Compounds for targeted degradation of proto-oncogene tyrosine protein kinase receptor

Abstract

Novel compounds which act as protein degradation inducing moieties for proto-oncogene tyrosine-protein kinase receptor (RET), which may be either wild type RET or a mutant form of RET.

Description

[0001] COMPOUNDS FOR TARGETED DEGRADATION OF PROTO-ONCOGENE TYROSINE PROTEIN KINASE RECEPTOR CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 614,330 filed on December 22, 2023, the entirety of which is hereby incorporated by reference for all purposes. FIELD OF THE INVENTION This invention provides rearranged during transfection (RET) proto-oncogene tyrosine- protein kinase receptor degrading compounds for therapeutic applications as described further herein. BACKGROUND Protein degradation is a highly regulated and essential process that maintains cellular homeostasis. The selective identification and removal of damaged, misfolded, or excess proteins is achieved via the ubiquitin-proteasome pathway (UPP). The UPP is central to the regulation of almost all cellular processes, including antigen processing, apoptosis, biogenesis of organelles, cell cycling, DNA transcription and repair, differentiation and development, immune response and inflammation, neural and muscular degeneration, morphogenesis of neural networks, modulation of cell surface receptors, ion channels and the secretory pathway, the response to stress and extracellular modulators, ribosome biogenesis and viral infection. Covalent attachment of multiple ubiquitin molecules to a protein substrate by an E3 ubiquitin ligase to a terminal lysine residue marks the protein for proteasome degradation, where the protein is digested into small peptides and eventually into its constituent amino acids that serve as building blocks for new proteins. Defective proteasomal degradation has been linked to a variety of disorders including cancer and others. The drug thalidomide and its analogs lenalidomide and pomalidomide have garnered interest as immunomodulators and antineoplastics, especially in multiple myeloma. (Kim SA et. al., “A novel cereblon modulator for targeted protein degradation”, Eur J Med Chem. 2019 Mar 15; 166:65-74; R. Verma et. al., “Identification of a Cereblon-Independent Protein Degradation Pathway in Residual Myeloma Cells Treated with Immunomodulatory Drugs” Blood (2015) 126 (23): 913. Liu Y, et al., “A novel effect of thalidomide and its analogs: suppression of cereblon ubiquitination enhances ubiquitin ligase function” FASEB J. 2015 Dec;29(12):4829-39; Martiniani, R. et al., “Biological activity of lenalidomide and its underlying therapeutic effects in multiple myeloma” Adv Hematol, 2012, 2012:842945; and Terpos, E. et al., “Pomalidomide: a novel drug to treat relapsed and refractory multiple myeloma” Oncotargets and Therapy, 2013, 6:531). There are also clinical and preclinical studies with thalidomide and its analogs related to the treatment of renal cell carcinoma, glioblastoma, prostate cancer, melanoma, colorectal cancer, Crohn’s disease, rheumatoid arthritis, Behcet’s syndrome, breast cancer, head and neck cancer, ovarian cancer, chronic heart failure, graft-versus-host disease, and tuberculous meningitis. Thalidomide and its analogues have been found to bind to the ubiquitin ligase cereblon and redirect its ubiquitination activity (see Ito, T. et al. “Identification of a primary target of thalidomide teratogenicity” Science, 2010, 327:1345). Cereblon (CRBN) forms part of an E3 ubiquitin ligase complex with damaged DNA binding protein 1, Cullin 4, and the E2-binding protein ROC1 (known as RBX1). In this complex CRBN functions as a substrate receptor to select proteins for ubiquitination. The binding of lenalidomide to cereblon facilitates subsequent binding of cereblon to Ikaros and Aiolos, leading to their ubiquitination and degradation by the proteasome (see Lu, G. et al. “The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins” Science, 2014, 343:305-309; Krönke, J. et al. “Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells” Science, 2014, 343:301-305). Celgene has also disclosed imides for similar uses, including those in U.S. Patents 6,045,501; 6,315,720; 6,395,754; 6,561,976; 6,561,977; 6,755,784; 6,869,399; 6,908,432; 7,141,018; 7,230,012; 7,820,697; 7,874,984; 7,959,566; 8,204,763; 8,315,886; 8,589,188; 8,626,531; 8,673,939; 8,735,428; 8,741,929; 8,828,427; 9,056,120; 9,101,621; 9,101,622, 9,587,281, 9,857,359, and 10,092,555. The disclosure that thalidomide binds to the cereblon E3 ubiquitin ligase led to research investigating incorporating thalidomide and certain derivatives into compounds for the targeted destruction of proteins. This research led to a patent application filed by Proteinex, Inc. in February 1999 that issued as U.S. Patent No. 6,306,663 claiming compounds comprising a target protein binding element and a ubiquitination recognition element for the degradation of a target protein. Proteinex described that the invention can be used to control protein levels in eukaryotes. Patent applications filed by C4 Therapeutics, Inc., that describe compounds capable of binding to an E3 ubiquitin ligase and a target protein for degradation include: WO / 2022 / 251539 titled “EGFR Degraders to Treat Cancer Metastasis to the Brain or CNS”; WO / 2022 / 081928 titled “Tricyclic Heterobifunctional Compounds for Degradation of Targeted Proteins”; WO / 2022 / 081927 titled “Tricyclic Compounds to Degrade Neosubstrates for Medical Therapy”; WO / 2022 / 081925 titled “Tricyclic Ligands for Degradation of IKZF2 or IKZF4”; WO / 2022 / 032132 titled “Advantageous Therapies for Disorders Mediated by Ikaros or Aiolos”; WO / 2021 / 255213 titled “Heterobifunctional Compounds as Degraders of BRAF”; WO / 2021 / 255212 titled “BRAF Degraders”; WO / 2021 / 178920 titled “Compounds for Targeted Degradation of BRD9”; WO / 2021 / 127561 titled “Isoindolinone And Indazole Compounds For The Degradation Of EGFR”; WO / 2021 / 086785 titled “Bifunctional Compounds”; WO / 2021 / 083949 titled “Bifunctional Compounds for the Treatment of Cancer”; WO / 2020 / 210630 titled “Tricyclic Degraders of Ikaros and Aiolos”; WO / 2020 / 181232 titled “Heterocyclic Compounds for Medical Treatment”; WO / 2020 / 132561 titled “Targeted Protein Degradation”; WO / 2019 / 236483 titled “Spirocyclic Compounds”; WO2020 / 051235 titled “Compounds for the degradation of BRD9 or MTH1”; WO / 2019 / 191112 titled “Cereblon binders for the Degradation of Ikaros”; WO / 2019 / 204354 titled “Spirocyclic Compounds”; WO / 2019 / 099868 titled “Degraders and Degrons for Targeted Protein Degradation”; WO / 2018 / 237026 titled “N / O-Linked Degrons and Degronimers for Protein Degradation”; WO 2017 / 197051 titled “Amine-Linked C3-Glutarimide Degronimers for Target Protein Degradation”; WO 2017 / 197055 titled “Heterocyclic Degronimers for Target Protein Degradation”; WO 2017 / 197036 titled “Spirocyclic Degronimers for Target Protein Degradation”; WO 2017 / 197046 titled “C3-Carbon Linked Glutarimide Degronimers for Target Protein Degradation”; and WO 2017 / 197056 titled “Bromodomain Targeting Degronimers for Target Protein Degradation.” Other patent applications that describe protein degrading compounds include: WO 2015 / 160845; WO 2016 / 105518; WO 2016 / 118666; WO 2016 / 149668; WO 2016 / 197032; WO 2016 / 197114; WO 2017 / 007612; WO 2017 / 011371; WO 2017 / 011590; WO 2017 / 030814; WO 2017 / 046036; WO2017 / 079267; WO 2017 / 176708; WO 2017 / 176957; WO 2017 / 180417; WO 2018 / 053354; WO 2018 / 071606; WO 2018 / 102067; WO 2018 / 102725; WO 2018 / 118598; WO 2018 / 119357; WO 2018 / 119441; WO 2018 / 119448; WO 2018 / 140809; WO 2018 / 144649; WO 2018 / 119448; WO 2018 / 226542; WO 2019 / 023553; WO 2019 / 060693; WO 2019 / 060742; WO 2019 / 140380; WO 2019 / 140387; WO 2019 / 195201; WO 2019 / 199816; WO 2019 / 099926; WO 2019 / 195609; WO 2020 / 023851; WO 2020 / 041331; WO 2020 / 051564; WO 2021 / 053495; WO 2021 / 053555; WO 2021 / 162493; and WO 2022 / 012622. The rearranged during transfection (RET) proto-oncogene receptor tyrosine-protein kinase, a cell surface receptor tyrosine kinase, is widely known for its essential role in cell survival, differentiation, proliferation, migration, and chemotaxis. RET germline missense and somatic mutations cause medullary thyroid cancer (MTC) and neuroendocrine tumors, whereas RET fusion proteins, overexpression, and copy number gains are present in a broad spectrum of additional cancers such as papillary thyroid cancer, pancreatic cancer, melanoma, leukemia, lung adenocarcinomas, and breast cancer. (Liu Xuan et al., “RET kinase alterations in targeted cancer therapy”, Cancer Drug Resist, 2020; and Mulligan LM., “RET revisited: expanding the oncogenic portfolio”, Nat Rev Cancer., 2014, 14(3), 173–186). RET forms a complex with its natural ligands, a family of glial-derived neurotrophic factors, and with glycosyl phosphatidylinositol-linked co-receptors, resulting in dimerization and subsequent activation of the kinase domain through the formation of a multimeric signaling complex consisting of RET's soluble ligand glial derived neurotrophic factor (GDNF) and a membrane-bound coreceptor (GDNF family receptor α1). This complex causes autophosphorylation of tyrosine residues. As a result of this mechanism, glial family ligand mediated activation of wildtype RET is an increasingly recognized mechanism related to tumor growth and dissemination of a much broader group of cancers. (Mulligan LM., “GDNF and the RET Receptor in Cancer: New Insights and Therapeutic Potential”, Front. Physiol., 2019, 9(1873), 1-13; and Airaksinen MS, and Saarma M., “The GDNF family: signaling, biological functions and therapeutic value”, Nat Rev Neurosci., 2002, 3(5), 383-94). There are multiple protein isoforms of RET including RET9, RET51 and RET43 each of which differs in the lengths of carboxyl-terminal tails and their ability to bind SHC, GRB2, c-CBL, and SHANK3. Each RET isoform has a unique C-terminal tail sequence that recruits distinct protein complexes to mediate signals. (Lorenzo MJ, et al., “RET alternative splicing influences the interaction of activated RET with the SH2 and PTB domains of Shc, and the SH2 domain of Grb2”, Oncogene, 1997, 14, 763-771). Studies on acute myeloid leukemia (AML) have shown that AML subtypes are dependent on expression of the RET receptor tyrosine kinase (RTK), and that depletion of RET by shRNA knockdown or CRISPR / Cas9-mediated knockout leads to cell cycle arrest in the G0 / G1 phase, increased apoptosis, and reduced clonogenic activity. Analysis of known RET ligand / co-receptor pairs (GDNF / GFRA1, NRTN / GFRA2, ARTN / GFRA3, PSPN / GFRA4) by quantitative real-time PCR and shRNA knockdown indicates that RET signaling is facilitated mainly through NTRN / GFRA2 or ARTN / GFRA3. (Rudat S., et al., “The RET Receptor Tyrosine Kinase Promotes Acute Myeloid Leukemia through Protection of FLT3- ITD Mutants from Autophagic Degradation”, Blood, 2016, 128(22), 2849). The RET fusions genes are mutually exclusive with other known drivers of lung adenocarcinoma (e.g., KRAS, epidermal growth factor receptor (EGFR), EML4-anaplastic lymphoma kinase (ALK)), further supporting a role for RET as a unique driver of malignancy in these tumors. Selpercatinib (formerly LOXO-292) is a FDA approved highly selective, small molecule RET tyrosine kinase inhibitor with nanomolar potency against diverse RET alterations. Patent applications and publications describing selpercatinib include: US20190106438; US20190262322; US20180133222; Dolgin, Elie, “LOXO-292 Reins In RET-Driven Tumors”, Cancer discovery, 2018, 8(8), 904-905; Markham, Anthony, “Selpercatinib: First Approval”, Drugs (2020), 80(11), 1119-1124; Brandhuber BB, et al, “ENA-0490 The development of LOXO- 292, a potent, KDR / VEGFR2-sparing RET kinase inhibitor for treating patients with RET- dependent cancers”, AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, Munich, Germany, November 29-December 2, 2016; and Subbiah, V. et. al. “Selective RET kinase inhibition for patients with RET-altered cancers,” Ann Oncol., 2018, 29(8), 1869-1876). Pralsetinib (formerly BLU-667) is a FDA approved small molecule RET tyrosine kinase inhibitor which is used in the treatment of non-small cell lung cancer. Patent applications and publications describing pralsetinib include: 10,030,005, 11, 273,160, and Vivek Subbiah, et al., “Pan-cancer efficacy of pralsetinib in patients with RET fusion-positive solid tumors from the phase 1 / 2 ARROW trial” Nature Medicine, 2022, 28, 1640-1645. The academic and clinical interest in RET has led to the identification of several RET mutations that are clinically relevant including RET G810R, RET G810S, and RET G810C. (Solomon, et al., “RET Solvent Front Mutations Mediated Acquired Resistance to Selective RET Inhibition in RET-driven malignancies”, J Thoracic Oncolog., 2020). Treatment of patients with non-small cell lung cancer selpercatinib has been shown to cause RET mutations that infer resistances including the RET G810R, RET G810S, and RET G810C mutations. Other approved tyrosine kinase inhibitors such as sunitinib, sorafenib, ponatinib and lenvatinib have also shown some RET activity in pre-clinical trials and are currently under investigation in numerous phase II clinical trials for treatment of RET fusion positive lung adenocarcinoma (LAD). (Song M., “Progress in Discovery of KIF5B-RET Kinase Inhibitors for the Treatment of Non-Small-Cell Lung Cancer”, J Med Chem., 2015, 58(9), 3672–3681; Watson AJ., et al., “Identification of selective inhibitors of RET and comparison with current clinical candidates through development and validation of a robust screening cascade”, F1000Research 2016, 5:1005). Examples of RET inhibitor patents and patent applications include US 10,138,243; US 10,172,851; US 10,441,581; US 10,174,028; US 10,137,124; US 10,172,845; US 10,555,944; US 10,023,570; US 10,112,942; US 10,144,734; US 10,174,027; WO 2017 / 011776; WO 2017 / 026718; WO 2018 / 136661; WO2018 / 071447; WO / 2018 / 136663; WO 2019 / 126121; WO 2019 / 143991; WO 2019 / 143994; WO 2019 / 143977; and WO 2020 / 055672. C4 Therapeutics, Inc., filed patent application WO 2022 / 032026 titled “Compounds for Targeted Degradation of RET.” The application describes novel compounds which act as protein degraders for RET receptor. Despite these efforts, there remains a need for new RET modulators to treat disorders mediated by RET in hosts in need thereof, including humans. SUMMARY OF THE INVENTION Compounds and their uses and manufacture are provided that degrade the proto-oncogene tyrosine-protein kinase receptor rearranged during transfection (RET) via the ubiquitin proteasome pathway (UPP). The present invention provides compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, and Formula X, or a pharmaceutically acceptable salt thereof that include a Targeting Ligand that binds to RET, an E3 Ligase binding portion (typically via a cereblon subunit), and a Linker that covalently links the Targeting Ligand to the E3 Ligase binding portion. In certain embodiments, the Targeting Ligand is a RET Targeting Ligand described herein, the Linker is a moiety LI, and the remainder of the molecule is the Cereblon Ligand portion of the molecule. RET is widely known for its essential role in cell survival, differentiation, proliferation, migration, and chemotaxis. Thus, by degrading RET, the compounds of the present invention can be used to treat RET mediated disorders such as Hirschsprung disease, medullary thyroid cancer (MTC), thyroid carcinoma, familial medullary thyroid carcinoma, multiple endocrine neoplasia, multiple endocrine neoplasia type 2 (MEN-2, MEN-2A, MEN-2B), neuroendocrine tumors, central nervous system tumors, central hypoventilation syndrome, renal agenesis, pheochromocytoma and parathyroid hyperplasia. In another embodiment, a compound of the present invention is used to treat a disorder mediated by RET fusion proteins, overexpression, or copy number gains, such as papillary thyroid cancer, pancreatic cancer, melanoma, leukemia, acute myeloid leukemia (AML), chronic myelomonocytic leukemia, lung adenocarcinomas, lung cancer, non-small cell lung cancer (NSCLC), nonsyndromic paraganglioma, breast cancer, nonhereditary (sporadic) cancers, colorectal, or a hematologic malignancy. A compound of the present invention provided herein or its pharmaceutically acceptable salt and / or its pharmaceutically acceptable composition can be used to treat a disorder which is mediated by RET. In some embodiments, a method to treat a patient with a disorder mediated by RET is provided that includes administering an effective amount of one or more compounds as described herein, or a pharmaceutically acceptable salt thereof, to the patient, typically a human, optionally in a pharmaceutically acceptable composition. In certain aspects, the present invention provides a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, or Formula X: (I); ; ); ;

[0002] or a pharmaceutically acceptable salt thereof; wherein X3is N, CH, or CR3a; X4is N, CH, or CR3b; X5is N, CH, or CR3c; X6is N, CH, or CR3d; X6Bis CH or CR3d; wherein no more than 3 of X3, X4, X5, and X6are N; X7is N or CR1c; Q1is -NR6-, -CH2-, -O-, or -S-, wherein if X7is N then Q1is CH2; R1a, R1b, R1c, and R1dare each independently hydrogen, C1-C4alkyl, or C1-C4haloalkyl; or R1aand R1care combined to form a 1 or 2 carbon atom bridge, for example ; R3a, R3b, R3c, and R3d, are independently at each occurrence selected from the group consisting of hydrogen, hydroxyl, alkoxy, C1-C4alkyl, C1-C4haloalkyl, cycloalkyl, fluorine, chlorine, bromine, and iodine; , ,

[0003] r ; is a heteroaryl, heterocycle, or carbocycle, each of which is optionally substituted with 0, 1, 2, 3, or 4 substituents independently selected from R9; X9is NR13or O; X11is N, CH, CCH3, CF, or C1haloalkyl; X10, X16, X17, and X18are independently selected from the group consisting of N, CH, and CRA; X12, and X13are independently selected from the group consisting of N, CH, and CRB; each R4and R13is independently selected from the group consisting of hydrogen, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4haloalkyl, cycloalkyl, heteroaryl, aryl, heterocycle, -alkyl-heteroaryl, -alkyl-aryl, -alkyl-heterocycle, -C(O)R5, and -alkyl-C(O)R5, each of which C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4haloalkyl, cycloalkyl, heteroaryl, aryl, heterocycle, -alkyl-heteroaryl, -alkyl-aryl, and -alkyl-heterocycle groups is optionally substituted with 0, 1, 2, or 3 substituents independently selected from R8; R5is hydrogen, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4haloalkyl, cycloalkyl, heteroaryl, aryl, heterocycle, bicycle, -alkyl-heteroaryl, -alkyl-aryl, -alkyl-heterocycle, -OR6, or -NR6R7, each of which C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4haloalkyl, cycloalkyl, heteroaryl, aryl, heterocycle, -alkyl-heteroaryl, -alkyl-aryl, and -alkyl-heterocycle group is optionally substituted with 0, 1, 2, or 3 substituents independently selected from R10; R6and R7are independently selected at each instance from the group consisting of hydrogen, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4haloalkyl, cycloalkyl, heteroaryl, aryl, heterocycle, -alkyl-heteroaryl, -alkyl-aryl, and -alkyl-heterocycle, each of which R6and R7groups other than hydrogen is optionally substituted with 0, 1, 2, or 3 substituents independently selected from R10; R8is independently at each occurrence selected from the group consisting of hydrogen, C1-C4haloalkyl, C1-C4alkyl, halogen, -OR6, -NR6R7, -OC(O)R5, -NR6C(O)R5, -C(O)R5, and -alkyl-C(O)R5; R9is independently at each occurrence selected from the group consisting of hydrogen, aryl, -alkyl-aryl, heteroaryl, alkyl-heteroaryl, heterocycle, alkyl-heterocycle, cycloalkyl, -alkyl-cycloalkyl, C1-C4haloalkyl, C1-C4alkyl, halogen, -OR6, -NR6R7, -C(O)OR6, -C(O)NR6R7, -alkyl-C(O)OR6, and -alkyl-C(O)NR6R7, each of which aryl, -alkyl-aryl, heteroaryl, -alkyl-heteroaryl, heterocycle, -alkyl-heterocycle, -alkyl-cycloalkyl, and cycloalkyl group is optionally substituted with 0, 1, 2, or 3 substituents selected from -S(O)2alkyl, C1-C4haloalkyl, C1- C4alkyl, halogen, -OR6, -NR6R7, -C(O)OR6, -C(O)NR6R7, -alkyl-C(O)OR6, and -alkyl- C(O)NR6R7; R10is independently at each occurrence selected from the group consisting of hydrogen, halogen, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4haloalkyl, cycloalkyl, heteroaryl, aryl, heterocycle, -alkyl-heteroaryl, -alkyl-aryl, halogen, and -alkyl-heterocycle; R11is hydrogen, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4haloalkyl, cycloalkyl, heteroaryl, aryl, heterocycle, -alkyl-heteroaryl, -alkyl-aryl, or -alkyl-heterocycle; each RAand RBis independently at each occurrence selected from the group consisting of hydrogen, C1-C4haloalkyl, C1-C4alkyl, halogen, cyano, nitro, -OR6, -NR6R7, -C(O)OR6, and -C(O)NR6R7; R14is hydrogen, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4haloalkyl, cycloalkyl, heteroaryl, aryl, heterocycle, -alkyl-heteroaryl, -alkyl-aryl, -alkyl-heterocycle, -C(O)R5, -alkyl-C(O)R5, -OC(O)R5, or -NR6C(O)R5, each of which C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4haloalkyl, cycloalkyl, heteroaryl, aryl, heterocycle, -alkyl-heteroaryl, -alkyl-aryl, and -alkyl- heterocycle groups is optionally substituted with 0, 1, 2, or 3 substituents independently selected from R8; and Linker is a bivalent linking group, for example, a bivalent linking group of Formula LI. In certain embodiments Linker is of formula: wherein, X1and X2are independently at each occurrence selected from bond, heterocycle, NR2, C(R2)2, O, C(O), and S; R2is independently at each occurrence selected from the group consisting of hydrogen, alkyl, aliphatic, heteroaliphatic, heterocycle, aryl, heteroaryl, -C(O)H, -C(O)OH, -C(O)alkyl, -C(O)Oalkyl, -C(O)(aliphatic, aryl, heteroaliphatic or heteroaryl), -C(O)O(aliphatic, aryl, heteroaliphatic, or heteroaryl), alkene, and alkyne; R20, R21, R22, R23, and R24are independently at each occurrence selected from the group consisting of a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR2-, -NR2C(O)-, -O-, -S-, -NR2-, -P(O)(OR26)O-, -P(O)(OR26)-, bicycle, alkene, alkyne, haloalkyl, alkoxy, aryl, heterocycle, aliphatic, heteroaliphatic, heteroaryl, lactic acid, glycolic acid, and carbocycle; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R40; R26is independently at each occurrence selected from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocycle, aliphatic and heteroaliphatic; and R40is independently at each occurrence selected from the group consisting of hydrogen, alkyl, alkene, alkyne, fluoro, bromo, chloro, hydroxyl, alkoxy, azide, amino, cyano, -NH(aliphatic, including alkyl), -N(aliphatic, including alkyl)2, -NHSO2(aliphatic, including alkyl), -N(aliphatic, including alkyl)SO2alkyl, -NHSO2(aryl, heteroaryl or heterocycle), -N(alkyl)SO2(aryl, heteroaryl or heterocycle), -NHSO2alkenyl, -N(alkyl)SO2alkenyl, -NHSO2alkynyl, -N(alkyl)SO2alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocycle, and cycloalkyl. Every combination of variables, substituents, embodiments, and the compounds that result from these combinations, is deemed specifically and individually disclosed, as such depiction is for convenience of space only and not intended to describe only a genus or even a subgenus of compounds. In certain embodiments, a compound of the present invention penetrates the blood brain barrier and can be used for the treatment of a cancer that has metastasized to the brain or a CNS involved cancer. In certain embodiments, the compound of the present invention degrades multiple mutants of RET and degrades wildtype RET as well (i.e., the compound is a pan-RET degrader). In certain embodiments, a method of treatment is provided comprising administering an effective amount of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, or Formula X or a pharmaceutically acceptable salt thereof to a patient in need thereof, for example, a human, optionally in a pharmaceutically acceptable carrier. For example, in certain embodiments, a compound Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, or Formula X, is administered to a human to treat a cancer. In certain embodiments, a compound of the present invention is used to treat sporadic medullary thyroid cancer. In certain embodiments, a compound of the present invention is used to treat non-sporadic medullary thyroid cancer. In certain embodiments, a compound of the present invention is used to treat lung cancer, for example, non-small cell lung cancer. In certain embodiments, the compound of the present invention provides one or more, and even may provide multiple advantages over traditional treatment with a RET ligand. For example, the RET degrading compound of the present invention may a) overcome resistance in certain cases; b) prolong the kinetics of drug effect by destroying the protein, thus requiring resynthesis of the protein even after the compound has been metabolized; c) target all functions of a protein at once rather than a specific catalytic activity or binding event; and / or d) have increased potency compared to inhibitors due to the possibility of the small molecule acting catalytically. In certain embodiments, a compound of the present invention is used to treat a tumor or cancer with a RET protein that has mutated. In certain embodiments, a compound of the present invention is used to treat a tumor or cancer with a RET protein solvent front mutation, for example, G810R, G810S, or G810C. In certain embodiments, a compound of the present invention is used to treat a tumor or cancer with a RET G810R mutation. In certain embodiments, a compound of the present invention is used to treat a tumor or cancer with a RET G810S mutation. In certain embodiments, a compound of the present invention is used to treat a tumor or cancer with a RET G810C mutation. In certain embodiments, a compound of the present invention is used to treat a tumor or cancer in the CNS with a RET protein that has mutated. In certain embodiments, a compound of the present invention is used to treat a tumor or cancer in the CNS with a RET protein solvent front mutation, for example, G810R, G810S, or G810C. In certain embodiments, a compound of the present invention is used to treat a tumor or cancer in the CNS with a RET G810R mutation. In certain embodiments, a compound of the present invention is used to treat a tumor or cancer in the CNS with a RET G810S mutation. In certain embodiments, a compound of the present invention is used to treat a tumor or cancer in the CNS with a RET G810C mutation. In certain embodiments, the tumor or cancer in the CNS metastasized from a primary cancer elsewhere in the body. In other embodiments the tumor or cancer in the CNS is a primary cancer such as glioblastoma or head and neck cancer. In certain embodiments, a compound of the present invention can be used to treat a RET mediated disorder without first testing its mutation status. In certain embodiments, a compound of the present invention is used to treat a tumor or cancer with a RET protein gatekeeper mutation, for example, V804L or V804M. In certain embodiments, a compound of the present invention is used to treat a tumor or cancer with a RET protein activating mutation. In one aspect the RET activating mutation is M918T. In certain embodiments, a compound of the present invention is used to treat a drug resistant RET altered tumor or cancer. In certain embodiments, the tumor is resistant to a drug selected from selpercatinib, pralsetinib, TPX-0046, and / or selumetinib. In certain embodiments, a compound of the present invention is used to treat a tumor or cancer with a RET protein fused to another protein, for example KIF5B-RET fusion, CCDC6-RET fusion, or NCOA4-RET fusion. In certain embodiments, a compound of the present invention is used to treat a tumor or cancer with a KIF5B-RET fusion. In certain embodiments, a compound of the present invention is used to treat a tumor or cancer with a CCDC6-RET fusion or NCOA4- RET fusion. In certain embodiments, a compound of the present invention is used to treat a tumor or cancer with a CCDC6-RET fusion. In certain embodiments, a compound of the present invention is used to treat a tumor or cancer with a NCOA4-RET fusion In certain embodiments, a compound of the present invention is used to treat a tumor or cancer that is resistant to RET inhibitors, for example selpercatinib, pralsetinib, and / or TPX-0046. In certain embodiments, a compound of the present invention is used to treat a tumor or cancer that has acquired resistance to a RET inhibitor, for example selpercatinib, pralsetinib, and / or TPX- 0046. In certain embodiments, a compound of the present invention provides an improved efficacy and / or safety profile relative to known RET inhibitors. In certain embodiments, a bifunctional compound of the present invention has one or more advantages in the treatment of a RET mediated disorders than using the targeting ligand portion alone. In certain embodiments, less of a bifunctional compound described herein is needed for the treatment of a RET mediated disorder, than by mole of the targeting ligand portion alone. In certain embodiments, a bifunctional compound of the present invention has less of at least one side-effect in the treatment of a RET mediated disorder, than by mole of the targeting ligand portion alone. In certain embodiments, a less frequent dose regimen of a selected compounds described herein is needed for the treatment of a RET mediated disorders, than the dose by mole of the targeting ligand portion alone. Another aspect of the present invention provides a compound as described herein, or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition, for use in the manufacture of a medicament for inhibiting or preventing a disorder mediated by RET or for modulating or decreasing the amount of RET. Another aspect of the present invention provides a compound as described herein, or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, or solvate thereof, or its pharmaceutical composition, for use in the manufacture of a medicament for treating or preventing a disease mediated by RET. In certain embodiments, a selected compound as described herein is useful to treat a disorder comprising an abnormal cellular proliferation, such as a tumor or cancer, wherein RET is an oncogenic protein or a signaling mediator of the abnormal cellular proliferative pathway and its degradation decreases abnormal cell growth. In certain embodiments, the selected compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, or Formula X, or its pharmaceutically acceptable salt thereof, has at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., enriched. In certain embodiments, the compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, or Formula X, or its pharmaceutically acceptable salt thereof, includes a deuterium atom or multiple deuterium atoms. Other features and advantages of the present application will be apparent from the following detailed description. The present invention thus includes at least the following features: (a) A compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, or Formula X, as described herein, or a pharmaceutically acceptable salt or isotopic derivative (including a deuterated derivative) thereof; (b) A method to treat a RET mediated disorder, such as an abnormal cellular proliferation, including cancer, comprising administering an effective amount of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, or Formula X, or pharmaceutically acceptable salt thereof, as described herein, to a patient in need thereof; (c) A compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, or Formula X, or a pharmaceutically acceptable salt, or isotopic derivative (including a deuterated derivative) thereof for use in the treatment of a disorder that is mediated by RET, for example an abnormal cellular proliferation such as a tumor or cancer; (d) Use of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, or Formula X, or a pharmaceutically acceptable salt thereof, in an effective amount in the treatment of a patient in need thereof, typically a human, with a RET mediated disorder, for example an abnormal cellular proliferation such as a tumor or cancer; (e) Use of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, or Formula X, or a pharmaceutically acceptable salt or isotopic derivative (including a deuterated derivative) thereof in the manufacture of a medicament for the treatment of a RET mediated disorder, for example an abnormal cellular proliferation such as a tumor or cancer; (f) A pharmaceutical composition comprising an effective patient-treating amount of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, or Formula X, or a pharmaceutically acceptable salt, isotopic derivative thereof; and optionally a pharmaceutically acceptable carrier or diluent; (g) A compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, or Formula X, as described herein as a mixture of enantiomers or diastereomers (as relevant), including as a racemate; (h) A compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, or Formula X, as described herein in enantiomerically or diastereomerically (as relevant) enriched form, including an isolated enantiomer or diastereomer (i.e., greater than about 85, 90, 95, 97, or 99% pure); and (i) A process for the preparation of therapeutic products that contain an effective amount of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, or Formula X, or a pharmaceutically acceptable salt thereof, as described herein. DETAILED DESCRIPTION OF THE INVENTION I. DEFINITIONS Compounds are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. The compounds in any of the Formulas described herein may be in the form of a racemate, enantiomer, mixture of enantiomers, diastereomer, mixture of diastereomers, tautomer, N-oxide, isomer; such as rotamer, as if each is specifically described unless specifically excluded by context. The terms “a” and “an” do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item. The term “or” means “and / or”. Recitation of ranges of values are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The endpoints of all ranges are included within the range and independently combinable. All methods described herein can be performed in a suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of examples, or exemplary language (e.g., “such as”), is intended merely to better illustrate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. The present invention includes compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, or Formula X, or its pharmaceutically acceptable salt thereof, with at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., enriched. Isotopes are atoms having the same atomic number but different mass numbers, i.e., the same number of protons but a different number of neutrons. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine such as2H,3H,11C,13C,14C,15N,17O,18O,18F31P,32P,35S,36Cl, and125I respectively. In one non- limiting embodiment, isotopically labelled compounds can be used in metabolic studies (with, for example14C), reaction kinetic studies (with, for example2H or3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an18F labeled compound may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. Isotopic substitutions, for example deuterium substitutions, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted with deuterium. In certain embodiments, the isotope is 90, 95 or 99% or more enriched in an isotope at any location of interest. In one non-limiting embodiment, deuterium is 90, 95 or 99% enriched at a desired location. In one non-limiting embodiment, the substitution of a hydrogen atom for a deuterium atom can be provided in any compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, or Formula X, or a pharmaceutically acceptable salt thereof. In one non-limiting embodiment, the substitution of a hydrogen atom for a deuterium atom occurs within one or more groups selected from any of R’s or variables described herein, Linker, and Targeting Ligand. For example, when any of the groups are, or contain for example through substitution, methyl, ethyl, or methoxy, the alkyl residue may be deuterated (in non-limiting embodiments, CDH2, CD2H, CD3, CH2CD3, CD2CD3, CHDCH2D, CH2CD3, CHDCHD2, OCDH2, OCD2H, or OCD3 etc.). In certain other embodiments, when two substituents are combined to form a cycle, the unsubstituted carbons may be deuterated. The compound of the present invention may form a solvate with a solvent (including water). Therefore, in one non-limiting embodiment, the invention includes a solvated form of the compound. The term "solvate" refers to a molecular complex of a compound of the present invention (including a salt thereof) with one or more solvent molecules. Non-limiting examples of solvents are water, ethanol, isopropanol, dimethyl sulfoxide, acetone and other common organic solvents. The term "hydrate" refers to a molecular complex comprising a compound of the invention and water. Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent may be isotopically substituted, e.g., D2O, d6-acetone, d6-DMSO (dimethyl sulfoxide). A solvate can be in a liquid or solid form. A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -(C=O)NH2is attached through carbon of the carbonyl (C=O) group. “Alkyl” is a branched, straight chain, or cyclic saturated aliphatic hydrocarbon group. Unless otherwise indicated “alkyl” refers to a C1-C6alkyl. In certain embodiments, the alkyl is C1- C2, C1-C3, C1-C4, C1-C5, or C1-C6. The specified ranges as used herein indicate an alkyl group having each member of the range described as an independent species. For example, the term C1- C6alkyl as used herein indicates a straight or branched alkyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that each of these is described as an independent species and therefore each subset is considered separately disclosed. For example, the term C1-C4 alkyl as used herein indicates a straight or branched alkyl group having from 1, 2, 3, or 4 carbon atoms and is intended to mean that each of these is described as an independent species. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t- butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2- dimethylbutane, and 2,3-dimethylbutane. In an alternative embodiment, the alkyl group is optionally substituted. The term “alkyl” also encompasses cycloalkyl or carbocyclic groups. For example, when a term is used that includes “alk” then “cycloalkyl” or “carbocyclic” can be considered part of the definition, unless unambiguously excluded by the context. For example, and without limitation, the terms alkyl, alkoxy, haloalkyl, etc., can all be considered to include the cyclic forms of alkyl, unless unambiguously excluded by context. In certain embodiments “alkyl” is a C1-C6alkyl, C1-C5alkyl, C1-C4alkyl, C1-C3alkyl, or C1- C2alkyl. In certain embodiments “alkyl” has one carbon. In certain embodiments “alkyl” has two carbons. In certain embodiments “alkyl” has three carbons. In certain embodiments “alkyl” has four carbons. In certain embodiments “alkyl” has five carbons. In certain embodiments “alkyl” has six carbons. Non-limiting examples of “alkyl” include: methyl, ethyl, propyl, butyl, pentyl, and hexyl. Additional non-limiting examples of “alkyl” include: isopropyl, isobutyl, isopentyl, and isohexyl. Additional non-limiting examples of “alkyl” include: sec-butyl, sec-pentyl, and sec-hexyl. Additional non-limiting examples of “alkyl” include: tert-butyl, tert-pentyl, and tert-hexyl. Additional non-limiting examples of “alkyl” include: neopentyl, 3-pentyl, and active pentyl. In an alternative embodiment “alkyl” is “optionally substituted” with 1, 2, 3, or 4 substituents. In certain embodiments “cycloalkyl” is a C3-C8cycloalkyl, C3-C7cycloalkyl, C3- C6cycloalkyl, C3-C5cycloalkyl, C3-C4cycloalkyl, C4-C8cycloalkyl, C5-C8cycloalkyl, or C6- C8cycloalkyl. In certain embodiments “cycloalkyl” is a bridged cycloalkyl. In certain embodiments “cycloalkyl” is a spiro cycloalkyl. In certain embodiments “cycloalkyl” has three carbons. In certain embodiments “cycloalkyl” has four carbons. In certain embodiments “cycloalkyl” has five carbons. In certain embodiments “cycloalkyl” has six carbons. In certain embodiments “cycloalkyl” has seven carbons. In certain embodiments “cycloalkyl” has eight carbons. In certain embodiments “cycloalkyl” has nine carbons. In certain embodiments “cycloalkyl” has ten carbons. Non-limiting examples of “cycloalkyl” include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl. Additional non-limiting examples of “cycloalkyl” include dihydro-indene and tetrahydronaphthalene wherein the point of attachment for each group is on the cycloalkyl ring. For example: is an “cycloalkyl” group. However, group. In an alternative embodiment “cycloalkyl” is a “optionally substituted” with 1, 2, 3, or 4 substituents. “Alkenyl” is a linear or branched aliphatic hydrocarbon groups having one or more carbon- carbon double bonds that may occur at a stable point along the chain. Unless otherwise indicated “alkenyl” refers to a C2-C6alkenyl. The specified ranges as used herein indicate an alkenyl group having each member of the range described as an independent species, as described above for the alkyl moiety. Examples of alkenyl radicals include, but are not limited to ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl. The term “alkenyl” also embodies “cis” and “trans” alkenyl geometry, or alternatively, “E” and “Z” alkenyl geometry. In an alternative embodiment, the alkenyl group is optionally substituted. The term “Alkenyl” also encompasses cycloalkyl or cycloalkyl groups possessing at least one point of unsaturation. In an alternative embodiment “alkenyl” is “optionally substituted” with 1, 2, 3, or 4 substituents. “Alkynyl” is a branched or straight chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds that may occur at any stable point along the chain. Unless otherwise indicated “alkynyl” refers to a C2-C6alkynyl. The specified ranges as used herein indicate an alkynyl group having each member of the range described as an independent species, as described above for the alkyl moiety. Examples of alkynyl include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2- hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl. In an alternative embodiment, the alkynyl group is optionally substituted. The term “Alkynyl” also encompasses cycloalkyl or cycloalkyl groups possessing at least one triple bond. In an alternative embodiment “alkynyl” is “optionally substituted” with 1, 2, 3, or 4 substituents. “Alkylene” is a bivalent saturated hydrocarbon. Alkylenes, for example, can be a 1, 2, 3, 4, 5, 6, 7 to 8 carbon moiety, 1 to 6 carbon moiety, or an indicated number of carbon atoms, for example C1-C2alkylene, C1-C3alkylene, C1-C4alkylene, C1-C5alkylene, or C1-C6alkylene. “Alkenylene” is a bivalent hydrocarbon having at least one carbon-carbon double bond. Alkenylenes, for example, can be a 2 to 8 carbon moiety, 2 to 6 carbon moiety, or an indicated number of carbon atoms, for example C2-C4alkenylene. “Alkynylene” is a bivalent hydrocarbon having at least one carbon-carbon triple bond. Alkynylenes, for example, can be a 2 to 8 carbon moiety, a 2 to 6 carbon moiety, or an indicated number of carbon atoms, for example C2-C4alkynylene. “Halo” and “Halogen” refers independently to fluorine, chlorine, bromine or iodine. “Haloalkyl” is a branched or straight-chain alkyl groups substituted with 1 or more halo atoms described above, up to the maximum allowable number of halogen atoms. Unless otherwise indicated “haloalkyl” refers to a C1-C4haloalkyl. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. “Perhaloalkyl” means an alkyl group having all hydrogen atoms replaced with halogen atoms. Examples include but are not limited to, trifluoromethyl and pentafluoroethyl. In certain embodiments “haloalkyl” is a C1-C4haloalkyl, C1-C3haloalkyl, or C1-C2haloalkyl. In certain embodiments “haloalkyl” has one carbon. In certain embodiments “haloalkyl” has one carbon and one halogen. In certain embodiments “haloalkyl” has one carbon and two halogens. In certain embodiments “haloalkyl” has one carbon and three halogens. In certain embodiments “haloalkyl” has two carbons. In certain embodiments “haloalkyl” has three carbons. In certain embodiments “haloalkyl” has four carbons. In certain embodiments “haloalkyl” has five carbons. In certain embodiments “haloalkyl” has six carbons. Non-limiting examples of “haloalkyl” include: , , and . Additional non-limiting examples of “haloalkyl” include: , , , Additional non-limiting examples of “haloalkyl” include: , , and . Additional non-limiting examples of “haloalkyl” include: , , and . “Chain” indicates a linear chain to which all other chains, long or short or both, may be regarded as being pendant. Where two or more chains could equally be considered to be the main chain, “chain” refers to the one which leads to the simplest representation of the molecule. “Haloalkoxy” indicates a haloalkyl group as described herein attached through an oxygen bridge (oxygen of an alcohol radical). “Heterocycloalkyl” is an alkyl group as described herein substituted with a heterocyclo group as described herein. “Arylalkyl” is an alkyl group as described herein substituted with an aryl group as described herein. Non-limiting examples of “arylalkyl” include: . aryl group. Non-limiting examples of “arylalkyl” include: In certain embodiments the “arylalkyl” refers to a 3-carbon alkyl group substituted with an aryl group. “Heteroarylalkyl” is an alkyl group as described herein substituted with a heteroaryl group as described herein. As used herein, “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6–14aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C6aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“C10 aryl”; e.g., naphthyl such as 1– naphthyl and 2–naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“C14aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocycle groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. The one or more fused carbocyclyl or heterocycle groups can be 4 to 7 or 5 to 7-membered saturated or partially unsaturated carbocyclyl or heterocycle groups that optionally contain 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, phosphorus, sulfur, silicon and boron, to form, for example, a 3,4- methylenedioxyphenyl group. In one non-limiting embodiment, aryl groups are pendant. An example of a pendant ring is a phenyl group substituted with a phenyl group. In an alternative embodiment, the aryl group is optionally substituted as described above. In certain embodiments, the aryl group is an unsubstituted C6–14aryl. In certain embodiments, the aryl group is a substituted C6–14 aryl. In certain embodiments “aryl” is a 6-carbon aromatic group (phenyl). In certain embodiments “aryl” is a 10-carbon aromatic group (napthyl). In certain embodiments “aryl” is a 6-carbon aromatic group fused to a heterocycle wherein the point of attachment is the aryl ring. Non-limiting examples of “aryl” include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran wherein the point of attachment for each group is on the aromatic ring. F up. In certain embodiments “aryl” is a 6-carbon aromatic group fused to a cycloalkyl wherein the point of attachment is the aryl ring. Non-limiting examples of “aryl” include dihydro-indene and tetrahydronaphthalene wherein the point of attachment for each group is on the aromatic ring. F . In an alternative embodiment “aryl” is “optionally substituted” with 1, 2, 3, or 4 substituents. The term “heterocyclyl”, “heterocycle”, and “heterocyclo” includes saturated, and partially saturated heteroatom-containing ring radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. Heterocyclic rings comprise monocyclic 3, 4, 5, 6, 7, 8, 9, or 10 membered rings, as well as 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14 membered bicyclic ring systems (which can include bridged fused and spiro-fused bicyclic ring systems). It does not include rings containing -O-O-, -O-S- or -S-S- portions. Examples of saturated heterocyclo groups include saturated 3, 4, 5, or 6-membered heteromonocyclic groups containing 1, 2, 3, or 4 nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl]; saturated 3, 4, 5, or 6- membered heteromonocyclic group containing 1 or 2 oxygen atoms and 1, 2, or 3 nitrogen atoms [e.g. morpholinyl]; saturated 3, 4, 5, or 6-membered heteromonocyclic group containing 1 or 2 sulfur atoms and 1, 2, or 3 nitrogen atoms [e.g., thiazolidinyl]. Examples of partially saturated heterocycle radicals include, but are not limited to, dihydrothienyl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl. Examples of partially saturated and saturated heterocyclo groups include, but are not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro- benzo[l,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2-dihydroquinolyl, 1,2,3,4- tetrahydro-isoquinolyl, 1 ,2,3,4- tetrahydro-quinolyl, 2,3,4,4a,9,9a-hexahydro-lH-3-aza-fluorenyl, 5,6,7- trihydro-l,2,4- triazolo[3,4-a]isoquinolyl, 3,4-dihydro-2H-benzo[l,4]oxazinyl, benzo[l,4]dioxanyl, 2,3- dihydro- lH-lλ’-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryl, isoquinolin-1(2H)-onyl, benzo[d]oxazol-2(3H)-onyl, 1,3-dihydro-2H-benzo[d]midazol-2-onyl, benzo[d]thiazole-2(3H)- onyl, 1,2-dihydro-3H-pyrazol-3-onyl, 2(1H)-pyridinonyl, 2-piperazinonyl, indolinyl, and dihydrothiazolyl. In certain embodiments said “heterocycle” group may be optionally substituted, for example, with 1, 2, 3, 4 or more substituents that include but are not limited to, hydroxyl, Boc, halo, haloalkyl, cyano, alkyl, aralkyl, oxo, alkoxy, and amino. The term “heterocyclyl”, “heterocycle”, and “heterocyclo” groups also include moieties where heterocycle radicals are fused / condensed with aryl or heteroaryl radicals such as unsaturated condensed heterocycle group containing 1, 2, 3, 4, or 5 nitrogen atoms, for example, indoline, isoindoline, unsaturated condensed heterocycle group containing 1 or 2 oxygen atoms and 1, 2, or 3 nitrogen atoms, unsaturated condensed heterocycle group containing 1 or 2 sulfur atoms and 1, 2, or 3 nitrogen atoms, and saturated, partially unsaturated and unsaturated condensed heterocycle group containing 1 or 2 oxygen or sulfur atoms. In certain embodiments “heterocycle” refers to a cyclic ring with one nitrogen and 3, 4, 5, 6, 7, or 8 carbon atoms. In certain embodiments “heterocycle” refers to a cyclic ring with one nitrogen and one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms. In certain embodiments “heterocycle” refers to a cyclic ring with two nitrogens and 3, 4, 5, 6, 7, or 8 carbon atoms. In certain embodiments “heterocycle” refers to a cyclic ring with one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms. In certain embodiments “heterocycle” refers to a cyclic ring with one sulfur and 3, 4, 5, 6, 7, or 8 carbon atoms. Non-limiting examples of “heterocycle” include aziridine, oxirane, thiirane, azetidine, 1,3- diazetidine, oxetane, and thietane. Additional non-limiting examples of “heterocycle” include pyrrolidine, 3-pyrroline, 2- pyrroline, pyrazolidine, and imidazolidine. Additional non-limiting examples of “heterocycle” include tetrahydrofuran, 1,3-dioxolane, tetrahydrothiophene, 1,2-oxathiolane, and 1,3-oxathiolane. Additional non-limiting examples of “heterocycle” include piperidine, piperazine, tetrahydropyran, 1,4-dioxane, thiane, 1,3-dithiane, 1,4-dithiane, morpholine, and thiomorpholine. Additional non-limiting examples of “heterocycle” include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran wherein the point of attachment for each group is on the heterocycle ring. For example, group. However, group. Non-limiting examples of “heterocycle” also include: .Additional non-limiting examples of “heterocycle” include: .Additional non-limiting examples of “heterocycle” include: .Non-limiting examples of “heterocycle” also include: . Additional non-limiting examples of “heterocycle” include: . Additional non-limiting examples of “heterocycle” include: In an alternative embodiment “heterocycle” is “optionally substituted” with 1, 2, 3, or 4 substituents. The term “heteroaryl” denotes a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) and 1, 2, 3, 4, 5, or 6, heteroatoms independently selected from O, N, and S, wherein the ring nitrogen and sulfur atom(s) are optionally oxidized, and nitrogen atom(s) are optionally quaternized. Examples include, but are not limited to, unsaturated 5 to 6 membered heteromonocyclyl groups containing 1, 2, 3, or 4 nitrogen atoms, such as pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-l,2,4-triazolyl, 1H-1 ,2,3-triazolyl, 2H-l,2,3- triazolyl]; unsaturated 5- or 6-membered heteromonocyclic groups containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5- or 6-membered heteromonocyclic groups containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- or 6-membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl]; unsaturated 5 or 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl]. Additional examples include 8-, 9-, or 10-membered heteroaryl bicyclic groups such as indazolyl, indolyl, imidazo[1,5-a]pyridinyl, benzimidazolyl, 4(3H)-quinazolinonyl, quinolinyl, isoquinolinyl, isoindolyl, thienothienyl, indolizinyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, benzoxazolyl, benzothiazolyl, purinyl, coumarinyl, cinnolinyl, and triazolopyridinyl. In certain embodiments “heteroaryl” is a 5 membered aromatic group containing 1, 2, 3, or 4 nitrogen atoms. Non-limiting examples of 5 membered “heteroaryl” groups include pyrrole, furan, thiophene, pyrazole, imidazole, triazole, tetrazole, isoxazole, oxazole, oxadiazole, oxatriazole, isothiazole, thiazole, thiadiazole, and thiatriazole. Additional non-limiting examples of 5 membered “heteroaryl” groups include: , In certain embodiments “heteroaryl” is a 6 membered aromatic group containing 1, 2, or 3 nitrogen atoms (i.e., pyridinyl, pyridazinyl, triazinyl, pyrimidinyl, and pyrazinyl). Non-limiting examples of 6 membered “heteroaryl” groups with 1 or 2 nitrogen atoms include: . In certain embodiments “heteroaryl” is a 9 membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur. Non-limiting examples of “heteroaryl” groups that are bicyclic include indole, benzofuran, isoindole, indazole, benzimidazole, azaindole, azaindazole, purine, isobenzofuran, benzothiophene, benzoisoxazole, benzoisothiazole, benzooxazole, and benzothiazole. Additional non-limiting examples of “heteroaryl” groups that are bicyclic include: . Additional non-limiting examples of “heteroaryl” groups that are bicyclic include: . Additional non-limiting examples of “heteroaryl” groups that are bicyclic include: . In certain embodiments “heteroaryl” is a 10 membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur. Non-limiting examples of “heteroaryl” groups that are bicyclic include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, and naphthyridine. Additional non-limiting examples of “heteroaryl” groups that are bicyclic include: . In an alternative embodiment “heteroaryl” is “optionally substituted” with 1, 2, 3, or 4 substituents. The term “bicycle” refers to a ring system wherein two rings are fused together and each ring is independently selected from carbocycle, heterocycle, aryl, and heteroaryl. Non-limiting examples of bicycle groups include: , When the term “bicycle” is used in the context of a bivalent residue such as Linker the attachment points can be on separate rings or on the same ring. In certain embodiments both attachment points are on the same ring. In certain embodiments both attachment points are on different rings. Non-limiting examples of bivalent bicycle groups include: . In an alternative embodiment “bicycle” is “optionally substituted” with 1, 2, 3, or 4 substituents. The term “optionally substituted” denotes the substitution of a group herein by a moiety including, but not limited to, C1-C10alkyl, C2-C10alkenyl, C2-C10alkynyl, C3-C12cycloalkyl, C3- C12 cycloalkenyl, C1–C12 heterocycloalkyl, C3-C12 heterocycloalkenyl, C1-C10 alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, amino, C1-C10 alkylamino, C1–C10 dialkylamino, arylamino, diarylamino, C1-C10alkylsulfonamino, arylsulfonamino, C1-C10alkylimino, arylimino, C1-C10alkylsulfonimino, arylsulfonimino, hydroxyl, halo, thio, C1-C10alkylthio, arylthio, C1-C10alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothioacyl, amidino, guanidine, ureido, cyano, nitro, azido, acyl, thioacyl, acyloxy, carboxyl, and carboxylic ester. In one alternative embodiment any suitable group may be present on a “substituted” or “optionally substituted” position if indicated that forms a stable molecule and meets the desired purpose of the invention and includes, but is not limited to, e.g., halogen (which can independently be F, Cl, Br or I); cyano; hydroxyl; nitro; azido; alkanoyl (such as a C2-C6alkanoyl group); carboxamide; alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy such as phenoxy; thioalkyl including those having one or more thioether linkages; alkylsulfinyl; alkylsulfonyl groups including those having one or more sulfonyl linkages; aminoalkyl groups including groups having more than one N atoms; aryl (e.g., phenyl, biphenyl, naphthyl, or the like, each ring either substituted or unsubstituted); arylalkyl having for example, 1 to 3 separate or fused rings and from 6 to about 14 or 18 ring carbon atoms, with benzyl being an exemplary arylalkyl group; arylalkoxy, for example, having 1 to 3 separate or fused rings with benzyloxy being an exemplary arylalkoxy group; or a saturated or partially unsaturated heterocycle having 1 to 3 separate or fused rings with one or more N, O or S atoms, or a heteroaryl having 1 to 3 separate or fused rings with one or more N, O or S atoms, e.g. coumarinyl, quinolinyl, isoquinolinyl, quinazolinyl, pyridyl, pyrazinyl, pyrimidinyl, furanyl, pyrrolyl, thienyl, thiazolyl, triazinyl, oxazolyl, isoxazolyl, imidazolyl, indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, and pyrrolidinyl. Such groups may be further substituted, e.g., with hydroxy, alkyl, alkoxy, halogen and amino. In certain embodiments “optionally substituted” includes one or more substituents independently selected from halogen, hydroxyl, amino, cyano, -CHO, -COOH, -CONH2, alkyl including C1-C6alkyl, alkenyl including C2-C6alkenyl, alkynyl including C2-C6alkynyl, -C1- C6alkoxy, alkanoyl including C2-C6alkanoyl, C1-C6alkylester, (mono- and di-C1- C6alkylamino)C0-C2alkyl, haloalkyl including C1-C6haloalkyl, hydoxyC1-C6alkyl, ester, carbamate, urea, sulfonamide,-C1-C6alkyl(heterocyclo), C1-C6alkyl(heteroaryl), -C1-C6alkyl(C3- C7cycloalkyl), O-C1-C6alkyl(C3-C7cycloalkyl), B(OH)2, phosphate, phosphonate and haloalkoxy including C1-C6haloalkoxy. In some embodiments, the suitable group present on a “substituted” or “optionally substituted” is divalent including, but not limited to, oxo (=O), =S, =CH2, etc. The suitable group on a “substituted” or “optional substituted” position may be monovalent, divalent, or trivalent such that it forms a stable molecule and meets the desired purpose of the invention. In certain embodiments, a group described herein that can be substituted with 1, 2, 3, or 4 substituents is substituted with one substituent. In certain embodiments, a group described herein that can be substituted with 1, 2, 3, or 4 substituents is substituted with two substituents. In certain embodiments, a group described herein that can be substituted with 1, 2, 3, or 4 substituents is substituted with three substituents. In certain embodiments, a group described herein that can be substituted with 1, 2, 3, or 4 substituents is substituted with four substituents. “Aliphatic” refers to a saturated or unsaturated, straight, branched, or cyclic hydrocarbon. "Aliphatic" is intended herein to include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties. In certain embodiments, "aliphatic" is used to indicate those aliphatic groups having 1-6 carbon atoms. The aliphatic chain can be, for example, mono-unsaturated, di- unsaturated, tri-unsaturated, or polyunsaturated, or alkynyl. Unsaturated aliphatic groups can be in a cis or trans configuration. In certain embodiments, the aliphatic group contains from 1 to about 12 carbon atoms, more generally from 1 to about 6 carbon atoms or from 1 to about 4 carbon atoms. In certain embodiments, the aliphatic group contains from 1 to about 8 carbon atoms. In certain embodiments, the aliphatic group is C1-C2, C1-C3, C1-C4, C1-C5 or C1-C6. The specified ranges as used herein indicate an aliphatic group having each member of the range described as an independent species. For example, the term C1-C6aliphatic as used herein indicates a straight or branched alkyl, alkenyl, or alkynyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that each of these is described as an independent species. For example, the term C1-C4 aliphatic as used herein indicates a straight or branched alkyl, alkenyl, or alkynyl group having from 1, 2, 3, or 4 carbon atoms and is intended to mean that each of these is described as an independent species. In certain embodiments, the aliphatic group is substituted with one or more functional groups that results in the formation of a stable moiety. The term “heteroaliphatic” refers to an aliphatic moiety that contains at least one heteroatom in the chain, for example, a nitrogen, carbonyl, oxo, thio, phosphorus, silicon, or boron atoms in place of a carbon atom. In certain embodiments, the only heteroatom is nitrogen. In certain embodiments, the only heteroatom is oxygen. In certain embodiments, the only heteroatom is sulfur. “Heteroaliphatic" is intended herein to include, but is not limited to, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, and heterocycloalkynyl moieties. In certain embodiments, "heteroaliphatic" is used to indicate a heteroaliphatic group (cyclic, acyclic, substituted, unsubstituted, branched or unbranched) having 1-6 carbon atoms and 1, 2, 3, or 4 heteroatoms. In certain embodiments, the heteroaliphatic group is optionally substituted in a manner that results in the formation of a stable moiety. Nonlimiting examples of heteroaliphatic moieties are polyethylene glycol, polyalkylene glycol, amide, polyamide, polylactide, polyglycolide, thioether, ether, alkyl-heterocycle-alkyl, -O-alkyl-O-alkyl, alkyl-O- haloalkyl, etc. A “dosage form” means a unit of administration of an active agent. Examples of dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, implants, particles, spheres, creams, ointments, suppositories, inhalable forms, transdermal forms, buccal, sublingual, topical, gel, mucosal, and the like. A “dosage form” can also include an implant, for example an optical implant. An “effective amount” as used herein, means an amount which provides a therapeutic or prophylactic benefit. As used herein “endogenous” refers to any material from or produced inside an organism, cell, tissue or system. As used herein, the term “exogenous” refers to any material introduced from or produced outside an organism, cell, tissue or system. By the term “modulating,” as used herein, is meant mediating a detectable increase or decrease in the level of a response in a patient compared with the level of a response in the patient in the absence of a treatment or compound, and / or compared with the level of a response in an otherwise identical but untreated patient. The term encompasses perturbing and / or affecting a native signal or response thereby mediating a beneficial therapeutic response in a patient, preferably, a human. “Parenteral” administration of a pharmaceutical composition includes, e.g., subcutaneous (s.c.), intravenous (i.v.), intramuscular (i.m.), intrasternal injection, or infusion techniques. As used herein, the terms “peptide,” “polypeptide,” and “protein” are used interchangeably, and refer to a compound comprised of amino acid residues covalently linked by peptide bonds. A protein or peptide must contain at least two amino acids, and the maximum number of amino acids present within the protein or peptide’s sequence is typically comparable to up to that found in nature. Polypeptides include any peptide or protein comprising two or more amino acids joined to each other by peptide bonds. As used herein, the term refers to both short chains, which also commonly are referred to in the art as peptides, oligopeptides and oligomers, for example, and to longer chains, which generally are referred to in the art as proteins, of which there are many types. “Polypeptides” include, for example, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, variants of polypeptides, modified polypeptides, derivatives, analogs, fusion proteins, among others. The polypeptides include natural peptides, recombinant peptides, synthetic peptides, or a combination thereof. To “treat” a disease as the term is used herein, means to reduce the frequency or severity of at least one sign or symptom of a disease or disorder experienced by a patient (i.e., palliative treatment) or to decrease a cause or effect of the disease or disorder (i.e. disease-modifying treatment). Throughout this disclosure, various aspects of the invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and should not be construed as a limitation on the scope of the invention. The description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range. As used herein, “pharmaceutical compositions” are compositions comprising at least one active agent, and at least one other substance, such as a carrier. “Pharmaceutical combinations” are combinations of at least two active agents which may be combined in a single dosage form or provided together in separate dosage forms with instructions that the active agents are to be used together to treat any disorder described herein. As used herein, “pharmaceutically acceptable salt” is a derivative of the disclosed compound in which the parent compound is modified by making inorganic and organic, non-toxic, acid or base addition salts thereof. The salts of the present compounds can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical, where practicable. Salts of the present compounds further include solvates of the compounds and of the compound salts. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC-(CH2)n- COOH where n is 0-4, and the like, or using a different acid that produces the same counterion. Lists of additional suitable salts may be found, e.g., in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p.1418 (1985). The term “carrier” applied to pharmaceutical compositions / combinations of the invention refers to a diluent, excipient, or vehicle with which an active compound is provided. A “pharmaceutically acceptable carrier” means a carrier or excipient that is useful in preparing a pharmaceutical composition / combination that is generally safe, non-toxic and neither biologically nor otherwise inappropriate for administration to a patient, typically a human. In certain embodiments, an excipient is used that is acceptable for veterinary use. A “patient” or “subject” is a human or domesticated animal in need of treatment for any of the disorders as specifically described herein, for example, a disorder that is modulated by a natural (wild-type) or modified (non-wild type) RET protein that can be degraded according to the present invention, resulting in a therapeutic effect. Non-limiting examples of domesticated animals include dogs, cats, horses, and livestock. As described further herein, the words patient or subject typically refers to a human patient or subject, and unless otherwise indicated by the text is assumed to refer to a human. In an alternative embodiment, the patient or subject is a domesticated animal in need of such therapy and responsive thereto. "Livestock" refers to animals that are generally kept for agricultural purposes, including, for example, cows, sheep, goats, pigs, and poultry. A “therapeutically effective amount” of a pharmaceutical composition / combination of this invention means an amount effective, when administered to a patient, to provide a therapeutic benefit such as an amelioration of symptoms or reduction or diminution of the disease itself. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. In the specification, singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed application. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting. II. COMPOUNDS OF FORMULA I, FORMULA II, FORMULA III, FORMULA IV, FORMULA V, FORMULA VI, FORMULA VII, FORMULA VIII, FORMULA IX, OR FORMULA X In other aspects, the present invention provides a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, or Formula X, wherein the compound is of Formula: ; ĨX); or a pharmaceutically acceptable salt thereof; wherein X3is N, CH, or CR3a; X4is N, CH, or CR3b; X5is N, CH, or CR3c; X6is N, CH, or CR3d; wherein no more than 3 of X3, X4, X5, and X6are N; X7is N or CR1c; Q1is -NR6-, -CH2-, -O-, or -S-, wherein if X7is N then Q1is CH2; R1a, R1b, R1c, and R1dare each independently hydrogen, C1-C4alkyl, or C1-C4haloalkyl; or R1aand R1care combined to form a 1 or 2 carbon atom bridge, for example ; R3a, R3b, R3c, and R3d, are independently at each occurrence selected from the group consisting of hydrogen, hydroxyl, alkoxy, C1-C4alkyl, C1-C4haloalkyl, cycloalkyl, fluorine, chlorine, bromine, and iodine;

[0004] , is a heteroaryl, heterocycle, or carbocycle, each of which is optionally substituted with 0, 1, 2, 3, or 4 substituents independently selected from R9; X9is NR13or O; X10, X11, X16, and X17are independently selected from the group consisting of N, CH, and CRA; X12, X13, X14, and X15are independently selected from the group consisting of N, CH, and CRB; each R4, R12, and R13is independently selected from the group consisting of hydrogen, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4haloalkyl, cycloalkyl, heteroaryl, aryl, heterocycle, -alkyl-heteroaryl, -alkyl-aryl, -alkyl-heterocycle, -C(O)R5, and -alkyl-C(O)R5, each of which C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4haloalkyl, cycloalkyl, heteroaryl, aryl, heterocycle, -alkyl-heteroaryl, -alkyl-aryl, and -alkyl-heterocycle groups is optionally substituted with 0, 1, 2, or 3 substituents independently selected from R8; R5is hydrogen, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4haloalkyl, cycloalkyl, heteroaryl, aryl, heterocycle, bicycle, -alkyl-heteroaryl, -alkyl-aryl, -alkyl-heterocycle, -OR6, or -NR6R7, each of which C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4haloalkyl, cycloalkyl, heteroaryl, aryl, heterocycle, -alkyl-heteroaryl, -alkyl-aryl, and -alkyl-heterocycle group is optionally substituted with 0, 1, 2, or 3 substituents independently selected from R10; R6and R7are independently selected at each instance from the group consisting of hydrogen, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4haloalkyl, cycloalkyl, heteroaryl, aryl, heterocycle, -alkyl-heteroaryl, -alkyl-aryl, and -alkyl-heterocycle, each of which R6and R7groups other than hydrogen is optionally substituted with 0, 1, 2, or 3 substituents independently selected from R10; R8is independently at each occurrence selected from the group consisting of hydrogen, C1-C4haloalkyl, C1-C4alkyl, halogen, -OR6, -NR6R7, -OC(O)R5, -NR6C(O)R5, -C(O)R5, and -alkyl-C(O)R5; R9is independently at each occurrence selected from the group consisting of hydrogen, aryl, -alkyl-aryl, heteroaryl, alkyl-heteroaryl, heterocycle, alkyl-heterocycle, cycloalkyl, -alkyl-cycloalkyl, C1-C4haloalkyl, C1-C4alkyl, halogen, -OR6, -NR6R7, -C(O)OR6, -C(O)NR6R7, -alkyl-C(O)OR6, and -alkyl-C(O)NR6R7, each of which aryl, -alkyl-aryl, heteroaryl, -alkyl-heteroaryl, heterocycle, -alkyl-heterocycle, -alkyl-cycloalkyl, and cycloalkyl group is optionally substituted with 0, 1, 2, or 3 substituents selected from -S(O)2alkyl, C1-C4haloalkyl, C1- C4alkyl, halogen, -OR6, -NR6R7, -C(O)OR6, -C(O)NR6R7, -alkyl-C(O)OR6, and -alkyl- C(O)NR6R7; R10is independently at each occurrence selected from the group consisting of hydrogen, halogen, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4haloalkyl, cycloalkyl, heteroaryl, aryl, heterocycle, -alkyl-heteroaryl, -alkyl-aryl, halogen, and -alkyl-heterocycle; R11is hydrogen, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4haloalkyl, cycloalkyl, heteroaryl, aryl, heterocycle, -alkyl-heteroaryl, -alkyl-aryl, or -alkyl-heterocycle; each RAand RBis independently at each occurrence selected from the group consisting of hydrogen, C1-C4haloalkyl, C1-C4alkyl, halogen, cyano, nitro, -OR6, -NR6R7, -C(O)OR6, and -C(O)NR6R7; R14is hydrogen, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4haloalkyl, cycloalkyl, heteroaryl, aryl, heterocycle, -alkyl-heteroaryl, -alkyl-aryl, -alkyl-heterocycle, -C(O)R5, -alkyl-C(O)R5, -OC(O)R5, or -NR6C(O)R5, each of which C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4haloalkyl, cycloalkyl, heteroaryl, aryl, heterocycle, -alkyl-heteroaryl, -alkyl-aryl, and -alkyl- heterocycle groups is optionally substituted with 0, 1, 2, or 3 substituents independently selected from R8; and Linker is a bivalent linking group, for example, a bivalent linking group of Formula LI. In certain embodiments Linker is of formula: wherein, X1and X2are independently at each occurrence selected from bond, heterocycle, NR2, C(R2)2, O, C(O), and S; R2is independently at each occurrence selected from the group consisting of hydrogen, alkyl, aliphatic, heteroaliphatic, heterocycle, aryl, heteroaryl, -C(O)H, -C(O)OH, -C(O)alkyl, -C(O)Oalkyl, -C(O)(aliphatic, aryl, heteroaliphatic or heteroaryl), -C(O)O(aliphatic, aryl, heteroaliphatic, or heteroaryl), alkene, and alkyne; R20, R21, R22, R23, and R24are independently at each occurrence selected from the group consisting of a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR2-, -NR2C(O)-, -O-, -S-, -NR2-, -P(O)(OR26)O-, -P(O)(OR26)-, bicycle, alkene, alkyne, haloalkyl, alkoxy, aryl, heterocycle, aliphatic, heteroaliphatic, heteroaryl, lactic acid, glycolic acid, and carbocycle; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R40; R26is independently at each occurrence selected from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocycle, aliphatic and heteroaliphatic; and R40is independently at each occurrence selected from the group consisting of hydrogen, alkyl, alkene, alkyne, fluoro, bromo, chloro, hydroxyl, alkoxy, azide, amino, cyano, -NH(aliphatic, including alkyl), -N(aliphatic, including alkyl)2, -NHSO2(aliphatic, including alkyl), -N(aliphatic, including alkyl)SO2alkyl, -NHSO2(aryl, heteroaryl or heterocycle), -N(alkyl)SO2(aryl, heteroaryl or heterocycle), -NHSO2alkenyl, -N(alkyl)SO2alkenyl, -NHSO2alkynyl, -N(alkyl)SO2alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocycle, and cycloalkyl. In certain embodiments, the compound of the present invention is selected from:

[0005] or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from:

[0006] or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from:

[0007] or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from:

[0008] or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from: or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from: or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from:

[0009] or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is: or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is: or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is: or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from: or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from:

[0010] or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from

[0011] , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from , ,

[0012] ,

[0013] , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from , ’

[0014] , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from ,

[0015] , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from , and

[0016] , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from ,

[0017] , , , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from , , ,

[0018] , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from , ,

[0019] , , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from ,

[0020] , , , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from

[0021] , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from

[0022] , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from

[0023] , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from , , , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from

[0024] , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from

[0025] , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from

[0026] , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from

[0027] or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from ,

[0028] or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from

[0029] or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from , ,

[0030] , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from ,

[0031] or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from ,

[0032] , , or a pharmaceutically acceptable salt thereof.

[0033] In certain embodiments, the compound of the present invention is selected from or a pharmaceutically acceptable salt thereof.

[0034] In certain embodiments, the compound of the present invention is selected from ,

[0035] , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from

[0036] or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from , ,

[0037] , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from ,

[0038] , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from ,

[0039] or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from ,

[0040] or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from

[0041] , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from or a pharmaceutically acceptable salt thereof. ADDITIONAL EMBODIMENTS OF THE PRESENT INVENTION 1. A compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, or Formula X: ; ; ĨX); or a pharmaceutically acceptable salt thereof; wherein X3is N, CH, or CR3a; X4is N, CH, or CR3b; X5is N, CH, or CR3c; X6is N, CH, or CR3d; X6Bis CH or CR3d; wherein no more than 3 of X3, X4, X5, and X6are N; X7is N or CR1c; Q1is -NR6-, -CH2-, -O-, or -S-, wherein if X7is N then Q1is CH2; R1a, R1b, R1c, and R1dare each independently hydrogen, C1-C4alkyl, or C1-C4haloalkyl; or R1aand R1care combined to form a 1 or 2 carbon atom bridge; R3a, R3b, R3c, and R3d, are independently at each occurrence selected from the group consisting of hydrogen, hydroxyl, alkoxy, C1-C4alkyl, C1-C4haloalkyl, cycloalkyl, fluorine, chlorine, bromine, and iodine; RET Targeting Ligand is ,

[0042] , r is a heteroaryl, heterocycle, or carbocycle, each of which is optionally substituted with 0, 1, 2, 3, or 4 substituents independently selected from R9; X9is NR13or O; X10, X16, X17, and X18are independently selected from the group consisting of N, CH, and CRA; X11, X12, and X13are independently selected from the group consisting of N, CH, and CRB; each R4and R13is independently selected from the group consisting of hydrogen, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4haloalkyl, cycloalkyl, heteroaryl, aryl, heterocycle, -alkyl-heteroaryl, -alkyl-aryl, -alkyl-heterocycle, -C(O)R5, and -alkyl-C(O)R5, each of which C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4haloalkyl, cycloalkyl, heteroaryl, aryl, heterocycle, -alkyl-heteroaryl, -alkyl-aryl, and -alkyl-heterocycle groups is optionally substituted with 0, 1, 2, or 3 substituents independently selected from R8; R5is hydrogen, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4haloalkyl, cycloalkyl, heteroaryl, aryl, heterocycle, bicycle, -alkyl-heteroaryl, -alkyl-aryl, -alkyl-heterocycle, -OR6, or -NR6R7, each of which C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4haloalkyl, cycloalkyl, heteroaryl, aryl, heterocycle, -alkyl-heteroaryl, -alkyl-aryl, and -alkyl-heterocycle group is optionally substituted with 0, 1, 2, or 3 substituents independently selected from R10; R6and R7are independently selected at each instance from the group consisting of hydrogen, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4haloalkyl, cycloalkyl, heteroaryl, aryl, heterocycle, -alkyl-heteroaryl, -alkyl-aryl, and -alkyl-heterocycle, each of which R6and R7groups other than hydrogen is optionally substituted with 0, 1, 2, or 3 substituents independently selected from R10; R8is independently at each occurrence selected from the group consisting of hydrogen, C1-C4haloalkyl, C1-C4alkyl, halogen, -OR6, -NR6R7, -OC(O)R5, -NR6C(O)R5, -C(O)R5, and -alkyl-C(O)R5; R9is independently at each occurrence selected from the group consisting of hydrogen, aryl, -alkyl-aryl, heteroaryl, alkyl-heteroaryl, heterocycle, alkyl-heterocycle, cycloalkyl, -alkyl-cycloalkyl, C1-C4haloalkyl, C1-C4alkyl, halogen, -OR6, -NR6R7, -C(O)OR6, -C(O)NR6R7, -alkyl-C(O)OR6, and -alkyl-C(O)NR6R7, each of which aryl, -alkyl-aryl, heteroaryl, -alkyl-heteroaryl, heterocycle, -alkyl-heterocycle, -alkyl-cycloalkyl, and cycloalkyl group is optionally substituted with 0, 1, 2, or 3 substituents selected from -S(O)2alkyl, C1-C4haloalkyl, C1- C4alkyl, halogen, -OR6, -NR6R7, -C(O)OR6, -C(O)NR6R7, -alkyl-C(O)OR6, and -alkyl- C(O)NR6R7; R10is independently at each occurrence selected from the group consisting of hydrogen, halogen, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4haloalkyl, cycloalkyl, heteroaryl, aryl, heterocycle, -alkyl-heteroaryl, -alkyl-aryl, and -alkyl-heterocycle; R11is hydrogen, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4haloalkyl, cycloalkyl, heteroaryl, aryl, heterocycle, -alkyl-heteroaryl, -alkyl-aryl, or -alkyl-heterocycle; each RAand RBis independently at each occurrence selected from the group consisting of hydrogen, C1-C4haloalkyl, C1-C4alkyl, halogen, cyano, nitro, -OR6, -NR6R7, -C(O)OR6, and -C(O)NR6R7; R14is hydrogen, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4haloalkyl, cycloalkyl, heteroaryl, aryl, heterocycle, -alkyl-heteroaryl, -alkyl-aryl, -alkyl-heterocycle, -C(O)R5, -alkyl-C(O)R5, -OC(O)R5, or -NR6C(O)R5, each of which C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4haloalkyl, cycloalkyl, heteroaryl, aryl, heterocycle, -alkyl-heteroaryl, -alkyl-aryl, and -alkyl- heterocycle groups is optionally substituted with 0, 1, 2, or 3 substituents independently selected from R8; Linker is of formula: wherein, X1and X2are independently at each occurrence selected from bond, heterocycle, NR2, C(R2)2, O, C(O), and S; R2is independently at each occurrence selected from the group consisting of hydrogen, alkyl, aliphatic, heteroaliphatic, heterocycle, aryl, heteroaryl, -C(O)H, -C(O)OH, -C(O)alkyl, -C(O)Oalkyl, -C(O)(aliphatic, aryl, heteroaliphatic or heteroaryl), -C(O)O(aliphatic, aryl, heteroaliphatic, or heteroaryl), alkene, and alkyne; R20, at each occurrence selected from the group consisting of a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR2-, -NR2C(O)-, -O-, -S-, -NR2-, -P(O)(OR26)O-, -P(O)(OR26)-, bicycle, alkene, alkyne, haloalkyl, alkoxy, aryl, heterocycle, aliphatic, heteroaliphatic, heteroaryl, lactic acid, glycolic acid, and carbocycle; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R40; R26is independently at each occurrence selected from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocycle, aliphatic and heteroaliphatic; and R40is independently at each occurrence selected from the group consisting of hydrogen, alkyl, alkene, alkyne, fluoro, bromo, chloro, hydroxyl, alkoxy, azide, amino, cyano, -NH(alkyl), -N(alkyl)2, -NHSO2(alkyl), -N(alkyl)SO2alkyl, -NHSO2(aryl, heteroaryl or heterocycle), -N(alkyl)SO2(aryl, heteroaryl or heterocycle), -NHSO2alkenyl, -N(alkyl)SO2alkenyl, -NHSO2alkynyl, -N(alkyl)SO2alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocycle, and cycloalkyl. 2. The compound of embodiment 1 wherein the compound is of formula: ; ĨVIII); or a pharmaceutically acceptable salt thereof. 3. The compound of embodiment 1 or embodiment 2, wherein R40is independently at each occurrence selected from the group consisting of hydrogen, C1-C3alkyl, fluoro, chloro, and C1-C3haloalkyl. 4. The compound of any one of embodiments 1-3, wherein the compound is of formula: ; or a pharmaceutically acceptable salt thereof. 5. The compound of any one of embodiments 1-4, wherein Q1is -NH-. 6. The compound of any one of embodiments 1-4, wherein Q1is -NCH3-. 7. The compound of any one of embodiments 1-3, wherein the compound is of formula: ; or a pharmaceutically acceptable salt thereof. 8. The compound of any one of embodiments 1-7, wherein X5is CH. 9. The compound of any one of embodiments 1-7, wherein X5is N. 10. The compound of any one of embodiments 1-7, wherein X5is CR3c. 11. The compound of any one of embodiments 1-7, wherein X5is C-F. 12. The compound of any one of embodiments 1-7, wherein X5is C-OCH3. 13. The compound of any one of embodiments 1-3, wherein the compound is of formula: ; or a pharmaceutically acceptable salt thereof. 14. The compound of any one of embodiments 1-3, wherein the compound is of formula: ; or a pharmaceutically acceptable salt thereof. 15. The compound of any one of embodiments 1-14, wherein X7is N. 16. The compound of any one of embodiments 1-14, wherein X7is CH. 17. The compound of any one of embodiments 1-14, wherein X7is CR1c. 18. The compound of any one of embodiments 1-3, wherein the compound is of formula: ; or a pharmaceutically acceptable salt thereof. 19. The compound of any one of embodiments 1-18, wherein X3is CR3a. 20. The compound of any one of embodiments 1-18, wherein X3is CH. 21. The compound of any one of embodiments 1-18, wherein X3is N. 22. The compound of any one of embodiments 1-18, wherein X3is C-OCH3. 23. The compound of any one of embodiments 1-18, wherein X3is C-F. 24. The compound of any one of embodiments 1-18, wherein X3is C-CF3. 25. The compound of any one of embodiments 1-24, wherein X4is CR3b. 26. The compound of any one of embodiments 1-24, wherein X4is CH. 27. The compound of any one of embodiments 1-24, wherein X4is N. 28. The compound of any one of embodiments 1-24, wherein X4is C-F. 29. The compound of any one of embodiments 1-24, wherein X4is C-Cl. 30. The compound of any one of embodiments 1-24, wherein X4is C-CF3. 31. The compound of any one of embodiments 1-24, wherein X4is C-OCH3. 32. The compound of any one of embodiments 1-31, wherein X6is CR3d. 33. The compound of any one of embodiments 1-31, wherein X6is CH. 34. The compound of any one of embodiments 1-31, wherein X6is N. 35. The compound of any one of embodiments 1-31, wherein X6is C-F. 36. The compound of any one of embodiments 1-31, wherein X6is C-CF3. 37. The compound of any one of embodiments 1-31, wherein X6is C-OCH3. 38. The compound of any one of embodiments 1-37, wherein R1ais hydrogen. 39. The compound of any one of embodiments 1-38, wherein R1bis hydrogen. 40. The compound of any one of embodiments 1-39, wherein R1cis hydrogen. 41. The compound of any one of embodiments 1-40, wherein R1dis hydrogen. 42. The compound of any one of embodiments 1-41, wherein the RET Targeting Ligand is of formula: . 43. The compound of any one of embodiments 1-41, wherein the RET Targeting Ligand is of formula: . 44. The compound of any one of embodiments 1-41, wherein the RET Targeting Ligand is of formula: . 45. The compound of any one of embodiments 1-41, wherein the RET Targeting Ligand is of formula: r

[0043] . . . The compound of any one of embodiments 1-45, wherein . The compound of any one of embodiments 1-45, wherein . The compound of any one of embodiments 1-45, wherein is . The compound of any one of embodiments 1-45, wherein . 55. The compound of any one of embodiments 1-41, wherein the RET Targeting Ligand is selected from: , , 56. The compound of any one of embodiments 1-41, wherein the RET Targeting Ligand is: . 57. The compound of any one of embodiments 1-56, wherein Linker is of formula. . 58. The compound of embodiment 57, wherein X1is bond. 59. The compound of embodiment 57, wherein X1is heterocycle. 60. The compound of embodiment 57, wherein X1is -NR2-. 61. The compound of embodiment 57, wherein X1is -C(O)-. 62. The compound of embodiment 57, wherein X1is -C(R2)2-. 63. The compound of embodiment 57, wherein X1is -O-. 64. The compound of embodiment 57, wherein X1is -S-. 65. The compound of any one of embodiments 57-64, wherein X2is bond. 66. The compound of embodiment 57-64, wherein X2is heterocycle. 67. The compound of embodiment 57-64, wherein X2is -NR2-. 68. The compound of embodiment 57-64, wherein X2is -C(O)-. 69. The compound of embodiment 57-64, wherein X2is -C(R2)2-. 70. The compound of embodiment 57-64, wherein X2is -O-. 71. The compound of embodiment 57-64, wherein X2is -S-. 72. The compound of any one of embodiments 57-71, wherein R20is bond. 73. The compound of any one of embodiments 57-71, wherein R20is -CH2-. 74. The compound of any one of embodiments 57-71, wherein R20is heterocycle. 75. The compound of any one of embodiments 57-71, wherein R20is aryl. 76. The compound of any one of embodiments 57-71, wherein R20is phenyl. 77. The compound of any one of embodiments 57-71, wherein R20is bicycle. 78. The compound of any one of embodiments 57-77, wherein R21is bond. 79. The compound of any one of embodiments 57-77, wherein R21is -CH2-. 80. The compound of any one of embodiments 57-77, wherein R21is heterocycle. 81. The compound of any one of embodiments 57-77, wherein R21is aryl. 82. The compound of any one of embodiments 57-77, wherein R21is phenyl. 83. The compound of any one of embodiments 57-77, wherein R21is bicycle. 84. The compound of embodiment 57, wherein Linker is of formula: . 85. The compound of any one of embodiments 57-84, wherein R22is bond. 86. The compound of any one of embodiments 57-84, wherein R22is -CH2-. 87. The compound of any one of embodiments 57-84, wherein R22is heterocycle. 88. The compound of any one of embodiments 57-84, wherein R22is aryl. 89. The compound of any one of embodiments 57-84, wherein R22is phenyl. 90. The compound of any one of embodiments 57-84, wherein R22is bicycle. 91. The compound of any one of embodiments 57-84, wherein R22is glycolic acid. 92. The compound of embodiment 57, wherein Linker is of formula: . 93. The compound of any one of embodiments 57-92, wherein R23is bond. 94. The compound of any one of embodiments 57-92, wherein R23is -CH2-. 95. The compound of any one of embodiments 57-92, wherein R23is heterocycle. 96. The compound of any one of embodiments 57-92, wherein R23is aryl. 97. The compound of any one of embodiments 57-92, wherein R23is phenyl. 98. The compound of any one of embodiments 57-92, wherein R23is bicycle. 99. The compound of embodiment 57, wherein linker is of formula: . 100. The compound of any one of embodiments 57-99, wherein R24is bond. 101. The compound of any one of embodiments 57-99, wherein R24is -CH2-. 102. The compound of any one of embodiments 57-99, wherein R24is heterocycle. 103. The compound of any one of embodiments 57-99, wherein R24is aryl. 104. The compound of any one of embodiments 57-99, wherein R24is phenyl. 105. The compound of any one of embodiments 57-99, wherein R24is bicycle. 106. The compound of any one of embodiments 57-99, wherein R24is -C(O)-. 107. A compound of structure: or a pharmaceutically acceptable salt thereof. 108. A compound of structure: or a pharmaceutically acceptable salt thereof. 109. A compound of structure: or a pharmaceutically acceptable salt thereof. 110. A compound of structure: or a pharmaceutically acceptable salt thereof. 111. A compound of structure: or a pharmaceutically acceptable salt thereof. 112. A compound of structure: or a pharmaceutically acceptable salt thereof. 114. A compound of structure: or a pharmaceutically acceptable salt thereof. 115. A compound of structure: or a pharmaceutically acceptable salt thereof. 116. A compound of structure: or a pharmaceutically acceptable salt thereof. 117. A pharmaceutical composition comprising a compound of any one of embodiments 1-116 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 118. A method of treating a RET mediated disorder comprising administering an effective amount of a compound of any one of embodiments 1-116 or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, to a patient in need thereof. 119. The method of embodiment 118, wherein the patient is a human. 120. The method of embodiment 118 or embodiment 119, wherein the RET mediated disorder is a RET mediated cancer. 121. The method of embodiment 120, wherein the RET mediated cancer is non-small cell lung cancer. 122. The method of embodiment 120, wherein the RET mediated cancer has metastasized to the brain. 123. The method of any one of embodiments 120-122, wherein the RET mediated cancer is mediated by a mutant RET. 124. The method of any one of embodiments 120-123, wherein the RET mediated cancer is a relapsed or refractory cancer. 125. A compound of any one of embodiments 1-116 or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, for use in the treatment of a RET mediated disorder. 126. The compound of embodiment 125, wherein the RET mediated disorder is a RET mediated cancer. 127. The compound of embodiment 126, wherein the RET mediated cancer is non-small cell lung cancer. 128. The compound of embodiment 126, wherein the RET mediated cancer has metastasized to the brain. 129. The compound of any one of embodiments 126-128, wherein the RET mediated cancer is mediated by a mutant RET. 130. The compound of any one of embodiments 126-129, wherein the RET mediated cancer is a relapsed or refractory cancer. 131. Use of a compound of any one of embodiments 1-116 or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, in the treatment of a RET mediated disorder. 132. The use of embodiment 131, wherein the RET mediated disorder is a RET mediated cancer. 133. The use of embodiment 132, wherein the RET mediated cancer is non-small cell lung cancer. 134. The use of embodiment 132, wherein the RET mediated cancer has metastasized to the brain. 135. The use of any one of embodiments 132-134, wherein the RET mediated cancer is mediated by a mutant RET. 136. The use of any one of embodiments 132-135, wherein the RET mediated cancer is a relapsed or refractory cancer. 137. Use of a compound of any one of embodiments 1-116 or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, in the manufacture of a medicament for the treatment of a RET mediated disorder. 138. The use of embodiment 137, wherein the RET mediated disorder is a RET mediated cancer. 139. The use of embodiment 138, wherein the RET mediated cancer is non-small cell lung cancer. 140. The use of embodiment 138, wherein the RET mediated cancer has metastasized to the brain. 141. The use of any one of embodiments 138-140, wherein the RET mediated cancer is mediated by a mutant RET. 142. The use of any one of embodiments 138-141, wherein the RET mediated cancer is a relapsed or refractory cancer. Embodiments of Cycle I I I I I In certain embodiments In certain embodiments In certain embodiments In certain embodiments In certain embodiments In certain embodiments In certain embodiments In certain embodiments In certain embodiments In certain embodiments In certain embodiments In certain embodiments Embodiments of X3, X4, X5, and X6In certain embodiments, X3is N. In certain embodiments, X3is CH. In certain embodiments, X3is CR3a. In certain embodiments, X3is CF. In certain embodiments, X3is CCl. In certain embodiments, X3is CBr. In certain embodiments, X3is C(C1-C4haloalkyl). In certain embodiments, X3is C(C1-C4alkyl). In certain embodiments, X3is CH2F. In certain embodiments, X3is CHF2. In certain embodiments, X3is CF3. In certain embodiments, X3is CH2Cl. In certain embodiments, X3is CHCl2. In certain embodiments, X3is CCl3. In certain embodiments, X3is CH2Br. In certain embodiments, X3is CHBr2. In certain embodiments, X3is CBr3. In certain embodiments, X4is N. In certain embodiments, X4is CH. In certain embodiments, X4is CR3b. In certain embodiments, X4is CF. In certain embodiments, X4is CCl. In certain embodiments, X4is CBr. In certain embodiments, X6is CF. In certain embodiments, X6is CCl. In certain embodiments, X6is CBr. In certain embodiments, X6is C(C1-C4haloalkyl). In certain embodiments, X6is C(C1-C4alkyl). In certain embodiments, X6is CH2F. In certain embodiments, X6is CHF2. In certain embodiments, X6is CF3. In certain embodiments, X6is CH2Cl. In certain embodiments, X6is CHCl2. In certain embodiments, X6is CCl3. In certain embodiments, X6is CH2Br. In certain embodiments, X6is CHBr2. In certain embodiments, X6is CBr3In certain embodiments, no more than three of X3, X4, X5, and X6are N. In certain embodiments, all of X3, X4, X5and X6are CH. In certain embodiments, X4or X6is N. In certain embodiments, X4and X6are both N. In certain embodiments, X4or X6is CH. In certain embodiments, X4and X6are both CH. Embodiments of X7In certain embodiments, X7is N. In certain embodiments, X7is CH. In certain embodiments, X7is CR1c. In certain embodiments, X7is C(C1-C4alkyl). In certain embodiments, X7is C(C1-C4haloalkyl). Embodiments of X9In certain embodiments, X9is NR13. In certain embodiments, X9is O. In certain embodiments, X9is NH. In certain embodiments, X9is N(C1-C4alkyl). In certain embodiments, X9is N(C2-C4alkenyl). In certain embodiments, X9is N(C2-C4alkynyl). In certain embodiments, X9is N(C1-C4haloalkyl). In certain embodiments, X9is N(cycloalkyl). In certain embodiments, X9is N(heteroaryl). In certain embodiments, X9is N(aryl). In certain embodiments, X9is N(heterocycle). In certain embodiments, X9is N(alkyl-heteroaryl). In certain embodiments, X9is N(alkyl-aryl). In certain embodiments, X9is N(alkyl-heterocycle). In certain embodiments, X9is N-C(O)R5. In certain embodiments, X9is N-alkyl-C(O)R5. In certain embodiments, X9is NR13, wherein R13is substituted with one substituent R8. In certain embodiments, X9is NR13, wherein R13is substituted with two substituents R8. In certain embodiments, X9is NR13, wherein R13is substituted with three substituents R8. Embodiments of X11, X12, X13, X14and X15In certain embodiments, X11is N. In certain embodiments, X11is CH. In certain embodiments, X11is CCH3. In certain embodiments, X11is CF. In certain embodiments, X11is C1-C2haloalkyl. In certain embodiments, X11is CRA. In certain embodiments, X12is N. In certain embodiments, X12is CH. In certain embodiments, X12is CRB. In certain embodiments, X13is N. In certain embodiments, X13is CH. In certain embodiments, X13is CRB. In certain embodiments, X14is N. In certain embodiments, X14is CH. In certain embodiments, X14is CRB. In certain embodiments, X15is N. In certain embodiments, X15is CH. In certain embodiments, X15is CRB. In certain embodiments, X16is N. In certain embodiments, X16is CH. In certain embodiments, X16is CRB. In certain embodiments, X17is N. In certain embodiments, X17is CH. In certain embodiments, X17is CRB. In certain embodiments, X18is N. In certain embodiments, X18is CH. In certain embodiments, X18is CRB. Embodiments of RAIn certain embodiments, RAis hydrogen. In certain embodiments, RAis C1-C4haloalkyl. In certain embodiments, RAis C1-C4alkyl. In certain embodiments, RAis halogen. In certain embodiments, RAis cyano. In certain embodiments, RAis nitro. In certain embodiments, RAis -OR6. In certain embodiments, RAis -NR6R7. In certain embodiments, RAis -C(O)OR6. In certain embodiments, RAis -C(O)NR6R7. Embodiments of RBIn certain embodiments, RBis hydrogen. In certain embodiments, RBis C1-C4haloalkyl. In certain embodiments, RBis C1-C4alkyl. In certain embodiments, RBis halogen. In certain embodiments, RBis cyano. In certain embodiments, RBis nitro. In certain embodiments, RBis -OR6. In certain embodiments, RBis -NR6R7. In certain embodiments, RBis -C(O)OR6. In certain embodiments, RBis -C(O)NR6R7. Embodiments of Q1In certain embodiments, Q1is -NR6-. In certain embodiments, Q1is -NH-. In certain embodiments, Q1is -O-. In certain embodiments, Q1is -S-. In certain embodiments, Q1is -CH2-. In certain embodiments, Q1is -N(C1-C4alkyl)-. In certain embodiments, Q1is -N(C1-C4haloalkyl)-. Embodiments of R1a, R1b, R1c, and R1dIn certain embodiments, R1ais hydrogen. In certain embodiments, R1ais C1-C4haloalkyl. In certain embodiments, R1ais C1-C4alkyl. In certain embodiments, R1ais methyl. In certain embodiments, R1ais CH2F. In certain embodiments, R1ais CHF2. In certain embodiments, R1ais CF3. In certain embodiments, R1ais CH2Cl. In certain embodiments, R1ais CHCl2. In certain embodiments, R1ais CCl3. In certain embodiments, R1bis hydrogen. In certain embodiments, R1bis C1-C4haloalkyl. In certain embodiments, R1bis C1-C4alkyl. In certain embodiments, R1bis methyl. In certain embodiments, R1bis CH2F. In certain embodiments, R1bis CHF2. In certain embodiments, R1bis CF3. In certain embodiments, R1bis CH2Cl. In certain embodiments, R1bis CHCl2. In certain embodiments, R1bis CCl3. In certain embodiments, R1cis hydrogen. In certain embodiments, R1cis C1-C4haloalkyl. In certain embodiments, R1cis C1-C4alkyl. In certain embodiments, R1cis methyl. In certain embodiments, R1cis CH2F. In certain embodiments, R1cis CHF2. In certain embodiments, R1cis CF3. In certain embodiments, R1cis CH2Cl. In certain embodiments, R1cis CHCl2. In certain embodiments, R1cis CCl3. In certain embodiments, R1dis hydrogen. In certain embodiments, R1dis C1-C4haloalkyl. In certain embodiments, R1dis C1-C4alkyl. In certain embodiments, R1dis methyl. In certain embodiments, R1dis CH2F. In certain embodiments, R1dis CHF2. In certain embodiments, R1dis CF3. In certain embodiments, R1dis CH2Cl. In certain embodiments, R1dis CHCl2. In certain embodiments, R1dis CCl3. Embodiments of R2In certain embodiments, R2is hydrogen. In certain embodiments, R2is alkyl. In certain embodiments, R2is aliphatic. In certain embodiments, R2is heteroaliphatic. In certain embodiments, R2is heterocycle. In certain embodiments, R2is aryl. In certain embodiments, R2is heteroaryl. In certain embodiments, R2is -C(O)H. In certain embodiments, R2is -C(O)OH. In certain embodiments, R2is -C(O)alkyl. In certain embodiments, R2is -C(O)Oalkyl. In certain embodiments, R2is -C(O)(aliphatic, aryl, heteroaliphatic or heteroaryl). In certain embodiments, R2is -C(O)O(aliphatic, aryl, heteroaliphatic or heteroaryl). In certain embodiments, R2is alkene. In certain embodiments, R2is alkyne. Embodiments of R3a, R3b, R3c, and R3dIn certain embodiments, R3ais hydrogen. In certain embodiments, R3ais hydroxyl. In certain embodiments, R3ais alkoxy. In certain embodiments, R3ais C1-C4alkyl. In certain embodiments, R3ais C1-C4haloalkyl. In certain embodiments, R3ais cycloalkyl. In certain embodiments, R3ais fluorine. In certain embodiments, R3ais chlorine. In certain embodiments, R3ais bromine. In certain embodiments, R3ais iodine. In certain embodiments, R3bis hydrogen. In certain embodiments, R3bis hydroxyl. In certain embodiments, R3bis alkoxy. In certain embodiments, R3bis C1-C4alkyl. In certain embodiments, R3bis C1-C4haloalkyl. In certain embodiments, R3bis cycloalkyl. In certain embodiments, R3bis fluorine. In certain embodiments, R3bis chlorine. In certain embodiments, R3bis bromine. In certain embodiments, R3bis iodine. In certain embodiments, R3cis hydrogen. In certain embodiments, R3cis hydroxyl. In certain embodiments, R3cis alkoxy. In certain embodiments, R3cis C1-C4alkyl. In certain embodiments, R3cis C1-C4haloalkyl. In certain embodiments, R3cis cycloalkyl. In certain embodiments, R3cis fluorine. In certain embodiments, R3cis chlorine. In certain embodiments, R3cis bromine. In certain embodiments, R3cis iodine. In certain embodiments, R3dis hydrogen. In certain embodiments, R3dis hydroxyl. In certain embodiments, R3dis alkoxy. In certain embodiments, R3dis C1-C4alkyl. In certain embodiments, R3dis C1-C4haloalkyl. In certain embodiments, R3dis cycloalkyl. In certain embodiments, R3dis fluorine. In certain embodiments, R3dis chlorine. In certain embodiments, R3dis bromine. In certain embodiments, R3dis iodine. Embodiments of R4In certain embodiments, R4is hydrogen. In certain embodiments, R4is C1-C4alkyl. In certain embodiments, R4is C2-C4alkenyl. In certain embodiments, R4is C2-C4alkynyl. In certain embodiments, R4is C1-C4haloalkyl. In certain embodiments, R4is C1-C5cycloalkyl. In certain embodiments, R4is heteroaryl. In certain embodiments, R4is aryl. In certain embodiments, R4is heterocycle. In certain embodiments, R4is -alkyl-heteroaryl. In certain embodiments, R4is -alkyl-aryl. In certain embodiments, R4is -alkyl-heterocycle. In certain embodiments, R4is -C(O)R5. In certain embodiments, R4is -alkyl-C(O)R5. In certain embodiments, R4is C1-C4alkyl substituted with one R8. In certain embodiments, R4is C2-C4alkenyl substituted with one R8. In certain embodiments, R4is C2-C4alkynyl substituted with one R8. In certain embodiments, R4is C1-C4haloalkyl substituted with one R8. In certain embodiments, R4is cycloalkyl substituted with one R8. In certain embodiments, R4is heteroaryl substituted with one R8. In certain embodiments, R4is aryl substituted with one R8. In certain embodiments, R4is heterocycle substituted with one R8. In certain embodiments, R4is -alkyl-heteroaryl substituted with one R8. In certain embodiments, R4is -alkyl-aryl substituted with one R8. In certain embodiments, R4is -alkyl-heterocycle substituted with one R8. Embodiments of R5In certain embodiments, R5is hydrogen. In certain embodiments, R5is C1-C4alkyl. In certain embodiments, R5is C2-C4alkenyl. In certain embodiments, R5is C2-C4alkynyl. In certain embodiments, R5is C1-C4haloalkyl. In certain embodiments, R5is cycloalkyl. In certain embodiments, R5is heteroaryl. In certain embodiments, R5is aryl. In certain embodiments, R5is heterocycle. In certain embodiments, R5is bicycle. In certain embodiments, R5is -alkyl-heteroaryl. In certain embodiments, R5is -alkyl-aryl. In certain embodiments, R5is -alkyl-heterocycle. In certain embodiments, R5is -OR6. In certain embodiments, R5is -NR6R7. In certain embodiments, R5is C1-C4alkyl substituted with one R10. In certain embodiments, R5is C2-C4alkenyl substituted with one R10. In certain embodiments, R5is C2-C4alkynyl substituted with one R10. In certain embodiments, R5is C1-C4haloalkyl substituted with one R10. In certain embodiments, R5is cycloalkyl substituted with one R10. In certain embodiments, R5is heteroaryl substituted with one R10. In certain embodiments, R5is aryl substituted with one R10. In certain embodiments, R5is heterocycle substituted with one R10. In certain embodiments, R5is -alkyl-heteroaryl substituted with one R10. In certain embodiments, R5is -alkyl-aryl substituted with one R10. In certain embodiments, R5is -alkyl-heterocycle substituted with one R10. Embodiments of R6and R7In certain embodiments, R6is hydrogen. In certain embodiments, R6is C1-C4alkyl. In certain embodiments, R6is C2-C4alkenyl. In certain embodiments, R6is C2-C4alkynyl. In certain embodiments, R6is C1-C4haloalkyl. In certain embodiments, R6is cycloalkyl. In certain embodiments, R6is heteroaryl. In certain embodiments, R6is aryl. In certain embodiments, R6is heterocycle. In certain embodiments, R6is -alkyl-heteroaryl. In certain embodiments, R6is -alkyl-aryl. In certain embodiments, R6is -alkyl-heterocycle. In certain embodiments, R7is hydrogen. In certain embodiments, R7is C1-C4alkyl. In certain embodiments, R7is C2-C4alkenyl. In certain embodiments, R7is C2-C4alkynyl. In certain embodiments, R7is C1-C4haloalkyl. In certain embodiments, R7is cycloalkyl. In certain embodiments, R7is heteroaryl. In certain embodiments, R7is aryl. In certain embodiments, R7is heterocycle. In certain embodiments, R7is -alkyl-heteroaryl. In certain embodiments, R7is -alkyl-aryl. In certain embodiments, R7is -alkyl-heterocycle. In certain embodiments, R6is substituted with one R10substituent. In certain embodiments, R6is substituted with two R10substituents. In certain embodiments, R6is substituted with three R10substituents. In certain embodiments, R7is substituted with one R10substituent. In certain embodiments, R7is substituted with two R10substituents. In certain embodiments, R7is substituted with three R10substituents. Embodiments of R8In certain embodiments, R8is hydrogen. In certain embodiments, R8is C1-C4alkyl. In certain embodiments, R8is C1-C4haloalkyl. In certain embodiments, R8is halogen. In certain embodiments, R8is -OR6. In certain embodiments, R8is -NR6R7. In certain embodiments, R8is -OC(O)R5. In certain embodiments, R8is -NR6C(O)R5. In certain embodiments, R8is -C(O)R5. In certain embodiments, R8is -alkyl-C(O)R5. Embodiments of R9In certain embodiments, R9is hydrogen. In certain embodiments, R9is aryl. In certain embodiments, R9is alkyl-aryl. In certain embodiments, R9is heteroaryl. In certain embodiments, R9is alkyl-heteroaryl. In certain embodiments, R9is heterocycle. In certain embodiments, R9is alkyl-heterocycle. In certain embodiments, R9is cycloalkyl. In certain embodiments, R9is -alkyl-cycloalkyl. In certain embodiments, R9is C1-C4haloalkyl. In certain embodiments, R9is C1-C4alkyl. In certain embodiments, R9is halogen. In certain embodiments, R9is -OR6. In certain embodiments, R9is -NR6R7. In certain embodiments, R9is -C(O)OR6. In certain embodiments, R9is -C(O)NR6R7. In certain embodiments, R9is -alkyl-C(O)OR6. In certain embodiments, R9is -alkyl-C(O)NR6R7. In certain embodiments, R9is C1-C4alkyl with one substituent. In certain embodiments, R9is cycloalkyl with one substituent. In certain embodiments, R9is aryl with one substituent. In certain embodiments, R9is -alkyl-cycloalkyl with one substituent. In certain embodiments, R9is heterocycle with one substituent. In certain embodiments, R9is heteroaryl with one substituent. In certain embodiments, R9is alkyl-aryl with one substituent. In certain embodiments, R9is alkyl-heteroaryl with one substituent. In certain embodiments, R9is cycloalkyl with two substituents. In certain embodiments, R9is heteroaryl with two substituents. In certain embodiments, R9is heterocycle with two substituents. In certain embodiments, R9is aryl with two substituents. In certain embodiments, R9is alkyl-aryl with two substituents. In certain embodiments, R9is alkyl-heteroaryl with two substituents. In certain embodiments, R9is C1-C4alkyl with two substituents. In certain embodiments, R9is -alkyl-cycloalkyl with two substituents. In certain embodiments, R9is cycloalkyl with three substituents. In certain embodiments, R9is heteroaryl with three substituents. In certain embodiments, R9is heterocycle with three substituents. In certain embodiments, R9is aryl with three substituents. In certain embodiments, R9is alkyl-aryl with three substituents. In certain embodiments, R9is alkyl-heteroaryl with three substituents. In certain embodiments, R9is C1-C4alkyl with three substituents. In certain embodiments, R9is -alkyl-cycloalkyl with three substituents. In certain embodiments, the substituent on R9is -S(O)2alkyl. In certain embodiments, the substituent on R9is C1-C4haloalkyl. In certain embodiments, the substituent on R9is C1-C4alkyl. In certain embodiments, the substituent on R9is halogen. In certain embodiments, the substituent on R9is -OR6. In certain embodiments, the substituent on R9is -NR6R7. In certain embodiments, the substituent on R9is -C(O)OR6. In certain embodiments, the substituent on R9is -C(O)NR6R7. In certain embodiments, the substituent on R9is -alkyl-C(O)OR6. In certain embodiments, the substituent on R9is -alkyl-C(O)NR6R7. Embodiments of R10In certain embodiments, R10is hydrogen. In certain embodiments, R10is halogen. In certain embodiments, R10is C1-C4alkyl. In certain embodiments, R10is C2-C4alkenyl. In certain embodiments, R10is C2-C4alkynyl. In certain embodiments, R10is C1-C4haloalkyl. In certain embodiments, R10is cycloalkyl. In certain embodiments, R10is heteroaryl. In certain embodiments, R10is aryl. In certain embodiments, R10is heterocycle. In certain embodiments, R10is -alkyl-heteroaryl. In certain embodiments, R10is -alkyl-aryl. In certain embodiments, R10is -alkyl-heterocycle. Embodiments of R11In certain embodiments, R11is hydrogen. In certain embodiments, R11is C1-C4alkyl. In certain embodiments, R11is C2-C4alkenyl. In certain embodiments, R11is C2-C4alkynyl. In certain embodiments, R11is C1-C4haloalkyl. In certain embodiments, R11is cycloalkyl. In certain embodiments, R11is heteroaryl. In certain embodiments, R11is aryl. In certain embodiments, R11is heterocycle In certain embodiments, R11is -alkyl-heteroaryl. In certain embodiments, R11is -alkyl-aryl. In certain embodiments, R11is -alkyl-heterocycle. Embodiments of R12In certain embodiments, R12is hydrogen. In certain embodiments, R12is C1-C4alkyl. In certain embodiments, R12is C2-C4alkenyl. In certain embodiments, R12is C2-C4alkynyl. In certain embodiments, R12is C1-C4haloalkyl. In certain embodiments, R12is cycloalkyl. In certain embodiments, R12is heteroaryl. In certain embodiments, R12is aryl. In certain embodiments, R12is heterocycle. In certain embodiments, R12is -alkyl-heteroaryl. In certain embodiments, R12is -alkyl-aryl. In certain embodiments, R12is -alkyl-heterocycle. In certain embodiments, R12is -C(O)R5. In certain embodiments, R12is -alkyl-C(O)R5. In certain embodiments, R12is C1-C4alkyl substituted with one R8. In certain embodiments, R12is C2-C4alkenyl substituted with one R8. In certain embodiments, R12is C2-C4alkynyl substituted with one R8. In certain embodiments, R12is C1-C4haloalkyl substituted with one R8. In certain embodiments, R12is cycloalkyl substituted with one R8. In certain embodiments, R12is heteroaryl substituted with one R8. In certain embodiments, R12is aryl substituted with one R8. In certain embodiments, R12is heterocycle substituted with one R8. In certain embodiments, R12is -alkyl-heteroaryl substituted with one R8. In certain embodiments, R12is -alkyl-aryl substituted with one R8. In certain embodiments, R12is -alkyl-heterocycle substituted with one R8. Embodiments of R13In certain embodiments, R13is hydrogen. In certain embodiments, R13is C1-C4alkyl. In certain embodiments, R13is C2-C4alkenyl. In certain embodiments, R13is C2-C4alkynyl. In certain embodiments, R13is C1-C4haloalkyl. In certain embodiments, R13is cycloalkyl. In certain embodiments, R13is heteroaryl. In certain embodiments, R13is aryl. In certain embodiments, R13is heterocycle. In certain embodiments, R13is -alkyl-heteroaryl. In certain embodiments, R13is -alkyl-aryl. In certain embodiments, R13is -alkyl-heterocycle. In certain embodiments, R13is -C(O)R5. In certain embodiments, R13is -alkyl-C(O)R5. In certain embodiments, R13is C1-C4alkyl substituted with one R8. In certain embodiments, R13is C2-C4alkenyl substituted with one R8. In certain embodiments, R13is C2-C4alkynyl substituted with one R8. In certain embodiments, R13is C1-C4haloalkyl substituted with one R8. In certain embodiments, R13is cycloalkyl substituted with one R8. In certain embodiments, R13is heteroaryl substituted with one R8. In certain embodiments, R13is aryl substituted with one R8. In certain embodiments, R13is heterocycle substituted with one R8. In certain embodiments, R13is -alkyl-heteroaryl substituted with one R8. In certain embodiments, R13is -alkyl-aryl substituted with one R8. In certain embodiments, R13is -alkyl-heterocycle substituted with one R8. Embodiments of R14In certain embodiments, R14is hydrogen. In certain embodiments, R14is C1-C4alkyl. In certain embodiments, R14is C2-C4alkenyl. In certain embodiments, R14is C2-C4alkynyl. In certain embodiments, R14is C1-C4haloalkyl. In certain embodiments, R14is C3-C4cycloalkyl. In certain embodiments, R14is heteroaryl. In certain embodiments, R14is aryl. In certain embodiments, R14is heterocycle. In certain embodiments, R14is -alkyl-heteroaryl. In certain embodiments, R14is -alkyl-aryl. In certain embodiments, R14is -alkyl-heterocycle. In certain embodiments, R14is -C(O)R5. In certain embodiments, R14is -alkyl-C(O)R5. In certain embodiments, R14is -OC(O)R5. In certain embodiments, R14is -NR6C(O)R5. In certain embodiments, R14is C1-C4alkyl substituted with one R8. In certain embodiments, R14is C2-C4alkenyl substituted with one R8. In certain embodiments, R14is C2-C4alkynyl substituted with one R8. In certain embodiments, R14is C1-C4haloalkyl substituted with one R8. In certain embodiments, R14is cycloalkyl substituted with one R8. In certain embodiments, R14is heteroaryl substituted with one R8. In certain embodiments, R14is aryl substituted with one R8. In certain embodiments, R14is heterocycle substituted with one R8. In certain embodiments, R14is -alkyl-heteroaryl substituted with one R8. In certain embodiments, R14is -alkyl-aryl substituted with one R8. In certain embodiments, R14is -alkyl-heterocycle substituted with one R8. Embodiments of R20In certain embodiments, R20is a bond. In certain embodiments, R20is alkyl. In certain embodiments, R20is -C(O)-. In certain embodiments, R20is -C(O)O-. In certain embodiments, R20is -OC(O)-. In certain embodiments, R20is -SO2-. In certain embodiments, R20is -S(O)-. In certain embodiments, R20is -C(S)-. In certain embodiments, R20is -C(O)NR2-. In certain embodiments, R20is -NR2C(O)-. In certain embodiments, R20is -O-. In certain embodiments, R20is -S-. In certain embodiments, R20is -NR2-. In certain embodiments, R20is -P(O)(OR26)O-. In certain embodiments, R20is -P(O)(OR26)-. In certain embodiments, R20is bicycle. In certain embodiments, R20is alkene. In certain embodiments, R20is alkyne. In certain embodiments, R20is haloalkyl. In certain embodiments, R20is alkoxy. In certain embodiments, R20is aryl. In certain embodiments, R20is heterocycle. In certain embodiments, R20is aliphatic. In certain embodiments, R20is heteroaliphatic. In certain embodiments, R20is heteroaryl. In certain embodiments, R20is lactic acid. In certain embodiments, R20is glycolic acid. In certain embodiments, R20is carbocycle. In certain embodiments, R20is substituted with one R40substituent. In certain embodiments, R20is substituted with two R40substituents. In certain embodiments, R20is substituted with three R40substituents. In certain embodiments, R20is substituted with four R40substituents. Embodiments of R21In certain embodiments, R21is a bond. In certain embodiments, R21is alkyl. In certain embodiments, R21is -C(O)-. In certain embodiments, R21is -C(O)O-. In certain embodiments, R21is -OC(O)-. In certain embodiments, R21is -SO2-. In certain embodiments, R21is -S(O)-. In certain embodiments, R21is -C(S)-. In certain embodiments, R21is -C(O)NR2-. In certain embodiments, R21is -NR2C(O)-. In certain embodiments, R21is -O-. In certain embodiments, R21is -S-. In certain embodiments, R21is -NR2-. In certain embodiments, R21is -P(O)(OR26)O-. In certain embodiments, R21is -P(O)(OR26)-. In certain embodiments, R21is bicycle. In certain embodiments, R21is alkene. In certain embodiments, R21is alkyne. In certain embodiments, R21is haloalkyl. In certain embodiments, R21is alkoxy. In certain embodiments, R21is aryl. In certain embodiments, R21is heterocycle. In certain embodiments, R21is aliphatic. In certain embodiments, R21is heteroaliphatic. In certain embodiments, R21is heteroaryl. In certain embodiments, R21is lactic acid. In certain embodiments, R21is glycolic acid. In certain embodiments, R21is carbocycle. In certain embodiments, R21is substituted with one R40substituent. In certain embodiments, R21is substituted with two R40substituents. Embodiments of R22In certain embodiments, R22is a bond. In certain embodiments, R22is alkyl. In certain embodiments, R22is -C(O)-. In certain embodiments, R22is -C(O)O-. In certain embodiments, R22is -OC(O)-. In certain embodiments, R22is -SO2-. In certain embodiments, R22is -S(O)-. In certain embodiments, R22is -C(S)-. In certain embodiments, R22is -C(O)NR2-. In certain embodiments, R22is -NR2C(O)-. In certain embodiments, R22is -O-. In certain embodiments, R22is -S-. In certain embodiments, R22is -NR2-. In certain embodiments, R22is -P(O)(OR26)O-. In certain embodiments, R22is -P(O)(OR26)-. In certain embodiments, R22is bicycle. In certain embodiments, R22is alkene. In certain embodiments, R22is alkyne. In certain embodiments, R22is haloalkyl. In certain embodiments, R22is alkoxy. In certain embodiments, R22is aryl. In certain embodiments, R22is heterocycle. In certain embodiments, R22is aliphatic. In certain embodiments, R22is heteroaliphatic. In certain embodiments, R22is heteroaryl. In certain embodiments, R22is lactic acid. In certain embodiments, R22is glycolic acid. In certain embodiments, R22is carbocycle. In certain embodiments, R22is substituted with one R40substituent. In certain embodiments, R22is substituted with two R40substituents. In certain embodiments, R22is substituted with three R40substituents. In certain embodiments, R22is substituted with four R40substituents. Embodiments of R23In certain embodiments, R23is a bond. In certain embodiments, R23is alkyl. In certain embodiments, R23is -C(O)-. In certain embodiments, R23is -C(O)O-. In certain embodiments, R23is -OC(O)-. In certain embodiments, R23is -SO2-. In certain embodiments, R23is -S(O)-. In certain embodiments, R23is -C(S)-. In certain embodiments, R23is -C(O)NR2-. In certain embodiments, R23is -NR2C(O)-. In certain embodiments, R23is -O-. In certain embodiments, R23is -S-. In certain embodiments, R23is -NR2-. In certain embodiments, R23is -P(O)(OR26)O-. In certain embodiments, R23is -P(O)(OR26)-. In certain embodiments, R23is bicycle. In certain embodiments, R23is alkene. In certain embodiments, R23is alkyne. In certain embodiments, R23is haloalkyl. In certain embodiments, R23is alkoxy. In certain embodiments, R23is aryl. In certain embodiments, R23is heterocycle. In certain embodiments, R23is aliphatic. In certain embodiments, R23is heteroaliphatic. In certain embodiments, R23is heteroaryl. In certain embodiments, R23is lactic acid. In certain embodiments, R23is glycolic acid. In certain embodiments, R23is carbocycle. In certain embodiments, R23is substituted with one R40substituent. In certain embodiments, R23is substituted with two R40substituents. In certain embodiments, R23is substituted with three R40substituents. In certain embodiments, R23is substituted with four R40substituents. Embodiments of R24In certain embodiments, R24is a bond. In certain embodiments, R24is alkyl. In certain embodiments, R24is -C(O)-. In certain embodiments, R24is -C(O)O-. In certain embodiments, R24is -OC(O)-. In certain embodiments, R24is -SO2-. In certain embodiments, R24is -S(O)-. In certain embodiments, R24is -C(S)-. In certain embodiments, R24is -C(O)NR2-. In certain embodiments, R24is -NR2C(O)-. In certain embodiments, R24is -O-. In certain embodiments, R24is -S-. In certain embodiments, R24is -NR2-. In certain embodiments, R24is -P(O)(OR26)O-. In certain embodiments, R24is -P(O)(OR26)-. In certain embodiments, R24is bicycle. In certain embodiments, R24is alkene. In certain embodiments, R24is alkyne. In certain embodiments, R24is haloalkyl. In certain embodiments, R24is alkoxy. In certain embodiments, R24is aryl. In certain embodiments, R24is heterocycle. In certain embodiments, R24is aliphatic. In certain embodiments, R24is heteroaliphatic. In certain embodiments, R24is heteroaryl. In certain embodiments, R24is lactic acid. In certain embodiments, R24is glycolic acid. In certain embodiments, R24is carbocycle. In certain embodiments, R24is substituted with one R40substituent. In certain embodiments, R24is substituted with two R40substituents. In certain embodiments, R24is substituted with three R40substituents. In certain embodiments, R24is substituted with four R40substituents. Embodiments of R26In certain embodiments, R26is hydrogen. In certain embodiments, R26is alkyl. In certain embodiments, R26is arylalkyl. In certain embodiments, R26is heteroarylalkyl. In certain embodiments, R26is alkene. In certain embodiments, R26is alkyne. In certain embodiments, R26is aryl. In certain embodiments, R26is heteroaryl. In certain embodiments, R26is heterocycle. In certain embodiments, R26is aliphatic. In certain embodiments, R26is heteroaliphatic. Embodiments of R40In preferred embodiments when there are two R40s on a methylene unit of the linker each R40is selected from CH3and hydrogen. For example when the linker includes in this embodiment is selected from , , , , . In certain embodiments, R40is hydrogen. In certain embodiments, R40is alkyl. In certain embodiments, R40is alkene. In certain embodiments, R40is alkyne. In certain embodiments, R40is fluoro. In certain embodiments, R40is bromo. In certain embodiments, R40is chloro. In certain embodiments, R40is hydroxyl. In certain embodiments, R40is alkoxy. In certain embodiments, R40is azide. In certain embodiments, R40is amino. In certain embodiments, R40is cyano. In certain embodiments, R40is -NH(aliphatic, including alkyl). In certain embodiments, R40is -N(aliphatic, including alkyl)2. In certain embodiments, R40is -NHSO2(aliphatic, including alkyl). In certain embodiments, R40is -N(aliphatic, including alkyl)SO2alkyl. In certain embodiments, R40is -NHSO2(aryl, heteroaryl or heterocycle). In certain embodiments, R40is -N(alkyl)SO2(aryl, heteroaryl or heterocycle). In certain embodiments, R40is -NHSO2alkenyl. In certain embodiments, R40is -N(alkyl)SO2alkenyl. In certain embodiments, R40is -NHSO2alkynyl. In certain embodiments, R40is -N(alkyl)SO2alkynyl. In certain embodiments, R40is haloalkyl. In certain embodiments, R40is aliphatic. In certain embodiments, R40is heteroaliphatic. In certain embodiments, R40is aryl. In certain embodiments, R40is heteroaryl. In certain embodiments, R40is heterocycle. In certain embodiments, R40is cycloalkyl. In certain embodiments selected from the group consisting of: . In an alternative embodiment the para-connected structures in the embodiments herein are in the meta configuration.

[0044] . consisting of:

[0045] o

[0046] c

[0047] o

[0048] o

[0049] In certain embodiments, the Cereblon Ligand is selected from the group consisting of: In certain embodiments, the Cereblon Ligand is selected from the group consisting of: . In certain embodiments, the Cereblon Ligand is selected from the group consisting of:

[0050] c a consisting of:

[0051] , selected from the group consisting of: .

[0052] In certain embodiments, selected from the group consisting of: In certain embodiments, the Cereblon Ligand is selected from the group consisting of:

[0053] In certain embodiments, the Cereblon ligand is selected from the group consisting of:

[0054] In certain embodiments selected from the group consisting of: .

[0055] c . In certain embodiments, the structure of the compound is typically selected such that it is sufficiently stable to sustain a shelf life of at least two, three, four, or five months under ambient conditions. To accomplish this, each of the variables described herein must be sufficiently stable to sustain the corresponding desired shelf life of at least two, three, four, or five months under ambient conditions. One of ordinary skill in the art is well aware of the stability of chemical moieties and can avoid those that are not stable or are too reactive under appropriate conditions. In certain alternative embodiments, the compound of the present invention including any of the variable groups described herein, may be optionally substituted as described below in Section I. Definitions, if desired to achieve the target effect, results in a stable moiety and final compound that makes chemical sense to the routineer, and if a final compound for therapy, is pharmaceutically acceptable. Also, all variables, with or without optional substituents, should be interpreted in a manner that does not include redundancy (i.e., as known in the art, alkyl substituted with alkyl is redundant; however, for example, alkoxy substituted with alkoxy is not redundant). III. RET TARGETING LIGAND RET forms a complex with its natural ligands, a family of glial-derived neurotrophic factors, and with glycosyl phosphatidylinositol-linked co-receptors, resulting in dimerization and subsequent activation of the kinase domain through the formation of a multimeric signaling complex consisting of RET's soluble ligand glial derived neurotrophic factor (GDNF) and a membrane-bound coreceptor (GDNF family receptor α1). This complex causes autophosphorylation of tyrosine residues. As a result of this mechanism glial family ligand mediated activation of wildtype RET is an increasingly recognized mechanism related to tumor growth and dissemination of a much broader group of cancers. (Mulligan LM., “GDNF and the RET Receptor in Cancer: New Insights and Therapeutic Potential”, Front. Physiol., 2019, 9(1873), 1-13; and Airaksinen MS, and Saarma M., “The GDNF family: signaling, biological functions and therapeutic value”, Nat Rev Neurosci., 2002, 3(5), 383-94). There are multiple protein isoforms of RET including RET9, RET51 and RET43 each of which differs in the lengths of carboxyl-terminal tails and their ability to bind SHC, GRB2, c-CBL, and SHANK3. Each RET isoform has a unique C-terminal tail sequences that recruits distinct protein complexes to mediate signals. (Lorenzo MJ, et al., “RET alternative splicing influences the interaction of activated RET with the SH2 and PTB domains of Shc, and the SH2 domain of Grb2”, Oncogene, 1997, 14, 763-771). Studies on Acute myeloid leukemia (AML) have shown that AML subtypes were dependent on expression of the RET receptor tyrosine kinase (RTK), and that depletion of RET by shRNA knockdown or CRISPR / Cas9-mediated knockout led to cell cycle arrest in the G0 / G1 phase, increased apoptosis, and reduced clonogenic activity. Analysis of known RET ligand / co-receptor pairs (GDNF / GFRA1, NRTN / GFRA2, ARTN / GFRA3, PSPN / GFRA4) by quantitative real-time PCR and shRNA knockdown indicated that RET signaling is facilitated mainly through NTRN / GFRA2 or ARTN / GFRA3. (Rudat S., et al., “The RET Receptor Tyrosine Kinase Promotes Acute Myeloid Leukemia through Protection of FLT3- ITD Mutants from Autophagic Degradation”, Blood, 2016, 128(22), 2849). The RET fusions genes are mutually exclusive with other known drivers in lung adenocarcinoma (e.g., KRAS, epidermal growth factor receptor (EGFR), EML4-anaplastic lymphoma kinase (ALK)), further supporting a role for RET as a unique driver of malignancy in these tumors. In certain embodiments the RET Targeting Ligand is: . In certain embodiments the RET Targeting Ligand is selected from the group consisting of: . In certain embodiments the RET Targeting Ligand is: . In certain embodiments the RET Targeting Ligand is selected from the group consisting of: . In certain embodiments the RET Targeting Ligand is: . In certain embodiments the RET Targeting Ligand is selected from the group consisting of: .

[0056] In certain embodiments the RET Targeting Ligand is: . In certain embodiments the RET Targeting Ligand is: . In certain embodiments the RET Targeting Ligand is: . In the embodiments below R is hydrogen, halogen, C1-C3alkyl, or C1-C3haloalkyl. In certain embodiments, the RET Targeting Ligand is , . In certain embodiments, the RET Targeting Ligand is . In certain embodiments, the RET Targeting Ligand is selected from the group consisting of: ,

[0057] ,,

[0058] In certain embodiments, is selected from the group consisting of: . In certain embodiments, selected from the group consisting of: . In certain embodiments, the RET Targeting Ligand is selected from the group consisting of: , , , , , IV. LINKERS A Linker is included in the compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, or Formula X. Linker is a chemically stable bivalent group that attaches an E3 Ligase binding portion to a Targeting Ligand. According to the invention, any desired linker, as described herein, can be used as long as the resulting compound has a stable shelf life for at least 2 months, 3 months, 6 months or 1 year as part of a pharmaceutically acceptable dosage form, and itself is pharmaceutically acceptable. Linker as described herein can be used in either direction, i.e., either the left end is linked to the E3 Ligase Binding portion and the right end to the RET Targeting Ligand, or the left end is linked to the RET Targeting Ligand and the right end is linked to the E3 Ligase Binding portion. In certain embodiments, the Linker has a chain of 2 to 14, 15, 16, 17, 18 or 20 or more carbon atoms of which one or more carbons can be replaced by a heteroatom such as O, N, S, or P. In certain embodiments, the chain has 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous atoms in the chain. For example, the chain may include 1 or more ethylene glycol units that can be contiguous, partially contiguous or non-contiguous (for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ethylene glycol units). In certain embodiments, the chain has at least 1, 2, 3, 4, 5, 6, 7, or 8 contiguous chains which can have branches which can be independently alkyl, aryl, heteroaryl, alkenyl, or alkynyl, aliphatic, heteroaliphatic, cycloalkyl or heterocycle substituents. In other embodiments, the linker can include or be comprised of one or more of ethylene glycol, propylene glycol, lactic acid and / or glycolic acid. Lactic acid segments tend to have a longer half-life than glycolic acid segments. Block and random lactic acid-co-glycolic acid moieties, as well as ethylene glycol and propylene glycol, are known in the art to be pharmaceutically acceptable and can be modified or arranged to obtain the desired half-life and hydrophilicity. In certain aspects, these units can be flanked or interspersed with other moieties, such as aliphatic, including alkyl, heteroaliphatic, aryl, heteroaryl, heterocycle, cycloalkyl, etc., as desired to achieve the appropriate drug properties. In certain embodiments, Linker is selected from: . In one aspect, Linker is selected from the group consisting of a moiety of Formula LI, Formula LII, Formula LIII, Formula LIV, Formula LV, Formula LVI, Formula LVII Formula LVIII, Formula IX and Formula LX:

[0059] ; wherein, X1and X2are independently at each occurrence selected from bond, heterocycle, NR2, C(R2)2, O, C(O), and S; R2is independently at each occurrence selected from the group consisting of hydrogen, alkyl, aliphatic, heteroaliphatic, heterocycle, aryl, heteroaryl, -C(O)H, -C(O)OH, -C(O)alkyl, -C(O)Oalkyl, -C(O)(aliphatic, aryl, heteroaliphatic or heteroaryl), -C(O)O(aliphatic, aryl, heteroaliphatic, or heteroaryl), alkene, and alkyne; R20, R21, R22, R23, and R24are independently at each occurrence selected from the group consisting of a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR2-, -NR2C(O)-, -O-, -S-, -NR2-, -P(O)(OR26)O-, -P(O)(OR26)-, alkene, alkyne, haloalkyl, alkoxy, aryl, heterocycle, aliphatic, heteroaliphatic, heteroaryl, lactic acid, glycolic acid, and carbocycle; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R40; R26is independently at each occurrence selected from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocycle, aliphatic and heteroaliphatic; and R40is independently at each occurrence selected from the group consisting of hydrogen, alkyl, alkene, alkyne, fluoro, bromo, chloro, hydroxyl, alkoxy, azide, amino, cyano, -NH(aliphatic, including alkyl), -N(aliphatic, including alkyl)2, -NHSO2(aliphatic, including alkyl), -N(aliphatic, including alkyl)SO2alkyl, -NHSO2(aryl, heteroaryl or heterocycle), -N(alkyl)SO2(aryl, heteroaryl or heterocycle), -NHSO2alkenyl, -N(alkyl)SO2alkenyl, -NHSO2alkynyl, -N(alkyl)SO2alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocycle, and cycloalkyl. In certain embodiments, Linker selected from: . In one aspect, Linker is selected from the group consisting of a moiety of Formula LDI, Formula LDII, Formula LDIII, Formula LDIV, Formula LDV, Formula LDVI, and Formula LDVII: , wherein all variables are described herein. The following are non-limiting examples of Linkers that can be used in this invention. Based on this elaboration, those of skill in the art will understand how to use the full breadth of Linkers that will accomplish the goal of the invention. Non-limiting examples of Linker include: Non-limiting examples of Linker include:

[0060] . In certain embodiments, X2is attached to the RET Targeting Ligand. In other embodiments, X1is attached to the RET Targeting Ligand. Non-limiting examples of moieties of R20, R21, R22, R23, and R24include: . Additional non-limiting examples of moieties of R20, R21, R22, R23, and R24include:

[0061] . Additional non-limiting examples of moieties of R20, R21, R22, R23, and R24include: . In additional embodiments, the Linker moiety is an optionally substituted (poly)ethylene glycol having at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, ethylene glycol units, or optionally substituted alkyl groups interspersed with optionally substituted, O, N, S, P or Si atoms. In certain embodiments, the Linker is flanked, substituted, or interspersed with an aryl, phenyl, benzyl, alkyl, alkylene, or heterocycle group. In certain embodiments, the Linker may be asymmetric or symmetrical. In certain embodiments, Linker can be a nonlinear chain, and can be, or include, aliphatic or aromatic or heteroaromatic cyclic moieties. In any of the embodiments of the compounds described herein, the Linker group may be any suitable moiety as described herein. In certain embodiments, Linker is selected from or contains a moiety selected from the group consisting of: In certain embodiments, Linker is selected from or contains a moiety selected from the group consisting of: In certain embodiments, Linker is selected from or contains a moiety selected from the group consisting of: In certain embodiments, Linker is selected from or contains a moiety selected from the group consisting of: . In certain embodiments, Linker is selected from or contains a moiety selected from the group consisting of: In certain embodiments, Linker is selected from or contains a moiety selected from the group consisting of:

[0062] . In certain embodiments, Linker is selected from or contains a moiety selected from the group consisting of: In certain embodiments, Linker is selected from or contains a moiety selected from the group consisting of: , ,

[0063] . In certain embodiments, the right bond of the Linker drawn above is attached to the RET Targeting Ligand. In certain embodiments, the left bond of the Linker drawn above is attached to the RET Targeting Ligand. In certain embodiments, the compound of the present invention is selected from the group consisting of:

[0064] or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from the group consisting of: nd or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from the group consisting of:

[0065] or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is or a pharmaceutically acceptable salt thereof. V. METHODS OF TREATMENT A compound described herein can be used in an effective amount to treat a patient, typically a human, in need thereof, who has a disorder mediated by RET which can be a wild-type RET or mutant RET as described generally herein. Another aspect of the present invention provides a compound as described herein, or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition, for use in the manufacture of a medicament for treating or preventing cancer in a patient in need thereof; wherein there is a need of RET inhibition for the treatment or prevention of cancer. In certain embodiments, the method comprises administering an effective amount of the active compound or its salt as described herein, optionally including a pharmaceutically acceptable excipient, carrier, or adjuvant (i.e., a pharmaceutically acceptable composition), or optionally in combination or alternation with another bioactive agent or combination of agents, to a patient in need thereof. In certain embodiments, the present invention provides a method of treating any of the disorders described herein, in a patient in need thereof. In other embodiments, the patient is administered an additional therapeutic agent. In other embodiments, the compound as described herein, and the additional therapeutic agent are administered simultaneously or sequentially. In certain embodiments, the application provides a method of preventing any of the disorders described herein, in a patient in need thereof. In certain embodiments, the patient is a human. Another aspect of the present invention provides a method of treating or preventing a proliferative disease. The method comprises administering an effective amount of a pharmaceutical composition comprising a compound as described herein, or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, or solvate thereof and optionally a pharmaceutically acceptable carrier to a patient in need thereof. In some embodiments, the disease is mediated by RET, for example, RET plays a role in the initiation or development of the disease. In certain embodiments, the RET mediated disorder is a benign growth, metastasis, neoplasm, tumor, solid tumor, rhabdoid tumor, carcinoma, leukemia, cancer, abnormal cellular proliferation, an amyloid-based proteinopathy, a proteinopathy, fibrotic disorder, inflammation, arthritis, pulmonary disorders, or immune disorders. In certain embodiments, the RET mediated disorder is a cancer that has metastasized, for example a cancer that has metastasized to the brain. In certain embodiments, the RET mediated disorder is a cancer that has metastasized to the brain, lungs bone, liver, peritoneum, adrenal gland, skin, or muscle. In certain embodiments, a compound of the present invention penetrates the blood brain barrier and can be used for the treatment of a CNS involved cancer or a cancer that has metastasized to the brain. In certain embodiments, the disease or disorder is cancer or a proliferation disease. In certain embodiments, the RET mediated disorder is an abnormal cell proliferation, including, but not limited to, a tumor or cancer, or a myelo- or lymphoproliferative disorder such as B- or T-cell lymphomas, multiple myeloma, Waldenstrom’s macroglobulinemia, Wiskott- Aldrich syndrome, or a post-transplant lymphoproliferative disorder. In certain embodiments, the hematological cancer is acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), lymphoblastic T-cell leukemia, chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), hairy-cell leukemia, chronic neutrophilic leukemia (CNL), acute lymphoblastic T-cell leukemia, acute monocytic leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryoblastic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, mixed lineage leukemia (MLL), erythroleukemia, malignant lymphoma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, lymphoblastic T-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, B cell acute lymphoblastic leukemia, diffuse large B cell lymphoma, Myc and B-Cell Leukemia (BCL)2 and / or BCL6 rearrangements / overexpression [double- and triple-hit lymphoma], myelodysplastic / myeloproliferative neoplasm, mantle cell lymphoma including bortezomib resistant mantle cell lymphoma. Solid tumors that can be treated with the compounds described herein include, but are not limited to lung cancers, including small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), breast cancers including inflammatory breast cancer, ER-positive breast cancer including tamoxifen resistant ER-positive breast cancer, and triple negative breast cancer, colon cancers, midline carcinomas, liver cancers, renal cancers, prostate cancers including castrate resistant prostate cancer (CRPC), brain cancers including gliomas, glioblastomas, neuroblastoma, and medulloblastoma including MYC-amplified medulloblastoma, colorectal cancers, Wilm's tumor, Ewing's sarcoma, rhabdomyosarcomas, ependymomas, head and neck cancers, melanomas, squamous cell carcinomas, ovarian cancers, pancreatic cancers including pancreatic ductal adenocarcinomas (PDAC) and pancreatic neuroendocrine tumors (PanNET), osteosarcomas, giant cell tumors of bone, thyroid cancers, bladder cancers, urothelial cancers, vulval cancers, cervical cancers, endometrial cancers, mesotheliomas, esophageal cancers, salivary gland cancers, gastric cancers, nasopharyngeal cancers, buccal cancers, cancers of the mouth, GIST (gastrointestinal stromal tumors), NUT-midline carcinomas, testicular cancers, squamous cell carcinomas, hepatocellular carcinomas (HCC), MYCN driven solid tumors, and NUT midline carcinomas (NMC). In further embodiments, the disease or disorder is sarcoma of the bones, muscles, tendons, cartilage, nerves, fat, or blood vessels. In further embodiments, the disease or disorder is soft tissue sarcoma, bone sarcoma, or osteosarcoma. In further embodiments, the disease or disorder is angiosarcoma, fibrosarcoma, liposarcoma, leiomyosarcoma, Kaposi’s sarcoma, osteosarcoma, gastrointestinal stromal tumor, synovial sarcoma, Pleomorphic sarcoma, chondrosarcoma, Ewing's sarcoma, reticulum cell sarcoma, hemangiosarcoma, botryoid sarcoma, rhabdomyosarcoma, or embryonal rhabdomyosarcoma. In further embodiments, the disease or disorder is multiple myeloma. In other embodiments, the disease or disorder is inflammation, arthritis, rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, juvenile arthritis, and other arthritic conditions, neuroinflammation, allergy, pain, neuropathic pain, fever, pulmonary disorders, lung inflammation, adult respiratory distress chronic pulmonary inflammatory disease, and chronic obstructive pulmonary disease (COPD), liver disease and nephritis, gastrointestinal conditions, inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, ulcerative diseases, gastric ulcers, autoimmune disease, graft vs. host reaction and allograft rejections, cancer, leukemia, lymphoma, colorectal cancer, brain cancer, bone cancer, epithelial call-derived neoplasia (epithelial carcinoma), basal cell carcinoma, adenocarcinoma, gastrointestinal cancer, lip cancer, mouth cancer, esophageal cancer, small bowel cancer, stomach cancer, colon cancer, liver cancer, bladder cancer, pancreas cancer, ovarian cancer, ovarian epithelial carcinoma, cervical cancer, lung cancer, breast cancer, skin cancer, squamous cell and / or basal cell cancers, prostate cancer, renal cell carcinoma, and other known cancers that affect epithelial cells throughout the body, chronic myelogenous leukemia (CML), acute myeloid leukemia (AML) and acute promyelocytic leukemia (APL), angiogenesis including neoplasia, metastasis, central nervous system disorders, central nervous system disorders having an inflammatory or apoptotic component, peripheral neuropathy, or B-Cell Lymphoma. In other embodiments, the pharmaceutical composition comprising the compound as described herein and the additional therapeutic agent are administered simultaneously or sequentially. In other embodiments, the disease or disorder is cancer. In further embodiments, the cancer is lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, pancreas cancer, brain cancer, kidney cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, gastric cancer, pancreatic cancer, glioma, glioblastoma, hepatocellular carcinoma, papillary renal carcinoma, head and neck squamous cell carcinoma, leukemias, lymphomas, myelomas, solid tumors, hematological cancers or solid cancers. In certain embodiments, the cancer is medullary thyroid cancer. In certain embodiments, the cancer is papillary thyroid cancer. In certain embodiments, the cancer is non-small cell lung cancer. In some embodiments, said method is used to treat or prevent a condition selected from autoimmune diseases, inflammatory diseases, proliferative and hyperproliferative diseases, and immunologically-mediated diseases. In other embodiments, said condition is selected from a proliferative disorder. In certain embodiments, the RET mediated disorder is an immune disorder, including but not limited to, autoimmune disorders such as Addison disease, Celiac disease, dermatomyositis, Graves’ disease, thyroiditis, multiple sclerosis, pernicious anemia, reactive arthritis, lupus, or type I diabetes. One aspect of this application provides compounds that are useful for the treatment of diseases, disorders, and conditions characterized by excessive or abnormal cell proliferation. Such diseases include, but are not limited to, a proliferative or hyperproliferative disease. Examples of proliferative and hyperproliferative diseases include, without limitation, cancer. The term "cancer" includes, but is not limited to, the following cancers: breast; ovary; cervix; prostate; testis, genitourinary tract; esophagus; larynx, glioblastoma; neuroblastoma; stomach; skin, keratoacanthoma; lung, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma; bone; colon; colorectal; adenoma; pancreas, adenocarcinoma; colorectal adenocarcinoma; thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma; seminoma; melanoma; sarcoma; bladder carcinoma; liver carcinoma and biliary passages; kidney carcinoma; myeloid disorders; lymphoid disorders, Hodgkin's, hairy cells; buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx; small intestine; colorectum, large intestine, rectum, brain and central nervous system; chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), and leukemia. The term "cancer" includes, but is not limited to, the following cancers: myeloma, lymphoma, or a cancer selected from gastric, renal, or and the following cancers: head and neck, oropharyngeal, non-small cell lung cancer (NSCLC), endometrial, hepatocarcinoma, non-Hodgkin’s lymphoma, and pulmonary. The term "cancer" refers to any cancer caused by the proliferation of malignant neoplastic cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, lymphomas and the like. For example, cancers include, but are not limited to, mesothelioma, leukemias and lymphomas such as cutaneous T-cell lymphomas (CTCL), noncutaneous peripheral T-cell lymphomas, lymphomas associated with human T-cell lymphotrophic virus (HTLV) such as adult T-cell leukemia / lymphoma (ATLL), B-cell lymphoma, acute nonlymphocytic leukemias, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myelomonocytic leukemia, acute myelogenous leukemia, lymphomas, and multiple myeloma, non-Hodgkin lymphoma, acute lymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), Hodgkin's lymphoma, Burkitt lymphoma, adult T-cell leukemia lymphoma, acute-myeloid leukemia (AML), chronic myeloid leukemia (CML), or hepatocellular carcinoma. Further examples include myelodysplastic syndrome, childhood solid tumors such as brain tumors, neuroblastoma, retinoblastoma, Wilms' tumor, bone tumors, and soft-tissue sarcomas, common solid tumors of adults such as head and neck cancers, such as oral, laryngeal, nasopharyngeal and esophageal, genitourinary cancers, such as prostate, bladder, renal, uterine, ovarian, testicular, lung cancer, such as small-cell and non- small cell, breast cancer, pancreatic cancer, melanoma and other skin cancers, stomach cancer, brain tumors, tumors related to Gorlin's syndrome, such as medulloblastoma or meningioma, and liver cancer. Additional exemplary forms of cancer include, but are not limited to, cancer of skeletal or smooth muscle, stomach cancer, cancer of the small intestine, rectum carcinoma, cancer of the salivary gland, endometrial cancer, adrenal cancer, anal cancer, rectal cancer, parathyroid cancer, and pituitary cancer. Additional cancers that the compounds described herein may be useful in preventing, treating and studying are, for example, colon carcinoma, familial adenomatous polyposis carcinoma and hereditary non-polyposis colorectal cancer, or melanoma. Further, cancers include, but are not limited to, labial carcinoma, larynx carcinoma, hypopharynx carcinoma, tongue carcinoma, salivary gland carcinoma, gastric carcinoma, adenocarcinoma, thyroid cancer (medullary thyroid carcinoma and papillary thyroid carcinoma), renal carcinoma, kidney parenchyma carcinoma, cervix carcinoma, uterine corpus carcinoma, endometrium carcinoma, chorion carcinoma, testis carcinoma, urinary carcinoma, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumors, gall bladder carcinoma, bronchial carcinoma, multiple myeloma, basalioma, teratoma, retinoblastoma, choroidea melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma, and plasmacytoma. In one aspect of the application, the present application provides for the use of one or more compound as described herein, in the manufacture of a medicament for the treatment of cancer, including without limitation the various types of cancer disclosed herein. In some embodiments, the compounds of this application are useful for treating cancer, such as colorectal, thyroid, breast, and lung cancer; and myeloproliferative disorders, such as polycythemia vera, thrombocythemia, myeloid metaplasia with myelofibrosis, chronic myelogenous leukemia, chronic myelomonocytic leukemia, hypereosinophilic syndrome, juvenile myelomonocytic leukemia, and systemic mast cell disease. In some embodiments, the compound as described herein is useful for treating hematopoietic disorders, in particular, acute-myelogenous leukemia (AML), chronic-myelogenous leukemia (CML), acute-promyelocytic leukemia, and acute lymphocytic leukemia (ALL). In certain embodiments, a compound or it’s corresponding pharmaceutically acceptable salt, or isotopic derivative, as described herein can be used in an effective amount to treat a host, for example a human, with a lymphoma or lymphocytic or myelocytic proliferation disorder or abnormality. For example, a compound as described herein can be administered to a host suffering from a Hodgkin’s Lymphoma or a Non-Hodgkin’s Lymphoma. For example, the host can be suffering from a Non-Hodgkin’s Lymphoma such as, but not limited to: an AIDS-Related Lymphoma; Anaplastic Large-Cell Lymphoma; Angioimmunoblastic Lymphoma; Blastic NK- Cell Lymphoma; Burkitt’s Lymphoma; Burkitt-like Lymphoma (Small Non-Cleaved Cell Lymphoma); diffuse small-cleaved cell lymphoma (DSCCL); Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma; Cutaneous T-Cell Lymphoma; Diffuse Large B-Cell Lymphoma; Enteropathy-Type T-Cell Lymphoma; Follicular Lymphoma; Hepatosplenic Gamma- Delta T-Cell Lymphoma; Lymphoblastic Lymphoma; Mantle Cell Lymphoma; Marginal Zone Lymphoma; Nasal T-Cell Lymphoma; Pediatric Lymphoma; Peripheral T-Cell Lymphomas; Primary Central Nervous System Lymphoma; T-Cell Leukemias; Transformed Lymphomas; Treatment-Related T-Cell Lymphomas; Langerhans cell histiocytosis; or Waldenstrom's Macroglobulinemia. In another embodiment, a compound or it’s corresponding pharmaceutically acceptable salt, or isotopic derivative, as described herein can be used in an effective amount to treat a patient, for example a human, with a Hodgkin’s lymphoma, such as, but not limited to: Nodular Sclerosis Classical Hodgkin’s Lymphoma (CHL); Mixed Cellularity CHL; Lymphocyte-depletion CHL; Lymphocyte-rich CHL; Lymphocyte Predominant Hodgkin’s Lymphoma; or Nodular Lymphocyte Predominant HL. This application further embraces the treatment or prevention of cell proliferative disorders such as hyperplasias, dysplasias and pre-cancerous lesions. Dysplasia is the earliest form of pre- cancerous lesion recognizable in a biopsy by a pathologist. The compounds may be administered for the purpose of preventing said hyperplasias, dysplasias or pre-cancerous lesions from continuing to expand or from becoming cancerous. Examples of pre-cancerous lesions may occur in skin, esophageal tissue, breast and cervical intra-epithelial tissue. In certain embodiments, a compound of the present invention is used to treat an abnormal cell proliferation such as a tumor or cancer that has a RET protein with a mutation, wherein the mutation is at one of the below listed amino acid sites. The mutation may, for example, be selected from one of the listed exemplary mutations, or may be a different mutation.

[0066] In certain embodiments, the RET protein has two mutations selected from the table above. In other embodiments the RET protein has three mutations selected from the table above. In other embodiments the RET protein has four or more mutations, which may optionally be selected from the table above. In certain embodiments, the tumor or cancer has a mutation in a RET protein that is a substantial or partial driver of tumor of cancer cell proliferation. In another embodiment the tumor or cancer has a RET altered protein that is not acting significantly as a driver of abnormal cell proliferation but can be used therapeutically to kill the tumor cell using a selected RET degrader as described herein. In certain embodiments, a compound of the present invention is used to treat a tumor or cancer with a RET protein V804L mutation. In certain embodiments, a compound of the present invention is used to treat a tumor or cancer with a RET protein V804M mutation. In certain embodiments, a compound of the present invention is used to treat a tumor or cancer with a RET protein M918T mutation. In certain embodiments, a compound of the present invention is used to treat a tumor or cancer with a RET protein S891A mutation. In certain embodiments, a compound of the present invention is used to treat a tumor or cancer with a RET protein L790F mutation. In certain embodiments, a compound of the present invention is used to treat a tumor or cancer with a RET protein E768D mutation. In certain embodiments, a compound of the present invention is used to treat a tumor or cancer with a RET protein C618S mutation. In certain embodiments, a compound of the present invention is used to treat a tumor or cancer with a RET protein C618R mutation. In certain embodiments, a compound of the present invention is used to treat a tumor or cancer with a RET protein 634 missense. In certain embodiments, a compound of the present invention is used to treat a tumor or cancer with a RET protein C634R mutation. In certain embodiments, a compound of the present invention is used to treat a tumor or cancer with a RET protein C634Y mutation. In certain embodiments, a compound of the present invention is used to treat a tumor or cancer with a RET protein C634G mutation. In certain embodiments, a compound of the present invention, or a pharmaceutically acceptable salt thereof, is used to treat an abnormal cell proliferation such as a tumor or cancer that has a RET protein with a G810R mutation. In certain embodiments, a compound of the present invention, or a pharmaceutically acceptable salt thereof, is used to treat an abnormal cell proliferation such as a tumor or cancer that has a RET protein with a G810S mutation. In certain embodiments, a compound of the present invention, or a pharmaceutically acceptable salt thereof, is used to treat an abnormal cell proliferation such as a tumor or cancer that has a RET protein with a G810C mutation. In certain embodiments, a compound of the present invention, or a pharmaceutically acceptable salt thereof, is used to treat an abnormal cell proliferation such as a tumor or cancer that has a RET protein with a C634W mutation. In certain embodiments, a compound of the present invention, or a pharmaceutically acceptable salt thereof, is used to treat an abnormal cell proliferation such as a tumor or cancer that has a RET protein with a M918T mutation. In certain embodiments, a compound of the present invention, or a pharmaceutically acceptable salt thereof, is used to treat an abnormal cell proliferation such as a tumor or cancer that has a RET protein with a V804L mutation. In certain embodiments, a compound of the present invention, or a pharmaceutically acceptable salt thereof, is used to treat an abnormal cell proliferation such as a tumor or cancer that has a RET protein with a V804M mutation. In certain embodiments, a compound of the present invention, or a pharmaceutically acceptable salt thereof, is used to treat an abnormal cell proliferation such as a tumor or cancer that has a RET protein fused to another protein, for example a fusion selected from CCDC6-RET, NCOA4-RET, KIF5B-RET, PRKAR1A-RET, TRIM24-RET, TRIM33-RET, GOLGA5-RET, HOOK3-RET, KTN1-RET, ERC1-RET, MBD1-RET, TRIM27-RET, BRC-RET, FGFR10P-RET, PCM1-RET, AKAP13-RET, FKBP15-RET, SPECC1L-RET, TBL1XR1-RET, CUX1-RET, KIAA1468-RET, and KIAA1217-RET. In certain embodiments, a compound of the present invention, or a pharmaceutically acceptable salt thereof, is used to treat an abnormal cell proliferation such as a tumor or cancer that has a CCDC6-RET fusion. In certain embodiments, a compound of the present invention, or a pharmaceutically acceptable salt thereof, is used to treat an abnormal cell proliferation such as a tumor or cancer that has a NCOA4-RET fusion. In certain embodiments, a compound of the present invention, or a pharmaceutically acceptable salt thereof, is used to treat an abnormal cell proliferation such as a tumor or cancer that has a KIF5B-RET fusion. In accordance with the foregoing, the present application further provides a method for preventing or treating any of the diseases or disorders described above in a patient in need of such treatment, which method comprises administering to said patient a therapeutically effective amount of a compound as described herein, or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, or solvate thereof. For any of the above uses, the required dosage will vary depending on the mode of administration, the particular condition to be treated and the effect desired. VI. COMBINATION THERAPY A compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, or Formula X, or a pharmaceutically acceptable salt thereof can be used in an effective amount, either alone or in combination, to treat a patient such as a human with a disorder as described herein or a RET mediated disorder. The disclosed compounds described herein can be used in an effective amount alone or in combination with another compound of the present invention or another bioactive agent or second therapeutic agent to treat a patient such as a human with a disorder, including but not limited to those described herein. The term “bioactive agent” is used to describe an agent, other than the selected compound according to the present invention, which can be used in combination or alternation with a compound of the present invention to achieve a desired result of therapy. In certain embodiments, the compound of the present invention and the bioactive agent are administered in a manner that they are active in vivo during overlapping time periods, for example, have time-period overlapping Cmax, Tmax, AUC or another pharmacokinetic parameter. In another embodiment, the compound of the present invention and the bioactive agent are administered to a patient in need thereof that do not have overlapping pharmacokinetic parameter, however, one has a therapeutic impact on the therapeutic efficacy of the other. In one aspect of this embodiment, the bioactive agent is an immune modulator, including but not limited to a checkpoint inhibitor, including as non-limiting examples, a PD-1 inhibitor, PD-L1 inhibitor, PD-L2 inhibitor, CTLA-4 inhibitor, LAG-3 inhibitor, TIM-3 inhibitor, V-domain Ig suppressor of T-cell activation (VISTA) inhibitors, small molecule, peptide, nucleotide, or another inhibitor. In certain aspects, the immune modulator is an antibody, such as a monoclonal antibody. PD-1 inhibitors that blocks the interaction of PD-1 and PD-L1 by binding to the PD-1 receptor, and in turn inhibit immune suppression include, for example, nivolumab (Opdivo), pembrolizumab (Keytruda), pidilizumab, AMP-224 (AstraZeneca and MedImmune), PF- 06801591 (Pfizer), MEDI0680 (AstraZeneca), PDR001 (Novartis), REGN2810 (Regeneron), SHR-12-1 (Jiangsu Hengrui Medicine Company and Incyte Corporation), TSR-042 (Tesaro), and the PD-L1 / VISTA inhibitor CA-170 (Curis Inc.). PD-L1 inhibitors that block the interaction of PD-1 and PD-L1 by binding to the PD-L1 receptor, and in turn inhibits immune suppression, include for example, atezolizumab (Tecentriq), durvalumab (AstraZeneca and MedImmune), KN035 (Alphamab), and BMS-936559 (Bristol-Myers Squibb). CTLA-4 checkpoint inhibitors that bind to CTLA-4 and inhibits immune suppression include, but are not limited to, ipilimumab, tremelimumab (AstraZeneca and MedImmune), AGEN1884 and AGEN2041 (Agenus). LAG-3 checkpoint inhibitors include, but are not limited to, BMS-986016 (Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline), IMP321 (Prima BioMed), LAG525 (Novartis), and the dual PD-1 and LAG-3 inhibitor MGD013 (MacroGenics). An example of a TIM-3 inhibitor is TSR- 022 (Tesaro). In certain embodiments, the checkpoint inhibitor is selected from nivolumab / OPDIVO®; pembrolizumab / KEYTRUDA®; and pidilizumab / CT-011, MPDL3280A / RG7446; MEDI4736; MSB0010718C; BMS 936559, a PDL2 / lg fusion protein such as AMP 224 or an inhibitor of B7- H3 (e.g., MGA271 ), B7-H4, BTLA, HVEM, TIM3, GAL9, LAG 3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1 , CHK2, A2aR, B-7 family ligands, or a combination thereof. In yet another embodiment, one of the active compounds described herein can be administered in an effective amount for the treatment of abnormal tissue of the female reproductive system such as breast, ovarian, endometrial, or uterine cancer, in combination or alternation with an effective amount of an estrogen inhibitor including, but not limited to, a SERM (selective estrogen receptor modulator), a SERD (selective estrogen receptor degrader), a complete estrogen receptor degrader, or another form of partial or complete estrogen antagonist or agonist. Partial anti-estrogens like raloxifene and tamoxifen retain some estrogen-like effects, including an estrogen-like stimulation of uterine growth, and also, in some cases, an estrogen-like action during breast cancer progression which actually stimulates tumor growth. In contrast, fulvestrant, a complete anti-estrogen, is free of estrogen-like action on the uterus and is effective in tamoxifen- resistant tumors. Non-limiting examples of anti-estrogen compounds are provided in WO 2014 / 19176 assigned to Astra Zeneca, WO2013 / 090921, WO 2014 / 203129, WO 2014 / 203132, and US2013 / 0178445 assigned to Olema Pharmaceuticals, and U.S. Patent Nos.9,078,871, 8,853,423, and 8,703, 810, as well as US 2015 / 0005286, WO 2014 / 205136, and WO 2014 / 205138. Additional non-limiting examples of anti-estrogen compounds include: SERMS such as anordrin, bazedoxifene, broparestriol, chlorotrianisene, clomiphene citrate, cyclofenil, lasofoxifene, ormeloxifene, raloxifene, tamoxifen, toremifene, and fulvestrant; aromatase inhibitors such as aminoglutethimide, testolactone, anastrozole, exemestane, fadrozole, formestane, and letrozole; and antigonadotropins such as leuprorelin, cetrorelix, allylestrenol, chloromadinone acetate, cyproterone acetate, delmadinone acetate, dydrogesterone, medroxyprogesterone acetate, megestrol acetate, nomegestrol acetate, norethisterone acetate, progesterone, and spironolactone. Other estrogenic ligands that can be used according to the present invention are described in U.S. Patent Nos.4,418,068; 5,478,847; 5,393,763; and 5,457,117, WO2011 / 156518, US Patent Nos. 8,455,534 and 8,299,112, U.S. Patent Nos. 9,078,871; 8,853,423; 8,703,810; US 2015 / 0005286; and WO 2014 / 205138, US2016 / 0175289, US2015 / 0258080, WO 2014 / 191726, WO 2012 / 084711; WO 2002 / 013802; WO 2002 / 004418; WO 2002 / 003992; WO 2002 / 003991; WO 2002 / 003990; WO 2002 / 003989; WO 2002 / 003988; WO 2002 / 003986; WO 2002 / 003977; WO 2002 / 003976; WO 2002 / 003975; WO 2006 / 078834; US 6821989; US 2002 / 0128276; US 6777424; US 2002 / 0016340; US 6326392; US 6756401; US 2002 / 0013327; US 6512002; US 6632834; US 2001 / 0056099; US 6583170; US 6479535; WO 1999 / 024027; US 6005102; EP 0802184; US 5998402; US 5780497, US 5880137, WO 2012 / 048058 and WO 2007 / 087684. In another embodiment, an active compounds described herein can be administered in an effective amount for the treatment of abnormal tissue of the male reproductive system such as prostate or testicular cancer, in combination or alternation with an effective amount of an androgen (such as testosterone) inhibitor including, but not limited to a selective androgen receptor modulator, a selective androgen receptor degrader, a complete androgen receptor degrader, or another form of partial or complete androgen antagonist. In certain embodiments, the prostate or testicular cancer is androgen-resistant. Non-limiting examples of anti-androgen compounds are provided in WO 2011 / 156518 and US Patent Nos. 8,455,534 and 8,299,112. Additional non-limiting examples of anti-androgen compounds include: enzalutamide, apalutamide, cyproterone acetate, chlormadinone acetate, spironolactone, canrenone, drospirenone, ketoconazole, topilutamide, abiraterone acetate, and cimetidine. In certain embodiments, the bioactive agent is an ALK inhibitor. Examples of ALK inhibitors include but are not limited to Crizotinib, Alectinib, ceritinib, TAE684 (NVP-TAE684), GSK1838705A, AZD3463, ASP3026, PF-06463922, entrectinib (RXDX-101), and AP26113. In certain embodiments, the bioactive agent is an EGFR inhibitor. Examples of EGFR inhibitors include erlotinib (Tarceva), gefitinib (Iressa), afatinib (Gilotrif), rociletinib (CO-1686), osimertinib (Tagrisso), olmutinib (Olita), naquotinib (ASP8273), nazartinib (EGF816), PF- 06747775 (Pfizer), icotinib (BPI-2009), neratinib (HKI-272; PB272); avitinib (AC0010), EAI045, tarloxotinib (TH-4000; PR-610), PF-06459988 (Pfizer), tesevatinib (XL647; EXEL-7647; KD- 019), transtinib, WZ-3146, WZ8040, CNX-2006, and dacomitinib (PF-00299804; Pfizer). In certain embodiments, the bioactive agent is an HER-2 inhibitor. Examples of HER-2 inhibitors include trastuzumab, lapatinib, ado-trastuzumab emtansine, and pertuzumab. In certain embodiments, the bioactive agent is a CD20 inhibitor. Examples of CD20 inhibitors include obinutuzumab, rituximab, ofatumumab, ibritumomab, tositumomab, and ocrelizumab. In certain embodiments, the bioactive agent is a JAK3 inhibitor. Examples of JAK3 inhibitors include tasocitinib. In certain embodiments, the bioactive agent is a BCL-2 inhibitor. Examples of BCL-2 inhibitors include venetoclax, ABT-199 (4-[4-[[2-(4-Chlorophenyl)-4,4-dimethylcyclohex-1-en- 1-yl]methyl]piperazin-l-yl]-N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4- yl)methyl]amino]phenyl]sulfonyl]-2-[(lH- pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide), ABT-737 (4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl]-N-[4- [[(2R)-4-(dimethylamino)-1- phenylsulfanylbutan-2-yl] amino]-3- nitrophenyl]sulfonylbenzamide) (navitoclax), ABT-263 ((R)-4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[l, l'-biphenyl]-2-yl)methyl)piperazin-1-yl)- N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)- 3((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide), GX15-070 (obatoclax mesylate, (2Z)-2- [(5Z)-5-[(3,5- dimethyl-lH-pyrrol-2-yl)methylidene]-4-methoxypyrrol-2-ylidene]indole; methanesulfonic acid))), 2-methoxy-antimycin A3, YC137 (4-(4,9-dioxo-4,9- dihydronaphtho[2,3-d]thiazol-2-ylamino)-phenyl ester), pogosin, ethyl 2-amino-6-bromo-4-(1- cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate, Nilotinib-d3, TW-37 (N-[4-[[2-(1,1- Dimethylethyl)phenyl]sulfonyl]phenyl]-2,3,4-trihydroxy-5-[[2-(1- methylethyl)phenyl]methyl]benzamide), Apogossypolone (ApoG2), HA14-1, AT101, sabutoclax, gambogic acid, or G3139 (Oblimersen). In certain embodiments, the bioactive agent is a kinase inhibitor. In certain embodiments, the kinase inhibitor is selected from a phosphoinositide 3-kinase (PI3K) inhibitor, a Bruton’s tyrosine kinase (BTK) inhibitor, or a spleen tyrosine kinase (Syk) inhibitor, or a combination thereof. Examples of PI3 kinase inhibitors include, but are not limited to, Wortmannin, demethoxyviridin, perifosine, idelalisib, Pictilisib , Palomid 529, ZSTK474, PWT33597, CUDC- 907, and AEZS-136, duvelisib, GS-9820, BKM120, GDC-0032 (Taselisib) (2-[4-[2-(2-Isopropyl- 5-methyl-1,2,4-triazol-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl]pyrazol-1-yl]-2- methylpropanamide), MLN-1117 ((2R)-1-Phenoxy-2-butanyl hydrogen (S)-methylphosphonate; or Methyl(oxo) {[(2R)-l-phenoxy-2-butanyl]oxy}phosphonium)), BYL-719 ((2S)-N1-[4-Methyl- 5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]-2-thiazolyl]-1,2-pyrrolidinedicarboxamide), GSK2126458 (2,4-Difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3- pyridinyl}benzenesulfonamide) (omipalisib), TGX-221 ((±)-7-Methyl-2-(morpholin-4-yl)-9-(l- phenylaminoethyl)-pyrido[l,2-a]-pyrimidin-4-one), GSK2636771 (2-Methyl-1-(2-methyl-3- (trifluoromethyl)benzyl)-6-morpholino-lH-benzo[d]imidazole-4-carboxylic acid dihydrochloride), KIN-193 ((R)-2-((l-(7-methyl-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid), TGR-1202 / RP5264, GS-9820 ((S)- l-(4-((2-(2-aminopyrimidin-5- yl)-7-methyl-4-mohydroxypropan- 1 -one), GS-1101 (5-fluoro-3-phenyl-2-([S)]-1-[9H-purin-6- ylamino]-propyl)-3H-quinazolin-4-one), AMG-319, GSK-2269557, SAR245409 (N-(4-(N-(3- ((3,5-dimethoxyphenyl)amino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4 methylbenzamide), BAY80-6946 (2-amino-N-(7-methoxy-8-(3-morpholinopropoxy)-2,3- dihydroimidazo[l,2-c]quinaz), AS 252424 (5-[l-[5-(4-Fluoro-2-hydroxy-phenyl)-furan-2-yl]- meth-(Z)-ylidene]-thiazolidine-2,4-dione), CZ 24832 (5-(2-amino-8-fluoro-[l,2,4]triazolo[l,5- a]pyridin-6-yl)-N-tert-butylpyridine-3-sulfonamide), Buparlisib (5-[2,6-Di(4-morpholinyl)-4- pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine), GDC-0941 (2-(lH-Indazol-4-yl)-6-[[4- (methylsulfonyl)-l-piperazinyl]methyl]-4-(4-morpholinyl)thieno[3,2-d]pyrimidine), GDC-0980 ((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6 yl)methyl)piperazin-l-yl)-2-hydroxypropan-l-one (also known as RG7422)), SF1126 ((8S,14S,17S)-14-(carboxymethyl)-8-(3-guanidinopropyl)-17-(hydroxymethyl)-3,6,9,12,15- pentaoxo-1-(4-(4-oxo-8-phenyl-4H-chromen-2-yl)morpholino-4-ium)-2-oxa-7,10,13,16- tetraazaoctadecan-18-oate), PF-05212384 (N-[4-[[4-(Dimethylamino)-1- piperidinyl]carbonyl]phenyl]-N'-[4-(4,6-di-4-morpholinyl-l,3,5-triazin-2-yl)phenyl]urea) (gedatolisib), LY3023414, BEZ235 (2-Methyl-2-{4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3- dihydro-lH-imidazo[4,5-c]quinolin-l-yl]phenyl}propanenitrile) (dactolisib), XL-765 (N-(3-(N-(3- (3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4-methylbenzamide), and GSK1059615 (5-[[4-(4-Pyridinyl)-6-quinolinyl]methylene]-2,4-thiazolidenedione), PX886 ([(3aR,6E,9S,9aR,10R,11aS)-6-[[bis(prop-2-enyl)amino]methylidene]-5-hydroxy-9- (methoxymethyl)-9a,11a-dimethyl-l,4,7-trioxo-2,3,3a,9,10,ll-hexahydroindeno[4,5h]isochromen- 10-yl] acetate (also known as sonolisib)), LY294002, AZD8186, PF-4989216, pilaralisib, GNE- 317, PI-3065, PI-103, NU7441 (KU-57788), HS 173, VS-5584 (SB2343), CZC24832, TG100- 115, A66, YM201636, CAY10505, PIK-75, PIK-93, AS-605240, BGT226 (NVP-BGT226), AZD6482, voxtalisib, alpelisib, IC-87114, TGI100713, CH5132799, PKI-402, copanlisib (BAY 80-6946), XL 147, PIK-90, PIK-293, PIK-294, 3-MA (3-methyladenine), AS-252424, AS-604850, apitolisib (GDC-0980; RG7422). Examples of BTK inhibitors include ibrutinib (also known as PCI-32765)(Imbruvica™)(1- [(3R)-3-[4-amino-3-(4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en- 1-one), dianilinopyrimidine-based inhibitors such as AVL-101 and AVL-291 / 292 (N-(3-((5- fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide) (Avila Therapeutics) (see US Patent Publication No 2011 / 0117073, incorporated herein in its entirety), Dasatinib ([N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2- methylpyrimidin-4-ylamino)thiazole-5-carboxamide], LFM-A13 (alpha-cyano-beta-hydroxy- beta-methyl-N-(2,5-ibromophenyl) propenamide), GDC-0834 ([R-N-(3-(6-(4-(1,4-dimethyl-3- oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)- 4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide], CGI-560 4-(tert-butyl)-N-(3-(8- (phenylamino)imidazo[1,2-a]pyrazin-6-yl)phenyl)benzamide, CGI-1746 (4-(tert-butyl)-N-(2- methyl-3-(4-methyl-6-((4-(morpholine-4-carbonyl)phenyl)amino)-5-oxo-4,5-dihydropyrazin-2- yl)phenyl)benzamide), CNX-774 (4-(4-((4-((3-acrylamidophenyl)amino)-5-fluoropyrimidin-2- yl)amino)phenoxy)-N-methylpicolinamide), CTA056 (7-benzyl-1-(3-(piperidin-1-yl)propyl)-2- (4-(pyridin-4-yl)phenyl)-1H-imidazo[4,5-g]quinoxalin-6(5H)-one), GDC-0834 ((R)-N-(3-(6-((4- (1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2- methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), GDC-0837 ((R)-N-(3-(6- ((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)- 2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), HM-71224, ACP-196, ONO-4059 (Ono Pharmaceuticals), PRT062607 (4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2- (((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), QL-47 (1-(1- acryloylindolin-6-yl)-9-(1-methyl-1H-pyrazol-4-yl)benzo[h][1,6]naphthyridin-2(1H)-one), and RN486 (6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1- yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one), and other molecules capable of inhibiting BTK activity, for example those BTK inhibitors disclosed in Akinleye et ah, Journal of Hematology & Oncology, 2013, 6:59, the entirety of which is incorporated herein by reference. Syk inhibitors include, but are not limited to, Cerdulatinib (4-(cyclopropylamino)-2-((4- (4-(ethylsulfonyl)piperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide), entospletinib (6-(1H- indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine), fostamatinib ([6-({5- Fluoro-2-[(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl}amino)-2,2-dimethyl-3-oxo-2,3- dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl]methyl dihydrogen phosphate), fostamatinib disodium salt (sodium (6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2- dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methyl phosphate), BAY 61-3606 (2-(7- (3,4-Dimethoxyphenyl)-imidazo[1,2-c]pyrimidin-5-ylamino)-nicotinamide HCl), RO9021 (6- [(1R,2S)-2-Amino-cyclohexylamino]-4-(5,6-dimethyl-pyridin-2-ylamino)-pyridazine-3- carboxylic acid amide), imatinib (Gleevec; 4-[(4-methylpiperazin-1-yl)methyl]-N-(4-methyl-3- {[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide), staurosporine, GSK143 (2- (((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-4-(p-tolylamino)pyrimidine-5- carboxamide), PP2 (1-(tert-butyl)-3-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine), PRT-060318 (2-(((1R,2S)-2-aminocyclohexyl)amino)-4-(m-tolylamino)pyrimidine-5- carboxamide), PRT-062607 (4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2- aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), R112 (3,3'-((5- fluoropyrimidine-2,4-diyl)bis(azanediyl))diphenol), R348 (3-Ethyl-4-methylpyridine), R406 (6- ((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-2H- pyrido[3,2-b][1,4]oxazin-3(4H)-one), piceatannol (3-Hydroxyresveratol), YM193306 (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643), 7-azaindole, piceatannol, ER-27319 (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in its entirety herein), Compound D (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem.2012, 55, 3614-3643 incorporated in its entirety herein), PRT060318 (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem.2012, 55, 3614-3643 incorporated in its entirety herein), luteolin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem.2012, 55, 3614-3643 incorporated in its entirety herein), apigenin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in its entirety herein), quercetin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in its entirety herein), fisetin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem.2012, 55, 3614-3643 incorporated in its entirety herein), myricetin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in its entirety herein), morin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem.2012, 55, 3614-3643 incorporated in its entirety herein). In certain embodiments, the bioactive agent is a MEK inhibitor. MEK inhibitors are well known, and include, for example, trametinib / GSKl120212 (N-(3-{3-Cyclopropyl-5-[(2-fluoro-4- iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H- yl}phenyl)acetamide), selumetinib (6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)- 3-methylbenzimidazole-5-carboxamide), pimasertib / AS703026 / MSC 1935369 ((S)-N-(2,3- dihydroxypropyl)-3-((2-fluoro-4- iodophenyl)amino)isonicotinamide), XL-518 / GDC-0973 (l- ({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2- yl]azetidin-3-ol), refametinib / BAY869766 / RDEAl 19 (N-(3,4-difluoro-2-(2-fluoro-4- iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide), PD-0325901 (N-[(2R)-2,3-Dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]- benzamide), TAK733 ((R)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8- methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione), MEK162 / ARRY438162 (5-[(4-Bromo-2- fluorophenyl)amino]-4-fluoro-N-(2- hydroxyethoxy)-1-methyl-1H-benzimidazole-6- carboxamide), R05126766 (3-[[3-Fluoro-2- (methylsulfamoylamino)-4-pyridyl]methyl]-4- methyl-7-pyrimidin-2-yloxychromen-2-one), WX-554, R04987655 / CH4987655 (3,4-difluoro-2- ((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3-oxo-l,2-oxazinan- 2yl)methyl)benzamide), or AZD8330 (2-((2-fluoro-4-iodophenyl)amino)-N-(2 hydroxyethoxy)- 1 ,5-dimethyl-6-oxo-l,6-dihydropyridine-3-carboxamide), U0126-EtOH, PD184352 (CI-1040), GDC-0623, BI-847325, cobimetinib, PD98059, BIX 02189, BIX 02188, binimetinib, SL-327, TAK-733, PD318088. In certain embodiments, the bioactive agent is a Raf inhibitor. Raf inhibitors are known and include, for example, Vemurafenib (N-[3-[[5-(4-Chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3- yl]carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide), sorafenib tosylate (4-[4-[[4-chloro-3- (trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridine-2-carboxamide;4- methylbenzenesulfonate), AZ628 (3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(3-methyl-4-oxo-3,4- dihydroquinazolin-6-ylamino)phenyl)benzamide), NVP-BHG712 (4-methyl-3-(1-methyl-6- (pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)-N-(3- (trifluoromethyl)phenyl)benzamide), RAF-265 (1-methyl-5-[2-[5-(trifluoromethyl)-1H-imidazol- 2-yl]pyridin-4-yl]oxy-N-[4-(trifluoromethyl)phenyl]benzimidazol-2-amine), 2-Bromoaldisine (2-Bromo-6,7-dihydro-1H,5H-pyrrolo[2,3-c]azepine-4,8-dione), Raf Kinase Inhibitor IV (2- chloro-5-(2-phenyl-5-(pyridin-4-yl)-1H-imidazol-4-yl)phenol), Sorafenib N-Oxide (4-[4-[[[[4- Chloro-3(trifluoroMethyl)phenyl]aMino]carbonyl]aMino]phenoxy]-N-Methyl- 2pyridinecarboxaMide 1-Oxide), PLX-4720, dabrafenib (GSK2118436), GDC-0879, RAF265, AZ 628, SB590885, ZM336372, GW5074, TAK-632, CEP-32496, LY3009120, and GX818 (Encorafenib). In certain embodiments, the bioactive agent is an AKT inhibitor, including, but not limited to, MK-2206, GSK690693, Perifosine, (KRX-0401), GDC-0068, Triciribine, AZD5363, Honokiol, PF-04691502, and Miltefosine, a FLT-3 inhibitor, including, but not limited to, P406, Dovitinib, Quizartinib (AC220), Amuvatinib (MP-470), Tandutinib (MLN518), ENMD-2076, and KW-2449, or a combination thereof. In certain embodiments, the bioactive agent is an mTOR inhibitor. Examples of mTOR inhibitors include, but are not limited to, rapamycin and its analogs, everolimus (Afinitor), temsirolimus, ridaforolimus, sirolimus, and deforolimus. Examples of MEK inhibitors include but are not limited to tametinib / GSKl120212 (N-(3-{3-Cyclopropyl-5-[(2-fluoro-4- iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H- yl}phenyl)acetamide), selumetinib (6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)- 3-methylbenzimidazole-5-carboxamide), pimasertib / AS703026 / MSC1935369 ((S)-N-(2,3- dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide), XL-518 / GDC-0973 (l- ({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2- yl]azetidin-3-ol) (cobimetinib), refametinib / BAY869766 / RDEAl19 (N-(3,4-difluoro-2-(2-fluoro- 4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide), PD-0325901 (N-[(2R)-2,3-Dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]- benzamide), TAK733 ((R)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8- methylpyrido[2,3d]pyrimidine-4,7(3H,8H)-dione), MEK162 / ARRY438162 (5-[(4-Bromo-2- fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6 carboxamide), R05126766 (3-[[3-Fluoro-2-(methylsulfamoylamino)-4-pyridyl]methyl]-4- methyl-7-pyrimidin-2-yloxychromen-2-one), WX-554, R04987655 / CH4987655 (3,4-difluoro-2- ((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3-oxo-l,2-oxazinan-2 yl)methyl)benzamide), or AZD8330 (2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)- 1,5-dimethyl-6-oxo-l,6-dihydropyridine-3-carboxamide). In certain embodiments, the bioactive agent is a RAS inhibitor. Examples of RAS inhibitors include but are not limited to Reolysin and siG12D LODER. In certain embodiments, the bioactive agent is a HSP inhibitor. HSP inhibitors include but are not limited to Geldanamycin or 17-N-Allylamino-17-demethoxygeldanamycin (17AAG), and Radicicol. Additional bioactive compounds include, for example, everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY- 142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK- 0457, MLN8054, PHA-739358, R-763, AT-9263, a FLT-3 inhibitor, a VEGFR inhibitor, an aurora kinase inhibitor, a PIK-1 modulator, an HDAC inhibitor, a c-MET inhibitor, a PARP inhibitor, a Cdk inhibitor, an IGFR-TK inhibitor, an anti-HGF antibody, a focal adhesion kinase inhibitor, a Map kinase (MEK) inhibitor, a VEGF trap antibody, pemetrexed, panitumumab, amrubicin, oregovomab, LEP-ETU, nolatrexed, azd2171, batabulin, ofatumumab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131- I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR1KRX-0402, lucanthone, LY317615, neuradiab, vitespan, Rta 744, Sdx 102, talampanel, atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, liposomal doxorubicin, 5′-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib; PD0325901, AZD-6244, capecitabine, L-Glutamic acid, N- [4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole, DES(diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258); 3-[5-(methylsulfonylpiperadinemethyl)-indolyl- quinolone, vatalanib, AG-013736, AVE-0005, goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI- 272, erlotinib, lapatanib, canertinib, ABX-EGF antibody, erbitux, EKB-569, PKI-166, GW- 572016, Ionafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoyl analide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, arnsacrine, anagrelide, L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, adriamycin, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gleevec, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deooxyuridine, cytosine arabinoside, 6-mecaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat, COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin diftitox, gefitinib, bortezimib, paclitaxel, cremophor-free paclitaxel, docetaxel, epithilone B, BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, topotecan, PTK787 / ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP- 23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating factor, zolendronate, prednisone, cetuximab, granulocyte macrophage colony- stimulating factor, histrelin, pegylated interferon alfa-2a, interferon alfa-2a, pegylated interferon alfa-2b, interferon alfa-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-transretinoic acid, ketoconazole, interleukin-2, megestrol, immune globulin, nitrogen mustard, methylprednisolone, ibritgumomab tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium 89, casopitant, netupitant, an NK-1 receptor antagonist, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa, darbepoetin alfa and mixtures thereof. In certain embodiments, the bioactive agent is selected from, but are not limited to, Imatinib mesylate (Gleevac®), Dasatinib (Sprycel®), Nilotinib (Tasigna®), Bosutinib (Bosulif®), Trastuzumab (Herceptin®), trastuzumab-DM1, Pertuzumab (PerjetaTM), Lapatinib (Tykerb®), Gefitinib (Iressa®), Erlotinib (Tarceva®), Cetuximab (Erbitux®), Panitumumab (Vectibix®), Vandetanib (Caprelsa®), Vemurafenib (Zelboraf®), Vorinostat (Zolinza®), Romidepsin (Istodax®), Bexarotene (Tagretin®), Alitretinoin (Panretin®), Tretinoin (Vesanoid®), Carfilizomib (KyprolisTM), Pralatrexate (Folotyn®), Bevacizumab (Avastin®), Ziv-aflibercept (Zaltrap®), Sorafenib (Nexavar®), Sunitinib (Sutent®), Pazopanib (Votrient®), Regorafenib (Stivarga®), and Cabozantinib (CometriqTM). In certain aspects, the bioactive agent is an anti-inflammatory agent, a chemotherapeutic agent, a radiotherapeutic, an additional therapeutic agent, or an immunosuppressive agent. Suitable chemotherapeutic bioactive agents include, but are not limited to, a radioactive molecule, a toxin, also referred to as cytotoxin or cytotoxic agent, which includes any agent that is detrimental to the viability of cells, and liposomes or other vesicles containing chemotherapeutic compounds. General anticancer pharmaceutical agents include: Vincristine (Oncovin®) or liposomal vincristine (Marqibo®), Daunorubicin (daunomycin or Cerubidine®) or doxorubicin (Adriamycin®), Cytarabine (cytosine arabinoside, ara-C, or Cytosar®), L-asparaginase (Elspar®) or PEG-L-asparaginase (pegaspargase or Oncaspar®), Etoposide (VP-16), Teniposide (Vumon®), 6-mercaptopurine (6-MP or Purinethol®), Methotrexate, Cyclophosphamide (Cytoxan®), Prednisone, Dexamethasone (Decadron), imatinib (Gleevec®), dasatinib (Sprycel®), nilotinib (Tasigna®), bosutinib (Bosulif®), and ponatinib (Iclusig™). Examples of additional suitable chemotherapeutic agents include, but are not limited to 1- dehydrotestosterone, 5-fluorouracil decarbazine, 6-mercaptopurine, 6-thioguanine, actinomycin D, adriamycin, aldesleukin, an alkylating agent, allopurinol sodium, altretamine, amifostine, anastrozole, anthramycin (AMC)), an anti-mitotic agent, cis-dichlorodiamine platinum (II) (DDP) cisplatin), diamino dichloro platinum, anthracycline, an antibiotic, an antimetabolite, asparaginase, BCG live (intravesical), betamethasone sodium phosphate and betamethasone acetate, bicalutamide, bleomycin sulfate, busulfan, calcium leucouorin, calicheamicin, capecitabine, carboplatin, lomustine (CCNU), carmustine (BSNU), Chlorambucil, Cisplatin, Cladribine, Colchicin, conjugated estrogens, Cyclophosphamide, Cyclothosphamide, Cytarabine, Cytarabine, cytochalasin B, Cytoxan, Dacarbazine, Dactinomycin, dactinomycin (formerly actinomycin), daunirubicin HCL, daunorucbicin citrate, denileukin diftitox, Dexrazoxane, Dibromomannitol, dihydroxy anthracin dione, Docetaxel, dolasetron mesylate, doxorubicin HCL, dronabinol, E. coli L-asparaginase, emetine, epoetin-α, Erwinia L-asparaginase, esterified estrogens, estradiol, estramustine phosphate sodium, ethidium bromide, ethinyl estradiol, etidronate, etoposide citrororum factor, etoposide phosphate, filgrastim, floxuridine, fluconazole, fludarabine phosphate, fluorouracil, flutamide, folinic acid, gemcitabine HCL, glucocorticoids, goserelin acetate, gramicidin D, granisetron HCL, hydroxyurea, idarubicin HCL, ifosfamide, interferon α-2b, irinotecan HCL, letrozole, leucovorin calcium, leuprolide acetate, levamisole HCL, lidocaine, lomustine, maytansinoid, mechlorethamine HCL, medroxyprogesterone acetate, megestrol acetate, melphalan HCL, mercaptipurine, mesna, methotrexate, methyltestosterone, mithramycin, mitomycin C, mitotane, mitoxantrone, nilutamide, octreotide acetate, ondansetron HCL, paclitaxel, pamidronate disodium, pentostatin, pilocarpine HCL, plimycin, polifeprosan 20 with carmustine implant, porfimer sodium, procaine, procarbazine HCL, propranolol, rituximab, sargramostim, streptozotocin, tamoxifen, taxol, teniposide, tenoposide, testolactone, tetracaine, thioepa chlorambucil, thioguanine, thiotepa, topotecan HCL, toremifene citrate, trastuzumab, tretinoin, valrubicin, vinblastine sulfate, vincristine sulfate, and vinorelbine tartrate. In some embodiments, the compound of the present invention is administered in combination with a chemotherapeutic agent (e.g., a cytotoxic agent or other chemical compound useful in the treatment of cancer). Examples of chemotherapeutic agents include alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodophyllotoxins, antibiotics, L-Asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione substituted urea, methyl hydrazine derivatives, adrenocortical suppressant, adrenocorticosteroids, progestins, estrogens, antiestrogen, androgens, antiandrogen, and gonadotropin-releasing hormone analog. Also included is 5-fluorouracil (5-FU), leucovorin (LV), irinotecan, oxaliplatin, capecitabine, paclitaxel, and docetaxel. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CB1-TM1 ); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammall and calicheamicin omegall (see, e.g., Agnew, Chem. Inti. Ed Engl.33:183- 186 (1994)); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromophores), aclacinomycins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo- 5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin, including morpholino-doxorubicin, cyanomorpholino- doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5- FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6- mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6- azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; trichothecenes (especially T- 2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara- C"); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL® (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE®, cremophor-free, albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, IL), and TAXOTERE® docetaxel (Rhone-Poulenc Rorer, Antony, France); chlorambucil; GEMZAR® gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum coordination complexes such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE® vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan (e.g., CPT-11); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above. Two or more chemotherapeutic agents can be used in a cocktail to be administered in combination with the compound of the present invention. Suitable dosing regimens of combination chemotherapies are known in the art. For example combination dosing regimes are described in Saltz et al., Proc. Am. Soc. Clin. Oncol.18:233a (1999) and Douillard et al., Lancet 355(9209): 1041 -1047 (2000). Additional therapeutic agents that can be administered in combination with a Compound disclosed herein can include bevacizumab, sunitinib, sorafenib, 2-methoxyestradiol or 2ME2, finasunate, vatalanib, vandetanib, aflibercept, volociximab, etaracizumab (MEDI-522), cilengitide, erlotinib, cetuximab, panitumumab, gefitinib, trastuzumab, dovitinib, figitumumab, atacicept, rituximab, alemtuzumab, aldesleukine, atlizumab, tocilizumab, temsirolimus, everolimus, lucatumumab, dacetuzumab, HLL1, huN901-DM1, atiprimod, natalizumab, bortezomib, carfilzomib, marizomib, tanespimycin, saquinavir mesylate, ritonavir, nelfinavir mesylate, indinavir sulfate, belinostat, panobinostat, mapatumumab, lexatumumab, dulanermin, ABT-737, oblimersen, plitidepsin, talmapimod, P276-00, enzastaurin, tipifarnib, perifosine, imatinib, dasatinib, lenalidomide, thalidomide, simvastatin, celecoxib, bazedoxifene, AZD4547, rilotumumab, oxaliplatin (Eloxatin), PD0332991, ribociclib (LEE011), amebaciclib (LY2835219), HDM201, fulvestrant (Faslodex), exemestane (Aromasin), PIM447, ruxolitinib (INC424), BGJ398, necitumumab, pemetrexed (Alimta), and ramucirumab (IMC-1121B). In certain embodiments, the additional therapy is a monoclonal antibody (MAb). Some MAbs stimulate an immune response that destroys cancer cells. Similar to the antibodies produced naturally by B cells, these MAbs may “coat” the cancer cell surface, triggering its destruction by the immune system. For example, bevacizumab targets vascular endothelial growth factor (VEGF), a protein secreted by tumor cells and other cells in the tumor’s microenvironment that promotes the development of tumor blood vessels. When bound to bevacizumab, VEGF cannot interact with its cellular receptor, preventing the signaling that leads to the growth of new blood vessels. Similarly, cetuximab and panitumumab target the epidermal growth factor receptor (EGFR), and trastuzumab targets the human epidermal growth factor receptor 2 (HER-2). MAbs that bind to cell surface growth factor receptors prevent the targeted receptors from sending their normal growth-promoting signals. They may also trigger apoptosis and activate the immune system to destroy tumor cells. In one aspect of the present invention, the bioactive agent is an immunosuppressive agent. The immunosuppressive agent can be a calcineurin inhibitor, e.g. a cyclosporin or an ascomycin, e.g. Cyclosporin A (NEORAL®), FK506 (tacrolimus), pimecrolimus, a mTOR inhibitor, e.g. rapamycin or a derivative thereof, e.g. Sirolimus (RAPAMUNE®), Everolimus (Certican®), temsirolimus, zotarolimus, biolimus-7, biolimus-9, a rapalog, e.g.ridaforolimus, azathioprine, campath 1H, a S1P receptor modulator, e.g. fingolimod or an analogue thereof, an anti IL-8 antibody, mycophenolic acid or a salt thereof, e.g. sodium salt, or a prodrug thereof, e.g. Mycophenolate Mofetil (CELLCEPT®), OKT3 (ORTHOCLONE OKT3®), Prednisone, ATGAM®, THYMOGLOBULIN®, Brequinar Sodium, OKT4, T10B9.A-3A, 33B3.1, 15- deoxyspergualin, tresperimus, Leflunomide ARAVA®, CTLAI-Ig, anti-CD25, anti-IL2R, Basiliximab (SIMULECT®), Daclizumab (ZENAPAX®), mizorbine, methotrexate, dexamethasone, ISAtx-247, SDZ ASM 981 (pimecrolimus, Elidel®), CTLA4lg (Abatacept), belatacept, LFA3lg,, etanercept (sold as Enbrel® by Immunex), adalimumab (Humira®), infliximab (Remicade®), an anti-LFA-1 antibody, natalizumab (Antegren®), Enlimomab, gavilimomab, antithymocyte immunoglobulin, siplizumab, Alefacept efalizumab, pentasa, mesalazine, asacol, codeine phosphate, benorylate, fenbufen, naprosyn, diclofenac, etodolac and indomethacin, aspirin and ibuprofen. In some embodiments, the bioactive agent is a therapeutic agent which is a biologic such a cytokine (e.g., interferon or an interleukin (e.g., IL-2)) used in cancer treatment. In some embodiments the biologic is an anti-angiogenic agent, such as an anti-VEGF agent, e.g., bevacizumab (AVASTIN®). In some embodiments the biologic is an immunoglobulin-based biologic, e.g., a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein or a functional fragment thereof) that agonizes a target to stimulate an anti-cancer response, or antagonizes an antigen important for cancer. Such agents include RITUXAN® (rituximab); ZENAPAX® (daclizumab); SIMULECT® (basiliximab); SYNAGIS® (palivizumab); REMICADE® (infliximab); HERCEPTIN® (trastuzumab); MYLOTARG® (gemtuzumab ozogamicin); CAMPATH® (alemtuzumab); ZEVALIN® (ibritumomab tiuxetan); HUMIRA® (adalimumab); XOLAIR® (omalizumab); BEXXAR® (tositumomab I-131); RAPTIVA® (efalizumab); ERBITUX® (cetuximab); AVASTIN® (bevacizumab); TYSABRI® (natalizumab); ACTEMRA® (tocilizumab); VECTIBIX® (panitumumab); LUCENTIS® (ranibizumab); SOURIS® (eculizumab); CIMZIA® (certolizumab pegol); SIMPONI® (golimumab); ILARIS® (canakinumab); STELARA® (ustekinumab); ARZERRA® (ofatumumab); PROLIA® (denosumab); NUMAX® (motavizumab); ABTHRAX® (raxibacumab); BENLYSTA® (belimumab); YERVOY® (ipilimumab); ADCETRIS® (brentuximab vedotin); PERJETA® (pertuzumab); KADCYLA® (ado- trastuzumab emtansine); and GAZYVA® (obinutuzumab). Also included are antibody-drug conjugates. The combination therapy may include a therapeutic agent which is a non-drug treatment. For example, the compound could be administered in addition to radiation therapy, cryotherapy, hyperthermia, and / or surgical excision of tumor tissue. In certain embodiments, the first and second therapeutic agents are administered simultaneously or sequentially, in either order. The first therapeutic agent may be administered immediately, up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to, 8 hours, up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13 hours, 14 hours, up to hours 16, up to 17 hours, up 18 hours, up to 19 hours up to 20 hours, up to 21 hours, up to 22 hours, up to 23 hours up to 24 hours or up to 1-7, 1-14, 1-21 or 1-30 days before or after the second therapeutic agent. In certain embodiments, the second therapeutic agent is administered on a different dosage schedule than the compound of the present invention. For example, the second therapeutic agent may have a treatment holiday of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days per treatment cycle. In another embodiment the first therapeutic agent has a treatment holiday. For example, the first therapeutic agent may have a treatment holiday of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days per treatment cycle. In certain embodiments both the first and second therapeutic have a treatment holiday. VII. PHARMACEUTICAL COMPOSITIONS A compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, or Formula X, or its pharmaceutically acceptable salt thereof, as described herein can be administered as the neat chemical, but is more typically administered as a pharmaceutical composition, that includes an effective amount for a patient, typically a human, in need of such treatment for any of the disorders described herein. Accordingly, the disclosure provides pharmaceutical compositions comprising an effective amount of compound or pharmaceutically acceptable salt together with at least one pharmaceutically acceptable carrier for any of the uses described herein. The pharmaceutical composition may contain a compound or salt as the only active agent, or, in an alternative embodiment, the compound and at least one additional active agent. In general, the compositions of the disclosure will be administered in a therapeutically effective amount by any of the accepted modes of administration. Suitable dosage ranges depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, the indication towards which the administration is directed, and the preferences and experience of the medical practitioner involved. One of ordinary skill in the art of treating such diseases will be able, without undue experimentation and in reliance upon personal knowledge and the disclosure of this application, to ascertain a therapeutically effective amount of the compositions of the disclosure for a given disease. In certain embodiments, the pharmaceutical composition is in a dosage form that contains from about 0.1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of the active compound and optionally from about 0.1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of an additional active agent in a unit dosage form. Examples are dosage forms with at least about 0.1, 1, 5, 10, 25, 30, 35, 40, 45, 50, 100, 200, 250, 300, 400, 500, 600, 700, or 750 mg of active compound, or its salt. In certain embodiments, the patient can be treated with low dosage therapy with a compound of the present invention. For example, the pharmaceutical composition can be in a dosage form that contains from about 0.1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of the active compound. Examples are dosage forms with at least about 0.1, 1, 5, 10, 25, 50, 100, 200, 250, 300, 400, 500, 600, 700, or 750 mg of active compound, or its salt. In certain embodiments, the dose ranges from about 0.01-100 mg / kg of patient bodyweight, for example at least about 0.01 mg / kg, at least about 0.05 mg / kg, at least about 0.1 mg / kg, at least about 0.5 mg / kg, at least about 1 mg / kg, at least about 1.5 mg / kg, at least about 2 mg / kg, at least about 2.5 mg / kg, at least about 3 mg / kg, at least about 3.5 mg / kg, at least about 4 mg / kg, at least about 4.5 mg / kg, at least about 5 mg / kg, at least about 10 mg / kg, at least about 15 mg / kg, at least about 20 mg / kg, at least about 25 mg / kg, at least about 30 mg / kg, at least about 35 mg / kg, at least about 40 mg / kg, at least about 45 mg / kg, at least about 50 mg / kg, at least about 55 mg / kg, at least about 60 mg / kg, at least about 65 mg / kg, at least about 70 mg / kg, at least about 75 mg / kg, at least about 80 mg / kg, at least about 85 mg / kg, at least about 90 mg / kg, at least about 95 mg / kg, or at least about 100 mg / kg. A pharmaceutically or therapeutically effective amount of the composition will be delivered to the patient. The precise effective amount will vary from patient to patient, and will depend upon the species, age, the subject’s size and health, the nature and extent of the condition being treated, recommendations of the treating physician, and the therapeutics or combination of therapeutics selected for administration. The effective amount for a given situation can be determined by routine experimentation. For purposes of the disclosure, a therapeutic amount may for example be in the range of about 0.01 mg / kg to about 250 mg / kg body weight, more typically about 0.1 mg / kg to about 10 mg / kg, in at least one dose. The subject can be administered as many doses as is required to reduce and / or alleviate the signs, symptoms, or causes of the disorder in question, or bring about any other desired alteration of a biological system. When desired, formulations can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient. In some embodiments, compounds disclosed herein or used as described are administered once a day (QD), twice a day (BID), or three times a day (TID). In some embodiments, compounds disclosed herein or used as described are administered at least once a day for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 26 days, at least 27 days, at least 28 days, at least 29 days, at least 30 days, at least 31 days, at least 35 days, at least 45 days, at least 60 days, at least 75 days, at least 90 days, at least 120 days, at least 150 days, at least 180 days, or longer. In certain embodiments, the compound of the present invention is administered once a day, twice a day, three times a day, or four times a day. In certain embodiments, the compound of the present invention is administered orally once a day. In certain embodiments, the compound of the present invention is administered orally twice a day. In certain embodiments, the compound of the present invention is administered orally three times a day. In certain embodiments, the compound of the present invention is administered orally four times a day. In certain embodiments, the compound of the present invention is administered intravenously once a day. In certain embodiments, the compound of the present invention is administered intravenously twice a day. In certain embodiments, the compound of the present invention is administered intravenously three times a day. In certain embodiments, the compound of the present invention is administered intravenously four times a day. In some embodiments the compound of the present invention is administered with a treatment holiday in between treatment cycles. For example, the compound may have a treatment holiday of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days per treatment cycle. The pharmaceutical composition may also include a molar ratio of the active compound and an additional active agent. For example, the pharmaceutical composition may contain a molar ratio of about 0.5:1, about 1:1, about 2:1, about 3:1 or from about 1.5:1 to about 4:1 of an anti- inflammatory or immunosuppressing agent. These compositions can contain any amount of active compound that achieves the desired result, for example between 0.1 and 99 weight % (wt. %) of the compound and usually at least about 5 wt. % of the compound. Some embodiments contain from about 25 wt. % to about 50 wt. % or from about 5 wt. % to about 75 wt. % of the compound. The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form. In certain embodiments, the compound is administered as a pharmaceutically acceptable salt. Non-limiting examples of pharmaceutically acceptable salts include: acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and valerate salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine. Thus, the composition of the disclosure can be administered as a pharmaceutical formulation including one suitable for oral (including buccal and sub-lingual), rectal, nasal, topical, transdermal, pulmonary, vaginal or parenteral (including intramuscular, intra-arterial, intrathecal, subcutaneous and intravenous), injections, inhalation or spray, intra-aortal, intracranial, subdermal, intraperitioneal, subcutaneous, or by other means of administration containing conventional pharmaceutically acceptable carriers. A typical manner of administration is oral, topical or intravenous, using a convenient daily dosage regimen which can be adjusted according to the degree of affliction. Depending on the intended mode of administration, the pharmaceutical compositions can be in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, syrup, suspensions, creams, ointments, lotions, paste, gel, spray, aerosol, foam, or oil, injection or infusion solution, a transdermal patch, a subcutaneous patch, an inhalation formulation, in a medical device, suppository, buccal, or sublingual formulation, parenteral formulation, or an ophthalmic solution, or the like, preferably in unit dosage form suitable for single administration of a precise dosage. Some dosage forms, such as tablets and capsules, are subdivided into suitably sized unit doses containing appropriate quantities of the active components, e.g., an effective amount to achieve the desired purpose. The compositions will include an effective amount of the selected drug in combination with a pharmaceutically acceptable carrier and, in addition, can include other pharmaceutical agents, adjuvants, diluents, buffers, and the like. Carriers include excipients and diluents and must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the patient being treated. The carrier can be inert or it can possess pharmaceutical benefits of its own. The amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound. Classes of carriers include, but are not limited to adjuvants, binders, buffering agents, coloring agents, diluents, disintegrants, excipients, emulsifiers, flavorants, gels, glidents, lubricants, preservatives, stabilizers, surfactants, solubilizer, tableting agents, wetting agents or solidifying material. Some carriers may be listed in more than one class, for example vegetable oil may be used as a lubricant in some formulations and a diluent in others. Exemplary pharmaceutically acceptable carriers include sugars, starches, celluloses, powdered tragacanth, malt, gelatin, talc, petroleum jelly, lanoline, polyethylene glycols, alcohols, transdermal enhancers and vegetable oils. Optional active agents may be included in a pharmaceutical composition, which do not substantially interfere with the activity of the compound of the present invention. Some excipients include, but are not limited to, liquids such as water, saline, glycerol, polyethylene glycol, hyaluronic acid, ethanol, and the like. The compound can be provided, for example, in the form of a solid, a liquid, spray dried material, a microparticle, nanoparticle, controlled release system, etc., as desired according to the goal of the therapy. Suitable excipients for non-liquid formulations are also known to those of skill in the art. A thorough discussion of pharmaceutically acceptable excipients and salts is available in Remington’s Pharmaceutical Sciences, 18th Edition (Easton, Pennsylvania: Mack Publishing Company, 1990). Additionally, auxiliary substances, such as wetting or emulsifying agents, biological buffering substances, surfactants, and the like, can be present in such vehicles. A biological buffer can be any solution which is pharmacologically acceptable, and which provides the formulation with the desired pH, i.e., a pH in the physiologically acceptable range. Examples of buffer solutions include saline, phosphate buffered saline, Tris buffered saline, Hank’s buffered saline, and the like. For solid compositions, conventional nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like. Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, and the like, an active compound as described herein and optional pharmaceutical adjuvants in an excipient, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension. If desired, the pharmaceutical composition to be administered can also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and the like. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington’s Pharmaceutical Sciences, referenced above. In yet another embodiment provided is the use of permeation enhancer excipients including polymers such as: polycations (chitosan and its quaternary ammonium derivatives, poly-L- arginine, aminated gelatin); polyanions (N-carboxymethyl chitosan, poly-acrylic acid); and thiolated polymers (carboxymethyl cellulose-cysteine, polycarbophil-cysteine, chitosan- thiobutylamidine, chitosan-thioglycolic acid, chitosan-glutathione conjugates). The pharmaceutical compositions / combinations can be formulated for oral administration. For oral administration, the composition will generally take the form of a tablet, capsule, a softgel capsule or can be an aqueous or nonaqueous solution, suspension or syrup. Tablets and capsules are typical oral administration forms. Tablets and capsules for oral use can include one or more commonly used carriers such as lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. Typically, the compositions of the disclosure can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like. When liquid suspensions are used, the active agent can be combined with any oral, non- toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like and with emulsifying and suspending agents. If desired, flavoring, coloring and / or sweetening agents can be added as well. Other optional components for incorporation into an oral formulation herein include, but are not limited to, preservatives, suspending agents, thickening agents, and the like. For ocular delivery, the compound can be administered, as desired, for example, via intravitreal, intrastromal, intracameral, sub-tenon, sub-retinal, retro-bulbar, peribulbar, suprachoroidal, conjunctival, subconjunctival, episcleral, periocular, transscleral, retrobulbar, posterior juxtascleral, circumcorneal, or tear duct injections, or through a mucus, mucin, or a mucosal barrier, in an immediate or controlled release fashion or via an ocular device. Parenteral formulations can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solubilization or suspension in liquid prior to injection, or as emulsions. Typically, sterile injectable suspensions are formulated according to techniques known in the art using suitable carriers, dispersing or wetting agents and suspending agents. The sterile injectable formulation can also be a sterile injectable solution or a suspension in an acceptably nontoxic parenterally acceptable diluent or solvent. Among the acceptable vehicles and solvents that can be employed are water, Ringer’s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils, fatty esters or polyols are conventionally employed as solvents or suspending media. In addition, parenteral administration can involve the use of a slow release or sustained release system such that a constant level of dosage is maintained. Parenteral administration includes intraarticular, intravenous, intramuscular, intradermal, intraperitoneal, and subcutaneous routes, and include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. Administration via certain parenteral routes can involve introducing the formulations of the disclosure into the body of a patient through a needle or a catheter, propelled by a sterile syringe or some other mechanical device such as a continuous infusion system. A formulation provided by the disclosure can be administered using a syringe, injector, pump, or any other device recognized in the art for parenteral administration. Preparations according to the disclosure for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate. Such dosage forms can also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They can be sterilized by, for example, filtration through a bacteria retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured using sterile water, or some other sterile injectable medium, immediately before use. Sterile injectable solutions are prepared by incorporating one or more of the compounds of the disclosure in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, typical methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile- filtered solution thereof. Thus, for example, a parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution is made isotonic with sodium chloride and sterilized. Alternatively, the pharmaceutical compositions of the disclosure can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable nonirritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols. The pharmaceutical compositions of the disclosure can also 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, propellants such as fluorocarbons or nitrogen, and / or other conventional solubilizing or dispersing agents. Formulations for buccal administration include tablets, lozenges, gels and the like. Alternatively, buccal administration can be affected using a transmucosal delivery system as known to those skilled in the art. The compounds of the disclosure can also be delivered through the skin or mucosal tissue using conventional transdermal drug delivery systems, i.e., transdermal “patches” wherein the agent is typically contained within a laminated structure that serves as a drug delivery device to be affixed to the body surface. In such a structure, the drug composition is typically contained in a layer, or “reservoir,” underlying an upper backing layer. The laminated device can contain a single reservoir, or it can contain multiple reservoirs. In certain embodiments, the reservoir comprises a polymeric matrix of a pharmaceutically acceptable contact adhesive material that serves to affix the system to the skin during drug delivery. Examples of suitable skin contact adhesive materials include, but are not limited to, polyethylenes, polysiloxanes, polyisobutylenes, polyacrylates, polyurethanes, and the like. Alternatively, the drug-containing reservoir and skin contact adhesive are present as separate and distinct layers, with the adhesive underlying the reservoir which, in this case, can be either a polymeric matrix as described above, or it can be a liquid or gel reservoir, or can take some other form. The backing layer in these laminates, which serves as the upper surface of the device, functions as the primary structural element of the laminated structure and provides the device with much of its flexibility. The material selected for the backing layer should be substantially impermeable to the active agent and any other materials that are present. The compositions of the disclosure can be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration. The compound may, for example, generally have a small particle size for example of the order of 5 microns or less. Such a particle size can be obtained by means known in the art, for example by micronization. The active ingredient is provided in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide or other suitable gas. The aerosol can conveniently also contain a surfactant such as lecithin. The dose of drug can be controlled by a metered valve. Alternatively, the active ingredients can be provided in a form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP). The powder carrier will form a gel in the nasal cavity. The powder composition can be presented in unit dose form, for example in capsules or cartridges of e.g., gelatin or blister packs from which the powder can be administered by means of an inhaler. Formulations suitable for rectal administration are typically presented as unit dose suppositories. These may be prepared by admixing the active compound with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture. In certain embodiments, the pharmaceutical composition is suitable for topical application to the skin using a mode of administration and defined above. In certain embodiments, the pharmaceutical composition is suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Formulations suitable for transdermal administration may also be delivered by iontophoresis (see, for example, Pharmaceutical Research 3 (6):318 (1986)) and typically take the form of an optionally buffered aqueous solution of the active compound. In certain embodiments, microneedle patches or devices are provided for delivery of drugs across or into biological tissue, particularly the skin. The microneedle patches or devices permit drug delivery at clinically relevant rates across or into skin or other tissue barriers, with minimal or no damage, pain, or irritation to the tissue. Formulations suitable for administration to the lungs can be delivered by a wide range of passive breath driven and active power driven single / multiple dose dry powder inhalers (DPI). The devices most commonly used for respiratory delivery include nebulizers, metered-dose inhalers, and dry powder inhalers. Several types of nebulizers are available, including jet nebulizers, ultrasonic nebulizers, and vibrating mesh nebulizers. Selection of a suitable lung delivery device depends on parameters, such as nature of the drug and its formulation, the site of action, and pathophysiology of the lung. VIII. GENERAL SYNTHESIS The compounds described herein can be prepared by methods known by those skilled in the art. In one non-limiting example, the disclosed compounds can be made using the schemes below. Compounds of the present invention with stereocenters may be drawn without stereochemistry for convenience. One skilled in the art will recognize that pure enantiomers and diastereomers can be prepared by methods known in the art. Examples of methods to obtain optically active materials include at least the following: i) physical separation of crystals – a technique whereby macroscopic crystals of the individual enantiomers are manually separated. This technique can be used if crystals of the separate enantiomers exist, i.e., the material is a conglomerate, and the crystals are visually distinct; ii) simultaneous crystallization – a technique whereby the individual enantiomers are separately crystallized from a solution of the racemate, possible only if the enantiomer is a conglomerate in the solid state; iii) enzymatic resolutions – a technique whereby partial or complete separation of a racemate by virtue of differing rates of reaction for the enantiomers with an enzyme; iv) enzymatic asymmetric synthesis – a synthetic technique whereby at least one step in the synthesis uses an enzymatic reaction to obtain an enantiomerically pure or enriched synthetic precursor of the desired enantiomer; v) chemical asymmetric synthesis – a synthetic technique whereby the desired enantiomer is synthesized from an achiral precursor under conditions that produce asymmetry (i.e. chirality) in the product, which may be achieved by chiral catalysts or chiral auxiliaries; vi) diastereomer separations – a technique whereby a racemic compound is reaction with an enantiomerically pure reagent (the chiral auxiliary) that converts the individual enantiomers to diastereomers. The resulting diastereomers are then separated by chromatography or crystallization by virtue of their now more distinct structural differences the chiral auxiliary later removed to obtain the desired enantiomer; vii) first- and second-order asymmetric transformations – a technique whereby diastereomers from the racemate quickly equilibrate to yield a preponderance in solution of the diastereomer from the desired enantiomer of where preferential crystallization of the diastereomer from the desired enantiomer perturbs the equilibrium such that eventually in principle all the material is converted to the crystalline diastereomer from the desired enantiomers. The desired enantiomer is then released from the diastereomer; viii) kinetic resolutions – this technique refers to the achievement of partial or complete resolution of a racemate (or of a further resolution of a partially resolved compound) by virtue of unequal reaction rates of the enantiomers with a chiral, non-racemic reagent or catalyst under kinetic conditions; ix) enantiospecific synthesis from non-racemic precursors – a synthetic technique whereby the desired enantiomer is obtained from non-chiral starting materials and where the stereochemical integrity is not or is only minimally compromised over the course of the synthesis; x) chiral liquid chromatography – a technique whereby the enantiomers of a racemate are separated in a liquid mobile phase by virtue of their differing interactions with a stationary phase (including vial chiral HPLC). The stationary phase can be made of chiral material or the mobile phase can contain an additional chiral material to provoke the differing interactions; xi) chiral gas chromatography – a technique whereby the racemate is volatilized and enantiomers are separated by virtue of their differing interactions in the gaseous mobile phase with a column containing a fixed non-racemic chiral adsorbent phase; xii) extraction with chiral solvents – a technique whereby the enantiomers are separated by virtue of preferential dissolution of one enantiomer into a particular chiral solvent; xiii) transport across chiral membranes – a technique whereby a racemate is placed in contact with a thin membrane barrier. The barrier typically separates two miscible fluids, one containing the racemate, and a driving force such as concentration or pressure differential causes preferential transport across the membrane barrier. Separation occurs as a result of the non-racemic chiral nature of the membrane that allows only one enantiomer of the racemate to pass through; xiv) simulated moving bed chromatography is used in certain embodiments. A wide variety of chiral stationary phases are commercially available. SYNTHESIS A. Abbreviations ACN – acetonitrile AcOH – acetic acid BINAP – 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene Bn – benzyl Boc – tert-butyloxycarbonyl Cbz – benzyloxycarbonyl COMU – (1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate dba – dibenzylideneacetone DCE - dichloroethane DCM - dichloromethane DIEA – N,N-diisopropylethylamine DIPEA or DIEA – N,N-diisopropylethylamine DMA – N,N-dimethylacetamide DMAc – N,N-dimethylacetamide DMAP – N,N-dimethylaminopyridine DMF – N,N-dimethylformamide DMSO - dimethylsulfoxide Dppf – 1,1’-bis(diphenylphosphino)ferrocene EA or EtOAc – ethyl acetate EDCI or EDC – 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide ES or ESI – electrospray ionization FA – formic acid HATU – 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate HMDS – hexamethyldisilazane HOBt - hydroxybenzotriazole HPLC – high performance liquid chromatography IPA – isopropyl alcohol LAH – lithium aluminum hydride LCMS – liquid chromatography mass spectrometry LDA – lithium diisopropylamide LiHMDS – lithium bis(trimethylsilyl)amide MeCN – acetonitrile MeOH - methanol MOM - methyloxymethyl MS – molecular sieves MsCl – mesyl chloride MTBE – methyl tert-butyl ether NaCNBH3 or NaBH3CN – sodium cyanoborohydride Na2SO4 – sodium sulfate Na2S2O3– sodium thiosulfate NaOCN – sodium cyanate NBS – N-bromosuccinimide NFSI -N-fluorobenzenesulfonimide NIS – N-iodosuccinimide NMR – nuclear magnetic resonance Pd2(dba)3– tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl2·DCM – [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane Pd-PEPPSI-iHeptCl – dichloro[1,3-bis(2,6-di-4-heptylphenyl)imidazol-2-ylidene](3- chloropyridyl)palladium(II) PE or Pet ether – petroleum ether PhN(OTf)2 – N-phenyl-bis(trifluoromethanesulfonimide) PTSA – pyridinium p-toluenesulfonate PyBOP - benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate RT – room temperature SFC – super critical fluid chromatography Si-CBH – SiliaBond Cyanoborohydride TBAF – tetrabutylammonium fluoride TBAI – tetrabutylammonium iodide TEA or Et3N – triethylamine TFA – trifluoroacetic acid THF – tetrahydrofuran TLC – thin layer chromatography TMS – trimethylsilyl Xantphos – 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene XPhos – 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl B. General Methods The compounds of the Examples were analyzed or purified according to one of the purification methods referred to below unless otherwise described. Silica gel column chromatography was performed using 20−40 μM (particle size), 100-200 mesh, 300−400 mesh, or 1000 mesh silica gel, using Biotage® Flash Isolera Prime ISO-1SV or similar chromatography systems to drive solvent through the column (“flash chromatography”). Except where otherwise noted, reactions were run under an atmosphere of nitrogen gas. Where indicated, solutions and reaction mixtures were concentrated by rotary evaporation under vacuum. C. Analytical Methods NMR Instrument specifications: Bruker AVANCE NEO 400 Bruker AVANCE NEO 300 Bruker AVANCE III 400 Bruker AVANCE III 400 HD LC / MS Instrument specifications: UHPLC Agilent 1290 Series LC / MSD system with DAD\ELSD and Agilent LC\MSD (G6125B) mass-spectrometer. Agilent 1290 Infinity II- 6130 Quadrupole MS Waters Acquity UPLC H-Class-SQ Detector 2 Agilent 1200 Series LC / MSD system with DAD and Agilent LC\MS G6110A, mass-spectrometer Agilent (Degasser:1200; Pump:1260; Hip-ALS:1200; TCC:1200;DAD:1100) Series LC / MS system with DAD\ELSD and Agilent LC\MS G6110A, mass- spectrometer Agilent (Degasser:1200; Pump:1260; Hip-ALS:1100;TCC:1260;DAD:1100) Series LC / MS system with DAD and Agilent LC\MS G1956A, mass-spectrometer Agilent (Degasser:1200; Pump:1200;Hip-ALS:1100;TCC:1200;DAD:1200) Series LC / MS system with DAD and Agilent LC\MS G1956A, mass-spectrometer SHIMADZU LC-20A (LC)-SHIMADZU LCMS-2020 (mass spec detector) Agilent 1100 (LC)-Agilent G1956A, mass-spectrometer. Agilent 1260 (LC)-Agilent G6110A, mass-spectrometer. SHIMADZU LC-20AD Series LC / MS system with SPD-M20A and SHIMADZU LC\MS LCMS-2020, mass-spectrometer. SHIMADZU LC-20AD Series LC / MS system with SPD-M20A\ELSD and SHIMADZU LC\MS LCMS-2020, mass-spectrometer SHIMADZU LC-20AD Series LC / MS system with SPD-M40 and SHIMADZU LC\MS LCMS-2020, mass-spectrometer SHIMADZU LC-40ADXR Series LC / MS system with SPD-M40 and SHIMADZU LC\MS LCMS-2020, mass-spectrometer SHIMADZU LC-20AB Series LC / MS system with SPD-M20A and SHIMADZU LC\MS LCMS-2020, mass-spectrometer. SHIMADZU LC-20AB Series LC / MS system with SPD-M20A\ELSD and SHIMADZU LC\MS LCMS-2020, mass-spectrometer. HPLC Instrument specifications: Agilent 1260 Infinity II LC system with PDA detector / 1260 ELSD(G4260B) SHIMADZU LC-20AD Series LC system with SPD-M20A SHIMADZU LC-20AB Series LC system with SPD-M40 SHIMADZU LC-20AB Series LC system with SPD-M20A SHIMADZU LC-20AB S40ADXR Series LC system with SPD-M40 Prep-HPLC Instrument specifications: Agilent 1260 infinity series LC / MSD(G7110B)1260 ISO pump and & auto- sampler Agilent 1290 infinity II series with fraction collector Shimadzu LC-20AP HPLC pump system Gilson GX-281 with auto sampler and auto fraction collector Gilson 322 HPLC pump system SFC Instrument specifications: SFC-PIC LAB HYBRID 10-20 SFC-PIC LAB ANALYTIC 10-M \PDA-AZURA \ELSD-SEDEX 90 \MS- ADVION SFC-PIC LAB PREP 175 / ELSD SEDEX 85 SFC-PIC LAB PREP100 SFC-PIC LAB HYBRID 10-150 SFC-PIC LAB PREP 400 Waters 150Mgm / 80Q purification system D. LC-MS Methods Method 1 (Formic Acid Method) Column: CSH C-18 (30×2.1mm) 1.7 µm Column Temp: 40 °C Mobile Phase: A :0.1% HCOOH in H2O Method 2 (Ammonium Bicarbonate Method) Method 3 Acid methods: Column (Kinetex EVO C1830*2.1 mm, 5 um), Eluent (Mobile phase A: 0.0375% TFA in H2O, v / v; Mobile phase B: 0.01875% TFA in ACN, v / v), gradient (5-95AB_R_220&254, 0-60AB_0_R_220&254, B% over 1.55 min), Ionization source: ESI. Detector: PDA (220 &254 nm). Flow rate: 1.5 mL / min. Column temperature: 50°C. Method 4 Basic methods: Column (Kinetex EVO C1830*2.1 mm, 5 um), Eluent (Mobile phase A: 0.025% NH3.H2O in H2O, v / v; Mobile phase B: ACN), gradient (5- 95CD_R_220&254_Pos, 0-60CD_R_220&254_Pos, B% over 1.55 min). Ionization source: ESI, Detector: PDA (220 &254 nm). Flow rate: 1.5 mL / min. Column temperature: 50°C. D. HPLC Methods Method 1 (TFA Method) Column: X-Bridge C8(50×4.6)mm,3.5µm Mobile Phase: A: 0.1% TFA in water Mobile Phase: B: Acetonitrile Flow: 2.0mL / min Time (min) % B 0.0 05 8.0 100 8.1 100 8.5 05 10.0 05 Method 2 (Ammonium Bicarbonate Method) Column: X-Bridge C8(50×4.6)mm,3.5µm Mobile Phase: A:10mM Ammonium bicarbonate in water Mobile Phase: B: Acetonitrile Flow:1.0mL / min Time (min) % B 0.0 05 8.0 100 8.1 100 8.5 05 10.0 05 Method 3 (Ammonium Acetate Method) Column: Phenomenex Gemini C18 (150×4.6)mm, Mobile Phase A:10mM Ammonium acetate in Milli-Q water SYNTHESIS OF CRBN BINDERS Example 1: 3-((4-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dione (C-1) Compound 3-((4-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dione was prepared using the method described on page 265 of WO2018237026 A1. Example 2: 3-((4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione hydrochloride (C-2) Compound 3-((4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione hydrochloride was prepared using the method described on page 268 of WO2018237026 A1. Example 3: Synthesis of (3S)-3-[4-(4-piperidyl)anilino]piperidine-2,6-dione (C-3) and (3R)- 3-[4-(4-piperidyl)anilino]piperidine-2,6-dione (C-4) Step-1: To a 100 mL sealed-tube reaction vessel containing a well-stirred solution of tert-butyl 4-(4- aminophenyl)piperidine-1-carboxylate 1 (10 g, 36.18 mmol) in anhydrous DMF (100 mL) was added sodium bicarbonate (9.12 g, 108.55 mmol) and 3-bromopiperidine-2,6-dione 2 (10.42 g, 54.27 mmol) at ambient temperature under nitrogen atmosphere and the reaction mixture was heated at 60 °C for 16 h. After completion of the reaction as determined by UPLC, the reaction mixture was cooled to ambient temperature, quenched with ice cold water (70 ml) and then extracted with EtOAc (3 × 100 ml). The organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (60-120 mesh silica-gel) using a gradient of 0- 100% EtOAc / Pet ether to afford tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperidine- 1-carboxylate (9.5 g, 24.42 mmol, 67.49% yield) as a pale yellow solid. LCMS (ESI): m / z 332.2 [M - isobutene + H]+. The racemic product tert-butyl 4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperidine-1-carboxylate was separated by chiral SFC (Column Name : Lux A1; Co-Solvent : 50% IPA; Injected Volume : 15 µL; Outlet Pressure: 100 bar; Temperature : 35 °C; Flow Rate : 5 mL / minutes) to give tert-butyl 4-[4-[[(3S)-2,6-dioxo-3- piperidyl]amino]phenyl]piperidine-1-carboxylate 3 (early-eluting peak) and tert-butyl 4-[4- [[(3R)-2,6-dioxo-3-piperidyl]amino]phenyl]piperidine-1-carboxylate 4 (late-eluting peak). Step-2: To a 100 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[4- [[(3S)-2,6-dioxo-3-piperidyl]amino]phenyl]piperidine-1-carboxylate 3 (1.0 g, 2.58 mmol) in anhydrous DCM (10 mL) was added 4 M hydrogen chloride in 1,4-dioxane (7 mL, 28 mmol) dropwise at room temperature under nitrogen atmosphere. The resulting reaction mixture was stirred at ambient temperature for 2 h under nitrogen atmosphere. After completion of the reaction as determined by UPLC, the excess solvent was removed under reduced pressure and the crude product was triturated with methyl tert-butyl ether (2 × 10 mL), then dried under reduced pressure to afford (3S)-3-[4-(4-piperidyl)anilino]piperidine-2,6-dione 5 (0.83 g, 2.56 mmol, 99.23% yield, HCl salt) as an off-white solid. LCMS (ESI): m / z 288.2 [M + H]+. Step-3: To a 100 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[4- [[(3R)-2,6-dioxo-3-piperidyl]amino]phenyl]piperidine-1-carboxylate 4 (1.0 g, 2.58 mmol) in anhydrous DCM (10 mL) was added 4 M hydrogen chloride in 1,4-dioxane (7 mL, 28 mmol) dropwise at room temperature under nitrogen atmosphere. The resulting reaction mixture was stirred at ambient temperature for 2 h under nitrogen atmosphere. After completion of the reaction as determined by UPLC, the excess solvent was removed under reduced pressure and the crude product was triturated with methyl tert-butyl ether (2 × 10 mL), then dried under reduced pressure to afford (3R)-3-[4-(4-piperidyl)anilino]piperidine-2,6-dione 6 (0.81 g, 2.48 mmol, 96.20% yield, HCl salt) as an off-white solid. LCMS (ESI): m / z 288.2 [M + H]+. Example 4: Synthesis of 3-[4-[(2S,6R)-2,6-dimethyl-4-piperidyl]anilino]piperidine-2,6-dione (C-5) (Configuration was arbitrarily assigned) Step-1: To a solution of tert-butyl (2S,6R)-2,6-dimethyl-4-oxo-piperidine-1-carboxylate 1 (300 mg, 1.32 mmol) in THF (3 mL) was added LiHMDS (1 M, 1.45 mL) dropwise at -60 °C under N2and the solution was stirred at -60 °C for 1 hr. Then a solution of PhN(OTf)2 (518.67 mg, 1.45 mmol) in THF (1.5 mL) was added and stirred at 20 °C for 11 hrs. The reaction mixture was then poured into sat. NH4Cl (20 mL) to give a suspension, which was filtered. The resulting filter cake was washed with brine (20 mL) and concentrated in vacuo and the obtained residue was purified by prep-TLC (PE: EA=5:1) to yield tert-butyl (2S,6R)-2,6-dimethyl-4-(trifluoromethylsulfonyloxy)- 3,6-dihydro-2H-pyridine-1-carboxylate 2 (238 mg, 629.17 μmol, 47.67% yield) as white solid. LCMS (ESI): m / z 304.3 [M + H]+. Step-2: To a solution of tert-butyl (2S,6R)-2,6-dimethyl-4-(trifluoromethylsulfonyloxy)-3,6-dihydro-2H- pyridine-1-carboxylate 2 (5.5 g, 9.95 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)aniline 3 (2.29 g, 10.45 mmol) and Pd(dppf)Cl2 (406.20 mg, 497.41 μmol) in dioxane (36 mL) was added aq. Na2CO3(2 M, 9.90 mL) and the solution was stirred at 50 °C for 12 hr. The reaction was then quenched with water (100 ml) and the mixture was extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The obtained residue was purified by flash silica gel chromatography (40 g silica flash column, eluent of 0-30% EA / PE, 50 mL / min) to yield tert-butyl (2S,6R)-4-(4- aminophenyl)-2,6-dimethyl-3,6-dihydro-2H-pyridine-1-carboxylate 4 (2.8 g, 9.26 mmol, 93.07% yield) as a yellow solid. LCMS (ESI): m / z 302.9 [M + H]+. Step-3: To a solution of 3-bromopiperidine-2,6-dione 5 (2.67 g, 13.89 mmol), (2R,6S)-tert-butyl 4-(4- aminophenyl)-2,6-dimethyl-5,6-dihydropyridine-1(2H)-carboxylate 4 (2.8 g, 9.26 mmol) and TBAI (171.00 mg, 462.95 μmol) in MeCN (0.5 mL) was added NaHCO3(1.56 g, 18.52 mmol). After addition, the solution was stirred at 90 °C for 12 hr. The reaction solution was then concentrated in vacuo and the residue was purified by column chromatography (SiO2, DCM: MeOH = 30:1-20:1) to afford tert-butyl (2S,6R)-4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-2,6- dimethyl-3,6-dihydro-2H-pyridine-1-carboxylate 6 (2 g, 4.50 mmol, 48.58% yield) as a blue solid. LCMS (ESI): m / z 414.0 [M + H]+. Step-4: To a solution of tert-butyl (2S,6R)-4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-2,6-dimethyl-3,6- dihydro-2H-pyridine-1-carboxylate 6 (800 mg, 1.93 mmol) in EA (16 mL) and MeOH (16 mL) was added 10 wt.% Pd / C (234.97 mg, 193.47 μmol) under N2 atmosphere. The suspension was degassed and purged with H23 times and stirred under H2(15 Psi) at 20 °C for 12 hr. Upon completion of the reaction, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by prep-HPLC (Phenomenex Luna C18150×40mm×15um, 0.225% formic acid / water-MeCN, gradient of 45%-75%, 60 ml / min, 10 min) to give tert-butyl (2R,6S)-4-[4-[(2,6- dioxo-3-piperidyl)amino]phenyl]-2,6-dimethyl-piperidine-1-carboxylate 7 (250 mg, 571.57 μmol, 29.54% yield) as white solid. LCMS (ESI): m / z 416.0 [M + H]+.1H NMR (400 MHz, DMSO-d6): δ 10.77 (s, 1H), 6.97 (d, J = 8.4 Hz, 2H), 6.61 (d, J = 8.4 Hz, 2H), 5.66 (d, J = 7.6 Hz, 1H), 4.33 - 4.08 (m, 3H), 2.81 - 2.69 (m, 1H), 2.62 - 2.54 (m, 1H), 2.48 - 2.39 (m, 1H), 2.18 - 2.02 (m, 3H), 1.86 (dq, J = 4.0, 12.0 Hz, 1H), 1.48 - 1.37 (m, 11H), 1.22 (d, J = 6.8 Hz, 6H). Step-5: To a solution of tert-butyl (2R,6S)-4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-2,6-dimethyl- piperidine-1-carboxylate 7 (600 mg, 1.44 mmol) in DCM (2 mL) was added 4 M HCl / dioxane (6.00 mL). After addition, the solution was stirred at 20 °C for 30 min. Upon complete consumption of the reactant, the reaction solution was concentrated in vacuo to give 3-[4-[(2S,6R)- 2,6-dimethyl-4-piperidyl]anilino]piperidine-2,6-dione hydrochloride 8 (420 mg, 1.19 mmol, 82.66% yield) as blue solid. LCMS (ESI): m / z 316.1 [M + H]+. Example 5: 3-((3-fluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (A-1) (C-6) Compound 3-((3-fluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione was prepared using the method described on page 447-449 of WO2021178920 A1. Example 6: 3-((3-fluoro-4-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dione (C-7) Compound 3-((3-fluoro-4-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dione was prepared using the method described on 209-211 of WO2022032026 A1. Example 7: Synthesis of 3-[4-(1,4-diazepan-1-yl)-3-fluoro-anilino]piperidine-2,6-dione (C-8) Step-1: To a 100 ml single-neck round-bottom flask containing a well-stirred solution of tert-butyl 1,4- diazepane-1-carboxylate 1 (3.0 g, 14.98 mmol, 2.94 mL) and 1,2-difluoro-4-nitro-benzene 2 (3.10 g, 19.47 mmol, 2.15 mL) in DMSO (40 mL) was added N,N-diisopropylethylamine (5.81 g, 44.94 mmol, 7.83 mL) at ambient temperature under nitrogen atmosphere and the reaction mixture was heated at 100 °C for 2 h. After completion of reaction as determined by TLC and UPLC, the reaction mixture was cooled to room temperature and poured into ice water (150 ml) and extracted with ethyl acetate (2 × 250 mL). The combined organic phase was washed with brine (250 ml), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (230-400 mesh silica-gel) using a gradient of 0-100% EtOAc / Pet ether to afford tert-butyl 4-(2-fluoro-4-nitro-phenyl)-1,4-diazepane-1- carboxylate 3 (4.7 g, 13.82 mmol, 92.25% yield) as a yellow solid. LCMS (ESI): m / z 284.2 [M – isobutene + H]+. Step-2: To a 250 mL single-neck round-bottom flask containing a well-stirred suspension of tert-butyl 4- (2-fluoro-4-nitro-phenyl)-1,4-diazepane-1-carboxylate 3 (4.7 g, 13.85 mmol) in EtOAc (50 mL) and ethanol (50 mL) mixture (1:1) was added 10% palladium on carbon, type 487 (2.95 g, 27.70 mmol) at ambient temperature under nitrogen atmosphere. The resulting suspension was stirred at ambient temperature under hydrogen atmosphere (balloon) for 24 h. After complete consumption of the starting material as determined by TLC, the reaction mixture was filtered through a pad of Celite and the Celite bed was washed with a 1:1 EtOAc / EtOH mixture (200 mL). The combined filtrate was concentrated under reduced pressure and the crude product was co-distilled with DCM (2 × 50 mL) to afford tert-butyl 4-(4-amino-2-fluoro-phenyl)-1,4-diazepane-1-carboxylate 4 (4.1 g, 13.13 mmol, 94.83% yield) as a brown gum. LCMS (ESI): m / z 310.2 [M + H]+. Step-3: To a 250 mL two-neck round-bottom flask containing a well-stirred suspension of tert-butyl 4-(4- amino-2-fluoro-phenyl)-1,4-diazepane-1-carboxylate 4 (2.5 g, 8.08 mmol) and 3- bromopiperidine-2,6-dione 5 (3.88 g, 20.20 mmol) in anhydrous DMF (40 mL) was added sodium bicarbonate (2.04 g, 24.24 mmol) at ambient temperature. The resulting reaction mixture was heated at 70 °C for 48 h and progress of the reaction was monitored by TLC and UPLC. The reaction mixture was then quenched by the addition of ice-water (100 mL) and extracted with EtOAc (2 × 200 mL). The organic phases were combined, washed with brine (200 ml), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (230-400 mesh silica-gel) using a gradient of 0-100% EtOAc / Pet ether to afford tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]-1,4- diazepane-1-carboxylate 6 (2.7 g, 6.41 mmol, 79.35% yield) as a dark blue gum. LCMS (ESI): m / z 421.2 [M + H]+and 365.2 [M – isobutene + H]+. Step-4: To a 100 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[4- [(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]-1,4-diazepane-1-carboxylate 6 (2.7 g, 6.42 mmol) in anhydrous DCM (30 mL) was added 4.0 M hydrogen chloride in 1,4-dioxane (27 mL) and stirred at ambient temperature for 2 h. Upon completion of the reaction, the excess solvent was removed under reduced pressure and the crude product was triturated with MTBE (2 × 25 ml), then dried under reduced pressure to afford 3-[4-(1,4-diazepan-1-yl)-3-fluoro-anilino]piperidine- 2,6-dione 7 (2.2 g, 5.84 mmol, 90.96% yield, HCl salt) as a pale blue solid. LCMS (ESI): m / z 321.1 [M + H]+. Example 8: 3-[4-(3,9-diazaspiro[5.5]undecan-3-yl)-3-fluoro-anilino]piperidine-2,6-dione (C- 9) Compound 3-[4-(3,9-diazaspiro[5.5]undecan-3-yl)-3-fluoro-anilino]piperidine-2,6-dione was prepared substantially following the procedure in the synthesis of 3-[4-(1,4-diazepan-1-yl)-3- fluoro-anilino]piperidine-2,6-dione (Example 7), using tert-butyl 3,9-diazaspiro[5.5]undecane-3- carboxylate instead of tert-butyl 1,4-diazepane-1-carboxylate in Step-1. LCMS (ESI): m / z 375.2 [M + H]+. Example 9: 3-[4-[4-(azetidin-3-yl)-1-piperidyl]-3-fluoro-anilino]piperidine-2,6-dione (C-10) Compound 3-[4-[4-(azetidin-3-yl)-1-piperidyl]-3-fluoro-anilino]piperidine-2,6-dione was prepared substantially following the procedure in the synthesis of 3-[4-(1,4-diazepan-1-yl)-3- fluoro-anilino]piperidine-2,6-dione (Example 7), using tert-butyl 3-(4-piperidyl)azetidine-1- carboxylate instead of tert-butyl 1,4-diazepane-1-carboxylate in Step-1. Example 10: Synthesis of 2-[1-[2-fluoro-4-[[(3S)-2,6-dioxo-3-piperidyl]amino]phenyl]-4- hydroxy-4-piperidyl]acetic acid (C-11) and 2-[1-[2-fluoro-4-[[(3R)-2,6-dioxo-3- piperidyl]amino]phenyl]-4-hydroxy-4-piperidyl]acetic acid (C-12)

[0067] Step-1: To a solution of 1,2-difluoro-4-nitro-benzene 2 (1.11 g, 6.97 mmol, 769.75 µL) and tert-butyl 2- (4-hydroxy-4-piperidyl)acetate 1 (1.5 g, 6.97 mmol) in MeCN (22.2 mL) was added triethylamine (2.12 g, 20.90 mmol, 2.91 mL) and the reaction was heated at 80 °C for 6 h. The reaction was then cooled and concentrated in vacuo. The crude material was purified by column chromatography (10-55% EtOAc in hexane) to afford tert-butyl 2-[1-(2-fluoro-4-nitro-phenyl)-4- hydroxy-4-piperidyl]acetate 3 (2.08 g, 5.58 mmol, 80.03% yield). LCMS (ES+): m / z 355.7 [M + H]+. Step-2: To a solution of tert-butyl 2-[1-(2-fluoro-4-nitro-phenyl)-4-hydroxy-4-piperidyl]acetate 3 (2.08 g, 5.87 mmol) in EtOH (25 mL) and water (6 mL) were added iron powder (1.65 g, 29.58 mmol) and ammonium chloride (653.06 mg, 12.21 mmol) and the mixture was stirred at 50 °C for 4 h. After completion of the reaction, the reaction was cooled to room temperature and filtered through a pad of celite, and the celite pad was washed with EtOAc. The combined filtrate was dried over anhydrous Na2SO4 and concentrated in vacuo to afford tert-butyl 2-[1-(4-amino-2-fluoro-phenyl)- 4-hydroxy-4-piperidyl]acetate 4 (1.86 g, 5.45 mmol, 92.80% yield), which was carried forward without further purification. LCMS (ES+): m / z 325.6 [M + H]+. Step-3: To a mixture of 3-bromopiperidine-2,6-dione 5 (1.76 g, 9.17 mmol) and tert-butyl 2-[1-(4-amino- 2-fluoro-phenyl)-4-hydroxy-4-piperidyl]acetate 4 (1.86 g, 5.73 mmol) in DMF (14 mL) was added sodium bicarbonate (1.45 g, 17.20 mmol) and the resulting mixture was stirred at 80 °C overnight. After cooling, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The crude material was purified by column chromatography (40-80% EtOAc in hexane) to afford tert- butyl 2-[1-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]-4-hydroxy-4-piperidyl]acetate 6 (2.5 g, 5.45 mmol, 95.11% yield). LCMS (ES+): m / z 436.3 [M + H]+. Step-4: To a solution of tert-butyl 2-[1-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]-4-hydroxy-4- piperidyl]acetate 6 (2.5 g, 5.74 mmol) in dioxane (100 mL) was added 4 M hydrogen chloride in 1,4-dioxane, 99% (50.23 mL). The resulting solution was stirred at room temperature for 72 h and concentrated in vacuo. The resulting solid was isolated by vacuum filtration, washing with MTBE to afford 2-[1-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]-4-hydroxy-4-piperidyl]acetic acid 7 (1.69 g, 2.43 mmol, 42.40% yield, HCl salt), which was used without further purification. LCMS (ES+): m / z 380.3 [M + H]+. Step-5: Compound 2-[1-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]-4-hydroxy-4- piperidyl]acetic acid 7 (2.8 g, 7.38 mmol) was separated by chiral SFC to yield 2-[1-[4-[[(3S)-2,6- dioxo-3-piperidyl]amino]-2-fluoro-phenyl]-4-hydroxy-4-piperidyl]acetic acid 8 (815 mg, 2.06 mmol, 27.92% yield) as the early eluting isomer (arbitrarily assigned as the S-isomer) and 2-[1-[4- [[(3R)-2,6-dioxo-3-piperidyl]amino]-2-fluoro-phenyl]-4-hydroxy-4-piperidyl]acetic acid 9 (800 mg, 2.08 mmol, 28.12% yield) as the late eluting isomer (arbitrarily assigned as the R-isomer) Chiral SFC Method: Column: Chiralpak IG (250x21 mm) 5µ; Flow: 25 g / min; Mobile Phase: 30 % CO2 + 70 % Isopropyl alcohol; ABPR: 100 bar; Temperature: 35º C; Diluent: TFE + IPA 8:1H NMR (400 MHz, DMSO-d6): ^ 10.77 (bs, 1H), 6.86-6.81 (m, 1H), 6.48 (d, J=15.3 Hz, 1H), 6.40 (d, J=8.7 Hz, 1H), 5.76 (d, J=7.7 Hz, 1H), 4.30-4.20 (m, 1H), 2.90-2.76 (m, 4H), 2.73-2.68 (m, 1H), 2.50 (bs, 1H), 2.28 (s, 2H), 2.11-2.04 (m, 1H), 1.85-1.82 (m, 1H), 1.74-1.69 (m, 2H), 1.64-1.61 (m, 2H). 9:1H NMR (400 MHz, DMSO-d6): ^ 10.77 (bs, 1H), 6.84 (t, J=9.0 Hz,1H), 6.48 (d, J=15.1 Hz, 1H), 6.40 (d, J=8.3 Hz, 1H), 5.76 (d, J=6.9 Hz, 1H), 4.27-4.23 (m, 1H), 2.90-2.83 (m, 4H), 2.74- 2.67 (m, 1H), 2.58 (bs, 1H), 2.31 (s, 2H), 2.11-2.06 (m, 1H), 1.89-1.82 (m, 1H), 1.76-1.71 (m, 2H), 1.65-1.62 (m, 2H). Example 11: Synthesis of 3-(2-fluoro-3-piperazin-1-yl-anilino)piperidine-2,6-dione (C-13) Step-1: To a 250 mL single-neck round-bottom flask containing a well-stirred solution of 1-bromo-2- fluoro-3-nitro-benzene 1 (3 g, 13.64 mmol) and tert-butyl piperazine-1-carboxylate 2 (5.08 g, 27.27 mmol) in dry 1,4-dioxane (30 mL) was added cesium carbonate (11.11 g, 34.09 mmol) under nitrogen atmosphere. The reaction mixture was degassed with nitrogen gas for 5 minutes. Subsequently, Pd2(dba)3 (0.624 g, 0.681 mmol) and Xantphos (0.394 g, 0.681 mmol) were added and the resulting mixture was stirred at 110 °C for 16 h. The reaction progress was monitored by UPLC. After complete consumption of starting materials, the reaction mixture was cooled to ambient temperature, poured into ice-cold water and the aqueous phase was extracted with DCM (2 × 150 mL). The combined organic phase was washed with brine (50 mL) and dried over anhydrous Na2SO4and filtered. The filtrate was concentrated under reduced pressure and the obtained crude residue was purified by flash column chromatography (100-200 mesh silica-gel, 100 g SNAP) column with a gradient of 0-100% EtOAc / pet ether to afford tert- butyl 4-(2-fluoro-3-nitro-phenyl)piperazine-1-carboxylate 3 (3.5 g, 8.07 mmol, 59.2% yield) as a pale yellow gummy liquid. LCMS (ESI): m / z 270.0 [M - isobutene + H]+. Step-2: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-(2- fluoro-3-nitro-phenyl)piperazine-1-carboxylate 3 (1 g, 3.07 mmol) in 2:1 MeOH / H2O (15 mL) were added iron powder (0.858 g, 15.37 mmol) and ammonium chloride (0.82 g, 15.37 mmol) under nitrogen atmosphere at 0 °C. The reaction mixture was stirred at 80 °C for 4 h and the reaction progress was monitored by TLC. After complete consumption of starting materials, the reaction mixture was cooled to ambient temperature, filtered through a pad of Celite and the Celite bed was washed with EtOAc (100 mL). The filtrate was washed with brine (10 mL) and dried over anhydrous Na2SO4and filtered. The filtrate was concentrated under reduced pressure and the obtained crude residue was purified by flash column chromatography (60-120 mesh silica-gel, 50 g SNAP) column with a gradient of 0-60% EtOAc / pet ether to afford tert-butyl 4-(3-amino-2-fluoro-phenyl)piperazine-1-carboxylate 4 (650 mg, 1.94 mmol, 63.11% yield) as a pale yellow solid. LCMS (ESI): m / z 296.2 [M + H]+. Step-3: To a 100 mL sealed tube containing a well-stirred solution of tert-butyl 4-(3-amino-2-fluoro- phenyl)piperazine-1-carboxylate 4 (600 mg, 2.03 mmol) and 3-bromopiperidine-2,6-dione 5 (0.58 g, 3.05 mmol) in dry DMF (10 mL) was added sodium bicarbonate (0.511 g, 6.09 mmol) at ambient temperature under nitrogen atmosphere. The reaction mixture was stirred at 60 °C for 48 h and the reaction progress was monitored by UPLC. After complete consumption of starting materials, the reaction mixture was cooled to ambient temperature, diluted with water (50 mL) and extracted with EtOAc (2 × 80 mL). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na2SO4and filtered. The filtrate was concentrated under reduced pressure and the obtained crude residue was purified by flash column chromatography (230-400 mesh silica-gel, 25 g SNAP) with a gradient of 0-80% EtOAc / pet ether to afford tert-butyl 4-[3-[(2,6- dioxo-3-piperidyl)amino]-2-fluoro-phenyl]piperazine-1-carboxylate 6 (205 mg, 0.197 mmol, 9.74% yield) as a brown gummy liquid. LCMS (ESI): m / z 407.2 [M + H]+. Step-4: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[3- [(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]piperazine-1-carboxylate 6 (210 mg, 0.516 mmol) in dry DCM (3 mL) was added 4 N HCl in 1,4-dioxane (0.64 mL) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at ambient temperature for 3 h and the reaction progress was monitored by UPLC. After complete consumption of starting materials, the reaction mixture was concentrated under reduced pressure (co-distilled with toluene) and the residue was triturated with Et2O (10 mL) to afford 3-(2-fluoro-3-piperazin-1-yl-anilino)piperidine-2,6-dione hydrochloride 7 (200 mg, 0.367 mmol, 71.2% yield) as a pale-yellow solid. LCMS (ESI): m / z 307.1 [M + H]+. Example 12: 3-((3,5-difluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (C-14) Compound 3-((3,5-difluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione was prepared using the method described on page 167-168 of WO2022032026 A1. Example 13: 3-((3,5-difluoro-4-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dione (C-15) Compound 3-((3,5-difluoro-4-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dione was prepared using the method described on page 356-358 of WO2021178920 A1.

[0068] Example 14: Synthesis of 3-(3,5-difluoro-N-methyl-4-piperazin-1-yl-anilino)piperidine-2,6- dione (C-16) Compound tert-butyl 4-[4-[(2,6-dibenzyloxy-3-pyridyl)amino]-2,6-difluoro-phenyl]piperazine-1- carboxylate was synthesized according to the method described on page 167-168 of WO2022032026 A1. Step-1: To a 100 mL round-bottom flask containing a well-stirred solution of tert-butyl 4-[4-[(2,6- dibenzyloxy-3-pyridyl)amino]-2,6-difluoro-phenyl]piperazine-1-carboxylate 1 (2.0 g, 3.32 mmol) in DMF (20 mL) were added iodomethane (1.41 g, 9.96 mmol, 619.78 μL) and sodium hydride (182.72 mg, 4.77 mmol; 60% dispersion in mineral oil) at 0 °C under nitrogen atmosphere. The resulting reaction mixture was stirred at 25 °C for 16 h. After completion of the reaction as indicated by TLC, the reaction mixture was quenched with cold water (70 ml) and extracted with EtOAc (2 × 70 ml). The combined organic phase was washed with brine (50 ml), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (230-400 mesh silica-gel, 50 g) using a gradient of 0- 20% EtOAc / Pet ether to afford tert-butyl 4-[4-[(2,6-dibenzyloxy-3-pyridyl)-methyl-amino]-2,6- difluoro-phenyl]piperazine-1-carboxylate 2 (1.6 g, 2.59 mmol, 78.18% yield) as a brown solid. UPLC (ESI): m / z 617.9 [M + H]+. Step-2: To a 250 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[4- [(2,6-dibenzyloxy-3-pyridyl)-methyl-amino]-2,6-difluoro-phenyl]piperazine-1-carboxylate 2 (1.5 g, 2.43 mmol) in anhydrous 1,4-dioxane (20 mL) was added 20 wt.% palladium hydroxide on carbon, 50% water (375.00 mg, 2.67 mmol) under nitrogen atmosphere at ambient temperature. The resulting suspension was stirred under hydrogen atmosphere (balloon) for 16 h. Afterwards, the reaction mixture was filtered through a pad of Celite and the Celite pad was washed with 50 mL of a 1:1 mixture of methanol and EtOAc. The filtrate was concentrated under reduced pressure and the crude product was purified by flash column chromatography (230-400 mesh silica-gel, 50 g) using a gradient of 0-80% EtOAc / Pet ether to afford tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)- methyl-amino]-2,6-difluoro-phenyl]piperazine-1-carboxylate 3 (400 mg, 906.61 μmol, 37.27% yield) as a brown solid. LCMS (ESI): m / z 439.2 [M + H]+. Step-3: To a 100 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[4- [(2,6-dioxo-3-piperidyl)-methyl-amino]-2,6-difluoro-phenyl]piperazine-1-carboxylate 3 (350 mg, 798.24 μmol) in anhydrous DCM (10 mL) was added 4 M hydrochloric acid in 1,4-dioxane (8 mL) at ambient temperature under nitrogen atmosphere. The contents were stirred for 2 h at ambient temperature. After completion consumption of the starting material as indicated by UPLC, the excess solvent was removed under reduced pressure and the crude product was washed with MTBE (10 mL) to afford 3-(3,5-difluoro-N-methyl-4-piperazin-1-yl-anilino)piperidine-2,6-dione 4 (290 mg, 620.68 μmol, 77.76% yield, HCl salt) as a green solid. UPLC (ESI): m / z 339.5 [M + H]+. Example 15: Synthesis of 3-[4-(2,6-diazaspiro[3.3]heptan-2-yl)-3,5-difluoro- anilino]piperidine-2,6-dione (C-17) Step-1: To a solution of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate 1 (3.4 g, 17.15 mmol) in MeCN (30 mL) was added 1,2,3-trifluoro-5-nitro-benzene 2 (3.04 g, 17.15 mmol) and DIPEA (6.65 g, 51.45 mmol, 8.96 mL) and the mixture was stirred at 90°C for 3h. Upon completion of the reaction, the reaction mixture was poured into water (100 mL). The resulting yellow precipitate was filtered and triturated with pet-ether (20 mL) at 15 °C for 30 min to afford tert-butyl 6-(2,6-difluoro-4-nitro-phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate 3 (4.6 g, 12.95 mmol, 75.49% yield) as yellow solid. LCMS (ESI): m / z 356.1 [M + H]+. Step-2: To a solution of methyl tert-butyl 6-(2,6-difluoro-4-nitro-phenyl)-2,6-diazaspiro[3.3]heptane-2- carboxylate 3 (1.6 g, 4.50 mmol) in EtOH (15 mL) was added 10 wt.% Pd / C (300 mg, 4.22 mmol) under N2atmosphere. The suspension was degassed and purged with H2several times and stirred under H2 (15 Psi) at 20°C for 16 hrs. Upon completion of the reaction, the reaction mixture was filtered through a pad of Celite and the Celite was washed with MeOH (20 mL×3). The combined filtrate was concentrated in vacuo to yield tert-butyl 6-(4-amino-2,6-difluoro-phenyl)- 2,6-diazaspiro[3.3]heptane-2-carboxylate 4 (1.45 g, 4.23 mmol, 94.03% yield) as a white solid.1H NMR (400 MHz, DMSO-d6): δ = 6.19 - 6.05 (m, 2H), 5.00 (br s, 2H), 4.04 - 3.88 (m, 8H), 1.37 (s, 9H). Step-3: To a clear solution of tert-butyl 6-(4-amino-2,6-difluoro-phenyl)-2,6-diazaspiro[3.3]heptane-2- carboxylate 4 (1.45 g, 4.46 mmol) in CH3CN (25 mL) was added 3-bromopiperidine-2,6-dione 5 (1.28 g, 6.69 mmol) and sodium bicarbonate (935.98 mg, 11.14 mmol) at 20 °C. After addition, the solution was concentrated in vacuo to remove most of the solvent. The formed creamy paste was kept at 95 °C for 16 hrs. Upon completion of the reaction, the reaction mixture was diluted with H2O (30 mL) and solvent (PE / EtOAc=2:1, 30 mL), and the resulting mixture was stirred at 20°C for 1 h and filtered. The filter cake was washed with water (15 mL×3) and dried in vacuo to give tert-butyl 6-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-2,6- diazaspiro[3.3]heptane-2-carboxylate 6 (1.8 g, 3.71 mmol, 83.28% yield) as blue solid. LCMS (ESI): m / z 437.2 [M + H]+.Step-4: To a 100 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 6-[4- [(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate 6 (315 mg, 721.73 μmol) in anhydrous DCM (5 mL) was added trifluoroacetic acid (2.22 g, 19.47 mmol, 1.5 mL) at 0°C under nitrogen atmosphere. The contents were stirred at ambient temperature for 1 h. After completion consumption of the starting material as indicated by UPLC, excess solvent was removed and the crude product was washed with MTBE (60 mL) to give 3-[4- (2,6-diazaspiro[3.3]heptan-2-yl)-3,5-difluoro-anilino]piperidine-2,6-dione trifluoroacetate 7 (350 mg, 284.44 μmol, 39.41% yield) as a brown gum. LCMS (ESI): m / z 337.0 [M + H]+. Example 16: Synthesis of 3-((3,5-difluoro-4-(2-azaspiro[3.3]heptan-6- yl)phenyl)amino)piperidine-2,6-dione (C-18) Step-1: To a 100 mL multi-neck round-bottom flask containing a well-stirred solution of tert-butyl 6-oxo- 2-azaspiro[3.3]heptane-2-carboxylate 1 (10 g, 47.34 mmol) in dry THF (100 mL) was added 1M LiHMDS, (56.8 mL) at -78 °C under nitrogen atmosphere. After 30 minutes, 1,1,1-trifluoro-N-(2- pyridyl)-N-(trifluoromethylsulfonyl)methanesulfonamide (22.04 g, 61.54 mmol) in dry THF (50 mL) was added dropwise over 15 minutes. The reaction mixture was stirred at -78 °C for 2 h and the progress of the reaction was monitored by UPLC. After complete consumption of the starting material, the reaction mixture was quenched with saturated aq. NH4Cl solution (200 ml) and extracted with EtOAc (2 × 300 ml). The combined organic phase was washed with brine (300 ml), dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (230-400 mesh silica-gel, 100 g SNAP) with a gradient of 5-10% EtOAc / pet ether to give tert-butyl 6-(((trifluoromethyl)sulfonyl)oxy)-2- azaspiro[3.3]hept-5-ene-2-carboxylate 2 (3.5 g, 10.18 mmol, 21.5% yield) as an off-white solid. LCMS (ESI): m / z 244.0 [M -isobutene+ H]+. Step-2: To a 250 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 6- (((trifluoromethyl)sulfonyl)oxy)-2-azaspiro[3.3]hept-5-ene-2-carboxylate 2 (6.5 g, 18.93 mmol) and bis(pinacolato)diboron (7.21 g, 28.40 mmol) in dry 1,4-dioxane (60 mL) was added potassium acetate (5.57 g, 56.80 mmol) at ambient temperature under nitrogen atmosphere. The reaction mixture was purged with nitrogen gas for 5 minutes. Subsequently 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (1.55 g, 1.89 mmol) was added at ambient temperature and the resulting reaction mixture was stirred at 90 °C for 16 h. The reaction progress was monitored by GCMS. After complete consumption of the starting material, the reaction mixture was cooled to ambient temperature and the reaction mixture was filtered through a pad of Celite and the Celite bed was washed with EtOAc (500 mL). The filtrate was concentrated under reduced pressure to afford tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-2-azaspiro[3.3]hept-5-ene-2-carboxylate 3 (6.5 g, 13.94 mmol, 73.6% yield) as a brown gum. GCMS (ESI): m / z 239.1 [M - 82]. Step-3: To a 250 mL single-neck round-bottom flask containing a well-stirred solution of 2-bromo-1,3- difluoro-5-nitrobenzene 4 (4 g, 16.81 mmol) and tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-2-azaspiro[3.3]hept-5-ene-2-carboxylate (3; 5.94 g, 18.49 mmol) in dry 1, 4- dioxane (100 mL) was added sodium carbonate (5.34 g, 50.42 mmol) in H2O (20 mL) at ambient temperature under nitrogen atmosphere and the resulting reaction mixture was purged with nitrogen gas for 10 minutes. Subsequently, Pd(dppf)Cl2·DCM (1.37 g, 1.68 mmol) was added and the reaction mixture was stirred at 90 °C for 16 h. After completion consumption of the starting material, the reaction mixture was cooled to ambient temperature and poured into water (100 mL) and the aqueous phase was extracted with EtOAc (2 × 150 mL). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (100-200 mesh silica- gel, 100 g SNAP) with a gradient of 0-100% EtOAc / pet ether to afford tert-butyl 6-(2,6-difluoro- 4-nitrophenyl)-2-azaspiro[3.3]hept-5-ene-2-carboxylate 5 (2.5 g, 6.39 mmol, 38% yield) as a pale yellow solid.1H NMR (400 MHz, DMSO-d6): δ 8.09 (d, J = 8.4 Hz, 2H), 6.85 (s, 1H), 4.08 (s, 4H), 3.19 (s, 2H) and 1.39 (s, 9H). Step-4: To a 100 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 6-(2,6- difluoro-4-nitrophenyl)-2-azaspiro[3.3]hept-5-ene-2-carboxylate 5 (1 g, 2.84 mmol) in dry 1,4- dioxane (15 mL) was added 20 wt.% Pd(OH)2 / C (996.47 mg, 1.42 mmol) at ambient temperature under nitrogen atmosphere. The reaction was stirred under hydrogen atmosphere (balloon) for 12 h at ambient temperature and monitored by UPLC. After completion consumption of the starting material, the reaction mixture was filtered through a pad of Celite and the Celite bed was washed with 1,4-dioxnae (200 mL). The filtrate was concentrated under reduced pressure and the crude residue was purified by flash column chromatography (230-400 mesh silica-gel, 100 g SNAP) with a gradient of 0-100% EtOAc / pet ether to afford tert-butyl 6-(4-amino-2,6- difluorophenyl)-2-azaspiro[3.3]heptane-2-carboxylate 6 (800 mg, 2.33 mmol, 82.1% yield) as an pale yellow solid. UPLC-MS (ESI): m / z 323.3 [M - H]-. Step-5: To a 100 mL sealed-tube containing a well-stirred solution of tert-butyl 6-(4-amino-2,6- difluorophenyl)-2-azaspiro[3.3]heptane-2-carboxylate 6 (800 mg, 2.47 mmol) and 3- bromopiperidine-2,6-dione 7 (2.37 g, 12.33 mmol) in dry DMF (30 mL) was added sodium bicarbonate (1.04 g, 12.33 mmol) at ambient temperature under nitrogen atmosphere. The reaction mixture was stirred at 70 °C for 48 h and the reaction progress was monitored by TLC. After complete consumption of the starting material, the reaction mixture was cooled to ambient temperature, poured into water (50 mL), and extracted with EtOAc (3 × 100 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (100-200 mesh silica-gel, 50 g SNAP) with a gradient of 0-100% EtOAc / pet ether to afford tert-butyl 6-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)-2- azaspiro[3.3]heptane-2-carboxylate 8 (320 mg, 0.71 mmol, 28.9% yield) as a green solid. LCMS (ESI): m / z 336.2 [M -isobutene+ H]+. Step-6: To a 50 mL single-neck round-bottom flask containing a well stirred solution of tert-butyl 6-(4- ((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)-2-azaspiro[3.3]heptane-2-carboxylate 8 (300 mg, 0.69 mmol) in dry DCM (10 mL) was added TFA (14.60 mmol, 1.13 mL) under nitrogen atmosphere at 0 °C. The reaction mixture was stirred for 3 h at ambient temperature under nitrogen atmosphere and monitored by UPLC. After complete consumption of the starting material, the reaction mixture was concentrated under reduced pressure and the crude residue was triturated with MTBE (2 × 10 mL) to afford 3-((3,5-difluoro-4-(2-azaspiro[3.3]heptan-6- yl)phenyl)amino)piperidine-2,6-dione trifluoroacetate 9 (280 mg, 0.60 mmol, 87.3% yield) as a brown gummy liquid. UPLC-MS (ESI): m / z 334.3 [M - H]-. Example 17: Synthesis of 3-(3-chloro-4-piperazin-1-yl-anilino)piperidine-2,6-dione (C-19) Step-1: To a 500 mL single-neck round-bottom flask containing a well-stirred solution of 2-chloro-1- fluoro-4-nitro-benzene 1 (10 g, 56.97 mmol) and tert-butyl piperazine-1-carboxylate 2 (15.91 g, 85.45 mmol) in anhydrous DMF (100 mL) was added DIPEA (22.09 g, 170.90 mmol, 29.77 mL) at ambient temperature. The resulting reaction was heated to 80 °C for 16 h. After complete consumption of the starting material as indicated by UPLC, the reaction was cooled to ambient temperature and diluted with ice cold water (300 mL), at which time a precipitate formed. The solid precipitate was filtered and dried in vacuo to afford tert-butyl 4-(2-chloro-4-nitro- phenyl)piperazine-1-carboxylate 3 (19 g, 53.57 mmol, 94.03% yield) as a yellow solid. LCMS (ESI): m / z 286.0 [M + H - isobutene]+. Step-2: To a 500 mL single-neck round-bottom flask containing a well-stirred suspension of tert-butyl 4- (2-chloro-4-nitro-phenyl)piperazine-1-carboxylate 3 (8.0 g, 23.41 mmol) in ethanol (70 mL), water (40 mL) and THF (30 mL) was added iron powder (9.15 g, 163.84 mmol) and ammonium chloride (6.26 g, 117.03 mmol) at ambient temperature under nitrogen atmosphere. The resulting suspension was heated to 90 °C for 2 h. After complete consumption of the starting material as indicated by TLC, the reaction was cooled to ambient temperature, filtered through a pad of Celite, and Celite bed was washed with EtOAc (200 mL). The combined filtrate was diluted with water (150 mL) and extracted with EtOAc (2 × 150 mL). The organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (100 g silica-gel) using a gradient of 0-65% EtOAc / Pet ether to afford tert-butyl 4-(4-amino-2-chloro-phenyl)piperazine-1-carboxylate 4 (6.1 g, 18.71 mmol, 79.93% yield) as a yellow solid. UPLC-MS (ESI): m / z 312.2 [M + H]+. Step-3: To a 250 mL sealed-tube reaction vessel containing a well-stirred solution of tert-butyl 4-(4- amino-2-chloro-phenyl)piperazine-1-carboxylate 4 (6.0 g, 19.24 mmol) and 3-bromopiperidine- 2,6-dione 5 (5.54 g, 28.86 mmol) in anhydrous DMF (60 mL) was added sodium bicarbonate (4.85 g, 57.73 mmol) at ambient temperature under nitrogen atmosphere. The reaction mixture was heated to 60 °C for 24 h. Upon completion of the reaction, the reaction mixture was cooled to ambient temperature, diluted with water (150 mL), and extracted with EtOAc (2 × 150 mL). The organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (230-400 mesh silica-gel, 100 g Biotage® SNAP column) using a gradient of 0-80% EtOAc / Pet ether to afford tert-butyl 4-[2-chloro-4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazine-1-carboxylate 6 (6.2 g, 14.03 mmol, 72.89% yield) as a green solid. UPLC-MS (ESI): m / z 423.2 [M + H]+. Step-4: To a 250 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[2- chloro-4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazine-1-carboxylate 6 (2.5 g, 5.91 mmol) in anhydrous DCM (30 mL) was added 4 M hydrochloric acid in 1,4-dioxane (25 mL, 100 mmol) at ambient temperature under nitrogen atmosphere. The contents were stirred for 2 h at the same temperature. After consumption of the starting material as indicated by UPLC, the excess solvent was removed under reduced pressure and the crude product was washed with MTBE (80 mL) to afford 3-(3-chloro-4-piperazin-1-yl-anilino)piperidine-2,6-dione 7 (2.1 g, 5.65 mmol, 95.54% yield, HCl salt) as a green solid. LCMS (ESI): m / z 323.2 [M + H]+. Example 18: 3-((3-chloro-4-(piperidin-...

Claims

CLAIMS We claim:

1. A compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, or Formula X: ;; or a pharmaceutically acceptable salt thereof; wherein X3is N, CH, or CR3a; X4is N, CH, or CR3b; X5is N, CH, or CR3c; X6is N, CH, or CR3d; X6Bis CH or CR3d; wherein no more than 3 of X3, X4, X5, and X6are N; X7is N or CR1c; Q1is -NR6-, -CH2-, -O-, or -S-, wherein if X7is N then Q1is CH2; R1a, R1b, R1c, and R1dare each independently hydrogen, C1-C4alkyl, or C1-C4haloalkyl; or R1aand R1care combined to form a 1 or 2 carbon atom bridge; R3a, R3b, R3c, and R3d, are independently at each occurrence selected from the group consisting of hydrogen, hydroxyl, alkoxy, C1-C4alkyl, C1-C4haloalkyl, cycloalkyl, fluorine, chlorine, bromine, and iodine; RET Targeting Ligand is,, ris a heteroaryl, heterocycle, or carbocycle, each of which is optionally substituted with 0, 1, 2, 3, or 4 substituents independently selected from R9; X9is NR13or O; X10, X16, X17, and X18are independently selected from the group consisting of N, CH, and CRA; X11, X12, and X13are independently selected from the group consisting of N, CH, and CRB;each R4and R13is independently selected from the group consisting of hydrogen, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4haloalkyl, cycloalkyl, heteroaryl, aryl, heterocycle, -alkyl-heteroaryl, -alkyl-aryl, -alkyl-heterocycle, -C(O)R5, and -alkyl-C(O)R5, each of which C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4haloalkyl, cycloalkyl, heteroaryl, aryl, heterocycle, -alkyl-heteroaryl, -alkyl-aryl, and -alkyl-heterocycle groups is optionally substituted with 0, 1, 2, or 3 substituents independently selected from R8; R5is hydrogen, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4haloalkyl, cycloalkyl, heteroaryl, aryl, heterocycle, bicycle, -alkyl-heteroaryl, -alkyl-aryl, -alkyl-heterocycle, -OR6, or -NR6R7, each of which C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4haloalkyl, cycloalkyl, heteroaryl, aryl, heterocycle, -alkyl-heteroaryl, -alkyl-aryl, and -alkyl-heterocycle group is optionally substituted with 0, 1, 2, or 3 substituents independently selected from R10; R6and R7are independently selected at each instance from the group consisting of hydrogen, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4haloalkyl, cycloalkyl, heteroaryl, aryl, heterocycle, -alkyl-heteroaryl, -alkyl-aryl, and -alkyl-heterocycle, each of which R6and R7groups other than hydrogen is optionally substituted with 0, 1, 2, or 3 substituents independently selected from R10; R8is independently at each occurrence selected from the group consisting of hydrogen, C1-C4haloalkyl, C1-C4alkyl, halogen, -OR6, -NR6R7, -OC(O)R5, -NR6C(O)R5, -C(O)R5, and -alkyl-C(O)R5; R9is independently at each occurrence selected from the group consisting of hydrogen, aryl, -alkyl-aryl, heteroaryl, alkyl-heteroaryl, heterocycle, alkyl-heterocycle, cycloalkyl, -alkyl-cycloalkyl, C1-C4haloalkyl, C1-C4alkyl, halogen, -OR6, -NR6R7, -C(O)OR6, -C(O)NR6R7, -alkyl-C(O)OR6, and -alkyl-C(O)NR6R7, each of which aryl, -alkyl-aryl, heteroaryl, -alkyl-heteroaryl, heterocycle, -alkyl-heterocycle, -alkyl-cycloalkyl, and cycloalkyl group is optionally substituted with 0, 1, 2, or 3 substituents selected from -S(O)2alkyl, C1-C4haloalkyl, C1- C4alkyl, halogen, -OR6, -NR6R7, -C(O)OR6, -C(O)NR6R7, -alkyl-C(O)OR6, and -alkyl- C(O)NR6R7; R10is independently at each occurrence selected from the group consisting of hydrogen, halogen, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4haloalkyl, cycloalkyl, heteroaryl, aryl, heterocycle, -alkyl-heteroaryl, -alkyl-aryl, and -alkyl-heterocycle;R11is hydrogen, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4haloalkyl, cycloalkyl, heteroaryl, aryl, heterocycle, -alkyl-heteroaryl, -alkyl-aryl, or -alkyl-heterocycle; each RAand RBis independently at each occurrence selected from the group consisting of hydrogen, C1-C4haloalkyl, C1-C4alkyl, halogen, cyano, nitro, -OR6, -NR6R7, -C(O)OR6, and -C(O)NR6R7; R14is hydrogen, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4haloalkyl, cycloalkyl, heteroaryl, aryl, heterocycle, -alkyl-heteroaryl, -alkyl-aryl, -alkyl-heterocycle, -C(O)R5, -alkyl-C(O)R5, -OC(O)R5, or -NR6C(O)R5, each of which C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4haloalkyl, cycloalkyl, heteroaryl, aryl, heterocycle, -alkyl-heteroaryl, -alkyl-aryl, and -alkyl- heterocycle groups is optionally substituted with 0, 1, 2, or 3 substituents independently selected from R8; Linker is of formula:. wherein, X1and X2are independently at each occurrence selected from bond, heterocycle, NR2, C(R2)2, O, C(O), and S; R2is independently at each occurrence selected from the group consisting of hydrogen, alkyl, aliphatic, heteroaliphatic, heterocycle, aryl, heteroaryl, -C(O)H, -C(O)OH, -C(O)alkyl, -C(O)Oalkyl, -C(O)(aliphatic, aryl, heteroaliphatic or heteroaryl), -C(O)O(aliphatic, aryl, heteroaliphatic, or heteroaryl), alkene, and alkyne; R20,at each occurrence selected from the group consisting of a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR2-, -NR2C(O)-, -O-, -S-, -NR2-, -P(O)(OR26)O-, -P(O)(OR26)-, bicycle, alkene, alkyne, haloalkyl, alkoxy, aryl, heterocycle, aliphatic, heteroaliphatic, heteroaryl, lactic acid, glycolic acid, and carbocycle; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R40; R26is independently at each occurrence selected from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocycle, aliphatic and heteroaliphatic; andR40is independently at each occurrence selected from the group consisting of hydrogen, alkyl, alkene, alkyne, fluoro, bromo, chloro, hydroxyl, alkoxy, azide, amino, cyano, -NH(alkyl), -N(alkyl)2, -NHSO2(alkyl), -N(alkyl)SO2alkyl, -NHSO2(aryl, heteroaryl or heterocycle), -N(alkyl)SO2(aryl, heteroaryl or heterocycle), -NHSO2alkenyl, -N(alkyl)SO2alkenyl, -NHSO2alkynyl, -N(alkyl)SO2alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocycle, and cycloalkyl.

2. The compound of claim 1 wherein the compound is of formula: ;ĨVIII); or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 or claim 2, wherein R40is independently at each occurrence selected from the group consisting of hydrogen, C1-C3alkyl, fluoro, chloro, and C1-C3haloalkyl.

4. The compound of any one of claims 1-3, wherein the compound is of formula:; or a pharmaceutically acceptable salt thereof.

5. The compound of any one of claims 1-4, wherein Q1is -NH-.

6. The compound of any one of claims 1-4, wherein Q1is -NCH3-.

7. The compound of any one of claims 1-3, wherein the compound is of formula:; or a pharmaceutically acceptable salt thereof.

8. The compound of any one of claims 1-7, wherein X5is CH.

9. The compound of any one of claims 1-7, wherein X5is N.

10. The compound of any one of claims 1-7, wherein X5is CR3c.

11. The compound of any one of claims 1-7, wherein X5is C-F.

12. The compound of any one of claims 1-7, wherein X5is C-OCH3.

13. The compound of any one of claims 1-3, wherein the compound is of formula:; or a pharmaceutically acceptable salt thereof.

14. The compound of any one of claims 1-3, wherein the compound is of formula:; or a pharmaceutically acceptable salt thereof.

15. The compound of any one of claims 1-14, wherein X7is N.

16. The compound of any one of claims 1-14, wherein X7is CH.

17. The compound of any one of claims 1-14, wherein X7is CR1c.

18. The compound of any one of claims 1-3, wherein the compound is of formula:; or a pharmaceutically acceptable salt thereof.

19. The compound of any one of claims 1-18, wherein X3is CR3a.

20. The compound of any one of claims 1-18, wherein X3is CH.

21. The compound of any one of claims 1-18, wherein X3is N.

22. The compound of any one of claims 1-18, wherein X3is C-OCH3.

23. The compound of any one of claims 1-18, wherein X3is C-F.

24. The compound of any one of claims 1-18, wherein X3is C-CF3.

25. The compound of any one of claims 1-24, wherein X4is CR3b.

26. The compound of any one of claims 1-24, wherein X4is CH.

27. The compound of any one of claims 1-24, wherein X4is N.

28. The compound of any one of claims 1-24, wherein X4is C-F.

29. The compound of any one of claims 1-24, wherein X4is C-Cl.

30. The compound of any one of claims 1-24, wherein X4is C-CF3.

31. The compound of any one of claims 1-24, wherein X4is C-OCH3.

32. The compound of any one of claims 1-31, wherein X6is CR3d.

33. The compound of any one of claims 1-31, wherein X6is CH.

34. The compound of any one of claims 1-31, wherein X6is N.

35. The compound of any one of claims 1-31, wherein X6is C-F.

36. The compound of any one of claims 1-31, wherein X6is C-CF3.

37. The compound of any one of claims 1-31, wherein X6is C-OCH3.

38. The compound of any one of claims 1-37, wherein R1ais hydrogen.

39. The compound of any one of claims 1-38, wherein R1bis hydrogen.

40. The compound of any one of claims 1-39, wherein R1cis hydrogen.

41. The compound of any one of claims 1-40, wherein R1dis hydrogen.

42. The compound of any one of claims 1-41, wherein the RET Targeting Ligand is of formula:.

43. The compound of any one of claims 1-41, wherein the RET Targeting Ligand is of formula:.

44. The compound of any one of claims 1-41, wherein the RET Targeting Ligand is of formula:.

45. The compound of any one of claims 1-41, wherein the RET Targeting Ligand is of formula:r.

46. The compound of any one of claims 1-45, whereinis heteroaryl.

47. The compound of any one of claims 1-45, wherein.

48. The compound of any one of claims 1-45, wherein.

49. The compound of any one of claims 1-45, wherein.

50. The compound of any one of claims 1-45, wherein. 5 . The compound of any one of claims 1-45, wherein. 5 The compound of any one of claims 1-45, wherein.

53. The compound of any one of claims 1-45, wherein. 5 The compound of any one of claims 1-45, wherein.

55. The compound of any one of claims 1-41, wherein the RET Targeting Ligand is selected from: ,56. The compound of any one of claims 1-41, wherein the RET Targeting Ligand is:.

57. The compound of any one of claims 1-56, wherein Linker is of formula..

58. The compound of claim 57, wherein X1is bond.

59. The compound of claim 57, wherein X1is heterocycle.

60. The compound of claim 57, wherein X1is -NR2-.

61. The compound of claim 57, wherein X1is -C(O)-.

62. The compound of claim 57, wherein X1is -C(R2)2-.

63. The compound of claim 57, wherein X1is -O-.

64. The compound of claim 57, wherein X1is -S-.

65. The compound of any one of claims 57-64, wherein X2is bond.

66. The compound of claim 57-64, wherein X2is heterocycle.

67. The compound of claim 57-64, wherein X2is -NR2-.

68. The compound of claim 57-64, wherein X2is -C(O)-.

69. The compound of claim 57-64, wherein X2is -C(R2)2-.

70. The compound of claim 57-64, wherein X2is -O-.

71. The compound of claim 57-64, wherein X2is -S-.

72. The compound of any one of claims 57-71, wherein R20is bond.

73. The compound of any one of claims 57-71, wherein R20is -CH2-.

74. The compound of any one of claims 57-71, wherein R20is heterocycle.

75. The compound of any one of claims 57-71, wherein R20is aryl.

76. The compound of any one of claims 57-71, wherein R20is phenyl.

77. The compound of any one of claims 57-71, wherein R20is bicycle.

78. The compound of any one of claims 57-77, wherein R21is bond.

79. The compound of any one of claims 57-77, wherein R21is -CH2-.

80. The compound of any one of claims 57-77, wherein R21is heterocycle.

81. The compound of any one of claims 57-77, wherein R21is aryl.

82. The compound of any one of claims 57-77, wherein R21is phenyl.

83. The compound of any one of claims 57-77, wherein R21is bicycle.

84. The compound of claim 57, wherein Linker is of formula:.

85. The compound of any one of claims 57-84, wherein R22is bond.

86. The compound of any one of claims 57-84, wherein R22is -CH2-.

87. The compound of any one of claims 57-84, wherein R22is heterocycle.

88. The compound of any one of claims 57-84, wherein R22is aryl.

89. The compound of any one of claims 57-84, wherein R22is phenyl.

90. The compound of any one of claims 57-84, wherein R22is bicycle.

91. The compound of any one of claims 57-84, wherein R22is glycolic acid.

92. The compound of claim 57, wherein Linker is of formula:.

93. The compound of any one of claims 57-92, wherein R23is bond.

94. The compound of any one of claims 57-92, wherein R23is -CH2-.

95. The compound of any one of claims 57-92, wherein R23is heterocycle.

96. The compound of any one of claims 57-92, wherein R23is aryl.

97. The compound of any one of claims 57-92, wherein R23is phenyl.

98. The compound of any one of claims 57-92, wherein R23is bicycle.

99. The compound of claim 57, wherein linker is of formula:.

100. The compound of any one of claims 57-99, wherein R24is bond.

101. The compound of any one of claims 57-99, wherein R24is -CH2-.

102. The compound of any one of claims 57-99, wherein R24is heterocycle.

103. The compound of any one of claims 57-99, wherein R24is aryl.

104. The compound of any one of claims 57-99, wherein R24is phenyl.

105. The compound of any one of claims 57-99, wherein R24is bicycle.

106. The compound of any one of claims 57-99, wherein R24is -C(O)-.

107. A compound of structure:or a pharmaceutically acceptable salt thereof.

108. A compound of structure:or a pharmaceutically acceptable salt thereof.

109. A compound of structure:or a pharmaceutically acceptable salt thereof.

110. A compound of structure:or a pharmaceutically acceptable salt thereof.

111. A compound of structure:or a pharmaceutically acceptable salt thereof.

112. A compound of structure:or a pharmaceutically acceptable salt thereof.

113. A compound of structure:or a pharmaceutically acceptable salt thereof.

114. A compound of structure:or a pharmaceutically acceptable salt thereof.

115. A compound of structure:or a pharmaceutically acceptable salt thereof.

116. A compound of structure:or a pharmaceutically acceptable salt thereof.

117. A pharmaceutical composition comprising a compound of any one of claims 1-116 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

118. A method of treating a RET mediated disorder comprising administering an effective amount of a compound of any one of claims 1-116 or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, to a patient in need thereof.

119. The method of claim 118, wherein the patient is a human.

120. The method of claim 118 or claim 119, wherein the RET mediated disorder is a RET mediated cancer.

121. The method of claim 120, wherein the RET mediated cancer is non-small cell lung cancer.

122. The method of claim 120, wherein the RET mediated cancer has metastasized to the brain.

123. The method of any one of claims 120-122, wherein the RET mediated cancer is mediated by a mutant RET.

124. The method of any one of claims 120-123, wherein the RET mediated cancer is a relapsed or refractory cancer.

125. A compound of any one of claims 1-116 or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, for use in the treatment of a RET mediated disorder.

126. The compound of claim 125, wherein the RET mediated disorder is a RET mediated cancer.

127. The compound of claim 126, wherein the RET mediated cancer is non-small cell lung cancer.

128. The compound of claim 126, wherein the RET mediated cancer has metastasized to the brain.

129. The compound of any one of claims 126-128, wherein the RET mediated cancer is mediated by a mutant RET.

130. The compound of any one of claims 126-129, wherein the RET mediated cancer is a relapsed or refractory cancer.

131. Use of a compound of any one of claims 1-116 or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, in the treatment of a RET mediated disorder.

132. The use of claim 131, wherein the RET mediated disorder is a RET mediated cancer.

133. The use of claim 132, wherein the RET mediated cancer is non-small cell lung cancer.

134. The use of claim 132, wherein the RET mediated cancer has metastasized to the brain.

135. The use of any one of claims 132-134, wherein the RET mediated cancer is mediated by a mutant RET.

136. The use of any one of claims 132-135, wherein the RET mediated cancer is a relapsed or refractory cancer.

137. Use of a compound of any one of claims 1-116 or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, in the manufacture of a medicament for the treatment of a RET mediated disorder.

138. The use of claim 137, wherein the RET mediated disorder is a RET mediated cancer.

139. The use of claim 138, wherein the RET mediated cancer is non-small cell lung cancer.

140. The use of claim 138, wherein the RET mediated cancer has metastasized to the brain.

141. The use of any one of claims 138-140, wherein the RET mediated cancer is mediated by a mutant RET.

142. The use of any one of claims 138-141, wherein the RET mediated cancer is a relapsed or refractory cancer.

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