Compounds and compositions useful as MK2 kinase degradation agents

Abstract

The present disclosure provides compounds and compositions useful for degrading MK2 kinase.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 483,569, filed February 7, 2023, the entire contents of which are hereby incorporated by reference herein. Incorporation by Reference into the Sequence Listing

[0002] This application is submitted together with a sequence listing in electronic format. The sequence listing is provided as a 3 kilobyte file named 055920-574001WO_SeqList_ST26.xml, created on January 30, 2024. The electronic format of the sequence listing is incorporated herein by reference in its entirety. Background Art

[0003] In recent years, a better understanding of the structure of enzymes and other biomolecules associated with disease has greatly facilitated the search for new therapeutic agents. One important class of enzymes that has been the subject of extensive research is the protein kinases.

[0004] Protein kinases constitute a large family of structurally related enzymes that control a variety of signal transduction processes within cells. Protein kinases are thought to have evolved from a common ancestral gene due to the conservation of their structure and catalytic function. Almost all kinases contain a similar 250-300 amino acid catalytic domain. Kinases can be classified into several families based on the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine / threonine, lipids, etc.).

[0005] Protein degradation is a highly regulated and crucial process for maintaining cellular homeostasis. Selective identification and removal of damaged, misfolded or excessive proteins is achieved via the ubiquitin-proteasome pathway (UPP). UPP is central to regulating almost all cellular processes, including antigen processing, apoptosis, organelle biogenesis, cell cycle, DNA transcription and repair, differentiation and development, immune response and inflammation, nerve and muscle degeneration, neural network morphogenesis, regulation of cell surface receptors, ion channels and secretory pathways, response to stress and extracellular regulators, ribosome biogenesis and viral infection. Multiple ubiquitin molecules are covalently attached to terminal lysine residues by E3 ubiquitin ligases to mark proteins for proteasome degradation, where proteins are digested into small peptides and ultimately digested into their constituent amino acids, which serve as building blocks for new proteins. Defective proteasome degradation is associated with a variety of disorders including cancer and others.

[0006] Cereblon forms part of an E3 ubiquitin ligase complex that interacts with damaged DNA binding protein 1 to form an E3 ubiquitin ligase complex with Cullin 4 and E2 binding protein ROC1 (called RBX1), in which it acts as a substrate receptor to select proteins for ubiquitination. The binding of lenalidomide to cereblon promotes the subsequent binding of cereblon to Ikaros and Aiolos, resulting in ubiquitination of Ikaros and Aiolos and degradation by the proteasome (see Lu, G. et al. "The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins" Science, 2014, 343: 305-309; J. et al. "Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiplemyeloma cells" Science, 2014, 343: 301-305).

[0007] Mitogen-activated protein kinase-activated protein kinase 2 (MAPKAP K2 or MK2) mediates a variety of p38 MAPK-dependent cellular responses. MK2 (SEQ ID NO. 1) is an important intracellular regulator of the production of cytokines such as tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and interferon gamma (IFNγ), which are involved in many acute and chronic inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease. MK2 is present in the nucleus of unstimulated cells, and upon stimulation, it translocates to the cytoplasm and phosphorylates and activates tuberin and HSP27. MK2 has also been implicated in heart failure, cerebral ischemic injury, the regulation of stress resistance, and the production of TNF-α. (See Deak et al., EMBO. 17:4426-4441 (1998); Shi et al., Biol. Chem. 383:1519-1536 (2002); Staklatvala., Curr. Opin. Pharmacol. 4:372-377 (2004); and Shiroto et al., J. Mol. Cardiol. 38:93-97 (2005)).

[0008] SEQ ID NO.1: MLSNSQGQSPPVPFPAPAPPPQPPTPALPHPHPPAQPPPPPPQQFPQFHV KSGLQIKKNAIIDDYKVTSQVLGLGINGKVLQIFNKRTQEKFALK MLQDCPKARREVELHWRASQCPHIVRIVDVYENLYAGRKCLLIV MECLDGGELFSRIQDRGDQAFTEREASEIMKSIGEAIQYLHSINIAH RDVKPENLLYTSKRPNAILKLTDFGFAKETTSHNSLTTPCYTPYYV APEVLGPEKYDKSCDMWSLGVIMYILLCGYPPFYSNHGLAISPGM KTRIRMGQYEFPNPEWSEVSEEVKMLIRNLLKTEPTQRMTITEFM NHPWIMQSTKVPQTPLHTSRVLKEDKERWEDVKEEMTSALATMR VDYEQIKIKKIEDASNPLLLKRRKKARALEAALAH.

[0009] As mentioned above, many diseases are associated with abnormal cellular responses triggered by events mediated by protein kinases. These diseases include, but are not limited to, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, nervous system and neurodegenerative diseases, cancer, cardiovascular disease, allergies and asthma, Alzheimer's disease, and hormone-related diseases. Given the importance of p38α and MK2 in many cellular processes, the activities of these two kinases should be controlled. Therefore, there remains a need to identify protein kinase degraders that can be used as therapeutic agents for the degradation of MK2 and p38α. Summary of the Invention

[0010] In certain embodiments, the present disclosure provides compounds of Formula I: or a pharmaceutically acceptable salt thereof, wherein X, R z , L d , loop F, t, the linker and the E3 binding portion are as defined below.

[0011] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound as described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, excipient, or vehicle. In some embodiments, the pharmaceutical composition provided is suitable for oral, parenteral, mucosal, transdermal, or topical administration.

[0012] In some embodiments, the present disclosure provides a method of degrading MK2 kinase or a mutant thereof, the method comprising contacting a biological sample with a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0013] In some embodiments, the present disclosure provides a method of treating an MK2-mediated disorder comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof. Such disorders or conditions include, among others, ankylosing spondylitis, rheumatoid arthritis, psoriatic arthritis, and psoriasis. DETAILED DESCRIPTION 1. General Description of the Compounds of the Invention:

[0014] In certain embodiments, the present disclosure provides irreversible degraders of MK2. In some embodiments, such compounds include those of the formula described herein, or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0015] In certain embodiments, the present disclosure provides compounds of Formula I: or a pharmaceutically acceptable salt thereof, wherein: The linker is a divalent group; The E3 binding portion is a portion that binds to the E3 ubiquitin ligase protein; Ring F is phenylene, a 5- to 6-membered heteroarylene ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 3- to 7-membered saturated or partially unsaturated heterocyclylene ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L d Selected from covalent bonds, -O-, -S-, -N(R)- and C1-6 aliphatic; X is selected from -O-, -S- and -N(R)-; R z an optionally substituted group selected from halogen, -OR, -SR, -CN, -NO, -SONR, -SOR, -SOR, -C(O)R, -C0R, -C(O)N(R), -NRC(O)R, -NRC(O)OR, -NRC(O)N(R), -NRSOR, -N(R), or a C1-6 aliphatic, phenyl, a 3- to 8-membered saturated or partially unsaturated carbocycle, a 4- to 7-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R is independently hydrogen or an optionally substituted C1-6 aliphatic; and t is 0, 1, 2, or 3. 2. Compounds and Definitions:

[0016] The compounds of the present disclosure include those generally described above and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, unless otherwise indicated, the following definitions shall apply. For the purposes of the present disclosure, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics 75th edition. In addition, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th edition, editors: Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0017] As used herein, the term "aliphatic" or "aliphatic group" means a straight chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon (also referred to herein as "carbocycle," "carbocyclic," "alicyclic," or "cycloalkyl") that is fully saturated or contains one or more unsaturated units but is not aromatic, having a single point of attachment to the rest of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In still other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in yet other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "carbocycle" (or "alicyclic" or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C8 hydrocarbon that is fully saturated or contains one or more unsaturated units but is not aromatic. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0018] As used herein, the term "bridged bicyclic" refers to any bicyclic system with at least one bridge, i.e., a saturated or partially unsaturated carbocyclic or heterocyclic ring. As defined by IUPAC, a "bridge" is an unbranched chain of atoms or an atom or valence bond connecting two bridgeheads, wherein a "bridgehead" is any backbone atom of a ring system bonded to three or more backbone atoms (excluding hydrogen). In some embodiments, the bicyclic group of the bridge has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Such bicyclic groups of bridges are well known in the art and include those groups shown below, wherein each group is attached to the remainder of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise indicated, the bicyclic group of the bridge is optionally substituted by one or more substituents shown in the aliphatic group. Additionally or alternatively, any substitutable nitrogen of the bicyclic group of the bridge is optionally substituted. Exemplary bridged bicyclic compounds include:

[0019] The term "lower alkyl" refers to a C 1-4 Straight or branched chain alkyl groups. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.

[0020] The term "lower haloalkyl" refers to a C 1-4 Straight-chain or branched-chain alkyl.

[0021] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; any basic nitrogen or substitutable nitrogen of a heterocyclic ring, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (as in N-substituted pyrrolidinyl)).

[0022] As used herein, the term "unsaturated" means that the moiety has one or more units of unsaturation.

[0023] 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 and includes integers from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. Substituted alkylene chains are polymethylene chains in which one or more methylene hydrogen atoms are replaced by substituents. Suitable substituents include those described below for substituted aliphatic groups.

[0024] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0025] The term "halogen" means F, Cl, Br or I.

[0026] The term "aryl" as used alone or as part of a larger moiety in "aralkyl," "aralkyloxy," or "aryloxyalkyl" refers to a monocyclic or bicyclic ring system having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains 3 to 7 ring members. The term "aryl" can be used interchangeably with the term "aromatic ring." In certain embodiments of the present disclosure, "aryl" refers to an aromatic ring system, and exemplary groups include phenyl, biphenyl, naphthyl, anthracenyl, and the like, which may carry one or more substituents. As used herein, the scope of the term "aryl" also includes groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthalimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.

[0027] The terms "heteroaryl" and "heteroar-", used alone or as part of a larger moiety, such as "heteroaralkyl" or "heteroaralkoxy", refer to groups having 5 to 10 ring atoms (including 5, 6, or 9 ring atoms); having 6, 10, or 14 pi electrons shared in a cyclic array; and having one to five heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur and any quaternized form of a basic nitrogen. Exemplary heteroaryl groups include thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. As used herein, the terms "heteroaryl" and "heteroaryl-" also include groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic or heterocyclic rings, wherein the free radical or point of attachment is on the heteroaromatic ring. Exemplary groups include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolyl, tetrahydroisoquinolyl and pyrido [2,3-b] -1,4-oxazine -3 (4H) -one. The heteroaryl group can be monocyclic or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl," or "heteroaromatic," any of which terms include optionally substituted rings. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0028] As used herein, the terms "heterocycle," "heterocyclyl," "heterocyclic radical," and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is saturated or partially unsaturated and has one or more (including one to four) heteroatoms as defined above in addition to carbon atoms. The term "nitrogen" when used with respect to a ring atom of a heterocycle includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or + NR (as in N-substituted pyrrolidinyl).

[0029] The heterocycle can be attached to its side group at any heteroatom or carbon atom to produce a stable structure, and any ring atom can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include tetrahydrofuranyl, tetrahydrothienylpyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolane, diazepine, oxazepine, thiazepine, morpholinyl, and quinuclidine. The terms "heterocycle," "heterocyclyl," "heterocyclyl ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclic radical" are used interchangeably herein and also include groups in which the heterocyclyl ring is fused to one or more aryl, heteroaryl, or alicyclic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, wherein the radical or point of attachment is on the heterocyclyl ring. The heterocyclyl group can be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

[0030] As used herein, the term "partially unsaturated" refers to a ring moiety containing 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 defined herein.

[0031] As described herein, the compounds provided herein may contain "optionally substituted" moieties. In general, the term "substituted," whether or not preceded by the term "optionally," means that one or more hydrogen atoms of the designated moiety are replaced with a suitable substituent. "Substituted" applies to one or more hydrogen atoms that are explicitly or implicitly removed from the structure (e.g., means at least and means at least ). Unless otherwise indicated, an "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 particular group, the substituents may be the same or different at each position. Combinations of substituents contemplated by the present disclosure include those that result in the formation of stable or chemically feasible compounds. As used herein, the term "stable" refers to a compound that does not substantially change when subjected to conditions that allow its production, detection, and in certain embodiments, recovery, purification, and use for one or more of the purposes disclosed herein.

[0032] Suitable monovalent substituents on the substitutable carbon atoms of an "optionally substituted" group are independently halogen; -(CH2) 0-4 R o ; -(CH2) 0-4 OR o ;-O(CH2) 0-4 R o ;-O-(CH2) 0-4 C(O)OR o ; -(CH2) 0-4 CH(OR o )2;-(CH2) 0- 4SR o ; -(CH2) 0-4 Ph, which can be R o Substitution; -(CH2) 0-4 O(CH2) 0-1 Ph, which can be R o Substituted; -CH=CHPh, which can be R o Substitution; -(CH2) 0-4 O(CH2) 0-1 -pyridyl, which may be replaced by R o Substitution; -NO2; -CN; -N3; ​​-(CH2) 0-4 N(R o )2;-(CH2) 0-4 N(R o )C(O)R o ;-N(R o )C(S)R o ; -(CH2) 0-4 N(R o )C(O)NR o 2;-N(R o )C(S)NR o 2; -(CH2) 0-4 N(R o )C(O)OR o ;-N(Ro )N(R o )C(O)R o ;-N(R o )N(R o )C(O)NR o 2;-N(R o )N(R o )C(O)OR o ;-(CH2) 0-4 C(O)R o ;-C(S)R o ;-(CH2) 0-4 C(O)OR o ;-(CH2) 0-4 C(O)SR o ;-(CH2) 0-4 C(O)OSiR o 3;-(CH2) 0-4 OC(O)R o ;-OC(O)(CH2) 0-4 SR o ;-(CH2) 0-4 SC(O)R o ;-(CH2) 0-4 C(O)NR o 2;-C(S)NR o 2;-C(S)SR o ;-SC(S)SR o 、-(CH2) 0- 4OC(O)NR o 2;-C(O)N(OR o )R o ;-C(O)C(O)R o ;-C(O)CH2C(O)R o ;-C(NOR o )R o ;-(CH2) 0-4 SSR o ;-(CH2) 0-4 S(O)2R o ;-(CH2) 0-4 S(O)2OR o ;-(CH2) 0-4 OS(O)2R o ;-S(O)2NR o 2;-(CH2) 0-4 S(O)R o ;-N(R o )S(O)2NR o 2;-N(R o)S(O)2R o ;-N(OR o )R o ;-C(NH)NR o 2;-P(O)2R o ;-P(O)R o 2;-OP(O)R o 2;-OP(O)(OR o )2;SiR o 3;-(C 1-4 linear or branched alkylene)ON(R o )2; or -(C 1-4 linear or branched alkylene) C(O)ON(R o )2, where each R o may be substituted as defined below and are independently hydrogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -CH2-(5-6 membered heteroaryl ring), or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, notwithstanding the above definitions, two independent occurrences of R o Together with one or more of their intermediate atoms, they form a 3-12 membered saturated, partially unsaturated or aromatic monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which ring may be substituted as defined below.

[0033] R o (or by two independent occurrences of R o Suitable monovalent substituents on the ring formed by the atoms thereof are independently halogen, -(CH2) 0-2 R · 、-(halogenated R · ), -(CH2) 0-2 OH, -(CH2) 0-2 OR · 、-(CH2) 0-2 CH(OR · )2;-O(halogenated R · )、-CN、-N3、-(CH2) 0-2 C(O)R · 、-(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR · 、-(CH2) 0-2 SR · 、-(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2)0-2 NHR · 、-(CH2) 0-2 NR · 2. -NO2, -SiR · 3. -OSiR · 3. -C(O)SR · 、-(C 1-4 linear or branched alkylene)C(O)OR · or -SSR · , where each R · is unsubstituted or, when preceded by "halo", is substituted only by one or more halogens, and is independently selected from C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. R o Suitable divalent substituents on a saturated carbon atom of include =0 and =S.

[0034] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include the following: =0 ("oxo"), =S, =NNR * 2. =NNHC(O)R * 、=NNHC(O)OR * 、=NNHS(O)2R * 、=NR * 、=NOR * 、-O(C(R * 2)) 2- 3O-or-S(C(R * 2)) 2-3 S-, where each independent occurrence of R * Selected from hydrogen, C 1-6 aliphatic (optionally substituted as defined below), or unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents attached to an adjacent substitutable carbon of an "optionally substituted" group include: -O(CR * 2) 2-3 O-, where each independent occurrence of R * Selected from hydrogen, C 1-6 an aliphatic (optionally substituted as defined below), or unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0035] R * Suitable substituents on the aliphatic group include halogen, -R · 、-(halogenated R· ), -OH, -OR · 、-O(halogenated R · )、-CN、-C(O)OH、-C(O)OR · 、-NH2、-NHR · 、-NR · 2 or -NO2, where each R · is unsubstituted or, when preceded by "halo", is substituted only by one or more halogens, and is independently C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0036] Suitable substituents on the substitutable nitrogen of an "optionally substituted" group include or Each of these are independently hydrogen, C 1-6 aliphatic (optionally substituted as defined below), unsubstituted -OPh, or an unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, notwithstanding the above definitions, two independent occurrences of Together with one or more of their intermediate atoms, they form an unsubstituted 3-12 membered saturated, partially unsaturated or aromatic monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0037] Suitable substituents on the aliphatic group are independently halogen, -R · 、-(halogenated R · ), -OH, -OR · 、-O(halogenated R · )、-CN、-C(O)OH、-C(O)OR · 、-NH2、-NHR · 、-NR · 2 or -NO2, where each R · is unsubstituted or, when preceded by "halo", is substituted only by one or more halogens, and is independently C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0038] As used herein, the term "pharmaceutically acceptable salt" refers to salts that are suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and that are commensurate with a reasonable benefit / risk ratio, within the scope of reasonable medical judgment. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19 (incorporated herein by reference). Pharmaceutically acceptable salts of the compounds provided herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed of amino groups with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid) or by using other methods used in the art (such as ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like.

[0039] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Where appropriate, additional pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0040] Unless otherwise stated, structures depicted herein are also intended to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the invention are within the scope of this disclosure. Unless otherwise stated, all tautomeric forms of the compounds provided herein are within the scope of this disclosure. In addition, unless otherwise stated, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, including replacement of hydrogen by deuterium or tritium or replacement of carbon by 13 C- or 14 Compounds having the structures of the present invention that are C-enriched, carbon-substituted, and have the structures of the present invention are within the scope of the present disclosure. Such compounds are useful, for example, as analytical tools in biological assays, probes, or therapeutic agents according to the present disclosure.

[0041] The combinations of substituents and variables contemplated by this disclosure are only those that result in the formation of stable compounds. As used herein, the term "stable" refers to compounds that have sufficient stability to allow manufacture and maintain the integrity of the compound for a sufficient period of time to be used for the purposes detailed herein (e.g., therapeutically or prophylactically administered to a subject).

[0042] The recitation of a list of chemical groups in any definition of a variable herein includes defining that variable as any single group or combination of the listed groups. The recitation of an embodiment of a variable herein includes that embodiment as any single embodiment or in combination with any other embodiment or portion thereof.

[0043] As used herein, the terms "treatment," "treat," and "treating" refer to partially or completely alleviating, suppressing, delaying the onset of, preventing, ameliorating, and / or alleviating an disorder or condition as described herein, or one or more symptoms of a disorder or condition. In some embodiments, treatment may be administered after the onset of one or more symptoms. In some embodiments, the term "treatment" includes preventing or stopping the progression of a disease or disorder. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual before the onset of symptoms (e.g., based on a history of symptoms and / or based on genetic or other susceptibility factors). Treatment may also be continued after symptoms subside, for example to prevent or delay their recurrence. Therefore, in some embodiments, the term "treatment" includes preventing the relapse or recurrence of a disease or disorder.

[0044] As used herein, the term "inhibitor" is defined as a compound that binds to and / or inhibits the target protein kinase MK2 with measurable affinity. In certain embodiments, the inhibitor has an IC of less than about 50 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, or less than about 10 nM. 50 and / or binding constants.

[0045] As used herein, the terms "degradation" and "degrading" and "MK2 degradation" refer to the process in which MK2 protein is destroyed in cells to maintain protein homeostasis or protein balance in the human body.

[0046] As used herein, the terms "measurable affinity" and "measurable degradation" mean a measurable change in MK2 activity between a sample comprising a compound of the disclosure or composition thereof and MK2 and an equivalent sample comprising MK2 in the absence of the compound or composition thereof.

[0047] As used herein, the term "biological sample" includes, but is not limited to, cell cultures or extracts thereof; biopsy material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof. Inhibiting the activity of a protein kinase (e.g., MK2 or a mutant thereof) in a biological sample can be used for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, biological specimen storage, and bioassays.

[0048] As used herein, "a disease or disorder associated with MK2," or alternatively "a disease or disorder mediated by MK2," means any disease or other deleterious condition in which MK2 or a mutant thereof is known or suspected to play a role.

[0049] As used herein, the term "subject" means a mammal and includes human and animal subjects, such as livestock (e.g., horses, dogs, cats, etc.). The terms "subject" and "patient" are used interchangeably. In some embodiments, "patient" or "subject" means an animal, including mammals and humans.

[0050] As used herein, the phrases "compounds of the disclosure," "degradants of the disclosure," and "degradants" refer to those compounds disclosed generally and specifically herein.

[0051] The term "pharmaceutically acceptable carrier, adjuvant or vehicle" refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound formulated therewith. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of the present disclosure include, but are not limited to, ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids), water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone), cellulose-based substances, polyethylene glycol, sodium hydroxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and lanolin. The amount of the compound of the present disclosure that can be combined with the carrier material to produce a composition in a single dosage form will vary depending on the host being treated, the specific mode of administration, etc. The provided compositions can be further formulated so that the degrading agent can be administered to a patient receiving these compositions at a dosage of between 0.01 and about 100 mg / kg of subject body weight / day, or about 0.1 mg / kg of subject body weight / day to about 50 mg / kg of subject body weight / day, and from about 1 mg / kg of subject body weight / day to about 25 mg / kg of subject body weight / day to achieve the desired therapeutic effect. The amount of a compound of the present disclosure in the composition will also depend on the specific compound in the composition.

[0052] As used herein, the expression "unit dosage form" refers to a physically discrete unit of a provided compound and / or composition thereof suitable for the subject to be treated. However, it will be understood that the total daily dosage of the active agent (i.e., the compounds and compositions of the present disclosure) will be determined by the attending physician within the scope of sound medical judgment. The specific effective dosage level for any particular subject (i.e., patient) or organism will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific active agent employed; the specific composition employed; the age, weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active agent employed; the duration of treatment; and similar factors well known in the medical arts.

[0053] The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.

[0054] As used herein, "therapeutically effective amount" means the amount of a substance (e.g., a therapeutic agent, composition and / or formulation) that elicits a desired biological response. In some embodiments, a therapeutically effective amount of a substance is an amount that is sufficient to treat, diagnose, prevent and / or delay the onset of a disease, disorder and / or condition when administered as part of a dosing regimen to a subject suffering from or susceptible to a disease, disorder and / or condition. As will be understood by one of ordinary skill in the art, the effective amount of a substance can vary depending on factors such as the desired biological endpoint, the substance to be delivered, the target cell or tissue, etc. For example, the effective amount of a provided compound in a formulation for treating a disease, disorder and / or condition is an amount that alleviates, improves, alleviates, inhibits, prevents one or more symptoms or features of a disease, disorder and / or condition, delays the onset of one or more symptoms or features, reduces the severity of one or more symptoms or features and / or reduces the incidence of one or more symptoms or features. In some embodiments, a "therapeutically effective amount" is at least the minimum amount of a provided compound or a composition containing a provided compound that is sufficient to treat one or more symptoms of a MK2-mediated disease or disorder. 3. Description of exemplary embodiments:

[0055] In some embodiments, the present disclosure provides compounds of Formula I: or a pharmaceutically acceptable salt thereof, wherein: The linker is a divalent group; The E3 binding portion is a portion that binds to the E3 ubiquitin ligase protein; Ring F is phenylene, a 5- to 6-membered heteroarylene ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 3- to 7-membered saturated or partially unsaturated heterocyclylene ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L d Selected from covalent bonds, -O-, -S-, -N(R)- and C 1-6 aliphatic; X is selected from -O-, -S- and -N(R)-; R zan optionally substituted group selected from halogen, -OR, -SR, -CN, -NO, -SONR, -SOR, -SOR, -C(O)R, -C0R, -C(O)N(R), -NRC(O)R, -NRC(O)OR, -NRC(O)N(R), -NRSOR, -N(R), or a C1-6 aliphatic, phenyl, a 3- to 8-membered saturated or partially unsaturated carbocycle, a 4- to 7-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R is independently hydrogen or an optionally substituted C1-6 aliphatic; and t is 0, 1, 2, or 3.

[0056] In some embodiments, Ring F is phenylene.

[0057] Thus, in some embodiments, the present disclosure provides compounds of Formula Ia: or a pharmaceutically acceptable salt thereof.

[0058] Thus, in some embodiments, the present disclosure provides compounds of Formula Ib: or a pharmaceutically acceptable salt thereof.

[0059] In some embodiments, the present disclosure provides compounds of Formula Ic: or a pharmaceutically acceptable salt thereof.

[0060] In some embodiments, the present disclosure provides compounds of Formula Id: or a pharmaceutically acceptable salt thereof.

[0061] As generally defined above, X is selected from -O-, -S-, and -N(R)-.

[0062] In some embodiments of Formula I, Ia, Ib, Ic, and Id, X is -O-. In some embodiments of Formula I, Ia, Ib, Ic, and Id, X is -S-. In some embodiments of Formula I, Ia, Ib, Ic, and Id, X is -N(R)-. In some such embodiments, X is -N(H)-.

[0063] In some embodiments, the disclosure provides compounds of Formulas Ia, Iai, Ia-ii, Ia-iii, Ia-iv, Iav, Ib, Ibi, Ib-ii, Ib-iii, Ib-iv, Ibv, Ic, Ici, Ic-ii, Ic-iii, Ic-iv, Icv, Id, Idi, and Id-ii: or a pharmaceutically acceptable salt thereof.

[0064] As generally defined above, Ring F is phenylene, a 5- to 6-membered heteroarylene ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 3- to 7-membered saturated or partially unsaturated heterocyclylene ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0065] In some embodiments of any formula described herein, Ring F is a phenylene ring. In some embodiments of any formula described herein, Ring F is a 5- to 6-membered heteroarylene ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any formula described herein, Ring F is a 5-membered heteroarylene ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any formula described herein, Ring F is a 5-membered heteroarylene ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any formula described herein, Ring F is a 5-membered heteroarylene ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any formula described herein, Ring F is a 6-membered heteroarylene ring having 1-2 nitrogen atoms.

[0066] In some embodiments of any formula described herein, Ring F is a 3- to 7-membered saturated or partially unsaturated heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any formula described herein, Ring F is a 3-membered saturated heterocyclylene having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments of any formula described herein, Ring F is a 4-membered saturated heterocyclylene having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments of any formula described herein, Ring F is a 5-membered saturated or partially unsaturated heterocyclylene having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments of any formula described herein, Ring F is a 6-membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0067] As generally defined above, L d Selected from covalent bonds, -O-, -S-, -N(R)- and C 1-6 In some embodiments of any of the formulas described herein, L d is a covalent bond. In some embodiments of any of the formulas described herein, L d Selected from -O-, -S-, -N(R)- and C 1-6 In some embodiments of any of the formulas described herein, L d Is -O-. In some embodiments of any of the formulae described herein, L d Is -S-. In some embodiments of any of the formulae described herein, L d is -N(R)-. In some embodiments of any of the formulae described herein, L d It is C 1-6 In some embodiments of any of the formulas described herein, L d It is C 1-4 In some embodiments of any of the formulas described herein, L d It is C 1-2 In some such embodiments, L d It is -CH2-, -CH(CH3)- or -CH2CH2-.

[0068] As generally defined above, R z an optionally substituted group selected from halogen, -OR, -SR, -CN, -NO, -SONR, -SOR, -SOR, -C(O)R, -C0R, -C(O)N(R), -NRC(O)R, -NRC(O)OR, -NRC(O)N(R), -NRSOR, -N(R), or a group selected from: C 1-6 aliphatic, phenyl, 3 to 8 membered saturated or partially unsaturated carbocyclic ring, 4 to 7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, and 5 to 6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments of any of the formulas described herein, R z is halogen. In some embodiments of any of the formulae described herein, R z is -OR. In some embodiments of any of the formulae described herein, R z Is -SR. In some embodiments of any of the formulas described herein, R z is -CN. In some embodiments of any of the formulae described herein, R z is -NO2. In some embodiments of any of the formulae described herein, R zIs -SO2NR. In some embodiments of any of the formulas described herein, R z Is -SO2R. In some embodiments of any of the formulas described herein, R z is -SOR. In some embodiments of any of the formulae described herein, R z is -C(O)R. In some embodiments of any of the formulae described herein, R z Is -CO2R. In some embodiments of any of the formulas described herein, R z is -C(O)N(R)2. In some embodiments of any of the formulae described herein, R z Is -NRC(O)R. In some embodiments of any of the formulas described herein, R z is -NRC(O)OR. In some embodiments of any of the formulae described herein, R z is -NRC(O)N(R)2. In some embodiments of any of the formulas described herein, R z Is -NRSO2R. In some embodiments of any of the formulas described herein, R z It is -N(R)2.

[0069] In some embodiments of any of the formulae described herein, R z is an optionally substituted C 1-6 In some embodiments of any of the formulas described herein, R z is an optionally substituted C 1-4 In some embodiments of any of the formulas described herein, R z is an optionally substituted C 1-2 In some embodiments of any of the formulas described herein, R z is -CH3 or CH2CH3. In some embodiments of any of the formulae described herein, R z is C optionally substituted by halogen 1-6 In some such embodiments, R z It is -CF3, -CF2H, -CFH2 or -CH2CF3.

[0070] In some embodiments of any of the formulae described herein, R z is optionally substituted phenyl.

[0071] In some embodiments of any of the formulae described herein, R z is an optionally substituted 3- to 8-membered saturated or partially unsaturated carbocyclic ring. In some embodiments of any of the formulae described herein, R z is an optionally substituted 3-membered saturated carbocyclic ring. In some embodiments of any of the formulae described herein, R zis an optionally substituted 4-membered saturated carbocyclic ring. In some embodiments of any of the formulae described herein, R z is an optionally substituted 5-membered saturated or partially unsaturated carbocyclic ring. In some embodiments of any of the formulae described herein, R z is an optionally substituted 6-membered saturated or partially unsaturated carbocyclic ring. In some embodiments of any of the formulae described herein, R z is an optionally substituted 7-membered saturated or partially unsaturated carbocyclic ring. In some embodiments of any of the formulae described herein, R z is an optionally substituted 8-membered saturated or partially unsaturated carbocyclic ring.

[0072] In some embodiments of any of the formulae described herein, R z is an optionally substituted 4- to 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments of any of the formulas described herein, R z is an optionally substituted 4-membered heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, or sulfur. In some embodiments of any of the formulas described herein, R z is an optionally substituted 5-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments of any of the formulas described herein, R z is an optionally substituted 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments of any of the formulas described herein, R z is an optionally substituted 7-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0073] In some embodiments of any of the formulae described herein, R z is an optionally substituted 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments of any of the formulas described herein, R z is an optionally substituted 5-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments of any of the formulas described herein, R z is an optionally substituted 5-membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments of any of the formulas described herein, R z is an optionally substituted 5-membered monocyclic heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments of any of the formulas described herein, R z is an optionally substituted 6-membered monocyclic heteroaryl ring having 1-2 nitrogen atoms.

[0074] As generally defined above, each R is independently hydrogen or an optionally substituted C1-6 In some embodiments of any of the formulas described herein, R is hydrogen. In some embodiments of any of the formulas described herein, R is optionally substituted C 1-6 In some embodiments of any of the formulae described herein, R is optionally substituted C 1-4 In some embodiments of any of the formulae described herein, R is optionally substituted C 1-2 In some such embodiments, R is -CH3, -CH2CH3, -CF3, -CF2H, -CFH2, or -CH2CF3.

[0075] As generally defined above, each t is 0, 1, 2, or 3. In some embodiments of any of the formulas described herein, t is 0. In some embodiments of any of the formulas described herein, t is 1. In some embodiments of any of the formulas described herein, t is 2. In some embodiments of any of the formulas described herein, t is 3. connector

[0076] As defined above, a linker is a divalent group that connects the E3 binding moiety to the rest of the compound. In some embodiments, the linker is an optionally substituted divalent C 2-20 A straight or branched aliphatic chain wherein one, two, three, four or five methylene units of the aliphatic chain are optionally and independently replaced by a group selected from: -N(R)-, -C(O)-, -C(O)N(R)-, a divalent 3 to 6 membered monocyclic saturated ring having 0 to 2 heteroatoms independently selected from nitrogen, a divalent 6 to 8 membered saturated or partially unsaturated bridged bicyclic, fused bicyclic or spirofused heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, each monocyclic, bridged bicyclic, fused bicyclic, spirofused ring or phenylene being replaced by R L 0-4 examples of substitution, where R L independently selected from halogen, -OR, -SR, -CN, -NO2, -SO2NR, -SO2R, -SOR, -C(O)R, -C02R, -C(O)N(R)2, -NRC(O)R, -NRC(O)OR, -NRC(O)N(R)2, -NRSO2R, -N(R)2, or an optionally substituted group selected from: C 1-6 aliphatic, phenyl, 3- to 8-membered saturated or partially unsaturated carbocyclic rings, 4- to 7-membered heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, and 5- to 6-membered monocyclic heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, the linker is an optionally substituted divalent C 2-20A linear or branched aliphatic chain wherein two, three or four methylene units of the aliphatic chain are optionally and independently replaced by a group selected from: -N(R)-, -O-, -C(O)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)-, -C(O)O-, and a divalent 3- to 6-membered monocyclic saturated or partially unsaturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the monocyclic ring is replaced by R L In some embodiments, the linker is an optionally substituted divalent C 2-20 A linear or branched aliphatic chain wherein two, three, four or five methylene units of the aliphatic chain are optionally and independently replaced by a group selected from the group consisting of: -C(O)N(R)-, -N(R)-, -C(O)-, In some embodiments, the linker is an optionally substituted divalent C 2-20 A linear or branched aliphatic chain wherein two, three, four or five methylene units of the aliphatic chain are optionally and independently replaced by a group selected from the group consisting of: -C(O)N(R)-, -N(R)-, -C(O)-,

[0077] In some embodiments, the linker is an optionally substituted divalent C 3-17 a straight or branched aliphatic chain wherein one, two, three, four or five methylene units of the aliphatic chain are optionally and independently replaced by a group selected from: -N(R)-, -O-, -C(O)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)-, -C(O)O-, a divalent 3 to 6 membered monocyclic saturated or partially unsaturated ring having 0 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a divalent 6 to 8 membered saturated or partially unsaturated bridged bicyclic, fused bicyclic or spirofused heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and phenylene, wherein each monocyclic, bridged bicyclic, fused bicyclic, spirofused ring or phenylene is replaced by R L In some embodiments, the linker is an optionally substituted divalent C 3-17 A linear or branched aliphatic chain wherein two, three or four methylene units of the aliphatic chain are optionally and independently replaced by a group selected from: -N(R)-, -O-, -C(O)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)-, -C(O)O-, and a divalent 3- to 6-membered monocyclic saturated or partially unsaturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the monocyclic ring is replaced by R L 0-4 examples are replaced.

[0078] In some embodiments, the linker is an optionally substituted divalent C 3-17 A linear or branched aliphatic chain wherein two, three, four or five methylene units of the aliphatic chain are optionally and independently replaced by a group selected from the group consisting of: -C(O)N(R)-, -N(R)-, -C(O)-,

[0079] In some embodiments, the linker is an optionally substituted divalent C 3-17 A linear or branched aliphatic chain wherein two, three, four or five methylene units of the aliphatic chain are optionally and independently replaced by a group selected from the group consisting of: -C(O)N(R)-, -N(R)-, -C(O)-,

[0080] In some embodiments, the linker is an optionally substituted divalent C 2-10 a straight or branched aliphatic chain wherein one, two, three, four or five methylene units of the aliphatic chain are optionally and independently replaced by a group selected from: -N(R)-, -O-, -C(O)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)-, -C(O)O-, a divalent 3 to 6 membered monocyclic saturated or partially unsaturated ring having 0 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a divalent 6 to 8 membered saturated or partially unsaturated bridged bicyclic, fused bicyclic or spirofused heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and phenylene, wherein each monocyclic, bridged bicyclic, fused bicyclic, spirofused ring or phenylene is replaced by R L In some embodiments, the linker is an optionally substituted divalent C 2-10 A linear or branched aliphatic chain wherein two, three or four methylene units of the aliphatic chain are optionally and independently replaced by a group selected from: -N(R)-, -O-, -C(O)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)-, -C(O)O-, and a divalent 3- to 6-membered monocyclic saturated or partially unsaturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the monocyclic ring is replaced by R L 0-4 examples are replaced.

[0081] In some embodiments, the linker is an optionally substituted divalent C 2-10 A linear or branched aliphatic chain wherein two, three, four or five methylene units of the aliphatic chain are optionally and independently replaced by a group selected from the group consisting of: -C(O)N(R)-, -N(R)-, -C(O)-, In some embodiments, the linker is an optionally substituted divalent C2-10 A linear or branched aliphatic chain wherein two, three, four or five methylene units of the aliphatic chain are optionally and independently replaced by a group selected from the group consisting of: -C(O)N(R)-, -N(R)-, -C(O)-,

[0082] In some embodiments, the linker is an optionally substituted divalent C 2-6 a straight or branched aliphatic chain wherein one, two, three, four or five methylene units of the aliphatic chain are optionally and independently replaced by a group selected from: -N(R)-, -O-, -C(O)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)-, -C(O)O-, a divalent 3 to 6 membered monocyclic saturated or partially unsaturated ring having 0 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a divalent 6 to 8 membered saturated or partially unsaturated bridged bicyclic, fused bicyclic or spirofused heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and phenylene, wherein each monocyclic, bridged bicyclic, fused bicyclic, spirofused ring or phenylene is replaced by R L In some embodiments, the linker is an optionally substituted divalent C 2-6 A linear or branched aliphatic chain wherein two, three or four methylene units of the aliphatic chain are optionally and independently replaced by a group selected from: -N(R)-, -O-, -C(O)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)-, -C(O)O-, and a divalent 3- to 6-membered monocyclic saturated or partially unsaturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the monocyclic ring is replaced by R L 0-4 examples are replaced.

[0083] In some embodiments, the linker is an optionally substituted divalent C 2-6 A linear or branched aliphatic chain wherein two, three, four or five methylene units of the aliphatic chain are optionally and independently replaced by a group selected from the group consisting of: -C(O)N(R)-, -N(R)-, -C(O)-,

[0084] In some embodiments, the linker is an optionally substituted divalent C 2-6 A linear or branched aliphatic chain wherein two, three, four or five methylene units of the aliphatic chain are optionally and independently replaced by a group selected from the group consisting of: -C(O)N(R)-, -N(R)-, -C(O)-,

[0085] In some embodiments, the linker is an optionally substituted divalent C4-6 a straight or branched aliphatic chain wherein one, two, three, four or five methylene units of the aliphatic chain are optionally and independently replaced by a group selected from: -N(R)-, -O-, -C(O)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)-, -C(O)O-, a divalent 3 to 6 membered monocyclic saturated or partially unsaturated ring having 0 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a divalent 6 to 8 membered saturated or partially unsaturated bridged bicyclic, fused bicyclic or spirofused heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and phenylene, wherein each monocyclic, bridged bicyclic, fused bicyclic, spirofused ring or phenylene is replaced by R L In some embodiments, the linker is an optionally substituted divalent C 4-6 A linear or branched aliphatic chain wherein two, three or four methylene units of the aliphatic chain are optionally and independently replaced by a group selected from: -N(R)-, -O-, -C(O)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)-, -C(O)O-, and a divalent 3- to 6-membered monocyclic saturated or partially unsaturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the monocyclic ring is replaced by R L 0-4 examples are replaced.

[0086] In some embodiments, the linker is an optionally substituted divalent C 4-6 A linear or branched aliphatic chain wherein two, three, four or five methylene units of the aliphatic chain are optionally and independently replaced by a group selected from the group consisting of: -C(O)N(R)-, -N(R)-, -C(O)-, In some embodiments, the linker is an optionally substituted divalent C 4-6 A linear or branched aliphatic chain wherein two, three, four or five methylene units of the aliphatic chain are optionally and independently replaced by a group selected from the group consisting of: -C(O)N(R)-, -N(R)-, -C(O)-,

[0087] In some embodiments, the linker is selected from:

[0088] In some embodiments, the linker is selected from: E3 binding part

[0089] The proteasome is a large protein complex responsible for degrading proteins within the cell. The polymerization of ubiquitin, a key molecule known to coordinate the work of the proteasome, acts as a degradation signal for many target proteins; the covalent attachment of a chain consisting of several ubiquitin copies (more than four ubiquitin molecules) triggers the destruction of the protein through the coordinated action of a network of proteins including E1 (ubiquitin activation), E2 (ubiquitin conjugation) and E3 (ubiquitin ligation) enzymes. The polymerized ubiquitin chain acts as a signal to transport the target protein to the proteasome, where the substrate is broken down by proteolysis. This group of E3 proteins is highly diverse because each E3 enzyme selectively recognizes protein substrates for ubiquitination. The ubiquitin-proteasome system (UPS) controls almost all fundamental cellular processes, such as progression of the cell cycle, signal transduction, cell death, immune response, metabolism, protein quality control and development, by degrading short-lived regulatory proteins or structurally abnormal proteins. Cerebrolysin (CRBN) is a CRL4 CRBN Substrate receptor for E3 ubiquitin ligases and induces cell death by targeting key new substrates for ubiquitination and subsequent degradation.

[0090] In some embodiments, the compounds disclosed herein degrade MK2 kinase via the ubiquitin-proteasome system.

[0091] As generally defined above, an E3 binding moiety is a moiety that binds to an E3 ubiquitin ligase protein. In some embodiments, the E3 binding moiety is a cereblon protein binding moiety.

[0092] In some embodiments, the cereblon protein binding moiety is selected from the group consisting of:

[0093] In some embodiments, the cereblon protein binding moiety is selected from the group consisting of:

[0094] In some embodiments, the compound of Formula I is selected from Table 1. Table 1: Exemplary compounds or a pharmaceutically acceptable salt thereof.

[0095] In some embodiments, the compounds or pharmaceutically acceptable salts of the present disclosure have the formula: or a pharmaceutically acceptable salt thereof, wherein: The linker is a divalent group; The E3 binding portion is a portion that binds to the E3 ubiquitin ligase protein; Ring F is phenylene, a 5- to 6-membered heteroarylene ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 3- to 7-membered saturated or partially unsaturated heterocyclylene ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L d Selected from covalent bonds, -O-, -S-, -N(R)- and C 1-6 aliphatic; X is selected from -O-, -S- and -N(R)-; R z an optionally substituted group selected from halogen, -OR, -SR, -CN, -NO, -SONR, -SOR, -SOR, -C(O)R, -C0R, -C(O)N(R), -NRC(O)R, -NRC(O)OR, -NRC(O)N(R), -NRSOR, -N(R), or a group selected from: C 1-6 aliphatic, phenyl, 3- to 8-membered saturated or partially unsaturated carbocyclic rings, 4- to 7-membered heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and 5- to 6-membered monocyclic heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R is independently hydrogen or an optionally substituted C 1-6 aliphatic; and t is 0, 1, 2, or 3.

[0096] In some embodiments of the compounds of the present disclosure, Ring F is phenylene.

[0097] In some embodiments of the compounds of the present disclosure, L d It is a covalent bond.

[0098] In some embodiments of the compounds of the present disclosure, X is -O-.

[0099] In some embodiments of the compounds of the present disclosure, X is -N(R)-.

[0100] In some embodiments of the compounds of the present disclosure, R is hydrogen.

[0101] In some embodiments of the compounds of the present disclosure, R z is selected from halogen, -OR, -SR, -CN, -NO2, -SO2NR, -SO2R, -SOR, -C(O)R, -CO2R and -C(O)N(R)2.

[0102] In some embodiments of the compounds of the present disclosure, R z Selected from halogen, -OR, -SR, -CN and -NO2.

[0103] In some embodiments of the compounds of the present disclosure, t is 0.

[0104] In some embodiments of the compounds of the present disclosure, t is 1.

[0105] In some embodiments of the compounds of the present disclosure, the compound is of any one of Formulas Ia, Iai, Ia-ii, Ia-iii, Ia-iv, Iav, Ib, Ibi, Ib-ii, Ib-iii, Ib-iv, Ibv, Ic, Ici, Ic-ii, Ic-iii, Ic-iv, Icv, Id, Idi, and Id-ii: or a pharmaceutically acceptable salt thereof.

[0106] In some embodiments of the compounds of the present disclosure, the linker is an optionally substituted divalent C 2-20 a straight or branched aliphatic chain wherein one, two, three, four or five methylene units of the aliphatic chain are optionally and independently replaced by a group selected from: -N(R)-, -O-, -C(O)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)-, -C(O)O-, a divalent 3 to 6 membered monocyclic saturated or partially unsaturated ring having 0 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a divalent 6 to 8 membered saturated or partially unsaturated bridged bicyclic, fused bicyclic or spirofused heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and phenylene, wherein each monocyclic, bridged bicyclic, fused bicyclic, spirofused ring or phenylene is replaced by R L 0-4 examples are replaced. and R Lindependently selected from halogen, -OR, -SR, -CN, -NO2, -SO2NR, -SO2R, -SOR, -C(O)R, -C02R, -C(O)N(R)2, -NRC(O)R, -NRC(O)OR, -NRC(O)N(R)2, -NRSO2R, -N(R)2, or an optionally substituted group selected from: C 1-6 aliphatic, phenyl, 3- to 8-membered saturated or partially unsaturated carbocyclic rings, 4- to 7-membered heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, and 5- to 6-membered monocyclic heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0107] In some embodiments of the compounds of the present disclosure, the linker is an optionally substituted divalent C 2-20 A linear or branched aliphatic chain wherein two, three or four methylene units of the aliphatic chain are optionally and independently replaced by a group selected from: -N(R)-, -O-, -C(O)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)-, -C(O)O-, and a divalent 3- to 6-membered monocyclic saturated or partially unsaturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the monocyclic ring is replaced by R L 0-4 examples are replaced.

[0108] In some embodiments of the compounds of the present disclosure, the linker is an optionally substituted divalent C 2-20 A linear or branched aliphatic chain wherein two, three, four or five methylene units of the aliphatic chain are optionally and independently replaced by a group selected from the group consisting of: -C(O)N(R)-, -N(R)-, -C(O)-,

[0109] In some embodiments of the compounds of the present disclosure, the linker is an optionally substituted divalent C 2-20 A linear or branched aliphatic chain wherein two, three, four or five methylene units of the aliphatic chain are optionally and independently replaced by a group selected from the group consisting of: -C(O)N(R)-, -N(R)-, -C(O)-,

[0110] In some embodiments of the compounds of the present disclosure, the linker is an optionally substituted divalent C 3-17a straight or branched aliphatic chain wherein one, two, three, four or five methylene units of the aliphatic chain are optionally and independently replaced by a group selected from: -N(R)-, -O-, -C(O)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)-, -C(O)O-, a divalent 3 to 6 membered monocyclic saturated or partially unsaturated ring having 0 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a divalent 6 to 8 membered saturated or partially unsaturated bridged bicyclic, fused bicyclic or spirofused heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and phenylene, wherein each monocyclic, bridged bicyclic, fused bicyclic, spirofused ring or phenylene is replaced by R L 0-4 examples are replaced.

[0111] In some embodiments of the compounds of the present disclosure, the linker is an optionally substituted divalent C 3-17 A linear or branched aliphatic chain wherein two, three or four methylene units of the aliphatic chain are optionally and independently replaced by a group selected from: -N(R)-, -O-, -C(O)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)-, -C(O)O-, and a divalent 3- to 6-membered monocyclic saturated or partially unsaturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the monocyclic ring is replaced by R L 0-4 examples are replaced.

[0112] In some embodiments of the compounds of the present disclosure, the linker is an optionally substituted divalent C 3-17 A linear or branched aliphatic chain wherein two, three, four or five methylene units of the aliphatic chain are optionally and independently replaced by a group selected from the group consisting of: -C(O)N(R)-, -N(R)-, -C(O)-,

[0113] In some embodiments of the compounds of the present disclosure, the linker is an optionally substituted divalent C 3-17 A linear or branched aliphatic chain wherein two, three, four or five methylene units of the aliphatic chain are optionally and independently replaced by a group selected from the group consisting of: -C(O)N(R)-, -N(R)-, -C(O)-,

[0114] In some embodiments of the compounds of the present disclosure, the linker is an optionally substituted divalent C 2-10a straight or branched aliphatic chain wherein one, two, three, four or five methylene units of the aliphatic chain are optionally and independently replaced by a group selected from: -N(R)-, -O-, -C(O)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)-, -C(O)O-, a divalent 3 to 6 membered monocyclic saturated or partially unsaturated ring having 0 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a divalent 6 to 8 membered saturated or partially unsaturated bridged bicyclic, fused bicyclic or spirofused heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and phenylene, wherein each monocyclic, bridged bicyclic, fused bicyclic, spirofused ring or phenylene is replaced by R L 0-4 examples are replaced.

[0115] In some embodiments of the compounds of the present disclosure, the linker is an optionally substituted divalent C 2-10 A linear or branched aliphatic chain wherein two, three or four methylene units of the aliphatic chain are optionally and independently replaced by a group selected from: -N(R)-, -O-, -C(O)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)-, -C(O)O-, and a divalent 3- to 6-membered monocyclic saturated or partially unsaturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the monocyclic ring is replaced by R L 0-4 examples are replaced.

[0116] In some embodiments of the compounds of the present disclosure, the linker is an optionally substituted divalent C 2-10 A linear or branched aliphatic chain wherein two, three, four or five methylene units of the aliphatic chain are optionally and independently replaced by a group selected from the group consisting of: -C(O)N(R)-, -N(R)-, -C(O)-,

[0117] In some embodiments of the compounds of the present disclosure, the linker is an optionally substituted divalent C 2-10 A linear or branched aliphatic chain wherein two, three, four or five methylene units of the aliphatic chain are optionally and independently replaced by a group selected from the group consisting of: -C(O)N(R)-, -N(R)-, -C(O)-,

[0118] In some embodiments of the compounds of the present disclosure, the linker is an optionally substituted divalent C 2-6a straight or branched aliphatic chain wherein one, two, three, four or five methylene units of the aliphatic chain are optionally and independently replaced by a group selected from: -N(R)-, -O-, -C(O)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)-, -C(O)O-, a divalent 3 to 6 membered monocyclic saturated or partially unsaturated ring having 0 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a divalent 6 to 8 membered saturated or partially unsaturated bridged bicyclic, fused bicyclic or spirofused heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and phenylene, wherein each monocyclic, bridged bicyclic, fused bicyclic, spirofused ring or phenylene is replaced by R L 0-4 examples are replaced.

[0119] In some embodiments of the compounds of the present disclosure, the linker is an optionally substituted divalent C 2-6 A linear or branched aliphatic chain wherein two, three or four methylene units of the aliphatic chain are optionally and independently replaced by a group selected from: -N(R)-, -O-, -C(O)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)-, -C(O)O-, and a divalent 3- to 6-membered monocyclic saturated or partially unsaturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the monocyclic ring is replaced by R L 0-4 examples are replaced.

[0120] In some embodiments of the compounds of the present disclosure, the linker is an optionally substituted divalent C 2-6 A linear or branched aliphatic chain wherein two, three, four or five methylene units of the aliphatic chain are optionally and independently replaced by a group selected from the group consisting of: -C(O)N(R)-, -N(R)-, -C(O)-,

[0121] In some embodiments of the compounds of the present disclosure, the linker is an optionally substituted divalent C 2-6 A linear or branched aliphatic chain wherein two, three, four or five methylene units of the aliphatic chain are optionally and independently replaced by a group selected from the group consisting of: -C(O)N(R)-, -N(R)-, -C(O)-,

[0122] In some embodiments of the compounds of the present disclosure, the linker is an optionally substituted divalent C 4-6a straight or branched aliphatic chain wherein one, two, three, four or five methylene units of the aliphatic chain are optionally and independently replaced by a group selected from: -N(R)-, -O-, -C(O)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)-, -C(O)O-, a divalent 3 to 6 membered monocyclic saturated or partially unsaturated ring having 0 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a divalent 6 to 8 membered saturated or partially unsaturated bridged bicyclic, fused bicyclic or spirofused heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and phenylene, wherein each monocyclic, bridged bicyclic, fused bicyclic, spirofused ring or phenylene is replaced by R L 0-4 examples are replaced.

[0123] In some embodiments of the compounds of the present disclosure, the linker is an optionally substituted divalent C 4-6 A linear or branched aliphatic chain wherein two, three or four methylene units of the aliphatic chain are optionally and independently replaced by a group selected from the group consisting of: -N(R)-, -O-, -C(O)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)-, -C(O)O-, and a divalent 3- to 6-membered monocyclic saturated or partially unsaturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the monocyclic ring is replaced by R L 0-4 examples are replaced.

[0124] In some embodiments of the compounds of the present disclosure, the linker is an optionally substituted divalent C 4-6 A linear or branched aliphatic chain wherein two, three, four or five methylene units of the aliphatic chain are optionally and independently replaced by a group selected from the group consisting of: -C(O)N(R)-, -N(R)-, -C(O)-,

[0125] In some embodiments of the compounds of the present disclosure, the linker is an optionally substituted divalent C 4-6 A linear or branched aliphatic chain wherein two, three, four or five methylene units of the aliphatic chain are optionally and independently replaced by a group selected from the group consisting of: -C(O)N(R)-, -N(R)-, -C(O)-,

[0126] In some embodiments of the compounds of the present disclosure, the linker is selected from:

[0127] In some embodiments of the compounds of the present disclosure, the linker is selected from:

[0128] In some embodiments of the compounds of the present disclosure, the E3 binding moiety is a cerebrolin protein binding moiety.

[0129] In some embodiments of the compounds of the present disclosure, the cereblon protein binding moiety is selected from the group consisting of:

[0130] In some embodiments of the compounds of the present disclosure, the cereblon protein binding moiety is selected from the group consisting of:

[0131] In some embodiments, the compound or pharmaceutically acceptable salt is selected from Table 1: Table 1: Exemplary compounds or a pharmaceutically acceptable salt thereof.

[0132] In other embodiments of the present disclosure, the pharmaceutical compositions described herein comprise a compound described herein and a pharmaceutically acceptable excipient, carrier, or diluent.

[0133] In other embodiments of the present disclosure, methods of degrading the activity of MK2 or a mutant thereof comprise contacting a biological sample with a compound of the present disclosure.

[0134] In another embodiment of the present disclosure, a method of treating a disease, disorder, or condition mediated by MK2 or a mutant thereof comprises administering a compound or composition of the present disclosure to a patient in need thereof. 4. Use, formulation and application Pharmaceutically acceptable compositions

[0135] According to another embodiment, the present disclosure provides a composition comprising a compound described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In certain embodiments, the amount of compound in the provided composition is sufficient to measurably degrade MK2 or a mutant thereof in a biological sample or patient. In certain embodiments, the provided composition is formulated for administration to a patient in need of such a composition. In some embodiments, the provided composition is formulated for oral administration to a patient.

[0136] According to the methods provided, the compounds and compositions are administered using any amount and any route of administration that is effective for treating the disorders provided herein (i.e., MK2-mediated diseases or disorders) or reducing the severity of the disorder. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the specific agent, its mode of administration, etc. The compounds described herein can be further formulated into unit dosage forms for ease of administration and uniform dosage.

[0137] The compositions provided herein can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, intraperitoneally, intracisternal, or via an implanted reservoir. In some embodiments, the compositions are administered orally, intraperitoneally, or intravenously.

[0138] The sterile injectable form of the composition provided herein can be an aqueous or oily suspension. Suitable dispersants or wetting agents and suspending agents can be used to prepare these suspensions according to techniques known in the art. Sterile injectable formulations can also be sterile injectable solutions or suspensions in nontoxic parenteral acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, conventionally, sterile fixed oils are used as solvents or suspending media.

[0139] For this purpose, any mild fixed oil can be used, including synthetic mono- or diglycerides. Fatty acids (such as oleic acid) and their glyceride derivatives can be used to prepare injectables, as can natural pharmaceutically acceptable oils such as olive oil or castor oil, especially their polyoxyethylated forms. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, such as carboxymethyl cellulose or similar dispersants commonly used in the preparation of pharmaceutically acceptable dosage forms (including emulsions and suspensions). Other commonly used surfactants, such as Tweens, Spans and other emulsifiers or bioavailability enhancers, which are commonly used to prepare pharmaceutically acceptable solids, liquids or other dosage forms, can also be used for the purpose of formulation.

[0140] The injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0141] In order to prolong the effect of the compound provided herein, it is generally desirable to slow down the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous materials with poor water solubility. The absorption rate of the compound then depends on its dissolution rate, and the dissolution rate can then depend on the crystal size and crystalline form. Alternatively, delayed absorption of the compound form administered parenterally can be achieved by dissolving or suspending the compound in an oily vehicle. Injectable depot forms are manufactured by forming a microcapsule matrix of the compound in a biodegradable polymer such as polylactide-polyglycolide. Depending on the ratio of the compound to the polymer and the properties of the specific polymer used, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by embedding the compound in liposomes or microemulsions compatible with body tissues.

[0142] In some embodiments, the pharmaceutically acceptable compositions provided are formulated for oral administration. Such formulations can be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions provided herein are not administered with food. In other embodiments, the pharmaceutically acceptable compositions provided herein are administered with food. The pharmaceutically acceptable compositions provided herein can be orally administered in any orally acceptable dosage form (including but not limited to capsules, tablets, aqueous suspensions, or solutions). In the case of tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are typically also added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When an aqueous suspension is required for oral use, the active ingredient is combined with an emulsifier and a suspending agent. If desired, certain sweeteners, flavorings, or coloring agents may also be added.

[0143] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the provided compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as (a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, such as glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (e) solution retarding agents, such as paraffin; (f) absorption promoters, such as quaternary ammonium compounds; (g) wetting agents, such as, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin and bentonite; and / or (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain a buffer.

[0144] Solid compositions of similar types also can be used as fillers for use in soft and hard filled gelatin capsules of excipients such as lactose or milk sugar and high molecular weight polyethylene glycol.Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, and these coatings and shells are other coatings known in the field of enteric coatings and pharmaceutical formulations.They can optionally contain opacifiers and can also have the following composition, that is, they only release one or more active ingredients, in a certain part of intestinal tract, preferably in a delayed manner.The example of operable embedded composition includes polymeric substances and wax.Solid compositions of similar types also can be used as fillers for use in soft and hard filled gelatin capsules of excipients such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0145] Active compound can also be in the form of microencapsulation with one or more excipients as indicated above. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, and these coatings and shells are such as enteric coatings, controlled release coatings and other coatings known in the field of pharmaceutical formulations. In such solid dosage forms, the compound provided can be mixed with at least one inert diluent such as sucrose, lactose or starch. These dosage forms can also include (as common practice) other substances other than inert diluents such as tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage form can also include a buffer. They can optionally contain an opacifier and can also have the following composition, i.e., only releasing one or more active ingredients, in a certain part of the intestinal tract, preferably in a delayed manner. The example of an embedding composition that can be used includes polymeric substances and waxes.

[0146] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the compound provided, these liquid dosage forms can contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oil (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters, and mixtures thereof. In addition to inert diluents, these oral compositions can also include adjuvants, such as wetting agents, emulsifiers, and suspending agents, sweeteners, flavorings, and aromatics.

[0147] Alternatively, the pharmaceutically acceptable compositions provided herein can be used in the form of suppositories for rectal administration. These can be prepared by mixing the medicament with a suitable non-irritating excipient, which is solid at room temperature and liquid at rectal temperature, and will therefore dissolve in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0148] Compositions for rectal or vaginal administration may also be suppositories which can be prepared by mixing a compound provided herein with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or a suppository wax which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity and releases the active compound.

[0149] The pharmaceutically acceptable compositions provided herein can also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, skin, or lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0150] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation.Topical transdermal patches may also be used.

[0151] For topical application, the pharmaceutically acceptable compositions provided can be formulated in a suitable ointment containing a compound described herein suspended or dissolved in one or more carriers. Carriers for topical application of the compound provided include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutically acceptable compositions provided can be formulated in a suitable lotion or cream containing a compound described herein suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0152] For ophthalmic use, provided pharmaceutically acceptable compositions can be formulated as micronized suspensions in isotonic, pH-adjusted sterile saline, including solutions in isotonic, pH-adjusted sterile saline, with or without preservatives such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutically acceptable compositions can be formulated in an ointment such as petrolatum.

[0153] The pharmaceutically acceptable compositions provided herein can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and can be prepared as saline solutions using benzyl alcohol or other suitable preservatives, adsorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional stabilizers or dispersants.

[0154] The dosage form for topical or transdermal administration of the compound described herein includes ointment, paste, cream, lotion, gel, powder, solution, spray, inhalant or patch. Under sterile conditions, the compound can be mixed with a pharmaceutically acceptable carrier and any required preservative or buffer as may be needed. Ophthalmic preparations, ear drops and eye drops are also expected to be within the scope of this disclosure. In addition, the present disclosure of the present invention contemplates the use of transdermal patches, which have the advantage of providing controlled delivery of the compound to the body. Such dosage forms can be prepared by dissolving or distributing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. Rate control can be achieved by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel. Uses of compounds and pharmaceutically acceptable compositions

[0155] The compounds and compositions described herein are generally useful for degrading the kinase activity of one or more enzymes and for treating diseases and disorders associated with MK2 degradation.Examples of kinases that are degraded by the compounds and compositions described herein and for which the methods described herein are useful include MK2 or mutants thereof.

[0156] The activity of compounds used as degradation agents for MK2 kinase or its mutants can be determined in vitro, in vivo or in cell lines. In vitro assays include assays that determine the phosphorylation activity of activated MK2 kinase or its mutants and / or the subsequent functional consequences or inhibition of ATPase activity. Alternative in vitro assays quantify the ability of the provided compounds to bind to MK2. Degrader activity can be measured by radiolabeling the test compound before binding, isolating the compound / MK2 complex and determining the amount of radiolabeled binding. Alternatively, degradation agent activity can be determined by running a competition experiment in which the test compound is incubated with an MK2 kinase bound to a known radioligand. The detailed conditions for determining the compounds used as degradation agents for MK2 or its mutants in this disclosure are described in the following examples.

[0157] According to one embodiment, the present disclosure relates to a method of degrading protein kinase activity in a biological sample, comprising the step of contacting the biological sample with a compound provided herein or a composition comprising the compound.

[0158] According to another embodiment, the present disclosure relates to a method for degrading the activity of MK2 kinase or a mutant thereof in a biological sample, the method comprising the step of contacting the biological sample with a compound provided herein or a composition comprising the compound. In certain embodiments, the present disclosure relates to a method for irreversibly degrading the activity of MK2 kinase or a mutant thereof in a biological sample, the method comprising the step of contacting the biological sample with a compound provided herein or a composition comprising the compound.

[0159] According to another embodiment, the present disclosure relates to a method for degrading the activity of MK2 kinase or a mutant thereof in a patient, comprising the step of administering to the patient a compound as provided herein or a composition comprising the compound. According to certain embodiments, the present disclosure relates to a method for irreversibly degrading the activity of MK2 kinase or a mutant thereof in a patient, comprising the step of administering to the patient a compound as provided herein or a composition comprising the compound. In other embodiments, the present disclosure provides a method for treating an MK2-mediated disease or disorder in a patient in need thereof, comprising the step of administering to the patient a compound as provided herein or a pharmaceutically acceptable composition thereof. Such disorders are described in detail herein. MK2 kinase

[0160] MAP kinase-activated protein kinase 2 ("MK2") is an enzyme encoded by the MAPKAPK2 gene in humans. This gene encodes a member of the Ser / Thr protein kinase family. This kinase is regulated by direct phosphorylation of p38 MAP kinase. Along with p38 MAP kinase, this kinase is known to be involved in many cellular processes, including stress and inflammatory responses, nuclear export, gene expression regulation, and cell proliferation. Heat shock protein HSP27 has been shown to be one of the in vivo substrates of this kinase. Two transcript variants encoding two different isoforms have been found for this gene.

[0161] MK2 is a multi-domain protein consisting of an N-terminal proline-rich domain, a catalytic domain, an autoinhibitory domain, and a nuclear export signal (NES) and a nuclear localization signal (NLS) at the C-terminus. Two isoforms of human MK2 have been characterized. One isoform consists of 400 amino acids, and the other isoform consists of 370 residues (considered to be a splice variant lacking the C-terminal NLS). MK2 is located in the nucleus, and after being bound and phosphorylated by p38, the MK2 NES becomes functional and the two kinases are co-transported out of the nucleus to the cytoplasm. Interestingly, the transport of the MK2 / p38 complex does not require catalytically active MK2, as the active site mutant Asp207Ala is still transported to the cytoplasm. The phosphorylation of human MK2 by p38 on residues T222, S272, and T334 is thought to activate the enzyme by inducing conformational changes in the autoinhibitory domain, thereby exposing the active site for substrate binding. Mutation of two autoinhibitory domain residues, W332A and K326E, in murine MK2 demonstrated an increase in basal activity, and C-terminal deletion of the autoinhibitory domain rendered the enzyme constitutively active, providing additional evidence for a role for this domain in inhibiting MK2 activity.

[0162] Diseases or disorders associated with MK2 that are treated by the compounds of the present disclosure include autoimmune disorders, chronic inflammatory disorders, acute inflammatory disorders, autoinflammatory disorders, fibrotic disorders, metabolic disorders, neoplasia, or cardiovascular or cerebrovascular disorders. Thus, in some embodiments, the present disclosure provides methods for treating MK2-mediated diseases or disorders in patients in need thereof, wherein the methods comprise administering to the patient a therapeutically effective amount of a provided compound or composition thereof. Such MK2-mediated diseases or disorders include, but are not limited to, those described herein.

[0163] In some embodiments, the MK2-mediated disease or disorder is an autoimmune disorder, a chronic and / or acute inflammatory disorder, and / or an autoinflammatory disorder. Exemplary autoimmune and / or inflammatory and / or autoinflammatory disorders include: inflammatory bowel disease (e.g., ulcerative colitis or Crohn's disease), multiple sclerosis, psoriasis, arthritis, rheumatoid arthritis, osteoarthritis, juvenile arthritis, psoriatic arthritis, reactive arthritis, ankylosing spondylitis, cryptopyrin-associated periodic syndromes, Mueller-Weiss syndrome, familial cold autoinflammatory syndrome, multisystem inflammatory disease of neonatal onset, TNF receptor-associated periodic syndromes, acute and chronic pancreatitis, atherosclerosis, gout, ankylosing spondylitis, fibrotic disorders (e.g., liver fibrosis or idiopathic pulmonary fibrosis), kidney disease, sarcoidosis, scleroderma, Allergic reactions, diabetes (e.g., type 1 diabetes, type 2 diabetes), diabetic retinopathy, Still's disease, vasculitis, sarcoidosis, lung inflammation, acute respiratory distress syndrome, wet and dry age-related macular degeneration, autoimmune hemolytic syndrome, autoimmune and inflammatory hepatitis, autoimmune neuropathy, autoimmune ovarian failure, autoimmune orchitis, autoimmune thrombocytopenia, silicone implant-related autoimmune diseases, Sjögren's syndrome, familial Mediterranean fever, systemic lupus erythematosus, vasculitic syndromes (e.g., temporal arteritis, Takayasu arteritis, and giant cell arteritis, Behçet's disease or Wegener's granulomatosis), vitiligo, autoimmune Secondary hematologic manifestations of autoimmune diseases (e.g., anemia), drug-induced autoimmunity, Hashimoto's thyroiditis, hypophysitis, idiopathic thrombocytic purpura, metal-induced autoimmunity, myasthenia gravis, pemphigus, autoimmune deafness (e.g., Meniere's disease), Goodpasture's syndrome, Graves' disease, Herceptin-related autoimmune syndromes, Guillain-Barré disease, Addison's disease, antiphospholipid syndrome, asthma, atopic dermatitis, celiac disease, Cushing's syndrome, dermatomyositis, idiopathic adrenal atrophy, idiopathic thrombocytopenia, Kawasaki syndrome, Lambert-Eaton syndrome, pernicious anemia, hay fever, polyarteritis nodosa, primary biliary cirrhosis, Sclerosing cholangitis, Raynaud's syndrome, Reiter's syndrome, relapsing polychondritis, Schmidt's syndrome, thyrotoxicosis, sepsis, septic shock, endotoxic shock, exotoxin-induced toxic shock, Gram-negative sepsis, toxic shock syndrome, glomerulonephritis, peritonitis, interstitial cystitis, hyperoxia-induced inflammation, chronic obstructive pulmonary disease (COPD), vasculitis, graft-versus-host reaction (e.g., graft-versus-host disease), allograft rejection (e.g., acute allograft rejection or chronic allograft rejection), early transplant rejection (e.g., acute allograft rejection), reperfusion injury, pain (e.g.,acute pain, chronic pain, neuropathic pain or fibromyalgia), chronic infection, meningitis, encephalitis, myocarditis, gingivitis, postoperative trauma, tissue damage, head injury, enterocolitis, sinusitis, uveitis, eye inflammation, optic neuritis, gastric ulcer, esophagitis, peritonitis, periodontitis, dermatomyositis, gastritis, myositis, polymyalgia, pneumonia and bronchitis.

[0164] In some embodiments, the MK2-mediated disease or disorder is a fibrotic disorder. Exemplary fibrotic disorders include systemic sclerosis / scleroderma, lupus nephritis, connective tissue disease, wound healing, surgical scarring, spinal cord injury, CNS scarring, acute lung injury, pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis or cystic fibrosis), chronic obstructive pulmonary disease, adult respiratory distress syndrome, acute lung injury, drug-induced lung injury, glomerulonephritis, chronic kidney disease (e.g., diabetic nephropathy), hypertension-induced nephropathy, digestive or gastrointestinal fibrosis, renal fibrosis, liver fibrosis or biliary fibrosis, liver fibrosis (e.g., non-alcoholic steatohepatitis, hepatitis C, or hepatocellular carcinoma), Cirrhosis (e.g., cirrhosis due to primary biliary cirrhosis or fatty liver disease (e.g., alcoholic and nonalcoholic steatosis)), radiation-induced fibrosis (e.g., head and neck, gastrointestinal tract, or lung), primary sclerosing cholangitis, restenosis, cardiac fibrosis (e.g., endomyocardial fibrosis or atrial fibrosis), ocular scarring, fibrosclerosis, fibrotic cancers, fibroids (fibromas), fibroadenomas, fibrosarcomas, transplant arteriopathy, keloids, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, and nephrogenic systemic fibrosis.

[0165] In some embodiments, the MK2-mediated disease or disorder is a metabolic disorder. Exemplary metabolic disorders include obesity, steroid resistance, glucose intolerance, and metabolic syndrome.

[0166] In some embodiments, the MK2-mediated disease or disorder is a neoplasia. Exemplary neoplasias include cancer. In some embodiments, exemplary neoplasias include angiogenic disorders, multiple myeloma, leukemia (e.g., acute lymphocytic leukemia, acute and chronic myeloid leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, or promyelocytic leukemia), lymphoma (e.g., B-cell lymphoma, T-cell lymphoma, mantle cell lymphoma, hairy cell lymphoma, Burkitt lymphoma, mast cell tumor, Hodgkin's disease or non-Hodgkin's disease), myelodysplastic syndrome, fibrosarcoma, rhabdomyosarcoma; astrocytoma, neuroblastoma, glioma, and schwannoma; melanoma, spermatoma, blastoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular thyroid cancer, Kaposi's sarcoma, melanoma, teratoma, rhabdomyosarcoma, metastatic and bone disorders, as well as bone cancer, mouth / pharynx cancer, esophageal cancer, laryngeal cancer, stomach cancer, intestinal cancer, colon cancer, rectal cancer, lung cancer (e.g., non-small cell lung cancer or small cell lung cancer), liver cancer, pancreatic cancer, nerve cancer, brain cancer (e.g., glioma or glioblastoma multiforme), head and neck cancer, pharyngeal cancer, ovarian cancer, uterine cancer, prostate cancer, testicular cancer, bladder cancer, kidney cancer, breast cancer, gallbladder cancer, cervical cancer, thyroid cancer, prostate cancer, and skin cancer.

[0167] In some embodiments, the MK2-mediated disorder is a cardiovascular or cerebrovascular disorder. Exemplary cardiovascular disorders include atherosclerosis, restenosis of atherosclerotic coronary arteries, acute coronary syndrome, myocardial infarction, cardiac allograft vasculopathy, and stroke. Exemplary cerebrovascular diseases include central nervous system disorders with inflammatory or apoptotic components, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal cord injury, neuronal ischemia, and peripheral neuropathy.

[0168] Diseases or disorders associated with MK2 that are treated by the compounds provided herein include autoimmune disorders, chronic inflammatory disorders, acute inflammatory disorders, autoinflammatory disorders, fibrotic disorders, metabolic disorders, neoplasia, or cardiovascular or cerebrovascular disorders. Thus, in some embodiments, the present disclosure provides methods for treating MK2-mediated diseases or disorders in patients in need thereof, wherein the methods comprise administering to the patient a composition comprising a therapeutically effective amount of a compound provided herein. Such MK2-mediated diseases or disorders include, but are not limited to, those described herein.

[0169] In some embodiments, the MK2-mediated disease or disorder is an autoimmune disorder, a chronic and / or acute inflammatory disorder, and / or an autoinflammatory disorder. Exemplary autoimmune and / or inflammatory and / or autoinflammatory disorders include: inflammatory bowel disease (e.g., ulcerative colitis or Crohn's disease), multiple sclerosis, psoriasis, arthritis, rheumatoid arthritis, osteoarthritis, juvenile arthritis, psoriatic arthritis, reactive arthritis, ankylosing spondylitis, cryptopyrin-associated periodic syndromes, Mueller-Weiss syndrome, familial cold autoinflammatory syndrome, multisystem inflammatory disease of neonatal onset, TNF receptor-associated periodic syndromes, acute and chronic pancreatitis, atherosclerosis, gout, ankylosing spondylitis, fibrotic disorders (e.g., liver fibrosis or idiopathic pulmonary fibrosis), kidney disease, sarcoidosis, scleroderma, Allergic reactions, diabetes (e.g., type 1 diabetes, type 2 diabetes), diabetic retinopathy, Still's disease, vasculitis, sarcoidosis, lung inflammation, acute respiratory distress syndrome, wet and dry age-related macular degeneration, autoimmune hemolytic syndrome, autoimmune and inflammatory hepatitis, autoimmune neuropathy, autoimmune ovarian failure, autoimmune orchitis, autoimmune thrombocytopenia, silicone implant-related autoimmune diseases, Sjögren's syndrome, familial Mediterranean fever, systemic lupus erythematosus, vasculitic syndromes (e.g., temporal arteritis, Takayasu arteritis, and giant cell arteritis, Behçet's disease or Wegener's granulomatosis), vitiligo, autoimmune Secondary hematologic manifestations of autoimmune diseases (e.g., anemia), drug-induced autoimmunity, Hashimoto's thyroiditis, hypophysitis, idiopathic thrombocytic purpura, metal-induced autoimmunity, myasthenia gravis, pemphigus, autoimmune deafness (e.g., Meniere's disease), Goodpasture's syndrome, Graves' disease, Herceptin-related autoimmune syndromes, Guillain-Barré disease, Addison's disease, antiphospholipid syndrome, asthma, atopic dermatitis, celiac disease, Cushing's syndrome, dermatomyositis, idiopathic adrenal atrophy, idiopathic thrombocytopenia, Kawasaki syndrome, Lambert-Eaton syndrome, pernicious anemia, hay fever, polyarteritis nodosa, primary biliary cirrhosis, Sclerosing cholangitis, Raynaud's syndrome, Reiter's syndrome, relapsing polychondritis, Schmidt's syndrome, thyrotoxicosis, sepsis, septic shock, endotoxic shock, exotoxin-induced toxic shock, Gram-negative sepsis, toxic shock syndrome, glomerulonephritis, peritonitis, interstitial cystitis, hyperoxia-induced inflammation, chronic obstructive pulmonary disease (COPD), vasculitis, graft-versus-host reaction (e.g., graft-versus-host disease), allograft rejection (e.g., acute allograft rejection or chronic allograft rejection), early transplant rejection (e.g., acute allograft rejection), reperfusion injury, pain (e.g.,acute pain, chronic pain, neuropathic pain or fibromyalgia), chronic infection, meningitis, encephalitis, myocarditis, gingivitis, postoperative trauma, tissue damage, head injury, enterocolitis, sinusitis, uveitis, eye inflammation, optic neuritis, gastric ulcer, esophagitis, peritonitis, periodontitis, dermatomyositis, gastritis, myositis, polymyalgia, pneumonia and bronchitis.

[0170] In some embodiments, the MK2-mediated disease or disorder is a fibrotic disorder. Exemplary fibrotic disorders include systemic sclerosis / scleroderma, lupus nephritis, connective tissue disease, wound healing, surgical scarring, spinal cord injury, CNS scarring, acute lung injury, pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis or cystic fibrosis), chronic obstructive pulmonary disease, adult respiratory distress syndrome, acute lung injury, drug-induced lung injury, glomerulonephritis, chronic kidney disease (e.g., diabetic nephropathy), hypertension-induced nephropathy, digestive or gastrointestinal fibrosis, renal fibrosis, liver fibrosis or biliary fibrosis, liver fibrosis (e.g., non-alcoholic steatohepatitis, hepatitis C, or hepatocellular carcinoma), Cirrhosis (e.g., cirrhosis due to primary biliary cirrhosis or fatty liver disease (e.g., alcoholic and nonalcoholic steatosis)), radiation-induced fibrosis (e.g., head and neck, gastrointestinal tract, or lung), primary sclerosing cholangitis, restenosis, cardiac fibrosis (e.g., endomyocardial fibrosis or atrial fibrosis), ocular scarring, fibrosclerosis, fibrotic cancers, fibroids (fibromas), fibroadenomas, fibrosarcomas, transplant arteriopathy, keloids, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, and nephrogenic systemic fibrosis.

[0171] In some embodiments, the MK2-mediated disease or disorder is a metabolic disorder. Exemplary metabolic disorders include obesity, steroid resistance, glucose intolerance, and metabolic syndrome.

[0172] In some embodiments, the MK2-mediated disease or disorder is a neoplasia. Exemplary neoplasias include cancer. In some embodiments, exemplary neoplasias include angiogenic disorders, multiple myeloma, leukemia (e.g., acute lymphocytic leukemia, acute and chronic myeloid leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, or promyelocytic leukemia), lymphoma (e.g., B-cell lymphoma, T-cell lymphoma, mantle cell lymphoma, hairy cell lymphoma, Burkitt lymphoma, mast cell tumor, Hodgkin's disease or non-Hodgkin's disease), myelodysplastic syndrome, fibrosarcoma, rhabdomyosarcoma; astrocytoma, neuroblastoma, glioma, and schwannoma; melanoma, spermatoma, blastoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular thyroid cancer, Kaposi's sarcoma, melanoma, teratoma, rhabdomyosarcoma, metastatic and bone disorders, as well as bone cancer, mouth / pharynx cancer, esophageal cancer, laryngeal cancer, stomach cancer, intestinal cancer, colon cancer, rectal cancer, lung cancer (e.g., non-small cell lung cancer or small cell lung cancer), liver cancer, pancreatic cancer, nerve cancer, brain cancer (e.g., glioma or glioblastoma multiforme), head and neck cancer, pharyngeal cancer, ovarian cancer, uterine cancer, prostate cancer, testicular cancer, bladder cancer, kidney cancer, breast cancer, gallbladder cancer, cervical cancer, thyroid cancer, prostate cancer, and skin cancer.

[0173] In some embodiments, the MK2-mediated disorder is a cardiovascular or cerebrovascular disorder. Exemplary cardiovascular disorders include atherosclerosis, restenosis of atherosclerotic coronary arteries, acute coronary syndrome, myocardial infarction, cardiac allograft vasculopathy, and stroke. Exemplary cerebrovascular diseases include central nervous system disorders with inflammatory or apoptotic components, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal cord injury, neuronal ischemia, and peripheral neuropathy.

[0174] Thus, in some embodiments, provided formulations are useful for treating MK2-mediated diseases or disorders.In certain embodiments, the present disclosure provides methods of administering provided formulations to human subjects.

[0175] Administration of the provided formulations can be advantageous for treating, stabilizing, or lessening the severity or progression of one or more diseases and conditions associated with MK2, comprising the step of administering to a subject a provided formulation as described herein. Such disorders or conditions include, among others, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, nervous system and nervous system degenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease, and hormone-related diseases.

[0176] In some embodiments, the disease or disorder associated with MK2 is an autoimmune disease or disorder. In some embodiments, the disease or disorder associated with MK2 is an inflammatory disease or disorder. In some such embodiments, the inflammatory disease or disorder is selected from a chronic inflammatory disorder, an acute inflammatory disorder, or an autoinflammatory disorder. In some embodiments, such autoimmune or inflammatory diseases and disorders are selected from rheumatoid arthritis, psoriatic arthritis, psoriasis, and ankylosing spondylitis.

[0177] In some embodiments, the present disclosure provides a method for preventing the progression of an autoimmune or inflammatory disease or disorder associated with MK2, comprising administering to a patient in need thereof a composition comprising a therapeutically effective amount of a compound provided herein. In some embodiments, such autoimmune or inflammatory diseases and disorders are selected from rheumatoid arthritis, psoriatic arthritis, psoriasis, and ankylosing spondylitis. ankylosing spondylitis

[0178] Ankylosing spondylitis (AS) is a chronic form of arthritis that primarily affects the spine, although other joints can be affected. Ankylosing spondylitis is a systemic inflammatory disease of unknown etiology that affects the axial spine (spondylitis) and is characterized by sacroiliitis. The most common symptoms are chronic back pain and progressive spinal stiffness, which are the result of inflammation affecting the spine and sacroiliac joints (Feld et al. Axial disease in psoriatic arthritis and ankylosing spondylitis: a critical comparison. Nat Rev Rheumatol 2018;14(6):363-71). In more severe cases, this inflammation can lead to ankylosis (formation of new bone in the spine), causing the parts of the spine to fuse in a fixed, immobile position.

[0179] Ankylosing spondylitis can also cause inflammation, pain, and stiffness in other parts of the body, such as the shoulders, hips, ribs, heels, and small joints in the hands and feet. Sometimes the eyes can be affected (called iritis or uveitis), and rarely the lungs and heart can be affected. A hallmark of ankylosing spondylitis is involvement of the sacroiliac (SI) joints as the disease progresses. The SI joints are located at the base of the spine, where it connects to the pelvis.

[0180] Ankylosing spondylitis is typically diagnosed in people under 40 years of age, and approximately 80% of patients develop their first symptoms before the age of 30 (Hanson et al. Genetics and the Causes of Ankylosing Spondylitis. Rheum Dis Clin North Am. 2017; 43(3): 401-14). It is estimated that approximately 70% of patients with AS are male (de Winter et al. Prevalence of peripheral and extra-articular disease in ankylosing spondylitis versus non-radiographic axial spondyloarthritis: ameta-analysis. Arthritis Res Ther 2016; 18: 196). Recent studies have reported a prevalence of AS in the general population of 9 to 30 per 10,000, depending on the geographic region, study population or data source, case definition, and ascertainment method. In general, there is a clear correlation between the prevalence of AS in a given population and the prevalence of HLA-B27 in that group, with the prevalence of AS being approximately 5% to 6% in HLA-B27-positive people (Reveille et al. The Epidemiology of Back Pain, Axial Spondyloarthritis and HLA-B27 in the United States. Am J Med Sci. 2013; 345(6): 431-6). Approximately 94% of individuals with AS are HLA-B27-positive (Brown et al. HLA class I associations of ankylosing spondylitis in the white population in the United Kingdom. Ann Rheum Dis. 1996; 55(4): 268-70).

[0181] Although HLA-B27 is the largest single genetic contributor to disease pathophysiology, numerous other genetic loci, including those associated with the interleukin (IL)-17A pathway, have been associated with AS (Brown et al. Genetics of ankylosing spondylitis—insights into pathogenesis. Nat Rev Rheumatol. 2016;12(2):81-91; Costantino et al. Genetics and Functional Genomics of Spondyloarthritis. Front Immunol. 2018:9:2933). The chronic inflammation in AS is believed to be driven by CD4+ and / or CD8+ T lymphocytes (including innate-like lymphocytes) and cytokines such as tumor necrosis factor (TNF)-α and IL-17A (Ranganathan et al. Macrophage Migration Inhibitory Factor Induces Inflammation and Predicts Spinal Progression in Ankylosing Spondylitis. Arthritis Rheumatol 2017; 69(9): 1796-1806). The classification criteria for AS were proposed in the 1960s based on clinical reasons and were later modified to include radiological criteria, known as the revised New York Criteria for the diagnosis of AS (van der Linden et al. Evaluation of Diagnostic Criteria for Ankylosing Spondylitis. A Proposal for Modification of the New York Criteria. Arthritis Rheum. 1984; 27(4): 361-8).Recently, the International Society for the Assessment of Spondyloarthritis (ASAS) developed classification criteria for axial spondyloarthritis (axSpA) based on radiographic, clinical, and laboratory criteria, with AS being considered the prototypical disease (Rudwaleit et al. The development of Assessment of SpondyloArthritis international Society classification criteria for axial spondyloarthritis (part I): classification of paper patients by expert opinion including uncertainty appraisal. Ann Rheum Dis. 2009; 68(6): 770-6; Rudwaleit et al. The development of Assessment of SpondyloArthritis international Society classification criteria for axial spondyloarthritis (part II): validation and final selection. Ann Rheum Dis 2009; 68(6): 777-83). The disease classification of axSpA was established in people who had a history of back pain for three or more consecutive months before reaching the age of 45, the presence of sacroiliitis confirmed by magnetic resonance imaging (MRI) or plain radiography, and at least one clinical or laboratory finding characteristic of spondyloarthritis (SpA). Alternatively, people with a history of this disease who had a positive HLA-B27 test result and ≥2 clinical or laboratory features of SpA also met the classification criteria for axSpA.Individuals with axSpA who had established radiographic evidence of sacroiliitis were considered to meet the definition of AS (Rudwaleit et al. The development of Assessment of SpondyloArthritis international Society classification criteria for axial spondyloarthritis (part I): classification of paper patients by expert opinion including uncertainty appraisal. Ann Rheum Dis. 2009; 68(6): 770-6; Rudwaleit et al. The development of Assessment of SpondyloArthritis international Society classification criteria for axial spondyloarthritis (part II): validation and final selection. Ann Rheum Dis 2009; 68(6): 777-83).

[0182] The goal of treatment for patients with AS is to optimize long-term health-related quality of life and social participation by controlling signs and symptoms, preventing structural damage, normalizing or maintaining function, avoiding toxicity, and minimizing comorbidities (Smolen et al. Treating axial spondyloarthritis and peripheral spondyloarthritis, especially psoriatic arthritis, to target: 2017 update of recommendations by an international task force. Ann Rheum Dis. 2018;77(1):3-17). Current treatment guidelines for active AS (Bath Ankylosing Spondylitis Disease Activity Index [BASDAI] of at least 4 or Ankylosing Spondylitis Disease Activity Score-C-reactive protein [ASDAS-CRP] of at least 2.1) strongly recommend the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and conditionally recommend their continued use based on very low-quality evidence (van der Heijde D et al. 2016 update of the ASAS-EULAR management recommendations for axial spondyloarthritis. Ann Rheum Dis. 2017;76(6):978-91). Tumor necrosis factor (TNF) blockers and anti-IL-17A monoclonal antibody (mAb) agents have become standard of care for patients who do not respond to or are intolerant to NSAIDs.Based on the results of pivotal trials of currently approved biologics in AS, approximately 30% to 40% of patients treated with biologics do not meet the International Spondyloarthritis Assessment Society response criteria of at least a 20% improvement (ASAS20), and up to 64% of patients do not meet the International Spondyloarthritis Assessment Society response criteria of at least a 40% improvement (ASAS40) (Sieper et al., Secukinumab efficacy in anti-TNF-naive and anti-TNF-experienced subjects with active ankylosing spondylitis: results from the MEASURE 2 Study. Ann Rheum Dis. 2017;76:571-75; Deodhar et al., Efficacy and Safety of Ixekizumab in the Treatment of Radiographic Axial Spondyloarthritis: Sixteen-Week Results From a Phase III Randomized, Double-Blind, Placebo–Controlled Trial in Patients With Prior Inadequate Response to or Intolerance of Tumor Necrosis Factor. Inhibitors. Arthritis Rheumatol 2019;71(4):599-611).

[0183] Although biologics can reduce inflammation and improve symptoms, there is only indirect evidence that currently available biologic TNF blockers affect spinal radiographic progression (Haroon et al. Effect of TNF-alpha inhibitor treatment on bone mineral density in patients with ankylosing spondylitis: A systematic review and meta-analysis. Semin Arthritis Rheum. 2014; 44(22): 155-61; Maas et al. Reduction in Spinal Radiographic Progression in Ankylosing Spondylitis Patients Receiving Prolonged Treatment With Tumor Necrosis Factor Inhibitors. Arthritis Care Res (Hoboken). 2017; 69(7): 1011-19; Molnar et al. TNFblockers inhibit spinal radiographic progression in ankylosing spondylitis by reducing disease activity: results from the Swiss Clinical Quality Management cohort. Ann Rheum. Dis. 2018; 77(1): 63-69), which continues to occur despite treatment (Poddubnyy et al. Physical Function and Spinal Mobility Remain Stable Despite Radiographic Spinal Progression in Patients with Ankylosing Spondylitis Treated with TNF-α Inhibitors for Up to 10 Years. J Rheumatol 2016; 43(12); 2142-8). Biologics require parenteral administration and are associated with the production of autoantibodies, which can neutralize the drug and limit its effectiveness. In addition, the deep inhibition of TNF by currently available TNF-directed biologics is associated with an increased risk of serious infections and malignancies.

[0184] In some embodiments, the present disclosure provides the recognition that AS patients who fail or cannot tolerate NSAID treatment, as well as those who also fail biologic therapy, represent a patient population with a high unmet medical need who currently have no approved oral medications available to treat the underlying disease.

[0185] In some embodiments, the present disclosure provides a method for treating ankylosing spondylitis in a patient or reducing its severity, the method comprising administering to the patient a composition comprising a compound as provided herein. In some embodiments, a composition comprising a compound as provided herein is administered to a subject with radiologically confirmed AS. In some such embodiments, the subject has had an inadequate response to nonsteroidal anti-inflammatory drugs (NSAIDs).

[0186] In some embodiments, the term "treating or lessening the severity of ankylosing spondylitis" refers to improving long-term health-related quality of life and social participation by one or more of: (i) controlling the signs and symptoms of AS, (ii) preventing structural damage, (iii) normalizing or maintaining function, and (iv) avoiding toxicity and minimizing complications.

[0187] In some embodiments, the present disclosure provides methods for administering a composition comprising a compound provided herein to an HLA-B-27 positive subject. In some embodiments, the methods provided include administering a composition comprising a compound provided herein to a subject in need thereof, wherein the subject suffers from chronic inflammation associated with or mediated by one or more lymphocytes and / or cytokines. In some such embodiments, one or more lymphocytes and / or cytokines are or are selected from CD4+T lymphocytes, CD8+T lymphocytes, innate-like lymphocytes, tumor necrosis factor (TNF)-α and IL-17A.

[0188] In some embodiments, the present disclosure provides methods of administering a composition comprising a compound provided herein to a subject meeting the classification criteria for axial spondyloarthritis (axSpA). In some such embodiments, the classification criteria for axSpA are based on imaging, clinical, and laboratory criteria. In some embodiments, the subject suffers from or is diagnosed with imaging axSpA. In some embodiments, the subject suffers from or is diagnosed with non-imaging axSpA. Such subjects exhibit clinical signs and symptoms of SpA but do not exhibit characteristic imaging changes on pelvic X-rays.

[0189] In some embodiments, the subject who meets the axSpA classification criteria is a subject who has a history of back pain for 3 or more consecutive months before reaching the age of 45, confirmed sacroiliitis, and at least one clinical or laboratory finding that is characteristic of spondyloarthritis (SpA). As used herein, "confirmed sacroiliitis" means sacroiliitis that is or has been confirmed on magnetic resonance imaging (MRI) or plain film radiography. In some embodiments, the subject who meets the axSpA classification criteria is a subject with a positive test result for HLA-B27 and ≥2 clinical or laboratory features of SpA. In some embodiments, the subject with AS is a subject who has axSpa and established radiographic evidence of sacroiliitis.

[0190] In some embodiments, the present disclosure provides methods for preventing or slowing the progression of structural damage and / or preserving function in a subject suffering from or diagnosed with ankylosing spondylitis. In some embodiments, the subject suffering from or diagnosed with ankylosing spondylitis exhibits one or more of the following criteria: a. Lower back pain and stiffness for more than 3 months that improves with exercise but is not relieved by rest; b. Limited lumbar spine motion in the sagittal and coronal planes; c. Limited chest expansion relative to normal values ​​associated with age and sex; and d. Sacroiliitis is grade 2 or higher on both sides or grade 3 to 4 on one side.

[0191] In some embodiments, the subject has been diagnosed with AS according to the revised New York Ankylosing Spondylitis Criteria (1984). In some embodiments, the subject has symptoms of active AS based on a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score of ≥4. In some embodiments, the subject has an overall back pain numerical rating scale (NRS) score of ≥4. In some embodiments, the subject meets one or more of the following criteria: a. diagnosed with AS according to the revised New York Criteria for Ankylosing Spondylitis (1984); b. Symptoms of active AS based on a BASDAI score ≥ 4; and c. Overall back pain Numeric Rating Scale (NRS) score ≥ 4.

[0192] In some embodiments, the present disclosure provides a method of treating AS in a subject, the method comprising: administering to the subject a composition comprising a compound provided herein, wherein the subject experiences improvement or response in at least three of the following Spondyloarthritis Assessment International Society (ASAS) criteria: a. Overall disease assessment of the patient; b. General back pain; c. Functionality; and d. Inflammation.

[0193] In some embodiments, the subject experiences an improvement or response of at least 20% and a minimum of one unit on a scale of 0 to 10 in at least three of the ASAS criteria, and for the remaining criteria, the subject does not experience a deterioration relative to baseline of no more than 20% and a minimum of one unit on a scale of 0 to 10. In some such embodiments, such improvement or response criteria are referred to as "ASAS 20 improvement criteria."

[0194] Thus, in some embodiments, the present disclosure provides a method of treating AS in a subject, the method comprising: administering to the subject a composition comprising a compound provided herein, Where the subject experiences an improvement or response of at least 20% and a minimum of one unit in at least three of the following ASAS criteria: a. Patient's global disease assessment (0 to 10 numeric rating scale); b. Overall back pain (0 to 10 numeric rating scale); c. Function (assessed by the Bath Ankylosing Spondylitis Functional Index (BASFI)); and d. Inflammation (average of the numeric rating scale of items 5 and 6 on the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI); and For the remaining criteria, the subject did not experience a worsening of more than 20% from baseline and a minimum of one unit on a scale of 0 to 10.

[0195] In some embodiments, the disclosure provides methods of improving disease activity (e.g., signs and symptoms of AS) in a subject having or diagnosed with AS, comprising administering to the subject a composition comprising a compound provided herein, wherein disease activity is assessed by the ASAS20 improvement criteria.

[0196] In some embodiments, the subject experiences an improvement or response of at least 40% and a minimum of two units on a scale of 0 to 10 in at least three of the ASAS criteria, and for the remaining criteria, the subject does not experience a worsening relative to baseline. In some embodiments, the subject experiences an improvement or response of at least 40% and a minimum of two units on a scale of 0 to 10 in at least three of the ASAS criteria, and for the remaining criteria, the subject does not experience a worsening of no more than 20% and a minimum of one unit on a scale of 0 to 10 relative to baseline. In some such embodiments, such improvement or response criteria are referred to as "ASAS 40 improvement criteria."

[0197] Thus, in some embodiments, the present disclosure provides a method of treating AS in a subject, the method comprising: administering to the subject a composition comprising a compound provided herein, Where the subject experiences an improvement or response of at least 40% and a minimum of two units in at least three of the following ASAS criteria: a. Patient's global disease assessment (0 to 10 numeric rating scale); b. Overall back pain (0 to 10 numeric rating scale); c. Function (assessed by the Bath Ankylosing Spondylitis Functional Index (BASFI)); and d. Inflammation (average of the numeric rating scale of items 5 and 6 on the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI); and For the remaining criteria, the subject did not experience a worsening of more than 20% from baseline and a minimum of one unit on a scale of 0 to 10.

[0198] In some embodiments, the disclosure provides methods of improving disease activity (e.g., signs and symptoms of AS) in a subject suffering from or diagnosed with AS, comprising administering to the subject a composition comprising a compound provided herein, wherein disease activity is assessed by the ASAS 40 improvement criteria.

[0199] In some embodiments, the present disclosure provides a method for improving disease activity (e.g., signs and symptoms of AS) in a subject suffering from or diagnosed with AS, the method comprising administering to the subject a composition comprising a compound as provided herein, wherein disease activity is assessed by ankylosing spondylitis disease activity score-C-reactive protein (ASDAS-CRP). In some embodiments, the subject achieves an ASDAS-CRP score of ≥1.1. In some such embodiments, the subject achieves an ASDAS-CRP score of ≥2.0. In some such embodiments, the subject achieves an ASDAS-CRP score of <1.3.

[0200] In some embodiments, the disclosure provides methods of improving disease activity (e.g., signs and symptoms of AS) in a subject suffering from or diagnosed with AS, comprising administering to the subject a composition comprising a compound provided herein, wherein disease activity is assessed by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI).

[0201] In some embodiments, the disclosure provides methods of improving physical function in a subject suffering from or diagnosed with AS, comprising administering to the subject a composition comprising a compound provided herein, wherein physical function is assessed by the Bath Ankylosing Spondylitis Functional Index (BASFI).

[0202] In some embodiments, the disclosure provides methods of reducing inflammation of the spine and sacroiliac joints in a subject having or diagnosed with AS, comprising administering to the subject a composition comprising a compound provided herein, wherein the spine and sacroiliac joint inflammation is assessed by the Spondyloarthritis Research Consortium of Canada (SPARCC) Sacroiliac Joint and Spine MRI score.

[0203] In some embodiments, the subject having or diagnosed with ankylosing spondylitis has failed treatment with at least two nonsteroidal anti-inflammatory drugs (NSAIDs). In some embodiments, the subject having or diagnosed with ankylosing spondylitis has not received one or more therapies selected from: a. Cell-depleting biologics, such as anti-CD20 antibodies (e.g., rituximab), anti-CD4 antibodies, anti-CD3 antibodies, denosumab, anti-IL-6 antibodies (e.g., tocilizumab and sarrelumab), and anti-IL-23 antibodies (e.g., ustekinumab), at least 6 months prior to administration of a compound provided herein; b. systemic oral administration of corticosteroids (eg, prednisone, etc.) in an amount greater than 10 mg / day for at least 2 weeks prior to administration of the compounds provided herein; c. any amount of intramuscular, intravenous, or intraarticular corticosteroids within at least 4 weeks of administration of a compound provided herein; d. Vitamin K antagonists (e.g., warfarin); e. isoniazid within at least 4 weeks of administration of a compound provided herein; and f. Any drug that is a substrate for one or more of the following transporters and has a narrow therapeutic index: p-glycoprotein (P-gp) (e.g., aliskiren, ambrisentan, colchicine, cyclosporine, dabigatran etexilate, digoxin, irolimus, fexofenadine, methotrexate, ranolazine, rivaroxaban, saxagliptin, sirolimus, sitagliptin, talinolol, ticagrelor, tolvaptan, etc.), breast cancer resistance protein (BCRP) (e.g., methotrexate, sulfasalazine, leflunomide, statin, rosuvastatin, etc.), organic cation transporter 1 (OCT1) (e.g., metformin, gabapentin, pramipexole, tramadol, varenicline, etc.), organic anion transporting polypeptide 1B1 and 1B3 (OATP1B1 and OATP1B3, respectively) (e.g., ambrisentan, atorvastatin, ezetimibe, fluvastatin, glyburide, rosuvastatin, simvastatin acid, pitavastatin, pravastatin, repaglinide, telmisartan, valsartan, olmesartan, mycophenolic acid, etc.).

[0204] In some embodiments, the subject having or diagnosed with ankylosing spondylitis has failed treatment with at least 2 nonsteroidal anti-inflammatory drugs (NSAIDs) and no more than 1 biologic. In some embodiments, the subject who has failed treatment with no more than 1 biologic is a subject who has had an inadequate response and / or unacceptable safety / tolerability to at least 1 dose of a biologic for AS (e.g., a TNF antagonist or an IL-17A monoclonal antibody) within at least 12 weeks.

[0205] In some such embodiments, a composition comprising a therapeutically effective amount of a compound provided herein is administered to a patient. In some embodiments, a unit dose of a compound provided herein is administered to a patient.

[0206] In some embodiments, the present disclosure provides the use of a compound provided herein in the preparation of a medicament for treating ankylosing spondylitis. In some embodiments, the present disclosure provides a compound described herein for use in treating ankylosing spondylitis.

[0207] Biomarkers of AS. In some embodiments, the present disclosure provides methods of administering to a subject a composition comprising a compound provided herein and monitoring the levels of one or more biomarkers associated with or correlated with AS. Proinflammatory cytokines and chemokines, including TNF-α, monocyte chemoattractant protein-1 (MCP-1), and IL-17A, have been shown to be increased in AS patients (Braun et al. Anti-tumor necrosis factor atherapy for ankylosing spondylitis: international experience. Ann Rheum Dis 2002; 61(Suppl III): iii51-iii60; West et al. Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor-neutralizing therapy in patients with inflammatory bowel disease. Nat Med. 2017; 23(5): 579-89; Romero-Sanchez et al. Serum monocyte chemotactic protein-1 concentrations distinguish patients with ankylosing spondylitis from patients with mechanical low back pain. J Spinal Disord Tech. 2011; 24(3): 202-7). In addition, elevated serum TNF-α levels are associated with elevated CRP levels in AS patients (Wagner et al. Serum markers associated with clinical improvement in patients with ankylosing spondylitis treated with golimumab. Ann Rheum Dis. 2012; 71(5): 674-80). Thus, in some embodiments, the biomarkers associated with or associated with AS are selected from proinflammatory cytokines or chemokines. In some such embodiments, the proinflammatory cytokines or chemokines are selected from TNF-α, monocyte chemoattractant protein-1 (MCP-1), and IL-17A. In some embodiments, the level of a proinflammatory cytokine or chemokine decreases over a period of time relative to a reference standard.In some such embodiments, the reference standard is the level of a pro-inflammatory cytokine or chemokine in a given subject or a given population prior to exposure to a compound provided herein.

[0208] In AS, several bone remodeling processes occur simultaneously: pathological new bone formation in the form of syndesmophytes and bone loss in the form of bone erosion, osteolysis, and loss of bone mineral density (BMD), leading to osteoporosis (Klingberg et al. Osteoporosis in ankylosing spondylitis-prevalence, risk factors and methods of assessment. Arthritis Res Ther 2012: 14(3): R108). In some embodiments, the biomarker associated with or associated with AS is a bone formation marker. In some such embodiments, the bone formation marker is selected from type 1 procollagen N-terminal propeptide (P1NP) and bone resorption markers such as the carboxyl terminal cross-linked telopeptide of type 1 collagen (CTX-1). In some embodiments, the level of the bone formation marker decreases over a period of time relative to a reference standard. In some embodiments, the level of the bone formation marker increases over a period of time relative to a reference standard. In some embodiments, the reference standard is the level of the bone formation marker in a given subject or a given population before exposure to the compounds provided herein.

[0209] Bone destruction is mediated by the recruitment of osteoclast precursors (OCPs) into inflamed tissues and their differentiation into mature osteoclasts. TNF inhibition results in the sustained loss of circulating OCPs that can differentiate into osteoclasts (Lam et al. TNF-alpha induces sosteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand. J Clin Invest. 2000; 106(12): 1481-8; Li et al. Systemic tumor necrosis factor alpha mediates an increase in peripheral CD11bhigh osteoclast precursors in tumor necrosis factor alpha-transgenic mice. Arthritis Rheum. 2004; 50(1): 265-76). In some embodiments, the biomarker associated with or associated with AS is osteoclast precursors (OCPs). In some embodiments, the level of osteoclast precursors decreases over a period of time relative to a reference standard. In some such embodiments, the reference standard is the level of osteoclast precursors in a given subject or a given population before exposure to the compounds provided herein.

[0210] In some embodiments, the biomarker associated or correlated with AS is a genetic marker. In some such embodiments, the genetic marker is selected from HLA-B27 and a polygenic risk score constructed using public AS data (see, e.g., Rostami et al. Prediction of Ankylosing Spondylitis in the HUNT Study by a Genetic Risk Score Combining 110 Single-nucleotide Polymorphisms of Genome-wide Significance. J Rheumatol 2019; 46: 1-7). Rheumatoid arthritis

[0211] Rheumatoid arthritis is a chronic autoimmune disorder in which the body's immune system attacks its own tissues, including the joint linings, synovial tissue, cartilage, and bone, leading to painful swelling. The inflammation caused by the immune system attack causes the synovium (the tissue lining the inside of the joints) to thicken, leading to swelling and pain in and around the joints. Over time, the inflammation associated with rheumatoid arthritis damages the cartilage (the elastic tissue that covers the ends of the bones in the joints) as well as the bones themselves. Over time, the cartilage is lost and the joint space between the bones can become smaller. The joints can become loose, unstable, painful, and lose their flexibility. Joint deformities can also occur. Joint damage is irreversible, and because it can occur early, doctors recommend early diagnosis and aggressive treatment to control rheumatoid arthritis. In severe cases, rheumatoid arthritis attacks internal organs.

[0212] Patients with rheumatoid arthritis can be divided into different subgroups, including lymphoid, myeloid, and fibrotic subgroups. Dennis et al., “Synovial phenotypes in rheumatoid arthritis correlate with response to biologic therapeutics,” Arthritis Research & Therapy 2014, 16: R90, 1-18; Setiadi et al., “Synovial Subset-Derived Baseline Serum Biomarkers Segregate Rheumatoid Arthritis Patients into Subgroups with Distinct Serum Protein and Clinical Characteristics,” Abstract Number 1307, 2013 ACR / ARHP Annual Meeting.

[0213] In some embodiments, the disclosure provides a method for treating rheumatoid arthritis in a patient, comprising administering to the patient a composition comprising a compound provided herein. In some such embodiments, the patient is administered a composition comprising a therapeutically effective amount of a compound provided herein. In some embodiments, the patient is administered a unit dose of a compound provided herein.

[0214] In some embodiments, the disclosure provides a method for treating one or more of the lymphoid, myeloid, and fibroid subgroups of rheumatoid arthritis, comprising administering a composition comprising a compound provided herein to a patient in one or more subgroups. Such subgroups are classified by the presence of certain biomarkers, which are described in detail in: Dennis et al., "Synovial phenotypes in rheumatoid arthritis correlate with response to biologic therapeutics," Arthritis Research & Therapy 2014, 16: R90, 1-18; Setiadi et al., "Synovial Subset-Derived Baseline Serum Biomarkers Segregate Rheumatoid Arthritis Patients into Subgroups with Distinct Serum Protein and Clinical Characteristics," Abstract Number 1307, 2013 ACR / ARHP Annual Meeting, each of which is hereby incorporated by reference.

[0215] In some embodiments, the present disclosure provides a method for treating rheumatoid arthritis in a patient or reducing its severity, wherein the patient has one or more biomarkers of a lymphoid subpopulation of rheumatoid arthritis, the method comprising administering to the patient a composition comprising a compound provided herein. Such biomarkers of a lymphoid subpopulation of rheumatoid arthritis include, for example, high CXCL13 and low soluble ICAM1 expression levels. In some embodiments, the present disclosure provides a method for treating rheumatoid arthritis in a patient or reducing its severity, wherein the patient has one or more biomarkers of a myeloid subpopulation of rheumatoid arthritis, the method comprising administering to the patient a composition comprising a compound provided herein. In some embodiments, the present disclosure provides a method for treating rheumatoid arthritis in a patient or reducing its severity, wherein the patient has one or more biomarkers of a fibroid subpopulation of rheumatoid arthritis, the method comprising administering to the patient a composition comprising a compound provided herein. In some embodiments, the present disclosure provides a method for treating at least one subpopulation of rheumatoid arthritis or reducing its severity, the method comprising administering to the patient a composition comprising a compound provided herein. In some embodiments, the subpopulation of rheumatoid arthritis is lymphoid. In some embodiments, the subpopulation of rheumatoid arthritis is myeloid. In some embodiments, the subpopulation of rheumatoid arthritis is fibroid.

[0216] In some embodiments, the disclosure provides the use of a compound provided herein in the preparation of a medicament for treating rheumatoid arthritis. In some embodiments, the disclosure provides a compound described herein for use in treating rheumatoid arthritis. Psoriasis and psoriatic arthritis

[0217] Psoriasis is a chronic inflammatory disease of the skin, scalp, nails, and joints. It is characterized by a scaly rash that most commonly occurs on the elbows, knees, and scalp, but can cover most of the body. While normal skin cells mature and are shed from the body within 28 to 30 days, psoriatic skin cells mature and accumulate on the body surface in just three to four days, forming lesions.

[0218] Up to 30% of people with psoriasis also develop psoriatic arthritis. In most cases (though not always), psoriasis will precede arthritis, sometimes by many years. When psoriasis presents with arthritis symptoms, it is called psoriatic arthritis (PsA). In these cases, the joints at the ends of the fingers are most often affected, causing inflammation and pain, but other joints in the wrists, knees, and ankles can also be affected. Symptoms of the fingernails and toenails range from small pits in the nails to almost complete destruction and crumbling, as seen in reactive arthritis or fungal infections.

[0219] Approximately 20% of patients with PsA will develop spinal involvement, a condition called psoriatic spondylitis. The inflammation of the spine can lead to complete fusion, as in ankylosing spondylitis (AS), or affect only certain areas, such as the lower back or neck. Patients who are HLA-B27 positive are more likely than others to have the disease progress to the spine.

[0220] PsA and AS are considered genetically and clinically related because both are inflammatory rheumatic diseases linked to the HLA-B27 gene. HLA-B27 is a strong susceptibility gene associated with several rheumatic diseases. The gene itself does not cause disease but can make a person more susceptible. While many genes have been associated with PsA, HLA-B27 has been noted to have the highest predictive value.

[0221] In some embodiments, the present disclosure provides a method for treating psoriasis and / or psoriatic arthritis of a patient or alleviating its severity, comprising administering to the patient a composition comprising a compound provided herein. In some such embodiments, a composition comprising a therapeutically effective amount of a compound provided herein is administered to the patient. In some embodiments, a unit dose of a compound provided herein is administered to the patient.

[0222] In some embodiments, the disclosure provides the use of a compound provided herein for the preparation of a medicament for treating psoriasis and / or psoriatic arthritis. In some embodiments, the disclosure provides a compound as described herein for use in treating psoriasis and / or psoriatic arthritis. Example General information: LCMS method 1.

[0223] Luna C18(2) 50X 3.0mm, 3.0um. Temperature: 45°C, flow rate: 1.5mL / min, run time: 2.5min. Mobile phase conditions: Initial 95% H2O + 0.1% FA / 5% MeCN + 0.1% FA, then linear gradient to 95% MeCN + 0.1% FA over 1.3min. Then hold at 95% MeCN + 0.1% FA for 1.2min. MSD: ESI positive ion LCMS method 2.

[0224] SunFire C18 75 x 4.6 mm, 3.5 μm. Temperature: 45°C, flow rate: 1.5 mL / min, run time: 6.0 min. Mobile phase conditions: Initial 95% H2O + 0.1% FA / 5% MeCN + 0.1% FA, followed by a 4.0 min linear gradient to 95% MeCN + 0.1% FA. Then, hold at 95% MeCN + 0.1% FA for 2.0 min. MSD: ESI positive ionization LCMS method 3.

[0225] Column: HALO C18, 3.0 x 30 mm, 2.7 μm particles; Mobile phase A: Water with 0.05% trifluoroacetic acid; Mobile phase B: Acetonitrile with 0.05% trifluoroacetic acid; Temperature: 40°C; Gradient: 5% B to 100% B over 1.3 min, then hold at 100% B for 0.50 min; Flow rate: 1.5 mL / min Synthesis of exemplary compounds Preparation method

[0226] The compounds exemplified below and the intermediates used to prepare the compounds exemplified below can be prepared using the procedures and related procedures shown in the following examples. The methods and conditions used in these examples and the actual compounds prepared in these examples are not meant to be limiting, but rather to demonstrate how the compounds exemplified below can be prepared. When not performed by the method procedures described herein, the starting materials and reagents used in these examples are generally commercially available, reported in the chemical literature, or can be prepared by using procedures described in the chemical literature.

[0227] Abbreviations used herein are defined as follows: "1x" for once, "2x" for twice, "3x" for three times, "°C" for degrees Celsius, "equiv" for equivalents, "g" for grams, "mg" for milligrams, "L" for liters, "mL" for milliliters, "μL" for microliters, "N" for equivalents, "M" for moles, "mmol" for millimolar, "min" for minutes, "h" for hours, "rt" for room temperature, "ON" for overnight, "RT" for retention time, "atm" for atmospheric pressure, "psi" for pounds per square inch, "conc." for concentrated, "sat" or "saturated" for saturated, "CV" for column volume, "MW" for molecular weight, "mp" for melting point, "ee" for enantiomeric excess, "MS" or "Mass Spec" for mass spectrometry, "ESI" for electrospray ionization mass spectrometry, "HR" for high resolution, "HRMS" for high resolution mass spectrometry, "LCMS" or "LC / MS" for liquid chromatography mass spectrometry, "HPLC" for high pressure liquid chromatography, "RPMS" for liquid chromatography mass spectrometry, "HPLC" stands for reversed-phase HPLC, "TLC" or "tlc" stands for thin-layer chromatography, "NMR" stands for nuclear magnetic resonance spectroscopy, "nOe" stands for nuclear Ostwald effect spectroscopy, 1 "H" stands for proton, "δ" stands for delta, "s" stands for singlet, "d" stands for doublet, "t" stands for triplet, "q" stands for quartet, "m" stands for multiplet, "br" stands for broad, "MHz" stands for megahertz, and "α", "β", "R", "S", "E" and "Z" are stereochemical designations familiar to those skilled in the art.

[0228] List of exemplary abbreviations:

[0229] The compounds of the present invention can be synthesized by many methods available to those skilled in the art of organic chemistry (Smith, MB, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th edition (2013)). General synthetic schemes for preparing the compounds of the present invention are described below. These schemes are illustrative and are not intended to limit the possible techniques that those skilled in the art can use to prepare the compounds disclosed herein. The different methods for preparing the compounds of the present invention will be apparent to those skilled in the art. In addition, the multiple steps in the synthesis can be performed in an alternating order to give the desired one or more compounds.

[0230] Examples of compounds of the invention prepared by the methods described in the general schemes are given in the Intermediates and Examples section presented below. Typically, the example compounds are prepared as racemic mixtures. The preparation of pure chiral examples can be carried out by techniques known to those skilled in the art. For example, pure chiral compounds can be prepared by separating the racemic product by chiral phase preparative HPLC. Alternatively, the example compounds can be prepared by methods known to give enantiomerically enriched products. These include, but are not limited to, incorporating chiral auxiliary functional groups into the racemic intermediates, which are used to control the diastereoselectivity of the transformation, providing enantiomerically enriched products upon cleavage by the chiral auxiliary.

[0231] Scheme 1 illustrates a method for synthesizing compounds exemplified by 8a. Intermediate 3 can be synthesized by a Pd-catalyzed Suzuki cross-coupling (Miyaura, N. and Suzuki, A. Chemical Reviews, 95: 2457-2483, 1995) of 1 (previously reported in: Anderson et al., J. Med. Chem., 2007, 50, 2647-2654) and 2. The resulting ester 3 can be saponified to the desired acid 4 by treatment with a base such as LiOH. Solution 1

[0232] The synthesis of amine coupling partners 7a and 7b can be carried out by treating 5a or 5b with aldehyde 6 with NaBH (OAc) 3 in the presence of a base (Afanasyev, OI et al. Chemical Reviews, 2019 11857-11911). The deprotection of the obtained boc-protected amine can be carried out by treating with an acid (such as 4.0M HCl in 1,4-dioxane) to produce 7a or 7b. Finally, in the presence of a base, 4 and 7a (or 7b) are coupled by amide formation by a coupling reagent (such as HATU) to produce a compound exemplified by 8a. Alternative amination conditions can also be used in this step. The approach to preparing the compound exemplified by 14a is shown in Scheme 2. Option 2

[0233] Pd-catalyzed Suzuki cross-coupling of compound 9 with various aryl boronates (10) followed by acid-promoted boc deprotection of the amine afforded compounds illustrated by 11. Boric acid, potassium trifluoroborate, or MIDA-borate intermediates will also be functional under similar conditions. Aldehyde 13 can be synthesized by reductive amination of commercially available aldehyde 12 followed by acid-promoted deprotection of the resulting dimethoxy acetal. Alkylation of acetals with similar halogen substitutions can also be applied. Reductive amination of 13 with intermediates similar to 5a or 5b will yield heterobifunctional compounds exemplified by 14a. Scheme 3 illustrates a synthetic route applicable to compounds that cannot be assembled by the double reductive amination strategy used above. Option 3

[0234] In this case, piperidine-4-carboxaldehyde 15 is coupled to 16 via a copper-catalyzed Chan-Lam coupling (West, MJ et al. Chemical Reviews, 2019, 12491-12523). The resulting aldehyde is then protected by treatment with ethylene glycol and p-TsOH to afford intermediate 17. The coupling of aryl bromide 17 with stannane 18 is completed via a Pd-catalyzed Steele cross-coupling reaction. The resulting aldehyde is then subjected to reductive amination with intermediate 5a via acid-promoted deprotection of 19 to complete the synthesis of 20. In other embodiments, the order of the above steps is changed, as shown in Scheme 4. Option 4

[0235] In these cases, the intermediate (like 5a) (or other glutarimides) is first treated with an aldehyde (such as 21) in the presence of sodium cyanoborohydride to give compounds exemplified by 22a (after TFA-promoted deprotection of the boc group). 22a is then subjected to a Chan-Lam coupling with 23 at room temperature by treatment with copper(II) acetate and triethylamine to give 23a. Finally, 23a is subjected to a Steele coupling with 18 catalyzed by Pd2(dba)3 and P(o-Tol)3 in DMF to give products exemplified by 24a. Schemes 5, 6, and 7 detail cases where compounds of the type 11 (Scheme 2) cannot be obtained by Suzuki cross-coupling. Option 5

[0236] Scheme 5 shows a method for obtaining N-linked triazoles such as 27. Aryl chloride 1 is treated with NaN3 in DMSO to provide azide 25. A copper-catalyzed click reaction between azide 25 and alkyne 26, followed by TFA-promoted boc deprotection, provides intermediate 27. Intermediate 27 is then subjected to the steps outlined in Scheme 2 to provide the fully elaborated heterobifunctional compound exemplified by 14a. Option 6

[0237] The corresponding C-linked triazoles were obtained via the route detailed in Scheme 6. In this case, aryl chloride 1 was converted to alkyne 29 via a two-step procedure. Steele cross-coupling was performed by treating 1 and stannane 28 with Pd(PPh3)4. The resulting silyl-protected alkyne was then desilylated by treatment with potassium carbonate in water to afford alkyne 29. A copper-catalyzed click reaction between alkyne 29 and azide 30 was carried out via CuSO4·5H2O and chiral tetraol 31. The resulting piperidinyl triazole was then deprotected by TFA in DCM to afford compound 32, which was then subjected to the steps outlined in Scheme 2 to afford the fully refined heterobifunctional compound exemplified by 14a. Option 7

[0238] Alkyne-linked heterobifunctional compounds were obtained by a similar strategy. Sonogaoka cross-coupling of aryl chloride 33 with alkyne 34 was accomplished by treatment with copper(I) iodide and Pd(PPh3)2Cl2 and TEA. The resulting boc-protected alkynylpiperidine was then deprotected with TFA and DCM to afford 35, which was then further elaborated by the procedure outlined in Scheme 2. Option 8

[0239] The bisamide-linked compounds exemplified by 39 were synthesized via a three-step sequence of amide formation, saponification, and amide coupling. Piperazinyl-substituted 36 was treated with ethyl oxalyl chloride and DIPEA. The resulting ethyl ester was then saponified with LiOH in 3:1 THF / water to afford the free acid 38. Finally, the free acid 38 was coupled with glutarimide (e.g., 5a) in the presence of HATU and DIPEA to afford the bisamide compounds exemplified by 39.

[0240] Purification of intermediates and final products was carried out via normal or reverse phase chromatography. Unless otherwise indicated, normal phase chromatography was performed on an ISCO system using prepacked SiO2 cartridges (eluting with a gradient of hexanes and EtOAc or a gradient of DCM and MeOH). Reverse-phase preparative HPLC or LCMS was performed using a C18 column (elution was performed with a gradient of solvent A (90% water, 10% MeOH, 0.1% TFA) and solvent B (10% water, 90% MeOH, 0.1% TFA, UV 220 nm); or a gradient of solvent A (95% water, 5% MeCN, 0.1% TFA) and solvent B (5% water, 95% MeCN, 0.1% TFA, UV 220 nm); or a gradient of solvent A (98% water, 2% MeCN, 0.05% TFA) and solvent B (98% MeCN, 2% water, 0.05% TFA, UV 254 nm); or a gradient of solvent A (95% water, 5% MeCN containing 10 mM ammonium acetate) and solvent B (95% MeCN, 5% water containing 10 mM ammonium acetate)).

[0241] In most examples, purity was determined using one of the following LC / MS conditions:

[0242] LC / MS Method 1

[0243] Luna C18(2) 50X 3.0mm, 3.0mm. Temperature: 45°C, flow rate: 1.5 mL / min, run time: 2.5 min. Mobile phase conditions: Initial 95% H2O + 0.1% FA / 5% CH3CN + 0.1% FA, then linear gradient to 95% CH3CN + 0.1% FA over 1.3 min. Then hold at 95% CH3CN + 0.1% FA for 1.2 min. MSD: ESI positive ion

[0244] LC / MS method 2

[0245] SunFire C18 75 x 4.6 mm, 3.5 μm. Temperature: 45°C, flow rate: 1.5 mL / min, run time: 6.0 min. Mobile phase conditions: Initial 95% H2O + 0.1% FA / 5% CH3CN + 0.1% FA, followed by a 4.0 min linear gradient to 95% CH3CN + 0.1% FA. Then, hold at 95% CH3CN + 0.1% FA for 2.0 min. MSD: ESI positive ionization

[0246] LC / MS Method 3

[0247] Column: HALO C18, 3.0 x 30 mm, 2.7 μm particles; Mobile phase A: H2O with 0.05% trifluoroacetic acid; Mobile phase B: CH3CN with 0.05% trifluoroacetic acid; Temperature: 40°C; Gradient: 5% B to 100% B over 1.3 min, then hold at 100% B for 0.50 min; Flow rate: 1.5 mL / min

[0248] LC / MS Method 4

[0249] ACQUITY BEH C18 1.7 μM, 2.1 x 150 mm. Temperature: 25°C. Flow rate: 0.8 mL / min. Run time: 3.0 min. Mobile phase conditions: Initial start at 95% H2O (0.1% formic acid) and 5% acetonitrile (0.1% formic acid), then linear gradient to 95% acetonitrile (0.1% formic acid) for 1.5 min. Maintain gradient for 0.5 min, then return to 95% H2O (0.1% formic acid) and 5% acetonitrile (0.1% formic acid) for 0.1 min. Waters TM SQ detector 2: ESI positive ion

[0250] Example I1.1. Intermediate 1: Synthesis of 3-(4-(piperazin-1-yl)phenyl)piperidine-2,6-dione

[0251] (2,6-bis(benzyloxy)pyridin-3-yl)boronic acid. To a solution of 2,6-bis(benzyloxy)-3-bromopyridine (400.0 g, 1.08 mol) in THF (4.0 L) was added n-BuLi (2.5 M, 475.0 mL) dropwise at -70 ° C, and the solution was stirred for 0.5 h at -70 ° C. Then, B(OMe) 3 (146.0 g, 1.40 mol, 159.0 mL) was added dropwise to the reaction solution at -70 ° C, and the reaction mixture was further stirred for 0.5 h at -70 ° C. The reaction solution was poured into a saturated NH 4 Cl aqueous solution (4.0 L) and the organic layer was separated. The aqueous phase was extracted with EtOAc (2 x 5.0 L). The combined organic layers were washed with brine (5.0 L), dried over Na 2 SO 4, filtered and concentrated. The residue was triturated with (PE / EtOAc=10 / 1, 1.5 L) for 1 h, and the solid was collected by filtration and dried under vacuum at 45 °C for 2 h to give 3-(4-(piperazin-1-yl)phenyl)piperidine-2,6-dione (980.0 g, 64% yield) as a light blue solid. 1H NMR (400MHz, CDCl3) δppm 8.05 (d, J = 8.0 Hz, 1H), 7.27-7.44 (m, 10H), 6.48 (d, J = 8.0 Hz, 1H), 5.93 (s, 2H), 5.45 (s, 2H), 5.38 (s, 2H).

[0252] tert-Butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperazine-1-carboxylate. A mixture of tert-butyl 4-(4-bromophenyl)piperazine-1-carboxylate (220.0 g, 645 mmol) and (2,6-bis(benzyloxy)pyridin-3-yl)boric acid (261.0 g, 677 mmol), K PO (645 mL, 1.29 mol 2.0 M, aqueous solution), Pd(PPh ) (37.3 g, 32.2 mmol) in 1,4-dioxane (2.2 L) was degassed and purged three times with internal nitrogen. The mixture was then stirred at 90 ° C under an N atmosphere for 16 h. After the reaction mixture was cooled to room temperature, it was filtered and the filtrate was extracted with EtOAc (3 x 500 mL). The combined organic phases were washed with brine (500 mL), dried over NaSO (anhydrous), filtered, and concentrated under vacuum. The residue was purified by column chromatography (PE / EtOAc=50 / 1 to 0 / 1) to give tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperazine-1-carboxylate (670.0 g) as a green solid. 1 H NMR (400MHz, CDCl3) δppm 7.59-7.61(m,1H),7.50-7.53(m,2H),7.34-7.43(m,10H),6.96(d,J=8.8Hz,2H),6.70(d,J=8. 0Hz, 1H), 5.44 (s, 2H), 5.37 (s, 2H), 3.61 (t, J = 5.2Hz, 4H), 3.18 (t, J = 5.2Hz, 4H), 1.51 (s, 9H).

[0253] tert-Butyl 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazine-1-carboxylate. Under N2 atmosphere, to a mixture of tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperazine-1-carboxylate (85.0 g, 154 mmol) in THF (400.0 mL) and EtOH (400.0 mL) was added 10% Pd / C (20.0 g), 20% Pd(OH)2 / C (20.0 g) and AcOH (9.3 g, 154 mmol). The suspension was degassed under vacuum and purged with hydrogen (H2) several times. The resulting mixture was stirred at 50 ° C under H2 (40 psi) for 12 h. The reaction mixture was filtered and concentrated. The obtained crude product was triturated with EtOAc (100 mL) at 15 ° C for 30 min to give tert-butyl 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazine-1-carboxylate (220 g (100% purity) and 180 g of a second batch containing impurities). 180 g of the crude material was purified by column chromatography (SiO , PE / EtOAc = 20 / 1 to 0 / 1) to give 100 g of the product, obtaining tert-butyl 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazine-1-carboxylate (320 g, 80% average yield) as a white solid. 1 H NMR (400MHz, CDCl3) δppm 10.8(s,1H),7.07(d,J=8.8Hz,2H),6.92(d,J=8.8Hz,2H),3.74(dd,J=11.2Hz,6.4Hz,1H),3.44-3.45(m,4H ), 3.07 (t, J = 6.4Hz, 4H), 2.61-2.64 (m, 1H), 2.44-2.48 (m, 1H), 2.13 (m, 1H), 2.01-2.02 (m, 1H), 1.42 (s, 9H).

[0254] 3-(4-(piperazine-1-yl)phenyl)piperidine-2,6-dione. Two batches were carried out: HCl / EtOAc (4M, 500mL) was added dropwise to a solution of tert-butyl 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazine-1-carboxylate (105g, 281mmol) in DCM (600mL) cooled to 15°C. After addition, the mixture was stirred at 15°C for 3h. The two batches were combined and the reaction mixture was filtered and the filter cake was dried. The crude product was ground with EtOAc (500mL) for 30min at 15°C. 3-(4-(piperazine-1-yl)phenyl)piperidine-2,6-dione, 2HCl (194g, 560mmol, quantitative yield) was obtained as a white solid. 1HNMR(400MHz,DMSO-d6)δppm 10.8(s,1H),9.24(s,2H),7.11(d,J=8.4Hz,2H),6.96(d,J=8.8Hz,2H),3.77(q,J=5.2Hz,1H),3.3 4-3.36(m,4H),3.20(s,4H),2.61-2.64(m,1H),2.44-2.48(m,1H),2.14(m,1H),1.90-2.01(m,1H).

[0255] Example I1.2. Intermediate 2: Synthesis of 3-(4-(piperidin-4-yl)phenyl)piperidine-2,6-dione

[0256] 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidine-1-carboxylic acid tert-butyl ester. To a solution of tert-butyl 4-(4-bromophenyl)piperidine-1-carboxylate (2.0 g, 5.9 mmol), (2,6-dibenzyloxy-3-pyridinyl)boric acid (2.96 g, 8.8 mmol) and K2CO3 (1.6 g, 11.8 mmol) in 1,4-dioxane (20.0 mL) and water (2.0 mL) was added Pd(PPh3)4 (497.0 mg, 0.6 mmol). The resulting solution was stirred at 50 ° C for 3 h under an inert atmosphere. LCMS showed that the reaction was complete. The resulting solution was diluted with water (50 mL) and extracted with ethyl acetate (3x 50 mL). The combined organic layer was washed with brine (2x 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with petroleum ether / ethyl acetate (3:1)) to give tert-butyl 4-[4-(2,6-dibenzyloxy-3-pyridinyl)phenyl]piperidine-1-carboxylate (2.8 g, 86% yield) as a white solid. MS (ESI, m / z) [M+H] + 551.

[0257] tert-Butyl 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-1-carboxylate. To a stirred solution of tert-butyl 4-[4-(2,6-dibenzyloxy-3-pyridinyl)phenyl]piperidine-1-carboxylate (1.5 g, 2.7 mmol, 1.0 equiv) in ethanol (10.0 mL) and THF (10.0 mL) was added Pd / C (300.0 mg, 20% w / w), Pd(OH)2 / C (300.0 mg, 20% w / w) and AcOH (0.16 mL, 2.7 mmol, 1.0 equiv). The resulting solution was stirred at 50 ° C under a hydrogen atmosphere of 40 psi for 18 h. LCMS showed that the reaction was complete. The solid was filtered off. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with petroleum ether / ethyl acetate (3:1) to give tert-butyl 4-[4-(2,6-dioxo-3-piperidinyl)phenyl]piperidine-1-carboxylate (850 mg, 83.7% yield) as a white solid. MS (ESI, m / z) [M+H] + 373.

[0258] 3-(4-(piperidin-4-yl)phenyl)piperidine-2,6-dione. To a solution of tert-butyl 4-[4-(2,6-dioxo-3-piperidinyl)phenyl]piperidine-1-carboxylate (850.0 mg, 2.3 mmol, 1.0 equiv) in HCl (20 mL, 2.0 M in EtOAc). The resulting solution was stirred at room temperature for 2 h. LCMS showed that the reaction was complete. The resulting solution was concentrated under reduced pressure to give crude 3-[4-(4-piperidinyl)phenyl]piperidine-2,6-dione (800.0 mg) as a white solid. The crude product was used directly in the next step without further purification. MS (ESI, m / z) [M+H] + 273.

[0259] Example I1.3. Intermediate 3: Synthesis of 3-(1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione

[0260] tert-Butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate. A mixture of 6-bromo-3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazole (30.0 g, 60.0 mmol), tert-butyl piperazine-1-carboxylate (16.8 g, 89.9 mmol), RuPhos-Pd-G3 (10 g, 12.0 mmol) and Cs2CO3 (23.4 g, 71.9 mmol) in degassed 1,4-dioxane (150 mL) was heated to 75 ° C. for 18 h and then cooled to room temperature. The mixture was filtered through celite and the filter cake was washed with EtOAc (3×150 mL). The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using a 0-40% gradient of EtOAc in hexanes to give the title compound tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate (35.6 g, 98% yield) as a solid. MS (ESI, m / z) [M+H] + 607.5.

[0261] tert-Butyl 4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate. A mixture of tert-butyl 4-[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazol-6-yl]piperazine-1-carboxylate (35.6 g, 58.8 mmol) and Pearlman's catalyst (8.90 g, 25 wt.% loading) in EtOH (300 mL) and THF (300 mL) was subjected to hydrogenation (1.0 atm) at 50° C. for 10 h. The mixture was filtered through celite and the filter cake was washed with a 1:1 mixture of MeCN and MeOH (4×250 mL). The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using a 0-100% gradient of EtOAc in hexanes to give the title compound tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate (21.0 g, 84% yield) as a solid. MS (ESI, m / z) [M+H] + 428.3.

[0262] 3-(1-Methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione. To a solution of tert-butyl 4-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazol-6-yl]piperazine-1-carboxylate (21.0 g, 49.1 mmol) in 1,4-dioxane (150 mL) was added 4.0 N HCl in 1,4-dioxane (98.2 mL, 393 mmol) and the reaction mixture was stirred at room temperature for 20 h. Et2O (250 mL) was added and the precipitate was collected by filtration, washed with Et2O (3×30 mL), then dried under vacuum and lyophilized to give the title compound 3-(1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione (17.6 g, 98% yield) as a solid. MS (ESI, m / z) [M+H] + 328.2. 1 H NMR(500MHz,DMSO-d6)δppm 10.85(s,1H),9.46(s,2H),7.56(d,J=8.9Hz,1H),7.04–6.90(m,2H),4.28(dd,J=9.4,5.0Hz,1H),3. 92(s,3H),3.53–3.41(m,4H),3.23(s,4H),2.73–2.55(m,2H),2.39–2.26(m,1H),2.23–2.08(m,1H).

[0263] Example I1.4. Intermediate 4: Synthesis of 3-(1-methyl-7-(piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione

[0264] 7-Bromo-3-iodo-1-methyl-1H-indazole. Three batches were carried out: at 0 ° C, t-BuOK (334 g, 2.97 mol) was added portionwise to a solution of 7-bromo-3-iodo-1H-indazole (480 g, 1.49 mol) in THF (2.4 L). After addition, the suspension was stirred at 0 ° C for 1 h. A solution of CH3I (422 g, 2.97 mol, 185 mL) in THF (400 mL) was then added dropwise to the cooled (0 ° C) reaction mixture. The suspension was then stirred at 25 ° C for 3 h. TLC (PE / EtOAc=5 / 1, R f=0.5) shows that the reaction is complete. The mixture of the three reactions is merged and the resulting suspension is poured into water (10L) and stirred for 10min. Aqueous phase is extracted with EtOAc (5.0L x 1, then 3.0L x 1). The organic phases merged are washed with salt water (3.0L), over anhydrous Na2SO4, dried, filtered and concentrated in a vacuum. Residue is purified by silica gel column chromatography (PE / EtOAc=25 / 1,5 / 1) to obtain 7- bromo-3- iodo-1- methyl -1H- indazole (900g, 60% yield) as a yellow solid. 1 HNMR (400MHz, DMSO-d6) δppm 7.72 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 7.2 Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H), 4.34 (s, 3H).

[0265] 3-(2,6-bis(benzyloxy)pyridin-3-yl)-7-bromo-1-methyl-1H-indazole. Carry out three batches: to 7-bromo-3-iodo-1-methyl-1H-indazole (313g, 929mmol) in 1,4-dioxane (2.0L) and H2O (1.0L) in a solution of (2,6-bis(benzyloxy)pyridin-3-yl)boric acid (389g, 929mmol, 80% purity), K3PO4 (493g, 2.32mol) and Pd(PPh3)4 (21.5g, 18.6mmol). The suspension is then purged with N2 three times and stirred at 90°C for 12h. The three batches are combined for post-processing and the reaction mixture is then poured into water (10L) and stirred for 10min. The aqueous phase is extracted with EtOAc (5L x 1, then 3L x 1). The combined organic phases were washed with brine (3 L), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE / EtOAc=25 / 1, 5 / 1). The filtered residue was ground with PE / EtOAc (2 / 1) for 3 h at 25 ° C, and the solid was then collected by vacuum filtration to obtain 3- (2,6- bis (benzyloxy) pyridin-3-yl) -7- bromo-1-methyl -1H- indazole (920 g, 63% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δppm 7.86(d,J=8.4Hz,1H),7.54(dd,J=8.0,0.8Hz,1H),7.37(dd,J=7.2,0.8Hz,1H),7.33(m, 2H), 7.28 (m, 8H), 6.94 (t, J = 7.6Hz, 1H), 6.60 (d, J = 7.6Hz, 1H), 5.43 (s, 4H), 4.36 (s, 3H).

[0266] tert-Butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-7-yl)piperazine-1-carboxylate. To a solution of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-7-bromo-1-methyl-1H-indazole (100 g, 200 mmol) and tert-butyl piperazine-1-carboxylate (55.8 g, 300 mmol) in 1,4-dioxane (700 mL) were added CsCO (130 g, 400 mmol), RuPhos (18.6 g, 40 mmol) and Pd(dba) (18.3 g, 20 mmol), and the suspension was purged with N three times and stirred at 110° C. for 12 h. TLC (PE / EtOAc=3 / 1, R f =0.6) shows that the reaction is complete. The reaction is cooled to 20 DEG C and filtered through a diatomaceous earth pad. The filtrate is concentrated under vacuum and the residue is passed through silica gel chromatography (100-200 mesh silica gel, PE / EtOAc=20 / 1,3 / 1) to obtain the product. The product is further ground and purified for 1h with PE / EtOAc=(2 / 1,200mL). The solid is collected by filtration and dried under vacuum to obtain 4- (3- (2,6- bis (benzyloxy) pyridin-3-yl) -1- methyl -1H- indazole -7- bases) piperazine -1- tert-butyl formate (84g, 67% yield) as a yellow solid. 1 H NMR(400MHzDMSO-d6)δppm 7.85(d,J=8.4Hz,1H),7.27-7.45(m,12H),6.96-6.99(m,2H),6.53(d,J=8.0Hz,1H),5.47(s,2H) ,5.40(s,2H),4.41(s,3H),4.10-4.16(m,2H),3.20-3.23(m,4H),2.84-2.89(m,2H),1.51(s,9H).

[0267] tert-Butyl 4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)piperazine-1-carboxylate. To a suspension of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-7-yl)piperazine-1-carboxylate (42 g, 69.3 mmol) and AcOH (4.16 g, 69.3 mmol, 3.97 mL) in THF (210 mL) and EtOH (210 mL) was added 10% Pd / C (8.0 g) and 20% Pd(OH) (8.0 g, 57 mmol), and the black suspension was purged with H three times and stirred at 50° C. at 50 psi for 12 h. The suspension was filtered through a pad of celite and the filter cake was washed with hot THF (2 L). The filtrate was concentrated under vacuum at 45 ° C to give a crude product. The crude material was purified by silica gel chromatography (100-200 mesh silica gel, 0% to 10% MeOH in DCM) to give a solid. The solid was further ground with MTBE (50 mL) for 1 h. The solid was collected by filtration and dried under vacuum. tert-Butyl 4- (3- (2,6-dioxopiperidin-3-yl) -1-methyl -1H- indazole -7- yl) piperazine -1- carboxylate (18.6 g, 30% yield) was obtained as a blue solid. MS (ESI, m / z) [M + H] + 428.4.

[0268] 3-(1-methyl-7-(piperazine-1-yl)-1H-indazole-3-yl)piperidine-2,6-dione. To a solution of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazole-7-yl)piperazine-1-carboxylate (18.6 g, 43.5 mmol) in DCM (420 mL) was added HCl / EtOAc (4.0 M, 93.0 mL), and the suspension was stirred at 20 ° C for 2 h. The solid was collected by filtration and dried under vacuum at 45 ° C for 2 h. The solid was suspended in MeCN (100 mL) and dried under vacuum at 45 ° C for 2 h. The operation was repeated twice more. 3-(1-Methyl-7-(piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione was obtained as a light blue solid (16.5 g, 95% yield). 1 H NMR(400MHz,DMSO-d6)δppm 10.87(s,1H),9.49-9.58(m,2H),7.45(d,J=6.8Hz,1H),7.03-7.06(m,2H),4.33-4.37(m,1H ),4.24(s,3H),3.15-3.44(m,8H),2.60-2.67(m,2H),2.31-2.50(m,1H),2.14-2.18(m,1H).

[0269] Example I1.5. Intermediate 5: Synthesis of (R)-3-chloro-10-methyl-8-oxo-10,11-dihydro-[1,4]oxazepino[7',6':4,5]thieno[3,2-f]quinoline-9(8H)-carboxylic acid tert-butyl ester

[0270] 1- bromothieno [3,2-f] quinoline -2- methyl formate. At 0 DEG C under N2, to 1- aminothieno [3,2-f] quinoline -2- methyl formate (30.0g, 116.0mmol) in acetonitrile (750mL) solution of tert-butyl nitrite (24.0g, 232.0mmol) was added dropwise. After the reaction mixture was stirred at 0 DEG C for 1h, CuBr (31.1g, 139.0mmol) was added at 0 DEG C, and then the reaction mixture was stirred at 25 DEG C for 3h under N2. The mixture was concentrated and water (300mL) was added, the mixture was extracted with DCM / i-PrOH (3 / 1, 600mL x 3). The combined organic layer was concentrated to obtain 1- bromothieno [3,2-f] quinoline -2- methyl formate (34.0g, 90.8% yield) as a yellow solid. MS (ESI+) [M+H] + 321.9. 1 HNMR (400MHz, DMSO-d6) δppm 10.12(d,J=8.4Hz,1H),9.14-9.05(m,1H),8.42(d,J=8.4Hz,1H),8.16(d,J=8.4Hz,1H),7.81-7.78(m,1H),3.94(s,3H).

[0271] (R)-1-(2-aminopropoxy)thieno[3,2-f]quinoline-2-carboxylic acid methyl ester. To a solution of (R)-1-(2-((tert-butoxycarbonyl)amino)propoxy)thieno[3,2-f]quinoline-2-carboxylic acid methyl ester (20.0 g, 48.0 mmol) in DCM (200 mL) was added TFA (67 mL, 875 mmol) dropwise at 0°C, and the reaction mixture was stirred at 20°C for 3 h. The reaction mixture was concentrated, then water (100 mL) was added, and extracted with petroleum ether (PE) / EtOAc (2:1, 15 mL x 2). The aqueous phase was adjusted to pH = 7 with saturated NaHCO3 (aq.), and the solid was slowly precipitated and filtered. The filtrate was concentrated under vacuum to give methyl 1-[(2R)-2-aminopropoxy]thieno[3,2-f]quinoline-2-carboxylate (13.0 g, 85.6% yield) as a yellow solid. 1H NMR(400MHz,DMSO-d6)δppm 9.20(d,J=8.0Hz,1H),9.01-9.00(m,1H),8.31(d,J=9.2Hz,1H),8.23-8.10(m,3H),7.74( d,J=4.4Hz,1H),4.43-4.31(m,2H),3.93(s,3H),3.92-3.90(m,1H),1.36(d,J=6.4Hz,3H).

[0272] (R)-10-Methyl-10,11-dihydro-[1,4]oxazepino[7',6':4,5]thieno[3,2-f]quinolin-8(9H)-one. To a solution of (R)-1-(2-aminopropoxy)thieno[3,2-f]quinoline-2-carboxylic acid methyl ester (13.0 g, 41.1 mmol) in methanol (400 mL) at 20°C was added sodium methoxide (14.8 g, 82.2 mmol, 30 w / w% in MeOH), and the reaction mixture was stirred at 75°C for 14 h. The reaction mixture was concentrated and then triturated with MTBE / water (1 / 1, 60 mL) for 30 min. The mixture was filtered, and the filtrate was concentrated under vacuum to give (R)-10-methyl-10,11-dihydro-[1,4]oxazepino[7′,6′:4,5]thieno[3,2-f]quinolin-8(9H)-one (9.9 g, 84.7% yield) as a yellow solid. 1 HNMR(400MHz,DMSO-d6)δppm 9.28(dd,J=0.8Hz,8.0Hz,1H),8.95(dd,J=2.0Hz,4.4Hz,1H),8.48(d,J=4.0Hz,1H),8.20(d,J=9.2Hz,1 H), 8.02 (d, J = 8.8Hz, 1H), 7.68 (q, J = 4.4Hz, 1H), 4.61 (s, 2H), 3.88-3.84 (m, 1H), 1.28 (d, J = 6.8Hz, 3H).

[0273] (R)-10-methyl-8-oxo-10,11-dihydro-[1,4]oxazepino[7',6':4,5]thieno[3,2-f]quinoline-9(8H)-carboxylic acid tert-butyl ester. To a solution of (R)-10-methyl-10,11-dihydro-[1,4]oxazepino[7',6':4,5]thieno[3,2-f]quinolin-8(9H)-one (4.4 g, 15.5 mmol) and BoC2O (6.8 g, 31.0 mmol) in THF (100.0 mL) was added DMAP (189 mg, 1.6 mmol). The resulting mixture was stirred at 60° C. under a nitrogen atmosphere for 2 h. The resulting solution was concentrated under vacuum. The residue was purified by silica gel column chromatography with ethyl acetate / petroleum ether (1:1) to give (R)-10-methyl-8-oxo-10,11-dihydro-[1,4]oxazepino[7′,6′:4,5]thieno[3,2-f]quinoline-9(8H)-carboxylic acid tert-butyl ester (5.5 g, 93%) as an off-white solid. MS (ESI, m / z) [M+H] + 385.1

[0274] (R)-tert-Butyl 10-methyl-4-(11-oxoalkyl)-8-oxo-10,11-dihydro-414-[1,4]oxazepino[7',6':4,5]thieno[3,2-f]quinoline-9(8H)-carboxylate. To a solution of tert-butyl (R)-10-methyl-8-oxo-10,11-dihydro-[1,4]oxazepino[7',6':4,5]thieno[3,2-f]quinoline-9(8H)-carboxylate (5.0 g, 13.0 mmol) in DCM (120.0 mL) was added dropwise 3-chloroperoxybenzoic acid (3.4 g, 19.5 mmol) under ice. The resulting mixture was stirred at 30°C for 2 h. The resulting solution was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with sodium carbonate (50 mL x 3) and brine (50 mL x 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 5.2 g of crude product. The crude product was used directly in the next step without further purification. MS (ESI, m / z) [M+H] + 401.1.

[0275] (R)-3-chloro-10-methyl-8-oxo-10,11-dihydro-[1,4]oxazepino[7',6':4,5]thieno[3,2-f]quinoline-9(8H)-carboxylic acid tert-butyl ester. To a solution of (R)-10-methyl-4-(11-oxoalkyl)-8-oxo-10,11-dihydro-414-[1,4]oxazepino[7',6':4,5]thieno[3,2-f]quinoline-9(8H)-carboxylic acid tert-butyl ester (5.2 g, 13.0 mmol) in DMF (60.0 mL) at 0°C was added oxalyl chloride (2.5 g, 19.5 mmol) dropwise. The resulting mixture was allowed to warm to room temperature and stirred overnight under a nitrogen atmosphere. The reaction mixture was diluted with water (600 mL) and stirred for 10 minutes. The precipitated solid was collected by filtration, washed with petroleum ether (2 x 300 mL) and dried under vacuum to give (R)-tert-butyl 3-chloro-10-methyl-8-oxo-10,11-dihydro-[1,4]oxazepino[7',6':4,5]thieno[3,2-f]quinoline-9(8H)-carboxylate (5.0 g, 80% yield) as an off-white solid. MS (ESI, m / z) [M+H] + 418.2 Example I1.6. Intermediate 6: Synthesis of (R)-3-bromo-10-methyl-8-oxo-10,11-dihydro-[1,4]oxazepino[7',6':4,5]thieno[3,2-f]quinoline-9(8H)-carboxylic acid tert-butyl ester

[0276] (R)-10-methyl-8-oxo-10,11-dihydro-[1,4]oxazepino[7',6':4,5]thieno[3,2-f]quinoline-9(8H)-carboxylic acid tert-butyl ester. To a solution of (R)-10-methyl-10,11-dihydro-[1,4]oxazepino[7',6':4,5]thieno[3,2-f]quinolin-8(9H)-one (4.4 g, 15.5 mmol) and di-tert-butyl dicarbonate (6.8 g, 31.0 mmol) in THF (100 mL) was added DMAP (189 mg, 1.55 mmol). The resulting mixture was stirred at 60° C. under a nitrogen atmosphere for 2 h. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluted with 1:1 ethyl acetate / petroleum ether) to give (R)-10-methyl-8-oxo-10,11-dihydro-[1,4]oxazepino[7',6':4,5]thieno[3,2-f]quinoline-9(8H)-carboxylic acid tert-butyl ester (5.5 g, 93% yield) as an off-white solid. MS (ESI, m / z) [M+H] + 385.2.

[0277] (R)-9-(tert-Butyloxycarbonyl)-10-methyl-8-oxo-8,9,10,11-tetrahydro-[1,4]oxazepino[7',6':4,5]thieno[3,2-f]quinoline 4-oxide. To a solution of (R)-10-methyl-8-oxo-10,11-dihydro-[1,4]oxazepino[7',6':4,5]thieno[3,2-f]quinoline-9(8H)-carboxylic acid tert-butyl ester (5.0 g, 13.0 mmol) in DCM (120 mL) at 0° C. was added 3-chloroperoxybenzoic acid (3.4 g, 19.5 mmol) dropwise. The resulting mixture was stirred at 30° C. for 2 h. After the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3), the combined organic layers were washed with saturated aqueous sodium carbonate solution (50 mL x 3) and brine (50 mL x 2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give (R)-9-(tert-butoxycarbonyl)-10-methyl-8-oxo-8,9,10,11-tetrahydro-[1,4]oxazepino[7',6':4,5]thieno[3,2-f]quinoline 4-oxide (5.2 g) as a crude product, MS (ESI, m / z) [M+H] + 401.3. The product was used in the next step without further purification.

[0278] (R)-3-Bromo-10-methyl-8-oxo-10,11-dihydro-[1,4]oxazepino[7',6':4,5]thieno[3,2-f]quinoline-9(8H)-carboxylic acid tert-butyl ester. To a solution of (R)-9-(tert-butoxycarbonyl)-10-methyl-8-oxo-8,9,10,11-tetrahydro-[1,4]oxazepino[7',6':4,5]thieno[3,2-f]quinoline 4-oxide (5.2 g, 13.0 mmol) in DMF (60 mL) at 0° C. was added phosphorus oxybromide (5.6 g, 19.5 mmol) dropwise. The resulting mixture was allowed to warm to room temperature and stirred continuously overnight under a nitrogen atmosphere. After the reaction was quenched with water (600 mL) at 0° C., the mixture was extracted with dichloromethane (3×100 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with 1:2 ethyl acetate / dichloromethane) to give (R)-3-bromo-10-methyl-8-oxo-10,11-dihydro-[1,4]oxazepine[7′,6′:4,5]thieno[3,2-f]quinoline-9(8H)-carboxylic acid tert-butyl ester (4.5 g, 75% yield) as a white solid. 1H NMR(400MHz,DMSO-d6)δppm 9.15(d,J=8.8Hz,1H),8.29(d,J=9.2Hz,1H),8.00(d,J=9.2Hz,1H),7.86(d,J=8.8Hz,1H),5 .03-4.98(m,1H),4.82-4.76(m,1H),4.59-4.56(m,1H),1.50(s,9H),1.28(d,J=6.8Hz,3H).

[0279] Example I1.7. Intermediate 7: Synthesis of (R)-10-methyl-3-(tributylstannyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-8-one

[0280] To a solution of (R)-3-chloro-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-8-one (10.0 g, 31.4 mmol) and hexa-n-butylditin (22 g, 37.7 mmol) in DMF (200.0 mL) was added Pd(PPh3)2Cl2 (1.1 g, 1.57 mmol) and LiCl (2.0 g, 47.2 mmol). The resulting mixture was stirred at 90 ° C under a nitrogen atmosphere overnight (16h). After dilution with saturated potassium fluoride aqueous solution (1.0L), the mixture was extracted with ethyl acetate (500mL x 5). The combined organic layer was washed with brine (300mL x2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate / petroleum ether (8: 1) to obtain (R) -10- methyl -3- (tributyl stannyl) -9,10,11,12- tetrahydro -8H- [1,4] diazepine and [5 ', 6 ': 4,5] thieno [3,2-f] quinoline -8- one (7.5g, 41% yield) as a yellow solid. MS (ESI, m / z) [M + H] + 574.2 1H NMR(400MHz,DMSO-d6)δppm 8.95(d,J=8.4Hz,1H),8.07(s,1H),8.06(d,J=9.2Hz,1H),7.94(d,J=9.2Hz,1H),7.69-7.53(m,3H),7.08(t,J=5.2Hz,1H ),3.62-3.57(m,1H),3.47-3.44(m,2H),1.63-1.53(m,6H),1.37-1.28(m,6H),1.19–1.15(m,9H),0.85(t,J=7.2Hz,3H).

[0281] Example 1: Synthesis of N-(1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-4-yl)-3-fluoro-4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)benzamide

[0282] (R)-3-Fluoro-4-(10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)benzoic acid. A reaction tube was initially charged with (R)-3-chloro-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-8-one (2.0 g, 6.29 mmol) and then 4-dihydroxyborono-3-fluoro-benzoic acid (1.7 g, 9.44 mmol), Cs2CO3 (6.1 g, 18.9 mmol) and Pd(dppf)Cl2 (0.51 g, 0.63 mmol). After 1,4-dioxane (45.0 mL) and water (15.0 mL) were added to the reaction tube, the resulting mixture was degassed with N2 for 20 min, capped and stirred at 90 ° C for 18 h. After cooling to room temperature, it was filtered through a celite pad and then washed with EtOAc (10 mL x 2). The collected liquid was concentrated under vacuum, and the residue was purified by reverse phase chromatography (RPC) using H2O (with 0.1% formic acid) and acetonitrile as mobile phases to obtain (R)-3-fluoro-4-(10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepine[5',6':4,5]thieno[3,2-f]quinolin-3-yl)benzoic acid in quantitative yield. MS (ESI, m / z) [M+H] + 422.1.

[0283] N-(1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-4-yl)-3-fluoro-4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)benzamide. A round-bottom flask was charged with 3-(1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione (121.5 mg, 0.36 mmol) and then (R)-3-fluoro-4-(10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)benzoic acid and DIPEA (0.52 mL, 2.97 mmol). After DMF (2.0 mL) was added to the flask, the reaction mixture was stirred at room temperature for 10 min. HATU (169.2 mg, 0.44 mmol) was then added. The resulting mixture was stirred at room temperature for 1.0 h. LCMS indicated complete conversion to the desired product. The reaction mixture was purified by reverse phase chromatography (RPC) using H2O (with 0.1% formic acid) and acetonitrile as mobile phase to give the desired product (30.1 mg, 13.4% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δppm 1.20(d,J=6.6Hz,3H),1.70-1.82(m,2H),1.91-1.99(m,2H),2.13-2.21(m,1H),2.25-2.36(m,1H),2.55-2.65(m,2H),2.93(br, t,J=11.5Hz,2H),3.45-3.52(m,2H),3.58-3.66(m,1H),3.86-3.94(m,5H),4.02-4.12(m,1H),4.26(dd,J=9.2,5.0Hz,1H),6.89 -6.93(m,1H),6.93-6.99(m,1H),7.18(br t,J=5.0Hz,1H),7.51(d,J=9.0Hz,1H),7.84-7.96(m,2H),8.03-8.13(m,3H), 8.15-8.27(m,2H),8.53(d,J=7.6Hz,1H),9.28(d,J=8.8Hz,1H),10.85(s,1H). MS(ESI,m / z)[M+H] + 745.2.

[0284] Example 2: Synthesis of N-(2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazin-1-yl)ethyl)-3-fluoro-4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)benzamide

[0285] tert-Butyl (2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazole-6-yl)piperazine-1-yl)ethyl)carbamate. A round-bottom flask was charged with 3-(1-methyl-6-(piperazine-1-yl)-1H-indazole-3-yl)piperidine-2,6-dione dihydrochloride (0.2 g, 0.50 mmol) and subsequently added tert-butyl (2-oxoethyl)carbamate (118.7 mg, 0.75 mmol) and DIPEA (0.17 mL, 0.99 mmol). After adding DCE (5.0 mL), the resulting mixture was stirred at 25 ° C for 10 min, and then NaBH (OAc) (189.6 mg, 0.89 mmol) was added. The reaction mixture was stirred at room temperature overnight for 16 h. Additional NaBH(OAc)3 (0.5 mmol) was added and stirred at room temperature for another 4.0 h. After evaporation of the solvent, the residue was purified by reverse phase chromatography (RPC) using H2O (with 0.1% formic acid) and acetonitrile as mobile phases to give the desired product in quantitative yield as a white solid. MS (ESI+) [M+H] + 471.2.

[0286] 3-(6-(4-(2-aminoethyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; hydrochloride. In a round-bottom flask, tert-butyl N-[2-[4-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazol-6-yl]piperazin-1-yl]ethyl]carbamate (0.24 g mg, 0.51 mmol) and HCl (4.0 M) in dioxane (0.02 mL, 0.51 mmol) were added. The solution was stirred at room temperature for 2.0 h and LCMS spectroscopy indicated complete conversion to the desired product. After solvent removal, the crude product was used directly in the next step reaction without further purification. MS (ESI, m / z) [M+H] + 371.2.

[0287] N-(2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazin-1-yl)ethyl)-3-fluoro-4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)benzamide. A round-bottom flask was charged with 3-[6-[4-(2-aminoethyl)piperazin-1-yl]-1-methyl-indazol-3-yl]piperidine-2,6-dione; hydrochloride (0.58 g, 0.14 mmol), and then (R)-3-fluoro-4-(10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)benzoic acid (0.05 g, 0.12 mmol) and DIPEA (0.21 mL, 1.19 mmol). After adding DMF (1.5 mL), the resulting mixture was stirred at room temperature for 10 min, and then HATU (0.68 g, 0.18 mmol) was added. The reaction was stirred at room temperature for 2.0 h, and LCMS indicated complete conversion to the desired product. The reaction mixture was purified by reverse phase chromatography (RPC) using H2O (with 0.1% formic acid) and acetonitrile as mobile phase to give the desired product. 1 H NMR(400MHz,DMSO-d6)δppm 1.20(d,J=6.8Hz,3H),2.11-2.21(m,1H),2.24-2.32(m,1H),2.57-2.67(m,8H),3.21-3.28(m,4H),3.44-3.54(m ,4H),3.58-3.66(m,1H),3.89(s,3H),4.26(dd,J=9.2,5.0Hz,1H),6.84-6.87(m,1H),6.91-6.96(m,1H),7.18(br t,J=4.9Hz,1H),7.50(d,J=9.0Hz,1H),7.82-7.93(m,2H),8.02-8.13(m,3H), 8.15-8.27(m,2H),8.69(t,J=5.6Hz,1H),9.28(d,J=9.0Hz,1H),10.85(s,1H). MS(ESI,m / z)[M+H] + 774.2.

[0288] Example 3: Synthesis of N-((trans)-3-((4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazin-1-yl)methyl)cyclobutyl)-3-fluoro-4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)benzamide

[0289] Solution of N-[3-(hydroxymethyl) cyclobutyl] tert-butyl carbamate (0.3g, 1.49mmol) and PCC (0.64g, 2.98mmol) in DCM (15.0mL) is at room temperature stirred to 4h.Mixture is filtered through celite pad and pad is washed with DCM (10mL x 2).After solvent evaporation, crude product is carried out to purify to obtain the desired product (201.7mg, 68% productive rate) in white solid with EtOAc and heptane as mobile phase by normal phase chromatography.

[0290] A suspension of tert-butyl ((trans)-3-((4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazin-1-yl)methyl)cyclobutyl)carbamate in DCM (8.0 mL) was sonicated for 5-10 minutes, and additional DMSO (1.0 mL) was added. After 5 minutes, NaBH(OAc) (0.41 g, 1.93 mmol) was added, and the reaction was stirred at room temperature overnight. After concentration under vacuum, the residue was purified by reverse phase chromatography (RPC) using H2O (with 0.1% formic acid) and acetonitrile as mobile phase to give the desired product (366.7 mg, yield = 92%). MS (ESI, m / z) [M+H] + 511.4.

[0291] 3-(6-(4-(((trans)-3-aminocyclobutyl)methyl)piperazine-1-yl)-1-methyl-1H-indazole-3-yl)piperidine-2,6-dione. Into a 100mL round-bottom flask were introduced tert-butyl N-[3-[[4-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]piperazine-1-yl]methyl]cyclobutyl]carbamate (366.7mg, 0.72mmol) and HCl (4.0N) (3.6mL, 14.36mmol) in 1,4-dioxane, and the solution was stirred at room temperature for 2.0h. The reaction mixture was diluted with MTBE. After filtration, the precipitate was recovered, washed with MTBE (5.0mL x 2), and dried under vacuum to obtain the desired product (406mg) as a white solid. MS (ESI, m / z) [M+H] + 411.2.

[0292] N-((trans)-3-((4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazin-1-yl)methyl)cyclobutyl)-3-fluoro-4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)benzamide. To a solution of 3-[6-[4-[(3-aminocyclobutyl)methyl]piperazin-1-yl]-1-methyl-indazol-3-yl]piperidine-2,6-dione; dihydrochloride (0.21 g, 0.43 mmol) in DMF (2.0 mL) was charged (R)-3-fluoro-4-(10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)benzoic acid (0.15 g, 0.36 mmol) and DIPEA (0.62 mL, 3.56 mmol), and then sonicated and stirred for 5 min. After adding HATU (135.3 mg, 0.36 mmol), the reaction mixture was stirred at room temperature for 2.0 h. After concentration under vacuum, the residue was purified by reverse phase chromatography (RPC) using H2O (with 0.1% formic acid) and acetonitrile as mobile phase to give the desired product (51 mg, 18% yield) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δppm 1.20 (d, J=6.8Hz, 3H), 2.07 -2.34(m,6H),2.52-2.69(m,9H),3.21-3.25(m,4H),3.46-3.51(m,2H),3.59-3.67(m,1 H),3.89(s,3H),4.26(dd,J=9.2,5.0Hz,1H),4.53(q,J=7.8Hz,1H),6.85(d,J=1.5Hz,1 H),6.93(dd,J=9.0,1.7Hz,1H),7.18(t,J=5.1Hz,1H),7.50(d,J=9.0Hz,1H),7.85–7.9 5(m,2H),8.01–8.28(m,6H),8.88(d,J=7.1Hz,1H),9.29(d,J=9.0Hz,1H),10.85(s,1H). MS(ESI,m / z)[M+H] + 814.3.

[0293] Example 4: Synthesis of N-(trans-3-(2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazin-1-yl)ethyl)cyclobutyl)-3-fluoro-4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)benzamide

[0294] Tert-butyl ((trans)-3-(2-(methoxy(methyl)amino)-2-oxoethyl)cyclobutyl)carbamate.

[0295] At a solution of 2-[3-(tert-butoxycarbonylamino)cyclobutyl]acetic acid (250.0 mg, 1.09 mmol) in DCM (5.0 mL), N-methoxymethylamine hydrochloride (159.5 mg, 1.64 mmol) and DIPEA (0.95 mL, 5.45 mmol) were added. After adding HATU (621.9 mg, 1.64 mmol), the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into 3.0 mL of NaOH (1.0 M, aqueous solution) and stirred for 10 min. The organic layer was separated and washed with HCl (2.0 mL, 1.0 M), water (2.0 mL x 1), brine (2.0 mL x 1) and dried over Na2SO4. After filtering and concentrating, the crude product was purified by chromatography using heptane and EtOAc as mobile phase to obtain the desired product (283 mg, 95% yield) as a white solid.

[0296] Tert-butyl ((trans)-3-(2-oxoethyl)cyclobutyl)carbamate. To a solution of tert-butyl (3-(2-(methoxy(methyl)amino]-2-oxo-ethyl)cyclobutyl)carbamate (280.7 mg, 1.03 mmol) in THF (5.0 mL) was added dropwise 60% (0.44 mL, 1.34 mmol). After stirring at -40 °C for 30 min, the reaction mixture was continuously stirred at room temperature overnight. The reaction was quenched by the addition of EtOAc (4.0 mL) and Rochelle salt (4.0 mL, aqueous solution) and stirred vigorously for 1.0 h. The organic layer was separated and washed with brine (4.0 mL x 1), water (4.0 mL x 1), and dried over Na2SO4. After filtration and concentration, a colorless oil (259.7 mg) was obtained and used in the next step without further purification.

[0297] To a suspension of 3-(1-methyl-6-piperazine-1-yl-indazole-3-yl)piperidine-2,6-dione hydrochloride (329.2 mg, 0.90 mmol) in DCM (9.0 mL) was added tert-butyl N-[3-(2-oxoethyl)cyclobutyl]carbamate (193.0 mg, 0.90 mmol) and DIPEA (1.1 mL, 6.33 mmol) and then sonicated for 3 min. The mixture was charged with DMSO (1.0 mL) and NaBH(OAc) (479.5 mg, 2.26 mmol), and the resulting mixture was stirred at room temperature overnight. After concentration in vacuo, the residue was purified by reverse phase chromatography (RPC) using H2O (with 0.1% formic acid) and acetonitrile as mobile phases to give the desired product (293.0 mg, 60% yield) as a tan foam.

[0298]

[0266] 3-(6-(4-(2-((trans)-3-aminocyclobutyl)ethyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione. To a round-bottom flask was added tert-butyl (3-(2-(methoxy(methyl)amino]-2-oxo-ethyl)cyclobutyl)carbamate (293.0 mg, 0.56 mmol) and 4.0 M HCl in 1,4-dioxane (0.41 mL, 11.17 mmol). The resulting solution was stirred at room temperature for 2.0 h. MTBE (5.0 mL) was added to the reaction mixture, and the resulting precipitate was collected by filtration to give the desired product (302.6 mg) as a white solid.

[0299] N-(trans-3-(2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazin-1-yl)ethyl)cyclobutyl)-3-fluoro-4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)benzamide to 3-[6-[4-[2-(3-aminocyclobutyl)ethyl]piperazin-1-yl]-1-methyl-indazol-6-yl] To a solution of (R)-3-fluoro-4-(10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)benzoic acid (125.0 mg, 0.30 mmol) and DIPEA (0.52 mL, 2.97 mmol) in DMF (3.0 mL) was added (177.1 mg, 0.36 mmol). After stirring for 5 min, HATU (112.8 mg, 0.30 mmol) was added and the resulting mixture was stirred at room temperature overnight. After removal of the solvent, the residue was purified by reverse phase chromatography (RPC) using H2O (with 0.1% formic acid) and acetonitrile as mobile phase to give the desired product (18.6 mg, 7.5% yield) as a yellow solid. MS (ESI, m / z) [M+H] + 822.4 1 H NMR(400MHz,DMSO-d6)δppm 1.20(d,J=6.6Hz,3H),1.68-1.77(m,2H),2.02-2.10(m,2H),2.12-2.20(m,1H),2.23-2.29(m,3H),2.30-2.36(m,3H) ,2.55-2.64(m,6H),3.20-3.26(m,4H),3.46-3.50(m,2H),3.57-3.67(m,1H),3.90(s,3H),4.26(dd,J=9.2,5.0Hz,1H) ,4.48-4.60(m,1H),6.83-6.87(m,1H),6.90(dd,J=9.3,1.0Hz,1H),7.15-7.21(m,1H),7.48-7.53(m,1H),7.85-7.94( m,2H),8.03-8.12(m,3H),8.14(s,1H),8.16-8.25(m,2H),8.86(d,J=7.1Hz,1H),9.28(d,J=8.8Hz,1H),10.85(s,1H).

[0300] Example 5: Synthesis of N-(trans-4-((4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazin-1-yl)methyl)cyclohexyl)-3-fluoro-4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)benzamide

[0301] tert-Butyl ((1R,4R)-4-((4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazin-1-yl)methyl)cyclohexyl)carbamate. To a solution of 3-(1-methyl-6-piperazin-1-yl-indazol-3-yl)piperidine-2,6-dione; hydrochloride (660.0 mg, 1.81 mmol) in DCM (10.0 mL) was charged DIPEA (1.44 mL, 8.25 mmol) and tert-butyl N-(4-formylcyclohexyl)carbamate (374.8 mg, 1.65 mmol). After the addition of NaBH(OAc)3 (873.76 mg, 4.12 mmol), the resulting mixture was stirred at room temperature overnight. The solvent was evaporated under vacuum and the crude product was purified by reverse phase chromatography (RPC) using H2O (with 0.1% formic acid) and acetonitrile as mobile phase to give the desired product (735 mg, 76% yield) as an off-white solid. MS (ESI, m / z) [M-HCOOH+H] + 539.4. 1 H NMR(400MHz,DMSO-d6)δppm 0.82-0.98(m,2H),1.06-1.22(m,2H),1.37(s,9H),1.42-1.50(m,1H),1.78(br d,J=10.5Hz,4H),2.11-2.22(m,3H),2.24-2.36(m,1H),2.52-2.69(m,5H),3.22(brs,6H),3.89(s,3H),4.25(dd,J=9.2,5.0Hz,1H),6.70(br d, J=7.6Hz, 1H), 6.83 (d, J=1.5Hz, 1H), 6.91 (dd, J=9.0, 2.0Hz, 1H), 7.49 (d, J=9.0Hz, 1H), 8.13 (s, 1H), 10.84 (s, 1H).

[0302] 3-(6-(4-((4-aminocyclohexyl)methyl)piperazine-1-yl)-1-methyl-1H-indazole-3-yl)piperidine-2,6-dione. To a solution of tert-butyl N-[4-[[4-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]piperazine-1-yl]methyl]cyclohexyl]carbamate (735.0 mg, 1.36 mmol) in DCM (5.0 mL) was added a solution of 4.0 M HCl in 1,4-dioxanes (5.0 mL, 20.5 mmol) and the resulting mixture was stirred at room temperature overnight. After evaporation of the solvent under vacuum, the residue was further azeotropically dried with toluene (5.0 mL x 2) to give (700 mg, quantitative yield) as an off-white solid. MS (ESI, m / z)[M+H] + 439.2. 1 H NMR (400MHz, DMSO-d6) δppm 1.01-1.15 (m, 2H), 1.37 (brd, J = 10.5Hz, 2H), 1.81 (br d, J = 2.7Hz, 1H), 1.97 (br d,J=11.0Hz,4H),2.12-2.21(m,1H),2.31(dt,J=13.8,4.5Hz,1H),2.55-2.69(m,2H),2.88-3.04(m,3H),3.09-3.22(m,2H),3.38(br t,J=12.1Hz,2H),3.60(br s,1H),3.64-3.73(m,1H),3.87(br d,J=13.0Hz,2H),3.92(s,3H),4.28(br dd,J=9.4,5.0Hz,1H),6.93-7.00(m,2H),7.52-7.60(m,1H),8.09(br s,3H),8.14(s,1H),10.68(br d,J=1.5Hz,1H),10.86(s,1H).

[0303] N-(trans-4-((4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazin-1-yl)methyl)cyclohexyl)-3-fluoro-4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)benzamide. To a solution of (R)-3-fluoro-4-(10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)benzoic acid (145.0 mg, 0.34 mmol) in DMF (3.0 mL) was charged DIPEA (0.42 mL, 2.41 mmol). After 10 min, HATU (196.2 mg, 0.52 mmol) was added, and the resulting mixture was then stirred at room temperature for 2.0 h. The mixture was purified by reverse phase chromatography (RPC) using H2O (with 0.1% formic acid) and acetonitrile as the mobile phase to give the desired product (75.0 mg, 52.4% yield) as a yellow solid. MS (ESI, m / z) [M+H] + 842.5 1 H NMR(400MHz,DMSO-d6)δppm 0.95-1.08(m,2H),1.20(d,J=6.6Hz,4H),1.33-1.48(m,2H),1.50-1.61(m,1H),1. 83-1.99(m,4H),2.11-2.23(m,3H),2.25-2.33(m,1H),2.52-2.65(m,5H),3.23(br s,4H),3.45-3.55(m,2H),3.62(td,J=7.0,3.9Hz,1H),3.73-3.85(m,1H),3.89(s,3H),4.26(dd,J=9.2,5.3Hz,1H),6.85(br s,1H),6.93(br d,J=8.8Hz,1H),7.18(br t,J=5.1Hz,1H),7.50(d,J=8.8Hz,1H),7.82-7.95(m,2H),8.02-8.12(m,3H) ,8.17-8.25(m,2H),8.39-8.51(m,1H),9.28(d,J=8.8Hz,1H),10.85(s,1H).

[0304] Example 6: Synthesis of N-(trans-4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazin-1-yl)ethyl)cyclohexyl)-3-fluoro-4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)benzamide

[0305] tert-Butyl ((1r,4r)-4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazin-1-yl)ethyl)cyclohexyl)carbamate. A round-bottom flask was charged with 3-(1-methyl-6-piperazin-1-yl-indazol-3-yl)piperidine-2,6-dione dihydrochloride (150.0 mg, 0.37 mmol), tert-butyl N-[4-(2-oxoethyl)cyclohexyl]carbamate (90.4 mg, 0.37 mmol) and DIPEA (0.65 mL, 3.75 mmol) in DMSO (1.5 mL). After the mixture was stirred at room temperature for 10 min, NaBH(OAc)3 (238.3 mg, 1.12 mmol) was added. The resulting mixture was stirred continuously at room temperature overnight. DCM was evaporated under vacuum and the residue was purified by reverse phase chromatography (RPC) using H2O (with 0.1% formic acid) and acetonitrile as mobile phase to give the desired product (130.0 mg, 63% yield). MS (ESI, m / z) [M+H] + 553.2.

[0306] 3-(6-(4-(2-((1r,4r)-4-aminocyclohexyl)ethyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione. A round-bottom flask was charged with tert-butyl N-[4-[2-[4-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazol-6-yl]piperazin-1-yl]ethyl]cyclohexyl]carbamate (130.0 mg, 0.24 mmol) and a solution of 4.0 M HCl in dioxane (0.06 mL, 0.24 mmol) was added. The reaction mixture was stirred at room temperature for 2.0 h. After evaporation of the solvent under vacuum, the residue was further azeotropically dried with toluene (2.0 mL x 2) to give the desired product (120 mg, 93% yield) as a white solid. MS (ESI, m / z) [M+H] + 453.2.

[0307] N-(trans-4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazin-1-yl)ethyl)cyclohexyl)-3-fluoro-4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)benzamide. To a round-bottom flask was added 3-[6-[4-[2-(4-aminocyclohexyl)ethyl]piperazin-1-yl]-1-methyl-indazol-3-yl]piperidine-2,6-dione dihydrochloride (104.7 mg, 0.20 mmol), (R)-3-fluoro-4-(10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)benzoic acid (70.0 mg, 0.17 mmol), and DIPEA (0.29 mL, 1.66 mmol) in DMF (2.0 mL). The mixture was stirred at room temperature for 10 min, and then HATU (94.7 mg, 0.25 mmol) was added. The reaction mixture was stirred continuously at room temperature for 2.0 h. The residue was purified by reverse phase chromatography (RPC) using H2O (with 0.1% formic acid) and acetonitrile as mobile phase to give the desired product (25.9 mg, 17.8% yield) as a yellow solid. MS (ESI, m / z) [M+H] + 856.3 1H NMR (400MHz, DMSO-d6) δppm 1.01-1.13(m,2H),1.20(d,J=6.8Hz,3H),1.24-1.46(m,5H),1.82(br d,J=11.7Hz,2H),1.90(br d,J=9.4Hz,2H),2.11-2.21(m,1H),2.25-2.32(m,1H),2.39(br t,J=7.3Hz,2H),2.52-2.57(m,4H),2.58-2.65(m,2H),3.19-3.26(m,4H),3.45-3.51(m,2H),3.57-3.67(m,1H),3. 73-3.83(m,1H),3.89(s,3H),4.26(dd,J=9.2,5.0Hz,1H),6.83-6.86(m,1H),6.92(dd,J=9.0,1.7Hz,1H),7.18(br t,J=4.9Hz,1H),7.50(d,J=8.8Hz,1H),7.82-7.92(m,2H),8.03-8.13(m,3H), 8.16-8.26(m,2H),8.42(d,J=7.8Hz,1H),9.28(d,J=8.8Hz,1H),10.85(s,1H).

[0308] Example 7: Synthesis of N-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)-3-fluoro-4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)benzamide

[0309] (1,5-dioxopentan-3-yl)t-butyl carbamate. At room temperature, NaIO4(177.8mg, 0.83mmol) was added to a solution of t-butyl N-(3,4-dihydroxycyclopentyl)carbamate (150.4mg, 0.69mmol) in THF(2.8mL) / water (1.4mL). The resulting mixture was stirred at room temperature for 1h. THF was removed under vacuum, and salt water (5mL) was added. The resulting aqueous solution was extracted with EtOAc(10mL x 3). The combined organic layer was washed with salt water, dried over MgSO4, filtered, and concentrated. The residue was dissolved in dichloromethane (10mL), and MgSO4(3g) was added. The mixture was stirred at room temperature over the weekend. The mixture was filtered and concentrated to obtain the product (1,5-dioxopentan-3-yl)t-butyl carbamate (156.6mg, quantitative yield) as a yellow solid, which was used without further purification.

[0310] (1- (4- (2,6- dioxopiperidin-3-yl) phenyl) piperidin-4-yl) tert-butyl carbamate. At room temperature, to 3- (4- aminophenyl) piperidine -2,6- dione (159.0mg, 0.78mmol) (which can be prepared according to the method described in WO 2022012622 A1, and the patent is hereby incorporated by reference in its entirety) and N- [3- (1,5- dioxopentan-3-yl) tert-butyl carbamate (202mg, 0.94mmol) in DCE (5mL) solution NaBH (OAc) 3 (396.3mg, 1.87mmol). The resulting solution was stirred for one hour. LCMS analysis showed incomplete conversion. More NaBH (OAc) 3 (176.9mg, 0.83mmol) was added, and the reaction was stirred for another 1.0h. LCMS analysis still showed incomplete conversion. To the 4- (2,6- dioxopiperidin-3-yl) phenyl) piperidin-4-yl) tert-butyl carbamate (203 mg, 67% yield) of 1- (4- (2,6- dioxopiperidin-3-yl) phenyl) piperidin-4-yl) t-butyl carbamate (203 mg, 67% yield) of tan solid was added more NaBH (OAc) (186.6 mg, 0.88 mmol) and the reaction was stirred for 2 h. The reaction was quenched with saturated NH4Cl (5.0 mL) and the mixture was extracted with dichloromethane (10 mL). The organic phase was separated, and the aqueous layer was further extracted with dichloromethane (10 mLx3). The combined organic layer was washed with salt water, dried over MgSO4, filtered, and concentrated. The residue was purified by reverse phase chromatography (RPC) using H2O (with 0.1% formic acid) and acetonitrile as mobile phases to obtain the desired product (1- (4- (2,6- dioxopiperidin-3-yl) phenyl) piperidin-4-yl) t-butyl carbamate (203 mg, 67% yield) of tan solid. MS (ESI, m / z) [M+H] + 388.4.

[0311] 3-(4-(4-aminopiperidin-1-yl)phenyl)piperidine-2,6-dione. Tert-butyl N-[1-[4-(2,6-dioxo-3-piperidinyl)phenyl]-4-piperidinyl]carbamate (201 mg, 0.52 mmol) was suspended in 4.0 M HCl (5 mL, 20 mmol) in dioxane, and the resulting mixture was stirred at room temperature for 2 h. The mixture was then concentrated under vacuum to give the product, 3-(4-(4-aminopiperidin-1-yl)phenyl)piperidine-2,6-dione; trihydrochloride salt (215.8 mg, quantitative) as a tan solid. MS (ESI, m / z) [M+H] + 288.2.

[0312] N-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)-3-fluoro-4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)benzamide. To a suspension of (R)-3-fluoro-4-(10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)benzoic acid (50 mg, 0.12 mmol) and 3-(4-(4-aminopiperidin-1-yl)phenyl)piperidine-2,6-dione trihydrochloride (51.6 mg, 0.13 mmol) in DMF (1 mL) at room temperature was added DIPEA (150 μL, 0.86 mmol). The resulting mixture was stirred for 7 min, then pyAOP (74 mg, 0.14 mmol) was added in one portion. The resulting mixture was stirred at room temperature for 1.0 h. After removal of the solvent under vacuum, the residue was purified by reverse phase chromatography (RPC) using H2O (with 0.1% formic acid) and acetonitrile as mobile phase to give the desired product, N-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)-3-fluoro-4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)benzamide (6.9 mg, 8% yield) as a yellow solid. MS (ESI, m / z) [M+H] + 691.3 1H NMR (400MHz, DMSO-d6) δppm 10.78 (s, 1H), 9.28 (brd, J = 8.8Hz, 1H), 8.52 (br d,J=7.8Hz,1H),8.15–8.29(m,2H),8.01–8.14(m,3H),7.84–7.95(m,2H),7.14–7.23(m,1H),7.06(br d,J=8.6Hz,2H),6.94(br d,J=8.8Hz,2H),3.95–4.10(m,1H),3.69–3.84(m,3H),3.58–3.67(m,1H),3.45–3.52(m,2H),2.80–2.89(m ,2H),2.09–2.20(m,1H),1.98–2.05(m,1H),1.85–1.94(m,2H),1.64–1.77(m,2H),1.23(brs,1H),1.20(br d,J=6.6Hz,3H),1.15(s,1H).

[0313] Example 8: Synthesis of N-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)ethyl)-3-fluoro-4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)benzamide

[0314] tert-Butyl (2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)ethyl)carbamate. To a solution of 3-(4-piperazin-1-ylphenyl)piperidine-2,6-dione; dihydrochloride (250 mg, 0.72 mmol) in DCM (5 mL) was added DIPEA (0.63 mL, 3.61 mmol) at room temperature, followed by tert-butyl N-(2-oxoethyl)carbamate (149 mg, 0.94 mmol) and NaBH(OAc)3 (382 mg, 1.81 mmol). The reaction was then stirred at room temperature for 2 h. After evaporation of the solvent under vacuum, the residue was purified by reverse phase chromatography (RPC) using H2O (with 0.1% formic acid) and acetonitrile as mobile phase to give the desired product (tert-butyl 2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)ethyl)carbamate (190 mg, 63% yield) as an off-white solid. MS (ESI, m / z) [M+H] + 417.4.

[0315] 3-(4-(4-(2-aminoethyl)piperazine-1-yl)phenyl)piperidine-2,6-dione. To a solution of tert-butyl (2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazine-1-yl)ethyl)carbamate (190 mg, 0.46 mmol) in DCM (3 mL) was added HCl (3 mL, 11.4 mmol) at room temperature. After 1.5 h, LCMS showed complete conversion. The solvent was evaporated under vacuum and co-evaporated with MeCN (4x) and DCM (2x) to give the product 3-(4-(4-(2-aminoethyl)piperazine-1-yl)phenyl)piperidine-2,6-dione dihydrochloride (170 mg, 96% yield) as an off-white solid. MS (ESI, m / z) [M+H] + 317.2

[0316] N-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)ethyl)-3-fluoro-4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)benzamide. To a solution of 3-[4-[4-(2-aminoethyl)piperazin-1-yl]phenyl]piperidine-2,6-dione dihydrochloride (167 mg, 0.4300 mmol) and (R)-3-fluoro-4-(10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)benzoic acid (165 mg, 0.39 mmol) in DMF (2 mL) was added DIPEA (0.48 mL, 2.74 mmol) at room temperature. After 10 min, HATU (223.3 mg, 0.59 mmol) was added, and the reaction mixture was stirred at room temperature for 2 h. LCMS showed complete conversion. The mixture was stirred at room temperature overnight. After evaporation of the solvent under vacuum, the residue was purified by reverse phase chromatography (RPC) using H2O (with 0.1% formic acid) and acetonitrile as mobile phase to give the desired product N-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)ethyl)-3-fluoro-4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)benzamide (53 mg, 19% yield) as a yellow solid. MS (ESI, m / z) [M+H] + 720.3 1H NMR(400MHz,DMSO-d6)δppm 10.77(s,1H),9.28(d,J=8.8Hz,1H),8.69(t,J=5.7Hz,1H),8.17–8.27(m,2H),8.02–8.13(m,3H),7.81–7.93(m,2H),7.18(br t,J=5.1Hz,1H),7.05(d,J=8.8Hz,2H),6.90(d,J=8.8Hz,2H),3.73(dd,J=11.0,4.9H z,1H),3.62(m,1H),3.43–3.52(m,4H),3.11–3.20(m,4H),2.54–2.65(m,7H),2.44(br d,J=4.4Hz,1H),2.08–2.20(m,1H),1.96–2.05(m,1H),1.20(d,J=6.6Hz,3H).

[0317] Example 9: Synthesis of N-(trans-4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)-3-fluoro-4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)benzamide

[0318] N-[4-[[4-[4-(2,6-dioxo-3-piperidinyl)phenyl]piperazine-1-yl]methyl]cyclohexyl]t-butyl carbamate.To 3-(4-piperazine-1-ylphenyl)piperidine-2,6-dione (200mg, 0.73mmol) and N-(4-formylcyclohexyl)t-butyl carbamate (249mg, 1.1mmol) and TEA (0.2mL, 1.15mmol) and NaBH cN (92mg, 1.44mmol) stirred solution, add MeOH (2mL).Mixture is stirred at room temperature for 3h.LC / MS illustrates and is converted into desired product completely.Then reaction is quenched with water (30mL) and extracted with EtOAc (30mL x 3).By the organic layer merged through Na sO dry, filter, and concentrate. The residue was purified by silica gel column chromatography and eluted with PE / EtOAc (0-70%) to give tert-butyl N-[4-[[4-[4-(2,6-dioxo-3-piperidinyl)phenyl]piperazin-1-yl]methyl]cyclohexyl]carbamate (240 mg, 68% yield) as a white solid. MS (ESI, m / z) [M+H] + 485.4.

[0319] 3-[4-[4-[(4-aminocyclohexyl)methyl]piperazin-1-yl]phenyl]piperidine-2,6-dione. To a stirred solution of tert-butyl N-[4-[[4-[4-(2,6-dioxo-3-piperidinyl)phenyl]piperazin-1-yl]methyl]cyclohexyl]carbamate (240 mg, 0.50 mmol) was added HCl (10 mL, 0.50 M) in EtOAc. The mixture was stirred at room temperature for 1 h. LC / MS showed complete conversion to the desired product. After filtration, the crude product 3-[4-[4-[(4-aminocyclohexyl)methyl]piperazin-1-yl]phenyl]piperidine-2,6-dione (180 mg) was obtained as a white solid. MS (ESI, m / z) [M+H] + 385.1.

[0320] N-(trans-4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)-3-fluoro-4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)benzamide. To a round-bottom flask was added 3-[4-[4-[(4-aminocyclohexyl)methyl]piperazin-1-yl]phenyl]piperidine-2,6-dione dihydrochloride (65 mg, 0.14 mmol) and (R)-3-fluoro-4-(10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)benzoic acid (50 mg, 0.12 mmol) in DMF (1.2 mL). The reaction mixture was stirred at room temperature for 10 min and then HATU (45 mg, 0.12 mmol) was added. The reaction mixture was continuously stirred at room temperature for 1 h and then directly purified by reverse phase chromatography (RPC) using H2O (with 0.1% formic acid) and acetonitrile as mobile phase to give the desired product, N-(trans-4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)-3-fluoro-4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)benzamide (29.3 mg, 30% yield) as a yellow solid. MS (ESI, m / z) [M+H] + 788.3 1H NMR (400MHz, DMSO-d6) δppm10.77(s,1H),9.28(d,J=8.8Hz,1H),8.45(d,J=7 .8Hz,1H),8.16–8.25(m,2H),8.03–8.12(m,3H),7.83–7.93(m,2H),7.18(br t,J=5.0Hz,1H),7.05(d,J=8.8Hz,2H),6.89(d,J=8.8Hz,2H),3.76–3.85(m,1H),3.73(dd,J=11.0,4.9Hz,1 H),3.58–3.66(m,1H),3.44–3.52(m,2H),3.08–3.15(m,4H),2.58–2.66(m,1H),2.42–2.49(m,5H),2.17(br d,J=7.1Hz,2H),2.07–2.15(m,1H),1.97–2.05(m,1H),1.89(br t,J=13.7Hz,4H),1.46–1.60(m,1H),1.39(q,J=11.6Hz,2H),1.20(d,J=6.6Hz,3H),0.92–1.07(m,2H).

[0321] Example 10: Synthesis of N-((trans)-4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)ethyl)cyclohexyl)-3-fluoro-4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)benzamide

[0322] To a stirred solution of 3-(4-piperazine-1-ylphenyl)piperidine-2,6-dione (150mg, 0.55mmol) and N-[4-(2-oxoethyl)cyclohexyl]t-butyl carbamate (264.9mg, 1.1mmol) in MeOH (5mL) was added ZnCl (2.0M in 2-Me-THF, 0.1mL, 0.55mmol) and NaBHCN (70.24mg, 1.1mmol). The mixture was stirred at 60°C for 4h. The reaction was quenched with HO (30mL) and extracted with EtOAc (30mL x 3). The combined organic phases were dried over NaSO, filtered and concentrated. The residue was purified by silica gel column chromatography using hexane / EtOAc (0-70%) as eluent to give tert-butyl N-[4-[2-[4-[4-(2,6-dioxo-3-piperidinyl)phenyl]piperazin-1-yl]ethyl]cyclohexyl]carbamate (220 mg, 80% yield) as a white solid. MS (ESI, m / z) [M+H] + 499.4.

[0323] 3-[4-[4-[2-(4-aminocyclohexyl)ethyl]piperazin-1-yl]phenyl]piperidine-2,6-dione. To a stirred solution of tert-butyl N-[4-[2-[4-[4-(2,6-dioxo-3-piperidinyl)phenyl]piperazin-1-yl]ethyl]cyclohexyl]carbamate (220 mg, 0.44 mmol) was added HCl (10 mL, 0.38 mmol) in EtOAc. The mixture was stirred at room temperature for 1 h. The solvent was removed under vacuum to give 3-[4-[4-[2-(4-aminocyclohexyl)ethyl]piperazin-1-yl]phenyl]piperidine-2,6-dione (160 mg, 90.9%) as a yellow solid. MS (ESI) [M+H] + 399.3.

[0324] N-((trans)-4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)ethyl)cyclohexyl)-3-fluoro-4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)benzamide. To a solution of (R)-3-fluoro-4-(10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)benzoic acid (100 mg, 0.24 mmol) in DMF (2.4 mL) was added 3-[4-[4-[2-(4-aminocyclohexyl)ethyl]piperazin-1-yl]phenyl]piperidine-2,6-dione; dihydrochloride (134 mg, 0.28 mmol). DIPEA (0.41 mL, 2.37 mmol) was then added and the reaction mixture was sonicated and stirred for 10 min. HATU (90 mg, 0.24 mmol) was then added and the reaction mixture was stirred at room temperature for 1 h. After removal of the solvent under vacuum, the residue was purified by reverse phase chromatography (RPC) using H2O (with 0.1% FA) and acetonitrile as mobile phase to give the product N-((trans)-4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)ethyl)cyclohexyl)-3-fluoro-4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)benzamide (58 mg, 0.072 mmol, 30% yield) as a yellow solid after lyophilization. MS (ESI, m / z) [M+H] + 802.4 1H NMR(400MHz,DMSO-d6)δppm 10.77(s,1H),9.28(d,J=9.5Hz,1H),8.42(d,J=8.1Hz,1H),8.13–8.25( m,3H),8.07–8.12(m,2H),8.02–8.07(m,2H),7.81–7.93(m,2H),7.18(br t,J=5.0Hz,1H),7.05(d,J=8.8Hz,2H),6.89(d,J=8.8Hz,2H),3.75–3.83(m,1H ),3.73(dd,J=11.1,4.5Hz,1H),3.56–3.67(m,1H),3.44–3.53(m,3H),3.12(br s,5H),2.57-2.66(m,1H),2.37(br d,J=0.7Hz,3H),2.06–2.20(m,1H),1.96–2.06(m,1H),1.89(br d,J=10.8Hz,2H),1.81(br d,J=10.8Hz,2H),1.23-1.45(m,6H),1.20(d,J=6.6Hz,3H),0.99-1.16(m,3H).

[0325] Example 11: Synthesis of 3-(4-(4-(2-(4-(3-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6-dione

[0326] (R)-10-Methyl-3-(3-(piperazin-1-yl)phenyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-8-one. 3-(4-tert-Butoxycarbonylpiperazinyl)phenylboronic acid pinacol ester (147 mg, 0.38 mmol), (R)-3-chloro-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-8-one (100 mg, 0.31 mmol), cesium carbonate (308 mg, 0.94 mmol), and Pd(dppf)Cl2 (34.5 mg, 0.05 mmol) were weighed into a 20 mL vial with a stir bar. The bottle is sealed, evacuated and filled with nitrogen (x 3). Then 1,4-dioxane (3mL) and water (0.3mL) are added. The reaction is heated to 100 ° C and stirred overnight. The reaction is diluted with EtOAc and transferred to a separatory funnel containing water. The organic layer is removed and the aqueous layer is extracted with EtOAc (20mL x3). The organic layer is dried over sodium sulfate, filtered, and concentrated. The crude product is purified by normal phase column chromatography (0% to 5% MeOH in DCM). After the fraction is concentrated, the solid is then dissolved in a solution of DCM and TFA (4: 1), and stirred at room temperature for 1h. LC / MS indicates that the reaction is complete. After removing the solvent under vacuum, the residue was purified by reverse phase chromatography (RPC) using H2O (with 0.1% TFA) and acetonitrile as mobile phase to give the product (R)-10-methyl-3-(3-(piperazin-1-yl)phenyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-8-one trifluoroacetate (148 mg, 0.27 mmol, 86%) as an orange solid after lyophilization. MS (ESI, m / z) [M+H] + 444.4

[0327] (R)-3-(3-(4-(2,2-dimethoxyethyl)piperazin-1-yl)phenyl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-8-one. To a solution of (R)-10-methyl-3-(3-(piperazin-1-yl)phenyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-8-one trifluoroacetate (350 mg, 0.63 mmol) in CHCl (5 mL) was added DIPEA (0.55 mL, 3.14 mmol). The reaction mixture was stirred at room temperature for 10 min. Then, 2,2-dimethoxyacetaldehyde (110 μL, 0.75 mmol) and NaBH (OAc) 3 (332 mg, 1.57 mmol) were added. The reaction was stirred at room temperature overnight. LCMS showed complete conversion. After removing the solvent under vacuum, the residue was purified by reverse phase chromatography (RPC) using H 2 O (with 0.1% FA) and acetonitrile as mobile phase to obtain the product (R) -3- (3- (4- (2,2-dimethoxyethyl) piperazine -1- base) phenyl) -10- methyl -9,10,11,12- tetrahydro -8H- [1,4] diazepine and [5 ', 6 ': 4,5] thieno [3,2-f] quinoline -8- one formate (295 mg, 88% yield) as a yellow solid. MS (ESI, m / z) [M + H] + 532.2.

[0328] (R)-2-(4-(3-(10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)acetaldehyde. To a solution of (R)-3-(3-(4-(2,2-dimethoxyethyl)piperazin-1-yl)phenyl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-8-one formate (295 mg, 0.55 mmol) in 1,4-dioxane (2 mL) and water (0.25 mL) was added 4.0 M HCl in 1,4-dioxane (3 mL, 11.1 mmol). The reaction mixture was stirred at room temperature overnight. LCMS showed that 50% was converted to the desired product. A solution of HCl (2.0 mL, 4.0 M in 1,4-dioxane) was added and then heated to 40 ° C. After 1.5 h, LCMS showed complete conversion. The solvent was evaporated under vacuum and co-evaporated with MeCN (3x) and CH2Cl2 (2x) to give (R) -2- (4- (3- (10-methyl -8- oxo -9,10,11,12- tetrahydro -8H- [1,4] diazepine [5', 6': 4,5] thieno [3,2-f] quinolin-3-yl) phenyl) piperazine -1- base) acetaldehyde dihydrochloride (300 mg, 97%) as a red solid. MS (ESI, m / z) [M + H] + 488.2.

[0329] 3-(4-(4-(2-(4-(3-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6-dione. To a solution of (R)-2-(4-(3-(10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)acetaldehyde; dihydrochloride (160 mg, 0.29 mmol) and 3-(4-piperazin-1-ylphenyl)piperidine-2,6-dione dihydrochloride (119.0 mg, 0.34 mmol) in CHCl (2 mL) and DMSO (0.75 mL) was added DIPEA (0.4 mL, 2.29 mmol) under an inert atmosphere. The solution was stirred at room temperature for 10 min. Then, NaBH(OAc) (182 mg, 0.86 mmol) was added, and the reaction mixture was stirred at room temperature overnight. After removal of the solvent under vacuum, the residue was purified by reverse phase chromatography (RPC) using H2O (with 0.1% FA) and acetonitrile as mobile phase to give the product 3-(4-(4-(2-(4-(3-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6-dione as a yellow solid (49 mg, 23% yield). MS (ESI, m / z) [M+H] + 743.3. 1H NMR (400MHz, DMSO-d6) δppm 10.77(s,1H),9.21(d,J=8.8Hz,1H),8.22(d,J=9.0Hz,1H),8.14(s,1H),8.08(br d,J=4.4Hz,1H),8.02(d,J=8.8Hz,1H),7.86(s,1H),7.63-7.76(m,1H),7.40(t,J=7.9Hz,1H),7.15(br d, J = 8.8 Hz, 2H), 3.72 (dd, J = 10.9, 5.0 Hz, 1H), 3.62 (td, J = 7.0, 3.2 Hz, 1H), 3.48 (br s, 3H), 3.13 (br s, 5H), 2.54-2.73 (m, 13H), 1.95-2.21 (m, 2H), 1.20 (d, J = 6.8 Hz, 3H). Three protons were not observed.

[0330] Example 12: Synthesis of 3-(1-methyl-6-(4-(2-(4-(3-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)ethyl)piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione

[0331] 3-(1-methyl-6-(4-(2-(4-(3-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)ethyl)piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione. To a solution of (R)-2-(4-(3-(10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)acetaldehyde dihydrochloride (160 mg, 0.29 mmol) and 3-(1-methyl-6-piperazin-1-yl-indazol-3-yl)piperidine-2,6-dione; hydrochloride (125 mg, 0.34 mmol) in CHCl (2 mL) and DMSO (0.75 mL) was added DIPEA (0.4 mL, 2.29 mmol) under an inert atmosphere. The solution was stirred at room temperature for 10 min. Then, NaBH(OAc) (182 mg, 0.86 mmol) was added, and the reaction mixture was stirred at room temperature overnight. After removal of the solvent under vacuum, the residue was purified by reverse phase chromatography (RPC) using H2O (with 0.1% FA) and acetonitrile as mobile phase to give the product 3-(1-methyl-6-(4-(2-(4-(3-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)ethyl)piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione (69 mg, 30% yield) as a yellow solid. MS (ESI, m / z) [M+H] + 797.4 1H NMR(400MHz,DMSO-d6)δppm 10.85(s,1H),9.22(d,J=9.0Hz,1H),8.22(d,J=9.0Hz,1H),8.14(s,1H),8.08(d,J=4.2Hz,1H),8.02(d,J=9.0Hz,1H),7 .86(s,1H),7.63–7.74(m,1H),7.50(d,J=8.8Hz,1H),7.40(t,J=7.9Hz,1H),7.15(t,J=5.3Hz,1H),7.10(dd,J=8.1,2.0 Hz,1H),6.93(dd,J=8.9,1.8Hz,1H),6.85(d,J=1.5Hz,1H),4.26(dd,J=9.0,5.1Hz,1H),3.89(s,3H),3.58-3.68(m,1H) ,3.43–3.52(m,3H),3.22–3.26(m,5H),2.56–2.73(m,14H),2.27–2.37(m,1H),2.11–2.23(m,1H),1.20(d,J=6.8Hz,3H).

[0332] Example 13: Synthesis of 3-(4-(4-(2-(4-(3-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)-2-oxoacetyl)piperazin-1-yl)phenyl)piperidine-2,6-dione

[0333] (R)-2-(4-(3-(10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)-2-oxoacetic acid. A 20 mL vial equipped with a stir bar was charged with (R)-10-methyl-3-(3-(piperazin-1-yl)phenyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-8-one trifluoroacetate (100 mg, 0.18 mmol) and then DCM / DMSO (5 mL, 10:1) was added followed by DIPEA (125 μL, 0.72 mmol) and ethyl 2-chloro-2-oxoacetate (21 μL, 0.19 mmol). After LCMS analysis revealed the formation of the desired ethyl ester, the resulting mixture was allowed to stir at room temperature for 2 h. The reaction mixture was concentrated and lithium hydroxide (21.5 mg, 0.9 mmol) was added followed by THF / water (5 mL, 3:2). After stirring at room temperature for 1.0 h, the reaction mixture was concentrated under vacuum. The residue was purified by reverse phase chromatography (RPC) using H2O (with 0.1% TFA) and acetonitrile as mobile phase to give the product (R)-2-(4-(3-(10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)-2-oxoacetic acid trifluoroacetate (43 mg, 32% yield, 85% purity) as a red solid. MS (ESI, m / z) [M+H] + 516.2.

[0334] 3-(4-(4-(2-(4-(3-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)-2-oxoacetyl)piperazin-1-yl)phenyl)piperidine-2,6-dione. In a 2 dram vial, DMF (1.5 mL) was charged and then (R)-2-(4-(3-(10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)-2-oxoacetic acid (19.0 mg, 37 mmol), HATU (26.6 mg, 74 mmol), and 3-(4-(piperazin-1-yl)phenyl)piperidine-2,6-dione (11.2 mg, 41 mmol) were added. To the resulting mixture was added DIPEA (0.02 mL, 0.11 mmol), and the reaction was then allowed to stir at room temperature overnight. After the reaction mixture was filtered, the filtrate was purified by reverse phase chromatography (RPC) using H2O (with 0.05% TFA) and acetonitrile as mobile phase to give 3-(4-(4-(2-(4-(3-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)-2-oxoacetyl)piperazin-1-yl)phenyl)piperidine-2,6-dione (20.9 mg, 72% yield). MS (ESI, m / z) [M+H] + 771.4

[0335] Example 14: Synthesis of 3-(1-methyl-6-(4-(2-(4-(3-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)-2-oxoacetyl)piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione

[0336] 3-(1-methyl-6-(4-(2-(4-(3-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)-2-oxoacetyl)piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione. In a 2 dram vial, DMF (1.5 mL) was charged and then (R)-2-(4-(3-(10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)-2-oxoacetic acid (19.0 mg, 37 mmol), HATU (26.6 mg, 74 mmol), and 3-(1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione (13.4 mg, 41 mmol) were added. To the resulting mixture was added DIPEA (0.02 mL, 0.11 mmol), and the reaction was then allowed to stir at room temperature overnight. After the reaction mixture was filtered, the filtrate was purified by reverse phase chromatography (RPC) using H2O (with 0.05% TFA) and acetonitrile as mobile phase to give 3-(1-methyl-6-(4-(2-(4-(3-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)-2-oxoacetyl)piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione (17.9 mg, 59% yield). MS (ESI, m / z) [M+H] + 825.5.

[0337] Example 15: Synthesis of 3-(1-methyl-6-(4-(2-(3-(3-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)-3,6-diazabicyclo[3.1.1]hept-6-yl)ethyl)piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione

[0338] 3- (3- bromophenyl) -3,6- diazabicyclo [3.1.1] heptane -6- tert-butyl formate. To 3,6- diazabicyclo [3.1.1] heptane -6- tert-butyl formate (1.0g, 5.0mmol) and 1- bromo -3- iodo- benzene (2.1g, 7.6mmol) and Pd2 (dba) 3 (279.0mg, 0.25mmol) and XantPhos (241.0mg, 0.50mmol) in toluene (10.0mL) stirred solution, add t-BuONa (1.5g, 15.1mmol). The resulting solution is stirred at 60 DEG C for 3h under an inert atmosphere. After cooling to room temperature, the reaction mixture is diluted with water (300mL) and then extracted with ethyl acetate (100mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (2:1) as mobile phase to give tert-butyl 3-(3-bromophenyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (1.5 g, 84%) as a yellow solid. MS (ESI, m / z) [M+H] + 353.1

[0339] 3-(3-bromophenyl)-3,6-diazabicyclo[3.1.1]heptane. To a solution of tert-butyl 3-(3-bromophenyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (1.5 g, 4.25 mmol) in DCM (20.0 mL) was added TFA (10.0 mL). The resulting solution was stirred at room temperature for 2 h. After concentration under vacuum to remove the solvent, the crude product 3-(3-bromophenyl)-3,6-diazabicyclo[3.1.1]heptane (1.2 g) was obtained and used directly in the next step without further purification. MS (ESI, m / z) [M+H] + 253.2.

[0340] 3-(3-bromophenyl)-6-(2,2-dimethoxyethyl)-3,6-diazabicyclo[3.1.1]heptane. To a solution of 3-(3-bromophenyl)-3,6-diazabicyclo[3.1.1]heptane (1.2 g, 4.74 mmol) and 2,2-dimethoxyacetaldehyde (0.71 g, 6.85 mmol) in MeOH (5.0 mL) was added NaBHCN (896 mg, 14.229 mmol, 3.00 equiv). The resulting mixture was stirred at room temperature for 4 h. After concentration under vacuum to remove the solvent, the residue was purified by reverse phase silica gel flash chromatography with water (0.05% TFA) / MeCN (1:2) to give 3-(3-bromophenyl)-6-(2,2-dimethoxyethyl)-3,6-diazabicyclo[3.1.1]heptane (1.4 g, 90%) as a white solid. MS (ESI, m / z) [M+H] + 341.2.

[0341] 6-(2,2-dimethoxyethyl)-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3,6-diazabicyclo[3.1.1]heptane. To a solution of 3-(3-bromophenyl)-6-(2,2-dimethoxyethyl)-3,6-diazabicyclo[3.1.1]heptane (700.0 mg, 2.05 mmol), B2pin2 (628.0 mg, 2.47 mmol), and Pd(dppf)Cl2 (167.0 mg, 0.21 mmol) in 1,4-dioxane (10.0 mL) was added KOAc (605.0 mg, 6.16 mmol). The resulting solution was stirred at 80° C. under an inert atmosphere for 6 h. After cooling to room temperature, the reaction mixture was diluted with water (100.0 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layer was washed with brine (100 mL x 2). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel with dichloromethane / methanol (15: 1) to obtain 6- (2,2- dimethoxyethyl) -3- [3- (4,4,5,5- tetramethyl -1,3,2- dioxaborolane -2- bases) phenyl] -3,6- diazabicyclo [3.1.1] heptane (380 mg, 48%). MS (ESI, m / z) [M + H] +389.1 To a solution of 6-(2,2-dimethoxyethyl)-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3,6-diazabicyclo[3.1.1]heptane (350.0 mg, 0.90 mmol) and (R)-3-chloro-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazapipro[5',6':4,5]thieno[3,2-f]quinolin-8-one (200.0 mg, 0.63 mmol) and Pd(dtbpf)Cl2 (70.0 mg, 0.06 mmol) in 1,4-dioxane (5.0 mL) and water (1.0 mL) was added K3PO4 (268.0 mg, 1.26 mmol). The obtained solution is stirred at 90 DEG C under an inert atmosphere and spend the night.After being cooled to room temperature, reaction mixture is diluted with water (100mL) and extracted by ethyl acetate (100mL x 3).By the organic layer salt water (100mL x 2) washing merged, through anhydrous sodium sulfate drying, filter, and concentrate under vacuum.Residue is used H by reverse phase chromatography (RPC) o (with 0.05% TFA) and acetonitrile (MeCN) are purified as mobile phase to obtain (10R) -3- (3- (6- (2,2- dimethoxyethyl) -3,6- diazabicyclo [3.1.1] hept- 3- yl) phenyl) -10- methyl -9,10,11,12- tetrahydro -8H- [1,4] diaza quinoline and [5 ', 6 ': 4,5] thieno [3,2-f] quinoline -8- one (270mg, 79% yield) in red solid. MS (ESI, m / z) [M+H] + 544.2.

[0342] 2-(3-(3-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)-3,6-diazabicyclo[3.1.1]hept-6-yl)acetaldehyde. To a solution of (10R)-3-(3-(6-(2,2-dimethoxyethyl)-3,6-diazabicyclo[3.1.1]hept-3-yl)phenyl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-8-one (100.0 mg, 0.18 mmol) in 1,4-dioxane (1.0 mL) and water (0.50 mL) was added HCl (1.0 mL, 12.1 M). The resulting solution was stirred at 40° C. for 24 h. After concentration under vacuum, the crude product 2-(3-(3-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)-3,6-diazabicyclo[3.1.1]hept-6-yl)acetaldehyde (80.0 mg) was obtained and used in the next step without further purification. MS (ESI, m / z) [M+H] + 518.1.

[0343] 3-(1-methyl-6-(4-(2-(3-(3-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)-3,6-diazabicyclo[3.1.1]hept-6-yl)ethyl)piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione. To a solution of 2-(3-(3-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)-3,6-diazabicyclo[3.1.1]hept-6-yl)acetaldehyde (91.0 mg, 0.18 mmol) and 3-(1-methyl-6-piperazin-1-yl-indazol-3-yl)piperidine-2,6-dione (90.0 mg, 0.27 mmol) in methanol (5.0 mL) was added NaBHCN (34.0 mg, 0.54 mmol). The resulting solution was stirred at room temperature overnight. The reaction mixture was diluted with DMSO (1.0 mL) and purified by reverse phase chromatography (RPC) using H2O (with 0.05% TFA) and acetonitrile (MeCN) as mobile phase to give the desired product 3-(1-methyl-6-(4-(2-(3-(3-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)-3,6-diazabicyclo[3.1.1]hept-6-yl)ethyl)piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione (51.0 mg, 33% yield) as a red solid. MS (ESI, m / z) [M+H] + 810.1 1H NMR(400MHz,DMSO-d6)δppm 9.25(d,J=8.8Hz,1H),8.25(d,J=9.2Hz,1H),8.17(d,J=8.8Hz,1H),8.05(d,J=8.8Hz,1H) ,7.76(s,1H),7.67(d,J=7.6Hz,1H),7.60–7.49(m,2H),7.04–6.93(m,3H),4.72-4.63(m, 2H),4.28(s,1H),3.95-3.90(m,6H),3.65(d,J=6.8Hz,1H),3.52–3.39(m,13H),2.96–2.9 0(m,1H),2.72-2.62(m,3H),2.30-2.20(m,2H),2.17-2.11(m,2H),1.22(d,J=6.8Hz,3H).

[0344] Example 16: Synthesis of 3-(4-(4-(2-(4-(3-((R)-10-methyl-8-oxo-8,9,10,11-tetrahydro-[1,4]oxazepino[7',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6-dione

[0345] 1- (3-bromophenyl) -4- (2,2-dimethoxyethyl) piperazine. To a solution of NaBH3CN (398 mg, 6.2 mmol) in methanol (10.0 mL) was added ZnCl2 (1.9 M, 7.9 mL, 2.1 mmol) in THF. After the mixture was stirred at room temperature for 10 min, 1- (3-bromophenyl) piperazine (500 mg, 2.1 mmol) and 2,2-dimethoxyacetaldehyde (431 mg, 4.2 mmol) were added. The resulting solution was stirred at room temperature overnight. LCMS showed that the reaction was complete. The resulting solution was then concentrated under vacuum. The residue was purified by reverse phase column chromatography (0% to 10% MeCN in water (containing 0.1% TFA)) to give 1- (3-bromophenyl) -4- (2,2-dimethoxyethyl) piperazine (550 mg, 80%) as an off-white solid. MS (ESI, m / z) [M + H] + 329.4.

[0346] 1-(2,2-dimethoxyethyl)-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine. To a solution of 1-(3-bromophenyl)-4-(2,2-dimethoxyethyl)piperazine (550 mg, 1.7 mmol) in 1,4-dioxane (10 mL) was added B2pin2 (636 mg, 2.5 mmol), Pd(dppf)Cl2 (68 mg, 0.08 mmol) and KOAc (491 mg, 5.1 mmol). The resulting solution was stirred at 100 ° C under a nitrogen atmosphere overnight. LCMS showed that the reaction was complete. The resulting solution was diluted with water (50.0 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography with ethyl acetate / petroleum ether (1:1) to give 1-(2,2-dimethoxyethyl)-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine (370 mg, 59%) as a yellow solid. MS (ESI, m / z) [M+H] + 377.3.

[0347] (R)-tert-Butyl 3-(3-(4-(2,2-dimethoxyethyl)piperazin-1-yl)phenyl)-10-methyl-8-oxo-10,11-dihydro-[1,4]oxazepino[7',6':4,5]thieno[3,2-f]quinoline-9(8H)-carboxylate. To a solution of 1-(2,2-dimethoxyethyl)-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine (100 mg, 0.27 mmol) in 1,4-dioxane (3.0 mL) and water (0.5 mL) was added (R)-tert-butyl 3-chloro-10-methyl-8-oxo-10,11-dihydro-[1,4]oxazepino[7',6':4,5]thieno[3,2-f]quinoline-9(8H)-carboxylate (166 mg, 0.398 mmol), Pd(PPh3)4 (31 mg, 0.027 mmol), and K2CO3 (110 mg, 0.80 mmol). The resulting solution was stirred at 100° C. under a nitrogen atmosphere overnight. LCMS showed the reaction was complete. The resulting solution was diluted with water (50.0 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography with ethyl acetate / petroleum ether (1: 1) to give (R)-3-(3-(4-(2,2-dimethoxyethyl)piperazine-1-yl)phenyl)-10-methyl-8-oxo-10,11-dihydro-[1,4]oxazepine[7',6':4,5]thieno[3,2-f]quinoline-9(8H)-carboxylic acid tert-butyl ester (100 mg, 60% yield) as a yellow solid. MS (ESI, m / z) [M+H] + 633.2.

[0348] (R)-tert-Butyl 10-methyl-8-oxo-3-(3-(4-(2-oxoethyl)piperazin-1-yl)phenyl)-10,11-dihydro-[1,4]oxazepino[7',6':4,5]thieno[3,2-f]quinoline-9(8H)-carboxylate. To a solution of tert-butyl (R)-3-(3-(4-(2,2-dimethoxyethyl)piperazin-1-yl)phenyl)-10-methyl-8-oxo-10,11-dihydro-[1,4]oxazepino[7',6':4,5]thieno[3,2-f]quinoline-9(8H)-carboxylate (100 mg, 0.16 mmol) in 1,4-dioxane (5.0 mL) was added 4M HCl(aq) (10 mL). The resulting solution was stirred at 40°C for 2 h. LCMS analysis showed that the reaction was complete. The resulting solution was concentrated under vacuum to give crude (R)-10-methyl-8-oxo-3-(3-(4-(2-oxoethyl)piperazin-1-yl)phenyl)-10,11-dihydro-[1,4]oxazepino[7',6':4,5]thieno[3,2-f]quinoline-9(8H)-carboxylic acid tert-butyl ester (80 mg). MS (ESI, m / z) [M+H] + 487.1.

[0349] 3-(4-(4-(2-(4-(3-((R)-10-methyl-8-oxo-8,9,10,11-tetrahydro-[1,4]oxazepino[7',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6-dione. In a 20 mL vial with (R)-2-(4-(3-(10-methyl-8-oxo-8,9,10,11-tetrahydro-[1,4]oxazepino[7',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)acetaldehyde in crude form (33.2 mg, 68 mmol), 1,2-dichloroethane (2 mL) and THF (1.0 mL) were charged to the vial. To the mixture was added DIPEA (0.034 mL, 0.194 mmol), 3-(4-(piperazin-1-yl)phenyl)piperidine-2,6-dione (0.311 mL, 78 mmol), and NaBH(OAc) (0.518 mL, 0.5 M in THF). The resulting mixture was stirred at room temperature overnight. After adding additional NaBH(OAc) (0.272 mL, 0.5 M in THF), the reaction was continuously stirred and heated at 50° C. for 4.0 h. After removal of the solvent, the residue was dissolved in 2.0 mL of DMSO and purified by reverse phase chromatography (RPC) using H 2 O (with 0.1% formic acid) and acetonitrile as mobile phases to give the desired product, 3-(4-(4-(2-(4-(3-((R)-10-methyl-8-oxo-8,9,10,11-tetrahydro-[1,4]oxazepino[7′,6′:4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6-dione, formate salt (4.0 mg, 7.4% yield) as a light yellow solid. MS (ESI, m / z) [M+H] + 744.5.

[0350] Example 17: Synthesis of 3-(1-methyl-6-(4-(2-(4-(3-((R)-10-methyl-8-oxo-8,9,10,11-tetrahydro-[1,4]oxazepino[7',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)ethyl)piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione

[0351] 3-(1-methyl-6-(4-(2-(4-(3-((R)-10-methyl-8-oxo-8,9,10,11-tetrahydro-[1,4]oxazepino[7',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)ethyl)piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione. To a solution of 3-(1-methyl-6-piperazin-1-yl-indazol-3-yl)piperidine-2,6-dione (67 mg, 0.21 mmol) in DCM (5.0 mL) was added TEA until the pH of the solution reached 9-10. Then, (R)-10-methyl-8-oxo-3-(3-(4-(2-oxoethyl)piperazin-1-yl)phenyl)-10,11-dihydro-[1,4]oxazepino[7',6':4,5]thieno[3,2-f]quinoline-9(8H)-carboxylic acid tert-butyl ester (80 mg, 0.16 mmol) was added to the solution. The pH of the solution was then adjusted to 5-6 with HOAc, and NaBH(OAc) (130 mg, 0.62 mmol) was then added and the resulting solution was stirred at room temperature for 2 h. LCMS showed that the reaction was complete. After concentration to remove the solvent under vacuum, the residue was purified by reverse phase chromatography (RPC) using H2O with 0.05% TFA and acetonitrile with 0.05% TFA as mobile phase to give the product 3-(1-methyl-6-(4-(2-(4-(3-((R)-10-methyl-8-oxo-8,9,10,11-tetrahydro-[1,4]oxazepino[7',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)ethyl)piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione as an orange solid (33.9 mg, 20% yield). MS (ESI) [M+H] + 798. 1 H NMR (400MHz, DMSO-d6): δppm 9.35(d,J=8.8Hz,1H),8.29–8.22(m,2H),8.10(d,J=9.2Hz,1H),7.91(s,1H),7.77 (d,J=7.2Hz,1H),7.58(d,J=9.2Hz,1H),7.49(t,J=8.0Hz,1H),7.21(d,J=8.0Hz,1 H), 7.00 (d, J = 6.4 Hz, 1H), 4.62 (s, 2H), 4.30–4.27 (m, 1H), 3.92 (s, 3H), 3.87 (s, 1H), 3.80–3.50 (m, 18H), 2.80–2.50 (m, 4H), 2.38–2.10 (m, 2H), 1.30 (d, J = 6.4 Hz, 3H). Three protons were not observed.19 F NMR (376MHz, DMSO-d6): δppm-74.41.

[0352] Example 18: Synthesis of 3-(4-(4-(2-(4-(3-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6-dione

[0353] (R)-10-methyl-3-(3-(piperidin-4-yl)phenyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-8-one tert-butyl 4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine-1-carboxylate (145 mg, 0.38 mmol), (R)-3-chloro-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepine [5',6':4,5]thieno [3,2-f]quinoline-8-one (100 mg, 0.31 mmol), cesium carbonate (306 mg, 0.94 mmol) and Pd(dppf)Cl2 (23 mg, 0.03 mmol) were weighed into a 20 mL vial with a stirring bar. The vial was evacuated and refilled three times with nitrogen, and then 1,4-dioxane (3.1 mL) and water (0.3 mL) were added to the vial. The reaction was then heated at 100 ° C for 2 h. LCMS analysis revealed that the reaction was complete. The reaction was then diluted with EtOAc, washed with saturated NaHCO3 aqueous solution and the water layer was extracted with EtOAc (x 3). The collected organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by normal phase column chromatography (0 to 10% MeOH in DCM). The collected fractions were concentrated, and the residue was dissolved in 4:1 DCM / TFA and stirred at room temperature for 1.5 h. LCMS indicated that the deprotection was complete. After removing the solvent under vacuum, the residue was purified by reverse phase chromatography (RPC) using H2O with 0.05% TFA and acetonitrile with 0.05% TFA as mobile phases to obtain (R)-3-(3-(4-(2,2-dimethoxyethyl)piperazin-1-yl)phenyl)-10-methyl-8-oxo-10,11-dihydro-[1,4]oxazepine[7',6':4,5]thieno[3,2-f]quinoline-9(8H)-carboxylic acid tert-butyl ester (151 mg, 86% yield). MS (ESI, m / z) [M+H] + 443.4.

[0354] (R)-3-(3-(1-(2,2-dimethoxyethyl)piperidin-4-yl)phenyl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-8-one. To a solution of (R)-10-methyl-3-(3-(piperidin-4-yl)phenyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-8-one-trifluoroacetic acid (349.4 mg, 0.63 mmol) in DCM (5.0 mL) was added DIPEA (0.55 mL, 3.14 mmol) and then 2,2-dimethoxyacetaldehyde (0.11 mL, 0.75 mmol) and NaBH(OAc) (332.6 mg, 1.57 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h and the solvent was then evaporated under vacuum. The crude product was purified by reverse phase chromatography (RPC) using H2O (with 0.1% formic acid (FA) and methanol as mobile phase to give the desired product (262.0 mg, 79% yield) as a yellow solid. MS (ESI, m / z) [M+H] + 531.2.

[0355] (R)-2-(4-(3-(10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperidin-1-yl)ethanal. To a solution of (R)-3-(3-(1-(2,2-dimethoxyethyl)piperidin-4-yl)phenyl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-8-one (260.0 mg, 0.49 mmol) in 1,4-dioxane (2.0 mL) was added water (0.25 mL) and HCl (3.0 mL, 12.3 mmol) at room temperature. The reaction mixture was heated at 40 ° C for 2 h and then stirred continuously at room temperature overnight. After removing the solvent under vacuum, the residue was further evaporated with MeCN (5.0 mL) and DCM (5.0 mL) to give a crude product (280.0 mg) as a red solid, which was used in the next step reaction without further purification. MS (ESI, m / z) [M + H] + 485.2

[0356] 3-(4-(4-(2-(4-(3-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6-dione. Under inert atmosphere, to a solution of (R)-2-(4-(3-(10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperidin-1-yl)acetaldehyde hydrochloride (140.0 mg, 0.27 mmol) and 3-(4-piperazin-1-ylphenyl)piperidine-2,6-dione; dihydrochloride (102.3 mg, 0.30 mmol) in DCM (1.5 mL) and DMSO (0.5 mL) was added DIPEA (0.33 mL, 1.88 mmol) and the resulting mixture was stirred at room temperature for 10 min. After the addition of NaBH(OAc)3 (142.4 mg, 0.67 mmol), the reaction mixture was stirred at room temperature overnight. The solvent was evaporated under vacuum and the crude product was purified by reverse phase chromatography (RPC) using water (with 0.1% formic acid) and acetonitrile (MeCN) as mobile phase to give the desired product (49.5 mg, 24% yield) as a yellow solid. MS (ESI, m / z) [M+H] + 742.4. 1 H NMR (400MHz, DMSO-d6) δppm 1.20 (d, J=6.6Hz, 3H), 1.72-1.88 (m, 4H), 1.96-2.06 (m, 1H), 2.08-2.22 (m, 3H), 2.44 (br d,J=4.4Hz,1H),2.53-2.69(m,10H),3.07-3.13(m,6H),3.48(br s,2H),3.61(dt,J=7.0,3.6Hz,1H),3.73(dd,J=11.0,4.9Hz,1H),6.89(d,J=8.8 Hz,2H),7.05(d,J=8.8Hz,2H),7.16(t,J=5.1Hz,1H),7.40(d,J=7.8Hz,1H),7.47 -7.52(m,1H),8.01-8.06(m,1H),8.08(d,J=4.2Hz,1H),8.10-8.15(m,2H),8.17 (s,1H),8.19(s,1H),8.25(d,J=9.0Hz,1H),9.23(d,J=8.8Hz,1H),10.77(s,1H).

[0357] Example 19: Synthesis of 3-(1-methyl-6-(4-(2-(4-(3-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperidin-1-yl)ethyl)piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione

[0358] 3-(1-methyl-6-(4-(2-(4-(3-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperidin-1-yl)ethyl)piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione. Under inert atmosphere, to a solution of (R)-2-(4-(3-(10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperidin-1-yl)acetaldehyde hydrochloride (140.0 mg, 0.27 mmol) and 3-(1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione dihydrochloride (102.3 mg, 0.30 mmol) in DCM (1.5 mL) were added DMSO (0.50 mL) and DIPEA (0.33 mL, 1.88 mmol). After stirring at room temperature for 10 min, NaBH (OAc) 3 (142.4 mg, 0.67 mmol) was added and the resulting mixture was continuously stirred at room temperature overnight. The solvent was evaporated under vacuum and the crude product was purified by reverse phase chromatography (RPC) using water with 0.1% formic acid and acetonitrile with 0.1% formic acid as mobile phases to give the desired product (64 mg, 43.1% yield) as a yellow solid. MS (ESI, m / z) [M + H] + 796.4. 1H NMR (400MHz, DMSO-d6) δppm 1.20 (d, J=6.6Hz, 3H), 1.74-1.89 (m, 4H), 2.13-2.24 (m, 3H), 2.25-2.34 (m, 1H), 2.55-2.68 (m, 11H), 3.12 (br d,J=11.5Hz,2H),3.22-3.25(m,4H),3.48(br d,J=4.4Hz,2H),3.62(td,J=7.2,3.4Hz,1H),3.89(s,3H),4.26(dd,J=9.3,5.1Hz,1H),6. 85(d,J=1.7Hz,1H),6.93(dd,J=9.0,1.7Hz,1H),7.16(t,J=5.3Hz,1H),7.40(d,J=7.8Hz, 1H),7.47-7.53(m,2H),8.03(d,J=9.0Hz,1H),8.08(d,J=4.2Hz,1H),8.10-8.15(m,2H),8 .16(s,1H),8.19-8.22(m,1H),8.25(d,J=9.0Hz,1H),9.23(d,J=9.0Hz,1H),10.85(s,1H).

[0359] Example 20: Synthesis of 3-(4-(1-(2-(4-(4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)ethyl)piperidin-4-yl)phenyl)piperidine-2,6-dione

[0360] (R)-10-methyl-3-(4-(piperazin-1-yl)phenyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-8-one. tert-Butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine-1-carboxylate (147 mg, 0.38 mmol), (R)-3-chloro-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-8-one (100 mg, 0.31 mmol), cesium carbonate (307 mg, 0.94 mmol) and Pd(dppf)Cl2 (35 mg, 0.05 mmol) were charged into a 20 mL vial with a stir bar. The vial was sealed and evacuated and refilled with nitrogen three times, and then 1,4-dioxane (3 mL) and water (0.3 mL) were added. The resulting mixture was stirred and heated at 100°C overnight. In 40mL 4- (piperazine -1- bases) phenyl) -9,10,11,12- tetrahydrochysene -8H- [1,4] diazepine [5 ', 6 ': 4,5] thieno [3,2-f] quinoline -8- one (60mg, 43% yield) in 4:1DCM: TFA.After being cooled to room temperature, reaction is diluted with EtOAc and water layer is extracted with EtOAc (20mL x 3).Organic layer is dried over sodium sulfate, filtered, and concentrated.Residue is passed through silica gel column chromatography (0% to 5% MeOH in DCM) purifying to obtain desired product, it is further converted into TFA salt by being stirred at room temperature for 1h in 4:1DCM: TFA.After removing solvent, residue is passed through reverse phase chromatography (RPC) using water (with 0.1% formic acid (FA)) and acetonitrile (MeCN) as mobile phase to purify to obtain desired product (R) -10- methyl -3- (4- (piperazine -1- bases) phenyl) -9,10,11,12- tetrahydrochysene -8H- [1,4] diazepine [5 ', 6 ': 4,5] thieno [3,2-f] quinoline -8- one (60mg, 43% yield) in orange solid. MS (ESI, m / z) [M+H] + 444.5.

[0361] (R)-3-(4-(4-(2,2-dimethoxyethyl)piperazin-1-yl)phenyl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-8-one. To a solution of (R)-10-methyl-3-(4-(piperazin-1-yl)phenyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-8-one dihydrochloride (120 mg, 0.23 mmol, 1.0 equiv) and DIPEA (0.2 mL, 1.2 mmol) in CHCl (3 mL) and DMSO (1 mL) was added 2,2-dimethoxyacetaldehyde (42 μL, 0.28 mmol) and NaBH(OAc) (148 mg, 0.70 mmol) at room temperature. The mixture was stirred at room temperature overnight. LCMS showed the reaction was complete. The reaction mixture was concentrated under vacuum, and the residue was purified by reverse phase column chromatography (0% to 100% MeOH in water (containing 0.1% formic acid)) to give the product (R)-10-methyl-3-(4-(piperazin-1-yl)phenyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-8-one (113 mg, 86% yield) as a red solid. MS (ESI, m / z) [M+2H] 2+ 266.8.

[0362] (R)-2-(4-(4-(10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)acetaldehyde. To a round-bottom flask containing (R)-10-methyl-3-(4-(piperazin-1-yl)phenyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-8-one (160 mg, 0.30 mmol) was added water (0.3 mL) and 4M HCl in 1,4-dioxane (1.1 mL, 4.5 mmol) at room temperature. The mixture was stirred at 50° C. After 5 h, LCMS showed the reaction was complete. After removing the solvent under vacuum, the residue was washed with MeCN and dried under vacuum to give (R)-2-(4-(4-(10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)acetaldehyde hydrochloride (160 mg, quantitative) as a yellow solid. MS (ESI, m / z) [M+2H]2+ 243.8.

[0363] 3-(4-(1-(2-(4-(4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)ethyl)piperidin-4-yl)phenyl)piperidine-2,6-dione. To (R)-2-(4-(4-(10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)acetaldehyde (80.0 mg, 0.17 mmol) in methanol (1.0 mL) was added 3-[4-(4-piperidinyl)phenyl]piperidine-2,6-dione (67 mg, 0.25 mmol) and NaBHCN (20 mg, 0.33 mmol). The resulting solution was stirred at room temperature for 18 h. LCMS showed the reaction was complete. The resulting solution was concentrated under vacuum and the residue was purified by reverse phase chromatography (RPC) using water (with 0.05% trifluoroacetic acid (TFA)) and acetonitrile (MeCN) as mobile phase to give 3-(4-(1-(2-(4-(4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)ethyl)piperidin-4-yl)phenyl)piperidine-2,6-dione as a red solid (2.5 mg, 2.0% yield). MS (ESI, m / z) [M+H] + 742. 1 H NMR(400MHz,DMSO-d6)δppm 9.30–9.20(m,1H),8.30–8.15(m,4H),8.13–7.99(m,1H),7.32–7.15(m,6H),3.76–3.74(m,3H),3.65–3.58(m,7H),3.56–3.40(m,3H), 3.39–3.25(m,5H),3.24–3.16(m,3H),2.99–2.80(m,2H),2.71–2.69(m,1H),2.21–2.01(m,5H),1.97–1.90(m,1H),1.22–1.20(m,3H). 19 F NMR (376MHz, DMSO-d6) δ-74.53.

[0364] Example 21: Synthesis of 3-(1-methyl-6-(4-(2-(4-(4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)ethyl)piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione

[0365] 3-(1-methyl-6-(4-(2-(4-(4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)ethyl)piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione. To a suspension of (R)-2-(4-(4-(10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)acetaldehyde hydrochloride (155 mg, 0.3 mmol) and DIPEA (360 μL, 2.1 mmol) in CHCl (2.3 mL) and DMSO (0.8 mL) at room temperature was added 3-(1-methyl-6-piperazin-1-yl-indazol-3-yl)piperidine-2,6-dione hydrochloride (119 mg, 0.33 mmol) and NaBH(OAc) (130 mg, 0.6 mmol). The reaction was then stirred at room temperature overnight. After removal of the solvent under vacuum, the residue was purified by reverse phase column chromatography (0% to 100% MeCN in water with 0.1% formic acid) to give 3-(1-methyl-6-(4-(2-(4-(4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)ethyl)piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione as a yellow solid (22 mg, 9% yield). MS (ESI, m / z) [M+H] + 797.3. 1H NMR(400MHz,DMSO-d6)δppm 10.85(s,1H),9.15(d,J=9.0Hz,1H),8.19(d,J=9.0Hz,2H),8.14(d,J=9.3Hz,1H),8.04 -8.11(m,2H),7.96(d,J=9.0Hz,1H),7.50(d,J=8.8Hz,1H),7.06-7.15(m,3H),6.93(br d,J=8.6Hz,1H),6.85(s,1H),4.26(dd,J=9.0,4.9Hz,1H),3.89(s,3H),3.57-3.65(m,1H),3.44-3.50(m,2H),3.20 -3.25(m,4H),2.58-2.65(m,10H),2.53-2.58(m,4H),2.24-2.32(m,1H),2.10-2.20(m,1H),1.20(d,J=6.6Hz,3H).

[0366] Example 22: Synthesis of 3-(4-(4-(2-(4-(4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6-dione

[0367] 3-(4-(4-(2-(4-(4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6-dione. To a suspension of (R)-2-(4-(4-(10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)acetaldehyde hydrochloride (160 mg, 0.31 mmol) and DIPEA (370 μL, 2.15 mmol) in CHCl (1.5 mL) and DMSO (0.5 mL) at room temperature were added 3-(4-piperazin-1-ylphenyl)piperidine-2,6-dione dihydrochloride (117 mg, 0.34 mmol) and NaBH(OAc) (130 mg, 0.61 mmol). The reaction was then stirred at room temperature overnight. After removal of the solvent under vacuum, the residue was purified by reverse phase column chromatography (0% to 100% MeCN in water with 0.1% formic acid) to give the product 3-(4-(4-(2-(4-(4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6-dione as a yellow solid (37 mg, 16% yield). MS (ESI, m / z) [M+H] + 743.3. 1 H NMR(400MHz,DMSO-d6)δppm 10.77(s,1H),9.14(d,J=9.0Hz,1H),8.19(d,J=8.8Hz,2H),8.03-8.16(m,3H),7.95(d,J=8.8Hz,1H) ,7.02-7.13(m,5H),6.89(d,J=8.6Hz,2H),3.72(dd,J=10.9,4.8Hz,1H),3.57-3.65(m,1H),3.47(br s,2H),3.25-3.28(m,3H),3.08-3.15(m,4H),2.55-2.64(m,9H),2.54(s,4H),2 .42-2.47(m,2H),2.08-2.20(m,1H),1.96-2.05(m,1H),1.20(d,J=6.6Hz,3H).

[0368] Example 23: Synthesis of 3-(4-(4-(2-(4-(4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)-2-oxoacetyl)piperazin-1-yl)phenyl)piperidine-2,6-dione

[0369] (R)-2-(4-(4-(10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)-2-oxoacetic acid. A 20 mL vial equipped with a stir bar was charged with (R)-10-methyl-3-(3-(piperazin-1-yl)phenyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-8-one trifluoroacetate (100 mg, 0.18 mmol). Then DCM / DMSO (5mL, 10: 1) was added, followed by DIPEA (125 μL, 0.72mmol) and ethyl 2-chloro-2-oxoacetate (21 μL, 0.19mmol). The resulting reaction was allowed to stir at room temperature for 2h, and LCMS indicated that the reaction was complete. The reaction mixture was concentrated under vacuum, and lithium hydroxide (21.5mg, 0.9mmol) was then added, followed by THF / water (5mL, 3:2) and stirred for 1.0h. After removal of the solvent, the residue was purified by reverse phase column chromatography (0% to 100% MeCN in water with 0.1% TFA) to give the product (R)-2-(4-(3-(10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)-2-oxoacetic acid trifluoroacetate as a red solid.

[0370] 3-(4-(4-(2-(4-(4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)-2-oxoacetyl)piperazin-1-yl)phenyl)piperidine-2,6-dione. In a 2-dram vial, DMF (1.5 mL) was charged followed by (R)-2-(4-(4-(10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)-2-oxoacetic acid (8.8 mg, 0.017 mmol) and HATU (0.068 mL, 0.034 mmol). To the resulting mixture was added 3-(4-(piperazin-1-yl)phenyl)piperidine-2,6-dione (0.075 mL, 0.019 mmol). After the addition of DIPEA (8.9 μl, 0.05 mmol), the reaction mixture was allowed to stir at room temperature overnight. After the reaction mixture was filtered, the filtrate was purified by reverse phase chromatography (RPC) using H2O and acetonitrile (both with 0.05% TFA) as mobile phase to give 3-(4-(4-(2-(4-(4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)-2-oxoacetyl)piperazin-1-yl)phenyl)piperidine-2,6-dione (3.0 mg, 24% yield). LCMS Method 4: MS (ESI, m / z) [M+H] + 771.5,rt:1.21min.

[0371] Example 24: Synthesis of 3-(4-(4-(2-(3-(4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)-3,6-diazabicyclo[3.1.1]hept-6-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6-dione

[0372] 3- (4- bromophenyl) -3,6- diazabicyclo [3.1.1] heptane -6- tert-butyl formate. To a solution of 3,6- diazabicyclo [3.1.1] heptane -6- tert-butyl formate (1.0 g, 5.0 mmol), 1- bromo -4- iodo- benzene (2.1 g, 7.6 mmol) and t-BuONa (968.0 mg, 10.1 mmol) in toluene (15.0 mL), XantPhos (258 mg, 0.5 mmol) and Pd (dba) (520.0 mg, 0.5 mmol) were added. The resulting solution was stirred at 60 ° C for 18 h under a nitrogen atmosphere. LCMS shows that the reaction is complete. The reaction is diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layer is washed with salt water (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography using ethyl acetate / petroleum ether (1:4) to give the desired product, tert-butyl 3-(4-bromophenyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (1.6 g, 90.0%) as a yellow solid. MS (ESI, m / z) [M+H] + 353.2.

[0373] 3- (4- bromophenyl) -3,6-diazabicyclo [3.1.1] heptane. To a solution of tert-butyl 3- (4- bromophenyl) -3,6-diazabicyclo [3.1.1] heptane-6-carboxylate (1.6 g, 4.5 mmol) in DCM (30.0 mL) was added TFA (10.0 mL) dropwise. The resulting solution was stirred at room temperature for 1 h. LCMS showed that the reaction was complete. The resulting solution was concentrated under vacuum. The residue was purified by reverse phase silica gel flash chromatography with water (0.05% TFA) / MeCN (1: 1) to give 3- (4- bromophenyl) -3,6-diazabicyclo [3.1.1] heptane (1.1 g, 96.0%) as a white solid. MS (ESI, m / z) [M + H] + 254.1.

[0374] 3-(4-bromophenyl)-6-(2,2-dimethoxyethyl)-3,6-diazabicyclo[3.1.1]heptane. To a solution of 3-(4-bromophenyl)-3,6-diazabicyclo[3.1.1]heptane (1.0 g, 4.0 mmol) in methanol (20.0 mL) was added 2,2-dimethoxyacetaldehyde (1.2 g, 11.9 mmol) and NaBH3CN (756.0 mg, 11.9 mmol). The resulting solution was stirred at room temperature for 18 h. LCMS showed that the reaction was complete. The resulting solution was concentrated under vacuum, and the residue was purified by reverse phase silica gel flash chromatography with water (0.05% TFA) / MeCN (1:1) to give the desired product, 3-(4-bromophenyl)-6-(2,2-dimethoxyethyl)-3,6-diazabicyclo[3.1.1]heptane (1.3 g, 96%), as a yellow oil. MS (ESI, m / z) [M+H] + 341.3.

[0375] (10R)-3-(4-(6-(2,2-dimethoxyethyl)-3,6-diazabicyclo[3.1.1]hept-3-yl)phenyl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazapizo[5',6':4,5]thieno[3,2-f]quinolin-8-one. To a solution of 3-(4-bromophenyl)-6-(2,2-dimethoxyethyl)-3,6-diazabicyclo[3.1.1]heptane (200.0 mg, 0.6 mmol), (R)-10-methyl-3-(tributylstannyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-8-one (503.0 mg, 0.9 mmol) in 1,4-dioxane (10.0 mL) was added XPhos Pd G3 (50.0 mg, 0.05 mmol) and XPhos (50 mg, 0.10 mmol). The resulting solution was stirred at 90 ° C. under a nitrogen atmosphere for 5 h. LCMS showed that the reaction was complete. The resulting solution was concentrated under vacuum, and the residue was purified by reverse phase silica gel flash chromatography with water (0.05% TFA) / MeCN (3:2) to give the desired product (10R)-3-(4-(6-(2,2-dimethoxyethyl)-3,6-diazabicyclo[3.1.1]hept-3-yl)phenyl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazapizo[5',6':4,5]thieno[3,2-f]quinolin-8-one (180.0 mg, 56.0%) as a red solid. MS (ESI, m / z) [M+H] + 544.1.

[0376] 2-(3-(4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)-3,6-diazabicyclo[3.1.1]hept-6-yl)acetaldehyde. To a solution of (10R)-3-(4-(6-(2,2-dimethoxyethyl)-3,6-diazabicyclo[3.1.1]hept-3-yl)phenyl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-8-one (90 mg, 0.170 mmol, 1.00 equiv) in 1,4-dioxane (2.0 mL) and water (1.0 mL) was added 4 M HCl in 1,4-dioxane (2.0 mL). The resulting solution was stirred at 40 °C for 18 h. LCMS showed the reaction was complete. The resulting solution was concentrated under vacuum to give the crude product, which was used directly in the next step without further purification. MS (ESI, m / z) [M+H+18] + 544.

[0377] 3-(4-(4-(2-(3-(4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)-3,6-diazabicyclo[3.1.1]hept-6-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6-dione. To a solution of 3-(4-piperazin-1-ylphenyl)piperidine-2,6-dione (49.0 mg, 0.18 mmol) in methanol (3.0 mL) was added 2-(3-(4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)-3,6-diazabicyclo[3.1.1]hept-6-yl)acetaldehyde (90.0 mg, 0.18 mmol) and NaBHCN (34.0 mg, 0.5 mmol). The resulting solution was stirred at room temperature for 5 h and then concentrated under vacuum. The residue was dissolved in DMSO (2.0 mL) and filtered, and the filtrate was purified by reverse phase chromatography (RPC) using water and acetonitrile (MeCN) (both with 0.05% trifluoroacetic acid) as mobile phases to give the desired product 3-(4-(4-(2-(3-(4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)-3,6-diazabicyclo[3.1.1]hept-6-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6-dione (46.0 mg, 32.0%) as a red solid. MS (ESI, m / z) [M+H] + 755. 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.25(d,J=9.2Hz,1H),8.26(d,J=8.0Hz,2H),8.26–8.17(m,2H),8.04(d,J=9 .2Hz,1H),7.10(d,J=8.0Hz,2H),7.00(d,J=9.2Hz,2H),4.69–4.54(m,2H),4. 17–3.84(m,5H),3.82–3.73(m,1H),3.57–3.21(m,15H),2.72–2.61(m,1H),2. 49–2.42(m,1H),2.18–2.05(m,2H),2.06–1.96(m,1H),1.16(d,J=6.8Hz,3H). 19 F NMR (376MHz, DMSO-d6) δ-74.28.

[0378] Example 25: Synthesis of 3-(4-(4-(2-(4-(4-((R)-10-methyl-8-oxo-8,9,10,11-tetrahydro-[1,4]oxazepino[7',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6-dione

[0379] 1- (4- bromophenyl) -4- (2,2- dimethoxyethyl) piperazine. To a solution of NaBH3CN (796 mg, 12.44 mmol) in methanol (10.0 mL) was added 1.9 M ZnCl2 (15.8 mL, 4.14 mmol) in THF. The mixture was stirred at room temperature for 10 min. 1- (4- bromophenyl) piperazine (1.0 g, 4.14 mmol) and 2,2- dimethoxyacetaldehyde (520 mg, 5.01 mmol) were added to the solution. The resulting solution was stirred at room temperature overnight. LCMS showed that the reaction was complete. The resulting product was concentrated under vacuum. The residue was purified by reverse phase flash chromatography with water (0.05% TFA) / MeCN (2: 3) to give 1- (4- bromophenyl) -4- (2,2- dimethoxyethyl) piperazine (1.1 g, 80%) as a colorless oil. LCMS (ESI, m / z) [M+H] + 329.1

[0380] 1-(2,2-dimethoxyethyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine. To a solution of 1-(4-bromophenyl)-4-(2,2-dimethoxyethyl)piperazine (550 mg, 1.67 mmol) in 1,4-dioxane (10.0 mL) was added B2pin2 (636 mg, 2.50 mmol), Pd(dppf)Cl2 (136 mg, 0.167 mmol) and KOAc (491 mg, 5.01 mmol). The resulting solution was stirred at 100 ° C under vacuum overnight. LCMS showed that the reaction was complete. The resulting solution was diluted with water (50.0 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography using ethyl acetate / petroleum ether (1:1) to give 1-(2,2-dimethoxyethyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine (370 mg, 59%) as a yellow solid. LCMS (ESI, m / z) [M+H] + 377.

[0381] (R)-3-(4-(4-(2,2-dimethoxyethyl)piperazin-1-yl)phenyl)-10-methyl-10,11-dihydro-[1,4]oxazepino[7',6':4,5]thieno[3,2-f]quinolin-8(9H)-one. To a solution of 1-(2,2-dimethoxyethyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine (100 mg, 0.265 mmol) in 1,4-dioxane (3.0 mL) and water (0.5 mL) was added (R)-3-(4-chlorophenyl)-10-methyl-10,11-dihydro-[1,4]oxazepino[7',6':4,5]thieno[3,2-f]quinolin-8(9H)-one (166 mg, 0.398 mmol), Pd(PPh3)4 (31 mg, 0.027 mmol), and K2CO3 (110 mg, 0.795 mmol). The resulting solution was stirred at 100° C. overnight. LCMS showed the reaction was complete. The resulting solution was diluted with water (50.0 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography using ethyl acetate / petroleum ether (2: 1) to give (R)-3-(4-(4-(2,2-dimethoxyethyl)piperazin-1-yl)phenyl)-10-methyl-8-oxo-10,11-dihydro-[1,4]oxazepine[7',6':4,5]thieno[3,2-f]quinoline-9(8H)-carboxylic acid tert-butyl ester (100 mg, 60%) as a yellow solid. LCMS (ESI, m / z) [M+H] + 633.1.

[0382] (R)-2-(4-(4-(10-methyl-8-oxo-8,9,10,11-tetrahydro-[1,4]oxazepino[7',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)acetaldehyde. To a solution of tert-butyl (R)-3-(4-(4-(2,2-dimethoxyethyl)piperazin-1-yl)phenyl)-10-methyl-8-oxo-10,11-dihydro-[1,4]oxazepino[7',6':4,5]thieno[3,2-f]quinoline-9(8H)-carboxylate (100 mg, 0.158 mmol) in 1,4-dioxane (4.0 mL) was added 4M HCl(aq) (10 mL). The resulting solution was stirred at 40° C. for 2 h. LCMS showed the reaction was complete. The resulting solution was concentrated under vacuum to give crude (R)-2-(4-(4-(10-methyl-8-oxo-8,9,10,11-tetrahydro-[1,4]oxazepino[7',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)acetaldehyde (80 mg), which was used in the next step without further purification. MS (ESI, m / z) [M+H] + 487.2.

[0383] 3-(4-(4-(2-(4-(4-((R)-10-methyl-8-oxo-8,9,10,11-tetrahydro-[1,4]oxazepino[7',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6-dione. To a solution of 3-(1-methyl-6-piperazin-1-yl-indazol-3-yl)piperidine-2,6-dione (67 mg, 0.21 mmol) in DCM (5.0 mL), the pH of the solution was adjusted to 9-10 with TEA. Then, (R)-2-(4-(4-(10-methyl-8-oxo-8,9,10,11-tetrahydro-[1,4]oxazepino[7',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)acetaldehyde (80 mg, 0.164 mmol) was added to the resulting solution and the pH of the solution was adjusted to 5-6 with HOAc. NaBH(OAc)3 (130 mg, 0.62 mmol) was then added to the resulting solution and stirred at room temperature for 2 h. LCMS showed that the reaction was complete. The resulting solution was concentrated under vacuum. The residue was purified by reverse phase chromatography (RPC) using H2O and acetonitrile (both with 0.05% TFA) as mobile phases to give the desired product 3-(4-(4-(2-(4-(4-((R)-10-methyl-8-oxo-8,9,10,11-tetrahydro-[1,4]oxazepino[7',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6-dione as an orange solid (25.1 mg, 14% yield). Analytical conditions: Column: SPM20A C18 100A column 4.6 x 100 mm, 3.5 μm; Mobile phase A: water / 0.05% TFA, Mobile phase B: acetonitrile / 0.05% TFA; Flow rate: 1.5000 mL / min; Gradient: 10% B to 40% B over 6 min; 254 nm; Rt: 4.751 min. MS (ESI, m / z) [M+H] + 743. 1H NMR (400MHz, DMSO-d6): δppm 9.33(d,J=8.8Hz,1H),8.23–8.18(m,4H),8.07(d,J=8.8Hz,1H),7.20(d,J=8.8Hz,2H),7.12(d,J=8.8Hz,2H),6.99(d,J=8.8Hz,2H),4.62(s,2 H),3.90–3.70(m,15H),3.61–3.42(m,7H),2.72–2.60(m,1H),2.45–2. 43(m,1H),2.25–2.10(m,1H),2.10–1.95(m,1H),1.30(d,J=6.4Hz,3H).

[0384] Example 26: Synthesis of 3-(1-methyl-6-(4-(2-(4-(4-((R)-10-ethyl-8-oxo-8,9,10,11-tetrahydro-[1,4]oxazepino[7',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)ethyl)piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione

[0385] 3-(1-methyl-6-(4-(2-(4-(4-((R)-10-ethyl-8-oxo-8,9,10,11-tetrahydro-[1,4]oxazepino[7',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)ethyl)piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione. A 20 mL vial equipped with a stir bar was charged with (R)-2-(4-(4-(10-methyl-8-oxo-8,9,10,11-tetrahydro-[1,4]oxazepino[7',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)acetaldehyde (36.5 mg, 0.075 mmol), 1,2-dichloroethane (1.0 mL) and THF (1.0 mL) were added. DIPEA (0.039 mL, 0.23 mmol) and 3-(1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione (0.36 mL, 0.090 mmol) were added, followed by sodium triacetoxyborohydride (0.60 mL, 0.30 mmol). The resulting mixture was stirred at 23° C. overnight. An additional 2 equivalents of NaBH(OAc)3 were added, and the reaction was heated at 50°C and stirred for 4.0 h. After removal of the solvent, the residue was dissolved in 1.5 mL of DMSO. After filtration, the solution was purified by reverse phase preparative HPLC (0% to 100% MeCN in water (containing 0.1% formic acid)) to give the product 3-(1-methyl-6-(4-(2-(4-(4-((R)-10-methyl-8-oxo-8,9,10,11-tetrahydro-[1,4]oxazepino[7',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperazin-1-yl)ethyl)piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione (2.0 mg, 3.0% yield). MS (ESI, m / z) [M+H] + 798.5. 1 H NMR (400MHz, CDCl3) δppm 9.31-9.16(m,1H),8.23-8.08(m,3H),8.02-7.83(m,3H),7.22-7.05(m,3H),7.03-6.86(m,2H),6.19-6.07(m,1H),4.78-4.66(m,1H), 4.59-4.47(m,1H),4.07-3.98(m,1H),3.80-3.65(m,4H),3.54-3.26(m,8H),3.07-2.60(m,13H),2.34-2.17(m,3H),1.54-1.44(m,3H).

[0386] Example 27: Synthesis of 3-(4-(4-(2-(4-(4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6-dione

[0387] (R)-10-methyl-3-(4-(piperidin-4-yl)phenyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-8-one. tert-Butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-1-carboxylate (145 mg, 0.38 mmol), (R)-3-chloro-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-8-one (100 mg, 0.31 mmol), cesium carbonate (306 mg, 0.94 mmol) and Pd(dppf)Cl2 (23 mg, 0.03 mmol) were weighed into a 20 mL vial with a stir bar. The vial was evacuated and refilled with nitrogen three times, and 1,4-dioxane (3.1 mL) and water (0.3 mL) were added to the vial. The reaction was then heated at 100°C for 2 h. 4-[ ... After removal of the solvent, the residue was purified using reverse phase column chromatography (0 to 100% MeCN in water (containing 0.1% TFA)) to give the product (R)-10-methyl-3-(4-(piperidin-4-yl)phenyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-8-one (131 mg, 0.23 mmol, 75% yield). MS (ESI) [M+2H / 2] + 222.3.

[0388] (R)-3-(4-(1-(2,2-dimethoxyethyl)piperidin-4-yl)phenyl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-8-one. To a solution of (R)-10-methyl-3-(4-(piperidin-4-yl)phenyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepine[5',6':4,5]thieno[3,2-f]quinolin-8-one dihydrochloride (325 mg, 0.63 mmol) in DCM (3 mL) was added DIPEA (550 μL, 3.15 mmol) at room temperature, followed by 2,2-dimethoxyacetaldehyde (110 μL, 0.76 mmol) and NaBH(OAc) (400 mg, 1.89 mmol). The reaction was stirred at room temperature for 2 h. LCMS indicated that the reaction was complete. The reaction mixture was diluted with DCM and water. The aqueous phase was extracted with DCM (20 mL x 3) and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by reverse phase column chromatography (0% to 100% MeOH in water (with 0.1% formic acid)) to give the product (R)-3-(4-(1-(2,2-dimethoxyethyl)piperidin-4-yl)phenyl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-8-one (170 mg, 0.32 mmol, 51% yield) as a yellow solid. MS (ESI) [M+H] + 531.2.

[0389] (R)-2-(4-(4-(10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperidin-1-yl)ethanal. To a solution of (R)-3-(4-(1-(2,2-dimethoxyethyl)piperidin-4-yl)phenyl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-8-one (170 mg, 0.32 mmol) in 1,4-dioxane (2 mL) and water (250 μL) was added HCl (3 mL, 12.8 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight. LCMS indicates that about 85% is converted into product. Additional HCl (2mL, 8.5mmol) is added and the reaction mixture is heated to 40°C for 3h. After removing the solvent, the solid is co-evaporated with MeCN (5mL x 3) and MTBE (5mL x 2) to obtain the product (R) -2- (4- (4- (10- methyl -8- oxo -9,10,11,12- tetrahydro -8H- [1,4] diazepine [5', 6': 4,5] thieno [3,2-f] quinolin-3-yl) phenyl) piperidin-1-yl) acetaldehyde hydrochloride (180mg, quantitative yield) as a red solid. MS (ESI) [M+H] + 485.2.

[0390] 3-(4-(4-(2-(4-(4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6-dione. To a solution of (R)-2-(4-(4-(10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperidin-1-yl)acetaldehyde (90 mg, 0.17 mmol) and 3-(4-piperazin-1-ylphenyl)piperidine-2,6-dione dihydrochloride (65.8 mg, 0.19 mmol) in DCM (1.5 mL) and DMSO (0.5 mL) was added DIPEA (210 μL, 1.21 mmol) under a nitrogen atmosphere. The resulting solution was stirred at room temperature for 10 min. Then, NaBH(OAc)3 (73 mg, 0.35 mmol) was added and the reaction mixture was stirred at room temperature overnight. LCMS analysis indicated the reaction was complete. The reaction mixture was concentrated under vacuum and purified by reverse phase column chromatography (0% to 100% MeCN in water with 0.1% formic acid) to give the product 3-(4-(4-(2-(4-(4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6-dione as a yellow solid (24.8 mg, 19% yield). MS (ESI) [M+H] + 742.3 1HNMR(400MHz,DMSO-d6)δppm 10.77(s,1H),9.16-9.28(m,1H),8.19-8.27(m,3H),8.16(s,1H),8.12(d,J=9.0Hz,1H),8.08(br d,J=3.9Hz,1H),8.00(d,J=9.0Hz,1H),7.45(d,J=8.6Hz,2H),7.15(br t,J=4.9Hz,1H),7.05(d,J=8.8Hz,2H),6.89(d,J=8.8Hz,2H),3.73(dd,J=11.0,4.9Hz,1H),3.61(td,J=6.8,3.7Hz,1H),3.48(br s, 2H), 3.03-3.16 (m, 7H), 2.52-2.66 (m, 9H), 2.44 (br d, J = 4.6 Hz, 1H), 2.07-2.23 (m, 3H), 1.95-2.05 (m, 1H), 1.67-1.87 (m, 4H), 1.20 (d, J = 6.8 Hz, 3H), no proton was observed.

[0391] Example 28: Synthesis of 3-(1-methyl-6-(4-(2-(4-(4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperidin-1-yl)ethyl)piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione

[0392] 3-(1-methyl-6-(4-(2-(4-(4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperidin-1-yl)ethyl)piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione: Preparation of (R)-2-(4-(4-(10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperidin-1-yl)ethyl)piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione under nitrogen atmosphere A solution of 1-(9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperidin-1-yl)acetaldehyde hydrochloride (97 mg, 0.19 mmol) and 3-(1-methyl-6-piperazin-1-yl-indazol-3-yl)piperidine-2,6-dione hydrochloride (74 mg, 0.20 mmol) in DCM (1.5 mL) and DMSO (0.5 mL) was added. DIPEA (0.23 mL, 1.3 mmol) was added to the solution and the resulting solution was stirred at room temperature for 10 min. Then, NaBH(OAc) 3 (79 mg, 0.37 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction was concentrated under vacuum and directly purified by reverse phase column chromatography (0% to 100% MeCN in water with 0.1% formic acid) to give the product 3-(1-methyl-6-(4-(2-(4-(4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperidin-1-yl)ethyl)piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione as a yellow solid (21 mg, 14% yield). MS (ESI) [M+H] + 796.3 1H NMR (400MHz, DMSO-d6) δppm 10.85 (s, 1H), 9.14-9.28 (m, 1H), 8.24 (d, J = 8.3Hz, 2H), 8.21 (d, J = 9.0Hz, 1H), 8.12 (d, J = 8.8Hz, 1H), 8.08 (br d,J=4.2Hz,1H),8.00(d,J=8.8Hz,1H),7.50(d,J=9.0Hz,1H),7.45(d,J=8.6Hz,2H),7.15(br t,J=5.0Hz,1H),6.93(dd,J=9.0,1.7Hz,1H),6.85(d,J=1.5Hz,1H),4.26(dd,J=9.0,5.1Hz, 1H),3.89(s,3H),3.61(td,J=6.8,3.7Hz,1H),3.46-3.50(m,2H),3.21-3.25(m,4H),3.06(br d,J=11.5Hz,2H),2.52-2.65(m,11H),2.25-2.36(m,1H),2.05-2.21(m,3H),1.66-1.86(m,4H),1.20(d,J=6.6Hz,3H).

[0393] Example 29: Synthesis of 3-(4-(1-(2-(4-(4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperidin-1-yl)ethyl)piperidin-4-yl)phenyl)piperidine-2,6-dione

[0394] 3-(4-(1-(2-(4-(4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperidin-1-yl)ethyl)piperidin-4-yl)phenyl)piperidine-2,6-dione: (R)-2-(4-(4-(10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperidin-1-yl)ethyl)piperidin-4-yl)phenyl)piperidine-2,6-dione To a solution of 1,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperidin-1-yl)acetaldehyde (40 mg, 0.08 mmol) in methanol (1 mL) was added 3-(4-piperazin-1-ylphenyl)piperidine-2,6-dione (33 mg, 0.12 mmol) and NaBH3CN (8 mg, 0.12 mmol). The resulting solution was stirred at room temperature for 2 h. LCMS indicated the reaction was complete. The resulting solution was concentrated under vacuum and the residue was purified by preparative HPLC (0 to 40% MeCN in water with 0.1% TFA) to give the product 3-(4-(1-(2-(4-(4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperidin-1-yl)ethyl)piperidin-4-yl)phenyl)piperidine-2,6-dione as a red solid (4.9 mg, 8% yield). MS (ESI) [M+H] + 741. 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.25 (d, J = 9.0 Hz, 1H), 8.31–8.13 (m, 3H), 8.10–8.02 (m, 1H), 7.51 (d, J = 8.0 Hz, 2H), 7.31–7.19 (m, 4H), 3.71–3.68 (m, 7H), 3.63–3.56 (m, 4H), 3.54–3.45 (m, 2H), 3.28–3.22 (m, 4H), 3.07–3.01 (m, 1H), 2.95–2.92 (m, 1H), 2.76–2.68 (m, 1H), 2.21–1.88 (m, 10H), 1.22 (d, J = 6.8 Hz, 3H), 4 protons overlapped with residual solvent.

[0395] Example 30: Synthesis of 3-(4-(4-(2-(3-(4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)azetidin-1-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6-dione

[0396] 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)azetidine-1-carboxylic acid tert-butyl ester. 3-(4-bromophenyl)azetidine-1-carboxylic acid tert-butyl ester (312mg, 1.0mmol), (bis) pinacol diboron (267mg, 1.05mmol), potassium acetate (196mg, 2.0mmol) and Pd(dppf)Cl2 (73mg, 0.1mmol) were filled in a 20mL vial equipped with a stirring bar. The vial was evacuated and refilled with nitrogen three times. 1,4-dioxane (5.0mL) was then added to the vial and the reaction was then heated and stirred at 80°C overnight. The reaction mixture was filtered through a silica gel pad, washed with 1:1 EtOAc / heptane. The filtrate was then concentrated under vacuum and used for the next step without further purification.

[0397] (R)-3-(4-(azetidin-3-yl)phenyl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-8-one. A 20 mL vial equipped with a stir bar was charged with (R)-3-bromo-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-8-one (290 mg, 0.8 mmol), tert-butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)azetidine-1-carboxylate (60 wt.%, 555 mg), Pd(dppf)Cl2 (58.5 mg, 8 mol%), and cesium carbonate (782 mg, 24 mmol). The vial was evacuated and refilled with nitrogen three times. 1,4-Dioxane (3.6 mL) was then added and the reaction was stirred and heated at 100°C overnight. The reaction mixture is concentrated under vacuum, treated with 4: 1DCM / TFA and allowed to stir for 4h. LCMS indicates that the reaction is complete. After removing the solvent, the residue is purified by reverse phase column chromatography (0% to 100% MeCN in water (containing 0.1% TFA)) to obtain the product (R) -3- (4- (azetidin-3-yl) phenyl) -10- methyl -9,10,11,12- tetrahydro -8H- [1,4] diazepine and [5', 6': 4,5] thieno [3,2-f] quinoline -8- one TFA salt (423 mg, 98% yield) as an orange solid. MS (ESI) [M+H] + 415.4.

[0398] (R)-3-(4-(1-(2,2-dimethoxyethyl)azetidin-3-yl)phenyl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-8-one. A 20 mL vial equipped with a stir bar was charged with (R)-3-(4-(azetidin-3-yl)phenyl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-8-one trifluoroacetic acid (200 mg, 0.38 mmol). The material was then suspended in dichloromethane (3.4 mL) and DIPEA (264 μL, 1.5 mmol) was added. The obtained mixture was allowed to stir for 5 minutes.Then a solution of 60wt.% 2,2-dimethoxyacetaldehyde in water (86 μL) was added and sodium triacetoxyborohydride (160 mg, 0.76 mmol) was subsequently added. The reaction was stirred at room temperature for 2 h, and LCMS analysis revealed that it was completely converted into the desired product. The mixture was concentrated under vacuum and purified by reverse phase column chromatography (0% to 100% MeCN in water (containing 0.1% TFA)) to obtain product (R) -3- (4- (1- (2,2- dimethoxyethyl) azetidine -3- base) phenyl) -10- methyl -9,10,11,12- tetrahydro -8H- [1,4] diazepine and [5', 6': 4,5] thieno [3,2-f] quinoline -8- one (195 mg, 82% yield) as an orange solid. MS (ESI) [M+H] + 503.4.

[0399] (R)-3-(4-(1-(2,2-dihydroxyethyl)azetidin-3-yl)phenyl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-8-one. A 20 mL vial equipped with a stir bar was charged with (R)-3-(4-(1-(2,2-dimethoxyethyl)azetidin-3-yl)phenyl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-8-one (154 mg, 0.25 mmol). Water (0.1 mL) was then added, followed by 4M HCl in dioxane (7.5 mmol, 1.9 mL). The reaction was heated and stirred at 50 ° C for 4 hours. The precipitate was filtered and LCMS analysis revealed that it was the product (R) -3- (4- (1- (2,2-dihydroxyethyl) azetidin-3-yl) phenyl) -10-methyl-9,10,11,12-tetrahydro-8H- [1,4] diazepino [5 ',6 ': 4,5] thieno [3,2-f] quinolin-8-one (quantitative yield), which was used in the next step without further purification. MS (ESI) [M + 2H] / 2 + 238.4.

[0400] 3-(4-(4-(2-(3-(4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)azetidin-1-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6-dione. A 20 mL vial equipped with a stir bar was charged with (R)-3-(4-(1-(2,2-dihydroxyethyl)azetidin-3-yl)phenyl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-8-one (119 mg, 0.25 mmol), 3-(4-(piperazin-1-yl)phenyl)piperidine-2,6-dione (68.3 mg, 0.25 mmol), and sodium triacetoxyborohydride (142 mg, 0.75 mmol). After adding DCM (1.25 mL) and DIPEA (2.5 mmol, 435 μL), the reaction mixture was stirred at 40 ° C for 2 h. LCMS indicated complete conversion to the desired product. The reaction mixture was then concentrated under vacuum, and the residue was purified by reverse phase column chromatography (0% to 100% MeCN in water (containing 0.1% TFA)) to give the product 3-(4-(4-(2-(3-(4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)azetidin-1-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6-dione as an orange solid (22 mg, 9% yield). MS (ESI) [M+2H] / 2 + 358.02. 1 H NMR (400 MHz, methanol-d4) δ ppm 9.24-9.36 (m, 1H), 8.03-8.22 (m, 5H), 7.56-7.69 (m, 2H), 7.16-7.28 (m, 2H), 7.01-7.15 (m, 2H), 4.61-4.74 (m, 2H), 4.30-4.54 (m, 3H), 3.67-3.90 (m, 4H), 3.54-3.67 (m, 2H), 3.41-3.54 (m, 4H), 3.19-3.28 (m, 6H), 2.54-2.77 (m, 2H), 2.13-2.30 (m, 2H), 1.24-1.42 (m, 3H). Three exchangeable protons were not observed due to the use of methanol-d4.

[0401] Example 31: Synthesis of 3-(4-(4-(2-(4-(4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6-dione

[0402] 4- (4- bromophenyl) -1- (2,2- dimethoxyethyl) -1,2,3,6- tetrahydropyridine. To a solution of 4- (4- bromophenyl) -1,2,3,6- tetrahydropyridine hydrochloride (1.0 g, 3.64 mmol) and 2,2- dimethoxyacetaldehyde (379 mg, 3.64 mmol) in methanol (20.0 mL) was added NaBH3CN (699 mg, 10.93 mmol). The resulting solution was stirred at room temperature for 3 h. LCMS indicated that the reaction was complete. The reaction mixture was concentrated under vacuum, and the residue was purified by reverse phase column chromatography (0% to 100% MeCN in water (containing 0.1% TFA)) to give the product 4- (4- bromophenyl) -1- (2,2- dimethoxyethyl) -1,2,3,6- tetrahydropyridine (1.1 g, 92% yield) as a white solid. MS (ESI) [M + H] + 326.1.

[0403] 1-(2,2-dimethoxyethyl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,2,3,6-tetrahydropyridine. To a solution of 4-(4-bromophenyl)-1-(2,2-dimethoxyethyl)-1,2,3,6-tetrahydropyridine (600 mg, 1.84 mmol), B2pin2 (700 mg, 2.76 mmol) and KOAc (361 mg, 3.68 mmol) in 1,4-dioxane (8.0 mL) was added Pd(dppf)Cl2 (150 mg, 0.184 mmol). The resulting solution was stirred at 90 ° C under a nitrogen atmosphere for 4 h. LCMS indicated that the reaction was complete. The resulting mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL x 2). The organic layer was then dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate; 1:2 ratio) to obtain the product 1-(2,2-dimethoxyethyl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)phenyl)-1,2,3,6-tetrahydropyridine (320 mg, 47% yield) as a yellow solid. MS (ESI) [M+H]+ 374.2.

[0404] (R)-3-(4-(1-(2,2-dimethoxyethyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-8-one. To a mixture of 1-(2,2-dimethoxyethyl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,2,3,6-tetrahydropyridine (300 mg, 0.80 mmol), K 3 PO 4 (340 mg, 1.60 mmol) and (R)-3-chloro-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-8-one (255 mg, 0.80 mmol) in 1,4-dioxane (5.0 mL) and water (1.0 mL) was added Pd(PPh 3 ) 4 (93 mg, 0.080 mmol). The resulting mixture was stirred at 90° C. under a nitrogen atmosphere for 18 h. LCMS showed that the reaction was complete. The reaction mixture was diluted with DMSO and then filtered. The filtrate was purified by reverse phase column chromatography (0% to 100% MeCN in water (containing 0.1% TFA)) to give the product (R) -3- (4- (1- (2,2- dimethoxyethyl) -1,2,3,6- tetrahydropyridin-4-yl) phenyl) -10- methyl -9,10,11,12- tetrahydro -8H- [1,4] diazepine [5 ', 6 ': 4,5] thieno [3,2-f] quinolin-8-one (170 mg, 34% yield) as an orange solid. MS (ESI) [M + H] + 529.1.

[0405] (R)-2-(4-(4-(10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)acetaldehyde. To a solution of (R)-3-(4-(1-(2,2-dimethoxyethyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-8-one (150 mg, 0.28 mmol) in 1,4-dioxane (2.0 mL) and water (1.0 mL) was added 4 M HCl in 1,4-dioxane (2.0 mL). The resulting solution was stirred at 40 °C for 18 h. LCMS showed that the reaction was complete. The reaction mixture was concentrated under vacuum to give the product (R)-2-(4-(4-(10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)acetaldehyde, which was used in the next step without further purification. MS (ESI) [M+H2O] + 501.2.

[0406] 3-(4-(4-(2-(4-(4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6-dione. To a solution of 3-(4-piperazin-1-ylphenyl)piperidine-2,6-dione (89 mg, 0.29 mmol) in methanol (4.0 mL) at 0°C was added TEA to adjust the pH of the solution to 8-10, and then (R)-2-(4-(4-(10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)acetaldehyde hydrochloride (150 mg, 0.29 mmol) was added. Still at 0° C., HOAc (0.04 mL, 0.58 mmol) was added to adjust the pH of the solution to 4-6, then NaBH 3 CN (55 mg, 0.87 mmol) was added, and the resulting solution was stirred at room temperature for 18 h, and LCMS showed that the reaction was complete. The resulting solution was concentrated under vacuum and the residue was purified by preparative HPLC (0% to 100% MeCN in water with 0.1% TFA) to give the product, 3-(4-(4-(2-(4-(4-((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6-dione (18.4 mg, 8% yield) as an orange solid. MS (ESI) [M+H] + 741.2 1H NMR(400MHz,DMSO-d6)δppm 9.22(d,J=8.8Hz,1H),8.30(dd,J=8.4,4.8Hz,2H),8.22(d,J=8.8Hz,1H),8.13(d,J=8 .8Hz,1H),8.02(d,J=8.8Hz,1H),7.71(d,J=8.4Hz,2H),7.14–7.07(m,2H),6.97(d,J=8 .8 Hz, 2H), 6.36 (s, 1H), 3.99 (s, 2H), 3.85-3.78 (m, 2H), 3.70–3.20 (m, 17H), 2.88 (s, 2H), 2.74–2.62 (m, 1H), 2.11 (d, J = 9.5 Hz, 1H), 2.04–1.95 (m, 1H), 1.18 (d, J = 6.8 Hz, 3H). Three protons were not observed.

[0407] Example 32: 3-(4-(4-(2-(4-(4-((R)-10-methyl-8-oxo-8,9,10,11-tetrahydro-[1,4]oxazepino[7',6':4,5]thieno[3,2-f]quinolin-3-yl)phenyl)piperidin-1-yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6-dione

[0408] (R)-tert-Butyl 3-(4-(1-(tert-Butoxycarbonyl)piperidin-4-yl)phenyl)-10-methyl-8-oxo-10,11-dihydro-[1,4]oxazepino[7',6':4,5]thieno[3,2-f]quinoline-9(8H)-carboxylate. To a solution of tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine-1-carboxylate (300 mg, 0.77 mmol), (R)-tert-butyl 3-chloro-10-methyl-8-oxo-10,11-dihydro-[1,4]oxazepino[7',6':4,5]thieno[3,2-f]quinoline-9(8H)-carboxylate (389 mg, 0.93 mmol) and KCO (320 mg, 2.32 mmol) in 1,4-dioxane (20.0 mL) and water (2.0 mL) was added Pd(dppf)Cl (63 mg, 0.080 mmol, 0.10). The reaction mixture was ...

Claims

1. A compound of formula I: or a pharmaceutically acceptable salt thereof, wherein: The linker is a divalent group; The E3 binding portion is a portion that binds to the E3 ubiquitin ligase protein; Ring F is phenylene, a 5- to 6-membered heteroarylene ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 3- to 7-membered saturated or partially unsaturated heterocyclylene ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L d Selected from covalent bonds, -O-, -S-, -N(R)- and C 1-6 aliphatic; X is selected from -O-, -S- and -N(R)-; R z an optionally substituted group selected from halogen, -OR, -SR, -CN, -NO, -SONR, -SOR, -SOR, -C(O)R, -C0R, -C(O)N(R), -NRC(O)R, -NRC(O)OR, -NRC(O)N(R), -NRSOR, -N(R), or a group selected from: C 1-6 aliphatic, phenyl, 3- to 8-membered saturated or partially unsaturated carbocyclic rings, 4- to 7-membered heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and 5- to 6-membered monocyclic heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R is independently hydrogen or an optionally substituted C 1-6 aliphatic; and t is 0, 1, 2, or 3. The compound according to claim 1 , wherein ring F is phenylene.

3. The compound according to claim 1 or claim 2, wherein L d It is a covalent bond.

4. The compound according to any one of claims 1 to 3, wherein X is -O-.

5. The compound according to any one of claims 1 to 3, wherein X is -N(R)-. The compound according to claim 5 , wherein R is hydrogen.

7. The compound according to any one of claims 1 to 6, wherein R z is selected from halogen, -OR, -SR, -CN, -NO2, -SO2NR, -SO2R, -SOR, -C(O)R, -CO2R and -C(O)N(R)2.

8. A compound according to any one of claims 1 to 6, wherein R z Selected from halogen, -OR, -SR, -CN and -NO2.

9. The compound according to any one of claims 1 to 8, wherein R z It's a halogen.

10. The compound according to any one of claims 1 to 6, wherein t is 0.

11. The compound according to any one of claims 1 to 9, wherein t is 0.

12. The compound of claim 1 , wherein the compound is of any one of Formulas Ia, Iai, Ia-ii, Ia-iii, Ia-iv, Iav, Ib, Ibi, Ib-ii, Ib-iii, Ib-iv, Ibv, Ic, Ici, Ic-ii, Ic-iii, Ic-iv, Icv, Id, Idi, and Id-ii: or a pharmaceutically acceptable salt thereof.

13. The compound according to any one of claims 1 to 12, wherein: The linker is an optionally substituted divalent C 2-20 A linear or branched aliphatic chain wherein one, two, three, four or five methylene units of the aliphatic chain are optionally and independently replaced by a group selected from the group consisting of: -N(R)-, -O-, -C(O)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)-, -C(O)O-, a divalent 3- to 6-membered monocyclic saturated or partially unsaturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a divalent 6- to 8-membered saturated or partially unsaturated bridged bicyclic, fused bicyclic or spirofused heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and phenylene, wherein each monocyclic, bridged bicyclic, fused bicyclic, spirofused ring or phenylene is replaced by R L 0-4 examples of replacement, where R L independently selected from halogen, -OR, -SR, -CN, -NO2, -SO2NR, -SO2R, -SOR, -C(O)R, -C02R, -C(O)N(R)2, -NRC(O)R, -NRC(O)OR, -NRC(O)N(R)2, -NRSO2R, -N(R)2, or an optionally substituted group selected from: C 1-6 aliphatic, phenyl, 3- to 8-membered saturated or partially unsaturated carbocyclic rings, 4- to 7-membered heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, and 5- to 6-membered monocyclic heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

14. The compound of claim 13, wherein the linker is selected from:

15. The compound of any one of claims 1-14, wherein the E3 binding moiety is a cerebrolin protein binding moiety.

16. The compound of claim 15, wherein the cereblon protein binding moiety is selected from the group consisting of:

17. The compound according to claim 1, wherein the compound of formula I is selected from: or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 17 and a pharmaceutically acceptable excipient, carrier or diluent.

19. A method of inhibiting the activity of MK2 or a mutant thereof, the method comprising contacting a biological sample with a compound according to any one of claims 1 to 18.

20. A method of treating a disease, disorder or condition mediated by MK2 or a mutant thereof, the method comprising administering to a patient in need thereof a compound according to any one of claims 1 to 17 or a pharmaceutical composition according to claim 18.

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