Dihydrouracil derivatives useful for the targeted degradation of VAV1

Abstract

This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt thereof) that degrades Proto-oncogene VAV 1 protein (VAV1). The chemical entities are useful for treating subjects having a disorder or disease that can be treated by reducing the level of VAV1, such as cancer, inflammatory or autoimmune disorders.

Description

[0001] PAT059977-WO-PCT TARGETED DEGRADATION OF VAV1 TECHNICAL FIELD This disclosure features chemical entities (e.g., a compound or a pharmaceutically 5 acceptable salt thereof) that degrade human Proto-oncogene VAV 1 protein (VAV1). These chemical entities are useful, e.g., for treating a subject (e.g., a human subject) having a disorder or disease that can be treated by reducing the level of VAV1. This disclosure also features compositions containing these chemical entities as well as methods of using and making these chemical entities. 10 BACKGROUND The ubiquitin proteasome system can be manipulated with different small molecules to trigger targeted degradation of specific proteins of interest. Promoting the targeted degradation of proteins using small molecule degraders is emerging as a new modality in the treatment of 15 diseases. One such modality relies on redirecting the activity of E3 ligases such as cereblon (a phenomenon known as E3 reprogramming) using low molecular weight compounds, which have been termed molecular glues (also called molecular glue degraders; “MGDs”), to promote the poly-ubiquitination and ultimately proteasomal degradation of new protein substrates involved in the development of diseases. Molecular glues bind to both the E3 ligase and the target protein. It20is believed that the interaction between the molecular glue and the E3 ligase creates a surface that promotes formation of a complex with the target protein, permitting subsequent degradation of the target protein. Examples of molecular glues for the E3 ligase cereblon include: Thalidomide, Lenalidomide and Pomalidomide, all of which are immunomodulatory imide drugs (IMiDs) approved by the FDA for use in hematological cancers. 25 VAV family proteins, including VAV1, VAV2 and VAV3, are guanine nucleotide exchange factors (GEFs) for Rho family GTPases. VAV1 is a 95 kDa protein that is a positive regulator of T cell receptor and B cell receptor signaling. VAV1 expression is normally highly restricted to hematopoietic cells. VAV1 becomes rapidly phosphorylated on tyrosine in response to a variety of stimuli, including stimulation of T-cell receptor (TCR), B cell receptor (BCR), and30various cytokine receptors. VAV1 regulates multiple cellular functions and signaling pathways in hematopoietic-derived cells (e.g., T- and B-cells, natural killer cells, and osteoclasts) through activation of certain GTPases. VAV1-mediated functions include gene transcription, development and activation of immune cells (e.g., T- and B-cells). VAV1 is a positive regulator of (TCR) 1

[0002] PAT059977-WO-PCT signaling including nuclear factor of activated T cells (NFAT), interferon gamma (IFNɣ) and Interleukin-2 (IL-2) cytokine secretion. Knock-in mice having a mutated VAV1 with disrupted GEF activity, but intact GEF- independent function, show reduced T cells proliferation and activation in response to allogeneic 5 stimulation and showed reduced expansion of T cells in a systemic graft-versus-host model (Haubert et al. 2012 Transplantation Immunology 26: 212, 2012). VAV1 deficient mice are resistant to MOG(5-55)-induced experimental autoimmune encephalomyelitis (EAE), a commonly used model of multiple sclerosis (Korn et al. 2003 Journal of Neuroimmunology 139:17). Finally, genome-wide CRISPR activation (CRISPRa) and interference (CRISPRi) 10 screens in primary human T cells identified VAV1 as an important positive regulator of T cell function (Schmidt et al.2022 Science 375:6580). SUMMARY This disclosure features chemical entities (e.g., a compound or a pharmaceutically 15 acceptable salt thereof) that degrade Proto-oncogene VAV 1 protein (VAV1). These chemical entities are useful, e.g., for treating a subject (e.g., a human subject) having a disorder or disease that can be treated by reducing the level of VAV1, thereby reducing VAV activity in cells. By reducing the level of VAV1, the chemical entities can reduce signaling in certain immune cell activation pathways. For example, the chemical entities may be used to reduce inflammation or 20 autoimmune activity. They may be useful for treating, for example, multiple sclerosis, rheumatoid arthritis, myasthenia gravis, chronic lymphocytic leukemia, ulcerative colitis, psoriasis, cutaneous lupus, axial spondylarthritis graft versus host disease, and other disorders referred to herein. This disclosure also features compositions containing the chemical entities as well as methods of using and making the same. 25 VAV1 is a dominant signal transduction protein in the adaptive immune system. It is a positive regulator of immune receptor signaling in both T cells and B cells. Thus, reduction in VAV1 can reduce immune cell activation, immune cell proliferation and the production of various cytokines. For at least these reasons, degradation of VAV1 can be therapeutically beneficial in a variety of disease conditions. 30 In one aspect, this disclosure features compounds of Formula (I) or pharmaceutically acceptable salts thereof, 2

[0003] PAT059977-WO-PCT Formula (I) in which Ring A, Ring B, L, R2, R3, R4and R5can be as defined anywhere herein. 5 DEFINITIONS The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate 10 with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1–19. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group15formed 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, 20 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, picrate, pivalate,25propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p–toluenesulfonate, undecanoate, valerate salts, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1–4alkyl)4salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic 3

[0004] PAT059977-WO-PCT ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate. As used herein, “VAV1” refers to naturally occurring VAV1, also known as Vav or p95vav, (e.g. mammalian, preferably human (Homo sapiens) VAV1) and encompasses naturally 5 occurring variants, such as allelic variants and splice variants, which retain VAV1 functional activity. A “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g, infant, child, adolescent) or adult subject (e.g., young adult, middle–aged adult or senior adult)) and / or a non-human animal, 10 e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. Preferably, the subject is a human. Disease, disorder, and condition are used interchangeably herein. As used herein, and unless otherwise specified, the terms “treat,” “treating” and15“treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition (“therapeutic treatment”). In general, the “effective amount” of a compound refers to an amount sufficient to elicit the desired biological response. As will be appreciated by those of ordinary skill in this art, the 20 effective amount of a compound of the present disclosure may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and condition of the subject. As used herein, and unless otherwise specified, a “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease,25disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or 30 causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent. The compounds described herein also include isotopically labeled compounds which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds described herein include35isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 4

[0005] PAT059977-WO-PCT 2H,3H,13C,14C,15N,18O,17O,31P,32P,35S,18F, and36Cl, respectively. For example, a compound of the disclosure may have one or more H atom replaced with deuterium. The term "halo" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I). The term "alkyl" refers to a saturated acyclic hydrocarbon radical that may be a straight 5 chain or branched chain, containing the indicated number of carbon atoms. For example, C1-10 indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it. Non-limiting examples include methyl, ethyl, iso-propyl, tert-butyl, n-hexyl. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms and other available valences occupied by hydrogen and / or other substituents as defined herein. 10 The term "haloalkyl" refers to an alkyl, in which one or more hydrogen atoms is / are replaced with an independently selected halo. The term "alkoxy" refers to an -O-alkyl radical (e.g., -OCH3). The term "alkylene" refers to a divalent alkyl (e.g., -CH2-). The term "alkenyl" refers to an acyclic hydrocarbon chain that may be a straight chain or15branched chain having one or more carbon-carbon double bonds. The alkenyl moiety contains the indicated number of carbon atoms. For example, C2-6indicates that the group may have from 2 to 6 (inclusive) carbon atoms in it. The term "alkynyl" refers to an acyclic hydrocarbon chain that may be a straight chain or branched chain having one or more carbon-carbon triple bonds. The alkynyl moiety contains the 20 indicated number of carbon atoms. For example, C2-6indicates that the group may have from 2 to 6 (inclusive) carbon atoms in it. The term "aryl" refers to a 6-20 carbon mono-, bi-, tri- or polycyclic group wherein at least one ring in the system is aromatic (e.g., 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system). Examples of aryl groups include phenyl, naphthyl,25tetrahydronaphthyl, dihydro-1H-indenyl and the like. The term "cycloalkyl" as used herein refers to cyclic saturated hydrocarbon groups having, e.g., 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. 30 Cycloalkyl may include multiple fused and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyl includes: bicyclo[1.1.0]butanyl, bicyclo[2.1.0]pentanyl, bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, bicyclo[2.1.1]hexanyl, bicyclo[3.2.0]heptanyl, bicyclo[4.1.0]heptanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[4.2.0]octanyl, bicyclo[3.2.1]octanyl, bicyclo[2.2.2]octanyl, and the like. Cycloalkyl also includes spirocyclic35rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non- 5

[0006] PAT059977-WO-PCT limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentanyl, spiro[2.5]octanyl, spiro[3.5]nonanyl, spiro[3.5]nonanyl, spiro[3.5]nonanyl, spiro[4.4]nonanyl, spiro[2.6]nonanyl, spiro[4.5]decanyl, spiro[3.6]decanyl, spiro[5.5]undecanyl, and the like. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms. 5 The term "cycloalkenyl" as used herein means partially unsaturated cyclic hydrocarbon groups having 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons. Examples of cycloalkenyl groups include, without limitation, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. As partially unsaturated cyclic hydrocarbon groups, cycloalkenyl groups may have any degree of unsaturation 10 provided that one or more double bonds is present in the ring, none of the rings in the ring system are aromatic, and the cycloalkenyl group is not fully saturated overall. Cycloalkenyl may include multiple fused and / or bridged and / or spirocyclic rings. The term “heteroaryl”, as used herein, means a mono-, bi-, tri- or polycyclic group having 5 to 10 ring atoms and having pi electrons shared in a cyclic array; wherein at least one ring in the15system is aromatic, and at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, and S (but the aromatic ring does not have to be a ring which contains a heteroatom, e.g. tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl). Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, 20 pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3- b]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[4,3-b]pyridinyl, tetrazolyl,25chromanyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, benzo[d][1,3]dioxolyl, 2,3-dihydrobenzofuranyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[b][1,4]oxathiinyl, isoindolinyl, and others. In some embodiments, the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl. The term "heterocyclyl" refers to a mono-, bi-, tri-, or polycyclic saturated ring system 30 having 5-10 ring atoms (e.g., a 4-6-membered monocyclic, or 7-9-membered bicyclic ring system), wherein one or more ring atoms are heteroatoms, said heteroatoms selected from O, N, or S. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like. Heterocyclyl may include multiple fused and bridged rings. Non- limiting examples of fused / bridged heteorocyclyl includes: 2-azabicyclo[1.1.0]butanyl, 2-35azabicyclo[2.1.0]pentanyl, 2-azabicyclo[1.1.1]pentanyl, 3-azabicyclo[3.1.0]hexanyl, 5- 6

[0007] PAT059977-WO-PCT azabicyclo[2.1.1]hexanyl, 3-azabicyclo[3.2.0]heptanyl, octahydrocyclopenta[c]pyrrolyl, 3- azabicyclo[4.1.0]heptanyl, 7-azabicyclo[2.2.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 7- azabicyclo[4.2.0]octanyl, 2-azabicyclo[2.2.2]octanyl, 3-azabicyclo[3.2.1]octanyl, 2- oxabicyclo[1.1.0]butanyl, 2-oxabicyclo[2.1.0]pentanyl, 2-oxabicyclo[1.1.1]pentanyl, 3- 5 oxabicyclo[3.1.0]hexanyl, 5-oxabicyclo[2.1.1]hexanyl, 3-oxabicyclo[3.2.0]heptanyl, 3- oxabicyclo[4.1.0]heptanyl, 7-oxabicyclo[2.2.1]heptanyl, 6-oxabicyclo[3.1.1]heptanyl, 7- oxabicyclo[4.2.0]octanyl, 2-oxabicyclo[2.2.2]octanyl, 3-oxabicyclo[3.2.1]octanyl, and the like. Heterocyclyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic heterocyclyls include 2-10 azaspiro[2.2]pentanyl, 4-azaspiro[2.5]octanyl, 1-azaspiro[3.5]nonanyl, 2-azaspiro[3.5]nonanyl, 7- azaspiro[3.5]nonanyl, 2-azaspiro[4.4]nonanyl, 6-azaspiro[2.6]nonanyl, 1,7- diazaspiro[4.5]decanyl, 7-azaspiro[4.5]decanyl 2,5-diazaspiro[3.6]decanyl, 3- azaspiro[5.5]undecanyl, 2-oxaspiro[2.2]pentanyl, 4-oxaspiro[2.5]octanyl, 1- oxaspiro[3.5]nonanyl, 2-oxaspiro[3.5]nonanyl, 7-oxaspiro[3.5]nonanyl, 2-oxaspiro[4.4]nonanyl,156-oxaspiro[2.6]nonane, 1,7-dioxaspiro[4.5]decanyl, 2,5-dioxaspiro[3.6]decanyl, 1- oxaspiro[5.5]undecanyl, 3-oxaspiro[5.5]undecanyl, 3-oxa-9-azaspiro[5.5]undecanyl and the like. The term “saturated” as used in this context means only single bonds present between constituent ring atoms and other available valences occupied by hydrogen and / or other substituents as defined herein. 20 The term "heterocycloalkenyl" as used herein means partially unsaturated cyclic ring system with 5-10 ring atoms (e.g., a monocyclic bicyclic or tricyclic ring system), wherein one or more ring atoms are heteroatoms, said heteroatoms selected from O, N, or S. Examples of heterocycloalkenyl groups include, without limitation, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl. As partially unsaturated25cyclic groups, heterocycloalkenyl groups may have any degree of unsaturation provided that one or more double bonds is present in the ring, none of the rings in the ring system are aromatic, and the heterocycloalkenyl group is not fully saturated overall. Heterocycloalkenyl may include multiple fused and / or bridged and / or spirocyclic rings. Certain groups, such as , can be considered as either: (i) a heterocycloalkenyl 30 which is substituted with an oxo group; or (ii) a heteroaryl group. As used herein, when a ring is described as being “aromatic”, it means said ring has a continuous, delocalized π-electron system. Typically, the number of out of plane π-electrons corresponds to the Hückel rule (4n+2). Examples of such rings include: benzene, pyridine, 7

[0008] PAT059977-WO-PCT pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thioazole, isoxazole, isothiazole, and the like. As used herein, when a ring is described as being “partially unsaturated”, it means said ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation 5 attributed to the ring itself; e.g., one or more double or triple bonds between constituent ring atoms), provided that the ring is not aromatic. Examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like. For the avoidance of doubt, and unless otherwise specified, for rings and cyclic groups 10 (e.g., aryl, heteroaryl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, cycloalkyl, and the like described herein) containing a sufficient number of ring atoms to form bicyclic or higher order ring systems (e.g., tricyclic, polycyclic ring systems), it is understood that such rings and cyclic groups encompass those having fused rings, including those in which the points of fusion are located (i) on adjacent ring atoms (e.g., [x.x.0] ring systems, in which 0 represents a zero atom 15 , ystems having In addition, atoms making up the compounds of the present embodiments are intended to 20 include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include13C and14C. In addition, the compounds generically or specifically disclosed herein include all25tautomeric forms, or “tautomers” of said compounds. To give a non-limiting example, a disclosure 8

[0009] PAT059977-WO-PCT of a compound with the group is also a disclosure of a tautomer of that compound, for instance with the group . The compounds generically or specifically disclosed herein include all stereoisomeric forms, including all diastereomeric and entantiomeric forms, unless it is specifically stated or the 5 context indicates otherwise. Compounds with chiral centers can occur as racemates, individual enantiomers (e.g. as the (R) enantiomer or (S) entantiomer) or diastereomers, and mixtures thereof. All such stereoisomeric forms are included within the embodiments disclosed herein, including mixtures thereof. Similarly, a compound comprising a chiral center disclosed herein without its enantiomeric 10 form indicated encompasses the isolated entantiomer and a mixture, such as a racemic mixture, of the (R) and (S) entantiomers if the enantiomers epimerise. As used herein, the phrase “optionally substituted” when used in conjunction with a structural moiety (e.g., alkyl) is intended to encompass both the unsubstituted structural moiety (i.e., none of the substitutable hydrogen atoms are replaced with one or more non-hydrogen15 substituents) and substituted structural moieties substituted with the indicated range of non- hydrogen substituents. For example, “C1-C4 alkyl optionally substituted with 1-4 Ra” is intended to encompass both unsubstituted C1-C4alkyl and C1-C4alkyl substituted with 1-4 Ra. As used herein, the term "antibody" encompasses an immunoglobulin, whether natural or partly or wholly synthetically produced, and fragments thereof. The term also covers any protein 20 having a binding domain that is homologous to an immunoglobulin binding domain. “Antibody” further includes a polypeptide comprising a framework region from an immunoglobulin gene or fragments thereof that specifically binds and recognizes an antigen. Use of the term antibody is meant to include whole antibodies, polyclonal, monoclonal and recombinant antibodies, fragments thereof, and further includes single-chain antibodies, humanized antibodies, murine antibodies, 25 chimeric, mouse-human, mouse-primate, primate-human monoclonal antibodies, anti-idiotype antibodies, antibody fragments, such as, e.g., scFv, (scFv)2, Fab, Fab', and F(ab')2, F(abl)2, Fv, dAb, and Fd fragments, diabodies, and antibody-related polypeptides. Antibody includes bispecific antibodies and multispecific antibodies so long as they exhibit the desired biological activity or function. 9

[0010] PAT059977-WO-PCT As used herein, an “antibody fragment” comprises a portion of an intact antibody, generally the antigen binding or variable region thereof. Examples of antibody fragments include Fab, Fab', F(ab').sub.2, and Fv fragments; diabodies; linear antibodies; fragments produced by a Fab expression library, anti-idiotypic (anti-Id) antibodies, CDR (complementary determining region), 5 and epitope-binding fragments of any of the above which immunospecifically bind to cancer cell antigens, viral antigens or microbial antigens, single-chain antibody molecules; and multispecific antibodies formed from antibody fragments. As used herein, the term "antibody-drug conjugate" refers to an antibody or antibody fragment linked, e.g., covalently, to a compound of the disclosure. 10 The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features and advantages of the invention will be apparent from the description and drawings, and from the claims. DESCRIPTION OF DRAWINGS 15 FIG. 1 shows compound VAV1 MGD concentration in serum (left) after seven consecutive daily doses at increasing doses and associated VAV1 levels normalized to b-actin protein levels in PBMCs relative to vehicle 6 and 24 hours after 7 consecutive daily oral doses of VAV1 MGD at indicated doses (right). FIG.2 shows dose-dependent decrease in VAV1 levels in primary human CD3+ T cells, 20 CD19+ B cells, and CD14+ monocytes following 24h VAV1 MGD treatment relative to DMSO control as assessed by flow cytometry (y-axis represents normalized VAV1 levels to DMSO control; x-axis depicts doses of VAV1 MGD). FIG. 3 shows that VAV1 degradation results in inhibition of various hallmarks of TCR- mediated activity following TCR stimulation of primary human T-cells. Cells were treated with 25 VAV1 MGD for 24h followed by TCR stimulation (anti-CD3 / anti-CD28). CD69 surface expression (24 hr), IL-2 secretion (48 hr), and proliferation (96 hr) were evaluated at various timepoints following TCR stimulation (y-axis depicts percent of CD69 activation, IL-2 secretion, or proliferation relative to TCR-stimulated DMSO control; x-axis depicts doses of VAV1 MGD). Data from N=2 donors is shown for CD69 surface expression. Data from N=1 donor is shown for 30 IL-2 secretion and proliferation, with individual data points representing technical replicates. FIG. 4 shows a schematic diagram of the role of VAV1 in B cell receptor signaling. Following the ligation of the B cell receptor and / or CD19, VAV1 is recruited to mediate phosphorylation cascades that lead to activation, cytokine secretion, and antibody production by B cells. 10

[0011] PAT059977-WO-PCT FIG. 5 shows a schematic diagram of the role of VAV1 in T cell receptor signaling. Following the ligation of the T cell receptor, VAV1 is recruited to mediate phosphorylation cascades that lead to activation, cytokine secretion, and proliferation. FIG. 6 shows that VAV1 MGD-mediated degradation of VAV1 reduces BCR-mediated 5 CD69 expression and secretion of IL-6 and IgG of primary human B cells. Purified human primary B-cells were treated with MGD for 24 hrs followed by stimulation with anti-IgM and recombinant human IL-4 for 24 hours (for CD69 expression and IL-6 secretion) or with anti-IgM, BAFF, IL- 21, and sCD40L for 5 days (for IgG secretion). CD69 expression was then assessed on CD19+ B cells by flow cytometry. CD69 expression is shown as a percentage (%) change relative to 10 stimulated DMSO controls. X-axis shows relative percentage of CD19+ B cells expressing CD69 and y-axis shows concentration of VAV1 MGD. IL-6 secretion was assessed in the supernatant by Alphalisa. IL-6 secretion is shown as a percentage (%) change relative to stimulated DMSO controls. X-axis shows relative percentage of IL-6 level and y-axis shows concentration of VAV1 MGD. IgG secretion was assessed in the supernatant by Alphalisa. IgG secretion is shown as a15percentage (%) change relative to stimulated DMSO controls. X-axis shows relative percentage of IgG level and y-axis shows concentration of VAV1 MGD. FIG.7 shows that VAV1 degradation results in inhibition TNF secretion following FcγR stimulation of primary human monocytes. Cells were treated with VAV1 MGD for 24h followed by FCγR stimulation (200 μg / mL immobilized IgG). TNF secretion was measured at 24 hours 20 following stimulation (y-axis depicts percent of TNF secretion, relative to stimulated DMSO control; x-axis depicts doses of VAV1 MGD). FIG.8 shows that VAV1 MGD treatment of REC-1 cell line degraded VAV1 in a concentration-dependent manner. REC-1 were treated for 24 hours with the indicated concentrations of VAV1 MGD. After treatment, VAV1 levels were assessed by western blot.25Data shows VAV1 levels normalized to β-actin and relative to DMSO control. FIG.9 shows that VAV1 MGD treatment of REC-1 cell line decreases growth with increasing concentration. REC-1 were treated for 5 days with the indicated concentrations of VAV1 MGD. After 5 days of treatment, cell growth was measured by cell titer glow and normalized to T0 and DMSO. 30 FIG.10A shows that oral dosing of VAV1 MGDs inhibits disease progression in a mouse model of EAE. EAE was induced in C57BL / 6J mice and mice were treated orally and daily from Day 11 with either vehicle (10% captisol in water) or Compound 1 at 10 mg / kg or Compound 24 at 30, 10, and 1 mg / kg. Mice were assessed for disease severity every 3 days until 11

[0012] PAT059977-WO-PCT disease onset, then daily from Day 11 until Day 17. Graph shows disease score as assessed from Day 11, points indicate mean±SEM. FIG.10B shows that oral dosing of peripherally-restricted VAV1 MGDs degrades VAV1 in peripheral blood mononuclear cells (PBMC). At study termination, PBMCs were 5 enriched from cardiac punctures and assessed for VAV1 and β-actin levels by western blot. Image shows representative VAV1 levels in each treatment group as indicated. Quantification shows relative levels in VAV1 normalized to vehicle-treated group for all mice. Bars indicate mean±SEM. FIG.10C shows that oral dosing of peripherally-restricted VAV1 MGDs does not 10 degrade VAV1 in brain tissue. At study termination, brain tissue was excised, homogenized, and assessed for VAV1 and β-actin levels by western blot. Image shows representative VAV1 levels in each treatment group as indicated. Quantification shows relative levels in VAV1 normalized to vehicle-treated group for all mice. Bars indicate mean±SEM.15DETAILED DESCRIPTION This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt thereof) that degrade and / or otherwise inhibit Proto-oncogene VAV 1 protein (VAV1). Said chemical entities are useful, e.g., for treating a subject (e.g., a human subject) having a disorder or disease associated with VAV1 polymorphisms. This disclosure also features 20 compositions containing the same as well as methods of using and making the same. Compounds This disclosure features compounds of Formula (I) or pharmaceutically acceptable salts thereof, 25Formula (I) wherein: Ring A is selected from the group consisting of: 12

[0013] PAT059977-WO-PCT • , wherein * is the point of attachment to L, X1, X2and X3are each selected from the group consisting of CR6Dand N, and wherein a maximum of one of X1, X2and X3may be N; • , wherein Z is the point of attachment to L, Y and Z are 5 independently selected from the group consisting of CH, CR14and N, and wherein m is 0 or 1; L is selected from the group consisting of: • a bond; or • *-O(C1-C4 alkylene)-, *-C1-C4 alkylene-, *-NR9(C0-C4 alkylene)-, *-NR9(C=O)(C0- 10 C4alkylene)-, -NR9(C=O)(C0-C4alkylene)-*, -(C1-C4alkylene)-C(=O)-*, or *-(C1-C4alkylene)-C(=O)-, wherein the alkylene is optionally substituted with 1-2 R7and wherein * indicates the point of attachment of L to Ring A, wherein L is a bond or *- C1-C4 alkylene- when Z is N; Ring B is selected from the group consisting of: 15 • heterocyclyl or heterocycloalkenyl including 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R1) and O, and S(O)0-2, and wherein one or more of the carbon atoms of the heterocyclyl or heterocycloalkenyl are optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R8; 20 • heteroaryl including 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R1), O, and S(O)0-2, wherein at least one ring in the system is aromatic and wherein one or more of the carbon atoms of the heteroaryl are optionally substituted with from 1-4 substituents independently selected from oxo and R8; 25 each occurrence of R1is independently selected from the group consisting of: deuterium, halo, C1-6alkyl optionally substituted with from 1-3 independently selected R13; -C(O)(C1-4alkyl); -C(O)O(C1-4alkyl); -CONR10R10; -S(O)1-2NR10R10; -S(O)1-2(C1-4alkyl); -OH; C1-4alkoxy; -C0-13

[0014] PAT059977-WO-PCT 6alkylene(C3-6 cycloalkyl) optionally substituted with from 1-3 independently selected R13; and - C0-6alkylene(C3-6 heterocyclyl) optionally substituted with from 1-3 independently selected R13; R2is selected from the group consisting of hydrogen, deuterium, CH3, CHF2, CF3, OMe, F, Cl and Br; 5 each of R3, R4and R5is independently selected from the group consisting of hydrogen, deuterium, halo, cyano, C1-4alkyl which is optionally substituted with from 1-4 independently selected R10, C3-4 cycloalkyl which is optionally substituted with from 1-3 independently selected R10, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, NR9R9, –OH, -NO2, and -C(=O)OH; each of R6A, R6B, R6C, and R6Dis independently selected from the group consisting of: 10 hydrogen; oxo; deuterium, halo; cyano; C1-4alkyl which is optionally substituted with from 1-4 independently selected R11; C3-4 cycloalkyl which is optionally substituted with from 1-4 independently selected R11; C2-4 alkenyl which is optionally substituted with from 1-4 independently selected R11; C2-4alkynyl which is optionally substituted with from 1-4 independently selected R11; C1-4 alkoxy which is optionally substituted with from 1-415independently selected R11;–OH; -NO2; and -C(=O)OH; each occurrence of R7is independently selected from the group consisting of: –OH; -halo; –NR9R9; C1-4alkylene; C1-4alkoxy; C1-4haloalkoxy; -C(=O)O(C1-4alkyl); -C(=O)(C1-4alkyl); - C(=O)OH; -S(O)1-2(C1-4 alkyl); and cyano; or two R7can be taken together to form a C3-4cycloalkyl ring; 20 each occurrence of R8is independently selected from the group consisting of: deuterium; halo; cyano; C1-5 alkyl which is optionally substituted with from 1-6 independently selected R12; C1-5 haloalkyl which is optionally substituted with from 1-6 independently selected R12; C3-6 cycloalkyl which is optionally substituted with from 1-4 independently selected R12; C2-6alkenyl which is optionally substituted with from 1-6 independently selected R12; C2-6alkynyl which is25optionally substituted with from 1-6 independently selected R12; C1-4 alkoxy which is optionally substituted with from 1-6 independently selected R12; C1-4haloalkoxy which is optionally substituted with from 1-6 independently selected R12; -NR9R9; –OH; -NO2; and -C(=O)OH; each occurrence of R9is independently selected from the group consisting of: hydrogen, deuterium, C1-4 alkoxy; and C1-4 alkyl; 30 each occurrence of R10, R11, and R13is independently selected from the group consisting of: –OH; -halo; –NR9R9; C1-4 alkyl; C1-4 haloalkyl; C1-4 alkoxy; -C(=O)O(C1-4 alkyl); -C(=O)(C1- 4 alkyl); -C(=O)OH; -S(O)1-2(C1-4 alkyl); and cyano; each occurrence of R12, is independently selected from the group consisting of: –OH; - halo; –NR9R9; C1-4alkyl; C1-4alkoxy; C1-4haloalkoxy; -C(=O)O(C1-4alkyl); -C(=O)(C1-4alkyl);35-C(=O)OH; -S(O)1-2(C1-4 alkyl); C3-6 cycloalkyl; and cyano; 14

[0015] PAT059977-WO-PCT each occurrence of R14is independently selected from the group consisting of: deuterium; -OH; -halo; C1-2 alkyl; C1-2 alkoxy; C1-2 haloalkyl; and C1-2 haloalkoxy. In some embodiments, the compound has Formula (II): 5 wherein X1, X2and X3are each selected from the group consisting of CR6Dand N, and 10 wherein a maximum of one of X1, X2and X3may be N. In some embodiments, the compound has Formula (III): 15 wherein Y and Z are independently selected from the group consisting of CH, CR14and N, wherein at least one of Y and Z is N and wherein m is 0 or 1. In some embodiments, the compound has Formula (IV): 20 Formula (IV) wherein Y is selected from the group consisting of CH, CR14and N. 15

[0016] PAT059977-WO-PCT In some embodiments, R2is Cl. In some embodiments, at least one of R3, R4and R5is H. In some embodiments, at least two of 5 R3, R4and R5is H. In some embodiments, all of R3, R4and R5are H. In some embodiments, R9is hydrogen. In some embodiments, the compound is of Formula (V): 10 Formula (V) or a pharmaceutically acceptable salt thereof. In some embodiments, Ring A is selected from the group consisting of:15• , wherein * is the point of attachment to L, X1, X2and X3are each selected from the group consisting of CH and N, and wherein a maximum of one of X1, X2and X3may be N; or • , wherein Z is the point of attachment to L, and Y and Z are independently selected from the group consisting of CH and N; 20 Ring B is selected from the group consisting of: • heterocyclyl or heterocycloalkenyl including 5-9 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R1) and O, and wherein one or more of the carbon atoms of the heterocyclyl or heterocycloalkenyl are optionally substituted with from 1-4 substituents independently 25 selected from the group consisting of oxo and R8; or • heteroaryl including 5-9 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R1), and O, wherein at 16

[0017] PAT059977-WO-PCT least one ring in the system is aromatic and wherein one or more of the carbon atoms of the heteroaryl are optionally substituted with from 1-4 substituents independently selected from oxo and R8; and L is selected from the group consisting of a bond, *-O(C1-C4 alkylene)-, and *-C1-C4 alkylene-, 5 wherein the alkylene is optionally substituted with 1-2 R7, wherein * denotes the point of attachment of L to Ring A, wherein L is a bond or *-C1-C4alkylene- when Z is N. In some embodiments, Ring A is selected from the group consisting of: • , wherein * is the point of attachment to L, wherein X1and X210 are each selected from the group consisting of CH and N and wherein a maximum of one of X1and X2may be N; or • , wherein N is the point of attachment to L, and wherein Y is selected from the group consisting of CH and N; Ring B is selected from the group consisting of:15• heterocyclyl or heterocycloalkenyl including 5-9 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R1) and O, wherein one or more of the carbon atoms of the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R8; or 20 • heteroaryl including 5-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R1), and O, wherein at least one ring in the system is aromatic, wherein one or more of the carbon atoms of the heteroaryl is optionally substituted with from 1-4 substituents independently selected from oxo and R8; and 25 L is selected from the group consisting of a bond, *-O(C1-C4alkylene)-, and *-C1-C4alkylene-, wherein the alkylene is optionally substituted with 1-2 R7, wherein * denotes the point of attachment of L to Ring A, wherein L is a bond or *-C1-C4 alkylene- when Z is N. In some embodiments, Ring A is selected from the group consisting of: 17

[0018] PAT059977-WO-PCT • , wherein * is the point of attachment to L, X1, X2and X3are each selected from the group consisting of CH and N, and wherein a maximum of one of X1, X2and X3may be N; or • , wherein Z is the point of attachment to L and Y and Z are 5 independently selected from the group consisting of CH and N. In some embodiments, Ring A is selected from the group consisting of: • , wherein * is the point of attachment to L, wherein X1and X2are each selected from the group consisting of CH and N and wherein a maximum10of one of X1and X2may be N. • , wherein Z is the point of attachment to L and at least one of Y and Z are N. In some embodiments, Ring , wherein * is the point of attachment to L, X1, X2and X3are each selected from the group consisting of CH and N, and wherein a maximum of 15 one of X1, X2and X3may be N. In some embodiments, Ring , wherein * is the point of attachment to L, X1and X2are each selected from the group consisting of CH and N, and wherein a maximum of one of X1and X2may be N. 18

[0019] PAT059977-WO-PCT In some embodiments, Ring , wherein * is the point of attachment to L, and wherein X1is selected from the group consisting of CH and N. In some embodiments, Ring , wherein * is the point of attachment to L. In some embodiments, Ring . 5 In some embodiments, Ring , wherein Z is the point of attachment to L, Y and Z are independently selected from the group consisting of CH and N. In some embodiments, Ring . In some embodiments, Ring 10 In some embodiments, Ring A is selected from the group consisting of: , In some embodiments, L is selected from the group consisting of a bond, *-O(C1-C4alkylene)-, 15 and *-C1-C4alkylene-, wherein the alkylene is optionally substituted with 1-2 R7, wherein * 19

[0020] PAT059977-WO-PCT denotes the point of attachment of L to Ring A, wherein L is a bond or *-C1-C4 alkylene- when Z is N. In some embodiments, L is selected from the group consisting of a bond, *-methylene and *-O- 5 methylene, wherein * indicates the point of attachment of L to Ring A. In some embodiments, L is a bond. In some embodiments, Ring B is selected from the group consisting of: 10 • heterocyclyl or heterocycloalkenyl including 5-9 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R1) and O, and wherein one or more of the carbon atoms of the heterocyclyl or heterocycloalkenyl are optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R8; 15 • heteroaryl including 5-9 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R1), and O, wherein at least one ring in the system is aromatic and wherein one or more of the carbon atoms of the heteroaryl are optionally substituted with from 1-4 substituents independently selected from oxo and R8. 20 In some embodiments, Ring B is selected from the group consisting of: • heterocyclyl or heterocycloalkenyl including 5-9 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R1) and O, wherein one or more of the carbon atoms of the heterocyclyl or heterocycloalkenyl 25 is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R8; • heteroaryl including 5-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R1), and O, wherein at least one ring in the system is aromatic, wherein one or more of the carbon atoms of the30heteroaryl is optionally substituted with from 1-4 substituents independently selected from oxo and R8. In some embodiments, Ring B is heterocyclyl including 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R1) 35 and O, and S(O)0-2, and wherein one or more of the carbon atoms of the heterocyclyl are optionally 20

[0021] PAT059977-WO-PCT substituted with from 1-4 substituents independently selected from the group consisting of oxo and R8. In some embodiments, Ring B is heterocycloalkenyl including 5-10 ring atoms, wherein from 1- 5 4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R1) and O, and S(O)0-2, and wherein one or more of the carbon atoms of the heterocycloalkenyl are optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R8. 10 In some embodiments, Ring B is heteroaryl including 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R1), O, and S(O)0-2, wherein at least one ring in the system is aromatic and wherein one or more of the carbon atoms of the heteroaryl are optionally substituted with from 1-4 substituents independently selected from oxo and R8.15In some embodiments, Ring B is as defined herein, wherein the ring atoms that are heteroatoms are each independently selected from the group consisting of N, N(H), N(R1), and O. In some embodiments, Ring B contains 5-9 ring atoms. 20 In some embodiments, Ring B contains 5-6 ring atoms. In some embodiments, Ring B contains from 1-3 heteroatoms.25In some embodiments, Ring B contains from 1-2 heteroatoms. In some embodiments, one of the carbon atoms of Ring B is substituted with oxo. In some embodiments, R1is selected from the group consisting of: C1-6alkyl optionally substituted 30 with from 1-3 independently selected R13; and -C0-6alkyl(C3-6cycloalkyl) optionally substituted with from 1-3 independently selected R13. In some embodiments, R1is selected from the group consisting of: C1-6alkyl; and -C0-6alkyl(C3-6cycloalkyl).3521

[0022] PAT059977-WO-PCT In some embodiments, R1is C1-6 alkyl optionally substituted with from 1-3 independently selected R13. In some embodiments, R1is C1-6 alkyl. 5 In some embodiments, R1is methyl or ethyl optionally substituted with from 1-3 independently selected R13. In some embodiments, R13is selected from the group consisting of -C1-4alkoxy; and halo. 10 In some embodiments, R13is selected from the group consisting of -methoxy; ethoxy and F. In some embodiments, Ring B is selected from the group consisting of: , , 15 , wherein one or more of the carbon atoms is optionally substituted with from 1-4 R8substituents. 22

[0023] PAT059977-WO-PCT In some embodiments, Ring B is selected from the group consisting of: , 5 , 23

[0024] PAT059977-WO-PCT , wherein one or more of the carbon atoms is optionally substituted with from 1-4 R8substituents. In some embodiments, R8is C1-5alkyl which is optionally substituted with from 1-6 independently 5 selected R12. In some embodiments, R8is C1-3alkyl which is optionally substituted with from 1-2 independently selected R12. 10 In some embodiments, R8is selected from the group consisting of: methyl, propyl, and isopropyl each of which may be optionally substituted with from 1-2 independently selected R12. In some embodiments, R12is selected from the group consisting of -C1-4 alkoxy; and -OH. 15 In some embodiments, R12is selected from the group consisting of methoxy and -OH. In some embodiments, Ring B is selected from the group consisting of: , , 24

[0025] PAT059977-WO-PCT 5 , . 10 In preferred embodiments, the compound is a compound of Formula (VI): 25

[0026] PAT059977-WO-PCT Formula (VI) or a pharmaceutically acceptable salt thereof, wherein: 5 Ring A is selected from the group consisting of: • , wherein * is the point of attachment to L, wherein X1and X2are each selected from the group consisting of CH and N and wherein a maximum of one of X1and X2may be N; or • , wherein Z is the point of attachment to L, Y is selected from the10group consisting of CH and N, and wherein Z is N; Ring B is selected from the group consisting of: • heterocyclyl or heterocycloalkenyl including 5-9 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R1) and O, wherein one or more of the carbon atoms of the heterocyclyl or 15 heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R8; or • heteroaryl including 5-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R1), and O, wherein at least one ring in the system is aromatic, wherein one or more of the carbon atoms of the 20 heteroaryl is optionally substituted with from 1-4 substituents independently selected from oxo and R8; and L is selected from the group consisting of a bond, *-O(C1-C4 alkylene)-, and *-C1-C4 alkylene-, wherein the alkylene is optionally substituted with 1-2 R7, wherein * denotes the point 25 of attachment of L to Ring A, wherein L is a bond or *-C1-C4 alkylene- when Z is N. 26

[0027] PAT059977-WO-PCT In some embodiments, the compound is selected from the group consisting of the compounds in Table 1, or a pharmaceutically acceptable salt thereof. Pharmaceutical Compositions 5 In another aspect, the present disclosure provides a pharmaceutical composition that includes any one of the compounds described herein, or a pharmaceutically acceptable salt thereof (e.g., a therapeutically effective amount of the compound or salt), and a pharmaceutically acceptable excipient. The pharmaceutical compositions provided herein can be administered by a variety of 10 routes including, but not limited to, oral (enteral) administration, parenteral (by injection) administration, rectal administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous (SC) administration, intravenous (IV) administration, intramuscular (IM) administration, and intranasal administration. Details of such formulations and processing thereof are set forth in Part 8 of Remington’s Pharmaceutical Sciences, 17th edition,151985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference. Methods of Use In one aspect, this disclosure features methods of degrading VAV1 in a subject, which 20 include administering to the subject an effective amount of a compound described herein, or pharmaceutically acceptable salt thereof. The compounds described herein can bind to a specific amino acid sequence of VAV1, thereby causing degradation of VAV1. In some embodiments, the compound mediates the interaction of a VAV1 protein with an E3 ligase, thereby increasing degradation of the VAV1 protein. In some embodiments, VAV1 is a regulator of a lymphocyte.25In an embodiment, the compound interacts with the E3 ligase prior to the interaction of VAV1 with the E3 ligase. In some embodiments, the E3 ligase comprises cereblon. Degradation of VAV1 is mediated by the compound interacting with both the specific amino acid sequence of VAV1 and an E3 ligase. Thus, in another aspect, this disclosure features methods of degrading VAV1, which include: (i) contacting a compound described herein or a 30 pharmaceutically acceptable salt thereof with an E3 ligase; and (ii) interacting the contacted E3 ligase with VAV1, thereby degrading VAV1. In some embodiments, the E3 ligase comprises cereblon. In a further aspect, this disclosure features methods of treating a variety of disorders which include administering the compounds and pharmaceutical compositions described herein. Such 27

[0028] PAT059977-WO-PCT disorders include, without limitation, autoimmune diseases (e.g., multiple sclerosis, rheumatoid arthritis, myasthenia gravis), transplantation setting disease (e.g., graft-versus-host disease), and cancers, tumours or other malignancies, (e.g. a T cell or B cell malignancy). In an aspect, this disclosure features methods of treating a disorder caused by or associated 5 with disregulation of lymphocyte development or activation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the disorder is autoimmune disease (e.g., multiple sclerosis, psoriatic arthritis, rheumatoid arthritis, myasthenia gravis). In some embodiments, the disorder is transplantation setting disease (e.g., graft-versus- 10 host disease). In some embodiments, the disorder is a cancer or tumor. In some embodiments, the disorder is a malignancy (e.g., T cell or B cell malignancy). In some embodiment, the lymphocyte is T-cell. In some embodiments, the lymphocyte is B-cell. In an aspect, this disclosure features methods of treating a disorder caused by or associated with dysregulation of T-cell receptor signaling in a subject in need thereof, comprising15administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the T-cell receptor signaling are enhanced CD69 surface expression, IFNɣ or IL-2. In an aspect, this disclosure features methods of treating a disorder caused by or associated with VAV1 polymorphisms in a subject in need thereof, comprising administering to the subject 20 a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. In an aspect, this disclosure features methods of treating a disorder caused by or associated with immunopathologies in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable25salt thereof. In some embodiments, the disorder is autoimmune disorder. In some embodiments, the autoimmune disorder is selected from the group consisting of multiple sclerosis, psoriatic arthritis, rheumatoid arthritis, systemic lupus, erythematosus, Hashimoto’s thyroiditis, myasthenia gravis, diabetes type I or II, and the disorders associated therewith, vasculitis, pernicious anemia, Sjoegren 30 syndrome, uveitis, psoriasis, Graves ophthalmopathy, alopecia areata and others, allergic diseases (e.g., allergic asthma, atopic dermatitis, allergic rhinitis / conjunctivitis, allergic contact dermatitis), inflammatory diseases optionally with underlying aberrant reactions (e.g., inflammatory bowel disease, Crohn’s disease or ulcerative colitis, intrinsic asthma, inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury), atherosclerosis, osteoarthritis, irritant35contact dermatitis and further eczematous dermatitis, seborrheic dermatitis, cutaneous 28

[0029] PAT059977-WO-PCT manifestations of immunologically-mediated disorders, inflammatory eye disease, keratoconjunctivitis, myocarditis or hepatitis. In some embodiments, the disorder is a cancer, tumour or other malignancy, optionally wherein the disorder is a T cell or B cell malignancy. In some embodiments, the disorder is selected 5 from the group consisting of: leukemia, lymphoma, T-cell prolymphocytic leukemia, T-cell granular lymphocytic leukemia, aggressive NK cell leukemia, hairy-cell leukemia, nasal and nasal- type NK / T cell lymphoma, mycosis fungoides and Sezary syndrome, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma unspecified, adult T-cell leukemia / lymphoma (HTLV1+), anaplastic large cell lymphoma, primary cutaneous CD-30 positive T-cell lymphoproliferative 10 disorders, cutaneous T-cell lymphoma, subcutaneous panniculitis like T-cell lymphoma, intestinal T-cell lymphoma (+enteropathy), hepatosplenic gamma / delta T-cell lymphoma, and non-Hodgkin lymphomas (e.g., B-cell non-Hodgkin lymphomas; e.g., Burkitt lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), diffuse large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma).15In some embodiments, the disorder is a transplantation setting disease. In some embodiments, the disorder is selected from graft-versus-host disease, chronic graft rejection, acute graft rejection, transplant vasculopathy, graft vessel disease, graft atherosclerosis, and transplant coronary disease. In some embodiments, the disorder is T-cell mediated. In some embodiments, the disorder 20 is selected from the group consisting of Diabetes Type I or II, pernicious anemia, uveitis, psoriasis, alopecia areata, ulcerative colitis, Chron’s disease, atherosclerosis, myocarditis, pericarditis, pulmonary fibrosis, systemic sclerosis, morphea, Alzheimer’s disease, Acute Graft-vs. Host Disease or T-cell mediated kidney disease. In some embodiments, the disorder is T / B-cell mediated. In some embodiments, the25disorder is selected from the group consisting of multiple sclerosis, psoriatic arthritis, rheumatoid arthritis, myasthenia gravis, Sjogren’s syndrome, Grave’s disease, an allergic disorder (e.g., asthma, allergic contact dermatitis, rhinitis or contact dermatitis), an autoimmune liver disease (e.g., biliary sclerosis or sclerosing cholangitis), chronic inflammatory demyelinating polyradiculoneuropathy, macular degeneration, systemic lupus erythematosus, Hashimoto’s 30 thyroiditis, amyloidosis, inflammatory eye diseases, pemphigus, systemic lupus erythematosus, Chronic Graft vs. Host Disease, lupus nephritis, pulmonary arterial hypertension or vasculitis. In some embodiments, the disorder is selected from the group consisting of ulcerative colitis, psoriatic arthritis, rheumatoid arthritis, psoriasis, multiple sclerosis, myasthenia gravis, cutaneous lupus or axial spondylarthritis. 29

[0030] PAT059977-WO-PCT In some embodiments, the disorder is selected from the group consisting of B-cell lymphoma, B-cell leukemia, T-cell lymphoma, T-cell leukemia or acute myeloid leukemia. In some embodiments, the disorder is a non-Hodgkin lymphoma. In some embodiments, the disorder is selected from mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL) 5 and Diffuse large B cell lymphoma (DLBCL). In some embodiments, the disorder is chronic lymphocytic leukemia (CLL). In some embodiments, the disorder is multiple sclerosis (MS). In some embodiments, the disclosure relates to a method of treating patients exhibiting CD226 overexpression. 10 In some embodiments, the disclosure relates to a method of treating patients having a CD226 risk variant. In some embodiments, the disclosure relates to a method of treating patients having a CD226 polymorphism. In some embodiments, the disclosure relates to a method of treating patients having a15Gly307Ser (G307S) amino acid substitution in CD226 (rs763361T allele). In an aspect, the disclosure provides a compound or pharmaceutically acceptable salt for use in any of the above-recited methods of treatment. In some embodiments, the compound or pharmaceutically acceptable salt thereof is a compound or pharmaceutically acceptable salt 20 thereof as described herein. In a further aspect, the disclosure provides the use of a compound or pharmaceutically acceptable salt for the manufacture of a medicament for any of the above-recited methods of treatment. In some embodiments, the compound or pharmaceutically acceptable salt thereof is a compound or pharmaceutically acceptable salt thereof as described herein. In an aspect, the disclosure provides a degrader conjugate as described herein for use in any of the above-recited25methods of treatment. Degrader Conjugates In an aspect is a conjugate comprising a compound of Formula (I). For instance, in an aspect is an 30 antibody-degrader conjugate or pharmaceutically acceptable salt thereof comprising a compound of Formula (I). The conjugate includes a compound of Formula (I) or pharmaceutically acceptable salt thereof which is conjugated to an antibody via a linker structure moiety. In some embodiments, the conjugate has a structure according to Formula (A) below:3530

[0031] PAT059977-WO-PCT Bm – (– M– I)aFormula (A) in which I is a compound of Formula (I) or a pharmaceutically acceptable salt thereof as defined 5 herein, M is a linker moiety, Bm is a binding moiety that is capable of specifically binding to an antigen, and a is from 1 to 10. The binding moiety may be an antibody, antibody fragment or an antibody-binding fragment. In some embodiments, I is one of Compounds 1-77. 10 In some embodiments, the disclosure provides an antibody-drug conjugate or pharmaceutically acceptable salt thereof according to Formula (A1): Formula (A1)15in which Ring A, Ring B, L, R2, R3, R4and R5can be as defined anywhere here, M is a linker moiety, Bm is a binding moiety that is capable of specifically binding to a protein, as defined above, and a is from 1 to 10. In some embodiments, Ring A, Ring B, L, R2, R3, R4and R5are defined to provide a compound selected from any one of Compounds 1-77. 20 In some embodiments, the disclosure provides an antibody-drug conjugate or pharmaceutically acceptable salt thereof according to Formula (A4): Formula (A4) 25 31

[0032] PAT059977-WO-PCT in which Ring A, Ring B, L, R2, R3, R4and R5can be as defined anywhere here, M is a linker moiety, Bm is a binding moiety that is capable of specifically binding to a protein, as defined above, and a is from 1 to 10. In some embodiments, Ring A, Ring B, L, R2, R3, R4and R5are defined to provide a compound selected from any one of Compounds 1-77. 5 In some embodiments, the disclosure provides an antibody-drug conjugate or pharmaceutically acceptable salt thereof according to Formula (A5): 10 in which Ring A, Ring B, L, R2, R3, R4and R5can be as defined anywhere here, M is a linker moiety, Bm is a binding moiety that is capable of specifically binding to a protein, as defined above, a is from 1 to 10, RXis selected from hydrogen, -(CH2CH2O)v-CH3, C2-C6alkenyl, C1-C6alkyl, C2-C6alkynyl, benzyl, C3-C6cycloalkyl, and C3-C6cycloalkyl(C1-C3alkyl), and v is from 15 1 to 24. In some embodiments, Ring A, Ring B, L, R2, R3, R4and R5are defined to provide a compound selected from any one of Compounds 1-77. In some embodiments, M is a linker as defined in WO 2021 / 198966, which is incorporated by reference in its entirety. The linker may be a cleavable linker or non-cleavable linker. In certain 20 aspects, the linker can contain a heterobifunctional group. In the present disclosure, the term "heterobifunctional group" refers to a chemical moiety that connects the linker of which it is a part to the binding moiety. Heterobifunctional groups are characterized as having different reactive groups at either end of the chemical moiety. Attachment to Bm, can be accomplished through chemical or enzymatic conjugation, or a combination of both. Chemical conjugation involves the 25 controlled reaction of accessible amino acid residues on the surface of the binding moiety with a reaction handle on the heterobifunctional group. Examples of chemical conjugation include, but are not limited to, lysine amide coupling, cysteine mediated coupling, and coupling via a non- natural amino acid incorporated by genetic engineering, wherein non-natural amino acid residues with a desired reaction handle are installed onto Bm. In enzymatic conjugation, an enzyme 32

[0033] PAT059977-WO-PCT mediates the coupling of the linker with an accessible amino residue on the binding moiety. Examples of enzymatic conjugation include, but are not limited to, transpeptidation using sortase, transpeptidation using microbial transglutaminase, and N-glycan engineering. Chemical conjugation and enzymatic conjugation may also be used sequentially. For example, enzymatic 5 conjugation can also be used for installing unique reaction handles on Bm to be utilized in subsequent chemical conjugation. In some embodiments, M is a linker as defined in WO 2023 / 037268, which is incorporated by reference in its entirety. In some embodiments, M is selected from the group consisting of 10wherein: q is from 2 to 10; Z1, Z2, Z3, Z4, and Z5are each independently absent or a naturally-occurring amino acid residue in the L- or D-configuration, provided that at least two of Z1, Z2, Z3, Z4, and Z5are amino acid 15 residues; is the point of attachment to the parent molecular (degrader) moiety; and is the point of attachment to the binding moiety. In some embodiments, Z1, Z2, Z3, Z4, and Z5are independently absent or selected from the group20 consisting of L-valine, D-valine, L-citrulline, D-citrulline, L-alanine, D-alanine, L- glutamine, D- glutamine, L-glutamic acid, D-glutamic acid, L-aspartic acid, D-aspartic acid, L- asparagine, D- asparagine, L-phenylalanine, D-phenylalanine, L-lysine, D-lysine, and glycine; provided that at least two of Z1, Z2, Z3, Z4, and Z5are amino acid residues.25The term “binding moiety” as used herein refers to any molecule that recognizes and binds to a cell surface marker or receptor. The binding moiety may be an antibody, antibody fragment, or an 33

[0034] PAT059977-WO-PCT antigen-binding fragment. An antibody is a protein generated by the immune system that is capable of recognizing and binding to a specific antigen. A target antigen generally has numerous binding sites, also called epitopes, recognized by CDRs on multiple antibodies. Each antibody that specifically binds to a different epitope has a different structure. Thus, one antigen may have more 5 than one corresponding antibody. The term "antibody" herein is used in the broadest sense and specifically covers monoclonal antibodies, single domain antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, so long as they exhibit the desired biological activity. Antibodies may be murine, human, humanized, chimeric, or derived from other species. A monoclonal antibody (mAb) to an antigen-of-interest can be 10 prepared by using any technique known in the art which provides for the production of antibody molecules by continuous cell lines in culture. These include, but are not limited to, the hybridoma technique, the human B cell hybridoma technique, and the EBV-hybridoma technique. Such antibodies may be of any immunoglobulin class including IgG, IgM, IgE, IgA, and IgD and any subclass thereof. The hybridoma producing the mAbs of use in this disclosure may be cultivated15in vitro or in vivo. The skilled person would understand how to provide an appropriate binding moiety for use in a conjugate depending on the intended therapeutic use. This is described, for example, in Nature Reviews Drug Discovery volume 22, pages 641–661 (2023), which is incorporated by reference 20 in its entirety. In particular, an antibody, antibody fragment or an antibody-binding fragment used as a binding moiety must be capable of targeting a particular cell surface marker or receptor associated with the disorder to be treated. For example, the antibody trastuzumab can be employed if the desired target is HER2. 25 In some embodiments, the binding moiety is capable of binding to an antigen selected from ⍺4β7, CD3, CD4, CD20, OX40, CD28, PD-1, ICOS, BCMA / TACl, CD52, CD30, CD19, CCR8, CD79b, CD22, CD4, CD7, CD38, CD33 or CD8 or combinations thereof. In preferred embodiments, the binding moiety is capable of binding to an antigen selected from CD19, CD20, CD33, CD4, CD8, PD-1, ICOS and CD38.30In some embodiments, the binding moiety comprises an antibody selected from Vedolizumab, Etrolizumab, Teplizumab, Zanolimumab, Rituximab, Ublituximab, Ofatumumab, Ocrelizumab, Inebilizumab, Rocatinlimab, Nivolumab, Pembrolizumab, Alemtuzumab, Brentuximab vedotin, Tafasitamab, Loncastuximab, Mogamulizumab, Polatuzumab, Inotuzumab, Epratuzumab, 35 Isatuximab and Daratumumab. 34

[0035] PAT059977-WO-PCT In some embodiments, the binding moiety is capable of binding to CD19 and is preferably Tafasitamab, Loncastuximab or Inebilizumab. In some embodiments, the binding moiety is capable of binding to CD20 and is preferably Rituximab, Ublituximab, Ofatumumab, Ocrelizumab 5 or Inebilizumab. In some embodiments, the binding moiety is capable of binding to CD33. In some embodiments, the binding moiety is capable of binding to CD4 and is preferably Zanolimumab. In some embodiments, the binding moiety is capable of binding to CD8. In some embodiments, the binding moiety is capable of binding to PD-1 and is preferably Nivolumab or Pembrolizumab. In some embodiments, the binding moiety is capable of binding to ICOS. In some embodiments, 10 the binding moiety is capable of binding to CD38 and is preferably Isatuximab or Daratumumab. In some embodiments, the disclosure provides a method of treating ulcerative colitis (UC), Crohn’s disease (CD), human immunodeficiency virus (HIV) / acquired immunodeficiency syndrome (AIDS), immune-mediated colitis (PhI open label), type 1 diabetes (T1D), pouchitis,15graft-versus-host disease (GvHD), Celiac disease, rheumatoid arthritis (RA), psoriasis (PsO), late onset rejection, Pemphigus vulgaris, cutaneous lupus erythematosus (CLE), systemic sclerosis (SSc), Grave’s disease, relapse-remitting / primary progressive multiple sclerosis (RR / PP MS), lupus nephritis, systemic lupus erythematosus (SLE), thrombotic thrombocytopenic purpura, nephrotic syndrome; idiopathic thrombocytopenic purpura, microscopic polyangiitis, atopic 20 dermatitis (AD), transplant rejection, juvenile idiopathic arthritis, multiple sclerosis (MS), chronic lymphocytic leukemia (CLL), T-cell prolymphocytic leukemia, precursor cell lymphoblastic leukemia-lymphoma, Anaplastic large cell lymphoma; Hodgkin's disease; Mycosis fungoides; Peripheral T-cell lymphoma; Primary cutaneous anaplastic large cell lymphoma; T-cell lymphoma, adult T-cell leukemia-lymphoma; diffuse scleroderma; Germ cell cancer; malignant-25mesothelioma; mastocytosis; non-Hodgkin's lymphoma; Sezary syndrome; Solid tumors, HIV-1 infections, Chronic lymphocytic leukemia; Follicular lymphoma; Granulomatosis with polyangiitis; idiopathic thrombocytopenic purpura; lymphoproliferative disorders; microscopic polyangiitis; marginal zone B-cell lymphoma, relapsed-refractory diffuse large B cell lymphoma (R / R DLBCL), B-cell lymphoma, precursor B-cell lymphoblastic leukemia-lymphoma, precursor 30 cell lymphoblastic leukemia-lymphoma, mantle cell lymphoma, Waldenstrom’s macroglobulinemia, cutaneous T-cell lymphoma; Richter’s syndrome, relapsed / refractory acute lymphoblastic leukemia (R / R-ALL), precursor cell lymphoblastic leukemia-lymphoma, precursor B-cell lymphoblastic leukemia-lymphoma, chronic myelogenous leukemia (CML), cutaneous and peripheral T lymphoma, acute biphenotypic leukemia; Burkitt's lymphoma, T-cell acute35lymphoblastic leukemia (T-ALL), relapsed / refractory multiple myeloma (R / R MM), melanoma, 35

[0036] PAT059977-WO-PCT acute myeloid leukemia; chronic lymphocytic leukemia; Myelodysplastic syndromes; Plasmablastic lymphoma; precursor T-cell lymphoblastic leukemia-lymphoma; amyloid light- chain amyloidosis, multiple myeloma (MM) and solid tumors in a subject in need thereof, wherein the method comprises administering the antibody-drug conjugate to the subject. 5 Exemplary combinations of antibodies, target antigens, and associated therapeutic indications are listed in the table below. In some embodiments, the binding moiety of the antibody-drug conjugate comprises an antibody listed in the table below and targets an antigen listed in the table below. In some aspects, the disclosure provides a method of treating a disorder listed in the table below 10 comprising administering to a subject in need thereof an antibody-drug conjugate comprising an antibody listed in the table below. 36

[0037] PAT059977-WO-PCT 37

[0038] PAT059977-WO-PCT 38

[0039] PAT059977-WO-PCT 39

[0040] PAT059977-WO-PCT Exemplary combinations of target antigens, and associated therapeutic indications are listed in the table below. In some embodiments, the binding moiety of the antibody-drug conjugate comprises targets an antigen listed in the table below. In some aspects, the disclosure provides a method of 5 treating a disorder listed in the table below comprising administering to a subject in need thereof an antibody-drug conjugate comprising a binding moiety which targets an antigen listed in the table below. In some aspects, the disclosure provides a method of treating a disorder listed in the table below comprising administering to a subject in need thereof an antibody-drug conjugate comprising an antibody listed in the table below.10 40

[0041] PAT059977-WO-PCT The antibody-drug conjugate may be administered as part of a pharmaceutical composition. The pharmaceutical composition may include excipients such as those recited herein. 5 Non-Limiting Exemplary Compounds In some embodiments is a compound of Table 1 or a pharmaceutically acceptable salt thereof. Table 1: 41

[0042] PAT059977-WO-PCT 42

[0043] PAT059977-WO-PCT 43

[0044] PAT059977-WO-PCT 44

[0045] PAT059977-WO-PCT Examples Abbreviations: Å = Angstrom; APhos Pd G3: [4-(Di-tert-butylphosphino)-N,N-dimethylaniline- 5 2-(2′-aminobiphenyl)]palladium(II) methanesulfonate; B2Pin2: bis(pinacolato)diboron; Boc: tert- butyloxycarbonyl; BrettPhos Pd G3: [(2-Di-cyclohexylphosphino-3,6-dimethoxy-2′,4′,6′- triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′ -biphenyl)]palladium(II) methanesulfonate; brd: broad doublet; brdd: broad doublet of doublet; brs: broad singlet; brt: broad triplet; [n-Bu4NCuI2]2: Bis[(tetrabutylammonium iodide)copper(I) iodide]; eq: equivalents; CuI: copper iodide; Cs2CO3: 10 caesium carbonate; d: doublet; dd: doublet of doublet; ddd: doublet of doublet of doublet; DCM: dichloromethane; DMAC: dimethylacetamide; DMEDA: N,N′-Dimethylethylenediamine; DMF: dimethylformamide; DMSO: dimethyl sulfoxide; DPEO: N,N′-Bis(2-phenylethyl)ethanediamide; ESI: electrospray ionization; h: hours; HCl: hydrochloric acid; HPLC: high-performance liquid chromatography; K2CO3: potassium carbonate; KOAc: potassium acetate; K3PO4: potassium15phosphate; LED: light-emitting diode; m: multiplet; MOM: methoxymethyl ether; MS: mass spectrometry; NMP: N-methyl pyrrolidine; NMR: nuclear magnetic resonance; Phth: phthalimide; q: quartet; s: singlet; Pd(dppf)Cl2: [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II); PSI: pounds per square inch; Pd-PEPPSI-IHeptCl: 3-chloropyridine 4,5-dichloro-1,3-bis[2,6- di(heptan-4-yl)phenyl]-2H-imidazol-2-ide dichloropalladium; Pd-PEPPSI-IPentCl: 3- 20 chloropyridine-4,5-dichloro-1,3-bis[2,6-di(pentan-4-yl)phenyl]-2H-imidazol-2-ide dichloropalladium; quin: quintet; RuPhos Pd G3: (2-Dicyclohexylphosphino-2′,6′-diisopropoxy- 1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate; sat. sol.: saturated solution; t: triplet; tBuONa: sodium tert-butoxide; td: triplet of doublet; Tf: triflate; tt: triplet of triplet; XPhos Pd G4: (SP-4-3)-[Dicyclohexyl[2′,4′,6′-tris(1-methylethyl)[1,1′-biphenyl]-2-25yl]phosphine](methanesulfonato-κO)[2′-(methylamino-κN)[1,1′-biphenyl]-2-yl-κC]palladium. General Schemes and Procedures General Scheme 1 45

[0046] PAT059977-WO-PCT A general synthetic strategy that may be used to prepare compounds of Formula II is depicted in General Scheme 1. Compounds of Formula II may also be used as compounds of Formula I. An aryl halide AA, where Hal is any suitable halogen (e.g. Br or I), may be coupled with an aryl 5 boronate AB using any suitable metal catalyzed coupling conditions. The specific groups X1, X2, X3, L1, R2, R3, R4, R5, R6A, and Ring B are selected on the basis of the desired groups in the compound of Formula II. The desired compound can be prepared using a Suzuki coupling reaction with a palladium catalyst complex such as Pd(dppf)Cl2 (DPPF = 1,1′-Ferrocenediyl- bis(diphenylphosphine)) in the presence of a base such as potassium phosphate. A solvent 10 mixture such as dioxane and water may be used. Alternatively, compounds of Formula II may be prepared from reaction of an aryl boronate of formula AC and an aryl halide of formula AD using Suzuki cross-coupling conditions. LG1 is any leaving group (for example, Br, I or triflate) which can be used in a metal catalyzed coupling reaction of AD to boronate AC.15Aryl boronate AC may be prepared from aryl halides AA using Bis(pinacolato)diboron and a catalyst such as Pd(dppf)Cl2. A weak base such as potassium acetate in a solvent such as dioxane may be used. The reaction may be performed at an elevated temperature, for example 85 degrees Celsius. 46

[0047] PAT059977-WO-PCT General Scheme 2 General Scheme 2 provides a synthetic procedure to prepare compounds of Formula IIIA. 5 Compounds of Formula IIIA may also be used as compounds of Formula I. Intermediate AE can be coupled with a coupling partner such as AF to obtain intermediate AG, where Y and Z are nucleophiles suitable for a Buchwald-Hartwig coupling reaction, such as amines. PG1 is any suitable protecting group that is labile to treatment with acid. Intermediate AH may be obtained from AG upon treatment with an acid, such as HCl 2M in dioxane, at room 10 temperature. Finally, the desired compounds of Formula IIIA can be prepared from intermediates AH and AA using a Buchwald-Hartwig coupling reaction with a palladium catalyst complex such as Pd- PEPPSI-IHeptCl (PEPPSI = 2,6-Di-3-heptylphenyl)imidazol-2-ylidene) in the presence of a base such as caesium carbonate. A solvent such as dioxane may be used. 47

[0048] PAT059977-WO-PCT General Scheme 3 General Scheme 3 provides an alternative synthetic procedure to prepare compounds of Formula IIIA. Compounds of Formula IIIA may also be used as compounds of Formula I. 5 Aryl halide AA, where Hal is any halogen (e.g. Br or I) suitable for metal catalyzed coupling conditions, may be coupled with compound AI, where W1 is a suitable organoboronic acid or ester group. PG2 is any suitable protecting group that is labile to treatment with acid. The desired compound AJ can be prepared via a photocatalyzed coupling reaction with an iridium photosensitizer such as [Ir[dF(CF3)ppy]2(dtbbpy)]PF6 (dF(CF3)ppy = 3,5-difluoro-2-[5- 10 (trifluoromethyl)-2-pyridinyl; dtbbpy = 4,4'-Di-tert-butyl-2,2'-bipyridine) together with a nickel coupling catalyst such as (4,4′-dtbbpy)NiCl2 under irradiation with a LED lamp of suitable wavelength (wavelengths of 395 nm may be used). A solvent such as DMF may be used. Intermediate AK may be obtained from AJ upon treatment with an acid, such as HCl 2M in dioxane, at room temperature.15Finally, the desired compounds of Formula IIIA can be prepared from intermediates AK and AL using a Buchwald-Hartwig coupling reaction with a palladium catalyst complex such as Pd- PEPPSI-IPentCl (PEPPSI = 2,6-Di-3-pentylphenyl)imidazol-2-ylidene) in the presence of a base such as cesium carbonate. A solvent such as DMF may be used. Coupling partners AL are pyridones, where Hal is any halogen (e.g. Br or I) suitable for metal catalyzed coupling 20 conditions. General Scheme 4 48

[0049] PAT059977-WO-PCT General Scheme 4 provides an exemplary synthetic procedure for the preparation of starting material AA used in General Scheme 1. Aniline AL, where Hal is a suitable halogen atom (e.g. Br or I) may be converted into the (phenylamino)propionic acid of formula AM using Michael 5 addition reaction conditions. For example, acrylic acid in the presence of HCl at elevated temperatures (e.g.100 degrees Celsius) affords AM. Compound AM may be converted to intermediate AA upon treatment with urea in a solvent such as acetic acid, at elevated temperatures (e.g.120 degrees Celsius). General Scheme 510 General Scheme 5 provides an exemplary synthetic strategy for the preparation of aryl boronates of formula BD, which may be used as starting materials AB in General Scheme 1. A compound of formula BC may be prepared from BA via a metal-catalyzed coupling reaction with intermediate BB in the presence of a copper(II) catalyst such as copper acetate and a base 15 such as triethylamine, under oxygen atmosphere. A solvent such as dichloromethane may be used. Hal is any halogen (e.g. Br or I) and W1 is an organoboronic acid or ester group suitable for metal catalyzed coupling conditions. X1, X2And X3are CR6D, or N, and R6Aand R8are any suitable substituents which provide a compound of Formula II. Intermediate BD can be prepared by treatment of intermediate BC with bis(pinacolato)diboron in the presence of a 20 palladium catalyst such as Pd(dppf)Cl2 (DPPF = 1,1′-Ferrocenediyl-bis(diphenylphosphine)) and a base such as potassium acetate, at elevated temperature (e.g.80 degrees Celsius) in a solvent such as dioxane. 49

[0050] PAT059977-WO-PCT General Scheme 6 General Scheme 6 provides an exemplary synthetic strategy for the preparation of aryl boronates of formula BG, which may be used as starting materials AB in General Scheme 1. A 5 compound of formula BF may be prepared from BE via an alkylation reaction with intermediate BB in the presence of a base such as potassium carbonate. A solvent such as water may be used. Hal is any halogen (e.g. Br or I), X1, X2And X3are CR6D, or N, and R6A, R6Dand R8are any suitable substituents which provide a compound of formula II. Intermediate BG can be prepared by treatment of intermediate BC with bis(pinacolato)diboron in the presence of a palladium 10 catalyst such as Pd(dppf)Cl2(DPPF = 1,1′-Ferrocenediyl-bis(diphenylphosphine)) and a base such as potassium acetate, at elevated temperature (e.g.100 degrees Celsius) in a solvent such as dioxane. General Scheme 7 15 General Scheme 7 provides an exemplary synthetic strategy for the preparation of aryl triflates of formula CH, which may be used as starting materials AD in General Scheme 1. L is a carbon atom, oxygen atom, or a bond, and n = 1 or 2. X1, X2And X3are CR6D, or N. PG3 is an alkyl or 50

[0051] PAT059977-WO-PCT alkoxyalkyl group that may be removed with BBr3 or an acid (such as HCl). R6A, R6Dand R1are any suitable substituents which provide a compound of Formula II. A compound of formula CC may be prepared from CA via a metal-catalyzed coupling reaction with CB in the presence of a palladium catalyst complex such as t-BuXPhos Pd G3 and a base 5 such as caesium carbonate. A solvent such as 2-methylbutan-2-ol may be used. CD can be afforded from CC via reduction of the nitrile group in the presence of di-tert-butyl dicarbonate, for example with Raney nickel and an H2atmosphere, in a solvent such as THF. Intermediate CE can be prepared by treatment of intermediate CD with a base such as potassium tert-butoxide at elevated temperature (e.g.60 degrees Celsius) in a solvent such as THF. Intermediate CF can be 10 prepared by alkylation of intermediate CE with an appropriate alkylating reagent and in the presence of a base such as sodium hydride, at elevated temperature (e.g.50 degrees Celsius) in a solvent such as THF. Triflate intermediate CH may be formed in two steps from intermediate CF, first by treatment with an acid, such as HCl 2M in dioxane, to afford phenol intermediate CG, then by triflation with any triflating reagent, for example trifluoromethanesulfonyl chloride,15in presence of a base such as triethylamine. General Scheme 8 General Scheme 8 provides an exemplary synthetic strategy for the preparation of aryl halides of formula DG, which may be used as starting materials AD in General Scheme 1. Hal is any20suitable halogen (e.g. Br or I) which may be coupled with an aryl boronate AC in scheme 1. X1, X2And X3are CR6D, or N. R6Aand R6Dare any suitable substituents which provides a compound of Formula II. L is a carbon atom, oxygen atom, or a bond; n = 1 or 2, and m = 0 or 1. PG4 is any suitable protecting group that is labile to treatment with acid. A compound of formula DB may be prepared from DA upon treatment with a reagent such as di- 25 tert-butyldicarbonate in the presence of any trialkylamine base (for example, triethylamine). Oxidation of intermediate DB can provide amide intermediate DC, using an oxidizing system 51

[0052] PAT059977-WO-PCT such as ruthenium (IV) oxide hydrate in the presence of sodium periodate. Intermediate DE may be obtained from DC upon treatment with an acid, such as HCl 2M in dioxane, at room temperature. Compounds of formula DG can be prepared from intermediates DE and DF via a coupling reaction with a copper(I) catalyst such as Cu(I)I in the presence of a base such as 5 potassium phosphate. A solvent such as NMP may be used. General Scheme 9 General Scheme 9 provides exemplary synthetic strategies for the preparation of aryl halides of10formula EB, which may be used as starting materials AD in General Scheme 1. Hal is any suitable halogen (e.g. Br or I) which may be coupled with an aryl boronate AC in General Scheme 1. X1, X2And X3are CR6D, or N. R6Aand R6Dare any suitable substituents which provides a compound of Formula II. Q1 and Q2 are carbon or oxygen atoms, and n = 0 or 1. W2and W3are H, alkyl, or alkoxyalkyl substituents, which may or may not be cyclic. 15 A compound of formula EB may be prepared from EA via a metal-catalyzed coupling reaction in the presence of a copper catalyst such as Cu(I)I and a base such as potassium carbonate. A solvent such as dioxane may be used. General Scheme 10 20 General Scheme 10 provides exemplary synthetic strategies for the preparation of compounds of formula FB, which may be used as starting materials EA in General Scheme 9. W2and W3are H, alkyl, or alkoxyalkyl substituents, which may or may not be cyclic; n = 0 or 1. W4is a substituent containing a carbamate (for example, NH-Boc). Compounds with the formula FB can 52

[0053] PAT059977-WO-PCT be accessed from compounds FA by treatment with a strong base, such as potassium tert- butoxide, in any aprotic solvent, such as THF. The Exemplary Compounds 1-77 were synthesized according to the following schemes. 5 Scheme 1. Synthesis of Exemplary Compounds via Intermediates A and Intermediate B-2 General purification methods Purification Method 1: The residue was purified by Prep-HPLC with a C18 column (type: Phenomenex luna, YMC-Actus Triart, or Welch Xtimate) of the appropriate size. A mobile phase containing a mixture of water10(formic acid condition) [Solvent A] and acetonitrile [Solvent B] was used. An appropriate gradient ranging from 0 to 80% of solvent B was applied. The pure compounds were then lyophilized. Purification Method 2: The residue was purified by column chromatography or prep-TLC (eluting with an appropriate mixture of Petroleum ether and Ethyl acetate) to afford the desired products. 15 General Procedures Step 1: General Procedure 1 Variant 1 Intermediate A (1.00 eq.), Intermediate B-2 (1.50 - 2.20 eq.) and potassium phosphate (2.00 - 3.00 eq.) were dissolved in the appropriate solvent (DMF, dioxane, or a mixture of 10:1 dioxane:water; 20 0.05 - 0.4 M relative to Intermediate A) under nitrogen atmosphere. Pd(dppf)Cl2 (0.10 - 0.15 eq.) was added, then the reaction was heated (90 - 100°C) and stirred until reaction completion (1 - 16 53

[0054] PAT059977-WO-PCT h). The mixture was cooled to room temperature and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 1 to afford the Exemplary Compounds. (If necessary, the residue was first purified via Purification Method 2, then Purification Method 1 to afford the exemplary compounds.) 5 Variant 2 Intermediate A (1.00 eq.) and Intermediate B (1.20 - 3.00 eq.) were dissolved in dioxane (0.03 - 0.2 M relative to Intermediate A) under nitrogen atmosphere. Potassium phosphate (3.00 eq.) and BrettPhos Pd G3 (0.10 eq.) were added, then the reaction was heated (80 - 100°C) and stirred until reaction completion (1 - 12 h). The mixture was cooled to room temperature and concentrated 10 under reduced pressure to give a residue. The residue was purified via Purification Method 1 to afford the Exemplary Compounds. Scheme 2. Synthesis of Intermediates B-0, B-1, and B-215Step 1: Intermediate B-0 To a solution of 3-bromo-2-chloroaniline (4.35 g, 21.1 mmol, 1.00 eq.) and acrylic acid (2.28 g, 31.6 mmol, 2.17 mL, 1.50 eq.) in hydrochloric acid (10 mL) was added tetrabutylammonium iodide (777 mg, 2.10 mmol, 0.10 eq.). The reaction was stirred at 100°C for 12 h. The mixture was cooled to 25°C extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried 20 over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford Intermediate B-0 (5.85 g, 20.2 mmol, 96% yield) as a brown solid. Step 2: Intermediate B-1 A mixture of Intermediate B-0 (1.00 g, 3.59 mmol, 1.00 eq.) and urea (668 mg, 11.1 mmol, 3.1025eq.) in acetic acid (10 mL) was stirred at 120°C for 12 h. The mixture was cooled to 25°C and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with water (3 × 20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a 54

[0055] PAT059977-WO-PCT residue. The residue was purified via Purification Method 2 to afford Intermediate B-1 (496 mg, 1.57 mmol, 44% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ = 10.53 (s, 1H), 7.79 (dd, J = 1.2, 8.0 Hz, 1H), 7.54 (dd, J = 1.2, 8.0 Hz, 1H), 7.41 - 7.33 (m, 1H), 3.80 - 3.69 (m, 1H), 3.64 - 3.58 (m, 1H), 2.79 - 2.64 (m, 5 2H). MS (ESI) m / z 301.0 [M-H]+Step 3: Intermediate B-2 A mixture of Intermediate B-1 (2.00 g, 6.59 mmol, 1.00 eq.), bis(pinacolato)diboron (1.84 g, 7.25 mmol, 1.10 eq.), Pd(dppf)Cl2 (482 mg, 659 μmol, 0.10 eq.), and potassium acetate (1.94 g, 19.8 mmol, 3.00 eq.) in dioxane (30 mL) was degassed by purging with nitrogen, then the reaction was 10 stirred at 85°C for 4 h under nitrogen. The mixture was cooled to 25°C, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford Intermediate B-2 (2.8 g, 4.63 mmol, 70% yield) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ = 10.46 (s, 1H), 7.59 (dd, J = 12.0, 7.6 Hz, 2H), 7.43 - 7.38 (m, 1H), 3.73 - 3.55 (m, 2H), 2.80 - 2.68 (m, 2H), 1.32 (s, 12H). MS (ESI) m / z 351.2 [M+H]+15Table 2. Structures of Intermediates A 55

[0056] PAT059977-WO-PCT 56

[0057] PAT059977-WO-PCT Representative examples Example 1 57

[0058] PAT059977-WO-PCT 2 (190 mg, 434 μmol, 2.00 eq.) and potassium phosphate (138 mg, 650 μmol, 3.00 eq.) were dissolved in a mixture of dioxane:water 10:1 (1.1 mL) under nitrogen. 5 Pd(dppf)Cl2 (16.0 mg, 21.9 μmol, 0.10 eq.) was added, then the reaction was heated to 100°C and stirred until reaction completion (1 h). The mixture was cooled to room temperature and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2, then Purification Method 1 to afford Exemplary Compound 1 (36 mg, 75.0 μmol, 35% yield) as a white solid. 101H NMR (400 MHz, DMSO-d6) δ = 10.49 (s, 1H), 7.54 - 7.41 (m, 5H), 7.19 (d, J = 8.4 Hz, 2H), 3.79 - 3.73 (m, 1H), 3.68 - 3.64 (m, 1H), 3.60 (s, 2H), 3.52 - 3.49 (m, 2H), 3.42 - 3.38 (m, 2H), 3.29 (s, 3H), 2.79 - 2.73 (m, 2H), 0.74 - 0.68 (m, 2H), 0.67 - 0.62 (m, 2H). MS (ESI) m / z 469.1 [M+H]+Example 7 According to General Procedure 1, Variant 2: Intermediate A-7 (40.0 mg, 109 μmol, 1.00 eq.) and Intermediate B- 2 (193 mg, 165 μmol, 1.50 eq.) were dissolved in dioxane (2.00 mL) under nitrogen. Potassium phosphate (69.9 mg, 329 μmol, 3.00 eq.) and BrettPhos Pd G3 (9.95 mg, 10.9 μmol, 0.10 eq.) were added, then the reaction was heated to 80°C and stirred until reaction 20 completion (1 h). The mixture was cooled to room temperature, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 1 to afford Exemplary Compound 7 (25 mg, 54.9 μmol, 49% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 10.49 (s, 1H), 7.57 - 7.49 (m, 2H), 7.48 - 7.43 (m, 3H), 7.17 (d, J = 8.4 Hz, 2H), 6.61 (s, 1H), 3.83 - 3.72 (m, 1H), 3.67 (td, J = 6.4, 12.4 Hz, 1H), 3.25 (br s,252H), 2.81 - 2.71 (m, 2H), 2.16 - 2.03 (m, 4H), 1.87 (br t, J = 9.2 Hz, 2H), 1.60 (br d, J = 10.0 Hz, 1H), 1.40 (br d, J = 10.0 Hz, 1H). MS (ESI) m / z 439.2 [M+H]+Example 22 According to General Procedure 1, Variant 1: Intermediate A-22 (30.0 mg, 101 μmol, 1.00 eq.), Intermediate B-2 (71 mg, 203 μmol, 2.00 eq.) and potassium phosphate (65 mg, 304 μmol, 3.00 eq.) were dissolved in a mixture of dioxane:water 10:1 (1.1 mL) under nitrogen. 58

[0059] PAT059977-WO-PCT Pd(dppf)Cl2 (11.1 mg, 15.2 μmol, 0.15 eq.) was added, then the reaction was heated to 100°C and stirred until reaction completion (1 h). The mixture was cooled to room temperature and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 1 to afford Exemplary Compound 22 (34.1 mg, 76.9 μmol, 75% yield) as a white solid. 51H NMR (400 MHz, DMSO-d6) δ = 10.48 (s, 1H), 7.53 - 7.45 (m, 2H), 7.43 - 7.34 (m, 3H), 7.19 (br d, J = 7.8 Hz, 2H), 3.79 - 3.71 (m, 1H), 3.65 (td, J = 6.4, 12.4 Hz, 1H), 3.43 (br t, J = 6.0 Hz, 2H), 2.90 (s, 3H), 2.75 (br t, J = 6.4 Hz, 2H), 1.98 (br t, J = 5.8 Hz, 2H), 0.76 - 0.67 (m, 2H), 0.57 - 0.48 (m, 2H). MS (ESI) m / z 439.2 [M+H]+Example 24 B-2 (134 mg, 383 μmol, 2.00 eq.) and potassium phosphate (81.4 mg, 383 μmol, 2.00 eq.) were dissolved in DMF (2.0 mL) under nitrogen. Pd(dppf)Cl2(14.0 mg, 19.2 μmol, 0.10 eq.) was added, then the reaction was heated to 100°C and stirred until reaction15completion (2 h). The reaction mixture was quenched by adding water (8 mL) and the mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 1 to afford Exemplary Compound 24 (44 mg, 99.67 μmol, 52% yield) as a white solid. 201H NMR (400 MHz, DMSO-d6) δ = 10.48 (br s, 1H), 7.55 - 7.45 (m, 2H), 7.38 (s, 5H), 3.69 (td, J = 6.0, 11.2 Hz, 4H), 3.51 - 3.43 (m, 6H), 3.28 (s, 3H), 2.80 - 2.72 (m, 2H), 2.03 (td, J = 6.0, 11.2 Hz, 2H). MS (ESI) m / z 457.2 [M+H]+Example 35 According to General Procedure 1, Variant 1: Intermediate A-35 (120 mg, 425 μmol, 1.00 eq.), Intermediate B-2 (224 mg, 638 μmol, 1.50 eq.) and potassium phosphate (271 mg, 1.28 mmol, 3.00 eq.) were dissolved in DMF (2.0 mL) under nitrogen. Pd(dppf)Cl2(31.1 mg, 42.5 μmol, 0.10 eq.) was added, then the reaction was heated to 100°C and stirred until reaction completion (2 h). The mixture was cooled to room temperature and concentrated under reduced 30 pressure to give a residue. The residue was purified via Purification Method 1 to afford Exemplary Compound 35 (111.18 mg, 258 μmol, 60% yield) as a white solid. 59

[0060] PAT059977-WO-PCT 1H NMR (400 MHz, DMSO-d6) δ = 10.50 (s, 1H), 7.56 - 7.48 (m, 4H), 7.46 - 7.42 (m, 1H), 7.24 (d, J = 8.4 Hz, 2H), 4.36 (s, 2H), 3.90 (s, 2H), 3.81 - 3.72 (m, 1H), 3.70 - 3.61 (m, 1H), 2.80 - 2.71 (m, 2H), 0.83 - 0.76 (m, 2H), 0.62 - 0.55 (m, 2H). MS (ESI) m / z 426.1 [M+H]+Example 38 According to General Procedure 1, Variant 1: Intermediate A-38 (60.0 mg, 0.212 mmol, 1.00 eq.), Intermediate B- 2 (149 mg, 0.424 mmol, 2.00 eq.) and potassium phosphate (135 mg, 0.636 mmol, 3.00 eq.) were dissolved in a mixture of dioxane:water 10:1 (1.1 mL) under nitrogen. Pd(dppf)Cl2(16.0 mg, 0.0212 mmol, 0.10 eq.) was added, then the reaction was heated to 100°C 10 and stirred until reaction completion (1 h). The mixture was cooled to room temperature and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 1 to afford Exemplary Compound 38 (25.41 mg, 58.9 μmol, 28% yield) as a yellow solid. 1H NMR (400 MHz, CD3OD) δ = 7.49 - 7.39 (m, 5H), 7.31 (d, J = 8.4 Hz, 2H), 4.10 - 3.98 (m, 1H), 3.82 (t, J = 6.8 Hz, 2H), 3.59 (dt, J = 4.4, 11.2 Hz, 1H), 3.43 - 3.37 (m, 1H), 2.99 (s, 3H),152.94 - 2.78 (m, 2H), 2.37 - 2.26 (m, 1H), 1.94 (qd, J = 4.4, 13.2 Hz, 1H), 1.21 (d, J = 6.4 Hz, 3H). MS (ESI) m / z 427.2 [M+H]+Example 45 According to General Procedure 1, Variant 1: Intermediate A-45 (20.0 mg, 64.4 μmol, 1.00 eq.), Intermediate B-2 20 (45.2 mg, 128 μmol, 2.00 eq.) and potassium phosphate (41.0 mg, 193 μmol, 3.00 eq.) were dissolved in DMF (1.0 mL) under nitrogen. Pd(dppf)Cl2 (4.72 mg, 6.45 μmol, 0.10 eq.) was added, then the reaction was heated to 100°C and stirred until reaction completion (2 h). The mixture was cooled to room temperature and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 followed by Purification25Method 1 to afford Exemplary Compound 45 (4.10 mg, 8.94 μmol, 19% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 10.50 (s, 1H), 8.36 (d, J = 2.4 Hz, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.84 (dd, J = 2.4, 8.8 Hz, 1H), 7.60 - 7.42 (m, 3H), 3.83 - 3.72 (m, 1H), 3.70 - 3.61 (m, 1H), 3.31 (s, 2H), 2.82 (s, 3H), 2.79 - 2.73 (m, 2H), 2.59 (br d, J = 8.8 Hz, 2H), 2.02 - 1.85 (m, 2H), 1.62 (br d, J = 5.2 Hz, 4H). MS (ESI) m / z 454.1 [M+H]+60

[0061] PAT059977-WO-PCT Example 46 According to General Procedure 1, Variant 1: Intermediate A-46 (100 mg, 393 μmol, 1.00 eq.), Intermediate B-2 (303 mg, 865 μmol, 2.20 eq.) and potassium phosphate (250 mg, 1.18 5 mmol, 3.00 eq.) were dissolved in DMF (1.0 mL) under nitrogen. Pd(dppf)Cl2 (28.7 mg, 39.3 μmol, 0.10 eq.) was added, then the reaction was heated to 100°C and stirred until reaction completion (2 h). The mixture was cooled to room temperature and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 followed by Purification Method 1 to afford Exemplary Compound 46 (459 mg, 146 μmol, 37% yield) as a 10 white solid. 1H NMR (400 MHz, DMSO-d6) δ = 10.49 (br s, 1H), 7.55 - 7.38 (m, 7H), 3.82 - 3.72 (m, 1H), 3.71 - 3.63 (m, 3H), 2.81 - 2.72 (m, 2H), 2.43 (t, J = 6.4 Hz, 2H), 1.98 - 1.80 (m, 4H). MS (ESI) m / z 398.2 [M+H]+The other Exemplary Compounds shown in Table 2 were synthesized in analogy to the above15examples and according to General Procedure 1 (Variant 1 or 2). Table 3. Exemplary compounds synthesized according to Scheme 1. 61

[0062] PAT059977-WO-PCT 62

[0063] PAT059977-WO-PCT 63

[0064] PAT059977-WO-PCT 64

[0065] PAT059977-WO-PCT 65

[0066] PAT059977-WO-PCT 66

[0067] PAT059977-WO-PCT 67

[0068] PAT059977-WO-PCT 68

[0069] PAT059977-WO-PCT 69

[0070] PAT059977-WO-PCT 70

[0071] PAT059977-WO-PCT 71

[0072] PAT059977-WO-PCT 72

[0073] PAT059977-WO-PCT 73

[0074] PAT059977-WO-PCT 74

[0075] PAT059977-WO-PCT Synthesis of Intermediates A When not commercially available, Intermediates A were synthesized as follows. Intermediate A-1 5 Step 1. 1-bromo-4-(methoxymethoxy)benzene (3.66 g, 16.8 mmol, 1.00 eq.) and 1- aminocyclopropane-1-carbonitrile*HCl (2.00 g, 16.8 mmol, 1.00 eq.) were dissolved in 2- 75

[0076] PAT059977-WO-PCT methylbutan-2-ol (20 mL), and caesium carbonate (16.5 g, 50.6 mmol, 3.00 eq.) and t-BuXPhos Pd G3 (1.34 g, 1.69 mmol, 0.10 eq.) were added. The reaction was heated to 80°C for 12 h under nitrogen. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified via Purification Method 2 to afford 1-((4-(methoxymethoxy)phenyl)- 5 amino)cyclopropane-1-carbonitrile (2.40 g, 9.90 mmol, 59% yield) as a yellow oil. Step 2. 1-((4-(methoxymethoxy)phenyl)amino)cyclopropane-1-carbonitrile (2.60 g, 10.7 mmol, 1.00 eq.), di-tert-butyl dicarbonate (7.40 mL, 32.2 mmol, 3.00 eq.) and triethylamine (4.50 mL, 32.3 mmol, 3.02 eq.) were dissolved in tetrahydrofuran (26 mL) and added Raney-Nickel (1.29 g, 15.1 mmol, 1.41 eq.) was added under nitrogen atmosphere. The suspension was degassed via 10 purging with hydrogen (3 ×). The reaction was stirred at 25°C for 12 h under hydrogen (15 psi). The mixture was filtered over Celite, and the filter cake was washed with methanol (80 mL). The filtrate was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford tert-butyl ((1-((4- (methoxymethoxy)phenyl)amino)cyclopropyl)methyl)carbamate (2.90 g, 7.65 mmol, 71% yield)15as a yellow oil. Step 3. To a solution of tert-butyl ((1-((4-(methoxymethoxy)phenyl)amino)cyclopropyl)methyl) carbamate (2.70 g, 7.12 mmol, 1.00 eq.) in tetrahydrofuran (27 mL) was added potassium tert- butoxide (2.40 g, 21.4 mmol, 3.01 eq.) at 25°C. Then the mixture was stirred at 60°C for 3 h. After cooling to room temperature, the mixture was concentrated under reduced pressure to give a20 residue. The residue was purified via Purification Method 2 to afford 4-(4- (methoxymethoxy)phenyl)-4,6-diazaspiro[2.4]heptan-5-one (1.00 g, 3.91 mmol, 55% yield) as an off-white solid. Step 4. 4-(4-(methoxymethoxy)phenyl)-4,6-diazaspiro[2.4]heptan-5-one (500 mg, 1.95 mmol, 1.00 eq.) was dissolved in tetrahydrofuran (10 mL) and placed under nitrogen, then sodium hydride2560% dispersion in mineral oil (195 mg, 4.88 mmol, 2.50 eq.) was added at 0°C. The reaction was stirred at 0°C for 30 min, then 1-iodo-2-methoxyethane (729 mg, 3.92 mmol, 2.01 eq.) was added at 0°C. The reaction was stirred at 25°C for 1 h, then at 50°C for 1 h. After cooling to room temperature, the reaction was quenched with water (30 mL) and the aqueous layer was extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (30 mL), 30 dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford 6-(2-methoxyethyl)-4-(4- (methoxymethoxy)phenyl)-4,6-diazaspiro[2.4]heptan-5-one (440 mg, 1.42 mmol, 73% yield) as a yellow solid. 76

[0077] PAT059977-WO-PCT Step 5. A solution of 6-(2-methoxyethyl)-4-(4-(methoxymethoxy)phenyl)-4,6- diazaspiro[2.4]heptan-5-one (440 mg, 1.42 mmol, 1.00 eq.) in HCl / dioxane (3 mL) was stirred at 25°C for 2 h. The mixture was concentrated under reduced pressure to afford 4-(4-hydroxyphenyl)- 6-(2-methoxyethyl)-4,6-diazaspiro[2.4]-heptan-5-one (420 mg, crude, hydrochloride) as a black 5 oil. Step 6.4-(4-hydroxyphenyl)-6-(2-methoxyethyl)-4,6-diazaspiro-[2.4]heptan-5-one (210 mg, 703 μmol, 1.00 eq., hydrochloride) and triethylamine (284 mg, 2.80 mmol, 3.99 eq.) were dissolved in dichloromethane (2 mL) under nitrogen. Trifluoromethanesulfonyl chloride (350 mg, 2.08 mmol, 2.96 eq.) was added at 0°C. The reaction was stirred at 0°C for 2 h, then it was concentrated under 10 reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford Intermediate A-1 (90.0 mg, 217 μmol, 31% yield) as a white solid. Intermediate A-16 Intermediate A-16 was synthesized in analogy to Intermediate A-1, using 1-iodo-4- methoxybenzene instead of 1-bromo-4-(methoxymethoxy)benzene in Step 1. The following15conditions were used for Step 5. Step 5: To a solution of 6-ethyl-4-(4-methoxyphenyl)-4,6-diazaspiro[2.4]heptan-5-one (160 mg, 649 μmol, 1.00 eq.) in dichloromethane (1.00 mL) was added boron tribromide (2.00 M, 1.62 mL, 5.00 eq.) at 0°C. The reaction was stirred at 0°C for 1 h, then it was quenched with water (20 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic phases were washed with 20 brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 6-ethyl-4-(4-hydroxyphenyl)-4,6-diazaspiro[2.4]heptan-5-one (150 mg, crude) as a brown oil. Intermediate A-27 Intermediate A-27 was synthesized in analogy to Intermediate A-16, using methyl iodide as the25nucleophile in Step 4. Intermediate A-29 Intermediate A-29 was synthesized in analogy to Intermediate A-16, using 2,2,2-trifluoroethyl trichloromethanesulfonate as the nucleophile in Step 4. Intermediate A-17 77

[0078] PAT059977-WO-PCT Step 1. Cyclobutanone (606 μL, 8.12 mmol, 1.00 eq.) was dissolved in in acetic acid (16.0 mL) and 4-methoxyaniline (1.00 g, 8.12 mmol, 1.00 eq.) and trimethylsilyl formonitrile (1.02 mL, 8.12 mmol, 1.00 eq.) were added. The reaction was stirred at 25°C for 4 h. The mixture was poured into 5 water (20 mL) and adjusted to pH = 8 with saturated sodium bicarbonate (80 mL). The aqueous layer was extracted with ethyl acetate (3 × 60 mL). The combined organic layers were washed with brine (80 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford 1-((4- methoxyphenyl)amino)cyclobutane-1-carbonitrile (520 mg, 2.57 mmol, 31% yield) as a yellow 10 oil. Intermediate A-17 was obtained from 1-((4-methoxyphenyl)amino)cyclobutane-1-carbonitrile in analogy to Intermediate A-16 (Steps 2-6), using methyl iodide as the nucleophile in Step 4. Intermediate A-10 15Step 1.2-cyclobutylideneacetonitrile (2.00 g, 21.5 mmol, 1.00 eq.) was dissolved in a mixture of ammonia / methanol (7.00 M, 30.7 mL, 10.0 eq.). The reaction was stirred at 100°C for 12 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford 2-(1-aminocyclobutyl) acetonitrile (1.70 g, 15.4 mmol, 71% yield) as a yellow oil. 20 Intermediate A-10 was obtained from 2-(1-aminocyclobutyl) acetonitrile in analogy to Intermediate A-16 (Steps 1-6), using methyl iodide as the nucleophile in Step 4. Intermediate A-7 Intermediate A-7 was synthesized in analogy to intermediate A-10, while omitting alkylation Step 4.25Intermediate A-25 78

[0079] PAT059977-WO-PCT Intermediate A-25 was synthesized in analogy to intermediate A-10, starting from 2-(oxetan-3- ylidene)acetonitrile and using 2,2-difluoroethyl trifluoromethanesulfonate as the nucleophile in Step 4. Intermediate A-28 5 Intermediate A-28 was synthesized in analogy to intermediate A-25, using ethyl trifluoromethane-sulfonate as the nucleophile in Step 4. Intermediate A-33 Intermediate A-33 was synthesized in analogy to intermediate A-25, using methyl iodide as the nucleophile in Step 4. 10 Intermediate A-22 Step 1. tert-butyl (1-(2-hydroxyethyl)cyclopropyl)carbamate (1.10 g, 5.47 mmol, 1.00 eq.), isoindoline-1,3-dione (1.06 g, 7.18 mmol, 1.31 eq.) and triphenylphosphine (1.87 g, 7.13 mmol, 1.30 eq.) were dissolved in tetrahydrofuran (10 mL) under nitrogen, and the mixture was cooled 15 to 0°C. Diisopropyl (E)-diazene-1,2-dicarboxylate (1.45 g, 7.18 mmol, 1.31 eq.) was added, and the reaction was stirred at 25°C for 12 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 then Purification Method 1 to afford tert-butyl (1-(2-(1,3-dioxoisoindolin-2-yl)ethyl)cyclopropyl)carbamate (1.64 g, 4.72 mmol, 86% yield) as a white solid. 20 Step 2. To a solution of tert-butyl (1-(2-(1,3-dioxoisoindolin-2-yl)ethyl)cyclopropyl)carbamate (1.64 g, 4.96 mmol, 1.00 eq.) in dichloromethane (15 mL) was added hydrogen chloride / ethyl acetate (4 M, 15 mL). The reaction was stirred at 25°C for 1 h. The mixture was concentrated under reduced pressure to afford 2-(2-(1-aminocyclopropyl)ethyl)isoindoline-1,3-dione hydrochloride (1.32 g, 4.70 mmol, 95% yield) as a white solid. 79

[0080] PAT059977-WO-PCT Step 3.2-(2-(1-aminocyclopropyl)ethyl)isoindoline-1,3-dione hydrochloride (1.32 g, 4.70 mmol, 1.00 eq.) and potassium carbonate (1.32 g, 9.53 mmol, 2.03 eq.) were dissolved in dimethyl sulfoxide (10 mL) and 4-bromo-1-fluoro-2-nitrobenzene (2.07 g, 9.41 mmol, 1.16 mL, 2.00 eq.) was added. The reaction was heated to 80°C for 2 h. After cooling to room temperature, the mixture 5 was diluted with ethyl acetate (20 mL). The organic layer was washed with brine (3 × 20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford 2-(2-(1-((4-bromo-2- nitrophenyl)amino)cyclopropyl)ethyl)isoindoline-1,3-dione (1.67 g, 3.69 mmol, 78% yield) as a yellow solid. 10 Step 4. 2-(2-(1-((4-bromo-2-nitrophenyl)amino)cyclopropyl)ethyl)isoindoline-1,3-dione (800 mg, 1.86 mmol, 1.00 eq.) was dissolved in ethanol (20 mL) and hydrazine monohydrate (2.19 g, 43.8 mmol, 23.5 eq.) was added. The reaction was stirred at 80°C for 2 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (100 mL). The organic layer was washed with brine (3 × 100 mL), dried over sodium sulfate, filtered, and concentrated under reduced15pressure to afford N-(1-(2-aminoethyl)cyclopropyl)-4-bromo-2-nitroaniline (207 mg, 655 μmol, 35% yield) as a yellow solid. Step 5. N-(1-(2-aminoethyl)cyclopropyl)-4-bromo-2-nitroaniline (207 mg, 690 μmol, 1.00 eq.) was dissolved in tetrahydrofuran (2 mL) and 1,1'-carbonyldiimidazole (134 mg, 826 μmol, 1.20 eq.) was added. The mixture was stirred at 25°C for 1 h, then potassium tert-butoxide (154 mg, 20 1.37 mmol, 2.00 eq.) was added. The reaction was stirred at 25°C for 2 h. The mixture was poured into brine (20 mL), and the aqueous layer was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford 4-(4-bromo-2-nitrophenyl)-4,6-diazaspiro[2.5]octan-5-one (210 mg, 612 μmol,2589% yield) as a yellow solid. Step 6. 4-(4-bromo-2-nitrophenyl)-4,6-diazaspiro[2.5]octan-5-one (220 mg, 675 μmol, 1.00 eq.) was dissolved in tetrahydrofuran (5 mL) under nitrogen and cooled to 0°C. Sodium hydride 60% dispersion in mineral oil (33.0 mg, 825 μmol, 1.22 eq.) was added. The reaction was stirred at 0°C for 0.5 h, then methyl iodide (193 mg, 1.36 mmol, 2.02 eq.) was added at 0°C. The reaction was 30 stirred at 25°C for 12 h. The mixture was poured into brine (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford 4-(4-bromo-2-nitrophenyl)-6-methyl-4,6- diazaspiro[2.5]octan-5-one (210 mg, 586 μmol, 87% yield) as a yellow solid. 80

[0081] PAT059977-WO-PCT Step 7. 4-(4-bromo-2-nitrophenyl)-6-methyl-4,6-diazaspiro[2.5]octan-5-one (160 mg, 470 μmol, 1.00 eq.) was dissolved in acetic acid (2 mL) and iron (263 mg, 4.70 mmol, 10.0 eq.) was added. The reaction was stirred at 100°C for 1 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (50 mL). The mixture was filtered, and the filtrate was washed with 5 water (3 × 50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford 4-(2-amino-4- bromophenyl)-6-methyl-4,6-diazaspiro[2.5]octan-5-one (90.0 mg, 276 μmol, 59% yield) as a yellow solid. Step 8. 4-(2-amino-4-bromophenyl)-6-methyl-4,6-diazaspiro[2.5]octan-5-one (70.0 mg, 226 10 μmol, 1.00 eq.) was suspended in a mixture of water (1 mL) and hydrochloric acid (0.05 mL, 37% in water), then sodium nitrite (19.0 mg, 275 μmol, 1.22 eq.) and phosphinic acid (73.3 mg, 1.13 mmol, 5.00 eq.) were added. The reaction was stirred at 25°C for 12 h. The mixture was diluted with ethyl acetate (20 mL), and the organic layer was washed with brine (3 × 20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue15was purified via Purification Method 2 to afford Intermediate A-22 (60.0 mg, 193 μmol, 70% yield) as a yellow solid. Intermediate A-2 Intermediate A-2 was synthesized in analogy to Intermediate A-22, while omitting the alkylation Step 6. 20 Intermediate A-11 Step 1. 4-(4-bromophenyl)-4,6-diazaspiro[2.5]octan-5-one (90.0 mg, 320 μmol, 1.00 eq.) and ethyl iodide (149 mg, 960 μmol, 76.8 μL, 3.00 eq.) were dissolved in dimethylformamide (1.00 mL) under nitrogen, and the mixture was cooled to 0°C. Sodium hydride 60% dispersion in mineral 25 oil (19.2 mg, 480 μmol, 1.50 eq.) was added, and the reaction was stirred at 25°C for 1 h. The reaction was quenched with ammonium chloride (50 mL). The aqueous layer was extracted with ethyl acetate (3 × 40 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. 81

[0082] PAT059977-WO-PCT The residue was purified via Purification Method 1 to afford Intermediate A-11 (90.0 mg, 291 μmol, 91% yield) as a white solid. Intermediate A-5 5 Step 1. To a solution of 5-azaspiro[3.5]nonane (500 mg, 3.09 mmol, 1.00 eq.), 1-bromo-4- (methoxymethoxy)benzene (1.01 g, 4.64 mmol, 1.50 eq.) and sodium tert-butoxide (1.19 g, 12.3 mmol, 4.00 eq.) in 2-methylbutan-2-ol (15.0 mL) was added XPhos Pd G4 (532 mg, 618 μmol, 0.20 eq.). The reaction was stirred at 90°C under nitrogen. After 12h, the mixture was poured into water (80 mL) and extracted with ethyl acetate (3 × 40 mL). The combined organic layers were10washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 1 to afford 5-(4-(methoxymethoxy)phenyl)-5-azaspiro[3.5]nonane (700 mg, 2.68 mmol, 86% yield) as a yellow solid. Step 2. To a solution of sodium periodate (159 μL, 2.87 mmol, 5.00 eq.) in water (3.00 mL) was 15 added ruthenium(IV) oxide hydrate (26.0 mg, 172 μmol, 0.30 eq.). The mixture was stirred at 25°C for 5 min, then 5-(4-(methoxymethoxy)phenyl)-5-azaspiro[3.5]nonane (150 mg, 573 μmol, 1.00 eq.) in ethyl acetate (3.00 mL) was added at 0°C. The reaction was stirred at 25°C for 4 h, then it was quenched with saturated aqueous disodium sulfite (50 mL) and then poured into water (50 mL). The aqueous layer was extracted with ethyl acetate (3 × 60 mL). The combined organic layers20were washed with brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford -(4-(methoxymethoxy)phenyl)-5-azaspiro[3.5]nonan-6-one (70.0 mg, 254 μmol, 22% yield) as a yellow solid. Step 3. To a solution of -(4-(methoxymethoxy)phenyl)-5-azaspiro[3.5]nonan-6-one (60.0 mg, 217 25 μmol, 1.00 eq.) in dichloromethane (1.00 mL) was added trifluoroacetic acid (1.54 g, 13.4 mmol, 1.00 mL, 61.8 eq.). The reaction was stirred at 0°C for 1 h, then it was concentrated under reduced pressure to afford 5-(4-hydroxyphenyl)-5-azaspiro[3.5]nonan-6-one (50 mg, 216 μmol, 99% yield) as a yellow oil. Step 4. To a solution of 5-(4-hydroxyphenyl)-5-azaspiro[3.5]nonan-6-one (50.0 mg, 216 μmol, 30 1.00 eq.) and triethylamine (120 μL, 864 μmol, 4.00 eq.) in dichloromethane (1.00 mL) was added trifluoromethanesulfonyl chloride (68.6 μL, 648 μmol, 3.00 eq.). The reaction was stirred at 25°C 82

[0083] PAT059977-WO-PCT for 2 h, then it was poured into water (50 mL). The aqueous layer was extracted with ethyl acetate (3 × 25 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford Intermediate A-5 (60.0 mg, 165 μmol, 76% 5 yield) as a yellow solid. Intermediate A-43 Intermediate A-43 was synthesized in analogy to Intermediate A-5, with 2-oxa-5- azaspiro[3.5]nonane as the starting material. Intermediate A-8 10 Step 1. 1-azaspiro[4.4]nonane (200 mg, 1.24 mmol, 1.00 eq., hydrochloride) was dissolved in dichloromethane (3.00 mL) and di-tert-butyldicarbonate (341 μL, 1.48 mmol, 1.20 eq.) and triethylamine (344 μL, 2.47 mmol, 2.00 eq.) were added. The reaction was stirred at 25°C for 12 h. The mixture was diluted with water (50 mL) and the aqueous layer was extracted with 15 dichloromethane (3 × 20 mL). The combined organic layers were washed with brine (30 mL) and 1M hydrochloric acid (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford tert-butyl 1-azaspiro[4.4]nonane-1-carboxylate (270 mg, crude) as a colourless oil. Step 2. tert-butyl 1-azaspiro[4.4]nonane-1-carboxylate (270 mg, 1.20 mmol, 1.00 eq.) was 20 dissolved in ethyl acetate (3.00 mL) and sodium periodate (1.28 g, 5.99 mmol, 5.00 eq.) was added, followed by a mixture of ruthenium (IV) oxide hydrate (54.3 mg, 359 μmol, 0.30 eq.) in water (3.00 mL). The reaction was stirred at 25°C for 2 h. The mixture was diluted with water (50 mL) and the aqueous layer was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated under 25 reduced pressure to afford tert-butyl 2-oxo-1-azaspiro[4.4]nonane-1-carboxylate (280 mg, crude) as a colourless oil. Step 3. A mixture of tert-butyl 2-oxo-1-azaspiro[4.4]nonane-1-carboxylate (280 mg, 1.17 mmol, 1.00 eq.) and trifluoroacetic acid (200 μL) in dichloromethane (2.00 mL) was stirred at 25°C for 1 h. The mixture was concentrated under reduced pressure to give residue. The residue was purified 83

[0084] PAT059977-WO-PCT via Purification Method 2 to afford 1-azaspiro[4.4]nonan-2-one (130 mg, 933 μmol, 80% yield) as a white solid. Step 4. 1-bromo-4-iodobenzene (317 mg, 1.12 mmol, 1.20 eq.) and 1-azaspiro[4.4]nonan-2-one (130 mg, 933 μmol, 1.00 eq.) were dissolved in N-methyl pyrrolidone (3 mL), and copper iodide 5 (35.5 mg, 186 μmol, 0.20 eq.) and potassium phosphate (396 mg, 1.87 mmol, 2.00 eq.) were added under nitrogen. The reaction was stirred at 135°C for 12 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 1 to afford Intermediate A-8 (50.0 mg, 169 μmol, 18% yield) as a brown solid. 10 Intermediate A-36 Intermediate A-36 was synthesized in analogy to Intermediate A-8, with 7-oxa-1- azaspiro[4.4]nonane as the starting material. Intermediate A-53 Intermediate A-53 was synthesized in analogy to Intermediate A-8, with 5-azaspiro[3.5]nonane15as the starting material. Intermediate A-54 Intermediate A-54 was synthesized in analogy to Intermediate A-8, with tert-butyl 2-oxa-5- azaspiro[3.4]octane-5-carboxylate as the starting material. Intermediate A-57 20 Step 1. To a solution of tert-butyl (1-formylcyclobutyl)carbamate (1.50 g, 7.53 mmol, 1.00 eq.) and 4-bromoaniline (1.30 g, 7.53 mmol, 1.00 eq.) in dichloromethane (20.0 mL) was added acetic acid (431 μL, 7.53 mmol, 1.00 eq.) and sodium triacetoxyhydroborate (1.91 g, 9.03 mmol, 1.20 eq.) at 0°C. The reaction was stirred at 25°C for 12 h. The mixture was filtered, and 25 the filtrate was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 1 to afford tert-butyl (1-(((4- 84

[0085] PAT059977-WO-PCT bromophenyl)amino)methyl)cyclobutyl)carbamate (0.470 g, 1.32 mmol, 17% yield) as a brown solid. Step 2. tert-butyl (1-(((4-bromophenyl)amino)methyl)cyclobutyl)carbamate (0.470 g, 1.32 mmol, 1.00 eq.) was dissolved in DMAC (2.00 mL) and 2-bromoacetyl bromide (173 μL, 1.98 mmol, 5 1.50 eq.) was added at 0°C. The reaction was stirred at 0°C for 10 min, then it was poured into saturated aqueous ammonium chloride (20 mL). The aqueous layer was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 1 to afford tert-butyl (1-((2-bromo-N-(4- 10 bromophenyl)acetamido)methyl) cyclobutyl)carbamate (0.200 g, 420 μmol, 32% yield) as a white solid. Step 3. To a solution of tert-butyl (1-((2-bromo-N-(4-bromophenyl)acetamido)methyl)cyclobutyl) carbamate (0.200 g, 420 μmol, 1.00 eq.) in tetrahydrofuran (10.0 mL) was added potassium tert- butoxide (70.7 mg, 630 μmol, 1.50 eq.) at 0°C. The reaction was stirred at 60°C for 2 h. The15mixture was quenched by addition ammonium chloride 2 mL at 0°C, and the aqueous layer was extracted with ethyl acetate (3 × 5 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 1 to afford tert-butyl 8-(4- bromophenyl)-7-oxo-5,8-diazaspiro[3.5]nonane-5-carboxylate (82.0 mg, 205 μmol, 49% yield) as 20 a white solid. Step 4. To a solution of tert-butyl 8-(4-bromophenyl)-7-oxo-5,8-diazaspiro[3.5]nonane-5- carboxylate (82.0 mg, 207 μmol, 1.00 eq.) in dichloromethane (4.00 mL) was added hydrochloric acid (2 M in dioxane, 4.00 mL, 38.6 eq.). The reaction was stirred at 25°C for 12 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to afford 8-(4-bromophenyl)-255,8-diazaspiro[3.5]nonan-7-one (60.0 mg, 181 μmol, 87% yield, hydrochloride) as a white solid. Step 5. To a solution of 8-(4-bromophenyl)-5,8-diazaspiro[3.5]nonan-7-one (60.0 mg, 181 μmol, 1.00 eq., hydrochloride) and formaldehyde (44.1 mg, 543 μmol, 40.4 μL, 3.00 eq.) in methanol (4.00 mL) was added sodium triacetoxyhydroborate (154 mg, 724 μmol, 4.00 eq.) under nitrogen. The reaction was stirred at 25°C for 2 h. Then additional formaldehyde (44.1 mg, 543 μmol, 40.4 30 μL, 3.00 eq.) and sodium triacetoxyhydroborate (154 mg, 724 μmol, 4.00 eq.) were added, and the reaction was stirred at 25°C for 12 h. The mixture was concentrated under reduced pressure to give the residue. The residue was purified via Purification Method 1 to afford Intermediate A-57 (30.0 mg, 96.1 μmol, 53% yield) as a white solid. 85

[0086] PAT059977-WO-PCT Intermediate A-64 Intermediate A-64 was synthesized in analogy to Intermediate A-57, with tert-butyl (1- formylcyclopropyl)carbamate as the starting material. Intermediate A-66 5 Intermediate A-66 was synthesized in analogy to Intermediate A-54, using acetaldehyde as the aldehyde in Step 5. Intermediate A-13 Step 1. To a solution of (1-aminocyclopentyl)methanol (1.00 g, 8.68 mmol, 1.00 eq.) in 10 tetrahydrofuran (10.0 mL) were added di(1H-imidazol-1-yl)methanone (2.82 g, 17.4 mmol, 2.00 eq.) and triethylamine (2.64 g, 26.0 mmol, 3.63 mL, 3.00 eq.). The reaction was stirred at 25°C for 1 h, then the mixture was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford 3-oxa-1-azaspiro[4.4]nonan-2-one (1.12 g, 7.93 mmol, 91% yield) as a colourless oil. 15 Step 2. To a solution of 3-oxa-1-azaspiro[4.4]nonan-2-one (1.00 g, 7.08 mmol, 1.00 eq.) and 1,4- dibromobenzene (907 μL, 7.08 mmol, 1.00 eq.) in dioxane (15.0 mL) were added N1,N2- dimethylethane-1,2-diamine (762 μL, 7.08 mmol, 1.00 eq.), potassium carbonate (2.94 g, 21.2 mmol, 3.00 eq.) and copper iodide (1.35 g, 7.08 mmol, 1.00 eq.) under nitrogen. The reaction was stirred at 100°C for 12 h. The mixture was concentrated under reduced pressure to give a residue. 20 The residue was purified via Purification Method 1 to afford Intermediate A-13 (340 mg, 1.14 mmol, 16% yield) as a white solid. Intermediate A-31 Intermediate A-31 was synthesized in analogy to Intermediate A-13, with (1-aminocyclobutyl) methanol as the starting material. 25 Intermediate A-58 Intermediate A-58 was synthesized in analogy to Intermediate A-13, Step 2, starting from morpholin-3-one. 86

[0087] PAT059977-WO-PCT Intermediate A-12 Step 1. To a solution of tert-butyl (1-(2-hydroxyethyl)cyclopropyl)carbamate (200 mg, 993 μmol, 1.00 eq.) in tetrahydrofuran (2.00 mL) was added potassium tert-butoxide (167 mg, 1.49 mmol, 5 1.50 eq.) at 0°C. The reaction was stirred at 25°C for 2 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford 6-oxa-4-azaspiro[2.5]octan-5-one (170 mg, 1.34 mmol, 67% yield) as a white solid. Step 2. To a solution of 6-oxa-4-azaspiro[2.5]octan-5-one (170 mg, 1.34 mmol, 1.00 eq.) and 1- bromo-4-iodobenzene (491 mg, 1.74 mmol, 1.30 eq.) in N-methyl pyrrolidone (4.00 mL) were 10 added potassium phosphate (567 mg, 2.67 mmol, 2.00 eq.) and copper iodide (50.9 mg, 267 μmol, 0.20 eq.) under nitrogen. The reaction was stirred at 135°C for 12 h under nitrogen. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 1 to afford Intermediate A-12 (80.0 mg, 283 μmol, 21% yield) as a brown solid. 15 Intermediate A-21 and Intermediate A-4 were synthesized in analogy to Intermediate A-12 with the appropriate starting materials. Intermediate A-62 Step 1. To a solution of 3-oxa-1-azaspiro[4.4]nonan-2-one (320 mg, 2.27 mmol, 1.00 eq.) in20dimethyl sulfoxide (5.00 mL) were added 5-bromo-2-iodopyridine (707 mg, 2.49 mmol, 1.10 eq.), potassium phosphate hydrate (1.04 g, 4.53 mmol, 2.00 eq.), copper (II) acetate (41.1 mg, 226 μmol, 0.10 eq.) and 3,4,7,8-tetramethyl-o-phenanthrolin (80.3 mg, 340 μmol, 0.15 eq.) under nitrogen. The reaction was stirred at 80°C for 6 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified via Purification 25 Method 1 to afford Intermediate A-62 (490 mg, 1.55 mmol, 68% yield) as a white solid. Intermediate A-65 87

[0088] PAT059977-WO-PCT Step 1. A mixture of 5-azaspiro[3.4]octan-6-one (100 mg, 798 μmol, 1.00 eq.), 5-bromo-2- iodopyridine (226 mg, 798 μmol, 1.00 eq.), tris(dibenzylideneacetone)dipalladium(0) (21.9 mg, 23.9 μmol, 0.03 eq.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (46.2 mg, 79.8 μmol, 0.10 5 eq.) and caesium carbonate (520 mg, 1.60 mmol, 2.00 eq.) in dioxane (2.00 mL) was degassed by purging with nitrogen. The reaction was stirred at 100 °C for 12 h under nitrogen. The mixture was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford Intermediate A-65 (130 mg, 457 μmol, 57% yield) as a colourless oil. Intermediate A-24 10 Step 1. To a solution of 1-chloro-3-isocyanatopropane (1.75 g, 14.7 mmol, 1.10 eq.) in dichloromethane (10.0 mL) was added 2-methoxyethan-1-amine (1.00 g, 13.3 mmol, 1.16 mL, 1.00 eq.) at 0°C. The reaction was stirred at 25°C for 1 h. The mixture was concentrated to give the residue. The residue was triturated with petroleum ether (10 mL) at 25°C for 30 min,15then filtered to afford 1-(3-chloropropyl)-3-(2-methoxyethyl)urea (2.50 g, 12.8 mmol, 96% yield) as white solid. Step 2. To a solution of 1-(3-chloropropyl)-3-(2-methoxyethyl)urea (1.50 g, 7.71 mmol, 1.00 eq.) in tetrahydrofuran (20.0 mL) was added sodium hydride (925 mg, 23.1 mmol, 60% purity, 3.00 eq.) at 0 °C under nitrogen atmosphere. The reaction was stirred at 25°C for 2 h, then it was 20 quenched with water (20 ml) and the aqueous layer was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 1-(2- methoxyethyl)tetrahydropyrimidin-2(1H)-one (0.90 g, 5.69 mmol, 74% yield) as colourless oil. Step 3. To a solution of 1-(2-methoxyethyl)tetrahydropyrimidin-2(1H)-one (0.300 g, 1.90 mmol, 25 1.00 eq.) and 1,4-dibromobenzene (447 mg, 1.90 mmol, 243 μL, 1.00 eq.) in dioxane (3.00 mL) was added cuprous iodide (36.2 mg, 190 μmol, 0.10 eq.) , N1,N2-dimethylethane-1,2-diamine 88

[0089] PAT059977-WO-PCT (33.4 mg, 379 μmol, 40.8 μL, 0.20 eq.) and potassium phosphate (805 mg, 3.79 mmol, 2.00 eq.). The reaction was stirred at 100 °C for 12 h. The mixture was filtered and concentrated under reduced pressure to give the residue. The residue was purified via Purification Method 1 to afford Intermediate A-24 (219 mg, 678 μmol, 18 % yield) as a white solid. 5 Intermediate A-34 Intermediate A-34 was synthesized in analogy to Intermediate A-24, using trifluoroethan-1- amine as the amine partner in Step 1. Intermediate A-39 Intermediate A-39 was synthesized in analogy to Intermediate A-34, using 2,2-difluoroethan-1- 10 amine as the amine partner in Step 1. Intermediate A-60 Step 1. To a solution of 1-(2,2,2-trifluoroethyl)tetrahydropyrimidin-2(1H)-one (500 mg, 2.75 mmol, 1.00 eq.) in tetrahydrofuran (6 mL) was added sodium hydride 60% dispersion in mineral15 oil (329 mg, 8.24 mmol, 3.00 eq.) at 0°C. The mixture was stirred for 0.5 h, then 1-bromo-4- (bromomethyl)benzene (823 mg, 3.29 mmol, 1.20 eq.) in tetrahydrofuran (6 mL) was added dropwise at 0°C. The reaction was stirred at 25°C for 1.5 h. The mixture was quenched by addition saturated aqueous ammonium chloride solution (10 mL) and the aqueous layer was extracted with dichloromethane (3 × 10 mL). The combined organic layers were dried over sodium sulfate, 20 filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford Intermediate A-60 (780 mg, 2.22 mmol, 80% yield) as a yellow oil. Intermediate A-35 89

[0090] PAT059977-WO-PCT Step 1. To a solution of 7-oxa-4-azaspiro[2.5]octan-5-one (100 mg, 786 μmol, 1.00 eq.) in N- methyl pyrrolidone (2.00 mL) were added 1-bromo-4-iodobenzene (289 mg, 1.02 mmol, 1.30 eq.), potassium phosphate (334 mg, 1.57 mmol, 2.00 eq.) and copper iodide (30.0 mg, 157 μmol, 0.20 eq.). The reaction was stirred at 100 °C for 12 h under nitrogen atmosphere. The mixture was 5 filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford Intermediate A-35 (90.0 mg, 319 μmol, 40% yield) as a white solid. Table 4. Intermediates synthesized in analogy to Intermediate A-35. The following intermediates were synthesized in analogy to Intermediate A-35 with 1-bromo-4- 10 iodobenzene, but using varying copper catalysts, solvents, bases, and reaction times, and (if necessary) with a Cu ligand. Intermediate A-37 90

[0091] PAT059977-WO-PCT Step 1. To a solution of methyl (S)-2-amino-4-((tert-butoxycarbonyl)amino)butanoate (2.00 g, 7.44 mmol, 1.00 eq., hydrochloride), (4-bromophenyl)boronic acid (4.49 g, 22.4 mmol, 3.00 eq.), triethylamine (2.26 g, 22.3 mmol, 3.00 eq.) and 4Å molecular sieves (4.00 g) in dichloromethane (5 mL) was added copper(II) acetate (6.76 g, 37.2 mmol, 5.00 eq.) at 25°C. The reaction was stirred 5 at 25°C for 12 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford methyl (S)-2-((4-bromophenyl)amino)-4- ((tert-butoxycarbonyl)amino)-butanoate (316 mg, 742.5 μmol, 10% yield) as a white solid. Step 2. To a solution of methyl (S)-2-((4-bromophenyl)amino)-4-((tert-butoxycarbonyl) amino)butanoate (266 mg, 687 μmol, 1.00 eq.) in dichloromethane (3 mL) was added hydrogen 10 chloride / dioxane (2 M, 3 mL) at 25°C. The mixture was stirred at 25°C for 0.5 h, then concentrated under reduced pressure to afford methyl (S)-4-amino-2-((4-bromophenyl) amino)butanoate (222 mg, crude, hydrochloride) as a brown oil. Step 3. To a solution of methyl (S)-4-amino-2-((4-bromophenyl)amino)butanoate (222 mg, 686 μmol, 1.00 eq., hydrochloride) and N,N-diisopropylethylamine (266 mg, 2.06 mmol, 3.00 eq.) in15tetrahydrofuran (5 mL) was added 1,1'-carbonyldiimidazole (134 mg, 826 μmol, 1.20 eq.) at 25°C. The reaction was stirred at 25°C for 12 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford methyl (S)-3-(4- bromophenyl)-2-oxohexahydropyrimidine-4-carboxylate (130 mg, 407 μmol, 59% yield) as a white solid. 20 Step 4. To a solution of methyl (S)-3-(4-bromophenyl)-2-oxohexahydropyrimidine-4-carboxylate (110 mg, 351 μmol, 1.00 eq.) in tetrahydrofuran (1 mL) was added lithium aluminium hydride (2.5 M in tetrahydrofuran, 281 μL, 703 μmol, 2.00 eq.) at 0°C under nitrogen. The reaction was stirred at 0°C for 1 h. The mixture was warmed to room temperature and quenched by addition of sodium sulfate decahydrate until gas evolution ceased. The reaction mixture was filtered, and the filter25cake was washed with tetrahydrofuran (20 mL). The filtrate was concentrated under reduced pressure to afford (S)-1-(4-bromophenyl)-6-(hydroxymethyl)tetrahydro-pyrimidin-2(1H)-one (74.0 mg, 249 μmol, 71% yield) as a white solid. Step 5. Under nitrogen atmosphere, to a solution of (S)-1-(4-bromophenyl)-6- (hydroxymethyl)tetrahydropyrimidin-2(1H)-one (74.0 mg, 260 μmol, 1.00 eq.) in tetrahydrofuran 30 (1 mL) was added sodium hydride 60% dispersion in mineral oil (32.0 mg, 800 μmol, 3.08 eq.) at 0°C. The reaction was stirred at 0°C for 0.5 h, then methyl iodide (111 mg, 782 μmol, 3.01 eq.) was added at 0°C. The reaction was stirred at 25°C for an additional 0.5 h, then it was poured into brine (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were 91

[0092] PAT059977-WO-PCT washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford Intermediate A-37 (60.0 mg, 190 μmol, 73% yield) as a colourless oil. Intermediate A-44, Intermediate A-50, and Intermediate A-56 were synthesized in analogy to 5 Intermediate A-37, using the corresponding starting materials. Intermediate A-38 Step 1. tert-butyl (S)-(3-aminobutyl)carbamate (750 mg, 3.98 mmol, 1.00 eq.), (4- bromophenyl)boronic acid (2.40 g, 12.0 mmol, 3.00 eq.), copper(II) acetate (3.62 g, 20.0 mmol, 10 5.00 eq.), and triethylamine (1.21 g, 12.0 mmol, 3.00 eq.) were dissolved in dichloromethane (20 mL) and 4Å molecular sieves (70.0 mg) were added. The reaction was stirred at 25°C for 12 h under oxygen. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford tert-butyl (S)-(3-((4- bromophenyl)amino) butyl)carbamate (300 mg, 0.874 mmol, 22% yield) as a yellow oil. 15 Step 2. To a solution of tert-butyl (S)-(3-((4-bromophenyl)amino)butyl)carbamate (300 mg, 0.874 mmol, 1.00 eq.) in tetrahydrofuran (3 mL) was added potassium tert-butoxide (392 mg, 3.50 mmol, 4.00 eq.). The reaction was stirred at 60°C for 2 h. Ethyl acetate (30 mL) and water (30 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (40 mL), dried over sodium sulfate,20 filtered, and concentrated under reduced pressure to afford (S)-1-(4-bromophenyl)-6- methyltetrahydropyrimidin-2(1H)-one (200 mg, crude) as a yellow solid. Step 3. To a solution of (S)-1-(4-bromophenyl)-6-methyltetrahydropyrimidin-2(1H)-one (200 mg, 0.743 mmol, 1.00 eq.) in tetrahydrofuran (3 mL) was added sodium hydride 60% dispersion in mineral oil (36.0 mg, 0.90 mmol, 1.21 eq.) and methyl iodide (211 mg, 1.49 mmol, 2.00 eq.) at 25 0°C under nitrogen. The reaction was stirred at 25°C for 12 h. The mixture was quenched by dropwise addition of water (50 mL) while stirring at 0°C under nitrogen. The aqueous layer was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (40 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford Intermediate A-38 (170 mg, crude) as a yellow oil. 92

[0093] PAT059977-WO-PCT Intermediate A-47, Intermediate A-48, Intermediate A-49, Intermediate A-59, and Intermediate A-61 were synthesized in analogy to Intermediate A-38, using the appropriate starting materials in Step 1 and nucleophiles in Step 3. Intermediate A-40 5 Step 1. To a solution of tert-butyl ((3-aminooxetan-3-yl)methyl)carbamate (1.00 g, 4.94 mmol, 1.00 eq.) and 1,4-dibromobenzene (1.17 g, 4.94 mmol, 1.00 eq.) in 2-methylbutan-2-ol (3 mL) were added t-BuXPhos Pd G3 (0.393 g, 0.494 mmol, 10 mol%) and caesium carbonate (4.83 g, 14.8 mmol, 3.00 eq.) at 25°C. The reaction was stirred at 90°C for 12 h. The mixture was cooled 10 to room temperature and filtered over Celite. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 1 to afford tert-butyl ((3-((4- bromophenyl)amino)oxetan-3-yl)methyl)carbamate (0.130 g, 0.364 mmol, 7% yield) as a white solid. Step 2. To a solution of tert-butyl ((3-((4-bromophenyl)amino)oxetan-3-yl)methyl)carbamate 15 (0.100 g, 0.280 mmol, 1.00 eq.) in tetrahydrofuran (2 mL) was added potassium tert-butoxide (0.094 g, 0.840 mmol, 3.00 eq.) at 0°C. The reaction was stirred at 60°C for 3 h. The mixture was cooled to room temperature and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford 5-(4-bromophenyl)-2-oxa-5,7- diazaspiro[3.4]octan-6-one (0.055 g, 0.194 mmol, 69% yield) as a white solid. 20 Step 3. To a solution of 5-(4-bromophenyl)-2-oxa-5,7-diazaspiro[3.4]octan-6-one (0.0450 g, 0.159 mmol, 1.00 eq.) in tetrahydrofuran (1 mL) was added sodium hydride (0.0130 g, 0.325 mmol, 60% purity, 2.00 eq.) at 0°C under nitrogen. The reaction was stirred at 0°C for 1 h. Then ethyl iodide (0.078 g, 0.50 mmol, 3.00 eq.) was added at 0°C, and the reaction was stirred at 25°C for 1 h under nitrogen. The reaction was quenched with saturated ammonium chloride solution (3 mL) under 25 nitrogen, then extracted with ethyl acetate (3 × 3 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford Intermediate A- 40 (0.04 g, 0.129 mmol, 81% yield) as a yellow solid. Intermediate A-42 was synthesized in analogy to Intermediate A-40 using methyl iodide as the nucleophile in Step 3. 93

[0094] PAT059977-WO-PCT Intermediate A-9 Step 1. To a solution of 4-methoxyaniline (3.00 g, 24.3 mmol, 1.00 eq.) and acetone (1.79 mL, 24.3 mmol, 1.00 eq.) in acetic acid (30.0 mL) was added trimethylsilanecarbonitrile (3.63 g, 36.5 5 mmol, 4.57 mL, 1.50 eq.) at 0°C. The reaction was stirred at 25°C for 12 h. Sodium bicarbonate solution (50 mL) was added, and the aqueous layer was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford 2-((4-methoxyphenyl)amino)-2-methylpropanenitrile 10 (3.80 g, 19.9 mmol, 82% yield) as a colourless oil. Step 2. To a solution of Raney nickel (1.00 g) in tetrahydrofuran (30.0 mL) was added a mixture of 2-((4-methoxyphenyl)amino)-2-methylpropanenitrile (3.80 g, 19.9 mmol, 1.00 eq.), di-tert- butyldicarbonate (13.7 mL, 59.9 mmol, 3.00 eq.) and triethylamine (8.34 mL, 59.9 mmol, 3.00 eq.) in tetrahydrofuran (30.0 mL). The reaction was stirred at 25°C for 12 h under hydrogen 15 atmosphere. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford tert-butyl (2-((4- methoxyphenyl)amino)-2-methylpropyl)carbamate (1.40 g, 4.76 mmol, 24% yield) as a colourless oil. Step 3. To a solution of tert-butyl (2-((4-methoxyphenyl)amino)-2-methylpropyl)carbamate (200 20 mg, 679 μmol, 1.00 eq.) and 2-chloroacetyl chloride (108 μL, 1.36 mmol, 2.00 eq.) in dichloromethane (5.00 mL) was added sodium bicarbonate (52.8 μL, 1.36 mmol, 2.00 eq.) at 0°C. The reaction was stirred at 25°C for 2 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 1 to afford tert-butyl (2-(2-chloro- N-(4-methoxyphenyl)acetamido)-2-methylpropyl)carbamate (800 mg, 2.16 mmol, 45% yield) as 25 a white solid. Step 4. To a solution of tert-butyl (2-(2-chloro-N-(4-methoxyphenyl)acetamido)-2- methylpropyl)carbamate (830 mg, 2.24 mmol, 1.00 eq.) in dimethylformamide (8.00 mL) was added sodium hydride (134 mg, 3.36 mmol, 60% purity, 1.50 eq.) at 0°C. The reaction was stirred at 25°C for 2 h. The reaction was quenched with ammonium chloride (50 mL) and extracted with 94

[0095] PAT059977-WO-PCT ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford tert-butyl 4-(4-methoxyphenyl)-3,3- dimethyl-5-oxopiperazine-1-carboxylate (600 mg, 1.79 mmol, 80% yield) as a white solid. 5 Step 5. tert-butyl 4-(4-methoxyphenyl)-3,3-dimethyl-5-oxopiperazine-1-carboxylate (500 mg, 1.50 mmol, 1.00 eq.) was dissolved in dichloromethane (4.00 mL) and trifluoroacetic acid (1.00 mL) was added. The reaction was stirred at 25°C for 1 h. The mixture was concentrated under reduced pressure to afford 1-(4-methoxyphenyl)-6,6-dimethylpiperazin-2-one (350 mg, crude) as a colourless oil. 10 Steps 6, 7 and 8 were performed in analogy to Steps 4, 5 and 6 of Intermediate A-16, to afford Intermediate A-9. Intermediate A-18 Step 1. To a solution of tert-butyl (3-amino-3-methylbutyl)carbamate (1.00 g, 4.94 mmol, 1.0015eq.) and 1-fluoro-4-nitrobenzene (1.05 mL, 9.89 mmol, 2.00 eq.) in dimethyl sulfoxide (10.0 mL) was added potassium carbonate (1.37 g, 9.89 mmol, 2.00 eq.). The reaction was stirred at 100°C for 12 h. The mixture was concentrated to give a residue. The residue was purified via Purification Method 2 to afford tert-butyl (3-methyl-3-((4-nitrophenyl)amino)butyl)carbamate (800 mg, 2.47 mmol, 50% yield) as a yellow solid. 20 Step 2. To a solution of tert-butyl (3-methyl-3-((4-nitrophenyl)amino)butyl)carbamate (800 mg, 2.47 mmol, 1.00 eq.) in tetrahydrofuran (1.00 mL) was added potassium tert-butoxide (832 mg, 7.42 mmol, 3.00 eq.). The reaction was stirred at 60°C for 0.5 h. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under25reduced pressure to afford 6,6-dimethyl-1-(4-nitrophenyl) tetrahydropyrimidin-2(1H)-one (430 mg, crude) as a brown solid. 95

[0096] PAT059977-WO-PCT Step 3. To a solution of 6,6-dimethyl-1-(4-nitrophenyl)tetrahydropyrimidin-2(1H)-one (350 mg, 1.40 mmol, 1.00 eq.) in dimethylformamide (3.00 mL) was added sodium hydride (84.2 mg, 2.11 mmol, 60% purity, 1.50 eq.) and iodomethane (174 μL, 2.81 mmol, 2.00 eq.) at 0°C. The reaction was stirred at 25°C for 1 h. The reaction was quenched with ammonium chloride (50 mL) and 5 extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 1,4,4-trimethyl-3-(4-nitrophenyl)tetrahydropyrimidin-2(1H)-one (350 mg, crude) as a yellow solid. Step 4. To a solution of 1,4,4-trimethyl-3-(4-nitrophenyl)tetrahydropyrimidin-2(1H)-one (350 mg, 10 1.33 mmol, 1.00 eq.) in ethanol (1.00 mL) and water (200 μL) was added ammonium chloride (284 mg, 5.32 mmol, 4.00 eq.) and iron powder (371 mg, 6.65 mmol, 5.00 eq.). The reaction was stirred at 80°C for 2 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 1 to afford 3-(4-aminophenyl)- 1,4,4-trimethyltetrahydropyrimidin-2(1H)-one (130 mg, 557 μmol, 42% yield) as a brown solid.15Step 5. To a solution of copper(I) bromide (159 mg, 1.11 mmol, 33.9 μL, 2.00 eq.) and t-butyl nitrite (132 μL, 1.11 mmol, 2.00 eq.) in acetonitrile (3.00 mL) was added 3-(4-aminophenyl)-1,4,4- trimethyltetrahydropyrimidin-2(1H)-one (130 mg, 557 μmol, 1.00 eq.). The reaction was stirred at 60°C for 2 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 1 to afford Intermediate A- 20 18 (90.0 mg, 302 μmol, 54% yield) as a brown solid. Intermediate A-20 Step 1. To a solution of 3-bromo-4-methylpyridin-2(1H)-one (1.50 g, 7.98 mmol, 1.00 eq.) in acetonitrile (10.0 mL) were added potassium carbonate (2.21 g, 15.9 mmol, 2.00 eq.) and methyl 25 iodide (993 μL, 15.9 mmol, 2.00 eq.) at 0°C. The reaction was stirred at 25°C for 12 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 1 to afford 3-bromo-1,4-dimethylpyridin-2(1H)-one (1.50 g, 7.42 mmol, 93% yield) as a white solid. Step 2. To a solution of 3-bromo-1,4-dimethylpyridin-2(1H)-one (1.50 g, 7.42 mmol, 1.00 eq.) 30 and (4-bromophenyl)boronic acid (4.47 g, 22.2 mmol, 3.00 eq.) in dioxane (10.0 mL) and water 96

[0097] PAT059977-WO-PCT (1.00 mL) were added Pd(dppf)Cl2 (543 mg, 742 μmol, 0.10 eq.) and potassium carbonate (3.08 g, 22.2 mmol, 3.00 eq.). The reaction was stirred at 100°C for 12 h under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 1 to afford Intermediate A-20 (90.0 mg, 323 μmol, 4% yield) as 5 a white solid. Intermediate A-23 Step 1. To a solution of methyl 3-cyanopropanoate (5.00 g, 44.2 mmol, 1.00 eq.) and titanium(IV) isopropoxide (13.8 g, 48.6 mmol, 1.10 eq.) in tetrahydrofuran (30 mL) was added ethylmagnesium 10 bromide (3 M in tetrahydrofuran, 32.4 mL, 2.20 eq.) slowly over 4 h at 25°C under nitrogen. The reaction was stirred at 25°C for 12 h. The mixture was quenched with water (2 mL) and filtered over Celite. The filter cake was washed with dichloromethane (40 mL). The filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified via Purification Method 2 to afford 4-azaspiro[2.4]heptan-5-one (1.1 g, 9.90 mmol, 22% yield) as a 15 yellow oil. Step 2. To a solution of 1-bromo-4-iodobenzene (694 mg, 2.46 mmol, 1.30 eq.) and 4- azaspiro[2.4]heptan-5-one (210 mg, 1.89 mmol, 1.00 eq.) in N-methyl pyrrolidone (3.00 mL) were added potassium phosphate (401 mg, 1.89 mmol, 1.00 eq.) and copper iodide (71.9 mg, 377 μmol, 0.20 eq.) under nitrogen. The reaction was stirred at 135°C for 2 h. The mixture was filtered, and 20 the filtrate was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 1 to afford Intermediate A-23 (240 mg, 901 μmol, 48% yield) as a brown solid. Intermediate A-26 25Step 1. A mixture of 4-bromoaniline (1.00 g, 5.81 mmol, 1.00 eq.), dihydrofuran-3(2H)-one (0.551 g, 6.39 mmol, 1.10 eq.), trimethylsilylformonitrile (0.865 g, 8.72 mmol, 1.50 eq.), 1,1'-binaphthyl- 2,2'-diyl hydrogen phosphate (0.202 g, 0.581 mmol, 0.10 eq.), 4Å molecular sieves (1.60 g) and 97

[0098] PAT059977-WO-PCT phenol (0.547 g, 5.81 mmol, 1.00 eq.) in toluene (20 mL) was stirred at 40°C for 12 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford 3-((4-bromophenyl)amino) tetrahydrofuran-3-carbonitrile (0.520 g, 1.95 mmol, 34% yield) as a white solid. 5 Step 2. Borane tetrahydrofuran (1 M, 4.68 mL, 2.50 eq.) was added to a solution of 3-((4- bromophenyl)-amino)tetrahydrofuran-3-carbonitrile (0.50 g, 1.87 mmol, 1.00 eq.) in tetrahydrofuran (25 mL) under nitrogen at 0°C. The reaction was stirred at 60°C for 12 h. The mixture was cooled to room temperature and quenched with methanol (10 mL) under nitrogen at 0°C. After 0.5 h, the mixture was stirred at 70°C for 1 h and then concentrated under reduced10 pressure to give a residue. The residue was purified via Purification Method 1 to afford 3- (aminomethyl)-N-(4-bromophenyl)tetrahydrofuran-3-amine (0.320 g, 1.18 mmol, 63% yield) as a white solid. Step 3. To a solution of 3-(aminomethyl)-N-(4-bromophenyl)tetrahydrofuran-3-amine (0.20 g, 0.738 mmol, 1.00 eq.) in dimethyl formamide (6 mL) were added 1,1'-carbonyldiimidazole (0.18015g, 1.11 mmol, 1.50 eq.) and N,N-diisopropylethylamine (0.39 mL, 2.21 mmol, 3.00 eq.) at 25°C. The reaction was stirred at 60°C for 12 h. The mixture was cooled to room temperature and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 1 to afford 1-(4-bromophenyl)-7-oxa-1,3-diazaspiro[4.4]nonan-2-one (0.09 g, 0.303 mmol, 41% yield) as a white solid. 20 Step 4. To a solution of 1-(4-bromophenyl)-7-oxa-1,3-diazaspiro[4.4]nonan-2-one (0.09 g, 0.38 mmol, 1.00 eq.) in tetrahydrofuran (5 mL) under nitrogen was added sodium hydride (0.0303 g, 0.757 mmol, 60% purity, 2.50 eq.) at 0°C. The reaction was stirred at 0°C for 1 h, then methyl iodide (0.06 mL, 0.909 mmol, 3.00 eq.) was added at 0°C. The reaction was stirred at 25°C for 1 h, then it was quenched with saturated aqueous ammonium chloride (10 mL) and extracted with25ethyl acetate (3 × 10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford Intermediate A-26 (0.085 g, 0.273 mmol, 90% yield) as a yellow solid. Intermediate A-32 98

[0099] PAT059977-WO-PCT Step 1. To a mixture of 6-(hydroxymethyl)piperidin-2-one (500 mg, 3.87 mmol, 1.00 eq.), 1- bromo-4-iodo-benzene (1.42 g, 5.03 mmol, 1.30 eq.) and potassium phosphate (1.64 g, 7.74 mmol, 2.00 eq.) in N-methyl pyrrolidone (5.00 mL) was added copper(I) iodide (147 mg, 774 μmol, 0.20 eq.) under nitrogen. The reaction was stirred at 135°C for 12 h. The mixture was diluted with water 5 (20.0 mL) and extracted with ethyl acetate (3 × 50.0 mL). The combined organic layers were washed with brine (40.0 mL) and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford 1-(4-bromophenyl)-6- (hydroxymethyl)piperidin-2-one (350 mg, 1.23 mmol, 31% yield) as a yellow solid. Step 2. To a mixture of 1-(4-bromophenyl)-6-(hydroxymethyl)piperidin-2-one (200 mg, 703 μmol, 10 1.00 eq.) in tetrahydrofuran (1.00 mL) were added sodium hydride (56.3 mg, 1.41 mmol, 60% purity, 2.00 eq.) and iodomethane (199 mg, 1.41 mmol, 87.6 μL, 2.00 eq.) at 0°C under nitrogen. The reaction was stirred at 0°C. After 2h, the reaction was quenched by addition of saturated aqueous ammonium chloride solution (20.0 mL), and the aqueous layer was extracted with ethyl acetate (3 × 50.0 mL). The combined organic layers were washed with brine (35.0 mL), dried over15anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford Intermediate A-32 (140 mg, 469 μmol, 66% yield) as a transparent oil. Intermediate A-45 20Step 1. To a solution of tert-butyl ((1-aminocyclopentyl)methyl)carbamate (800 mg, 3.73 mmol, 1.00 eq.) in dichloromethane (10.0 mL) was added 1,1'-carbonyldiimidazole (907 mg, 5.60 mmol, 1.50 eq.). The reaction was stirred at 25°C for 12 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 1 to afford tert-butyl 2-oxo-1,3-diazaspiro[4.4]nonane-3-carboxylate (750 mg, 3.12 mmol, 84% yield) as a white solid. 25 Step 2. To a solution of tert-butyl 2-oxo-1,3-diazaspiro[4.4]nonane-3-carboxylate (300 mg, 1.25 mmol, 1.00 eq.) and 5-bromo-2-iodopyridine (425 mg, 1.50 mmol, 1.20 eq.) in dimethyl sulfoxide (3.00 mL) were added 3,4,7,8-tetramethyl-1,10-phenanthroline (44.2 mg, 187 μmol, 0.15 eq.), copper (II) acetate (22.6 mg, 124 μmol, 0.10 eq.) and potassium phosphate hydrate (574 mg, 2.50 mmol, 2.00 eq.) under nitrogen. The reaction was stirred at 80°C for 2 h. The reaction was filtered,30and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified 99

[0100] PAT059977-WO-PCT via Purification Method 1 to afford tert-butyl 1-(5-bromopyridin-2-yl)-2-oxo-1,3- diazaspiro[4.4]nonane-3-carboxylate (480 mg, 1.21 mmol, 97% yield) as a brown oil. Step 3. A mixture of tert-butyl 1-(5-bromopyridin-2-yl)-2-oxo-1,3-diazaspiro[4.4]nonane-3- carboxylate (480 mg, 1.21 mmol, 1.00 eq.) and trifluoroacetic acid (500 μL) in dichloromethane 5 (5.00 mL) was stirred at 25°C for 2 h. The mixture was concentrated under reduced pressure to afford 1-(5-bromopyridin-2-yl)-1,3-diazaspiro[4.4]nonan-2-one (350 mg, crude) as a colourless oil. Step 4. To a solution of 1-(5-bromopyridin-2-yl)-1,3-diazaspiro[4.4]nonan-2-one (350 mg, 1.18 mmol, 1.00 eq.) in dimethylformamide (3.00 mL) were added sodium hydride (71.0 mg, 1.78 10 mmol, 60% purity, 1.50 eq.) and iodomethane (342 mg, 2.41 mmol, 150 μL, 2.04 eq.) at 0°C. The reaction was stirred at 25°C for 2 h. The reaction was quenched with ammonium chloride (2 mL), and the volatiles were removed under reduced pressure to give a residue. The residue was purified via Purification Method 1 to afford Intermediate A-45 (140 mg, 451 μmol, 38% yield) as a colourless oil.15Intermediate A-52 Step 1. To a solution of methyl 6-oxopiperidine-2-carboxylate (100 mg, 636 μmol, 1.00 eq.) and 1,4-dibromobenzene (106 μL, 827 μmol, 1.30 eq.) in dioxane (1.00 mL) were added caesium carbonate (415 mg, 1.27 mmol, 2.00 eq.), N1,N2-dimethylethane-1,2-diamine (13.7 μL, 127 μmol, 20 0.200 eq.) and copper(I) iodide (24.2 mg, 127.3 μmol, 0.20 eq.) under nitrogen. The reaction was stirred at 80°C for 2 h. The reaction was quenched with water (5 mL) and the aqueous layer was extracted with ethyl acetate (3 × 5 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford methyl 1-(4-bromophenyl)-6- 25 oxopiperidine-2-carboxylate (180 mg, 577 μmol, 18% yield) as a white solid. Step 2. To a solution of methyl 1-(4-bromophenyl)-6-oxopiperidine-2-carboxylate (210 mg, 673 μmol, 1.00 eq.) in tetrahydrofuran (4.00 mL) was added methyllithium (3 M, 2.24 mL, 10.0 eq.) at -78°C under nitrogen. The reaction was stirred at 25°C for 12 h. The reaction was quenched by addition solution of ammonium chloride (2 mL) at 0°C, and then diluted with water (3 mL) and 30 extracted with ethyl acetate (3 × 5 mL). The combined organic layers were washed with brine, 100

[0101] PAT059977-WO-PCT dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 1 to afford Intermediate A-52 (15.0 mg, 48.1 μmol, 7% yield) as a yellow solid. Intermediate A-55 5 Step 1. To a solution of nitrocyclopentane (1.00 g, 8.69 mmol, 1.00 eq.) in dioxane (10.0 mL) under nitrogen were added benzyl(trimethyl)ammonium hydroxide 40% in methanol (395 μL, 869 μmol, 0.10 eq.) and acrylic acid methyl ester (1.56 mL, 17.4 mmol, 2.00 eq.). The reaction was stirred at 70°C for 3 h. The mixture was cooled, diluted with ethyl acetate (50 mL), and washed 10 with 1N hydrochloric acid (50 mL), water (50 mL) and saturated sodium bicarbonate (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford methyl 3-(1-nitrocyclopentyl)propanoate (1.60 g, 7.95 mmol, 92% yield) as a yellow oil. Step 2. To a solution of methyl 3-(1-nitrocyclopentyl)propanoate (1.00 g, 4.97 mmol, 1.00 eq.) in ethyl alcohol (10.0 mL) was added palladium 10% on carbon (0.30 g, 282 μmol, 0.10 eq.) under 15 nitrogen. The reaction was purged with hydrogen, then it was stirred at 50°C for 16 h under hydrogen (30 psi). The mixture was filtered, and the filtrate was concentrated under reduced pressure to afford 1-azaspiro[4.4]nonan-2-one (140 mg, 835 μmol, 17% yield) as a colourless oil. Step 3. Intermediate A-55 was afforded from 1-azaspiro[4.4]nonan-2-one in analogy to Step 1, Intermediate A-62. 20 Scheme 3. Synthesis of Exemplary Compounds via Intermediates C and Intermediate B-1 Table 5. Structures of Intermediates C 101

[0102] PAT059977-WO-PCT Representative Examples Example 41 Intermediate C-41 (85.8 mg, 289 μmol, 1.20 eq.), Intermediate B-1 (73.0 mg, 240 μmol, 1.00 eq.) and potassium phosphate (210 mg, 988 µmol, 3.00 eq.) were dissolved in DMF (2.0 mL). Pd(dppf)Cl2 (17.6 mg, 24.1 μmol, 0.10 eq.) was added, and the mixture was degassed by purging with nitrogen 3 times. The reaction was heated to 100°C and stirred for 16 h. The mixture was cooled to room temperature, filtered, and concentrated under reduced pressure to give a residue. The residue was10purified using Purification Method 1 to afford Exemplary Compound 41 (30 mg, 74.9 μmol, 31% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 10.50 (s, 1H), 8.14 (s, 1H), 7.73 (dd, J = 2.0, 6.8 Hz, 1H), 7.63 - 7.49 (m, 7H), 7.48 - 7.44 (m, 1H), 6.51 (d, J = 9.0 Hz, 1H), 6.34 (t, J = 6.8 Hz, 1H), 3.82 - 3.74 (m, 1H), 3.67 (td, J = 6.4, 12.4 Hz, 1H), 2.81 - 2.71 (m, 2H). MS (ESI) m / z 394.2 [M+H]+15 Example 51 g, . o , . eq. we e sso ve . . os Pd G3 (41.9 mg, 65.9 μmol, 0.10 eq.) was added, and the mixture was degassed by purging with 20 nitrogen 3 times. The reaction was heated to 80°C and stirred for 16 h. The mixture was cooled to room temperature, filtered, and concentrated under reduced pressure to give a residue. The residue was purified using Purification Method 2 then Purification Method 1 to afford Exemplary Compound 51 (33 mg, 76.3 μmol, 12% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 10.47 (s, 1H), 7.67 (d, J = 2.0 Hz, 1H), 7.51 - 7.42 (m, 2H), 25 7.40 - 7.33 (m, 3H), 7.14 - 7.08 (m, 2H), 6.33 (d, J = 2.0 Hz, 1H), 5.05 (s, 2H), 3.84 (s, 3H), 3.79 - 3.70 (m, 1H), 3.69 - 3.60 (m, 1H), 2.78 - 2.71 (m, 2H). MS (ESI) m / z 411.1 [M+H]+Example 63 102

[0103] PAT059977-WO-PCT Exemplary Compound 63 was synthesized in analogy to Exemplary Compound 41, starting from Intermediate C-63 and with Intermediate B-1. Grey solid.1H NMR (400 MHz, DMSO-d6) δ = 10.47 (s, 1H), 7.86 (dd, J = 1.6, 6.8 Hz, 1H), 7.53 5 - 7.40 (m, 5H), 7.39 - 7.34 (m, 3H), 6.44 (d, J = 8.8 Hz, 1H), 6.28 (dt, J = 1.2, 6.8 Hz, 1H), 5.16 (s, 2H), 3.82 - 3.70 (m, 1H), 3.64 (td, J = 6.4, 12.4 Hz, 1H), 2.81 - 2.69 (m, 2H). MS (ESI) m / z 408.2 [M+H]+Synthesis of Intermediates C Intermediate C-4110 Step 1. A mixture of (4-bromophenyl)boronic acid (3.00 g, 14.9 mmol, 1.00 eq.), pyridin-2(1H)- one (1.70 g, 17.9 mmol, 1.20 eq.), copper acetate (2.71 g, 14.9 mmol, 1.00 eq.) and triethylamine (6.24 mL, 44.8 mmol, 3.00 eq.) in dichloroethane (5 mL) was purged with oxygen. The reaction was stirred at 25°C for 3 h under oxygen, then concentrated under reduced pressure to give a15 residue. The residue was purified via Purification Method 2 to afford 1-(4-bromophenyl)pyridin- 2(1H)-one (1.6 g, 6.33 mmol, 42% yield) as a white solid. Step 2. A mixture of 1-(4-bromophenyl)pyridin-2(1H)-one (500 mg, 2.00 mmol, 1.00 eq.), bis(pinacolato)diboron (558 mg, 2.20 mmol, 1.10 eq.), Pd(dppf)Cl2(146 mg, 199 μmol, 0.10 eq.) and potassium acetate (588 mg, 6.00 mmol, 3.00 eq.) in dioxane (5 mL) was degassed and purged 20 with nitrogen, and then the reaction was stirred at 80°C for 3 h under nitrogen. The mixture was cooled to 25°C and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford Intermediate C-41 (500 mg, 1.53 mmol, 76% yield) as a white solid. Intermediate C-51 25 103

[0104] PAT059977-WO-PCT Step 1. To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (2.53 g, 11.5 mmol, 1.50 eq.) in acetic acid (20 mL) were added potassium carbonate (2.12 g, 15.3 mmol, 2.00 eq.) and 3-(chloromethyl)-1-methyl-1H-pyrazole (1.00 g, 7.66 mmol, 1.00 eq.). The reaction was stirred at 65°C for 16 h. The mixture was filtered over Celite, and the filter cake was washed with acetonitrile 5 (100 mL). The filtrate was concentrated under reduce pressure to give a residue. The residue was purified via Purification Method 2 to afford Intermediate C-51 (2.32 g, 7.09 mmol, 93% yield) as a yellow oil. Intermediate C-63 10Step 1. To a solution of cetyltrimethylammonium bromide (300 mg, 823 μmol, 0.08 eq.) in water (150 mL) was added pyridin-2(1H)-one (1.00 g, 10.5 mmol, 1.00 eq.) followed by potassium carbonate (2.18 g, 15.8 mmol, 1.50 eq.). The mixture was stirred at 20°C for 15 min. Then 1- bromo-4-(bromomethyl)benzene (2.18 g, 15.8 mmol, 1.50 eq.) was added, and the reaction was stirred at 50°C for 4 h. The mixture was partitioned between ethyl acetate (15 mL) and water (15 15 mL). The aqueous layer was separated and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was triturated with ethyl acetate (10 mL), filtered, and dried under vacuum to afford 1-(4-bromobenzyl)pyridin-2(1H)-one (1.96 g, 7.36 mmol, 70% yield) as a white solid.20Step 2. To a solution of 1-(4-bromobenzyl)pyridin-2(1H)-one (500 mg, 1.89 mmol, 1.00 eq.), B2Pin2(529 mg, 2.08 mmol, 1.10 eq.), and potassium acetate (557 mg, 5.68 mmol, 3.00 eq.) in dioxane (200 mL) was added Pd(dppf)Cl2(48.4 mg, 66.1 μmol, 0.10 eq.) under nitrogen. The reaction was stirred at 100°C for 3 h. The mixture was cooled to 20°C, filtered over Celite, and the Celite was washed with ethyl acetate (40 mL). The filtrate was concentrated under reduced 25 pressure to give a residue. The residue was purified via Purification Method 2 to afford Intermediate C-63 (350 mg, 1.11 mmol, 59% yield) as a white solid. 104

[0105] PAT059977-WO-PCT Scheme 4. Synthesis of Exemplary compounds with Intermediates F and Intermediate E Step 1: Intermediate D Intermediate B-1 (0.250 g, 0.824 mmol, 1.00 eq.) was dissolved in DMF (30 mL) and tert-butyl 5 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)piperidine-1-carboxylate (0.513 g, 1.65 mmol, 2.00 eq.), morpholine (0.108 g, 1.24 mmol, 1.50 eq.), [4,4′-bis(1,1-dimethylethyl)-2,2′- bipyridine]nickel(II)dichloride (16.4 mg, 41.2 μmol, 0.05 eq.) and 4,4-bis(tert-butyl)-2,2- bipyridine]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2pyridinyl]phenyl]Iridium(III)- hexafluorophosphate (9.24 mg, 8.24 μmol, 0.01 eq.) were added. The reaction was stirred and 10 irradiated with a 24W blue LED lamp (395 nm) at 25°C under nitrogen. After 1.5h, the mixture was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 1 to afford Intermediate D (130 mg, 0.32 mmol, 39% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 10.45 (s, 1H), 7.39 - 7.35 (m, 3H), 4.16 - 4.09 (m, 2H), 3.72 - 3.66 (m, 1H), 3.61 - 3.55 (m, 1H), 2.96 - 2.82 (m, 2H), 2.75 - 2.72 (m, 2H), 2.61 (s, 1H), 1.76 (d,15J = 12.0 Hz, 2H), 1.60 - 1.47 (m, 2H), 1.42 (s, 9H) Step 2: Intermediate E Intermediate D (130 mg, 0.32 mmol, 1.00 eq.) was dissolved in HCl 2M in dioxane (5.00 mL, 10.05 mmol, 31.4 eq.). The reaction was stirred at 25°C for 12 h, then it was concentrated under reduced pressure to afford Intermediate E (108 mg, 0.32 mmol, 99% yield, hydrochloride) as a 20 yellow solid. 105

[0106] PAT059977-WO-PCT 1H NMR (400 MHz, MeOD-d4) δ = 7.47 - 7.38 (m, 3H), 3.79 - 3.74 (m, 2H), 3.55 - 3.44 (m, 3H), 3.21 (t, J = 12.8 Hz, 2H), 2.89 - 2.81 (m, 2H), 2.16 - 2.10 (m, 2H), 1.98 - 1.91 (m, 2H) Step 3: Intermediates F, General Procedure 2 Variant 1 5 Intermediate F (1.00 eq.) and Intermediate E (1.00 eq.) were dissolved in DMF (0.58 M relative to Intermediate F) and caesium carbonate (3.00 eq.) and Pd-PEPPSI-IPentCl (0.05 eq.) were added. The reaction was stirred for 2h at 100°C under nitrogen, then concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 1 to afford the Exemplary Compounds. 10 Variant 2 Intermediate F (1.00 eq.) and Intermediate E (1.00 - 1.50 eq.) were dissolved in dioxane (0.05 - 0.25 M relative to Intermediate F) and caesium carbonate (3.00 - 5.00 eq.) and Pd-PEPPSI- IHeptCl (0.10 eq.) were added. The reaction was stirred at 90 - 100°C under nitrogen until reaction completion (4 - 12h). In some cases, an extraction was performed: the mixture was diluted with15water, and the aqueous layer was extracted with ethyl acetate (3 ×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. In other cases, the reaction mixture was concentrated directly to give a residue. The residue was purified via Purification Method 1 (if necessary, it was purified first with Purification Method 2 followed by Purification Method 1) to afford the Exemplary Compounds. 20 Table 6. Structures of Intermediates F 106

[0107] PAT059977-WO-PCT Representative Example: Example 68 Intermediate E (0.133 g, 0.387 mmol, 1.00 eq.) were dissolved in 5 dioxane (6 mL) and caesium carbonate (0.631 g, 1.94 mmol, 5.00 eq.) and Pd-PEPPSI-IHeptCl (37.6 mg, 38.7 μmol, 0.10 eq.) were added. The reaction was stirred at 100°C under nitrogen until reaction completion (12h). The mixture was diluted with water (20 mL), and the aqueous layer was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a 10 residue. The residue was purified via Purification Method 2 followed by Purification Method 1 to afford Exemplary Compound 68 (13.3 mg, 26.1 μmol, 7% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 10.45 (s, 1H), 7.48 - 7.45 (m, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.38 - 7.35 (m, 1H), 7.28 (dd, J = 1.6, 6.8 Hz, 1H), 6.76 (dd, J = 1.6, 7.2 Hz, 1H), 6.17 (t, J = 7.2 Hz, 1H), 4.15 (s, 2H), 3.79 (d, J = 10.8 Hz, 2H), 3.74 - 3.65 (m, 1H), 3.60 (td, J = 6.4, 12.4 Hz,151H), 3.25 (s, 3H), 3.18 - 3.07 (m, 1H), 2.77 - 2.70 (m, 2H), 2.60 - 2.52 (m, 2H), 1.90 - 1.73 (m, 4H), 0.77 (d, J = 3.2 Hz, 2H), 0.73 (d, J = 3.2 Hz, 2H). MS (ESI) m / z 485.2 [M+H]+Table 7. Synthesis of Exemplary Compounds via General Procedure 2 107

[0108] PAT059977-WO-PCT 108

[0109] PAT059977-WO-PCT 109

[0110] PAT059977-WO-PCT Synthesis of Intermediates F Intermediate F-67 5 Step 1. To a solution of 3-iodopyridin-2(1H)-one (500 mg, 2.26 mmol, 1.00 eq.) and (bromomethyl)cyclopropane (648 μL, 6.79 mmol, 3.00 eq.) in dimethylformamide (1.00 mL) was added potassium carbonate (938 mg, 6.79 mmol, 3.00 eq.). The reaction was stirred at 25°C for 12 h. The mixture was filtered, and the filtrate was purified via Purification Method 1 to afford Intermediate F-67 (500 mg, 1.82 mmol, 80% yield) as a colourless oil. 10 Intermediate F-69 (with 1-iodo-2-methylpropane), Intermediate F-72 (with 1-bromopropane), Intermediate F-74 (with 1-iodo-2-methoxyethane), Intermediate F-75 (with 1-bromo-2- ethoxyethane), and Intermediate F-76 (with 2,2,2-trifluoroethyl trifluoromethanesulfonate) were synthesized in analogy to Intermediate F-67 with the appropriate nucleophile. Intermediate F-68 110

[0111] PAT059977-WO-PCT Step 1. To a solution of 3-bromopyridin-2(1H)-one (10.0 g, 57.4 mmol, 1.00 eq.) and methyl 2- bromoacetate (10.5 g, 68.9 mmol, 1.20 eq.) in dimethyl formamide (100 mL) was added potassium carbonate (15.8 g, 114 mmol, 2.00 eq.). The reaction was stirred at 25°C for 12 h. The mixture was 5 diluted with water (100 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford methyl 2-(3-bromo-2-oxopyridin-1(2H)-yl) acetate (10.5 g, 42.6 mmol, 74% yield) as a white solid. 10 Step 2. To a solution of methyl 2-(3-bromo-2-oxopyridin-1(2H)-yl)acetate (4.50 g, 18.2 mmol, 1.00 eq.) in tetrahydrofuran (100 mL) was added titanium(IV) isopropoxide (10.4 g, 36.5 mol, 10.8 mL, 2.00 eq.) at 0°C. Then methylmagnesium bromide (3 M, 18.2 mL, 3.00 eq.) was added. The reaction was stirred at 25°C for 12 h under nitrogen. The mixture was quenched with saturated ammonium chloride solution (200 mL) at 0°C, and the aqueous layer was extracted with ethyl 15 acetate (3 × 200 mL). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 followed by Purification Method 1 to afford 3-bromo-1- ((1-hydroxycyclopropyl)-methyl)pyridin-2(1H)-one (0.300 g, 1.23 mmol, 7% yield) as a white solid. 20 Step 3. To a mixture of 3-bromo-1-((1-hydroxycyclopropyl)methyl)pyridin-2(1H)-one (0.30 g, 1.23 mmol, 1.00 eq.) in tetrahydrofuran (5 mL) was added sodium hydride (0.08 g, 1.84 mmol, 60% purity, 1.50 eq.) at 0°C under nitrogen. The mixture was stirred at 0°C for 0.5 h, then methyl iodide (0.26 g, 1.84 mmol, 1.50 eq.) was added. The reaction was stirred at 25°C for 1 h under nitrogen, then quenched with saturated ammonium chloride solution (30 mL) at 0°C. the aqueous 25 layer was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford Intermediate F-68 (0.280 g, 1.08 mmol, 88% yield) as a yellow solid. Intermediate F-70 111

[0112] PAT059977-WO-PCT Step 1. To a solution of 2-methoxy-2-methylpropan-1-ol (5.00 g, 48.0 mmol, 1.00 eq.) in pyridine (50 mL) was added 4-methylbenzenesulfonyl chloride (10.1 g, 52.8 mmol, 1.10 eq.) at 0°C. The reaction was stirred at 25°C for 12 h. The reaction was quenched with aqueous hydrochloric acid 5 (1 M, 100 mL), and the aqueous layer was extracted with ethyl acetate (3 × 80 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford 2-methoxy-2-methylpropyl 4-methylbenzenesulfonate (1.50 g, 5.23 mmol, 11% yield) as an off-white solid.10Step 2 was performed in analogy to Intermediate F-68, Step 1, with 2-methoxy-2-methylpropyl 4- methylbenzenesulfonate to afford Intermediate F-70. Intermediate F-71 Intermediate F-71 was synthesized in analogy to Intermediate F-70 starting from 2- methoxypropan-1-ol. 15 Example 77 Step 1. To a solution of 3-iodo-1-(2,2,2-trifluoroethyl)pyridin-2(1H)-one (0.500 g, 1.65 mmol, 1.00 eq.) in tetrahydrofuran (20 mL) were added tert-butyl piperazine-1-carboxylate (0.369 g, 1.98 mmol, 1.20 eq.) and RuPhos Pd G3 (0.138 g, 0.165 mmol, 0.10 eq.) followed by caesium carbonate20(2.69 g, 8.25 mmol, 5.00 eq.) at 25°C under nitrogen. The reaction was stirred at 85°C for 12 h under nitrogen. After cooling to room temperature, the mixture was diluted with saturated aqueous ammonium chloride (40 mL) and extracted with ethyl acetate (3 × 40 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered, and 112

[0113] PAT059977-WO-PCT concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford tert-butyl 4-(2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridin-3- yl)piperazine-1-carboxylate (500 mg, 1.38 mmol, 84% yield) as a light yellow solid. Step 2. To a solution of tert-butyl 4-(2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridin-3- 5 yl)piperazine-1-carboxylate (0.500 g, 1.38 mmol, 1.00 eq.) in dioxane (2 mL) was added HCl / dioxane (2 M, 10 mL) at 25°C. The reaction was stirred at 25°C for 12 h. The mixture was concentrated under reduced pressure to afford 3-(piperazin-1-yl)-1-(2,2,2-trifluoroethyl)pyridin- 2(1H)-one (0.400 g, 1.34 mmol, 97% yield, hydrochloride) as a white solid. Step 3. To a solution of 3-(piperazin-1-yl)-1-(2,2,2-trifluoroethyl)pyridin-2(1H)-one (0.200 g, 10 0.672 mmol, 1.00 eq., hydrochloride) in dioxane (14 mL) were added Intermediate B-1 (0.244 g, 0.804 mmol, 1.20 eq.) and caesium carbonate (1.10 g, 3.38 mmol, 5.00 eq.) followed by Pd- PEPPSI-IHetpCl (65.0 mg, 66.8 μmol, 0.10 eq.) at 25°C under nitrogen. The reaction was stirred at 100°C for 16 h. After cooling to room temperature, the mixture was filtered over celite. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified via15Purification Method 1 to afford Exemplary Compound 77 (16.11 mg, 0.0329 mmol, 5% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ = 10.44 (s, 1H), 7.41 - 7.30 (m, 2H), 7.23 (dd, J = 1.4, 8.2 Hz, 1H), 7.18 (dd, J = 1.4, 7.8 Hz, 1H), 6.84 (dd, J = 1.4, 7.4 Hz, 1H), 6.27 (t, J = 7.2 Hz, 1H), 4.97 - 4.80 (m, 2H), 3.73 - 3.56 (m, 2H), 3.29 - 3.19 (m, 4H), 3.12 (br d, J = 4.3 Hz, 4H), 2.76 - 2.70 (m, 20 2H). MS (ESI) m / z 484.1 [M+H]+Example 73 analogy to 1H NMR (400 MHz, DMSO-d6) δ = 10.43 (s, 1H), 7.40 - 7.34 (m,251H), 7.28 - 7.21 (m, 2H), 7.18 (d, J = 7.6 Hz, 1H), 6.79 (d, J = 6.4 Hz, 1H), 6.15 (t, J = 7.2 Hz, 1H), 4.06 (t, J = 5.2 Hz, 2H), 3.72 - 3.66 (m, 1H), 3.63 - 3.56 (m, 3H), 3.24 (s, 7H), 3.12 (d, J = 3.6 Hz, 4H), 2.76 - 2.70 (m, 2H). MS (ESI) m / z 460.1 [M+H]+Biological Assay 30 Example A: VAV1 Degradation Activity A VAV1 C-terminal HiBiT knock-in pool was generated at Monte Rosa Therapeutics from 113

[0114] PAT059977-WO-PCT a clonal Jurkat cell stably expressing LgBiT and possessing a homozygous GSPT1-G575N mutation. Cells were plated at 10,000 cells per well using Multiflo (BioTek / Agilent) in 384-well white solid bottom plates (Corning, 3570BC) in 25 ul volume in RPMI 1640 media (Thermo Fischer, 22400105) containing 10% FBS (Corning, 35-075-CV), 1% Peniciliin / Streptomycin 5 (ThermoFisher Scientific, 15140-122), and 1% Endurazine (Nano-Glo Endurazine Live Cell Substrate (Promega, N2571)). Cells were incubated for ~16 hours at 37°C, 5% CO2. 25nL of a compound dilution series ranging from 10 µM to 0.5 nM were dosed into the plate using an Echo® 650 liquid handler (Beckman Coulter). Cells were incubated at 37 °C, 5% CO2 and signal was read at 6 and 24 hours after compound addition on a Pherastar FSX (BMG Biolabs) using “LUM 10 plus” optic module. Analysis was performed in Genedata Screener (Genedata, Basel, CH). Luminescence response (R) was calculated by the formula: response = 100 * (S - N) / (P-N) where S is the signal of the well, N and P the mean negative and positive control values respectively of the same plate. The luminescence response was then fitted in Genedata using a 4-parameter antagonist logistic fit15(hillslopeunconstrained, EC50 > 0, top / bottom unconstrained). The results of this study are presented in Table 8. Table 8: VAV1 Degradation Activity 114

[0115] PAT059977-WO-PCT 115

[0116] PAT059977-WO-PCT Examples B-J Examples B – J present biological activity data generated using compound 24 from Table 1. The same compound (“the VAV1 MGD”) was used in Examples B-J. 5 Example B: VAV1 degradation in PBMCs after seven consecutive doses Mice were treated orally with seven consecutive doses of VAV1 MGD at 10, 1, and 0.1 mg / kg or vehicle. Compound formulation was prepared fresh the day of administration in 10% Captisol in water. Serum and PBMCs were collected either 6 or 24 hours post-dosing for analysis 10 of pharmacokinetics and pharmacodynamics. Serum samples were analyzed by LC-MS / MS to evaluate compound concentration in ng / mL and PBMCs were used to assess VAV1 protein levels and b-actin as loading control by western blotting. Briefly, PBMCs were rinsed with PBS then lysed using 100 µL RIPA lysis buffer (Pierce 89901) supplemented with 1% protease inhibitor cocktail [Roche 06493124001] and 1% phosphatase cocktail inhibitor [Sigma; P5726]) 15 respectively. Samples were run on 4-12% precast gels (Thermo Fisher Scientific; WG1402BOX) at 10-15 µg / lane and transferred to a Transfer Stack (Thermo Fisher Scientific IB23001). Primary antibodies (mouse VAV1, CST; 2502S and b-actin, CST; 4967) were diluted 1:1000 in Intercept blocking buffer (LI-COR; 927-60001) and incubated with the membranes overnight at 4°C. After three washes with 1X TBST (5 minutes each), secondary antibody IRDye 800CW Goat anti-rabbit20IgG (LI-COR; 926-32211), was diluted in Intercept blocking buffer, added to membranes, and incubated for 1 hour at room temperature. Signals were detected using a WB image system. VAV1 protein levels were normalized to b-actin levels within the same samples, then the relative levels of VAV1 MGD compared to vehicle groups were calculated and used for representation. The results of this study are shown in FIG.1. 25 Example C: VAV1 MGD induces degradation of VAV1 in lymphocytes and myeloid cells Frozen human PBMCs (STEMCELL technologies; 70025.2; Lot: 2209401007 ) were thawed, washed with 1X PBS & resuspended in complete cell culture medium (RPMI + 10% FBS + 25mM HEPES + 1X Sodium Pyruvate (100X) + 1X MEM Non-Essential Amino Acids Solution30(100X) + 1% Penicillin-Streptomycin (10’000 U / mL) + 50 μM β-mercaptoethanol) . Cells were plated at 1x106cells / mL in U-bottom 96 well plate (Corning; 3799) and treated with VAV1 MGD 116

[0117] PAT059977-WO-PCT using a serial dilution ranging from 0.1 nM to 1000 nM and including a DMSO control. Plates were incubated for 24 hrs at 5% CO2, 37°C. Cells were then surface stained in FACS Buffer (PBS containing 10% FBS) with Live / Dead staining (Thermo Fisher Scientific; 34980) and Human TruStain FcX (BioLegend; 422302) for 20 minutes at 4ºC. Cells were then washed with FACS 5 Buffer and surface antigens were stained in FACS Buffer (CD45, CD3, CD14, CD19) for 20 minutes at 4ºC. Cells were then fixed with Cytofix (BD; 554655 ) and permeabilized with Phosflow Perm / Wash Buffer I (BD; 557885) and then and stained with anti-VAV1 antibody (CST; 2502) for 20 minutes at 4ºC. Following staining with VAV1 antibody cells were washed with Perm buffer and incubated with Aleza Fluor 647-conjugated anti-rabbit IgG secondary 10 antibody (Biolegend; 406414) for 1 hour at 4ºC. Cells were then washed with Perm / Wash Buffer and evaluated by flow cytometry. Cells were first gated on CD45+, then respective cell marker (CD3+, CD19+, or CD14+). To assess VAV1 levels, Alexa Fluor 647 geometric mean fluorescence intensity for each population was normalized to respective DMSO control levels. The results of this study are shown in FIG.2.15Example D: Degradation of VAV1 results in inhibition of TCR-mediated CD69 activation, IL-2 secretion, and proliferation of Primary T-cells Frozen human Pan T cells (STEMCELL Technologies; 70024) were thawed, washed with 1X PBS & resuspended in complete cell culture medium (RPMI+10% FBS ). Cells were plated 20 at optimized cell density in U-bottom 96 well plate (Costar; Z707899) and treated with VAV1 MGD using a serial dilution ranging from 0.01 nM to 1000 nM and including a DMSO control and incubated for 24 hrs at 5% CO2, 37°C. Cells were transferred from treatment plate to anti-CD3 coated plate (5 μg / mL anti-CD3 antibody, clone OKT3, Thermo Fisher; 16-0037-85) and co- stimulated with anti-CD28 (1 μg / mL, clone CD28.2, Thermo Fisher; 16-0289-85). Cells were25incubated at 37°C with 5% CO2 and cells and / or supernatants harvested at various timepoints following anti-CD3 / anti-CD28 co-stimulation for various readouts (24h: CD69; 48h: IL-2; 96h: proliferation). For CD69 surface evaluation, cells were washed with PBS and stained for 20 minutes at 4°C with anti-CD69 allophycocyanin (APC) antibody (BioLegend ; 310910). Cells washed with PBS and evaluated by flow cytometry. APC fluorophore signal intensity (CD69) 30 reported as % CD69+cells normalized to anti-CD3 / anti-CD28 co-stimulated DMSO control levels. IL-2 was evaluated within cellular supernatants using an IL-2 ELISA kit (Abcam; ab270883) according to manufacturer protocol. Optical density (O.D.) values (IL-2) were obtained at 450 nM. For proliferation assays, cells were labeled with Cell Trace Violet (Thermo Fisher Scientific; C34557) according to the manufacturer's instructions. Cells were analyzed as a percentage of35diluted Cell Trace Violet dye (relative to unstimulated cells) by flow cytometry. For all assays, 117

[0118] PAT059977-WO-PCT data were normalized to anti-CD3 / anti-CD28 co-stimulated DMSO control levels. The results of this study are shown in FIG.3. Example E: VAV1 is involved in B Cell Receptor Signaling 5 FIG. 4 shows a schematic diagram of the role of VAV1 in B cell receptor signaling. Following the ligation of the B cell receptor and / or CD19, VAV1 is recruited to mediate phosphorylation cascades that lead to activation, cytokine secretion, and antibody production by B cells. Example F: VAV1 is involved in T Cell Receptor Signalling 10 FIG.5 shows a schematic diagram of the role of VAV1 in T cell receptor signaling. Following the ligation of the T cell receptor, VAV1 is recruited to mediate phosphorylation cascades that lead to activation, cytokine secretion, and proliferation. Example G: VAV1 MGD Attenuates BCR-Mediated Activity in Primary Human B-cells15Peripheral blood mononuclear cells (PBMC) were first isolated from human blood leukopaks. Each leukopak was diluted by adding 40 mL of the leukopak contents into 60mL of 1x PBS into a disposable Nalgene 150 mL bottle. The diluted blood mixture was transferred evenly among three Accupsin tubes (~30mL / tube). The mixture in Accuspin tubes was centrifuged at 720 x g for 20 minutes without brake at room temperature. Peripheral blood mononuclear cells) were 20 collected from the interphase with a sterile transfer pipette and transferred into new 50 mL tubes. PBMCs were washed with 1X PBS and counted using Nexcelom cell counter. From the isolated PBMCs, B cells were isolated using EasySep B cell isolation kit (Stemcell; 17954) following the manufacturer’s manual magnetic isolation technique. Cells were treated with VAV1 MGD at the indicated final concentrations or DMSO control and incubated at 37°C in a humidified incubator25with 5% CO2 . After treatment, B cells were cultured in RPMI 1640 (Gibco; 22400089) supplemented with 10% fetal bovine serum (Gibco; #A31605-01; Lot 2408990P), 2mM L- glutamine (Gibco; 35050061), 100 IU / mL penicillin / streptomycin (Gibco; 15140122), 1 mM sodium pyruvate (Gibco, 11360070), 0.01 M HEPES (Gibco, 15630080), 1% non-essential amino acids (Gibco; 11140050), and 55 μM β-mercaptoethanol (Gibco; 21985023), and stimulated with 30 assay-dependent stimuli. For CD69 expression and IL-6 secretion, B cells were stimulated with anti-IgM (1 μg / mL; Southern Biotech; 2022-14) and recombinant human IL-4 (10 ng / mL; R&D Systems; 305-IL-010) for 24 hrs. For IgG secretion, B cells were stimulated with anti-IgM (1 μg / mL), BAFF (30 ng / mL; R&D Systems; #7537-BF-025), IL-21 (100 ng / mL; PeproTech; 200- 2), and soluble CD40L (50 ng / mL; R&D Systems; 245-C) for 5 days. For CD69 expression, cells35were blocked with TruStain FcX (BioLegend; 422302), stained with mouse anti-human CD19- 118

[0119] PAT059977-WO-PCT BV421 (BD; 562440; Clone HIB19) and anti-human CD69-APC (BioLegend; 310910; Clone FN50), then assessed by flow cytometry. For IL-6 and IgG, supernatants were assessed by Alphalisa as per the manufacturer’s instructions. Mean fluorescence intensity (MFI) of CD69-APC was calculated on the CD19+population using FlowJo (BD). MFI of CD69 for VAV1 MGD 5 treated samples was normalized to DMSO stimulated and unstimulated control. Normalized data were transferred to Prism 9.3.1 (GraphPad) and fitted with a four-parameter model ([Inhibitor] vs. response -- Variable slope). The results of this study are shown in FIG.6. Example H: VAV1 MGD Attenuates FcR-Mediated Activity in Primary Human Monocytes 10 Monocytes were first isolated from human blood leukopaks. Each leukopak was diluted by adding 40 mL of the leukopak contents into 60mL of 1x PBS into a disposable Nalgene 150 mL bottle. The diluted blood mixture was transferred evenly among three Accupsin tubes (~30mL / tube). The mixture in Accuspin tubes was centrifuged at 720 x g for 20 minutes without brake at room temperature. Peripheral blood mononuclear cells) were collected from the interphase15with a sterile transfer pipette and transferred into new 50 mL tubes. PBMCs were washed with 1X PBS and counted using Nexcelom cell counter. From the isolated PBMCs, monocytes were isolated using Pan Monocyte Isolation Kit (Miltenyi Biotec; 130-096-537) following the manufacturer’s instructions. Cells (1x106 / mL) were treated for 24 hours in X-VIVO15 (Lonza; 02-053Q) supplemented with 10% fetal bovine serum with VAV1 MGD at the indicated final 20 concentrations or DMSO control and incubated at 37°C in a humidified incubator with 5% CO2 . On the day of treatment, flat-bottom 96-well plates were coated with 200 μg / mL IgG (Sigma; I1886-2ML) resuspended in PBS and incubated at 4ºC overnight, then 37ºC for 2 hours, then washed with PBS. Monocytes were transferred onto plates containing immobilized IgG and incubated for 24 hours at 37°C in a humidified incubator with 5% CO2. After 24 hours,25supernatants were then collected, and TNF levels were assessed by Alphalisa (Revvity; AL3157HV) as per the manufacturer’s instructions. TNF levels for VAV1 MGD treated samples were normalized to DMSO stimulated and unstimulated control. Normalized data were transferred to Prism 9.3.1 (GraphPad) and fitted with a four-parameter model ([Inhibitor] vs. response -- Variable slope). The results of this study are shown in FIG.7. 30 Example I: VAV1 MGDs Degrade VAV1 in REC-1 Cell Line VAV1 degradation in REC-1 cells was measured by western blot quantification. REC-1 cells were seeded in RPMI-1640 (Gibco, CAT# A10491-01) + 10% FBS (Corning, CAT# 35- 016-CV, LOT# 16821001) at a density of 1 x 106cells / mL and treated with a dose response of35VAV1 MGDs for 24 hours. Then, cells were harvested, washed with PBS and lysed using RIPA 119

[0120] PAT059977-WO-PCT buffer (Thermo, CAT# 89901) supplemented with protease inhibitor (Sigma, CAT# P8340) and phosphatase inhibitors (Sigma, CAT# P5726 + P0044). Protein concentration was determined with BCA Rapid Gold (Thermo, CAT# A53225) and subsequently normalized to 1.25 µg / µL. Samples were prepared with 1X NuPAGE™ LDS Sample Buffer (Invitrogen, CAT# NP0007) + 5 5% DTT (Sigma, CAT# 43816) and denaturated at 95°C for 5 minutes.12 µL of each samples was loaded onto a 26-well Gel (Bio-Rad, CAT# 5678095) and run for ~45 minutes at 150 V. Then, proteins were transferred to a nitrocellulose membrane (Bio-Rad, CAT# 1704159) using the Turbo™ Transfer System (Bio-Rad, CAT# 1704150) with 25 V for 7 minutes. The membrane was blocked with EveryBlot Blocking Buffer (Bio-Rad, CAT# 12010020) followed 10 by overnight incubation with anti-VAV1 (CST, CAT# 2502) and anti-β-actin (CST, CAT# 3700S) primary antibodies. Then, the membrane was 3x washed with 1X TBS / T (Bio-Rad, CAT# BUF028) and incubated with anti-rabbit IgG HRP (Invitrogen, CAT# A16110) and anti- mouse IgG HRP (Invitrogen, CAT# 31432) secondary antibody followed by 3x wash with 1X TBS / T. Western blot images were acquired with ChemiDocTM MP Imaging System (Bio-Rad,15CAT# 12003154) and quantified using Image Lab software (Bio-Rad, version 6.1.0). VAV1 levels were normalized to β-actin relative to DMSO control and final graphs were generated with GraphPad Prism 10.2.3. The results are shown in FIG.8. Example J: VAV1 MGDs Inhibit REC-1 Cell Line Proliferation 20 To measure growth inhibition of REC-1 cell line (ATCC; #CRL-3004), 3500 cells per well were plated in 75 µL medium of RPMI-1640 (Gibco; #A10491-01) supplemented with 10% FBS (Corning; #35-016-CV) and 100 U / mL penicillin / streptomycin (Gibco; #15140122) in 384- well plates (Corning; #3570) and settled overnight in a 37ºC incubator with 5% CO2. The cells were treated the following day with increasing concentrations of VAV1 MGDs. DMSO was used25as a control. Each treatment was performed in triplicate. CellTiter Glow (Promega; #G7573) readouts were performed as per the manufacturer’s instructions on Day 0 (pre-treatment) and Day 5 by adding 15 µL CTG reagent (Promega; #G7573) per well, incubating at room temperature for 5 minutes, followed by luminescence measurement using a PHERAstar FSX (BMG Labtech). For calculating growth %, medium-only control was subtracted from all wells, 30 and data were normalized to day 0 and DMSO to assess proliferation or cell death using the following equation: if Readcombination >= Read0, 100 * (Readcombination - Read0) / (ReadDMSO - Read0); if Readcombination< Read0, 100 * (Readcombination- Read0) / Read0. The results are shown in FIG.9.35120

[0121] PAT059977-WO-PCT Example K: Oral dosing of VAV1 MGDs inhibit EAE disease progression in a dose- dependent manner 5 To induce experimental autoimmune encephalomyelitis (EAE), J C57BL / 6 (Beijing Vital River Laboratory Animal Co; #213) mice were injected subcutaneously with an emulsified mixture consisting of 100 μg of the synthetic peptide derived from myelin oligodendrocyte glycoprotein (MOG35-55; GL Biochem Ltd; #51716)) and 200 µg M. tuberculosis (Difco; #231141) were mixed with incomplete Freund’s adjuvant (Sigma-Alrich; 10 #F5506) using a high-speed homogenizer (IKA T10 basic). Mice were additionally injected intraperitoneally with 200 ng pertussis toxin (List Biological Laboratories; #180235AIA) at 0 and 48 hours post immunization. This immunization induces the activation and expansion of peripheral myelin-specific encephalitogenic T cells and their migration into the CNS. Once in the CNS, the activated T-cells initiate an inflammatory cascade, which ultimately leads to myelin15destruction and symptoms of paralysis. From the day of disease induction (day -12), the mice were monitored every 3 days for clinical signs of EAE disease as follows: 0=no signs of disease; 1=limp tail or hind limb weakness; 2=limp tail and hind limb weakness; 3=partial hind limb paralysis; 4=complete hind limb paralysis; 5=moribund. On day 11, at disease onset, mice were treated orally and daily with vehicle (10% captisol in water) or Compound 1 at 10 mg / kg or 20 Compound 24) at 30, 10, or 1 mg / kg (VAV1 MGDs resuspended in 10% captisol in water) from day 12 to day 24 and monitored every 3 days for clinical signs of EAE disease as described above. VAV1 MGDs were formulated fresh the day of administration by dissolving the VAV1 MGDs in 10% captisol in water then vortexed until a clear solution or a uniform suspension was obtained. At the end of the study (Day 17 post-immunization), mice were euthanized then25peripheral blood mononuclear cells (PBMC) were enriched from cardiac puncture samples and brain tissue was excised then snap frozen for subsequent assessment of VAV1 levels by western blot. For brain sample preparation, frozen samples were defrosted, 30-100 mg of tissue was placed in a 2 mL microcentrifuge tube, and 400 μL RIPA buffer (Sigma; #R0278) containing 1% 30 protease inhibitor cocktail (Roche; #04693124001) and 1% phosphatase inhibitor cocktail 2 (Sigma; #P5726) was added to each tube. Tissues were ground using a Tissuelyser (Shanghai Jingzin; #JXSTPRP-CL) at 50 hZ for 5 mins. Samples were then incubated on ice for 30 mins. After incubation, samples were centrifuged at 13, 523 x g for 10 mins at 4ºC, then transferred into new, pre-chilled microcentrifuge tubes. For PBMC sample preparation, frozen samples were35defrosted, placed in a 2 mL microcentrifuge tube, and 400 μL RIPA buffer (Sigma; #R0278) 121

[0122] PAT059977-WO-PCT containing 1% protease inhibitor cocktail (Roche; #04693124001) and 1% phosphatase inhibitor cocktail 2 (Sigma; #P5726) was added to each tube, then sonicated. Samples were then incubated on ice for 30 mins. After incubation, samples were centrifuged at 13, 523 x g for 10 mins at 4ºC, then transferred into new, pre-chilled microcentrifuge tubes. 5 Protein concentrations were determined using a BCA assay kit (Thermo Fisher; #23225)) and samples were diluted to a final concentration of 2 μg / μL in RIPA buffer containing 4X LDS sample buffer (Invitrogen; #NP0007) and 10X sample reducing agent (Invitrogen; #NP0009). Once diluted, samples were boiled at 100ºC for 10 mins. Denatured samples were then stored at - 80ºC. For western blotting, protein samples were defrosted and 15 μL of each sample was loaded 10 in 4-12% Bis-Tris gels (Invitrogen; #WG1402BOX). Electrophoresis was then run in MES running buffer (Invitrogen; #NP0002) at 80 V for 30 mins then 120 V for 90 mins. Proteins were transferred to a nitrocellulose membrane with an iBlot 2 Gel Transfer Device (Invitrogen) using P3 for 7 mins. After transfer, membranes were washed (10 mL 1X TBST, 5 mins, 3 times), blocked (TBS Blocking Buffer (LI-COR;#927-60001), 1 h with agitation, room temperature),15and washed again (1X TBST (Bio-Serve; #BS-P-15), 10 mins, 3 times). VAV1 and β-actin were detected by incubation with anti-VAV1 (CST; 2502) and β-actin (CST; #4967) antibodies (1:1000 or 1:2000 respectively in TBS Blocking Buffer containing 0.1% Tween-20 (Sigma; #P2287) at 4ºC overnight with gentle agitation). Membranes were then washed (10 mL 1X TBST, 10 mins, 3 times) and then incubated with secondary detection goat anti-mouse IgG-20 IRDye 860RD (LI-COR; #926-68070) and goat anti-rabbit IgG-IRDye 800CW (LI-COR; #926- 32211) antibodies (both 1:10000 in TBD Blocking Buffer containing 0.1% Tween-20 for 1h at room temperature with gentle agitation, protected from light). Membranes were then washed (10 mL 1X TBST, 5 mins, 5 times) and protein levels were detected by fluorescence signal using an Odessey CLx Imaging System (LI-COR). VAV1 protein levels were quantified by fluorescence25intensity relative to β-actin and normalized to the vehicle treatment group. The results of this study are shown in FIGS.10A, 10B, and 10C. These data show that both Compound 1 and Compound 24 inhibit disease progression in a mouse model of EAE, with dose-dependent activity observed with Compound 24 (FIG.10A), consistent with degradation observed in PBMCs. Both Compound 1 and Compound 24 degrade 30 VAV1 in peripheral PBMCs, with dose-dependent activity observed with Compound 24 (FIG. 10B), but not within brain tissue (FIG.10C) due peripheral-restriction of these compounds. Therefore, degradation of VAV1 in peripheral PBMCs is sufficient to inhibit disease progression of a T cell-mediated EAE model. 122

[0123] PAT059977-WO-PCT Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims.5123

Claims

PAT059977-WO-PCT CLAIMS 1. A compound of Formula (I) 5Formula (I) or a pharmaceutically acceptable salt thereof, wherein: 10 Ring A is selected from the group consisting of: •, wherein * is the point of attachment to L, X1, X2and X3are each selected from the group consisting of CR6Dand N, and wherein a maximum of one of X1, X2and X3may be N; •, wherein Z is the point of attachment to L, Y and Z are 15 independently selected from the group consisting of CH, CR14and N, and wherein m is 0 or 1; L is selected from the group consisting of: • a bond; or20• *-O(C1-C4 alkylene)-, *-C1-C4 alkylene-, *-NR9(C0-C4 alkylene)-, *-NR9(C=O)(C0-C4 alkylene)-, -NR9(C=O)(C0-C4alkylene)-*, -(C1-C4alkylene)-C(=O)-*, or *-(C1-C4alkylene)-C(=O)-, wherein the alkylene is optionally substituted with 1-2 R7and124PAT059977-WO-PCT wherein * indicates the point of attachment of L to Ring A, wherein L is a bond or *-C1- C4 alkylene- when Z is N; Ring B is selected from the group consisting of: 5 • heterocyclyl or heterocycloalkenyl including 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R1) and O, and S(O)0-2, and wherein one or more of the carbon atoms of the heterocyclyl or heterocycloalkenyl are optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R8; 10 • heteroaryl including 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R1), O, and S(O)0-2, wherein at least one ring in the system is aromatic and wherein one or more of the carbon atoms of the heteroaryl are optionally substituted with from 1-4 substituents independently selected from oxo and R8; 15 each occurrence of R1is independently selected from the group consisting of: deuterium, halo, C1-6 alkyl optionally substituted with from 1-3 independently selected R13; -C(O)(C1-4 alkyl); - C(O)O(C1-4 alkyl); -CONR10R10; -S(O)1-2NR10R10; -S(O)1-2(C1-4 alkyl); -OH; C1-4 alkoxy; -C0- 6alkylene(C3-6cycloalkyl) optionally substituted with from 1-3 independently selected R13; and -C0-20 6alkylene(C3-6 heterocyclyl) optionally substituted with from 1-3 independently selected R13; R2is selected from the group consisting of hydrogen, deuterium, CH3, CHF2, CF3, OMe, F, Cl and Br;25each of R3, R4and R5is independently selected from the group consisting of hydrogen, deuterium, halo, cyano, C1-4alkyl which is optionally substituted with from 1-4 independently selected R10, C3-4 cycloalkyl which is optionally substituted with from 1-3 independently selected R10, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, NR9R9, –OH, -NO2, and -C(=O)OH; 30 each of R6A, R6B, R6C, and R6Dis independently selected from the group consisting of: hydrogen; oxo; deuterium, halo; cyano; C1-4 alkyl which is optionally substituted with from 1-4 independently selected R11; C3-4cycloalkyl which is optionally substituted with from 1-4 independently selected R11; C2-4alkenyl which is optionally substituted with from 1-4 independently selected R11; C2-4 alkynyl which is optionally substituted with from 1-4 independently selected R11;125PAT059977-WO-PCT C1-4alkoxy which is optionally substituted with from 1-4 independently selected R11;–OH; -NO2; and -C(=O)OH; each occurrence of R7is independently selected from the group consisting of: –OH; -halo; – 5 NR9R9; C1-4 alkylene; C1-4 alkoxy; C1-4 haloalkoxy; -C(=O)O(C1-4 alkyl); -C(=O)(C1-4 alkyl); - C(=O)OH; -S(O)1-2(C1-4alkyl); and cyano; or two R7can be taken together to form a C3-4cycloalkyl ring; each occurrence of R8is independently selected from the group consisting of: deuterium;10 halo; cyano; C1-5alkyl which is optionally substituted with from 1-6 independently selected R12; C1-5 haloalkyl which is optionally substituted with from 1-6 independently selected R12; C3-6 cycloalkyl which is optionally substituted with from 1-4 independently selected R12; C2-6 alkenyl which is optionally substituted with from 1-6 independently selected R12; C2-6alkynyl which is optionally substituted with from 1-6 independently selected R12; C1-4alkoxy which is optionally substituted with15from 1-6 independently selected R12; C1-4 haloalkoxy which is optionally substituted with from 1-6 independently selected R12; -NR9R9; –OH; -NO2; and -C(=O)OH; each occurrence of R9is independently selected from the group consisting of: hydrogen, deuterium, C1-4 alkoxy; and C1-4 alkyl; 20 each occurrence of R10, R11, and R13is independently selected from the group consisting of: –OH; -halo; –NR9R9; C1-4 alkyl; C1-4 haloalkyl; C1-4 alkoxy; -C(=O)O(C1-4 alkyl); -C(=O)(C1-4 alkyl); -C(=O)OH; -S(O)1-2(C1-4alkyl); and cyano;25each occurrence of R12, is independently selected from the group consisting of: –OH; -halo; –NR9R9; C1-4 alkyl; C1-4 alkoxy; C1-4 haloalkoxy; -C(=O)O(C1-4 alkyl); -C(=O)(C1-4 alkyl); - C(=O)OH; -S(O)1-2(C1-4alkyl); C3-6cycloalkyl; and cyano; each occurrence of R14is independently selected from the group consisting of: deuterium; - 30 OH; -halo; C1-2alkyl; C1-2alkoxy; C1-2haloalkyl; and C1-2haloalkoxy.126PAT059977-WO-PCT 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has Formula (II):5 Formula (II) wherein X1, X2and X3are each selected from the group consisting of CR6Dand N, and wherein a maximum of one of X1, X2and X3may be N. 10 3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has Formula (III):15 wherein Y and Z are independently selected from the group consisting of CH, CR14and N, wherein at least one of Y and Z is N and wherein m is 0 or 1.

4. The compound of claim 1 or claim 3, or a pharmaceutically acceptable salt thereof, wherein the compound has Formula (IV):20Formula (IV) wherein Y is selected from the group consisting of CH, CR14and N.127PAT059977-WO-PCT 5. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein R2is Cl. 5 6. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein at least one of R3, R4and R5is H.

7. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein at least two of R3, R4and R5is H. 10 8. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein all of R3, R4and R5are H.

9. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein15R9is hydrogen.

10. The compound of claim 1, wherein the compound is of Formula (V):Formula (V) 20 or a pharmaceutically acceptable salt thereof.

11. The compound of any one of claims 1 and 5-10, or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from the group consisting of:25•, wherein * is the point of attachment to L, X1, X2and X3are each selected from the group consisting of CH and N, and wherein a maximum of one of X1, X2and X3may be N; or128PAT059977-WO-PCT •, wherein Z is the point of attachment to L, and Y and Z are independently selected from the group consisting of CH and N; and Ring B is selected from the group consisting of: 5 • heterocyclyl or heterocycloalkenyl including 5-9 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R1) and O, and wherein one or more of the carbon atoms of the heterocyclyl or heterocycloalkenyl are optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R8; or 10 • heteroaryl including 5-9 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R1), and O, wherein at least one ring in the system is aromatic and wherein one or more of the carbon atoms of the heteroaryl are optionally substituted with from 1-4 substituents independently selected from oxo and R8; and15L is selected from the group consisting of a bond, *-O(C1-C4alkylene)-, and *-C1-C4alkylene-, wherein the alkylene is optionally substituted with 1-2 R7, wherein * denotes the point of attachment of L to Ring A, wherein L is a bond or *-C1-C4 alkylene- when Z is N. 20 12. The compound of any one of claims 1 and 5-11, or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from the group consisting of: •, wherein * is the point of attachment to L, wherein X1and X2are each selected from the group consisting of CH and N and wherein a maximum of25one of X1and X2may be N; or •, wherein N is the point of attachment to L, and wherein Y is selected from the group consisting of CH and N;129PAT059977-WO-PCT Ring B is selected from the group consisting of: • heterocyclyl or heterocycloalkenyl including 5-9 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R1) and O, wherein one or more of the carbon atoms of the heterocyclyl 5 or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R8; or • heteroaryl including 5-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R1), and O, wherein at least one ring in the system is aromatic, wherein one or more of the 10 carbon atoms of the heteroaryl is optionally substituted with from 1-4 substituents independently selected from oxo and R8; and L is selected from the group consisting of a bond, *-O(C1-C4alkylene)-, and *-C1-C4alkylene-, wherein the alkylene is optionally substituted with 1-2 R7, wherein * denotes the15point of attachment of L to Ring A, wherein L is a bond or *-C1-C4 alkylene- when Z is N.

13. The compound of any one of claims 1 and 5-10, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from the group consisting of: • , wherein * is the point of attachment to L, X1, X2and X3are 20 each selected from the group consisting of CH and N, and wherein a maximum of one of X1, X2and X3may be N; or •, wherein Z is the point of attachment to L and Y and Z are independently selected from the group consisting of CH and N. 25 14. The compound of any one of claims 1, 5-10 and 13, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from the group consisting of:130PAT059977-WO-PCT •, wherein * is the point of attachment to L, wherein X1and X2are each selected from the group consisting of CH and N and wherein a maximum of one of X1and X2may be N. •, wherein Z is the point of attachment to L and at least one of Y 5 and Z are N.

15. The compound of any one of claims 1, 5-10, 13 and 14, or a pharmaceutically acceptable salt thereof, wherein Ring, wherein * is the point of attachment to L, X1, X2and X3are each selected from the group consisting of CH and N, and wherein a maximum of one of X1, X2and X3may be N.1016. The compound of any one of claims 1, 5-10 and 13-15, or a pharmaceutically acceptable salt thereof, wherein Ring A is , wherein * is the point of attachment to L, X1and X2are each selected from the group consisting of CH and N, and wherein a maximum of one of X1and X2may be N.

17. The compound of any one of claims 1, 5-10 and 13-16, or a pharmaceutically acceptable salt15thereof, wherein Ring A is , wherein * is the point of attachment to L, and wherein X1is selected from the group consisting of CH and N.

18. The compound of any one of claims 1, 5-10 and 13-17, or a pharmaceutically acceptable salt thereof, wherein Ring, wherein * is the point of attachment to L.131PAT059977-WO-PCT 19. The compound of any one of claims 1, 5-10 and 13-17, or a pharmaceutically acceptable salt thereof, wherein Ring.

20. The compound of any one of claims 1, 5-10, 13 and 14, or a pharmaceutically acceptable salt thereof, wherein Ring, wherein Z is the point of attachment to L, Y 5 and Z are independently selected from the group consisting of CH and N.

21. The compound of any one of claims 1, 5-10 and 13-15, or a pharmaceutically acceptable salt thereof, wherein Ring.

22. The compound of any one of claims 1, 5-10 and 13-15, or a pharmaceutically acceptable salt thereof, wherein Ring, wherein N is the point of attachment to L.1023. The compound of any one of claims 1, 5-10, 13 and 14, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from the group consisting of:,, wherein * is the point of attachment to L.1524. The compound of any one of claims 1-10 and 13-23, or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of a bond, *-O(C1-C4alkylene)-, and *-C1-C4alkylene-, wherein the alkylene is optionally substituted with 1-2 R7, wherein * denotes the point of attachment of L to Ring A, wherein L is a bond or *-C1-C4 alkylene- when Z is N. 20132PAT059977-WO-PCT 25. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of a bond, *-methylene and *-O-methylene, wherein * indicates the point of attachment of L to Ring A. 5 26. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein L is a bond.

27. The compound of any one of claims 1-10 and 13-26, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from the group consisting of: 10 • heterocyclyl or heterocycloalkenyl including 5-9 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R1) and O, and wherein one or more of the carbon atoms of the heterocyclyl or heterocycloalkenyl are optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R8;15• heteroaryl including 5-9 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R1), and O, wherein at least one ring in the system is aromatic and wherein one or more of the carbon atoms of the heteroaryl are optionally substituted with from 1-4 substituents independently selected from oxo and R8. 20 28. The compound of any one of claims 1-10 and 13-27, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from the group consisting of: • heterocyclyl or heterocycloalkenyl including 5-9 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R1) and 25 O, wherein one or more of the carbon atoms of the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R8; • heteroaryl including 5-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R1), and O, wherein at least 30 one ring in the system is aromatic, wherein one or more of the carbon atoms of the heteroaryl is optionally substituted with from 1-4 substituents independently selected from oxo and R8.

29. The compound of any one of claims 1-10 and 13-28, or a pharmaceutically acceptable salt thereof, wherein Ring B is heterocyclyl including 5-10 ring atoms, wherein from 1-4 ring133PAT059977-WO-PCT atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R1) and O, and S(O)0-2, and wherein one or more of the carbon atoms of the heterocyclyl are optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R8. 5 30. The compound of any one of claims 1-10 and 13-28, or a pharmaceutically acceptable salt thereof, wherein Ring B is heterocycloalkenyl including 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R1) and O, and S(O)0-2, and wherein one or more of the carbon atoms of the 10 heterocycloalkenyl are optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R8.

31. The compound of any one of claims 1-10 and 13-28, or a pharmaceutically acceptable salt thereof, wherein Ring B is heteroaryl including 5-10 ring atoms, wherein from 1-4 ring atoms 15 are heteroatoms, each independently selected from the group consisting of N, N(H), N(R1), O, and S(O)0-2, wherein at least one ring in the system is aromatic and wherein one or more of the carbon atoms of the heteroaryl are optionally substituted with from 1-4 substituents independently selected from oxo and R8. 20 32. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein the ring atoms that are heteroatoms are each independently selected from the group consisting of N, N(H), N(R1), and O.

33. The compound of any one of claims 1-11, 13-26 or 29-32, or a pharmaceutically acceptable25salt thereof, wherein Ring B contains 5-9 ring atoms.

34. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein Ring B contains 5-6 ring atoms. 30 35. The compound of any one of claims 1-11, 13-26 or 29-34, or a pharmaceutically acceptable salt thereof, wherein Ring B contains from 1-3 heteroatoms.

36. The compound of claim 35, or a pharmaceutically acceptable salt thereof, wherein Ring B contains from 1-2 heteroatoms.35134PAT059977-WO-PCT 37. The compound of claim 29 or claim 30, or a pharmaceutically acceptable salt thereof, wherein one of the carbon atoms of Ring B is substituted with oxo.

38. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein 5 R1is selected from the group consisting of: C1-6 alkyl optionally substituted with from 1-3 independently selected R13; and -C0-6alkyl(C3-6cycloalkyl) optionally substituted with from 1-3 independently selected R13.

39. The compound of claim 38, or a pharmaceutically acceptable salt thereof, wherein R1is 10 selected from the group consisting of: C1-6alkyl; and -C0-6alkyl(C3-6cycloalkyl).

40. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof, wherein R1is C1-6alkyl optionally substituted with from 1-3 independently selected R13.1541. The compound of claim 40, or a pharmaceutically acceptable salt thereof, wherein R1is C1-6 alkyl.

42. The compound of claim 40, or a pharmaceutically acceptable salt thereof, wherein R1is methyl or ethyl optionally substituted with from 1-3 independently selected R13. 20 43. The compound of any one of claims 1-38, 40 and 42, or a pharmaceutically acceptable salt thereof, wherein R13is selected from the group consisting of -C1-4alkoxy; and halo.

44. The compound of claim 43, or a pharmaceutically acceptable salt thereof, wherein R13is 25 selected from the group consisting of -methoxy; ethoxy and F.

45. The compound of any one of claims 1-28, 31-33, 35 and 38-44, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from the group consisting of:,, , , , , , ,135PAT059977-WO-PCT 5substituted with from 1-4 R8substituents.

46. The compound of any one of claims 1-28, 31-33, 35 and 38-45, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from the group consisting of: 10 ,, , , , , , ,136PAT059977-WO-PCT 54 R8substituents. 10 47. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt thereof, wherein R8is C1-4 alkyl which is optionally substituted with from 1-6 independently selected R12.

48. The compound of claim 47, or a pharmaceutically acceptable salt thereof, wherein R8is C1-315alkyl which is optionally substituted with from 1-2 independently selected R12.137PAT059977-WO-PCT 49. The compound of claim 48, or a pharmaceutically acceptable salt thereof, wherein R8is selected from the group consisting of: methyl, propyl, and isopropyl each of which may be optionally substituted with from 1-2 independently selected R12. 5 50. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein R12is selected from the group consisting of -C1-4alkoxy; and -OH.

51. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein R12is selected from the group consisting of methoxy and -OH. 10 52. The compound of any one of claims 1-28, 31-33, 35 and 38-51, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from the group consisting of: ,15, ,, , , , , ,138PAT059977-WO-PCT 553. The compound of any preceding claim, wherein the compound is selected from the group consisting of the compounds in Table 1, or a pharmaceutically acceptable salt thereof. 10 54. A pharmaceutical composition comprising the compound of any preceding claim, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

55. A method of degrading Proto-oncogene vav 1 protein (VAV1) in a subject, comprising administering to the subject an effective amount of the compound of any one of claims 1-53 15 or a pharmaceutically acceptable salt thereof.

56. The method of claim 55, wherein the compound mediates the interaction of a VAV1 protein with an E3 ligase, thereby increasing degradation of the VAV1 protein. 20 57. The method of any of claims 55-56, wherein VAV1 is a regulator of a lymphocyte.139PAT059977-WO-PCT 58. The method of any of claims 55-56, wherein the compound interacts with the E3 ligase prior to the interaction of VAV1 with the E3 ligase. 5 59. The method of any one of claims 56-58, wherein the E3 ligase comprises cereblon.

60. A method of degrading Proto-oncogene vav 1 protein (VAV1), comprising: (i) contacting the compound of any one of claims 1-53 or a pharmaceutically acceptable salt thereof with an E3 ligase; and 10 (ii) interacting the contacted E3 ligase with VAV1, thereby degrading VAV1.

61. A method of treating a disorder caused by or associated with disregulation of lymphocyte development or activation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-53 or a 15 pharmaceutically acceptable salt thereof.

62. The method of claim 57 or claim 61, wherein the lymphocyte is T-cell.

63. The method of claim 57 or claim 61, where in the lymphocyte is B-cell. 20 64. A method of treating a disorder caused by or associated with disregulation of T-cell receptor signaling in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-53 or a pharmaceutically acceptable salt thereof. 25 65. The method of claim 64, wherein the T-cell receptor signaling is IFNɣ, CD69, and / or IL-2.

66. A method of treating a disorder caused by or associated with VAV1 polymorphisms in a subject in need thereof, comprising administering to the subject a therapeutically effective 30 amount of a compound of any one of claims 1-53 or a pharmaceutically acceptable salt thereof.

67. A method of treating a disorder caused by or associated with immunopathologies in a subject in need thereof, comprising administering to the subject a therapeutically effective140PAT059977-WO-PCT amount of a compound of any one of claims 1-53 or a pharmaceutically acceptable salt thereof.

68. The method of claim 66 or claim 67, wherein the disorder is autoimmune disorder. 5 69. The method of claim 68, wherein the autoimmune disorder is selected from the group consisting of multiple sclerosis, psoriatic arthritis, rheumatoid arthritis, systemic lupus, erythematosus, Hashimoto’s thyroiditis, myasthenia gravis, diabetes type I or II, and the disorders associated therewith, vasculitis, pernicious anemia, Sjoegren syndrome, uveitis, 10 psoriasis, Graves ophthalmopathy, alopecia areata and others, allergic diseases (e.g., allergic asthma, atopic dermatitis, allergic rhinitis / conjunctivitis, allergic contact dermatitis), inflammatory diseases optionally with underlying aberrant reactions (e.g., inflammatory bowel disease, Crohn’s disease or ulcerative colitis, intrinsic asthma, inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury), atherosclerosis, 15 osteoarthritis, irritant contact dermatitis and further eczematous dermatitis, seborrheic dermatitis, cutaneous manifestations of immunologically-mediated disorders, inflammatory eye disease, keratoconjunctivitis, myocarditis or hepatitis.

70. The method of claim 66 or claim 67, wherein the disorder is a cancer, tumour or other 20 malignancy, optionally wherein the disorder is a hematologic malignancy (e.g. T and B cell malignancy).

71. The method of claim 70, wherein the disorder is selected from the group consisting of: leukemia, lymphoma, Acute myeloid leukemia (AML), T-cell prolymphocytic leukemia, T- 25 cell granular lymphocytic leukemia, aggressive NK cell leukemia, hairy-cell leukemia, nasal and nasal-type NK / T cell lymphoma, mycosis fungoides and Sezary syndrome, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma unspecified, adult T-cell leukemia / lymphoma (HTLV1+), anaplastic large cell lymphoma, primary cutaneous CD-30 positive T-cell lymphoproliferative disorders, cutaneous T-cell lymphoma, subcutaneous 30 panniculitis like T-cell lymphoma, intestinal T-cell lymphoma (+enteropathy), hepatosplenic gamma / delta T-cell lymphoma, and non-Hodgkin lymphomas (e.g., B-cell non-Hodgkin lymphomas; e.g., Burkitt lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), diffuse large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma).141PAT059977-WO-PCT 72. The method of claim 66 or claim 67, wherein the disorder is selected from the group consisting of diabetes Type I or II, pernicious anemia, uveitis, psoriasis, alopecia areata, ulcerative colitis, Crohn’s disease, atherosclerosis, myocarditis, pericarditis, pulmonary 5 fibrosis, systemic sclerosis, morphea, Alzheimer’s disease, Acute Graft-vs. Host Disease or T-cell mediated kidney disease.

73. The method of claim 66 or claim 67, wherein the disorder is a non-Hodgkin lymphoma. 10 74. The method of claim 73, wherein the disorder is selected from mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL) and Diffuse large B cell lymphoma (DLBCL).

75. The method of claim 74, wherein the disorder is chronic lymphocytic leukemia (CLL). 15 76. The method of claim 66 or claim 67, wherein the disorder is selected from the group consisting of multiple sclerosis, psoriatic arthritis, rheumatoid arthritis, myasthenia gravis, Sjogren’s syndrome, Grave’s disease, an allergic disorder, an autoimmune liver disease, chronic inflammatory demyelinating polyradiculoneuropathy, macular degeneration, systemic lupus erythematosus, Hashimoto’s thyroiditis, amyloidosis, inflammatory eye 20 diseases, pemphigus, systemic lupus erythematosus, Chronic Graft vs. Host Disease, lupus nephritis, pulmonary arterial hypertension or vasculitis.

77. The method of claim 66 or claim 67, wherein the disorder is selected from the group consisting of multiple sclerosis, psoriatic arthritis, rheumatoid arthritis, myasthenia gravis, 25 Sjogren’s syndrome, Grave’s disease, asthma, allergic contact dermatitis, rhinitis, contact dermatitis, biliary sclerosis, sclerosing cholangitis, chronic inflammatory demyelinating polyradiculoneuropathy, macular degeneration, systemic lupus erythematosus, Hashimoto’s thyroiditis, amyloidosis, inflammatory eye diseases, pemphigus, systemic lupus erythematosus, Chronic Graft vs. Host Disease, lupus nephritis, pulmonary arterial 30 hypertension or vasculitis.

78. The method of claim 66 or claim 67, wherein the disorder is selected from the group consisting of ulcerative colitis, rheumatoid arthritis, psoriasis, multiple sclerosis, myasthenia gravis, cutaneous lupus or axial spondylarthritis.142PAT059977-WO-PCT 79. The method of claim 66 or claim 67, wherein the disorder is selected from the group consisting of B-cell lymphoma, B-cell leukemia, T-cell lymphoma, T-cell leukemia, or acute myeloid leukemia. 5 80. A method of treating a transplantation setting disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-53 or a pharmaceutically acceptable salt thereof. 10 81. The method of claim 80, wherein the transplantation setting disease is selected from the group consisting of graft-versus-host disease, chronic graft rejection, acute graft rejection, transplant vasculopathy, graft vessel disease, graft atherosclerosis, and transplant coronary disease. 15 82. A method of degrading proto-oncogene vav 1 protein (VAV1) in a subject suffering from an autoimmune disease, or a transplantation setting disease, comprising administering to the subject an effective amount of the compound of any one of claims 1-53 or a pharmaceutically acceptable salt thereof. 20 83. The method of claim 82, wherein the autoimmune disorder is selected from the group consisting of multiple sclerosis, psoriatic arthritis, rheumatoid arthritis, systemic lupus, erythematosus, Hashimoto’s thyroiditis, myasthenia gravis, diabetes type I or II, and the disorders associated therewith, vasculitis, pernicious anemia, Sjogren syndrome, uveitis, psoriasis, Graves ophthalmopathy, alopecia areata and others, allergic diseases (e.g., allergic 25 asthma, atopic dermatitis, allergic rhinitis / conjunctivitis, allergic contact dermatitis), inflammatory diseases optionally with underlying aberrant reactions (e.g., inflammatory bowel disease, Crohn’s disease or ulcerative colitis, intrinsic asthma, inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury), atherosclerosis, osteoarthritis, irritant contact dermatitis and further eczematous dermatitis, seborrheic 30 dermatitis, cutaneous manifestations of immunologically-mediated disorders, inflammatory eye disease, keratoconjunctivitis, myocarditis or hepatitis.

84. The method of claim 82, wherein the transplantation setting disease is selected from the group consisting of graft-versus-host disease, chronic graft rejection, acute graft rejection,143PAT059977-WO-PCT transplant vasculopathy, graft vessel disease, graft atherosclerosis, and transplant coronary disease.

85. The method of any one of claims 69, 76-78 and 83, wherein the disorder is multiple 5 sclerosis.144

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