Compounds for targeted degradation of RET

Abstract

A novel compound that is a protein degradation-inducing part of the proto-oncogene tyrosine protein kinase receptor (RET), wherein the RET may be wild-type RET or a mutant form of RET.

Description

[0001] Cross-references to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 061,741, filed August 5, 2020, and U.S. Provisional Application No. 63 / 136,586, filed January 12, 2021. The entire contents of these applications are incorporated herein by reference for all purposes. Technical Field

[0003] This invention provides a compound that degrades the (RET) proto-oncogene tyrosine protein kinase receptor rearranged during transfection for therapeutic applications further described herein. Background Technology

[0004] Protein degradation is a highly regulated and essential process for maintaining cellular homeostasis. The selective identification and removal of damaged, misfolded, or excess proteins is achieved through the ubiquitin-proteasome pathway (UPP). UPP is central to regulating almost all cellular processes, including antigen processing, apoptosis, organelle biogenesis, cell cycle, DNA transcription and repair, differentiation and development, immune responses and inflammation, neural and muscular degeneration, neural network morphogenesis, regulation of cell surface receptors, ion channels and secretory pathways, responses to stress and extracellular regulators, ribosome biogenesis, and viral infection.

[0005] The covalent attachment of multiple ubiquitin molecules to terminal lysine residues via E3 ubiquitin ligase marks the degradation of a protein by the proteasome, in which the protein is digested into small peptides and ultimately broken down into its constituent amino acids, which then form the building blocks of new proteins. Defects in proteasome degradation are associated with a variety of diseases, including cancer and others.

[0006] Thalidomide and its analogues lenalidomide and pomalidomide have attracted interest as immunomodulators and antitumor drugs, especially in multiple myeloma (Kim SA et al., “A novel cerebellar protein modulator for targeted protein degradation”, Eur J Med Chem. 2019, March 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; Martinini, R. et al., “Biological activity of lenalidomide and its underlying therapeutic effects in multiple myeloma”). myeloma" Adv Hematol, 2012, 2012: 842945; and Terpos, E. et al., "Pomalidomide: a novel drug to treatrelapsed and refractory multiple myeloma" Oncotargets and Therapy, 2013, 6: 531).

[0007] There are also clinical and preclinical studies on thalidomide and its analogues for the treatment of renal cell carcinoma, glioblastoma, prostate cancer, melanoma, colorectal cancer, Crohn's disease, rheumatoid arthritis, Bechtel syndrome, breast cancer, head and neck cancer, ovarian cancer, chronic heart failure, graft-versus-host disease, and tuberculous meningitis.

[0008] Thalidomide and its analogues have been found to bind to the ubiquitin ligase cerebellum and redirect its ubiquitination activity (see Ito, T. et al., “Identification of a primary target of thalidomide teratogenicity” Science, 2010, 327:1345). Cerebellum is part of an E3 ubiquitin ligase complex that interacts with impaired DNA-binding protein 1 to form an E3 ubiquitin ligase complex with Cullin 4 and E2-binding protein ROC1 (called RBX1), where it acts as a substrate acceptor to select proteins for ubiquitination. The binding of lenalidomide to cerebellum promotes the subsequent binding of cerebellum 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). J. et al. "Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiplemyeloma cells" Science, 2014, 343: 301-305).

[0009] Celgene also discloses imides for similar uses, including 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; 7,9 Those among 59,566; 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.

[0010] The disclosure of thalidomide binding to the cerebellar protein E3 ubiquitin ligase spurred research into incorporating thalidomide and certain derivatives into compounds to target and destroy proteins. This research led to a patent application filed by Proteinex, Inc. in February 1999 as U.S. Patent No. 6,306,663, which claims a method for generating compounds to activate the ubiquitination of target proteins, the method comprising covalently linking a target protein binding element capable of specifically binding the target protein via a ubiquitination recognition element. Proteinex describes the invention as being applicable to the control of protein levels in eukaryotes. While the '663 patent may be based on a first patent application describing a high-level concept of how to manipulate the UPP system to degrade selected proteins in vivo, the patent does not provide sufficient detail to allow a person skilled in the art to readily construct the range of proposed compounds. For example, for 25 ubiquitination recognition elements, a person skilled in the art would be advised to use standard methods for drug discovery and screening for suitable small molecules that can bind to the ligase. Proteinex also emphasizes the use of peptides as ubiquitination recognition elements, which could pose significant challenges for oral drug delivery.

[0011] The patent applications filed by C4 Therapeutics, Inc. describe compounds capable of binding to E3 ubiquitin ligases and degrading target proteins, including: WO / 2021 / 127561, entitled "Isoindolinone and Indazole Compounds For The Degradation Of EGFR"; WO / 2021 / 086785, entitled "Bifunctional Compounds"; WO / 2021 / 083949, entitled "Bifunctional Compounds for the Treatment of Cancer"; WO / 2020 / 210630, entitled "Tricyclic Degraders of Ikaros and Aiolos"; WO / 2020 / 181232, entitled "Heterocyclic Compounds for Medical Treatment"; and WO / 2020 / 132561, entitled "Targeted Protein". 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"; WO2017 / 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."

[0012] Other patent applications describing 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; WO2017 / 011371; WO 2017 / 011590; WO 2017 / 030814; WO 2017 / 046036; WO 2017 / 176708; WO2017 / 176957; WO 2017 / 180417; WO 2018 / 053354; WO 2018 / 071606; WO 2018 / 102067; WO2018 / 102725; WO 2018 / 118598; WO 2018 / 119357; WO 2018 / 119441; WO 2018 / 119448; WO2018 / 140809; WO2018 / 144649; WO 2018 / 119448; WO 2018 / 226542; WO 2019 / 023553; WO / 2019 / 195201; WO2019 / 199816; WO / 2019 / 099926; WO 2019 / 195609; WO 2020 / 041331; WO2020 / 051564; and WO2020 / 023851.

[0013] Rearrangement (RET) of proto-oncogene tyrosine protein kinase receptors during transfection is well-known for its important role in cell survival, differentiation, proliferation, migration, and chemotaxis. RET germline missense and somatic mutations lead to medullary thyroid carcinoma (MTC) and neuroendocrine tumors, while RET fusion proteins, overexpression, and copy number increases are present in a wide range of other cancers, such as papillary thyroid carcinoma, pancreatic cancer, melanoma, leukemia, lung adenocarcinoma, and breast cancer. (Liu Xuan et al., “RET kinase alterations in targeted cancertherapy”, Cancer Drug Resist, 2020; and Mulligan LM., “RET revisited: expanding the oncogenic portfolio”, Nat Rev Cancer., 2014, 14(3), 173-186).

[0014] RET forms a complex with its natural ligand (glial-derived neurotrophic factor family) and a coreceptor bound to glycosylphosphatidylinositol. This complex leads to dimerization of the kinase domain and subsequent activation by forming 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 induces autophosphorylation of tyrosine residues. As a result of this mechanism, glial family ligand-mediated activation of wild-type RET is an increasingly recognized mechanism associated with tumor growth and the broader spread of cancer cells. (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).

[0015] RET has several protein isoforms, including RET9, RET51, and RET43, each with different C-terminal tail lengths and varying abilities to bind SHC, GRB2, c-CBL, and SHANK3. Each RET isoform has a unique C-terminal tail sequence that can recruit different protein complexes to mediate signaling, thus exhibiting varying abilities to recruit E3 ubiquitin ligases to their unique C-termini (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 in acute myeloid leukemia (AML) have shown that AML isoforms depend on RET receptor tyrosine kinase (RTK) expression, and that shRNA knockout or CRISPR / Cas9-mediated knockdown leads to RET depletion, resulting in cell cycle arrest in the G0 / G1 phase, increased apoptosis, and decreased 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 showed that RET signaling is mainly mediated 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). RET fusion genes are mutually exclusive with other known drivers in LAD (e.g., KRAS, epidermal growth factor receptor (EGFR), EML4-anaplastic lymphoma kinase (ALK)), further supporting the role of RET as a unique driver of these malignant tumors.

[0016] Selpercatinib (formerly known as LOXO-292) is a clinically approved, highly selective small molecule RET tyrosine kinase inhibitor with nanomolar levels of efficacy against multiple RET alterations. Patent applications and publications describing selpercatinib include: US20190106438; US20190262322; US20180133222 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 “Selective RET kinase inhibition for patients with RET-altered cancers,” Ann Oncol., 2018, 29(8), 1869-1876).

[0017] The academic and clinical interest in RETs has led to the discovery of several clinically relevant RET mutations, 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 non-small cell lung cancer patients has shown that selpercatinib induces RET mutations, leading to the inference of resistance, including RET G810R, RET G810S, and RET G810C mutations.

[0018] Other approved tyrosine kinase inhibitors, such as sunitinib, sorafenib, ponatinib, and lenvatinib, have also shown some RET activity in preclinical trials and are currently being studied in numerous phase II clinical trials for the 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).

[0019] Examples of RET inhibitor 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 2018 / 136661; WO2018 / 071447; WO / 2018 / 136663; WO 2019 / 126121; WO 2019 / 143991; WO 2019 / 143994; WO 2019 / 143977; and WO2020 / 055672.

[0020] Despite these efforts, new RET modulators are still needed to treat RET-mediated disorders in hosts (including humans) in need. Summary of the Invention

[0021] Compounds for degrading proto-oncogene tyrosine protein kinase receptor (RET) via the ubiquitin-proteasome pathway (UPP) are provided, along with their uses and manufacture. This invention provides compounds of formulas I, II, III, IV, V, VI, and VII, or pharmaceutically acceptable salts thereof, comprising a RET-binding targeting ligand, an E3 ligase-binding moiety (typically via a cerebellar protein subunit), and a linker covalently linking the targeting ligand to the E3 ligase-binding moiety. In some embodiments, the targeting ligand is part B of the following formula, the linker is part L1, and the remainder of the molecule is the E3 ligase-binding moiety.

[0022] RET is well known for its important roles in cell survival, differentiation, proliferation, migration, and chemotaxis. Therefore, by degrading RET, the compounds of the present invention can be used to treat RET-mediated disorders such as congenital megacolon, medullary thyroid carcinoma (MTC), thyroid cancer, familial medullary thyroid carcinoma, multiple endocrine tumors, type 2 multiple endocrine tumors (MEN-2, MEN-2A, MEN-2B), neuroendocrine tumors, central nervous system tumors, central ventilatory insufficiency syndrome, renal dysplasia, pheochromocytoma, and parathyroid hyperplasia. In another embodiment, the compounds of the present invention are used to treat diseases mediated by RET fusion proteins, overexpression, or copy number increase, such as papillary thyroid carcinoma, pancreatic cancer, melanoma, leukemia, acute myeloid leukemia (AML), chronic myeloid monocytic leukemia, lung adenocarcinoma, lung cancer, non-small cell lung cancer (NSCLC), non-syndromic paraganglioma, breast cancer, non-hereditary (sporadic) cancer, colorectal cancer, or hematologic malignancies.

[0023] The compounds of the present invention provided herein, or pharmaceutically acceptable salts thereof, and / or pharmaceutically acceptable compositions thereof, may be used to treat RET-mediated disorders. In some embodiments, a method of treating a patient suffering from a RET-mediated disorder is provided, the method comprising administering an effective amount of one or more compounds as described herein, or pharmaceutically acceptable salts thereof, to the patient, typically a person, optionally in a pharmaceutically acceptable composition.

[0024] In some aspects, the present invention provides compounds of formula I, II, III or IV:

[0025]

[0026]

[0027] Or its pharmaceutically acceptable salt;

[0028] in

[0029] X 3 X 4 X 5 and X 6 Choose from the following groups: N, CH, and CR 3 , where X 3 X 4 X 5 X 6 No more than 3 of them are N;

[0030] X 7 Is it N or CR? 1c ;

[0031] Q 1 Yes -NR 6 -, -CH2-, or -O-, where if X 7 If it's N, then Q 1 It is CH2;

[0032] R 1a R 1b R 1c R 1d Each is independently hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, or cycloalkyl; or

[0033] R 1a and R 1c They combine to form 1 or 2 atomic bridges, for example include

[0034] R 3Each time it appears, it is independently selected from the group consisting of: hydrogen, hydroxyl, alkoxy, C1-C4 alkyl, C1-C4 haloalkyl, cycloalkyl, fluorine, chlorine, bromine, and iodine;

[0035] RET targeting ligands are selected from

[0036]

[0037]

[0038] It is a heteroaryl, heterocyclic, aryl, or cycloalkyl group, each optionally selected independently by 0, 1, 2, 3, or 4 R groups. 9 Substituents, wherein Directly bonded to the connector and

[0039] or It is a heteroaryl, heterocyclic, aryl, or cycloalkyl group, each optionally selected independently by 0, 1, 2, 3, or 4 R groups. 9 Substituents, wherein yes

[0040] Directly bonded to the connector and

[0041] X 8 Is it N or CR? 4 ;

[0042] X 9 It is NR 4 CR 4 R 11 、 or O;

[0043] X 10 X 11 X 12 and X 13 Choose from the following groups: N, CH, and CR, where X 10 X 11 X 12 X 13 No more than 3 of them are N;

[0044] X 14 It is CR 27 Or N;

[0045] Each R 4 Independently, it is hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, cycloalkyl, heteroaryl, aryl, heterocyclic, -alkyl-heteroaryl, -alkyl-aryl, -alkyl-heterocyclic, -C(O)R 5 ,-alkyl-C(O)R5 -OC(O)R 5 , or -NR 6 C(O)R 5 Each C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, cycloalkyl, heteroaryl, aryl, heterocyclic, -alkyl-heteroaryl, -alkyl-aryl, and -alkyl-heterocyclic group is optionally represented by 0, 1, 2, or 3 independently selected from R 8 Substituents of the substituents;

[0046] R 5 It is hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, cycloalkyl, heteroaryl, aryl, heterocyclic, bicyclic, -alkyl-heteroaryl, -alkyl-aryl, -alkyl-heterocyclic, -OR 6 or -NR 6 R 7 Each C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, cycloalkyl, heteroaryl, aryl, heterocyclic, -alkyl-heteroaryl, -alkyl-aryl, and -alkyl-heterocyclic group is optionally represented by 0, 1, 2, or 3 independently selected from R 9 Substituents of the substituents;

[0047] R 6 and R 7 In each case, the following groups are independently selected: hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, cycloalkyl, heteroaryl, aryl, heterocyclic, -alkyl-heteroaryl, -alkyl-aryl, and -alkyl-heterocyclic, wherein each R 6 and R 7 The group other than hydrogen is optionally composed of 0, 1, 2 or 3 independently selected from R. 10 Substituents of the substituents;

[0048] R 8 Each occurrence is independently selected from the following groups: hydrogen, C1-C4 haloalkyl, C1-C4 alkyl, halogen, -OR 6 -NR 6 R 7 -OC(O)R 5 -NR 6 C(O)R 5 -C(O)R 5 and -alkyl-C(O)R 5 ;

[0049] R 9Each occurrence is independently selected from the group consisting of: hydrogen, aryl, heteroaryl, heterocyclic, cycloalkyl, C1-C4 haloalkyl, C1-C4 alkyl, halogen, -OR 6 -NR 6 R 7 -C(O)OR 6 -C(O)NR 6 R 7 ,-alkyl-C(O)OR 6 and -alkyl-C(O)NR 6 R 7 Each aryl, heteroaryl, heterocyclic, and cycloalkyl group is optionally surrounded by 0, 1, 2, or 3 groups selected from C1-C4 haloalkyl, C1-C4 alkyl, halogen, -OR 6 -NR 6 R 7 -C(O)OR 6 -C(O)NR 6 R 7 ,-alkyl-C(O)OR 6 and -alkyl-C(O)NR 6 R 7 Substituents of the substituents;

[0050] Or R 9 Each occurrence is independently selected from the group consisting of: hydrogen, aryl, -alkyl-aryl, heteroaryl, alkyl-heteroaryl, heterocyclic, alkyl-heterocyclic, cycloalkyl, -alkyl-cycloalkyl, C1-C4 haloalkyl, C1-C4 alkyl, halogen, -OR 6 -NR 6 R 7、 -C(O)OR 6 -C(O)NR 6 R 7 ,-alkyl-C(O)OR 6 and -alkyl-C(O)NR 6 R 7 Each aryl, -alkyl-aryl, heteroaryl, -alkyl-heteroaryl, heterocyclic, -alkyl-heterocyclic, -alkyl-cycloalkyl, and cycloalkyl group is optionally surrounded by 0, 1, 2, or 3 groups selected from -S(O)2alkyl, C1-C4 haloalkyl, C1-C4 alkyl, halogen, -OR 6 -NR 6 R 7 -C(O)OR 6 -C(O)NR 6 R 7 ,-alkyl-C(O)OR 6 and -alkyl-C(O)NR 6 R 7 Substituents of the substituents;

[0051] R 10 Each time it appears, it is independently selected from the group consisting of: C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, cycloalkyl, heteroaryl, aryl, heterocyclic, -alkyl-heteroaryl, -alkyl-aryl and -alkyl-heterocyclic;

[0052] Or R 10 Each time it appears, it is independently selected from the group consisting of: C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, cycloalkyl, heteroaryl, aryl, heterocyclic, -alkyl-heteroaryl, -alkyl-aryl, halogen and -alkyl-heterocyclic;

[0053] R 11 It is hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, cycloalkyl, heteroaryl, aryl, heterocycle, -alkyl-heteroaryl, -alkyl-aryl, -alkyl-heterocycle, -alkyl-OR 6 -OC(O)R 6 -OR 6 ,-alkyl-NR 6 R 7 -NR 6 C(O)R 7 or -NR 6 R 7 ;

[0054] R, R 27 R 28 and R 29 Each time it appears, it is independently selected from the following groups: hydrogen, C1-C4 haloalkyl, C1-C4 alkyl, halogen, cyano, nitro, -OR 6 -NR 6 R 7 -C(O)OR 6 and -C(O)NR 6 R 7 ;

[0055] R 12 R 13 R 14 R 15 R 16 R 17 R 18 and R 19 Each occurrence is independently selected from the group consisting of: hydrogen, C1-C4 haloalkyl, C1-C4 alkyl, and halogen; or

[0056] R 12 and R 13Combined to form carbonyl or 3-6 membered spirocyclic rings, for example include or

[0057] R 14 and R 15 Combining to form carbonyl or 3-6 membered spirocyclic rings; or

[0058] R 16 and R 17 Combining to form carbonyl or 3-6 membered spirocyclic rings; or

[0059] R 18 and R 19 Combining to form carbonyl or 3-6 membered spirocyclic rings; or

[0060] R 12 and R 14 Combining to form 3-6 fused rings, for example include or

[0061] R 12 and R 4 Combining to form 3-6 fused rings; or

[0062] R 16 and R 18 Combining to form 3-6 fused rings; or

[0063] R 12 and R 17 Combining to form 1 or 2 atomic bridges, for example include or

[0064] R 12 and R 19 Combined to form 1 or 2 atomic bridges; or

[0065] R 14 and R 17 Combined to form 1 or 2 atomic bridges; or

[0066] R 14 and R 19 Combining to form 1 or 2 atomic bridges; and

[0067] The connector is a divalent linker, such as the divalent linker of formula LI.

[0068] In some implementations, the connector has the following formula:

[0069]

[0070] in,

[0071] X 1 and X2 Each occurrence is independently selected from bonds, heterocycles, and NR. 2 C(R) 2 2. O, C(O) and S;

[0072] R 2 Each time it appears, it is independently selected from the group consisting of: hydrogen, alkyl, aliphatic, heteroaliphatic, heterocyclic, 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), alkenes and alkynes;

[0073] R 20 R 21 R 22 R 23 and R 24 Each time it appears, it is independently selected from the following groups: bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR 2 -、-NR 2 C(O)-, -O-, -S-, -NR 2 -、-C(R 40 R 40 )-、-P(O)(OR 26 )O-、-P(O)(OR 26 )-, bicyclic, olefinic, alkyne, haloalkyl, alkoxy, aryl, heterocyclic, aliphatic, heteroaliphatic, heteroaryl, lactic acid, glycolic acid, and carbocyclic; wherein each is optionally selected independently by 1, 2, 3, or 4 from R 40 Substituents of the substituents;

[0074] R 26 Each time it appears, it is independently selected from the group consisting of: hydrogen, alkyl, arylalkyl, heteroarylalkyl, olefin, alkyne, aryl, heteroaryl, heterocyclic, aliphatic, and heteroaliphatic; and

[0075] R 40Each time it appears, it is independently selected from the group consisting of: hydrogen, alkyl, olefin, alkyne, fluorine, bromine, chlorine, 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 heterocyclic), -N (alkyl)SO2 (aryl, heteroaryl or heterocyclic), -NHSO2 alkenyl, -N (alkyl)SO2 alkenyl, -NHSO2 ynyl, -N (alkyl)SO2 ynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocyclic and cycloalkyl.

[0076] In other respects, the present invention provides compounds of formula V, VI or VII:

[0077]

[0078] in

[0079] Cerebellar protein-binding ligands were selected from:

[0080]

[0081]

[0082] R 50 Selected from R 5 and R 51

[0083] R 51 Selected from

[0084]

[0085] And all other variables as defined in this document.

[0086] The variables, substituents, embodiments, and each combination of compounds resulting from these combinations are considered specific and individually disclosed, because such descriptions are for spatial convenience only and are not intended to describe only the class or even subclass of compounds.

[0087] In some embodiments, the compounds of the present invention can penetrate the blood-brain barrier and can be used to treat cancers that have metastasized to the brain or involve the CNS.

[0088] In some embodiments, a treatment method is provided, comprising administering to a patient in need, such as a human, an effective amount of a compound of formula I, II, III, IV, V, VI, or VII, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. For example, in one embodiment, a compound of formula I, II, III, IV, V, VI, or VII is administered to a human to treat cancer.

[0089] In some embodiments, the compounds of the present invention are used to treat sporadic medullary thyroid carcinoma. In some embodiments, the compounds of the present invention are used to treat non-sporadic medullary thyroid carcinoma. In some embodiments, the compounds of the present invention are used to treat lung cancer, such as non-small cell lung cancer.

[0090] In some embodiments, the compounds of the present invention provide one or more, and may even provide, a number of advantages over conventional therapies using RET ligands. For example, the RET-degrading compounds of the present invention can a) overcome resistance in certain cases; b) prolong the kinetics of drug action by disrupting proteins, thus requiring protein resynthesis even after the compound is metabolized; c) target all functions of the protein simultaneously rather than specific catalytic activities or binding events; and / or d) have higher potency than inhibitors because small molecules may act as catalysts.

[0091] In some embodiments, the compounds of the present invention are used to treat tumors or cancers with mutated RET proteins. In some embodiments, the compounds of the present invention are used to treat tumors or cancers with solvent front mutations in the RET protein (e.g., G810R, G810S, or G810C). In some embodiments, the compounds of the present invention are used to treat tumors or cancers with RET G810R mutations. In some embodiments, the compounds of the present invention are used to treat tumors or cancers with RET G810S mutations. In some embodiments, the compounds of the present invention are used to treat tumors or cancers with RET G810C mutations.

[0092] In some embodiments, the compounds of the present invention are used to treat tumors or cancers in the CNS having a mutated RET protein. In some embodiments, the compounds of the present invention are used to treat tumors or cancers in the CNS having a solvent front mutation in the RET protein (e.g., G810R, G810S, or G810C). In some embodiments, the compounds of the present invention are used to treat tumors or cancers in the CNS having a RET G810R mutation. In some embodiments, the compounds of the present invention are used to treat tumors or cancers in the CNS having a RET G810S mutation. In some embodiments, the compounds of the present invention are used to treat tumors or cancers in the CNS having a RET G810C mutation. In some embodiments, the tumor or cancer in the CNS has metastasized from a primary cancer in another part of the body. In other embodiments, the tumor or cancer in the CNS is a primary cancer, such as glioblastoma or head and neck cancer.

[0093] In some embodiments, the compounds of the present invention are used to treat tumors or cancers with RET protein gate mutations such as V804L or V804M.

[0094] In some embodiments, the compounds of the present invention are used to treat tumors or cancers having RET protein activating mutations. One such RET activating mutation is M918T.

[0095] In some embodiments, the compounds of the present invention are used to treat drug-resistant RET-altered tumors or cancers. In some embodiments, the tumor is resistant to a drug selected from selpercatinib, pralsetinib, TPX-0046, and / or selmetinib.

[0096] In some embodiments, the compounds of the present invention are used to treat tumors or cancers having a RET protein fused with another protein (e.g., KIF5B-RET fusion, CCDC6-RET fusion, or NCOOA4-RET fusion). In some embodiments, the compounds of the present invention are used to treat tumors or cancers having a KIF5B-RET fusion. In some embodiments, the compounds of the present invention are used to treat tumors or cancers having a CCDC6-RET fusion or an NCOOA4-RET fusion. In some embodiments, the compounds of the present invention are used to treat tumors or cancers having a CCDC6-RET fusion. In some embodiments, the compounds of the present invention are used to treat tumors or cancers having an NCOOA4-RET fusion.

[0097] In some embodiments, the compounds of the present invention are used to treat tumors resistant to RET inhibitors such as selpercatinib, pralsetinib, and / or TPX-0046. In some embodiments, the compounds of the present invention are used to treat tumors or cancers with acquired resistance to RET inhibitors such as selpercatinib, pralsetinib, and / or TPX-0046.

[0098] In some embodiments, the compounds of the present invention provide improved efficacy and / or safety compared to known RET inhibitors.

[0099] In some embodiments, the compounds of the present invention have one or more advantages in treating RET-mediated disorders compared to using the targeting ligand portion alone.

[0100] In some implementations, fewer of the compounds described herein are required to treat RET-mediated barriers compared to a molar dose of the target ligand portion alone.

[0101] In some embodiments, the compounds of the present invention have at least one less side effect in treating RET-mediated disorders than a molar dose of the target ligand moiety alone.

[0102] In some implementations, a lower frequency dosing regimen of the selected compounds described herein is required to treat RET-mediated disorders compared to the molar dose of the target ligand portion alone.

[0103] Another aspect of the invention provides the compounds described herein, or their enantiomers, diastereomers, or stereoisomers, or pharmaceutically acceptable salts, hydrates, or solvates, or pharmaceutical compositions thereof, for the preparation of medicaments for inhibiting or preventing RET-mediated disorders or for regulating or reducing RET levels.

[0104] Another aspect of the invention provides the compounds described herein, or their enantiomers, diastereomers, or stereoisomers, or pharmaceutically acceptable salts, hydrates, or solvates, or pharmaceutical compositions thereof, for the preparation of a medicament for the treatment or prevention of RET-mediated disorders.

[0105] In some embodiments, the selected compounds described herein can be used to treat disorders including abnormal cell proliferation, such as tumors or cancer, wherein RET is an oncogenic protein or a signaling mediator of abnormal cell proliferation pathways, the degradation of which can reduce abnormal cell growth.

[0106] In some embodiments, the selected compound of formula I, II, III, IV, V, VI or VII, or its pharmaceutically acceptable salt, has at least one desired atomic isotope substitution in an amount higher than the natural abundance of that isotope, i.e., it is enriched.

[0107] In one embodiment, a compound of formula I, II, III, IV, V, VI or VII, or a pharmaceutically acceptable salt thereof, comprises one or more deuterium atoms.

[0108] Other features and advantages of this application will become clear from the following detailed description.

[0109] Therefore, the present invention includes at least the following features:

[0110] (a) Compounds of Formula I, II, III, IV, V, VI or VII as described herein, or their pharmaceutically acceptable salts or isotopic derivatives (including deuterated derivatives).

[0111] (b) A method of treating RET-mediated disorders (e.g., abnormal cell proliferation, including cancer) comprising administering an effective amount of a compound of formula I, II, III, IV, V, VI or VII as described herein, or a pharmaceutically acceptable salt thereof, to a patient in need.

[0112] (c) A compound of formula I, II, III, IV, V, VI or VII or a pharmaceutically acceptable salt or isotope derivative thereof (including deuterated derivatives) for the treatment of RET-mediated disorders, such as abnormal cell proliferation, like tumors or cancer.

[0113] (d) The use of compounds of formula I, II, III, IV, V, VI or VII or pharmaceutically acceptable salts thereof in effective amounts in human patients in need of treatment of RET-mediated disorders (e.g., abnormal cell proliferation, such as tumors or cancers).

[0114] (e) Use of compounds of formula I, II, III, IV, V, VI or VII or pharmaceutically acceptable salts or isotopic derivatives thereof (including deuterated derivatives) in the preparation of medicaments for treating RET-mediated disorders (e.g., abnormal cell proliferation, such as tumors or cancer).

[0115] (f) A pharmaceutical composition comprising a patient-effective therapeutic amount of a compound of formula I, II, III, IV, V, VI or VII or a pharmaceutically acceptable salt or isotopic derivative thereof; and optionally a pharmaceutically acceptable carrier or diluent;

[0116] (g) Compounds of formula I, II, III, IV, V, VI or VII as described herein, in the form of enantiomers or mixtures of diastereomers (as related), including racemates;

[0117] (h) Compounds of formula I, II, III, IV, V, VI, or VII as described herein, in enantiomeric or diastereomeric (related) enriched forms, including isolated enantiomers or diastereomers (i.e., with a purity greater than about 85, 90, 95, 97, or 99%); and

[0118] (i) A method for preparing a therapeutic product containing an effective amount of a compound of formula I, II, III, IV, V, VI or VII as described herein, or a pharmaceutically acceptable salt thereof. Attached Figure Description

[0119] Figure 1 Dose-response curves describing the effect of compound 87 (diamond) on the survival of the lung cancer cell line LC-2 / ad carrying the endogenous CCDC6-RET fusion and the thyroid cancer cell line TT carrying the endogenous C634W mutation are provided. Parallel tests were conducted on the RET-selective inhibitors pralsetinib (triangle), selpercatinib (square), and compound 5 (WO2019 / 126121) labeled “RET inhibitor” (circle). The x-axis represents the compound concentration in nM, and the y-axis represents the percentage of cell survival after 120 hours. Experimental procedures are provided in Example 224.

[0120] Figure 2A , 2B Tables 2C, 2D, and 2E provide dose-response curves describing the effect of compound 87 (diamond) on the survival of Ba / F3 cell lines engineered to express various RET alterations. Parallel tests were conducted on the RET-selective inhibitors pralsetinib (triangle), selpercatinib (square), and compound 5 (WO2019 / 126121) labeled “RET inhibitor” (circle). The x-axis represents the compound concentration in nM, and the y-axis represents the percentage of cell survival after 72 hours. Experimental procedures are provided in Example 224.

[0121] Figure 3This is a line graph showing the in vivo efficacy of compound 122 in treating female athymic naked-Foxn1nu (immune-impaired) mice carrying CTG-0838NSCLC PDX tumors. Mice were administered either the vector control or compound 122 once daily via intravenous infusion at 5 mg / kg / day or orally at 30 mg / kg / day for 21 days. The x-axis is time measured in days, and the y-axis is in mm. 3 The volume of the CTG-0838 tumor was measured. The experimental procedure is provided in Example 225.

[0122] Figure 4 This is a line graph showing the changes in body weight induced by compound 122 in female athymic naked-Foxn1nu (immune-impaired) mice carrying CTG-0838NSCLC PDX tumors. Mice were administered either the vector control or compound 122 once daily via intravenous infusion at 5 mg / kg / day or orally at 30 mg / kg / day for 21 days. The x-axis represents time measured in days, and the y-axis represents the percentage change in body weight. The experimental procedure is provided in Example 225.

[0123] Figure 5 This is a line graph showing the in vivo efficacy of compound 122 in treating female BALB / c nude mice carrying CR2518 CRC PDX tumors. Mice were administered either the vector control or compound 122 intravenously once daily for 14 days at a dose of 5 mg / kg / day. The x-axis is time measured in days, and the y-axis is in mm. 3 The volume of the CR2518 tumor was measured. The experimental procedure is provided in Example 226.

[0124] Figure 6 This is a line graph showing the changes in body weight induced by compound 122 in female BALB / c nude mice carrying CR2518 CRC PDX tumors. Mice were administered either the vector control or compound 122 intravenously once daily for 14 days at a dose of 5 mg / kg / day. The x-axis represents time measured in days, and the y-axis represents the percentage change in body weight. The experimental procedure is provided in Example 226.

[0125] Figure 7 This is a bar graph showing the concentrations of compound 122 in plasma and brain tumors after a single intravenous (IV) dose of 30 mg / kg. The experimental procedure is provided in Example 227.

[0126] Figure 8 This is a bar graph showing the levels of RET and phosphate-SHC proteins in brain tumors five hours after a single intravenous (IV) administration of compound 122 at 5 mg / kg or 30 mg / kg. The experimental procedure is provided in Example 227.

[0127] Figure 9Representative chemical formulas of the present invention are described, wherein the variables are defined herein. Detailed Implementation

[0128] I. Definition

[0129] Compounds are described using standard nomenclature. 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 subject belongs.

[0130] The compounds in any of the formulas described herein can be racemic, enantiomers, mixtures of enantiomers, diastereomers, mixtures of diastereomers, tautomers, N-oxides, isomers; for example, rotational isomers, as each is specifically described unless the context explicitly excludes them.

[0131] The terms “an” and “a” do not indicate a limitation of quantity, but rather the presence of at least one referenced item. The term “or” means “and / or”. Unless otherwise indicated, statements herein relating to ranges of values ​​are intended only as a shorthand way of individually referring to each independent value within that range, and each independent value is incorporated into the specification as if it were individually stated herein. The endpoints of all ranges are included within the range and can be combined independently. All methods described herein can be performed in a suitable order unless otherwise indicated herein or otherwise obviously contradicted by the context. The use of examples or exemplary language (e.g., “for example”) is intended only to better illustrate the invention and not to limit the scope of the otherwise claimed invention.

[0132] This invention includes compounds of formula I, II, III, IV, V, VI, or VII, or pharmaceutically acceptable salts thereof, having at least one desired atomic isotopic substitution in an amount higher than the natural abundance of that isotope, i.e., enriched. An isotope is an atom with the same atomic number but different mass numbers, i.e., the same number of protons but different numbers of neutrons.

[0133] Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, respectively, for example... 2 H, 3 H, 11 C 13 C 14 C 15 N、 17 O、 18 O、 18 F 31 P, 32 P, 35 S, 36 Cl and 125I. In a non-limiting example, isotope-labeled compounds can be used for metabolic studies (e.g., using...) 14 C) Reaction kinetic studies (e.g., using...) 2 H or 3 H), detection or imaging techniques (e.g., positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays), or for use in the patient's radiation therapy. Specifically, 18 F-labeled compounds may be particularly desirable for PET or SPECT studies. The isotope-labeled compounds and their prodrugs of the present invention can generally be prepared by performing the procedures disclosed in the following schemes or examples, and the formulations described below, by replacing non-isotope-labeled reagents with readily available isotope-labeled reagents.

[0134] Isotope substitution, such as deuterium substitution, can be partial or complete. Partial deuterium substitution means that at least one hydrogen atom is substituted with deuterium. In some embodiments, the isotope is enriched at any desired location by 90%, 95%, or 99% or more. In a non-limiting embodiment, deuterium is enriched at the desired location by 90%, 95%, or 99%.

[0135] In one non-limiting embodiment, the substitution of a hydrogen atom for a deuterium atom may be provided in any compound of formula I, II, III, IV, V, VI, or VII, or a compound of a pharmaceutically acceptable salt thereof. In one non-limiting embodiment, the substitution of the hydrogen atom for the deuterium atom occurs within one or more groups selected from any R or variable, linker, and targeting ligand described herein. For example, when any group is substituted with or contains, for example, methyl, ethyl, or methoxy, the alkyl residue may be deuterated (in non-limiting examples, CDH2, CD2H, CD3, CH2CD3, CD2CD3, CHDCH2D, CH2CD3, CHDCHD2, OCDH2, OCD2H, or OCD3, etc.). In some other embodiments, the unsubstituted carbon may be deuterated when the two substituents combine to form a ring.

[0136] The compounds of the present invention can form solvates with solvents, including water. Therefore, in a non-limiting embodiment, the present invention includes the solvated form of the compounds. The term "solvate" refers to a molecular complex of a compound of the present invention (including its salts) 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 present invention and water. Pharmaceutically acceptable solvents according to the present invention include those in which the solvent can be isotopically substituted, such as D2O, d6-acetone, and d6-DMSO (dimethyl sulfoxide). Solvates can be in liquid or solid form.

[0137] A dash ("-") not between two letters or symbols is used to indicate the attachment point of a substituent. For example, -(C=O)NH2 is attached to the carbon of a carbonyl (C=O) group.

[0138] "Alkyl" is a branched or straight-chain saturated aliphatic hydrocarbon group. In one non-limiting embodiment, the alkyl group contains 1 to about 12 carbon atoms, more typically 1 to about 6 carbon atoms or 1 to about 4 carbon atoms. In one non-limiting embodiment, the alkyl group contains 1 to about 8 carbon atoms. In some embodiments, the alkyl group is C1-C2, C1-C3, C1-C4, C1-C5, or C1-C 6。 As used herein, the specified range refers to alkyl groups having each member of the range described as an independent species. For example, the term C1-C6 alkyl as used herein refers to straight-chain or branched alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms, and it is meant that each of these is described as an independent species, and thus each subset is considered to be disclosed separately. For example, the term C1-C4 alkyl as used herein refers to straight-chain or branched alkyl groups having 1, 2, 3, or 4 carbon atoms, and it is meant that each of these is described as an independent species. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, and 2,3-dimethylbutane. In alternative embodiments, the "alkyl" group is optionally substituted. The term "alkyl" also includes cycloalkyl or carbocyclic groups. For example, when a term including "alkane" is used, then "cycloalkyl" or "carbocyclic" can be considered part of the definition unless the context explicitly excludes it. For example, but not limited to, the terms alkyl, alkoxy, haloalkyl, etc., can all be considered to include cyclic forms of alkyl groups unless the context explicitly excludes them.

[0139] In one embodiment, "alkyl" is C1-C 10 Alkyl, C1-C9 alkyl, C1-C8 alkyl, C1-C7 alkyl

[0140] C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, or C1-C2 alkyl.

[0141] In one implementation, "alkyl" has one carbon atom.

[0142] In one implementation, "alkyl" has two carbon atoms.

[0143] In one implementation, "alkyl" has three carbon atoms.

[0144] In one implementation, "alkyl" has four carbon atoms.

[0145] In one implementation, "alkyl" has five carbon atoms.

[0146] In one implementation, "alkyl" has six carbon atoms.

[0147] Non-limiting examples of "alkyl" include: methyl, ethyl, propyl, butyl, pentyl, and hexyl.

[0148] Other non-limiting examples of "alkyl" include isopropyl, isobutyl, isopentyl, and isohexyl.

[0149] Other non-limiting examples of "alkyl" include sec-butyl, sec-pentyl, and sec-hexyl.

[0150] Other non-limiting examples of "alkyl" include tert-butyl, tert-pentyl, and tert-hexyl.

[0151] Other non-limiting examples of "alkyl" include neopentyl, 3-pentyl, and reactive pentyl.

[0152] In alternative embodiments, the "alkyl" is "optionally" replaced by 1, 2, 3 or 4 substituents.

[0153] In one embodiment, "cycloalkyl" is a C3-C8 cycloalkyl, C3-C7 cycloalkyl, C3-C6 cycloalkyl, C3-C5 cycloalkyl, C3-C4 cycloalkyl, C4-C8 cycloalkyl, C5-C8 cycloalkyl, or C6-C8 cycloalkyl.

[0154] In one implementation, "cycloalkyl" has three carbon atoms.

[0155] In one implementation, "cycloalkyl" has four carbon atoms.

[0156] In one implementation, "cycloalkyl" has five carbons.

[0157] In one implementation, "cycloalkyl" has six carbons.

[0158] In one implementation, "cycloalkyl" has seven carbons.

[0159] In one implementation, "cycloalkyl" has eight carbons.

[0160] In one implementation, "cycloalkyl" has nine carbons.

[0161] In one implementation, "cycloalkyl" has ten carbon atoms.

[0162] Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl.

[0163] Other non-limiting examples of "cycloalkyl" include dihydroindene and tetrahydronaphthalene, wherein the connection point of each group is on the cycloalkyl ring.

[0164] For example: It is a "cycloalkyl" group.

[0165] However, It is an "aryl" group.

[0166] In alternative embodiments, "cycloalkyl" is "optionally substituted" and has 1, 2, 3 or 4 substituents.

[0167] "Alkenyl" is a straight-chain or branched aliphatic hydrocarbon group having one or more carbon-carbon double bonds that may appear at stable points along the chain. The specified range used herein refers to alkenyl groups having each member of the range described as a separate class, as described above with respect to the alkyl portion. Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, allyl, propenyl, butenyl, and 4-methylbutenyl. The term "alkenyl" also includes "cis" and "trans" alkenyl geometries, or alternatively, "E" and "Z" alkenyl geometries. In alternative embodiments, the alkenyl group is optionally substituted. The term "alkenyl" also includes cycloalkyl or cycloalkyl groups having at least one unsaturation point. In alternative embodiments, the "alkenyl" group is "optionally" substituted with 1, 2, 3, or 4 substituents.

[0168] "Alynyl" is a branched or straight-chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds that can appear at any stable point on the chain. The specified range used herein refers to an alkynyl group having each member of the range described as a separate class, as described above with respect to the alkyl portion. Examples of alkynyl groups 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 alternative embodiments, the alkynyl group is optionally substituted. The term "alkynyl" also includes cycloalkyl or cycloalkyl having at least one triple bond. In alternative embodiments, the "alkynyl" group is "optionally" substituted with 1, 2, 3, or 4 substituents.

[0169] "alkylene" is a divalent saturated hydrocarbon. For example, an alkylene can have 1, 2, 3, 4, 5, 6, 7 to 8 carbon motifs, 1 to 6 carbon motifs, or a specified number of carbon atoms, such as C1-C2 alkylene, C1-C3 alkylene, C1-C4 alkylene, C1-C5 alkylene, or C1-C6 alkylene.

[0170] "Alkenyl" is a divalent hydrocarbon having at least one carbon-carbon double bond. Alkenyl can be, for example, a hydrocarbon with 2 to 8 carbon motifs, 2 to 6 carbon motifs, or a specified number of carbon atoms, such as a C2-C4 alkenyl.

[0171] "Imyynyl" is a divalent hydrocarbon having at least one carbon-carbon triple bond. Imyynyl can be, for example, a hydrocarbon with 2 to 8 carbon motifs, 2 to 6 carbon motifs, or a specified number of carbon atoms, such as a C2-C4 ynylyl.

[0172] "Halogen" and "halogen" refer independently to fluorine, chlorine, bromine, or iodine.

[0173] "Haloalkyl" is a branched or straight-chain alkyl group that is substituted with one or more of the aforementioned halogen atoms (up to the maximum permissible number of halogen atoms). 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. "Hyperhaloalkyl" refers to an alkyl group in which all hydrogen atoms are substituted with halogen atoms. Examples include, but are not limited to, trifluoromethyl and pentafluoroethyl.

[0174] In one embodiment, "haloalkyl" is a C1-C603 ... 10 Halogenated alkyl, C1-C9 halogenated alkyl, C1-C8 halogenated alkyl, C1-C7 halogenated alkyl, C1-C6 halogenated alkyl, C1-C5 halogenated alkyl, C1-C4 halogenated alkyl, C1-C3 halogenated alkyl and C1-C2 halogenated alkyl.

[0175] In one implementation, the "halogenated alkyl" has one carbon atom.

[0176] In one implementation, the "halogenated alkyl" has one carbon atom and one halogen.

[0177] In one implementation, the "halogenated alkyl" has one carbon atom and two halogens.

[0178] In one implementation, the "halogenated alkyl" has one carbon atom and three halogens.

[0179] In one implementation, the "halogenated alkyl" has two carbon atoms.

[0180] In one implementation, the "halogenated alkyl" has three carbon atoms.

[0181] In one implementation, the "halogenated alkyl" has four carbon atoms.

[0182] In one implementation, the "halogenated alkyl" has five carbons.

[0183] In one implementation, the "halogenated alkyl" has six carbons.

[0184] Non-limiting examples of “halogenated alkyl” include:

[0185] Other non-limiting examples of “haloalkyl” include:

[0186] Other non-limiting examples of “haloalkyl” include:

[0187] Other non-limiting examples of “haloalkyl” include:

[0188] The term "chain" refers to a linear chain, to which all other chains, long or short, or both, can be considered dangling. In cases where two or more chains can be equally considered as the main chain, "chain" refers to the one that results in the simplest representation of the molecule.

[0189] "Haloalkoxy" refers to a haloalkyl group as described herein, attached via an oxygen bridge (the oxygen in the alcohol group).

[0190] "Heterocyclic alkyl" is an alkyl group as described herein that has been substituted with a heterocyclic group as described herein.

[0191] "Arylalkyl" is an alkyl group as described herein that has been substituted with an aryl group as described herein.

[0192] Non-limiting examples of “arylalkyl” include:

[0193]

[0194] In one implementation, "arylalkyl" is

[0195] In one implementation, "arylalkyl" refers to a 2-carbon alkyl group substituted with an aryl group.

[0196] Non-limiting examples of “arylalkyl” include:

[0197]

[0198] In one implementation, "arylalkyl" refers to a 3-carbon alkyl group substituted with an aryl group.

[0199] "Heteroarylalkyl" is an alkyl group as described herein that has been substituted with a heteroaryl group as described herein.

[0200] As used herein, “aryl” refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons in the ring array) having 6–14 ring atoms and providing zero heteroatoms in the aromatic ring system (“C”). 6-14 Aryl group (“C6 aryl”). In some embodiments, the aryl group has 6 ring atoms (“C6 aryl”; for example, phenyl). In some embodiments, the aryl group has 10 ring carbon atoms (“C6 aryl”). 10 Aryl; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms (“C14”). 14 "Aryl"; for example, anthracene. "Aryl" also includes a ring system in which an aryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein the group or connecting point is on the aryl ring, and in this case, the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. The one or more fused carbocyclic or heterocyclic groups may be 4 to 7 or 5 to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic groups, optionally containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen, phosphorus, sulfur, silicon and boron to form, for example, 3,4-methylenedioxyphenyl. In a non-limiting embodiment, the aryl group is dangling. An example of a dangling ring is a phenyl group substituted with a phenyl group. In alternative embodiments, the aryl group is optionally substituted as described above. In some embodiments, the aryl group is an unsubstituted C 6-14 Aryl group. In some embodiments, the aryl group is a substituted C. 6-14 Aryl group. The aryl group may optionally be substituted with one or more functional groups, including but not limited to halogen, hydroxyl, nitro, amino, cyano, haloalkyl, aryl, heteroaryl and heterocyclic groups.

[0201] In one implementation, "aryl" is a 6-carbon aromatic group (phenyl).

[0202] In one implementation, "aryl" is a 10-carbon aromatic group (naphthyl).

[0203] In one embodiment, "aryl" is a 6-carbon aromatic group fused with a heterocycle, wherein the linking point is an aryl ring. Non-limiting examples of "aryl" include dihydroindole, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran, wherein the linking point of each group is on an aromatic ring.

[0204] For example, It is an "aryl" group.

[0205] However, It is a "heterocyclic" group.

[0206] In one embodiment, "aryl" is a 6-carbon aromatic group fused with a cycloalkyl group, wherein the linking point is an aryl ring. Non-limiting examples of "aryl" include dihydroindene and tetrahydronaphthalene, wherein the linking point of each group is on an aromatic ring.

[0207] For example, It is an "aryl" group.

[0208] However, It is a "cycloalkyl" group.

[0209] In alternative implementations, the aryl group is optionally replaced by one, two, three or four substituents.

[0210] The terms "heterocyclic group," "heterocycle," and "heterocyclic" include saturated and partially saturated cyclic groups containing heteroatoms, wherein the heteroatoms may be selected from nitrogen, sulfur, and oxygen. Heterocycles include monocyclic 3, 4, 5, 6, 7, 8, 9, or 10-membered rings, and 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16-membered bicyclic systems (which may include bridged fused and spirofused bicyclic systems). It does not include rings containing -OO-, -OS-, or -SS- portions. Examples of saturated heterocyclic groups include saturated 3, 4, 5, or 6-membered heterocyclic groups containing 1, 2, 3, or 4 nitrogen atoms [e.g., pyrrolyl, imidazoyl, piperidinyl, pyrrololinyl, piperazineyl]; saturated 3, 4, 5, or 6-membered heterocyclic groups containing 1 or 2 oxygen atoms and 1, 2, or 3 nitrogen atoms [e.g., morpholinyl]; and saturated 3, 4, 5, or 6-membered heterocyclic groups containing 1 or 2 sulfur atoms and 1, 2, or 3 nitrogen atoms [e.g., thiazolyl]. Examples of partially saturated heterocyclic groups include, but are not limited to, dihydrothiophene, dihydropyranyl, dihydrofuranyl, and dihydrothiazolyl. Examples of partially saturated and saturated heterocyclic groups include, but are not limited to, pyrrolyl, imidazoyl, piperidinyl, pyrrololinyl, pyrazolyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazoyl, dihydrothiopheneyl, 2,3-dihydro-benzo[1,4]dioxyl, indololinyl, isoyindololinyl, dihydrobenzothiopheneyl, dihydrobenzofuranyl, isochromyl, chromanyl, 1,2-dihydroquinolinyl, 1,2,3,4-tetrahydro-isoquinolinyl, 1,2,3,4-tetrahydro-quinolinyl, 2,3,4,4a,9,9a-hexahydro-1H-3-azafluorenyl, 5,6,7-trihydro-1,2, 4-Triazolo[3,4-a]isoquinolinyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxalkyl, 2,3-dihydro-1H-1λ'-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuranyl, isoquinolin-1(2H)-keto, benzo[d]oxazol-2(3H)-keto, 1,3-dihydro-2H-benzo[d]imidazol-2-keto, benzo[d]thiazol-2(3H)-keto, 1,2-dihydro-3H-pyrazole-3-keto, 2(1H)-pyridinone, 2-piperazinone, dihydroindolyl, and dihydrothiazolyl. In some embodiments, the "heterocyclic" group may optionally be substituted, for example, by one, two, three, four or more substituents, including but not limited to hydroxyl, Boc, halogen, haloalkyl, cyano, alkyl, aralkyl, oxo, alkoxy and amino.

[0211] The terms “heterocyclic group”, “heterocycle”, and “heterocyclo” also include portions in which the heterocyclic group is fused / condensed with an aryl or heteroaryl group: for example, unsaturated fused heterocyclic groups containing 1, 2, 3, 4, or 5 nitrogen atoms, such as dihydroindole or isodihydroindole; unsaturated condensed heterocyclic groups containing 1 or 2 oxygen atoms and 1, 2, or 3 nitrogen atoms; unsaturated condensed heterocyclic groups containing 1 or 2 sulfur atoms and 1, 2, or 3 nitrogen atoms; and saturated, partially unsaturated, and unsaturated condensed heterocyclic groups containing 1 or 2 oxygen or sulfur atoms.

[0212] In one implementation, a "heterocycle" refers to a cyclic ring having one nitrogen atom and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0213] In one implementation, a "heterocycle" refers to a cyclic ring having one nitrogen atom, one oxygen atom, and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0214] In one implementation, a "heterocycle" refers to a cyclic ring having two nitrogen atoms and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0215] In one implementation, a "heterocycle" refers to a cyclic ring having one oxygen atom and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0216] In one implementation, a "heterocycle" refers to a cyclic ring having one sulfur atom and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0217] Non-limiting examples of "heterocycles" include aziridine, ethylene oxide, thioheteropropane, azirobutane, 1,3-diazaheterobutane, oxoheterobutane, and thioheterobutane.

[0218] Other non-limiting examples of "heterocyclic" compounds include pyrrolidine, 3-pyrrolidine, 2-pyrrolidine, pyrazolidine, and imidazoline.

[0219] Other non-limiting examples of "heterocyclic rings" include tetrahydrofuran, 1,3-dioxolane, tetrahydrothiophene, 1,2-oxothiocyclopentane, and 1,3-oxothiocyclopentane.

[0220] Other non-limiting examples of "heterocyclic" compounds include piperidine, piperazine, tetrahydropyran, 1,4-dioxane, thiazide, 1,3-dithiazide, 1,4-dithiazide, morpholine, and thiomorpholine.

[0221] Other non-limiting examples of "heterocycles" include dihydroindole, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran, wherein the linking point of each group is on the heterocycle.

[0222] For example, It is a "heterocyclic" group.

[0223] However, It is an "aryl" group.

[0224] Non-limiting examples of "heterocycles" also include:

[0225]

[0226] Other non-limiting examples of "heterocycles" include:

[0227]

[0228] Other non-limiting examples of "heterocycles" include:

[0229]

[0230] Non-limiting examples of "heterocycles" also include:

[0231]

[0232] Non-limiting examples of "heterocycles" also include:

[0233]

[0234] Other non-limiting examples of "heterocycles" include:

[0235]

[0236] Other non-limiting examples of "heterocycles" include:

[0237]

[0238] In alternative implementations, the heterocyclic ring is optionally replaced by one, two, three, or four substituents.

[0239] The term “heteroaryl” refers to 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 ring array) and 1, 2, 3, 4, 5, or 6 heteroatoms independently selected from O, N, and S, wherein the cyclic nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. Examples include, but are not limited to, unsaturated 5- to 6-membered heteromonocyclic groups containing 1, 2, 3, or 4 nitrogen atoms, such as pyrroloyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl]; unsaturated 5- or 6-membered heteromonocyclic groups containing oxygen atoms, such as pyranyl, 2-furanyl, 3-furanyl, etc.; and unsaturated 5- or 6-membered heteromonocyclic groups containing sulfur atoms. Examples include 2-thienyl, 3-thienyl, etc.; unsaturated 5- or 6-membered heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl]; unsaturated 5- or 6-membered heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl]. Other examples include 8-, 9-, or 10-membered heteroaryl bicyclic groups such as indazole, indolyl, imidazo[1,5-a]pyridyl, benzimidazolyl, 4(3H)-quinazolinyl, quinolinyl, isoquinolinyl, isoindolyl, thienzothienyl, inazinyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, benzooxazolyl, benzothiazolyl, purinyl, coumarinyl, cinnamyl, and triazolylpyridyl.

[0240] In one implementation, "heteroaryl" is a five-membered aromatic group containing one, two, three, or four nitrogen atoms.

[0241] Non-limiting examples of 5-membered "heteroaryl" groups include pyrrole, furan, thiophene, pyrazole, imidazole, triazole, tetraazole, isoxazole, oxazole, oxadiazole, oxtriazole, isothiazole, thiazole, thiazolium, and thiatriazole.

[0242] Other non-limiting examples of 5-membered "heteroaryl" groups include:

[0243]

[0244] In one embodiment, "heteroaryl" is a six-membered aromatic group (i.e., pyridinyl, pyridazinyl, triazinyl, pyrimidinyl, and pyrazinyl) containing one, two, or three nitrogen atoms.

[0245] Non-limiting examples of 6-membered "heteroaryl" groups having one or two nitrogen atoms include:

[0246]

[0247] In one embodiment, "heteroaryl" is a 9-membered bicyclic aromatic group containing one or two atoms selected from nitrogen, oxygen, and sulfur.

[0248] Non-limiting examples of bicyclic "heteroaryl" groups include indole, benzofuran, isoindole, indazole, benzimidazole, azaindole, azaindazole, purine, isobenzofuran, benzothiophene, benzoisoxazole, benzoisothiazol, benzoxazole, and benzothiazol.

[0249] Other non-limiting examples of bicyclic "heteroaryl" groups include:

[0250]

[0251] Other non-limiting examples of bicyclic "heteroaryl" groups include:

[0252]

[0253] Other non-limiting examples of bicyclic "heteroaryl" groups include:

[0254]

[0255] In one embodiment, "heteroaryl" is a 10-membered bicyclic aromatic group containing one or two atoms selected from nitrogen, oxygen, and sulfur.

[0256] Non-limiting examples of bicyclic "heteroaryl" groups include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cyclophosphine, and naphthidine.

[0257] Other non-limiting examples of bicyclic "heteroaryl" groups include:

[0258]

[0259] In alternative implementations, the "heteroaryl" group is "optionally" replaced by 1, 2, 3 or 4 substituents.

[0260] The term "bicyclic" refers to a ring system in which two rings are fused together, and each ring is independently selected from carbocyclic, heterocyclic, aryl, and heteroaryl rings. Non-limiting examples of bicyclic groups include:

[0261]

[0262] When the term "bicyclic" is used in the context of divalent residues such as linkers, the linkage sites can be on different rings or on the same ring. In some embodiments, the two linkage sites are on the same ring. In some embodiments, the two linkage sites are on different rings. Non-limiting examples of bicyclic groups include:

[0263]

[0264] In alternative implementations, the "bicyclic" is "optionally" replaced by 1, 2, 3 or 4 substituents.

[0265] The term "optionally substituted" means that the groups described herein are partially substituted, including but not limited to C1-C1 groups. 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, C1-C 12 Heterocyclic alkyl, C3-C 12 Heterocyclic alkenyl, C1-C 10 Alkyl, aryl, aryloxy, heteroaryl, heteroaryloxy, amino, C1-C 10 Alkylamino, C1-C 10 Dialkylamino, arylamino, diarylamino, C1-C 10 Alkyl sulfonamide, aryl sulfonamide, C1-C 10 Alkylimino, arylimino, C1-C 10 Alkyl sulfonamide, aryl sulfonamide, hydroxyl, halogenated, thiolated, C1-C 10 Alkylthio, Arylthio, C1-C 10 Alkyl sulfonyl, aryl sulfonyl, acylamino, aminoacyl, aminothioacyl, amido, guanidinyl, urea, cyano, nitro, azide, acyl, thioacyl, acyloxy, carboxyl, and carboxylic acid esters.

[0266] In an alternative embodiment, if the formation of a stable molecule is indicated and the desired purpose of the invention is satisfied, any suitable group may be present at a “substituted” or “optionally substituted” position, and includes, but is not limited to, halogens (which may independently be F, Cl, Br, or I); cyano; hydroxyl; nitro; azide; alkanoyl (e.g., C2-C6 alkanoyl); formamide; alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy such as phenoxy; thioalkyl, including those having one or more thioether bonds; alkylsulfinyl; alkylsulfonyl, including those having one or more sulfonyl groups; aminoalkyl, including groups having more than one N atom; aryl (e.g., phenyl, biphenyl, naphthyl, etc., each ring may be substituted or unsubstituted); having, for example, 1 to 3 An arylalkyl group having 1 to 3 separate or fused rings and 6 to about 14 or 18 ring carbon atoms, wherein benzyl is an exemplary arylalkyl group; an arylalkoxy group having 1 to 3 separate or fused rings, wherein benzyloxy is an exemplary arylalkoxy group; or a saturated or partially unsaturated heterocyclic group having 1 to 3 separate or fused rings having one or more N, O or S atoms, or a heteroaryl group having 1 to 3 separate or fused rings having one or more N, O or S atoms, such as coumarinyl, quinolinyl, isoquinolinyl, quinazolinyl, pyridyl, pyrazinyl, pyrimidinyl, furanyl, pyrroleyl, thiophenyl, thiazolyl, triazinyl, oxazolyl, isoxazolyl, imidazolyl, indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl and piperazinyl. Such groups can be further substituted, for example, by hydroxyl, alkyl, alkoxy, halogen and amino groups.

[0267] In some embodiments, “optionally substituted” includes one or more substituents independently selected from the following: halogen, hydroxyl, amino, cyano, -CHO, -COOH, -CONH2, alkyl including C1-C6 alkyl, alkenyl including C2-C6 alken, alkynyl including C2-C6 alkynyl, -C1-C6 alkoxy, alkanoyl including C2-C6 alkanoyl, C1-C6 alkyl ester, (mono- and di-C1-C6 alkylamino)C0-C2 alkyl, haloalkyl including C1-C6 haloalkyl, hydroxy C1-C6 alkyl, ester, carbamate, urea, sulfonamide, -C1-C6 alkyl (heterocyclic), C1-C6 alkyl (heteroaryl), -C1-C6 alkyl (C3-C7 cycloalkyl), O-C1-C6 alkyl (C3-C7 cycloalkyl), B(OH)2, phosphate ester, phosphonate, and haloalkoxy, including C1-C6 haloalkoxy.

[0268] In some embodiments, suitable groups present at the "substituted" or "optionally substituted" positions are divalent, including but not limited to oxo (=O), =S, =CH2, etc. Suitable groups at the "substituted" or "optionally substituted" positions can be monovalent, divalent, or trivalent to form stable molecules and satisfy the intended purpose of this invention.

[0269] In one embodiment, a group described herein that can be substituted by 1, 2, 3 or 4 substituents is substituted by one substituent.

[0270] In one embodiment, the group described herein that can be substituted by 1, 2, 3 or 4 substituents is substituted by two substituents.

[0271] In one embodiment, the group described herein that can be substituted by 1, 2, 3 or 4 substituents is substituted by three substituents.

[0272] In one embodiment, the group described herein that can be substituted by 1, 2, 3 or 4 substituents is substituted by four substituents.

[0273] “Aliphatic” refers to a saturated or unsaturated straight-chain, branched, or cyclic hydrocarbon. “Aliphatic” is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties, and is therefore incorporated into each of these definitions. In one embodiment, “aliphatic” is used to refer to aliphatic groups having 1 to 20 carbon atoms. The aliphatic chain can be, for example, monounsaturated, diunsaturated, triunsaturated, or polyunsaturated, or alkynyl. Unsaturated aliphatic groups can be in cis or trans configurations. In one embodiment, the aliphatic group contains 1 to about 12 carbon atoms, more typically 1 to about 6 carbon atoms or 1 to about 4 carbon atoms. In one embodiment, the aliphatic group contains 1 to about 8 carbon atoms. In some embodiments, the aliphatic group is C1-C2, C1-C3, C1-C4, C1-C5, or C1-C6. The specified ranges as used herein represent aliphatic groups having each member of the range described as an independent class. For example, as used herein, the term C1-C6 aliphatic refers to a straight-chain or branched alkyl, alkenyl, or alkynyl group having 1, 2, 3, 4, 5, or 6 carbon atoms, and means that each of these is described as a separate class. For example, as used herein, the term C1-C4 aliphatic refers to a straight-chain or branched alkyl, alkenyl, or alkynyl group having 1, 2, 3, or 4 carbon atoms, and means that each of these is described as a separate class. In one embodiment, the aliphatic group is replaced by one or more functional groups that result in the formation of a stable moiety.

[0274] The term "heteroaliphatic" refers to an aliphatic moiety containing at least one heteroatom in the chain, such as amine, carbonyl, carboxyl, oxo, thio, phosphate ester, phosphonate, nitrogen, phosphorus, silicon, or boron atoms replacing carbon atoms. In one embodiment, the only heteroatom is nitrogen. In one embodiment, the only heteroatom is oxygen. In one embodiment, the only heteroatom is sulfur. "Heteroaliphatic" is intended herein to include, but is not limited to, heteroalkyl, heteroalkenyl, heteroynyl, heterocyclic alkyl, heterocyclic alkenyl, and heterocyclic ynynyl moieties. In one embodiment, "heteroaliphatic" is used to denote a heteroaliphatic group (cyclic, acyclic, substituted, unsubstituted, branched, or unbranched) having 1-20 carbon atoms. In one embodiment, the heteroaliphatic group is optionally substituted in a manner that results in the formation of a stable moiety. Non-limiting examples of heteroaliphatic moieties are polyethylene glycol, polyalkylene glycol, amide, polyamide, polylactide, polyglycolic acid, thioether, ether, alkyl-heterocyclic-alkyl, -O-alkyl-O-alkyl, alkyl-O-haloalkyl, etc.

[0275] "Dosage form" refers to the unit of administration of the active ingredient. Examples of dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, implants, granules, balls, creams, ointments, suppositories, inhalable dosage forms, transdermal dosage forms, sublingual tablets, topical preparations, gels, and mucosal preparations. "Dosage form" can also include implants, such as optical implants.

[0276] As used in this article, "effective amount" refers to the amount that provides therapeutic or preventative benefits.

[0277] As used in this article, “endogenous” means any material that originates from or is produced within an organism, cell, tissue, or system.

[0278] As used herein, the term “exogenous” means any material introduced from or generated outside of an organism, cell, tissue, or system.

[0279] As used herein, the term "modulation" refers to mediating a detectable increase or decrease in a patient's response level compared to the patient's response level in the absence of treatment or a compound and / or compared to the response levels of other patients who are otherwise identical but have not received treatment. This term includes disrupting and / or influencing natural signals or responses, thereby mediating a beneficial therapeutic response in the patient, preferably in a patient.

[0280] "Parenteral" administration of a pharmaceutical composition includes techniques such as subcutaneous (sc), intravenous (iv), intramuscular (im), intrasternal injection, or infusion.

[0281] As used herein, the terms “peptide,” “polypeptide,” and “protein” are used interchangeably and refer to compounds comprising 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 in a protein or peptide sequence is generally comparable to the maximum number of amino acids found in nature. A polypeptide includes any peptide or protein comprising two or more amino acids linked together by peptide bonds. As used herein, the term refers to a short chain, such as those commonly referred to in the art as peptides, oligopeptides, and oligomers, and also to a longer chain, commonly referred to in the art as proteins, of which there are many types. “Polypeptide” includes, for example, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, variants of polypeptides, modified polypeptides, derivatives, analogs, fusion proteins, etc. Polypeptides include native peptides, recombinant peptides, synthetic peptides, or combinations thereof.

[0282] “Treatment” of disease, as used in this article, means reducing the frequency or severity of at least one sign or symptom of a disease or disorder experienced by a patient (i.e., palliative care) or reducing the cause or effect of a disease or disorder (i.e., disease improvement treatment).

[0283] Throughout this disclosure, various aspects of the invention can be presented in a scope manner. It should be understood that the scope description is for convenience only and should not be construed as limiting the scope of the invention. It should be assumed that the description of the scope specifically discloses all possible sub-scopes and the individual values ​​within those scopes. For example, it should be assumed that the description of a scope such as 1 to 6 specifically discloses sub-scopes, 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., and the individual numbers within those scopes, such as 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the scope.

[0284] As used herein, a “pharmaceutical composition” is a composition comprising at least one active agent and at least one other substance such as a carrier. A “pharmaceutical combination” is a combination of at least two active agents that may be combined in a single dosage form or provided together in separate dosage forms and includes instructions for using the active agents together to treat any of the disorders described herein.

[0285] As used herein, a "pharmaceutically acceptable salt" is a derivative of the disclosed compound, wherein the parent compound is modified by preparing its inorganic and organic, non-toxic acid or base addition salt. Salts of the compounds of the present invention can be synthesized by conventional chemical methods from a parent compound containing a basic or acidic moiety. Typically, such salts can be prepared by reacting the free acidic form of these compounds with a stoichiometric amount of a suitable base (e.g., sodium hydroxide, calcium hydroxide, magnesium hydroxide, or potassium hydroxide, carbonate, bicarbonate, etc.), or by reacting the free basic form of these compounds with a stoichiometric amount of a suitable acid. Such reactions are typically carried out in water or an organic solvent or a mixture of both. Typically, where feasible, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical. Salts of the compounds of the present invention further comprise the compound and a solvate of the compound salt.

[0286] Pharmaceutically acceptable examples of salts include mineral or organic acid salts with basic residues, such as amines; and basic or organic salts with acidic residues, such as carboxylic acids. Pharmaceutically acceptable salts include, for example, conventional non-toxic salts and quaternary ammonium salts of parent compounds formed from non-toxic inorganic or organic acids. For example, conventional non-toxic acid salts include those derived from inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, phosphoric acid, nitric acid, etc.); and salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, mesylic acid, esylic acid, besylic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isothionic acid, and HOOC-(CH2). 1-4 -COOH (where n is 0-4), or different acids that produce the same counterion. A list of other suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa., page 1418 (1985).

[0287] The term "carrier" used in pharmaceutical compositions / combinations of the present invention refers to a diluent, excipient, or carrier that provides the active compound.

[0288] "Pharmaceutically acceptable carrier" refers to a carrier or excipient that can be used to prepare a pharmaceutical composition / combination that is generally safe, non-toxic, and biologically or otherwise unsuitable for administration to a patient, typically a human. In one embodiment, a veterinary-acceptable excipient is used.

[0289] "Patient" or "subject" is a person or domestic animal requiring treatment for any disorder as specifically described herein, such as a disorder regulated by a naturally occurring (wild-type) or modified (non-wild-type) RET protein that is degradable according to the invention, to produce a therapeutic effect. Non-limiting examples of domestic animals include dogs, cats, horses, and livestock. As further described herein, the terms patient or subject generally refer to a person, and are assumed to refer to a person unless otherwise stated in the text. In alternative embodiments, the patient or subject is a domestic animal that requires and responds to such treatment.

[0290] "Livestock" refers to animals that are typically raised for agricultural purposes, including, for example, cattle, sheep, goats, pigs, and poultry.

[0291] The "therapeutic effective amount" of the pharmaceutical composition / combination of the present invention refers to the amount that effectively provides therapeutic benefits, such as improvement of symptoms or reduction or alleviation of the disease itself, when administered to a patient.

[0292] 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 pertains. In the specification, singular forms also include plural forms unless the context clearly requires otherwise. While methods and materials similar to or equivalent to those described herein may be used in the practice or testing of this application, suitable methods and materials are described below. All disclosures, patent applications, patents, and other references mentioned herein are incorporated by reference. References cited herein are not acknowledged as prior art to the claimed application. In the event of conflict, this specification, including its definitions, shall prevail. Furthermore, materials, methods, and embodiments are illustrative only and are not intended to be restrictive.

[0293] II. Compounds of formula I, II, III, IV, V, VI or VII

[0294] On the one hand, the present invention provides compounds of formula I, formula II, formula III or formula IV:

[0295]

[0296] Or its pharmaceutically acceptable salt;

[0297] All variables are defined as above.

[0298] In some embodiments, the compounds of the present invention are selected from:

[0299]

[0300]

[0301]

[0302] Or its pharmaceutically acceptable salt.

[0303] In some embodiments, the compounds of the present invention are selected from:

[0304]

[0305]

[0306] Or its pharmaceutically acceptable salt.

[0307] In some embodiments, the compounds of the present invention are selected from:

[0308]

[0309]

[0310] Or its pharmaceutically acceptable salt.

[0311] In some embodiments, the compounds of the present invention are selected from:

[0312] Or its pharmaceutically acceptable salt.

[0313] In some embodiments, the compounds of the present invention are selected from:

[0314] Or its pharmaceutically acceptable salt.

[0315] In some embodiments, the compound of the present invention is:

[0316]

[0317] Or its pharmaceutically acceptable salt.

[0318] In some embodiments, the compound of the present invention is:

[0319]

[0320] Or its pharmaceutically acceptable salt.

[0321] In some embodiments, the compound of the present invention is:

[0322]

[0323] Or its pharmaceutically acceptable salt.

[0324] In some embodiments, the compounds of the present invention are selected from:

[0325]

[0326]

[0327] Or its pharmaceutically acceptable salt.

[0328] In some embodiments, the compounds of the present invention are selected from...

[0329]

[0330]

[0331] Or its pharmaceutically acceptable salt.

[0332] In some embodiments, the compounds of the present invention are selected from...

[0333]

[0334]

[0335] Or its pharmaceutically acceptable salt.

[0336] In some embodiments, the compounds of the present invention are selected from...

[0337]

[0338] Or its pharmaceutically acceptable salt.

[0339] In some embodiments, the compounds of the present invention are selected from...

[0340]

[0341]

[0342] Or its pharmaceutically acceptable salt.

[0343] In some embodiments, the compounds of the present invention are selected from...

[0344]

[0345] Or its pharmaceutically acceptable salt.

[0346] In some embodiments, the compounds of the present invention are selected from...

[0347]

[0348] In some embodiments, the compounds of the present invention are selected from...

[0349]

[0350]

[0351] Or its pharmaceutically acceptable salt.

[0352] In some embodiments, the compounds of the present invention are selected from...

[0353]

[0354] Or its pharmaceutically acceptable salt.

[0355] In some embodiments, the compounds of the present invention are selected from...

[0356]

[0357] Or its pharmaceutically acceptable salt.

[0358] In some embodiments, the compounds of the present invention are selected from...

[0359]

[0360]

[0361] Or its pharmaceutically acceptable salt.

[0362] In some embodiments, the compounds of the present invention are selected from...

[0363]

[0364]

[0365] Or its pharmaceutically acceptable salt.

[0366] In some embodiments, the compounds of the present invention are selected from...

[0367]

[0368]

[0369] In some embodiments, the compounds of the present invention are selected from...

[0370]

[0371]

[0372] In some embodiments, the compounds of the present invention are selected from:

[0373]

[0374] Or its pharmaceutically acceptable salt.

[0375] In some embodiments, the compounds of the present invention are selected from:

[0376]

[0377] Or its pharmaceutically acceptable salt.

[0378] Embodiments of the present invention

[0379] In some implementations, yes

[0380] In some implementations, yes

[0381] In some implementations, yes

[0382] In some implementations, yes

[0383] In some implementations, yes

[0384] In some implementations, yes

[0385] In some implementations, yes

[0386] In some implementations, yes

[0387] In some implementations, yes

[0388] In some implementations, yes

[0389] In some implementations, yes

[0390] In some implementations, X3 X 4 X 5 and X 6 At most two of them are N.

[0391] In some implementations, X 3 X 4 X 5 and X 6 All of them are CH.

[0392] In some implementations, X 3 X 4 X 5 and X 6 One of them is CR 3 ;where R 3 Selected from the group consisting of: fluorine, chlorine, and bromine. In some embodiments, R 3 It is a C1-C4 haloalkyl group. In some embodiments, R 3 It is a C1-C4 alkyl group.

[0393] In some implementations, X 3 X 4 X 5 and X 6 One of them is CR 3 , where R 3 It is a C1-C4 alkyl group.

[0394] In some implementations, X 4 or X 6 It is N. In some implementations, X 4 and X 6 Both are N. In some implementations, X 4 or X 6 It is CH. In some implementations, X 4 and X 6 Both are CH.

[0395] In some implementations, X 4 or X 6 It is CR 3 ;where R 3 Choose from the following groups: fluorine, chlorine, and bromine.

[0396] In some implementations, X 4 or X 6 It is CR 3 , where R 3 Choose from the following groups: C1-C4 haloalkyl, CH2F, CHF2, CF3, CH2Cl, CHCl2, CCl3, CH2Br, CHBr2, and CBr3.

[0397] In some implementations, X 4 or X 6 It is CR 3 ;where R 3 It is a C1-C4 alkyl group.

[0398] In some implementations, X 7 It is N and Q 1 It is CH2. In some implementations, X 7 It is CH. In some implementations, X 7 It is a C1-C4 alkyl group. In some embodiments, X 7 It is a C1-C4 haloalkyl group.

[0399] In some implementations, X 8 It is CH.

[0400] In some implementations, X 8 It is N.

[0401] In some implementations, X 9 It is NR 4 .

[0402] In some implementations, X 9 It is O.

[0403] In some implementations, X 9 It is CR 4 R 11 .

[0404] In some implementations, Q 1 It is NH. In some implementations, Q 1 It is O. In some implementations, Q 1 It is S. In some implementations, Q 1 It is CH2. In some implementations, Q 1 It is N (alkyl), wherein the alkyl group is a C1-C4 alkyl group or a C1-C4 haloalkyl group. In some embodiments, Q 1 It is N (haloalkyl), where the haloalkyl is C1-C4 haloalkyl.

[0405] In some embodiments, R is hydrogen. In some embodiments, R is selected from the group consisting of fluorine, chlorine, and bromine. In some embodiments, R is a C1-C4 haloalkyl, CH2F, CHF2, CF3, CH2Cl, CHCl2, CCl3, CH2Br, CHBr2, or CBr3. In some embodiments, R is a C1-C4 alkyl.

[0406] In some implementations, R 1aIt is hydrogen. In some implementations, R 1a Selected from the group consisting of: fluorine, chlorine, and bromine. In some embodiments, R 1a It is a C1-C4 haloalkyl group, CH2F, CHF2, CF3, CH2Cl, CHCl2, CCl3, CH2Br, CHBr2, or CBr3. In some embodiments, R 1a It is a cycloalkyl group.

[0407] In some implementations, R 1b It is hydrogen. In some implementations, R 1b Selected from the group consisting of: fluorine, chlorine, and bromine. In some embodiments, R 1b It is a C1-C4 haloalkyl group, CH2F, CHF2, CF3, CH2Cl, CHCl2, CCl3, CH2Br, CHBr2, or CBr3. In some embodiments, R 1b It is a cycloalkyl group.

[0408] In some implementations, R 1c It is hydrogen. In some implementations, R 1c Selected from the group consisting of: fluorine, chlorine, and bromine. In some embodiments, R 1c It is a C1-C4 haloalkyl group, CH2F, CHF2, CF3, CH2Cl, CHCl2, CCl3, CH2Br, CHBr2, or CBr3. In some embodiments, R 1c It is a cycloalkyl group.

[0409] In some implementations, R 1d It is hydrogen. In some implementations, R 1d Selected from the group consisting of: fluorine, chlorine, and bromine. In some embodiments, R 1d It is a C1-C4 haloalkyl group, CH2F, CHF2, CF3, CH2Cl, CHCl2, CCl3, CH2Br, CHBr2, or CBr3. In some embodiments, R 1d It is a cycloalkyl group.

[0410] In some implementations, R 3 It is hydrogen. In some implementations, R 3 Selected from the group consisting of: fluorine, chlorine, and bromine. In some embodiments, R 3 It is a C1-C4 haloalkyl group, CH2F, CHF2, CF3, CH2Cl, CHCl2, CCl3, CH2Br, CHBr2, or CBr3. In some embodiments, R 3 It is a C1-C4 alkoxy group. In some embodiments, R 4It is a C1-C4 alkyl group. In some embodiments, R 3 It is a cycloalkyl group.

[0411] In some implementations, R 4 It is hydrogen. In some implementations, R 4 Selected from the group consisting of: fluorine, chlorine, and bromine. In some embodiments, R 4 It is a C1-C4 haloalkyl group, CH2F, CHF2, CF3, CH2Cl, CHCl2, CCl3, CH2Br, CHBr2, or CBr3. In some embodiments, R 4 It is a C1-C4 alkoxy group. In some embodiments, R 4 It is a C1-C4 alkyl group. In some embodiments, R 4 It is a C1-C4 haloalkoxy group.

[0412] In some implementations, R 5 It is hydrogen. In some implementations, R 5 It is a C1-C4 alkyl group. In some embodiments, R 5 It is allyl. In some embodiments, R 5 It is crotonyl. In some implementations, R 5 It is an alkenyl group. In some embodiments, R 5 It is an alkynyl group. In some embodiments, R 5 It is a haloalkyl group. In some embodiments, R 5 It is a cycloalkyl group.

[0413] In the alternative implementation, R 5 It is a double ring, which is replaced by the following: -OR 6 -NR 6 R 7 -OC(O)R 5' -NR 6 C(O)R 5' -C(O)R 5' ,-alkyl-OR 6 ,-alkyl-NR 6 R 7 ,-alkyl-OC(O)R 5' ,-alkyl-NR 6 C(O)R 5' , or -alkyl-C(O)R 5' And optionally selected by 1, 2 or 3 from R 8 Substituents of R; where R 5'Hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, cycloalkyl, heteroaryl, aryl, heterocyclic, bicyclic, -alkyl-heteroaryl, -alkyl-aryl, -alkyl-heterocyclic, -OR 6 , or -NR 6 R 7 Each C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, cycloalkyl, heteroaryl, aryl, heterocyclic, -alkyl-heteroaryl, -alkyl-aryl, and -alkyl-heterocyclic group is optionally represented by 0, 1, 2, or 3 independently selected from R 9 Substituents are substituted.

[0414] In some implementations, R 6 It is hydrogen. In some implementations, R 6 Selected from the group consisting of: fluorine, chlorine, and bromine. In some embodiments, R 6 It is a C1-C4 haloalkyl group, CH2F, CHF2, CF3, CH2Cl, CHCl2, CCl3, CH2Br, CHBr2, or CBr3. In some embodiments, R 6 It is a C1-C4 alkyl group.

[0415] In some implementations, R 7 It is hydrogen. In some implementations, R 7 Selected from the group consisting of: fluorine, chlorine, and bromine. In some embodiments, R 7 It is a C1-C4 haloalkyl group, CH2F, CHF2, CF3, CH2Cl, CHCl2, CCl3, CH2Br, CHBr2, or CBr3. In some embodiments, R 7 It is a C1-C4 alkyl group.

[0416] In some implementations, R 8 It is hydrogen. In some implementations, R 8 It is a C1-C4 alkyl group. In some embodiments, R 8 It is a haloalkyl group. In some embodiments, R 8 It is a cycloalkyl group.

[0417] In some implementations, Choose from the following groups:

[0418]

[0419] In alternative implementations, the antithetical structure in this embodiment is in a meta-configuration. In some implementations, Choose from the following groups:

[0420]

[0421] In some implementations, Choose from the following groups:

[0422]

[0423]

[0424] In some implementations, Choose from the following groups:

[0425]

[0426]

[0427] In some implementations, Selected from

[0428]

[0429]

[0430] In some implementations, Selected from

[0431]

[0432]

[0433] In some implementations, Selected from

[0434]

[0435]

[0436] In some implementations, Selected from

[0437]

[0438]

[0439] In some implementations, Selected from

[0440]

[0441] In some implementations, Selected from

[0442]

[0443]

[0444] In some implementations, Selected from

[0445]

[0446] In some embodiments, the structure of the compound is typically chosen to be sufficiently stable to maintain a shelf life of at least two, three, four, or five months under ambient conditions. To achieve this, each variable described herein must be sufficiently stable to maintain the desired shelf life of at least two, three, four, or five months under ambient conditions. Those skilled in the art are familiar with the stability of chemical components and can avoid those that are unstable or overly reactive under appropriate conditions.

[0447] In some alternative embodiments, compounds of the present invention, including any variable groups described herein, may optionally be substituted, as described in Section I below. A term is defined as the production of a stable moiety and final compound that is chemically meaningful to a person of ordinary skill and is pharmaceutically acceptable if the final compound for therapeutic use is desired to achieve the desired effect. Furthermore, all variables, with or without optional substituents, should be interpreted in a manner that excludes redundancy (i.e., alkyl substitution by alkyl is redundant, as is known in the art; however, alkoxy substitution by alkoxy, for example, is not redundant).

[0448] III. Targeted Ligands

[0449] RET forms a complex with its natural ligand (glial-derived neurotrophic factor family) and a coreceptor bound to glycosylphosphatidylinositol. This complex leads to dimerization of the kinase domain and subsequent activation by forming 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 induces autophosphorylation of tyrosine residues. As a result of this mechanism, glial family ligand-mediated activation of wild-type RET is an increasingly recognized mechanism associated with tumor growth and the broader spread of cancer cells. (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).

[0450] RET has several protein isoforms, including RET9, RET51, and RET43, each with different C-terminal tail lengths and varying abilities to bind SHC, GRB2, c-CBL, and SHANK3. Each RET isoform has a unique C-terminal tail sequence that can recruit different protein complexes to mediate signaling, thus exhibiting varying abilities to recruit E3 ubiquitin ligases to their unique C-termini (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 in acute myeloid leukemia (AML) have shown that AML isoforms depend on RET receptor tyrosine kinase (RTK) expression, and that shRNA knockout or CRISPR / Cas9-mediated knockdown leads to RET depletion, resulting in cell cycle arrest in the G0 / G1 phase, increased apoptosis, and decreased 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 showed that RET signaling is mainly mediated 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). RET fusion genes are mutually exclusive with other known drivers in LAD (e.g., KRAS, epidermal growth factor receptor (EGFR), EML4-anaplastic lymphoma kinase (ALK)), further supporting the role of RET as a unique driver of these malignant tumors.

[0451] In some implementations, the RET targeting ligand is selected from...

[0452]

[0453] In some implementations, the RET targeting ligand is selected from...

[0454]

[0455] In some implementations, the RET targeting ligand is selected from...

[0456]

[0457] In some implementations, the RET targeting ligand is selected from...

[0458]

[0459] In some implementations, the RET targeting ligand is selected from...

[0460]

[0461]

[0462]

[0463]

[0464] In some implementations, the RET targeting ligand is selected from...

[0465]

[0466]

[0467]

[0468]

[0469]

[0470]

[0471] In some implementations, the RET targeting ligand is selected from:

[0472]

[0473]

[0474] In some implementations, the RET targeting ligand is selected from:

[0475]

[0476] In some implementations, the RET targeting ligand is selected from:

[0477]

[0478] In some implementations, the RET targeting ligand is selected from:

[0479]

[0480] In some implementations, the RET targeting ligand is selected from:

[0481]

[0482] In some implementations, the RET targeting ligand is:

[0483]

[0484] In some implementations, the RET targeting ligand is selected from:

[0485]

[0486]

[0487] In some implementations, the RET targeting ligand is selected from:

[0488]

[0489]

[0490] In some implementations, the RET targeting ligand is selected from:

[0491]

[0492]

[0493] In some implementations, the RET targeting ligand is selected from:

[0494]

[0495] In some implementations, the RET targeting ligand is selected from:

[0496]

[0497] In some implementations, the RET targeting ligand is selected from:

[0498]

[0499]

[0500]

[0501]

[0502]

[0503]

[0504] In some implementations, the RET targeting ligand is selected from:

[0505]

[0506]

[0507] In some alternative embodiments, a compound is provided, wherein the compound has the structure illustrated herein, wherein the cyano group is R 27 Group substitution. For example, in this alternative embodiment, when the RET targeting ligand is

[0508]

[0509] In some embodiments, the compounds of the present invention are selected from:

[0510]

[0511]

[0512]

[0513]

[0514] Or its pharmaceutically acceptable salt.

[0515] In some implementations, R 27 It is hydrogen.

[0516] In some implementations, R 27 It is halogen.

[0517] In some implementations, R 27 It is a nitro group.

[0518] IV. Connector

[0519] Linkers are included in compounds of formula I, II, III, IV, V, VI, or VII. A linker is a chemically stable divalent group that can link the E3 ligase-binding moiety to a targeting ligand. According to the invention, any desired linker described herein may be used, provided that the resulting compound, as part of a pharmaceutically acceptable dosage form, has a stable shelf life of at least 2 months, 3 months, 6 months, or 1 year, and is itself pharmaceutically acceptable.

[0520] The adapter described herein can be used in either direction, i.e., the left end is connected to the E3 ligase-binding site and the right end is connected to the RET-targeting ligand, or the left end is connected to the RET-targeting ligand and the right end is connected to the E3 ligase-binding site.

[0521] In some embodiments, the connector has a chain of 2 to 14, 15, 16, 17, 18 or 20 or more carbon atoms, wherein one or more carbon atoms may be replaced by heteroatoms such as O, N, S or P.

[0522] In some embodiments, the chain has 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive atoms. For example, the chain may include one or more ethylene glycol units that may be continuous, partially continuous, or discontinuous (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 ethylene glycol units).

[0523] In some embodiments, the chain has at least 1, 2, 3, 4, 5, 6, 7 or 8 consecutive chains, which may have branches that can be independently alkyl, aryl, heteroaryl, alkenyl or alkynyl, aliphatic, heteroaliphatic, cycloalkyl or heterocyclic substituents.

[0524] In other embodiments, the linker may comprise one or more of ethylene glycol, propylene glycol, lactic acid, and / or glycolic acid, or a combination thereof. Typically, propylene glycol increases hydrophobicity, while propylene glycol increases hydrophilicity. Lactic acid segments tend to have a longer half-life than glycolic acid segments. Block and random lactic-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 achieve the desired half-life and hydrophilicity. In some aspects, these units may be side-attached or dispersed with other moieties, such as aliphatic, including alkyl, heteroaliphatic, aryl, heteroaryl, heterocyclic, cycloalkyl, etc., to achieve suitable pharmaceutical properties.

[0525] In some implementations, the connector is selected from:

[0526]

[0527] On the one hand, the connector is selected from the following groups: parts of Formula LI, Formula LII, Formula LIII, Formula LIV, Formula LV, Formula LVI, Formula LVII, Formula LVIII, Formula IX, and Formula LX:

[0528]

[0529]

[0530] in,

[0531] X 1 and X 2 Each occurrence is independently selected from bonds, heterocycles, and NR. 2 C(R) 2 2. O, C(O) and S;

[0532] R 2 Each time it appears, it is independently selected from the group consisting of: hydrogen, alkyl, aliphatic, heteroaliphatic, heterocyclic, 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), alkenes and alkynes;

[0533] R 20 R 21 R 22 R 23 and R 24 Each time it appears, it is independently selected from the following groups: bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR 2 -、

[0534] -NR 2 C(O)-, -O-, -S-, -NR 2 -、-C(R 40 R 40 )-、-P(O)(OR 26 )O-、-P(O)(OR 26 )-, alkenes, alkynes, haloalkyls, alkoxys, aryl groups, heterocyclics, aliphatic, heteroaliphatic, heteroaryl, lactic acids, glycolic acids, and carbocyclics; wherein each is optionally selected independently by 1, 2, 3, or 4 from R 40 Substituents of the substituents;

[0535] R 26 Each time it appears, it is independently selected from the group consisting of: hydrogen, alkyl, arylalkyl, heteroarylalkyl, olefin, alkyne, aryl, heteroaryl, heterocyclic, aliphatic, and heteroaliphatic; and

[0536] R 40 Each time it appears, it is independently selected from the group consisting of: hydrogen, alkyl, olefin, alkyne, fluorine, bromine, chlorine, 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 heterocyclic), -N (alkyl)SO2 (aryl, heteroaryl or heterocyclic), -NHSO2 alkenyl, -N (alkyl)SO2 alkenyl, -NHSO2 ynyl, -N (alkyl)SO2 ynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocyclic and cycloalkyl.

[0537] In some implementations, the connector is selected from:

[0538]

[0539] On the one hand, the connector is selected from the following groups: parts of type LDI, type LDII, type LDIII, type LDIV, type LDV, type LDVI, and type LDVII:

[0540]

[0541] All of these variables are described in this article.

[0542] The following are non-limiting examples of connectors that can be used in this invention. Based on this description, those skilled in the art will understand how to use all connectors that will achieve the objectives of this invention.

[0543] Non-limiting examples of connectors include:

[0544]

[0545]

[0546] Non-limiting examples of connectors include:

[0547]

[0548]

[0549] In one implementation, X 2 Connected to the RET-targeting ligand. In another implementation, X 1 Connect to the RET targeting ligand.

[0550] R 20 R 21 R 22 R 23 and R 24 include:

[0551]

[0552] R 20 R 21 R 22 R 23 and R 24 Other non-limiting examples of the part include:

[0553]

[0554]

[0555] R20 R 21 R 22 R 23 and R 24 Other non-limiting examples of the part include:

[0556]

[0557] In another embodiment, the connector portion 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, or at least 10 ethylene glycol units, or an optionally substituted alkyl group dispersed with optionally substituted O, N, S, P, or Si atoms.

[0558] In some embodiments, the connector is side-mounted, substituted, or dispersed with aryl, phenyl, benzyl, alkyl, alkylene, or heterocyclic groups.

[0559] In some implementations, the connector can be asymmetrical or symmetrical.

[0560] In some implementations, the connector may be a nonlinear chain and may be or include an aliphatic, aromatic, or heteroaromatic cyclic portion.

[0561] In any embodiment of the compounds described herein, the linker group may be any suitable part described herein.

[0562] In some implementations, the connector is selected from the group consisting of:

[0563]

[0564]

[0565] In some implementations, the connector is selected from the group consisting of:

[0566]

[0567] In some implementations, the connector is selected from the group consisting of:

[0568]

[0569]

[0570] In some implementations, the connector is selected from the group consisting of:

[0571]

[0572] In some implementations, the connector is selected from the group consisting of:

[0573]

[0574]

[0575] In some implementations, the connector is selected from:

[0576]

[0577] In some implementations, the connector is selected from

[0578]

[0579]

[0580] In some embodiments, the right connector of the connector shown above is connected to the RET targeting ligand. In some embodiments, the left connector of the connector shown above is connected to the RET targeting ligand.

[0581] In some embodiments, the compounds of the present invention are selected from:

[0582]

[0583]

[0584] Or its pharmaceutically acceptable salt.

[0585] In some embodiments, the compounds of the present invention are selected from:

[0586]

[0587] Or its pharmaceutically acceptable salt.

[0588] In some embodiments, the compounds of the present invention are selected from:

[0589]

[0590]

[0591] Or its pharmaceutically acceptable salt.

[0592] In some embodiments, the compounds of the present invention are selected from:

[0593]

[0594] Or its pharmaceutically acceptable salt.

[0595] V. Treatment Methods

[0596] The compounds described herein can be used in effective amounts to treat patients, typically humans, who suffer from RET-mediated disorders, which may be wild-type RET or mutant RET as generally described herein. In some embodiments, the compounds of the present invention degrade additional proteins, such as aurora kinase or VEGFR2. In some embodiments, the compounds of the present invention degrade RET and aurora A kinase (AURKA).

[0597] Another aspect of the invention provides the compounds described herein, or their enantiomers, diastereomers, or stereoisomers, or pharmaceutically acceptable salts, hydrates, or solvates, or pharmaceutical compositions thereof, for the preparation of medicaments for the treatment or prevention of cancer in patients in need of such treatment or prevention; wherein RET inhibition is required for the treatment or prevention of cancer.

[0598] In some embodiments, the method includes administering an effective amount of an active compound or salt thereof as described herein, optionally including a pharmaceutically acceptable excipient, carrier, or adjuvant (i.e., a pharmaceutically acceptable composition), or optionally in combination with another or alternating bioactive agent or pharmaceutical agent, to a patient in need.

[0599] In some embodiments, the present invention provides a method for treating any of the barriers described herein in a patient in need.

[0600] In other embodiments, the patient is administered additional therapeutic agents. In other embodiments, the compounds described herein and additional therapeutic agents are administered simultaneously or sequentially.

[0601] In some implementations, this application provides a method for preventing any of the barriers described herein in patients in need.

[0602] In some implementations, the patient is a person.

[0603] Another aspect of the invention provides a method for treating or preventing proliferative diseases. The method includes administering an effective amount of a pharmaceutical composition to a patient in need, said pharmaceutical composition comprising a compound as described herein, or an enantiomer, diastereomer, or stereoisomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and optionally a pharmaceutically acceptable carrier.

[0604] In some implementations, the disease is mediated by RETs, for example, RETs play a role in the occurrence or development of the disease.

[0605] In some implementations, RET-mediated disorders are benign growth, metastasis, tumor, neoplasm, solid tumor, rhabdomyosarcoma, carcinoma, leukemia, cancer, abnormal cell proliferation, amyloid-based protein diseases, protein diseases, fibrotic disorders, inflammation, arthritis, pulmonary disorders, or immune disorders.

[0606] In some implementations, the RET-mediated barrier is a cancer that has metastasized, such as cancer that has metastasized to the brain. In other implementations, the RET-mediated barrier is a cancer that has metastasized to the brain, lungs, bone, liver, peritoneum, adrenal glands, skin, or muscle.

[0607] In some embodiments, the compounds of the present invention can penetrate the blood-brain barrier and can be used to treat cancers involving the central nervous system or cancers that have metastasized to the brain.

[0608] In some implementations, the disease or disorder is cancer or a proliferative disease.

[0609] In some implementations, RET-mediated disorders are abnormal cell proliferation, including but not limited to tumors or cancers, or myeloproliferative disorders or lymphoproliferative disorders such as B-cell or T-cell lymphomas, multiple myeloma, Waldenström macroglobulinemia, Wiskott-Aldrich syndrome, or post-transplant lymphoproliferative disorders.

[0610] In some implementations, blood cancers include acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), lymphocytic T-cell leukemia, chronic myeloid 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, megakaryocytic leukemia, and acute megakaryocytic leukemia. Promyelocytic leukemia, mixed lineage leukemia (MLL), erythroleukemia, malignant lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoblastic lymphoma, Burkitt lymphoma, follicular lymphoma, B-cell acute lymphoblastic leukemia, diffuse large B-cell lymphoma, Myc and B-cell leukemia (BCL) 2 and / or BCL6 rearrangement / overexpression [double and triple hit lymphomas], myelodysplastic dysplasia / myeloproliferative neoplasms, mantle cell lymphoma, including bortezomib-resistant mantle cell lymphoma.

[0611] Solid tumors that can be treated with the compounds described herein include, but are not limited to, lung cancer, including small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC); breast cancer, including inflammatory breast cancer, ER-positive breast cancer, including tamoxifen-resistant ER-positive breast cancer and triple-negative breast cancer; colon cancer; midline cancer; liver cancer; kidney cancer; prostate cancer (including castration-resistant prostate cancer (CRPC)); brain cancer (including glioma, glioblastoma, neuroblastoma) and medulloblastoma (including MYC-amplified medulloblastoma); colorectal cancer; nephroblastoma; Ewing's sarcoma; Rhabdomyosarcoma, ependymoma, head and neck cancer, melanoma, squamous cell carcinoma, ovarian cancer, pancreatic cancer (including pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumor (PanNET)), osteosarcoma, giant cell tumor of bone, thyroid cancer, bladder cancer, urothelial carcinoma, vulvar cancer, cervical cancer, endometrial cancer, mesothelioma, esophageal cancer, salivary gland cancer, gastric cancer, nasopharyngeal carcinoma, oral cancer, oral cavity cancer, GIST (gastrointestinal stromal tumor), midline NUT carcinoma, testicular cancer, squamous cell carcinoma, hepatocellular carcinoma (HCC), MYCN-driven solid tumors, and midline NUT carcinoma (NMC).

[0612] In a further implementation, the disease or disorder is a sarcoma of the bones, muscles, tendons, cartilage, nerves, fat, or blood vessels.

[0613] In a further implementation plan, the disease or disorder is soft tissue sarcoma, osteosarcoma, or osteosarcoma.

[0614] In a further implementation plan, 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, meningeal sarcoma, botryoid sarcoma, germinal myoma, or embryonal rhabdomyosarcoma.

[0615] In a further implementation plan, the disease or disorder is multiple myeloma.

[0616] In other implementations, the disease or disorder is inflammation, arthritis, rheumatoid arthritis, spondyloarthritis, gouty arthritis, osteoarthritis, juvenile arthritis and other arthritis disorders, neuroinflammation, allergic reactions, pain, neuropathic pain, fever, lung disease, lung inflammation, painful chronic lung inflammation and chronic obstructive pulmonary disease (COPD) in adults, liver disease and nephritis, gastrointestinal disease, inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, ulcerative diseases, gastric ulcers, autoimmune diseases, graft-versus-host disease and allogeneic graft rejection, cancer, leukemia, lymphoma, colorectal cancer, brain cancer. Bone cancer, epithelial cell-derived carcinoma (epithelial carcinoma), basal cell carcinoma, adenocarcinoma, gastrointestinal cancer, lip cancer, oral cancer, esophageal cancer, small bowel cancer, gastric cancer, colon cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancer, squamous cell and / or basal cell carcinoma, prostate cancer, renal cell carcinoma, and other known cancers affecting epithelial cells throughout the body, chronic myeloid leukemia (CML), acute myeloid leukemia (AML) and acute promyelocytic leukemia (APL), angiogenesis, including tumor formation, metastasis, central nervous system disorders, central nervous system disorders with inflammatory or apoptotic components, peripheral neuropathy, or B-cell lymphoma.

[0617] In other embodiments, the pharmaceutical composition comprising the compounds described herein and additional therapeutic agents are administered simultaneously or sequentially.

[0618] In other implementations, the disease or disorder is cancer. In further implementations, the cancer is lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, kidney cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, gastric cancer, glioma, glioblastoma, hepatocellular carcinoma, papillary renal cell carcinoma, head and neck squamous cell carcinoma, leukemia, lymphoma, myeloma, solid tumor, blood cancer, or solid carcinoma.

[0619] In some embodiments, the method is used to treat or prevent disorders selected from autoimmune diseases, inflammatory diseases, proliferative and hyperproliferative diseases, and immune-mediated diseases. In other embodiments, the disorder is selected from proliferative diseases.

[0620] In some implementations, the RET-mediated disorder is an immune disorder, including but not limited to autoimmune disorders such as Addison's disease, celiac disease, dermatomyositis, Graves' disease, thyroiditis, multiple sclerosis, pernicious anemia, reactive arthritis, lupus, or type I diabetes.

[0621] One aspect of this application provides compounds that can be used to treat diseases, disorders, and conditions characterized by excessive or abnormal cell proliferation. Such diseases include, but are not limited to, proliferative disorders or hyperproliferative disorders. Examples of proliferative and hyperproliferative disorders include, but are not limited to, cancer. The term "cancer" includes, but is not limited to, the following cancers: breast cancer; ovary; cervix; prostate; testis; urogenital tract; esophagus; larynx; glioblastoma; neuroblastoma; stomach; skin; keratoacanthoma; lung cancer, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma; bone; colon; colorectal cancer; adenoma; pancreatic cancer, adenocarcinoma; thyroid cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma; seminoma; melanoma; sarcoma; bladder cancer; liver cancer and biliary tract cancer; kidney cancer; bone marrow disorders; lymphoid disorders, Hodgkin's disease, hair cell carcinoma; oral cavity and pharynx (oral cavity), lips, tongue, mouth, pharynx; small intestine; colon, rectum, large intestine, rectum, brain and central nervous system; chronic myeloid leukemia (CML) and leukemia. The term “cancer” includes, but is not limited to, the following cancers: myeloma, lymphoma, or cancers selected from stomach cancer, kidney cancer, or the following cancers: head and neck cancer, oropharyngeal cancer, non-small cell lung cancer (NSCLC), endometrial cancer, liver cancer, non-Hodgkin lymphoma, and lung cancer.

[0622] The term "cancer" refers to any cancer caused by the proliferation of malignant tumor cells, such as tumors, cysts, carcinomas, sarcomas, leukemias, lymphomas, etc. For example, cancers include, but are not limited to, mesotheliomas, leukemias, and lymphomas such as cutaneous T-cell lymphoma (CTCL), non-cutaneous peripheral T-cell lymphomas, lymphomas associated with human T-cell nutritional lymphovirus (HTLV) such as adult T-cell leukemia / lymphoma (ATLL), B-cell lymphomas, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, acute myeloid leukemia, lymphomas and multiple myeloma, non-Hodgkin lymphoma, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), Hodgkin lymphoma, Burkitt lymphoma, adult T-cell leukemia lymphoma, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), or hepatocellular carcinoma. Other examples include myelodysplastic syndromes, childhood solid tumors such as brain tumors, neuroblastoma, retinoblastoma, nephroblastoma, bone tumors, and soft tissue sarcomas; common adult solid tumors such as head and neck cancers, including oral, laryngeal, nasopharyngeal, and esophageal cancers; genitourinary cancers such as prostate, bladder, kidney, uterine, ovarian, and testicular cancers; lung cancers such as small cell and non-small cell lung cancers; breast cancer, pancreatic cancer, melanoma, and other skin cancers; stomach cancer; brain tumors; tumors associated with Goring syndrome, such as medulloblastoma or meningioma; and liver cancer.

[0623] Other exemplary forms of cancer include, but are not limited to, bone cancer or smooth muscle cancer, stomach cancer, small bowel cancer, rectal cancer, salivary gland cancer, endometrial cancer, adrenal cancer, anal cancer, rectal cancer, parathyroid cancer, and pituitary cancer.

[0624] Other cancers for which the compounds described herein can be used for prevention, treatment, and research include, for example, colon cancer, familial adenomatous polyposis (FAP) cancer, and hereditary nonpolyposis colorectal cancer or melanoma. In addition, cancers include, but are not limited to, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, thyroid cancer (medullary and papillary thyroid carcinoma), kidney cancer, renal parenchymal carcinoma, cervical cancer, uterine cancer, endometrial cancer, choriocarcinoma, testicular cancer, urinary tract cancer, melanoma, brain tumors (e.g., glioblastoma, astrocytoma, meningioma, medulloblastoma, and peripheral neuroectodermal tumors), gallbladder cancer, bronchial cancer, multiple myeloma, basal cell carcinoma, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myoma, liposarcoma, fibrosarcoma, Ewing's sarcoma, and plasmacytoma. In one aspect of this application, the use of one or more compounds described herein in the preparation of a medicament for treating cancer, including but not limited to the various types of cancer disclosed herein.

[0625] In some embodiments, the compounds of this application can be used to treat cancers such as colorectal cancer, thyroid cancer, breast cancer, and lung cancer; and myeloproliferative disorders such as polycythemia vera, thrombocythemia, myelomecosis with myelofibrosis, chronic myeloid leukemia, chronic myelomonocytic leukemia, eosinophilia syndrome, juvenile myelomonocytic leukemia, and systemic mast cell disease. In some embodiments, the compounds described herein can be used to treat hematopoietic disorders, particularly acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute promyelocytic leukemia, and acute lymphoblastic leukemia (ALL).

[0626] In one embodiment, the compounds described herein or their corresponding pharmaceutically acceptable salts or isotope derivatives can be used in effective amounts to treat a subject (e.g., a human) suffering from lymphoma or lymphocyte or myeloid cell proliferation disorders or abnormalities. For example, the compounds described herein can be administered to a host suffering from Hodgkin lymphoma or non-Hodgkin lymphoma. For example, the host may have non-Hodgkin's lymphoma, such as, but not limited to: 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 lymphoma; primary central nervous system lymphoma; T-cell leukemia; transformed lymphoma; treatment-related T-cell lymphoma; Langerhans cell histiocytosis; or Waldenström macroglobulinemia.

[0627] In another embodiment, the compounds described herein or their corresponding pharmaceutically acceptable salts or isotope derivatives may be used in effective amounts to treat patients, such as humans, who suffer from Hodgkin lymphoma, such as, but not limited to: tuberous sclerosis classical Hodgkin lymphoma (CHL); mixed cellularity CHL; lymphocyte-depleted CHL; lymphocyte-rich CHL; lymphocyte-predominant Hodgkin lymphoma; or nodular lymphocyte-predominant HL.

[0628] This application also includes treatment or prevention of cell proliferation disorders, such as hyperplasia, developmental abnormalities, and precancerous lesions. Developmental abnormalities are the earliest forms of precancerous lesions that a pathologist can identify in a biopsy. The compound can be administered to prevent said hyperplasia, developmental abnormality, or precancerous lesion from continuing to grow or becoming cancerous. Examples of precancerous lesions may occur in the skin, esophageal tissue, breast, and cervical intraepithelial tissue.

[0629] In some embodiments, the compounds of the present invention are used to treat abnormal cell proliferation, such as tumors or cancers, with a mutation in the RET protein, wherein the mutation is located at one of the amino acid sites listed below. For example, the mutation may be selected from one of the exemplary mutations listed, or it may be a different mutation.

[0630] amino acid sites Exemplary mutations G810 G810R, G810S, G810C, G810N C634 C634W, C634R M918 M918T A883 A883F E762 E762Q G691 G691S L790 L790F R749 R749T R813 R813Q S891 S891A S904 S904A, S904F V778 V778I V804 V804L, V804M, V804E Y791 Y791F Y806 Y806H

[0631] In some 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 still other embodiments, the RET protein has four or more mutations, which may optionally be selected from the table above.

[0632] In some embodiments, the tumor or cancer has a mutation in the RET protein, which is a major or partial driver of tumor or cancer cell proliferation. In another embodiment, the tumor or cancer has a RET-altered protein that does not significantly function as a driver of abnormal cell proliferation but can be therapeutically used to kill tumor cells using selected RET degraders described herein.

[0633] In some embodiments, the compounds of the present invention are used to treat tumors or cancers with RET protein V804L mutations. In some embodiments, the compounds of the present invention are used to treat tumors or cancers with RET protein V804M mutations. In some embodiments, the compounds of the present invention are used to treat tumors or cancers with RET protein M918T mutations. In some embodiments, the compounds of the present invention are used to treat tumors or cancers with RET protein S891A mutations. In some embodiments, the compounds of the present invention are used to treat tumors or cancers with RET protein L790F mutations. In some embodiments, the compounds of the present invention are used to treat tumors or cancers with RET protein E768D mutations. In some embodiments, the compounds of the present invention are used to treat tumors or cancers with RET protein C618S mutations. In some embodiments, the compounds of the present invention are used to treat tumors or cancers with RET protein C618R mutations. In some embodiments, the compounds of the present invention are used to treat tumors or cancers with RET protein 634 missense mutations. In some embodiments, the compounds of the present invention are used to treat tumors or cancers with RET protein C634R mutations. In some embodiments, the compounds of the present invention are used to treat tumors or cancers with RET protein C634Y mutations. In some embodiments, the compounds of the present invention are used to treat tumors or cancers with RET protein C634G mutations.

[0634] In some embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof are used to treat abnormal cell proliferation, such as tumors or cancers, of RET protein with a G810R mutation.

[0635] In some embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof are used to treat abnormal cell proliferation, such as tumors or cancers, of RET protein with a G810S mutation.

[0636] In some embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof are used to treat abnormal cell proliferation, such as tumors or cancers, of RET protein with a G810C mutation.

[0637] In some embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof are used to treat abnormal cell proliferation, such as tumors or cancers, of RET protein with a C634W mutation.

[0638] In some embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof are used to treat abnormal cell proliferation, such as tumors or cancers, of RET protein with an M918T mutation.

[0639] In some embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof are used to treat abnormal cell proliferation, such as tumors or cancers, of RET protein with a V804L mutation.

[0640] In some embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof are used to treat abnormal cell proliferation, such as tumors or cancers, of RET protein with a V804M mutation.

[0641] In some embodiments, the compounds of the present invention, or pharmaceutically acceptable salts thereof, are used to treat abnormal cell proliferation, such as tumors or cancers, having a RET protein fused with another protein, such as fusions selected from the following: 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.

[0642] In some embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof are used to treat abnormal cell proliferation, such as tumors or cancers having CCDC6-RET fusions.

[0643] In some embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof are used to treat abnormal cell proliferation, such as tumors or cancers having NCOOA4-RET fusions.

[0644] In some embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof are used to treat abnormal cell proliferation, such as tumors or cancers having KIF5B-RET fusions.

[0645] In accordance with the foregoing, this application further provides a method for preventing or treating any of the aforementioned diseases or disorders in a patient in need, the method comprising administering to the patient a therapeutically effective amount of the compound as described herein, or its enantiomers, diastereomers, or stereoisomers, or pharmaceutically acceptable salts, hydrates, or solvates thereof. For any of the above uses, the required dosage will vary depending on the method of administration, the specific disorder to be treated, and the desired effect.

[0646] VI. Combination therapy

[0647] Compounds of Formula I, II, III, IV, V, VI or VII, or pharmaceutically acceptable salts thereof, may be used alone or in combination in effective amounts to treat patients, such as humans, with the disorders described herein or RET-mediated disorders.

[0648] The compounds disclosed herein can be used alone in effective amounts or in combination with another compound of the present invention or another bioactive agent or a second therapeutic agent to treat patients, such as humans, with disorders (including, but not limited to, those described herein).

[0649] The term "bioactive agent" is used to describe pharmaceutical agents other than those selected according to the invention, which can be used in combination with or alternately with the compounds of the invention to achieve a desired therapeutic outcome. In one embodiment, the compounds and bioactive agents of the invention are administered in such a manner that they are active in vivo over overlapping time periods, for example, having overlapping Cmax, Tmax, AUC, or other pharmacokinetic parameters. In another embodiment, the compounds and bioactive agents of the invention are administered to a patient in need, which do not have overlapping pharmacokinetic parameters; however, one has a therapeutic effect on the efficacy of the other.

[0650] In one aspect of this implementation, the bioactive agent is an immunomodulatory agent, including but not limited to checkpoint inhibitors, such as PD-1 inhibitors, PD-L1 inhibitors, PD-L2 inhibitors, CTLA-4 inhibitors, LAG-3 inhibitors, TIM-3 inhibitors, V-domain Ig inhibitors of T cell activation (VISTA) inhibitors, small molecules, peptides, nucleotides, or other inhibitors as non-limiting examples. In some aspects, the immunomodulatory agent is an antibody, such as a monoclonal antibody.

[0651] PD-1 inhibitors that block the interaction between PD-1 and PD-L1 and thus inhibit immunosuppression by binding to the PD-1 receptor include, for example, nivolumab (Opdivo), pembrolizumab (Keytruda), pildizumab, 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, which block the interaction between PD-1 and PD-L1 and thus inhibit immunosuppression by binding to the PD-L1 receptor, include, for example, atezolizumab (Tecentriq), duvarubicin (AstraZeneca and MedImmune), KN035 (Alphamab), and BMS-936559 (Bristol-Myers Squibb). CTLA-4 checkpoint inhibitors, which bind to CTLA-4 and inhibit immunosuppression, include, but are not limited to, ipilimumab, trimerlimumab (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).

[0652] In some implementations, the checkpoint inhibitor is selected from nivolumab / Pembrolizumab / Pildizumab / CT-011, MPDL3280A / RG7446, MEDI4736, MSB0010718C, BMS 936559, PDL2 / lg fusion proteins such as AMP224 or B7-H3 inhibitors (e.g., MGA271), B7-H4, BTLA, HVEM, TIM3, GAL9, LAG 3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B-7 family ligands, or combinations thereof.

[0653] In yet another embodiment, one of the active compounds described herein may be administered in combination with or alternately with an effective amount of an estrogen inhibitor for treating abnormal tissues of the female reproductive system, such as breast cancer, ovarian cancer, endometrial cancer, or uterine cancer. The estrogen inhibitor includes, but is not limited to, SERMs (selective estrogen receptor modulators), SERDs (selective estrogen receptor degraders), complete estrogen receptor degraders, or another form of partial or complete estrogen antagonist or agonist. Some anti-estrogens, such as raloxifene and tamoxifen, retain some estrogen-like effects, including estrogen-like stimulation of uterine growth and, in some cases, estrogen-like effects during breast cancer progression, which actually stimulate tumor growth. In contrast, fulvestrant is a completely anti-estrogenic agent with no estrogen-like effects on the uterus and is effective against tamoxifen-resistant tumors.

[0654] Non-limiting examples of anti-estrogenic compounds are provided in WO 2014 / 19176 assigned to Astra Zeneca, WO 2013 / 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.

[0655] Other non-limiting examples of anti-estrogenic compounds include: SERMS, such as diacetylcholine, bardoxifene, bromhexine, chlorobenzyl anisole, clomiphene citrate, cyclofennig, lasoxifene, olmexifen, raloxifene, tamoxifen, toremifene, and fulvesta; aromatase inhibitors, such as aminoglutethimide, testosterone, anastrozole, exemestane, faldazole, formestane, and letrozole; and anti-gonadotropic hormones, such as leuprorelin, cetrorexone, allylestradiol, chlormedrone acetate, cyproterone acetate, dimagestrol acetate, dydrogesterone, medroxyprogesterone acetate, megestrol acetate, norethindrone acetate, progesterone, and spironolactone.

[0656] Other estrogen ligands that can be used according to the present invention are in U.S. Patent Nos. 4,418,068; 5,478,847; 5,393,763; and 5,457,117, WO2011 / 156518, U.S. 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; WO 2014 / 205138, US2016 / 0175289, US2015 / 0258080, WO 2014 / 191726, WO 2012 / 084711; WO 2002 / 013802; WO 2002 / 004418; WO2002 / 003992; WO 2002 / 003991; WO 2002 / 003990; WO 2002 / 003989; WO 2002 / 003988; WO2002 / 003986; WO 2002 / 003977; WO 2002 / 003976; WO 2002 / 003975; WO 2006 / 078834; US6821989; US 2002 / 0128276; US 6777424; US 2002 / 0016340; US 6326392; US 6756401; US2002 / 0013327; US 6512002; US 6632834; US 2001 / 0056099;US It is described in 6583170; US 6479535; WO1999 / 024027; US 6005102; EP 0802184; US 5998402; US 5780497, US 5880137, WO 2012 / 048058 and WO 2007 / 087684.

[0657] In another embodiment, the active compound described herein may be administered in combination with or alternately with an effective amount of an androgen (e.g., testosterone) inhibitor for treating male reproductive system abnormalities such as prostate or testicular cancer. The androgen inhibitor includes, but is not limited to, selective androgen receptor modulators, selective androgen receptor degraders, complete androgen receptor degraders, or other forms of partial or complete androgen antagonists. In one embodiment, the prostate or testicular cancer is androgen-resistant.

[0658] Non-limiting examples of antiandrogen compounds are provided in WO 2011 / 156518 and U.S. Patent Nos. 8,455,534 and 8,299,112. Other non-limiting examples of antiandrogen compounds include: enzalutamide, apalutamide, cyproterone acetate, chlormadinone acetate, spironolactone, canristone, drospirenone, ketoconazole, topilutamide, abiraterone acetate, and cimetidine.

[0659] In one implementation, 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.

[0660] In one implementation, the bioactive agent is an EGFR inhibitor. Examples of EGFR inhibitors include erlotinib (Tarceva), gefitinib (Iressa), afatinib (Gilotrif), roxitinib (CO-1686), osimertinib (Tagrisso), omamotinib (Olita), naquintinib (ASP8273), nazatinib (EGF816), PF-06747775 (Pfizer), icotinib (BPI-2009), neratinib (HKI-272), PB272), Avitinib (AC0010), EAI045, tarloxotinib (TH-4000, PR-610), PF-06459988 (Pfizer), tevatinib (XL647, EXEL-7647, KD-019), transtinib, WZ-3146, WZ8040, CNX-2006, and dacomitinib (PF-00299804, Pfizer).

[0661] In one implementation, the bioactive agent is a HER-2 inhibitor. Examples of HER-2 inhibitors include trastuzumab, lapatinib, ado-trastuzumab emtansine conjugate, and pertuzumab.

[0662] In one implementation, the bioactive agent is a CD20 inhibitor. Examples of CD20 inhibitors include obinutuzumab, rituximab, famucumab, ibritumomab, tostumomab, and ocrelizumab.

[0663] In one implementation, the bioactive agent is a JAK3 inhibitor. Examples of JAK3 inhibitors include tastocitinib.

[0664] In one embodiment, the bioactive agent is a BCL-2 inhibitor. Examples of BCL-2 inhibitors include venetum, ABT-199 (4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-1-en-1-yl]methyl]piperazin-1-yl]-N-[[3-nitro-4-[[((tetrahydro-2H-pyran-4-yl)methyl]amino]phenyl]sulfonyl]-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide), and ABT-737 (4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl]piperazin-1-yl]methyl ... -[4-[[(2R)-4-(dimethylamino)-1-phenylthiobutyl-2-yl]amino]-3-nitrophenyl]sulfonylbenzamide)(Navitolac), 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)but-2-yl)amino)-3((trifluoromethyl)sulfonyl)phenyl)sulfonyl (2Z) benzamide), GX15-070 (Obutura mesylate, (2Z)-2-[(5Z)-5-[(3,5-dimethyl-1H-pyrrolo-2-yl)methylene]-4-methoxypyrrolo-2-yl]indole, methanesulfonic acid), 2-methoxy-antimycin A3, YC137 (4-(4,9-dioxo-4,9-dihydronaphtho[2,3-d]thiazolyl-2-ylamino)-phenyl ester), pogosin, ethyl 2-amino-6-bromo-4-(1-cyano-2-yl) -Ethoxy-2-oxoethyl)-4H-chromium-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, gambogeylic acid, or G3139 (Oblimersen).

[0665] In one embodiment, the bioactive agent is a kinase inhibitor. In one embodiment, the kinase inhibitor is selected from phosphoinositol 3-kinase (PI3K) inhibitors, Bruton's tyrosine kinase (BTK) inhibitors, or spleen tyrosine kinase (Syk) inhibitors, or combinations thereof.

[0666] Examples of PI3 kinase inhibitors include, but are not limited to, womanzine, demethovirine, pirivoxetine, idelalisib, pitilis, and 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]benzoxazonyl-9-yl]pyrazol-1-yl]-2-methylpropionamide), MLN-1117 ((2R)-1-phenoxy-2-butyryl hydrogen(S)-methyl phosphate, or methyl(oxo){[(2R)-1-phenoxy-2-butyl]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-(methoxy)-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-1H-benzo[d]imidazol-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-hydroxyprop-1-one), GS-1101(5-fluoro-3-phenyl-2-([S)]-1-[9H-purin-6-ylamino]-propyl)-3H-quinazolino-4-one), AMG-319 GSK-2269557, SAR245409(N-(4-(N-(3-((3,5-dimethoxyphenyl)amino)quinoxalin-2-yl)aminosulfonyl)phenyl)-3-methoxy-4-methylbenzamide), BAY80-6946(2-amino-N-(7-methoxy-8-(3-morpholinopropoxy)-2,3-dihydroimidazo[l,2-c]quinacrine), AS252424(5-[l-[5-(4-fluoro-2-hydroxy-phenyl)-furan-2-yl]-methyl-(Z)-ylidene]-thiazoline-2,4-dione), CZ24832(5-(2-amino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-tert-butylpyridine-3-sulfonamide), Buparlisib (5-[2,6-di(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinylamine), GDC-0941 (2-(1H-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]pyrimidine-6yl)methyl)piperidine (Azine-l-yl)-2-hydroxyprop-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-onyl)-2-oxa-7,10,13,16-tetraazaoctadec-18-ester), PF-05212384 (N-[4-[[4-(dimethylamino)-1-piperidinyl]carbonyl]phenyl]-N'-[4-(4,6-di- 4-morpholino-1,3,5-triazin-2-yl)phenyl]urea)(gedatolisib), LY3023414, BEZ235(2-methyl-2-{4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl]phenyl}propionitrile)(dactolisib), XL-765(N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxolin-2-yl)aminosulfonyl)phenyl)-3-methoxy-4-methylbenzamide), and GSK1059615(5-[ [4-(4-pyridyl)-6-quinolinyl]methylene]-2,4-thiazolyldione), PX886 ([(3aR,6E,9S,9aR,10R,11aS)-6-[[bis(prop-2-enyl)amino]methylene]-5-hydroxy-9-(methoxymethyl)-9a,11a-dimethyl-1,4,7-trioxo-2,3,3a,9,10,11-hexahydroindo[4,5h]isocyanen-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, apeliximab, IC-87114, TGI100713, CH5132799, PKI-402, cyclophosphamide (BAY80-6946), XL 147, PIK-90, PIK-293, PIK-294, 3-MA (3-methyladenine), AS-252424, AS-604850, Atorlis (GDC-0980, RG7422).

[0667] Examples of BTK inhibitors include ibrutinib (also known as PCI-32765) (Imbruvica). TM(1-[(3R)-3-[4-amino-3-(4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one), diphenylaminopyrimidine-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 U.S. Patent Publication No. 2011 / 0117073, all of which are incorporated herein by reference), dasatinib ([N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazolyl-5-carboxamide], LFM-A13 (α-cyano-β-hydroxy-β-methyl-N-(2,5-isobromophenyl)acrylamide), GDC-0834 ([RN-(3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2- (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-(morpholin-4-carbonyl)phenyl)amino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl) )benzamide), CNX-774(4-(4-((4-((3-acylamidophenyl)amino)-5-fluoropyrimidin-2-yl)amino)phenoxy)-N-methylpyridinecarboxamide), CTA056(7-benzyl-1-(3-(piperidin-1-yl)propyl)-2-(4-(pyridin-4-yl)phenyl)-1H-imidazo[4,5-g]quinoxaline-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-oxopirarin-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-acryloylindoline-6-yl)-9-(1-methyl-1H-pyrazol-4-yl)benzo[h][1,6]naphthidin-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-isoquinoline-1-one), and other molecules capable of inhibiting BTK activity, such as those BTK inhibitors disclosed in Akinleye et al., Journal of Hematology & Oncology, 2013, 6:59, the entire contents of which are incorporated herein by reference.

[0668] Syk inhibitors include, but are not limited to, cerdulatinib (4-(cyclopropylamino)-2-((4-(4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)amino)pyrimidin-5-carboxamide), entospletinib (6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine), flotatinib ([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]dihydromethyl phosphate), flotatinib (… Sodium nicotinamide (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]oxazine-4(3H)-yl)methyl phosphate), BAY61-3606 (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-carboxylate), imatinib (Gleevec, 4-[(4-methylpiperazine- 1-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide), astrococcus, GSK143(2-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-4-(p-tolylamino)pyrimidin-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)pyrimidin-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))diol), R348(3-ethyl-4-methylpyridine), R406(6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidine-4-yl)amino)-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazine-3(4H)-one) spleen tyrosine (3-hydroxyresveratrol), YM193306 (see Singh et al. Discovery and Development of SpleenTyrosine Kinase (SYK) Inhibitors, J. Med.)Compounds included in this paper: 7-azaindole, leucine, ER-27319 (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, all incorporated herein by reference), compound D (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, all incorporated herein by reference), PRT060318 (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, all incorporated herein by reference), and luteolin (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, all incorporated herein by reference), and luteolin (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, all incorporated herein by reference). of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (all incorporated herein by reference), apigenin (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (all incorporated herein by reference), quercetin ...)), quercetin (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (all incorporated herein), myricetin (see Singh et al. Discovery and Development of SpleenTyrosine Kinase (SYK) Inhibitors, J. Med. Chem.).2012, 55, 3614-3643 (all incorporated in this article), morin (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (all incorporated in this article)).

[0669] In one embodiment, 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-1(2H-yl}phenyl)acetamide, sumetinib (6-(4-bromo-2-chloroaniline)-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]azacyclobut-3-ol), refametinib / BAY869766 / RDEAl19(N-(3,4-difluoro-2-(2-fluoro-4-iodophenyl)amino)-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-(methylaminosulfonylamino)-4-pyridyl]methyl]-4-methyl-7-pyrimidine-2-yloxychromene- 2-keto), WX-554, R04987655 / CH4987655 (3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3-oxo-1,2-oxazinyl-2-methyl)benzamide), or AZD8330 (2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide), U0126-EtOH, PD184352 (CI-1040), GDC-0623, BI-847325, cobistinib, PD98059, BIX 02189, BIX 02188, binimetinib, SL-327, TAK-733, PD318088.

[0670] In one embodiment, the bioactive agent is a Raf inhibitor. Raf inhibitors are known and include, for example, Vemurafinib (N-[3-[[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide) and sorafenib tosylate (4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridin-2-carboxamide) ; 4-methylbenzenesulfonate), AZ628(3-(2-cyanopropyl-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]benzimidazole-2-amine), 2-bromoaldisine (2-bromo-6,7-dihydro-1H,5H-pyrrolo[2,3-c]azacycloheptatrien-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-2-pyridinecarboxamide 1-oxide), PLX-4720, dabrafenib (GSK2118436), GDC-0879, RAF265, AZ 628, SB590885, ZM336372, GW5074, TAK-632, CEP-32496, LY3009120, and GX818 (Encorafenib).

[0671] In one embodiment, the bioactive agent is an AKT inhibitor, including but not limited to MK-2206, GSK690693, perifol, (KRX-0401), GDC-0068, tricirebin, AZD5363, honokiol, PF-04691502, and mitefol, and an FLT-3 inhibitor, including but not limited to P406, dovirtinib, quezatinib (AC220), amuvatinib (MP-470), tandotinib (MLN518), ENMD-2076, and KW-2449, or combinations thereof.

[0672] In one embodiment, the bioactive agent is an mTOR inhibitor. Examples of mTOR inhibitors include, but are not limited to, rapamycin and its analogues, everolimus (Afinitor), tesimolimus, desfolimus, sirolimus, and difolimus. 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-1(2H-yl}phenyl)acetamide, selumetinob(6-(4-bromo-2-chloroaniline)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide), and 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]azacyclobut-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-benzimidazolo[le-6-carboxamide), R05126766(3- [[3-fluoro-2-(methylaminosulfonylamino)-4-pyridyl]methyl]-4-methyl-7-pyrimidin-2-ylpyridinylchromene-2-one), WX-554, R04987655 / CH4987655 (3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3-oxo-1,2-oxazin-2-yl)methyl)benzamide), or AZD8330 (2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide).

[0673] In one implementation, the bioactive agent is a RAS inhibitor. Examples of RAS inhibitors include, but are not limited to, Reolysin and si G12D LODER.

[0674] In one embodiment, the bioactive agent is an HSP inhibitor. HSP inhibitors include, but are not limited to, geldmycin or 17-N-allylamino-17-demethoxygeldmycin (17AAG) and rhizocarpine.

[0675] Other bioactive compounds include, for example, everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, Enzastaurin, Vanditanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 inhibitors, VEGFR inhibitors, Aurora kinase inhibitors, PIK-1 modulators, HDAC inhibitors, c-MET inhibitors, PARP inhibitors, CdK inhibitors, IGFR-TK inhibitors, anti-HGF antibodies, focal adhesion kinase inhibitors, Map kinase kinase (mek) inhibitors, VEGF trap antibodies, Pemetrexed Panitumumab, Amrubicin, Oregorumab, Lep-etu, Nolatrexed, Azd2171, Batabulin, Atomomumab, Zanolimumab, Etotecarin, Tetrandrine, Rubitecan, Tesmilifene, Olimerson, Ticilimumab, Ipilimumab, Gossypol, Bio111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR1 KRX-0402, thioanthrone, LY317615, neuradiab, vitespan, Rta 744, Sdx 102, talepane, atrasentan, Xr 311, Lomidin, ADS-100380, Sunitinib, 5-Fluorouracil, Vorinostat, Etoposide, Gemcitabine, Doxorubicin, Liposome Doxorubicin, 5'-Deoxy-5-Fluorouracil, 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, anastrozole, exemestane, letrozole, DES (diethylstilbestrol), estradiolEstrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258), 3-[5-(methylsulfonylpiperidinylmethyl)-indolyl-quinolone, vatalanib, AG-013736, AVE-0005, goserelin acetate, leuprorelin acetate, triptorelin dihydroxynaphthyl ester, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilumethoxazole, megestrol acetate, CP-724714, TAK-165, HKI-272, erlotinib, lapatinib, canenatinib, ABX-EG F antibody, Erbitux, EKB-569, PKI-166, GW-572016, Ionafarnib, BMS-214662, Ipifarnib, Amifostine, NVP-LAQ824, S-dimethylaminoxamic acid, Valproic acid, Trichostatin A, FK-228, SU11248, Sorafenib, KRN951, Aminoglutethimide, Arnsacrine, Anagrel, L-L-asparaginase, BCG vaccine, Doxorubicin, Bleomycin, Buserellin, Busulfan, Carboplatin, Carmustine, Chlorambucil, Cisplatin Platinum, cladribine, clophosphamide, cyproterone acetate, cytarabine, dacarbazine, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, glimepiride, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide Levamisole, roxarsone, dichloromethyldiethylamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilumethicone, octreotide, oxaliplatin, pamidronate, pentostatin, procarbazine, raltitrexed, rituximab, streptozotocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, retinoic acid, vinorelbine, 13-cis-retinoic acid, phenylalanine mustard, uramustine.Estramustine, hexamethylmelamine, fluorouridine, 5-deoxyuridine, cytosine arabinoside arabinoside, 6-mercaptopurine, deoxymyopicrin, calcitriol, pentorubicin, photomycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat, COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxyfene, spironolactone, finasteride, cimetidine, trastuzumab, detoxine, interleukin, gefitinib, bortezomib, paclitaxel, paclitaxel without clemovir, docetaxel, epihilone B, BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, piperacixifene, ERA-923, azoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, topotecan, PTK787 / ZK 222584, VX-745, PD 184352, Rapamycin, 40-O-(2-hydroxyethyl)-Rapamycin, Tarmolis, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, Wortmannin, ZM336372, L-779,450, PEG-Fibraseline, Dabipoetin, Erythropoietin, Granulocyte Colony-Stimulating Factor, Zolendronate, Prescription Nisone, Cetuximab, Granulocyte-Macrophage Colony-Stimulating Factor, Histamine Relin, Pegylated Interferon Alpha-2a, Interferon Alpha-2a, Pegylated Interferon Alpha-2b, Interferon Alpha-2b, Azacitidine, PEG-L-Asparaginase, Lenalidomide, Gemtuzumab, Hydrocortisone, Interleukin-11, Dextromethorphan, Alemumab, All-trans Retinoic Acid, Ketoconazole, Interleukin-2, Medroxyprogesterone acetate, ImmunoglobulinsNitrogen mustard, methylprednisolone, and ibritgumomab Tiuxetan), androgens, decitabine, bexarotene, tostomomumab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium-89, caspitant, netupitane, NK-1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, fluphenazine, drocannabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, polyethylene glycol filgrastim, erythropoietin, alfa-ebertheline, dabenopril α, and mixtures thereof.

[0676] In one embodiment, the bioactive agent is selected from, but not limited to, imatinib mesylate. Dasatinib Nilotinib Bosutinib Trastuzumab Trastuzumab-DM1, Pertuzumab (Perjeta™), Lapatinib Gefitinib Erlotinib cetuximab Panitumumab Van der Thani Verafinil Vorinostat Romidesin Besarodine Alivitamin Acid Retinoic acid Carfilzomib (Kyprolis™), Prattrixa bevacizumab Ziv-Abersipu Sorafenib Sunitinib Pazopanib Regorafenib And cabozantinib (Cometriq™).

[0677] In some respects, bioactive agents are anti-inflammatory agents, chemotherapeutic agents, radiotherapy agents, other therapeutic agents, or immunosuppressants.

[0678] Suitable chemotherapeutic bioactive agents include, but are not limited to, radioactive molecules, toxins, also known as cytotoxic agents or cytotoxic agents, which include any agent harmful to cell viability, and liposomes or other vesicles containing chemotherapeutic compounds. Common anticancer drugs include vincristine. Or liposomal vincristine daunomycin or Or Dorothy Star Cytarabine (ara-C, or...) L-asparaginase Or PEG-L-asparaginase (pegasparginase or Etoposide (VP-16), Teniposide 6-Mercaptopurine (6-MP or Methotrexate, cyclophosphamide Prednisone, Dexamethasone (Decadron), Imatinib Dasatinib Nilotinib Besutinib and panatinib (Iclusig) TM ).

[0679] Examples of other suitable chemotherapeutic agents include, but are not limited to, 1-dehydrotestosterone, 5-fluorouracil decarbazine, 6-mercaptopurine, 6-thioguanine, actinomycin D, doxorubicin, interleukin, alkylating agents, allopurinol sodium, hexamethylmelamine, amifostine, anastrozole, anthraxomycin (AMC), antimitotic agents, cis-dichlorodiamineplatin(II)(DDP), diaminodichloroplatinum, anthracyclines, antibiotics, antimetabolites, asparaginase, live BCG (intravesical), betamethasone sodium phosphate and betamethasone acetate, bicalutamide, bleomycin sulfate, busulfan, calcium calcium. Leucouorin), galic acid, capecitabine, carboplatin, lomustine (CCNU), carmustine (BSNU), chlorambucil, cisplatin, cladribine, colchicine, conjugated estrogens, cyclophosphamide, cyclophosphamide, cytarabine, cytarabine, cytochalasin B, anti-cancer agent, dacarbazine, actinomycin, actinomycin (formerly known as actinomycin), daunorubicin hydrochloride, daunorubicin citrate, ditodine-dini interleukin, dexazosin, dibromomannitol, dihydroxyanthraxetine dione, docetaxel, dolasetron mesylate, doxorubicin hydrochloride, drocannabinol, Escherichia coli L-asparaginase, ipecacine, erythropoietin-α, Erwinia L-Asparaginase, Esterified Estrogen, Estradiol, Estrogenustine Sodium Phosphate, Ethidium Bromide, Ethinyl Estradiol, Etidronate, Citrororum Factor Etoposide, Etoposide Phosphate, Filgrasting, Fluorouracil, Fluconazole, Fludarabine Phosphate, Fluuracil, Flutamide, Leucovorin, Gemcitabine HCl, Glucocorticoids, Goserelin Acetate, Bacitracin D, Granisetron HCl, Hydroxyurea, Idarubicin HCl, Ifosfamide, Interferon Alpha-2b, Irinotecan HCl, Letrozole, Calcium Leucovorin, Leuprorelin Acetate, Levamisole HCl, Lidocaine, Romaine Mustard, Maytenus Alkaloids Dichloromethyldiethylamine HCl, medroxyprogesterone acetate, megestrol acetate, melphalan HCl, mercaptopurine, mesna, methotrexate, methyltestosterone, photomycin, mitomycin C, mitotane, mitoxantrone, nilumethicone, octreotide acetate, ondansetron HCl, paclitaxel, disodium pamidronate, pentostatin, pilocarpine HCl, primycin, polyphenylpropionate 20 with carmustine implant, porphyrin sodium, procaine, procarbazine HCl, propranolol, rituximab, saxaglastine, streptozotocin, tamoxifen, paclitaxel, teniposide, tenoposide;Testolactone, tetracaine, thioguanine, thiotepa, topotecan HCl, toremifene citrate, trastuzumab, retinoic acid, pentorubicin, vincristine sulfate, vincristine sulfate, and vinorelbine tartrate.

[0680] In some embodiments, the compounds of the present invention are administered in combination with chemotherapeutic agents (e.g., cytotoxic agents or other compounds that can be used to treat cancer). Examples of chemotherapeutic agents include alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodophyllotoxin, antibiotics, L-asparaginase, topoisomerase inhibitors, interferon, platinum coordination complexes, anthrone-substituted ureas, methylhydrazine derivatives, adrenocortical inhibitors, adrenocortical hormones, progestins, estrogens, antiestrogens, androgens, antiandrogens, and gonadotropin-releasing hormone analogs. Also included are 5-fluorouracil (5-FU), leucovorin (LV), erinotecan, oxaliplatin, capecitabine, paclitaxel, and docetaxel.Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide, alkyl sulfonates such as busulfan, endosulfan, and pipolesulfan, aziridines such as benzodopa, carboquinone, meturedopa, and urdopa, ethyleneimine and methylmelamine, including hexamethylmelamine, triethylene melamine, triethylene phosphoramide, triethylene thiophosphamide, and trimethylol melamine, polyacetogenins (especially bullatacin and bullatacinone), camptothecin (including its synthetic analogue topotecan), bryophytes, callystatin, CC-1065 (including its synthetic analogues adolexin, carzelin, and bizelin), cryptophycins (specifically cryptophycin 1 and cryptophycin 8), and sulphurin (…). dolastatin), duocarmycin (including synthetic analogs, KW-2189 and CB1-TM1), eleutherobin, pancratistatin, sarcodictyin, spongistatin, nitrogen mustard, such as chlorambucil, naphthiamethoxam, chlorphosphamide, estramustine, ifosfamide, dichloromethyldiethylamine, methoxymethacin hydrochloride, melphalan, neo-embezzin, benzyl mustard cholesterol, prednisamide, chlorotetraphosphamide, uracil mustard, nitrosourea, such as carmustine, chloramphenicol, formustine, roximate, nimotuzumab, and ranitidine. Nitrosourea antibiotics, such as enediyne antibiotics (e.g., galicarmycin, especially galicarmycin γll and galicarmycin Ωll (see, for example, Agnew, Chem. Inti. Ed.). Engl.33:183-186 (1994)), dynemicin, including dynein A, bisphosphonates such as clophosphonate, esperamicin, and new tumor suppressor chromophores and related chromophores enediyne antibiotic chromophores), aclacinomysins, actinomycin, autramycin, azoserine, bleomycin, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-leucine. (Amycin, including morpholine doxorubicin, cyanomorpholine doxorubicin, 2-pyrrolinoline-doxorubicin, and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, ephedrine, mitomycin (e.g., mitomycin C), mycophenolic acid, nogamycin, olivomycin, pepromycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptozotocin, streptozotocin, tuberculin, ubenimex, fenestrated statin, zorubicin, antimetabolites, such as methotrexate and 5-fluorouracil (5-FU), folic acid analogs, such as norpterin, methotrexate Pterin, trimethopterin; purine analogs such as fludarabine, 6-mercaptopurine, thioguanine, and pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmoflurane, cytarabine, dideoxyuridine, deoxyfluorouridine, enoxabin, fluorouridine; androgens such as calusterone, dromostatone propionate, cyclothiosterol, meandrosten, testolactone; antiadrenergics such as aminoglutethimide, mitotane, tralostertan; folic acid supplements such as folinic acid, glucuronolactone, and aldophosphamide. glycoside), aminolevulinic acid, emuramicin, acridine, bestrabucil, bisantrene, edatraxate, defofamine, demecolcine, diaziquone, elfomithine, elliptinium acetate, epothilone, etoglucid, gallium nitrate, hydroxyurea, lentinan, lonidainine, maytansine alkaloids such as maytansine and ansamitocins; mitoxantrone, mitoxantrone, mopidanmol, nitraerine, pentostatin, phenamet, pirarubicin, losoxantrone, podophyllinic acid acid), 2-ethylhydrazine, procarbazine Polysaccharide complexes (JHS Natural Products, Eugene, OR); razoxane, rhizomycin, sizofuran, spirogermanium, Alternaria alternifolia ketoacid, triamine, 2,2',2"-trichlorotriethylamine, trichothecene toxins (especially T-2 toxin, verracurin A, lacryma-jobi A, and anguidine), urethan, vinblastine, dacarbazine, mannitol mustard, dibromomannitol, dibromoeusine, piperobromo, gacytosine, arabinoside ("Ara-C"), cyclophosphamide, thiotepa, taxanes, for example, (Paclitaxel, Bristol-Myers Squibb Oncology, Princeton, NJ) Free of levofloxacin, albumin-engineered paclitaxel nanoparticle formulation (American Pharmaceutical Partners, Schaumberg, IL), and Docetaxel (Rhone-PoulencRorer, Antony, France), chloranbucil Gemcitabine, 6-thioguanine, mercaptopurine, methotrexate, platinum coordination complexes such as cisplatin, oxaliplatin and carboplatin, vinblastine, platinum, etoposide (VP-16), ifosfamide, mitoxantrone, vincristine, Vinorelbine, novantrone, teniposide, edatrexate, daunomycin, aminopterin, capecitabine, ibandronate, irinotecan (e.g., CPT-11), topoisomerase inhibitor RFS 2000, difluoromethylornithine (DMFO). Retinoids, such as retinoic acid, capecitabine, and any pharmaceutically acceptable salts, acids, or derivatives thereof. Two or more chemotherapeutic agents may be used in combination with the compounds of the present invention. Suitable dosing regimens for combination chemotherapy are known in the art. For example, combination dosing regimens are described in Saltz et al., Proc. Am. Soc. Clin. Oncol. 18:233a (1999) and Douillard et al., Lancet 355 (9209):1041-1047 (2000).

[0681] Other therapeutic agents that can be administered in combination with the compounds disclosed herein may include bevacizumab, sutinib, sorafenib, 2-methoxyestradiol or 2ME2, finasunate, vatalanib, vaditanib, aflibercept, voloxeximab, ilexizine (MEDI-522), cilengitide, erlotinib, cetuximab, panitumumab, gefitinib, trastuzumab, and dovir. Tinib, Figetolimumab, Asceticip, Rituximab, Alemumab, Interleukin, Atlizumab, Tocilizumab, Tarolimus, Everolimus, Lucatumumab, Dasametuzumab, HLL1, huN901-DM1, Atemod, Natalizumab, Bortezomib, Carfilzomib, Marizomib, Tanespimycin, Saquinavir Mesylate, Rito Naver, Nefinavir Mesylate, Indinavir Sulfate, Benosat, Panobinostat, Mapatumumab, Lesatumumab, Duralem, ABT-737, Olimerson, Plitidepsin, Tapimod, P276-00, Enzastaurin, Ipifarnib, Perifoxine, Imatinib, Dasatinib, Lenalidomide, Thalidomide, Simvastatin Ting, Celecoxib, Badoxifene, AZD4547, Relotumumab, Oxaliplatin, PD0332991, Ribociclib, Amebaciclib, HDM201, Fulvestrant, Exemestane, PIM447, Ruxolitinib, BGJ398, Nesetumab, Pemetrexed, and Ramucirumab (IMC-1121B).

[0682] In one implementation, another therapy is a monoclonal antibody (MAb). Some MAbs stimulate an immune response that destroys cancer cells. Similar to antibodies naturally produced by B cells, these MAbs can “coat” the surface of cancer cells, triggering the immune system to destroy them. For example, bevacizumab targets vascular endothelial growth factor (VEGF), a protein secreted by tumor cells and other cells in the tumor microenvironment that promotes tumor angiogenesis. When bound to bevacizumab, VEGF cannot interact with its cellular receptors, thus blocking the signaling that leads to new blood vessel growth. Similarly, cetuximab and panitumumab target the epidermal growth factor receptor (EGFR), and trastuzumab targets 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.

[0683] In one aspect of the invention, the bioactive agent is an immunosuppressant. The immunosuppressant may be a neurotrophin inhibitor, such as cyclosporine or ascomycin, for example, cyclosporine A. FK506 (tacrolimus), pimecrolimus, mTOR inhibitors such as rapamycin or its derivatives such as sirolimus Everolimus Tarmol, Zotamoli, Biolimus-7, Biolimus-9, Rapamycin analogues such as Desfomol, Azathioprine, Campath-1H, S1P receptor modulators such as Fingolimod or their analogues, anti-IL-8 antibodies, Mycophenolic acid or its salts, such as sodium salts, or its prodrugs, such as mycophenolate mofetil. OKT3 (ORTHOCLONE) Prednisone Buquina sodium, OKT4, T10B9.A-3A, 33B3.1, 15-deoxyspergualin, tropelimus, leflunomide CTLAI-Ig, anti-CD25, anti-IL2R, balithiba Dalizumab Imidazolidin, methotrexate, dexamethasone, ISAtx-247, SDZASM981 (pimecrolimus) ), CTLA4lg (abatacept), berazepam, LFA3lg, etanercept (Immunex) (For Sale) Adalimumab Infliximab Anti-LFA-1 antibody, nastatin Enmumab, Gavelimumab, Anti-thymocyte Immunoglobulin, Ciprizumab, Alfacillin, Pentasa, Mesalazine, Mesalazine Tablets, Codeine Phosphate, Benorilate, Fenbufen, Naproxen, Diclofenac, Etoduolic Acid and Indomethacin, Aspirin and Ibuprofen.

[0684] In some embodiments, the bioactive agent is a therapeutic agent, which is a biological agent used for cancer treatment, such as a cytokine (e.g., interferon or interleukin (e.g., IL-2)). In some embodiments, the biological agent is an anti-angiogenic agent, such as an anti-VEGF agent, such as bevacizumab. In some implementations, the biologic is an immunoglobulin-based biologic, such as a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein, or a functional fragment thereof), which agonizes a target to stimulate an anticancer response or antagonizes an antigen important for cancer. Such drugs include... (rituximab), (Dalizumab) (Bariximab) (palizumab) (Infliximab), (trastuzumab) (O-Ginotuzumab) (alemumab) (Titan-Eritumomab) (adalimumab) (Omalizumab) (Tosimomab-l-131) (Efazolidin) (Cetuximab) (bevacizumab) (Natazumab) (Tocilizumab) (panitumab) (Rabbitzium bromide) (eculizumab) (Cetuximab) (golimumab) (canalimumab) (Utetracycline) (Ophamumab) (Denozamab) (Movizumab) (Rexibakumab) (Belimumab) (Ipilimumab) (Brentuximab-Vidotine) (pertuzumab) (trastuzumab-ertatoxin conjugate, and) (Obinutuzumab). Also includes antibody-drug conjugates.

[0685] Combination therapy may include therapeutic agents as non-pharmacological treatments. For example, the compound may be administered in addition to radiation therapy, cryotherapy, hyperthermia, and / or surgical resection of tumor tissue.

[0686] In some embodiments, the first and second therapeutic agents are administered simultaneously or sequentially in any order. The first therapeutic agent may be administered immediately before or after the second therapeutic agent for 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 16 hours, up to 17 hours, up to 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.

[0687] In some embodiments, the second therapeutic agent is administered at a different dosage regimen than the compound of the present invention. For example, the second therapeutic agent may have a treatment holiday of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 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, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 days, or 14 days per treatment cycle. In some embodiments, both the first and second therapeutic agents have treatment holidays.

[0688] VII. Pharmaceutical Composition

[0689] Compounds of formula I, II, III, IV, V, VI, or VII, or pharmaceutically acceptable salts thereof, as described herein, may be administered as pure chemicals, but more typically as pharmaceutical compositions comprising an effective amount for a patient (typically a human) requiring treatment of any of the disorders described herein. Therefore, this disclosure provides pharmaceutical compositions comprising an effective amount of a compound or pharmaceutically acceptable salt and at least one pharmaceutically acceptable carrier for any of the uses described herein. The pharmaceutical composition may comprise a compound or salt as the sole active agent, or, in alternative embodiments, the compound and at least one additional active agent.

[0690] Typically, the compositions of this disclosure will be administered in a therapeutically effective amount via any acceptable method of administration. The appropriate dosage range depends on a variety of 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 for which administration is intended, and the preferences and experience of the relevant physician. A person skilled in the art of treating such diseases will be able to determine the therapeutically effective amount of the compositions of this disclosure for a given disease without extensive experimentation and relying on personal knowledge and the disclosure of this application.

[0691] In some embodiments, the pharmaceutical composition is a dosage form containing, in a unit dosage form, an active mixture of about 0.1 mg to about 2000 mg, about 10 mg to about 1000 mg, about 100 mg to about 800 mg, or about 200 mg to about 600 mg, and optionally, an additional active agent of about 0.1 mg to about 2000 mg, about 10 mg to about 1000 mg, about 100 mg to about 800 mg, or about 200 mg to about 600 mg. Examples are dosage forms having at least about 0.1, 1, 5, 10, 25, 50, 100, 200, 250, 300, 400, 500, 600, 700, or 750 mg of the active compound or a salt thereof.

[0692] In some embodiments, patients can be treated with low-dose therapy of the compounds of the present invention. For example, the pharmaceutical composition may be a dosage form comprising about 0.1 μg to about 2000 μg, about 10 μg to about 1000 μg, about 100 μg to about 800 μg, or about 200 μg to about 600 μg of the active compound. Examples are dosage forms having at least about 0.1, 1, 5, 10, 25, 50, 100, 200, 250, 300, 400, 500, 600, 700, or 750 μg of the active compound or a salt thereof.

[0693] In some implementations, the dosage range is about 0.01-100 mg / kg of patient body weight, 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... Approximately 15 mg / kg, at least approximately 20 mg / kg, at least approximately 25 mg / kg, at least approximately 30 mg / kg, at least approximately 35 mg / kg, at least approximately 40 mg / kg, at least approximately 45 mg / kg, at least approximately 50 mg / kg, at least approximately 55 mg / kg, at least approximately 60 mg / kg, at least approximately 65 mg / kg, at least approximately 70 mg / kg, at least approximately 75 mg / kg, at least approximately 80 mg / kg, at least approximately 85 mg / kg, at least approximately 90 mg / kg, at least approximately 95 mg / kg, or at least approximately 100 mg / kg.

[0694] A drug or therapeutically effective amount of the composition will be delivered to the patient. The precise effective amount varies from patient to patient and depends on species, age, the subject's body size and health condition, the nature and extent of the disorder being treated, the advice of the treating physician, and the choice of the therapeutic agent or combination of therapeutic agents for administration. The effective amount in a given situation can be determined through routine testing. For the purposes of this disclosure, the therapeutic amount in at least one dose can, for example, range from about 0.01 mg / kg to about 250 mg / kg body weight, more typically from about 0.1 mg / kg to about 10 mg / kg. Any dose may be given to the subject as desired to reduce and / or alleviate the signs, symptoms, or cause of the condition in question, or to induce any other desired biological systemic changes. When necessary, formulations with an enteric coating suitable for sustained or controlled release administration of the active ingredient can be prepared.

[0695] In some embodiments, the compounds disclosed herein or used as described are administered once daily (QD), twice daily (BID), or three times daily (TID). In some embodiments, the compounds disclosed herein or used as described are administered at least once daily 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.

[0696] In some embodiments, the compounds of the present invention are applied once, twice, three times, or four times a day.

[0697] In some embodiments, the compound of the present invention is administered orally once daily. In some embodiments, the compound of the present invention is administered orally twice daily. In some embodiments, the compound of the present invention is administered orally three times daily. In some embodiments, the compound of the present invention is administered orally four times daily.

[0698] In some embodiments, the compound of the present invention is administered intravenously once daily. In some embodiments, the compound of the present invention is administered intravenously twice daily. In some embodiments, the compound of the present invention is administered intravenously three times daily. In some embodiments, the compound of the present invention is administered intravenously four times daily.

[0699] In some embodiments, the compounds of the invention are applied, wherein there are treatment breaks between treatment cycles. For example, the compounds may have treatment breaks 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, or 13 days, or each treatment cycle may be 14 days.

[0700] The pharmaceutical composition may also include an active compound and other active agents in a molar ratio. For example, the pharmaceutical composition may contain an anti-inflammatory agent or immunosuppressant in a molar ratio of about 0.5:1, about 1:1, about 2:1, about 3:1, or about 1.5:1 to about 4:1.

[0701] These compositions may contain any amount of an active compound that achieves the desired results, such as 0.1-99 wt.% of the compound, typically at least about 5 wt.%. Some embodiments contain about 25 wt.% to about 50 wt.% or about 5 wt.% to about 75 wt.%.

[0702] Pharmaceutical formulations are preferably unit dosage forms. In this form, the formulation is subdivided into unit doses containing appropriate amounts of the active ingredient. A unit dosage form can be a packaged formulation, where the package contains discrete amounts of the formulation, such as tablets, capsules, and powders packaged in vials or ampoules. Furthermore, the unit dosage form itself can be a capsule, tablet, sachets, or lozenge, or it can be any of these packaging forms in appropriate quantities.

[0703] In some implementations, the compound is administered as a pharmaceutically acceptable salt. Non-limiting examples of pharmaceutically acceptable salts include: acetates, adipates, alginates, ascorbic acid salts, aspartates, benzenesulfonates, benzoates, hydrogen sulfates, borates, butyrates, camphorates, camphor sulfonates, citrates, cyclopentanepropionates, diglucurons, dodecyl sulfates, ethanesulfonates, fumarates, glucohepanoates, glycerophosphates, hemisulfates, heptarates, hexanoates, hydrobromide, hydrochlorides, hydroiodates, 2-hydroxyethanesulfonates, lactobionates, lactates, laurates, dodecyl sulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, dihydroxynaphthalates, pectates, persulfates, 3-phenylpropionates, phosphates, picrates, neopentanoates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, toluenesulfonates, undecanoates, and valerates. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.

[0704] Therefore, the compositions disclosed herein can be administered as pharmaceutical preparations, including for oral (including oral and sublingual), rectal, nasal, topical, transdermal, pulmonary, vaginal, or parenteral (including intramuscular, intra-arterial, intrathecal, subcutaneous, and intravenous) administration, injection, inhalation or spray, intra-aortic, intracranial, subdermal, intraperitoneal, subcutaneous, or other routes of administration containing conventionally pharmaceutically acceptable carriers. Typical routes of administration are oral, topical, or intravenous, using convenient daily dosing regimens that can be adjusted according to the severity of the ailment.

[0705] Depending on the intended method of administration, the pharmaceutical composition may be a solid, semi-solid, or liquid dosage form, such as tablets, suppositories, pills, capsules, powders, liquids, syrups, suspensions, creams, ointments, lotions, pastes, gels, sprays, aerosols, foams, or oils, injections or infusions, transdermal patches, subcutaneous patches, inhaled preparations, in medical devices, suppositories, sublingual or oral preparations, parenteral preparations, or ophthalmic solutions, preferably in a single-dose form suitable for precise dosage.

[0706] Some dosage forms, such as tablets and capsules, are subdivided into appropriately sized unit doses containing an adequate amount of the active ingredient, such as an effective amount to achieve the desired purpose. The composition will contain an effective amount of the selected drug and a pharmaceutically acceptable carrier, and may also contain other agents, adjuvants, diluents, buffers, etc.

[0707] The carrier includes excipients and diluents, and must have sufficiently high purity and low toxicity to make it suitable for administration to the treated patient. The carrier can be inert or may have its own pharmaceutical benefits. The amount of carrier used with the compound is sufficient to provide a practical amount of material for the administration of each unit dose of the compound.

[0708] The categories of carriers include, but are not limited to, adjuvants, binders, buffers, colorants, diluents, disintegrants, excipients, emulsifiers, flavoring agents, gels, glidants, lubricants, preservatives, stabilizers, surfactants, solubilizers, tablets, wetting agents, or curing materials.

[0709] Some carriers may be listed in more than one class; for example, vegetable oils may be used as lubricants in some formulations and as diluents in others.

[0710] Exemplary pharmaceutically acceptable carriers include sugars, starches, cellulose, powdered astragalus, malt, gelatin; talc, petrolatum, lanolin, polyethylene glycol, alcohol, transdermal penetration enhancers, and vegetable oils. The pharmaceutical composition may contain optional active agents that substantially do not interfere with the activity of the compounds of the present invention.

[0711] Some excipients include, but are not limited to, liquids such as water, saline, glycerol, polyethylene glycol, hyaluronic acid, ethanol, etc. Depending on the therapeutic purpose, compounds may be provided in the form of solids, liquids, spray-dried materials, microparticles, nanoparticles, controlled-release systems, etc. Excipients suitable for non-liquid formulations are also known to those skilled in the art. A detailed discussion of pharmaceutically acceptable excipients and salts is provided in Remington's Pharmaceutical Sciences, 18th edition (Easton, Pennsylvania: Mack Publishing Company, 1990).

[0712] In addition, such carriers may contain auxiliary substances, such as wetting agents or emulsifiers, biological buffers, and surfactants. Biological buffers can be any pharmacologically acceptable solution that provides the formulation with the required pH, i.e., a pH within a physiologically acceptable range. Examples of buffer solutions include saline, phosphate-buffered saline, Tris-buffered saline, and Hank-buffered saline.

[0713] For solid compositions, conventional non-toxic solid carriers include, for example, pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, etc. Liquid pharmaceutically acceptable compositions can be prepared, for example, by dissolving, dispersing, etc., the active compound described herein and optional adjuvants in an excipient, such as water, saline, aqueous glucose solution, glycerol, ethanol, etc., to form a solution or suspension. If desired, the administered pharmaceutical composition may also contain small amounts of non-toxic excipients, such as wetting agents or emulsifiers, pH buffers, etc., such as sodium acetate, sorbitol monolaurate, triethanolamine acetate sodium, triethanolamine oleate, etc. Practical methods for preparing such dosage forms are known or will be obvious to those skilled in the art; see, for example, Remington's Pharmaceutical Sciences cited above.

[0714] In another embodiment, the use of penetration enhancer excipients is provided, including polymers such as: polycationic (chitosan and its quaternary ammonium derivatives, poly-L-arginine, amination gelatin); polyanionic (N-carboxymethyl chitosan, polyacrylic acid); thiolized polymers (carboxymethyl cellulose-cysteine, polycarbofil-cysteine, chitosan-thiobutylamidine, chitosan-thioglycolic acid, chitosan-glutathione conjugate).

[0715] Pharmaceutical compositions / combinations can be formulated for oral administration. For oral administration, the compositions are typically in the form of tablets, capsules, soft capsules, or may be aqueous or non-aqueous solutions, suspensions, or syrups. Tablets and capsules are typical forms of oral administration. Orally administered tablets and capsules may include one or more commonly used carriers, such as lactose and corn starch. Lubricants, such as magnesium stearate, are often added. Typically, the compositions disclosed herein can be combined with orally available, non-toxic, pharmaceutically acceptable inert carriers, such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, etc. In addition, suitable binders, lubricants, disintegrants, and colorants may be incorporated into the mixture as needed or necessary. Suitable binders include starch, gelatin, natural sugars such as glucose or β-lactose, corn sweeteners, natural and synthetic gums such as gum arabic, astragalus gum, or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes, etc. The lubricants used in these formulations include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, and sodium chloride. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, and xanthan gum.

[0716] When using liquid suspensions, the active agent may be combined with any orally administered, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, etc., as well as emulsifiers and suspending agents. Flavoring agents, coloring agents, and / or sweeteners may also be added if desired. Other optional components for incorporation into the oral formulations described herein include, but are not limited to, preservatives, suspending agents, thickeners, etc.

[0717] For ocular delivery, the compound can be administered as needed, for example via intravitreal, intrastromal, anterior chamber, subtendon, subretinal, posterior to the eyeball, periglottally, suprachoroidal, conjunctival, subconjunctival, extrascleral, periocular, transscleral, posterior to the eyeball, posterior to the sclera, annular cornea, or lacrimal duct injection, or via mucus, mucin, or mucosal barrier, in an immediate or controlled release manner, or through a visual device.

[0718] Parenteral formulations can be prepared in conventional forms, such as liquid solutions or suspensions, solid forms suitable for dissolving or suspending in a liquid prior to injection, or emulsions. Typically, sterile injectable suspensions are formulated using suitable carriers, dispersants or wetting agents, and suspending agents according to techniques known in the art. Sterile injectable formulations can also be sterile injectable solutions or suspensions in acceptable, non-toxic parenteral diluents or solvents. Water, Ringer's solution, and isotonic sodium chloride solutions are acceptable carriers and solvents. Furthermore, sterile fixed oils, fatty esters, or polyols are commonly used as solvents or suspension media. Additionally, parenteral administration may involve the use of sustained-release or continuous-release systems to maintain a constant dose level.

[0719] Parenteral administration includes intra-articular, intravenous, intramuscular, intradermal, intraperitoneal, and subcutaneous routes, and includes aqueous and non-aqueous isotonic sterile injectable solutions (which may contain antioxidants, buffers, antibacterial agents, and solutes that make the formulation isotonic with the blood of the intended recipient), as well as aqueous and non-aqueous sterile suspensions (which include suspending agents, solubilizers, thickeners, stabilizers, and preservatives). Administration via certain parenteral routes may involve introducing the formulation of the present invention into a patient via a needle or catheter propelled by a sterile syringe or some other mechanical device such as a continuous infusion system. The formulations provided in this disclosure can be administered using syringes, pumps, or any other devices known in the art for parenteral administration.

[0720] The parenteral formulations according to this disclosure include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Examples of anhydrous solvents or carriers 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 may also contain adjuvants, such as preservatives, wetting agents, emulsifiers, and dispersants. They can be sterilized, for example, by filtration through a bacterial trap, by incorporating a sterilizing agent into the composition, by irradiating the composition, or by heating the composition. They can also be manufactured immediately before use using sterile water or some other sterile injectable medium.

[0721] A sterile injectable solution is prepared by mixing a desired amount of one or more of the disclosed compounds in a suitable solvent with various other ingredients listed above as needed, followed by filtration and sterilization. Generally, dispersions are prepared by incorporating various sterilized active ingredients into a sterile medium containing an alkaline dispersion medium and desired other ingredients from those listed above. For sterile powders used to prepare sterile injectable solutions, typical preparation methods include vacuum drying and freeze-drying techniques, which produce powders of the active ingredient and any other desired components from its previous sterile filtered solution. Thus, for example, a parenteral composition suitable for injection is prepared by stirring 1.5% by weight of the active ingredient in 10% by volume propylene glycol and water. The solution is isotonicized with sodium chloride and sterilized.

[0722] Alternatively, the pharmaceutical compositions of this disclosure can be administered in the form of suppositories for rectal use. These can be prepared by mixing the pharmaceutical agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and thus melts in the rectum to release the drug. These materials include cocoa butter, beeswax, and polyethylene glycol.

[0723] The pharmaceutical compositions disclosed herein can also be administered via nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the field of pharmaceutical formulation and can be prepared as saline solutions using benzyl alcohol or other suitable preservatives, absorption enhancers to improve bioavailability, propellants such as fluorocarbons or nitrogen, and / or other conventional solubilizers or dispersants.

[0724] Formulations for oral administration include tablets, lozenges, gels, etc. Alternatively, oral administration can be achieved using transmucosal delivery systems known to those skilled in the art. The compounds of this disclosure can also be delivered via skin or mucosal tissue using conventional transdermal drug delivery systems, i.e., transdermal “patches” (where the drug is typically contained within a layered structure that serves as a drug delivery device for attachment to a body surface). In such a structure, the drug composition is typically contained in a layer or “reservoir” beneath an upper backing layer. The lamination device may contain a single reservoir or may contain multiple reservoirs. In one embodiment, the reservoir contains a polymer matrix of a pharmaceutically acceptable contact adhesive material for securing the system to the skin during drug delivery. Examples of suitable skin contact adhesive materials include, but are not limited to, polyethylene, polysiloxane, polyisobutylene, polyacrylate, polyurethane, etc.

[0725] Alternatively, the drug-containing reservoir and skin-contact adhesive exist as separate and distinct layers, with the adhesive positioned beneath the reservoir. In this case, the reservoir can be a polymer matrix as described above, or it can be a liquid or gel reservoir, or take some other form. The backing layer in these laminates serves as the upper surface of the device, acting as a major structural element of the laminate and providing most of the device's flexibility. The material chosen for the backing layer should be substantially impermeable to the active agent and any other materials present.

[0726] The compositions disclosed herein can be formulated for aerosol administration, particularly for respiratory application and including intranasal administration. The compounds can typically have small particle sizes, for example, on the order of 5 micrometers or smaller. Such particle sizes can be obtained by methods known in the art, such as micronization. The active ingredient is provided in a pressurized package with a suitable propellant, such as a chlorofluorocarbon (CFC), such as dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. The aerosol may also conveniently contain surfactants such as lecithin. The dosage of the drug can be controlled by a metering valve.

[0727] Alternatively, the active ingredient can be provided in the form of a dry powder, such as a powder mixture of the compound in a suitable powder matrix such as lactose, starch, starch derivatives such as hydroxypropyl methylcellulose, and polyvinylpyrrolidone (PVP). The powder carrier will form a gel in the nasal cavity. The powder composition can be present in unit dose form, such as in capsules or cartridges packaged in gelatin or blister packs, and the powder can be administered from the capsules or cartridges via an inhaler.

[0728] Formulations suitable for rectal administration are typically available as unit-dose suppositories. These can be prepared by mixing the active compound with one or more conventional solid carriers, such as cocoa butter, and then molding the resulting mixture.

[0729] In some embodiments, the pharmaceutical composition is suitable for topical application to the skin using the administration methods defined above.

[0730] In some embodiments, pharmaceutical compositions suitable for transdermal administration may be present as discrete patches adapted to maintain close contact with the recipient's epidermis for extended periods. Formulations suitable for transdermal administration may also be delivered via iontophoresis (see, for example, Pharmaceutical Research 3(6):318(1986)) and are typically in the form of an optional buffered aqueous solution of the active compound.

[0731] In one embodiment, a microneedle patch or device is provided for delivering drugs through or into biological tissues, particularly the skin. The microneedle patch or device allows drugs to penetrate or enter the skin or other tissue barriers at a clinically relevant rate with minimal or no damage, pain, or irritation to the tissue.

[0732] Formulations intended for pulmonary administration can be delivered via a wide range of passively driven and actively powered single / multi-dose dry powder inhalers (DPIs). The most commonly used devices 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. The selection of a suitable pulmonary delivery device depends on parameters such as the nature of the drug and its formulation, the site of action, and the pathophysiology of the lungs.

[0733] VIII. General Synthesis

[0734] The compounds described herein can be prepared using methods known to those skilled in the art. In one non-limiting embodiment, the disclosed compounds can be prepared using the following method.

[0735] For convenience, the compounds of this invention having a stereocenter can be drawn without stereochemistry. Those skilled in the art will recognize that pure enantiomers and diastereomers can be prepared by methods known in the art. Examples of methods for obtaining optically active materials include at least the following:

[0736] i) Physical separation of crystals – a technique in which macroscopic crystals of individual enantiomers are manually separated. This technique can be used if individual enantiomers of crystals exist (i.e., the material is an aggregate) and the crystals are visually distinct;

[0737] ii) Simultaneous crystallization – a technique in which individual enantiomers are crystallized separately from a solution of a racemic compound, which is only possible when the enantiomers are solid aggregates;

[0738] iii) Enzymatic resolution - a technique in which racemic mixtures are partially or completely separated by different reaction rates of enantiomers with enzymes;

[0739] iv) Enzymatic asymmetric synthesis - a synthetic technique in which at least one synthetic step uses an enzymatic reaction to obtain a synthetic precursor of enantiomer purity or enrichment of the desired enantiomer.

[0740] v) Chemical asymmetric synthesis - a synthetic technique in which the desired enantiomer is synthesized from an achiral precursor under conditions that produce asymmetry (i.e., chirality) in the product, which can be achieved using a chiral catalyst or chiral auxiliaries.

[0741] vi) Diastereomer Separation - A technique in which a racemic compound reacts with an enantiomer-pure reagent (chiral auxiliary agent) that converts a single enantiomer into a diastereomer. The diastereomers are then separated by chromatography or crystallization, taking advantage of their now more pronounced structural differences, and the chiral auxiliary agent is subsequently removed to obtain the desired enantiomer.

[0742] vii) Primary and secondary asymmetric transformations – a technique in which diastereomers from a racemic compound rapidly equilibrate to produce diastereomers in solution primarily from the desired enantiomer, or in which preferential crystallization of diastereomers from the desired enantiomer disrupts the equilibrium such that, in principle, all material is ultimately transformed from the desired enantiomer to the crystalline diastereomer. The desired enantiomer is then released from the diastereomer.

[0743] viii) Kinetic resolution - This technique refers to the partial or complete resolution (or further resolution of partially resolved compounds) of racemates due to the different reaction rates of enantiomers with chiral, non-racemic reagents or catalysts under kinetic conditions.

[0744] ix) Enantiomer-specific synthesis from non-racemic precursors - a synthetic technique in which the desired enantiomer is obtained from an achiral starting material and the stereochemical integrity is not or only minimally impaired during the synthesis.

[0745] x) Chiral liquid chromatography – a technique in which enantiomers of racemic compounds are separated in a liquid mobile phase by means of their different interactions with a stationary phase (including vial-type chiral HPLC). The stationary phase may be made of a chiral material, or the mobile phase may contain additional chiral materials to induce different interactions;

[0746] xi) Chiral gas chromatography - a technique in which racemic compounds volatilize and enantiomers are separated according to their different interactions with a column containing a fixed non-racemic chiral adsorption phase in a gaseous mobile phase.

[0747] xii) Chiral solvent extraction - a technique in which enantiomers are separated by preferentially dissolving an enantiomer into a specific chiral solvent;

[0748] xiii) Transchiral membrane transport – a technique in which a racemic mixture is contacted with a membrane barrier. The barrier typically separates two miscible fluids, one containing the racemic mixture, and driving forces such as concentration or pressure differential cause preferential transport across the membrane barrier. Separation occurs due to the non-racemic chiral nature of the membrane, which allows only one enantiomer of the racemic mixture to pass through;

[0749] xiv) In one implementation, simulated moving bed chromatography is used. A wide variety of chiral stationary phases are available.

[0750] synthesis

[0751]

[0752]

[0753] Synthesis of cerebellar protein (CRBN) binders

[0754] Example 1: Synthesis of 3-((4-(piperidin-4-yl)phenyl)amino)piperidin-2,6-dione

[0755]

[0756] 3-((4-(piperidin-4-yl)phenyl)amino)piperidin-2,6-dione HCl salt was prepared according to the method described on page 265 of WO 2018237026A1.

[0757] Example 2: Synthesis of 3-((5-fluoro-2-methoxy-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione

[0758]

[0759] Step 1: Cesium carbonate (7.82 g, 24.00 mmol) was added to a sealed 250 mL tube containing a solution of tert-butylpiperazine-1-carboxylate (1, 4.47 g, 24.00 mmol) and 1-bromo-2-fluoro-5-methoxy-4-nitrobenzene (2, 3 g, 12.00 mmol) in anhydrous 1,4-dioxane (60 mL) under a nitrogen atmosphere and the resulting mixture was degassed by purging the reaction mixture with nitrogen for 10 minutes. Subsequently, Xantphos (694.28 mg, 1.20 mmol) and Pd2(dba)3 (549.38 mg, 0.560 mmol) were added to the reaction mixture, and the reaction mixture was heated to 100 °C for 16 hours. The reaction mixture was cooled to ambient temperature and filtered through a diatomaceous earth pad, washed with DCM (100 mL). The combined filtrates were concentrated under reduced pressure to obtain a crude residue. The crude product was purified by passing it through a rapid silica gel (230-400 mesh, 100 g) column with 0-40% EtOAc / petroleum ether to give tert-butyl 4-(2-fluoro-5-methoxy-4-nitro-phenyl)piperazine-1-carboxylate (3, 3.2 g, 8.04 mmol, 67% yield) as a yellow gel-like solid. LCMS (ES) + ):300.2[M-tBu+H] +

[0760] Step 2: Iron powder (3.52 g, 63.03 mmol) and ammonium chloride (2.41 g, 45.02 mmol) were added to a 250 mL single-necked round-bottom flask containing a well-stirred suspension of tert-butyl-4-(2-fluoro-5-methoxy-4-nitro-phenyl)piperazine-1-carboxylate (3, 3.2 g, 9.00 mmol) in EtOH (80 mL), water (40 mL), and THF (20 mL) under ambient temperature and a nitrogen atmosphere. The resulting suspension was heated to 90 °C for 2 hours, and the reaction mixture was cooled to ambient temperature. After completion, the reaction mixture was filtered through a diatomaceous earth mat and washed with EtOAc (100 mL). The combined filtrates were diluted with water (80 mL), and the product was extracted with EtOAc (2 x 100 mL). The organic phases were combined, dried (using anhydrous Na₂SO₄), filtered, and the filtrate was concentrated under reduced pressure to obtain a crude residue. The crude product was purified by passing it through a rapid silica gel column (230-400 mesh, 100 g) with 0-40% EtOAc / petroleum ether to give tert-butyl 4-(4-amino-2-fluoro-5-methoxy-phenyl)piperazine-1-carboxylate (4, 2.8 g, 8.61 mmol, yield 96%) as a yellow gel-like solid. UPLC-MS (ES) + ):326.5[M+H] +

[0761] Step 3: Under a nitrogen atmosphere at ambient temperature, sodium bicarbonate (2.17 g, 25.82 mmol) was added to a 250 mL sealed tube containing a thoroughly stirred solution of tert-butyl 4-(4-amino-2-fluoro-5-methoxy-phenyl)piperazine-1-carboxylate (4 g, 2.8 g, 8.61 mmol) and 3-bromopiperidin-2,6-dione (5 g, 2.48 g, 12.91 mmol) in anhydrous DMF (30 mL). The reaction mixture was heated to 60 °C for 24 hours and then cooled to ambient temperature. The reaction mixture was quenched with water (80 mL), and the product was extracted with EtOAc (2 x 150 mL). The organic phases were combined, dried (using anhydrous Na₂SO₄), filtered, and the filtrate was concentrated under reduced pressure to obtain a crude residue. The crude product was purified by passing it through a rapid silica gel (230-400 mesh, 100 g) column with 0-60% EtOAc / petroleum ether to give tert-butyl 4-[4-[(2,6-dioxo-3-piperidinyl)amino]-2-fluoro-5-methoxy-phenyl]piperazine-1-carboxylate (6, 3.1 g, 7.03 mmol, 82% yield) as a green solid. 1H NMR (400MHz, DMSO-d6): δ10.85(s,1H),6.63(d,J=8Hz,1H),6.56(d,J=14.4Hz,1H),5.13(d,J=6.8Hz,1H),4.30-4.24(m ,1H),3.79(s,3H),3.45(bs,4H),2.90-2.75(m,5H),2.55(m,1H),2.15(m,1H),1.98-1.85(m,1H),1.42(s,9H).LCMS(ES + ):437.6[M+H] +

[0762] Step 4: Under a nitrogen atmosphere at ambient temperature, 4M HCl (2 mL) in 1,4-dioxane was added to a well-stirred solution containing tert-butyl-4-[4-[(2,6-dioxo-3-piperidinyl)amino]-2-fluoro-5-methoxy-phenyl]piperazine-1-carboxylate (6, 100 mg, 0.229 mmol) in anhydrous DCM (3 mL). The resulting mixture was stirred at ambient temperature for 1 hour. After the initial material was complete, excess solvent was removed under reduced pressure to obtain the crude product. The crude product was washed with MTBE (10 mL) to give 3-(5-fluoro-2-methoxy-4-piperazine-1-yl-aniline)piperidine-2,6-dione hydrochloride (7, 70 mg, 0.075 mmol, yield 33%) as a light green solid. LCMS (ES) + ):337.1[M+H] +

[0763] Example 3: Synthesis of 3-((3,5-difluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione

[0764]

[0765] Step 1: K₂CO₃ (14.84 g, 107.38 mmol) was added to a solution of tert-butylpiperazine-1-carboxylate (1, 10 g, 53.69 mmol) and 1,2,3-trifluoro-5-nitrobenzene (2, 9.51 g, 53.69 mmol) in DMSO (100 mL), and the reaction mixture was stirred at 80 °C for 16 hours. The reaction mixture was poured into water, forming a large amount of yellow precipitate. The yellow solid was filtered and concentrated under vacuum to give tert-butyl-4-(2,6-difluoro-4-nitrophenyl)piperazine-1-carboxylate (3, 17 g, 41.59 mmol, 78% yield) as a yellow solid. 1¹H NMR (400MHz, chloroform-d) δ=7.78(d, J=9.6Hz, 2H), 3.61-3.51(m, 4H), 3.32(br s, 4H), 1.49(s, 9H)

[0766] Step 2: Pd / C (1.70 g, 15.95 mmol) was added to a solution of tert-butyl-4-(2,6-difluoro-4-nitrophenyl)piperazine-1-carboxylate (3, 16.97 g, 49.43 mmol) in methanol (1 L). The reaction mixture was stirred at 20 °C for 12 h under a H2 (15 Psi) atmosphere. The reaction mixture was filtered and concentrated under vacuum to give tert-butyl-4-(4-amino-2,6-difluorophenyl)piperazine-1-carboxylate (4, 15.49 g, 48.45 mmol, 98% yield) as a white solid. LCMS (ES) + ):258.1[M+H] +

[0767] Step 3: To a solution of tert-butyl 4-(4-amino-2,6-difluoro-phenyl)piperazine-1-carboxylate (4.6 g, 19.15 mmol) in dioxane (60 mL), 2,6-bis(benzyloxy)-3-bromopyridine (5.8.51 g, 22.98 mmol), Cs₂CO₃ (12.48 g, 38.30 mmol), dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphine (913 mg, 1.92 mmol), and (1E,4E)-1,5-diphenylpentanol-1,4-dien-3-one:palladium (1.75 g, 1.91 mmol) were added. The reaction mixture was stirred at 100 °C for 16 hours under a nitrogen atmosphere. The reaction mixture was extracted with ethyl acetate (300 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 10 / 1) to give tert-butyl 4-[4-[(2,6-dibenzyloxy-3-pyridyl)amino]-2,6-difluoro-phenyl]piperazine-1-carboxylate (6,7 g, 10.34 mmol, 54% yield) as a black oil. 1 ¹H NMR (400MHz, chloroform-d) δ = 7.51–7.47 (m, 1H), 7.42 (s, 2H), 7.41–7.31 (m, 8H), 6.41–6.35 (m, 2H), 5.57–5.49 (m, 1H), 5.39 (s, 2H), 5.32 (s, 2H), 3.62–3.46 (m, 4H), 3.04 (d, J = 4.4 Hz, 4H), 1.49 (s, 9H)

[0768] Step 4: Pd(OH)₂ / C (4.50 g, 32.03 mmol) was added to a solution of tert-butyl 4-[4-[(2,6-dibenzyloxy-3-pyridinyl)amino]-2,6-difluoro-phenyl]piperazine-1-carboxylate (6, 4.5 g, 7.47 mmol) in dioxane (100 mL). The reaction mixture was stirred at 35 °C for 16 h under a H₂ (15 Psi) atmosphere. The reaction mixture was filtered through a diatomaceous earth filter and washed with ethyl acetate (200 mL). The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 1 / 1) to give tert-butyl 4-[4-[(2,6-dioxo-3-piperidinyl)amino]-2,6-difluoro-phenyl]piperazine-1-carboxylate (7, 2.38 g, 5.55 mmol, 74% yield) as a blue solid.

[0769] 1 H NMR (400MHz, chloroform-d) δ = 8.21 (br s,1H),6.18(d,J=10.8Hz,2H),4.92-4.64(m,1H),4.00(dd,J=4.8,12.8Hz,1H),3.59-3.45(m,4H),3.08-2.9 7(m,4H),2.95-2.84(m,1H),2.82-2.70(m,1H),2.56-2.46(m,1H),1.90(dq,J=4.8,13.2Hz,1H),1.48(s,9H)

[0770] Step 5: Add HCl / dioxane (4M, 40.00 mL) to a solution of tert-butyl-4-[4-[(2,6-dioxo-3-piperidinyl)amino]-2,6-difluoro-phenyl]piperazine-1-carboxylate (7, 2 g, 4.71 mmol) in DCM (20 mL). Stir the reaction mixture at 25 °C for 1 hour. Concentrate the reaction mixture under vacuum to give 3-(3,5-difluoro-4-piperazine-1-yl-anilino)piperidine-2,6-dione hydrochloride (8, 1.76 g, 4.59 mmol, 97% yield) as a white solid. LCMS (ES) + ):325.2[M+H] +

[0771] Example 4: Synthesis of 3-[3-fluoro-4-(4-piperidinyl)anilino]piperidine-2,6-dione

[0772]

[0773] Step 1: A solution of 1-bromo-2-fluoro-4-nitrobenzene (1.6 g, 27.27 mmol) and tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (2.8.43 g, 27.27 mmol) in dioxane (60 mL) and water (15 mL) in a round-bottom flask was purged with argon for 10 min, followed by the addition of granular potassium carbonate (11.31 g, 81.82 mmol). The solution was purged with argon again for 20 min, followed by the addition of palladium; triphenylphosphine (1.58 g, 1.36 mmol), and the reaction was stirred at 90 °C for 16 h. After the reaction was complete, the reaction mixture was filtered through a diatomaceous earth bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, the crude product was diluted with water, and extracted with ethyl acetate (2 x 150 mL). The combined organic layers were concentrated under vacuum and purified by normal-phase column chromatography (Davisil silica gel, 5% ethyl acetate in petroleum ether) to obtain tert-butyl 4-(2-fluoro-4-nitro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (3, 5.95 g, 18.27 mmol, 67% yield), as a pale yellow solid. LC-MS (ES) + ):267.15[M-tBu+H] + .

[0774] Step 2: Palladium, 10% carbon, type 487, dried (3 g, 28.19 mmol), was added to a stirred solution of tert-butyl-4-(2-fluoro-4-nitro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (3.3 g, 9.31 mmol) in methanol (70 mL) at room temperature. The reaction mixture was stirred at this temperature under a hydrogen atmosphere for 6 hours. After completion, the reaction mixture was filtered through diatomaceous earth and concentrated under reduced pressure to give tert-butyl-4-(4-amino-2-fluoro-phenyl)piperidine-1-carboxylate (4.25 g, 5.95 mmol, 64% yield) as a purple solid, which was used directly for the next step without further purification. LC-MS (ES) + ):239.30[M-tBu+H] + .

[0775] Step 3: In a sealed tube, tert-butyl-4-(4-amino-2-fluoro-phenyl)piperidine-1-carboxylate (4, 2.5 g, 8.49 mmol) and 3-bromopiperidine-2,6-dione (5, 4.08 g, 21.23 mmol) were stirred in DMF (40 mL) for 10 minutes, followed by the addition of sodium bicarbonate (3.57 g, 42.46 mmol) and heating the reaction mixture at 60 °C for 16 hours. After completion, the reaction mixture was filtered and concentrated under vacuum. The crude product was purified by column chromatography (Devisil silica, 0-30% ethyl acetate in petroleum ether solution) to provide tert-butyl-4-[4-[(2,6-dioxo-3-piperidinyl)amino]-2-fluoro-phenyl]piperidine-1-carboxylate (6, 1.8 g, 3.64 mmol, 43% yield) as a brown solid. LC-MS (ES) - ):404.3[MH] - .

[0776] Step 4: Add HCl / dioxane (2 mL) to a solution of tert-butyl 4-(4-((2,6-dioxadiazin-3-yl)amino)-2-fluorophenyl)piperidine-1-carboxylate (6,100 mg, 246.63 μmol) in DCM (1 mL). Stir the mixture at 25 °C for 0.5 h. After completion, remove the solvent and dissolve the residue in MeCN (30 mL), adjust the pH to 7 with NaHCO3, and filter. Concentrate the filtrate under vacuum to give 3-[3-fluoro-4-(4-piperidinyl)anilino]piperidine-2,6-dione (7,75 mg, 233.34 μmol, 95% yield) as a white solid, which can be used without further purification. LC-MS (ES) + ):306.2[M+H] + .

[0777] Example 5: Synthesis of 3-(5-(piperidin-4-yl)indololin-1-yl)piperidin-2,6-dione

[0778]

[0779] Step 1: A mixture of 5-bromodihydroindole (1.3 g, 15.15 mmol), tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (2.4.68 g, 15.15 mmol), and tripotassium phosphate (2 M, 15 mL) in dioxane (40 mL) was degassed and purged three times with N2. The mixture was then stirred at 70 °C for 12 hours under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1). Tert-butyl-4-(indoline-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (3.3 g, 8.59 mmol, 58% yield) was given as a white solid. LCMS (ES) + ):301.1[M+H] +

[0780] Step 2: A solution of 3-bromopiperidin-2,6-dione (4, 2.30 g, 11.98 mmol), tert-butyl-4-(indoline-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (3, 3 g, 9.99 mmol), and sodium bicarbonate (1.68 g, 19.97 mmol, 776.82 μL) in MeCN (10 mL). After addition, the solution was stirred at 90 °C for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was poured into water (40 mL), filtered, and the filter cake was dried under reduced pressure. The filter cake was ground with MTBE (40 mL) at 25 °C for 0.5 h, filtered, and dried to give tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)indoline-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (5.3 g, 7.14 mmol, 72% yield), as a blue solid. LCMS(ES) + ):412.0[M+H] +

[0781] Step 3: Under a nitrogen atmosphere, 10 wt.% Pd / C (121.89 mg, 100.37 μmol) was added to a solution of tert-butyl 4-[1-(2,6-dioxo-3-piperidinyl)indolin-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (413 mg, 1.00 mmol). The suspension was degassed and purged three times with H2. The mixture was stirred at 30 °C for 2 hours under H2 (15 Psi). After completion, the reaction solution was filtered, and the filtrate was concentrated under vacuum to give tert-butyl 4-[1-(2,6-dioxo-3-piperidinyl)dihydroindolin-5-yl]piperidin-1-carboxylate (6,415 mg, 903.25 μmol, 90% yield) as a yellow solid, which could be used directly without further purification. LCMS (ES) +):m / z 414.2[M+H] + .

[0782] Step 4: HCl / dioxane (4.0 M, 1.21 mmol, 8 mL) was added to a solution of tert-butyl 4-(1-(2,6-dioxadiidine-3-yl)indolin-5-yl)piperidin-1-carboxylate (6, 1 g, 2.42 mmol) in DCM (10 mL). The reaction was stirred at 16 °C for 2 hours. The reaction was concentrated under reduced pressure to give 3-(5-(piperidin-4-yl)indolin-1-yl)piperidin-2,6-dione (7,840 mg, 2.35 mmol, 97% yield, hydrochloride) as a pink solid, ready for use without further purification. LCMS (ES) + ):313.9[M+H] + .

[0783] Example 6: Synthesis of 3-(5-(piperazin-1-yl)dihydroindol-1-yl)piperidine-2,6-dione

[0784]

[0785] Step 1: Added benzenesulfonyl chloride (2, 3.21 g, 18.18 mmol) was added to a mixture of 5-bromodihydroindole (1, 3 g, 15.15 mmol) and pyridine (4.79 g, 60.59 mmol, 4.90 mL) in DCM (30 mL) at 0 °C. The solution was then stirred at 15 °C for 14 hours. The reaction mixture was poured into saturated NH4Cl (50 mL) and extracted with DCM (20 mL x 2). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (SiO2, petroleum ether:EtOAc = 10:1-2:1) to give 5-bromo-1-(benzenesulfonyl)dihydroindole (3, 4.95 g, 14.64 mmol, 97% yield) as a white solid. LCMS (ES) + ):339.7[M+H] +

[0786] Step 2: Under a nitrogen atmosphere, sodium was added to a solution of tert-butylpiperazine-1-carboxylate (4, 5.94 g, 31.87 mmol), 5-bromo-1-(benzenesulfonyl)dihydroindole (3, 9.8 g, 28.98 mmol), (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one:palladium (2.65 g, 2.90 mmol), and [1-(2-diphenylphosphyl-1-naphthyl)-2-naphthyl]-diphenylphosphine (3.61 g, 5.80 mmol) in dioxane (100 mL); 2-methylprop-2-ol (5.57 g, 57.95 mmol). After addition, the solution was stirred at 100 °C for 12 hours. The reaction mixture was diluted with DCM (100 mL) and filtered through a diatomaceous earth pad, and washed with DCM (100 mL). The filtrate was washed with water (100 mL), and the organic layer was evaporated under reduced pressure to obtain the crude product. The residue was purified by column chromatography (SiO2, petroleum ether:EtOAc = 10:1-2:1) to give tert-butyl 4-(1-(benzenesulfonyl)dihydroindole-5-yl)piperazine-1-carboxylate (5, 9.8 g, 22.09 mmol, 76% yield), as a pale yellow solid. LCMS (ES) + ):444.1[M+H] +

[0787] Step 3: A sodium naphthide solution in DME was prepared by adding sodium (3.05 g, 132.56 mmol) to a mixture of naphthalene (16.99 g, 132.56 mmol, 17.65 mL) in 100 mL of DME and stirring at 15 °C for 2 hours. The above-mentioned dark green sodium naphthide solution was added dropwise to a solution of tert-butyl 4-(1-(benzenesulfonyl)indoline-5-yl)piperazine-1-carboxylate (5, 9.8 g, 22.09 mmol) in 300 mL of DME at -78 °C until a light green color persisted. The reaction was stirred at -78 °C for 0.5 hours. The reaction mixture was quenched with water (500 mL) and extracted with DCM (200 mL x 3). The combined organic layers were washed with brine (500 mL), dried over Na₂SO₄, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (SiO2, petroleum ether:EtOAc = 50:1-1:1) to give tert-butyl 4-(indoline-5-yl)piperazine-1-carboxylate (6, 4.2 g, 13.51 mmol, 61% yield) as a gray solid. LCMS (ES) + ):304.1[M+H] +

[0788] Step 4: The reaction mixture of tert-butyl 4-(indoline-5-yl)piperazine-1-carboxylate (6, 4.2 g, 13.84 mmol), 3-bromopiperidin-2,6-dione (7, 5.32 g, 27.69 mmol), sodium bicarbonate (3.49 g, 41.53 mmol), and tetrabutylammonium iodide (511.32 mg, 1.38 mmol) in MeCN (20 mL) was stirred at 95 °C for 14 hours. The mixture was then added to a mixture of water (100 mL) and MTBE (100 mL) and stirred for 1 hour. The mixture was filtered and the filter cake was vacuum dried. The residue was purified by column chromatography (SiO2, DCM:EtOAc = 100:1-2:1) to give tert-butyl 4-(1-(2,6-dioxopiridin-3-yl)indololin-5-yl)piperazine-1-carboxylate (8, 4.7 g, 11.23 mmol, 81% yield), as a gray solid. LCMS (ES) + ):415.2[M+H] +

[0789] Step 5: The reaction mixture of tert-butyl 4-(1-(2,6-dioxadiazin-3-yl)indol-5-yl)piperazine-1-carboxylate (8, 1.5 g, 3.62 mmol) in HCl / dioxane (4 M, 15 mL) was stirred at 15 °C for 4 hours. The mixture was concentrated under vacuum to obtain 3-(5-(piperazin-1-yl)dihydroindol-1-yl)piperidine-2,6-dione (9, 1.2 g, 3.08 mmol, 85% yield, HCl salt), as a gray solid. LCMS (ES) + ):314.1[M+H] + . 1 H NMR (400MHz, DMSO-d6): δ = 10.81 (s, 1H), 9.53-9.22 (m, 2H), 7.18-6.83 (m, 2H), 6.66-6.39 (m, 1H), 4.74-4.53 (m, 1H) ,3.46-3.25(m,11H),3.02-2.86(m,2H),2.82-2.72(m,1H),2.64-2.54(m,1H),2.28-2.13(m,1H),2.00-1.83(m,1H).

[0790] Example 7: Synthesis of 1-(7-fluoro-1-methyl-6-piperazin-1-yl-indazol-3-yl)hexahydropyrimidine-2,4-dione hydrochloride

[0791]

[0792] Step 1: A 250 mL sealed tube containing a well-stirred solution of 4-bromo-2,3-difluorobenzonitrile (1, 10 g, 45.87 mmol) in EtOH was added dropwise over 10 minutes to an aqueous solution of methylhydrazine (2, 12.43 g, 229.36 mmol, 85% purity). The resulting mixture was stirred at 80 °C. The reaction was complete after 12 hours. The mixture was concentrated under reduced pressure to give a crude solid. The crude solid was suspended in water (100 mL) and filtered to give 6-bromo-7-fluoro-1-methyl-indazole-3-amine (3, 10.1 g, 39.64 mmol, 86% yield) as a pale yellow solid. UPLC-MS (ES) + ):244.2[M+H] +

[0793] Step 2: Lactic acid (5.25 g, 49.54 mmol, 7.39 mL, 85% purity) was added to a 250 mL single-necked round-bottom flask containing 1,8-diazabicyclo[5.4.0]-1,6-mono-7-ene (7.54 g, 49.54 mmol, 7.39 mL). The resulting solution was stirred at ambient temperature under a nitrogen atmosphere for 20 hours. 6-Bromo-7-fluoro-1-methyl-indazole-3-amine (3, 10 g, 38.10 mmol) and ethyl propionate (4, 26.70 g, 266.73 mmol, 28.90 mL) were added to the flask at ambient temperature. The resulting suspension was heated at 85 °C for 40 hours. Ice-cold water (250 mL) was added to the mixture, and the aqueous phase was extracted with EtOAc (30 x 100 mL). The combined organic phases were washed successively with water (2 x 100 mL) and brine (100 mL), dried (with anhydrous Na₂SO₄), and then filtered. The filtrate was concentrated under reduced pressure to obtain a crude residue, which was purified by passing it through a rapid silica gel (230-400 mesh) column with 50-100% EtOAc / petroleum ether to give ethyl 3-[(6-bromo-7-fluoro-1-methyl-indazole-3-yl)amino]propionate (5, 6.9 g, 19.45 mmol, 51% yield) as a yellow solid. LC-MS (ES) + ):344.2[M+H] +

[0794] Step 3: 95% sodium cyanate (2.21 g, 33.97 mmol) was added to a sealed 250 mL tube containing a well-stirred solution of ethyl 3-[(6-bromo-7-fluoro-1-methyl-indazole-3-yl)amino]propionate (5, 6.0 g, 16.98 mmol) in ice-cold AcOH (75.10 mL) at ambient temperature. The resulting mixture was stirred at 80 °C for 40 hours. After 40 hours, the reaction was found to be complete. The reaction mixture was cooled to ambient temperature and carefully added to ice-cold water (400 mL). The aqueous layer was extracted with EtOAc (3 x 150 mL). The combined organic phases were washed successively with saturated NaHCO3 aqueous solution (500 mL) and brine (300 mL), dried (anhydrous Na2SO4), and filtered. The filtrate was concentrated under reduced pressure to give the crude compound. The crude material was purified by passing it through a rapid silica gel (230-400 mesh) column with 50-100% EtOAc / petroleum ether to provide ethyl 3-[(6-bromo-7-fluoro-1-methyl-indazole-3-yl)-carbamoyl-amino]propionate (6, 3.8 g, 9.32 mmol, 55% yield), as a light pink solid. UPLC-MS (ES) + ):387.1[M+H] +

[0795] Step 4: At ambient temperature, benzyltrimethylammonium hydroxide (1.11 g, 2.65 mmol, 40% purity) was added to a 100 mL single-necked round-bottom flask containing a well-stirred solution of ethyl 3-[(6-bromo-7-fluoro-1-methyl-indazole-3-yl)-carbamoyl-amino]propionate (6, 3.6 g, 8.83 mmol) in MECN (50 mL). The resulting mixture was stirred at ambient temperature. After 2 hours, the reaction was observed to be complete. The mixture was concentrated under reduced pressure to give a crude residue, which was suspended in water (50 mL) and filtered to give 1-(6-bromo-7-fluoro-1-methyl-indazole-3-yl)hexahydropyrimidine-2,4-dione (7, 2.4 g, 6.96 mmol, 79% yield) as a white solid. LCMS (ES) + ):341.0[M+H] +

[0796] Step 5: Cesium carbonate (2.84 g, 8.71 mmol) was added to a well-stirred solution of 1-(6-bromo-7-fluoro-1-methyl-indazol-3-yl)hexahydropyrimidine-2,4-dione (7, 1.2 g, 3.48 mmol) and tert-butylpiperazine-1-carboxylate (8, 1.30 g, 6.96 mmol) in 1,4-dioxane (75 mL), and the mixture was degassed by purging nitrogen for 5 minutes. Subsequently, Pd-PEPPSI-iHeptCl (169.25 mg, 0.174 mmol) was added, and the resulting mixture was stirred at 100 °C. The reaction was complete after 16 hours. The mixture was cooled to ambient temperature, filtered through a diatomaceous earth bed, and the bed was washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure to obtain the crude substance. The crude material was purified by passing it through a rapid silica gel (230-400 mesh) column with 50-100% EtOAc / petroleum ether to give tert-butyl 4-[3-(2,4-dioxane-1-yl)-7-fluoro-1-methyl-indazole-6-yl]piperazine-1-carboxylate (9, 1.15 g, 2.40 mmol, 69% yield) as a beige solid. LCMS (ES) + ):447.8[M+H] +

[0797] Step 6: At ambient temperature, 4M HCl (15 mL) in 1,4-dioxane was added to a 100 mL single-necked round-bottom flask containing a well-stirred solution of tert-butyl-4-[3-(2,4-dioxane-1-yl)-7-fluoro-1-methyl-indazole-6-yl]piperazine-1-carboxylate (9, 1.14 g, 2.37 mmol) in DCM (20 mL). The resulting mixture was stirred at ambient temperature for 2 hours. Excess solvent was removed under reduced pressure to provide crude material. The crude material was ground with MTBE (40 mL), and the resulting solid was filtered to give 1-(7-fluoro-1-methyl-6-piperazine-1-yl-indazole-3-yl)hexahydropyrimidine-2,4-dione hydrochloride (10, 950 mg, 2.31 mmol, 97% yield) as a beige solid. 1 H NMR (400MHz, DMSO-d6).δ10.60(s,1H),9.16(bs,2H),7.40(d,J=8.8Hz,1H),6.97(t,J=8.8Hz,1H), 4.08(s,3H),3.91(t,J=6.8Hz,2H),3.34-3.32(m,4H),3.27(m,4H),2.76(t,J=6.8Hz,2H).LCMS(ES + ):347.5[M+H] +

[0798] Example 8: Synthesis of tert-butyl 4-[4-[(2,6-dioxo-3-piperidinyl)amino]-2-fluoro-phenyl]piperazine-1-carboxylate (6), tert-butyl(S)-4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate (7) and tert-butyl(R)-4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate (8) (arbitrarily allocated configurations)

[0799]

[0800]

[0801] Step 1: Under a nitrogen atmosphere, 99% anhydrous potassium carbonate (13.03 g, 94.3 mmol) was added to a sealed 250 mL tube containing a well-stirred solution of tert-butylpiperazine-1-carboxylate (1, 14.05 g, 75.43 mmol) and 1,2-difluoro-4-nitrobenzene (2, 10 g, 62.86 mmol, 6.94 mL) in 100 mL of anhydrous DMF. The resulting mixture was stirred at 60 °C for 16 hours. The mixture was cooled to ambient temperature and carefully added to ice-cold water (400 mL). The resulting solid was filtered to provide tert-butyl-4-(2-fluoro-4-nitro-phenyl)piperazine-1-carboxylate (3, 20.3 g, 57.7 mmol, 92% yield) as a yellow solid. UPLC-MS (ES) + ):270[M-tBu+H] +

[0802] Step 2: Under ambient temperature and a nitrogen atmosphere, iron powder (4.29 g, 76.84 mmol) and ammonium chloride (4.11 g, 76.84 mmol) were subsequently added to a well-stirred suspension containing tert-butyl 4-(2-fluoro-4-nitro-phenyl)piperazine-1-carboxylate (3.5 g, 15.37 mmol) in a mixture of THF (40 mL), EtOH (40 mL), and water (30 mL). The resulting suspension was heated to 85 °C for 2 hours. The mixture was cooled to ambient temperature and filtered through a diatomaceous earth pad, then washed with DCM (400 mL). The filtrate was concentrated under reduced pressure to obtain a crude residue. The crude residue was purified by passing it through a rapid silica gel (230-400 mesh) column with 0-50% EtOAc / petroleum ether to give tert-butyl 4-(4-amino-2-fluoro-phenyl)piperazine-1-carboxylate (4, 4.4 g, 14.6 mmol, 95% yield) as a pale yellow solid. LCMS (ES) + ):296.2[M+H] +

[0803] Step 3: Under a nitrogen atmosphere, add sodium bicarbonate (3.7 g, 44.7 mmol) to a sealed 250 mL tube containing a well-stirred solution of tert-butyl 4-(4-amino-2-fluoro-phenyl)piperazine-1-carboxylate (4, 4.4 g, 14.9 mmol) and 3-bromopiperidine-2,6-dione (5, 4.29 g, 22.35 mmol) in anhydrous DMF (81.70 mL). Stir the mixture at 60 °C for 16 hours. Cool the mixture to ambient temperature. Add an additional amount of the mixture of 3-bromopiperidine-2,6-dione (5, 4.3 g, 22.3 mmol) and sodium bicarbonate (3.7 g, 44.7 mmol, 1.7 mL). Stir the mixture at 60 °C for 24 hours. Cool the mixture to ambient temperature and carefully add it to ice-cold water (100 mL). Extract the aqueous layer with DCM (2 x 300 mL). The combined organic layers were washed with brine (300 mL) and dried (using anhydrous Na₂SO₄), filtered, and concentrated under reduced pressure to obtain a crude residue. The crude product was purified by passing it through a rapid silica gel (230-400 mesh) column with 0-75% EtOAc / petroleum ether to give tert-butyl 4-[4-[(2,6-dioxo-3)-piperidinyl)amino]-2-fluoro-phenyl]piperazine-1-carboxylate (6, 4.4 g, 10.5 mmol, 70% yield) as a light green solid. LCMS (ES) + ):407.2[M+H] + . 1 H NMR (400MHz, DMSO-d6).δ10.79(s,1H),6.85(t,J=9.6Hz,1H),6.52(dd,J=14.8,2.4Hz,1H),6.43(dd,J=8.8,2Hz,1H),5 .87(d,J=7.6Hz,1H),4.30-4.24(m,1H),3.44(m,4H),2.80(m,4H),2.70(m,1H),2.60(m,1H),2.10(m,1H),1.42(s,9H).

[0804] Step 4: Tert-butyl 4-[4-[(2,6-dioxo-3-piperidinyl)amino]-2-fluoro-phenyl]piperazine-1-carboxylate (6,200 mg, enantiomeric mixture) was passed through an SFC (instrument: PIC175 column: YMC Amylose). SA (250x30) mm, 5 μm; Mobile phase: CO2: {0.1% isopropylamine in IPA: acetonitrile (1:1)} (50:50)%; Total flow rate: 100 g / min; Back pressure: 100 bar; Wavelength: 254 nm; Cycle time: 5 min) Separation; Dissolve approximately 0.210 mg of the mixture in 2.0 mL of CAN / isopropanol and inject at 700 μL / time; Combine fractions with RT = 2.62 min and concentrate under reduced pressure at 30 °C to give rapidly eluted enantiomeric tert-butyl(S)-4-(4-((2,6-dioxopiridine-3-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate (7,90 mg, 98.8% chiral purity) as a light brown solid.

[0805] The fractions at RT = 4.28 min were combined and concentrated under reduced pressure at 30 °C to give the late-eluted enantiomer - tert-butyl(R)-4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate (8,85 mg, 83% chiral purity) as a light brown solid.

[0806] Example 9: Synthesis of 3-[3-chloro-4-(4-piperidinyl)anilino]piperidine-2,6-dione

[0807]

[0808] Step 1: Under a nitrogen atmosphere, cyclopentyl(diphenyl)phosphine, dichloromethane, dichloropalladium, and iron (800 mg, 979.63 μmol) were added to a solution of 4-bromo-3-chloroaniline (1, 4.03 g, 19.52 mmol) and tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (2, 6.05 g, 19.55 mmol) in dioxane (80 mL). Then, a tripotassium aqueous solution was added. Phosphate (2 M, 20 mL) was added to the above solution. The solution was then stirred at 60 °C for 12 hours. The reaction solution was quenched with water (200 mL), and the mixture was extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na₂SO₄, and concentrated under vacuum. The residue was purified by rapid silica gel chromatography (SiO2, 20 g Silica Flash Column, 0-30% EtOAc / Petether, 40 mL / min eluent) to provide tert-butyl 4-(4-amino-2-chloro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (3, 3.18 g, 9.87 mmol, 51% yield), as a yellow oil. LCMS (ES) + ):309.4[M+H] +

[0809] Step 2: Under a nitrogen atmosphere, dioxin (607.84 mg, 2.68 mmol) was added to a solution of tert-butyl-4-(4-amino-2-chloro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (3.2 g, 6.48 mmol) in EtOAc (10 mL). The suspension was degassed and purged with H2 (3 times). The mixture was stirred for 12 hours at 25 °C under H2 (3.24 mmol). The reaction mixture was filtered, and the filtrate was concentrated under vacuum to give tert-butyl-4-(4-amino-2-chloro-phenyl)piperidine-1-carboxylate (4.1 g, 3.22 mmol, 50% yield) as a pink solid, ready for use without further purification. LCMS (ES) + ):255.1[M+H-tBu] +

[0810] Step 3: To a solution of tert-butyl 4-(4-amino-2-chlorophenyl)piperidine-1-carboxylate (4, 1.3 g, 4.18 mmol) and 3-bromopiperidine-2,6-dione (5, 1 g, 5.21 mmol) in MeCN (20 mL), TBAI (155 mg, 419.64 μmol) and NaHCO3 (1.05 g, 12.55 mmol, 488.00 μL) were added. After addition, the solution was stirred at 90 °C for 12 hours. The reaction solution was then concentrated under vacuum. The residue was purified by rapid silica gel chromatography (SiO2, 10 g rapid silica gel column, eluent 0-40% EtOAc / petroleum ether, 40 mL / min) to give tert-butyl-4-(2-chloro-4-((2,6-dioxopiridin-3-yl)amino)phenyl)piperidin-1-carboxylate (6,500 mg, 1.17 mmol, 28% yield) as a blue solid. LCMS (ES) + ):m / z 365.9[M+H] + . 1 HNMR (400MHz, DMSO-d6) δ = 10.78 (s, 1H), 7.03 (d, J = 8.8Hz, 1H), 6.70 (d, J = 2.4Hz, 1H), 6.60 (dd, J = 2.4, 8.4Hz, 1H), 4.33 (br dd,J=4.8,11.6Hz,1H),4.07(br s,1H),2.98-2.87(m,1H),2.84-2.65(m,3H),2.62-2.54(m,2H),2.43(t,J=6.4Hz,3H),1.86-1.77(m,2H),1.66(br d,J=12.4Hz,2H),1.40(s,9H)

[0811] Step 4: Add HCl (4 M, 0.5 mL) in dioxane to a solution of tert-butyl 4-(2-chloro-4-((2,6-dioxadiazin-3-yl)amino)phenyl)piperidin-1-carboxylate (50 mg, 118.51 μmol) in DCM (0.5 mL). Stir the mixture at 20 °C for 0.5 h. After completion, concentrate the reaction mixture under reduced pressure to remove the solvent. The crude product 3-[3-chloro-4-(4-piperidinyl)anilino]piperidin-2,6-dione (38 mg, 106.28 μmol, 90% yield) can be used for the next step without further purification. LCMS (ES) + ):322.1[M+H] + .

[0812] Example 10: Synthesis of 2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-methoxypiperidin-4-yl)acetic acid

[0813]

[0814]

[0815] Step 1: Tert-butyl 2-(dimethoxyphosphoryl)acetate (1a, 5.33 g, 23.78 mmol, 385.94 μL) was carefully added to a solution of NaH (60% dispersion in mineral oil) (728.86 mg, 19.02 mmol) in THF (30 mL) at -10 °C. After addition, the mixture was stirred at 0 °C for 30 min. Then, a solution of 1-benzylpiperidin-4-one (1.3 g, 15.85 mmol, 2.83 mL) in THF (10 mL) was added dropwise to the mixture, keeping the reaction temperature below 0 °C. After addition, the reaction was stirred at 20 °C for 12 h. The reaction mixture was added to NH4Cl (sat, 200 mL), diluted with EtOAc (300 mL), and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by column chromatography (SiO₂, petroleum ether:EtOAc = 20:1-10:1-8:1) to give tert-butyl 2-(1-benzylpiperidin-4-yl)acetate (2, 4.1 g, 13.84 mmol, 87% yield) as a white solid. LCMS (ES) + ):288.1[M+H] +

[0816] Step 2: Sodium methoxide (4M, 1.74 mL) was carefully added to a solution of tert-butyl-2-(1-benzylpiperidin-4-yl)acetate (2,500 mg, 1.74 mmol) in methanol (3 mL) at -10 °C, and the reaction was stirred at 20 °C for 12 hours. The reaction was quenched with Py / HOAc (2 mL), the reaction mixture was added to water (20 mL), and then extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by preparative TLC (petroleum ether:EtOAc = 2:1, Rf = 0.3) to give tert-butyl-2-(1-benzyl-4-methoxypiperidin-4-yl)acetate (3,150 mg, 469.58 μmol, 27% yield) as a yellow solid. LCMS (ES) + ):320.1[M+H] +

[0817] Step 3: Under N2, 10 wt.% Pd(OH)2 / C (50 mg, 494.39 μmol) was added to a solution of tert-butyl 2-(1-benzyl-4-methoxypiperidin-4-yl) acetate (3,150 mg, 469.58 μmol) in MeOH (5 mL). The suspension was degassed under vacuum and purged with H2. The mixture was stirred at 20 °C and H2 (15 PSI) for 12 hours. The reaction was filtered and the filtrate was concentrated under vacuum to give tert-butyl 2-(4-methoxypiperidin-4-yl) acetate (4,80 mg, 348.87 μmol, 74% yield) as a colorless oil, ready for use without further purification. LCMS (ES) + ):230.1[M+H] +

[0818] Step 4: 1,2-Difluoro-4-nitrobenzene (4a, 520.32 mg, 3.27 mmol, 361.33 μL) was added to a solution of tert-butyl 2-(1-(2-fluoro-4-nitrophenyl)-4-methoxypiperidin-4-yl)acetate (4,500 mg, 2.18 mmol) and DIEA (10.90 mmol, 1.52 mL) in CH3CN (1 mL) at 25 °C, and the mixture was stirred at 90 °C for 2 hours. The reaction was concentrated under reduced pressure to give a residue. The yellow residue was purified by column chromatography (SiO2, petroleum ether:EtOAc = 50:1-15:1-10:1) to give tert-butyl 2-(1-(2-fluoro-4-nitrophenyl)-4-methoxypiperidin-4-yl)acetate (5,320 mg, 816.51 μmol, 37% yield) as a pale yellow solid. LCMS (ES) + ):369.1[M+H] +

[0819] Step 5: Under N2, 10 wt.% Pd / C (80 mg) was added to a solution of tert-butyl 2-(1-(2-fluoro-4-nitrophenyl)-4-methoxypiperidin-4-yl acetate (5,300 mg, 814.33 μmol) in MeOH (15 mL). The suspension was degassed under vacuum and purged with H2. The mixture was stirred at H2 (15 PSI) and 20 °C for 12 hours. The reaction was filtered and concentrated under vacuum to give tert-butyl 2-(1-(4-amino-2-fluorophenyl)-4-methoxypiperidin-4-yl) acetate (6,270 mg, 797.83 μmol, 98% yield) as a brown solid, ready for use without purification. LCMS (ES) + ):339.0[M+H] +

[0820] Step 6: 3-Bromopiperidin-2,6-dione (7,229.79 mg, 1.20 mmol) was added to a solution of tert-butyl-2-(1-(4-amino-2-fluorophenyl)-4-methoxypiperidine-4-yl)acetate (6,270 mg, 797.83 μmol) and NaHCO3 (335.12 mg, 3.99 mmol) in CH3CN (3 mL) at 25 °C, and the mixture was stirred at 90 °C for 12 hours. The reaction was concentrated under reduced pressure to obtain the residue. The residue was washed with water (20 mL) and ground at 25 °C with petroleum ether:EtOAc = 6:1 (100 mL) for 20 minutes. The mixture was filtered and the filter cake was dried to give tert-butyl 2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-methoxypiperidin-4-yl)acetate (8,300 mg, 667.39 μmol, 84% yield) as a blue solid. LCMS (ES) + ):450.1[M+H] +

[0821] Step 7: HCl (12 M, 0.5 mL) was added to a solution of tert-butyl 2-(1-(4-((2,6-dioxopiridine-3-yl)amino)-2-fluorophenyl)-4-methoxypiperidine-4-yl)acetate (8,300 mg, 667.39 μmol) in DCM (2 mL). The mixture was stirred at 25 °C for 2 hours. The reaction was concentrated under reduced pressure to give 2-(1-(4-((2,6-dioxopiridine-3-yl)amino)-2-fluorophenyl)-4-methoxypiperidine-4-yl)acetic acid (9,240 mg, 558.31 μmol, 84% yield, HCl salt), a blue solid, which was ready for use without further purification. LCMS (ES) + ):394.0[M+H] + .

[0822] Example 11: Synthesis of 2-(1-(2-chloro-4-((2,6-dioxadiazin-3-yl)amino)-5-methoxyphenyl)-4-hydroxypiperidin-4-yl)acetic acid

[0823]

[0824] Step 1: To a solution of tert-butyl 2-(4-hydroxypiperidin-4-yl)acetate (1,500 mg, 2.32 mmol) in MECN (5 mL), 1-chloro-2-fluoro-4-methoxy-5-nitrobenzene (2,525.17 mg, 2.55 mmol) and N-ethyl-N-isopropyl-prop-2-amine (900.48 mg, 6.97 mmol, 1.21 mL) were added. The mixture was stirred at 90 °C for 12 hours. The residue was poured into water (10 mL), filtered, and the filter cake was concentrated under reduced pressure. The filter cake was ground with petroleum ether (20 mL) at 25 °C for 0.5 hours to give tert-butyl 2-(1-(2-chloro-5-methoxy-4-nitrophenyl)-4-hydroxypiperidin-4-yl)acetate (3,702 mg, 1.73 mmol, 75% yield) as a yellow solid. LCMS (ES) + ):401.1[M+H] +

[0825] Step 2: Ammonia, hydrochloride (373.64 mg, 6.99 mmol), and iron (390.08 mg, 6.99 mmol) were added to a solution of tert-butyl 2-(1-(2-chloro-5-methoxy-4-nitrophenyl)-4-hydroxypiperidin-4-yl) acetate (3,700 mg, 1.75 mmol) in water (1.2 mL) and ethanol (5.5 mL). The mixture was stirred at 70 °C for 12 hours. The residue was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) to give tert-butyl 2-(1-(4-amino-2-chloro-5-methoxyphenyl)-4-hydroxypiperidin-4-yl)acetate (4,633 mg, 1.67 mmol, 96% yield) as a white solid. LCMS (ES) + ):371.2[M+H] +

[0826] Step 3: Add NaHCO3 (407.72 mg, 4.85 mmol, 188.76 μL) and TBAI (119.51 mg, 323.56 μmol) to a solution of 3-bromopiperidin-2,6-dione (5,621.27 mg, 3.24 mmol), tert-butyl-2-(1,4-amino-2-chloro-5-methoxyphenyl)-4-hydroxypiperidin-4-yl) acetate (4,600 mg, 1.62 mmol) in MECN (3 mL). Stir the mixture at 90 °C for 12 hours. Concentrate the reaction mixture under reduced pressure. Pour the residue into water (20 mL) and extract with EtOAc (15 mL x 3). Wash the combined organic layers with brine (50 mL x 2), dry to Na2SO4, filter, and concentrate under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, DCM:EtOAc = 10:1-3:1) to give tert-butyl 2-(1-(2-chloro-4-((2,6-dioxopiperidin-3-yl)amino)-5-methoxyphenyl)-4-hydroxypiperidin-4-yl)acetate (6,600 mg, 1.12 mmol, 69% yield) as a blue solid. LCMS (ES) + ):482.1[M+H] +

[0827] Step 4: Hydrochloric acid (12M, 864.51 μL) was added to a solution of tert-butyl 2-(1-(2-chloro-4-((2,6-dioxopiperidin-3-yl)amino)-5-methoxyphenyl)-4-hydroxypiperidin-4-yl)acetic acid (6,500 mg, 1.04 mmol) in DCM (4 mL). The mixture was stirred at 25 °C for 2 hours. The reaction was concentrated under reduced pressure to give 2-(1-(2-chloro-4-((2,6-dioxopiperidin-3-yl)amino)-5-methoxyphenyl)-4-hydroxypiperidin-4-yl)acetic acid (7,470 mg, 813.28 μmol, 78% yield, HCl salt), a brown solid, which could be used directly without purification. LCMS (ES) + ):426.1[M+H] + .

[0828] Example 12: Synthesis of 2-[1-[4-[(2,6-dioxo-3-piperidinyl)amino]-2-fluoro-5-methoxy-phenyl]-4-hydroxy-4-piperidinyl]acetic acid

[0829]

[0830] Step 1: A solution of 5-chloro-4-fluoro-2-nitrophenol (2A, 1 g, 5.22 mmol) and dipotassium carbonate (1.80 g, 13.05 mmol) in MeCN (10 mL) was stirred for 0.5 h at 25 °C. A solution of iodomethane (3.71 g, 26.10 mmol, 1.63 mL) in MeCN (10 mL) was added. The mixture was stirred at 90 °C for 12 h. The reaction mixture was quenched by adding H2O (2 mL) at 25 °C and concentrated under reduced pressure to remove MeCN. The mixture was then diluted with H2O (10 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 5 / 1). 1-Chloro-2-fluoro-5-methoxy-4-nitrobenzene (2.1 g, 4.82 mmol, 92% yield) was given as a yellow solid. LCMS (ES) + ):206.0[M+H] +

[0831] Step 2: To a solution of tert-butyl 2-(4-hydroxy-4-piperidinyl)acetate (1,500 mg, 1.51 mmol) in MeCN (5 mL), add 1-chloro-2-fluoro-5-methoxy-4-nitrobenzene (2,341.36 mg, 1.66 mmol) and N-ethyl-N-isopropyl-propyl-2-amine (585.30 mg, 4.53 mmol, 788.82 μL). Stir the mixture at 90 °C for 4 hours. Dilute the residue with water (10 mL) and extract with EtOAc (10 mL x 3). Wash the combined organic layers with brine (30 mL), dry to Na2SO4, filter, and concentrate under reduced pressure. Purify the residue by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 4 / 1). tert-butyl 2-[1-(2-fluoro-5-methoxy-4-nitro-phenyl)-4-hydroxy-4-piperidinyl]acetate was given (3,510 mg, 1.27 mmol, 84% yield) as a yellow solid. LCMS (ES) + ):385.1[M+H] +

[0832] Step 3: Under a nitrogen atmosphere, 10 wt.% Pd / C (50 mg, 46.98 μmol) was added to a solution of tert-butyl 2-[1-(2-fluoro-5-methoxy-4-nitro-phenyl)-4-hydroxy-4-piperidinyl]acetate (3,490 mg, 1.27 mmol) in DMF (7 mL). The suspension was degassed and purged with H2 (3 times). The mixture was stirred at 25 °C for 12 hours under H2 (15 Psi). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was ground with MTBE (10 mL) at 25 °C for 0.5 min to give tert-butyl 2-[1-(4-amino-2-fluoro)-5-methoxy-phenyl)-4-hydroxy-4-piperidinyl]acetate (4,380 mg, 1.05 mmol, 82.43% yield) as a yellow solid. LCMS (ES) + ):355.3[M+H] +

[0833] Step 4: Sodium bicarbonate (263.10 mg, 3.13 mmol, 121.81 μL) was added to a solution of tert-butyl-2-[1-(4-amino-2-fluoro-5-methoxy-phenyl)-4-hydroxy-4-piperidinyl]acetate (4,370 mg, 1.04 mmol) and 3-bromopiperidin-2,6-dione (5,240.54 mg, 1.25 mmol) in MeCN (2 mL). The mixture was stirred at 90 °C for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was poured into water (5 mL), filtered, and the filter cake was concentrated under reduced pressure. The filtrate was extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The filter cake was ground with EtOAc (10 mL) at 25 °C for 0.5 hours. The residue was purified by column chromatography (SiO2, DCM:EtOAc = 10:1–3:1) to provide tert-butyl 2-[1-[4-[(2,6-dioxo-3-piperidinyl)amino]-2-fluoro-5-methoxy-phenyl]-4-hydroxy-4-piperidinyl]acetate (6,266 mg, 570.84 μmol, 55% yield) as a black solid. LCMS (ES) + ):466.2[M+H] +

[0834] Step 5: Add hydrochloric acid (12M, 200.50 μL) to a solution of tert-butyl-2-[1-[4-[(2,6-dioxo-3-piperidinyl)amino]-2-fluoro-5-methoxy-phenyl]-4-hydroxy-4-piperidinyl]acetate (6,112 mg, 240.59 μmol) in DCM (1 mL). Stir the mixture at 25 °C for 1 hour. Concentrate the reaction under reduced pressure to give 2-[1-[4-[(2,6-dioxo-3-piperidinyl)amino]-2-fluoro-5-methoxy-phenyl]-4-hydroxy-4-piperidinyl]acetic acid (7,107 mg, 230.38 μmol, 96% yield, HCl salt) as a white solid, ready for use without further purification. LCMS (ES) + ):410.3[M+H] +

[0835] Example 13: Synthesis of 2-[1-[3-(2,4-dioxanepyrimidin-1-yl)-1-methyl-indazol-6-yl]-4-hydroxy-4-piperidine]acetic acid

[0836]

[0837] Step 1: Sodium tert-butoxide (467.33 mg, 4.86 mmol) and 1,4-dioxazopyrimidine-2,4-dione (1, 1.5 g, 4.05 mmol) in DMSO (15 mL) were added at room temperature and under nitrogen. The reaction mixture was degassed with nitrogen for 5 min. Bis(tri-tert-butylphosphine)palladium(0) (414.20 mg, 810.49 μmol) was added, and the reaction mixture was stirred at 100 °C for 1 h under microwave irradiation. The reaction mixture was diluted with water (50 mL), and the aqueous phase was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by silica gel column chromatography at 60-120 nm using a 3-4% methanol-dichloromethane solution as eluent to give 1-[6-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-1-methyl-indazole-3-yl]hexahydropyrimidine-2,4-dione (3,850 mg, 1.85 mmol, 46% yield), a light brown semi-solid. LCMS (ESI+): 386.1 [M+H] + .

[0838] Step 2: Under nitrogen atmosphere, hydrochloric acid (36% w / w aqueous solution, 6.40 g, 175.53 mmol, 8 mL) was added to a solution of 1-[6-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-1-methyl-indazole-3-yl]hexahydropyrimidine-2,4-dione (3,850 mg, 2.21 mmol) in tetrahydrofuran (4 mL). The reaction mixture was stirred at room temperature for 16 hours. Saturated sodium bicarbonate aqueous solution (50 mL) was slowly added to adjust the pH to 8.0, and the product was extracted with ethyl acetate (3 x 75 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. This crude product was then ground with diethyl ether (15 mL) to give 1-[1-methyl-6-(4-oxo-1-piperidinyl)indazol-3-yl]hexahydropyrimidine-2,4-dione (4,400 mg, 1.00 mmol, yield 45%), a brown solid. LCMS (ESI+): 342.1 [M+H] + .

[0839] Step 3: Lithium (diisopropylamino) (2M solution, 2.17 mL) was added to a stirred solution of tert-butyl acetate (5,503.61 mg, 4.34 mmol, 583.56 μL) in tetrahydrofuran (25 mL) at -78 °C, and stirred for 1 hour at the same temperature. The resulting solution was then rapidly added using a syringe at -78 °C to a solution of 1-[1-methyl-6-(4-oxo-1-piperidinyl)inzol-3-yl]hexahydropyrimidine-2,4-dione (4,370 mg, 1.08 mmol) in tetrahydrofuran (25 mL). The reaction mixture was slowly heated to room temperature and stirred for 16 hours at room temperature. The reaction was terminated with saturated ammonium chloride aqueous solution (50 mL), and the product was extracted with ethyl acetate (4 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography on silica gel at 60-120 °C using acetone and petroleum ether as eluents to give tert-butyl 2-[1-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazole-6-yl]-4-hydroxy-4-piperidinyl]acetate (6, 180 mg, 374.54 μmol, yield 35%), as a light brown solid. LCMS (ESI+): 458.0 [M+H] + .

[0840] Step 4: A solution of hydrogen chloride (4.0 M in 1,4-dioxane, 4.00 g, 109.71 mmol, 5 mL) was added to a stirred solution of tert-butyl-2-[1-[3-(2,4-dioxane-1-yl)-1-methyl-indazole-6-yl]-4-hydroxy-4-piperidinyl]acetic acid (6,180 mg, 393.42 μmol) in 1,4-dioxane (0.2 mL) at 0–5 °C. The reaction mixture was stirred at room temperature for 16 hours. The solvent was removed by concentrating the reaction mixture under reduced pressure to give 2-[1-[3-(2,4-dioxane-1-yl)-1-methyl-indazole-6-yl]-4-hydroxy-4-piperidinyl]acetic acid (7,145 mg, 307.63 μmol, 78% yield, hydrochloride) as a pale yellow solid, which was ready for the next step without further purification. LCMS(ESI+): 402.2 [M+H] + .

[0841] Example 14: Synthesis of 2-[3-[4-[(2,6-dioxo-3-piperidinyl)amino]-2-fluoro-phenyl]-8-azabicyclo[3.2.1]octane-8-yl]acetic acid

[0842]

[0843] Step 1: Tert-butoxycarbonyl tert-butyl carbonate (2.03 g, 9.28 mmol, 2.13 mL) was added to the reaction mixture of compound 1 (1, 1 g, 6.19 mmol, 0.21) and DIPEA (2.00 g, 15.47 mmol, 2.69 mL) in dioxane (20 mL) and water (5 mL). The reaction mixture was stirred at 25 °C for 12 hours. The reaction mixture was poured into saturated NH4Cl (20 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (SiO2, petroleum ether: EtOAc = 50:1-10:1) to give tert-butyl 3-oxo-8-azabicyclo[3.2].1]octane-8-carboxylate (2, 1.3 g, 5.48 mmol, 89% yield) as a white solid. 1 HNMR (400MHz, CDCl3-d): δ=4.64-4.33(m,2H),2.80-2.54(m,2H),2.38-2.28(m,2H),2.15-2.03(m,2H),1.72-1.61(m,2H),1.50(s,9H).

[0844] Step 2: Under N2 at -50°C, bis(trimethylsilyl)lithium azide (1M, 6.92mL) was added dropwise to a solution of tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (2, 1.3g, 5.77mmol) in THF (25mL), and the solution was warmed to -30°C and stirred for 1 hour. A solution of [N-(trifluoromethanesulfonyloxy)anilino]trifluoromethanesulfonate (2.70g, 6.92mmol) in THF (2mL) was added dropwise at -30°C, and the resulting mixture was heated to 25°C and stirred for another 4 hours. The reaction mixture was poured into saturated NH4Cl (5mL) and extracted with EtOAc (2mL x 3). The combined organic layers were washed with brine (5mL), dried over Na2SO4, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (SiO2, petroleum ether:EtOAc = 1:0-10:1) to give tert-butyl 3-(trifluoromethanesulfonyloxy)-8-azabicyclo[3.2.1]oct-3-ene-8-carboxylate (3, 1.4 g, 3.53 mmol, 61% yield), as a white solid. LCMS (ES) + ):301.9[M+H] +

[0845] Step 3: A solution of tert-butyl 3-(trifluoromethanesulfonyloxy)-8-azabicyclo[3.2.1]oct-3-en-8-carboxylate (3, 1.4 g, 3.92 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1,3,2-dioxoborane (1.99 g, 7.84 mmol) in dioxane (20 mL) was supplemented with cyclopentyl(diphenyl)phosphine; dichloromethane, dichloropalladium ferric (159.97 mg, 195.89 μmol) and potassium acetate (769.00 mg, 7.84 mmol). The reaction mixture was stirred at 90 °C for 12 hours under N2. The reaction mixture was diluted with EtOAc (50 mL) and filtered through a diatomaceous earth mat, and washed with EtOAc (50 mL). The filtrate was washed with water (50 mL), and the organic layer was evaporated under reduced pressure to obtain the crude product. The residue was purified by column chromatography (SiO2, petroleum ether:EtOAc = 1:0-10:1) to give 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-8-azabicyclo[3.2.1]oct-3-en-8-carboxylate (4, 1.2 g, 3.22 mmol, 82% yield), as a white solid. LCMS (ES) + ):280.0[M+H-tBu] +

[0846] Step 4: Under a nitrogen atmosphere, cyclopentyl(diphenyl)phosphine dichloromethane dichloropalladium iron (121.80 mg, 149.14 μmol) was added to a solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-8-azabicyclo[3.2.1]oct-3-en-8-carboxylate (4,500 mg, 1.49 mmol), 4-bromo-3-fluoroaniline (5,283.39 mg, 1.49 mmol), and tripotassium phosphate (2 M, 1.49 mL) in dioxane (7 mL). After addition, the solution was stirred at 70 °C for 12 hours. The reaction solution was poured into water (30 mL). The aqueous solution was extracted with EtOAc (10 mL x 2), the combined organic layers were washed with brine (20 mL x 2), dried with Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether:EtOAc = 1:0-3:1) to give tert-butyl 3-(4-amino-2-fluoro-phenyl)-8-azabicyclo[3.2.1]oct-3-en-8-carboxylate (6,350 mg, 1.09 mmol, 73% yield), as a gray solid. LCMS (ES) + ):319.1[M+H] +

[0847] Step 5: Under N2, 10 wt.% Pd / C (50 mg, 1.10 mmol) was added to a mixture of tert-butyl 3-(4-amino-2-fluoro-phenyl)-8-azabicyclo[3.2.1]octane-3-en-8-carboxylate (6,350 mg, 1.10 mmol) in MeOH (5 mL). The suspension was degassed under vacuum and purged with H2 (3 times). The reaction mixture was stirred at H2 (15 psi) and 25 °C for 14 hours. The reaction mixture was filtered and the filtrate was concentrated to obtain tert-butyl 3-(4-amino-2-fluoro-phenyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (7,300 mg, 827.71 μmol, 75% yield) as a white solid. LCMS (ES) + ):321.1[M+H] +

[0848] Step 6: A mixture of tert-butyl 3-(4-amino-2-fluoro-phenyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (7,300 mg, 936.33 μmol), 3-bromopiperidin-2,6-dione (8,269.68 mg, 1.40 mmol), tetrabutylammonium iodide (34.58 mg, 93.63 μmol), and sodium bicarbonate (157.32 mg, 1.87 mmol, 72.83 μL) in MeCN (1 mL) was stirred at 90 °C for 14 hours. The reaction mixture was poured into water (5 mL) and extracted with EtOAc (2 mL x 3). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (SiO2, petroleum ether:EtOAc = 10:1-1:1) to give 3-[4-[(2,6-dioxo-3-piperidinyl)amino]-2-fluoro-phenyl]-8-azabicyclo[3.2.1]octane-8-carboxylate (9,240 mg, 521.72 μmol, 56% yield), as a gray solid. LCMS (ES) + ):321.1[M+H] + .

[0849] Step 7: A mixture of 3-[4-[(2,6-dioxo-3-piperidinyl)amino]-2-fluoro-phenyl]-8-azabicyclo[3.2.1]octane-8 carboxylate (9,240 mg, 556.20 μmol) in HCl / dioxane (4 M, 3 mL) was stirred at 25 °C for 14 hours. The reaction mixture was concentrated under vacuum to obtain 3-[4-(8-azabicyclo[3.2.1]oct-3-yl)-3-fluoro-aniline]piperidin-2,6-dione (10,200 mg, 538.27 μmol, 97% yield, HCl salt), as a gray solid. LCMS (ES) + ):321.1[M+H] + .

[0850] Step 8: The mixture of 3-[4-(8-azabicyclo[3.2.1]oct-3-yl)-3-fluoro-aniline]piperidine-2,6-dione (390 mg, 1.06 mmol, 0.21), tert-butyl-2-bromoacetate (10, 206.80 mg, 1.06 mmol, 155.49 μL) and DIPEA (411.08 mg, 3.18 mmol, 554.02 μL) in MeCN (5 mL) was stirred at 25 °C for 14 hours. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether:EtOAc = 10:1-1:1) to give tert-butyl 2-[3-[4-[(2,6-dioxo-)3-piperidinyl)amino]-2-fluoro-phenyl]-8-azabicyclo[3.2.1]oct-8-yl]acetate (11,287 mg, 630.01 μmol, 59% yield), as a pale yellow solid. LCMS (ES) + ):446.1[M+H] +

[0851] Step 9: Chlorine (12M, 355.39μL) was added to a mixture of tert-butyl-2-[3-[4-[(2,6-dioxo-3-piperidinyl)amino]-2-fluoro-phenyl]-8-azabicyclo[3.2.1]oct-8-yl]acetate (11, 190 mg, 426.46 μmol) in DCM (2 mL). The mixture was then stirred at 25 °C for 1 hour. The reaction mixture was concentrated under vacuum and then azeotropically with toluene (5 mL x 2), followed by azeotropically with toluene / THF (5 mL: 5 mL). The residue was diluted with EtOAc (10 mL), and the mixture was stirred at 25 °C for 12 hours. The reaction was filtered, and the filter cake was collected to give 2-[3-[4-[(2,6-dioxo-3-piperidinyl)amino]-2-fluoro-phenyl]-8-azabicyclo[3.2.1]octane-8-yl]acetic acid (12,166 mg, 350.80 μmol, yield 82%, HCl salt), as a gray solid. LCMS (ES) + ):390.0[M+H] + . 1 H NMR (400MHz, D2O-d6): δ=7.42-7.13(m,1H),6.72-6.61(m,2H),4.46-4.37(m,1H),4 .14-4.00(m,2H),3.92-3.82(m,2H),3.43-3.32(m,1H),2.79-2.73(m,2H),2.53(br s,2H),2.34-2.25(m,2H),2.22-2.11(m,3H),2.03-1.93(m,3H).

[0852] Example 15: Synthesis of 2-[3-[4-[(2,6-dioxo-3-piperidinyl)amino]-2-fluoro-phenyl]azacyclobutane-1-yl]acetic acid

[0853]

[0854]

[0855] Step 1: Add (2,2,2-trifluoroacetyl) 2,2,2-trifluoroacetate (6.63 g, 31.58 mmol, 4.45 mL) to a solution of 4-bromo-3-fluoroaniline (1.5 g, 26.31 mmol), TEA (5.33 g, 52.63 mmol, 7.34 mL), and DCM (20 mL) at 10 °C. Stir the mixture at 20 °C under N2 for 12 hours. Pour the reaction mixture into water (100 mL) and extract with EtOAc (150 mL x 3). Wash the combined organic layers with brine (50 mL), dry to Na2SO4, filter, and concentrate. The residue was purified by column chromatography (SiO2, petroleum ether:EtOAc = 1:0-25:1-10:1) to give N-(4-bromo-3-fluoro-phenyl)-2,2,2-trifluoroacetamide (2.6.2 g, 20.81 mmol, 79% yield) as a yellow solid. LCMS (ES) + ):288.0&286.0[M+H] +

[0856] Step 2: A solution of N-(4-bromo-3-fluoro-phenyl)-2,2,2-trifluoroacetamide (2.3 g, 10.49 mmol), tert-butyl-3-iodoazacyclobutane-1-carboxylate (3.3.27 g, 11.54 mmol), zinc (4 g, 61.17 mmol), nickel(II) glycol dimethyl ether chloride (460.92 mg, 2.10 mmol), and pyridine-2-formamidine hydrochloride (330.61 mg, 2.10 mmol) in DMAC (30 mL) was stirred at 100 °C under N2 for 4 hours. The reaction mixture was filtered, and the filtrate was poured into water (200 mL) and extracted with EtOAc (150 mL x 5). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether:EtOAc = 20:1-5:1-2:1) to give tert-butyl 3-[2-fluoro-4-[(2,2,2-trifluoroacetyl)amino]phenyl]azacyclobutane-1-carboxylate (4, 2.2 g, 5.71 mmol, 54% yield), as a yellow solid. LCMS (ES) + ):307.0[M+H-tBu]+

[0857] Step 3: A solution of tert-butyl 3-[2-fluoro-4-[(2,2,2-trifluoroacetyl)amino]phenyl]azacyclobutane-1-carboxylate (4.2 g, 5.52 mmol), K₂CO₃ (2.29 g, 16.56 mmol), and Cs₂CO₃ (1.80 g, 5.52 mmol) in MeOH (3 mL) was stirred at 60 °C under N₂ for 12 hours. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether:EtOAc = 1:0-3:1-2:1) to give tert-butyl 3-(4-amino-2-fluoro-phenyl)azacyclobutane-1-carboxylate (5, 1.5 g, 5.18 mmol, 94% yield) as a yellow solid. LCMS (ES) + ):201.1[M+H-tBu] +

[0858] Step 4: A solution of tert-butyl 3-(4-amino-2-fluoro-phenyl)azacyclobutane-1-carboxylate (5, 1.5 g, 5.63 mmol), 3-bromopiperidin-2,6-dione (6, 1.62 g, 8.45 mmol), and NaHCO3 (1.42 g, 16.90 mmol) in CH3CN (10 mL) was stirred at 90 °C under N2 for 24 hours. The reaction was filtered, and the solid was washed with water (20 mL) to obtain the crude product. The crude product was purified by column chromatography (SiO2, DCM:EtOAc = 1:0-2:1-1:1) to give tert-butyl 3-(4-((2,6-dioxoperidin-3-yl)amino)-2-fluorophenyl)azacyclobutane-1-carboxylate (7,860 mg, 2.28 mmol, 40% yield) as a blue solid. LCMS (ES) + ):322.1[M+H-tBu] +

[0859] Step 5: A solution of tert-butyl-3-[4-[(2,6-dioxo-3-piperidinyl)amino]-2-fluoro-phenyl]azacyclobutane-1-formate (7,860 mg, 2.28 mmol) and TFA (55.81 mmol, 4.30 mL) in DCM (10 mL) was stirred at 20 °C for 4 hours under N2. The reaction was concentrated under reduced pressure to obtain 3-[4-(azacyclobutane-3-yl)-3-fluoro-aniline]piperidin-2,6-dione (8,810 mg, 1.45 mmol, 64% yield, TFA salt), a blue solid, ready for use without purification. LCMS (ES)+ ):278.0[M+H] +

[0860] Step 6: Benzyl 2-bromoacetate (768.79 mg, 3.36 mmol, 526.57 μL) was added to a solution of 3-[4-(azacyclobutan-3-yl)-3-fluoroaniline]piperidine-2,6-dione (8,810 mg, 2.58 mmol, HCl salt) and TEA (12.91 mmol, 1.80 mL) in DCM (20 mL), and the mixture was stirred under N2 for 4 hours. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether:EtOAc = 1:0-2:1-1:1) to give benzyl 2-[3-[4-[(2,6-dioxo-3-piperidinyl)amino]-2-fluoro-phenyl]azacyclobutane-1-yl]acetate (9,420 mg, 908.21 μmol, yield 35%) as a blue solid. LCMS (ES) + ):426.0[M+H] +

[0861] Step 7: Under N2, add Pd(OH) to a solution of benzyl 2-[3-[4-[(2,6-dioxo-3-piperidinyl)amino]-2-fluoro-phenyl]azacyclobut-1-yl]acetate (9, 50 mg, 117.52 μmol) in EtOH (10 mL). 2 / C (12 mg, 117.52 μmol). The suspension was degassed under vacuum and purged with H2 (3 times). The mixture was then stirred at 20 °C for 4 hours under H2. The reaction was filtered and concentrated under vacuum to give 2-[3-[4-[(2,6-dioxo-3-piperidinyl)amino]-2-fluoro-phenyl]azacyclobutan-1-yl]acetic acid (10, 30 mg, 89.46 μmol, 76% yield), as a blue solid, which could be used immediately without purification. LCMS (ES) + ):336.0[M+H] + . 1H NMR (400MHz, DMSO-d6) δ = 10.80 (s, 1H), 7.41-7.32 (m, 1H), 7.24-7.17 (m, 1H), 6.56-6.44 (m, 2H), 6.20 (d,J=8.0Hz,1H),4.41-4.29(m,1H),4.22-4.08(m,2H),4.06-3.97(m,1H),3.91-3.83(m,2H),3.67(br s,2H),2.83-2.65(m,2H),2.12-2.05(m,1H),1.94-1.83(m,1H)

[0862] Example 16: Synthesis of 2-(4'-((2,6-dioxopiridine-3-yl)amino)-2'-fluoro-[1,1'-biphenyl]-4-yl)acetic acid

[0863]

[0864] Step 1: Under a nitrogen atmosphere, KOAc (2M, 1.81mL) was added to a solution of methyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron-2-yl)phenyl)acetate (1,500mg, 1.81mmol), 4-bromo-3-fluoroaniline (2,344.06mg, 1.81mmol), and Pd(dppf)Cl2 (147.87mg, 181.07μmol) in dioxane (7mL). After addition, the solution was stirred at 70°C for 12 hours. The reaction solution was poured into water (30mL). The aqueous solution was extracted with EtOAc (30mL x 3). The combined organic layers were washed with brine (50mL x 2), dried over Na2SO4, and concentrated under vacuum. The residue was purified by rapid silica gel chromatography (20 g, rapid silica gel column, 40%-50% EtOAc / petroleum ether eluent, 30 mL / min) to provide methyl 2-(4'-amino-2'-fluoro-[1,1'-biphenyl]-4-yl) acetate (3,426 mg, 1.48 mmol, 82% yield) as a white solid. 1 ¹H NMR (400 MHz, chloroform-d) δ = 7.42–7.35 (m, 2H), 7.27–7.21 (m, 2H), 7.13 (t, J = 8.8 Hz, 1H), 6.43 (dd, J = 2.4, 8.3 Hz, 1H), 6.38 (dd, J = 2.4, 12.5 Hz, 1H), 3.63 (s, 3H), 3.58 (s, 2H)

[0865] Step 2: NaHCO3 (324.01 mg, 3.86 mmol) was added to a solution of methyl 2-(4'-amino-2'-fluoro-[1,1'-biphenyl]-4-yl)acetate (3,500 mg, 1.93 mmol), 3-bromopiperidin-2,6-dione (4,555.42 mg, 2.89 mmol), and TBAI (142.46 mg, 385.69 μmol) in MeCN (0.4 mL). After addition, the solution was stirred at 90 °C for 12 hours. The reaction solution was poured into water (5 mL). The aqueous solution was extracted with EtOAc (5 mL x 3), the combined organic layers were washed with brine (10 mL x 2), dried over Na2SO4, and concentrated under vacuum. The residue was purified by rapid silica gel chromatography (12 g silica gel column, 40%-50% EtOAc / petroleum ether eluent, 20 mL / min) to provide methyl 2-(4'-((2,6-dioxopiridin-3-yl)amino)-2'-fluoro-[1,1'-biphenyl]-4-yl)acetate (5,512 mg, 1.24 mmol, 65% yield), as a white solid. LCMS (ES) + ):371.2[M+H] +

[0866] Step 3: Concentrated HCl (12M, 9.62 mL) was added to a solution of methyl 2-(4'-((2,6-dioxopiperidin-3-yl)amino)-2'-fluoro-[1,1'-biphenyl]-4-yl)acetic acid (5,481 mg, 1.30 mmol) in DCM (2 mL). After addition, the solution was stirred at 30 °C for 1 hour. The reaction solution was poured into water to obtain a suspension. The suspension was then filtered, the filter cake was washed with water (2 mL), and concentrated under vacuum to give 2-(4'-((2,6-dioxopiperidin-3-yl)amino)-2'-fluoro-[1,1'-biphenyl]-4-yl)acetic acid (6,406 mg, 1.08 mmol, 83% yield) as a white solid. 1 H NMR (400MHz, chloroform-d) δ = 12.96-11.85 (m, 1H), 10.84 (s, 1H), 7.40 (br d, J = 7.3Hz, 2H), 7.33-7.19 (m, 3H), 6.66-6.54 (m, 2H), 6.35 (br d,J=1.8Hz,1H),4.54-4.30(m,1H),3.59(s,2H),2.84-2.71(m,1H),2.60(br d,J=17.6Hz,1H),2.20-2.07(m,1H),2.00-1.83(m,1H)

[0867] Example 17: Synthesis of 2-[4-[1-(2,6-dioxo-3-piperidinyl)indoline-5-yl]-1-piperidinyl]acetic acid

[0868]

[0869] Step 1: A well-stirred solution of 5-bromodihydroindole (1, 1.0 g, 5.05 mmol) in anhydrous THF (100 mL) was treated with sodium hydride (60% dispersion in mineral oil) (1.93 g, 50.49 mmol) at 0 °C under an inert atmosphere. The reaction mixture was stirred at room temperature for 1 hour. 3-Bromopiperidin-2,6-dione (2, 3.03 g, 15.15 mmol) in THF (8 mL) was added to the reaction mixture, and the mixture was stirred at 60 °C for 16 hours. The reaction was quenched at 0 °C with NH4Cl solution (15 mL) and extracted with ethyl acetate (2 x 150 mL). The combined organic layers were concentrated and purified by column chromatography (230-400 silica gel) using 50-60% ethyl acetate in petroleum ether to give 3-(5-bromoindololin-1-yl)piperidine-2,6-dione (3,550 mg, 1.60 mmol, 32% yield) as a pale yellow solid. LCMS (ES) + ):311.0[M+H] +

[0870] Step 2: To a 25 mL pressure tube containing a well-stirred solution of 3-(5-bromoindololin-1-yl)piperidin-2,6-dione (3,300 mg, 834.52 μmol) and tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (4,516.08 mg, 1.67 mmol) in DMF (5 mL), cesium fluoride (316.92 mg, 2.09 mmol) and Pd(dppf)Cl2·CH2Cl2 (204.45 mg, 250.36 μmol) were added. The reaction mixture was degassed by purging with nitrogen for 10 minutes. The mixture was then stirred at 90 °C for 16 hours. The reaction mixture was filtered through diatomaceous earth and washed with ethyl acetate (150 mL). The filtrate was washed successively with water (100 mL) and brine (100 mL). The organic layer was dried over Na₂SO₄, filtered, concentrated, and purified by rapid silica gel column chromatography (70% EtOAc in petroleum ether) to give tert-butyl-4-[1-(2,6-dioxo-3-piperidinyl)indoline-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (5,130 mg, 301.77 μmol, 36% yield) as a brown solid. LCMS (ES+): 412.3 [M+H] +

[0871] Step 3: Add 20 wt.% carbon-supported palladium hydroxide (106.17 mg, 151.20 μmol) to a well-stirred solution of tert-butyl-4-[1-(2,6-dioxo-3-piperidinyl)indoline-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (5,130 mg, 302.40 μmol) in 1,4-dioxane (1.5 mL). Stir the suspension at room temperature under a hydrogen atmosphere for 16 hours. Filter the reaction mixture through diatomaceous earth, wash with 1,4-dioxane (150 mL), and concentrate under reduced pressure to give tert-butyl-4-[1-(2,6-dioxo-3-piperidinyl)indoline-5-yl]piperidin-1-carboxylate (6,120 mg, 275.69 μmol, 91% yield) as a brown solid. LCMS(ES+):358.2[M–tBu+H] +

[0872] Step 4: Add TFA (5.51 mmol, 424.80 μL) to a well-stirred 50 mL single-necked round-bottom flask containing tert-butyl-4-[1-(2,6-dioxo-3-piperidinyl)indoline-5-yl]piperidin-1-carboxylate (6,120 mg, 275.69 μmol) in DCM (2 mL) and stir the reaction mixture at room temperature for 2 h. After completion, concentrate the reaction mixture to dryness and wash with MTBE (25 mL) to give 3-[5-(4-piperidinyl)indoline-1-yl]piperidin-2,6-dione (7,120 mg, 255.69 μmol, 93% yield, TFA salt) as a brown solid. LCMS (ES+): 314.2 [M+H] +

[0873] Step 5: Add DIPEA (165.10 mg, 1.28 mmol, 222.51 μL) and tert-butyl-bromoacetate (8.39.87 mg, 204.39 μmol, 29.98 μL) to a 20 mL vial containing a well-stirred solution of 3-[5-(4-piperidinyl)indoline-1-yl]piperidin-2,6-dione (7, 120 mg, 255.49 μmol, TFA salt) in 1 mL of DMF at 0 °C. After 30 minutes, quench the reaction with cold water at 0 °C and extract with ethyl acetate (2 x 100 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give tert-butyl-2-[4-[1-(2,6-dioxo-3-piperidinyl)indoline-5-yl]-1-piperidinyl]acetate (9.90 mg, 178.93 μmol, 70% yield), as a brown solid. LCMS (ES+): 428.2 [M+H] +

[0874] Step 6: Add TFA (408.05 mg, 3.58 mmol, 275.71 μL) to a 25 mL single-necked round-bottom flask containing a well-stirred solution of tert-butyl 2-[4-[1-(2,6-dioxo-3)-piperidinyl)indoline-5-yl]-1-piperidinyl]acetate (9, 90 mg, 178.93 μmol) in DCM (1.5 mL) and stir the reaction mixture at ambient temperature for 3 hours. The reaction mixture was concentrated to dryness and washed with MTBE (50 mL) and purified by reversed-phase preparative HPLC [purification method: column: XSelect C18 (150x19) mm 5 μm; mobile phase A: 0.1% TFA aqueous solution; mobile phase B: MeCN] to give 2-[4-[1-(2,6-dioxo-3-piperidinyl)indoline-5-yl]-1-piperidinyl]acetic acid (10, 90 mg, 174.95 μmol, 98% yield, TFA salt), as a brown viscous solid. LCMS (ES+): 372.2 [M+H] + . 1 HNMR (400MHz, DMSO-d6): δ10.81(s,1H),6.91(s,1H),6.82(d,J=8.00Hz,1H),6.41(d,J=8.40Hz,1H),4.60-4.57(m,1H),3.4 0-3.26(m,6H),3.17(s,2H),2.94-2.79(m,2H),2.79-2.69(m,1H),2.21-2.17(m,1H),1.93-1.82(m,1H),1.81-1.71(m,4H).

[0875] Example 18: Synthesis of 1-[7-fluoro-1-methyl-6-(4-piperidinyl)indazol-3-yl]hexahydropyrimidine-2,4-dione

[0876]

[0877] Step 1: Add sodium carbonate (233.02 mg, 2.20 mmol) to a 25 mL sealed tube containing a well-stirred solution of 1-(6-bromo-7-fluoro-1-methyl-indazol-3-yl)hexahydropyrimidine solution-2,4-dione (1,250 mg, 0.732 mmol) and tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (2,226.60 mg, 0.732 mmol) in 1,4-dioxane (5 mL) and water (1 mL), and degas the mixture under nitrogen for 5 minutes. Then add Pd(dppf)Cl2·DCM (59.85 mg, 0.073 mmol), and stir the resulting mixture at 80 °C for 5 hours. The mixture was filtered through a diatomaceous earth bed, which was then washed with EtOAc (15 mL). The filtrate was washed successively with water (10 mL) and brine (10 mL), dried (with anhydrous Na₂SO₄), filtered, and concentrated under reduced pressure to give tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-7-fluoro-1-methyl-indazole-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (3,300 mg, 0.514 mmol, 70% yield), as a light brown semi-solid. LCMS (ES) + ):444.6[M+H] +

[0878] Step 2: To a 250 mL single-necked round-bottom flask containing a well-stirred solution of tert-butyl-4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-7-fluoro-1-methyl-indazole-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (3; 1.3 g, 2.58 mmol) in a mixture of EtOAc (75 mL) and MeOH (50 mL), carbon-supported palladium hydroxide, 20 wt.% 50% water (700 mg) was added, and the suspension was hydrogenated under hydrogen pressure. The reaction was stirred for 16 hours. The reaction mixture was filtered through a diatomaceous earth mat and washed with EtOAc (100 mL) and MeOH (100 mL). The combined filtrates were concentrated under reduced pressure to give tert-butyl 4-[3-(2,4-dioxane-1-yl)-7-fluoro-1-methyl-indazole-6-yl]piperidin-1-carboxylate (4; 1.1 g, 2.43 mmol, 94% yield), as a pale yellow solid. UPLC-MS (ES) + ):444.5[M+H] +

[0879] Step 3: At ambient temperature, a solution of 4M HCl in 1,4-dioxane (10 mL) was added dropwise to a well-stirred solution of tert-butyl-4-[3-(2,4-dioxane-1-yl)-7-fluoro-1-methyl-indazole-6-yl]piperidine-1-carboxylate (4, 1.1 g, 2.43 mmol) in anhydrous DCM (20 mL). The resulting mixture was stirred at ambient temperature for 3 hours. Excess solvent was removed under reduced pressure to provide a crude residue. The crude residue was ground together with MTBE (25 mL) and the precipitate was filtered to give 1-[7-fluoro-1-methyl-6-(4-piperidine)indazole-3-yl]hexahydropyrimidine-2,4-dione hydrochloride (5,940 mg, 2.42 mmol, 99% yield) as a grayish-white solid. LCMS (ES) + ):346.5[M+H] +

[0880] Example 19: Synthesis of 1-[6-(3,3-difluoro-4-piperidinyl)-5-fluoro-1-methyl-indazol-3-yl]hexahydropyrimidine-2,4-dione

[0881]

[0882]

[0883] Step 1: To a solution of 4-bromo-2,5-difluorobenzonitrile (1,40 g, 183.49 mmol) in ethanol (400 mL), methylhydrazine (40.42 g, 366.98 mmol, 40% purity) was added. The mixture was stirred at 80 °C for 12 hours. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 1 / 1) to give 6-bromo-5-fluoro-1-methyl-indazole-3-amine (2,29 g, 118.82 mmol, 65% yield) as a white solid. 1 HNMR (400MHz, DMSO-d6) δ = 7.82 (d, J = 5.6Hz, 1H), 7.63 (d, J = 8.8Hz, 1H), 5.52 (s, 2H), 3.72 (s, 3H).

[0884] Step 2: Tetrabutylammonium bromide (2.91 g, 9.01 mmol) was added to a solution of 6-bromo-5-fluoro-1-methyl-indazole-3-amine (2.22 g, 90.14 mmol) and acrylic acid (3.94 g, 135.21 mmol, 9.28 mL) in 2 M HCl aqueous solution (220 mL). The mixture was stirred at 100 °C for 12 hours. The reaction mixture was alkalized with a saturated solution of NaHCO3 to adjust the pH to 8. Then, the mixture was acidified with acetic acid to adjust the pH to 5. A white precipitate formed, which was filtered and washed with water (250 mL) to give 3-[(6-bromo-5-fluoro-1-methyl-indazole-3-yl)amino]propionic acid (4.28 g, 88.57 mmol, 98% yield) as a white solid. LCMS (ES) + ):318.2[M+H] +

[0885] Step 3: Sodium cyanate (2.47 g, 37.96 mmol, 1.31 mL) was added to a solution of 3-[(6-bromo-5-fluoro-1-methyl-indazole-3-yl)amino]propionic acid (4.6 g, 18.98 mmol) in acetic acid (60 mL). The mixture was stirred at 60 °C for 14 hours. Then, 2 M HCl aqueous solution (60 mL) was added, and the mixture was stirred at 60 °C for another 3 hours. The reaction mixture was cooled to 20 °C. A white solid precipitated out, which was filtered and washed with water (100 mL) to give 1-(6-bromo-5-fluoro-1-methyl-indazole-3-yl)hexahydropyrimidine-2,4-dione (5.3.1 g, 9.09 mmol, 48% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ = 10.62 (s, 1H), 8.17 (d, J = 5.6Hz, 1H), 7.62 (d, J = 9.2Hz, 1H), 4.00 (s, 3H), 3.92 (t, J = 6.8Hz, 2H), 2.76 (t, J = 6.8Hz, 2H).

[0886] Step 4: Initially, 1-(6-bromo-5-fluoro-1-methyl-indazol-3-yl)hexahydropyrimidine-2,4-dione (5,826.39 mg, 2.42 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1,3,2-dioxacyclopentaborane (6,676.67 mg, 2.66 mmol) were dissolved in 1,4-dioxane (14.70 mL) with potassium acetate (713.24 mg, 7.27 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II)dichloromethane complex (197.83 mg, 242.25 μmol). The mixture was heated to 90 °C for 16 hours and then treated using a standard protocol to give 1-[5-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)indazol-3-yl]hexahydropyrimidine-2,4-dione (7, 1.10 g, 2.40 mmol, 99% yield), which could be used without further purification. LCMS(ES) + ):389.5[M+H] + .

[0887] Step 5: To a solution of 1-[5-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)indazol-3-yl]hexahydropyrimidine-2,4-dione (7,350 mg, 901.60 μmol) and tert-butyl-3,3-difluoro-4-(trifluoromethylsulfonyloxy)-2,6-dihydropyridine-1-carboxylate (8,397.38 mg, 1.08 mmol) in dioxane (4.10 mL) and water (409.82 μL), cyclopentyl(diphenyl)phosphine; palladium dichlorophosphate; iron (65.97 mg, 90.16 μmol) and Na₂CO₃ (286.71 mg, 2.70 mmol) were added. The mixture was stirred at 80 °C for 3 hours under a nitrogen atmosphere. After the reaction was complete, the mixture was quenched with water and extracted with EtOAc(x2), then dried with sodium sulfate. The solution was concentrated, and the crude product was ground with ethyl acetate (30 ml) for 15 min to give tert-butyl 4-[3-(2,4-dioxane-1-pyrimidin-1-yl)-5-fluoro-1-methyl-indazole-6-yl]-3,3-difluoro-2,6-dihydropyridine-1-carboxylate (9,200 mg, 396.29 μmol, 44% yield), as a yellow solid on LCMS (ES). + ):444.2[M+H] + . 1H NMR (400MHz, CDCl3) δ = 7.74 (s, 1H), 7.40 (d, J = 8.4Hz, 1H), 7.03-6.96 (m, 1H), 5.97 (br, 1H), 4.19 (d, J = 1.2Hz,3H),4.15-4.08(m,4H),3.67(t,J=5.6Hz,2H),2.91(t,J=6.8Hz,2H),2.57(br,2H),1.53(s,9H).

[0888] Step 6: Under nitrogen atmosphere, add carbon-supported palladium hydroxide and 20 wt.% 50% water (60 mg, 427.24 μmol) to a solution of tert-butyl 4-[3-(2,4-dioxane-1-yl)-5-fluoro-1-methyl-indazole-6-yl]-3,3-difluoro-2,6-dihydropyridine-1-carboxylate (9, 180 mg, 375.43 μmol). Degas the suspension under vacuum. Stir the mixture at room temperature for 16 hours under 5 kg pressure. After completion, the reaction mixture was filtered through diatomaceous earth, washed with 300 mL of DCM containing 10% MeOH, and the filtrate was concentrated under reduced pressure to give tert-butyl 4-[3-(2,4-dioxane-1-pyrimidin-1-yl)-5-fluoro-1-methyl-indazole-6-yl]-3,3-difluoro-piperidine-1-carboxylate (10, 170 mg, 340.62 μmol, 91% yield), as a grayish-white solid. LCMS (ES) + ):426.2[M+H] + .

[0889] Step 7: Hydrogen chloride (4M in 1,4-dioxane, 99%) (800.00 mg, 21.94 mmol, 1 mL) was added to a 50 mL single-necked round-bottom flask containing a solution of tert-butyl-4-[3-(2,4-dioxane-1-yl)-5-fluoro-1-methyl-indazole-6-yl]-3,3-difluoro-piperidin-1-carboxylate (10, 70 mg, 145.39 μmol) in DCM (10 mL) at 0 °C. The resulting reaction mixture was stirred at room temperature for 1 hour. After completion, the reaction mixture was concentrated under vacuum and washed with diethyl ether to give the product 1-[6-(3,3-difluoro-4-piperidinyl)-5-fluoro-1-methyl-indazole-3-yl]hexahydropyrimidine-2,4-dione hydrochloride (11, 60 mg, 119.77 μmol, 82% yield) as a grayish-white solid. LCMS (ES) + ):382.2[M+H] + .

[0890] Example 20: Synthesis of 2-[1-[2-chloro-4-[(2,6-dioxo-3-piperidinyl)amino]phenyl]-4-hydroxy-4-piperidinyl]acetic acid

[0891]

[0892] Step 1: Potassium carbonate (10.80 g, 78.13 mmol) was added to a DMSO (50 mL) solution of tert-butyl 2-(4-hydroxy-4-piperidinyl)acetate (1, 6.17 g, 28.65 mmol) and 1,2-dichloro-4-nitrobenzene (2, 5 g, 26.04 mmol). The mixture was stirred at 110 °C for 1 hour. The reaction was cooled to 20 °C and poured into water (500 mL), and the mixture was extracted with EtOAc (200 mL x 3). The combined organic phases were washed with brine (200 x 2 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give tert-butyl 2-[1-(2-chloro-4-nitro-phenyl)-4-hydroxy-4-piperidinyl]acetate (3, 9.4 g, 22.8 mmol, 88% yield). 1 H NMR (400MHz, DMSO-d6) δ = 8.20 (d, J = 2.8Hz, 1H), 8.12 (dd, J = 2.8, 8.8Hz, 1H), 7.28 (d, J = 8.8Hz, 1H), 4.65 (s, 1H), 3.29 (br d,J=12.0Hz,2H),3.19-3.08(m,2H),2.39(s,2H),1.88-1.78(m,2H),1.76-1.67(m,2H),1.41(s,9H).

[0893] Step 2: Tert-butyl 2-[1-(2-chloro-4-nitro-phenyl)-4-hydroxy-4-piperidinyl]acetate (3, 9.4 g, 25.35 mmol) was added to a mixture of ethanol (190 mL) and water (38 mL) with ammonium chloride (4.07 g, 76.05 mmol) and iron powder (4.25 g, 76.05 mmol). The reaction mixture was stirred at 90 °C for 16 hours. After completion, the reaction mixture was filtered to remove the iron powder and concentrated. It was then poured into water (400 mL) and extracted with EtOAc (200 mL x 3). The combined organic phases were washed with brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give tert-butyl 2-[1-(4-amino-2-chloro-phenyl)-4-hydroxy-4-piperidinyl]acetate (4, 8.64 g, 22.94 mmol, 90% yield). 1H NMR (400MHz, DMSO-d6) δ = 6.88 (d, J = 8.4Hz, 1H), 6.61 (d, J = 2.4Hz, 1H), 6.47 (dd, J = 2.4, 8.4Hz, 1H), 4.96 (br s,2H),4.43(s,1H),2.89-2.80(m,2H),2.79-2.72(m,2H),2.34(s,2H),1.82-1.72(m,2H),1.68-1.60(m,2H),1.41(s,9H).

[0894] Step 3: TBAI (13 g, 9.39 mmol) and NaHCO3 (4.41 g, 56.33 mmol) were added to a stirred solution of tert-butyl-2-[1-(4-amino-2-chloro-phenyl)-4-hydroxy-4-piperidinyl]acetate (4, 6.4 g, 18.78 mmol) in acetonitrile (100 mL). After stirring for 5 minutes, 3-bromopiperidin-2,6-dione (5, 3.61 g, 18.78 mmol) was added at room temperature. After 10 minutes, the reaction temperature was raised to 90 °C, and the reaction was continued for 72 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with water (400 mL) and extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1:1) to give tert-butyl 2-[1-[2-chloro-4-[(2,6-dioxo-3-piperidinyl)amino]phenyl]-4-hydroxy-4-piperidinyl]acetylcarbamate (6, 4.0 g, 8.41 mmol, 45% yield) as a blue solid. 1 H NMR (400MHz, DMSO-d6) δ = 10.78 (s, 1H), 6.95 (d, J = 8.8Hz, 1H), 6.74 (d, J = 2.4Hz, 1H), 6.59 (d d,J=2.4,8.8Hz,1H),5.83(d,J=8.0Hz,1H),4.47(s,1H),4.32-4.25(m,1H),2.91-2.83(m,2H ),2.81-2.75(m,2H),2.74-2.68(m,1H),2.58(t,J=4.0Hz,1H),2.35(s,2H),2.11-2.03(m,1H ),1.85(dd,J=4.4,12.0Hz,1H),1.81-1.73(m,2H),1.68-1.61(m,2H),1.41(s,9H).LC-MS(ES + ):452.2[M+H] + .

[0895] Step 4: Under ambient temperature and a nitrogen atmosphere, 4M HCl (331.90 μmol, 3 mL) in 1,4-dioxane was added to a well-stirred solution of tert-butyl-2-[1-[2-chloro-4-[(2,6-dioxo-3-piperidinyl)amino]phenyl]-4-hydroxy-4-piperidinyl]acetic acid (6,150 mg, 331.90 μmol) in anhydrous DCM (2 mL). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to give 2-[1-[2-chloro-4-[(2,6-dioxo-3-piperidinyl)amino]phenyl]-4-hydroxy-4-piperidinyl]acetic acid (7,140 mg, 320.61 μmol, 97% yield, HCl salt) as a grayish-white solid. LC-MS (ES) + ):396.1[M+H] + .

[0896] Example 21: Synthesis of 2-[1-[4-[(2,6-dioxo-3-piperidinyl)amino]-2-fluoro-phenyl]-4-hydroxy-4-piperidinyl]acetic acid

[0897]

[0898] Step 1: Piperidin-4-one hydrochloride (1.20 g, 147.50 mmol) and 1,2-difluoro-4-nitrobenzene (2.26.99 g, 169.63 mmol, 18.74 mL) were added to a stirred solution of DMSO (200 mL), followed by N,N-diisopropylethylamine (147.50 mmol, 25.69 mL). The reaction was stirred at 80 °C for 16 hours. Ice-cold water was added to the reaction mixture, and the solid was filtered through a Buchner funnel. Drying gave 1-(2-fluoro-4-nitro-phenyl)piperidin-4-one (3.28 g, 115.66 mmol, 78% yield). LC-MS (ES) was then performed. - ):237.1[MH] - .

[0899] Step 2: At -78°C, lithium diisopropylamino (13.49 g, 125.94 mmol) was added to a stirred solution of tert-butyl acetate (4, 7.31 g, 62.97 mmol, 8.47 mL) in THF. The mixture was stirred for 1 hour, then 1-(2-fluoro-4-nitro-phenyl)piperidin-4-one (3, 15 g, 62.97 mmol) was added and the reaction was stirred for 2 hours. After completion, the reaction mixture was quenched with saturated ammonium chloride solution, and the product was extracted with ethyl acetate (2 x 200 mL) and concentrated to give a crude product. The crude product was purified by rapid column chromatography (silica gel, 40% ethyl acetate in petroleum ether solution) to give tert-butyl-2-[1-(2-fluoro-4-nitro-phenyl)-4-hydroxy-4-piperidinyl]acetate (5, 17.6 g, 43.71 mmol, 69% yield) as a viscous brown liquid. LC-MS (ES) + ):355.2[M+H] + .

[0900] Step 3: 10% palladium on carbon, type 487, dried (15 g, 140.95 mmol), was added to tert-butyl-2-[1-(2-fluoro-4-nitro-phenyl)-4-hydroxy-4-piperidinyl]acetate (5, 17.6 g, 49.67 mmol) in a stirred solution of ethanol (200 mL). The reaction was carried out at room temperature under a hydrogen atmosphere for 5 hours. After completion, the reaction mixture was concentrated and the crude product was purified by rapid column chromatography (silica gel, 45% ethyl acetate in petroleum ether solution) to give tert-butyl-2-[1-(4-)amino-2-fluoro-phenyl)-4-hydroxy-4-piperidinyl]acetate (6, 13 g, 38.99 mmol, 79% yield). LC-MS (ES) + ):325.2[M+H] + .

[0901] Step 4: Sodium bicarbonate (6.73 g, 80.15 mmol) was added to a stirred solution of tert-butyl-2-[1-(4-amino-2-fluoro-phenyl)-4-hydroxy-4-piperidinyl]acetate (6.13 g, 40.08 mmol) and 3-bromopiperidin-2,6-dione (7.15.39 g, 80.15 mmol) in 100 mL of DMF. The reaction was carried out overnight at 65 °C. After the reaction was complete, the product was extracted with ethyl acetate and water. The extracted organic layer was dried over anhydrous sodium sulfate and concentrated to obtain a crude product, which was then subjected to rapid column chromatography (silica gel, petroleum ether solution of 45% ethyl acetate) to give tert-butyl-2-[1-[4-[(2,6-dioxo-3-piperidinyl)amino]-2-fluoro-phenyl]-4-hydroxy-4-piperidinyl]acetate (8.11.5 g, 65% yield). LC-MS (ES) was then performed. + ):436.2[M+H]+ .

[0902] Step 5: At 0 °C, a solution of hydrogen chloride in 1,4-dioxane, 99% (4 M, 4.72 mL) of tert-butyl-2-[1-[4-[(2,6-dioxo-3-piperidinyl)amino]-2-fluoro-phenyl]-4-hydroxy-4-piperidinyl]acetic acid (8,411 mg, 943.77 μmol) was added dropwise to a stirred solution of tert-butyl-2-[1-[4-[(2,6-dioxo-3-piperidinyl)amino]-2-fluoro-phenyl]-4-hydroxy-4-piperidinyl]acetic acid (9,365 mg, 789.96 μmol, 84% yield, HCl salt) was added dropwise to a stirred solution of tert-butyl-2-[1-[4-[(2,6-dioxo-3-piperidinyl)amino]-2-fluoro-phenyl]-4-hydroxy-4-piperidinyl]acetic acid. LC-MS (ES) + ):380.3[M+H] + .

[0903] Example 22: Synthesis of 2-(1-(2-(difluoromethyl)-4-((2,6-dioxopiperidin-3-yl)amino)phenyl)-4-hydroxypiperidin-4-yl)acetic acid

[0904]

[0905] Step 1: Under a nitrogen atmosphere, N,N-diisopropylethylamine (88.50 mmol, 15.41 mL) was added to a 250 mL sealed tube containing a well-stirred solution of piperidine-4-one hydrochloride (1.3 g, 22.13 mmol) and 2-(difluoromethyl)-1-fluoro-4-nitrobenzene (2.423 g, 22.13 mmol) in anhydrous DMSO (30 mL). The resulting mixture was heated at 80 °C for 5 hours. After completion, the reaction mixture was poured into ice-cold water, and a solid precipitated. The solid was filtered and dried to give 1-(2-(difluoromethyl)-4-nitrophenyl)piperidine-4-one (3.47 g, 16.32 mmol, 74% yield) as a yellow solid. LC-MS (ES) - ):269.0[MH] - .

[0906] Step 2: Under a nitrogen atmosphere at -78°C, a solution of 2M diisopropylaminolithium in THF (2.79 g, 26.09 mmol, 13 mL) was added dropwise over 10 minutes to a well-stirred (30 mL) solution of tert-butyl acetate (2.42 g, 20.87 mmol, 2.81 mL) in anhydrous THF. The resulting suspension was further stirred at -78°C for 1 hour. Then, a freshly prepared solution of 1-(2-(difluoromethyl)-4-nitrophenyl)piperidin-4-one (3, 4.7 g, 17.39 mmol) in anhydrous THF (20 mL) was added dropwise to the reaction mixture (while maintaining -78°C) and stirring was continued for 3 hours. After completion, the reaction mixture was allowed to reach room temperature, and excess reagent was quenched with saturated ammonium chloride solution. The organic layer was separated, and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (100 mL) and concentrated under reduced pressure. The crude residue was purified by passing it through a rapid silica gel (230-400 mesh) column with 0-40% EtOAc / petroleum ether to give tert-butyl 2-(1-(2-(difluoromethyl)-4-nitrophenyl)-4-hydroxypiperidin-4-yl)acetate (4, 4.55 g, 11.26 mmol, 65% yield). LC-MS (ES) + ):387.2[M+H] + .

[0907] Step 3: Under ambient temperature and a nitrogen atmosphere, 10% carbon-supported palladium was added to a well-stirred 250 mL single-necked round-bottom flask containing a thoroughly stirred solution of tert-butyl 2-[1-[2-(difluoromethyl)-4-addonitrophenyl]-4-hydroxy-4-piperidinyl]acetate (4, 4.1 g, 10.61 mmol) in EtOAc (40 mL), and dried (1.58 g, 14.86 mmol). The resulting suspension was stirred for 6 hours at ambient temperature under a hydrogen atmosphere (gas chamber). After completion, the reaction mixture was filtered through a diatomaceous earth pad and washed with EtOAc (100 mL). The filtrate was concentrated under reduced pressure to produce tert-butyl 2-(1-(4-amino-2-(difluoromethyl)phenyl)-4-hydroxypiperidin-4-yl)acetate (5, 3.5 g, 9.40 mmol, 89% yield). LC-MS (ES) + ):357.2[M+H] + .

[0908] Step 4: Under a nitrogen atmosphere and at room temperature, add (35 mL) sodium bicarbonate (1.60 g, 19.08 mmol) to a 100 mL sealed tube containing a well-stirred solution of tert-butyl-2-[1-[4-amino-2-(difluoromethyl)phenyl]-4-hydroxy-4-piperidinyl]acetate (5, 3.4 g, 9.54 mmol) and 3-bromopiperidin-2,6-dione (6, 2.75 g, 14.31 mmol) in anhydrous DMF. Heat the resulting suspension at 60 °C for 16 hours. After this, allow the reaction mixture to reach room temperature and add water (30 mL). Extract the aqueous phase with EtOAc (2 x 100 mL). Combine the organic phases, dry (to anhydrous Na₂SO₄), filter, and concentrate the filtrate under reduced pressure to obtain a crude residue. Pass the crude residue through a rapid silica gel column (230-400 mesh; 100 g SNAP) with 60%... Purified with EtOAc / petroleum ether, tert-butyl 2-[1-[2-(difluoromethyl)-4-[(2,6-dioxo-3-piperidinyl)amino]phenyl]-4-hydroxy-4-piperidinyl]acetate (7, 3.3 g, 6.78 mmol, 71% yield). LC-MS (ES) + ):468.2[M+H] + .

[0909] Step 5: Under a nitrogen atmosphere and at 0°C, add 4M HCl (8.6 mL) to a well-stirred solution of tert-butyl 2-[1-[2-(difluoromethyl)-4-[(2,6-dioxo-3-piperidinyl)amino]phenyl]-4-hydroxy-4-piperidinyl]acetate (7, 3.2 g, 6.84 mmol) in anhydrous DCM (30 mL). Stir the resulting mixture under a nitrogen atmosphere at ambient temperature for 8 hours. After the reaction is complete, remove excess solvent from the reaction mixture to obtain a crude product. Grind the crude product with Et2O (30 mL) to give 2-[1-[2-(difluoromethyl)-4-[(2,6-dioxo-3-piperidinyl)amino]phenyl]-4-hydroxy-4-piperidinyl]acetate (8; 3.11 g, 6.61 mmol, 97% yield, HCl salt), as a grayish-white solid. LC-MS(ES + ):412.0[M+H] + .

[0910] Example 23: Synthesis of 2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-1-yl)acetic acid

[0911]

[0912]

[0913] Step 1: Anhydrous tripotassium phosphate (28.95 g, 136.37 mmol) was added to a well-stirred solution of tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (2, 21.08 g, 68.18 mmol) and 1-bromo-2-fluoro-4-nitrobenzene (1, 10.0 g, 45.46 mmol) in 1,4-dioxane (100 mL). The resulting mixture was purged with nitrogen for 15 min. Subsequently, a complex of 1,1'-bis(dipheny...

Claims

1. A compound of the following formula: Or its pharmaceutically acceptable salt; wherein X 3 X 4 X 5 and X 6 Selected from: CR 3 ; X 7 It is N or CH; Q 1 It is NH-, -N(C1-C4 alkyl)-, -CH2- or -O-, wherein if X 7 If it's N, then Q 1 It is CH2; R 1a R 1b and R 1c Each is hydrogen; R 1d It is hydrogen or C1-C4 alkyl; R 3 Each time it appears, it is independently selected from the group consisting of: hydrogen, C1-C4 alkoxy, C1-C4 alkyl, C1-C4 haloalkyl, fluorine, chlorine, and bromine; RET targeting ligands are selected from It is a 5- or 6-membered heteroaryl or phenyl group containing one or two nitrogen atoms, wherein Directly bonded to the connector and X 8 It is N or CH; X 9 It is NR 4 CR 4 R 11 Or O; X 10 X 11 X 12 and X 13 Choose from the following groups: N and CH, where X 10 X 11 X 12 X 13 No more than two of them are N; X 14 It is CR 27 Or N; R 27 R 28 and R 29 It is hydrogen; Each R 4 Independently selected from the group consisting of: hydrogen, C1-C4 alkyl, heteroaryl, phenyl, heterocyclic, -C1-C4 alkyl-heteroaryl, -C1-C4 alkyl-phenyl, -C1-C4 alkyl-heterocyclic, -C(O)R 5 or -NR 6 C(O)R 5 Each C1-C4 alkyl, heteroaryl, phenyl, heterocyclic, -C1-C4 alkyl-heteroaryl, -C1-C4 alkyl-phenyl, and -C1-C4 alkyl-heterocyclic group is optionally selected from one or two independently selected from R 8 Substituents of the substituents; R 5 It is hydrogen, C1-C4 alkyl, heteroaryl, phenyl, heterocyclic, -C1-C4 alkyl-heteroaryl, -C1-C4 alkyl-phenyl, -C1-C4 alkyl-heterocyclic or -NR 6 R 7 Each C1-C4 alkyl, heteroaryl, phenyl, heterocyclic, -C1-C4 alkyl-heteroaryl, -C1-C4 alkyl-phenyl, and -C1-C4 alkyl-heterocyclic group is optionally selected from one or two independently selected from R 9 Substituents of the substituents; R 6 and R 7 In each case, the group consisting of the following groups is chosen independently: hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, heteroaryl, phenyl, and heterocyclic, wherein each R 6 and R 7 The group other than hydrogen is optionally composed of one or two independently selected R groups. 10 Substituents of the substituents; R 8 Each occurrence is independently selected from the following groups: hydrogen, C1-C4 alkyl, fluorine, chlorine, and -OR. 6 ; R 9 Each time it appears, it is independently selected from the following groups: hydrogen, heteroaryl, fluorine, chlorine, and -OR. 6 The heteroaryl group is optionally substituted by one or two substituents selected from fluorine and chlorine; R 10 Each time it appears, choose independently from the following groups: fluorine and chlorine; R 11 It is hydrogen, C1-C4 alkyl, -C1-C4 alkyl-OR 6 -OR 6 or -NR 6 R 7 ; R 12 R 13 R 14 R 15 R 16 R 17 R 18 and R 19 Each time it appears, it is independently selected from the group consisting of: hydrogen, C1-C4 haloalkyl, C1-C4 alkyl, fluorine, and chlorine; or R 12 and R 4 Combining to form 3-6 fused rings; or R 12 and R 19 They can combine to form one or two atomic bridges; The connector is a divalent linker of the following formula: in: X 1 and X 2 It is a key; R 2 Each time it appears, it is independently selected from the group consisting of: hydrogen and -C1-C4 alkyl; R 20 R 21 R 22 R 23 and R 24 Each occurrence is independently selected from the following groups: bond, C1-C6 alkyl, -C(O)-, -O-, -NR. 2 - phenyl, heterocyclic and heteroaryl; wherein each is optionally selected independently by one or two from R 40 Substituents; and R 40 Each time it appears, it is independently selected from the following groups: hydrogen, C1-C4 alkyl, fluorine, chlorine, hydroxyl; in The heteroaryl group is a 5- or 6-membered monocyclic heteroaryl group containing 1, 2, 3, or 4 nitrogen atoms; a 5- or 6-membered monocyclic heteroaryl group containing an oxygen atom; a 5- or 6-membered monocyclic heteroaryl group containing a sulfur atom; a 5- or 6-membered monocyclic heteroaryl group containing an oxygen atom and 1 to 2 nitrogen atoms; or a 5- or 6-membered monocyclic heteroaryl group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms; and The heterocyclic group is selected from monocyclic 3- to 10-membered heteroatom-containing rings or bicyclic 5- to 16-membered heteroatom-containing rings, wherein the heteroatom is selected from nitrogen, sulfur and oxygen.

2. The compound of claim 1, wherein the compound has the formula: And among them: It is a 5- or 6-membered heteroaryl group containing one or two nitrogen atoms; R 9 Each time it appears, choose independently from the following groups: chlorine, fluorine, and -OR. 6 .

3. The compound of claim 1, wherein the compound has the formula:

4. The compound according to any one of claims 1 and 3, wherein Q 1 It is NH.

5. The compound according to any one of claims 1 and 3, wherein Q 1 It is NCH3.

6. The compound of claim 1, wherein the compound has the formula:

7. The compound of claim 6, wherein X 7 It is N.

8. The compound according to any one of claims 1, 3 and 6, wherein X 3 It is CH.

9. The compound according to any one of claims 1, 3 and 6, wherein X 3 It is CR 3 .

10. The compound according to any one of claims 1, 3 and 6, wherein X 5 It is CH.

11. The compound according to any one of claims 1, 3 and 6, wherein X 5 It is CR 3 .

12. The compound of claim 1, wherein the compound has the formula:

13. The compound according to any one of claims 1, 3, 6 and 12, wherein X 7 It is CH.

14. The compound according to any one of claims 1, 3, 6 and 12, wherein X 4 It is CR 3 .

15. The compound according to any one of claims 1, 3, 6 and 12, wherein X 4 It's CF.

16. The compound of any one of claims 1, 3, 6 and 12, wherein X 4 It is CH.

17. The compound of any one of claims 1, 3, 6 and 12, wherein X 6 It is CH.

18. The compound of any one of claims 1, 3, 6 and 12, wherein X 6 It is CR 3 .

19. The compound according to any one of claims 1 and 12, wherein R 1d It is hydrogen.

20. The compound of any one of claims 1, 3, 6, and 12, wherein the RET-targeting ligand is:

21. The compound of any one of claims 1, 3, 6, and 12, wherein the RET-targeting ligand is:

22. The compound according to any one of claims 1, 3, 6 and 12, wherein It is a 5- or 6-membered heteroaryl group containing 1 or 2 nitrogen atoms.

23. The compound according to any one of claims 1, 3, 6 and 12, wherein yes 24. The compound of any one of claims 1, 3, 6, and 12, wherein the RET-targeting ligand is:

25. The compound of any one of claims 1, 3, 6, and 12, wherein the RET-targeting ligand is:

26. The compound of any one of claims 1, 3, 6 and 12, wherein the connector has the formula: in: R 20 R 21 R 22 R 23 and R 24 Each occurrence is independently selected from the following groups: bond, C1-C6 alkyl, -C(O)-, -O-, -NR. 2 - phenyl, heterocyclic and heteroaryl; wherein each is optionally selected independently by one or two from R 40 Substituents of the substituents; R 40 Each time it appears, it is independently selected from the following groups: hydrogen, C1-C4 alkyl, fluorine, and chlorine.

27. The compound of claim 26, wherein R 20 It is a key.

28. The compound of claim 26, wherein R 20 It is CH2.

29. The compound of claim 26, wherein R 20 It is a heterocyclic group.

30. The compound of claim 26, wherein R 20 It is phenyl.

31. The compound of claim 26, wherein R 21 It is a key.

32. The compound of claim 26, wherein R 21 It is CH2.

33. The compound of claim 26, wherein R 21 It is a heterocyclic group.

34. The compound of claim 26, wherein R 21 It is phenyl.

35. The compound of claim 26, wherein the connector has the formula:

36. The compound of claim 35, wherein R 22 It is a key.

37. The compound of claim 35, wherein R 22 It is CH2.

38. The compound of claim 35, wherein R 22 It is a heterocyclic group.

39. The compound of claim 35, wherein R 22 It is phenyl.

40. The compound of claim 26, wherein the connector has the formula:

41. The compound of claim 40, wherein R 23 It is a key.

42. The compound of claim 40, wherein R 23 It is CH2.

43. The compound of claim 40, wherein R 23 It is a heterocyclic group.

44. The compound of claim 40, wherein R 23 It is phenyl.

45. The compound of claim 26, wherein the connector has the formula:

46. ​​The compound of claim 45, wherein R 24 It is a key.

47. The compound of claim 45, wherein R 24 It is CH2.

48. The compound of claim 45, wherein R 24 It is a heterocyclic group.

49. The compound of claim 45, wherein R 24 It is phenyl.

50. The compound of claim 45, wherein R 24 It is C(O).

51. A compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof:

52. A compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof:

53. A compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof:

54. A compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof:

55. A compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof:

56. A compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof:

57. A compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof:

58. A compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof:

59. A compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof:

60. A compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof:

61. A compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof:

62. A compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof:

63. A compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof:

64. A compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof:

65. A compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof:

66. A compound with the following structure: Or its pharmaceutically acceptable salt.

67. A compound with the following structure: Or its pharmaceutically acceptable salt.

68. A pharmaceutical composition comprising a compound as claimed in any one of claims 1-67 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

69. Use of any compound of claims 1-67 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating RET-mediated cancer in patients in need.

70. The use as described in claim 69, wherein the patient is a person.

71. The use as described in claim 70, wherein the RET-mediated cancer is non-small cell lung cancer.

72. The use as claimed in claim 70, wherein the RET-mediated cancer has metastasized to the brain.

73. The use as claimed in claim 70, wherein the RET-mediated cancer is mediated by a mutated RET.

74. The use as described in claim 70, wherein the RET-mediated cancer is a recurrent or refractory cancer.

Images