Protein tyrosine phosphatase targeting ligands

Abstract

Provided herein are compounds, compositions, and methods useful for degrading protein tyrosine phosphatase, 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 favorably responsive to PTPN1 or PTPN2 inhibitor treatment, e.g., a cancer or a metabolic disease.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 290,235, filed December 16, 2021, which is hereby incorporated in its entirety by reference. This application claims the benefit of U.S. Provisional Application No. 63 / 231,646, filed August 10, 2021, which is hereby incorporated in its entirety by reference. BACKGROUND Cancer immunotherapy regimens targeting 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 in a variety of cancers, and dramatically improving outcomes in some populations refractory to conventional therapies. However, incomplete clinical responses and the development of intrinsic or acquired resistance continue to limit the subject populations who could benefit from checkpoint blockade. 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 phospho-tyrosine specific phosphatases that control multiple cellular regulatory processes by removing phosphate groups from tyrosine substrates. PTPN2 is ubiquitously expressed, but expression is highest in hematopoietic and placental cells (Mosinger, B. Jr. et al., Proc Natl Acad Sci USA 89:499-503; 1992). In humans, PTPN2 expression is controlled post-transcriptionally by the existence of two splice variants: a 45 kDa form that contains a nuclear localization signal at the C-terminus upstream of the splice junction, and a 48 kDa canonical form which has a C-terminal ER retention motif (Tillmann U. et al., Mol Cell Biol 14:30303040; 1994). The 45 kDa isoform can passively transfuse into the cytosol under certain cellular stress conditions. Both isoforms share an N-terminal phospho-tyrosine phosphatase catalytic domain. PTPN2 negatively regulates signaling of non-receptor tyrosine kinases (e.g. JAKI, 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, Lek). As a critical negative regulator of the JAK-STAT pathway, PTPN2 functions to directly regulate signaling through cytokine receptors, including IFNy. The PTPN2 catalytic domain shares 74% sequence homology with PTPN1 (also called PTP IB), and shares similar enzymatic kinetics (Romsicki Y. et al., Arch Biochem Biophys 414:40-50; 2003). Data from a loss of function in vivo genetic screen using CRISPR / Cas9 genome editing in a mouse B16F10 transplantable tumor model show that deletion of Ptpn2 gene in tumor cells improved response to the immunotherapy regimen of a GM-CSF secreting vaccine (GVAX) plus PD-1 checkpoint blockade (Manguso R. T. et al., Nature 547:413-418; 2017). Loss of Ptpn2 sensitized tumors to immunotherapy by enhancing IFNy-mediated effects on antigen presentation and growth suppression. The same screen also revealed that genes known to be involved in immune evasion, including PD-L1 and CD47, were also depleted under immunotherapy selective pressure, while genes involved in the IFNy signaling pathway, including IFNGR, JAKI, and STAT1, were enriched. These observations point to a putative role for therapeutic strategies that enhance IFNy sensing and signaling in enhancing the efficacy of cancer immunotherapy regimens. Protein tyrosine phosphatase non-receptor type 1 (PTPN1), also known as protein tyrosine phosphatase-IB (PTPIB), has been shown to play a key role in insulin and leptin signaling and is a primary mechanism for down-regulating both the insulin and leptin receptor signaling pathways (Kenner K. A. et al., J Biol Chern 271: 19810-19816,1996). Animals deficient in 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). One approach to externally impact protein activity is by decreasing levels of a particular protein by targeted protein 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 is central to the regulation of almost all cellular processes, including antigen processing, apoptosis, biogenesis of organelles, cell cycling, DNA transcription and repair, differentiation and development, immune response and inflammation, neural and muscular degeneration, morphogenesis of neural networks, modulation of cell surface receptors, ion channels and the secretory pathway, the response to stress and extracellular modulators, ribosome biogenesis and viral infection. Covalent attachment of multiple ubiquitin molecules by an E3 ubiquitin ligase to a terminal lysine residue marks the protein for proteasome degradation, where the protein is digested into small peptides and eventually into its constituent amino acids that serve as building blocks for new proteins. There are over 600 E3 ubiquitin ligases which facilitate the ubiquitination of different proteins in vivo, which can be divided into four families: HECT-domain E3s, U-box E3s, monomeric RING E3s and multi-subunit E3s. See generally Li et al. (PLOS One, 2008, 3, 1487); Bemdsen et al. (Nat. Struct. Mol. Biol., 2014, 21, 301307); Deshaies et al. (Ann. Rev. Biochem., 2009, 78, 399-434); Spratt et al. (Biochem. 2014, 458, 421437); and Wang et al. (Nat. Rev. Cancer., 2014, 14, 233-347). The first E3 ligase successfully targeted with a small molecule was SCFpTrCP, using a hybrid of the small molecule MetAP2 inhibitor linked to a IkBoi phosphopeptide epitope known to bind to the ubiquitin E3 ligase. (Sakamoto et al, PNAS 2001, 98 (15) 8554). Schneekloth et al. describe a degradation agent (PROTAC3) that targets the FK506 binding protein (FKBP12) and shows that both PROTAC2 and PROTAC3 hit their respective targets with green fluorescent protein (GFP) imaging. Schneekloth et al. (Chem Bio Chem 2005, 6, 40-46). In unrelated parallel research, scientists were investigating thalidomide toxicity, and discovered that cereblon is a thalidomide binding protein. Ito et al. (Science 2010, 327, 1345-1350). Cereblon forms part of an E3 ubiquitin ligase protein complex which interacts with damaged DNA binding protein 1, forming an E3 ubiquitin ligase complex with Cullin 4 and the E2-binding protein ROC1 (also known as RBX1) where it functions as a substrate receptor to select proteins for ubiquitination. The study revealed that thalidomide-cereblon binding in vivo may be responsible for thalidomide teratogenicity. After the discovery that thalidomide binds to the cereblon E3 ubiquitin ligase led to research to investigate incorporating thalidomide and certain derivatives into compounds for the targeted destruction of proteins. See G. Lu et al., (Science, 343, 305-309 (2014)); and J. Kronke et al., (Science, 343, 301-305 (2014)). While progress has been made in the area of modulation of the UPP for in vivo protein degradation, it would be useful to have additional compounds and approaches to more fully harness the UPP for therapeutic treatments, for example, for the development of targeted PTP IB degraders useful for the treatment of type 2 diabetes, obesity, and metabolic syndrome. It is an object of the present invention to provide new compounds, methods, compositions, and methods of manufacture that are useful to degrade selected proteins, e.g., PTP IB, in vivo. SUMMARY The present disclosure is directed, at least in part, to compounds, compositions, and methods that cause degradation of a protein tyrosine phosphatase, 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-IB (PTPIB) via the ubiquitin proteasome pathway (UPP). In some embodiments, the compounds described herein comprise a “Targeting Ligand” that binds to a protein tyrosine phosphatase, a “Degron” which binds (e.g., non- covalently) to an E3 Ligase (e.g., the cereblon component) and a linker that covalently links the Targeting Ligand to the Degron. Some embodiments provide a compound of Formula (I): O^OH or a pharmaceutically acceptable salt thereof, wherein: R1; R2; R3; R4; R5; R6; R7; R8A; R8B; R9; R10; R11; R12; RA; RB; Rc; Rx; RY; Ring A; Ring B; Q1; J; W; X; Y; Y2; Z; p; p1; p2; p3; q; s; and t are as defined herein. Some embodiments provide a pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof. 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. 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 invention belongs. Methods and materials are described herein for use in the present invention; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and 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. Other features and advantages of the invention will be apparent from the following detailed description and figures, and from the claims. BRIEF DESCRIPTION OF THE DRAWINGS These and other features, aspects, and advantages of the present invention will become better understood with regard to the following description, and accompanying drawings, where: FIG. 1 illustrates the anticancer and tumor growth inhibition activity in vivo of an exemplary compound of this disclosure in an syngeneic mouse tumor model. The graph shows tumor growth inhibition of MC-38 tumor-bearing mice treated with Compound 187b monotherapy (arrows labelled “3”; QWx3) and in combination with anti-PD-1 therapy (arrows labelled “2”; Q4Dx2). Each point on the curve represents the mean of 10 tumor volume of 10 mice. Error bars depict the standard error of the mean. ** = p < 0.01. BRIEF DESCRIPTION OF THE SEQUENCE LISTING Incorporated herein by reference in its entirety is a Sequence Listing entitled, “45629 0002P01SEQ”, comprising SEQ ID NO: 1 through SEQ ID NO: 3, which includes the amino acid sequences disclosed herein. The Sequence listing has been submitted herewith in ASCII text format via EFS. The Sequence Listing was first created on May 20, 2020 and is 13 KB in size. DETAILED DESCRIPTION The present disclosure is directed, at least in part, to compounds, compositions, and methods for the inhibition of protein tyrosine phosphatase, e.g., protein tyrosine phosphatase non-receptor type 2 (PTPN2) and / or protein tyrosine phosphatase non-receptor type 1 (PTPN1 or PTP1B). Definitions Chemical Definitions Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, 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. The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts. Compounds described herein can comprise one or more asymmetric centers or double bonds, and thus can exist in various isomeric forms, e.g., enantiomers, diastereomers, racemates, geometric isomers, stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)-. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. 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 syntheses. 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 (E.L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972). The present disclosure includes compounds in racemic and optically pure forms. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. The disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers. The articles “a” and “an” may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article. By way of example “an analogue” means one analogue or more than one analogue. When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example “C1-C6 alkyl” is intended to encompass, Cl, C2, C3, C4, C5, C6, C1-C6, C1-C5, Cl-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. The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present disclosure. “Alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms (“Cl-CIO alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-C8 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-C6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-C5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-C4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-C3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-C2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Cl alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-C6 alkyl”). Examples of C1-C6 alkyl groups include methyl (Cl), 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). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8) and the like. Each instance of an alkyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkyl group is unsubstituted C1-C10 alkyl (e.g., -CH3). In certain embodiments, the alkyl group is substituted C1-C6 alkyl.            Common alkyl abbreviations include Me (-CH3), Et (-CH2CH3), iPr (-CH(CH3)2), nPr (-CH2CH2CH3), n-Bu (-CH2CH2CH2CH3), or i-Bu (-CH2CH(CH3)2). “Alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 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 carboncarbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 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 the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Each instance of an alkenyl group may be independently optionally substituted, e.g., unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents, e.g., from 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. “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, the halo group is either fluorine or chlorine. “Haloalkyl” refers to an alkyl group as described herein (e.g., a C1-C6 alkyl group) in which one or more of the hydrogen atoms are replaced by a 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. “Alkoxy” refers to an alkyl group as described herein (e.g., a C1-C6 alkyl group), which is attached to a molecule via oxygen atom. This includes moieties where the alkyl part may be linear or branched, such as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy and n-hexoxy. “Haloalkoxy” refers to an alkoxy group as described herein (e.g., a C1-C6 alkoxy group), in which one or more of the hydrogen atoms are replaced by a 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. “Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 n electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-C14 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C6 aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“CIO aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14 aryl”; e.g., anthracyl). An aryl group may be described as, e.g., a C6-C10 aryl. Aryl groups include, but are not limited to, phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Each instance of an aryl group may be independently optionally substituted, e.g., unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is unsubstituted C6-C14 aryl. In certain embodiments, the aryl group is substituted C6-C14 aryl. “Heteroaryl” refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 n electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-10 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl). A heteroaryl group may be described as, e.g., a 6-10-membered heteroaryl, wherein the term “membered” refers to the non-hydrogen ring atoms within the moiety. In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Each instance of a heteroaryl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is substituted 5-14 membered heteroaryl. Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. “Cycloalkyl” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C3-C10 cycloalkyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-C8cycloalkyl”). 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 may be described as, e.g., a C4-C7-membered cycloalkyl. Exemplary C3-C6 cycloalkyl groups include, without limitation, 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, without limitation, the aforementioned C3-C6 cycloalkyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), cubanyl (C8), bicyclofl.l.l]pentanyl (C5), bicyclo[2.2.2]octanyl (C8), bicyclo[2.1.1]hexanyl (C6), bicyclo[3.1.1]heptanyl (C7), and the like. Exemplary C3-C10 cycloalkyl groups include, without limitation, the aforementioned C3-C8 cycloalkyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (CIO), cyclodecenyl (CIO), octahydro-1 H-indenyl (C9), decahydronaphthalenyl (CIO), spiro[4.5]decanyl (CIO), and the like. As the foregoing examples illustrate, in certain embodiments, the cycloalkyl group is either monocyclic (“monocyclic cycloalkyl”) or contain a fused, bridged, or spiro ring system such as a bicyclic system (“bicyclic cycloalkyl”) and can be saturated or can be partially unsaturated. “Cycloalkyl” also includes ring systems wherein the cycloalkyl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is on the cycloalkyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the cycloalkyl ring system. Each instance of a cycloalkyl group may be independently optionally substituted, e.g., unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is unsubstituted C3-C10 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-C10 cycloalkyl. In some embodiments, “cycloalkyl” is a monocyclic, saturated cycloalkyl group having from 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 (C5) and cyclohexyl (C5). Examples of C3-C6 cycloalkyl groups include the aforementioned C5-C6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-C8 cycloalkyl groups include the aforementioned C3-C6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is unsubstituted C3-C10 cycloalkyl. In certain embodiments, the cycloalkyl group is substituted C3-C10 cycloalkyl. “Heterocyclyl” refers to a radical of a 3- to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatomic groups, wherein each heteroatomic group is independently selected from nitrogen, oxygen, sulfur and oxidized forms of sulfur (for example, S, S(O) and S(O)2), boron, phosphorus, and silicon (“3-12 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged, or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more cycloalkyl groups wherein the point of attachment is either on the cycloalkyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. A heterocyclyl group may be described as, e.g., a 3-7-membered heterocyclyl, wherein the term “membered” refers to the non-hydrogen ring atoms, i.e., carbon, nitrogen, oxygen, and sulfur and oxidized forms of sulfur (for example, S, S(O) and 8(0)2), within the moiety. Each instance of heterocyclyl may be independently optionally substituted, e.g., unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. 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 46 membered heterocyclyl. Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4—membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, 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, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. “Amino” refers to the radical -NH2. “Cyano” refers to the radical -CN. “Hydroxy” or “hydroxyl” refers to the radical -OH. “Oxo” refers to a =0 group. In some embodiments one or more of the nitrogen atoms of a disclosed compound if present are oxidized to the corresponding A-oxide. The term "pharmaceutically acceptable salts" is meant to include salts that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. Certain compounds described herein can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure. The term “tautomer” as used herein refers to compounds whose structures differ markedly in arrangement of atoms, but which exist in easy and rapid equilibrium, and it is to be understood that compounds provided herein may be depicted as different tautomers, and when compounds have tautomeric forms, all tautomeric forms are intended to be within the scope of the invention, and the naming of the compounds does not exclude any tautomer. An example of a tautomeric forms includes the following example: OH             O It will be apparent to one skilled in the art that certain compounds of this disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the disclosure. Compounds provided herein may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. That is, an atom, in particular when mentioned in relation to a compound according to Formula (I), comprises all isotopes and isotopic mixtures of that atom, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form. For example, when hydrogen is mentioned, it is understood to refer to 'H, 2H, 3H or mixtures thereof; when carbon is mentioned, it is understood to refer to HC, 12C, 13C, 14C or mixtures thereof; when nitrogen is mentioned, it is understood to refer to 13N, 14N, 15N or mixtures thereof; when oxygen is mentioned, it is understood to refer to 14O, 15O, 16O, 17O, 18O or mixtures thereof; and when fluoro is mentioned, it is understood to refer to 18F, 19F or mixtures thereof; unless expressly noted otherwise. For example, in deuteroalkyl and deuteroalkoxy groups, where one or more hydrogen atoms are specifically replaced with deuterium (2H). As some of the aforementioned isotopes are radioactive, the compounds provided herein therefore also comprise compounds with one or more isotopes of one or more atoms, and mixtures thereof, including radioactive compounds, wherein one or more non-radioactive atoms has been replaced by one of its radioactive enriched isotopes. Radiolabeled compounds are useful as additional 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 invention. 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. In the compounds described herein, it is understood that the W-X-Y group does not include compounds, for example, where X is a bond and W and Y are both heteroatoms (e.g., W and Y are both -((CRARB)pO)t-*, where p is 0 and t is 1). Likewise, W and Y groups do not include compounds with multiple heteroatom-heteroatom bonds for example, when W and / or Y is -((CRARB)pO)t-*, where p is 0 and t is 2 or 3). “Treating” or “treatment” refers to reducing the symptoms or arresting or inhibiting further development of the disease (in whole or in part). “Treating” or “treatment” includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the disease and the like. For example, certain methods herein treat cancer by decreasing or reducing the occurrence, growth, metastasis, or progression of cancer or decreasing a symptom of cancer. An "effective amount" is an amount sufficient to accomplish a stated purpose (e.g. achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, or reduce 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 a symptom or symptoms of a disease, which could also be referred to as a "therapeutically effective amount. " A "prophylactically effective amount" of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of a disease, or reducing the likelihood of the onset (or reoccurrence) of a disease or its symptoms. A “reduction” of a symptom or symptoms means decreasing of the severity or frequency of the symptom(s), or the complete elimination of the symptom(s). “Contacting” refers to the process of allowing at least two distinct species to become sufficiently proximal to react, interact, and / or physically touch. It should be appreciated, however, that the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents which can be produced in the reaction mixture. The term “contacting” includes allowing two species to react, interact, and / or physically touch, wherein the two species may be a compound as 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 (PTP IB). As defined herein, the term “inhibition”, “inhibit”, “inhibiting” and the like in reference to a protein-inhibitor (e.g., antagonist) interaction means negatively affecting (e.g., decreasing) the activity or function of the protein relative to the activity or function of the protein in the absence of the inhibitor. In some embodiments, inhibition refers to reduction in the progression of a disease and / or symptoms of disease. In some embodiments, inhibition refers to a reduction in the activity of a signal transduction pathway or signaling pathway. Thus, inhibition includes, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or downregulating signal transduction or enzymatic activity or the amount of a protein. 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 may include, at least in part, partially or totally decreasing stimulation, decreasing or reducing activation, or inactivating, desensitizing, or down-regulating signal transduction or enzymatic activity or the amount of a protein tyrosine phosphatase, e.g., protein tyrosine phosphatase non-receptor type 2 (PTPN2) or protein tyrosine phosphatase non-receptor type 1 (PTPIB). A “subject,” as used herein, refers to a living organism suffering from or prone to a disease that can be treated by administration of a compound or pharmaceutical composition, as provided herein. Nonlimiting examples include mammals such as humans. In some embodiments, a subject is human. In some embodiments, a subject is a newborn human. In some embodiments, a subject is an elderly human. In some embodiments, the subject is a pediatric subject (e.g., a subject 21 years of age or less). "Disease" refers to a state of being or health status of a subject or subject capable of being treated with a compound, pharmaceutical composition, or method provided herein. In some embodiments, the compounds and methods described herein comprise reduction or elimination of one or more symptoms of the disease, e.g., through administration of a compound described herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof. The term “PTPN2” as used herein refers to protein tyrosine phosphatase non-receptor type 2. The term “PTPN1 ” refers to protein tyrosine phosphatase non-receptor type 1 (PTPN1), also known as protein tyrosine phosphatase-IB (PTP1B). Compounds Some embodiments provide a compound of Formula (I): or a pharmaceutically acceptable salt thereof: wherein: R1 and R2 are independently hydrogen or C1-C6 alkyl; or R1 and R2, together with the carbon atom to which they are attached, come together to form a C3-C4 cycloalkyl or a 3-4 membered heterocyclyl; R3 and R4 are independently hydrogen, C1-C6 alkyl, or phenyl; or R3 and R4, together with the carbon atom to which they are attached, come together to form a C3-C4 cycloalkyl or a 3-4 membered heterocyclyl; each R5 and R6 is independently halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, or -NR8AR8B; R7 is hydrogen, C1-C6 alkyl, or C3-C4 cycloalkyl; or wherein R7 and Rc of W, together with the nitrogen atoms to which they are attached, come together to form a 5-6 membered heterocyclyl; R8A and R8b are independently hydrogen or C1-C6 alkyl; Ring A and Ring B are independently phenyl or 6-membered heteroaryl; n and m are independently 0, 1, or 2; Q1 is O or NR9; R9 is hydrogen or C1-C6 alkyl; J is a bond or -C(=O)-; W and Y are independently -(CRARB)p-*, -((CRARB)pO)t-*, -(O(CRARB)p)t-*, -((CRARB)pO)t-(CRARB)p-*, -((CRARB)2O(CRARB)z))p-*5 —NRc(CRARB)p-,* -(CRARB)pNRc(C=O)(CRARB)p-*,-(CRARB)p(C=O)NRc(CRARB)p-*,-(CRARB)pNRc-*, -(CRARB)pNRc(C=O)(CRARB)p-O-*, -(CRARB)p(C=O)NRc(CRARB)s-O-*, -(CRARB)pNRc(C=O)(CRARB)p-NRc-*, 4CRARB)p(C=0)NRc(CRARB)s-NRc-*; -NRc(CRARB)s-NRc(C=O)(CRARB)p-^-NRc((CRARB)p)C=C-*,-C=C((CRARB)p)NRc-*, -(C=O)(CRARB)p-O-*, -O-*, -O-(CRARB)p-(C=O)-*, -(C=O)(CRARB)p-NRc-*, -NRc-(CRARB)p-(C=O)-*, -(C=O)((CRaRb)p)-*, -(C=O)(CRaRb)p-O-(CRaRb)p-*, or -((CRARB)p)(C=O)-*, wherein the asterisk represents the point of attachment of W to X and the point of attachment of Y to Z; each p is independently 0, 1, 2, 3, 4, or 5; each s is independently 2, 3, 4, or 5; each t is independently 1, 2, or 3; each RA and RB are independently hydrogen, fluoro, or C1-C6 alkyl; or RA and RB, together with the carbon atom to which they are attached, come together to form a C3-C4 cycloalkyl; each Rc is independently hydrogen or C1-C6 alkyl; or wherein Rc of W and R7, together with the nitrogen atoms to which they are attached, come together to form a 5-6 membered heterocyclyl; X is a bond, C3-C6 cycloalkyl, phenyl optionally substituted with 1-3 independently selected halogen atoms, 3 to 10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from halogen, C1-C6 alkyl, and hydroxyl, or 5 to 10 membered heteroaryl optionally substituted with 1-3 independently selected halogen; Z is selected from the group consisting of R10 is hydrogen, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclyl; and R11 is hydrogen or C1-C6 alkyl; 5           each R12 is independently halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C5 cycloalkoxy; and q is 0, 1, or 2. In some embodiments, Ring A is phenyl. In some embodiments, Ring A is:         " <R5>m . In some embodiments, m is 1. In some embodiments, R5 is halogen. In some embodiments, R5 is -F. 10          In some embodiments, m is 0. In some embodiments, Q1 is NR9. In some embodiments, R9 is hydrogen. In some embodiments, Q1 is -O-. In some embodiments, R1 and R2 are independently hydrogen or C1-C6 alkyl. In some embodiments, R1 and R2 are independently hydrogen or C1-C3 alkyl. In some embodiments, R1 and R2 are both hydrogen. In some embodiments, R1 and R2 are independently a C1-C3 alkyl. In some embodiments, R1 and R2 are both methyl. In some embodiments, R3 and R4 are independently hydrogen, C1-C6 alkyl, or phenyl. In some embodiments, R3 and R4 are both hydrogen. In some embodiments, Ring B is phenyl. In some embodiments, Ring B is:      ' (R6)n. in some embodiments, n is 1. In some embodiments, R6 is halogen. In some embodiments, R6 is -F. In some embodiments, n is 0. In some embodiments, R7 is hydrogen or C1-C3 alkyl. In some embodiments, R7 is hydrogen. In some embodiments, W is -(CRARB)p-*. In some embodiments, W is -((CRARB)pO)t-*, -((CRARB)pO)t-(CRARB)p-*, or -((CRARB)2O(CRARB)2))p-*. In some embodiments, W is -(CRARB)pO-*, -O(CRARB)p-*, or -(CRARB)pNRc-*. In some embodiments, Y is -(CRARB)p-*. In some embodiments, Y is -(C=O)(CRARB)p-O-*, -(C=O)(CRARB)p-NRc-*, or-(C=O)(CRARB)p-*. In some embodiments, Y is -(C=O)(CRARB)p-NRc-*. In some embodiments, Y is -(CRARB)p(C=O)NRc(CRARB)p-*, -(CRARB)pNRc(C=O)(CRARB)p-*,                         -(CRARB)pNRc(C=O)(CRARB)pO-*, -(CRARB)pNRc(C=O)(CRARB)p-NRc-*, or -OC((CRARB)p)NRc-*. In some embodiments, Y is -(CRARB)pO-*, -O(CRARB)p-*, or -(CRARB)pNRc-*. In some embodiments, Rc of W and R7, together with the nitrogen atoms to which they are attached, come together to form a 5-6 membered heterocyclyl. In some embodiments, the 5-6 membered heterocyclyl is an imidazoline-2-one or a tetrahydropyrimidine-2(lH)-one. In some embodiments, each p is independently 0, 1, or 2. In some embodiments, one or more p is 0. In some embodiments, one or more p is 1 or 2. In some embodiments, one or more p is 1. In some embodiments, one or more p is 2. In some embodiments, one p is 3, 4, or 5; and each remaining p, if present, is independently 0, 1, or 2. In some embodiments, one p is 3, 4, or 5; and each remaining p, if present, is 0. In some embodiments, one p is 3, 4, or 5; and each remaining p, if present, is 1. In some embodiments, one p is 3, 4, or 5; and each remaining p, if present, is 2. In some embodiments, each p is 1. In some embodiments, each p is 2. In some embodiments, RA and RB are independently hydrogen, fluoro, or C1-C3 alkyl. In some embodiments, RA and RB are both hydrogen. In some embodiments, from 1-2 RA and / or RB is fluoro or C1-C3 alkyl; and each remaining RA and / or RB is hydrogen. In some embodiments, X is 3 to 10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from halogen, C1-C6 alkyl, and hydroxyl. In some embodiments, X is 4-6 membered monocyclic heterocyclyl optionally substituted with 1-3 substituents independently selected from halogen, C1-C6 alkyl, and hydroxyl. In some embodiments, X is azetidinyl, piperidinyl, or piperazinyl optionally substituted with 1-3 substituents independently selected from halogen, C1-C6 alkyl, H0H l-<H HCH HCH 9                                  9                                    9                                    9 and hydroxyl. In some embodiments, X is In some embodiments, X is 6-10 membered bicyclic heterocyclyl. In some embodiments, X is 6 10 membered bicyclic fused heterocyclyl. In some embodiments, X is 7-10 membered bicyclic In some embodiments, X is C3-C6 cycloalkyl. In some embodiments, X is cyclohexyl. In some embodiments, X is phenyl or 5 to 10 membered heteroaryl, wherein each is optionally substituted with 1-3 independently selected halogen. In some embodiments, X is phenyl optionally substituted with 1-3 independently selected halogen. In some embodiments, X is selected from the groups In some embodiments, X is 5-6 membered heteroaryl. In some embodiments, X is 1,2,3-triazolyl, pyrazolyl, or imidazolyl. In some embodiments, X is selected from the group consisting of In some embodiments, X is a bond. In some embodiments, J is a bond. In some embodiments, J is -C(=O)-. In some embodiments, X is 4-10 membered heterocyclyl; and W is -(CRARB)p1-*. In some embodiments, X is 4-10 membered heterocyclyl; and W is -(CRARB)p1O-*, -O(CRARB)p1-*, or -(CRARB)p'-NRc-*. In some embodiments, Y is -(CRARB)p2-*. In some embodiments, Y is -(C=O)(CRARB)p2-O-*, -(C=O)(CRARB)p2-NRc-*, or-(C=O)(CRARB)p2-*. In some embodiments, Y is -(C=O)(CRARB)p2-NRc-*.        In some embodiments, Y is -(CRARB)p2-O-*, -O(CRARB)p2-*, - NRc-(CRARB)p2-*, or -(CRARB)p2-NRc-*. In some embodiments, X is a bond; and W is -((CRARB)pO)t-*. In some embodiments, -((CRARB)pO)t-* is -((CRARB)2O)t-*. In some embodiments, -((CRARB)pO)t-* is -((CRARB)2O)t-*. In some embodiments, Y is -(CRARB)p2—*.     In some embodiments, Y is -(C=O)(CRARB)p2-O-*, -(C=O)(CRARB)p2-NRc-*, or-(C=O)(CRARB)p2-*. In some embodiments, Y is -(CRARB)p2(C=O)NRc(CRARB)p3-*,                         -(CRARB)p2-NRc(C=O)(CRARB)p3-*, -(CRARB)p2-NRc(C=O)(CRARB)p3-O-*, or4CRARB)p2-NRc(C=O)(CRARB)p3-NRc-*. In some embodiments, p1 is 0,1,2,3,4, or 5. In some embodiments, p1 is 0. In some embodiments, p1 is 1. In some embodiments, p1 is 2. In some embodiments, p1 is 3. In some embodiments, p1 is 4. In some embodiments, p1 is 5. In some embodiments, p2 is 0,1,2,3,4, or 5. In some embodiments, p2 is 0. In some embodiments, p2 is 1. In some embodiments, p2 is 2. In some embodiments, p2 is 3. In some embodiments, p2 is 4. In some embodiments, p2 is 5. In some embodiments, p3 is 0,1,2,3,4, or 5. In some embodiments, p3 is 0. In some embodiments, p3 is 1. In some embodiments, p2 is 2. In some embodiments, p3 is 3. In some embodiments, p3 is 4. In some embodiments, p3 is 5. In some embodiments, p1 and p2 are independently 0, 1,2, 3,4, or 5. In some embodiments, p2 and p3 are independently 0, 1, 2, 3, 4, or 5. In some embodiments, p1 + p2 = 0. In some embodiments, p1 + p2 = 1 or 2. In some embodiments, p1 + p2 = 1. In some embodiments, p1 + p2 = 2. In some embodiments, p1 + p2 < 3. In some embodiments, p1 + p2 = 3. In some embodiments, p1 + p2 = 4. In some embodiments, p1 + p2 = 5. In some embodiments, p1 + p2 = 6. In some embodiments, p1 + p2 = 7. In some embodiments, p1 + p2 = 8. In some embodiments, p1 + p2 = 9. In some embodiments, p1 + p2 = 10. In some embodiments, p1 + p2 = 4, 5, 6, 7, 8, or 9. In some embodiments, p2 + p3 = 0. In some embodiments, p2 + p3 = 1 or 2. In some embodiments, p2 + p3 = 1. In some embodiments, p2 + p3 = 2. In some embodiments, p2 + p3 < 3. In some embodiments, p2 + p3 = 3. In some embodiments, p2 + p3 = 4. In some embodiments, p2 + p3 = 5. In some embodiments, p2 + p3 = 6. In some embodiments, p2 + p3 = 7. In some embodiments, p2 + p3 = 8. In some embodiments, p2 + p3 = 9. In some embodiments, p2 + p3 = 10. In some embodiments, p2 + p3 = 4, 5, 6, 7, 8, or 9. In some embodiments, t is 1, 2, or 3. In some embodiments, t is 1. In some embodiments, t is 2. In some embodiments, t is 3. In some embodiments, t + p2 = 3, 4, 5, or 6. In some embodiments, t + p2 = 3. In some embodiments, t + p2 = 4. In some embodiments, t + p2 = 5. In some embodiments, t + p2 = 6. In some embodiments, t + p2 + p3 = 3, 4, 5, or 6. In some embodiments, t + p2 + p3 = 3. In some embodiments, t + p2 + p3 = 4. In some embodiments, t + p2 + p3 = 5. In some embodiments, t + p2 + p3 5   =6. In some embodiments, RA and RB are independently hydrogen, fluoro, or C1-C3 alkyl. In some embodiments, RA and RB are both hydrogen. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. 10 is In some embodiments, Z is is embodiments, In some embodiments, Z is o o In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, R10 is C1-C4 alkyl optionally substituted with C1-C6 alkoxy. In some 5 embodiments, R10 is methyl, ethyl, isopropyl, or t-butyl. In some embodiments, R10 is -(CH2)2OCH3. In some embodiments, R10 is 3-oxetanyl. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-a): (R5)m         O 10           or a pharmaceutically acceptable salt thereof; wherein Rx and RY are both H; or Rx and RY, together with the carbon atom to which they are attached, combine to form C=O. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-al): or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-a2): 5 or a pharmaceutically acceptable salt thereof. In some embodiments, both Rx and RY are hydrogen. In some embodiments, Rx and RY, together with the carbon atom to which they are attached, combine to form C=O. 10           In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-b): or a pharmaceutically acceptable salt thereof; wherein R10 is hydrogen, C1-C4 alkyl optionally substituted with C1-C6 alkoxy, C1-C6 haloalkyl, 15   C3-C6 cycloalkyl, or 4-6 membered heterocyclyl. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-b 1): or a pharmaceutically acceptable salt thereof; wherein R10 is methyl, ethyl, or isopropyl. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, 5 is a compound of Formula (I-b2): or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, 10 is a compound of Formula (I-b3): or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-c): (R5)m         O or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-d): (R5)m         O (I-d) In some embodiments, m is 0. In some embodiments, m is 1; and R5 is -F. In some embodiments, Q1 is NH; or wherein QI is —O-. In some embodiments, R1 and R2 are both hydrogen. In some embodiments, R1 and R2 are independently C1-C3 alkyl. In some embodiments, R1 and R2 are both methyl. In some embodiments, R3 and R4 are independently hydrogen, C1-C6 alkyl, or phenyl. In some embodiments, R3 and R4 are both hydrogen. In some embodiments, n is 0. In some embodiments, n is 1; and R6 is -F. In some embodiments, R7 is hydrogen. In some embodiments, W is -(CRARB)p1-*, wherein the asterisk represents the point of attachment to X. In some embodiments, W is -NRc(CRARB)p1-* or -(CRARB)p1-NRc-*, wherein the asterisk represents the point of attachment to X. In some embodiments, Y is -(CRARB)p2-*, wherein the asterisk represents the point of attachment to Z. In some embodiments, Y is -(CRARB)p2-NRc-*, wherein the asterisk represents the point of attachment to Z. In some embodiments, Y is -NRc(CRARB)p2-*, wherein the asterisk represents the point of attachment to Z. In some embodiments, Y is -(C=O)(CRARB)p2-NRc-*, wherein the asterisk represents the point of attachment to Z. In some embodiments, Y is -(CRARB)p2(C=O)NRc(CRARB)p3-*, wherein the asterisk represents the point of attachment to Z. In some embodiments, X is a bond; and W is -((CRARB)pO)t-*. In some embodiments, -((CRARB)pO)t-* is -((CRARB)2O)t-*. In some embodiments, RA and RB are independently hydrogen, fluoro, or C1-C3 alkyl. In some embodiments, RA and RB are both hydrogen. In some embodiments, p1 is 0,1,2,3,4, or 5. In some embodiments, p1 is 0. In some embodiments, p1 is 1. In some embodiments, p1 is 2. In some embodiments, p1 is 3. In some embodiments, p1 is 4. In some embodiments, p1 is 5. In some embodiments, p2 is 0,1,2,3,4, or 5. In some embodiments, p2 is 0. In some embodiments, p2 is 1. In some embodiments, p2 is 2. In some embodiments, p2 is 3. In some embodiments, p2 is 4. In some embodiments, p2 is 5. In some embodiments, p3 is 0,1,2,3,4, or 5. In some embodiments, p3 is 0. In some embodiments, p3 is 1. In some embodiments, p2 is 2. In some embodiments, p3 is 3. In some embodiments, p3 is 4. In some embodiments, p3 is 5. In some embodiments, p1 and p2 are independently 0, 1,2, 3,4, or 5. In some embodiments, p2 and p3 are independently 0, 1, 2, 3, 4, or 5. In some embodiments, p1 + p2 = 0. In some embodiments, p1 + p2 = 1 or 2. In some embodiments, p1 + p2 = 1. In some embodiments, p1 + p2 = 2. In some embodiments, p1 + p2 < 3. In some embodiments, p1 + p2 = 3. In some embodiments, p1 + p2 = 4. In some embodiments, p1 + p2 = 5. In some embodiments, p1 + p2 = 6. In some embodiments, p1 + p2 = 7. In some embodiments, p1 + p2 = 8. In some embodiments, p1 + p2 = 9. In some embodiments, p1 + p2 = 10. In some embodiments, p1 + p2 = 4, 5, 6, 7, 8, or 9. In some embodiments, p2 + p3 = 0. In some embodiments, p2 + p3 = 1 or 2. In some embodiments, p2 + p3 = 1. In some embodiments, p2 + p3 = 2. In some embodiments, p2 + p3 < 3. In some embodiments, p2 + p3 = 3. In some embodiments, p2 + p3 = 4. In some embodiments, p2 + p3 = 5. In some embodiments, p2 + p3 = 6. In some embodiments, p2 + p3 = 7. In some embodiments, p2 + p3 = 8. In some embodiments, p2 + p3 = 9. In some embodiments, p2 + p3 = 10. In some embodiments, p2 + p3 = 4, 5, 6, 7, 8, or 9. In some embodiments, t is 1, 2, or 3. In some embodiments, t is 1. In some embodiments, t is 2. In some embodiments, t is 3. In some embodiments, t + p2 = 3, 4, 5, or 6. In some embodiments, t + p2 = 3. In some embodiments, t + p2 = 4. In some embodiments, t + p2 = 5. In some embodiments, t + p2 = 6. In some embodiments, t + p2 + p3 = 3, 4, 5, or 6. In some embodiments, t + p2 + p3 = 3. In some embodiments, t + p2 + p3 = 4. In some embodiments, t + p2 + p3 = 5. In some embodiments, t + p2 + p3 = 6. In some embodiments, X is 4-6 membered monocyclic heterocyclyl optionally substituted with 13 substituents independently selected from halogen atoms , C1-C6 alkyl, and hydroxyl. In some embodiments, X is selected from the group consisting of azetidinyl, piperidinyl, and piperazinyl. In some In some embodiments, X is 6-10 membered bicyclic heterocyclyl. In some embodiments, X is 6- 5    10 membered bicyclic fused heterocyclyl. In some embodiments, X is 7-10 membered bicyclic spiroheterocyclyl. In some embodiments, X is fOOh FOCH fCOh , fOCh FCOH HX, hO-H 10 In some embodiments, X is triazolyl. In some embodiments, X is pyrazolyl. In some embodiments, W-X-Y is selected from the group consisting of: 15 , wherein the asterisk represents the point of attachment to Z. In some embodiments, W-X-Y is selected from the group consisting of: wherein the asterisk represents the point of attachment to Z. In some embodiments, W-X-Y is selected from the group consisting of: wherein the asterisk represents the point of attachment to Z. In some embodiments, W-X-Y is selected from the group consisting of: wherein the asterisk represents the point of attachment to Z. In some embodiments, W-X-Y is selected from the group consisting of: 15 wherein the asterisk represents the point of attachment to Z. In some embodiments, W-X-Y is selected from the group consisting of: * , wherein the asterisk represents the point of attachment to Z. In some embodiments, the asterisk represents the point of attachment to Z. In some embodiments, W-X-Y is selected from the group consisting of: wherein the asterisk represents the point of attachment to Z. In some embodiments, W-X-Y is selected from the group consisting of: NMe, O, or CH2; and the asterisk represents the point of attachment to Z. In some embodiments, Y2 is NH. In some embodiments, Y2 is NMe. In some embodiments, Y2 is O. In some embodiments, Y2 is CH2. In some embodiments, t is 1, 2, or 3. In some embodiments, t is 1. In some embodiments, t is 2. In some embodiments, t is 3. In some embodiments, each p is independently 1, 2, or 3. In some embodiments, each p is 1. In some embodiments, each p is 2. In some embodiments, each p is 3. In some embodiments, W-X-Y is selected from the group consisting of: wherein the asterisk represents the point of attachment to Z. In some embodiments, W-X-Y is selected from the group consisting of: , wherein the asterisk represents the point of attachment to Z. In some embodiments, W-X-Y is selected from the group consisting of: asterisk represents the point of attachment to Z. , wherein the In some embodiments, the shortest distance between Ring B and Z is from about 7 A to about 25 A, for example, about 7 A, about 8A, about 9A, about 10 A, about 11 A, about 12 A, about 13 A, about 14 A, about 15 A, about 16 A, about 17 A, about 18 A, about 19 A, about 20 A, about 21 A, about 22 A, about 23 A, about 24 A, about 25 A, or any value in between. In some embodiments, the shortest distance between Ring B and Z is from about 7 A to about 22.5 A. In some embodiments, the shortest distance between Ring B and Z is from about 7 A to about 20 A. In some embodiments, the shortest distance between Ring B and Z is from about 7 A to about 17.5 A. In some embodiments, the shortest distance between Ring B and Z is from about 7 A to about 15 A. In some embodiments, the shortest distance between Ring B and Z is from about 7 A to about 12.5 A. In some embodiments, the shortest distance between Ring B and Z is from about 7 A to about 10 A. In some embodiments, the shortest path, by number of bonds, between the atom of Ring B connected to the NR7 group and the atom serving as the point of attachment in the Z group is about 7 bonds to about 18 bonds, for example, about 7 bonds, about 8 bonds, about 9 bonds, about 10 bonds, about 11 bonds, about 12 bonds, about 13 bonds, about 14 bonds, about 15 bonds, about 16 bonds, about 17 bonds, about 18 bonds, or any value in between. In some embodiments, the shortest path, by number of bonds, between the atom of Ring B connected to the NR7 group and the atom serving as the point of attachment in the Z group is about 7 bonds to about 16 bonds. In some embodiments, the shortest path, by number of bonds, between the atom of Ring B connected to the NR7 group and the atom serving as the point of attachment in the Z group is about 7 bonds to about 14 bonds. In some embodiments, the shortest path, by number of bonds, between the atom of Ring B connected to the NR7 group and the atom serving as the point of attachment in the Z group is about 7 bonds to about 12 bonds. In some embodiments, the shortest path, by number of bonds, between the atom of Ring B connected to the NR7 group and the atom serving as the point of attachment in the Z group is 7 bonds, 8 bonds, or 9 bonds. In some embodiments, the shortest path, by number of bonds, between the atom of Ring B connected to the NR7 group and the atom serving as the point of attachment in the Z group is about 8 bonds to about 16 bonds. In some embodiments, the shortest path, by number of bonds, between the atom of Ring B connected to the NR7 group and the atom serving as the point of attachment in the Z group is about 8 bonds to about 14 bonds. In some embodiments, the shortest path, by number of bonds, between the atom of Ring B connected to the NR7 group and the atom serving as the point of attachment in the Z group is about 8 bonds to about 12 bonds. In some embodiments, the shortest path, by number of bonds, between the atom of Ring B connected to the NR7 group and the atom serving as the point of attachment in the Z group is 8 bonds or 9 bonds. In some embodiments, the shortest path, by number of bonds, between the atom of Ring B connected to the NR7 group and the atom serving as the point of attachment in the Z group is 10 bonds, 11 bonds, 12 bonds, or 13 bonds. In some embodiments, one of J, U, V, W, and X is a bond. In some embodiments, two of J, U, V, W, and X is a bond. In some embodiments, three of J, U, V, W, and X is a bond. In some embodiments, 5 J, U, V, W, and X cannot each be a bond. In some embodiments, the compound of Formula (I) is selected from the compounds described in Table 1, or a pharmaceutically acceptable salt thereof. Table 1 10 OH Pharmaceutical Compositions Some embodiments provide a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Methods of Treatment The present disclosure features compounds, compositions, and methods comprising 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. Some embodiments provide a method for 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, or a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Some embodiments provide a method for inhibiting mammalian cell proliferation, comprising contacting the mammalian cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Some embodiments provide a method for decreasing levels of a protein in a mammalian cell, comprising contacting the mammalian cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof; wherein the protein is PTPN1, PTPN2, or a combination thereof. In some embodiments, the contacting occurs in vivo. In some embodiments, the contacting occurs in vitro. In some embodiments, the mammalian cell is a mammalian cancer cell. Some embodiments provide a method for inhibiting metastasis in a subject having a particular cancer in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Some embodiments provide a method for treating a metabolic disease 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, or a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the metabolic disease is NAFLD, NASH, type 2 diabetes, or a combination of any of the foregoing. In some embodiments, the metabolic disease is type 2 diabetes. Some embodiments provide a method for decreasing BMI 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, or a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Some embodiments provide a method for inhibiting weight gain 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, or a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has an average BMI of between about 25 and about 45 prior to initiation of treatment with a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Some embodiments provide a method for increasing proliferation of mammalian T-cells in the presence of T-cell receptor stimulation, comprising contacting a mammalian thymus cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof; wherein the protein is PTPN1, PTPN2, or a combination thereof. Some embodiments provide a method for activating mammalian T-cells in the presence of T-cell receptor stimulation, comprising contacting the mammalian T-cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof; wherein the protein is PTPN1, PTPN2, or a combination thereof. In some embodiments, the contacting occurs in vivo. In some embodiments, the contacting occurs in vitro. EXAMPLES 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 their scope. Synthetic Protocols The compounds provided herein can be prepared from readily available starting materials using modifications to the specific synthesis protocols set forth below that would be well known to those of skill in the art. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by those skilled in the art by routine optimization procedures. General scheme relating to methods of making exemplary compounds of the invention are additionally described in the section entitled Methods of Making Exemplary Compounds. 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 choice 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 el al., Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein. Preparation of Exemplary Intermediates 2-((5-(3-((l-((3-aminobenzyl)sulfonyl)piperidin-4-yl)amino)phenyl)-2-(tert-butoxycarbonyl)-4- chlorothiophen-3-yl)oxy)acetic acid (A-10) NaBH3CN, AcOH EtOH, 80°C, 17h Step 5 Step 1: methyl 4,5-dichloro-3-hydroxythiophene-2-carboxylate (A-2) To a well-stirred solution of methyl 3-hydroxythiophene-2-carboxylate (A-l, 13 g, 82.19 mmol) in acetic acid (65 mL) in a 250 mL three neck flask was added N-chlorosuccinimide (28.53 g, 213.69 mmol, 17.29 mL) slowly in portions. The resulting reaction mixture was heated at 85 °C for 5 h. Upon completion, the 10 reaction mixture was cooled to ambient temperature and poured into ice water (225 mL) while stirring before extracting with diethyl ether (3 x 250 mL). The combined organic layers were washed with brine (2 x 250 mL) and then with aqueous sodium bicarbonate solution until the washings were basic. The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure. The residue was dissolved in acetic acid (45 mL) and dry HC1 gas was bubbled through the mixture for 15 min. The reaction mixture was allowed to stand for 48 h at room temperature. The solvent was decanted and water (250 mL) was added, stirred and filtered to afford methyl 4,5-dichloro-3-hydroxythiophene-2-carboxylate (A-2, 9.5 g, 41.0 mmol, 50% yield) as a light yellow solid. LCMS (ES-): m / z 224.9 [M - H]’. Step 2: tert-butyl 4,5-dichloro-3-hydroxythiophene-2-carboxylate (A-3) To a well-stirred solution of potassium tert-butoxide (49.42 g, 440.40 mmol) in DMF (60 mL) was added a solution of methyl 4,5-dichloro-3-hydroxy-thiophene-2-carboxylate (A-2, 10 g, 44.04 mmol) in DMF (60 mL) dropwise over a period of 30 min at 0 °C . The reaction mixture was allowed to come to room temperature and stirred for 2.5 h. The reaction mixture was quenched with ice water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with water (300 mL) and brine (200 mL), dried over anhydrous sodium sulfate and filtered. The solvent was removed under reduced pressure and the residue was purified by flash silica gel column chromatography (1-2% Ethyl acetate in petroleum ether) to afford tert-butyl 4,5-dichloro-3-hydroxythiophene-2-carboxylate (A-3, 8.5 g, 30.0 mmol, 68% yield) as a beige solid. LCMS (ES-): m / z 267.0 [M - H]’. Step 3: tert-butyl 4,5-dichloro-3-(2-ethoxy-2-oxoethoxy)thiophene-2-carboxylate (A-4) To a solution of tert-butyl 4,5-dichloro-3-hydroxythiophene-2-carboxylate (A-3, 17 g, 63.16 mmol) in DMF (150 mL) in a 250 mL round bottom flask was added anhydrous potassium carbonate (17.46 g, 126.33 mmol) and the suspension was cooled to 0 °C. Then ethyl bromoacetate (A-3a, 15.82 g, 94.74 mmol, 10.48 mL) was added dropwise over a period of 5 min. The reaction mixture was stirred for 5 h at room temperature. The reaction mixture was quenched with water (600 mL) and extracted with diethyl ether (3 x 150 mL). The combined organic layers were washed with brine (250 mL), dried over anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure. The residue was purified by flash silica gel column chromatography (5-8% Ethyl acetate in petroleum ether) to afford tert-butyl 4,5-dichloro-3-(2-ethoxy-2-oxoethoxy)thiophene-2-carboxylate (A-4, 20 g, 56.30 mmol, 59% yield) as an off white solid. LCMS (ES+): m / z 299.0 [M - tBu + H]+. Step 4: tert-butyl 5-(3-aminophenyl)-4-chloro-3-(2-ethoxy-2-oxo-ethoxy)thiophene-2-carboxylate (A-5) To a solution of tert-butyl 4,5-dichloro-3-(2-ethoxy-2-oxo-ethoxy)thiophene-2-carboxylate (A-4, 10 g, 28.15 mmol) and (3-aminophenyl)boronic acid (A-4a, 7.71 g, 56.30 mmol) in 1,4-dioxane (75 mL) in a pressure tube was added potassium fluoride (4.91 g, 84.45 mmol) and the mixture was purged by bubbling nitrogen gas through for 5 min. Then tri-tert-butylphosphonium tetrafluoroborate (816.72 mg, 2.82 mmol) and tete(dibenzylideneacetone)dipalladium (0) (1.29 g, 1.41 mmol) were added and the tube was sealed. The reaction mixture was heated at 70 °C for 17 h. The reaction mixture was cooled to room temperature, diluted with 1,4-dioxane and filtered through Celite. The filtrate was concentrated under reduced pressure, and the residue purified by flash silica gel column chromatography (10% Ethyl acetate in petroleum ether) to afford tert-butyl 5-(3-aminophenyl)-4-chloro-3-(2-ethoxy-2-oxo-ethoxy)thiophene-2-carboxylate (A-5, 5.5 g, 12.47 mmol, 44% yield) as a pale yellow solid. LCMS (ES+): m / z 356.0 [M -tBu + H]+. Step 5: tert-butyl 4-((3-(5-(tert-butoxycarbonyl)-3-chloro-4-(2-ethoxy-2-oxoethoxy)thiophen-2-yl)phenyl)amino)piperidine-l-carboxylate (A-6) To a solution of tert-butyl 5-(3-aminophenyl)-4-chloro-3-(2-ethoxy-2-oxo-ethoxy)thiophene-2-carboxylate (A-5, 5 g, 12.14 mmol) in ethanol (50 mL) in a pressure tube was added tert-butyl 4-oxopiperidine-1-carboxylate (A-5a, 12.09 g, 60.69 mmol) followed by acetic acid (3.64 g, 60.69 mmol, 3.47 mL). The tube was sealed and the reaction mixture heated at 80 °C for 3 h. The reaction mixture was cooled to room temperature and sodium cyanoborohydride (3.81 g, 60.69 mmol) added in portions. The reaction mixture was heated at 80 °C for 17 h. The solvent was removed under reduced pressure and the residue diluted with ethyl acetate (100 mL). The organic layer was washed with water (75 mL) and brine solution (75 mL), dried over anhydrous sodium sulfate and filtered. The solvent was removed under reduced pressure and the residue purified by flash silica gel column chromatography (8-10% Ethyl acetate in petroleum ether) to afford tert-butyl 4-((3-(5-(tert-butoxycarbonyl)-3-chloro-4-(2-ethoxy-2-oxoethoxy)thiophen-2-yl)phenyl)amino)piperidine-l-carboxylate (A-6, 5.5 g, 9.00 mmol, 74% yield) as a yellow solid. LCMS (ES+): m / z 439.0 [M - tBu +H]+. Step 6: tert-butyl 4-chloro-3-(2-ethoxy-2-oxoethoxy)-5-(3-(piperidin-4-ylamino)phenyl)thiophene-2-carboxylate hydrochloride (A-7) Into a 250 mL multi-neck round bottom flask containing a well-stirred solution of tert-butyl 4-((3-(5-(tert-butoxycarbonyl)-3-chloro-4-(2-ethoxy-2-oxoethoxy)thiophen-2-yl)phenyl)amino)piperidine-l-carboxylate (A-6, 5.63 g, 9.46 mmol) in ethanol (25 mL) was added IM HC1 in ethyl acetate (50 mL) at 0 °C and the mixture was allowed to come to room temperature and stirred for 2 h. The volatiles were removed under reduced pressure to afford tert-butyl 4-chloro-3-(2-ethoxy-2-oxoethoxy)-5-(3-(piperidin-4-ylamino)phenyl)thiophene-2-carboxylate hydrochloride (A-7, 4.9 g, 9.89 mmol, 90% yield) as a pale yellow solid. LCMS (ES+): m / z 495.0 [M + H]+. Step 7: tert-butyl 4-chloro-3-(2-ethoxy-2-oxo-ethoxy)-5-[3-[[l-[(3-nitrophenyl)methylsulfonyl]-4-piperidyl] am ino] phenyl] thiophene-2-carboxylate (A-8) To a solution of tert-butyl 4-chloro-3-(2-ethoxy-2-oxoethoxy)-5-(3-(piperidin-4-ylamino)phenyl)thiophene-2-carboxylate hydrochloride (A-7,4.9 g, 9.22 mmol) in a mixture of DCM (150 mL) and saturated aqueous sodium bicarbonate solution (150 mL) was added (3-nitrophenyl)methanesulfonyl chloride (A-7a, 2.61 g, 11.06 mmol) slowly in portions at 0 °C . The reaction was stirred at room temperature for 6 h. The organic layer was separated, and the aqueous layer extracted with DCM (2 x 100 mL). The combined organic layers were washed with water (150 mL), saturated brine (150 mL), dried over anhydrous sodium sulfate and filtered. The solvent was removed under reduced pressure and the residue purified by flash silica gel column chromatography (20-25% Ethyl acetate in petroleum ether) to afford tert-butyl 4-chloro-3-(2-ethoxy-2-oxo-ethoxy)-5-[3-[[l-[(3- nitrophenyl)methylsulfonyl]-4-piperidyl]amino]phenyl]thiophene-2-carboxylate (A-8, 5.4 g, 7.55 mmol, 82% yield) as a yellow solid. LCMS (ES+): m / z 638.1 [M - tBu +H]+. Step 8:      2-((2-(tert-butoxycarbonyl)-4-chloro-5-(3-((l-((3-nitrobenzyl)sulfonyl)piperidin-4- yl)amino)phenyl)thiophen-3-yl)oxy)acetic acid (A-9) To a solution of ZerZ-butyl 4-chloro-3-(2-ethoxy-2-oxo-ethoxy)-5-[3-[[l-[(3-nitrophenyl)methylsulfonyl]-4-piperidyl]amino]phenyl]thiophene-2-carboxylate (A-8, 5.3 g, 7.63 mmol) in a mixture of THF (120 mL) and water (40 mL) at 0 °C was added LiOH monohydrate (1.60 g, 38.17 mmol) portion wise and stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure and diluted with water (100 mL). The mixture was cooled to 0 °C and carefully acidified with 1.5 N HC1. The reaction was stirred for 30 min and the precipitate was filtered to afford 2-((2-(ZerZ-butoxycarbonyl)-4-chloro-5-(3-((l-((3-nitrobenzyl)sulfonyl)piperidin-4-yl)amino)phenyl)thiophen-3-yl)oxy)acetic acid (A-9,4.5 g, 6.6 mmol, 92% yield) as an off white solid. The material was used in the next step without further purification. LCMS (ES+): m / z 666.3 [M + H]+. Step 9: 2-((5-(3-((l-((3-aminobenzyl)sulfonyl)piperidin-4-yl)amino)phenyl)-2-( / ert-butoxycarbonyl)-4-chlorothiophen-3-yl)oxy)acetic acid (A-10) To a solution of 2-((2-(ZerZ-butoxycarbonyl)-4-chloro-5-(3-((1-((3-nitrobenzyl)sulfonyl)piperidin-4-yl)amino)phenyl)thiophen-3-yl)oxy)acetic acid (A-9, 4.6 g, 6.91 mmol) in a mixture of methanol (50 mL) and THF (50 mL) at 0 °C was added zinc powder (325 mesh) (2.26 g, 34.53 mmol) and acetic acid (4.15 g, 69.05 mmol, 3.95 mL) dropwise over a period of 5 min. After 3 h, the reaction mixture was diluted with THF (50 mL) and filtered through Celite. The filtrate was concentrated under reduced pressure, diluted with ethyl acetate (100 mL) and washed with sodium bicarbonate solution (40 mL), followed by water (40 mL) and brine solution (40 mL). The mixture was dried over anhydrous sodium sulfate, filtered and solvent removed under reduced pressure. The residue was purified by reverse phase prep HPLC to obtain 2-((5-(3-((l-((3-aminobenzyl)sulfonyl)piperidin-4-yl)amino)phenyl)-2-(tert-butoxycarbonyl)-4-chlorothiophen-3-yl)oxy)acetic acid (A-10, 3.8 g, 5.92 mmol, 86% yield) as an off white solid. LCMS (ES-): m / z 634.1 [M - H]-. 'H NMR (400 MHz, DMSO-d6): 8 7.21 (t, J = 10.40 Hz, 1H), 7.00 (t, J= 10.40 Hz, 1H), 6.88 (s, 1H), 6.81 (d, J= 10.00 Hz, 1H), 6.70 (d, J= 11.20 Hz, 1H), 6.59-6.61 (m, 1H), 6.53 (dd, J= 2.40, 10.20 Hz, 2H), 5.90 (d, J= 10.40 Hz, 1H), 4.83 (s, 2H), 4.19 (s, 2H), 3.39-3.56 (m, 3H), 2.89-2.96 (m, 2H), 1.921.97 (m, 2H), 1.52 (s, 9H), 1.34-1.38 (m, 2H). 2,2-dimethyl-l-((3-nitrobenzyl)sulfonyl)piperidin-4-one (A-13) Step 1: 2,2-dimethylpiperidin-4-one hydrochloride (A-12) To a 250 tnL single neck round bottom flask containing a well-stirred suspension of / er / -butyl 2,2-dimethyl-4-oxo-piperidine-l-carboxylate (A-ll, 15 g, 65.99 mmol) in 1,4-dioxane (150 mL) was added 4 M HC1 in dioxane (129.77 g, 600.00 mmol, 250 mL) dropwise at 0 °C. The mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to afford 2,2-dimethylpiperidin-4-5 one hydrochloride (A-12, 11g, crude) as an off-white solid. The material was used in the next step without further purification. Step 2: 2,2-dimethyl-l-[(3-nitrophenyl)methylsulfonyl]piperidin-4-one (A-13) To a well-stirred suspension of 2,2-dimethylpiperidin-4-one hydrochloride (A-12, 11g, 67.22 mmol) in DMF (200 mL) in a 500 mL round bottom flask were added DIPEA (13.03 g, 100.83 mmol, 17.56 mL) and 10 DMAP (821.21 mg, 6.72 mmol) at room temperature followed by (3-nitrophenyl)methanesulfonyl chloride (A-7a, 23.76 g, 100.83 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, diluted with water (500 mL) and extracted with dichloromethane (550 mL). The organic layer was washed with brine solution (400 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash silica 15 gel column chromatography (40% Ethyl acetate in petroleum ether) to afford 2,2-dimethyl-l-[(3-nitrophenyl)methylsulfonyl]piperidin-4-one (A-13, 7.8 g, 12.67 mmol, 19% yield) as a pale yellow solid. LCMS (ES+): m / z 327.1 [M + H]+. 5-[3-||(4S)-l-[(3-aminophenyl)methylsulfonyl|-2,2-dimethyl-4-piperidyl|amino|phenyl|-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-19a) i.Zn, NH4CI, THF, water, O°C-rt, 4h ii. Chiral SFC Step 4 Step 1: methyl 3-(2-tert-butoxy-2-oxo-ethoxy)-4,5-dichloro-thiophene-2-carboxylate A-15) Methyl 3-(2-ZerZ-butoxy-2-oxo-ethoxy)-4,5-dichloro-thiophene-2-carboxylate (A-15, 12.4 g, 34.52 mmol, 71% yield) was synthesized from methyl 4,5-dichloro-3-hydroxy-thiophene-2-carboxylate (A-2) and tert-5 butyl 2-bromoacetate (A-14) in a similar fashion to Compound A-4, except using 1.2 eq. A-14. LCMS (ES+): m / z 284.9 [M - tBu + H]+. Step 2: methyl 5-(3-aminophenyl)-3-(2-Zert-butoxy-2-oxo-ethoxy)-4-chloro-thiophene-2-carboxylate (A-16) Methyl 5-(3-aminophenyl)-3-(2-ZerZ-butoxy-2-oxo-ethoxy)-4-chloro-thiophene-2-carboxylate (A-16, 6.2 10 g, crude) was synthesized from methyl 3-(2-ZerZ-butoxy-2-oxo-ethoxy)-4,5-dichloro-thiophene-2-carboxylate (A-15) and (3-aminophenyl)boronic acid (A-4a) in a similar fashion to Compound A-5, except using 1 eq. A-4a and 3 eq. potassium fluoride. The material was used in the next step without purification. LCMS (ES+): m / z 342.1 [M + H]+. Step 3:       methyl 3-(2-(tert-butoxy)-2-oxoethoxy)-4-chloro-5-(3-((2,2-dimethyl-l-((3- 15 nitrobenzyl)sulfonyl)piperidin-4-yl)amino)phenyl)thiophene-2-carboxylate (A-17) Into a 500 mL two neck round bottom flask containing a well-stirred suspension of methyl 5-(3-aminophenyl)-3-(2-ZerZ-butoxy-2-oxo-ethoxy)-4-chloro-thiophene-2-carboxylate (A-16, 9.5 g, 23.88 mmol) in DCE (250 mL) was added acetic acid (3.58 g, 59.69 mmol, 3.41 mL), 2,2-dimethyl-l-((3- nitrobenzyl)sulfonyl)piperidin-4-one (A-13,7.79 g, 23.88 mmol) and sodium triacetoxyborohydride (50.60 g, 238.77 mmol). After 16 h the reaction mixture was diluted with water (350 mL), extracted with dichloromethane (450 mL) and washed with brine solution (300 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (30% Ethyl acetate in petroleum ether) to afford methyl 3-(2-ZerZ-butoxy-2-oxo-ethoxy)-4-chloro-5-[3-[[2,2-dimethyl-l-[(3-nitrophenyl)methylsulfonyl]-4- piperidyl]amino]phenyl]thiophene-2-carboxylate (A-17, 7.1 g, 8.72 mmol, 37% yield) as a pale yellow solid. LCMS (ES+): m / z 708.1 [M + H]+. Step 4:        methyl 5-[3-[[(4S)-l-[(3-aminophenyl)methylsulfonyl]-2,2-dimethyl-4- piperidyl]amino]phenyl]-3-(2-tert-butoxy-2-oxo-ethoxy)-4-chloro-thiophene-2-carboxylate (A-18a, first eluted fraction) and methyl 5-[3-[[(4R)-l-[(3-aminophenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]phenyl]-3-(2-tert-butoxy-2-oxo-ethoxy)-4-chlorothiophene-2-carboxylate (A-18b, second eluted fraction) Into a 250 mL two neck round bottom flask containing a well-stirred suspension of methyl 3-(2-tert-butoxy-2-oxo-ethoxy)-4-chloro-5-[3-[[2,2-dimethyl-l-[(3-nitrophenyl)methylsulfonyl]-4- piperidyl]amino]phenyl]thiophene-2-carboxylate (A-17, 5.31 g, 7.49 mmol) in THF (60 mL) and water (60 mL) was added zinc powder (4.90 g, 74.90 mmol) in portions at room temperature. The mixture was cooled to 0 °C and ammonium chloride (4.01 g, 74.90 mmol) was added in portions. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with THF (200 mL) and filtered through Celite, washing with acetone (100 mL). The filtrate was concentrated under reduced pressure, the residue taken up in dichloromethane (400 mL) and washed with water (350 mL) and brine solution (300 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure. The residue was purified by flash silica gel column chromatography (40% Ethyl acetate in petroleum ether) to afford methyl 5-(3-((l-((3-aminobenzyl)sulfonyl)-2,2-dimethylpiperidin-4-yl)amino)phenyl)-3-(2-(tert-butoxy)-2-oxoethoxy)-4-chlorothiophene-2-carboxylate (18a / b, 4.2 g, 5.57 mmol, 74% yield) as an off-white solid. The enantiomers were separated by chiral SFC: Method details: Column Name: YMC Amylose- SA; Co-Solvent: 40% and Co-Solvent Name: IPA; Outlet Pressure: 100 bar; Temperature: 35 °C. After concentration, the first eluted fraction at RT 3.7 min: methyl 5-[3-[[(4S)-l-[(3-aminophenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]phenyl]-3-(2-tert-butoxy-2-oxo-ethoxy)-4-chloro-thiophene-2-carboxylate (A-18a, first eluted fraction, 2 g, 2.65 mmol, 35% yield) was isolated as an off-white solid. LCMS (ES+): m / z 678.1 [M + H]+. Second eluted fraction at RT 5.37 min: methyl 5-[3-[[(4R)-l-[(3-aminophenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]phenyl]-3-(2-tert-butoxy-2-oxo-ethoxy)-4-chlorothiophene-2-carboxylate (A-18b, second eluted fraction, 2.2 g, 2.92 mmol, 39% yield) was isolated as an off-white solid. LCMS (ES+): m / z 678.1 [M + H]+. Step 5: 5-[3-[[(4S)-l-[(3-aminophenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-19a) 5-[3-[[(4S)-l-[(3-aminophenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-19a, 1.75 g, 2.76 mmol, 94% yield) was synthesized from methyl 5-[3-[[(4S)-l-[(3-aminophenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]phenyl]-3-(2-ZerZ-butoxy-2-oxo-ethoxy)-4-chloro-thiophene-2-carboxylate (A-18a) in a similar fashion to Compound A-9, except using 3 eq. LiOH monohydrate. The product was purified by reverse phase prep HPLC [Prep Method: column: XSELECT -C18 150 MM, Mobile phase: 0.1% TFA in Water / MeCN]. LCMS (ES+): m / z 608.3 [M + H]+. 'H NMR (400 MHz, DMSO-d6): 5 7.30-7.32 (m, 1H), 7.19-7.21 (m, 1H), 7.04-7.10 (m, 3H), 6.89 (s, 1H), 6.82 (d, J= 10.40 Hz, 1H), 6.71 (d, J= 10.00 Hz, 1H), 4.92 (s, 2H), 4.29-4.34 (m, 2H), 3.44-3.49 (m, 2H), 0.17 (s, 2H), 3.10-3.14 (m, 1H), 1.78-1.82 (m, 2H), 1.48 (s, 3H), 1.40 (s, 3H), 1.09-1.12 (m, 1H). 5-[3-[[(4R)-l-[(3-aminophenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-19b) Step 1: 5-[3-[[(4R)-l-[(3-aminophenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-19b) 5-[3-[[(4R)-l-[(3-aminophenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-19b, 110 mg, 135.7 pmol, 58% yield) was synthesized from methyl 5-[3-[[(4R)-l-[(3-aminophenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]phenyl]-3-(2-ter / -butoxy-2-oxo-ethoxy)-4-chloro-thiophene-2-carboxylate (A-18b) in a similar fashion to Compound A-9, except using 2 eq. LiOH monohydrate. The product was purified by reverse phase prep HPLC [Prep Method: column: X-SELECT-C18 150 MM, Mobile phase: 0.1% TFA in Water / MECN]. LCMS (ES+): m / z 608.1 [M + H]+. 5-[3-||l-[l-(3-aminophenyl)-l-methyl-ethyl|sulfonyl-4-piperidyl|amino|phenyl|-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-26) Zn, AcOH ------► MeOH, THF, O°C-rt, 2h Step 6 Step 1: 8-[(3-nitrophenyl)methylsulfonyl]-l,4-dioxa-8-azaspiro[4.5]decane (A-20) Into a 100 mL three neck round bottom flask containing a well-stirred solution of l,4-dioxa-8-azaspiro[4.5]decane (A-20a, 2 g, 13.97 mmol, 1.79 mL) in saturated aqueous sodium bicarbonate (15 5 mL) and DCM (15 mL) was added (3-nitrophenyl)methane sulfonyl chloride (A-7a, 3.29 g, 13.97 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. Water (100 mL) was added to the mixture and the aqueous phase was extracted with DCM (2 x 100 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Sodium sulfate, filtered and the solvent removed under reduced pressure to afford 8-[(3-nitrophenyl)methylsulfonyl]-l,4-dioxa-8-azaspiro[4.5]decane (A-20, 3.2 g, 8.97 10 mmol, 64% yield) as a pale yellow solid. The material was used in the next step without further purification. LCMS (ES+): m / z 343.0 [M + H]+. Step 2: 8-[l-methyl-l-(3-nitrophenyl)ethyl|sulfonyl-l,4-dioxa-8-azaspiro|4.5|decane (A-21) Into a 100 mL three neck round bottom flask containing a well-stirred solution of 8-[(3-nitrophenyl)methylsulfonyl]-l,4-dioxa-8-azaspiro[4.5]decane (A-20, 2 g, 5.84 mmol) in THF (25 mL) at -15   78 °C were added sodium bis(trimethylsilyl)amide solution (14.60 mmol, 8 mL) and methyl iodide (2.07 g, 14.60 mmol, 909.17 pL). The resulting mixture was stirred at room temperature for 16 h. The reaction was quenched with aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (2 x 100 mL). The organic layer was dried over Sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (30-35% ethyl acetate in pet-ether) to afford 8-[l-20   methyl-l-(3-nitrophenyl)ethyl]sulfonyl-l,4-dioxa-8-azaspiro[4.5]decane (A-21, 700 mg, 1.21 mmol, 21% yield) as a pale yellow solid. LCMS (ES+): m / z 393.4 [M + Na]+. Step 3: l-[l-methyl-l-(3-nitrophenyl)ethyl]sulfonylpiperidin-4-one (A-22) To a suspension of 8-[l-methyl-l-(3-nitrophenyl)ethyl]sulfonyl-l,4-dioxa-8-azaspiro[4.5]decane (A-21, 700 mg, 1.89 mmol) in water (3 mL) was added trifluoroacetic acid (20.72 g, 181.72 mmol, 14.00 mL) at 25   0 °C. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was cooled to 0 °C and neutralized with aqueous sodium bicarbonate solution. The product was extracted with ethyl acetate (2 x 50 ml). The combined organic layers were dried over anhydrous Sodium sulfate, filtered and concentrated under reduced pressure to afford l-[l-methyl-l-(3-nitrophenyl)ethyl]sulfonylpiperidin-4-one (A-22,700 mg, 1.24 mmol, 66% yield). The material was used in the next step without further purification. LCMS (ES+): m / z 349.3 [M + Na]+. Step 4: / ert-butyl 4-chloro-3-(2-ethoxy-2-oxoethoxy)-5-(3-((l-((2-(3-nitrophenyl)propan-2-yl)sulfonyl)piperidin-4-yl)amino)phenyl)thiophene-2-carboxylate (A-23) Into a 50 ml round bottom flask containing a well-stirred solution of tert-butyl 5-(3-aminophenyl)-4-chloro-3-(2-ethoxy-2-oxo-ethoxy)thiophene-2-carboxylate (A-5, 550 mg, 1.34 mmol) in ethanol (15 mL)was added l-[l-methyl-l-(3-nitrophenyl)ethyl]sulfonylpiperidin-4-one (A-22, 737.49 mg, 1.47 mmol), MP-cyanoborohydride (1.22 g, 10.68 mmol) and acetic acid (8.02 mg, 133.53 pmol, 7.64 pL). The reaction mixture was heated at 85 °C for 16 h. The reaction mixture was filtered through a cotton plug and the filtrate was evaporated to afford tert-butyl 4-chloro-3-(2-ethoxy-2-oxo-ethoxy)-5-[3-[[l-[l-methyl-l-(3-nitrophenyl)ethyl]sulfonyl-4-piperidyl]amino]phenyl]thiophene-2-carboxylate (A-23, 550 mg, 494.97 pmol, 37% yield) as an off-white solid. The material was used in the next step without further purification. LCMS (ES+): m / z 724.50 [M + H]+. Step 5: 2-[[2-tert-butoxycarbonyl-4-chloro-5-[3-[[l-[l-methyl-l-(3-nitrophenyl)ethyl]sulfonyl-4-piperidyl]amino]phenyl]-3-thienyl]oxy]acetic acid (A-24) 2-[[2-tert-butoxycarbonyl-4-chloro-5-[3-[[l-[l-methyl-l-(3-nitrophenyl)ethyl]sulfonyl-4-piperidyl]amino]phenyl]-3-thienyl]oxy]acetic acid (A-24, 500 mg, crude, purity 55%) was synthesized from tert-butyl 4-chloro-3-(2-ethoxy-2-oxo-ethoxy)-5-[3-[[l-[l-methyl-l-(3-nitrophenyl)ethyl]sulfonyl-4-piperidyl]amino]phenyl]thiophene-2-carboxylate (A-23) in a similar fashion to Compound A-9, except using 3 eq. LiOH monohydrate. The material was used in the next step without further purification. LCMS (ES+): m / z 694.80 [M + H]+. Step 6: 2-||5-[3-|[l-[l-(3-aminophenyl)-l-methyl-ethyl|sulfonyl-4-piperidyl|amino|phenyl|-2-tert-butoxycarbonyl-4-chloro-3-thienyl] oxy]acetic acid (A-25) 2-[[5-[3-[[l-[l-(3-aminophenyl)-l-methyl-ethyl]sulfonyl-4-piperidyl]amino]phenyl]-2-tert-butoxycarbonyl-4-chloro-3-thienyl]oxy]acetic acid (A-25, 300 mg, 293.57 pmol, 75% yield) was synthesized from 2-[[2-tert-butoxycarbonyl-4-chloro-5-[3-[[ 1 -[1 -methyl-1 -(3-nitrophenyl)ethyl] sulfonyl-4-piperidyl]amino]phenyl]-3-thienyl]oxy]acetic acid (A-24) in a similar fashion to Compound A-10, except using 3 eq. Zinc and 4 eq. Acetic acid. Upon completion, the reaction mixture was filtered through Celite, and the filtrate concentrated under reduced pressure. The residue was washed with aqueous sodium bicarbonate solution and extracted with 10% MeOH / DCM (2 x 25 mL). The combined organic layers were dried over anhydrous Sodium sulfate, filtered and concentrated under reduced pressure. The material was used in the next step without purification. LCMS (ES+): m / z 665.1 [M + H]+. Step 7:     5-[3-[[l-[l-(3-aminophenyl)-l-methyl-ethyl]sulfonyl-4-piperidyl]amino]phenyl]-3- (carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-26) Into a 25 mL three neck round bottom flask containing a well-stirred solution of 2-[[5-[3-[[l-[l-(3-aminophenyl)-l-methyl-ethyl]sulfonyl-4-piperidyl]amino]phenyl]-2-fer / -butoxycarbonyl-4-chloro-3-thienyl]oxy]acetic acid (A-25, 50 mg, 75.28 pmol) in DCM (2 mL) was added trifluoroacetic acid (25.75 mg, 225.83 pmol, 17.40 pL) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The 5 solvent was evaporated and the residue triturated with diethyl ether (2x5 mL) to afford 5-[3-[[l-[l-(3-aminophenyl)-l-methyl-ethyl]sulfonyl-4-piperidyl]amino]phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-26, 50 mg, 92% yield) as a brown solid. LCMS (ES+): m / z 608.00[M + H]+. ’H NMR (400 MHz, DMSO-c / 6): 8 7.16-7.17 (m, 1H), 7.00-7.01 (m, 1H), 6.74-6.76 (m, 4H), 6.656.67 (m, 1H), 6.53-6.55 (m, 1H), 5.82 (bs, 1H), 4.84 (s, 2H), 2.68-2.81 (m, 2H), 1.80-1.82 (m, 2H), 1.65 10    (s, 6H), 1.52-1.54 (m, 1H), 1.25-1.26 (m, 3H). 5-[3-[[l-[(3-aminophenyl)-phenyl-methyl]sulfonyl-4-piperidyl]amino]phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-34) Step 1: 4-methyl-7V-[(Z)-[(3-nitrophenyl)-phenyl-methylene]amino]benzenesulfonamide (A-28) 15 Into a 100 mL sealed tube containing a well-stirred suspension of (4-nitrophenyl)-phenyl-methanone (A-27, 4 g, 17.60 mmol) in ethanol (6 mL) was added p-toluenesulfonyl hydrazide (3.93 g, 21.13 mmol, 2.81 mL) followed by acetic acid (105.71 mg, 1.76 mmol, 100.68 pL). The reaction mixture was heated at 85 °C for 16 h. The solvent was removed and the residue purified by silica-gel (230-400 mesh) flash column, eluting with 0-100% Ethyl acetate / petroleum ether to afford 4-methyl-IV-[(Z)-[(3-nitrophenyl)-phenyl-methylene]amino]benzenesulfonamide (A-28, 4 g, 10.11 mmol, 57% yield) as an off-white solid. LCMS (ESI): m / z 396.0 [M + H]+. 'H NMR (400 MHz, DMSO-A): 5 8.24-8.20 (m, 1H), 7.92-7.88 (m, 2H), 7.827.75 (m, 2H), 7.61-7.59 (m, 3H), 7.52-7.48 (m, 1H), 7.47-7.32 (m, 4H), 7.20-7.13 (m, 1H), 2.48 (s, 3H). Step 2: 8-[(3-nitrophenyl)-phenyl-methyl]sulfonyl-l,4-dioxa-8-azaspiro[4.5]decane (A-29) Into a 250 mL sealed tube containing a well-stirred solution of 4-methyl-7V-[(Z)-[(3-nitrophenyI)-phenyl-methylene]amino]benzenesulfonamide (A-28, 4 g, 10.12 mmol) in anhydrous DMSO (40 mL) were added l,4-dioxa-8-azaspiro[4.5]decane (A-20a,   1.45 g, 10.12 mmol, 1.29 mL) and 1,4- Diazabicyclo[2.2.2]octane-l,4-diium-l,4-disulfinate (DABSO) (1.34 g, 5.56 mmol). The reaction mixture was heated to 100 °C for 16 h. The reaction mixture was poured into 50% brine solution (250 mL) and extracted with Ethyl acetate (3 x 150 mL). Organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (50 g-Biotage column, prepacked with 230-400 silica gel using Isolera), eluting with 0100% Ethyl acetate / petroleum ether to afford 8-[(3-nitrophenyl)-phenyl-methyl]sulfonyl-l,4-dioxa-8-azaspiro[4.5]decane (A-29,2 g, 4.78 mmol, 47% yield) as an off-white solid. 'H NMR (400 MHz, DMSO-d^. <5 8.57 (s, 1H), 8.24 (d, J= 11.2 Hz, 1H), 8.16 (d, J= 10.4 Hz, 1H), 7.74 (t, J= 22 Hz, 3H), 7.48-7.39 (m, 3H), 6.26 (s, 1H), 3.81 (s, 4H), 3.10-3.01 (m, 4H), 1.46-1.35 (m, 4H). Step 3: l-[(3-nitrophenyl)-phenyl-methyl]sulfonylpiperidin-4-one (A-30) Into a 100 mL single neck round bottom flask containing 8-[(3-nitrophenyl)-phenyl-methyl]sulfonyl-l,4-dioxa-8-azaspiro[4.5]decane (A-29, 2 g, 4.78 mmol) was added 4:1 TFA / water (11.84 g, 103.84 mmol, 10 mL) at 0 °C. The reaction mixture was allowed to slowly come to room temperature and stirred for 3 h. The reaction mixture was carefully poured into ice cold saturated sodium bicarbonate solution. The aqueous layer was extracted with Ethyl acetate (3 x 100 mL). Organic layers were combined, washed with brine (50 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue purified by silica gel flash column (50 g-Biotage column, prepacked with 230-400 silica gel using Isolera), eluting with 0-100 % Ethyl acetate / petroleum ether to afford l-[(3-nitrophenyl)-phenyl-methyl]sulfonylpiperidin-4-one (A-30, 1.5 g, 4.01 mmol, 84% yield) as an off-white solid. LCMS (ESI): m / z 373.0 [M - H]'. ’H NMR (400 MHz, DMSO-A): <5 8.49 (t, J = 4 Hz, 1H), 8.24 (m, 1H), 8.07 (d, J = 7.6 Hz, 1H), 7.66-7.60 (m, 3H), 7.49-7.44 (m, 3H), 5.45 (s, 1H), 3.50-3.40 (m, 2H), 3.32-3.31 (m, 2H), 2.45-2.29 (m, 4H). Step 4:     tert-butyl 4-chloro-3-(2-ethoxy-2-oxo-ethoxy)-5-[3-[[l-[(3-nitrophenyl)-phenyl- methyl] sulfonyl-4-piperidyl] amino] phenyl] thiophene-2-carboxylate (A-31) tert-butyl 4-chloro-3-(2-ethoxy-2-oxo-ethoxy)-5-[3-[[l-[(3-nitrophenyl)-phenyl-methyl]sulfonyl-4-piperidyl]amino]phenyl]thiophene-2-carboxylate (A-31,600 mg, 778.91 pmol, 58% yield) was synthesized from l-[(3-nitrophenyl)-phenyl-methyl]sulfonylpiperidin-4-one (A-30) and tert-butyl 5-(3-aminophenyl)-4-chloro-3-(2-ethoxy-2-oxo-ethoxy)thiophene-2-carboxylate (A-5) in a similar fashion to Compound A-23, except using 10 eq. MP-cyanoborohydride. 'H NMR (400 MHz, DMSO-ds): <5 8.49 (s, 1H), 8.23 (m, 1H), 8.09 (d, J= 8 Hz, 1H), 7.67 (d, J= 7.6 Hz, 2H), 7.61 (t, J= 16 Hz, 1H), 7.51-7.45 (m, 3H), 7.23 (t, J = 16 Hz, 1H), 6.98 (d, J= 7.6 Hz, 1H), 6.83 (s, 1H), 6.59 (dd, J= 8,1.2 Hz, 1H), 5.41 (s, 1H), 4.90 (s, 2H), 4.31 (q, J= 21.2 Hz, 2H), 3.65-3.49 (tn, 3H), 3.46-3.35 (m, 3H), 2.87 (tn, 1H), 2.50 (m, 1H), 2.11-1.91 (m, 2H), 1.38-1.30 (m, 12H). Step 5: 2-[[2-tert-butoxycarbonyl-4-chloro-5-[3-[[l-[(3-nitrophenyl)-phenyl-methyl]sulfonyl-4-piperidyl]amino]phenyl]-3-thienyl]oxy]acetic acid (A-32) 2-[ [2-ZerZ-butoxy carbonyl-4-chloro-5 -[3 - [[ 1 -[(3 -nitrophenyl)-phenyl-methyl] sulfonyl-4 -piperidyl]amino]phenyl]-3-thienyl]oxy]acetic acid (A-32, 400 mg, 0.490 mmol, crude) was synthesized from ZerZ-butyl 4-chloro-3-(2-ethoxy-2-oxo-ethoxy)-5-[3-[[l-[(3-nitrophenyl)-phenyl-methyl]sulfonyl-4-piperidyl]amino]phenyl]thiophene-2-carboxylate (A-31) in a similar fashion to Compound A-9, except using 2 eq. LiOH monohydrate. Upon completion, the aqueous layer was acidified with 1.5 N HC1, diluted with water and extracted with Ethyl acetate. Organic layer was separated, and aqueous layer was extracted with Ethyl acetate (2 x). Organic layers were combined and washed with brine, dried over anhydrous Sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue triturated with diethyl ether (2 x). The material was taken to the next step without further purification. LCMS (ESI): m / z 740.0 [M-H]-. 'H NMR (400 MHz, DMSO-^): 3 8.57 (s, 1H), 8.25-8.16 (m, 2H), 7.77-7.70 (m, 3H), 7.48-7.39 (m, 3H), 7.21-7.15 (m, 1H), 6.81 (t, J= 20 Hz, 2H), 6.66 (d, J= 10.8 Hz, 1H), 6.25 (s, 1H), 4.84 (s, 2H), 3.17 (s, 2H), 1.82-1.73 (m, 2H), 1.52 (s, 9H), 1.27-1.24 (m, 7H). Step 6:   2- [ [5- [3- [ [1- [(3-aminophenyl)-phenyl-methyl] sulfonyl-4-piperidyl] amino] phenyl] -2-tert- butoxycarbonyl-4-chloro-3-thienyl] oxy] acetic acid (A-33) 2-[[5-[3-[[l-[(3-aminophenyl)-phenyl-methyl]sulfonyl-4-piperidyl]amino]phenyl]-2-ZerZ-butoxycarbonyl-4-chloro-3-thienyl]oxy]acetic acid (A-33, 400 mg, 0.444 mmol, crude) was synthesized from 2-[[2-tert-butoxycarbonyl-4-chloro-5-[3-[[l-[(3-nitrophenyl)-phenyl-methyl]sulfonyl-4-piperidyl]amino]phenyl]-3-thienyl]oxy]acetic acid (A-32) in a similar fashion to Compound A-10, except upon completion the reaction mixture was filtered through Celite, washing with methanol and the filtrate was evaporated under reduced pressure. The residue was triturated with diethyl ether and the material was used in the next step without further purification. LCMS (ESI): m / z 712.1 [M+H]+. 'H NMR (400 MHz, DMSO-A): 3 7.67 (d, J = 9.6 Hz, 2H), 7.00 (m, 4H), 7.19-7.14 (m, 1H), 7.04-6.78 (m, 5H), 6.58 (m, 2H), 5.79 (d, J= 10 Hz, 1H), 5.60 (s, 1H), 5.18 (s, 2H), 5.18 (s, 2H), 3.52-3.49 (m, 2H), 2.73-2.62 (m, 3H), 1.82-1.78 (m, 4H), 1.36 (s, 9H). Step 7:      5-|3-[|l-|(3-aminophenyl)-phenyl-methyl|sulfonyl-4-piperidyl|amino|phenyl|-3- (carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-34) 5 - [3 - [[ 1 - [(3 -aminophenyl)-phenyl-methyl] sulfonyl-4-piperidyl]amino]phenyl]-3 -(carboxymethoxy )-4-chloro-thiophene-2-carboxylic acid (A-34, 200 mg, 294.74 pmol, 52% yield) was synthesized from 2-[[5-[3-[[l-[(3-aminophenyl)-phenyl-methyl]sulfonyl-4-piperidyl]amino]phenyl]-2-ZerZ-butoxycarbonyl-4-chloro-3-thienyl]oxy]acetic acid (A-33) in a similar fashion to Compound A-26, except using 30 eq. TFA. The product was purified by reverse phase chromatography. LCMS (ESI): m / z 655 [M - H]’. 'H NMR (400 MHz, DMSO-<4): 3 7.69 (d, J= 9.20 Hz, 2H), 7.46-7.34 (m, 6H), 7.19 (t, J= 20.8 Hz, 1H), 7.07 (d, J= 9.2 Hz, 1H), 6.82 (t, J= 18 Hz, 2H), 6.67 (d, J= 10.8 Hz, 1H), 5.90 (s, 1H), 4.93 (s, 2H), 3.51 (s, 2H), 3.27 (m, 2H), 2.73-2.57 (m, 4H), 2.08 (s, 2H), 1.82-1.78 (m, 2H), 1.18-1.16 (m, 2H). 5-(3-((1-((3-Aminobenzyl)sulfonyl)piperidin-4-yl)oxy)phenyl)-3-(carboxymethoxy)-4-chlorothiophene-2-carboxylic acid (A-43) 5                                     A-43 Step 1: tert-butyl 4-chloro-3-(2-ethoxy-2-oxo-ethoxy)-5-(3-hydroxyphenyl)thiophene-2-carboxylate (A-36) tert-butyl 4-chloro-3-(2-ethoxy-2-oxo-ethoxy)-5-(3-hydroxyphenyl)thiophene-2-carboxylate (A-36, 1.4 g, 2.71 mmol, 60% yield) was prepared from tert-butyl 4,5-dichloro-3-(2-ethoxy-2-oxo-ethoxy)thiophene-2-10 carboxylate (A-4) and (3-hydroxyphenyl)boronic acid (A-35) in a similar fashion to Compound A-5, except using 1.5 eq. A-35. LCMS (ESI): m / z 411.0 [M - H]“. Step 2:      tert-butyl 4-[3-[5-tert-butoxycarbonyl-3-chloro-4-(2-ethoxy-2-oxo-ethoxy)-2- thienyl]phenoxy]piperidine-l-carboxylate (A-38) Into a 50 mL single neck round bottom flask containing a well-stirred solution of tert-butyl 4-chloro-3-(2-15 ethoxy-2-oxo-ethoxy)-5-(3-hydroxyphenyl)thiophene-2-carboxylate (A-36, 1.4 g, 3.39 mmol) and tertbutyl 4-hydroxypiperidine-l-carboxylate (A-37, 2.05 g, 10.17 mmol) in anhydrous toluene (15 mL) were added triphenylphosphine (2.67 g, 10.17 mmol) and diethylazodicarboxylate (1.77 g, 10.17 mmol). After 16 h, the solvent was removed under reduced pressure and the residue purified by silica gel flash column (50 g-Biotage column, prepacked with 230-400 silica gel using Isolera), eluting with 0-100% Ethyl acetate / pet ether to afford Zert-butyl 4-[3-[5-ZerZ-butoxycarbonyl-3-chloro-4-(2-ethoxy-2-oxo-ethoxy)-2-thienyl]phenoxy]piperidine-l-carboxylate (A-38, 1.2 g, 1.88 mmol, 56% yield) as a pale-yellow solid. LCMS (ESI): m / z 484.0 [M - 2 tBu + H]+. 'H NMR (400 MHz, DMSO-A): J 7.39-7.35 (m, 1H), 7.25 (d, J= 2.0 Hz, 2H), 6.98 (dd, J= 8.0,1.6 Hz, 1H), 4.92 (s, 2H), 4.57-4.51 (m, 2H), 4.33-4.28 (m, 1H), 3.763.70 (m, 2H), 3.42-3.35 (m, 2H), 1.98-1.95 (m, 2H), 1.84-1.78 (m, 2H), 1.58 (s, 9H), 1.48 (s, 9H), 1.33 (t, .7= 7.2 Hz, 3H). Step 3: tert-butyl 4-chloro-3-(2-ethoxy-2-oxo-ethoxy)-5-[3-(4-piperidyloxy)phenyl]thiophene-2-carboxylate (A-39) Into a 50 mL single neck round bottom flask containing a well-stirred solution of ZerZ-butyl 4-[3-[5-Zert-butoxycarbonyl-3-chloro-4-(2-ethoxy-2-oxo-ethoxy)-2-thienyl]phenoxy]piperidine-l-carboxylate (A-38, 1.2 g, 2.01 mmol) in ethanol (10 mL) was added hydrogen chloride (IM in Ethyl acetate) (8.00 g, 219.41 mmol, 10 mL) at 0 °C. The resulting mixture was stirred at room temperature for 5 h. The crude reaction mixture was concentrated and azeotroped with toluene (2 x 20 mL). The residue was triturated with diethyl ether (10 mL) to afford ZerZ-butyl 4-chloro-3-(2-ethoxy-2-oxo-ethoxy)-5-[3-(4-piperidyloxy)phenyl]thiophene-2-carboxylate (A-39, 800 mg, 1.38 mmol, 69% yield, HC1 salt) as an off-white solid. LCMS (ESI): m / z 495.9 [M + H]+. ’H NMR (400 MHz, DMSO-^): 5 8.51 (d, J= 9.6 Hz, 2H), 7.49-7.46 (m, 1H), 7.29-7.27 (m, 2H), 7.16 (d, J= 11.2 Hz, 1H), 4.95 (s, 2H), 4.75-4.73 (m, 2H), 4.22-4.14 (m, 5H), 3.14-3.12 (m, 4H), 1.52 (s, 9H), 1.22 (t, J= 18.4 Hz, 3H). Step 4: tert-butyl 4-chloro-3-(2-ethoxy-2-oxo-ethoxy)-5-[3-[[l-[(3-nitrophenyl)methylsulfonyl]-4-piperidyl]oxy]phenyl]thiophene-2-carboxylate (A-40) Zert-butyl               4-chloro-3-(2-ethoxy-2-oxo-ethoxy)-5-[3-[[l-[(3-nitrophenyl)methylsulfonyl]-4- piperidyl]oxy]phenyl]thiophene-2-carboxylate (A-40, 600 mg, 0.7336 mmol, 49% yield) was synthesized from ZerZ-butyl 4-chloro-3-(2-ethoxy-2-oxo-ethoxy)-5-[3-(4-piperidyloxy)phenyl]thiophene-2-carboxylate hydrochloride (A-39) and (3-nitrophenyl)methane sulfonyl chloride (A-7a) in a similar fashion to Compound A-8, except using 1.5 eq. A-39. LCMS (ESI): 638.08 m / z [M - tBu + H]+. Step 5:        2- [ [5- [3 - [ [ 1 - [(3-aminophenyl)m ethylsulfonyl] -4-piperidyl] oxy] phenyl] -2-tert- butoxycarbonyl-4-chloro-3-thienyl] oxy] acetic acid (A-41) Into a 50 mL single neck round bottom flask containing a well-stirred solution of Zert-butyl 4-chloro-3-(2-ethoxy-2-oxo-ethoxy)-5-[3-[[l-[(3-nitrophenyl)methylsulfonyl]-4-piperidyl]oxy]phenyl]thiophene-2-carboxylate (A-40, 600 mg, 0.89935 mmol) in a mixture of tetrahydrofuran and water (1:1) (12 mL) was added LiOH (64.61 mg, 2.70 mmol). The resulting mixture was stirred for 3 h. The reaction mixture was cooled to 10 °C, acidified with 0.5 M aqueous HC1 and the aqueous phase extracted with ethyl acetate (2 x 50 mL). The organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was washed with ethyl acetate to afford 2-[[5-[3-[[l-[(3-aminophenyl)methylsulfonyl]-4-piperidyl]oxy]phenyl]-2-Zert-butoxycarbonyl-4-chloro-3-thienyl]oxy]acetic acid (A-41, 350 mg, 0.54 mmol, 60% yield) as an off-white solid. The material was used in the next step without further purification. LCMS (ESI): m / z 665.0 [M - H]“. 'H NMR (400 MHz, DMSO- d6): 3 8.33 (s, 1H), 8.24-8.23 (m, 1H), 7.90-7.88 (m, 1H), 7.71 (tn, 1H), 7.45-7.40 (m, 1H), 7.23 (tn, 2H), 7.08 (m, 1H), 4.69-4.67 (m, 3H), 4.37 (s, 2H), 3.22 (m, 4H), 1.98-1.97 (m, 4H), 1.50 (s, 9H). Step        6:        2- [ [5- [3- [[ 1- [(3-aminophenyl)m ethylsulfonyl] -4-piperidyl] oxy] phenyl] -2-tert- butoxycar bonyl-4-chloro-3-thienyl | oxy | acetic acid (A-42) 2-[[5-[3-[[l-[(3-aminophenyl)methylsulfonyl]-4-piperidyl]oxy]phenyl]-2-tert-butoxycarbonyl-4-chloro-3-thienyl]oxy]acetic acid (A-42, 150 mg, 0.219 mmol, 42% yield) was synthesized from 2-[[2-tert-butoxycarbonyl-4-chloro-5- [3- [ [ 1 - [(3 -nitrophenyl)methylsulfonyl] -4-piperidyl]oxy]phenyl] -3 - thienyl]oxy]acetic acid (A-41) in a similar fashion to Compound A-10, except using 3 eq. Zinc. Upon completion, the reaction mixture was concentrated, and the residue purified by reverse phase column chromatography. LCMS (ESI): m / z 635.0 [M - H]’. Step 7: 5- [3- [ [1- [(3-aminophenyl)methylsulfonyl] -4-piperidyl] oxy] phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-43) 5-[3 - [[ 1 - [(3 -aminophenyl)methy lsulfonyl]-4-piperidyl] oxy]phenyl] -3 -(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-43, 80 mg, crude) was prepared from 2-[[5-[3-[[l-[(3-aminophenyl)methylsulfonyl]-4-piperidyl]oxy]phenyl]-2-tert-butoxycarbonyl-4-chloro-3- thienyl]oxy]acetic acid (A-42) in a similar fashion to Compound A-26, except using 20 eq. TFA. LCMS (ESI): m / z 581.0 [M + H]+. 2-((5-(3-(A-(l-((3-Aminobenzyl)sulfonyl)piperidin-4-yl)benzamido)phenyl)-2-(tert-butoxycarbonyl)-4-chlorothiophen-3-yl)oxy)acetic acid (A-46) Step 1: tert-butyl 5-[3-[benzoyl-[l-[(3-nitrophenyl)methylsulfonyl]-4-piperidyl]amino]phenyl]-4-chloro-3-(2-ethoxy-2-oxo-ethoxy)thiophene-2-carboxylate (A-44) Into a 25 mL single neck round bottom flask containing a well-stirred solution of tert-butyl 4-chloro-3-(2-ethoxy-2-oxo-ethoxy)-5-[3-[[l-[(3-nitrophenyl)methylsulfonyl]-4-piperidyl]amino]phenyl]thiophene-2-carboxylate (A-8, 220 mg, 316.91 pmol) in anhydrous dichloromethane (10 mL) were added benzoyl chloride (44.55 mg, 316.91 pmol) and triethylamine (32.07 mg, 316.91 pmol, 44.17 pL). After 4 h the reaction mixture was concentrated under reduced pressure and the residue purified by Isolera (230-400 mesh silica-gel column), eluting with 30-40% Ethyl acetate / petroleum ether to afford tert-butyl 5-[3-[benzoyl-[l-[(3-nitrophenyl)methylsulfonyl]-4-piperidyl]amino]phenyl]-4-chloro-3-(2-ethoxy-2-oxo- ethoxy)thiophene-2-carboxylate (A-44, 270 mg, 43.97 pmol, 14% yield) as a yellow foam. LCMS (ESI): m / z 798.32 [M + H]+. Step 2: 2-((2-(tert-butoxycarbonyl)-4-chloro-5-(3-(N-(l-((3-nitrobenzyl)sulfonyl)piperidin-4-yl)benzamido)phenyl)thiophen-3-yl)oxy)acetic acid (A-45) 2-((2-(tert-butoxycarbonyl)-4-chloro-5-(3-(N-(l-((3-nitrobenzyl)sulfonyl)piperidin-4-yl)benzamido)phenyl)thiophen-3-yl)oxy)acetic acid (A-45,0.266 g, crude) was synthesized from tert-butyl 5-[3-[benzoyl-[l-[(3-nitrophenyl)methylsulfonyl]-4-piperidyl]amino]phenyl]-4-chloro-3-(2-ethoxy-2-oxo-ethoxy)thiophene-2-carboxylate (A-44) in a similar fashion to Compound A-9 except using one eq. LiOH monohydrate. Upon completion, the reaction mixture was concentrated under reduced pressure. The aqueous layer was acidified with 1.5 N HC1 and diluted with Ethyl acetate and water. The layers were separated, and the aqueous layer extracted with Ethyl acetate (2 x). Combined organic phases were washed with brine and dried over anhydrous Sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The material was used in the next step without purification. LCMS (ESI): m / z 770.27 [M + H]+. Step 3:     2-((5-(3-(7V-(l-((3-Aminobenzyl)sulfonyl)piperidin-4-yl)benzamido)phenyl)-2-( / ert- butoxycarbonyl)-4-chlorothiophen-3-yl)oxy)acetic acid (A-46) Into a 50 mL single neck round bottom flask containing a well-stirred solution of 2-((2-(tert-butoxycarbonyl)-4-chloro-5-(3-(N-(l-((3-nitrobenzyl)sulfonyl)piperidin-4-yl)benzamido)phenyl)thiophen-3-yl)oxy)acetic acid (A-45, 266.77 mg, 346.34 pmol) in a mixture of methanol and tetrahydrofuran (1:1) (6 mL) was added Zinc dust (50.40 mg, 770.73 pmol). The reaction mixture was cooled to 0 °C and acetic acid (20.80 mg, 346.34 pmol, 19.81 pL) was added. The reaction mixture was stirred at rt for 3 h. The reaction mixture was filtered through Celite, washing with methanol. The filtrate was evaporated under reduced pressure at 35 °C and the residue purified by reverse phase chromatography on a SunFire Cis column (19x150 mm; with solvent A: 0.1 % formic acid in water and solvent B: acetonitrile; Flow rate: 15 mL / min; RT = 15.08 min to obtain 2-((5-(3-( / V-( 1-((3-Aminobenzyl)sulfonyl)piperidin-4-yl)benzamido)phenyl)-2-( / er / -butoxycarbonyl)-4-chlorothiophen-3-yl)oxy)acetic acid (A-46,170 mg, 195.20 pmol, 56% yield) as a pale yellow foam. LCMS (ESI): m / z 740.28 [M + H]+. 2-((5-(3-( / V-(l-((3-Aminobenzyl)sulfonyl)-2,2-dimethylpiperidin-4-yl)benzamido)phenyl)-2-(tert-butoxycarbonyl)-4-chlorothiophen-3-yl)oxy)acetic acid (A-50) Step 1:      tert-butyl 5-[3-[benzoyl-[2,2-dimethyl-l-[(3-nitrophenyl)methylsulfonyl]-4- piperidyl]amino]phenyl]-4-chloro-3-(2-ethoxy-2-oxo-ethoxy)thiophene-2-carboxylate (A-48) Into a 25 mL single neck round bottom flask containing a well-stirred solution of tert-butyl 4-chloro-5-[3-[[2,2-dimethyl-l-[(3-nitrophenyl)methylsulfonyl]-4-piperidyl]amino]phenyl]-3-(2-ethoxy-2-oxo- ethoxy)thiophene-2-carboxylate (A-17, 300 mg, 315.80 pmol) in dichloromethane (3 mL) were added triethylamine (95.87 mg, 947.39 pmol, 132.05 pL) and benzoyl chloride (A-47,66.59 mg, 473.70 pmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (2x10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica-gel column (100-200 mesh) to afford tert-butyl 5-[3-[benzoyl-[2,2-dimethyl-l-[(3-nitrophenyl)methylsulfonyl]-4-piperidyl]amino]phenyl]-4-chloro-3-(2-ethoxy-2-oxo-ethoxy)thiophene-2-carboxylate (A-48, 240 mg, 244.42 pmol, 77% yield) as a brown gummy liquid. LCMS (ESI): m / z 826.1 [M + H]+. Step            2:             2-[[5-[3-[benzoyI-[2,2-dimethyl-l-[(3-nitrophenyl)methylsulfonyl]-4- piperidyl]amino]phenyl]-2-tert-butoxycarbonyl-4-chloro-3-thienyl]oxy]acetic acid (A-49) 2-[[5-[3-[benzoyl-[2,2-dimethyl-l-[(3-nitrophenyl)methylsulfonyl]-4-piperidyl]amino]phenyl]-2-tert-butoxycarbonyl-4-chloro-3-thienyl]oxy]acetic acid (A-49, 150 mg, crude) was synthesized from tert-butyl 5-[3-[benzoyl-[2,2-dimethyl-l-[(3-nitrophenyl)methylsulfonyl]-4-piperidyl]amino]phenyl]-4-chloro-3-(2-ethoxy-2-oxo-ethoxy)thiophene-2-carboxylate (A-48) in a similar fashion to Compound A-9, except a 1:1 ratio of water / THF was used, and upon completion the reaction mixture was diluted with water and extracted with ethyl acetate (2 x). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was washed with pentane. The material was used in the next step without further purification. LCMS (ESI): m / z 796.0 [M + H]+. Step 3: 2-((5-(3-( / V-(l-((3-Aminobenzyl)sulfonyl)-2,2-dimethylpiperidin-4-yl)benzamido)phenyl)-2-(tert-butoxycarbonyl)-4-chlorothiophen-3-yl)oxy)acetic acid (A-50) 2-((5-(3 -( / V-( 1-((3 -Aminobenzy l)sulfony 1)-2,2-dimethylpiperidin-4-yl)benzamido)phenyl)-2-(tert-butoxycarbonyl)-4-chlorothiophen-3-yl)oxy)acetic acid (A-50, 80 mg, 102.57 pmol, 68% yield) was synthesized from 2-[[5-[3-[benzoyl-[2,2-dimethyl-l-[(3-nitrophenyl)methylsulfonyl]-4- piperidyl]amino]phenyl]-2-ZerZ-butoxycarbonyl-4-chloro-3-thienyl]oxy]acetic acid (A-49) in a similar fashion to Compound A-10, except using 10 eq. Zinc powder and 5 eq. Acetic acid. Upon completion, the reaction mixture was filtered through Celite, washing with methanol. The solvent was removed, and the residue purified by reverse phase chromatography. LCMS (ESI): m / z 766.1 [M - H]’. 'H NMR (400 MHz, DMSO-rfs): ^7.52 - 7.47 (m, 2H), 7.37 (s, 1H), 7.29 - 7.19 (m, 6H), 6.59 - 6.57 (m, 1H), 6.52 (s, 1H), 6.37 (d, J= 8.04 Hz, 1H), 6.26 (d, J= 7.24 Hz, 1H), 4.84 (s, 2H), 4.19 - 4.01 (m, 3H), 3.61-3.59 (m, 1H), 3.34 - 3.32 (m, 2H), 1.78 - 1.75 (m, 3H), 1.52 (s, 9H), 1.47 - 1.37 (m, 7H), 1.19 - 1.16 (t, J= 1A2 Hz, 1H). 2-((5-(3-( / V-(l-((3-Aminobenzyl)sulfonyl)piperidin-4-yl)isobutyramido)phenyl)-2-( / er / -butoxycarbonyl)-4-chlorothiophen-3-yl)oxy)acetic acid (A-54) o Step        1:         / ert-butyl-4-chloro-3-(2-ethoxy-2-oxo-ethoxy)-5-[3-[2-methylpropanoyl-[l-[(3- nitrophenyl)methylsulfonyl]-4-piperidyl]amino]phenyl]thiophene-2-carboxylate (A-52) ZerZ-butyl-4-chloro-3-(2-ethoxy-2-oxo-ethoxy)-5-[3-[2-methylpropanoyl-[l-[(3-nitrophenyl)methylsulfonyl]-4-piperidyl]amino]phenyl]thiophene-2-carboxylate (A-52, 240 mg, 159.02 pmol, 32% yield) was synthesized from ZerZ-butyl-4-chloro-3-(2-ethoxy-2-oxo-ethoxy)-5-[3-[[l-[(3-nitrophenyl)methylsulfonyl]-4-piperidyl]amino]phenyl]thiophene-2-carboxylate (A-17) and isobutyryl chloride (A-51) in a similar fashion to Compound A-48. LCMS (ESI): m / z 708 [M - tBu + H]+. Step             2:             2- [ [2-tert-butoxycar bonyl-4-chloro-5- [3- [2-methylpropanoyl- [1-((3- nitrophenyl)methylsulfonyl]-4-piperidyl] amino]phenyl]-3-thienyl] oxy] acetic acid (A-53) 2-[[2-ZerZ-butoxycarbonyl-4-chloro-5-[3-[2-methylpropanoyl-[l-[(3-nitrophenyl)methylsulfonyl]-4-piperidyl]amino]phenyl]-3-thienyl]oxy]acetic acid (A-53,180 mg, crude) was synthesized from ZerZ-butyl-4-chloro-3-(2-ethoxy-2-oxo-ethoxy)-5-[3-[2-methylpropanoyl-[l-[(3-nitrophenyl)methylsulfonyl]-4-piperidyl]amino]phenyl]thiophene-2-carboxylate (A-52) in a similar fashion to Compound A-9, except upon completion water was added and the resulting solution was acidified with 1.5 N HC1 and the aqueous phase was extracted with Ethyl acetate. The organic layers were dried over anhydrous Sodium sulfate, filtered and concentrated under reduced pressure. The material was used in the next step without purification. LCMS (ESI): m / z 734 [M - H]’. Step 3: 2-((5-(3-( / V-(l-((3-Aminobenzyl)sulfonyl)piperidin-4-yl)isobutyramido)phenyl)-2-(tert-butoxycarbonyl)-4-chlorothiophen-3-yl)oxy)acetic acid (A-54) 2-((5-(3-(N-( 1-((3 - Aminobenzyl)sulfonyl)piperidin-4-yl)isobutyramido)pheny 1)-2-( tert-butoxycarbony 1)-4-chlorothiophen-3-yl)oxy)acetic acid (A-54, 100 mg, 112.11 pmol, 46% yield) was synthesized from 2-[[2-tert-butoxycarbonyl-4-chloro-5-[3-[2-methylpropanoyl-[l-[(3-nitrophenyl)methylsulfonyl]-4-piperidyl]amino]phenyl]-3-thienyl]oxy]acetic acid (A-53) in a similar fashion to Compound A-10, except using 5 eq. Zinc and 4 eq. Acetic acid. Upon completion, the reaction mixture was filtered through Celite and the solvent evaporated under reduced pressure. The residue was purified by reverse phase chromatography. LCMS (ESI): m / z 706 [M + H]+. 'H NMR (400 MHz, DMSO-A): 3 7.76-7.71 (m, 1H), 7.69-7.62 (m, 1H), 7.54 (s, 1H), 7.42-7.35 (m, 1H), 7.11-6.93 (m, 1H), 6.72-6.63 (m, 3H), 4.85 (s, 2H), 4.52-4.48 (m, 2H), 4.21 (s, 2H), 3.56-3.53 (m, 4H), 2.80 (t, J= 11.6 Hz, 4H), 1.52 (s, 9H), 0.92 (bs, 6H). 2- [ [5-[3- [ [1- |(3-aminophenyl)methylsulfonyl| -4-piperidyl] -methyl-amino] phenyl] -2-tert- butoxycarbonyl-4-chloro-3-thienyl] oxy] acetic acid (A-59) Step 1 A-6                                                  A-55 A-58 Zn, AcOH THF, MeOH rt,1 h Step 5 A-59 Step 1: tert-butyl 4-[3-[5-tert-butoxycarbonyl-3-chloro-4-(2-ethoxy-2-oxo-ethoxy)-2-thienyl]-N-methyl-anilino] piperidine-l-carboxylate (A-55) Into a 100 mL single neck round bottom flask containing a well-stirred solution of tert-butyl 4-[3-[5-tert-butoxycarbonyl-3-chloro-4-(2-ethoxy-2-oxo-ethoxy)-2-thienyl]anilino]piperidine-l-carboxylate (A-6,600 mg, 1.01 mmol) in 1,2-dichloroethane (25 mL)was added formaldehyde solution (37 wt. % in water) (60.54 mg, 2.02 mmol) followed by tetramethylammonium triacetoxyborohydride (397.86 mg, 1.51 mmol). The reaction mixture was stirred at room temperature for 6 h. The mixture was diluted with water (25 mL) and extracted with ethyl acetate (2 x 50 mL), the combined organic layer was washed with brine (25 mL) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue purified by flash silica gel (230-400 mesh) column chromatography (15-20% of Ethyl acetate in petroleum ether) to afford tert-butyl 4-[3-[5-tert-butoxycarbonyl-3-chloro-4-(2-ethoxy-2-oxo-ethoxy)- 2-thienyl]-N-methyl-anilino] piperidine-1-carboxylate (A-55,500 mg, 738.71 pmol, 73% yield) as a yellow solid. LCMS (ES+): m / z 497.1 [M - 2 tBu + H]+. Step                2:                tert- butyl-4-chloro-3-(2-ethoxy-2-oxo-ethoxy)-5- [3- [methyl(4- piperidyl)am ino] phenyl] thiophene-2-carboxylate (A-56) Into a 100 mL round bottom flask containing a well-stirred solution of ZerZ-butyl 4-[3-[5-tert-butoxycarbonyl-3-chloro-4-(2-ethoxy-2-oxo-ethoxy)-2-thienyl]-N-methyl-anilino]piperidine-l-carboxylate (A-55, 0.500 g, 820.79 pmol) in ethanol (2 mL) was added IM HC1 in Ethyl acetate (820.79 pmol) dropwise at 0 °C. The reaction mixture was stirred for 3 h at room temperature. The volatiles were removed under reduced pressure and the residue triturated with diethyl ether, filtered and concentrated under reduced pressure to afford ZerZ-butyl 4-chloro-3-(2-ethoxy-2-oxo-ethoxy)-5-[3-[methyl(4-piperidyl)amino]phenyl]thiophene-2-carboxylate (A-56, 0.400 g, 593.93 pmol, 72% yield, HC1 salt) as a yellow solid. The material was used in the next step without further purification. LCMS (ES+): m / z 509.2 [M + H]+. Step         3:         tert- butyl         4-chloro-3-(2-ethoxy-2-oxo-ethoxy)-5-[3-[methyl-[l-[(3- nitrophenyl)methylsulfonyl]-4-piperidyl]amino]phenyl]thiophene-2-carboxylate (A-57) Into a 100 mL round bottom flask containing a well-stirred solution of ZerZ-butyl 4-chloro-3-(2-ethoxy-2-oxo-ethoxy)-5-[3-[methyl(4-piperidyl)amino]phenyl]thiophene-2-carboxylate (A-56, 0.400 g, 733.25 pmol) in dichloromethane (5 mL) was added an aqueous solution (10%) of sodium bicarbonate (20 mL). The reaction mixture was cooled to 0 °C. Then, (3-nitrophenyl)methanesulfonyl chloride (A-7a, 172.79 mg, 733.25 pmol) was added. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was extracted with DCM (2 x 100 mL). The organic layer was washed with water (75 mL) and brine (25 mL) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue purified by flash silica gel (230-400 mesh) column chromatography (25-30% of Ethyl acetate in petroleum ether) to afford ZerZ-butyl 4-chloro-3-(2-ethoxy-2-oxo-ethoxy)-5-[3-[methyl-[l-[(3-nitrophenyl)methylsulfonyl]-4-piperidyl]amino]phenyl]thiophene-2-carboxylate (A-57, 0.480 g, 521.86 pmol, 71% yield) as a yellow solid. LCMS (ES+): m / z 709.1 [M + H]+. Step 4: 2-||2-ZerZ-butoxycarbonyl-4-chloro-5-[3-[methyl-|l-[(3-nitrophenyl)methylsulfonyl|-4-piperidyl]amino]phenyl]-3-thienyl]oxy]acetic acid (A-58) 2-[ [2-ZerZ-butoxy carbonyl-4-chloro-5 -[3 - [methyl- [ 1 -[(3 -nitrophenyl)methylsulfonyl]-4-piperidyl]amino]phenyl]-3-thienyl]oxy]acetic acid (A-58, 400 mg, 317.56 pmol, 47% yield) was synthesized from ZerZ-butyl 4-chloro-3-(2-ethoxy-2-oxo-ethoxy)-5-[3-[methyl-[l-[(3-nitrophenyl)methylsulfonyl]-4-piperidyl]amino]phenyl]thiophene-2-carboxylate (A-57) in a similar fashion to Compound A-9, except using 1 eq. LiOH monohydrate. Upon completion, the reaction was acidified with 1.5 N HC1 in water (pH 4-5) and extracted with Ethyl acetate (2 x 50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and solvent removed under reduced pressure. The material was used in the next step without further purification. LCMS (ES+): m / z 680.0 [M + H]+. Step 5:   2-[ [5- [3- [ [1- |(3-aminophenyl)methylsulfonyl| -4-piperidyl] -methyl-amino ] phenyl] -2-tert- butoxycarbonyl-4-chloro-3-thienyl] oxy] acetic acid (A-59) 2-[[5-[3-[[l-[(3-aminophenyl)methylsulfonyl]-4-piperidyl]-methyl-amino]phenyl]-2-Zer / -butoxycarbonyl-4-chloro-3-thienyl]oxy]acetic acid (A-59, 0.250 g, 230.70 pmol, 39% yield, Formic acid salt) was synthesized from 2-[[2-ZerZ-butoxycarbonyl-4-chloro-5-[3-[methyl-[l-[(3-nitrophenyl)methylsulfonyl]-4-piperidyl]amino]phenyl]-3-thienyl]oxy]acetic acid (A-58) in a similar fashion to Compound A-10, except using 5 eq. Acetic acid. LCMS (ES+): m / z 650.2 [M + H]+. 3-(carboxymethoxy)-4-chloro-5-[3-[[(4S)-2,2-dimethyl-l-[[3-(piperidine-4- car bonylamino)phenyl] methylsulfonyl] -4-piperidyl] amino] phenyl] thiophene-2-carboxylic acid (A-62) Step                    1:                    5-[3-[[(4S)-l-[[3-[(l-tert-butoxycarbonylpiperidine-4- carbonyl)amino|phenyl|methylsulfonyl|-2,2-dimethyl-4-piperidyl|amino|phenyl|-3- (carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-61) Into a 25 mL single neck round bottom flask containing a well-stirred solution ofl-ZerZ-butoxycarbonylpiperidine-4-carboxylic acid (A-60, 50 mg, 218.08 pmol) in anhydrous THF (3 mL) and DMF (0.5 mL) was added 1,1'-carbonyldiimidazole (70.72 mg, 436.16 pmol). The reaction mixture was stirred for 2 h. Then, 5-[3-[[(4S)-l-[(3-aminophenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-19a, 66.31 mg, 109.04 pmol) was added. After 16 h, the solvent was removed under reduced pressure and the residue purified by reverse phase prep HPLC [Purification method: C18, Aq gold; Mobile phase A: 0.1% TFA in water; Mobile phase B: MeCN] to afford 5-[3-[[(4S)-l-[[3-[(l-ZerZ-butoxycarbonylpiperidine-4-carbonyl)amino]phenyl]methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-61, 35 mg, 40.99 pmol, 19% yield) as an off-white solid. LCMS (ES+): m / z 819.3 [M + H]+. Step         2:         3-(carboxymethoxy)-4-chloro-5-[3-[[(4S)-2,2-dimethyl-l-[[3-(piperidine-4- carbonylamino)phenyl] methylsulfonyl] -4-piperidyl] amino] phenyl] thiophene-2-carboxylic acid (A-62) Into a 25 mL single neck round bottom flask containing a well-stirred solution of 5-[3-[[(4S)-l-[[3-[(l-tert-5 butoxycarbonylpiperidine-4-carbonyl)amino]phenyl]methylsulfonyl]-2,2-dimethyl-4- piperidyl]amino]phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-61, 30 mg, 36.61 pmol) in anhydrous DCM (2 mL) was added TFA (740.00 mg, 6.49 mmol, 0.5 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The volatiles were removed under reduced pressure and azeotroped with toluene to afford 3-(carboxymethoxy)-4-chloro-5-[3-[[(4S)-2,2-dimethyl-l-[[3-10 (piperidine-4-carbonylamino)phenyl]methylsulfonyl]-4-piperidyl]amino]phenyl]thiophene-2-carboxylic acid (A-62,35 mg, 32.04 pmol, 92% yield, TFA salt) as an off-white solid, which was used in the next step without further purification. LCMS (ES+): m / z 719.2 [M + H]+. 5-[3-||(4S)-l-[[3-(azetidine-3-carbonylamino)phenyl|methylsulfonyl|-2,2-dimethyl-4- piperidyl]amino]phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-65) 15                                                                 HO^0 Step                     1:                     5-[3-[[(4S)-l-[[3-[(l-tert-butoxycarbonylazetidine-3- carbonyl)amino]phenyl]methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-64) 5-[3-[[(4S)-l-[[3-[(l-tert-butoxycarbonylazetidine-3-carbonyl)amino]phenyl]methylsulfonyl]-2,2- 20 dimethyl-4-piperidyl]amino]phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-64, 55 mg, 56.50 pmol, 20% yield, TFA salt) was synthesized from l- / er / -butoxycarbonylazetidine-3-carboxylic acid (A-63) and 5-[3-[[(4S)-l-[(3-aminophenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-19a) in a similar fashion to Compound A-61, except using only THF. LCMS (ESI): m / z 791.3 [M + H]+. 25 Step 2:    5-[3-[[(4S)-l-[[3-(azetidine-3-carbonylamino)phenyl]methylsulfonyl]-2,2-dimethyl-4- piperidyl]amino]phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-65) 5-[3-[[(4S)-l-[[3-(azetidine-3-carbonylamino)phenyl]methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-65, 60 mg, 53.65 pmol, 88% yield, TFA salt) was synthesized from 5-[3-[[(4S)-l-[[3-[(l-tert-butoxycarbonylazetidine-3- carbonyl)amino]phenyl]methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-64) in a similar fashion to Compound A-62 except using 1 eq. TFA. LCMS (ESI): m / z 691.3 [M + H]+. 2-[[2- / er / -butoxycarbonyl-4-chloro-5-[3-||l-|[3-|3-(4-oxo-l- piperidyl)propanoylamino]phenyl]methylsulfonyl]-4-piperidyl]amino]phenyl]-3-thienyl]oxy]acetic acid (A-70) Step 1: ZerZ-butyl 3-(4-oxo-l-piperidyl)propanoate (A-68) Into a 50 mL two neck round bottom flask containing a well-stirred suspension of piperidin-4-one hydrochloride (A-66, 500 mg, 3.69 mmol) inMeCN (10 mL) was added DBU (1.24 g, 8.11 mmol) dropwise over a period of 5 min at 0 °C. After 10 min, tert-butyl prop-2-enoate (A-67, 567.15 mg, 4.43 mmol, 642.30 pL) was added dropwise over a period of 5 min. The resulting mixture was stirred at room temperature for 6 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash silica gel column chromatography (2-5% of MeOH in DCM) to afford tert-butyl 3-(4-oxo-l-piperidyl)propanoate (A-68, 350 mg, 1.35 mmol, 37% yield) as a brown liquid. LCMS (ES+): m / z 228.1 [M + H]+. Step 2: 3-(4-oxopiperidin-l-yl)propanoic acid (A-69) 3-(4-oxo-l-piperidyl)propanoic acid (A-69, 340 mg, 1.09 mmol, 73% yield, TFA salt) was synthesized from tert-butyl 3-(4-oxo-l-piperidyl)propanoate (A-68) in a similar fashion to Compound A-26, except using 20 eq. TFA. Upon completion, the volatiles were removed under reduced pressure to afford the product as a light brown syrup, which was used in the next step without purification. LCMS (ES+): m / z 172.1 [M + H]+. Step                  3:                  2- [ [2-tert-butoxycarbonyl-4-chloro-5- [3-[[l-[[3- [3-(4-oxo-1 - piperidyl)propanoylamino]phenyl]methylsulfonyl]-4-piperidyl]amino]phenyl]-3-thienyl]oxy]acetic acid (A-70) Into a 10 mL single neck round bottom flask containing a well-stirred solution of 3-(4-oxo-l-piperidyl)propanoic acid (A-69,200 mg, 1.17 mmol, TFA salt) in DMF (4 mL) was added DIPEA (754.95 mg, 5.84 mmol, 1.02 mL) followed by 1-propanephosphonic anhydride (50% in ethyl acetate) (748.14 mg, 2.34 mmol). After 30 min, 2-[[5-[3-[[l-[(3-aminophenyl)methylsulfonyl]-4-piperidyl]amino]phenyl]-2- / er / -butoxycarbonyl-4-chloro-3-thienyl]oxy]acetic acid (A-10, 445.94 mg, 700.96 pmol). After 16 h, the solvent was removed under reduced pressure and the residue was subjected to reverse phase preparative HPLC (Column: Zorbax-SB18,21.2 x 150mm; Mobile phase A: 0.1% TFA in water; Mobile phase B: MeCN)         to         afford         2-[[2-tert-butoxycarbonyl-4-chloro-5-[3-[[l-[[3-[3-(4-oxo-l- piperidyl)propanoylamino]phenyl]methylsulfonyl]-4-piperidyl]amino]phenyl]-3-thienyl]oxy]acetic acid (A-70, 80 mg, 73.16 pmol, 6% yield, TFA salt) as an off white solid. LCMS (ES-): m / z 787.1 [M - H]’. Zert-Butyl 5-(3-aminophenyl)-3-(2-(tert-butoxy)-2-oxoethoxy)-4-chlorothiophene-2-carboxylate (A-73) HO I Step 2 Step 1: tert-Butyl 3-(2-(tert-butoxy)-2-oxoethoxy)-4,5-dichlorothiophene-2-carboxylate (A-72) To a solution of 3-(carboxymethoxy)-4,5-dichlorothiophene-2-carboxylic acid (A-71, 1.0 g, 3.0 mmol) in / -BuOH (40 mL) at ambient temperature was added DMAP (0.036 g, 0.30 mmol), pyridine (0.96 mL, 12 mmol) and di-tert-butyl dicarbonate (3.4 mL, 15 mmol) as a solution in t-BuOH (4 mL). The mixture was heated to 50 °C and stirred for 12 h. The mixture was concentrated under reduced pressure and the residue purified by silica gel chromatography eluting with 10:1 petroleum ether:ethyl acetate to afford tert-butyl 3-(2-(tert-butoxy)-2-oxoethoxy)-4,5-dichlorothiophene-2-carboxylate (A-72, 698.2 mg, 1.59 mmol, 53% yield) as yellow oil. LCMS (ES+): m / z 270.6 [M - 2 / Bu + H ]+. Step 2: tert-Butyl 5-(3-aminophenyl)-3-(2-(tert-butoxy)-2-oxoethoxy)-4-chlorothiophene-2-carboxylate (A-73) tert-butyl 5-(3-aminophenyl)-3-(2-(tert-butoxy)-2-oxoethoxy)-4-chlorothiophene-2-carboxylate (A-73) was synthesized from tert-butyl 3-(2-(tert-butoxy)-2-oxoethoxy)-4,5-dichlorothiophene-2-carboxylate (A-72) and 3-aminophenylboronic acid monohydrate (A-4a) in a similar fashion to Compound A-5, except using THF as the solvent. Upon completion, the mixture was diluted with ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether:ethyl acetate = 3:1) to afford tert-butyl 5-(3-aminophenyl)-3-(2-(tert-butoxy)-2-oxoethoxy)-4-chlorothiophene-2-carboxylate (A-73,0.80 g, 1.5 mmol, 77% yield) as light yellow solid. LCMS (ES+): m / z 327.8 [M - 2tBu] , tert-butyl              (J?)-4-((3-(((4-((3-(4-(2-(tert-butoxy)-2-oxoethoxy)-5-(tert-butoxycarbonyl)-3- chlorothiophen-2-yl)phenyl)amino)-2,2-dimethylpiperidin-l- yl)sulfonyl)methyl)phenyl)(methyl)carbamoyl)piperidine-l-carboxylate (A-74a, first eluted fraction) and tert-butyl (>S)-4-((3-(((4-((3-(4-(2-(tert-butoxy)-2-oxoethoxy)-5-(tert-butoxycarbonyl)-3-chlorothiophen-2-yl)phenyl)amino)-2,2-dimethylpiperidin-l- yl)sulfonyl)methyl)phenyl)(methyl)carbamoyl)piperidine-l-carboxylate (A-74b, second eluted fraction) A-74b Step 1: l-[(3-aminophenyl)methylsulfonyl]-2,2-dimethyl-piperidin-4-one (A-74) l-[(3-aminophenyl)methylsulfonyl]-2,2-dimethyl-piperidin-4-one (A-74, 1.8 g, 4.09 mmol, 67% yield)) was synthesized from 2,2-dimethyl-l-[(3-nitrophenyl)methylsulfonyl]piperidin-4-one (A-13) in a similar fashion to Compound A-10 except using 1 eq. Zinc and 1 eq. Acetic acid. Upon completion, the reaction was filtered through Celite washing with THF, DCM and Methanol. The solvent was removed under reduced pressure and residue diluted with ice cold water and stirred for 10 min. Precipitate was filtered and dried under vacuum and the solid triturated with diethyl ether. The material was used in the next step without further purification. LCMS (ES+): m / z 297.1 [M+H]+. Step 2: 2,2-dimethyl-l-((3-(methylamino)benzyl)sulfonyl)piperidin-4-one (A-75) Into a 100 mL sealed tube containing a well-stirred solution of l-[(3-aminophenyl)methylsulfonyl]-2,2-dimethyl-piperidin-4-one (A-74,1.6 g, 5.40 mmol) in anhydrous 1,4-dioxane (20 mL) was added copper(II) acetate (1.18 g, 6.48 mmol) and pyridine (1.28 g, 16.20 mmol, 1.31 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 30 min and cooled to room temperature. Methyl boronic acid (484.72 mg, 8.10 mmol) was added and the resulting mixture stirred at 100 °C for 16 h. The reaction mixture was poured over ice cold water and extracted with Ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous Sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue purified by flash silica gel (100-200 mesh) column chromatography (80% Ethyl acetate in petroleum ether) to afford 2,2-dimethyl-l-((3-(methylamino)benzyl)sulfonyl)piperidin-4-one (A-75, 600 mg, 1.74 mmol, 32% yield) as an off-white solid. rH NMR (400 MHz, DMSO-t / 6): 5 7.07 (t, J= 7.96 Hz, 1H), 6.59-6.50 (m, 3H), 5.72-5.71 (m, 1H), 4.29 (s, 2H), 3.61 (t, J= 6.04 Hz, 2H), 2.67 (d, J= 5.08 Hz, 3H), 2.54 (s, 2H), 2.26 (t, J= 5.96 Hz, 3H), 1.38 (s, 3H), 1.37 (s, 3H). Step                       3:                       tert-butyl4-((3-(((2,2-dimethyl-4-oxopiperidin-l- yl)sulfonyl)methyl)phenyl)(methyl)carbamoyl)piperidine-l-carboxylate (A-76) Into a 50 mL single neck round bottom flask containing a well-stirred solution of 1-tert-butoxycarbonylpiperidine-4-carboxylic acid (A-60, 553.96 mg, 2.42 mmol) in anhydrous DCM (15 mL) was added oxalyl chloride (306.67 mg, 2.42 mmol, 210.05 pL) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The volatiles were removed to obtain the crude acid chloride, which was taken up in DCM (15 mL) and treated with 2,2-dimethyl-l-((3-(methylamino)benzyl)sulfonyl)piperidin-4-one (A-75,500 mg, 1.61 mmol), DIPEA (1.04 g, 8.05 mmol, 1.40 mL) and DMAP (19.68 mg, 161.08 pmol) at 0 °C. After 1 h, the reaction mixture was diluted with DCM (60 mL) and washed with 1.5 N HC1 (2 x 20 mL). The organic layer was dried over anhydrous Sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel (230-400 mesh) column chromatography (3% MeOH in         DCM)         to         afford         tert-butyl4-((3 -(((2,2-dimethyl-4-oxopiperidin-l- yl)sulfonyl)methyl)phenyl)(methyl)carbamoyl)piperidine-l-carboxylate (A-76, 450 mg, 837.17 pmol, 52% yield) as light yellow solid. LCMS (ES+): m / z 422.2 [M - Boe + H]+. Step 4: tert-butyl (J?)-4-((3-(((4-((3-(4-(2-(tert-butoxy)-2-oxoethoxy)-5-(tert-butoxycarbonyl)-3-chlorothiophen-2-yl)phenyl)amino)-2,2-dimethylpiperidin-l- yl)sulfonyl)methyl)phenyl)(methyl)carbamoyl)piperidine-l-carboxylate (A-74a, first eluted fraction) and tert-butyl (S)-4-((3-(((4-((3-(4-(2-(tert-butoxy)-2-oxoethoxy)-5-(tert-butoxycarbonyl)-3-chlorothiophen-2-yl)phenyl)amino)-2,2-dimethylpiperidin-l- yl)sulfonyl)methyl)phenyl)(methyl)carbamoyl)piperidine-l-carboxylate (A-74b, second eluted fraction) Configurations are arbitrarily assigned. Into a 50 mL single neck round bottom flask containing well-stirred solution of tert-butyl4-((3-(((2,2-dimethyl-4-oxopiperidin-l-yl)sulfonyl)methyl)phenyl)(methyl)carbamoyl)piperidine-l-carboxylate (A-76, 450 mg, 862.62 pmol) and tert-butyl 5-(3-aminophenyl)-3-(2-tert-butoxy-2-oxo-ethoxy)-4-chloro-thiophene-2-carboxylate (A-73, 379.51 mg, 862.62 pmol) in anhydrous ethanol (20 mL) were added acetic acid (155.41 mg, 2.59 mmol, 148.01 pL) and MP-cyanoborohydride (800 mg, 1.6 mmol). After 24 h, the reaction mixture was filtered, concentrated under reduced pressure and the residue purified by flash silica gel (230-400 mesh) column chromatography (35% Ethyl acetate in petroleum ether) to obtain tert-butyl 4((3-(((4-((3 -(4-(2-(tert-butoxy)-2-oxoethoxy)-5 -(tert-butoxycarbonyl)-3 -chlorothiophen-2-yl)phenyl)amino)-2,2-dimethylpiperidin-1 -yl)sulfonyl)methyl)phenyl)(methyl)carbamoyl)piperidine-1 -carboxylate (A-74a / b), which was subjected to chiral SFC [Purification method: Column Name : Chiral CCS; Flow rate : 3 mL / min; Co-Solvent : 15%; Co-Solvent Name : 0.5% Isopropyl amine in methanol; Outlet Pressure: 100 bar; Injected Volume : 15 pl; Temperature : 35 °C] to afford tert-butyl (2^)-4-((3-(((4-((3-(4-(2-(tert-butoxy)-2-oxoethoxy)-5-(tert-butoxycarbonyl)-3-chlorothiophen-2-yl)phenyl)amino)-2,2- dimethylpiperidin-1 -yl)sulfonyl)methyl)phenyl)(methyl)carbamoyl)piperidine-1 -carboxylate (A-74a, first eluted fraction, 140 mg, 142.43 pmol, 17% yield) as an off-white solid. LCMS (ES+): m / z 945.3 [M + H]+. and ZerZ-butyl (5)-4-((3-(((4-((3-(4-(2-(tert-butoxy)-2-oxoethoxy)-5-(ZerZ-butoxycarbonyl)-3-chlorothiophen-2-yl)phenyl)amino)-2,2-dimethylpiperidin-l- yl)sulfonyl)methyl)phenyl)(methyl)carbamoyl)piperidine-l-carboxylate (A-74b, second eluted fraction, 120 mg, 109.77 pmol, 13% yield) as an off-white solid. LCMS (ES+): m / z 945.3 [M + H]+. 3-(carboxymethoxy)-4-chloro-5-[3-[[2,2-dimethyl-l-[[3-[methyl-[3-(4-oxo-l- piperidyl)propanoyl] amino] phenyl] methylsulfonyl] -4-piperidyl] amino] phenyl] thiophene-2-carboxylic acid (A-80) Step 1:     3-chloro-N-[3-[(2,2-dimethyl-4-oxo-l-piperidyl)sulfonylmethyl]phenyl]-N-methyl- propanamide (A-77) Into a 50 mL single neck round bottom flask containing well-stirred solution of 2,2-dimethyl-l-[[3-(methylamino)phenyl]methylsulfonyl]piperidin-4-one (A-75b, 300 mg, 966.46 pmol) in anhydrous DCM (15 mL) was added 3-chloropropanoyl chloride (A-76b, 184.07 mg, 1.45 mmol, 138.40 pL). After 3 h, the solvent was removed to afford 3-chloro-N-[3-[(2,2-dimethyl-4-oxo-l-piperidyl)sulfonylmethyl]phenyl]-N-methyl-propanamide (A-77, 310 mg, 607.44 pmol, 63% yield) as a sticky brown solid. This material was used in the next step without purification. LCMS (ES+): m / z 401.2 [M + H]+. Step          2:          tert-butyl          3-(2- / ert-butoxy-2-oxo-ethoxy)-4-chloro-5-[3-[[l-[[3-[3- chloropropanoyl(methyl)amino]phenyl]methylsulfonyl]-2,2-dimethyl-4- piperidyl] am ino] phenyl] thiophene-2-carboxylate (A-78) ZerZ-butyl                                        3-(2-Zert-butoxy-2-oxo-ethoxy)-4-chloro-5-[3-[[l-[[3-[3- chloropropanoyl(methyl)amino]phenyl]methylsulfonyl]-2,2-dimethyl-4- piperidyl]amino]phenyl]thiophene-2-carboxylate (A-78,320 mg, 318.11 pmol, 41% yield) was synthesized from / er / -butyl 5-(3-aminophenyl)-3-(2-tert-butoxy-2-oxo-ethoxy)-4-chloro-thiophene-2-carboxylate (A-73) and 3-chloro-N-[3-[(2,2-dimethyl-4-oxo-l-piperidyl)sulfonylmethyl]phenyl]-N-methyl-propanamide (A-77) in a similar fashion to Compound A-74a / b. LCMS (ES+): m / z 822.0 [M - H]’. Step 3:     tert-butyl 3-(2-tert-butoxy-2-oxo-ethoxy)-4-chloro-5-[3-[[l-[[3-[3-(l,4-dioxa-8- azaspiro [4.5] decan-8-yl)propanoyl-methyl-amino] phenyl] methylsulfonyl]-2,2-dimethyl-4-piperidyl] am ino] phenyl] thiophene-2-carboxylate (A-79) Into a 50 mL sealed tube containing a well-stirred solution of tert-butyl 3-(2-tert-butoxy-2-oxo-ethoxy)-4-chloro-5-[3-[[l-[[3-[3-chloropropanoyl(methyl)amino]phenyl]methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]phenyl]thiophene-2-carboxylate (A-78,   0.6 g, 727.39 pmol), l,4-dioxa-8- azaspiro[4.5]decane (A-20a, 208.30 mg, 1.45 mmol, 185.98 pL) in anhydrous acetonitrile (15 mL) was added CS2CO3 (473.99 mg, 1.45 mmol) at room temperature. The mixture was stirred at 60 °C for 8 h. The reaction mixture was filtered, concentrated under reduced pressure and the residue purified by reverse phase prep HPLC [Purification method: Column: SunFire C18 (19 x 150 mm) 5 pm, mobile phase: 0.1% TFA in water and MeCN] to afford tert-butyl 3-(2-tert-butoxy-2-oxo-ethoxy)-4-chloro-5-[3-[[l-[[3-[3-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)propanoyl-methyl-amino]phenyl]methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]phenyl]thiophene-2-carboxylate (A-79, 350 mg, 334.03 pmol, 46% yield, TFA salt) as off-white solid. LCMS (ES+): m / z 931.4 [M + H]+. Step 4:         3-(carboxym ethoxy)-4-chloro-5- [3- [[2,2-dim ethyl-1- [ [3- [m ethyl- [3-(4-oxo-1- piperidyl)propanoyl] amino] phenyl] methylsulfonyl] -4-piperidyl] amino] phenyl] thiophene-2-carboxylic acid (A-80) Into a 50 mL single neck round bottom flask containing well-stirred solution of tert-butyl 3-(2-tert-butoxy-2-oxo-ethoxy)-4-chloro-5-[3-[[l-[[3-[3-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)propanoyl-methyl-amino]phenyl]methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]phenyl]thiophene-2-carboxylate (A-79, 300 mg, 322.03 pmol) in water (3.00 mL) was added TFA (4.44 g, 38.94 mmol, 3.00 mL) at room temperature. The contents were stirred at 50 °C for 16 h. The solvent was removed to afford 3-(carboxymethoxy)-4-chloro-5-[3-[[2,2-dimethyl-l-[[3-[methyl-[3-(4-oxo-l-piperidyl)propanoyl]amino]phenyl]methylsulfonyl]-4-piperidyl]amino]phenyl]thiophene-2-carboxylic acid (A-80, 300 mg, 182.16 pmol, 57% yield, TFA salt) as light brown sticky solid. The material was used in the next step without purification. LCMS (ES+): m / z 775.4 [M + H]+. 5-[3-[[(4S)-l-[[3-(azetidin-3-yloxycarbonylamino)phenyl]methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-86) A-81                               n°2 A-86 Step 1: tert-butyl 3-(4-nitrophenoxy)carbonyloxyazetidine-l-carboxylate (A-83) Into a 50 mL single neck round bottom flask containing a well-stirred solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (A-81, 1 g, 5.77 mmol) in anhydrous DCM (10 mL) were added triethylamine (1.75 g, 17.32 mmol, 2.41 mL) and 4-nitrophenyl chloroformate (A-82, 1.75 g, 8.66 mmol) at 0 °C under nitrogen atmosphere. The resulting solution was stirred at room temperature for 6 h. The reaction mixture was diluted with water (30 mL) and extracted with DCM (2 x 20 mL). The combined organic layer was washed with brine solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford tert-butyl 3-(4-nitrophenoxy)carbonyloxyazetidine-l-carboxylate (A-83, 500 mg, 1.00 mmol, 17% yield) as a pale yellow colour viscus oil. The material was used in the next step without purification. LCMS (ES+): m / z 239.1 [M - Boc + H]+. Step                     2:                      5-[3-[[(4S)-l-[[3-[(l-tert-butoxycarbonylazetidin-3- yl)oxycarbonylamino]phenyl]methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-85) Into a 10 mL single neck round bottom flask containing a well-stirred solution of 5-[3-[[(4S)-l-[(3-aminophenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-19a, 100 mg, 0.164 mmol) in anhydrous DMF (1 mL) were added tertbutyl 3-(4-nitrophenoxy)carbonyloxyazetidine-l-carboxylate (A-83, 69.54 mg, 0.205 mmol), DIPEA (42.50 mg, 0.328 mmol, 57.28 pL) and HOBt (23.33 mg, 0.172 mmol). After 16 h, the solvent was removed under reduced pressure and the residue was washed with diethyl ether (2x15 mL) and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography [Purification method: Column: XSelect (150 x 19) mm, 5 pm; Mobile phase A: 0.1% TFA in MQ-water; Mobile phase B: Acetonitrile]           to           afford           5-[3-[[(4S)-l-[[3-[(l-tert-butoxycarbonylazetidin-3- yl)oxycarbonylamino]phenyl]methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-85, 15 mg, 0.015 mmol, 9% yield, TFA salt) as an off-white solid. LCMS (ES-): m / z 805.1 [M - H]’. Step 3: 5- [3- [ [(4S)-1- [ [3-(azetidin-3-yloxycar bonylamino)phenyl] methylsulfonyl|-2,2-dim ethyl-4-piperidyl]amino]phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-86) 5-[3-[[(4S)-l-[[3-(azetidin-3-yloxycarbonylamino)phenyl]methylsulfbnyl]-2,2-dimethyl-4- piperidyl]amino]phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-86, 15 mg, 0.016 mmol, 88% yield, TFA salt) was synthesized from 5-[3-[[(4S)-l-[[3-[(l- / erZ-butoxycarbonylazetidin-3-yl)oxycarbonylamino]phenyl]methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-85) in a similar fashion to Compound A-62, except using 10 eq. TFA. LCMS (ES+): m / z 707.1 [M + H]+. 5-[3-[[(4S)-l-[[3-[[(15,5 / ?)-3-azabicyclo[3.1.0|hexane-6-carbonyl|amino|phenyl|methylsulfonyl|-2,2-dimethyl-4-piperidyl]amino]phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-89) A-19a                                                                      A'88 Step 1:        5- [3- [[(4S)-1 -((3-(((15,57?)-3-tert-butoxycarbonyl-3-azabicyclo [3.1.0] hexane-6- carbonyl]amino]phenyl]methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-88) Into a capped vial containing a well-stirred solution of (15,57?)-3- / erZ-butoxycarbonyl-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (A-87, 150.00 mg, 660.05 pmol) in DMF (1 mL) was added DIPEA (426.53 mg, 3.30 mmol, 574.84 pL) followed by 1-propanephosphonic anhydride (50% in ethyl acetate) (273.02 mg, 858.06 pmol, 0.55 mL). After 5 min, 5-[3-[[(4S)-l-[(3-aminophenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-19a, 321.11 mg, 528.04 pmol) was added. After 16 h, the volatiles were removed under reduced pressure, and the residue purified by reverse phase column chromatography (5055% of MeCN in 0.1% TFA in water) to afford 5-[3-[[(4S)-1-((3-((( 15,57?)-3-tert-butoxycarbonyl-3-azabicyclo[3.1.0]hexane-6-carbonyl]amino]phenyl]methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-88, 95 mg, 100.91 pmol, 15% yield, TFA salt) as a pale yellow solid. LCMS (ES+): m / z 817.1 [M + H]+. Step                   2:                   5-|3-|[(4S)-l-[|3-[|(15,5 / ?)-3-azabicyclo|3.1.0|hexane-6- carbonyl|amino|phenyl|methylsulfonyl|-2,2-dimethyl-4-piperidyl|amino|phenyl|-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-89) 5-[3-[[(4S)-l-[[3-[[(lS,57?)-3-azabicyclo[3.1.0]hexane-6-carbonyl]amino]phenyl]methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylicacid (A-89, 80 mg, 93.36 pmol, 97% yield, TFA salt) was synthesized from 5-[3-[[(4S)-l-[[3-[[(15,57?)-3-ZerZ-butoxycarbonyl-3-azabicyclo[3.1.0]hexane-6-carbonyl]amino]phenyl]methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-88) in a similar fashion to Compound A-62, except using 68 eq. TFA and triturating the product with diethyl ether. LCMS (ES+): m / z 717.1 [M + H]+. 5-[3-[[(4S)-l-[[3-[[(3aR,6aS)-l,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-5-carbonyl|amino|phenyl|methylsulfonyl|-2,2-dimethyl-4-piperidyl|amino|phenyl|-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-92) Step 1:       5-[3-[[(4S)-l-[[3-[[(3aR,6aS)-2-tert-butoxycarbonyl-3,3a, 4,5,6,6a-hexahydro-lH- cyclopenta[c]pyrrole-5-carbonyl]amino]phenyl]methylsulfonyl]-2,2-dimethyl-4- piperidyl]amino]phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-91) 5-[3-[[(4S)-l-[[3-[[(3aR,6aS)-2-tert-butoxycarbonyl-3,3a,4,5,6,6a-hexahydro-17 / -cyclopenta[c]pyrrole-5-carbonyl]amino]phenyl]methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-91, 87 mg, 93.19 pmol, 16% yield, formate salt) was synthesized from (3aR,6aS)-2-tert-butoxycarbonyl-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrole-5-carboxylic acid (A-90) and 5-[3-[[(4S)-l-[(3-aminophenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-19a) in a similar fashion to Compound A-88. LCMS (ES+): m / z 846.1 [M + H]+. Step              2:5-[3-[[(4S)-l-[[3-[[(3aR,6aS)-l,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-5- carbonyl|amino|phenyl|methylsulfonyl|-2,2-dimethyl-4-piperidyl|amino|phenyl|-3- (carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-92) 5-[3-[[(4S)-l-[[3-[[(3aR,6aS)-l,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-5- carbonyl]amino]phenyl]methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-92, 87 mg, 91.11 pmol, 90% yield, TFA salt) was synthesized from 5-[3-[[(4S)-l-[[3-[[(3aR,6aS)-2-ZerZ-butoxycarbonyl-3,3a,4,5,6,6a-hexahydro-17 / -cyclopenta[c]pyrrole-5-carbonyl]amino]phenyl]methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]phenyl]-3-(carboxymethoxy)-4- chloro-thiophene-2-carboxylic acid (A-91b) in a similar fashion to Compound A-62, except using 74 eq. TFA and triturating the product with diethyl ether. LCMS (ES+): m / z 745.2 [M + H]+. / erf-butyl        3- [ [5- [ [(4R)-4- [3- [5-tert- butoxy carbonyl-4-(2-tert-butoxy-2-oxo-ethoxy)-3-chloro-2- thienyl|anilino|-2,2-dimethyl-l-piperidyl|sulfonylmethyl|-2-fluoro-phenyl|carbamoyl|azetidine-l- 5 carboxylate (A-97a, first eluted fraction) and tert-butyl 3-[[5-[[(4S)-4-[3-[5- / ert-butoxycarbonyl-4-(2- / ert-butoxy-2-oxo-ethoxy)-3-chloro-2-thienyl]anilino]-2,2-dimethyl-l-piperidyl]sulfonylmethyI]-2- fluoro-phenyl|carbamoyl|azetidine-l-carboxylate (A-97b, second eluted fraction) t3p, dipea DMF, r.t. Step 3 A-97b Step 1: l-[(4-fluoro-3-nitro-phenyl)methylsulfonyl]-2,2-dimethyl-piperidin-4-one (A-94) 10 Into a 50 mL single neck round bottom flask containing a well-stirred solution of 2,2-dimethylpiperidin-4-one hydrochloride (A-12,1.0 g, 6.11 mmol) and (4-fluoro-3-nitro-phenyl)methanesulfonyl chloride (A-93, 6.20 g, 24.44 mmol) in anhydrous DMF (15 mL) was added DMAP (1.49 g, 12.22 mmol). After 16 h, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated under 15 reduced pressure. The residue was purified by flash silica-gel (230-400 mesh) column with 50-60% EtOAc / pet ether to afford l-[(4-fluoro-3-nitro-phenyl)methylsulfonyl]-2,2-dimethyl-piperidin-4-one (A-94, 300 mg, 0.59 mmol, 10% yield) as a pale-yellow solid. LCMS (ESI): m / z 343.1 [M - H]-. 'H NMR (400 MHz, DMSO-^). ^8.26 - 8.24 (m, 1H), 7.89 - 7.85 (m, 1H), 7.67 - 7.62 (m, 1H), 4.63 (s, 2H), 3.68 (t, J= 5.6 Hz, 2H), 2.59 (s, 2H), 2.40 (t, J= 6 Hz, 2H) and 1.38 (s, 6H). Step 2: l-[(3-amino-4-fluoro-phenyl)methylsulfonyl]-2,2-dimethyl-piperidin-4-one (A-95) Into a 50 mL single neck round bottom flask containing a well-stirred solution of l-[(4-fluoro-3-nitro-phenyl)methylsulfonyl]-2,2-dimethyl-piperidin-4-one (A-94, 300 mg, 0.87 mmol) in a mixture of water (8 mL) and EtOH (8 mL) were added Fe powder (243.26 mg, 4.36 mmol) and ammonium chloride (233.01 mg, 4.36 mmol). The resulting mixture was stirred at 85 °C for 4 h. The reaction mixture was filtered through a pad of Celite and washed with dichloromethane (10 mL). Filtrate was diluted with water (10 mL) and extracted with DCM (2 xlO mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford l-[(3-amino-4-fluoro-phenyl)methylsulfonyl]-2,2-dimethyl-piperidin-4-one (A-95, 300 mg, 0.77 mmol, 89% yield) as a pale-yellow solid. This material was used in the next step without purification. LCMS (ESI): m / z 315.0 [M + H]+. 'H NMR (400 MHz, DMSO-<7a). 5 6.99 - 6.94 (m, 1H), 6.83 (dd, J= 8.8, 2.4 Hz, 1H), 6.55 - 6.51 (m, 1H), 5.23 (s, 2H), 4.27 (m, 2H), 3.60 (d, J= 6.0 Hz, 2H), 2.56 (s, 2H), 2.30 (d, J= 6.0 Hz, 2H) and 1.38 (s, 6H). Step 3:       tert-butyl 3-[[5-[(2,2-dimethyl-4-oxo-l-piperidyl)sulfonylmethyl]-2-fluoro- phenyl] carbamoyl] azetidine- 1-carboxylate (A-96) tert-butyl 3-[[5-[(2,2-dimethyl-4-oxo-1 -piperidyl)sulfonylmethyl]-2-fluoro-phenyl]carbamoyl]azetidine-1-carboxylate (A-96, 300 mg, 0.39 mmol, 41% yield) was synthesized from l-[(3-amino-4-fluoro-phenyl)methylsulfonyl]-2,2-dimethyl-piperidin-4-one (A-95) and l-tert-butoxycarbonylazetidine-3-carboxylic acid (A-63) in a similar fashion to Compound A-88 except using 2 eq. 1-propanephosphonic anhydride (50% in ethyl acetate) and 1.5 eq. A-63. Upon completion, the reaction mixture was diluted water and extracted with Ethyl acetate. Combined organic layers were dried over Sodium sulfate, filtered and concentrated under reduced pressure. This material was used in the next step without further purification. LCMS (ESI): m / z 496.1 [M - H]’. 'H NMR (400 MHz, DMSO-A): ^9.94 (s, 1H), 8.03 - 7.96 (s, 1H), 7.31 - 7.26 (m, 1H), 7.22 -7.19 (m, 1H), 4.44 (s, 2H), 4.02 - 3.93 (m, 5H), 3.64 - 3.60 (m, 3H), 2.57 (s, 2H), 2.34 (t, J= 6 Hz, 1H), 1.41 - 1.36 (m, 15H). Step 4: tert-butyl 3- [ [5- [ [(4R)-4- [3- [5-tert-butoxycarbonyl-4-(2-tert-butoxy-2-oxo-ethoxy)-3-chloro-2-thienyl]anilino]-2,2-dimethyl-l-piperidyl]sulfonylmethyl]-2-fluoro-phenyl]carbamoyl]azetidine-l-carboxylate (A-97a, first eluted fraction) and tert-butyl 3-[[5-[[(4S)-4-[3-[5-tert-butoxycarbonyl-4-(2-tert-butoxy-2-oxo-ethoxy)-3-chloro-2-thienyl]anilino]-2,2-dimethyl-l-piperidyl]sulfonylmethyl]-2-fluoro-phenyl]carbamoyl]azetidine-l-carboxylate (A-97b, second eluted fraction) tert-butyl           3-[[5-[[(4R)-4-[3-[5-tert-butoxycarbonyl-4-(2-tert-butoxy-2-oxo-ethoxy)-3-chloro-2- thienyl]anilino] -2,2-dimethyl-1 -piperidyl] sulfonylmethyl] -2-fluoro-phenyl] carbamoyl] azetidine-1 -carboxylate (A-97a) and tert-butyl 3-[[5-[[(4S)-4-[3-[5-tert-butoxycarbonyl-4-(2-tert-butoxy-2-oxo-ethoxy)-3-chloro-2-thienyl]anilino]-2,2-dimethyl-l-piperidyl]sulfonylmethyl]-2-fluoro- phenyl]carbamoyl]azetidine-1-carboxylate (A-97b) were synthesized from tert-butyl 3-[[5-[(2,2-dimethyl-4-oxo-l-piperidyl)sulfonylmethyl]-2-fluoro-phenyl]carbamoyl]azetidine-l-carboxylate (A-96) and tertbutyl 5-(3-aminophenyl)-3-(2-tert-butoxy-2-oxo-ethoxy)-4-chloro-thiophene-2-carboxylate (A-73) in a similar fashion to Compound A-74a / b except using 1 eq. MP-cyanoborohydride and 29 eq. Acetic acid. tert-butyl 3-((5-(((4-((3-(4-(2-(tert-butoxy)-2-oxoethoxy)-5-(tert-butoxycarbonyl)-3-chlorothiophen-2-yl)phenyl)amino)-2,2-dimethylpiperidin-1 -yl)sulfonyl)methy 1)-2-fluorophenyl)carbamoyl)azetidine-1 -carboxylate (A-97a / b) was subjected to SFC chiral HPLC separation following the method: Column: (R,R)-Whelk-01; Co-Solvent: 0.5% 'PrNH2 in 1:1 MeOH: IPA, Injected volume : 15 pL; Flow rate : 4 mL / min; RT = 5.15 min to afford ZerZ-butyl 3-[[5-[[(4R)-4-[3-[5-ZerZ-butoxycarbonyl-4-(2-ZerZ-butoxy-2-oxo-ethoxy)-3-chloro-2-thienyl]anilino]-2,2-dimethyl-l-piperidyl]sulfonylmethyl]-2-fluoro- phenyl]carbamoyl]azetidine-1-carboxylate (A-97a, first eluted fraction, 100 mg, 0.11 mmol, 18% yield) as an off-white solid. LCMS (ESI+): m / z 921.0 [M + H]+. rHNMR (400 MHz, DMSO-^): ^9.92 (s, 1H), 8.03 - 8.00 (m, 1H), 7.30 - 7.26 (m, 1H), 7.21 - 7.17 (m, 2H), 6.86 (s, 1H), 6.81 (d, J= 7.6 Hz, 1H), 6.70 -6.67 (m, 1H), 5.68 (d, J= 7.6 Hz, 1H), 4.85 (s, 2H), 4.46 - 4.30 (m, 2H), 4.01 - 3.93 (m, 5H), 3.65 - 3.61 (m, 1H), 3.51-3.43 (m, 2H), 3.15 - 3.08 (m, 1H), 1.88 - 1.77 (m, 2H), 1.52 (s, 9H), 1.46 - 1.38 (m, 25H). and RT = 5.94 min to afford ZerZ-butyl 3-[[5-[[(4S)-4-[3-[5-ZerZ-butoxycarbonyl-4-(2-ZerZ-butoxy-2-oxo-ethoxy)-3-chloro-2-thienyl]anilino]-2,2-dimethyl-l-piperidyl]sulfonylmethyl]-2-fluoro- phenyl]carbamoyl]azetidine-1-carboxylate (A-97b, second eluted fraction, 100 mg, 0.107 mmol, 18% yield) as an off-white solid. LCMS (ESI-): m / z 919.2 [M - H]'. ’H NMR (400 MHz, DMSO-A): J”9.92 (s, 1H), 8.03 - 8.00 (s, 1H), 7.30 - 7.26 (m, 1H), 7.21 - 7.17 (m, 2H), 6.86 (s, 1H), 6.86 - 6.80 (d, 1H), 6.70 - 6.67 (m, 1H), 5.68 (d, J= 8 Hz, 1H), 4.85 (s, 2H), 4.58 - 4.42 (m, 1H), 4.33 - 4.30 (m, 1H), 4.01 - 3.92 (m, 4H), 3.65-3.61 (m, 2H), 3.53-3.51 (m, 2H), 3.45-3.42 (m, 1H), 3.12 (t, J= 12.4 Hz, 1H), 1.88 (d, J= 11.6 Hz, 1H), 1.79 (d, J=9.6Hz, 1H), 1.52 (s, 9H), 1.46- 1.38 (m, 24H). tert-butyl (lR,5S,6r)-6-((5-((((S)-4-((3-(4-(2-(tert-butoxy)-2-oxoethoxy)-5-(tert-butoxycarbonyl)-3-chlorothiophen-2-yl)phenyl)amino)-2,2-dimethylpiperidin-l-yl)sulfonyl)methyl)-2- fluorophenyl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (A-99a, first eluted fraction) and tert-butyl (lR,5S,6r)-6-((5-((((R)-4-((3-(4-(2-(tert-butoxy)-2-oxoethoxy)-5-(tert-butoxycarbonyl)-3-chlorothiophen-2-yl)phenyl)amino)-2,2-dimethylpiperidin-l-yl)sulfonyl)methyl)-2- fluorophenyl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (A-99b, second eluted fraction) t3p, dipea, DMF, r.t., 16 h Step 1 A-98 A-99b Step 1: tert-butyl (lJ?,55,6r)-6-((5-(((2,2-dimethyl-4-oxopiperidin-l-yl)sulfonyl)methyl)-2-fluorophenyl)carbam oyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (A-98) tert-butyl (lS,5R)-6-[[5-[(2,2-dimethyl-4-oxo-l-piperidyl)sulfonylmethyl]-2-fluoro-phenyl]carbamoyl]-3-azabicyclo [3.1.0]hexane-3-carboxy late (A-98, 320 mg, 505.41 pmol, 53% yield) was synthesized from 1-[(3-amino-4-fluoro-phenyl)methylsulfonyl]-2,2-dimethyl-piperidin-4-one (A-95) and (lS,5R)-3-tert-butoxycarbonyl-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (A-87) in a similar fashion to Compound A-88 except using 1 eq. acid, 2 eq. 1-propanephosphonic anhydride (50% in ethyl acetate) and 4 eq. DIPEA. Upon completion, the reaction was quenched with cold water and extracted with ethyl acetate (3 x). Combined organic layer was washed with 1.5 N aqueous HC1 (2x15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. LCMS (ES-): m / z 522.1 [M - H]’. Step 2: tert-butyl (lR,5S,6r)-6-((5-((((S)-4-((3-(4-(2-(tert-butoxy)-2-oxoethoxy)-5-(tert-butoxycarbonyl)-3-chlorothiophen-2-yl)phenyl)amino)-2,2-dimethylpiperidin-l-yl)sulfonyl)methyl)-2-fluorophenyl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (A-99a, first eluted fraction) and tert-butyl (lR,5S,6r)-6-((5-((((R)-4-((3-(4-(2-(tert-butoxy)-2-oxoethoxy)-5-(tert-butoxycarbonyl)-3-chlorothiophen-2-yl)phenyl)amino)-2,2-dimethylpiperidin-l-yl)sulfonyl)methyl)-2- fluorophenyl)carbamoyl)-3-azabicyclo[3.1.0|hexane-3-carboxylate (A-99b, second eluted fraction) tert-butyl (lR,5S,6r)-6-((5-((((S)-4-((3-(4-(2-(tert-butoxy)-2-oxoethoxy)-5-(tert-butoxycarbonyl)-3-chlorothiophen-2-yl)phenyl)amino)-2,2-dimethylpiperidin-l-yl)sulfonyl)methyl)-2- fluorophenyl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (A-99a, first eluted fraction) and tertbutyl           (lR,5S,6r)-6-((5-((((R)-4-((3-(4-(2-(tert-butoxy)-2-oxoethoxy)-5-(tert-butoxycarbonyl)-3- chlorothiophen-2-yl)phenyl)amino)-2,2-dimethylpiperidin-l-yl)sulfonyl)methyl)-2- fluorophenyl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (A-99b, second eluted fraction) were synthesized from ZerZ-butyl (lS,5R)-6-[[5-[(2,2-dimethyl-4-oxo-l-piperidyl)sulfonyhnethyl]-2-fluoro-phenyl]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (A-98) and ZerZ-butyl 5-(3-aminophenyl)-3-(2-tert-butoxy-2-oxo-ethoxy)-4-chloro-thiophene-2-carboxylate (A-73) in a similar fashion to Compound A-74a / b except using 28 eq. Acetic acid and 2.5 eq. MP-cyanoborohydride. tert-butyl (lR,5S,6r)-6-((5-(((4-((3-(4-(2-(tert-butoxy)-2-oxoethoxy)-5-(tert-butoxycarbonyl)-3-chlorothiophen-2-yl)phenyl)amino)-2,2-dimethylpiperidin-l-yl)sulfonyl)methyl)-2-fluorophenyl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (A-99a / b) was subjected to chiral SFC to separate isomers. [Purification method: Column Name : Lux Al; Flow rate : 3 mL / min; Co-Solvent: 30%; Co-Solvent Name : 0.5% Isopropyl Amine in IPA; Outlet Pressure: 100 bar; Injected Volume : 9 pl; Temperature : 35 °C] to afford tert-butyl (lR,5S,6r)-6-((5-((((S)-4-((3-(4-(2-(tert-butoxy)-2-oxoethoxy)-5-(tert-butoxycarbonyl)-3-chlorothiophen-2-yl)phenyl)amino)-2,2-dimethylpiperidin-l-yl)sulfonyl)methyl)-2-fluorophenyl)carbamoyl)-3- azabicyclo[3.1.0]hexane-3-carboxylate (A-99a, first eluted fraction, 90 mg, 91.09 pmol, 15% yield) as an off-white solid. LCMS (ES-): m / z 945.2 [M - H]". and tert-butyl (lR,5S,6r)-6-((5-((((R)-4-((3-(4-(2-(tert-butoxy)-2-oxoethoxy)-5-(tert-butoxycarbonyl)-3-chlorothiophen-2-yl)phenyl)amino)-2,2-dimethylpiperidin-l-yl)sulfonyl)methyl)-2- fluorophenyl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (A-99b, second eluted fraction, 70 mg, 70.42 pmol, 12% yield) as an off-white solid. LCMS (ES-): m / z 945.2 [M - H]“. Zert-butyl                   5-[3-[[(4S)-l-[(3-amino-4-fluoro-phenyl)methylsulfonyl]-2,2-dimethyl-4- piperidyl]amino]phenyl]-3-(2-tert-butoxy-2-oxo-ethoxy)-4-chloro-thiophene-2-carboxylate (A-lOla, first eluted fraction) and tert-butyl 5-[3-[|(4R)-l-|(3-amino-4-fluoro-phenyl)methylsulfonyl|-2,2-dimethyl-4-piperidyl]amino]phenyl]-3-(2-tert-butoxy-2-oxo-ethoxy)-4-chloro-thiophene-2-carboxylate (A-lOlb, second eluted fraction) i. Fe / NH4CI, EtOH.H2O , 75°C, 4 h ii. Chiral SFC Step 2 A-101a A-101b Step 1:     tert-butyl 3-(2-tert-butoxy-2-oxo-ethoxy)-4-chloro-5-[3-[[l-[(4-fluoro-3-nitro- phenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]phenyl]thiophene-2-carboxylate (A-100) tert-butyl 3-(2-tert-butoxy-2-oxo-ethoxy)-4-chloro-5-[3-[[l-[(4-fluoro-3-nitro-phenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]phenyl]thiophene-2-carboxylate (A-100, 300 mg, 324.09 pmol, 56% yield) was synthesized from l-[(4-fluoro-3-nitro-phenyl)methylsulfonyl]-2,2-dimethyl-piperidin-4-one (A-94) and 5-(3-aminophenyl)-3-(2-tert-butoxy-2-oxo-ethoxy)-4-chloro-thiophene-2-carboxylate (A-73) in a similar fashion to Compound A-74a / b except using 1 eq. MP-cyanoborohydride and 30 eq. Acetic acid. LCMS (ES+): m / z 657.3 [M - 2 tBu + H]+. Step 2: tert-butyl 5-[3-[[(4S)-l-[(3-amino-4-fluoro-phenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]phenyl]-3-(2-tert-butoxy-2-oxo-ethoxy)-4-chloro-thiophene-2-carboxylate (A-lOla, first eluted fraction) and tert-butyl 5-[3-[[(4R)-l-[(3-amino-4-fluoro-phenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]phenyl]-3-(2-tert-butoxy-2-oxo-ethoxy)-4-chloro-thiophene-2-carboxylate (A-lOlb, second eluted fraction) Into a 10 mL single neck round bottom flask containing a well-stirred solution of tert-butyl 3-(2-tert-butoxy-2-oxo-ethoxy)-4-chloro-5-[3-[[l-[(4-fluoro-3-nitro-phenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]phenyl]thiophene-2-carboxylate (A-100, 300 mg, 390.47 pmol) in ethanol (5 mL) and water (5 mL) were added iron powder (109.03 mg, 1.95 mmol, 13.87 pL) and ammonium chloride (104.43 mg, 1.95 mmol, 68.26 pL). The suspension was stirred at 75 °C for 4 h. The reaction mixture was filtered through Celite and washed with DCM (10 mL). The filtrate was diluted with water (10 mL) and extracted with DCM (2x10 mL), and the combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue purified by reverse phase column chromatography (30 g, C18-column, compound eluted with 80 -85 % acetonitrile in 0.1% TFA in water) to afford tert-butyl 5-(3-((l-((3-amino-4-fluorobenzyl)sulfonyl)-2,2-dimethylpiperidin-4-yl)amino)phenyl)-3 -(2-(tert-butoxy)-2-oxoethoxy)-4-chlorothiophene-2-carboxylate (A-l 01 a / b), which was subjected to chiral SFC. Purification method: Column Name: YMC Amylose-SA; Flow rate: 5 mL / min; Co-Solvent: 40%; Co-Solvent Name : 0.5% Isopropyl amine in IP A; Outlet Pressure: 100 bar; Injected Volume : 15 pl; Temperature : 35 °C to afford tert-butyl 5-[3-[[(4S)-l-[(3-amino-4-fluoro-phenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]phenyl]-3-(2-tert-butoxy-2-oxo-ethoxy)-4- chloro-thiophene-2-carboxylate (A-lOla, first eluted fraction, 70 mg, 93.86 pmol, 24% yield). LCMS (ES+): m / z 626.2 [M - 2 tBu + H]+. and tert-butyl 5-[3-[[(4R)-l-[(3-amino-4-fluoro-phenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]phenyl]-3-(2-tert-butoxy-2-oxo-ethoxy)-4-chloro-thiophene-2-carboxylate (A-lOlb, second eluted fraction, 70 mg, 93.86 pmol, 24% yield) as an off-white solid. LCMS (ES+): m / z 626.2 [M - 2 tBu + H]+. tert-butyl                   5-[3-[[(4S)-l-[(3-amino-2-fluoro-phenyl)methylsulfonyl]-2,2-dimethyl-4- piperidyl]amino]phenyl]-3-(2-tert-butoxy-2-oxo-ethoxy)-4-chloro-thiophene-2-carboxylate (A-105a, first eluted fraction) and tert-butyl 5-[3-[[(4R)-l-[(3-amino-2-fluoro-phenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]phenyl]-3-(2-tert-butoxy-2-oxo-ethoxy)-4-chloro-thiophene-2- carboxylate (A-l 05b, second eluted fraction) A-102           r.t., 16 h                 A-103                                 Step 2 Step 1 O A-104 A-105a                                                     A-105b Step 1: l-[(2-fluoro-3-nitro-phenyl)methylsulfonyl]-2,2-dimethyl-piperidin-4-one (A-103) Into a 500 mL single neck round bottom flask containing a well-stirred solution of 2,2-dimethylpiperidin-4-one hydrochloride (A-12, 2 g, 12.22 mmol) and (2-fluoro-3-nitro-phenyl)methane sulfonyl chloride (A-102, 9.30 g, 36.66 mmol) in anhydrous DCM (20 mL) was added DMAP (2.99 g, 24.44 mmol). After 16 hthe reaction mixture was diluted with water (250 mL) and extracted with DCM (2 x 100 mL). The combined organic layer was washed with brine solution (100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel (60-120 mesh) column chromatography (50-60% ethyl acetate in petroleum ether) to afford l-[(2-fluoro-3-nitro-phenyl)methylsulfonyl]-2,2-dimethyl-piperidin-4-one (A-103, 1.2 g, 3.28 mmol, 27% yield) as a pale yellow solid. LCMS (ES-): m / z 343.2 [M - H]-. Step 2:      tert-butyl 3-(2-tert-butoxy-2-oxo-ethoxy)-4-chloro-5-[3-[[l-[(2-fluoro-3-nitro- phenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]phenyl]thiophene-2-carboxylate (A-104) tert-butyl 3-(2-tert-butoxy-2-oxo-ethoxy)-4-chloro-5-[3-[[l-[(2-fluoro-3-nitro-phenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]phenyl]thiophene-2-carboxylate (A-104, 2.56 g, 2.82 mmol, 81% yield) was synthesized from l-[(2-fluoro-3-nitro-phenyl)methylsulfonyl]-2,2-dimethyl-piperidin-4-one (A-103) and tert-butyl 5-(3-aminophenyl)-3-(2-tert-butoxy-2-oxo-ethoxy)-4-chloro-thiophene-2-carboxylate (A-73) in a similar fashion to Compound A-74a / b, except using 8 eq. MP-cyanoborohydride and 1 eq. Acetic acid. The material was used in next step without purification. LCMS (ESI+) m / z 769.2 [M + H]+. Step 3: tert-butyl 5-[3-[[(4S)-l-[(3-amino-2-fluoro-phenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]phenyl]-3-(2-tert-butoxy-2-oxo-ethoxy)-4-chloro-thiophene-2-carboxylate (A-105a, first eluted fraction) and tert-butyl 5-[3-[[(4R)-l-[(3-amino-2-fluoro-phenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]phenyl]-3-(2-tert-butoxy-2-oxo-ethoxy)-4-chloro-thiophene-2-carboxylate (A-105b, second eluted fraction) Into a 250mL single neck round bottom flask containing a well-stirred solution of tert-butyl 3-(2-tert-butoxy-2-oxo-ethoxy)-4-chloro-5-[3-[[l-[(2-fluoro-3-nitro-phenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]phenyl]thiophene-2-carboxylate (A-104, 2.56 g, 3.33 mmol) in a mixture of ethanol (25 mL) and water (15 mL) were added iron powder (930.37 mg, 16.66 mmol) and ammonium chloride (891.16 mg, 16.66 mmol). The resulting suspension was stirred at 85 °C for 4 h. The reaction mixture filtered through Celite, washing with ethanol. The filtrate was concentrated under reduced pressure and the residue was taken up in Ethyl acetate (100 mL) and washed with water (2 x 50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography [Method: Column: RediSep ISCO C18(30g); Mobile phase A: 0.1% TFAin MQ-water; Mobile phase B: Acetonitrile] to afford tert-butyl 5-(3-((1-((3-amino-2-fluorobenzyl)sulfonyl)-2,2-dimethylpiperidin-4-yl)amino)phenyl)-3-(2-(tert-butoxy)-2-oxoethoxy)-4-chlorothiophene-2-carboxylate (A-105a / b), which was subjected to chiral SFC. Method: Chiralcel-OJ-H (250 x 30mm) 5.0 pm with Mobile Phase : CO2: 0.5% Isopropyl amine in methanol (60:40) to afford tertbutyl 5-[3-[[(4S)-l-[(3-amino-2-fluoro-phenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]phenyl]-3-(2-tert-butoxy-2-oxo-ethoxy)-4-chloro-thiophene-2-carboxylate (A-105a, first eluted fraction, 0.6 g, 0.813mmol, 24% yield) and tert-butyl 5-[3-[[(4R)-l-[(3-amino-2-fluoro-phenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]phenyl]-3-(2-tert-butoxy-2-oxo-ethoxy)-4-chloro-thiophene-2-carboxylate (A-105b, second eluted fraction, 1.5 g, 2.032mmol, 61% yield) as an off-white solid. LCMS (ESI+): m / z 626.1 [M-tBu + H]+. tert-butyl 5-(3-amino-4-fluorophenyl)-4-chloro-3-(2-ethoxy-2-oxoethoxy)thiophene-2-carboxylate (A-107) Step 1: tert-butyl 5-(3-amino-4-fluorophenyl)-4-chloro-3-(2-ethoxy-2-oxoethoxy)thiophene-2-5 carboxylate (A-107) A mixture of tert-butyl 4,5-dichloro-3-(2-ethoxy-2-oxoethoxy)thiophene-2-carboxylate (A-4, 10.0 g, 28.1 mmol), (3-amino-4-fluorophenyl)boronic acid (A-106, 5.23 g, 33.8 mmol), Pd(PPh3)4 (3.25 g, 2.82 mmol), and Na2COs (2 M in water, 42.2 mL) in dioxane (150 mL) was purged with N2 three times, and stirred for 8 h at 75 °C. The reaction mixture was acidified to pH 6 using IN HC1, diluted with water (500 mL) and 10 extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with water (500 mL) and brine (500 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 8 / 1) to afford tert-butyl 5-(3-amino-4-fluorophenyl)-4-chloro-3-(2-ethoxy-2-oxoethoxy)thiophene-2-carboxylate (A-107, 5.95 g, 49% yield) as a yellow solid. LCMS (ES+): 430.1 [M + H]+. ’H NMR (400 MHz, CDCI3): 15    3 6.97-7.12 (m, 3 H), 4.87-4.91 (m, 2 H), 4.25-4.32 (m, 2 H), 3.79-3.91 (m, 2 H), 1.56-1.59 (m, 9 H), 1.29 1.35 (m, 3 H). 2-[[5-[3-[[l- [(3-aminophenyl)methylsulfonyl] -4-piperidyl] amino] -4-fluoro-phenyl] -2-tert-butoxycarbonyl-4-chloro-3-thienyl] oxy] acetic acid (A-lll) Step 1: l-((3-nitrobenzyl)sulfonyl)piperidin-4-one (A-108) l-((3-nitrobenzyl)sulfonyl)piperidin-4-one (A-108, 15.5 g, 44.51 mmol, 60% yield) was synthesized from piperidin-4-one hydrochloride (A-66) and (3-nitrophenyl)methanesulfonyl chloride (A-7a) in a similar fashion to Compound A-8, except the product was used in the next step without purification. 'H NMR (400 MHz, DMSO-rfd): 8 8.35 (s, 1H), 8.25 (dd, J= 1.60, 8.20 Hz, 1H), 7.91 (d, J= 7.60 Hz, 1H), 7.72 (t, J= 8.00 Hz, 1H), 4.77 (s, 2H), 3.50 (t, J= 6.00 Hz, 4H), 2.40 (t, J= 6.00 Hz, 4H). Step 2:         tert-butyl 4-chloro-3-(2-ethoxy-2-oxoethoxy)-5-(4-fluoro-3-((l-((3- nitrobenzyl)sulfonyl)piperidin-4-yl)amino)phenyl)thiophene-2-carboxylate (A-109) Into a 100 mL pressure tube containing a well-stirred solution of tert-butyl 5-(3-amino-4-fluorophenyl)-4-chloro-3-(2-ethoxy-2-oxoethoxy)thiophene-2-carboxylate (A-107, 300 mg, 697.85 pmol) in ethanol (20 mL) were added l-[(3-nitrophenyl)methylsulfonyl]piperidin-4-one (A-108, 1.04 g, 3.49 mmol), acetic acid (209.54 mg, 3.49 mmol, 199.56 pL) and MP-cyanoborohydride (600 mg, 697.85 pmol). The resulting suspension was heated at 80 °C for 15 h. The reaction mixture was cooled to ambient temperature, filtered, the solvent removed under reduced pressure and the residue taken up in ethyl acetate (100 mL). The organic layer was washed with water (75 mL) and brine (75 mL), dried over sodium sulfate and filtered. The solvent was removed under reduced pressure and the residue purified by flash silica gel column chromatography (20-30% of Ethyl acetate in petroleum ether) to afford tert-butyl 4-chloro-3-(2-ethoxy-2-oxoethoxy)-5-(4-fluoro-3-((1-((3-nitrobenzyl)sulfonyl)piperidin-4-yl)amino)phenyl)thiophene-2-carboxylate (A-109, 300 mg, 388.88 pmol, 56% yield) as yellow gummy solid. LCMS (ES+): m / z 655.6 [M - tBu + H]+. Step 3: 2-[[2-tert-butoxycarbonyl-4-chloro-5-[4-fluoro-3-[[l-[(3-nitrophenyl)methylsulfonyl]-4-piperidyl]amino]phenyl]-3-thienyl]oxy]acetic acid (A-110) 2-[[2-tert-butoxycarbonyl-4-chloro-5-[4-fluoro-3-[[l-[(3-nitrophenyl)methylsulfonyl]-4-piperidyl]amino]phenyl]-3-thienyl]oxy]acetic acid (A-110, 160 mg, 206.11 pmol, 49% yield) was synthesized from tert-butyl       4-chloro-3-(2-ethoxy-2-oxoethoxy )-5-(4-fluoro-3 -((1-((3 - nitrobenzyl)sulfonyl)piperidin-4-yl)amino)phenyl)thiophene-2-carboxylate (A-109) in a similar fashion to Compound A-9 except using 3 eq. LiOH monohydrate. Upon completion, the reaction mixture was concentrated to almost dryness and the residue acidified to pH ~2 with 1.5 N HC1. The product was extracted into Ethyl acetate (2 x). The combined organic layer was washed with brine, dried over sodium sulfate and the solvent removed under reduced pressure. LCMS (ES+): m / z 627.6 [M - tBu + H]+. Step 4: 2-[[5-[3-[[l-[(3-aminophenyl)methylsulfonyl]-4-piperidyl]amino]-4-fluoro-phenyl]-2-tert-butoxycarbonyl-4-chloro-3-thienyl] oxy] acetic acid (A-lll) 2-[[5-[3-[[l-[(3-aminophenyl)methylsulfonyl]-4-piperidyl]amino]-4-fluoro-phenyl]-2-tert-butoxycarbonyl-4-chloro-3-thienyl]oxy]acetic acid (A-lll, 100 mg, 128.04 pmol, 55% yield) was synthesized from 2-[[2-ter / -butoxycarbonyl-4-chloro-5-[4-fluoro-3-[[l-[(3-nitrophenyl)methylsulfonyl]-4-piperidyl]amino]phenyl]-3-thienyl]oxy]acetic acid (A-110) in a similar fashion to Compound A-10, except using 3 eq. zinc powder and 4 eq. Acetic acid. The product was used in the next step without purification. LCMS (ES+): m / z 654.1 [M + H]+. tert-butyl 5-(3-amino-2-fluorophenyl)-4-chloro-3-(2-ethoxy-2-oxoethoxy)thiophene-2-carboxylate (A-115) Step 1: 2-fluoro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (A-114) To a solution of 3-bromo-2-fluoroaniline (A-112, 30.0 g, 157 mmol), 4,4,4',4',5,5,5,,5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (A-113, 48.1 g, 189 mmol) and KOAc (30.0 g, 315 mmol) in DMF (100 mL) was added Pd(dppf)Ch (5.78 g, 7.89 mmol) under N2 atmosphere. The mixture was stirred at 100 °C for 16 h. The reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (3 x 500 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 4 / 1) to afford 2-fhioro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (A-114, 24.2 g, 65 % yield) as a white solid. Step 2: tert-butyl 5-(3-amino-2-fluorophenyl)-4-chloro-3-(2-ethoxy-2-oxoethoxy)thiophene-2- carboxylate (A-115) 5 tert-butyl 5-(3-amino-2-fluorophenyl)-4-chloro-3-(2-ethoxy-2-oxoethoxy)thiophene-2-carboxylate (A-115, 7.52 g, 52 % yield) was synthesized from tert-butyl 4,5-dichloro-3-(2-ethoxy-2-oxoethoxy)thiophene-2-carboxylate (A-4) and 2-fluoro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (A-114) in a similar fashion to Compound 107. LCMS (ES+): m / z 374.0 [M - tBu + H]+. 'H NMR (400 MHz, CDC13): 8 6.96-7.03 (m, 1 H), 6.83-6.90 (m, 1 H), 6.77-6.83 (m, 1 H), 4.88-4.92 (m, 2 H), 4.24-4.32 (m, 2 H), 3.77 10    3.93 (m, 2 H), 1.55-1.59 (m, 9 H), 1.32 (t, J= 7.15 Hz, 3 H). 2-[[5-[3-[[l- [(3-aminophenyl)methylsulfonyl] -4-piperidyl] amino] -2-fluoro-phenyl] -2-tert-butoxycarbonyl-4-chloro-3-thienyl] oxy] acetic acid (A-118) Step         1:         tert-butyl 4-chloro-3-(2-ethoxy-2-oxo-ethoxy)-5-[2-fluoro-3-[[l-[(3- 15 nitrophenyl)methylsulfonyl]-4-piperidyl]amino]phenyl]thiophene-2-carboxylate (A-116) Into a 50 ml pressure tube containing a well-stirred solution of tert-buty 1-5-(3-amino-2-fluoro-pheny 1)-4-chloro-3-(2-ethoxy-2-oxo-ethoxy)thiophene-2-carboxylate (A-115, 500.00 mg, 1.16 mmol) in ethanol (15 mL) were added l-[(3-nitrophenyl)methylsulfonyl]piperidin-4-one (A-108, 346.97 mg, 1.16 mmol) and acetic acid (279.37 mg, 4.65 mmol, 266.07 pL). The mixture was stirred at 80 °C for 3 h. The reaction mixture was cooled to room temperature and MP-cyanoborohydride (73.09 mg) was added. The reaction was continued at 80 °C for 12 h. The reaction mixture was filtered and washed with ethanol. The solvent was removed under reduced pressure, the residue diluted with water (25 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with brine (25 mL) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and purified by flash silica gel (230-400 mesh) column chromatography (8-10% of Ethyl acetate in petroleum ether) to afford tert-butyl 4-chloro-3-(2-ethoxy-2-oxo-ethoxy)-5-[2-fluoro-3-[[l-[(3-nitrophenyl)methylsulfonyl]-4- piperidyl]amino]phenyl]thiophene-2-carboxylate (A-116, 600 mg, 782.14 pmol, 67% yield) as a yellow solid. LCMS (ES+): m / z 655.7 [M - tBu + H]+. Step 2: 2-[|2- / ert-butoxycarbonyl-4-chloro-5-|2-fluoro-3-||l-[(3-nitrophenyl)methylsulfonyl|-4-piperidyl]amino]phenyl]-3-thienyl]oxy]acetic acid (A-117) 2-[[2-tert-butoxycarbonyl-4-chloro-5-[2-fluoro-3-[[l-[(3-nitrophenyl)methylsulfonyl]-4-piperidyl]amino]phenyl]-3-thienyl]oxy]acetic acid (A-117, 500 mg, 594.90 pmol, 77% yield) was synthesized from tert-butyl 4-chloro-3-(2-ethoxy-2-oxo-ethoxy)-5-[2-fluoro-3-[[l-[(3-nitrophenyl)methylsulfonyl]-4-piperidyl]amino]phenyl]thiophene-2-carboxylate (A-116) in a similar fashion to Compound A-9, except using 1 eq. LiOH monohydrate. Upon completion, the reaction mixture was acidified with 1.5N HC1 (pH 4-5) and extracted with Ethyl acetate (2 x). The organic layer was dried over anhydrous sodium sulfate and solvent was removed under reduced pressure to afford 2-[[2-tert-butoxycarbonyl-4-chloro-5-[2-fluoro-3-[[l-[(3-nitrophenyl)methylsulfonyl]-4-piperidyl]amino]phenyl]-3-thienyl]oxy]acetic acid (A-117) as a yellow solid. LCMS (ES+): m / z 628.0 [M - tBu + H]+. Step 3: 2-[[5-[3-[[l-[(3-aminophenyl)methylsulfonyl]-4-piperidyl]amino]-2-fluoro-phenyl]-2- / ert-butoxycarbonyl-4-chloro-3-thienyl] oxy] acetic acid (A-118) 2-[[5-[3-[[l-[(3-aminophenyl)methylsulfonyl]-4-piperidyl]amino]-2-fluoro-phenyl]-2-tert-butoxycarbonyl-4-chloro-3-thienyl]oxy]acetic acid (A-118, 170 mg, 228.34 pmol, 38% yield, Formic acid salt) was synthesized from 2-[[2- / er / -butoxycarbonyl-4-chloro-5-[2-fluoro-3-[[l-[(3-nitrophenyl)methylsulfonyl]-4-iperidyl]amino]phenyl]-3-thienyl]oxy]acetic acid (A-117) in a similar fashion to Compound A-10, except using 3 eq. zinc powder and 4 eq. Acetic acid. LCMS (ES+): m / z 597.7 [M-tBu + H]+. 5-(3-((l-((3-(7-aminoheptanamido)benzyl)sulfonyl)piperidin-4-yl)amino)phenyl)-3-(carboxymethoxy)-4-chlorothiophene-2-carboxylic acid hydrochloride (A-121) Step                        1:                        2-[[2-terf-butoxycarbonyl-5-[3-[[l-[[3-[7-(ZerZ- butoxycarbonylamino)heptanoylamino]phenyl]methylsulfonyl]-4-piperidyl]amino]phenyl]-4-chloro-3-thienyl] oxy] acetic acid (A-120) Into a 10 mL single neck round bottom flask containing a well-stirred solution of7-(ZerZ-butoxycarbonylamino)heptanoic acid (A-119, 77.12 mg, 314.38 pmol) in DMF (2 mL) were added DIPEA (203.16 mg, 1.57 mmol, 273.79 pL) andHATU (131.49 mg, 345.82 pmol). The reaction mixture was stirred at room temperature for 3 h. Then a solution of 2-[[5-[3-[[l-[(3-aminophenyl)methylsulfonyl]-4-piperidyl]amino]phenyl]-2-ZerZ-butoxycarbonyl-4-chloro-3-thienyl]oxy]acetic acid (A-10, 200 mg, 314.38 pmol) in DMF (1 mL) was added. After 20 h, the solvent was evaporated and the residue was purified by reverse phase preparative HPLC [Purification method: Column: SunFire prep OBD 19 x 50 mm (5 pm), Mobile phase A: 0.1% TFA in water and Mobile phase B: MeCN] to afford 2-[[2-terZ-butoxycarbonyl-5-[3-[[l-[[3-[7-(ZerZ-butoxycarbonylamino)heptanoylamino]phenyl]methylsulfonyl]-4-piperidyl]amino]phenyl]-4-chloro-3-thienyl]oxy]acetic acid (A-120, 140 mg, 159.70 pmol, 51% yield, TFA salt) as a light yellow solid. LCMS (ES+): m / z 863.2 [M + H]+. Step     2:     5-(3-((1 -((3-(7-aminoheptanamido)benzyl)sulfonyl)piperidin-4-yl)amino)phenyl)-3- (carboxymethoxy)-4-chlorothiophene-2-carboxylic acid hydrochloride (A-121) 5-(3-((l-((3-(7-aminoheptanamido)benzyl)sulfonyl)piperidin-4-yl)amino)phenyl)-3-(carboxymethoxy)-4-chlorothiophene-2-carboxylic acid hydrochloride (A-121, 137 mg) was synthesized from 2-[[2-tert-butoxycarbonyl-5-[3-[[l-[[3-[7-(ZerZ-butoxycarbonylamino)heptanoylamino]phenyl]methylsulfonyl]-4-piperidyl]amino]phenyl]-4-chloro-3-thienyl]oxy]acetic acid (A-120) in a similar fashion to Compound A-12. UPLC (ES+): m / z 101.1 [M + H]+. 5-[3-||(4S)-l-[(3-aminophenyl)methylsulfonyl|-2,2-dimethyl-4-piperidyl|amino|-4-fluoro-phenyl|-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-125) Step 1:      tert-butyl 4-chloro-5-[3-[[2,2-dimethyl-l-[(3-nitrophenyl)methylsulfonyl]-4- piperidyl]amino]-4-fluoro-phenyl]-3-(2-ethoxy-2-oxo-ethoxy)thiophene-2-carboxylate (A-122) tert-butyl   4-chloro-5-[3 - [[2,2-dimethyl-1 - [(3 -nitrophenyl)methylsulfonyl] -4-piperidy 1] amino] -4-fluoro- 5 phenyl]-3-(2-ethoxy-2-oxo-ethoxy)thiophene-2-carboxylate (A-122, 1.2 g, 1.59 mmol, 68% yield) was synthesized from tert-butyl 5-(3-amino-4-fluorophenyl)-4-chloro-3-(2-ethoxy-2-oxoethoxy)thiophene-2-carboxylate (A-107) and 2,2-dimethyl-l-((3-nitrobenzyl)sulfonyl)piperidin-4-one (A-13) in a similar fashion to Compound A-74a / b, except using 38 eq. Acetic acid. LCMS (ES+): m / z 683.7 [M - tBu + H]+. Step 2: tert-butyl 5-[3-[[(4S)-l-[(3-aminophenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]-4- 10 fluoro-phenyl]-4-chloro-3-(2-ethoxy-2-oxo-ethoxy)thiophene-2-carboxylate (A-123a, first eluted fraction) and tert-butyl 5-[3-[[(4R)-l-[(3-aminophenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl] am ino] -4-fluoro-phenyl] -4-chloro-3-(2-ethoxy-2-oxo-ethoxy)thiophene-2-carboxylate (A-123b, second eluted fraction) Configurations are arbitrarily assigned. 15 Into a 100 mL single neck round bottom flask containing a well-stirred solution of tert-butyl 4-chloro-5-[3-[[2,2-dimethyl-l-[(3-nitrophenyl)methylsulfonyl]-4-piperidyl]amino]-4-fluoro-phenyl]-3-(2-ethoxy-2-oxo-ethoxy)thiophene-2-carboxylate (A-122,1.1 g, 1.49 mmol) in ethanol (20 mL) and water (20 mL) were added iron powder (414.96 mg, 7.43 mmol) and ammonium chloride (397.42 mg, 7.43 mmol). The reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was filtered through Celite, the filtrate was diluted with water (20 mL) and extracted with dichloromethane (2 x 50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with diethyl ether, filtered and dried under vacuum to obtain tert-butyl 5-(3-((1-((3-aminobenzyl)sulfonyl)-2,2-dimethylpiperidin-4-yl)amino)-4-fluorophenyl)-4-chloro-3-(2-ethoxy-2-oxoethoxy)thiophene-2-carboxylate (A-123a / b). This material was subjected to chiral SFC to separate isomers. Purification method: Column Name: Chiralcel OJ-H; Flow rate: 5 mL / min; Co-solvent: 50%; Cosolvent Name: 0.5% isopropyl amine in IPA; Outlet Pressure: 100 bar; Injected Volume: 5 pL / min; Temperature: 35 °C] to afford ZerZ-butyl 5-[3-[[(4S)-l-[(3-aminophenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]-4-fluoro-phenyl]-4-chloro-3-(2-ethoxy-2-oxo-ethoxy)thiophene-2-carboxylate (A-123a, first eluted fraction, 500 mg, 682.83 pmol, 46% yield) and ZerZ-butyl 5-[3-[[(4R)-l-[(3-aminophenyl)methylsulfonyl] -2,2-dimethyl-4-piperidyl] amino] -4-fluoro-phenyl]-4-chloro-3 -(2-ethoxy-2-oxo-ethoxy)thiophene-2-carboxylate (A-123b, second eluted fraction, 500 mg, 647.64 pmol, 44% yield). LCMS (ES-): m / z 709.8 [M - H]“. Step 3: 2-[[5-[3-[[(4S)-l-[(3-aminophenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]-4-fluoro-phenyl] -2- / ert-butoxycarbonyl-4-chloro-3-thienyl] oxy] acetic acid (A-124) 2-[[5-[3-[[(4S)-l-[(3-aminophenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]-4-fluoro-phenyl]-2-ZerZ-butoxycarbonyl-4-chloro-3-thienyl]oxy]acetic acid (A-124, 460 mg, 648.65 pmol, 92% yield) was synthesized from ZerZ-butyl 5-[3-[[(4S)-l-[(3-aminophenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]-4-fluoro-phenyl]-4-chloro-3-(2-ethoxy-2-oxo-ethoxy)thiophene-2-carboxylate (A-123a) in a similar fashion to Compound A-9, except using a 1:1 ratio of THF / water. Upon completion, the reaction mixture was diluted with water and extracted with ethyl acetate (2 x). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. LCMS (ES+): m / z 682.8 [M + H]+. Step 4: 5-[3-[|(4S)-l-|(3-aminophenyl)methylsulfonyl|-2,2-dimethyl-4-piperidyl|amino|-4-fluoro-phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-125) 5-[3-[[(4S)-l-[(3-aminophenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]-4-fluoro-phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-125, 130 mg, 167.39 pmol, 76% yield, TFA salt) was synthesized from 2-[[5-[3-[[(4S)-l-[(3-aminophenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]-4-fluoro-phenyl]-2-ZerZ-butoxycarbonyl-4-chloro-3-thienyl]oxy]acetic acid (A-124) in a similar fashion to Compound A-26, except using 30 eq. TFA. LCMS (ES-): m / z 625.7 [M - H]“. 5-[3-[[(4R)-l-[(3-ammophenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]-4-fluoro-phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-127) Step 1: 2-[[5-[3-[[(4R)-l-[(3-aminophenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]-4-fluoro-phenyl]-2-fert-butoxycarbonyl-4-chloro-3-thienyl]oxy]acetic acid (A-126) 2-[[5-[3-[[(4R)-l-[(3-aminophenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]-4-fluoro-phenyl]-2-ZerZ-butoxycarbonyl-4-chloro-3-thienyl]oxy]acetic acid (A-126, 450 mg, 631 pmol, 90% yield) was synthesized from tert-butyl 5-[3-[[(4R)-l-[(3-aminophenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]-4-fluoro-phenyl]-4-chloro-3-(2-ethoxy-2-oxo-ethoxy)thiophene-2-carboxylate (A-123b) in a similar fashion to Compound A-9, except using a 1:1 mixture of THF / water. Upon completion, the reaction mixture was diluted with water and extracted with ethyl acetate (2 x). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. LCMS (ES+): m / z 682.8 [M + H]+. Step 2: 5-[3-[[(4R)-l-[(3-aminophenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]-4-fluoro-phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-127) 5-[3-[[(4R)-l-[(3-aminophenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]-4-fluoro-phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-127, 135 mg, 175 pmol, 80% yield, TFA salt) was synthesized from 2-[[5-[3-[[(4R)-l-[(3-aminophenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]-4-fluoro-phenyl]-2-tert-butoxycarbonyl-4-chloro-3-thienyl]oxy]acetic acid (A-126) in a similar fashion to Compound A-26, except using 30 eq. TFA. LCMS (ES-): m / z 625.7 [M - H]“. 5-[3-[[(4>S)-l-[(3-aminophenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]-2-fluoro-phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-131) Step 1:      tert-butyl 4-chloro-5-[3-[[2,2-dimethyl-l-[(3-nitrophenyl)methylsulfonyl]-4- piperidyl]amino]-2-fluoro-phenyl]-3-(2-ethoxy-2-oxo-ethoxy)thiophene-2-carboxylate (A-128) tert-butyl 4-chloro-5-[3 - [[2,2-dimethyl-1 - [(3 -nitrophenyl)methylsulfonyl] -4-piperidyl] amino] -2-fluoro- 5 phenyl]-3-(2-ethoxy-2-oxo-ethoxy)thiophene-2-carboxylate (A-128, 1.3 g, 1.58 mmol, 68% yield) was synthesized from tert-butyl 5-(3-amino-2-fluorophenyl)-4-chloro-3-(2-ethoxy-2-oxoethoxy)thiophene-2-carboxylate (A-115) and 2,2-dimethyl-l-[(3-nitrophenyl)methylsulfonyl] piperidin-4-one (A-13B) in a similar fashion to Compound A-74a / b, except using 1.2 eq. A-13, 1.7 eq. MP-cyanoborohydride and 15 eq. acetic acid. LCMS (ES+): m / z 683.7 [M + H]+ (tert-butyl cleaved mass). Step 2: tert-butyl 5- [3- [ [(41?)-1 -[(3-aminophenyl)methylsulfonyl] -2,2-dimethyl-4-piperidyl| am ino] -2-fluoro-phenyl]-4-chloro-3-(2-ethoxy-2-oxo-ethoxy)thiophene-2-carboxylate (A-129a, first eluted fraction) and tert-butyl 5-[3-[[(45)-l-[(3-aminophenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl] am ino] -2-fluoro-phenyl] -4-chloro-3-(2-ethoxy-2-oxo-ethoxy)thiophene-2-carboxylate (A-129b, second eluted fraction) Configurations are arbitrarily assigned. Into a 50 mL single neck round bottom flask containing a well-stirred solution of tert-butyl 4-chloro-5-[3-[ [2,2-dimethyl-1 - [(3 -nitrophenyl)methylsulfonyl]-4-piperidyl] amino] -2-fluoro-phenyl] -3 -(2-ethoxy-2-oxo-ethoxy)thiophene-2-carboxylate (A-128, 1.3 g, 1.76 mmol) in a mixture of water (10 mL) and EtOH (10 mL) were added iron powder (490.36 mg, 8.78 mmol) and ammonium chloride (469.69 mg, 8.78 mmol). The reaction mixture was heated at 80 °C for 3 h. The reaction mixture was filtered through Celite, washing with DCM (30 mL). The filtrate was diluted with water (40 mL) and extracted with DCM (3 x 30 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (50-60% Ethyl acetate in pet-ether) to afford tert-butyl 5-(3-((l-((3-aminobenzyl)sulfonyl)-2,2-dimethylpiperidin-4-yl)amino)-2-fluorophenyl)-4-chloro-3-(2-ethoxy-2-oxoethoxy)thiophene-2-carboxylate (A-129a / b). This material was subjected to chiral SFC [Purification method: Column: Chiralpak OXH, Co-Solvent : 40%; Co-Solvent Name : 0.5% Isopropyl amine in IPA; Outlet Pressure: 100 bar; Injected volume : 10 pl\min; Temperature : 35 °C] to afford tert-butyl 5-[3-[[(41?)-l-[(3-aminophenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]-2-fluoro-phenyl]-4-chloro-3-(2-ethoxy-2-oxo-ethoxy)thiophene-2-carboxylate (A-129a, first eluted fraction, 380 mg, 520.72 pmol, 30% yield) as an off-white solid and tert-butyl 5-(3-(((45)-1-((3-aminophenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]-2-fluoro-phenyl]-4-chloro-3-(2-ethoxy-2-oxo-ethoxy)thiophene-2-carboxylate (A-129b, second eluted fraction, 290 mg, 401.07 pmol, 23% yield) as an off-white solid. LCMS (ES+): m / z 732.1 [M + Na]+. Step 3: 2- [ [5- [3- [ [(45)-1- |(3-aminophenyl)methylsulfonyl| -2,2-dimethyl-4-piperidyl] amino]-2-fluoro-phenyl] -2-fert-butoxycarbonyl-4-chloro-3-thienyl] oxy] acetic acid (A-130) 2-[[5-[3-[[(45)-l-[(3-aminophenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]-2-fluoro-phenyl]-2-tert-butoxycarbonyl-4-chloro-3-thienyl]oxy]acetic acid (A-130, 250 mg, 360.04 pmol, 91% yield) was synthesized from tert-butyl 5-[3-[[(45)-l-[(3-aminophenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]-2-fluoro-phenyl]-4-chloro-3-(2-ethoxy-2-oxo-ethoxy)thiophene-2-carboxylate (A-129b) in a similar fashion to Compound A-9, except using 3 eq. LiOH monohydrate in a 1:1 THF / water mixture. Upon completion, the reaction mixture was diluted with water and extracted with ethyl acetate (2 x). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. LCMS (ES-): m / z 679.8 [M - H]“. Step 4: 5-[3-[[(45)-l-[(3-aminophenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]-2-fluoro-phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-131) 5-[3-[[(45)-l-[(3-aminophenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]-2-fluoro-phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-131, 140 mg, 178.64 pmol, 81% yield, TFA salt) was synthesized from 2-[[5-[3-[[(4S)-l-[(3-aminophenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]-2-fluoro-phenyl]-2-tert-butoxycarbonyl-4-chloro-3-thienyl]oxy]acetic acid (A-130) in a similar fashion to Compound A-26, except using 59 eq. TFA. The residue was azeotroped with toluene (2 x). LCMS (ES+): m / z 626.2 [M + H]+. 5-[3-||(4J?)-l-|(3-aminophenyl)methylsulfonyl|-2,2-dimethyl-4-piperidyl|amino|-2-fluoro-phenyl|-3- (carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-133) Step 1:2-[[5-[3-[[(4 / f)-l-[(3-aminophenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]-2-fluoro-phenyl] -2- / ert-butoxycarbonyl-4-chloro-3-thienyl] oxy] acetic acid (A-132) 2-[[5-[3-[[(42?)-l-[(3-aminophenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]-2-fluoro-phenyl]-2-ZerZ-butoxycarbonyl-4-chloro-3-thienyl]oxy]acetic acid (A-133, 340 mg, 0.491 mmol, 94% yield) was synthesized from ZerZ-butyl 5-[3-[[(41?)-l-[(3-aminophenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]-2-fluoro-phenyl]-4-chloro-3-(2-ethoxy-2-oxo-ethoxy)thiophene-2-carboxylate (A-129a) in a similar fashion to Compound A-9, except using 3 eq. LiOH monohydrate in a 1:1 THF / water mixture. Upon completion, the reaction mixture was diluted with water and extracted with ethyl acetate (2 x). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. LCMS (ES-): m / z 680.1 [M - H]~. Step 2: 5-[3-[[(4.R)-l-[(3-aminophenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]-2-fluoro-phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-133) 5-[3-[[(47?)-l-[(3-aminophenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]-2-fluoro-phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-133, 140 mg, 0.174 mmol, 79% yield, TFA salt) was synthesized from 2-[[5-[3-[[(42?)-l-[(3-aminophenyl)methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]-2-fluoro-phenyl]-2- / ert-butoxycarbonyl-4-chloro-3-thienyl]oxy]acetic acid (A-132) in a similar fashion to Compound A-26, except using 59 equiv. TFA. The residue was azeotroped with toluene (2 x). LCMS (ES+): m / z 626.7 [M + H]+. 5-[3-[[l-[[3-(2-aminoethylamino)phenyl]methylsulfonyl]-4-piperidyl]amino]phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-136) o Step 1: tert-butyl 5-[3-|[l-|[3-|2-(tert-butoxycarbonylamino)ethylamino|phenyl|methylsulfonyl|-4-piperidyl]amino]phenyl]-3-(2- / ert-butoxy-2-oxo-ethoxy)-4-chloro-thiophene-2-carboxylate (A-135) tert-butyl              5-[3-[[l-[[3-[2-(tert-butoxycarbonylamino)ethylamino]phenyl]methylsulfonyl]-4- piperidyl]amino]phenyl]-3-(2-tert-butoxy-2-oxo-ethoxy)-4-chloro-thiophene-2-carboxylate (A-135, 350 mg, 273.85 pmol, 63% yield) was synthesized from tert-butyl 5-[3-[[l-[(3-aminophenyl)methylsulfonyl]-4-piperidyl]amino]phenyl]-3-(2-tert-butoxy-2-oxo-ethoxy)-4-chloro-thiophene-2-carboxylate (A-10) and tert-butyl A-(2-oxoethyl)carbamate (A-134) in a similar fashion to Compound A-74a / b, except using 2.3 eq. MP-cyanoborohydride. The material was which was triturated with diethyl ether and used in the next step without further purification. LCMS (ES+): m / z 835.2 [M + H]+. Step 2: 5-[3-[[l-[[3-(2-aminoethylamino)phenyl]methylsulfonyl]-4-piperidyl]amino]phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-136) 5-[3 - [[ 1 - [[3 -(2-aminoethylamino)phenyl]methylsulfonyl] -4-piperidyl] amino]phenyl]-3 -(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-136, 160 mg, 184.67 pmol, 36% yield, TFA salt)          was          synthesized          from          tert-butyl          5-[3-[[l-[[3-[2-(tert- butoxycarbonylamino)ethylamino]phenyl]methylsulfonyl]-4-piperidyl]amino]phenyl]-3-(2-tert-butoxy-2-oxo-ethoxy)-4-chloro-thiophene-2-carboxylate (A-135) in a similar fashion to Compound A-62, except using 67 eq. TFA. The material was triturated with diethyl ether. LCMS (ES+): m / z 623.1 [M + H]+. 5-[3-[[(4S)-l-[[3-(azetidine-3-carbonylamino)-4-fluoro-phenyl]methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]-2-fluoro-phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-139) Step 1: tert-butyl 3-[[5-[[(4S)-4-[3-[5-tert-butoxycarbonyl-3-chloro-4-(2-ethoxy-2-oxo-ethoxy)-2-thienyl]-2-fluoro-anilino]-2,2-dimethyl-l-piperidyl]sulfonylmethyl]-2-fluoro- phenyl] carbamoyl] azetidine-1-carboxylate (A-137a, first eluted fraction) and tert-butyl 3-[[5-[[(4R)-5 4-[3-[5- / ert-butoxycarbonyl-3-chloro-4-(2-ethoxy-2-oxo-ethoxy)-2-thienyl]-2-fluoro-anilino]-2,2- dimethyl-l-piperidyl]sulfonylmethyl]-2-fluoro-phenyl]carbamoyl]azetidine-l-carboxylate (A-137b, second eluted fraction) Configurations are arbitrarily assigned. tert-butyl 3-[[5-[[(4)-4-[3-[5-tert-butoxycarbonyl-3-chloro-4-(2-ethoxy-2-oxo-ethoxy)-2-thienyl]-2- 10 fluoro-anilino]-2,2-diniethyl-l-piperidyl]sulfonylmethyl]-2-fluoro-phenyl]carbamoyl]azetidine-l- carboxylate (A-137a / b, 900 mg, 96.5%) was synthesized from tert-butyl 3-[[5-[(2,2-dimethyl-4-oxo-l-piperidyl)sulfonylmethyl]-2-fluoro-phenyl]carbamoyl]azetidine-l-carboxylate (A-96) and tert-butyl 5-(3-amino-2-fluorophenyl)-4-chloro-3-(2-ethoxy-2-oxoethoxy)thiophene-2-carboxylate (A-115) in a similar fashion to Compound A-74a / b, except using 1.2 eq. A-115,1.7 eq. MP-cyanoborohydride and 1 mL acetic 15 acid. LCMS (ES-): m / z 909.2 [M - H]“. A-137a / b was subjected to chiral SFC to separate isomers [Purification method: Column Name: Lux Al; Flow rate: 4 mL / min; Co-Solvent: 30%; Co-Solvent Name: IPA; Outlet Pressure: 100 bar; Injected Volume: 6 pL\min; Temperature: 35 °C] to afford ZerZ-butyl 3-[[5-[[(4S)-4-[3-[5-ZerZ-butoxycarbonyl-3-chloro-4-(2-ethoxy-2-oxo-ethoxy)-2-thienyl]-2-fluoro-anilino]-2,2-dimethyl-l-piperidyl]sulfonylmethyl]-2-fluoro-phenyl]carbamoyl]azetidine-1-carboxylate (A-137a, first eluted fraction, 380 mg, 416.91 pmol, 36% yield) and ZerZ-butyl 3 -[ [5- [[(4R)-4-[3-[5-ZerZ-butoxycarbonyl-3-chloro-4-(2-ethoxy-2-oxo-ethoxy)-2-thienyl]-2-fluoro-anilino]-2,2-dimethyl-l-piperidyl]sulfonylmethyl]-2-fluoro- phenyl]carbamoyl]azetidine-1-carboxylate (A-137b, second eluted fraction, 340 mg, 369.29 pmol, 32% yield). Step 2:        2-[[2-fert-butoxycarbonyl-5-[3-[[(4S)-l-[[3-[(l-fert-butoxycarbonylazetidine-3- carbonyl)amino]-4-fluoro-phenyl]methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]-2-fluoro-phenyl]-4-chloro-3-thienyl] oxy] acetic acid (A-138) 2-[[2-rerr-butoxycarbonyl-5-[3-[[(4S)-l-[[3-[(l-Zerr-butoxycarbonylazetidine-3-carbonyl)amino]-4-fluoro-phenyl]methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]-2-fluoro-phenyl]-4-chloro-3- thienyl]oxy]acetic acid (A-138, 320 mg, 328.91 pmol, 79% yield) was synthesized from ZerZ-butyl 3-[[5-[[(4S)-4-[3-[5-ZerZ-butoxycarbonyl-3-chloro-4-(2-ethoxy-2-oxo-ethoxy)-2-thienyl]-2-fluoro-anilino]-2,2-dimethyl-l-piperidyl]sulfonylmethyl]-2-fluoro-phenyl]carbamoyl]azetidine-l-carboxylate (A-137a) in a similar fashion to Compound A-9, except using 3 eq. LiOH monohydrate in a 1:1 mixture of THF / water. Upon completion, the mixture was diluted with water and extracted with Ethyl acetate (2 x). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. LCMS (ES-): m / z 883.42 [M - H]“. Step 3: 5-[3-[[(4S)-l-[[3-(azetidine-3-carbonylamino)-4-fluoro-phenyl]methylsulfonyl]-2,2-dimethyl-4-piperidyl|amino|-2-fluoro-phenyl|-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-139) 5-[3-[[(4S)-l-[[3-(azetidine-3-carbonylamino)-4-fluoro-phenyl]methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]-2-fluoro-phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-139, 295 mg, 324.14 pmol, 99% yield, TFA salt) was synthesized from 2-[[2-ZerZ-butoxycarbonyl-5-[3-[[(4S)-l-[[3-[(l-ZerZ-butoxycarbonylazetidine-3-carbonyl)amino]-4-fluoro-phenyl]methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]-2-fluoro-phenyl]-4-chloro-3-thienyl]oxy]acetic acid (A-138) in a similar fashion to Compound A-62, except using 5 eq. TFA. The material was triturated with diethyl ether. LCMS (ES+): m / z 727.1 [M + H]+. 5-[3-||l-[|3-(azetidine-3-carbonylamino)-4-fluoro-phenyl|methylsulfonyl|-2,2-dimethyl-4-piperidyl|amino|-2-fluoro-phenyl|-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-141) Step 1: 2-[[2-tert-butoxycarbonyl-5-[3-[[l-[[3-[(l-ter / -butoxycarbonylazetidine-3-carbonyl)amino]-4-fluoro-phenyl]methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]-2-fluoro-phenyl]-4-chloro-3-thienyl] oxy] acetic acid (A-140) 2-[[2-tert-butoxycarbonyl-5-[3-[[l-[[3-[(l-tert-butoxycarbonylazetidine-3-carbonyl)amino]-4-fluoro-phenyl]methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]-2-fluoro-phenyl]-4-chloro-3-thienyl]oxy]acetic acid (A-140, 110 mg, 92.14 pmol, 65% yield) was synthesized from tert-butyl 3-[[5-[[4-[3-[5-tert-butoxycarbonyl-3-chloro-4-(2-ethoxy-2-oxo-ethoxy)-2-thienyl]-2-fluoro-anilino]-2,2-dimethyl-l-piperidyl]sulfonylmethyl]-2-fluoro-phenyl]carbamoyl]azetidine-l-carboxylate (A-137a / b) in a similar fashion to Compound A-9, except using 3 eq. LiOH monohydrate in a 1:1 THF / water mixture. Upon completion, the reaction mixture was diluted with water and extracted with ethyl acetate (2 x). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. LCMS (ES-): m / z 881.2 [M - H]“. Step 2: 5-[3-[[l-[[3-(azetidine-3-carbonylamino)-4-fluoro-phenyl]methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]-2-fluoro-phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-141) 5-[3 - [[ 1 - [[3 -(azetidine-3 -carbonylamino)-4-fluoro-phenyl]methylsulfonyl] -2,2-dimethyl-4-piperidyl]amino]-2-fluoro-phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-141) was synthesized from 2-[[2-tert-butoxycarbonyl-5-[3-[[l-[[3-[(l-tert-butoxycarbonylazetidine-3-carbonyl)amino]-4-fluoro-phenyl]methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]-2-fluoro-phenyl]-4-chloro-3-thienyl]oxy]acetic acid (A-140) in a similar fashion to Compound A-62, except using 5 eq. TFA. The material was triturated with diethyl ether. LCMS (ES+): m / z 727.0 [M + H]+. 5-[3-||(4R)-l-[|3-(azetidine-3-carbonylamino)-4-fluoro-phenyl|methylsulfonyl|-2,2-dimethyl-4-piperidyl]amino]-2-fluoro-phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-143) Step 1:       2-[[2-tert-butoxycarbonyl-5-[3-[[(4R)-l-[[3-[(l-tert-butoxycarbonylazetidine-3- carbonyl)amino]-4-fluoro-phenyl]methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]-2-fluoro-phenyl]-4-chloro-3-thienyl] oxy] acetic acid (A-142) 2-[[2-tert-butoxycarbonyl-5-[3-[[(4R)-l-[[3-[(l-tert-butoxycarbonylazetidine-3-carbonyl)amino]-4-fluoro-phenyl]methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]-2-fluoro-phenyl]-4-chloro-3-thienyl]oxy]acetic acid (A-142, 280 mg, 71% yield) was synthesized from tert-butyl 3-[[5-[[(4R)-4-[3-[5-tert-butoxycarbonyl-3-chloro-4-(2-ethoxy-2-oxo-ethoxy)-2-thienyl]-2-fluoro-anilino]-2,2-dimethyl-l-piperidyl]sulfonylmethyl]-2-fluoro-phenyl]carbamoyl]azetidine-l-carboxylate (A-137b) in a similar fashion to Compound A-9, except using 3 eq. LiOH monohydrate in a 1:1 THF / water mixture. Upon completion, the reaction mixture was diluted with water and extracted with ethyl acetate (2 x). The combined organic layers were washed with brine (10 mL) and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. LCMS (ES+): m / z 783.2 [M - Boc + H]+. Step 2: 5-[3-[[(4R)-l-[[3-(azetidine-3-carbonylamino)-4-fluoro-phenyl]methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]-2-fluoro-phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-143) 5-[3-[[(4R)-l-[[3-(azetidine-3-carbonylamino)-4-fluoro-phenyl]methylsulfonyl]-2,2-dimethyl-4-piperidyl]amino]-2-fluoro-phenyl]-3-(carboxymethoxy)-4-chloro-thiophene-2-carboxylic acid (A-143, 250 mg, 96% yield, TFA salt) was synthesized from 2-[[2-ZerZ-butoxycarbonyl-5-[3-[[(4R)-l-[[3-[(l-ZerZ-butoxy carbonylazetidine-3 -carbonyl)amino] -4-fluoro-phenyl]methylsulfonyl] -2,2-dimethyl-4- piperidyl]amino]-2-fluoro-phenyl]-4-chloro-3-thienyl]oxy]acetic acid (A-142) in a similar fashion to Compound A-62, except using 1 eq. TFA. The material was triturated with diethyl ether. LCMS (ES+): 5   m / z 727.0 [M + H]+. 3-[2-|2-|3-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl|propoxy|ethoxy|ethoxy|propanoic acid (B-7) Step 2 B-5 10 Step 1: ZerZ-butyl 3-[2-(2-prop-2-ynoxyethoxy)ethoxy]propanoate (B-3) Into a 100 mL two neck round bottom flask containing a well-stirred suspension of ZerZ-butyl 3-[2-(2-hydroxyethoxy)ethoxy]propanoate (B-l, 1 g, 4.27 mmol) in THF (20 mL) was added sodium hydride (60% dispersion in mineral oil) (88.31 mg, 3.84 mmol) and 3-bromoprop-1-yne (B-2, 507.75 mg, 4.27 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction was quenched with water 15   (10 mL) and the volatiles were removed under reduced pressure. The residue was diluted with Ethyl acetate (200 mL) and washed with water (2 x 150 mL). The Ethyl acetate layer was dried over anhydrous sodium sulfate and solvent was removed under reduced pressure. The residue was purified by flash silica gel column chromatography (40% Ethyl acetate in petroleum ether) to afford ZerZ-butyl 3-[2-(2-prop-2-ynoxyethoxy)ethoxy]propanoate (B-3, 340 mg, 1.25 mmol, 29% yield) as a pale yellow liquid. 'H NMR (400 MHz, DMSO-t / 6): 8 4.13 (t, J= 2.32 Hz, 2H), 3.59-3.32 (m, 11H), 2.41 (t, J= 6.20 Hz, 2H), 1.39 (s, 9H). Step 2: tert-butyl 3-[2-[2-[3-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]prop-2-ynoxy] ethoxy] ethoxy] propanoate (B-5) Into a 25 mL pressure tube containing a well-stirred solution of 4-bromo-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (B-4, 340 mg, 1.01 mmol) and tert-butyl 3-[2-(2-prop-2-ynoxyethoxy)ethoxy]propanoate (B-3, 329.59 mg, 1.21 mmol) in DMF (5 mL) was added triethylamine (1.53 g, 15.13 mmol, 2.11 mL) at room temperature. The reaction mixture was purged with nitrogen gas for 15 min. Then PdCh(PPh3) (70.79 mg, 100.85 pmol), copper (I) iodide (38.41 mg, 201.71 pmol, 6.84 pL) and triphenylphosphine (26.45 mg, 100.85 pmol) were added and purged with nitrogen gas for another 5 min. The tube was sealed, and the reaction mixture was stirred at 90 °C for 16 h. The mixture was cooled to room temperature, diluted with Ethyl acetate (40 mL) and washed with water (2 x 30 mL). The Ethyl acetate layer was dried over anhydrous sodium sulfate and solvent was removed under reduced pressure. The residue was purified by flash silica gel column chromatography (40% Ethyl acetate in petroleum ether) to obtain tert-butyl 3-[2-[2-[3-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]prop-2-ynoxy]ethoxy]ethoxy]propanoate (B-5, 240 mg, 354.18 pmol, 35% yield) as a pale yellow solid. LCMS (ES-): m / z 527.6 [M - H]-. Step 3:        tert-butyl 3-[2-[2-[3-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4- yl] propoxy] ethoxy] ethoxy] propanoate (B-6) In to a 100 mL tinyclave containing a well-stirred solution of tert-butyl 3-[2-[2-[3-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]prop-2-ynoxy]ethoxy]ethoxy]propanoate (B-5,240mg, 454.07 pmol) in ethanol (15 mL) was added palladium (10% on carbon) (106.31 mg, 99.9 pmol) under nitrogen atmosphere. The reaction mixture was then hydrogenated under 5 kg pressure for 16 h. The reaction mixture was filtered through Celite, washed with ethanol (20 mL) and the filtrate concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (40% Ethyl acetate in petroleum ether) to obtain tert-butyl 3-[2-[2-[3-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]propoxy]ethoxy]ethoxy]propanoate (B-6, 130 mg, 244.09 pmol, 54% yield) as a pale yellow solid. LCMS (ES-): m / z 531.6 [M - H]“. Step                 4:                 3-[2-[2-[3-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4- yl] propoxy] ethoxy] ethoxy] propanoic acid (B-7) 3-[2-[2-[3-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]propoxy]ethoxy]ethoxy]propanoic acid (B-7,90 mg, 179.44 pmol, 35% yield, TFA salt) was synthesized from tert-butyl 3-[2-[2-[3-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]propoxy]ethoxy]ethoxy]propanoate (B-6) in a similar fashion to Compound A-26, except using 5 eq. TFA. LCMS (ES+): m / z 477.5 [M + H]+. 7-[[2-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]amino]acetyl]amino]heptanoic acid (B-ll) Step          1:          methyl          7-[[2-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4- yl] amino] acetyl] amino] heptanoate (B-l 0) Into a 50 mL round bottom flask containing a well-stirred solution of 2-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl] amino] acetic acid (B-8, 0.190 g, 573.53 pmol) in anhydrous DMF (0.5 mL) was added triethylamine (174.11 mg, 1.72 mmol, 239.82 pL) and 1-propanephosphonic anhydride solution (50% in Ethyl acetate) (202.00 mg, 630.89 pmol, 0.40 mL). After 10 min, methyl 7-aminoheptanoate (B-9, 91.32 mg, 573.53 pmol) was added. After 16 h, the volatiles were removed under reduced pressure and the residue diluted with water (50 mL) and extracted with Ethyl acetate (2 x 100 mL). Combined organic layers were dried over sodium sulfate, filtered and the solvent removed under reduced pressure. The residue was purified by flash silica gel (230-400 mesh) column chromatography (30-40% Ethyl acetate in petroleum ether) to afford methyl 7-[[2-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]amino]acetyl]amino]heptanoate (B-10, 120 mg, 180.32 pmol, 31% yield) as an off white solid. LCMS (ES+): m / z 473.3 [M + H]+. Step 2: 7-[[2-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]amino]acetyl]amino]heptanoic acid (B-ll) Into a 50 mL single neck round bottom flask containing a well-stirred solution of methyl 7-[[2-[[2-(2,6-dioxo-3-piperidy 1)-1,3-dioxo-isoindolin-4-yl]amino]acetyl]amino]heptanoate (B-10, 120.00 mg, 253.97 pmol) in 1,2-dichloroethane (15 mL) was added trimethyltin hydroxide (742.80 mg, 4.11 mmol). The reaction mixture was heated at 80 °C for 16 h. The volatiles were removed under reduced pressure and the residue purified by reverse phase prep HPLC [Purification method: Column: SunFire C18 (19 x 150mm) 5 pm, Mobile phase A: 0.1% formic acid in water, Mobile phase B: MeCN; Flow Rate: 15.0 mL / min] to afford 7-[[2-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]amino]acetyl]amino]heptanoic acid (fill, 100 mg, 207.21 pmol, 82% yield, Formic acid salt) as a white solid. LCMS (ES+): m / z 459.1 [M + H]+. 3- [2- [2- [ [2- [2-(2,6-dioxo-3-piperidyl)-l ,3-dioxo-isoindolin-4- yl] oxyacetyl] amino] ethoxy] ethoxy] propanoic acid (B-15) o                 o Step 1:        tert-butyl 3-[2-[2-[[2-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4- yl] oxyacetyl] amino] ethoxy] ethoxy] propanoate (B-l 4) tert-butyl                                   3-[2-[2-[[2-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4- 5 yl]oxyacetyl]amino]ethoxy]ethoxy]propanoate (B-14, 120 mg, 206.01 pmol, 46% yield) was synthesized from 2-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]oxyacetic acid (B-12) and tert-butyl 3-[2-(2-aminoethoxy)ethoxy]propanoate (B-13) in a similar fashion to Compound B-10, except using 2 eq. propanephosphonic anhydride (50% in ethyl acetate). LCMS (ES-): m / z 546.2 [M - H]“. Step                 2:                 3-[2-[2-[[2-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4- 10   yl] oxyacetyl] amino] ethoxy] ethoxy] propanoic acid (B-15) 3-[2-[2-[[2-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4- yl]oxyacetyl]amino]ethoxy]ethoxy]propanoic acid (B-15,65 mg, 117.71 pmol, 72% yield) was synthesized from               tert-butyl               3-[2-[2-[[2-[2-(2,6-dioxo-3-piperidyl)-l ,3-dioxo-isoindolin-4- yl]oxyacetyl]amino]ethoxy]ethoxy]propanoate (B-14) in a similar fashion to Compound A-26, except 15 using 5 eq. TFA. The material was used in the next step without purification. LCMS (ES+): m / z 492.1 [M + H]+. 7-[[2-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]-methyl-amino]acetyl]amino]heptanoic acid (B-19) Step 1:       methyl 7-[[2-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxoisoindolin-4-yl]-methyl- amino] acetyl] amino] heptanoate (B-l 8) Into a 50 mL single neck round bottom flask containing a well-stirred solution of 2-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]-methyl-amino]acetic acid (B-16, 150 mg, 434.40 pmol) in DMF (5 mL) were added EtsN (219.78 mg, 2.17 mmol, 302.73 pL) and 1-propanephosphonic anhydride (50% in Ethyl acetate) (207.33 mg, 651.60 pmol, 0.415 mL) at room temperature. After 10 min, 7-amino-heptanoic acid methyl ester hydrochloride (B-17, 102.01 mg, 521.28 pmol) was added. After 16 h, additional 7-aminoheptanoic acid methyl ester hydrochloride (B-17,425 mg, 2170 pmol) andEtsN (438 mg, 4.34 mmol) were added in two portions over 2 h and stirring was continued for another 20 h. The reaction mixture was diluted with Ethyl acetate (30 mL) and washed with water (2 x 10 mL) and brine (10 mL), dried over sodium sulfate, filtered and solvent removed to obtain methyl 7-[[2-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]-methyl-amino]acetyl]amino]heptanoate (B-18, 250 mg, 272.34 pmol, 63% yield) as a yellow solid. The material was used in the next step without further purification. LCMS (ES-): m / z 485.2 [M - H]“. Step              2:               7- [ [2- [ [2-(2,6-dioxo-3-piperidyl)- l,3-dioxo-isoindolin-4-yl] -methyl amino] acetyl] amino] heptanoic acid (B-19) 7-[[2-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]-methyl-amino]acetyl]amino]heptanoic acid (B-19, 32 mg, 50.12 pmol, 12% yield) was synthesized from methyl 7-[[2-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]-methyl-amino]acetyl]amino]heptanoate (B-18) in a similar fashion to Compound B-ll, except using 20 eq. trimethyltin hydroxide added in two portions over 16 h. Upon completion, the reaction mixture was concentrated to dryness before Ethyl acetate (50 mL) and 0.5 N HC1 solution (20 mL) were added and stirred for 30 min. The layers were separated, the aqueous layer was extracted with Ethyl acetate (30 mL) and 15% MeOH in DCM. The combined organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by reverse phase preparative HPLC [Column: SunFire C18 (19 x 150 mm) 5 pm, Mobile phase: 0.1% TFA in water and MeCN], LCMS (ES+): m / z 473.3 [M + H]+. 3-[2-[2-[2-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]oxyethoxy]ethoxy]ethoxy]propanoic Step 1: tert-butyl 3-[2-[2-(2-bromoethoxy)ethoxy]ethoxy]propanoate (B-21) Into a 50 mL two neck round bottom flask containing a well-stirred solution of tert-butyl 3-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]propanoate (B-20,1.0 g, 3.59 mmol) in THF (15 mL) were added triphenyl phosphine (1.41 g, 5.39 mmol) and carbon tetrabromide (2.38 g, 7.19 mmol, 696.75 pL) at room temperature. After 16 h, the reaction mixture was diluted with ice water (75 mL) and extracted with ethyl acetate (3 x 75 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel (100-200 mesh) column chromatography (50% Ethyl acetate in petroleum ether) to afford tert-butyl 3-[2-[2-(2-bromoethoxy)ethoxy]ethoxy]propanoate (B-21,1.2 g, 3.49 mmol, 97% yield) as colourless liquid. LCMS (ES+): m / z 285.0 [M - tBu + H]+. Step 2: tert-butyl 3-[2-[2-[2-(l,3-dioxoisobenzofuran-4-yl)oxyethoxy]ethoxy]ethoxy]propanoate (B-23) Into a 20 mL microwave vial containing a well-stirred solution of 4-hydroxyisobenzofuran-1,3-dione (B-22, 0.5 g, 3.05 mmol) in DMF (10 mL) was added potassium acetate (448.51 mg, 4.57 mmol, 285.67 pL) and stirred for 10 min. Then, tert-butyl 3-[2-[2-(2-bromoethoxy)ethoxy]ethoxy]propanoate (B-21, 1.25 g, 3.66 mmol) was added. The tube was sealed and irradiated under microwave conditions at 100 °C for 3 h. The reaction mixture was diluted with water and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with ice water (2 x 20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford / er / -butyl 3-[2-[2-[2-(l,3-dioxoisobenzofuran-4-yl)oxyethoxy]ethoxy]ethoxy]propanoate (B-23, 1.5 g, 397.58 pmol, 13% yield) as thick red liquid which was used in the next step without further purification. LCMS (ES+): m / z 369.2 [M -tBu + H]+. Step             3:             ter / -butyl3- [2- [2- [2- [2-(2,6-dioxo-3-piperidyl)-l ,3-dioxo-isoindolin-4- yl] oxyethoxy] ethoxy] ethoxy] propanoate (B-25) Into a 100 mL microwave vial containing a well-stirred solution of tert-butyl 3-[2-[2-[2-(l,3-dioxoisobenzofuran-4-yl)oxyethoxy]ethoxy]ethoxy]propanoate (B-23, 1.5 g, 3.53 mmol) in acetic acid (10 mL) was added sodium acetate (579.80 mg, 7.07 mmol, 378.95 pL) and the suspension was stirred for 10 min. Then, 3-aminopiperidine-2,6-dione hydrochloride (B-24, 581.67 mg, 3.53 mmol) was added. The tube was sealed and subjected to microwave irradiation at 110 °C for 5 h. The reaction mixture was diluted with water (75 mL) and extracted with Ethyl acetate (3 x 75 mL). The combined organic layer was washed with ice water (2 x 50 mL) and brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase prep HPLC [Purification method: Column: SunFire Cl 8 (19 x 150 mm) 5 pm; Mobile phase A: 0.1% TFA in water and Mobile phase B: MeCN] to afford tertbutyl                                        3-[2-[2-[2-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4- yl]oxyethoxy]ethoxy]ethoxy]propanoate (B-25, 320 mg, 573.07 pmol, 16% yield) as a light yellow solid. LCMS (ES+): m / z 479.0 [M - tBu + H]+. Step                  4:                  3- [2- [2- [2- [2-(2,6-dioxo-3-piperidyl)-l ,3-dioxo-isoindolin-4- yl] oxyethoxy] ethoxy] ethoxy] propanoic acid (B-26) 3-[2-[2-[2-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]oxyethoxy]ethoxy]ethoxy]propanoic acid (B-26, 300 mg, 508.27 pmol, 85% yield) was synthesized from / er / -butyl 3-[2-[2-[2-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]oxyethoxy]ethoxy]ethoxy]propanoate (B-25) in a similar fashion to Compound A-26, except using 6.5 eq. TFA. The material was used in the next step without further purification. LCMS (ES+): m / z 479.1 [M + H]+. 3- [2-12- [ [2- [2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4- yl] oxyacetyl] amino] ethoxy] ethoxy] propanoic acid (B-29) Step 1: tert-butyl 3-[2-[2-[[2-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]oxyacetyl]-amino] ethoxy] ethoxy] propanoate (B-28) Into a 50 mL single neck round bottom flask containing a well-stirred solution of 2-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]oxyacetic acid (B-27, 125 mg, 392.73 pmol) and tert-butyl 3-[2-(2-aminoethoxy)ethoxy]propanoate (B-13, 91.63 mg, 392.73 pmol) in DMF (2 mL) were added DIPEA (152.27 mg, 1.18 mmol, 205.22 pL) and HATU (225.18 mg, 589.10 pmol). After 3 h, Ethyl acetate (30 mL) was added to the reaction mixture and washed with water (2x10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash silica gel (230-400 mesh) column chromatography (85% Ethyl acetate in pet. ether) to afford tert-butyl 3-[2-[2-[[2-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]oxyacetyl]amino]ethoxy]ethoxy]propanoate (B-28, 140 mg, 220.85 pmol, 56% yield) as an off-white solid. LCMS (ES-): m / z 532.2 [M - H]“. Step                    2:                    3- [2- [2- [ [2- [2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4- yl] oxyacetyl] amino] ethoxy] ethoxy] propanoic acid (B-29) 3-[2-[2-[[2-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]oxyacetyl]amino]ethoxy]ethoxy]propanoic acid (B-29, 70 mg, 143.53 pmol, 48% yield) was synthesized from tert-butyl 3-[2-[2-[[2-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]oxyacetyl]amino]ethoxy]ethoxy]propanoate (B-28) in a similar fashion to Compound A-26, except the material was purified by reverse phase preparative HPLC [Column: SunFire C18 (19 x 150 mm) 5 pm, Mobile phase: 0.1% TFA in water and MeCN], LCMS (ES+): m / z 478.2 [M + H]+. 7-[[2-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]oxyacetyl]amino]heptanoic acid (B-31) o            o Step 1: methyl 7-[[2-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]oxyacetyl]amino]heptanoate (B-30) methyl 7-[[2-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]oxyacetyl]amino]heptanoate (B-30, 280 mg, 539.11 pmol, 66% yield) was synthesized from 2-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]oxyacetic acid (B-27) and methyl 7-aminoheptanoate hydrochloride (B-9) in a similar fashion to Compound B-10, except using 2 eq. triethylamine and 2 eq. 1-propanephosphonic anhydride solution (50% in Ethyl acetate). UPLC-MS (ES+): m / z 460.5 [M + H]+. Step 2: 7-[[2-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]oxyacetyl]amino]heptanoic acid (B-31) 7-[[2-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]oxyacetyl]amino]heptanoic acid (B-31, 52 mg, 115.56 pmol, 19% yield) was synthesized from methyl 7-[[2-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]oxyacetyl]amino]heptanoate (B-30) in a similar fashion to Compound B-l 1, except upon completion, the solvent was removed under reduced pressure and the residue was partitioned between Ethyl acetate and aq. 0.5 N HC1 solution and stirred for 30 min. The layers were separated, the aqueous layer was extracted with ethyl acetate (2 x) and the combined organic layer was washed with 0.5 N HC1 and brine, dried over sodium sulfate, concentrated and purified by reverse phase prep HPLC [Purification method: Column: SunFire C18 (19 x 150 mm) 5 pm, Mobile phase: 0.1% TFA in water andMeCN]. LCMS (ES+): m / z 446.2 [M + H]+. 1 - [2- [[2-(2,6-dioxo-3-piperidyl)-l ,3-dioxo-isoindolin-4-yl] amino] acetyl] piperidine-4-carboxylic acid (B-33) o B-8                Step 1                     B-33 Step 1:     l-[2-||2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl|amino|acetyl|piperidine-4- carboxylic acid (B-33) l-[2-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]amino]acetyl]piperidine-4-carboxylic acid (B-33, 55 mg, 121.83 pmol, 45% yield, TFA salt) was synthesized from 2-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]amino]acetic acid (B-8) and piperidine-4-carboxylic acid (B-32) in a similar fashion to Compound B-10, except using 5 eq. triethylamine and 2 eq. 1-propanephosphonic anhydride solution (50% in ethyl acetate). Upon completion, the volatiles were removed under reduced pressure and the residue was purified by reverse phase prep HPLC [Purification method: Column: SunFire -Cl8 100 mm, Mobile phase A: 0.1% TFA in Water; Mobile phase B: MeCN, Flow Rate:15.0mL / min], LCMS (ES+): m / z 443.1 [M + H]+. 7-[[2-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]amino]acetyl]amino]heptanoic acid (B-36) o Step            1:            methyl            7-[[2-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4- yl] amino] acetyl] amino] heptanoate (B-35) methyl 7-[[2-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]amino]acetyl]amino]heptanoate (B-35, 125 mg, 150.03 pmol, 10% yield) was synthesized from 2-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl] amino] acetic acid (B-34) and methyl 7-aminoheptanoate hydrochloride (B-9) in a similar fashion to Compound B-10, except using 2 eq. 1-propanephosphonic anhydride solution (50% in Ethyl acetate). LCMS (ES+): m / z 459.1 [M + H]+. Step 2: 7-[[2-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]amino]acetyl]amino]heptanoic acid (B-36) 7-[[2-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]amino]acetyl]amino]heptanoic acid (B-36, 80 mg, 172.35 pmol, 32% yield) was synthesized from methyl 7-[[2-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]amino]acetyl]amino]heptanoate (B-35) in a similar fashion to Compound B-ll, except using 5 eq. trimethyltin hydroxide. LCMS (ES+): m / z 445.1[M + H]+. 3-(2-(2-(3-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)propoxy)ethoxy)ethoxy)propanoic acid Step 1: tert-butyl   3-(2-(2-((3-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)prop-2-yn-l- yl)oxy)ethoxy)ethoxy)propanoate (B-38) tert-butyl                      3-(2-(2-((3-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)prop-2-yn-l- yl)oxy)ethoxy)ethoxy)propanoate (B-38, 100 mg, 153.53 pmol, 12 % yield) was synthesized from tertbutyl 3-[2-(2-prop-2-ynoxyethoxy)ethoxy]propanoate (B-3) and 3-(5-bromo-l-oxo-isoindolin-2-yl)piperidine-2,6-dione (B-37) in a similar fashion to Compound B-5, except using 0.1 eq. Cui. LCMS (ES+): m / z 459.1 [M - tBu + H]+. Step 2:     tert-butyl     3-(2-(2-(3-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)propoxy) ethoxy)ethoxy)propanoate (B-39) tert-butyl                                      3-(2-(2-(3-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5- yl)propoxy)ethoxy)ethoxy)propanoate (B-39, 60 mg, 65.9 pmol, 27% yield) was synthesized from tertbutyl                          3 -(2-(2-((3 -(2-(2,6-dioxopiperidin-3-y 1)-1 -oxoisoindolin-5 -yl)prop-2-yn-1 - yl)oxy)ethoxy)ethoxy)propanoate (B-38) in a similar fashion to Compound B-6, except using 0.1 eq. palladium (10% on carbon). The material was used in the next step without further purification. LCMS (ES+): m / z 463.1 [M - tBu + H]+. Step                  3:                   3-(2-(2-(3-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5- yl)propoxy)ethoxy)ethoxy)propanoic acid (B-40) 3-(2-(2-(3-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)propoxy)ethoxy)ethoxy)propanoic acid (B-40, 50 mg, 104.87 pmol, 47% yield) was synthesized from tert-butyl 3-(2-(2-(3-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)propoxy)ethoxy)ethoxy)propanoate (B-39) in a similar fashion to Compound A-26, except using 15 eq. TFA. The material was purified by reverse phase preparative HPLC [Purification method: Column: SunFire prep OBD (19x50 mm), 5 pm; Mobile phase A: 0.1% TFA in water and Mobile phase B: MeCN]. LCMS (ES+): m / z 462.9 [M + H]+. 3-[2-|3-|2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl|propoxy|ethoxy|propanoic acid (B-45) Step 1: tert-butyl 3-(2-prop-2-ynoxyethoxy)propanoate (B-42) tert-butyl 3-(2-prop-2-ynoxyethoxy)propanoate (B-42, 500 mg, 2.17 mmol, 26% yield) was synthesized from tert-butyl 3-(2-hydroxyethoxy)propanoate (B-41) and 3-bromoprop-1-yne (80% in toluene) in a similar fashion to Compound B-3. Step 2:      tert-butyl 3-[2-[3-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]prop-2- ynoxy] ethoxy] propanoate (B-43) tert-butyl 3-[2-[3-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]prop-2-ynoxy]ethoxy]propanoate (B-43, 180 mg, 158.93 pmol, 18% yield) was synthesized from 4-bromo-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (B-4) and tert-butyl 3-(2-prop-2-ynoxyethoxy)propanoate (B-42) in a similar fashion to Compound B-5, except using 1.1 eq. B-4 and 0.2 eq. Cui. LCMS (ES-): m / z 483.3 [M -H]“. Step         3:         tert-butyl         3-[2-[3-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4- yl] propoxy] ethoxy] propanoate (B-44) tert-butyl 3-[2-[3-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]propoxy]ethoxy]propanoate (B-44, 150 mg, 128.96 pmol, 35% yield) was synthesized from tert-butyl 3-[2-[3-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]prop-2-ynoxy]ethoxy]propanoate (B-43) in a similar fashion to Compound B-6, except adding 0.2 eq. TFA. The material was used in the next step without further purification. LCMS (ES-):w / z487 [M-H]-. Step 4: 3-[2- [3- [2-(2,6-dioxo-3-piperidyl)- l,3-dioxo-isoindolin-4-yl] propoxy]ethoxy]propanoic acid (B-45) 3-[2-[3-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]propoxy]ethoxy]propanoic acid (B-45, 45 mg, 99.90 pmol, 33% yield) was synthesized from tert-butyl 3-[2-[3-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]propoxy]ethoxy]propanoate (B-44) in a similar fashion to Compound A-26, except using 42 eq. TFA. The material was purified by reverse-phase preparative HPLC [Column: SunFire Cl8 (19 x 150 mm) 5 pm, mobile phase: 0.1% TFA in water and MeCN], LCMS (ES+): m / z 433.2 [M + H]+. 6-[[2-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]amino]acetyl]amino]hexanoic acid (B-48) Step 1: methyl 6- [[2- [[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl] amino] acetyl] amino]hexanoate (B-47) methyl 6-[[2-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]amino]acetyl]amino]hexanoate (B-47, 0.23 g, 320.82 pmol, 34% yield) was synthesized from 2-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]amino]acetic acid (B-34) and methyl 6-aminohexanoate hydrochloride (B-46) in a similar fashion to Compound B-10, except using 2 eq. B-46 and 1 eq. 1-propanephosphonic anhydride solution (50 wt. % in ethyl acetate). LCMS (ES+): m / z 444.9 [M + H]+. Step 2: 6-[[2-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]amino]acetyl]amino]hexanoic acid (B-48) 6-[[2-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]amino]acetyl]amino]hexanoic acid (B-48, 45 mg, 82.72 pmol, 16% yield, TFA salt) was synthesized from methyl 6-[[2-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]amino]acetyl]amino]hexanoate (B-47) in a similar fashion to Compound B-ll, except using 6 eq. trimethyltin hydroxide. LCMS (ES+): m / z 430.9 [M + H]+. 5-[[2-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]amino]acetyl]amino]pentanoic acid (B-51) T3P, TEA, DMF, r.t., 6 h Step 1 Step          1:          methyl 5- [ 12- [ [2-(2,6-dioxo-3-piperidyl)- l-oxo-isoindolin-4- yl] amino] acetyl] amino] pentanoate (B-50) methyl 5-[[2-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]amino]acetyl]amino]pentanoate (B-50, 230 mg, 309.91 pmol, 33% yield) was synthesized from 2-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]amino]acetic acid (B-34) and methyl 5-aminopentanoate hydrochloride (B-49) in a similar fashion to Compound B-10, except using 2 eq. B-49 and 1.5 eq. propylphosphonic acid anhydride solution (50 wt. % in ethyl acetate), LCMS (ES+): m / z 431.1 [M + H]+. Step 2: 5-[[2-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]amino]acetyl]amino]pentanoic acid (B-51) 5-[[2-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]amino]acetyl]amino]pentanoic acid (B-51, 70 mg, 132.07 pmol, 25% yield, TFA salt) was synthesized from methyl 5-[[2-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]amino]acetyl]amino]pentanoate (B-50) in a similar fashion to Compound B-ll, except using 10 eq. trimethyltin hydroxide. LCMS (ES+): m / z 417.2 [M + H]+. 2-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-5-yl]amino]acetic acid (B-54) tert-butyl Il                 aminoacetate,           II H           P / --\ DIPEA, NMP,                            y— NH ° °             Step 1                          o B-52                                     B-53 TFA, DCM, r.t.,, 6 h Step 2 o B-54 Step 1: tert-butyl 2-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-5-yl]amino]acetate (B-53) Into a 250 mL sealed tube containing a well-stirred solution of 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-1,3-dione (B-52, 8 g, 28.96 mmol) in anhydrous NMP (50 mL) were added tert-butyl 2-aminoacetate (7.28 g, 43.44 mmol) and N,N-diisopropylethylamine (18.72 g, 144.81 mmol, 25.22 mL) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at 110 °C for 16 h. The solvent was removed under reduced pressure and the residue was purified by flash silica gel (230-400 mesh) column chromatography (30% Ethyl acetate in petroleum ether) to afford tert-butyl 2-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-5-yl]amino]acetate (B-53, 2.1 g, 3.98 mmol, 14% yield) as a yellow solid. LCMS (ES+): m / z 332.0 [M - tBu + H]+. Step 2: 2-[|2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-5-yl|amino|acetic acid (B-54) 2-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-5-yl]amino]acetic acid (B-54, 1.5 g, 3.14 mmol, 58% yield, TFA salt) was synthesized from tert-butyl 2-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-5-yl]amino]acetate (B-53) in a similar fashion to Compound A-26, except using 10 eq. TFA. The material was azeotroped with toluene and used in the next step without further purification. LCMS (ES+): m / z 332.0 [M + H]+. 3-[2-[[2-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-5-yl]amino]acetyl]amino]ethoxy]propanoic acid (B-57) Step 1:         tert-butyl 3-[2-[[2-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-5- yl] amino] acetyl] amino] ethoxy] propanoate (B-56) Into a 25 mL single neck round bottom flask containing a well-stirred solution of 2-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-5-yl]amino]acetic acid (B-54, 100 mg, 301.86 pmol) in anhydrous DMF were added tert-butyl 3-(2-aminoethoxy)propanoate (B-55, 68.55 mg, 362.23 pmol), DIPEA (117.04 mg, 905.58 pmol, 157.74 pL)andPyBOP (172.79 mg, 332.05 pmol) at room temperature. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (5 mL) and extracted with 10% MeOH in DCM (20 mL). The organic layer was washed with brine (5 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (4-5% MeOH in DCM) to afford tert-butyl 3-[2-[[2-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-5-yl]amino]acetyl]amino]ethoxy]propanoate (B-56, 150 mg, 256.71 pmol, 85% yield) as a pale yellow liquid. LCMS (ES+): m / z 447.1 [M - tBu + H]+. Step                   2:                   3- [2- [[2- [ [2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5- yl] amino] acetyl] amino] ethoxy] propanoic acid (B-57) 3-[2-[[2-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-5-yl]amino]acetyl]amino]ethoxy]propanoic acid (B-57,100 mg, 210.57 pmol, 82% yield, TFA salt) was synthesized from tert-butyl 3-[2-[[2-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-5-yl]amino]acetyl]amino]ethoxy]propanoate (B-56) in a similar fashion to Compound A-26, except using 3 eq. TFA. The material was purified by reverse phase prep HPLC [Prep Method: Column: SunFire C18 (19 x 150mm) 5 pm, Mobile phase A: 0.1% TFA in water: MeCN]. LCMS (ES+): m / z 446.9 [M + H]+. 7-[[2-|[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl|amino|acetyl|amino|heptanoic acid (B-62) Step 1: 2-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]amino]acetic acid (B-60) Into a 50 mL single neck round bottom flask containing a well-stirred solution of glyoxylic acid (B-59, 350 mg, 4.73 mmol, 261.19 pL) in anhydrous THF (20 mL) were added 3-(5-amino-l-oxo-isoindolin-2-yl)piperidine-2,6-dione (B-58,2.45 g, 9.45 mmol), dibutyltin dichloride (1.44 g, 4.73 mmol, 1.06 mL) and phenylsilane (613.89 mg, 5.67 mmol). The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was cooled to room temperature, the volatiles were removed under reduced pressure and the residue was purified by reverse phase column chromatography (60 g, C18 column, compound eluted with 10-15 % acetonitrile in 0.1% TFA in water) to afford 2-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]amino]acetic acid (B-60, 450 mg, 1.11 mmol, 23% yield) as an off-white solid. LCMS (ES+): m / z 318.1 [M + H]+. Step           2:            methyl            7-[[2-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5- yl] amino] acetyl] amino] heptanoate (B-61) methyl 7-[[2-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]amino]acetyl]amino]heptanoate (B-61, 370 mg, 728.93 pmol, 46% yield) was synthesized from 2-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]amino]acetic acid (B-60) and methyl 7-aminoheptanoate (B-9) in a similar fashion to Compound B-10, except using 1.5 eq. B-9, 1.5 eq. 1-propanephosphonic anhydride solution (50% in Ethyl acetate). LCMS (ES+): m / z 459.3 [M + H]+. Step 3: 7-[|2-||2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl|amino|acetyl|amino|heptanoic acid (B-62) 7-[[2-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]amino]acetyl]amino]heptanoic acid (B-62, 130 mg, 236.91 pmol, 29% yield) was synthesized from methyl 7-[[2-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]amino]acetyl]amino]heptanoate (B-61) in a similar fashion to Compound B-ll, except using 6 eq. trimethyltin hydroxide. LCMS (ES+): m / z 445.2 [M + H]+. 7-[2-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]amino]propanoylamino]heptanoic acid (B-67) o B-63                                B-65 Step 1: 2-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]amino]propanoic acid (B-65) 2-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]amino]propanoic acid (B-65, 3.5 g, 72% purity) was synthesized from 3-(4-amino-l-oxo-isoindolin-2-yl)piperidine-2,6-dione (B-63) and 2-oxopropanoic acid (B-64) in a similar fashion to Compound B-60, except using 1.2 eq. B-64. Upon removal of the solvent, the residue was washed with hexanes (2 x) and dried under vacuum. The material was used in the next step without further purification. LCMS (ES+): m / z 332.3 [M + H]+. Step            2:            methyl            7-[2-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4- yl]amino]propanoylamino]heptanoate (B-66) methyl 7-[2-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]amino]propanoylamino]heptanoate (B-66, 900 mg, 1.18 mmol, 27% yield) was synthesized from 2-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]amino]propanoic acid (B-65) and methyl 7-aminoheptanoate hydrochloride (B-9) in a similar fashion to Compound B-10, except using 1.3 eq. B-9, 4 eq. triethylamine and 3 eq. 1-propanephosphonic anhydride solution (50% in Ethyl acetate). LCMS (ES+): m / z 472.9 [M + H]+. Step 3: 7-[2-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]amino]propanoylamino]heptanoic acid (B-67) 7-[2-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]amino]propanoylamino]heptanoic acid (B-67, 95 mg, 196.63 pmol, 33% yield, TFA salt) was synthesized from methyl 7-[2-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]amino]propanoylamino]heptanoate (B-66) in a similar fashion to Compound B-ll, except using 6 eq. trimethyltin hydroxide. LCMS (ES+): m / z 458.9 [M + H]+. 3-[3-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]propoxy]propanoic acid (B-71) o Step 1: tert-butyl    3-((3-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)prop-2-yn-l- yl)oxy)propanoate (B-69) tert-butyl 3-((3-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)prop-2-yn-l-yl)oxy)propanoate (B-5   69, 105 mg, 243.75 pmol, 14% yield) was synthesized from tert-butyl 3-prop-2-ynoxypropanoate (B-68) and 4-bromo-2-(2,6-dioxo-3-piperidyl)isoindoline-l,3-dione (B-4) in a similar fashion to Compound B-5, except using 1.2 eq. B-4 and 0.2 eq. Cui. LCMS (ES+): m / z 385.2 [M -tBu + H]+. Step 2: tert-butyl 3-[3-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]propoxy]propanoate (B-70) 10 tert-butyl 3-[3-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]propoxy]propanoate (B-70, 90 mg, 180.21 pmol, 76% yield) was synthesized from tert-butyl 3-[3-[l,3-dioxo-2-(2-oxo-3-piperidyl)isoindolin-4-yl]prop-2-ynoxy]propanoate (B-69) in a similar fashion to Compound B-6, except using 0.1 eq. palladium (10% on carbon).LCMS (ES+): m / z 444.9 [M + H]+. Step 3: 3-[3-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]propoxy]propanoic acid (B-71) 15 3-[3-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]propoxy]propanoic acid (B-71, 60mg, 77% yield, TFA salt) was synthesized from tert-butyl 3-[3-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]propoxy]propanoate (B-70) in a similar fashion to Compound A-26, except using 5 eq. TFA. 4-[[2-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]amino]acetyl]amino]butanoic acid (B-74) TFA CH2CI2, rt, 2 h Step 2 Step           1:           tert-butyl           4-((2-((2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4- yl] amino] acetyl] amino] butanoate (B-73) tert-butyl 4-[[2-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]amino]acetyl]amino]butanoate (B-73, 0.3 g, 416.59 pmol, 26% yield) was synthesized from 2-((2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]amino]acetic acid (B-34) and tert-butyl 4-aminobutanoate (B-72) in a similar fashion to Compound B-10, except using 2.5 eq. triethylamine, 1.6 eq. 1-propanephosphonic anhydride solution (50% in Ethyl acetate) and 1.2 eq. B-72. LCMS (ES+): m / z 403.2 [M - tBu + H]+. Step 2: 4-((2-((2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]amino]acetyl]amino]butanoic acid (B-74) 4-((2-((2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]amino]acetyl]amino]butanoic acid (B-74, 0.080 g, 174.43 pmol, 20% yield, TFA salt) was synthesized from tert-butyl 4-((2-((2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]amino]acetyl]amino]butanoate (B-73) in a similar fashion to Compound A-26, except using 6 eq. TFA. The material was purified by reverse-phase preparative HPLC (Column: SunFire Cl8 (19 x 150 mm) 5 pm, Mobile phase A: 0.1% TFA in water:MeCN). LCMS (ES+): m / z 403.2 [M + H]+. 2-((2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-4-yl]amino]acetic acid (B-76) B-75                                           B-76 Step 1: 2-((2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-4-yl]amino]acetic acid (B-76) Into a 50 mL single neck round bottom flask containing a well-stirred solution of 3-(7-amino-l-oxo-isoindolin-2-yl)piperidine-2,6-dione (B-75, 2 g, 7.71 mmol) and glyoxylic acid (B-59,1.14 g, 15.43 mmol, 852.43 pL) in methanol (20 mL)was added acetic acid (2.32 g, 38.57 mmol, 2.21 mL) followed by portionwise addition of 2-picoline borane complex (1.65 g, 15.43 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 18 h. Upon completion, water (10 mL) was added to the reaction mixture and solvent removed under reduced pressure to afford the crude product, which was purified by reverse phase prep HPLC [Purification method: Column: SunFire prep OBD 19 x 50 mm (5 pm), Mobile phase A: 0.1% TFA in water and Mobile phase B: MeCN] to afford 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-4-yl]amino]acetic acid (B-76, 130 mg, 406.72 pmol, 5% yield, TFA salt) as an off-white solid. LCMS (ES+):w / z 318.1 [M + H]+. 6-[4-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]amino]-l-piperidyl]hexanoic acid (B-82) Step 1: tert-butyl 4-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]amino] piperidine-1-carboxylate (B-79) Into a 25 mL pressure tube containing a well-stirred solution of 2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3-dione (B-77, 0.7 g, 2.53 mmol) in dimethylacetamide (10 mL) at room temperature were added tert-butyl 4-aminopiperidine-l-carboxylate (B-78, 507.54 mg, 2.53 mmol) followed byN,N-diisopropylethylamine (982.59 mg, 7.60 mmol, 1.32 mL). The reaction mixture was stirred at 90 °C for 16 h. The mixture was cooled to room temperature, diluted with water (30 mL) and filtered. The solid was washed with water (30 mL) followed by petroleum ether (30 mL) to afford a tert-butyl 4-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]amino]piperidine-l-carboxylate (B-79, 0.6 g, 802.95 pmol, 32% yield) as a brown solid. LCMS (ES+): m / z 356.9 [M - Boc + H]+. Step 2: 2-(2,6-dioxo-3-piperidyl)-4-(4-piperidylammo)isoindoline-l,3-dione (B-80) 2-(2,6-dioxo-3-piperidyl)-4-(4-piperidylamino)isoindoline-l,3-dione (B-80, 0.4 g, 583.42 pmol, 73% yield, 69% purity, TFA salt) was synthesized from tert-butyl 4-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]amino]piperidine-l-carboxylate (B-79) in a similar fashion to Compound A-62, except using 10 eq. TFA. The material was triturated with diethyl ether. LCMS (ES+): m / z 357.0 [M + H]+. Step 3: 6-[4-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]amino]-l-piperidyl]hexanoic acid (B-82) Into a 25 mL pressure tube containing a well-stirred solution of 2-(2,6-dioxo-3-piperidy 1)-4-(4-piperidylamino)isoindoline-l,3-dione (B-80, 0.4 g, 583.42 pmol, 72.66 % yield, 69% purity) inDMF (5 mL) were added 6-bromohexanoic acid (B-81, 113.80 mg, 583.42 pmol) and N,N-diisopropylethylamine (377.02 mg, 2.92 mmol, 508.11 pL) at room temperature. The reaction mixture was stirred at 100 °C for 16 h. The mixture was cooled to room temperature, diluted with water (25 mL) and extracted with ethyl acetate (3 x 25 mL). The combined organic layer was washed with water (15 mL) and brine (15 mL), dried over anhydrous sodium sulfate and filtered. The solvent was removed under reduced pressure to afford 6-[4-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]amino]-l-piperidyl]hexanoic acid (B-82, 0.15 g, 304.96 pmol, 52% yield) as yellow solid. The material was used in the next step without further purification. LCMS (ES+): m / z 471.2 [M + H]+. 6-[4-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]amino]-l-piperidyl]hexanoic acid (B-84) / —Br B-83               Step 1                     B-84 Step 1: 6-[4-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]amino]-l-piperidyl]hexanoic acid (B-84) 6-[4-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]amino]-l-piperidyl]hexanoic acid (B-84, 80 mg, 154.21 pmol, 11% yield, TFA salt) was synthesized from 3-[l-oxo-4-(4-piperidyl amino)isoindolin-2-yl]piperidine-2,6-dione (B-83) and 6-bromohexanoic acid (B-81) in a similar fashion to Compound B-82, except using 1.2 eq. B-81. Upon completion, the volatiles were removed under reduced pressure and the residue purified by reverse phase prep HPLC [Purification method: Column: SunFire -C18 100 mm, Mobile phase A: 0.1% TFA in water, Mobile phase B: MeCN; Flow Rate :15.0 mL / min], LCMS (ES+): m / z 457.0 [M + H]+. 3-[4-[[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]amino]methyl]pyrazol-l-yl]propanoic acid (B-88) B-85               B-86          e. <                  B-87 THF, 80°C, 16h Step 2 Step 1: 3-(4-formylpyrazol-l-yl)propanoic acid (B-87) Into a 100 mL three neck round bottom flask containing a well-stirred solution of l / f-pyrazole-4-carbaldehyde (B-86, 1.0 g, 10.41 mmol) in DMF (10 mL) was added cesium carbonate (6.78 g, 20.81 mmol) and the suspension was stirred for 5 min. Then, 3-bromopropanoic acid (B-85, 3.18g, 20.81 mmol, 2.15 mL) was added and the reaction mixture was stirred at 80 °C for 16 h. The reaction was concentrated under reduced pressure and the residue was diluted with water (50 mL) and acidified using 2N HC1 and extracted with Ethyl acetate (3 x 50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 3-(4-formylpyrazol-l-yl)propanoic acid (B-87,1.8 g, 4.50 mmol, 43% yield) as thick red liquid. LCMS (ES+): m / z 169.0 [M + H]+. Step 2: 3-[4-[[ [2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl] amino]methyl]pyrazol- 1-yl]propanoic acid (B-88) 3-[4-[[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]amino]methyl]pyrazol-l-yl]propanoic acid (B-88, 40 mg, 94.50 pmol, 25% yield) was synthesized from 3-(4-amino-l-oxo-isoindolin-2-yl)piperidine-2,6-dione (B-63) and 3-(4-formylpyrazol-l-yl)propanoic acid (B-87) in a similar fashion to Compound B-60, except using 1.2 eq. B-87. LCMS (ES+): m / z 412.1 [M + H]+. 2-[4-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]-l-piperidyl]acetic acid (B-90) Step 1: 2-[4-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]-l-piperidyl]acetic acid (B-90) 2-[4-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]-l-piperidyl]acetic acid (B-90, 102 mg, 262.72 pmol, 86% yield) was synthesized from 3-[l-oxo-5-(4-piperidyl)isoindolin-2-yl]piperidine-2,6-dione (B-89) and glyoxylic acid monohydrate in a similar fashion to Compound B-60, except using 1.5 eq. glyoxylic acid monohydrate. Upon completion, the solvent was evaporated under reduced pressure and the residue was triturated ethyl acetate and diethyl ether, filtered and dried. The material was used in the next step without further purification. LCMS (ES+): m / z 385.9 [M + H]+. 3-(4-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)amino)piperidin-l-yl)propanoic acid (B-92) Step 1:       tert-butyl 3-[4-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]amino]-l- piperidyl]propanoate (B-91) tert-butyl 3-[4-[[2-(2,6-dioxo-3-piperidyl)-1 -oxo-isoindolin-4-yl]amino]-1 -piperidyl]propanoate (B-91, 510 mg, 1.02 mmol, 75% yield) was synthesized from 3-(4-amino-l-oxo-isoindolin-2-yl)piperidine-2,6-dione (B-63) and tert-butyl 3-(4-oxo-l-piperidyl)propanoate (A-68) in a similar fashion to Compound B-60, except using 1.5 eq. A-68 and 1.2 eq. phenyl silane. LCMS (ES+): m / z 471.6 [M + H]+. Step 2: 3-(4-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)amino)piperidin-l-yl)propanoic acid (B-92) 3-(4-((2-(2,6-dioxopiperidin-3 -yl)-1 -oxoisoindolin-4-yl)amino)piperidin-1 -yl)propanoic acid (B-92, 3 00 mg, 89% yield) was synthesized from tert-butyl 3-[4-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]amino]-l -piperidyl]propanoate (B-91) in a similar fashion to Compound A-26. LCMS (ES+): m / z 415.0 [M + H]+. 3-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl|propanoic acid (B-95) Step 1: tert-butyl (£)-3-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)acrylate (B-93) Into a 100 mL pressure tube containing a well-stirred solution of 3-(5-bromo-l-oxo-isoindolin-2-yl)piperidine-2,6-dione (B-37,2.00 g, 3.09 mmol) in anhydrous DMF (20 mL) were added tert-butyl prop-2-enoate (A-67, 594.95 mg, 4.64 mmol, 673.78 p.L) and triethylamine (939.43 mg, 9.28 mmol, 1.29 mL) at room temperature under nitrogen atmosphere. The reaction mixture was purged by bubbling nitrogen through the solution for 5 min before adding l,l'-Bis(diphenylphosphino)ferrocene palladium(II)chloride dichloromethane complex (252.72 mg, 0.309 mmol). The tube was sealed, and the suspension was heated at 100 °C for 16 h. Upon completion, the mixture was cooled to room temperature and poured into cold water (200 mL) and extracted with Ethyl acetate (2 x 100 mL). The combined organic layer was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue purified by flash silica-gel (230-400 mesh) column chromatography (0-100% Ethyl acetate in petroleum ether) to obtain tert-butyl (£)-3-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]prop-2-enoate (B-93, 600 mg, 1.51 mmol, 49% yield) as a light brown solid. LCMS (ES+): m / z 371.3 [M + H]+. Step 2: tert-butyl 3-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)propanoate (B-94) tert-butyl 3-(2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]propanoate (B-94, 300 mg) was synthesized from tert-butyl (£)-3-(2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]prop-2-enoate (B-93) in a similar fashion to Compound B-6, except using 0.1 eq. Palladium (10% on carbon, dry) using a hydrogen bladder. 5 After triturating with diethyl ether, the material was used in the next step without further purification. LCMS (ES+): m / z 373.3 [M + H]+. Step 3: 3-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]propanoic acid (B-95) 3-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]propanoic acid (B-95,250 mg, 0.790 mmol, 98% yield, TFA salt) was synthesized from tert-butyl 3-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]propanoate 10   (B-94) in a similar fashion to Compound A-26, except using 16 eq. TFA. LCMS (ES+): m / z 316.9 [M + H]+. 3-(1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propanoic acid (B-104) B-96                  B-97 tri phosgene pyridine DCM Step 3 B-100 Fe, NH4CI EtOH, H2O Step 2 Step 1: 2,6-dibenzyloxy-N-(4-bromo-2-nitro-phenyl)pyridin-3-amine (B-98) 15 To a stirred solution of 4-bromo-l-fluoro-2-nitro-benzene (B-96, 25 g, 113.64 mmol, 13.97 mL) in NMP (250 mL) in a sealed tube was added 2,6-dibenzyloxypyridin-3-amine (B-97, 34.81 g, 113.64 mmol) followed by DIPEA (73.43 g, 568.19 mmol, 98.97 mL) and stirred for 56 h at 100 °C. The solvent was removed, and the residue diluted with DCM (3 x 800 mL) and Water (500 mL). The organic layer was dried over sodium sulfate, filtered and solvent removed under reduced pressure. The residue was slurried with a mixture of Petroleum ether and Ethyl acetate and stirred for 30 min. The precipitate was filtered and dried under vacuum to afford 2,6-dibenzyloxy-N-(4-bromo-2-nitro-phenyl)pyridin-3-amine (B-98, 30 g, 57.86 mmol, 51% yield) as a yellow solid. LCMS (ES+): m / z 505.9 [M+H]+. Step 2: 4-bromo-Nl-(2,6-dibenzyloxy-3-pyridyl)benzene-l,2-diamine (B-99) Into a 2 L two neck round bottom flask containing a well-stirred solution of 2,6-dibenzyloxy-N-(4-bromo-2-nitro-phenyl)pyridin-3-amine (B-98, 31 g, 45.04 mmol) in Water (310 mL) and Ethanol (310 mL) was added iron powder (15.09 g, 270.25 mmol) and ammonium chloride (14.46 g, 270.25 mmol) at room temperature. The reaction mixture was heated at 70 °C for 16 h. The mixture was filtered through Celite, washing with DCM (500 mL). The volatiles were removed and the material extracted with DCM (1 L). The organic layer was dried over sodium sulfate, filtered and solvent removed to afford 4-bromo-N 1-(2,6-dibenzyloxy-3-pyridyl)benzene-l,2-diamine (B-99, 22 g, 33.98 mmol, 75% yield) as a thick brown colored mass. The material was used in the next step without further purification. LCMS (ES+): m / z 478.0 [M+H]+. Step 3: 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-lH-benzimidazol-2-one (B-100) To a solution of4-bromo-Nl-(2,6-dibenzyloxy-3-pyridyl)benzene-l,2-diamine (B-99, 28 g, 42.32 mmol) in DCM (70 mL) was added pyridine (33.48 g, 423.21 mmol, 34.23 mL). After 5 min, the mixture was cooled to 0 °C and triphosgene (25.12 g, 84.64 mmol) dissolved in 10 mL DCM was added via an addition funnel. After 16 h, the reaction was quenched with ice while stirring and the product was extracted into DCM (3 x 250 mL). The organic layer was concentrated and the residue purified via flash column chromatography (35% Ethyl acetate:Hexanes) to afford 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-lH-benzimidazol-2-one (B-100, 18 g, 35.47 mmol, 84% yield) as an off white solid. LCMS (ES+): m / z 503.1 [M+H]+. Step 4: 5-bromo-l-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-benzimidazol-2-one (B-101) 5-bromo-l-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-benzimidazol-2-one (B-101, 20 g, 38.38 mmol, 96% yield) was synthesized from 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-lH-benzimidazol-2-one (B-100) and iodomethane in a similar fashion to Compound B-3, except sing 1.5 eq. NaH and 2 eq. iodomethane. The reaction was quenched with saturated ammonium chloride solution, and the material was used in the next step without further purification. LCMS (ES+): m / z 516.0 [M+H]+. Step 5: tert-butyl (E)-3-[l-(2, 6-dibenzyloxy-3-pyridyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-enoate (B-102) tert-butyl (E)-3-[l-(2, 6-dibenzyloxy-3-pyridyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-enoate (B-102, 145 mg, 174.19 pmol, 60% yield) was synthesized from 5-bromo-l-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-benzimidazol-2-one (B-101) and tert-butyl prop-2-enoate (A-67) in a similar fashion to Compound B-93, except using 4 eq. A-67 and 5 eq. triethylamine. The reaction was heated at 110 °C for 16 h. Upon completion, the reaction was filtered through Celite, washing with ethyl acetate. The filtrate was washed with water (2 x) and brine, dried over anhydrous sodium sulfate and filtered. The solvent was removed under reduced pressure and the residue purified by flash silica gel column chromatography (5-10% Ethyl acetate in petroleum ether). MS (ESI) m / z = 564.30 [M+H]+. Step 6: tert-butyl 3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d|imidazol-5-yl)propanoate (B-103) Into a 100 mL single neck round bottom flask containing a well-stirred solution of tert-butyl (E)-3-(l-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)acrylate (B-102, 145 5 mg, 257.26 pmol) in 1,4-dioxane (50 mL) was added palladium hydroxide (10% on carbon) (78.0 mg, 55.55 pmol). The reaction mixture was stirred under hydrogen atmosphere at 1 atm for 16 h. The reaction mixture was filtered through Celite and washed with Ethyl acetate (50 mL). The solvent was removed under reduced pressure to obtain tert-butyl 3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)propanoate (B-103, 100 mg, 212.93 pmol, 83% yield) as a pale green solid. The 10 material was used in the next step without further purification. MS (ESI): m / z 388.40 [M+H]+. Step 7: 3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl] propanoic acid (B-104) 3-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propanoic acid (B-104, 150 mg, 253.47 pmol, 98% yield) was synthesized from tert-butyl 3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)propanoate (B-103) in a similar fashion to Compound A-26, except 15 using 4 eq. TFA. MS (ESI): m / z 331.9 [M+H]+. 3-[3-methyl-2-oxo-4-(4-piperidyl)benzimidazol-l-yl]piperidine-2,6-dione (B-113) OBn Step 1 Fe, NH4CI THF, H2O Step 2 B-106 B-105              B-97 triphosgene pyridine DCM Step 3 B-107 NaH Mel DMF Step 4 B-109 Step 1: 2,6-dibenzyloxy-N-(3-bromo-2-nitro-phenyl)pyridin-3-amine (B-106) To a solution of 2,6-dibenzyloxypyridin-3-amine (B-97, 3 g, 9.79 mmol) in THF (100 mL) was added Lithium bis(trimethylsilyl)amide (IM in THF) (3.60 g, 21.54 mmol, 22 mL) at 0 °C via dropwise addition. 5 The reaction mixture was stirred for 15 min at 0 °C before 1-bromo-3-fluoro-2-nitro-benzene (B-105, 2.37 g, 10.77 mmol) dissolved in 2 mL THF was added. After 4 h at room temperature, the reaction was quenched with water (50 mL) at 0 °C and extracted with ethyl acetate (2 x 100 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated. The residue was purified by Isolera using 230-400 silica. At 15-20% Ethyl acetate in petroleum ether to afford 2,6-dibenzyloxy-N-(3-bromo-2-nitro- phenyl)pyridin-3-amine (B-106, 3.3 g, 4.30 mmol, 44% yield) as brown viscous liquid. LCMS (ES-): m / z 404.0 [M - H]’. Step 2: 3-bromo-Nl-(2,6-dibenzyloxy-3-pyridyl)benzene-l,2-diamine (B-107) A mixture of 2,6-dibenzyloxy-N-(3-bromo-2-nitro-phenyl)pyridin-3-amine (B-106, 1 g, 1.97 mmol), Iron powder (1.10 g, 19.75 mmol, 140.32 pL), and Ammonium Chloride (1.06 g, 19.75 mmol, 690.47 pL) in THF (40 mL) and Water (20 mL) was heated at 70 °C for 7 h . Upon completion, the reaction mixture was passed through Celite and 20 mL water was added to the filtrate. The product was extracted with ethyl acetate (3 x 50 mL). The combined organic layer was dried over sodium sulfate and evaporated to afford 3-bromo-Nl-(2,6-dibenzyloxy-3-pyridyl)benzene-l,2-diamine (B-107,1.00 g, 1.53 mmol, 77% yield, 73% purity). The material was used in the next step without further purification. LCMS (ES+): m / z 476.21 [M + H]+. Step 3: 7-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-lH-benzimidazol-2-one (B-108) 7-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-lH-benzimidazol-2-one (B-108,1.9 g, 3.44 mmol, 66% yield) was synthesized from 3-bromo-Nl-(2,6-dibenzyloxy-3-pyridyl)benzene-1,2-diamine (B-107) in a similar fashion to Compound B-100, except using 1.5 eq. triphosgene Upon completion, the reaction mixture was diluted with Ethyl acetate and water. The organic layer was washed with 10% sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated. The material was used in the next step without further purification. LCMS (ES+): m / z 503.9 [M + H]+. Step 4: 4-bromo-l-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-benzimidazol-2-one (B-109) 4-bromo-l-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-benzimidazol-2-one (B-109, 2.8 g, 5.15 mmol, 91% yield) was synthesized from 7-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-lH-benzimidazol-2-one (B-108) and methyl iodide in a similar fashion to Compound B-3, except using 1.5 eq. NaH and 1.5 eq. methyl iodide. 1HNMR (400 MHz, DMSO-d6): 5 7.83-7.81(d, J=8 Hz, 1H), 7.45-7.43 (m, 2H), 7.40-7.33 (m, 3H), 7.277.24 (m, 6H), 6.92 (t, J=8 Hz, 1H), 6.69-6.67 (d, J=8 Hz,lH), 6.63-6.61(d, J=8 Hz, 1H), 5.43-5.33 (m, 4H), 3.67 (s, 3H). LCMS (ES+): m / z 516.1 [M + H]+. Step 5: fert-butyl 4-[l-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-2-oxo-benzimidazol-4-yl]-3,6-dihydro-2H-pyridine-l-carboxylate (B-lll) Into a 10 mL pressure tube containing a well-stirred-solution of 4-bromo-1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-benzimidazol-2-one (B-109, 100 mg, 193.65 pmol) and tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-l-carboxylate (B-110, 59.88 mg, 193.65 pmol) in 1,2-dimethoxyethane (3 mL) was added anhydrous potassium carbonate (26.76 mg, 193.65 pmol) and the mixture was purged by bubbling nitrogen gas through for 5 min. Then Pd(dppf)C12.DCM (158.15 mg, 193.65 pmol) was added and the tube was sealed. The reaction mixture was heated at 80 °C for 16 h. Upon completion, the reaction mixture was cooled to ambient temperature, diluted with ethyl acetate (15 mL) and filtered through Celite. The filtrate was concentrated under reduced pressure and the residue purified by flash silica gel column chromatography (60-80% of Ethyl acetate in petroleum ether) to afford / er / -butyl 4-[l-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-2-oxo-benzimidazol-4-yl]-3,6-dihydro-2H-pyridine-l- carboxylate (B-lll, 100 mg, 144.33 pmol, 75% yield) as an off white solid. LCMS (ES+): m / z 618.9 [M + H]+. Step 6: tert-butyl  4-(1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]piperidine-l- carboxylate (B-112) tert-butyl 4-(1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]piperidine-l-carboxylate (B-112, 80 mg, 170.54 pmol, 95% yield) was synthesized from tert-butyl 4-(1-(2,6-dibenzyloxy-3-pyridy 1)-3-methyl-2-oxo-benzimidazol-4-yl]-3,6-dihydro-2H-pyridine-l-carboxylate (B-lll) in a similar fashion to Compound B-103, except using 0.1 eq. palladium hydroxide (10% on carbon). LCMS (ES+): m / z 387.3 [M-tBu + H]+. Step 7: 3-[3-methyl-2-oxo-4-(4-piperidyl)benzimidazol-l-yl]piperidine-2,6-dione (B-113) 3-[3-methyl-2-oxo-4-(4-piperidyl)benzimidazol-l-yl]piperidine-2,6-dione (B-113, 70 mg, 128.02 pmol, 66% yield, TFA salt) was synthesized from tert-butyl4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]piperidine-l-carboxylate (B-112) in a similar fashion to Compound A-62, except using 1 eq. TFA. The material was triturated with diethyl ether. LCMS (ES+): m / z 343.0 [M + H]+. 3-(1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propanoic acid (B-116) Step 1: tert-butyl (E)-3-[l-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-2-oxo-benzimidazol-4-yl] prop-2-enoate (B-114) tert-butyl (E)-3-[l-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-enoate (B-114, 80 mg, 136.26 pmol, 70% yield) was synthesized from 4-bromo-l-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-benzimidazol-2-one (B-109) and tert-butyl prop-2-enoate (A-67) in a similar fashion to Compound B-93, except using 5 eq. A-67 and 5 eq. triethylamine. The reaction was heated at 110 °C for 16 h. Upon completion, the reaction was filtered through Celite, washing with ethyl acetate. The filtrate was washed with water (2 x), dried over anhydrous sodium sulfate and filtered. The solvent was removed under reduced pressure and the residue purified by silica gel column chromatography (5-10% of Ethyl acetate in petroleum ether). LCMS (ES+): m / z 564.3 [M + H]+. Step 2: tert-butyl 3-(1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propanoate (B-115) tert-butyl 3-(1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propanoate (B-115, 80 mg, 172.82 pmol, 97% yield) was synthesized from tert-butyl (E)-3-[ 1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-enoate (B-114) in a similar fashion to Compound B-103, except using 0.3 eq. palladium hydroxide (10% on carbon) and washing the Celite bed with 1,4-dioxane. LCMS (ES+): m / z331.9 [M-tBu + H]+. Step 3: 3-(1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propanoic acid (B-116) 3-(1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propanoic acid (B-116, 70 mg, 123.08 pmol, 60% yield) was synthesized from tert-butyl 3-(1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propanoate (B-115) in a similar fashion to Compound A-26, except using 44 eq. TFA. LCMS (ES+): m / z 331.9 [M + H]+. 1-(2-(2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]oxyacetyl]piperidine-4-carboxylic acid (B-117) o Step 1: 1-(2-(2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]oxyacetyl]piperidine-4-carboxylic acid(B-117) Into a 25 mL single neck round bottom flask containing a well-stirred solution of 2-(2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]oxyacetic acid (B-12, 300 mg, 902.90 pmol)ina mixture of anhydrous THF (5 mL) and anhydrous DMF (0.5 mL) was added 1,1'-carbonyldiimidazole (CDI) (366.01 mg, 2.26 mmol). After 4 h a solution of piperidine-4-carboxylic acid (B-32, 116.61 mg, 902.90 pmol, TFA salt) in anhydrous DMF (2 mL) was added. The reaction mixture was stirred for 12 h. The volatiles were removed under reduced pressure and the residue purified using reverse phase prep HPLC [Method: Column-SunFire C18 (150 x 19) mm, 5 pm; Mobile phase A: 0.1% TFA in water and Mobile phase B: MeCN] to obtain 1-(2-(2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]oxyacetyl]piperidine-4-carboxylic acid (B-117, 180 mg, 395.39 pmol, 44% yield, TFA salt) as an off-white solid. LCMS (ES+): m / z 444.2 [M + H]+. 3-[l-oxo-4-(4-piperidylamino)isoindolin-2-yl]piperidine-2,6-dione (B-119) J A e p O             Boc      A-5a /            NaBH(OAc)3, TFA DCM, ft NH,                       „    , Step 1 B-63 .Boc p n                  IT HIT---n                                    HIT---(-, 1        \\                TFA             1       \\ (^^Sr-^x y-NH      -----------►   (-'^Sy-'X y-NH 0 T / 1-\         DCM, rt, 2h      fi Tn—pO O                  Step 2               q B-118                                 B-119 Step 1: tert-butyl 4-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]amino]piperidine-l-carboxylate (B-118) Into a 10 mL single neck round bottom flask containing a well-stirred solution of 3-(4-amino-l-oxo-isoindolin-2-yl)piperidine-2,6-dione (B-63,2.0 g, 7.71 mmol) and tert-butyl 4-oxopiperidine-l-carboxylate 5   (A-5a, 2.31 g, 11.57 mmol) inDCM(30 mL) was addedTFA (879.60 mg, 7.71 mmol, 594.33 pL) dropwise at 0 °C and the reaction mixture was stirred for 10 min at 0 °C. Then, sodium triacetoxyborohydride (4.09 g, 19.29 mmol) was added and the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (30 mL) and the organic layer was extracted with DCM (3 x 30 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue 10 was triturated with acetone (30 mL), filtered and dried to afford ZerZ-butyl 4-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]amino]piperidine-l-carboxylate (B-118, 3.0 g, 6.66 mmol, 87% yield) as an off-white solid, which was used for the next step without further purification. LCMS (ES+): m / z 386.9 [M - tBu + H]+. Step 2: 3-[l-oxo-4-(4-piperidylamino)isoindolin-2-yl]piperidine-2,6-dione (B-119) 15    3-[l-oxo-4-(4-piperidylamino)isoindolin-2-yl]piperidine-2,6-dione (B-119, 3.0 g, 5.86 mmol, 28% yield, TFA salt) was synthesized from ZerZ-butyl 4-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]amino]piperidine-l-carboxylate (B-118) in a similar fashion to Compound A-62, except using 4 eq. TFA. LCMS (ES+): m / z 343.3 [M + H]+. 3-(l-oxo-4-(3-oxo-3-(piperazin-l-yl)propyl)isoindolin-2-yl)piperidine-2,6-dione (B-126) A-67 Pd(dppf)CI2,CH2CI2, Br B-120 Et3N, DMF, 100 °C,16 h Pd / C, H2, EtOH, ----► r.t., 36 h Step 2 Step 1 B-123 TFA DCM, rt, 4 h Step 3 B-125 Step 1: tert-butyl 3-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)acrylate (B-121) tert-butyl 3-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)acrylate (B-121, 2.5 g, 6.48 mmol, 70% yield) was synthesized from 3-(4-bromo-l-oxo-isoindolin-2-yl)piperidine-2,6-dione (B-120) and tert-butyl 5 prop-2-enoate (A-67) in a similar fashion to Compound B-93, except using 3 eq. A-67. Upon completion, the mixture was filtered through Celite, solvent removed under reduced pressure and the residue purified by flash silica gel (230-400 mesh) column chromatography (80% Ethyl acetate in petroleum ether). LCMS (ES+): w / z 371.2 [M + H]+. Step 2: tert-butyl 3-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)propanoate (B-122) 10    tert-butyl 3-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)propanoate (B-122, 2.1 g, 4.73 mmol, 70% yield) was synthesized from tert-butyl 3-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]prop-2-enoate (B-121) in a similar fashion to Compound B-6, except using 0.27 eq. palladium (10% on carbon, wet) under hydrogen bladder. The material was used in the next step without further purification. LCMS (ES+): m / z 373.1 [M + H]+. 15 Step 3: 3-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)propanoic acid (B-123) 3-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)propanoic acid (B-123,1.65 g, 4.96 mmol, 88% yield) was synthesized from tert-butyl 3-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]propanoate (B-122) in a similar fashion to Compound A-26, except using 46 eq. TFA. LCMS (ES+): m / z 317.0 [M + H]+. Step 4: tert-butyl 4-(3-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)propanoyl)piperazine-l-carboxylate (B-125) tert-butyl 4-(3-(2-(2,6-dioxopiperidin-3-yl)-1 -oxoisoindolin-4-yl)propanoyl)piperazine-1 -carboxylate (B-125, 130 mg, 250.59 pmol, 40% yield) was synthesized from tert-butyl piperazine-1-carboxylate (B-124) and 3-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)propanoic acid (B-123) in a similar fashion to Compound B-10, except using 1.5 eq. B-124 and 2 eq. 1-propanephosphonic anhydride solution (50% in Ethyl acetate). LCMS (ES+): m / z 483.2 [M - H]’. Step 5: 3-(l-oxo-4-(3-oxo-3-(piperazin-l-yl)propyl)isoindolin-2-yl)piperidine-2,6-dione (B-126) 3-(l-oxo-4-(3-oxo-3-(piperazin-l-yl)propyl)isoindolin-2-yl)piperidine-2,6-dione (B-126, 100 mg, 157.49 pmol, 59% yield, TFA salt) was synthesized from tert-butyl 4-[3-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]propanoyl]piperazine-l-carboxylate (B-125) in a similar fashion to Compound A-62, except using 48 eq. TFA. LCMS (ES+): m / z 385.2 [M + H]+. 1-(3-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)propanoyl)piperidine-4-carboxylic acid (B-129) B-129 Step 1: tert-butyl 1-(3-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)propanoyl)piperidine-4-carboxylate (B-128) tert-butyl l-(3-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)propanoyl)piperidine-4-carboxylate (B-128, 50 mg, 95.49 pmol, 30% yield) was synthesized from tert-butyl piperidine-4-carboxylate (B-127) and 3-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)propanoic acid (B-123) in a similar fashion to Compound B-10, except using 1.5 eq. B-127 and 2 eq. 1-propanephosphonic anhydride solution (50% in Ethyl acetate). LCMS (ES+): m / z 482.2 [M - H]’. Step 2:   1-(3-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)propanoyl)piperidine-4-carboxylic acid (B-129) 1-(3-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)propanoyl)piperidine-4-carboxylic acid (B-129, 40 mg, 87.60 pmol, 85% yield) was synthesized from tert-butyl l-[3-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]propanoyl]piperidine-4-carboxylate (B-128) in a similar fashion to Compound A-26, except using 25 eq. TFA. LCMS (ES+): m / z 426.2 [M - H]’. 3-(l-oxo-4-((2-oxo-2-(piperazin-l-yl)ethyl)amino)isoindolin-2-yl)piperidine-2,6-dione (B-131) B-34                                              B-130 B-131 Step 1: tert-butyl    4-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)glycyl)piperazine-l- carboxylate (B-130) tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1 -oxoisoindolin-4-yl)glycyl)piperazine-1 -carboxylate (B-130, 250 mg, 378.97 pmol, 35% yield) was synthesized from tert-butyl piperazine-1-carboxylate (B-124) and 2-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]amino]acetic acid (B-34) in a similar fashion to Compound B-10, except using 0.8 eq. B-124 and 1.5 eq. 1-propanephosphonic anhydride solution (50% in Ethyl acetate). LCMS (ES-): m / z 484.3 [M - H]’. Step 2:3-(l-oxo-4-((2-oxo-2-(piperazin-l-yl)ethyl)amino)isoindolin-2-yl)piperidine-2,6-dione (B-131) 3-(l-oxo-4-((2-oxo-2-(piperazin-l-yl)ethyl)amino)isoindolin-2-yl)piperidine-2,6-dione (B-131, 200 mg, 272.31 pmol, 53% yield, TFA salt) was synthesized from tert-butyl 4-[2-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]amino]acetyl]piperazine-l-carboxylate (B-130) in a similar fashion to Compound A-62, except using 13 eq. TFA. LCMS (ES+): m / z 386.2 [M + H]+. 2-[4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-l-piperidyl]acetic acid (B-137) Step 1: tert-butyl 4-(1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-3,6-dihydro-2H-pyridine-l-carboxylate (B-133) Into a 50 mL sealed tube reactor containing a well-stirred solution of 3-(5-bromo-3-methyl-2-oxo-benzimidazol-l-yl)piperidine-2,6-dione (B-132, 1 g, 2.96 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-l-carboxylate (B-110,1.19 g, 3.84 mmol) in anhydrous DMF (8 mL) was added CsF (1.35 g, 8.87 mmol) under nitrogen atmosphere and the resulting mixture was purged by bubbling nitrogen gas into the reaction mixture for 10 min. Subsequently, [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (143.74 mg, 0.176 mmol) was added and the reaction mixture was heated at 90 °C for 16 h. The reaction mixture was poured into water (50 mL) and extracted with Ethyl acetate (2 x 150 mL). Organic phases were combined and washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash silica-gel (230-400 mesh) column, eluting with 0-100% Ethyl acetate / petroleum ether to afford tert-butyl 4-(1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-3,6-dihydro-2H-pyridine-l-carboxylate (B-133, 0.7 g, 1.49 mmol, 50% yield) as an off-white solid. LCMS (ESI): m / z 441.2 [M + H]+. Step 2: tert-butyl 4-(1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperidine-l-carboxylate (B-134) tert-butyl 4-(1-(2,6-dioxo-3-piperidyl)-3 -methyl-2-oxo-benzimidazol-5-yl]piperidine-1 -carboxylate (B-134, 0.35 g, 0.696 mmol, 88% yield) was synthesized from tert-butyl 4-(1-(2,6-dioxo-3-piperidy 1)-3-methyl-2-oxo-benzimidazol-5-yl]-3,6-dihydro-2H-pyridine-l-carboxylate (B-133) in a similar fashion to Compound B-103, except using 0.15 eq. palladium hydroxide on carbon (20% by weight, 50% water). The Celite bed was washed with dioxane and 1:1 Ethyl acetate / DCM. Following removal of solvent, the material was triturated with diethyl ether. LCMS (ESI): m / z 387 [M - tBu + H]+. Step 3: 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-l-yl]piperidine-2,6-dione (B-135) 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-l-yl]piperidine-2,6-dione (B-135, 500 mg, 1.28 mmol, 81% yield, TFA salt) was synthesized from tert-butyl 4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperidine-l-carboxylate (B-134) in a similar fashion to Compound A-62, except using 15 eq. TFA. The material was triturated with diethyl ether. LCMS (ESI): m / z 343.0 [M + H]+. Step 4:     tert-butyl 2-[4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-l- piperidyl]acetate (B-136) tert-butyl 2-[4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-l-piperidyl]acetate (B-136, 235 mg, 502.39 pmol, 83% yield) was synthesized from 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-l-yl]piperidine-2,6-dione (B-135) and tert-butyl 2-bromoacetate (A-14) in a similar fashion to Compound B-82, except using 1.3 eq. A-14 and 5 eq. triethylamine. Upon completion, the reaction was diluted with water (35 ml) and the precipitate was filtered and washed with water. The solid was dried under vacuum and used in the next step without further purification. LCMS (ES+): m / z 457.2 [M + H]+. Step 5: 2-[4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-l-piperidyl]acetic acid (B-137) 2-[4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-l-piperidyl]acetic acid (B-137, 200 mg, 349.89 pmol, 71% yield, TFA salt) was synthesized from / erZ-butyl 2-[4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-l-piperidyl]acetate (B-136) in a similar fashion to Compound A-26, except using 20 eq. TFA. LCMS (ES+): m / z 400.1 [M + H]+. 2-[4-[3-(2,6-dioxo-3-piperidyl)-2-oxo-l,3-benzoxazol-6-yl]-l-piperidyl]acetic acid (B-145) Step 1: 3-(6-bromo-2-oxobenzo[d]oxazol-3(2H)-yl)piperidine-2,6-dione (B-140) To a stirred solution of 6-bromo-3H-l,3-benzoxazol-2-one (B-138, 6 g, 28.04 mmol) in THF (200 mL) was added sodium hydride (60% dispersion in mineral oil) (1.29 g, 56.07 mmol) portion wise and the mixture was heated at 60 °C for 1 h. This mixture was added dropwise via cannula to a stirred solution of3-bromopiperidine-2,6-dione (B-139, 8.07 g, 42.05 mmol) in THF (50 mL) at 60 °C and stirred for 2 h. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (50% Ethyl acetate:Hexanes) to afford 3-(6-bromo-2-oxobenzo[d]oxazol-3(2H)-yl)piperidine-2,6-dione (B-140, 2.9 g, 8.71 mmol, 31% yield). LCMS (ES-): m / z 323.0 [M-H]’. 1HNMR(400MHz,DMSO-D6) ^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) Step 2: tert-butyl 4-(3-(2,6-dioxo-3-piperidyl)-2-oxo-l,3-benzoxazol-6-yl]-3,6-dihydro-2H-pyridine-l-carboxylate (B-141) Into a20 mL sealed tube containing a well-stirred solution of 3-(6-bromo-2-oxo-l,3-benzoxazol-3-yl)piperidine-2,6-dione (B-140, 200 mg, 0.615 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-l-carboxylate (B-110, 247.28 mg, 0.800 mmol) in 1,4-dioxane (2 mL) was added anhydrous potassium phosphate tribasic (522.32 mg, 2.46 mmol) under nitrogen atmosphere and the resulting mixture was degassed by bubbling nitrogen gas through the reaction mixture for 10 min. Finally, 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 h. The reaction was cooled to room temperature and the reaction mixture was poured into water (10 mL) and extracted with Ethyl acetate (2x10 mL). The combined organic layer was washed with brine solution (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica-gel (230-400 mesh) flash column, eluting with 0-100% Ethyl acetate / petroleum ether to afford tert-butyl 4-(3-(2,6-dioxo-3-piperidyl)-2-oxo-l,3-benzoxazol-6-yl]-3,6-dihydro-2H-pyridine-l-carboxylate (B-141,200 mg, 0.429 mmol, 70% yield) as an off-white solid. LCMS (ESI): m / z 426.2 [M - H]\ Step 3: tert-butyl 4-(3-(2,6-dioxo-3-piperidyl)-2-oxo-l,3-benzoxazol-6-yl]piperidine-l-carboxylate (B-142) tert-butyl 4-(3-(2,6-dioxo-3-piperidyl)-2-oxo-l,3-benzoxazol-6-yl]piperidine-l-carboxylate (B-142, 190 mg, 0.384 mmol, 82% yield) was synthesized from tert-butyl 4-(3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-6-yl]-3,6-dihydro-2H-pyridine-l-carboxylate (B-141) in a similar fashion to Compound B-103, except using 0.3 eq. palladium hydroxide on carbon (20% by weight, 50% water). The Celite pad was washed with 1:1 Ethyl acetate / DCM, and the material was triturated with diethyl ether. LCMS (ESI): m / z 427.9 [M - H]\ Step 4: 3-[2-oxo-6-(4-piperidyl)-l,3-benzoxazol-3-yl]piperidine-2,6-dione (B-143) 3-[2-oxo-6-(4-piperidyl)-l,3-benzoxazol-3-yl]piperidine-2,6-dione (B-143, 170 mg, 0.303 mmol, 47% yield, TFA salt) was synthesized from tert-butyl 4-(3-(2,6-dioxo-3-piperidyl)-2-oxo-l,3-benzoxazol-6- yl]piperidine-l-carboxylate (B-142) in a similar fashion to Compound A-62, except using 45 eq. TFA. The material was triturated with diethyl ether. LCMS (ESI): m / z 330.2 [M + H]+. Step 5: tert-butyl 2-(4-(3-(2,6-dioxo-3-piperidyl)-2-oxo-l,3-benzoxazol-6-yl]-l-piperidyl]acetate (fl-144) tert-butyl 2-(4-(3-(2,6-dioxo-3-piperidyl)-2-oxo-l,3-benzoxazol-6-yl]-l-piperidyl]acetate (B-144,150 mg, 0.305 mmol, 67% yield) was synthesized from 3-[2-oxo-6-(4-piperidyl)-l,3-benzoxazol-3-yl]piperidine-2,6-dione (B-143) and tert-butyl 2-bromoacetate (A-14) in a similar fashion to Compound B-82, except using 1.1 eq. A-14 and 5 eq. triethylamine. Upon completion, the reaction mixture was poured into ice cold water and the precipitate filtered and dried under reduced pressure. The material was used in the next step without further purification. LCMS (ESI): m / z 444.0 [M + H]+. Step 6: 2-(4-(3-(2,6-dioxo-3-piperidyl)-2-oxo-l,3-benzoxazol-6-yl]-l-piperidyl]acetic acid (B-145) 2-(4-(3-(2,6-dioxo-3-piperidyl)-2-oxo-l,3-benzoxazol-6-yl]-l-piperidyl]acetic acid (B-145, 150 mg, 0.234 mmol, 55% yield) was synthesized from tert-butyl 2-(4-(3-(2,6-dioxo-3-piperidyl)-2-oxo-l,3-benzoxazol-6-yl]-l-piperidyl]acetate (B-144) in a similar fashion to Compound A-26, except using 45 eq. TFA. The material was azeotroped with toluene (2 x 20 ml) and subsequently triturated with diethyl ether (2x10 mL). LCMS (ESI): m / z 387.9 [M + H]+. 3-(4-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)oxy)piperidin-l-yl)propanoic acid (B-150) A-37 CH3SO2CI, TEA DCM, r.t. Step 1             B-146 B-63 HCI, 36%w / w aq. NaNO2, water, 80°C B-147 CS2CO3 B-148 Step 2 B-149 DMF, 80”C Step 3 B-150 Step 1: tert-butyl 4-methylsulfonyloxypiperidine-l-carboxylate (B-146) Into a 100 mL single neck round bottom flask containing a well-stirred solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (A-37, 3.0 g, 14.91 mmol) in anhydrous DCM (30 mL)were added triethylamine (3.77 g, 37.26 mmol, 5.19 mL) and methanesulfonyl chloride (2.56 g, 22.36 mmol, 1.73 mL) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water (2 x 50 mL) and extracted with DCM (2x30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford ZerZ-butyl 4-methylsulfonyloxypiperidine-l-carboxylate (B-146, 2.5 g, 72% yield) as an off-white solid. The material was used in the next step without further purification. GCMS (ESI): m / z 279.1 [M]+. 'H NMR (400 MHz, CDClj). J"4.92- 4.88 (m, 1H), 3.75-3.69 (m, 2H), 3.35-3.29 (m, 2H), 3.05 (s, 3H), 2.001.95 (m, 2H), 1.87-1.81 (m, 2H) and 1.47 (s, 9H). Step 2: 3-(4-hydroxy-l-oxo-isoindolin-2-yl)piperidine-2,6-dione (B-147) Into a 250 mL single neck round bottom flask containing a well-stirred solution of 3-(4-amino-l-oxo-isoindolin-2-yl)piperidine-2,6-dione (B-63, 5 g, 19.29 mmol) in water (70 mL) was added sodium nitrite (2.00 g, 28.93 mmol, 919.78 pL) in water (5 mL) at 0 °C. The reaction mixture was stirred at room temperature for 5 min. Subsequently, hydrochloric acid (36% w / w aq. soln.) (6.40 g, 175.53 mmol, 8 mL) was added to the reaction at 0 °C and was stirred at room temperature for 15 min before stirring at 80 °C for 2 h. The solvent was removed under reduced pressure and the residue was purified by reverse phase column chromatography (compound eluted by 35% acetonitrile in water (0.1% TFA in water)) to afford 3-(4-hydroxy-l-oxo-isoindolin-2-yl)piperidine-2,6-dione (B-147, 2.1 g, 6.29 mmol, 33% yield) as a brown solid. LCMS (ES+): m / z 261.1 [M + H]+. 'H NMR (400 MHz, DMSO-^) 310.99 (s, 1H), 10.13 (s, 1H), 7.36 - 7.32 (m, 1H), 7.19 (d, J= 7.2 Hz, 1H), 7.02 (d, J= 7.6 Hz, 1H), 5.10 (dd, J= 13.2, 5.2 Hz, 1H), 4.35-4.17 (m, 2H), 2.96-2.87 (m, 1H), 2.67-2.51 (m, 1H),2.46- 2.33 (m, 1H) and 2.03-1.97 (m, 1H). Step 3: ZerZ-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)oxy)piperidine-l-carboxylate (B-148) Into a 50 mL sealed tube containing a well-stirred solution of 3-(4-hydroxy-l-oxoisoindolin-2-yl)piperidine-2,6-dione (B-147, 700 mg, 2.10 mmol) and ZerZ-butyl 4-((methylsulfonyl)oxy)piperidine-l-carboxylate (B-146, 879.13 mg, 3.15 mmol) in anhydrous DMF (8 mL) was added cesium carbonate (1.37 g, 4.20 mmol). The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was diluted with water (30 mL) and extracted with Ethyl acetate (2 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica-gel (60-120 mesh) column chromatography, eluting with 80% Ethyl acetate / petroleum ether to afford ZerZ-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-l -oxoisoindolin-4-yl)oxy)piperidine-l-carboxylate (B-148, 700 mg, 0.751 mmol, 36% yield) as a green gummy liquid. LCMS (ESI): m / z 442.2 [M - H]’. 'H NMR (400 MHZ, CDCh). <T8.18 (s, 1H), 7.51-7.42 (m, 2H), 7.05 (d, J= 8.0 Hz, 1H), 5.26-5.22 (m, 1H), 4.634.61 (m, 1H), 4.46-4.28 (m, 2H), 3.72-3.66 (m, 2H), 3.42-3.37 (m, 2H), 2.42-2.38 (m, 1H), 2.26-2.24 (m, 1H), 2.00-1.95 (m, 2H), 1.85-1.77 (m, 4H) and 1.48 (s, 9H). Step 4: 3-[l-oxo-4-(4-piperidyloxy)isoindolin-2-yl]piperidine-2,6-dione (B-149) 3-[l-oxo-4-(4-piperidyloxy)isoindolin-2-yl]piperidine-2,6-dione (B-149, 600 mg, 1.06 mmol, 67% yield) was synthesized from ZerZ-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)oxy)piperidine-l-carboxylate (B-148) in a similar fashion to Compound A-62, except using 41 eq. TFA. LCMS (ES+): m / z 344.1 [M + H]+. Step 5: 3-(4-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)oxy)piperidin-l-yl)propanoic acid (B-150) 3-(4-((2-(2,6-dioxopiperidin-3 -yl)-1 -oxoisoindolin-4-yl)oxy)piperidin-1 -yl)propanoic acid (B-150, 100 mg, 229.56 pmol, 23% yield) was synthesized from 3-[l-oxo-4-(4-piperidyloxy)isoindolin-2-yl]piperidine-2,6-dione (B-149) and 3-bromopropanoic acid (B-85) in a similar fashion to Compound B-82, except using 1.1 eq. B-85, and 3 eq. N,N-diisopropylethylamine. Upon completion, the reaction mixture was 5 concentrated under reduced pressure and the residue was purified by reverse phase prep HPLC (Column: XSelect C18 150mm; Mobile phase: 0.1% TFA in water / MeCN). LCMS (ES+): m / z 416.3[M+H]+. 1 - [2- [[2-(2,6-dioxo-3-piperidyl)-l -oxo-isoindolin-4-yl| amino] acetyl] -N- [2-fluoro-5- [(4-oxo-l-piperidyl)sulfonylmethyl]phenyl]azetidine-3-carboxamide (B-160) T3P DMF, DIPEA, rt Step 1 10 Step 1: tert-butyl 3-(benzotriazole-2-carbonyl)azetidine-l-carboxylate (B-152): tert-butyl 3-(benzotriazole-2-carbonyl)azetidine-l-carboxylate (B-152, 1.8 g, 5.36 mmol, 32% yield) was synthesized from 1-tert-butoxy carbonylazetidine-3-carboxylic acid (A-63) and IH-benzotriazole (B-151) in a similar fashion to Compound A-88, except using 1 eq. B-151, 3 eq. DIPEA and 1.5 eq. 1-propanephosphonic anhydride (50% in ethyl acetate). Upon completion, the reaction was quenched with 15 water and extracted with diethyl ether (3 x). The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash silica-gel (230-400 mesh) column, eluting with 30% Ethyl acetate / petroleum ether. 'H NMR (400 MHz, CDCI3). 3 8.32 (d, J= 8.2 Hz, 1H), 8.15 (d, J= 8.2 Hz, 1H), 7.73-7.69 (m, 1H), 7.57-7.54 (m, 1H), 4.71-4.63 (m, 1H), 4.39 (d, J = 7.5 Hz, 4H) and 1.47 (s, 9H). Step 2: sodium (4-fluoro-3-nitrophenyl)methanesulfonate (B-154) Into a 500 mL single neck round bottom flask containing a well-stirred solution of 4-(bromomethyl)-l-fluoro-2-nitro-benzene (B-153,10 g, 42.73 mmol) in water (100 mL) was added anhydrous sodium sulphite (5.92 g, 47.00 mmol, 2.25 mL) and the resulting reaction mixture was stirred for 16 h at 100 °C. The solvent was removed under reduced pressure and the residue was co-distilled with toluene (3 x 75 mL) to afford sodium (4-fluoro-3-nitrophenyl)methanesulfonate (B-154, 13 g) as a crude fine powder. This material was taken to the next step without further purification. Step 3: (4-fluoro-3-nitro-phenyl)methanesulfonyl chloride (B-155) Into a 500 mL single neck round bottom flask containing a well-stirred solution of sodium (4-fluoro-3-nitrophenyl)methanesulfonate (B-154, 13 g, crude) in anhydrous toluene (80 mL) was added phosphorus pentachloride (26.69 g, 128.19 mmol, 16.68 mL). Reaction mixture was stirred at 90 °C for 3 h. The solvent was removed under reduced pressure and the residue was dissolved in DCM (300 mL) and washed with cold water (2 x 100 mL). Combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford (4-fluoro-3-nitro-phenyl)methanesulfonyl chloride (B-155, 10 g) as a brown-coloured syrupy material. The material was used in the next step without further purification. Step 4: l-[(4-fluoro-3-nitro-phenyl)methylsulfonyl] piperidin-4-one (B-156) l-[(4-fluoro-3-nitro-phenyl)methylsulfonyl]piperidin-4-one (B-156, 2.5 g, 7.11 mmol, 19% yield) was synthesized from piperidin-4-one (A-66) and (4-fluoro-3-nitro-phenyl)methanesulfonyl chloride (B-155) in a similar fashion to Compound A-8, except using 1 eq. B-155. Upon completion, the layers were separated, and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash silica-gel (230-400 mesh) column eluting with 40% Ethyl acetate / petroleum ether. 'H NMR (400 MHz, DMSO-<76) 3 8.27 (dd, J= 12, 2.4 Hz, 1H), 7.89-7.85 (m, 1H), 7.67-7.62 (m, 1H), 4.71 (s, 2H), 3.48 (t, J= 6.4 Hz, 4H) and 2.40 (t, J= 6.0 Hz, 4H). Step 5: l-|(3-amino-4-fluoro-phenyl)methylsulfonyl|piperidin-4-one (B-157) l-[(3-amino-4-fluoro-phenyl)methylsulfonyl]piperidin-4-one (B-157, 1 g, 2.61 mmol, 55% yield) was synthesized from l-[(4-fluoro-3-nitro-phenyl)methylsulfonyl]piperidin-4-one (B-156) in a similar fashion to Compound B-99, except the filtrate was diluted with Ethyl acetate and the organic layer was washed with water. LCMS (ESI): m / z 287.1 [M + H]+. 'H NMR (400 MHz, DMSO-ok) 3 7.00-6.95 (m, 1H), 6.83 (dd, J= Z2, 1.9 Hz, 1H), 6.57-6.54 (m, 1H), 5.24 (s, 2H), 4.34 (s, 2H), 3.44 (t, J= 6.0 Hz, 4H) and 2.37 (t, .7= 6.0 Hz, 4H). Step 6: tert-butyl 3-[[2-fluoro-5-[(4-oxo-l-piperidyl)sulfonylmethyl]phenyl]carbamoyl]azetidine-l-carboxylate (B-158) Into a 50 mL single neck round bottom flask containing a well-stirred solution of l-[(3-amino-4-fluoro-phenyl)methylsulfonyl]piperidin-4-one (B-157, 0.5 g, 1.75 mmol) and tert-butyl 3-(benzotriazole-2- carbonyl)azetidine-l-carboxylate (B-152, 580.75 mg, 1.92 mmol) in a mixture of 2:1 anhydrous DCM / toluene (9 mL) was added trifluoroacetic (398.23 mg, 3.49 mmol, 269.08 pL) at room temperature under nitrogen atmosphere. After addition of trifluoroacetic acid, precipitation was observed and THF (6 mL) was added to dissolve the precipitate. The reaction mixture was stirred at room temperature for 24 h. The solvent was removed under reduced pressure to afford ZerZ-butyl 3-[[2-fluoro-5-[(4-oxo-l-piperidyl)sulfonylmethyl]phenyl]carbamoyl]azetidine-l-carboxylate (B-158, 1.1 g, 918.37 pmol, 53% yield, 39% purity) as a black-coloured syrup. The material was taken to the next step without purification. LCMS (ESI): m / z 468.1 [M - H]’. Step 7: 7V-[2-fluoro-5-[(4-oxo-l-piperidyl)sulfonylmethyl]phenyl]azetidine-3-carboxamide (B-159) A-[2-fluoro-5-[(4-oxo-l-piperidyl)sulfonylmethyl]phenyl]azetidine-3-carboxamide (B-159, 0.5 g, 725.23 pmol, 79% yield) was synthesized from ZerZ-butyl 3-[[2-fluoro-5-[(4-oxo-l-piperidyl)sulfonylmethyl]phenyl]carbamoyl]azetidine-l-carboxylate (B-158) in a similar fashion to Compound A-62, except using 28 eq. TFA. The material was triturated with MTBE. LCMS (ESI): m / z 370.1 [M + H]+. Step 8: l-[2-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]amino]acetyl]-7V-[2-fluoro-5-[(4-oxo-l-piperidyl)sulfonylmethyl|phenyl|azetidine-3-carboxamide (B-160) l-[2-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]amino]acetyl]-A-[2-fluoro-5-[(4-oxo-l-piperidyl)sulfonylmethyl]phenyl]azetidine-3-carboxamide (B-160, 50 mg, 46.75 pmol, 13% yield) was synthesized from A-[2-fluoro-5-[(4-oxo-l-piperidyl)sulfonylmethyl]phenyl]azetidine-3-carboxamide (B-159) and 2-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]amino]acetic acid (B-34) in a similar fashion to Compound A-88, except using 2 eq. B-34,5 eq. DIPEA and 3 eq. 1 -propanephosphonic anhydride (50% in ethyl acetate). LCMS (ESI): m / z 669.1 [M + H]+. 1 - [2- [[2-(2,6-dioxo-3-piperidyl)-l -oxo-isoindolin-4-yl| amino] acetyl] -N- [2-fluoro-3- [(4-oxo-l-piperidyl)sulfonylmethyl]phenyl]azetidine-3-carboxamide (B-168) B-161 NBS , AIBN, Chlorobenzene i.N^SOj, H2O, 100 °C, 16h B-162 ii.PCI5, toluene, 90 °C 85 °C Step 1 Step 2 T3P, DIPEA, DMF r.t. B-168 Step 7 Step 1: l-(bromomethyl)-2-fluoro-3-nitro-benzene (B-162) Into a IL three neck round bottom flask containing a well-stirred solution of 2-fluoro-l-methy 1-3-nitrobenzene (B-161, 20 g, 128.93 mmol) in anhydrous chlorobenzene (150 mL)were added N- 5 bromosuccinimide (25.24 g, 141.82 mmol, 12.02 mL) and 2-[(£)-(l-cyano-l-methyl-ethyl)azo]-2-methyl-propanenitrile (3.18 g, 19.34 mmol). The reaction mixture was heated to 85 °C for 16 h. The reaction mixture was cooled to room temperature, filtered and the solvent removed. The residue was dissolved in DCM (60 mL) and filtered again. The filtrate was evaporated to dryness under reduced pressure, and the residue was purified by silica-gel (230-400 mesh) flash column chromatography, eluting with 0-100% 10 Ethyl acetate / petroleum ether to afford l-(bromomethyl)-2-fluoro-3-nitro-benzene (B-162, 18 g, 62.21 mmol, 48% yield) as a yellow-coloured solid. GCMS (ESI): m / z 233.9 [M]+. 'H NMR (400 MHz, DMSO-d6) S 8.04-8.00 (m, 1H), 7.74-7.70 (m, 1H), 7.33-7.27 (m, 1H) and 4.56 (s, 2H). Step 2: (2-fluoro-3-nitrophenyl)methanesulfonyl chloride (B-163) Into a 500 mL single neck round bottom flask containing a well-stirred solution of l-(bromomethyl)-2-15 fluoro-3-nitro-benzene (B-162 ,15 g, 64.10 mmol) in water (150 mL) was added sodium sulphite (8.08 g, 64.10 mmol, 3.07 mL) and the reaction mixture was heated to 100 °C for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was azeotroped with toluene (3 x 100 mL) and washed with Ethyl acetate (3 x 100 mL) to afford crude sodium (2-fluoro-3-nitrophenyl)methane sulfonate (18 g) as an off-white solid. About 15 g of this crude was added to a 500 mL single neck round bottom flask in anhydrous toluene (60 mL) and treated with phosphorus pentachloride (26.69 g, 128.19 mmol, 16.68 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 3 h. The reaction mixture was concentrated under reduced pressure and the residue diluted with water (100 mL) and extracted with DCM (2 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with MTBE (2 x 50 mL) to afford (2-fluoro-3-nitrophenyl)methanesulfonyl chloride (B-163, 8 g) as a darkbrown liquid which was taken to the next step without further purification. Step 3: l-[(2-fluoro-3-nitro-phenyl)methylsulfonyl]piperidin-4-one (B-164) l-[(2-fluoro-3-nitro-phenyl)methylsulfonyl]piperidin-4-one (B-164 ,600 mg, 1.90 mmol, 17% yield) was synthesized from piperidin-4-one hydrochloride (A-66) and (2-fluoro-3-nitrophenyl)methanesulfonyl chloride (B-163) in a similar fashion to Compound A-8, except using 1.5 eq. B-163. Upon completion, water was added and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica-gel (230-400 mesh) flash column eluting with 0-100% Ethyl acetate / petroleum ether. 'H NMR (400 MHz, DMSO-ds) 3 8.18 (t, J = 14 Hz, 1H), 7.91 (t, J= 12.4 Hz, 1H), 7.50 (t, J= 16 Hz, 1H), 4.73 (s, 2H), 3.53 (t, J= 12.4 Hz, 4H) and 2.43 (t, J= 12.4 Hz, 4H). Step 4: l-|(3-amino-2-fluoro-phenyl)methylsulfonyl|piperidin-4-one (B-165) l-[(3-amino-2-fluoro-phenyl)methylsulfonyl]piperidin-4-one (B-165, 420 mg, 1.47 mmol, 77% yield) was synthesized from l-[(2-fluoro-3-nitro-phenyl)methylsulfonyl]piperidin-4-one (B-164) in a similar fashion to Compound B-99, except Celite was washed with Ethyl acetate and the organic layer was dried over sodium sulfate, filtered and solvent removed. 'H NMR (400 MHz, DMSO-A) 3 6.87 (t, J= 15.28 Hz, 1H) 6.75 (t, J= 16.4 Hz, 1H), 6.59 (t, J= 14.4 Hz, 1H), 5.21 (s, 2H), 4.42 (s, 2H), 3.47 (t, J= 12.4 Hz, 4H) and 2.41 (m, 4H). Step 5: tert-butyl 3-[[2-fluoro-3-[(4-oxo-l-piperidyl)sulfonylmethyl]phenyl]carbamoyl]azetidine-l-carboxylate (B-166) tert-butyl 3-[[2-fluoro-3-[(4-oxo-l-piperidyl)sulfonylmethyl]phenyl]carbamoyl]azetidine-l-carboxylate (B-166, 300 mg, 0.226 mmol, 43% yield) was synthesized from l-[(3-amino-2-fluoro-phenyl)methylsulfonyl]piperidin-4-one (B-165) and tert-butyl 3-(benzotriazole-2-carbonyl)azetidine-l-carboxylate (B-152) in a similar fashion to Compound B-158, except using 1 eq. B-152.The material was triturated with diethyl ether. LCMS (ESI): m / z 468.1 [M - H]’. Step 6: 7V-[2-fluoro-3-[(4-oxo-l-piperidyl)sulfonylmethyl]phenyl]azetidine-3-carboxamide (B-167) A-[2-fluoro-3-[(4-oxo-l-piperidyl)sulfonylmethyl]phenyl]azetidine-3-carboxamide (B-167,190 mg, 0.198 mmol, 31% yield, TFA salt) was synthesized from tert-butyl 3-[[2-fluoro-3-[(4-...

Claims

1. A compound of Formula (I):or a pharmaceutically acceptable salt thereof: wherein:R1 and R2 are independently hydrogen or C1-C6 alkyl; or R1 and R2, together with the carbon atom to which they are attached, come together to form a C3-C4 cycloalkyl or a 3-4 membered heterocyclyl;R3 and R4 are independently hydrogen, C1-C6 alkyl, or phenyl; or R3 and R4, together with the carbon atom to which they are attached, come together to form a C3-C4 cycloalkyl or a 3-4 membered heterocyclyl;each R5 and R6 is independently halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, or -NR8AR8B;R7 is hydrogen, C1-C6 alkyl, or C3-C4 cycloalkyl; or wherein R7 and RC of W, together with the nitrogen atoms to which they are attached, come together to form a 5-6 membered heterocyclyl;R8A and R8B are independently hydrogen or C1-C6 alkyl;Ring A and Ring B are independently phenyl or 6-membered heteroaryl;n and m are independently 0, 1, or 2;Q1 is O or NR9;R9 is hydrogen or C1-C6 alkyl;J is a bond or -C(=O)-;W and Y are independently -(CRARB)p-*, -((CRARB)pO)t-*, -(O(CRARB)p)t-*, -((CRARB)pO)t-(CRARB)p-*, -((CRARB)2O(CRARB)2))p-*, -NRC(CRARB)p-*, -(CRARB)pNRC(C=O)(CRARB)p-*, -(CRARB)p(C=O)NRC(CRARB)p-*, -(CRARB)pNRC-*, -(CRARB)pNRC(C=O)(CRARB)p-O-*, -(CRARB)p(C=O)NRC(CRARB)s-O-*, -(CRARB)pNRC(C=O)(CRARB)p-NRC-*, -(CRARB)p(C=O)NRC(CRARB)s-NRC-*;-NRC(CRARB)s-NRC(C=O)(CRARB)p-*, \RC((CRARB)p)C C *, C C((CRARB)p)\RC *, -(C=O)(CRARB)p-O-*, -O-*, -O-(CRARB)p-(C=O)-*, -(C=O)(CRARB)p-NRC-*, -NRC-(CRARB)p-(C=O)-*, -(C=O)((CRARB)p)-*, -(C=O)(CRARB)p-O-(CRARB)p-*, or -((CRARB)p)(C=O)-*, wherein the asterisk represents the point of attachment of W to X and the point of attachment of Y to Z;2022326553   30 Sep 2026each p is independently 0, 1, 2, 3, 4, or 5;each s is independently 2, 3, 4, or 5;each t is independently 1, 2, or 3;each RA and RB are independently hydrogen, fluoro, or C1-C6 alkyl; or RA and RB, together with the carbon atom to which they are attached, come together to form a C3-C4 cycloalkyl;each RC is independently hydrogen or C1-C6 alkyl; or wherein RC of W and R7, together with the nitrogen atoms to which they are attached, come together to form a 5-6 membered heterocyclyl;X is a bond, C3-C6 cycloalkyl, phenyl optionally substituted with 1-3 independently selected halogen atoms, 3 to 10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from halogen, C1-C6 alkyl, and hydroxyl, or 5 to 10 membered heteroaryl optionally substitutedwith 1-3 independently selected halogen;Z is selected from the group consisting ofR10 is hydrogen, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclyl; andR11 is hydrogen or C1-C6 alkyl;each R12 is independently halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C52022326553   30 Sep 2026cycloalkoxy; andq is 0, 1, or 2.2.The compound of claim 1, wherein Ring A is:

3. The compound of claim 1 or 2, wherein R5 is halogen.

4. The compound of any one of claims 1-3, wherein m is 0 or 1.

5. The compound of any one of claims 1-4, wherein R1 and R2 are independently hydrogenor C1-C6 alkyl.

6. The compound of any one of claims 1-5, wherein R3 and R4 are independently hydrogen,C1-C6 alkyl, or phenyl.

7. The compound of any one of claims 1-6, wherein Ring B is:              .

8. The compound of any one of claims 1-7, wherein R6 is halogen.

9. The compound of any one of claims 1-8, wherein n is 0 or 1.

10. The compound of any one of claims 1-9, wherein R7 is hydrogen or C1-C3 alkyl.

11. The compound of any one of claims 1-10, wherein W is -(CRARB)p-*, -((CRARB)pO)t-*,-((CRARB)pO)t-(CRARB)p-*-((CRARB)2O(CRARB)2))p-*, -(CRARB)pO-*, -O(CRARB)p-*, or -(CRARB)pNRC-*.

12. The compound of any one of claims 1-11, wherein Y is -(CRARB)p-*, -(C=O)(CRARB)p-O-*,   -(C=O)(CRARB)p-NRC-*,   -(C=O)(CRARB)p-*,   -(CRARB)p(C=O)NRC(CRARB)p-*,   -(CRARB)pNRC(C=O)(CRARB)p-*,             -(CRARB)pNRC(C=O)(CRARB)pO-*,             -(CRARB)pNRC(C=O)(CRARB)p-NRC-*,  C C((CR ARB)p)\RC *, -(CRARB)p(C=O)NRC(CRARB)p-*, -(CRARB)pNRC(C=O)(CRARB)p-*,-(CRARB)pNRC(C=O)(CRARB)pO-*,2022326553   30 Sep 2026(CRARB)pNRC(C=O)(CRARB)p-NRC-*,  C C((CR ARB)p)\RC *, -(CRARB)pO-*, -O(CRARB)p-*, or -(CRARB)pNRC-*.

13. The compound of any one of claims 1-12, wherein Z is selected from:

14. The compound of claim 1, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-a):(I-a)or a pharmaceutically acceptable salt thereof;wherein RX and RY are both H; or RX and RY, together with the carbon atom to which they are attached, combine to form C=O.

15. The compound of claim 1, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-b):2022326553   30 Sep 2026(I-b)or a pharmaceutically acceptable salt thereof;wherein R10 is hydrogen, C1-C4 alkyl optionally substituted with C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclyl.

16. The compound of claim 1, wherein the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is a compound of Formula (I-c):

17. The compound of claim 1, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-d):

18. The compound of claim 1, wherein the compound of Formula (I) is selected from the group consisting of:- 660--661 -- 662 -- 663 --664-- 665 -- 666-- 667 -- 668 -- 669 -- 670--671 -- 672 -- 673 -- 674--9L9--9L9-- 677 -- 678 -- 679 -- 680--681 -- 682 -- 683 -- 684-- 685 -- 686-- 687 -- 688 -- 689 -- 690--691 -- 692 -- 693 -- 694-- 695 -- 696-- 697 -- 698 -- 699 -- 700--701 -- 702 -- 703 --704-- 705 -- 706-- 707 -- 708 -- 709 --710--711 --712-2022326553   30 Sep 202619. A pharmaceutical composition comprising a compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof.

20. A method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-18 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 19.

21. A method for inhibiting mammalian cell proliferation, comprising contacting the mammalian cell with an effective amount of a compound of any one of claims 1-18 or a pharmaceutically acceptable salt thereof.

22. A method for decreasing the level of a protein in a mammalian cell, comprising contacting the mammalian cell with an effective amount of a compound of any one of claims 1-18 or a pharmaceutically acceptable salt thereof; wherein the protein is PTPN1, PTPN2, or a combination thereof.

23. The method of claim 21 or 22, wherein the contacting occurs in vivo.

24. The method of claim 21 or 22, wherein the contacting occurs in vitro.2022326553   30 Sep 202625. The method of any one of claims 21-24, wherein the mammalian cell is a mammalian cancer cell.

26. A method for inhibiting metastasis in a subject having a cancer in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 19.

27. A method for treating a metabolic disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 19.

28. The method of claim 27, wherein the metabolic disease is NAFLD, NASH, type 2 diabetes, or a combination of any of the foregoing.

29. The method of claim 27 or 28, wherein the metabolic disease is type 2 diabetes.

30. A method for decreasing BMI in a subject in need thereof, comprising administering tothe subject a therapeutically effective amount of a compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 19.

31. A method for inhibiting weight gain in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 19.

32. The method of any one of claims 27-31 wherein the subject has an average BMI of between about 25 and about 45 prior to initiation of treatment with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

33. A method for increasing proliferation of mammalian T-cells in the presence of T-cell receptor stimulation, comprising contacting a mammalian thymus cell with an effective amount of a compound of any one of claims 1-18 or a pharmaceutically acceptable salt thereof; wherein the protein is PTPN1, PTPN2, or a combination thereof.

34. A method for activating mammalian T-cells in the presence of T-cell receptor stimulation, comprising contacting the mammalian T-cell with an effective amount of a compound of any one of claims 1-18 or a pharmaceutically acceptable salt thereof; wherein the protein is PTPN1, PTPN2, or a combination thereof.2022326553   30 Sep 202635. The method of claim 33 or 34, wherein the contacting occurs in vivo.

36. The method of claim 33 or 34, wherein the contacting occurs in vitro.

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