Protein tyrosine phosphatase decomposing agent and method of use thereof

Abstract

Provided herein are compounds, compositions, and methods useful for degrading protein tyrosine phosphatases (e.g., protein tyrosine phosphatase non-receptor type 2 (PTPN2) and / or protein tyrosine phosphatase non-receptor type 1 (PTPN1)) and for treating related diseases (e.g., cancer or metabolic diseases) that respond favorably to PTPN1 or PTPN2 inhibitor treatment.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is an international application and claims the benefit of U.S. Provisional Application No. 62 / 952,097, filed December 20, 2019, U.S. Provisional Application No. 63 / 121,721, filed December 4, 2020, U.S. Provisional Application No. 63 / 125,937, filed December 15, 2020, and U.S. Provisional Application No. 62 / 952,161, filed December 20, 2019. The disclosures of the foregoing applications are incorporated herein by reference in their entireties. [Background technology]

[0002] Cancer immunotherapy regimens that target immune evasion mechanisms, including checkpoint blockade (e.g., PD-1 / PD-L1 and CTLA-4 blocking antibodies), have been shown to be effective in treating a variety of cancers and dramatically improved outcomes in subsets of patients resistant to conventional therapies. However, incomplete clinical responses and the development of intrinsic or acquired resistance will continue to limit the populations that can benefit from checkpoint blockade.

[0003] Protein tyrosine phosphatase non-receptor type 2 (PTPN2), also known as T-cell protein tyrosine phosphatase (TC-PTP), is an intracellular member of the class 1 subfamily of phosphotyrosine-specific phosphatases that regulates various cellular regulatory processes by removing phosphate groups from tyrosine substrates. PTPN2 is ubiquitously expressed, with highest expression in hematopoietic and placental cells (Mosinger, B. Jr. et al., Proc Natl Acad Sci USA 89:499-503; 1992). In humans, PTPN2 expression is posttranscriptionally regulated by the existence of two splice variants: a 45-kDa form containing a nuclear localization signal C-terminally upstream of the splice junction, and a 48-kDa form with a C-terminal ER retention motif (Tillmann U. et al., Mol Cell Biol 14:3030-3040; 1994). The 45 kDa isoform can passively penetrate the cytoplasm under certain cellular stress conditions. Both isoforms share an N-terminal phosphotyrosine phosphatase catalytic domain. PTPN2 negatively regulates signal transduction of nonreceptor tyrosine kinases (e.g., JAK1, JAK3), receptor tyrosine kinases (e.g., INSR, EGFR, CSF1R, PDGFR), transcription factors (e.g., STAT1, STAT3, STAT5a / b), and Src family kinases (e.g., Fyn, Lck). PTPN2 functions as a key negative regulator of the JAK-STAT pathway, directly regulating signal transduction through cytokine receptors, including IFNγ. The PTPN2 catalytic domain shares 74% sequence identity with PTPN1 (also known as PTP1B) and shares similar enzymatic kinetics (Romsicki Y. et al., Arch Biochem Biophys 414:40-50; 2003).

[0004] Data from a loss-of-function in vivo genetic screen using CRISPR / Cas9 genome editing in the mouse B16F10 transplantable tumor model showed that deletion of the Ptpn2 gene in tumor cells improved response to immunotherapy regimens involving GM-CSF-secreting vaccine (GVAX) and PD-1 checkpoint blockade (Manguso RT et al., Nature 547:413-418; 2017). Loss of Ptpn2 sensitized tumors to immunotherapy by enhancing IFNγ-mediated effects on antigen presentation and growth suppression. The same screen also revealed that genes known to be involved in immune evasion (PD-L1 and CD47) were depleted under immunotherapy selection pressure, while genes involved in the IFNγ signaling pathway (including IFNGR, JAK1, and STAT1) were enriched. These observations point to a putative role for therapeutic strategies that enhance IFNγ sensing and signaling to enhance the efficacy of cancer immunotherapy regimens.

[0005] Protein tyrosine phosphatase non-receptor type 1 (PTPN1), also known as protein tyrosine phosphatase-1B (PTP1B), has been shown to play an important role in insulin and leptin signaling and is a major mechanism for downregulating both the insulin and leptin receptor signaling pathways (Kenner KA et al., J Biol Chem 271:19810-19816, 1996). Animals lacking PTP1B have improved glucose regulation and lipid profiles and are resistant to weight gain when treated with a high-fat diet (Elchebly M. et al., Science 283:1544-1548, 1999).

[0006] One approach to externally influencing protein activity is to reduce the levels of specific proteins through targeted degradation. Protein degradation is a highly regulated and essential process that maintains cellular homeostasis. The selective identification and removal of damaged, misfolded, or excess proteins is achieved via the ubiquitin-proteasome pathway (UPP). The UPP plays a central role in regulating nearly all cellular processes, including antigen processing, apoptosis, organelle biogenesis, cell cycle, DNA transcription and repair, differentiation and development, immune response and inflammation, nerve and muscle degeneration, neural network morphogenesis, regulation of cell surface receptors, ion channels, and secretory pathways, response to stress and extracellular regulators, ribosome biogenesis, and viral infection.

[0007] E3 ubiquitin ligases covalently attach multiple ubiquitin molecules to terminal lysine residues of proteins, thereby marking them for proteasomal degradation and degrading them into small peptides and ultimately their component amino acids, which serve as building blocks for new proteins. There are over 600 E3 ubiquitin ligases that promote the ubiquitination of various proteins in vivo, and these can be classified into four families: HECT domain E3s, U-box E3s, monomeric RING E3s, and multisubunit E3s. For overviews, see Li et al. (PLOS One, 2008, 3, 1487), Berndsen et al. (Nat. Struct. Mol. Biol., 2014, 21, 301-307), Deshaies et al. (Ann. Rev. Biochem., 2009, 78, 399-434), Spratt et al. (Biochem. 2014, 458, 421-437), and Wang et al. (Nat. Rev. Cancer., 2014, 14, 233-347).

[0008] The first E3 ligase to be successfully targeted with a small molecule was SCFβTrCP, which could be targeted using a hybrid of a small molecule MetAP2 inhibitor linked to an IκBα phosphopeptide epitope known to bind ubiquitin E3 ligases (Sakamoto et al, PNAS 2001, 98(15)8554). Schneekloth et al. described a degrader (PROTAC3) that targets FK506-binding protein (FKBP12) and demonstrated by green fluorescent protein (GFP) imaging that both PROTAC2 and PROTAC3 attack their respective targets. Schneekloth et al. (Chem Bio Chem 2005, 6, 40-46).

[0009] In an unrelated, parallel study, scientists investigating thalidomide toxicity discovered that cereblon is a thalidomide-binding protein. (Ito et al., Science 2010, 327, 1345-1350) Cereblon is part of an E3 ubiquitin ligase protein complex that interacts with damaged DNA-binding protein 1 and, together with Cullin 4 and the E2-binding protein ROC1 (also known as RBX1), forms an E3 ubiquitin ligase complex that functions as a substrate receptor that selects proteins for ubiquitination. This study revealed that in vivo thalidomide-cereblon binding may be involved in thalidomide's teratogenicity. Following the discovery that thalidomide binds to cereblon E3 ubiquitin ligase, studies were conducted to incorporate thalidomide and certain derivatives into compounds for targeted destruction of proteins. See G. Lu et al., (Science, 343, 305-309 (2014)) and J. Kronke et al., (Science, 343, 301-305 (2014)).

[0010] Although progress has been made in the field of modulating the UPP for proteolysis in vivo, additional compounds and approaches would be useful to more fully harness the UPP for therapeutic treatments, e.g., for the development of targeted PTP1B degraders useful for the treatment of type 2 diabetes, obesity, and metabolic syndrome. It is an object of the present disclosure to provide novel compounds, methods, compositions, and methods of manufacture useful for degrading selected proteins, e.g., PTP1B, in vivo. Summary of the Invention

[0011] The present disclosure is directed, at least in part, to compounds, compositions, and methods for degrading protein tyrosine phosphatases (e.g., protein tyrosine phosphatase non-receptor type 2 (PTPN2) and / or protein tyrosine phosphatase non-receptor type 1 (PTPN1), also known as protein tyrosine phosphatase-1B (PTP1B)) via the ubiquitin proteasome pathway (UPP). In some embodiments, the compounds described herein include a "targeting ligand" that binds to the protein tyrosine phosphatase, a "degron" that binds (e.g., non-covalently) to an E3 ligase (e.g., a cereblon component), and a linker that covalently attaches the targeting ligand to the degron.

[0012] Some embodiments are of formula (I):

[0013] [ka]

[0014] or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R A, R B, Rx, L, U, V, W, X, Y, Z, Q, p, and q are as defined herein.

[0015] Some embodiments provide a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0016] Some embodiments provide a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0017] 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 disclosure belongs. Methods and materials for use in this disclosure are described herein; however, other suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and are not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0018] Other features and advantages of the disclosure will be apparent from the following detailed description and drawings, and from the claims.

[0019] Brief description of the sequence listing The Sequence Listing entitled "45629_0007W01_ST25" is incorporated herein by reference in its entirety, and includes SEQ ID NOs:1-3, which contain the amino acid sequences disclosed herein. This Sequence Listing has been submitted herewith by EFS in ASCII text format. This Sequence Listing was first created on December 19, 2019, and is 7.25 KB in size. DETAILED DESCRIPTION OF THE INVENTION

[0020] The present disclosure is directed, at least in part, to compounds, compositions, and methods for inhibiting protein tyrosine phosphatases (e.g., protein tyrosine phosphatase non-receptor type 2 (PTPN2) and / or protein tyrosine phosphatase non-receptor type 1 (PTPN1 or PTP1B)).

[0021] definition chemical definition Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. (back cover), and specific functional groups are generally defined as described therein. Furthermore, general principles of organic chemistry and specific functional moieties and reactivities are explained in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March's Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987.

[0022] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulas set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0023] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various isomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of a mixture of stereoisomers (including racemic mixtures and mixtures enriched in one or more stereoisomers). Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962), and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present disclosure further encompasses the compounds described herein as individual isomers substantially free of other isomers or as mixtures of various isomers.

[0024] The articles "a" and "an" may be used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an analogue" means one analogue or multiple analogues.

[0025] When a range of values ​​is recited, it is intended to encompass each value and subrange within that range. For example, "C1-C6 alkyl" is intended to include C1, C2, C3, C4, C5, C6, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6 alkyl.

[0026] The following terms are intended to have the meanings presented below and are useful in understanding the description and intended scope of the present disclosure.

[0027] "Alkyl" refers to the radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms ("C1-C10 alkyl"). In some embodiments, the alkyl group has from 1 to 8 carbon atoms ("C1-C8 alkyl"). In some embodiments, the alkyl group has from 1 to 6 carbon atoms ("C1-C6 alkyl"). In some embodiments, the alkyl group has from 1 to 5 carbon atoms ("C1-C5 alkyl"). In some embodiments, the alkyl group has from 1 to 4 carbon atoms ("C1-C4 alkyl"). In some embodiments, the alkyl group has from 1 to 3 carbon atoms ("C1-C3 alkyl"). In some embodiments, the alkyl group has from 1 to 2 carbon atoms ("C1-C2 alkyl"). In some embodiments, the alkyl group has 1 carbon atom ("C1 alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C2-C6 alkyl"). Examples of C1-C6 alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Each instance of an alkyl group independently may be optionally substituted, i.e., unsubstituted (an "unsubstituted alkyl") or substituted with one or more substituents (e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent) (a "substituted alkyl"). In certain embodiments, the alkyl group is an unsubstituted C1-C10 alkyl (e.g., -CH3). In certain embodiments, the alkyl group is a substituted C1-C6 alkyl. Common abbreviations for alkyl include Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3), or i-Bu (-CH2CH(CH3)2).

[0028] "Alkenyl" refers to the radical of a straight-chain or branched hydrocarbon group having 2 to 10 carbon atoms, one or more carbon-carbon double bonds, and no triple bonds ("C2-C10 alkenyl"). In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C2-C8 alkenyl"). In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C2-C6 alkenyl"). In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C2-C5 alkenyl"). In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C2-C4 alkenyl"). In some embodiments, an alkenyl group has 2 to 3 carbon atoms ("C2-C3 alkenyl"). In some embodiments, an alkenyl group has 2 carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (e.g., 2-butenyl) or terminal (e.g., 1-butenyl). Examples of C2-C4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-C6 alkenyl groups include, in addition to the aforementioned C2-4 alkenyl groups, pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Further examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Each instance of an alkenyl group independently may be optionally substituted, e.g., unsubstituted (an "unsubstituted alkenyl") or substituted (a "substituted alkenyl") with one or more substituents (e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent). In certain embodiments, the alkenyl group is unsubstituted C2-C10 alkenyl. In certain embodiments, the alkenyl group is substituted C2-C6 alkenyl.

[0029] The term “alkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from alkyl, including, but not limited to, An example is -CH2CH2CH2CH2-. Typically, alkyl (or alkylene) groups have 1 to 10 carbon atoms, although groups having 6 or fewer carbon atoms are preferred in this disclosure. The term "alkenylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene. An alkylene group can be straight-chain or branched. An alkylene group can be expressed, for example, as C1-C6 alkylene, which represents an alkylene moiety having 1 to 6 carbon atoms.

[0030] "Halo" or "halogen," independently or as part of another substituent, means a fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) atom. The term "halide," by itself or as part of another substituent, refers to a fluoride, chloride, bromide, or iodide atom. In certain embodiments, a halo group is either fluorine or chlorine.

[0031] "Haloalkyl" refers to an alkyl group, as described herein (e.g., a C1-C6 alkyl group), in which one or more hydrogen atoms are replaced by halogen (e.g., mono-haloalkyl, di-haloalkyl, and tri-haloalkyl). Such groups include, but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloro-fluoroalkyl, chloro-difluoroalkyl, and 2-fluoroisobutyl.

[0032] "Alkoxy" refers to an alkyl group, as described herein (e.g., a C1-C6 alkyl group), attached to the molecule via an oxygen atom. It includes moieties where the alkyl portion can be straight or branched, e.g., methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy.

[0033] "Haloalkoxy" refers to an alkoxy group, as described herein (e.g., a C1-C6 alkoxy group), in which one or more hydrogen atoms are replaced by halogen (e.g., mono-haloalkoxy, di-haloalkoxy, and tri-haloalkoxy). Such groups include, but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloro-fluoroalkoxy, chloro-difluoroalkoxy, and 2-fluoroisobutoxy.

[0034] "Aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., a ring system having 6, 10, or 14 π-electrons shared in a cyclic arrangement) having 6 to 14 ring carbon atoms and no heteroatoms provided by the aromatic ring system ("C6-C14 aryl"). In some embodiments, an aryl group has 6 ring carbon atoms ("C6 aryl", e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C10 aryl", e.g., naphthyl (e.g., 1-naphthyl and 2-naphthyl)). In some embodiments, an aryl group has 14 ring carbon atoms ("C14 aryl", e.g., anthracyl). An aryl group can be described, for example, as C6-C10 aryl. Aryl groups include, but are not limited to, phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Each instance of an aryl group can independently be optionally substituted, e.g., unsubstituted (an "unsubstituted aryl") or substituted with one or more substituents (a "substituted aryl"). In certain embodiments, an aryl group is an unsubstituted C6-C14 aryl. In certain embodiments, an aryl group is a substituted C6-C14 aryl.

[0035] "Heteroaryl" refers to a radical of a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., a ring system having 6 or 10 π-electrons shared in a cyclic arrangement) having ring carbon atoms and 1 to 4 ring heteroatoms (each heteroatom independently selected from nitrogen, oxygen, and sulfur) provided in the aromatic ring system ("5- to 10-membered heteroaryl"). For heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be at a carbon atom or a nitrogen atom, as valence permits. Heteroaryl bicyclic ring systems can contain one or more heteroatoms in one or both rings. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more aryl groups, with the point of attachment being on either the aryl or heteroaryl ring; in such cases, the number of ring members continues to refer to the number of ring members in the fused (aryl / heteroaryl) ring system. The point of attachment of a bicyclic heteroaryl group in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.) can be on either ring, i.e., on the ring with a heteroatom (e.g., 2-indolyl) or on the ring without a heteroatom (e.g., 5-indolyl). A heteroaryl group can be described, for example, as a 6- to 10-membered heteroaryl, where the term "member" refers to a non-hydrogen ring atom within the moiety.

[0036] In some embodiments, a heteroaryl group is a 5- to 10-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided by the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In some embodiments, a heteroaryl group is a 5- to 8-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided by the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heteroaryl"). In some embodiments, a heteroaryl group is a 5- to 6-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided by the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heteroaryl"). In some embodiments, a 5- to 6-membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has one ring heteroatom selected from nitrogen, oxygen, and sulfur. Each instance of a heteroaryl group independently may be optionally substituted, i.e., unsubstituted (an "unsubstituted heteroaryl") or substituted with one or more substituents (a "substituted heteroaryl"). In certain embodiments, the heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5- to 14-membered heteroaryl.

[0037] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl and pyridonyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0038] The terms "arylene" and "heteroarylene," alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. Non-limiting examples of heteroaryl include pyridinyl, pyrimidinyl, thiophenyl, thienyl, furanyl, indolyl, benzoxadiazolyl, benzodioxolyl, benzodioxanyl, thianaphthalyl, pyrrolopyridinyl, indazolyl, quinolinyl, quinoxalinyl, pyridopyrazinyl, quinazolinonyl, benzisoxazolyl, imidazopyridinyl, benzofuranyl, benzothienyl, benzothiophenyl, phenyl, naphthyl, biphenyl, and pyrrolyl. , pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furylthienyl, pyridyl, pyrimidinyl, benzothiazolyl, purinyl, benzimidazolyl, isoquinolyl, thiadiazolyl, oxadiazolyl, pyrrolyl, diazolyl, triazolyl, tetrazolyl, benzothiadiazolyl, isothiazolyl, pyrazolopyrimidinyl, pyrrolopyrimidinyl, benzotriazolyl, benzoxazolyl, or quinolyl. The above examples may be substituted or unsubstituted as described herein, and the divalent radical in each of the above heteroaryl examples is a non-limiting example of heteroarylene.

[0039] "Aryloxy" refers to an aryl group, as defined herein (e.g., a C6-C10 aryl group), attached to a molecule via an oxygen atom. This includes, but is not limited to, phenoxy and naphthoxy groups.

[0040] "Heteroaryloxy" refers to a heteroaryl group, as described herein (e.g., a 5- to 10-membered heteroaryl group), that is attached to the molecule via an oxygen atom. This includes, but is not limited to, groups such as pyridinoxy and pyrazinoxy.

[0041] "Cycloalkyl" refers to the radical of a saturated or partially unsaturated (i.e., non-aromatic) cyclic hydrocarbon group having 3 to 10 ring carbon atoms in a non-aromatic ring system ("C3-C10 cycloalkyl") and no heteroatoms. In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C3-C8 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C3-C6 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C3-C6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C5-C10 cycloalkyl"). A cycloalkyl group can be described, for example, as a C4-C7 membered cycloalkyl. Exemplary C3-C6 cycloalkyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-C8 cycloalkyl groups include, but are not limited to, cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), cubanyl (C8), bicyclo[1.1.1]pentanyl (C5), bicyclo[2.2.2]octanyl (C8), bicyclo[2.1.1]hexanyl (C6), bicyclo[3.1.1]heptanyl (C7), and the like, in addition to the aforementioned C3-C6 cycloalkyl groups. Exemplary C3-C10 cycloalkyl groups include, but are not limited to, cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like, in addition to the aforementioned C3-C8 cycloalkyl groups.As the foregoing examples illustrate, in certain embodiments, a cycloalkyl group is monocyclic ("monocyclic cycloalkyl") or includes fused, bridged, or spiro ring systems (e.g., bicyclic ("bicyclic cycloalkyl")), which may be saturated or partially unsaturated. "Cycloalkyl" also includes ring systems in which a cycloalkyl ring, as defined above, is fused to one or more aryl groups, with the point of attachment being on the cycloalkyl ring; in such cases, the number of carbons continues to refer to the number of carbons in the cycloalkyl ring system. Each instance of a cycloalkyl group may independently be optionally substituted, e.g., unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, a cycloalkyl group is an unsubstituted C3-C10 cycloalkyl. In certain embodiments, a cycloalkyl group is a substituted C3-C10 cycloalkyl.

[0042] In some embodiments, "cycloalkyl" is a monocyclic or bicyclic, saturated or partially unsaturated group having 3 to 10 ring carbon atoms ("C3-C10 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C3-C8 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C3-C6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C5-C6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C5-C10 cycloalkyl"). Examples of C5-C6 cycloalkyl groups include cyclopentyl and cyclopentenyl (C5), and cyclohexyl and cyclohexenyl (C6). Examples of C3-C6 cycloalkyl groups include cyclopropyl (C3) and cyclobutyl (C4) in addition to the aforementioned C5-C6 cycloalkyl groups. Examples of C3-C8 cycloalkyl groups include cycloheptyl (C7) and cyclooctyl (C8), in addition to the aforementioned C3-C6 cycloalkyl groups. Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted ("substituted cycloalkyl") with one or more substituents. In certain embodiments, a cycloalkyl group is an unsubstituted C3-C10 cycloalkyl. In certain embodiments, a cycloalkyl group is a substituted C3-C10 cycloalkyl.

[0043] "Heterocyclyl" refers to the radical of a 3- to 12-membered saturated or partially unsaturated (i.e., non-aromatic) ring system having ring carbon atoms and 1 to 4 ring heteroatom groups, each heteroatom group independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 12-membered heterocyclyl"). For heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be at a carbon atom or a nitrogen atom, where valence allows. Heterocyclyl groups can be either monocyclic ("monocyclic heterocyclyl") or fused, bridged, or spiro ring systems (e.g., bicyclic systems ("bicyclic heterocyclyl")), which can be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems can contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring, as defined above, is fused to one or more cycloalkyl groups, with the point of attachment either on the cycloalkyl ring or on the heterocyclyl ring, or to one or more aryl or heteroaryl groups, with the point of attachment on the heterocyclyl ring; in such cases, the number of ring members continues to refer to the number of ring members in the heterocyclyl ring system. A heterocyclyl group can be represented, for example, as a 3- to 7-membered heterocyclyl, where the term "member" refers to the non-hydrogen ring atoms in the moiety, i.e., carbon (including oxo groups), nitrogen, oxygen, sulfur, and oxidized forms of sulfur (e.g., S, S(O), and S(O)). Each instance of heterocyclyl can independently be optionally substituted, e.g., unsubstituted (an "unsubstituted heterocyclyl") or substituted with one or more substituents (a "substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is unsubstituted 3-12 membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3-12 membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 4-6 membered heterocyclyl.

[0044] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, pyrrolidon-2-yl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocyclic rings) fused to an aryl ring include tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0045] "Cycloalkylene" and "heterocyclylene," alone or as part of another substituent, mean divalent radicals derived from cycloalkyl and heterocyclyl, respectively. The above examples may be substituted or unsubstituted as described herein, with the divalent radical of each of the above examples of heterocyclyl being a non-limiting example of heterocyclylene, and the divalent radical of each of the above examples of cycloalkyl being a non-limiting example of cycloalkylene.

[0046] "Cycloalkoxy" refers to a cycloalkyl group, as described herein (e.g., a C3-C6 cycloalkyl group), attached to the molecule via an oxygen atom. This includes, but is not limited to, groups such as cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy.

[0047] "Heterocyclyloxy" refers to a heterocyclyl group, as described herein (e.g., a 4- to 8-membered heterocyclyl group), that is attached to the molecule via an oxygen atom. This includes, but is not limited to, groups such as azetidinyloxy, oxetanyloxy, piperidinyloxy, and piperazinyloxy.

[0048] "Halocycloalkoxy" refers to a cycloalkoxy group, as described herein (e.g., a C3-C6 cycloalkoxy group), in which one or more hydrogen atoms are replaced by halogen (e.g., mono-halocycloalkoxy, di-halocycloalkoxy, tri-halocycloalkoxy, and tetra-halocycloalkoxy). Such groups include, but are not limited to, fluorocyclobutoxy, difluorocyclopentoxy, tetrafluorocyclobutoxy, chloro-fluorocycloalkoxy, chloro-difluorocycloalkoxy, and difluorocyclohexoxy.

[0049] "Amino" refers to the -NH2 radical.

[0050] "Cyano" refers to the -CN radical.

[0051] "Hydroxy" or "hydroxyl" refers to the --OH radical.

[0052] "Oxo" refers to the =O group.

[0053] In some embodiments, if present, one or more of the nitrogen atoms of the compounds of the present disclosure are oxidized to the corresponding N-oxide.

[0054] As used herein, a ring is described as "partially unsaturated" to mean that it has one or more double or triple bonds between constituent ring atoms, provided that the ring is not aromatic. Examples of such rings include cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like.

[0055] The term "pharmaceutically acceptable salts" is intended to include salts prepared using relatively non-toxic acids or bases, depending on the particular substituents found on the compounds described herein.

[0056] Certain compounds described in this invention can exist in unsolvated as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to the unsolvated forms and are included within the scope of the present disclosure.

[0057] Certain compounds described herein possess asymmetric carbon atoms (optical or chiral centers) or double bonds; enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms that may be defined in terms of overall stereochemistry as (R)- or (S)- with respect to amino acids, or as (D)- or (L), and individual isomers are included within the scope of the present invention. The compounds described herein do not include those known in the art to be unstable to synthesis and / or isolation. The present disclosure includes compounds in racemic and optically pure forms. Optically active (R)- and (S)-, or (D)- and (L)-isomers, can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When a compound described herein contains an olefinic bond or other center of geometric asymmetry, the compound is intended to include E and Z geometric isomers, unless otherwise specified.

[0058] As used herein, the term "isomers" refers to compounds that have the same number and kinds of atoms, and therefore the same molecular weight, but that differ in terms of the structural arrangement or configuration of the atoms.

[0059] As used herein, the term "tautomer" refers to a compound that differs significantly in structure in the arrangement of atoms, but that readily and rapidly exists in equilibrium; the compounds provided herein may be represented as different tautomers; it is understood that when a compound has tautomers, all tautomers are intended to be within the scope of the present disclosure, and the name of the compound does not exclude any tautomer. Examples of tautomeric forms include the following:

[0060] [ka]

[0061] It will be apparent to one of ordinary skill in the art that some compounds of the present disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the present disclosure.

[0062] The compounds provided herein may also contain unnatural proportions of atomic isotopes in one or more atoms comprising such compounds. That is, when an atom, particularly an atom when referred to in connection with a compound according to formula (I), is intended to include all isotopes and isotopic mixtures of that atom, whether natural or synthetic, in natural abundance or isotopically enriched form. For example, unless expressly stated otherwise, a reference to hydrogen is understood to refer to 1H, 2H, 3H, or mixtures thereof; a reference to carbon is understood to refer to 11C, 12C, 13C, 14C, or mixtures thereof; a reference to nitrogen is understood to refer to 13N, 14N, 15N, or mixtures thereof; a reference to oxygen is understood to refer to 14O, 15O, 16O, 17O, 18O, or mixtures thereof; and a reference to fluoro is understood to refer to 18F, 19F, or mixtures thereof. For example, in the case of deuteroalkyl and deuteroalkoxy groups, one or more hydrogen atoms are specifically replaced with deuterium (H). Some of the aforementioned isotopes are radioactive. Therefore, the compounds provided herein also include compounds having one or more isotopes of one or more atoms, including radioactive compounds (in which one or more non-radioactive atoms are replaced with one of their radioactively enriched isotopes), and mixtures thereof. Radiolabeled compounds are useful as additional pharmaceutical agents (e.g., therapeutic agents), research reagents (e.g., assay reagents), and diagnostic agents (e.g., in vivo imaging agents). All isotopic variations of the compounds provided herein, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure. For example, in some embodiments, one or more C—H groups in the naphthyl ring shown in Formula (I) are replaced with C—D groups.

[0063] It is understood that in the compounds described herein, the linker group L does not include compounds in which, for example, U and V, V and W, or U, V, and W are all heteroatoms (e.g., —O—).

[0064] "Treating" or "treatment" refers to reducing symptoms or preventing or inhibiting (in whole or in part) further development of a disease. The term "treating" or "treatment" includes any effect that results in improvement of a disease or the like (e.g., narrowing, reduction, modulation, or elimination). For example, certain methods herein treat cancer by reducing or diminishing the onset, growth, metastasis, or progression of cancer, or reducing the symptoms of cancer.

[0065] An "effective amount" is an amount sufficient to achieve a stated purpose (e.g., achieving the effect for which administration is intended, treating a disease, reducing enzyme activity, increasing enzyme activity, or reducing one or more symptoms of a disease). An example of an "effective amount" is an amount sufficient to contribute to the treatment, prevention, or reduction of one or more symptoms of a disease, which can also be referred to as a "therapeutically effective amount." A "prophylactically effective amount" of a drug is the amount of the drug that, when administered to a subject, is expected to have the intended prophylactic effect (e.g., preventing or delaying the onset (or recurrence) of a disease, or reducing the likelihood of the onset (or recurrence) of a disease or its symptoms).

[0066] "Reduction" of a symptom(s) means a decrease in the severity or frequency of the symptom(s), or complete elimination of the symptom(s).

[0067] "Contacting" refers to the process of bringing at least two different species into sufficient proximity to react, interact, and / or physically contact each other. However, it is understood that the resulting reaction product may be produced directly from the reaction between the added reagents or from an intermediate of one or more of the added reagents that may be produced in the reaction mixture. The term "contacting" includes reacting, interacting, and / or physically contacting two species, which may be a compound described herein and a protein or enzyme (e.g., a protein tyrosine phosphatase, e.g., protein tyrosine phosphatase non-receptor type 2 (PTPN2) or protein tyrosine phosphatase non-receptor type 1 (PTP1B)).

[0068] As defined herein, the terms "inhibition," "inhibit," "inhibiting," and the like refer to the interaction of a protein inhibitor (e.g., an antagonist) to negatively affect (e.g., decrease) the activity or function of a protein compared to the activity or function of the protein in the absence of the inhibitor. In some embodiments, inhibition refers to a reduction in disease progression and / or disease symptoms. In some embodiments, inhibition refers to a reduction in the activity of a signaling pathway or a signal pathway. Thus, inhibition includes, at least in part, partial or total blocking of stimulation, reduction, prevention, or delay of activation, or inactivation, desensitization, or downregulation of signaling or enzymatic activity or protein amount. In some embodiments, inhibition refers to a decrease in the activity of a protein tyrosine phosphatase (e.g., protein tyrosine phosphatase non-receptor type 2 (PTPN2) or protein tyrosine phosphatase non-receptor type 1 (PTP1B)). Thus, inhibition can include, at least in part, a partial or total decrease in stimulation, a decrease or reduction in activation, or inactivation, desensitization, or downregulation of the amount of signal transduction or enzymatic activity or protein tyrosine phosphatase (e.g., protein tyrosine phosphatase non-receptor type 2 (PTPN2) or protein tyrosine phosphatase non-receptor type 1 (PTP1B)).

[0069] As used herein, "subject" refers to an organism suffering from or susceptible to a disease that can be treated by administering a compound or pharmaceutical composition provided herein. Non-limiting examples include mammals such as humans. In some embodiments, the subject is a human. In some embodiments, the subject is a newborn human. In some embodiments, the subject is an elderly human. In some embodiments, the subject is a pediatric subject (e.g., a subject under the age of 21).

[0070] "Disease" refers to a condition or state of a subject that is treatable by a compound, pharmaceutical composition, or method provided herein. In some embodiments, the compounds and methods described herein include the reduction or elimination of one or more symptoms of the disease, e.g., by administering a compound described herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof.

[0071] As used herein, the term "PTPN2" refers to protein tyrosine phosphatase non-receptor type 2.

[0072] The term "PTPN1" refers to protein tyrosine phosphatase non-receptor type 1 (PTPN1), which is also known as protein tyrosine phosphatase-1B (PTP1B).

[0073] compound Some embodiments are of formula (I):

[0074] [ka]

[0075] or a pharmaceutically acceptable salt thereof, wherein: R1 is hydrogen or halogen; R2 is hydrogen, halogen, C1-C3 alkoxy, C3-C6 cycloalkoxy, C1-C3 haloalkoxy, C3-C5 halocycloalkoxy, C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, or -LZ; R3 is hydrogen, halogen, C1-C3 alkoxy, C3-C5 cycloalkoxy, C1-C3 haloalkoxy, C3-C5 halocycloalkoxy, C1-C3 alkyl, C1-C3 haloalkyl, C3-C5 cycloalkyl, or -LZ; One of R2 and R3 is -LZ and the other of R2 and R3 is not -LZ; Rx is hydrogen or halogen; L is -UVWXY-, U is a bond, -(NR4)-, -O-, C1-C3 alkylene, C2-C3 alkenylene, C2-C3 alkynylene, C3-C6 cycloalkylene, 4- to 10-membered heterocyclylene, 5- to 10-membered heteroarylene, -(C=O)NR4-, -NR4(C=O)-, -OR5-, -R5O-, -NR4R5-, -R5NR4-, or -(NR4)(C=O)(NR4)-; each R4 is independently hydrogen, C1-C6 alkyl, or C3-C5 cycloalkyl; R5 is C1-C3 alkylene, C3-C7 cycloalkylene, or 4-12 membered heterocyclylene; V is a bond, -(NR4)-, -O-, C1-C6 alkylene, C2-C6 alkenylene, -(C=O)NR4-, -(NR4)R5-, -(NR4)(C=O)-, -NH(C=O)NH-, -OR5-, -R5O-, 4- to 10-membered heterocyclylene, 5- to 10-membered heteroarylene, C6-C10 arylene, or C3-C6 cycloalkylene; W is a bond, C1-C3 alkylene optionally substituted with hydroxyl, C3-C6 cycloalkylene, 4-12 membered heterocyclylene, -O-, -(NR4)-, -R5(NR4)-, -(NR4)R5-, -(NR4)(C=O)-, -R5(NR4)(C=O)-, -(C=O)(NR4)R5-, -R5(C=O)(NR4)-, -(C=O)(NR4)-, -R5(C=O)-, -(C=O)R5-, -(C=O)-, -(S=O)-, or -S(O2)-; X is a bond, C1-C3 alkylene, C3-C6 cycloalkylene, 4-12 membered heterocyclylene, C6-C10 arylene, 5-10 membered heteroarylene, -R5(NR4)(C=O)-, -(C=O)R5(NR4)-, -R5(C=O)(NR4)-, -(NR4)(C=O)R5-, -R5(C=O)(NR4)-, -(C=O)(NR4)R5-, -(NR4)R5(C=O)-, -R5(C=O)(NR4)R5-, -R5(NR4)(C=O)R5-, -(C=O)R5-, or -R5(C=O)-; Y is R, R(CRARB)pQ-, or -Q-(CRARB)pR6-; Q is selected from the group consisting of -(NR4)-, -O-, and -(CRARB)p-; p is 0, 1, 2, or 3; R6 is a C1-C3 alkylene, a C3-C7 cycloalkylene, a 4- to 12-membered heterocyclylene, a C6-C10 arylene, or a 5- to 10-membered heteroarylene; The heterocyclylene, heteroarylene, arylene, and cycloalkylene groups of U, V, W, X, and R6 are each optionally substituted with 1 to 3 substituents independently selected from fluoro, hydroxyl, C1-C6 alkoxy, and C1-C6 alkyl; each R A and R B is independently hydrogen, fluoro, or C1-C6 alkyl; or R A and R B together with the carbon atoms to which they are attached form a C3-C4 cycloalkyl, or R A and R B combine to form oxo; Z is selected from the group consisting of:

[0076] [ka]

[0077] R7 is hydrogen, C1-C6 alkyl optionally substituted with one group selected from hydroxyl, cyano, and C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, -(CRARB)(4- to 12-membered heterocyclyl), or -(CRARB)(C3-C6 cycloalkyl); R8 is hydrogen or C1-C6 alkyl; each R9 is hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C5 cycloalkoxy, 5-10 membered heteroaryloxy, or phenoxy; and q is 0, 1, or 2; Each R10 is independently hydrogen, halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 haloalkyl.

[0078] In some embodiments, L is -UVWXY-, where -Y- is, for example, the point of attachment to Z and -U- is the point of attachment to the remainder of Formula (I) (e.g., the naphthyl ring shown in Formula (I)).

[0079] In some embodiments of the compound of Formula (I), R1 is halogen. In some embodiments of the compound of Formula (I), R1 is -F. In some embodiments of the compound of Formula (I), R1 is -Cl. In some embodiments of the compound of Formula (I), R1 is hydrogen.

[0080] In some embodiments of the compound of Formula (I), Rx is halogen. In some embodiments of the compound of Formula (I), Rx is -F or -Cl. In some embodiments of the compound of Formula (I), Rx is hydrogen.

[0081] In some embodiments of the compounds of Formula (I), R2 is -LZ.

[0082] In some embodiments of the compound of Formula (I), R3 is hydrogen. In some embodiments of the compound of Formula (I), R3 is halogen. In some embodiments of the compound of Formula (I), R3 is C1-C3 alkoxy or C1-C3 haloalkoxy. In some embodiments of the compound of Formula (I), R3 is C3-C5 cycloalkoxy or C3-C5 halocycloalkoxy. In some embodiments of the compound of Formula (I), R3 is C1-C3 alkyl or C3-C5 cycloalkyl. In some embodiments of the compound of Formula (I), R3 is C1-C3 haloalkyl.

[0083] In some embodiments of the compound of Formula (I), R2 is -LZ and R3 is hydrogen. In some embodiments of the compound of Formula (I), R2 is -LZ and R3 is halogen. In some embodiments of the compound of Formula (I), R2 is -LZ and R3 is C1-C3 alkoxy or C1-C3 haloalkoxy. In some embodiments of the compound of Formula (I), R2 is -LZ and R3 is C3-C5 cycloalkoxy or C3-C5 halocycloalkoxy. In some embodiments of the compound of Formula (I), R2 is -LZ and R3 is C1-C3 alkyl or C3-C5 cycloalkyl.

[0084] In some embodiments of the compounds of Formula (I), R3 is -LZ.

[0085] In some embodiments of the compound of Formula (I), R2 is hydrogen. In some embodiments of the compound of Formula (I), R2 is halogen. In some embodiments of the compound of Formula (I), R2 is C1-C3 alkoxy or C1-C3 haloalkoxy. In some embodiments of the compound of Formula (I), R2 is C3-C5 cycloalkoxy or C3-C5 halocycloalkoxy. In some embodiments of the compound of Formula (I), R2 is C1-C3 alkyl or C3-C5 cycloalkyl. In some embodiments of the compound of Formula (I), R2 is C1-C3 haloalkyl.

[0086] In some embodiments of the compound of Formula (I), R3 is -LZ and R2 is hydrogen. In some embodiments of the compound of Formula (I), R3 is -LZ and R2 is halogen. In some embodiments of the compound of Formula (I), R3 is -LZ and R2 is C1-C3 alkoxy or C1-C3 haloalkoxy. In some embodiments of the compound of Formula (I), R3 is -LZ and R2 is C3-C5 cycloalkoxy or C3-C5 halocycloalkoxy. In some embodiments of the compound of Formula (I), R3 is -LZ and R2 is C1-C3 alkyl or C3-C5 cycloalkyl.

[0087] In some embodiments of the compound of Formula (I), R1 is -F and Rx is hydrogen, -F, or -Cl. In some embodiments of the compound of Formula (I), R1 is -F, Rx is hydrogen, R2 is -LZ, and R3 is hydrogen. In some embodiments of the compound of Formula (I), R1 is -F, Rx is hydrogen, R2 is hydrogen, and R3 is -LZ.

[0088] In some embodiments, U is a bond, —(NR4)—, —O—, C1-C3 alkylene, C2-C3 alkenylene, C2-C3 alkynylene, C3-C6 cycloalkylene, 4-10 membered heterocyclylene, 5-10 membered heteroarylene, —(C═O)NR4—, —NR4(C═O)—, —OR5—, —R5O—, —NR4R5—, —R5NR4—, or —(NR4)(C═O)(NR4)—. In some embodiments, U is —(NR4)—, —NR4R5—, or —R5NR4—. In some embodiments, U is —(NR4)—. In some embodiments, R4 is hydrogen. In some embodiments, R4 is C1-C6 alkyl. In some embodiments, U is —O—, —OR5—, or —R5O—. In some embodiments, U is —O—. In some embodiments, U is —NR4(C═O)—, —(C═O)NR4—, or —(NR4)(C═O)(NR4)—. In some embodiments, U is —NR4(C═O)—. In some embodiments, each R4 in U is independently hydrogen or C1-C6 alkyl. In some embodiments, each R4 in U is hydrogen.

[0089] In some embodiments, U is C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene. In some embodiments, U is C2-C3 alkenylene. In some embodiments, U is C2-C3 alkynylene. In some embodiments, U is C3-C6 cycloalkylene, 4-10 membered heterocyclylene, or 5-10 membered heteroarylene, each of which is optionally substituted with 1-3 substituents independently selected from fluoro, hydroxyl, C1-C6 alkoxy, and C1-C6 alkyl. In some embodiments, U is a bond.

[0090] In some embodiments, V is a bond, —(NR4)—, —O—, C1-C6 alkylene, C2-C6 alkenylene, —(C═O)NR4—, —(NR4)R5—, —(NR4)(C═O)—, —NH(C═O)NH—, —OR5—, —R5O—, 4-10 membered heterocyclylene, 5-10 membered heteroarylene, C6-C10 arylene, or C3-C6 cycloalkylene. In some embodiments, V is C1-C6 alkylene or C2-C6 alkenylene. In some embodiments, V is C1-C6 alkylene. In some embodiments, V is C1-C3 alkylene. In some embodiments, V is methylene or ethylene.

[0091] In some embodiments, V is 4-10 membered heterocyclylene, 5-10 membered heteroarylene, C6-C10 arylene, or C3-C6 cycloalkylene, each of which is optionally substituted with 1-3 substituents independently selected from fluoro, hydroxyl, C1-C6 alkoxy, and C1-C6 alkyl. In some embodiments, V is 4-10 membered heterocyclylene, 5-10 membered heteroarylene, C6-C10 arylene, or C3-C6 cycloalkylene, each of which is substituted with 1-3 substituents independently selected from fluoro, hydroxyl, C1-C6 alkoxy, and C1-C6 alkyl. In some embodiments, V is 4-10 membered heterocyclylene, 5-10 membered heteroarylene, C6-C10 arylene, or C3-C6 cycloalkylene.

[0092] In some embodiments, V is 4-10 membered heterocyclylene. In some embodiments, V is 4-6 membered heterocyclylene. In some embodiments, V is selected from the group consisting of:

[0093] [ka]

[0094] In some embodiments, V is a 5- to 10-membered heteroarylene. In some embodiments, V is a 5- to 6-membered heteroarylene. In some embodiments, V is selected from the group consisting of:

[0095] [ka]

[0096] In some embodiments, V is C6-C10 arylene. In some embodiments, V is phenyl. In some embodiments, V is naphthyl.

[0097] In some embodiments, V is C3-C6 cycloalkylene. In some embodiments, V is selected from the group consisting of cyclobutylene, cyclopentylene, and cyclohexylene.

[0098] In some embodiments, V is -(C=O)NR-, -(NR)R-, -(NR)(C=O)-, or -NH(C=O)NH-. In some embodiments, V is -(NR)- or -(NR)R-. In some embodiments, V is -O-, -OR-, or -RO-. In some embodiments, V is a bond.

[0099] In some embodiments, W is a bond, C1-C3 alkylene optionally substituted with hydroxyl, C3-C6 cycloalkylene, 4-12 membered heterocyclylene, -O-, -(NR4)-, -R5(NR4)-, -(NR4)R5-, -(NR4)(C=O)-, -R5(NR4)(C=O)-, -(C=O)(NR4)R5-, -R5(C=O)(NR4)-, -(C=O)(NR4)-, -R5(C=O)-, -(C=O)R5-, -(C=O)-, -(S=O)-, or -S(O2)-.

[0100] In some embodiments, W is a bond. In some embodiments, W is C1-C3 alkylene optionally substituted with hydroxyl. In some embodiments, W is C1-C3 alkylene substituted with hydroxyl. In some embodiments, W is C1-C3 alkylene. In some embodiments, W is C3-C6 cycloalkylene or 4-12 membered heterocyclylene, each of which is optionally substituted with 1-3 substituents independently selected from fluoro, hydroxyl, C1-C6 alkoxy, and C1-C6 alkyl. In some embodiments, W is -O-, -(NR4)-, -R5(NR4)-, or -(NR4)R5-. In some embodiments, W is -O- or -(NR4)-. In some embodiments, each R4 of W is hydrogen.

[0101] In some embodiments, W is —(NR4)(C═O)—, —R5(NR4)(C═O)—, —(C═O)(NR4)R5—, —R5(C═O)(NR4)—, or —(C═O)(NR4)—. In some embodiments, W is —(NR4)(C═O)—. In some embodiments, W is —R5(NR4)(C═O)—. In some embodiments, W is —(C═O)(NR4)—. In some embodiments, R4 in W is hydrogen. In some embodiments, each R4 in W is independently C1-C3 alkyl. In some embodiments, each R5 in W is C1-C3 alkylene. In some embodiments, W is —R5(C═O)—, —(C═O)R5—, —(C═O)—, —(S═O)—, or —S(O2)—. In some embodiments, W is —(C═O)—. In some embodiments, W is —R 5 (C═O)— or —(C═O)R 5 —, where R 5 is C1-C3 alkylene.

[0102] In some embodiments, X is a bond, C1-C3 alkylene, C3-C6 cycloalkylene, 4-12 membered heterocyclylene, C6-C10 arylene, 5-10 membered heteroarylene, -R5(NR4)(C=O)-, -(C=O)R5(NR4)-, -R5(C=O)(NR4)-, -(NR4)(C=O)R5-, -R5(C=O)(NR4)-, -(C=O)(NR4)R5-, -(NR4)R5(C=O)-, -R5(C=O)(NR4)R5-, -R5(NR4)(C=O)R5-, -(C=O)R5-, or -R5(C=O)-.

[0103] In some embodiments, X is C1-C3 alkylene. In some embodiments, X is methylene or ethylene.

[0104] In some embodiments, X is a C3-C6 cycloalkylene, a 4-12-membered heterocyclylene, a C6-C10 arylene, or a 5-10-membered heteroarylene, each of which is optionally substituted with 1-3 substituents independently selected from fluoro, hydroxyl, C1-C6 alkoxy, and C1-C6 alkyl. In some embodiments, X is a C3-C6 cycloalkylene, a 4-12-membered heterocyclylene, a C6-C10 arylene, or a 5-10-membered heteroarylene, each of which is substituted with 1-3 substituents independently selected from fluoro, hydroxyl, C1-C6 alkoxy, and C1-C6 alkyl. In some embodiments, X is a C3-C6 cycloalkylene, a 4-12-membered heterocyclylene, a C6-C10 arylene, or a 5-10-membered heteroarylene.

[0105] In some embodiments, X is C3-C6 cycloalkylene or 4-12 membered heterocyclylene. In some embodiments, X is 4-10 membered heterocyclylene. In some embodiments, X is 4-6 membered heterocyclylene. In some embodiments, X is selected from the group consisting of:

[0106] [ka]

[0107] In some embodiments, X is

[0108] [ka]

[0109] is.

[0110] In some embodiments, X is C3-C6 cycloalkylene (eg, cyclopentyl or cyclohexyl).

[0111] In some embodiments, X is a 5- to 10-membered heteroarylene. In some embodiments, X is a 5- to 6-membered heteroarylene. In some embodiments, V is selected from the group consisting of:

[0112] [ka]

[0113] In some embodiments, X is C6-C10 arylene. In some embodiments, X is phenyl. In some embodiments, X is naphthyl.

[0114] In some embodiments, X is selected from the group consisting of —R5(NR4)(C═O)—, —(C═O)R5(NR4)—, —R5(C═O)(NR4)—, —(NR4)(C═O)R5—, —R5(C═O)(NR4)—, —(C═O)(NR4)R5—, —(NR4)R5(C═O)—, —R5(C═O)(NR4)R5—, or —R5(NR4)(C═O)R5—. In some embodiments, X is —(C═O)R5— or —R5(C═O)—. In some embodiments, each R4 in X is independently hydrogen or C1-C3 alkyl. In some embodiments, each R4 in X is hydrogen. In some embodiments, R5 is C1-C3 alkylene. In some embodiments, X is a bond.

[0115] In some embodiments, U is -NR4(C=O)- or -(C=O)NR4-, V is a bond or C1-C6 alkylene, W is a bond, and X is a bond. In some embodiments, U is -NR4(C=O)- or -(C=O)NR4-, V is a bond or C1-C6 alkylene, W is a bond, and X is a 4-12 membered heterocyclylene. In some embodiments, U is -NR4(C=O)-. In some embodiments, U is -(C=O)NR4-. In some embodiments, V is a bond. In some embodiments, V is C1-C3 alkylene. In some embodiments, V is methylene or ethylene.

[0116] In some embodiments, U is -O-, V is C1-C6 alkylene, C3-C6 cycloalkylene, or 4-10 membered heterocyclylene, and W is -C(=O)-, -N(R4)-, -C(=O)NR4-, -NR4C(=O)-, or -NR4C(=O)R5-. In some embodiments, V is C1-C6 alkylene. In some embodiments, V is C1-C3 alkylene. In some embodiments, V is methylene or ethylene. In some embodiments, W is -C(=O)- or -C(=O)NR4-. In some embodiments, W is -NR4C(=O)-. In some embodiments, W is -NR4C(=O)R5-. In some embodiments, each R4 in W is hydrogen. In some embodiments, each R5 in W is independently C1-C3 alkylene.

[0117] In some embodiments, U is -NR4-, V is C1-C6 alkylene or a bond, W is -C(=O)- or -C(=O)R5-, and X is a bond. In some embodiments, U is -NH-. In some embodiments, U is -N(C1-C3 alkyl)-. In some embodiments, V is C1-C3 alkylene. In some embodiments, V is methylene or ethylene. In some embodiments, W is -C(=O)-. In some embodiments, W is -C(=O)R5-. In some embodiments, each R5 within W is independently C1-C3 alkylene.

[0118] In some embodiments, U is a bond, C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene, V is a bond, W is a bond or C(=O), and X is a bond or C6-C10 arylene. In some embodiments, U is a bond. In some embodiments, U is a C2-C3 alkenylene. In some embodiments, U is a C2-C3 alkynylene. In some embodiments, W is a bond. In some embodiments, W is C(=O). In some embodiments, X is a bond. In some embodiments, X is a C6-C10 arylene.

[0119] In some embodiments, Y is R6, R6(CRARB)pQ-, or -Q-(CRARB)pR6-.

[0120] In some embodiments, Y is R6. In some embodiments, R6 is a 4-12 membered heterocyclylene optionally substituted with 1-3 substituents independently selected from fluoro, hydroxyl, C1-C6 alkoxy, and C1-C6 alkyl. In some embodiments, R6 is a 4-8 membered heterocyclylene optionally substituted with 1-3 substituents independently selected from fluoro, hydroxyl, C1-C6 alkoxy, and C1-C6 alkyl. In some embodiments, R6 is a 4-6 membered heterocyclylene optionally substituted with 1-3 substituents independently selected from fluoro, hydroxyl, C1-C6 alkoxy, and C1-C6 alkyl.

[0121] In some embodiments, R6 is a 4- to 12-membered heterocyclylene substituted with 1-3 substituents independently selected from fluoro, hydroxyl, C1-C6 alkoxy, and C1-C6 alkyl. In some embodiments, R6 is a 4- to 8-membered heterocyclylene substituted with 1-3 substituents independently selected from fluoro, hydroxyl, C1-C6 alkoxy, and C1-C6 alkyl. In some embodiments, R6 is a 4- to 6-membered heterocyclylene substituted with 1-3 substituents independently selected from fluoro, hydroxyl, C1-C6 alkoxy, and C1-C6 alkyl.

[0122] In some embodiments, R6 is a 4-8 membered heterocyclylene substituted with hydroxyl. In some embodiments, R6 is a 4-8 membered heterocyclylene substituted with C1-C6 alkyl (e.g., methyl). In some embodiments, R6 is a 4-8 membered heterocyclylene substituted with fluoro. In some embodiments, R6 is a 4-8 membered heterocyclylene substituted with two fluoro.

[0123] In some embodiments, R6 is 4-12 membered heterocyclylene. In some embodiments, R6 is 4-8 membered heterocyclylene. In some embodiments, R6 is 4-6 membered heterocyclylene.

[0124] In some embodiments, R6 is selected from the group consisting of:

[0125] [ka]

[0126] In some embodiments, R6 is

[0127] [ka]

[0128] In some embodiments, R6 is

[0129] [ka]

[0130] is.

[0131] In some embodiments, R6 is a 7-12 membered bicyclic heterocyclylene. In some embodiments, R6 is a 7-12 membered bicyclic spirocyclic heterocyclylene. In some embodiments, R6 is

[0132] [ka]

[0133] is.

[0134] In some embodiments, R6 is a 5-10 membered heteroarylene optionally substituted with 1-3 substituents independently selected from fluoro, hydroxyl, C1-C6 alkoxy, and C1-C6 alkyl. In some embodiments, R6 is a 5-6 membered heteroarylene optionally substituted with 1-3 substituents independently selected from fluoro, hydroxyl, C1-C6 alkoxy, and C1-C6 alkyl. In some embodiments, R6 is a 5-6 membered heteroarylene. In some embodiments, R6 is selected from the group consisting of:

[0135] [ka]

[0136] In some embodiments, R6 is C1-C3 alkylene.

[0137] In some embodiments, -Y is -R6(CRARB)pQ-. In some embodiments, -Y- is -Q-(CRARB)pR6-. In some embodiments, -Q- is -(NR4)-. In some embodiments, R4 is hydrogen. In some embodiments, R4 is C1-C3 alkyl. In some embodiments, -Q- is -O-.

[0138] In some embodiments, p is 0, 1, or 2. In some embodiments, p is 0 or 1. In some embodiments, p is 1 or 2. p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0139] In some embodiments, each R A and R B is independently hydrogen, fluoro, or C1-C3 alkyl. In some embodiments, a pair of R A and R B on the same carbon are linked to form oxo. In some embodiments, each R A and R B is hydrogen. In some embodiments, one or two of R A and R B are independently fluoro or C1-C3 alkyl, and each remaining R A and R B is hydrogen. In some embodiments, a pair of R A and R B on the same carbon are linked to form oxo, and each remaining R A and R B, if present, is hydrogen.

[0140] In some embodiments, Y is -R6(CRARB)pQ-, and p is 0. In some embodiments, Y is -R6NR4- or -R6O-. In some embodiments, Y is -R6NR4-. In some embodiments, Y is -R6O-. In some embodiments, Y is R6(CRARB)pQ- or -Q-(CRARB)pR6-, and p is 1 or 2, and each of R and R is hydrogen. In some embodiments, Y is -R6CH2-O- or -R6CH2-N(R4)-. In some embodiments, Y is -R6CH2-O-. In some embodiments, Y is -R6CH2-NH.

[0141] In some embodiments, Y is -R(CRARB)pQ- or -Q-(CRARB)pR6-, where p is 1 or 2, and each R and R is independently hydrogen or C1-C3 alkyl, or one pair of R and R together with the carbon atom to which they are attached form a C3-C4 cycloalkyl, and each remaining R and R, if present, is hydrogen. In some embodiments, Y is -R(CRARB)pQ-. In some embodiments, Y is -Q-(CRARB)pR6-.

[0142] In some embodiments, the -(CRARB)pQ- portion of Y is selected from the group consisting of:

[0143] [ka]

[0144] In some embodiments, Y is -RC(=O)(CRARB)-Q-, where each R and R is independently hydrogen, fluoro, or C1-C3 alkyl. In some embodiments, Y is -Q-(CRARB)pR6-, where each R and R is independently hydrogen, fluoro, or C1-C3 alkyl. In some embodiments, the -(CRARB)pQ- portion of Y is selected from the group consisting of:

[0145] [ka]

[0146] In some embodiments, R6 is a 5- to 10-membered heteroarylene optionally substituted with 1-3 substituents independently selected from fluoro, hydroxyl, C1-C6 alkoxy, and C1-C6 alkyl. In some embodiments, R6 is a 5- to 6-membered heteroarylene optionally substituted with 1-3 substituents independently selected from fluoro, hydroxyl, C1-C6 alkoxy, and C1-C6 alkyl. In some embodiments, R6 is a 5- to 10-membered heteroarylene substituted with 1-3 substituents independently selected from fluoro, hydroxyl, C1-C6 alkoxy, and C1-C6 alkyl. In some embodiments, R6 is a 5- to 6-membered heteroarylene substituted with 1-3 substituents independently selected from fluoro, hydroxyl, C1-C6 alkoxy, and C1-C6 alkyl. In some embodiments, R6 is a 5- to 10-membered heteroarylene. In some embodiments, R6 is a 5- to 6-membered heteroarylene.

[0147] In some embodiments, R6 is a 5- to 6-membered heteroarylene. In some embodiments, R6 is a triazolylene, pyrazolylene, or pyridinylene. In some embodiments, R6 is selected from the group consisting of:

[0148] [ka]

[0149] In some embodiments, R6 is C6-C10 arylene. In some embodiments, R6 is phenylene.

[0150] In some embodiments, Z is

[0151] [ka]

[0152] is.

[0153] In some embodiments, Z is selected from the group consisting of:

[0154] [ka]

[0155] In some embodiments, Z is

[0156] [ka]

[0157] is.

[0158] In some embodiments, Z is

[0159] [ka]

[0160] is.

[0161] In some embodiments, Z is

[0162] [ka]

[0163] is.

[0164] In some embodiments, Z is

[0165] [ka]

[0166] is.

[0167] In some embodiments, Z is selected from the group consisting of:

[0168] [ka]

[0169] In some embodiments, Z is

[0170] [ka]

[0171] is.

[0172] In some embodiments, Z is

[0173] [ka]

[0174] is.

[0175] In some embodiments, Z is

[0176] [ka]

[0177] is.

[0178] In some embodiments, Z is selected from the group consisting of:

[0179] [ka]

[0180] In some embodiments, Z is selected from the group consisting of:

[0181] [ka]

[0182] In some embodiments, Z is selected from the group consisting of:

[0183] [ka]

[0184] In some embodiments, Z is

[0185] [ka]

[0186] is.

[0187] In some embodiments, Z is

[0188] [ka]

[0189] is.

[0190] In some embodiments, Z is

[0191] [ka]

[0192] is.

[0193] In some embodiments, Z is

[0194] [ka]

[0195] is.

[0196] In some embodiments, Z is

[0197] [ka]

[0198] is.

[0199] In some embodiments, Z is

[0200] [ka]

[0201] is.

[0202] In some embodiments, R7, when present, is hydrogen. In some embodiments, R7, when present, is C1-C6 alkyl. In some embodiments, R7, when present, is C1-C3 alkyl. In some embodiments, R7, when present, is methyl. In some embodiments, R7, when present, is C1-C6 alkyl substituted with one group selected from hydroxyl, cyano, and C1-C6 alkoxy. In some embodiments, R7, when present, is C1-C6 haloalkyl. In some embodiments, R7, when present, is C3-C6 cycloalkyl, or 4-6 membered heterocyclyl, -(CRARB)(4-12 membered heterocyclyl), or -(CRARB)(C3-C6 cycloalkyl). In some embodiments, each of R and R is hydrogen.

[0203] In some embodiments, R8, when present, is hydrogen. In some embodiments, R8, when present, is C1-C6 alkyl. In some embodiments, R8, when present, is C1-C3 alkyl.

[0204] In some embodiments, q is 0 or 1. In some embodiments, q is 0. In some embodiments, q is 1.

[0205] In some embodiments, R9, if present, is hydrogen. In some embodiments, R9, if present, is halogen. In some embodiments, R9, if present, is cyano. In some embodiments, R9, if present, is C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments, R9, if present, is C1-C6 alkoxy, C1-C5 cycloalkoxy, 5-10 membered heteroaryloxy, or phenoxy.

[0206] In some embodiments, each R10, if present, is hydrogen. In some embodiments, one R10 is cyano and the remaining R10, if present, are hydrogen. In some embodiments, one R10 is halogen and the remaining R10, if present, are hydrogen. In some embodiments, the halogen is fluoro. In some embodiments, one R10 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl and the remaining R10, if present, are hydrogen.

[0207] In some embodiments, the compound of Formula (I) has the formula (Ia):

[0208] [ka]

[0209] or a pharmaceutically acceptable salt thereof.

[0210] In some embodiments, the compound of Formula (I) has the formula (Ib):

[0211] [ka]

[0212] or a pharmaceutically acceptable salt thereof, wherein B1 is O or NR7.

[0213] In some embodiments, the compound of Formula (Ib) has the formula (I-b1):

[0214] [ka]

[0215] or a pharmaceutically acceptable salt thereof.

[0216] In some embodiments, the compound of Formula (Ib) has the formula (I-b2):

[0217] [ka]

[0218] or a pharmaceutically acceptable salt thereof.

[0219] In some embodiments of the compound of Formula (Ib), B1 is NR7. In some embodiments of the compound of Formula (Ib), R7 is C1-C3 alkyl. In some embodiments of the compound of Formula (Ib), R7 is methyl, ethyl, or isopropyl. In some embodiments of the compound of Formula (Ib), R7 is methyl. In some embodiments of the compound of Formula (Ib), R7 is hydrogen. In some embodiments, B1 is O.

[0220] In some embodiments, the compound of Formula (I) has the formula (Ic):

[0221] [ka]

[0222] or a pharmaceutically acceptable salt thereof, wherein Rz1 and Rz2 are both hydrogen or Rz1 and Rz2 are joined to form oxo.

[0223] In some embodiments, the compound of Formula (Ic) has the formula (I-c1):

[0224] [ka]

[0225] or a pharmaceutically acceptable salt thereof.

[0226] In some embodiments, the compound of Formula (Ic) has the formula (I-c2):

[0227] [ka]

[0228] or a pharmaceutically acceptable salt thereof.

[0229] In some embodiments of compounds of Formula (I-c2), RZ1 and RZ2 are both hydrogen. In some embodiments of compounds of Formula (I-c2), RZ1 and RZ2 are linked to form oxo.

[0230] In some embodiments, the compound of Formula (I) has the formula (Id):

[0231] [ka]

[0232] or a pharmaceutically acceptable salt thereof, wherein B2 is CH or N. In some embodiments of a compound of Formula (Id), B2 is CH. In some embodiments of a compound of Formula (Id), R9 is hydrogen. In some embodiments of a compound of Formula (Id), R9 is halogen. In some embodiments of a compound of Formula (Id), R9 is fluoro. In some embodiments of a compound of Formula (Id), R7 is hydrogen.

[0233] In some embodiments, the compound of Formula (I) has the formula (Ie):

[0234] [ka]

[0235] or a pharmaceutically acceptable salt thereof. In some embodiments of the compound of Formula (Ie), R2 is hydrogen. In some embodiments of the compound of Formula (Ie), R2 is halogen. In some embodiments of the compound of Formula (Ie), R2 is C1-C3 alkoxy, C3-C6 cycloalkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, or C3-C5 halocycloalkoxy. In some embodiments of the compound of Formula (Ie), R2 is C1-C3 alkyl or C3-C6 cycloalkyl.

[0236] In some embodiments, the compound of Formula (I) has the formula (II-a):

[0237] [ka]

[0238] or a pharmaceutically acceptable salt thereof.

[0239] In some embodiments, the compound of Formula (I) has the formula (II-b):

[0240] [ka]

[0241] or a pharmaceutically acceptable salt thereof, wherein B1 is O or NR7.

[0242] In some embodiments, the compound of formula (II-b) has the formula (II-b1):

[0243] [ka]

[0244] or a pharmaceutically acceptable salt thereof.

[0245] In some embodiments, the compound of Formula (II-b) has the formula (II-b2):

[0246] [ka]

[0247] or a pharmaceutically acceptable salt thereof. In some embodiments of the compound of Formula (II-b2), B1 is NR7. In some embodiments of the compound of Formula (II-b2), R7 is C1-C3 alkyl. In some embodiments of the compound of Formula (II-b2), R7 is methyl, ethyl, or isopropyl. In some embodiments of the compound of Formula (II-b2), R7 is methyl. In some embodiments of the compound of Formula (II-b2), R7 is hydrogen. In some embodiments of the compound of Formula (II-b2), B1 is O.

[0248] In some embodiments, the compound of Formula (I) has the formula (II-c):

[0249] [ka]

[0250] or a pharmaceutically acceptable salt thereof, wherein Rz1 and Rz2 are both hydrogen or Rz1 and Rz2 are joined to form oxo.

[0251] In some embodiments, the compound of Formula (II-c) has the formula (II-c1):

[0252] [ka]

[0253] or a pharmaceutically acceptable salt thereof.

[0254] In some embodiments, the compound of Formula (II-c) has the formula (II-c2):

[0255] [ka]

[0256] or a pharmaceutically acceptable salt thereof. In some embodiments, R and R are both hydrogen. In some embodiments of the compound of Formula (II-c2), R and R are linked to form oxo.

[0257] In some embodiments, the compound of Formula (I) has the formula (II-d):

[0258] [ka]

[0259] or a pharmaceutically acceptable salt thereof, wherein B2 is CH or N. In some embodiments of a compound of Formula (II-d), B2 is CH. In some embodiments of a compound of Formula (II-d), R9 is hydrogen. In some embodiments of a compound of Formula (II-d), R9 is halogen. In some embodiments of a compound of Formula (II-d), R9 is fluoro. In some embodiments of a compound of Formula (II-d), R7 is hydrogen.

[0260] In some embodiments, the compound of Formula (I) has the formula (II-e):

[0261] [ka]

[0262] or a pharmaceutically acceptable salt thereof. In some embodiments of a compound of Formula (II-e), R3 is hydrogen. In some embodiments of a compound of Formula (II-e), R3 is halogen. In some embodiments of a compound of Formula (II-e), R3 is C1-C3 alkoxy, C3-C6 cycloalkoxy, C1-C3 haloalkoxy, or C3-C5 halocycloalkoxy. In some embodiments of a compound of Formula (II-e), R3 is C1-C3 alkyl or C3-C6 cycloalkyl. In some embodiments of a compound of Formula (II-e), Rx is hydrogen. In some embodiments of a compound of Formula (II-e), Rx is halogen.

[0263] In some embodiments of the compounds of Formula (Ia) through Formula (II-e), L is -UVWXY-. In some embodiments of the compounds of Formula (Ia) through Formula (II-e), U is -NR4(C=O)- or -(C=O)NR4-, V is a bond or C1-C6 alkylene, W is a bond, and X is a bond. In some embodiments of the compounds of Formula (Ia) through Formula (II-e), U is -NR4(C=O)- or In some embodiments of the compounds of Formula (Ia) through Formula (II-e), U is -NR4(C=O)-, V is a bond or C1-C6 alkylene, W is a bond, and X is 4-12 membered heterocyclylene. In some embodiments of the compounds of Formula (Ia) through Formula (II-e), U is -NR4(C=O)-. In some embodiments of the compounds of Formula (Ia) through Formula (II-e), U is -(C=O)NR4-. In some embodiments of the compounds of Formula (Ia) through Formula (II-e), V is a bond. In some embodiments of the compounds of Formula (Ia) through Formula (II-e), V is C1-C3 alkylene. In some embodiments of the compounds of Formula (Ia) through Formula (II-e), V is methylene or ethylene.

[0264] In some embodiments of the compounds of Formula (Ia) through Formula (II-e), U is -O-; V is C1-C6 alkylene, C3-C6 cycloalkylene, or 4-10-membered heterocyclylene; and W is -C(=O)-, -N(R4)-, -C(=O)NR4-, -NR4C(=O)-, -NR4C(=O)R5-, -(S=O)-, or -S(O2)-. In some embodiments of the compounds of Formula (Ia) through Formula (II-e), V is C1-C6 alkylene. In some embodiments of the compounds of Formula (Ia) through Formula (II-e), V is C1-C3 alkylene. In some embodiments of the compounds of Formula (Ia) through Formula (II-e), V is methylene or ethylene. In some embodiments of the compounds of Formula (Ia) through Formula (II-e), W is -C(=O)- or -C(=O)NR4-. In some embodiments of the compounds of Formula (Ia) through Formula (II-e), W is -NR4C(=O)-. In some embodiments of the compounds of Formula (Ia) through Formula (II-e), W is -NR4C(=O)R5-. In some embodiments of the compounds of Formula (Ia) through Formula (II-e), R4 is hydrogen. In some embodiments of the compounds of Formula (Ia) through Formula (II-e), R5 is C1-C3 alkylene.

[0265] In some embodiments of the compounds of Formula (Ia) through Formula (II-e), U is -NR4-, V is C1-C6 alkylene or a bond, W is -C(=O)- or -C(=O)R5-, and X is a bond. In some embodiments of the compounds of Formula (Ia) through Formula (II-e), U is -NH-. In some embodiments of the compounds of Formula (Ia) through Formula (II-e), U is -N(C1-C3 alkyl)-. In some embodiments of the compounds of Formula (Ia) through Formula (II-e), V is C1-C3 alkylene. In some embodiments of the compounds of Formula (Ia) through Formula (II-e), V is methylene or ethylene. In some embodiments of the compounds of Formula (Ia) through Formula (II-e), W is -C(=O)-. In some embodiments of the compounds of Formula (Ia) through Formula (II-e), W is -C(=O)R5-. In some embodiments of the compounds of Formula (Ia) through Formula (II-e), R5 is C1-C3 alkylene.

[0266] In some embodiments of the compounds of Formula (Ia) through Formula (II-e), U is a bond, C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene; V is a bond; W is a bond or C(═O); and X is a bond or C6-C10 arylene. In some embodiments of the compounds of Formula (Ia) through Formula (II-e), U is a bond. In some embodiments of the compounds of Formula (Ia) through Formula (II-e), U is a C2-C3 alkenylene. In some embodiments of the compounds of Formula (Ia) through Formula (II-e), U is a C2-C3 alkynylene. In some embodiments of the compounds of Formula (Ia) through Formula (II-e), W is a bond. In some embodiments of the compounds of Formula (Ia) through Formula (II-e), W is C(═O). In some embodiments of the compounds of Formula (Ia) through Formula (II-e), X is a bond. In some embodiments of compounds of Formula (Ia) through Formula (II-e), X is a C6-C10 arylene.

[0267] In some embodiments of the compounds of Formula (Ia) through Formula (II-e), Y is R6. In some embodiments of the compounds of Formula (Ia) through Formula (II-e), R6 is a 4- to 12-membered heterocyclylene optionally substituted with 1-3 substituents independently selected from fluoro, hydroxyl, C1-C6 alkoxy, and C1-C6 alkyl. In some embodiments of the compounds of Formula (Ia) through Formula (II-e), R6 is a 4- to 8-membered heterocyclylene optionally substituted with 1-3 substituents independently selected from fluoro, hydroxyl, C1-C6 alkoxy, and C1-C6 alkyl. In some embodiments of the compounds of Formula (Ia) through Formula (II-e), R6 is selected from the group consisting of:

[0268] [ka]

[0269] In some embodiments of compounds of Formula (Ia) through Formula (II-e), R6 is

[0270] [ka]

[0271] In some embodiments of the compounds of Formula (Ia) to Formula (II-e), R6 is

[0272] [ka]

[0273] In some embodiments of the compounds of Formula (Ia) through Formula (II-e), R6 is a 7-12 membered bicyclic heterocyclylene. In some embodiments of the compounds of Formula (Ia) through Formula (II-e), R6 is a 7-12 membered bicyclic spirocyclic heterocyclylene. In some embodiments of the compounds of Formula (Ia) through Formula (II-e), R6 is

[0274] [ka]

[0275] In some embodiments of the compounds of Formula (Ia) through Formula (II-e), R6 is C1-C3 alkylene.

[0276] In some embodiments of Formula (Ia) to Formula (II-e), R6 is a 5- to 10-membered heteroarylene. In some embodiments of Formula (Ia) to Formula (II-e), R6 is a 5- to 6-membered heteroarylene. In some embodiments of Formula (Ia) to Formula (II-e), R6 is selected from the group consisting of:

[0277] [ka]

[0278] In some embodiments of the compounds of Formula (Ia) through Formula (II-e), R6 is C1-C3 alkylene.

[0279] In some embodiments of the compounds of Formula (Ia) through Formula (II-e), Y is -R(CRARB)pQ-, and p is 0. In some embodiments of the compounds of Formula (Ia) through Formula (II-e), Y is -R6NR4- or -R6O-. In some embodiments of the compounds of Formula (Ia) through Formula (II-e), Y is -R6NH. In some embodiments of the compounds of Formula (Ia) through Formula (II-e), Y is -R6O-. In some embodiments of the compounds of Formula (Ia) through Formula (II-e), Y is R6(CRARB)pQ- or -Q-(CRARB)pR6-, and p is 1 or 2, and each of R and R is hydrogen. In some embodiments of the compounds of Formula (Ia) through Formula (II-e), Y is -R6CH2-O- or -R6CH2-N(R4)-. In some embodiments of the compounds of Formula (Ia) through Formula (II-e), Y is -R6CH2-O-. In some embodiments of the compounds of Formula (Ia) through Formula (II-e), Y is -R6CH2-NH. In some embodiments of the compounds of Formula (Ia) through Formula (II-e), Y is -R6(CRARB)pQ- or -Q-(CRARB)pR6-, where p is 1 or 2, and each R and R is independently hydrogen or C1-C3 alkyl, or one pair of R and R together with the carbon atom to which they are attached form a C3-C4 cycloalkyl, and the remaining each R and R, if present, is hydrogen.

[0280] In some embodiments of the compounds of Formula (Ia) through Formula (II-e), the -(CRARB)pQ- moiety of Y is selected from the group consisting of:

[0281] [ka]

[0282] In some embodiments of the compounds of Formula (Ia) through Formula (II-e), Y is —RC(═O)(CRARB)—Q—, and each R and R is independently hydrogen, fluoro, or C-C alkyl.

[0283] In some embodiments of the compounds of Formula (Ia) through Formula (II-e), the -(CRARB)pQ- moiety of Y is selected from the group consisting of:

[0284] [ka]

[0285] In some embodiments of a compound of Formula (Ia) through Formula (II-e), R6 is a 4-12 membered heterocyclylene optionally substituted with 1-3 substituents independently selected from fluoro, hydroxyl, C1-C6 alkoxy, and C1-C6 alkyl. In some embodiments of a compound of Formula (Ia) through Formula (II-e), R6 is a 4-8 membered heterocyclylene optionally substituted with 1-3 substituents independently selected from fluoro, hydroxyl, C1-C6 alkoxy, and C1-C6 alkyl. In some embodiments of a compound of Formula (Ia) through Formula (II-e), R6 is selected from the group consisting of:

[0286] [ka]

[0287] In some embodiments of compounds of Formula (Ia) through Formula (II-e), R6 is

[0288] [ka]

[0289] In some embodiments of the compounds of Formula (Ia) to Formula (II-e), R6 is

[0290] [ka]

[0291] In some embodiments of the compounds of Formula (Ia) through Formula (II-e), R6 is a 7-12 membered bicyclic heterocyclylene. In some embodiments of the compounds of Formula (Ia) through Formula (II-e), R6 is a 7-12 membered bicyclic spirocyclic heterocyclylene. In some embodiments of the compounds of Formula (Ia) through Formula (II-e), R6 is

[0292] [ka]

[0293] is.

[0294] In some embodiments of the compounds of Formula (Ia) through Formula (II-e), R6 is C6-C10 arylene. In some embodiments of the compounds of Formula (Ia) through Formula (II-e), R6 is phenylene.

[0295] In some embodiments of the compounds of Formula (Ia) through Formula (II-e), R6 is a 5- to 10-membered heteroarylene. In some embodiments of the compounds of Formula (Ia) through Formula (II-e), R6 is a 5- to 6-membered heteroarylene. In some embodiments of the compounds of Formula (Ia) through Formula (II-e), R6 is a 5- to 6-membered heteroarylene. In some embodiments of the compounds of Formula (Ia) through Formula (II-e), R6 is triazolylene, pyrazolylene, or pyridinylene. In some embodiments of the compounds of Formula (Ia) through Formula (II-e), R6 is selected from the group consisting of:

[0296] [ka]

[0297] In some embodiments, R1 is fluoro, Rx is hydrogen, R2 is hydrogen, and R3 is -LZ; Z is

[0298] [ka]

[0299] and R7 is hydrogen or C1-C6 alkyl.

[0300] In some embodiments, R1 is fluoro, Rx is hydrogen, R2 is -LZ, and R3 is hydrogen.

[0301] Z is

[0302] [ka]

[0303] and R7 is hydrogen or C1-C6 alkyl.

[0304] In some embodiments, U is —(NR4)(C═O)—, —(C═O)NR4—, or —(NR4)(C═O)(NR4)—; V is a bond, C1-C6 alkylene, or a 4-6 membered heterocyclylene optionally substituted with methyl, hydroxyl, methoxy, or one or two fluoro; W is a bond or C1-C3 alkylene; X is a bond or C1-C3 alkylene; Y is R6, R6 is a C3-C7 cycloalkylene, a 4- to 12-membered heterocyclylene, a C6-C10 arylene, or a 5- to 10-membered heteroarylene; R4 is hydrogen or C1-C6 alkyl.

[0305] In some embodiments, U is —(NR4)(C═O)—, —(C═O)NR4—, or —(NR4)(C═O)(NR4)—; V is a bond or a 4-6 membered heterocyclylene optionally substituted with methyl, hydroxyl, methoxy, or one or two fluoro; W is a bond or C1-C3 alkylene; X is a bond or C1-C3 alkylene; Y is R6, R6 is a 4- to 8-membered heterocyclylene, phenyl, or 5- to 6-membered heteroarylene; R4 is hydrogen or C1-C6 alkyl.

[0306] In some embodiments, V and X are bonds.

[0307] In some embodiments, R6 is piperidinyl, piperazinyl, phenyl, pyridinyl, or pyridonyl.

[0308] In some embodiments, W is C1-C3 alkylene and R4 is hydrogen.

[0309] In some embodiments, U is —(NR 4 )(C═O)—, V is a bond, W is C1-C3 alkylene, X is a bond, and Y is R 6 .

[0310] In some embodiments, R4 is hydrogen or methyl and R6 is 5-6 membered heterocyclylene, phenyl, or 5-6 membered heteroarylene.

[0311] In some embodiments, R6 is piperidinyl, piperazinyl, phenyl, pyridinyl, or pyridonyl.

[0312] In some embodiments, R1 is fluoro, Rx is hydrogen, R2 is hydrogen, and R3 is -LZ; Z is

[0313] [ka]

[0314] wherein R7 is hydrogen or C1-C6 alkyl, L is -UVWXY-, U is -(NH)(C=O)-, -(C=O)NH-, or -(NH)(C=O)(NH)-, V is a bond, W is methylene or ethylene, X is a bond, Y is R6, and R6 is piperidinyl, piperazinyl, phenyl, pyridinyl, or pyridonyl.

[0315] In some embodiments, R1 is fluoro, Rx is hydrogen, R2 is -LZ, and R3 is hydrogen.

[0316] Z is

[0317] [ka]

[0318] wherein R7 is hydrogen or C1-C6 alkyl, L is -UVWXY-, and U is -(NH)(C=O)-, -(C=O)NH-, or -(NH)(C=O)(NH)-, V is a bond, W is methylene or ethylene, X is a bond, Y is R6, and R6 is piperidinyl, piperazinyl, phenyl, pyridinyl, or pyridonyl.

[0319] In some embodiments, L is selected from the group consisting of:

[0320] [ka]

[0321] In some embodiments, L is selected from the group consisting of:

[0322] [ka]

[0323] In some embodiments, L is selected from the group consisting of:

[0324] [ka]

[0325] In some embodiments, L is selected from the group consisting of:

[0326] [ka]

[0327] In some embodiments, L is selected from the group consisting of:

[0328] [ka]

[0329] In some embodiments, L is selected from the group consisting of:

[0330] [ka]

[0331] In some embodiments, L is selected from the group consisting of:

[0332] [ka]

[0333] In some embodiments, L is selected from the group consisting of:

[0334] [ka]

[0335] In some embodiments, L is selected from the group consisting of:

[0336] [ka]

[0337] Some embodiments are of formula (I):

[0338] [ka] of

[0339] providing a compound, or a pharmaceutically acceptable salt thereof, During the ceremony, R1 is hydrogen or halogen; R2 is hydrogen, halogen, C1-C3 alkoxy, C3 cycloalkoxy, C1-C3 haloalkoxy, C3-C5 halocycloalkoxy, C1-C3 alkyl, C3 cycloalkyl, or -LZ; R3 is hydrogen, halogen, C1-C3 alkoxy, C3-C5 cycloalkoxy, C1-C3 haloalkoxy, C3-C5 halocycloalkoxy, C1-C3 alkyl, C3-C5 cycloalkyl, or -LZ; One of R2 and R3 is -LZ and the other of R2 and R3 is not -LZ; Rx is hydrogen or halogen; L is selected from the group consisting of:

[0340] [ka]

[0341] [ka]

[0342] [ka]

[0343] [ka]

[0344] Z is selected from the group consisting of:

[0345] [ka]

[0346] R7 is hydrogen, C1-C6 alkyl optionally substituted with one group selected from hydroxyl, cyano, and C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, -(CRARB)(4- to 12-membered heterocyclyl), or -(CRARB)(C3-C6 cycloalkyl); R8 is hydrogen or C1-C6 alkyl; each R9 is halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C5 cycloalkoxy, 5-10 membered heteroaryloxy, or phenoxy; q is 0, 1, or 2; Each R10 is independently hydrogen, halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 haloalkyl.

[0347] In some embodiments, the compound of formula (I) is selected from the compounds set forth in Table 1.

[0348] [Table 1-1]

[0349] [Table 1-2]

[0350] Table 1-3

[0351] Table 1-4

[0352] Table 1-5

[0353] Table 1-6

[0354] Table 1-7

[0355] Table 1-8

[0356] Table 1-9

[0357] Table 1-10

[0358] Table 1-11

[0359] Table 1-12

[0360] Table 1-13

[0361] Table 1-14

[0362] Table 1-15

[0363] Table 1-16

[0364] Table 1-17

[0365] Table 1-18

[0366] Table 1-19

[0367] Table 1-20

[0368] Table 1-21

[0369] Table 1-22

[0370] Table 1-23

[0371] Table 1-24

[0372] Table 1-25

[0373] Table 1-26

[0374] Table 1-27

[0375] Table 1-28

[0376] Table 1-29

[0377] Table 1-30

[0378] Table 1-31

[0379] Table 1-32

[0380] Table 1-33

[0381] Table 1-34

[0382] Table 1-35

[0383] Table 1-36

[0384] Table 1-37

[0385] Table 1-38

[0386] Table 1-39

[0387] Table 1-40

[0388] Table 1-41

[0389] Table 1-42

[0390] Table 1-43

[0391] [Table 1-44]

[0392] [Table 1-45]

[0393] In some embodiments, the compound of formula (I) is selected from the compounds set forth in Table 2.

[0394] [Table 2-1]

[0395] [Table 2-2]

[0396] [Table 2-3]

[0397] [Table 2-4]

[0398] [Table 2-5]

[0399] [Table 2-6]

[0400] [Table 2-7]

[0401] Table 2-8

[0402] Table 2-9

[0403] Table 2-10

[0404] Table 2-11

[0405] Table 2-12

[0406] Table 2-13

[0407] Table 2-14

[0408] Table 2-15

[0409] Table 2-16

[0410] Table 2-17

[0411] Table 2-18

[0412] Table 2-19

[0413] Table 2-20

[0414] Table 2-21

[0415] Table 2-22

[0416] Table 2-23

[0417] Table 2-24

[0418] Table 2-25

[0419] Table 2-26

[0420] Table 2-27

[0421] Table 2-28

[0422] Table 2-29

[0423] Table 2-30

[0424] Table 2-31

[0425] Table 2-32

[0426] Table 2-33

[0427] Table 2-34

[0428] Table 2-35

[0429] Table 2-36

[0430] Table 2-37

[0431] Table 2-38

[0432] Table 2-39

[0433] Table 2-40

[0434] Table 2-41

[0435] Table 2-42

[0436] Table 2-43

[0437] Table 2-44

[0438] Table 2-45

[0439] Table 2-46

[0440] Table 2-47

[0441] Table 2-48

[0442] Table 2-49

[0443] Table 2-50

[0444] Table 2-51

[0445] Table 2-52

[0446] Table 2-53

[0447] Table 2-54

[0448] Table 2-55

[0449] Table 2-56

[0450] Table 2-57

[0451] Table 2-58

[0452] Table 2-59

[0453] Table 2-60

[0454] Table 2-61

[0455] Table 2-62

[0456] Table 2-63

[0457] Table 2-64

[0458] Table 2-65

[0459] Table 2-66

[0460] Table 2-67

[0461] Table 2-68

[0462] Table 2-69

[0463] Table 2-70

[0464] Table 2-71

[0465] Table 2-72

[0466] Table 2-73

[0467] Table 2-74

[0468] Table 2-75

[0469] Table 2-76

[0470] Table 2-77

[0471] Table 2-78

[0472] [Table 2-79]

[0473] [Table 2-80]

[0474] Some embodiments are of formula (III):

[0475] [ka]

[0476] or a pharmaceutically acceptable salt thereof, wherein: R1 is hydrogen or halogen; R2 is hydrogen, halogen, C1-C3 alkoxy, C3-C6 cycloalkoxy, C1-C3 haloalkoxy, C3-C5 halocycloalkoxy, C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, or -L-Q1; R3 is hydrogen, halogen, C1-C3 alkoxy, C3-C5 cycloalkoxy, C1-C3 haloalkoxy, C3-C5 halocycloalkoxy, C1-C3 alkyl, C1-C3 haloalkyl, C3-C5 cycloalkyl, or -L-Q1; One of R2 and R3 is -L-Q1, and the other of R2 and R3 is not -L-Q1; Rx is hydrogen or halogen; L is -UVWXY-, U is a bond, -(NR4)-, -O-, C1-C3 alkylene, C2-C3 alkenylene, C2-C3 alkynylene, C3-C6 cycloalkylene, 4- to 10-membered heterocyclylene, 5- to 10-membered heteroarylene, -(C=O)NR4-, -NR4(C=O)-, -OR5-, -R5O-, -NR4R5-, -R5NR4-, or -(NR4)(C=O)(NR4)-; each R4 is independently hydrogen, C1-C6 alkyl, or C3-C5 cycloalkyl; R5 is C1-C3 alkylene, C3-C7 cycloalkylene, or 4-12 membered heterocyclylene; V is a bond, -(NR4)-, -O-, C1-C6 alkylene, C2-C6 alkenylene, -(C=O)NR4-, -(NR4)R5-, -(NR4)(C=O)-, -NH(C=O)NH-, -OR5-, -R5O-, 4- to 10-membered heterocyclylene, 5- to 10-membered heteroarylene, C6-C10 arylene, or C3-C6 cycloalkylene; W is a bond, C1-C3 alkylene optionally substituted with hydroxyl, C3-C6 cycloalkylene, 4-12 membered heterocyclylene, -O-, -(NR4)-, -R5(NR4)-, -(NR4)R5-, -(NR4)(C=O)-, -R5(NR4)(C=O)-, -(C=O)(NR4)R5-, -R5(C=O)(NR4)-, -(C=O)(NR4)-, -R5(C=O)-, -(C=O)R5-, -(C=O)-, -(S=O)-, or -S(O2)-; X is a bond, C1-C3 alkylene, C3-C6 cycloalkylene, 4-12 membered heterocyclylene, C6-C10 arylene, 5-10 membered heteroarylene, -R5(NR4)(C=O)-, -(C=O)R5(NR4)-, -R5(C=O)(NR4)-, -(NR4)(C=O)R5-, -R5(C=O)(NR4)-, -(C=O)(NR4)R5-, -(NR4)R5(C=O)-, -R5(C=O)(NR4)R5-, -R5(NR4)(C=O)R5-, -(C=O)R5-, or -R5(C=O)-; Y is R, R(CRARB)pQ-, or -Q-(CRARB)pR6-; Q is selected from the group consisting of -(NR4)-, -O-, and -(CRARB)p-; p is 0, 1, 2, or 3; R6 is a C1-C3 alkylene, a C3-C7 cycloalkylene, a 4- to 12-membered heterocyclylene, a C6-C10 arylene, or a 5- to 10-membered heteroarylene; The heterocyclylene, heteroarylene, arylene, and cycloalkylene groups of U, V, W, X, and R6 are each optionally substituted with 1 to 3 substituents independently selected from fluoro, hydroxyl, C1-C6 alkoxy, and C1-C6 alkyl; each R A and R B is independently hydrogen, fluoro, or C1-C6 alkyl; or R A and R B together with the carbon atoms to which they are attached form a C3-C4 cycloalkyl, or RA and RB combine to form oxo Q1 is -NH2, -OH, -CO2H, -(C=O)Cl, -N3, or a C2-C6 alkyne.

[0477] Pharmaceutical Composition Some embodiments provide a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0478] Treatment method The present disclosure features compounds, compositions, and methods that include a compound of Formula (I). In some embodiments, the compounds, compositions, and methods described herein are used in the prevention or treatment of a disease. Exemplary diseases include, but are not limited to, cancer, type 2 diabetes, metabolic syndrome, obesity, NAFLD, NASH, or another metabolic disease. [Example]

[0479] In order that the invention described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and are not to be construed in any way as limiting the scope thereof.

[0480] Synthesis protocol The compounds provided herein can be prepared from readily available starting materials using modifications to the specific synthetic protocols described below that would be well known to those skilled in the art. Where typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it is understood that other process conditions may be used unless otherwise specified. Optimal reaction conditions may vary depending on the specific reactants or solvents used, but such conditions can be determined by those skilled in the art by routine optimization procedures. Additional general schemes for making exemplary compounds of the present disclosure are described herein.

[0481] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The selection of a suitable protecting group for a particular functional group, as well as suitable conditions for protection and deprotection, are well known in the art. For example, numerous protecting groups and their introduction and removal are described in Greene et al., "Protecting Groups in Organic Synthesis," Second Edition, Wiley, New York, 1991, and references cited therein.

[0482] Abbreviation APCI: atmospheric pressure chemical ionization, DCI: desorption chemical ionization, DMSO: dimethyl sulfoxide, ESI: electrospray ionization, HPLC: high performance liquid chromatography, LC / MS: liquid chromatography / mass spectrometry, LED: light emitting diode, MS: mass spectrum, NMR: nuclear magnetic resonance, psi: pounds per square inch, TLC: thin layer chromatography.

[0483] Preparation of exemplary intermediates 5-(3-(benzyloxy)-6-bromo-1-fluoronaphthalen-2-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (8):

[0484] [ka]

[0485] Step 1: 3-(benzyloxy)-1,6-dibromonaphthalen-2-amine (2) 3-(Benzyloxy)naphthalen-2-amine ([1092455-29-2]; 20.0 g, 60.2 mmol) in CHCl (300 mL) was treated dropwise with Br (6.82 mL, 132 mmol) at room temperature. After 12 h, the mixture was poured into water and basified (pH = 8) by adding solid NaCO. The aqueous mixture was extracted with ethyl acetate (3 × 200 mL), and the organic layers were combined, washed with brine (200 mL), dried over NaSO, filtered, and concentrated to give 3-(benzyloxy)-1,6-dibromonaphthalen-2-amine (23 g, 51 mmol, 85% yield; 90% purity) as a dark solid. LCMS (TFA;ESI+): m / z 407.9 [M + H]+ 1H NMR (400 MHz, CDCl3) δ 5.06 - 5.30 (m, 3H), 7.01 (s, 1H), 7.34 - 7.52 (m, 7H), 7.76 (d, J = 2.0 Hz, 1H), 7.83 (d, J = 9.0 Hz, 1H).

[0486] Step 2: 3-(benzyloxy)-6-bromonaphthalen-2-amine (3) 3-(Benzyloxy)-1,6-dibromonaphthalen-2-amine (180 g, 80% purity, 354 mmol) was taken up in EtOH (1500 mL) and treated with tin metal (63 g, 531 mmol). 37% HCl (500 mL) was then added to the slurry, and the mixture was heated to 90 °C for 1 h. The reaction was cooled to room temperature, filtered, and the filtrate was poured into water (500 mL). The mixture was adjusted to pH 8 with solid NaHCO and extracted with ethyl acetate (3 × 300 mL). The combined organic phases were washed with brine (2 × 100 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give 3-(benzyloxy)-6-bromonaphthalen-2-amine (100 g, 274 mmol, 78% yield, 90% purity) as a khaki solid. LCMS (TFA, ESI+): m / z 328.2 [M + H]+ 1H NMR (400 MHz, DMSO-d6) δ 5.15 - 5.36 (m, 4H), 6.93 (s, 1H), 7.24 - 7.30 (m, 2H), 7.32 - 7.38 (m, 1H), 7.38 - 7.48 (m, 3H), 7.56 (d, J = 7.3 Hz, 2H), 7.80 (d, J = 1.6 Hz, 1H).

[0487] Step 3: 3-(benzyloxy)-6-bromo-1-fluoronaphthalen-2-amine (4) To a solution of 3-(benzyloxy)-6-bromonaphthalen-2-amine (100 g, 95% purity, 289 mmol) in THF (1500 mL) was added N-fluorobenzenesulfonimide (100 g, 318 mmol) at room temperature. After 12 h, the mixture was quenched with saturated aqueous sodium thiosulfate (500 mL) and extracted with ethyl acetate (3 × 500 mL). The organic layers were combined, washed with brine (400 mL), then dried (NaSO), filtered, and concentrated. The oil was purified by silica gel chromatography (0% to 5% ethyl acetate:petroleum ether) to give 3-(benzyloxy)-6-bromo-1-fluoronaphthalen-2-amine (58 g, 142 mmol, 49% yield, 85% purity) as a yellow solid. LCMS (TFA, ESI+): m / z 345.9 [M + H]+ 1H NMR (400 MHz, DMSO-d6) δ 5.22 - 5.32 (m, 4H) 7.23 - 7.26 (m, 1H) 7.33 - 7.38 (m, 1H) 7.40 - 7.45 (m, 3H) 7.55 - 7.60 (m, 2H) 7.62 - 7.67 (m, 1H) 7.91 - 7.95 (m, 1H).

[0488] Step 4: Methyl 2-((3-(benzyloxy)-6-bromo-1-fluoronaphthalen-2-yl)amino)acetate (5) To a solution of 3-(benzyloxy)-6-bromo-1-fluoronaphthalen-2-amine (7.5 g, 82% purity, 17.8 mmol) in DMF (70 mL) at room temperature was added N,N-diisopropylethylamine (12.4 mL, 71.1 mmol) and methyl 2-bromoacetate (16.3 g, 107 mmol). The mixture was heated to 65° C. for 12 hours. The reaction was cooled to room temperature, poured into water (100 mL), and then extracted with ethyl acetate (3×80 mL). The organic phase was washed with brine (50 mL), then dried over NaSO, filtered, and concentrated. The crude product was triturated with 80% petroleum ether:ethyl acetate (20 mL) and the solid was filtered and dried to give methyl 2-((3-(benzyloxy)-6-bromo-1-fluoronaphthalen-2-yl)amino)acetate (5 g, 10 mmol, 50% yield; 80% purity) as a brown solid. LCMS (TFA, ESI+): m / z 418.1 [M + H]+ 1H NMR (400 MHz, DMSO-d6) δ 3.63 (s, 3H), 4.21 (dd, J = 6.5, 3.9 Hz, 2H), 5.29 (s, 2H), 5.57 - 5.63 (m, 1H), 7.28 (s, 1H), 7.34 - 7.45 (m, 4H), 7.55 (d, J = 7.3 Hz, 2H), 7.63 (d, J = 8.8 Hz, 1H), 7.94 (s, 1H)

[0489] Step 5: Methyl 2-((3-(benzyloxy)-6-bromo-1-fluoronaphthalen-2-yl)(N-(tert-butoxycarbonyl)sulfamoyl)amino)acetate (6) To a solution of sulfurisocyanatidic chloride (18.3 g, 129 mmol) in CHCl (60 mL) at 0 °C was added t-BuOH (12.4 mL, 129 mmol) in CHCl (30 mL), then warmed to room temperature and stirring continued for 1 h. The reaction was recooled to 0 °C and treated with a solution of triethylamine (36 mL, 260 mmol) and methyl 2-((3-(benzyloxy)-6-bromo-1-fluoronaphthalen-2-yl)amino)acetate (30 g, 90% purity, 65 mmol) as a solution in CHCl (90 mL). The cold bath was removed and stirring continued at room temperature for 2 h. The reaction was concentrated to remove most of the solvent, and the crude methyl 2-((3-(benzyloxy)-6-bromo-1-fluoronaphthalen-2-yl)(N-(tert-butoxycarbonyl)sulfamoyl)amino)acetate (75 g, 96% yield; 45% purity) was used directly in the next step as a yellow oil. LCMS (TFA, ESI+): m / z 497.1 [M - Boc]+ 1H NMR (400 MHz, DMSO-d6) δ 1.30 (s, 9H), 3.53 (s, 3H), 4.45 (d, J = 18.0 Hz, 1H), 4.76 (d, J = 18.0 Hz, 1H), 5.17 - 5.35 (m, 2H), 7.31-7.37 (m, 2H), 7.38-7.44 (m, 2H), 7.52 - 7.62 (m, 3H), 7.92 (d, J = 8.8 Hz, 1H), 8.12 (s, 1H)

[0490] Step 6: Methyl 2-((3-(benzyloxy)-6-bromo-1-fluoronaphthalen-2-yl)(sulfamoyl)amino)acetate (7) A crude sample of methyl 2-((3-(benzyloxy)-6-bromo-1-fluoronaphthalen-2-yl)(N-(tert-butoxycarbonyl)sulfamoyl)amino)acetate (130 g, 50% purity, 109 mmol) in CHCl (700 mL) was treated with TFA (250 mL, 3.3 mol) at 0 °C. After 1 h at room temperature, the reaction was concentrated and the residue was treated with saturated sodium bicarbonate solution. The aqueous mixture was extracted with ethyl acetate (3 × 1 L), and the organic phases were combined, washed with brine (1 L), then dried over NaSO, filtered, and concentrated under reduced pressure to give methyl 2-((3-(benzyloxy)-6-bromo-1-fluoronaphthalen-2-yl)(sulfamoyl)amino)acetate (46 g, 83 mmol, 77% yield, 90% purity) as a white solid. LCMS (TFA, ESI+): m / z 497.1 [M + H]+ 1H NMR (400 MHz, DMSO-d6) δ 3.56 (s, 3H), 4.29 - 4.34 (m, 1H), 4.44 - 4.53 (m, 1H), 5.26 (s, 2H), 7.11 (s, 2H), 7.33 - 7.44 (m, 5H), 7.58 (d, J = 7.5 Hz, 3H), 7.92 (d, J = 8.9 Hz, 1H), 8.14 (s, 1H).

[0491] Step 7: 5-(3-(benzyloxy)-6-bromo-1-fluoronaphthalen-2-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (8) To a solution of methyl 2-((3-(benzyloxy)-6-bromo-1-fluoronaphthalen-2-yl)(sulfamoyl)amino)acetate (54 g, 90% purity, 98 mmol) in THF (500 mL) at room temperature was added 30% sodium methoxide in methanol (148 mL, 42 g, 146 mmol). After 15 min, the reaction was quenched with 150 mL of 1 M HCl and extracted with ethyl acetate (3 × 300 mL). The combined organic phases were washed with brine (200 mL), dried over Na SO , filtered, and concentrated under reduced pressure to give 5-(3-(benzyloxy)-6-bromo-1-fluoronaphthalen-2-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (27 g, 52 mmol, 63% yield, 90% purity) as a yellow solid. LCMS (NH4HCO3, ESI-): m / z 463.0 [M - H]- 1H NMR (400 MHz, DMSO-d6) δ 4.27 (s, 2H), 5.26 (s, 2H), 7.26 - 7.46 (m, 4H), 7.51 - 7.64 (m, 3H), 7.91 (d, J = 8.9 Hz, 1H), 8.15 (s, 1H).

[0492] 5-(6-amino-1-fluoro-3-hydroxynaphthalen-2-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide, ammonium salt (6)

[0493] [ka]

[0494] Step 1: Methyl 7-(benzyloxy)-6-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-5-fluoro-2-naphthoate (2) To a solution of 5-(3-(benzyloxy)-6-bromo-1-fluoronaphthalen-2-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (40 g, 90% purity, 77 mmol) in MeOH (400 mL) was added triethylamine (32.4 mL, 232 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (17.0 g, 23.2 mmol), and the reaction was placed under an atmosphere of carbon monoxide (40 psi). The solution was heated to 50°C and stirred for 12 h. After consumption of the starting material, the solvent was removed under reduced pressure to give methyl 7-(benzyloxy)-6-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-5-fluoro-2-naphthoate (70 g, 95 mmol, 81% yield; 60% purity) as a red solid, which was used directly in the next step. LCMS (NH4HCO3, ESI-): m / z 443.1 [M - H]- 1H NMR (400 MHz, DMSO-d6) δ 3.92 (s, 3H), 3.97-4.27 (m, 2H), 5.28 (s, 2H), 7.26-7.41 (m, 3H), 7.45 - 7.68 (m, 3H), 7.78 (s, 1H), 7.84 - 8.02 (m, 1H), 8.23 ​​(d, J = 8.8 Hz, 1H), 8.55 (d, J = 1.3 Hz, 1H).

[0495] Step 2: 7-(benzyloxy)-6-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-5-fluoro-2-naphthoic acid (3) To a solution of methyl 7-(benzyloxy)-6-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-5-fluoro-2-naphthoate (8 g, 80% pure, 14.4 mmol) in THF (20 mL), MeOH (5 mL), and water (5 mL) was added LiOH (0.345 g, 14.4 mmol) at 0 °C. The mixture was warmed to room temperature and stirred for 2 h. The reaction was concentrated to remove most of the THF and diluted with water (100 mL). The aqueous phase was washed with ethyl acetate (3 × 100 mL) and then acidified with 1 M hydrochloric acid to pH = 2. The aqueous solution was extracted with ethyl acetate (3 × 150 mL) and the combined organic layers were washed with brine (150 mL), then dried over NaSO, filtered, and concentrated under reduced pressure to give 7-(benzyloxy)-6-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-5-fluoro-2-naphthoic acid (6.8 g, 13 mmol, 88% yield, 80% purity) as a yellow solid. LCMS (NH4HCO3, ESI-): m / z 429.1 [M - H]- 1H NMR (400 MHz, DMSO-d6) δ 4.55 (s, 2H), 5.30 (s, 2H), 7.30 - 7.43 (m, 3H), 7.49 - 7.58 (m, 2H), 7.71 (s, 1H), 7.94 (dd, J = 8.7, 1.4 Hz, 1H), 8.04 - 8.14 (m, 1H), 8.55 (s, 1H).

[0496] Step 3: tert-butyl (7-(benzyloxy)-6-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-5-fluoronaphthalen-2-yl)carbamate (4) To a solution of 7-(benzyloxy)-6-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-5-fluoro-2-naphthoic acid (1.3 g, 93% purity, 2.8 mmol) in t-BuOH (50 mL) at room temperature was added triethylamine (0.78 mL, 5.6 mmol) and diphenylphosphoryl azide (1.14 g, 4.17 mmol). The reaction was heated to 100° C. and stirred for 12 hours. The solution was concentrated under reduced pressure and diluted with water (50 mL). The aqueous mixture was extracted with ethyl acetate (3 × 30 mL) and the combined organic phases were washed with brine (30 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give tert-butyl (7-(benzyloxy)-6-(1,1-dihydro-4-oxo-1,2,5-thiadiazolidin-2-yl)-5-fluoronaphthalen-2-yl)carbamate (1.5 g, 1.9 mmol, 70.0% yield, 65% purity) as an off-white solid. LCMS (NH4HCO3, ESI-): m / z 500.2 [M - H]- 1H NMR (400 MHz, DMSO-d6) δ 1.47 (s, 9H), 4.30 (s, 2H), 5.22 (s, 2H), 7.18 (s, 1H), 7.28 - 7.42 (m, 4H), 7.49 (d, J = 7.5 Hz, 2H), 7.84 (d, J = 8.8 Hz, 1H), 8.00 (s, 1H).

[0497] Step 4: tert-butyl (6-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-5-fluoro-7-hydroxynaphthalen-2-yl)carbamate (5) To a solution of tert-butyl (7-(benzyloxy)-6-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-5-fluoronaphthalen-2-yl)carbamate (0.9 g, 90% purity, 1.6 mmol) in THF (10 mL) was added Pd / C (17 mg, 0.16 mmol) at room temperature. Stirring was continued under a hydrogen atmosphere (15 psi) for 12 hours. The resulting suspension was filtered through a Celite pad, and the pad was washed with MeOH (75 mL). The combined filtrate was concentrated to dryness to give tert-butyl (6-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-5-fluoro-7-hydroxynaphthalen-2-yl)carbamate (0.8 g, 1.6 mmol, 96% yield, 80% purity) as a white solid, which was used directly in the next step. LCMS (NH4HCO3, ESI-): m / z 410.1 [M - H]- 1H NMR (400 MHz, DMSO-d6) δ 1.50 (s, 9H), 4.06 (s, 2H), 6.90 (s, 1H), 7.35 (dd, J = 9.1, 1.8 Hz, 1H), 7.76 (d, J = 8.9 Hz, 1H), 7.91 (s, 1H), 9.56 - 9.70 (m, 2H).

[0498] Step 5: 5-(6-amino-1-fluoro-3-hydroxynaphthalen-2-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide, ammonium salt (6) A solution of tert-butyl (6-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-5-fluoro-7-hydroxynaphthalen-2-yl)carbamate (5 g, 90% purity, 11 mmol) in ethyl acetate (30 mL) was treated with 4 M HCl (2.7 mL, 11 mmol) at 0° C. After the addition was complete, the mixture was warmed to room temperature and stirring was continued for 2 h. The solution was concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC. The columns used for chromatography were as follows: [Column: Xbridge Shield RP18, 2.1 × 50 mm, 5 μm particles; Detection: DAD; MS: negative electrospray, range: 100–1000; Mobile phase A: 10 mM ammonium bicarbonate (aqueous); Mobile phase B: acetonitrile; Gradient: 5–95% B (2.05 min), 5% B (0.01 min), 5–95% B (0.01–1.00 min), 95–100% B (1.00–1.80 min), 5% B (1.81 min), 5% B (1.81 min). B, hold for 0.24 min; flow rate: 1.0 mL / min]. Appropriate fractions were collected and the sample lyophilized to give 5-(6-amino-1-fluoro-3-hydroxynaphthalen-2-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide, ammonium salt (3.28 g, 9.49 mmol, 87% yield, 95% purity) as an off-white solid. LCMS (NH4HCO3, ESI-): m / z 310.0 [M - H]- 1H NMR (400 MHz, DMSO-d6) δ 4.05 (s, 2H), 6.63 (d, J = 13.6 Hz, 2H), 6.77 (dd, J = 8.9, 2.0 Hz, 1H), 6.97 (s, 1H), 7.10 (s, 1H), 7.22 (s, 1H), 7.57 (d, J = 8.9 Hz, 1H), 9.29 (br s, 1H).

[0499] 5-(6-amino-3-(benzyloxy)-1-fluoronaphthalen-2-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (2)

[0500] [ka]

[0501] Step 1: 5-(6-amino-3-(benzyloxy)-1-fluoronaphthalen-2-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (2) A stirred solution of tert-butyl N-[7-benzyloxy-5-fluoro-6-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]carbamate (1, 1.0 g, 1.99 mmol) in DCM (10 mL) at 0 °C was treated dropwise with trifluoroacetic acid (227.35 mg, 1.99 mmol, 153.62 μL). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, azeotroped with toluene, and triturated with diethyl ether to give 5-(6-amino-3-benzyloxy-1-fluoro-2-naphthyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (2, 850 mg, 1.58 mmol, 79.44% yield, TFA salt) as an off-white solid. LCMS (ES+): m / z 402.1 [M+H]+

[0502] 5-(3-(benzyloxy)-7-bromo-1-fluoronaphthalen-2-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (12)

[0503] [ka]

[0504] Step 1: Benzyl 3-(benzyloxy)-7-bromo-2-naphthoate (2) A 100 mL round-bottom flask was charged with 7-bromo-3-hydroxy-2-naphthoic acid ([1779-11-9], 5 g, 18.7 mmol) and cesium carbonate (18.30 g, 56.2 mmol), followed by DMF (35 mL). The mixture was rapidly stirred to suspend the reactants and then treated with benzyl bromide (4.45 mL, 37.4 mmol) at room temperature. After 2 h, the mixture was poured into water (70 mL), and the resulting white solid precipitate was collected by filtration. The resulting solid was washed with water (3 × 50 mL), triturated with 30% methyl tert-butyl methyl ether / petroleum ether (20 mL), filtered, and dried under vacuum to give benzyl 3-(benzyloxy)-7-bromo-2-naphthoate (8 g, 17.2 mmol, 92% yield, 96% purity) as a white solid. LCMS (TFA, ESI+): m / z 447.1 [M + H]+ 1H NMR (400 MHz, DMSO-d6) δ 5.27 (s, 2H), 5.35 (s, 2H), 7.30 - 7.45 (m, 8H), 7.49 (d, J = 6.8 Hz, 2H), 7.60 - 7.71 (m, 2H), 7.82 (d, J = 8.8 Hz, 1H), 8.28 (d, J = 1.5 Hz, 1H), 8.32 (s, 1H).

[0505] Step 2: 3-(benzyloxy)-7-bromo-2-naphthoic acid (3) To a room temperature solution of benzyl 3-(benzyloxy)-7-bromo-2-naphthoate (4 g, 8.5 mmol) in MeOH (60 mL) and water (30.0 mL) was added LiOH (0.407 g, 17.0 mmol). The mixture was heated to 70 °C for 2 hours and then concentrated. The resulting residue was diluted with water (500 mL). The aqueous layer was acidified with 1 M HCl to pH = 3, and the solid was filtered and dried under vacuum to give 3-(benzyloxy)-7-bromo-2-naphthoic acid (3 g, 8.0 mmol, 94% yield, 95% purity) as a white solid. LCMS (TFA, ESI+): m / z 357.0 [M + H]+ 1H NMR (400 MHz, DMSO-d6) δ 5.29 (s, 2H), 7.29 - 7.45 (m, 3H), 7.54 (d, J = 7.28 Hz, 2H), 7.60 (s, 1H), 7.66 (dd, J = 8.8, 2.0 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 8.20 - 8.27 (m, 2H), 13.06 (br s, 1H).

[0506] Step 3: tert-butyl (3-(benzyloxy)-7-bromonaphthalen-2-yl)carbamate (4) A 250 mL three-neck round-bottom flask was charged with 3-(benzyloxy)-7-bromo-2-naphthoic acid (6 g, 16.8 mmol), toluene (48 mL), t-BuOH (48 mL), and triethylamine (2.48 mL, 17.8 mmol). Diphenylphosphoryl azide (4.90 g, 17.8 mmol) was then added, and the reaction mixture was heated at 110 °C for 4 h. The solution was cooled to room temperature and concentrated to give a crude solid. The solid was triturated with ethanol (50 mL), filtered, washed with ethanol (10 mL), and dried under vacuum to give tert-butyl (3-(benzyloxy)-7-bromonaphthalen-2-yl)carbamate (6.6 g, 13.9 mmol, 83% yield, 90% purity) as a white solid. LCMS (NH4HCO3, ESI-): m / z 426.1 [M - H]- 1H NMR (400 MHz, DMSO-d6) δ 1.48 (s, 9H), 5.29 (s, 2H), 7.34-7.50 (m, 5H), 7.57 (d, J = 7.0 Hz, 2H), 7.68 (d, J = 8.8 Hz, 1H), 8.02 (d, J = 1.7 Hz, 1H), 8.13 (s, 1H), 8.21 (s, 1H).

[0507] Step 4: 3-(benzyloxy)-7-bromonaphthalen-2-amine (5) To a solution of tert-butyl (3-(benzyloxy)-7-bromonaphthalen-2-yl)carbamate (8 g, 86% purity, 16 mmol), diethylenetriamine (26.2 g, 254 mmol) was added and the mixture was stirred at 130 °C for 3 h. The reaction was cooled to room temperature, and water (50 mL) was added to the mixture and stirred for 10 min. The solid was filtered, and the filter cake was washed with 10 mL of i-PrOH and dried under vacuum to give 3-(benzyloxy)-7-bromonaphthalen-2-amine (4.5 g, 12.3 mmol, 78% yield, 90% purity) as a pink solid. LCMS (TFA, ESI+): m / z 328.1 [M + H]+ 1H NMR (400 MHz, DMSO-d6) δ 5.25 (s, 2H), 5.37 (s, 2H), 6.89 (s, 1H), 7.18 (dd, J = 8.6, 2.0 Hz, 1H), 7.27 - 7.37 (m, 2H), 7.38 - 7.45 (m, 2H), 7.54 (t, J = 7.7 Hz, 3H), 7.70 (d, J = 1.7 Hz, 1H).

[0508] Step 5: 3-(benzyloxy)-7-bromo-1-fluoronaphthalen-2-amine (6) To a solution of 3-(benzyloxy)-7-bromonaphthalen-2-amine (20 g, 90% purity, 54.8 mmol) in THF (100 mL) was added a solution of N-fluorobenzenesulfonimide (19.0 g, 60.3 mmol) in THF (100 mL) at 0 °C over 1 h. The mixture was warmed to room temperature and stirred for an additional 1 h. Residual oxidant was then quenched by the addition of a solution of sodium thiosulfate pentahydrate (17.3 g, 110 mmol) in water (100 mL), and the mixture was stirred at room temperature for 20 min. The aqueous phase was extracted with ethyl acetate (3 × 100 mL), and the combined organic phases were washed with brine (2 × 100 mL), then dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0% to 10% ethyl acetate:petroleum ether) to give 3-(benzyloxy)-7-bromo-1-fluoronaphthalen-2-amine (8 g, 20.8 mmol, 38% yield, 90% purity) as a yellow solid. LCMS (TFA, ESI+): m / z 346.2 [M + H]+ 1H NMR (400 MHz, DMSO-d6) δ 5.28 (s, 2H), 5.31 (s, 2H), 7.25 (s, 1H), 7.30 - 7.36 (m, 2H), 7.39 - 7.44 (m, 2H), 7.56 (br d, J = 7.1 Hz, 2H), 7.65 (dd, J = 8.6, 1.3 Hz, 1H), 7.82 (d, J = 1.6 Hz, 1H).

[0509] Step 6: N-(3-(benzyloxy)-7-bromo-1-fluoronaphthalen-2-yl)-2,2,2-trifluoroacetamide (7) To a solution of 3-(benzyloxy)-7-bromo-1-fluoronaphthalen-2-amine (2 g, 90% purity, 5.2 mmol) in acetonitrile (40 mL) and pyridine (1.3 mL, 15.6 mmol) at 0 °C, trifluoroacetic anhydride (1.49 mL, 10.4 mmol) was added, and the mixture was allowed to warm slowly to room temperature. After 2 h, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The organic layer was washed with brine (20 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give N-(3-(benzyloxy)-7-bromo-1-fluoronaphthalen-2-yl)-2,2,2-trifluoroacetamide (2.5 g, 4.8 mmol, 92% yield, 85% purity) as an off-white solid, which was used directly in the next step. LCMS (TFA, ESI+): m / z 442.0 [M + H]+ 1H NMR (400 MHz, DMSO-d6) δ 5.28 (s, 2H), 7.30 - 7.35 (m, 1H), 7.39 (t, J = 7.3 Hz, 2H), 7.46 (br d, J = 7.0 Hz, 2H), 7.53 (s, 1H), 7.70 - 7.75 (m, 1H), 7.88 (d, J = 8.4 Hz, 1H), 8.15 (s, 1H).

[0510] Step 7: Methyl 2-(N-(3-(benzyloxy)-7-bromo-1-fluoronaphthalen-2-yl)-2,2,2-trifluoroacetamido)acetate (8) To a solution of N-(3-(benzyloxy)-7-bromo-1-fluoronaphthalen-2-yl)-2,2,2-trifluoroacetamide (2.5 g, 85% purity, 4.81 mmol) in DMF (30 mL) was added KCO (1.33 g, 9.61 mmol) and methyl 2-bromoacetate (1.10 g, 7.21 mmol). The reaction was heated to 80 °C and stirred for 1 h. The mixture was cooled to room temperature and diluted with water (30 mL). The aqueous mixture was extracted with ethyl acetate (3 × 20 mL) and the combined organic phases were washed with brine (3 × 20 mL), dried over NaSO, filtered, and concentrated under reduced pressure to afford methyl 2-(N-(3-(benzyloxy)-7-bromo-1-fluoronaphthalen-2-yl)-2,2,2-trifluoroacetamido)acetate (3.4 g, 5.95 mmol, 93% yield, 90% purity) as an off-white solid, which was used directly in the next step. LCMS (TFA, ESI+): m / z 514.0 [M + H]+ 1H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J = 2.0 Hz, 1H), 8.11 (d, J = 9.0 Hz, 1H), 7.78 - 7.66 (m, 2H), 7.51 - 7.33 (m, 5H), 5.27 (q, J = 11.9 Hz, 2H), 4.45 (d, J = 1.7 Hz, 2H), 3.59 (s, 3H).

[0511] Step 8: Methyl 2-((3-(benzyloxy)-7-bromo-1-fluoronaphthalen-2-yl)amino)acetate (9) To a solution of methyl 2-(N-(3-(benzyloxy)-7-bromo-1-fluoronaphthalen-2-yl)-2,2,2-trifluoroacetamido)acetate (3.4 g, 85% purity, 5.6 mmol) in MeOH (40 mL) was added sodium methoxide (4.29 g, 23.8 mmol) at room temperature. The mixture was heated to 60 °C and stirred for 3 h. Upon completion, the mixture was cooled to room temperature, diluted with water (30 mL), and the aqueous mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with brine (2 × 20 mL), dried over Na SO , filtered, and concentrated under reduced pressure to give methyl 2-((3-(benzyloxy)-7-bromo-1-fluoronaphthalen-2-yl)amino)acetate (1.9 g, 4.1 mmol, 69% yield, 90% purity) as an off-white solid, which was used directly in the next step. LCMS (TFA, ESI+): m / z 418.2 [M + H]+ 1H NMR (400 MHz, DMSO-d6) δ 3.63 (s, 3H), 4.22 (dd, J = 6.7, 4.0 Hz, 2H), 5.30 (s, 2H), 7.30 (s, 1H), 7.34 - 7.39 (m, 2H), 7.41 - 7.45 (m, 2H), 7.55 (d, J = 7.1 Hz, 2H), 7.67 (dd, J = 8.7, 1.5 Hz, 1H), 7.80 (d, J = 1.7 Hz, 1H).

[0512] Step 9: Methyl 2-((3-(benzyloxy)-7-bromo-1-fluoronaphthalen-2-yl)(N-(tert-butoxycarbonyl)sulfamoyl)amino)acetate (10) To a solution of sulfur isocyanathidic chloride (1.22 g, 8.61 mmol) in CHCl (10 mL) was added dropwise a solution of t-BuOH (1.30 g, 17.5 mmol) in CHCl (10 mL) at 0 °C. The mixture was warmed to room temperature and stirred for an additional 1 h. After cooling to 0 °C, a solution of triethylamine (2.40 mL, 17.2 mmol) and methyl 2-((3-(benzyloxy)-7-bromo-1-fluoronaphthalen-2-yl)amino)acetate (2 g, 90% purity, 4.30 mmol) in CHCl (20 mL) was slowly added to the reaction mixture. After the addition was complete, the solution was warmed to room temperature and stirred for 2 h. The mixture was concentrated under pressure to give methyl 2-((3-(benzyloxy)-7-bromo-1-fluoronaphthalen-2-yl)(N-(tert-butoxycarbonyl)sulfamoyl)amino)acetate (5 g, 6.70 mmol, 89% yield, 80% purity) as a yellow oil. This crude product was used in the next step without further purification. LCMS (TFA, ESI+): m / z 497.2 [M - Boc + H]+ 1H NMR (400 MHz, DMSO-d6) δ 11.40 (s, 1H), 8.15 (d, J = 2.0 Hz, 1H), 7.83 (dd, J = 8.9, 1.3 Hz, 1H), 7.71 (dd, J = 8.9, 2.0 Hz, 1H), 7.60 - 7.48 (m, 2H), 7.47 - 7.30 (m, 4H), 5.31 (q, J = 12.8 Hz, 2H), 4.75 (d, J = 17.9 Hz, 1H), 4.48 (d, J = 17.9 Hz, 1H), 3.56 (s, 3H), 1.32 (s, 9H).

[0513] Step 10: Methyl 2-((3-(benzyloxy)-7-bromo-1-fluoronaphthalen-2-yl)(sulfamoyl)amino)acetate (11) To a solution of methyl 2-((3-(benzyloxy)-7-bromo-1-fluoronaphthalen-2-yl)(N-(tert-butoxycarbonyl)sulfamoyl)amino)acetate (15 g, 75% purity, 18.8 mmol) in CHCl (100 mL) at 0 °C was added 2,2,2-trifluoroacetic acid (35 mL, 18.8 mmol), then warmed to room temperature and stirred for 1 h. The mixture was concentrated under reduced pressure, and the residue was diluted with water (300 mL). The aqueous mixture was basified (pH = 8) by adding solid NaHCO and extracted with ethyl acetate (3 × 150 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give methyl 2-((3-(benzyloxy)-7-bromo-1-fluoronaphthalen-2-yl)(sulfamoyl)amino)acetate (12 g, 16.9 mmol, 90% yield, 70% purity) as a white solid, which was used in the next step without further purification. LCMS (TFA, ESI+): m / z 496.9 [M + H]+ 1H NMR (400 MHz, DMSO-d6) δ 3.56 (s, 3H), 4.29 - 4.36 (m, 1H), 4.46 - 4.53 (m, 1H), 5.27 (s, 2H), 7.11 (s, 2H), 7.39 - 7.46 (m, 4H), 7.58 (d, J = 7.2 Hz, 2H), 7.69 (dd, J = 8.8, 2.0 Hz, 1H), 7.81 - 7.86 (m, 1H), 8.13 (d, J = 2.0 Hz, 1H).

[0514] Step 11: 5-(3-(benzyloxy)-7-bromo-1-fluoronaphthalen-2-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (12) To a solution of methyl 2-((3-(benzyloxy)-7-bromo-1-fluoronaphthalen-2-yl)(sulfamoyl)amino)acetate (9 g, 85% purity, 15.4 mmol) in THF (100 mL) at room temperature was added 30% sodium methoxide in methanol (29.3 mL, 8.31 g, 46.1 mmol) and stirring was continued for 1 h. The reaction was concentrated, taken up in water (10 mL), and acidified with 1 M HCl (pH = 5). The aqueous mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic phase was dried over anhydrous NaSO, filtered, and concentrated to give 5-(3-(benzyloxy)-7-bromo-1-fluoronaphthalen-2-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (9 g, 17.4 mmol, 90% yield, 90% purity) as a light brown solid. LCMS (NH4HCO3, ESI-): m / z 463.0 [M - H]- 1H NMR (400 MHz, DMSO-d6) δ 4.53 (s, 2H), 5.28 (s, 2H), 7.30 - 7.43 (m, 4H), 7.52 (br d, J = 7.6 Hz, 3H), 7.74 (dd, J = 8.8, 1.8 Hz, 1H), 7.87 (d, J = 8.8 Hz, 1H), 8.16 (d, J = 1.4 Hz, 1H).

[0515] 5-(7-(2-aminoethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (6)

[0516] [ka]

[0517] Step 1: 5-(3-(benzyloxy)-1-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (2) To a solution of 5-(3-(benzyloxy)-7-bromo-1-fluoronaphthalen-2-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (19 g, 80% purity, 32.7 mmol) in dioxane (200 mL) was added bis(pinacolato)diboron (16.6 g, 65.3 mmol), potassium acetate (9.62 g, 98 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.87 g, 3.92 mmol). The mixture was heated to 100 °C. After 3 h, the solvent was evaporated and the residue was taken up in water (200 mL) and extracted with ethyl acetate (3 × 300 mL). The combined organic phases were washed with brine (2 × 100 mL), dried over NaSO, filtered, and concentrated. The residue was purified by silica gel chromatography (50% to 60% heptane:ethyl acetate) to give 5-(3-(benzyloxy)-1-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (16 g, 28.1 mmol, 86% yield, 90% purity) as a yellow solid. LCMS (NH4HCO3, ESI-): m / z 511.1 [M - H]- 1H NMR (600 MHz, DMSO-d6) δ 8.30 (q, J = 0.9 Hz, 1H), 7.88 (dd, J = 8.5, 1.3 Hz, 1H), 7.80 (dd, J = 8.3, 1.2 Hz, 1H), 7.56 - 7.51 (m, 2H), 7.48 (s, 1H), 7.42 - 7.36 (m, 2H), 7.36 - 7.31 (m, 1H), 5.30 (s, 2H), 4.49 (s, 2H), 1.34 (s, 12H).

[0518] Step 2: 5-(3-(benzyloxy)-1-fluoro-7-hydroxynaphthalen-2-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (3) To a solution of 5-(3-(benzyloxy)-1-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (16 g, 78% purity, 28.1 mmol) in acetone (160 mL) at 0 °C was added a solution of potassium peroxymonosulfate (24.19 g, 39.3 mmol) in water (160 mL). After 1 h, the mixture was allowed to warm to room temperature and stirred for an additional 3 h. The acetone was removed in vacuo, and the remaining aqueous mixture was treated with sodium thiosulfate pentahydrate (8.88 g, 56.2 mmol), stirred for 15 min, and extracted with ethyl acetate (3 × 200 mL). The combined organic phases were washed with brine (2 × 100 mL), dried over NaaSO, filtered, and concentrated to give 5-(3-(benzyloxy)-1-fluoro-7-hydroxynaphthalen-2-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (14 g, 24.4 mmol, 87% yield, 70% purity) as a dark solid. LCMS (NH4HCO3, ESI-): m / z 401.1 [M - H]- 1H NMR (400 MHz, DMSO-d6) δ 4.51 (s, 2H), 5.22 (s, 2H), 7.16 - 7.19 (m, 2H), 7.33 (br d, J = 7.0 Hz, 1H), 7.37 (br d, J = 8.1 Hz, 3H), 7.51 (br d, J = 7.1 Hz, 3H), 7.75 (br d, J = 8.9 Hz, 1H).

[0519] Step 3: tert-butyl (2-((6-(benzyloxy)-7-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoronaphthalen-2-yl)oxy)ethyl)carbamate (4) To a solution of 5-(3-(benzyloxy)-1-fluoro-7-hydroxynaphthalen-2-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (20 g, 70% purity, 34.8 mmol) and CsCO (45.3 g, 139 mmol) in DMF (200 mL) was added 2-((tert-butoxycarbonyl)amino)ethyl methanesulfonate (71.4 g, 209 mmol) in one portion and the slurry was heated to 60 °C for 4 h. The reaction was cooled to room temperature and diluted with water (500 mL). The aqueous mixture was extracted with ethyl acetate (3 × 300 mL) and the combined organic layers were washed with brine (2 × 100 mL), dried over NaSO, filtered, and concentrated to give tert-butyl (2-((6-(benzyloxy)-7-(1,1-dihydro-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoronaphthalen-2-yl)oxy)ethyl)carbamate (19 g, 34.8 mmol, 79% yield) as a yellow solid. LCMS (NH4HCO3, ESI-): m / z 544.0 [M - H]- 1H NMR (400 MHz, CDCl3) δ 1.44 (s, 9H), 3.50 (br s, 2H), 3.94 (br t, J = 4.8 Hz, 2H), 4.44 (br s, 2H), 5.09 - 5.14 (m, 2H), 6.93 (s, 1H), 7.06 - 7.12 (m, 2H), 7.15 - 7.22 (m, 1H), 7.25 (s, 1H), 7.29 (br s, 1H), 7.37 (br d, J = 7.3 Hz, 2H), 7.51 (br d, J = 8.7 Hz, 1H), 8.03 (s, 1H).

[0520] Step 4: tert-butyl (2-((7-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoro-6-hydroxynaphthalen-2-yl)oxy)ethyl)carbamate (5) To a solution of tert-butyl (2-((6-(benzyloxy)-7-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoronaphthalen-2-yl)oxy)ethyl)carbamate (4 g, 7.3 mmol) in methanol (50 mL) at room temperature was added Pd(OH) (1.0 g) under a N atmosphere. The suspension was degassed (vacuum / purge H × 3), and the mixture was stirred under a hydrogen balloon atmosphere for 12 h. Upon completion, the slurry was filtered through a Celite pad, and the filter cake was washed with methanol (100 mL). The filtrate was concentrated under reduced pressure, and the crude product was purified by reverse-phase column chromatography (50% water:acetonitrile) to afford tert-butyl (2-((7-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoro-6-hydroxynaphthalen-2-yl)oxy)ethyl)carbamate (10 g, 21.96 mmol, 29% yield) as a white solid. LCMS (NH4HCO3, ESI-): m / z 454.2 [M - H]- 1H NMR (400 MHz, DMSO-d6) δ 1.38 (s, 9H), 3.34 (br d, J = 5.6 Hz, 2H), 4.06 (br d, J = 4.5 Hz, 2H), 4.44 (s, 2H), 7.03 - 7.07 (m, 2H), 7.14 - 7.22 (m, 2H), 7.71 (d, J = 9.0 Hz, 1H), 10.12 - 10.35 (m, 1H).

[0521] Step 5: 5-(7-(2-aminoethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide, hydrochloride (6) A solution of tert-butyl (2-((7-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoro-6-hydroxynaphthalen-2-yl)oxy)carbamate (2 g, 90% purity, 3.95 mmol) in 4 M HCl in EtOAc (10 mL, 40.0 mmol) was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The residue was triturated with 95% i-PrOH, and the solid was collected by filtration and dried under vacuum to give 5-(7-(2-aminoethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide, hydrochloride salt (1.01 g, 2.52 mmol, 64% yield, 98% purity) as a white solid. LCMS (NH4HCO3, ESI-): m / z 354.0 [M - H]- 1H NMR (400 MHz, DMSO-d6) δ 3.27 (br d, J = 5.1 Hz, 2H), 4.18 (s, 2H), 4.27 (br t, J = 5.0 Hz, 2H), 7.06 (s, 1H), 7.20 (dd, J = 8.9, 2.3 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 7.73 (d, J = 9.0 Hz, 1H), 8.00 (br s, 3H), 9.77 (br s, 1H).

[0522] 5-(7-(2-aminoethoxy)-3-(benzyloxy)-1-fluoronaphthalen-2-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (2)

[0523] [ka]

[0524] Step 1: 5-(7-(2-aminoethoxy)-3-(benzyloxy)-1-fluoronaphthalen-2-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (2) To a 50 mL round-bottom flask containing a solution of tert-butyl N-[2-[[6-benzyloxy-8-fluoro-7-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]oxy]ethyl]carbamate (1, 500 mg, 916.46 μmol) in DCM (5 mL) at 0° C., TFA (104.50 mg, 916.46 μmol, 70.61 μL) was added dropwise. The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, and the residue was triturated with diethyl ether (2 × 8 mL) to give 5-[7-(2-aminoethoxy)-3-benzyloxy-1-fluoro-2-naphthyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (2, 520 mg, 873.81 μmol, 95.35% yield, TFA salt) as an off-white solid. LCMS (ES+): m / z 446.1 [M+H]+

[0525] 3-(4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)methyl)-1H-1,2,3-triazol-1-yl)propanoic acid (4)

[0526] [ka]

[0527] Step 1: 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-1,3-dione (2) To a 250 mL three-necked round-bottom flask containing a well-stirred solution of 5-fluoroisobenzofuran-1,3-dione (1, 5 g, 30.10 mmol, 3.33 mL) and 3-aminopiperidine-2,6-dione (1a, 4.24 g, 33.11 mmol) in acetic anhydride (50 mL) was added NaOAc (4.94 g, 60.20 mmol, 3.23 mL). The reaction was stirred at 80 °C for 16 h. The reaction mixture was concentrated to dryness, and the residue was diluted with ice-cold water (100 mL) to give a solid, which was filtered, washed with petroleum ether, and dried to give 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-1,3-dione (2, 8 g, 28.90 mmol, 96% yield) as a light brown solid. LCMS (ES+): m / z 277 [M + H]+

[0528] Step 2: 2-(2,6-dioxopiperidin-3-yl)-5-(prop-2-yn-1-ylamino)isoindoline-1,3-dione (3) To a 25 mL pressure tube containing a well-stirred suspension of 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-1,3-dione (2, 500 mg, 1.81 mmol) and prop-2-yn-1-amine (2a, 179.46 mg, 3.26 mmol, 208.68 μL) in anhydrous DMSO (5 mL) was added DIPEA (701.85 mg, 5.43 mmol, 945.89 μL). The tube was sealed, and the reaction mixture was stirred at 80° C. for 24 h. The reaction mixture was concentrated to dryness under reduced pressure. The resulting residue was diluted with ice-cold water (50 mL), and the precipitate thus formed was collected by filtration, washed with petroleum ether, dried, and purified by flash column chromatography (neutral alumina, 10% MeOH / DCM) to afford 2-(2,6-dioxopiperidin-3-yl)-5-(prop-2-yn-1-ylamino)isoindoline-1,3-dione (3, 180 mg, 511.16 μmol, 28% yield) as a yellow solid. LCMS (ES+): m / z 312.3 [M + H]+

[0529] Step 3: 3-(4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)methyl)-1H-1,2,3-triazol-1-yl)propanoic acid (4) To a 50 mL single-neck round-bottom flask containing a well-stirred solution of 2-(2,6-dioxo-3-piperidyl)-5-(prop-2-ynylamino)isoindoline-1,3-dione (3, 180 mg, 578.24 μmol) and 3-azidopropanoic acid (3a, 99.82 mg, 867.35 μmol) in anhydrous THF (5 mL) was added sodium ascorbate (229.10 mg, 1.16 mmol) and copper(II) sulfate pentahydrate (288.75 mg, 1.16 mmol). The reaction was stirred at ambient temperature for 16 h. The reaction mixture was poured into ice-cold water (10 mL), and the aqueous layer was extracted with ethyl acetate (2 × 15 mL). The organic layers were combined, washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC [Column: X BRIDGE C18 column (19 x 150) mm 5 micron; Mobile phase A: 0.1% TFA in water and Mobile phase B: MeCN] to give 3-(4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)methyl)-1H-1,2,3-triazol-1-yl)propanoic acid (4, 100 mg, 177.64 μmol, 31% yield, TFA salt). LCMS (ES+): m / z 427.0 [M + H]+

[0530] 3-[4-[[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]amino]methyl]pyrazol-1-yl]propanoic acid (6)

[0531] [ka]

[0532] Step 1a: 3-(4-formylpyrazol-1-yl)propanoic acid (3a) To a 50 mL single-neck round-bottom flask containing a well-stirred solution of 1H-pyrazole-4-carbaldehyde (1a, 1 g, 10.41 mmol) in DMF (10 mL) was added cesium carbonate (6.78 g, 20.81 mmol), followed by 3-bromopropanoic acid (2a, 1.91 g, 12.49 mmol, 1.29 mL). The reaction mixture was stirred at 100 °C for 6 h. The reaction mixture was concentrated under reduced pressure and diluted with water (45 mL). The reaction mixture was acidified (pH ∼6) using 1.5 N HCl and extracted with 10% MeOH in DCM (5 × 25 mL). The combined organic layers were washed with water (2 × 25 mL), brine (25 mL), dried over anhydrous sodium sulfate, and filtered. The solvent was removed under reduced pressure, and the residue was purified by flash silica gel (230-400) column chromatography (10-12% MeOH in DCM) to give 3-(4-formylpyrazol-1-yl)propanoic acid (3a, 800 mg, 3.76 mmol, 36% yield) as a brown liquid. LCMS (ES+): m / z 169.0 [M + H] +

[0533] Step 1: Methyl 2-(bromomethyl)-4-nitro-benzoate (2) To a 250 mL single-neck round-bottom flask containing a well-stirred solution of methyl 4-bromo-2-methyl-benzoate (1, 10 g, 51.24 mmol) in chlorobenzene (100 mL), NBS (9.12 g, 51.24 mmol) was added, followed by AIBN (841 mg, 5.124 mmol). The reaction mixture was heated at 80 °C for 16 h. The reaction mixture was cooled to room temperature, quenched with water (100 mL), and extracted with DCM (3 × 100 mL). The organic layer was washed with water (2 × 100 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash silica gel column chromatography (3–4% EtOAc in petroleum ether) to give methyl 2-(bromomethyl)-4-nitro-benzoate (2, 10 g, 28.28 mmol, 55% yield) as a pale yellow liquid. GCMS: m / z 272.9

[0534] Step 2: 3-(5-nitro-1-oxo-isoindolin-2-yl)piperidine-2,6-dione (4) To a 250 mL single-neck round-bottom flask containing a well-stirred solution of methyl 2-(bromomethyl)-4-nitrobenzoate (2, 10 g, 36.49 mmol, 77.5% purity) in DMF (100 mL) was added TEA (18.46 g, 182.44 mmol, 25.43 mL), followed by 3-aminopiperidine-2,6-dione hydrochloride (3, 5.61 g, 34.08 mmol). The reaction mixture was stirred at room temperature for 15 hours. The reaction was concentrated under reduced pressure, water (100 mL) was added, and the mixture was extracted with EtOAc (3 x 250 mL). The combined organic layers were washed with water (2 x 250 mL), brine (250 mL), dried over anhydrous sodium sulfate, and filtered. The organic layer was concentrated under reduced pressure. The residue was suspended in toluene (100 mL) and heated at 110 °C for 15 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give 3-(5-nitro-1-oxo-isoindolin-2-yl)piperidine-2,6-dione (4, 8 g, 15.49 mmol, 42% yield) as a brown solid. LCMS (ES+): m / z 290.0 [M + H] +

[0535] Step 3: 3-(5-amino-1-oxo-isoindolin-2-yl)piperidine-2,6-dione (5) To a 100 mL single-neck round-bottom flask containing a well-stirred solution of 3-(5-nitro-1-oxo-isoindolin-2-yl)piperidine-2,6-dione (4, 4 g, 13.83 mmol, 56% purity) in MeOH (50 mL), Pd / C (dry 10 wt%) (1.47 g, 13.83 mmol) was added and stirred under a hydrogen atmosphere at room temperature for 2 hours. The reaction mixture was filtered through a Celite pad and washed with MeOH (1 mL). The solvent was removed under reduced pressure to give 3-(5-amino-1-oxo-indolin-2-yl)piperidine-2,6-dione (5, 2.5 g, 6.56 mmol, 85% yield) as a brown solid. LCMS (ES+): m / z 260.1 [M + H] +

[0536] Step 4: 3-[4-[[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]amino]methyl]pyrazol-1-yl]propanoic acid (6) To a 50 mL single-neck round-bottom flask containing a well-stirred solution of 3-(4-formylpyrazol-1-yl)propanoic acid (3a, 129.72 mg, 771.43 μmol, 79% purity) and 3-(5-amino-1-oxo-isoindolin-2-yl)piperidine-2,6-dione (5, 200 mg, 771.43 μmol) in MeOH (10 mL), AcOH (463.24 mg, 772.00 μmol) was added, followed by the addition of 2-picoline borane complex (107.27 mg, 100.0 μmol) in portions at 10° C. After stirring at room temperature for 18 hours, water (1 mL) was added to the reaction mixture, which was then concentrated to dryness under reduced pressure. The residue was purified by reverse-phase preparative HPLC [purification method: Column X Bridge C18, 10 mm x 250 mm, 5μ, Mobile phase A: 0.1% TFA in water and Mobile phase B: MeCN] to give 3-[4-[[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]amino]methyl]pyrazol-1-yl]propanoic acid (6, 130 mg, 230.47 μmol, 38% yield, TFA salt) as an off-white solid. LCMS (ES+): m / z 412.2 [M + H]+

[0537] 4-(((1-(azetidin-3-yl)-1H-1,2,3-triazol-4-yl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (8)

[0538] [ka]

[0539] Step 1: tert-Butyl 3-methylsulfonyloxyazetidine-1-carboxylate (2) To a 100 mL two-necked round-bottom flask containing a well-stirred solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (1, 2.5 g, 14.43 mmol) in DCM (25 mL) was added EtN (3.65 g, 36.08 mmol, 5.03 mL) and methanesulfonyl chloride (1.65 g, 14.43 mmol, 1.12 mL) at 0° C. After stirring at room temperature for 3 h, the reaction was quenched with water (100 mL) and extracted with DCM (3×150 mL). The organic layers were combined, washed with water (150 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford tert-butyl 3-methylsulfonyloxyazetidine-1-carboxylate (2, 3.5 g, 13.91 mmol, 96% yield) as an off-white solid, which was used in the next step without further purification. LCMS (ES+): m / z 152.0 [M - Boc + H]+

[0540] Step 2: tert-Butyl 3-azidoazetidine-1-carboxylate (3) To a 100 mL two-necked round-bottom flask containing a well-stirred solution of tert-butyl 3-methylsulfonyloxyazetidine-1-carboxylate (2, 3.5 g, 13.93 mmol) in DMF (30 mL) was added NaN (2.26 g, 34.82 mmol), and the reaction mixture was stirred at 80 °C for 16 h. The reaction was quenched with ice-water (200 mL) and extracted with EtOAc (2 × 200 mL). The organic layers were combined, washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl 3-azidoazetidine-1-carboxylate (3, 2.5 g, 12.54 mmol, 90% yield) as a viscous liquid, which was used in the next step without further purification. 1HNMR (400 MHz, DMSO-d6): δ 4.23-4.17 (m, 3H), 3.91-3.89 (m, 2H), 1.45 (s, 9H)

[0541] Step 3: 2-(2,6-dioxo-3-piperidyl)-4-(prop-2-ynylamino)isoindoline-1,3-dione (6) To a 100 mL two-necked round-bottom flask containing a well-stirred solution of 2-(2,6-dioxo-3-piperidyl)-4-fluoroisoindoline-1,3-dione (4, 8.0 g, 28.96 mmol) and propargylamine (5, 2.39 g, 43.44 mmol, 2.78 mL) in DMSO (80 mL) was added DIPEA (22.46 g, 173.77 mmol, 30.27 mL), and the reaction mixture was stirred at 90 °C for 48 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 × 100 mL). The organic layers were combined, washed with ice-water (100 mL), brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (50% EtOAc in petroleum ether) to give 2-(2,6-dioxo-3-piperidyl)-4-(prop-2-ynylamino)isoindoline-1,3-dione (6, 1.0 g, 2.95 mmol, 10%) as a pale yellow solid. LCMS (ES+): m / z 312.0 [M + H]+

[0542] Step 4: tert-Butyl 3-[4-[[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]methyl]triazol-1-yl]azetidine-1-carboxylate (7) To a 50 mL single-neck round-bottom flask containing a well-stirred solution of 2-(2,6-dioxo-3-piperidyl)-4-(prop-2-ynylamino)isoindoline-1,3-dione (6, 100 mg, 321.24 μmol) in DMSO (2 mL), copper sulfate (5.13 mg, 32.12 μmol, 1.42 μL), tert-butyl 3-azidoazetidine-1-carboxylate (3, 63.68 mg, 321.24 μmol), and sodium (+)-L-ascorbate (19.09 mg, 96.37 μmol) were added at room temperature. After 16 h, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 × 50 mL). The organic phases were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was triturated with EtO, filtered, and dried to give tert-butyl 3-[4-[[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]methyl]triazol-1-yl]azetidine-1-carboxylate (7, 150 mg, 183.32 μmol, 57% yield) as a pale yellow solid. LCMS (ES+): m / z 510.3 [M + H]+

[0543] Step 5: 4-[[1-(azetidin-3-yl)triazol-4-yl]methylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (8) To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 3-[4-[[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-indolin-4-yl]amino]methyl]triazol-1-yl]azetidine-1-carboxylate (7, 150 mg, 294.40 μmol) in DCM (5 mL) was added TFA (335.67 mg, 2.94 mmol, 226.81 μL) at room temperature. After 2 h, the reaction mixture was concentrated under reduced pressure to give 4-[[1-(azetidin-3-yl)triazol-4-yl]methylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (8, 100 mg, 135.57 μmol, 46% yield, TFA salt) as a brown, viscous liquid, which was used in the next step without further purification. LCMS (ES+): m / z 410.2 [M + H]+

[0544] 3-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propan-2-yl)-1H-1,2,3-triazol-1-yl)propanoic acid (5)

[0545] [ka]

[0546] Step 1: 4-(1,1-dimethylprop-2-ynylamino)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (3) To a well-stirred pressure tube solution of 2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3-dione (1, 0.500 mg, 1.81 mmol) in DMSO (5 mL) was added 2-methylbut-3-yn-2-amine (2, 225.72 mg, 2.72 mmol, 285.72 μL) and DIPEA (1.40 g, 10.86 mmol, 1.89 mL). The vial was sealed and the reaction mixture was stirred at 90° C. for 48 h. The reaction mixture was poured into ice water, and the precipitate was collected by filtration, washed with water, and dried under vacuum to give 4-(1,1-dimethylprop-2-ynylamino)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (3, 160 mg, 457.35 μmol, 26% yield) as a green solid, which was used in the next step without further purification. LCMS (ES+): m / z 340.3 [M + H]+

[0547] Step 2: 3-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propan-2-yl)-1H-1,2,3-triazol-1-yl)propanoic acid (5) To a 50 mL single-neck round-bottom flask containing a well-stirred solution of 4-(1,1-dimethylprop-2-ynylamino)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (3, 0.160 g, 471.50 μmol) in THF (4 mL) and water (1 mL), 3-azidopropanoic acid (4, 54.26 mg, 471.50 μmol), copper(II) sulfate pentahydrate (117.73 mg, 471.50 μmol), and sodium (+)-L-ascorbate (93.41 mg, 471.50 μmol) were added. The reaction mixture was stirred at ambient temperature for 16 hours. After completion of the reaction, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with water (100 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered, and the solvent was removed under reduced pressure to give 3-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propan-2-yl)-1H-1,2,3-triazol-1-yl)propanoic acid (5, 0.090 g, 180.22 μmol, 42% yield) as a green solid. LCMS (ES-): m / z 453.2 [M - H]-

[0548] 3-[4-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]oxymethyl]triazol-1-yl]propanoic acid (6)

[0549] [ka]

[0550] Step 1: 3-(4-hydroxy-1-oxo-isoindolin-2-yl)piperidine-2,6-dione (2) To a 250 mL single-neck round-bottom flask containing a well-stirred solution of 3-(4-amino-1-oxo-isoindolin-2-yl)piperidine-2,6-dione (1, 4 g, 15.43 mmol) in water (50 mL) was added concentrated hydrochloric acid (30% aqueous solution, 10 mL) at 0 °C. After 10 min, a solution of NaNO (1.60 g, 23.14 mmol) in water (10 mL) was added dropwise over 5 min. The reaction mixture was allowed to reach room temperature and then heated to 70 °C for 3 h. The reaction mixture was filtered to give a brown solid, which was purified by reverse-phase column chromatography (C18-column; mobile phase A: 0.1% HCOOH in water and mobile phase B: MeCN) to give 3-(4-hydroxy-1-oxo-isoindolin-2-yl)piperidine-2,6-dione (2, 1.5 g, 5.59 mmol) as a light brown solid. LCMS (ES+): m / z 261.1 [M + H] +

[0551] Step 2: 3-(1-oxo-4-prop-2-ynoxy-isoindolin-2-yl)piperidine-2,6-dione (4) To a 50 mL single-neck round-bottom flask containing a well-stirred solution of 3-(4-hydroxy-1-oxo-isoindolin-2-yl)piperidine-2,6-dione (2, 1 g, 3.84 mmol) in DMF (20 mL) was added KCO (637.29 mg, 4.61 mmol). After 10 min, 3-bromoprop-1-yne, 80% in toluene (3, 685.66 mg, 4.61 mmol, 0.857 mL) was added dropwise, and the reaction mixture was stirred at room temperature for 16 h. The reaction was quenched with HCl (80 mL) and extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with water (2 × 40 mL), brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC [purification method: column; Sunfire C18 (150 × 19 mm), 5 μm; mobile phase A: 0.1% TFA in water and mobile phase B: MeCN] to give 3-(1-oxo-4-prop-2-ynoxy-isoindolin-2-yl)piperidine-2,6-dione (4, 250 mg, 830.81 μmol, 22% yield) as an off-white solid. LCMS (ES+): m / z 299.0 [M + H] +

[0552] Step 3: 3-[4-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]oxymethyl]triazol-1-yl]propanoic acid (6) To a 25 mL single-neck round-bottom flask containing a well-stirred solution of 3-(1-oxo-4-prop-2-ynoxy-isoindolin-2-yl)piperidine-2,6-dione (4, 240 mg, 804.58 μmol) and 3-azidopropanoic acid (5, 185.20 mg, 1.61 mmol) in a mixture of THF (6 mL), DMSO (1 mL), and water (2 mL) at room temperature, sodium (+)-L-ascorbate (159.40 mg, 804.58 μmol) was added, followed by CuSO (128.42 mg, 804.58 μmol). After 16 h, the reaction mixture was filtered through a pad of Celite and washed with DMSO (10 mL). The solvent was removed under reduced pressure, and the residue was purified by reverse-phase preparative HPLC [purification method: column; Atlantis C18 (150 × 19 mm), 5 μm; mobile phase A: 0.1% TFA in water and mobile phase B: MeCN] to give 3-[4-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]oxymethyl]triazol-1-yl]propanoic acid (6, 210 mg, 391.41 μmol, 49% yield, TFA salt) as a white solid. LCMS (ES+): m / z 414.1 [M + H] +

[0553] 3-[4-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]oxymethyl]triazol-1-yl]propanoic acid (7)

[0554] [ka]

[0555] Step 1: Methyl 4-acetoxy-2-methylbenzoate (2) To a 500 mL single-neck round-bottom flask containing a well-stirred solution of methyl 4-hydroxy-2-methyl-benzoate (1, 8 g, 48.14 mmol) in CHCl (250 mL) was added EtN (12.18 g, 120.36 mmol, 16.78 mL) and acetyl chloride (5.67 g, 72.21 mmol, 4.39 mL). The resulting mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with water (100 mL) and extracted with CHCl (2 × 200 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (30% EtOAc in petroleum ether) to give methyl 4-acetoxy-2-methyl-benzoate (2, 7.4 g, 35.54 mmol, 74% yield) as a pale yellow liquid. GCMS: m / z 208

[0556] Step 2: Methyl 4-acetoxy-2-(bromomethyl)benzoate (3) To a 250 mL single-neck round-bottom flask containing a well-stirred solution of methyl 4-acetoxy-2-methyl-benzoate (2, 7.4 g, 0.035 mol) in chlorobenzene (100 mL) was added NBS (7.59 g, 0.426 mol) and AIBN (0.58 g, 0.0035 mol). The resulting solution was stirred at 75 °C for 16 h. The reaction was quenched with (100 mL) and extracted with dichloromethane (2 × 200 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (20% EtOAc in petroleum ether) to give methyl 4-acetoxy-2-(bromomethyl)benzoate (3, 5 g, 0.017 mol, 41% yield) as a brown viscous liquid. GCMS: m / z 285

[0557] Step 3: Methyl 2-(bromomethyl)-4-hydroxybenzoate (4) To a 500 mL single-neck round-bottom flask containing a well-stirred solution of methyl 4-acetoxy-2-(bromomethyl)benzoate (3, 5 g, 17.42 mmol) in 1,4-dioxane (50 mL), HCl (4.0 M in dioxane) (100 mL) was added at 0° C. The resulting mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography (20% EtOAc in petroleum ether) to give methyl 2-(bromomethyl)-4-hydroxybenzoate (4, 2.7 g, 11.02 mmol, 63% yield) as an off-white solid. GCMS: m / z 243.9

[0558] Step 4: Methyl 2-(bromomethyl)-4-prop-2-ynoxy-benzoate (5) To a 100 mL single-neck round-bottom flask containing a well-stirred solution of anhydrous KCO (1.56 g, 11.26 mmol) in CHCN (10 mL) was added 3-bromoprop-1-yne (4a, 5.82 g, 48.97 mmol), followed by methyl 2-(bromomethyl)-4-hydroxybenzoate (4, 2.4 g, 9.79 mmol) in CHCN (10 mL). The reaction was heated at 50 °C for 2 h. The solvent was removed under reduced pressure, and the residue was partitioned between EtOAc (50 mL) and water (50 mL). The organic layer was separated, washed with brine (25 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0–100% EtOAc in petroleum ether) to give methyl 2-(bromomethyl)-4-prop-2-ynoxy-benzoate (5, 0.75 g, 2.65 mmol, 27% yield) as a pale yellow semi-solid. 1H NMR (400 MHz, DMSO-d6): δ 7.92 (d, J = 8.80 Hz, 1H), 7.22 (d, J = 2.40 Hz, 1H), 7.07 (dd, J = 2.80, 8.80 Hz, 1H), 5.02 (s, 2H), 4.92 (s, 2H), 3.84 (s, 3H), 3.34 (s, 1H).

[0559] Step 5: 3-(1-oxo-5-prop-2-ynoxy-isoindolin-2-yl)piperidine-2,6-dione (6) To a 50 mL single-neck round-bottom flask containing a well-stirred solution of methyl 2-(bromomethyl)-4-prop-2-ynoxy-benzoate (5, 0.75 g, 2.65 mmol) in anhydrous toluene (10 mL) was added 3-aminopiperidine-2,6-dione hydrochloride (5a, 654.02 mg, 3.97 mmol) and EtN (804.18 mg, 7.95 mmol, 1.11 mL). After 16 h, water (50 mL) was added to the reaction mixture and extracted with EtOAc (3 × 150 mL). The organic layers were combined, dried over NaSO, and filtered. The filtrate was concentrated under reduced pressure to give a crude residue, which was taken up in anhydrous DMF (10 mL) and refluxed for 16 h. The reaction mixture was allowed to reach room temperature, and the solvent was removed under reduced pressure. The residue was triturated with MTBE (3 x 25 mL) to give 3-(1-oxo-5-prop-2-ynoxy-isoindolin-2-yl)piperidine-2,6-dione (6, 1.2 g, 935.68 μmol, 35% yield) as a grey solid. This material was used in the next step without further purification. LCMS (ES+): m / z 299.1 [M + H]+

[0560] Step 6: 3-[4-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]oxymethyl]triazol-1-yl]propanoic acid (7) To a 50 mL single-neck round-bottom flask containing a well-stirred solution of 3-azidopropanoic acid (6a, 350 mg, 3.04 mmol) and 3-(1-oxo-5-prop-2-ynoxy-isoindolin-2-yl)piperidine-2,6-dione (6, 907.13 mg, 3.04 mmol) in DMSO (5 mL) and water (5 mL), sodium ascorbate (602.46 mg, 3.04 mmol) and copper(II) sulfate pentahydrate (759.31 mg, 3.04 mmol) were added. After 4 h, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 × 10 mL). The organic layers were combined, dried over NaSO, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by reverse-phase preparative HPLC [YMC C18 (150 × 20) mm, 5.0 μm and solvent A: 10 mm ammonium acetate in water; solvent B: acetonitrile] to give 3-[4-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]oxymethyl]triazol-1-yl]propanoic acid (7, 100 mg, 240.14 μmol, 8% yield) as a pale yellow solid. LCMS (ESI+): m / z 414.0 [M + H]+

[0561] 3-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoindolin-4-yl)oxy)methyl)-1H-pyrazol-1-yl)propanoic acid (9)

[0562] [ka]

[0563] Step 1: tert-Butyl 3-(4-formyl-1H-pyrazol-1-yl)propanoate (3) To a 100 mL single-neck round-bottom flask containing a well-stirred solution of 1H-pyrazole-4-carbaldehyde (1, 1 g, 10.41 mmol) in anhydrous DMF (10 mL) was added cesium carbonate (6.78 g, 20.81 mmol) under a nitrogen atmosphere at 0 °C. After 15 min, tert-butyl 3-bromopropanoate (2, 4.35 g, 20.81 mmol, 2.15 mL) was added. The resulting suspension was stirred at 100 °C for 16 h. The reaction was quenched with HCl (30 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (5% MeOH in DCM) to give tert-butyl 3-(4-formylpyrazol-1-yl)propanoate (3, 2 g, 8.63 mmol, 83% yield) as a colorless liquid. 1H-NMR (400 MHz, DMSO-d6): δ 9.79 (s, 1H), 8.46 (s, 1H), 7.99 (s, 1H), 4.38 (t, J = 8.00 Hz, 2H), 2.82 (t, J = 8.00 Hz, 2H), 1.35 (s, 9H).

[0564] Step 2: tert-Butyl 3-(4-(hydroxymethyl)-1H-pyrazol-1-yl)propanoate (4) To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 3-(4-formylpyrazol-1-yl)propanoate (3, 2 g, 8.92 mmol) in anhydrous methanol (15 mL) was added sodium borohydride (506.11 mg, 13.38 mmol, 473.00 μL) under a nitrogen atmosphere at 0° C. The reaction mixture was stirred at room temperature for 3 h. The solvent was removed under reduced pressure and quenched with water (30 mL). The aqueous layer was extracted with EtOAc (2 × 20 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (80% EtOAc in petroleum ether) to give tert-butyl 3-[4-(hydroxymethyl)pyrazol-1-yl]propanoate (4, 1.2 g, 4.34 mmol, 49% yield) as a colorless liquid. LCMS (ES+): m / z 227.2 [M + H]+

[0565] Step 3: tert-butyl 3-(4-((methylsulfonyl)oxy)methyl)-1H-pyrazol-1-yl)propanoate (6) To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 3-[4-(hydroxymethyl)pyrazol-1-yl]propanoate (4, 1.2 g, 5.30 mmol) in anhydrous DCM (10 mL) was added TEA (1.61 g, 15.91 mmol, 2.22 mL) and methanesulfonyl chloride (5, 911.26 mg, 7.96 mmol, 615.72 μL) at 0 °C. The mixture was stirred at room temperature for 2 h. The reaction was quenched with HCl (30 mL) and extracted with DCM (2 × 20 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to afford tert-butyl 3-[4-(methylsulfonyloxymethyl)pyrazol-1-yl]propanoate (6, 750 mg, 2.46 mmol, 47% yield) as a colorless liquid, which was used without further purification.

[0566] Step 4: tert-butyl 3-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoindolin-4-yl)oxy)methyl)-1H-pyrazol-1-yl)propanoate (8) To a 50 mL pressure tube containing a well-stirred solution of 3-(4-hydroxy-1-oxo-isoindolin-2-yl)piperidine-2,6-dione (7, 500 mg, 1.92 mmol) in anhydrous DMF (10 mL) was added tert-butyl 3-[4-(methylsulfonyloxymethyl)pyrazol-1-yl]propanoate (6, 877.14 mg, 2.88 mmol) and cesium carbonate (1.25 g, 3.84 mmol). The tube was sealed, and the mixture was stirred at 50 °C for 16 h. The reaction was quenched with HCl (30 mL) and extracted with EtOAc (2 × 20 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude residue contained a mixture of two mono-alkylated products (16% and 17%) and a di-alkylated product (10%). This mixture was first purified by silica gel chromatography (5% MeOH in DCM) to give a mixture of two mono-alkylated products. This mixture of two mono-alkylated products was then purified by reverse-phase preparative HPLC [purification method: column Sunfire C18 (19 × 150 mm) 5 micron, mobile phase: water and 0.1% FA in MeCN] to give tert-butyl 3-[4-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]oxymethyl]pyrazol-1-yl]propanoate (8, 70 mg, 107.58 μmol, 6% yield) as an off-white solid. LCMS (ES+): m / z 469.1 [M + H]+

[0567] Step 5: 3-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoindolin-4-yl)oxy)methyl)-1H-pyrazol-1-yl)propanoic acid (9) To a 10 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 3-[4-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]oxymethyl]pyrazol-1-yl]propanoate (8, 70 mg, 107.58 μmol) in anhydrous DCM (2 mL) was added TFA (0.5 mL, 6.49 mmol) under a nitrogen atmosphere at 0° C. The mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure and azeotroped with toluene to give 3-[4-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]oxymethyl]pyrazol-1-yl]propanoic acid (9, 65 mg, 101.19 μmol, 92% yield) as an off-white solid. LCMS (ES+): m / z 413.2 [M + H]+

[0568] 2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-1-yl)acetic acid (13)

[0569] [ka]

[0570] Step 1: 5-Bromo-N-methyl-2-nitroaniline (2) To a stirred solution of 4-bromo-2-fluoro-1-nitrobenzene (1, 300 g, 1.36 mol) in DCM (3 L), K2CO3 (0.94 kg, 6.8 mol) and methylamine (2 M in THF) (2.04 L, 4.09 mol) were added at room temperature and stirred for 16 hours. The two reaction batches were combined. After completion of the reaction, the reaction mixture was diluted with water (3.0 L) and extracted with DCM (2.5 L x 2). The combined organic layer was washed with saturated sodium bicarbonate solution (1.5 L x 2) and brine (1.5 L x 2). The organic layer was dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure to give 5-bromo-N-methyl-2-nitroaniline (2, 600 g, 95% yield) as a yellow solid. LCMS (ES+): m / z 231.1 [M+H]+

[0571] Step 2: tert-butyl 4-(3-(methylamino)-4-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (4) To a stirred solution of 5-bromo-N-methyl-2-nitroaniline (2, 75.0 g, 0.326 mol) in 1,4-dioxane (1.2 L) and water (0.3 L) was added K2CO3 (270.3 g, 1.956 mol), and the mixture was stirred for 5 minutes. tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (3, 151.0 g, 0.489 mol) was added to the reaction mixture under a nitrogen atmosphere, and the reaction mixture was purged with nitrogen for 10 minutes. Palladium(0) tetrakis(triphenylphosphine) (37.66 g, 0.032 mol) was added to the reaction mixture under a nitrogen atmosphere. After purging with nitrogen for 10 minutes, the reaction was stirred at 110 °C for 4 hours. The two reaction batches were combined. The reaction mixture was cooled to room temperature and filtered through Celite. The filtrate was diluted with water (1.5 L) and extracted with ethyl acetate (500 mL x 2). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (0-20% EtOAc in petroleum ether as eluent) to give tert-butyl 4-(3-(methylamino)-4-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (4, 150 g, 69% yield) as a red solid. LCMS (ES+): m / z 334.3 [M+H]+

[0572] Step 3: tert-butyl 4-(4-amino-3-(methylamino)phenyl)piperidine-1-carboxylate (5) A solution of tert-butyl 4-(3-(methylamino)-4-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (4, 50 g, 0.149 mol) in methanol (1 L) in a Parr shaker flask was degassed. Palladium on carbon (10%, wet) (25.0 g) was added, and the reaction mixture was placed under a hydrogen atmosphere (70-75 psi). The reaction progress was monitored by TLC / LCMS. Four batches were combined. After 8 h, the reaction mixture was filtered through Celite and washed with methanol. The filtrate was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (0-20% ethyl acetate and petroleum ether as eluent) to give tert-butyl 4-(4-amino-3-(methylamino)phenyl)piperidine-1-carboxylate (5, 120.0 g, 65% yield) as a dark brown solid. LCMS (ES-): m / z 304.2 [MH]-

[0573] Step 4: tert-Butyl 4-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine-1-carboxylate (6) To a stirred solution of tert-butyl 4-(4-amino-3-(methylamino)phenyl)piperidine-1-carboxylate (5, 60 g, 0.196 mol) in THF (900 mL) at 0° C. was added CDI (33.45 g, 0.206 mol), and the reaction mixture was stirred at room temperature for 16 h. The two batches were combined. The solvent was removed under reduced pressure. The residue was triturated with MTBE and filtered to give tert-butyl 4-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine-1-carboxylate (6, 88.0 g, 67.5% yield) as an off-white solid. LCMS (ES+): m / z 332.3 [M+H]+

[0574] Step 5: tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine-1-carboxylate (8) To an ice-cooled, stirred solution of tert-butyl 4-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine-1-carboxylate (6, 44 g, 0.133 mol) in anhydrous THF (900 mL) at 0 °C, 1 M LiHMDS (403 mL, 0.387 mol) was added. The reaction mixture was stirred for 10 min, and then 3-bromopiperidine-2,6-dione (7, 43.34 g, 0.225 mol) was added. After the addition, the reaction mixture was stirred at 70–75 °C for 16 h. The two batches were combined. The reaction mixture was cooled to 0 °C and quenched by the slow addition of 1 N aqueous HCl (620 mL). The mixture was diluted with EtOAc (1 L), and the layers were separated. The organic layer was washed with 0.5 N HCl (1.4 L), water (1.5 L × 2), and brine (1.5 L). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (20-50% EtOAc in petroleum ether) to give tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine-1-carboxylate (8, 51.0 g, 43.4% yield) as a gray-off-white solid. LCMS (ES-): m / z 441.1 [MH]-

[0575] Step 6: 3-(3-methyl-2-oxo-5-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (10) To a stirred solution of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine-1-carboxylate (8, 25.5 g, 0.057 mol) in DCM (250 mL) at 0° C. was added TFA (87.2 ml) dropwise. The reaction mixture was stirred at room temperature for 4 hours. The two batches were combined. The volatiles were evaporated under reduced pressure and azeotroped twice with toluene. The residue was triturated with diethyl ether and dried under reduced pressure to give 3-(3-methyl-2-oxo-5-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (10, 26 g, 43.12 mmol, TFA salt) as an off-white solid. LCMS (ES+): m / z 343.3 [M+H]+

[0576] Step 7: tert-Butyl 2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]acetate (12) To a 50 mL round-bottom flask containing a well-stirred solution of 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidine-2,6-dione (10, 500 mg, 733.98 μmol) in DMF (5 mL) was added triethylamine (371.36 mg, 3.67 mmol, 511.51 μL). The mixture was cooled to 0° C., and tert-butyl bromoacetate (11, 186.12 mg, 954.18 μmol, 139.94 μL) was added. The reaction mixture was stirred at ambient temperature for 16 hours. The reaction was quenched with water (15 mL) and the precipitate was collected by filtration, washed with water (15 mL) and dried under reduced pressure to give tert-butyl 2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]acetate (12, 270 mg, 560.54 μmol, 76% yield) as a pink solid. LCMS (ES+): m / z 456.9 [M + H]+

[0577] Step 8: 2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-1-yl)acetic acid (13) To a 25 mL round-bottom flask containing a well-stirred solution of tert-butyl 2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]acetate (12, 300 mg, 657.13 μmol) in DCM (3 mL) was added TFA (224.78 mg, 1.97 mmol, 151.88 μL) dropwise at 0° C. The reaction mixture was stirred at ambient temperature for 3 h. The volatiles were removed under reduced pressure and the residue was triturated with diethyl ether (2×10 mL) to give 2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-1-yl)acetic acid (13, 280 mg, 622.34 μmol, 95% yield) as a light brown solid. LCMS (ES+): m / z 401.3 [M + H] +

[0578] 3-[5-(azetidin-3-ylamino)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (10)

[0579] [ka]

[0580] Step 1: 2,6-Dibenzyloxypyridin-3-amine (3) Benzyl alcohol (2, 3.32 g, 30.67 mmol, 3.16 mL) was dissolved in THF (40 mL) and purged with nitrogen for 30 minutes at room temperature. Potassium tert-butoxide (3.44 g, 30.67 mmol) was added portionwise over 10 minutes. The reaction was stirred at room temperature for 2 hours, and 2,6-dichloropyridin-3-amine (1, 2 g, 12.27 mmol) was added. The mixture was heated to reflux for 24 hours. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over MgSO4, filtered, and the residue was purified by silica gel chromatography (0-10% EtOAc in hexanes) to give 2,6-dibenzyloxypyridin-3-amine (3, 2.39 g, 7.80 mmol, 64% yield) as a dark orange oil. LCMS (ES+): m / z 306.7 [M+H]+

[0581] Step 2: 4-Bromo-N1-(2,6-dibenzyloxy-3-pyridyl)-N2-methyl-benzene-1,2-diamine (5) To a stirred solution of 2,6-dibenzyloxypyridin-3-amine (3, 2.5 g, 8.16 mmol) and 5-bromo-2-iodo-N-methyl-aniline (4, 3.03 g, 8.16 mmol) in tert-butanol (30 mL) in a sealed tube was added cesium carbonate (5.32 g, 16.32 mmol). The mixture was purged with nitrogen for 10 minutes, followed by the addition of dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (380.79 mg, 816.04 μmol) and tris(dibenzylideneacetone)dipalladium(0) (373.63 mg, 408.02 μmol). The mixture was purged with nitrogen for an additional 10 minutes, capped, and heated at 90°C for 12 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The mixture was washed with water and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (2-8% ethyl acetate / petroleum ether) to give 4-bromo-N1-(2,6-dibenzyloxy-3-pyridyl)-N2-methyl-benzene-1,2-diamine (5, 1.2 g, 1.71 mmol, 21% yield) as a yellow semi-solid. This material was used in the next step without further purification. LCMS (ES+): m / z 490.2 [M+H]+

[0582] Step 3: 5-Bromo-1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-benzimidazol-2-one (6) To a stirred solution of 4-bromo-N1-(2,6-dibenzyloxy-3-pyridyl)-N2-methyl-benzene-1,2-diamine (5, 1.4 g, 2.43 mmol) in DCM (30 mL) at 0 °C, pyridine (1.94 g, 24.27 mmol, 1.98 mL) was added, followed by triphosgene (1.52 g, 4.85 mmol, 95% purity). After stirring at room temperature for 16 h, the reaction mixture was diluted with DCM and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 to 40% ethyl acetate in hexanes) to give 5-bromo-1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-benzimidazol-2-one (6, 1.21 g, 2.33 mmol, 96% yield) as an off-white solid. LCMS (ES+): m / z 516.2 [M+H]+ 1H NMR (400 MHz, DMSO-d6): δ 7.82-7.80 (d, J=8Hz, 1H), 7.49-7.25 (m, 11H), 7.16-7.13 (m, 1H), 6.65-6.60 (m, 2H), 5.38-5.36 (m, 4H), 3.38 (s, 3H).

[0583] Step 4: tert-butyl 3-[[1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-2-oxo-benzimidazol-5-yl]amino]azetidine-1-carboxylate (8): To a 20 mL sealed tube containing a well-stirred solution of 5-bromo-1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-benzimidazol-2-one (6, 300 mg, 0.580 mmol) in 1,4-dioxane (3 mL), tert-butyl 3-aminoazetidine-1-carboxylate (7, 250.14 mg, 1.45 mmol) and cesium carbonate (567.87 mg, 1.74 mmol) were added. The reaction mixture was deoxygenated by bubbling nitrogen through it for 5 minutes. Next, tris(dibenzylideneacetone)dipalladium(0) (79.80 mg, 0.087 mmol) and XPhos (69.24 mg, 0.145 mmol) were added to the reaction mixture, and the reaction mixture was heated to 90 °C for 16 hours. The reaction mixture was cooled to room temperature and poured into water (20 mL). The aqueous layer was extracted with EtOAc (2 x 30 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% EtOAc / petroleum ether) to afford tert-butyl 3-[[1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-2-oxo-benzimidazol-5-yl]amino]azetidine-1-carboxylate (8, 280 mg, 0.437 mmol, 75% yield) as a pale yellow foam. LCMS (ESI): m / z 608.2 [M + H]+

[0584] Step 5: tert-Butyl 3-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]amino]azetidine-1-carboxylate (9): To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 3-[[1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-2-oxo-benzimidazol-5-yl]amino]azetidine-1-carboxylate (8, 280 mg, 0.460 mmol) in 1,4-dioxane (5 mL), Pd(OH) (20 wt% on carbon, 50% water) (64.71 mg, 0.460 mmol) was added at room temperature under a nitrogen atmosphere. The reaction mixture was then placed under a balloon atmosphere of hydrogen at room temperature for 16 hours. The reaction mixture was filtered through a Celite pad and washed with 1,4-dioxane (200 mL). The filtrate was concentrated under reduced pressure, and the residue was triturated with diethyl ether (2×25 mL) to give tert-butyl 3-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]amino]azetidine-1-carboxylate (9, 160 mg, 0.219 mmol, 48% yield) as a dark brown solid. LCMS (ESI): m / z 428.1 [M − H]-

[0585] Step 6: 3-[5-(azetidin-3-ylamino)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (10): To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 3-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]amino]azetidine-1-carboxylate (9, 50 mg, 0.116 mmol) in anhydrous DCM (3 mL) was added TFA (370.00 mg, 3.25 mmol, 0.25 mL) at 0° C. The reaction mixture was warmed to room temperature and stirred for 3 h. The reaction mixture was concentrated under reduced pressure, and the residue was azeotroped with toluene (2 x 5 mL) and then triturated with diethyl ether to give 3-[5-(azetidin-3-ylamino)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (10, 45 mg, 0.071 mmol, 61% yield) as a dark brown thick gum. LCMS (ESI): m / z 330.1 [M + H]+.

[0586] 3-(3-methyl-2-oxo-4-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (8)

[0587] [ka]

[0588] Step 1: 2-Bromo-N-methyl-6-nitroaniline (2) To a solution of 1-bromo-2-fluoro-3-nitrobenzene (1, 300 g, 1.36 mol) in DCM (3000 mL) was added KCO (188.47 g, 1.36 mol). The mixture was cooled to 0 °C, and MeNH (2 M, 681.83 mL, 1.36 mol) was added. The mixture was stirred at 0 °C for 1 hour and then at 25 °C for 3 hours. The mixture was filtered, and the filter cake was washed with DCM (1000 mL). The filtrate was concentrated under reduced pressure to give 2-bromo-N-methyl-6-nitroaniline (2, 600 g, crude) as a yellow liquid, which was used in the next reaction without further purification.

[0589] Step 2: 6-Bromo-N1-methylbenzene-1,2-diamine (3) To a solution of 2-bromo-N-methyl-6-nitroaniline (2, 200 g, 865.63 mmol) in THF (3000 mL) was added Fe (241.71 g, 4.33 mol), followed by NH₄Cl (463.04 g, 8.66 mol) in HO (300 mL). After stirring at 75 °C for 18 h, the mixture was filtered through Celite and washed with ethyl acetate (1000 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (500 mL). The combined organic phase was washed with brine (1000 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 50 / 1 to 5 / 1) to give 6-bromo-N₁-methylbenzene-1,2-diamine (3, 240 g, 1.19 mol, 46% yield) as a yellow solid.

[0590] Step 3: 7-Bromo-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (4) To a solution of 6-bromo-N1-methylbenzene-1,2-diamine (3, 240 g, 1.19 mol) in THF (2000 mL) was added CDI (967.75 g, 5.97 mol) and stirred at 60° C. for 6 hours. The mixture was then stirred at 25° C. for 12 hours. The mixture was concentrated under reduced pressure, and the residue was triturated with ethyl acetate (1500 mL) at 25° C. for 2 hours to give 7-bromo-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (4, 150 g, 660.63 mmol, 55% yield) as an off-white solid. This solid was used directly in the next step without further purification.

[0591] Step 5: 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (5) To a solution of 7-bromo-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (4, 150 g, 660.62 mmol) in THF (1500 mL) was added LiHMDS (1 M in THF, 1.98 L) dropwise at 0 °C. After 15 min, 3-bromopiperidine-2,6-dione (4_2, 190.27 g, 990.94 mmol) in THF (300 mL) was added dropwise at 0 °C. The reaction was stirred at 70 °C for 15 h. The reaction mixture was cooled to 0 °C, and the reaction was quenched with HO (1000 mL). The resulting mixture was adjusted to pH = 2-3 with 1 M HCl (approximately 800 mL), and the precipitate was collected by suction filtration to give 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (5, 65 g, 192.22 mmol, 29% yield) as a white solid.

[0592] Step 6: tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (6) To a solution of 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (5, 45 g, 133.07 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (5_2, 61.72 g, 199.61 mmol) in DMF (450 mL) and HO (50 mL) was added CsF (20.21 g, 133.07 mmol, 4.91 mL) and 1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (17.35 g, 26.61 mmol). The mixture was stirred at 85° C. for 4 hours. The mixture was added to water (1500 mL) and filtered. The filtrate was concentrated and purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (6, 40 g, 90.81 mmol, 68% yield) as a gray solid.

[0593] Step 7: tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidine-1-carboxylate (7) To a solution of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (6, 40 g, 90.81 mmol) in DCM (1200 mL) and MeOH (800 mL) was added Pd / C (200 g, 10%). The mixture was stirred under H atmosphere (15 psi) at 25° C. for 4 hours. The mixture was filtered through Celite, washed with DCM:MeOH=3:2 (1500 mL), and concentrated in vacuo. The residue was triturated with DCM (50 mL) to give tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidine-1-carboxylate (7, 28 g, 63.28 mol, 70% yield) as a white solid.

[0594] Step 8: 3-(3-methyl-2-oxo-4-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (8) To a solution of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidine-1-carboxylate (7, 28 g, 63.28 mmol) in DCM (200 mL) was added TFA (123.20 g, 1.08 mol, 80.00 mL). After stirring at room temperature for 6 hours, the mixture was concentrated, and the residue was triturated with MTBE (200 mL) to give 3-(3-methyl-2-oxo-4-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (8, 27 g, 58.57 mmol, 93% yield, TFA salt) as an off-white solid. LCMS: m / z 343.0 [M+H]+

[0595] 2-(4-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)piperidin-1-yl)acetic acid (10)

[0596] [ka]

[0597] Step 1: 3-(6-bromo-2-oxobenzo[d]oxazol-3(2H)-yl)piperidine-2,6-dione (3) To a stirred solution of 6-bromo-3H-1,3-benzoxazol-2-one (1, 6 g, 28.04 mmol) in THF (200 mL), sodium hydride (60% dispersion in mineral oil) (1.29 g, 56.07 mmol) was added portionwise, and the mixture was heated at 60° C. for 1 h. The mixture was added dropwise via cannula to a stirred solution of 3-bromopiperidine-2,6-dione (2, 8.07 g, 42.05 mmol) in THF (50 mL) at 60° C. and stirred for 2 h. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organics were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (50% ethyl acetate:hexanes) to give 3-(6-bromo-2-oxobenzo[d]oxazol-3(2H)-yl)piperidine-2,6-dione (3, 2.9 g, 8.71 mmol, 31% yield). LCMS (ES-): m / z 323.0 [MH]- 1H NMR (400 MHz, DMSO-D6) δ 11.23 (s, 1H), 7.73 (s, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.26 (d, J=8.36 Hz, 1H), 5.41-5.37 (m, 1H), 2.87-2.84 (m, 1H), 2.71-2.64 (m, 2H), 2.18-2.15 (m, 1H)

[0598] Step 2: (tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (5) To a 20 mL sealed tube containing a well-stirred solution of 3-(6-bromo-2-oxo-1,3-benzoxazol-3-yl)piperidine-2,6-dione (3, 200 mg, 0.615 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (4, 247.28 mg, 0.800 mmol) in 1,4-dioxane (2 mL), anhydrous potassium phosphate tribasic (522.32 mg, 2.46 mmol) was added under a nitrogen atmosphere. The resulting mixture was purged with nitrogen for 10 minutes. XPhos-Pd-G2 (48.40 mg, 0.0615 mmol) was added to the reaction mixture, and the reaction was heated to 90 °C for 16 hours. The reaction was cooled to room temperature, poured into water (10 mL), and extracted with EtOAc (2 x 10 mL). The organic phases were combined and washed with brine solution (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue that was purified by silica gel (230-400 mesh) flash column with 0-100% EtOAc / petroleum ether to give tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (5, 200 mg, 0.429 mmol, 70% yield) as an off-white solid. LCMS (ESI): m / z 426.2 [M - H]-

[0599] Step 3: (tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-6-yl]piperidine-1-carboxylate (6) To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (5, 200 mg, 0.467 mmol) in 1,4-dioxane (10 mL) was added Pd(OH) (20 wt% on carbon, 50% water) (100 mg, 0.712 mmol) at room temperature under a nitrogen atmosphere. The resulting suspension was stirred at room temperature under a hydrogen atmosphere for 16 h. The reaction mixture was filtered through a Celite pad and washed with 1:1 EtOAc / DCM (200 mL). The filtrate was concentrated under reduced pressure to give a residue which was triturated with EtO (2 × 15 mL) to give tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-6-yl]piperidine-1-carboxylate (6, 190 mg, 0.384 mmol, 82% yield) as an off-white solid. LCMS (ESI): m / z 427.9 [M - H]-

[0600] Step 4: (3-[2-oxo-6-(4-piperidyl)-1,3-benzoxazol-3-yl]piperidine-2,6-dione (7) To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-6-yl]piperidine-1-carboxylate (6, 280 mg, 0.651 mmol) in DCM (3 mL) was added trifluoroacetic acid (3.38 g, 29.63 mmol, 2.28 mL) at room temperature, and the resulting reaction mixture was stirred for 3 h. The reaction mixture was concentrated under reduced pressure and azeotroped with toluene (2 × 20 mL). The residue was triturated with diethyl ether (2 × 10 mL) to give 3-[2-oxo-6-(4-piperidyl)-1,3-benzoxazol-3-yl]piperidine-2,6-dione (7, 170 mg, 0.303 mmol, 47% yield, TFA salt) as a grey foam, which was used in the next step without further purification. LCMS (ESI): m / z 330.2 [M + H]

[0601] Step 5: (tert-Butyl 2-[4-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-6-yl]-1-piperidyl]acetate (9) To a 25 mL single-neck round-bottom flask containing a well-stirred solution of 3-[2-oxo-6-(4-piperidyl)-1,3-benzoxazol-3-yl]piperidine-2,6-dione (7, 150 mg, 0.455 mmol) in DMF (5 mL), triethylamine (230.43 mg, 2.28 mmol, 317.40 μL) and tert-butyl bromoacetate (8, 102.16 mg, 0.523 mmol, 76.81 μL) were added at room temperature, and the resulting mixture was stirred for 16 h. The reaction mixture was poured into ice-cold water (20 mL). The precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure to give tert-butyl 2-[4-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-6-yl]-1-piperidyl]acetate (9, 150 mg, 0.305 mmol, 67% yield) as an off-white solid, which was used in the next step without further purification. LCMS (ESI): m / z 444.0 [M + H]

[0602] Step 6: (2-[4-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-6-yl]-1-piperidyl]acetic acid (10) To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 2-[4-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-6-yl]-1-piperidyl]acetate (9, 190 mg, 0.428 mmol) in DCM (3 mL) was added trifluoroacetic acid (2.22 g, 19.47 mmol, 1.5 mL) at room temperature, and the resulting mixture was stirred for 6 h. The reaction mixture was concentrated under reduced pressure to give a residue that was azeotroped with toluene (2 x 20 mL) and triturated with diethyl ether (2 x 10 mL) to give 2-[4-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-6-yl]-1-piperidyl]acetic acid (10, 150 mg, 0.234 mmol, 55% yield) as a grey foam, which was used without further purification. LCMS (ESI): m / z 387.9 [M + H]

[0603] 2-[4-[1-(2,6-dioxo-3-piperidyl)-3-isopropyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]acetic acid (14)

[0604] [ka]

[0605] Step 1: 5-Bromo-N-isopropyl-2-nitro-aniline (3) To a solution of 4-bromo-2-fluoro-1-nitro-benzene (1, 2.4 g, 10.91 mmol) in DCM (25 mL) was added isopropylamine (2, 644.9 mg, 10.91 mmol, 0.933 mL) and potassium carbonate (3.02 g, 21.8 mmol). After 16 h, the reaction was diluted with DCM (50 mL) and washed with water (3 x 40 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to give 5-bromo-N-isopropyl-2-nitro-aniline (3, 2.8 g, 10.78 mmol, 98.8%) as a bright yellow solid. This material was used in the next step without purification. LCMS (ES+): m / z 261 [M+H]+

[0606] Step 2: 4-Bromo-N2-isopropyl-benzene-1,2-diamine (4) To a solution of 5-bromo-N-isopropyl-2-nitro-aniline (3, 2.8 g, 10.81 mmol) in ethanol (60 mL) was added a solution of sodium dithionite (8.47 g, 48.63 mmol) in water (25 mL). After 3 h, the reaction mixture was concentrated under reduced pressure. The residue was taken up in ethyl acetate (50 mL) and washed with water (3×40 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to give 5-bromo-N1-isopropyl-benzene-1,2-diamine (4, 2.2 g, 8.41 mmol, 78% yield) as a pale yellow liquid. This material was used in the next step without further purification. LCMS (ES-): m / z 229 [M−H]-

[0607] Step 3: 5-Bromo-3-isopropyl-1H-benzimidazol-2-one (5) To a solution of 5-bromo-N1-isopropyl-benzene-1,2-diamine (4, 2.2 g, 9.60 mmol) in THF (25 mL) was added CDI (2.34 g, 14.40 mmol). After 16 h, the mixture was diluted with ethyl acetate (50 mL) and washed with water (3 x 40 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (40% EtOAc:hexanes) to give 5-bromo-3-isopropyl-1H-benzimidazol-2-one (5, 1.48 g, 5.80 mmol, 60% yield) as a white solid. LCMS (ES+): m / z 257 [M+H]+

[0608] Step 4: 3-(5-bromo-3-isopropyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (7) A solution of 5-bromo-3-isopropyl-1H-benzimidazol-2-one (5, 1.5 g, 6.20 mmol) in THF (20 mL) was cooled to 0 °C, and lithium bis(trimethylsilyl)amide (1.04 g, 6.20 mmol) was added dropwise. After 15 minutes, a solution of 3-bromopiperidine-2,6-dione (6, 1.19 g, 6.20 mmol) in THF (1.5 mL) was added. The reaction mixture was allowed to reach room temperature and then heated at 60 °C for 4 hours. The mixture was cooled to room temperature and quenched with 1.5 N HCl solution. The reaction mixture was diluted with EtOAc (20 mL) and washed with 1.5 N HCl (3 × 25 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (50% EtOAc:hexanes) to give 3-(5-bromo-3-isopropyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (7, 480 mg, 1.31 mmol, 21% yield) as an off-white solid. LCMS (ES+): m / z 366 [M+H]+

[0609] Step 5: tert-Butyl 4-[1-(2,6-dioxo-3-piperidyl)-3-isopropyl-2-oxo-benzimidazol-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (9) A solution of 3-(5-bromo-3-isopropyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (7, 1.3 g, 3.55 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (8, 2.20 g, 7.10 mmol) in DMF (15 mL) was purged with N gas for 10 minutes in a sealed tube. Potassium carbonate (1.47 g, 10.65 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (289.9 mg, 354.99 μmol) were then added. After complete addition, the tube was sealed and heated to 70 °C. After 16 h, the reaction was cooled to room temperature, extracted with EtOAc (75 mL), and washed with water (3 x 20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl 4-[1-(2,6-dioxo-3-piperidyl)-3-isopropyl-2-oxo-benzimidazol-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (9, 1.02 g, 1.72 mmol, 48% yield) as an off-white solid. This material was used directly in the next step. LCMS (ES+): m / z 469.2 [M+H]+

[0610] Step 6: tert-Butyl 4-[1-(2,6-dioxo-3-piperidyl)-3-isopropyl-2-oxo-benzimidazol-5-yl]piperidine-1-carboxylate (10) To a solution of tert-butyl 4-[1-(2,6-dioxo-3-piperidyl)-3-isopropyl-2-oxo-benzimidazol-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (9, 350 mg, 746.99 μmol) in 1,4-dioxane (5 mL) was added palladium hydroxide on carbon (10 wt %, 50% water) (209.81 mg, 1.49 mmol). The reaction was placed under a hydrogen balloon atmosphere. After 16 h, the reaction was filtered through Celite. The filtrate was concentrated and the residue was purified by silica gel chromatography (70% EtOAc:hexanes) to give tert-butyl 4-[1-(2,6-dioxo-3-piperidyl)-3-isopropyl-2-oxo-benzimidazol-5-yl]piperidine-1-carboxylate (10, 345 mg, 554.29 μmol, 74% yield) as a white solid. LCMS (ES-): m / z 469 [MH]-

[0611] Step 7: 3-[3-isopropyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidine-2,6-dione (11) To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[1-(2,6-dioxo-3-piperidyl)-3-isopropyl-2-oxo-benzimidazol-5-yl]piperidine-1-carboxylate (10, 500 mg, 1.06 mmol) in anhydrous DCM (5 mL) was added TFA (1.48 g, 12.98 mmol, 1 mL) at 0° C. The reaction was stirred at ambient temperature for 2 h. The volatiles were removed under reduced pressure and the residue was azeotroped with toluene (2 x 15 mL) and then triturated with diethyl ether (20 mL) to give 3-[3-isopropyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidine-2,6-dione (11, 505 mg, 1.03 mmol, 97% yield, TFA salt) as an off-white solid. LCMS (ES+): m / z 371.0 [M + H]+

[0612] Step 8: tert-Butyl 2-[4-[1-(2,6-dioxo-3-piperidyl)-3-isopropyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]acetate (13) To a 25 mL single-neck round-bottom flask containing a well-stirred solution of 3-[3-isopropyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidine-2,6-dione (11, 500 mg, 1.35 mmol) in anhydrous DMF (5 mL) was added DIPEA (523.33 mg, 4.05 mmol, 705.30 μL) and tert-butyl bromoacetate (12, 289.60 mg, 1.48 mmol, 217.74 μL). After 2 h, the reaction mixture was poured into ice-cold water (20 mL), and the aqueous layer was extracted with DCM (2 × 25 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous NaSO, and filtered. The residue was triturated with diethyl ether, filtered, and dried to give tert-butyl 2-[4-[1-(2,6-dioxo-3-piperidyl)-3-isopropyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]acetate (13, 500 mg, 829.88 μmol, 61% yield) as an off-white solid. LCMS (ES+): m / z 485.0 [M + H]+

[0613] Step 9: 2-[4-[1-(2,6-dioxo-3-piperidyl)-3-isopropyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]acetic acid (14) To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 2-[4-[1-(2,6-dioxo-3-piperidyl)-3-isopropyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]acetate (13, 500 mg, 1.03 mmol) in anhydrous DCM (5 mL) was added TFA (1.48 g, 12.98 mmol, 1 mL) at 0° C. The mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure, azeotroped with toluene (2 x 15 mL), and triturated with diethyl ether (20 mL) to afford 2-[4-[1-(2,6-dioxo-3-piperidyl)-3-isopropyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]acetic acid (14, 440 mg, 656.95 μmol, 64% yield, TFA salt) as an off-white solid. LCMS (ES+): m / z 428.9 [M + H]+

[0614] tert-Butyl 4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidine-1-carboxylate (6)

[0615] [ka]

[0616] Step 1: tert-Butyl 4-(1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (a-2) A mixture of compound 6-bromo-1H-indazole (a-1, 57.0 g, 289 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1-3, 134 g, 433 mmol), Pd(dppf)Cl CHCl (12.0 g, 14.6 mmol), and NaCO (100 g, 943 mmol) in dioxane (480 mL) and HO (120 mL) was stirred at 105 °C for 12 h. The mixture was filtered through a Celite pad and washed with ethyl acetate (500 mL). The filtrate was washed with brine (150 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-30% ethyl acetate / petroleum ether) to give tert-butyl 4-(1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (a-2, 80.0 g, 239 mmol, 83% yield) as a yellow oil. LCMS: m / z 300.1 [M+H]

[0617] Step 2: tert-butyl 4-(3-iodo-1-methyl-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (a) To a solution of tert-butyl 4-(1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (a-2, 75.0 g, 224 mmol) in DMF (700 mL) was added KOH (37.7 g, 672 mmol) and I2 (85.3 g, 336 mmol, 67.7 mL). The mixture was stirred at 25 °C for 12 hours and cooled to 0 °C. Then MeI (44.6 g, 314 mmol, 19.6 mL) was added. The resulting mixture was stirred at 25 °C for 1 hour. The mixture was poured into water (1500 mL) and extracted with ethyl acetate (500 mL × 3). The combined organic phase was washed with brine (500 mL × 3), dried over Na2SO4, filtered, and concentrated in vacuo to give a residue that was purified by silica gel chromatography (0-8% ethyl acetate / petroleum ether) to give tert-butyl 4-(3-iodo-1-methyl-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (a, 23.0 g, 52.3 mmol, 23% yield) as a yellow oil. LCMS: m / z 440.1 [M+H] +

[0618] Step 3: 2,6-Bis(benzyloxy)pyridine (2) To a solution of t-BuOK (190 g, 1.69 mol) in THF (1.00 L) was added phenylmethanol (1-1, 73.4 g, 679 mmol, 70.6 mL) at 0 °C. 2,6-Dichloropyridine (1, 50.0 g, 338 mmol) was added to the mixture at 25 °C and stirred at 75 °C for 12 h. The reaction was quenched with saturated aqueous NH4Cl (200 mL) at 0 °C, diluted with ethyl acetate (200 mL), and extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was triturated with petroleum ether (150 mL) to give 2,6-bis(benzyloxy)pyridine (2, 84.0 g, 85% yield) as a yellow solid. LCMS: m / z 292.2 [M+H] +

[0619] Step 4: 2,6-Bis(benzyloxy)-3-bromopyridine (3) To a solution of 2,6-bis(benzyloxy)pyridine (2, 34.0 g, 116 mmol) in MeCN (100 mL) was added a solution of NBS (21.0 g, 118 mmol, 1.01 equiv.) in MeCN (200 mL) at 40 °C, and the reaction mixture was stirred at 85 °C for 12 h. The reaction mixture was concentrated under reduced pressure, diluted with water (500 mL), and extracted with ethyl acetate (300 mL × 3). The combined organic layers were washed with brine (200 mL), dried over NaSO, filtered, and concentrated. The residue was triturated with petroleum ether (60 mL) to give 2,6-bis(benzyloxy)-3-bromopyridine (3, 27.7 g, 64% yield). LCMS: m / z 371.9 [M+H]

[0620] Step 5: 2,6-Bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (4) To a solution of 2,6-bis(benzyloxy)-3-bromopyridine (3, 52.4 g, 139 mmol) in dioxane (500 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1-2, 37.1 g, 146 mmol), KOAc (41.0 g, 418 mmol), and Pd(dppf)Cl2·CHCl2 (5.69 g, 6.97 mmol). The reaction mixture was stirred at 105 °C for 12 h. The reaction mixture was filtered through a Celite pad. The filtrate was diluted with water (500 mL) and extracted with ethyl acetate (500 mL × 2). The extract was washed with brine (400 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to give 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (4, 35.0 g, 60.1% yield) as a yellow oil. LCMS: m / z 418.3 [M+H]

[0621] Step 6: tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (5) To a solution of 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (4, 20.0 g, 45.53 mmol), tert-butyl 4-(1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (a, 26.6 g, 63.7 mmol), and CsCO (44.5 g, 136 mmol) in dioxane (200 mL) and HO (40 mL) was added Pd(dppf)Cl·CHCl (3.72 g, 4.55 mmol, 0.10 equiv). The reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was filtered through a Celite pad, and the filtrate was washed with brine (60 mL × 3 mL), dried over NaSO, filtered, and concentrated. The residue was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to give tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (5, 20.0 g, 73% yield) as a yellow oil. LCMS: m / z 603.3 [M+H]

[0622] Step 7: tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidine-1-carboxylate (6) To a solution of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (5, 18.0 g, 29.8 mmol, 1.00 equiv) in EtOH (270 mL) and EtOAc (270 mL) was added Pd / C (4.00 g, 10% purity) under a N atmosphere. The suspension was degassed and purged with H three times. The mixture was stirred under H (15 psi) at 30 °C for 24 h. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated. The residue was purified by silica gel chromatography (ethyl acetate / petroleum ether) to give tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidine-1-carboxylate (6, 5.3 g, 41% yield) as a white solid. LCMS: m / z 427.2 [M+H]

[0623] Step 8: 3-[1-methyl-6-(4-piperidyl)indazol-3-yl]piperidine-2,6-dione (7) To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]piperidine-1-carboxylate (6, 500 mg, 1.17 mmol) in anhydrous DCM (5 mL) was added TFA (668.35 mg, 5.86 mmol, 451.59 μL) at 0 °C. After stirring at room temperature for 3 h, the reaction mixture was concentrated under reduced pressure. The residue was azeotroped with toluene (2 × 15 mL) and triturated with diethyl ether (20 mL) to give 3-[1-methyl-6-(4-piperidyl)indazol-3-yl]piperidine-2,6-dione (7, 500 mg, 1.12 mmol, 95% yield, TFA salt) as an off-white solid. LCMS (ESI) m / z 326.9 [M+H]+

[0624] 3-[3-methyl-2-oxo-4-(4-piperidyloxy)benzimidazol-1-yl]piperidine-2,6-dione (11):

[0625] [ka]

[0626] Step 1: tert-butyl N-(2-bromo-6-nitrophenyl)-N-methyl-carbamate (2) To a solution of 2-bromo-N-methyl-6-nitro-aniline (1, 6 g, 25.97 mmol) in THF (50 mL) was added N,N-dimethylpyridin-4-amine (4.76 g, 38.95 mmol), tert-butoxycarbonyl tert-butyl carbonate (22.67 g, 103.88 mmol, 23.84 mL), and diisopropylethylamine (10.07 g, 77.91 mmol, 13.57 mL) at 0 °C, and the reaction was heated at 50 °C for 16 h. The reaction was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give tert-butyl N-(2-bromo-6-nitro-phenyl)-N-methyl-carbamate (2, 3 g, 8.88 mmol, 34% yield). LCMS: m / z 331.2 [M+H]+

[0627] Step 2: tert-butyl N-(2-amino-6-bromo-phenyl)-N-methyl-carbamate (3) To a stirred solution of tert-butyl N-(2-bromo-6-nitro-phenyl)-N-methyl-carbamate (2, 4 g, 12.08 mmol) in ethanol (10 mL) and THF (10 mL) was added ammonium chloride (6.46 g, 120.79 mmol, 4.22 mL) and zinc (7.90 g, 120.79 mmol, 1.11 mL). The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered through Celite and washed with ethanol. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (35% ethyl acetate-hexane) to give tert-butyl N-(2-amino-6-bromo-phenyl)-N-methyl-carbamate (3, 2.54 g, 7.76 mmol, 64% yield). LCMS: m / z 300.9 [M+H]+

[0628] Step 3: tert-butyl N-[2-bromo-6-[(2,6-dibenzyloxy-3-pyridyl)amino]phenyl]-N-methyl-carbamate (5) To a stirred solution of tert-butyl N-(2-amino-6-bromophenyl)-N-methylcarbamate (3, 3.8 g, 12.62 mmol) and 2,6-dibenzyloxy-3-iodopyridine (4, 6.32 g, 15.14 mmol) in t-butanol (60 mL) was added cesium carbonate (12.33 g, 37.85 mmol). The resulting mixture was purged with argon, and 2-dicyclohexylphosphino-2,6-diidopropoxy-1,1-biphenyl (588.76 mg, 1.26 mmol) and tris(dibenzylideneacetone)dipalladium(0) (577.68 mg, 630.85 μmol) were added. The resulting mixture was heated at 100° C. for 18 hours. The reaction mixture was diluted with ethyl acetate, filtered through Celite, and washed with ethyl acetate. The filtrate was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to give tert-butyl N-[2-bromo-6-[(2,6-dibenzyloxy-3-pyridyl)amino]phenyl]-N-methyl-carbamate (5, 1.8 g, 3.05 mmol, 24%) and 4-bromo-1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-benzimidazol-2-one (6, 360 mg, 697.15 μmol, 6% yield). LCMS: m / z 590.2 [M+H] +

[0629] Step 4: 4-Bromo-1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-benzimidazol-2-one (6) To a stirred solution of tert-butyl N-[2-bromo-6-[(2,6-dibenzyloxy-3-pyridyl)amino]phenyl]-N-methyl-carbamate (5, 1.4 g, 2.37 mmol) in THF (20 mL) was added potassium tert-butoxide (319.25 mg, 2.85 mmol). The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated, then diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (30% ethyl acetate-hexane) to give 4-bromo-1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-benzimidazol-2-one (6, 0.92 g, 1.76 mmol, 74% yield). LCMS: m / z 516.0 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 7.82 (d, J=8.2 Hz, 1H), 7.45-7.32 (m, 5H), 7.27-7.24 (m, 6H), 6.92 (t, J=8.0 Hz, 1H), 6.68 (d, J=7.7 Hz, 1H), 6.62 (d, J=8.3 Hz, 1H), 5.43-5.33 (m, 4H), 3.68 (s, 3H).

[0630] Step 5: 1-(2,6-Dibenzyloxy-3-pyridyl)-4-hydroxy-3-methyl-benzimidazol-2-one (7) To a stirred solution of 4-bromo-1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-benzimidazol-2-one (6, 1.05 g, 2.03 mmol) in dioxane (8 mL) and water (8 mL) was added potassium hydroxide (250.98 mg, 4.47 mmol, 123.03 μL). The mixture was purged with argon, and tris(dibenzylideneacetone)dipalladium(0) (186.20 mg, 203.34 μmol) and tBuXPhos (345.38 mg, 813.35 μmol) were added. The resulting mixture was heated at 90° C. for 16 hours. The reaction mixture was diluted with ethyl acetate, filtered through Celite, and washed with ethyl acetate. The filtrate was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (35% ethyl acetate-hexane) to give 1-(2,6-dibenzyloxy-3-pyridyl)-4-hydroxy-3-methyl-benzimidazol-2-one (7, 831 mg, 1.83 mmol, 90% yield). LCMS: m / z 454.3 [M+H]+

[0631] Step 6: tert-butyl 4-[1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-2-oxo-benzimidazol-4-yl]oxypiperidine-1-carboxylate (9) To a stirred solution of 1-(2,6-dibenzyloxy-3-pyridyl)-4-hydroxy-3-methyl-benzimidazol-2-one (7, 0.8 g, 1.76 mmol) in DMF (8 mL) was added cesium carbonate (1.72 g, 5.29 mmol) and tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (8, 511.04 mg, 1.83 mmol). The solution was heated at 90° C. for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give tert-butyl 4-[1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-2-oxo-benzimidazol-4-yl]oxypiperidine-1-carboxylate (9, 0.56 g, 879.49 μmol, 50% yield). LCMS: m / z 637.5 [M+H]

[0632] Step 7: tert-Butyl 4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]oxypiperidine-1-carboxylate (10) To a solution of tert-butyl 4-[1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-2-oxo-benzimidazol-4-yl]oxypiperidine-1-carboxylate (9, 3.5 g, 5.50 mmol) in ethyl acetate (30 mL) was added Pd / C (10 wt%, 50% wet) (3.5 g, 5.50 mmol). The resulting mixture was stirred under hydrogen balloon pressure for 16 hours. The reaction mixture was filtered through Celite, washed with ethyl acetate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (50% ethyl acetate in hexanes) to give tert-butyl 4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]oxypiperidine-1-carboxylate (10, 1.42 g, 3.10 mmol, 56% yield). LCMS: m / z 459.4 [M+H]+

[0633] Step 8: 3-[3-methyl-2-oxo-4-(4-piperidyloxy)benzimidazol-1-yl]piperidine-2,6-dione (11) HCl (4 M in dioxane) (32.71 mmol, 7.5 mL) was added to tert-butyl 4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]oxypiperidine-1-carboxylate (10, 1.5 g, 3.27 mmol) at 10° C. The mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, triturated with ether, and lyophilized to give 3-[3-methyl-2-oxo-4-(4-piperidyloxy)benzimidazol-1-yl]piperidine-2,6-dione (11, 1.25 g, 3.13 mmol, 96% yield, HCl salt) as an off-white solid. LCMS: m / z 359.3 [M+H]+ 1H NMR (400 MHz,DMSO-d6) δ 11.09 (s, 1H), 9.08 (bs, 1H), 8.85 (bs, 1H), 6.97 (t, J=8.0 Hz, 1H), 6.83 (d, J=8.3 Hz, 1H), 6.77 (d, J=7.7 Hz, 1H), 5.37-5.33 (m, 1H), 4.76 (s, 1H), 3.55 (s, 3H), 3.20 (s, 2H), 3.10 (s, 2H), 2.92-2.85 (m, 1H), 2.72-2.59 (m, 2H), 2.15-2.14 (m, 2H), 2.00-1.97 (m, 3H).

[0634] 2-[4-[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]-1-piperidyl]acetic acid (11)

[0635] [ka]

[0636] Step 1: 6-Bromo-1H-benzo[cd]indol-2-one (2): To a 1 L two-necked round-bottom flask containing a well-stirred solution of 1H-benzo[cd]indol-2-one (1, 5 g, 29.55 mmol, 60.24 μL) in CHCl3 (300 mL) was added bromine (3.59 g, 44.33 mmol, 2.41 mL) at 0 °C. The reaction mixture was stirred at room temperature for 20 h. The reaction mixture was quenched with aqueous sodium thiosulfate (200 mL) at 0 °C. The yellow precipitate was filtered and washed with cold water (250 mL) and diethyl ether (150 mL) to give 6-bromo-1H-benzo[cd]indol-2-one (2, 5.8 g, 21.51 mmol, 73% yield) as a yellow solid. LCMS (ES+): m / z 250.1 [M + H]+

[0637] Step 2: tert-butyl 4-(2-oxo-1H-benzo[cd]indol-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (4): To a 250 mL pressure tube containing a well-stirred suspension of 6-bromo-1H-benzo[cd]indol-2-one (2, 4 g, 16.12 mmol, 60.24 μL) in DMF (30 mL) was added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (3, 5.48 g, 17.74 mmol) and cesium fluoride (4.90 g, 32.25 mmol, 1.19 mL). The mixture was purged with nitrogen for 5 minutes. Then, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1.5 g, 2.42 mmol) was added. The reaction mixture was heated at 90 °C for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (50-60% EtOAc in petroleum ether) to give tert-butyl 4-(2-oxo-1H-benzo[cd]indol-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (4, 2.1 g, 3.23 mmol, 31% yield) as a pale yellow solid. LCMS (ES+): m / z 351.2 [M + H]+

[0638] Step 3: tert-butyl 4-(2-oxo-1H-benzo[cd]indol-6-yl)piperidine-1-carboxylate (5): To a 250 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-(2-oxo-1H-benzo[cd]indol-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (4, 2.2 g, 6.28 mmol) in 1,4-dioxane (80 mL), palladium hydroxide (20% on carbon) (1.5 g, 6.28 mmol) was added, and the mixture was stirred at room temperature under a hydrogen balloon atmosphere for 16 hours. The reaction mixture was filtered through Celite and washed with EtOAc (300 mL). The solvent was removed under reduced pressure to give tert-butyl 4-(2-oxo-1H-benzo[cd]indol-6-yl)piperidine-1-carboxylate (5, 2 g, 4.90 mmol, 78% yield) as a pale yellow solid. LCMS (ES+): m / z 353.1 [M + H]+

[0639] Step 4: tert-butyl 4-[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]piperidine-1-carboxylate (7): To a 250 mL two-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-(2-oxo-1H-benzo[cd]indol-6-yl)piperidine-1-carboxylate (5, 2 g, 5.67 mmol) in THF (20 mL), lithium bis(trimethylsilyl)amide (1.0 M in THF) (12.2 mmol, 12 mL) was added at 0 °C. After 30 min at 0 °C, 3-bromopiperidine-2,6-dione (6, 1.09 g, 5.67 mmol) was added portionwise. The reaction mixture was stirred at 60 °C for 5 h. The reaction mixture was cooled to 0 °C, and the pH was adjusted to 3-4 by the addition of 1.5 N HCl (4 mL). The mixture was diluted with EtOAc (400 mL), and the layers were partitioned. The organic layer was washed with water (200 mL) and brine (150 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and purified by reverse-phase preparative HPLC (column: YMC C-18 (150 x 30 mm), 5 um, mobile phase A: 0.1% TFA in water; mobile phase B: MeCN) to give tert-butyl 4-[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]piperidine-1-carboxylate (7, 1 g, 1.69 mmol, 30% yield) as a pale yellow solid. LCMS (ES-): m / z 462.2 [M - H]-

[0640] Step 5: 3-[2-oxo-6-(4-piperidyl)benzo[cd]indol-1-yl]piperidine-2,6-dione (8): To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]piperidine-1-carboxylate (7, 100 mg, 215.74 μmol) in DCM (1 mL) was added trifluoroacetic acid (740.00 mg, 6.49 mmol, 0.5 mL) at 0° C. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was triturated with diethyl ether (0.7 mL) and filtered to give 3-[2-oxo-6-(4-piperidyl)benzo[cd]indol-1-yl]piperidine-2,6-dione (8, 80 mg, 163.21 μmol, 76%) as a pale yellow solid. LCMS (ES+): m / z 364.1 [M + H]+

[0641] Step 6: Preparation of tert-butyl 2-[4-[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]-1-piperidyl]acetate (10): To a 10 mL single-neck round-bottom flask containing a well-stirred solution of 3-[2-oxo-6-(4-piperidyl)benzo[cd]indol-1-yl]piperidine-2,6-dione (8, 65 mg, 136.15 μmol) in DMF (1 mL) was added triethylamine (68.88 mg, 680.73 μmol, 94.88 μL) at room temperature. Then, tert-butyl 2-bromoacetate (9, 31.87 mg, 163.37 μmol, 23.96 μL) was added at 0° C. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was quenched and stirred with cold water (0.5 mL), and the pale yellow precipitate was collected by filtration and washed with cold water (0.5 mL) and diethyl ether (1 mL) to give tert-butyl 2-[4-[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]-1-piperidyl]acetate (10, 64 mg, 132.14 μmol, 97% yield) as a pale yellow solid. LCMS (ES+): m / z 478.1 [M + H]+

[0642] Step 7: Preparation of 2-[4-[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]-1-piperidyl]acetic acid (11): To a 10 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 2-[4-[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]-1-piperidyl]acetate (10, 70 mg, 146.58 μmol) in DCM (1 mL) was added trifluoroacetic acid (382.23 mg, 3.35 mmol, 258.26 μL) at 0 °C. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure. The resulting residue was washed with diethyl ether (0.6 mL) to give 2-[4-[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]-1-piperidyl]acetic acid (11, 71 mg, 128.75 μmol, 88% yield) as an off-white solid. LCMS (ES+): m / z 422.1 [M + H]+

[0643] 2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]-1-piperidyl]acetic acid (9)

[0644] [ka]

[0645] Step 1a: 2,6-Dibenzyloxy-3-iodo-pyridine (A) To a stirred solution of 2,6-dibenzyloxypyridine (7, 50 g, 171.62 mmol) in acetonitrile (900 mL) was added N-iodosuccinimide (38.61 g, 171.62 mmol) in portions and stirred at room temperature for 10 minutes before heating at 80 °C. After 16 hours, the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate and washed with saturated sodium thiosulfate (2 × 50 mL), water (2 × 20 mL), and brine (1 × 10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give 2,6-dibenzyloxy-3-iodo-pyridine (A, 60 g, 115.04 mmol, 67% yield). LCMS (ES +): m / z 418.2 [M+H]+

[0646] Step 1: 4-(4-amino-2-fluoro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (3) To a stirred solution of 4-bromo-3-fluoroaniline (1, 5.00 g, 26.31 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (2, 8.95 g, 28.95 mmol) in water (12 mL), THF (60 mL), and methanol (24 mL) was added sodium carbonate (6.14 g, 57.89 mmol), and the mixture was purged with argon. PdCl(dppf) dichloromethane complex (429.78 mg, 526.28 μmol) was added and purged again. The reaction mixture was heated at 80° C. for 12 hours. The reaction mixture was diluted with ethyl acetate, filtered through a Celite pad, and washed with ethyl acetate. The filtrate was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (15% ethyl acetate-hexanes) to give tert-butyl 4-(4-amino-2-fluoro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (3, 6.1 g, 20.87 mmol, 79% yield) as a pale yellow solid. LCMS (ES+): m / z 293 [M+H]+.

[0647] Step 2: 4-[4-(2,6-bis-benzyloxy-pyridin-3-ylamino)-2-fluoro-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (4) To a stirred solution of tert-butyl 4-(4-amino-2-fluorophenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (3, 5.9 g, 20.18 mmol) and 2,6-dibenzyloxy-3-iodo-pyridine (A, 9.26 g, 22.20 mmol) in t-BuOH (60 mL) was added cesium carbonate (19.73 g, 60.54 mmol). The resulting mixture was purged with argon, and Pd2(dba)3 (924.02 mg, 1.01 mmol) and RuPhos (941.73 mg, 2.02 mmol) were added under an inert atmosphere. The mixture was heated at 100 °C for 18 h. The reaction mixture was diluted with ethyl acetate, filtered through Celite, and washed with ethyl acetate. The combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (15% ethyl acetate-hexanes) to give tert-butyl 4-[4-[(2,6-dibenzyloxy-3-pyridyl)amino]-2-fluoro-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate (4, 5.9 g, 10.14 mmol, 50% yield) as a pale yellow solid. LCMS (ES+): m / z 582 [M+H]+

[0648] Step 3: 4-[4-(2,6-dioxo-piperidin-3-ylamino)-2-fluoro-phenyl]-piperidine-1-carboxylic acid tert-butyl ester (5) To a stirred solution of tert-butyl 4-[4-[(2,6-dibenzyloxy-3-pyridyl)amino]-2-fluoro-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate (4, 4.6 g, 7.91 mmol) in ethyl acetate (40 mL) was added 10% Pd—C (50% wet, 4.6 g). The resulting mixture was stirred under a hydrogen atmosphere at room temperature for 20 hours. The reaction mixture was filtered through Celite and washed with ethyl acetate. The solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography (40% ethyl acetate-hexane) to give tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]piperidine-1-carboxylate (5, 2.6 g, 6.41 mmol, 81% yield) as a blue solid. LCMS (ES+): m / z 406 [M+H]+

[0649] Step 4: 3-(3-fluoro-4-piperidin-4-yl-phenylamino)-piperidine-2,6-dione (6) To a stirred solution of tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]piperidine-1-carboxylate (1 g, 2.47 mmol) in DCM (6 mL) was added 2,2,2-trifluoroacetic acid (1.69 g, 14.80 mmol, 1.14 mL) at 0° C., followed by stirring at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, diluted with ether, and stirred for 1 hour. The ether was decanted to give 3-[3-fluoro-4-(4-piperidyl)anilino]piperidine-2,6-dione (0.87 g, 1.87 mmol, 75.70% yield) as an off-white solid. LCMS (ES+): m / z 306 [M+H]+

[0650] Step 5: tert-Butyl 2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]-1-piperidyl]acetate (8) To a 250 mL round-bottom flask containing a well-stirred solution of 3-[3-fluoro-4-(4-piperidyl)anilino]piperidine-2,6-dione (6, 4 g, 13.10 mmol) and tert-butyl 2-bromoacetate (7, 2.81 g, 14.41 mmol, 2.11 mL) in anhydrous DMF (50 mL), TEA (3.98 g, 39.30 mmol, 5.48 mL) was added. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with water and extracted with EtOAc (200 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% ethyl acetate in petroleum ether) to give tert-butyl 2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]-1-piperidyl]acetate (8.4 g, 9.43 mmol, 72% yield). LCMS (ESI): m / z 420.3 [M+H]+

[0651] Step 6: 2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]-1-piperidyl]acetic acid (9) To a stirred solution of tert-butyl 2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]-1-piperidyl]acetate (8, 2.4 g, 5.72 mmol) in DCM (30 mL) was added TFA (5,22 g, 45.77 mmol, 3.53 mL) at 0 °C. The reaction mixture was stirred at room temperature for 8 h. The solvent was removed and the residue was triturated with diethyl ether. The final compound was dried under reduced pressure to give 2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]-1-piperidyl]acetic acid (9, 2.7 g, 5.22 mmol, 91% yield, TFA salt) as a blue-green solid. LCMS (ES+): m / z 364.0 [M+H]+

[0652] Preparation of exemplary compounds of formula (I) Synthesis of N-(2-((7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoro-6-hydroxynaphthalen-2-yl)oxy)ethyl)-1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperidine-4-carboxamide (Example 1)

[0653] [ka]

[0654] Step 1: tert-Butyl 1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperidine-4-carboxylate (2) To a 25 mL single-neck round-bottom flask containing a solution of tert-butyl piperidine-4-carboxylate hydrochloride (1a, 93.34 mg, 421.06 μmol) in DMF (2.5 mL) was added a propylphosphonic anhydride solution (50 wt % in EtOAc) (107.18 mg, 336.85 μmol, 214 μL) and EtN (102.26 mg, 1.01 mmol, 140.85 μL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 5 minutes. 2-[[2-(2,6-Dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]acetic acid (1, 150 mg, 336.85 μmol, TFA salt) was then added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was triturated with EtO (2 × 20 mL) to give tert-butyl 1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperidine-4-carboxylate (2, 180 mg, 312.68 μmol, 93% yield) as an off-white solid. LCMS (ES+): m / z 499.0 [M + H]+

[0655] Step 2: 1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperidine-4-carboxylic acid (3) To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 1-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]acetyl]piperidine-4-carboxylate (2, 180 mg, 361.06 μmol) in DCM (3 mL) at room temperature under a nitrogen atmosphere was added TFA (1.48 g, 12.98 mmol, 1.0 mL), and the resulting mixture was stirred for 2 h. The reaction mixture was concentrated under reduced pressure, azeotroped with toluene (2 x 10 mL), triturated with EtO (2 x 20 mL), filtered, and dried to afford 1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperidine-4-carboxylic acid (3, 150 mg, 233.45 µmol, 65% yield, TFA salt) as an off-white solid, which was used without further purification. LCMS (ES+): m / z 443.0 [M + H]+

[0656] Step 3: N-(2-((7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoro-6-hydroxynaphthalen-2-yl)oxy)ethyl)-1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperidine-4-carboxamide (Example 1) To a 25 mL single-neck round-bottom flask containing a solution of 5-[7-(2-aminoethoxy)-1-fluoro-3-hydroxy-2-naphthyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one hydrochloride (3a, 35.21 mg, 89.86 μmol) in DMF (0.2 mL) was added DIPEA (34.84 mg, 269.57 μmol, 46.95 μL) and HATU (68.33 mg, 179.71 μmol) under a nitrogen atmosphere and stirred at room temperature for 4 hours. 1-[2-[[2-(2,6-Dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]acetyl]piperidine-4-carboxylic acid (3, 50 mg, 89.86 μmol, TFA salt) in 1,2-DCE (0.2 mL) was then added and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase preparative HPLC [Column: X-BRIDGE C18 (19 × 150 mm) 5.0 μm, Mobile phase A: 0.1% TFA in water; Mobile phase B: acetonitrile] to give N-(2-((7-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoro-6-hydroxynaphthalen-2-yl)oxy)ethyl)-1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperidine-4-carboxamide (Example 1, 8 mg, 8.60 μmol, 10% yield, TFA salt) as a yellow solid. LCMS (ES+): m / z 780.1 [M + H]+ 1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.52 (s, 1H), 8.11 (dd, J = 5.6 Hz, 1H), 7.67 (d, J = 9.0 Hz, 1H), 7.60 (t, J = 7.8 Hz, 1H), 7.22 - 7.18 (m, 1H), 7.17 - 7.02 (m, 5H), 5.06 (dd, J = 12.8, 5.4 Hz, 1H), 4.35 (d, J = 13.1 Hz, 1H), 4.25 - 4.15 (m, 3H), 4.13 - 4.06 (m, 4H), 3.89 (d, J = 13.3 Hz, 1H), 2.95 - 2.82 (m, 4H), 2.75 - 2.62 (m, 3H), 2.09 - 2.00 (m, 1H), 1.80 - 1.70 (m, 2H), 1.64 - 1.53 (m, 1H), 1.52 - 1.36 (m, 1H).

[0657] Synthesis of N-(2-((7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoro-6-hydroxynaphthalen-2-yl)oxy)ethyl)-1-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)glycyl)piperidine-4-carboxamide (Example 2)

[0658] [ka]

[0659] Step 1: tert-Butyl 1-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)glycyl)piperidine-4-carboxylate (3) To a 50 mL single-neck round-bottom flask containing a well-stirred solution of 2-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]amino]acetic acid (1, 516.16 mg, 1.63 mmol), tert-butyl piperidine-4-carboxylate hydrochloride (2, 0.35 g, 1.36 mmol) in anhydrous DMF (8 mL), propylphosphonic anhydride solution (50 wt % in ethyl acetate) (1.72 mL, 862.66 mg, 2.71 mmol) and TEA (548.70 mg, 5.42 mmol, 755.79 μL) were added. After 16 h, the reaction mixture was poured into ice-cold water and extracted with EtOAc (2 × 30 mL). The combined organic layers were dried over anhydrous NaSO and filtered. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (100% EtOAc) to give tert-butyl 1-[2-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]amino]acetyl]piperidine-4-carboxylate (3, 0.35 g, 571 μmol, 33% yield) as an off-white solid. LCMS (ES-): m / z 483.3 [M - H]-

[0660] Step 2: 1-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)glycyl)piperidine-4-carboxylic acid (4) To a 100 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 1-[2-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]amino]acetyl]piperidine-4-carboxylate (3, 0.35 g, 571 μmol) in DCM (10 mL) was added TFA (1.49 g, 13.06 mmol, 1 mL) at room temperature. The resulting solution was stirred at room temperature for 3 hours. The reaction mixture was stripped of volatiles, and the residue was washed with petroleum ether (30 mL) to afford 1-[2-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]amino]acetyl]piperidine-4-carboxylic acid (4, 0.2 g, 260.59 μmol, 45% yield, TFA salt) as an off-white solid. LCMS (ES-): m / z 427.2 [M - H]-

[0661] Step 3: N-(2-((7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoro-6-hydroxynaphthalen-2-yl)oxy)ethyl)-1-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)glycyl)piperidine-4-carboxamide (Example 2) To a 10 mL single-neck round-bottom flask containing a well-stirred solution of 5-[7-(2-aminoethoxy)-1-fluoro-3-hydroxy-2-naphthyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (5, 40 mg, 102.09 μmol, HCl salt) and 1-[2-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]amino]acetyl]piperidine-4-carboxylic acid (4, 43.74 mg, 80.63 μmol, TFA salt) in anhydrous DMF (0.5 mL) was added DIPEA (65.97 mg, 510.46 μmol, 88.91 μL) and propylphosphonic anhydride (50 wt % in ethyl acetate) (0.13 mL, 64.97 mg, 204.18 μmol) at room temperature. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with water, separated, and the organic layer was concentrated under reduced pressure and purified by reverse-phase preparative HPLC (purification method: column: Sunfire C18 (19 × 150 mm) 5 μm, mobile phase: water and 0.1% TFA in MeCN) to give 1-[2-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]amino]acetyl]-N-[2-[[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]oxy]ethyl]piperidine-4-carboxamide (Example 2, 22 mg, 23.12 μmol, 23% yield, TFA salt) as a colorless solid. LCMS (ES+): m / z 766.4 [M + H]+ 1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 10.24 (s, 1H), 8.12 (t, J = 5.6 Hz, 1H), 7.72 (d, J = 9.0 Hz, 1H), 7.29 (t, J = 7.7 Hz, 1H), 7.24 - 7.22 (m, 1H), 7.21 - 7.17 (m, 1H), 7.07 (s, 1H), 6.98 (d, J = 7.4 Hz, 1H), 6.77 (d, J = 8.1 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.44 (s, 2H), 4.38 - 4.27 (m, 2H), 4.17 (d, J = 17.0 Hz, 1H), 4.13 - 4.08 (m, 2H), 4.06 - 4.03 (m, 2H), 3.99 - 3.92 (m, 1H), 3.52 - 3.45 (m, 3H), 3.05 (t, J = 12.7 Hz, 1H), 2.99 - 2.85 (m, 1H), 2.70 - 2.57 (m, 2H), 2.44 - 2.31 (m, 2H), 2.06 - 1.99 (m, 1H), 1.78 - 1.68 (m, 2H), 1.63 - 1.35 (m, 3H), 1.01 - 0.91 (m, 1H).

[0662] 1-[2-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]oxyacetyl]-N-[2-[[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]oxy]ethyl]piperidine-4-carboxamide (Example 3):

[0663] [ka]

[0664] Step 1: tert-butyl 1-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoindolin-4-yl)oxy)acetyl)piperidine-4-carboxylate (2) To a 25 mL single-neck round-bottom flask containing a well-stirred solution of 2-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]oxyacetic acid (1, 200 mg, 628.38 μmol) in DMF (2.5 mL) was added propylphosphonic anhydride (50 wt% in EtOAc) (199.94 mg, 628.38 μmol, 400 μL) and EtN (190.76 mg, 1.89 mmol, 262.75 μL). The resulting mixture was stirred at room temperature for 15 min. tert-Butyl piperidine-4-carboxylate hydrochloride (1a, 167.19 mg, 754.05 μmol) was then added, and the reaction mixture was stirred at room temperature for 16 h. The reaction was concentrated under reduced pressure and purified by silica gel chromatography (0-20% MeOH / DCM) to afford tert-butyl 1-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperidine-4-carboxylate (2, 210 mg, 415.22 μmol, 66% yield) as an off-white solid. LCMS (ES+): m / z 430.1 [M − t-Bu + H]+

[0665] Step 2: 1-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoindolin-4-yl)oxy)acetyl)piperidine-4-carboxylic acid (3) To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 1-[2-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]oxyacetyl]piperidine-4-carboxylate (2, 200 mg, 411.92 μmol) in DCM (3 mL) was added TFA (469.67 mg, 4.12 mmol, 317.35 μL). After 2 h, the reaction mixture was concentrated under reduced pressure and the residue was azeotroped with toluene (2 x 10 mL) and triturated with diethyl ether (2 x 20 mL) to afford 1-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoindolin-4-yl)oxy)acetyl)piperidine-4-carboxylic acid (3, 170 mg, 367.14 μmol, 89% yield) as an off-white solid, which was used without further purification. LCMS (ES+): m / z 430.0 [M + H]+

[0666] Step 3: 1-[2-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]oxyacetyl]-N-[2-[[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]oxy]ethyl]piperidine-4-carboxamide (Example 3) To a well-stirred 10 mL single-neck round-bottom flask containing a solution of 1-[2-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]oxyacetyl]piperidine-4-carboxylic acid (3, 40 mg, 0.0931 mmol) in DMF (0.5 mL) was added 5-[7-(2-aminoethoxy)-1-fluoro-3-hydroxy-2-naphthyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one hydrochloride (3a, 40.14 mg, 0.102 mmol), DIPEA (36.09 mg, 0.279 mmol, 48.64 μL), and propylphosphonic anhydride (50 wt % in EtOAc) (37.02 mg, 0.116 mmol, 74 μL). After 16 h, the reaction was diluted with cold water (1 mL), concentrated under reduced pressure, and purified by reverse-phase preparative HPLC [Column: X-BRIDGE C18 (19 × 150 mm) 5.0 μm and mobile phase A: 0.1% TFA in water; mobile phase B: acetonitrile] to give 1-[2-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]oxyacetyl]-N-[2-[[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]oxy]ethyl]piperidine-4-carboxamide (Example 3, 20 mg, 21.42 μmol, 29% yield, TFA salt) as an off-white solid. LCMS (ES+): m / z 767.4 [M + H]+ 1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 10.18 (s, 1H), 8.12 (t, J = 5.6 Hz, 1H), 7.74 - 7.68 (m, 1H), 7.45 (t, J = 7.8 Hz, 1H), 7.31 (d, J = 7.4 Hz, 1H), 7.23 (d, J = 2.6 Hz, 1H), 7.18 (dd, J = 9.0, 2.5 Hz, 1H), 7.13 (d, J = 8.2 Hz, 1H), 7.06 (s, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 5.01 (d, J = 3.8 Hz, 2H), 4.43 - 4.36 (m, 3H), 4.31 - 4.23 (m, 2H), 4.10 (t, J = 5.7 Hz, 2H), 3.52 - 3.44 (m, 3H), 3.05 (t, J = 12.7 Hz, 1H), 2.91 (ddd, J = 17.9, 13.4, 5.3 Hz, 1H), 2.65 - 2.57 (m, 2H), 2.46 - 2.39 (m, 2H), 2.04 - 1.95 (m, 1H), 1.78 - 1.67 (m, 2H), 1.66 - 1.35 (m, 3H).

[0667] N-(2-((7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoro-6-hydroxynaphthalen-2-yl)oxy)ethyl)-2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-1-yl)acetamide (Example 4):

[0668] [ka]

[0669] Step 1: N-(2-((7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoro-6-hydroxynaphthalen-2-yl)oxy)ethyl)-2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-1-yl)acetamide (Example 4) 1,1'-Carbonyldiimidazole (145.84 mg, 899.43 μmol) was added to a well-stirred solution of 2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]acetic acid (1, 120 mg, 233.26 μmol, TFA salt) in DMF (2.5 mL) at room temperature. The resulting mixture was stirred at room temperature for 4 hours. Next, 5-[7-(2-aminoethoxy)-1-fluoro-3-hydroxy-2-naphthyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (2, 120 mg, 338 μmol) was added to the reaction mixture, and the resulting mixture was stirred at room temperature for 12 hours. The reaction was concentrated and the residue purified by reverse phase HPLC [purification method: Column X bridge (150 × 19 mm), 5 μm; mobile phase A: 0.1% TFA in MQ water; mobile phase B: acetonitrile] to give 2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]-N-[2-[[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]oxy]ethyl]acetamide (Example 4, 53 mg, 59.33 μmol, 18%, TFA salt) as an off-white powder. LCMS (ES+): m / z 737.76 [M + H]+ 1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.59 (s, 1H), 8.86 (s, 1H), 7.69 (dd, J = 9.2, 1.5 Hz, 1H), 7.28 - 7.22 (m, 2H), 7.17 - 7.12 (m, 2H), 7.09 - 7.00 (m, 3H), 6.92 (d, J = 8.2 Hz, 1H), 5.34 (dd, J = 12.8, 5.4 Hz, 1H), 4.18 (dd, J = 5.4 Hz, 2H), 4.10 (s, 2H), 4.01 - 3.92 (m, 2H), 3.65 - 3.57 (m, 2H), 3.56 - 3.49 (m, 2H), 3.34 (s, 3H), 3.18 - 3.08 (m, 2H), 2.96 - 2.79 (m, 2H), 2.76 - 2.59 (m, 2H), 2.11 - 1.91 (m, 5H).

[0670] 2-[4-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-6-yl]-1-piperidyl]-N-[2-[[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]oxy]ethyl]acetamide (Example 5):

[0671] [ka]

[0672] Step 1: 2-[4-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-6-yl]-1-piperidyl]-N-[2-[[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]oxy]ethyl]acetamide (Example 5) To a 10 mL single-neck round-bottom flask containing a well-stirred solution of 2-[4-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-6-yl]-1-piperidyl]acetic acid (1, 90 mg, 0.232 mmol, TFA salt) in DMF (2 mL) was added 1,1'-carbonyldiimidazole (94.18 mg, 0.580 mmol) at room temperature, and the reaction was stirred for 4 h. 5-[7-(2-aminoethoxy)-1-fluoro-3-hydroxy-2-naphthyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (2, 109.23 mg, 0.278 mmol) was then added, and the resulting suspension was stirred at ambient temperature for 12 h. The reaction mixture was diluted with water (2 mL) and concentrated under reduced pressure to give a residue that was purified by reverse-phase preparative HPLC [purification method: Column: Sunfire C18 (19 × 150 mm) 5.0 μm; Mobile phase A: 0.1% TFA in water; Mobile phase B: acetonitrile] to give 2-[4-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-6-yl]-1-piperidyl]-N-[2-[[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]oxy]ethyl]acetamide (Example 5, 45 mg, 0.049 mmol, 21% yield, TFA salt) as an off-white solid. LCMS (ES+): m / z 723.1 [MH] - 1H NMR (400 MHz, DMSO-d6) δ 11.21 (s, 1H), 9.55 (s, 1H), 8.84 (s, 1H), 7.69 (d, J = 9.1 Hz, 1H), 7.29 (s, 1H), 7.25 - 7.19 (m, 2H), 7.14 (dd, J = 9.0, 2.5 Hz, 1H), 7.09 (d, J = 8.5 Hz, 1H), 7.03 (s, 1H), 5.35 (dd, J = 13.0, 5.4 Hz, 1H), 4.18 (t, J = 5.4 Hz, 2H), 4.10 (s, 2H), 3.96 (s, 2H), 3.65 - 3.57 (m, 2H), 3.56 - 3.46 (m, 2H), 3.19 - 3.06 (m, 2H), 2.96 - 2.79 (m, 2H), 2.74 - 2.61 (m, 2H), 2.20 - 2.09 (m, 1H), 2.06 - 1.90 (m, 4H).

[0673] N-(2-((7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoro-6-hydroxynaphthalen-2-yl)oxy)ethyl)-3-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-1-yl)propanamide (Example 6):

[0674] [ka]

[0675] Step 1: tert-butyl 3-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-1-yl)propanoate (2) To a well-stirred 50 mL single-neck round-bottom flask containing a solution of 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidine-2,6-dione (1, 300 mg, 876.19 μmol) in anhydrous DMF (10 mL) was added DIPEA (339.72 mg, 2.63 mmol, 457.85 μL) and tert-butyl 3-bromopropanoate (1a, 219.83 mg, 1.05 mmol). After 16 h, the mixture was concentrated under reduced pressure and purified by reverse-phase column chromatography [Redisep ISCO C18 (30 g) column; mobile phase A: 0.1% TFA in MQ water; mobile phase B: acetonitrile] to give tert-butyl 3-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]propanoate (2, 160 mg, 257.26 μmol, 29% yield, TFA salt) as an off-white solid. LCMS (ES+): m / z 471.2 [M + H]+

[0676] Step 2: 3-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-1-yl)propanoic acid (3) To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 3-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]propanoate (2, 160 mg, 0.340 mmol) in anhydrous DCM (4 mL) was added TFA (193.84 mg, 1.70 mmol, 0.13 mL) at room temperature, and the resulting solution was stirred for 3 h. The reaction mixture was concentrated under reduced pressure, and the residue was azeotroped with toluene (2 × 5 mL), triturated with MTBE (2 × 10 mL), filtered, and dried to give 3-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]propanoic acid (3, 140 mg, 236.38 μmol, 70% yield, TFA salt) as a gray solid. LCMS (ES+): m / z 414.9 [M + H]+

[0677] Step 3: N-(2-((7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoro-6-hydroxynaphthalen-2-yl)oxy)ethyl)-3-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-1-yl)propanamide (Example 6) To a 25 mL single-neck round-bottom flask containing a well-stirred solution of 3-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]propanoic acid (3, 60 mg, 113.53 μmol, TFA salt) in anhydrous DMF (3.5 mL) was added DIPEA (44.02 mg, 340.60 μmol, 59.33 A solution of 3a (3a, 48.9 mg, 124.89 μmol), propylphosphonic anhydride solution (50 wt % in EtOAc) (0.1 mL, 54.19 mg, 170.30 μmol), and 5-[7-(2-aminoethoxy)-1-fluoro-3-hydroxy-2-naphthyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (3a, 48.9 mg, 124.89 μmol, HCl salt) was added at 0° C. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (2 mL), concentrated under reduced pressure, and purified by reverse-phase preparative HPLC [purification method: X-BRIDGE C18 (19 × 150 mm) 5.0 μm; mobile phase A: 0.1% TFA in water; mobile phase B: acetonitrile] to give 3-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]-N-[2-[(8-fluoro-6-hydroxy)-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-2-naphthyl]oxy]ethyl]propanamide (Example 6, 13 mg, 13.99 μmol, 12% yield, TFA salt) as an off-white solid. LCMS (ES+): m / z 752.3 [M + H]+ 1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 10.13 (s, 1H), 9.64 (s, 1H), 8.57 - 8.48 (m, 1H), 7.68 (d, J = 9.0 Hz, 1H), 7.23 - 7.20 (m, 1H), 7.15 (dd, J = 9.0, 2.5 Hz, 1H), 7.08 - 7.02 (m, 3H), 6.92 - 6.84 (m, 1H), 5.36 (dd, J = 12.7, 5.3 Hz, 1H), 4.14 (t, J = 6.4 Hz, 2H), 4.11 (s, 1H), 3.56 - 3.49 (m, 4H), 3.36 - 3.30 (m, 5H), 3.10 - 2.99 (m, 2H), 2.97 - 2.79 (m, 2H), 2.77 - 2.59 (m, 5H), 2.08 - 1.91 (m, 4H).

[0678] N-(2-((7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoro-6-hydroxynaphthalen-2-yl)oxy)ethyl)-2-(4-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)piperidin-1-yl)acetamide (Example 7):

[0679] [ka]

[0680] Step 1: N-(2-((6-(benzyloxy)-7-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoronaphthalen-2-yl)oxy)ethyl)-2-(4-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)piperidin-1-yl)acetamide (3) A mixture of 5-[7-(2-aminoethoxy)-3-benzyloxy-1-fluoro-2-naphthyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (1,270 mg, 482.59 μmol, TFA salt) and 2-[4-[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]-1-piperidin- To a 25 mL single-neck round-bottom flask containing a solution of [2, 258.41 mg, 482.59 μmol, TFA salt] propylphosphonic anhydride (T3P) (≥50 wt% in ethyl acetate) (307.10 mg, 965.17 μmol, 680 μL) and DIPEA (742.00 mg, 5.74 mmol, 1 mL) were added at room temperature. The resulting mixture was stirred at room temperature for 5 h. The solvent was removed from the reaction mixture, and the residue was purified by reverse-phase preparative HPLC [purification method: column: X-Select C18 (10 × 150 mm) 5 μm, mobile phase: water and 0.1% TFA in MeCN] to give N-[2-[[6-benzyloxy-8-fluoro-7-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]oxy]ethyl]-2-[4-[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]-1-piperidyl]acetamide (3, 140 mg, 133.92 μmol, 28% yield, TFA salt) as a pale yellow solid. LCMS (ES+): m / z 849.7 [M + H]+

[0681] Step 2: N-(2-((7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoro-6-hydroxynaphthalen-2-yl)oxy)ethyl)-2-(4-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)piperidin-1-yl)acetamide (Example 7): To a well-stirred 25 mL single-neck round-bottom flask containing a solution of N-[2-[[6-benzyloxy-8-fluoro-7-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]oxy]ethyl]-2-[4-[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]-1-piperidyl]acetamide (3, 100 mg, 103.85 μmol, TFA salt) and pentamethylbenzene (87.32 mg, 589.00 μmol, 95.22 μL) in anhydrous DCM (7.5 mL) and toluene (7.5 mL) was added boron trichloride (1.0 M in methylene chloride) (276.05 mg, 2.36 mmol, 2.36 mL) at −78° C. The reaction mixture was stirred at ambient temperature for 6 hours. The reaction was quenched with 5% MeOH in DCM (3 mL) at −78° C., and excess solvent was removed under reduced pressure. The residue was washed with MTBE (20 mL) and purified by reverse-phase preparative HPLC [purification method: Column: Agilent C18 (50 × 21.2) 5 microns; Mobile Phase A: 10 mM NHOAC in water and Mobile Phase B: MeCN] to give 2-[4-[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]-1-piperidyl]-N-[2-[[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]oxy]ethyl]acetamide (Example 7, 20 mg, 26.19 μmol, 22% yield) as a yellow solid. LCMS (ES+): m / z 759.0 [M + H]+ 1H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 9.81 (s, 1H), 9.55 (s, 1H), 8.90 (s, 1H), 8.47 (d, J = 8.4 Hz, 1H), 8.13 (d, J = 7.0 Hz, 1H), 7.89 (t, J = 7.6 Hz, 1H), 7.69 (d, J = 9.0 Hz, 1H), 7.34 (d, J = 7.5 Hz, 1H), 7.26 - 7.23 (m, 1H), 7.18 - 7.12 (m, 2H), 7.03 (s, 1H), 5.45 (dd, J = 12.9, 5.4 Hz, 1H), 4.24 - 4.17 (m, 2H), 4.09 (s, 2H), 4.01 (s, 2H), 3.68 - 3.54 (m, 5H), 3.03 - 2.90 (m, 1H), 2.82 - 2.72 (m, 1H), 2.71 - 2.61 (m, 2H), 2.26 - 1.94 (m, 6H).

[0682] 2-[4-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]-1-piperidyl]-N-[2-[[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]oxy]ethyl]acetamide (Example 8):

[0683] [ka]

[0684] Step 1: tert-Butyl 2-[4-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]-1-piperidyl]acetate (2) To a 50 mL single-neck round-bottom flask containing a well-stirred solution of 3-[1-methyl-6-(4-piperidyl)indazol-3-yl]piperidine-2,6-dione (1, 500 mg, 1.14 mmol, TFA salt) in anhydrous DMF (7 mL) was added DIPEA (440.19 mg, 3.41 mmol, 593.24 μL) and tert-butyl bromoacetate (1a, 221.44 mg, 1.14 mmol, 166.50 μL). The reaction was stirred at ambient temperature for 2 h. The reaction mixture was poured into ice-cold water (20 mL), and the aqueous layer was extracted with DCM (2 × 30 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous NaSO, and filtered. The residue was triturated with diethyl ether, filtered, and dried to give tert-butyl 2-[4-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]-1-piperidyl]acetate (2, 350 mg, 555.35 μmol, 49% yield) as an off-white solid. LCMS (ES+): m / z 440.9 [M + H] +

[0685] Step 2: 2-[4-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]-1-piperidyl]acetic acid (3) To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 2-[4-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]-1-piperidyl]acetate (2, 350 mg, 794.49 μmol) in anhydrous DCM (5 mL) was added TFA (905.90 mg, 7.94 mmol, 612.10 μL) at 0° C. The reaction was stirred at ambient temperature for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was azeotroped with toluene (2 × 15 mL), triturated with diethyl ether (20 mL), filtered and dried to give 2-[4-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]-1-piperidyl]acetic acid (3, 300 mg, 505.87 μmol, 64% yield, TFA salt) as an off-white solid. LCMS (ES+): m / z 385.0 [M + H] +

[0686] Step 3: N-[2-[[6-benzyloxy-8-fluoro-7-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]oxy]ethyl]-2-[4-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]-1-piperidyl]acetamide (4) To a 25 mL single-neck round-bottom flask containing a well-stirred solution of 2-[4-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]-1-piperidyl]acetic acid (3, 300 mg, 601.86 μmol) in anhydrous DMF (5 mL), 5-[7-(2-aminoethoxy)-3-benzyloxy-1-fluoro-2-naphthyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (3a, 336.73 mg, 601.86 μmol, TFA salt), 1-propanephosphonic anhydride (50% in EtOAc) (383.00 mg, 1.20 mmol), and DIPEA (233.36 mg, 1.81 mmol, 314.50 μL) were added. The resulting mixture was stirred at ambient temperature for 16 h. After completion of the reaction, the volatiles were removed under reduced pressure and the residue was purified by reverse-phase preparative HPLC [Column: YMC C18 (19 × 150) mm, 5 microns; Mobile phase A: 0.1% TFA in water, Mobile phase B: MeCN] to give N-[2-[[6-benzyloxy-8-fluoro-7-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]oxy]ethyl]-2-[4-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]-1-piperidyl]acetamide (4, 160 mg, 167.62 μmol, 28% yield, TFA salt) as an off-white solid. LCMS (ES+): m / z 811.8 [M + H] +

[0687] Step 4: 2-[4-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]-1-piperidyl]-N-[2-[[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]oxy]ethyl]acetamide (Example 8) To a 50 mL single-neck round-bottom flask containing a 1:1 solution of N-[2-[[6-benzyloxy-8-fluoro-7-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]oxy]ethyl]-2-[4-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]-1-piperidyl]acetamide (4, 160 mg, 172.81 μmol, TFA salt) in anhydrous DCM (4 mL) and anhydrous toluene (4 mL), pentamethylbenzene (128.09 mg, 864.03 μmol, 139.68 μL) was added. The reaction mixture was cooled to −78 °C, and BC1 (1.0 M in methylene chloride) (303.71 mg, 2.59 mmol) was slowly added to the reaction mixture. The resulting mixture was stirred at ambient temperature for 16 hours. The reaction was quenched with 5% MeOH in DCM (6 mL) at -78°C, the volatiles were removed under reduced pressure, and the residue was purified by reverse-phase preparative HPLC [Column: Redisep C18 (19 x 150) mm, 5 microns; Mobile Phase A: 0.1% TFA in water and Mobile Phase B: MeCN] to give 2-[4-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]-1-piperidyl]-N-[2-[[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]oxy]ethyl]acetamide (Example 8, 14.5 mg, 16.36 µmol, 9% yield, TFA salt) as an off-white solid. LCMS (ES+): m / z 722.2 [M + H] + 1H NMR (300 MHz, DMSO-d6) δ 10.89 (s, 1H), 9.71 (s, 1H), 9.55 (s, 1H), 8.88 (s, 1H), 7.73 - 7.64 (m, 2H), 7.41 (s, 1H), 7.26 - 7.21 (m, 1H), 7.19 - 7.12 (m, 1H), 7.07 - 7.01 (m, 2H), 4.34 (dd, J = 9.8, 5.0 Hz, 1H), 4.23 - 4.15 (m, 2H), 4.10 (s, 2H), 3.98 (s, 4H), 3.59 (dd, J = 14.2, 8.6 Hz, 3H), 2.95 (s, 2H), 2.75 - 2.57 (m, 3H), 2.41 - 2.26 (m, 3H), 2.23 - 1.97 (m, 5H).

[0688] 2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]oxy-1-piperidyl]-N-[2-[[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]oxy]ethyl]acetamide (Example 9):

[0689] [ka]

[0690] Step 1: tert-butyl 2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]oxy-1-piperidyl]acetate (2) To a 50 mL single-neck round-bottom flask containing a well-stirred solution of 3-[3-methyl-2-oxo-4-(4-piperidyloxy)benzimidazol-1-yl]piperidine-2,6-dione (1, 120 mg, 334.83 μmol) in anhydrous DMF (5 mL), tert-butyl 2-bromoacetate (1a, 71.84 mg, 368.31 μmol, 54.02 μL) and DIPEA (129.82 mg, 1.00 mmol, 174.96 μL) were added. After 16 h, the reaction mixture was poured into ice-cold water (20 mL). The precipitate was collected by filtration and dried under vacuum to give tert-butyl 2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]oxy-1-piperidyl]acetate (2, 110 mg, 229.99 μmol, 69% yield) as a pale yellow solid. LCMS (ES+): m / z 473.2 [M + H]+

[0691] Step 2: 2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]oxy-1-piperidyl]acetic acid (3) To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]oxy-1-piperidyl]acetate (2, 110 mg, 232.79 μmol) in anhydrous DCM (2 mL) was added TFA (132.72 mg, 1.16 mmol, 89.67 μL) at 0° C. After stirring at room temperature for 3 h, the reaction mixture was concentrated under reduced pressure, and the residue was azeotroped with toluene (2 × 15 mL) and triturated with diethyl ether (20 mL) to give 2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]oxy-1-piperidyl]acetic acid (3, 110 mg, 192.30 μmol, 83% yield, TFA salt) as an off-white solid. LCMS (ES+): m / z 416.90 [M + H]+

[0692] Step 3: 2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]oxy-1-piperidyl]-N-[2-[[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]oxy]ethyl]acetamide (Example 9) To a 25 mL single-neck round-bottom flask containing a well-stirred solution of 2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]oxy-1-piperidyl]acetic acid (3, 100 mg, 188.52 μmol, TFA salt) in anhydrous DMF (3 mL), CDI (61.14 mg, 377.04 μmol) was added under a nitrogen atmosphere at ambient temperature and stirred for 4 hours. Next, 5-[7-(2-aminoethoxy)-1-fluoro-3-hydroxy-2-naphthyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (4, 81.25 mg, 207.37 μmol, HCl salt) was added to the reaction mixture. After 12 hours, the reaction mixture was concentrated under reduced pressure and purified by reverse-phase preparative HPLC using [Column: XBRIDGE C18 (19 × 150) mm, 5 micron: Mobile phase A: 0.1% TFA in water and Mobile phase B: MeCN] to give 2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]oxy-1-piperidyl]-N-[2-[[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]oxy]ethyl]acetamide (Example 9, 40 mg, 44.27 μmol, 23% yield, TFA salt) as an off-white solid. LCMS (ES+): m / z 754.3 [M + H]+ 1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.81 (s, 1H), 9.54 (s, 1H), 8.80 (s, 1H), 7.68 (d, J = 9.0 Hz, 1H), 7.22 (d, J = 2.5 Hz, 1H), 7.13 (dd, J = 9.0, 2.5 Hz, 1H), 7.03 (s, 1H), 6.97 (t, J = 8.2 Hz, 1H), 6.86 - 6.74 (m, 2H), 5.33 (dd, J = 12.8, 5.4 Hz, 1H), 4.90 - 4.58 (m, 1H), 4.17 (t, J = 5.4 Hz, 2H), 4.09 (s, 2H), 4.03 - 3.89 (m, 2H), 3.66 - 3.50 (m, 5H), 2.95 - 2.83 (m, 1H), 2.76 - 2.58 (m, 3H), 2.28 - 1.91 (m, 5H).

[0693] 2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]-1-piperidyl]-N-[2-[[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]oxy]ethyl]acetamide (Example 10):

[0694] [ka]

[0695] Step 1: 2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]-1-piperidyl]-N-[2-[[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]oxy]ethyl]acetamide (Example 10): 2-[4-[4-[(2,6-Dioxo-3-piperidyl)amino]-2-fluoro-phenyl]-1-piperidyl]acetic acid (1, 24.54 mg, 67.54 μmol) and 5-[7-(2-aminoethoxy)-1-fluoro-3-hydroxy-2-naphthyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (2, 20 mg, 56.28 μmol) in DMF (500 μL) were treated with DIPEA (36.37 mg, 281.42 μmol, 49.02 μL). The mixture was cooled to 0° C., and then propylphosphonic anhydride (T3P) (50% in EtOAc) (39.40 mg, 61.91 μmol, 36.82 μL) was added. The reaction mixture was allowed to warm to room temperature and stirred for 16 hours. The mixture was purified by reverse-phase chromatography, eluting with 5–100% MeCN in HO (0.1% TFA modifier) ​​to give 2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]-1-piperidyl]-N-[2-[[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]oxy]ethyl]acetamide (Example 10, 7.17 mg, 8.44 μmol, 15% yield) as a gray solid. LCMS (ES+): m / z 701.3 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 9.67 (s, 1H), 9.54 (s, 1H), 8.86 (t, J = 5.2 Hz, 1H), 7.70 (d, J = 9.0 Hz, 1H), 7.23 (d, J = 2.5 Hz, 1H), 7.14 (dd, J = 9.0, 2.5 Hz, 1H), 7.04 (s, 1H), 6.99 - 6.91 (m, 1H), 6.52 - 6.42 (m, 2H), 6.10 (s, 1H), 4.37 - 4.27 (m, 1H), 4.18 (t, J = 5.3 Hz, 2H), 4.11 (s, 2H), 3.95 (d, J = 4.8 Hz, 2H), 3.61 (q, J = 5.5 Hz, 2H), 3.52 (d, J = 10.4 Hz, 1H), 3.21 - 3.09 (m, 1H), 2.96 - 2.84 (m, 1H), 2.74 (ddd, J = 17.4, 12.3, 5.4 Hz, 1H), 2.62 - 2.58 (m, 1H), 2.15 - 1.94 (m, 2H), 1.95 - 1.79 (m, 3H).

[0696] 3-(7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoro-6-hydroxynaphthalen-2-yl)-N-(1-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoindolin-4-yl)oxy)acetyl)piperidin-4-yl)acrylamide (Example 11):

[0697] [ka]

[0698] Step 1: tert-Butyl N-[1-[2-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]oxyacetyl]-4-piperidyl]carbamate (2) To a well-stirred 25 mL round-bottom flask containing a solution of 2-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]oxyacetic acid (1, 340 mg, 1.07 mmol) in anhydrous DMF (4 mL) was added DIPEA (276.12 mg, 2.14 mmol, 372.14 μL) and T3P (50% in EtOAc) (1 mL, 509.55 mg, 1.60 mmol). After 5 min, tert-butyl N-(4-piperidyl)carbamate (1a, 427.89 mg, 2.14 mmol) was added. After 2 h, the volatiles were removed under reduced pressure and the residue was purified by reverse-phase column chromatography [purification method: C18, mobile phase A: 0.1% TFA in water; mobile phase B: MeCN] to afford tert-butyl N-[1-[2-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]oxyacetyl]-4-piperidyl]carbamate (2, 250 mg, 421.04 μmol, 39% yield) as a pale yellow solid. LCMS (ES+): m / z 401.2 [M − Boc + H] +

[0699] Step 2: 3-[4-[2-(4-amino-1-piperidyl)-2-oxo-ethoxy]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (3) To a 10 mL round-bottom flask containing a well-stirred solution of tert-butyl N-[1-[2-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]oxyacetyl]-4-piperidyl]carbamate (2, 250 mg, 421.04 μmol) in DCM (3 mL) was added TFA (480.09 mg, 4.21 mmol, 324.38 μL) dropwise at 0° C. The reaction mixture was stirred at room temperature for 1 h. Volatiles were removed under reduced pressure. The residue was triturated with diethyl ether (2 x 10 mL) to give 3-[4-[2-(4-amino-1-piperidyl)-2-oxo-ethoxy]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (3, 209 mg, 347.03 μmol, 82% yield, TFA salt) as a pale yellow solid. LCMS (ES+): m / z 401.0 [M + H]+

[0700] Step 3: tert-butyl (E)-3-(6-(benzyloxy)-7-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoronaphthalen-2-yl)acrylate (5) To a 25 mL pressure tube containing a well-stirred solution of tert-butyl acrylate (4a, 99.16 mg, 773.71 μmol, 112.30 μL) and 5-(3-(benzyloxy)-7-bromo-1-fluoronaphthalen-2-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (4, 90 mg, 193.43 μmol) in DMF (5 mL) was added triethylamine (97.86 mg, 967.13 μmol, 134.80 μL). The reaction mixture was degassed by bubbling nitrogen gas through it for 5 minutes, and then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (15.80 mg, 19.34 μmol) was added and degassed for an additional 5 minutes. The tube was sealed, and the reaction mixture was stirred at 110 °C. After 16 h, the reaction mixture was cooled to ambient temperature, filtered through Celite, and washed with ethyl acetate (10 mL). The filtrate was concentrated under reduced pressure, and the residue was diluted with EtOAc (50 mL) and washed with water (3 × 40 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent removed under reduced pressure. The residue was purified by reverse-phase column chromatography [mobile phase: 0.1% TFA and MeCN in water] to afford tert-butyl (E)-3-(6-(benzyloxy)-7-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoronaphthalen-2-yl)acrylate (5, 60 mg, 111.19 μmol, 57% yield) as an off-white solid. LCMS (ES-): m / z 511.0 [M - H]-

[0701] Step 4: (E)-3-[6-benzyloxy-8-fluoro-7-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]prop-2-enoic acid (6) To a 10 mL round-bottom flask containing a well-stirred solution of tert-butyl (E)-3-(6-(benzyloxy)-7-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoronaphthalen-2-yl)acrylate (5, 110 mg, 214.61 μmol) in DCM (1.2 mL) was added TFA (244.71 mg, 2.15 mmol, 165.34 μL) dropwise at 0° C. The reaction mixture was stirred at room temperature for 2 h. The volatiles were removed under reduced pressure, and the residue was triturated with diethyl ether (2 × 10 mL) and filtered to give (E)-3-[6-benzyloxy-8-fluoro-7-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]prop-2-enoic acid (6, 90 mg, 130.35 μmol, 61% yield) as a pale yellow solid. LCMS (ES-): m / z 455.1 [M - H]-

[0702] Step 5: 3-(6-(benzyloxy)-7-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoronaphthalen-2-yl)-N-(1-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperidin-4-yl)acrylamide (7) To a well-stirred 25 mL round-bottom flask containing a solution of (£)-3-[6-benzyloxy-8-fluoro-7-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]prop-2-enoic acid (6, 80 mg, 175.27 µmol) in DMF (2 mL) was added triethylamine (53.21 mg, 525.81 µmol, 73.29 µL) and propylphosphonic anhydride (50% in EtOAc) (0.11 mL, 55.79 mg, 175.27 µmol). After 30 minutes, 3-(4-(2-(4-aminopiperidin-1-yl)-2-oxoethoxy)-1-oxoindolin-2-yl)piperidine-2,6-dione (3, 126.67 mg, 210.32 μmol, TFA salt) was added, and the reaction mixture was stirred at ambient temperature for 18 hours. The volatiles were removed under reduced pressure and the residue was purified by reverse-phase preparative HPLC [Purification method: Column: X-Bridge C18 (19 x 150 mm) 5.0 micron; Mobile phase: 0.1% TFA in water; Mobile phase B: MeCN] to give 3-(6-(benzyloxy)-7-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoronaphthalen-2-yl)-N-(1-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperidin-4-yl)acrylamide (7, 80 mg, 77.86 μmol, 44% yield, TFA salt) as a brown solid. LCMS (ES+): m / z 838.8 [M + H]+

[0703] Step 6: 3-(7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoro-6-hydroxynaphthalen-2-yl)-N-(1-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoindolin-4-yl)oxy)acetyl)piperidin-4-yl)acrylamide (Example 11) To a 25 mL round-bottom flask containing a well-stirred solution of 3-(6-(benzyloxy)-7-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoronaphthalen-2-yl)-N-(1-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperidin-4-yl)acrylamide (7, 70 mg, 73.46 μmol, TFA salt) and pentamethylbenzene (108.90 mg, 734.62 μmol, 118.76 μL) in a mixture of DCM (2 mL) and toluene (2 mL) was added boron trichloride (1 M in DCM) (0.73 mL, 86.08 mg, 734.62 μmol) dropwise at −78° C. The reaction mixture was then stirred at room temperature for 18 hours. The reaction mixture was cooled to -78°C and quenched by the dropwise addition of a 10:1 mixture of DCM and MeOH (5 mL). The volatiles were removed under reduced pressure, and the residue was purified by reverse-phase preparative HPLC [Purification method: Column: Sunfire (19 x 150 mm), 5 micron; Mobile phase A: 0.1% TFA in water and Mobile phase B: MeCN] to afford 3-(7-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoro-6-hydroxynaphthalen-2-yl)-N-(1-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperidin-4-yl)acrylamide (Example 11, 8 mg, 9.01 µmol, 12% yield, TFA salt) as an off-white solid. LCMS (ES+): m / z 749.1 [M + H] + 1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 10.67 (s, 1H), 8.15 (d, J = 7.5 Hz, 1H), 8.06 (s, 1H), 7.80 (d, J = 8.6 Hz, 1H), 7.70 (d, J = 8.9 Hz, 1H), 7.58 (d, J = 15.7 Hz, 1H), 7.46 (t, J = 7.8 Hz, 1H), 7.33 (d, J = 7.6 Hz, 1H), 7.19 - 7.09 (m, 2H), 6.72 (d, J = 15.7 Hz, 1H), 5.17 - 4.95 (m, 3H), 4.47 - 4.37 (m, 3H), 4.28 (d, J = 17.4 Hz, 1H), 4.17 (d, J = 13.0 Hz, 1H), 4.03 - 3.92 (m, 1H), 3.86 - 3.76 (m, 2H), 2.99 - 2.83 (m, 3H), 2.09 - 1.97 (m, 1H), 1.95 - 1.79 (m, 2H), 1.56 - 1.20 (m, 3H).

[0704] 3-[4-[[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]methyl]pyrazol-1-yl]-N-[5-fluoro-7-hydroxy-6-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]propanamide (Example 12):

[0705] [ka]

[0706] Step 1: 3-[4-[[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]methyl]pyrazol-1-yl]propanoic acid (2) To a 10 mL pressure tube containing a well-stirred solution of 4-amino-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (1, 150 mg, 548.96 μmol) in anhydrous THF (2 mL) was added 3-(4-formylpyrazol-1-yl)propanoic acid (1a, 138.46 mg, 823.44 μmol), dibutyltin dichloride (166.80 mg, 548.96 μmol, 122.65 μL), and phenylsilane (71.29 mg, 658.75 μmol). The tube was sealed, and the reaction was stirred at 80° C. for 16 h. The volatiles were removed under reduced pressure and the residue was purified by reverse-phase preparative HPLC [Column: Xselect C18 column (19 × 150) mm, 5 micron; Mobile phase A: 0.1% formic acid in water and Mobile phase B: MeCN] to give 3-[4-[[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]methyl]pyrazol-1-yl]propanoic acid (2, 220 mg, 457.11 μmol, 83% yield, formate salt) as an off-white solid. LCMS (ES+): m / z 426.0 [M + H]+

[0707] Step 2: 3-[4-[[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]methyl]pyrazol-1-yl]-N-[5-fluoro-7-hydroxy-6-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]propanamide (Example 12) To a 10 mL single-neck round-bottom flask containing a well-stirred solution of 3-[4-[[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]methyl]pyrazol-1-yl]propanoic acid (2, 40 mg, 84.85 μmol, formate salt) in anhydrous DMF (0.5 mL) was added 5-(6-amino-1-fluoro-3-hydroxy-2-naphthyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (2a, 26.41 mg, 84.85 μmol), EtN (34.34 mg, 339.40 μmol, 47.31 μL), and 1-propanephosphonic anhydride (50 wt% in EtOAc) (110 μL, 169.70 μmol). The reaction was stirred at ambient temperature for 16 h. The volatiles were removed under reduced pressure and the residue was purified by reverse-phase preparative HPLC [Column: Xselect C18 column (19 × 150) mm, 5 micron; Mobile phase A: 0.1% TFA in water and Mobile phase B: MeCN] to give 3-[4-[[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]methyl]pyrazol-1-yl]-N-[5-fluoro-7-hydroxy-6-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]propanamide (Example 12, 5.5 mg, 6.30 μmol, 7% yield, TFA salt) as an off-white solid. LCMS (ES+): m / z 719.1 [M + H]+ 1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 10.43 (s, 1H), 10.25 (s, 1H), 8.12 (s, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.71 (s, 1H), 7.52 - 7.43 (m, 2H), 7.40 - 7.34 (m, 1H), 7.15 - 7.08 (m, 1H), 7.02 - 6.93 (m, 2H), 6.84 (s, 1H), 5.02 (dd, J = 12.6, 5.7 Hz, 1H), 4.42 - 4.31 (m, 8H), 2.97 - 2.82 (m, 4H), 2.69 - 2.58 (m, 1H), 2.11 - 1.96 (m, 1H).

[0708] 3-[4-[[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]amino]methyl]pyrazol-1-yl]-N-[5-fluoro-7-hydroxy-6-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]propanamide (Example 13):

[0709] [ka]

[0710] Step 1: 3-[4-[[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]amino]methyl]pyrazol-1-yl]propanoic acid (3) To a 100 mL pressure tube containing a well-stirred solution of 3-(4-formylpyrazol-1-yl)propanoic acid (1, 250 mg, 1.49 mmol) in anhydrous THF (20 mL) was added 3-(4-amino-1-oxo-isoindolin-2-yl)piperidine-2,6-dione (2, 385.46 mg, 1.49 mmol), dibutyltin dichloride (451.75 mg, 1.49 mmol, 332.17 μL), and phenylsilane (193.07 mg, 1.78 mmol). The vial was sealed, and the suspension was stirred at 80° C. for 16 h. The solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography (0–5% MeOH in DCM) to give 3-[4-[[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]amino]methyl]pyrazol-1-yl]propanoic acid (3, 230 mg, 409.79 μmol, 28% yield) as an off-white solid. LCMS (ES-): m / z 410.2 [M - H]-

[0711] Step 2: 3-[4-[[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]amino]methyl]pyrazol-1-yl]-N-[5-fluoro-7-hydroxy-6-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]propanamide (Example 13) To a well-stirred 10 mL single-neck round-bottom flask containing a solution of 3-[4-[[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]amino]methyl]pyrazol-1-yl]propanoic acid (3, 35 mg, 85.07 μmol) in anhydrous DMF (1 mL) was added 5-(6-amino-1-fluoro-3-hydroxy-2-naphthyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (3a, 26.48 mg, 85.07 μmol), triethylamine (25.83 mg, 255.22 μmol, 35.57 μL), and 1-propanephosphonic anhydride (50% in EtOAc) (40.60 mg, 127.61 μmol, 90 μL). After 16 h, the solvent was evaporated under reduced pressure and the residue was purified by reverse-phase preparative HPLC [purification method: Column: X select (150 × 19) mm, 5 μm; Mobile phase A: 0.1% TFA in MQ water; Mobile phase B: acetonitrile] to give 3-[4-[[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]amino]methyl]pyrazol-1-yl]-N-[5-fluoro-7-hydroxy-6-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]propanamide (Example 13, 5.5 mg, 6.58 μmol, 8% yield, TFA salt) as an off-white solid. LCMS (ES+): m / z 705.4 [M + H]+ 1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 10.42 - 10.14 (m, 2H), 8.13 (s, 1H), 7.83 (d, J = 9.0 Hz, 1H), 7.68 (s, 1H), 7.43 (s, 1H), 7.38 (dd, J = 9.1, 1.9 Hz, 1H), 7.21 (t, J = 7.7 Hz, 1H), 6.97 - 6.89 (m, 2H), 6.78 (d, J = 8.1 Hz, 1H), 5.09 (dd, J = 13.3, 5.1 Hz, 1H), 4.37 (t, J = 6.7 Hz, 2H), 4.31 - 4.25 (m, 2H), 4.23 - 4.10 (m, 4H), 2.97 - 2.86 (m, 3H), 2.64 - 2.57 (m, 2H), 2.33 - 2.22 (m, 1H), 2.06 - 1.95 (m, 1H).

[0712] N-(6-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-5-fluoro-7-hydroxynaphthalen-2-yl)-3-(4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)methyl)-1H-1,2,3-triazol-1-yl)propanamide (Example 14)

[0713] [ka]

[0714] Step 1: N-(6-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-5-fluoro-7-hydroxynaphthalen-2-yl)-3-(4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)methyl)-1H-1,2,3-triazol-1-yl)propanamide (Example 14) To a 10 mL three-necked round-bottom flask containing a well-stirred solution of 3-[4-[[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]amino]methyl]triazol-1-yl]propanoic acid (1, 30 mg, 55.51 μmol, TFA salt) in anhydrous DMF (1 mL) was added EtN (16.85 mg, 166.54 μmol, 23.21 μL), 1-propanephosphonic anhydride (50% in EtOAc) (90 μL, 138.78 μmol), and 5-(6-amino-1-fluoro-3-hydroxy-2-naphthyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (2, 19.30 mg, 55.51 μmol, HCl salt) in anhydrous DMF (0.5 mL). The reaction was stirred at ambient temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase preparative HPLC [Column: X-BRIDGE C18 column (19 × 150) mm 5 micron; Mobile phase A: 0.1% TFA in water and Mobile phase B: MeCN] to give N-(6-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-5-fluoro-7-hydroxynaphthalen-2-yl)-3-(4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)methyl)-1H-1,2,3-triazol-1-yl)propanamide (Example 14, 5.2 mg, 5.61 μmol, 10% yield, TFA salt) as a yellow solid. LCMS (ES+): m / z 720.0 [M + H]+ 1H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 10.28 (s, 1H), 9.90 (s, 1H), 8.09 (s, 1H), 8.03 (s, 1H), 7.81 (d, J = 9.0 Hz, 1H), 7.57 - 7.53 (m, 2H), 7.35 (d, J = 9.0 Hz, 1H), 7.05 (s, 1H), 6.96 - 6.90 (m, 2H), 5.02 (dd, J = 12.7, 5.4 Hz, 1H), 4.65 (dd, J = 6.7 Hz, 2H), 4.45 (d, J = 3.9 Hz, 2H), 4.10 (s, 2H), 3.05 - 2.98 (m, 3H), 2.93 - 2.80 (m, 3H), 2.03 - 1.94 (m, 1H).

[0715] 3-[4-[[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]amino]methyl]triazol-1-yl]-N-[5-fluoro-7-hydroxy-6-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]propanamide (Example 15):

[0716] [ka]

[0717] Step 1: 3-[1-oxo-5-(prop-2-ynylamino)isoindolin-2-yl]piperidine-2,6-dione (2) To a 25 mL single-neck round-bottom flask containing a well-stirred solution of 3-(5-amino-1-oxo-isoindolin-2-yl)piperidine-2,6-dione (1, 0.200 g, 771.43 μmol) in anhydrous DMF (5 mL), DIPEA (199.40 mg, 1.54 mmol, 268.74 μL) and 3-bromoprop-1-yne (1a, 91.77 mg, 771.43 μmol) were added. The mixture was stirred at 80 °C for 4 h. The volatiles were removed under reduced pressure, and the residue was purified by silica gel chromatography (30-40% EtOAc in petroleum ether) to give 3-[1-oxo-5-(prop-2-ynylamino)isoindolin-2-yl]piperidine-2,6-dione (2, 0.110 g, 351.49 μmol, 46% yield) as a yellow solid. LCMS (ES+): m / z 298.1 [M + H]+

[0718] Step 2: 3-[4-[[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]amino]methyl]triazol-1-yl]propanoic acid (3) To a 25 mL single-neck round-bottom flask containing a well-stirred solution of 3-azidopropanoic acid (2a, 38.71 mg, 336.35 μmol) and 3-[1-oxo-5-(prop-2-ynylamino)isoindolin-2-yl]piperidine-2,6-dione (2, 0.100 g, 336.35 μmol) in a mixture of THF (5 mL) and water (5 mL) was added sodium ascorbate (66.63 mg, 336.35 μmol), followed by copper sulfate (53.69 mg, 336.35 μmol, 14.91 μL). After 4 h, the organic layer was separated and the solvent removed. The residue was purified by preparative HPLC [Column: Biotage snap Ultra C18 (30 g) (19 × 150 mm), 25 μm, Mobile Phase A: 0.1% ammonium acetate in HO, Mobile Phase B: ACN; Flow Rate: 15.0 mL / min]. The product-containing fractions were combined, the solvent removed, and the solid was dissolved in EtOAc (10 mL) and washed with water (15 mL). The organic layer was dried over sodium sulfate, filtered, and the solvent removed to give 3-[4-[[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]amino]methyl]triazol-1-yl]propanoic acid (3, 0.080 g, 188.17 μmol, 56% yield) as a yellow solid. LCMS (ES+): m / z 413.2 [M+H]+

[0719] Step 3: 3-[4-[[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]amino]methyl]triazol-1-yl]-N-[5-fluoro-7-hydroxy-6-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]propanamide (Example 15) To a 50 mL round-bottom flask containing a well-stirred solution of 3-[4-[[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]amino]methyl]triazol-1-yl]propanoic acid (3, 13.25 mg, 32.12 μmol) in anhydrous DMF (0.2 mL) was added DIPEA (8.30 mg, 64.25 μmol, 11.19 μL) and T3P (50 wt% in EtOAc, 20.4 μL, 10.22 mg, 32.12 μmol). After 10 min, 5-(6-amino-1-fluoro-3-hydroxy-2-naphthyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (4, 10 mg, 32.12 μmol) was added. After 4 h, the volatiles were removed under reduced pressure. The residue was purified by reverse-phase preparative HPLC [purification method: Column X-Bridge C18 (19 × 150 mm) 5 μm, mobile phase A: 0.1% ammonium acetate in HO, mobile phase B: ACN; flow rate: 15.0 mL / min] to give 3-[4-[[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]amino]methyl]triazol-1-yl]-N-[5-fluoro-7-hydroxy-6-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]propanamide (Example 15, 2.3 mg, 3.03 μmol, 9% yield) as a yellow solid. LCMS (ES+): m / z 706.2 [M + H]+ 1H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 10.26 (s, 1H), 9.74 (s, 1H), 8.10 (s, 1H), 8.00 (s, 1H), 7.81 (d, J = 8.9 Hz, 1H), 7.41 - 7.34 (m, 2H), 7.08 (s, 4H), 6.93 (s, 1H), 6.88 - 6.82 (m, 1H), 6.75 - 6.70 (m, 2H), 5.00 (dd, J = 13.4, 5.1 Hz, 1H), 4.65 (t, J = 6.8 Hz, 2H), 4.36 (d, J = 5.7 Hz, 2H), 4.25 (d, J = 16.7 Hz, 1H), 4.12 (d, J = 16.7 Hz, 1H), 4.06 (s, 2H), 3.02 (t, J = 6.7 Hz, 2H), 2.94 - 2.82 (m, 4H), 1.97 - 1.87 (m, 1H).

[0720] 3-[4-[[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]amino]methyl]pyrazol-1-yl]-N-[5-fluoro-7-hydroxy-6-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]propanamide (Example 16):

[0721] [ka]

[0722] Step 1: N-[7-benzyloxy-5-fluoro-6-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]-3-[4-[[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]amino]methyl]pyrazol-1-yl]propanamide (3) To a 10 mL single-neck round-bottom flask containing a well-stirred solution of 3-[4-[[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]amino]methyl]pyrazol-1-yl]propanoic acid (1, 139.63 mg, 247.41 μmol, TFA salt) in DMF (2 mL) was added DIPEA (159.88 mg, 1.24 mmol, 215.48 μL) and 1-propanephosphonic anhydride (50 wt% in EtOAc) (0.19 mL, 94.47 mg, 296.90 μmol), and the reaction mixture was stirred for 10 min at room temperature. A solution of 5-(6-amino-3-benzyloxy-1-fluoro-2-naphthyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (2, 127.53 mg, 247.41 μmol, TFA salt) in DMF (0.5 mL) and DIPEA (0.5 mL) was then added dropwise and the reaction mixture was heated at 50° C. for 16 h. The solvent was removed under reduced pressure. The residue was purified by reverse-phase preparative HPLC [purification method: Column: Sunfire C18, (19 × 150 mm), 5 μm, Mobile phase A: 0.1 TFA in water and Mobile phase B: MeCN] to give N-[7-benzyloxy-5-fluoro-6-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]-3-[4-[[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]amino]methyl]pyrazol-1-yl]propanamide (3, 90 mg, 65.75 μmol, 27% yield, TFA salt) as an off-white solid. LCMS (ES+): m / z 795.1 [M + H] +

[0723] Step 2: 3-[4-[[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]amino]methyl]pyrazol-1-yl]-N-[5-fluoro-7-hydroxy-6-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]propanamide (Example 16) To a 10 mL single-neck round-bottom flask containing a well-stirred solution of N-[7-benzyloxy-5-fluoro-6-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]-3-[4-[[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]amino]methyl]pyrazol-1-yl]propanamide (3, 35 mg, 25.57 μmol, TFA salt) in a mixture of toluene (0.5 mL) and DCM (0.5 mL) was added pentamethylbenzene (11.37 mg, 76.71 μmol), and the reaction mixture was cooled to −78° C. Then, BCl (1 M in DCM) (4 mmol, 4 mL) was added dropwise over 2 min, and the reaction mixture was stirred at room temperature for 20 h. The reaction mixture was cooled to −78° C., quenched with 10% DCM in MeOH (4 mL), brought to room temperature, and concentrated under reduced pressure at 35° C. The residue was purified by reverse-phase preparative HPLC [purification method: Column: X-Bridge C18, (150 × 19 mm, 5 μm, Mobile Phase A: 0.1% TFA in water, Mobile Phase B: MeCN] to give 3-[4-[[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]amino]methyl]pyrazol-1-yl]-N-[5-fluoro-7-hydroxy-6-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]propanamide (Example 16, 2.75 mg, 3.30 μmol, 13% yield, TFA salt) as an off-white solid. LCMS (ES+): m / z 705.3 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 10.24 (s, 1H), 10.13 (s, 1H), 8.14 (s, 1H), 7.83 (d, J = 9.0 Hz, 1H), 7.70 (s, 1H), 7.43 (s, 1H), 7.41 - 7.35 (m, 2H), 6.95 (s, 1H), 6.73 - 6.66 (m, 2H), 5.00 (dd, J = 13.3, 5.1 Hz, 1H), 4.39 (t, J = 6.7 Hz, 2H), 4.29 - 4.18 (m, 3H), 4.14 (s, 2H), 3.15 - 3.05 (m, 1H), 2.93 (t, J = 6.7 Hz, 2H), 2.91 - 2.80 (m, 1H), 2.60 - 2.55 (m, 1H), 2.37 - 2.23 (m, 1H), 1.98 - 1.88 (m, 1H).

[0724] 3-[4-[[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]methyl]triazol-1-yl]-N-[5-fluoro-7-hydroxy-6-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]azetidine-1-carboxamide (Example 17):

[0725] [ka]

[0726] Step 1: 3-[4-[[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]methyl]triazol-1-yl]-N-[5-fluoro-7-hydroxy-6-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]azetidine-1-carboxamide (Example 17) To a 50 mL single-neck round-bottom flask containing a well-stirred solution of 5-(6-amino-1-fluoro-3-hydroxy-2-naphthyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (2, 30 mg, 70.54 μmol, TFA salt) in DCM (1 mL), DIPEA (742.00 mg, 5.74 mmol, 1.0 mL) and CDI (57.19 mg, 352.68 μmol) were added, and the resulting reaction mixture was stirred for 3 h. To this was added 4-[[1-(azetidin-3-yl)triazol-4-yl]methylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (1, 28.88 mg, 70.54 μmol). After 16 hours, the reaction mixture was concentrated under reduced pressure and the residue was purified by reverse-phase preparative HPLC [Column: PFP(pentafluorophenyl)-YMC (20×250 mm) 5 micron; Mobile phase A: 0.1% TFA in water and Mobile phase B: MeCN] to give 3-[4-[[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-indolin-4-yl]amino]methyl]triazol-1-yl]-N-[5-fluoro-7-hydroxy-6-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]azetidine-1-carboxamide (Example 17, 30 mg, 31.71 μmol, 44.95% yield, TFA salt) as a yellow solid. LCMS (ES+): m / z 747.2 [M + H]+ 1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 9.84 (s, 1H), 8.88 (s, 1H), 8.32 (d, J = 3.3 Hz, 1H), 7.98 - 7.91 (m, 1H), 7.82 - 7.76 (m, 1H), 7.62 - 7.54 (m, 1H), 7.52 - 7.45 (m, 1H), 7.24 - 7.16 (m, 1H), 7.14 - 7.04 (m, 2H), 5.56 - 5.44 (m, 1H), 5.10 - 5.01 (m, 1H), 4.68 - 4.61 (m, 2H), 4.57 - 4.47 (m, 2H), 4.35 - 4.24 (m, 2H), 4.16 (s, 2H), 2.95 - 2.81 (m, 2H), 2.71 - 2.58 (m, 2H), 2.07 - 1.97 (m, 1H).

[0727] N-(6-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-5-fluoro-7-hydroxynaphthalen-2-yl)-3-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propan-2-yl)-1H-1,2,3-triazol-1-yl)propanamide (Example 18):

[0728] [ka]

[0729] Step 1: N-(6-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-5-fluoro-7-hydroxynaphthalen-2-yl)-3-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propan-2-yl)-1H-1,2,3-triazol-1-yl)propanamide (Example 18) To a 20 mL capped vial containing a well-stirred solution of 3-[4-[1-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]-1-methyl-ethyl]triazol-1-yl]propanoic acid (5, 0.050 g, 110.03 μmol) in DMF (1 mL) was added 5-(6-amino-1-fluoro-3-hydroxy-2-naphthyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (6, 34.25 mg, 110.03 μmol) and N,N-diisopropylethylamine (71.10 mg, 550.13 μmol, 95.82 μL), and the mixture was stirred at room temperature for 5 minutes. A solution of 1-propanephosphonic anhydride (50% in ethyl acetate) (0.077 mL, 38.51 mg, 121.03 μmol) was added slowly and the resulting mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and the residue was purified by reverse-phase preparative HPLC [purification method: Column: X-bridge, C18 (150 × 19) mm, 5 micron; mobile phase A: 0.1% HCOOH in water and mobile phase B: MeCN] to give N-(6-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-5-fluoro-7-hydroxynaphthalen-2-yl)-3-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propan-2-yl)-1H-1,2,3-triazol-1-yl)propanamide (Example 18, 7 mg, 8.40 μmol, 8% yield, formate salt) as a yellow solid.LCMS (ES-): m / z 746.4 [M - H]- 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 10.35 - 10.21 (m, 2H), 8.11 - 8.07 (m, 2H), 7.83 (d, J = 9.0 Hz, 1H), 7.35 (dd, J = 9.1, 1.9 Hz, 1H), 7.25 - 7.18 (m, 1H), 6.97 - 6.93 (m, 1H), 6.90 (d, J = 7.1 Hz, 1H), 6.87 (s, 1H), 6.56 (d, J = 8.6 Hz, 1H), 5.05 (dd, J = 12.8, 5.4 Hz, 1H), 4.64 (t, J = 6.7 Hz, 2H), 4.33 (s, 2H), 3.01 (t, J = 6.8 Hz, 2H), 2.94 - 2.80 (m, 1H), 2.62 - 2.54 (m, 2H), 2.07 - 1.98 (m, 1H), 1.70 (d, J = 1.9 Hz, 6H).

[0730] N-(6-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-5-fluoro-7-hydroxynaphthalen-2-yl)-3-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoindolin-4-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)propanamide (Example 19):

[0731] [ka]

[0732] Step 1: N-(6-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-5-fluoro-7-hydroxynaphthalen-2-yl)-3-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)propanamide (Example 19) To a 20 mL capped vial containing a well-stirred solution of 3-[4-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]oxymethyl]triazol-1-yl]propanoic acid (6, 60 mg, 113.76 μmol) in DMF (1 mL) was added DIPEA (93.79 mg, 725.72 μmol, 126.40 μL) followed by 1-propanephosphonic anhydride (50% in EtOAc) (138.5 μL, 69.27 mg, 217.72 μmol). After 5 minutes, 5-(6-amino-1-fluoro-3-hydroxy-2-naphthyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (7, 27.11 mg, 87.09 μmol) in DMF (0.3 mL) was added and the reaction mixture was stirred for 18 hours. The reaction mixture was concentrated under reduced pressure and purified by reverse-phase preparative HPLC [purification method: column; X-Select C18 (150 × 19 mm), 5 μm; mobile phase A: 0.1% TFA in water and mobile phase B: MeCN] to give N-(6-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-5-fluoro-7-hydroxynaphthalen-2-yl)-3-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoindolin-4-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)propanamide (Example 19, 8.8 mg, 10.24 μmol, 9% yield, TFA salt) as an off-white solid.LCMS (ES+): m / z 707.0 [M + H] + 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 10.31 (s, 1H), 10.25 (s, 1H), 8.28 (s, 1H), 8.13 (s, 1H), 7.84 (d, J = 9.0 Hz, 1H), 7.50 - 7.42 (m, 2H), 7.39 (dd, J = 9.1, 2.0 Hz, 1H), 7.34 - 7.29 (m, 1H), 6.95 (d, J = 2.7 Hz, 1H), 5.29 (s, 2H), 5.09 (dd, J = 13.4, 5.1 Hz, 1H), 4.69 (t, J = 6.6 Hz, 2H), 4.38 - 4.29 (m, 3H), 4.18 (d, J = 17.5 Hz, 1H), 3.07 (t, J = 6.7 Hz, 2H), 2.89 (ddd, J = 18.0, 13.6, 5.4 Hz, 2H), 2.45 - 2.36 (m, 2H), 2.02 - 1.90 (m, 1H).

[0733] 3-[4-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]oxymethyl]triazol-1-yl]-N-[5-fluoro-7-hydroxy-6-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]propanamide (Example 20)

[0734] [ka]

[0735] Step 1: N-[7-benzyloxy-5-fluoro-6-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]-3-[4-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]oxymethyl]triazol-1-yl]propanamide (3) To a 10 mL single-neck round-bottom flask containing a well-stirred solution of 5-(6-amino-3-benzyloxy-1-fluoro-2-naphthyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (2, 24.28 mg, 60.48 μmol) and 3-[4-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]oxymethyl]triazol-1-yl]propanoic acid (1, 25 mg, 60.48 μmol) in anhydrous DMF (0.25 mL) was added DIPEA (23.45 mg, 181.43 μmol, 31.60 μL). Propylphosphonic anhydride (50 wt % in EtOAc) (57.72 μL, 28.86 mg, 90.71 μmol) was added to the reaction at 0° C. and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase preparative HPLC [X-BRIDGE C18 (19 × 150) mm, 5.0 μm and solvent A: 0.1% TFA in water; solvent B: acetonitrile] to give N-[7-benzyloxy-5-fluoro-6-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]-3-[4-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]oxymethyl]triazol-1-yl]propanamide (3, 20 mg, 21.60 μmol, 36% yield, TFA salt) as an off-white powder. LCMS (ESI+): m / z 797.6 [M + H]+

[0736] Step 2: 3-[4-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]oxymethyl]triazol-1-yl]-N-[5-fluoro-7-hydroxy-6-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]propanamide (Example 20) To a 10 mL single-neck round-bottom flask containing a well-stirred solution of N-[7-benzyloxy-5-fluoro-6-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]-3-[4-[[2-(2,6-dioxo-3-piperidyl)-1-oxoisoindoli-5-yl]oxymethyl]triazol-1-yl]propanamide (3, 20 mg, 25.10 μmol) in anhydrous CHCl (1.2 mL) and anhydrous toluene (1.2 mL) was added pentamethylbenzene (5.58 mg, 37.65 μmol, 6.09 μL). The reaction mixture was cooled to −78 °C, and BCl (1 M in DCM) (14.71 mg, 125.51 μmol, 2 mL) was added. The resulting solution was stirred at room temperature for 36 h. The reaction mixture was cooled to −78° C. and quenched with 5% MeOH in DCM (5 mL). The reaction mixture was concentrated under reduced pressure and purified by reverse-phase preparative HPLC [Purification method: Column: X-BRIDGE C18 (19 × 150) mm, 5.0 μm; Mobile phase A: 0.1% TFA in water; Mobile phase B: acetonitrile] to give 3-[4-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]oxymethyl]triazol-1-yl]-N-[5-fluoro-7-hydroxy-6-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]propanamide (Example 20, 8 mg, 9.68 μmol, 39% yield, TFA salt) as an off-white solid.LCMS (ESI+): m / z 707.0 [M + H]+ 1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 10.31 (s, 1H), 9.93 (s, 1H), 8.26 (s, 1H), 8.09 (s, 1H), 7.81 (d, J = 9.0 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.36 (dd, J = 9.0, 1.9 Hz, 1H), 7.29 - 7.25 (m, 1H), 7.12 (dd, J = 8.3, 2.3 Hz, 1H), 6.93 (s, 1H), 5.22 (s, 2H), 5.04 (dd, J = 13.3, 5.2 Hz, 1H), 4.69 (t, J = 6.6 Hz, 2H), 4.38 (d, J = 17.3 Hz, 1H), 4.25 (d, J = 17.2 Hz, 1H), 4.07 (s, 2H), 3.05 (t, J = 6.5 Hz, 2H), 2.95 - 2.82 (m, 1H), 2.61 (d, J = 3.0 Hz, 2H), 2.42 - 2.30 (m, 1H), 2.02 - 1.93 (m, 1H).

[0737] N-(6-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-5-fluoro-7-hydroxynaphthalen-2-yl)-3-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoindolin-4-yl)oxy)methyl)-1H-pyrazol-1-yl)propanamide (Example 21):

[0738] [ka]

[0739] Step 1: N-(6-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-5-fluoro-7-hydroxynaphthalen-2-yl)-3-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoindolin-4-yl)oxy)methyl)-1H-pyrazol-1-yl)propanamide (Example 21) To a 10 mL single-neck round-bottom flask containing a well-stirred solution of 3-[4-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]oxymethyl]pyrazol-1-yl]propanoic acid (1, 50 mg, 77.83 μmol) in anhydrous DMF (2 mL), 5-(6-amino-1-fluoro-3-hydroxy-2-naphthyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (2, 37.74 mg, 121.24 μmol), DIPEA (47.01 mg, 363.73 μmol, 63.36 μL), and 1-propanephosphonic anhydride (50% in EtOAc) (0.11 mL, 57.87 mg, 181.86 μmol) were added. The resulting mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure and the residue was purified by reverse-phase preparative HPLC [purification method: column: X-Select C18 (150 × 19 mm) 5 micron, mobile phase: 0.1% TFA and MeCN in water] to give 3-[4-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]oxymethyl]pyrazol-1-yl]-N-[5-fluoro-7-hydroxy-6-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]propanamide (Example 21, 14.3 mg, 19.79 μmol, 16% yield) as an off-white solid.LCMS (ES+): m / z 704.0 [M - H]- 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 10.49 (s, 1H), 10.28 (s, 1H), 8.15 (s, 1H), 7.89 (s, 1H), 7.85 (d, J = 9.0 Hz, 1H), 7.57 (s, 1H), 7.45 (t, J = 7.8 Hz, 1H), 7.40 (dd, J = 9.1, 1.9 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.29 (d, J = 7.4 Hz, 1H), 6.96 (s, 1H), 5.11 - 5.04 (m, 3H), 4.46 - 4.38 (m, 4H), 4.33 (d, J = 17.4 Hz, 1H), 4.17 (d, J = 17.5 Hz, 1H), 2.96 (t, J = 6.8 Hz, 2H), 2.93 - 2.83 (m, 1H), 2.46 - 2.37 (m, 2H), 2.01 - 1.89 (m, 1H).

[0740] N-(6-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-5-fluoro-7-hydroxynaphthalen-2-yl)-2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-1-yl)acetamide (Example 22)

[0741] [ka]

[0742] Step 1: N-(7-(benzyloxy)-6-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-5-fluoronaphthalen-2-yl)-2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-1-yl)acetamide (3) To a 25 mL round-bottom flask containing a well-stirred solution of 2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-1-yl)acetic acid (1, 200 mg, 499.47 μmol) in DMF (2 mL) was added triethylamine (151.62 mg, 1.50 mmol, 208.85 μL) and propylphosphonic anhydride (T3P) (50% solution in EtOAc) (158.92 mg, 499.47 μmol, 0.3 mL), and the reaction mixture was stirred at room temperature for 30 min. 5-(6-amino-3-benzyloxy-1-fluoro-2-naphthyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (2, 257.44 mg, 499.47 μmol, TFA salt) was then added, and the reaction mixture was stirred at ambient temperature for 4 hours. The volatiles were removed under reduced pressure and the residue was purified by reverse-phase preparative HPLC [purification method: X-Bridge C18 (19 x 150 mm) 5.0 micron, mobile phase A: 0.1% TFA in water; mobile phase B: MeCN] to give N-(7-(benzyloxy)-6-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-5-fluoronaphthalen-2-yl)-2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-1-yl)acetamide (3, 90 mg, 86.22 μmol, 17% yield, TFA salt) as a brown sticky solid. LCMS (ES+): m / z 784.2 [M + H] +

[0743] Step 2: N-(6-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-5-fluoro-7-hydroxynaphthalen-2-yl)-2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-1-yl)acetamide (Example 22) To a 25 mL round-bottom flask containing a well-stirred solution of N-(7-(benzyloxy)-6-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-5-fluoronaphthalen-2-yl)-2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-1-yl)acetamide (3, 90 mg, 100.24 μmol, TFA salt) and pentamethylbenzene (44.58 mg, 300.72 μmol, 48.62 μL) in a mixture of DCM (2 mL) and toluene (2 mL) was added boron trichloride (1 M in DCM) (3.00 mmol, 3 mL) dropwise at −78° C. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was cooled to -78°C and quenched by dropwise addition of a 10:1 mixture of DCM and MeOH (5 mL). The volatiles were removed under reduced pressure and the residue was purified by reverse-phase preparative HPLC [Purification method: Column: X Bridge C18 (19 x 150 mm), 5.0 μm; Mobile phase A: 0.1% TFA in water and Mobile phase B: MeCN] to give N-(6-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-5-fluoro-7-hydroxynaphthalen-2-yl)-2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-1-yl)acetamide (Example 22, 17 mg, 20.72 μmol, 21% yield, TFA salt) as an off-white solid. LCMS (ES+): m / z 694.2 [M + H] + 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 10.81 (s, 1H), 9.91 (s, 1H), 9.82 (s, 1H), 8.12 (s, 1H), 7.90 (d, J = 8.9 Hz, 1H), 7.50 - 7.44 (m, 1H), 7.11 (d, J = 9.6 Hz, 1H), 7.09 - 7.05 (m, 1H), 7.00 (d, J = 4.1 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 5.36 (dd, J = 12.7, 5.4 Hz, 1H), 4.23 (s, 2H), 4.10 (s, 2H), 3.67 (d, J = 11.4 Hz, 2H), 2.98 - 2.83 (m, 3H), 2.78 - 2.60 (m, 4H), 2.18 - 1.93 (m, 6H), 1.51 (d, J = 7.0 Hz, 1H), 1.23 (s, 1H).

[0744] 2-[4-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-6-yl]-1-piperidyl]-N-[5-fluoro-7-hydroxy-6-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]acetamide (Example 23):

[0745] [ka]

[0746] Step 1: 2-[4-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-6-yl]-1-piperidyl]-N-[5-fluoro-7-hydroxy-6-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]acetamide (Example 23): To a 10 mL single-neck round-bottom flask containing a well-stirred solution of 2-[4-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-6-yl]-1-piperidyl]acetic acid (1, 35 mg, 0.069 mmol, TFA salt) and 5-(6-amino-1-fluoro-3-hydroxy-2-naphthyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (2, 24.27 mg, 0.069 mmol, HCl salt) in DMF (0.5 mL) was added DIPEA (9.02 mg, 0.069 mmol, 12.16 μL) and a solution of propylphosphonic anhydride (T3P) (≥50 wt % in EtOAc) (22.21 mg, 0.069 mmol, 50 μL) at 0° C. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (2 mL) and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC (purification method: column: X-BRIDGE C18 (19 × 150 mm) 5.0 μm and mobile phase A: 0.1% TFA in water; mobile phase B: acetonitrile) to give 2-[4-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-6-yl]-1-piperidyl]-N-[5-fluoro-7-hydroxy-6-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]acetamide (Example 23, 12 mg, 0.014 mmol, yield 21%, TFA salt) as an off-white solid.LCMS (ES+): m / z 681.0 [M + H] + 1H NMR (400 MHz, DMSO-d6) δ 11.23 (s, 1H), 10.80 (s, 1H), 9.97 (s, 1H), 9.84 (s, 1H), 8.12 (s, 1H), 7.91 (d, J = 8.9 Hz, 1H), 7.47 (d, J = 9.1 Hz, 1H), 7.32 (s, 1H), 7.24 (d, J = 8.1 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 7.00 (s, 1H), 5.37 (dd, J = 13.0, 5.3 Hz, 1H), 4.23 (s, 2H), 4.13 (s, 2H), 3.72 - 3.61 (m, 2H), 3.30 - 3.22 (m, 4H), 2.98 - 2.85 (m, 2H), 2.76 - 2.62 (m, 2H), 2.23 - 2.12 (m, 1H), 2.09 - 1.94 (m, 4H), 1.02 - 0.80 (m, 1H).

[0747] 2-[4-[1-(2,6-dioxo-3-piperidyl)-3-isopropyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]-N-[5-fluoro-7-hydroxy-6-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]acetamide (Example 24)

[0748] [ka]

[0749] Step 1: N-[7-benzyloxy-5-fluoro-6-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]-2-[4-[1-(2,6-dioxo-3-piperidyl)-3-isopropyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]acetamide (3) To a 25 mL single-neck round-bottom flask containing a well-stirred solution of 2-[4-[1-(2,6-dioxo-3-piperidyl)-3-isopropyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]acetic acid (1, 220 mg, 513.44 μmol, TFA salt) in anhydrous DMF (5 mL) was added 5-(6-amino-3-benzyloxy-1-fluoro-2-naphthyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (2, 206.10 mg, 513.44 μmol, TFA salt), DIPEA (199.08 mg, 1.54 mmol, 268.30 μL), and 1-propanephosphonic anhydride (50% in EtOAc) (0.49 mL, 245.05 mg, 770.16 μmol). After 16 hours, the volatiles were removed under reduced pressure and the residue was purified by reverse-phase preparative HPLC [column: C18 aq gold (19 x 150) mm, 5 micron; mobile phase A: 0.1% TFA in water and mobile phase B: MeCN] to give N-[7-benzyloxy-5-fluoro-6-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]-2-[4-[1-(2,6-dioxo-3-piperidyl)-3-isopropyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]acetamide (3, 200 mg, 192.25 μmol, 37% yield, TFA salt) as an off-white solid. LCMS (ES+): m / z 812.3 [M + H]+

[0750] Step 2: 2-[4-[1-(2,6-dioxo-3-piperidyl)-3-isopropyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]-N-[5-fluoro-7-hydroxy-6-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]acetamide (Example 24) To a 50 mL single-neck round-bottom flask containing a solution of N-[7-benzyloxy-5-fluoro-6-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]-2-[4-[1-(2,6-dioxo-3-piperidyl)-3-isopropyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]acetamide (3, 200 mg, 246.34 μmol, TFA salt) in anhydrous DCM (5 mL) and anhydrous toluene (5 mL) was added pentamethylbenzene (36.52 mg, 246.34 μmol). The reaction mixture was cooled to −78° C., and BC1 (1 M in methylene chloride) (2.46 mL, 2.46 mmol) was added dropwise. The resulting solution was stirred at ambient temperature for 3 hours. The reaction mixture was quenched with 5% MeOH in DCM (5 mL) at −78° C., and the volatiles were removed under reduced pressure. The residue was purified by reverse-phase preparative HPLC [Column: C18 aq gold (19 × 150) mm, 5 micron; Mobile Phase A: 0.1% TFA in water and Mobile Phase B: MeCN] to give 2-[4-[1-(2,6-dioxo-3-piperidyl)-3-isopropyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]-N-[5-fluoro-7-hydroxy-6-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]acetamide (Example 24, 45 mg, 51.95 μmol, 21% yield, TFA salt) as an off-white solid.LCMS (ES+): m / z 722.7 [M + H]+ 1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 10.82 (s, 1H), 10.18 (s, 1H), 9.77 (s, 1H), 8.12 (d, J = 1.9 Hz, 1H), 7.92 (d, J = 9.0 Hz, 1H), 7.48 (dd, J = 9.1, 2.0 Hz, 1H), 7.22 - 7.18 (m, 1H), 7.07 (d, J = 8.1 Hz, 1H), 7.01 (s, 1H), 6.93 (d, J = 8.1 Hz, 1H), 5.33 (dd, J = 12.8, 5.4 Hz, 1H), 4.63 (p, J = 6.9 Hz, 1H), 3.68 (d, J = 11.5 Hz, 2H), 3.32 - 3.23 (m, 2H), 2.97 - 2.83 (m, 2H), 2.75 - 2.58 (m, 2H), 2.19 - 1.93 (m, 5H), 1.49 (s, 3H), 1.47 (s, 3H).

[0751] 2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-1-piperidyl]-N-[5-fluoro-7-hydroxy-6-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]acetamide (Example 25)

[0752] [ka]

[0753] Step 1: 2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-1-piperidyl]-N-[5-fluoro-7-hydroxy-6-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]acetamide (Example 25) 2-[4-[1-(2,6-Dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-1-piperidyl]acetic acid (1, 50 mg, 124.87 μmol) and 5-(6-amino-1-fluoro-3-hydroxy-2-naphthyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (2, 38.87 mg, 124.87 μmol) in DMF (500 μL) was treated with DIPEA (64.55 mg, 499.47 μmol, 87.00 μL) and cooled to 0° C. Propylphosphonic anhydride (50% wt in EtOAc) (239.89 mg, 374.60 μmol, 480 μL) was added and the reaction was allowed to reach room temperature. After 16 hours, the mixture was directly purified by reverse-phase chromatography, eluting with 5 to 100% acetonitrile in water with 0.1% TFA modifier to give 2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-1-piperidyl]-N-[5-fluoro-7-hydroxy-6-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]acetamide (Example 25, 17.7 mg, 19.94 μmol, 16% yield, TFA salt) as a gray solid. LCMS: 694.5 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 10.79 (s, 1H), 9.84 (s, 2H), 8.12 (s, 1H), 7.91 (d, J = 9.0 Hz, 1H), 7.51 - 7.45 (m, 1H), 7.13 - 6.96 (m, 4H), 5.39 (dd, J = 12.6, 5.5 Hz, 1H), 4.23 (s, 1H), 4.10 (s, 2H), 3.71 - 3.56 (m, 6H), 2.95 - 2.84 (m, 1H), 2.79 - 2.58 (m, 2H), 2.25 - 2.12 (m, 2H), 2.10 - 1.95 (m, 3H), 1.00 - 0.90 (m, 2H), 0.89 - 0.81 (m, 1H).

[0754] 2-[4-[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]-1-piperidyl]-N-[5-fluoro-7-hydroxy-6-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]acetamide (Example 26):

[0755] [ka]

[0756] Step 1: Preparation of N-[7-benzyloxy-5-fluoro-6-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]-2-[4-[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]-1-piperidyl]acetamide (3) To a well-stirred 10 mL single-neck round-bottom flask containing a solution of 5-(6-amino-3-benzyloxy-1-fluoro-2-naphthyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (2, 80 mg, 199.30 μmol, TFA salt) and 2-[4-[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]-1-piperidyl]acetic acid (1, 92.39 mg, 219.23 μmol, TFA salt) in DMF (2 mL) was added N,N-diisopropylethylamine (148.40 mg, 1.15 mmol, 0.2 mL) and propylphosphonic anhydride (T3P) (50 wt % in EtOAc) (23.20 mg, 219.23 μmol, 0.05 mL) at room temperature. The reaction mixture was stirred at room temperature for 18 hours. Volatiles were removed under reduced pressure, and the residue was purified by reverse-phase preparative HPLC [Purification method: Column: X-BRIDGE C8 (19 x 150 mm), 5 microns; Mobile phase A: 0.1% TFA in HO; Mobile phase B: MeCN] to give N-[7-benzyloxy-5-fluoro-6-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]-2-[4-[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]-1-piperidyl]acetamide (3, 50 mg, 49.70 μmol, 25% yield, TFA salt) as a pale yellow solid. LCMS (ES+): m / z 805.0 [M + H]+

[0757] Step 2: Preparation of 2-[4-[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]-1-piperidyl]-N-[5-fluoro-7-hydroxy-6-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]acetamide (Example 26) To a 10 mL single-neck round-bottom flask containing a well-stirred solution of N-[7-benzyloxy-5-fluoro-6-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-2-naphthyl]-2-[4-[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]-1-piperidyl]acetamide (3, 50 mg, 62.12 μmol, TFA salt) in toluene (1 mL) and DCM (1 mL) was added pentamethylbenzene (46.05 mg, 310.62 μmol, 50.22 μL) at room temperature. Boron trichloride (1 M in DCM) (0.5 mmol, 0.5 mL) was then added at −78° C. The reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was cooled to −78° C. and quenched with 10% MeOH in DCM (1.5 mL). Volatiles were removed under reduced pressure, and the residue was purified by reverse-phase preparative HPLC [Purification method: Column: X-BRIDGE C8 (19 × 150 mm), 5 micron; Mobile phase A: 0.1% TFA in HO; Mobile phase B: MeCN] to give 2-[4-[1-(2,6-dioxo-3-pipe...

Claims

1. Formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, During the ceremony, R1 is halogen; R2 is hydrogen, halogen, C1-C3 alkoxy, C3-C6 cycloalkoxy, C1-C3 haloalkoxy, C3-C5 halocycloalkoxy, C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, or -L-Z; R3 is hydrogen, halogen, C1-C3 alkoxy, C3-C5 cycloalkoxy, C1-C3 haloalkoxy, C3-C5 halocycloalkoxy, C1-C3 alkyl, C1-C3 haloalkyl, C3-C5 cycloalkyl, or -L-Z; one of R2 and R3 is -LZ and the other of R2 and R3 is not -LZ; Rx is hydrogen or halogen; L is -U-V-W-X-Y-; U is a bond, —(NR4)—, —O—, C1-C3 alkylene, C2-C3 alkenylene, C2-C3 alkynylene, C3-C6 cycloalkylene, 4- to 10-membered heterocyclylene, 5- to 10-membered heteroarylene, —(C═O)NR4—, —NR4(C═O)—, —OR5—, —R5O—, —NR4R5—, —R5NR4—, or —(NR4)(C═O)(NR4)—; each R4 is independently hydrogen, C1-C6 alkyl, or C3-C5 cycloalkyl; R5 is C1-C3 alkylene, C3-C7 cycloalkylene, or 4-12 membered heterocyclylene; V is a bond, —(NR4)—, —O—, C1-C6 alkylene, C2-C6 alkenylene, —(C═O)NR4—, —(NR4)R5—, —(NR4)(C═O)—, —NH(C═O)NH—, —OR5—, —R5O—, 4- to 10-membered heterocyclylene, 5- to 10-membered heteroarylene, C6-C10 arylene, or C3-C6 cycloalkylene; W is a bond, C1-C3 alkylene optionally substituted with hydroxyl, C3-C6 cycloalkylene, 4-12 membered heterocyclylene, —O—, —(NR4)—, —R5(NR4)—, —(NR4)R5—, —(NR4)(C═O)—, —R5(NR4)(C═O)—, —(C═O)(NR4)R5—, —R5(C═O)(NR4)—, —(C═O)(NR4)—, —R5(C═O)—, —(C═O)R5—, —(C═O)—, —(S═O)—, or —S(O2)—; X is a bond, C1-C3 alkylene, C3-C6 cycloalkylene, 4- to 12-membered heterocyclylene, C6-C10 arylene, 5- to 10-membered heteroarylene, —R5(NR4)(C═O)—, —(C═O)R5(NR4)—, —R5(C═O)(NR4)—, —(NR4)(C═O)R5—, —R5(C═O)(NR4)—, —(C═O)(NR4)R5—, —(NR4)R5(C═O)—, —R5(C═O)(NR4)R5—, —R5(NR4)(C═O)R5—, —(C═O)R5—, or —R5(C═O)—; Y is R, R(CRARB)p-Q-, or -Q-(CRARB)pR6-; Q is —(NR4)—, —O—, or —(CRARB)p-; p is 0, 1, 2, or 3; R6 is C1-C3 alkylene, C3-C7 cycloalkylene, 4- to 12-membered heterocyclylene, C6-C10 arylene, or 5- to 10-membered heteroarylene; the heterocyclylene, heteroarylene, arylene, and cycloalkylene groups of U, V, W, X, and R6 are each optionally substituted with 1 to 3 substituents independently selected from fluoro, hydroxyl, C1-C6 alkoxy, and C1-C6 alkyl; each RA and RB is independently hydrogen, fluoro, or C1-C6 alkyl; or RA and RB together with the carbon atoms to which they are attached form a C3-C4 cycloalkyl, or R A and R B combine to form oxo, Z is selected from the group consisting of: 【Chemistry 2】 R7 is hydrogen, C1-C6 alkyl optionally substituted with one group selected from hydroxyl, cyano, and C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, -(CRARB)(4- to 12-membered heterocyclyl), or -(CRARB)(C3-C6 cycloalkyl); R8 is hydrogen or C1-C6 alkyl; each R9 is hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C5 cycloalkoxy, 5-10 membered heteroaryloxy, or phenoxy; q is 0, 1, or 2; each R10 is independently hydrogen, halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 haloalkyl; The compound or a pharmaceutically acceptable salt thereof.

2. (i) U is -NR4(C=O)- or -(C=O)NR4-, V is a bond or C1-C6 alkylene, W is a bond, and X is a bond; or (ii) U is -NR4(C=O)- or -(C=O)NR4-, V is a bond or C1-C6 alkylene, W is a bond, and X is 4- to 12-membered heterocyclylene; (iii) U is —O—, V is C1-C6 alkylene, C3-C6 cycloalkylene, or 4-10 membered heterocyclylene, and W is —C(═O)—, —N(R)—, —C(═O)NR—, —NRC(═O)—, or —NRC(═O)R—; (iv) U is -NR4-, V is C1-C6 alkylene or a bond, W is -C(=O)- or -C(=O)R5-, and X is a bond; or (v) U is a bond, C1-C3 alkylene, C2-C3 alkylene or C2-C3 alkylene; V is a bond; W is a bond or -C(=O); and X is a bond or C6-C10 arylene; (vi) U is —NR4(C═O) or —(C═O)NR4, V is a bond, W is C1-C3 alkylene, and X is a bond; The compound of claim 1.

3. Y is R6; Y is -R6(CRARB)p-Q-; Y is -R6(CRARB)p-Q-, and p is 0; Y is R6(CRARB)pQ-, p is 1 or 2, and each of RA and RB is hydrogen; Y is -R6(CRARB)p-Q-, p is 1 or 2, and each RA and RB is independently hydrogen or C1-C3 alkyl, or one pair of RA and RB together with the carbon atom to which they are attached form a C3-C4 cycloalkyl, and the remaining each RA and RB, if present, is hydrogen; Y is —R6(CRARB)p-Q-, and each RA and RB is independently hydrogen, fluoro, or C1-C3 alkyl; The compound of claim 1.

4. (i) Z is 【Transformation 3】 Or (ii) Z is selected from the group consisting of: 【Chemistry 4】 (iii) Z is 【Transformation 5】 Or (iv) Z is 【Transformation 6】 Or (v) Z is selected from the group consisting of: 【Transformation 7】 (vi) Z is 【Transformation 8】 Or (vii) Z is selected from the group consisting of: 【Chemistry 9】 (viii) Z is selected from the group consisting of: 【Chemistry 10】 (ix) Z is selected from the group consisting of: 【Chemistry 11】 (x) Z is 【Chemistry 12】 Or (xi) Z is 【Chemistry 13】 Or (xii) Z is 【Chemistry 14】 Or (xiii) Z is 【Chemistry 15】 2. The compound of claim 1, wherein:

5. The compound of formula (I) is represented by formula (I-a): 【Chemistry 16】 10. The compound of claim 1, wherein the compound is:

6. The compound of formula (I) is represented by formula (I-b): 【Chemistry 17】 or a pharmaceutically acceptable salt thereof, The compound of claim 1, wherein B1 is O or NR7.

7. The compound of formula (I) is represented by formula (I-c): [Chemistry 18] or a pharmaceutically acceptable salt thereof, 2. The compound of claim 1, wherein Rz1 and Rz2 are both hydrogen or Rz1 and Rz2 are linked to form oxo.

8. The compound of formula (I) is represented by formula (I-d): 【Chemistry 19】 or a pharmaceutically acceptable salt thereof, 2. The compound of claim 1, wherein B2 is CH or N.

9. The compound of formula (I) is represented by formula (I-e): 【Chemistry 20】 10. The compound of claim 1, wherein the compound is:

10. The compound of formula (I) is represented by formula (II-a): 【Chemistry 21】 10. The compound of claim 1, wherein the compound is:

11. The compound of formula (I) is represented by formula (II-b): 【Chemistry 22】 or a pharmaceutically acceptable salt thereof, The compound of claim 1, wherein B1 is O or NR7.

12. The compound of formula (I) is represented by formula (II-c): 【Chemistry 23】 or a pharmaceutically acceptable salt thereof, 2. The compound of claim 1, wherein Rz1 and Rz2 are both hydrogen or Rz1 and Rz2 are linked to form oxo.

13. The compound of formula (I) is represented by formula (II-d): 【Chemistry 24】 or a pharmaceutically acceptable salt thereof, 2. The compound of claim 1, wherein B2 is CH or N.

14. The compound of formula (I) is represented by formula (II-e): 【Chemistry 25】 10. The compound of claim 1, wherein the compound is:

15. (i) L is selected from the group consisting of: 【Chemistry 26】 (ii) L is selected from the group consisting of: 【Chemistry 27】 (iii) L is selected from the group consisting of: 【Chemistry 28】 (iv) L is selected from the group consisting of: 【Chemistry 29】 (v) The compound of claim 1, wherein L is selected from the group consisting of: 【Transformation 30】

16. R1 is fluoro; Rx is hydrogen; Z is 【Chemistry 31】 and R7 is hydrogen or C1-C6 alkyl, and 2. The compound of claim 1, wherein R2 is hydrogen and R3 is -LZ, or R2 is -LZ and R3 is hydrogen.

17. (i) U is —(NR4)(C═O)—, —(C═O)NR4—, or —(NR4)(C═O)(NR4)—; V is a bond, C1-C6 alkylene, or a 4-6 membered heterocyclylene optionally substituted with methyl, hydroxyl, methoxy, or 1 or 2 fluoro; W is a bond or C1-C3 alkylene; X is a bond or C1-C3 alkylene; Y is R6, R6 is a C3-C7 cycloalkylene, a 4- to 12-membered heterocyclylene, a C6-C10 arylene, or a 5- to 10-membered heteroarylene; R4 is hydrogen or C1-C6 alkyl; (ii) U is —(NR4)(C═O)—, —(C═O)NR4—, or —(NR4)(C═O)(NR4)—; V is a bond or a 4-6 membered heterocyclylene optionally substituted with methyl, hydroxyl, methoxy, or one or two fluoro; W is a bond or C1-C3 alkylene; X is a bond or C1-C3 alkylene; Y is R6, R6 is a 4- to 8-membered heterocyclylene, phenyl, or 5- to 6-membered heteroarylene; R4 is hydrogen or C1-C6 alkyl; The compound of claim 1.

18. V and X are bonds; R6 is piperidinyl, piperazinyl, phenyl, pyridinyl, or pyridonyl; W is C1-C3 alkylene and R4 is hydrogen; U is -(NR4)(C=O)-, V is a bond, W is C1-C3 alkylene, X is a bond, and Y is R6, where R4 is hydrogen or methyl and R6 is a 5- to 6-membered heterocyclylene, phenyl, or 5- to 6-membered heteroarylene; The compound of claim 1.

19. Formula (I): 【Chemistry 32】 or a pharmaceutically acceptable salt thereof, During the ceremony, R1 is hydrogen or halogen; R2 is hydrogen, halogen, C1-C3 alkoxy, C3 cycloalkoxy, C1-C3 haloalkoxy, C3-C5 halocycloalkoxy, C1-C3 alkyl, C3 cycloalkyl, or -L-Z; R3 is hydrogen, halogen, C1-C3 alkoxy, C3-C5 cycloalkoxy, C1-C3 haloalkoxy, C3-C5 halocycloalkoxy, C1-C3 alkyl, C3-C5 cycloalkyl, or -L-Z; one of R2 and R3 is -LZ and the other of R2 and R3 is not -LZ; Rx is hydrogen or halogen; L is selected from the group consisting of: 【Transformation 33】 【Transformation 34】 【Chemistry 35】 【Transformation 36】 Z is selected from the group consisting of: 【Chemistry 37】 R7 is hydrogen, C1-C6 alkyl optionally substituted with one group selected from hydroxyl, cyano, and C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, -(CRARB)(4- to 12-membered heterocyclyl), or -(CRARB)(C3-C6 cycloalkyl); R8 is hydrogen or C1-C6 alkyl; each R9 is halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C5 cycloalkoxy, 5-10 membered heteroaryloxy, or phenoxy; q is 0, 1, or 2; The compound, or a pharmaceutically acceptable salt thereof, wherein each R10 is independently hydrogen, halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 haloalkyl.

20. The compound of formula (I) is the following compound Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 Table 1-35 Table 1-36 Table 1-37 Table 1-38 Table 1-39 Table 1-40 Table 1-41 Table 1-42 Table 1-43 Table 1-44 Table 1-45 Table 2-1 Table 2-2 Table 2-3 Table 2-4 Table 2-5 Table 2-6 Table 2-7 Table 2-8 Table 2-9 Table 2-10 Table 2-11 Table 2-12 Table 2-13 Table 2-14 Table 2-15 Table 2-16 Table 2-17 Table 2-18 Table 2-19 Table 2-20 Table 2-21 Table 2-22 Table 2-23 Table 2-24 Table 2-25 Table 2-26 Table 2-27 Table 2-28 Table 2-29 Table 2-30 Table 2-31 Table 2-32 Table 2-33 Table 2-34 Table 2-35 Table 2-36 Table 2-37 Table 2-38 Table 2-39 Table 2-40 Table 2-41 Table 2-42 Table 2-43 Table 2-44 Table 2-45 Table 2-46 Table 2-47 Table 2-48 Table 2-49 Table 2-50 Table 2-51 Table 2-52 Table 2-53 Table 2-54 Table 2-55 Table 2-56 Table 2-57 Table 2-58 Table 2-59 Table 2-60 Table 2-61 Table 2-62 Table 2-63 Table 2-64 Table 2-65 Table 2-66 Table 2-67 Table 2-68 Table 2-69 Table 2-70 Table 2-71 Table 2-72 Table 2-73 Table 2-74 Table 2-75 Table 2-76 Table 2-77 Table 2-78 Table 2-79 Table 2-80 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from one of:

21. 21. A pharmaceutical composition comprising a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof.

22. 22. The pharmaceutical composition of claim 21 for the treatment of cancer.

23. 22. The pharmaceutical composition of claim 21 for inhibiting the proliferation of mammalian cells.

24. 22. The pharmaceutical composition of claim 21 for reducing the level of a protein in a mammalian cell, wherein the protein is PTPN1, PTPN2, or a combination thereof.

25. 22. The pharmaceutical composition of claim 21 for inhibiting metastasis.

26. 22. The pharmaceutical composition of claim 21 for the treatment of a metabolic disease.

27. 22. The pharmaceutical composition of claim 21 for reducing BMI.

28. The pharmaceutical composition according to claim 21 for suppressing weight gain.

29. 22. The pharmaceutical composition of claim 21, for increasing the proliferation of mammalian T cells in the presence of T cell receptor stimulation, wherein the protein is PTPN1, PTPN2, or a combination thereof.

30. 22. The pharmaceutical composition of claim 21, for activating mammalian T cells in the presence of T cell receptor stimulation, wherein the protein is PTPN1, PTPN2, or a combination thereof.

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