Piperidine-2, 6-dione derivatives useful for the targeted degradation of VAV1

Abstract

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

Description

[0001] PIPERIDINE-2, 6-DIONE DERIVATIVES USEFUL FOR THE TARGETED DEGRADATION OF VAV1

[0002] TECHNICAL FIELD

[0003] This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt thereof) that degrade human Proto-oncogene VAV 1 protein (VAV1). These chemical entities are useful, e.g., for treating a subject (e.g., a human subject) having a disorder or disease that can be treated by reducing the level of VAV1. This disclosure also features compositions containing these chemical entities as well as methods of using and making these chemical entities.

[0004] BACKGROUND

[0005] 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 diseases. One such modality relies on redirecting the activity of E3 ligases such as cereblon (a phenomenon known as E3 reprogramming) using low molecular weight compounds, which have been termed molecular glues (also called molecular glue degraders; “MGDs”), to promote the poly-ubiquitination and ultimately proteasomal degradation of new protein substrates involved in the development of diseases. Molecular glues bind to both the E3 ligase and the target protein. 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 cancers.

[0006] VAV family proteins, including VAV1, VAV2 and VAV3, are guanine nucleotide exchange factors (GEFs) for Rho family GTPases. VAV1 is a 95 kDa protein that is a positive regulator of T cell receptor and B cell receptor signaling. VAV1 expression is normally highly restricted to hematopoietic cells. VAV1 becomes rapidly phosphorylated on tyrosine in response to a variety of stimuli, including stimulation of T-cell receptor (TCR), B cell receptor (BCR), 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 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 (NF AT), interferon gamma (IFNy) and Interleukin-2 (IL-2) cytokine secretion. Knock-in mice having a mutated VAV1 with disrupted GEF activity, but intact GEF- independent function, show reduced T cells proliferation and activation in response to allogeneic stimulation and showed reduced expansion of T cells in a systemic graft-versus-host model (Haubert et al. 2012 Transplantation Immunology 26: 212, 2012). VAV1 deficient mice are resistant to MOG(5-55)-induced experimental autoimmune encephalomyelitis (EAE), a commonly used model of multiple sclerosis (Korn et al. 2003 Journal of Neuroimmunology 139: 17). Finally, genome-wide CRISPR activation (CRISPRa) and interference (CRISPRi) screens in primary human T cells identified VAV1 as an important positive regulator of T cell function (Schmidt et al. 2022 Science 375:6580).

[0007] SUMMARY

[0008] This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt thereof) that degrade Proto-oncogene VAV 1 protein (VAV1). These chemical entities are useful, e.g., for treating a subject (e.g., a human subject) having a disorder or disease that can be treated by reducing the level of VAV1, thereby reducing VAV activity in cells. By reducing the level of VAV1, the chemical entities can reduce signaling in certain immune cell activation pathways. For example, the chemical entities may be used to reduce inflammation or autoimmune activity. They may be useful for treating, for example, multiple sclerosis, rheumatoid arthritis, myasthenia gravis, chronic lymphocytic leukemia, ulcerative colitis, psoriasis, cutaneous lupus, axial spondylarthritis, graft versus host disease, and other disorders referred to herein. This disclosure also features compositions containing the chemical entities as well as methods of using and making the same.

[0009] VAV1 is a dominant signal transduction protein in the adaptive immune system. It is a positive regulator of immune receptor signaling in both T cells and B cells. Thus, reduction in VAV 1 can reduce immune cell activation, immune cell proliferation and the production of various cytokines. For at least these reasons, degradation of VAV 1 can be therapeutically beneficial in a variety of disease conditions.

[0010] In one aspect, this disclosure features compounds of Formula (I) or pharmaceutically acceptable salts thereof,

[0011] Formula (I) in which Ring A, Ring B, L, R2, R3, R4, R5and R15can be as defined anywhere here.

[0012] DEFINITIONS

[0013] The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1-19. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino 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 using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, 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, alkaline earth metal, ammonium and N+(Cwalkyl)4 salts. 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, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0014] As used herein, “VAV1” refers to naturally occurring VAV1, also known as Vav or p95vav, (e.g. mammalian, preferably human (Homo sapiens) VAV1) and encompasses naturally occurring variants, such as allelic variants and splice variants, which retain VAV1 functional activity.

[0015] A “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g, infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and / or a nonhuman animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. Preferably, the subject is a human.

[0016] Disease, disorder, and condition are used interchangeably herein.

[0017] 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 specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition (“therapeutic treatment”).

[0018] 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 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.

[0019] As used herein, and unless otherwise specified, a “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, 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 therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0020] The compounds described herein also include isotopically labeled compounds which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as2H,3H,13C,14C,15N,180,170,31P,32P,35S,18F, and36C1, respectively. For example, a compound of the disclosure may have one or more H atom replaced with deuterium.

[0021] The term "halo" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

[0022] The term "alkyl" refers to a saturated acyclic hydrocarbon radical that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, Ci-io indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it. Non-limiting examples include methyl, ethyl, Ao-propyl, tert-butyl, n-hexyl. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms and other available valences occupied by hydrogen and / or other substituents as defined herein.

[0023] The term "haloalkyl" refers to an alkyl, in which one or more hydrogen atoms is / are replaced with an independently selected halo.

[0024] The term "alkoxy" refers to an -O-alkyl radical (e.g., -OCH3).

[0025] The term "alkylene" refers to a divalent alkyl (e.g., -CH2-).

[0026] 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 have from 2 to 6 (inclusive) carbon atoms in it.

[0027] The term "alkynyl" refers to an acyclic hydrocarbon chain that may be a straight chain or branched chain having one or more carbon-carbon triple bonds. The alkynyl moiety contains the indicated number of carbon atoms. For example, C2-6 indicates that the group may have from 2 to 6 (inclusive) carbon atoms in it.

[0028] The term "aryl" refers to a 6-20 carbon mono-, bi-, tri- or polycyclic group wherein at least one ring in the system is aromatic (e.g., 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system). Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, dihydro- IH-indenyl and the like.

[0029] The term "cycloalkyl" as used herein refers to cyclic saturated hydrocarbon groups having, e.g., 3 to 12 ring carbons, more preferably, 3-10 ring carbons or more preferably 3-6 ring carbons. 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[l.l.l]pentanyl, bicyclo[3.1.0]hexanyl, bicyclo[2.1.1]hexanyl, bicyclo[3.2.0]heptanyl, bicyclo[4.1.0]heptanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[4.2.0]octanyl, bicyclo[3.2.1]octanyl, bicyclo[2.2.2]octanyl, and the like. Cycloalkyl also includes 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, 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.

[0030] The term "cycloalkenyl" as used herein means partially unsaturated cyclic hydrocarbon groups having 3 to 12 ring carbons, preferably 3 to 10 ring carbons, and more preferably 3 to 6. 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 aromatic, and the cycloalkenyl group is not fully saturated overall. Cycloalkenyl may include multiple fused and / or bridged and / or spirocyclic rings.

[0031] The term “heteroaryl”, as used herein, means a mono-, bi-, tri- or polycyclic group having 5 to 10 ring atoms, and having pi electrons shared in a cyclic array; wherein at least one ring in 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). Examples of heteroaryl include 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-<i]pyrimidinyl, pyrrolo[2,3- Z?]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-Z?]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[4,3-Z?]pyridinyl, tetrazolyl, chromanyl, 2,3-dihydrobenzo[Z?][l,4]dioxinyl, benzo[<7][l,3]dioxolyl, 2, 3 -dihydrobenzofuranyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[Z?][l,4]oxathiinyl, isoindolinyl, and others. In some embodiments, the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl.

[0032] The term "heterocyclyl" refers to a mon-, bi-, tri-, or polycyclic saturated ring system with 5-10 ring atoms (e.g., 4-6 membered monocyclic, or 7-9 membered bicyclic, ring system), wherein one or more ring atoms are heteroatoms, said heteroatoms selected from O, N, or S. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like. Heterocyclyl may include multiple fused and bridged rings. Non-limiting examples of fused / bridged heteorocyclyl includes: 2-azabicyclo[1.1.0]butanyl, 2-azabicyclo[2.1.0]pentanyl,

[0033] 2-azabicyclo[l.l.l]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-oxabicyclo[l.l.l]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., 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, l-azaspiro[3.5]nonanyl, 2-azaspiro[3.5]nonanyl, 7-azaspiro[3.5]nonanyl, 2- azaspiro[4.4]nonanyl, 6-azaspiro[2.6]nonanyl, l,7-diazaspiro[4.5]decanyl, 7- azaspiro[4.5]decanyl 2,5-diazaspiro[3.6]decanyl, 3-azaspiro[5.5]undecanyl, 2- oxaspiro[2.2]pentanyl, 4-oxaspiro[2.5]octanyl, l-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, l-oxaspiro[5.5]undecanyl, 3- oxaspiro[5.5]undecanyl, 3-oxa-9-azaspiro[5.5]undecanyl and the like. The term “saturated” as used in this context means only single bonds present between constituent ring atoms and other available valences occupied by hydrogen and / or other substituents as defined herein.

[0034] The term "heterocycloalkenyl" as used herein means partially unsaturated cyclic ring system with 5-10 ring atoms (e.g., a monocyclic, bicyclic, or tricyclic ring system) wherein one or more ring atoms are heteroatoms, said heteroatoms selected from O, N, or S. Examples of heterocycloalkenyl groups include, without limitation, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl. As partially 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.

[0035] Certain groups, such as , can be considered as either: (i) a heterocycloalkenyl which is substituted with an oxo group; or (ii) a heteroaryl group.

[0036] As used herein, when a ring is described as being “aromatic”, it means said ring has a continuous, delocalized 7t-electron system. Typically, the number of out of plane 7t-electrons corresponds to the Hiickel rule (4n+2). Examples of such rings include: benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thioazole, isoxazole, isothiazole, and the like.

[0037] 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 triple bonds between constituent ring atoms), provided that the ring is not aromatic. Examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like. For the avoidance of doubt, and unless otherwise specified, for rings and cyclic groups

[0038] (e.g., aryl, heteroaryl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, cycloalkyl, and the like described herein) containing a sufficient number of ring atoms to form bicyclic or higher order ring systems (e.g., tricyclic, polycyclic ring systems), it is understood that such rings and cyclic groups encompass those having fused rings, including those in which the points of fusion are located (i) on adjacent ring atoms (e.g., [x.x.O] ring systems, in which 0 represents a zero atom stems having all bridge lengths

[0039] 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 limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include13C and14C.

[0040] 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 disclosure of a compound with the group also a disclosure of a compound with the group

[0041] OH s another non-limiting example, a disclosure of a compound with the group also a disclosure of a compound with the group

[0042] 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, and mixtures thereof. All such stereoisomeric forms are included within the embodiments disclosed herein, including mixtures thereof.

[0043] Further, compounds having 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 racemic mixture, of the (R) and (S) stereoisomers if the stereoisomers epimerise. For example, a stereoisomeric form indicated encompasses the isolated entantiomer and a mixture, such as a racemic mixture. For example a disclosure of a compound according to Formula (I), As used herein, the phrase “optionally substituted” when used in conjunction with a structural moiety (e.g., alkyl) is intended to encompass both the unsubstituted structural moiety (i.e., none of the substitutable hydrogen atoms are replaced with one or more non-hydrogen substituents) and substituted structural moieties substituted with the indicated range of nonhydrogen 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.

[0044] As used herein, the term "antibody" encompasses an immunoglobulin, whether natural or partly or wholly synthetically produced, and fragments thereof. The term also covers any protein having a binding domain that is homologous to an immunoglobulin binding domain. “Antibody” further includes a polypeptide comprising a framework region from an immunoglobulin gene or fragments thereof that specifically binds and recognizes an antigen. Use of the term antibody is meant to include whole antibodies, polyclonal, monoclonal and recombinant antibodies, fragments thereof, and further includes single-chain antibodies, humanized antibodies, murine antibodies, chimeric, mouse-human, mouse-primate, primate-human monoclonal antibodies, anti-idiotype antibodies, antibody fragments, such as, e.g., scFv, (scFv)2, Fab, Fab', and F(ab')2, F(abl)2, Fv, dAb, and Fd fragments, diabodies, and antibody-related polypeptides. Antibody includes bispecific antibodies and multispecific antibodies so long as they exhibit the desired biological activity or function.

[0045] As used herein, an “antibody fragment” compnses a portion of an intact antibody, generally the antigen binding or variable region thereof. Examples of antibody fragments include Fab, Fab', F(ab').sub.2, and Fv fragments; diabodies; linear antibodies; fragments produced by a Fab expression library, anti-idiotypic (anti-Id) antibodies, CDR (complementary determining region), and epitope-binding fragments of any of the above which immunospecifically bind to cancer cell antigens, viral antigens or microbial antigens, single-chain antibody molecules; and multispecific antibodies formed from antibody fragments.

[0046] As used herein, the term "antibody-drug conjugate" refers to an antibody or antibody fragment linked, e.g., covalently, to a compound of the disclosure.

[0047] The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features and advantages of the invention will be apparent from the description and drawings, and from the claims.

[0048] DESCRIPTION OF DRAWINGS

[0049] FIG. 1 shows Compound 37 (“VAV1 MGD”) concentration in serum 6 hours after seven consecutive daily doses at indicated doses (left) 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).

[0050] FIG. 2 shows Compound 16 (“VAV1 MGD”) concentration in serum (left) after seven consecutive daily doses at increasing doses and associated VAV1 levels normalized to b-actin protein levels in PBMCs relative to vehicle 6 and 24 hours after 7 consecutive daily oral doses of VAV1 MGD at indicated doses (right).

[0051] FIG. 3 shows Compound 35 (“VAV1 MGD”) concentration in serum (left) after seven consecutive daily doses at increasing doses and associated VAV1 levels normalized to b-actin protein levels in PBMCs relative to vehicle 6 and 24 hours after 7 consecutive daily oral doses of VAV1 MGD at indicated doses (right).

[0052] FIG. 4 shows dose-dependent decrease in VAV 1 levels in primary human CD3+ T cells, CD 19+ B cells, and CD 14+ monocytes following 24h treatment with Compound 16 (“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).

[0053] FIG. 5 shows dose-dependent decrease in VAV 1 levels in primary human CD3+ T cells, CD 19+ B cells, and CD 14+ monocytes following 24h treatment with Compound 35 (“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).

[0054] FIG. 6 shows that VAV1 degradation results in inhibition of various hallmarks of TCR- mediated activity following TCR stimulation of primary human T-cells. Cells were treated with Compound 16 (“VAV1 MGD”) for 24h followed by TCR stimulation (anti-CD3 / anti-CD28). CD69 surface expression (24 hr), IL-2 secretion (48 hr), and proliferation (96 hr) were evaluated at various timepoints following TCR stimulation (y-axis depicts percent of CD69 activation, IL-2 secretion, or proliferation relative to TCR- stimulated DMSO control ; x-axis depicts doses of VAV1 MGD). Data from N=2 donors is shown for CD69 surface expression. Data from N=1 donor is shown for IL-2 secretion and proliferation, with individual data points representing technical replicates.

[0055] FIG. 7 shows that VAV1 degradation results in inhibition of various hallmarks of TCR- mediated activity following TCR stimulation of primary human T-cells. Cells were treated with Compound 35 (“VAV1 MGD”) for 24h followed by TCR stimulation (anti-CD3 / anti-CD28). CD69 surface expression (24 hr), IL-2 secretion (48 hr), and proliferation (96 hr) were evaluated at various timepoints following TCR stimulation (y-axis depicts percent of CD69 activation, IL-2 secretion, or proliferation relative to TCR- stimulated DMSO control ; x-axis depicts doses of VAV1 MGD). Data from N=2 donors is shown for CD69 surface expression. Data from N=1 donor is shown for IL-2 secretion and proliferation, with individual data points representing technical replicates.

[0056] FIG. 8 shows a schematic diagram of the role of VAV 1 in B cell receptor signaling. Following the ligation of the B cell receptor and / or CD 19, VAV 1 is recruited to mediate phosphorylation cascades that lead to activation, cytokine secretion, and antibody production by B cells.

[0057] FIG. 9 shows a schematic diagram of the role of VAV1 in T cell receptor signaling. Following the ligation of the T cell receptor, VAV 1 is recruited to mediate phosphorylation cascades that lead to activation, cytokine secretion, and proliferation.

[0058] FIG. 10 shows 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 IgG secretion). CD69 expression was then assessed on CD 19+ B cells by flow cytometry. CD69 expression is shown as a percentage (%) change relative to stimulated DMSO controls. X-axis shows relative percentage of CD 19+ B cells expressing CD69 and y-axis shows concentration of VAV1 MGD. IL-6 secretion was assessed in the supernatant by Alphalisa. IL-6 secretion is shown as a percentage (%) change relative to stimulated DMSO controls. X-axis shows relative percentage of IL-6 level and y-axis shows concentration of VAV1 MGD. IgG secretion was assessed in the supernatant by Alphalisa. IgG secretion is shown as a percentage (%) change relative to stimulated DMSO controls. X-axis shows relative percentage of IgG level and y-axis shows concentration of VAV 1 MGD.

[0059] FIG. 11 shows 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 35 (“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 IgG secretion). CD69 expression was then assessed on CD 19+ B cells by flow cytometry. CD69 expression is shown as a percentage (%) change relative to stimulated DMSO controls. X-axis shows relative percentage of CD 19+ B cells expressing CD69 and y-axis shows concentration of VAV1 MGD. IL-6 secretion was assessed in the supernatant by Alphalisa. IL-6 secretion is shown as a percentage (%) change relative to stimulated DMSO controls. X-axis shows relative percentage of IL-6 level and y-axis shows concentration of VAV1 MGD. IgG secretion was assessed in the supernatant by Alphalisa. IgG secretion is shown as a percentage (%) change relative to stimulated DMSO controls. X-axis shows relative percentage of IgG level and y-axis shows concentration of VAV1 MGD.

[0060] FIG. 12 shows that VAV1 degradation results in inhibition TNF secretion following FcyR stimulation of primary human monocytes. Cells were treated with either Compound 16 or Compound 35 (“VAV1 MGD”) for 24h followed by FcyR stimulation (200 pg / 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).

[0061] FIG. 13 shows that VAV1 MGD treatment of REC- 1 cell line degraded VAV1 in a concentration-dependent manner. REC-1 were treated for 24 hours with the indicated concentrations of either Compound 16 or Compound 35 (“VAV1 MGD”). After treatment, VAV1 levels were assessed by western blot. Data shows VAV1 levels normalized to P-actin and relative to DMSO control.

[0062] FIG. 14 shows that VAV1 MGD treatment of REC- 1 cell line decreases growth with increasing concentration. REC-1 were treated for 5 days with the indicated concentrations of either Compound 16 or Compound 35 (“VAV1 MGDs”). After 5 days of treatment, cell growth was measured by cell titer glow and normalized to To and DMSO.

[0063] DETAILED DESCRIPTION

[0064] This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt thereof) that degrade and / or otherwise inhibit Proto-oncogene VAV 1 protein (VAV1). Said chemical entities are useful, e.g., for treating a subject (e.g., a human subject) having a disorder or disease associated with VAV1 polymorphisms. This disclosure also features compositions containing the same as well as methods of using and making the same.

[0065] Compounds

[0066] This disclosure features compounds of Formula (I) or pharmaceutically acceptable salts thereof,

[0067] Formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0068] 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, CR14and N, and wherein m is 0 or 1 ; or 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

[0069] 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 , optionally substituted with from 1 to 4 independently selected R6substituents, wherein s, t, u and v are independently 1 or 2;

[0070] L is selected from the group consisting of:

[0071] • a bond; or

[0072] • *-O(Ci-C4 alkylene)-, *-Ci-C4 alkylene-, *-C(=O)(O)-, *-Ci-C4 cycloalkylene, *- *- NR9(CO-C4alkylene)-, *-NR9(C=0)(Co-C4alkylene)-, -NR9(C=0)(Co-C4alkylene)-*, -(C1-C4 alkylene)-C(=O)-*, or *-(Ci-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;

[0073] Ring B is selected from the group consisting of:

[0074] • 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;

[0075] • 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(RX) and O, and S(0)o-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;

[0076] • phenyl, wherein the phenyl is optionally substituted with from 1-4 R8substituents;

[0077] • 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(RX), O, and S(0)o-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 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)(Ci-4 alkyl) optionally substituted with from 1-4 independently selected R13; -C(O)O(Ci-4 alkyl) optionally substituted with from 1-4 independently selected R13; -S(O)i-2(Ci-4 alkyl) optionally substituted with from 1- 4 independently selected R13; -OH; C1-4 alkoxy optionally substituted with from 1-4 independently selected R13; -Co-6alkyl(C3-6 cycloalkyl) optionally substituted with from 1-4 independently selected R13; and -Co-6alkyl(C3-6 heterocyclyl) optionally substituted with from 1-4 independently selected R13;

[0078] 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, 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 independently selected R10, C1-4 alkoxy which is optionally substituted with from 1-4 independently selected R10, -NR9R9, -OH, -NO2, and -C(=O)OH; 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 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; 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 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; C1-4 alkoxy; and Ci-4 alkyl; each of R7, R10, R11, R12, and R13is independently selected from the group consisting of: deuterium, -OH; -halo; -NR9R9; Ci-4 alkoxy; Ci-4 haloalkoxy; -C(=O)O(Ci-4 alkyl); -C(=O)(Ci-4 alkyl); -C(=O)OH; -S(O)i-2(Ci-4 alkyl); and cyano; each occurrence of R14is independently selected from the group consisting of: deuterium; -OH; -halo; C1-2 alkyl; C1-2 alkoxy; Ci-2haloalkyl; and C1-2 haloalkoxy; and

[0079] R15is selected from the group consisting of hydrogen, deuterium, fluorine, and methyl.

[0080] In some embodiments, the compound has Formula (IA):

[0081] Formula (IA) wherein at least one of Y and Z is N.

[0082] In some embodiments, the compound has Formula (IB):

[0083] Formula (IB) wherein at least one of Y and Z is N.

[0084] In some embodiments, Y and Z are both N or Y is CH or CR14and Z is N.

[0085] In some embodiments, Y and Z are both N.

[0086] In some embodiments, Y is CH or CR14and Z is N.

[0087] In some embodiments, R6A, R6B, R6Cand R6Dare each hydrogen, deuterium or oxo. In some embodiments, R6A, R6B, R6Cand R6Dare all hydrogen.

[0088] In some embodiments, Ring A is selected from: wherein * denotes the point of attachment to L.

[0089] In some embodiments, Ring optionally substituted with from 1 to 4 independently selected R6substituents.

[0090] In some embodiments, Ring A is selected from: , wherein * denotes the point of attachment to L.

[0091] In some embodiments, Ring independently selected R6substituents.

[0092] In some embodiments, Ring In some embodiments, Ring wherein Z is the point of attachment to L,

[0093] 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.

[0094] In some embodiments, Ring

[0095] 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 oxo substituent ; 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.

[0096] In some embodiments, Ring A is substituted with an oxo substituent. In some embodiments, Ring A is selected from the group consisting of: .

[0097] In some embodiments, R2is Cl.

[0098] In some embodiments, at least one of R3, R4and R5is H.

[0099] In some embodiments, at least two of R3, R4and R5is H.

[0100] In some embodiments, all of R3, R4and R5are H.

[0101] In some embodiments, the compound has Formula (II):

[0102] Formula (II) or a pharmaceutically acceptable salt thereof.

[0103] 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 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 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 , 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.

[0104] 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 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 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

[0105] • , 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;

[0106] Ring B is selected from the group consisting of:

[0107] • cycloalkyl including 5-6 ring atoms;

[0108] • 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(R') 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;

[0109] • phenyl, wherein the phenyl is optionally substituted with one R8substituent;

[0110] • 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(R'), 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

[0111] L is selected from the group consisting of a bond, *-Ci-C4 alkylene-, *-C(=O)(O)-, and -(Ci- 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, Ring A is selected from the group consisting of:

[0112] Ring B is selected from the group consisting of:

[0113] • 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(R') 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;

[0114] • 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(R'), 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; and

[0115] L is selected from the group consisting of a bond, *-Ci-C4 alkylene-, *-C(=O)(O)-, and - (C1-C4 alkylene)-C(=O)-*, wherein * indicates the point of attachment of L to Ring A.

[0116] In some embodiments, L is selected from the group consisting of a bond, *-Ci-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.

[0117] In some embodiments, L is selected from the group consisting of a bond, *-Ci-C4 alkylene-, *- C(=O)(O)-, and -(C1-C4 alkylene)-C(=O)-*, wherein * indicates the point of attachment of L to Ring A.

[0118] In some embodiments, L is a bond. In some embodiments, Ring B is selected from the group consisting of:

[0119] • cycloalkyl including 5-6 ring atoms;

[0120] • 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(R') 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;

[0121] • phenyl, wherein the phenyl is optionally substituted with one R8substituent;

[0122] • 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(R'), 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.

[0123] In some embodiments, Ring B is selected from the group consisting of:

[0124] • 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(R') 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;

[0125] • 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(R'), 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.

[0126] In some embodiments, one of the carbon atoms of the heterocyclyl, heterocycloalkenyl or heteroaryl in Ring B is substituted with an oxo substituent.

[0127] In some embodiments, R8is selected from the group consisting of: halo; Ci-4 alkoxy which is optionally substituted with from 1-6 independently selected R12; Ci-6 alkyl which is optionally substituted with from 1-6 independently selected R12. 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.

[0128] 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.

[0129] In some embodiments, R8is selected from the group consisting of: halo; methoxy, ethoxy, methyl, ethyl, propyl and butyl.

[0130] In some embodiments, R12is selected from the group consisting of: C1-4 alkoxy; and halo.

[0131] In some embodiments, R12is selected from the group consisting of: methoxy; and F.

[0132] In some embodiments, R1is selected from the group consisting of: C1-6 alkyl optionally substituted with from 1-4 independently selected R13; -Co-6alkyl(C3-6 cycloalkyl) optionally substituted with from 1-4 independently selected R13; and -Co-6alkyl(C3-6 heterocyclyl) optionally substituted with from 1-4 independently selected R13.

[0133] In some embodiments, R1is C1-6 alkyl optionally substituted with from 1-4 independently selected R13.

[0134] In some embodiments, R13is selected from the group consisting of: C1-4 alkoxy; halo; and C1-4 haloalkoxy.

[0135] In some embodiments, R13is selected from the group consisting of: methoxy; ethoxy; fluoro; and difluoromethoxy .

[0136] In some embodiments, Ring B is selected from the group consisting of: O

[0137] optionally substituted with from 1-4 R8substituents.

[0138] 5

[0139] 10

[0140] carbon atoms is optionally substituted with from 1-4 R8substituents.

[0141] 5

[0142] In some embodiments, Ring B is selected from the group consisting of:

[0143]

[0144] In some embodiments, Ring wherein * indicates the point of attachment of L to Ring A.

[0145] In some embodiments, Ring alkylene)-C(=O)-*, wherein * indicates the point of attachment of L to Ring A.

[0146] 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, -NH2, -NHR9, -NR’R9.

[0147] In some embodiments, Ring B is phenyl substituted with 1-2 halo substituents.

[0148] In some embodiments, R15is H.

[0149] In some embodiments, the compound is of Formula (IIIA): or a pharmaceutically acceptable salt thereof.

[0150] In some embodiments, the compound is of Formula (IIIA):

[0151] Formula (HIA) or a pharmaceutically acceptable salt thereof.

[0152] In some embodiments, the compound exists in a racemic mixture.

[0153] In preferred embodiments, the compound is of Formula (IV):

[0154] Formula (IV) or a pharmaceutically acceptable salt thereof, wherein:

[0155] Ring A is selected from the group consisting of:

[0156] • , 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

[0157] • , 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 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;

[0158] Ring B is selected from the group consisting of:

[0159] • cycloalkyl including 5-6 ring atoms;

[0160] • 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(R') 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;

[0161] • phenyl, wherein the phenyl is optionally substituted with one R8substituent;

[0162] • 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(R'), 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

[0163] L is selected from the group consisting of a bond, *-Ci-C4 alkylene-, *-C(=O)(O)-, and -(Ci- 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.

[0164] In some embodiments, the compound is selected from the group consisting of the compounds in Table 1, or a pharmaceutically acceptable salt thereof. Pharmaceutical Compositions

[0165] In another aspect, the present disclosure provides a pharmaceutical composition that includes any one of the compounds described herein, or a pharmaceutically acceptable salt thereof (e.g., a therapeutically effective amount of the compound or salt), and a pharmaceutically acceptable excipient.

[0166] The pharmaceutical compositions provided herein can be administered by a variety of routes including, but not limited to, oral (enteral) administration, parenteral (by injection) administration, rectal administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous (SC) administration, intravenous (IV) administration, intramuscular (IM) administration, and intranasal administration.

[0167] Details of such formulations and processing thereof are set forth in Part 8 of Remington ’s Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0168] Methods of Use

[0169] In one aspect, this disclosure features methods of degrading VAV1 in a subject, which include administering to the subject an effective amount of a compound described herein, or pharmaceutically acceptable salt thereof. The compounds described herein can bind to a specific amino acid sequence of VAV 1 , thereby causing degradation of VAV 1. In some embodiments, the compound mediates the interaction of a VAV1 protein with an E3 ligase, thereby increasing degradation of the VAV1 protein. In some embodiments, VAV1 is a regulator of a lymphocyte. In an embodiment, the compound interacts with the E3 ligase prior to the interaction of VAV1 with the E3 ligase. In some embodiments, the E3 ligase comprises cereblon.

[0170] Degradation of VAV1 is mediated by the compound interacting with both the specific amino acid sequence of VAV1 and an E3 ligase. Thus, in another aspect, this disclosure features methods of degrading VAV1, which include: (i) contacting a compound described herein or a pharmaceutically acceptable salt thereof with an E3 ligase; and (ii) interacting the contacted E3 ligase with VAV1, thereby degrading VAV1. In some embodiments, the E3 ligase comprises cereblon.

[0171] In a further aspect, this disclosure features methods of treating a variety of disorders which include administering the compounds and pharmaceutical compositions described herein. Such disorders include, without limitation, autoimmune diseases (e.g., multiple sclerosis, rheumatoid arthritis, myasthenia gravis), transplantation setting disease (e.g., graft-versus-host disease), and cancers, tumours or other malignancies, (e.g. a T cell or B cell malignancy). In an aspect, this disclosure features methods of treating a disorder caused by or associated with disregulation of lymphocyte development or activation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the disorder is autoimmune disease (e.g., multiple sclerosis, psoriatic arthritis, rheumatoid arthritis, myasthenia gravis). In some embodiments, the disorder is transplantation setting disease (e.g., graft-versus- host disease). In some embodiments, the disorder is a cancer or tumor. In some embodiments, the disorder is a malignancy (e.g., T cell or B cell malignancy). In some embodiment, the lymphocyte is T-cell. In some embodiments, the lymphocyte is B-cell.

[0172] In an aspect, this disclosure features methods of treating a disorder caused by or associated with dysregulation of T-cell receptor signaling in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the T-cell receptor signaling are enhanced CD69 surface expression, IFNy or IL-2.

[0173] In an aspect, this disclosure features methods of treating a disorder caused by or associated with VAV1 polymorphisms in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof.

[0174] In an aspect, this disclosure features methods of treating a disorder caused by or associated with immunopathologies in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof.

[0175] In some embodiments, the disorder is autoimmune disorder. In some embodiments, the autoimmune disorder is selected from the group consisting of multiple sclerosis, psoriatic arthritis, rheumatoid arthritis, systemic lupus, erythematosus, Hashimoto’s thyroiditis, myasthenia gravis, diabetes type I or II, and the disorders associated therewith, vasculitis, pernicious anemia, Sjoegren syndrome, uveitis, psoriasis, Graves ophthalmopathy, alopecia areata and others, allergic diseases (e.g., allergic asthma, atopic dermatitis, allergic rhinitis / conjunctivitis, allergic contact dermatitis), inflammatory diseases optionally with underlying aberrant reactions (e.g., inflammatory bowel disease, Crohn’s disease or ulcerative colitis, intrinsic asthma, inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury), atherosclerosis, osteoarthritis, irritant contact dermatitis and further eczematous dermatitis, seborrheic dermatitis, cutaneous manifestations of immunologically-mediated disorders, inflammatory eye disease, keratoconjunctivitis, myocarditis or hepatitis. In some embodiments, the disorder is a cancer, tumour or other malignancy, optionally wherein the disorder is a T cell or B cell malignancy. In some embodiments, the disorder is selected from the group consisting of: leukemia, lymphoma, T-cell prolymphocytic leukemia, T-cell granular lymphocytic leukemia, aggressive NK cell leukemia, hairy-cell leukemia, nasal and nasaltype NK / T cell lymphoma, mycosis fungoides and Sezary syndrome, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma unspecified, adult T-cell leukemia / lymphoma (HTLV 1+), anaplastic large cell lymphoma, primary cutaneous CD-30 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, and mantle cell lymphoma).

[0176] In some embodiments, the disorder is a transplantation setting disease. In some embodiments, the disorder is selected from graft- versus-host disease, chronic graft rejection, acute graft rejection, transplant vasculopathy, graft vessel disease, graft atherosclerosis, and transplant coronary disease.

[0177] 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, myocarditis, pericarditis, pulmonary fibrosis, systemic sclerosis, morphea, Alzheimer’s disease, Acute Graft-vs. Host Disease or T-cell mediated kidney disease.

[0178] 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, 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, systemic lupus erythematosus, Chronic Graft vs. Host Disease, lupus nephritis, pulmonary arterial hypertension or vasculitis.

[0179] 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.

[0180] In some embodiments, the disorder is selected from the group consisting of B-cell lymphoma, B-cell leukemia, T-cell lymphoma, T-cell leukemia or acute myeloid leukemia. In some embodiments, the disorder is a non-Hodgkin lymphoma. In some embodiments, the disorder is selected from mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL) and Diffuse large B cell lymphoma (DLBCL).

[0181] In some embodiments, the disorder is chronic lymphocytic leukemia (CLL).

[0182] In some embodiments, the disorder is multiple sclerosis (MS).

[0183] In some embodiments, the disclosure relates to a method of treating patients exhibiting

[0184] CD226 overexpression.

[0185] In some embodiments, the disclosure relates to a method of treating patients having a CD226 risk variant.

[0186] In some embodiments, the disclosure relates to a method of treating patients having a CD226 polymorphism.

[0187] In some embodiments, the disclosure relates to a method of treating patients having a

[0188] Gly307Ser (G307S) amino acid substitution in CD226 (rs763361T allele).

[0189] In an aspect, the disclosure provides a compound or pharmaceutically acceptable salt for use in any of the above -recited methods of treatment. In some embodiments, the compound or pharmaceutically acceptable salt thereof is a compound or pharmaceutically acceptable salt thereof as described herein. In a further aspect, the disclosure provides the use of a compound or pharmaceutically acceptable salt for the manufacture of a medicament for any of the above-recited methods of treatment. In some embodiments, the compound or pharmaceutically acceptable salt thereof is a compound or pharmaceutically acceptable salt thereof as described herein. In an aspect, the disclosure provides a degrader conjugate as described herein for use in any of the above-recited methods of treatment.

[0190] Degrader Conjugates

[0191] In an aspect is a conjugate comprising a compound of Formula (I). For instance, in an aspect is an antibody-degrader conjugate or pharmaceutically acceptable salt thereof comprising a compound of Formula (I). The conjugate includes a compound of Formula (I) or pharmaceutically acceptable salt thereof which is conjugated to an antibody via a linker structure moiety.

[0192] In some embodiments, the conjugate has a structure according to Formula (A) below:

[0193] Formula (A) in which I is a compound of Formula (I) or a pharmaceutically acceptable salt thereof as defined herein, M is a linker moiety, Bm is a binding moiety that is capable of specifically binding to an antigen, and a is from 1 to 10. The binding moiety may be an antibody, antibody fragment or an antibody-binding fragment.

[0194] In some embodiments, I is one of Compounds 1-113.

[0195] In some embodiments, the disclosure provides an antibody-drug conjugate or pharmaceutically acceptable salt thereof according to Formula (Al): in which Ring A, Ring B, L, R2, R3, R4, R5and R15can be as defined anywhere here, M is a linker moiety, Bm is a binding moiety that is capable of specifically binding to a protein, as defined above, and a is from 1 to 10. In some embodiments, Ring A, Ring B, L, R2, R3, R4, R5and R15are defined to provide a compound selected from any one of Compounds 1-113.

[0196] In some embodiments, the disclosure provides an antibody-drug conjugate or pharmaceutically acceptable salt thereof according to Formula (A4):

[0197] Formula (A4) in which Ring A, Ring B, L, R2, R3, R4, R5and R15can be as defined anywhere here, M is a linker moiety, Bm is a binding moiety that is capable of specifically binding to a protein, as defined above, and a is from 1 to 10. In some embodiments, Ring A, Ring B, L, R2, R3, R4, R5and R15are defined to provide a compound selected from any one of Compounds 1-113.

[0198] In some embodiments, the disclosure provides an antibody-drug conjugate or pharmaceutically acceptable salt thereof according to Formula (A5):

[0199] Formula (A5) in which Ring A, Ring B, L, R2, R3, R4, R5and R15can be as defined anywhere here, M is a linker moiety, Bm is a binding moiety that is capable of specifically binding to a protein, as defined above, a is from 1 to 10, Rxis selected from hydrogen, -(CFhCFhO -CHs, C2-C6 alkenyl, Ci-Ce alkyl, C2-C6 alkynyl, benzyl, C3-C6 cycloalkyl, and C3-C6 cycloalkyl(Ci-C3 alkyl), and v is from 1 to 24. In some embodiments, Ring A, Ring B, L, R2, R3, R4, R5and R15are defined to provide a compound selected from any one of Compounds 1-113.

[0200] In some embodiments, M is a linker as defined in WO 2021 / 198966, which is incorporated by reference in its entirety. The linker may be a cleavable linker or non-cleavable linker. In certain aspects, the linker can contain a heterobifunctional group. In the present disclosure, the term "heterobifunctional group" refers to a chemical moiety that connects the linker of which it is a part to the binding moiety. Heterobifunctional groups are characterized as having different reactive groups at either end of the chemical moiety. Attachment to Bm, can be accomplished through chemical or enzymatic conjugation, or a combination of both. Chemical conjugation involves the controlled reaction of accessible amino acid residues on the surface of the binding moiety with a reaction handle on the heterobifunctional group. Examples of chemical conjugation include, but are not limited to, lysine amide coupling, cysteine mediated coupling, and coupling via a nonnatural amino acid incorporated by genetic engineering, wherein non-natural amino acid residues with a desired reaction handle are installed onto Bm. In enzymatic conjugation, an enzyme mediates the coupling of the linker with an accessible amino residue on the binding moiety. Examples of enzymatic conjugation include, but are not limited to, transpeptidation using sortase, transpeptidation using microbial transglutaminase, and N-glycan engineering. Chemical conjugation and enzymatic conjugation may also be used sequentially. For example, enzymatic conjugation can also be used for installing unique reaction handles on Bm to be utilized in subsequent chemical conjugation.

[0201] In some embodiments, M is a linker as defined in WO 2023 / 037268, which is incorporated by reference in its entirety. In some embodiments, M is selected from the group consisting of wherein: q is from 2 to 10;

[0202] Z1, Z2, Z3, Z4, and Z5are each independently absent or a naturally-occurring amino acid residue in the L- or D-configuration, provided that at least two of Z1, Z2, Z3, Z4, and Z5are amino acid residues; is the point of attachment to the parent molecular (degrader) moiety; and r / is the point of attachment to the binding moiety.

[0203] In some embodiments, Z1, Z2, Z3, Z4, and Z5are independently absent or selected from the group consisting of L-valine, D-valine, L-citrulline, D-citrulline, L-alanine, D-alanine, L- glutamine, D- glutamine, L-glutamic acid, D-glutamic acid, L-aspartic acid, D-aspartic acid, L- asparagine, D- asparagine, L-phenylalanine, D-phenylalanine, L-lysine, D-lysine, and glycine; provided that at least two of Z1, Z2, Z3, Z4, and Z5are amino acid residues.

[0204] The term “binding moiety” as used herein refers to any molecule that recognizes and binds to a cell surface marker or receptor. The binding moiety may be an antibody, antibody fragment, or an antigen-binding fragment. An antibody is a protein generated by the immune system that is capable of recognizing and binding to a specific antigen. A target antigen generally has numerous binding sites, also called epitopes, recognized by CDRs on multiple antibodies. Each antibody that specifically binds to a different epitope has a different structure. Thus, one antigen may have more than one corresponding antibody. The term "antibody" herein is used in the broadest sense and specifically covers monoclonal antibodies, single domain antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments , so long as they exhibit the desired biological activity. Antibodies may be murine, human, humanized, chimeric, or derived from other species. A monoclonal antibody (mAb) to an antigen-of-interest can be prepared by using any technique known in the art which provides for the production of antibody molecules by continuous cell lines in culture. These include, but are not limited to, the hybridoma technique, the human B cell hybridoma technique, and the EBV-hybridoma technique. Such antibodies may be of any immunoglobulin class including IgG, IgM, IgE, IgA, and IgD and any subclass thereof. The hybridoma producing the mAbs of use in this disclosure may be cultivated in vitro or in vivo.

[0205] The skilled person would understand how to provide an appropriate binding moiety for use in a conjugate depending on the intended therapeutic use. This is described, for example, in Nature Reviews Drug Discovery volume 22, pages 641-661 (2023), which is incorporated by reference in its entirety. In particular, an antibody, antibody fragment or an antibody-binding fragment used as a binding moiety must be capable of targeting a particular cell surface marker or receptor associated with the disorder to be treated. For example, the antibody trastuzumab can be employed if the desired target is HER2.

[0206] In some embodiments, the binding moiety is capable of binding to an antigen selected from a4p7, CD3, CD4, CD20, 0X40, CD28, PD-1, ICOS, BCMA / TAC1, CD52, CD30, CD19, CCR8, CD79b, CD22, CD4, CD7, CD38, CD33 or CD8 or combinations thereof. In preferred embodiments, the binding moiety is capable of binding to an antigen selected from CD19, CD20, CD33, CD4, CD8, PD-1, ICOS and CD38.

[0207] In some embodiments, the binding moiety comprises an antibody selected from Vedolizumab, Etrolizumab, Teplizumab, Zanolimumab, Rituximab, Ublituximab, Ofatumumab, Ocrelizumab, Inebilizumab, Rocatinlimab, Nivolumab, Pembrolizumab, Alemtuzumab, Brentuximab vedotin, Tafasitamab, Loncastuximab, Mogamulizumab, Polatuzumab, Inotuzumab, Epratuzumab, Isatuximab and Daratumumab. In some embodiments, the binding moiety is capable of binding to CD 19 and is preferably Tafasitamab, Loncastuximab or Inebilizumab. In some embodiments, the binding moiety is capable of binding to CD20 and is preferably Rituximab, Ublituximab, Ofatumumab, Ocrelizumab or Inebilizumab. In some embodiments, the binding moiety is capable of binding to CD33. In some embodiments, the binding moiety is capable of binding to CD4 and is preferably Zanolimumab. In some embodiments, the binding moiety is capable of binding to CD8. In some embodiments, the binding moiety is capable of binding to PD-1 and is preferably Nivolumab or Pembrolizumab. In some embodiments, the binding moiety is capable of binding to ICOS. In some embodiments, the binding moiety is capable of binding to CD38 and is preferably Isatuximab or Daratumumab.

[0208] In some embodiments, the disclosure provides a method of treating ulcerative colitis (UC), Crohn’s disease (CD), human immunodeficiency virus (HIV) / acquired immunodeficiency syndrome (AIDS), immune-mediated colitis (Phi open label), type 1 diabetes (T1D), pouchitis, graft- versus- host disease (GvHD), Celiac disease, rheumatoid arthritis (RA), psoriasis (PsO), late onset rejection, Pemphigus vulgaris, cutaneous lupus erythematosus (CLE), systemic sclerosis (SSc), Grave’s disease, relapse-remitting / primary progressive multiple sclerosis (RR / PP MS), lupus nephritis, systemic lupus erythematosus (SLE), thrombotic thrombocytopenic purpura, nephrotic syndrome; idiopathic thrombocytopenic purpura, microscopic polyangiitis, atopic dermatitis (AD), transplant rejection, juvenile idiopathic arthritis, multiple sclerosis (MS), chronic lymphocytic leukemia (CLL), T-cell prolymphocytic leukemia, precursor cell lymphoblastic leukemia- lymphoma, Anaplastic large cell lymphoma; Hodgkin's disease; Mycosis fungoides; Peripheral T-cell lymphoma; Primary cutaneous anaplastic large cell lymphoma; T-cell lymphoma, adult T-cell leukemia-lymphoma; diffuse scleroderma; Germ cell cancer; malignant- mesothelioma; mastocytosis; non-Hodgkin's lymphoma; Sezary syndrome; Solid tumors, HIV-1 infections, Chronic lymphocytic leukemia; Follicular lymphoma; Granulomatosis with polyangiitis; idiopathic thrombocytopenic purpura; lymphoproliferative disorders; microscopic polyangiitis; marginal zone B-cell lymphoma, relapsed-refractory diffuse large B cell lymphoma (R / R DLBCL), B-cell lymphoma, precursor B-cell lymphoblastic leukemia- lymphoma, precursor cell lymphoblastic leukemia-lymphoma, mantle cell lymphoma, Waldenstrom’s macroglobulinemia, cutaneous T-cell lymphoma; Richter’s syndrome, relapsed / refractory acute lymphoblastic leukemia (R / R- ALL), precursor cell lymphoblastic leukemia-lymphoma, precursor B-cell lymphoblastic leukemia-lymphoma, chronic myelogenous leukemia (CML), cutaneous and peripheral T lymphoma, acute biphenotypic leukemia; Burkitt's lymphoma, T-cell acute lymphoblastic leukemia (T-ALL), relapsed / refractory multiple myeloma (R / R MM), melanoma, acute myeloid leukemia; chronic lymphocytic leukemia; Myelodysplastic syndromes; Plasmablastic lymphoma; precursor T-cell lymphoblastic leukemia-lymphoma; amyloid lightchain amyloidosis, multiple myeloma (MM) and solid tumors in a subject in need thereof, wherein the method comprises administering the antibody-drug conjugate to the subject. Exemplary combinations of antibodies, target antigens, and associated therapeutic indications are listed in the table below. In some embodiments, the binding moiety of the antibody-drug conjugate comprises an antibody listed in the table below and targets an antigen listed in the table below. In some aspects, the disclosure provides a method of treating a disorder listed in the table below comprising administering to a subject in need thereof an antibody-drug conjugate comprising an antibody listed in the table below.

[0209]

[0210]

[0211]

[0212] Exemplary combinations of target antigens, and associated therapeutic indications are listed in the table below. In some embodiments, the binding moiety of the antibody-drug conjugate comprises targets an antigen listed in the table below. In some aspects, the disclosure provides a method of treating a disorder listed in the table below comprising administering to a subject in need thereof an antibody-drug conjugate comprising a binding moiety which targets an antigen listed in the table below. In some aspects, the disclosure provides a method of treating a disorder listed in the table below comprising administering to a subject in need thereof an antibody-drug conjugate comprising an antibody listed in the table below.

[0213] The antibody-drug conjugate may be administered as part of a pharmaceutical composition. The pharmaceutical composition may include excipients such as those recited herein.

[0214] Non-Limiting Exemplary Compounds

[0215] In some embodiments, the compound is selected from the group consisting of the compounds delineated in Table 1 or a pharmaceutically acceptable salt thereof. Table 1:

[0216]

[0217]

[0218] Examples

[0219] Abbreviations: A = Angstrom; BiPim: bis(pinacolato)diboron; Boc: tert-butyloxycarbonyl; brd: broad doublet; brdd: broad doublet of doublet; brs: broad singlet; brt: broad triplet; [eq: equivalents; d: doublet; DBU: l,8-Diazabicyclo(5.4.0)undec-7-ene; dd: doublet of doublet; ddd: doublet of doublet of doublet; DMAC: dimethylacetamide; DMAP: 4 -Dimethylaminopyridine; DIPEA: diisopropylethylamine; DMEDA: N,N'-Dimethylethylenediamine; DMF: dimethylformamide; DMPAO : 2-((2,6-dimethylphenyl)amino)-2-oxoacetic acid; DMSO: dimethyl sulfoxide; EDCI: l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide; ESI: electrospray ionization; EtOAc: ethyl acetate; h: hours; HATU: l-[Bis(dimethylamino)methylene]-lH-l,2,3- triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; HC1: hydrochloric acid; HMPA: hexamethylphosphoramide; HPLC: high-performance liquid chromatography; [Ir{dF(CF3)ppy}2(dtbpy)]PF6: [4,4'-Bis(l,l-dimethylethyl)-2,2'-bipyridine-Nl,Nl']bis[3,5- difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]Iridium(III) hexafluorophosphate; K2CO3: potassium carbonate; FED: light-emitting diode; m: multiplet; MOM: methoxymethyl ether; MS: mass spectrometry; NaHCOs: sodium bicarbonate; Nal: sodium iodide; NH4CI: ammonium chloride; NMR: nuclear magnetic resonance; Pd(dppf)Ch: [1,1'- Bis(diphenylphosphino)ferrocene]dichloropalladium(II); Pd-PEPPSI-IHeptCl: 3 -chloropyridine 4,5-dichloro-l,3-bis[2,6-di(heptan-4-yl)phenyl]-2H-imidazol-2-ide dichloropalladium; Pd- PEPPSI-IPentCl: 3 -chloropyridine 4,5-dichloro-l,3-bis[2,6-di(pentan-4-yl)phenyl]-2H-imidazol- 2-ide dichloropalladium; Pd(PPh3)4: tetrakis(triphenylphosphine)-palladium(0); PSI: pounds per square inch; quin: quintet; q: quartet; RuPhos Pd G3: (2-Dicyclohexylphosphino-2',6'- diisopropoxy- 1 , 1 '-biphenyl)[2-(2'-amino- 1 , 1 '-biphenyl)]palladium(II) methanesulfonate; s: singlet; sat. sol.: saturated solution; Selectfluor: l-(Chloromethyl)-4-fluoro-l,4- diazabicyclo[2.2.2]octane-l,4-diium ditetrafluoroborate; t: triplet; td: triplet of doublet; TEA: triethylamine; Tf: triflate; THF: tetrahydrofuran; tt: triplet of triplet; XPhos Pd G4: (SP-4-3)- [Dicyclohexyl[2',4',6'-tris(l-methylethyl)[l,r-biphenyl]-2-yl]phosphine](methanesulfonato- KO) [2 '-(methylamino-KN) [1,1 '-biphenyl] -2-yl-KC]palladium .

[0220] General Schemes and Procedures

[0221] General Scheme 1

[0222] Photochemical coupling

[0223] Removal of PG1

[0224] Formula IA or IB A general synthetic strategy that may be used to prepare compounds of formula IA or IB is depicted in General Scheme 1. Compounds of formula IA or IB may also be used as compounds of formula I or II

[0225] 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 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)]PFe and NiCh*dtbbpy may be used, under irradiation with a blue light LED (suitable wavelengths include, for example, 455 nm) in the presence of bis(trimethylsilyl)silyl-trimethylsilane and an inorganic base (for example, sodium carbonate). A solvent such as 1,2-dimethoxy ethane 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.

[0226] Removal of PG1in the presence of a strong acid such as HC1 4M in dioxane affords intermediates AA-1 or AA-2.

[0227] Finally, the desired compounds of formula IA or IB 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. 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 IA or IB.

[0228] General Scheme 2

[0229] General Scheme 2 provides an alternative synthetic procedure to prepare compounds of formula IA or IB. 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 IA or IB.

[0230] Catalysts such as Pd-PEPPSI-IHept-Cl or copper(II)acetate may be used, in the 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 is a bond, a C atom, a CHz-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 IA or IB. General Scheme 3

[0231] General Scheme 3 provides an exemplary synthetic procedure for the preparation of starting materials AA-3 and AA-4 used in General Scheme 1 and General Scheme 2. Compound DA, where Hal is a suitable halogen atom (e.g. Br or I), may be converted into a 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.

[0232] A benzyl nitrile intermediate such as DC may be prepared from benzyl halide DB upon treatment with a cyanating reagent such as trimethyl silyl cyanide, in the presence of a desilylation reagent such as tert-butyl silyl fluoride and a solvent such as dichloromethane.

[0233] 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. Aik is any suitable alkyl group which is labile to treatment with acid. For example, Aik may be tert-butyl.

[0234] Compound DE may be converted to intermediate AA-3 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).

[0235] Aryl boronate AA-4 may be prepared from aryl halide AA-3 using Bis(pinacolato)diboron and a catalyst such as Pd(dppf)C12. 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). General Scheme 4

[0236] General Scheme 4 provides an exemplary synthetic strategy for the preparation of halo- pyridones, pyridazinones, pyrimidinones, and pyrazinones of formula EC, which may be used as starting materials BA in General Scheme 1. General Scheme 4 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 2.

[0237] A compound of formula EA may be alkylated with compound EB to afford intermediate EC 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.

[0238] A 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 acid.

[0239] Removal of PG1in the presence of a strong acid such as HC1 4M in dioxane affords intermediate EF. The specific groups R6A'D, R8and R1are selected on the basis of the desired groups in the compound of formula IA or IB. General Scheme 5

[0240] General Scheme 5 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 1. General Scheme 5 also provides an exemplary synthetic strategy for the preparation of piperazine-heterobicyclic compounds of formula FD, which may be used as starting materials BB in General Scheme 2.

[0241] A compound of formula FB may be prepared by halogenation of intermediate FA in the presence of dihaloethane and w-butyllithium, at low temperature (e.g. -78 degrees Celsius) and in a solvent such as THF. W may be C, O, N or N(RX). Hal2is any suitable halogen. For example, Hal2may be I.

[0242] A 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 treatment with acid.

[0243] Removal of PG1in the presence of a strong acid such as HC1 4M in dioxane affords intermediate FD. The specific groups R6A'D, R8and R1are selected on the basis of the desired groups in the compound of formula IA or IB.

[0244] General Scheme 6

[0245] General Scheme 6 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

[0246] General Scheme 2.

[0247] An aldehyde of formula GA may undergo a reductive amination 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.

[0248] Removal of PG1in the presence of a strong acid such as HC1 4M in dioxane affords intermediate GC. The specific groups R6A'D, R8and R1are selected on the basis of the desired groups in the compound of formula IA or IB. General Scheme 7

[0249] General Scheme 7 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 2. 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 (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 HC1 4M in dioxane affords intermediate HC. The specific groups R6A'Dand R8are selected on the basis of the desired groups in the compound of formula IA or IB.

[0250] General Scheme 8

[0251] EC

[0252] General Scheme 8 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 2.

[0253] 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 compounds of formula IB. A palladium catalyst complex such as CPhos Pd G3 may be used, in the presence of an inorganic base (for example, caesium carbonate) and in a solvent such as dioxane, at elevated temperatures (e.g. 80 degrees Celsius). Aik is any suitable alkyl group which is labile to treatment with acid. For example, Aik 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 from intermediate IC via coupling with A-hydroxy compound ID in the presence of a peptide coupling reagent. For example, EDCI and DMAP may be used, in a solvent such as THE

[0254] 1.1 Synthesis of Key Intermediates: AA-E AA-2, AA-3 and AA-4 The Exemplary Compounds shown in Table 1 were synthesized in various ways from Intermediates AA-1, AA-2, AA-3 and AA-4 shown in Scheme 1.

[0255] Step 4 Step 5A Step 6A

[0256] Intermediate AA-3

[0257] Intermediate AA-1

[0258] Intermediate AA-4 Intermediate AA-2

[0259] Scheme 1. Synthesis of Intermediates AA-1 , AA-2, AA-3 and AA-4.

[0260] General purification methods

[0261] Purification Method 1:

[0262] The residue was purified by E / v -HPLC with a C18 column (type: Phenomenex luna, YMC- Actus Triart, or Welch Xtimate) of the appropriate size. A mobile phase containing a mixture of water (formic acid condition) [Solvent A] and acetonitrile [Solvent B] was used. An appropriate gradient ranging from 0 to 80% of solvent B was applied. The pure compounds were then lyophilized.

[0263] Purification Method 2:

[0264] The residue was purified by silica gel column chromatography, reversed-phase column chromatography, or / v -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 the desired products.

[0265] Step 1. To a solution of l-bromo-2-chl oro-3 -methylbenzene (30.0 g, 146 mmol, 1.00 eq.) in tetrachloromethane (240 mL) were added A-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 x 75 mL). The filtrate was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford l-bromo-3-(bromomethyl)-2-chlorobenzene (20.8 g, 73.1 mmol, 50% yield) as a colourless liquid.

[0266] 'H NMR (400 MHz, CDCh) 3 = 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).

[0267] Step 2. To a solution of l-bromo-3-(bromomethyl)-2-chlorobenzene (20.0 g, 70.3 mmol, 1.00 eq.) and trimethyl silyl 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 x 150 mL), and the organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford 2-(3- bromo-2-chlorophenyl)acetonitrile (13.2 g, 57.3 mmol, 81% yield) as a white solid.

[0268] 'H NMR (400 MHz, CDCh) 3 = 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. 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 x 50 mL). The combined organic layers were washed with brine (3 x 80 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford tert-butyl 4-(3-bromo-2-chlorophenyl)-4- cyanobutanoate (7.50 g, 19.0 mmol, 33% yield) as a colourless liquid.

[0269] 'H NMR (400 MHz, CDCh) 3 = 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).

[0270] Step 4. 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 x 50 mL), then dried under reduced pressure to afford Intermediate AA-3 (2.89 g, 9.46 mmol, 79% yield) as a white solid.

[0271] 'H NMR (400 MHz, DMSO-tL) 3 = 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]+

[0272] Step 5A. To a solution of Intermediate AA-3 (815 mg, 2.69 mmol, 1.20 eq.) and tert-butyl piperazine- 1 -carboxylate (500 mg, 2.25 mmol, 1.00 eq, hydrochloric acid) in dioxane (10.0 mL) was added Pd PEPPSI-IHept-Cl (109 mg, 112 / / mol, 0.05 eq.) and caesium carbonate (2.19 g, 6.74 mmol, 3.00 eq.) under nitrogen. The reaction was stirred at 100°C for 2 h under nitrogen. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 1 to afford tert-butyl 4-(2-chl oro-3 - (2,6-dioxopiperidin-3-yl)phenyl)piperazine-l-carboxylate (100 mg, 245 mol, 11% yield) as a colourless oil.

[0273] Hl NMR (400 MHz, DMSO-tL) 3 = 10.89 (s, 1H), 7.31 - 7.26 (m, 1H), 7.12 (dd, J= 1.2, 8.0 Hz, 1H), 7.03 (dd, J= 1.2, 7.6 Hz, 1H), 4.31 - 4.21 (m, 1H), 3.51 - 3.47 (m, 4H), 2.96 - 2.86 (m, 4H), 2.76 (ddd, J= 5.2, 12.4, 17.2 Hz, 1H), 2.55 (br s, 1H), 2.30 - 2.22 (m, 1H), 1.99 (ddd, J= 3.6, 4.8, 8.0 Hz, 1H), 1.43 (s, 9H). Step 6A. A mixture of tert-butyl 4-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)piperazine-l- carboxylate (80.0 mg, 196 / / mol, 1.00 eq.) in hydrochloric acid 4M in dioxane (2.00 mL) was stirred at 25°C for 2 h. The mixture was concentrated under reduced pressure to afford Intermediate AA-1 (60.0 mg, 194 mol, 99% yield) as a white solid.

[0274] MS (ESI) m / z 308.2 [M+H]+

[0275] Step 5B. A mixture of Intermediate AA-3 (61.0 mg, 201 / / mol, 1.00 eq.), tert-butyl 4- bromopiperidine-1 -carboxylate (69.2 mg, 262 / / mol, 1.30 eq.), [Ir{dF(CF3)ppy}2(dtbpy)]PFe (2.26 mg, 2.02 / / mol, 0.01 eq.), NiCh*dtbbpy (401 / / g, 1.01 / / mol, 0.005 eq.), bis(trimethylsilyl)silyl-trimethylsilane (62.2 / / L, 201 / / mol, 1.00 eq.) and sodium carbonate (42.7 mg, 403 / / mol, 2.00 eq.) in 1,2-dimethoxy ethane (2.00 mL) was degassed by purging with nitrogen. The reaction was stirred at 25°C for 16 h and irradiated with a 455 nm blue LED. The mixture was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford tert-butyl 4-(2-chl oro-3 -(2, 6-dioxopiperi din-3 - yl)phenyl)piperidine-l -carboxylate (31.0 mg, 76.1 / / mol, 37% yield) as a white solid.

[0276] 'H NMR (400 MHz, DMSO-tL) b = 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= 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 -

[0277] 1.95 (m, 1H), 1.76 (br t, J= 10.8 Hz, 2H), 1.55 - 1.47 (m, 2H), 1.43 (s, 9H).

[0278] Step 6B. A mixture of tert-butyl 4-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-l- carboxylate (70.0 mg, 172 / / mol, 1.00 eq.) in hydrochloric acid 2M in ethyl acetate (2.00 mL) was stirred at 25°C for 2 h. The reaction mixture was concentrated under reduced pressure to afford Intermediate AA-2 (160 mg, crude) as a white solid.

[0279] 'H NMR (400 MHz, DMSO-tL) b = 10.89 (s, 1H), 8.81 - 8.70 (m, 1H), 8.65 (br s, 1H), 7.40 - 7.32 (m, 1H), 7.31 - 7.19 (m, 2H), 4.29 (dd, J= 4.4, 12.0 Hz, 1H), 3.41 - 3.38 (m, 3H), 3.12 - 3.04 (m, 2H), 2.82 - 2.72 (m, 1H), 2.56 - 2.54 (m, 1H), 2.35 - 2.25 (m, 1H), 2.04 - 1.96 (m, 1H),

[0280] 1.96 - 1.76 (m, 4H) Step 5C. To a solution of Intermediate AA-3 (5.00 g, 16.5 mmol, 1.00 eq.) in dioxane (80 mL) was added B2Pin2 (5.04 g, 19.8 mmol, 1.20 eq.), Pd(dppf)C12 (1.21 g, 1.65 mmol, 0.10 eq.) and potassium acetate (4.87 g, 49.6 mmol, 3.00 eq.) in one portion at 20°C under nitrogen atmosphere. The reaction was stirred at 85°C for 3 h. The mixture was filtered, and the filter cake was washed with ethyl acetate (2 ^ 30 mL). The filtrate was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford Intermediate AA-4 (3.80 g, 8.70 mmol, 52% yield) as a white solid.

[0281] 'H NMR (400 MHz, DMSO4) 3 = 10.90 (s, 1H), 7.52 (dd, J= 2.0, 7.2 Hz, 1H), 7.41 (dd, J = 2.0, 7.6 Hz, 1H), 7.32 (d, J= 7.6 Hz, 1H), 4.26 (dd, J= 5.2, 12.4 Hz, 1H), 2.81 - 2.70 (m, 1H), 2.59 - 2.53 (m, 1H), 2.33 - 2.23 (m, 1H), 1.99 - 1.93 (m, 1H), 1.31 (s, 12H). MS (ESI) m / z

[0282] 350.2 / 352.2 [M+H]+

[0283] 1.2 Synthesis of Exemplary Compounds via Intermediate AA-1 or AA-2 and Intermediate BA

[0284] Intermediate AA-2

[0285] Scheme 2. Synthesis of Exemplary Compounds from Intermediate AA-1 or AA-2 and Intermediate BA

[0286] Table 2. Structures of Intermediates BA

[0287] Exemplary Compounds of the formula depicted in Scheme 2 were synthesized as follows.

[0288] General 1

[0289] • Variant 1

[0290] A mixture of Intermediate BA (1.00 eq.), Intermediate AA-1 or AA-2 (0.90 - 1.20 eq.), a base (caesium carbonate or sodium tert-butoxide, 3.00 - 4.00 eq.), and Pd PEPPSI-IHept-Cl (0.05 - 0.10 eq.) in a polar aprotic solvent (DMF or dioxane, 0.1 - 0.25 M relative to Intermediate BA) was degassed by purging with nitrogen, then the reaction was stirred at elevated temperature (50 - 100°C) under nitrogen until reaction completion (1 - 28 h). In some cases, a workup was performed: the mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. In other cases, no workup was performed: the mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue directly. The residue was purified via Purification Method 1 (if necessary, the residue was first purified via Purification Method 2, then Purification Method 1) to afford the corresponding Exemplary Compound.

[0291] • Variant 2

[0292] To a mixture of Intermediate AA-1 or AA-2 (1.00 eqfi Intermediate BA (1.00 - 1.10 eq.), and potassium phosphate (4.00 eq .) in DMSO (0.15 M relative to Intermediate AA-1 or AA-2) was added 2-((2,6-dimethylphenyl)amino)-2-oxoacetic acid (0.40 eq.) and copper(I) iodide (0.20 eq.). The reaction was stirred at elevated temperature (120°C) under nitrogen until reaction completion (12 h). The mixture was cooled to room temperature, and water was added. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 1 (if necessary, the residue was first purified via Purification Method 2, then Purification Method 1) to afford the corresponding Exemplary Compound. Variant 3

[0293] To a solution of 3 Intermediate AA-1 or AA-2 (1.00 eq.), Intermediate BA (0.80 - 1.20 eq.), in a polar aprotic solvent (DMF or MeCN, 0.06 - 0.30 M relative to Intermediate AA-1 or AA-2) was added a base (DIPEA, TEA or K2CO3, 3.00 eq.). The mixture was stirred at the appropriate temperature (25 - 100°C) until reaction completion (2 - 24 h). In some cases, a workup was performed: the mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. In other cases, no workup was performed: the mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue directly. The residue was purified via Purification Method 1 (if necessary, the residue was first purified via Purification Method 2, then Purification Method 1) to afford the corresponding Exemplary Compound.

[0294] • Variant 4

[0295] A mixture of Intermediate BA (1.00 eq.), Intermediate AA-1 or AA-2 (0.90 - 1.10 eq.), K2CO3 (2.00 - 3.00 eq.), and Nal (0.10 - 1.00 eq.) in DMF (0.10 - 0.30 M relative to Intermediate BA) was stirred at elevated temperature (80 - 100°C) until reaction completion (12 h). In some cases, a workup was performed: the mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. In other cases, no workup was performed: the mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue directly. The residue was purified via Purification Method 1 (if necessary, the residue was first purified via Purification Method 2, then Purification Method 1) to afford the corresponding Exemplary Compound.

[0296] 1.2.1 Representative Examples

[0297] Example 4: According to General Procedure 1, Variant 1 : eq.), , , , Cl

[0298] (7.93 mg, 8.15 / / mol, 0.05 eq.) in DMF (1.50 mL) was degassed by purging with nitrogen. The reaction was stirred at 100°C for 2.5 h under nitrogen. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 1 to afford Exemplary Compound 4 (13.9 mg, 30.0 / / mol, 4% yield) as a white solid.

[0299] 'H NMR (400 MHz, DMSO-tL) d = 10.87 (br s, 1H), 7.40 - 7.36 (m, 1H), 7.36 - 7.30 (m, 1H), 7.22 (br dd, J= 7.2, 14.6 Hz, 2H), 6.76 (br d, J= 7.6 Hz, 1H), 6.19 - 6.10 (m, 1H), 4.29 (br dd, J = 3.6, 11.6 Hz, 1H), 4.06 (br d, J= 4.4 Hz, 2H), 3.80 (br d, J= 10.8 Hz, 2H), 3.58 (br d, J= 4.4 Hz, 2H), 3.24 (d, J= 1.2 Hz, 3H), 3.14 (br s, 1H), 2.76 (br d, J= 13.2 Hz, 1H), 2.59 - 2.55 (m, 2H), 2.54 (br s, 1H), 2.30 (br d, J= 11.6 Hz, 1H), 2.05 - 1.98 (m, 1H), 1.88 - 1.76 (m, 4H). MS

[0300] (ESI) m / z 458.2 [M+H]+

[0301] Example 16: According to General Procedure 1, Variant 1 : .), 3 , , de 2

[0302] M in THF (1.48 mL, 3.00 eq.) in DMF (5 mL) was degassed by purging with nitrogen, then the reaction was stirred at 80°C for 2 h under nitrogen. The mixture was filtered through a pad of Celite. The filtrate was diluted with water (40 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 1 to afford Exemplary Compound 16 (249 mg, 576 / / mol, 29% yield) as a grey solid. 'H NMR (400 MHz, DMSO4) d = 10.89 (s, 1H), 7.42 - 7.28 (m, 3H), 7.20 (d, J= 7.6 Hz, 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).

[0303] MS (ESI) m / z 428.2 [M+H]+

[0304] Example 25: According to General Procedure 1, Variant 4: .), , , , , , q.) in DMF (3.00 mL) was stirred at 80°C for 12 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2, then Purification Method 1 to afford Exemplary Compound 25 (20.44 mg, 44.9 / / mol, 9% yield) as a white solid.

[0305] 'H NMR (400 MHz, DMSO-fifc) d = 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, 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]+

[0306] Example 35: According to General Procedure 1, Variant 1 : .), , , .42 g, 7.42 mmol, 3.00 eq.) in DMF(10 mL) was degassed by purging with nitrogen, then the reaction was stirred at 100°C for 4 h under nitrogen. After cooling to room temperature, the mixture was filtered through a pad of Celite. The filtrate was diluted with water (80 mL) and extracted with ethyl acetate (3 x 80 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 1 to afford Exemplary Compound 35 (1.12 g, 2.59 mmol, 26% yield) as a brown solid. 'H NMR (400 MHz, DMSO4) d = 10.88 (s, 1H), 7.38 - 7.25 (m, 2H), 7.22 - 7.13 (m, 1H), 7.08 - 6.95 (m, 1H), 6.76 (dd, J= 1.2, 7.2 Hz, 1H), 6.18 (t, J= 7.2 Hz, 1H), 4.27 (dd, J= 4.8, 2.0 Hz, 1H), 3.92 (q, J= 7.2 Hz, 2H), 3.22 (s, 4H), 3.08 (d, J= 4.0 Hz, 4H), 2.76 (ddd, J= 5.2, 12.4, 17.2 Hz, 1H), 2.53 (d, J= 4.0 Hz, 1H), 2.36 - 2.21 (m, 1H), 2.05 - 1.93 (m, 1H), 1.21 (t, J= 7.2 Hz, 3H). MS (ESI) m / z 429.1 [M+H]+

[0307] Example 55: According to General Procedure 1, Variant 3: To a solution of Intermediate AA-1 (70.0 mg, 227 / / mol, 1.00 eq.) and Intermediate BA-55 (52.0 mg, 272 mol, 1.20 eq.) in DMF (2.00 mL) wasadded DIPEA (118 / / L, 682 / / mol, 3.00 eq.), and the reaction was stirred at 80°C for 12 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 1 to afford Exemplary Compound 55 (21.43 mg, 57.3 / / mol, 25% yield) as a white solid.

[0308] 'H NMR (400 MHz, CD3CN) d = 8.73 (br s, 1H), 8.07 (s, 1H), 7.30 - 7.21 (m, 1H), 7.10 (dd, J= 1.2, 8.0 Hz, 1H), 6.96 (dd, J= 1.6, 7.6 Hz, 1H), 4.26 (dd, J= 5.2, 12.4 Hz, 1H), 3.34 - 3.27 (m, 1H), 3.21 - 3.14 (m, 2H), 3.05 - 2.95 (m, 6H), 2.84 (s, 3H), 2.80 - 2.71 (m, 3H), 2.71 - 2.60 (m, 3H), 2.36 - 2.28 (m, 1H), 2.12 - 2.08 (m, 1H), 1.91 - 1.90 (m, 1H), 1.80 - 1.73 (m, 1H). MS (ESI) m / z 419.2 [M+H]+

[0309] Example 87: According to General Procedure 1, Variant 2: TO a mixture of Intermediate AA-1 (0.100 g, 0.290 mmol, 1.00 eq.), Intermediate BA-87 (0.06 g, 0.307 mmol, 1.06 eq.) and potassium phosphate (0.246 g, 1.16 mmol, 4.00 eq.) in DMSO (2 mL) was added DMPAO (0.0224 g, 0.116 mmol, 0.40 eq.) and copper(I) iodide (0.01 g, 58.1 / / mol, 0.20 eq.).

[0310] The mixture was stirred at 120°C for 12 h under nitrogen. The mixture was cooled to room temperature and EtOAc (30 mL) and water (30 mL) were added. The layers were separated, and the aqueous phase was extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 1 to afford Exemplary Compound 87 (11.1 mg, 24.9 / / mol, 9% yield) as a white solid. 'H NMR (400 MHz, DMSO4) d = 10.89 (s, 1H), 8.04 (d, J= 6.4 Hz, 1H), 7.60 (s, 1H), 7.35 - 7.27 (m, 1H), 7.25 - 7.17 (m, 1H), 7.04 (dd, J= 1.2, 7.6 Hz, 1H), 6.70 (t, J= 7.2 Hz, 1H), 6.47 (d, J= 7.6 Hz, 1H), 4.28 (dd, J= 5.2, 12.0 Hz, 1H), 3.66 (s, 4H), 3.17 (s, 4H), 2.83 - 2.71 (m, 1H), 2.58 - 2.53 (m, 1H), 2.32 (s, 3H), 2.31 - 2.25 (m, 1H), 2.05 - 1.97 (m, 1H). MS (ESI) m / z 438.2 [M+H]+

[0311] Example 89: According to General Procedure 1, Variant 1 : eq}, added Pd-PEPPSI-IHept-Cl (0.117 g, 0.120 mmol, 0.05 eq}. The reaction was stirred at 100°C for 12 h under nitrogen. The mixture was cooled to room temperature, and EtOAc (50 mL) and water (50 mL) were added. The layers were separated, and the aqueous phase was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (40 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 followed by Purification Method 1 to afford Exemplary Compound 89 (111.4 mg, 0.268 mmol, 11% yield) as a white solid.

[0312] 'H NMR (400 MHz, DMSO4) 3 = 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, 1H). MS (ESI) m / z 442.2 [M+H]+

[0313] The other Exemplary Compounds shown in Table 3 were synthesized in analogy to the above examples and according to General Procedure 1 (Variant 1 - 4).

[0314] Table 3. Exemplary compounds synthesized according to Scheme 2.

[0315]

[0316] 1.2.2 Synthesis of Intermediates of formula BA

[0317] In the cases where Intermediates BA were not commercially available, they were synthesized as follows.

[0318] Intermediate BA-2

[0319] Intermediate BA-2 Step 1. To a solution of 5-bromopyrimidin-4(3J7)-one (1.00 g, 5.71 mmol, 1.00 eq.) and cyclobutylmethanamine (694 mg, 5.71 mmol, 1.00 eq, hydrochloride) in acetonitrile (10.0 mL) were added HATU (2.39 g, 6.29 mmol, 1.10 eq.) and DBU (2.15 mL, 14.2 mmol, 2.50 eq.). The reaction was stirred at 45°C for 20 h. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford Intermediate BA-2 (340 mg, 1.40 mmol, 24% yield) as a yellow oil.

[0320] Intermediates BA-3, BA-19, and BA-34 were synthesized in analogy to Intermediate BA-2 using the appropriate amine partners.

[0321] Intermediate BA-4

[0322] Intermediate

[0323] To a solution of l-iodo-2-methoxy ethane (320 mg, 1.72 mmol, 1.50 eq.) and 3-bromopyridin- 2(177)-one (200 mg, 1.15 mmol, 1.00 eq.) in DMF (3.00 mL) was added potassium carbonate (317 mg, 2.30 mmol, 2.00 eq.). The reaction was stirred at 25°C for 12 h, then it was quenched with water (30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford Intermediate BA-4 (255 mg, 1.09 mmol, 95% yield) as a white solid.

[0324] Intermediate BA-25 was synthesized in analogy to BA-4:

[0325] Intermediate BA-25 To a solution of 5 -chloro- l / Z-pyridazin-6-one (500 mg, 3.83 mmol, 1.00 eq.) and potassium carbonate (1.59 g, 11.5 mmol, 3.00 eq.) in DMF (5.00 mL) was added bromomethylcyclopropane (365 / / L, 3.83 mmol, 1.00 eq.). The reaction was stirred at 25°C for 12 h, then it was poured into water (40 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford Intermediate BA-25 (90.0 mg, 487 / / mol, 13% yield) as a yellow oil.

[0326] Intermediates BA-22, BA-23, BA-27, BA-38, BA-43, BA-49 BA-54, BA-58 and BA-61 were synthesized in analogy to Intermediate BA-4 and BA-25, using the appropriate starting materials and alkylating partners.

[0327] Intermediate BA-5

[0328] Intermediate BA-5

[0329] Step 1. To a solution of 2-bromoethan-l-ol (1.63 mL, 23.0 mmol, 4.00 eq.) and 3-bromopyridin- 2(177)-one (1.00 g, 5.75 mmol, 1.00 eq.) in acetone (10.0 mL) was added potassium carbonate (1.99 g, 14.4 mmol, 2.50 eq.) and potassium iodide (286 mg, 1.72 mmol, 0.30 eq.). The reaction was stirred at 25°C for 4 h, then it was filtered, and the filter cake was washed with ethyl acetate (25 mL). The filtrate was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford 3-bromo- l -(2-hydroxyethyl)pyridin-2( IT / )-one (723 mg, 3.32 mmol, 58% yield) as a yellow oil.

[0330] Step 2. To a solution of 3-bromo-l-(2-hydroxyethyl)pyridin-2(177)-one (600 mg, 2.75 mmol, 1.00 eq.) in acetonitrile (6.00 mL) was added 2,2-difluoro-2-fluorosulfonyl-acetic acid (569 / / L, 5.50 mmol, 2.00 eq.) and copper(I) iodide (105 mg, 550 mol, 0.20 eq.). The reaction was stirred at 50°C for 1 h, then it was cooled to 0°C. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford Intermediate BA-5 (205 mg, 765 / / mol, 28% yield) as a yellow oil.

[0331] Step 1. To a solution of methyl 7-hydroxy-5-oxo-l,2,3,5-tetrahydroindolizine-3-carboxylate (0.800 g, 3.82 mmol, 1.00 eq.) in dichloromethane (8.00 mL) was added pyridine (617 / / L, 7.65 mmol, 2.00 eq.) and trifluoromethanesulfonic anhydride (757 / / L, 4.59 mmol, 1.20 eq.) at 0°C. The reaction was stirred at 25°C for 2 h, then it was quenched by addition of water (20 mL) at 25°C, and extracted with dichloromethane (3 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford methyl 5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-l,2,3,5-tetrahydroindolizine-3- carboxylate (1.00 g, 2.84 mmol, 74% yield) as a brown solid.

[0332] Step 2. A mixture of methyl 5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-l, 2,3,5- tetrahydroindolizine-3-carboxylate (1.00 g, 2.93 mmol, 1.00 eq.), triethylsilane (936 / / L, 5.86 mmol, 2.00 eq.) and Pd(PPh3)4 (678 mg, 587 mol, 0.20 eq.) in DMF (10.0 mL) was degassed by purging with nitrogen, then the reaction was stirred at 60°C for 1 h under nitrogen. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford methyl 5-oxo-l,2,3,5-tetrahydroindolizine-3-carboxylate (0.400 g, 1.97 mmol, 67% yield) as a white solid. Step 3. To a solution of methyl 5-oo-l,2,3,5-tetrahydroindolizine-3-carboxylate (0.400 g, 2.07 mmol, 1.00 eq.) in THF (6.00 mL) was added lithium hydroxide (1.00 M, 3.11 mL, 1.50 eq.). The reaction was stirred at 25°C for 2 h. The pH was adjusted to 5-6 with hydrochloric acid (IM), then the mixture was extracted with isopropanokchloroform = 3: 1 (3 * 20 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 5-oxo-l,2,3,5-tetrahydroindolizine-3- carboxylic acid (0.300 g, 1.67 mmol, 81% yield) as a brown solid.

[0333] Step 4. To a solution of 3-(hydroxymethyl)-2,3-dihydroindolizin-5(U7)-one (0.300 g, 1.82 mmol, 1.00 eq.) in DMF (5.00 mL) was added sodium hydride 60% dispersion in mineral oil (146 mg, 3.63 mmol, 2.00 eq.) at 0°C under nitrogen. The reaction was stirred at 0°C for 30 min, then iodomethane (170 / / L, 2.72 mmol, 1.50 eq.) was added, and the reaction was stirred for a further 2 h at 25°C. The reaction was quenched with water (10 mL) at 0°C, and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford 3-(methoxymethyl)-2,3- dihydroindolizin-5(U7)-one (0.100 g, 524 / / mol, 29% yield) as a brown oil.

[0334] Step 5. To a solution of 5-oxo-l,2,3,5-tetrahydroindolizine-3-carboxylic acid (0.420 g, 2.34 mmol, 1.00 eq.) in THF (5.00 mL) was added borane dimethyl sulfide complex (10.0 M, 281.3 / / L, 1.20 eq.) at 0°C dropwise under nitrogen. The reaction was stirred at 60°C for 1 h, then it was quenched by addition methanol (10 mL) until bubbling ceased. The mixture was concentrated under reduced pressure to afford 3-(hydroxymethyl)-2,3-dihydroindolizin-5( IT / )- one (0.400 g, 2.03 mmol, 87% yield) as a yellow solid.

[0335] Step 6. To a solution of 3-(methoxymethyl)-2,3-dihydroindolizin-5(U7)-one (0.130 g, 725 mol, 1.00 eq.) in DMF (2.00 mL) was added / V-bromosuccinimide (129 mg, 725 / / mol, 1.00 eq.). The reaction was stirred at 25°C for 2 h, then it was concentrated under reduced pressure to give the residue. The residue was purified via Purification Method 2 to afford Intermediate BA-10 (64.0 mg, 230 / / mol, 31% yield) as a white solid.

[0336] Intermediate BA-16

[0337] Intermediate BA-16 Step 1. To a solution of 3-bromopyridin-2(177)-one (5.00 g, 28.7 mmol, 1.00 eq.) in DMF (100 mL) was added sodium hydride 60% dispersion in mineral oil (1.72 g, 43.1 mmol, 1.50 eq.) slowly at 0°C under nitrogen. The reaction was stirred at 0°C for 10 min, then iodoethane (4.60 mL, 57.5 mmol, 2.00 eq.) was added. The reaction was stirred at 25°C for 50 min, then it was quenched by addition of NH4CI sat. sol. (2 mL), diluted with water (30 mL), and extracted with ethyl acetate (3 x 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 via Purification Method 2 to afford Intermediate BA-16 (4.20 g, 20.6 mmol, 72% yield) as light yellow oil.

[0338] Intermediate BA-1, BA-15, and BA-36 was synthesized in analogy to Intermediate BA- 16 using the appropriate starting materials and alkylating partners.

[0339] Intermediate BA-17

[0340] Intermediate BA-17

[0341] Step 1. To a solution of 3-bromo-6-fluoropyridin-2-amine (2.00 g, 10.5 mmol, 1.00 eq.) and sulfuric acid 65% (4.19 mL, 78.6 mmol, 7.50 eq.) in water (50 mL) was added sodium nitrite (0.867 g, 12.6 mmol, 1.20 eq.) at 0°C. The reaction was stirred at 25°C for 12 h, then it was filtered. The filter cake was collected and dried in vacuo to afford 3-bromo-6-fluoropyridin- 2(177)-one (1.60 g, 7.50 mmol, 72% yield) as a white solid.

[0342] Step 2. To a solution of 3-bromo-6-fluoropyridin-2( IT / )-one (1.60 g, 8.33 mmol, 1.00 eq.) and 1- iodo-2-methoxyethane (3.10 g, 16.7 mmol, 2.00 eq.) in DMF (40 mL) was added caesium carbonate (4.07 g, 12.5 mmol, 1.50 eq.). The reaction was stirred at 25°C for 12 h. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford Intermediate BA-17 (0.080 g, 0.288 mmol, 3% yield) as a yellow oil.

[0343] Intermediate BA-20

[0344] Intermediate BA-20

[0345] Step 1. To a solution of 2,2-difluoroethyl trifluoromethanesulfonate (7.27 g, 33.9 mmol, 2.50 eq.) and 3-iodopyridin-2(177)-one (3.00 g, 13.5 mmol, 1.00 eq.) in DMF (10.0 mL) was added DIPEA (2.36 mL, 13.5 mmol, 1.00 eq.). The reaction was stirred at 25°C for 12 h. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were wash with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford Intermediate BA-20 (1.50 g, 5.26 mmol, 39% yield) as a white solid.

[0346] Intermediates BA-51 and BA-52 were synthesized in analogy to Intermediate BA- 15 with the appropriate starting materials.

[0347] Intermediate BA-45

[0348] Step 1. To a solution of l-methyl-6-oxo-l,6-dihydropyridine-2-carboxylic acid (5.00 g, 32.7 mmol, 1.00 eq.) in THF (150 mL) was added borane dimethyl sulfide complex (10 M, 16.3 mL, 5.00 eq.) under nitrogen. The mixture was stirred at 50°C for 12 h under nitrogen. The reaction mixture was cooled to room temperature and then quenched with methanol (30 mL) under nitrogen at 25°C for 0.5 h, then at 50°C for 1 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford 6- (hydroxymethyl)-l-methylpyridin-2(177)-one (1.20 g, 8.62 mmol, 26% yield) as a white solid.

[0349] Step 2. To a solution of 6-(hydroxymethyl)-l-methylpyridin-2(177)-one (0.800 g, 5.75 mmol, 1.00 eq.) in dimethyl formamide (10 mL) was added sodium hydride 60% dispersion in mineral oil (0.690 g, 17.3 mmol, 3.00 eq.) at 0°C under nitrogen. Methyl iodide (2.45 g, 17.3 mmol, 3.00 eq.) was added at 0°C. The reaction was stirred at 25°C for 2 h, then it was quenched with NH4Q sat. sol. (10 mL) at 25°C for 10 min. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were wash with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford 6-(methoxymethyl)- 1 -methyl pyridin-2(U7)-one (0.500 g, 3.17 mmol, 55% yield) as a white solid.

[0350] Step 3. A mixture of 6-(methoxymethyl)-l-methylpyridin-2(177)-one (0.500 g, 3.26 mmol, 1.00 eq.) and iodopyrrolidine-2, 5-dione (1.10 g, 4.90 mmol, 1.50 eq.) in acetonitrile (9 mL) was stirred at 25°C for 12 h. NaHCOs sat. sol. (10 mL) was added, and the mixture was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were washed with brine (3 x 5 mL), dried over sodium sulfate, filtered, and concentrated der reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford Intermediate BA-45 (0.780 g, 2.79 mmol, 86% yield) as a white solid.

[0351] Intermediate BA-59

[0352] Intermediate BA-59

[0353] Step 1. To a solution of 5-chloro-17 / -pyridazin-6-one (500 mg, 3.83 mmol, 1.00 eq.) in dioxane (1.00 mL) was added silver oxide (888 mg, 3.83 mmol, 1.00 eq.) and iodoethane (3.06 mL, 38.3 mmol, 10.0 eq.). The reaction was stirred at 60°C for 5 h. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic layers were washed with brine (8 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford Intermediate BA- 59 (40.0 mg, 252 / / mol, 33% yield) as a yellow liquid.

[0354] Intermediate BA-62 was synthesized in analogy to Intermediate BA-59 using methyl iodide as the alkylating partner.

[0355] Intermediate BA-77

[0356] Intermediate BA-77 Step 1. To a mixture of pyrazolo[l,5-a]pyridin-2-ylmethanol (0.200 g, 1.35 mmol, 1.00 eq.) in THF (3 mL) was added sodium hydride 60% dispersion in mineral oil (80.9 mg, 2.02 mmol, 1.50 eq.) at 0°C under nitrogen. The reaction was stirred at 0°C for 0.5 h, then methyl iodide (0.287 g, 2.02 mmol, 1.50 eq.) was added at 0°C. The reaction was stirred for a further 0.5 h at 25°C under nitrogen, then it was quenched with NH4CI sat. sol. (10 mL) at 0°C. The mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated der reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford 2-(methoxymethyl)-pyrazolo[l,5- a]pyridine (0.170 g, 1.05 mmol, 78% yield) as a yellow oil.

[0357] Step 2. To a mixture of 2-(methoxymethyl)pyrazolo[l,5-a]pyridine (0.170 g, 1.05 mmol, 1.00 eq.) in THF (3 mL) was added w-butyllithium (2.5 M, 1.30 eq.) at -78°C. The reaction was stirred at -78°C for 1 h, then 1,2-diiodoethane (0.443 g, 1.57 mmol, 1.50 eqi) in THF (3 mL) was added at -78°C. The reaction was stirred for additional 1 h at -78°C under nitrogen atmosphere, then it was quenched with NH4CI sat. sol. (10 mL) at 0°C under nitrogen. The mixture was extracted with ethyl acetate (3 x 30 mL), and the combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, red, and concentrated der reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford Intermediate BA-77 (0.230 g, 0.798 mmol, 76% yield) as a yellow oil.

[0358] Intermediate BA-78 was synthesized in analogy to Intermediate BA-77.

[0359] Intermediate BA-79

[0360] Step 1. To a solution of pyrazolo[l,5-a]pyridine-3-carboxylic acid (6.00 g, 37.0 mmol, 1.00 eq.) in THF (240 mL) was added l,l'-carbonyldiimidazole (18.0 g, 111 mmol, 3.00 eq.). The reaction was stirred at 25°C for 12 h under nitrogen. Then sodium borohydride (7.07 g, 186.9 mmol, 5.05 eq.) in water (120 mL) was added dropwise at 0°C, and the reaction was stirred at 25°C for 0.5 h. The reaction was quenched with NaHCOs sat. sol., and THF was removed under reduced pressure. Water (60 mL) was added, and the mixture was extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with brine (3 x 60 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford pyrazolo[l,5-a]pyridin-3-ylmethanol (1.90 g, 12.2 mmol, 33% yield) as a colourless oil.

[0361] Steps 2 and 3 were performed in analogy to Intermediate BA-77 to afford Intermediate BA-79.

[0362] Intermediate BA-81 was synthesized in analogy to Intermediate BA-79.

[0363] Intermediate BA-83

[0364] Step 1. To a mixture of pyrazolo[l,5-a]pyridine-3-carbaldehyde (2.00 g, 13.6 mmol, 1.00 eq.) in dichloromethane (50 mL) was added potassium fluoride (1.19 g, 20.5 mmol, 1.50 eq.) and 3- chlorobenzoperoxoic acid 85% (4.17 g, 20.5 mmol, 1.50 eq.) at 0°C. The reaction was stirred at 25°C for 2 h under nitrogen. The reaction was quenched with NaHCOs sat. sol. (100 mL) and extracted with ethyl acetate (3 * 100 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford pyrazolo[l,5-a]pyridin-3-ol (0.720 g, 5.37 mmol, 39% yield) as a yellow solid.

[0365] Steps 2 and 3 were performed in analogy to Intermediate BA-77 to afford Intermediate BA-83.

[0366] Intermediate BA-89

[0367] Intermediate

[0368] BA-89

[0369] Step 1. To a solution of ethyl 7-bromo-4-fluoropyrazolo[l,5-a] pyridine-3 -carboxylate (0.200 g, 696 / / mol, 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 x 10 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford Intermediate BA-89 (0.110 g, 511 / / mol, 73% yield) as a pink solid.

[0370] Intermediate BA-91

[0371] Step 1. A mixture of tert-butyl ((mesitylsulfonyl)oxy)carbamate (3.00 g, 9.51 mmol, 1.00 eq.) in trifluoroacetic acid (20.0 mL) was stirred at 25°C for 1 h. The reaction mixture was poured into water (50.0 mL) and stirred for 5 min, and the resulting precipitate was filtered off. The precipitate was dissolved in di chloromethane (30.0 mL) and used in the next step directly.

[0372] Step 2. A mixture of 4-fluoropyridin-2-amine (989 mg, 8.83 mmol, 1.00 eq.) and amino O- (mesitylsulfonyl)hydroxylamine (1.90 g, 8.83 mmol, 1.00 eq.) in dichloromethane (30.0 mL) was stirred at 25°C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was triturated with petroleum ether (50.0 mL) at 25°C for 5 min to afford l,2-diamino-4-fluoropyridin-l-ium 2,4,6-trimethylbenzenesulfonate (1.70 g, 5.19 mmol, 59% yield) as a white solid.

[0373] Step 3. To a solution of l,2-diamino-4-fluoropyridin-l-ium 2,4,6-trimethylbenzenesulfonate (100 mg, 305 mol, 1.00 eq.) in DMF (2.00 mL) was added potassium carbonate (126 mg, 916 / / mol, 3.00 eq.) and methyl prop-2-ynoate (51.0 / / L, 610 / / mol, 2.00 eq.). The reaction was stirred at 25°C for 12 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 then Purification Method 1 to afford methyl 7-amino-5-fluoropyrazolo[l,5-a]pyridine-3-carboxylate (70.0 mg, 334 / / mol, 11% yield) as a yellow solid. Step 4. To a solution of cuprous bromide (82.3 mg, 573 / / mol, 2.00 eq.) and tert-butyl nitrite (68.2 / / L, 573 / mol, 2.00 eq.) in acetonitrile (2.00 mL) was added methyl 7-amino-5- fluoropyrazolo[l,5-a]pyridine-3-carboxylate (60.0 mg, 286 / / mol, 1.00 eq.). The reaction was stirred at 80°C for 1 h. The mixture was concentrated to give a residue. The residue was purified via Purification Method 2 to afford methyl 7-bromo-5-fluoropyrazolo[l,5-a]pyridine-3- carboxylate (20.0 mg, 73.2 / / mol, 25% yield) as a white solid.

[0374] Step 5. To a solution of methyl 7-bromo-5-fluoropyrazolo[l,5-a]pyridine-3-carboxylate (30.0 mg, 109 / / mol, 1.00 eq.) in acetic acid (0.500 mL) and water (0.500 mL) was added hydrochloric acid 36% (0.500 mL). The reaction was stirred at 100°C for 1 h, then the mixture was poured into NaHCOs sat. sol. (30.0 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford Intermediate BA-91 (20.0 mg, 93.0 / / mol, 84% yield) as a yellow oil.

[0375] Intermediate BA-92

[0376] Step 1. To a solution of UT-pyrazol-5-amine (1.00 g, 12.0 mmol, 1.00 eq.) in acetic acid (10 mL) under nitrogen was added ethyl 4,4-difluoro-3-oxobutanoate (2.00 g, 12.0 mmol, 1.00 eq.) at 25°C. The reaction was stirred at 120°C for 4 h. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with acetic acid (10 mL) and water (10 mL). The solid was dried under vacuum to afford 5-(difluoromethyl)pyrazolo[l,5-a]pyrimidin-7-ol (1.40 g, 7.56 mmol, 63% yield) as a white solid.

[0377] Step 2. To a solution of 5-(difluoromethyl)pyrazolo[l,5-a]pyrimidin-7-ol (0.500 g, 2.70 mmol, 1.00 eq.) in acetonitrile (10 mL) was added phosphoryl trichloride (1.30 mL, 13.5 mmol, 5.00 eq.). The reaction was stirred at 90°C for 12 h. After cooling to room temperature, the mixture was poured into water (40 mL) and stirred for 30 min, then the pH was adjusted to 7 with NaHCOs sat. sol.. The mixture was extracted with ethyl acetate (3 x 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 via Purification Method 2 to afford Intermediate BA-92 (0.440 g, 2.16 mmol, 80% yield) as a yellow solid.

[0378] Intermediate BA-93

[0379] Intermediate

[0380] BA-93

[0381] Step 1. To a solution of 7-bromopyrazolo[l,5-a]pyridine (200 mg, 1.02 mmol, 1.00 eq.) in acetonitrile (2.00 mL) was added Selectfluor (539 mg, 1.52 mmol, 1.50 eq.). The reaction was stirred at 25°C for 2 h, then it was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford Intermediate BA-93 (80.0 mg, 372 / / mol, 37% yield) as a yellow solid.

[0382] Intermediate BA-95 was synthesized in analogy to Intermediate BA-93 starting from 7- chloropyrazolof 1 , 5-a]pyrimidine.

[0383] Intermediate BA-96

[0384] Intermediate BA-96

[0385] Step 1. A mixture of 5-chloropyrazolo[l,5-a]pyrimidin-7(4J7)-one (300 mg, 1.77 mmol, 1.00 eq.) in sodium methoxide (5 M, 6 mL) was stirred at 100°C for 12 h. Then the reaction mixture was concentrated to give a residue. The residue was dissolved in water (20.0 mL), and the pH was adjusted to pH = 5~6 with formic acid (3 mL). The resulting precipitate was filtered and lyophilized to afford 5-methoxypyrazolo[l,5-a]pyrimidin-7(4J7)-one (200 mg, 1.21 mmol, 68% yield) as a white solid.

[0386] Step 2. To a solution of 5-methoxypyrazolo[l,5-a]pyrimidin-7(4J7)-one (40.0 mg, 242 mol, 1.00 eq.) in toluene (1.00 mL) was added phosphorus oxychloride (225 / / L, 2.42 mmol, 10.0 eq.). The reaction was stirred at 100°C for 1 h. After cooling to room temperature, the reaction was quenched with NaHCOs sat. sol. (20 mL), then extracted with ethyl acetate (3 / | 5 mL). The combined organic layers were washed with brine (30 mL), dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford Intermediate BA-96 (30.0 mg, 163 / / mol, 67% yield) as a yellow solid.

[0387] Intermediate BA-110

[0388] Intermediate BA-110 Step 1. Imidazo[l,2-Z>]pyridazine (0.500 g, 4.20 mmol, 1.00 eq.) was dissolved in DMF (5 mL) under nitrogen, and 1 -iodopyrrolidine-2, 5-dione (1.13 g, 5.04 mmol, 1.20 eq.) was added. The reaction was stirred at 80°C for 12 h. The mixture was diluted with water (20 mL) and ethyl acetate (20 mL), and then it was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford Intermediate BA-110 (0.670 g, 2.73 mmol, 67% yield) as a brown solid.

[0389] 1.3 Synthesis of Exemplary Compounds via Intermediate AA-3 and AA-4 with Intermediates BB

[0390] Intermediate BB

[0391] General Procedure 2 Variant 1-2

[0392] X = Br: Intermediate AA-3

[0393] X = BPin: Intermediate AA-4 Exemplary Compounds

[0394] Scheme 3. Synthesis of Exemplary Compounds via Intermediates BB and Intermediate AA-3 or

[0395] Intermediate AA-4

[0396] Table 4. Structures of Intermediates BB

[0397] General procedure 2

[0398] • Variant 1

[0399] A mixture of Intermediate AA-3 (1.00 eq.) and Intermediate BB (0.70 - 1.20 eq.) was dissolved in a polar aprotic solvent (DMF or dioxane, 0.1 - 0.25 M relative to Intermediate AA- 3) and caesium carbonate (3.00 - 5.00 eq.) was added, followed by Pd-PEPPSI-IHept-Cl (0.05 - 0.10 eq.). The mixture was degassed by purging with nitrogen, then the reaction was stirred at elevated temperature (90 - 100°C) under nitrogen until reaction completion (1 - 12 h). In some cases, a workup was performed: the mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. In other cases, no workup was performed: the mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue directly. The residue was purified via Purification Method 1 (if necessary, the residue was first purified via Purification Method 2, then Purification Method 7) to afford the corresponding Exemplary Compound.

[0400] • Variant 2

[0401] To a solution of Intermediate BB (1.00 eq.) and Intermediate AA-4 (1.00 - 1.20 eq.) in dichloromethane (0.08 - 0.20 M relative to Intermediate BB) were added copper(II)acetate (1.00 - 1.40 eq.) and triethylamine (6.00 - 10.00 eq.). The reaction was stirred at 25°C under oxygen atmosphere until reaction completion (16 - 20 h). Then it was concentrated under reduced pressure to give a residue, which was purified via Purification Method 1 (if necessary, the residue was first purified via Purification Method 2, then Purification Method 7) to afford the corresponding Exemplary Compound. 1.3.1 Representative examples

[0402] Example 11: According to General Procedure 2, Variant 1 , mmol, 3.00 eq.) followed by Pd-PEPPSI-IHept-Cl (0.161 g, 0.166 mmol, 0.10 eq.) at 25°C. The reaction was stirred at 100°C for 12 h under nitrogen atmosphere. The mixture was cooled to room temperature and filtered over Celite. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2, then Purification Method 1 to afford Exemplary Compound 11 (0.178 g, 0.384 mmol, 23% yield) as a white solid.

[0403] 'H NMR (400 MHz, DMSO-tA) d = 10.89 (s, 1H), 7.33 - 7.24 (m, 2H), 7.18 (dd, J= 1.2, 8.0 Hz, 1H), 7.03 (dd, J= 1.2, 7.6 Hz, 1H), 6.78 (dd, J= 1.6, 7.6 Hz, 1H), 6.15 (t, J= 6.8 Hz, 1H), 4.27 (dd, J= 5.6, 12.4 Hz, 1H), 4.06 (t, J= 5.6 Hz, 2H), 3.57 (t, J= 5.6 Hz, 2H), 3.27 - 3.17 (m, 7H), 3.12 - 3.04 (m, 4H), 2.82 - 2.71 (m, 1H), 2.55 - 2.52 (m, 1H), 2.33 - 2.26 (m, 1H), 2.03 - 1.96 (m, 1H). MS (ESI) m / z 459.3 [M+H]+

[0404] Example 37: According to General Procedure 2, Variant 1

[0405] To a solution of Intermediate BB-37 (500 mg, 2.02 mmol, 1.00 eq.) and Intermediate AA-3 (610 mg, 2.02 mmol, 1.00 eq.) in dioxane (10.0 mL) was added caesium carbonate (1.97 g, 6.06 mmol, 3.00 eq.) and Pd-PEPPSI-IHept-Cl (98.1 mg, 100 / / mol, 0.05 eq.) under nitrogen atmosphere. The reaction was stirred at 100°C for 12 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2, then Purification Method 1 to afford Exemplary Compound 37 (751.6 mg, 1.72 mmol, 11% yield) as an off-white solid.

[0406] 'H NMR (400 MHz, DMSO ) d = 10.89 (s, 1H), 7.57 (t, J= 7.6 Hz, 1H), 7.38 - 7.24 (m, 1H), 7.16 (dd, J= 1.6, 8.0 Hz, 1H), 7.02 (dd, J= 1.2, 7.6 Hz, 1H), 6.26 (dd, J= 7.6, 9.2 Hz, 1H), 4.27 (dd, J= 5.2, 12.0 Hz, 1H), 3.32 (s, 3H), 3.27 (br d, J= 3.6 Hz, 4H), 3.10 - 2.95 (m, 4H), 2.83 - 2.72 (m, 1H), 2.57 - 2.52 (m, 1H), 2.35 - 2.24 (m, 1H), 2.06 - 1.93 (m, 1H). MS (ESI) m / z 433.1 [M+H]+ Example 63: According to General Procedure 2, Variant 2

[0407] To a solution of Intermediate BB-63 (80.0 mg, 385 / / mol, 1.00 eq.) and Intermediate AA-4 (161 mg, 463 mol, 1.20 eq.) in dichloromethane (2.00 mL) was added copper(II)acetate (70.1 mg,

[0408] 385 / / mol, 1.00 eq.) and triethylamine (429 / / L, 3.09 mmol, 8.00 eq.). The reaction was stirred at 25°C for 16 h, then it was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 1 to afford Exemplary Compound 63 (10.3 mg, 23.7 / / mol, 6% yield) as a yellow solid.

[0409] 'H NMR (400 MHz, DMSO-tL) <5 = 10.89 (s, 1H), 7.63 (d, J= 5.2 Hz, 1H), 7.44 (d, J= 6.0 Hz, 1H), 7.33 - 7.22 (m, 1H), 7.12 (d, J= 7.6 Hz, 1H), 7.00 (d, = 7.6 Hz, 1H), 6.23 (t, J= 6.4 Hz, 1H), 4.26 (dd, J= 11.6, 5.2 Hz, 1H), 3.45 (s, 3H), 3.39 (s, 2H), 2.97 (s, 4H), 2.80 - 2.72 (m, 1H), 2.59 (s, 5H), 2.32 - 2.22 (m, 1H), 2.04 - 1.93 (m, 1H). MS (ESI) m / z 429.2 [M+H]+

[0410] Example 80: According to General Procedure 2, Variant 1

[0411] A mixture of Intermediate BB-80 (0.08 g, 0.317 mmol, 1.00 eq.), Intermediate AA-3 (0.192 g, 0.633 mmol, 2.00 eq.), Pd-PEPPSI- IHept-Cl (30.8 mg, 31.7 / / mol, 0.10 eq.), and caesium carbonate

[0412] (0.309 g, 0.950 mol, 3.00 eq.) in dioxane (2 mL) was degassed by purging with nitrogen. The reaction was stirred at 90°C for 12 h under nitrogen. The mixture was cooled to room temperature and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 then Purification Method 1 to afford Exemplary Compound 80 (4.24 mg, 9.40 / / mol, 3% yield) as a white solid.

[0413] 'H NMR (400 MHz, DMSO-fifc) h = 10.90 (s, 1H), 7.36 - 7.30 (m, 1H), 7.29 - 7.21 (m, 2H), 7.19 - 7.11 (m, 1H), 7.06 (dd, J= 1.2, 7.6 Hz, 1H), 6.38 (s, 1H), 6.31 (d, J = 6.4 Hz, 1H), 4.30 (dd, J= 4.8, 12.0 Hz, 1H), 3.56 (s, 4H), 3.22 (s, 4H), 2.81 - 2.76 (m, 1H), 2.58 - 2.53 (m, 1H), 2.42 (s, 3H), 2.36 - 2.23 (m, 1H), 2.07 - 1.94 (m, 1H). MS (ESI) m / z 438.2 [M+H]+

[0414] The other Exemplary Compounds shown in Table 5 were synthesized in analogy to the above examples and according to General Procedure 2 (Variant 1 - 2).

[0415] Table 5. Exemplary compounds synthesized according to Scheme 3. 1.3.2 Synthesis of Intermediates of formula BB

[0416] Intermediate BB-11

[0417] Step 1. To a solution of Intermediate BA-4 (0.600 g, 2.59 mmol, 1.00 eq.) in THF (15.0 mL) was added tert-butyl piperazine- 1 -carboxylate (0.588 g, 3.16 mmol, 1.22 eq.) followed by caesium carbonate (4.20 g, 12.9 mmol, 4.99 eq.) and RuPhos Pd G3 (0.216 g, 0.258 mmol, 0.10 eq.). The reaction was stirred at 85°C for 12 h under nitrogen. After cooling to room temperature, the mixture was diluted with water (20.0 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford tert-butyl 4-( 1 -(2 -methoxy ethyl)-2-oxo- 1,2- dihydropyridin-3-yl)piperazine-l-carboxylate (0.550 g, 1.63 mmol, 63% yield) as a yellow solid.

[0418] Step 2. A solution of tert-butyl 4-(l-(2-methoxyethyl)-2-oxo-l,2-dihydropyridin-3-yl)piperazine- 1-carboxylate (0.550 g, 1.63 mmol, 1.00 eq.) in hydrogen chi oride / di oxane (2 M, 8.59 mL, 10.5 eq.) was stirred at 25°C for 4 h under nitrogen. The reaction mixture was concentrated under reduced pressure to afford Intermediate BB-11 (0.530 g, crude, hydrochloride) as a yellow solid.

[0419] Intermediates BB-6, BB-8, BB-9, BB-24, BB-26, BB-29, BB-32, BB-33, BB-44, and BB-48 were synthesized in analogy to Intermediate BB-11 using the appropriate alkylating agents in Step 1. In Step 2, other palladium catalyst systems than RuPhos Pd G3 may be used, for example: XPhos Pd G3, CPhos Pd G3, or Pd2(dba)3 and XPhos.

[0420] Intermediate BB-14

[0421] Intermediate BB-14

[0422] Step 1. To a solution of 3-bromopyridin-2(lJ7)-one (2.59 g, 14.9 mmol, 1.00 eq.) and 3- (bromomethyl)oxetane (2.70 g, 17.9 mmol, 1.20 eq.) in acetonitrile (80 mL) was added potassium carbonate (6.18 g, 44.7 mmol, 3.00 eq.). The reaction was stirred at 80°C for 12 h. After cooling to room temperature, the mixture was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford 3-bromo-l-(oxetan-3- ylmethyl)pyridin-2(lrt)-one (2.00 g, 8.19 mmol, 55% yield) as a white solid.

[0423] Step 2. A mixture of 3-bromo-l-(oxetan-3-ylmethyl)pyridin-2(177)-one (2.00 g, 8.19 mmol, 1.00 eq.), piperazine (1.06 g, 12.3 mmol, 1.50 eq.), Pd PEPPSI-IHept Cl (0.651 g, 0.819 mmol, 10 mol%), and sodium / c / 7-butoxide (2.36 g, 24.6 mmol, 3.00 eq.) in 2-methylbutan-2-ol (50 mL) was degassed by purging with nitrogen, then the reaction was stirred at 90°C for 12 h under nitrogen. After cooling to room temperature, the mixture was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 then Purification Method 1 to afford Intermediate BB-14 (0.295 g, 1.18 mmol, 15% yield) as a white solid.

[0424] Intermediate BB-37

[0425] Step 1. To a solution of 4-fluoropyridin-2(lrt)-one (5.00 g, 44.2 mmol, 1.00 eq.) in DMF (20 mL) was added potassium carbonate (12.2 g, 88.4 mmol, 2.00 eq.) followed by Mel (9.41 g, 66.3 mmol, 1.50 eq.). The reaction was stirred at 25°C for 4 h. The mixture was diluted with ethyl acetate (40 mL) and filtered over Celite. The filtrate was concentrated under reduced pressure to afford 4-fluoro-l-methylpyridin-2(177)-one (5.50 g, 43.3 mmol, 98% yield) as a light-yellow oil.

[0426] Step 2. To a solution of 4-fluoro-l-methylpyridin-2(lrt)-one (4.50 g, 35.4 mmol, 1.00 eq.) in acetonitrile (60 mL) was added 1 -iodopyrrolidine-2, 5-dione (8.76 g, 38.9 mmol, 1.10 eq.) at 25°C under nitrogen. The reaction was stirred at 25°C for 16 h. The mixture was diluted with Na2SCh sat. sol. (40 mL) and extracted with ethyl acetate (3 x 90 mL). The combined organic layers were washed with K2CO3 sat. sol. (90 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford 4-fluoro-3-iodo-l-methylpyridin-2(177)-one (1.50 g, 5.93 mmol, 17% yield) as a white solid.

[0427] Step 3. To a solution of 4-fluoro-3-iodo-l-methylpyridin-2(lrt)-one (0.500 g, 1.98 mmol, 1.00 eq.) in dioxane (5 mL) was added tert-butyl piperazine- 1 -carboxylate (0.550 g, 2.95 mmol, 1.49 eq.) and caesium carbonate (1.93 g, 5.92 mmol, 3.00 eq.) followed by CPhos Pd G3 (0.160 g, 0.198 mmol, 0.100 eq.) at 25°C under nitrogen. The reaction was stirred at 90°C for 12 h. After cooling to room temperature, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford tert-butyl 4-(4-fhioro-l- methyl-2-oxo-l,2-dihydropyri din-3 -yl)piperazine-l -carboxylate (1.00 g, 2.89 mmol, 73% yield) as a yellow solid.

[0428] Step 4. To a solution of tert-butyl 4-(4-fluoro-l-methyl-2-oxo-l,2-dihydropyri din-3 - yl)piperazine-l -carboxylate (0.360 g, 1.16 mmol, 1.00 eq.) in dioxane (2 mL) was added HC1 2M in dioxane (12 mL, 21.0 eq.). The reaction was stirred at 25°C for 12 h. The mixture was concentrated under reduced pressure to afford Intermediate BB-37 (0.280 g, 1.13 mmol, 98% yield, hydrochloride) as a yellow solid.

[0429] Intermediates BB-7, BB-28, and BB-18 were synthesized in analogy to Intermediate BB-37 using the appropriate alkylating agents in Step 1.

[0430] Intermediate BB-40

[0431] Intermediate BB-40

[0432] Step 1. To a mixture of 5 -(hydroxymethyl) pyridin-2(lrt)-one (3.20 g, 25.5 mmol, 1.00 eqi) in THF (50 mL) was added sodium hydride (3.07 g, 76.7 mmol, 60% purity, 3.00 eq.) at 0°C. The reaction was stirred at 0°C for 1 h, then Mel (18.1 g, 128 mmol, 5.00 eq.) was added at 0°C, and the reaction was stirred for an additional 1 h at 25°C under nitrogen. The reaction was quenched with NH4Q sat. sol. (100 mL) at 0°C for 0.5 h under nitrogen, then the mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford 5-(methoxymethyl)-l- methylpyridin-2(lrt)-one (2.20 g, 14.3 mmol, 56% yield) as a yellow oil.

[0433] Step 2. To a mixture of 5-(methoxymethyl)-l-methylpyridin-2(lrt)-one (0.500 g, 3.26 mmol, 1.00 eq.) in trifluoroacetic acid (6.91 g, 60.5 mmol, 18.5 eq.) and sulfuric acid (0.920 g, 9.38 mmol, 2.87 eq.) was added iodopyrrolidine-2, 5-dione (0.807 g, 3.59 mmol, 1.1 eq.). The reaction was stirred at 25°C for 0.5 h, then it was quenched with ice water (100 mL) at 0°C. The mixture was extracted with ethyl acetate (3 * 100 mL). The combined organic layers were washed with NaHCOs sat. sol. (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford 3-iodo-5- (methoxymethyl)-l-methylpyridin-2(177)-one (0.870 g, 3.12 mmol, 24% yield) as a yellow solid.

[0434] Step 3. To a mixture of 3 -iodo-5-(m ethoxymethyl)- l-methylpyridin-2(177)-one (0.870 g, 3.12 mmol, 1.00 eq.), tert-butyl piperazine- 1 -carboxylate (0.870 g, 4.68 mmol, 1.50 eq.) and caesium carbonate (3.05 g, 9.35 mmol, 3.00 eq.) in dioxane (10 mL) was added Pd PEPPS IHept Cl (0.260 g, 0.311 mmol, 0.1 eq.). The reaction was stirred at 90°C for 12 h under nitrogen. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford tert-butyl 4-(5-(methoxymethyl)-l- methyl-2-oxo-l,2-dihydropyri din-3 -yl)piperazine-l -carboxylate (0.810 g, 2.40 mmol, 77% yield) as a yellow oil.

[0435] Step 4. A mixture of tert-butyl 4-(5-(methoxymethyl)-l-methyl-2-oxo-l,2-dihydropyridin-3- yl)piperazine-l -carboxylate (0.200 g, 0.592 nmol, 1.00 eq.) in HC1 2M in dioxane (3 mL) was stirred at 25°C for 12 h. The mixture was concentrated under reduced pressure to afford Intermediate BB-40 (0.170 g, crude, hydrochloride) as a white solid.

[0436] Intermediate BB-47

[0437] Step 1. To a solution of 3-bromo-l,5-dimethylpyridin-2(177)-one (100 mg, 0.495 mmol, 1.00 eq.) and tert-butyl piperazine- 1 -carboxylate (185 mg, 0.994 mmol, 2.01 eq.) in dioxane (3 mL) was added caesium carbonate (323 mg, 0.991 mmol, 2.00 eq.), Pd2(dba)3 (45.0 mg, 0.0491 mmol, 0.100 eq.) and XPhos (47.0 mg, 0.0986 mmol, 0.200 eq.) under nitrogen. The reaction was stirred at 110°C for 12 h. After cooling to room temperature, ethyl acetate (20 mL) and water (20 mL) were added, and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (60 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford tert-butyl 4-(l,5-dimethyl-2-oxo-l,2- dihydropyridin-3-yl)piperazine-l-carboxylate (120 mg, 0.390 mmol, 79% yield) as a yellow solid.

[0438] Step 2. To a solution of tert-butyl 4-(l,5-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)piperazine-l- carboxylate (100 mg, 0.325 mmol, 1.00 eq.) in dioxane (4 mL) was added HC1 2M in dioxane (2 mL). The reaction was stirred at 25°C for 12 h. The mixture was concentrated under reduced pressure to afford Intermediate BB-47 (100 mg, crude, hydrochloride) as a yellow solid.

[0439] Intermediate BB-57

[0440] Step 1. To a solution of 3 -bromopyridine (2.00 g, 12.7 mmol, 1.00 eq.) in acetonitrile (10 mL) were added 2-hydroperoxy-2-methyl-propane (3.26 g, 25.3 mmol, 70% purity, 2.00 eq.), ethyl 2- bromo-2,2-difluoro-acetate (5.14 g, 25.3 mmol, 2.00 eq.) and DBU (2.89 g, 19.0 mmol, 1.50 eq.) under argon. The reaction was stirred at 80°C for 12 h. After cooling to room temperature, the mixture was filtered over Celite and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford 3-bromo-l- (difluoromethyl)pyridin-2(177)-one (0.800 g, 2.86 mmol, 23% yield) as a yellow solid.

[0441] Step 2. To a solution of 3-bromo-l-(difluoromethyl)pyridin-2(lJ7)-one (0.300 g, 1.07 mmol, 1.00 eq.) and tert-butyl piperazine- 1 -carboxylate (0.239 g, 1.29 mmol, 1.20 eq.) in THF (10 mL) were added caesium carbonate (1.75 g, 5.36 mmol, 5.00 eq.) and RuPhos Pd G3 (0.0896 g, 0.107 mmol, 0.100 eq.). The reaction was stirred at 85°C for 12 h under nitrogen. After cooling to room temperature, the mixture was filtered over Celite and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford tert-butyl 4-(l-(difluoromethyl)-2-oxo-l,2-dihydropyridin-3-yl)piperazine-l-carboxylate (0.260 g, 0.789 mmol, 74% yield) as a yellow solid.

[0442] Step 3. To a solution of tert-butyl 4-(l-(difluoromethyl)-2-oxo-l,2-dihydropyridin-3- yl)piperazine-l -carboxylate (0.200 g, 0.607 mmol, 1.00 eq.) in HC1 2M in dioxane (1.52 mL, 5.00 eq.). The reaction was stirred at 25°C for 12 h, then it was was concentrated under reduced pressure to afford Intermediate BB-57 (0.180 g, crude, hydrochloride) as a yellow solid.

[0443] Intermediate BB-63

[0444] Step 1. A mixture of l-methyl-2-oxo-l, 2-dihydropyridine-3-carbaldehyde (300 mg, 2.19 mmol, 1.00 eq.), tert-butyl piperazine- 1 -carboxylate (611 mg, 3.28 mmol, 1.50 eq.) and sodium triacetoxy borohydride (927 mg, 4.38 mmol, 2.00 eq.) in di chloromethane (3 mL) was stirred at 20°C for 30 min, followed by addition of methanol (3 mL). The reaction was stirred at 20°C for 12 h. The mixture was concentrated under reduced pressure to give a residue, which was purified via Purification Method 2 to afford tert-butyl 4-((l-methyl-2-oxo-l,2-dihydropyridin-3-yl) methyl) piperazine- 1 -carboxylate (236 mg, 767 / / mol, 35% yield) as a white solid.

[0445] Step 2. To a solution of tert-butyl 4-((l-methyl-2-oxo-l,2-dihydropyri din-3 -yl) methyl) piperazine- 1 -carboxylate (200 mg, 650 mol, 1.00 eq.) in ethyl acetate (2 mL) was added HC1 4M in ethyl acetate (2 mL). The reaction was stirred at 25°C for 1 h. The mixture was concentrated under reduced pressure to afford Intermediate BB-63 (260 mg, crude) as a white solid.

[0446] Intermediate BB-65

[0447] Step 1. To a solution of tert-butyl piperazine- 1 -carboxylate (500 mg, 2.68 mmol, 1.00 eq.) in acetonitrile (20 mL) was added potassium carbonate (1.11 g, 8.05 mmol, 3.00 eq.). The reaction was stirred at 25°C for 0.5 h, then l-(bromomethyl)-2-chlorobenzene (606.78 mg, 2.95 mmol, 1.10 eq.) was added. The reaction was stirred at 45°C for 4.5 h. The mixture was cooled to 25°C, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford tert-butyl 4-(2-chlorobenzyl)piperazine-l -carboxylate (690 mg, 2.13 mmol, 79% yield) as a colourless oil.

[0448] Step 2. To a solution of tert-butyl 4-(2-chlorobenzyl)piperazine-l -carboxylate (420 mg, 1.35 mmol, 1.00 eq.) in ethyl acetate (5 mL) was added HC1 4M in ethyl acetate (10 mL) at 0°C. The reaction was stirred at 25°C for 16 h. The resulting precipitate was filtered and washed with ethyl acetate (20 mL), then dried under vacuum to afford Intermediate BB-65 (320 mg, 1.28 mmol) as a white solid.

[0449] Intermediate BB-69 was synthesized in analogy to Intermediate BB-65 using the appropriate benzyl bromide in Step 1.

[0450] Intermediate BB-68

[0451] Step 1. To a solution of l-amino-3,3-dimethylbutan-2-one (500 mg, 3.30 mmol, 1.00 eq, hydrochloric acid) and triethylamine (688 / / L, 4.95 mmol, 1.50 eq.) in THF (2.00 mL) was added di(17 / -imidazol-l-yl)methanone (641 mg, 3.96 mmol, 1.20 eq.). The reaction was stirred at 25°C for 1 h, then tert-butyl piperazine- 1 -carboxylate (614 mg, 3.30 mmol, 1.00 eq.) was added, and the reaction was stirred at 25°C for another 12 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford tert-butyl 4-((3, 3 -dimethyl-2-oxobutyl)carbamoyl)piperazine-l -carboxylate (800 mg, 2.44 mmol, 74% yield) as a white solid.

[0452] Step 2. To a solution of tert-butyl 4-((3,3-dimethyl-2-oxobutyl)carbamoyl)piperazine-l- carboxylate (300 mg, 916 / / mol, 1.00 eq.) in toluene (3.00 mL) was added phosphorus oxychloride (256 / / L, 2.75 mmol, 3.00 eq.). The reaction was stirred at 100°C for 2 h. The mixture was concentrated under reduced pressure to give a residue. The residue was triturated with ethyl acetate (10.0 mL) to give a crude product, the crude product was purified via Purification Method 2 to afford Intermediate BB-68 (170 mg, 665 mol, 72% yield, formic acid) as a colourless oil. Intermediate BB-80

[0453] Step 1. A mixture of ethyl but-2-ynoate (6.06 g, 54.1 mmol, 1.20 eq.), 1-aminopyridin-l-ium iodide (10.0 g, 45.0 mmol, 1.00 eq.) and potassium carbonate (7.47 g, 54.1 mmol, 1.20 eq.) in DMF (50 mL) was degassed by purging with nitrogen, and the reaction was stirred at 25°C for 12 h under nitrogen. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford ethyl 2- methylpyrazolo[l,5-a]pyridine-3-carboxylate (8.50 g, crude) as a yellow solid.

[0454] Step 2. A mixture of ethyl 2-methylpyrazolo[l,5-a]pyridine-3-carboxylate (8.5 g, 41.62 mmol, 1.00 eq.) and sodium hydroxide (8 M, 50 mL, 9.61 eq.) in methanol (100 mL) was stirred at 70°C for 12 h. The mixture was cooled to room temperature and concentrated under reduced pressure. Water (100 mL) was added, and the pH was acidified to 2 with hydrochloric acid (6 N in water). The resulting precipitate was filtered and dried under vacuum to afford 2- methylpyrazolo[l,5-a]pyridine-3-carboxylic acid (4.35 g, 24.7 mmol, 59% yield) as a yellow solid.

[0455] Step 3. A mixture of 2-methylpyrazolo[l,5-a]pyridine-3-carboxylic acid (4.35 g, 24.7 mmol, 1.00 eq.) and sulfuric acid (5.89 g, 60.0 mmol, 2.43 eq.) in water (80 mL) was stirred at 80°C for 12 h. The pH was basified to 8 with NaHCCh sat. sol., and the mixture was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 2- methylpyrazolo[l,5-a]pyridine (2.50 g, 18.9 mmol, 77% yield) as a yellow solid.

[0456] Step 4. To a solution of 2-methylpyrazolo[l,5-a]pyridine (1.00 g, 7.57 mmol, 1.00 eq.) in THF (20 mL) was added / / -butyllithium (2.5 M, 3.93 mL, 1.30 eq.) at -78°C under nitrogen. The mixture was stirred at -78°C for 1 h. Perchloroethane (2.33 g, 9.84 mmol, 1.30 eq.) was added at -78°C, and the reaction was stirred at -78°C. After 1 h, the reaction was quenched by addition of NH4Q sat. sol. (10 mL) at 0°C. The mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford 7-chloro-2-methylpyrazolo[l,5-a]pyridine (1.00 g, 6.00 mmol, 79% yield) as a white solid.

[0457] Step 5. A mixture of tert-butyl piperazine- 1 -carboxylate (0.335 g, 1.80 mmol, 1.50 eq.), 7- chloro-2-methyl-pyrazolo[l,5-a]pyridine (0.200 g, 1.20 mmol, 1.00 eq.), caesium fluoride (0.729 g, 4.80 mmol, 4.00 eq.) in DMSO (3 mL) was stirred at 140°C for 12 h. After cooling to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford tert-butyl 4-(2-methylpyrazolo[l,5-a]pyridin-7- yl)piperazine-l -carboxylate (0.143 g, 0.452 mmol, 38% yield) as a white solid.

[0458] Step 6. A mixture of tert-butyl 4-(2-methylpyrazolo[l,5-a]pyridin-7-yl)piperazine-l-carboxylate (0.140 g, 0.443 mmol, 1.00 eq.) in HC1 2M in dioxane (5 mL) was stirred at 25°C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was triturated with ethyl acetate (5 mL) at 25°C for 10 min and filtered. The filter cake was dried under vacuum to afford Intermediate BB-80 (0.100 g, 0.396 mmol, 89% yield, hydrochloride) as a white solid.

[0459] Intermediate BB-84

[0460] Step 1. To a solution of pyrazolo[l,5-a]pyridin-4-ol (500 mg, 3.73 mmol, 1.00 eq.) and caesium carbonate (3.64 g, 11.2 mmol, 3.00 eq.) in DMF (5 mL) under nitrogen was added Mel (0.4 mL, 6.43 mmol, 1.72 eq.). The reaction was stirred at 80°C for 1 h, then it was quenched with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 4- methoxypyrazolo[l,5-a]pyridine (480 mg, crude) as a yellow solid. Step 2. To a mixture of 4-methoxypyrazolo[l,5-a]pyridine (450 mg, 2.73 mmol, 1.00 eq.) in THF (9 mL) was added / / -butyllithium (2.5 M, 1.44 mL, 1.32 eq.) at -78°C. The reaction was stirred for 1 h under nitrogen, then perchloroethane (846 mg, 3.57 mmol, 1.31 eq.) was added at - 78°C. The reaction was stirred for a further 1 h at -78°C, then it was quenched with NH4Q sat. sol. (30 mL). The mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford 7-chloro-4-methoxypyrazolo[l,5-a]pyridine (414 mg, 1.81 mmol, 66% yield) as a white solid.

[0461] Step 3. To a solution of 7-chloro-4-methoxypyrazolo[l,5-a]pyridine (250 mg, 1.10 mmol, 1.00 eq.) in dioxane (5 mL) was added tert-butyl piperazine- 1 -carboxylate (250 mg, 1.34 mmol, 1.23 eq.) and caesium carbonate (1.07 g, 3.30 mmol, 3.01 eq.), followed by Pd PEPPS IHept-Cl (107 mg, 110 / / mol, 0.100 eq.) at 25°C under nitrogen. The reaction was stirred at 100°C for 12 h. After cooling to room temperature, the mixture was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford tert-butyl 4-(4- methoxypyrazolo[l,5-a]pyridin-7-yl)piperazine-l-carboxylate (130 mg, 336 mol, 31% yield) as a yellow solid.

[0462] Step 4. A solution of tert-butyl 4-(4-methoxypyrazolo[l,5-a]pyridin-7-yl)piperazine-l- carboxylate (130 mg, 336 / / mol, 1.00 eq.) in HC1 4M in dioxane (4 mL) was stirred at 25°C for 2 h. The mixture was concentrated under reduced pressure to afford Intermediate BB-84 (90.0 mg, crude, hydrochloride) as a yellow solid.

[0463] Intermediate BB-101

[0464] Step 1. A mixture of 5,7-dichloropyrazolo[l,5-a]pyrimidine (5.00 g, 26.6 mmol, 1.00 eq.), tertbutyl piperazine- 1 -carboxylate (7.43 g, 39.9 mmol, 1.50 eq.) and potassium carbonate (11.0 g, 79.8 mmol, 3.00 eq.) in DMF (50 mL) was stirred at 80°C for 12 h. After cooling to room temperature, water (100 mL) was added, then the mixture was extracted with ethyl acetate (2 x 200 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford tert-butyl 4-(5-chloropyrazolo[l,5-a]pyrimidin-7- yl)piperazine-l -carboxylate (7.60 g, 22.5 mmol, 85% yield) as a yellow solid.

[0465] Step 2. A mixture of tert-butyl 4-(5-chloropyrazolo[l,5-a]pyrimidin-7-yl)piperazine-l- carboxylate (3.00 g, 8.88 mmol, 1.00 eq.), sodium iodide (6.66 g, 44.4 mmol, 5.00 eq.), DMEDA (0.157 g, 1.78 mmol, 0.200 eq.) and copper(I) iodide (0.169 g, 0.888 mmol, 0.100 eq.) in dioxane (30 mL) was degassed by purging with nitrogen, and the reaction was stirred at 110°C for 12 h under nitrogen. After cooling to room temperature, the mixture was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 1 to afford tert-butyl 4-(5-iodopyrazolo[l,5-a]pyrimidin-7-yl)piperazine-l -carboxylate (0.450 g, 1.02 mmol, 12% yield) as a yellow solid.

[0466] Step 3. A mixture of tert-butyl 4-(5-iodopyrazolo[l,5-a]pyrimidin-7-yl)piperazine-l-carboxylate (0.450 g, 1.05 mmol, 1.00 eq.), methyl 2,2-difhioro-2-fhiorosulfonyl-acetate (1.41 g, 7.34 mmol, 7.00 eq.), copper(I) iodide (1.40 g, 7.34 mmol, 7.00 eq.) and HMPA (1.32 g, 7.34 mmol, 7.00 eq.) in DMF (5 mL) was degassed by purging with nitrogen, and the reaction was stirred at 80°C for 2 h under nitrogen. After cooling to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford tert-butyl 4-(5-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)piperazine-l-carboxylate (0.170 g, 0.458 mmol, 44% yield) as a yellow solid.

[0467] Step 4. A mixture of tert-butyl 4-[5-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl]piperazine- 1-carboxylate (0.170 g, 0.458 mmol, 1.00 eq.) in HC1 2M in dioxane (5 mL, 21.8 eq.) was stirred at 25°C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was triturated with ethyl acetate (5 mL) at 25°C for 10 min and the resulting solid was filtered. The solid was dried under vacuum to afford Intermediate BB-101 (0.120 g, 0.390 mmol, 85% yield, hydrochloride) as a white solid. Intermediate BB-107

[0468] Step 1. To a solution of sodium (4.12 g, 179 mmol, 2.98 eq.) in ethanol (50 mL) were added 1H- pyrazol-5-amine (5.00 g, 60.2 mmol, 1.00 eq.) and diethyl 2-fluoropropanedioate (10.7 g, 60.2 mmol, 1.00 eq.). The reaction was stirred at 80°C for 4 h. After cooling to room temperature, the mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in water (50 mL), and the pH was adjusted with hydrochloric acid (1 M) to 5-6. The resulting precipitate was filtered, washed with cold ethanol (50 mL) and dried under vacuum to afford 6- fluoropyrazolo[l,5-a]pyrimidine-5,7-diol (4.00 g, 23.7 mmol, 39% yield) as a yellow solid.

[0469] Step 2. To a solution of 6-fhioropyrazolo[l,5-a]pyrimidine-5,7-diol (2.00 g, 11.8 mmol, 1.00 eq.) in phosphorus oxychloride (9.07 g, 59.1 mmol, 5.00 eq.) was added A,A-dimethylaniline (1.91 g, 15.8 mmol, 1.33 eq.). The reaction was stirred at 110°C for 12 h under nitrogen. The mixture was cooled to room temperature and concentrated under reduced pressure to give a residue. Ethyl acetate was added (50 mL) followed by NaHCOs sat. sol. (30 mL). The mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford 5,7-dichloro-6-fluoropyrazolo[l,5- a]pyrimidine (1.44 g, 6.99 mmol, 59% yield) as a yellow solid.

[0470] Step 3. To a mixture of 5,7-dichloro-6-fluoropyrazolo[l,5-a]pyrimidine (0.430 g, 2.09 mmol, 1.00 eq.) in DMF (8 mL) were added DIPEA (0.809 g, 6.26 mmol, 3.00 eq.) and tert-butyl piperazine- 1 -carboxylate (0.430 g, 2.31 mmol, 1.11 eq.). The reaction was stirred at 80°C for 12 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (20 mL) and water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford tert-butyl 4-(5-chloro-6-fluoropyrazolo[l,5-a]pyrimidin-7-yl)piperazine-l -carboxylate (0.840 g. crude) as a yellow solid. Step 4. To a mixture of tert-butyl 4-(5-chloro-6-fluoropyrazolo[l,5-a]pyrimidin-7-yl)piperazine- 1-carboxylate (0.840 g, 2.36 mmol, 1.00 eq.) in methanol (8 mL) and THF (8 mL) was added palladium on active carbon (0.200 g, 0.188 mmol, 10% purity) under nitrogen. After purging with hydrogen gas, the reaction was stirred at 25°C for 12 h under hydrogen (15 psi). The mixture was filtered over Celite, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford tert-butyl 4-(6- fluoropyrazolo[l,5-a]pyrimidin-7-yl)piperazine-l -carboxylate (0.240 g, 0.749 mmol, 32% yield) as a white solid.

[0471] Step 5. To a solution of tert-butyl 4-(6-fluoropyrazolo[l,5-a]pyrimidin-7-yl)piperazine-l- carboxylate (0.240 g, 0.747 mmol, 1.00 eq.) in methanol (3.0 mL) was added acetyl chloride (0.586 g, 7.47 mmol, 10.0 eq.). The reaction was stirred at 25°C for 14 h, then it was concentrated under reduced pressure to afford Intermediate BB-107 (0.230 g, crude, hydrochloride) as a white solid.

[0472] 1.4 Other Syntheses of Exemplary Compounds

[0473] Step 1. A mixture of l-ethyl-4-fluoro-3-iodopyridin-2(177)-one (400 mg, 1.50 mmol, 1.00 eq.), tert-butyl piperidine-4-carboxylate (416 mg, 2.25 mmol, 1.50 eq.), caesium carbonate (1.46 g, 4.49 mmol, 3.00 eq.) and CPhos Pd G3 (60.4 mg, 74.9 / / mol, 0.0500 eq.) in dioxane (4.00 mL) was degassed by purging with nitrogen, and the reaction was stirred at 80°C for 16 h under nitrogen. After cooling to room temperature, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 8 mL). The combined organic layers were wash with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford tert-butyl l-(l-ethyl-4- fluoro-2-oxo-l,2-dihydropyri din-3 -yl)piperidine-4-carboxylate (160 mg, 493 / / mol, 33% yield) as an off-white solid.

[0474] Step 2. A mixture of tert-butyl l-(l-ethyl-4-fluoro-2-oxo-l,2-dihydropyri din-3 -yl)piperidine-4- carboxylate (160 mg, 493 mol, 1.00 eq.) in dichloromethane (1.00 mL) and trifluoroacetic acid (1.00 mL) was stirred at 25°C for 2 h. The reaction mixture was concentrated under reduced pressure to afford l-(l-ethyl-4-fluoro-2-oxo-l,2-dihydropyridin-3-yl)piperidine-4-carboxylic acid (130 mg, crude) as a yellow oil.

[0475] Step 3. To a solution of l-(l-ethyl-4-fluoro-2-oxo-l,2-dihydropyridin-3-yl)piperidine-4- carboxylic acid (130 mg, 484 / / mol, 1.00 eq.) and 2-hydroxyisoindoline-l, 3-dione (79.0 mg, 484 / / mol, 1.00 eq.) in THF (2.00 mL) was added EDCI (120 mg, 629 / / mol, 1.30 eq.) and DMAP (59.2 mg, 484 / / mol, 1.00 eq.). The reaction was stirred at 25°C for 2 h, then it was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford l,3-dioxoisoindolin-2-yl l-(l-ethyl-4-fluoro-2-oxo-l,2-dihydropyridin-3-yl)piperidine-4- carboxylate (150 mg, 362 / / mol, 75% yield) as a yellow solid.

[0476] Step 4. To a solution of [(bipy)2Ni2( / / -Cl)2(Cl)2(H2O)2] (73.4 mg, 120 / / mol, 0.50 eq.), 1,3- dioxoisoindolin-2-yl l-(l-ethyl-4-fluoro-2-oxo-l,2-dihydropyridin-3-yl)piperidine-4-carboxylate (100 mg, 241 / / mol, 1.00 eq.), Intermediate AA-3 (73.1 mg, 241 / / mol, 1.00 eq.) and 4 A molecular sieves (100 mg) in DMAC (1.00 mL) was added zinc powder (125 mg, 1.91 mmol, 7.90 eq.) and trimethyl silyl chloride (78.8 mg, 725 / / mol, 92.1 / / L, 3 .00 eq.) under nitrogen at 0°C. The reaction was stirred at 0°C for 2 h, then it was filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 1 to afford Exemplary Compound 13 (11.42 mg, 25.3 / / mol, 10% yield) as a white solid.

[0477] 'H NMR (400 MHz, DMSO-tL) 3 = 10.89 (br s, 1H), 7.54 (t, J= 7.6 Hz, 1H), 7.43 - 7.27 (m, 2H), 7.20 (dd, J= 1.6, 7.2 Hz, 1H), 6.26 (dd, J= 7.6, 9.2 Hz, 1H), 4.29 (br dd, J= 4.8, 12.4 Hz, 1H), 3.90 (q, J= 6.8 Hz, 2H), 3.27 (br s, 2H), 3.22 - 3.08 (m, 3H), 2.88 - 2.70 (m, 1H), 2.54 (br d, J= 4.0 Hz, 1H), 2.36 - 2.27 (m, 1H), 2.08 - 1.94 (m, 1H), 1.84 - 1.65 (m, 4H), 1.21 (t, J= 7.2 Hz, 3H). MS (ESI) m / z 446.2 [M+H]+

[0478] Example 41 was synthesized in analogy to Example 13, starting from Intermediate BB-37 (see Exemplary Compound 37). Example 97

[0479] Step 1. To a solution of Intermediate AA-2 (80.0 mg, 232 / / mol, 1.10 eq.) and 3-fluoro-2- nitrobenzaldehyde (35.7 mg, 211 mol, 1.00 eq.) in acetonitrile (2.00 mL) were added sodium iodide (3.17 mg, 21.1 / / mol, 0.100 eq.) and potassium carbonate (64.2 mg, 464 / / mol, 2.20 eq.). The reaction was stirred at 50°C for 12 h. The reaction was quenched by addition of water (20 mL) and extracted with ethyl acetate (3 ^ 30 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford 3-(4-(2-chloro-3- (2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)-2-nitrobenzaldehyde (35.0 mg, 76.6 / / mol, 36% yield) as a yellow solid.

[0480] Step 2. To a solution of 3-(4-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)-2- nitrobenzaldehyde (35.0 mg, 76.6 / / mol, 1.00 eq.) in hydrochloric acid 37% (1.00 mL) was added tin(II) chloride dihydrate (69.1 mg, 306 / / mol, 4.00 eq.). The reaction was stirred at 25°C for 1 h. The reaction was quenched by addition of water (10 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with brine (20.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford Exemplary Compound 97 (11.85 mg, 27.6 / / mol, 36% yield) as a yellow solid.

[0481] XH NMR (400 MHz, DMSO-tL) 3 = 10.90 (s, 1H), 9.75 (s, 1H), 7.35 - 7.28 (m, 1H), 7.25 - 7.18 (m, 2H), 7.06 (br d, J= 6.8 Hz, 1H), 7.01 - 6.94 (m, 1H), 6.58 (d, J= 7.2 Hz, 1H), 4.29 (br dd, J = 5.2, 12.0 Hz, 1H), 3.60 (br s, 4H), 3.19 (br d, J= 4.0 Hz, 4H), 2.80 - 2.73 (m, 1H), 2.55 (br d, J = 3.6 Hz, 1H), 2.30 (br dd, J= 3.6, 12.4 Hz, 1H), 2.05 - 1.98 (m, 1H). MS (ESI) m / z 425.2 [M+H]+

[0482] Exemplary compounds 100, 108 and 111 were synthesized in analogy to Example 97: Example 100

[0483] Step 1. To a solution of Intermediate AA-1 (200 mg, 581 / / mol, 1.00 eq.) and 3-fluoro-2- nitrophenol (182 mg, 1.16 mmol, 2.00 eq.) in acetonitrile (2.00 mL) was added potassium carbonate (176 mg, 1.28 mmol, 2.20 eq.). The reaction was stirred at 50°C for 12 h, then it was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 afford 3 -(2-chl oro-3 -(4-(3 -hydroxy -2-nitrophenyl)piperazin- 1 -yl)phenyl)piperi dine- 2, 6-dione (80.0 mg, 179 / / mol, 31% yield) as a yellow oil.

[0484] Step 2. To a solution of 3 -(2-chl oro-3 -(4-(3 -hydroxy -2-nitrophenyl)piperazin-l- yl)phenyl)piperidine-2, 6-dione (80.0 mg, 179 mol, 1.00 eq.) in hydrochloric acid 37% (1.00 mL) was added tin(II) chloride dihdyrate (162 mg, 719 / / mol, 4.00 eq.). The reaction was stirred at 25°C for 2 h. The reaction was quenched by addition of water (10 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with brine (20.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford 3-(3-(4-(2-amino-3- hydroxyphenyl)piperazin-l-yl)-2-chlorophenyl)piperidine-2, 6-dione (25.0 mg, 60.2 / / mol, 34% yield) as a white solid.

[0485] Step 3. To a solution of 3-(3-(4-(2-amino-3-hydroxyphenyl)piperazin-l-yl)-2- chlorophenyl)piperidine-2, 6-dione (25.0 mg, 60.2 / / mol, 1.00 eq.) in trimethoxymethane (1.00 mL) was added -TsOH (1.04 mg, 6.03 / / mol, 0.100 eq.). The reaction was stirred at 80°C for 1 h, then it was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 1 to afford Exemplary Compound 104 (5.24 mg, 11.7 / / mol, 19% yield) as a white solid.

[0486] 'H NMR (400 MHz, DMSO-tL) d = 10.90 (br s, 1H), 8.62 (s, 1H), 7.36 - 7.28 (m, 2H), 7.26 - 7.19 (m, 2H), 7.05 (dd, J= 1.2, 7.6 Hz, 1H), 6.82 (d, J= 7.6 Hz, 1H), 4.29 (dd, J= 5.2, 12.0 Hz, 1H), 3.70 (br s, 4H), 3.25 - 3.13 (m, 4H), 2.78 (ddd, J= 5.2, 12.4, 17.2 Hz, 1H), 2.57 - 2.52 (m, 1H), 2.35 - 2.25 (m, 1H), 2.06 - 1.95 (m, 1H). MS (ESI) m / z 425.3 [M+H]+

[0487] Example 50

[0488] Step 1. To a solution of the mixture of 3-iodo-l-methylpyridin-2(lrt)-one (2.00 g, 8.42 mmol, 1.00 eq.), tert-butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,5-dihydro-lJ / -pyrrole-l- carboxylate (7.39 g, 25.0 mmol, 2.97 eq.) and sodium carbonate (2.68 g, 25.3 mmol, 3.00 eq.) in dioxane (40 mL) under nitrogen was added Pd(dppf)C12 (615 mg, 841 / / mol, 0.100 eq.) and water (4 mL) at 25°C. The reaction was stirred at 100°C for 1 h. After cooling to room temperature, the mixture was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 followed by Purification Method 1 to afford tert-butyl 3-(l-methyl-2-oxo- l,2-dihydro-pyridin-3-yl)-2,5-dihydro-17 / -pyrrole-l-carboxylate (1.32 g, 4.28 mmol, 51% yield) as a brown solid.

[0489] Step 2. To a solution of tert-butyl 3-(l-methyl-2-oxo-l,2-dihydropyridin-3-yl)-2,5-dihydro-17T- pyrrole-1 -carboxylate (750 mg, 2.63 mmol, 1.00 eq.) in methanol (15 mL) was added palladium on carbon (375 mg, 10 wt%) at 25°C under nitrogen. The suspension was purged with hydrogen, and the reaction was stirred at 25°C for 12 h under hydrogen (50 psi). The mixture was filtered over Celite, and the filtrate was concentrated under reduced pressure to afford tert-butyl 3-(l- methyl-2-oxo-l,2-dihydropyridin-3-yl)-pyrrolidine-l-carboxylate (683 mg, 1.96 mmol, 75% yield) as a brown oil.

[0490] Step 3. To a solution of tert-butyl 3-(l-methyl-2-oxo-l,2-dihydropyridin-3-yl)pyrrolidine-l- carboxylate (683 mg, 1.96 mmol, 1.00 eq.) in dioxane (2 mL) was added HC1 2M in dioxane (6 mL) at 25°C. The reaction was stirred at 25°C for 1 h, then it was concentrated under reduced pressure to afford l-methyl-3-(pyrrolidin-3-yl)pyridin-2(U7)-one (520 mg, crude, hydrochloride) as a brown oil. Step 4. To a solution of the mixture of l-methyl-3-(pyrrolidin-3-yl)pyridin-2(U7)-one (100 mg, 466 / / mol, 1.00 eq, hydrochloride), Intermediate AA-3 (141 mg, 466 / mol, 1.00 eq.) and caesium carbonate (758 mg, 2.33 mmol, 4.99 eq.) in DMF (2 mL) under nitrogen was added Pd PEPPSI-IHept-Cl (46.0 mg, 47.3 / / mol, 0.100 eq.). The reaction was stirred at 100°C for 2 h. After cooling to room temperature, the mixture was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 followed by Purification Method 1 to afford Exemplary Compound 50 (34.98 mg, 86.6 / / mol, 5% yield) as an off-white solid.

[0491] 'H NMR (400 MHz, DMSO ) 3 = 10.85 (s, 1H), 7.60 (d, J= 6.4 Hz, 1H), 7.45 - 7.34 (m, 1H), 7.23 - 7.11 (m, 1H), 6.98 (d, J= 8.0 Hz, 1H), 6.80 (d, J= 7.2 Hz, 1H), 6.20 (t, J = 6.8 Hz, 1H), 4.22 (dd, J= 5.2, 11.6 Hz, 1H), 3.50 - 3.42 (m, 6H), 3.27 - 3.08 (m, 2H), 2.82 - 2.68 (m, 1H), 2.54 - 2.51 (m, 1H), 2.34 - 2.15 (m, 2H), 2.04 - 1.95 (m, 2H). MS (ESI) m / z 400.2 [M+H]+

[0492] Step 1. Intermediate AA-3 (3.00 g, 9.92 mmol, 1.00 eq.), tert-butyl 3 -bromopiperidine- 1- carboxylate (3.41 g, 12.9 mmol, 1.30 eq.), [Ir{dF(CF3)ppy}2(dtbpy)]PFe (111 mg, 99.2 / / mol, 0.010 eq.), NiCh*dtbbpy (59.2 mg, 149 / / mol, 0.015 eq.), tris(trimethylsilyl)silane (2.47 g, 9.92 mmol, 3.06 mL, 1.00 eq.) and 2,6-dimethylpyridine (9.65 g, 89.2 mmol, 9.00 eq.) were dissolved in 1,2-dimethoxy ethane (2.00 mL) under nitrogen. The reaction was stirred and irradiated with a blue 10 W LED lamp at 25°C for 14 h. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 * 100 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford tert-butyl 3-(2-chloro-3-(2, 6-di oxopiperi din-3 -yl)phenyl)piperi dine- 1 -carboxylate (1.20 g, 2.95 mmol, 29% yield) as a yellow solid.

[0493] Step 2. A mixture of tert-butyl 3 -(2-chl oro-3 -(2, 6-di oxopiperi din-3 -yl) phenyl) piperidine-1- carboxylate (600 mg, 1.47 mmol, 1.00 eq.) in concentrated hydrochloric acid / dioxane (2.00 M, 6.00 mL) was stirred at 25°C for 1 h. The mixture was concentrated under reduced pressure to afford 3 -(2-chl oro-3 -(piperi din-3 -yl) phenyl)piperidine-2, 6-dione (475 mg, crude) as a yellow solid.

[0494] Step 3. To a mixture of 3-(2-chloro-3-(piperidin-3-yl) phenyl)piperidine-2, 6-dione (50.0 mg, 163 / / mol, 1.00 eq.) and 4-bromo-l -methyl -pyridin-2-one (36.8 mg, 196 mol, 1.20 eq.) in DMF (1.00 mL) was added Pd PEPPSI-IHept-Cl (15.9 mg, 16.3 / / mol, 0.100 eq.) and caesium carbonate (159 mg, 489 / / mol, 3.00 eq.). The reaction was stirred at 100°C for 1 h under nitrogen. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 1 to afford Exemplary Compound 53 (42.8 mg, 102 / / mol, 15% yield) as a pink solid.

[0495] 'H NMR (400 MHz, DMS04) d = 10.89 (br s, 1H), 7.40 (d, J= 7.6 Hz, 2H), 7.36 - 7.28 (m, 1H), 7.23 (d, J= 7.6 Hz, 1H), 6.07 (d, J= 7.6 Hz, 1H), 5.52 (s, 1H), 4.30 (dd, J= 4.8, 12.0 Hz, 1H), 3.96 - 3.71 (m, 2H), 3.26 (s, 3H), 3.18 (t, J= 11.2 Hz, 1H), 3.01 - 2.88 (m, 2H), 2.83 - 2.70 (m, 1H), 2.54 (s, 1H), 2.35 - 2.21 (m, 1H), 2.05 - 1.88 (m, 2H), 1.86 - 1.73 (m, 2H), 1.68 - 1.49 (m, 1H). MS (ESI) m / z 414.0 [M+H]+

[0496] Example 56

[0497] Step 1. To a solution of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (794 mg, 2.75 mmol, 1.00 eq, oxalic acid) and Intermediate AA-3 (1.00 g, 3.31 mmol, 1.20 eq.) in dioxane (10.0 mL) was added Pd2(dba)3 (252 mg, 275 / / mol, 0.100 eq.), XPhos (263 mg, 551 / / mol, 0.200 eq.) and caesium carbonate (2.69 g, 8.26 mmol, 3.00 eq.) under nitrogen. The reaction was stirred at 100°C for 12 h. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford tert-butyl 6-(2-chl oro-3 - (2,6-dioxopiperidin-3-yl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (620 mg, 1.48 mmol, 54% yield) as a yellow oil. Step 2. To a solution of tert-butyl 6-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)-2,6- diazaspiro[3.3]heptane-2-carboxylate (80.0 mg, 191 / / mol, 1.00 eq.) in dichloromethane (1.00 mL) was added trifluoroacetic acid (263 / / L, 3.54 mmol, 18.6 eq.). The reaction was stirred at 25°C for 1 h. The mixture was concentrated under reduced pressure to afford 3-(2-chloro-3-(2,6- diazaspiro[3.3]heptan-2-yl)phenyl)piperidine-2, 6-dione (60.0 mg, crude) as a yellow oil.

[0498] Step 3. To a solution of 3-fluoro-4-(trifluoromethyl)pyridin-2( lrt)-one (2.00 g, 11.0 mmol, 1.00 eq.) in dimethylformamide (10.0 mL) was added sodium hydride (663 mg, 16.6 mmol, 60% purity, 1.50 eq.) at 0°C. The reaction was stirred at 0°C for 0.5 h, then iodomethane (2.35 g, 16.6 mmol, 1.03 mL, 1.50 eq.) was added, and the reaction was stirred for a further 1.5 h at 25°C. The reaction was quenched by addition of NH4Q sat. sol. (10.0 mL). The mixture was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford 3-fluoro-l-methyl-4-(trifluoromethyl)pyridin-2(lJ7)-one (1.40 g, 7.18 mmol, 65% yield) as a pink solid.

[0499] Step 4. To a solution of 3-(2-chloro-3-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl)piperidine-2,6- dione (150 mg, 469 mol, 1.00 eq.) and 3-fluoro-l-methyl-4-(trifluoromethyl)pyridin-2(lJ7)-one (91.5 mg, 469 / / mol, 1.00 eq.) in acetonitrile was added DIPEA (245 / / L, 1.41 mmol, 3.00 eq.). The reaction was stirred at 70°C for 12 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 1 to afford Exemplary Compound 56 (10.34 mg, 20.9 / / mol, 4% yield) as a white solid.

[0500] 'H NMR (400 MHz, DMSO4) 3 = 10.86 (br s, 1H), 7.15 (t, J= 7.8 Hz, 1H), 6.99 (d, J= 7.2 Hz, 1H), 6.71 (d, J= 6.8 Hz, 1H), 6.58 - 6.53 (m, 1H), 6.16 (d, J= 7.2 Hz, 1H), 4.54 (br s, 4H), 4.18 (br d, J= 6.8 Hz, 1H), 4.13 (s, 4H), 3.36 (br s, 3H), 2.78 - 2.70 (m, 1H), 2.47 (br s, 1H), 2.24 (br dd, J= 4.0, 12.4 Hz, 1H), 2.01 - 1.92 (m, 1H). MS (ESI) m / z 495.1 [M+H]+

[0501] Example 60

[0502] Step 1. To a solution of 3-bromo-4-methylpyridin-2(177)-one (5.00 g, 26.6 mmol, 1.00 eq.) and potassium carbonate (7.35 g, 53.2 mmol, 2.00 eq.) in acetonitrile (50 mL) was added methyl iodide (5.66 g, 39.9 mmol, 1.50 eq.) at 25°C. The reaction was stirred at 65°C for 12 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (500 mL) and washed with brine (3 x 500 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 3-bromo-l,4-dimethylpyridin-2(177)-one (3.58 g, 16.5 mmol, 62% yield) as a yellow solid.

[0503] Step 2. To a solution of 3-bromo-l,4-dimethylpyridin-2(177)-one (550 mg, 2.72 mmol, 1.00 eq.), tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(177)-carboxylate (693 mg, 3.26 mmol, 1.20 eq.) and caesium carbonate (2.66 g, 8.17 mmol, 3.00 eq.) in dioxane (10 mL) under nitrogen was added RuPhos Pd G3 (231 mg, 276 / / mol, 0.101 eq.). The reaction was stirred at 100°C for 12 h. After cooling to room temperature, the mixture was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford tert-butyl 5-(l,4-dimethyl- 2-oxo-l,2-dihydropyridin-3-yl)hexahydropyrrolo[3,4-c]pyrrole-2(177)-carboxylate (417 mg, 1.24 mmol, 45% yield) as a yellow solid.

[0504] Step 3. To a solution of tert-butyl 5-(l,4-dimethyl-2-oxo-l,2-dihydropyridin-3- yl)hexahydropyrrolo[3,4-c]pyrrole-2(177)-carboxylate (200 mg, 600 mol, 1.00 eq.) in methanol (5 mL) under nitrogen was added acetyl chloride (236 mg, 3.01 mmol, 5.01 eq.) at 0°C. The reaction was stirred at 25°C for 1 h. The mixture was concentrated under reduced pressure to afford 3-(hexahydropyrrolo[3,4-c]pyrrol-2(177)-yl)-l,4-dimethylpyridin-2(lJ7)-one hydrochloride (160 mg, 563 / / mol, 94% yield) as a white solid. Step 4. To a solution of 3-(hexahydropyrrolo[3,4-c]pyrrol-2(U7)-yl)-l,4-dimethylpyridin-2(U7)- one hydrochloride (160 mg, 563 / / mol, 1.00 eq.) , Intermediate AA-3 (190 mg, 628 mol, 1.11 eq.) and caesium carbonate (551 mg, 1.69 mmol, 3.00 eq.) in DMF (4 mL) under nitrogen was added RuPhos Pd G3 (57.0 mg, 58.6 / / mol, 0.104 eq.). The reaction was stirred at 100°C for 12 h. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 1 to afford Exemplary Compound 60 (15.65 mg, 33.4 / / mol, 6% yield) as a white solid.

[0505] 'H NMR (400 MHz, DMSO ) <5 = 10.87 (s, 1H), 7.42 (d, J= 6.8 Hz, 1H), 7.28 - 7.18 (m, 1H), 7.05 (d, J= 7.2 Hz, 1H), 6.93 (d, J= 7.6 Hz, 1H), 6.04 (d, J= 6.8 Hz, 1H), 4.26 (dd, J= 5.2, 12.0 Hz, 1H), 3.61 - 3.47 (m, 4H), 3.42 - 3.38 (m, 3H), 2.96 - 2.83 (m, 4H), 2.82 - 2.71 (m, 3H), 2.55 - 2.51 (m, 1H), 2.34 - 2.21 (m, 1H), 2.15 (s, 3H), 2.04 - 1.94 (m, 1H). MS (ESI) m / z 455.2 [M+H]+

[0506] Step 1. To a solution of tert-butyl l-oxo-2,9-diazaspiro[5.5]undecane-9-carboxylate (0.500 g, 1.86 mmol, 1.00 eq.) in THF (5.00 mL) and DMF (5.00 mL) was added sodium hydride (112 mg, 2.79 mmol, 60% purity, 1.50 eq.) at 0°C. The reaction was stirred for 0.5 h, then tetra-( / / - butyl)ammonium iodide (68.8 mg, 186 / / mol, 0.100 eq.) and l-(bromomethyl)-2-chloro-benzene (574 mg, 2.79 mmol, 363 / / L, 1.50 eq.) were added at 0°C. The reaction was stirred at 45°C for 12 h. The reaction was quenched with NH4Q sat. sol. (10 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford tert-butyl 2-(2-chlorobenzyl)-l-oxo-2,9- diazaspiro[5.5]undecane-9-carboxylate (1.50 g, 3.44 mmol, 92% yield) as a white solid.

[0507] Step 2. tert-butyl 2-(2-chlorobenzyl)-l-oxo-2,9-diazaspiro[5.5]undecane-9-carboxylate (400 mg, 1.02 mmol, 1.00 eq.) was dissolved in HC1 2M in dioxane (5.00 mL). The reaction was stirred at 25°C for 1 h, then it was concentrated under reduced pressure to afford 2-(2-chlorobenzyl)-2,9- diazaspiro[5.5]undecan-l-one (350 mg, crude) as a white solid.

[0508] Step 3. A mixture of 2-(2-chlorobenzyl)-2,9-diazaspiro[5.5]undecan-l-one (50.0 mg, 171 / / mol, 1.00 eq.), Intermediate AA-3 (51.7 mg, 171 / mol, 1.00 eq.), caesium carbonate (167 mg, 512 / / mol, 3.00 eq.), and Pd PEPPSI-IPent-Cl (13.5 mg, 17.1 / / mol, 0.100 eq.) in DMF (1.00 mL) under nitrogen was heated 100°C (microwave irradiation) for 1 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 1 to afford Exemplary Compound 66 (5.86 mg, 11.4 / / mol, 9% yield) as a white solid. 'H NMR (400 MHz, DMSO-t / c) b = 10.87 (br s, 1H), 7.46 (dd, J= 1.6, 7.6 Hz, 1H), 7.34 (dd, J = 1.6, 7.2 Hz, 1H), 7.32 - 7.28 (m, 1H), 7.26 (t, J= 7.6 Hz, 1H), 7.16 - 7.11 (m, 2H), 6.99 - 6.96 (m, 1H), 4.57 (s, 2H), 4.25 (dd, J= 5.4, 12.0 Hz, 1H), 3.26 (br s, 3H), 3.16 - 3.07 (m, 2H), 2.86 (br d, J= 11.2 Hz, 2H), 2.79 - 2.71 (m, 1H), 2.30 - 2.18 (m, 3H), 2.03 - 1.95 (m, 1H), 1.91 (br d, J= 6.4 Hz, 2H), 1.84 (br d, J= 4.8 Hz, 2H), 1.67 - 1.60 (m, 2H). MS (ESI) m / z 514.1 [M+H]+Exemplary compounds 71 and 75 were synthesized in analogy to Example 66 with the relevant amide starting materials:

[0509] Example 71 , . , , . . , , . , . , .

[0510] Hz, 1H), 3.89 (br s, 2H), 3.49 - 3.28 (m, 4H), 2.87 - 2.62 (m, 2H), 2.38 - 2.16 (m, 2H). MS (ESI) m / z 446.1 [M+H]+ Example 73

[0511] Step 1. To a solution of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (1.90 g, 6.59 mmol, 1.00 eq.) and l-amino-3,3-dimethylbutan-2-one*hydrochloride (1.00 g, 6.59 mmol, 1.00 eq.) in THF (10.0 mL) were added l,l'-carbonyldiimidazole (1.60 g, 9.89 mmol, 1.50 eq.) and TEA (2.00 g, 19.7 mmol, 2.75 mL, 3.00 eq.). The reaction was stirred at 25°C for 12 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford tert-butyl 6-((3,3-dimethyl-2-oxobutyl)carbamoyl)-2,6- diazaspiro[3.3]heptane-2-carboxylate (650 mg, 1.91 mmol, 29% yield) as a white solid.

[0512] Step 2. To a solution of tert-butyl 6-((3,3-dimethyl-2-oxobutyl)carbamoyl)-2,6- diazaspiro[3.3]heptane-2-carboxylate (400 mg, 1.18 mmol, 1.00 eq.) in pyridine (3.00 mL) was added trichlorophosphate (549 / / L, 5.89 mmol, 5.00 eq.) at 0°C. The reaction was stirred at 25°C for 2 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford tert-butyl 6-(5-(tert-butyl)oxazol-2-yl)-2,6- diazaspiro[3.3]heptane-2-carboxylate (80.0 mg, 248 / / mol, 21% yield) as a colourless oil.

[0513] Step 3. A mixture of tert-butyl 6-(5-(tert-butyl)oxazol-2-yl)-2,6-diazaspiro[3.3]heptane-2- carboxylate (80.0 mg, 248 / / mol, 1.00 eq.) in dichloromethane (1.00 mL) and trifluoroacetic acid (200 / / L) was stirred at 25°C for 1 h. The reaction was concentrated under reduced pressure to afford 5-(tert-butyl)-2-(2,6-diazaspiro[3.3]heptan-2-yl)oxazole (55.0 mg, crude) as a colourless oil.

[0514] Step 4. To a solution of Intermediate AA-3 (36.9 mg, 122 / / mol, 1.00 eq.) and 5-(tert-butyl)-2- (2,6-diazaspiro[3.3]heptan-2-yl)oxazole (27.0 mg, 122 mol, 1.00 eq.) in DMF (1.00 mL) was added caesium carbonate (119 mg, 366 / / mol, 3.00 eq.) and Pd PEPPSI-IHept-Cl (11.8 mg, 12.2 / / mol, 0.100 eq.) under nitrogen. The reaction was stirred at 100°C for 2 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 followed by Purification Method 1 to afford Exemplary Compound 73 (15.35 mg, 34.3 mol, 14% yield) as a white solid.

[0515] 'H NMR (400 MHz, DMSO-z / s) d = 10.86 (br s, 1H), 7.15 (t, J= 7.6 Hz, 1H), 6.72 (dd, J= 1.2, 7.6 Hz, 1H), 6.60 - 6.53 (m, 1H), 6.39 (s, 1H), 4.17 (s, 9H), 2.78 - 2.67 (m, 1H), 2.56 - 2.53 (m, 1H), 2.24 (br dd, J= 3.6, 12.4 Hz, 1H), 1.97 (dt, J= 4.4, 8.8 Hz, 1H), 1.19 (s, 9H). MS (ESI) m / z 443.2 [M+H]+

[0516] Biological Assay

[0517] Example A: VAV1 Degradation Activity

[0518] A VAV1 C-terminal HiBiT knock-in pool was generated at Monte Rosa Therapeutics from a clonal Jurkat cell stably expressing LgBiT and possessing a homozygous GSPT1-G575N mutation. Cells were plated at 10,000 cells per well using Multiflo (BioTek / Agilent) in 384-well white solid bottom plates (Corning, 3570BC) in 25 ul volume in RPMI 1640 media (Thermo Fischer, 22400105) containing 10% FBS (Coming, 35-075-CV), 1% Peniciliin / Streptomycin (ThermoFisher Scientific, 15140-122), and 1% Endurazine (Nano-Gio Endurazine Live Cell Substrate (Promega, N2571)). Cells were incubated for ~16 hours at 37°C, 5% CO2. 25nL of a compound dilution series ranging from 10 pM to 0.5 nM were dosed into the plate using an Echo® 650 liquid handler (Beckman Coulter). Cells were incubated at 37 °C, 5% CO2 and signal was read at 6 and 24 hours after compound addition on a Pherastar FSX (BMG Biolabs) using “LUM plus” optic module.

[0519] Analysis was performed in Genedata Screener (Genedata, Basel, CH). Luminescence response (R) was calculated by the formula: response = 100 * (S - N) / (P-N) where S is the signal of the well, N and P the mean negative and positive control values respectively of the same plate. The luminescence response was then fitted in Genedata using a 4-parameter antagonist logistic fit (hillslope unconstrained, EC50 > 0, top / bottom unconstrained).

[0520] The results of this study are presented in Table 6.

[0521] Table 6: VAV1 Degradation Activity

[0522] Examples B-K

[0523] Examples B - K present biological activity data generated using compounds 16, 35 and 37 from Table 1. The compound used in each example is specified below.

[0524] Example B: VAV1 degradation in PBMCs seven consecutive doses

[0525] In this example, Compound 37 (referred to as “VAV1 MGD”) was tested. Mice were treated orally with seven consecutive doses of VAV1 MGD at 10, 1, and 0.1 mg / kg or vehicle. Compound formulation was prepared fresh the day of administration in 10% Captisol in water. Serum and PBMCs were collected either 6 or 24 hours post-dosing for analysis of pharmacokinetics and pharmacodynamics. Serum samples were analyzed by LC-MS / MS to evaluate compound concentration in ng / mL and PBMCs were used to assess VAV1 protein levels and b-actin as loading control by western blotting. Briefly, PBMCs were rinsed with PBS then lysed using 100 pF RIPA lysis buffer (Pierce 89901) supplemented with 1% protease inhibitor cocktail [Roche 06493124001] and 1% phosphatase cocktail inhibitor [Sigma; P5726]) respectively. Samples were run on 4-12% precast gels (Thermo Fisher Scientific; WG1402BOX) at 10-15 pg / lanc and transferred to a Transfer Stack (Thermo Fisher Scientific IB23001). Primary antibodies (mouse VAV1, CST; 2502S and b-actin, CST; 4967) were diluted 1: 1000 in Intercept blocking buffer (EI-COR; 927-60001) and incubated with the membranes overnight at 4°C. After three washes with IX TBST (5 minutes each), secondary antibody IRDye 800CW Goat anti-rabbit IgG (EI-COR; 926-32211), was diluted in Intercept blocking buffer, added to membranes, and incubated for 1 hour at room temperature. Signals were detected using a WB image system. VAV1 protein levels were normalized to b-actin levels within the same samples, then the relative levels of VAV1 MGD compared to vehicle groups were calculated and used for representation. The results of this study are shown FIG. 1. Example C: VAV1 degradation in PBMCs seven consecutive doses

[0526] In this example, Compound 16 and Compound 35 were used as VAV1 MGDs. Mice were treated orally with seven consecutive doses of each VAV1 MGD at 30, 10, and 1 mg / kg or vehicle. Compound formulation was prepared fresh the day of administration in 10% Captisol in water. Twenty-four hours post-dosing, serum and PBMCs were collected for analysis of pharmacokinetics and pharmacodynamics. Serum samples were analyzed by LC-MS / MS to evaluate compound concentration in ng / mL and PBMCs were used to assess VAV1 protein levels and b-actin as loading control by western blotting. Briefly, PBMCs were rinsed with PBS then lysed using 100 pL RIPA lysis buffer (Pierce 89901) supplemented with 1% protease inhibitor cocktail [Roche 06493124001] and 1% phosphatase cocktail inhibitor [Sigma; P5726]) respectively. Samples were run on 4-12% precast gels (Thermo Fisher Scientific; WG1402BOX) at 10-15 pg / lanc and transferred to a Transfer Stack (Thermo Fisher Scientific IB23001). Primary antibodies (mouse VAV1, CST; 2502S and b-actin, CST; 4967) were diluted 1: 1000 in Intercept blocking buffer (LI-COR; 927-60001) and incubated with the membranes overnight at 4°C. After three washes with IX TBST (5 minutes each), secondary antibody IRDye 800CW Goat anti-rabbit IgG (LI-COR; 926-32211), was diluted in Intercept blocking buffer, added to membranes, and incubated for 1 hour at room temperature. Signals were detected using a WB image system. VAV1 protein levels were normalized to b-actin levels within the same samples, then the relative levels of VAV1 MGD compared to vehicle groups were calculated and used for representation. The results for Compound 16 are shown in FIG. 2 and the results for Compound 35 are shown in FIG. 3.

[0527] Example D: VAV1 MGD induces degradation of VAV1 in lymphocytes and myeloid cells In this example, Compound 16 and Compound 35 were used as VAV1 MGDs. Frozen human PBMCs (STEMCELL technologies; 70025.2; Lot: 2209401007 ) were thawed, washed with IX PBS & resuspended in complete cell culture medium (RPMI + 10% FBS + 25mM HEPES + IX Sodium Pyruvate (100X) + IX MEM Non-Essential Amino Acids Solution (100X) + 1% Penicillin-Streptomycin (10’000 U / mL) + 50 pM P-mercaptoethanol) . Cells were plated at IxlO6cells / mL in U-bottom 96 well plate (Corning; 3799) and treated with each VAV1 MGD using a serial dilution ranging from 0.1 nM to 1000 nM and including a DMSO control. Plates were incubated for 24 hrs at 5% CO2, 37°C. Cells were then surface stained in FACS Buffer (PBS containing 10% FBS) with Live / Dead staining (Thermo Fisher Scientific; 34980) and Human TruStain FcX (BioLegend; 422302) for 20 minutes at 4°C. Cells were then washed with FACS Buffer and surface antigens were stained in FACS Buffer (CD45, CD3, CD14, CD19) for 20 minutes at 4°C. Cells were then fixed with Cytofix (BD; 554655 ) and permeabilized with Phosflow Perm / Wash Buffer I (BD; 557885) and then and stained with anti-VAVl antibody (CST; 2502) for 20 minutes at 4°C. Following staining with VAV1 antibody cells were washed with Perm buffer and incubated with Aleza Fluor 647 -conjugated anti-rabbit IgG secondary antibody (Biolegend; 406414) for 1 hour at 4°C. Cells were then washed with Perm / Wash Buffer and evaluated by flow cytometry. Cells were first gated on CD45+, then respective cell marker (CD3+, CD19+, or CD14+). To assess VAV1 levels, Alexa Fluor 647 geometric mean fluorescence intensity for each population was normalized to respective DMSO control levels. The results for Compound 16 are shown FIG. 4 and the results for Compound 35 are shown in FIG. 5.

[0528] Example E: Degradation of VAV1 results in inhibition of TCR-mediated CD69 activation, IL-2 secretion, and proliferation of Primary T-cells

[0529] In this example, Compound 16 and Compound 35 were used as VAV1 MGDs. Frozen human Pan T cells (STEMCELL Technologies; 70024) were thawed, washed with IX PBS & resuspended in complete cell culture medium (RPMI+10% FBS ). Cells were plated at optimized cell density in U-bottom 96 well plate (Costar; Z707899) and treated with each VAV1 MGD using a serial dilution ranging from 0.01 nM to 1000 nM and including a DMSO control and incubated for 24 hrs at 5% CO2, 37°C. Cells were transferred from treatment plate to anti- CD3 coated plate (5 pg / mL anti-CD3 antibody, clone OKT3, Thermo Fisher; 16-0037-85) and co-stimulated with anti-CD28 (1 pg / mL, clone CD28.2, Thermo Fisher; 16-0289-85). Cells were incubated at 37°C with 5% CO2 and cells and / or supernatants harvested at various timepoints following anti-CD3 / anti-CD28 co- stimulation for various readouts (24h: CD69; 48h: IL-2; 96h: proliferation). For CD69 surface evaluation, cells were washed with PBS and stained for 20 minutes at 4°C with anti-CD69 allophycocyanin (APC) antibody (BioLegend ; 310910). Cells washed with PBS and evaluated by flow cytometry. APC fluorophore signal intensity (CD69) reported as % CD69+cells normalized to anti-CD3 / anti-CD28 co-stimulated DMSO control levels. IL-2 was evaluated within cellular supernatants using an IL-2 ELISA kit (Abeam; ab270883) according to manufacturer protocol. Optical density (O.D.) values (IL-2) were obtained at 450 nM. For proliferation assays, cells were labeled with Cell Trace Violet (Thermo Fisher Scientific; C34557) according to the manufacturer's instructions. Cells were analyzed as a percentage of diluted Cell Trace Violet dye (relative to unstimulated cells) by flow cytometry. For all assays, data were normalized to anti-CD3 / anti-CD28 co-stimulated DMSO control levels. The results for Compound 16 are shown FIG. 6 and the results for Compound 35 are shown in FIG. 7. Example F: VAV1 is involved in B Cell Receptor Signaling

[0530] Figure 8 shows a schematic diagram of the role of VAV1 in B cell receptor signaling. Following the ligation of the B cell receptor and / or CD 19, VAV1 is recruited to mediate phosphorylation cascades that lead to activation, cytokine secretion, and antibody production by B cells.

[0531] Example G: VAV1 is involved in T Cell Receptor Signalling

[0532] Figure 9 shows a schematic diagram of the role of VAV1 in T cell receptor signaling. Following the ligation of the T cell receptor, VAV1 is recruited to mediate phosphorylation cascades that lead to activation, cytokine secretion, and proliferation.

[0533] Example H: VAV1 MGD Attenuates BCR- Mediated Activity in Primary Human B-cells In this example, Compound 16 and Compound 35 were used as VAV1 MGDs. Peripheral blood mononuclear cells (PBMC) were first isolated from human blood leukopaks. Each leukopak was diluted by adding 40 mL of the leukopak contents into 60mL of lx PBS into a disposable Nalgene 150 mL bottle. The diluted blood mixture was transferred evenly among three Accupsin tubes (~30mL / tube). The mixture in Accuspin tubes was centrifuged at 720 x g for 20 minutes without brake at room temperature. Peripheral blood mononuclear cells) were collected from the interphase with a sterile transfer pipette and transferred into new 50 mL tubes. PBMCs were washed with IX PBS and counted using Nexcelom cell counter. From the isolated PBMCs, B cells were isolated using EasySep B cell isolation kit (Stemcell; 17954) following the manufacturer’s manual magnetic isolation technique. Cells were treated with each VAV1 MGD at the indicated final concentrations or DMSO control and incubated at 37°C in a humidified incubator with 5% CO2 . After treatment, B cells were cultured in RPMI 1640 (Gibco; 22400089) supplemented with 10% fetal bovine serum (Gibco; #A31605-01; Lot 2408990P), 2mM L-glutamine (Gibco; 35050061), 100 lU / mL penicillin / streptomycin (Gibco; 15140122), 1 mM sodium pyruvate (Gibco, 11360070), 0.01 M HEPES (Gibco, 15630080), 1% non-essential amino acids (Gibco; 11140050), and 55 pM P-mercaptoethanol (Gibco; 21985023), and stimulated with assay-dependent stimuli. For CD69 expression and IL-6 secretion, B cells were stimulated with anti-IgM (1 pg / mL; Southern Biotech; 2022-14) and recombinant human IL-4 (10 ng / mL; R&D Systems; 305-IL-010) for 24 hrs. For IgG secretion, B cells were stimulated with anti-IgM (1 pg / mL), BAFF (30 ng / mL; R&D Systems; #7537-BF-025), IL-21 (100 ng / mL; PeproTech; 200-2), and soluble CD40L (50 ng / mL; R&D Systems; 245-C) for 5 days. For CD69 expression, cells were blocked with TruStain FcX (BioLegend; 422302), stained with mouse anti-human CD19-BV421 (BD; 562440; Clone HIB 19) and anti-human CD69-APC (BioLegend; 310910; Clone FN50), then assessed by flow cytometry. For IL-6 and IgG, supernatants were assessed by Alphalisa as per the manufacturer’s instructions. Mean fluorescence intensity (MFI) of CD69-APC was calculated on the CD19+population using FlowJo (BD). MFI of CD69 for VAV1 MGD treated samples was normalized to DMSO stimulated and unstimulated control. Normalized data were transferred to Prism 9.3.1 (GraphPad) and fitted with a four-parameter model ([Inhibitor] vs. response — Variable slope). The results for Compound 16 are shown FIG. 10 and the results for Compound 35 are shown in FIG. 11.

[0534] Example I: VAV1 MGD Attenuates FcR- Mediated Activity in Primary Human Monocytes In this example, Compound 16 and Compound 35 were used as VAV1 MGDs. Monocytes were first isolated from human blood leukopaks. Each leukopak was diluted by adding 40 mL of the leukopak contents into 60mL of lx PBS into a disposable Nalgene 150 mL bottle. The diluted blood mixture was transferred evenly among three Accupsin tubes (~30mL / tube). The mixture in Accuspin tubes was centrifuged at 720 x g for 20 minutes without brake at room temperature. Peripheral blood mononuclear cells) were collected from the interphase with a sterile transfer pipette and transferred into new 50 mL tubes. PBMCs were washed with IX PBS and counted using Nexcelom cell counter. From the isolated PBMCs, monocytes were isolated using Pan Monocyte Isolation Kit (Miltenyi Biotec; 130-096-537) following the manufacturer’s instructions. Cells (lxlO6 / mL) were treated for 24 hours in X-VIVO15 (Lonza; 02-053Q) supplemented with 10% fetal bovine serum with each VAV1 MGD at the indicated final concentrations or DMSO control and incubated at 37°C in a humidified incubator with 5% CO2 . On the day of treatment, flat-bottom 96-well plates were coated with 200 pg / mL IgG (Sigma; I1886-2ML) resuspended in PBS and incubated at 4°C overnight, then 37°C for 2 hours, then washed with PBS. Monocytes were transferred onto plates containing immobilized IgG and incubated for 24 hours at 37°C in a humidified incubator with 5% CO2. After 24 hours, supernatants were then collected, and TNF levels were assessed by Alphalisa (Revvity;

[0535] AL3157HV) as per the manufacturer’s instructions. TNF levels for VAV1 MGD treated samples were normalized to DMSO stimulated and unstimulated control. Normalized data were transferred to Prism 9.3.1 (GraphPad) and fitted with a four-parameter model ([Inhibitor] vs. response — Variable slope). The results of this study are shown in FIG. 12.

[0536] Example J: VAV1 MGDs Degrade VAV1 in REC-1 Cell Line

[0537] In this example, Compound 16 and Compound 35 were used as VAV1 MGDs. VAV1 degradation in REC-1 cells was measured by western blot quantification. REC-1 cells were seeded in RPML1640 (Gibco, CAT# A10491-01) + 10% FBS (Corning, CAT# 35-016-CV, LOT# 16821001) at a density of 1 x 106cells / mL and treated with a dose response of VAV1 MGDs for 24 hours. Then, cells were harvested, washed with PBS and lysed using RIPA buffer (Thermo, CAT# 89901) supplemented with protease inhibitor (Sigma, CAT# P8340) and phosphatase inhibitors (Sigma, CAT# P5726 + P0044). Protein concentration was determined with BCA Rapid Gold (Thermo, CAT# A53225) and subsequently normalized to 1.25 pg / pL. Samples were prepared with IX NuPAGE™ LDS Sample Buffer (Invitrogen, CAT# NP0007) + 5% DTT (Sigma, CAT# 43816) and denaturated at 95°C for 5 minutes. 12 pL of each samples was loaded onto a 26-well Gel (Bio-Rad, CAT# 5678095) and run for ~45 minutes at 150 V. Then, proteins were transferred to a nitrocellulose membrane (BioRad, CAT# 1704159) using the Turbo™ Transfer System (Bio-Rad, CAT# 1704150) with 25 V for 7 minutes. The membrane was blocked with EveryBlot Blocking Buffer (Bio-Rad, CAT# 12010020) followed by overnight incubation with anti-VAVl (CST, CAT# 2502) and anti-P- actin (CST, CAT# 3700S) primary antibodies. Then, the membrane was 3x washed with IX TBS / T (Bio-Rad, CAT# BUF028) and incubated with anti-rabbit IgG HRP (Invitrogen, CAT# A16110) and anti-mouse IgG HRP (Invitrogen, CAT# 31432) secondary antibody followed by 3x wash with IX TBS / T. Western blot images were acquired with ChemiDocTM MP Imaging System (Bio-Rad, CAT# 12003154) and quantified using Image Lab software (Bio-Rad, version 6.1.0). VAV1 levels were normalized to P-actin relative to DMSO control and final graphs were generated with GraphPad Prism 10.2.3. The results of this study are shown in FIG. 13.

[0538] Example K: VAV1 MGDs Inhibit REC-1 Cell Line Proliferation

[0539] In this example, Compound 16 and Compound 35 were used as VAV1 MGDs. To measure growth inhibition of REC-1 cell line (ATCC; #CRL-3004), 3500 cells per well were plated in 75 pL medium of RPML1640 (Gibco; #A10491-01) supplemented with 10% FBS (Corning; #35- 016-CV) and 100 U / mL penicillin / streptomycin (Gibco; #15140122) in 384- well plates (Corning; #3570) and settled overnight in a 37°C incubator with 5% CO2. The cells were treated the following day with increasing concentrations of VAV1 MGDs. DMSO was used as a control. Each treatment was performed in triplicate. CellTiter Glow (Promega; #G7573) readouts were performed as per the manufacturer’s instructions on Day 0 (pre-treatment) and Day 5 by adding 15 pL CTG reagent (Promega; #G7573) per well, incubating at room temperature for 5 minutes, followed by luminescence measurement using a PHERAstar FSX (BMG Labtech). For calculating growth %, medium-only control was subtracted from all wells, and data were normalized to day 0 and DMSO to assess proliferation or cell death using the following equation: if Readcombination >=Reado, 100 * (Readcombination - Reado) / (ReadDMso - Reado); if Readcombination Reado, 100 * (Readcombination - Reado) / Reado. The results of this study are shown in FIG. 14.

[0540] Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims.

Claims

CLAIMS1. A compound of Formula (I)Formula (I) 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, CR14and N, and wherein m is 0 or 1 ; or, 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 ofY 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, 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; or• *-O(Ci-C4 alkylene)-, *-Ci-C4 alkylene-, *-C(=O)(O)-, *-Ci-C4 cycloalkylene, *- *- NR9(CO-C4alkylene)-, *-NR9(C=0)(Co-C4alkylene)-, -NR9(C=0)(Co-C4alkylene)-*, -(C1-C4 alkylene)-C(=O)-*, or *-(Ci-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;Ring B is selected from the group consisting of:• 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 of N, N(H), N(RX) and O, and S(0)o-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, each independently selected from the group consisting of N, N(H), N(RX), O, and S(0)o-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 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)(Ci-4 alkyl) optionally substituted with from 1-4 independently selected R13; -C(O)O(Ci-4 alkyl) optionally substituted with from 1-4 independently selected R13; -S(O)i-2(Ci-4 alkyl) optionally substituted with from 1-4 independently selected R13; -OH; C1-4 alkoxy optionally substituted with from 1-4 independently selected R13; -Co-6alkyl(C3-6 cycloalkyl) optionally substituted with from 1-4 independently selected R13; and -Co-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, 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 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; 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 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; 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 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; C1-4 alkoxy; and Ci-4 alkyl;each of R7, R10, R11, R12, and R13is independently selected from the group consisting of: deuterium, -OH; -halo; -NR9R9; Ci-4 alkoxy; Ci-4 haloalkoxy; -C(=O)O(Ci-4 alkyl); -C(=O)(Ci-4 alkyl); -C(=O)OH; -S(O)i-2(Ci-4 alkyl); and cyano; each occurrence of R14is independently selected from the group consisting of: deuterium; -OH; -halo; C1-2 alkyl; C1-2 alkoxy; Ci-2haloalkyl; and C1-2 haloalkoxy; andR15is selected from the group consisting of hydrogen, deuterium, fluorine, and methyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has Formula (IA):Formula (IA) wherein at least one of Y and Z is N.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound has Formula (IB):Formula (IB) wherein at least one of Y and Z is N.

4. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein Y and Z are both N or Y is CH or CR14and Z is N.

5. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein Y and Z are both N.

6. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein Y is CH or CR14and Z is N.

7. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein R6A, R6B, R6Cand R6Dare each hydrogen, deuterium or oxo.

8. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein R6A, R6B, R6Cand R6Dare all hydrogen.

9. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from:wherein * denotes the point of attachment to L.

10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring Aoptionally substituted with from 1 to 4 independently selected R6substituents.

11. The compound of claim 1 or claim 10, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from:wherein * denotes the point of attachment to L.

12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring Aoptionally substituted with from 1 to 4 independently selected R6substituents.

13. The compound of claim 1 or claim 12, or a pharmaceutically acceptable salt thereof, wherein Ring14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring Awherein 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.

15. The compound of claim 1 or claim 14, or a pharmaceutically acceptable salt thereof, wherein Ring16. The compound of any of claims 1 and 4-6, or a pharmaceutically acceptable salt thereof, wherein 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 oxo substituent ; 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.

17. The compound of any one of claims 1, 10, 12, 14 and 16, or a pharmaceutically acceptable salt thereof, wherein one of the carbon atoms of Ring A is substituted with an oxo substituent.

18. The compound of claim 1 or 16, or a pharmaceutically acceptable salt thereof, wherein, p .

19. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein R2is Cl.

20. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein at least one of R3, R4and R5is H.

21. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein at least two of R3, R4and R5is H.

22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, wherein all of R3, R4and R5are H.

23. The compound of any of claims 1-22, according to Formula (II):Formula (II) or a pharmaceutically acceptable salt thereof.

24. The compound of claim 1 or claim 23, 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 one of Y and Z is N and wherein one of the carbon atoms is optionally substituted with an oxo substituent; orVO• ' , 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 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.

25. The compound of any one of claims 1 and 23-24, 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 one of Y and Z isN 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 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•, 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;• 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(R') 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, each independently selected from the group consisting of N, N(H), N(R'), 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; andL is selected from the group consisting of a bond, *-Ci-C4 alkylene-, *-C(=O)(O)-, and -(Ci- 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.

26. The compound of any one of claims 1 and 22-24, or a pharmaceutically acceptable salt thereof, wherein:Ring A is selected from the group consisting of: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 N, N(H), N(R') 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(R'), 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; andL is selected from the group consisting of a bond, *-Ci-C4 alkylene-, *-C(=O)(O)-, and - (C1-C4 alkylene)-C(=O)-*, wherein * indicates the point of attachment of L to Ring A.

27. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of a bond, *-Ci-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.

28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of a bond, *-Ci-C4 alkylene-, *- C(=O)(O)-, and -(C1-C4 alkylene)-C(=O)-*, wherein * indicates the point of attachment of L to Ring A.

29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt thereof, wherein L is a bond.

30. The compound of any one of claims 1-22 and 27-29, or a pharmaceutically acceptable salt thereof, wherein 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 N, N(H), N(R') 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, each independently selected from the group consisting of N, N(H), N(R'), 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.

31. The compound of any one of claims 1-22 and 26-29, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from the group consisting of:• heterocyclyl or heterocycloalkenyl including 5-9 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R') 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(R'), 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.

32. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein one of the carbon atoms of the heterocyclyl, heterocycloalkenyl or heteroaryl in Ring B is substituted with an oxo substituent.

33. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein R8is selected from the group consisting of: halo; Ci-4 alkoxy which is optionally substituted with from 1-6 independently selected R12; Ci-6 alkyl which is optionally substituted with from 1-6 independently selected R12.

34. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein R8is selected from the group consisting of: halo; Ci-4 alkoxy which is optionally substituted with from 1-3 independently selected R12; and Ci-6 alkyl which is optionally substituted with from 1-3 independently selected R12.

35. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein 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.

36. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein R8is selected from the group consisting of: halo; methoxy, ethoxy, methyl, ethyl, propyl and butyl.

37. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein R12is selected from the group consisting of: C1-4 alkoxy; and halo.

38. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein R12is selected from the group consisting of: methoxy; and F.

39. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein R1is selected from the group consisting of: C1-6 alkyl optionally substituted with from 1-4 independently selected R13; -Co-6alkyl(C3-6 cycloalkyl) optionally substituted with from 1-4 independently selected R13; and -Co-6alkyl(C3-6 heterocyclyl) optionally substituted with from 1-4 independently selected R13.

40. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein R1is C1-6 alkyl optionally substituted with from 1-4 independently selected R13.

41. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein R13is selected from the group consisting of: C1-4 alkoxy; halo; and C1-4 haloalkoxy.

42. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein R13is selected from the group consisting of: methoxy; ethoxy; fluoro; and difluoromethoxy.

43. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from the group consisting of:,optionally substituted with from 1-4 R8substituents.

44. The compound of claim 43, or a pharmaceutically acceptable salt thereof, wherein Ring Bwherein one or more of the carbon atoms is optionally substituted with from 1-4 R8substituents.

45. The compound of claim 43 or 44, or a pharmaceutically acceptable salt thereof, whereinRing B is selected from the group consisting of:

46. The compound of any of claims 1-25, 27, 28, 30 and 43-45, or a pharmaceutically acceptable salt thereof, wherein Ringwherein * indicates the point of attachment of L to Ring A.

47. The compound of any one of claims 1-28, 30, 31 and 43-45, or a pharmaceutically acceptable salt thereof, wherein Ringalkylene)-1*, wherein * indicates the point of attachment of L to Ring A.

48. The compound of any one of claims 1-30 and 43, or a pharmaceutically acceptable salt thereof, wherein 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, Ci-4 alkoxy, -NH2, -NHR9, -NR9R9.

49. The compound of claim 48, or a pharmaceutically acceptable salt thereof, wherein Ring B is phenyl substituted with 1-2 halo substituents.

50. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein R15is H.

51. The compound of any one of claims 1-50, wherein the compound is of Formula (IIIA):Formula (IIIA) or a pharmaceutically acceptable salt thereof.

52. The compound of any one of claims 1-50, wherein the compound is of Formula (IIIB):Formula (IIIB) or a pharmaceutically acceptable salt thereof.

53. The compound of any one of claims 1-48, or a pharmaceutically acceptable salt thereof, wherein the compound exists in a racemic mixture.

54. The compound of any preceding claim, wherein the compound is selected from the group consisting of the compounds in Table 1, or a pharmaceutically acceptable salt thereof.

55. A pharmaceutical composition comprising the compound of any one of claims 1-54, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

56. A method of degrading Proto -oncogene vav 1 protein (VAV1) in a subject, comprising administering to the subject an effective amount of the compound of any one of claims 1- 54 or a pharmaceutically acceptable salt thereof.

57. The method of claim 56, wherein the compound mediates the interaction of a VAV1 protein with an E3 ligase, thereby increasing degradation of the VAV1 protein.

58. The method of any of claims 56-57, wherein VAV1 is a regulator of a lymphocyte.

59. The method of any of claims 56-57, wherein the compound interacts with the E3 ligase prior to the interaction of VAV 1 with the E3 ligase.

60. The method of any one of claims 57-59, wherein the E3 ligase comprises cereblon.

61. A method of degrading Proto-oncogene vav 1 protein (VAV1), comprising:(i) contacting the compound of any one of claims 1-52 or a pharmaceutically acceptable salt thereof with an E3 ligase; and(ii) interacting the contacted E3 ligase with VAV1, thereby degrading VAV1.

62. A method of treating a disorder caused by or associated with disregulation of lymphocyte development or activation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-54 or a pharmaceutically acceptable salt thereof.

63. The method of claim 58 or claim 62, wherein the lymphocyte is a T-cell.

64. The method of claim 58 or claim 62, wherein the lymphocyte is a B-cell.

65. A method of treating a disorder caused by or associated with disregulation of T-cell receptor signaling in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-54 or a pharmaceutically acceptable salt thereof.

66. The method of claim 65, wherein the T-cell receptor signaling is IFNy, CD69, and / or IL- 2.

67. A method of treating a disorder caused by or associated with VAV1 polymorphisms in a subject in need thereof, comprising administering to the subject a therapeuticallyeffective amount of a compound of any one of claims 1-54 or a pharmaceutically acceptable salt thereof.

68. A method of treating a disorder caused by or associated with immunopathologies in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-54 or a pharmaceutically acceptable salt thereof.

69. The method of claim 67 or claim 68, wherein the disorder is autoimmune disorder.

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

71. The method of claim 67 or claim 68, wherein the disorder is a cancer, tumour or other malignancy, optionally wherein the disorder is a hematologic malignancy (e.g. T and B cell malignancy).

72. The method of claim 71, wherein the disorder is selected from the group consisting of: leukemia, lymphoma, Acute myeloid leukemia (AML), T-cell prolymphocytic leukemia, T-cell granular lymphocytic leukemia, aggressive NK cell leukemia, hairy-cell leukemia, nasal and nasal-type NK / T cell lymphoma, mycosis fungoides and Sezary syndrome, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma unspecified, adult T- cell leukemia / lymphoma (HTLV1+), anaplastic large cell lymphoma, primary cutaneous CD-30 positive T-cell lymphoproliferative disorders, cutaneous T-cell lymphoma, subcutaneous panniculitis like T-cell lymphoma, intestinal T-cell lymphoma(+enteropathy), hepatosplenic gamma / delta T-cell lymphoma, and non-Hodgkin lymphomas (e.g., B-cell non-Hodgkin lymphomas; e.g., Burkitt lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), diffuse large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma).

73. The method of claim 67 or claim 68, wherein the is a non-Hodgkin lymphoma.

74. The method of claim 73, wherein the disorder is selected from mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL) and Diffuse large B cell lymphoma (DLBCL).

75. The method of claim 74, wherein the disorder is chronic lymphocytic leukemia (CLL).

76. The method of claim 67 or claim 68, wherein the disorder is selected from the group consisting of diabetes Type I or II, pernicious anemia, uveitis, psoriasis, alopecia areata, ulcerative colitis, Crohn’s disease, atherosclerosis, myocarditis, pericarditis, pulmonary fibrosis, systemic sclerosis, morphea, Alzheimer’s disease, Acute Graft-vs. Host Disease or T-cell mediated kidney disease.

77. The method of claim 67 or claim 68, wherein the disorder is selected from the group consisting of multiple sclerosis, psoriatic arthritis, rheumatoid arthritis, myasthenia gravis, Sjogren’s syndrome, Grave’s disease, an allergic disorder, an autoimmune liver disease, chronic inflammatory demyelinating polyradiculoneuropathy, macular degeneration, systemic lupus erythematosus, Hashimoto’s thyroiditis, amyloidosis, inflammatory eye diseases, pemphigus, systemic lupus erythematosus, Chronic Graft vs. Host Disease, lupus nephritis, pulmonary arterial hypertension or vasculitis.

78. The method of claim 67 or claim 68, wherein the disorder is selected from the group consisting of multiple sclerosis, psoriatic arthritis, rheumatoid arthritis, myasthenia gravis, Sjogren’s syndrome, Grave’s disease, asthma, allergic contact dermatitis, rhinitis, contact dermatitis, biliary sclerosis, sclerosing cholangitis, chronic inflammatory demyelinating polyradiculoneuropathy, macular degeneration, systemic lupus erythematosus, Hashimoto’s thyroiditis, amyloidosis, inflammatory eye diseases, pemphigus, systemic lupus erythematosus, Chronic Graft vs. Host Disease, lupus nephritis, pulmonary arterial hypertension or vasculitis.

79. The method of claim 67 or claim 68, wherein the disorder is selected from the group consisting of ulcerative colitis, rheumatoid arthritis, psoriasis, multiple sclerosis, myasthenia gravis, cutaneous lupus or axial spondylarthritis.

80. The method of claim 67 or claim 68, wherein the disorder is selected from the group consisting of B -cell lymphoma, B-cell leukemia, T-cell lymphoma, T-cell leukemia or acute myeloid leukemia.

81. A method of treating an transplantation setting disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of any of claims 1-54 or a pharmaceutically acceptable salt thereof.

82. The method of claim 81, wherein the transplantation setting disease is selected from the group consisting of graft-versus-host disease, chronic graft rejection, acute graft rejection, transplant vasculopathy, graft vessel disease, graft atherosclerosis, and transplant coronary disease.

83. A method of degrading proto -oncogene vav 1 protein (VAV1) in a subject suffering from an autoimmune disease, or a transplantation setting disease, comprising administering to the subject an effective amount of the compound of any of claims 1-54 or a pharmaceutically acceptable salt thereof.

84. The method of claim 83, wherein the autoimmune disorder is selected from the group consisting of multiple sclerosis, psoriatic arthritis, rheumatoid arthritis, systemic lupus, erythematosus, Hashimoto’s thyroiditis, myasthenia gravis, diabetes type I or II, and the disorders associated therewith, vasculitis, pernicious anemia, Sjogren syndrome, uveitis, psoriasis, Graves ophthalmopathy, alopecia areata and others, allergic diseases (e.g., allergic asthma, atopic dermatitis, allergic rhinitis / conjunctivitis, allergic contact dermatitis), inflammatory diseases optionally with underlying aberrant reactions (e.g., inflammatory bowel disease, Crohn’s disease or ulcerative colitis, intrinsic asthma, inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury), atherosclerosis, osteoarthritis, irritant contact dermatitis and further eczematous dermatitis, seborrheic dermatitis, cutaneous manifestations of immunologically-mediated disorders, inflammatory eye disease, keratoconjunctivitis, myocarditis or hepatitis.

85. The method of claim 83, wherein the transplantation setting disease is selected from the group consisting of graft-versus-host disease, chronic graft rejection, acute graft rejection, transplant vasculopathy, graft vessel disease, graft atherosclerosis, and transplant coronary disease.

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