'NR 8< CON(R 9< )R", R'NR 8< C(S)R", R'NR 8< S(O)R", R'NR 8< S(O) 2 R", and R'NR 8< S(O) 2 N(R 9< )R",wherein R' and R" are independently selected from null, optionally substituted R r< -(C 1 -C 8 alkyl), 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 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, 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 8 alkoxyC 1 -C 8 alkylene, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkylene, optionally substituted C 1 -C 8 haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C 3 -C 13 fused cycloalkyl, optionally substituted C 3 -C 13 fused heterocyclyl, optionally substituted C 3 -C 13 bridged cycloalkyl, optionally substituted C 3 -C 13 bridged heterocyclyl, optionally substituted C 3 -C 13 spiro cycloalkyl, optionally substituted C 3 -C 13 spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R r< is selected from optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C 3 -C 13 fused cycloalkyl, optionally substituted C 3 -C 13 fused heterocyclyl, optionally substituted C 3 -C 13 bridged cycloalkyl, optionally substituted C 3 -C 13 bridged heterocyclyl, optionally substituted C 3 -C 13 spiro cycloalkyl, optionally substituted C 3 -C 13 spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R 7< , R 8< and R 9< 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 8 alkylaminoC 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R' and R", R 8< and R 9< , R' and R 8< , R' and R 9< , R" and R 8< , R" and R 9< together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring; m, at each occurrence, is 0 to 15; n, at each occurrence, is 0 to 15; o is 0 to 15; and p is 0 to 15.

[0086] The invention is defined in the appended claims, but generally, a linker moiety can be of FORMULA 9C: wherein X is selected from O, NH, and NR 7< ; R 1< , R 2< , R 3< , R 4< , R 5< , and R 6< , at each occurrence, are independently selected from hydrogen, halogen, CN, OH, NH 2 , optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 3 -C 6 cycloalkoxy, optionally substituted 3-6 membered heterocyclyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 1 -C 6 alkoxyalkyl, optionally substituted C 1 -C 6 haloalkyl, optionally substituted C 1 -C 6 hydroxyalkyl, optionally substituted C 1 -C 6 alkylamino, and optionally substituted C 1 -C 6 alkylaminoC 1 -C 6 alkyl; A and B, at each occurrence, are independently selected from null, CO, CO 2 , C(O)NR 7< , C(S)NR 7< , O, S, SO, SO 2 , SO 2 NR 7< , NR 7< , NR 7< CO, NR 7< CONR 8< , NR 7< C(S), optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 3 -C 8 cycloalkoxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 3 -C 13 fused cycloalkyl, optionally substituted C 3 -C 13 fused heterocyclyl, optionally substituted C 3 -C 13 bridged cycloalkyl, optionally substituted C 3 -C 13 bridged heterocyclyl, optionally substituted C 3 -C 13 spiro cycloalkyl, and optionally substituted C 3 -C 13 spiro heterocyclyl, wherein R 7< and R 8< are independently selected from hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 3 -C 6 cycloalkoxy, optionally substituted 3-6 membered heterocyclyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 1 -C 6 alkoxyalkyl, optionally substituted C 1 -C 6 haloalkyl, optionally substituted C 1 -C 6 hydroxyalkyl, optionally substituted C 1 -C 6 alkylamino, and optionally substituted C 1 -C 6 alkylaminoC 1 -C 6 alkyl; each m is 0 to 15; each n is 0 to 15; o is 0 to 15; and p is 0 to 15.

[0087] The invention is defined in the appended claims, but generally, in FORMULA 9C, m and n can be 1, and p is 1 to 15;

[0088] The invention is defined in the appended claims, but generally, in FORMULA 9C, X can be selected from O and NH;

[0089] The invention is defined in the appended claims, but generally, in FORMULA 9C, R 1< , R 2< , R 3< , R 4< , R 5< , and R 6< , can be independently selected from hydrogen, optionally substituted C 1 -C 6 alkyl.

[0090] The invention is defined in the appended claims, but generally, a linker moiety can comprise a ring selected from the group consisting of a 3 to 13 membered ring, a 3 to 13 membered fused ring, a 3 to 13 membered bridged ring, and a 3 to13 membered spiro ring.

[0091] The invention is defined in the appended claims, but generally, a linker moiety can comprise a ring selected from the group consisting of Formula C1, C2, C3, C4 and C5: and

[0092] The invention is defined in the appended claims, but generally, A, B and W, at each occurrence, can be independently selected from null, CO, NH, NH-CO, CO-NH, CH 2 -NH-CO, CH 2 -CO-NH, NH-CO-CH 2 , CO-NH-CH 2 , CH 2 -NH-CH 2 -CO-NH, CH 2 -NH-CH 2 -NH-CO, NH-CO-CH 2 -NH-CH 2 CO-NH- CH 2 -NH-CH 2 , and CH 2 -NH-CH 2 , R r -CO, R r -NH, R r -NH-CO, R r -CO-NH, R r -CH 2 -NH-CO, R r -CH 2 -CO-NH, R r -NH-CO-CH 2 , R r -CO-NH-CH 2 , R r -CH 2 -NH-CH 2 -CO-NH, R r -CH 2 -NH-CH 2 -NH-CO, R r -NH-CO-CH 2 -NH-CH 2 , R r - CO-NH-CH 2 -NH-CH 2 , R r -CH 2 -NH-CH 2∘ ∘

[0093] The invention is defined in the appended claims, but generally, R r< can be of Formula C1, C2, C3, C4 or C5.

[0094] Generall,y R r< can be selected from

[0095] The invention is defined in the appended claims, but generally, length of the linker can be 0 to 40 linear atoms.

[0096] The invention is defined in the appended claims, but generally, the length of a linker can be 0 to 20 linear atoms.

[0097] The invention is defined in the appended claims, but generally, the length of a linker can be 0 to 8 linear atoms.

[0098] The invention is defined in the appended claims, but generally, a linker can be 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 2 CH 2 ) 1-7 -, -(CH 2 ) 0-1 -(CO)-(CH 2 ) 1-3 -(OCH 2 CH 2 ) 1-7 -, -(CO)-(CH 2 ) 0-3 -( alkenylene)-(CH 2 ) 0-3 -, -(CO)-(CH 2 ) 0-3 -( alkynylene)-(CH 2 ) 0-3 -, -(CO)-(CH 2 ) 0-3 -(3-8 membered carbocyclyl)-(CH 2 ) 0-3 -, -(CO)-(CH 2 ) 0-3 -(3-8 membered heterocarbocyclyl)-(CH 2 ) 0-3 -, -(CH 2 ) 0-3 -( alkenylene)-(CH 2 ) 0-3 -, -(CH 2 ) 0-3 -( alkynylene)-(CH 2 ) 0-3 -, -(CH 2 ) 0-3 -(3-8 membered carbocyclyl)-(CH 2 ) 0-3 -, and -(CH 2 ) 0-3 -(3-8 membered heterocarbocyclyl)-(CH 2 ) 0-3 -, R r< -(CO)-(CH 2 ) 1-8 -, R r< -(CH 2 ) 1-9 -, R r< -(CH 2 ) 1-2 -(CO)-NH-(CH 2 ) 2-9 -, R r< -(CH 2 ) 1-2 -(CO)-NH-(CH 2 ) 1-3 -(OCH 2 CH 2 ) 1-7 -, R r< -(CH 2 ) 0-1 -(CO)-(CH 2 ) 1-3 -(OCH 2 CH 2 ) 1-7 -, R r< -(CO)-(CH 2 ) 0-3 -( alkenylene)-(CH 2 ) 0-3 -, R r< -(CO)-(CH 2 ) 0-3 -( alkynylene)-(CH 2 ) 0-3 -, R r< -(CO)-(CH 2 ) 0-3 -(3-8 membered carbocyclyl)-(CH 2 ) 0-3 -, R r< -(CO)-(CH 2 ) 0-3 -(3-8 membered heterocarbocyclyl)-(CH 2 ) 0-3 -, R r< -(CH 2 ) 0-3 -( alkenylene)-(CH 2 ) 0-3 -, R r< -(CH 2 ) 0-3 -( alkynylene)-(CH 2 ) 0-3 -, R r< -(CH 2 ) 0-3 -(3-8 membered carbocyclyl)-(CH 2 ) 0-3 -, and R r< -(CH 2 ) 0-3 -(3-8 membered heterocarbocyclyl)-(CH 2 ) 0-3 -.

[0099] Without wishing to be bound by any particular theory, it is contemplated herein that attaching pomalidomide or VHL-1 to either portion of the molecule can generally recruit the cereblon E3 ligase or VHL E3 ligase to TRK.

[0100] The bivalent compounds disclosed herein can selectively affect TRK-mediated disease cells compared to WT (wild type) cells (i.e., an bivalent compound able to kill or inhibit the growth of an TRK-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 TRK-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 TRK-mediated disease cells.Cross-reactivity with Protein Kinases

[0101] A TRK ligand can be bound to TRK, TRK fusion proteins, and / or TRK mutant proteins. A TRK ligand can be bound to ROS1, ROS1 fusion proteins, and / or ROS1 mutant proteins. A TRK ligand can be bound to ALK, ALK fusion proteins, and / or ALK mutant proteins. A TRK ligand can be bound to TRK, ROS1, or ALK. A TRK ligand can be bound to TRK or ROS1. A TRK ligand can be bound to TRK or ALK. A TRK ligand can be bound to ROS1 or ALK.Synthesis and Testing of Bivalent Compounds

[0102] The binding affinity of novel synthesized bivalent 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 bivalent compound's ability to induce TRK degradation and inhibit cancer cell proliferation. Besides evaluating a bivalent compound's induced changes in the protein levels of TRK, TRK mutants, or TRK fusion proteins, 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, cancer cell lines: 1); KM12, 2); CUTO3.29, 3); MO91, 4); HEL. 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.

[0103] By way of non-limiting example, detailed synthesis protocols are described in the Examples for specific exemplary bivalent compounds.

[0104] 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., 2< H, 3< H, 13< C, 14< C, 15< N, 17< O, 18< O, 32< P, 35< S, 18< F, and 36< Cl.

[0105] Isotopic variations (e.g., isotopic variations containing 2< H) 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 ( 3< H) and carbon-14 ( 14< C) are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

[0106] 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 2 O in place of H 2 O, d 6 -acetone in place of acetone, or d 6 -DMSO in place of DMSO).Characterization of Exemplary Bivalent Compounds

[0107] Specific bivalent compounds (comparative and according to the invention) were characterized in KM12 cells. KM12 cells that express TPM3-TRKA fusion protein were treated with 100 nM entrectinib (Entrec) or the bivalent compounds disclosed herein (CPD-001 - CPD-065) for 16 hours. Cells were collected, lysed and subject to immunoblotting using an antibody specific to TRK proteins. GAPDH was included as the loading control. DMSO was used as the negative control. Following a 16-hour treatment of various bivalent compounds at 100 nM, TPM3-TRKA levels in KM12 cells were significantly decreased (Figures 1A-1C).

[0108] Bi-functional compounds, exemplified by CPD-027, CPD-053, and CPD-060, were found to be partiucalrly effective in reducing TPM3-TRKA protein levels in KM12 cells (Figures 1A-1C). Treated with 100 nM CPD-027, CPD-053, or CPD-060 for various time points, significant degradation of TPM3-TRKA in KM12 cells was readily detected 15 minutes after adding the bivalent compounds (Figure 2). Additionally, a panel of selected compounds demonstrated the ability to induce significant degradation of TPM3-TRKA at concentration below 10 nM (Figures 5, 6 and 13). In addition to TPM3-TRKA, other TRK fusion proteins, such as AGBL4-TRKB and ETV6-TRKC, were also subject to bispecific compound-induced degradation (Figure 7). The interaction with cereblon is critical to the ability of bispecific compounds to induce degradation of TRK proteins, as a chemical modification that disrupted cereblon binding abolished TRKA degradation induced by TR-123 (Figure 8). The degradation was also dependent on the ubiquitin-proteasome system, because it could be neutralized by co-administration of proteasome inhibitors, MG-132 and bortezomib, a cullin E3 ligase inhibitor, MLN4924, or high concentration of pomalidomide that compete for cereblon binding (Figure 9). These findings collectively demonstrate that bispecific compounds induce degradation of TRK family proteins via a mechanism specifically mediated by cereblon, cullin E3 ligases, and the proteasome.

[0109] In addition to cultured cells, athymic nude mice bearing KM12 subcutaneous xenograft tumors at the right flank were intraperitoneally treated with 10, 20, or 50 mg / kg CPD-053, CPD-027, or CPD-060. Four hours after drug administration, animals were sacrificed for immunoblotting of TPM3-TPKA in homogenized xenograft tumor masses. The label "a" or "b" represents two different samples of the same xenograft tumor. Bivalent compounds, CPD-027, CPD-053, and CPD-060, exhibited the ability of significantly reducing TPM3-TRKA protein levels in KM12 subcutaneous xenograft tumors within 4 hours after a single dose of drug administration (Figure 3). Additionl compounds, as exemplified by TR-123, TR-171, TR-172, TR-173, TR-177, and TR-181, also exhibited the activities to induce TPM3-TRKA degradation in KM12 subcutaneous tumors through intraperitoneal or oral administration (Figure 10).

[0110] To investigate the pharmacokinetics of bi-functional compounds, exemplified by TR-123, a single 20 mg / kg intraperitoneal injection was evaluated. Plasma concentration of TR-123 reported at each time point represents the mean value derived from 3 experimental animals. Our data showed significant plasma exposure of TR-123 over 12 hours (Figure 11). Additionally, doses of 2mg / kg TR-198 via intravenous injection and 20 mg / kg TR-198 via oral gavage were evaluated in mice. Data showed that the oral bioavailability of TR-198 in mice was approximiately 16% (Figure 14).

[0111] The kinase activity of TRK is known to play important roles in tumors expressing TRK-fusion proteins, as TRK kinase inhibitors compromise cell proliferation, survival, and induce marked clinical responses (Amatu et al., 2016; Drilon et al., 2018; Drilon et al., 2017; Khotskaya et al., 2017). KM12 cells seeded in 96-well plates were treated with 500 nM entrectinib or bivalent compounds, i.e. CPD-010, CPD-053, and CPD-057 following a 12-point 2-fold serial dilution. Three days after treatment, cell viability was determined using the CellTiter-Glo kit following manufacturer's instructions. Cell viability was normalized to the mean values of 3 replicates of untreated cells. Dose-dependent response was analyzed following the least-squares non-linear regression method using the GraphPad Prism 5.0 software. Each data point in the figure represents the mean values of three technical replicates ± standard deviation. Bivalent compounds also dose-dependently suppressed viability of TPM3-TRKA-expressing KM12 cells, as exemplified by CPD-010, CPD-053, and CPD-057 (Figure 4A). More specifically, all bivalent compounds that had IC 50 values smaller than 1000 nM in KM12 cells induced degradation of TPM3-TRKA (Figure 1 and Table 2-4). In contrast, when KM12 or H358 cells were treated with 1000 nM CPD-053 following an 8-point 3-fold serial dilution, bivalent compounds, as exemplified by CPD-053, did not affect cell viability in KRAS-mutant H358 cells (Figure 4B). Finally, administration of bivalent compounds, as exemplified by CPD-060, TR-181, and TR-198, significantly repressed the growth of KM12 subcutaneous xenograft tumors without inducing substantial weight losses (Figure 12 and 15). Take together, these results indicate that bivalent compounds impair KM12 cell proliferation, survival and tumorigenic potential through specifically inducing degradation of TPM3-TRKA.

[0112] NGF and its primary receptor TRKA have been well recognized for their roles in pain sensory (Denk et al., 2017). Targeting TRKA represents a promising therapeutic strategy for chronic pain management. Bivalent compounds, exemplified by TR-123, have demonstrated the ability to induce significant degradation of full-length TRKA, same as TPM3-TRKA fusion (Figure 8, and 9). The analgesic activities of bivalent compounds were assessed using a widely used chronic pain model associated with osteoarthritis. Osteoarthritis was induced in the right knee of adult male rats or guinea pigs following monoiodoacetate injection. One week later, animals were treated with TR-181 with ibuprofen as the positive control. The pain sensory was assessed as weight distribution between the injured limb and the contralateral limb using an incapacitance meter. Data showed significant analgesic activity of TR-181 in the osteoarthritis models of rats and guinea pigs (Figure 16).Definition of Terms

[0113] As used herein, the terms "comprising" and "including" are used in their open, non-limiting sense.

[0114] "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. An alkyl can comprise one to fifteen carbon atoms (e.g., C 1 -C 15 alkyl). An alkyl can comprise one to thirteen carbon atoms (e.g., C 1 -C 13 alkyl). An alkyl can comprise one to eight carbon atoms (e.g., C 1 -C 8 alkyl). An alkyl can comprise five to fifteen carbon atoms (e.g., C 5 -C 15 alkyl). An alkyl can comprise five to eight carbon atoms (e.g., C 5 -C 8 alkyl). An alkyl can be 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.

[0115] "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. An alkenyl can comprise two to twelve carbon atoms (e.g., C 2 -C 12 alkenyl). An alkenyl can comprise two to eight carbon atoms (e.g., C 2 -C 8 alkenyl). An alkenyl can comprise two to six carbon atoms (e.g., C 2 -C 6 alkenyl). An alkenyl can comprise two to four carbon atoms (e.g., C 2 -C 4 alkenyl). An alkenyl can be 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.

[0116] The term "allyl," as used herein, means a -CH 2 CH=CH 2 group.

[0117] 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. An alkynyl can comprise two to twelve carbon atoms (e.g., C 2 -C 12 alkynyl). An alkynyl can comprise two to eight carbon atoms (e.g., C 2 -C 8 alkynyl). An alkynyl can have two to six carbon atoms (e.g., C 2 -C 6 alkynyl). An alkynyl can have two to four carbon atoms (e.g., C 2 -C 4 alkynyl). An alkynyl can be attached to the rest of the molecule by a single bond. Examples of such groups include, ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, and the like.

[0118] 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, methoxy, ethoxy, n-propyloxy, iso-propyloxy, n-butoxy, iso-butoxy, tert-butoxy, pentyloxy, hexyloxy, and the like.

[0119] 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. An aryl can comprise six to fourteen carbon atoms (C 6 -C 14 aryl). An aryl can comprise six to ten carbon atoms (C 6 -C 10 aryl). Examples of such groups include, phenyl, fluorenyl and naphthyl. The terms "Ph" and "phenyl," as used herein, mean a -C 6 H 5 group.

[0120] The term "heteroaryl", refers to a radical derived from a 3- to 18-membered aromatic ring radical 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. Heteroaryl includes fused or bridged ring systems. A heteroaryl can refer to a radical derived from a 3- to 10-membered aromatic ring radical (3-10 membered heteroaryl). A heteroaryl can refer 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, 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. A heteroaryl can be attached to the rest of the molecule via a ring carbon atom. A heteroaryl can be 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).

[0121] 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, or 13 atoms in its ring system, and containing from 3 to 12 carbon atoms and from 1 to 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. A hetercyclyl group can comprise 3 to 10 ring atoms (3-10 membered heterocyclyl). A hetercyclyl group can comprise 3 to 8 ring atoms (3-8 membered heterocyclyl). A hetercyclyl group can comprise 4 to 8 ring atoms (4-8 membered heterocyclyl). A hetercyclyl group can comprise 3 to 6 ring atoms (3-6 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, 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).

[0122] The term " cycloalkyl" means a saturated, monocyclic, bicyclic, tricyclic, or tetracyclic radical having a total of from 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. A cycloalkyl can comprise 3 to 8 carbon ring atoms (C 3 -C 8 cycloalkyl). A cycloalkyl comprises 3 to 6 carbon ring atoms (C 3 -C 6 cycloalkyl). Examples of such groups include, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptyl, adamantyl, and the like.

[0123] 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, cyclopropylene, cyclobutylene, cyclopentylene, cyclopentenylene, cyclohexylene, cycloheptylene, and the like.

[0124] 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.

[0125] The term cyano" refers to a -C≡N group.

[0126] An "aldehyde" group refers to a -C(O)H group.

[0127] An "alkoxy" group refers to both an -O-alkyl, as defined herein.

[0128] An "alkoxycarbonyl" refers to a -C(O)-alkoxy, as defined herein.

[0129] An "alkylaminoalkyl" group refers to an -alkyl-NR-alkyl group, as defined herein.

[0130] An "alkylsulfonyl" group refers to a -SO 2 alkyl, as defined herein.

[0131] An "amino" group refers to an optionally substituted -NH 2 .

[0132] An "aminoalkyl" group refers to an -alky-amino group, as defined herein.

[0133] An "aminocarbonyl" refers to a -C(O)-amino, as defined herein.

[0134] An "arylalkyl" group refers to -alkylaryl, where alkyl and aryl are defined herein.

[0135] An "aryloxy" group refers to both an -O-aryl and an -O-heteroaryl group, as defined herein.

[0136] An "aryloxycarbonyl" refers to -C(O)-aryloxy, as defined herein.

[0137] An "arylsulfonyl" group refers to a -SO 2 aryl, as defined herein.

[0138] A "carbonyl" group refers to a -C(O)- group, as defined herein.

[0139] A "carboxylic acid" group refers to a -C(O)OH group.

[0140] A "cycloalkoxy" refers to a -O-cycloalkyl group, as defined herein.

[0141] A "halo" or "halogen" group refers to fluorine, chlorine, bromine or iodine.

[0142] A "haloalkyl" group refers to an alkyl group substituted with one or more halogen atoms.

[0143] A "hydroxy" group refers to an -OH group.

[0144] A "nitro" group refers to a -NO 2 group.

[0145] An "oxo" group refers to the =O substituent.

[0146] A "trihalomethyl" group refers to a methyl substituted with three halogen atoms.

[0147] 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 2 H, -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 2 NH 2 , -SO 2 NH(C 1 -C 4 alkyl), -SO 2 NH(phenyl), -NHSO 2 (C 1 -C 4 alkyl), -NHSO 2 (phenyl), and -NHSO 2 (C 1 -C 4 haloalkyl).

[0148] The term "null" means the absence of an atom or moiety, and there is a bond between adjacent atoms in the structure.

[0149] 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 disclosed herein 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 disclosed herein 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.

[0150] 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.

[0151] 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.

[0152] "Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the bivalent 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.

[0153] "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)). 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.

[0154] "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, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, 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

[0155] 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 disclosed herein, 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, saline, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration.

[0156] In particular, pharmaceutically acceptable excipients, adjuvants, and vehicles that can be used in the pharmaceutical compositions disclosed herein include 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.

[0157] Depending on the dosage form selected to deliver the bivalent 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.

[0158] As used herein, the bivalent 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, 5th Edition, Vol. 1: Principles and Practice.

[0159] The bivalent 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.

[0160] The invention is defined in the appended claims, but generally, compositions can include an effective amount of one or more bivalent 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). The invention is defined in the appended claims, but generally, 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).

[0161] The invention is defined in the appended claims, but generally, 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

[0162] 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 / DevelopmentApprovalProce ss / 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.

[0163] 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.

[0164] For example, pharmaceutical compositions disclosed herein can be orally administered in any orally acceptable dosage form including, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions.

[0165] For example, the pharmaceutical compositions disclosed herein can be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound disclosed herein 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, cocoa butter, beeswax, and polyethylene glycols.

[0166] For example, the pharmaceutical compositions disclosed herein 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.

[0167] For example, the pharmaceutical compositions disclosed herein 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 nontoxic 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, Ringer's 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.

[0168] An effective dose of a pharmaceutical composition disclosed herein can include, 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.

[0169] When the pharmaceutical compositions disclosed herein include a combination of the bivalent 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 bivalent 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 disclosed herein. Alternatively, those agents can be part of a single dosage form, mixed together with the compounds disclosed herein in a single composition.

[0170] The invention is defined in the appended claims, but generally, pharmaceutical compositions disclosed herein can be included in a container, pack, or dispenser together with instructions for administration.Methods of Treatment

[0171] 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 disclosed herein 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.

[0172] In some aspects, provided herein is a pharmaceutical comporisition as defined in the claims for use in a method of treating a TRK-mediated disease or condition as defined in the claims. In certain embodiments of the invention as defined in the claims, the disease or condition is resulted from TRK expression, mutation, or fusion. In certain embodiments of the invention as defined in the claims, the disease or condition comprises non-small cell lung cancer, colorectal cancer, gastric cancer, liver cancer, invasive breast cancer, lung adenocarcinoma, uterine cancer, adrenal cancer, pancreatic cancer, ovarian cancer, esophageal cancer, urinary bladder cancer, endometrial cancer, prostate cancer low-grade glioma, glioblastoma, Spitzoid cancer, soft tissue sarcoma, papillary thyroid carcinoma, head and neck squamous cell carcinoma, congenital fibrosarcoma, congenital mesoblastic nephroma, secretory breast carcinoma, mammary analogue secretory carcinoma, acute myeloid leukemia, ductal carcinoma, pulmonary neuroendocrine tumors, pheochromocytoma, and Wilms' tumor. In certain embodiments of the invention as defined in the claims, the disease or condition comprises cancer, inflammatory diseases, acute and chronic pain, pruritus, bone-related diseases, neurodegenerative diseases, infectious diseases, and other diseases, including neuroblastoma, prostate cancer, pancreatic cancer, melanoma, head and neck cancer, gastric carcinoma, lung carcinoma, liver cancer, uterine cancer, adrenal cancer, biliary tree cancer, intestinal cancer, colorectal cancer, ovarian cancer, lung carcinoma, small cell lung cancer, non-small cell lung cancer, gastric carcinoma, breast cancer, esophageal cancer, urinary bladder cancer, endometrial cancer, brain cancer, low-grade glioma, glioblastoma, medulloblastoma, secratory breast cancer, secretory breast carcinoma, salivary gland cancer, papillary thyroid carcinoma, ductal carcinoma, adult myeloid leukemia, acute myeloid leukemia, large cell neuroendocrine tumors , pulmonary neuroendocrine tumors, sarcomas, pheochromocytoma, fibrosarcoma, congenital fibrosarcoma, congenital mesoblastic nephroma, secretory breast carcinoma, malignant fibrous histiocytoma, embryonal rhabdomysocarcoma, leiomysosarcoma, neuro-fibrosarcoma, neoplasms of the central nervous systems, osteosarcoma, synovial sarcoma, liposarcoma, alveolar soft part sarcoma, , Spitzoid cancer, Wilms' tumor, lymphomas (e.g. including Hodgkin's lymphoma, lymphoplasmacytoid lymphoma, follicular lymphoma, mucosa-associated lymphoid tissue lymphoma, mantle cell lymphoma, B-lineage large cell lymphoma, Burkitt's lymphoma, and T-cell anaplastic large cell lymphoma), inflammatory lung diseases (e.g. asthma), inflammatory bowel diseases, (e.g. ulcerative colitis, Crohn's disease), inflammatory skin diseases (e.g. atopic dermatitis, eczema and psoriasis), interstitial cystitis, rhinitis, acute pain, chronic pain, cancer pain, surgical pain, inflammatory pain, neuropathic pain, nociceptive pain, pain of osteoarthritis, chronic low back pain, low back pain of osteoporosis, pain of bone fracture, pain of rheumatoid arthritis, postherpetic pain, pain of diabetic neuropathy, fibromyalgia, pain of pancreatitis, pain of interstitial cystitis, pain of endometriosis, pain of irritable bowel syndrome, migraine, pain of pulpitis, interstitial cystitis pain, painful bladder syndrome, central pain syndromes, postsurgical pain syndromes, bone and joint pain, repetitive motion pain, dental pain, myofascial pain, perioperative pain, dysmennorhea, myofascial pain, angina pain, headache, primary hyperalgesia, secondary hyperalgesia, primary allodynia, secondary allodynia, other pain caused by central sensitization, systemic cutaneous pruritus, localized cutaneous pruritus, senile cutaneous pruritus, gestational pruritus, pruritus ani, vulvar pruritus, metastatic bone disease, treatment-induce bone loss, osteoporosis, rheumatoid arthritis, bone metastases, ankylosing spondylitis, Paget's disease, periodontal disease, osteolytic disease, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Chagas disease, cachexia, anorexia, demyelination and dysmyelination. In certain embodiments of the invention as defined in the claims, the disease or condition is a relapsed disease. In certain embodiments of the invention as defined in the claims, the disease or condition is a relapsed cancer. In certain embodiments of the invention as defined in the claims, the disease or condition is refractory to one or more previous treatments.

[0173] 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).

[0174] 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.

[0175] 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 bivalent compounds, compositions and methods disclosed herein. The invention is defined in the appended claims, but generally, 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.

[0176] 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. The invention is defined in the appended claims, but generally, the subject can have an elevated risk of developing one or more TRK-mediated diseases. Exemplary TRK-mediated diseases that can be treated with bivalent compounds include, for example, non-small cell lung cancer, colorectal cancer, gastric cancer, liver cancer, invasive breast cancer, lung adenocarcinoma, uterine cancer, adrenal cancer, pancreatic cancer, ovarian cancer, esophageal cancer, urinary bladder cancer, endometrial cancer, prostate cancer low-grade glioma, glioblastoma, spitzoid cancer, soft tissue sarcoma, papillary thyroid carcinoma, head and neck squamous cell carcinoma, congenital fibrosarcoma, congenital mesoblastic nephroma, secretory breast carcinoma, mammary analogue secretory carcinoma, acute myeloid leukemia, ductal carcinoma, pulmonary neuroendocrine tumors, pheochromocytoma, and Wilms' tumor. Exemplary TRK-mediated diseases that can be treated with bivalent compounds include, for example, cancer, inflammatory diseases, acute and chronic pain, pruritus, bone-related diseases, neurodegenerative diseases, infectious diseases, and other diseases, including neuroblastoma, prostate cancer, pancreatic cancer, melanoma, head and neck cancer, gastric carcinoma, lung carcinoma, liver cancer, uterine cancer, adrenal cancer, biliary tree cancer, intestinal cancer, colorectal cancer, ovarian cancer, lung carcinoma, small cell lung cancer, non-small cell lung cancer, gastric carcinoma, breast cancer, esophageal cancer, urinary bladder cancer, endometrial cancer, brain cancer, low-grade glioma, glioblastoma, medulloblastoma, secratory breast cancer, secretory breast carcinoma, salivary gland cancer, papillary thyroid carcinoma, ductal carcinoma, adult myeloid leukemia, acute myeloid leukemia, large cell neuroendocrine tumors , pulmonary neuroendocrine tumors, sarcomas, pheochromocytoma, fibrosarcoma, congenital fibrosarcoma, congenital mesoblastic nephroma, secretory breast carcinoma, malignant fibrous histiocytoma, embryonal rhabdomysocarcoma, leiomysosarcoma, neuro-fibrosarcoma, neoplasms of the central nervous systems, osteosarcoma, synovial sarcoma, liposarcoma, alveolar soft part sarcoma, , Spitzoid cancer, Wilms' tumor, lymphomas (e.g. including Hodgkin's lymphoma, lymphoplasmacytoid lymphoma, follicular lymphoma, mucosa-associated lymphoid tissue lymphoma, mantle cell lymphoma, B-lineage large cell lymphoma, Burkitt's lymphoma, and T-cell anaplastic large cell lymphoma), inflammatory lung diseases (e.g. asthma), inflammatory bowel diseases, (e.g. ulcerative colitis, Crohn's disease), inflammatory skin diseases (e.g. atopic dermatitis, eczema and psoriasis), interstitial cystitis, rhinitis, acute pain, chronic pain, cancer pain, surgical pain, inflammatory pain, neuropathic pain, nociceptive pain, pain of osteoarthritis, chronic low back pain, low back pain of osteoporosis, pain of bone fracture, pain of rheumatoid arthritis, postherpetic pain, pain of diabetic neuropathy, fibromyalgia, pain of pancreatitis, pain of interstitial cystitis, pain of endometriosis, pain of irritable bowel syndrome, migraine, pain of pulpitis, interstitial cystitis pain, painful bladder syndrome, central pain syndromes, postsurgical pain syndromes, bone and joint pain, repetitive motion pain, dental pain, myofascial pain, perioperative pain, dysmennorhea, myofascial pain, angina pain, headache, primary hyperalgesia, secondary hyperalgesia, primary allodynia, secondary allodynia, other pain caused by central sensitization, systemic cutaneous pruritus, localized cutaneous pruritus, senile cutaneous pruritus, gestational pruritus, pruritus ani, vulvar pruritus, metastatic bone disease, treatment-induce bone loss, osteoporosis, rheumatoid arthritis, bone metastases, ankylosing spondylitis, Paget's disease, periodontal disease, osteolytic disease, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Chagas disease, cachexia, anorexia, demyelination and dysmyelination.

[0177] 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.

[0178] 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 the severity of the disease or disorder, previous treatments, the general health or age of the subject, and other diseases present.

[0179] 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.

[0180] The present disclosure is also described and demonstrated by way of the following examples.EXAMPLES Comparative Example 1: 4-((2-Aminoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 1)

[0181]

[0182] A solution of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (1.66 g, 6.0 mmol), tert-butyl (2-aminoethyl)carbamate (1.25 g, 6.6 mmol) and N,N-diisopropylethylamine (2.32 g, 18 mmmol) in DMF (12 mL) was heated to 85 °C 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 separated organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluted with 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 a yellow solid. MS (ESI) m / z = 317.1 [M-100+H] +< . A solution of tert-butyl (2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl) amino)ethyl)carbamate (2.0 g, 4.5 mmol) in DCM (10 mL) and TFA (5 mL) was stirred at room temperature for 2 h. The reaction was concentrated and triturated with EtOAc. The solid precipitate was filtered. And the solid was washed with MTBE, and dried to give 4-((2-aminoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione as a yellow solid (Linker 1) (1.3 g, yield: 98%). 1< H 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] +< .Comparative Example 2: 4-((3-Aminopropyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 2)

[0183]

[0184] Linker 2 was synthesized following the same procedures as Linker 1 as described in Example 1. (1.2 g, yield: 11% over 2 steps). 1< H NMR (400 MHz, DMSO-d6) 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] +< .Comparative Example 3: 4-((4-Aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 3)

[0185]

[0186] Linker 3 was synthesized following the same procedures as Linker 1 as described in Example 1. (1.4 g, yield: 15% over 2 steps). 1< H NMR (400 MHz, DMSO-d6) 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]+.Comparative Example 4: 4-((5-Aminopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 4)

[0187]

[0188] Linker 4 was synthesized following the same procedures as Linker 1 as described in Example 1. (2.3 g, yield: 26% over 2 steps). 1< H 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] +< .Comparative Example 5: 4-((6-Aminohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 5)

[0189]

[0190] Linker 5 was synthesized following the same procedures as Linker 1 as described in Example 1. (1.8 g, yield: 20% over 2 steps). 1< H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 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] +< .Comparative Example 6: 4-((7-Aminoheptyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 6)

[0191]

[0192] Linker 6 was synthesized following the same procedures as Linker 1 as described in Example 1. (2.0 g, yield: 25% over 2 steps). 1< H NMR (400 MHz, DMSO-d6) 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] +< .Comparative Example 7: 4-((8-Aminooctyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 7)

[0193]

[0194] Linker 7 was synthesized following the same procedures as Linker 1 as described in Example 1. (1.1 g, yield: 18% over 2 steps). 1< H 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, 4H), 1.35 - 1.27 (m, 8H). MS (ESI) m / z = 401.2 [M+H] +< .Comparative Example 8: 4-((2-(2-Aminoethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 8)

[0195]

[0196] Linker 8 was synthesized following the same procedures as Linker 1 as described in Example 1. (2.0 g, yield: 23% over 2 steps). 1< H 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] +< .Comparative Example 9: 4-((2-(2-(2-Aminoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 9)

[0197]

[0198] Linker 9 was synthesized following the same procedures as Linker 1 as described in Example 1. (1.1 g, yield: 17% over 2 steps). 1< H NMR (400 MHz, DMSO-d6) 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] +< .Comparative Example 10: 4-((2-(2-(2-(2-Aminoethoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 10)

[0199]

[0200] Linker 10 was synthesized following the same procedures as Linker 1 as described in Example 1. (1.3 g, yield: 17% over 2 steps). 1< H NMR (400 MHz, DMSO-d6) 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] +< .Comparative Example 11: 4-((14-Amino-3,6,9,12-tetraoxatetradecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 11)

[0201]

[0202] Linker 11 was synthesized following the same procedures as Linker 1 as described in Example 1. (1.2 g, yield: 16% over 2 steps). 1< H NMR (400 MHz, DMSO-d6) 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] +< .Comparative Example 12: 4-((17-Amino-3,6,9,12,15-pentaoxaheptadecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 12)

[0203]

[0204] Comparative Linker 12 was synthesized following the same procedures as Linker 1 as described in Example 1. (1.2 g, yield: 15% over 2 steps). 1< H NMR (400 MHz, DMSO-d6) 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] +< .Comparative Example 13: (2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycine (Linker 13)

[0205]

[0206] Linker 13 was synthesized following the same procedures as Linker 1 as described in Example 1. (840 mg, yield: 16% over 2 steps). 1< H NMR (400 MHz, DMSO-d6) 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] -< .Comparative Example 14: 3-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propanoic acid (Linker 14)

[0207]

[0208] Linker 14 was synthesized following the same procedures as Linker 1 as described in Example 1. (1.42 g, yield: 24% over 2 steps). 1< H 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] +< .Comparative Example 15: 4-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butanoic acid (Linker 15)

[0209]

[0210] Linker 15 was synthesized following the same procedures as Linker 1 as described in Example 1. (1.27 g, yield: 13% over 2 steps). 1< H NMR (400 MHz, DMSO-d6) 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] +< .Comparative Example 16: 5-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentanoic acid (Linker 16)

[0211]

[0212] Linker 16 was synthesized following the same procedures as Linker 1 as described in Example 1. (1.4 g, yield: 15% over 2 steps). 1< H NMR (400 MHz, DMSO-d 6 ) δ12.02 (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] +< .Comparative Example 17: 6-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexanoic acid (Linker 17)

[0213]

[0214] Linker 17 was synthesized following the same procedures as Linker 1 as described in Example 1. (1.43 g, yield: 18% over 2 steps). 1< H 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] +< .Comparative Example 18: 7-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptanoic acid (Linker 18)

[0215]

[0216] Linker 18 was synthesized following the same procedures as Linker 1 as described in Example 1. (2.3 g, yield: 24% over 2 steps). 1< H NMR (400 MHz, DMSO-d6) δ 11.92 (br, 1 H), 11.08 (s, 1 H), 7.57 (t, J = 8.0 Hz, 1H), 7.13 (d, J = 8.8 Hz, 1H), 7.03 (d, J = 6.8 Hz, 1H), 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] +< .Comparative Example 19: 8-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octanoic acid (Linker 19)

[0217]

[0218] Linker 19 was synthesized following the same procedures as Linker 1 as described in Example 1. (1.14 g, yield: 35% over 2 steps). 1< H NMR (400 MHz, DMSO-d6) 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] +< .Comparative Example 20: 3-(2-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy) propanoic acid (Linker 20)

[0219]

[0220] Linker 20 was synthesized following the same procedures as Linker 1 as described in Example 1. (3.5 g, yield: 18% over 2 steps). 1< H NMR (400 MHz, DMSO-d6) 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] +< .Comparative Example 21: 3-(2-(2-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanoic acid (Linker 21)

[0221]

[0222] Linker 21 was synthesized following the same procedures as Linker 1 as described in Example 1. (2.0 g, yield: 24% over 2 steps). 1< H NMR (400 MHz, DMSO-d6) 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] +< .Comparative 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)

[0223]

[0224] Linker 22 was synthesized following the same procedures as Linker 1 as described in Example 1. (3.2 g, yield: 42% over 2 steps). 1< H NMR (400 MHz, DMSO-d6) δ 12.14 (s, 1H), 11.08 (s, 1H), 7.58 (dd, J = 7.2 Hz, 8.4 Hz, 1H), 7.14 (d, J = 8.8 Hz, 1H), 7.04 (d, J = 6.8 Hz, 1H), 6.60 (t, J= 6.0 Hz, 1H), 5.05 (dd, J = 5.2 Hz, 12.8 Hz, 1H), 3.63 - 3.45 (m, 14H), 2.88 - 2.85 (m, 1H), 2.61 - 2.49 (m, 2H), 2.44 - 2.40 (m, 2H), 2.04 - 2.01 (m, 1H). MS (ESI) m / z = 478.2 [M+H] +< .Comparative 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)

[0225]

[0226] Linker 23 was synthesized following the same procedures as Linker 1 as described in Example 1. (2.3 g, yield: 31% over 2 steps). 1< H NMR (400 MHz, DMSO-d6) δ 12.14 (s, 1H), 11.08 (s, 1H), 7.58 (dd, J = 7.2 Hz, 8.8 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 7.2 Hz, 1H), 6.60 (t, J = 6.0 Hz, 1H), 5.05 (dd, J = 5.2 Hz, 12.8 Hz, 1H), 3.63 - 3.48 (m, 18H), 2.898 - 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] +< .Comparative 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)

[0227]

[0228] Linker 24 was synthesized following the same procedures as Linker 1 as described as Example 1. (2.4 g, yield: 36% over 2 steps). 1< H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1 H), 7.58 (dd, J = 7.2, 8.4 Hz, 1 H), 7.13 (d, J = 8.4 Hz, 1H), 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] +< .Comparative 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)

[0229]

[0230] 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) were added EDCI (1.07 g, 5.60 mmol), HOBt (756 mg, 5.60 mmol) at 0 °C. The mixture was stirred at room temperature for 16 hours. The mixture was poured into water and extracted with DCM. The combined organic layers were concentrated and the 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] +< .

[0231] 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). The mixture was stirred at room temperature for 3 hours 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%). 1< H 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] +< .Comparative 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)

[0232]

[0233] Linker 26 was synthesized following the same procedures as Linker 25 as described in Example 25. (1.38 g, yield: 37% over 2 steps). 1< H 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] +< .Comparative 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)

[0234]

[0235] Linker 27 was synthesized following the same procedures as Linker 25 as described in Example 25. (1.38 g, yield: 46% over 2 steps). 1< H 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] +< .Comparative 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)

[0236]

[0237] Linker 28 was synthesized following the same procedures as Linker 25 as described in Example 25. (1.50 g, yield: 57% over 2 steps). 1< H 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] +< .Comparative 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)

[0238]

[0239] Linker 29 was synthesized following the same procedures as Linker 25 as described in Example 25. (2.70 g, yield: 87% over 2 steps). 1< H NMR (400 MHz, DMSO-d6): 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] +< .Comparative 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)

[0240]

[0241] Linker 30 was synthesized following the same procedures as Linker 25 as described in Example 25. (2.13 g, yield: 76% over 2 steps). 1< H NMR (400 MHz, DMSO-d6): 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] +< .Comparative 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)

[0242]

[0243] Linker 31 was synthesized following the same procedures as Linker 25 as described in Example 25. (1.81 g, yield: 65% over 2 steps). 1< H NMR (400 MHz, DMSO-d6): 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] +< .Comparative 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)

[0244]

[0245] Linker 32 was synthesized following the same procedures as Linker 25 as described in Example 25. (2.32 g, yield: 80% over 2 steps). 1< H NMR (400 MHz, DMSO-d6): 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). MS (ESI) m / z = 586.3 [M+H] +< .Comparative 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)

[0246]

[0247] Linker 33 was synthesized following the same procedures as Linker 25 as described as Example 25. (2.29 g, yield: 77% over 2 steps). 1< H NMR (400 MHz, DMSO-d6): 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] +< .Comparative 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)

[0248]

[0249] Linker 34 was synthesized following the same procedures as Linker 25 as described as Example 25. (1.10 g, yield: 37% over 2 steps). 1< H NMR (400 MHz, DMSO-d6): 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] +< .Comparative 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)

[0250]

[0251] Linker 35 was synthesized following the same procedures as Linker 25 as described in Example 25. (1.35 g, yield: 55% over 2 steps). 1< H 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] +< . Comparative 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)

[0252]

[0253] Linker 36 was synthesized following the same procedures as Linker 25 as described in Example 25. (1.32 g, yield: 49% over 2 steps). 1< H 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] +< .Comparative 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)

[0254]

[0255] Linker 37 was synthesized following the same procedures as Linker 25 as described as Example 25. (1.2 g, yield: 49% over 2 steps). 1< H NMR (400 MHz, DMSO-d6) 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] +< .Comparative 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)

[0256]

[0257] Linker 38 was synthesized following the same procedures as Linker 25 as described as Example 25. (1.34 g, yield: 49% over 2 steps). 1< H 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] +< .Comparative 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)

[0258]

[0259] Linker 39 was synthesized following the same procedures as Linker 25 as described as Example 25. (1.53 g, yield: 56% over 2 steps). 1< H NMR (400 MHz, DMSO-d6) 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] +< .Comparative 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)

[0260]

[0261] Linker 40 was synthesized following the same procedures as Linker 25 as described as Example 25. (1.52 g, yield: 51% over 2 steps). 1< H NMR (400 MHz, DMSO-d6) 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] +< .Comparative 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)

[0262]

[0263] Linker 41 was synthesized following the same procedures as Linker 25 as described as Example 25. (1.12 g, yield: 37% over 2 steps). 1< H NMR (400 MHz, DMSO-d6) 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] +< .Comparative 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)

[0264]

[0265] Linker 42 was synthesized following the same procedures as Linker 25 as described as Example 25. (1.1 g, 1.52 mmol, yield: 32% over 2 steps). 1< H 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] +< .Comparative 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)

[0266]

[0267] A mixture of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (1.0 g, 2.3 mmol) and succinic anhydride (465 mg, 4.65 mmol) in pyridine (5 mL) was stirred at room temperature for overnight. The mixture was concentrated. The residue was purified by flash chromatography (reversed-phase, MeCN / H 2 O) to give the title compound Linker 43 (1.05 g, yield: 86%). 1< H 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). 13< C 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] +< .Comparative 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)

[0268]

[0269] Linker 44 was synthesized following the same procedures as Linker 43 as described as Example 43. (1.5 g, yield: 79%). 1< H 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). 13< C 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] -< .Comparative 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)

[0270]

[0271] Linker 45 was synthesized following the same procedures as Linker 25 as described as Example 25. (1.2 g, yield: 55% over 2 steps). 1< H 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] +< .Comparative 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)

[0272]

[0273] Linker 46 was synthesized following the same procedures as Linker 45 as described as Example 45. (1.1 g, yield: 33% over 2 steps). 1< H 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] +< .Comparative 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)

[0274]

[0275] Linker 47 was synthesized following the same procedures as Linker 45 as described as Example 45. (1.08 g, yield: 52% over 2 steps). 1< H NMR (400 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.55 (t, J = 2.4 Hz, 1H), 7.83 (d, J = 9.2 Hz, 1H), 7.44 - 7.38 (m, 4H), 4.55 (d, J = 9.6 Hz, 1H), 4.52 - 4.41 (m, 2H), 4.36 (s, 1H), 4.25 - 4.21 (m, 1H), 3.67 - 3.66 (m, 2H), 2.45 (s, 3H), 2.30 - 1.91 (m, 6H), 1.49 - 1.47 (m, 4H), 1.26 - 1.24 (m, 4H), 0.92 (s, 9H). MS (ESI) m / z = 587.3 [M+H] +< .Comparative 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)

[0276]

[0277] Linker 48 was synthesized following the same procedures as Linker 45 as described in Example 45. (1.16 g, yield: 44% over 2 steps). 1< H 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] +< .Comparative 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)

[0278]

[0279] Linker 49 was synthesized following the same procedure as Linker 45 as described as Example 45. (1.1 g, yield: 35%). 1< H 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). 13< C 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] +< .Comparative 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)

[0280]

[0281] Linker 50 was synthesized following the same procedure as Linker 45 as described as Example 45. (1.1 g, yield: 50%). 1< H 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). 13< C 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] +< .Comparative 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)

[0282]

[0283] Linker 51 was synthesized following the same procedure as Linker 45 as described in Example 45. (1.1 g, yield: 42%). 1< H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.55 (t, J = 6.0 Hz, 1H), 7.91 (d, J = 9.2 Hz, 1H), 7.43 - 7.37 (m, 4H), 4.55 - 4.53 (m, 1H), 4.45 - 4.40 (m, 2H), 4.35 (s, 1H), 4.24 - 4.19 (m, 1H), 3.68 - 3.52 (m, 6H), 2.54 - 2.56 (m, 1H), 2.45 - 2.37 (m, 5H), 2.34 - 2.30 (m, 1H), 2.05 - 2.00 (m, 1H), 1.93 - 1.86 (m, 1H), 0.93 (s, 9H). MS (ESI) m / z = 575 [M+H] +< .Comparative 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)

[0284]

[0285] Linker 52 was synthesized following the same procedure as Linker 43 as described as Example 43. (1.2 g, yield: 63%). 1< H NMR (400 MHz, DMSO-d6) 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] +< .Comparative 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)

[0286]

[0287] Linker 53 was synthesized following the same procedures as Linker 45 as described as Example 45. (1.4 g, yield 23% over 2 steps). 1< H 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] +< .Comparative 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)

[0288]

[0289] Linker 54 was synthesized following the same procedures as Linker 53 as described as Example 53. (1.13 g, yield 20% over 2 steps). 1< H 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] +< .Comparative 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)

[0290]

[0291] Linker 55 was synthesized following the same procedure as Linker 45 as described in Example 45. (1.7 g, yield 37%). 1< H 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] -< .Comparative 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)

[0292]

[0293] Linker 56 was synthesized following the same procedures as Linker 45 as described as Example 45. (1.21 g, yield 31% over 2 steps). 1< H 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] +< .Comparative 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)

[0294]

[0295] Linker 57 was synthesized following the same procedure as Linker 45 as described as Example 45. (1.6 g, yield 43%). 1< H 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] +< .Comparative 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)

[0296]

[0297] Linker 58 was synthesized following the same procedure as Linker 45 as described as Example 45. (1.2 g, yield: 23%). 1< H 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] +< .Comparative 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)

[0298]

[0299] Linker 59 was synthesized following the same procedure as Linker 45 as described as Example 45. (1.3 g, yield: 39%). 1< H 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] +< .Comparative Example 60. Synthesis of TRKi-1

[0300] Step 1

[0301]

[0302] To a solution of 3-cyano-4-fluorophenylboronic acid (1) (3.3 g, 20 mmol) in toluene (30 mL) were added potassium phosphate (8.5 g, 40 mmol) and tetrakis(triphenylphosphine)palladium (462 mg, 0.4 mmol), followed by 3,5-difluorobenzyl bromide (2) (4.2 g, 10 mmol). The reaction mixture was heated at 100 °C for 2 hours. After the reaction was completed, the resulting black mixture was diluted with ether (200 mL), washed with saturated aqueous ammonium chloride (2 x 50 mL) and brine (3 x 50 mL). The organic layer was dried over sodium sulphate, evaporated and purified by silica gel flash chromatography (n-hexane / ethyl acetate 95:5) to yield 5-(3,5-difluorobenzyl)-2-fluorobenzonitrile (3) (2.9 g, yield 59%) as a white solid. 1< H NMR (400 MHz, DMSO-d 6 ) 7.90 (dd, J = 6.0 Hz, 2.0 Hz, 1H), 7.73 - 7.69 (m, 1H), 7.46 (t, J= 8.8 Hz, 1H), 7.09 - 7.04 (m, 3H), 4.01 (s, 2H). MS (ESI)m / z = 248.2[M+H] +< .Step 2

[0303]

[0304] A mixture of 5-(3,5-difluoro-benzyl)-2-fluoro-benzonitrile (3) (2.9 g, 11.74 mmol) and hydrazine hydrate (1.76 mL, 35.22 mmol) in n-butanol (200 mL) was heated at 120 °C overnight. The reaction mixture was diluted with water and ethyl acetate. The organic phase was washed twice with brine, dried and concentratted. The resulting residue was purified by silica gel chromatography(DCM / MeOH = 95:5) to afford 5-(3,5-difluorobenzyl)-1H-indazol-3-amine (4) (2.7 g, yield 89%) as a white solid. 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.32 (s, 1H), 7.52 (s, 1H), 7.18 - 7.11 (m, 2H), 7.04 (t, J=9.6 Hz, 1H), 6.95 - 6.93 (m, 2H), 5.26 (s, 2H), 4.00 (s, 2H). MS (ESI) m / z = 260.0 [M+H] +< .Step 3

[0305]

[0306] A solution of 4-fluoro-2-nitro-benzoic acid (5) (10 g, 54 mmol), di-tert-butyl-dicarbonate (23.6 g, 108 mmol) and 4-dimethylaminopyridine (1.98 g, 16.2 mmol) in tert- butanol (100 mL) and dichloromethane (100 mL) was stirred at room temperature overnight. The reaction mixture was then diluted with ethyl acetate (500 mL), washed with 1N hydrochloric acid (500 mL), water (500 mL) and brine (500 mL). The organic phase was dried over sodium sulfate, concentrated and purified by silica gel chromatography column (DCM / MeOH = 20 / 1) to afford tert-butyl 4-fluoro-2-nitrobenzoate (6) as a yellow solid (10.7 g, yield 82%). 1< H NMR (400 MHz, DMSO-d 6 ): δ 8.04 (dd, J = 8.4 Hz, 2.8 Hz, 1H), 7.94 (dd, J = 8.8 Hz, 1.6 Hz, 1H), 7.71 (ddd, J = 8.4 Hz, 2.4 Hz, 1H), 1.50 (s, 9H). MS (ESI) m / z = 242.2 [M+H] +< .Step 4

[0307]

[0308] To a solution of piperazine (13.7 g, 159.75 mmol) in tetrahydrofuran (150 mL) was added tert-butyl 4-fluoro-2-nitrobenzoate (6) (7.7 g, 31.95 mmol). The mixture was stirred at 70 °C for 16 h, before being poured into water and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with water, brine, dried over sodium sulfate and concentrated to give crude tert-butyl 2-nitro-4-(piperazin-1-yl)benzoate (7) (9.7 g, yield 99%) as yellow oil, which was used in the next step without further purification. MS (ESI) m / z = 308.1 [M+H] +< .Step 5

[0309]

[0310] To a solution of 2-nitro-4-piperazin-1-yl-benzoic acid tert-butyl ester (7) (13.5 g, 44.12 mmol) in dichloromethane (200 mL) were added triethylamine (13.4 g, 132.35 mmol) and trifluoroacetic anhydride (18.5 g, 88.24 mmol) at 0 °C. The mixture was stirred at room temperature for 1 h. The solvent was evaporated to give a residue, which was purified by flash chromatography silica gel column (petroleum ether / ethyl acetate = 1 / 1) to give tert-butyl 2-nitro-4-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)benzoate (8) (16.5 g, yield: 93%) as a yellow solid. 1< H NMR (400 MHz, DMSO-d 6 ): δ 7.72 (d, J = 9.2 Hz, 1H), 7.32 (d, J = 2.8 Hz, 1H), 7.16 (dd, J = 2.8, 9.2 Hz, 1H), 3.72 - 3.70 (m, 4H), 3.56 - 3.52 (m, 4H), 1.45 (s, 9H). MS (ESI) m / z = 404.3 [M+H] +< .Step 6

[0311]

[0312] tert-butyl 2-nitro-4-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)benzoate (8) (8.0 g, 19.85 mmol) was dissolved in methanol (150 ml), before Pd / C (1.0 g) was added. The resulting mixture was stirred under hydrogen at atmosphere pressure for 16 h. The solution was filtered over a pad of celite and washed with methanol several times. The filtrate was concentrated under vacuum to afford tert-butyl 2-amino-4-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)benzoate (9) (6.3 g, yield 85%) as a yellow solid. 1< H NMR (400 MHz, DMSO-d 6 ): δ 7.51 (d, J = 9.2 Hz, 1H), 6.47 (br, 2H), 6.20 (dd, J = 2.8, 9.2 Hz, 1H), 6.13 (d, J = 2.8 Hz, 1H), 3.71 - 3.69 (m, 4H), 3.31 - 3.29 (m, 4H), 1.50 (s, 9H). MS (ESI) m / z = 374.0 [M+H] +< .Step 7

[0313]

[0314] To a solution of tert-butyl 2-amino-4-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)benzoate (6.3 g, 16.89 mmol) in dichloromethane (9) (150 mL) were added tetrahydro-pyran-4-one (2.1 g, 21.11 mmol), trifluoroacetic acid (3.5 mL) and tetramethylammonium triacetoxyborohydride (6.7 g, 25.34 mmol). The mixture was stirred at room temperature for 16 h, before being washed sequentially with 0.5 N hydrochloric acid, 0.5 N sodium hydroxide, and a saturated solution of sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated to afford tert-butyl 2-((tetrahydro-2H-pyran-4-yl)amino)-4-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)benzoate (10) (3.5 g, yield 50%) as a pale yellow solid. 1< HNMR (400 MHz, DMSO-d 6 ): δ 7.72 (d, J = 7.6 Hz, 1H), 7.60 (d, J= 9.2Hz, 1H), 6.20 (dd, J= 2.4, 9.2 Hz, 1H), 6.09 (d, J = 2.0 Hz, 1H), 3.86 - 3.82 (m, 2H), 3.70 - 3.69 (m, 5H), 3.52 - 3.46 (m, 2H), 3.39 - 3.38 (m, 4H), 1.97 - 1.94 (m, 2H), 1.50 (s, 9H), 1.43 - 1.34 (m, 2H). MS (ESI) m / z = 458.1 [M+H] +< .Step 8

[0315]

[0316] tert-butyl 2-((tetrahydro-2H-pyran-4-yl)amino)-4-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)benzoate (10) (3.8 g, 8.32 mmol) was dissolved in dichloromethane (100 ml) and cooled to 0 °C. To the resulting solution was added triethylamine (1.3 g, 12.47 mmol) followed by a slow addition of trifluoroacetic anhydride (2.3 g, 10.81 mmol). After being stirred for1 h, the reaction was quenched with water and diluted with DCM. The organic layer was washed with a saturated solution of aqueous sodium bicarbonate and brine. The organic layer was dried over sodium sulfate, concentrated and purified by silica gel chromatography column (petroleum ether / ethyl acetate = 2 / 1) to give tert-butyl 2-(2,2,2-trifluoro-N-(tetrahydro-2H-pyran-4-yl)acetamido)-4-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)benzoate (11) (4.2 g, yield 91%) as a yellow solid. 1< HNMR (400 MHz, DMSO-d 6 ): δ 7.85 (d, J = 8.8 Hz, 1H), 7.08 (dd, J= 2.4, 8.8 Hz, 1H), 6.85 (d, J = 2.4 Hz, 1H), 4.52 - 4.44 (m, 1H), 3.89 - 3.77 (m, 2H), 3.75 - 3.72 (m, 4H), 3.55 - 3.49 (m, 4H), 345 - 3.32 (m, 2H), 1.99 - 1.97 (m, 1H), 1.65 - 1.53 (m, 1H), 1.48 - 1.45 (m, 1H), 1.45 (s, 9H), 1.08 - 0.96 (m, 1H). MS (ESI) m / z = 554.1 [M+H] +< .Step 9

[0317]

[0318] To a solution of tert-butyl 2-(2,2,2-trifluoro-N-(tetrahydro-2H-pyran-4-yl)acetamido)-4-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)benzoate (11) (4.2 g, 7.59 mmol) in DCM (50 ml) was added TFA (50 mL) at 0 °C. After the reaction was stirred at room temperature for 16 h, the solvent was removed under vacuum. The residue was washed with diethyl ether to give 2-(2,2,2-trifluoro-N-(tetrahydro-2H-pyran-4-yl)acetamido)-4-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)benzoic acid (12) (3.5 g, yield 93%) as a white solid. 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.70 (s, 1H), 7.90(d, J = 8.8 Hz, 1H), 7.06 (dd, J = 2.8, 9.2 Hz,1H), 6.86 (d, J = 2.0 Hz, 1H), 4.51 - 4.43 (m, 1H), 3.88 - 3.79 (m,2H), 3.75 - 3.72 (m, 4H), 3.55 - 3.41 (m, 6H), 1.97 - 1.94 (m, 1H), 1.64 - 1.49 (m, 2H), 1.12 - 1.02 (m, 1H). MS (ESI) m / z = 498.0 [M+H] +< .Step 10

[0319]

[0320] To a suspension of 2-(2,2,2-trifluoro-N-(tetrahydro-2H-pyran-4-yl)acetamido)-4-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)benzoic acid (12) (3.5 g, 7.04 mmol) in dry dichloromethane (150 mL) were added catalytic amount of N,N-dimethylformamide, oxalyl chloride (2.7 g, 21.13mmol) at 0 °C. The mixture was stirred for about 1.5 h before being concentrated. The residue was azeotroped with dry dichloromethane twice. The acyl chloride was dissolved in dry dichloromethane (50 mL). The resulting suspension was added slowly to a solution of 5-(3,5-difluoro-benzyl)-1H-indazol-3-ylamine (1.86 g, 7.04 mol) and triethylamine (2.2 g, 21.13 mmol) in dry tetrahydrofuran (100 mL) at -20 °C. The mixture was stirred at room temperature for 16 h before being concentrated. The resulting residue was purified by silica gel chromatography column (petroleum ether / ethyl acetate = 1 / 1) to give N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-2-(2,2,2-trifluoro-N-(tetrahydro-2H-pyran-4-yl)acetamido)-4-(4-(2,2,2-trifluoroacetyl) piperazin-1-yl)benzamide (13) (4.0 g, yield 77%) as a yellow solid. 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.70 (s, 1H), 10.58 (s, 1 H), 7.86 (d, J = 8.4 Hz, 1H), 7.43 - 7.41(m, 2H), 7.27 (d, J = 9.2 Hz, 1H), 7.18 - 7.11 (m, 1H),7.04 - 6.99 (m, 1H),6.95 - 6.93 (m, 3H),4.47 - 4.41 (m, 1H), 4.01 (s, 2H), 3.80 - 3.72 (m,4H), 3.22 - 3.17 (m, 4H), 3.51 - 3.47 (m, 4H), 1.93 - 1.90 (m, 1H), 1.67 - 1.64 (m, 1H), 1.60 - 1.50 (m, 1H), 1.37 - 1.26 (m, 1H). MS (ESI) m / z = 739.0 [M+H] +< .Step 11

[0321]

[0322] To a solution of N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-2-(2,2,2-trifluoro-N-(tetrahydro-2H-pyran-4-yl)acetamido)-4-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)benzamide (13) (4.0 g, 5.42 mmol) in methanol (100 mL) was added potassium carbonate (3.7 g, 27.1 mmol). The mixture was stirred at room temperature for 2 h before being filtered. The filtrate was evaporated and the residue was purified by silica gel chromatography(DCM / MeOH = 10:1) to give N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino) benzamide (TRKi-1) (1.9 g, yield: 64%) as a blue solid. 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.68 (s, 1H), 10.12 (s, 1 H), 8.31 (d, J = 6.8 Hz, 1 H), 7.81 (d, J = 8.4 Hz, 1H), 7.50 (s, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 7.03 - 6.98 (m, 3 H), 6.23 (d, J = 8.4 Hz, 1H), 6.13 (s, 1H), 4.04 (s, 2H), 3.83 - 3.80 (m, 2H), 3.68 - 3.62 (m, 1H), 3.52 - 3.47 (m, 2H), 3.22 - 3.17 (m, 4H), 2.87 - 2.80 (m, 4H), 1.95 - 1.92 (m, 2 H), 1.36 - 1.34 (m, 2 H). MS (ESI) m / z = 547.2 [M+H] +< .Comparative Example 61. Synthesis of TRKi-2

[0323] Step 1

[0324]

[0325] To a solution of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (14) (4.6 g, 20.0 mmol ) in dimethylsuphoxide (40 mL) were added potassium fluoride (20 g, 362 mmol) and (R)-2-(3-fluorophenyl)pyrrolidine (15) (3 g, 18.2 mmol). The resulting mixture was stirred at 100 °C for 12 h. The mixture was diluted with ethyl acetate, washed with water. The organic layer was concentrated and the residue was purified by column chromatography (ethyl acetate) to give (R)-3-bromo-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine (16) (1.8 g, yield 28%) as a yellow solid. MS (ESI) m / z = 360.9 [M+H] +< .Step 2

[0326]

[0327] To a solution of (R)-3-bromo-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine (16) (2.17 g, 6.03 mmol ) in toluene (50 mL) were added 2-fluoro-6-(tributylstannyl)pyridine (17) (3.5 g, 9.04 mmol) and tetrakis(triphenylphosphine)palladium (566 mg, 0.49 mmol). The resulting mixture was stirred at 110 °C for 12 h under nitrogen atmosphere before being poured into ethyl acetate and sat. potassium fluoride. After stirring at room temperature for 2 h, the mixture was extracted with ethyl acetate. The combined organic layers were concentrated and purified by column chromatography (hexanes: ethyl acetate = 1:1 to 100% ethyl acetate) to give (R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-fluoropyridin-2-yl)imidazo[1,2-b]pyridazine (18) (2.2 g, yield 97%) as yellow oil. MS (ESI) m / z = 378.0 [M+H] +< .Step 3

[0328]

[0329] To a solution of (R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-fluoropyridin-2-yl)imidazo[1,2-b]pyridazine (18, 1.4 g, 3.7 mmol ) in dimethylsuphoxide (40 mL) was added piperazine (6.4 g, 74 mmol), followed by potassium fluoride (8.6 g, 148 mmol). The resulting mixture was stirred at 130 °C for 12 h before being poured into water and extracted with ethyl acetate. The combined organic layers were washed with water, concentrated and purified by column chromatography (dichloromethane : methanol = 10:1 to 5:1) to give desired product as a yellow oil, which was dissolved in hydrochloric acid / ethyl acetate (4 M), and stirred for 1h, concentrated to give (R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-(piperazin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazine hydrochloride (TRKi-2) (1.168 g, yield 66%) as a yellow solid. 1< H NMR (400 MHz, DMSO-d 6 ): δ 9.62 (s, 2H), 8.63 (s, 1H), 8.21 (s, 1H), 7.62-7.19 (m, 6H), 7.06-7.01 (m, 2H), 5.26-5.25 (m, 1H), 4.07-4.02 (m, 1H), 3.86-3.85 (m, 4H), 3.74-3.72 (m, 1H), 3.16-3.15 (m, 4H), 2.08-2.07 (m, 2H), 1.92-1.91 (m, 2H). MS (ESI) m / z = 444.2 [M+H] +< .Comparative Example 62. Synthesis of TRKi-3

[0330]

[0331] To a solution of (R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-(piperazin-1-yl)pyridine -2-yl)imidazo[1,2-b]pyridazine (TRKi-2) (1 g, 2.25 mmol) in DMF (40 ml) were added K 2 CO 3 (621 mg, 4.50 mmol) and tert-butyl 2-bromoacetate(510 mg, 2.60 mmol). The resulting mixture was stirred at room temperature for 3 hours. After the amine was totally consumed, the reaction was poured into water ( 300 mL) and extracted with ethyl acetate ( 3 X 50 mL). The combined organic layers were washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give tert-butyl (R)-2-(4-(6-(6-(2-(3-fluoro phenyl)pyrrolidin-1-yl) imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetate (1.05g, yield: 84%) as a light yellow solid. MS (ESI) m / z: 558.7 [M+H] +< .

[0332] To a solution of tert-butyl (R)-2-(4-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b] pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetate (1 g, 1.79 mmol) in dichloromethane (20 ml) was added trifluoroacetic acid (20 mL). The resulting mixture was stirred at room temperature for 3 hours. After the starting material was totally consumed, the reaction was evaporated under reduced pressure. The resulting residue was purified by reverse-phase chromatography to give (R)-2-(4-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b] pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetic acid (TRKi-3) (860 mg, yield: 79% over two steps) as a light yellow solid. MS (ESI) m / z: 502.6 [M+H] +< .Comparative Example 63. Synthesis of TRKi-4

[0333]

[0334] To a solution of N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(piperazin-1-yl)-2-((tetra hydro-2H-pyran-4-yl)amino)benzamide (TRKi-1) (1.0 g, 1.83 mmol) in DMF (40 ml) were added K 2 CO 3 (505 mg, 3.66 mmol) and tert-butyl 2-bromoacetate(357 mg, 1.83 mmol). The resulting mixture was stirred at room temperature for 3 hours. After the amine was totally consumed, the reaction was poured into water ( 300 mL) and extracted with ethyl acetate ( 3 X 50 mL). The combined organic layers were washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give tert-butyl 2-(4-(4-((5-(3,5-difluorobenzyl)-1H-indazol-3-yl) carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)acetate (1.03g, yield: 85%) as a light yellow solid. MS (ESI) m / z: 661.3 [M+H] +< .

[0335] To a solution of tert-butyl 2-(4-(4-((5- (3,5-difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)acetate (1 g, 1.51 mmol) in dichloromethane (20 ml) was added trifluoroacetic acid (20 mL). The resulting mixture was stirred at room temperature for 3 hours. After the starting material was totally consumed, the reaction was evaporated under reduced pressure. The resulting residue was purified by reverse-phase chromatography to give 2-(4-(4-((5-(3,5-difluorobenzyl)-1H-indazol-3-yl) carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)acetic acid (TRKi-4) (790 mg, yield 73%) as a light yellow solid. MS (ESI) m / z: 605.3 [M+H] +< .Comparative Example 64: N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (CPD-053)

[0336]

[0337] To a solution of 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butanoic acid (657 mg, 1.83 mmol) in DMSO (30 mL) were added NMM (926 mg, 9.15 mmol), HOAT (373 mg, 2.74 mmol), EDCI (526 mg, 2.74 mmol) and N-(5-(3,5-difluorobenzyl)-1H-indazol -3-yl)-4-(piperazin -1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TRKi-1) (1 g, 1.83 mmol) sequentially. The resulting solution was stirred at room temperature for 16 hours, before the reaction was poured into water (200 mL) and extracted with ethyl acetate ( 3 X 50 mL). The combined organic layers were washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse-phase chromatography to give N-(5-(3,5-difluoro benzyl)-1H-indazol-3-yl)-4-(4-(4-((2-(2,6-dioxopiperidin -3-yl)-1,3-dioxoisoindolin-4-yl) amino)butanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (CPD-053) (1.2 g, yield 74%) as a light yellow solid. 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.09 (s, 1H), 10.28 (s, 1H), 7.89 (d, J = 9.0 Hz, 1H), 7.59 (dd, J = 8.4, 7.2 Hz, 1H), 7.52 (s, 1H), 7.42 (d, J = 8.6 Hz, 1H), 7.26 (d, J = 9.9 Hz, 1H), 7.19 (d, J = 8.6 Hz, 1H), 7.08 - 6.94 (m, 4H), 6.47 - 6.28 (m, 2H), 5.06 (dd, J = 12.9, 5.3 Hz, 1H), 4.04 (s, 2H), 3.84 (s, 2H), 3.63 (s, 5H), 3.57 (s, 1H), 3.46 (t, J = 10.5 Hz, 3H), 3.40 - 3.24 (m, 6H), 3.17 (s, 1H), 2.87 (d, J = 12.0 Hz, 1H), 2.57 (dd, J = 19.7, 10.5 Hz, 1H), 2.47 (d, J = 6.8 Hz, 2H), 2.08 - 1.76 (m, 5H), 1.48 - 1.34 (m, 2H), 1.23 (s, 1H). MS (ESI) m / z: 888.6 [M+H] +< .Comparative Example 65: (2S,4R)-1-((S)-2-(6-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-6-oxohexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (CPD-

[0338] 001)

[0339] CPD-001 was synthesized following the standard procedure for preparing CPD-053 (12 mg, yield 76%). MS (ESI) m / z: 984.7 [M+H] +< .Comparative Example 66: (2S,4R)-1-((S)-2-(2-(2-(2-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-2-oxoethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (CPD-

[0340] 002)

[0341] CPD-002 was synthesized following the standard procedure for preparing CPD-053 (11 mg, yield 69%). MS (ESI) m / z: 1016.6 [M+H] +< .Comparative Example 67: (2S,4R)-1-((S)-2-(tert-butyl)-20-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)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(CPD-003)

[0342]

[0343] CPD-003 was synthesized following the standard procedure for preparing CPD-053 (14 mg, yield 72%). MS (ESI) m / z: 1148.8 [M+H] +< .Comparative Example 68: (2S,4R)-1-((S)-2-(7-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-7-oxoheptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (CPD-004)

[0344]

[0345] CPD-004 was synthesized following the standard procedure for preparing CPD-053 (11 mg, yield 70%). MS (ESI) m / z: 997.8 [M+H] +< .Comparative Example 69: (2S,4R)-1-((S)-2-(tert-butyl)-22-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)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(CPD-005)

[0346]

[0347] CPD-005 was synthesized following the standard procedure for preparing CPD-053 (13 mg, yield 76%). MS (ESI) m / z: 1176.6 [M+H] +< .Comparative Example 70: (2S,4R)-1-((S)-2-(4-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-4-oxobutanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (CPD- 006)

[0348]

[0349] CPD-006 was synthesized following the standard procedure for preparing CPD-053 (9 mg, yield 63%). MS (ESI) m / z: 956.4 [M+H] +< .Comparative Example 71: (2S,4R)-1-((S)-2-(3-(3-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-3-oxopropoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (CPD- 007)

[0350]

[0351] CPD-007 was synthesized following the standard procedure for preparing CPD-053 (12 mg, yield 73%). MS (ESI) m / z: 1000.5 [M+H] +< .Comparative Example 72: (2S,4R)-1-((S)-2-(2-(2-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-2-oxoethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(CPD-008)

[0352]

[0353] CPD-008 was synthesized following the standard procedure for preparing CPD-053 (11 mg, yield 75%). MS (ESI) m / z: 972.4 [M+H] +< .Comparative Example 73: 2-(2,6-Dioxopiperidin-3-yl)-4-((7-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-7-oxoheptyl)amino)isoindoline-1,3-dione (CPD-009)

[0354]

[0355] CPD-009 was synthesized following the standard procedure for preparing CPD-053 (13 mg, yield 79%). MS (ESI) m / z: 827.4 [M+H] +< .Comparative Example 74: 2-(2,6-Dioxopiperidin-3-yl)-4-((2-(2-(2-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethoxy)ethyl)amino)isoindoline-1,3-dione (CPD-010)

[0356]

[0357] CPD-010 was synthesized following the standard procedure for preparing CPD-053 (11 mg, yield 73%). MS (ESI) m / z: 903.4 [M+H] +< .Comparative Example 75: (2S,4R)-1-((S)-2-(tert-butyl)-14-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-4,14-dioxo-6,9,12-trioxa-3-azatetradecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (CPD-011)

[0358]

[0359] CPD-011 was synthesized following the standard procedure for preparing CPD-053 (15 mg, yield 81%). MS (ESI) m / z: 1060.5 [M+H] +< .Comparative Example 76: (2S,4R)-1-((S)-2-(5-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-5-oxopentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (CPD-012)

[0360]

[0361] CPD-012 was synthesized following the standard procedure for preparing CPD-053 (11 mg, yield 72%). MS (ESI) m / z:970.4 [M+H] +< .Comparative Example 77: 2-(2,6-Dioxopiperidin-3-yl)-4-((4-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-4-oxobutyl)amino)isoindoline-1,3-dione (CPD-013)

[0362]

[0363] CPD-013 was synthesized following the standard procedure for preparing CPD-053 (8 mg, yield 69%). MS (ESI) m / z: 785.3 [M+H] +< .Comparative Example 78: 2-(2,6-Dioxopiperidin-3-yl)-4-((5-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-5-oxopentyl)amino)isoindoline-1,3-dione (CPD-014)

[0364]

[0365] CPD-014 was synthesized following the standard procedure for preparing CPD-053 (11 mg, yield 73%). MS (ESI) m / z: 799.3 [M+H] +< .Comparative Example 79: 2-(2,6-Dioxopiperidin-3-yl)-4-((6-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-6-oxohexyl)amino)isoindoline-1,3-dione (CPD-015)

[0366]

[0367] CPD-015 was synthesized following the standard procedure for preparing CPD-053 (11 mg, yield 74%). MS (ESI) m / z: 813.4 [M+H] +< .Comparative Example 80: (2S,4R)-1-((S)-2-(tert-butyl)-16-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-4,16-dioxo-7,10,13-trioxa-3-azahexadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(CPD-016)

[0368]

[0369] CPD-016 was synthesized following the standard procedure for preparing CPD-053 (13 mg, yield 73%). MS (ESI) m / z: 1088.5 [M+H] +< .Comparative Example 81: (2S,4R)-1-((S)-2-(10-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-10-oxodecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (CPD-017)

[0370]

[0371] CPD-017 was synthesized following the standard procedure for preparing CPD-053 (11 mg, yield 70%). 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.09 (s, 1H), 8.21 (s, 1H), 7.97 (d, J = 9.9 Hz, 1H), 7.54 (dd, J = 20.1, 12.4 Hz, 2H), 7.39 (dd, J = 14.1, 7.9 Hz, 1H), 7.26 - 7.08 (m, 2H), 7.02 (dt, J = 15.3, 7.8 Hz, 2H), 6.76 (d, J = 8.6 Hz, 1H), 6.58 (s, 1H), 5.19 (d, J = 5.9 Hz, 1H), 5.03 (dd, J = 12.8, 5.2 Hz, 1H), 4.01 (d, J = 5.0 Hz, 1H), 3.76 - 3.66 (m, 2H), 3.65 - 3.50 (m, 8H), 3.45 (s, 3H), 2.94 - 2.79 (m, 1H), 2.77 (d, J = 4.9 Hz, 1H), 2.64 (t, J = 6.4 Hz, 1H), 2.56 (d, J = 7.2 Hz, 1H), 2.53 (s, 1H), 2.47 - 2.43 (m, 1H), 2.33 (s, 1H), 2.02 (dd, J = 15.7, 8.4 Hz, 3H), 1.90 (s, 1H), 1.27 (d, J = 25.3 Hz, 3H), 0.84 (d, J = 6.8 Hz, 1H). MS (ESI) m / z: 1040.5 [M+H] +< .Comparative Example 82: (2S,4R)-1-((S)-2-(9-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-9-oxononanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (CPD-018)

[0372]

[0373] CPD-018 was synthesized following the standard procedure for preparing CPD-053 (9 mg, yield 72%). MS (ESI) m / z: 1026.5 [M+H] +< .Comparative Example 83: (2S,4R)-1-((S)-2-(tert-butyl)-19-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)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 (CPD-019)

[0374]

[0375] CPD-019 was synthesized following the standard procedure for preparing CPD-053 (12 mg, yield 78%). MS (ESI) m / z: 1132.5 [M+H] +< .Comparative Example 84: (2S,4R)-1-((S)-2-(3-(2-(3-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (CPD-020)

[0376]

[0377] CPD-020 was synthesized following the standard procedure for preparing CPD-053 (10 mg, yield 71%). MS (ESI) m / z: 1044.5 [M+H] +< .Comparative Example 85: 2-(2,6-Dioxopiperidin-3-yl)-4-((15-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl)amino)isoindoline-1,3-dione (CPD-021)

[0378]

[0379] CPD-021 was synthesized following the standard procedure for preparing CPD-053 (12 mg, yield 76%). MS (ESI) m / z: 947.4 [M+H] +< .Comparative Example 86: (2S,4R)-1-((S)-2-(11-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-11-oxoundecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (CPD-022)

[0380]

[0381] CPD-022 was synthesized following the standard procedure for preparing CPD-053 (13 mg, yield 78%). MS (ESI) m / z: 1054.5 [M+H] +< .Comparative Example 87: 2-(2,6-Dioxopiperidin-3-yl)-4-((2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-2-oxoethyl)amino)isoindoline-1,3-dione (CPD-023)

[0382]

[0383] CPD-023 was synthesized following the standard procedure for preparing CPD-053 (11 mg, yield 72%). MS (ESI) m / z: 757.3 [M+H] +< .Example 88: 2-(2,6-Dioxopiperidin-3-yl)-4-((8-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-8-oxooctyl)amino)isoindoline-1,3-dione (CPD-024)

[0384]

[0385] CPD-024 was synthesized following the standard procedure for preparing CPD-053 (13 mg, yield 75%). MS (ESI) m / z: 841.4 [M+H] +< .Comparative Example 89: 2-(2,6-Dioxopiperidin-3-yl)-4-((18-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-18-oxo-3,6,9,12,15-pentaoxaoctadecyl)amino)isoindoline-1,3-dione (CPD-025)

[0386]

[0387] CPD-025 was synthesized following the standard procedure for preparing CPD-053 (14 mg, yield 76%). MS (ESI) m / z: 991.4 [M+H] +< .Comparative Example 90: 2-(2,6-Dioxopiperidin-3-yl)-4-((3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-3-oxopropyl)amino)isoindoline-1,3-dione (CPD-026)

[0388]

[0389] CPD-026 was synthesized following the standard procedure for preparing CPD-053 (12 mg, yield 71%). MS (ESI) m / z: 771.3 [M+H] +< .Comparative Example 91: 2-(2,6-Dioxopiperidin-3-yl)-4-((2-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-3-oxopropoxy)ethyl)amino)isoindoline-1,3-dione (CPD-027)

[0390]

[0391] CPD-027 was synthesized following the standard procedure for preparing CPD-053 (14 mg, yield 77%). MS (ESI) m / z: 815.3 [M+H] +< .Comparative Example 92: 2-(2,6-Dioxopiperidin-3-yl)-4-((2-(2-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethyl)amino)isoindoline-1,3-dione (CPD-028)

[0392]

[0393] CPD-028 was synthesized following the standard procedure for preparing CPD-053 (11 mg, yield 72%). MS (ESI) m / z: 859.4 [M+H] +< .Comparative Example 93: (2S,4R)-1-((S)-2-(8-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-8-oxooctanamido)-3,3dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (CPD- 029)

[0394]

[0395] CPD-029 was synthesized following the standard procedure for preparing CPD-053 (14 mg, yield 76%). MS (ESI) m / z: 1012.5 [M+H] +< .Comparative Example 94: N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(3-(2-((2-(2,6dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)propanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (CPD-030)

[0396]

[0397] CPD-030 was synthesized following the standard procedure for preparing CPD-053 (10 mg, yield 72%). MS (ESI) m / z: 918.4 [M+H] +< .Comparative Example 95: N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-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)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (CPD-031)

[0398]

[0399] CPD-031 was synthesized following the standard procedure for preparing CPD-053 (13 mg, yield 76%). MS (ESI) m / z: 1050.4 [M+H] +< .Comparative Example 96: N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (CPD-032)

[0400]

[0401] CPD-032 was synthesized following the standard procedure for preparing CPD-053 (10 mg, yield 71%). MS (ESI) m / z: 962.4 [M+H] +< .Comparative Example 97: (2S,4R)-1-((S)-2-(8-(4-(4-((5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-8-oxooctanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (CPD-033)

[0402]

[0403] CPD-033 was synthesized following the standard procedure for preparing CPD-053 (13 mg, yield 73%). MS (ESI) m / z: 1115.5 [M+H] +< .Comparative Example 98: (2S,4R)-1-((S)-2-(10-(4-(4-((5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-10-oxodecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (CPD-034)

[0404]

[0405] CPD-034 was synthesized following the standard procedure for preparing CPD-053 (12 mg, yield 71%). MS (ESI) m / z: 1143.6 [M+H] +< .Comparative Example 99: (2S,4R)-1-((S)-2-(11-(4-(4-((5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-11-oxoundecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (CPD-035)

[0406]

[0407] CPD-035 was synthesized following the standard procedure for preparing CPD-053 (13 mg, yield 75%). MS (ESI) m / z: 1157.6 [M+H] +< .Comparative Example 100: (2S,4R)-1-((S)-2-(5-(4-(4-((5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-5-oxopentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (CPD-036)

[0408]

[0409] CPD-036 was synthesized following the standard procedure for preparing CPD-053 (10 mg, yield 71%). MS (ESI) m / z: 1073.5 [M+H] +< .Comparative Example 101: (2S,4R)-1-((S)-2-(9-(4-(4-((5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-9-oxononanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (CPD- 037)

[0410]

[0411] CPD-037 was synthesized following the standard procedure for preparing CPD-053 (13 mg, yield 76%). MS (ESI) m / z: 1129.5 [M+H] +< .Comparative Example 102: (2S,4R)-1-((S)-2-(3-(2-(3-(4-(4-((5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-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 (CPD-038)

[0412]

[0413] CPD-038 was synthesized following the standard procedure for preparing CPD-053 (10 mg, yield 72%). 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.09 (s, 1H), 9.65 (s, 1H), 8.06 (d, J = 99.8 Hz, 1H), 7.87 - 7.50 (m, 1H), 7.42 - 7.18 (m, 1H), 7.18 (s, 1H), 7.24 - 7.01 (m, 3H), 6.87 (dd, J = 73.2, 17.7 Hz, 1H), 6.96 - 6.71 (m, 1H), 6.96 - 6.61 (m, 1H), 6.52 (s, 1H), 5.32 (s, 1H), 5.11 (dd, J= 53.0, 7.1 Hz, 1H), 4.00 (s, 1H), 3.68-3.57 (m, 10H), 3.30 (m, 4H), 2.86 -2.77 (m, 4H), 2.58 (d, J = 16.2 Hz, 1H), 2.35 (s, 1H), 1.97 (d, J = 59.9 Hz, 2H), 1.54 (d, J = 22.7 Hz, 4H), 1.28 (d, J = 37.7 Hz, 6H), 0.91 (s, 1H), 0.85 (s, 1H). MS (ESI) m / z: 1147.5 [M+H] +< .Comparative Example 103: (2S,4R)-1-((S)-2-(tert-butyl)-16-(4-(4-((5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-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 (CPD-039)

[0414]

[0415] CPD-039 was synthesized following the standard procedure for preparing CPD-053 (13 mg, yield 77%). MS (ESI) m / z: 1191.5 [M+H] +< .Comparative Example 104: (2S,4R)-1-((S)-2-(tert-butyl)-20-(4-(4-((5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-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 (CPD-040)

[0416]

[0417] CPD-040 was synthesized following the standard procedure for preparing CPD-053 (10 mg, yield 71%). MS (ESI) m / z: 1251.6 [M+H] +< .Comparative Example 105: (2S,4R)-1-((S)-2-(tert-butyl)-19-(4-(4-((5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-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 (CPD-041)

[0418]

[0419] CPD-041 was synthesized following the standard procedure for preparing CPD-053 (12 mg, yield 78%). MS (ESI) m / z: 1235.6 [M+H] +< .Comparative Example 106: (2S,4R)-1-((S)-2-(2-(2-(2-(4-(4-((5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-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 (CPD-042)

[0420]

[0421] CPD-042 was synthesized following the standard procedure for preparing CPD-053 (13 mg, yield 76%). MS (ESI) m / z: 1119.5 [M+H] +< .Comparative Example 107: (2S,4R)-1-((S)-2-(tert-butyl)-22-(4-(4-((5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-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 (CPD-043)

[0422]

[0423] CPD-043 was synthesized following the standard procedure for preparing CPD-053 (10 mg, yield 72%). MS (ESI) m / z: 1279.6 [M+H] +< .Comparative Example 108: (2S,4R)-1-((S)-2-(6-(4-(4-((5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-6-oxohexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (CPD-044)

[0424]

[0425] CPD-044 was synthesized following the standard procedure for preparing CPD-053 (13 mg, yield 76%). 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.09 (s, 1H), 8.09 (s, 1H), 7.88 (d, J = 9.8 Hz, 1H), 7.68 - 7.54 (m, 2H), 7.49 (s, 1H), 7.38 (dd, J = 14.1, 7.9 Hz, 1H), 7.17 (t, J = 8.9 Hz, 3H), 7.03 (t, J = 9.2 Hz, 2H), 6.78 (t, J = 19.4 Hz, 2H), 5.17 (d, J = 7.9 Hz, 1H), 5.06 (dd, J = 12.8, 5.3 Hz, 1H), 4.00 (dd, J = 9.9, 5.2 Hz, 1H), 3.63 (dt, J = 43.4, 13.8 Hz, 9H), 2.87 (dd, J = 21.7, 9.7 Hz, 1H), 2.67 - 2.53 (m, 3H), 2.47 (t, J = 6.3 Hz, 3H), 2.04 (s, 3H), 1.93 - 1.75 (m, 3H), 1.34 - 1.15 (m, 2H). MS (ESI) m / z: 1087.5 [M+H] +< .Comparative Example 109: (2S,4R)-1-((S)-2-(2-(2-(4-(4-((5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-2-oxoethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (CPD-045)

[0426]

[0427] CPD-045 was synthesized following the standard procedure for preparing CPD-053 (15 mg, yield 79%). MS (ESI) m / z: 1075.5 [M+H] +< .Comparative Example 110: (2S,4R)-1-((S)-2-(4-(4-(4-((5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-4-oxobutanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (CPD-046)

[0428]

[0429] CPD-046 was synthesized following the standard procedure for preparing CPD-053 (11 mg, yield 73%). MS (ESI) m / z: 1059.5 [M+H] +< .Comparative Example 111: (2S,4R)-1-((S)-2-(7-(4-(4-((5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-7-oxoheptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (CPD-047)

[0430]

[0431] CPD-047 was synthesized following the standard procedure for preparing CPD-053 (15 mg, yield 78%). MS (ESI) m / z: 1101.5 [M+H] +< .Comparative Example 112: (2S,4R)-1-((S)-2-(3-(3-(4-(4-((5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-3-oxopropoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (CPD-048)

[0432]

[0433] CPD-048 was synthesized following the standard procedure for preparing CPD-053 (11 mg, yield 72%). MS (ESI) m / z: 1103.5 [M+H] +< .Comparative Example 113: N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (CPD-049)

[0434]

[0435] CPD-049 was synthesized following the standard procedure for preparing CPD-053 (15 mg, yield 81%). MS (ESI) m / z: 930.4 [M+H] +< .Comparative Example 114: N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (CPD-050)

[0436]

[0437] CPD-050 was synthesized following the standard procedure for preparing CPD-053 (12 mg, yield 76%). MS (ESI) m / z: 902.4 [M+H] +< .Comparative Example 115: N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (CPD-051)

[0438]

[0439] CPD-051 was synthesized following the standard procedure for preparing CPD-053 (11 mg, yield 72%). 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.64 (s, 1H), 11.09 (s, 1H), 10.11 (s, 1H), 8.29 (s, 1H), 7.82 (s, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.49 (s, 1H), 7.41 (d, J = 8.5 Hz, 1H), 7.25 (d, J = 8.7 Hz, 1H), 7.18 (d, J = 8.5 Hz, 1H), 7.01 (dd, J = 24.2, 7.5 Hz, 4H), 6.24 (d, J = 8.8 Hz, 1H), 6.13 (s, 1H), 5.04 (d, J = 8.3 Hz, 1H), 3.81 (s, 2H), 3.59 (m, 8H), 3.49 (t, J = 10.0 Hz, 3H), 3.29 (s, 4H), 2.86 (d, J = 13.9 Hz, 1H), 2.73 (s, 2H), 1.94 (d, J= 12.9 Hz, 4H), 1.35 (d, J= 10.2 Hz, 2H), 1.24 (s, 1H). MS (ESI) m / z: 874.3 [M+H] +< .Comparative Example 116: N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (CPD-052)

[0440]

[0441] CPD-052 was synthesized following the standard procedure for preparing CPD-053 (14 mg, yield 77%). MS (ESI) m / z: 944.4 [M+H] +< .Comparative Example 117: N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-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)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (CPD-054)

[0442]

[0443] CPD-054 was synthesized following the standard procedure for preparing CPD-053 (12 mg, yield 73%). MS (ESI) m / z: 1094.5 [M+H] +< .Comparative Example 118: N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (CPD-055)

[0444]

[0445] CPD-055 was synthesized following the standard procedure for preparing CPD-053 (14 mg, yield 79%). MS (ESI) m / z: 860.3 [M+H] +< .Comparative Example 119: N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(CPD-056)

[0446]

[0447] CPD-056 was synthesized following the standard procedure for preparing CPD-053 (11 mg, yield 71%). 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.65 (s, 1H), 11.10 (s, 1H), 10.12 (s, 1H), 8.30 (s, 1H), 7.82 (d, J = 9.0 Hz, 1H), 7.67 - 7.54 (m, 1H), 7.49 (s, 1H), 7.41 (d, J = 8.6 Hz, 1H), 7.25 (d, J = 8.6 Hz, 1H), 7.17 - 6.90 (m, 3H), 6.60 (d, J = 42.5 Hz, 1H), 6.25 (d, J = 8.4 Hz, 1H), 6.14 (s, 1H), 5.33 (d, J = 4.8 Hz, 1H), 5.05 (dd, J = 12.8, 5.2 Hz, 1H), 4.04 (s, 1H), 3.82 (d, J = 11.5 Hz, 1H), 3.74 - 3.44 (m, 5H), 3.26 (dd, J = 39.1, 19.2 Hz, 5H), 3.00 - 2.52 (m, 3H), 2.37 (t, J = 7.2 Hz, 2H), 2.12 - 1.81 (m, 3H), 1.58 (dd, J = 14.2, 7.0 Hz, 3H), 1.51 - 1.08 (m,8H), 0.84 (d, J = 6.9 Hz, 1H). MS (ESI) m / z: 916.4 [M+H] +< .Comparative Example 120: N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-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)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (CPD-057)

[0448]

[0449] CPD-057 was synthesized following the standard procedure for preparing CPD-053 (14 mg, yield 78%). 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.75 (d, J = 68.8 Hz, 1H), 11.09 (s, 1H), 10.20 (d, J= 59.5 Hz, 1H), 7.82 (d, J = 9.0 Hz, 1H), 7.64 - 7.53 (m, 1H), 7.46 (d, J = 17.1 Hz, 1H), 7.41 (d, J = 8.6 Hz, 1H), 7.29 - 7.20 (m, 1H), 7.20 - 7.07 (m, 1H), 6.99 (dt, J = 38.9, 17.1 Hz, 3H), 6.63 (d, J = 20.8 Hz, 1H), 6.24 (d, J = 7.8 Hz, 1H), 6.15 (s, 1H), 5.32 (t, J = 4.7 Hz, 1H), 5.06 (dd, J = 12.9, 5.3 Hz, 1H), 4.04 (s, 2H), 3.89 - 3.74 (m, 2H), 3.72 - 3.56 (m, 8H), 3.24 (dd, J = 28.3, 24.5 Hz, 3H), 2.99 - 2.81 (m, 1H), 2.77 (d, J = 4.8 Hz, 1H), 2.70 - 2.51 (m, 9H), 2.11 - 1.84 (m, 3H), 1.53 - 1.10 (m, 7H), 0.85 (t, J = 6.6 Hz, 1H). MS (ESI) m / z: 1006.4 [M+H] +< .Comparative Example 121: (2S,4R)-1-((S)-2-(tert-butyl)-14-(4-(4-((5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-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 (CPD-058)

[0450]

[0451] CPD-058 was synthesized following the standard procedure for preparing CPD-053 (11 mg, yield 72%). MS (ESI) m / z: 1163.5 [M+H] +< .Comparative Example 122:N-(2-(2-(2-(2-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)ethyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide (CPD-059)

[0452]

[0453] CPD-059 was synthesized following the standard procedure for preparing CPD-053 (14 mg, yield 76%). MS (ESI) m / z: 932.4 [M+H] +< .Comparative Example 123:N-(2-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide (CPD-060)

[0454]

[0455] CPD-060 was synthesized following the standard procedure for preparing CPD-053 (13 mg, yield 78%). 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.12 (d, J = 8.8 Hz, 1H), 10.50 (s, 1H), 8.94 (t, J = 5.4 Hz, 1H), 8.51 (s, 1H), 8.13 (d, J = 10.9 Hz, 1H), 7.61 (dt, J = 13.9, 7.0 Hz, 2H), 7.45 - 7.35 (m, 1H), 7.26 - 7.12 (m, 3H), 7.05 (t, J = 7.2 Hz, 2H), 6.95 (d, J = 8.9 Hz, 1H), 6.76 (s, 1H), 5.23 (d, J = 6.3 Hz, 1H), 5.07 (dd, J = 12.8, 5.5 Hz, 1H), 4.47 (s, 2H), 4.14 - 3.93 (m, 4H), 3.72 (dd, J = 17.8, 8.2 Hz, 3H), 3.42 - 3.36 (m, 4H), 3.21 (s, 3H), 2.95 - 2.80 (m, 1H), 2.65 - 2.53 (m, 2H), 2.04 (dd, J= 31.3, 12.8 Hz, 3H), 1.91 (s, 2H), 1.25 (d, J = 10.1 Hz, 1H). MS (ESI) m / z: 800.3 [M+H] +< .Comparative Example 124:(2S,4R)-1-((S)-2-(8-(2-(4-(4-((5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)acetamido)octanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (CPD-061)

[0456]

[0457] CPD-061 was synthesized following the standard procedure for preparing CPD-053 (10 mg, yield 76%). MS (ESI) m / z: 1158.6 [M+H] +< .Comparative Example 125:N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(2-((2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)amino)-2-oxoethyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(CPD-062)

[0458]

[0459] CPD-062 was synthesized following the standard procedure for preparing CPD-053 (12 mg, yield 72%). MS (ESI) m / z: 903.4 [M+H] +< .Comparative Example 126:(2S,4R)-1-((S)-2-(2-(2-(4-(4-((5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)acetamido)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (CPD-063)

[0460]

[0461] CPD-063 was synthesized following the standard procedure for preparing CPD-053 (15 mg, yield 76%). MS (ESI) m / z: 1073.5 [M+H] +< .Comparative Example 127:N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-2-oxo-6,9,12-trioxa-3-azatetradecyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (CPD-064)

[0462]

[0463] CPD-064 was synthesized following the standard procedure for preparing CPD-053 (11 mg, yield 77%). MS (ESI) m / z: 1035.4 [M+H] +< .Comparative Example 128:N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(20-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-2-oxo-6,9,12,15,18-pentaoxa-3-azaicosyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (CPD-065)

[0464]

[0465] CPD-065 was synthesized following the standard procedure for preparing CPD-053 (13 mg, yield 79%). MS (ESI) m / z: 1123.5 [M+H] +< .Comparative Example 129: 5-((2-(2-Aminoethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 60)

[0466]

[0467] A mixture of 5-fluoroisobenzofuran-1,3-dione (87 g, 524 mmol), 3-aminopiperidine-2,6-dione (85.7 g, 524 mmol) and NaOAc (85.9 g, 1050 mmol) in acetic acid (500 mL) was stirred at 130 °C overnight. After cooling 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] +< .

[0468] 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 °C 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 2 SO 4 , filtered and concentrated to give a crude product which was purified by silica gel chromatography (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] +< .

[0469] 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. 1< H 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] +< .Comparative Example 130: 5-((2-(2-(2-Aminoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 61)

[0470]

[0471] Linker 61 was synthesized following the same procedure as Linker 60 as described for Example 60. (1.4 g, yield: 71%). 1< H 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] +< .Comparative Example 131: 5-((2-(2-(2-(2-Aminoethoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 62)

[0472]

[0473] Linker 62 was synthesized following the same procedure as Linker 60 as described for Example 60. (1.19 g, yield: 59%). 1< H 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] +< .Comparative Example 132: 5-((14-Amino-3,6,9,12-tetraoxatetradecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 63)

[0474]

[0475] Linker 63 was synthesized following the same procedure as Linker 60 as described for Example 60. (1.2 g, yield: 73%). 1< H 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] +< .Comparative Example 133: 5-((17-Amino-3,6,9,12,15-pentaoxaheptadecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 64)

[0476]

[0477] Linker 64 was synthesized following the same procedure as Linker 60 as described for Example 60. (1.73 g, yield: 88%). 1< H 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] +< .Comparative Example 134: (2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycine (Linker 65)

[0478]

[0479] Linker 65 was synthesized following the same procedure as Linker 60 as described for Example 60. (1.0 g, yield: 84%). 1< H 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] +< .Comparative Example 135: 3-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)propanoic acid (Linker 66)

[0480]

[0481] Linker 66 was synthesized following the same procedure as Linker 60 as described for Example 60. (1.24 g, yield: 60%). 1< H 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] +< .Comparative Example 136: 4-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butanoic acid (Linker 67)

[0482]

[0483] Linker 67 was synthesized following the same procedure as Linker 60 as described for Example 60. (0.52 g, yield: 25%). 1< H 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] +< .Comparative Example 137: 5-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)pentanoic acid (Linker 68)

[0484]

[0485] Linker 68 was synthesized following the same procedure as Linker 60 as described for Example 60. (0.66 g, yield: 51%). 1< H 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] +< .Comparative Example 138: 6-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)hexanoic acid (Linker 69)

[0486]

[0487] Linker 69 was synthesized following the same procedure as Linker 60 as described for Example 60. (1.33 g, yield: 66%). 1< H 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] +< .Comparative Example 139: 7-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)heptanoic acid (Linker 70)

[0488]

[0489] Linker 70 was synthesized following the same procedure as Linker 60 as described for Example 60. (1.06 g, yield: 39%). 1< H 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] +< .Comparative Example 140: 8-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)octanoic acid (Linker 71)

[0490]

[0491] Linker 71 was synthesized following the same procedure as Linker 60 as described for Example 60. (1.66 g, yield: 51%). 1< H 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] +< .Comparative Example 141: 5-((2-Aminoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 72)

[0492]

[0493] Linker 72 was synthesized following the same procedure as Linker 60 as described for Example 60. (1.74 g, yield: 80%). 1< H 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] +< .Comparative Example 142: 5-((3-Aminopropyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 73)

[0494]

[0495] Linker 73 was synthesized following the same procedure as Linker 60 as described for Example 60. (1.3 g, yield: 57%). 1< H 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] -< .Comparative Example 143: 5-((4-Aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 74)

[0496]

[0497] Linker 74 was synthesized following the same procedure as Linker 60 as described for Example 60. (2.9 g, yield: 85%). 1< H 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] +< .Comparative Example 144: 5-((5-Aminopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 75)

[0498]

[0499] Linker 75 was synthesized following the same procedure as Linker 60 as described for Example 60. (1.8 g, yield: 78%). 1< H 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] +< .Comparative Example 145: 5-((6-Aminohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 76)

[0500]

[0501] Linker 76 was synthesized following the same procedure as Linker 60 as described for Example 60. (1.8 g, yield: 62%). 1< H 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] +< .Comparative Example 146: 5-((7-Aminoheptyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 77)

[0502]

[0503] Linker 77 was synthesized following the same procedure as Linker 60 as described for Example 60. (1.3 g, yield: 70%). 1< H 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] +< .Comparative Example 147: 5-((8-Aminooctyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 78)

[0504]

[0505] Linker 78 was synthesized following the same procedure as Linker 60 as described for Example 60. (1.6 g, yield: 62%). 1< H 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] +< .Comparative Example 148: 3-(2-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)propanoic acid (Linker 79)

[0506]

[0507] Linker 79 was synthesized following the same procedure as Linker 60 as described for Example 60. (1.7 g, yield: 60%). 1< H 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] +< .Comparative Example 149: 3-(2-(2-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)propanoic acid (Linker 80)

[0508]

[0509] Linker 80 was synthesized following the same procedure as Linker 60 as described for Example 60. (2.3 g, yield: 78%). 1< H 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] +< .Comparative Example 150: 3-(2-(2-(2-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)ethoxy)propanoic acid (Linker 81)

[0510]

[0511] Linker 81 was synthesized following the same procedure as Linker 60 as described for Example 60. (1.2 g, yield: 52%). 1< H 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] +< .Comparative Example 151: 1-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)-3,6,9,12-tetraoxapentadecan-15-oic acid (Linker 82)

[0512]

[0513] Linker 82 was synthesized following the same procedure as Linker 60 as described for Example 60. (1.3 g, yield: 55%). 1< H 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] +< .Comparative Example 152: 1-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)-3,6,9,12,15-pentaoxaoctadecan-18-oic acid (Linker 83)

[0514]

[0515] Linker 83 was synthesized following the same procedure as Linker 60 as described for Example 60. (1.0 g, yield: 50%). 1< H 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] -< .Comparative Example 153: N-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3- yl)pyridin-2-yl)piperazin-1-yl)acetamide (TR-102)

[0516]

[0517] TR-102 was synthesized following the standard procedure for preparing TR-059 (12 mg, yield 65%). MS (ESI) m / z: 884.7 [M+H] +< .Comparative Example 154: N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide (TR-103)

[0518]

[0519] TR-103 was synthesized following the standard procedure for preparing TR-059 (11 mg, yield 63%). MS (ESI) m / z: 842.7 [M+H] +< .Comparative Example 155: N-(17-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12,15-pentaoxaheptadecyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide (TR-104)

[0520]

[0521] TR-104 was synthesized following the standard procedure for preparing TR-059 (12 mg, yield 60%). MS (ESI) m / z: 1020.9 [M+H] +< .Comparative Example 156: N-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide (TR-105)

[0522]

[0523] TR-105 was synthesized following the standard procedure for preparing TR-059 (11 mg, yield 63%). MS (ESI) m / z: 888.8 [M+H] +< .Comparative Example 157: N-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide (TR-106)

[0524]

[0525] TR-106 was synthesized following the standard procedure for preparing TR-059 (10 mg, yield 55%). MS (ESI) m / z: 844.6 [M+H] +< .Comparative Example 158: N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide (TR-107)

[0526]

[0527] TR-107 was synthesized following the standard procedure for preparing TR-059 (11.5 mg, yield 62%). MS (ESI) m / z: 828.6 [M+H] +< .Comparative Example 159: N-(14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxatetradecyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide (TR-108)

[0528]

[0529] TR-108 was synthesized following the standard procedure for preparing TR-059 (13 mg, yield 64%). MS (ESI) m / z: 976.8 [M+H] +< .Comparative Example 160: N-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide (TR-109)

[0530]

[0531] TR-109 was synthesized following the standard procedure for preparing TR-059 (12 mg, yield 63%). MS (ESI) m / z: 814.6 [M+H] +< .Comparative Example 161: N-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide (TR-110)

[0532]

[0533] TR-110 was synthesized following the standard procedure for preparing TR-059 (10 mg, yield 61%). MS (ESI) m / z: 870.7 [M+H] +< .Comparative Example 162: N-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide (TR-111)

[0534]

[0535] TR-111 was synthesized following the standard procedure for preparing TR-059 (8.6 mg, yield 60%). MS (ESI) m / z: 856.7 [M+H] +< .Comparative Example 163: 2-(2,6-Dioxopiperidin-3-yl)-5-((2-(2-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethyl)amino)isoindoline-1,3-dione (TR-113)

[0536]

[0537] TR-113 was synthesized following the standard procedure for preparing TR-053 (7.7 mg, yield 59%). MS (ESI) m / z: 859.8 [M+H] +< .Comparative Example 164: 2-(2,6-Dioxopiperidin-3-yl)-5-((2-(2-(2-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethoxy)ethyl)amino)isoindoline-1,3-dione (TR-114)

[0538]

[0539] TR-114 was synthesized following the standard procedure for preparing TR-053 (8.6 mg, yield 61%). MS (ESI) m / z: 903.9 [M+H] +< .Comparative Example 165: 2-(2,6-Dioxopiperidin-3-yl)-5-((5-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-5-oxopentyl)amino)isoindoline-1,3-dione (TR-115)

[0540]

[0541] TR-115 was synthesized following the standard procedure for preparing TR-053 (8.1 mg, yield 66%). MS (ESI) m / z: 799.8 [M+H] +< .Comparative Example 166: 2-(2,6-Dioxopiperidin-3-yl)-5-((18-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-18-oxo-3,6,9,12,15-pentaoxaoctadecyl)amino)isoindoline-1,3-dione (TR-116)

[0542]

[0543] TR-116 was synthesized following the standard procedure for preparing TR-053 (8.6 mg, yield 64%). MS (ESI) m / z: 991.6 [M+H] +< .Comparative Example 167: 2-(2,6-Dioxopiperidin-3-yl)-5-((7-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-7-oxoheptyl)amino)isoindoline-1,3-dione (TR-117)

[0544]

[0545] TR-117 was synthesized following the standard procedure for preparing TR-053 (8.8 mg, yield 61%). MS (ESI) m / z: 827.6 [M+H] +< .Comparative Example 168: 2-(2,6-Dioxopiperidin-3-yl)-5-((8-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-8-oxooctyl)amino)isoindoline-1,3-dione (TR-118)

[0546]

[0547] TR-118 was synthesized following the standard procedure for preparing TR-053 (8.8 mg, yield 61%). MS (ESI) m / z: 841.6 [M+H] +< .Comparative Example 169: 2-(2,6-Dioxopiperidin-3-yl)-5-((2-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-3-oxopropoxy)ethyl)amino)isoindoline-1,3-dione (TR-119)

[0548]

[0549] TR-119 was synthesized following the standard procedure for preparing TR-053 (8.9 mg, yield 61%). MS (ESI) m / z: 815.5 [M+H] +< .Comparative Example 170: 2-(2,6-Dioxopiperidin-3-yl)-5-((15-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl)amino)isoindoline-1,3-dione (TR-120)

[0550]

[0551] TR-120 was synthesized following the standard procedure for preparing TR-053 (8.9 mg, yield 61%). MS (ESI) m / z: 947.6 [M+H] +< .Comparative Example 171: 2-(2,6-Dioxopiperidin-3-yl)-5-((3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-3-oxopropyl)amino)isoindoline-1,3-dione (TR-121)

[0552]

[0553] TR-121 was synthesized following the standard procedure for preparing TR-053 (10.2 mg, yield 63%). MS (ESI) m / z: 1542.5 [M+H] +< .Comparative Example 172: 2-(2,6-Dioxopiperidin-3-yl)-5-((6-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-6-oxohexyl)amino)isoindoline-1,3-dione (TR-122)

[0554]

[0555] TR-122 was synthesized following the standard procedure for preparing TR-053 (10.6 mg, yield 62%). MS (ESI) m / z: 813.9 [M+H] +< .Comparative Example 173: 2-(2,6-Dioxopiperidin-3-yl)-5-((2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-2-oxoethyl)amino)isoindoline-1,3-dione (TR-123)

[0556]

[0557] TR-123 was synthesized following the standard procedure for preparing TR-053 (10.6 mg, yield 62%). MS (ESI) m / z: 1514.8 [M+H] +< .Comparative Example 174: N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide (TR-124)

[0558]

[0559] TR-124 was synthesized following the standard procedure for preparing TR-059 (9.3 mg, yield 61%). MS (ESI) m / z: 828.5 [M+H] +< .Comparative Example 175: N-(14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)-3,6,9,12-tetraoxatetradecyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide (TR-125)

[0560]

[0561] TR-125 was synthesized following the standard procedure for preparing TR-059 (9.6 mg, yield 62%). MS (ESI) m / z: 976.8 [M+H] +< .Comparative Example 176: N-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)heptyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3- yl)pyridin-2-yl)piperazin-1-yl)acetamide (TR-126)

[0562]

[0563] TR-126 was synthesized following the standard procedure for preparing TR-059 (9.9 mg, yield 63%). MS (ESI) m / z: 870.7 [M+H] +< .Comparative Example 177: N-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)propyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide (TR-127)

[0564]

[0565] TR-127 was synthesized following the standard procedure for preparing TR-059 (9.3 mg, yield 61%). MS (ESI) m / z: 814.6 [M+H] +< .Comparative Example 178: N-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)hexyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide (TR-128)

[0566]

[0567] TR-128 was synthesized following the standard procedure for preparing TR-059 (9.7 mg, yield 62%). MS (ESI) m / z: 856.7 [M+H] +< .Comparative Example 179: N-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)ethoxy)ethyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide (TR-129)

[0568]

[0569] TR-129 was synthesized following the standard procedure for preparing TR-059 (9.7 mg, yield 62%). MS (ESI) m / z: 932.6 [M+H] +< .Comparative Example 180: N-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide (TR-130)

[0570]

[0571] TR-130 was synthesized following the standard procedure for preparing TR-059 (9.3 mg, yield 62%). MS (ESI) m / z: 800.6 [M+H] +< .Comparative Example 181: N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)pentyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide (TR-131)

[0572]

[0573] TR-131 was synthesized following the standard procedure for preparing TR-059 (10.5 mg, yield 65%). MS (ESI) m / z: 842.6 [M+H] +< .Comparative Example 182: N-(17-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)-3,6,9,12,15-pentaoxaheptadecyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide (TR-132)

[0574]

[0575] TR-132 was synthesized following the standard procedure for preparing TR-059 (7.5 mg, yield 55%). MS (ESI) m / z: 1020.9 [M+H] +< .Comparative Example 183: N-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)octyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide (TR-133)

[0576]

[0577] TR-133 was synthesized following the standard procedure for preparing TR-059 (8.6 mg, yield 55%). MS (ESI) m / z: 884.7 [M+H] +< .Comparative Example 184: N-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)ethyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide (TR-134)

[0578]

[0579] TR-134 was synthesized following the standard procedure for preparing TR-059 (8.8 mg, yield 59%). MS (ESI) m / z: 888.7 [M+H] +< .Comparative Example 185: N-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide (TR-135)

[0580]

[0581] TR-135 was synthesized following the standard procedure for preparing TR-059 (8.1 mg, yield 56%). MS (ESI) m / z: 844.7 [M+H] +< .Comparative Example 186: N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)octanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-136)

[0582]

[0583] TR-136 was synthesized following the standard procedure for preparing TR-053 (11 mg, yield 59%). MS (ESI) m / z: 944.4 [M+H] +< .Comparative Example 187: N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-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)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-137)

[0584] 137 was synthesized following the standard procedure for preparing TR-053 (13 mg, yield 64%). MS (ESI) m / z: 1094.5 [M+H] +< .Comparative Example 188: N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)hexanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-138)

[0585]

[0586] TR-138 was synthesized following the standard procedure for preparing TR-053 (14 mg, yield 55%). MS (ESI) m / z: 916.4 [M+H] +< .Comparative Example 189: N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)heptanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-139)

[0587]

[0588] TR-139 was synthesized following the standard procedure for preparing TR-053 (16 mg, yield 62%). MS (ESI) m / z: 930.4 [M+H] +< .Comparative Example 190: N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-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)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-140)

[0589]

[0590] TR-140 was synthesized following the standard procedure for preparing TR-053 (12 mg, yield 56%). MS (ESI) m / z: 1050.4 [M+H] +< .Comparative Example 191: N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)propanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-141)

[0591]

[0592] TR-141 was synthesized following the standard procedure for preparing TR-053 (15 mg, yield 65%). MS (ESI) m / z: 962.4 [M+H] +< .Comparative Example 192: N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)pentanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-142)

[0593]

[0594] TR-142 was synthesized following the standard procedure for preparing TR-053 (12 mg, yield 62%). MS (ESI) m / z: 902.4 [M+H] +< .Comparative Example 193: N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)octanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-143)

[0595]

[0596] TR-143 was synthesized following the standard procedure for preparing TR-053 (16 mg, yield 67%). MS (ESI) m / z: 918.4 [M+H] +< .Comparative Example 194: N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-144)

[0597]

[0598] TR-144 was synthesized following the standard procedure for preparing TR-053 (14 mg, yield 61%). MS (ESI) m / z: 860.3 [M+H] +< .Comparative Example 195: N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)propanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-145)

[0599]

[0600] TR-145 was synthesized following the standard procedure for preparing TR-053 (15 mg, yield 62%). MS (ESI) m / z: 874.3 [M+H] +< .Comparative Example 196: N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-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)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-146)

[0601]

[0602] TR-146 was synthesized following the standard procedure for preparing TR-053 (16 mg, yield 65%). MS (ESI) m / z: 1006.4 [M+H] +< .Comparative Example 197: N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(2-((6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)amino)-2-oxoethyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-147)

[0603]

[0604] TR-147 was synthesized following the standard procedure for preparing TR-053 (12 mg, yield 56%). MS (ESI) m / z: 959.4 [M+H] +< .Comparative Example 198: N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(2-((8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)amino)-2-oxoethyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-148)

[0605]

[0606] TR-148 was synthesized following the standard procedure for preparing TR-053 (16 mg, yield 62%). MS (ESI) m / z: 987.5 [M+H] +< .Comparative Example 199: N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(2-((5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentyl)amino)-2-oxoethyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-149)

[0607]

[0608] TR-149 was synthesized following the standard procedure for preparing TR-053 (14 mg, yield 52%). MS (ESI) m / z: 945.4 [M+H] +< .Comparative Example 200: N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(17-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TR-150)

[0609] [0...

Claims

1. A bivalent compound selected from the group consisting of: 2-(2,6-Dioxopiperidin-3-yl)-5-((1-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)azetidin-3-yl)amino)isoindoline-1,3-dione (TR-175), 2-(2,6-Dioxopiperidin-3-yl)-5-(((1-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)azetidin-3-yl)methyl)amino)isoindoline-1,3-dione (TR-179), 2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)azetidin-1-yl)isoindoline-1,3-dione (TR-184), 2-(2,6-Dioxopiperidin-3-yl)-5-((2-((1-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)azetidin-3-yl)amino)ethyl)amino)isoindoline-1,3-dione (TR-192), 2-(2,6-Dioxopiperidin-3-yl)-5-(3-((4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)methyl)azetidin-1-yl)isoindoline-1,3-dione (TR-198), 3-(5-(3-((4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)methyl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (TR-205), 3-(5-((1-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)azetidin-3-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (TR-206), 3-(5-(((1-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)azetidin-3-yl)methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (TR-210), 2-(2,6-Dioxopiperidin-3-yl)-5-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazine-1-carbonyl)azetidin-1-yl)isoindoline-1,3-dione (TR-211), 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)-N-(1-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)azetidin-3-yl)acetamide (TR-213), 3-(5-((1-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)azetidin-3-yl)ethynyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (TR-219), N-[5-[(3,5-Difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]azetidin-3-yl]methyl]piperazin-1-yl]-2-(tetrahydropyran-4-ylamino)benzamide (TR-231), 2-(2,6-dioxopiperidin-3-yl)-5-(3-((4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-yl)piperazin-1-yl)methyl)azetidin-1-yl)isoindoline-1,3-dione (TR-234), and 2-(2,6-dioxopiperidin-3-yl)-5-((3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)azetidin-1-yl)methyl)isoindoline-1,3-dione (TR-237), or a pharmaceutically acceptable salt thereof.

2. The bivalent compound of claim 1, wherein the bivalent compound is selected from the group consisting of: 2-(2,6-Dioxopiperidin-3-yl)-5-(3-((4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)methyl)azetidin-1-yl)isoindoline-1,3-dione (TR-198), 2-(2,6-Dioxopiperidin-3-yl)-5-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazine-1-carbonyl)azetidin-1-yl)isoindoline-1,3-dione (TR-211), and N-[5-[(3,5-Difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]azetidin-3-yl]methyl]piperazin-1-yl]-2-(tetrahydropyran-4-ylamino)benzamide (TR-231), or a pharmaceutically acceptable salt thereof.

3. The bivalent compound of claim 1, which is 2-(2,6-Dioxopiperidin-3-yl)-5-(3-((4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)methyl)azetidin-1-yl)isoindoline-1,3-dione (TR-198), or a pharmaceutically acceptable salt thereof.

4. The bivalent compound of claim 1, which is 2-(2,6-Dioxopiperidin-3-yl)-5-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazine-1-carbonyl)azetidin-1-yl)isoindoline-1,3-dione (TR-211), or a pharmaceutically acceptable salt thereof.

5. The bivalent compound of claim 1, which is N-[5-[(3,5-Difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]azetidin-3-yl]methyl]piperazin-1-yl]-2-(tetrahydropyran-4-ylamino)benzamide (TR-231), or a pharmaceutically acceptable salt thereof.

6. The bivalent compound of claim 1, which is selected from the group consisting of: and 7. A pharmaceutical composition comprising a bivalent compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

8. The pharmaceutical composition of claim 7 for use in a method of treating a tropomyosin receptor kinase (TRK)-mediated disease, the method comprising administering the pharmaceutical composition to a subject with a TRK-mediated disease.

9. The pharmaceutical composition for use according to claim 8, wherein the TRK-mediated disease is a cancer.

10. The pharmaceutical composition for use according to claim 8, wherein the TRK-mediated disease is selected from the group consisting of non-small cell lung cancer, colorectal cancer, gastric cancer, liver cancer, invasive breast cancer, lung adenocarcinoma, uterine cancer, adrenal cancer, pancreatic cancer, ovarian cancer, esophageal cancer, urinary bladder cancer, endometrial cancer, prostate cancer, low-grade glioma, glioblastoma, Spitzoid cancer, soft tissue sarcoma, papillary thyroid carcinoma, head and neck squamous cell carcinoma, congenital fibrosarcoma, congenital mesoblastic nephroma, secretory breast carcinoma, mammary analogue secretory carcinoma, acute myeloid leukemia, ductal carcinoma, pulmonary neuroendocrine tumors, pheochromocytoma, and Wilms' tumor.

11. The pharmaceutical composition for use according to claim 8, wherein the TRK-mediated disease is acute pain, chronic pain, cancer pain, surgical pain, inflammatory pain, neuropathic pain, nociceptive pain, pain of osteoarthritis, chronic low back pain, low back pain of osteoporosis, pain of bone fracture, pain of rheumatoid arthritis, postherpetic pain, pain of diabetic neuropathy, fibromyalgia, pain of pancreatitis, pain of interstitial cystitis, pain of endometriosis, pain of irritable bowel syndrome, migraine, pain of pulpitis, interstitial cystitis pain, painful bladder syndrome, central pain syndromes, postsurgical pain syndromes, bone and joint pain, repetitive motion pain, dental pain, myofascial pain, perioperative pain, dysmennorhea, myofascial pain, angina pain, headache, primary hyperalgesia, secondary hyperalgesia, primary allodynia, secondary allodynia, or other pain caused by central sensitization.

12. The pharmaceutical composition for use according to claim 8, wherein the TRK-mediated disease is chronic pain.