Combinations comprising VAV1-targeting degraders

Abstract

This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt thereof) that degrade human Proto-oncogene VAV 1 protein (VAV1), in combination with a therapeutic agent. This disclosure also features the use of these combinations as a medicament.

Description

[0001]PAT059979-WO-PCT COMBINATIONS COMPRISING VAV1-TARGETING DEGRADERS 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), in combination with a therapeutic agent. The VAV1-targeting 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 combinations as well as methods of using these combinations. 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 20 target protein. It is 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 25 cancers. 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 30 response to a variety of stimuli, including stimulation of T-cell receptor (TCR), B cell receptor (BCR), and various cytokine receptors. VAV1 regulates multiple cellular functions and signaling pathways in hematopoietic-derived cells (e.g., T- and B-cells, natural killer cells, and 1 PAT059979-WO-PCT 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) signaling including nuclear factor of activated T cells (NFAT), interferon gamma (IFNɣ) and Interleukin-2 (IL-2) cytokine secretion. 5 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 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), a10commonly used model of multiple sclerosis (Korn et al. 2003 Journal of Neuroimmunology 139:17). Finally, genome-wide CRISPR activation (CRISPRa) and interference (CRISPRi) screens in primary human T cells identified VAV1 as an important positive regulator of T cell function (Schmidt et al.2022 Science 375:6580). 15 SUMMARY This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt thereof) that degrade Proto-oncogene VAV 1 protein (VAV1), in combination with a therapeutic agent. 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 B20cells. 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. Moreover, degradation of VAV1 may be therapeutically beneficial in addition to modulation of other biological pathways. Indeed, it is demonstrated herein that VAV1 25 degraders are therapeutically effective in combination with over one thousand different therapeutic agents. Many of such combinations demonstrate an additive, or even synergistic therapeutic effect. Thus, in one aspect, the invention provides a VAV1 degrader for use as a medicament, wherein the VAV1 degrader is for use in combination with a therapeutic agent.30In another aspect, the invention provides a therapeutic agent for use as a medicament, wherein the therapeutic agent is for use in combination with a VAV1 degrader. In another aspect, the invention provides to a combination for use as a medicament, the combination comprising: (i) a VAV1 degrader; and (ii) a therapeutic agent. 2 PAT059979-WO-PCT In these aspects, the VAV1 degrader and the therapeutic agent may be administered simultaneously, separately, or sequentially. In another aspect, the invention provides a combination comprising: (i) a VAV1 5 degrader; and (ii) a therapeutic agent. The combination may be provided as a combined preparation for simultaneous, separate, or sequential use as a medicament. DEFINITIONS The term “pharmaceutically acceptable salt” refers to those salts which are, within the10scope 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 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 15 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 group formed 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 using20 other methods used in the art such as ion exchange. Other pharmaceutically acceptable saltsinclude adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate,25 lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2– naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p–toluenesulfonate, undecanoate, valerate salts, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline30earth 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 ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, 3 PAT059979-WO-PCT carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate. The VAV1 degrader and / or therapeutic agent of the invention may be provided in salt form or in free form. 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 5 naturally 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 a10non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. Preferably, the subject is a human. As used herein, a “therapeutic agent” is a molecular entity which treats a disease, disorder, or condition, otherwise known as a drug. The therapeutic agent may be, for instance, 15 a small molecule or an antibody. The therapeutic agent may be provided in free form, or as a pharmaceutically acceptable salt, hydrate, enantiomer, prodrug and / or metabolite thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, those disclosed above. As used herein, “inhibitor” refers to a therapeutic agent which slows down or prevents20 a particular chemical reaction or other process, and / or which reduces the activity of a particularprotein, either directly or indirectly. As used herein, a “VAV1 degrader” refers to a chemical entity (e.g., a compound or a pharmaceutically acceptable salt thereof) that degrades Proto-oncogene VAV 1 protein (VAV1). A VAV1 degrader may bind to a specific amino acid sequence of a VAV1 protein 25 and mediate the interaction of the VAV1 protein with an E3 ligase, thereby increasing degradation of the VAV1 protein. As used herein, “anti-[protein] compound” refers to a compound that targets the named protein, which may result in protein modulation and / or cell death. For example, an anti-CD20 compound as disclosed herein may facilitate complement dependent cytotoxicity and / or hyper-30crosslinking, resulting in cell death. Anti-[protein] compounds may be otherwise known as [protein] neutralizing antibodies, or [protein] inhibitors. Disease, disorder, and condition are used interchangeably herein. As used herein “haematologic disease” or “haematological disease”, also known as blood disorders, refers to a disease or disorder involving the blood, and includes problems with 4 PAT059979-WO-PCT red blood cells, white blood cells, platelets, bone marrow, lymph nodes and / or the spleen. Examples include anemia, leukemia, lymphoma, myeloma, thrombocytopenia, hemophillia, sickle cell disease, polycythemia vera, myelodysplastic syndrome, and hemochromatosis. A subset of haematologic disease is haematologic malignancy, which are blood cancers that 5 typically originate in blood-forming tissues, such as the bone marrow and lymphatic system. Examples include leukemia (for instance, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), or chronic myeloid leukemia (CML)), lymphoma (for instance Hodgkin lymphoma or non-Hodgkin lymphoma), and multiple myeloma.10A “serious disease” may involve an overnight stay in a hospital, hospice, or residential medical care facility or any further treatment in connection with that inpatient care. Alternatively, or in addition, a serious disease may involve any period of incapacity, including an inability to work or to perform regular daily activities, for more than three consecutive, full calendar days. Any later treatment or incapacity required or caused by a serious disease may 15 involve two treatments (an in-person visit to a health care provider), with the first treatment occurring within seven days of the first day of incapacity; or one treatment by a health care provider who prescribes continuing treatment. As used herein, and unless otherwise specified, the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified20 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”). As used herein, simultaneous administration refers to administration of the one or more therapeutic agents in the same dosage form at the same time. As used herein, separate 25 administration refers to administration of the one or more therapeutic agents in different dosage forms at the same time or one immediately after the other in any order. As used herein, sequential administration refers to administration of the one or more therapeutic agents in different dosage forms at different times. Sequential administration is particularly useful when the therapeutic agents in the combination therapy are in different dosage forms (one agent is a30tablet or capsule and another agent is a sterile liquid) and / or are administered on different dosing schedules. 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 effective amount of a compound of the present disclosure may vary depending on such 5 PAT059979-WO-PCT 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 5 disease, disorder 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 a VAV 1 degrader or therapeutic agent, which provides a therapeutic benefit in the treatment of the disease, disorder or condition when used according to the invention. The term “therapeutically effective amount” can encompass an amount that improves overall therapy,10reduces or avoids symptoms or 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 15 found in nature. Examples of isotopes that can be incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as2H,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).20 The term "alkyl" refers to a saturated acyclic hydrocarbon radical that may be a straightchain 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. Alkyl groups can either be unsubstituted or substituted with one or more substituents. Non-limiting examples include methyl, ethyl, iso-propyl, tert-butyl, n-hexyl. The term “saturated” as used in this 25 context means only single bonds present between constituent carbon atoms and other available valences occupied by hydrogen and / or other substituents as defined herein. 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).30The 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 or branched chain having one or more carbon-carbon double bonds. The alkenyl moiety contains the indicated number of carbon atoms. For example, C2-6 indicates that the group may 6 PAT059979-WO-PCT have from 2 to 6 (inclusive) carbon atoms in it. Alkenyl groups can either be unsubstituted or substituted with one or more substituents. 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 5 the indicated number of carbon atoms. For example, C2-6 indicates that the group may have from 2 to 6 (inclusive) carbon atoms in it. Alkynyl groups can either be unsubstituted or substituted with one or more substituents. 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 14-10carbon tricyclic aromatic ring system); and wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, 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 15 ring carbons or 3-10 ring carbons or 3-6 ring carbons, wherein the cycloalkyl group may be optionally substituted. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. 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,20 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 spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentanyl, spiro[2.5]octanyl, spiro[3.5]nonanyl, 25 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. 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 to3012 ring carbons or 3-10 ring carbons or 3-6 ring carbons, wherein the cycloalkenyl group may be optionally substituted. 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 provided that one or more double bonds is present in the ring, none of the rings in the ring system are 7 PAT059979-WO-PCT 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 20 ring atoms, alternatively 5, 6, 9, 10, or 14 ring atoms; and having 6, 10, or 14 pi 5 electrons shared in a cyclic array; wherein at least one ring in the system 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). Heteroaryl groups can either be unsubstituted or substituted with one or more substituents. Examples of heteroaryl10include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, 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, 15 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, chromanyl, 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,20 isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl.The term "heterocyclyl" refers to a mon-, bi-, tri-, or polycyclic saturated ring system with 3-16 ring atoms (e.g., 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system) having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic, said heteroatoms selected from O, N, or 25 S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent. 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: 2-30azabicyclo[1.1.0]butanyl, 2-azabicyclo[2.1.0]pentanyl, 2-azabicyclo[1.1.1]pentanyl, 3- azabicyclo[3.1.0]hexanyl, 5-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- 8 PAT059979-WO-PCT oxabicyclo[1.1.1]pentanyl, 3-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., 5 spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic heterocyclyls include 2-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, 2-10oxaspiro[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, 6- 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 15 constituent ring atoms and other available valences occupied by hydrogen and / or other substituents as defined herein. The term "heterocycloalkenyl" as used herein means partially unsaturated cyclic ring system with 3-16 ring atoms (e.g., 5-8 membered monocyclic, 8-12 membered bicyclic, or 11- 14 membered tricyclic ring system) having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if20 bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic, said heteroatoms selected from O, N, orS (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent. Examples of heterocycloalkenyl groups include, without limitation, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, 25 dihydrothiophenyl. As partially unsaturated cyclic 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. 30 Certain groups, such as , can be considered as either: (i) a heterocycloalkenyl which is substituted with an oxo group; or (ii) a heteroaryl group. 9 PAT059979-WO-PCT 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, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thioazole, isoxazole, 5 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 attributed to the ring itself; e.g., one or more double or tirple bonds between constituent ring atoms), provided that the ring is not aromatic. Examples of such rings include:10cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like. For the avoidance of doubt, and unless otherwise specified, for rings and cyclic groups (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 15 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 bridge (e.g., (ii) a single ring atom (spiro-fused ring systems) ( , (iii) a contiguous array of ring atoms (bridged ring systems 20 In addition, atoms making up the compounds of the present embodiments are intended to 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 25 limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include 13C and14C. In addition, the compounds generically or specifically disclosed herein include all tautomeric forms, or “tautomers” of said compounds. To give a non-limiting example, a 10 PAT059979-WO-PCT disclosure of a compound with the group also a disclosure of a compound with the another non-limiting example, a disclosure of a compound with the group disclosure of a compound with the group . give another non-limiting example, a disclosure of a compound with the group also a disclosure 5 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 context indicates otherwise. Compounds with chiral centers can occur as racemates, individual enantiomers (e.g. as the (R) enantiomer or (S) entantiomer) or diastereomers, and10mixtures thereof. All such stereoisomeric forms are included within the embodiments disclosed herein, including mixtures thereof. Further, compounds of one enantiomeric form may epimerise into the other enantiomeric form. Thus, unless it is specifically stated or the context indicates otherwise, disclosure of one stereoisomer encompasses the isolated stereoisomer and a mixture, such as a 15 racemic mixture, of the (R) and (S) stereoisomers if the stereoisomers epimerise. For example, a disclosure amixture , including a racemic mixture11 PAT059979-WO-PCT of the two enantiomers. In another example, a disclosure of a compound according to Formula 5 Similarly, a compound comprising a chiral center disclosed herein without its stereoisomeric form indicated encompasses the isolated entantiomer and a mixture, such as a racemic mixture. 10 example, a disclosure of a compound according to Formula (III-E), encompasses both isolated , 12 PAT059979-WO-PCT a racemic mixture of the two stereoisomers. 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 5 (i.e., none of the substitutable hydrogen atoms are replaced with one or more non-hydrogen 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-C4 alkyl and C1-C4 alkyl substituted with 1-4 Ra. As used herein, the term “hydrogen bond acceptor” is intended to include any functional 10 group containing a heteroatom, usually oxygen or nitrogen, having one or more lone pairs suitable for formation of hydrogen bond with a polarized hydrogen atom. A more detailed discussion of hydrogen bond acceptors and a list of accepted hydrogen bond acceptors is found in Laurence et al., J. Med. Chem., 2009, 52, 4073-4086 and Kenny et al., J. Med Chem.2016, 59, 4278-4288, both of which are incorporated by reference in their entirety.15The 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 20 FIG. 1 is a schematic depiction of certain aspects of VAV1’s relationship to certain proteins involved in T cell receptor activation. VAV1 is a positive regular of T cell receptor signaling, including interferon gamma production and IL-2 secretion. FIGS.2A-2D show VAV1 MGD concentration in serum (left) after seven consecutive25daily 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). 13 PAT059979-WO-PCT FIG. 3 shows the concentration of VAV1 MGD in plasma over time and associated decrease in normalized VAV1 to b-actin protein levels relative to pre-treatment after a single oral dose of the selected VAV1 MGD at 10 mg / kg (y-axis represents hours post one single oral 5 dose of VAV1 MGD [hour]; left y-axis represents VAV1 MGD concentration in ng / ml in plasma, filled rhombi; right y-axis represents percentage [%] VAV1 protein levels normalized to b-actin protein levels and relative to pre-dose in blood cells, filled triangles). FIGS.4A-4C show dose-dependent decrease in VAV1 levels in primary human CD3+10T cells, 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. 5A shows dose-dependent decrease in VAV1 levels in primary human T-cells 15 upon 24h treatment with VAV1 MGD 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.5B shows that VAV1 is significantly and selectively degraded by VAV1 MGD in20 Jurkat cells following 24h treatment as assessed by quantitative TMT proteomics (y-axisrepresents confidence p-value [-log10]; x-axis represents protein fold-change [log2] relative to DMSO control samples). FIGS.6A-6D show that VAV1 degradation results in inhibition of various hallmarks 25 of TCR-mediated activity following TCR stimulation of primary human T-cells. Cells were treated with 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 of30VAV1 MGD). FIG. 7 shows that oral administration of VAV1 MGD in a MOG35-55-induced experimental autoimmune encephalomyelitis (EAE) model led to inhibition of disease 14 PAT059979-WO-PCT progression. Mice were immunized by subcutaneous injection at day 0 with an emulsified mixture consisting of the synthetic peptide derived from myelin oligodendrocyte glycoprotein (MOG35-55) and M. tuberculosis mixed with incomplete Freund’s adjuvant. Additionally, mice were injected intraperitoneally with pertussis toxin at 0 and 48 hours. Mice were followed for 5 development of symptoms and scored for EAE clinical signs disease (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), once a day (QD) dosing started at day 12 and ended at day 18. Dexamethasone dosed QD orally from day 12 to day 18 was used as comparative treatment.10 mg / kg of VAV1 MGD prevented the progression of EAE disease10as it was observed for the mice treated with Dexamethasone at 1 mg / kg (x-axis represents days post immunization initiation [days]; y-axis represents clinical EAE score, [mean ±SEM]; empty circle: vehicle, PO, QD; filled triangles inverted, VAV1 MGD 10 mg / kg, PO, QD; filled square, Dexamethasone 1 mg / kg, PO, QD). FIG. 8A shows that oral administration of VAV1 MGD in a MOG35-55-induced 15 experimental autoimmune encephalomyelitis (EAE) model led to inhibition of disease progression in a dose-dependent manner. Mice were immunized by subcutaneous injection at day -12 with an emulsified mixture consisting of the synthetic peptide derived from myelin oligodendrocyte glycoprotein (MOG35-55) and M. tuberculosis mixed with incomplete Freund’s adjuvant. Additionally, mice were injected intraperitoneally with pertussis toxin at20 day -12 and -10. Mice were followed for development of symptoms and scored for EAE clinicalsigns disease (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) every 3 days until day 0. Dosing started at day 0 and ended at day 13 with vehicle (PO, QD), dexamethasone (1 mg / kg, PO QD), and VAV1 MGD (1, 0.1, 0.01 mg / kg, PO, QD).1 mg / kg 25 VAV1 MGD prevented the progression of EAE disease as it was observed for the mice treated with Dexamethasone at 1 mg / kg (x-axis represents days post immunization initiation [days]; y-axis represents clinical EAE score, [mean ±SEM]; closed circle: vehicle; solid up triangle, VAV1 MGD 1 mg / kg; closed down triangle, VAV1 MGD 0.1 mg / kg; Open up triangle, VAV1 MGD 0.01 mg / kg; open circle, Dexamethasone 1 mg / kg).30FIG.8B shows that oral administration of VAV1 MGD degraded VAV1 in the spinal cord in a dose-dependent manner commensurate with reduction in clinical scores. On day 6, 4 mice per group were euthanized, spinal cords were excised and homogenized, and western blot 15 PAT059979-WO-PCT was then used to assess VAV1 levels normalized to β-actin and shown relative to vehicle treated mice. Statistical analysis was performed using a one-way ANOVA with Dunnett’s multiple comparisons. ns = not significant, ***p<0.001, ****p<0.0001. FIG. 9 shows that oral administration of VAV1 MGD in a T-cell transfer induced 5 model of colitis led to inhibition of disease progression. CD17-SCID mice were injected intraperitoneally with 0.5 x 106non-pathogenic activated CD45RBlow(no disease control group) or pathogenic naïve CD45RBhigh (treatment groups) CD4+ T cells. From the day of cell transfer (day 0), the mice were monitored daily for disease activity index (DAI) comprising weight loss and stool consistency assessment. On day 0, two hours post-cell transfer, mice were10treated orally (PO) daily (QD) with vehicle or VAV1 MGD 1 mg / kg for 42 days. 1 mg / kg VAV1 MGD prevented the progression of colitis (x-axis represents days post disease induction and treatment start [days]; y axis represents DAI score [mean ± SEM]; open circles, non- pathogenic control; closed black circles, vehicle; closed triangles, VAV1 MGD 1 mg / kg). FIG.10A shows that oral administration of VAV1 MGD in a collagen-induced arthritis 15 model led to inhibition of disease progression. To induce collagen-induced arthritis (CIA), fifteen DBA / 1 mice were injected intravenously with an emulsified mixture consisting of 100 μg of chicken collagen II emulsified in incomplete Freund’s adjuvant then 18 days later injected subcutaneously with chicken collagen II emulsified in complete Freund’s adjuvant. This immunization induces the activation and expansion of collagen specific T- and B-cells that20 migrate into the paw joints. Once in the paw joints, the activated T-cells induce destruction ofthe joint and bone tissue, leading to redness and swelling of the phalanges, and B-cells produce antibodies against collagen II. Following the second immunization, mice were monitored daily for clinical signs of disease as follows: 0=erythema and redness; 1=Erythema or mild redness near ear the tarsal, ankle, or metatarsal or one toe with erythema and redness; 2=Ankles and 25 metatarsals are slightly erythematous and swollen with two or more toes with erythema and redness; 3=Moderate erythema and swelling of the ankle, wrists, and metatarsals; 4=Ankles, wrists, metatarsals, and toes are severely red and swollen. Upon disease onset, mice were randomly enrolled into treatment groups: vehicle (PO, QD), anti-TNF (10 mg / kg, IP, Q3D), or VAV1 MGD (1 mg / kg, PO, QD) and treated for 21 days.1 mg / kg VAV1 MGD prevented the30progression of arthritis (x-axis represents days post disease onset and treatment start [days]; y axis represents clinical score [mean ± SEM]; circles, vehicle; triangles, VAV1 MGD 1 mg / kg). 16 PAT059979-WO-PCT FIG.10B shows that oral administration of VAV1 MGD in a collagen-induced arthritis model led to decreased production of anti-collagen II IgG1 antibodies. At the end of the study, serum was collected and the amount of anti-collagen II IgG1 antibodies was measured by ELISA. Statistical analysis was performed using an unpaired two-tailed t-test. *p<0.05. 5 FIG.11 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.10FIGS.12A-12D show that VAV1 MGD-mediated degradation of VAV1 reduces BCR-mediated CD69 expression and secretion of IL-6 and IgG of primary human B cells. Purified human primary B-cells were treated with Compound 16 (“VAV1 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 15 IgG secretion). CD69 expression was then assessed on CD19+ B cells by flow cytometry. CD69 expression is shown as a percentage (%) change relative to 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-20 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 a percentage (%) change relative to stimulated DMSO controls. X-axis shows relative percentage of IgG level and y-axis shows concentration of VAV1 MGD. 25 FIGS. 13A-13C show 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 following stimulation (y-axis depicts percent of TNF secretion, relative to stimulated DMSO control; x-axis depicts doses of VAV1 MGD). 30 FIG. 14 shows that VAV1 MGD treatment of selected B-cell lymphoma cell lines decrease growth with increasing concentration. REC-1, OCI-LY10, and SLVL cells were 17 PAT059979-WO-PCT treated for 5 days with the indicated concentrations of VAV1 MGD. At 5 days of treatment, cell growth was measured by cell titer glow and normalized to T0 and DMSO. FIGS.15A-15C show that VAV1 MGD treatment of REC-1 cell line degraded 5 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. Data shows VAV1 levels normalized to β-actin and relative to DMSO control. FIGS.16A-16C show that VAV1 MGD treatment of REC-1 cell line decreases growth with increasing concentration. REC-1 were treated for 5 days with the indicated10concentrations of VAV1 MGD. After 5 days of treatment, cell growth was measured by cell titer glow and normalized to T0 and DMSO. FIG.17 shows that a VAV1 MGD, together with a diverse range of 1040 therapeutic agents, inhibits proliferation of REC-1 cells. FIG.18A shows that a VAV1 MGD, together with 187 different therapeutic agents for 15 hematologic diseases inhibits proliferation of REC-1 cells. FIG.18B shows that a VAV1 MGD, together with 179 different therapeutic agents for hematologic malignancies inhibits proliferation of REC-1 cells.20FIG. 18C shows that a VAV1 MGD, together with 8 different therapeutic agents for non-hematologic malignancies inhibits proliferation of REC-1 cells (i.e. the difference between figures 18A and 18B). FIGS.19A, 19C, 19E, and 19G show cell growth inhibition as a function of varying a 25 concentration of VAV1 MGD and a therapeutic agent targeting IKZF1 / 3, mTOR, BCL-2, BTK, DNA or SYK in a REC-1 cell line. FIG.19A shows the results obtained when the VAV1 MGD is Compound 60. FIG. 19C shows the results obtained when the VAV1 MGD is Compound 432. FIG.19E shows the results obtained when the VAV1 MGD is Compound 520. FIG.19G shows the results obtained when the VAV1 MGD is Compound 501. 30 FIGS.19B, 19D, 19F and 19H show that VAV1 MGDs display additive or synergistic combinational effects with clinically approved therapies targeting IKZF1 / 3, mTOR, BCL-2, 18 PAT059979-WO-PCT BTK, DNA and SYK on cell growth in a REC-1 cell line. FIG.19B shows the results obtained when the VAV1 MGD is Compound 60. FIG.19D shows the results obtained when the VAV1 MGD is Compound 432. FIG. 19F shows the results obtained when the VAV1 MGD is Compound 520. FIG.19H shows the results obtained when the VAV1 MGD is Compound 501. 5 FIGS. 19I-O show that VAV1 MGDs display additive (>0) or synergistic (≥10) combinational effects with clinically approved therapies targeting IKZF1 / 3, mTOR, BCL-2, BTK, DNA and SYK in REC-1.10FIGS.20A and 20B show the impact of a VAV1 MGD alone or in combination with 0.2 nM BTKi on B cell receptor (BCR)-mediated CD69 expression and IL-6 secretion in primary human B cells. FIG. 21A shows that oral administration of BTKi alone and in combination with a 15 VAV1 MGD reduces the population of circulating CD19+ cells. FIG. 21B shows that oral administration of BTKi and a VAV1 MGD alone and in combination shows increase in circulating Naïve B (IgM+IgD+) cells compared to vehicle control. 20 FIG.21C shows that oral administration of BTKi and a VAV1 MGD in combination shows increase in circulating immature B (IgM+IgD-) cells compared to vehicle control. FIG. 21D shows that oral administration of BTKi and VAV1 MGD alone and in 25 combination shows decrease in circulating mature B (IgM-IgD+) cells compared to vehicle control. FIGS.22A and 22B show that VAV1 MGD treatment alone or in combination with a BTK inhibitor (ibrutinib), of subcutaneously implanted REC-1 CDX decreases growth in vivo. 30 DETAILED DESCRIPTION 19 PAT059979-WO-PCT In one aspect, the invention provides a VAV1 degrader for use as a medicament, wherein the VAV1 degrader is for use in combination with a therapeutic agent. In another aspect, the invention provides a therapeutic agent for use as a medicament, wherein the therapeutic agent is for use in combination with a VAV1 degrader. In another 5 aspect, the invention provides a combination for use as a medicament, the combination comprising: (i) a VAV1 degrader; and (ii) a therapeutic agent. In another aspect, the invention provides the use of a VAV1 degrader in the manufacture of a medicament for treating a disease or disorder in combination with a therapeutic agent.10In another aspect, the invention provides the use of therapeutic agent a VAV1 degrader in the manufacture of a medicament for treating a disease or disorder in combination with a therapeutic agent. In another aspect, the invention provides the use of a VAV1 degrader in the manufacture of a medicament for treating a disease or disorder in combination with a 15 therapeutic agent. In another aspect, the invention provides a method of treating a disease or disorder, the method comprising administering a therapeutically effective amount of a VAV1 degrader, and a therapeutic agent. The VAV1 degrader and the therapeutic agent may be administered simultaneously,20 separately, or sequentially.Disorders and diseases to be treated The VAV1 degrader, the therapeutic agent, or the combination disclosed herein may be for use as a medicament in the treatment or prevention of a disease or disorder. The disease 25 may be caused by or associated with dysregulation of B-cell receptor signaling or T-cell receptor signaling (e.g., IFNɣ, CD69, and / or IL-2). The disorder may be caused by or associated with dysregulation of lymphocyte development or activation in a subject in need thereof. The VAV1 degrader, the therapeutic agent, or the combination disclosed herein may be30for use in the treatment or prevention of an autoimmune disease, a transplantation setting 20 PAT059979-WO-PCT disease, a hematologic disease, or a cancer, or tumour. Preferably, the disease is a cancer or tumour (for instance a hematologic malignancy), or an autoimmune disorder. The VAV1 degrader, the therapeutic agent, or the combination disclosed herein may be for use in the treatment or prevention of a cancer or tumour, for example, in the treatment of 5 carcinoma, sarcoma, myeloma, leukemia, lymphoma, and combinations thereof. The VAV1 degrader, the therapeutic agent, or the combination disclosed herein may be for use in the treatment or prevention of a hematological disorder. The hematological disorder may be selected from the group consisting of anemia, leukemia, lymphoma, myeloma, thrombocytopenia, hemophillia, sickle cell disease, polycythemia vera, myelodysplastic10syndrome, and hemochromatosis. More particularly, the hematologic disease may be a hematologic malignancy, such as leukemia, lymphoma, or multiple myeloma. Preferably, the VAV1 degrader, the therapeutic agent, or the combination disclosed herein may be for use in the treatment or prevention of a hematologic disease, including a T and / or B cell malignancy. For instance, the VAV1 degrader, the therapeutic agent, or the 15 combination disclosed herein may be for use in the treatment or prevention of leukemia or lymphoma. The hematologic malignancy may be multiple myeloma, chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), lymphoid leukemia, acute myeloid leukemia (AML), neoplasm of mature B-cells, non-Hodgkin's lymphoma (NHL), Hodgkin's lymphoma (HL), acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL),20 myelodysplastic syndrome (MDS), Burkitt's lymphoma, hairy cell leukemia, Waldenströmmacroglobulinemia (WM), marginal zone B-cell lymphoma, mast-cell leukemia, T-cell prolymphocytic leukemia (T-PLL), prolymphocytic leukemia (PLL), classic Hodgkin lymphoma, hematopoietic and lymphoid cell neoplasm, lymphoid neoplasm, follicular lymphoma, chronic myelogenous leukemia (CML), T-cell acute lymphoblastic leukemia, 25 cutaneous T-cell lymphoma (CTCL), blast phase chronic myelogenous leukemia, childhood acute lymphoblastic leukemia, lymphoblastic lymphoma, T-lymphoblastic lymphoma, anaplastic large cell lymphoma (ALCL), acute leukemia of ambiguous lineage, B-cell acute lymphoblastic leukemia (B-ALL), AL amyloidosis, acute monocytic leukemia, acute promyelocytic leukemia (APL), MALT lymphoma (mucosa-associated lymphoid tissue30lymphoma), myelofibrosis, essential thrombocythemia, polycythemia vera, asymptomatic myeloma, myeloproliferative disorder, plasma cell leukemia, plasmacytoma, chronic myelomonocytic leukemia (CMML), T-cell non-Hodgkin lymphoma, adult T-cell leukemia / lymphoma (ATLL), Langerhans cell histiocytosis, extranodal nasal NK / T cell lymphoma, lymphoid neoplasm, primary myelofibrosis, juvenile myelomonocytic leukemia 21 PAT059979-WO-PCT (JMML), Sézary's disease, sickle cell anemia, aplastic anemia, mycosis fungoides, acute megakaryoblastic leukemia, acute myeloblastic leukemia without maturation, acute basophilic leukemia, acute myelomonocytic leukemia, acute erythroblastic leukemia, granulocytic sarcoma, myeloid sarcoma, acute erythroleukemia, acute myeloblastic leukemia with 5 maturation, or lymphoproliferative syndrome, and combinations thereof. Preferably, the VAV1 degrader, the therapeutic agent, or the combination disclosed herein may be for use in the treatment or prevention of a hematologic malignancy, including a T and / or B cell malignancy. For instance, the VAV1 degrader, the therapeutic agent, or the combination disclosed herein may be for use in the treatment or prevention of multiple10myeloma, chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), lymphoid leukemia, acute myeloid leukemia (AML), neoplasm of mature B-cells, non-Hodgkin's lymphoma (NHL), Hodgkin's lymphoma (HL), acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), myelodysplastic syndrome (MDS), Burkitt's lymphoma, hairy cell leukemia, Waldenström macroglobulinemia (WM), marginal zone B-cell lymphoma, 15 mast-cell leukemia, T-cell prolymphocytic leukemia (T-PLL), prolymphocytic leukemia (PLL), classic Hodgkin lymphoma, hematopoietic and lymphoid cell neoplasm, lymphoid neoplasm, follicular lymphoma, chronic myelogenous leukemia (CML), T-cell acute lymphoblastic leukemia, cutaneous T-cell lymphoma (CTCL), blast phase chronic myelogenous leukemia, childhood acute lymphoblastic leukemia, lymphoblastic lymphoma,20 T-lymphoblastic lymphoma, anaplastic large cell lymphoma (ALCL), acute leukemia ofambiguous lineage, B-cell acute lymphoblastic leukemia (B-ALL), acute monocytic leukemia, acute promyelocytic leukemia (APL), MALT lymphoma (mucosa-associated lymphoid tissue lymphoma), myelofibrosis, essential thrombocythemia, asymptomatic myeloma, myeloproliferative disorder, plasma cell leukemia, plasmacytoma, chronic myelomonocytic 25 leukemia (CMML), T-cell non-Hodgkin lymphoma, adult T-cell leukemia / lymphoma (ATLL), Langerhans cell histiocytosis, extranodal nasal NK / T cell lymphoma, lymphoid neoplasm, primary myelofibrosis, juvenile myelomonocytic leukemia (JMML), Sézary's disease, mycosis fungoides, acute megakaryoblastic leukemia, acute myeloblastic leukemia without maturation, acute basophilic leukemia, acute myelomonocytic leukemia, acute erythroblastic leukemia,30granulocytic sarcoma, myeloid sarcoma, acute erythroleukemia, acute myeloblastic leukemia with maturation, or lymphoproliferative syndrome, and combinations thereof. The leukemia or lymphoma may be B-cell lymphoma, B-cell leukemia, T-cell lymphoma, T-cell leukemia and acute myeloid leukemia. The leukemia or lymphoma may be acute myeloid leukemia (AML), T-cell prolymphocytic leukemia, T-cell granular lymphocytic 22 PAT059979-WO-PCT leukemia, aggressive NK cell leukemia, hairy-cell leukemia, chronic lymphocytic 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 5 positive T-cell lymphoproliferative 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, or mantle cell10lymphoma), and combinations thereof. Preferably, the leukemia or lymphoma is mantle cell lymphoma, diffuse large B-cell lymphoma, or chronic lymphocytic leukemia. The VAV1 degrader, the therapeutic agent, or the combination disclosed herein may be for use in the treatment or prevention of an autoimmune disorder. In some embodiments, the 15 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, psoriasis, Graves ophthalmopathy, alopecia areata and others, allergic diseases (e.g., allergic asthma, atopic dermatitis, allergic20 rhinitis / conjunctivitis, allergic contact dermatitis), inflammatory diseases optionally withunderlying 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 dermatitis, cutaneous manifestations of immunologically- 25 mediated disorders, inflammatory eye disease, keratoconjunctivitis, myocarditis or hepatitis. The VAV1 degrader, the therapeutic agent, or the combination disclosed herein may be for use in the treatment or prevention of 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, and30transplant coronary disease. In some embodiments, the disorder is T-cell mediated. In some embodiments, the disorder is selected from the group consisting of Diabetes Type I or II, pernicious anemia, uveitis, psoriasis, alopecia areata, ulcerative colitis, Chron’s disease, atherosclerosis, 23 PAT059979-WO-PCT 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, the disorder is selected from the group consisting of multiple sclerosis, psoriatic arthritis, 5 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 thyroiditis, amyloidosis, inflammatory eye diseases, pemphigus,10systemic 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. 15 In some embodiments, the disclosure relates to a method of treating patients exhibiting CD226 overexpression. 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 a Gly307Ser (G307S) amino acid20 substitution in CD226 (rs763361T allele).Combinations In an aspect, the invention provides a combination comprising: (i) a VAV1 degrader; and (ii) a therapeutic agent. 25 The combination may be provided as a combined preparation for simultaneous, separate, or sequential use as a medicament. According to the invention, any VAV1 degrader described herein may be combined30with any one, two, three, or more therapeutic agents described herein. The therapeutic agent may be defined in terms of a disease or condition it is suitable for treating – i.e. a disease or condition in which that therapeutic agent itself is indicated on account of it being effective in the treatment of that disease. This does not mean that the invention (i.e. the therapeutic agent and the VAV1 degrader in combination) can only be used 24 PAT059979-WO-PCT in the disease in which a given therapeutic agent is indicated. However, in any embodiment or aspect herein, the invention may be used for the treatment of the same disease or condition for which the therapeutic agent is a treatment. The therapeutic agent may be a treatment for a serious disease. For example, the 5 therapeutic agent may be a treatment for a life-threatening disease. The disease may be a chronic or acute disease. The therapeutic agent may have a curative effect on a disease, for instance on a serious or life threatening, chronic or acute disease. The therapeutic agent may be a treatment for a disease or condition selected from the group consisting of: cancer, infectious disease, autoimmune disease, cardiovascular disease,10and haematologic disease. When such therapeutic agents are used in the invention, the VAV1 degrader may be a degrader of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I-J), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), or (III-G), or a pharmaceutically acceptable salt thereof, or a compound of Table 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof. Such therapeutic agents and 15 VAV1 degraders may be used according to the invention in the treatment of a cancer, haematologic disease, or an autoimmune disease. Preferably, the therapeutic agent may be a treatment for a haematologic disease. For instance, the therapeutic agent may be thalidomide, lenalidomide, pomalidomide, paclitaxel, doxorubicin, fulvestrant, dexamethasone, erlotinib, sirolimus, palbociclib, venetoclax,20 etoposide, ibrutinib, memantine hydrochloride, tranexamic acid, prednisolone, verapamilhydrochloride, amiodarone, sunitinib, carmustine, fedratinib, captopril, trimethoprim, metformin hydrochloride, clofarabine, metoclopramide, zileuton, thiotepa, propranolol, tetracycline, omeprazole, paricalcitol, amifostine, clopidogrel, everolimus, simvastatin, voriconazole, ketoconazole, aprepitant, procarbazine hydrochloride, levetiracetam, 25 pyrimethamine, levonorgestrel, zidovudine, palonosetron, brigatinib, bupropion, capecitabine, digoxin, lovastatin, sildenafil, vinblastine sulfate, apixaban, methoxsalen, fosfomycin, moxifloxacin, famotidine, eltrombopag, crizotinib, rivaroxaban, disulfiram, aspirin, nicotinamide, pazopanib, 5-fluorouracil, diphenhydramine, tofacitinib, didanosine, cytarabine, gemcitabine, gefitinib, mycophenolic acid, chlorambucil, sulfamethoxazole,30granisetron, warfarin, clioquinol, atovaquone, hydroxyurea, rosiglitazone, carboplatinum, letrozole, metronidazole, sulfasalazine, plerixafor, allopurinol, lamivudine, theophylline, decitabine, altretamine, temozolomide, vandetanib, tolbutamide, imatinib, azathioprine, ibandronate, azithromycin, fluconazole, gabapentin, adenosine, acetaminophen, linezolid, clarithromycin, celecoxib, fenofibrate, pamidronic acid, tadalafil, leflunomide, furosemide, 25 PAT059979-WO-PCT pemetrexed, loratadine, olanzapine, hydrocortisone, ribavirin, valproic acid, nintedanib, niclosamide, cephalexin, raltegravir, meropenem, folic acid, ciprofloxacin, acetylcysteine, azacitidine, pentostatin, mannitol, mesna, tafamidis, tacrolimus, bortezomib, busulfan, amoxicillin, l-glutamine, prednisone, fostamatinib, isosorbide, dacarbazine, piperacillin, 5 succimer, levamisole, aminolevulinic acid hydrochloride, ascorbic acid, medroxyprogesterone, efavirenz, curcumin, cortisone acetate, vancomycin, quercetin, bendamustine, axitinib, dimethyl fumarate, regorafenib, niacin, rifampicin, ceritinib, tazarotene, pentoxifylline, nilotinib, deferasirox, lenvatinib, bezafibrate, atazanavir, mycophenolate, bosutinib, erythromycin, ponatinib, ethinylestradiol, ganciclovir, vorinostat,10carvedilol, propofol, pyridoxine, maraviroc, docetaxel, caprylic acid, anagrelide, pioglitazone, colchicine, auranofin, pentamidine, mitoxantrone, amphotericin b, spironolactone, olaparib, sorafenib, fludarabine phosphate, or cisplatin, and combinations thereof. Preferably, the therapeutic agent may be a treatment for a hematologic malignancy. For instance, the therapeutic agent may be thalidomide, lenalidomide, pomalidomide, 15 paclitaxel, doxorubicin, fulvestrant, dexamethasone, erlotinib, sirolimus, palbociclib, venetoclax, etoposide, ibrutinib, tranexamic acid, prednisolone, verapamil hydrochloride, sunitinib, carmustine, fedratinib, captopril, trimethoprim, metformin hydrochloride, clofarabine, metoclopramide, zileuton, thiotepa, propranolol, tetracycline, omeprazole, paricalcitol, amifostine, everolimus, simvastatin, voriconazole, ketoconazole, aprepitant,20 procarbazine hydrochloride, levetiracetam, pyrimethamine, levonorgestrel, zidovudine,palonosetron, brigatinib, bupropion, capecitabine, digoxin, lovastatin, sildenafil, vinblastine sulfate, apixaban, methoxsalen, fosfomycin, moxifloxacin, eltrombopag, crizotinib, rivaroxaban, disulfiram, aspirin, nicotinamide, pazopanib, 5-fluorouracil, diphenhydramine, tofacitinib, didanosine, cytarabine, gemcitabine, gefitinib, mycophenolic acid, chlorambucil, 25 sulfamethoxazole, granisetron, warfarin, clioquinol, atovaquone, hydroxyurea, rosiglitazone, carboplatinum, letrozole, metronidazole, sulfasalazine, plerixafor, allopurinol, lamivudine, theophylline, decitabine, altretamine, temozolomide, vandetanib, tolbutamide, imatinib, azathioprine, ibandronate, fluconazole, adenosine, acetaminophen, linezolid, clarithromycin, celecoxib, fenofibrate, pamidronic acid, tadalafil, leflunomide, furosemide, pemetrexed,30loratadine, olanzapine, hydrocortisone, ribavirin, valproic acid, nintedanib, niclosamide, cephalexin, raltegravir, meropenem, folic acid, ciprofloxacin, acetylcysteine, azacitidine, pentostatin, mannitol, mesna, tacrolimus, bortezomib, busulfan, amoxicillin, l-glutamine, prednisone, fostamatinib, isosorbide, dacarbazine, piperacillin, succimer, aminolevulinic acid hydrochloride, ascorbic acid, medroxyprogesterone, efavirenz, curcumin, cortisone acetate, 26 PAT059979-WO-PCT vancomycin, quercetin, bendamustine, axitinib, dimethyl fumarate, regorafenib, niacin, rifampicin, ceritinib, tazarotene, pentoxifylline, nilotinib, deferasirox, lenvatinib, bezafibrate, atazanavir, mycophenolate, bosutinib, erythromycin, ponatinib, ethinylestradiol, ganciclovir, vorinostat, carvedilol, propofol, pyridoxine, maraviroc, docetaxel, caprylic acid, anagrelide, 5 pioglitazone, colchicine, auranofin, pentamidine, mitoxantrone, amphotericin b, spironolactone, olaparib, sorafenib, fludarabine phosphate, or cisplatin, and combinations thereof. When such therapeutic agents are used in the invention, the VAV1 degrader may be a degrader of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I-J), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), or10(III-G), or a pharmaceutically acceptable salt thereof, or a compound of Table 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof. Such therapeutic agents and VAV1 degraders may be used according to the invention in the treatment of a cancer, haematologic disease, or autoimmune disease, preferably a hematologic disease (e.g., leukemia, lymphoma or multiple myeloma). 15 The therapeutic agent may be a treatment for a disease or condition selected from the group consisting of: a heart condition (e.g., hypertension), thrombocytopenia, malaria, cancer (e.g., leukemia or lymphoma), and an autoimmune disease. When such therapeutic agents are used in the invention, the VAV1 degrader may be a degrader of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I-J), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (III-20 A), (III-B), (III-C), (III-D), (III-E), (III-F), or (III-G), or a pharmaceutically acceptable saltthereof, or a compound of Table 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof. Such therapeutic agents and VAV1 degraders may be used according to the invention in the treatment of cancer, haematologic disease, or an autoimmune disease. The therapeutic agent may be a treatment for a disease or condition selected from the 25 group consisting of: ulcerative colitis, Crohn’s disease, psoriatic arthritis, rheumatoid arthritis, multiple sclerosis, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, or mantle cell lymphoma, and combinations thereof. When such therapeutic agents are used in the invention, the VAV1 degrader may be a degrader of formula (I-A), (I-B), (I-C), (I-D), (I- E), (I-F), (I-G), (I-H), (I-I), (I-J), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (III-A), (III-30B), (III-C), (III-D), (III-E), (III-F), or (III-G), or a pharmaceutically acceptable salt thereof, or a compound of Table 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof. Such therapeutic agents and VAV1 degraders may be used according to the invention in the treatment of cancer, such as diffuse large B-cell lymphoma, chronic lymphocytic leukemia, 27 PAT059979-WO-PCT or mantle cell lymphoma, or an autoimmune disease, such as ulcerative colitis, Crohn’s disease, psoriatic arthritis, rheumatoid arthritis, or multiple sclerosis. The therapeutic agent may be a product that contains an active pharmaceutical ingredient that has been approved for marketing for at least one indication by a governmental 5 authority. Preferably, the therapeutic agent is approved for marketing for one of the indications for which it is a treatment, as indicated above. Examples of governmental authorities include, but are not limited to: the United States Food and Drug Administration (FDA), the European Medicines Agency (EMA), the United Kingdom Medicines and Healthcare products Regulatory Agency (MHRA), Health Canada, the Australian Therapeutic10Goods Administration (TGA), the Japanese Pharmaceuticals and Medical Devices Agency (PMDA), the Chinese National Medical Products Administration (NMPA), the Indian Central Drugs Standard Control Organization (CDSCO), the Brazilian Agência Nacional de Vigilância Sanitária (ANVISA), and the Russian Federal Service for Surveillance in Healthcare (Roszdravnadzor). Preferably, the therapeutic agent is a product that contains an 15 active pharmaceutical ingredient that has been approved for marketing for at least one indication by the FDA and / or EMA. The therapeutic agent may be a T- and / or B-cell depletor. T- and / or B-cell depletors are used in the treatment of diseases caused by or associated with immunopathologies, for instance autoimmune diseases (e.g., psoriatic arthritis, rheumatoid arthritis, multiple sclerosis,20 and immune thrombocytopenia) and cancer (e.g., chronic lymphocytic leukemia and mantlecell lymphoma) and may be used in the treatment of diseases caused by or associated with immunopathologies, for instance autoimmune diseases (e.g., psoriatic arthritis, rheumatoid arthritis, multiple sclerosis, and immune thrombocytopenia) and cancer (e.g., chronic lymphocytic leukemia, mantle cell lymphoma and diffuse large B cell lymphoma) in 25 combination with the VAV1 degraders described herein (e.g. the VAV1 degraders of formulas (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I-J), (II-A), (II-B), (II- C), (II-D), (II-E), (II-F), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), and (III-G), or a pharmaceutically acceptable salt thereof. The VAV1 degrader and the therapeutic agent together may reduce cell proliferation30relative to a negative control when tested in a cell proliferation assay. The VAV1 degrader and the therapeutic agent, when tested together in a cell proliferation assay, may produce a Bliss synergy score of > 0, preferably > 5, most preferably > 10, wherein the Bliss synergy score is calculated according to the following formula: Bliss synergy score = 28 PAT059979-WO-PCT InhibitionCombination – 100 (1-(1-(InhibitionDrugA / 100))((1-(InhibitionDrugB / 100)))). The VAV1 degrader and the therapeutic agent may be tested together in a cell growth assay. The cell growth assay may comprise treating cells (e.g. cancer cells) with one or more concentrations of the VAV1 degrader and the therapeutic agent alone and together for up to a 5 week, and measuring cell growth (for example by cell tier glow). For instance, the assay may be performed according to Example 4B. Classes of therapeutic agent The therapeutic agent may be selected from the group consisting of: BTK inhibitors,10BCL2 inhibitors, anti-CD20 agents (inducers of ADCC, and anti-CD20 depletors), DNA synthesis inhibitors, DNA crosslinkers / intercalators, topoisomerase inhibitors, proteasome inhibitors, tyrosine kinase inhibitors, HDAC inhibitors, mTOR inhibitors, tubulin inhibitors, IKZF1 / 3 inhibitors, SYK inhibitors, TNFα inhibitors (for example, a TNFα-neutralising antibody), S1PR modulators, JAK inhibitors, IL-23 inhibitors (for example, IL-23- 15 neutralising antibodies), IL-17 inhibitors (for example, IL-17-neutralising antibodies), A4b7 inhibitors, CD28 inhibitors, IL-6 inhibitors (for example, IL-6-neutralising antibodies), IL-1R antagonists, Anti-CD19 agents (for example, by inducing ADCC), Anti-CD79b agents (for example, anti-CD79b B cell specific release of apoptosis inducers), exportin-1 inhibitors, anti-CD52 agents (for example, by inducing ADCC), corticosteroids, PI3K-δ inhibitors, 26S20 proteasome inhibitors, tubulin inhibitors, CD19-targeting CAR T-cells, fungicides, oxidativestress inducers (for example, free radical producers), inhibitors of Na-K ATPase and / or the Na-K ATPase membrane pump, mitochondrial respiration complex 1 inhibitors, thioredoxin reductase inhibitors, antiarrhythmic agents, cathepsin B inhibitors, amebicides, cyclooxygenase inhibitors, nitric oxide synthase inhibitors, bacterial membrane disruptors, 25 anthelminthic agents, bacterial biofilm inhibitors, aldehyde dehydrogenase inhibitors, iron, copper and / or zinc chelators, sodium channel blockers, Na-K-Cl cotransporter inhibitors, superoxide dismutase inhibitors, 5-hydroxytryptamine receptor agonists, blood schizonticides, metalloproteinase inhibitors, inosine monophosphate dehydrogenase inhibitors, D2 receptor antagonists, D2 receptor agonists, serotonin reuptake inhibitors30(SRIs), haem polymerase inhibitors, acetylcholinesterase inhibitors, lanosterol 14-α- demethylase inhibitors, selective estrogen receptor modulators, dihydrofolate reductase inhibitors, HIV protease inhibitors, vitamin D receptor agonists, calcium-sending receptor (CaR) modulators, norepinephrine reuptake inhibitors, 17α-hydroxylase / C17,20-lyase (CYP17) inhibitors, HMG-CoA reductase inhibitors, H1-receptor antagonists, μ-receptor 29 PAT059979-WO-PCT agonists, pancreatic lipase inhibitors, progesterone receptor modulators, NS5A inhibitors, β- adrenoceptor antagonists, phosphodiesterase 4 (PDE4) inhibitors, monoamine oxidase inhibitors, 5α-reductase inhibitors, calcium channel blockers, muscarinic M(3) receptor antagonists, nuclear progesterone receptor agonists, NK1 receptor antagonists, RNA 5 polymerase inhibitors, melanin synthesis inhibitors, folic acid synthesis inhibitors, DNA alkylators; thrombopoietin receptor agonists, and combinations thereof. When such therapeutic agents are used in the invention, the VAV1 degrader may be a degrader of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I-J), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), or (III-G), or a10pharmaceutically acceptable salt thereof, or a compound of Table 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof. Such therapeutic agents and VAV1 degraders may be used according to the invention in the treatment of cancer, a haematologic disease, or an autoimmune disease. The therapeutic agent may be selected from the group consisting of: BTK inhibitors, 15 BCL2 inhibitors, Anti-CD20 agents, DNA crosslinkers / intercalators, Proteasome inhibitors, mTOR inhibitors, Tubulin inhibitors, IKZF1 / 3 inhibitors; and SYK inhibitors, and combinations thereof. Such agents are used in the treatment of cancer (e.g., renal cell carcinoma or small cell lung cancer) and hematologic disease (e.g. leukemia such as chronic lymphocytic leukemia, lymphoblastic leukemia, acute myeloblastic leukemia, lymphoma20 such as Hodgkin lymphoma, non-Hodgkin lymphoma, mantle cell lymphoma, myeloma, andthrombocytopenia), and autoimmune disorders, and may be used in treatment of such disorders in combination with the VAV1 degraders described herein (e.g. the VAV1 degraders of formulas (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I-J), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), and 25 (III-G), or a pharmaceutically acceptable salt thereof. In the invention, the therapeutic agent may be an agent as defined above, and the VAV1 degrader may be a degrader of formula (I- A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I-J), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), or (III-G), or a pharmaceutically acceptable salt thereof, or a compound of Table 1, 2, 3, or 4, or a30pharmaceutically acceptable salt thereof. BTK inhibitors BTK inhibitors are a class of drugs that target and inhibit the activity of Bruton's tyrosine kinase (BTK), an enzyme crucial for the development and functioning of B-cells. 30 PAT059979-WO-PCT BTK plays a significant role in the signaling pathways that regulate B-cell growth, differentiation, and survival. Dysregulation of BTK is associated with several B-cell malignancies and autoimmune diseases. The VAV1 degraders described herein (e.g. the VAV1 degraders of formulas (I-A), 5 (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I-J), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), and (III-G), or a pharmaceutically acceptable salt thereof, may be used in combination with BTK inhibitors (and vice versa) in the treatment of cancer (e.g., a haematological malignancy) or autoimmune disease. In some embodiments, the cancer may be a haematological malignancy which is multiple myeloma,10chronic lymphocytic leukemia, mantle cell lymphoma, lymphoid leukemia, acute myeloid leukemia, neoplasm of mature B-cells, non-Hodgkins lymphoma, Hodgkins lymphoma, acute lymphoblastic leukemia, diffuse large B-cell lymphoma, myelodysplastic syndrome, Burkitt’s lymphoma, hairy cell leukemia, Waldenstrom macroglobulinemia, marginal zone B-cell lymphoma, mast-cell leukemia, T-Cell prolymphocytic leukemia, prolymphocytic leukemia, 15 classic Hodgkin lymphoma, hematopoietic and lymphoid cell neoplasm, lymphoid neoplasm, or follicular lymphoma. In some embodiments, the haematological malignancy may be mantle cell lymphoma, chronic lymphocytic leukemia, or diffuse large B cell lymphoma. In some embodiments, the autoimmune disease may be psoriatic arthritis, Sjogren’s syndrome, rheumatoid arthritis, ulcerative colitis / Crohn’s disease, or multiple sclerosis.20 The therapeutic agent is preferably a BTK inhibitor, for example ibrutinib,acalabrutinib, remibrutinib, pirtobrutinib, or zanubrutinib, and combinations thereof. Preferably, the therapeutic agent is ibrutinib. Preferably, the therapeutic agent is acalabrutinib. Preferably, the therapeutic agent is remibrutinib. Preferably, the therapeutic agent is pirtobrutinib. Preferably, the therapeutic agent is zanubrutinib. Most preferably, the 25 therapeutic agent is remibrutinib. In the invention, the therapeutic agent may be a BTK inhibitor, for example, ibrutinib, acalabrutinib, remibrutinib, pirtobrutinib, or zanubrutinib, and combinations thereof, and the VAV1 degrader may be a degrader of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I-J), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (III-A), (III-B), (III-C), (III-30D), (III-E), (III-F), or (III-G), or a pharmaceutically acceptable salt thereof, or a compound of Table 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof. Preferably, in the invention, the therapeutic agent is a BTK inhibitor, for example, ibrutinib, acalabrutinib, remibrutinib, pirtobrutinib, or zanubrutinib, and combinations 31 PAT059979-WO-PCT thereof, and the VAV1 degrader is a degrader of formula (I-J), (II-F), or (III-G), or a pharmaceutically acceptable salt thereof. Preferably, in the invention, the therapeutic agent is a BTK inhibitor and the VAV1 degrader i , pharmaceutically acceptable salt thereof. 5 Preferably, in the invention, the therapeutic agent is remibrutinib and the VAV1 BCL-2 inhibitors BCL-2 inhibitors function by binding to the BCL-2 (B-cell lymphoma 2) protein,10thereby neutralizing its ability to prevent apoptosis. This reinstates the cell’s natural ability to undergo programmed cell death, specifically targeting cancer cells that rely on BCL-2 for survival. By restoring apoptosis, BCL-2 inhibitors help reduce the number of malignant cells. BCL2 inhibitors are primarily used in the treatment of haematological cancers. The VAV1 degraders described herein (e.g. the VAV1 degraders of (I-A), (I-B), (I- 15 C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I-J), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), or (III-G), or a pharmaceutically acceptable salt thereof, may be used in combination with BCL-2 inhibitors (and vice versa) in the treatment of cancer, (e.g., a haematological malignancy) or autoimmune disease. In some embodiments, the haematological malignancy may be chronic lymphocytic leukemia,20multiple myeloma, non-Hodgkins lymphoma, myelodysplastic syndrome, acute myeloid leukemia, Burkitt’s lymphoma, chronic myelogenous leukemia, diffuse large B-cell lymphoma, mantle cell lymphoma, T-cell acute lymphoblastic leukemia, acute lymphoblastic leukemia, cutaneous T-cell lymphoma, Waldenstrom macroglobulinemia, blast phase chronic myelogenous leukemia, T-Cell prolymphocytic leukemia, childhood acute lymphoblastic25 leukemia, lymphoblastic lymphoma, prolymphocytic leukemia, follicular lymphoma, T- lymphoblastic lymphoma, neoplasm of mature B-cells, hematopoietic and lymphoid cell neoplasm, anaplastic large cell lymphoma, acute leukemia of ambiguous lineage, B-cell acute lymphoblastic leukemia, lymphoid leukemia, AL amyloidosis, acute monocytic leukemia, or 32 PAT059979-WO-PCT acute promyelocytic leukemia. In some embodiments, the haematological malignancy may be mantle cell lymphoma, chronic lymphocytic leukemia, or diffuse large B cell lymphoma. The therapeutic agent may be a BCL-2 inhibitor, for example, venetoclax, navitoclax, or obatoclax, and combinations thereof. 5 In the invention, the therapeutic agent may be a BCL-2 inhibitor, for example, venetoclax, navitoclax, or obatoclax, and combinations thereof, and the VAV1 degrader may be a degrader of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I-J), (II- A), (II-B), (II-C), (II-D), (II-E), (II-F), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), or (III-G), or a pharmaceutically acceptable salt thereof, or a compound of Table 1, 2, 3, or 4,10or a pharmaceutically acceptable salt thereof. In the invention, the therapeutic agent may be a BCL-2 inhibitor, for example, venetoclax, navitoclax, or obatoclax, and combinations thereof, and the VAV1 degrader may be a degrader of formula (I-J), (II-F), or (III-G), or a pharmaceutically acceptable salt thereof. 15 IKZF1 / 3 inhibitors IKZF1 / 3 inhibition is a type of targeted cancer therapy that focuses on inhibiting the activity of two specific proteins, Ikaros (IKZF1) and Aiolos (IKZF3), which are transcription factors involved in the regulation of immune cell development and function. These inhibitors20 are primarily used in the treatment of certain haematological cancers, such as multiplemyeloma and acute lymphoblastic leukemia (ALL). The VAV1 degraders described herein (e.g. the VAV1 degraders of formulas (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I-J), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), and (III-G), or a pharmaceutically 25 acceptable salt thereof, may be used in combination with IKZF1 / 3 inhibitors (and vice versa) in the treatment of cancer, (e.g., a haematological malignancy) or autoimmune disease. In some embodiments, the haematological malignancy may be Mantle cell lymphoma, chronic lymphocytic leukemia, Hodgkins lymphoma, MALT lymphoma, myelodysplastic syndrome, acute myeloid leukemia, multiple myeloma, T-cell acute lymphoblastic leukemia,30myelofibrosis, non-Hodgkins lymphoma, diffuse large B-cell lymphoma, neoplasm of mature B-cells, unspecified peripheral T-cell lymphoma, acute lymphoblastic leukemia, Burkitt’s lymphoma, essential thrombocythemia, polycythemia vera, cutaneous T-cell lymphoma, asymptomatic myeloma, myeloproliferative disorder, plasma cell leukemia, plasmacytoma, marginal zone B-cell lymphoma, chronic myelomonocytic leukemia, chronic myelogenous 33 PAT059979-WO-PCT leukemia, Waldenstrom macroglobulinemia, prolymphocytic leukemia, B-cell neoplasm, T- cell non-Hodgkin lymphoma, follicular lymphoma, adult T-cell leukemia / lymphoma, hematopoietic and lymphoid cell neoplasm, myelofibrosis, mature T-cell and NK-cell non- Hodgkin lymphoma, B-cell non-Hodgkins lymphoma, Langerhans Cell Histiocytosis, and 5 extranodal nasal NK / T cell lymphoma. In some embodiments, the haematological malignancy may be mantle cell lymphoma, chronic lymphocytic leukemia, or diffuse large B cell lymphoma. The therapeutic agent may be an IKZF1 / 3 inhibitor, for example lenalidomide, pomalidomide, or thalidomide, and combinations thereof.10In the invention, the therapeutic agent may be an IKZF1 / 3 inhibitor, for example, lenalidomide, pomalidomide, or thalidomide, and combinations thereof, and the VAV1 degrader may be a degrader of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I-J), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), or (III-G), or a pharmaceutically acceptable salt thereof, or a compound of 15 Table 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof. In the invention, the therapeutic agent may be a IKZF1 / 3 inhibitor, for example, for example lenalidomide, pomalidomide, or thalidomide, and combinations thereof, and the VAV1 degrader may be a degrader of formula (I-J), (II-F), or (III-G), or a pharmaceutically acceptable salt thereof. 20 mTOR inhibitors mTOR inhibitors block the activity of the mammalian target of rapamycin (mTOR), a protein kinase that plays a crucial role in regulating cell growth, proliferation, metabolism, and survival. mTOR inhibitors are used in various medical treatments, including cancer 25 therapy and organ transplantation. The VAV1 degraders described herein (e.g. the VAV1 degraders of formulas (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I-J), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), and (III-G), or a pharmaceutically acceptable salt thereof, may be used in combination with mTOR inhibitors (and vice versa) in30the treatment of cancer, (e.g., a haematological malignancy) or autoimmune disease. In some embodiments, the haematological malignancy may be chronic lymphocytic leukemia, Hodgkins lymphoma, myelodysplastic syndrome, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myelogenous leukemia, diffuse large B-cell lymphoma, multiple myeloma, lymphoid neoplasm, primary myelofibrosis, non-Hodgkins lymphoma, plasma cell 34 PAT059979-WO-PCT leukemia, Juvenile myelomonocytic leukemia, Sezary's disease, mycosis fungoides, mantle cell lymphoma, neoplasm of mature B-cells, unspecified peripheral T-cell lymphoma, angioimmunoblastic T-cell lymphoma, Burkitt’s lymphoma, polycythemia vera, anaplastic large cell lymphoma, Waldenstrom macroglobulinemia, hairy cell leukemia, chronic 5 myelomonocytic leukemia, childhood acute lymphoblastic leukemia, lymphoblastic lymphoma, T-cell non-Hodgkin lymphoma, follicular lymphoma, T-cell large granular lymphocyte leukemia, adult T-cell leukemia / lymphoma, extranodal nasal NK / T cell lymphoma, hematopoietic and lymphoid cell neoplasm, myelofibrosis, blast phase chronic myelogenous leukemia, hematopoietic and lymphoid system neoplasm, or MALT lymphoma.10The haematological malignancy may be mantle cell lymphoma, chronic lymphocytic leukemia, or diffuse large B cell lymphoma. The therapeutic agent may be an mTOR inhibitor, for example, sirolimus, everolimus, or temsirolimus, and combinations thereof. In the invention, the therapeutic agent may be an mTOR inhibitor, for example, 15 sirolimus, everolimus, or temsirolimus, and combinations thereof, and the VAV1 degrader may be a degrader of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I-J), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (III-A), (III-B), (III-C), (III-D), (III-E), (III- F), or (III-G), or a pharmaceutically acceptable salt thereof, or a compound of Table 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof.20 In the invention, the therapeutic agent may be an mTOR inhibitor, for example,sirolimus, everolimus, or temsirolimus, and combinations thereof, and the VAV1 degrader may be a degrader of formula (I-J), (II-F), or (III-G), or a pharmaceutically acceptable salt thereof. 25 DNA crosslinkers and DNA intercalators DNA crosslinkers form covalent bonds between two DNA strands or between two different sites on the same strand, leading to DNA crosslinks that prevent the strands from separating. This inhibits DNA replication and transcription, leading to cell death. DNA intercalators insert themselves between the base pairs of the DNA double helix, disrupting the30structure of the DNA and preventing replication and transcription. The VAV1 degraders described herein (e.g. the VAV1 degraders of formulas (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I-J), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), and (III-G), or a pharmaceutically acceptable salt thereof, may be used in combination with DNA crosslinkers / intercalators (and 35 PAT059979-WO-PCT vice versa) in the treatment of cancer, (e.g., a haematological malignancy) or autoimmune disease. In some embodiments, the haematological malignancy may be acute lymphoblastic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, mantle cell lymphoma, B- cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, neoplasm of mature B- 5 cells, Hodgkins lymphoma, myelodysplastic syndrome, T-cell acute lymphoblastic leukemia, unspecified peripheral T-cell lymphoma, acute monocytic leukemia, acute myelomonocytic leukemia, Burkitt’s lymphoma, chronic myelogenous leukemia, diffuse large B-cell lymphoma, multiple myeloma, acute megakaryoblastic leukaemia, acute myeloblastic leukemia without maturation, acute basophilic leukemia, anaplastic large cell lymphoma,10lymphoid leukemia, non-Hodgkins lymphoma, plasma cell leukemia, granulocytic sarcoma, juvenile myelomonocytic leukemia, myeloid sarcoma, acute erythroblastic leukemia, chronic myelomonocytic leukemia, acute erythroleukemia, essential thrombocythemia, polycythemia vera, acute myeloblastic leukemia with maturation, blast phase chronic myelogenous leukemia, childhood acute lymphoblastic leukemia, lymphoblastic lymphoma, classic 15 Hodgkin lymphoma, follicular lymphoma, acute leukemia of ambiguous lineage, adult T-cell leukemia / lymphoma, hematopoietic and lymphoid cell neoplasm, myelofibrosis, or T- lymphoblastic lymphoma. In some embodiments, the haematological malignancy may be mantle cell lymphoma, chronic lymphocytic leukemia, or diffuse large B cell lymphoma. The therapeutic agent may be a DNA crosslinker / intercalator, for example,20 doxorubicin, cyclophosphamide, bendamustin (e.g. bendamustin hydrochloride),mitoxantrone (e.g., mitoxantrone dihydrochloride), thioptepa, thioguanine, quinacrine, epirubicin, idarubicin, cisplatin, trioxalen, or busulfan, and combinations thereof. In the invention, the therapeutic agent may be, a DNA crosslinker / intercalator, for example, sirolimus, everolimus, or temsirolimus, and combinations thereof, and the VAV1 25 degrader may be a degrader of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I-J), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), or (III-G), or a pharmaceutically acceptable salt thereof, or a compound of Table 1, 2, 3, or 4,, or a pharmaceutically acceptable salt thereof. In the invention, the therapeutic agent may be a DNA crosslinker / intercalator, for30example, doxorubicin, cyclophosphamide, bendamustin (e.g. bendamustin hydrochloride), mitoxantrone (e.g., mitoxantrone dihydrochloride), thioptepa, thioguanine, quinacrine, epirubicin, idarubicin, cisplatin, trioxalen, or busulfan, and combinations thereof, and the VAV1 degrader may be a degrader of formula (I-J), (II-F), or (III-G), or a pharmaceutically acceptable salt thereof. 36 PAT059979-WO-PCT SYK inhibitors SYK (Spleen Tyrosine Kinase) inhibitors are a class of drugs that target the SYK enzyme, which plays a crucial role in the signaling pathways of various immune cells, 5 including B cells and myeloid cells. By inhibiting SYK, these drugs can modulate immune responses and have therapeutic applications in both autoimmune diseases and cancer treatment. The VAV1 degraders described herein (e.g. the VAV1 degraders of formulas (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I-J), (II-A), (II-B), (II-C), (II-D), (II-E),10(II-F), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), and (III-G), or a pharmaceutically acceptable salt thereof, may be used in combination with SYK inhibitors (and vice versa) in the treatment of cancer, (e.g., a haematological malignancy) or autoimmune disease. In some embodiments, the haematological malignancy may be chronic lymphocytic leukemia, myelofibrosis, acute myeloid leukemia, diffuse large B cell lymphoma, non-Hodgkin 15 lymphoma, or mantle cell lymphoma. The haematological malignancy may be mantle cell lymphoma, chronic lymphocytic leukemia, or diffuse large B cell lymphoma. The autoimmune disease may be psoriatic arthritis, rheumatoid arthritis or ulcerative colitis / Crohn’s disease. The therapeutic agent may be a SYK inhibitor, for example, fostamatinib.20 In the invention, the therapeutic agent may be a SYK inhibitor, for example, fostamatinib,and the VAV1 degrader may be a degrader of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I-J), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (III-A), (III-B), (III- C), (III-D), (III-E), (III-F), or (III-G), or a pharmaceutically acceptable salt thereof, or a compound of Table 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof. 25 In the invention, the therapeutic agent may be a SYK inhibitor, for example, fostamatinib, and the VAV1 degrader may be a degrader of formula (I-J), (II-F), or (III-G), or a pharmaceutically acceptable salt thereof. Proteasome inhibitors30Proteasome inhibitors are a class of drugs that block the proteasome, a complex that degrades unneeded or damaged proteins within the cell. By inhibiting the proteasome, these drugs interfere with various cellular processes, leading to the accumulation of toxic proteins and subsequent cell death, particularly in rapidly dividing cells such as cancer cells. Proteasome inhibitors are mainly used in the treatment of certain types of haematological 37 PAT059979-WO-PCT cancers. The term “proteasome inhibitor” includes 26S proteasome inhibitors, and inhibitors of the proteasomal degradation of pro-apoptotic factors. The VAV1 degraders described herein (e.g. the VAV1 degraders of formulas (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I-J), (II-A), (II-B), (II-C), (II-D), (II-E), 5 (II-F), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), and (III-G), or a pharmaceutically acceptable salt thereof, may be used in combination with proteasome inhibitors (and vice versa) in the treatment of cancer, (e.g., a haematological malignancy) or autoimmune disease. In some embodiments, the haematological malignancy may be multiple myeloma, acute promyelocytic leukemia, myelodysplastic syndrome, neoplasm of mature B-cells, acute10myeloid leukemia, mantle cell lymphoma, diffuse large B-cell lymphoma, B-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkins lymphoma, MALT lymphoma, T-cell acute lymphoblastic leukemia, unspecified peripheral T-cell lymphoma, acute lymphoblastic leukemia, chronic myelogenous leukemia, lymphoid neoplasm, asymptomatic myeloma, non-Hodgkins lymphoma, plasma cell leukemia, plasmacytoma, 15 myeloid sarcoma, Waldenstrom macroglobulinemia, angioimmunoblastic T-cell lymphoma, Burkitt’s lymphoma, anaplastic large cell lymphoma, Sezary's disease, mycosis fungoides, lymphoblastic lymphoma, classic Hodgkin lymphoma, follicular lymphoma, acute leukemia of ambiguous lineage, adult T-cell leukemia / lymphoma, hematopoietic and lymphoid cell neoplasm, lymphoproliferative syndrome, lymphoid leukemia, or T-lymphoblastic20 lymphoma. The haematological malignancy may be chronic lymphocytic leukemia, mantlecell lymphoma, or diffuse large B cell lymphoma. The therapeutic agent may be a proteasome inhibitor, for example, bortezomib. In the invention, the therapeutic agent may be a proteasome inhibitor, for example, bortezomib, and the VAV1 degrader may be a degrader of formula (I-A), (I-B), (I-C), (I-D), 25 (I-E), (I-F), (I-G), (I-H), (I-I), (I-J), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), or (III-G), or a pharmaceutically acceptable salt thereof, or a compound of Table 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof. In the invention, the therapeutic agent may be a proteasome inhibitor, for example, bortezomib, and the VAV1 degrader may be a degrader of formula (I-J), (II-F), or (III-G),30or a pharmaceutically acceptable salt thereof. Anti-CD20 agents 38 PAT059979-WO-PCT Anti-CD20 agents (e.g., monoclonal antibodies) target the CD20 protein found on the surface of B cells. By binding to CD20, these agents help in the destruction of B cells, making them effective in the treatment of various B-cell malignancies and autoimmune diseases. The VAV1 degraders described herein (e.g. the VAV1 degraders of formulas (I-A), 5 (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I-J), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), and (III-G), or a pharmaceutically acceptable salt thereof, may be used in combination with anti-CD20 agents (and vice versa) in the treatment of cancer, (e.g., a haematological malignancy) or autoimmune disease. In some embodiments, the haematological malignancy may be mantle cell lymphoma, chronic10lymphocytic leukemia, diffuse large B cell lymphoma, or non-Hodgkin lymphoma. In some embodiments, the autoimmune disease may be psoriatic arthritis, rheumatoid arthritis, ulcerative colitis / Crohn’s disease, or multiple sclerosis. The therapeutic agent may be an anti-CD20 agent, for example, obinutuzumab and ofatumumab, rituximab, ocrelizumab, or ublituximab, and combinations thereof. 15 The therapeutic agent may be an anti-CD20 agent, for example, obinutuzumab and ofatumumab, rituximab, ocrelizumab, or ublituximab, and combinations thereof, and the VAV1 degrader may be a degrader of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I-J), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (III-A), (III-B), (III-C), (III- D), (III-E), (III-F), or (III-G), or a compound of Table 1, 2, 3, or 4, or a pharmaceutically20 acceptable salt thereof.In the invention, the therapeutic agent may be an anti-CD20 agent, for example, obinutuzumab and ofatumumab, rituximab, ocrelizumab, or ublituximab, and combinations thereof, and the VAV1 degrader may be a degrader of formula (I-J), (II-F), or (III-G), or a pharmaceutically acceptable salt thereof. 25 Tubulin inhibitors Tubulin inhibitors are a class of drugs that disrupt the function of tubulin, a key protein involved in the structure and function of microtubules. Microtubules are essential components of the cytoskeleton and play critical roles in cell division, intracellular transport,30and maintaining cell shape. By interfering with tubulin dynamics, these inhibitors effectively inhibit cell division and can induce cell death in rapidly dividing cells, such as cancer cells. The term “tubulin inhibitor” includes tubulin disruption and proliferation inhibitors. The VAV1 degraders described herein (e.g. the VAV1 degraders of formulas (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I-J), (II-A), (II-B), (II-C), (II-D), (II-E), 39 PAT059979-WO-PCT (II-F), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), and (III-G), or a pharmaceutically acceptable salt thereof, may be used in combination with tubulin inhibitors (and vice versa) in the treatment of cancer, (e.g., a haematological malignancy) or autoimmune disease. In some embodiments, the haematological malignancy may be a leukemia (e.g., chronic lymphocytic 5 leukemia), a lymphoma (e.g., mantle cell lymphoma, or diffuse large B cell lymphoma), or multiple myeloma. The therapeutic agent may be a tubulin inhibitor, for example, vincristine, podofilox, vinblastine (e.g., vinblastine sulfate), flubendazole, albendazole, mebendazole, colchicine, docetaxel, or paclitaxel, and combinations thereof.10In the invention, the therapeutic agent may be a tubulin inhibitor, for example, vincristine, podofilox, vinblastine (e.g., vinblastine sulfate), flubendazole, albendazole, mebendazole, colchicine, docetaxel, or paclitaxel, and combinations thereof, and the VAV1 degrader may be a degrader of formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I-J), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (III-A), (III-B), (III-C), (III-D), 15 (III-E), (III-F), or (III-G), or a pharmaceutically acceptable salt thereof, or a compound of Table 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof. In the invention, the therapeutic agent may be a tubulin inhibitor, for example, vincristine, podofilox, vinblastine (e.g., vinblastine sulfate), flubendazole, albendazole, mebendazole, colchicine, docetaxel, or paclitaxel, and combinations thereof, and the VAV120 degrader may be a degrader of formula (I-J), (II-F), or (III-G), or a pharmaceuticallyacceptable salt thereof. The therapeutic agent may be a DNA synthesis inhibitor, for example, cytarabine, 25 clofarabine, decitabine, gemcitabine, fludarabine (e.g., fludarabine phosphate), azacitidine, etoposide, floxuridine, 6-Mercaptopurine (e.g., 6-Mercaptopurine hydrate), azathioprine, lumefantrine, chlorambucil, capecitabine, zidovudine, didanosine, or stavudine, and combinations thereof. The therapeutic agent may be a topoisomerase inhibitor, for example, SN-38 (7-Ethyl-3010-hydroxycamptothecin), irinotecan (e.g., irinotecan hydrochloride), topotecan, or belotecan, and combinations thereof. The therapeutic agent may be a tyrosine kinase inhibitor, for example, fostamatinib, afatinib, ponatinib, bosutinib, ceritinib, fedratinib, dasatinib, vandetanib, axitinib, sunitinib, 40 PAT059979-WO-PCT crizotinib, sorafenib, nintedanib, brigatinib, pazopanib, nilotinib, or lapatinib, and combinations thereof. The therapeutic agent may be a HDAC inhibitor, for example, wherein compound is vorinostat, romidepsin, panobinostat, or belinostat, and combinations thereof. 5 The therapeutic agent may be a TNFα inhibitor, for example, for example, infliximab, adalimumab, golimumab, or etanercept, and combinations thereof. The therapeutic agent may be an S1PR modulator, for example, velsipity or fingolimod, and combinations thereof. The therapeutic agent may be a JAK inhibitor, for example, tofacitinib or10upadacitinib, and combinations thereof. The therapeutic agent may be an IL-23 inhibitor, for example, mirikizumab, guselkumab, Risankizumab-rzaa, tildrakizumab-asmn, or ustekinumab, and combinations thereof. The therapeutic agent may be an IL-17 inhibitor, for example, secukinumab, 15 ixekizumab, brodalumab, or bimekizumab, and combinations thereof. The therapeutic agent may be an A4b7 inhibitor, for example, natalizumab or vedolizumab, and combinations thereof. The therapeutic agent may be a CD28 inhibitor, for example, wherein compound is abatacept or lulizumab, and combinations thereof.20 The therapeutic agent may be an IL-6 inhibitor, for example, tocilizumab, siltuximab,or sarilumab, and combinations thereof. The therapeutic agent may be an IL-1R antagonist, for example, anakinra. The therapeutic agent may be an anti-CD19 compound, for example, loncastuximab tesirine-lpyl or tafasitamab, and combinations thereof. 25 The therapeutic agent may be an anti-CD79b compound, for example, polatuzumab vedotin-piiq. The therapeutic agent may be an anti-CD79b B cell specific release of apoptosis inducer (ADC), for example, polatuzumab vedotin-piiq. The therapeutic agent may be a selective inhibitor of nuclear export, for example, selinexor. The therapeutic agent may be an exportin-1 inhibitor, for example, selinexor.30The therapeutic agent may be an anti-CD52 compound, for example, alemtuzumab. The therapeutic agent may be an inducer of apoptosis, for example, dexamethasone. The therapeutic agent may be an immuno-suppressant, for example, dexamethasone. The therapeutic agent may inhibit tumour-promoting inflammatory factor production, for example, prednisone. 41 PAT059979-WO-PCT The therapeutic agent may be a corticosteroid, for example, dexamethasone or prednisone, and combinations thereof. The therapeutic agent may be a PI3K-mediated proliferation inhibitor, for example, duvelisib. 5 The therapeutic agent may inhibit PI3K BCR signaling and tumour cell chemotaxis, for example, idelalisib. The therapeutic agent may be a PI3K-δ inhibitor, for example, duvelisib or idelalisib, and combinations thereof. The therapeutic agent may be a proteasome inhibitor, for example, bortezomib.10The therapeutic agent may be a tubulin inhibitor, for example, vincristine, podofilox, vinblastine (e.g., vinblastine sulfate), flubendazole, albendazole, mebendazole, colchicine, docetaxel, or paclitaxel, and combinations thereof. The therapeutic agent may be a CD19-targeting CAR T-cell, for example, axicabtagene ciloleucel, lisocabtagene maraleuel, or tisagenlecleucel, and combinations 15 thereof. The therapeutic agent may be a fungicide, for example, thiram, pyrithione, ciclopirox, thimerosal, cetrimonium, oxyquinoline, aminacrine, chloroxine, or chlormidazole (e.g., chlormidazole hydrochloride), and combinations thereof. The therapeutic agent may be an oxidative stress inducer (for example, free radical20 producers), for example, dihydroartemisinin or artemether, and combinations thereof.The therapeutic agent may be an inhibitor of Na-K ATPase, and / or the Na-K ATPase membrane pump, for example, digoxin or digitoxin, and combinations thereof. The therapeutic agent may be a mitochondrial respiration complex 1 inhibitor, for example, pyrvinium (e.g., pyrvinium pamoate or pyrvinium methyl sulfate), and 25 combinations thereof. The therapeutic agent may be a thioredoxin reductase inhibitor, for example, auranofin. The therapeutic agent may be an antiarrhythmic compound, for example, dronedarone (e.g., dronedarone hydrochloride) or amiodarone (e.g., amiodarone hydrochloride), and30combinations thereof. The therapeutic agent may be a cathepsin B inhibitor, for example, nitroxoline. The therapeutic agent may be an amebicide, for example, iodoquinol. The therapeutic agent may be a cyclooxygenase inhibitor, for example, oxyphenbutazone. 42 PAT059979-WO-PCT The therapeutic agent may be a nitric oxide synthase inhibitor, for example, methylene blue. The therapeutic agent may be a bacterial membrane disruptor, for example, cetylpyridinium (e.g., cetylpyridinium chloride monohydrate). 5 The therapeutic agent may be an anthelminthic compound, for example niclosamide. The therapeutic agent may be a bacterial biofilm inhibitor, for example, chlorquinaldol. The therapeutic agent may be an aldehyde dehydrogenase inhibitor, for example, disulfiram.10The therapeutic agent may be an iron, copper and / or zinc chelator, for example, deferasirox or clioquinol, and combinations thereof. The therapeutic agent may be a sodium channel blocker, for example, oxcarbazepine or quinidine, and combinations thereof. The therapeutic agent may be a Na-K-Cl cotransporter inhibitor, for example, 15 etacrynic acid. The therapeutic agent may be a superoxide dismutase inhibitor, for example, diethyldithiocarbamate (e.g., sodium diethyldithiocarbamate trihydrate). The therapeutic agent may be a 5-hydroxytryptamine receptor agonist, for example, tegaserod.20 The therapeutic agent may be a blood schizonticide, for example, mefloquine (e.g.,mefloquine hydrochloride). The therapeutic agent may be a metalloproteinase inhibitor, for example, abametapir. The therapeutic agent may be an inosine monophosphate dehydrogenase inhibitor, for example, mycophenolate or mycophenolic acid, and combinations thereof. 25 The therapeutic agent may be a D2 receptor antagonist, for example, thioridazine (e.g., thioridazine hydrochloride), pimozide, trifluoperazine (e.g., trifluoperazine dihydrochloride), prochlorperazine (e.g., prochlorperazine dimaleate), perphenazine, triflupromazine (e.g., triflupromazine hydrochloride), asenapine (e.g., asenapine maleate), iloperidone, or lurasidone (e.g., lurasidone hydrochloride), and combinations thereof.30The therapeutic agent may be a serotonin reuptake inhibitor, for example, sertraline (e.g., sertraline hydrochloride), nortriptyline (e.g., nortriptyline hydrochloride), fluoxetine, clomipramine (e.g., clomipramine hydrochloride), paroxetine (e.g., paroxetine hydrochloride), or nefazodone (e.g., nefazodone hydrochloride), and combinations thereof. 43 PAT059979-WO-PCT The therapeutic agent may be a haem polymerase inhibitor, for example, amodiaquine (e.g., amodiaquine dihydrochloride dihydrate) or halofantrine (e.g., halofantrine hydrochloride), and combinations thereof. The therapeutic agent may be an acetylcholinesterase inhibitor, for example, carbaryl. 5 The therapeutic agent may be a selective estrogen receptor modulator, for example, tamoxifen or raloxifene (e.g., raloxifene hydrochloride), and combinations thereof. The therapeutic agent may be a D2 receptor agonist, for example, brexpiprazole, aripiprazole, or dopamine (e.g., dopamine hydrochloride), and combinations thereof. The therapeutic agent may be a lanosterol 14-α-demethylase inhibitor, for example,10itraconazole. The therapeutic agent may be a dihydrofolate reductase inhibitor, for example, pyrimethamine. The therapeutic agent may be a HIV protease inhibitor, for example, lopinavir. The therapeutic agent may be a vitamin D receptor agonist, for example, paricalcitol. 15 The therapeutic agent may be a calcium-sensing receptor (CaR) modulator, for example, cinacalcet (e.g., cinacalcet hydrochloride). The therapeutic agent may be a norepinephrine reuptake inhibitor, for example, maprotiline (e.g., maprotiline hydrochloride), duloxetine (e.g., duloxetine hydrochloride), or amoxapine, and combinations thereof.20 The therapeutic agent may be a 17α-hydroxylase / C17,20-lyase (CYP17) inhibitor, forexample, abiraterone (e.g., abiraterone acetate). The therapeutic agent may be a HMG-CoA reductase inhibitor, for example, bifonazole. The therapeutic agent may be a H1-receptor antagonist, for example, azelastine (e.g., 25 azelastine hydrochloride), clemastine (e.g., clemastine hydrochloride), or chlorpromazine (e.g., chlorpromazine hydrochloride), and combinations thereof. The therapeutic agent may be a μ-receptor agonist, for example, loperamide (e.g., loperamide hydrochloride). The therapeutic agent may be a pancreatic lipase inhibitor, for example, orlistat.30The therapeutic agent may be a progesterone receptor modulator, for example, mifepristone or ulipristal, and combinations thereof. The therapeutic agent may be a 14α-demethylase inhibitor, for example, sertaconazole. 44 PAT059979-WO-PCT The therapeutic agent may be an NS5A inhibitor, for example, daclatasvir (e.g., daclatasvir dihydrochloride). The therapeutic agent may be a monoamine oxidase inhibitor, for example, piperacetazine. 5 The therapeutic agent may be a β-adrenoceptor antagonist, for example, carvedilol. The therapeutic agent may be a phosphodiesterase 4 (PDE4) inhibitor, for example, drotaverine (e.g., drotaverine hydrochloride). The therapeutic agent may be a 5α-reductase inhibitor, for example, dutasteride. The therapeutic agent may be a calcium channel blocker, for example, amlodipine10(e.g., amlodipine besylate). The therapeutic agent may be a muscarinic M(3) receptor antagonist, for example, darifenacin (e.g., darifenacin hydrobromide). The therapeutic agent may be a nuclear progesterone receptor agonist, for example, progesterone. 15 The therapeutic agent may be an NK1 receptor antagonist, for example, aprepitant. The therapeutic agent may be an RNA polymerase inhibitor, for example, rifabutin. The therapeutic agent may be a melanin synthesis inhibitor, for example, monobenzone. The therapeutic agent may be a folic acid synthesis inhibitor, for example,20 sulfaguanidine.The therapeutic agent may be a DNA alkylator, for example, temozolomide. The therapeutic agent may be a thrombopoietin receptor agonist, for example, eltrombopag. The therapeutic agent may be selected from Table 1, 2, 3, or 4. The therapeutic agent 25 may be Compound 60, 84, 430, 432, 446, 501, 503, 510, 518, 520, 522, 527, or 574, and combinations thereof. The therapeutic agent may be ibrutinib, venetoclax, lenalidomide, pomalidomide, everolimus, cytarabine, clofarabine, decitabine, gemcitabine, doxorubicin, SN-38 (7-Ethyl- 10-hydroxycamptothecin), fostamatinib, or vorinostat, and combinations thereof. In this30embodiment, the VAV1 degrader may be a compound of formulas (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I-J), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), and (III-G), or a pharmaceutically acceptable salt thereof, for example formula (I-J), (II-F), or (III-G), or a pharmaceutically acceptable salt thereof. 45 PAT059979-WO-PCT The therapeutic agent may be venetoclax. In this embodiment, the VAV1 degrader may be a compound of formulas (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I- J), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), and (III-G), or a pharmaceutically acceptable salt thereof. 5 The therapeutic agent may be lenalidomide. In this embodiment, the VAV1 degrader may be a compound of formulas (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I- J), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), and (III-G), or a pharmaceutically acceptable salt thereof. The therapeutic agent may be pomalidomide. In this embodiment, the VAV1 degrader10may be a compound of formulas (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I- J), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), and (III-G), or a pharmaceutically acceptable salt thereof. The therapeutic agent may be everolimus. In this embodiment, the VAV1 degrader may be a compound of formulas (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I- 15 J), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), and (III-G), or a pharmaceutically acceptable salt thereof. The therapeutic agent may be cytarabine. In this embodiment, the VAV1 degrader may be a compound of formulas (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I- J), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (III-A), (III-B), (III-C), (III-D), (III-E),20 (III-F), and (III-G), or a pharmaceutically acceptable salt thereof.The therapeutic agent may be clofarabine. In this embodiment, the VAV1 degrader may be a compound of formulas (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I- J), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), and (III-G), or a pharmaceutically acceptable salt thereof. 25 The therapeutic agent may be decitabine. In this embodiment, the VAV1 degrader may be a compound of formulas (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I- J), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), and (III-G), or a pharmaceutically acceptable salt thereof. The therapeutic agent may be gemcitabine. In this embodiment, the VAV1 degrader30 may be a compound of formulas (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I- J), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), and (III-G), or a pharmaceutically acceptable salt thereof. The therapeutic agent may be doxorubicin. In this embodiment, the VAV1 degrader may be a compound of formulas (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I- 46 PAT059979-WO-PCT J), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), and (III-G), or a pharmaceutically acceptable salt thereof. The therapeutic agent may be SN-38 (7-Ethyl-10-hydroxycamptothecin). In this embodiment, the VAV1 degrader may be a compound of formulas (I-A), (I-B), (I-C), (I-D), 5 (I-E), (I-F), (I-G), (I-H), (I-I), (I-J), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), and (III-G), or a pharmaceutically acceptable salt thereof. The therapeutic agent may be fostamatinib. In this embodiment, the VAV1 degrader may be a compound of formulas (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I-10J), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), and (III-G), or a pharmaceutically acceptable salt thereof. The therapeutic agent may be vorinostat. In this embodiment, the VAV1 degrader may be a compound of formulas (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I- J), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (III-A), (III-B), (III-C), (III-D), (III-E), 15 (III-F), and (III-G), or a pharmaceutically acceptable salt thereof. The therapeutic agent may be not a VAV1 degrader. In this embodiment, the VAV1 degrader may be a compound of formulas (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I-J), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), and (III-G), or a pharmaceutically acceptable salt thereof.20 In some embodiments, the therapeutic agent is not an expectorant.In some embodiments, the therapeutic agent produces a therapeutic effect by eliciting a biological response outside of the gastric mucosa. In some embodiments, the therapeutic agent is not cetyl alcohol, phenol, or guaifenesin. 25 VAV1 degraders The VAV1 degrader used in the invention may be a compound (e.g. a small molecule) that binds to both an E3 ligase and VAV1 leading to degradation of VAV1. This may be shown in a protein degradation assay, for instance the protein degradation assay according to Example303A. The VAV1 degrader may be provided in salt form or in free form. While any VAV1 degrader may be used with the invention, in any embodiment or aspect herein, the VAV1 degrader can be of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, as defined below. 47 PAT059979-WO-PCT Degraders of Formula (I) The VAV1 degrader may be of Formula (I) or a pharmaceutically acceptable salt thereof, i.e. a VAV1 degrader of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I) or (I-J) 5 or a pharmaceutically acceptable salt thereof. The substituents listed in respect of Formula (I) apply to Formula (I) only. For example, the VAV1 degrader may be of Formula (I-A) or a pharmaceutically acceptable salt thereof, 10 Formula (I-A) wherein: L1is: 15 • a bond; • *-O(C0-C4 alkylene)-, *-S(C0-C4 alkylene)-, *-C1-C4 alkylene-, or *-NR’(C0-C4 alkylene)-, -(C1-C4 alkylene)-C(=O)-*, *-(C1-C4 alkylene)-C(=O)-, wherein the alkylene is optionally substituted with 1-2 Raand wherein * indicates the point of attachment of L1to the ring comprising X and Y;20• -(C=O)-; or • taken together with Y to form an additional ring fused with the ring containing X and Y, wherein the fused ring system includes 9 or 10 ring atoms, wherein from 1-4 ring atoms in the additional ring are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd) and O, wherein the additional ring is substituted with R1 and is 25 optionally further substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc; and each one of X and Y is independently selected from the group consisting of N and CH; R1is selected from the group consisting of hydrogen, deuterium, Rb, -ORb, -S(O)0-2Rb, -N(R’)Rb, CN, halo, and –NR’C(O)R’’; 48 PAT059979-WO-PCT R2is selected from the group consisting of hydrogen, deuterium, CH3, CHF2, CF3, OMe, F, Cl and Br; each of R3, R4and R5is independently selected from the group consisting of hydrogen and Rc; 5 each of R6is independently selected from the group consisting of: deuterium, halo; cyano; C1-10 alkyl which is optionally substituted with from 1-6 independently selected Ra; C3- 6 cycloalkyl which is optionally substituted with from 1-4 independently selected Ra; C2-6 alkenyl; C2-6 alkynyl; C1-4 alkoxy; -S(O)0-2(C1-4 alkyl); -NReRf; –OH; -S(O)1-2NR’R’’; -NO2; -C(=O)(C1-10 alkyl); -C(=O)O(C1-4 alkyl); -C(=O)OH; -N(R’)C(=O)(C1-4 alkyl), -10C(=O)NR’R’’, Rg, and –(CH2)1-2 Rg; n is selected from 0, 1, 2 and 3; R7is selected from the group consisting of hydrogen, deuterium, CH3, CHF2, CF3, OMe, F, Cl and Br; each occurrence of Rais independently selected from the group consisting of: –OH; -15 halo; –NReRf; C1-4 alkoxy; C1-4 haloalkoxy; -C(=O)O(C1-4 alkyl); -C(=O)(C1-4 alkyl); - C(=O)OH; -CONR’R’’; -S(O)1-2NR’R’’; -S(O)1-2(C1-4 alkyl); and cyano; each occurrence of Rbis independently selected from the group consisting of: • C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc;20 • heterocyclyl or heterocycloalkenyl including 3-10 ring atoms, wherein from 1- 3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc;25• 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(Rd), O, and S(O)0-2, wherein at least one ring in the system is aromatic and wherein the heteroaryl is optionally substituted with from 1-4 substituents independently selected from oxo and Rc; and • C6-10 aryl optionally substituted with from 1-4 substituents independently 30 selected Rc; each occurrence of Rcis independently selected from the group consisting of: deuterium; halo; cyano; C1-10 alkyl which is optionally substituted with from 1-6 independently selected Ra; C3-6 cycloalkyl which is optionally substituted with from 1-4 independently 49 PAT059979-WO-PCT selected Ra; C2-6 alkenyl; C2-6 alkynyl; C1-4 alkoxy; -S(O)0-2(C1-4 alkyl); -NReRf; –OH; -S(O)1- 2NR’R’’; -NO2; -C(=O)(C1-10 alkyl); -C(=O)O(C1-4 alkyl); -C(=O)OH; -N(R’)C(=O)(C1-4 alkyl), -C(=O)NR’R’’, Rg, and –(CH2)1-2 Rg; each occurrence of Rdis independently selected from the group consisting of: 5 hydrogen, deuterium, C1-6 alkyl optionally substituted with from 1-3 independently selected Ra; -C(O)(C1-4 alkyl); -C(O)O(C1-4 alkyl); -CONR’R’’; -S(O)1-2NR’R’’; -S(O)1-2(C1-4 alkyl); -OH; and C1-4 alkoxy; each occurrence of Reand Rfis independently selected from the group consisting of: H; deuterium; C1-6 alkyl; -C(O)(C1-4 alkyl); -C(O)O(C1-4 alkyl); -CONR’R’’; -S(O)1-2NR’R’’;10-S(O)1-2(C1-4 alkyl); -OH; and C1-4 alkoxy; and each occurrence of Rgis independently selected from the group consisting of: • C3-7 cycloalkyl or C3-7 cycloalkenyl, each of which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Ra; • heterocyclyl or heterocycloalkenyl including 3-7 ring atoms, wherein from 1-315ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Ra; • heteroaryl including 5-10 ring atoms, wherein from 1-4 ring atoms are 20 heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, wherein at least one ring in the system is aromatic and wherein the heteroaryl is optionally substituted with from 1-4 oxo or Ra; and • C6-10 aryl optionally substituted with from 1-4 Ra; each occurrence of R’ and R’’ is independently selected from the group consisting of:25hydrogen; and C1-4alkyl. This disclosure also features compounds of Formula (I-B) or a pharmaceutically acceptable salt thereof, 30 50 PAT059979-WO-PCT Formula (I-B) wherein L1, X, Y, R1, R2, R3, R4, R5, R6and n are as defined for Formula I-A above. 5 In certain embodiments, L1-R1does not include O-O, N-O, N-N, O-S, S-S, or N-S bonds. In certain embodiments, L1must be a bond when R1is CN, halo, or –NR’C(O)R’’. In certain embodiments, L1cannot be a bond when R1is hydrogen. In certain embodiments, L1-R1does not include O-O, N-O, N-N, O-S, S-S, or N-S10bonds, L1must be a bond when R1is CN, halo, or –NR’C(O)R’’; and L1cannot be a bond when R1is hydrogen. In certain embodiments: L1is a bond, -(C=O)-, *-O(C0-C4 alkylene)-, *-C1-C4 alkylene-, *-NR’(C0-C4 alkylene)-, *-NR’(C=O)(C0-C4 alkylene)-, or *-(C1-C4 alkylene)-C(=O)-, wherein the alkylene 15 is optionally substituted with 1-2 Raand wherein * indicates the point of attachment of L1to the ring; or when taken together with Y forms a heteroaryl ring including 9 or 10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd) and O, wherein at least one ring in the system is aromatic and20 wherein the heteroaryl is optionally substituted with from 1-4 substituents independentlyselected from the group consisting of oxo and Rc; X and Y are both CH or one of X and Y is N and the other is CH; R1is Rb; R2is hydrogen, chloro, fluoro or methyl; 25 R3, R4and R5are hydrogen or halo; R6is selected from the group consisting of deuterium, halo and unsubstituted C1-10 alkyl; and Rbis: • heterocyclyl or heterocycloalkenyl including 3-10 ring atoms, wherein from 1-3 ring 30 atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc; or 51 PAT059979-WO-PCT • 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(Rd), O, and S(O)0-2, wherein at least one ring in the system is aromatic and wherein the heteroaryl is optionally substituted with from 1-4 substituents independently selected from oxo and Rc. 5 In certain embodiments: L1is a bond, -(C=O)-, *-O(C0-C4 alkylene)-, *-C1-C4 alkylene-, *-NR’(C0-C4 alkylene)-, *-NR’(C=O)(C0-C4 alkylene)-, or *-(C1-C4 alkylene)-C(=O)-, wherein the alkylene is optionally substituted with 1-2 Raand wherein * indicates the point of attachment of L1to 10 the ring; or L1when taken together with Y forms a heteroaryl ring including 9 or 10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd) and O, wherein at least one ring in the system is aromatic and wherein the heteroaryl is optionally substituted with from 1-4 substituents independently 15 selected from the group consisting of oxo and Rc; X and Y are both CH or one of X and Y is N and the other is CH; R1is Rb; R2is hydrogen, chloro, fluoro or methyl; R3, R4and R5are hydrogen or halo; 20 R6is selected from the group consisting of deuterium, halo and unsubstituted C1-10 alkyl; and Rbcomprises a hydrogen bond acceptor within seven atoms of the carbon atom between X and Y. 25 In certain embodiments: L1is a bond, -(C=O)-, *-O(C0-C4 alkylene)-, *-C1-C4 alkylene-, *-NR’(C0-C4 alkylene)-, *-NR’(C=O)(C0-C4 alkylene)-, or *-(C1-C4 alkylene)-C(=O)-, wherein the alkylene is optionally substituted with 1-2 Raand wherein * indicates the point of attachment of L1to the ring; or 30 when taken together with Y forms a heteroaryl ring including 9 or 10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd) and O, wherein at least one ring in the system is aromatic and wherein the heteroaryl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc; 52 PAT059979-WO-PCT X and Y are both CH or one of X and Y is N and the other is CH; R1is Rb; R2is hydrogen, chloro, fluoro or methyl; R3, R4and R5are hydrogen or halo; 5 n is 0; and Rbis: • heterocyclyl or heterocycloalkenyl including 5-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally 10 substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc; or • 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(Rd), O, and S(O)0-2, wherein at least one ring in the system is aromatic and wherein the heteroaryl is optionally15substituted with from 1-4 substituents independently selected from oxo and Rc. Identity of RcIn certain embodiments, Rcis independently selected from the group consisting of: halo; C1-10 alkyl which is optionally substituted with from 1-6 independently selected Ra; C1-4 alkoxy; Rg, 20 and –(CH2)1-2 Rg. Identity of L1In some embodiments, L1: • is a bond; 25 • is *-O(C0-C4 alkylene)-, *-S(C0-C4 alkylene)-, *-C1-C4 alkylene-, or *-NR’(C0- C4 alkylene)-, *-NR’(C=O)(C0-C4 alkylene)-, -(C1-C4 alkylene)-C(=O)-*, *-(C1-C4 alkylene)- C(=O)-, wherein the alkylene is optionally substituted with 1-2 Raand wherein * indicates the point of attachment of L1to the ring comprising X and Y; or • is -(C=O)-. 30 In certain embodiments, L1is a bond, -(C=O)-, *-O(C0-C4 alkylene)-, *-C1-C4 alkylene-, *- NR’(C0-C4 alkylene)-, *-NR’(C=O)(C0-C4 alkylene)-, or *-(C1-C4 alkylene)-C(=O)-, wherein 53 PAT059979-WO-PCT the alkylene is optionally substituted with 1-2 Raand wherein * indicates the point of attachment of L1to the ring. In certain embodiments, L1is a bond, -(C=O)-, *-O(C0-C4 alkylene)-, *-C1-C4 alkylene-, *- NR’(C0-C4 alkylene)-, *-NR’(C=O)(C0-C4 alkylene)-, or *-(C1-C4 alkylene)-C(=O)-. 5 In certain embodiments, L1is a bond, -(C=O)-, *-O(C1-C4 alkylene, *-C1-C4 alkylene-, *-(C1- C4 alkylene)-C(=O)-, *-NH’(C0-C4 alkylene)-, or *-NH’(C=O)(C0-C4 alkylene)-, wherein the alkylene is optionally substituted with 1-2 Ra,and wherein * indicates the point of attachment of L1to the ring. In certain embodiments, L1is a bond, -(C=O)-, *-O(C1-C4 alkylene, *-C1-C4 alkylene-, or *-10(C1-C4 alkylene)-C(=O)-. In certain embodiments, L1is a bond, *-OCH2-, *-OCH2CH2, –CH2–, –CH(CH3)–, –C(CH3)2– , –CH2CH2CH2–, –(C=O)– or *-(CH2)-C(=O)-. In certain embodiments, L1is a bond or –CH2–. In certain embodiments, L1is a bond. 15 In certain embodiments, L1is taken together with Y to form an additional ring fused with the ring containing X and Y, wherein the fused ring system includes 9 or 10 ring atoms, wherein from 1-4 ring atoms in the additional ring are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd) and O, wherein the additional ring is substituted with R1and is optionally further substituted with from 1-4 substituents independently selected from20 the group consisting of oxo and Rc.Identity of X and Y In certain embodiments, X and Y are both CH or one of X and Y is N and the other is CH. In certain embodiments, X and Y are both CH. 25 Identity of R1In certain embodiments, R1is Rb. In certain embodiments, Rbcomprises a hydrogen bond acceptor within seven atoms of the carbon atom between X and Y.30In certain embodiments, Rbcomprises a hydrogen bond acceptor within seven atoms of the carbon atom between X and Y and the hydrogen bond acceptor is selected from a carbonyl group, a sulfonyl group, a nitrogen-containing heteroaromatic group, an oxygen-containing heteroaromatic group and an oxygen-containing aliphatic or cycloaliphatic group. 54 PAT059979-WO-PCT In certain embodiments, Rbcomprises a hydrogen bond acceptor within seven atoms of the carbon atom between X and Y and wherein the hydrogen bond acceptor is selected from an amide, a lactam, a carbamate, a pyridone, a pyrimidinone, a piperazinone, a piridazinone, a urea, a sulfonamide, a sulfone, a pyrimidine, a pyrazine, a pyridazine, a pyridine, an oxazole, 5 an isoxazole, an oxadiazole, a thiazole, a thiadiazole, an imidazole, a pyrazole, an oxazole, an isoxazole, an oxadiazole, an oxetane, a tetrahydrofuran, a tetrahydropyran or a methoxy alkyl group. In certain embodiments, Rbis: • heterocyclyl or heterocycloalkenyl including 3-10 ring atoms, wherein from 1-3 ring 10 atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc; or • heteroaryl including 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms,15each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, wherein at least one ring in the system is aromatic and wherein the heteroaryl is optionally substituted with from 1-4 substituents independently selected from oxo and Rc. In certain embodiments, Rbis: • heterocyclyl or heterocycloalkenyl including 5-10 ring atoms, wherein from 1-3 ring 20 atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc; or • heteroaryl including 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms,25each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, wherein at least one ring in the system is aromatic and wherein the heteroaryl is optionally substituted with from 1-4 substituents independently selected from oxo and Rc. In certain embodiments, Rbis: • heterocyclyl or heterocycloalkenyl including 5-10 ring atoms, wherein from 1-3 ring 30 atoms are heteroatoms each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, wherein at least one heteroatom is N or N(Rd), and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc; or 55 PAT059979-WO-PCT • 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(Rd), O, and S(O)0-2, wherein at least one heteroatom is N or N(Rd), wherein at least one ring in the system is aromatic and wherein the heteroaryl is optionally substituted with from 1-4 substituents 5 independently selected from oxo and Rc. In certain embodiments, Rcis independently selected from halo, C1-4 alkyl which is optionally substituted with from 1-3 independently selected halo atoms and C1-4 alkoxy. In certain embodiments, Rbis selected from the group consisting of:1015 ,56 PAT059979-WO-PCT 5 , each of which is optionally substituted with from 1-4 substituents independently selected Rc. In certain embodiments, Rbis heteroaryl including 5-10 ring atoms, wherein from 1-4 ring 10 atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-4 independently selected Rc. In certain embodiments, Rbis heteroaryl including 5-6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O,15and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-4 independently selected Rc. In certain embodiments, Rbis heteroaryl including 5 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), 57 PAT059979-WO-PCT N(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-2 independently selected Rc. In certain embodiments, Rbis heteroaryl including 5 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), 5 N(Rd), O, and S(O)0-2. In certain embodiments, Rbis selected from the group consisting of , , of which is optionally substituted with from 1-2 independently selected Rc. 10 In certain embodiments, Rb is selected from the group consisting of , , ,optionally wherein Rdis CH3. 15 In certain embodiments, Rbis selected from the group consisting of , optionally wherein Rdis CH3. In certain embodiments, Rbis selected from . In certain embodiments, . 58 PAT059979-WO-PCT In certain embodiments, Rbis selected from the group consisting of , , 5 In certain embodiments, Rcis selected from the group consisting of C1-10 alkyl which is optionally substituted with from 1-6 independently selected Raand -NReRf, optionally wherein Rcis methyl, or -NH2. In certain embodiments, Rbis selected from the group consisting 10 , . In certain embodiments, . In certain embodiments, Rcis C1-10 alkyl which is optionally substituted with from 1-6 independently selected Raand -NReRf, optionally wherein Rcis methyl. 15 In certain embodiments, . In certain embodiments, Rbis heteroaryl including 6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-4 substituents independently selected Rc. 59 PAT059979-WO-PCT In certain embodiments, Rbis heteroaryl including 6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2. In certain embodiments, Rb is selected from the group consisting ,5 , . In certain embodiments, Rbis heteroaryl including 7-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, wherein at least one ring in the system is aromatic and wherein the 10 heteroaryl is optionally substituted with from 1-4 independently selected oxo or Rc. In certain embodiments, Rbis heteroaryl including 9-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, wherein at least one ring in the system is aromatic and wherein the heteroaryl is optionally substituted with from 1-4 independently selected oxo or Rc. 15 In certain embodiments, Rbis heteroaryl including 9 ring atoms, wherein at least one ring in the system is aromatic, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-4 independently selected from the list consisting of oxo and Rc. 20 In certain embodiments, Rbis selected from the group consisting of , , ,60 PAT059979-WO-PCT , each of which is optionally substituted with from 1-4 independently selected Rc. In certain embodiments, Rbis selected from the group consisting , 5 , In certain embodiments, Rbis heteroaryl including 10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, wherein at least one ring in the system is aromatic and wherein the 10 heteroaryl is optionally substituted with from 1-4 independently selected oxo or Rc. In certain embodiments, Rbis selected from the group consisiting of , , each of which is optionally substituted with from 1-4 independently selected Rc. 61 PAT059979-WO-PCT In certain embodiments, Rbis selected from the group consisiting of , In certain embodiments, Rbis heterocyclyl or heterocycloalkenyl including 3-10 ring 5 atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc. In certain embodiments, Rbis heterocyclyl or heterocycloalkenyl including 4-6 ring10atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc. In certain embodiments, Rbis heterocyclyl or heterocycloalkenyl including 5-6 ring 15 atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc. In certain embodiments, Rbis heterocyclyl or heterocycloalkenyl including 6 ring20atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc. In certain embodiments, Rbis heterocycloalkenyl including 6 ring atoms, wherein from 25 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc. 62 PAT059979-WO-PCT In certain embodiments, In certain embodiments, Rdis CH3. In certain embodiments, Rbis , optionally substituted with from 1-2 independently selected Rcsubstituents. 5 In certain embodiments, . In certain embodiments, . In certain embodiments, Rcor each occurrence of Rcis selected from the group consisting of C1-10 alkyl optionally substituted with from 1-6 independently selected Ra, C1-410alkoxy, halo, and -NReRf. In certain embodiments, Rcis selected from the group consisting of methyl, ethyl, - CHF2, -CF3, methoxy, fluoro, chloro, and NH2. In certain embodiments, R1 is selected from the group consisting ,,15 In certain embodiments, Rbis heterocyclyl including 6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc. 20 63 PAT059979-WO-PCT In certain embodiments, Rb is selected from the group consisting ,, , , each of which is optionally substituted with 1-4 substituents 5 independently selected from the group consisting of oxo and Rc. In certain embodiments, Rcis methyl, halo, methoxy or CF3. In certain embodiments, Rbis selected from the group consisting of , ,10 In certain embodiments, Rbis selected from the group consisting of , 64 PAT059979-WO-PCT In certain embodiments, Rdis CH3. 5 In certain embodiments, . In certain embodiments, Rbis heterocyclyl or heterocycloalkenyl including 5 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected 10 from the group consisting of oxo and Rc. In certain embodiments, Rbis heterocyclyl including 5 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc.15 In certain embodiments, Rb is selected from the group consisting , is optionally substituted with 1-4 Rc. In certain embodiments, Rcis halo, or C1-6 alkyl. 65 PAT059979-WO-PCT In certain embodiments, Rbis selected from the group consisting of , 5 , . In certain embodiments, Rbis heterocycloalkenyl including 5 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocycloalkenyl is optionally substituted with 10 from 1-4 substituents independently selected from the group consisting of oxo and Rc. In certain embodiments, , optionally wherein . In certain embodiments, Rb is selected from the group consisting of , .15In certain embodiments, Rbis heterocyclyl or heterocycloalkenyl including 7-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc. 66 PAT059979-WO-PCT In certain embodiments, Rbis heterocyclyl including 7-10 ring atoms, wherein from 1- 3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo 5 and Rc. In certain embodiments, Rbis heterocyclyl including 7 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected Rc. 10 In certain embodiments, Rbis selected from the group consisting , which is optionally substituted with from 1-4 substituents independently selected Rc. In certain embodiments, Rbis selected from the group consisting of , 15 In certain embodiments, Rbis heterocyclyl including 8 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected Rc. 67 PAT059979-WO-PCT In certain embodiments, Rbis selected from the group consisting , with from 1-4 substituents independently selected Rc. 5 In certain embodiments, Rbis selected from the group consisting , In certain embodiments, Rbis heterocyclyl including 9 ring atoms, wherein from 1-3 10 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc. 15substituted with from 1-4 substituents independently selected Rc. In certain embodiments, Rdis CH3. 68 PAT059979-WO-PCT In certain embodiments, Rbis selected from the group consisting , In certain embodiments, Rbis C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with from 1-4 substituents independently selected from the group 5 consisting of oxo and Rc; In certain embodiments, Rbis , optionally substituted with one Rc. Identity of R2In certain embodiments, R2is hydrogen, chloro, fluoro or methyl. 10 In certain embodiments, R2is chloro. Identity of R2, R3, R4and R5and value of n In certain embodiments, R3, R4and R5are hydrogen or halo. In certain embodiments, R3is halo or hydrogen and R4and R5are hydrogen. 15 In certain embodiments, R3, R4and R5are hydrogen. In certain embodiments, R2is chloro, and R3, R4and R5are hydrogen. In certain embodiments, n is 0. In certain embodiments, n is 0 and R3, R4and R5are hydrogen; and / or L1is a bond, -(C=O)-, *-C1-C4 alkylene-, *-NR’(C0-C4 alkylene)-, *-NR’(C=O)(C0-C4 20 alkylene)-, or *-(C1-C4 alkylene)-C(=O)-, wherein the alkylene is optionally substituted with 1-2 Raand wherein * indicates the point of attachment of L1to the ring. In certain embodiments, n is 1 or 2. Identity of R625 In certain embodiments, R6is selected from the group consisting of deuterium, halo; cyano; C1-10 alkyl which is optionally substituted with from 1-6 independently selected Ra; C1- 4 alkoxy, C1-4 haloalkoxy; and -NReRf; optionally wherein R6is selected from the group 69 PAT059979-WO-PCT consisting of deuterium, cyano, chloro, fluoro, methyl, ethyl, -CHF2, methoxy, -OCHF2, and -NH2. In certain embodiments, R6is selected from the group consisting of deuterium, halo and unsubstituted C1-10 alkyl. 5 In certain embodiments, R6is selected from the group consisting of deuterium, fluoro and methyl. In certain embodiments, R6is deuterium, optionally wherein n is 4. Formulae I-C, I-D, I-E and I-F10In certain embodiments, the compound is a compound of formula (I-C) Formula (I-C). In certain embodiments, the compound is a compound of formula (I-D) Formula (I-D), wherein X is –NH- or –O-.15In certain embodiments, X is -O-. In certain embodiments, the compound is a compound of formula (I-E) Formula (I-E). In certain embodiments, the compound is a compound of formula (I-F) Formula (I-F). 20 In certain embodiments, R2is chloro. In certain embodiments, Rbis heterocyclyl or heterocycloalkenyl including 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the 70 PAT059979-WO-PCT group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc; or heteroaryl including 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, 5 each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, wherein at least one ring in the system is aromatic and wherein the heteroaryl is optionally substituted with from 1-4 substituents independently selected from oxo and Rc. In certain embodiments, Rbis heterocycloalkenyl including 6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N,10N(H), N(Rd), O, and S(O)0-2, and wherein the heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc. optionally substituted with from 1-2 substituents independently selected Rc. 15 In certain embodiments, Rbis , which is optionally substituted with from 1-2 independently selected Rc. In certain embodiments, . In certain embodiments, Rcor each occurrence of Rcis selected from the group20consisting of C1-10 alkyl optionallyl substituted with from 1-6 independently selected Ra, C1-4 alkoxy, halo, and -NReRf. In certain embodiments, Rcis selected from the group consisting of methyl, ethyl, - CHF2, -CF3, methoxy, fluoro, chloro, and NH2. 71 PAT059979-WO-PCT In certain embodiments, Rbis selected from the group consisiting , , , . 5 In certain embodiments, Rbis heteroaryl including 5 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-4 substituents independently selected Rc. In certain embodiments, Rbis selected from the group consisting of ,10 of which is optionally substituted with from 1-2 independently selected Rc. In certain embodiments, Rbis selected from the group consisting of , , ,72 PAT059979-WO-PCT ,optionally wherein Rdis CH3. In certain embodiments, Rbis , optionally wherein Rdis CH3. In certain embodiments, Rbis . 5 In certain embodiments, Rbis heterocyclyl including 6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc.10 In certain embodiments, Rb is selected from the group consisting ,,15 73 PAT059979-WO-PCT In certain embodiments, Rdis CH3. 5 In certain embodiments, Rbis . In certain embodiments, Rbis heteroaryl including 6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-4 independently selected Rc. 10 In certain embodiments, Rbis heteroaryl including 6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2. 15 , . In certain embodiments, Rbis heteroaryl including 9 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, wherein at least one ring in the system is aromatic and wherein the 74 PAT059979-WO-PCT heteroaryl is optionally substituted with from 1-4 independently selected from the group consisting of oxo and Rc. In certain embodiments, Rbis selected from the group consisting of , 5 , In certain embodiments, Rbis selected from the group consisting , 10 , In certain embodiments, Rbis heteroaryl including 10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), 75 PAT059979-WO-PCT N(Rd), O, and S(O)0-2, wherein at least one ring in the system is aromatic and wherein the heteroaryl is optionally substituted with from 1-4 independently selected oxo and Rc. In certain embodiments, Rbis selected from the group consisting of , each of which is optionally substituted with 5 from 1-4 independently selected Rc. In certain embodiments, Rbis selected from the group consisting of , In certain embodiments, Rbis heterocyclyl including 7-10 ring atoms, wherein from 1- 3 ring atoms are heteroatoms, each independently selected from the group consisting of N, 10 N(H), N(Rd), O, and S(O)0-2, wherein and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc. In certain embodiments, Rbis heterocyclyl including 7 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), 15 N(Rd), O, and S(O)0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected Rc. which is optionally substituted with from 1-4 substituents independently selected Rc. 76 PAT059979-WO-PCT In certain embodiments, Rbis selected from the group consisting of , In certain embodiments, Rbis heterocyclyl including 8 ring atoms, wherein from 1-3 5 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected Rc. In certain embodiments, Rbis selected from the group consisting , 10 with from 1-4 substituents independently selected Rc. In certain embodiments, Rbis selected from the group consisting , 15 In certain embodiments, Rbis heterocyclyl including 9 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), 77 PAT059979-WO-PCT N(Rd), O, and S(O)0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisiting of oxo and Rc. In certain embodiments, Rbis selected from the group consisting , 5 optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc. In certain embodiments, Rdis CH3. In certain embodiments, Rbis selected from the group consisting , 10 In certain embodiments, R2is chloro. Formulae (I-G) and (I-H) In certain embodiments, the compound is a compound of formula (I-G) 15 In certain embodiments, the compound is a compound of formula (I-H) Formula (I-H). 78 PAT059979-WO-PCT In some embodiments, the present disclosure provides a compound of Formula (I-I): Formula (I-I) 5 or a pharmaceutically acceptable salt thereof, wherein: L1is: • a bond; • *-O(C0-C4 alkylene)-, *-S(C0-C4 alkylene)-, *-C1-C4 alkylene-, or *-NR’(C0-C4 alkylene)-, *-NR’(C=O)(C0-C4 alkylene)-, -(C1-C4 alkylene)-C(=O)-*, *-(C1-C4 alkylene)-10C(=O)-, wherein the alkylene is optionally substituted with 1-2 Raand wherein * indicates the point of attachment of L1to the ring comprising X and Y; • -(C=O)-; or • taken together with Y to form an additional ring fused with the ring containing X and Y, wherein the fused ring system includes 9 or 10 ring atoms, wherein from 1-4 ring 15 atoms in the additional ring are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd) and O, wherein the additional ring is substituted with R1 and is optionally further substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc; and each one of X and Y is independently selected from the group consisting of N and CH; 20 R1is selected from the group consisting of hydrogen, deuterium, Rb, -ORb, -S(O)0-2Rb, -N(R’)Rb, CN, halo, and –NR’C(O)R’’; R2is selected from the group consisting of hydrogen, deuterium, CH3, CHF2, CF3, OMe, F, Cl and Br; each of R3, R4and R5is independently selected from the group consisting of hydrogen 25 and Rc; each of R6is independently selected from the group consisting of: deuterium, halo; cyano; C1-10 alkyl which is optionally substituted with from 1-6 independently selected Ra; C3- 6 cycloalkyl which is optionally substituted with from 1-4 independently selected Ra; C2-6 alkenyl; C2-6 alkynyl; C1-4 alkoxy; -S(O)0-2(C1-4 alkyl); -NReRf; –OH; -S(O)1-2NR’R’’; -NO2; 79 PAT059979-WO-PCT -C(=O)(C1-10 alkyl); -C(=O)O(C1-4 alkyl); -C(=O)OH; -N(R’)C(=O)(C1-4 alkyl), - C(=O)NR’R’’, Rg, and –(CH2)1-2 Rg; n is selected from 0, 1, 2 and 3; R7is selected from the group consisting of hydrogen, deuterium, CH3, CHF2, CF3, 5 OMe, F, Cl and Br; each occurrence of Rais independently selected from the group consisting of: –OH; - halo; –NReRf; C1-4 alkoxy; C1-4 haloalkoxy; -C(=O)O(C1-4 alkyl); -C(=O)(C1-4 alkyl); - C(=O)OH; -CONR’R’’; -S(O)1-2NR’R’’; -S(O)1-2(C1-4 alkyl); and cyano; each occurrence of Rbcomprises a hydrogen bond acceptor;10each occurrence of Rcis independently selected from the group consisting of: deuterium; halo; cyano; C1-10 alkyl which is optionally substituted with from 1-6 independently selected Ra; C3-6 cycloalkyl which is optionally substituted with from 1-4 independently selected Ra; C2-6 alkenyl; C2-6 alkynyl; C1-4 alkoxy; -S(O)0-2(C1-4 alkyl); -NReRf; –OH; -S(O)1- 2NR’R’’; -NO2; -C(=O)(C1-10 alkyl); -C(=O)O(C1-4 alkyl); -C(=O)OH; -N(R’)C(=O)(C1-4 15 alkyl), -C(=O)NR’R’’, Rg, and –(CH2)1-2 Rg; each occurrence of Rdis independently selected from the group consisting of: hydrogen, deuterium, C1-6 alkyl optionally substituted with from 1-3 independently selected Ra; -C(O)(C1- 4 alkyl); -C(O)O(C1-4 alkyl); -CONR’R’’; -S(O)1-2NR’R’’; -S(O)1-2(C1-4 alkyl); -OH; and C1-4 alkoxy;20 each occurrence of Re and Rf is independently selected from the group consisting of:H; deuterium; C1-6 alkyl; -C(O)(C1-4 alkyl); -C(O)O(C1-4 alkyl); -CONR’R’’; -S(O)1-2NR’R’’; -S(O)1-2(C1-4 alkyl); -OH; and C1-4 alkoxy; and each occurrence of Rgis independently selected from the group consisting of: • C3-7 cycloalkyl or C3-7 cycloalkenyl, each of which is optionally substituted with 25 from 1-4 substituents independently selected from the group consisting of oxo and Ra; • heterocyclyl or heterocycloalkenyl including 3-7 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo 30 and Ra; • 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(Rd), O, and 80 PAT059979-WO-PCT S(O)0-2, wherein at least one ring in the system is aromatic and wherein the heteroaryl is optionally substituted with from 1-4 oxo or Ra; and • C6-10 aryl optionally substituted with from 1-4 Ra; each occurrence of R’ and R’’ is independently selected from the group consisting of: 5 hydrogen; and C1-4 alkyl. In some embodiments where Rbcomprises a hydrogen bond acceptor, Rbcomprises a hydrogen bond acceptor within seven atoms of the carbon atom between X and Y. In some embodiments, Rbcomprises a hydrogen bond acceptor within six atoms of the carbon atom between X and Y. In some embodiments, Rbcomprises a hydrogen bond acceptor within five 10 atoms of the carbon atom between X and Y. In some embodiments, Rbcomprises a hydrogen bond acceptor within four atoms of the carbon atom between X and Y In some embodiments, Rbcomprises a hydrogen bond acceptor within three atoms of the carbon atom between X and Y. In preferred embodiments, the compound is a compound of Formula (I-J): 15 Formula (I-J) or a pharmaceutically acceptable salt thereof, wherein: L1is a bond, -(C=O)-, *-O(C0-C4 alkylene)-, *-C1-C4 alkylene-, *-NR’(C0-C420alkylene)-, *-NR’(C=O)(C0-C4 alkylene)-, or *-(C1-C4 alkylene)-C(=O)-, wherein the alkylene is optionally substituted with 1-2 Raand wherein * indicates the point of attachment of L1to the ring; or L1is taken together with Y to form an additional ring fused with the ring containing X and Y, wherein the fused ring system includes 9 or 10 ring atoms, wherein from 1-4 ring atoms 25 in the additional ring are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd) and O, wherein the additional ring is substituted with R1 and is optionally further substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc; wherein X and Y are both CH or one of X and Y is N and the other is CH;30wherein R1is Rb; 81 PAT059979-WO-PCT wherein R2is hydrogen, chloro, fluoro or methyl; wherein R3, R4and R5are hydrogen or halo; wherein R6is selected from the group consisting of deuterium, halo and unsubstituted C1-10 alkyl; 5 wherein R7is selected from the group consisting of hydrogen, deuterium, CH3, CHF2, CF3, OMe, F, Cl and Br; wherein each occurrence of Rais independently selected from the group consisting of: –OH; -halo; –NReRf; C1-4 alkoxy; C1-4 haloalkoxy; -C(=O)O(C1-4 alkyl); -C(=O)(C1-4 alkyl); - C(=O)OH; -CONR’R’’; -S(O)1-2NR’R’’; -S(O)1-2(C1-4 alkyl); and cyano;10wherein Rbis: • heterocyclyl or heterocycloalkenyl including 3-10 ring atoms, wherein from 1- 3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group 15 consisting of oxo and Rc; or • 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(Rd), O, and S(O)0-2, wherein at least one ring in the system is aromatic and wherein the heteroaryl is optionally substituted with from 1-4 substituents independently selected 20 from oxo and Rc; wherein Rcis independently selected from the group consisting of: halo; C1-10 alkyl which is optionally substituted with from 1-6 independently selected Ra; C1-4 alkoxy; Rg, and –(CH2)1-2 Rgwherein each occurrence of Rdis independently selected from the group consisting of: 25 hydrogen, deuterium, C1-6 alkyl optionally substituted with from 1-3 independently selected Ra; -C(O)(C1-4 alkyl); -C(O)O(C1-4 alkyl); -CONR’R’’; -S(O)1-2NR’R’’; -S(O)1-2(C1-4 alkyl); -OH; and C1-4 alkoxy; each occurrence of Reand Rfis independently selected from the group consisting of: H; deuterium; C1-6 alkyl; -C(O)(C1-4 alkyl); -C(O)O(C1-4 alkyl); -CONR’R’’; -S(O)1-2NR’R’’; 30 -S(O)1-2(C1-4 alkyl); -OH; and C1-4 alkoxy; each occurrence of Rgis independently selected from the group consisting of: • C3-7cycloalkyl or C3-7cycloalkenyl, each of which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Ra; 82 PAT059979-WO-PCT • heterocyclyl or heterocycloalkenyl including 3-7 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo 5 and Ra; • 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(Rd), O, and S(O)0-2, wherein at least one ring in the system is aromatic and wherein the heteroaryl is optionally substituted with from 1-4 oxo or Ra; and 10 • C6-10 aryl optionally substituted with from 1-4 Ra; and each occurrence of R’ and R’’ is independently selected from the group consisting of: hydrogen; and C1-4alkyl.. Particular compounds of Formula (I)15In certain embodiments, the compound is selected from the group consisting of the compounds in Table 1 or a pharmaceutically acceptable salt thereof. Table 1 83 PAT059979-WO-PCT 85 PAT059979-WO-PCT 88 PAT059979-WO-PCT 89 PAT059979-WO-PCT 90 PAT059979-WO-PCT 91 PAT059979-WO-PCT 92 PAT059979-WO-PCT 93 PAT059979-WO-PCT 94 PAT059979-WO-PCT 95 PAT059979-WO-PCT 96 PAT059979-WO-PCT 97 PAT059979-WO-PCT 98 PAT059979-WO-PCT 99 PAT059979-WO-PCT 100 PAT059979-WO-PCT 101 PAT059979-WO-PCT 102 PAT059979-WO-PCT 103 PAT059979-WO-PCT 104 PAT059979-WO-PCT 105 PAT059979-WO-PCT 106 PAT059979-WO-PCT 107 PAT059979-WO-PCT 108 PAT059979-WO-PCT In certain embodiments, the compound is a pharmaceutically acceptable salt thereof. 109 PAT059979-WO-PCT In certain embodiments, the compound is pharamceutically acceptable salt thereof. In certain embodiments, the compound is or a pharamceutically acceptable salt thereof. 5 In certain embodiments, the compound pharamceutically acceptable salt thereof. In certain embodiments, the compound exists in a racemic mixture. In certain embodiments, the compound in a racemic mixture pharamceutically acceptable salt thereof. 10 In certain embodiments, this disclosure features a pharmaceutical composition comprising any of the compounds described herein, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, the compound is not , 15 . In some embodiments, the compound has a Dmax% of 20% or greater. Degraders of Formula (II) 110 PAT059979-WO-PCT The VAV1 degrader may be of Formula (II) or a pharmaceutically acceptable salt thereof, i.e. a VAV1 degrader of Formula (II-A), (II-B), (II-C), (II-D), (II-E), or (II-F). The substituents listed in respect of Formula (II) apply to Formula (II) only. 5 The VAV1 degrader may be of Formula (II-A) or a pharmaceutically acceptable salt thereof, Formula (II-A) wherein: Ring A is selected from the group consisting of: 10 • , wherein * is the point of attachment to L, X1, X2and X3are each selected from 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 independently selected from the group consisting of CH, CR14and N, and wherein 15 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-C4 alkylene)-, -NR9(C=O)(C0-C4 alkylene)-*, -(C1-C4 alkylene)- 20 C(=O)-*, or *-(C1-C4 alkylene)-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: 111 PAT059979-WO-PCT • 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 5 substituents independently selected from the group consisting of oxo and R8; • 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 10 substituents independently selected from oxo and R8; 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(C3-6 cycloalkyl) optionally substituted with from 1-315independently 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; each of R3, R4and R5is independently selected from the group consisting of 20 hydrogen, deuterium, halo, cyano, C1-4 alkyl 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 25 of: hydrogen; oxo; deuterium, halo; cyano; C1-4 alkyl 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; C2-4 alkynyl which is optionally substituted with from 1-4 independently selected R11; C1-4 alkoxy which is optionally substituted with from 1-4 30 independently selected R11;–OH; -NO2; and -C(=O)OH; each occurrence of R7is independently selected from the group consisting of: –OH; - halo; –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(C1-4 alkyl); and cyano; or 112 PAT059979-WO-PCT two R7can be taken together to form a C3-4 cycloalkyl ring; 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 5 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; C2-6 alkynyl which is optionally substituted with from 1-6 independently selected R12; C1- 4 alkoxy which is optionally substituted with from 1-6 independently selected R12; C1-4 haloalkoxy which is optionally substituted with from 1-6 independently selected R12; -NR9R9;10–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; 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 15 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; C1-4 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(C1-4 alkyl); C3-6 cycloalkyl; and cyano; each occurrence of R14is independently selected from the group consisting of:20 deuterium; -OH; -halo; C1-2 alkyl; C1-2 alkoxy; C1-2 haloalkyl; and C1-2 haloalkoxy.In some embodiments, the compound has Formula (II-B): 25 Formula (II-B) 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. 30 In some embodiments, the compound has Formula (II-C): 113 PAT059979-WO-PCT wherein Y and Z are independently selected from the group consisting of CH, CR145and 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 (II-D): Formula (II-D) 10 wherein Y is selected from the group consisting of CH, CR14and N. In some embodiments, R2is Cl. In some embodiments, at least one of R3, R4and R5is H. In some embodiments, at least two 15 of 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 (II-E): 20 Formula (II-E) or a pharmaceutically acceptable salt thereof. 114 PAT059979-WO-PCT In some embodiments, 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 CH and N, and wherein a maximum of one of 5 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; Ring B is selected from the group consisting of: • heterocyclyl or heterocycloalkenyl including 5-9 ring atoms, wherein from 1-4 ring 10 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 • heteroaryl including 5-9 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each 15 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; and L is selected from the group consisting of a bond, *-O(C1-C4 alkylene)-, and *-C1-C4 20 alkylene-, 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: • , wherein * is the point of attachment to L, wherein X1and25X2are each selected from the group consisting of CH and N and wherein a maximum of one of X1and X2may be N; or 115 PAT059979-WO-PCT • , 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: • heterocyclyl or heterocycloalkenyl including 5-9 ring atoms, wherein from 1-3 5 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 • heteroaryl including 5-6 ring atoms, wherein from 1-2 ring atoms are 10 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 L is selected from the group consisting of a bond, *-O(C1-C4 alkylene)-, and *-C1-C415alkylene-, 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: • , 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 In some embodiments, Ring A is selected from the group consisting of: 116 PAT059979-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 5 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 one of X1, X2and X3may be N. In some embodiments, Ring , wherein * is the point of attachment to L, 10 X1and X2are each selected from the group consisting of CH and N, and wherein a maximum of one of X1and X2may be N. 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 15In some embodiments, Ring . 117 PAT059979-WO-PCT 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. , wherein N is the point of attachment to L. 5 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-C410alkylene)-, 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, L is selected from the group consisting of a bond, *-methylene and *- 15 O-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: 20 • 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 118 PAT059979-WO-PCT or heterocycloalkenyl are optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R8; • 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 5 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. In some embodiments, Ring B is selected from the group consisting of: 10 • 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;15• 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. 20 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) 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 group25consisting of oxo and R8. In some embodiments, 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 30 heterocycloalkenyl are optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R8. 119 PAT059979-WO-PCT 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 5 independently selected from oxo and R8. In 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.10In some embodiments, Ring B contains 5-9 ring atoms. In some embodiments, Ring B contains 5-6 ring atoms. In some embodiments, Ring B contains from 1-3 heteroatoms. 15 In some embodiments, Ring B contains from 1-2 heteroatoms. In some embodiments, one of the carbon atoms of Ring B is substituted with oxo. 20 In some embodiments, R1is selected from the group consisting of: C1-6 alkyl optionally substituted with from 1-3 independently selected R13; and -C0-6alkyl(C3-6 cycloalkyl) optionally substituted with from 1-3 independently selected R13. In some embodiments, R1is selected from the group consisting of: C1-6 alkyl; and -C0-6alkyl(C3- 25 6 cycloalkyl). In some embodiments, R1is C1-6 alkyl optionally substituted with from 1-3 independently selected R13. 30 In some embodiments, R1is C1-6 alkyl. In some embodiments, R1is methyl or ethyl optionally substituted with from 1-3 independently selected R13. 120 PAT059979-WO-PCT In some embodiments, R13is selected from the group consisting of -C1-4 alkoxy; and halo. In some embodiments, R13is selected from the group consisting of -methoxy; ethoxy and F. 5 10 , wherein one or more of the carbon atoms is optionally substituted with from 1-4 R8substituents. 121 PAT059979-WO-PCT5 , 122 PAT059979-WO-PCT , , , , wherein one or more of the carbon atoms is optionally substituted with from 1-4 R8substituents. In some embodiments, R8is C1-5 alkyl which is optionally substituted with from 1-6 5 independently selected R12. In some embodiments, R8is C1-3 alkyl 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: , , , 123 PAT059979-WO-PCT 5 10 124 PAT059979-WO-PCT Particular compounds of Formula (II) In certain embodiments, the compound is selected from the group consisting of the compounds in Table 2 or a pharmaceutically acceptable salt thereof. 5 Table 2 125 PAT059979-WO-PCT 126 PAT059979-WO-PCT 127 PAT059979-WO-PCT In preferred embodiments, the compound is a compound of Formula (II-F): 5 Formula (II-F) 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 X210are 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 the group consisting of CH and N, and wherein Z is N; Ring B is selected from the group consisting of: 128 PAT059979-WO-PCT • 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 5 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 heteroaryl is optionally substituted with from 1-4 substituents 10 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 of attachment of L to Ring A, wherein L is a bond or *-C1-C4 alkylene- when Z is N. 15 The VAV1 degrader may be of Formula (III) or a pharmaceutically acceptable salt thereof, i.e. a VAV1 degrader of Formula (III-A), (III-B), (III-C), (III-D), (III-E), (III-F) or (III-G), or 20 a pharmaceutically acceptable salt thereof. The substituents listed in respect of Formula (III) apply to Formula (III) only. This disclosure features compounds of Formula (III-A): 25 Formula (III-A) or a pharmaceutically acceptable salt thereof, wherein: 30 Ring A is selected from the group consisting of: 129 PAT059979-WO-PCT , wherein Z is the point of attachment to L, Y and Z are independently selected from the group consisting of CH, CR14and N, and wherein m is 0 or 1; or , 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 at least one of Y and Z must be N; or , optionally substituted with from 1 to 4 independently selected R6substituents, wherein p and q are independently 1, 2 or 3, and wherein n and r are independently 0 or 1; or 10 , optionally substituted with from 1 to 4 independently selected R6substituents, wherein s, t, u and v are independently 1 or 2; L is selected from the group consisting of: • a bond; or15• *-O(C1-C4alkylene)-, *-C1-C4alkylene-, *-C(=O)(O)-, *-C1-C4cycloalkylene, *- *-NR9(C0-C4 alkylene)-, *-NR9(C=O)(C0-C4 alkylene)-, -NR9(C=O)(C0-C4 alkylene)-*, -(C1-C4 alkylene)-C(=O)-*, or *-(C1-C4 alkylene)-C(=O)-, wherein 130 PAT059979-WO-PCT the alkylene is optionally substituted with 1-2 R7and wherein * indicates the point of attachment of L to Ring A; Ring B is selected from the group consisting of: 5 • cycloalkyl including 5-6 ring atoms, wherein the cycloalkyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R8; • heterocyclyl or heterocycloalkenyl including 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting 10 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; • phenyl, wherein the phenyl is optionally substituted with from 1-4 R8substituents; • heteroaryl including 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, 15 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; and 20 each R1is independently selected from the group consisting of:, deuterium, halo, C1-6 alkyl optionally substituted with from 1-4 independently selected R13; -C(O)(C1-4 alkyl) optionally substituted with from 1-4 independently selected R13; -C(O)O(C1-4 alkyl) optionally substituted with from 1-4 independently selected R13; -S(O)1-2(C1-4 alkyl) optionally substituted with from 1-4 independently selected R13; -OH; C1-4 alkoxy optionally substituted with from25 1-4 independently selected R13; -C0-6alkyl(C3-6 cycloalkyl) optionally substituted with from 1- 4 independently selected R13; and -C0-6alkyl(C3-6 heterocyclyl) optionally substituted with from 1-4 independently selected R13; R2is selected from the group consisting of hydrogen, deuterium, CH3, CHF2, CF3, 30 OMe, F, Cl and Br; each of R3, R4and R5is independently selected from the group consisting of hydrogen, deuterium, halo, cyano, C1-4 alkyl which is optionally substituted with from 1-4 independently selected R10, C3-4 cycloalkyl which is optionally substituted with from 1-4 131 PAT059979-WO-PCT independently selected R10, C2-4 alkenyl which is optionally substituted with from 1-4 independently selected R10, C2-4 alkynyl which is optionally substituted with from 1-4 independently selected R10, C1-4 alkoxy which is optionally substituted with from 1-4 independently selected R10, -NR9R9, –OH, -NO2, and -C(=O)OH; 5 each of R6, 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; C3-4 cycloalkyl which is optionally substituted with from 1-4 independently selected R11; C2-4 alkenyl which is optionally substituted with from 1-410independently selected R11; C2-4 alkynyl which is optionally substituted with from 1-4 independently selected R11; C1-4 alkoxy which is optionally substituted with from 1-4 independently selected R11; –OH; -NO2; and -C(=O)OH; each R8is independently selected from the group consisting of: deuterium; halo; cyano; 15 C1-6 alkyl which is optionally substituted with from 1-4 independently selected R12; C1-6 haloalkyl which is optionally substituted with from 1-4 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 1-4 independently selected R12; C2-6 alkynyl which is optionally substituted with from 1-4 independently selected R12; C1-4 alkoxy which is 20 optionally substituted with from 1-4 independently selected R12; C1-4 haloalkoxy which is optionally substituted with from 1-4 independently selected R12; -NR9R9; –OH; -NO2; and - C(=O)OH; each R9is independently selected from the group consisting of: hydrogen; deuterium; 25 C1-4 alkoxy; and C1-4 alkyl; each of R7, R10, R11, R12, and R13is independently selected from the group consisting of: deuterium, –OH; -halo; –NR9R9; C1-4 alkoxy; C1-4 haloalkoxy; -C(=O)O(C1-4 alkyl); - C(=O)(C1-4 alkyl); -C(=O)OH; -S(O)1-2(C1-4 alkyl); and cyano; 30 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; and R15is selected from the group consisting of hydrogen, deuterium, fluorine, and methyl. 132 PAT059979-WO-PCT In some embodiments, the compound has Formula (III-B): 5 Formula (III-B) wherein at least one of Y and Z is N. In some embodiments, the compound has Formula (III-C): 10Formula (III-C) wherein at least one of Y and Z is N. In some embodiments, Y and Z are both N or Y is CH or CR14 and Z is N.15In some embodiments, Y and Z are both N. In some embodiments, Y is CH or CR14and Z is N. In some embodiments, R6A, R6B, R6Cand R6Dare each hydrogen, deuterium or oxo. 20 In some embodiments, R6A, R6B, R6Cand R6Dare all hydrogen. 133 PAT059979-WO-PCT In some embodiments, Ring A is selected from: , wherein * denotes the point of attachment to L. In some embodiments, Ring , optionally substituted with from 1 to 4 5 independently selected R6substituents. In some embodiments, Ring A is selected from: , , , wherein * denotes the point of attachment to L. 10 In some embodiments, Ring independently selected R6substituents. In some embodiments, Ring . 134 PAT059979-WO-PCT In some embodiments, Ring A is , wherein Z is the point of attachment to L, Y and Z are independently selected from the group consisting of CH, CR14and N, and wherein at least one of Y and Z must be N. In some embodiments, Ring . 5 In some embodiments, Ring A is selected from the group consisting of: , wherein one of the carbon atoms is optionally substituted with an oxo substituent; or , wherein one of the carbon atoms is optionally substituted with an oxo10substituent ; or , wherein one of the carbon atoms is optionally substituted with an oxo substituent; or , wherein one of the carbon atoms is optionally substituted with an oxo substituent. 15 In some embodiments, Ring A is substituted with an oxo substituent. 135 PAT059979-WO-PCT In some embodiments, Ring A is selected from the group consisting of: , . 5 In some embodiments, R2is Cl. In some embodiments, at least one of R3, R4and R5is H. In some embodiments, at least two of R3, R4and R5is H. 10 In some embodiments, all of R3, R4and R5are H. In some embodiments, the compound has Formula (III-D): 15Formula (III-D) or a pharmaceutically acceptable salt thereof. In some embodiments, Ring A is selected from the group consisting of: • , wherein Z is the point of attachment to L, Y and Z are 20 independently selected from the group consisting of CH and N, wherein at least 136 PAT059979-WO-PCT one of Y and Z is N and wherein one of the carbon atoms is optionally substituted with an oxo substituent; or • , wherein Z is the point of attachment to L, Y and Z are independently selected from the group consisting of CH and N, wherein at 5 least one of Y and Z must be N, and wherein one of the carbon atoms is optionally substituted with an oxo substituent ; or • ,wherein p and q are independently 1, 2 or 3, wherein n and r are independently 0 or 1 and wherein one of the carbon atoms is optionally substituted with an oxo substituent; or 10 • , wherein s, t, u and v are independently 1 or 2 and wherein one of the carbon atoms is optionally substituted with an oxo substituent. In some embodiments, Ring A is selected from the group consisting of: • , wherein Z is the point of attachment to L, Y and Z are 15 independently selected from the group consisting of CH and N, wherein at least one of Y and Z is N and wherein one of the carbon atoms is optionally substituted with an oxo substituent; or • , wherein Z is the point of attachment to L, Y and Z are independently selected from the group consisting of CH and N, wherein at 137 PAT059979-WO-PCT least one of Y and Z must be N, and wherein one of the carbon atoms is optionally substituted with an oxo substituent; or • , wherein p and q are independently 1, 2 or 3, wherein n and r are independently 0 or 1 and wherein one of the carbon atoms is optionally 5 substituted with an oxo substituent; or , wherein s, t, u and v are independently 1 or 2 and wherein one of the carbon atoms is optionally substituted with an oxo substituent; Ring B is selected from the group consisting of: • cycloalkyl including 5-6 ring atoms; 10 • heterocyclyl or heterocycloalkenyl including 5-9 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, 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• phenyl, wherein the phenyl is optionally substituted with one R8substituent; • heteroaryl 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 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 20 independently selected from oxo and R8; and L is selected from the group consisting of a bond, *-C1-C4 alkylene-, *-C(=O)(O)-, and - (C1-C4 alkylene)-C(=O)-*, wherein the alkylene is optionally substituted with 1-2 R7and wherein * indicates the point of attachment of L to Ring A. 138 PAT059979-WO-PCT In some embodiments, Ring A is selected from the group consisting of: , , Ring B is selected from the group consisting of: 5 • heterocyclyl or heterocycloalkenyl including 5-9 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 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 5-9 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 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 1-2 substituents independently selected from oxo and R8; and15L is selected from the group consisting of a bond, *-C1-C4 alkylene-, *-C(=O)(O)-, and -(C1-C4 alkylene)-C(=O)-*, wherein * indicates the point of attachment of L to Ring A. In some embodiments, L is selected from the group consisting of a bond, *-C1-C4 alkylene-, 20 *-C(=O)(O)-, and -(C1-C4 alkylene)-C(=O)-*, wherein the alkylene is optionally substituted with 1-2 R7and wherein * indicates the point of attachment of L to Ring A. In some embodiments, L is selected from the group consisting of a bond, *-C1-C4 alkylene-, *-C(=O)(O)-, and -(C1-C4 alkylene)-C(=O)-*, wherein * indicates the point of attachment of25L to Ring A. 139 PAT059979-WO-PCT In some embodiments, L is a bond. In some embodiments, Ring B is selected from the group consisting of: • cycloalkyl including 5-6 ring atoms; 5 • heterocyclyl or heterocycloalkenyl including 5-9 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, 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• phenyl, wherein the phenyl is optionally substituted with one R8substituent; • heteroaryl 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 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 15 independently selected from oxo and R8. In some embodiments, Ring B is selected from the group consisting of: • heterocyclyl or heterocycloalkenyl including 5-9 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of 20 N, N(H), N(R1) and O, 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; • heteroaryl 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,25wherein 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 1-2 substituents independently selected from oxo and R8. In some embodiments, one of the carbon atoms of the heterocyclyl, heterocycloalkenyl or 30 heteroaryl in Ring B is substituted with an oxo substituent. In some embodiments, R8is selected from the group consisting of: halo; C1-4alkoxy which is optionally substituted with from 1-6 independently selected R12; C1-6 alkyl which is optionally substituted with from 1-6 independently selected R12. 140 PAT059979-WO-PCT In some embodiments, R8is selected from the group consisting of: halo; C1-4 alkoxy which is optionally substituted with from 1-3 independently selected R12; and C1-6 alkyl which is optionally substituted with from 1-3 independently selected R12. 5 In some embodiments, R8is selected from the group consisting of: halo; C1-2 alkoxy which is optionally substituted with from 1-3 independently selected R12; and C1-4 alkyl which is optionally substituted with from 1-3 independently selected R12. 10 In some embodiments, R8is selected from the group consisting of: halo; methoxy, ethoxy, methyl, ethyl, propyl and butyl. In some embodiments, R12is selected from the group consisting of: C1-4 alkoxy; and halo.15 In some embodiments, R12 is selected from the group consisting of: methoxy; and F.In some embodiments, R1is selected from the group consisting of: C1-6 alkyl optionally substituted with from 1-4 independently selected R13; -C0-6alkyl(C3-6 cycloalkyl) optionally substituted with from 1-4 independently selected R13; and -C0-6alkyl(C3-6 heterocyclyl)20optionally substituted with from 1-4 independently selected R13. In some embodiments, R1is C1-6 alkyl optionally substituted with from 1-4 independently selected R13. 25 In some embodiments, R13is selected from the group consisting of: C1-4 alkoxy; halo; and C1- 4 haloalkoxy. In some embodiments, R13is selected from the group consisting of: methoxy; ethoxy; fluoro; and difluoromethoxy. 30 141 PAT059979-WO-PCT In some embodiments, Ring B is selected from the group consisting of: , 5 optionally substituted with from 1-4 R8substituents. In some embodiments, Ring B is selected from the group consisting of: , 10 , , 142 PAT059979-WO-PCT 5 the carbon atoms is optionally substituted with from 1-4 R8substituents. In some embodiments, Ring B is selected from the group consisting of:,10 , 143 PAT059979-WO-PCT 5 , 144 PAT059979-WO-PCT 5 . In some embodiments, Ring wherein * indicates the point of attachment of L to Ring A. 10 In some embodiments, Ring alkylene)-C(=O)-*, wherein * indicates the point of attachment of L to Ring A. In some embodiments, Ring B is phenyl, wherein the phenyl is optionally substituted with from 1-4 R8substituents and R8is selected from the group consisting of: halo, -OH, C1-4 alkoxy,15-NH2, -NHR9, -NR9R9. 145 PAT059979-WO-PCT In some embodiments, Ring B is phenyl substituted with 1-2 halo substituents. In some embodiments, R15is H. 5 In some embodiments, the compound is of Formula (III-E): or a pharmaceutically acceptable salt thereof. 10 In some embodiments, the compound is of Formula (III-F): Formula (III-F) or a pharmaceutically acceptable salt thereof. 15 In some embodiments, the compound exists in a racemic mixture. Particular compounds of Formula (III) In certain embodiments, the compound is selected from the group consisting of 20 the compounds in Table 3 or a pharmaceutically acceptable salt thereof. 146 PAT059979-WO-PCT 147 PAT059979-WO-PCT 148 PAT059979-WO-PCT 149 PAT059979-WO-PCT 150 PAT059979-WO-PCT In preferred embodiments, the compound is of Formula (III-G): 5 Formula (III-G) or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from the group consisting of: 151 PAT059979-WO-PCT • , wherein Z is the point of attachment to L, Y and Z are independently selected from the group consisting of CH and N, wherein at least one of Y and Z is N and wherein one of the carbon atoms is optionally substituted with an oxo substituent; or 5 • , wherein Z is the point of attachment to L, Y and Z are independently selected from the group consisting of CH and N, wherein at least one of Y and Z must be N, and wherein one of the carbon atoms is optionally substituted with an oxo substituent; or • , wherein p and q are independently 1, 2 or 3, wherein n and r 10 are independently 0 or 1 and wherein one of the carbon atoms is optionally substituted with an oxo substituent; or • ,wherein s, t, u and v are independently 1 or 2 and wherein one of the carbon atoms is optionally substituted with an oxo substituent; Ring B is selected from the group consisting of:15• cycloalkyl including 5-6 ring atoms; • heterocyclyl or heterocycloalkenyl including 5-9 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, and wherein one or more of the carbon atoms of the heterocyclyl or heterocycloalkenyl are optionally substituted with from 1-4 20 substituents independently selected from the group consisting of oxo and R8; • phenyl, wherein the phenyl is optionally substituted with one R8substituent; 152 PAT059979-WO-PCT • heteroaryl 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 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 5 independently selected from oxo and R8; and L is selected from the group consisting of a bond, *-C1-C4 alkylene-, *-C(=O)(O)-, and - (C1-C4 alkylene)-C(=O)-*, wherein the alkylene is optionally substituted with 1-2 R7and wherein * indicates the point of attachment of L to Ring A. 10 Particular compounds of Formulas (I), (II), and (III) In certain embodiments, the compound is selected from the group consisting of the compounds in Table 4 or a pharmaceutically acceptable salt thereof. 15 20 25 30 153 PAT059979-WO-PCT Table 4 In some embodiments, the compound is selected from the group consisting of the compounds in any of Tables 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof. 5 Preferably, in the invention, the VAV1 degrader is of formula (I-J), (II-F), or (III-G), or a pharmaceutically acceptable salt thereof. EXAMPLES10Example 1: General synthetic methods General synthetic schemes 154 PAT059979-WO-PCT Throughout this section, starting materials, intermediates, and final compounds are defined and labelled according to the general scheme which refers to them. For example, intermediate BB of general scheme 8 is different to intermediate BB of general scheme 17. 5 General Schemes for synthesising compounds according to Formula (I): General Scheme 1 A general synthetic strategy that may be used to prepare compounds of Formula I is depicted in General Scheme 1. An aryl halide AA where Z1 is any suitable halogen (e.g. Br or I) may 10 be coupled with an aryl boronate AB using any suitable metal catalyzed coupling conditions. The specific groups X, Y, L1, R1, R2, R3, R4, R5, R6and R7are selected on the basis of the desired groups in the compound of Formula I. The desired compound can be prepared using a Suzuki coupling reaction with palladium catalyst complex such as Pd(dtbpf)Cl2 (DBTF = 1,1′-Bis(di-tert-butylphosphino)ferrocene) or Pd(dppf)Cl2 (dppf = 1,1’- 15 Bis(diphenylphosphino)ferrocene) in the presence of a base such as potassium phosphate. A 155 PAT059979-WO-PCT suitable solvent such as DMF (dimethylformamide) or dioxane may be used, or a suitable solvent mixture such as dioxane and water may be used. Alternatively compounds of Formula I may be prepared from reaction of an aryl boronate of formula AC and an aryl halide of formula AD using Suzuki cross-coupling conditions. Z2 is 5 any halide (Br, I, Cl) or triflate group which can be used in a metal catalyzed coupling reaction of AD to boronate AC. The desired compound can be prepared using a Suzuki coupling reaction with a palladium catalyst complex such as APhos Pd G3, Brettphos Pd G3, Pd(dppf)Cl2 or Pd(dppf)Cl2•CH2Cl2 in the presence of a suitable base such as K3PO4. A suitable solvent such as DMF (dimethylformamide) or dioxane may be used, or a suitable solvent mixture such10as dioxane and water may be used. Aryl boronate AC may be prepared from aryl halides AA using Bis(pinacolato)diboron, catalyst such as [PdcinnamylCl]2 , and a ligand such as Xphos. A weak base such as sodium acetate, in solvent such as iPrOH may be used. The reaction may be performed at an elevated temperature, for example 60 degrees Celsius, 80 degrees Celsius or 100 degrees Celsius. 15 General Scheme 2 General Scheme 2 provides an exemplary synthetic procedure for the preparation of starting20material AA used in General Scheme 1. Compound AE, where Z1 is a suitable halogen atom 156 PAT059979-WO-PCT (e.g. Br or I) may be converted into a benzylic halide of formula AF using conditions for benzylic halogenation. For example, N-bromosuccinimide and benzoyl peroxide in a solvent such as carbon tetrachloride at elevated temperatures (e.g. 80 degrees Celsius or 90 degrees Celsius) affords AF. A benzyl nitrile intermediate such as AG may be prepared from benzyl 5 halide AF upon treatment with a cyanating reagent such as trimethylsilyl cyanide, in the presence of a desilylation reagent such as tert-butyl silyl fluoride or tetra-n-butylammonium fluoride (TBAF) and a solvent such as dichloromethane at a temperature such as 0-25 degrees Celsius. Micheal addition of a compound of formula AG with an acrylate such as compound AH may be performed using a base such as sodium methoxide in a solvent such as10tetrahydrofuran at room temperature. Rs1 is any suitable alkyl group which is labile to treatment with acid. For example, Rs1 may be tert-butyl at a temperature such as 0-25 degrees Celsius. Compound AI may be converted to intermediate AA upon treatment with a strong acid such as sulfuric acid, in a solvent such as acetic acid, at elevated temperatures (for example, 90 degrees Celsius). 15 General Scheme 3 provides an alternative exemplary synthetic procedure for the preparation of starting material AA used in General Scheme 1. Compound AJ, where Z2 is a suitable20halide leaving group (e.g. fluorine), may be subjected to a nucleophilic aromatic substitution 157 PAT059979-WO-PCT (Hurtley Arylation) with a reagent such as tert-Butyl cyano acetate AK. A solvent such as dimethylacetamide in the presence of a base such as potassium phosphate may be used to afford AL. Benzyl nitriles of formula AG may be prepared by hydrolysis and decarboxylation of AL upon treatment with an acid such as p-toluene sulfonic acid, in a solvent such as toluene at 120 5 degrees Celsius. Benzyl nitrile AG may be converted into AI by a Michael addition reaction to an acrylate reagent such as AH, where Rs1 is an alkyl group which forms an ester. The ester formed by Rs1 must be labile to hydrolysis upon treatment with acid. The Michael addition reaction may be performed by treatment with a base such as sodium methoxide in a solvent such as toluene at zero degrees Celsius. Compound AA may be prepared from AI by treatment10with an acid such as p-toluene sulfonic acid in a solvent such as toluene at elevated temperatures (for example, 110 degrees Celsius). 15 General Scheme 4 provides a specific exemplary synthetic strategy for the preparation of a compound of formula AN where aryl halide AM may be used as starting material AD in General Scheme 1. W1 is any suitable substituent which provides a compound of formula I. Compound AN may be prepared by coupling AC and AM under metal catalyzed conditions. For example, treatment with [1,1′-Bis(diphenylphosphino)ferrocen]dichlorpalladium(II) and a20base such as potassium phosphate in a solvent such as dioxane. The reaction may be performed at temperature such as 80 degrees Celsius. General Scheme 5 158 PAT059979-WO-PCT General Scheme 5 provides a specific exemplary synthetic strategy for the preparation of a compound of formula AN where aryl boronate AO may be used as starting material AD in General Scheme 1. W1 is any suitable substituent which provides a compound of formula I. 5 Compound AN may be prepared by coupling AA and AO under metal catalyzed conditions. For example, treatment with [1,1′-Bis(diphenylphosphino)ferrocen]dichlorpalladium(II) and base such as potassium phosphate in a solvent such as dioxane. The reaction may be performed at an elevated temperature such as 80 degrees Celsius. 10 General Scheme 6 General Scheme 6 provides a specific exemplary synthetic strategy for the preparation of aryl halides of formula AM (where Z4is any suitable halide such as chlorine, bromine or iodine) and aryl boronates AO. Compounds AM and AO may be used as starting material AD and AB 15 respectively in General Scheme 1. W1 is any suitable substituent which provides a compound of Formula I. A substituted pyridone of formula AQ may be coupled to a dihaloaryl compound AP using copper catalyzed conditions. One synthetic strategy involves treatment with copper iodide and base such as potassium phosphate in a solvent such as dimethyl acetamide. The reaction may be performed at 115 degrees Celsius for 20 hours. Alternative20 conditions involve copper iodide catalyst in the presence of a ligand. For example, N1,N2- 159 PAT059979-WO-PCT Bis(furan-2-ylmethyl)oxalamide (BFMO) or 4,7-dimethoxy-1,10-phenanthroline ligand. An aryl boronate of formula AO may be prepared from AM and a suitable borylating agent (such as Bis(pinacolato)diboron) using any metal catalyzed conditions for borylation. For example, cinnamyl palladium chloride dimer in the presence of 0.4 mol% Xphos ligand, or Pd(dppf)Cl2 5 may be used. The reaction may be performed in a suitable solvent such as isopropanol or dioxane, at 80 degrees Celsius. General Scheme 7 10General Scheme 7 provides exemplary synthetic strategies for the preparation of diverse aryl halides of formula AT, AV and AX, which may be used as starting materials AD in General Scheme 1. In some instances, X and Y may be carbon, or X, Y, or both may be nitrogen depending on the desired substituents of Formula I. Z5 and Z6are any suitable halogens. W2, W3 and W4 are any suitable substituents which provide a compound of formula I. T1 = C, O, 15 or N-alkyl. A synthetic approach to a lactam, carbamate or pyrimidinone compound of formula AT involves a copper catalyzed coupling of lactams or pyrimidinone AS with aryl halides AR. Copper iodide and a ligand such as N,N′-Dimethylethylenediamine (DMEDA). The reaction may be performed in the presence of a base such as potassium phosphate or potassium carbonate, and a solvent such as toluene, DMSO, dioxane, DMF or NMP. Elevated temperature20such as 90 degrees Celsius or 110 degrees Celsius may be required. In some examples (where 160 PAT059979-WO-PCT X and Y = N or X = N and Y = C and Z6 = Cl) an ether of formula AV may be prepared by treatment of halide AR with alcohols of formula AU under basic conditions. In some examples, pretreatment of AU with a base such as sodium hydride in a solvent such as THF followed by addition of AR at 0 degrees Celsius. In some examples (where X = N and Y = C and Z6 = Cl), 5 compounds of formula AX may be prepared from reaction of AW with AR using any suitable nucleophilic substitution conditions. A base such as cesium carbonate in a solvent such as dimethyl sulfoxide (DMSO) at 100 degrees Celsius may be applied. General Scheme 8 10 General Scheme 8 provides a representative synthetic strategy towards intermediates of formula BA from a benzyl halide of formula AY and pyridone AZ. Z7is a suitable halide such as bromine, chlorine or iodine. W5is any suitable substituent that results in a compound of Formula I. N-Alkylation of pyridones AZ may be performed using a base 15 such as potassium carbonate in the presence of phase transfer catalyst cetyl trimethyl ammonium bromide (CTAB) in a solvent such as water. The reaction may be performed at temperatures such as 50 degrees Celsius. A compound of formula BN may be similarly prepared from a compound of formula AS and AY. A compound of formula BC may be prepared from AY and an aryl boronate or boronic acid of formula BB. V1 may be hydrogen20or any suitable alkyl that forms a boronate BB. 161 PAT059979-WO-PCT General Scheme 9 General Scheme 9 provides a representative synthetic strategy towards intermediates of 5 formula BF which may be used as starting material AD in General Scheme 1. Boronic acid or a boronic ester of formula BD may undergo coupling with an amide or pyridone BE to afford BF. Some representative conditions for this reaction include copper acetate (Cu(OAc)2) in the presence of pyridine and 4 Å molecular sieves. The reaction may be performed in a solvent such as dichloromethane at ambient temperature (approx.25 degrees 10 Celsius). General Scheme 10 General Scheme 10 provides a general synthetic strategy towards intermediates of formula BJ15which may be used as a starting material AD in General Scheme 1. Z8 is any suitable halide. W8 and W9 are any suitable substituents which provide a compound of Formula I. A compound of formula BI may be prepared by reaction of BG and BH in the presence of a catalyst such as [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) in the presence of a base such as potassium carbonate in a solvent mixture of dioxane and water. The reaction 20 may be performed at a temperature of 100 degrees Celsius. A triflate of formula BJ may be 162 PAT059979-WO-PCT prepared by treatment of alcohol BI with Trifluoromethanesulfonic anhydride and pyridine in dichloromethane at zero degrees Celsius. General Scheme 11 5 General Scheme 11 provides a general synthetic strategy towards intermediates of formula BM which may be used as a starting material AD in General Scheme 1. Z9and Z10are any suitable halides. A1is any suitable atom or group suitable to provide a compound of Formula I, for example, oxygen, NH or N-methyl. W10is heteroaryl or any suitable substituents which10 provide a compound of Formula I. A compound of formula BM may be prepared by N- alkylation of BK with any aryl halide BL. The reaction may occur in the presence of base, such as Cesium carbonatite, in a polar solvent such as dimethylformamide at temperatures such as 80 degrees Celsius. Compound of formula BM may undergo cross coupling reactions with compounds of formula AD using a catalyst such as BrettPhos Pd3 complex in the15presence of a base such as potassium phosphate. The reaction may be performed in a solvent such as dioxane at 100 degrees Celsius. General Scheme 12 20General Scheme 12 provides a general synthetic approach to the preparation of compounds of formula BP which may be used as starting material AD in General Scheme 1. W10is any suitable Aryl or heteroaryl group which provides a compound of Formula I. An organometallic zinc reagent may be prepared by treatment of compound AY with a Zn-Cu metal in the presence 163 PAT059979-WO-PCT of a solvent such as toluene and dimethylacetamde mixture at elevated temperatures (e.g 80 degrees Celsius). Addition of an aryl or hetereoaryl halide such as BO and a palladium catalyst such as Pd(PPh3)4 in a solvent such as toluene, at room temperature may be used to generate compounds of formula BP. 5 General Schemes for synthesising compounds according to Formula (II): General Scheme 13 10 A general synthetic strategy that may be used to prepare compounds of Formula II as depicted above is depicted in General Scheme 13. An aryl halide AA, where Hal is any suitable halogen (e.g. Br or I), may be coupled with an aryl boronate AB using any suitable metal catalyzed coupling conditions. The specific groups X1, X2, X3, L, R2, R3, R4, R5, R6A, and Ring B are selected on the basis of the desired groups in the compound of Formula II. 15 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 mixture such as dioxane and water may be used. 164 PAT059979-WO-PCT 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. Aryl boronate AC may be prepared from 5 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. General Scheme 14 10 General Scheme 14 provides a synthetic procedure to prepare compounds of Formula II as depicted above. 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 15 reaction, such as amines. PG1is 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 temperature. Finally, the desired compounds of Formula II 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-3-20heptylphenyl)imidazol-2-ylidene) in the presence of a base such as caesium carbonate. A solvent such as dioxane may be used. General Scheme 15 165 PAT059979-WO-PCT General Scheme 15 provides an alternative synthetic procedure to prepare the compounds of Formula II depicted above. Aryl halide AA, where Hal is any halogen (e.g. Br or I) suitable 5 for metal catalyzed coupling conditions, may be coupled with compound AI, where W1is 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-(trifluoromethyl)-2-pyridinyl; dtbbpy = 4,4'-Di-tert-butyl-102,2'-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. Finally, the desired compounds of Formula II can be prepared from intermediates AK and AL using a 15 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 conditions. 20 General Scheme 16 166 PAT059979-WO-PCT General Scheme 16 provides an exemplary synthetic procedure for the preparation of starting material AA used in General Scheme 13. Aniline AL, where Hal is a suitable halogen atom (e.g. Br or I) may be converted into the (phenylamino)propionic acid of 5 formula AM using Michael 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). 10 General Scheme 17 General Scheme 17 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 13. A compound of formula BC may be prepared from BA via a metal-catalyzed coupling 15 reaction with intermediate BB in the presence of a copper(II) catalyst such as copper acetate and a base such as triethylamine, under oxygen atmosphere. A solvent such as dichloromethane may be used. Hal is any halogen (e.g. Br or I) and W1is an organoboronic acid or ester group suitable for metal catalyzed coupling conditions. X1, X2And X3are CR6D, or N, and R6A, R6Dand R8are any suitable substituents which provide a compound of 20 formula II. Intermediate BD can be prepared by treatment of intermediate BC with is(pinacolato)diboron in the presence of a 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. 167 PAT059979-WO-PCT General Scheme 18 General Scheme 18 provides an exemplary synthetic strategy for the preparation of aryl 5 boronates of formula BG, which may be used as starting materials AB in General Scheme 13. A 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. 10 Intermediate BG can be prepared by treatment of intermediate BC with bis(pinacolato)diboron in the presence of a 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.100 degrees Celsius) in a solvent such as dioxane. 15 General Scheme 19 General Scheme 19 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 13. 168 PAT059979-WO-PCT 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 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 5 reaction with CB in the presence of a palladium catalyst complex such as t-BuXPhos Pd G3 and a base 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 H2 atmosphere, in a solvent such as THF. Intermediate CE can be prepared by treatment of intermediate CD with a base such as10potassium tert-butoxide at elevated temperature (e.g.60 degrees Celsius) in a solvent such as THF. Intermediate CF can be 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 15 2M in dioxane, to afford phenol intermediate CG, then by triflation with any triflating reagent, for example trifluoromethanesulfonyl chloride, in presence of a base such as triethylamine. General Scheme 20 20 General Scheme 20 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 13. Hal is any suitable halogen (e.g. Br or I) which may be coupled with an aryl boronate AC in General Scheme 13. X1, X2And X3are CR6D, or N. R6Aand R6Dare any suitable 25 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. PG4is any suitable protecting group that is labile to 169 PAT059979-WO-PCT treatment with acid. A compound of formula DB may be prepared from DA upon treatment with a reagent such as di-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 such as ruthenium (IV) oxide hydrate in the presence of sodium 5 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 potassium phosphate. A solvent such as NMP may be used.10General Scheme 21 General Scheme 21 provides exemplary synthetic strategies for the preparation of aryl halides of formula EB, which may be used as starting materials AD in General Scheme 13. Hal is any suitable halogen (e.g. Br or I) which may be coupled with an aryl boronate AC in 15 General Scheme 13. X1, X2And X3are CR6D, or N. R6Aand R6Dare any suitable substituents which provides a compound of formula II. Q1and Q2are carbon or oxygen atoms, and n = 0 or 1. W2and W3are H, alkyl, or alkoxyalkyl substituents, which may or may not be cyclic. 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 20 such as potassium carbonate. A solvent such as dioxane may be used. General Scheme 22 General Scheme 22 provides exemplary synthetic strategies for the preparation of25compounds of formula FB, which may be used as starting materials EA in General Scheme 170 PAT059979-WO-PCT 21. 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 be accessed from compounds FA by treatment with a strong base, such as potassium tert-butoxide, in any aprotic solvent, such as THF. 5 General Schemes for synthesising compounds according to Formula (III): General Scheme 23 10 A general synthetic strategy that may be used to prepare compounds of Formula III as depicted above is depicted in General Scheme 23. An aryl halide AA-3, where Hal1is any suitable halogen (e.g. Br or I), may be coupled with compound CA using any suitable metal catalyzed coupling conditions to afford intermediate CC-1. For example, a catalyst system such as Pd PEPPSI-IHept-Cl may be used in a polar aprotic solvent such as dioxane, in the 15 presence of a base such as caesium carbonate, at elevated temperature (e.g.100 degrees Celsius). AA-3 may be coupled with compound CB under photochemical coupling conditions to afford intermediate CC-2. A photosensitizer and catalyst pair such as [Ir{dF(CF3)ppy}2(dtbpy)]PF6 and NiCl2*dtbbpy may be used, under irradiation with a blue light LED (suitable wavelengths include, for example, 455 nm) in the presence of 20 bis(trimethylsilyl)silyl-trimethylsilane and an inorganic base (for example, sodium 171 PAT059979-WO-PCT carbonate). A solvent such as 1,2-dimethoxyethane may be used. Q1is any heteroatom or group suitable for metal catalyzed coupling conditions. Z is a heteroatom, for example N, and Y is C or N. PG1is any suitable protecting group that is labile to treatment with acid. Removal of PG1in the presence of a strong acid such as HCl 4M in dioxane affords 5 intermediates AA-1 or AA-2. Finally, the desired compounds of Formula III can be prepared from intermediates AA-1 or AA-2 together with intermediate BA using various methods, for example metal-catalyzed coupling or nucleophilic substitution. Hal2is any halogen (e.g. Cl, Br or I) suitable for the aforementioned reaction types. L is a bond, a C atom, a CH2-carbonyl group, or an ester. The10specific groups R15, R2, R3, R4, R5, R6A-D, and B are selected on the basis of the desired groups in the compound of Formula III. General Scheme 24 15General Scheme 24 provides an alternative synthetic procedure to prepare compounds of Formula III. An intermediate AA-3 (where LG1is any suitable halogen (e.g. Br or I)) or AA-4 (where LG1is any organoboronic acid or ester group) may be coupled with compound BB or CD using any suitable metal catalyzed coupling conditions, to afford compounds of formula III. Catalysts such as Pd-PEPPSI-IHept-Cl or copper(II)acetate may be used, in the 20 presence of a base (for example, caesium acetate or triethylamine). Z is a heteroatom, for example N. Q2is any heteroatom or group suitable for metal catalyzed coupling conditions. L 172 PAT059979-WO-PCT is a bond, a C atom, a CH2-carbonyl group, or an ester. The specific groups R15, R2, R3, R4, R5, R6A-D, and B are selected on the basis of the desired groups in the compound of Formula III. 5 General Scheme 25 General Scheme 25 provides an exemplary synthetic procedure for the preparation of starting materials AA-3 and AA-4 used in General Scheme 23 and General Scheme 24. Compound DA, where Hal is a suitable halogen atom (e.g. Br or I), may be converted into a10 benzylic halide of formula DB using conditions for benzylic halogenation. For example, N- bromosuccinimide and benzoyl peroxide in a solvent such as carbon tetrachloride at elevated temperatures (e.g.90 degrees Celsius) affords DB. A benzyl nitrile intermediate such as DC may be prepared from benzyl halide DB upon treatment with a cyanating reagent such as trimethylsilyl cyanide, in the presence of a desilylation reagent such as tert-butyl silyl 15 fluoride and a solvent such as dichloromethane. Michael addition of a compound of formula DC with an acrylate such as compound DD may be performed using a base such as sodium methoxide in a solvent such as tetrahydrofuran at room temperature. Alk is any suitable alkyl group which is labile to treatment with acid. For example, Alk may be tert-butyl. Compound DE may be converted to intermediate AA-3 upon treatment with a strong acid 20 such as sulfuric acid, in a solvent such as acetic acid, at elevated temperatures (for example, 90 degrees Celsius). Aryl boronate AA-4 may be prepared from aryl halide AA-3 using Bis(pinacolato)diboron and a catalyst such as Pd(dppf)Cl2. A weak base such as sodium acetate may be used in a solvent such as dioxane. The reaction may be performed at an elevated temperatures (for example, 80 degrees Celsius). 25 173 PAT059979-WO-PCT General Scheme 26 General Scheme 26 provides an exemplary synthetic strategy for the preparation of halo- 5 pyridones, pyridazinones, pyrimidinones, and pyrazinones of formula EC, which may be used as starting materials BA in General Scheme 23. General Scheme 26 also provides an exemplary synthetic strategy for the preparation of piperazine-containing compounds of formula EF, which may be used as starting materials BB in General Scheme 24. A compound of formula EA may be alkylated with compound EB to afford intermediate EC 10 under various conditions, including nucleophilic substitution or amide coupling conditions. Q3is a leaving group suitable for nucleophilic substitution reactions (Cl, Br, I or OTf) or a primary amine suitable for coupling reactions. One synthetic strategy involves treatment with a base such as potassium carbonate in a solvent such as dimethylformamide. Alternative conditions involve a coupling reagent and a base, for example, HATU and DBU.15A piperazine-containing intermediate such as EE may be prepared from halide EC upon treatment with intermediate ED under metal-catalyzed coupling conditions. A catalyst such as RuPhos Pd G3 may be used in the presence of an inorganic base such as caesium carbonate. The reaction may be carried out at elevated temperature (e.g.85 degrees Celsius) in a solvent such as THF. PG1is any suitable protecting group that is labile to treatment with 20 acid. Removal of PG1in the presence of a strong acid such as HCl 4M in dioxane affords 174 PAT059979-WO-PCT intermediate EF. The specific groups R6A-D, R8and R1are selected on the basis of the desired groups in the compound of Formula III. General Scheme 27 5 General Scheme 27 provides an exemplary synthetic strategy for the preparation of heterobicyclic compounds of formula FB, which may be used as starting materials BA in General Scheme 23. General Scheme 27 also provides an exemplary synthetic strategy for10the preparation of piperazine-heterobicyclic compounds of formula FD, which may be used as starting materials BB in General Scheme 24. A compound of formula FB may be prepared by halogenation of intermediate FA in the presence of dihaloethane and n- butyllithium, at low temperature (e.g. -78 degrees Celsius) and in a solvent such as THF. W may be C, O, N or N(R1). Hal2is any suitable halogen. For example, Hal2may be I. A 15 piperazine-containing intermediate such as FC may be prepared from halide FB upon treatment with intermediate ED under metal-catalyzed coupling conditions. A catalyst such as Pd PEPPSI-IHept-Cl may be used in the presence of an inorganic base such as caesium carbonate. The reaction may be carried out at elevated temperature (e.g.100 degrees Celsius) in a solvent such as dioxane. PG1is any suitable protecting group that is labile to treatment20with acid. Removal of PG1in the presence of a strong acid such as HCl 4M in dioxane 175 PAT059979-WO-PCT affords intermediate FD. The specific groups R6A-D, R8and R1are selected on the basis of the desired groups in the compound of Formula III. General Scheme 28 5 General Scheme 28 provides a specific exemplary synthetic strategy for the preparation of piperazines of formula GC (where X is C or N), which may be used as starting materials BB in General Scheme 24. An aldehyde of formula GA may undergo a reductive amination 10 reaction reaction with intermediate ED in the presence of a reducing agent (for example, sodium triacetoxyborohydride) in a solvent mixture such as dichloromethane / methanol 1 / 1 to afford compounds of formula GB. PG1is any suitable protecting group that is labile to treatment with acid. Removal of PG1in the presence of a strong acid such as HCl 4M in dioxane affords intermediate GC. The specific groups R6A-D, R8and R1are selected on the 15 basis of the desired groups in the compound of Formula III. General Scheme 29 20 General Scheme 29 provides a specific exemplary synthetic strategy for the preparation of piperazines of formula HC, which may be used as starting materials BB in General Scheme 24. A benzyl halide of formula HA, where Hal2is any suitable halogen (e.g. Cl, Br or I), may undergo a nucleophilic substitution reaction with intermediate ED in the presence of a base 176 PAT059979-WO-PCT (for example, potassium carbonate) in a solvent such as acetonitrile to afford compounds of formula HB. PG1is any suitable protecting group that is labile to treatment with acid. Removal of PG1in the presence of a strong acid such as HCl 4M in dioxane affords intermediate HC. The specific groups R6A-Dand R8are selected on the basis of the desired 5 groups in the compound of Formula III. General Scheme 30 10General Scheme 30 provides a specific exemplary synthetic strategy for the preparation of intermediates of formula IE, which may be used as starting materials CD in General Scheme 24. A compound of formula EC, where Hal2is any suitable halogen (e.g. Cl, Br or I), may undergo a metal-catalyzed coupling reaction with intermediate IA to afford intermediates of formula IB. A palladium catalyst complex such as CPhos Pd G3 may be used, in the presence 15 of an inorganic base (for example, caesium carbonate) and in a solvent such as dioxane, at elevated temperatures (e.g.80 degrees Celsius). Alk is any suitable alkyl group which is labile to treatment with acid. For example, Alk may be tert-butyl. Intermediate IB may be converted to intermediate IC upon treatment with a strong acid such as trifluoroacetic acid, in a solvent such as dichloromethane. Finally, intermediate IE may be obtained from20intermediate IC via coupling with N-hydroxy compound ID in the presence of a peptide coupling reagent. For example, EDCI and DMAP may be used, in a solvent such as THF. 177 PAT059979-WO-PCT Example 2: Exemplary synthetic methods Example 2A: Synthesis of Compound 446 5 Part 1: Synthesis of Intermediate 4 Step 1: Synthesis of Intermediate 2 - tert-butyl (S)-(3-((4- bromophenyl)amino)butyl)carbamate 10 A mixture of 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, 5.00 eq), triethylamine (1.21 g, 12.0 mmol, 3.00 eq) and 4A molecular sieve (70.0 mg, 3.98 mmol, 1.00 eq) in dichloromethane (20 mL), and then the mixture was stirred at 25 °C 15 for 12 h under oxygen atmosphere. The mixture was filtered, and concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0-50% Ethyl acetate / Petroleum ether gradient @ 60 mL / min) to give tert-butyl (S)-(3-((4-bromophenyl)amino)butyl)carbamate (300 mg, 0.874 mmol, 22% yield) as yellow oil. 178 PAT059979-WO-PCT 1H NMR (400 MHz, DMSO-d6) δ = 7.15 (d, J = 8.8 Hz, 2H), 6.82 (s, 1H), 6.49 (d, J = 8.8 Hz, 2H), 5.57 (d, J = 8.4 Hz, 1H), 3.43 - 3.35 (m, 1H), 2.97 (q, J = 6.8 Hz, 2H), 1.64 - 1.59 (m, 1H), 1.52 - 1.43 (m, 1H), 1.37 (s, 9H), 1.06 (d, J = 6.4 Hz, 3H) 5 Step 2: Synthesis of Intermediate 3 - (S)-1-(4-bromophenyl)-6-methyltetrahydropyrimidin- 2(1H)-one 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 10 mmol, 4.00 eq). The mixture was stirred at 60 °C for 2 h. Ethyl acetate (30 mL) and water (30 mL) were added and layers were separated. The aqueous phase was extracted with ethyl acetate (3 × 30 mL). Combined extracts were washed with brine (40 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to give (S)-1-(4-bromophenyl)-6- methyltetrahydropyrimidin-2(1H)-one (200 mg, crude) as a yellow solid.15 1H NMR (400 MHz, DMSO-d6) δ = 7.55 - 7.42 (m, 2H), 7.26 - 7.13 (m, 2H), 6.63 (s, 1H), 4.06 - 3.88 (m, 1H), 3.25 - 3.12 (m, 2H), 2.12 - 1.99 (m, 1H), 1.80 - 1.69 (m, 1H), 1.03 (d, J = 6.4 Hz, 3H) Step 3: Synthesis of Intermediate 4 - (S)-3-(4-bromophenyl)-1,4- 20 dimethyltetrahydropyrimidin-2(1H)-one Under nitrogen atmosphere, 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 (36.0 mg, 0.900. mmol, 60% purity, 1.21 eq) and methyl 25 iodide (211 mg, 1.49 mmol, 2.00 eq) at 0 °C. The mixture was stirred at 25 °C for 12 h. The mixture was quenched with water (50 mL) in slow drops while stirring at 0 °C under nitrogen atmosphere. The aqueous phase was extracted with ethyl acetate (3 × 50 mL). Combined 179 PAT059979-WO-PCT extracts were washed with brine (40 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to give (S)-3-(4-bromophenyl)-1,4- dimethyltetrahydropyrimidin-2(1H)-one (170 mg, crude) as yellow oil. 1H NMR (400 MHz, DMSO-d6) δ = 7.52 - 7.46 (m, 2H), 7.20 - 7.13 (m, 2H), 4.00 - 3.88 (m, 5 1H), 3.49 - 3.36 (m, 2H), 2.85 (s, 3H), 2.23 - 2.10 (m, 1H), 1.80 (dd, J = 4.4, 13.2 Hz, 1H), 1.05 (d, J = 6.4 Hz, 3H) Part 2: Synthesis of Intermediate 4A Step 1: Synthesis of 3-((3-bromo-2-chlorophenyl)amino) propanoic acid 10 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, 0.100 eq). The mixture was stirred at 100 °C for 12 h. The reaction mixture was cooled to 25 °C, and then extracted with ethyl acetate 15 (3 × 20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~40% Ethyl acetate / Petroleum ether gradient @ 60 mL / min) to give 3-((3-bromo-2- chlorophenyl)amino)propanoic acid (5.85 g, 20.2 mmol, 96% yield) as a brown solid. 201H NMR (400 MHz, DMSO-d6) δ = 12.30 (s, 1H), 7.12 - 7.03 (m, 1H), 6.94 (d, J = 7.6 Hz, 1H), 6.75 (d, J = 8.0 Hz, 1H), 5.65 (s, 1H), 3.37 (d, J = 6.0 Hz, 2H), 2.54 (s, 2H). MS (ESI) m / z 279.9 [M+H]+Step 2: Synthesis of 1-(3-bromo-2-chlorophenyl) dihydropyrimidine-2,4(1H,3H)-dione 25 180 PAT059979-WO-PCT A mixture of 3-((3-bromo-2-chlorophenyl)amino)propanoic acid (1.00 g, 3.59 mmol, 1.00 eq) and urea (668 mg, 11.1 mmol, 3.10 eq) in acetic acid (10 mL) was stirred at 120 °C for 12 h. The reaction mixture was cooled to 25 °C, then concentrated under reduced pressure to give a residue, and then extracted with ethyl acetate (3 × 20 mL). The combined organic layers 5 were washed with water (3 × 20mL), then dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate / Petroleum ether gradient @ 30 mL / min) to afford 1-(3-bromo-2- chlorophenyl)dihydropyrimidine-2,4(1H, 3H)-dione (496 mg, 1.57 mmol, 44% yield) as a10light 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, 2H). MS (ESI) m / z 301.0 [M-H]+15 Step 3: Synthesis of Intermediate 4A - 1-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione A mixture of 1-(3-bromo-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione (2.00 g, 6.59 mmol, 1.00 eq), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.84 g, 7.25 20 mmol, 1.10 eq), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (482 mg, 659 μmol, 0.100 eq), and potassium acetate (1.94 g, 19.8 mmol, 3.00 eq) in dioxane (30 mL) was degassed and purged with nitrogen for three times, and then the mixture was stirred at 85 °C for 4 h under nitrogen atmosphere. The reaction mixture was cooled to 25 °C, then filtered and concentrated under reduced pressure to give a residue, which was purified by flash silica 25 gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ether gradient @ 40 mL / min) to afford 1-(2-chloro-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (2.8 g, 4.63 mmol, 70% yield, 58% purity) as a black brown solid. 181 PAT059979-WO-PCT 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] Part 3: Synthesis of Compound 446 5 Synthesis of Compound 446 - (S)-1-(2-chloro-4'-(3,6-dimethyl-2-oxotetrahydro-pyrimidin- 1(2H)-yl)-[1,1'-biphenyl]-3-yl)dihydropyrimidine-2,4(1H,3H)-dione To a solution of (S)-3-(4-bromophenyl)-1,4-dimethyltetrahydropyrimidin-2(1H)-one (60.0 mg, 0.212 mmol, 1.00 eq) and 1-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- 10 yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (149 mg, 0.424 mmol, 2.00 eq) in dioxane (1 mL) and water (0.1 mL) was added [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (16.0 mg, 0.0212 mmol, 0.100 eq) and potassium phosphate (135 mg, 0.636 mmol, 3.00 eq). The mixture was stirred at 100 °C for 1 h under nitrogen. After being cooled to room temperature, the reaction mixture was 15 concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 10 g SepaFlash® Silica Flash Column, Eluent of 0-100% ethyl acetate / petroleum ether gradient @ 20 mL / min) and then re-purified by Prep-HPLC (column: Phenomenex luna C18 150 mm × 25 mm × 10 µm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 28%- 58% B over 10 min) and lyophilized to afford (S)-1-(2-chloro-4'-(3,6-dimethyl-2-20oxotetrahydropyrimidin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (25.41 mg, 58.9 μmol, 28% yield, 99% purity) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ = 10.49 (s, 1H), 7.54 - 7.45 (m, 2H), 7.44 - 7.37 (m, 3H), 7.33 - 7.27 (m, 2H), 4.08 - 3.96 (m, 1H), 3.81 - 3.72 (m, 1H), 3.66 (td, J = 6.4, 12.4 Hz, 1H), 3.47 (dd, J = 6.4, 11.2 Hz, 1H), 3.30 - 3.27 (m, 1H), 2.88 (s, 3H), 2.81 - 2.72 (m, 2H), 2.26 - 25 2.14 (m, 1H), 1.84 (qd, J = 4.4, 13.2 Hz, 1H), 1.14 (d, J = 6.4 Hz, 3H) 182 PAT059979-WO-PCT 1H NMR (400 MHz, METHANOL-d4) 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), 2.94 - 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]+. 5 Example 2B: Synthesis of Compound 432 Part 1: Synthesis of Intermediate 4 Step 1: Synthesis of Intermediate 2 - 1-(3-chloropropyl)-3-(2-methoxyethyl)urea 10 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 mixture was stirred at 25 °C for 1 h. The mixture was concentrated to give the residue. The crude product was triturated with petroleum ether (10 183 PAT059979-WO-PCT mL) at 25 °C for 30 min to obtained 1-(3-chloropropyl)-3-(2-methoxyethyl)urea (2.50 g, 12.8 mmol, 96 % yield) as white solid. 1H NMR (400 MHz, DMSO-d6) δ = 6.02 (br t, J = 5.6 Hz, 1H), 5.86 (br t, J = 5.6 Hz, 1H), 3.62 (t, J = 6.4 Hz, 2H), 3.30 (t, J = 5.6 Hz, 2H), 3.24 (s, 3H), 3.17 - 3.06 (m, 4H), 1.81 (t, J = 5 6.4 Hz, 2H). MS (ESI) m / z 195.0 [M+H]+Step 2: Synthesis of Intermediate 3 - 1-(2-methoxyethyl)tetrahydropyrimidin-2(1H)-one To a solution of 1-(3-chloropropyl)-3-(2-methoxyethyl)urea (1.50 g, 7.71 mmol, 1.00 10 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 mixture was stirred at 25 °C for 2 hr. The reaction was quenched with water (20 ml), then extracted with ethyl acetate (3 × 20 mL). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 1-(2- 15 methoxyethyl)tetrahydropyrimidin-2(1H)-one (0.900 g, 5.69 mmol, 74% yield) as colorless oil. MS (ESI) m / z 159.3 [M+H]+Step 3: Synthesis of Intermediate 4 - 1-(4-bromophenyl)-3-(2- methoxyethyl)tetrahydropyrimidin-2(1H)-one 20 To a solution of 1-(2-methoxyethyl)tetrahydropyrimidin-2(1H)-one (0.300 g, 1.90 mmol, 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, 0.100 eq) , N1,N2-dimethylethane-1,2- diamine (33.4 mg, 379 μmol, 40.8 μL, 0.200 eq) and potassium phosphate (805 mg, 3.79 184 PAT059979-WO-PCT mmol, 2.00 eq). The mixture was stirred at 100 °C for 12 hr. The mixture was filtered to give the residue. The crude product was purified by reversed-phase column (0.1% formic acid condition) to afford 1-(4-bromophenyl)-3-(2-methoxyethyl)tetrahydropyrimidin-2(1H)- one (219 mg, 678 μmol, 18 % yield, 97 % purity). MS (ESI) m / z 314.9 [M+3H]+5 Part 2: Synthesis of Intermediate 4A 1-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)dihydropyrimidine- 2,4(1H,3H)-dione (Intermediate 4A) was synthesised as described in Example 2A, Part 2.10Part 3: Synthesis of Compound 432 Synthesis of Compound 432 - 1-(2-chloro-4'-(3-(2-methoxyethyl)-2-oxotetrahydropyrimidin- 1(2H)-yl)-[1,1'-biphenyl]-3-yl)dihydropyrimidine-2,4(1H,3H)-dione To a solution of 1-(4-bromophenyl)-3-(2-methoxyethyl)tetrahydropyrimidin-2(1H)-one (60.015 mg, 192 μmol, 1.00 eq) and 1-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (134 mg, 383 μmol, 2.00 eq) in N, N- dimethylformamide (2.00 mL) was added [1,1- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (14.0 mg, 19.2 μmol, 0.100 eq) and potassium phosphate (81.4 mg, 383 μmol, 2.00 eq). The mixture was stirred at 20 100 °C for 2 hr. The reaction mixture was quenched by addition water (8 mL) and 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 by Prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(formic acid )- acetonitrile ]; gradient: 24%-54% B25 over 10 min) to afford 1-(2-chloro-4'-(3-(2-methoxyethyl)-2-oxotetrahydropyrimidin-1(2H)- 185 PAT059979-WO-PCT yl)-[1,1'-biphenyl]-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (43.95 mg, 99.67 μmol, 52% yield, 99% purity) as white solid. 1H 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 = 5 6.0, 11.2 Hz, 2H). MS (ESI) m / z 457.2 [M+H]+Example 2C: Synthesis of Compound 430 10Part 1: Synthesis of Intermediate 9 186 PAT059979-WO-PCT Step 1: Synthesis of Intermediate 2 - tert-butyl (1-(2-(1,3-dioxoisoindolin-2- yl)ethyl)cyclopropyl)carbamate Under nitrogen atmosphere, to a solution of tert-butyl (1-(2- 5 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) in tetrahydrofuran (10 mL) was added diisopropyl (E)-diazene-1,2-dicarboxylate (1.45 g, 7.18 mmol, 1.31 eq) at 0 °C. Then the mixture was stirred at 25 °C for 12 h. The mixture was concentrated under reduced pressure. The residue was purified by flash silica gel 10 chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, eluent of 0%–15% ethyl acetate / petroleum ether gradient at 70 mL / min) and reversed-phase column (column: C18, 80 g; mobile phase: [water (0.1% formic acid) - acetonitrile]; B%: 0%–50%) to give tert-butyl (1-(2-(1,3-dioxoisoindolin-2-yl)ethyl)cyclopropyl)carbamate (1.64 g, 4.72 mmol, 86% yield, 95% purity) as a white solid. 151H NMR (400 MHz, DMSO-d6) δ = 7.93 - 7.75 (m, 4H), 6.97 (s, 1H), 3.74 - 3.55 (m, 2H), 1.81 - 1.68 (m, 2H), 1.34 (s, 9H), 0.63 - 0.60 (m, 2H), 0.55 - 0.45 (m, 2H) Step 2: Synthesis of Intermediate 3 - 2-(2-(1-aminocyclopropyl)ethyl)isoindoline-1,3-dione hydrochloride 20 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) at 25 °C. Then the mixture was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure to give 2-(2-(1-aminocyclopropyl)ethyl)isoindoline- 25 1,3-dione hydrochloride (1.32 g, 4.70 mmol, 95% yield, 95% purity) as a white solid. 187 PAT059979-WO-PCT 1H NMR (400 MHz, DMSO-d6) δ = 8.54 (s, 3H), 7.94 - 7.76 (m, 4H), 3.84 - 3.69 (m, 2H), 1.93 - 1.82 (m, 2H), 0.98 - 0.94 (m, 2H), 0.74 - 0.64 (m, 2H) Step 3: Synthesis of Intermediate 4 - 2-(2-(1-((4-bromo-2-nitrophenyl)amino)- 5 cyclopropyl)ethyl)isoindoline-1,3-dione To a solution of 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) in dimethylsulfoxide (10 mL) was added 4-bromo-1-fluoro-2-nitrobenzene (2.07 g, 9.41 mmol, 10 1.16 mL, 2.00 eq) at 25 °C. Then the mixture was stirred at 80 °C for 2 h. After being cooled to room temperature, the reaction mixture was diluted with ethyl acetate (20 mL). The organic layer was washed with brine (3 × 20 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, eluent of 0%–15 30% ethyl acetate / petroleum ether gradient at 70 mL / min) to give 2-(2-(1-((4-bromo-2- nitrophenyl)amino)cyclopropyl)ethyl)isoindoline-1,3-dione (1.67 g, 3.69 mmol, 78% yield, 95% purity) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ = 8.42 (s, 1H), 8.11 (d, J = 2.4 Hz, 1H), 7.91 - 7.79 (m, 4H), 7.70 (dd, J = 2.4, 9.2 Hz, 1H), 7.28 (d, J = 9.2 Hz, 1H), 3.73 (t, J = 6.0 Hz, 2H), 2.02 - 20 1.67 (m, 2H), 0.75 (d, J = 5.6 Hz, 4H). To a solution of 2-(2-(1-((4-bromo-2-nitrophenyl)amino)cyclopropyl)ethyl)isoindoline-1,3- 25 dione (800 mg, 1.86 mmol, 1.00 eq) in ethanol (20 mL) was added hydrazine monohydrate (2.19 g, 43.8 mmol, 23.5 eq) at 25 °C. Then the mixture was stirred at 80 °C for 2 h. After 188 PAT059979-WO-PCT being cooled to room temperature, the reaction mixture was diluted with ethyl acetate (100 mL). The solvents were washed with brine (3 × 100 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give N-(1-(2- aminoethyl)cyclopropyl)-4-bromo-2-nitroaniline (207 mg, 655 μmol, 35% yield, 95% purity) 5 as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ = 8.26 (s, 1H), 8.16 (d, J = 2.4 Hz, 1H), 7.70 (dd, J = 2.4, 9.2 Hz, 1H), 7.33 (d, J = 9.2 Hz, 1H), 2.64 (t, J = 7.2 Hz, 2H), 1.64 (s, 2H), 0.83 (d, J = 9.8 Hz, 4H)10Step 5: Synthesis of Intermediate 6 - 4-(4-bromo-2-nitrophenyl)-4,6-diazaspiro[2.5]octan-5- one To a solution of N-(1-(2-aminoethyl)cyclopropyl)-4-bromo-2-nitroaniline (207 mg, 690 μmol, 1.00 eq) in tetrahydrofuran (2 mL) was added 1,1'-carbonyldiimidazole (134 mg, 82615μmol, 1.20 eq) at 25 °C. Then the mixture was stirred at 25 °C for 1 h. Then potassium tert- butoxide (154 mg, 1.37 mmol, 2.00 eq) was added at 25 °C. Then the mixture was stirred at 25 °C for 2 h. The mixture was poured into brine (20 mL). The mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. 20 The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, eluent of 0%–50% ethyl acetate / petroleum ether gradient at 70 mL / min) to give 4-(4-bromo-2-nitrophenyl)-4,6-diazaspiro[2.5]octan-5-one (210 mg, 612 μmol, 89% yield, 95% purity) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ = 8.09 (d, J = 2.4 Hz, 1H), 7.87 (dd, J = 2.4, 8.4 Hz, 1H),257.31 (d, J = 8.4 Hz, 1H), 6.98 (s, 1H), 3.32 - 3.28 (m, 2H), 2.02 - 1.68 (m, 2H), 0.68 (s, 4H) Step 6: Synthesis of Intermediate 7 - 4-(4-bromo-2-nitrophenyl)-6-methyl-4,6- diazaspiro[2.5]octan-5-one 189 PAT059979-WO-PCT Under nitrogen atmosphere, to a solution of 4-(4-bromo-2-nitrophenyl)-4,6- diazaspiro[2.5]octan-5-one (220 mg, 675 μmol, 1.00 eq) in tetrahydrofuran (5 mL) was added sodium hydride (33.0 mg, 825 μmol, 60% purity, 1.22 eq) at 0 °C. Then the mixture was 5 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 mixture was 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 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 20 g 10 SepaFlash® Silica Flash Column, eluent of 0%–20% ethyl acetate / petroleum ether gradient at 70 mL / min) to give 4-(4-bromo-2-nitrophenyl)-6-methyl-4,6-diazaspiro[2.5]octan-5-one (210 mg, 586 μmol, 87% yield, 95% purity) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ = 8.08 (d, J = 2.4 Hz, 1H), 7.87 (dd, J = 2.4, 8.4 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 3.41 (t, J = 6.0 Hz, 2H), 2.84 (s, 3H), 1.99 - 1.84 (m, 2H), 0.75 (s,152H), 0.66 (s, 2H). Step 7: Synthesis of Intermediate 8 - 4-(2-amino-4-bromophenyl)-6-methyl-4,6- diazaspiro[2.5]octan-5-one 20 To a solution of 4-(4-bromo-2-nitrophenyl)-6-methyl-4,6-diazaspiro[2.5]octan-5-one (160 mg, 470 μmol, 1.00 eq) in acetic acid (2 mL) was added iron (263 mg, 4.70 mmol, 10.0 eq) at 25 °C. The mixture was stirred at 100 °C for 1 h. After being cooled to room temperature, the mixture was diluted with ethyl acetate (50 mL). The mixture was filtered and the filtrate was washed with water (3 × 50 mL), dried over sodium sulfate, filtered and concentrated 25 under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, eluent of 0%–100% ethyl acetate / petroleum 190 PAT059979-WO-PCT ether gradient at 70 mL / min) to give 4-(2-amino-4-bromophenyl)-6-methyl-4,6- diazaspiro[2.5]octan-5-one (90.0 mg, 276 μmol, 59% yield, 95% purity) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ = 6.84 (d, J = 2.0 Hz, 1H), 6.68 - 6.61 (m, 1H), 6.59 - 6.52 (m, 1H), 5.04 (s, 2H), 3.50 - 3.34 (m, 2H), 2.86 (s, 3H), 2.43 - 2.22 (m, 1H), 1.67 (dd, J = 2.8, 5 6.0 Hz, 1H), 0.62 - 0.26 (m, 4H). Step 8: Synthesis of Intermediate 9 - 4-(4-bromophenyl)-6-methyl-4,6-diazaspiro[2.5]octan- 5-one 10 To a solution of 4-(2-amino-4-bromophenyl)-6-methyl-4,6-diazaspiro[2.5]octan-5-one (70.0 mg, 226 μmol, 1.00 eq) in water (1 mL) and hydrochloric acid (0.05 mL, 37% in water) was added sodium nitrite (19.0 mg, 275 μmol, 1.22 eq) and phosphinic acid (73.3 mg, 1.13 mmol, 5.00 eq) at 25 °C. The mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with ethyl acetate (20 mL). The solvents were washed with brine (3 × 20 mL), dried 15 over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, eluent of 0%–70% ethyl acetate / petroleum ether gradient at 70 mL / min) to give 4-(4-bromophenyl)-6-methyl-4,6-diazaspiro[2.5]octan-5-one (60.0 mg, 193 μmol, 70% yield, 95% purity) as a yellow solid. 201H NMR (400 MHz, CDCl3) δ = 7.44 (d, J = 8.8 Hz, 2H), 7.00 (d, J = 8.8 Hz, 2H), 3.46 (t, J = 6.0 Hz, 2H), 3.03 (s, 3H), 1.97 (t, J = 6.0 Hz, 2H), 0.63 (s, 4H). Part 2: Synthesis of Intermediate 9A 1-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)dihydropyrimidine-252,4(1H,3H)-dione (Intermediate 9A) was synthesised as described in Example 2A, Part 2. Part 3: Synthesis of Compound 430 Synthesis of Compound 430 – 1-(2-chloro-4'-(6-methyl-5-oxo-4,6-diazaspiro[2.5]octan-4-yl)- [1,1'-biphenyl]-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 191 PAT059979-WO-PCT To a solution of 4-(4-bromophenyl)-6-methyl-4,6-diazaspiro[2.5]octan-5-one (30.0 mg, 101 μmol, 1.00 eq) and 1-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (71.2 mg, 203 μmol, 2.00 eq) in dioxane 5 (1.00 mL) and water (0.100 mL) was added potassium phosphate (64.7 mg, 304 μmol, 3.00 eq), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (11.1 mg, 15.2 μmol, 0.15 eq). Then the reaction mixture was stirred at 100 °C for 1 h under nitrogen atmosphere. The reaction mixture was filtered and adjusted pH to 5-6 by formic acid (0.1 mL). Then the reaction mixture was concentrated in vacuum. The residue was purified by reversed-phase 10 HPLC (C18, 80 g; condition: water / acetonitrile = 1 / 0 to 0 / 1, 0.1% formic acid) and lyophilized to afford 1-(2-chloro-4'-(6-methyl-5-oxo-4,6-diazaspiro[2.5]octan-4-yl)-[1,1'- biphenyl]-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (34.1 mg, 76.9 μmol, 75% yield, 99% purity) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 10.48 (s, 1H), 7.53 - 7.45 (m, 2H), 7.43 - 7.34 (m, 3H), 15 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 2D: Synthesis of Compound 527 192 PAT059979-WO-PCT 5 Step 1: Synthesis of 1-bromo-3-(bromomethyl)-2-chlorobenzene To a solution of 1-bromo-2-chloro-3-methylbenzene (30.0 g, 146 mmol, 1.00 eq.) in tetrachloromethane (240 mL) were added N-bromosuccinimide (28.7 g, 161 mmol, 1.11 eq.) and benzoyl peroxide (1.77 g, 7.30 mmol, 0.05 eq.). The mixture was stirred at 90°C for 16 h. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (2 × 75 10 mL). The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography, reversed-phase column chromatography, or prep-TLC (eluting with an appropriate mixture of Petroleum ether and Ethyl acetate for silica gel or acetonitrile and water containing 0.1% formic acid for reversed phase) to afford 1- bromo-3-(bromomethyl)-2-chlorobenzene (20.8 g, 73.1 mmol, 50% yield) as a colourless 15 liquid. 193 PAT059979-WO-PCT 1H NMR (400 MHz, CDCl3) δ = 7.61 (dd, J = 8.0, 1.6 Hz, 1H), 7.41 (dd, J = 8.0, 1.6 Hz, 1H), 7.15 - 7.11 (m, 1H), 4.62 (s, 2H). Step 2: Synthesis of 2-(3-bromo-2-chlorophenyl)acetonitrile 5 To a solution of 1-bromo-3-(bromomethyl)-2-chlorobenzene (20.0 g, 70.3 mmol, 1.00 eq.) and trimethylsilyl cyanide (10.5 g, 105 mmol, 1.76 mL, 1.50 eq.) in dichloromethane (200 mL) was added tetrabutylammonium fluoride (1.0 M in THF, 105 mL, 1.50 eq.) dropwise at 0°C. The reaction was stirred at 20°C for 1.5 h. The mixture was washed with water (3 × 150 mL), and the organic layer was dried over sodium sulfate, filtered, and concentrated under10reduced pressure to give a residue. The residue was purified by silica gel column chromatography, reversed-phase column chromatography, or prep-TLC (eluting with an appropriate mixture of Petroleum ether and Ethyl acetate for silica gel or acetonitrile and water containing 0.1% formic acid for reversed phase) to afford 2-(3-bromo-2- chlorophenyl)acetonitrile (13.2 g, 57.3 mmol, 81% yield) as a white solid. 151H NMR (400 MHz, CDCl3) δ = 7.65 (d, J = 8.0 Hz, 1H), 7.50 (dd, J = 8.0, 0.8 Hz, 1H), 7.20 (t, J = 8.0 Hz, 1H), 3.89 (s, 2H). Step 3: Synthesis of tert-butyl 4-(3-bromo-2-chlorophenyl)-4-cyanobutanoate To a solution of 2-(3-bromo-2-chlorophenyl)acetonitrile (13.2 g, 57.3 mmol, 1.00 eq.) in THF20 (130 mL) were added sodium methoxide (620 mg, 11.5 mmol, 0.20 eq.) and tert-butylacrylate (8.31 mL, 57.3 mmol, 1.00 eq.) dropwise at 0°C. Then, the reaction was stirred at 20°C for 2 h. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (3 × 80 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The 25 residue was purified by silica gel column chromatography, reversed-phase column chromatography, or prep-TLC (eluting with an appropriate mixture of Petroleum ether and Ethyl acetate for silica gel or acetonitrile and water containing 0.1% formic acid for reversed phase) to afford tert-butyl 4-(3-bromo-2-chlorophenyl)-4-cyanobutanoate (7.50 g, 19.0 mmol, 33% yield) as a colourless liquid.30 1H NMR (400 MHz, CDCl3) δ = 7.65 (dd, J = 8.0, 1.6 Hz, 1H), 7.53 (dd, J = 8.0, 1.6 Hz, 1H), 7.22 (t, J = 8.0 Hz, 1H), 4.49 (dd, J = 8.8, 5.6 Hz, 1H), 2.54 - 2.38 (m, 2H), 2.29 - 2.09 (m, 2H), 1.46 (s, 9H). Step 4: Synthesis of Intermediate 1 - 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione 194 PAT059979-WO-PCT To a solution of tert-butyl 4-(3-bromo-2-chlorophenyl)-4-cyanobutanoate (4.70 g, 11.9 mmol, 1.00 eq.) in acetic acid (30 mL) was added sulfuric acid (3.00 ml, 56.3 mmol, 4.72 eq.). The reaction was stirred at 90°C for 3 h. After cooling to room temperature, the mixture was poured into ice water (120 mL) and filtered. The filter cake was washed with water (2 × 50 5 mL), then dried under reduced pressure to afford Intermediate 1 (2.89 g, 9.46 mmol, 79% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 10.93 (s, 1H), 7.72 (dd, J = 8.0, 0.8 Hz, 1H), 7.38 (dd, J = 8.0, 1.2 Hz, 1H), 7.30 - 7.26 (m, 1H), 4.32 (dd, J = 12.0, 4.8 Hz, 1H), 2.83 - 2.73 (m, 1H), 2.53 -2.53 (m, 1H), 2.30 - 2.34 (m, 1H), 2.03-1.97 (m, 1H). MS (ESI) m / z 303.9 [M+H]+10 Part 2: Synthesis of Intermediate 3 Step 1: Synthesis of Intermediate 2 - tert-butyl 4-(2-chloro-3-(2,6-dioxopiperidin-3- yl)phenyl)piperidine-1-carboxylate 15 A mixture of 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (61.0 mg, 201 μmol, 1.00 eq), tert-butyl 4-bromopiperidine-1-carboxylate (69.2 mg, 262 μmol, 1.30 eq), [4,4′-bis(1,1- dimethylethyl)-2,2′- bipyridine-N1,N1′]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl- N]phenyl-C]iridium(III)hexafluorophosphate (2.26 mg, 2.02 μmol, 0.0100 eq), nickel(II)(4,4'-di-tert-butyl-2,2'-bipyridine)dichloride (401 μg, 1.01 μmol, 0.00500 eq)， 20 bis(trimethylsilyl)silyl-trimethylsilane (50.1 mg, 201 μmol, 62.2 μL, 1.00 eq) and sodium carbonate (42.7 mg, 403 μmol, 2.00 eq) in 1,2-dimethoxyethane (2.00 mL) was degassed and purged with nitrogen, and then the mixture was stirred at 25 °C for 16 h irradiated with a 455 nm blue LED. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase column (0.1% formic acid condition) to 25 afford tert-butyl 4-(2-chloro-3-(2,6-dioxopiperidin- 3-yl)phenyl)piperidine-1-carboxylate (31.0 mg, 76.1 μmol, 37% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 10.89 (br s, 1H), 7.35 - 7.26 (m, 2H), 7.19 (dd, J = 2.0, 6.8 Hz, 1H), 4.29 (br dd, J = 5.2, 12.0 Hz, 1H), 4.10 (br d, J = 10.4 Hz, 2H), 3.17 (br t, J = 195 PAT059979-WO-PCT 11.6 Hz, 1H), 2.94 - 2.80 (m, 2H), 2.79 - 2.73 (m, 1H), 2.56 - 2.52 (m, 1H), 2.32 - 2.23 (m, 1H), 2.04 - 1.95 (m, 1H), 1.76 (br t, J = 10.8 Hz, 2H), 1.55 - 1.47 (m, 2H), 1.43 (s, 9H). Step 2: Synthesis of Intermediate 3 - 3-(2-chloro-3-(piperidin-4-yl)phenyl)piperidine-2,6- 5 dione A mixture of tert-butyl 4-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-1- carboxylate (70.0 mg, 172 μmol, 1.00 eq) in hydrochloric acid / ethyl acetate (2M, 2.00 mL) was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure 10 to afford 3-(2-chloro-3-(piperidin-4-yl)phenyl) piperidine- 2,6-dione (160 mg, crude) as a white solid. Part 3: Synthesis of Compound 527 Synthesis of Compound 527 - 3-(2-chloro-3-(1-(1-methyl-2-oxo-1,2-dihydropyridin-3-15yl)piperidin-4-yl)phenyl)piperidine-2,6-dione A mixture of 3-(2-chloro-3-(piperidin-4-yl)phenyl)piperidine-2,6-dione (50.0 mg, 162 μmol, 1.00 eq), 3-bromo-1-methylpyridin-2(1H)-one (30.6 mg, 162 μmol, 1.00 eq), cesium carbonate (159 mg, 488 μmol, 3.00 eq) and [1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5- 20 dichloro-imidazol-2-ylidene]-dichloro-(3- chloropyridin-1-ium-1-yl)palladium (15.8 mg, 16.3 μmol, 0.100 eq) in N,N-dimethylformamide (1.00 mL) was degassed and purged with 196 PAT059979-WO-PCT nitrogen for three times, and then the mixture was stirred at 100 °C for 12 h under nitrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase column (0.1% formic acid condition) to give crude product. Then the crude product was purified by Prep-HPLC 5 (column: Waters Xbridge 150*25mm* 5um;mobile phase: [water(ammonium bicarbonate) - acetonitrile];gradient:20%-40% B over 53 min) to afford 3-(2-chloro-3-(1-(1-methyl-2-oxo- 1,2-dihydropyridin-3-yl)piperidin-4-yl)phenyl)piperidine-2,6-dione (14.74 mg, 34.5 μmol, 7% yield, 97% purity) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ = 10.89 (dt, J = 4.4, 7.2 Hz, 1H), 7.41 - 7.27 (m, 3H), 7.2410- 7.17 (m, 1H), 6.80 - 6.71 (m, 1H), 6.21 - 6.08 (m, 1H), 4.36 - 4.24 (m, 1H), 3.82 (br s, 2H), 3.46 - 3.36 (m, 5H), 3.17 - 3.10 (m, 1H), 2.80 - 2.73 (m, 1H), 2.55 (br d, J = 1.6 Hz, 1H), 2.33 - 2.25 (m, 1H), 2.05 - 1.97 (m, 1H), 1.87 - 1.74 (m, 4H). 1H NMR (400 MHz, CDCl3-d) δ = 8.03 (br dd, J = 2.0, 6.0 Hz, 1H), 7.40 - 7.33 (m, 1H), 7.33 - 7.29 (m, 1H), 7.09 (br d, J = 7.6 Hz, 1H), 7.01 (br d, J = 6.8 Hz, 1H), 6.74 (br d, J = 7.2 Hz, 15 1H), 6.16 (t, J = 6.8 Hz, 1H), 4.30 (br dd, J = 4.4, 10.8 Hz, 1H), 3.99 - 3.83 (m, 2H), 3.58 (s, 3H), 3.33 - 3.20 (m, 1H), 2.84 - 2.60 (m, 4H), 2.40 - 2.22 (m, 2H), 2.04 - 1.93 (m, 4H). MS (ESI) m / z 414.1 [M+H]+Example 2E: Synthesis of Compound 574 20 197 PAT059979-WO-PCT Part 1: Synthesis of Intermediate 5 Step 1: Synthesis of Intermediate 2 – 2 - methyl 2-(3-bromo-2-chlorophenyl)acetate To a mixture of 2-(3-bromo-2-chlorophenyl) acetic acid (25.0 g, 100 mmol, 1.00 eq.) in 5 methanol (25 mL) was added trimethoxymethane (15.9 g, 150 mmol, 1.50 eq.) and sulfuric acid (0.982 g, 10.0 mmol, 0.100 eq.). The mixture was stirred at 25 °C for 2 h. The reaction was quenched with saturated sodium bicarbonate (200 mL). The mixture was extracted with ethyl acetate (3 × 200 mL). The combined organic extracts were washed with brine (200 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced10pressure to give methyl 2-(3-bromo-2-chloro-phenyl) acetate (25.0 g, 94.8 mmol, 95% yield) as yellow oil. 1H NMR (400 MHz, DMSO-d6) δ = 7.70 (dd, J = 1.6, 8.0 Hz, 1H), 7.44 (dd, J = 1.6, 7.6 Hz, 1H), 7.32 - 7.19 (m, 1H), 3.91 (s, 2H), 3.63 (s, 3H) 15 Step 2: Synthesis of Intermediate 3 - tert-butyl 4-(2-chloro-3-(2-methoxy-2 oxoethyl)phenyl)piperazine-1-carboxylate To a mixture of methyl 2-(3-bromo-2-chlorophenyl)acetate (20.0 g, 75.9 mmol, 1.00 eq.), tert-butyl piperazine-1-carboxylate (16.9 g, 91.0 mmol, 1.20 eq.) and cesium carbonate (74.120 g, 227 mmol, 3.00 eq.) in toluene (200 mL) was added 2-dicyclohexylphosphino-2,6- diisopropoxy-1,1-biphenyl (3.48 g, 3.79 mmol, 0.0500 eq.) and tris(dibenzylideneacetone)dipalladium(0) (3.54 g, 7.59 mmol, 0.100 eq.). The mixture was stirred at 120 °C for 12 h under nitrogen atmosphere. After being cooled to room 198 PAT059979-WO-PCT temperature, the reaction mixture was diluted water (300 mL) and extracted with ethyl acetate (3 × 500 mL). The combined organic extracts were washed with brine (100 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 330 g 5 SepaFlash® Silica Flash Column, Eluent of 0–80% Ethyl acetate / Petroleum ether gradient at 120 mL / min) to afford tert-butyl 4-(2-chloro-3-(2-methoxy-2-oxoethyl)phenyl)piperazine-1- carboxylate (16.7 g, 45.2 mmol, 60% yield) as yellow oil. 1H NMR (400 MHz, DMSO-d6) δ = 7.34 - 7.25 (m, 1H), 7.15 (d, J = 7.8 Hz, 2H), 3.85 (s, 2H), 3.66 (s, 3H), 3.51 (s, 4H), 2.93 (t, J = 4.8 Hz, 4H), 1.46 (s, 9H)10Step 3: Synthesis of Intermediate 4 - tert-butyl 4-(2-chloro-3-(2,6-dioxopiperidin-3- yl)phenyl)piperazine-1-carboxylate To a mixture of tert-butyl 4-(2-chloro-3-(2-methoxy-2-oxoethyl)phenyl)piperazine-1- 15 carboxylate (16.7 g, 45.2 mmol, 1.00 eq.) and acrylamide (2.90 g, 40.7 mmol, 0.9 eq.) in tetrahydrofuran (170 mL) was added potassium tert-butoxide (1 M in tetrahydrofuran, 49.8 mL, 1.10 eq.) at 0 °C. The mixture was stirred at 50 °C for 2 h. After the reaction mixture was cooled to room temperature. The reaction was quenched with saturated sodium bicarbonate (200 mL) at 0 °C for 0.5 h. The mixture was extracted with ethyl acetate (3 × 20 500 mL). The combined organic extracts were washed with brine (200 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 330g SepaFlash®Silica Flash Column, Eluent of 0 - 80% Ethyl acetate / petroleum ether gradient at 100 mL / min) to give tert-butyl 4-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)piperazine-1- 25 carboxylate (12.5 g, 30.6 mmol, 68% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ = 10.88 (s, 1H), 7.32 - 7.22 (m, 1H), 7.11 (dd, J = 1.2, 8.0 Hz, 1H), 7.02 (dd, J = 1.2, 7.6 Hz, 1H), 4.26 (dd, J = 5.2, 12.0 Hz, 1H), 3.48 (s, 4H), 2.97 - 199 PAT059979-WO-PCT 2.85 (m, 4H), 2.83 - 2.68 (m, 1H), 2.53 - 2.51 (m, 1H), 2.34 - 2.21 (m, 1H), 2.05 - 1.99 (m, 1H), 1.42 (s, 9H) Step 4: Synthesis of Intermediate 5 - 3-(2-chloro-3-(piperazin-1-yl)phenyl)piperidine-2,6- 5 dione A mixture of tert-butyl 4-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)piperazine-1- carboxylate (12.0 g, 29.4 mmol, 1.00 eq.) in hydrochloric acid / dioxane (2 M, 50 mL) was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to 10 give 3-(2-chloro-3-(piperazin-1-yl)phenyl)piperidine-2,6-dione (11.5 g, crude, hydrochloride) as yellow solid 1H NMR (400 MHz, DMSO-d6) δ = 10.89 (s, 1H), 9.25 (s, 2H), 7.35 - 7.28 (m, 1H), 7.15 (dd, J = 1.2, 8.0 Hz, 1H), 7.07 (dd, J = 1.2, 7.6 Hz, 1H), 4.27 (dd, J = 4.8, 12.0 Hz, 1H), 3.28 - 3.13 (m, 8H), 2.83 - 2.70 (m, 1H), 2.53 - 2.51 (m, 1H), 2.28 (dd, J = 4.0, 12.8 Hz, 1H), 2.03 - 15 1.93 (m, 1H) Part 2: Synthesis of Intermediate 5A Step 1: Synthesis of Intermediate 5A - 7-bromo-4-fluoropyrazolo[1,5-a]pyridine 20 To a solution of ethyl 7-bromo-4-fluoropyrazolo[1,5-a] pyridine-3-carboxylate (0.200 g, 696 μmol, 1.00 eq.) in water (1.20 mL) and acetic acid (1.20 mL) was added concentrated hydrochloric acid 36% (0.90 mL, 9.06 mmol, 13.0 eq.). The reaction was stirred at 100°C for 12 h. The mixture was diluted with water (5 mL), and the pH was adjusted to 8 with aqueous sodium hydroxide. The mixture was extracted with ethyl acetate (3 ×10 mL). The combined25organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and 200 PAT059979-WO-PCT concentrated under reduced pressure to afford 7-bromo-4-fluoropyrazolo[1,5-a]pyridine (0.110 g, 511 μmol, 73% yield) as a pink solid. Part 3: Synthesis of Compound 574 5 Synthesis of Compound 574 - 3-(2-chloro-3-(4-(4-fluoropyrazolo [1,5-a]pyridin-7- yl)piperazin-1-yl)phenyl)piperidine-2,6-dione To a mixture of 7-bromo-4-fluoropyrazolo[1,5-a]pyridine (0.520 g, 2.42 mmol, 1.00 eq.), 3- (2-chloro-3-piperazin-1-yl-phenyl)piperidine-2,6-dione (0.915 g, 2.66 mmol, 1.10 eq., 10 hydrochloride) and cesium carbonate (2.36 g, 7.26 mmol, 3.00 eq.) in dioxane (15 mL) was added 1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-ide;3- chloropyridine;dichloropalladium (0.117 g, 0.120 mmol, 0.0500 eq.). The mixture was stirred at 100 °C for 12 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature. Ethyl acetate (50 mL) and water (50 mL) were added and layers were 15 separated. The aqueous phase was extracted with ethyl acetate (2 × 50 mL). Combined extracts were washed with brine (40 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0–65% ethyl acetate / petroleum ether gradient at 80 mL / min) to give 280 mg of crude product. The 20 crude product was purified by Prep-HPLC (column: Phenomenex luna C18150 mm × 25 mm × 5 µm; mobile phase: [water (formic acid) - acetonitrile]; gradient: 45%-65% B over 10 min) and Prep-HPLC (column: Waters xbridge 150 mm × 25 mm × 5 µm; mobile phase: [water (ammonium bicarbonate) - acetonitrile]; gradient: 50%-70% B over 8 min). The desired fraction was collected and lyophilized to afford 3-(2-chloro-3-(4-(4-fluoropyrazolo 25 [1,5-a]pyridin-7-yl)piperazin-1-yl)phenyl)piperidine-2,6-dione (111.36 mg, 0.268 mmol, 11% yield, 99% purity) as a white solid. 201 PAT059979-WO-PCT 1H NMR (400 MHz, DMSO-d6) δ = 10.90 (s, 1H), 8.12 (d, J = 2.0 Hz, 1H), 7.36 - 7.28 (m, 1H), 7.26 - 7.20 (m, 1H), 7.12 (dd, J = 8.4, 9.6 Hz, 1H), 7.06 (d, J = 6.8 Hz, 1H), 6.79 (d, J = 2.4 Hz, 1H), 6.35 (dd, J = 4.4, 8.2 Hz, 1H), 4.29 (dd, J = 5.2, 12.0 Hz, 1H), 3.51 (s, 4H), 3.25 - 3.16 (m, 4H), 2.83 - 2.72 (m, 1H), 2.55 - 2.51 (m, 1H), 2.33 - 2.26 (m, 1H), 2.04 - 1.95 (m, 5 1H). Example 2F: Synthesis of Compound 510 10 Part 1: Synthesis of Intermediate 2 - 4-chloro-2-(cyclopropylmethyl)pyridazin-3(2H)-one To a solution of 5-chloro-1H-pyridazin-6-one (500 mg, 3.83 mmol, 1.00 eq) and potassium carbonate (1.59 g, 11.5 mmol, 3.00 eq) in dimethylformamide (5.00 mL) was added bromomethylcyclopropane (517 mg, 3.83 mmol, 365 μL, 1.00 eq), the mixture was stirred at 15 25 °C for 12 h. The reaction mixture was poured into water (40 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to afford 4-chloro-2-(cyclopropylmethyl)pyridazin-3(2H)-one (90.0 mg, 487 μmol, 13%20yield) as yellow oil. 202 PAT059979-WO-PCT 1H NMR (400 MHz, DMSO-d6) δ = 7.91 (d, J = 4.4 Hz, 1H), 7.79 (d, J = 4.4 Hz, 1H), 3.98 (d, J = 7.2 Hz, 2H), 1.33 - 1.20 (m, 1H), 0.53 - 0.46 (m, 2H), 0.40 - 0.32 (m, 2H). Part 2: Synthesis of Intermediate 2A 5 3-(2-chloro-3-(piperidin-4-yl)phenyl) piperidine- 2,6-dione (Intermediate 2A) was synthesised as described in Example 2D, Parts 1 and 2. Part 3: Synthesis d 510 Synthesis of Compound 510 - 3-(2-chloro-3-(1-(2-(cyclopropylmethyl)-3-oxo-2,3-10dihydropyridazin-4-yl)piperidin-4-yl)phenyl)piperidine-2,6-dione A mixture of 4-chloro-2-(cyclopropylmethyl)pyridazin-3(2H)-one (90.0 mg, 487 μmol, 1.00 eq), 3-(2-chloro-3-(piperidin-4-yl)phenyl)piperidine-2,6-dione (134 mg, 438 μmol, 0.900 eq), 15 potassium carbonate (202 mg, 1.46 mmol, 3.00 eq), sodium iodide (73.0 mg, 487 μmol, 1.00 eq) in dimethylformamide (3.00 mL) was stirred at 80 °C for 12 h. The reaction mixture was concentrated to give a residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to afford a crude product, the crude product was purified by Prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase:20 [water(formic acid) - acetonitrile];gradient:45%-63% B over 9 min) to afford 3-(2-chloro-3-(1- (2-(cyclopropylmethyl)-3-oxo-2,3-dihydropyridazin-4-yl)piperidin-4-yl)phenyl)piperidine- 2,6-dione (20.44 mg, 44.9 μmol, 9% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 10.90 (br s, 1H), 7.69 (d, J = 4.8 Hz, 1H), 7.39 - 7.28 (m, 2H), 7.24 - 7.15 (m, 1H), 6.54 (d, J = 5.2 Hz, 1H), 4.38 - 4.26 (m, 3H), 3.91 (d, J = 7.2 Hz, 203 PAT059979-WO-PCT 2H), 3.30 - 3.21 (m, 1H), 2.87 - 2.73 (m, 3H), 2.55 (m, 1H), 2.37 - 2.24 (m, 1H), 2.06 - 1.97 (m, 1H), 1.93 - 1.71 (m, 4H), 1.32 - 1.20 (m, 1H), 0.50 - 0.43 (m, 2H), 0.38 - 0.33 (m, 2H). MS (ESI) m / z 455.2 [M+H]+5 Example 2G: Synthesis of Compound 503 10 Part 1: Synthesis of Intermediate 5A 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (Intermediate 5A) was synthesised as described in Example 2D, Part 1. Part 2: Synthesis of Intermediate 5 15 To a solution of 4-fluoropyridin-2(1H)-one (2.00 g, 17.7 mmol, 1.00 eq.) in dimethyl formamide (10 mL) was added potassium carbonate (4.89 g, 35.4 mmol, 2.00 eq.) followed by 20 iodoethane (4.14 g, 26.5 mmol, 1.50 eq.) at 25 °C. Then the mixture was stirred at 25 °C for 204 PAT059979-WO-PCT 12 h. The mixture was diluted with ethyl acetate (100 mL) and filtered over celite. The mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40 g Sepa Flash ® Silica Flash Column, eluent of 50%–80% ethyl acetate / petroleum ether gradient at 70 mL / min) to give 1-ethyl-4-fluoropyridin-2(1H)-one 5 (4.40 g, 30.3 mmol, 83% yield) as yellow oil. 1H NMR (400 MHz, DMSO-d6) δ = 7.86 (t, J = 8.0 Hz, 1H), 6.34 - 6.25 (m, 1H), 6.16 (dd, J = 2.8, 11.6 Hz, 1H), 3.89 (q, J = 7.2 Hz, 2H), 1.23 - 1.16 (m, 3H). Step 2: Synthesis of Intermediate 3 - 1-ethyl-4-fluoro-3-iodopyridin-2(1H)-one 10 To a solution of 1-ethyl-4-fluoropyridin-2(1H)-one (2.20 g, 15.1 mmol, 1.00 eq.) in acetonitrile (20 mL) was added 1-iodopyrrolidine-2,5-dione (3.75 g, 16.7 mmol, 1.10 eq.) at 25 °C under nitrogen atmosphere. The reaction was stirred at 50 °C for 12 h. After being cooled to room temperature, the mixture was concentrated under reduced pressure. The residue was purified 15 by flash silica gel chromatography (ISCO®; 40 g Sepa Flash ® Silica Flash Column, eluent of 0%–30% ethyl acetate / petroleum ether gradient at 70 mL / min) to give 1-ethyl-4-fluoro-3- iodopyridin-2(1H)-one (2.00 g, 5.99 mmol, 20% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 7.91 (t, J = 8.0 Hz, 1H), 6.39 (dd, J = 6.0, 7.6 Hz, 1H), 3.97 (q, J = 7.2 Hz, 2H), 1.25 - 1.17 (m, 3H). 20 Step 3: Synthesis of Intermediate 4 - tert-butyl 4-(1-ethyl-4-fluoro-2-oxo-1,2-dihydropyridin- 3-yl)piperazine-1-carboxylate 25 To a solution of 1-ethyl-4-fluoro-3-iodopyridin-2(1H)-one (1.00 g, 3.00 mmol, 1.00 eq.), tert- butyl piperazine-1-carboxylate (0.840 g, 4.51 mmol, 1.51 eq.) and cesium carbonate (2.93 g, 205 PAT059979-WO-PCT 8.98 mmol, 3.00 eq.) in dioxane (10 mL) was added (2'-amino-[1,1'-biphenyl]-2- yl)palladium(II) (2'-(dicyclohexylphos-phaneyl)-2,6-bis-(dimethylamino)-1l5-[1,1'-biphenyl]- 1-yl)methanesulfonate (0.242 g, 0.300 mmol, 0.100 eq.) at 25 °C under nitrogen atmosphere. The mixture was stirred at 90 °C for 12 h. After being cooled to room temperature, the mixture 5 was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40 g Sepa Flash ® Silica Flash Column, eluent of 30%–50% ethyl acetate / petroleum ether gradient at 70 mL / min) and reversed-phase flash (0.1% formic acid condition) to give tert-butyl 4-(1-ethyl-4-fluoro-2-oxo-1,2-dihydropyridin-3-yl)piperazine-1- carboxylate (1.10 g, 3.01 mmol, 50% yield) as yellow oil.10 1H NMR (400 MHz, CDCl3) δ = 7.02 (t, J = 7.2 Hz, 1H), 6.05 (dd, J = 7.6, 9.2 Hz, 1H), 3.95 (q, J = 7.2 Hz, 2H), 3.58 - 3.47 (m, 4H), 3.17 – 3.16 (m, 4H), 1.46 (s, 9H), 1.33 (t, J = 7.2 Hz, 3H). Step 4: Synthesis of Intermediate 5 - 1-ethyl-4-fluoro-3-(piperazin-1-yl)pyridin-2(1H)-one 15 To a solution of tert-butyl 4-(1-ethyl-4-fluoro-2-oxo-1,2-dihydropyridin-3-yl)piperazine-1- carboxylate (200 mg, 547 µmol, 1.00 eq.) in dioxane (0.5 mL) was added hydrogen chlorid / dioxane (2 M, 3 mL) at 25 °C. The reaction was stirred at 25 °C for 4 h. The mixture was20 concentrated under reduced pressure to give 1-ethyl-4-fluoro-3-(piperazin-1-yl)pyridin-2(1H)- one (280 mg, crude, hydrochloride) as brown oil. 1H NMR (400 MHz, DMSO- d6) δ = 9.13 (s, 1H), 7.62 (t, J = 7.6 Hz, 1H), 6.29 (dd, J = 7.6, 9.2 Hz, 1H), 3.90 (q, J = 7.2 Hz, 2H), 3.37 - 3.23 (m, 4H), 3.11 (s, 4H), 1.19 (t, J = 7.2 Hz, 3H).25Part 3 : Synthesis of Compound 503 206 PAT059979-WO-PCT To a solution of 1-ethyl-4-fluoro-3-(piperazin-1-yl)pyridin-2(1H)-one (140 mg, 535 µmol, 1.00 eq., hydrochloride) and 3-(3-bromo-2-chloro-phenyl)piperidine-2,6-dione (178 mg, 588 µmol, 5 1.10 eq.) in dioxane (2 mL) was added cesium carbonate (871 mg, 2.67 mmol, 5.00 eq.) followed by 1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-ide;3- chloropyridine;dichloropalladium (52.0 mg, 53.5 µmol, 0.100 eq.) at 25 °C. The reaction was stirred at 100 °C for 12 h under nitrogen atmosphere. After being cooled to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by flash silica 10 gel chromatography (ISCO®; 20 g Sepa Flash ® Silica Flash Column, eluent of 50%–70% ethyl acetate / petroleum ether gradient at 70 mL / min) and Prep-HPLC (column: Phenomenex luna C18 150 mm × 25 mm × 10 µm; mobile phase: [water (formic acid) - acetonitrile]; gradient: 32%-62% B over 10 min) and lyophilized to afford 3-(2-chloro-3-(4-(1-ethyl-4- fluoro-2-oxo-1,2-dihydropyridin-3-yl)piperazin-1-yl)phenyl)piperidine-2,6-dione (20.14 mg, 15 44.6 µmol, 4% yield, 99% purity) as a white solid. 1H NMR (400 MHz, DMSO- d6) δ = 10.88 (s, 1H), 7.57 (t, J = 7.2 Hz, 1H), 7.35 - 7.24 (m, 1H), 7.20 - 7.10 (m, 1H), 7.02 (d, J = 6.4 Hz, 1H), 6.27 (dd, J = 7.6, 9.2 Hz, 1H), 4.27 (dd, J = 4.8, 12.0 Hz, 1H), 3.90 (q, J = 6.8 Hz, 2H), 3.30 - 3.25 (m, 4H), 3.07 - 2.95 (m, 4H), 2.80 - 2.72 (m, 1H), 2.55 - 2.52 (m, 1H), 2.37 - 2.22 (m, 1H), 2.09 - 1.91 (m, 1H), 1.20 (t, J = 7.2 Hz, 20 3H). MS (ESI) m / z 447.1 [M+H]+Example 2H: Synthesis of Compound 501 207 PAT059979-WO-PCT Part 1: Synthesis of Intermediate 1 - 3-bromo-1-ethylpyridin-2(1H)-one 5 To a solution of 3-bromopyridin-2(1H)-one (5.00 g, 28.7 mmol, 1.00 eq) in dimethylformamide (100 mL) was added sodium hydride (1.72 g, 43.1 mmol, 60% purity, 1.50 eq) slowly at 0 °C under nitrogen atmosphere. The mixture was stirred at 0 °C for 10 min. Then iodoethane (8.96 g, 57.5 mmol, 4.60 mL, 2.00 eq) was added to the mixture. The mixture was stirred at 25 °C for 50 min. The mixture was quenched by addition of saturated ammonium chloride solution10(2 mL), and then diluted with water (30 mL) and extracted with ethyl acetate (3 × 50 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 by flash silica gel chromatography (ISCO®; 50 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate / Petroleum ether gradient @ 50 mL / min) to afford 3-bromo-1- 15 ethylpyridin-2(1H)-one (4.20 g, 20.6 mmol, 72% yield) as light yellow oil. 1H NMR (400 MHz, DMSO-d6) δ = 7.89 (dd, J = 2.0, 7.2 Hz, 1H), 7.79 (dd, J = 2.0, 6.8 Hz, 1H), 6.25 - 6.10 (m, 1H), 3.97 (q, J = 7.2 Hz, 2H), 1.23 (t, J = 7.2 Hz, 3H). Part 2: Synthesis of Intermediate 1A - 3-(2-chloro-3-(piperidin-4-yl)phenyl)piperidine-2,6- 20 dione 3-(2-chloro-3-(piperidin-4-yl)phenyl) piperidine- 2,6-dione (Intermediate 1A) was synthesised as described in Example 2D, Parts 1 and 2. 208 PAT059979-WO-PCT Part 3: Synthesis of Compound 501 A mixture of 3-bromo-1-ethylpyridin-2(1H)-one (200 mg, 990 μmol, 1.00 eq), 3-(2-chloro-3- 5 (piperidin-4-yl)phenyl)piperidine-2,6-dione (306 mg, 891 μmol, 0.900 eq hydrochloride), 3- chloropyridine;4,5-dichloro-1,3-bis[2,6-di(heptan-4-yl)phenyl]-2H- imidazole;dichloropalladium (96.3 mg, 99.0 μmol, 0.100 eq) and sodium t-butanolate ((2 M, 1.48 mL, 3.00 eq) in N,N-dimethylformamide (5 mL) was degassed and purged with nitrogen for three times, and then the mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. 10 The reaction was carried out in two batches in parallel. The reaction mixture was filtered through a pad of Celite. The mixture was diluted with water (40 mL) and extracted with ethyl acetate (3 × 40 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (column: Phenomenex 15 luna C18 150 × 40 mm × 15 um; mobile phase: [water (formic acid) - acetonitrile]; gradient:15%-45% B over 15 min). The desired fraction was collected and lyophilized to afford 3-(2-chloro-3-(1-(1-ethyl-2-oxo-1,2-dihydropyridin-3-yl)piperidin-4- yl)phenyl)piperidine-2,6-dione (249 mg, 576 μmol, 29% yield) as a gray solid. 1H NMR (400 MHz, DMSO-d6) δ = 10.89 (s, 1H), 7.42 - 7.28 (m, 3H), 7.20 (d, J = 7.6 Hz, 20 1H), 6.74 (d, J = 7.2 Hz, 1H), 6.17 (t, J = 6.8 Hz, 1H), 4.29 (dd, J = 4.4, 12.0 Hz, 1H), 3.91 (q, J = 6.8 Hz, 2H), 3.81 (d, J = 11.2 Hz, 2H), 3.14 (t, J = 10.8 Hz, 1H), 2.84 - 2.71 (m, 1H), 2.53 (s, 3H), 2.35 - 2.23 (m, 1H), 2.01 (dd, J = 3.6, 8.8 Hz, 1H), 1.90 - 1.69 (m, 4H), 1.21 (t, J = 7.2 Hz, 3H). MS (ESI) m / z 428.2 [M+H]+25 Example 2I: Synthesis of Compound 518 209 PAT059979-WO-PCT Part 1: Synthesis of Intermediate 4 Step 1: Synthesis of Intermediate 2 - 3-bromo-1-(2,2-difluoroethyl)pyridin-2(1H)-one 5 To a solution of 3-bromopyridin-2(1H)-one (0.500 g, 2.87 mmol, 1.00 eq) in dimethyl formamide (6 mL) was added 1,1-difluoro-2-iodoethane (1.65 g, 8.62 mmol, 3.00 eq) followed by potassium carbonate (1.19 g, 8.61 mmol, 3.00 eq) at 25 °C. The reaction was stirred at 80 °C for 12 h. After being cooled to room temperature, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic 10 layers were washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography (silica, petroleum ether: ethyl acetate=3:1 to 2:1) to give 3-bromo-1-(2,2-difluoroethyl)pyridin- 2(1H)-one (0.440 g, 1.85 mmol, 64% yield) as light-yellow oil. 1H NMR (400 MHz,CDCl3) δ = 7.79 (dd, J = 1.6, 7.2 Hz, 1H), 7.35 - 7.24 (m, 1H), 6.38 - 15 5.91 (m, 2H), 4.29 (dt, J = 4.4, 12.8 Hz, 2H) 210 PAT059979-WO-PCT Step 2: Synthesis of Intermediate 3 - tert-butyl 4-(1-(2,2-difluoroethyl)-2-oxo-1,2- dihydropyridin-3-yl)piperazine-1-carboxylate 5 To a solution of 3-bromo-1-(2,2-difluoroethyl)pyridin-2(1H)-one (0.340 g, 1.43 mmol, 1.00 eq) in tetrahydrofuran (24 mL) was added tert-butyl piperazine-1-carboxylate (0.320 g, 1.72 mmol, 1.20 eq) and cesium carbonate (2.33 g, 7.14 mmol, 5.00 eq) followed by methanesulfonato(2-dicyclohexylphosphino-2',6'-di-i-propoxy-1,1'-biphenyl)(2'-amino-1,1'- biphenyl-2-yl)palladium(II) (0.119 g, 0.142 mmol, 0.100 eq) at 25°C under nitrogen10atmosphere. The reaction was stirred at 85 °C for 12 h. After being cooled to room temperature, the mixture was diluted with saturated aqueous ammonium chloride (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (3 × 30 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica 15 Flash Column, eluent of 20% - 50% ethyl acetate / petroleum ether gradient at 70 mL / min) to give tert-butyl 4-(1-(2,2-difluoroethyl)-2-oxo-1,2-dihydropyridin-3-yl)piperazine-1- carboxylate (0.400 g, 1.16 mmol, 82% yield) as light-yellow oil. 1H NMR (400 MHz,CDCl3) δ = 7.01 - 6.96 (m, 1H), 6.70 (dd, J = 1.6, 7.2 Hz, 1H), 6.33 - 6.00 (m, 2H), 4.25 (dt, J = 4.4, 13.2 Hz, 2H), 3.66 - 3.56 (m, 4H), 3.13 - 3.03 (m, 4H), 1.4920(s, 9H) Step 3: Synthesis of Intermediate 4 - 1-(2,2-difluoroethyl)-3-(piperazin-1-yl)pyridin-2(1H)- one 25 211 PAT059979-WO-PCT To a solution of tert-butyl 4-(1-(2,2-difluoroethyl)-2-oxo-1,2-dihydropyridin-3-yl)piperazine- 1-carboxylate (0.400 g, 1.16 mmol, 1.00 eq) in dioxane (2 mL) was added hydrogen chloride / dioxane (2 M, 16 mL, 27.5 eq) at 25 °C under nitrogen atmosphere. The reaction was stirred at 25 °C for 12 h. The mixture was concentrated under reduced pressure to give 1-(2,2- 5 difluoroethyl)-3-(piperazin-1-yl)pyridin-2(1H)-one (0.370 g, crude, hydrochloride) was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ = 9.45 (s, 2H), 7.37 (d, J = 6.8 Hz, 1H), 6.87 (d, J = 7.2 Hz, 1H), 6.43 (d, J = 4.0 Hz, 1H), 6.30 - 6.22 (m, 1H), 4.38 (dt, J = 4.0, 14.4 Hz, 2H), 3.28 (d, J = 4.4 Hz, 4H), 3.17 (s, 4H). 10 Part 2: Synthesis of Intermediate 4A 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (Intermediate 4A) was synthesised as described in Example 2D, Part 1. 15 Part 3: Synthesis d 518 Synthesis of Compound 518 - 3-(2-chloro-3-(4-(1-(2,2-difluoroethyl)-2-oxo-1,2- dihydropyridin-3-yl)piperazin-1-yl)phenyl)piperidine-2,6-dione To a solution of 1-(2,2-difluoroethyl)-3-(piperazin-1-yl)pyridin-2(1H)-one (0.370 g, 1.3220 mmol, 1.00 eq, hydrochloride) in dioxane (6 mL) was added 3-(3-bromo-2-chloro- phenyl)piperidine-2,6-dione (0.400 g, 1.32 mmol, 0.100 eq) and cesium carbonate (2.16 g, 6.63 mmol, 5.00 eq) followed by 1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-2H- imidazol-1-ium-2-ide;3-chloropyridine;dichloropalladium (0.126 g, 0.130 mmol, 0.100 eq) at 25 °C under nitrogen atmosphere. The reaction was stirred at 100 °C for 12 h. After being 25 cooled to room temperature, the mixture was filtered over celite. The filtrate was 212 PAT059979-WO-PCT concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: Phenomenex luna C18150 mm × 25 mm × 10 µm; mobile phase: [water (formic acid) - acetonitrile]; gradient: 30%-60% B over 10 min) and lyophilized to afford 3-(2-chloro-3-(4- (1-(2,2-difluoroethyl)-2-oxo-1,2-dihydropyridin-3-yl)piperazin-1-yl)phenyl)piperidine-2,6- 5 dione (36.21 mg, 0.0770 mmol, 6% yield, 99% purity) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 10.88 (s, 1H), 7.36 - 7.25 (m, 2H), 7.18 (d, J = 8.0 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.83 (d, J = 7.6 Hz, 1H), 6.49 - 6.15 (m, 2H), 4.38 (dt, J = 4.0, 14.4 Hz, 2H), 4.27 (dd, J = 4.8, 11.6 Hz, 1H), 3.29 - 3.17 (m, 4H), 3.08 (d, J = 3.2 Hz, 4H), 2.83 - 2.71 (m, 1H), 2.54 (s, 1H), 2.30 (dt, J = 4.0, 12.8 Hz, 1H), 2.05 - 1.95 (m, 1H)10MS (ESI) m / z 465.1 [M+H]+Example 2J: Synthesis of Compound 520 15 Part 1: Synthesis Intermediate 2 - 3-bromo-1-ethylpyridin-2(1H)-one 20 To a solution of 3-bromopyridin-2(1H)-one (5.00 g, 28.7 mmol, 1.00 eq) in dimethylformamide (100 mL) was added sodium hydride (1.72 g, 43.1 mmol, 60% purity, 1.50 eq) slowly at 0 °C under nitrogen atmosphere. The mixture was stirred at 0 °C for 10 213 PAT059979-WO-PCT min. Then iodoethane (8.96 g, 57.5 mmol, 4.60 mL, 2.00 eq) was added to the mixture. The mixture was stirred at 25 °C for 50 min. The mixture was quenched by addition of saturated ammonium chloride solution (2 mL), and then diluted with water (30 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (30 mL), 5 dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 50 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate / Petroleum ether gradient @ 50 mL / min) to afford 3-bromo-1-ethylpyridin-2(1H)-one (4.20 g, 20.6 mmol, 72% yield) as light yellow oil.10 1H NMR (400 MHz, DMSO-d6) δ = 7.89 (dd, J = 2.0, 7.2 Hz, 1H), 7.79 (dd, J = 2.0, 6.8 Hz, 1H), 6.25 - 6.10 (m, 1H), 3.97 (q, J = 7.2 Hz, 2H), 1.23 (t, J = 7.2 Hz, 3H). Part 2: Synthesis of Intermediate 2A - 3-(2-chloro-3-(piperazin-1-yl)phenyl)piperidine-2,6- dione 15 Step 1: Synthesis of 1-bromo-3-(bromomethyl)-2-chlorobenzene To a solution of 1-bromo-2-chloro-3-methylbenzene (30.0 g, 146 mmol, 1.00 eq.) in tetrachloromethane (240 mL) were added N-bromosuccinimide (28.7 g, 161 mmol, 1.11 eq.) and benzoyl peroxide (1.77 g, 7.30 mmol, 0.05 eq.). The mixture was stirred at 90°C for 16 h. 20 The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (2 × 75 mL). The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography, reversed-phase column chromatography, or prep-TLC (eluting with an appropriate mixture of Petroleum ether and Ethyl acetate for silica gel or acetonitrile and water containing 0.1% formic acid for reversed phase) to afford 1-25bromo-3-(bromomethyl)-2-chlorobenzene (20.8 g, 73.1 mmol, 50% yield) as a colourless liquid. 1H NMR (400 MHz, CDCl3) δ = 7.61 (dd, J = 8.0, 1.6 Hz, 1H), 7.41 (dd, J = 8.0, 1.6 Hz, 1H), 7.15 - 7.11 (m, 1H), 4.62 (s, 2H). 30 Step 2: Synthesis of 2-(3-bromo-2-chlorophenyl)acetonitrile 214 PAT059979-WO-PCT To a solution of 1-bromo-3-(bromomethyl)-2-chlorobenzene (20.0 g, 70.3 mmol, 1.00 eq.) and trimethylsilyl cyanide (10.5 g, 105 mmol, 1.76 mL, 1.50 eq.) in dichloromethane (200 mL) was added tetrabutylammonium fluoride (1.0 M in THF, 105 mL, 1.50 eq.) dropwise at 0°C. The reaction was stirred at 20°C for 1.5 h. The mixture was washed with water (3 × 150 5 mL), and the organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography, reversed-phase column chromatography, or prep-TLC (eluting with an appropriate mixture of Petroleum ether and Ethyl acetate for silica gel or acetonitrile and water containing 0.1% formic acid for reversed phase) to afford 2-(3-bromo-2-10chlorophenyl)acetonitrile (13.2 g, 57.3 mmol, 81% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ = 7.65 (d, J = 8.0 Hz, 1H), 7.50 (dd, J = 8.0, 0.8 Hz, 1H), 7.20 (t, J = 8.0 Hz, 1H), 3.89 (s, 2H). Step 3: Synthesis of tert-butyl 4-(3-bromo-2-chlorophenyl)-4-cyanobutanoate 15 To a solution of 2-(3-bromo-2-chlorophenyl)acetonitrile (13.2 g, 57.3 mmol, 1.00 eq.) in THF (130 mL) were added sodium methoxide (620 mg, 11.5 mmol, 0.20 eq.) and tert-butyl acrylate (8.31 mL, 57.3 mmol, 1.00 eq.) dropwise at 0°C. Then, the reaction was stirred at 20°C for 2 h. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (3 × 80 mL), dried over20 sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. Theresidue was purified by silica gel column chromatography, reversed-phase column chromatography, or prep-TLC (eluting with an appropriate mixture of Petroleum ether and Ethyl acetate for silica gel or acetonitrile and water containing 0.1% formic acid for reversed phase) to afford tert-butyl 4-(3-bromo-2-chlorophenyl)-4-cyanobutanoate (7.50 g, 19.0 mmol, 25 33% yield) as a colourless liquid. 1H NMR (400 MHz, CDCl3) δ = 7.65 (dd, J = 8.0, 1.6 Hz, 1H), 7.53 (dd, J = 8.0, 1.6 Hz, 1H), 7.22 (t, J = 8.0 Hz, 1H), 4.49 (dd, J = 8.8, 5.6 Hz, 1H), 2.54 - 2.38 (m, 2H), 2.29 - 2.09 (m, 2H), 1.46 (s, 9H).30Step 4: Synthesis of 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione To a solution of tert-butyl 4-(3-bromo-2-chlorophenyl)-4-cyanobutanoate (4.70 g, 11.9 mmol, 1.00 eq.) in acetic acid (30 mL) was added sulfuric acid (3.00 ml, 56.3 mmol, 4.72 eq.). The reaction was stirred at 90°C for 3 h. After cooling to room temperature, the mixture was poured into ice water (120 mL) and filtered. The fil...

Claims

PAT059979-WO-PCT Claims 1. A VAV1 degrader for use as a medicament, wherein the VAV1 degrader is for use in combination with a therapeutic agent. 5 2. A therapeutic agent for use as a medicament, wherein the therapeutic agent is for use in combination with a VAV1 degrader.

3. A combination for use as a medicament, the combination comprising: (i) a VAV110degrader; and (ii) a therapeutic agent.

4. The VAV1 degrader, the therapeutic agent, or the combination for use according to any of claims 1-3, wherein the VAV1 degrader and the therapeutic agent are administered simultaneously, separately, or sequentially. 15 5. The VAV1 degrader, the therapeutic agent, or the combination for use according to any of claims 1-4 in the treatment or prevention of a disease caused by or associated with dysregulation of B-cell receptor signalling or T-cell receptor signalling (e.g., IFNɣ, CD69, and / or IL-2). 20 6. The VAV1 degrader, the therapeutic agent, or the combination for use according to any of claims 1-5 in the treatment or prevention of an autoimmune disease, a transplantation setting disease, a hematologic disease, or a cancer, or tumour. 25 7. The VAV1 degrader, the therapeutic agent, or the combination for use according to claim 6 in the treatment or prevention of a cancer or tumour, for example carcinoma, sarcoma, myeloma, leukemia, lymphoma, and combinations thereof.

8. The VAV1 degrader, the therapeutic agent, or the combination for use according to30any of claims 1-7 in the treatment or prevention of a hematologic disease (e.g. a T and B cell malignancy).

9. The VAV1 degrader, the therapeutic agent, or the combination for use according to claim 8, wherein the hematologic disease is selected from the group consisting of 269PAT059979-WO-PCT anemia, leukemia, lymphoma, myeloma, thrombocytopenia, hemophillia, sickle cell disease, polycythemia vera, myelodysplastic syndrome, and hemochromatosis.

10. The VAV1 degrader, the therapeutic agent, or the combination for use according to 5 claim 8 or 9, wherein the hematologic disease is selected from the group consisting of: multiple myeloma, chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), lymphoid leukemia, acute myeloid leukemia (AML), neoplasm of mature B- cells, non-Hodgkin's lymphoma (NHL), Hodgkin's lymphoma (HL), acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL),10myelodysplastic syndrome (MDS), Burkitt's lymphoma, hairy cell leukemia, Waldenström macroglobulinemia (WM), marginal zone B-cell lymphoma, mast-cell leukemia, T-cell prolymphocytic leukemia (T-PLL), prolymphocytic leukemia (PLL), classic Hodgkin lymphoma, hematopoietic and lymphoid cell neoplasm, lymphoid neoplasm, follicular lymphoma, chronic myelogenous leukemia (CML), T-cell acute 15 lymphoblastic leukemia, cutaneous T-cell lymphoma (CTCL), blast phase chronic myelogenous leukemia, childhood acute lymphoblastic leukemia, lymphoblastic lymphoma, T-lymphoblastic lymphoma, anaplastic large cell lymphoma (ALCL), acute leukemia of ambiguous lineage, B-cell acute lymphoblastic leukemia (B-ALL), acute monocytic leukemia, acute promyelocytic leukemia (APL), MALT lymphoma20 (mucosa-associated lymphoid tissue lymphoma), myelofibrosis, essentialthrombocythemia, asymptomatic myeloma, myeloproliferative disorder, plasma cell leukemia, plasmacytoma, chronic myelomonocytic leukemia (CMML), T-cell non- Hodgkin lymphoma, adult T-cell leukemia / lymphoma (ATLL), Langerhans cell histiocytosis, extranodal nasal NK / T cell lymphoma, lymphoid neoplasm, primary 25 myelofibrosis, juvenile myelomonocytic leukemia (JMML), Sézary's disease, mycosis fungoides, acute megakaryoblastic leukemia, acute myeloblastic leukemia without maturation, acute basophilic leukemia, acute myelomonocytic leukemia, acute erythroblastic leukemia, granulocytic sarcoma, myeloid sarcoma, acute erythroleukemia, acute myeloblastic leukemia with maturation, or30lymphoproliferative syndrome, and combinations thereof.

11. The VAV1 degrader, the therapeutic agent, or the combination for use according to claim 7 or 8 in the treatment or prevention of leukemia or lymphoma, for example wherein the leukemia or lymphoma is selected from the group consisting of: B-cell 270PAT059979-WO-PCT lymphoma, B-cell leukemia, T-cell lymphoma, T-cell leukemia and acute myeloid leukemia.

12. The VAV1 degrader, the therapeutic agent, or the combination for use according to 5 claim 11, wherein the leukemia or lymphoma is mantle cell lymphoma, diffuse large B-cell lymphoma, or chronic lymphocytic leukemia, and combinations thereof.

13. The VAV1 degrader, the therapeutic agent, or the combination for use according to any of claims 1-5 in the treatment or prevention of a disease caused by or associated10with immunopathologies in a subject in need thereof, for instance autoimmune disease.

14. The VAV1 degrader, the therapeutic agent, or the combination for use according to claim 13, wherein the disease is an autoimmune disease selected from the group 15 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, psoriasis, Graves ophthalmopathy, alopecia areata and others, allergic diseases (e.g., allergic asthma, atopic dermatitis, allergic20 rhinitis / conjunctivitis, allergic contact dermatitis), inflammatory diseases optionallywith 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 dermatitis, cutaneous 25 manifestations of immunologically-mediated disorders, inflammatory eye disease, keratoconjunctivitis, myocarditis, hepatitis, uvetitis, pericarditis, pulmonary fibrosis, systematic sclerosis, morphea, Alzheimer’s disease, chronic or acute Graft versus Host disease, T-cell mediated kidney disease, autoimmune liver diseases (e.g., biliary sclerosis, sclerosing cholangitis), chronic inflammatory demyelinating30polyradiculoneuropathy, macular degeneration, amyloidosis, pemphigus, lupus nephritis, pulmonary arterial hypertension, and axial spondylarthritis.

15. The VAV1 degrader, the therapeutic agent, or the combination for use according to claim 14, wherein the disease is Crohn’s disease / ulcerative colitis, psoriatic arthritis, 271PAT059979-WO-PCT Sjoegren syndrome, rheumatoid arthritis, psoriasis, multiple sclerosis, myasthenia gravis, cutaneous lupus or axial spondylarthritis.

16. The VAV1 degrader, the therapeutic agent, or the combination for use according to 5 claim 15, wherein the disease or is Crohn’s disease / ulcerative colitis, psoriatic arthritis, Sjoegren syndrome, rheumatoid arthritis, or multiple sclerosis.

17. The VAV1 degrader, the therapeutic agent, or the combination for use according to claim 16, wherein the disease is Crohn’s disease / ulcerative colitis. 10 18. The VAV1 degrader, the therapeutic agent, or the combination for use according to claim 16, wherein the disease is rheumatoid arthritis.

19. The VAV1 degrader, the therapeutic agent, or the combination for use according to 15 claim 16, wherein the disease is multiple sclerosis.

20. A combination comprising: (i) a VAV1 degrader; and (ii) a therapeutic agent.

21. The combination of claim 20 as a combined preparation for simultaneous, separate or20 sequential use as a medicament.

22. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 1-21, wherein the therapeutic agent is a treatment for a serious disease. 25 23. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 1-22, wherein the therapeutic agent is a treatment for a life-threatening disease.3024. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 1-23, wherein the therapeutic agent has a curative effect on a disease. 272PAT059979-WO-PCT 25. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 1-24, wherein the therapeutic agent is a product that contains an active pharmaceutical ingredient that has been approved for marketing for at least one indication by a governmental authority, such as the FDA, or 5 EMA.

26. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 1-25, wherein the VAV1 degrader and the therapeutic agent together reduce cell proliferation relative to a negative control when10tested in a cell proliferation assay.

27. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 1-26, wherein the VAV1 degrader and the therapeutic agent, when tested together in a cell proliferation assay, produce a Bliss 15 synergy score of > 0, wherein the Bliss synergy score is calculated according to the following formula: Bliss synergy score = InhibitionCombination – 100 (1-(1-(InhibitionDrugA / 100))((1- (InhibitionDrugB / 100)))). 20 28. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to claim 27, wherein the Bliss synergy score is ≥ 10.

29. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or 25 the combination according to any of claims 26-28, wherein the VAV1 degrader and the therapeutic agent are tested together in an assay, for example an assay comprising treating cells (e.g. cancer cells) with one or more concentrations of the VAV1 degrader and the therapeutic agent alone and together for up to a week, and measuring cell growth (for example by cell tier glow). 30 30. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 1-29, wherein the therapeutic agent is a treatment for a disease or condition selected from the group consisting of: cancer, 273PAT059979-WO-PCT infectious disease, autoimmune disease, cardiovascular disease, and haematologic disease.

31. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or 5 the combination according to claim 30, wherein the therapeutic agent is a treatment for a haematologic disease selected from the group consisting of: multiple myeloma, chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), lymphoid leukemia, acute myeloid leukemia (AML), neoplasm of mature B-cells, non- Hodgkin's lymphoma (NHL), Hodgkin's lymphoma (HL), acute lymphoblastic10leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), myelodysplastic syndrome (MDS), Burkitt's lymphoma, hairy cell leukemia, Waldenström macroglobulinemia (WM), marginal zone B-cell lymphoma, mast-cell leukemia, T- cell prolymphocytic leukemia (T-PLL), prolymphocytic leukemia (PLL), classic Hodgkin lymphoma, hematopoietic and lymphoid cell neoplasm, lymphoid neoplasm, 15 follicular lymphoma, chronic myelogenous leukemia (CML), T-cell acute lymphoblastic leukemia, cutaneous T-cell lymphoma (CTCL), blast phase chronic myelogenous leukemia, childhood acute lymphoblastic leukemia, lymphoblastic lymphoma, T-lymphoblastic lymphoma, anaplastic large cell lymphoma (ALCL), acute leukemia of ambiguous lineage, B-cell acute lymphoblastic leukemia (B-ALL),20 AL amyloidosis, acute monocytic leukemia, acute promyelocytic leukemia (APL),MALT lymphoma (mucosa-associated lymphoid tissue lymphoma), myelofibrosis, essential thrombocythemia, polycythemia vera, asymptomatic myeloma, myeloproliferative disorder, plasma cell leukemia, plasmacytoma, chronic myelomonocytic leukemia (CMML), T-cell non-Hodgkin lymphoma, adult T-cell 25 leukemia / lymphoma (ATLL), Langerhans cell histiocytosis, extranodal nasal NK / T cell lymphoma, lymphoid neoplasm, primary myelofibrosis, juvenile myelomonocytic leukemia (JMML), Sézary's disease, mycosis fungoides, acute megakaryoblastic leukemia, acute myeloblastic leukemia without maturation, acute basophilic leukemia, acute myelomonocytic leukemia, acute erythroblastic leukemia, granulocytic sarcoma,30myeloid sarcoma, acute erythroleukemia, acute myeloblastic leukemia with maturation, or lymphoproliferative syndrome, and combinations thereof.

32. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to claim 30, wherein the therapeutic agent is a treatment 274PAT059979-WO-PCT for a haematologic disease, wherein the therapeutic agent is selected from the group consisting of: thalidomide, lenalidomide, pomalidomide, paclitaxel, doxorubicin, fulvestrant, dexamethasone, erlotinib, sirolimus, palbociclib, venetoclax, etoposide, ibrutinib, memantine hydrochloride, tranexamic acid, prednisolone, verapamil 5 hydrochloride, amiodarone, sunitinib, carmustine, fedratinib, captopril, trimethoprim, metformin hydrochloride, clofarabine, metoclopramide, zileuton, thiotepa, propranolol, tetracycline, omeprazole, paricalcitol, amifostine, clopidogrel, everolimus, simvastatin, voriconazole, ketoconazole, aprepitant, procarbazine hydrochloride, levetiracetam, pyrimethamine, levonorgestrel, zidovudine,10palonosetron, brigatinib, bupropion, capecitabine, digoxin, lovastatin, sildenafil, vinblastine sulfate, apixaban, methoxsalen, fosfomycin, moxifloxacin, famotidine, eltrombopag, crizotinib, rivaroxaban, disulfiram, aspirin, nicotinamide, pazopanib, 5- fluorouracil, diphenhydramine, tofacitinib, didanosine, cytarabine, gemcitabine, gefitinib, mycophenolic acid, chlorambucil, sulfamethoxazole, granisetron, warfarin, 15 clioquinol, atovaquone, hydroxyurea, rosiglitazone, carboplatinum, letrozole, metronidazole, sulfasalazine, plerixafor, allopurinol, lamivudine, theophylline, decitabine, altretamine, temozolomide, vandetanib, tolbutamide, imatinib, azathioprine, ibandronate, azithromycin, fluconazole, gabapentin, adenosine, acetaminophen, linezolid, clarithromycin, celecoxib, fenofibrate, pamidronic acid,20 tadalafil, leflunomide, furosemide, pemetrexed, loratadine, olanzapine,hydrocortisone, ribavirin, valproic acid, nintedanib, niclosamide, cephalexin, raltegravir, meropenem, folic acid, ciprofloxacin, acetylcysteine, azacitidine, pentostatin, mannitol, mesna, tafamidis, tacrolimus, bortezomib, busulfan, amoxicillin, l-glutamine, prednisone, fostamatinib, isosorbide, dacarbazine, 25 piperacillin, succimer, levamisole, aminolevulinic acid hydrochloride, ascorbic acid, medroxyprogesterone, efavirenz, curcumin, cortisone acetate, vancomycin, quercetin, bendamustine, axitinib, dimethyl fumarate, regorafenib, niacin, rifampicin, ceritinib, tazarotene, pentoxifylline, nilotinib, deferasirox, lenvatinib, bezafibrate, atazanavir, mycophenolate, bosutinib, erythromycin, ponatinib, ethinylestradiol, ganciclovir,30vorinostat, carvedilol, propofol, pyridoxine, maraviroc, docetaxel, caprylic acid, anagrelide, pioglitazone, colchicine, auranofin, pentamidine, mitoxantrone, amphotericin b, spironolactone, olaparib, sorafenib, fludarabine phosphate, or cisplatin, and combinations thereof. 275PAT059979-WO-PCT 33. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to claim 30, wherein the therapeutic agent is a treatment for a haematologic malignancy, wherein the therapeutic agent is selected from the group consisting of: thalidomide, lenalidomide, pomalidomide, paclitaxel, 5 doxorubicin, fulvestrant, dexamethasone, erlotinib, sirolimus, palbociclib, venetoclax, etoposide, ibrutinib, tranexamic acid, prednisolone, verapamil hydrochloride, sunitinib, carmustine, fedratinib, captopril, trimethoprim, metformin hydrochloride, clofarabine, metoclopramide, zileuton, thiotepa, propranolol, tetracycline, omeprazole, paricalcitol, amifostine, everolimus, simvastatin, voriconazole,10ketoconazole, aprepitant, procarbazine hydrochloride, levetiracetam, pyrimethamine, levonorgestrel, zidovudine, palonosetron, brigatinib, bupropion, capecitabine, digoxin, lovastatin, sildenafil, vinblastine sulfate, apixaban, methoxsalen, fosfomycin, moxifloxacin, eltrombopag, crizotinib, rivaroxaban, disulfiram, aspirin, nicotinamide, pazopanib, 5-fluorouracil, diphenhydramine, tofacitinib, didanosine, cytarabine, 15 gemcitabine, gefitinib, mycophenolic acid, chlorambucil, sulfamethoxazole, granisetron, warfarin, clioquinol, atovaquone, hydroxyurea, rosiglitazone, carboplatinum, letrozole, metronidazole, sulfasalazine, plerixafor, allopurinol, lamivudine, theophylline, decitabine, altretamine, temozolomide, vandetanib, tolbutamide, imatinib, azathioprine, ibandronate, fluconazole, adenosine,20 acetaminophen, linezolid, clarithromycin, celecoxib, fenofibrate, pamidronic acid,tadalafil, leflunomide, furosemide, pemetrexed, loratadine, olanzapine, hydrocortisone, ribavirin, valproic acid, nintedanib, niclosamide, cephalexin, raltegravir, meropenem, folic acid, ciprofloxacin, acetylcysteine, azacitidine, pentostatin, mannitol, mesna, tacrolimus, bortezomib, busulfan, amoxicillin, l- 25 glutamine, prednisone, fostamatinib, isosorbide, dacarbazine, piperacillin, succimer, aminolevulinic acid hydrochloride, ascorbic acid, medroxyprogesterone, efavirenz, curcumin, cortisone acetate, vancomycin, quercetin, bendamustine, axitinib, dimethyl fumarate, regorafenib, niacin, rifampicin, ceritinib, tazarotene, pentoxifylline, nilotinib, deferasirox, lenvatinib, bezafibrate, atazanavir, mycophenolate, bosutinib,30erythromycin, ponatinib, ethinylestradiol, ganciclovir, vorinostat, carvedilol, propofol, pyridoxine, maraviroc, docetaxel, caprylic acid, anagrelide, pioglitazone, colchicine, auranofin, pentamidine, mitoxantrone, amphotericin b, spironolactone, olaparib, sorafenib, fludarabine phosphate, or cisplatin, and combinations thereof. 276PAT059979-WO-PCT 34. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to claim 30, wherein the therapeutic agent is a treatment for a disease or condition selected from the group consisting of: a heart condition (e.g., hypertension), thrombocytopenia, malaria, cancer (e.g., leukemia or lymphoma), 5 and an autoimmune disease.

35. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 1-30, wherein the therapeutic agent is a treatment for a disease or condition selected from the group consisting of: ulcerative10colitis, Crohn’s disease, psoriatic arthritis, Sjoegren syndrome, rheumatoid arthritis, multiple sclerosis, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, or mantle cell lymphoma, and combinations thereof.

36. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or 15 the combination according to any of claims 1-35, wherein the therapeutic agent is a T- and / or B-cell depletor.

37. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 1-36, wherein the therapeutic agent is20 selected from the group consisting of:i. BTK inhibitors ii. BCL2 inhibitors iii. Anti-CD20 agents iv. DNA synthesis inhibitors 25 v. DNA crosslinkers / intercalators vi. Topoisomerase inhibitors vii. Proteasome inhibitors viii. Tyrosine kinase inhibitors ix. HDAC inhibitors30x. mTOR inhibitors xi. Tubulin inhibitors xii. IKZF1 / 3 inhibitors xiii. SYK inhibitors xiv. TNFα inhibitors 277PAT059979-WO-PCT xv. S1PR modulators xvi. JAK inhibitors xvii. IL-23 inhibitors xviii. IL-17 inhibitor 5 xix. A4b7 inhibitors xx. CD28 inhibitors xxi. IL-6 inhibitors xxii. IL-1R antagonists xxiii. Anti-CD19 agents10xxiv. Anti-CD79b agents xxv. Exportin-1 inhibitors xxvi. Anti-CD52 agents xxvii. Corticosteroids xxviii. PI3K-δ inhibitors 15 xxix. 26S proteasome inhibitors xxx. Tubulin disruption / proliferation inhibitors xxxi. CD19-targeting CAR T-cells xxxii. Fungicides xxxiii. Oxidative stress inducers (for example, free radical producers)20 xxxiv. Inhibitors of Na-K ATPase and / or the Na-K ATPase membrane pumpxxxv. Mitochondrial respiration complex 1 inhibitors xxxvi. Thioredoxin reductase inhibitors xxxvii. Antiarrhythmic agents xxxviii. Cathepsin B inhibitors 25 xxxix. Amebicides xl. Cyclooxygenase inhibitors xli. Nitric oxide synthase inhibitors xlii. Bacterial membrane disruptors xliii. Anthelminthic agents30xliv. Bacterial biofilm inhibitors xlv. Aldehyde dehydrogenase inhibitors xlvi. Iron, copper and / or zinc chelators xlvii. Sodium channel blockers xlviii. Na-K-Cl cotransporter inhibitors 278PAT059979-WO-PCT xlix. Superoxide dismutase inhibitors l. 5-hydroxytryptamine receptor agonists li. Blood schizonticides lii. Metalloproteinase inhibitors 5 liii. Inosine monophosphate dehydrogenase inhibitors liv. D2 receptor antagonists lv. D2 receptor agonists lvi. Serotonin reuptake inhibitors (SRIs) lvii. Haem polymerase inhibitors10lviii. Acetylcholinesterase inhibitors lix. lanosterol 14-α-demethylase inhibitors lx. Selective estrogen receptor modulators lxi. Dihydrofolate reductase inhibitors lxii. HIV protease inhibitors 15 lxiii. Vitamin D receptor agonists lxiv. Calcium-sending receptor (CaR) modulators lxv. Norepinephrine reuptake inhibitors lxvi. 17α-hydroxylase / C17,20-lyase (CYP17) inhibitors lxvii. HMG-CoA reductase inhibitors20 lxviii. H1-receptor antagonistslxix. μ-receptor agonists lxx. pancreatic lipase inhibitors lxxi. Progesterone receptor modulators lxxii. NS5A inhibitors 25 lxxiii. β-adrenoceptor antagonists lxxiv. phosphodiesterase 4 (PDE4) inhibitors lxxv. Monoamine oxidase inhibitors lxxvi. 5α-reductase inhibitors lxxvii. Calcium channel blockers30lxxviii. Muscarinic M(3) receptor antagonists lxxix. Nuclear progesterone receptor agonists lxxx. NK1 receptor antagonists lxxxi. RNA polymerase inhibitors lxxxii. Melanin synthesis inhibitors 279PAT059979-WO-PCT lxxxiii. Folic acid synthesis inhibitors lxxxiv. DNA alkylators; and lxxxv. Thrombopoietin receptor agonists and combinations thereof. 5 38. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to claim 37, wherein the therapeutic agent is selected from the group consisting of: i. BTK inhibitors10ii. BCL2 inhibitors iii. Anti-CD20 agents iv. DNA crosslinkers / intercalators v. Proteasome inhibitors vi. mTOR inhibitors 15 vii. Tubulin inhibitors viii. IKZF1 / 3 inhibitors; and ix. SYK inhibitors and combinations thereof.20 39. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, orthe combination according to claim 37 or 38, wherein the therapeutic agent is a BTK inhibitor, for example ibrutinib, acalabrutinib, remibrutinib, pirtobrutinib, or zanubrutinib, and combinations thereof. 25 40. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to claim 39, wherein the therapeutic agent is ibrutinib.

41. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to claim 39, wherein the therapeutic agent is acalabrutinib. 30 42. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to claim 39, wherein the therapeutic agent is remibrutinib. 280PAT059979-WO-PCT 43. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to claim 39, wherein the therapeutic agent is pirtobrutinib.

44. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or 5 the combination according to claim 39, wherein the therapeutic agent is zanubrutinib.

45. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-44, wherein the therapeutic agent is a BCL-2 inhibitor, for example venetoclax, navitoclax, or obatoclax, and combinations10thereof.

46. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-45, wherein the therapeutic agent is an IKZF1 / 3 inhibitor, for example lenalidomide, pomalidomide, or thalidomide, and 15 combinations thereof.

47. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-46, wherein the therapeutic agent is an mTOR inhibitor, for example sirolimus, everolimus, or temsirolimus, and20 combinations thereof.

48. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-47, wherein the therapeutic agent is a DNA synthesis inhibitor, for example cytarabine, clofarabine, decitabine, 25 gemcitabine, fludarabine (e.g., fludarabine phosphate), azacitidine, etoposide, floxuridine, 6-Mercaptopurine (e.g., 6-Mercaptopurine hydrate), azathioprine, lumefantrine, chlorambucil, capecitabine, zidovudine, didanosine, or stavudine, and combinations thereof.3049. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-48, wherein the therapeutic agent is a DNA crosslinker / intercalator, for example doxorubicin, cyclophosphamide, bendamustin (e.g. bendamustin hydrochloride), mitoxantrone (e.g., mitoxantrone 281PAT059979-WO-PCT dihydrochloride), thioptepa, thioguanine, quinacrine, epirubicin, idarubicin, cisplatin, trioxalen, or busulfan, and combinations thereof.

50. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or 5 the combination according to any of claims 37-49, wherein the therapeutic agent is a topoisomerase inhibitor, for example SN-38 (7-Ethyl-10-hydroxycamptothecin), irinotecan (e.g., irinotecan hydrochloride), topotecan, or belotecan, and combinations thereof.1051. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-50, wherein the therapeutic agent is a tyrosine kinase inhibitor, for example fostamatinib, afatinib, ponatinib, bosutinib, ceritinib, fedratinib, dasatinib, vandetanib, axitinib, sunitinib, crizotinib, sorafenib, nintedanib, brigatinib, pazopanib, nilotinib, or lapatinib, and combinations thereof. 15 52. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-51, wherein the therapeutic agent is a HDAC inhibitor, for example vorinostat, romidepsin, panobinostat, or belinostat, and combinations thereof. 20 53. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-52, wherein the therapeutic agent is a TNFα inhibitor, for example infliximab, adalimumab, golimumab, or etanercept, and combinations thereof. 25 54. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-53, wherein the therapeutic agent is an S1PR modulator, for example velsipity or fingolimod, and combinations thereof.3055. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-54, wherein the therapeutic agent is a JAK inhibitor, for example tofacitinib or upadacitinib, and combinations thereof. 282PAT059979-WO-PCT 56. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-55, wherein the therapeutic agent is an IL-23 inhibitor, for example mirikizumab, guselkumab, Risankizumab-rzaa, tildrakizumab-asmn, or ustekinumab, and combinations thereof. 5 57. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-56, wherein the therapeutic agent is an IL-17 inhibitor, for example secukinumab, ixekizumab, brodalumab, or bimekizumab, and combinations thereof. 10 58. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-57, wherein the therapeutic agent is an A4b7 inhibitor, for example natalizumab or vedolizumab, and combinations thereof. 15 59. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-58, wherein the therapeutic agent is a CD28 inhibitor, for example abatacept or lulizumab, and combinations thereof.

60. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or20 the combination according to any of claims 37-59, wherein the therapeutic agent is anIL-6 inhibitor, for example tocilizumab, siltuximab, or sarilumab, and combinations thereof.

61. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or 25 the combination according to any of claims 37-60, wherein the therapeutic agent is an IL-1R antagonist, for example anakinra.

62. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-61, wherein the therapeutic agent is an30anti-CD19 compound, for example Loncastuximab tesirine-lpyl or tafasitamab, and combinations thereof. 283PAT059979-WO-PCT 63. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-62, wherein the therapeutic agent is an anti-CD79b compound, for example Polatuzumab vedotin-piiq. 5 64. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-63, wherein the therapeutic agent is an exportin-1 inhibitor, for example selinexor.

65. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or10the combination according to any of claims 37-64, wherein the therapeutic agent is an anti-CD20 compound, for example obinutuzumab and ofatumumab, rituximab, ocrelizumab, or ublituximab, and combinations thereof.

66. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or 15 the combination according to any of claims 37-65, wherein the therapeutic agent is an anti-CD52 compound, for example alemtuzumab.

67. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-66, wherein the therapeutic agent is a20 corticosteroid, for example dexamethasone or prednisone, and combinations thereof.

68. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-67, wherein the therapeutic agent is a PI3K-δ inhibitors, for example duvelisib or idelalisib, and combinations thereof. 25 69. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-68, wherein the therapeutic agent is a 26S proteasome inhibitor, for example bortezomib.3070. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-69, wherein the therapeutic agent is a tubulin disruption / proliferation inhibitor, for example vincristine, podofilox, vinblastine (e.g., vinblastine sulfate), flubenzadole, albendazole, mebendazole, colchicine, docetaxel, or paclitaxel, and combinations thereof. 284PAT059979-WO-PCT 71. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-70, wherein the therapeutic agent is a CD19-targeting CAR T-cell, for example axicabtagene ciloleucel, lisocabtagene 5 maraleuel, or tisagenlecleucel, and combinations thereof.

72. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-71, wherein the therapeutic agent is a fungicide, for example thiram, pyrithione, ciclopirox, thimerosal, cetrimonium,10oxyquinoline, aminacrine, chloroxine, or chlormidazole (e.g., chlormidazole hydrochloride), and combinations thereof.

73. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-72, wherein the therapeutic agent is an 15 oxidative stress inducer (for example, free radical producers), for example dihydroartemisinin or artemether, and combinations thereof.

74. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-73, wherein the therapeutic agent is an20 inhibitor of Na-K ATPase, and / or the Na-K ATPase membrane pump, for exampledigoxin or digitoxin, and combinations thereof.

75. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-74, wherein the therapeutic agent is a 25 mitochondrial respiration complex 1 inhibitor, for example pyrvinium (e.g., pyrvinium pamoate or pyrvinium methyl sulfate), and combinations thereof.

76. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-75, wherein the therapeutic agent is a30thioredoxin reductase inhibitor, for example auranofin.

77. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-76, wherein the therapeutic agent is an antiarrhythmic compound, for example dronedarone (e.g., dronedarone 285PAT059979-WO-PCT hydrochloride) or amiodarone (e.g., amiodarone hydrochloride), and combinations thereof.

78. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or 5 the combination according to any of claims 37-77, wherein the therapeutic agent is a cathepsin B inhibitor, for example nitroxoline.

79. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-78, wherein the therapeutic agent is an10amebicide, for example iodoquinol.

80. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-79, wherein the therapeutic agent is a cyclooxygenase inhibitor, for example oxyphenbutazone. 15 81. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-80, wherein the therapeutic agent is a nitric oxide synthase inhibitor, for example methylene blue.20 82. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, orthe combination according to any of claims 37-81, wherein the therapeutic agent is a bacterial membrane disruptor, for example cetylpyridinium (e.g., cetylpyridinium chloride monohydrate). 25 83. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-82, wherein the therapeutic agent is an anthelminthic compound, for example niclosamide.

84. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or30the combination according to any of claims 37-83, wherein the therapeutic agent is a bacterial biofilm inhibitor, for example chlorquinaldol. 286PAT059979-WO-PCT 85. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-84, wherein the therapeutic agent is an aldehyde dehydrogenase inhibitor, for example disulfiram. 5 86. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-85, wherein the therapeutic agent is an iron, copper and / or zinc chelator, for example deferasirox or clioquinol, and combinations thereof.1087. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-86, wherein the therapeutic agent is a sodium channel blocker, for example oxcarbazepine or quinidine, and combinations thereof. 15 88. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-87, wherein the therapeutic agent is a Na-K-Cl cotransporter inhibitor, for example etacrynic acid.

89. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or20 the combination according to any of claims 37-88, wherein the therapeutic agent is asuperoxide dismutase inhibitor, for example diethyldithiocarbamate (e.g., sodium diethyldithiocarbamate trihydrate).

90. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or 25 the combination according to any of claims 37-89, wherein the therapeutic agent is a 5-hydroxytryptamine receptor agonist, for example tegaserod.

91. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-90, wherein the therapeutic agent is a30blood schizonticide, for example mefloquine (e.g., mefloquine hydrochloride).

92. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-91, wherein the therapeutic agent is a metalloproteinase inhibitor, for example abametapir. 287PAT059979-WO-PCT 93. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-92, wherein the therapeutic agent is an inosine monophosphate dehydrogenase inhibitor, for example mycophenolate or 5 mycophenolic acid, and combinations thereof.

94. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-93, wherein the therapeutic agent is a D2 receptor antagonist, for example thioridazine (e.g., thioridazine hydrochloride),10pimozide, trifluoperazine (e.g., trifluoperazine dihydrochloride), prochlorperazine (e.g., prochlorperazine dimaleate), perphenazine, triflupromazine (e.g., triflupromazine hydrochloride), asenapine (e.g., asenapine maleate), iloperidone, or lurasidone (e.g., lurasidone hydrochloride), and combinations thereof. 15 95. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-94, wherein the therapeutic agent is a serotonin reuptake inhibitor, for example sertraline (e.g., sertraline hydrochloride), nortriptyline (e.g., nortriptyline hydrochloride), fluoxetine, clomipramine (e.g., clomipramine hydrochloride), paroxetine (e.g., paroxetine hydrochloride), or20 nefazodone (e.g., nefazodone hydrochloride), and combinations thereof.

96. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-95, wherein the therapeutic agent is a haem polymerase inhibitor, for example amodiaquine (e.g., amodiaquine 25 dihydrochloride dihydrate) or halofantrine (e.g., halofantrine hydrochloride), and combinations thereof.

97. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-96, wherein the therapeutic agent is an30acetylcholinesterase inhibitor, for example carbaryl.

98. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-97, wherein the therapeutic agent is a 288PAT059979-WO-PCT selective estrogen receptor modulator, for example tamoxifen or raloxifene (e.g., raloxifene hydrochloride), and combinations thereof.

99. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or 5 the combination according to any of claims 37-98, wherein the therapeutic agent is a D2 receptor agonist, for example brexpiprazole, aripiprazole, or dopamine (e.g., dopamine hydrochloride), and combinations thereof.

100. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or10the combination according to any of claims 37-99, wherein the therapeutic agent is a lanosterol 14-α-demethylase inhibitor, for example itraconazole.

101. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-100, wherein the therapeutic agent is a 15 dihydrofolate reductase inhibitor, for example pyrimethamine.

102. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-101, wherein the therapeutic agent is a HIV protease inhibitor, for example lopinavir. 20 103. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-102, wherein the therapeutic agent is a vitamin D receptor agonist, for example paricalcitol. 25 104. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-103, wherein the therapeutic agent is a calcium-sensing receptor (CaR) modulator, for example cinacalcet (e.g., cinacalcet hydrochloride).30105. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-104, wherein the therapeutic agent is a norepinephrine reuptake inhibitor, for example maprotiline (e.g., maprotiline hydrochloride), duloxetine (e.g., duloxetine hydrochloride), or amoxapine, and combinations thereof. 289PAT059979-WO-PCT 106. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-105, wherein the therapeutic agent is a 17α-hydroxylase / C17,20-lyase (CYP17) inhibitor, for example abiraterone (e.g., 5 abiraterone acetate).

107. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-106, wherein the therapeutic agent is a HMG-CoA reductase inhibitor, for example bifonazole. 10 108. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-107, wherein the therapeutic agent is a H1-receptor antagonist, for example azelastine (e.g., azelastine hydrochloride), clemastine (e.g., clemastine hydrochloride), or chlorpromazine (e.g., chlorpromazine 15 hydrochloride), and combinations thereof.

109. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-108, wherein the therapeutic agent is a μ-receptor agonist, for example loperamide (e.g., loperamide hydrochloride). 20 110. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-109, wherein the therapeutic agent is a pancreatic lipase inhibitor, for example orlistat. 25 111. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-110, wherein the therapeutic agent is a progesterone receptor modulator, for example mifepristone or ulipristal, and combinations thereof.30112. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-111, wherein the therapeutic agent is a 14α-demethylase inhibitor, for example sertaconazole. 290PAT059979-WO-PCT 113. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-112, wherein the therapeutic agent is an NS5A inhibitor, for example daclatasvir (e.g., daclatasvir dihydrochloride). 5 114. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-113, wherein the therapeutic agent is a monoamine oxidase inhibitor, for example piperacetazine.

115. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or10the combination according to any of claims 37-114, wherein the therapeutic agent is a β-adrenoceptor antagonist, for example carvedilol.

116. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-115, wherein the therapeutic agent is a 15 phosphodiesterase 4 (PDE4) inhibitor, for example drotaverine (e.g., drotaverine hydrochloride).

117. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-116, wherein the therapeutic agent is a20 5α-reductase inhibitor, for example dutasteride.

118. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-117, wherein the therapeutic agent is a calcium channel blocker, for example amlodipine (e.g., amlodipine besylate). 25 119. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-118, wherein the therapeutic agent is a muscarinic M(3) receptor antagonist, for example darifenacin (e.g., darifenacin hydrobromide). 30 120. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-119, wherein the therapeutic agent is a nuclear progesterone receptor agonist, for example progesterone. 291PAT059979-WO-PCT 121. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-120, wherein the therapeutic agent is an NK1 receptor antagonist, for example aprepitant. 5 122. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-121, wherein the therapeutic agent is an RNA polymerase inhibitor, for example rifabutin.

123. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or10the combination according to any of claims 37-122, wherein the therapeutic agent is a melanin synthesis inhibitor, for example monobenzone.

124. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-123, wherein the therapeutic agent is a 15 folic acid synthesis inhibitor, for example sulfaguanidine.

125. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-124, wherein the therapeutic agent is a DNA alkylator, for example temozolomide. 20 126. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-125, wherein the therapeutic agent is a thrombopoietin receptor agonist, for example eltrombopag. 25 127. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-126, wherein the therapeutic agent is selected from Table 9.

128. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or30the combination according to any of claims 37-127, wherein the therapeutic agent is ibrutinib, venetoclax, lenalidomide, pomalidomide, everolimus, cytarabine, clofarabine, decitabine, gemcitabine, doxorubicin, SN-38 (7-Ethyl-10- hydroxycamptothecin), fostamatinib, or vorinostat, and combinations thereof. 292PAT059979-WO-PCT 129. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-128, wherein the therapeutic agent is venetoclax. 5 130. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-129, wherein the therapeutic agent is lenalidomide.

131. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or10the combination according to any of claims 37-130, wherein the therapeutic agent is pomalidomide.

132. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-131, wherein the therapeutic agent is 15 everolimus.

133. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-132, wherein the therapeutic agent is cytarabine. 20 134. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-133, wherein the therapeutic agent is clofarabine. 25 135. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-134, wherein the therapeutic agent is decitabine.

136. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or30the combination according to any of claims 37-135, wherein the therapeutic agent is gemcitabine. 293PAT059979-WO-PCT 137. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-136, wherein the therapeutic agent is doxorubicin. 5 138. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-137, wherein the therapeutic agent is SN-38 (7-Ethyl-10-hydroxycamptothecin).

139. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or10the combination according to any of claims 37-138, wherein the therapeutic agent is fostamatinib.

140. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 37-139, wherein the therapeutic agent is 15 vorinostat.

141. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 1-140, wherein the therapeutic agent is not a VAV1 degrader. 20 142. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 1-141, wherein the VAV1 degrader is a compound of Formula (I-A): 25or a pharmaceutically acceptable salt thereof, wherein: L1is: • a bond; 294PAT059979-WO-PCT • *-O(C0-C4 alkylene)-, *-S(C0-C4 alkylene)-, *-C1-C4 alkylene-, or *-NR’(C0-C4 alkylene)-, -(C1-C4 alkylene)-C(=O)-*, *-(C1-C4 alkylene)-C(=O)-, wherein the alkylene is optionally substituted with 1-2 Raand wherein * indicates the point of attachment of L1to the ring comprising X and Y; 5 • -(C=O)-; or • taken together with Y to form an additional ring fused with the ring containing X and Y, wherein the fused ring system includes 9 or 10 ring atoms, wherein from 1-4 ring atoms in the additional ring are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd) and O, wherein the additional ring is substituted with R1 and is 10 optionally further substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc; and each one of X and Y is independently selected from the group consisting of N and CH; R1is selected from the group consisting of hydrogen, deuterium, Rb, -ORb, -S(O)0-2Rb, -N(R’)Rb, CN, halo, and –NR’C(O)R’’;15R2is selected from the group consisting of hydrogen, deuterium, CH3, CHF2, CF3, OMe, F, Cl and Br; each of R3, R4and R5is independently selected from the group consisting of hydrogen and Rc; each of R6is independently selected from the group consisting of: deuterium, halo;20 cyano; C1-10 alkyl which is optionally substituted with from 1-6 independently selected Ra; C3- 6 cycloalkyl which is optionally substituted with from 1-4 independently selected Ra; C2-6 alkenyl; C2-6 alkynyl; C1-4 alkoxy; -S(O)0-2(C1-4 alkyl); -NReRf; –OH; -S(O)1-2NR’R’’; -NO2; -C(=O)(C1-10 alkyl); -C(=O)O(C1-4 alkyl); -C(=O)OH; -N(R’)C(=O)(C1-4 alkyl), - C(=O)NR’R’’, Rg, and –(CH2)1-2 Rg;25n is selected from 0, 1, 2 and 3; R7is selected from the group consisting of hydrogen, deuterium, CH3, CHF2, CF3, OMe, F, Cl and Br; each occurrence of Rais independently selected from the group consisting of: –OH; - halo; –NReRf; C1-4 alkoxy; C1-4 haloalkoxy; -C(=O)O(C1-4 alkyl); -C(=O)(C1-4 alkyl); - 30 C(=O)OH; -CONR’R’’; -S(O)1-2NR’R’’; -S(O)1-2(C1-4 alkyl); and cyano; each occurrence of Rbis independently selected from the group consisting of: • C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc; 295PAT059979-WO-PCT • heterocyclyl or heterocycloalkenyl including 3-10 ring atoms, wherein from 1- 3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo 5 and Rc; • 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(Rd), O, and S(O)0-2, wherein at least one ring in the system is aromatic and wherein the heteroaryl is optionally substituted with from 1-4 substituents independently selected from oxo and Rc; and 10 • C6-10 aryl optionally substituted with from 1-4 substituents independently selected Rc; each occurrence of Rcis independently selected from the group consisting of: deuterium; halo; cyano; C1-10 alkyl which is optionally substituted with from 1-6 independently selected Ra; C3-6 cycloalkyl which is optionally substituted with from 1-4 independently15selected Ra; C2-6 alkenyl; C2-6 alkynyl; C1-4 alkoxy; -S(O)0-2(C1-4 alkyl); -NReRf; –OH; -S(O)1- 2NR’R’’; -NO2; -C(=O)(C1-10 alkyl); -C(=O)O(C1-4 alkyl); -C(=O)OH; -N(R’)C(=O)(C1-4 alkyl), -C(=O)NR’R’’, Rg, and –(CH2)1-2 Rg; each occurrence of Rdis independently selected from the group consisting of: hydrogen, deuterium, C1-6 alkyl optionally substituted with from 1-3 independently selected 20 Ra; -C(O)(C1-4 alkyl); -C(O)O(C1-4 alkyl); -CONR’R’’; -S(O)1-2NR’R’’; -S(O)1-2(C1-4 alkyl); -OH; and C1-4 alkoxy; each occurrence of Reand Rfis independently selected from the group consisting of: H; deuterium; C1-6 alkyl; -C(O)(C1-4 alkyl); -C(O)O(C1-4 alkyl); -CONR’R’’; -S(O)1-2NR’R’’; -S(O)1-2(C1-4 alkyl); -OH; and C1-4 alkoxy; and25each occurrence of Rgis independently selected from the group consisting of: • C3-7 cycloalkyl or C3-7 cycloalkenyl, each of which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Ra; • heterocyclyl or heterocycloalkenyl including 3-7 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), 30 N(Rd), O, and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Ra; 296PAT059979-WO-PCT • 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(Rd), O, and S(O)0-2, wherein at least one ring in the system is aromatic and wherein the heteroaryl is optionally substituted with from 1-4 oxo or Ra; and 5 • C6-10 aryl optionally substituted with from 1-4 Ra; each occurrence of R’ and R’’ is independently selected from the group consisting of: hydrogen; and C1-4 alkyl.

143. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or 10 the combination according to claim 142, wherein the VAV1 degrader is a compound of Formula (I-B):Formula (I-B) or a pharmaceutically acceptable salt thereof, wherein L1, X, Y, R1, R2, R3, R4, R5, R615 and n are as defined for Formula I-A.

144. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to claim 142 or 143, wherein the VAV1 degrader is a compound of Formula (I-J): 20Formula (I-J) or a pharmaceutically acceptable salt thereof, wherein: L1is a bond, -(C=O)-, *-O(C0-C4 alkylene)-, *-C1-C4 alkylene-, *-NR’(C0-C425alkylene)-, *-NR’(C=O)(C0-C4 alkylene)-, or *-(C1-C4 alkylene)-C(=O)-, wherein the alkylene 297PAT059979-WO-PCT is optionally substituted with 1-2 Raand wherein * indicates the point of attachment of L1to the ring; or L1is taken together with Y to form an additional ring fused with the ring containing X and Y, wherein the fused ring system includes 9 or 10 ring atoms, wherein from 1-4 ring atoms 5 in the additional ring are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd) and O, wherein the additional ring is substituted with R1 and is optionally further substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc; wherein X and Y are both CH or one of X and Y is N and the other is CH;10wherein R1is Rb; wherein R2is hydrogen, chloro, fluoro or methyl; wherein R3, R4and R5are hydrogen or halo; wherein R6is selected from the group consisting of deuterium, halo and unsubstituted C1-10 alkyl; 15 wherein Rbis: • heterocyclyl or heterocycloalkenyl including 3-10 ring atoms, wherein from 1- 3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group 20 consisting of oxo and Rc; or • 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(Rd), O, and S(O)0-2, wherein at least one ring in the system is aromatic and wherein the heteroaryl is optionally substituted with from 1-4 substituents independently selected 25 from oxo and Rc; and wherein Rcis independently selected from the group consisting of: halo; C1-10 alkyl which is optionally substituted with from 1-6 independently selected Ra; C1-4 alkoxy; Rg, and –(CH2)1-2 Rg. 30 145. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 142-144, wherein: 298PAT059979-WO-PCT L1is a bond, -(C=O)-, *-O(C0-C4 alkylene)-, *-C1-C4 alkylene-, *- NR’(C0-C4 alkylene)-, *-NR’(C=O)(C0-C4 alkylene)-, or *-(C1-C4 alkylene)-C(=O)-, wherein the alkylene is optionally substituted with 1-2 Raand wherein * indicates the point of attachment of L1to the ring; or 5 L1is taken together with Y to form an additional ring fused with the ring containing X and Y, wherein the fused ring system includes 9 or 10 ring atoms, wherein from 1-4 ring atoms in the additional ring are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd) and O, wherein the additional ring is substituted with R1 and is optionally further substituted with from 1-4 substituents10independently selected from the group consisting of oxo and Rc; wherein X and Y are both CH or one of X and Y is N and the other is CH; wherein R1is Rb; wherein R2is hydrogen, chloro, fluoro or methyl; wherein R3, R4and R5are hydrogen or halo; 15 wherein n is 0; wherein Rbis: • heterocyclyl or heterocycloalkenyl including 5-10 ring atoms, wherein from 1- 3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl is 20 optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc; or • 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(Rd), O, and S(O)0-2, wherein at least one ring in the system is aromatic and wherein the 25 heteroaryl is optionally substituted with from 1-4 substituents independently selected from oxo and Rc.

146. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 1-141, wherein the VAV1 degrader is a 30 compound of Formula (II-A) 299PAT059979-WO-PCTor a pharmaceutically acceptable salt thereof, wherein: 5 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; 10 •, wherein Z is the point of attachment to L, Y and Z are 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:15• a bond; or • *-O(C1-C4 alkylene)-, *-C1-C4 alkylene-, *-NR9(C0-C4 alkylene)-, *- NR9(C=O)(C0-C4 alkylene)-, -NR9(C=O)(C0-C4 alkylene)-*, -(C1-C4 alkylene)- C(=O)-*, or *-(C1-C4 alkylene)-C(=O)-, wherein the alkylene is optionally substituted with 1-2 R7and wherein * indicates the point of attachment of L to 20 Ring A, wherein L is a bond or *-C1-C4 alkylene- when Z is N; Ring B is selected from the group consisting of: 300PAT059979-WO-PCT • 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 5 substituents independently selected from the group consisting of oxo and R8; • 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 10 substituents independently selected from oxo and R8; 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); -15OH; C1-4 alkoxy; -C0-6alkylene(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, 20 OMe, F, Cl and Br; each of R3, R4and R5is independently selected from the group consisting of hydrogen, deuterium, halo, cyano, C1-4 alkyl which is optionally substituted with from 1-4 independently selected R10, C3-4 cycloalkyl which is optionally substituted with from 1-325 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: hydrogen; oxo; deuterium, halo; cyano; C1-4 alkyl which is optionally substituted with from 30 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; C2-4 alkynyl which is optionally substituted with from 1-4 301PAT059979-WO-PCT independently selected R11; C1-4 alkoxy 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; - 5 halo; –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(C1-4 alkyl); and cyano; or two R7can be taken together to form a C3-4 cycloalkyl ring; each occurrence of R8is independently selected from the group consisting of:10deuterium; 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; C2-6 alkenyl which is optionally substituted with from 1-6 independently selected R12; C2-6 alkynyl which is optionally substituted with from 1-6 independently selected R12; C1- 15 4 alkoxy which is optionally substituted with from 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,20 deuterium, C1-4 alkoxy; and C1-4 alkyl;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; 25 each 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(C1-4 alkyl); C3-6 cycloalkyl; and cyano;30each 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. 302PAT059979-WO-PCT 147. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to claim 146, wherein the VAV1 degrader is of Formula (II-E):5 Formula (II-E) or a pharmaceutically acceptable salt thereof.

148. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to claim 146 or 147, 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 CH and N, and wherein a maximum of one of X1, X2and X3may be N; or 15 •, wherein Z is the point of attachment to L, and Y and Z are independently selected from the group consisting of CH and N; Ring B is selected from the group consisting of: • heterocyclyl or heterocycloalkenyl including 5-9 ring atoms, wherein from 1-4 ring20atoms 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 • heteroaryl including 5-9 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each 25 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 303PAT059979-WO-PCT 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 5 alkylene-, 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.

149. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or10the combination according to any of claims 146-148, 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 15 maximum of one of X1and X2may be N; or •, wherein N is the point of attachment to L and Y is selected from the group consisting of CH and N; Ring B is selected from the group consisting of: 20 • 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; or25• 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 304PAT059979-WO-PCT 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 of attachment of L to Ring A, wherein L is a bond or *-C1-C4 5 alkylene- when Z is N.

150. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to claim 146-149, wherein the VAV1 degrader is a compound of Formula (II-F):10Formula (II-F) or a pharmaceutically acceptable salt thereof, wherein:15Ring 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 20 the group 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 25 heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R8; or 305PAT059979-WO-PCT • 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 5 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 of attachment of L to Ring A, wherein L is a bond or *-C1-C4 alkylene- when Z is N. 10 151. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 1-141, wherein the VAV1 degrader is a compound of Formula (III-A): 15or a pharmaceutically acceptable salt thereof, wherein:20Ring A is selected from the group consisting of:, wherein Z is the point of attachment to L, Y and Z are independently selected from the group consisting of CH, CR14and N, and wherein m is 0 or 1; or 306PAT059979-WO-PCT, wherein Z is the point of attachment to L, Y and Z are independently selected from the group consisting of CH, CR14and N, and wherein at least one of Y and Z must be N; or, optionally substituted with from 1 to 4 independently selected R65substituents, wherein p and q are independently 1, 2 or 3, and wherein n and r are independently 0 or 1; or, optionally substituted with from 1 to 4 independently selected R6substituents, wherein s, t, u and v are independently 1 or 2; 10 L is selected from the group consisting of: • a bond; or • *-O(C1-C4 alkylene)-, *-C1-C4 alkylene-, *-C(=O)(O)-, *-C1-C4 cycloalkylene, *- *-NR9(C0-C4 alkylene)-, *-NR9(C=O)(C0-C4 alkylene)-, -NR9(C=O)(C0-C4 alkylene)-*, -(C1-C4 alkylene)-C(=O)-*, or *-(C1-C4 alkylene)-C(=O)-, wherein 15 the alkylene is optionally substituted with 1-2 R7and wherein * indicates the point of attachment of L to Ring A; Ring B is selected from the group consisting of: • cycloalkyl including 5-6 ring atoms, wherein the cycloalkyl is optionally20substituted with from 1-4 substituents independently selected from the group consisting of oxo and R8; 307PAT059979-WO-PCT • 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 5 substituents independently selected from the group consisting of oxo and R8; • phenyl, wherein the phenyl is optionally substituted with from 1-4 R8substituents; • 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 10 of the carbon atoms of the heteroaryl are optionally substituted with from 1-4 substituents independently selected from oxo and R8; and each R1is independently selected from the group consisting of:, deuterium, halo, C1-6 alkyl optionally substituted with from 1-4 independently selected R13; -C(O)(C1-4 alkyl)15optionally substituted with from 1-4 independently selected R13; -C(O)O(C1-4 alkyl) optionally substituted with from 1-4 independently selected R13; -S(O)1-2(C1-4 alkyl) optionally substituted with from 1-4 independently selected R13; -OH; C1-4 alkoxy optionally substituted with from 1-4 independently selected R13; -C0-6alkyl(C3-6 cycloalkyl) optionally substituted with from 1- 4 independently selected R13; and -C0-6alkyl(C3-6 heterocyclyl) optionally substituted with from 20 1-4 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, C1-4 alkyl which is optionally substituted with from 1-4 independently selected R10, C3-4 cycloalkyl which is optionally substituted with from 1-4 independently selected R10, C2-4 alkenyl which is optionally substituted with from 1-4 independently selected R10, C2-4 alkynyl which is optionally substituted with from 1-4 30 independently selected R10, C1-4 alkoxy which is optionally substituted with from 1-4 independently selected R10, -NR9R9, –OH, -NO2, and -C(=O)OH; 308PAT059979-WO-PCT each of R6, 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; C3-4 cycloalkyl which is optionally substituted with from 1-4 independently selected R11; C2-4 alkenyl which is optionally substituted with from 1-4 5 independently selected R11; C2-4 alkynyl which is optionally substituted with from 1-4 independently selected R11; C1-4 alkoxy which is optionally substituted with from 1-4 independently selected R11; –OH; -NO2; and -C(=O)OH; each R8is independently selected from the group consisting of: deuterium; halo; cyano;10C1-6 alkyl which is optionally substituted with from 1-4 independently selected R12; C1-6 haloalkyl which is optionally substituted with from 1-4 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 1-4 independently selected R12; C2-6 alkynyl which is optionally substituted with from 1-4 independently selected R12; C1-4 alkoxy which is 15 optionally substituted with from 1-4 independently selected R12; C1-4 haloalkoxy which is optionally substituted with from 1-4 independently selected R12; -NR9R9; –OH; -NO2; and - C(=O)OH; each R9is independently selected from the group consisting of: hydrogen; deuterium;;20 C1-4 alkoxy; and C1-4 alkyl;each of R7, R10, R11, R12, and R13is independently selected from the group consisting of: deuterium, –OH; -halo; –NR9R9; C1-4 alkoxy; C1-4 haloalkoxy; -C(=O)O(C1-4 alkyl); - C(=O)(C1-4 alkyl); -C(=O)OH; -S(O)1-2(C1-4 alkyl); and cyano; 25 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; and R15is selected from the group consisting of hydrogen, deuterium, fluorine, and methyl. 30 152. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to claim 151, wherein the VAV1 degrader is of Formula (III-D): 309PAT059979-WO-PCTFormula (III-D) or a pharmaceutically acceptable salt thereof. 5 153. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to claim 151 or 152, wherein: Ring A is selected from the group consisting of: •, wherein Z is the point of attachment to L, Y and Z are independently selected from the group consisting of CH and N, wherein at least10one of Y and Z is N and wherein one of the carbon atoms is optionally substituted with an oxo substituent; or •, wherein * indicates the point of attachment to L and wherein one of the carbon atoms is optionally substituted with an oxo substituent; or •, wherein p and q are independently 1, 2 or 3, wherein n and r15are independently 0 or 1 and wherein one of the carbon atoms is optionally substituted with an oxo substituent; or •, wherein s, t, u and v are independently 1 or 2 and wherein one of the carbon atoms is optionally substituted with an oxo substituent; 20 Ring B is selected from the group consisting of: 310PAT059979-WO-PCT • cycloalkyl including 5-6 ring atoms; • heterocyclyl or heterocycloalkenyl including 5-9 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, and wherein one or more of the carbon atoms of the 5 heterocyclyl or heterocycloalkenyl are optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R8; • phenyl, wherein the phenyl is optionally substituted with one R8substituent; • heteroaryl 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, 10 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; and L is selected from the group consisting of a bond, *-C1-C4 alkylene-, *-C(=O)(O)-, and - 15 (C1-C4 alkylene)-C(=O)-*, wherein the alkylene is optionally substituted with 1-2 R7and wherein * indicates the point of attachment of L to Ring A.

154. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 151-153, wherein the VAV1 degrader is 20 of Formula (III-E):Formula (III-E) or a pharmaceutically acceptable salt thereof; or 25 wherein the compound is of Formula (III-F): 311PAT059979-WO-PCTFormula (III-F) or a pharmaceutically acceptable salt thereof. 5 155. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to claim 151 or 152 wherein the VAV1 degrader is of Formula (III-G):10 Formula (III-G) or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from the group consisting of: •, wherein Z is the point of attachment to L, Y and Z are independently selected from the group consisting of CH and N, wherein at least 15 one of Y and Z is N and wherein one of the carbon atoms is optionally substituted with an oxo substituent; or •, wherein Z is the point of attachment to L, Y and Z are independently selected from the group consisting of CH and N, wherein at least one of Y and Z must be N, and wherein one of the carbon atoms is 20 optionally substituted with an oxo substituent; or 312PAT059979-WO-PCT •, wherein p and q are independently 1, 2 or 3, wherein n and r are independently 0 or 1 and wherein one of the carbon atoms is optionally substituted with an oxo substituent; or •, wherein s, t, u and v are independently 1 or 2 and wherein 5 one of the carbon atoms is optionally substituted with an oxo substituent; Ring B is selected from the group consisting of: • cycloalkyl including 5-6 ring atoms; • heterocyclyl or heterocycloalkenyl including 5-9 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of 10 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; • phenyl, wherein the phenyl is optionally substituted with one R8substituent; • heteroaryl including 5-9 ring atoms, wherein from 1-3 ring atoms are heteroatoms, 15 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; and L is selected from the group consisting of a bond, *-C1-C4 alkylene-, *-C(=O)(O)-, and -20(C1-C4 alkylene)-C(=O)-*, wherein the alkylene is optionally substituted with 1-2 R7and wherein * indicates the point of attachment of L to Ring A.

156. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 1-141, wherein the VAV1 degrader is 25 selected from any of Tables 1, 2, 3, or 4. 313PAT059979-WO-PCT 157. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to claim 156, wherein the VAV1 degrader is selected from Table 1. 5 158. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to claim 156, wherein the VAV1 degrader is selected from Table 2.

159. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or10the combination according to claim 156, wherein the VAV1 degrader is selected from Table 3.

160. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to claim 156, wherein the VAV1 degrader is selected from 15 Table 4.

161. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to any of claims 1-145, or 160, wherein the VAV1 degrader20therapeutic agent is a BTK inhibitor.

162. The VAV1 degrader for use, the therapeutic agent for use, the combination for use, or the combination according to claim 161, wherein the VAV1 degrader is, or a pharmaceutically acceptable salt thereof, and the 25 therapeutic agent is remibrutinib. 314

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