PI3k degrader compounds and uses thereof

Abstract

The present disclosure provides novel compounds with PI3K degradation activities, pharmaceutical compositions containing such compounds, and their use in prevention and treatment of diseases and conditions.

Description

PI3K DEGRADER COMPOUNDS AND USES THEREOF 1. BACKGROUND

[0001] Phosphoinositide 3-kinase (PI3K) is a broad family of enzymes that phosphorylate phosphatidylinositol, participating in cell growth, proliferation, metabolism, migration, and inflammation in different cell types (John G. Foster et al., Pharmacological Reviews, 2012, 64 (4) 1027-1054). Upregulation of the PI3K / Akt signaling pathway is a common feature in most cancers and genetic deviations in the pathway have been detected in many human cancers and act primarily to stimulate cell proliferation, migration and survival (Osaki M et al., Apoptosis, 2004, 9(6):667-76). Activation of the pathway occurs following activating point mutations or amplifications of the PIK3CA gene encoding the p110α (alpha) PI3K isoforms (Hennessy et al., Nat. Rev. Drug Discov.2005, 4:988-1004). Moreover, genetic deletion or loss of function mutations within the tumor suppressor PTEN, a phosphatase with opposing function to PI3K, also increases PI3K pathway signaling (Zhang and Yu, Clin. Cancer Res., 2010, 16:4325-30). These aberrations lead to increased downstream signaling through kinases such as Akt and mTOR and increased activity of the PI3K pathway has been proposed as a hallmark of resistance to cancer treatment (Razis et al., Breast Cancer Res. Treat., 2011, 128:447-56). [00n2] PI3Ks are heterodimers composed of regulatory (p85) and catalytic (p110) subunits. Hyperactivity of these enzymes can both induce and support tumors. There are three classes of PI3K members that have been identified, of which class I has been extensively studied. Class I PI3Ks are further divided into four isoforms: PI3Kα (alpha), β (beta), δ (delta), and γ (gamma), each consisting of a distinct 110 kDa catalytic subunit and a regulatory subunit. Catalytic subunits p110 alpha, p110 beta, and p110 delta interact with regulatory subunit p85 whereas p110 gamma interacts with regulatory subunit p101. The patterns of expression of each of these PI3Ks in human cells and tissues are distinct. In each of the PI3K alpha, beta, and delta subtypes, the p85 subunit acts to localize PI3 kinase to the plasma membrane by the interaction of its SH2 domain with phosphorylated tyrosine residues in target proteins (Rameh et al., Cell, 1995, 83:821-30).

[0003] PIK3CA, which encodes the p110α catalytic subunit of PI 3-kinase alpha (PI3Kα), is one of the most frequently genetically activated kinases in solid tumors. Activating mutations in PIK3CA are frequent across human cancers, particularly breast cancer. PI3Kα is most commonly associated with solid tumors via gene amplification or mutations of the PIK3CA gene. Aberrant PI3Kα signaling is observed in 29 % of breast cancers and approximately 40% of HR+ / HER2-breast cancers (Saal et al., Cancer Res., 2005, 65, 2554-2559; Stemke-Hale et al. Cancer Res., 2008, 68, 6084-6091). In particular, PI3Kα inhibitors may trigger receptor-tyrosine kinase (RTK)-dependent degradation of the mutant p110α proteinin breast cancer cells that are positive for the human epidermal growth factor receptor 2 (HER2) RTK, limiting feedback-mediated drug resistance and potentially widening the therapeutic index of PI3Kα inhibition.

[0004] Pan-class I PI3K inhibitors, such as buparlisib or pictilisib in combination with fulvestrant have shown moderate improvement in medial progression free survival but were also found to have significant side effects that may limit their use (Vuylsteke et al., Ann. Oncol.2016, 27, 2059−2066; Criscitiello et al., Breast Cancer: Targets Ther.2018, 10, 23−29). Moreover, significant side effects, such as gastrointestinal toxicities, were observed for selective PI3Kδ inhibitors (e.g., Zydelig, which is also known as idelalisib). In March 2016, the US Food and Drug Administration issued an alert that “six clinical trials exploring idelalisib (Zydelig®) in combination with other therapies have been halted due to reports of an increased rate of adverse events, including death” (Banerjee et al. JAMA Intern Med., 2023, 1;183(5):435-441).

[0005] Ubiquitin-Proteasome Pathway (UPP) is a critical pathway that regulates key regulatory proteins and degrades misfolded or abnormal proteins. UPP is central to multiple cellular processes, and if defective or imbalanced, leads to pathogenesis of a variety of diseases. The covalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases.

[0006] There are hundreds of known E3 ligases that 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), Berndsen et al. (Nat. Struct. Mol. Biol., 2014, 21, 301-307), Deshaies et al. (Ann. Rev. Biochem., 2009, 78, 399-437), and Wang et al. (Nat. Rev. Cancer., 2014, 14, 233-347)). Additionally, one of several hundred E3 ubiquitin-ligase enzyme complex components, such as cereblon (CRBN) and von Hippel Lindau (VHL) (Bricelj et al, Front Chem, 2021, 9:707317), facilitate the transfer of ubiquitin to a lysine on the substrate protein. The CRBN and VHL proteins function as critical components in Cullin RING E3 ubiquitin-ligase complexes (Cai and Wang, Cell Div, 2016, 11). Both CRBN and VHL are widely expressed across tissue types and are evolutionarily conserved among vertebrates. CRBN coordinates the ubiquitination and degradation of ion channels, the MEIS2 developmental transcription factor, the AMPK metabolic-regulating kinase, and glutamine synthase. CRBN can also be induced to degrade transcription factors IKZFl and IKZF3 along with casein kinase 1Al by immunomodulatory compounds (Kronke et al. Science, 2014, 343:301-5; Petzold et al., Nature, 2016, 532:127-30). VHL normally ubiquitinates hypoxia-inducible factor lα (HIFl A), the primary transcription factor responsible for promoting angiogenesis (Kaelin, Nat Rev Cancer, 2008, 8:865-73).

[0007] Targeted protein degradation (TPD) is a therapeutic modality to modulate proteins that have proved challenging to target with conventional small molecules. Some of these proteins have been intractable because, for example, their active sites are broad, have shallow pockets that are difficult to bridge with small molecules, have ‘smooth’ surfaces that offer few sites for a small molecule to bind, or may not even possess an active site to which small molecules could bind. Many of these difficult to target proteins play key roles in diseases, such as cancer. Protein-degrading molecules (hereinafter degraders) have the potential to enable the modulation of these difficult to target proteins via TPD. Degraders are heterobifunctional small molecules comprising two ligands (e.g., chemical moieties) joined by a linker. The roles of the two ligands are different. One ligand recruits and binds a protein of interest (i.e., target protein) while the other recruits and binds an E3 ubiquitin ligase. This simultaneous binding of the protein of interest and a ligase by the degrader induces ubiquitination of the protein of interest and its subsequent degradation by the ubiquitin–proteasome system (UPS), after which the degrader is available to target another copy of the protein of interest. This catalytic-type mechanism of action and event-driven pharmacology differentiate degraders from classical inhibitors, which have a one-to-one relationship with the protein of interest and whose pharmacology is driven by stoichiometry and, usually, by interactions with an active site (see Bekes, et al, Nature Reviews Drug Discovery 2022, 21, 181-200).

[0008] There remains an unmet medical need for compounds that can degrade and / or inhibit PI3K, such as PI3K isoforms (e.g., PI3Kα that is selective for mutant PI3Kα expressing tumors relative to non-mutant PI3Kα expressing cells). Compounds that can selectively degrade and / or inhibit the PI3Kα isoform relative to the PI3Kβ, PI3Kδ, and PI3Kγ isoforms may be expected to provide an enhanced therapeutic window. 2 SUMMARY

[0009] The present disclosure is directed to novel PI3K degraders using Protein-Protein Interaction Targeted Chimeras (PPI-TACs) technology. In some embodiments, the compounds disclosed herein show selective activity in modulating mutant forms of PI3Kα isoform. PPI-TACs possess many advantages over conventional biochemical enzyme inhibitors and other types of degraders. Unlike other degraders that rely only on proximity by projecting one small molecule simultaneously to a targeted protein and E3 ligase, the PPI-TACs disclosed herein not only possess the ability to facilitate target protein and E3 ligase ternary complex formation but are also believed to direct protein-protein interactions between the targeted protein and E3 ligase, thus leading to enhanced degradation potency and selectivity. In some embodiments, the PPI-TACs work sub-stoichiometrically by inducing multiple rounds of degradation of target proteins. This is attributed to the PPI-TAC molecule being released from the proteosome-degraded protein to bind another target protein and E3 ubiquitin ligase, which in turn results in a greater potencycompared to each isolated moiety binding to its respective target. In some embodiments, PPI-TACs disclosed herein can deplete target proteins that are not responsive to biochemical inhibition by binding accessible pockets that do not affect the biochemical activity of the target but still permit their degradation. It is believed that the PPI-TACs disclosed herein may achieve prolonged pharmacological effects compared to inhibitors.

[0010] In some embodiments, the present disclosure provides PI3K-degrader compounds, such as PI3Kα degraders, compositions comprising the disclosed compounds, and uses thereof. In some embodiments, the compounds disclosed herein comprise two ligands (e.g., two chemical scaffolds) joined by linker moieties, wherein the linkers (e.g., L in Formula (I)) facilitate the orientation and / or position of the two ligands to bind to their respective targets. In some embodiments, one ligand recruits and binds a protein of interest (e.g., PI3Kα) while the other ligand recruits and binds an E3 ubiquitin ligase. In some embodiments, one ligand binds selectively to a PI3K isoform, such as PI3Kα isoform. In some embodiments, the disclosed compounds may act as adapter molecules between the E3 ligase and the PI3K protein thus redirecting the activity of the cell’s natural protein degradation machinery, i.e. the ubiquitin- proteasome system (UPS).

[0011] In some embodiments, provided herein is a compound, wherein the compound is represented by Formula (I) or is a pharmaceutically acceptable salt thereof:wherein: Ring A is a 5-10 membered heteroaryl, 5-10 membered heterocyclic group, or 5-10 membered heteroaryl- fused-heterocyclic group, wherein the 5-10 membered heteroaryl, 5-10 membered heterocyclic group, or 5-10 membered heteroaryl-fused-heterocyclic group is independently substituted with 0, 1, 2, 3, or 4 Ra; each Rais independently selected from amino, halogen, hydroxyl, C1-C5alkyl, C1-C5alkoxy, C1-C5haloalkyl, C1-C5alkylamino, di-(C1-C5alkyl)amino, C1-C5hydroxyalkyl, C1-C5aminoalkyl, C1- C5alkyl-O-C1-C5alkyl, and an oxo group; Ring B is a 5-15 membered heteroaryl, 5-15 membered heterocyclic group, or 5-15 membered heteroaryl- fused-heterocyclic group, wherein the 5-15 membered heteroaryl, 5-15 membered heterocyclic group, or 5-15 membered heteroaryl-fused-heterocyclic group is independently substituted with 0,1, 2, 3, 4, or 5 Rb; each Rbis independently selected from amino, halogen, hydroxyl, C1-C5alkyl, C1-C5alkoxy, C1-C5haloalkyl, C1-C5alkylamino, di-(C1-C5alkyl)amino, C1-C5hydroxyalkyl, C1-C5aminoalkyl, C1- C5alkyl-O-C1-C5alkyl, and an oxo group; Lais linking group that covalently bonds Ring A and Ring B together; for example, Lais a bond, -NRL- ( -RLis hydrogen or an optionally substituted group selected from C1-C6alkyl, C3-C6cycloalkyl, and 3- to 6- membered heterocyclyl; G is a bond or a divalent group with a backbone of 1-10 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from oxygen, heterocyclene, heteroarylene, arylene, -NH-, -N(Rc)-, -C(=O)-, -C(=O)-NH-, -CH(Rc)-, -C(Rc)2-, - C(=O)-N(Rc)-, -NH-C(=O)-, -N(Rc)-C(=O)-, -NH-C(=O)-O-, -N(Rc)-C(=O)-O-, -NH-C(=O)-NH- , -N(Rc)-C(=O)-NH-, and -C(=O)-N(Rc)-, and wherein each of the heterocyclene, arylene and heteroarylene is independently substituted with 0, 1, 2, or 3 Rd; each Rcis independently selected from C1-C5alkyl, C(=O)-NH(C1-C5alkyl), -C(=O)-N(C1-C5alkyl)2, and -C(=O)-NH2; each Rdis independently selected from halogen, hydroxyl, C1-C5alkyl, C1-C5alkoxy, C1-C5haloalkyl, - C(=O)-NH2, and an oxo group; L is a linker with a backbone of 1-20 carbon atoms in length, wherein one or more carbon atoms are optionally substituted with halogen, hydroxyl, cyano, CFH2, CF2H, CF3, alkoxy, C1-C5alkyl, or - C(=O)-NH2, wherein one or more carbon atoms of the backbone are optionally replaced by a divalent group independently selected from oxygen, alkylamino, carbonyl, 3-7 membered cycloalkylene, 4-7 membered monocyclic heterocyclic group, 5-10 membered bridged heterocyclic group, 5-12 membered spiro heterocyclic group, 5-10 membered heteroarylene, and 7-12 membered heteroaryl-fused-heterocyclylene, and wherein each of the 3-7 membered cycloalkylene, 4-7 membered monocyclic heterocyclic group, 5-10 membered bridgedheterocyclic group, 5-12 membered spiro heterocyclic group, 5-10 membered heteroarylene, and 7-12 membered heteroaryl-fused-heterocyclylene is independently substituted with 0, 1, or 2 Re; each Reis independently selected from alkylamino, halogen, hydroxyl, C1-C5alkoxy, C1-C5alkyl, C1-C4alkenyl, C3-C5cycloalkyl, C1-C5haloalkyl, and an oxo group; X is N or CH; Q is a bond or a divalent group of 1-5 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from 5-6 membered arylene, 5-10 membered heteroarylene (e.g., a 9 membered heteroarylene, such as a fused 5-6 membered heteroarylene ring system; a 6 membered aryl or heteroaryl fused to a 5 membered heterocyclyl; and so forth), - NH-, -C(=O)-, -C(=O)-NH-, and -C(=O)N(Rc)-, and wherein each of the 5-6 membered arylene and 5-10 membered heteroarylene is independently substituted with 0, 1, 2, or 3 Rf; and each Rfis independently selected from halogen, hydroxyl, C1-C5alkyl, C1-C3alkoxy, C1-C3haloalkyl, and an oxo group.

[0012] In some embodiments, Ring A is selected from:wherein n is 0, 1, 2, or 3.

[0013] In some embodiments, Ring B is selected from:wherein: X1is CH or N; X2is selected from N, NH, O, and S; X3is selected from N, NH, O, and S; and m is 0, 1, or 2.

[0014] In some embodiments, the compound of Formula (I) is represented by a compound of Formula (II) or is a pharmaceutically acceptable salt thereof:wherein: Ring A is a 5-6 membered heteroaryl or 5-6 membered heterocyclic group; each Rais independently selected from amino, halogen, hydroxyl, C1-C5alkyl, C1-C5alkoxy, C1-C5haloalkyl, C1-C5alkylamino, di-(C1-C5alkyl)amino, C1-C5hydroxyalkyl, C1-C5aminoalkyl, C1- C5alkyl-O-C1-C5alkyl, and an oxo group; each Rbis independently selected from amino, halogen, hydroxyl, C1-C5alkyl, C1-C5alkoxy, and C1-C5haloalkyl; X1is CH or N; n is 0, 1, 2, or 3; and m is 0, 1, or 2.

[0015] In some embodiments, the compound of Formula (I) is represented by a compound of Formula (III) or is a pharmaceutically acceptable salt thereof:wherein:Ring A is a 5-6 membered heteroaryl or 5-6 membered heterocyclic group; each Rais independently selected from amino, halogen, hydroxyl, C1-C5alkyl, C1-C5alkoxy, C1-C5haloalkyl, C1-C5alkylamino, C1-C5hydroxyalkyl, and C1-C5aminoalkyl; each of X2and X3is independently selected from N, NH, O, and S; each Rbis independently selected from amino, halogen, hydroxyl, C1-C5alkyl, C1-C5alkoxy, C1-C5haloalkyl, and C1-C5alkylamino; n is 0, 1, 2, or 3; and m is 0 or 1.

[0016] In some embodiments, the compound of Formula (I) is represented by a compound of Formula (IV) or is a pharmaceutically acceptable salt thereof:wherein: Ring A is a 5-6 membered heteroaryl or 5-6 membered heterocyclic group; each Rais independently selected from amino, halogen, hydroxyl, C1-C5alkyl, C1-C5alkoxy, C1-C5haloalkyl, C1-C5alkylamino, di-(C1-C5alkyl)amino, C1-C5hydroxyalkyl, and C1-C5aminoalkyl; each Rbis independently selected from halogen, hydroxyl, C1-C5alkyl, and C1-C5alkoxy; n is 0, 1, or 2; and m is 0, 1, or 2.

[0017] In some embodiments, the present disclosure provides compositions (e.g., pharmaceutical compositions) comprising one or more compounds of disclosed herein (e.g., Formula (I)) and one or more pharmaceutically acceptable carriers, pharmaceutically acceptable vehicles, pharmaceutically acceptable excipients, or combinations thereof.

[0018] Also disclosed herein are methods of treatment. The disclosed methods may comprise treating a subject (e.g., a human subject) in need thereof, wherein the subject has a disease, such as a PI3K- mediated disease or disorder. The methods may comprise administering to the subject an effective amount of a compound disclosed herein. In some embodiments, the PI3K-mediated disease or disorder is cancer. In some embodiments, the cancer is selected from breast cancer, lung cancer, pancreatic cancer, small bowel cancer, colorectal cancer, gall bladder cancer, gastric cancer, thyroid cancer, liver cancer,lymphoma, sarcoma, bile duct cancer, ovarian cancer, endometrial cancer, cervical cancer, bladder cancer, prostate cancer, squamous cell carcinoma, head and neck cancer, esophageal cancer, and blood cancer. 3. DETAILED DESCRIPTION 3.1. Definitions

[0019] When describing the embodiments of the present disclosure, which may include compounds and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing such compounds and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated

[0020] It will be understood by those within the art that, in general, terms used herein, and especially in the appended claims (e.g., bodies of the appended claims) are generally intended as “open” terms (e.g., the term “including” should be interpreted as “including but not limited to,” the term “having” should be interpreted as “having at least,” the term “includes” should be interpreted as “includes but is not limited to,” etc.). It will be further understood by those within the art that if a specific number of an introduced claim recitation is intended, such an intent will be explicitly recited in the claim, and in the absence of such recitation no such intent is present. For example, as an aid to understanding, the following appended claims may contain usage of the introductory phrases “at least one” and “one or more” to introduce claim recitations. However, the use of such phrases should not be construed to imply that the introduction of a claim recitation by the indefinite articles “a” or “an” limits any particular claim containing such introduced claim recitation to embodiments containing only one such recitation, even when the same claim includes the introductory phrases “one or more” or “at least one” and indefinite articles such as “a” or “an” (e.g., “a” and / or “an” should be interpreted to mean “at least one” or “one or more”); the same holds true for the use of definite articles used to introduce claim recitations. In addition, even if a specific number of an introduced claim recitation is explicitly recited, those skilled in the art will recognize that such recitation should be interpreted to mean at least the recited number (e.g., the bare recitation of “two recitations,” without other modifiers, means at least two recitations, or two or more recitations). Furthermore, in those instances where a convention analogous to “at least one of A, B, and C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., “a system having at least one of A, B, and C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). In those instances where a convention analogous to “at least one of A, B, or C, etc.” is used, in general such a construction is intended in the sense one having skill in the artwould understand the convention (e.g., “a system having at least one of A, B, or C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). It will be further understood by those within the art that virtually any disjunctive word and / or phrase presenting two or more alternative terms, whether in the description, claims, or drawings, should be understood to contemplate the possibilities of including one of the terms, either of the terms, or both terms. For example, the phrase “A or B” will be understood to include the possibilities of “A” or “B” or “A and B.”

[0021] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0022] As will be understood by one skilled in the art, for any and all purposes, such as in terms of providing a written description, all ranges disclosed herein also encompass any and all possible sub- ranges and combinations of sub-ranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like include the number recited and refer to ranges which can be subsequently broken down into sub-ranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. Thus, for example, a group having 1-3 articles refers to groups having 1, 2, or 3 articles. Similarly, a group having 1-5 articles refers to groups having 1, 2, 3, 4, or 5 articles, and so forth.

[0023] Compounds of this disclosure include those described generally above, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5thEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0024] The abbreviations used herein have their conventional meaning without 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.

[0025] The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocyclyl”, “cycloaliphatic”, or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocyclyl” or “cycloalkyl”) refers to a monocyclic C3-C7hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0026] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substituted nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H- pyrrolyl), NH (as in pyrrolidinyl) or NR+(as in N-substituted pyrrolidinyl)).

[0027] The term “unsaturated”, as used herein, means that a moiety has one or more units of unsaturation.

[0028] The term “alkylene” refers to a divalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., -(CH2)n-, wherein n is a positive integer, for example, from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0029] As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the restof the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclics include:.

[0030] A dash (“-”) that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CN is attached through the carbon atom.

[0031] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, “C1-C6alkyl” is intended to encompass C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6alkyl.

[0032] The term “acyl” as used herein refers to R-C(O)- groups such as, but not limited to, (alkyl)-C(O)-, (alkenyl)-C(O)-, (alkynyl)-C(O)-, (aryl)-C(O)-, (cycloalkyl)-C(O)-, (heteroaryl)-C(O)-, and (heterocyclyl)-C(O)-, wherein the group is attached to the parent molecular structure through the carbonyl functionality. In some embodiments, it is a C1-10 acyl radical which refers to the total number of chain or ring atoms of the, for example, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, or heteroaryl, portion plus the carbonyl carbon of acyl. For example, a C4-acyl has three other ring or chain atoms plus carbonyl.

[0033] The term “alkenyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond, such as a straight or branched group of 28 carbon atoms, referred to herein as (C2-C8)alkenyl. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl,butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2 propyl 2-butenyl, and 4-(2-methyl-3-butene)-pentenyl.

[0034] The term “alkyl” as used herein refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1 to 8 carbon atoms, referred to herein as C1-8alkyl. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2- methyl-1-butyl, 3 methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3 methyl- 1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4 methyl-2-pentyl, 2,2-dimethyl-1- butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl. In some embodiments, “alkyl” is a straight-chain hydrocarbon. In some embodiments, “alkyl” is a branched hydrocarbon.

[0035] The term “alkoxy” means a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms containing a terminal “O” in the chain, e.g., -O(alkyl). Examples of alkoxy groups include, without limitation, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.

[0036] The term “alkylene” as used herein refers to a divalent alkyl radical. Representative examples of C1-10 alkylene include, but are not limited to, methylene, ethylene, n-propylene, iso-propylene, n- butylene, sec-butylene, iso-butylene, tert-butylene, n-pentylene, isopentylene, neopentylene, n-hexylene, 3-methylhexylene, 2,2-dimethylpentylene, 2,3-dimethylpentylene, n-heptylene, n-octylene, n-nonylene and n-decylene.

[0037] The term “alkynyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond, such as a straight or branched group of 2-8 carbon atoms, referred to herein as (C2-C8)alkynyl. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl-1-butynyl, 4-propyl-2-pentynyl, and 4 butyl 2 hexynyl.

[0038] The term “aryl” herein refers to an all carbon monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups having a completely conjugated pi-electron system. An aryl group may be selected from: monocyclic carbocyclic aromatic rings, for example, phenyl; bicyclic ring systems such as 7-12 membered, e.g., 9-10 membered, bicyclic ring systems wherein at least one ring is carbocyclic and aromatic, selected, for example, from naphthalene, indane, and 1,2,3,4- tetrahydroquinoline; and tricyclic ring systems such as 10-15 membered tricyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, fluorene.

[0039] For example, the aryl group may be a 6-membered carbocyclic aromatic ring fused to a 5- to 7- membered cycloalkyl or heterocyclic ring optionally comprising at least one heteroatom selected from N,O, and S, provided that the point of attachment is at the carbocyclic aromatic ring when the carbocyclic aromatic ring is fused with a heterocyclic ring, and the point of attachment can be at the carbocyclic aromatic ring or at the cycloalkyl group when the carbocyclic aromatic ring is fused with a cycloalkyl group. Divalent radicals formed from substituted benzene derivatives and having the free valences at ring atoms are named as substituted phenylene radicals. Divalent radicals derived from univalent polycyclic hydrocarbon radicals whose names end in “-yl” by removal of one hydrogen atom from the carbon atom with the free valence are named by adding “-idene” to the name of the corresponding univalent radical, e.g., a naphthyl group with two points of attachment is termed naphthylidene.

[0040] The term “heteroaryl” refers to a group having 5 to 10 ring atoms, 5, 6, or 9 ring atoms; having 6, 10, or 14π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The term “heteroaryl”, as used herein, also includes groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring (or in the case of a divalent fused heteroarylene ring system, at least one radical or point of attachment is on a heteroaromatic ring). Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbozolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydrquinolinyl, tetrahydroisoquinolinyl, pyrazolo[3,4- b]pyridine, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. A heteroaryl group may be mono- or bicyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”, any of which terms include rings that are optionally substituted.

[0041] The term “cyano” as used herein refers to CN.

[0042] The term “cycloalkyl” as used herein refers to a saturated or unsaturated cyclic, bicyclic, or bridged bicyclic hydrocarbon group of 3-16 carbons, or 3-8 carbons, referred to herein as “(C3- C8)cycloalkyl,” derived from a cycloalkane. Exemplary cycloalkyl groups include, but are not limited to, cyclohexanes, cyclohexenes, cyclopentanes, and cyclopentenes. Cycloalkyl groups may be substituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone. Cycloalkyl groups can be fused to other cycloalkyl (saturated or partially unsaturated), aryl, or heterocyclyl groups, to form abicycle, tetracycle, etc. The term “cycloalkyl” also includes bridged and spiro-fused cyclic structures which may or may not contain heteroatoms.

[0043] The terms “halo” or “halogen” as used herein refer to -F, -Cl, -Br, and / or -I.

[0044] “Haloalkyl” means an alkyl group substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc.

[0045] A “heterocyclyl” or “heterocyclic” group is a ring structure having from 3 to 12 atoms, for example 4 to 8 atoms, wherein one or more atoms are selected from the group consisting of N, O, and S wherein the ring N atom may be oxidized to N-O, and the ring S atom may be oxidized to SO or SO2, the remainder of the ring atoms being carbon. The heterocyclyl may be a monocyclic, a bicyclic, a spirocyclic, or a bridged ring system. The heterocyclic group is independently optionally substituted on a ring nitrogen atom with alkyl, aralkyl, alkylcarbonyl, or on sulfur with lower alkyl. Examples of heterocyclic groups include, without limitation, epoxy, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, imidazolidinyl, imidazopyridinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4-piperidinonyl, quinuclidinyl, thiomorpholinyl, morpholinyl, azepanyl, oxazepanyl, azabicyclohexanyls, azabicycloheptanyl, azabicyclooctanyls, azabicyclononanyls (e.g., octahydroindolizinyl), azaspiroheptanyls, dihydro-1H,3H,5H-oxazolo[3,4-c]oxazolyl, tetrahydro- 1'H,3'H- spiro[cyclopropane-1,2'-pyrrolizine], hexahydro-1H-pyrrolizinyl, hexahydro-1H-pyrrolo[2,1- c][1,4]oxazinyl, octahydroindolizinyl, oxaazaspirononanyls, oxaazaspirooctanyls, diazaspirononanyls, oxaazabiocycloheptanyls, hexahydropyrrolizinyl 4(1H)-oxide, tetrahydro- 2H-thiopyranyl 1-oxide and tetrahydro-2H-thiopyranyl 1,1-dioxide. Specifically excluded from the scope of this term are compounds having adjacent annular O and / or S atoms.

[0046] A “polycycle” refers to a saturated or unsaturated ring system having two or more rings (for example, heterocyclyl rings, heteroaryl rings, cycloalkyl, or aryl rings, and combinations thereof), having between 5 and 20 ring-member atoms, in which one or more carbon atoms are common to two adjacent rings. The rings in a polycyclic ring system may be fused (e.g., bicyclic or tricyclic), spirocyclic, or a combination thereof. Polycyclic ring systems may comprise an aryl fused to a heteroaryl, an aryl fused to a saturated heterocyclyl, or any combination of saturated, partially unsaturated, aromatic or heteroaromatic ring system.

[0047] A “spirocycle”, “spirocyclyl”, or “spirocyclylene” refers to a chemical entity having two heterocyclyl or two cycloalkyl moieties as defined herein, or to a combination of one or moreheterocyclyl and one or more cycloalkyl moiety, having one ring atom in common, i.e., the two rings are connected via one common ring atom. Some exemplary spirocyclic ring systems, yet non-limiting examples of spirocyclic ring systems, include, , ,

[0048] As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation but is not intended to include aryl or heteroaryl moieties, as herein defined.

[0049] As used herein and unless otherwise specified, the suffix “-ene” is used to describe a divalent group. Thus, any of the terms above can be modified with the suffix “-ene” to describe a divalent version of that moiety. For example, a divalent carbocycle is “carbocyclylene”, a divalent aryl ring is “arylene”, a divalent benzene ring is “phenylene”, a divalent heterocycle is “heterocyclylene”, a divalent heteroaryl ring is “heteroarylene”, a divalent alkyl chain is “alkylene”, a divalent alkenyl chain is “alkenylene”, a divalent alkynyl chain is “alkynylene”, and so forth.

[0050] As described herein, compounds of the disclosure may, when specified, contain “optionally substituted” moieties. In general, the term “substituted”, whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. “Substituted” applies to one or more hydrogens that are either explicit or implicit from the structure (e.g.,,). In addition, in a polycyclic ring system, substituents may, unless otherwise indicated, replace a hydrogen on any individual ring (e.g.,refers to at least“optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this disclosure are those that result in the formation of stable or chemically feasible compounds. The term “stable”, as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their purification, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0051] Those skilled in the art will appreciate that a bond designated as in a small molecule structure, as used herein, refers to a bond that, in some embodiments, is a single (e.g., saturated) bond, and in some embodiments, is a double (e.g., unsaturated) bond. For example the following structure:is intended to encompass both

[0052] The term “oxo”, as used herein, means an oxygen that is double bonded to a carbon atom thereby forming a carbonyl.

[0053] The terms “hydroxy” and “hydroxyl” as used herein refer to -OH.

[0054] Some of the compounds may exist with different points of attachment of hydrogen, referred to as “tautomers.” For example, compounds including carbonyl -CH2C(O)- groups (keto forms) may undergo tautomerism to form hydroxyl -CH=C(OH)- groups (enol forms). Both keto and enol forms, individually as well as mixtures thereof, are also intended to be included where applicable.

[0055] The compounds, tautomers, solvates, or pharmaceutically acceptable salts of the disclosure may contain an asymmetric center and may thus exist as enantiomers. For example, where the compounds possess two or more asymmetric centers, they may additionally exist as diastereoisomers. Enantiomers and diastereoisomers fall within the broader class of stereoisomers. All such possible stereoisomers as substantially pure resolved enantiomers, racemic mixtures thereof, as well as mixtures of diastereoisomers are intended to be included in this disclosure. All stereoisomers of the compounds, tautomers, solvates,and pharmaceutically acceptable salts thereof are intended to be included. Unless specifically mentioned otherwise, reference to one isomer applies to any of the possible isomers. Whenever the isomeric composition is unspecified, all possible isomers are included.

[0056] Diastereomeric mixtures can be separated into their individual diastereoisomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereoisomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers. Enantiomers can also be separated by use of a chiral HPLC column.

[0057] “Stereoisomer” or “optical isomer” means a stable isomer that has at least one chiral atom or restricted rotation giving rise to perpendicular dissymmetric planes (e.g., certain biphenyls, allenes, and spiro compounds) and can rotate plane-polarized light. Because asymmetric centers and other chemical structure exist in the compounds of the disclosure which may give rise to stereoisomerism, the disclosure contemplates stereoisomers and mixtures thereof. The compounds of the disclosure and their salts include asymmetric carbon atoms and may therefore exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers. Typically, such compounds will be prepared as a racemic mixture. If desired, however, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. As discussed in more detail below, individual stereoisomers of compounds are prepared by synthesis from optically active starting materials containing the desired chiral centers or by preparation of mixtures of enantiomeric products followed by separation or resolution, such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, use of chiral resolving agents, or direct separation of the enantiomers on chiral chromatographic columns. Starting compounds of particular stereochemistry are either commercially available or are made by the methods described below and resolved by techniques well-known in the art.

[0058] It is well-known in the art that the biological and pharmacological activity of a compound is sensitive to the stereochemistry of the compound. Thus, for example, enantiomers often exhibit strikingly different biological activity including differences in pharmacokinetic properties, including metabolism, protein binding, and the like, and pharmacological properties, including the type of activity displayed, the degree of activity, toxicity, and the like. Thus, one skilled in the art will appreciate that one enantiomer may be more active or may exhibit beneficial effects when enriched relative to the other enantiomer or when separated from the other enantiomer. Additionally, one skilled in the art would know how toseparate, enrich, or selectively prepare the enantiomers of the compounds of this disclosure and the knowledge of the prior art.

[0059] Thus, although the racemic form of drug may be used, it is often less effective than administering an equal amount of enantiomerically pure drug; indeed, in some cases, one enantiomer may be pharmacologically inactive and would merely serve as a simple diluent. For example, although ibuprofen had been previously administered as a racemate, it has been shown that only the S-isomer of ibuprofen is effective as an anti-inflammatory agent (in the case of ibuprofen, however, although the R-isomer is inactive, it is converted in vivo to the S-isomer, thus, the rapidity of action of the racemic form of the drug is less than that of the pure S-isomer). Furthermore, the pharmacological activities of enantiomers may have distinct biological activity. For example, S-penicillamine is a therapeutic agent for chronic arthritis, while R-penicillamine is toxic. Indeed, some purified enantiomers have advantages over the racemates, as it has been reported that purified individual isomers have faster transdermal penetration rates compared to the racemic mixture. See U.S. Pat. Nos.5,114,946 and 4,818,541.

[0060] In some embodiments, the compound is a racemic mixture of (S)- and (R)-isomers. In other embodiments, provided herein is a mixture of compounds wherein individual compounds of the mixture exist predominately in an (S)- or (R)-isomeric configuration. For example, the compound mixture has an (S)-enantiomeric excess of greater than 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, or more. In other embodiments, the compound mixture has an (S)-enantiomeric excess of greater than 55% to 99.5%, greater than 60% to 99.5%, greater than 65% to 99.5%, greater than 70% to 99.5%, greater than 75% to 99.5%, greater than 80% to 99.5%, greater than 85% to 99.5%, greater than 90% to 99.5%, greater than 95% to 99.5%, greater than 96% to 99.5%, greater than 97% to 99.5%, greater than 98% to greater than 99.5%, greater than 99% to 99.5%, or more. In other embodiments, the compound mixture has an (R)-enantiomeric purity of greater than 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5% or more. In some other embodiments, the compound mixture has an (R)-enantiomeric excess of greater than 55% to 99.5%, greater than 60% to 99.5%, greater than 65% to 99.5%, greater than 70% to 99.5%, greater than 75% to 99.5%, greater than 80% to 99.5%, greater than 85% to 99.5%, greater than 90% to 99.5%, greater than 95% to 99.5%, greater than 96% to 99.5%, greater than 97% to 99.5%, greater than 98% to greater than 99.5%, greater than 99% to 99.5% or more.

[0061] Individual stereoisomers of compounds of the present disclosure can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic / chiral centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by: (1) attachment of a mixture of enantiomers toa chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary; (2) salt formation employing an optically active resolving agent; or (3) direct separation of the mixture of optical enantiomers on chiral chromatographic columns. Stereoisomeric mixtures can also be resolved into their component stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Stereoisomers can also be obtained from stereomerically- pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

[0062] Thus, if one enantiomer is pharmacologically more active, less toxic, or has a preferred disposition in the body than the other enantiomer, it would be therapeutically more beneficial to administer that enantiomer preferentially.

[0063] The term “pharmaceutically acceptable carrier” as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.

[0064] Additionally, as used herein refers to pharmaceutical excipients, for example, pharmaceutically, physiologically, acceptable organic or inorganic carrier substances suitable for enteral or parenteral application that do not deleteriously react with the active agent. Suitable pharmaceutically acceptable carriers include water, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, and carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethylcellulose, and polyvinylpyrrolidone. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and / or aromatic substances and the like that do not deleteriously react with the compounds of the disclosure.

[0065] The term “pharmaceutically acceptable composition” as used herein refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.

[0066] The term “pharmaceutically acceptable salt(s)” refers to salts of acidic or basic groups that may be present in compounds used in the present compositions. Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition saltsof such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including but not limited to sulfate, citrate, matate, acetate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1,1’-methylene-bis-(2-hydroxy- 3-naphthoate)) salts. Compounds included in the present compositions that include an amino moiety may form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above. Compounds included in the present compositions, that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts.

[0067] Chemical names were generated using PerkinElmer ChemDraw® Professional, version 19.

[0068] Unless otherwise indicated, variable groups of Formula (I) are presented in the same orientation, e.g., left to right, as is Formula (I) and subgenera thereof. The compounds of the disclosure may contain one or more chiral centers and / or double bonds and, therefore, exist as stereoisomers, such as geometric isomers, enantiomers or diastereomers. The term “stereoisomers” when used herein consist of all geometric isomers, enantiomers or diastereomers. These compounds may be designated by the symbols “R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Stereoisomers include enantiomers and diastereomers. Mixtures of enantiomers or diastereomers may be designated “(±)” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. In some embodiments, an enantiomer or stereoisomer may be provided substantially free of the corresponding enantiomer.

[0069] As used herein, “cancer” refers to diseases, disorders, and conditions that involve abnormal cell growth with the potential to invade or spread to other parts of the body. Exemplary cancers include, but are not limited to, breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, and esophageal cancer.

[0070] As used herein, the term “subject” refers to an animal. Typically, the animal is a mammal. A subject also refers to for example, primates (e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the subject is a primate. In some embodiments, the subject is a human.

[0071] As used herein, the term “inhibit,” “inhibition,” or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0072] A “dosing regimen” (or “therapeutic regimen”), as that term is used herein, is a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by periods of time. In some embodiments, a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses. In some embodiments, a dosing regimen comprises a plurality of doses each of which are separated from one another by a time period of the same length; in some embodiments, a dosing regimen comprises a plurality of doses and at least two different time periods separating individual doses.

[0073] As used herein, the phrase “therapeutic agent” refers to any agent that has a therapeutic effect and / or elicits a desired biological and / or pharmacological effect, when administered to a subject.

[0074] As used herein, the term “therapeutically effective amount” refers to an amount of a therapeutic agent that confers a therapeutic effect on the treated subject, at a reasonable benefit / risk ratio applicable to any medical treatment. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect). In particular, the “therapeutically effective amount” refers to an amount of a therapeutic agent effective to treat, ameliorate, or prevent a desired disease or condition, or to exhibit a detectable therapeutic or preventive effect, such as by ameliorating symptoms associated with the disease, preventing or delaying the onset of the disease or condition, and / or also lessening the severity or frequency of symptoms of the disease or condition. A therapeutically effective amount is commonly administered in a dosing regimen that may comprise multiple doses. For any particular therapeutic agent, a therapeutically effective amount (and / or an appropriate unit dose within an effective dosing regimen) may vary, for example, depending on route of administration, on combination with other pharmaceutical agents. Also, the specific therapeutically effective amount (and / or unit dose) for any particular subject may depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific therapeutic agent employed; the specific composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and / or rate of excretion or metabolism of the specific therapeutic agent employed; the duration of the treatment; and like factors as is well known in the medical arts.

[0075] As used herein, the term “treat,” “treating,” or “treatment” of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment“treat,” “treating,” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient. In yet another embodiment, “treat,” “treating,” or “treatment” refers to modulating the disease or disorder, either physically (e.g., through stabilization of a discernible symptom), physiologically, (e.g., through stabilization of a physical parameter), or both. In yet another embodiment, “treat,” “treating,” or “treatment” refers to preventing or delaying the onset or development or progression of the disease or disorder.

[0076] As used herein, a subject is “in need of” a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.

[0077] Additionally, unless otherwise stated, structures described herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium (2H) or tritium (3H), or the replacement of a carbon by a13C- or14C-carbon atom are within the scope of this disclosure. Such compounds may be useful as, for example, analytical tools, probes in biological assays, or therapeutic agents. 3.2. Compounds

[0078] In some embodiments, provided herein is a compound, wherein the compound is represented by Formula (I) or is a pharmaceutically acceptable salt thereof:wherein: Ring A is a 5-10 membered heteroaryl, 5-10 membered heterocyclic group, or 5-10 membered heteroaryl- fused-heterocyclic group, wherein the 5-10 membered heteroaryl, 5-10 membered heterocyclic group, or 5-10 membered heteroaryl-fused-heterocyclic group is independently substituted with 0, 1, 2, 3, or 4 Ra; each Rais independently selected from amino, halogen, hydroxyl, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 haloalkyl, C1-C5alkylamino, di-(C1-C5alkyl)amino, C1-C5hydroxyalkyl, C1-C5aminoalkyl, C1- C5alkyl-O-C1-C5alkyl, and an oxo group; Ring B is a 5-15 membered heteroaryl, 5-15 membered heterocyclic group, or 5-15 membered heteroaryl- fused-heterocyclic group, wherein the 5-15 membered heteroaryl, 5-15 membered heterocyclicgroup, or 5-15 membered heteroaryl-fused-heterocyclic group is independently substituted with 0, 1, 2, 3, 4, or 5 Rb; each Rbis independently selected from amino, halogen, hydroxyl, C1-C5alkyl, C1-C5alkoxy, C1-C5haloalkyl, C1-C5alkylamino, di-(C1-C5alkyl)amino, C1-C5hydroxyalkyl, C1-C5aminoalkyl, C1- C5alkyl-O-C1-C5alkyl, and an oxo group;RLis hydrogen or an optionally substituted group selected from C1-C6alkyl, C3-C6cycloalkyl, and 3 to 6- membered heterocyclyl; G is a bond or a divalent group with a backbone of 1-10 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from oxygen, heterocyclene, heteroarylene, arylene, -NH-, -N(Rc)-, -C(=O)-, -C(=O)-NH-, -CH(Rc)-, -C(Rc)2-,-NH-C(=O)-NH-, -N(Rc)-C(=O)-NH-, and -C(=O)-N(Rc)-, and wherein each of the heterocyclene, arylene and heteroarylene is independently substituted with 0, 1, 2, or 3 Rd; each Rcis independently selected from C1-C5alkyl, , -C(=O)-NH(C1-C5alkyl), -C(=O)-N(C1-C5alkyl)2,each Rdis independently selected from halogen, hydroxyl, C1-C5alkyl, C1-C5alkoxy, C1-C5haloalkyl, - C(=O)-NH2, and an oxo group; L is a linker with a backbone of 1-20 carbon atoms in length, wherein one or more carbon atoms are optionally substituted with halogen, hydroxyl, cyano, CFH2, CF2H, CF3, alkoxy, C1-C5alkyl, or - C(=O)-NH2, wherein one or more carbon atoms of the backbone are optionally replaced by a divalent group independently selected from oxygen, alkylamino, carbonyl, 3-7 membered cycloalkylene, 4-7 membered monocyclic heterocyclic group, 5-10 membered bridged heterocyclic group, 5-12 membered spiro heterocyclic group, 5-10 membered heteroarylene, and 7-12 membered heteroaryl-fused-heterocyclylene, and wherein each of the 3-7 membered cycloalkylene, 4-7 membered monocyclic heterocyclic group, 5-10 membered bridgedheterocyclic group, 5-12 membered spiro heterocyclic group, 5-10 membered heteroarylene, and 7-12 membered heteroaryl-fused-heterocyclylene is independently substituted with 0, 1, or 2 Re; each Reis independently selected from alkylamino, halogen, hydroxyl, C1-C5alkoxy, C1-C5alkyl, C1-C4alkenyl, C3-C5cycloalkyl, C1-C5haloalkyl, and an oxo group; X is N or CH; Q is a bond or a divalent group of 1-5 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from 5-6 membered arylene, 5-10 membered heteroarylene (e.g., a 9 membered heteroarylene, such as a fused 5-6 membered heteroarylene ring system; a 6 membered aryl or heteroaryl fused to a 5 membered heterocyclyl; and so forth), - NH-, -C(=O)-, -C(=O)-NH-, and -C(=O)N(Rc)-, and wherein each of the 5-6 membered arylene and 5-10 membered heteroarylene is independently substituted with 0, 1, 2, or 3 Rf; and each Rfis independently selected from halogen, hydroxyl, C1-C5alkyl, C1-C5alkoxy, C1-C5haloalkyl, and an oxo group.

[0079] In some embodiments of Formula (I), X is CH.

[0080] In some embodiments of Formula (I), X is N.

[0081] In some embodiments, the compound of Formula (I) is represented by Formula (IX) or is a pharmaceutically acceptable salt thereof:Ring A is a 5-10 membered heteroaryl, 5-10 membered heterocyclic group, or 5-10 membered heteroaryl- fused-heterocyclic group, wherein the 5-10 membered heteroaryl, 5-10 membered heterocyclic group, or 5-10 membered heteroaryl-fused-heterocyclic group is independently substituted with 0, 1, 2, 3, or 4 Ra; each Rais independently selected from amino, halogen, hydroxyl, C1-C5alkyl, C1-C5alkoxy, C1-C5haloalkyl, C1-C5alkylamino, di-(C1-C5alkyl)amino, C1-C5hydroxyalkyl, C1-C5aminoalkyl, C1- C5alkyl-O-C1-C5alkyl, and an oxo group; Ring B is a 5-15 membered heteroaryl, 5-15 membered heterocyclic group, or 5-15 membered heteroaryl-fused-heterocyclic group, wherein the 5-15 membered heteroaryl, 5-15 membered heterocyclic group, or 5-15 membered heteroaryl-fused-heterocyclic group is independently substituted with 0, 1, 2, 3, 4, or 5 Rb; each Rbis independently selected from amino, halogen, hydroxyl, C1-C5alkyl, C1-C5alkoxy, C1-C5haloalkyl, C1-C5alkylamino, di-(C1-C5alkyl)amino, C1-C5hydroxyalkyl, C1-C5aminoalkyl, C1- C5alkyl-O-C1-C5alkyl, and an oxo group; Lais a bond, CH(-RLis hydrogen or an optionally substituted group selected from C1-C6alkyl, C3-C6cycloalkyl, and 3- to 6- membered heterocyclyl; G is a bond or a divalent group with a backbone of 1-10 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from oxygen, heterocyclene, heteroarylene, arylene, -NH-, -N(Rc)-, -C(=O)-, -C(=O)-NH-, -CH(Rc)-, -C(Rc)2-, - C(=O)-N(Rc)-, -NH-C(=O)-, -N(Rc)-C(=O)-, -NH-C(=O)-O-, -N(Rc)-C(=O)-O-, -NH-C(=O)-NH- , -N(Rc)-C(=O)-NH-, and -C(=O)-N(Rc)-, and wherein each of the heterocyclene, arylene and heteroarylene is independently substituted with 0, 1, 2, or 3 Rd; each Rcis independently selected from C1-C5 alkyl, , -C(=O)-NH(C1-C5 alkyl), -C(=O)-N(C1-C5 alkyl)2, and -C(=O)-NH2; each Rdis independently selected from halogen, hydroxyl, C1-C5alkyl, C1-C5alkoxy, C1-C5haloalkyl, - Coxo group; L is a linker with a backbone of 1-20 carbon atoms in length, wherein one or more carbon atoms are optionally substituted with halogen, hydroxyl, cyano, CFH2, CF2H, CF3, alkoxy, C1-C5alkyl, or - C(=O)-NH2, wherein one or more carbon atoms of the backbone are optionally replaced by a divalent group independently selected from oxygen, alkylamino, carbonyl, 3-7 membered cycloalkylene, 4-7 membered monocyclic heterocyclic group, 5-10 membered bridged heterocyclic group, 5-12 membered spiro heterocyclic group, 5-10 membered heteroarylene, and 7-12 membered heteroaryl-fused-heterocyclylene, and wherein each of the 3-7 membered cycloalkylene, 4-7 membered monocyclic heterocyclic group, 5-10 membered bridgedheterocyclic group, 5-12 membered spiro heterocyclic group, 5-10 membered heteroarylene, and 7-12 membered heteroaryl-fused-heterocyclylene is independently substituted with 0, 1, or 2 Re; each Reis independently selected from alkylamino, halogen, hydroxyl, C1-C5alkoxy, C1-C5alkyl, C1-C4alkenyl, C3-C5cycloalkyl, C1-C5haloalkyl, and an oxo group; Q is a bond or a divalent group of 1-5 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from 5-6 membered arylene, 5-10 membered heteroarylene, -NH-, -C(=O)-, -C(=O)-NH-, and -C(=O)N(Rc)-, and wherein each of the 5-6 membered arylene and 5-10 membered heteroarylene is independently substituted with 0, 1, 2, or 3 Rf; and each Rfis independently selected from halogen, hydroxyl, C1-C5alkyl, C1-C5alkoxy, C1-C5haloalkyl, and an oxo group.

[0082] In some embodiments, Ring A is a 5-10 membered heteroaryl, 5-10 membered heterocyclic group, or 5-10 membered heteroaryl-fused-heterocyclic group, wherein the 5-10 membered heteroaryl, 5- 10 membered heterocyclic group, or 5-10 membered heteroaryl-fused-heterocyclic group is independently substituted with 0, 1, or 2 Ra.

[0083] In some embodiments, Ring A is a 5-6 membered heteroaryl or 5-6 membered heterocyclic group, wherein the 5-6 membered heteroaryl or 5-6 membered heterocyclic group is independently substituted with 0, 1, or 2 Ra.

[0084] In some embodiments, each Rais independently selected from amino, halogen, hydroxyl, C1-C5 alkyl, C1-C5alkoxy, C1-C5haloalkyl, C1-C5alkylamino, C1-C5hydroxyalkyl, C1-C5aminoalkyl, C1-C5alkyl-O-C1-C5alkyl, and an oxo group.

[0085] In some embodiments, Ring A is selected from: ,, , , , , ,, , , , , and ;wherein n is 0, 1, 2, or 3.

[0086] In some embodiments, Ring B is a 5-15 membered heteroaryl, 5-15 membered heterocyclic group, or 5-15 membered heteroaryl-fused-heterocyclic group, wherein the 5-15 membered heteroaryl, 5- 15 membered heterocyclic group, or 5-15 membered heteroaryl-fused-heterocyclic group is independently substituted with 0, 1, 2, 3, 4, or 5 Rb.

[0087] In some embodiments, Ring B is a 5-15 membered heteroaryl, 5-15 membered heterocyclic group, or 5-15 membered heteroaryl-fused-heterocyclic group, wherein the 5-15 membered heteroaryl, 5- 15 membered heterocyclic group, or 5-15 membered heteroaryl-fused-heterocyclic group is independently substituted with 0, 1, 2, or 3 Rb.

[0088] In some embodiments, Ring B is a 10-14 membered heteroaryl, 10-14 membered heterocyclic group, or 10-14 membered heteroaryl-fused-heterocyclic group, wherein the 10-14 membered heteroaryl, 10-14 membered heterocyclic group, or 5-15 membered heteroaryl-fused-heterocyclic group is independently substituted with 0, 1, 2, or 3 Rb.

[0089] In some embodiments, Ring B is a 5-6 membered heteroaryl, 5-6 membered heterocyclic group, or 5-6 membered heteroaryl-fused-heterocyclic group, wherein the 5-6 membered heteroaryl, 5-6 membered heterocyclic group, or 5-6 membered heteroaryl-fused-heterocyclic group is independently substituted with 0, 1, 2, or 3 Rb.

[0090] In some embodiments, each Rbis independently selected from amino, halogen, hydroxyl, C1-C5alkyl, C1-C5alkoxy, C1-C5haloalkyl, C1-C5alkylamino, di-(C1-C5alkyl)amino, C1-C5hydroxyalkyl, C1-C5aminoalkyl, C1-C5 alkyl-O-C1-C5 alkyl, and an oxo group.

[0091] In some embodiments, Ring B is selected from:wherein: X1is CH or N; X2is selected from N, NH, O, and S; X3is selected from N, NH, O, and S; and m is 0, 1, or 2.

[0092] In some embodiments, Ring

[0093] In some embodiments, X1is CH. In some embodiments, X1is N. In some embodiments, X1is C(Rb).

[0094] In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 3.

[0095] In some embodiments, Ring.

[0096] In some embodiments, X2is selected from N, NH, N(Rb), O, and S.

[0097] In some embodiments, X2is N. In some embodiments, X2is NH. In some embodiments, X2is N(Rb). In some embodiments, X2is O. In some embodiments, X2is S.

[0098] In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 3.

[0099] In some embodiments, Ring.

[0100] In some embodiments, X3is selected from N, NH, O, and S.

[0101] In some embodiments, X3is N. In some embodiments, X3is NH. In some embodiments, X3is O. In some embodiments, X3is S.

[0102] In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 3.

[0103] In some embodiments, each Rbis independently selected from amino, halogen, hydroxyl, C1-C5alkyl, C1-C5alkoxy, C1-C5haloalkyl, C1-C5alkylamino, di-(C1-C5alkyl)amino, C1-C5hydroxyalkyl, C1-C5aminoalkyl, and C1-C5alkyl-O-C1-C5alkyl.

[0104] In some embodiments, each Rbis independently selected from halogen, hydroxyl, C1-C5alkyl, C1- C5alkoxy, C1-C5haloalkyl, C1-C5alkylamino, C1-C5hydroxyalkyl, C1-C5aminoalkyl, and C1-C5alkyl-O- C1-C5alkyl.

[0105] In some embodiments, Lais a linking group.

[0106] In some embodiments, Lais a bond or a divalent group with a backbone of 1-5 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by an NRL-C(=O)-, -C(=O)-NRL-, -

[0107] In some embodiments, RLis hydrogen or an optionally substituted group selected from C1-C6alkyl, C3-C6cycloalkyl, and 3- to 6-membered heterocyclyl.

[0108] In some embodiments, Lais a bond, -NH-C(=O)-, -C(=O)-NH-, -NH-C(=O)-O-, -O-C(=O)-NH-, -

[0109] In some embodiments, Lais a bond, -NH-C(=O)-, -C(=O)-NH-, -NH-C(=O)-O-, -O-C(=O)-NH-, or -NH-C(=O)-NH-.

[0110] In some embodiments, Lais a bond or -C(=O)-NH-.

[0111] In some embodiments, Lais a bond. In some embodiments, Lais -NH-C(=O)-. In some embodiments, Lais -C(=O)-NH-. In some embodiments, Lais -NH-C(=O)-O-. In some embodiments, Lais -O-C(=O)-NH-. In some embodiments, Lais -NH-C(=O)-NH-. In some embodiments, Lais -NH- CH(CF3)-. In some embodiments, Lais -(CF3)CH-NH-. In some embodiments, Lais -NH-S(O)2-. In some embodiments, Lais -S(O)2-NH-. In some embodiments, Lais. In some embodiments, Lais.

[0112] In some embodiments, the compound of Formula (I) or (IX) is represented by a compound of Formula (II) or is a pharmaceutically acceptable salt thereof:(II) wherein:Ring A is a 5-6 membered heteroaryl or 5-6 membered heterocyclic group; each Rais independently selected from amino, halogen, hydroxyl, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4alkylamino, di-(C1-C5alkyl)amino, C1-C4hydroxyalkyl, C1-C4aminoalkyl, C1- C5alkyl-O-C1-C5alkyl, and an oxo group; each Rbis independently selected from amino, halogen, hydroxyl, C1-C3alkyl, C1-C3alkoxy, and C1-C3haloalkyl; X1is CH or N; n is 0, 1, 2, or 3; and m is 0, 1, or 2.

[0113] In some embodiments, the compound of Formula (I) is represented by a compound of Formula (II’) or is a pharmaceutically acceptable salt thereof:Ring A is a 5-6 membered heteroaryl or 5-6 membered heterocyclic group; each Rais independently selected from amino, halogen, hydroxyl, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C5alkylamino, di-(C1-C5alkyl)amino, C1-C4hydroxyalkyl, C1-C4aminoalkyl, C1- C5alkyl-O-C1-C5alkyl, and an oxo group; each Rbis independently selected from amino, halogen, hydroxyl, C1-C3alkyl, C1-C3alkoxy, and C1-C3haloalkyl; X1is CH or N; n is 0, 1, 2, or 3; and m is 0, 1, or 2.

[0114] In some embodiments, the compound of Formula (II) is represented by a compound of Formula (IIA) or is a pharmaceutically acceptable salt thereof:(IIA).

[0115] In some embodiments, the compound of Formula (IIA) is represented by a compound of Formula (IIA’) or is a pharmaceutically acceptable salt thereof:wherein each Rais independently selected from hydroxyl, C1-C5alkyl, C1-C5alkoxy, C1-C5alkylamino, and C1-C5haloalkyl.

[0116] In some embodiments, the compound of Formula (II’) is represented by a compound of Formula (IIA”) or is a pharmaceutically acceptable salt thereof:

[0117] In some embodiments of Formulae (IIA’) or (II’), X1is CH;n is 0, 1, 2, or 3; and p is 0, 1, 2, or 3.

[0118] In some embodiments of Formulae (I) (IX) (II), (II'), (IIA), (IIA'), (IIA"), (IIB), (IIB'), (IIB"), (IIB"'), (III), (III'), (IIIA), (IIIA'), (IIIA"), (IIIA"'), (IV), (IV'), (IVA), or (IVA'), Q is .

[0119] In some embodiments of Formulae (I) (IX) (II), (II'), (IIA), (IIA'), (IIA"), (IIB), (IIB'), (IIB"),(IIB"'), (III), (III'), (IIIA), (IIIA'), (IIIA"), (IIIA"'), (IV), (IV'), (IVA), or (IVA'), Q is .

[0120] In some embodiments of Formulae (I) (IX) (II), (II'), (IIA), (IIA'), (IIA"), (IIB), (IIB'), (IIB"), (

[0121] In some embodiments, the compound of Formula (II) is represented by a compound of Formula (IIB) or is a pharmaceutically acceptable salt thereof:

[0122] In some embodiments, the compound of Formula (IIB) is represented by a compound of Formula (IIB’) or is a pharmaceutically acceptable salt thereof:wherein each Rais independently selected from C1-C5alkyl, C1-C5alkoxy, C1-C5haloalkyl, C1-C5hydroxyalkyl, and C1-C5aminoalkyl.

[0123] In some embodiments, the compound of Formula (II’) is represented by a compound of Formula (IIB”) or is a pharmaceutically acceptable salt thereof:

[0124] In some embodiments, the compound of Formula (IIB”) is represented by a compound of Formula (IIB”’) or is a pharmaceutically acceptable salt thereof: (IIB”’)wherein each Rais independently selected from C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C5hydroxyalkyl, and C1-C5aminoalkyl.

[0125] In some embodiments of Formulae (IIA”), (IIB), (IIB’), (IIB”), or (IIB”’), X1is N. In some embodiments of Formulae (IIA”), (IIB), (IIB’), (IIB”), or (IIB”’), X1is CH.

[0126] In some embodiments, the compound of Formula (I) is represented by a compound of Formula (III) or is a pharmaceutically acceptable salt thereof:wherein: Ring A is a 5-6 membered heteroaryl or 5-6 membered heterocyclic group; each Rais independently selected from amino, halogen, hydroxyl, C1-C5alkyl, C1-C5alkoxy, C1-C5haloalkyl, C1-C5alkylamino, C1-C5hydroxyalkyl, and C1-C5aminoalkyl; each of X2and X3is independently selected from N, NH, O, and S; each Rbis independently selected from amino, halogen, hydroxyl, C1-C5alkyl, C1-C5alkoxy, C1-C5haloalkyl, and C1-C5alkylamino; n is 0, 1, 2, or 3; and m is 0 or 1.

[0127] In some embodiments, the compound of Formula (I) is represented by a compound of Formula (III’) or is a pharmaceutically acceptable salt thereof:wherein: Ring A is a 5-6 membered heteroaryl or 5-6 membered heterocyclic group; each Rais independently selected from amino, halogen, hydroxyl, C1-C5alkyl, C1-C5alkoxy, C1-C5haloalkyl, C1-C5alkylamino, C1-C5hydroxyalkyl, and C1-C5aminoalkyl; each of X2and X3is independently selected from N, NH, O, and S; each Rbis independently selected from amino, halogen, hydroxyl, C1-C5alkyl, C1-C5alkoxy, C1-C5haloalkyl, and C1-C5alkylamino; n is 0, 1, 2, or 3; and m is 0 or 1.

[0128] In some embodiments, the compound of Formula (III) is represented by a compound of Formula (IIIA) or is a pharmaceutically acceptable salt thereof:

[0129] In some embodiments, the compound of Formula (IIIA) is represented by a compound of Formula (IIIA’) or is a pharmaceutically acceptable salt thereof:(IIIA’) wherein Rbis selected from amino, halogen, C1-C4 alkyl, C1-C4 alkoxy, and C1-C4 haloalkyl.

[0130] In some embodiments, the compound of Formula (III’) is represented by a compound of Formula (IIIA”) or is a pharmaceutically acceptable salt thereof:

[0131] In some embodiments, the compound of Formula (IIIA”) is represented by a compound of Formula (IIIA’”) or is a pharmaceutically acceptable salt thereof:(IIIA’”) wherein Rbis selected from amino, halogen, C1-C5alkyl, C1-C5alkoxy, and C1-C5haloalkyl.

[0132] In some embodiments, the compound of Formula (I) is represented by a compound of Formula (IV) or is a pharmaceutically acceptable salt thereof:wherein: Ring A is a 5-6 membered heteroaryl or 5-6 membered heterocyclic group; each Rais independently selected from amino, halogen, hydroxyl, C1-C5alkyl, C1-C5alkoxy, C1-C5haloalkyl, C1-C5alkylamino, di-(C1-C5alkyl)amino, C1-C5hydroxyalkyl, and C1-C5aminoalkyl; each Rbis independently selected from halogen, hydroxyl, C1-C4alkyl, and C1-C4alkoxy; n is 0, 1, or 2; and m is 0, 1, or 2.

[0133] In some embodiments, the compound of Formula (I) is represented by a compound of Formula (IV’) or is a pharmaceutically acceptable salt thereof:wherein: Ring A is a 5-6 membered heteroaryl or 5-6 membered heterocyclic group; each Rais independently selected from amino, halogen, hydroxyl, C1-C5alkyl, C1-C5alkoxy, C1-C5haloalkyl, C1-C5alkylamino, di-(C1-C5alkyl)amino, C1-C5hydroxyalkyl, and C1-C5aminoalkyl; each Rbis independently selected from halogen, hydroxyl, C1-C5alkyl, and C1-C5alkoxy; n is 0, 1, or 2; and m is 0, 1, or 2.

[0134] In some embodiments, the compound of Formula (IV) is represented by a compound of Formula (IVA) or is a pharmaceutically acceptable salt thereof: (IVA).

[0135] In some embodiments, the compound of Formula (IV’) is represented by a compound of Formula (IVA’) or is a pharmaceutically acceptable salt thereof:

[0136] In some embodiments, each Rais independently selected from -CH3, -CH2CF3, -CH(CH3)2, - CH2OH, -CH2-OCH3, -CH2F, -CHF2, -CF3, -C(CH3)2CF3, -OH, -OCH3, -NH2, and -CH2-NH2.

[0137] In some embodiments, each Rais independently selected from -CH(CH3)2, -CH2F, -CHF2, -Cand -NH2.

[0138] In some embodiments, Rais -CH3. In some embodiments, Rais -CH2CF3. In some embodiments, Rais -CH(CH3)2. In some embodiments, Rais -CH2OH. In some embodiments, Rais -CH2-OCH3. In some embodiments, Rais -CH2F. In some embodiments, Rais -CHF2. In some embodiments, Rais -CF3. In some embodiments, Rais -C(CH3)2CF3. In some embodiments, Rais -OH. In some embodiments, Rais - OCH3. In some embodiments, Rais -NH2. In some embodiments, Rais -CH2-NH2.

[0139] In some embodiments of Formulae (I), (IX), (II), (II’), (IIA), (IIA’), (IIA”), (IIB), (IIB”), (IIB”’), (III), (III’), (IIIA), (IIIA’), (IIIA”), (IIIA”’), (IV), (IV’), (IVA), or (IVA’), Ring A is selected from: ,, , , , , , ,, , , , , , , , ,, , , , , , , , , ,, , , and .

[0140] In some embodiments, Ring A is selected from: [ .[,

[0143] In some embodiments, Ring A is. In some embodiments, Ring A issome embodiments, Ring Asome embodiments, Ring Aome embodiments, Ring A is. , . In some embodiments,Ring A is. In some embodiments, Ring A is. In some embodiments, Ring A issome embodiments, Ring A issome embodiments, Ring A isInsome embodiments, Ring A isIn some embodiments, Ring A is . In someembodiments, Ring A is. In some embodiments, Ring A is. In some embodiments, Ring A is. , g . , g . In some embodiments, Ringsome embodiments, Ring A is. In someembodiments, Ring A is. In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is. In some embodiments, Ring A is. In some embodiments, Ring A is . In some embodiments, Ring A is. In some embodiments, Ring A is. In some embodiments, Ring A is. In some embodiments, Ringsome embodiments, Ring Asome embodiments, Ringsome embodiments, Ring Asome embodiments, Ringsome embodiments, Ringsome embodiments, Ring A is, some embodiments, Ring A is, , In some embodiments, Ring A isIn some embodiments, Ringsome embodiments, Ring Asome embodiments, R some embodiments, Ring Asome embodiments, Ring A isodiments, Ring A is. In some embodiments, Ring A is.

[0144] In some embodiments of Formulae (I) (IX) (II), (II'), (IIA), (IIA'), (IIA"), (IIB), (IIB'), (IIB"), (IIB"'), (III), (III'), (IIIA), (IIIA'), (IIIA"), (IIIA"'), (IV), (IV'), (IVA), or (IVA'), G is a divalent group witha backbone of 1-7 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from oxygen, heterocyclene, heteroarylene, arylene, -NH-, -C(Rc)-, and -N(Rc)-, and wherein each of the heterocyclene, arylene, and heteroarylene is independently substituted with 0, 1, 2, or 3 Rd.

[0145] In some embodiments, G is a divalent group with a backbone of 1-7 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from oxygen, heterocyclene, heteroarylene, arylene, -NH-, -C(Rc)-, and -N(Rc)-, and wherein each of the heterocyclene, arylene, and heteroarylene is independently substituted with 0, 1, 2, or 3 Rd.

[0146] In some embodiments, G is a divalent group with a backbone of 1-7 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from oxygen, heterocyclene, -NH-, -C(Rc)-, and -N(Rc)-, and wherein the heterocyclene is substituted with 0, 1, 2, or 3 Rd.

[0147] In some embodiments, G is a divalent group with a backbone of 1-7 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from oxygen, heterocyclene, -NH-, -C(Rc)-, and -N(Rc)-, and wherein the heterocyclene is substituted with 0, 1, or 2 Rd.

[0148] In some embodiments, each Rdis independently selected from halogen, hydroxyl, C1-C3alkyl, C1- C3alkoxy, C1-C3haloalkyl, and -C(=O)-NH2.

[0149] In some embodiments, Rdis halogen. In some embodiments, Rdis hydroxyl. In some embodiments, Rdis C1-C3alkyl. In some embodiments, Rdis C1-C3alkoxy. In some embodiments, Rdis C1-C3haloalkyl. In some embodiments, Rdis -C(=O)-NH2.

[0150] In some embodiments, G is selected from: ,, , , ,, , , ,[, , embodiments, G is. In some embodiments, G is. In someembodiments, G is. In some embodiments, G is. Insome embodiments,. In some embodiments, G. In some embodiments,. In some embodiments, G. In some embodiments,.

[0152] In some embodiments, G is selected from:, , ,, , , ,

[0153] In some embodiments, G is. In some embodiments, G is. In someembodiments, G is. In some embodiments, G is. In some embodiments, G is. In some embodiments, Gsome embodiments,. In some embodiments, G. In some embodiments,. In some embodiments, G is,

[0154] In some embodiments, G is selected from -O-(CH2)2-, -O-(CH2)3-, -O-(CH2)4-, -O-(CH2)5-, -O-(CH2)6-, -O-(CH2)3NH-, and -O-(CH2)3NH-CH2-.

[0155] In some embodiments, G is -O-(CH2)2-. In some embodiments, G is -O-(CH2)3-. In some embodiments, G is -O-(CH2)4-. In some embodiments, G is -O-(CH2)5-. In some embodiments, G is -O- (CH2)6-. In some embodiments, G is -O-(CH2)3NH-. In some embodiments, G is -O-(CH2)3NH-CH2-.

[0156] In some embodiments of Formulae (I) (IX) (II), (II'), (IIA), (IIA'), (IIA"), (IIB), (IIB'), (IIB"), (IIB"'), (III), (III'), (IIIA), (IIIA'), (IIIA"), (IIIA"'), (IV), (IV'), (IVA), or (IVA'), L is a linker with a backbone of 1 to 10 carbon atoms in length, wherein one or more carbon atoms are optionally substituted with halogen, hydroxyl, cyano, CFH2, CF2H, CF3, alkoxy, C1-C3alkyl, or -C(=O)-NH2, wherein one or more carbon atoms of the backbone are optionally replaced by a divalent group independently selected from oxygen, alkylamino, carbonyl, 5-7 membered cycloalkyl, 4-6 membered monocyclic heterocyclic group, 7-10 membered bridged heterocyclic group, 7-12 membered spiro heterocyclic group, 5-9 membered heteroaryl, and 9-10 membered heteroaryl fused heterocyclyl, and wherein each of the 5-7 membered cycloalkyl, 4-6 membered monocyclic heterocyclic group, 7-10 membered bridged heterocyclic group, 7-12 membered spiro heterocyclic group, 5-9 heteroaryl, and 9-10 heteroaryl-fused- heterocyclyl is independently substituted with 0, 1, or 2 Re.

[0157] In some embodiments, L is a linker with a backbone of 1 to 10 carbon atoms in length, wherein one or more carbon atoms are optionally substituted with halogen, hydroxyl, cyano, CFH2, CF2H, CF3, alkoxy, C1-C3alkyl, or -C(=O)-NH2, wherein one or more carbon atoms of the backbone are optionally replaced by a divalent group independently selected from oxygen, alkylamino, carbonyl, 5-7 membered cycloalkyl, 4-6 membered monocyclic heterocyclic group, 7-10 membered bridged heterocyclic group, 7- 12 membered spiro heterocyclic group, 5-9 membered heteroaryl, and 9-10 membered heteroaryl fused heterocyclyl, and wherein each of the 5-7 membered cycloalkyl, 4-6 membered monocyclic heterocyclicgroup, 7-10 membered bridged heterocyclic group, 7-12 membered spiro heterocyclic group, 5-9 heteroaryl, and 9-10 heteroaryl-fused-heterocyclyl is independently substituted with 0, 1, or 2 Re.

[0158] In some embodiments, L is a linker with a backbone of 1 to 7 carbon atoms in length, wherein one or more carbon atoms are optionally substituted with halogen, hydroxyl, cyano, CFH2, CF2H, CF3, alkoxy, C1-C3alkyl, or -C(=O)-NH2, wherein one or more carbon atoms of the backbone are optionally replaced by a divalent group independently selected from oxygen, alkylamino, carbonyl, 5-7 membered cycloalkyl, 4-6 membered monocyclic heterocyclic group, 7-10 membered bridged heterocyclic group, 7- 12 membered spiro heterocyclic group, 5-9 membered heteroaryl, and 9-10 membered heteroaryl fused heterocyclyl, and wherein each of the 5-7 membered cycloalkyl, 4-6 membered monocyclic heterocyclic group, 7-10 membered bridged heterocyclic group, 7-12 membered spiro heterocyclic group, 5-9 heteroaryl, and 9-10 heteroaryl-fused-heterocyclyl is independently substituted with 0, 1, or 2 Re.

[0159] In some embodiments, L is a linker with a backbone of 1 to 7 carbon atoms in length, wherein one or more carbon atoms are optionally substituted with halogen, hydroxyl, cyano, CFH2, CF2H, CF3, alkoxy, C1-C3alkyl, or -C(=O)-NH2, wherein one or more carbon atoms of the backbone are optionally replaced by a divalent group independently selected from oxygen, alkylamino, carbonyl, 5-7 membered cycloalkyl, 4-6 membered monocyclic heterocyclic group, 7-10 membered bridged heterocyclic group, 7- 12 membered spiro heterocyclic group, 5-9 membered heteroaryl, and 9-10 membered heteroaryl fused heterocyclyl, and wherein each of the 5-7 membered cycloalkyl, 4-6 membered monocyclic heterocyclic group, 7-10 membered bridged heterocyclic group, 7-12 membered spiro heterocyclic group, 5-9 heteroaryl, and 9-10 heteroaryl-fused-heterocyclyl is independently substituted with 0 or 1 Re.

[0160] In some embodiments, L is a linker with a backbone of 1 to 10 carbon atoms in length, wherein one or more carbon atoms are optionally substituted with halogen, hydroxyl, cyano, CFH2, CF2H, CF3, alkoxy, C1-C3alkyl, or -C(=O)-NH2, wherein one or more carbon atoms of the backbone are optionally replaced by a divalent group independently selected from oxygen, alkylamino, carbonyl, 5-7 membered cycloalkyl, 4-6 membered monocyclic heterocyclic group, 7-10 membered bridged heterocyclic group, 7- 12 membered spiro heterocyclic group, and 9-10 membered heteroaryl fused heterocyclyl, and wherein each of the 5-7 membered cycloalkyl, 4-6 membered monocyclic heterocyclic group, 7-10 membered bridged heterocyclic group, 7-12 membered spiro heterocyclic group, and 9-10 heteroaryl-fused- heterocyclyl is independently substituted with 0, 1, or 2 Re.

[0161] In some embodiments, each Reis independently selected from halogen, hydroxyl, C1-C3alkyl, C1- C3alkoxy, C1-C3haloalkyl, -C(=O)-NH2, and an oxo group.

[0162] In some embodiments, each Reis independently selected from halogen, C1-C3alkyl, C1-C3haloalkyl, and -C(=O)-NH2.

[0163] In some embodiments, each Reis independently selected from F, Cl, and methyl.

[0164] In some embodiments, Reis F.

[0165] In some embodiments, L is selected from: , ,, , ,, , ,, ,, ,, , , ,, , ,, , ,, , ,, , ,, , ,, , ,, , ,, , ,, ,, , ,, , ,, , ,, , ,the point of attachment to G, and * represents the point of attachment to Q.

[0166] In some embodiments, L is selected from: ,, ,

[0167] In some embodiments, L is selected from:

[0168] In some embodiments, L is selected from: ,, ,, , ,

[0169] In some embodiments, L is selected from:iembodiments, L isIn some embodiments, L isembodiments, L isIn some embodiments, L is . In some embodiments, L is . In someembodiments, L is . In some embodiments, L is . In some embodiments, L is . In some embodiments, L is . In some embodiments, L is . In some embodiments, L is . In some embodiments, L is . In some embodiments, L is . In some embodiments, L is . In some embodiments, L is . In some embodiments, L is . In some embodiments, L is . In some embodiments, L is . In some embodiments, L is . In some embodiments, L is . In some embodiments, L is . In some embodiments, L is . In someembodiments, L is. In some embodiments, L is . In some embodiments, L is . In some embodiments, L is . In some embodiments, L is . In some embodiments, L is. In some embodiments, L is . In some embodiments, L is. In some embodiments, L is . In some embodiments, L is . In some embodiments, L is . In some embodiments, L is . In some embodiments, L is . In some embodiments, L is . In some embodiments, L is . In some embodiments, L isembodiments,some embodiments, L is. , . In some embodiments, L is. In some embodiments, L is. Iembodiments, L. , . In some e e

[0170] Non-limiting examples of linkers, such as L, and methods of making them are described, for example, in International Patent Application No. PCT / US2023 / 81898, filed November 30, 2023, and International Patent Application No. PCT / US2023 / 81910, filed November 30, 2023, the contents of each are hereby incorporated by reference in their entirety.

[0171] In some embodiments of Formulae (I), (IX), (II), (II'), (IIA), (IIA'), (IIA"), (IIB), (IIB'), (IIB"), (IIB"'), (III), (III'), (IIIA), (IIIA'), (IIIA"), (IIIA"'), (IV), (IV'), (IVA), or (IVA'), Q is a bond or a divalent group of 1-5 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from 5-6 membered arylene, 5-10 membered heteroarylene, -NH-, -C(=O)-, - C(=O)-NH-, and -C(=O)N(Rc)-, and wherein each of the 5-6 membered arylene and 5-10 membered heteroarylene is independently substituted with 0, 1, 2, or 3 Rf.

[0172] In some embodiments, Q is a bond or a divalent group of 1-5 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from 5-6 membered arylene, 5-10 membered heteroarylene, -NH-, -C(=O)-, -C(=O)-NH-, and -C(=O)N(Rc)-, and wherein each of the 5-6 membered arylene and 5-10 membered heteroarylene is independently substituted with 0, 1, 2, or 3 Rf.

[0173] In some embodiments, Q is a bond or a divalent group of 1-5 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from 5-6 membered arylene, 6-9 membered heteroarylene, -NH-, -C(=O)-, -C(=O)-NH-, and -C(=O)N(Rc)-, and wherein each of the 6 membered arylene and 6-9 membered heteroarylene is independently substituted with 0, 1, 2, or 3 Rf.

[0174] In some embodiments, Q is a bond or a divalent group of 1-5 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from 5-6 membered arylene, 6-9 membered heteroarylene, -NH-, -C(=O)-, -C(=O)-NH-, and -C(=O)N(Rc)-, and wherein each of the 6 membered arylene and 6-9 membered heteroarylene is independently substituted with 0, 1, or 2 Rf.

[0175] In some embodiments, Q is selected from: ,, , , ,, , , , ,X4is selected from -O-, -N(C1-C5alkyl)-, -CH2-, and -C(CH3)2-; and p is 0, 1, 2, or 3. As an example,when Q isrepresents the point of attachment to L, and * represents the point ofa [some embodiments,embodiments,some embodiments, Qembodiments,esome embodiments,eembodiments,some embodiments, Qembodiments,embodiments,some embodiments, Qembodiments,embodiments,e

[0177] In some embodiments, X4is selected from -O-, -N(C1-C5alkyl)-, -CH2-, and -C(CH3)2-. In some embodiments, X4is selected from -O-, -N(C1-C5alkyl)-, and -C(CH3)2-. In some embodiments, X4is selected from -O-, -NCH3-, -NCH2H3-, -NCH(CH3)2-, -CH2-, and -C(CH3)2-. In some embodiments, X4is selected from -O-, -NCH3-, -NCH2H3-, -CH2-, and -C(CH3)2-. In some embodiments, X4is selected from - O-, -NCH3-, -NCH2H3-, and -C(CH3)2-. In some embodiments, X4is selected from -O-, -NCH3-, and - C(CH3)2-. In some embodiments, X4is -O- or -NCH3-. In some embodiments, X4is -O- or-C(CH3)2-. In some embodiments, X4is -O-. In some embodiments, X4is -N(C1-C5alkyl)-. In some embodiments, X4is -NCH3-. In some embodiments, X4is -NCH2H3-. In some embodiments, X4is -NCH(CH3)2-. In some embodiments, X4is -CH2-. In some embodiments, X4is -C(CH3)2-.

[0178] In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0, 1, or 2. In some embodiments, p is 0 or 1. In some embodiments p is 0. In some embodiments p is 1. In some embodiments p is 2. In some embodiments p is 3.

[0179] In some embodiments, each Rfis independently selected from halogen, hydroxyl, C1-C3alkyl, C1- C3alkoxy, C1-C3haloalkyl, and an oxo group.

[0180] In some embodiments, Q is selected from:, , , , ,, , , , ,, , , , , ,, , , , , ,, , , , ,, , , , ,, , , , ,[[ I sembodiments,some embodiments, Qembodiments,some embodiments, Q isembodiments,some embodiments,some embodiments, Q is . In some embodiments, Q is . In some embodiments, Q is . In some embodiments, Q is . In some embodiments, Q is . In some embodiments, Q is . In some embodiments, Q is . In some embodiments, Q is . In some embodiments, Q is . In some embodiments, Q is . In some embodiments, Q is . In some embodiments, Q is . In some embodiments, Q is . In somee e e eembodiments,embodiments,. In some embodiments, QIn some embodiments, Q is . In some embodiments, Q is . In some embodiments, Q is . In some embodiments, Q is . In some embodiments, Q is, In some embodiments, Q is. In some embodiments, Q is . In some embodiments, Q is . In some embodiments, Q is . In some embodiments, Q is . In some embodiments, Q is . In some embodiments, Q is . In some

[0183] In some embodiments, provided herein is a compound chosen from the compounds listed in Table 1 or a tautomer, stereoisomer, or mixture of stereoisomers, or a pharmaceutically acceptable salt of any of the foregoing. Table 1. Exemplary Compounds of the Present DisclosureCpd. No. Structure and IUPAC Name 23 (2S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-(1-((1-((1-(4-(2,6- dioxopiperidin-3-yl)-3,5-difluorophenyl)piperidin-4-yl)methyl)-4-fluoropiperidin-4- yl)methyl)piperidin-4-yl)acetamide 24 (2S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-(1-((1-((1-(1-(2,6- dioxopiperidin-3-yl)-3,3-dimethyl-2-oxoindolin-5-yl)piperidin-4- yl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)acetamide 25 (2S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-(1''-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-[1,4':1',4''-terpiperidin]-4-yl)acetamideCpd. No. Structure and IUPAC Name 29 (2S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-(1-((1-((1-(1-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5- yl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)acetamide 30 (2S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-(1-((1-((1-(4-(2,6- dioxopiperidin-3-yl)-3,5-difluorophenyl)piperidin-4-yl)methyl)piperidin-4- yl)methyl)piperidin-4-yl)acetamide 31 (2S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-(1-((1-((1-(3-(2,6- dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-4-yl)methyl)piperidin-4- yl)methyl)piperidin-4-yl)acetamideCpd. No. Structure and IUPAC Name (S)-2-(1-((1-((1-(2-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)- yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-2-((2-(3- (hydroxymethyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)acetamide 111 (S)-2-(1-((1-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2- methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-2-((2-(3- (hydroxymethyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)acetamide 112 (S)-2-(1-((7-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6- yl)piperidin-4-yl)methyl)-2-fluoro-7-azaspiro[3.5]nonan-2-yl)methyl)piperidin-4-yl)- 2-((2-(3-(hydroxymethyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)acetamide 113 (S)-2-(1-((7-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2- methylphenyl)piperidin-4-yl)methyl)-2-fluoro-7-azaspiro[3.5]nonan-2- yl)methyl)piperidin-4-yl)-2-((2-(3-(hydroxymethyl)-1-(2,2,2-trifluoroethyl)-1H- 1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9- yl)amino)acetamideCpd. No. Structure and IUPAC Name 121 (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-(1-((1-((1-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-6- yl)piperidin-4-yl)methyl)-4-fluoropiperidin-4-yl)methyl)piperidin-4-yl)acetamide 122 (2S,4R)-4-((1-((7-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H- pyrazolo[3,4-b]pyridin-6-yl)-7-azaspiro[3.5]nonan-2-yl)methyl)piperidin-4- yl)amino)-N1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4- yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide 123 (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-5-(((1-((1-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-6- yl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)amino)pentanamide

[0184] In some embodiments, the compound is selected from Table 1 or a pharmaceutically acceptable salt thereof. 3.3. Pharmaceutical Compositions

[0185] Pharmaceutical compositions of the present disclosure comprise at least one compound of Formula (I), or a tautomer, stereoisomer or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof formulated together with one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral, rectal, topical, buccal and parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) administration. The most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used.

[0186] Formulations suitable for oral administration may be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of a compound of the present disclosure as powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. As indicated, such formulations may be prepared by any suitable method of pharmacy which includes the step of bringing into association at least one compound of the present disclosure as the active compound and a carrier or excipient (which may constitute one or more accessory ingredients). The carrier must be acceptable in the sense of being compatible with the other ingredients of the formulation and must not be deleterious to the recipient. The carrier may be a solid or a liquid, or both, and may be formulated with at least one compound described herein as the active compound in a unit-dose formulation, for example, a tablet, which may contain from 0.05% to 95% by weight of the at least one active compound. Other pharmacologically active substances may also be present including other compounds. The formulations of the present disclosure may be prepared by any of the well-known techniques of pharmacy consisting essentially of admixing the components.

[0187] For solid compositions, conventional nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like. Liquid pharmacologically administrable compositions can, for example, be prepared by, for example, dissolving or dispersing, at least one active compound of the present disclosure as described herein and optional pharmaceutical adjuvants in an excipient, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension. In general, suitable formulations may be prepared by uniformly and intimately admixing the at least one active compound of the present disclosure with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the product. For example, a tablet may be prepared by compressing or molding a powder or granules of at least one compound of the present disclosure, which may be optionally combined with one or more accessory ingredients. Compressed tablets may be prepared by compressing, in a suitable machine, at least one compound of the present disclosure in a free-flowing form, such as a powder or granules, which may be optionally mixed with a binder, lubricant, inert diluent and / or surface active / dispersing agent(s). Molded tablets may be made by molding, in a suitable machine, where the powdered form of at least one compound of the present disclosure is moistened with an inert liquid diluent.

[0188] Compounds of the present disclosure can be prepared and administered in a wide variety of oral, parenteral, and topical dosage forms. Thus, the compounds of the present disclosure can be administered by injection (e.g., intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally). In some embodiments, compounds of the present disclosure are administered orally. Also, the compounds described herein can be administered by inhalation, for example, intranasally. Additionally, the compounds of the present disclosure can be administered transdermally. It is also envisioned that multiple routes of administration (e.g., intramuscular, oral, transdermal) can be used to administer compounds of the disclosure. Accordingly, the present disclosure also provides pharmaceutical compositions comprising pharmaceutically acceptable carrier or excipient and one or more compounds of the disclosure.

[0189] For preparing pharmaceutical compositions from the compounds of the present disclosure, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances that may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.

[0190] In powders, the carrier is finely divided solid in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

[0191] Formulations suitable for buccal (sub-lingual) administration include lozenges comprising at least one compound of the present disclosure in a flavored base, usually sucrose and acacia or tragacanth, and pastilles comprising the at least one compound in an inert base such as gelatin and glycerin or sucrose and acacia.

[0192] Formulations of the present disclosure suitable for parenteral administration comprise sterile aqueous preparations of at least one compound of Formula (I), or tautomers, stereoisomers, pharmaceutically acceptable salts, and hydrates thereof, which are approximately isotonic with the blood of the intended recipient. These preparations are administered intravenously, although administration may also be effected by means of subcutaneous, intramuscular, or intradermal injection. Such preparations may conveniently be prepared by admixing at least one compound described herein with water and rendering the resulting solution sterile and isotonic with the blood. Injectable compositions according to the present disclosure may contain from 0.1 to 5% w / w of the active compound.

[0193] Formulations suitable for rectal administration are presented as unit-dose suppositories. These may be prepared by admixing at least one compound as described herein with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.

[0194] Formulations suitable for topical application to the skin may take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carriers and excipients which may be used include Vaseline, lanoline, polyethylene glycols, alcohols, and combinations of two or more thereof. The active compound (i.e., at least one compound of Formula (I), or tautomers, stereoisomers, pharmaceutically acceptable salts, and hydrates thereof) is generally present at a concentration of from 0.1% to 15% w / w of the composition, for example, from 0.5 to 2%. 3.4. Effective Dosages

[0195] Pharmaceutical compositions provided by the present disclosure include compositions wherein the active ingredient is contained in a therapeutically effective amount, i.e., in an amount effective to achieve its intended purpose. The actual amount effective for a particular application will depend, inter alia, on the condition being treated. For example, when administered in methods to treat cancer, such compositions will contain an amount of active ingredient effective to achieve the desired result (e.g., inhibiting and / or degrading PI3K, such as PI3Kα isoform, and / or decreasing an amount of PI3K, such as PI3Kα isoform, in a subject).

[0196] The dosage and frequency (single or multiple doses) of compound administered can vary depending upon a variety of factors, including route of administration; size, age, sex, health, body weight, body mass index, and diet of the recipient; nature and extent of the symptoms of the disease being treated (e.g., the disease responsive treatment; and complications from any disease or treatment regimen. Other therapeutic regimens or agents can be used in conjunction with the methods and compounds of the disclosure.

[0197] For any provided compound or test agent, the therapeutically effective amount can be initially determined from cell culture assays. Target concentrations will be those concentrations of active compound(s) that are capable of decreasing PI3K protein expressed in a subject.

[0198] Therapeutically effective amounts for use in humans may be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring biomarkers associated with cancer and adjusting the dosage upwards or downwards, as described above.

[0199] Dosages may be varied depending upon the requirements of the patient and the compound being employed. The dose administered to a patient, in the context of the present disclosure, should be sufficient to effect a beneficial therapeutic response in the patient over time. The size of the dose also will be determined by the existence, nature, and extent of any adverse side effects.

[0200] In some embodiments, a compound of the disclosure or a pharmaceutical composition comprising the same is provided as a unit dose.

[0201] The amount of active compound administered may be dependent on the subject being treated, the subject's weight, the manner of administration and the judgment of the prescribing physician. For example, a dosing schedule may involve the daily or semi-daily administration of the encapsulated compound at a perceived dosage of 1 μg to 1000 mg. In another embodiment, intermittent administration, such as on a monthly or yearly basis, of a dose of the encapsulated compound may be employed. Encapsulation facilitates access to the site of action and allows the administration of the active ingredients simultaneously, in theory producing a synergistic effect. In accordance with standard dosing regimens, physicians will readily determine optimum dosages and will be able to readily modify administration to achieve such dosages.

[0202] A therapeutically effective amount of a compound or composition disclosed herein can be measured by the therapeutic effectiveness of the compound. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being used. In one embodiment, the therapeutically effective amount of a disclosed compoundis sufficient to establish a maximal plasma concentration. Preliminary doses as, for example, determined according to animal tests, and the scaling of dosages for human administration is performed according to art-accepted practices.

[0203] Toxicity and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50(the dose lethal to 50% of the population) and the ED50(the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50 / ED50.

[0204] Data obtained from the cell culture assays or animal studies can be used in formulating a range of dosage for use in humans. Therapeutically effective dosages achieved in one animal model may be converted for use in another animal, including humans, using conversion factors known in the art (see, e.g., Freireich et al., Cancer Chemother. Reports 50(4):219-244 (1966) and Table 2 below for Equivalent Surface Area Dosage Factors). Table 2. Equivalent Surface Area Dosage Factors.

[0205] The dosage of such compounds lies, for example, within a range of circulating concentrations that include the ED50with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. Generally, a therapeutically effective amount may vary with the subject's age, condition, and gender, as well as the severity of the medical condition in the subject. The dosage may be determined by a physician and adjusted, as necessary, to suit observed effects of the treatment.

[0206] In some embodiments, the disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I), or a tautomer, stereoisomer or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, and one or more of a pharmaceutically acceptable carrier, a pharmaceutically acceptable vehicle, a pharmaceutically acceptable excipient, or combinations thereof.

[0207] The compounds of the disclosure can be administered alone or can be co-administered to the subject. Co-administration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound). The preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation).

[0208] In some embodiments, a compound as described herein can be incorporated into a pharmaceutical composition for administration by methods known to those skilled in the art and described herein for provided compounds. 3.5. Methods of Treatment

[0209] In some embodiments, a compound of Formula (I), or a tautomer, stereoisomer or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, is administered to treat an PI3K-mediated disease or disorder in a subject in need thereof. In some embodiments, the PI3K-mediated disease or disorder is cancer. In some embodiments, the cancer is chosen from breast cancer, lung cancer, pancreatic cancer, small bowel cancer, colorectal cancer, gall bladder cancer, thyroid cancer, liver cancer, bile duct cancer, ovarian cancer, endometrial cancer, cervical cancer, bladder cancer, prostate cancer, esophageal cancer, and blood cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the lung cancer is non-small cell lung cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the pancreatic cancer is pancreatic adenocarcinoma. In some embodiments, the cancer is small bowel cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is gall bladder cancer. In some embodiments, the cancer is thyroid cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is bile duct cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is endometrial cancer. In some embodiments, the cancer is cervical cancer. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is esophageal cancer. In some embodiments, the cancer is blood cancer.

[0210] In some embodiments, the therapeutic treatment is for the treatment of diseases and conditions associated with PI3K dysregulation (e.g., PI3Kα dysregulation), such as cancer, diabetes, cardiovascular diseases, and neurological diseases.

[0211] In some embodiments, a compound of Formula (I), or a tautomer, stereoisomer or a mixture of stereoisomers, or a pharmaceutically acceptable salt, or hydrate, is administered as a pharmaceutical composition.

[0212] In some embodiments, the disclosure provides for methods for treating an PI3K-mediated disease or disorder (e.g., PI3Kα-mediated disease or disorder), such as cancer, in a subject (e.g., patient) in needthereof, comprising (a) determining that the disease or disorder is associated with PI3K; and (b) administering to the subject a therapeutically effective amount of at least one compound of Formula (I) or a tautomer, stereoisomer or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising at least one compound of Formula (I) or a tautomer, stereoisomer or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

[0213] In some embodiments, the disclosure provides for methods for treating a cancer associated with PI3K dysregulation (e.g., PI3Kα dysregulation) in a subject (e.g., patient) in need thereof, comprising administering to the subject a therapeutically effective amount of at least one compound of Formula (I) or a tautomer, stereoisomer or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising at least one compound of Formula (I) or a tautomer, stereoisomer or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof. In certain of such embodiments, the cancer has been determined to be associated with PI3K dysregulation (e.g., PI3Kα dysregulation) and / or the patient has been diagnosed as suffering from a cancer associated with PI3K dysregulation, such as PI3Kα dysregulation.

[0214] In some embodiments, the disclosure provides for methods for inhibiting and / or degrading PI3K, such as PI3Kα isoform, including PI3K (e.g., PI3Kα isoform) in a cell, comprising contacting the cell with at least one compound of Formula (I) or a tautomer, stereoisomer or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising at least one compound of Formula (I) or a tautomer, stereoisomer or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

[0215] In some embodiments, the disclosure provides for methods for degrading PI3K (e.g., PI3Kα isoform) in a cell, comprising contacting the cell in which degradation of PI3K (e.g., PI3Kα isoform) is desired with an effective amount of a compound of Formula (I), pharmaceutically acceptable salts thereof or pharmaceutical compositions containing the compound or pharmaceutically acceptable salt thereof. In one embodiment, the contacting is in vitro. In one embodiment, the contacting is in vivo.

[0216] As used herein, the term “contacting” refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, “contacting” PI3K (e.g., PI3Kα isoform) with a compound provided herein includes the administration of a compound provided herein to an individual or patient, such as a human, having PI3K (e.g., overexpression of PI3K , overexpression of PI3Kα isoform), as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing PI3K.

[0217] In some embodiments, a cell in which degradation of PI3K (e.g., PI3Kα isoform) is desired is contacted with an effective amount of a compound of Formula (I) to negatively modulate PI3K (e.g., PI3Kα isoform). In other embodiments, a therapeutically effective amount of pharmaceutically acceptable salt or pharmaceutical compositions containing the compound of Formula (I) may be used.

[0218] By negatively modulating PI3K, such as PI3Kα isoform (e.g., by degradation), the methods described herein are designed to halt undesired cellular proliferation resulting from enhanced PI3K presence within the cell. The cells may be contacted in a single dose or multiple doses in accordance with a particular treatment regimen to effect the desired negative modulation of PI3K.

[0219] The concentration and route of administration to the patient will vary depending on the cancer to be treated.

[0220] In some embodiments, a compound of Formula (I), or a tautomer, stereoisomer or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, is administered in combination with another therapeutic agent, e.g., chemotherapy, or used in combination with other treatments, such as radiation or surgical intervention, either as an adjuvant prior to surgery or post-operatively.

[0221] In some embodiments, a compound of Formula (I), or a tautomer, stereoisomer or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, is administered with an additional anti- cancer agent. In some embodiments, the compound of Formula (I) and / or the pharmaceutical composition comprising the compound of Formula (I), and the additional anti-cancer agent are administered concomitantly. In some embodiments, the compound of Formula (I) and / or the pharmaceutical composition comprising the compound of Formula (I), and the additional anti-cancer agent are administered sequentially.

[0222] Also provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof as defined herein for use in therapy.

[0223] Also provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate / hydrate thereof or a pharmaceutical composition thereof as defined herein for use in the treatment of cancer.

[0224] Also provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof for use in the inhibition and / or degradation of PI3K (e.g., PI3K isoforms, such as PI3Kα isoform).

[0225] Also provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof as defined herein, for use in the treatment of an PI3K-mediated disease or disorder (e.g., PI3Kα -mediated disease or disorder).

[0226] Also provided herein is the use of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, as defined herein in the manufacture of a medicament for the treatment of PI3K- mediated disease or disorder (e.g., PI3Kα -mediated disease or disorder), such as cancer.

[0227] Also provided herein is a use of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, as defined herein in the manufacture of a medicament for the inhibition of activity and / or degradation of PI3K. 3.6. Antiproliferative activity in PI3K mutant tumor cells

[0228] The ability of the compounds disclosed herein to act on PI3K mutant tumor cells can be determined by measuring mutant PIK3CA degradation and inhibition in breast cancer cell lines (e.g. T- 47D), such as cells having a PIK3CA H1047R mutation, as described in Examples 32 and 33. In some embodiments, the cancer expresses a PIK3CA mutant selected from E542K, E545K, Q546R, H1047L, and H1047R. In some embodiments, the PIK3CA mutant is H1047R. 4. ENUMERATED EMBODIMENTS Embodiment 1. A compound, wherein the compound is represented by Formula (I) or is a pharmaceutically acceptable salt thereof:wherein: Ring A is a 5-10 membered heteroaryl, 5-10 membered heterocyclic group, or 5-10 membered heteroaryl- fused-heterocyclic group, wherein each of the 5-10 membered heteroaryl, 5-10 membered heterocyclic group, and 5-10 membered heteroaryl-fused-heterocyclic group is independently substituted with 0, 1, 2, 3, or 4 Ra; each Rais independently selected from amino, halogen, hydroxyl, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 haloalkyl, C1-C5alkylamino, di-(C1-C5alkyl)amino, C1-C5hydroxyalkyl, C1-C5aminoalkyl, C1- C5alkyl-O-C1-C5alkyl, and an oxo group; Ring B is a 5-15 membered heteroaryl, 5-15 membered heterocyclic group, or 5-15 membered heteroaryl-fused-heterocyclic group, wherein each of the 5-15 membered heteroaryl, 5-15 membered heterocyclic group, and 5-15 membered heteroaryl-fused-heterocyclic group is independently substituted with 0, 1, 2, 3, 4, or 5 Rb; each Rbis independently selected from amino, halogen, hydroxyl, C1-C5alkyl, C1-C5alkoxy, C1-C5haloalkyl, C1-C5alkylamino, di-(C1-C5alkyl)amino, C1-C5hydroxyalkyl, C1-C5aminoalkyl, C1- C5alkyl-O-C1-C5alkyl, and an oxo group; Lais selected from a bond, -NH-C(=O)-, -C(=O)-NH-, -NH-C(=O)-O-, -O-C(=O)-NH-, -NH-C(=O)-NH-, -NH-CH(CF3)-, -(CF3)CH-NH-, -NH-C(=S)-, -C(=S)-NH-, -CH=CF-, -CF=CH-, -G is a bond or a divalent group with a backbone of 1-10 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from oxygen, heterocyclene, heteroarylene, arylene, -NH-, -N(Rc)-, -C(=O)-, -C(=O)-NH-, -CH(Rc)-, -C(Rc)2-, -, -N(Rc)-C(=O)-NH-, and -C(=O)-N(Rc)-, and wherein each of the heterocyclene, arylene and heteroarylene is independently substituted with 0, 1, 2, or 3 Rd; each Rcis independently selected from C1-C3alkyl, and -C(=O)-NH2; each Rdis independently selected from halogen, hydroxyl, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, - C(=O)-NH2, and an oxo group; L is a linker with a backbone of 1-20 carbon atoms in length, wherein one or more carbon atoms are optionally substituted with halogen, hydroxyl, cyano, CFH2, CF2H, CF3, alkoxy, C1-C5alkyl, or - C(=O)-NH2, wherein one or more carbon atoms of the backbone are optionally replaced by a divalent group independently selected from oxygen, alkylamino, carbonyl, 3-7 membered cycloalkylene, 4-7 membered monocyclic heterocyclic group, 5-10 membered bridged heterocyclic group, 5-12 membered spiro heterocyclic group, 5-10 membered heteroarylene, and 7-12 membered heteroaryl-fused-heterocyclylene, and wherein each of the 3-7 membered cycloalkylene, 4-7 membered monocyclic heterocyclic group, 5-10 membered bridged heterocyclic group, 5-12 membered spiro heterocyclic group, 5-10 membered heteroarylene, and 7-12 membered heteroaryl-fused-heterocyclylene is independently substituted with 0, 1, or 2 Re; each Reis independently selected from alkylamino, halogen, hydroxyl, C1-C3alkoxy, C1-C4alkyl, C1-C4alkenyl, C3-C5cycloalkyl, C1-C4haloalkyl, and an oxo group;X is N or CH; Q is a bond or a divalent group of 1-5 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from 5-6 membered arylene, 5-10 membered heteroarylene (e.g., a 9 membered heteroarylene, such as a fused 5-6 membered heteroarylene ring system; a 6 membered aryl or heteroaryl fused to a 5 membered heterocyclyl; and so forth), - NH-, -C(=O)-, -C(=O)-NH-, and -C(=O)N(Rc)-, and wherein each of the 5-6 membered arylene and 5-10 membered heteroarylene is independently substituted with 0, 1, 2, or 3 Rf; and each Rfis independently selected from halogen, hydroxyl, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, and an oxo group. Embodiment 2. The compound according to embodiment 1, wherein the compound of Formula (I) is represented by a compound of Formula (IX) or is a pharmaceutically acceptable salt thereof:wherein: Ring A is a 5-10 membered heteroaryl, 5-10 membered heterocyclic group, or 5-10 membered heteroaryl- fused-heterocyclic group, wherein each of the 5-10 membered heteroaryl, 5-10 membered heterocyclic group, and 5-10 membered heteroaryl-fused-heterocyclic group is independently substituted with 0, 1, 2, 3, or 4 Ra; each Rais independently selected from amino, halogen, hydroxyl, C1-C5alkyl, C1-C5alkoxy, C1-C5haloalkyl, C1-C5alkylamino, di-(C1-C5alkyl)amino, C1-C5hydroxyalkyl, C1-C5aminoalkyl, C1- C5alkyl-O-C1-C5alkyl, and an oxo group; Ring B is a 5-15 membered heteroaryl, 5-15 membered heterocyclic group, or 5-15 membered heteroaryl- fused-heterocyclic group, wherein each of the 5-15 membered heteroaryl, 5-15 membered heterocyclic group, and 5-15 membered heteroaryl-fused-heterocyclic group is independently substituted with 0, 1, 2, 3, 4, or 5 Rb; each Rbis independently selected from amino, halogen, hydroxyl, C1-C5alkyl, C1-C5alkoxy, C1-C5haloalkyl, C1-C5alkylamino, di-(C1-C5alkyl)amino, C1-C5hydroxyalkyl, C1-C5aminoalkyl, C1- C5alkyl-O-C1-C5alkyl, and an oxo group;Lais selected from a bond, -NH-C(=O)-, -C(=O)-NH-, -NH-C(=O)-O-, -O-C(=O)-NH-, -NH-C(=O)-NH-, -NH-CH(CF3)-, -(CF3)CH-NH-, -NH-C(=S)-, -C(=S)-NH-, -CH=CF-, -CF=CH-, -G is a bond or a divalent group with a backbone of 1-10 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from oxygen, heterocyclene, heteroarylene, arylene, -NH-, -N(Rc)-, -C(=O)-, -C(=O)-NH-, -CH(Rc)-, -C(Rc)2-, - C(=O)-N(Rc)-, -NH-C(=O)-, -N(Rc)-C(=O)-, -NH-C(=O)-O-, -N(Rc)-C(=O)-O-, -NH-C(=O)-NH- , -N(Rc)-C(=O)-NH-, and -C(=O)-N(Rc)-, and wherein each of the heterocyclene, arylene and heteroarylene is independently substituted with 0, 1, 2, or 3 Rd; each Rcis independently selected from C1-C3alkyl, and -C(=O)-NH2; each Rdis independently selected from halogen, hydroxyl, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, - C(=O)-NH2, and an oxo group; L is a linker with a backbone of 1-20 carbon atoms in length, wherein one or more carbon atoms are optionally substituted with halogen, hydroxyl, cyano, CFH2, CF2H, CF3, alkoxy, C1-C5alkyl, or - C(=O)-NH2, wherein one or more carbon atoms of the backbone are optionally replaced by a divalent group independently selected from oxygen, alkylamino, carbonyl, 3-7 membered cycloalkylene, 4-7 membered monocyclic heterocyclic group, 5-10 membered bridged heterocyclic group, 5-12 membered spiro heterocyclic group, 5-10 membered heteroarylene, and 7-12 membered heteroaryl-fused-heterocyclylene, and wherein each of the 3-7 membered cycloalkylene, 4-7 membered monocyclic heterocyclic group, 5-10 membered bridged heterocyclic group, 5-12 membered spiro heterocyclic group, 5-10 membered heteroarylene, and 7-12 membered heteroaryl-fused-heterocyclylene is independently substituted with 0, 1, or 2 Re; each Reis independently selected from alkylamino, halogen, hydroxyl, C1-C3alkoxy, C1-C4alkyl, C1-C4alkenyl, C3-C5cycloalkyl, C1-C4haloalkyl, and an oxo group; Q is a bond or a divalent group of 1-5 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from 5-6 membered arylene, 5-10 membered heteroarylene, -NH-, -C(=O)-, -C(=O)-NH-, and -C(=O)N(Rc)-, and wherein each of the 5-6 membered arylene and 5-10 membered heteroarylene is independently substituted with 0, 1, 2, or 3 Rf; and each Rfis independently selected from halogen, hydroxyl, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, andan oxo group. Embodiment 3. The compound according to embodiment 1, wherein Ring A is selected from:wherein n is 0, 1, 2, or 3. Embodiment 4. The compound according to any one of embodiments 13, wherein Ring B is selected from:wherein: X1is CH or N; X2is selected from N, NH, O, and S; X3is selected from N, NH, O, and S; and m is 0, 1, or 2. Embodiment 5. The compound according to any one of embodiments 1-4, wherein Lais a bond, -NH- C(=O)-, -C(=O)-NH-, -NH-C(=O)-O-, -O-C(=O)-NH-, -NH-C(=O)-NH-, -NH-CH(CF3)-, - (Embodiment 6. The compound according to embodiment 5, wherein Lais a bond, -NH-C(=O)-, -C(=O)- NH-, -NH-C(=O)-O-, -O-C(=O)-NH-, or -NH-C(=O)-NH-. Embodiment 7. The compound according to embodiment 6, wherein Lais a bond or -C(=O)-NH-, particularly a bond.Embodiment 8. The compound according to any one of embodiments 1-7, wherein the compound of Formula (I) is represented by a compound of Formula (II):(II) wherein: Ring A is a 5-6 membered heteroaryl or 5-6 membered heterocyclic group; each Rais independently selected from amino, halogen, hydroxyl, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4alkylamino, di-(C1-C5alkyl)amino, C1-C4hydroxyalkyl, C1-C4aminoalkyl, C1- C5alkyl-O-C1-C5alkyl, and an oxo group; each Rbis independently selected from amino, halogen, hydroxyl, C1-C3alkyl, C1-C3alkoxy, and C1-C3haloalkyl; X1is CH or N; n is 0, 1, 2, or 3; and m is 0, 1, or 2. Embodiment 9. The compound according to embodiment 8, wherein the compound of Formula (II) is represented by a compound of Formula (IIA):Embodiment 10. The compound according to embodiment 9, wherein the compound of Formula (IIA) is represented by a compound of Formula (IIA’):wherein each Rais independently selected from hydroxyl, C1-C3alkyl, C1-C3alkoxy, C1-C3alkylamino, and C1-C3haloalkyl. Embodiment 11. The compound according to embodiment 8, wherein the compound of Formula (II) is represented by a compound of Formula (IIB):Embodiment 12. The compound according to embodiment 11, wherein the compound of Formula (IIB) is represented by a compound of Formula (IIB’):wherein each Rais independently selected from C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C5hydroxyalkyl, and C1-C5aminoalkyl. Embodiment 13. The compound according to any one of embodiments 1-7, wherein the compound of Formula (I) is represented by a compound of Formula (III):wherein: Ring A is a 5-6 membered heteroaryl or 5-6 membered heterocyclic group; each Rais independently selected from amino, halogen, hydroxyl, C1-C5alkyl, C1-C5alkoxy, C1-C5haloalkyl, C1-C5alkylamino, C1-C5hydroxyalkyl, and C1-C5aminoalkyl; each of X2and X3is independently selected from N, NH, O, and S; each Rbis independently selected from amino, halogen, hydroxyl, C1-C5alkyl, C1-C5alkoxy, C1-C5haloalkyl, and C1-C5alkylamino; n is 0, 1, 2, or 3; and m is 0 or 1. Embodiment 14. The compound according to embodiment 13, wherein the compound of Formula (III) is represented by a compound of Formula (IIIA):Embodiment 15. The compound according to embodiment 14, wherein the compound of Formula (IIIA) is represented by a compound of Formula (IIIA’):(IIIA’) wherein Rbis selected from amino, halogen, C1-C4alkyl, C1-C4alkoxy, and C1-C4haloalkyl. Embodiment 16. The compound according to any one of embodiments 1-7, wherein the compound of Formula (I) is represented by a compound of Formula (IV):wherein: Ring A is a 5-6 membered heteroaryl or 5-6 membered heterocyclic group; each Rais independently selected from amino, halogen, hydroxyl, C1-C5alkyl, C1-C5alkoxy, C1-C5haloalkyl, C1-C5alkylamino, di-(C1-C5alkyl)amino, C1-C5hydroxyalkyl, and C1-C5aminoalkyl; each Rbis independently selected from halogen, hydroxyl, C1-C4alkyl, and C1-C4alkoxy; n is 0, 1, or 2; and m is 0, 1, or 2. Embodiment 17. The compound according to embodiment 16, wherein the compound of Formula (IV) is represented by a compound of Formula (IVA):Embodiment 18. The compound according to any one of embodiments 1-17, wherein each Rais independently selected from -CH3, -CH2CF3, -CH(CH3)2, -CH2OH, -CH2-OCH3, -CH2F, -CHF2, - CF3, -C(CH3)2CF3, -OH, -OCH3, -NH2, and -CH2-NH2. Embodiment 19. The compound according to embodiment 18, wherein each Rais independently selected from -CH(CH3)2, -CH2F, -CHF2, -CF3, and -NH2. Embodiment 20. The compound according to any one of embodiments 1-8, 13, 14, 16, or 17 wherein Ring A is selected from: ,, , , , ,, , , , , ,, , , , , , , ,, , , , , , ,, , , and .Embodiment 21. The compound according to embodiment 20, wherein Ring A is selected from:Embodiment 22. The compound according to embodiment 20, wherein Ring A is selected from:Embodiment 23. The compound according to any one of embodiments 1-22, wherein G is a divalent group with a backbone of 1-7 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from oxygen, heterocyclene, heteroarylene, arylene, -NH-, -C(Rc)-, and -N(Rc)-, and wherein each of the heterocyclene, arylene, and heteroarylene is independently substituted with 0, 1, 2, or 3 Rd. Embodiment 24. The compound according to any one of embodiments 1-23, wherein G is selected from:,Embodiment 25. The compound according to any one of embodiments 1-24, wherein G is selectedf,wherein ** represents the point of attachment to L. Embodiment 26. The compound according to any one of embodiments 1-23, wherein G is selected from -O-(CH2)2-, -O-(CH2)3-, -O-(CH2)4-, -O-(CH2)5-, -O-(CH2)6-, -O-(CH2)3NH-, and -O- (CH2)3NH-CH2-. Embodiment 27. The compound according to any one of embodiments 1-26, wherein L is a linkerwith a backbone of 1 to 10 carbon atoms in length, wherein one or more carbon atoms are optionally substituted with halogen, hydroxyl, cyano, CFH2, CF2H, CF3, alkoxy, C1-C3alkyl, or - C(=O)-NH2, wherein one or more carbon atoms of the backbone are optionally replaced by a divalent group independently selected from oxygen, alkylamino, carbonyl, 5-7 membered cycloalkyl, 4-6 membered monocyclic heterocyclic group, 7-10 membered bridged heterocyclic group, 7-12 membered spiro heterocyclic group, 5-9 membered heteroaryl, and 9-10 membered heteroaryl fused heterocyclyl, and wherein each of the 5-7 membered cycloalkyl, 4-6 membered monocyclic heterocyclic group, 7-10 membered bridged heterocyclic group, 7-12 membered spiro heterocyclic group, 5-9 heteroaryl, and 9-10 heteroaryl-fused-heterocyclyl is independently substituted with 0, 1, or 2 Re. Embodiment 28. The compound according to any one of embodiments 1-27, wherein L is selectedfrom: , , , ,, , ,, , ,, ,, , , ,, , ,, , ,, , ,, , ,,, , ,, , ,, , ,, , ,, , ,, , ,, , ,Embodiment 29. The compound according to any one of embodiments 1-28, wherein L is selected from:Embodiment 30. The compound according to any one of embodiments 1-28, wherein L is selected from: ,,. The compound according to any one of embodiments 1-30, wherein Q is selected,, , , ,, , , , ,, , , , , ,, , , , , ,, , , , ,, , , , ,, , , , ,, , , , ,, , , , , ,, , , , , ,, , , , ,, , , , , , , , , , , , and. Embodiment 32. The compound according to any one of embodiments 1-31, wherein Q is selectedf. Embodiment 33. The compound according to embodiment 1, wherein the compound is selected from Table 1 or is a pharmaceutically acceptable salt thereof. Embodiment 34. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of embodiments 1-33 and a pharmaceutically acceptable carrier. Embodiment 35. A method for inhibiting and / or degrading phosphoinositide 3-kinase (PI3K) in a cell, comprising contacting the cell with at least one compound according to any one of embodiments 1-33 or the pharmaceutical composition according to embodiment 34. Embodiment 36. The method of embodiment 34, wherein the PI3K is PI3Kα. Embodiment 37. A method for treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of at least one compound according to any one of embodiments 1 to 33, or a pharmaceutical composition of embodiment 34. Embodiment 38. The method according to embodiment 37, wherein the cancer is selected frombreast cancer, lung cancer, pancreatic cancer, small bowel cancer, colorectal cancer, gall bladder cancer, gastric cancer, thyroid cancer, liver cancer, lymphoma, sarcoma, bile duct cancer, ovarian cancer, endometrial cancer, cervical cancer, bladder cancer, prostate cancer, squamous cell carcinoma, head and neck cancer, esophageal cancer, and blood cancer. Embodiment 39. The method according to embodiment 38, wherein the cancer is selected from estrogen receptor positive (ER+) breast cancer, non-small cell lung cancer, colorectal cancer, gastric cancer, ovarian cancer, endometrial cancer, cervical cancer, prostate cancer, and squamous cell carcinoma. Embodiment 40. The method according to any one of embodiments 37-39, wherein the cancer is associated with PI3K or PI3Kα dysregulation or dysfunction. Embodiment 45. Use of a compound according to any one of embodiments 1-37 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 38, in the treatment of a disease or disorder. Embodiment 46. The use according to embodiment 45, wherein the disease or disorder is cancer. Embodiment 47. The use according to embodiment 46, wherein the cancer is selected from breast cancer, lung cancer, pancreatic cancer, small bowel cancer, colorectal cancer, gall bladder cancer, gastric cancer, glioblastoma, thyroid cancer, liver cancer, lymphoma, sarcoma, bile duct cancer, ovarian cancer, endometrial cancer, cervical cancer, bladder cancer, prostate cancer, squamous cell carcinoma, head and neck cancer, esophageal cancer, and blood cancer. Embodiment 48. The use of embodiment 47, wherein the cancer is selected from estrogen receptor positive (ER+) breast cancer, non-small cell lung cancer, colorectal cancer, gastric cancer, ovarian cancer, endometrial cancer, cervical cancer, prostate cancer, and squamous cell carcinoma. 5. EXAMPLES

[0229] The examples and preparations provided below further illustrate and exemplify the compounds as disclosed herein and methods of preparing such compounds. It is to be understood that the scope of the present disclosure is not limited in any way by the scope of the following examples and preparations.

[0230] The chemical entities described herein can be synthesized according to one or more illustrative schemes herein and / or techniques well known in the art. Unless specified to the contrary, the reactionsdescribed herein take place at atmospheric pressure, generally within a temperature range from -10 °C to 200 °C. Further, except as otherwise specified, reaction times and conditions are intended to be approximate, e.g., taking place at atmospheric pressure within a temperature range of -10 °C to 200 °C over a period that can be, for example, 1 to 24 hours; reactions left to run overnight in some embodiments can average a period of 16 hours.

[0231] Isolation and purification of the chemical entities and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer chromatography, or a combination of these procedures. See, e.g., Carey et al. Advanced Organic Chemistry, 3rdEd., 1990 New York: Plenum Press; Mundy et al., Name Reaction and Reagents in Organic Synthesis, 2ndEd., 2005 Hoboken, NJ: J. Wiley & Sons. Specific illustrations of suitable separation and isolation procedures are given by reference to the examples hereinbelow. However, other equivalent separation or isolation procedures can also be used.

[0232] In all of the methods, it is well understood that protecting groups for sensitive or reactive groups may be employed where necessary, in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T.W. Greene and P.G.M. Wuts (1999) Protective Groups in Organic Synthesis, 3rdEd., John Wiley & Sons). These groups may be removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art.

[0233] When desired, the (R)- and (S)-isomers of the nonlimiting exemplary compounds, if present, can be resolved by methods known to those skilled in the art, for example, by formation of diastereoisomeric salts or complexes which can be separated, e.g., by crystallization; via formation of diastereoisomeric derivatives which can be separated, e.g., by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, e.g., enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, e.g., on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent. Alternatively, a specific enantiomer can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.

[0234] The compounds described herein can be optionally contacted with a pharmaceutically acceptable acid to form the corresponding acid addition salts. Also, the compounds described herein can be optionally contacted with a pharmaceutically acceptable base to form the corresponding basic addition salts.

[0235] In some embodiments, disclosed compounds can generally be synthesized by an appropriate combination of generally well-known synthetic methods. Techniques useful in synthesizing these chemical entities are both readily apparent and accessible to those of skill in the relevant art, based on the instant disclosure. Many of the optionally substituted starting compounds and other reactants are commercially available, e.g., from Millipore Sigma or can be readily prepared by those skilled in the art using commonly employed synthetic methodology.

[0236] The discussion below is offered to illustrate certain of the diverse methods available for use in making the disclosed compounds and is not intended to limit the scope of reactions or reaction sequences that can be used in preparing the compounds provided herein. The skilled artisan will understand that standard atom valences apply to all compounds disclosed herein in genus or named compound for unless otherwise specified.

[0237] The following abbreviations have the definitions set forth below: ACN Acetonitrile AcOH acetic acid Bpin boronic acid pinacol Boc tert-Butyloxycarbonyl Bn Benzyl Cbz carbonyloxybenzyl DABCO 1,4-Diazabicyclo[2.2.2]octane DCE Dichloroethane DCM Dichloromethane DIEA Diisopropylethylamine DMA N,N-dimethylacetamide DMF N,N-dimethylformamide dba Dibenzylideneacetone DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DIAD diisopropyl azodicarboxylate DIBAL-H diisobutylaluminum hydride DME dimethyl ether DMP 2,2-dimethoxypropane DNP 2,4-Dinitrophenol dppf 1,1′-bis(diphenylphosphino)ferrocene dtbpy, dtbbpy 4,4'-Di-tert-butyl-2,2'-bipyridine DMSO Dimethyl sulfoxide ee enantiomeric excess EA Ethyl acetate EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide FA Formic acid HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HPLC High pressure liquid chromatography LAH Lithium aluminum hydride LC / MS Liquid chromatography / Mass spectroscopy MOM MethoxymethylMTBE Methyl tert-butyl ether m-CPBA meta-chloroperbenzoic acid MeOH methanol MOM methoxymethyl ether n-Bu butan-1-yl NMP N-methylpyrrolidone NMR Nuclear magnetic resonance PE: Petroleum ether PIV Pivalic acid Ppy Phenylpyridine Pd2(dba)3Tris(dibenzylideneacetone)dipalladium (0) Pd(dppf)Cl2[1,1’-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) ppy phenylpyridine prep-HPLC preparative high-performance liquid chromatography Prep-TLC preparative thin layer chromatography RF retention factors SEM 2-(Trimethylsilyl)ethoxymethyl SFC Supercritical fluid chromatography T3P Propylphosphonic anhydride TBS tert-Butyldimethylsilyl ether TEA Triethylamine THF Tetrahydrofuran TIPS Triisopropyl silane TLC Thin layer chromatography TR-FRET Time-resolved fluorescene energy transfer TBAB tetrabutylammonium bromide TBAF tetrabutylammonium fluoride TBS tert-Butyldimethylsilyl t-Bu Tert-butyl TFA trifluoroacetic acid TFAA trifluoroacetic anhydride THF tetrahydrofuran TLC thin layer chromatography TMS tetramethylsilane Tos toluenesulfonyl group TsOH p-toluenesulfonic acid TTMSS tris(trimethylsilyl)silane XantPhos (9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) 5.1. General Synthetic Schemes 5.1.1. Preparation of Intermediates:

[0238] The claimed compounds can be prepared according to the following schemes. The following schemes represent the general methods used in preparing these compounds. However, the synthesis of these compounds is not limited to these representative methods, as they can also be prepared through various other methods by those skilled in the art of synthetic chemistry.

[0239] Preparation of 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-4-carbaldehyde, Int 1

[0240] Step 1: Preparation of 3-(5-(4-(hydroxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione

[0241] A mixture of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (3 g, 9.28 mmol, 1 eq), piperidin-4-ylmethanol (1.39 g, 12.1 mmol, 1.3 eq), Cs2CO3(9.07 g, 27.8 mmol, 3 eq), and [1,3-bis[2,6- bis(1-ethylpropyl)phenyl]-4,5-dichloro-imidazol-2-ylidene]-dichloro-(3-chloropyridin-1-ium-1- yl)palladium (399 mg, 464 μmol, 0.05 eq) in dioxane (60 mL) was purged with N2for three times. Then the reaction mixture was stirred at 100 °C for 2 hours under N2atmosphere. LCMS indicated complete consumption of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione and formation of product with the desired mass (66.0% peak area). The reaction mixture was quenched with AcOH aqueous (10%, 150 mL), and neutralized with saturated NaHCO3aqueous solution to pH = 8. The solution was extracted with DCM (50 mL * 8). The organic layers were combined, washed with brine (50 mL), dried over anhydrous Na2SO4and filtered. The filtrate was concentrated under reduced pressure to give a crude residue, which was purified by reverse-phase chromatography (0.1% FA) and lyophilized to afford 3-(5-(4- (hydroxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (2 g, 5.60 mmol, 60.3% yield)as a white solid. LCMS: m / z [M+H]+= 358.3;1H NMR (400 MHz, DMSO-d6) δ = 10.95 (br s, 1H), 8.50 (s, 1H), 7.49 (d, J = 8.6 Hz, 1H), 7.08 - 6.99 (m, 2H), 5.11 - 4.94 (m, 1H), 4.68 - 4.38 (m, 1H), 4.38 - 4.12 (m, 2H), 3.88 (br d, J = 12.8 Hz, 2H), 3.27 (d, J = 6.4 Hz, 2H), 2.94 - 2.74 (m, 3H), 2.62 - 2.54 (m, 1H), 2.43 - 2.29 (m, 1H), 2.00 - 1.90 (m, 1H), 1.73 (br d, J = 11.4 Hz, 2H), 1.66 - 1.53 (m, 1H), 1.28 - 1.14 (m, 2H).

[0242] Step 2: Preparation of 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-4- carbaldehyde

[0243] To a solution of 3-(5-(4-(hydroxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione (1.9 g, 5.32 mmol, 1 eq) in DCM (50 mL) and DMSO (5 mL) was added DMP (2.71 g, 6.38 mmol,1.98 mL, 1.2 eq) at 0 °C. Then the mixture was stirred at 25 °C for 2 hours. LCMS indicated complete consumption of starting material and formation of the desired product (59.0% peak area). The reaction mixture was quenched with saturated Na2S2O3aqueous solution (50 mL) at 0 °C and then diluted with EA (10 mL). The solution was extracted with EA (50 mL *2) and the combined organic layers were washed with brine (30 mL *2), dried over anhydrous Na2SO4and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, PE: EA = 5: 1 to 0: 1) to afford 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-4-carbaldehyde (1.89 g, 5.32 mmol, 100% yield) as a yellow solid. LCMS: m / z [M+H]+= 356.3;1H NMR (400 MHz, DMSO-d6) δ = 10.98 (s, 1H), 9.67 (s, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.16 - 7.05 (m, 2H), 5.12 - 5.02 (m, 1H), 4.44 - 4.18 (m, 2H), 3.88 - 3.78 (m, 2H), 3.10 - 3.01 (m, 2H), 3.00 - 2.88 (m, 1H), 2.67 - 2.62 (m, 3H), 2.01 - 1.92 (m, 3H), 1.67 - 1.55 (m, 2H).

[0244] Preparation of (2S,3S)-N1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4- yl)thiazol-2-yl)-3-(2-(piperidin-4-yl)acetamido)pyrrolidine-1,2-dicarboxamide, Int 2

[0245] Step 1: Preparation of 1-(tert-butyl) 2-methyl (2S,3S)-3-azidopyrrolidine-1,2-dicarboxylate

[0246] To a mixture of O1-tert-butyl O2-methyl (2S,3R)-3-hydroxypyrrolidine-1,2-dicarboxylate (0.4 g, 1.63 mmol, 1 eq) and PPh3(642 mg, 2.45 mmol, 1.50 eq) in THF (2 mL) was added DIAD (494 mg, 2.44 mmol, 1.50 eq) in THF (1 mL) under 0 °C. Then DPPA (670 mg, 2.44 mmol, 1.49 eq) in THF (1 mL) was added to the mixture and stirred for 6.5 hours at 20 °C. TLC (PE: EA=5: 1) indicated complete consumption of the starting material (Rf= 0.1) and formation of a new spot (Rf=0.6). The reaction mixturewas concentrated under reduced pressure to afford the crude. The crude was purified by column chromatography (SiO2, PE: EA=15: 1 to PE: EA=10: 1) to afford 1-(tert-butyl) 2-methyl (2S,3S)-3- azidopyrrolidine-1,2-dicarboxylate (0.5 g, PPh3remained) as a colorless oil.1H NMR (400 MHz, DMSO- d6) δ = 4.44 (br d, J = 3.8 Hz, 1H), 4.17 - 4.04 (m, 1H), 3.74 - 3.68 (m, 3H), 3.51 - 3.39 (m, 2H), 2.18 - 2.05 (m, 1H), 2.04 - 1.87 (m, 1H), 1.41 - 1.33 (m, 9H).

[0247] Step 2: Preparation of 1-(tert-butyl) 2-methyl (2S,3S)-3-aminopyrrolidine-1,2-dicarboxylate

[0248] To a solution of Pd / C (50.0 mg, 10 % purity) in MeOH (5 mL) was added 1-(tert-butyl) 2-methyl (2S,3S)-3-azidopyrrolidine-1,2-dicarboxylate (0.5 g, 1.85 mmol, 1 eq), stirred at 20 °C for 12 hours under H2atmosphere (50 PSI). TLC (PE: EA=0: 1) indicated complete consumption of the starting material (Rf=1) and formation of a new spot (Rf=0.1). The reaction was filtered, concentrated under reduced pressure to afford the crude. The crude was purified by column chromatography (0.1 % TEA in PE), (SiO2, PE: EA=5: 1 to PE: EA=0: 1) to afford 1-(tert-butyl) 2-methyl (2S,3S)-3-aminopyrrolidine-1,2- dicarboxylate (0.24 g, 982 μmol, 53.1 % yield) as a yellow oil.1H NMR (400 MHz, CDCl3) δ = 4.06 - 3.88 (m, 1H), 3.75 (s, 3H), 3.67 - 3.51 (m, 3H), 2.16 (dd, J = 6.6, 12.8 Hz, 1H), 1.78 - 1.70 (m, 1H), 1.49 - 1.38 (m, 9H).

[0249] Step 3: Preparation of 1-(tert-butyl) 2-methyl (2S,3S)-3-(2-(1-((benzyloxy)carbonyl)piperidin-4- yl)acetamido)pyrrolidine-1,2-dicarboxylate

[0250] To a solution of 2-(1-benzyloxycarbonyl-4-piperidyl)acetic acid (262 mg, 946 μmol, 1.1 eq) in DMF (4 mL) was added DIEA (333 mg, 2.58 mmol, 449 μL, 3 eq), EDCI (247 mg, 1.29 mmol, 1.5 eq), HOBt (174 mg, 1.29 mmol, 1.5 eq), and 1-(tert-butyl) 2-methyl (2S,3S)-3-aminopyrrolidine-1,2- dicarboxylate (210 mg, 860 μmol, 1 eq) and the mixture was stirred at 20 °C for 1 hour. LCMS indicated that the reactant was completely consumed and the desired product was detected. The reaction was poured into water (40 mL) and extracted with EA (20 mL*3). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure to afford the crude. The crude was purified by column chromatography (SiO2, PE: EA=10: 1 to PE: EA=1: 4) to afford 1-(tert-butyl) 2- methyl (2S,3S)-3-(2-(1-((benzyloxy)carbonyl)piperidin-4-yl)acetamido)pyrrolidine-1,2-dicarboxylate (0.33 g, 609 μmol, 70.9 % yield, 93 % purity) as a yellow solid. LCMS: m / z [M+H]+= 504.2,1H NMR (400 MHz, CDCl3) δ = 7.40 - 7.33 (m, 5H), 5.66 (br d, J = 6.6 Hz, 1H), 5.13 (s, 2H), 4.56 (br d, J = 5.0 Hz, 1H), 4.28 - 4.14 (m, 2H), 3.75 (s, 3H), 3.68 - 3.50 (m, 2H), 2.86 - 2.73 (m, 2H), 2.28 - 2.20 (m, 1H), 2.13 - 2.07 (m, 2H), 2.05 - 1.98 (m, 1H), 1.89 - 1.78 (m, 1H), 1.72 (br d, J = 11.8 Hz, 2H), 1.48 - 1.39 (m, 9H), 1.18 - 1.05 (m, 2H).

[0251] Step 4: Preparation of benzyl 4-(2-(((2S,3S)-1-(tert-butoxycarbonyl)-2-carbamoylpyrrolidin-3- yl)amino)-2-oxoethyl)piperidine-1-carboxylate

[0252] To a mixture of 1-(tert-butyl) 2-methyl (2S,3S)-3-(2-(1-((benzyloxy)carbonyl)piperidin-4- yl)acetamido)pyrrolidine-1,2-dicarboxylate (0.66 g, 1.31 mmol, 1 eq) in MeOH (2 mL) was added NH3solution (7 M in MeOH, 10.0 mL, 53.4 eq) and the mixture was stirred at 100 °C for 12 hours. LCMS indicated 41% reactant remained and 34% desired product detected. The reaction mixture was concentrated under reduced pressure to afford the crude. The crude was purified by column chromatography (SiO2, PE: EA=1: 1 to DCM: MeOH=10: 1) to afford benzyl 4-[2-[[(2S,3S)-1-tert- butoxycarbonyl-2-carbamoyl-pyrrolidin-3-yl]amino]-2-oxo-ethyl]piperidine-1-carboxylate (200 mg, 307 μmol, 23.4 % yield, 75 % purity) as a yellow oil. LCMS: m / z [M+H]+= 489.2.

[0253] Step 5: Preparation of benzyl 4-(2-(((2S,3S)-2-carbamoylpyrrolidin-3-yl)amino)-2- oxoethyl)piperidine-1-carboxylate

[0254] benzyl 4-[2-[[(2S,3S)-1-tert-butoxycarbonyl-2-carbamoyl-pyrrolidin-3-yl]amino]-2-oxo- ethyl]piperidine-1-carboxylate (200 mg, 389 μmol, 1 eq) in HCl solution(2 M in dioxane, 4.22 mL, 21.7 eq) was stirred at 20 °C for 15 minutes. LCMS indicated that the starting material was consumed and the desired product was detected. The reaction was concentrated under reduced pressure to afford the crude. The crude was purified by Prep-HPLC (column: Phenomenex luna C18150*25 mm* 10 μm; mobile phase: [water (FA)-ACN]; gradient: 12 %-32 % B over 10 min) to afford benzyl 4-[2-[[(2S,3S)-2- carbamoylpyrrolidin-3-yl]amino]-2-oxo-ethyl]piperidine-1-carboxylate (50 mg, 118 μmol, 30.3 % yield, 100 % purity, HCl) as a white solid. LCMS: m / z [M+H]+= 777.3,1H NMR (400 MHz, CDCl3) δ = 7.40 - 7.28 (m, 5H), 5.12 (s, 2H), 4.63 - 4.13 (m, 4H), 3.59 - 3.41 (m, 1H), 2.93 - 2.67 (m, 2H), 2.11 - 1.96 (m, 5H), 1.71 (br d, J = 12.4 Hz, 2H), 1.54 - 1.37 (m, 9H), 1.21 - 1.05 (m, 2H).

[0255] Step 6: Preparation of N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4- yl)thiazol-2-yl)-1H-imidazole-1-carboxamide

[0256] The mixture of 4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-4-pyridyl]thiazol-2-amine (300 mg, 996 μmol, 1 eq) and CDI (242 mg, 1.49 mmol, 1.5 eq) in DCM (5 mL) was stirred at 40 °C for 12 hours. TLC (PE: EA=1: 1) indicated that the starting material was consumed (Rf=1) and a new spot was formed (Rf=0.5). The reaction was filtered directly to afford N-(4-methyl-5-(2-(1,1,1-trifluoro-2- methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)-1H-imidazole-1-carboxamide (230 mg, 582 μmol, 58.4 % yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ = 8.71 - 8.49 (m, 1H), 8.35 - 8.21 (m, 1H), 7.70 - 7.49 (m, 2H), 7.48 - 7.29 (m, 1H), 7.27 - 7.01 (m, 1H), 2.43 - 2.27 (m, 3H), 1.68 - 1.55 (m, 6H).

[0257] Step 7: Preparation of (2S,3S)-3-aminuteso-N1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan- 2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide

[0258] To a mixture of N-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2- yl)-1H-imidazole-1-carboxamide (61.4 mg, 155 μmol, 1.5 eq), benzyl 4-[2-[[(2S,3S)-2- carbamoylpyrrolidin-3-yl]amino]-2-oxo-ethyl]piperidine-1-carboxylate (45 mg, 104 μmol, 1 eq, FA) in DMF (2 mL) was added Et3N (31.4 mg, 311 μmol, 43.3μL, 3 eq) and the resulting mixture was stirred at 20 °C for 1 hour. LCMS indicated N-[4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-4- pyridyl]thiazol-2-yl]imidazole-1-carboxamide was consumed and the desired product was detected (75 % peak area). The mixture was purified by reversed phase HPLC (0.1 % Fa condition) to afford benzyl 4-[2- [[(2S,3S)-2-carbamoyl-1-[[4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-4-pyridyl]thiazol-2- yl]carbamoyl]pyrrolidin-3-yl]amino]-2-oxo-ethyl]piperidine-1-carboxylate (53 mg, 71.8 μmol, 69.4 % yield, 97 % purity) as white solid. LCMS: m / z [M+H]+= 717.2,1H NMR (400 MHz, CD3OD) δ = 8.55 (d, J = 5.4 Hz, 1H), 8.50 (s, 1H), 7.59 (s, 1H), 7.43 - 7.23 (m, 6H), 5.07 (br s, 2H), 4.46 - 4.43 (m, 1H), 4.17 - 4.05 (m, 2H), 3.82 - 3.67 (m, 2H), 3.39 - 3.33 (m, 1H), 2.91 - 2.70 (m, 2H), 2.41 (br s, 3H), 2.33 - 2.20 (m, 1H), 2.14 (br d, J = 7.2 Hz, 2H), 2.04 - 1.92 (m, 2H), 1.69 (br d, J = 10.8 Hz, 2H), 1.64 (s, 6H), 1.22 - 1.05 (m, 2H).

[0259] Step 8: Preparation of (2S,3S)-N1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4- yl)thiazol-2-yl)-3-(2-(piperidin-4-yl)acetamido)pyrrolidine-1,2-dicarboxamide

[0260] The mixture of benzyl 4-[2-[[(2S,3S)-2-carbamoyl-1-[[4-methyl-5-[2-(2,2,2-trifluoro-1,1- dimethyl-ethyl)-4-pyridyl]thiazol-2-yl]carbamoyl]pyrrolidin-3-yl]amino]-2-oxo-ethyl]piperidine-1- carboxylate (50 mg, 67.7 μmol, 1 eq) in HBr (1.49 g, 6.08 mmol, 1 mL, 33 % purity in AcOH, 89.7 eq), and DCM (1 mL) was stirred at 20 °C for 1 hour. LCMS indicated that the reactant was consumed and the desired product was detected (100 % peak area). The reaction was concentrated under reduced pressure to afford (2S,3S)-N1-[4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-4-pyridyl]thiazol-2-yl]-3-[[2-(4- piperidyl)acetyl]amino]pyrrolidine-1,2-dicarboxamide (54 mg, crude, HBr) as a yellow oil. LCMS: m / z [M+H]+= 582.2.1H NMR (400 MHz, DMSO-d6) δ = 5.82 (s, 1H), 3.45 (s, 3H), 3.31 - 3.24 (m, 4H), 2.07 (br t, J = 6.2 Hz, 2H), 1.96 - 1.86 (m, 2H), 1.38 (s, 9H), 1.37 - 1.25 (m, 8H).

[0261] Preparation of 3-(benzyloxy)-6-(4,5-dihydro-1H-imidazol-2-yl)-2-methoxyaniline, Int 3

[0262] Step 1: Preparation of 4-(benzyloxy)-3-methoxy-2-nitrobenzaldehyde

[0263] To a solution of 4-hydroxy-3-methoxy-2-nitro-benzaldehyde (15 g, 76.1 mmol, 1 eq) in DMF (150 mL) was added K2CO3(21.0 g, 152 mmol, 2 eq) and BnBr (15.6 g, 91.3 mmol, 10.8 mL, 1.2 eq). The mixture was stirred at 25 °C for 1 hour. LCMS indicated that the starting material was consumed completely and formation of desired mass (91.1 % peak area). TLC (PE: EA=4: 1) indicated 4-hydroxy-3- methoxy-2-nitro-benzaldehyde was consumed completely and two new spots formed. The reaction mixture was quenched with addition saturated NH4Cl (300 mL) at 0 °C, and then diluted with EA 20 mL and extracted with EA (200 mL *2). The combined organic layers were washed with water (200 mL *2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with solvent (PE=50 mL) at 25 °C for 10 minutes. The solid was filtered and concentrated under reduced pressure to afford 4-(benzyloxy)-3-methoxy-2-nitrobenzaldehyde (20.6 g, 71.4 mmol, 93.9 % yield, 99.6 % purity) as a yellow solid. LCMS: m / z [M+= 288.1,1H NMR (400 MHz, DMSO-d6) δ = 9.80 (s, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.55 - 7.49 (m, 2H), 7.46 - 7.36 (m, 3H), 5.37 (s, 2H), 3.85 (s, 3H)

[0264] Step 2: Preparation of 2-(4-(benzyloxy)-3-methoxy-2-nitrophenyl)-4,5-dihydro-1H-imidazole

[0265] To a solution of 4-(benzyloxy)-3-methoxy-2-nitrobenzaldehyde (20.6 g, 71.4 mmol, 1 eq) in MeOH (200 mL) was added ethane-1,2-diamine (6.63 g, 110 mmol, 7.38 mL, 1.54 eq). The mixture was stirred at 25 °C for 1 hour. Then NBS (16.7 g, 93.8 mmol, 1.31 eq) in ACN (160 mL) was added to the mixture at 0 °C and the mixture was stirred at 0 °C for 1.5 hours. The reaction mixture was stirred at 25 °C for another hour. LCMS indicated complete consumption of 4-(benzyloxy)-3-methoxy-2- nitrobenzaldehyde and formation of desired mass (95.3 % peak area). The reaction was quenched with a solution of 21.5 g NaHCO3and 5.5 g Na2SO3in 250 mL water. After 10 minutes, 600 mL water was added. The mixture was filtered, washed with 200 mL water and dried at 40 °C under reduced pressure to afford 2-(4-(benzyloxy)-3-methoxy-2-nitrophenyl)-4,5-dihydro-1H-imidazole (21 g, 64.2 mmol, 89.8 % yield) as a white solid. LCMS: m / z [M+H]+= 328.1,1δ = 7.53 - 7.46 (m, 3H), 7.45 - 7.33 (m, 4H), 6.89 (s, 1H), 5.29 (s, 2H), 3.82 (s, 3H), 3.75-3.67 (m, 2H), 3.33 - 3.27 (m, 2H)

[0266] Step 3: Preparation of 3-(benzyloxy)-6-(4,5-dihydro-1H-imidazol-2-yl)-2-methoxyaniline

[0267] To a solution of 2-(4-benzyloxy-3-methoxy-2-nitro-phenyl)-4,5-dihydro-1H-imidazole (8 g, 24.4 mmol, 1 eq) in THF (75 mL) and H2O (15 mL) was added NH4Cl (13.1 g, 244 mmol, 10 eq) and zinc;copper (31.5 g, 244 mmol, 10 eq) at 0 °C. The mixture was stirred at 25 °C for 20 minutes. LCMS indicated complete consumption of 2-(4-benzyloxy-3-methoxy-2-nitro-phenyl)-4,5-dihydro-1H-imidazole and formation of product with the desired mass (70.1 % peak area). The reaction mixture was filtered andconcentrated under reduced pressure to give a residue. The reaction mixture was partitioned between EA (10 mL) and H2O (100 mL). The organic phase was separated, washed with brine (50 mL *2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex luna C18 (250*70 mm,10 μm); mobile phase: [water (FA)-ACN]; gradient:13 %-43 % B over 17 min) to afford 3-(benzyloxy)-6-(4,5-dihydro- 1H-imidazol-2-yl)-2-methoxyaniline (5.9 g, 19.8 mmol, 81.2 % yield) as a white solid. LCMS: m / z [M+H]+= 298.1,1H NMR (400 MHz, DMSO-d6) δ = 7.50 - 7.45 (m, 2H), 7.43 - 7.38 (m, 2H), 7.34 (d, J = 7.2 Hz, 1H), 7.16 (d, J = 8.8 Hz, 1H), 6.47 (br d, J = 8.8 Hz, 1H), 5.15 (s, 2H), 3.70 (s, 3H), 3.63 - 3.58 (m, 4H).

[0268] Preparation of 2-amino-N-(7-methoxy-8-(3-(4-(piperidin-4-ylmethyl)piperazin-1-yl)propoxy)- 2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide, Int 4

[0269] Step 1: Preparation of 8-(benzyloxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine

[0270] To a solution of 3-benzyloxy-6-(4,5-dihydro-1H-imidazol-2-yl)-2-methoxy-aniline (12.8 g, 43.1 mmol, 1 eq) in ACN (140 mL) was added TEA (5.66 g, 56.0 mmol, 7.79 mL, 1.3 eq), CNBr (6.2 g, 58.5 mmol, 4.30 mL, 1.36 eq) in ACN (210 mL) dropwise for 1 hour at 0 °C. Then the mixture was stirred at 20 °C for 1 hour. LCMS indicated 10% of 3-benzyloxy-6-(4,5-dihydro-1H-imidazol-2-yl)-2-methoxy- aniline remained and 58.6% of desired product detected. The reaction was concentrated under reduced pressure to afford the crude. The crude product was purified by reverse-phase chromatography (0.1 % NH3•H2O) to afford 8-benzyloxy-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (4.8 g, 14.2 mmol, 32.9 % yield, 95 % purity) as a yellow solid. LCMS: m / z [M+H]+= 323.2,1H NMR (400 MHz, DMSO-d6) δ = 7.48 - 7.31 (m, 6H), 6.79 (d, J = 8.8 Hz, 1H), 6.67 (br s, 2H), 5.14 (s, 2H), 3.97 - 3.82 (m, 4H), 3.72 (s, 3H).

[0271] Step 2: Preparation of 5-amino-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-ol

[0272] To a mixture of Pd / C (400 mg, 10 % purity) in DMF (40 mL) was added 8-benzyloxy-7- methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (4 g, 12.4 mmol, 1 eq) and the reaction mixture was stirred at 60 °C for 12 hours under H2atmosphere (50 PSI). LCMS indicated that 11% of 8- benzyloxy-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine was remained and 81% of desired product was detected. The reaction was filtered, concentrated under reduced pressure to afford 5-amino-7- methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-ol (3.2 g, crude) as a white solid. LCMS: m / z [M+H]+= 232.1,1H NMR (400 MHz, DMSO-d6) δ = 7.95 (s, 1H), 7.33 (d, J = 8.6 Hz, 2H), 6.51 (d, J = 8.6 Hz, 2H), 3.89 (s, 2H), 3.72 (s, 2H), 3.17 (s, 3H)

[0273] Step 3: Preparation of tert-butyl 4-(3-((5-(2-aminopyrimidine-5-carboxamido)-7-methoxy-2,3- dihydroimidazo[1,2-c]quinazolin-8-yl)oxy)propyl)piperazine-1-carboxylate

[0274] To a mixture of 5-amino-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-ol (1.55 g, 6.66 mmol, 1 eq) and tert-butyl 4-(3-chloropropyl)piperazine-1-carboxylate (1.75 g, 6.66 mmol, 1 eq) in butan- 1-ol (12 mL), DMF (12 mL), H2O (12 mL) was added K2CO3(2.76 g, 20.0 mmol, 3.00 eq), and the reaction mixture was stirred at 90 °C for 5 hours. LCMS indicated complete consumption of tert-butyl 4- (3-chloropropyl)piperazine-1-carboxylate and formation of the desired product. The mixture was acidified with HCl (1 M) to pH=7. The mixture was purified by reverse-phase chromatography (0.1 % FA condition) to afford tert-butyl 4-(3-((5-amino-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8- yl)oxy)propyl)piperazine-1-carboxylate (0.7 g, 1.53 mmol, 23.0 % yield, 100 % purity) as a white solid. LCMS: m / z [M+H]+= 459.3.

[0275] Step 4: Preparation of 2-amino-N-(7-methoxy-8-(3-(piperazin-1-yl)propoxy)-2,3- dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide

[0276] To a mixture of tert-butyl 4-[3-[(5-amino-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8- yl)oxy]propyl]piperazine-1-carboxylate (550 mg, 1.20 mmol, 1 eq), 2-aminopyrimidine-5-carboxylic acid (184 mg, 1.32 mmol, 1.1 eq) in DMF (10 mL) was added EDCI (460 mg, 2.40 mmol, 2 eq), Et3N (728 mg, 7.20 mmol, 1.00 mL, 6 eq), HOBt (324 mg, 2.40 mmol, 2 eq) and stirred at 20 °C for 1 hour. LCMS indicated that the reactant was consumed and the 96% of desired product was detected. The reaction was poured into water (100 mL), filtered to afford tert-butyl 4-[3-[[5-[(2-aminopyrimidine-5-carbonyl)amino]- 7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-yl]oxy]propyl]piperazine-1-carboxylate (390 mg, 646 μmol, 53.9 % yield, 96 % purity) as a yellow solid. LCMS: m / z [M+H]+= 580.4.

[0277] Step 5: Preparation of 2-amino-N-(7-methoxy-8-(3-(4-(piperidin-4-ylmethyl)piperazin-1- yl)propoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide

[0278] A mixture of tert-butyl 4-[3-[[5-[(2-aminopyrimidine-5-carbonyl)amino]-7-methoxy-2,3- dihydroimidazo[1,2-c]quinazolin-8-yl]oxy]propyl]piperazine-1-carboxylate (330 mg, 547 μmol, 1 eq) in HCl solution (2 M in dioxane, 10 mL, 36.6 eq) was stirred for 15 minutes at 20 °C. LCMS indicated complete consumption of the reactant and formation of desired product (91 % peak area). The reaction mixture was concentrated under reduced pressure to afford 2-amino-N-[7-methoxy-8-(3-piperazin-1- ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide (280 mg, 543 μmol, 99.3 % yield, HCl) as a white solid. LCMS: m / z [M+H]+= 677.4,1H NMR (400 MHz, DMSO-d6) δ = 13.58 - 13.33 (m, 1H), 9.84 - 9.54 (m, 2H), 8.98 (s, 2H), 8.28 (d, J = 9.2 Hz, 1H), 7.77 - 7.49 (m, 2H), 7.42 (d, J = 9.4 Hz, 1H), 4.56 - 4.46 (m, 2H), 4.39 (br t, J = 5.8 Hz, 2H), 4.23 - 4.15 (m, 2H), 4.01 (s, 3H), 3.33 (br d, J = 8.0 Hz, 10H), 2.33 (br t, J = 7.0 Hz, 2H).

[0279] Preparation of (5-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-(2,2,2- trifluoroethyl)-1H-1,2,4-triazol-3-yl)methanol, Int 5; preparation of benzyl ((5-(9-bromo-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3- yl)methyl)carbamate, Int 6

[0280] Step 1: preparation of 9-bromo-2-(3-(methoxymethyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

[0281] To a solution of 9-bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (2.00 g, 5.12 mmol, 1.00 eq) and 2-methoxyacetimidamide (828 mg, 6.65 mmol, 1.30 eq) in DMF (30 mL) was added Pd(OAc)2 (115 mg, 512 μmol, 0.1 eq), Xantphos (296 mg, 512 μmol, 0.1 eq) and TEA (2.59 g, 25.6 mmol, 3.56 mL, 5.00 eq). The resulting mixture was stirred at 60 °C under CO (50 psi) for 1.3 hours. The reaction solution was cooled to 20 °C, then (2,2,2-trifluoroethyl)hydrazine (992 mg, 8.70 mmol, 1.70 eq) and AcOH (34.8 g, 580 mmol, 33.2 mL, 113 eq) were added. This mixture was stirred at 60 °C foranother 1.5 hours. LCMS indicated complete consumption of starting material and formation of desired product (35.0% peak area). The reaction solution was poured into water (50 mL), then extracted with EA (30 mL * 3). The organic layers were combined and washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified with silica gel column (PE / EA = 10 / 1, 0 / 1) to afford 9-bromo-2-(3-(methoxymethyl)-1-(2,2,2- trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine as a light yellow solid. LCMS: m / z [M+H]+= 458.0.

[0282] Step 2: preparation of (5-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1- (2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methanol and 9-bromo-2-(3-(bromomethyl)-1-(2,2,2- trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

[0283] A solution of 9-bromo-2-[5-(methoxymethyl)-2-(2,2,2-trifluoroethyl)-1,2,4-triazol-3-yl]-5,6- dihydroimidazo[1,2-d][1,4]benzoxazepine (800 mg, 1.75 mmol, 1 eq) in HBr (10 mL, 40% in water) was stirred at 100 °C for 24 hour. LCMS indicated complete consumption of starting material and formation of (5-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4- triazol-3-yl)methanol (44.7% peak area) and 9-bromo-2-(3-(bromomethyl)-1-(2,2,2-trifluoroethyl)-1H- 1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (51.9% peak area). The reaction solution was diluted with water (20 mL), then the pH was adjusted to 8 with NaOH (4 M). The mixture was extracted with DCM (20 mL * 3). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (DCM / MeOH=1 / 0, 10 / 1) to afford (5-(9-bromo-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methanol (300 mg, 670 μmol, 38.4% yield, 99.2% purity) as a white solid and 9-bromo-2-(3-(bromomethyl)-1- (2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (450 mg, 882 μmol, 50.5% yield, 99.4% purity) as a white solid. LCMS1: m / z [M+H]+= 444.0; LCMS2: m / z [M+H]+= 508.0.

[0284] Step 3: preparation of (5-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1- (2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methanamine

[0285] To a solution of 9-bromo-2-(3-(bromomethyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (450 mg, 887 μmol, 1 eq) in i-PrOH (5 mL) was added concentrated NH3∙H2O (5 mL). The resulting mixture was stirred at 80 °C for 1 hour. LCMS indicated complete consumption of the starting material and formation of the desired product (86.8% peak area). The reaction solution was concentrated under reduced pressure to afford (5-(9-bromo-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methanamine (394 mg, crude) as a white solid which used to the next step without purification. LCMS: m / z [M+H]+= 445.1.

[0286] Step 4: preparation of benzyl ((5-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2- yl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)carbamate

[0287] To a solution of (5-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-(2,2,2- trifluoroethyl)-1H-1,2,4-triazol-3-yl)methanamine (393 mg, 887 μmol, 1 eq) and DIEA (344 mg, 2.66 mmol, 463 μL, 3 eq) in DCM (10 mL) was added CbzCl (227 mg, 1.33 mmol, 190 μL, 1.5 eq) under nitrogen atmosphere at 0 °C. The resulting mixture was stirred at 20 °C for 0.5 hour. LCMS indicated complete consumption of the starting material and formation of the desired product (78.1% peak area). The reaction solution was concentrated under vacuum to give a residue. The residue was purified by column chromatography (PE:EA=10 / 0, 0 / 1) to afford benzyl ((5-(9-bromo-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3- yl)methyl)carbamate (500 mg, 833 μmol, 94% yield, 96.2% purity) as a white solid. LCMS: m / z [M+H]+= 579.1;1H NMR: (400 MHz, DMSO-d6) δ = 8.29 (d, J = 8.7 Hz, 1H), 8.08 (s, 1H), 7.81 (br t, J = 5.8 Hz, 1H), 7.41 - 7.21 (m, 7H), 5.89 - 5.74 (m, 2H), 5.18 - 5.16 (m, 1H), 5.05 (s, 2H), 4.54 (s, 4H), 4.27 (d, J = 6.1 Hz, 2H).

[0288] Preparation of (2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)-L-alanine, Int 7

[0289] Step 1: preparation of 9-bromo-2, 3-diiodo-5, 6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

[0290] for 16 hours. LCMS indicated complete consumption of starting material To a solution of 9- bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (2 g, 7.54 mmol, 1 eq) in DMF (25 mL) was added NIS (5.09 g, 22.6 mmol, 3 eq). The mixture was stirred at 60 °C. LCMS indicated formation of desired product (74.5% peak area). The reaction mixture was poured into water (60 mL) and a solid precipitated. After filtration, the solid was collected and dissolved in ethyl acetate (230 mL). Theresulting solution was washed with 1 M aqueous NaOH solution (200 mL * 2) and brine (100 mL), dried over anhydrous Na2S04and filtered. The filtrate was concentrated under reduced pressure to give 9- bromo-2, 3-diiodo-5, 6-dihydrobenzo[f] imidazo [1, 2-d] [1, 4] oxazepine (3.7 g, 6.81 mmol, 90.3% yield, 95.2% purity) as an orange solid. LCMS: m / z [M+H]+= 516.9.

[0291] Step 2: preparation of 9-bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

[0292] To a solution of 9-bromo-2, 3-diiodo-5, 6-dihydrobenzo[f]imidazo [1, 2-d] [1, 4] oxazepine (4 g, 7.74 mmol, 1 eq) in THF (45 mL) was added EtMgBr (3 M, 3.10 mL, 1.2 eq) at 0 °C. The mixture was stirred at 10 °C for 2 hours at N2atmosphere. LCMS indicated complete consumption of the starting material and formation of the desired product (86.6% peak area).

[0293] The reaction mixture was quenched by addition aqueous NH4Cl (70 mL) at 0 °C and the mixture was extracted with EA (60 mL * 3). The combined organic layers were washed with brine (100 mL * 1) and dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude residue. The residue was purified by column chromatography (SiO2, PE: EA = 1: 100 to 5: 1, Rf=0.18) to afford 9- bromo-2-iodo-5, 6-dihydrobenzo[f]imidazo [1, 2-d] [1, 4] oxazepine (2.98 g, 7.54 mmol, 86.2% yield, 98.9% purity) as a pink solid. LCMS: m / z [M+H]+= 390.9.

[0294] Step 3: preparation of (S)-3-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4- (difluoromethyl)oxazolidin-2-one

[0295] To a solution of 9-bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (172 mg, 441 μmol, 1.1 eq), (S)-4-(difluoromethyl)oxazolidin-2-one (55 mg, 401 μmol, 1 eq) in dioxane (4.5 mL) was added Cu(OAc)2(29.1 mg, 160 μmol, 0.4 eq), Cs2CO3(261 mg, 802 μmol, 2 eq) and (1R,2R)-N1,N2- dimethylcyclohexane-1,2-diamine (34.2 mg, 240 μmol, 0.6 eq). The mixture was stirred at 80 °C under N2for 4 hours. LCMS indicated complete consumption of the starting material and detection of a peak with desired mass (82.3% peak area). The residue was purified by prep-TLC and prep-HPLCcolumn: Welch Xtimate C 18150 * 25 mm * 5 μm; mobile phase: [water (FA)-ACN]; gradient: 54%-74% B over 10 min and lyophilized to afford (S)-3-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)- 4-(difluoromethyl)oxazolidin-2-one (300 mg, 750 μmol, 37.3% yield) as a white solid. LCMS: m / z [M+H]+= 400.1.

[0296] Step 4: preparation of (2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-L-alanine

[0297] To a solution of L-alanine (75.1 mg, 843 μmol, 3.07 eq) and (S)-3-(9-bromo-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-(difluoromethyl)oxazolidin-2-one (110 mg, 274 μmol, 1 eq) in DMSO (3 mL) was added K3PO4(176 mg, 832 μmol, 3.03 eq) and Cu2O (7.87 mg, 54.9μmol, 0.2 eq). The mixture was stirred at 95 °C for 12 hours under N2atmosphere. LCMS indicated complete consumption of (S)-3-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4- (difluoromethyl)oxazolidin-2-one and formation of desired product (91.6% peak area). The reaction mixture was filtered. The filtrate was purified by reversed-phase flash(0.1% HCl) and lyophilized to afford (2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)-L-alanine (40 mg, 86.7 μmol, 24.2% yield, 88.6% purity) as a violet solid. LCMS: m / z [M+H]+= 409.2. Example 1: Preparation of (2S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)acetamide (Compound 1)

[0298] Step 1: Preparation of (S)-3-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4- (difluoromethyl)oxazolidin-2-one

[0299] The mixture of 9-bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (5.3 g, 13.5 mmol), (S)-4-(difluoromethyl)oxazolidin-2-one (2.0 g, 15.2 mmol), (1R,2R)-N1,N2- dimethylcyclohexane-1,2-diamine (0.6 g, 4.0 mmol), Cs2CO3 (4.9 g, 27.1 mmol) and Cu(OAc)2 (0.9 g, 2.7mmol) in 2- Methyltetrahydrofuran (50 mL) was stirred at 78 ℃ for 48 hours. The reaction was quenched with 20 wt. % NaHSO4aqueous solution and extracted with EA. The organic phase was washed with brine and dried over Na2SO4. The solution was concentrated in vacuum and the residue was purified by flash chromatography on silica gel eluting with PE:EA = 5:1 to afford the desired compound (4.3 g, 79.6 % yield). LC / MS: 400.0 [M+H]+.

[0300] Step 2: Preparation of (S)-2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-((2-((S)-4-(difluorometh yl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)acetic acid

[0301] To a solution of (S)-3-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4- (difluoromethyl)oxazolidin-2-one (1.0 g, 2.5 mmol), (S)-2-amino-2-(1-(tert-butoxycarbon yl)piperidin-4- yl)acetic acid (1.9 g, 7.5 mmol) and K3PO4(1.6 g, 7.5 mmol) in DMSO (6 mL) was added Cu2O (0.07 g, 0.5 mmol). The mixture was stirred at 95 ℃ for 16 hours. The solution was concentrated in vacuum and the residue was purified by Prep-MPLC eluting with H2O / ACN = 4 / 1 to afford the desired compound (0.93 g, 64.3 % yield). LC / MS: 578.0 [M+H]+.

[0302] Step 3: Preparation of tert-butyl 4-((S)-2-amino-1-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3- yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-oxoethyl)piperidine-1-carboxylate

[0303] To a solution of (S)-2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-((2-((S)-4-(difluoromethyl)-2- oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)acetic acid (900 mg, 1.56 mmol) in THF (10 mL) stirred at room temperature was added HOSu (197 mg, 1.71 mmol), EDCI (596 mg, 3.11 mmol) and NH3 in THF (7.8 mL, 3.11 mmol, 0.4 mol / L). The mixture was stirred at room temperature for 4 hours. The reaction was quenched with H2O and extracted with DCM. The organic phase was washed with brine and dried over Na2SO4. The solution was concentrated in vacuum and the residue was purified by flash chromatography on silica gel eluting with DCM:MeOH = 10:1 to afford the desired compound (600 mg, 63.4 % yield). LC / MS: 577.1 [M+H]+.

[0304] Step 4: Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo [f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-(piperidin-4-yl)acetamide

[0305] To a solution of tert-butyl 4-((S)-2-amino-1-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)- 5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-oxoethyl)piperidine-1-carboxy late (60 mg, 0.1 mmol) in DCM (3 mL) was added TFA (1 mL). The reaction was stirred at room temperature for 1 hour. The mixture was concentrated in vacuum to give the title compound (50 mg, TFA salt, 85 % purity, 85.7 % yield) as a white solid. LC / MS: 477.1 [M+H]+.

[0306] Step 5: Preparation of 3-(5-(4-(dimethoxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)pi peridine-2,6-dione

[0307] A mixture of 3-(5-bromo-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (1.2 g, 4 mmol), 4- (dimethoxymethyl)piperidine (0.88 g, 5 mmol), Cs2CO3(3.62 g, 11 mmol) and Pd-PEPPSI-IPentCl (0.18 g, 000.1mmol) in dioxane (20 mL) was stirred at 100 ℃ for 2 hours under nitrogen. The reaction was quenched with water and extracted with EA. The organic phase was washed with brine, dried over Na2SO4,and concentrated in vacuum. The residue was purified by flash column chromatography with DCM / MeOH = 10 / 1 to afford the desired compound (540 mg, 95 % purity, 35.1 % yield) as a white solid. LC / MS: 402.2 [M+H]+.

[0308] Step 6: Preparation of 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-4- carbaldehyde

[0309] A solution of 3-{5-[4-(dimethoxymethyl)piperidin-1-yl]-1-oxo-3H-isoindol-2-yl}piperidine-2,6- dione (400 mg, 0.99 mmol) in DCM / TFA (4mL, 3 / 1) was stirred at 45 ℃ for 1 hour. The mixture was concentrated in vacuum to afford the desired compound (500 mg TFA salt, crude) as yellow oil which was used in the next step without further purification. LC / MS: 356.2 [M+H]+.

[0310] Step 7: Preparation of (2S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydroben zo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoin dolin-5- yl)piperidin-4-yl)methyl)piperidin-4-yl)acetamide

[0311] To a solution of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imi dazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-(piperidin-4-yl)acetamide (60 mg, 0.13 mmol) in DCM (3 mL) stirred at room temperature was added 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-4- carbaldehyde (67 mg, crude) and TEA (38 mg, 0.38 mmol). The mixture was stirred at room temperature for 0.5 hours. STAB (53 mg, 0.25 mmol) was added. The mixture was stirred at room temperature for 3 hours. The reaction was quenched with H2O and extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous Na2SO4,and concentrated in vacuum. The residue was purified by Prep-HPLC (Gemini-C18:150 x 21.2 mm, 5 μm. ACN-H2O (0.1 % FA, 10-40 %) to give the desired product (42 mg, 38 % yield) as a white solid. LC / MS: 816.2 [M+H]+.1H NMR (400 MHz, DMSO) δ 10.93 (s, 1H), 8.13 (s, 1H), 7.98 (d, J = 8.9 Hz, 1H), 7.50 (d, J = 8.9 Hz, 1H), 7.46 (s, 1H), 7.17 (s, 1H), 7.10 (s, 1H), 7.06 - 7.01 (m, 2H), 6.48 (d, J = 9.0 Hz, 1H), 6.19 (d, J = 1.8 Hz, 1H), 6.06 (d, J = 8.0 Hz, 1H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 5.00 - 4.90 (m, 1H), 4.61 - 4.52 (m, 2H), 4.37 - 4.29 (m, 5H), 4.22 - 4.16 (m, 1H), 3.91 - 3.82 (m, 2H), 3.62 - 3.56 (m, 1H), 3.06 - 2.92 (m, 2H), 2.91 - 2.77 (m, 3H), 2.62 - 2.52 (m, 3H), 2.42 - 2.34 (m, 1H), 2.30 - 2.21 (m, 1H), 2.00 - 1.90 (m, 2H), 1.86 - 1.74 (m, 4H), 1.70 - 1.57 (m, 2H), 1.50 - 1.31 (m, 2H), 1.22 - 1.11 (m, 2H).Example 2: Preparation of (2S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)pi peridin-4-yl)methyl)piperidin-4-yl)propanamide (Compound 2)

[0312] Step 1: Preparation of (S)-3-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-((2-((S)-4-(difluoro methyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino) propanoic acid

[0313] To a solution of (S)-3-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4- (difluoromethyl)oxazolidin-2-one (140 mg, 0.35 mmol), (S)-2-amino-3-(1-(tert-butoxycarbon yl)piperidin-4-yl)propanoic acid (287 mg, 1.05 mmol) and K3PO4(223 mg, 1.05 mmol) in DMSO (3 mL) was added Cu2O (15 mg, 0.11 mmol). The mixture was stirred at 95 ℃ for 16 hours. The solution was concentrated in vacuum and the residue was purified by Prep-MPLC eluting with H2O:ACN = 1:1 to afford the desired compound (110 mg, 53 % yield) as a yellow solid. LC / MS: 592.1 [M+H]+.

[0314] Step 2: Preparation of tert-butyl 4-((S)-3-amino-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3- yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-oxopropyl)piperidine-1-carboxylate

[0315] To a solution of (S)-3-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-((2-((S)-4-(difluoromethyl)-2- oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propanoic acid (90 mg, 0.15 mmol) in THF (3 mL) stirred at room temperature was added HOSu (19 mg, 0.17 mmol), EDCI (58 mg, 0.31 mmol) and NH3-THF (0.8 mL, 0.31 mmol, 0.4 mmol / L). The mixture was stirred at room temperature for 4 hours. The reaction was quenched with H2O and extracted with DCM. The organic phase was washed with brine and dried over Na2SO4. The solution was concentrated in vacuum and the residue was purified by flash chromatography on silica gel eluting with DCM:MeOH = 10:1 to afford the desired compound (59 mg, 65.9 % yield) as a white solid. LC / MS: 591.2 [M+H]+.

[0316] Step 3: Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo [f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-(piperidin-4-yl)propanamide

[0317] To a solution of tert-butyl 4-((S)-3-amino-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)- 5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-oxopropyl)piperidine-1-carboxy late (70 mg, 0.12 mmol) in DCM (3 mL) was added TFA (1 mL). The reaction was stirred at room temperature for 1 hour. The mixture was concentrated in vacuum to give the title compound which was used in the next step without further purification (60 mg TFA salt, 82.8 % yield).

[0318] Step 4: Preparation of (2S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydroben zo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoiso indolin-5- yl)piperidin-4-yl)methyl)piperidin-4-yl)propenamide

[0319] To a solution of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f] imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-(piperidin-4-yl)propanamide (28 mg, 0.06 mmol) in DCM (2 mL) stirred at room temperature was added 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoiso indolin-5- yl)piperidine-4-carbaldehyde (24 mg, 0.07 mmol) and TEA (29 mg, 0.29 mmol). The mixture was stirred at room temperature for 0.5 hours. STAB (24 mg, 0.11 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction was quenched with H2O and extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous Na2SO4,and concentrated in vacuum. The residue was purified by Prep-HPLC (Gemini-C18:150 x 21.2 mm, 5 μm. ACN-H2O (0.1 % FA, 10-30 %) to give the desired product (20 mg, 40 % yield). LC / MS: 830.2 [M+H]+.1H NMR (400 MHz, DMSO) δ 10.93 (s, 1H), 8.16 (s, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.49 (d, J = 8.9 Hz, 1H), 7.41 (s, 1H), 7.17 (s, 1H), 7.04 - 6.99 (m, 3H), 6.43 (dd, J = 8.9, 2.2 Hz, 1H), 6.17 - 6.07 (m, 2H), 5.08 - 5.01 (m, 1H), 5.00 - 4.89 (m, 1H), 4.63 - 4.52 (m, 2H), 4.37 - 4.29 (m, 5H), 4.23 - 4.17 (m, 1H), 3.85 (d, J = 12.2 Hz, 2H), 3.79 - 3.73 (m, 1H), 2.95 - 2.86 (m, 1H), 2.83 - 2.80 (m, 2H), 2.58 (d, J = 17.1 Hz, 1H), 2.41 - 2.34 (m, 1H), 2.16 - 2.08 (m, 2H), 2.02 - 1.89 (m, 2H), 1.88 - 1.79 (m, 2H), 1.78 - 1.69 (m, 4H), 1.65 - 1.53 (m, 4H), 1.45 - 1.38 (m, 1H), 1.26 - 1.09 (m, 5H). Example 3: Preparation of (2S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-((1-((3-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperidin-4-yl)amino)propanamide (Compound 3)

[0320] Step 1: Preparation of (S)-3-((tert-butoxycarbonyl)amino)-2-((2-((S)-4-(difluoromethyl)-2-oxo oxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propanoic acid

[0321] To a solution of (S)-3-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-(difluo romethyl)oxazolidin-2-one (150 mg, 0.37 mmol) in DMSO (5 mL) was added (S)-2-amino-3-((tert- butoxycarbonyl)amino)propanoic acid (383 mg, 1.87 mmol), Cu2O (268 mg, 1.87 mmol) and K3PO4(398 mg, 1.87 mmol). The mixture was stirred at 95 ℃ for 16 hours under argon atmosphere. The solution was filtrated and the residue was purified by Prep-HPLC (ACN-H2O: 15-60%) to give the desired product (120 mg, 60 % purity in 214 nm, 37.2 % yield) as a white solid. LC / MS: 524.1 [M+H]+.

[0322] Step 2: Preparation of tert-butyl ((S)-3-amino-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3- yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-oxopropyl)carbamate

[0323] To a solution of (S)-3-((tert-butoxycarbonyl)amino)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazo lidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propanoic acid (145 mg, 0.16 mmol, purity = 60%) in THF (5 mL) was added HOSU (48 mg, 0.41 mmol). The mixture was stirredunder nitrogen at 25 ℃ for 0.5 hours. EDCI (106 mg, 0.55 mmol) and NH3-THF (1 mL, 1.5eq, 0.4 M) were added. The final mixture was stirred at 25 ℃ for 16 hours. The reaction was quenched with water and extracted with EA. The solution was concentrated in vacuum and the residue was purified by TLC with DCM:MeOH = 15:1 to afford the desired compound (60 mg, 71.8% yield) as a white solid. LC / MS: 523.2 [M+H]+.

[0324] Step 3: Preparation of (S)-3-amino-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propanamide

[0325] A solution of tert-butyl ((S)-3-amino-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-oxopropyl)carbamate (90 mg, 0.17 mmol) in HCl-dioxane (4 N, 2 mL) and DCM (2 mL) was stirred at 25 ℃ for 1 hour. The solution was concentrated in vacuum to afford the desired compound which was used in the next step without further purification (90 mg, HCl salt, 98.2% yield) as a white solid. LC / MS: 423.1 [M+H]+.

[0326] Step 4: Preparation of tert-butyl 4-(((S)-3-amino-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin- 3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-oxopropyl)amino)piperidine-1- carboxylate

[0327] To a solution of (S)-3-amino-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydro benzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propanamide (90 mg, HCl salt, 0.21 mmol) in DMA (5 mL) was added tert-butyl 4-oxopiperidine-1-carboxylate (127 mg, 0.63 mmol) and DIEA (275 mg, 2.13 mmol). The reaction was stirred under nitrogen at 45 ℃ for 0.5 hours. STAB (135 mg, 0.63 mmol) was added. The final mixture was stirred at 45 ℃ for 4 hours. The solution was concentrated in vacuum and the residue was purified by TLC with DCM: MeOH = 15: 1 to afford the desired compound (60 mg, 46.5 % yield) as a white solid. LC / MS: 606.3 [M+H]+.

[0328] Step 5: Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo [f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-(piperidin-4-ylamino)propanamide

[0329] A solution of tert-butyl 4-(((S)-3-amino-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-oxopropyl)amino)piperidine-1-carboxylate (50 mg, 0.08 mmol) in HCl-dioxane (4 M, 2 mL) and DCM (2 mL) was stirred 25 ℃ for 1 hour. The solution was concentrated in vacuum to afford the desired compound which was used in the next step without further purification (50 mg, HCl salt, 94.4 % yield) as a white solid. LC / MS: 506.1 [M+H]+.

[0330] Step 6: Preparation of (2S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydro benzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-((1-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin- 5-yl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperidin-4-yl)amino)propanamide

[0331] To a solution of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f] imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-(piperidin-4-ylamino)propanamide (50 mg, 0.09 mmol) in DMA (5 mL) was added 3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-aza spiro[5.5]undecane- 9-carbaldehyde (39 mg, 0.09 mmol) and TEA (93 mg, 0.92 mmol). The mixture was stirred under nitrogen at 25 ℃ for 1 hour. STAB (59 mg, 0.27 mmol) was added. The reaction mixture was stirred at 25 ℃ for 3 hours. The mixture was concentrated in vacuum and the residue was purified by Prep-HPLC (Gemini-C18:150 x 21.2 mm, 5 μm. ACN-H2O (0.1% FA) 10-23%) to give the desired product (15.4 mg, 92.8 % purity in 214 nm, 15.3 % yield) as a white solid. LC / MS: 913.4 [M+H]+.1H NMR (400 MHz, DMSO) δ 10.93 (s, 1H), 8.23 (brs, 2H), 8.01 (d, J = 8.8 Hz, 1H), 7.54 - 7.46 (m, 2H), 7.18 (s, 1H), 7.10 (s, 1H), 7.02 (d, J = 7.7 Hz, 2H), 6.71 (t, 1H, JH-F= 56 Hz), 6.44 (dd, J = 8.8, 2.1 Hz, 1H), 6.17 - 6.07 (m, 2H), 5.06 - 4.90 (m, 2H), 4.62 - 4.53 (m, 2H), 4.36 - 4.28 (m, 5H), 4.18 (d, J = 16.9 Hz, 1H), 3.84 - 3.78 (m, 1H), 3.31 - 3.25 (m, 4H), 2.93 - 2.75 (m, 5H), 2.63 - 2.54 (m, 1H), 2.41 - 2.30 (m, 2H), 2.16 - 2.10 (m, 2H), 1.98 - 1.88 (m, 3H), 1.83 - 1.77 (m, 1H), 1.75 - 1.70 (m, 1H), 1.66 (d, J = 10.9 Hz, 2H), 1.58 - 1.51 (m, 4H), 1.47 - 1.39 (m, 3H), 1.31 - 1.22 (m, 2H), 1.18 - 0.95 (m, 5H). Example 4: Preparation of (2S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-(1-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)propenamide (Compound 4)

[0332] Step 1: Preparation of (2S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydro benzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-(1-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)propanamide

[0333] To a solution of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f] imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-(piperidin-4-yl)propanamide (28 mg, 0.06 mmol) in DCM (2 mL) stirred at room temperature was added 1-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoiso indolin-5- yl)piperidin-4-yl)methyl)piperidine-4-carbaldehyde (26 mg, 0.06 mmol) and TEA (29 mg, 0.29 mmol). The mixture was stirred at room temperature for 0.5 hours. STAB (24 mg, 0.11 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction was quenched with H2O and extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous Na2SO4,and concentrated in vacuum. The residue was purified by Prep-HPLC (Gemini-C18:150 x 21.2 mm, 5 μm. ACN-H2O (0.1 % FA, 10-30 %) to give the desired product (20 mg, 37 % yield). LC / MS: 927.1 [M+H]+.1H NMR (400 MHz, DMSO) δ 10.94 (s, 1H), 7.99 (d, J = 8.7 Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.43 (s, 1H), 7.18 (s, 1H), 7.10 - 6.98 (m, 3H), 6.43 (d, J = 9.5 Hz, 1H), 6.20 - 6.10 (m, 2H), 5.08 - 5.02 (m, 1H), 4.99 - 4.91 (m, 1H), 4.62 - 4.52 (m, 2H), 4.37 - 4.28 (m, 4H), 4.19 (d, J = 17.0 Hz, 1H), 3.88 (d, J = 11.7 Hz, 2H), 3.79 - 3.73 (m, 1H), 3.21 - 2.96 (m, 4H), 2.94 - 2.77 (m, 4H), 2.62 - 2.54 (m, 2H), 2.45 - 2.33 (m, 6H), 2.00 - 1.91 (m, 2H), 1.84 - 1.63 (m, 8H), 1.62 - 1.46 (m, 4H), 1.35 - 1.10 (m, 7H). Example 5: Preparation of (2S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d] [1,4]oxazepin-9-yl)amino)-2-(1-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)acetamide (Compound 5)

[0334] Step 1: Preparation of 3-(5-(4-((4-(dimethoxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione

[0335] To a solution 4-(dimethoxymethyl)piperidine (941 mg , 5.91 mmol) in DCM ( 20 mL ) stirred under argon at room temperature was added DIEA (1.5 g , 11.82 mmol) and 1-[2-(2,6-dioxo piperidin-3- yl)-1-oxo-3H-isoindol-5-yl]piperidine-4-carbaldehyde (700 mg, 1.97 mmol). The reaction mixture was stirred at room temperature for 10 minutes. STAB was added (1.2 g, 5.91 mmol) and the mixture was stirred at room temperature for 2 hours. The reaction was quenched with water (30 mL) and extractedwith DCM (30 mL 3). The organic phase was washed with brine and dried over Na2SO4. The solutionwas concentrated in vacuum and the residue was purified by Prep-TLC (MeOH:DCM = 1:10) to give the desired compound (900 mg, 91.6 % yield) as a white solid. LC / MS: 499.0 [M+H]+.

[0336] Step 2: Preparation of 1-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-4-yl)me thyl)piperidine-4-carbaldehyde

[0337] To a solution 3-(5-(4-((4-(dimethoxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindo lin-2-yl)piperidine-2,6-dione (100 mg, 0.25 mmol) in DCM (30 mL) stirred at room temperature was added TFA (10 mL). The reaction was stirred at 45 ℃ temperature for 1 hour. The mixture was concentrated in vacuum to give the desired compound (80 mg, crude) as a white solid which was used in the next step without further purification. LC / MS: 453.0 [M

[0338] Step 3: Preparation of (2S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydro benzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-(1-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)acetamide

[0339] To a solution of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f] imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-(piperidin-4-yl)acetamide (13 mg, 0.03 mmol) in DCM (2 mL) stirred at room temperature was added 1-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxo isoindolin-5- yl)piperidin-4-yl)methyl)piperidine-4-carbaldehyde (12 mg, 0.03 mmol) and TEA (14 mg, 0.14 mmol). The mixture was stirred at room temperature for 0.5 hours. STAB (12 mg, 0.05 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction was quenched with H2O and extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuum. The residue was purified by Prep-HPLC (Gemini-C18:150 x 21.2 mm, 5 μm. ACN-H2O (0.1 % FA, 10-30 %) to give the desired product (10 mg, 38.1 % yield) as a white solid. LC / MS: 913.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.14 (s, 1H), 7.98 (d, J = 9.2 Hz, 1H), 7.52 - 7.42 (m, 2H), 7.18 (s, 1H), 7.10 - 7.01 (m, 2H), 6.50 - 6.45 (m, 1H), 6.21 - 6.15 (m, 1H), 6.09 - 6.04 (m, 1H), 5.07 - 4.97 (m, 2H), 4.58 - 4.54 (m, 1H), 4.36 - 4.27 (m, 3H), 3.91 - 3.81 (m, 2H), 3.63 - 3.51 (m, 2H), 2.96 - 2.88 (m, 2H), 2.87 - 2.73 (m, 3H), 2.63 - 2.52 (m, 7H), 2.43 - 2.35 (m, 5H), 1.99 - 1.84 (m, 4H), 1.82 - 1.52 (m, 9H), 1.30 - 1.02 (m, 7H).Example 6: Preparation of (2S,4R)-1-(2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-4-((1-((3-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)-3-azaspiro [5.5]undecan-9-yl)methyl)piperidin-4-yl)amino)pyrrolidine-2- carboxamide (Compound 6)

[0340] Step 1: Preparation of 3-(5-(9-(hydroxymethyl)-3-azaspiro[5.5]undecan-3-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione

[0341] To a solution of (3-azaspiro[5.5]undecan-9-yl)methanol (851 mg, 4.64 mmol) in dioxane (20 mL) was added 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1000 mg, 3.09 mmol), Pd-PEPPSI- IPentCl-O (150 mg, 0.15 mmol) and Cs2CO3 (3025 mg, 9.28 mmol). The mixture was stirred at 90 ℃ for 16 hours under argon atmosphere. The reaction was quenched with water (20 mL) and extracted with EA(20 mL 3). The organic phase was washed with brine and dried over Na2SO4. The solution wasconcentrated in vacuum and the residue was purified by flash (DCM:MeOH = 10:1) to give the desired compound (530 mg, 40.1 % yield) as a white solid. LC / MS: 426.2 [M+H]+.

[0342] Step 2: Preparation of 3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3- azaspiro[5.5]undecane-9-carbaldehyde

[0343] To a solution of 3-{5-[9-(hydroxymethyl)-3-azaspiro[5.5]undecan-3-yl]-1-oxo-3H-isoindol-2- yl}piperidine-2,6-dione (200 mg, 0.47 mmol) in DMSO (5 mL) was added IBX (263 mg, 0.94 mmol). The mixture was stirred at 60 ℃ for 1 hour. The reaction was quenched with saturated NaHCO3solution and extracted with EA. The organic phase was washed with brine and dried over Na2SO4. The solution was concentrated in vacuum and the residue was purified by flash chromatography on silica gel with DCM:MeOH= 10:1 to afford the desired compound (170 mg, 85.4 % yield) as a white solid. LC / MS: 424.2 [M+H]+.

[0344] Step 3: Preparation of (2S,4R)-4-((tert-butoxycarbonyl)amino)-1-(2-((S)-4-(difluoromethyl)-2- oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)pyrrolidine-2-carboxylic acid

[0345] To a solution of (S)-3-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-(di fluoromethyl)oxazolidin-2-one (170 mg, 0.42 mmol) in DMSO (5 mL) was added (2S,4R)-4-((tert- butoxycarbonyl)amino)pyrrolidine-2-carboxylic acid (196 mg, 0.84 mmol), Cu2O (122 mg, 0.84 mmol) and K3PO4(271 mg, 1.27 mmol). The mixture was stirred at 95 ℃ for 16 hours under argon atmosphere. The mixture was purified by Prep-HPLC (Gemini-C18:150 x 21.2 mm, 5 μm. ACN-H2O 10-60%) to give the desired product (120 mg, 51.4% yield) as a white solid. LC / MS: 550.2 [M+H]+.

[0346] Step 4: Preparation of tert-butyl ((3R,5S)-5-carbamoyl-1-(2-((S)-4-(difluoromethyl)-2-oxooxazo lidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)pyrrolidin-3-yl)carbamate

[0347] A mixture of (2S,4R)-4-((tert-butoxycarbonyl)amino)-1-(2-((S)-4-(difluoromethyl)-2-oxooxazoli din-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)pyrrolidine-2-carboxylic acid (115 mg, 0.2 mmol) and CDI (51 mg, 0.31 mmol) in THF (5 mL) was stirred at room temperature for 2 hours. The mixture was treated with NH3-H2O (1 mL) and stirred at 45 °C for 2 hours. The solution was diluted with EA and washed sequentially with water and saturated Na2CO3solution. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuum. The residue was purified by TLC with DCM: MeOH = 15: 1 to afford the desired compound (75 mg, 65.3 % yield) as a brown solid. LC / MS: 549.2 [M+H]+.

[0348] Step 5: Preparation of (2S,4R)-4-amino-1-(2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide

[0349] A solution of tert-butyl ((3R,5S)-5-carbamoyl-1-(2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3- yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)pyrrolidin-3-yl)carbamate (70 mg, 0.12 mmol) in DCM (2 mL) and HCl-dioxane (4 N, 2 mL) was stirred at 25 ℃ for 1 hour. The mixture wasconcentrated in vacuum to give the product (70 mg, HCl salt, 98.3% yield) as a white solid. LC / MS: 449.1 [M+H]+.

[0350] Step 6: Preparation of tert-butyl 4-(((3R,5S)-5-carbamoyl-1-(2-((S)-4-(difluoromethyl)-2-oxooxa zolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)pyrrolidin-3-yl)amino)piperidine-1- carboxylate

[0351] To a solution of (2S,4R)-4-amino-1-(2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihy drobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide (70 mg, 0.15 mmol) in DMA (5 mL) was added tert-butyl 4-oxopiperidine-1-carboxylate (86 mg, 0.43 mmol) and DIEA (187 mg, 1.44 mmol). The reaction was stirred under nitrogen at 45 ℃ for 0.5 hours. STAB (92 mg, 0.43 mmol) was added and the mixture was stirred at 45 ℃ for 16 hours. The solution was concentrated in vacuum and the residue was purified by TLC with DCM:MeOH = 10:1 to afford the desired compound (60 mg, 60.8 % yield) as a white solid. LC / MS: 631.7 [M+H]+.

[0352] Step 7: Preparation of (2S,4R)-1-(2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydro benzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-4-(piperidin-4-ylamino)pyrrolidine-2-carboxamide

[0353] A solution of tert-butyl 4-(((3R,5S)-5-carbamoyl-1-(2-((S)-4-(difluoromethyl)-2-oxooxazolidin- 3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)pyrrolidin-3-yl)amino)piperidine-1- carboxylate (55 mg, 0.087 mmol) in HCl-dioxane (4 N, 2 mL) and DCM (2 mL) was stirred at 25 ℃ for 1 hour. The mixture was concentrated in vacuum to give the product (55 mg, HCl salt, 98.5 % yield) as a white solid. LC / MS: 532.2 [M+H]+.

[0354] Step 8: Preparation of (2S,4R)-1-(2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydro benzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-4-((1-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindo lin-5-yl)- 3-azaspiro[5.5]undecan-9-yl)methyl)piperidin-4-yl)amino)pyrrolidine-2-carboxamide

[0355] To a solution of (2S,4R)-1-(2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo [f]imidazo[1,2-d][1,4]oxazepin-9-yl)-4-(piperidin-4-ylamino)pyrrolidine-2-carboxamide (55 mg, 0.091 mmol, HCl salt) in DMA (5 mL) was added 3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindo lin-5-yl)-3- azaspiro[5.5]undecane-9-carbaldehyde (39 mg, 0.091 mmol) and TEA (92 mg, 0.9 mmol). The reaction was stirred under nitrogen at 25 ℃ for 1 hour. STAB (58 mg, 0.27 mmol) was added and the mixture was stirred at 25 ℃ for 4 hours. The solution was concentrated in vacuum and the residue was purified by TLC with DCM:MeOH = 10:1 to afford a desired crude compound. The crude product was purified by Prep-HPLC (Gemini-C18:150 x 21.2 mm, 5 μm. ACN-H2O (0.1% FA)) to give the desired product (34.2 mg, 31.6 % yield) as a white solid. LC / MS: 939.4 [M+H]+.1H NMR (400 MHz, DMSO) δ 10.93 (s, 1H), 8.19 (brs, 2H), 8.08 (d, J = 8.9 Hz, 1H), 7.54 - 7.43 (m, 2H), 7.20 (s, 1H), 7.04 (t, J = 12.3 Hz, 3H), 6.71(t, 1H, JH-F= 56 Hz), 6.29 (d, J = 7.7 Hz, 1H), 6.01 (s, 1H), 5.06 - 4.90 (m, 2H), 4.63 - 4.53 (m, 2H), 4.44 - 4.26 (m, 5H), 4.19 (d, J = 16.9 Hz, 1H), 4.02 (d, J = 8.0 Hz, 1H), 3.74 (d, J = 7.6 Hz, 1H), 3.68 - 3.61 (m, 1H), 3.36 - 3.22 (m, 4H), 3.01 - 2.81 (m, 4H), 2.63 - 2.52 (m, 4H), 2.39 - 2.32 (m, 1H), 2.22 - 1.90 (m, 7H), 1.85 - 1.75 (m, 2H), 1.67 (d, J = 9.6 Hz, 2H), 1.60 - 1.41 (m, 6H), 1.34 - 1.23 (m, 2H), 1.18 - 0.97 (m, 4H). Example 7: Preparation of (2S)-5-(((1-((1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6- yl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)amino)-2-((2-((R)-4-isopropyl-2-oxooxazolidin-3-yl)- 5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)pentanamide (Compound 11)

[0356] Step 1: Preparation (2S)-5-(((1-((1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)pipe ridin-4-yl)methyl)piperidin-4-yl)methyl)amino)-2-((2-((R)-4-isopropyl-2-oxooxazolidin-3-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)pentanamide

[0357] To a solution of (S)-5-amino-2-((2-((R)-4-isopropyl-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo [f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)pentanamide (700 mg, crude) and 1-((1-(3-(2,6-di oxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-4-yl)methyl)piperidine-4-carbaldehyde (825 mg, 1.83 mmol) in DMA (14 mL) was added DIEA (787 mg, 6.09 mmol) and MgSO4(731 mg, 6.09 mmol). The mixture was stirred at room temperature for 0.5 hours. STAB (774 mg, 3.65 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with H2O (10 mL)and extracted with DCM (15 mL 3). The organic phase was concentrated and purified by Prep-HPLC(AQ-C18. ACN-H2O (0.1% FA, 7-17%) to afford the desired compound (301.8 mg, 26 % yield) as a white solid. LC / MS: 878.3 [M+H]+.1H NMR (400 MHz, DMSO) δ 10.87 (s, 1H), 8.55 (brs, 2H), 7.95 (d, J = 8.8 Hz, 1H), 7.59 - 7.46 (m, 2H), 7.27 - 7.12 (m, 2H), 7.01 - 6.90 (m, 2H), 6.51 - 6.40 (m, 1H), 6.17 (d, J = 1.7 Hz, 1H), 4.51 - 4.42 (m, 3H), 4.38 - 4.33 (m, 3H), 4.29 - 4.26 (m, 3H), 3.90 (s, 3H), 3.85 - 3.75 (m, 3H), 3.58 (d, J = 11.1 Hz, 2H), 3.33 - 3.05 (m, 1H), 3.02 - 2.77 (m, 9H), 2.71 - 2.56 (m, 2H), 2.44 - 2.27 (m, 2H), 2.20 - 2.01 (m, 2H), 1.97 - 1.82 (m, 5H), 1.77 - 1.65 (m, 4H), 1.55 - 1.31 (m, 4H), 0.89 (d, J = 7.0 Hz, 3H), 0.78 (d, J = 6.8 Hz, 3H). Example 8: Preparation of (2S)-2-(1-((1-((1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6- yl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-2-((2-((R)-4-isopropyl-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)acetamide (Compound 14)

[0358] Step 1: Preparation of (S)-2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-((2-((R)-4-isopropyl-2- oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)acetic acid

[0359] To a solution of (R)-3-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4- isopropyloxazolidin-2-one (2 g, 0.005 mol) in DMSO (8 mL) stirred at room temperature was added (S)- 2-amino-2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid (2.63 g, 0.01 mol), K3PO4(3.25 g, 0.15 mol) and Cu2O (0.15 g, 0.001 mol). The reaction mixture was stirred at 95 ℃ for 1 hour in sealed tube under N2. The mixture was concentrated to give the title compound (2 g crude) as a brown oil and used directly. LC / MS: 570.2 [M+H]+.

[0360] Step 2: Preparation of tert-butyl 4-((S)-2-amino-1-((2-((R)-4-isopropyl-2-oxooxazolidin-3-yl)- 5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-oxoethyl)piperidine-1-carboxy late

[0361] To a solution of (S)-2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-((2-((R)-4-isopropyl-2-oxo oxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)acetic acid (2 g, crude) in THF (4 mL) stirred at room temperature was added HOSu (412 mg, 3.58 mmol) and EDCI (1413 mg, 7.37 mmol). After stirring at room temperature for 10 minutes, NH3-THF (5 mL) was added to the solution. The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with H2O and extracted with EA. The organic phase was washed with brine and dried over Na2SO4. The solution was concentrated in vacuum and the residue was purified by flash chromatography (DCM:MeOH = 20:1) to give the desired compound (700 mg, 35 % yield) as a purple solid. LC / MS: 569.2 [M+H]+.

[0362] Step 3: Preparation of (S)-2-((2-((R)-4-isopropyl-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imi dazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-(piperidin-4-yl)acetamide

[0363] A solution tert-butyl 4-((S)-2-amino-1-((2-((R)-4-isopropyl-2-oxooxazolidin-3-yl)-5,6-dihydro benzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-oxoethyl)piperidine-1-carboxylate (700 mg, 1.23mmol) in DCM (4 mL) and TFA (2 mL) was stirred at 25 ℃ for 1 hour. The mixture was concentrated in vacuum to give the product (500 mg TFA salt, 86 % yield ) as a purple solid. LC / MS: 469.2 [M+H]+.

[0364] Step 4: Preparation of (2S)-2-(1-((1-((1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6- yl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-2-((2-((R)-4-isopropyl-2-oxooxazolidin-3- yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)acetamide

[0365] To a solution of (S)-2-((2-((R)-4-isopropyl-2-oxooxazolidin-3-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-(piperidin-4-yl)acetamide (500 mg TFA salt, 1.07 mmol) in DMA (5 mL) stirred at room temperature was added 1-((1-(3-(2,6-dioxopiperidin-3-yl)-1- meth yl-1H-indazol-6-yl)piperidin-4-yl)methyl)piperidine-4-carbaldehyde (530 mg, 1.17 mmol) and DIEA (413.7 mg, 3.2 mmol). The mixture was stirred under nitrogen at 25 ℃ for 30 minutes. STAB (678.4 mg, 3.2 mmol) was added. The mixture was stirred at 25 ℃ for 1.5 hours. The solution was concentrated in vacuum and the residue was purified by Prep-HPLC (Gemini-C18:150 x 21.2 mm, 5 μm. ACN-H2O (0.1%FA, 12-15%) to give the desired product (205 mg, 21.2 % yield) as a yellow solid. LC / MS: 904.4 [M+H]+.1H NMR (400 MHz, DMSO) δ 10.84 (s, 1H), 8.15 (s, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.50 - 7.45 (m, 2H), 7.17 (s, 1H), 7.12 (s, 1H), 6.90 (d, J = 9.2 Hz, 1H), 6.83 (s, 1H), 6.47 (dd, J = 8.8, 2.0 Hz, 1H), 6.20 (d, J = 2.0 Hz, 1H), 6.04 (d, J = 8.4 Hz, 1H), 4.50 - 4.45 (m, 1H), 4.40 (t, J = 8.8 Hz, 1H), 4.36 - 4.29 (m, 5H), 4.27 - 4.23 (m, 1H), 3.88 (s, 3H), 3.79 (d, J = 12.0 Hz, 2H), 3.09 - 3.00 (m, 4H), 2.78 - 2.53 (m, 6H), 2.35 - 2.08 (m, 8H), 1.87 - 1.59 (m, 10H), 1.44 - 1.21 (m, 6H), 0.90 (d, J = 7.2 Hz, 3H), 0.77 (d, J = 6.8 Hz, 3H). Example 9: Preparation of (2S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-(1-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)piperidin-4-yl)methyl)-4-fluoropiperidin-4-yl)methyl)piperidin-4-yl)acetamide (Compound 22)

[0366] Step 1: Preparation of 3-(5-(4-((4-fluoro-4-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0367] To a solution of 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-4-carbaldehyde (80 mg, 0.23 mmol) in DCM (2 mL) stirred at room temperature was added (4-fluoropiperidin-4- yl)methanol (60 mg, 0.45 mmol) and TEA (114 mg, 1.13 mmol). The mixture was stirred at room temperature for 0.5 hours. STAB (95 mg, 0.45 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction was quenched with H2O and extracted with DCM. The organic phase was washed with brine and dried over Na2SO4. The solution was concentrated in vacuum and the residue was purified by flash chromatography on silica gel eluting with DCM:MeOH = 10:1 to give the desired product (78 mg, 59.2 % yield) as a yellow solid. LC / MS: 473.1 [M+H]+.

[0368] Step 2: Preparation of 1-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-4- yl)methyl)-4-fluoropiperidine-4-carbaldehyde

[0369] To a solution of 3-(5-(4-((4-fluoro-4-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (70 mg, 0.15 mmol) in DCM (2 mL) was added Dess-Martin reagent (126 mg, 0.30 mmol). The mixture was stirred at 25 ℃ for 2 hours. The reaction was quenched with water and extracted with DCM. The organic phase was washed with brine and dried over Na2SO4. The solution was concentrated in vacuum to give the title compound (50 mg, crude) as a white solid and used directly. LC / MS: 471.2 [M+H]+.

[0370] Step 3: Preparation of (2S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydroben zo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-(1-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoiso indolin- 5-yl)piperidin-4-yl)methyl)-4-fluoropiperidin-4-yl)methyl)piperidin-4-yl)acetamide

[0371] To a solution of 1-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-4-yl)methyl)- 4-fluoropiperidine-4-carbaldehyde (50 mg, crude) in DMA (2 mL) stirred at room temperature was added (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo [1,2- d][1,4]oxazepin-9-yl)amino)-2-(piperidin-4-yl)acetamide (76 mg, 0.16 mmol) and TEA (54 mg, 0.53 mmol). The mixture was stirred at room temperature for 0.5 hours. STAB (45 mg, 0.21 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction was quenched with H2O and extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous Na2SO4,and concentrated in vacuum. The residue was purified by Prep-HPLC (Gemini-C18:150 x 21.2 mm, 5 μm. ACN-H2O (0.1 % FA, 15-25 %) to give the desired product (10 mg, 9.8 % yield) as a yellow solid. LC / MS: 931.2 [M+H]+.1H NMR (400 MHz, DMSO) δ 10.95 (s, 1H), 9.64 - 9.53 (m, 1H), 8.00 (d, J = 8.7 Hz, 1H), 7.63 (brs, 1H), 7.52 (d, J = 8.6 Hz, 1H), 7.25 - 7.19 (m, 2H), 7.12 - 7.05 (m, 2H), 6.99 (s, 0.2H), 6.84 (s, 0.2H), 6.71 (s, 0.4H), 6.56 (s, 0.2H), 6.50 (d, J = 8.7 Hz, 1H), 6.25 - 6.21 (m, 1H), 5.05 (dd, J = 13.2, 5.1 Hz, 1H), 4.99 - 4.91 (m, 1H), 4.61 - 4.54 (m, 2H), 4.35 (s, 4H), 4.30 (s, 1H), 4.20 (d, J = 16.9 Hz, 2H), 3.91 (d, J = 11.8 Hz, 2H), 3.68 - 3.49 (m, 6H), 3.09 (s, 4H), 2.93 - 2.81 (m, 3H), 2.63 - 2.56 (m,1H), 2.44 - 2.37 (m, 1H), 2.36 - 2.31 (m, 1H), 2.28 - 2.24 (m, 1H), 2.13 - 2.04 (m, 2H), 2.03 - 1.94 (m, 4H), 1.82 (d, J = 11.4 Hz, 2H), 1.51 - 1.42 (m, 1H), 1.31 - 1.25 (m, 3H), 1.24 (s, 3H), 0.88 - 0.82 (m, 1H). Example 10: Preparation of (2S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-(1-((1-((1-(4-(2,6-dioxopiperidin-3-yl)- 3,5-difluorophenyl)piperidin-4-yl)methyl)-4-fluoropiperidin-4-yl)methyl)piperidin-4-yl)acetamide (Compound 23)

[0372] Step 1: Preparation of 3-(2,6-difluoro-4-(4-((4-fluoro-4-(hydroxymethyl)piperidin-1-yl)meth yl)piperidin-1-yl)phenyl)piperidine-2,6-dione

[0373] To a solution of 1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)piperidine-4-carbaldehyde (110 mg, 0.33 mmol) in DCM (2 mL) stirred at room temperature was added (4-fluoropiperidin-4- yl)methanol (131 mg, 0.98 mmol) and TEA (166 mg, 1.64 mmol). The mixture was stirred at room temperature for 1 hour. STAB (139 mg, 0.65 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction was quenched with H2O and extracted with DCM. The organic phase was washed with brine and dried over Na2SO4. The solution was concentrated in vacuum and the residue was purified by flash chromatography on silica gel eluting with DCM:MeOH = 10:1 to afford the desired compound (78 mg, 42.5 % yield) as a yellow solid. LC / MS: 454.2 [M+H]+.

[0374] Step 2: Preparation of 1-((1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)piperidin-4-yl)meth yl)-4-fluoropiperidine-4-carbaldehyde

[0375] To a solution of 3-(2,6-difluoro-4-(4-((4-fluoro-4-(hydroxymethyl)piperidin-1- yl)methyl)piperidin-1-yl)phenyl)piperidine-2,6-dione (70 mg, 0.15 mmol) in DCM (2 mL) was added Dess-Martin reagent (131 mg, 0.31 mmol). The mixture was stirred at 25 ℃ for 2 hours. The reaction was quenched with water and extracted with DCM. The organic phase was washed with brine and dried over Na2SO4. The solution was concentrated in vacuum to give the title compound (50 mg, crude) as a white solid and used directly. LC / MS: 470.2 [M+H2O+H]+.

[0376] Step 3: Preparation of (2S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydroben zo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-(1-((1-((1-(4-(2,6-dioxopiperidin-3-yl)-3,5-di fluorophenyl)piperidin-4-yl)methyl)-4-fluoropiperidin-4-yl)methyl)piperidin-4-yl)acetamide

[0377] To a solution of 1-((1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)piperidin-4-yl)methyl)-4- fluoropiperidine-4-carbaldehyde (60 mg, crude) in DMA (2 mL) stirred at room temperature was added (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)amino)-2-(piperidin-4-yl)acetamide (95 mg, 0.20 mmol) and TEA (67 mg, 0.66 mmol). The mixture was stirred at room temperature for 0.5 hours. STAB (56 mg, 0.27 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction was quenched with H2O and extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous Na2SO4,and concentrated in vacuum. The residue was purified by Prep-HPLC (Gemini-C18:150 x 21.2 mm, 5 μm. ACN-H2O (0.1 % FA, 15-25 %) to give the desired product (11 mg, 6.1 % yield) as a yellow solid. LC / MS: 912.1 [M+H]+.1H NMR (400 MHz, DMSO) δ 10.88 (s, 1H), 9.45 - 9.38 (m, 1H), 9.27 - 9.19 (m, 1H), 8.00 (d, J = 8.9 Hz, 1H), 7.29 - 7.18 (m, 2H), 6.84 (s, 0.2H), 6.72 - 6.69 (m, 0.5H), 6.66 (d, J = 13.0 Hz, 2H), 6.57 - 6.55 (m, 0.3H), 6.50 (d, J = 6.7 Hz, 1H), 6.23 (s, 1H), 6.22 - 6.08 (m, 1H), 4.99 - 4.91 (m, 1H), 4.63 - 4.52 (m, 3H), 4.36 - 4.33 (m, 3H), 4.05 (dd, J = 12.3, 4.9 Hz, 3H), 3.82 (d, J = 11.9 Hz, 4H), 3.69 - 3.49 (m, 8H), 3.12 - 3.02 (m, 5H), 2.83 - 2.74 (m, 3H), 2.32 - 2.20 (m, 2H), 2.11 - 1.91 (m, 7H), 1.80 - 1.75 (m, 2H), 1.31 - 1.19 (m, 3H). Example 11: Preparation of (2S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-(1-((1-((1-(1-(2,6-dioxopiperidin-3-yl)- 3,3-dimethyl-2-oxoin dolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)piperidin-4- yl)acetamide (Compound 24)

[0378] Step 1: Preparation of 1-(2,6-bis(benzyloxy)pyridin-3-yl)-5-bromo-3,3-dimethylindolin-2-one

[0379] To a solution of 5-bromo-3,3-dimethylindolin-2-one (0.98 g, 4.1 mmol) and 2,6-bis(benzyloxy)- 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.88 g, 4.5 mmol) in dioxane (20 mL) stirred under O2was added pyridine (0.97 g, 12.3 mmol), Cu(OAc)2(0.74 g, 4.1 mmol) and 4A molecular sieves (0.9 g). The mixture was stirred at 80 ℃ for 24 hours under O2. The mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by flash chromatography on silica gel eluting with PE:EA = 5:1 to afford the desired compound (0.93 g, 41.4 % yield) as a yellow oil. LC / MS: 529.1 [

[0380] Step 2: Preparation 1-(2,6-bis(benzyloxy)pyridin-3-yl)-5-(4-(dimethoxymethyl)piperidin-1-yl)- 3,3-dimethylindolin-2-one

[0381] To a solution of 1-(2,6-bis(benzyloxy)pyridin-3-yl)-5-bromo-3,3-dimethylindolin-2-one (930 mg, 1.8 mmol) in dioxane (20 mL) stirred under N2at room temperature was added 4- (dimethoxymethyl)piperidine (430 mg, 2.7 mmol), Pd2(dba)3(160 mg, 0.2 mmol), X-PHOS (170 mg, 0.4 mmol) and t-BuONa (520 mg, 5.4 mmol). The mixture was stirred at 90 ℃ for 16 hours. The mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by flash chromatography on silica gel eluting with DCM:MeOH = 10:1 to afford the desired compound (590 mg, 50 % yield) as a yellow solid. LC / MS: 608.2 [M+H]+.

[0382] Step 3: Preparation 3-(5-(4-(dimethoxymethyl)piperidin-1-yl)-3,3-dimethyl-2-oxoindolin-1- yl)piperidine-2,6-dione

[0383] To a solution of 1-(2,6-bis(benzyloxy)pyridin-3-yl)-5-(4-(dimethoxymethyl)piperidin-1-yl)-3,3- dimethylindolin-2-one (590 mg, 0.97 mmol) in dioxane (20 mL) was added Pd(OH)2 / C (409 mg, 2.91 mmol, 10 %). The mixture was stirred at 50 ℃ for 16 hours under H2with a balloon. The catalyst wasfiltered off and washed with dioxane (20 mL 3). The solution was concentrated in vacuum to give thedesired compound (382 mg, 91.7 % yield) as a yellow gum. LC / MS:430.2 [M+H]+.

[0384] Step 4: Preparation of 1-(1-(2,6-dioxopiperidin-3-yl)-3,3-dimethyl-2-oxoindolin-5-yl)piperidine- 4-carbaldehyde

[0385] To a solution of 3-(5-(4-(dimethoxymethyl)piperidin-1-yl)-3,3-dimethyl-2-oxoindolin-1- yl)piperidine-2,6-dione (450 mg, 1.05 mmol) in DCM (5 mL) was added TFA (5 mL). The reaction was stirred at room temperature for 2 hours. The mixture was concentrated in vacuum to give the title compound (450 mg TFA salt, crude) as a yellow oil. LC / MS: 384.1 [M+H]+.

[0386] Step 5: Preparation of 3-(5-(4-((4-(dimethoxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)-3,3- dimethyl-2-oxoindolin-1-yl)piperidine-2,6-dione

[0387] To a solution of 1-(1-(2,6-dioxopiperidin-3-yl)-3,3-dimethyl-2-oxoindolin-5-yl)piperidine-4- carbaldehyde (450 mg, 1.17 mmol) in DMA (10 mL) stirred at room temperature was added 4- (dimethoxymethyl)piperidine (280 mg, 1.76 mmol) and AcOH (141 mg, 2.35 mmol). The mixture was stirred at room temperature for 1 hour. NaBH3CN (148 mg, 2.35 mmol) was added. The mixture was stirred at room temperature for 0.5 hours. The solution was concentrated in vacuum and the residue was purified by flash chromatography on silica gel eluting with DCM:MeOH = 10:1 to afford the desired compound (331 mg, 53.6 % yield) as a yellow oil. LC / MS: 527.3 [M+H]+.

[0388] Step 6: Preparation of 1-((1-(1-(2,6-dioxopiperidin-3-yl)-3,3-dimethyl-2-oxoindolin-5- yl)piperidin-4-yl)methyl)piperidine-4-carbaldehyde

[0389] To a solution of 3-(5-(4-((4-(dimethoxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)-3,3-dimeth yl-2-oxoindolin-1-yl)piperidine-2,6-dione (360 mg, 0.68 mmol) in DCM (5 mL) was added TFA (5 mL). The reaction was stirred at room temperature for 1 hour. The mixture was concentrated in vacuum to give the title compound (400 mg TFA salt, crude) as a yellow gum. LC / MS: 481.2 [M+H]+.

[0390] Step 7: Preparation of (2S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydroben zo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-(1-((1-((1-(1-(2,6-dioxopiperidin-3-yl)-3,3-di methyl-2- oxoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)acetamide

[0391] To a solution of 1-((1-(1-(2,6-dioxopiperidin-3-yl)-3,3-dimethyl-2-oxoindolin-5-yl)piperidin-4- yl)methyl)piperidine-4-carbaldehyde (400 mg TFA salt, crude) in DMA (4 mL) stirred at room temperature was added (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydroben zo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-(piperidin-4-yl)acetamide (65 mg, 0.14 mmol) and DIEA (88 mg, 0.68 mmol). The mixture was stirred at room temperature for 1 hour. STAB (58 mg, 0.27 mmol) was added. The mixture was stirred at room temperature for 0.5 hours. The reaction was quenched with H2O and extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous Na2SO4,and concentrated in vacuum. The residue was purified by Prep-HPLC (Gemini-C18:150 x 21.2 mm, 5 μm. ACN-H2O (0.1 % FA, 5-30 %) to give the desired product (6 mg, 4.7 % yield) as a yellow solid. LC / MS: 941.3 [M+H]+.1H NMR (400 MHz, DMSO) δ 11.04 (s, 1H), 8.14 (s, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.53 (s, 1H), 7.18 (s, 1H), 7.14 (s, 1H), 7.08 (d, J = 2.0 Hz, 1H), 6.85 - 6.70 (m, 3H), 6.55 (d, J = 14.4 Hz, 1H), 6.49 (dd, J = 8.8, 2.0 Hz, 1H), 6.20 (d, J = 2.0 Hz, 1H), 6.11 (d, J = 8.8 Hz, 1H), 5.19 - 5.11 (m, 1H), 5.00 - 4.90 (m, 1H), 4.62 - 4.53 (m, 2H), 4.36 - 4.32 (m, 4H), 3.63 - 3.54 (m, 3H), 3.22 - 3.08 (m, 4H), 2.90 - 2.84 (m, 1H), 2.64 - 2.55 (m, 5H), 2.07 (s, 9H), 2.03 - 1.97 (m, 2H), 1.91 (s, 1H), 1.82 - 1.74 (m, 6H), 1.27 (d, J = 2.4 Hz, 6H), 1.24 (s, 3H). Example 12: Preparation of (2S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6- dihydrobenzo[f]imidazo [1,2-d][1,4]oxazepin-9-yl)amino)-2-(1''-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)-[1,4':1',4''-terpiperidin]-4-yl)acetamide (Compound 25)

[0392] Step 1: Preparation of tert-butyl 4-((S)-2-amino-1-((2-((S)-4-(difluoromethyl)-2-oxo oxazolidin- 3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-oxoethyl)-[1,4'-bipiperidine]-1'- carboxylate

[0393] To a solution of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydro benzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-(piperidin-4-yl)acetamide (50 mg, 0.10 mmol) in DMA (5 mL) was added tert-butyl 4-oxopiperidine-1-carboxylate (29 mg, 0.15 mmol) and DIEA (95 mg, 0.74 mmol). The mixture was stirred at 40 ℃ for 1 hour and STAB (47 mg, 0.22 mmol) was added. The mixture was stirred at 40 ℃ for 2 hours. The reaction was quenched with H2O and extracted with EA. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum. The residue was purified by Prep-TLC with DCM:MeOH = 10:1 to give the title compound (40 mg, 60.6 % yield) as a yellow oil. LC / MS: 660.3 [M+H]+.

[0394] Step 2: Preparation of (S)-2-([1,4'-bipiperidin]-4-yl)-2-((2-((S)-4-(difluoromethyl)-2-oxo oxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)acetamide

[0395] A solution tert-butyl 4-((S)-2-amino-1-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-oxoethyl)-[1,4'-bipiperidine]-1'-carboxylate (40 mg, 0.06 mmol) in DCM (6 mL) and TFA (2 mL) was stirred at room temperature for 1 hour. The mixture was concentrated in vacuum to give the title compound (40 mg, TFA salt, crude) as a yellow oil. LC / MS: 560.3 [M+H]+.

[0396] Step 3: Preparation of (2S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihy drobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-(1''-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin- 5-yl)-[1,4':1',4''-terpiperidin]-4-yl)acetamide

[0397] To a solution of (S)-2-([1,4'-bipiperidin]-4-yl)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazo lidin-3- yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)acetamide (35 mg, TFA salt, crude) in DMA (2 mL) was added 3-(1-oxo-5-(4-oxopiperidin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (36 mg, 0.10 mmol) and DIEA (92 mg, 0.71 mmol). The mixture was stirred at 40 ℃ for 1 hour and STAB (45 mg, 0.21 mmol) was added. The final mixture was stirred at 40 ℃ for 15 hours. The solution was concentrated in vacuum to give a crude compound. The crude product was purified by Prep-HPLC (Gemini-C18:150 x 21.2 mm, 5 μm. ACN-H2O (0.1% FA)) to give the desired product (2.8 mg, 3.1 % yield) as a white solid. LC / MS: 885.3 [M+H]+.1H NMR (400 MHz, DMSO) δ 10.95 (s, 1H), 8.21 (s, 2H), 7.97 (d, J = 8.8 Hz, 1H), 7.53 - 7.40 (m, 2H), 7.17 (s, 1H), 7.06 (t, J = 11.6 Hz, 2H), 6.84 - 6.56(m, 1H), 6.47 (d, J = 8.5 Hz, 1H), 6.17 (s, 1H), 6.06 (d, J = 8.2 Hz, 1H), 5.10 - 4.86 (m, 3H), 4.63 - 4.51 (m, 2H), 4.41 - 4.22 (m, 4H), 4.19 (d, J = 16.9 Hz, 1H), 3.91 (d, J = 12.4 Hz, 2H), 3.58 - 3.50 (m, 2H), 3.02 - 2.89(m, 4H), 2.80 (t, J = 11.7 Hz, 2H), 2.67 (s, 1H), 2.59 (s, 1H), 2.38 - 2.30 (m, 2H), 2.26 - 2.20 (m, 1H), 2.12 (t, J = 10.8 Hz, 4H), 1.98 - 1.87 (m, 2H), 1.76 (dd, J = 27.8, 10.1 Hz, 4H), 1.58 (d, J = 10.2 Hz, 2H), 1.52 - 1.33 (m, 5H). Example 13: Preparation of (2S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-(1-((1'-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)-[1,4'-bipiperidin]-4-yl)methyl)piperidin-4-yl)acetamide (Compound 26)

[0398] Step 1: Preparation of 3-(5-(4-(dimethoxymethyl)-[1,4'-bipiperidin]-1'-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione

[0399] To a solution of 3-(1-oxo-5-(4-oxopiperidin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (550 mg, 1.61 mmol) in DCM (10 mL) stirred at room temperature was added 4-(dimethoxymethyl)piperidine (770 mg, 4.83 mmol) and STAB (1024 mg, 4.83 mmol). The mixture was stirred at room temperature for 16 hours. The reaction was quenched with H2O and extracted with DCM. The organic phase was washed with brine and dried over Na2SO4. The solution was concentrated in vacuum and the residue was purified by flash chromatography on silica gel eluting with DCM:MeOH = 10:1 to afford the desired compound (300 mg, 38.4 % yield) as a yellow solid. LC / MS: 485.0 [M+H]+.

[0400] Step 2: Preparation of 1'-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-[1,4'-bipiperidine]-4- carbaldehyde

[0401] To a solution of 3-(5-(4-(dimethoxymethyl)-[1,4'-bipiperidin]-1'-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (70 mg, 0.14 mmol) in DCM (2 mL) was added TFA (2 mL). The reaction was stirred at room temperature for 1 hour. The mixture was concentrated to give the title compound (100 mg crude) as a brown oil. LC / MS: 457.2 [M+H2O+H]+.

[0402] Step 3: Preparation of (2S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydro benzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-(1-((1'-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin- 5-yl)-[1,4'-bipiperidin]-4-yl)methyl)piperidin-4-yl)acetamide

[0403] To a solution of 1'-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-[1,4'-bipiperidine]-4- carbaldehyde (100 mg, crude) in DMA (2 mL) stirred at room temperature was added (S)-2-((2-((S)-4- (difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2- (piperidin-4-yl)acetamide (50 mg, 0.11 mmol) and TEA (58 mg, 0.57 mmol). The mixture was stirred at room temperature for 0.5 hours. STAB (48 mg, 0.23 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction was quenched with H2O and extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous Na2SO4,and concentrated in vacuum. The residue was purified by Prep-HPLC (Gemini-C18:150 x 21.2 mm, 5 μm. ACN-H2O (0.1 % FA, 10-50 %) to give the desired product (25 mg, 19.5 % yield) as a white solid. LC / MS: 899.2 [M+H]+.1H NMR (400 MHz, DMSO) δ 10.94 (s, 1H), 8.15 (d, J = 4.4 Hz, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.44 (s, 1H), 7.23 - 7.158 (m, 1H), 7.07 (t, J = 8.8 Hz, 3H), 6.85 (s, 0.2H), 6.70 (s, 0.5H), 6.56 (s, 0.3H), 6.49 - 6.45 (m, 1H), 6.22 - 6.16 (m, 1H), 6.12 – 5.99 (m, 1H), 5.04 (dd, J = 13.2, 5.2 Hz, 1H), 5.01 - 4.93 (m, 1H), 4.61 - 4.54 (m, 2H), 4.41 - 4.32 (m, 6H), 4.19 (d, J = 16.8 Hz, 1H), 3.94 (d, J = 12.2 Hz, 2H), 3.58 - 3.53 (m, 1H), 3.02 - 2.95 (m, 2H), 2.90 - 2.78 (m, 5H), 2.61 - 2.54 (m, 5H), 2.39 - 2.35 (m, 1H), 2.19 - 2.10 (m, 2H), 2.00 - 1.91 (m, 2H), 1.90 - 1.81 (m, 4H), 1.75 - 1.68 (m, 2H), 1.59 - 1.50 (m, 4H), 1.41 - 1.26 (m, 2H), 1.16 - 1.03 (m, 2H). Example 14: Preparation of (2S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-(1-((1-((1-(3-(2,6-dioxopiperidin-3-yl)-2- oxo-2,3-dihydrobenzo[d]oxazol-6-yl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)piperidin-4- yl)acetamide (Compound 27)

[0404] Step 1: Preparation of 6-[4-(dimethoxymethyl)piperidin-1-yl]-3H-1,3-benzoxazol-2-one

[0405] A mixture of 6-bromo-3H-1,3-benzoxazol-2-one (1 g, 4.7 mmol), 4-(dimethoxymethyl)piperidine (1.5 g, 9.4 mmol), t-BuONa (1.36 g, 14 mmol), Pd2(dba)3(0.43 g, 0.5 mmol) and X-PHOS (0.45 g, 1 mmol) in dioxane (30 mL) was stirred at 90oC for 2 hours under N2. The reaction was quenched withwater (60 mL) and extracted with EA (60 mL 3). The organic phase was washed with brine and driedover Na2SO4. The solution was concentrated in vacuum and the residue was purified by silica column chromatography with PE in EA (0-50 %) to give the desired compound (0.8 g, 55.9 % yield) as a yellow solid. LC / MS: 293.1 [M+H]+.

[0406] Step 2: Preparation of 3-[2,6-bis(benzyloxy)pyridin-3-yl]-6-[4-(dimethoxymethyl)piperidin-1-yl] -1,3-benzoxazol-2-one

[0407] A mixture of 6-bromobenzo[d]oxazol-2(3H)-one (500 mg, 1.71 mmol), 2,6-bis(benzyloxy)-3- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (750 mg, 1.80 mmol), pyridine (406 mg, 5.13 mmol), Cu(OAc)2(311 mg, 1.71 mmol) and activated 4 A molecular sieve (0.5 g) in dry dioxane (20 mL) was stirred at 80oC for 16 hours under the atmosphere of oxygen. The mixture was diluted with ethyl acetate (400 mL) and filtered through a pad of celite. The filtration was washed with water (100 mL) and dried over Na2SO4. The solution was concentrated in vacuum and the residue was purified by silica column chromatography with PE in EA (0-50 %) to give the desired compound (400 mg, 40.2 % yield) as a black solid. LC / MS: 582.1 [M+H]+.

[0408] Step 3: Preparation of 3-{6-[4-(dimethoxymethyl)piperidin-1-yl]-2-oxo-1,3-benzoxazol-3-yl}pi peridine-2,6-dione

[0409] A mixture of 3-[2,6-bis(benzyloxy)pyridin-3-yl]-6-[4-(dimethoxymethyl)piperidin-1-yl]-1,3- benzoxazol-2-one (400 mg, 0.688 mmol) and Pd(OH)2 / C (732 mg, 6.88 mmol) in dioxane (10 mL) was stirred at 50 ℃ for 16 hours under H2with a balloon. The catalyst was filtered off and the filtrate was concentrated in vacuum to give the desired compound (185 mg, 66.6 % yield) as a white solid. LC / MS: 404.1 [M+H]+.

[0410] Step 4: Preparation of 1-[3-(2,6-dioxopiperidin-3-yl)-2-oxo-1,3-benzoxazol-6-yl]piperidine-4- carbaldehyde

[0411] To a solution of 3-{6-[4-(dimethoxymethyl)piperidin-1-yl]-2-oxo-1,3-benzoxazol-3- yl}piperidine-2,6-dione (250 mg, 0.62 mmol) in DCM (10 mL) was added THF + HCl (2M) (10 mL, 1:1). The reaction was stirred at room temperature for 2 hours. The mixture was neutralized with saturatedNaHCO3 solution at 0° C and extracted with DCM (10 mL 3). The combined organic layer was driedover Na2SO4and concentrated in vacuum to give the title compound (170 mg, 72.9 % yield) as an off- color oil. LC / MS: 358.1 [M+H]+.

[0412] Step 5: Preparation of 3-[6-(4-{[4-(dimethoxymethyl)piperidin-1-yl]methyl}piperidin-1-yl)-2- oxo-1,3-benzoxazol-3-yl]piperidine-2,6-dione

[0413] To a solution of 1-[3-(2,6-dioxopiperidin-3-yl)-2-oxo-1,3-benzoxazol-6-yl]piperidine-4- carbaldehyde (170 mg, 0.48 mmol) and DIEA (184 mg, 1.43 mmol) in DMA (5 mL) was added 4- (dimethoxymethyl)piperidine (152 mg, 0.95 mmol). The mixture was stirred at room temperature for 1 hour. STAB (202 mg, 0.95 mmol) was stirred at room temperature and the mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (20 mL) and extracted with EA (20mL 3). The organic phase was washed with brine and dried over Na2SO4. The solution was concentratedin vacuum and the residue was purified by Prep-TLC (DCM:MeOH = 10:1) to give the desired compound (130 mg, 54.6 % yield) as a white solid. LC / MS: 501.3 [M+H]+.

[0414] Step 6: Preparation of 1-({1-[3-(2,6-dioxopiperidin-3-yl)-2-oxo-1,3-benzoxazol-6-yl]piperidin-4- yl}methyl)piperidine-4-carbaldehyde

[0415] To a solution of 3-[6-(4-{[4-(dimethoxymethyl)piperidin-1-yl]methyl}piperidin-1-yl)-2-oxo-1,3- benzoxazol-3-yl]piperidine-2,6-dione(130 mg, 0.26 mmol) in DCM (9 mL) was added TFA (3 mL). The mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuum to give the desired compound (100 mg, crude) as a white solid. LC / MS: 455.1 [M+H]+.

[0416] Step 7: Preparation of (2S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydro benzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-(1-((1-((1-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3- dihydrobenzo[d]oxazol-6-yl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)acetamide

[0417] To a solution of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f] imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-(piperidin-4-yl)acetamide (105 mg, 0.22 mmol), 1-({1-[3- (2,6-dioxopiperidin-3-yl)-2-oxo-1,3-benzoxazol-6-yl]piperidin-4-yl}methyl)piperidine-4-carbaldehyde (100 mg, crude) and DIEA (85 mg, 0.66 mmol) in DMA (20 mL) was added STAB (93 mg, 0.44 mmol). The mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (20 mL)and extracted with EA (20 mL 3). The organic phase was washed with brine, dried over Na2SO4, andconcentrated in vacuum to give a crude product. The crude product was purified by Prep-HPLC (0.1 % FA in H2O / ACN = 5~30 %) to give the desired product (41 mg, 11.6 % yield). LC / MS: 915.2 [M+H]+.1H NMR (400 MHz, DMSO) δ11.21 (s, 1H), 9.36 (s, 2H), 8.00 (d, J = 8.8 Hz, 1H), 7.66 (s, 1H), 7.25 (s, 2H), 7.22 (s, 1H), 7.17 (d, J = 8.7 Hz, 1H), 6.94 (d, J = 8.2 Hz, 1H), 6.84 - 6.56 (m, 1H), 6.51 (dd, J = 8.9, 2.0 Hz, 1H), 6.23 (d, J = 2.0 Hz, 1H), 5.33 (dd, J = 13.0, 5.3 Hz, 1H), 5.01 - 4.89 (m, 1H), 4.65 - 4.52 (m,2H), 4.36 (d, J = 2.4 Hz, 4H), 3.68 - 3.59 (m, 6H), 3.26 - 3.10 (m, 1H), 3.05 - 2.96 (m, 3H), 2.94 - 2.82 (m, 7H), 2.72 - 2.63 (m, 2H), 2.17 - 2.10 (m, 1H), 2.09 - 1.78 (m, 10H), 1.69 - 1.34 (m, 6H). Example 15: Preparation of (2S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-(1-((1-((7-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)-7-azaspiro[3.5]nonan-2-yl)methyl)piperidin-4-yl)methyl)piperidin-4- yl)acetamide (Compound 28)

[0418] Step 1: Preparation of 3-(5-(2-(hydroxymethyl)-7-azaspiro[3.5]nonan-7-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione

[0419] To a solution of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1 g, 3.09 mmol) in dioxane (100 mL) stirred at room temperature was added (7-azaspiro[3.5]nonan-2-yl)methanol HCl salt (1.8 g, 9.28 mmol), Pd-PEPPSI-IPentCl (0.13 g, 0.15 mmol) and Cs2CO3(6.0 g, 18.57 mmol). The mixture was stirred at 100 ℃ for 16 hours. The reaction was quenched with H2O and extracted with EA. The organic phase was washed with brine and dried over Na2SO4. The solution was concentrated in vacuum and the residue was purified by flash chromatography on silica gel eluting with DCM: MeOH = 10: 1 to afford the desired compound (0.5 g, 40.6 % yield). LC / MS: 398.2 [M+H]+.

[0420] Step 2: Preparation of 7-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-7-azaspiro[3.5] nonane-2-carbaldehyde

[0421] To a solution of 3-(5-(2-(hydroxymethyl)-7-azaspiro[3.5]nonan-7-yl)-1-oxoisoindolin-2-yl)pi peridine-2,6-dione (300 mg, 0.75 mmol) in DCM (5 mL) was added Dess-Martin reagent (640 mg, 1.51 mmol). The mixture was stirred at 25 ℃ for 2 hours. The mixture was basified with saturated NaHCO3solution until pH = 8 and extracted with DCM. The organic phase was washed with brine and dried over Na2SO4. The solution was concentrated in vacuum and used in the next step without further purification (200 mg, 67 % yield). LC / MS: 396.2 [M+H]+.

[0422] Step 3: Preparation of 3-(5-(2-((4-(hydroxymethyl)piperidin-1-yl)methyl)-7-azaspiro[3.5]nonan- 7-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0423] To a solution of 7-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-7-azaspiro[3.5]nonane-2- carbaldehyde (200 mg, 0.51 mmol) in DCM (2 mL) stirred at room temperature was added piperidin-4- ylmethanol (175 mg, 1.52 mmol) and TEA (256 mg, 2.53 mmol). The mixture was stirred at room temperature for 0.5 hours. STAB (214 mg, 1.01 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction was quenched with H2O and extracted with DCM. The organic phase was washed with brine and dried over Na2SO4. The solution was concentrated in vacuum and the residue was purified by flash chromatography on silica gel eluting with DCM:MeOH = 10:1 to afford the desired compound (130 mg, 53.4 % yield). LC / MS: 295.3 [M+H / 2]+.

[0424] Step 4: Preparation of 1-((7-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-7-azaspiro[3.5] nonan-2-yl)methyl)piperidine-4-carbaldehyde

[0425] To a solution of 3-(5-(2-((4-(hydroxymethyl)piperidin-1-yl)methyl)-7-azaspiro[3.5]nonan-7-yl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione (110 mg, 0.22 mmol) in DCM (2 mL) was added Dess-Martin reagent (189 mg, 0.44 mmol). The mixture was stirred at 25 ℃ for 2 hours. The reaction was quenched with H2O and extracted with DCM. The organic phase was washed with brine and dried over Na2SO4. The solution was concentrated in vacuum to give the desired product (60 mg, crude) which was used in the next step without further purification. LC / MS: 493.2 [M+H]+.

[0426] Step 5: Preparation of (2S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydro benzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-(1-((1-((7-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)-7-azaspiro[3.5]nonan-2-yl)methyl)piperidin-4-yl)methyl)piperidin-4-yl) acetamide

[0427] To a solution of 1-((7-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-7-azaspiro[3.5]nonan-2- yl)methyl)piperidine-4-carbaldehyde (60 mg, crude) in DCM (2 mL) stirred at room temperature was added (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydro benzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)amino)-2-(piperidin-4-yl)acetamide (66 mg, 0.10 mmol) and TEA (49 mg, 0.49 mmol). The mixture was stirred at room temperature for 0.5 hours. STAB (41 mg, 0.19 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction was quenched with H2O and extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous Na2SO4,and concentrated in vacuum. The residue was purified by Prep-HPLC (Gemini-C18:150 x 21.2 mm, 5μm. ACN-H2O (0.1 % FA, 5-30 %) to give the desired product (10 mg, 10.8 % yield). LC / MS: 953.3 [1H NMR (400 MHz, DMSO) δ 10.94 (s, 1H), 8.17 (s, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.48 (d, J = 8.3 Hz, 1H), 7.43 (s, 1H), 7.17 (s, 1H), 7.09 - 7.01 (m, 3H), 6.85 (s, 0.2H), 6.71 (s, 0.5H), 6.58 - 6.53 (m, 0.4H), 6.47 (d, J = 8.4 Hz, 1H), 6.19 - 6.16 (m, 1H), 6.05 (d, J = 8.5 Hz, 1H), 5.03 (dd, J = 13.2, 5.1 Hz, 1H), 5.00 - 4.90 (m, 1H), 4.62 - 4.53 (m, 2H), 4.36 - 4.28 (m, 5H), 4.18 (d, J = 16.8 Hz, 1H), 3.55 (t, J = 8.1 Hz, 1H), 3.23 - 3.16 (m, 3H), 2.96 - 2.89 (m, 1H), 2.87 - 2.81 (m, 4H), 2.61 - 2.55 (m, 2H), 2.43 - 2.36 (m, 2H), 2.11 - 2.07 (m, 2H), 2.02 - 1.89 (m, 6H), 1.83 - 1.75 (m, 3H), 1.68 - 1.59 (m, 5H), 1.58 - 1.50 (m, 4H), 1.48 - 1.41 (m, 3H), 1.37 - 1.30 (m, 1H), 1.28 - 1.23 (m, 2H), 1.12 - 1.04 (m, 2H). Example 16: Preparation of (2S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-(1-((1-((1-(1-(2,6-dioxopiperidin-3-yl)-3- methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-4-yl)methyl)piperidin-4- yl)methyl)piperidin-4-yl) acetamide (Compound 29)

[0428] Step 1: Preparation of 6-(4-(dimethoxymethyl)piperidin-1-yl)-1-methyl-1,3-dihydro-2H-benzo [d]imidazol-2-one

[0429] To a solution of 6-bromo-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (2 g, 8.8 mmol) in dioxane (10 mL) stirred under N2at room temperature was added 4-(dimethoxymethyl)piperidine (4.2 g, 26.4 mmol), Pd2(dba)3(0.5 g, 0.88 mmol), X-PHOS (0.4 g, 0.88 mmol) and t-BuONa (2.5 g, 26 mmol). The mixture was stirred at 90 ℃ for 2 hours. The solution was concentrated in vacuum and the residue was purified by flash chromatography on silica gel eluting with PE:DCM = 20:1 to afford the desired compound (2.5 g, 93.1% yield) as a white solid. LC / MS: 306.1 [M+H]+.

[0430] Step 2: Preparation of 1-(2,6-bis(benzyloxy)pyridin-3-yl)-5-(4-(dimethoxymethyl)piperidin-1-yl) -3-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0431] To a solution of 6-(4-(dimethoxymethyl)piperidin-1-yl)-1-methyl-1,3-dihydro-2H-benzo[d]imida zol-2-one (500 mg, 1.64 mmol) in toluene (20 mL) stirred at room temperature was added N,N- dimethylethylenediamine (289 mg, 3.27 mmol), K2CO3(679 mg, 4.91 mmol), CuI (312 mg, 1.64 mmol) and 2,6-bis(benzyloxy)-3-bromopyridine (2.4 g, 6.55 mmol). The mixture was stirred at 120 ℃ for 48 hours. The reaction was quenched with H2O and extracted with EA. The organic phase was washed with brine and dried over Na2SO4. The solution was concentrated in vacuum and the residue was purified by flash chromatography on silica gel eluting with PE:EA = 3:1 to afford the desired compound (500 mg, 51.3 % yield) as a black solid. LC / MS: 595.3 [M+H]+.

[0432] Step 3: Preparation of 3-(5-(4-(dimethoxymethyl)piperidin-1-yl)-3-methyl-2-oxo-2,3-dihydro- 1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0433] To a solution of 1-(2,6-bis(benzyloxy)pyridin-3-yl)-5-(4-(dimethoxymethyl)piperidin-1-yl)-3- methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (0.5 g, 0.84 mmol) in dioxane (20 mL) was added Pd(OH)2 / C (1.2 g, 8.4 mmol, 10 %). The mixture was stirred at 50 ℃ for 3 hours under H2at 0.4 MPa. The catalyst was filtered off and washed with dioxane (3 20 mL). The mixture was concentrated in vacuum to give the desired compound (0.18 g, 51.4 % yield) as a grey solid. LC / MS: 417.1 [M+H]+.

[0434] Step 4: Preparation of 1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d] imidazol-5-yl)piperidine-4-carbaldehyde

[0435] To a solution of 3-(5-(4-(dimethoxymethyl)piperidin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-1-yl)piperidine-2,6-dione (70 mg, 0.17 mmol) in DCM (10 mL) was added TFA (3 mL). The reaction was stirred at room temperature for 1 hour. The mixture was concentrated in vacuum to give the title compound (60 mg TFA salt, crude) as a yellow solid. LC / MS: 371.2 [M+H]+.

[0436] Step 5: Preparation of 3-(5-(4-((4-(dimethoxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)-3- methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0437] To a solution of 1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imida zol-5-yl)piperidine-4-carbaldehyde (60 mg TFA salt, crude) in DCM (10 mL) stirred at room temperature was added 4-(dimethoxymethyl)piperidine (26 mg, 0.16 mmol) and DIEA (209 mg, 1.62 mmol). The mixture was stirred at 45 ℃ for 0.5 hours. STAB (86 mg, 0.41 mmol) was added. The mixture was stirred at 45 ℃ for 1 hour. The reaction was quenched with H2O and extracted with DCM. The organic phase was washed with brine and dried over Na2SO4. The solution was concentrated in vacuum and the residuewas purified by flash chromatography on silica gel eluting with DCM: MeOH = 10: 1 to afford the desired compound (30 mg, 36.1 % yield) as a yellow solid. LC / MS: 514.2 [M+H]+.

[0438] Step 6: Preparation of 1-((1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-ben zo[d]imidazol-5-yl)piperidin-4-yl)methyl)piperidine-4-carbaldehyde

[0439] To a solution of 3-(5-(4-((4-(dimethoxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)-3-methyl-2- oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (30 mg, 0.06 mmol) in DCM (10 mL) was added TFA (3 mL). The reaction was stirred at room temperature for 1 hour. The mixture was concentrated in vacuum to give the title compound (30 mg TFA salt, crude) as a white solid. LC / MS: 486.2 [M+H2O+H]+.

[0440] Step 7: Preparation of (2S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydro benzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-(1-((1-((1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2- oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)me thyl)piperidin-4- yl)acetamide

[0441] To a solution of 1-((1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imi dazol-5-yl)piperidin-4-yl)methyl)piperidine-4-carbaldehyde (30 mg TFA salt, crude) in DMA (2 mL) stirred at room temperature was added (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-(piperidin-4-yl)acetamide (30 mg, 0.06 mmol) and DIEA (81 mg, 0.63 mmol). The mixture was stirred at 45 ℃ for 0.5 hours. STAB (33 mg, 0.16 mmol) was added. The mixture was stirred at 45 ℃ for 1 hour. The reaction was quenched with H2O and extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous Na2SO4,and concentrated in vacuum. The residue was purified by Prep-HPLC (Gemini-C18:150 x 21.2 mm, 5 μm. ACN-H2O (0.1% FA, 10% − 40 %) to give the desired product (13.2 mg, 21.4 % yield). LC / MS: 928.3 [M+H]+.1H NMR (400 MHz, DMSO) δ 11.07 (s, 1H), 8.18 (s, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.46 (s, 1H), 7.18 (s, 1H), 7.10 (s, 1H), 6.92 (d, J = 8.6 Hz, 1H), 6.85 (s, 0.3H), 6.81 (s, 1H), 6.71 (s, 0.6H), 6.62 (d, J = 8.7 Hz, 1H), 6.57 (s, 0.3H), 6.48 (dd, J = 8.8, 1.6 Hz, 1H), 6.18 (d, J = 1.6 Hz, 1H), 6.07 (d, J = 8.2 Hz, 1H), 5.28 (dd, J = 12.8, 5.2 Hz, 1H), 4.99 - 4.91 (m, 1H), 4.60 - 4.53 (m, 2H), 4.36 - 4.31 (m, 4H), 3.60 - 3.52 (m, 4H), 2.96 - 2.85 (m, 5H), 2.69 - 2.58 (m, 4H), 2.25 (s, 2H), 2.16 (s, 2H), 2.01 - 1.75 (m, 8H), 1.72 - 1.50 (m, 6H), 1.40 - 1.08 (m, 8H). Example 17: Preparation of (2S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d] 1,4]oxazepin-9-yl)amino)-2-(1-((1-((1-(4-(2,6-dioxopiperidin-3-yl)- 3,5-difluorophenyl)pipe ridin-4-yl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)acetamide (Compound 30)

[0442] Step 1: Preparation of 3-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2,6-difluorophenyl)piperidine- 2,6-dione

[0443] To a solution of 3-(4-bromo-2,6-difluorophenyl)piperidine-2,6-dione (500 mg, 1.64 mmol) in dioxane (10 mL) stirred at room temperature was added 4-(dimethoxymethyl)piperidine (785 mg, 4.93 mmol), Pd-PEPPSI-IPentCl (69 mg, 0.08 mmol) and Cs2CO3(1.6 g, 4.93 mmol). The mixture was stirred at 100 ℃ for 16 hours. The reaction was quenched with H2O and extracted with EA. The organic phase was washed with brine and dried over Na2SO4. The solution was concentrated in vacuum and the residue was purified by flash chromatography on silica gel eluting with DCM:MeOH = 10:1 to afford the desired compound (300 mg, 47.6 % yield) as a brown solid. LC / MS: 383.0 [M+H]+.

[0444] Step 2: Preparation of 1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)piperidine-4- carbaldehyde

[0445] To a solution of 3-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2,6-difluorophenyl)piperidine-2,6- dione (300 mg, 0.78 mmol) in DCM (2 mL) was added TFA (2 mL). The reaction was stirred at room temperature for 1 hour. The mixture was concentrated in vacuum to give the title compound (260 mg TFA salt, crude) as a brown oil. LC / MS: 337.1 [M+H]+.

[0446] Step 3: Preparation of 3-(4-(4-((4-(dimethoxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)-2,6- difluorophenyl)piperidine-2,6-dione

[0447] To a solution of 1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)piperidine-4-carbaldehyde (300 mg TFA salt, crude) in DCM (2 mL) stirred at room temperature was added 4-(dimethoxy methyl)piperidine (284 mg, 1.78 mmol) and TEA (451 mg, 4.46 mmol). The mixture was stirred at room temperature for 1 hour. STAB (378 mg, 1.78 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction was quenched with H2O and extracted with DCM. The organic phase was washed with brine and dried over Na2SO4. The solution was concentrated in vacuum and the residue was purified by flash chromatography on silica gel eluting with DCM:MeOH = 10:1 to afford the desired compound (350 mg, 52.4 % yield) as a yellow solid. LC / MS: 480.2 [M+H]+.

[0448] Step 4: Preparation of 1-((1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)piperidin-4- yl)methyl)piperidine-4-carbaldehyde

[0449] To a solution of 3-(4-(4-((4-(dimethoxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)-2,6- difluorophenyl)piperidine-2,6-dione (250 mg, 0.52 mmol) in DCM (2 mL) was added TFA (2 mL). The reaction was stirred at room temperature for 1 hour. The mixture was concentrated to give the title compound (260 mg TFA salt, crude) as a brown oil. LC / MS: 434.2 [M+H]+.

[0450] Step 5: Preparation of (2S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydroben zo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-(1-((1-((1-(4-(2,6-dioxopiperidin-3-yl)-3,5-di fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)acetamide

[0451] To a solution of 1-((1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)piperidin-4-yl)methyl)pi peridine-4-carbaldehyde (150 mg, TFA salt, crude) in DCM (2 mL) stirred at room temperature was added (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo [1,2- d][1,4]oxazepin-9-yl)amino)-2-(piperidin-4-yl)acetamide (236 mg, 0.35 mmol) and TEA (175 mg, 1.73 mmol). The mixture was stirred at room temperature for 0.5 hours. STAB (147 mg, 0.69 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction was quenched with H2O and extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous Na2SO4,and concentrated in vacuum. The residue was purified by Prep-HPLC (Gemini-C18:150 x 21.2 mm, 5 μm. ACN-H2O (0.1% FA, 10 − 30%) to give the desired product (20 mg, 6.5 % yield) as a white solid. LC / MS: 447.8 [M / 2+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 8.99 (brs, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.62 (s, 1H), 7.27 - 7.18 (m, 2H), 6.84 (s, 0.2H), 6.70 (s, 0.4H), 6.66 (d, J = 13.0 Hz, 2H), 6.56 (s, 0.2H), 6.50 (d, J = 8.9 Hz, 1H), 6.27 - 6.12 (m, 2H), 5.02 - 4.88 (m, 1H), 4.64 - 4.54 (m, 2H), 4.35 (s, 3H), 4.09 - 4.02 (m, 1H), 3.81 (d, J = 12.4 Hz, 2H), 3.69 - 3.66 (m, 1H), 3.60 - 3.51 (m, 7H), 3.25 - 3.17 (m, 1H), 3.13 - 3.04 (m, 1H), 3.00 - 2.97 (m, 2H), 2.92 - 2.81 (m, 4H), 2.80 - 2.72 (m, 3H), 2.14 - 2.00 (m, 4H), 1.97 - 1.88 (m, 4H), 1.82 - 1.74 (m, 3H), 1.69 - 1.56 (m, 2H), 1.52 - 1.38 (m, 2H), 1.27 - 1.21 (m, 2H).Example 18: Preparation of (2S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-(1-((1-((1-(3-(2,6-dioxopiperidin-3-yl)-1- methyl-1H-indazol-6-yl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)acetamide (Compound 31)

[0452] Step 1: Preparation of 6-bromo-3-iodo-1-methyl-1H-indazole

[0453] To a solution of 6-bromo-3-iodo-1H-indazole (5.0 g, 15.5 mmol) and KOH (2.2 g, 38.7 mmol) in acetone (30 mL) stirred under N2was added iodomethane (3.3 g, 23.3 mmol). The mixture was stirred at 20 ℃ for 16 hours. The reaction was quenched with H2O and extracted with EA. The organic phase was washed with brine and dried over Na2SO4. The solution was concentrated in vacuum and the residue was purified by flash chromatography on silica gel eluting with PE:EA = 25:1 to afford the desired compound (3.3 g, 63.2 % yield) as a yellow solid. LC / MS:336.9 [M+H]+.

[0454] Step 2: Preparation of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-1-methyl-1H-indazole

[0455] To a solution of 6-bromo-3-iodo-1-methyl-1H-indazole (1.0 g, 3.0 mmol) in dioxane (4 mL) and H2O (1 mL) stirred at room temperature was added 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine (1.1 g, 3.6 mmol), Pd(dppf)Cl2(0.22 g, 0.3 mmol) and KF (0.7 g, 12.0 mmol). The mixture was stirred at 90 ℃ for 16 hours. The solution was concentrated in vacuum and the residue was purified by flash chromatography on silica gel eluting with DCM: EA = 20: 1 to afford the desired compound (0.6 g, 40 % yield) as a white solid. LC / MS: 500.0 [M+H]+.

[0456] Step 3: Preparation of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-(4-(dimethoxymethyl)piperidin-1-yl)- 1-methyl-1H-indazole

[0457] To a solution of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-1-methyl-1H-indazole (600 mg, 1.2 mmol) in dioxane (10 mL) stirred under N2at room temperature was added 4-(dimethoxymethyl) piperidine (573 mg, 3.6 mmol), Pd2(dba)3(138 mg, 0.2 mmol), X-PHOS (114 mg, 0.2 mmol) and t- BuONa (346 mg, 3.6 mmol). The mixture was stirred at 90 ℃ for 2 hours. The solution was concentrated in vacuum and the residue was purified by flash chromatography on silica gel eluting with PE: EA = 5: 1 + DCM (5 %) to afford the desired compound (480 mg, 69.1 % yield) as a white solid. LC / MS: 579.2 [M+H]+.

[0458] Step 4: Preparation of 3-(6-(4-(dimethoxymethyl)piperidin-1-yl)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione

[0459] To a solution of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-(4-(dimethoxymethyl)piperidin-1-yl)-1- methyl-1H-indazole (480 mg, 0.83 mmol) in THF (20 mL) was added Pd(OH)2 / C (582 mg, 4.15 mmol, 10 %). The mixture was stirred at 50 ℃ for 2 hours under H2at 0.4 MPa. The catalyst was filtered off and washed with THF (3 x 20 mL). The solution was concentrated in vacuum to give the desired compound (300 mg, 90.3 % yield) as a white solid. LC / MS:401.2 [M+H]+.

[0460] Step 5: Preparation of 1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidine-4- carbaldehyde

[0461] To a solution of 3-(6-(4-(dimethoxymethyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine- 2,6-dione (100 mg, 0.25 mmol) in DCM (10 mL) was added TFA (3 mL). The reaction was stirred at room temperature for 1 hour. The mixture was concentrated in vacuum to give the title compound (100 mg TFA salt, crude) as a yellow solid. LC / MS: 355.1 [M+H]+.

[0462] Step 6: Preparation of 3-(6-(4-((4-(dimethoxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)-1- methyl-1H-indazol-3-yl)piperidine-2,6-dione

[0463] To a solution of 1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidine-4- carbaldehyde (100 mg, 0.28 mmol) in DCM (10 mL) stirred at room temperature was added 4- (dimethoxymethyl)piperidine (45 mg, 0.28 mmol) and DIEA (364 mg, 2.82 mmol). The mixture was stirred at 45 ℃ for 0.5 hours. STAB (150 mg, 0.71 mmol) was added. The mixture was stirred at 45 ℃ for 1 hour. The solution was concentrated in vacuum and the residue was purified by flash chromatography on silica gel eluting with DCM:MeOH = 10:1 to afford the desired compound (80 mg, 57 % yield) as a yellow solid. LC / MS: 498.2 [M+H]+.

[0464] Step 7: Preparation of 1-((1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-4- yl)methyl)piperidine-4-carbaldehyde

[0465] To a solution of 3-(6-(4-((4-(dimethoxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)-1-methyl- 1H-indazol-3-yl)piperidine-2,6-dione (80 mg, 0.16 mmol) in DCM (10 mL) was added TFA (3 mL). The reaction was stirred at room temperature for 1 hour. The mixture was concentrated in vacuum to give the title compound (80 mg TFA salt, crude) as a yellow solid. LC / MS: 452.1 [M+H]+.

[0466] Step 8: Preparation of (2S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydro benzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-(1-((1-((1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H- indazol-6-yl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)acetamide

[0467] To a solution of 1-((1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-4-yl) methyl)piperidine-4-carbaldehyde (50 mg TFA salt, crude) in DMA (10 mL) stirred at room temperature was added (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydro benzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)amino)-2-(piperidin-4-yl)acetamide (50 mg, 0.1 mmol) and DIEA (135 mg, 1.0 mmol). The mixture was stirred at 45 ℃ for 0.5 hours. STAB (56 mg, 0.3 mmol) was added. The mixture was stirred at 45 ℃ for 1 hour. The reaction was quenched with H2O and extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous Na2SO4,and concentrated in vacuum. The residue was purified by Prep-HPLC (Gemini-C18:150 x 21.2 mm, 5 μm. ACN-H2O (0.1 % FA, 10-40%) to give the desired product (22.5 mg, 21.6 % yield) as a white solid. LC / MS: 912.2 [M+H]+.1H NMR (400 MHz, DMSO) δ 10.86 (s, 1H), 8.21 (s, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.47 (d, J = 8.8 Hz, 2H), 7.17 (s, 1H), 7.10 (s, 1H), 6.89 (d, J = 9.2 Hz, 1H), 6.84 - 6.56 (m, 2H), 6.48 (dd, J = 8.8, 1.6 Hz, 1H), 6.18 (s, 1H), 6.08 (d, J = 8.4 Hz, 1H), 5.00 - 4.90 (m, 1H), 4.62 - 4.53 (m, 2H), 4.40 - 4.30 (m, 4H), 4.26 - 4.23 (m, 1H), 3.77 (d, J = 11.6 Hz, 2H), 3.56 (t, J = 7.6 Hz, 1H), 2.95 - 2.85 (m, 4H), 2.71 (t, J = 11.6 Hz, 2H), 2.61 - 2.50 (m, 2H), 2.33 - 2.16 (m, 6H), 2.01 - 1.74 (m, 8H), 1.73 – 1.47 (m, 6H), 1.46 - 0.99 (m, 7H). Example 19: Preparation of (2S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6- dihydrobenzo[f]imidazo [1,2-d][1,4]oxazepin-9-yl)amino)-2-(1-((3-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindo lin-5-yl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperidin-4-yl)acetamide (Compound 32)

[0468] Step 1: Preparation of (2S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihy drobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-(1-((3-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperidin-4-yl)acetamide

[0469] To a solution of 3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-azaspiro[5.5]undecane-9- carbaldehyde (31mg, 0.07 mmol) in DCM (5 mL) was added (S)-2-((2-((S)-4-(di fluoromethyl)-2- oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-(piperidin-4- yl)acetamide (35 mg, 0.07 mmol) and TEA (37 mg, 0.37 mmol). The mixture was stirred at room temperature for 30 minutes and STAB (47 mg, 0.22 mmol) was added. The mixture was stirred at 25 ℃ for 2 hours. The solution was concentrated in vacuum to afford a crude compound. The crude product was purified by Prep-HPLC (Gemini-C18:150 x 21.2 mm, 5 μm. ACN-H2O (0.1% FA)) to give the desired product (23 mg, 94.4 % purity in 214 nm, 33.4 % yield) as a white solid. LC / MS: 884.3 [M+H]+.1H NMR (400 MHz, DMSO) δ 10.95 (s, 1H), 8.15 (s, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.51 - 7.43 (m, 2H), 7.17 (s, 1H), 7.10 (s, 1H), 7.02 (d, J = 7.8 Hz, 2H), 6.84 - 6.57 (m, 1H), 6.47 (dd, J = 8.9 Hz, 1H), 6.18 (d, J = 1.9 Hz, 1H), 6.07 (d, J = 8.2 Hz, 1H), 5.04 (dd, J = 13.2, 5.0 Hz, 1H), 4.99 - 4.90 (m, 1H), 4.63 - 4.52 (m, 2H), 4.37 - 4.27 (m, 5H), 4.18 (d, J = 16 Hz, 1H), 3.56 (t, J = 7.8 Hz, 1H), 2.94 - 2.84 (m, 3H), 2.58 (d, J = 16.9 Hz, 1H), 2.41 - 2.29 (m, 1H), 2.19 (s, 2H), 2.02 - 1.85 (m, 4H), 1.80 (d, J = 10.6 Hz, 1H), 1.72 - 1.19 (m, 16H), 1.17 - 1.02 (m, 4H).

[0470] Compounds in the following table were prepared with procedures described for the above examples. Cpd. No.#Analytical Data (LCMS and NMR)LCMS: 931.4 [M+H]+. 71H NMR (400 MHz, DMSO δ 10.96 (s, 1H), 9.90 (brs, 2H), 8.09 (d, J = 8.8 Hz, 1H), 7.72 (s, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.29 (d, J = 6.0 Hz, 2H), 7.15 - 7.07 (m, 2H), 6.38 (d, J = 8.8 Hz, 1H), 6.12 - 6.10 (m, 1H), 5.05 (dd, J = 13.2, 5.2 Hz, 2H), 4.52 - 4.45 (m, 2H), 4.44 - 4.39 (m, 4H), 4.35 - 4.34 (m, 1H), 4.33 - 4.30 (m, 1H),Example 20: Preparation of (2S,3S)-3-(2-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)piperidin-4-yl)methyl)piperidin-4-yl)acetamido)-N1-(4-methyl-5-(2-(1,1,1-trifluoro-2- methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide (Compound 66)

[0471] Step 1: Preparation of (2S,3S)-3-(2-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)piperidin-4-yl)methyl)piperidin-4-yl)acetamido)-N1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2- yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide

[0472] To a mixture of (2S,3S)-N1-[4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-4-pyridyl]thiazol- 2-yl]-3-[[2-(4-piperidyl)acetyl]amino]pyrrolidine-1,2-dicarboxamide (45 mg, 67.9 μmol, 1 eq, HBr), 1- [2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperidine-4-carbaldehyde (24.1 mg, 67.9 μmol, 1 eq) in DMSO (1 mL) was added AcOH (408 ug, 6.79 μmol, 3.89e-1 μL, 0.1 eq), and the reaction mixture was stirred for 30 minutes. NaBH(OAc)3(43.2 mg, 204 μmol, 3 eq) was then added to the mixture and the resulting mixture was stirred for 30 min at 20 °C. LCMS indicated the reactant was consumed and the desired product was detected (74 % peak area). The mixture was quenched with water (0.1 mL). The mixture solution was purified by Prep-HPLC column: Phenomenex Luna C18150*25 mm*10 μm; mobile phase: [water FA)-ACN]; radient:20 %-40 % B over 10 min) to afford (2S,3S)-3-(2-(1-((1-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)acetamido)-N1-(4- methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2- dicarboxamide (17.3 mg, 18.3 μmol, 27 % yield, 97.6 % purity) as a white solid. LCMS: m / z [M+H]+= 921.2.1H NMR (400 MHz, DMSO-d6) δ = 10.96 - 10.87 (m, 1H), 8.65 - 8.55 (m, 1H), 8.28 - 8.21 (m, 1H), 7.55 (s, 1H), 7.48 (d, J = 9.2 Hz, 1H), 7.41 (br d, J = 4.2 Hz, 2H), 7.17 - 7.05 (m, 1H), 7.04 - 6.93 (m, 2H), 5.03 (dd, J = 5.0, 13.4 Hz, 1H), 4.34 - 4.28 (m, 1H), 4.27 - 4.05 (m, 3H), 3.91 - 3.78 (m, 2H),3.72 - 3.57 (m, 2H), 2.98 - 2.84 (m, 2H), 2.81 - 2.70 (m, 4H), 2.62 - 2.55 (m, 2H), 2.42 (s, 3H), 2.13 - 2.03 (m, 3H), 2.02 - 1.98 (m, 2H), 1.93 (br d, J = 1.8 Hz, 1H), 1.87 - 1.77 (m, 3H), 1.76 - 1.66 (m, 3H), 1.61 (s, 6H), 1.55 (br s, 2H), 1.23 - 1.08 (m, 4H).

[0473] Compounds 70 and 71 were prepared via similar synthetic procedures as example 20.Example 21: Preparation of 2-amino-N-(8-(3-(4-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin- 5-yl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)piperazin-1-yl)propoxy)-7-methoxy-2,3- dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide (Compound 67)

[0474] Step 1: Preparation of tert-butyl 4-((4-(3-((5-(2-aminopyrimidine-5-carboxamido)-7-methoxy- 2,3-dihydroimidazo[1,2-c]quinazolin-8-yl)oxy)propyl)piperazin-1-yl)methyl)piperidine-1-carboxylate

[0475] To a mixture of 2-amino-N-[7-methoxy-8-(3-piperazin-1-ylpropoxy)-2,3-dihydroimidazo[1,2- c]quinazolin-5-yl]pyrimidine-5-carboxamide (280 mg, 543 μmol, 1 eq, HCl) and tert-butyl 4- formylpiperidine-1-carboxylate (150 mg, 705 μmol, 1.3 eq) in DMSO (5 mL) was added AcOH (3.26 mg, 54.3 μmol, 3.11 μL, 0.1 eq) and the reaction mixture was stirred for 0.5 hours. Then NaBH(OAc)3(345 mg, 1.63 mmol, 3 eq) was added to the mixture and the mixture was stirred at 20 °C for 0.5 hours. LCMS indicated that 2-amino-N-[7-methoxy-8-(3-piperazin-1-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin- 5-yl]pyrimidine-5-carboxamide was consumed and formation of desired product was detected. The reaction was poured into water (20 mL), filtered to afford tert-butyl 4-[[4-[3-[[5-[(2-aminopyrimidine-5- carbonyl)amino]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-yl]oxy]propyl]piperazin-1- yl]methyl]piperidine-1-carboxylate (360 mg, 463 μmol, 85.3 % yield, 87 % purity) as a white solid. LCMS: m / z [M+H]+= 677.4.

[0476] Step 2: Preparation of 2-amino-N-(7-methoxy-8-(3-(4-(piperidin-4-ylmethyl)piperazin-1- yl)propoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide

[0477] A solution of tert-butyl 4-[[4-[3-[[5-[(2-aminopyrimidine-5-carbonyl)amino]-7-methoxy-2,3- dihydroimidazo[1,2-c]quinazolin-8-yl]oxy]propyl]piperazin-1-yl]methyl]piperidine-1-carboxylate (100 mg, 148 μmol, 1 eq) in HCl solution (2 M in dioxane, 2 mL, 27.1 eq) was stirred for 1 hour at 20 °C. LCMS indicated that the reactant was consumed and formation of desired product was detected. The reaction was concentrated under reduced pressure to afford 2-amino-N-[7-methoxy-8-[3-[4-(4- piperidylmethyl)piperazin-1-yl]propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5- carboxamide (90 mg, 147 μmol, 99.3 % yield, HCl) as a white solid. LCMS: m / z [M+H]+= 577.4.

[0478] Step 3: Preparation of 2-amino-N-(8-(3-(4-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin- 5-yl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)piperazin-1-yl)propoxy)-7-methoxy-2,3- dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide

[0479] To a solution of 2-amino-N-[7-methoxy-8-[3-[4-(4-piperidylmethyl)piperazin-1-yl]propoxy]-2,3- dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide (40 mg, 65.2 μmol, 1 eq, HCl) in DMSO (1 mL) was added 1-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperidine-4-carbaldehyde (27.8 mg, 78.3 μmol, 1.2 eq), AcOH (15 mg, 250 μmol, 14.3 μL, 3.83 eq), and the mixture was stirred for 15 minutes . Then NaBH(OAc)3(60 mg, 283 μmol, 4.34 eq) was added to the mixture and the mixture was stirred for 15 minutes at 20 °C. LCMS indicated that 2-amino-N-[7-methoxy-8-[3-[4-(4- piperidylmethyl)piperazin-1-yl]propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5- carboxamide was consumed and formation of desired product (32 % peak area) was detected. The mixture was quenched with water (0.1 mL). The crude product was purified by preparative HPLC: (column: Phenomenex luna C18150*25 mm* 10 μm; mobile phase: [water(FA)-ACN]; gradient:0 %-30 % B over 10 min) to afford 2-amino-N-[8-[3-[4-[[1-[[1-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]-4- piperidyl]methyl]-4-piperidyl]methyl]piperazin-1-yl]propoxy]-7-methoxy-2,3-dihydroimidazo[1,2- c]quinazolin-5-yl]pyrimidine-5-carboxamide (14.8 mg, 15.3 μmol, 23.4 % yield, 94.8 % purity) as a white solid. LCMS: m / z [M+H]+= 916.5,1H NMR (400 MHz, DMSO-d6) δ = 12.76 (s, 1H), 10.94 (s, 1H), 8.92 (s, 1H), 8.18 (s, 2H), 7.60 (d, J = 9.0 Hz, 1H), 7.53 - 7.45 (m, 1H), 7.34 (br s, 1H), 7.08 - 7.00 (m, 2H), 5.11 - 4.98 (m, 1H), 4.37 - 4.29 (m, 1H), 4.27 - 4.20 (m, 1H), 4.17 (br d, J = 4.8 Hz, 2H), 4.10 - 4.02 (m, 2H), 4.02 - 3.97 (m, 1H), 3.95 (br d, J = 4.4 Hz, 3H), 3.88 - 3.79 (m, 3H), 3.08 - 2.91 (m, 4H), 2.87 - 2.76 (m, 4H), 2.61 (br s, 1H), 2.46 - 2.37 (m, 6H), 2.29 - 2.06 (m, 5H), 2.04 - 1.87 (m, 4H), 1.83 - 1.70 (m, 3H), 1.69 - 1.57 (m, 2H), 1.54 - 1.29 (m, 2H), 1.28 - 1.04 (m, 4H), 1.03 - 0.77 (m, 1H).

[0480] Compounds 68, 69 and 80 were prepared via similar synthetic procedures as example 2.Example 22 : Preparation of (2S,3S)-3-(((1-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3- azaspiro[5.5]undecan-9-yl)methyl)piperidin-4-yl)methyl)amino)-N1-(4-methyl-5-(2-(1,1,1-trifluoro- 2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide (Compound 73)

[0481] Step 1: Preparation of 3-(5-(9-((4-(dimethoxymethyl)piperidin-1-yl)methyl)-3- azaspiro[5.5]undecan-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0482] To a mixture of 3-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]-3-azaspiro[5.5]undecane-9- carbaldehyde (120 mg, 283 μmol, 1 eq), 4-(dimethoxymethyl)piperidine (45.1 mg, 283 μmol, 1 eq) in DMSO (2 mL) was added AcOH (15 mg, 250 μmol, 14.3 μL, 0.1 eq) and the reaction mixture was stirred at 20 °C for 0.5 hours. Then NaBH(OAc)3(120 mg, 567 μmol, 2 eq) was added to the mixture and the resulting mixture was stirred at 20 °C for 0.5 hours. LCMS indicated that the reactant was consumed and the desired product was detected. The reaction was quenched with water (10 mL). The mixture was purified by reversed phase HPLC (0.1 % FA condition) to afford 3-[5-[9-[[4-(dimethoxymethyl)-1- piperidyl]methyl]-3-azaspiro[5.5]undecan-3-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (140 mg, 180 μmol, 63.6 % yield, 73 % purity) as a yellow solid. LCMS: m / z [M+H]+=567.3,1H NMR (400 MHz, DMSO-d6) δ = 10.93 (s, 1H), 8.14 (s, 1H), 7.49 (d, J = 9.4 Hz, 1H), 7.03 (s, 1H), 5.03 (dd, J = 5.4, 13.2 Hz, 1H), 4.31 (br d, J = 16.8 Hz, 1H), 4.24 - 4.16 (m, 1H), 4.16 - 3.88 (m, 4H), 3.25 (s, 6H), 2.18 - 2.04 (m, 2H), 1.96 - 1.86 (m, 1H), 1.70 - 1.51 (m, 10H), 1.46 - 1.24 (m, 5H), 1.16 - 0.99 (m, 4H).

[0483] Step 2: Preparation of 1-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3- azaspiro[5.5]undecan-9-yl)methyl)piperidine-4-carbaldehyde

[0484] To a solution of 3-[5-[9-[[4-(dimethoxymethyl)-1-piperidyl]methyl]-3-azaspiro[5.5]undecan-3- yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (40 mg, 70.6 μmol, 1 eq) in THF (0.5 mL) was added HCl (2 M in H2O, 1 mL, 28.3 eq) and the mixture was stirred at 70 °C for 2 hours. LCMS indicated complete consumption of the reactant and formation of the desired product. The reaction was neutralized with saturated NaHCO3aqueous solution to pH=7 and extracted with DCM (10 mL*3). Then the organiclayers were combined and dried over anhydrous Na2SO4, concentrated under reduced pressure to afford 1- [[3-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]-3-azaspiro[5.5]undecan-9-yl]methyl]piperidine-4- carbaldehyde (40 mg, crude) as a yellow solid. LCMS: m / z [M+H]+= 521.4.

[0485] Step 3: Preparation of (2S,3S)-3-(((1-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3- azaspiro[5.5]undecan-9-yl)methyl)piperidin-4-yl)methyl)amino)-N1-(4-methyl-5-(2-(1,1,1-trifluoro-2- methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide

[0486] To a mixture of 1-[[3-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]-3-azaspiro[5.5]undecan- 9-yl]methyl]piperidine-4-carbaldehyde (40 mg, 76.8 μmol, 1 eq) and (2S,3S)-3-amino-N1-[4-methyl-5- [2-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-4-pyridyl]thiazol-2-yl]pyrrolidine-1,2-dicarboxamide (41.3mg, 76.8 μmol, 1 eq, HBr) in DMSO (1 mL) was added AcOH (4.61 mg, 76.8 μmol, 4.40 μL, 1 eq) and the mixture was stirred at 20 °C for 0.5 hours. Then NaBH(OAc)3(32.6 mg, 154 μmol, 2 eq) was added to the mixture and the resulting mixture was stirred at 20 °C for 0.5 hours. LCMS indicated the reactant was consumed and the desired product was detected. The reaction was quenched with water (1 mL). The reaction was purified by Prep-HPLC (column: Phenomenex luna C18150 * 25 mm * 10 μm; mobile phase: [water (FA)-ACN]; gradient:11 %-41 % B over 10 min) to afford (2S,3S)-3-[[1-[[3-[2-(2,6-dioxo- 3-piperidyl)-1-oxo-isoindolin-5-yl]-3-azaspiro[5.5]undecan-9-yl]methyl]-4-piperidyl]methylamino]-N1- [4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-4-pyridyl]thiazol-2-yl]pyrrolidine-1,2-dicarboxamide (18.8 mg, 18.7 μmol, 24.3 % yield, 95.7 % purity) as a white solid. LCMS: m / z [M+H]+= 961.5,1H NMR (400 MHz, DMSO-d6) δ = 10.94 (s, 1H), 8.61 (d, J = 5.4 Hz, 1H), 7.55 (s, 1H), 7.50 (d, J = 9.4 Hz, 1H), 7.41 (br d, J = 5.0 Hz, 1H), 7.06 - 7.01 (m, 2H), 5.04 (dd, J = 5.0, 13.0 Hz, 1H), 4.33 - 4.16 (m, 2H), 3.77 - 3.53 (m, 2H), 3.28 - 3.10 (m, 5H), 3.03 - 2.73 (m, 6H), 2.62 - 2.54 (m, 2H), 2.46 - 2.41 (m, 3H), 2.41 - 2.34 (m, 2H), 2.34 - 2.28 (m, 1H), 2.03 - 1.80 (m, 5H), 1.70 (br d, J = 7.8 Hz, 4H), 1.62 (s, 6H), 1.58 (br s, 5H), 1.51 - 1.35 (m, 4H), 1.21 - 1.10 (m, 4H).

[0487] Compounds 74 and 75 were prepared via similar synthetic procedures as example 22.Example 23: Preparation of (2S,4R)-4-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)piperidin-4-yl)methyl)piperidin-4-yl)amino)-N1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan- 2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide (Compound 76)

[0488] Step 1: Preparation of 3-(5-(4-((1,4-dioxa-8-azaspiro[4.5]decan-8-yl)methyl)piperidin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione

[0489] To a solution of 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-4-carbaldehyde (1.5 g, 2.95 mmol, 1 eq) and 1,4-dioxa-8-azaspiro[4.5]decane (423 mg, 2.95 mmol, 379 μL, 1 eq) in DMSO (8 mL) was added Ti(OEt)4(1.35 g, 5.91 mmol, 1.23 mL, 2 eq) and the mixture was stirred at 25 °C for 1 hour. Then NaBH3CN (371 mg, 5.91 mmol, 2 eq) was added to the reaction mixture at 0 °C and the resulting mixture was stirred at 25 °C for 0.5 hours. LCMS indicated complete consumption of 1-(2- (2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-4-carbaldehyde and formation of a product with desired mass (79.0% peak area). The reaction mixture was diluted with water (50 mL) and extracted with EA (50 mL * 3). The combined organic layers were washed with brine (50 mL * 2), dried over anhydrous Na2SO4and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by reverse-phase chromatography (0.1% FA) and lyophilized to afford 3-(5-(4-((1,4- dioxa-8-azaspiro[4.5]decan-8-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (350 mg, 725 μmol, 24.5% yield) as a white solid. LCMS: m / z [M+H]+= 483.3;1H NMR (400 MHz, DMSO- d6) δ = 10.94 (s, 1H), 7.49 (d, J = 8.7 Hz, 1H), 7.07 - 7.00 (m, 2H), 5.10 - 4.96 (m, 1H), 4.35 - 4.15 (m,2H), 3.93 - 3.76 (m, 7H), 2.99 - 2.75 (m, 3H), 2.60 (br s, 4H), 2.34 (br d, J = 4.4 Hz, 2H), 2.02 - 1.88 (m, 1H), 1.87 - 1.51 (m, 8H), 1.27 - 1.08 (m, 2H).

[0490] Step 2: Preparation of 3-(1-oxo-5-(4-((4-oxopiperidin-1-yl)methyl)piperidin-1-yl)isoindolin-2- yl)piperidine-2,6-dione

[0491] To a solution of 3-(5-(4-((1,4-dioxa-8-azaspiro[4.5]decan-8-yl)methyl)piperidin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (330 mg, 478 μmol, 1 eq) in THF (1 mL) was added HCl solution (2 M in water, 4 mL, 16.7 eq). The mixture was stirred at 70 °C for 2 hours. LC-MS indicated complete consumption of starting material and formation of a product with desired mass (90.0% peak area). The reaction mixture was adjusted with saturated NaHCO3aqueous solution to pH=7. Then the solution was diluted with water (30 mL) and extracted with DCM (15 mL * 5). The combined organic layers were washed with brine (15 mL * 2), dried over anhydrous Na2SO4and filtered. The filtrate was concentrated under reduced pressure to afford 3-(1-oxo-5-(4-((4-oxopiperidin-1-yl)methyl)piperidin-1-yl)isoindolin-2- yl)piperidine-2,6-dione (200 mg, 410 μmol, 85.7% yield, 90.0% purity) as a white solid without further purification. LCMS: m / z [M+H]+= 439.2;1H NMR (400 MHz, DMSO-d6) δ = 10.94 (s, 1H), 7.49 (s, 1H), 7.06 (s, 2H), 5.07 - 5.00 (m, 1H), 4.37 - 4.15 (m, 2H), 3.94 - 3.83 (m, 2H), 3.37 (br s, 2H), 2.96 - 2.77 (m, 3H), 2.67 (br t, J = 6.4 Hz, 3H), 2.34 (br t, J = 5.8 Hz, 4H), 2.28 (br d, J = 7.0 Hz, 2H), 1.98 - 1.91 (m, 1H), 1.86 - 1.73 (m, 3H), 1.27 - 1.13 (m, 3H).

[0492] Step 3: Preparation of (2S,4R)-4-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)piperidin-4-yl)methyl)piperidin-4-yl)amino)-N1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2- yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide

[0493] To a solution of 3-(1-oxo-5-(4-((4-oxopiperidin-1-yl)methyl)piperidin-1-yl)isoindolin-2- yl)piperidine-2,6-dione (100 mg, 205 μmol, 1 eq) and (2S,4R)-4-amino-N1-(4-methyl-5-(2-(1,1,1- trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide (74.9 mg, 164 μmol, 0.8 eq) in DMSO (5 mL) was added Ti(OEt)4(93.6 mg, 410 μmol, 85.1 μL, 2 eq), and the mixture was stirred at 25 °C for 1 hour. Then NaBH3CN (25.7 mg, 410 μmol, 2 eq) was added and the resulting mixture was stirred at 25 °C for 0.5 hours. LC-MS indicated complete consumption of 3-(1-oxo-5-(4-((4- oxopiperidin-1-yl)methyl)piperidin-1-yl)isoindolin-2-yl)piperidine-2,6-dione and formation of the desired product (60.0% peak area). The reaction mixture was added THF (20 mL) and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by Prep-HPLC (column: Waters Xbridge 150 * 25 mm 10 μm; mobile phase: [water ( NH4HCO3)-ACN]; gradient: 35% - 55% B over 8 min) and lyophilized to afford (2S,4R)-4-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)piperidin-4-yl)methyl)piperidin-4-yl)amino)-N1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2- yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide (19.7 mg, 22.4 μmol, 10.9% yield, 100%purity) as a white solid. LCMS: m / z [M+H]+= 879.3; HPLC: 98.3% purity (220 nm), RT = 1.65 min;1H NMR (400 MHz, DMSO-d6) δ = 10.94 (s, 1H), 8.60 (d, J = 5.2 Hz, 1H), 7.57 - 7.48 (m, 2H), 7.44 - 7.36 (m, 2H), 7.06 - 7.01 (m, 2H), 7.00 - 6.89 (m, 1H), 5.09 - 5.00 (m, 1H), 4.36 - 4.16 (m, 3H), 3.92 - 3.75 (m, 3H), 3.56 - 3.44 (m, 1H), 3.23 - 3.16 (m, 1H), 2.97 - 2.74 (m, 6H), 2.62 - 2.55 (m, 2H), 2.42 (s, 3H), 2.39 - 2.32 (m, 2H), 2.17 - 2.08 (m, 2H), 1.99 - 1.86 (m, 5H), 1.76 (br d, J = 11.2 Hz, 5H), 1.62 (s, 6H), 1.30 - 1.12 (m, 4H).

[0494] Compounds 77, 78, and 82 were prepared via similar synthetic procedures as example 23.Example 24: Preparation of (2S,4S)-4-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)piperidin-4-yl)methyl)piperidin-4-yl)amino)-N1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan- 2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide (Compound 79)

[0495] To a solution of 3-(1-oxo-5-(4-((4-oxopiperidin-1-yl)methyl)piperidin-1-yl)isoindolin-2- yl)piperidine-2,6-dione (100 mg, 205 μmol, 1 eq) and (2S,4S)-4-amino-N1-(4-methyl-5-(2-(1,1,1- trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide (74.9 mg, 164 μmol, 0.8 eq) in DMSO (5 mL) was added Ti(OEt)4(93.6 mg, 410 μmol, 85.1 μL, 2 eq) and the mixture was stirred at 25 °C for 1 hour. Then NaBH3CN (25.7 mg, 410 μmol, 2 eq) was added and the resulting mixture was stirred at 25 °C for another 0.5 hours. LCMS indicated complete consumption of 3-(1-oxo-5- (4-((4-oxopiperidin-1-yl)methyl)piperidin-1-yl)isoindolin-2-yl)piperidine-2,6-dione and formation of desired product (36.0% peak area). The mixture was diluted with THF (20 mL) and filtered. Then the filtrate was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (column: Waters Xbridge 150 * 25 mm 10 μm; mobile phase: [water ( NH4HCO3)-ACN]; gradient: 35% - 55% B over 8 min) and lyophilized to afford (2S,4S)-4-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)amino)-N1-(4-methyl-5-(2-(1,1,1-trifluoro-2- methyl-propan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide (17.1 mg, 18.8 μmol, 9.17% yield, 97.0% purity) as a white solid. LCMS: m / z [M+H]+= 879.4; HPLC: 96.2% purity (220 nm), RT = 1.71 min;1H NMR (400 MHz, DMSO-d6) δ = 10.93 (br s, 1H), 8.59 (d, J = 5.4 Hz, 1H), 7.57 - 7.47 (m, 3H), 7.43 - 7.38 (m, 1H), 7.05 - 7.01 (m, 2H), 6.99 - 6.91 (m, 1H), 5.09 - 4.99 (m, 1H), 4.31 - 4.16 (m, 2H), 3.88 - 3.78 (m, 3H), 3.37 - 3.36 (m, 1H), 3.25 (br s, 1H), 2.90 - 2.76 (m, 6H), 2.60 (br d, J = 2.8 Hz, 2H), 2.41 (s, 3H), 2.36 - 2.30 (m, 2H), 2.11 (br d, J = 6.2 Hz, 2H), 2.00 - 1.83 (m, 5H), 1.76 (br d, J = 10.8 Hz, 5H), 1.61 (s, 6H), 1.26 - 1.14 (m, 4H).

[0496] Compounds 81 and 83 were prepared via similar synthetic procedures as example 24.Example 25: Preparation of 2-amino-N-(8-(3-(2-(2-aminoethyl)-4-((1-((7-(2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)-7-azaspiro[3.5]nonan-2-yl)methyl)piperidin-4-yl)methyl)piperazin-1- yl)propoxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide

[0497] Step 1: Preparation of 3-(2-(((benzyloxy)carbonyl)amino)ethyl)piperazine-1-carboxylate

[0498] To a solution of 4-(tert-butyl) 1-(2-(trimethylsilyl)ethyl) 2-(2- (((benzyloxy)carbonyl)amino)ethyl)piperazine-1,4-dicarboxylate (2 g, 3.94 mmol, 1 eq) in DMF (20 mL) was added CsF (2.99 g, 19.7 mmol, 5 eq). The mixture was stirred at 50 °C for 2 hours. LCMS indicated complete consumption of starting material and formation of a product with desired mass (54% peak area). The reaction was quenched with water (100 mL), extracted with EA (50 mL * 3). The combined organiclayers were washed with brine (50 mL) and dried over anhydrous Na2SO4. The organic phase was filtered and the filtrate was concentrated under reduced pressure to afford tert-butyl 3-(2- (((benzyloxy)carbonyl)amino)ethyl)piperazine-1-carboxylate (1.2 g, 3.30 mmol, 83.8% yield) as a yellow oil. LCMS: m / z [M+H]+= 364.2;1H NMR (400 MHz, CDCl3) δ = 8.03 (s, 1H), 7.39 - 7.35 (m, 5H), 5.10 (s, 2H), 4.04 - 3.80 (m, 2H), 3.49 - 3.35 (m, 1H), 3.30 - 3.17 (m, 1H), 2.89 - 2.78 (m, 2H), 2.73 - 2.63 (m, 2H), 2.62 - 2.44 (m, 1H), 1.65 - 1.54 (m, 2H), 1.47 (s, 9H).

[0499] Step 2: Preparation of tert-butyl 4-(3-((5-(2-aminopyrimidine-5-carboxamido)-7-methoxy-2,3- dihydroimidazo[1,2-c]quinazolin-8-yl)oxy)propyl)-3-(2-(((benzyloxy)carbonyl)amino)ethyl)piperazine-1- carboxylate

[0500] To a solution of tert-butyl 3-(2-(((benzyloxy)carbonyl)amino)ethyl)piperazine-1-carboxylate (321 mg, 885 μmol, 1.2 eq) in DMSO (4 mL) was added DIPEA (476 mg, 3.69 mmol, 642 μL, 5 eq) and 2- amino-N-(8-(3-bromopropoxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5- carboxamide (350 mg, 737 μmol, 1 eq) and KI (122 mg, 737 μmol, 1 eq). The mixture was stirred at 80 °C for 12 hours. LCMS indicated that the starting material (40.1% peak area) remained and a product with desired mass (19.9% peak area) was detected. The reaction mixture was quenched with water (40 mL), filtered and the filtrate was concentrated under reduced pressure. The filter cake was triturated with EA (20 mL). Then the suspension was filtered and the filter cake was dried under reduced pressure to afford tert-butyl 4-(3-((5-(2-aminopyrimidine-5-carboxamido)-7-methoxy-2,3-dihydroimidazo[1,2- c]quinazolin-8-yl)oxy)propyl)-3-(2-(((benzyloxy)carbonyl)amino)ethyl)piperazine-1-carboxylate (340 mg, 84.9 μmol, 11.5% yield, 18.9% purity) as a yellow solid. LCMS: m / z [M+H]+= 757.4.

[0501] Step 3: Preparation of benzyl (2-(1-(3-((5-(2-aminopyrimidine-5-carboxamido)-7-methoxy-2,3- dihydroimidazo[1,2-c]quinazolin-8-yl)oxy)propyl)piperazin-2-yl)ethyl)carbamate

[0502] To a solution of tert-butyl 4-(3-((5-(2-aminopyrimidine-5-carboxamido)-7-methoxy-2,3- dihydroimidazo[1,2-c]quinazolin-8-yl)oxy)propyl)-3-(2-(((benzyloxy)carbonyl)amino)ethyl)piperazine-1- carboxylate (330 mg, 82.4 μmol, 1 eq) in DCM (5 mL) was added HCl solution (4 M in dioxane, 10 mL, 485 eq). The mixture was stirred at 25 °C for 10 minutes. LCMS indicated complete consumption of starting material and formation of product with the desired mass (18.1% peak area). The reaction was concentrated under reduced pressure. The residue was purified by Prep-HPLC [column: Phenomenex luna C 18150 * 25 mm * 10 μm; mobile phase: [water (FA) - ACN]; gradient: 12% - 21% B over 9 minutes] and lyophilized to afford benzyl (2-(1-(3-((5-(2-aminopyrimidine-5-carboxamido)-7-methoxy-2,3- dihydroimidazo[1,2-c]quinazolin-8-yl)oxy)propyl)piperazin-2-yl)ethyl)carbamate (45 mg, 52.5 μmol, 63.7% yield, 76.7% purity) as a yellow solid. LCMS: m / z [M+H]+= 657.3.

[0503] Step 4: Preparation of benzyl (2-(1-(3-((5-(2-aminopyrimidine-5-carboxamido)-7-methoxy-2,3- dihydroimidazo[1,2-c]quinazolin-8-yl)oxy)propyl)-4-((1-((7-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)-7-azaspiro[3.5]nonan-2-yl)methyl)piperidin-4-yl)methyl)piperazin-2- yl)ethyl)carbamate

[0504] To a solution of benzyl (2-(1-(3-((5-(2-aminopyrimidine-5-carboxamido)-7-methoxy-2,3- dihydroimidazo[1,2-c]quinazolin-8-yl)oxy)propyl)piperazin-2-yl)ethyl)carbamate (45 mg, 52.5 μmol, 1 eq) in DMSO (2 mL) and THF (2 mL) was added 1-((7-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)-7-azaspiro[3.5]nonan-2-yl)methyl)piperidine-4-carbaldehyde (38.8 mg, 78.8 μmol, 1.5 eq) and AcOH (6.31 mg, 105 μmol, 6.02 μL, 2 eq). The mixture was stirred at 35 °C for 12 hours. The NaBH(OAc)3(33.4 mg, 157 μmol, 3 eq) was added to the mixture and the mixture was stirred at 25 °C for 0.5 hours. LCMS indicated complete consumption of starting material and formation of a product with the desired mass (56.1% peak area). The reaction was concentrated under reduced pressure. The residue was purified by Prep-HPLC [column: Phenomenex luna C 18150 * 40 mm * 15 μm; mobile phase: [water (TFA) - ACN]; gradient: 9% - 39% B over 12 minutes] and lyophilized to afford benzyl (2-(1-(3-((5-(2- aminopyrimidine-5-carboxamido)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-yl)oxy)propyl)-4- ((1-((7-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-7-azaspiro[3.5]nonan-2-yl)methyl)piperidin-4- yl)methyl)piperazin-2-yl)ethyl)carbamate (50 mg, 38.3 μmol, 72.9% yield, 95.6% purity, TFA salt) as a white solid. LCMS: m / z [M+H]+= 1133.7; HPLC: 95.6% purity (220 nm), RT = 1.737 minutes.

[0505] Step 5: Preparation of 2-amino-N-(8-(3-(2-(2-aminoethyl)-4-((1-((7-(2-(2,6-dioxopiperidin-3-yl)- 1-oxoisoindolin-5-yl)-7-azaspiro[3.5]nonan-2-yl)methyl)piperidin-4-yl)methyl)piperazin-1-yl)propoxy)- 7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide

[0506] To a solution of benzyl (2-(1-(3-((5-(2-aminopyrimidine-5-carboxamido)-7-methoxy-2,3- dihydroimidazo[1,2-c]quinazolin-8-yl)oxy)propyl)-4-((1-((7-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)-7-azaspiro[3.5]nonan-2-yl)methyl)piperidin-4-yl)methyl)piperazin-2- yl)ethyl)carbamate (50 mg, 40.0 μmol, 1 eq, TFA salt) in DCM (3 mL) was added HBr (447 mg, 1.82 mmol, 0.3 mL, 33% purity, 45.4 eq). The mixture was stirred at 25 °C for 1 hour. LCMS indicated complete consumption of starting material and formation of product with the desired mass (64.6% peak area). The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC [column: Phenomenex luna C 18150 * 25 mm * 10 μm; mobile phase: [water (TFA) - ACN]; gradient: 4% - 34% B over 12 minutes] and lyophilized to afford 2-amino-N-(8-(3-(2-(2- aminoethyl)-4-((1-((7-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-7-azaspiro[3.5]nonan-2- yl)methyl)piperidin-4-yl)methyl)piperazin-1-yl)propoxy)-7-methoxy-2,3-dihydroimidazo[1,2- c]quinazolin-5-yl)pyrimidine-5-carboxamide (27 mg, 25.4 μmol, 63.3% yield, 94.0% purity, TFA salt) asa yellow solid. LCMS: m / z [M+H]+= 999.8; HPLC: 94.0% purity (220 nm), RT = 1.286 min;1H NMR(400 MHz, DMSO-d6) δ = 13.43 (br s, 1H), 10.94 (s, 1H), 9.49 - 9.32 (m, 1H), 8.97 (s, 2H), 8.01 (br d, J = 9.2 Hz, 1H), 7.95 (br s, 2H), 7.56 (br s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.40 (br d, J = 9.6 Hz, 1H), 7.10 - 7.00 (m, 2H), 5.04 (dd, J = 5.2, 13.2 Hz, 1H), 4.53 - 4.46 (m, 2H), 4.35 - 4.28 (m, 3H), 4.26 - 4.15 (m, 4H), 4.00 (s, 3H), 3.42 (br d, J = 10.0 Hz, 3H), 3.32 (br s, 4H), 3.24 - 3.15 (m, 6H), 2.96 - 2.80 (m, 7H), 2.72 - 2.57 (m, 4H), 2.39 - 2.29 (m, 2H), 2.23 - 2.12 (m, 2H), 2.09 - 2.01 (m, 3H), 1.98 - 1.86 (m, 5H), 1.69 (br s, 2H), 1.63 - 1.54 (m, 4H), 1.43 - 1.26 (m, 2H).

[0507] Compound 85 was prepared via similar synthetic procedures as example 25.Example 26: preparation of (2S)-2-((2-(3-(aminomethyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5- yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-(1-((1-((1-(3-(2,6-dioxopiperidin- 3-yl)-1-methyl-1H-indazol-6-yl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)piperidin-4- yl)acetamide (Compound 37)

[0508] Step 1: preparation of (S)-2-((2-(3-((((benzyloxy)carbonyl)amino)methyl)-1-(2,2,2- trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-(1- (tert-butoxycarbonyl)piperidin-4-yl)acetic acid

[0509] To a solution of benzyl N-[[5-(9-bromo-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-2-yl)-1- (2,2,2-trifluoroethyl)-1,2,4-triazol-3-yl]methyl]carbamate (327 mg, 566 μmol, 1 eq) and (2S)-2-amino-2- (1-tert-butoxycarbonyl-4-piperidyl)acetic acid (344 mg, 1.33 mmol, 2.35 eq) in DMSO (10 mL) was added Cu2O (81.0 mg, 566 μmol, 57.9 μL, 1 eq) and K3PO4 (361 mg, 1.70 mmol, 3 eq). The resulting mixture was stirred at 100 °C for 6 hours under microwave. LCMS indicated complete consumption of the starting material and formation of desired product (78.9% peak area). The reaction solution was used into next step directly without purification.

[0510] Step 2: preparation of tert-butyl (S)-4-(2-amino-1-((2-(3-((((benzyloxy)carbonyl)amino)methyl)- 1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9- yl)amino)-2-oxoethyl)piperidine-1-carboxylate

[0511] NH4Cl (303 mg, 5.66 mmol, 10 eq), TEA (5723 mg, 5.66 mmol, 7873 μL, 10 eq) and HATU (2.15 g, 5.66 mmol, 10 eq) were added to the crude mixture from step 1. The reaction mixture was stirred at 20 °C for 0.5 hour. LCMS indicated complete consumption of the starting material and formation of the desired product (61.8% peak area). The reaction mixture was filtered and the filtrate was purified by reverse phase flash (0.1% FA) and lyophilized to afford tert-butyl (S)-4-(2-amino-1-((2-(3- ((((benzyloxy)carbonyl)amino)methyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-oxoethyl)piperidine-1-carboxylate (300 mg, 380 μmol, 67.2% yield, 95.5% purity) as a yellow solid. LCMS: m / z [M+H]+= 754.4.

[0512] Step 3: preparation of benzyl (S)-((5-(9-((2-amino-2-oxo-1-(piperidin-4-yl)ethyl)amino)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3- yl)methyl)carbamate

[0513] To a solution of tert-butyl 4-[(1S)-2-amino-1-[[2-[5-(benzyloxycarbonylaminomethyl)-2-(2,2,2- trifluoroethyl)-1,2,4-triazol-3-yl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl]amino]-2-oxo- ethyl]piperidine-1-carboxylate (120 mg, 159 μmol, 1 eq) in DCM (1 mL) was added HCl / dioxane (4 M, 2 mL). The resulting mixture was stirred at 20 °C for 0.5 hour. LCMS indicated complete consumption of the starting material and formation of the desired product. (70.5% peak area). The reaction mixture was concentrated under vacuum to give benzyl (S)-((5-(9-((2-amino-2-oxo-1-(piperidin-4-yl)ethyl)amino)- 5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3- yl)methyl)carbamate (110 mg, crude, HCl salt) as a light yellow solid which used to the next step directly.

[0514] Step 4: preparation of benzyl ((5-(9-(((1S)-2-amino-1-(1-((1-((1-(3-(2,6-dioxopiperidin-3-yl)-1- methyl-1H-indazol-6-yl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-2-oxoethyl)amino)- 5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3- yl)methyl)carbamate

[0515] To a solution of 1-[[1-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]-4- piperidyl]methyl]piperidine-4-carbaldehyde (78.6 mg, 158 μmol, 1 eq, FA salt) and benzyl N-[[5-[9- [[(1S)-2-amino-2-oxo-1-(4-piperidyl)ethyl]amino]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-2-yl]-1- (2,2,2-trifluoroethyl)-1,2,4-triazol-3-yl]methyl]carbamate (110 mg, 158 μmol, 1 eq, HCl salt) in DMSO (4 mL) was added AcOH (948, 0.1 eq). The mixture was stirred at 20 °C for 1 hour, then NaBH(OAc)3(100 mg, 474 μmol, 3 eq) was added and the reaction mixture was stirred at 20 °C for 0.5 hour. LCMS indicated complete consumption of the starting material and formation of the desired product (51.9% peak area). The reaction mixture was diluted with THF (20 mL) and then quenched by water (1mL). This suspension was filtered and the filtrate was concentrated under reduce pressure to give a crude residue. The residue was purified by reverse phase flash (0.1%FA) and lyophilized to afford benzyl ((5-(9-(((1S)-2-amino-1-(1-((1-((1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-4- yl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-2-oxoethyl)amino)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)carbamate (60 mg, 50.0 μmol, 31.7% yield, 90.8% purity) as a white solid. LCMS: m / z [M+H]+= 1089.7

[0516] Step 5: preparation of (2S)-2-((2-(3-(aminomethyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5- yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-(1-((1-((1-(3-(2,6-dioxopiperidin-3- yl)-1-methyl-1H-indazol-6-yl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)acetamide

[0517] To a solution of benzyl N-[[5-[9-[[(1S)-2-amino-1-[1-[[1-[[1-[3-(2,6-dioxo-3-piperidyl)-1- methyl-indazol-6-yl]-4-piperidyl]methyl]-4-piperidyl]methyl]-4-piperidyl]-2-oxo-ethyl]amino]-5,6- dihydroimidazo[1,2-d][1,4]benzoxazepin-2-yl]-1-(2,2,2-trifluoroethyl)-1,2,4-triazol-3- yl]methyl]carbamate (50 mg, 45.9 μmol, 1 eq) in DCM (1 mL) was added HBr (0.5 mL, 33% in HOAc). This mixture was stirred at 20 °C for 0.5 hour. LCMS indicated complete consumption of the starting material and formation of the desired product (45.5% peak area). The reaction solution was concentrated under reduce pressure. The residue was purified by prep-HPLC(FA): column: Phenomenex luna C18 150*25mm* 10 μm; mobile phase: [water(FA)-ACN];gradient:3%-23% B over 10 min to afford (2S)-2- ((2-(3-(aminomethyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)amino)-2-(1-((1-((1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6- yl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)acetamide (24.3 mg, 23.4 μmol, 50.9% yield, 96.2% purity, FA salt) as an off-white solid. LCMS: m / z [M+H]+= 955.5; HPLC: 96.22% purity (220 nm), RT = 2.053 min;1H NMR: (400 MHz, METHANOL-d4) δ = 8.62 - 8.35 (m, 1H), 8.17 (d, J = 8.8 Hz, 1H), 7.79 (s, 1H), 7.54 (d, J = 8.9 Hz, 1H), 7.01 - 6.93 (m, 1H), 6.83 (d, J = 1.5 Hz, 1H), 6.58 - 6.47 (m, 1H), 6.29 (d, J = 2.3 Hz, 1H), 5.90 - 5.76 (m, 2H), 4.49 - 4.40 (m, 4H), 4.32 - 4.26 (m, 1H), 4.19 (s, 2H), 3.94 (s, 3H), 3.83 (br d, J = 13.3 Hz, 2H), 3.75 - 3.69 (m, 1H), 3.46 - 3.38 (m, 2H), 3.23 - 3.15 (m, 2H), 2.88 - 2.79 (m, 4H), 2.78 - 2.64 (m, 4H), 2.50 (br d, J = 3.1 Hz, 2H), 2.47 - 2.38 (m, 1H), 2.37 - 2.24 (m, 3H), 2.06 - 1.86 (m, 8H), 1.84 - 1.77 (m, 1H), 1.73 - 1.57 (m, 2H), 1.54 - 1.39 (m, 4H).Example 27: Preparation of (2S)-2-(1-((1-((1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6- yl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-2-((2-(3-(hydroxymethyl)-1-(2,2,2- trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9- yl)amino)acetamide (Compound 40)

[0518] Step 1: preparation of 9-bromo-2-(3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-(2,2,2- trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

[0519] To a solution of [5-(9-bromo-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-2-yl)-1-(2,2,2- trifluoroethyl)-1,2,4-triazol-3-yl]methanol (600 mg, 1.35 mmol, 1 eq) and TsOH (46.52 mg, 270 μmol, 0.2 eq) in THF (12 mL) was added DHP (227 mg, 2.70 mmol, 247 μL, 2 eq). The resulting mixture was stirred at 60 °C for 12 hours. LCMS indicated starting material (27.1% peak area) remained and formation of desired product (72.8% peak area). The reaction solution was concentrated to remove most solvent to give a residue. The residue was purified by silica column (DCM / MeOH=1 / 0, 10 / 1) to afford 9- bromo-2-(3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (525 mg, 934 μmol, 69.1% yield, 94.0% purity) as an off- white solid.528.2.

[0520] Step 2: preparation of (2S)-2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-((2-(3-(((tetrahydro-2H- pyran-2-yl)oxy)methyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)amino)acetic acid

[0521] To a solution of 9-bromo-2-[5-(tetrahydropyran-2-yloxymethyl)-2-(2,2,2-trifluoroethyl)-1,2,4- triazol-3-yl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine (243 mg, 460 μmol, 1 eq) and (2S)-2-amino- 2-(1-tert-butoxycarbonyl-4-piperidyl)acetic acid (262 mg, 1.01 mmol, 2.21 eq) in DMSO (6 mL) was added Cu2O (163 mg, 1.14 mmol, 2.48 eq) and K3PO4(293 mg, 1.38 mmol, 3 eq). The resulting mixture was stirred at 100 °C for 12 hours. LCMS indicated complete consumption of the starting material and formation of the desired product (68.9% peak area). The mixture was used into next step directly without purification.

[0522] Step 3: preparation of tert-butyl 4-((1S)-2-amino-2-oxo-1-((2-(3-(((tetrahydro-2H-pyran-2- yl)oxy)methyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-9-yl)amino)ethyl)piperidine-1-carboxylate

[0523] The crude mixture of (2S)-2-(1-tert-butoxycarbonyl-4-piperidyl)-2-[[2-[5-(tetrahydropyran-2- yloxymethyl)-2-(2,2,2-trifluoroethyl)-1,2,4-triazol-3-yl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9- yl]amino]acetic acid (324 mg, 459 μmol, 1 eq) from the previous step was diluted in DMSO (6 mL) and DCM (6 mL). Then NH4Cl (246 mg, 4.59 mmol, 10 eq), TEA (464 mg, 4.59 mmol, 639 μL, 10 eq) and HATU (1.75 g, 4.59 mmol, 10 eq) were added. The resulting mixture was stirred at 20 °C for 0.5 hour. LCMS indicated complete consumption of the start...

Claims

1. WHAT IS CLAIMED IS:

1. A compound, wherein the compound is represented by Formula (I) or is a pharmaceutically acceptable salt thereof:wherein: Ring A is a 5-10 membered heteroaryl, 5-10 membered heterocyclic group, or 5-10 membered heteroaryl-fused-heterocyclic group, wherein the 5-10 membered heteroaryl group, 5-10 membered heterocyclic group, or 5-10 membered heteroaryl-fused-heterocyclic group is independently substituted with 0, 1, 2, 3, or 4 Ra; each Rais independently selected from amino, halogen, hydroxyl, C1-C5alkyl, C1-C5alkoxy, C1- C5haloalkyl, C1-C5alkylamino, di-(C1-C5alkyl)amino, C1-C5hydroxyalkyl, C1-C5aminoalkyl, C1-C5alkyl-O-C1-C5alkyl, and an oxo group; Ring B is a 5-15 membered heteroaryl, 5-15 membered heterocyclic group, or 5-15 membered heteroaryl-fused-heterocyclic group, wherein the 5-15 membered heteroaryl group, 5-15 membered heterocyclic group, or 5-15 membered heteroaryl-fused-heterocyclic group is independently substituted with 0, 1, 2, 3, 4, or 5 Rb; each Rbis independently selected from amino, halogen, hydroxyl, C1-C5alkyl, C1-C5alkoxy, C1- C5haloalkyl, C1-C5alkylamino, di-(C1-C5alkyl)amino, C1-C5hydroxyalkyl, C1-C5aminoalkyl, C1-C5alkyl-O-C1-C5alkyl, and an oxo group; Lais selected from a bond, -NRL-C(=O)-, -C(=O)-NRL-, -NRL-C(=O)-O-, -O-C(=O)-NRL-, -NRL-C(=O)-NRL-, -NRL-CH(CF3)-, -(CF3)CH-NRL-, -NRL-C(=S)-, -C(=S)-NRL-, -CH=CF-, -CF=CH-, -RLis hydrogen or an optionally substituted group selected from C1-C6alkyl, C3-C6cycloalkyl,and 3- to 6-membered heterocyclyl; G is a bond or a divalent group with a backbone of 1-10 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from oxygen, heterocyclene, heteroarylene, arylene, -NH-, -N(Rc)-, -C(=O)-, -C(=O)- NH-, -CH(Rc)-, -C(Rc)2-, -C(=O)-N(Rc)-, -NH-C(=O)-, -N(Rc)-C(=O)-, -NH-C(=O)-O-, -wherein each of the heterocyclene, arylene and heteroarylene is independently substituted with 0, 1, 2, or 3 Rd; each Rcis independently selected from C1-C5alkyl, -C(=O)-NH(C1-C5alkyl), -C(=O)-N(C1-C5alkyl)2, and -C(=O)-NH2; each Rdis independently selected from halogen, hydroxyl, C1-C5alkyl, C1-C5alkoxy, C1-C5haloalkyl, -C(=O)-NH2, and an oxo group; L is a linker with a backbone of 1-20 carbon atoms in length, wherein one or more carbon atoms are optionally substituted with halogen, hydroxyl, cyano, CFH2, CF2H, CF3, alkoxy, C1- C5alkyl, or -C(=O)-NH2, wherein one or more carbon atoms of the backbone are optionally replaced by a divalent group independently selected from oxygen, alkylamino, carbonyl, 3-7 membered cycloalkylene, 4-7 membered monocyclic heterocyclic group, 5- 10 membered bridged heterocyclic group, 5-12 membered spiro heterocyclic group, 5-10 membered heteroarylene, and 7-12 membered heteroaryl-fused-heterocyclylene, and wherein each of the 3-7 membered cycloalkylene, 4-7 membered monocyclic heterocyclic group, 5-10 membered bridged heterocyclic group, 5-12 membered spiro heterocyclic group, 5-10 membered heteroarylene, and 7-12 membered heteroaryl-fused- heterocyclylene is independently substituted with 0, 1, or 2 Re; each Reis independently selected from alkylamino, halogen, hydroxyl, C1-C5alkoxy, C1-C5alkyl, C1-C4alkenyl, C3-C5cycloalkyl, C1-C5haloalkyl, and an oxo group; X is N or CH; Q is a bond or a divalent group of 1-5 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from 5-6 membered arylene, 5- 10 membered heteroarylene (e.g., a 9 membered heteroarylene, such as a fused 5-6membered heteroarylene ring system; a 6 membered aryl or heteroaryl fused to a 5 membered heterocyclyl; and so forth), -NH-, -C(=O)-, -C(=O)-NH-, and -C(=O)N(Rc)-, and wherein each of the 5-6 membered arylene and 5-10 membered heteroarylene is independently substituted with 0, 1, 2, or 3 Rf; and each Rfis independently selected from halogen, hydroxyl, C1-C5alkyl, C1-C5alkoxy, C1-C5haloalkyl, and an oxo group.

2. The compound according to claim 1, wherein the compound of Formula (I) is represented by a compound of Formula (IX) or is a pharmaceutically acceptable salt thereof:

3. The compound according to claim 1 or 2, wherein the compound of Formula (I) is represented by a compound of Formula (II’) or is a pharmaceutically acceptable salt thereof:wherein: Ring A is a 5-6 membered heteroaryl or 5-6 membered heterocyclic group; each Rais independently selected from amino, halogen, hydroxyl, C1-C5alkyl, C1-C5alkoxy, C1-C5haloalkyl, C1-C5alkylamino, di-(C1-C5alkyl)amino, C1-C5hydroxyalkyl, C1-C5aminoalkyl, C1-C5alkyl-O-C1-C5alkyl, and an oxo group; each Rbis independently selected from amino, halogen, hydroxyl, C1-C5alkyl, C1-C5alkoxy, and C1-C5haloalkyl; X1is CH or N; n is 0, 1, 2, or 3; and m is 0, 1, or 2.

4. The compound according to any one of claims 1-3, wherein Ring A is selected from:wherein n is 0, 1, 2, or 3.

5. The compound according to any one of claims 1-4, wherein Ring B is selected from:wherein: X1is CH or N; X2is selected from N, NH, O, and S; X3is selected from N, NH, O, and S; and m is 0, 1, or 2.

6. The compound according to any one of claims 1-5, wherein Lais a bond, -NH-C(=O)-, -7. The compound according to any one of claims 1-6, wherein Lais a bond, -NH-C(=O)-, - C(=O)-NH-, -NH-C(=O)-O-, -O-C(=O)-NH-, or -NH-C(=O)-NH-.

8. The compound according to any one of claims 1-7, wherein Lais a bond or -C(=O)-NH.

9. The compound according to any one of claims 1, 2, or 4-8, wherein the compound of Formula (I) is represented by a compound of Formula (II) or is a pharmaceutically acceptable salt thereof:wherein: Ring A is a 5-6 membered heteroaryl or 5-6 membered heterocyclic group; each Rais independently selected from amino, halogen, hydroxyl, C1-C5 alkyl, C1-C5 alkoxy, C1- C5haloalkyl, C1-C5alkylamino, di-(C1-C5alkyl)amino, C1-C5hydroxyalkyl, C1-C5aminoalkyl, C1-C5alkyl-O-C1-C5alkyl, and an oxo group; each Rbis independently selected from amino, halogen, hydroxyl, C1-C5alkyl, C1-C5alkoxy, and C1-C5haloalkyl; X1is CH or N; n is 0, 1, 2, or 3; and m is 0, 1, or 2.

10. The compound according to any one of claims 1, 2, 4-8, wherein the compound of Formula (II) is represented by a compound of Formula (IIA) or is a pharmaceutically acceptable salt thereof:

11. The compound according to any one of claims 1 or 3-8, wherein the compound of Formula (I) is represented by a compound of Formula (IIA’’) or is a pharmaceutically acceptable salt thereof:wherein each Rais independently selected from hydroxyl, C1-C5alkyl, C1-C5alkoxy, C1-C5alkylamino, and C1-C5haloalkyl.

12. The compound according to any one of claims 1, 2, 4-8, wherein the compound of Formula (II) is represented by a compound of Formula (IIB) or is a pharmaceutically acceptable salt thereof:

13. The compound according to claim 12, wherein the compound of Formula (IIB) is represented by a compound of Formula (IIB’) or is a pharmaceutically acceptable salt thereof:wherein each Rais independently selected from C1-C5alkyl, C1-C5alkoxy, C1-C5haloalkyl, C1- C5hydroxyalkyl, and C1-C5aminoalkyl.

14. The compound according to claim 3, wherein the compound of Formula (II’) is represented by a compound of Formula (IIB”) or is a pharmaceutically acceptable salt thereof:

15. The compound according to claim 14, wherein the compound of Formula (IIB”) is represented by a compound of Formula (IIB”’) or is a pharmaceutically acceptable salt thereof:wherein each Rais independently selected from C1-C5alkyl, C1-C5alkoxy, C1-C5haloalkyl, C1-C5hydroxyalkyl, and C1-C5aminoalkyl.

16. The compound according to any one of claims 1, 2, 4-7, wherein the compound of Formula (I) is represented by a compound of Formula (III) or is a pharmaceutically acceptable salt thereof:wherein: Ring A is a 5-6 membered heteroaryl or 5-6 membered heterocyclic group; each Rais independently selected from amino, halogen, hydroxyl, C1-C5alkyl, C1-C5alkoxy, C1- C5haloalkyl, C1-C5alkylamino, C1-C5hydroxyalkyl, and C1-C5aminoalkyl; each of X2and X3is independently selected from N, NH, O, and S; each Rbis independently selected from amino, halogen, hydroxyl, C1-C5alkyl, C1-C5alkoxy, C1- C5haloalkyl, and C1-C5alkylamino; n is 0, 1, 2, or 3; and m is 0 or 1.

17. The compound according to any one of claims 1-7, wherein the compound of Formula (I) is represented by a compound of Formula (III’) or is a pharmaceutically acceptable salt thereof:wherein: Ring A is a 5-6 membered heteroaryl or 5-6 membered heterocyclic group; each Rais independently selected from amino, halogen, hydroxyl, C1-C5alkyl, C1-C5alkoxy, C1- C5haloalkyl, C1-C5alkylamino, C1-C5hydroxyalkyl, and C1-C5aminoalkyl; each of X2and X3is independently selected from N, NH, O, and S; each Rbis independently selected from amino, halogen, hydroxyl, C1-C5alkyl, C1-C5alkoxy, C1-C5haloalkyl, and C1-C5alkylamino; n is 0, 1, 2, or 3; and m is 0 or 1.

18. The compound according to claim 16, wherein the compound of Formula (III) is represented by a compound of Formula (IIIA) or is a pharmaceutically acceptable salt thereof:

19. The compound according to claim 18, wherein the compound of Formula (IIIA) is represented by a compound of Formula (IIIA’) or is a pharmaceutically acceptable salt thereof:(IIIA’) wherein Rbis selected from amino, halogen, C1-C5alkyl, C1-C5alkoxy, and C1-C5haloalkyl.

20. The compound according to any one of claims 1, 5-8, or 17, wherein the compound of Formula (III’) is represented by a compound of Formula (IIIA”) or is a pharmaceutically acceptable salt thereof:

21. The compound according to any one of claims 1, 5-8, 17, or 18, wherein the compound of Formula (IIIA”) is represented by a compound of Formula (IIIA’”) or is a pharmaceutically acceptable salt thereof:(IIIA’”) wherein Rbis selected from amino, halogen, C1-C5alkyl, C1-C5alkoxy, and C1-C5haloalkyl.

22. The compound according to any one of claims 1, 2, 4-8, wherein the compound of Formula (I) is represented by a compound of Formula (IV) or is a pharmaceutically acceptable salt thereof:wherein: Ring A is a 5-6 membered heteroaryl or 5-6 membered heterocyclic group; each Rais independently selected from amino, halogen, hydroxyl, C1-C5alkyl, C1-C5alkoxy, C1- C5haloalkyl, C1-C5alkylamino, di-(C1-C5alkyl)amino, C1-C5hydroxyalkyl, and C1-C5aminoalkyl; each Rbis independently selected from halogen, hydroxyl, C1-C5alkyl, and C1-C5alkoxy; n is 0, 1, or 2; and m is 0, 1, or 2.

23. The compound according to any one of claims 1, 2, 4-8, wherein the compound of Formula (I) is represented by a compound of Formula (IV’) or is a pharmaceutically acceptable salt thereof:wherein:Ring A is a 5-6 membered heteroaryl or 5-6 membered heterocyclic group; each Rais independently selected from amino, halogen, hydroxyl, C1-C5alkyl, C1-C5alkoxy, C1- C haloalkyl, C1-C5alkylamino, di-(C1-C5alkyl)amino, C1-C5hydroxyalkyl, and C1-C5aminoalkyl; each Rbis independently selected from halogen, hydroxyl, C1-C5alkyl, and C1-C5alkoxy; n is 0, 1, or 2; and m is 0, 1, or 2.

24. The compound according to any one of claims 1, 2, 4-6, or 22, wherein the compound of Formula (IV) is represented by a compound of Formula (IVA) or is a pharmaceutically acceptable salt thereof:(IVA).

25. The compound according to any one of claims 1, 2, 4-8, or 23, wherein the compound of Formula (IV’) is represented by a compound of Formula (IVA’) or is a pharmaceutically acceptable salt thereof:(IVA’).

26. The compound according to any one of claims 1-25, wherein each Rais independently selected from -CH3, -CH2CF3, -CH(CH3)2, -CH2OH, -CH2-OCH3, -CH2F, -CHF2, -CF3, - C(CH3)2CF3, -OH, -OCH3, -NH2, and -CH2-NH2.

27. The compound according to any one of claims 1-26, wherein each Rais independently selected from -CH(CH3)2, -CH2F, -CHF2, -CF3, and -NH2.

28. The compound according to any one of claims 1-9, 16-18, 20, or 22-27, wherein Ring A is selected from:,29. The compound according to any one of claims 1-28, wherein G is a divalent group with a backbone of 1-7 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from oxygen, heterocyclene, heteroarylene, arylene, -NH-, -C(Rc)-, and -N(Rc)-, and wherein each of the heterocyclene, arylene, and heteroarylene is independently substituted with 0, 1, 2, or 3 Rd.

30. The compound according to any one of claims 1-29, wherein G is selected from: ,, , , ,,, , wherein ** represents the point of attachment to L.

31. The compound according to any one of claims 1-30, wherein L is a linker with a backbone of 1 to 10 carbon atoms in length, wherein one or more carbon atoms are optionally substituted with halogen, hydroxyl, cyano, CFH2, CF2H, CF3, alkoxy, C1-C3alkyl, or -C(=O)-NH2, wherein one or more carbon atoms of the backbone are optionally replaced by a divalent group independently selected from oxygen, alkylamino, carbonyl, 5-7 membered cycloalkyl, 4-6 membered monocyclic heterocyclic group, 7-10 membered bridged heterocyclic group, 7-12 membered spiro heterocyclic group, 5-9 membered heteroaryl, and 9-10 membered heteroaryl fused heterocyclyl, and wherein each of the 5- 7 membered cycloalkyl, 4-6 membered monocyclic heterocyclic group, 7-10 membered bridged heterocyclic group, 7-12 membered spiro heterocyclic group, 5-9 heteroaryl, and 9-10 heteroaryl-fused-heterocyclyl is independently substituted with 0, 1, or 2 Re.

32. The compound according to any one of claims 1-31, wherein L is selected from: ,, , ,, , ,, , ,, ,, , , ,, , ,, , ,, , ,, , ,, , ,, ,, ,, , ,, , ,33. The compound according to any one of claims 1-32, wherein L is selected from:

34. The compound according to any one of claims 1-33, wherein L is selected from:.

35. The compound according to any one of claims 1-34, wherein Q is selected from: ,, , and ; andwherein p is 0, 1, 2, or 3.

36. The compound according to any one of claims 1-34, wherein Q is selected from:wherein X4is selected from -O-, -N(C1-C5alkyl)-, -CH2-, and -C(CH3)2-; and p is 0, 1, 2, or 3.

37. The compound according to any one of claims 1-36, wherein Q is selected from:, , , , ,, , , , ,, , , , , ,, , , , , ,, , , , ,, , , , ,, , , , ,, , , , , ,, , , , ,, , , , ,, , , , ,, , , , , , , , , , , , , , , and .

38. The compound according to any one of claims 1-37, wherein Q is selected from: ,, , , ,, , , , and .

39. The compound according to claim 1, wherein the compound is selected from: Cpd. No. Structure 1 2 3 4 5or is a pharmaceutically acceptable salt of any of the above.

40. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1-39 and a pharmaceutically acceptable carrier.

41. A method for inhibiting and / or degrading phosphoinositide 3-kinase (PI3K) in a cell, comprising contacting the cell with at least one compound according to any one of claims 1-39 or the pharmaceutical composition according to claim 40.

42. The method of claim 41, wherein the PI3K is PI3Kα.

43. A method for treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of at least one compound according to any one of claims 1- 39, or a pharmaceutical composition of claim 40.

44. The method according to claim 43, wherein the cancer is selected from breast cancer, lung cancer, pancreatic cancer, small bowel cancer, colon cancer, colorectal cancer, gall bladder cancer, gastric cancer, glioblastoma, thyroid cancer, liver cancer, lymphoma, sarcoma, bile duct cancer, ovarian cancer, endometrial cancer, cervical cancer, bladder cancer, prostate cancer, squamous cell carcinoma, head and neck cancer, esophageal cancer, and blood cancer.

45. The method according to claim 44, wherein the cancer is selected from estrogen receptor positive (ER+) breast cancer, non-small cell lung cancer, colorectal cancer, gastriccancer, ovarian cancer, endometrial cancer, cervical cancer, prostate cancer, and squamous cell carcinoma.

46. The method according to any one of claims 43-45, wherein the cancer is associated with PI3K or PI3Kα dysregulation or dysfunction.

47. Use of a compound according to any one of claims 1-39 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 40, in the manufacture of a medicament for the treatment of a disease or disorder.

48. The use according to claim 47, wherein the disease or disorder is cancer.

49. The use according to claim 48, wherein the cancer is selected from breast cancer, lung cancer, pancreatic cancer, small bowel cancer, colorectal cancer, gall bladder cancer, gastric cancer, glioblastoma, thyroid cancer, liver cancer, lymphoma, sarcoma, bile duct cancer, ovarian cancer, endometrial cancer, cervical cancer, bladder cancer, prostate cancer, squamous cell carcinoma, head and neck cancer, esophageal cancer, and blood cancer.

50. The use of claim 49, wherein the cancer is selected from estrogen receptor positive (ER+) breast cancer, non-small cell lung cancer, colorectal cancer, gastric cancer, ovarian cancer, endometrial cancer, cervical cancer, prostate cancer, and squamous cell carcinoma.