Targeted degradation of VAV1

Abstract

The present disclosure features chemical entities (e.g., compounds or pharmaceutically acceptable salts thereof) that degrade the proto-oncogene VAV1 protein (VAV1). The chemical entities are useful, for example, for treating subjects (e.g., human subjects) with inflammatory or autoimmune disorders.

Description

[Technical Field]

[0001] This disclosure features chemical entities (e.g., compounds or pharmaceutically acceptable salts thereof) that degrade the human proto-oncogene VAV1 protein (VAV1). These chemical entities are useful, for example, for treating subjects (e.g., human subjects) having disorders or diseases that can be treated by reducing levels of VAV1. This disclosure also features compositions containing these chemical entities, as well as methods of using and making these chemical entities. [Background technology]

[0002] The ubiquitin-proteasome system can be manipulated with different small molecules to induce targeted degradation of specific proteins of interest. Using small molecule degraders to promote targeted protein degradation has emerged as a novel modality for the treatment of disease. One such modality relies on redirecting the activity of E3 ligases, such as cereblon, using low-molecular-weight compounds called molecular glues (also known as "molecular glue degraders" or "MGDs") to promote polyubiquitination and ultimately proteasomal degradation of novel protein substrates involved in disease pathogenesis (a phenomenon known as E3 reprogramming). The molecular glue binds to both the E3 ligase and the target protein. The interaction between the molecular glue and the E3 ligase is thought to create a surface that promotes complex formation with the target protein, enabling its subsequent degradation. 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.

[0003] 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 is rapidly phosphorylated on tyrosine in response to various stimuli, including stimulation of the 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 specific GTPases. VAV1-mediated functions include gene transcription, immune cell development, and activation (e.g., T and B cells). VAV1 is a positive regulator of TCR signaling, including nuclear factor of activated T cells (NFAT), interferon gamma (IFNγ), and interleukin-2 (IL-2) cytokine secretion.

[0004] Knockin mice carrying a mutant VAV1 with disrupted GEF activity but intact GEF-independent function exhibited reduced T cell proliferation and activation in response to allogeneic stimulation and reduced T cell proliferation 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, a genome-wide CRISPR activation (CRISPRa) and interference (CRISPRi) screen in primary human T cells identified VAV1 as a critical positive regulator of T cell function (Schmidt et al. 2022 Science 375:6580). Summary of the Invention

[0005] The present disclosure features chemical entities (e.g., compounds or pharmaceutically acceptable salts thereof) that degrade the proto-oncogene VAV1 protein (VAV1). These chemical entities are useful, for example, for treating subjects (e.g., human subjects) with disorders or diseases that can be treated by reducing the level of VAV1, thereby reducing cellular VAV activity. By reducing the level of VAV1, the chemical entities can reduce signaling in specific immune cell activation pathways. For example, the chemical entities can be used to reduce inflammation or autoimmune activity. They can be useful, for example, for treating multiple sclerosis, rheumatoid arthritis, myasthenia gravis, chronic lymphocytic leukemia, ulcerative colitis, psoriasis, cutaneous lupus, axial spondyloarthritis, and graft-versus-host disease. The present disclosure also features compositions containing the chemical entities, as well as methods of using and making the same.

[0006] VAV1 is a key signaling protein in the adaptive immune system. It is a positive regulator of immune receptor signaling in both T cells and B cells. Therefore, reduction of VAV1 can reduce immune cell activation, immune cell proliferation, and the production of various cytokines. For at least these reasons, degradation of VAV1 may be therapeutically beneficial in various disease states.

[0007] In one aspect, the disclosure features a compound of formula (I) or a pharmaceutically acceptable salt thereof: [ka] In the formula, X, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L 1 and n may be as defined anywhere herein.

[0008] In one aspect, the disclosure features a compound of formula (II) or a pharmaceutically acceptable salt thereof: [ka] In the formula, X, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L 1 and n may be as defined anywhere herein.

[0009] In one aspect, the disclosure features a compound of formula (III) or a pharmaceutically acceptable salt thereof: [ka] In the formula, X, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L 1 and n may be as defined anywhere herein.

[0010] In one aspect, the disclosure features a compound of formula (IV) or a pharmaceutically acceptable salt thereof: [ka] In the formula, X, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L 1 and n may be as defined anywhere herein.

[0011] definition The term "pharmaceutically acceptable salt" refers to a salt that is, 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 is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. provide a detailed description of pharmaceutically acceptable salts 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, non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or formed 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, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N-methyl-N ... + (C 1~4Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0012] As used herein, "VAV1" refers to naturally occurring VAV1, also known as Vav or p95vav (e.g., mammalian, preferably human (Homo sapiens) VAV1), and includes naturally occurring variants, e.g., allelic variants and splice variants, that retain the functional activity of VAV1.

[0013] "Subjects" to which administration is contemplated include, but are not limited to, humans (i.e., male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or an adult subject (e.g., young adult, middle-aged adult, or elderly)) and / or non-human animals, such as mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, 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. The terms "human," "patient," and "subject" are used interchangeably herein.

[0014] Disease, disorder, and condition are used interchangeably herein.

[0015] As used herein, unless otherwise specified, the terms "treat," "treating," and "treatment" contemplate an action that occurs while a subject is afflicted with a specified disease, disorder, or condition, which reduces the severity of the disease, disorder, or condition, or delays or slows the progression of the disease, disorder, or condition ("therapeutic treatment").

[0016] Generally, the "effective amount" of a compound refers to an amount sufficient to induce a desired biological response. As will be understood by those skilled in the art, the effective amount of the compounds of the present disclosure may vary depending on factors such 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.

[0017] As used herein, 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 a therapeutic agent that, alone or in combination with other treatments, provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can encompass an amount that improves overall treatment, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic effectiveness of another therapeutic agent.

[0018] The compounds described herein also include isotopically labeled compounds that are identical to those listed 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 normally found in nature. Examples of isotopes that can be incorporated into the compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example, 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 For example, compounds of the present disclosure may have one or more H atoms replaced with deuterium.

[0019] The term "halo" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

[0020] The term "alkyl" refers to a saturated acyclic hydrocarbon group, which may be straight or branched, containing the indicated number of carbon atoms. For example, C 1~10 indicates that there may be 1 to 10 (inclusive) carbon atoms in the group. Alkyl groups may be substituted or unsubstituted with one or more substituents. Non-limiting examples include methyl, ethyl, iso-propyl, tert-butyl, and n-hexyl. When used in this context, the term "saturated" means that there are only single bonds between the constituent carbon atoms and that other available valences are occupied by hydrogen and / or other substituents as defined herein.

[0021] The term "haloalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced with an independently selected halo.

[0022] The term "alkoxy" refers to an -O-alkyl group (e.g., -OCH3).

[0023] The term "alkylene" refers to a divalent alkyl group (eg, --CH.sub.2--).

[0024] The term "alkenyl" refers to an acyclic hydrocarbon chain that may be straight or branched and that has one or more carbon-carbon double bonds. The alkenyl moiety contains the number of carbon atoms indicated. For example, C 2~6 indicates that the group may have from 2 to 6 (inclusive) carbon atoms. Alkenyl groups may be substituted or unsubstituted with one or more substituents.

[0025] The term "alkynyl" refers to an acyclic hydrocarbon chain that may be straight or branched and that has one or more carbon-carbon triple bonds. The alkynyl moiety contains the number of carbon atoms indicated. For example, C 2~6 indicates that the group may have from 2 to 6 (inclusive) carbon atoms. Alkynyl groups may be unsubstituted or substituted with one or more substituents.

[0026] The term "aryl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic group of 6 to 20 carbons, in which at least one ring in the system is aromatic (e.g., a 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system), and 0, 1, 2, 3, or 4 atoms in each ring can be substituted by substituents. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, dihydro-1H-indenyl, and the like.

[0027] As used herein, the term "cycloalkyl" refers to a cyclic saturated hydrocarbon group having, for example, 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3 to 10 ring carbons or 3 to 6 ring carbons, where the cycloalkyl group can be optionally substituted. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The cycloalkyl can include multiple fused and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyls include bicyclo[1.1.0]butanyl, bicyclo[2.1.0]pentanyl, bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, bicyclo[2.1.1]hexanyl, bicyclo[3.2.0]heptanyl, bicyclo[4.1.0]heptanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[4.2.0]octanyl, bicyclo[3.2.1]octanyl, bicyclo[2.2.2]octanyl, etc. Cycloalkyl also includes spirocycles (e.g., spirocyclic bicycles in which the two rings are joined through only 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, etc. As used in this context, the term "saturated" means that only single bonds exist between the constituent carbon atoms.

[0028] As used herein, the term "cycloalkenyl" refers to a partially unsaturated cyclic hydrocarbon group having 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons, 3 to 10 ring carbons, or 3 to 6 ring carbons, and the cycloalkenyl group can be optionally substituted. Examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. As a partially unsaturated cyclic hydrocarbon group, the cycloalkenyl group can have any degree of unsaturation, provided that one or more double bonds are present in the ring, none of the rings in the ring system is aromatic, and the cycloalkenyl group as a whole is not fully saturated. The cycloalkenyl can include multiple fused and / or bridged and / or spiro rings.

[0029] As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic group having 5 to 20 ring atoms, or 5, 6, 9, 10, or 14 ring atoms, and 6, 10, or 14 pi electrons shared in a cyclic arrangement, 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 (although rings containing heteroatoms are not required, e.g., tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl). Heteroaryl groups can be substituted or unsubstituted with one or more substituents. 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, and pyrido[2,3-d]pyridinyl. and the like. In some embodiments, heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazolyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromanyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, benzo[d][1,3]dioxolyl, 2,3-dihydrobenzofuranyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[b][1,4]oxathiinyl, isoindolinyl, etc. In some embodiments, heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl.

[0030] The term "heterocyclyl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic saturated ring system containing 3 to 16 ring atoms (e.g., a 5- to 8-membered monocyclic ring system, an 8- to 12-membered bicyclic ring system, or an 11- to 14-membered tricyclic ring system), having 1 to 3 heteroatoms in the monocyclic ring, 1 to 6 heteroatoms in the bicyclic ring, or 1 to 9 heteroatoms in the tricyclic or polycyclic ring, the heteroatoms being selected from O, N, or S (e.g., carbon atoms and 1 to 3, 1 to 6, or 1 to 9 O, N, or S heteroatoms in the monocyclic, bicyclic, or tricyclic ring, respectively), and 0, 1, 2, or 3 atoms in each ring can be substituted by substituents. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like. A heterocyclyl can include multiple fused and bridged rings. Non-limiting examples of fused / bridged heterocyclyls include 2-azabicyclo[1.1.0]butanyl, 2-azabicyclo[2.1.0]pentanyl, 2-azabicyclo[1.1.1]pentanyl, 3-azabicyclo[3.1.0]hexanyl, 5-azabicyclo[2.1.1]hexanyl, 3-azabicyclo[3.2.0]heptanyl, octahydrocyclopenta[c]pyrrolyl, 3-azabicyclo[4.1.0]heptanyl, 7-azabicyclo[2.2.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 7-azabicyclo[4.2.0]octanyl, 2-azabicyclo[2.2.2]octanyl, 3-azabicyclo [3.2.1]octanyl, 2-oxabicyclo[1.1.0]butanyl, 2-oxabicyclo[2.1.0]pentanyl, 2-oxabicyclo[1.1.1]pentanyl, 3-oxabicyclo[3.1.0]hexanyl, 5-oxabicyclo[2.1.1]hexanyl, 3-oxabicyclo[3.2.0]heptanyl, 3-oxabicyclo[4.1.0]heptanyl, 7-oxabicyclo[2.2.1]heptanyl, 6-oxabicyclo[3.1.1]heptanyl, 7-oxabicyclo[4.2.0]octanyl, 2-oxabicyclo[2.2.2]octanyl, 3-oxabicyclo[3.2.1]octanyl, etc. Heterocyclyl also includes spirocycles (e.g., spirobicycles in which the two rings are joined through only one atom).Non-limiting examples of spirocyclic heterocyclyls include 2-azaspiro[2.2]pentanyl, 4-azaspiro[2.5]octanyl, 1-azaspiro[3.5]nonanyl, 2-azaspiro[3.5]nonanyl, 7-azaspiro[3.5]nonanyl, 2-azaspiro[4.4]nonanyl, 6-azaspiro[2.6]nonanyl, 1,7-diazaspiro[4.5]decanyl, 7-azaspiro[4.5]decanyl, 2,5-diazaspiro[3.6]decanyl, 3-azaspiro[5.5]undecanyl, 2-oxa ... .2]pentanyl, 4-oxaspiro[2.5]octanyl, 1-oxaspiro[3.5]nonanyl, 2-oxaspiro[3.5]nonanyl, 7-oxaspiro[3.5]nonanyl, 2-oxaspiro[4.4]nonanyl, 6-oxaspiro[2.6]nonane, 1,7-dioxaspiro[4.5]decanyl, 2,5-dioxaspiro[3.6]decanyl, 1-oxaspiro[5.5]undecanyl, 3-oxaspiro[5.5]undecanyl, 3-oxa-9-azaspiro[5.5]undecanyl, etc. When used in this context, the term "saturated" means that only single bonds exist between the constituent ring atoms and that other available valences are occupied by hydrogen and / or other substituents as defined herein.

[0031] As used herein, the term "heterocycloalkenyl" refers to a partially unsaturated cyclic ring system containing 3 to 16 ring atoms (e.g., a 5- to 8-membered monocyclic ring system, an 8- to 12-membered bicyclic ring system, or an 11- to 14-membered tricyclic ring system) having 1 to 3 heteroatoms in the monocyclic ring, 1 to 6 heteroatoms in the bicyclic ring, or 1 to 9 heteroatoms in the tricyclic or polycyclic ring, the heteroatoms being selected from O, N, or S (e.g., carbon atoms and 1 to 3, 1 to 6, or 1 to 9 O, N, or S heteroatoms in the monocyclic, bicyclic, or tricyclic ring, respectively), and 0, 1, 2, or 3 atoms in each ring can be substituted by substituents. Examples of heterocycloalkenyl groups include, but are not limited to, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, and dihydrothiophenyl. As a partially unsaturated cyclic group, a heterocycloalkenyl group can have any degree of unsaturation, provided that there is one or more double bonds within the ring, no ring within the ring system is aromatic, and the heterocycloalkenyl group as a whole is not fully saturated. A heterocycloalkenyl can include multiple fused and / or bridged and / or spiro rings.

[0032] Certain groups, such as [ka] can be considered either: (i) a heterocycloalkenyl substituted with an oxo group; or (ii) a heteroaryl group.

[0033] As used herein, when a ring is described as "aromatic," it means that the ring has a continuously delocalized π-electron system. Typically, the number of out-of-plane π-electrons corresponds to Huckel's rule (4n+2). Examples of such rings include benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thiazole, isoxazole, isothiazole, and the like.

[0034] As used herein, when a ring is described as "partially unsaturated," it means that the ring has one or more additional degrees of unsaturation (in addition to the unsaturation due 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, etc.

[0035] For the avoidance of doubt, and unless otherwise stated, with respect to rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, cycloalkyl, etc. as described herein) that contain a sufficient number of ring atoms to form bicyclic or higher ring systems (e.g., tricyclic ring systems, polycyclic ring systems), such rings and cyclic groups are understood to be those having fused rings, e.g., rings in which the point of fusion is (i) between adjacent ring atoms (e.g., [xx0] ring systems, where 0 represents a 0 atom bridge (e.g., [ka] ));(ii) a single ring atom (spiro-fused ring system) [ka] or (iii) an arrangement of adjacent ring atoms (bridged ring systems where all bridge lengths are >0). [ka] It will be understood that this includes those located above.

[0036] Additionally, atoms constituting the compounds of the present embodiments are intended to include all isotopic forms of such atoms. As used herein, isotopes include 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 include . 13 C and 14 Contains C.

[0037] Furthermore, compounds disclosed generically or specifically herein include all tautomeric forms or "tautomers" of such compounds. [ka] The disclosure of compounds having the group [ka] It also discloses a compound having the formula: Another non-limiting example is the group [ka] The disclosure of compounds having the group [ka] It also discloses a compound having the formula:

[0038] Compounds disclosed generally or specifically herein include all stereoisomers, including all diastereomeric and enantiomeric forms, unless otherwise stated or the context dictates otherwise. Compounds with chiral centers can exist as racemates, individual enantiomers (e.g., as (R) enantiomers or (S) enantiomers) or diastereomers, and mixtures thereof. All such stereoisomers, including mixtures thereof, are included in the embodiments disclosed herein.

[0039] Furthermore, a compound in one enantiomeric form can epimerize to the other enantiomeric form. Thus, unless otherwise specified or the context indicates otherwise, disclosure of one enantiomer encompasses the isolated enantiomer as well as mixtures of (R) and (S) enantiomers, e.g., racemic mixtures, where the enantiomers are epimerized. For example, [ka] The disclosure of both isolated compounds contains a racemic mixture of the two enantiomers. [ka] and [ka] and [ka] Similarly, compounds disclosed herein that contain chiral centers and whose enantiomeric form is not depicted include the isolated enantiomers as well as mixtures of (R) and (S) enantiomers, e.g., racemic mixtures, where the enantiomers epimerize. For example, [ka] contains a racemic mixture of the two enantiomers, both isolated [ka] and [ka] It includes mixtures of

[0040] As used herein, the phrase "optionally substituted" when used in conjunction with a structural moiety (e.g., alkyl) is intended to encompass both unsubstituted structural moieties (i.e., none of the substitutable hydrogen atoms are replaced with one or more non-hydrogen substituents) and substituted structural moieties that are substituted with the indicated range of non-hydrogen substituents. For example, "1 to 4 R a C1-C optionally substituted with 4 "Alkyl" refers to an unsubstituted C1-C4 alkyl and 1-4 R a C1~C substituted with 4 It is intended to encompass both alkyl and aryl.

[0041] As used herein, the term "hydrogen bond acceptor" is intended to include any functional group containing a heteroatom, usually oxygen or nitrogen, with one or more lone pairs of electrons suitable for forming a hydrogen bond with a polarizable hydrogen atom. A more detailed discussion of hydrogen bond acceptors and a list of accepted hydrogen bond acceptors can be found in Laurence et al., J. Med. Chem., 2009, 52, 4073-4086 and Kenny et al., J. Med. Chem. 2016, 59, 4278-4288, both of which are incorporated by reference in their entirety.

[0042] As used herein, the term "antibody" includes natural or partially or wholly synthetically produced immunoglobulins and fragments thereof. The term also encompasses any protein having a binding domain homologous to an immunoglobulin binding domain. "Antibody" further includes polypeptides comprising a framework region derived from an immunoglobulin gene or fragments thereof that specifically bind and recognize an antigen. The use of the term antibody is intended to include whole, polyclonal, monoclonal, and recombinant antibodies, as well as fragments thereof, including single-chain antibodies, humanized antibodies, murine antibodies, chimeric antibodies, mouse-human antibodies, mouse-primate antibodies, primate-human monoclonal antibodies, anti-idiotypic antibodies, antibody fragments such as scFv, (scFv)2, Fab, Fab', and F(ab')2, F(abl)2, Fv, dAb, and Fd fragments, diabodies, and antibody-related polypeptides. Antibodies also include bispecific and multispecific antibodies, so long as they exhibit the desired biological activity or function.

[0043] As used herein, an "antibody fragment" comprises a portion of an intact antibody, generally the antigen-binding or variable region thereof. Examples of antibody fragments include Fab, Fab', F(ab') sub2, and Fv fragments; diabodies; linear antibodies; Fab expression libraries, anti-idiotypic (anti-Id) antibodies, fragments produced by CDRs (complementarity-determining regions), and epitope-binding fragments of any of the above that immunospecifically bind to cancer cell antigens, viral antigens, or microbial antigens, single-chain antibody molecules; and multispecific antibodies formed from antibody fragments.

[0044] As used herein, the term "antibody-drug conjugate" refers to an antibody or antibody fragment linked, for example, by a covalent bond, to a compound of the disclosure.

[0045] 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. [Brief explanation of the drawings]

[0046] [Figure 1] Figure 1: Schematic representation of a particular aspect of the relationship of VAV1 to specific proteins involved in T cell receptor activation. VAV1 is a positive regulator of T cell receptor signaling, including interferon gamma production and IL-2 secretion. [Figure 2-1]Figure 2: Figure 2A shows the dose-dependent decrease in VAV1 levels in primary human T cells after 24 hours of treatment with the compounds shown in Table 1 ("selected VAV1 MGD") compared to DMSO control as assessed by flow cytometry (y-axis represents normalized VAV1 levels relative to DMSO control; x-axis represents dose of selected VAV1 MGD). Figure 2B shows that VAV1 is significantly and selectively degraded by selected VAV1 MGD in Jurkat cells after 24 hours of treatment as assessed by quantitative TMT proteomics (y-axis represents confidence p-value [-log10]; x-axis represents protein fold change [log2] relative to DMSO control sample). [Figure 2-2] (As mentioned above.) [Figure 3-1] Figure 3: VAV1 degradation results in inhibition of various features of TCR-mediated activity after TCR stimulation of primary human T cells. Cells were treated with selected VAV1 MGDs for 24 hours, followed by TCR stimulation (anti-CD3 / anti-CD28 antibodies). CD69 surface expression (24 hours), IL-2 secretion (48 hours), and proliferation (96 hours) were assessed at various time points after TCR stimulation (y-axis indicates percentage of CD69 activation, IL-2 secretion, or proliferation compared to the TCR-stimulated DMSO control; x-axis indicates dose of selected VAV1 MGD). [Figure 3-2] (As mentioned above.) [Figure 3-3] (As mentioned above.) [Figure 4] Figure 4: Concentrations of selected VAV1 MGD in plasma over time and associated decrease in VAV1 normalized to b-actin protein levels compared to before treatment after a single oral dose of 10 mg / kg selected VAV1 MGD (y-axis represents time after one single oral dose of selected VAV1 MGD [hours]; left y-axis represents selected VAV1 MGD concentration in plasma, filled diamonds; right y-axis represents VAV1 protein levels normalized to b-actin protein levels as percentage [%] of VAV1 protein levels relative to before administration in blood cells, filled triangles) compared to before treatment. [Figure 5]Figure 5: Oral administration of selected VAV1 MGD inhibitors in the MOG35-55-induced experimental autoimmune encephalomyelitis (EAE) model resulted in inhibition of disease progression. Mice were immunized on day 0 by subcutaneous injection with an emulsified mixture consisting of a synthetic peptide derived from myelin oligodendrocyte glycoprotein (MOG35-55) and M. tuberculosis bacteria mixed with incomplete Freund's adjuvant. Additionally, mice were intraperitoneally injected with pertussis toxin at 0 and 48 hours. Mice were followed for the onset of symptoms and scored for EAE clinical signs and disease (0 = no signs of disease; 1 = lame tail or hind limb weakness; 2 = lame tail and hind limb weakness; 3 = partial hind limb paralysis; 4 = complete hind limb paralysis; 5 = moribund). Mice were administered once daily (QD) starting on day 12 and ending on day 18. Dexamethasone administered orally QD from days 12 to 18 was used as a comparative treatment. 10 mg / kg of selected VAV1 MGD prevented EAE disease progression as observed in mice treated with 1 mg / kg dexamethasone (x-axis represents days after initiation of immunization [days]; y-axis represents clinical EAE score [mean ± SEM]; open circles: vehicle, PO, QD; black inverted triangles, VAV1 MGD 10 mg / kg, PO, QD; black squares, dexamethasone 1 mg / kg, PO, QD). [Figure 6-1]Figure 6: Figure 6A shows that oral administration of VAV1 MGD resulted in dose-dependent inhibition of disease progression in the MOG35-55-induced experimental autoimmune encephalomyelitis (EAE) model. Mice were immunized by subcutaneous injection on day -12 with an emulsified mixture of Mycobacterium tuberculosis (M. tuberculosis) mixed with incomplete Freund's adjuvant and a synthetic peptide derived from myelin oligodendrocyte glycoprotein (MOG35-55). Additionally, mice were intraperitoneally injected with pertussis toxin on days -12 and -10. Mice were followed for the development of symptoms and scored every 3 days for EAE clinical signs and disease (0 = no signs of disease; 1 = lame tail or hind limb weakness; 2 = lame tail and hind limb weakness; 3 = partial hind limb paralysis; 4 = complete hind limb paralysis; 5 = moribund). Treatment began on day 0 and ended on day 13 with vehicle (PO, QD), dexamethasone (1 mg / kg PO QD), and VAV1 MGD (1, 0.1, 0.01 mg / kg PO, QD). 1 mg / kg VAV1 MGD prevented EAE disease progression as observed in mice treated with 1 mg / kg dexamethasone (x-axis represents days after initiation of immunization [days]; y-axis represents clinical EAE score [mean ± SEM]; closed circles: vehicle; closed triangles, VAV1 MGD 1 mg / kg; closed triangles, VAV1 MGD 0.1 mg / kg; open triangles, VAV1 MGD 0.01 mg / kg; open circles, dexamethasone 1 mg / kg). Figure 6B shows that oral administration of VAV1 MGD degraded VAV1 in the spinal cord in a dose-dependent manner, consistent with a reduction in clinical scores. On day 6, four mice per group were euthanized, their spinal cords excised, homogenized, and then Western blot was used to assess VAV1 levels, normalized to β-actin and shown relative to vehicle-treated mice. Statistical analysis was performed using one-way ANOVA with Dunnett's multiple comparisons. ns = not significant, ***p < 0.001, ****p < 0.0001. [Figure 6-2] (As mentioned above.) [Figure 7]Figure 7: Oral administration of VAV1 MGD resulted in inhibition of disease progression in a T cell transfer-induced model of colitis. CD17-SCID mice were intraperitoneally injected with 0.5 x 10 non-pathogenic activated CD45RB low (no disease control group) or pathogenic naive CD45RB high (treated group) CD4 T cells. From the day of cell transfer (day 0), mice were monitored daily for disease activity index (DAI), including assessment of weight loss and stool consistency. On day 0, 2 hours after cell transfer, mice were treated orally (PO) with vehicle or VAV1 MGD at 1 mg / kg daily (QD) for 42 days. VAV1 MGD at 1 mg / kg prevented the progression of colitis (x-axis represents the number of days [days] after disease induction and initiation of treatment; y-axis represents DAI score [mean ± SEM]; open circles, non-pathogenic control; closed circles, vehicle; closed triangles, VAV1 MGD 1 mg / kg). [Figure 8-1]Figure 8: Figure 8A shows that oral administration of VAV1 MGD resulted in inhibition of disease progression in a collagen-induced arthritis model. To induce collagen-induced arthritis (CIA), 15 DBA / 1 mice were intravenously injected with an emulsified mixture consisting of 100 μg of chicken collagen II emulsified in incomplete Freund's adjuvant, followed 18 days later by subcutaneous injection of chicken collagen II emulsified in complete Freund's adjuvant. This immunization induces the activation and proliferation of collagen-specific T cells and B cells that migrate to the ankle joint. Once inside the ankle joint, activated T cells induce destruction of joint and bone tissue, resulting in redness and swelling of the phalanges, and B cells produce antibodies against collagen II. After the second immunization, mice were monitored daily for clinical signs of disease as follows: 0 = erythema and redness; 1 = erythema or mild redness near the ear, tarsus, ankle, or metatarsal, or one toe with erythema and redness; 2 = slight erythema and swelling of the ankle and metatarsal, and erythema and redness of two or more toes; 3 = moderate erythema and swelling of the ankle, wrist, and metatarsal; 4 = severe redness and swelling of the ankle, wrist, metatarsal, and toes. At the time of disease onset, mice were randomized into treatment groups: vehicle (PO, QD), anti-TNF (10 mg / kg, IP, Q3D), or VAV1 MGD (1 mg / kg, PO, QD) and treated for 21 days. VAV1 MGD at 1 mg / kg prevented the progression of arthritis (x-axis represents days after disease onset and treatment initiation [days]; y-axis represents clinical score [mean ± SEM]; circles, vehicle; triangles, VAV1 MGD 1 mg / kg). Figure 8B shows that oral administration of VAV1 MGD in a collagen-induced arthritis model resulted in a reduction in the production of anti-collagen type II IgG1 antibodies. At the end of the study, serum was collected, and the amount of anti-collagen type II IgG1 antibodies was measured by ELISA. Statistical analysis was performed using an unpaired two-tailed t-test. *p<0.05. [Figure 8-2] (As mentioned above.) [Figure 9]Figure 9: VAV1 as a key mediator downstream of the B cell receptor (BCR). Hallmarks of BCR pathway engagement include CD69 surface activation and secretion of IL-6 and IgG. [Figure 10-1] Figure 10: VAV1 MGD-mediated degradation of VAV1 reduces BCR-mediated CD69 expression and IL-6 and IgG secretion in primary human B cells. Purified human primary B cells were treated with VAV1 MGD for 24 hours and subsequently stimulated 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). Figure 10A shows CD69 expression, which was then assessed for CD19+ B cells by flow cytometry. CD69 expression is shown as a percentage (%) change compared to the stimulated DMSO control. The y-axis indicates the relative proportion of CD19+ B cells expressing CD69, and the x-axis indicates the concentration of VAV1 MGD. Figure 10B shows IL-6 secretion assessed in the supernatant by alphalisa. IL-6 secretion is shown as a percentage (%) change compared to the stimulated DMSO control. The y-axis shows the relative percentage of IL-6 levels, and the x-axis shows the concentration of VAV1 MGD. Figure 10C shows that IgG secretion in the supernatant was assessed by alphalisa. IgG secretion is shown as a percentage (%) change compared to the stimulated DMSO control. The y-axis shows the relative percentage of IgG levels, and the x-axis shows the concentration of VAV1 MGD. [Figure 10-2] (As mentioned above.) [Figure 10-3] (As mentioned above.) [Figure 11] Figure 11: VAV1 MGD treatment of selected B-cell lymphoma cell lines reduces proliferation with increasing concentrations. REC-1, OCI-LY10, and SLVL cells were treated with the indicated concentrations of VAV1 MGD for 5 days. On day 5 of treatment, cell proliferation was measured by cell titer growth and normalized to TO and DMSO. [Figure 12]Figure 12: VAV1 MGD treatment of subcutaneously implanted REC-1 CDX reduces growth in vivo. CB17 SCID mice (10 per group) were inoculated subcutaneously with 5 x 10 REC-1 cells in the right flank. After the mean tumor volume of all mice reached 100-150 mm, the mice were treated with either vehicle or 10 mg / kg VAV1 MGD PO QD. Tumor volumes were measured on the indicated days after treatment initiation. Mice were sacrificed when tumor volumes reached 2000 mm. [Figure 13] FIG. 13: X-ray powder diffraction (XRPD) pattern of crystalline form A of compound 185. DETAILED DESCRIPTION OF THE INVENTION

[0047] This disclosure features chemical entities (e.g., compounds or pharmaceutically acceptable salts thereof) that degrade and / or inhibit the proto-oncogene VAV1 protein (VAV1). The chemical entities are useful, for example, for treating subjects (e.g., human subjects) with disorders or diseases associated with VAV1 polymorphisms or dysregulated lymphocytes (e.g., T cells). This disclosure also features compositions including the chemical entities and methods of using and making the chemical entities.

[0048] compound Compounds of formula (I), (II), (III) and (IV) The disclosure features a compound of formula (I) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, L 1 teeth, ·It is a bond; *-O(C0-C4 alkylene)-, *-S(C0-C4 alkylene)-, *-C1-C4 alkylene-, or *-NR'(C0-C4 alkylene)-, -(C1-C4 alkylene)-C(=O)-*, *-(C1-C4 alkylene)-C(=O)-, wherein alkylene is selected from the group consisting of 1 to 2 R a and * represents L to the ring containing X and Y.1 indicates the point of attachment; -(C=O)-; or together with Y, form an additional ring fused to the ring containing X and Y, the fused ring system containing 9 or 10 ring atoms, 1 to 4 ring atoms in the additional ring being heteroatoms, each independently selected from N, N(H), N(R d ) and O, and the additional ring is substituted with R and is selected from the group consisting of oxo and R c optionally further substituted with 1 to 4 substituents independently selected from the group consisting of: each of X and Y is independently selected from the group consisting of N and CH; R 1 is hydrogen, deuterium, R b , -OR b , -S(O) 0~2 R b , -N(R')R b , CN, halo, and -NR'C(O)R'', R 2 is selected from the group consisting of hydrogen, deuterium, CH3, CHF2, CF3, OMe, F, Cl, and Br; R 3 , R 4 and R 5 each independently represents hydrogen and R c is selected from the group consisting of R 6 each independently selected from deuterium, halo; cyano; 1 to 6 independently selected R a optionally substituted with C 1~10 alkyl; 1 to 4 independently selected R a optionally substituted with C 3~6 Cycloalkyl; C 2~6 Alkenyl; C 2~6 Alkynyl; C 1~4 Alkoxy; -S(O) 0~2 (C 1~4 alkyl);-NR e R f ;-OH;-S(O) 1~2 NR'R'';-NO2;-C(=O)(C 1~10 alkyl);-C(=O)O(C1~4 alkyl);-C(=O)OH;-N(R')C(=O)(C 1~4 alkyl), -C(=O)NR'R'', R g , and -(CH2) 1~2 R g is selected from the group consisting of n is selected from 0, 1, 2 and 3; R 7 is selected from the group consisting of hydrogen, deuterium, CH3, CHF2, CF3, OMe, F, Cl, and Br; R a each occurrence independently represents -OH; -halo; -NR e R f ;C 1~4 Alkoxy;C 1~4 Haloalkoxy; -C(=O)O(C 1~4 alkyl);-C(=O)(C 1~4 alkyl);-C(=O)OH;-CONR'R'';-S(O) 1~2 NR'R'';-S(O) 1~2 (C 1~4 alkyl); and cyano; R b Each occurrence of is independently oxo and R respectively c C optionally substituted with 1 to 4 substituents independently selected from the group consisting of 3~10 Cycloalkyl or C 3~10 cycloalkenyl; Heterocyclyl or heterocycloalkenyl containing 3 to 10 ring atoms, of which 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 and heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R c heterocyclyl or heterocycloalkenyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d), O, and S(O) 0~2 wherein at least one ring in the system is aromatic and the heteroaryl is selected from the group consisting of oxo and R c heteroaryl, optionally substituted with 1 to 4 substituents independently selected from 1 to 4 independently selected substituents R c optionally substituted with C 6~10 Aryl is selected from the group consisting of R c each occurrence independently represents deuterium; halo; cyano; 1 to 6 independently selected R a optionally substituted with C 1~10 alkyl; 1 to 4 independently selected R a optionally substituted with C 3~6 Cycloalkyl; C 2~6 Alkenyl; C 2~6 Alkynyl; C 1~4 Alkoxy; -S(O) 0~2 (C 1~4 alkyl);-NR e R f ;-OH;-S(O) 1~2 NR'R'';-NO2;-C(=O)(C 1~10 alkyl);-C(=O)O(C 1~4 alkyl);-C(=O)OH;-N(R')C(=O)(C 1~4 alkyl), -C(=O)NR'R'', R g , and -(CH2) 1~2 R g is selected from the group consisting of R d Each occurrence of is independently selected from hydrogen, deuterium, and 1 to 3 independently selected R a optionally substituted with C 1~6 Alkyl; -C(O)(C 1~4 alkyl);-C(O)O(C 1~4 alkyl);-CONR'R'';-S(O) 1~2 NR'R'';-S(O) 1~2 (C 1~4 alkyl); -OH; and C 1~4 Alkoxy is selected from the group consisting of R e and R f Each occurrence of is independently H; deuterium; C 1~6 Alkyl; -C(O)(C 1~4 alkyl);-C(O)O(C 1~4 alkyl);-CONR'R'';-S(O) 1~2 NR'R'';-S(O) 1~2 (C 1~4 alkyl); -OH; and C 1~4 alkoxy; R g Each occurrence of is independently oxo and R respectively a C optionally substituted with 1 to 4 substituents independently selected from the group consisting of 3~7 Cycloalkyl or C 3~7 cycloalkenyl; Heterocyclyl or heterocycloalkenyl containing 3 to 7 ring atoms, of which 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 and heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R a heterocyclyl or heterocycloalkenyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 wherein at least one ring in the system is aromatic and the heteroaryl is selected from the group consisting of 1 to 4 oxo or R a heteroaryl, optionally substituted with; and 1 to 4 R a optionally substituted with C 6~10 Aryl is selected from the group consisting of Each occurrence of R′ and R″ is independently hydrogen; and C 1~4alkyl.

[0049] The disclosure also features a compound of formula (II) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, L is ·It is a bond; *-O(C0-C4 alkylene)-, *-S(C0-C4 alkylene)-, *-C1-C4 alkylene, or *-NR'(C0-C4 alkylene)-, *-NR'(C=O)(C0-C4 alkylene)-, -(C1-C4 alkylene)-C(=O)-*, *-(C1-C4 alkylene)-C(=O)-, wherein alkylene is selected from the group consisting of 1 to 2 R a and * represents L to the ring containing X and Y. 1 indicates the point of attachment of -(C=O)-; or together with Y, form an additional ring fused to the ring containing X and Y, the fused ring system containing 9 or 10 ring atoms, 1 to 4 ring atoms in the additional ring being heteroatoms, each independently selected from N, N(H), N(R d ) and O, and the additional ring is substituted with R and is selected from the group consisting of oxo and R c optionally further substituted with 1 to 4 substituents independently selected from the group consisting of: each of X and Y is independently selected from the group consisting of N and CH; R 1 is hydrogen, deuterium, R b , -OR b , -S(O) 0~2 R b , -N(R')R b , CN, halo, and -NR'C(O)R'', R 2 is selected from the group consisting of hydrogen, deuterium, CH3, CHF2, CF3, OMe, F, Cl, and Br; R 3 , R 4 and R 5each independently represents hydrogen and R c is selected from the group consisting of R 6 each of which is selected from deuterium, halo; cyano; and 1 to 6 independently selected R a optionally substituted with C 1~10 alkyl; 1 to 4 independently selected R a optionally substituted with C 3~6 Cycloalkyl; C 2~6 Alkenyl; C 2~6 Alkynyl; C 1~4 Alkoxy; -S(O) 0~2 (C 1~4 alkyl);-NR e R f ;-OH;-S(O) 1~2 NR'R'';-NO2;-C(=O)(C 1~10 alkyl);-C(=O)O(C 1~4 alkyl);-C(=O)OH;-N(R')C(=O)(C 1~4 alkyl), -C(=O)NR'R'', R g , and -(CH2) 1~2 R g is selected from the group consisting of n is selected from 0, 1, 2 and 3; R a each occurrence independently represents -OH; -halo; -NR e R f ;C 1~4 Alkoxy;C 1~4 Haloalkoxy; -C(=O)O(C 1~4 alkyl);-C(=O)(C 1~4 alkyl);-C(=O)OH;-CONR'R'';-S(O) 1~2 NR'R'';-S(O) 1~2 (C 1~4 alkyl); and cyano; R b Each occurrence of is independently oxo and R respectively c C optionally substituted with 1 to 4 substituents independently selected from the group consisting of 3~10 Cycloalkyl or C 3~10cycloalkenyl; Heterocyclyl or heterocycloalkenyl containing 3 to 10 ring atoms, of which 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 and heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R c heterocyclyl or heterocycloalkenyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O, and S(O) 0~2 wherein at least one ring in the system is aromatic and the heteroaryl is selected from the group consisting of oxo and R c heteroaryl, optionally substituted with 1 to 4 substituents independently selected from 1 to 4 independently selected substituents R c optionally substituted with C 6~10 Aryl is selected from the group consisting of R c each occurrence independently represents deuterium; halo; cyano; 1 to 6 independently selected R a optionally substituted with C 1~10 alkyl; 1 to 4 independently selected R a optionally substituted with C 3~6 Cycloalkyl; C 2~6 Alkenyl; C 2~6 Alkynyl; C 1~4 Alkoxy; -S(O) 0~2 (C 1~4 alkyl);-NR e R f ;-OH;-S(O) 1~2 NR'R'';-NO2;-C(=O)(C 1~10 alkyl);-C(=O)O(C 1~4 alkyl);-C(=O)OH;-N(R')C(=O)(C 1~4alkyl), -C(=O)NR'R'', R g , and -(CH2) 1~2 R g is selected from the group consisting of R d Each occurrence of is independently selected from hydrogen, deuterium, and 1 to 3 independently selected R a optionally substituted with C 1~6 Alkyl; -C(O)(C 1~4 alkyl);-C(O)O(C 1~4 alkyl);-CONR'R'';-S(O) 1~2 NR'R'';-S(O) 1~2 (C 1~4 alkyl); -OH; and C 1~4 Alkoxy is selected from the group consisting of R e and R f Each occurrence of is independently H; deuterium; C 1~6 Alkyl; -C(O)(C 1~4 alkyl);-C(O)O(C 1~4 alkyl);-CONR'R'';-S(O) 1~2 NR'R'';-S(O) 1~2 (C 1~4 alkyl); -OH; and C 1~4 alkoxy; R g Each occurrence of is independently oxo and R respectively a C optionally substituted with 1 to 4 substituents independently selected from the group consisting of 3~7 Cycloalkyl or C 3~7 cycloalkenyl; Heterocyclyl or heterocycloalkenyl containing 3 to 7 ring atoms, of which 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 and heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R a heterocyclyl or heterocycloalkenyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 wherein at least one ring in the system is aromatic and the heteroaryl is selected from the group consisting of 1 to 4 oxo or R a heteroaryl, optionally substituted with; and 1 to 4 R a optionally substituted with C 6~10 Aryl is selected from the group consisting of Each occurrence of R′ and R″ is independently hydrogen; and C 1~4 alkyl.

[0050] The disclosure also features a compound of formula (III) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, L 1 teeth: · Bonding *-O(C0-C4 alkylene)-, *-S(C0-C4 alkylene)-, *-C1-C4 alkylene, or *-NR'(C0-C4 alkylene)-, *-NR'(C=O)(C0-C4 alkylene)-, -(C1-C4 alkylene)-C(=O)-*, *-(C1-C4 alkylene)-C(=O)-, wherein alkylene is selected from the group consisting of 1 to 2 R a and * represents L to the ring containing X and Y. 1 indicates the point of attachment of -(C=O)-, each of X and Y is independently selected from the group consisting of N and CH; R 1 is hydrogen, deuterium, R b , -OR b , -S(O) 0~2 R b , -N(R')R b, CN, halo, and -NR'C(O)R'', However, -L 1 -R 1 does not contain OO, NO, NN, OS, SS or NS bonds, and R 1 When is CN, halo, or -NR'C(O)R'', L 1 must be a bond, and further provided that R 1 If is hydrogen, L 1 cannot be a bond, R 2 is selected from the group consisting of hydrogen, deuterium, CH3, CHF2, CF3, OMe, F, Cl, and Br; R 3 , R 4 and R 5 each independently represents hydrogen and R c is selected from the group consisting of R 6 each independently selected from deuterium; halo; cyano; 1 to 6 independently selected R a optionally substituted with C 1~10 alkyl; 1 to 4 independently selected R a optionally substituted with C 3~6 Cycloalkyl; C 2~6 Alkenyl; C 2~6 Alkynyl; C 1~4 Alkoxy; -S(O) 0~2 (C 1~4 alkyl);-NR e R f ;-OH;-S(O) 1~2 NR'R'';-NO2;-C(=O)(C 1~10 alkyl);-C(=O)O(C 1~4 alkyl);-C(=O)OH;-N(R')C(=O)(C 1~4 alkyl), -C(=O)NR'R'', R g , and -(CH2) 1~2 R g is selected from the group consisting of n is selected from 0, 1, 2 and 3; R a each occurrence independently represents -OH; -halo; -NRe R f ;C 1~4 Alkoxy;C 1~4 Haloalkoxy; -C(=O)O(C 1~4 alkyl);-C(=O)(C 1~4 alkyl);-C(=O)OH;-CONR'R'';-S(O) 1~2 NR'R'';-S(O) 1~2 (C 1~4 alkyl); and cyano; R b Each occurrence of is independently oxo and R respectively c C optionally substituted with 1 to 4 substituents independently selected from the group consisting of 3~10 Cycloalkyl or C 3~10 cycloalkenyl; Heterocyclyl or heterocycloalkenyl containing 3 to 10 ring atoms, of which 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 and heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R c heterocyclyl or heterocycloalkenyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O, and S(O) 0~2 wherein at least one ring in the system is aromatic and the heteroaryl is selected from the group consisting of oxo and R c heteroaryl, optionally substituted with 1 to 4 substituents independently selected from 1 to 4 independently selected substituents R c optionally substituted with C 6~10 aryl; R c each occurrence independently represents deuterium; halo; cyano; 1 to 6 independently selected R aoptionally substituted with C 1~10 alkyl; 1 to 4 independently selected R a optionally substituted with C 3~6 Cycloalkyl; C 2~6 Alkenyl; C 2~6 Alkynyl; C 1~4 Alkoxy; -S(O) 0~2 (C 1~4 alkyl);-NR e R f ;-OH;-S(O) 1~2 NR'R'';-NO2;-C(=O)(C 1~10 alkyl);-C(=O)O(C 1~4 alkyl);-C(=O)OH;-N(R')C(=O)(C 1~4 alkyl), -C(=O)NR'R'', R g , and -(CH2) 1~2 R g is selected from the group consisting of R d each occurrence of is independently selected from hydrogen, 1 to 3 independently selected R a optionally substituted with C 1~6 Alkyl; -C(O)(C 1~4 alkyl);-C(O)O(C 1~4 alkyl);-CONR'R'';-S(O) 1~2 NR'R'';-S(O) 1~2 (C 1~4 alkyl); -OH; and C 1~4 alkoxy; R e and R f Each occurrence of is independently H;C 1~6 Alkyl; -C(O)(C 1~4 alkyl);-C(O)O(C 1~4 alkyl);-CONR'R'';-S(O) 1~2 NR'R'';-S(O) 1~2 (C 1~4 alkyl); -OH; and C 1~4 alkoxy; R g Each occurrence of is independently oxo and R respectivelya C optionally substituted with 1 to 4 substituents independently selected from the group consisting of 3~7 Cycloalkyl or C 3~7 cycloalkenyl; Heterocyclyl or heterocycloalkenyl containing 3 to 7 ring atoms, of which 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 and heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R a heterocyclyl or heterocycloalkenyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 wherein at least one ring in the system is aromatic and the heteroaryl is selected from the group consisting of 1 to 4 oxo or R a heteroaryl, optionally substituted with; and 1 to 4 R a optionally substituted with C 6~10 aryl; Each occurrence of R′ and R″ is independently hydrogen; and C 1~4 alkyl.

[0051] The disclosure also features a compound of formula (IV) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, L 1 teeth, ·It is a bond; -O(C0-C4 alkylene)-, *-S(C0-C4 alkylene)-, *-C1-C4 alkylene, or *-NR'(C0-C4 alkylene)-, *-NR'(C=O)(C0-C4 alkylene)-, -(C1-C4 alkylene)-C(=O)-, *-(C1-C4 alkylene)-C(=O)-, wherein alkylene is selected from the group consisting of 1 to 2 R a and * represents L to the ring containing X and Y. 1 indicates the point of attachment of -(C=O)-, each of X and Y is independently selected from the group consisting of N and CH; R 1 is hydrogen, R b , -OR b , -SR b , -N(R')R b , CN, halo, and -NR'C(O)R'', However, -L 1 -R 1 does not contain OO, NO, NN, OS, SS or NS bonds, and R 1 When is CN, halo, or -NR'C(O)R'', L 1 must be a bond, and further provided that R 1 If is hydrogen, L 1 cannot be a bond, R 2 is selected from the group consisting of hydrogen, CH3, CHF2, CF3, OMe, F, and Cl; R 3 , R 4 and R 5 each independently represents hydrogen and R c is selected from the group consisting of R 6 Each of the is independently selected R c and n is selected from 0, 1, 2 and 3; R a each occurrence independently represents -OH; -halo; -NR e R f ;C 1~4 Alkoxy;C 1~4Haloalkoxy; -C(=O)O(C 1~4 alkyl);-C(=O)(C 1~4 alkyl);-C(=O)OH;-CONR'R'';-S(O) 1~2 NR'R'';-S(O) 1~2 (C 1~4 alkyl); and cyano; R b Each occurrence of is independently oxo and R respectively c C optionally substituted with 1 to 4 substituents independently selected from the group consisting of 3~10 Cycloalkyl or C 3~10 cycloalkenyl; Heterocyclyl or heterocycloalkenyl containing 3 to 10 ring atoms, of which 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 and heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R c heterocyclyl or heterocycloalkenyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 and 1 to 4 substituents R independently selected from the group consisting of c heteroaryl, optionally substituted with; and 1 to 4 independently selected substituents R c optionally substituted with C 6~10 aryl; R c each occurrence of is independently selected from halo; cyano; 1 to 6 independently selected R a optionally substituted with C 1~10 Alkyl; C 2~6 Alkenyl; C 2~6 Alkynyl; C 1~4Alkoxy; -S(O) 0~2 (C 1~4 alkyl);-NR e R f ;-OH;-S(O) 1~2 NR'R'';-NO2;-C(=O)(C 1~10 alkyl);-C(=O)O(C 1~4 alkyl);-C(=O)OH;-N(R')C(=O)(C 1~4 alkyl), -C(=O)NR'R'', R g , and -(CH2) 1~2 R g is selected from the group consisting of R d each occurrence of is independently selected from hydrogen, 1 to 3 independently selected R a optionally substituted with C 1~6 Alkyl; -C(O)(C 1~4 alkyl);-C(O)O(C 1~4 alkyl);-CONR'R'';-S(O) 1~2 NR'R'';-S(O) 1~2 (C 1~4 alkyl); -OH; and C 1~4 alkoxy; R e and R f Each occurrence of is independently H;C 1~6 Alkyl; -C(O)(C 1~4 alkyl);-C(O)O(C 1~4 alkyl);-CONR'R'';-S(O) 1~2 NR'R'';-S(O) 1~2 (C 1~4 alkyl); -OH; and C 1~4 alkoxy; R g Each occurrence of is independently oxo and R respectively a C optionally substituted with 1 to 4 substituents independently selected from the group consisting of 3~7 Cycloalkyl or C 3~7 cycloalkenyl; Heterocyclyl or heterocycloalkenyl containing 3 to 7 ring atoms, of which 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 and heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R a heterocyclyl or heterocycloalkenyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 and heteroaryl is selected from the group consisting of 1 to 4 R a heteroaryl, optionally substituted with; and 1 to 4 R a optionally substituted with C 6~10 aryl; Each occurrence of R′ and R″ is independently hydrogen; and C 1~4 alkyl.

[0052] In certain embodiments, L 1 -R 1 does not contain OO, NO, NN, OS, SS or NS bonds.

[0053] In certain embodiments, R 1 When is CN, halo, or -NR'C(O)R'', L 1 must be a bond.

[0054] In certain embodiments, R 1 If is hydrogen, L 1 cannot be a bond.

[0055] In certain embodiments, L 1 -R 1 does not contain OO, NO, NN, OS, SS, or NS bonds, and R 1When is CN, halo, or -NR'C(O)R'', L 1 must be a bond, and R 1 If is hydrogen, L 1 cannot be a bond.

[0056] In certain embodiments, L 1 is a bond, —(C═O)—, *—O(C0-C4 alkylene)-, *—C1-C4 alkylene-, *—NR′(C0-C4 alkylene)-, *—NR′(C═O)(C0-C4 alkylene), or *—(C1-C4 alkylene)-C(═O)—, where alkylene is 1 to 2R a and * is optionally substituted with L 1 indicates the point of attachment to the ring of together with Y to form a heteroaryl ring containing 9 or 10 ring atoms, 1 to 4 ring atoms being heteroatoms, each independently selected from N, N(H), N(R d ) and O, wherein at least one ring in the system is aromatic and heteroaryl is selected from the group consisting of oxo and R c optionally substituted with 1 to 4 substituents independently selected from the group consisting of: wherein X and Y are both CH, or one of X and Y is N and the other is CH; R 1 is R b and R 2 is hydrogen, chloro, fluoro or methyl, R 3 , R 4 and R 5 is hydrogen or halo, R 6 Deuterium, halo and unsubstituted C 1~10 is selected from the group consisting of alkyl, R b teeth, Heterocyclyl or heterocycloalkenyl containing 3 to 10 ring atoms, of which 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O)0~2 and heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R c heterocyclyl or heterocycloalkenyl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 wherein at least one ring in the system is aromatic and the heteroaryl is selected from the group consisting of oxo and R c is heteroaryl optionally substituted with 1 to 4 substituents independently selected from:

[0057] In certain embodiments, L 1 is a bond, —(C═O)—, *—O(C0-C4 alkylene)-, *—C1-C4 alkylene-, *—NR′(C0-C4 alkylene)-, *—NR′(C═O)(C0-C4 alkylene), or *—(C1-C4 alkylene)-C(═O)—, where alkylene is 1 to 2R a and * is optionally substituted with L 1 indicates the point of attachment to the ring of L 1 together with Y form a heteroaryl ring containing 9 or 10 ring atoms, 1 to 4 of which are heteroatoms, each independently selected from N, N(H), N(R d ) and O, wherein at least one ring in the system is aromatic and heteroaryl is selected from the group consisting of oxo and R c optionally substituted with 1 to 4 substituents independently selected from the group consisting of: wherein X and Y are both CH, or one of X and Y is N and the other is CH; R 1 is R b and R 2 is hydrogen, chloro, fluoro or methyl, R 3 , R4 and R 5 is hydrogen or halo, R 6 Deuterium, halo and unsubstituted C 1~10 is selected from the group consisting of alkyl, In the formula, R b contains a hydrogen bond acceptor within seven atoms of the carbon atom between X and Y.

[0058] In certain embodiments, L 1 is a bond, —(C═O)—, *—O(C0-C4 alkylene)-, *—C1-C4 alkylene-, *—NR′(C0-C4 alkylene)-, *—NR′(C═O)(C0-C4 alkylene), or *—(C1-C4 alkylene)-C(═O)—, where alkylene is 1 to 2R a and * is optionally substituted with L 1 indicates the point of attachment to the ring of together with Y to form a heteroaryl ring containing 9 or 10 ring atoms, 1 to 4 ring atoms being heteroatoms, each independently selected from N, N(H), N(R d ) and O, wherein at least one ring in the system is aromatic and heteroaryl is selected from the group consisting of oxo and R c optionally substituted with 1 to 4 substituents independently selected from the group consisting of: wherein X and Y are both CH, or one of X and Y is N and the other is CH; R 1 is R b and R 2 is hydrogen, chloro, fluoro or methyl, R 3 , R 4 and R 5 is hydrogen or halo, n is 0, R b teeth, Heterocyclyl or heterocycloalkenyl containing 5 to 10 ring atoms, of which 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(Rd ), O and S(O) 0~2 and heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R c heterocyclyl or heterocycloalkenyl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 wherein at least one ring in the system is aromatic and the heteroaryl is selected from the group consisting of oxo and R c is heteroaryl optionally substituted with 1 to 4 substituents independently selected from:

[0059] R c Identity of In certain embodiments, R c are independently halo; 1 to 6 independently selected R a optionally substituted with C 1~10 Alkyl; C 1~4 Alkoxy;R g and -(CH2) 1~2 R g is selected from the group consisting of:

[0060] L 1 Identity of In certain embodiments, L 1 is a bond, -(C=O)-, *-O(C0-C4 alkylene)-, *-C1-C4 alkylene-, *-NR'(C0-C4 alkylene)-, *-NR'(C=O)(C0-C4 alkylene), or *-(C1-C4 alkylene)-C(=O)-, where alkylene is selected from the group consisting of 1 to 2 R a and * is optionally substituted with L 1 The points of attachment to the ring are shown.

[0061] In certain embodiments, L 1is a bond, —(C═O)—, *—O(C0-C4 alkylene)-, *—C1-C4 alkylene-, *—NR′(C0-C4 alkylene)-, *—NR′(C═O)(C0-C4 alkylene), or *—(C1-C4 alkylene)-C(═O)—.

[0062] In certain embodiments, L 1 is a bond, -(C=O)-, *-O(C1-C4 alkylene, *-C1-C4 alkylene-, *-(C1-C4 alkylene)-C(=O)-, *-NH'(C0-C4 alkylene)-, or *-NH'(C=O)(C0-C4 alkylene)-, and alkylene is present in the presence of 1 or 2 R a and * indicates a L 1 The attachment points are shown.

[0063] In certain embodiments, L 1 is a bond, —(C═O)—, *—O(C1-C4 alkylene, *—C1-C4 alkylene, or *—(C1-C4 alkylene)-C(═O)—.

[0064] In certain embodiments, L 1 is a bond, *-OCH2-, *-OCH2CH2, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2CH2-, -(C=O)-, or *-(CH2)-C(=O)-.

[0065] In certain embodiments, L 1 is a bond or -CH2-.

[0066] In certain embodiments, L 1 is a bond.

[0067] In certain embodiments, L 1 together with Y form an additional ring fused to the ring containing X and Y, the fused ring system containing 9 or 10 ring atoms, wherein 1 to 4 ring atoms in the additional ring are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), and O, and the additional ring is 1substituted with oxo and R c and optionally further substituted with 1 to 4 substituents independently selected from the group consisting of:

[0068] Identity of X and Y In certain embodiments, X and Y are both CH, or one of X and Y is N and the other is CH.

[0069] In certain embodiments, X and Y are both CH.

[0070] R 1 Identity of In certain embodiments, R 1 is R b is.

[0071] In certain embodiments, R b contains a hydrogen bond acceptor within seven atoms of the carbon atom between X and Y.

[0072] In certain embodiments, R b comprises a hydrogen bond acceptor within 7 atoms of the carbon atom between X and Y, the hydrogen bond acceptor being selected from a carbonyl group, a sulfonyl group, a nitrogen-containing heteroaromatic group, an oxygen-containing heteroaromatic group, and an oxygen-containing aliphatic or alicyclic group.

[0073] In certain embodiments, R b contains a hydrogen bond acceptor within 7 atoms of the carbon atom between X and Y, and the hydrogen bond acceptor is selected from an amide, lactam, carbamate, pyridone, pyrimidinone, piperazinone, pyridazinone, urea, sulfonamide, sulfone, pyrimidine, pyrazine, pyridazine, pyridine, oxazole, isoxazole, oxadiazole, thiazole, thiadiazole, imidazole, pyrazole, oxazole, isoxazole, oxadiazole, oxetane, tetrahydrofuran, tetrahydropyran, or a methoxyalkyl group.

[0074] In certain embodiments, R b teeth, Heterocyclyl or heterocycloalkenyl containing 3 to 10 ring atoms, of which 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 and heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R c heterocyclyl or heterocycloalkenyl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 wherein at least one ring in the system is aromatic and the heteroaryl is selected from the group consisting of oxo and R c is heteroaryl optionally substituted with 1 to 4 substituents independently selected from:

[0075] In certain embodiments, R b teeth, Heterocyclyl or heterocycloalkenyl containing 5 to 10 ring atoms, of which 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 and heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R c heterocyclyl or heterocycloalkenyl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 wherein at least one ring in the system is aromatic and the heteroaryl is selected from the group consisting of oxo and R c is heteroaryl optionally substituted with 1 to 4 substituents independently selected from:

[0076] In certain embodiments, R b teeth, Heterocyclyl or heterocycloalkenyl containing 5 to 10 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O and S(O) 0~2 and at least one heteroatom is N or N(R d ) wherein heterocyclyl or heterocycloalkenyl is selected from oxo and R c heterocyclyl or heterocycloalkenyl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 and at least one heteroatom is selected from the group consisting of N or N(R d ), wherein at least one ring in the system is aromatic and the heteroaryl is selected from oxo and R c is heteroaryl optionally substituted with 1 to 4 substituents independently selected from:

[0077] In certain embodiments, each R c C optionally substituted with halo, 1 to 3 independently selected halo atoms 1~4 Alkyl and C 1~4 alkoxy.

[0078] In certain embodiments, Rb is [ka] [ka] each of which is selected from the group consisting of 1 to 4 independently selected substituents R c is optionally replaced by

[0079] In certain embodiments, R b is a heteroaryl containing 5 to 10 ring atoms, where 1 to 4 ring atoms are N, N(H), N(R d ), O and S(O) 0~2 wherein the heteroaryl is selected from 1 to 4 independently selected R c is optionally replaced by

[0080] In certain embodiments, R b is a heteroaryl containing 5-6 ring atoms, where 1-4 ring atoms are N, N(H), N(R d ), O and S(O) 0~2 wherein the heteroaryl is selected from 1 to 4 independently selected R c is optionally replaced by

[0081] In certain embodiments, R b is a heteroaryl containing 5 ring atoms, where 1 to 4 ring atoms are N, N(H), N(R d ), O and S(O) 0~2 wherein the heteroaryl is selected from 1 to 2 independently selected R c is optionally replaced by

[0082] In certain embodiments, R b is a heteroaryl containing 5 ring atoms, where 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O, and S(O) 0~2 is selected from the group consisting of:

[0083] In certain embodiments, R b teeth, [ka] each of which is selected from the group consisting of 1 to 2 independently selected R c is optionally replaced by

[0084] In certain embodiments, R b teeth, [ka] and optionally R d is CH3.

[0085] In certain embodiments, R b teeth, [ka] and optionally R d is CH3.

[0086] In certain embodiments, R b teeth, [ka] is selected from.

[0087] In certain embodiments, R b teeth, [ka] is.

[0088] In certain embodiments, R b teeth, [ka] is selected from the group consisting of:

[0089] In certain embodiments, R b teeth, [ka] is selected from the group consisting of:

[0090] In certain embodiments, R c is 1 to 6 independently selected R a and -NR e R f optionally substituted with C 1~10 alkyl, and optionally R c is methyl or -NH2.

[0091] In certain embodiments, R b teeth, [ka] is selected from the group consisting of:

[0092] In certain embodiments, R b teeth, [ka] is.

[0093] In certain embodiments, R b teeth, [ka] is.

[0094] In certain embodiments, R c is 1 to 6 independently selected R a and -NR e R f optionally substituted with C 1~10 alkyl, and optionally R c is methyl.

[0095] In certain embodiments, R b teeth, [ka] is.

[0096] In certain embodiments, Rb is a heteroaryl containing 6 ring atoms, where 1 to 4 ring atoms are N, N(H), N(R d ), O and S(O) 0~2 wherein the heteroaryl is selected from 1 to 4 independently selected substituents R c is optionally replaced by

[0097] In certain embodiments, R b is a heteroaryl containing 6 ring atoms, where 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O, and S(O) 0~2 is selected from the group consisting of:

[0098] In certain embodiments, R b teeth, [ka] is selected from the group consisting of:

[0099] In certain embodiments, R b teeth, [ka] is.

[0100] In certain embodiments, R b is a heteroaryl containing 7 to 10 ring atoms, 1 to 4 ring atoms being heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 wherein at least one ring in the system is aromatic and the heteroaryl is selected from the group consisting of 1 to 4 independently selected oxo or R c is optionally replaced by

[0101] In certain embodiments, R bis a heteroaryl containing 9 to 10 ring atoms, 1 to 4 ring atoms being heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 wherein at least one ring in the system is aromatic and the heteroaryl is selected from the group consisting of 1 to 4 independently selected oxo or R c is optionally replaced by

[0102] In certain embodiments, R b is a heteroaryl containing 9 ring atoms, wherein at least one ring in the system is aromatic and 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 and heteroaryl is selected from the group consisting of oxo and R c and optionally substituted with 1 to 4 independently selected from the list consisting of:

[0103] In certain embodiments, R b teeth, [ka] each of which is selected from the group consisting of 1 to 4 independently selected R c is optionally replaced by

[0104] In certain embodiments, R b teeth, [ka] is selected from the group consisting of:

[0105] In certain embodiments, R b is a heteroaryl containing 10 ring atoms, 1 to 4 ring atoms being heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 wherein at least one ring in the system is aromatic and the heteroaryl is selected from the group consisting of 1 to 4 independently selected oxo or Rc is optionally replaced by

[0106] In certain embodiments, R b teeth, [ka] each of which is selected from 1 to 4 independently selected R c is optionally replaced by

[0107] In certain embodiments, R b teeth, [ka] is selected from the group consisting of:

[0108] In certain embodiments, R b is a heterocyclyl or heterocycloalkenyl containing 3 to 10 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, and each independently is selected from N, N(H), N(R d ), O and S(O) 0~2 and heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R c and optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0109] In certain embodiments, R b is a heterocyclyl or heterocycloalkenyl containing 4 to 6 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, and each independently is selected from N, N(H), N(R d ), O and S(O) 0~2 and heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R c and optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0110] In certain embodiments, R bis a heterocyclyl or heterocycloalkenyl containing 5 to 6 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, and each independently is selected from N, N(H), N(R d ), O and S(O) 0~2 and heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R c and optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0111] In certain embodiments, R b is a heterocyclyl or heterocycloalkenyl containing 6 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 and heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R c and optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0112] In certain embodiments, R b is a heterocycloalkenyl containing 6 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 heterocycloalkenyl is selected from the group consisting of oxo and R c and optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0113] In certain embodiments, R b teeth, [ka] is.

[0114] In certain embodiments, R d is CH3.

[0115] In certain embodiments, R b but, [ka] and one to two independently selected R c It is optionally substituted with a substituent.

[0116] In certain embodiments, R b teeth, [ka] is selected from the group consisting of:

[0117] In certain embodiments, R b teeth, [ka] is selected from the group consisting of:

[0118] In certain embodiments, R c or R c Each occurrence of a , C 1~4 Alkoxy, halo, and -NR e R f optionally substituted with C 1~10 alkyl.

[0119] In certain embodiments, R c is selected from the group consisting of methyl, ethyl, -CHF2, -CF3, methoxy, fluoro, chloro, and NH2.

[0120] In certain embodiments, R 1 teeth, [ka] is selected from the group consisting of:

[0121] In certain embodiments, R b is a heterocyclyl containing 6 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(Rd ), O and S(O) 0~2 and heterocyclyl is selected from the group consisting of oxo and R c and optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0122] In certain embodiments, R b but, [ka] each of which is selected from the group consisting of oxo and R c and optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0123] In certain embodiments, R c is methyl, halo, methoxy or CF3.

[0124] In certain embodiments, R b teeth, [ka] is selected from the group consisting of:

[0125] In certain embodiments, R b teeth, [ka] is selected from the group consisting of:

[0126] In certain embodiments, R d is CH3.

[0127] In certain embodiments, R b teeth, [ka] is.

[0128] In certain embodiments, R bis a heterocyclyl or heterocycloalkenyl containing 5 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 and heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R c and optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0129] In certain embodiments, R b is a heterocyclyl containing 5 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 and heterocyclyl is selected from the group consisting of oxo and R c and optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0130] In certain embodiments, R b teeth, [ka] each of which is selected from the group consisting of 1 to 4 R c is optionally replaced by

[0131] In certain embodiments, R c is halo or C 1~6 It is alkyl.

[0132] In certain embodiments, R b teeth, [ka] is selected from the group consisting of:

[0133] In certain embodiments, R b teeth, [ka] is selected from the group consisting of:

[0134] In certain embodiments, R b teeth, [ka] is.

[0135] In certain embodiments, R b is a heterocycloalkenyl containing 5 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 heterocycloalkenyl is selected from the group consisting of oxo and R c and optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0136] In certain embodiments, R b teeth, [ka] and optionally, R b teeth, [ka] is.

[0137] In certain embodiments, R b teeth, [ka] is selected from the group consisting of:

[0138] In certain embodiments, R b is a heterocyclyl or heterocycloalkenyl containing 7 to 10 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, and each independently is selected from N, N(H), N(R d ), O and S(O) 0~2 and heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and Rc and optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0139] In certain embodiments, R b is a heterocyclyl containing 7 to 10 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 and heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R c and optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0140] In certain embodiments, R b is a heterocyclyl containing 7 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 wherein the heterocyclyl is selected from the group consisting of 1 to 4 independently selected substituents R c is optionally replaced by

[0141] In certain embodiments, R b teeth, [ka] each of which is selected from the group consisting of 1 to 4 independently selected substituents R c is optionally replaced by

[0142] In certain embodiments, R b teeth, [ka] is selected from the group consisting of:

[0143] In certain embodiments, R b is a heterocyclyl containing 8 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(Rd ), O and S(O) 0~2 wherein the heterocyclyl is selected from the group consisting of 1 to 4 independently selected substituents R c is optionally replaced by

[0144] In certain embodiments, R b teeth, [ka] each of which is selected from the group consisting of 1 to 4 independently selected substituents R c is optionally replaced by

[0145] In certain embodiments, R b teeth, [ka] is selected from the group consisting of:

[0146] In certain embodiments, R b is a heterocyclyl containing 9 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 and heterocyclyl is selected from the group consisting of oxo and R c and optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0147] In certain embodiments, R b teeth, [ka] each of which is selected from the group consisting of 1 to 4 independently selected substituents R c is optionally replaced by

[0148] In certain embodiments, R d is CH3.

[0149] In certain embodiments, R b teeth, [ka] is selected from the group consisting of:

[0150] In certain embodiments, R b C 3~10 Cycloalkyl or C 3~10 cycloalkenyl, each of which is oxo and R c and optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0151] In certain embodiments, R b but, [ka] and one R c is optionally replaced by

[0152] R 2 Identity of In certain embodiments, R 2 is hydrogen, chloro, fluoro or methyl.

[0153] In certain embodiments, R 2 is chloro.

[0154] R 2 , R 3 , R 4 and R 5 Identity of and value of n In certain embodiments, R 3 , R 4 and R 5 is hydrogen or halo.

[0155] In certain embodiments, R 3 is halo or hydrogen, and R 4 and R 5 is hydrogen.

[0156] In certain embodiments, R 3 , R 4 and R 5 is hydrogen.

[0157] In certain embodiments, R 2 is chloro and R 3 , R 4 and R 5 is hydrogen.

[0158] In certain embodiments, n is 0.

[0159] In certain embodiments, n is 0 and R 3 , R 4 and R 5 is hydrogen, and / or L 1 is a bond, —(C═O)—, *—C1-C4 alkylene-, *—NR′(C0-C4 alkylene)-, *—NR′(C═O)(C0-C4 alkylene), or *—(C1-C4 alkylene)-C(═O)—, where alkylene is selected from 1 to 2 R a and * indicates an L to the ring. 1 The attachment points are shown.

[0160] In certain embodiments, n is 1 or 2.

[0161] R 6 Identity of In certain embodiments, R 6 is deuterium; cyano; 1 to 6 independently selected R a optionally substituted with C 1~10 Alkyl; C 1~4 Alkoxy, C 1~4 haloalkoxy; and -NR e R f and optionally wherein R 6 is selected from the group consisting of deuterium, cyano, chloro, fluoro, methyl, ethyl, -CHF2, methoxy, -OCHF2, and -NH2.

[0162] In certain embodiments, R 6 Deuterium, halo and unsubstituted C 1~10 alkyl.

[0163] In certain embodiments, R 6 is selected from the group consisting of deuterium, fluoro and methyl.

[0164] In certain embodiments, R 6 is deuterium, and optionally n is 4.

[0165] Formulas I-1, I-2, I-3 and I-4 In certain embodiments, the compound is a compound of formula (I-1). [ka]

[0166] In certain embodiments, the compound is a compound of formula (I-2). [ka] In the formula, X is —NH— or —O—.

[0167] In certain embodiments, X is —O—.

[0168] In certain embodiments, the compound is a compound of formula (I-3). [ka]

[0169] In certain embodiments, the compound is a compound of formula (I-4). [ka]

[0170] In certain embodiments, R 2 is chloro.

[0171] In certain embodiments, R b is a heterocyclyl or heterocycloalkenyl containing 3 to 10 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, and each independently is selected from N, N(H), N(R d ), O and S(O) 0~2 and heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R c heterocyclyl or heterocycloalkenyl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Heteroaryl containing 5 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 wherein at least one ring in the system is aromatic and the heteroaryl is selected from the group consisting of oxo and R c is heteroaryl optionally substituted with 1 to 4 substituents independently selected from:

[0172] In certain embodiments, R b is a heterocycloalkenyl containing 6 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 heterocycloalkenyl is selected from the group consisting of oxo and R c and optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0173] In certain embodiments, R b teeth, [ka] each of which is selected from 1 to 2 substituents R c is optionally replaced by

[0174] In certain embodiments, R b but, [ka] which is a function of 1 to 2 independently selected R c is optionally replaced by

[0175] In certain embodiments, R b teeth, [ka] is.

[0176] In certain embodiments, R c or R c Each occurrence of a , C 1~4 Alkoxy, halo, and -NR e R f optionally substituted with C 1~10 alkyl.

[0177] In certain embodiments, R c is selected from the group consisting of methyl, ethyl, -CHF2, -CF3, methoxy, fluoro, chloro, and NH2.

[0178] In certain embodiments, R b teeth, [ka] is selected from the group consisting of:

[0179] In certain embodiments, R b teeth, [ka] is.

[0180] In certain embodiments, R b is a heteroaryl containing 5 ring atoms, where 1 to 4 ring atoms are N, N(H), N(R d), O and S(O) 0~2 wherein the heteroaryl is selected from 1 to 4 independently selected substituents R c is optionally replaced by

[0181] In certain embodiments, R b teeth, [ka] each of which is selected from the group consisting of 1 to 2 independently selected R c is optionally replaced by

[0182] In certain embodiments, R b teeth, [ka] and optionally R d is CH3.

[0183] In certain embodiments, R b teeth, [ka] and optionally wherein R d is CH3.

[0184] In certain embodiments, R b teeth, [ka] is.

[0185] In certain embodiments, R b is a heterocyclyl containing 6 ring atoms, wherein 1 to 3 ring atoms are each independently selected from N, N(R d ), O and S(O) 0~2 and heterocyclyl is selected from the group consisting of oxo and R cand optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0186] In certain embodiments, R b teeth, [ka] is selected from the group consisting of:

[0187] In certain embodiments, R b teeth, [ka] is selected from the group consisting of:

[0188] In certain embodiments, R d is CH3.

[0189] In certain embodiments, R b teeth, [ka] is.

[0190] In certain embodiments, R b is a heteroaryl containing 6 ring atoms, where 1 to 4 ring atoms are N, N(H), N(R d ), O and S(O) 0~2 wherein the heteroaryl is selected from 1 to 4 independently selected R c is optionally replaced by

[0191] In certain embodiments, R b is a heteroaryl containing 6 ring atoms, where 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O, and S(O) 0~2 is selected from the group consisting of:

[0192] In certain embodiments, R b teeth, [ka] is selected from the group consisting of:

[0193] In certain embodiments, R b teeth, [ka] is.

[0194] In certain embodiments, R b is a heteroaryl containing 9 ring atoms, 1 to 4 ring atoms being heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 wherein at least one ring in the system is aromatic and the heteroaryl is selected from the group consisting of oxo and R c and optionally substituted with 1 to 4 independently selected from the group consisting of:

[0195] In certain embodiments, R b teeth, [ka] each of which is selected from the group consisting of 1 to 4 independently selected R c is optionally replaced by

[0196] In certain embodiments, R b teeth, [ka] is selected from the group consisting of:

[0197] In certain embodiments, R b is a heteroaryl containing 10 ring atoms, 1 to 4 ring atoms being heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2wherein at least one ring in the system is aromatic and the heteroaryl is selected from the group consisting of 1 to 4 independently selected oxo and R c is optionally replaced by

[0198] In certain embodiments, R b teeth, [ka] each of which is selected from the group consisting of 1 to 4 independently selected R c is optionally replaced by

[0199] In certain embodiments, R b teeth, [ka] is selected from the group consisting of:

[0200] In certain embodiments, R b is a heterocyclyl containing 7 to 10 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 and heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R c and optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0201] In certain embodiments, R b is a heterocyclyl containing 7 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 wherein the heterocyclyl is selected from the group consisting of 1 to 4 independently selected substituents R c is optionally replaced by

[0202] In certain embodiments, R b teeth, [ka] each of which is selected from the group consisting of 1 to 4 independently selected substituents R c is optionally replaced by

[0203] In certain embodiments, R b teeth, [ka] is selected from the group consisting of:

[0204] In certain embodiments, R b is a heterocyclyl containing 8 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 wherein the heterocyclyl is selected from the group consisting of 1 to 4 independently selected substituents R c is optionally replaced by

[0205] In certain embodiments, R b teeth, [ka] each of which is selected from the group consisting of 1 to 4 independently selected substituents R c is optionally replaced by

[0206] In certain embodiments, R b teeth, [ka] is selected from the group consisting of:

[0207] In certain embodiments, R b is a heterocyclyl containing 9 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2and heterocyclyl is selected from the group consisting of oxo and R c and optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0208] In certain embodiments, R b but, [ka] each of which is selected from the group consisting of oxo and R c and optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0209] In certain embodiments, R d is CH3.

[0210] In certain embodiments, R b teeth, [ka] is selected from the group consisting of:

[0211] In certain embodiments, R 2 is chloro.

[0212] Formulas (Ia) and (Ib) In certain embodiments, the compound is of formula (Ia). [ka]

[0213] In certain embodiments, the compound is of formula (Ib). [ka]

[0214] Certain compounds of formula (I), (II), (III), (IV) and (V) In certain embodiments, the compound is selected from the group consisting of the compounds of Table C1 or a pharmaceutically acceptable salt thereof.

[0215] In certain embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0216] In certain embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0217] In certain embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0218] In certain embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0219] In certain embodiments, the compound is present in a racemic mixture. In certain embodiments, the compound in the racemic mixture is [ka] or a pharmaceutically acceptable salt thereof.

[0220] In certain embodiments, the disclosure features a pharmaceutical composition including any of the compounds described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0221] In some embodiments, the compound is [ka] isn't it.

[0222] In some embodiments, the compound has a % Dmax of 20% or greater.

[0223] In some embodiments, the present disclosure provides a compound of formula (V): [ka] or a pharmaceutically acceptable salt thereof, wherein L 1 teeth, ·It is a bond; *-O(C0-C4 alkylene)-, *-S(C0-C4 alkylene)-, *-C1-C4 alkylene, or *-NR'(C0-C4 alkylene)-, *-NR'(C=O)(C0-C4 alkylene)-, -(C1-C4 alkylene)-C(=O)-*, *-(C1-C4 alkylene)-C(=O)-, wherein alkylene is selected from the group consisting of 1 to 2 R a and * represents L to the ring containing X and Y. 1 indicates the point of attachment of -(C=O)-; or together with Y, form an additional ring fused to the ring containing X and Y, the fused ring system containing 9 or 10 ring atoms, 1 to 4 ring atoms in the additional ring being heteroatoms, each independently selected from N, N(H), N(R d ) and O, and the additional ring is substituted with R and is selected from the group consisting of oxo and R c optionally further substituted with 1 to 4 substituents independently selected from the group consisting of: each of X and Y is independently selected from the group consisting of N and CH; R 1 is hydrogen, deuterium, R b , -OR b , -S(O) 0~2 R b , -N(R')R b , CN, halo, and -NR'C(O)R'', R 2 is selected from the group consisting of hydrogen, deuterium, CH3, CHF2, CF3, OMe, F, Cl, and Br; R 3 , R 4 and R 5 each independently represents hydrogen and R c is selected from the group consisting of R 6 each of which is selected from deuterium, halo; cyano; and 1 to 6 independently selected R a optionally substituted with C 1~10 alkyl; 1 to 4 independently selected R a optionally substituted with C 3~6 Cycloalkyl; C 2~6 Alkenyl; C 2~6 Alkynyl; C 1~4 Alkoxy; -S(O) 0~2 (C 1~4 alkyl);-NR e R f ;-OH;-S(O) 1~2 NR'R'';-NO2;-C(=O)(C 1~10 alkyl);-C(=O)O(C 1~4 alkyl);-C(=O)OH;-N(R')C(=O)(C 1~4 alkyl), -C(=O)NR'R'', R g , and -(CH2) 1~2 R g and n is selected from 0, 1, 2 and 3; R 7 is selected from the group consisting of hydrogen, deuterium, CH3, CHF2, CF3, Ome, F, Cl and Br; R a each occurrence independently represents -OH; -halo; -NR e R f ;C 1~4 Alkoxy;C 1~4 Haloalkoxy; -C(=O)O(C 1~4 alkyl);-C(=O)(C 1~4 alkyl);-C(=O)OH;-CONR'R'';-S(O) 1~2 NR'R'';-S(O) 1~2(C 1~4 alkyl); and cyano; R b each occurrence of contains a hydrogen bond acceptor, R c each occurrence independently represents deuterium; halo; cyano; 1 to 6 independently selected R a optionally substituted with C 1~10 alkyl; 1 to 4 independently selected R a optionally substituted with C 3~6 Cycloalkyl; C 2~6 Alkenyl; C 2~6 Alkynyl; C 1~4 Alkoxy; -S(O) 0~2 (C 1~4 alkyl);-NR e R f ;-OH;-S(O) 1~2 NR'R'';-NO2;-C(=O)(C 1~10 alkyl);-C(=O)O(C 1~4 alkyl);-C(=O)OH;-N(R')C(=O)(C 1~4 alkyl), -C(=O)NR'R'', R g , and -(CH2) 1~2 R g is selected from the group consisting of R d Each occurrence of is independently selected from hydrogen, deuterium, and 1 to 3 independently selected R a optionally substituted with C 1~6 Alkyl; -C(O)(C 1~4 alkyl);-C(O)O(C 1~4 alkyl);-CONR'R'';-S(O) 1~2 NR'R'';-S(O) 1~2 (C 1~4 alkyl); -OH; and C 1~4 alkoxy; R e and R f Each occurrence of is independently H; deuterium; C 1~6 Alkyl; -C(O)(C 1~4 alkyl);-C(O)O(C 1~4alkyl);-CONR'R'';-S(O) 1~2 NR'R'';-S(O) 1~2 (C 1~4 alkyl); -OH; and C 1~4 alkoxy; R g Each occurrence of is independently oxo and R respectively a C optionally substituted with 1 to 4 substituents independently selected from the group consisting of 3~7 Cycloalkyl or C 3~7 cycloalkenyl; Heterocyclyl or heterocycloalkenyl containing 3 to 7 ring atoms, of which 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 and heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R a heterocyclyl or heterocycloalkenyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 wherein at least one ring in the system is aromatic and the heteroaryl is selected from the group consisting of 1 to 4 oxo or R a heteroaryl, optionally substituted with; and 1 to 4 R a optionally substituted with C 6~10 aryl; Each occurrence of R′ and R″ is independently hydrogen; and C 1~4 alkyl.

[0224] R b In some embodiments, R b contains a hydrogen bond acceptor within 7 atoms of the carbon atom between X and Y. In some embodiments, R bcontains a hydrogen bond acceptor within 6 atoms of the carbon atom between X and Y. In some embodiments, R b contains a hydrogen bond acceptor within 5 atoms of the carbon atom between X and Y. In some embodiments, R b contains a hydrogen bond acceptor within 4 atoms of the carbon atom between X and Y. In some embodiments, R b contains a hydrogen bond acceptor within 3 atoms of the carbon atom between X and Y.

[0225] Hydrogen bond acceptor groups R b In some embodiments where comprises a hydrogen bond acceptor, the hydrogen bond acceptor is selected from a carbonyl group, a sulfonyl group, a nitrogen-containing heteroaromatic group, an oxygen-containing heteroaromatic group, and an oxygen-containing aliphatic or alicyclic group.

[0226] R b In some embodiments, wherein comprises a hydrogen bond acceptor, the hydrogen bond acceptor is selected from an amide, a lactam, a carbamate, a pyridone, a pyrimidinone, a piperazinone, a pyridazinone, a urea, a sulfonamide, a sulfone, a pyrimidine, a pyrazine, a pyridazine, a pyridine, an oxazole, an isoxazole, an oxadiazole, a thiazole, a thiadiazole, an imidazole, a pyrazole, an oxazole, an isoxazole, an oxetan, a tetrahydrofuran, a tetrahydropyran, or a methoxyalkyl group.

[0227] R b In some embodiments, wherein comprises a hydrogen bond acceptor, the hydrogen bond acceptor is [ka] [ka] [ka] [ka] [ka] [ka] is selected from.

[0228] Compound of formula (IV) In one aspect, the disclosure features a compound of formula (IV) or a pharmaceutically acceptable salt thereof: [ka] or a pharmaceutically acceptable salt thereof, L 1 teeth, ·It is a bond; -O(C0-C4 alkylene)-, *-S(C0-C4 alkylene)-, *-C1-C4 alkylene, or *-NR'(C0-C4 alkylene)-, *-NR'(C=O)(C0-C4 alkylene)-, -(C1-C4 alkylene)-C(=O)-, *-(C1-C4 alkylene)-C(=O)-, wherein alkylene is selected from the group consisting of 1 to 2 R a and * represents L to the ring containing X and Y. 1 indicates the point of attachment of ·-(C=O)-; each of X and Y is independently selected from the group consisting of N and CH; R 1 is hydrogen, R b , -OR b , -SR b , -N(R')R b , CN, halo, and -NR'C(O)R'', However, -L 1 -R 1 does not contain OO, NO, NN, OS, SS or NS bonds, and R 1 When is CN, halo, or -NR'C(O)R'', L 1 must be a bond, and further provided that R 1 If is hydrogen, L 1 cannot be a bond, R 2is selected from the group consisting of hydrogen, CH3, CHF2, CF3, OMe, F, and Cl; R 3 , R 4 and R 5 each independently represents hydrogen and R c selected from the group consisting of: R 6 Each of the is independently selected R c and n is selected from 0, 1, 2 and 3; R a each occurrence independently represents -OH; -halo; -NR e R f ;C 1~4 Alkoxy;C 1~4 Haloalkoxy; -C(=O)O(C 1~4 alkyl);-C(=O)(C 1~4 alkyl);-C(=O)OH;-CONR'R'';-S(O) 1~2 NR'R'';-S(O) 1~2 (C 1~4 alkyl); and cyano; R b Each occurrence of is independently oxo and R respectively c C optionally substituted with 1 to 4 substituents independently selected from the group consisting of 3~10 Cycloalkyl or C 3~10 cycloalkenyl; Heterocyclyl or heterocycloalkenyl containing 3 to 10 ring atoms, of which 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 and heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R c heterocyclyl or heterocycloalkenyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O)0~2 and 1 to 4 substituents R independently selected from the group consisting of c heteroaryl, optionally substituted with; and 1 to 4 independently selected substituents R c optionally substituted with C 6~10 aryl; R c each occurrence of is independently selected from halo; cyano; 1 to 6 independently selected R a optionally substituted with C 1~10 Alkyl; C 2~6 Alkenyl; C 2~6 Alkynyl; C 1~4 Alkoxy; -S(O) 0~2 (C 1~4 alkyl);-NR e R f ;-OH;-S(O) 1~2 NR'R'';-NO2;-C(=O)(C 1~10 alkyl);-C(=O)O(C 1~4 alkyl);-C(=O)OH;-N(R')C(=O)(C 1~4 alkyl), -C(=O)NR'R'', R g , and -(CH2) 1~2 R g is selected from the group consisting of R d each occurrence of is independently selected from hydrogen, 1 to 3 independently selected R a optionally substituted with C 1~6 Alkyl; -C(O)(C 1~4 alkyl);-C(O)O(C 1~4 alkyl);-CONR'R'';-S(O) 1~2 NR'R'';-S(O) 1~2 (C 1~4 alkyl); -OH; and C 1~4 alkoxy; R e and R f Each occurrence of is independently H;C 1~6 Alkyl; -C(O)(C 1~4 alkyl);-C(O)O(C 1~4alkyl);-CONR'R'';-S(O) 1~2 NR'R'';-S(O) 1~2 (C 1~4 alkyl); -OH; and C 1~4 alkoxy; R g Each occurrence of is independently oxo and R respectively a C optionally substituted with 1 to 4 substituents independently selected from the group consisting of 3~7 Cycloalkyl or C 3~7 cycloalkenyl; Heterocyclyl or heterocycloalkenyl containing 3 to 7 ring atoms, of which 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 and heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R a heterocyclyl or heterocycloalkenyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 and heteroaryl is selected from the group consisting of 1 to 4 R a heteroaryl, optionally substituted with; and 1 to 4 R a optionally substituted with C 6~10 aryl; Each occurrence of R′ and R″ is independently hydrogen; and C 1~4 alkyl.

[0229] Variable L 1 In some embodiments, L 1is *-O(C0-C4 alkylene)-, *-S(C0-C4 alkylene)-, *-C1-C4 alkylene, or *-NR'(C0-C4 alkylene)-, and alkylene is one or two R a and * is L 1 The point of attachment to the phenyl ring is indicated.

[0230] In some embodiments, L 1 is *-O(C0-C4 alkylene)-, where the alkylene portion is one to two R a In some embodiments, L 1 is *-O(C1-C4 alkylene)-, and the alkylene portion is one to two R a In some embodiments, L 1 is unsubstituted —O(C1-C4 alkylene)-. For example, L 1 can be *-OCH2- or *-OCH2CH2.

[0231] In certain embodiments, L 1 is *-OCH2-.

[0232] In certain embodiments, L 1 is 1 to 2 R a In certain embodiments, L is —C1-C4 alkylene- optionally substituted with 1 is unsubstituted —C1-C4 alkylene. 1 is selected from the group consisting of -CH2-, -CH(CH3)-, -C(CH3)2-, and -CH2CH2CH2-. For example, L 1 can be -CH2-.

[0233] In certain embodiments, L 1 is *-NR'(C0-C4 alkylene)-, and the alkylene portion may optionally contain 1 to 2 R a In certain embodiments, L 1is -NR'(C1-C4 alkylene)-, and the alkylene portion may optionally be 1 to 2 R a In certain embodiments, L 1 is —NR′(C1-C4 alkylene)-, where the alkylene portion is unsubstituted. In certain embodiments, —R′— is H. For example, L 1 teeth, [ka] In yet another example, L 1 can be -NH-.

[0234] In certain embodiments, L 1 is -(C=O)-.

[0235] Variable X and Y In certain embodiments, X and Y are both CH.

[0236] In certain embodiments, one of X and Y is N and the other of X and Y is CH.

[0237] In certain embodiments, X is N and Y is CH.

[0238] In certain embodiments, Y is N and X is CH.

[0239] Variable R 1 In some embodiments, R 1 is hydrogen.

[0240] In some embodiments, R 1 is R b is.

[0241] In some embodiments, R 1 -OR b , and -N(R')R b is selected from the group consisting of:

[0242] In some embodiments, R b is a heteroaryl containing 5 to 10 ring atoms, where 1 to 4 ring atoms are N, N(H), N(R d ), O and S(O) 0~2 wherein the heteroaryl is selected from 1 to 4 independently selected R c In some embodiments, R b is a heteroaryl containing 5 to 6 ring atoms, wherein 1 to 4 ring atoms are each independently selected from N, N(H), (R d ), O and S(O) 0~2 and the heteroaryl is optionally a heteroatom selected from the group consisting of 1 to 4 independently selected R c is replaced by .

[0243] In certain embodiments, R b is a heteroaryl containing 5 ring atoms, where 1 to 4 ring atoms are N, N(H), N(R d ), O and S(O) 0~2 wherein the heteroaryl is selected from 1 to 2 independently selected R c is optionally replaced by

[0244] In certain embodiments, R b is a heteroaryl containing 5 ring atoms, where 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O, and S(O) 0~2 In certain embodiments, R b teeth, [ka] each of which is selected from the group consisting of 1 to 2 independently selected R c is optionally replaced by

[0245] In certain embodiments, R b teeth, [ka] and optionally R d is CH3.

[0246] In certain embodiments, R b teeth, [ka] and optionally R d is CH3.

[0247] In certain embodiments, R b teeth, [ka] is selected from.

[0248] For example, R b teeth, [ka] It could be.

[0249] In certain embodiments, R b teeth, [ka] In certain embodiments, R b teeth, [ka] In certain embodiments, R c is 1 to 6 independently selected R a and -NR e R f optionally substituted with C 1~10 alkyl, and optionally R cis methyl or -NH. In certain embodiments, R b teeth, [ka] is selected from the group consisting of:

[0250] In certain embodiments, R b teeth, [ka] In certain embodiments, R b teeth, [ka] In certain embodiments, R c is 1 to 6 independently selected R a and -NR e R f optionally substituted with C 1~10 alkyl, and optionally R c is methyl. In certain embodiments, R b teeth, [ka] is.

[0251] In some embodiments, R b is a heteroaryl containing 6 ring atoms, where 1 to 4 ring atoms are N, N(H), N(R d ), O and S(O) 0~2 wherein the heteroaryl is selected from 1 to 4 independently selected substituents R c In certain embodiments, R b is a heteroaryl containing 6 ring atoms, where 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O, and S(O) 0~2 In certain embodiments, Rb teeth, [ka] For example, R b teeth, [ka] It could be.

[0252] In some embodiments, R b is a heteroaryl containing 7 to 10 ring atoms, where 1 to 4 ring atoms are N, N(H), N(R d ), O and S(O) 0~2 wherein the heteroaryl is selected from 1 to 4 independently selected R c In some embodiments, R b is a heteroaryl containing 9 to 10 ring atoms, wherein 1 to 4 ring atoms are each independently selected from N, N(H), (R d ), O and S(O) 0~2 and the heteroaryl is optionally a heteroatom selected from the group consisting of 1 to 4 independently selected R c is replaced by .

[0253] In some embodiments, R b is a heteroaryl containing 9 ring atoms, where 1 to 4 ring atoms are N, N(H), N(R d ), O and S(O) 0~2 and R are heteroatoms independently selected from the group consisting of: c In certain embodiments, R b teeth, [ka] each of which is selected from the group consisting of 1 to 4 independently selected R cis optionally replaced by

[0254] In certain embodiments, R b teeth, [ka] is selected from the group consisting of:

[0255] In some embodiments, R b is a heteroaryl containing 10 ring atoms, where 1 to 4 ring atoms are N, N(H), N(R d ), O and S(O) 0~2 wherein the heteroaryl is selected from 1 to 4 independently selected R c In certain embodiments, R b teeth, [ka] each of which is selected from the group consisting of 1 to 4 independently selected R c In certain embodiments, R b teeth, [ka] is selected from the group consisting of:

[0256] In some embodiments, R b is a heterocyclyl or heterocycloalkenyl containing 3 to 10 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, and each independently is selected from N, N(H), N(R d ), O and S(O) 0~2 and heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R c and optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0257] In some embodiments, R bis a heterocyclyl or heterocycloalkenyl containing 4 to 6 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, and each independently is selected from N, N(H), N(R d ), O and S(O) 0~2 and heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R c and optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0258] In some embodiments, R b is a heterocyclyl or heterocycloalkenyl containing 5 to 6 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, and each independently is selected from N, N(H), N(R d ), O and S(O) 0~2 and heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R c and optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0259] In certain embodiments, R b is a heterocyclyl or heterocycloalkenyl containing 6 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 and heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R c and optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0260] In certain embodiments, R b is a heterocycloalkenyl containing 6 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 heterocycloalkenyl is selected from the group consisting of oxo and R c In certain embodiments, R b teeth, [ka] In certain embodiments, R d is CH3.

[0261] For example, R b teeth, [ka] It could be.

[0262] Another example is R b teeth, [ka] which is a group consisting of 1 to 2 independently selected substituents R c is replaced by .

[0263] In certain embodiments, R b teeth, [ka] In certain of these embodiments, R c Each occurrence of a , C 1~4 Alkoxy, halo, and -NR e R f optionally substituted with C 1~10 In certain embodiments, R c is selected from the group consisting of methyl, ethyl, -CHF2, -CF3, methoxy, fluoro, chloro, and NH2. In certain embodiments, R b teeth, [ka] is selected from the group consisting of:

[0264] In some embodiments, R bis a heterocyclyl containing 6 ring atoms, wherein 1 to 3 ring atoms are each independently selected from N, N(H), N(R d ), O, and S(O) 0~2 and heterocyclyl is selected from the group consisting of oxo and R c In certain embodiments, R b but, [ka] each of which is selected from the group consisting of oxo and R c In certain of these embodiments, R is optionally substituted with 1 to 4 substituents independently selected from the group consisting of: c is methyl, halo, methoxy or CF3.

[0265] In certain embodiments, R b teeth, [ka] is selected from the group consisting of:

[0266] In certain embodiments, R b teeth, [ka] In certain of these embodiments, R d is CH3.

[0267] For example, R b teeth, [ka] It could be.

[0268] In some embodiments, R bis a heterocyclyl or heterocycloalkenyl containing 5 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 and heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R c and optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0269] In some embodiments, R b is a heterocyclyl containing 5 ring atoms, wherein 1 to 3 ring atoms are each independently selected from N, N(H), N(R d ), O, and S(O) 0~2 and heterocyclyl is selected from the group consisting of oxo and R c In some embodiments, R b teeth, [ka] and 1 to 4 R c In certain of these embodiments, R c is halo or C 1~6 It is alkyl.

[0270] In certain embodiments, R b teeth, [ka] is selected from the group consisting of:

[0271] In some embodiments, R b teeth, [ka] is selected from the group consisting of:

[0272] For example, R b teeth, [ka] It could be.

[0273] In some embodiments, R b is a heterocycloalkenyl containing 5 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 heterocycloalkenyl is selected from the group consisting of oxo and R c and optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0274] In certain embodiments, R b teeth, [ka] and optionally, R b teeth, [ka] is.

[0275] In some embodiments, R b teeth, [ka] is selected from the group consisting of:

[0276] In some embodiments, R b is a heterocyclyl or heterocycloalkenyl containing 7 to 10 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, and each independently is selected from N, N(H), N(R d ), O and S(O) 0~2 and heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R c and optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0277] In some embodiments, R b is a heterocyclyl containing 7 to 10 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 and heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R c and optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0278] In some embodiments, R b is a heterocyclyl containing 7 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 wherein the heterocyclyl is selected from the group consisting of 1 to 4 independently selected substituents R c In certain embodiments, R b teeth, [ka] each of which is selected from the group consisting of 1 to 4 independently selected substituents R c In certain embodiments, R b teeth, [ka] is selected from the group consisting of:

[0279] In some embodiments, R b is a heterocyclyl containing 8 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 wherein the heterocyclyl is selected from the group consisting of 1 to 4 independently selected substituents R c In certain embodiments, R b teeth, [ka] each of which is selected from the group consisting of 1 to 4 independently selected substituents R c In certain embodiments, R b teeth, [ka] is selected from the group consisting of:

[0280] In some embodiments, R b is a heterocyclyl containing 9 ring atoms, wherein 1 to 3 ring atoms are each independently selected from N, N(H), N(R d ), O, and S(O) 0~2 and heterocyclyl is selected from the group consisting of oxo and R c In certain embodiments, R b teeth, [ka] each of which is selected from the group consisting of oxo and R c In some of these embodiments, R is optionally substituted with 1 to 4 substituents independently selected from the group consisting of: d is CH3. In certain embodiments, R b teeth, [ka] is selected from the group consisting of:

[0281] In some embodiments, R b C 3~10 Cycloalkyl or C 3~10 cycloalkenyl, each of which is oxo and R c In certain embodiments, R b teeth, [ka] and optionally one R c is replaced by

[0282] Variable R 2 , R 3 , R 4 , and R 5 In some embodiments, R 2 is hydrogen.

[0283] In some embodiments, R 2 is chloro or fluoro. In certain embodiments, R 2 is chloro.

[0284] In some embodiments, R 3 , R 4 and R 5 is hydrogen.

[0285] In some embodiments, R 2 is chloro and R 3 , R 4 and R 5 is hydrogen.

[0286] Variables n and R 6 In some embodiments, n is 0.

[0287] In some embodiments, n is 1 or 2.

[0288] In some embodiments, R 6 is halo; cyano; 1 to 6 independently selected R a optionally substituted with C 1~10 Alkyl; C 1~4 Alkoxy, C 1~4 haloalkoxy; and -NR e R f and optionally wherein R 6is selected from the group consisting of cyano, chloro, fluoro, methyl, ethyl, —CHF 2 , methoxy, —OCHF 2 and —NH 2 .

[0289] Non-limiting combinations Formula (I-1) In some embodiments, the compound of formula (IV) is a compound of formula (I-1). [ka]

[0290] Formula (I-2) In some embodiments, the compound of formula (IV) is a compound of formula (I-2). [ka] In the formula, X is —NH— or —O—.

[0291] In certain embodiments of Formula (I-2), X is —NH—.

[0292] In certain embodiments of formula (I-2), X is —O—.

[0293] In certain embodiments of Formula (I-2), R 2 is chloro.

[0294] In certain embodiments of Formula (I-2), R b is a heteroaryl containing 5 ring atoms, where 1 to 4 ring atoms are N, N(H), N(R d ), O and S(O) 0~2 wherein the heteroaryl is optionally selected from 1 to 4 independently selected R c is replaced by .

[0295] In certain embodiments of Formula (I-2), R b teeth, [ka] each of which is selected from the group consisting of 1 to 2 independently selected substituents R c In certain embodiments of formula (I-2), R b teeth, [ka] and optionally R d is CH3. In certain embodiments of Formula (I-2), R b teeth, [ka] and optionally R d is CH3.

[0296] In certain embodiments of Formula (I-2), R b teeth, [ka] is selected from the group consisting of:

[0297] In certain embodiments of Formula (I-2), R b teeth, [ka] is selected from the group consisting of:

[0298] Formula (I-3) In some embodiments, the compound of formula (IV) is a compound of formula (I-3). [ka]

[0299] In certain embodiments of Formula (I-3), R 2 is chloro.

[0300] In certain embodiments of Formula (I-2), R bis a heterocycloalkenyl containing 6 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 heterocycloalkenyl is selected from the group consisting of oxo and R c and optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0301] In certain embodiments of Formula (I-3), R b teeth, [ka] each of which is selected from 1 to 2 substituents R c In certain embodiments of formula (I-3), R b teeth, [ka] which is a function of 1 to 2 independently selected R c is optionally replaced by

[0302] For example, R b teeth, [ka] It could be.

[0303] In certain embodiments of Formula (I-3), R b teeth, [ka] In certain of these embodiments, R c Each occurrence of a , C 1~4 Alkoxy, halo, and -NR e R f optionally substituted with C 1~10 In certain embodiments, Rc is selected from the group consisting of methyl, ethyl, -CHF2, -CF3, methoxy, fluoro, chloro, and NH2. In some of these embodiments, R b teeth, [ka] is selected from the group consisting of:

[0304] In certain embodiments of Formula (I-3), R b is a heteroaryl containing 5 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is selected from the group consisting of 1 to 4 independently selected substituents R c In certain embodiments of formula (I-3), R b teeth, [ka] each of which is selected from the group consisting of 1 to 2 independently selected R c is optionally replaced by

[0305] In certain of these embodiments, R b teeth, [ka] and optionally R d is CH3.

[0306] For example, R b teeth, [ka] and possibly R d is CH3.

[0307] In yet another example, R b teeth, [ka] It could be.

[0308] In certain embodiments of Formula (I-3), R b is a heterocyclyl containing 6 ring atoms, wherein 1 to 3 ring atoms are each independently selected from N, N(R d ), O and S(O) 0~2 and heterocyclyl is selected from the group consisting of oxo and R c In some of these embodiments, R is optionally substituted with 1 to 4 substituents independently selected from the group consisting of: b teeth, [ka] is selected from the group consisting of:

[0309] In some of these embodiments, R b teeth, [ka] In certain of these embodiments, R d is CH3.

[0310] For example, R b teeth, [ka] It could be.

[0311] In certain embodiments of Formula (I-3), R b is a heteroaryl containing 6 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 and heteroaryl is selected from the group consisting of 1 to 4 independently selected R c is optionally replaced by

[0312] In certain embodiments of Formula (I-3), R b is a heteroaryl containing 6 ring atoms, where 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 is selected from the group consisting of:

[0313] In certain embodiments of Formula (I-3), R b teeth, [ka] For example, R b teeth, [ka] It could be.

[0314] In certain embodiments of Formula (I-3), R 2 is chloro.

[0315] Formula (I-4) In some embodiments, the compound of formula (IV) is a compound of formula (I-4). [ka]

[0316] In some embodiments of formula (I-4), R 2 is chloro.

[0317] In some embodiments of formula (I-4), R b is a heterocycloalkenyl containing 6 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 heterocycloalkenyl is selected from the group consisting of oxo and R c and optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0318] In some embodiments of formula (I-4), R b teeth, [ka] and 1 to 4 independently selected R c For example, R b teeth, [ka] is.

[0319] In some embodiments of formula (I-4), R b is a heterocyclyl containing 6 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 and heterocyclyl is selected from the group consisting of oxo and R c and optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0320] In certain embodiments, R b teeth, [ka] is selected from the group consisting of:

[0321] In certain embodiments, R b teeth, [ka] is selected from the group consisting of:

[0322] In certain of these embodiments, R d is CH3.

[0323] For example, R b teeth, [ka] It could be.

[0324] Formula (I-5) In some embodiments, the compound of formula (IV) is a compound of formula (I-5). [ka]

[0325] In some embodiments of formula (I-5), R 2 is chloro.

[0326] In some embodiments of formula (I-5), R b is a heterocyclyl containing 5 ring atoms, wherein 1 to 3 ring atoms are heteroatoms and each independently represent N, N(H), N(R d ), O and S(O) 0~2 and heterocyclyl is selected from the group consisting of oxo and R c In some of these embodiments, R is optionally substituted with 1 to 4 substituents independently selected from the group consisting of: b teeth, [ka] In some of these embodiments, R b teeth, [ka] For example, R b teeth, [ka] It could be.

[0327] In some embodiments of formula (I-1), (I-2, (I-3), (I-4), or (I-5), R b is a heteroaryl containing 9 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2and heteroaryl is selected from the group consisting of oxo and R c and optionally substituted with 1 to 4 independently selected from the group consisting of:

[0328] In some embodiments of formula (I-1), (I-2), (I-3), (I-4), or (I-5), R b teeth, [ka] each of which is selected from the group consisting of 1 to 4 independently selected R c In some of these embodiments, R b teeth, [ka] is selected from the group consisting of:

[0329] In some embodiments of formula (I-1), (I-2, (I-3), (I-4), or (I-5), R b is a heteroaryl containing 10 ring atoms, where 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 and heteroaryl is optionally selected from the group consisting of 1 to 4 independently selected R c In some of these embodiments, R b teeth, [ka] each of which is selected from the group consisting of 1 to 4 independently selected R c In some of these embodiments, R b teeth, [ka] is selected from the group consisting of:

[0330] In some embodiments of formula (I-1), (I-2, (I-3), (I-4), or (I-5), R b is a heterocyclyl containing 7 to 10 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 and heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R c and optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0331] In some embodiments of formula (I-1), (I-2, (I-3), (I-4), or (I-5), R b is a heterocyclyl containing 7 ring atoms, wherein 1 to 3 ring atoms are heteroatoms and each independently is selected from N, N(H), N(R d ), O and S(O) 0~2 and heterocyclyl is selected from the group consisting of 1 to 4 independently selected substituents R c In some of these embodiments, R b teeth, [ka] each of which is selected from the group consisting of 1 to 4 independently selected substituents R c In some of these embodiments, R b teeth, [ka] is selected from the group consisting of:

[0332] In some embodiments of formula (I-1), (I-2, (I-3), (I-4), or (I-5), R b is a heterocyclyl containing 8 ring atoms, wherein 1 to 3 ring atoms are heteroatoms and each independently is selected from N, N(H), N(R d ), O and S(O) 0~2and heterocyclyl is selected from the group consisting of 1 to 4 independently selected substituents R c In some of these embodiments, R b teeth, [ka] each of which is selected from the group consisting of 1 to 4 independently selected substituents R c In some of these embodiments, R b teeth, [ka] is selected from the group consisting of:

[0333] In some embodiments of formula (I-1), (I-2, (I-3), (I-4), or (I-5), R b is a heterocyclyl containing 9 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0~2 and heterocyclyl is selected from the group consisting of oxo and R c In some embodiments of formula (I-1), (I-2), (I-3), (I-4), or (I-5), R b teeth, [ka] and R c In certain embodiments, R d is CH3. In some of these embodiments, R b teeth, [ka] is selected from the group consisting of:

[0334] Formulas (Ia) and (Ib) In some embodiments, the compound of formula (IV) is a compound of formula (Ia). [ka]

[0335] In some embodiments, the compound of formula (IV) is a compound of formula (Ib). [ka]

[0336] Pharmaceutical Composition In another aspect, the disclosure provides a pharmaceutical composition comprising 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.

[0337] The pharmaceutical compositions provided herein can be administered by a variety of routes, including, but not limited to, oral (enteral), parenteral (by injection), rectal, transdermal, intradermal, intrathecal, subcutaneous (SC), intravenous (IV), intramuscular (IM), and intranasal administration.

[0338] Compositions for oral administration can be in the form of bulk liquid solutions or suspensions, or bulk powders. In some embodiments, the compositions are provided in unit dosage forms to facilitate accurate administration. The term "unit dosage form" refers to physically discrete units suitable as unit dosages for human subjects and other mammals, each unit containing a predetermined amount of active ingredient calculated to produce a desired therapeutic effect in combination with an appropriate pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampoules or syringes of liquid compositions, or pills, tablets, capsules, etc. for solid compositions. In such compositions, the compound is usually a minor component, with the remainder being various vehicles or excipients and processing aids useful for forming the desired dosage form.

[0339] Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors, etc. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth, or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetener such as sucrose or saccharin; or a flavoring such as peppermint, methyl salicylate, or orange flavoring.

[0340] Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline or other injectable excipients known in the art. As noted above, the active compound in such compositions is typically a minor component, with the remainder being the injectable excipient, etc.

[0341] Transdermal compositions are typically formulated as topical ointments or creams containing active ingredients.When formulated as an ointment, the active ingredient is typically combined with either a paraffinic ointment base or a water-miscible ointment base.Alternatively, the active ingredient may be formulated into a cream, for example, including an oil-in-water cream base.Such transdermal formulations are well known in the art and generally contain additional ingredients to enhance the transdermal penetration of the active ingredient or the stability of the formulation.All such known transdermal formulations and ingredients are included within the scope of the disclosure provided herein.

[0342] The compounds provided herein can also be administered by a transdermal device. Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type or of a solid matrix variety.

[0343] The above ingredients for orally administrable, injectable, or topically administrable compositions are merely representative. Other materials, processing techniques, and the like are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0344] How to use In one aspect, the disclosure features a method of degrading VAV1 in a subject, the method including administering to the subject an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the compound mediates the interaction of the VAV1 protein with an E3 ligase, thereby increasing degradation of the VAV1 protein. In some embodiments, VAV1 is a T cell regulator. In one embodiment, the compound interacts with an E3 ligase prior to the interaction of VAV1 with the E3 ligase. In some embodiments, the E3 ligase includes cereblon.

[0345] In another aspect, the disclosure features a method for degrading VAV1, the method including: (i) contacting an E3 ligase with a compound described herein or a pharmaceutically acceptable salt thereof; and (ii) allowing the contacted E3 ligase to interact with VAV1, thereby degrading VAV1.

[0346] In some embodiments, the compounds described herein can bind to a specific amino acid sequence in VAV1, thereby causing degradation of VAV1. In other embodiments, such degradation of VAV1 is mediated by a compound that interacts with both the specific amino acid sequence in VAV1 and an E3 ligase. In other embodiments, the E3 ligase comprises cereblon.

[0347] In a further aspect, the disclosure features methods of treating various disorders comprising administering the compounds and pharmaceutical compositions described herein. Such disorders include, but are not limited to, autoimmune diseases (e.g., multiple sclerosis, rheumatoid arthritis, myasthenia gravis) and post-transplant diseases (e.g., graft-versus-host disease). Other disorders include disorders caused by or associated with deregulated lymphocyte development or activation.

[0348] In one aspect, the disclosure features a method of treating a disorder caused by or associated with deregulated lymphocyte development or activation in a subject in need thereof, the method 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 an autoimmune disease (e.g., multiple sclerosis, rheumatoid arthritis, myasthenia gravis). In some embodiments, the disorder is a transplant-related disease (e.g., graft-versus-host disease). In some embodiments, the disorder is a malignancy (e.g., a T-cell malignancy or a B-cell malignancy). In some embodiments, the lymphocyte is a T cell.

[0349] In one aspect, the disclosure features a method of treating a disorder caused by or associated with dysregulation of T cell receptor signaling in a subject in need thereof, the method including 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 is enhanced CD69 surface expression, IFNγ, or IL-2.

[0350] In one aspect, the disclosure features a method of treating a disorder caused by or associated with a VAV1 polymorphism in a subject in need of treatment, the method comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof.

[0351] In one aspect, the disclosure features a method of treating a disorder caused by or associated with immunopathology in a subject in need thereof, the method 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 an autoimmune disorder. In some embodiments, the autoimmune disorder is selected from the group consisting of multiple sclerosis, rheumatoid arthritis, systemic lupus, lupus erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I or type II diabetes mellitus and disorders related thereto, vasculitis, pernicious anemia, Sjogren's syndrome, uveitis, psoriasis, Graves' ophthalmopathy, alopecia areata, and the like, allergic diseases (e.g., allergic asthma, atopic dermatitis, allergic rhinitis / conjunctivitis, allergic contact dermatitis), inflammatory diseases optionally with an underlying abnormal response (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, skin manifestations of immune-mediated disorders, inflammatory eye diseases, keratoconjunctivitis, myocarditis, or hepatitis. In some embodiments, the disorder is a cancer, tumor, or other malignancy, and optionally 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 nasal-type NK / T-cell lymphoma, mycosis fungoides, and Sézary syndrome, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma of unknown origin, adult T-cell leukemia / lymphoma (HTLV1+), anaplastic large cell lymphoma, primary cutaneous CD-30 positive T-cell lymphoproliferation, and primary cutaneous CD-30 positive T-cell lymphoproliferation. and / or cutaneous T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, intestinal T-cell lymphoma (+ enteropathy), hepatosplenic gamma / delta T-cell lymphoma, and non-Hodgkin's lymphoma (e.g., B-cell non-Hodgkin's lymphoma; e.g., Burkitt's lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), diffuse large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma).Transplant environment diseases include graft-versus-host disease, chronic graft rejection, acute graft rejection, transplant vasculopathy, transplant vascular disease, graft atherosclerosis, and transplant coronary artery disease.

[0352] In one aspect, the disclosure features a method of treating a disorder caused by or associated with a VAV1 polymorphism, or caused by or associated with an immunopathology in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0353] In some embodiments, the disorder is T cell mediated, hi some embodiments, the disorder is selected from the group consisting of type I or type II diabetes, pernicious anemia, uveitis, psoriasis, alopecia areata, ulcerative colitis, Crohn's disease, atherosclerosis, myocarditis, pericarditis, pulmonary fibrosis, systemic sclerosis, morphea, Alzheimer's disease, acute graft-versus-host disease, or T cell-mediated kidney disease.

[0354] In some embodiments, the disorder is T / B cell mediated. In some embodiments, the disorder is selected from the group consisting of multiple sclerosis, rheumatoid arthritis, myasthenia gravis, Sjogren's syndrome, Graves' 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), a chronic inflammatory demyelinating polyradicular neuropathy, macular degeneration, systemic lupus erythematosus, Hashimoto's thyroiditis, amyloidosis, an inflammatory eye disease, pemphigus, systemic lupus erythematosus, chronic graft-versus-host disease, lupus nephritis, pulmonary arterial hypertension, or vasculitis.

[0355] In some embodiments, the disorder is selected from the group consisting of ulcerative colitis, rheumatoid arthritis, psoriasis, multiple sclerosis, myasthenia gravis, cutaneous lupus, or axial spondyloarthritis. In a preferred embodiment, the disorder is ulcerative colitis.

[0356] 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 preferred embodiments, the disorder is chronic lymphocytic leukemia.

[0357] In one aspect, the disclosure provides a method of treating ulcerative colitis, rheumatoid arthritis, psoriasis, multiple sclerosis, myasthenia gravis, cutaneous lupus, or axial spondyloarthritis, comprising administering to a subject a therapeutically effective amount of a compound [ka] or a pharmaceutically acceptable salt thereof to a subject. In a preferred embodiment, the disorder is ulcerative colitis.

[0358] In one aspect, the disclosure provides a method of treating B-cell lymphoma, B-cell leukemia, T-cell lymphoma, T-cell leukemia, or acute myeloid leukemia, comprising administering to a subject a therapeutically effective amount of a compound [ka] or a pharmaceutically acceptable salt thereof to a subject. In a preferred embodiment, the method is a method for treating chronic lymphocytic leukemia.

[0359] In some embodiments, the present disclosure relates to methods of treating a patient exhibiting CD226 overexpression.

[0360] In some embodiments, the present disclosure relates to methods of treating patients with CD226 risk variants.

[0361] In some embodiments, the present disclosure relates to methods of treating a patient having a CD226 polymorphism.

[0362] In some embodiments, the present disclosure relates to methods of treating a patient with a Gly307Ser (G307S) amino acid substitution in CD226 (rs763361T allele).

[0363] In one aspect, the present disclosure relates to a method of treating a disorder caused by or associated with dysregulated lymphocyte development or activation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound that binds to cereblon and degrades VAV1 or a pharmaceutically acceptable salt thereof.

[0364] In some embodiments, the lymphocytes are T cells.

[0365] In some embodiments, the lymphocytes are B cells.

[0366] In one aspect, the present disclosure relates to a method of treating a disorder caused by or associated with dysregulated T cell receptor signaling in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound that binds to cereblon and degrades VAV1 or a pharmaceutically acceptable salt thereof.

[0367] In one aspect, the disclosure relates to a method of treating a disorder caused by or associated with a VAV1 polymorphism in a subject in need of treatment, the method comprising administering to the subject a therapeutically effective amount of a compound that binds to cereblon and degrades VAV1 or a pharmaceutically acceptable salt thereof.

[0368] In one aspect, the present disclosure relates to a method of treating a disorder caused by or associated with an immunopathology in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound that binds to cereblon and degrades VAV1 or a pharmaceutically acceptable salt thereof.

[0369] In some embodiments, the disorder is an autoimmune disorder.

[0370] In some embodiments, the autoimmune disorder is selected from the group consisting of multiple sclerosis, rheumatoid arthritis, systemic lupus, lupus erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I or type II diabetes mellitus and disorders related thereto, vasculitis, pernicious anemia, Sjogren's syndrome, uveitis, psoriasis, Graves' ophthalmopathy, alopecia areata, and the like, allergic diseases (e.g., allergic asthma, atopic dermatitis, allergic rhinitis / conjunctivitis, allergic contact dermatitis), inflammatory diseases optionally with an underlying abnormal response (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, skin manifestations of immune-mediated disorders, inflammatory eye diseases, keratoconjunctivitis, myocarditis, or hepatitis.

[0371] In one aspect, the disclosure provides a compound or a pharmaceutically acceptable salt thereof for use in any of the above methods of treatment. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound or a pharmaceutically acceptable salt thereof as described herein. In a further aspect, the disclosure provides the use of a compound or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for any of the above methods of treatment. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound or a pharmaceutically acceptable salt thereof as described herein.

[0372] Process for producing compound 185 and its intermediates In one aspect, the disclosure provides a process for making an intermediate of compound 185, the process comprising: (i) [ka] Compounds of formula [ka] By coupling the compound [ka] followed by forming a compound of (ii) [ka] Boronation of [ka] (Intermediate I).

[0373] In some embodiments, step (i) comprises performing an Ullmann coupling. In some embodiments, step (i) comprises catalyzing the reaction using copper(I) iodide. In some embodiments, step (i) comprises adding a ligand that is N,N-bis(furan-2-ylmethyl)oxalamide (BFMO). In some embodiments, step (i) comprises adding BFMO and copper(I) iodide.

[0374] In some embodiments, step (i) comprises reacting a compound of formula [ka] Compounds of formula [ka] in a suitable solvent, followed by the addition of BFMO, which then catalyzes the reaction with copper(I) iodide.

[0375] In some embodiments, step (ii) comprises performing Miyaura borylation.

[0376] This process offers improved selectivity compared to other processes for producing compound 185. In particular, the starting material [ka] The use of [ka] This provides improved selectivity of the boronation step compared to the use of other substituted benzene rings such as

[0377] In one aspect, the disclosure provides a process for making an intermediate of compound 185, the process comprising: (i) [ka] The compound [ka] By reacting with the compound [ka] followed by forming a compound of (ii) [ka] by deprotecting the compound [ka] followed by forming a compound of (iii) [ka] The compound [ka] By reacting with the compound [ka] followed by forming a compound of (iv) [ka] By cyclizing the compound [ka] (Intermediate II).

[0378] In some embodiments, step (i) comprises performing a Hurtley arylation.

[0379] In some embodiments, step (iii) comprises performing a Michael addition.

[0380] Previously, intermediate II was [ka] and reacting with N-bromosuccinimide and benzoyl peroxide, [ka] Then, TMSCN was added, [ka] This method is advantageous compared to the previous method because intermediate II can be synthesized without the need for benzoyl peroxide, which can be explosive and therefore is not a safe reagent for large-scale use. Furthermore, intermediate II can be synthesized without the need for TMSCN, which is toxic and therefore not suitable for large-scale synthesis.

[0381] In one aspect, the disclosure provides a process for making compound 185, (i) [ka] Compounds of formula [ka] By coupling the compound [ka] followed by forming a compound of (ii) [ka] The compound is boronated to [ka] (Intermediate I) is formed, (iii) [ka] A compound of formula [ka] By reacting with the compound [ka] followed by forming a compound of (iv) [ka] Deprotecting the compound of formula (I) [ka] followed by forming a compound of (v) [ka] The compound [ka] By reacting with the compound [ka] followed by forming a compound of (vi) [ka] By cyclizing the compound [ka] (Intermediate II), (vii) coupling intermediate I and intermediate II to provide compound 185.

[0382] This process takes advantage of the improved selectivity in the reaction that produces intermediate I, as well as the improved safety and reduced toxicity of the reaction that produces intermediate II.

[0383] In one embodiment, step (i) comprises the steps of: (1) Formula [ka] Compounds of formula [ka] in a suitable solvent, for example a compound of formula [ka] in a three-fold volume of N,N-dimethylacetamide; (2) adding N1,N2-bis(furan-2-ylmethyl)oxalamide (BFMO, 6 mol%) and tripotassium phosphate (K3PO4, 2 equivalents) to the mixture obtained in (1); (3) adding copper(I) iodide (CuI, 4 mol%) to the mixture obtained in (2) and stirring at a temperature of 115°C for 20 hours; (4) The mixture obtained in (3) is reacted with a suitable solvent, for example, with a compound of the formula [ka] adding an aqueous solution of ammonium hydroxide (NH4OH) in an amount six times the volume of the compound used in step (1), and stirring the resulting mixture at a temperature of 50°C for 1 hour; (5) The mixture obtained in (4) is filtered, and the resulting solid is dissolved in a suitable solvent, for example, the same solvent as in step (1) [ka] washing twice with NH4OH in a volume twice the volume of the compound of (6) The solid obtained in (5) is dissolved in a suitable solvent, for example, the same solvent as in step (1) [ka] washing the compound twice with water in an amount twice the volume of the compound; (7) The solid obtained in (6) is dissolved in a suitable solvent, for example, the same solvent as in step (1) [ka] in a volume of dichloromethane (DCM) that is five times the volume of the compound of formula (I); (8) adding silica to the mixture obtained in (7) and stirring for 2 hours; (9) The mixture obtained in (8) is filtered, and the resulting solid is dissolved in a suitable solvent, such as the compound of formula (I) used in step (1). [ka] washing the compound with a volume of DCM that is 7 times the volume of the compound; It includes at least one of the following:

[0384] In one embodiment, step (ii) comprises the steps of: (1) dissolving [Pd cinnamyl Cl] (0.2 mol%) and XPhos (0.8 mol%) in a suitable solvent, for example, 0.4 volumes of iPrOH, to form a preformed [Pd] solution, and stirring the mixture at a temperature of 30°C for 30-60 minutes; Equation (2) [ka] in a suitable solvent, for example 9 volumes of iPrOH; (3) adding potassium acetate (KOAc, 2.5 equivalents) to the mixture obtained in (2); (4) Formula [ka] (B2pin2, 1.5 equivalents) to the mixture obtained in (3) and degassing the mixture; (5) adding the preformed [Pd] solution obtained in (1) to the mixture obtained in (4), and rinsing the resulting mixture with a suitable solvent, e.g., iPrOH (2 times 0.4 volumes); (6) Heat the mixture obtained in (5) at 80°C for 2 hours; (7) The mixture obtained in (6) was cooled to 25°C and stirred for 2 hours; (8) filtering the mixture obtained in (7) and rinsing the solid with a suitable solvent, e.g., iPrOH (2.4 volumes); (9) Distilling the combined filtrate and washings from (8) to remove 10 volumes of solvent, e.g., iPrOH; (10) Precipitating the mixture obtained in (9) by adding a suitable solvent, for example, heptane (4 volumes); (11) The mixture obtained in (10) was cooled to 5°C and stirred for 1 hour; (12) The mixture obtained in (11) was filtered to obtain a compound of formula [ka] Obtaining a solid containing the compound of formula (I); (13) Washing the solid obtained in (12) with a suitable solvent, for example cold heptane (2x2 volumes); (14) dissolving the solid obtained in (13) in a suitable solvent, for example iPrOH (13 volumes), adding a suitable scavenger (0.13% by weight) and stirring at a temperature of 20° C. for 2 hours; (15) filtering off the scavenger and washing the resulting mixture with a suitable solvent, for example, iPrOH (2 volumes); (16) Concentrating the mixture obtained in (15) to dryness at 45°C under reduced pressure; It includes at least one of the following:

[0385] In one embodiment, step (iii) comprises the steps of: (1) Formula [ka] in a suitable solvent, for example DMAc (5 volumes at 20° C.); (2) adding KPO (5 equivalents) to the mixture obtained in (1); Equation (3) [ka] (0.6 equivalents) to the mixture obtained in (2) at 20°C; (4) Stirring the mixture obtained in (3) at 120°C for 2 hours; Equation (5) [ka] (0.6 equivalents) to the mixture obtained in (4) at 120°C; (6) Stir the mixture obtained in (5) at 120°C for 16 hours; (7) adding HO (5 volumes) to the mixture obtained in (6) at 20°C to effect phase separation to obtain an organic phase; (8) washing the organic phase obtained in (7) with HO (1 volume) and 25% NaCl (1 volume) aqueous solution at 20°C and subjecting it to phase separation to obtain an aqueous phase; (9) washing the aqueous phase obtained in (8) with 8% NaHCO3 (6 volumes) aqueous solution and iPrOAc (5 volumes) at 20°C and subjecting it to phase separation to obtain an organic phase; (10) washing the organic phase obtained in (9) with 25% NH4Cl (6 volumes) at 20°C and subjecting it to phase separation to obtain an organic phase; (11) A step of distilling off the organic phase obtained in (10) to remove the solvent; (12) The mixture obtained in (11) is filtered through a polish filter to obtain a filtrate of the formula [ka] obtaining a compound of formula (I); It includes at least one of the following:

[0386] In one embodiment, step (iv) comprises the steps of: (1) Formula [ka] in a suitable solvent, for example toluene (3 volumes at 20° C.); (2) adding PTSA (p-toluenesulfonic acid, 0.17 equivalents) to the mixture obtained in (1) at 20°C; (3) heating the mixture obtained in (2) to 110°C and stirring for 20 hours; (4) washing the mixture obtained in (3) with 8% aqueous NaHCO3 (2 volumes) at 20°C and subjecting it to phase separation to obtain an organic phase; (5) washing the organic phase obtained in (4) with 25% NaCl (3 volumes) aqueous solution; (6) Distilling the mixture obtained in (5) to remove the solvent; (7) The mixture obtained in (6) is filtered through a polish filter to obtain a filtrate of the formula [ka] obtaining a compound of formula (I); It includes at least one of the following:

[0387] In one embodiment, step (v) comprises the steps of: (1) Formula [ka] in a suitable solvent, for example THF (8 volumes at 20° C.); (2) adding NaOMe (0.05 equivalents) to the mixture obtained in (1); (3) cooling the mixture obtained in (2) to 0°C; (4) The mixture obtained in (3) is treated with the formula [ka] adding (1.00 equivalents dissolved in a suitable solvent, e.g., 2 volumes of THF) (5) adding NaHCO3 (8% aqueous solution, 1 volume) to the mixture obtained in (4); (6) A step of filtering the mixture obtained in (5) to obtain a filtrate; (7) Distilling the filtrate obtained in (6) under reduced pressure to remove the solvent, for example, 6 volumes of THF; (8) Diluting the mixture obtained in (7) with a suitable solvent, such as 4 volumes of toluene and 2 volumes of NaCl (25% aqueous solution), to allow rapid layer separation; (9) washing the organic phase obtained in (8) with a suitable solvent, for example, 1 volume of NaCl (25% aqueous solution); (10) Distilling the mixture obtained in (9) under reduced pressure to remove 4 volumes of solvent; (11) Diluting the mixture obtained in (10) with 2 volumes of toluene; (12) Distilling the filtrate obtained in (11) under reduced pressure to remove the solvent, for example, 2 volumes of solvent; (13) The mixture obtained in (12) was polished and filtered to obtain a solution of the formula [ka] obtaining a compound of formula (I); It includes at least one of the following:

[0388] In one embodiment, step (vi) comprises the steps of: (1) dissolving p-toluenesulfonic acid (PTSA) in a suitable solvent, such as toluene, at a temperature of 110°C; Equation (2) [ka] (dissolved in a suitable solvent, e.g., toluene) to the mixture obtained in (1) over an extended period of time, e.g., 1.5 hours; (3) diluting the mixture obtained in (2) by adding a suitable solvent, for example, NaHCO3 (8% aqueous solution, 1 volume) at a temperature of 75°C, and allowing the resulting mixture to phase separate; (4) seeding with the organic phase obtained in (3), then cooling the resulting mixture to 20°C over 2 hours and maintaining the temperature at 20°C for an extended period of time, e.g., 14 hours; (5) The mixture obtained in (4) is filtered, and the obtained formula [ka] with a suitable solvent, for example EtOH (1 volume); (6) A step of drying the solid obtained in (5) under reduced pressure at 40 to 50°C; It includes at least one of the following:

[0389] In one embodiment, step (vii) comprises the steps of: (1) Formula [ka] A compound of formula [ka] Dissolving the compound, Pd(dtbpf)Cl2, in a suitable solvent, for example, THF (10 volumes); (2) adding Na2CO3 (5.5 volumes of aqueous solution, i.e., 2.5 equivalents of base) to the mixture obtained in (1) and stirring at a temperature of 30°C for an extended period of time, for example, 17 hours; (3) quenching the reaction mixture obtained in (2) with a suitable solvent, for example, 13 volumes of NH4Cl; (4) The mixture obtained in (3) is filtered to obtain a solution of the formula [ka] obtaining a solid of (5) washing the solid obtained in (4) with a suitable solvent, for example, washing the solid with THF:HO in an 8:2 ratio, followed by EtOH, and finally with heptane; It includes at least one of the following:

[0390] Polymorphs of Compound 185 In one aspect, the present disclosure provides crystalline Form A of the free base of Compound 185. [ka] wherein Form A exhibits an XRPD pattern comprising peaks at about 16.5±0.5, 17±0.5, and 17.8±0.5 degrees 2θ using copper K-α radiation. In some embodiments, Form A exhibits an XRPD pattern comprising peaks at about 14±0.5, 16.5±0.5, 17±0.5, 17.8±0.5, and 19.5±0.5 degrees 2θ using copper K-α radiation. In some embodiments, Form A exhibits an XRPD pattern comprising peaks at about 14±0.5, 16.5±0.5, 17±0.5, 17.8±0.5, and 19.5±0.5 degrees 2θ using copper K-α radiation, and peaks between 21.5-23, 25.5-27, 27-28, and 29.5-31 degrees 2θ using copper K-α radiation.

[0391] In some embodiments, the margin of error is ±0.4; ±0.3; ±0.2; ±0.1; or ±0.05.

[0392] In some embodiments, crystalline form A exhibits an XRPD pattern comprising the peaks shown in Table 2 below.

[0393] [Table 1]

[0394] In some embodiments, crystalline form A of compound 185 exhibits an XRPD pattern substantially similar to that in FIG.

[0395] Degrader Conjugates In one embodiment, the conjugate comprises a compound capable of degrading VAV1. For example, in one embodiment, the conjugate comprises an antibody-degrading agent conjugate, or a pharmaceutically acceptable salt thereof, comprising a compound capable of degrading VAV1. The conjugate comprises a compound capable of degrading VAV1 or a pharmaceutically acceptable salt thereof, conjugated to the antibody via a linker structure moiety. In some embodiments, the compound is a compound of any of Formulas (I), (II), (III), (IV), (V), (I-1), (I-2), (I-3), (I-4), (Ia), and (Ib), or a pharmaceutically acceptable salt thereof.

[0396] In some embodiments, the conjugate has a structure according to formula (A): Bm-(-MI) a Formula (A) wherein I is a compound capable of degrading VAV1, such as a compound of formula (I), (II), (III), (IV), (V), (I-1), (I-2), (I-3), (I-4), (Ia) or (Ib) as defined herein, or a pharmaceutically acceptable salt thereof, M is a linker moiety, and Bm is a binding moiety capable of specifically binding to an antigen. The binding moiety may be an antibody, antibody fragment or antibody-binding fragment.

[0397] In some embodiments, M is a linker as defined in WO 2021 / 198966, which is incorporated by reference in its entirety. The linker can be a cleavable linker or a non-cleavable linker. In certain aspects, the linker can comprise a heterobifunctional group. In this disclosure, the term "heterobifunctional group" refers to a chemical moiety that connects the linker to the binding moiety. A heterobifunctional group is characterized by having different reactive groups at both ends of the chemical moiety. Conjugation to Bm can be achieved by 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 reactive handles on the heterobifunctional group. Examples of chemical conjugation include, but are not limited to, lysine amide coupling, cysteine-mediated coupling, and coupling via unnatural amino acids incorporated by genetic engineering, where a nonnatural amino acid residue bearing a desired reactive handle is placed on Bm. In enzymatic conjugation, an enzyme mediates the coupling of the linker to an accessible amino acid 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 and enzymatic conjugation can also be used sequentially. For example, enzymatic conjugation can be used to install a unique reactive handle on Bm that is utilized in subsequent chemical conjugation.

[0398] In some embodiments, M is a linker as defined in WO 2023 / 037268, which is incorporated by reference in its entirety. [ka] is selected from the group consisting of where: q is from 2 to 10, Z1 , Z 2 , Z 3 , Z 4 , and Z 5 is Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are amino acid residues that are independently not present or naturally occurring in the L- or D-configuration, provided that at least two of [ka] is the point of attachment to the parent molecular (degrader) moiety, and [ka] is the point of attachment to the binding moiety.

[0399] In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 is 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, with the proviso that Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 At least two of these are amino acid residues.

[0400] 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 antigen-binding fragment. Antibodies are proteins produced by the immune system that can recognize and bind to a specific antigen. A target antigen generally has multiple 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 two or more corresponding antibodies. The term "antibody" is used in the broadest sense herein and specifically encompasses 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. Monoclonal antibodies (mAbs) against an antigen of interest can be prepared using any technique known in the art that provides for the production of antibody molecules by continuous cell lines in culture. These include, but are not limited to, hybridoma technology, human B-cell hybridoma technology, and EBV-hybridoma technology. Such antibodies can be of any immunoglobulin class, including IgG, IgM, IgE, IgA, and IgD, and any subclass thereof. The hybridoma producing the mAb for use in this disclosure can be cultivated in vitro or in vivo.

[0401] Those skilled in the art will understand how to provide an appropriate binding moiety for use in the conjugate depending on the intended therapeutic application. This is described, for example, in Nature Reviews Drug Discovery volume 22, pages 641-661 (2023), the entire contents of which are incorporated by reference. In particular, the antibody, antibody fragment, or antibody-binding fragment used as the binding moiety must be capable of targeting a specific cell surface marker or receptor associated with the disorder being treated. For example, if the desired target is HER2, the antibody trastuzumab can be used.

[0402] In some embodiments, the binding moiety is capable of binding to an antigen selected from α4β7, CD3, CD4, CD20, OX40, CD28, PD-1, ICOS, BCMA / TACI, CD52, CD30, CD19, CCR8, CD79b, CD22, CD4, CD7, and CD38, or a combination thereof.

[0403] In some embodiments, the binding moiety comprises an antibody selected from vedolizumab, etrolizumab, teplizumab, zanolimumab, rituximab, ublituximab, ofatumumab, ocrelizumab, inebilizumab, locatinlimab, nivolumab, pembrolizumab, alemtuzumab, brentuximab vedotin, tafasitamab, roncastaximab, mogamulizumab, polatuzumab, inotuzumab, epratuzumab, isatuximab, and daratumumab.

[0404] In some embodiments, the present disclosure provides a method for the treatment of ulcerative colitis (UC), Crohn's disease (CD), human immunodeficiency virus (HIV) / acquired immune deficiency 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 rejection, pemphigus vulgaris, cutaneous lupus erythematosus (CLE), systemic sclerosis (SSc), Graves' disease, relapsing-remitting / primary-progressive multiple sclerosis (RR / PP) in a subject in need thereof. MS), lupus nephritis, systemic lupus erythematosus (SLE), thrombotic thrombocytopenic purpura, renal 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 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 carcinoma; malignant mesothelioma; mastocytosis; non-Hodgkin's lymphoma; Sezary syndrome; solid tumors, HIV-1 infection, 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 B-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 B-cell lymphoblastic leukemia / lymphoma, precursor B-cell lymphoblastic leukemia / lymphoma, chronic myeloid 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 syndrome; plasmablastic lymphoma; precursor T-cell lymphoblastic leukemia / lymphoma;Provided are methods for treating amyloid light chain amyloidosis, multiple myeloma (MM), and solid tumors, the methods comprising administering to a subject an antibody-drug conjugate;

[0405] 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 present disclosure provides a method of treating a disorder listed in the table below, comprising administering to a subject in need of treatment an antibody-drug conjugate comprising an antibody listed in the table below.

[0406] [Table 2]

[0407] [Table 3]

[0408] [Table 4]

[0409] [Table 5]

[0410] In some embodiments, I is one of compounds 101-510.

[0411] In some embodiments, the present disclosure provides an antibody-drug conjugate according to formula (A1) or a pharmaceutically acceptable salt thereof: [ka] R in the formula 1 , R 2 , R 3 , R 4 , R5 , R 6 , R 7 , L 1 may be as defined anywhere herein, M is a linker moiety, and Bm is a binding moiety capable of specifically binding to a protein, as defined above. 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , L 1 and n is defined to provide a compound selected from any one of compounds 101-510.

[0412] In some embodiments, the present disclosure provides an antibody-drug conjugate according to Formula (A2) or (A3), or a pharmaceutically acceptable salt thereof. [ka]

[0413] In some embodiments, the present disclosure provides an antibody-drug conjugate according to formula (A4) or a pharmaceutically acceptable salt thereof: [ka] R in the formula 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , L 1 may be as defined anywhere herein, M is a linker moiety, and Bm is a binding moiety capable of specifically binding to a protein, as defined above. 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , L 1and n is defined to provide a compound selected from any one of compounds 101-510.

[0414] In some embodiments, the present disclosure provides an antibody-drug conjugate according to formula (A5) or (A6), or a pharmaceutically acceptable salt thereof. [ka]

[0415] The antibody-drug conjugate can be administered as part of a pharmaceutical composition, which can include excipients as listed herein.

[0416] Non-limiting exemplary compounds In some embodiments, the compound is selected from the group consisting of the compounds set forth in Table C1 or a pharmaceutically acceptable salt thereof.

[0417] Unless otherwise indicated, the symbol * at a chiral center indicates that this chiral center is resolved (ie, is a single epimer) and that the absolute stereochemistry at that center has not been determined.

[0418] [Table 6]

[0419] [Table 7]

[0420] [Table 8]

[0421] [Table 9]

[0422] [Table 10]

[0423] Table 11

[0424] Table 12

[0425] Table 13

[0426] Table 14

[0427] Table 15

[0428] Table 16

[0429] Table 17

[0430] Table 18

[0431] Table 19

[0432] Table 20

[0433] Table 21

[0434] Table 22

[0435] Table 23

[0436] Table 24

[0437] Table 25

[0438] Table 26

[0439] Table 27

[0440] Table 28

[0441] Table 29

[0442] Table 30

[0443] Table 31

[0444] Table 32

[0445] Table 33

[0446] Table 34

[0447] Table 35

[0448] Table 36

[0449] Table 37

[0450] Table 38

[0451] Table 39

[0452] Table 40

[0453] Table 41

[0454] Table 42

[0455] Table 43

[0456] Table 44

[0457] Table 45

[0458] Table 46

[0459] Table 47

[0460] Table 48

[0461] Table 49

[0462] Table 50

[0463] Table 51

[0464] Table 52

[0465] Table 53

[0466] Table 54

[0467] Table 55

[0468] Table 56

[0469] Table 57

[0470] Table 58

[0471] Table 59

[0472] Table 60

[0473] Table 61

[0474] Table 62

[0475] [Table 63]

[0476] [Table 64]

[0477] [Table 65]

[0478] [Table 66]

[0479] General synthetic scheme General Scheme 1 [ka] A general synthetic strategy that can be used to prepare compounds of Formula I is shown in General Scheme 1. An aryl halide AA, where Z1 is any suitable halogen (e.g., Br or I), can be coupled with an aryl boronate AB using any suitable metal-catalyzed coupling conditions. 1 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7is selected based on the desired group in the compound of Formula I. The desired compound can be prepared using a Suzuki coupling reaction with a palladium catalyst complex such as Pd(dtbpf)Cl2 (DBTF = 1,1'-bis(di-tert-butylphosphino)ferrocene) or Pd(dppf)Cl2 (dppf = 1,1'-bis(diphenylphosphino)ferrocene) in the presence of a base such as potassium phosphate. A suitable solvent such as DMF (dimethylformamide) or dioxane may be used, or a suitable solvent mixture such as dioxane and water may be used.

[0480] Alternatively, compounds of Formula I can be prepared from the reaction of an aryl boronate of Formula AC with an aryl halide of Formula AD using Suzuki cross-coupling conditions. Z2 is any halide (Br, I, Cl) or triflate group that can be used in the metal-catalyzed coupling reaction of AD to the boronate AC. The desired compounds can be prepared using Suzuki coupling reactions with palladium catalyst complexes such as APhos Pd G3, Brettphos Pd G3, Pd(dppf)Cl2, or Pd(dppf)Cl2·CH2Cl2 in the presence of a suitable base such as K3PO4. A suitable solvent such as DMF (dimethylformamide) or dioxane can be used, or a suitable solvent mixture such as dioxane and water can be used.

[0481] Arylboronates AC can be prepared from aryl halides AA using a catalyst such as bis(pinacolato)diboron[PdcinnamylCl]2 and a ligand such as Xphos. A weak base such as sodium acetate in a solvent such as iPrOH may also be used. The reaction may be carried out at elevated temperatures, such as 60°C, 80°C, or 100°C.

[0482] General Scheme 2 [ka] General Scheme 2 provides an exemplary synthetic procedure for preparing starting material AA used in General Scheme 1. Compounds AE, where Z1 is a suitable halogen atom (e.g., Br or I), can be converted to benzyl halides of formula AF using benzyl halogenation conditions. For example, N-bromosuccinimide and benzoyl peroxide in a solvent such as carbon tetrachloride at elevated temperatures (e.g., 80 or 90 degrees Celsius) provide AF.

[0483] Benzyl nitrile intermediates such as AG can be prepared from benzyl halides AF upon treatment with a cyanating reagent (such as trimethylsilyl cyanide) in the presence of a desilylation reagent such as tert-butylsilyl fluoride or tetra-n-butylammonium fluoride (TBAF) and a solvent such as dichloromethane at temperatures such as 0-25°C.

[0484] The Michael addition of a compound of formula AG with an acrylate such as compound AH can be carried out using a base such as sodium methoxide in a solvent such as tetrahydrofuran at room temperature. Rs1 is any suitable alkyl group that is labile to treatment with acid. For example, Rs1 can be tert-butyl at temperatures such as 0-25°C. Compound AI can be converted to intermediate AA upon treatment with a strong acid, such as sulfuric acid, in a solvent, such as acetic acid, at elevated temperature (eg, 90 degrees Celsius).

[0485] General Scheme 3 [ka] General Scheme 3 provides an alternative exemplary synthetic procedure for preparing starting material AA used in General Scheme 1. Compound AJ, where Z2 is a suitable halide leaving group (e.g., fluorine), can be subjected to nucleophilic aromatic substitution (Hurtley Arylation) with a reagent such as tert-butyl cyanoacetate AK. Solvents such as dimethylacetamide in the presence of a base such as potassium phosphate can be used to provide AL.

[0486] Benzyl nitriles of formula AG can be prepared by hydrolysis and decarboxylation of AL upon treatment with an acid such as p-toluenesulfonic acid at 120° C. in a solvent such as toluene.

[0487] Benzyl nitrile AG can be converted to AI by Michael addition to an acrylate reagent such as AH, where Rs1 is an alkyl group that forms an ester. The ester formed by Rs1 must be unstable to hydrolysis upon treatment with acid. The Michael addition can be carried out by treatment with a base such as sodium methoxide in a solvent such as toluene at 0°C.

[0488] Compound AA can be prepared from AI by treatment with an acid such as p-toluenesulfonic acid in a solvent such as toluene at elevated temperature (eg, 110 degrees Celsius).

[0489] General Scheme 4 [ka] General Scheme 4 provides a specific exemplary synthetic strategy for preparing compounds of formula AN, which can use aryl halide AM as the starting material AD in General Scheme 1. W1 is any suitable substituent that provides compounds of formula I.

[0490] Compound AN can be prepared by coupling AC and AM under metal-catalyzed conditions, for example, treatment with dichloropalladium(II) and a base such as potassium phosphate in a solvent such as [1,1'-bis(diphenylphosphino)ferrocene]dioxane. The reaction can be carried out at a temperature such as 80 degrees Celsius.

[0491] General Scheme 5 [ka] General Scheme 5 provides a specific exemplary synthetic strategy for preparing compounds of formula AN, which can use arylboronates AO as starting materials AD in General Scheme 1. W1 is any suitable substituent that provides compounds of formula I.

[0492] Compound AN can be prepared by coupling AA and AO under metal-catalyzed conditions, for example, by treatment with [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and a base, such as potassium phosphate, in a solvent such as dioxane. The reaction can be carried out at elevated temperatures, such as 80 degrees Celsius.

[0493] General Scheme 6 [ka] General Scheme 6 provides a specific exemplary synthetic strategy for preparing aryl halides and aryl boronates AO of formula AM, where Z is any suitable halide, such as chlorine, bromine, or iodine. Compounds AM and AO can be used as starting materials AD and AB, respectively, in General Scheme 1. W is any suitable substituent that provides a compound of formula I.

[0494] Substituted pyridones of formula AQ can be coupled to dihaloaryl compounds AP using copper-catalyzed conditions. One synthetic strategy involves treatment with copper iodide and a base such as potassium phosphate in a solvent such as dimethylacetamide. The reaction can be carried out at 115 degrees Celsius for 20 hours. Alternative conditions involve the use of copper iodide catalyst in the presence of a ligand, such as N1,N2-bis(furan-2-ylmethyl)oxalamide (BFMO) or 4,7-dimethoxy-1,10-phenanthroline.

[0495] Arylboronates of formula AO can be prepared from AM and an appropriate boronating agent (such as bis(pinacolato)diboron) using any metal-catalyzed boronation conditions. For example, cinnamylpalladium chloride dimer in the presence of 0.4 mol% of Xphos ligand, or Pd(dppf)Cl2, can be used. The reaction can be carried out at 80°C in a suitable solvent such as isopropanol or dioxane.

[0496] General Scheme 7 [ka] General Scheme 7 provides an exemplary synthetic strategy for preparing a variety of aryl halides of formulas AT, AV, and AX that can be used as starting materials AD in General Scheme 1. In some instances, depending on the desired substituents in Formula I, X and Y can be carbon, or X, y, or both can be nitrogen. Z5 and Z 6 is any suitable halogen. W2, W3 and W4 are any suitable substituents providing compounds of formula I T1 = C, O or N-alkyl.

[0497] A synthetic approach to lactam, carbamate, or pyrimidinone compounds of formula AT involves copper-catalyzed coupling of a lactam or pyrimidinone AS with an aryl halide AR using copper iodide and a ligand such as N,N'-dimethylethylenediamine (DMEDA). The reaction may be carried out in the presence of a base such as potassium phosphate or potassium carbonate and a solvent such as toluene, DMSO, dioxane, DMF, or NMP. Elevated temperatures such as 90°C or 110°C may be required.

[0498] In some instances (where X and Y = N or X = N and Y = C and Z = Cl), ethers of formula AV can be prepared by treating a halide AR with an alcohol of formula AU under basic conditions. In some instances, AU is pretreated with a base such as sodium hydride in a solvent such as THF, followed by addition of AR at 0°C.

[0499] In some instances (X=N and Y=C and Z=Cl), compounds of formula AX can be prepared from the reaction of AW with AR using any suitable nucleophilic substitution conditions. A base such as cesium carbonate in a solvent such as dimethyl sulfoxide (DMSO) at 100° C. can be applied.

[0500] General Scheme 8 [ka] General Scheme 8 provides a representative synthetic strategy for intermediates of formula BA from benzyl halides of formula AY and pyridones AZ. 7 is a suitable halide such as bromine, chlorine or iodine. 5 is any suitable substituent that results in a compound of formula I. N-Alkylation of pyridone AZ can be carried out using a base such as potassium carbonate in the presence of the phase transfer catalyst cetyltrimethylammonium bromide (CTAB) in a solvent such as water. The reaction can be carried out at a temperature such as 50 degrees Celsius. Compounds of formula BN can be similarly prepared from compounds of formula AS and AY.

[0501] Compounds of formula BC can be prepared from AY and an arylboronic acid or boronic acid of formula BB. V1 can be hydrogen or any suitable alkyl that forms the boronate BB.

[0502] General Scheme 9 [ka] General Scheme 9 provides a representative synthetic strategy for intermediates of formula BF that can be used as starting materials AD in General Scheme 1. A boronic acid or boronic ester of formula BD can be coupled with an amide or pyridone BE to give BF. Some representative conditions for this reaction include copper acetate (Cu(OAc)2) in the presence of pyridine and 4 Å molecular sieves. The reaction can be carried out in a solvent such as dichloromethane at ambient temperature (about 25° C.).

[0503] General Scheme 10 [ka] General Scheme 10 provides a general synthetic strategy for intermediates of formula BJ that can be used as starting materials AD in General Scheme 1. Z8 is any suitable halide. W8 and W9 are any suitable substituents that provide compounds of formula I. Compounds of formula BI can be prepared by reacting BG with BH in the presence of a catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and a base such as potassium carbonate in a solvent mixture of dioxane and water. The reaction can be carried out at a temperature of 100 degrees Celsius. Triflates of formula BJ can be prepared by treating alcohol BI with trifluoromethanesulfonic anhydride and pyridine in dichloromethane at 0°C.

[0504] General Scheme 11 [ka] General Scheme 11 provides a general synthetic strategy for intermediates of formula BM that can be used as starting materials AD in General Scheme 1. 9 and Z 10 is any suitable halide. 1 is any suitable atom or group suitable for providing a compound of formula I, e.g., oxygen, NH, or N-methyl. 10 is a heteroaryl or any suitable substituent to provide a compound of formula I. Compounds of formula BM can be prepared by N-alkylation of BK with any aryl halide BL. The reaction can occur in a polar solvent such as dimethylformamide at a temperature such as 80 degrees Celsius in the presence of a base such as cesium carbonatite. Compounds of formula BM can be cross-coupled with compounds of formula AD using a catalyst such as BrettPhos Pd3 complex in the presence of a base such as potassium phosphate. The reaction can be carried out in a solvent such as dioxane at 100°C.

[0505] General Scheme 12 [ka] Scheme 12 provides a general synthetic approach for preparing compounds of formula BP that can be used as starting materials AD in Scheme 1. 10 is any suitable aryl or heteroaryl group that provides a compound of formula I. An organometallic zinc reagent can be prepared by treatment of compound AY with Zn-Cu metal at elevated temperature (e.g., 80 degrees Celsius) in the presence of a solvent such as a mixture of toluene and dimethylacetamide. The addition of an aryl or heteroaryl halide such as BO and a palladium catalyst such as Pd(PPh3)4 in a solvent such as toluene at room temperature can be used to generate a compound of formula BP. [Example]

[0506] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. Where typical or preferred process conditions (i.e., reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are given, it will be understood that other process conditions can also be used unless otherwise specified. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one of ordinary skill in the art by routine optimization.

[0507] Abbreviations: DCM: dichloromethane; DIEA: N,N-diisopropylethylamine; DMF: dimethylformamide; DMSO: dimethyl sulfoxide; EtOH: ethanol; ESI: electrospray ionization; h: time; HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; HPLC: high-performance liquid chromatography; MeCN: acetonitrile; MS: mass spectrometry; NCS: N-chlorosuccinimide; NMR: nuclear magnetic resonance triethylamine; and THF: tetrahydrofuran.

[0508] Synthesis of 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione (Intermediate A) [ka] To a solution of 1-bromo-2-chloro-3-methylbenzene (30.0 g, 146 mmol, 1.00 equiv.) in tetrachloromethane (240 mL) was added N-bromosuccinimide (28.7 g, 161 mmol, 1.11 equiv.) and benzoyl peroxide (1.77 g, 7.30 mmol, 0.05 equiv.). The mixture was stirred at 90 °C for 16 h. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (2 × 75 mL). The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 200 g SepaFlash® silica flash column, eluent: 0–3% ethyl acetate / petroleum ether gradient @ 150 mL / min) to afford 1-bromo-3-(bromomethyl)-2-chlorobenzene (20.8 g, 73.1 mmol, 50% yield) as a colorless liquid. 1 H NMR(400MHz,CDCl3)δ=7.61(dd,J=8.0,1.6Hz,1H),7.41(dd,J=8.0,1.6Hz,1H),7.15-7.11(m,1H),4.62(s,2H).

[0509] [ka] To a solution of 1-bromo-3-(bromomethyl)-2-chlorobenzene (20.0 g, 70.3 mmol, 1.00 equiv) and trimethylsilane (10.5 g, 105 mmol, 1.76 mL, 1.50 equiv) in dichloromethane (200 mL) was added tetrabutylammonium fluoride (1.0 M in THF, 105 mL, 1.50 equiv) dropwise at 0° C. The mixture was stirred at 20° C. for 1.5 h. The reaction mixture was washed with water (3×150 mL), and the organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® silica flash column, eluent 0-60% ethyl acetate / petroleum ether gradient @ 60 mL / min) to give 2-(3-bromo-2-chlorophenyl)acetonitrile (13.2 g, 57.3 mmol, 81% yield) as a white solid. 1 H NMR(400MHz, CDCl3)δ=7.65(d,J=8.0Hz,1H),7.50(dd,J=8.0,0.8Hz,1H),7.20(t,J=8.0Hz,1H),3.89(s,2H).

[0510] [ka] To a solution of 2-(3-bromo-2-chlorophenyl)acetonitrile (13.2 g, 57.3 mmol, 1.00 equiv) in tetrahydrofuran (130 mL) was added sodium methylate (620 mg, 11.5 mmol, 0.200 equiv) and tert-butyl acrylate (7.34 g, 57.3 mmol, 8.31 mL, 1.00 equiv) dropwise at 0° C. The mixture was then stirred at 20° C. for 2 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×80 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by elution on a reverse-phase column (C18, 330 g, flow rate: 100 mL / min; gradient: 10 to 65% water (0.1% formic acid) in acetonitrile over 40 min) to afford tert-butyl 4-(3-bromo-2-chlorophenyl)-4-cyanobutanoate (7.50 g, 19.0 mmol, 33% yield) as a colorless liquid. 1 H NMR(400MHz,CDCl3)δ=7.65(dd,J=8.0,1.6Hz,1H),7.53(dd,J=8.0,1.6Hz,1H),7.22(t,J= 8.0Hz,1H),4.49(dd,J=8.8,5.6Hz,1H),2.54-2.38(m,2H),2.29-2.09(m,2H),1.46(s,9H)

[0511] [ka] To a solution of tert-butyl 4-(3-bromo-2-chlorophenyl)-4-cyanobutanoate (4.70 g, 11.9 mmol, 1.00 equiv.) in acetic acid (30 mL) was added sulfuric acid (5.52 g, 56.3 mmol, 3.00 mL, 4.72 equiv.). The mixture was stirred at 90° C. for 3 hours. After cooling to room temperature, the reaction mixture was poured into ice water (120 mL) and the filter cake was washed with water (2×50 mL). The filter cake was dried under reduced pressure to give 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (2.89 g, 9.46 mmol, 79% yield, 99% purity) as a white solid. 1H NMR(400MHz,DMSO-d6)δ=10.93(s,1H),7.72(dd,J=8.0,0.8Hz,1H),7.38(dd,J=8.0,1.2Hz,1H),7.30-7.26(m, 1H),4.32(dd,J=12.0,4.8Hz,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] +

[0512] [ka] To a solution of 3-(3-bromo-2-chloro-phenyl)piperidine-2,6-dione (5.00 g, 16.5 mmol, 1.00 equiv.) in dioxane (80 mL), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (5.04 g, 19.8 mmol, 1.20 equiv.), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.21 g, 1.65 mmol, 0.10 equiv.), and potassium acetate (4.87 g, 49.6 mmol, 3.00 equiv.) were added in one portion under a nitrogen atmosphere at 20 °C. The mixture 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 combined filtrate was concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® silica flash column, eluent: 0 to 50% ethyl acetate / petroleum ether gradient at 60 mL / min) to afford 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-piperidine-2,6-dione (3.80 g, 8.70 mmol, 52% yield) as a white solid. 1H NMR(400MHz,DMSO-d6)δ=10.90(s,1H),7.52(dd,J=2.0,7.2Hz,1H),7.41(dd,J=2.0,7.6Hz,1H),7.32(d,J=7.6Hz,1H), 4.26(dd,J=5.2,12.4Hz,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 350.2 / 352.2[M+H] +

[0513] Synthesis of 3-(4'-(bromomethyl)-2-chloro-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Intermediate B) [ka] To a solution of 1-bromo-2-chloro-3-methylbenzene (30.0 g, 146 mmol, 1 equiv.) in carbon tetrachloride (240 mL) was added N-bromosuccinimide (28.8 g, 162 mmol, 1.11 equiv.) and benzoyl peroxide (1.77 g, 7.30 mmol, 0.0500 equiv.). The mixture was stirred at 90 °C for 16 h. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (2 × 75 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give 1-bromo-3-(bromomethyl)-2-chlorobenzene (25.1 g, crude) and 1-bromo-3-(bromomethyl)-2-chlorobenzene (7.90 g, 26.3 mmol, 18% yield), both as colorless liquids. 1 H NMR(400MHz,DMSO-d6)δ =7.77(dd,J=1.2,8.0Hz,1H),7.65(dd,J=0.8,7.6Hz,1H),7.29(t,J=8.0Hz,1H),4.80(s,2H).

[0514] [ka] To a solution of 1-bromo-3-(bromomethyl)-2-chlorobenzene (33.0 g, 116 mmol, 1.00 equiv) and trimethylsilylformonitrile (17.3 g, 174 mmol, 21.8 mL, 1.50 equiv) in dichloromethane (330 mL) was added tris((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)amine (1 M, 174 mL, 1.50 equiv) (1.0 M in tetrahydrofuran, 105 mL, 1.50 equiv) dropwise at 0° C. The mixture was stirred at 20° C. for 1.5 h. The reaction mixture was washed with water (3×150 mL), and the organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=1 / 0 to 0 / 1) to give 2-(3-bromo-2-chlorophenyl)acetonitrile (5.80 g, 25.2 mmol, 21% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ=7.80(dd,J=1.0,8.0Hz,1H),7.57(dd,J=0.8,7.6Hz,1H),7.35(t,J=8.0Hz,1H),4.18(s,2H).

[0515] [ka] A mixture of 2-(3-bromo-2-chloro-phenyl)acetonitrile (13.3 g, 57.7 mmol, 1.00 equiv), tert-butyl acrylate (7.40 g, 57.7 mmol, 8.38 mL, 1.00 equiv), and sodium methoxide (623 mg, 11.5 mmol, 0.200 equiv) in tetrahydrofuran (130 mL) was added at 0° C. The reaction was stirred at 20° C. for 2 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×80 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=1 / 0 to 0 / 1) to give tert-butyl 4-(3-bromo-2-chloro-phenyl)-4-cyano-butanoate (25.0 g, crude) as a yellow oil. 1 H NMR(400MHz,DMSO-d6)δ=7.82(dd,J=1.4,8.0Hz,1H),7.60(dd,J=1.6,8.0Hz,1H),7.38(t,J =8.0Hz,1H),4.62(dd,J=6.8,8.0Hz,1H),2.45-2.30(m,2H),2.20-2.08(m,2H),1.38(s,9H)

[0516] [ka] A mixture of tert-butyl 4-(3-bromo-2-chlorophenyl)-4-cyanobutanoate (10.0 g, 27.9 mmol, 1.00 equiv.), (4-(hydroxymethyl)phenyl)boronic acid (4.66 g, 30.7 mmol, 1.10 equiv.), and potassium carbonate (7.71 g, 55.7 mmol, 2.00 equiv.), palladium; and triphenylphosphane (3.22 g, 2.79 mmol, 0.100 equiv.) in 1,2-dimethoxyethane (9.00 mL) and water (3.00 mL) was stirred at 90 °C for 3 h under a nitrogen atmosphere. The mixture was cooled to room temperature, poured into water (30 mL), and the two layers were separated. The aqueous phase was extracted with ethyl acetate (3 × 30 mL), and the organic layer was washed with brine (30 mL). The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give tert-butyl 4-(2-chloro-4'-(hydroxymethyl)-[1,1'-biphenyl]-3-yl)-4-cyanobutanoate (6.07 g, 15.7 mmol, 56% yield) as a yellow oil. 1 H NMR(400MHz,DMSO-d6)δ=7.60(dd,J=1.6,8.0Hz,1H),7.51(t,J=7.6Hz,1H),7.45-7.34(m,5H),5.25(t,J=6.0 Hz,1H),4.63(dd,J=6.8,8.0Hz,1H),4.56(d,J=6.0Hz,2H),2.46-2.37(m,2H),2.23-2.14(m,2H),1.39(s,9H)

[0517] [ka] A mixture of tert-butyl 4-(2-chloro-4'-(hydroxymethyl)-[1,1'-biphenyl]-3-yl)-4-cyanobutanoate (6.00 g, 15.6 mmol, 1.00 equiv.) and sulfuric acid (5.52 g, 56.3 mmol, 3.00 mL, 3.62 equiv.) in acetic acid (30.0 mL) was stirred at 90 °C for 3 h. After cooling to room temperature, the reaction mixture was poured into water (120 mL) and the filter cake was washed with saturated sodium bicarbonate (3 × 20 mL). The filter cake was dried under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / (ethyl acetate / methanol / dichloromethane = 2 / 2 / 1) = 1 / 0 to 0 / 1), triturated with 2-methoxy-2-methylpropane (20 mL) at 25 °C for 15 min, and filtered. The filter cake was dried to give 3-(2-chloro-4'-(hydroxymethyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (2.78 g, 7.08 mmol, 45% yield, 84% purity) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ=10.92(s,1H),7.48-7.34(m,6H),7.31(dd,J=2.0,7.2Hz,1H),5.13(s,2H),4. 34(dd,J=4.8,12.0Hz,1H),2.87-2.71(m,1H),2.60-2.51(m,1H),2.40-2.27(m,1H),2.08-2.00(m,1H) MS(ESI)m / z 312.0[M-17] +

[0518] [ka] To a mixture of 3-(2-chloro-4'-(hydroxymethyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (1.40 g, 4.25 mmol, 1.00 equiv.) in dichloromethane (5.00 mL) was added hydrogen bromide (2.98 g, 12.2 mmol, 2.00 mL, 33% purity in acetic acid, 2.86 equiv.) at 0°C. The reaction was warmed to 25°C and stirred for 3 hours. The mixture was poured into saturated sodium bicarbonate solution (30.0 mL) and filtered. The filter cake was dried under reduced pressure to give the crude product. The crude product was triturated with ethyl acetate (10 mL) at 20°C for 10 minutes and filtered. The filter cake was dried under reduced pressure to give 3-(4'-(bromomethyl)-2-chloro-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (1.33 g, 2.85 mmol, 67% yield, 84% purity) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ=10.92(s,1H),7.57-7.51(m,2H),7.43-7.35(m,4H),7.34-7.30(m,1H),4.77 (s,2H),4.40-4.30(m,1H),2.85-2.74(m,1H),2.54-2.51(m,1H),2.40-2.27(m,1H),2.09-2.02(m,1H) MS(ESI)m / z 392.2[M+H] +

[0519] Characterization of other key intermediates in the preparation of compounds of formula I Characterization of intermediates of general formula AA was used to prepare compounds of formula I. Intermediates AA-2 through AA-9 were prepared analogously to 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione described in general Scheme 2 or 3 and the preparation of intermediate A.

[0520] [Table 67]

[0521] [Table 68]

[0522] General synthetic procedure for preparing compounds of formula I from aryl bromide intermediate AA and commercially or synthetically available boronic acids or esters [ka] 3-(3-Bromo-2-chlorophenyl)piperidine-2,6-dione (1 equiv.) and the appropriate boronic acid or pinacolate (approx. 1.5–2 equiv.) were mixed in 20:1 DMF-water (approx. 0.7 ml). CataCXium A Pd G3 (0.05 equiv.), RuPhos Pd G4 (0.05 equiv.), and sodium bicarbonate (NaHCO3) were then added in one portion under an inert atmosphere. The reaction mixture was sealed and heated at 90 °C for 15 h. The mixture was then cooled to ambient temperature, and trifluoroacetic acid (TFA) was added dropwise to neutral pH. The mixture was evaporated under reduced pressure, and the residue was dissolved in DMSO (approx. 0.7 ml). The DMSO solution was treated with scavenger SiliaMetS DMT, filtered, analyzed by LCMS, and transferred for HPLC purification.

[0523] Example 1. Synthesis of 3-(2-chloro-4'-((1-methyl-1H-pyrazol-3-yl)methoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 154) [ka] To a solution of 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (250 mg, 826 μmol, 1.00 equiv., 2 batches), 1-methyl-3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)-1H-pyrazole (286 mg, 909 μmol, 1.10 equiv.) in dimethylformamide (8 mL) was added [1,1-bis(diphen-ylphosphino)ferrocene]dichloropalladium(II) (60.5 mg, 82.6 μmol, 0.10 equiv.) and potassium phosphate (526 mg, 2.48 mmol, 3.00 equiv.). The mixture was degassed and purged with nitrogen three times, then stirred at 100° C. for 16 h. The reaction mixture was cooled to 25°C, filtered through a pad of Celite, washed with ethyl acetate (50 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent: 0-80% ethyl acetate / petroleum ether gradient @ 60 mL / min). The desired fractions were collected and concentrated under reduced pressure. The residue was then triturated with dimethylformamide (4 mL) at 25°C for 10 min, filtered, washed with n-hexane (5 mL), and dried under reduced pressure to give 3-(2-chloro-4'-((1-methyl-1H-pyrazol-3-yl)methoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (278.9 mg, 673.64 μmol, 41% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ=10.91(s,1H),7.67(d,J=2.0Hz,1H),7.41-7.26(m,5H),7.17-7.05(m,2H),6.33(d,J=2.0Hz,1H),5 .04(s,2H),4.33(dd,J=5.2,12.0Hz,1H),3.84(s,3H),2.79(m,1H),2.56(m,1H),2.32(m,1H),2.11-1.99(m,1H);MS(ESI)m / z 410.0[M+H] + .

[0524] Example 2. Synthesis of 3-(2-chloro-4'-((2-oxopyridin-1(2H)-yl)methyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 156) [ka] A mixture of 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (450 mg, 1.34 mmol, 90% purity, 1.00 equiv.), 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyridin-2(1H)-one (502 mg, 1.34 mmol, 83% purity, 1.00 equiv.), potassium phosphate (852 mg, 4.01 mmol, 3.00 equiv.), and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (196 mg, 268 μmol, 0.20 equiv.) in N,N-dimethylformamide (23 mL) was degassed and purged with nitrogen three times. The mixture was stirred at 100° C. under a nitrogen atmosphere for 16 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent 100-100% ethyl acetate / petroleum ether gradient @ 40 mL / min), followed by preparative HPLC (column: Phenomenex Luna C18 150x25 mmx10 μm; mobile phase: [water(formic acid)-acetonitrile]; B%: 24%-54%, 10 min) and lyophilized to give 3-(2-chloro-4'-((2-oxopyridin-1(2H)-yl)methyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (327 mg, 788 μmol, 59% yield) as an off-white solid. 1H NMR(400MHz,DMSO-d6)δ=10.91(s,1H),7.86(dd,J=2.0,6.8Hz,1H),7.45(ddd,J=2.0, 6.8,9.2Hz,1H),7.41-7.31(m,6H),7.28(dd,J=2.0,7.2Hz,1H),6.44(d,J=9.2Hz,1H) ,6.27(dt,J=1.2,6.8Hz,1H),5.16(s,2H),4.34(dd,J=5.2,12.0Hz,1H),2.85-2.70(m ,1H),2.58-2.51(m,1H),2.32(dq,J=4.0,12.8Hz,1H),2.09-1.98(m,1H);MS(ESI)m / z 407.0[M+H] +

[0525] Example 3. Synthesis of 3-(2-chloro-3'-(((tetrahydrofuran-3-yl)oxy)methyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 190) 3-(2-Chloro-3′-(((tetrahydrofuran-3-yl)oxy)methyl)-[1,1′-biphenyl]-3-yl)piperidine-2,6-dione was prepared from 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione and 4,4,5,5-tetramethyl-2-(3-(((tetrahydrofuran-3-yl)oxy)methyl)phenyl)-1,3,2-dioxaborolane according to general scheme 1. 1 H NMR(400MHz,DMSO-d6)δ=11.01-10.87(m,1H),7.50-7.28(m,7H),4.59-4.44(m,2H),4.34(dd,J=5.2,12.0Hz,1H),4.27- 4.17(m,1H),3.78-3.64(m,4H),2.84-2.74(m,1H),2.58-2.55(m,1H),2.40-2.27(m,1H),2.11-1.92(m,3H);MS(ESI)m / z 398.1[MH] -

[0526] Example 4. Synthesis of 3-(2-chloro-3'-methyl-4'-(2-morpholinoethoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 155) [ka] To a solution of 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (141 mg, 0.466 mmol, 1.00 equiv.), 4-(2-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)morpholine (178 mg, 0.512 mmol, 1.10 equiv.) in dimethylformamide (5 mL) was added [1,1-bis(diphen-ylphosphino)ferrocene]dichloropalladium(II) (34.1 mg, 46.6 μmol, 0.10 equiv.) and tripotassium phosphate (296 mg, 1.40 mmol, 3.00 equiv.). The mixture was degassed and purged with nitrogen three times, then stirred at 100° C. for 16 hours. The reaction mixture was cooled to 25° C. and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent: 0-80% ethyl acetate / petroleum ether gradient @ 50 mL / min). The desired fractions were collected and concentrated under reduced pressure, then purified by preparative HPLC (column: Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: [water (formic acid)-acetonitrile]; B%: 8%-38%, 10 min) and lyophilized to give 3-(2-chloro-3'-methyl-4'-(2-morpholinoethoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (82.6 mg, 185 μmol, 40% yield) as a white solid. 1H NMR(400MHz,CDCl3)δ=8.11(s,1H),7.33-7.26(m,2H),7.22-7.18(m,2H),7 .17-7.14(m,1H),6.86(d,J=9.0Hz,1H),4.35-4.29(m,1H),4.19(t,J=5.6H z,2H),3.80-3.72(m,4H),2.91(t,J=5.6Hz,2H),2.84-2.76(m,1H),2.75-2 .71(m,1H),2.70-2.64(m,4H),2.37-2.29(m,2H),2.26(s,3H);MS(ESI)m / z 443.1[M+H] +

[0527] Example 5. Synthesis of 3-(2-fluoro-4'-((1-methyl-1H-pyrazol-3-yl)methoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 150) (3-Bromo-2-fluorophenyl)piperidine-2,6-dione was prepared from 1-bromo-2-fluoro-3-methyl-benzene according to general scheme 2. [ka]

[0528] To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (2.53 g, 11.5 mmol, 1.50 equiv.) in acetic acid (20 mL) was added potassium carbonate (2.12 g, 15.3 mmol, 2.00 equiv.) and 3-(chloromethyl)-1-methyl-1H-pyrazole (1.00 g, 7.66 mmol, 1.00 equiv.). The mixture was stirred at 65° C. for 16 hours. The reaction mixture was filtered through a pad of Celite, and the filter cake was washed with acetonitrile (100 mL). The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent 0-50% ethyl acetate / petroleum ether gradient @ 40 mL / min) to give 1-methyl-3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)-1H-pyrazole (2.32 g, 7.09 mmol, 93% yield) as a yellow oil.

[0529] 3-(2-Fluoro-4'-((1-methyl-1H-pyrazol-3-yl)methoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione was prepared according to general scheme 1 from 1-methyl-3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)-1H-pyrazole and 3-(3-bromo-2-fluorophenyl)piperidine-2,6-dione. MS(ESI)m / z 394.3[M+H] +

[0530] Example 6. Synthesis of -3-(2,4-dichloro-4'-((1-methyl-1H-pyrazol-3-yl)methoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 146) 3-(3-Bromo-2,6-dichlorophenyl)piperidine-2,6-dione was prepared from 1-bromo-2,4-dichloro-3-methylbenzene according to general scheme 2.

[0531] 3-(2,4-Dichloro-4'-((1-methyl-1H-pyrazol-3-yl)methoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione was prepared according to general scheme 1 from 3-(3-bromo-2,6-dichlorophenyl)piperidine-2,6-dione and 1-methyl-3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)-1H-pyrazole. MS(ESI)m / z 444.1[M+H] +

[0532] Example 7. Synthesis of 3-(2-chloro-4-fluoro-4'-((1-methyl-1H-pyrazol-3-yl)methoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 144) 3-(3-Bromo-2-chloro-6-fluorophenyl)piperidine-2,6-dione was prepared from 1-bromo-2-chloro-4-fluoro-3-methylbenzene according to general scheme 2. [ka]

[0533] 3-(2-Chloro-4-fluoro-4'-((1-methyl-1H-pyrazol-3-yl)methoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione was prepared according to general scheme 1 from 3-(3-bromo-2-chloro-6-fluorophenyl)piperidine-2,6-dione and 1-methyl-3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)-1H-pyrazole. 1H NMR(400MHz,DMSO-d6)δ=10.99(s,1H),7.68(d,J=2.0Hz,1H),7.40-7.29(m,4H),7.09(d,J=8.8Hz,2H),6.33(d,J=2.0Hz,1H),5.04(s,2H) ,4.50(dd,J=5.2,12.0Hz,1H),3.84(s,3H),2.91-2.79(m,1H),2.56(s,1H),2.16-2.08(m,1H),2.07(s,1H),2.07-1.96(m,1H);MS(ESI)m / z 428.1[M+H] +

[0534] Example 8. Synthesis of 3-(4-chloro-2-fluoro-4'-((1-methyl-1H-pyrazol-3-yl)methoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 145) 3-(3-Bromo-6-chloro-2-fluorophenyl)piperidine-2,6-dione was prepared according to general scheme 2 from 1-bromo-4-chloro-3-(chloromethyl)-2-fluorobenzene. [ka]

[0535] 3-(4-Chloro-2-fluoro-4'-((1-methyl-1H-pyrazol-3-yl)methoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione was prepared according to general scheme 1 from 3-(3-bromo-6-chloro-2-fluorophenyl)piperidine-2,6-dione and 1-methyl-3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)-1H-pyrazole. 1H NMR(400MHz,DMSO-d6)δ=10.99(s,1H),7.67(d,J=2.0Hz,1H),7.49-7.39(m,4H),7.12(d,J=8.4Hz,2H),6.32(d,J=2.0Hz,1H),5.0 4(s,2H),4.48-4.41(m,1H),3.83(s,3H),2.90-2.81(m,1H),2.58-2.55(m,1H),2.20-2.13(m,1H),2.04-2.01(m,1H);MS(ESI)m / z 428.1[M+H] +

[0536] Example 9. Synthesis of -3-(2',4-dichloro-4'-((1-methyl-1H-pyrazol-3-yl)methoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 153) [ka] To a solution of 4-bromo-3-chlorophenol (715 mg, 3.45 mmol, 1.50 equiv) in acetonitrile (150 mL) was added potassium carbonate (635 mg, 4.6 mmol, 2.00 equiv). The mixture was stirred at 25° C. for 0.5 h. Then, 1-3-(chloromethyl)-1-methyl-1H-pyrazole (300 mg, 2.30 mmol, 1.00 equiv) was added, and the reaction mixture was stirred at 65° C. for 15.5 h. The reaction mixture was cooled to 25° C., filtered through a pad of Celite, washed with ethyl acetate (10 mL), and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent 0-50% ethyl acetate / petroleum ether gradient @ 40 mL / min) to give 3-((4-bromo-3-chlorophenoxy)methyl)-1-methyl-1H-pyrazole (678 mg, 2.11 mmol, 92% yield) as a white solid. [ka]

[0537] To a solution of 3-((4-bromo-3-chlorophenoxy)methyl)-1-methyl-1H-pyrazole (200 mg, 663 μmol, 1.00 equiv.), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (185 mg, 730 μmol, 1.10 equiv.), potassium acetate (195 mg, 1.99 mmol, 3.00 equiv.), and [1,1-bis(diphen-ylphosphino)ferrocene]dichloropalladium(II) (48.5 mg, 66.3 μmol, 0.10 equiv.) in dioxane (8 mL) was added. The mixture was degassed and purged with nitrogen three times, then stirred at 100 °C for 3 h. The mixture was cooled to 20 °C, filtered through a pad of Celite, and washed with ethyl acetate (10 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluting with a 0-50% ethyl acetate / petroleum ether gradient at 40 mL / min) followed by reverse-phase column chromatography (0.1% formic acid) to afford 3-((3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)-1-methyl-1H-pyrazole (62 mg, 128 μmol, 19% yield) as a white solid. [ka]

[0538] 3-(2′,4-Dichloro-4′-((1-methyl-1H-pyrazol-3-yl)methoxy)-[1,1′-biphenyl]-3-yl)piperidine-2,6-dione was prepared according to general scheme 1 from 3-(5-bromo-2-chlorophenyl)piperidine-2,6-dione and 3-((3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)-1-methyl-1H-pyrazole. MS(ESI)m / z 444.1[M+H] +

[0539] Example 10. Synthesis of 3-(4-chloro-2-fluoro-4'-((1-methyl-1H-pyrazol-3-yl)methoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 152) [ka] 1-Methyl-3-((3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)-1H-pyrazole was prepared from 4-bromo-3-methylphenol in a similar manner to Example 9. 1 H NMR(400MHz,DMSO-d6)δ=7.65(d,J=2.0Hz,1H),7.58-7.53(m,1H),6.82-6.75(m,2H),6 .28(d,J=2.0Hz,1H),4.98(s,2H),3.82(s,3H),2.42(s,3H),1.27(s,12H);MS(ESI)m / z 329.0[M+H] + [ka]

[0540] 3-(4-Chloro-2-fluoro-4'-((1-methyl-1H-pyrazol-3-yl)methoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione was prepared according to general scheme 1 from 3-(5-bromo-2-chlorophenyl)piperidine-2,6-dione and 1-methyl-3-((3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)-1H-pyrazole. 1H NMR(400MHz,DMSO-d6)δ=10.89(s,1H),7.66(d,J=2.0Hz,1H),7.49(d,J=8.0Hz,1H) ,7.30-7.22(m,2H),7.12(d,J=8.4Hz,1H),6.95(d,J=2.4Hz,1H),6.93-6.87(m,1H), 6.30(d,J=2.0Hz,1H),5.01(s,2H),4.25(dd,J=5.2,12.0Hz,1H),3.83(s,3H),2.84 -2.71(m,1H),2.56-2.53(m,1H),2.38-2.32(m,1H),2.21(s,3H),2.07-1.96(m,1H). MS(ESI)m / z 424.1[M+H] +

[0541] Example 11. Synthesis of 3-(4'-amino-2-chloro-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 130) [ka] 3-(4'-Amino-2-chloro-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione was prepared according to general scheme 1 from Add Back NMR of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline and 3-(3-bromo-2-chloro-phenyl)piperidine-2,6-dione. 1 H NMR(400MHz,DMSO-d6)δ=10.89(s,1H),7.28-7.35(m,1H),7.19-7.27(m,2H),7.07(d,J=8.4Hz,2H),6.61(d,J=8.4Hz,2H),5.24( MS(ESI)m / z 314.9[M+H] +

[0542] Example 12. Synthesis of 3-(2-chloro-4'-(methylamino)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 134) [ka] 3-(2-Chloro-4'-(methylamino)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione was prepared from 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione and N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline according to general scheme 1. 1 H NMR(400MHz,DMSO-d6)δ=10.9(s,1H),7.38-7.29(m,1H),7.28-7.19(m,2H),7.15(d,J=8.8Hz,2H),6.59(d,J=8.8Hz,2H),5.83(d,J=4.4 Hz,1H),4.31(dd,J=5.2,12.0Hz,1H),2.82-2.73(m,1H),2.73-2.67(m,3H),2.55(d,J=3.6Hz,1H),2.37-2.27(m,1H),2.08-1.98(m,1H). MS(ESI)m / z 329.0[M+H] +

[0543] Example 13. Synthesis of 3-(2-chloro-4'-(isopropylamino)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 129) 3-(2-Chloro-4'-(isopropylamino)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione was prepared according to general scheme 1 from N-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline and 3-(3-bromo-2-chloro-phenyl)piperidine-2,6-dione. MS(ESI)m / z 357.2, 359.2[M+H] +

[0544] Example 14. Synthesis of 3-(2-chloro-6-iodo-4'-((1-methyl-1H-pyrazol-3-yl)methoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 179) [ka] To a solution of 3-(2-chloro-6-iodo-4'-((1-methyl-1H-pyrazol-3-yl)methoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (70.0 mg, 130 μmol, 1.00 equiv.) in dimethylformamide (2 mL) was added zinc cyanide (170 mg, 1.45 mmol, 11.1 equiv.), tris(dibenzylideneacetone)dipalladium (23.9 mg, 26.1 μmol, 0.200 equiv.), and 1,1-bis(diphenylphosphino)ferrocene (14.5 mg, 26.1 μmol, 0.200 equiv.). The mixture was stirred at 110°C under a nitrogen atmosphere for 16 hours. The mixture was cooled to 25°C and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica flash column, eluent: 0-50% ethyl acetate / petroleum ether gradient @ 20 mL / min). The residue was then purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (formic acid)-acetonitrile]; B%: 25%-58%, 9 min) to give 3-(2-chloro-6-iodo-4'-((1-methyl-1H-pyrazol-3-yl)methoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (26.5 mg, 60.3 μmol, 46% yield) as a white solid. 1H NMR(400MHz,DMSO-d6)δ=10.99(s,1H),7.91(d,J=8.0Hz,1H),7.68(d,J=2.0Hz, 1H),7.57(d,J=8.0Hz,1H),7.33(t,J=8.0Hz,2H),7.15(d,J=8.8Hz,2H),6.35(d ,J=2.0Hz,1H),5.07(s,2H),4.44(dd,J=5.2,12.4Hz,1H),3.85(s,3H),2.85-2. 75(m,1H),2.60-2.56(m,1H),2.39-2.32(m,1H),2.08-2.00(m,1H).MS(ESI)m / z 435.1[M+H] +

[0545] Example 15. Synthesis of 3-(2-chloro-6-ethynyl-4'-((1-methyl-1H-pyrazol-3-yl)methoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 172) [ka] 3-(2-chloro-6-iodo-4′-((1-methyl-1H-pyrazol-3-yl)methoxy)-[1,1′-biphenyl]-3-yl)piperidine-2,6-dione was prepared similarly to Example 14. To a solution of 3-(2-chloro-6-iodo-4'-((1-methyl-1H-pyrazol-3-yl)methoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (200 mg, 373 μmol, 1.00 equiv.) and ethynyltrimethylsilane (110 mg, 1.12 mmol, 155 μL, 3.00 equiv.) in tetrahydrofuran (5 mL) was added bis(triphenylphosphine)palladium(II) chloride (52.4 mg, 74.7 μmol, 0.200 equiv.), copper iodide (35.6 mg, 187 μmol, 0.500 equiv.), and triethylamine (151 mg, 1.49 mmol, 208 μL, 4.00 equiv.). The mixture was stirred under a nitrogen atmosphere at 25° C. for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica flash column, eluent 0-50% ethyl acetate / petroleum ether gradient @ 18 mL / min) to give 3-(2-chloro-4'-((1-methyl-1H-pyrazol-3-yl)methoxy)-6-((trimethylsilyl)ethynyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (100 mg, 170 μmol, 46% yield) as a brown gum. [ka]

[0546] To a solution of 3-(2-chloro-4'-((1-methyl-1H-pyrazol-3-yl)methoxy)-6-((trimethylsilyl)ethynyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (100 mg, 170 μmol, 1.00 equiv.) in acetonitrile (4 mL) was added cesium fluoride (150 mg, 988 μmol, 5.00 equiv.). The mixture was stirred at 25°C for 5 hours. The mixture was filtered and concentrated under reduced pressure. The residue was purified by Prep-NPLC (column: Welch Ultimate XB-SiOH 250*50*10 μm; mobile phase: [hexane-ethanol]; B%: 5%~45%, 15 min) to give 3-(2-chloro-6-ethynyl-4'-((1-methyl-1H-pyrazol-3-yl)methoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (51.5 mg, 117 μmol, yield 59%, purity 99%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ=10.93(s,1H),7.68(d,J=2.0Hz,1H),7.53(d,J=8.0Hz, 1H),7.34(d,J=8.0Hz,1H),7.20(t,J=7.6Hz,2H),7.08(d,J=8.4Hz,2H),6.35(d ,J=2.0Hz,1H),5.03(s,2H),4.32(dd,J=5.2,12.0Hz,1H),4.07(s,1H),3.85(s, 3H),2.85-2.71(m,1H),2.61-2.52(m,1H),2.40-2.23(m,1H),2.10-1.95(m,1H) MS(ESI)m / z 434.1[M+H] +

[0547] Example 16. Synthesis of 3-(4'-((1H-imidazol-4-yl)methoxy)-2-chloro-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 167) [ka] tert-Butyl 4-(hydroxymethyl)-1H-imidazole-1-carboxylate (500 mg, 2.52 mmol, 1.00 equiv.), 4-iodophenol (666 mg, 3.03 mmol, 1.20 equiv.), and triphenylphosphine (992 mg, 3.78 mmol, 1.50 equiv.) were added to a solution of (E)-2,2′-(diazene-1,2-diylbis(methylene))bis(2-methylmalonic acid) (765 mg, 3.78 mmol, 736 μL, 1.50 equiv.) in tetrahydrofuran (15 mL) at 0° C. The mixture was then stirred at 20° C. for 6 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 25 g SepaFlash® silica flash column, eluent 0-20% ethyl acetate / petroleum ether gradient @ 80 mL / min) to afford tert-butyl 4-[(4-iodophenoxy)methyl]imidazole-1-carboxylate (434 mg, 1.07 mmol, 43% yield) as a white solid. [ka]

[0548] To a solution of tert-butyl 4-((4-iodophenoxy)methyl)-1H-imidazole-1-carboxylate (150 mg, 0.375 mmol, 1.00 equiv.), 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione (172 mg, 0.412 mmol, 84% purity, 1.10 equiv.), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (27.4 mg, 0.0375 mmol, 0.100 equiv.), and potassium phosphate (239 mg, 1.12 mmol, 3.00 equiv.) in 1,4-dioxane (5 mL) was added. The mixture was then degassed and purged with nitrogen three times and stirred at 80 °C under a nitrogen atmosphere for 16 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue: the crude product (170 mg, 0.343 mmol) was obtained as a green solid and used in the next step without further purification. [ka]

[0549] To a solution of tert-butyl 4-[[4-[2-chloro-3-(2,6-dioxo-3-piperidyl)phenyl]phenoxy]methyl]imidazole-1-carboxylate (170 mg, 0.343 mmol, crude, 1.00 equiv) in ethyl acetate (2 mL) was added dropwise hydrochloric acid / ethyl acetate (4 M, 2 mL, 23.3 equiv) at 0° C. The mixture was stirred at 25° C. for 16 hours. The reaction mixture was quenched by adding 5 mL of water at 25° C., then neutralized with saturated sodium bicarbonate (15 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent 0-100% ethyl acetate / petroleum ether gradient @ 30 mL / min), followed by preparative HPLC (column: Phenomenex luna C18 150*25 mm*10 um; mobile phase: [water (formic acid)-acetonitrile]; B%: 10%-30%, 9 min) to give 3-(4'-((1H-imidazol-4-yl)methoxy)-2-chloro-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (10.4 mg, 0.0261 mmol, 8% yield, 99% purity) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ=10.91(s,1H),8.14(s,1H),7.66(s,1H),7.39-7.27(m,5H),7.20(s,1H),7.10(d,J=8.8Hz,2H) ,5.01(s,2H),4.33(dd,J=5.2,12.0Hz,1H),2.79(s,1H),2.52-2.51(m,1H),2.33-2.26(m,1H),2.06(s,1H);MS(ESI)m / z 396.1[M+H] +

[0550] Example 17. Synthesis of 3-(2-chloro-4'-((1-methyl-1H-imidazol-4-yl)methoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 183) [ka] 4-((4-iodophenoxy)methyl)-1-methyl-1H-imidazole was prepared from 4-iodophenol and (1-methyl-1H-imidazol-4-yl)methanol as in Example 16.

[0551] 3-(2-Fluoro-3-(indolin-5-yl)phenyl)piperidine-2,6-dione was prepared from 4-((4-iodophenoxy)methyl)-1-methyl-1H-imidazole and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione according to general scheme 1. 1 H NMR(400MHz,DMSO-d6)δ=10.92(s,1H),7.60(s,1H),7.38-7.27(m,5H),7.25(s,1H),7.12-7.05(m,2H) ,4.96(s,2H),4.33(dd,J=5.2,12.0Hz,1H),3.65(s,3H),2.79(ddd,J=5.2,12.4,17.6Hz,1H),2.55(br d,J=3.6Hz,1H),2.39-2.26(m,1H),2.10-2.00(m,1H);MS(ESI)m / z 410.0[M+H] +

[0552] Example 18. Synthesis of 3-(2-chloro-4'-((1-methyl-1H-imidazol-5-yl)methoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 186) 5-((4-iodophenoxy)methyl)-1-methyl-1H-imidazole was prepared from 4-iodophenol and (1-methyl-1H-imidazol-5-yl)methanol as in Example 16.

[0553] 3-(2-Chloro-4'-((1-methyl-1H-imidazol-5-yl)methoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione was prepared from 5-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-imidazole and 3-(4-iodophenoxy)piperidine-2,6-dione according to Scheme 1. 1 H NMR(400MHz,DMSO-d6)δ=10.92(s,1H),8.17(s,1H),7.66(s,1H),7.40-7.32(m,4H),7.32-7.28(m,1H),7.15-7.10(m,2H),7.06(s,1H),5.15( MS(ESI)m / z 410.0[M+H] +

[0554] Example 19. Synthesis of 3-(2-chloro-4'-(1-(1-methyl-1H-pyrazol-3-yl)ethoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 173) 3-(2-chloro-4'-(1-(1-methyl-1H-pyrazol-3-yl)ethoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione was prepared from 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-1H-pyrazole and 3-(1-(4-iodophenoxy)piperidine-2,6-dione according to Scheme 1. 1H NMR(400MHz,DMSO-d6)δ=10.91(s,1H),7.61(d,J=2.0Hz,1H),7.38-7.24( m,5H),7.06-7.00(m,2H),6.25(d,J=2.4Hz,1H),5.51(q,J=6.4Hz,1H),4.3 2(dd,J=5.2,12.0Hz,1H),3.81(s,3H),2.85-2.71(m,1H),2.58-2.53(m,1H ),2.38-2.24(m,1H),2.09-1.99(m,1H),1.59(d,J=6.4Hz,3H);MS(ESI)m / z 424.1[M+H] +

[0555] Example 20. Synthesis of 3-(2-chloro-4'-((3-methyl-2-oxopyridin-1(2H)-yl)methyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 187) [ka] 1-(4-Bromobenzyl)-3-methylpyridin-2(1H)-one was prepared from 3-methylpyridin-2(1H)-one and 1-bromo-4-(bromomethyl)benzene according to general scheme 8. [ka]

[0556] 3-(2-Chloro-4'-((3-methyl-2-oxopyridin-1(2H)-yl)methyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione was prepared according to general scheme 1 from 1-(4-bromobenzyl)-3-methylpyridin-2(1H)-one and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione. 1H NMR(400MHz,DMSO-d6)δ=10.92(s,1H),7.76-7.69(m,1H),7.43-7.32(m,7H),7.31-7.25(m,1H),6.20(t,J=6.8Hz,1H),5. 17(s,2H),4.38-4.27(m,1H),2.86-2.72(m,1H),2.56(t,J=3.2Hz,1H),2.34-2.25(m,1H),2.11-1.95(m,4H);MS(ESI)m / z 421.2[M+H] +

[0557] Example 21. Synthesis of 3-(2-chloro-4'-((6-methyl-2-oxopyridin-1(2H)-yl)methyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 184) 1-(4-Bromobenzyl)-6-methylpyridin-2(1H)-one was prepared from 1-bromo-4-(bromomethyl)benzene according to general scheme 8. [ka]

[0558] 3-(2-Chloro-4'-((6-methyl-2-oxopyridin-1(2H)-yl)methyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione was prepared from 1-(4-bromobenzyl)-6-methylpyridin-2(1H)-one and 1-(4-bromobenzyl)-6-methylpyridin-2(1H)-one according to general scheme 1. 1H NMR(400MHz,DMSO-d6)δ=10.91(s,1H),7.43-7.32(m,5H),7.29(dd,J=2.0,7.2H z,1H),7.19(d,J=8.4Hz,2H),6.37(d,J=9.2Hz,1H),6.18(d,J=6.8Hz,1H),5.34 (s,2H),4.33(dd,J=5.2,12.0Hz,1H),2.79(ddd,J=5.2,12.0,17.6Hz,1H),2.55 (d,J=3.6Hz,1H),2.38-2.32(m,1H),2.31(s,3H),2.08-1.99(m,1H);MS(ESI)m / z 421.0[M+H] +

[0559] Example 22. Synthesis of 3-(2-chloro-4'-((5-methyl-2-oxopyridin-1(2H)-yl)methyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 188) [ka] 1-(4-Bromobenzyl)-5-methylpyridin-2(1H)-one was prepared from 5-methylpyridin-2(1H)-one and 1-bromo-4-(bromomethyl)benzene according to general scheme 8. [ka]

[0560] 3-(2-chloro-4'-((5-methyl-2-oxopyridin-1(2H)-yl)methyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione was prepared according to general scheme 1 from 1-(4-bromobenzyl)-5-methylpyridin-2(1H)-one and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione. 1H NMR(400MHz,DMSO-d6)δ=10.91(br s,1H),7.65(s,1H),7.42-7.26(m,8H),6.39(d,J=9.2Hz,1H),5.10(s,2H),4.34(dd,J=5.2,12.0Hz,1H) ,2.85-2.71(m,1H),2.55(d,J=3.6Hz,1H),2.32(dq,J=4.4,12.8Hz,1H),2.10-1.95(m,4H);MS(ESI)m / z 421.1 / 423.1[M+H] +

[0561] Example 23. Synthesis of 3-(2-chloro-4'-((4-methyl-2-oxopyridin-1(2H)-yl)methyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 189) [ka] 1-(4-Bromobenzyl)-4-methylpyridin-2(1H)-one was prepared from 4-methylpyridin-2(1H)-one and 1-bromo-4-(bromomethyl)benzene according to general scheme 8. [ka]

[0562] 3-(2-chloro-4'-((4-methyl-2-oxopyridin-1(2H)-yl)methyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione was prepared according to general scheme 1 from 1-(4-bromobenzyl)-4-methylpyridin-2(1H)-one and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione. 1H NMR(400MHz,DMSO-d6)δ=10.91(br s,1H),7.72(d,J=6.8Hz,1H),7.38-7.27(m,7H),6.25(s,1H),6.13(d,J=6.4Hz,1H),5.11(s,2H),4.35-4.31(m ,1H),2.82-2.76(m,1H),2.55(d,J=3.6Hz,1H),2.33-2.31(m,1H),2.14(s,3H),2.07-2.02(m,1H);MS(ESI)m / z 421.1 / 423.0[M+H,M+2+H] +

[0563] Example 24. Synthesis of 3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 185) [ka] To a solution of 1,4-diiodobenzene (1.00 g, 3.03 mmol, 1.00 equiv.) and pyridin-2(1H)-one (28.26 mg, 3.03 mmol, 1.00 equiv.) in dimethyl sulfoxide (20 mL) was added copper(I) iodide (578 mg, 3.03 mmol, 1.00 equiv.) and potassium carbonate (2.01 g, 14.6 mmol, 4.80 equiv.) under nitrogen. The mixture was stirred at 120° C. under nitrogen for 3 hours. The reaction mixture was partitioned between ethyl acetate (30 mL) and water (30 mL). The organic phase was separated, washed with 60 mL of water (2×30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica flash column, eluent 0-10% ethyl acetate / petroleum ether gradient @ 20 mL / min) to afford 1-(4-iodophenyl)pyridin-2(1H)-one (800 mg, 2.42 mmol, 79.9% yield) as a white solid. 1H NMR(400MHz,DMSO-d6)δ=7.91-7.80(m,2H),7.69-7.60(m,1H),7.51(ddd,J=2.0,6. 8,9.2Hz,1H),7.27-7.17(m,2H),6.48(d,J=9.2Hz,1H),6.32(dt,J=1.2,6.8Hz,1H) MS(ESI)m / z 298.0[M+H] +

[0564] [ka] To a solution of 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione (142 mg, 404 μmol, 1.20 equiv.) and 1-(4-iodophenyl)pyridin-2(1H)-one (100 mg, 337 μmol, 1.00 equiv.) in dioxane (5 mL) was added potassium phosphate (215 mg, 1.01 mmol, 3.00 equiv.) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (25.0 mg, 34.0 μmol, 0.100 equiv.). The mixture was stirred at 80° C. for 12 hours. The reaction mixture was filtered through a pad of Celite and washed with ethyl acetate (30 mL). The filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10μm; mobile phase: [water (formic acid)-acetonitrile]; B%: 36%-56%, 2 min), and then by preparative HPLC (column: YMC Triart C18 150*25mm*5μm; mobile phase: [water (hydrochloric acid)-acetonitrile]; B%: 30%-60%, 10 min) to give 3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (18.6 mg, 46.40 μmol, 13.79% yield) as a white solid. 1H NMR(400MHz,DMSO-d6)δ=10.94(s,1H),7.76-7.71(m,1H),7.58-7.49(m,5H),7.46-7.35(m,3H),6.51(d,J=9.2Hz,1H), 6.34(t,J=6.8Hz,1H),4.37(dd,J=4.8,12.0Hz,1H),2.88-2.72(m,2H),2.35(dd,J=4.0,12.8Hz,1H),2.12-2.01(m,1H) MS(ESI)m / z 393.0[M+H] + .

[0565] An alternative synthesis of compound 185 is provided below. [ka]

[0566] A mixture of (4-bromophenyl)boronic acid (3.00 g, 14.9 mmol, 1.00 equiv), pyridin-2(1H)-one (1.70 g, 17.9 mmol, 1.20 equiv), copper acetate (2.71 g, 14.9 mmol, 1.00 equiv) and triethylamine (4.53 g, 44.8 mmol, 6.24 mL, 3.00 equiv) in dichloroethane (5 mL) was degassed and purged with oxygen three times, then stirred at 25 °C for 3 h. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent 0-80% ethyl acetate / petroleum ether gradient @ 40 mL / min) to give 1-(4-bromophenyl)pyridin-2(1H)-one (1.6 g, 6.33 mmol, 42% yield) as a white solid. 1H NMR(400MHz,DMSO-d6)δ=7.75-7.67(m,2H),7.67-7.60(m,1H)7.51(ddd,J=9.2,6.8,2.0H z,1H),7.44-7.34(m,2H),6.48(d,J=9.2Hz,1H),6.32(dt,J=6.8,1.2Hz,1H).MS(ESI)m / z 251.6[M+H]+

[0567] A mixture of 1-(4-bromophenyl)pyridin-2(1H)-one (500 mg, 2.00 mmol, 1.00 equiv), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (558 mg, 2.20 mmol, 1.10 equiv), [1,1-bis(diphenylphosphino)ferrocene]dichloro-palladium(II) (146 mg, 199 μmol, 0.100 equiv) and potassium acetate (588 mg, 6.00 mmol, 3.00 equiv) in dioxane (5 mL) was degassed and purged with nitrogen three times, then the mixture was stirred at 80° C. under a nitrogen atmosphere for 3 h. The reaction mixture was cooled to 25° C. and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (ISCO®; 25 g SepaFlash® silica flash column, eluent 0-100% ethyl acetate / petroleum ether gradient @ 60 mL / min) to give 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridin-2(1H)-one (500 mg, 1.53 mmol, 76% yield) as a white solid. 1H NMR(400MHz,DMSO-d6)δ=7.79(d,J=7.6Hz,2H),7.64-7.60(m,1H),7.54-7.47(m,1H),7.4 2(d,J=7.6Hz,2H),6.48(d,J=9.2Hz,1H),6.32(t,J=6.8Hz,1H),1.31(s,12H).MS(ESI)m / z 298.0[M+H]+

[0568] [ka] A mixture of 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (2.78 g, 9.20 mmol, 1.00 equiv.), 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridin-2(1H)-one (3.00 g, 10.1 mmol, 1.10 equiv.), [1,1-bis(diphen-ylphosphino)ferrocene]dichloropalladium(II) (672 mg, 918 μmol, 0.10 equiv.) and potassium phosphate (5.84 g, 27.5 mmol, 3.00 equiv.) in dimethylformamide (60 mL) was degassed and purged with nitrogen three times, and then the mixture was stirred under a nitrogen atmosphere at 100° C. for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® silica flash column, eluent 100-100% ethyl acetate and dichloromethane / petroleum ether gradient @ 80 mL / min), followed by preparative HPLC (column: Phenomenex luna C18 (250 × 70 mm, 10 μm); mobile phase: [water (formic acid)-acetonitrile]; B%: 20%-50%, 20 min) and lyophilized to give 3-(2-chloro-4′-(2-oxopyridin-1(2H)-yl)-[1,1′-biphenyl]-3-yl)piperidine-2,6-dione (926 mg, 2.33 mmol, 25% yield) as a white solid. 1H NMR(400MHz,DMSO-d6)δ=10.94(s,1H),7.73(dd,J=1.6,6.8Hz,1H),7.58-7.49(m,5H),7.47-7.35(m,3H),6.51(d,J=8.8Hz,1H),6.3 4(dt,J=1.6,6.8Hz,1H),4.43-4.33(m,1H),2.87-2.74(m,1H),2.60-2.54(m,1H),2.42-2.29(m,1H),2.12-2.02(m,1H);MS(ESI)m / z 392.9[M+H] +

[0569] Example 25. Synthesis of 3-(2,4-difluoro-4'-((2-oxopyridin-1(2H)-yl)methyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 147) [ka] To a solution of N,N,N-trimethylhexadecan-1-aminium bromide (450 mg, 1.23 mmol, 0.08 equiv) in water (20 mL) was added pyridin-2(1H)-one (1.50 g, 15.8 mmol, 1.00 equiv), followed by potassium carbonate (3.27 g, 23.7 mmol, 1.50 equiv). The mixture was stirred at 25° C. for 15 minutes. 1-Bromo-4-(bromomethyl)benzene (4.34 g, 17.4 mmol, 1.10 equiv) was then added, and the mixture was stirred at 50° C. for 4 hours. The reaction mixture was cooled to 20° C. The reaction mixture was diluted with water (50 mL). The mixture was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was triturated with petroleum ether / ethyl acetate = 10 / 1 (66 mL) for 60 minutes at 25 ° C. The mixture was filtered, and the filter cake was dried under reduced pressure to give 1-(4-bromobenzyl)pyridin-2(1H)-one (3.30 g, 12.4 mmol, 78% yield) as an off-white solid. [ka]

[0570] To a solution of 1-(4-bromobenzyl)pyridin-2(1H)-one (3.30 g, 12.5 mmol, 1.00 equiv.) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (3.48 g, 13.7 mmol, 1.10 equiv.) in dioxane (60 mL) was added potassium acetate (3.68 g, 37.5 mmol, 3.00 equiv.) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (911 mg, 1.25 mmol, 0.10 equiv.). The mixture was stirred at 100° C. under a nitrogen atmosphere for 3 hours. The reaction mixture was cooled to 20° C., and the reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® silica flash column, eluent 40-60% ethyl acetate / petroleum ether gradient @ 80 mL / min) to give 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyridin-2(1H)-one (3.03 g, 8.08 mmol, 65% yield, 83% purity) as a yellow solid. [ka]

[0571] To a solution of 3-(3-bromo-2,6-difluorophenyl)piperidine-2,6-dione (100 mg, 329 μmol, 1.00 equivalents) and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyridin-2(1H)-one (113 mg, 301 μmol, 83% purity, 0.90 equivalents) in dioxane (3 mL) was added potassium phosphate (210 mg, 989 μmol, 3.01 equivalents) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (25.0 mg, 34.2 μmol, 0.10 equivalents). The mixture was stirred at 100° C. under a nitrogen atmosphere for 16 hours. The reaction mixture was cooled to 25° C. and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica flash column, eluent 78-90% ethyl acetate / petroleum ether gradient @ 15 mL / min), followed by preparative HPLC (column: Phenomenex luna C18 150x25 mmx10 μm; mobile phase: [water(formic acid)-acetonitrile]; B%: 18%-38%, 10 min) and lyophilized to give 3-(2,4-difluoro-4'-((2-oxopyridin-1(2H)-yl)methyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (49.2 mg, 119 μmol, 36% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ=10.99(s,1H),7.83(dd,J=2.0,6.8Hz,1H),7.54-7.41(m ,4H),7.38(d,J=8.4Hz,2H),7.22(t,J=9.2Hz,1H),6.43(d,J=9.2Hz,1H),6.26(d t,J=1.2,6.8Hz,1H),5.15(s,2H),4.32(dd,J=5.2,12.4Hz,1H),2.90-2.77(m,1H ),2.59-2.52(m,1H),2.19(dq,J=3.6,13.2Hz,1H),2.12-2.02(m,1H);MS(ESI)m / z 409.0[M+H] +

[0572] Example 26. Synthesis of 3-(2-chloro-4'-(((1-methyl-1H-pyrazol-3-yl)methyl)amino)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 180) 3-(2-chloro-4'-(((1-methyl-1H-pyrazol-3-yl)methyl)amino)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione was prepared according to general scheme 1 from 4-iodo-N-((1-methyl-1H-pyrazol-3-yl)methyl)aniline and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione. MS(ESI)m / z 409.1[M+H] +

[0573] Example 27. Synthesis of 3-(2-chloro-4'-(pyrrolidine-1-carbonyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 181) [ka] A mixture of (4-bromophenyl)(pyrrolidin-1-yl)methanone (100 mg, 394 μmol, 1.00 equiv.), 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione (172 mg, 394 μmol, 80% purity, 1.00 equiv.), potassium phosphate (251 mg, 1.18 mmol, 3.00 equiv.), and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (29.0 mg, 39.6 μmol, 0.10 equiv.) in dioxane (3 mL) was degassed and purged with nitrogen three times, and then the mixture was stirred under a nitrogen atmosphere at 100° C. for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent 85-95% ethyl acetate / petroleum ether gradient @ 40 mL / min), followed by preparative HPLC (column: Phenomenex luna C18 150x25 mmx10 μm; mobile phase: [water (formic acid)-acetonitrile]; B%: 26%-56%, 10 min) and lyophilized to give 3-(2-chloro-4'-(pyrrolidine-1-carbonyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (57.8 mg, 141 μmol, 36% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ=10.93(br s,1H),7.60(d,J=8.4Hz,2H),7.50-7.43(m,2H),7.43-7.37(m,2H),7.36-7.31(m,1H),4.36(dd,J=4.8,12.8Hz,1H),3.47(td,J=6.4, MS(ESI)m / z 397.0[M+H] +

[0574] Example 28. Synthesis of 3-(2-chloro-4-fluoro-4'-((2-oxopyridin-1(2H)-yl)methyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 143) [ka] 3-(2-Chloro-4-fluoro-4'-((2-oxopyridin-1(2H)-yl)methyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione was prepared according to general scheme 1 from 3-(3-bromo-2-chloro-6-fluorophenyl)piperidine-2,6-dione and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyridin-2(1H)-one. 1 H NMR(400MHz,DMSO-d6)δ=10.98(d,J=6.4Hz,1H),7.86(dd,J=2.0,6.8Hz,1H),7.45( ddd,J=2.0,6.8,9.2Hz,1H),7.39(s,1H),7.38-7.35(m,4H),7.32(s,1H),6.44(d,J =9.2Hz,1H),6.30-6.25(m,1H),5.16(s,2H),4.50(dd,J=5.2,12.4Hz,1H),2.92-2. 77(m,1H),2.56(d,J=3.2Hz,1H),2.21-2.07(m,1H),2.06-1.95(m,1H);MS(ESI)m / z 425.0[M+H] +

[0575] Example 29. Synthesis of 3-(4'-((1-methyl-1H-pyrazol-3-yl)methoxy)-2-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 191) 3-(3-Bromo-2-(trifluoromethyl)phenyl)piperidine-2,6-dione was prepared from 1-bromo-3-methyl-2-(trifluoromethyl)benzene according to general scheme 2.

[0576] 3-(4'-((1-Methyl-1H-pyrazol-3-yl)methoxy)-2-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione was prepared according to general scheme 1 from 3-(3-bromo-2-(trifluoromethyl)phenyl)piperidine-2,6-dione and 1-methyl-3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)-1H-pyrazole. MS(ESI)m / z 444.3[M+H] +

[0577] Example 30. Synthesis of 3-(2-methyl-4'-((1-methyl-1H-pyrazol-3-yl)methoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 192) [ka] To a solution of 1,3-dibromo-2-methylbenzene (477 mg, 1.91 mmol, 3.00 equiv.), 1-methyl-3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)-1H-pyrazole (200 mg, 0.636 mmol, 1.00 equiv.) in dioxane (4 mL) and water (1 mL) was added [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (46.6 mg, 63.7 μmol, 0.100 equiv.) and sodium carbonate (202 mg, 1.91 mmol, 3.00 equiv.). The reaction mixture was stirred at 100° C. under a nitrogen atmosphere for 16 hours. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (3 × 30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: 0–30% ethyl acetate / petroleum ether gradient at 25 mL / min) to afford 3-(((3′-bromo-2′-methyl-[1,1′-biphenyl]-4-yl)oxy)methyl)-1-methyl-1H-pyrazole (190 mg, 0.457 mmol, 72% yield) as a yellow gum. 1 H NMR(400MHz,DMSO-d6)δ=7.67(d,J=2.0Hz,1H),7.58(dd,J=2.4,6.8Hz,1H),7.24(d,J=8.8Hz,2H),7.21-7. 14(m,2H),7.08(d,J=8.8Hz,2H),6.33(d,J=2.0Hz,1H),5.03(s,2H),3.84(s,3H),2.26(s,3H);MS(ESI)m / z 357.0[M+H] +

[0578] [ka] To a solution of (2,6-bis(benzyloxy)pyridin-3-yl)boronic acid (214 mg, 0.638 mmol, 1.20 equiv.), 3-(((3'-bromo-2'-methyl-[1,1'-biphenyl]-4-yl)oxy)methyl)-1-methyl-1H-pyrazole (190 mg, 0.532 mmol, 1.00 equiv.) in dimethylformamide (4 mL) was added [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (38.9 mg, 53.2 μmol, 0.100 equiv.) and sodium carbonate (339 mg, 1.60 mmol, 3.00 equiv.). The reaction mixture was stirred at 80° C. under a nitrogen atmosphere for 16 hours. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (3 × 30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: 0–30% ethyl acetate / petroleum ether gradient at 30 mL / min) to afford 2,6-bis(benzyloxy)-3-(2-methyl-4′-((1-methyl-1H-pyrazol-3-yl)methoxy)-[1,1′-biphenyl]-3-yl)pyridine (160 mg, 0.259 mmol, 49% yield) as a white solid. 1H NMR(400MHz,DMSO-d6)δ=7.67(d,J=2.0Hz,1H),7.57(d,J=8.0Hz,1H),7.48-7.43(m,2H),7.41-7.37(m,2H),7.36-7.28(m,6H),7.26-7.1 8(m,3H),7.16-7.05(m,4H),6.54(d,J=8.0Hz,1H),6.33(d,J=2.0Hz,1H),5.37(s,4H),5.03(s,2H),3.84(s,3H),1.92(s,3H);MS(ESI)m / z 568.3[M+H] +

[0579] [ka] To a solution of 2,6-bis(benzyloxy)-3-(2-methyl-4'-((1-methyl-1H-pyrazol-3-yl)methoxy)-[1,1'-biphenyl]-3-yl)pyridine (80.0 mg, 0.141 mmol, 1.00 equiv) in dioxane (2 mL) was added palladium on carbon (150 mg, 10% purity), and the mixture was then degassed three times with nitrogen and three times with hydrogen. The resulting mixture was stirred under hydrogen (15 psi) at 40°C for 16 hours. The reaction mixture was filtered through diatomaceous earth, the filter cake was washed with ethyl alcohol (50 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*40mm*15um; mobile phase: [water (formic acid)-acetonitrile]; B%: 31%~64%, 9 min) and lyophilized to give 3-(2-methyl-4'-((1-methyl-1H-pyrazol-3-yl)methoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (47.1 mg, 0.119 mmol, 85% yield, 99% purity) as a white solid. 1H NMR(400MHz,DMSO-d6)δ=10.85(s,1H),7.67(d,J=2.0Hz,1H),7.24-7.16(m,3H),7.12-7.05(m,4H),6.33(d,J=2.0Hz,1H),5.03(s,2H),4.14( m / z 390.1[M+H] +

[0580] Example 31. Synthesis of 3-(2,2'-dichloro-4'-((1-methyl-1H-pyrazol-3-yl)methoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 177) [ka] A solution of 4-bromo-3-chlorophenol (715 mg, 3.45 mmol, 1.50 equiv.) and potassium carbonate (635 mg, 4.60 mmol, 2.00 equiv.) in acetonitrile (5.00 mL) was stirred at 25° C. for 20 minutes, and then 3-(chloromethyl)-1-methyl-1H-pyrazole (300 mg, 2.30 mmol, 1.00 equiv.) was added at 65° C. The mixture was stirred at 65° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give 3-((4-bromo-3-chlorophenoxy)methyl)-1-methyl-1H-pyrazole (708 mg, purity 90%) as a white solid.

[0581] 3-(2,2'-Dichloro-4'-((1-methyl-1H-pyrazol-3-yl)methoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione was prepared according to general scheme 1 from 3-((4-bromo-3-chlorophenoxy)methyl)-1-methyl-1H-pyrazole and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione. MS(ESI)m / z 444.0[M+H] +

[0582] Example 32. Synthesis of 3-(4'-((1-methyl-1H-pyrazol-3-yl)methoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 151) [ka] 3-(4'-((1-Methyl-1H-pyrazol-3-yl)methoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione was prepared from 1,3-dibromobenzene, 1-methyl-3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)-1H-pyrazole and (2,6-bis(benzyloxy)pyridin-3-yl)boronic acid in analogy to Example 30. MS(ESI)m / z 376.1[M+H] +

[0583] Example 33. Synthesis of 3-(2-chloro-4'-(2-(2-oxopyridin-1(2H)-yl)ethyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 182) 3-(2-chloro-4'-(2-(2-oxopyridin-1(2H)-yl)ethyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione was prepared according to general scheme 1 from 1-(4-bromophenethyl)pyridin-2(1H)-one and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione. MS(ESI)m / z 421.1[M+H] +

[0584] Example 34. Synthesis of 3-(2-chloro-4'-(3-(2-oxopyridin-1(2H)-yl)propyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 178) [ka] To a solution of N,N,N-trimethylhexadecan-1-aminium bromide (24.0 mg, 65.9 μmol, 0.09 equiv.) in water (4 mL), potassium carbonate (152 mg, 1.10 mmol, 1.53 equiv.) and pyridin-2(1H)-one (72.0 mg, 757 μmol, 1.05 equiv.) were added. The mixture was stirred at 25° C. for 15 minutes. Then, 1-bromo-4-(3-bromopropyl)benzene (200 mg, 720 μmol, 1.00 equiv.) was added. The mixture was stirred at 50° C. for 6 hours. The reaction mixture was cooled to 25° C. and diluted with water (20 mL). The mixture was extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica flash column, eluent 80-100% ethyl acetate / petroleum ether gradient @ 30 mL / min) to give 1-(3-(4-bromophenyl)propyl)pyridin-2(1H)-one (90.0 mg, 260 μmol, 40% yield) as a yellow solid. 3-(2-chloro-4'-(3-(2-oxopyridin-1(2H)-yl)propyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione was prepared according to general scheme 1 from 1-(3-(4-bromophenyl)propyl)pyridin-2(1H)-one and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione. 1 H NMR(400MHz,DMSO-d6)δ=10.92(s,1H),7.69(dd,J=2.0,6.4Hz,1H),7.43-7.25(m,8H),6.37(d,J=9.2Hz,1H),6.21(dt,J=1.2,6.8Hz,1H),4.34(dd,J =5.2,12.0Hz,1H),3.95(t,J=7.6Hz,2H),2.85-2.72(m,1H),2.69-2.62(m ,2H),2.59-2.52(m,1H),2.40-2.25(m,1H),2.09-1.93(m,3H);MS(ESI)m / z 435.1[M+H] +

[0585] Example 35. Synthesis of 3-(4'-((1H-imidazol-1-yl)methyl)-2-chloro-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 140) 3-(4'-((1H-imidazol-1-yl)methyl)-2-chloro-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione was prepared according to general scheme 1 from 1-(4-bromobenzyl)-1H-imidazole and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione. 1H NMR(400MHz,DMSO-d6)δ=10.92(br d,J=2.4Hz,1H),7.81(s,1H),7.46-7.23(m,8H),6.94(s,1H),5.27(s,2H),4.34(dd,J=5.2,12.4Hz,1H),2.85-2.73(m,1H),2.56(br d,J=3.2Hz,1H),2.34-2.27(m,1H),2.09-1.98(m,1H);MS(ESI)m / z 380.0[M+H] +

[0586] Example 36. Synthesis of 3-(2-chloro-4'-((1-methyl-1H-pyrazol-3-yl)methyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 176) [ka] 3-(4-Bromobenzyl)-1-methyl-1H-pyrazole was prepared from 1-bromo-4-(bromomethyl)benzene and 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole according to general scheme 8. [ka]

[0587] 3-(2-Chloro-4'-((1-methyl-1H-pyrazol-3-yl)methyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione was prepared according to general scheme 1 from 3-(4-bromobenzyl)-1-methyl-1H-pyrazole and 3-[2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine-2,6-dione. 1H NMR(400MHz,DMSO-d6)δ=10.91(s,1H),7.57(d,J=2.0Hz,1H),7.37-7.26(m,7H),6.07(d,J=2.0Hz,1H),4.34(dd,J=5.2,12.0Hz ,1H),3.91(s,2H),3.79(s,3H),2.79(m,1H),2.56(d,J=3.6Hz,1H),2.33(dd,J=4.0,12.8Hz,1H),2.11-1.97(m,1H);MS(ESI)m / z 394.0[M+H] +

[0588] Example 37. Synthesis of 3-(2-chloro-4'-(4-((2-oxopyridin-1(2H)-yl)methyl)piperidin-1-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 166) 3-(2-chloro-4'-(4-((2-oxopyridin-1(2H)-yl)methyl)piperidin-1-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione was prepared according to general scheme 1 from 1-((1-(4-bromophenyl)piperidin-4-yl)methyl)pyridin-2(1H)-one and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione. 1H NMR(400MHz,DMSO-d6)δ=10.90(s,1H),7.66(dd,J=1.6,6.8Hz,1H),7.41(ddd,J=2.0,6.8,8.8Hz,1H),7.3 7-7.32(m,1H),7.30-7.22(m,4H),6.99(d,J=8.8Hz,2H),6.39(d,J=8.8Hz,1H),6.20(dt,J=1.6,6.8Hz,1H ),4.32(dd,J=5.2,12.0Hz,1H),3.87-3.73(m,4H),2.84-2.72(m,1H),2.72-2.63(m,2H),2.57-2.52(m,1H) ),2.39-2.26(m,1H),2.10-1.91(m,2H),1.58(d,J=11.2Hz,2H),1.35(dq,J=3.2,12.4Hz,2H);MS(ESI)m / z 490.1[M+H] +

[0589] Example 38. Synthesis of 3-(2-chloro-4'-(1-(2-oxopyridin-1(2H)-yl)ethyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 174) [ka] To a solution of 1-bromo-4-(1-bromoethyl)benzene (500 mg, 1.89 mmol, 1.00 equiv.) in dimethylformamide (6 mL), cesium carbonate (1.23 g, 3.79 mmol, 2.00 equiv.) and pyridin-2(1H)-one (216 mg, 2.27 mmol, 1.20 equiv.) were added. The mixture was then stirred at 20 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica flash column, eluent: 0-50% ethyl acetate / petroleum ether gradient @ 20 mL / min). The compound 1-(1-(4-bromophenyl)ethyl)pyridin-2(1H)-one (310 mg, 1.10 mmol, 58% yield) was obtained as a white solid.

[0590] 3-(2-chloro-4'-(1-(2-oxopyridin-1(2H)-yl)ethyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione was prepared according to general scheme 1 from 1-(1-(4-bromophenyl)ethyl)pyridin-2(1H)-one and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione. MS(ESI)m / z 421.1[M+H] +

[0591] Example 39. Synthesis of 3-(2-chloro-4'-(1-(pyridin-2-yloxy)ethyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 165) [ka] To a solution of 1-bromo-4-(1-bromoethyl)benzene (500 mg, 1.89 mmol, 1.00 equiv.) in dimethylformamide (6 mL) was added cesium carbonate (1.23 g, 3.79 mmol, 2.00 equiv.) and pyridin-2(1H)-one (216 mg, 2.27 mmol, 1.20 equiv.). The mixture was degassed and purged with nitrogen three times and then stirred at 20°C under a nitrogen atmosphere for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica flash column, eluting with a 0-50% ethyl acetate / petroleum ether gradient at 20 mL / min). 2-[1-(4-bromophenyl)ethoxy]pyridine (160 mg, 546 μmol, 28.8% yield) was obtained as a colorless oil.

[0592] 3-(2-chloro-4'-(1-(pyridin-2-yloxy)ethyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione was prepared from 2-(1-(4-bromophenyl)ethoxy)pyridine and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione according to General Scheme 1. MS (ESI) m / z 443.1 [M+Na] +

[0593] Example 40. Synthesis of 3-(2-chloro-4'-((2-oxopiperidin-1-yl)methyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 168) [ka] To a solution of piperidin-2-one (1.00 g, 10.0 mmol, 1.00 equiv.) and sodium hydride (806 mg, 20.1 mmol, 60% purity, 2.00 equiv.) in tetrahydrofuran (10.0 mL) was added a solution of 1-bromo-4-(bromomethyl)benzene (2.52 g, 10.0 mmol, 1.00 equiv.) in tetrahydrofuran (10.0 mL) at 0° C., and the mixture was stirred at 25° C. for 16 hours. The mixture was quenched with saturated ammonium chloride solution (150 mL) and extracted with ethyl acetate (3×30.0 mL). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate=5 / 1 to 2 / 1) to give 1-(4-bromobenzyl)piperidin-2-one (1.54 g, 5.74 mmol, 56% yield) as a colorless oil. 1 H NMR(400MHz,DMSO-d6)δ=7.57-7.43(m,2H),7.18(d,J=8.4Hz,2H),4.46(s,2H),3.14(s,2H),2.37-2.21(m,2H),1.68(td,J=3.2,6.4Hz,4H). MS(ESI)m / z 270.0[M+3H] +

[0594] [ka] To a solution of 1-(4-bromobenzyl)piperidin-2-one (100 mg, 372 μmol, 1.00 equiv.), 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione (179 mg, 410 μmol, 80% pure, 1.10 equiv.), and methanesulfonate ([4-(N,N-dimethylamino)phenyl]di-t-butylphosphino)(2-amino-1,1-biphenyl-2-yl)palladium(II) (47.3 mg, 74.5 μmol, 0.200 equiv.) in dioxane (4.00 mL) under a nitrogen atmosphere, tripotassium phosphate (237 mg, 1.12 mmol, 3.00 equiv.) was added in one portion. The mixture was stirred at 100° C. for 12 hours. The mixture was diluted with saturated ammonium chloride solution (10.0 mL) and extracted with ethyl acetate (3 × 10.0 mL). The combined organic layers were concentrated to give the crude product. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 2 / 1 to 0 / 1) to give the crude product, which was then purified by preparative HPLC (column: Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: [water (formic acid)-acetonitrile]; B%: 30% to 60%, 10 min) and lyophilized to give 3-(2-chloro-4'-((2-oxopiperidin-1-yl)methyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (16.09 mg, 38.9 μmol, 10% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ=10.92(s,1H),7.43-7.33(m,4H),7.32-7.26(m,3H),4.55(s,2H),4. 34(dd,J=5.2,12.0Hz,1H),3.28-3.22(m,2H),2.86-2.72(m,1H),2.64-2.64(m,1H),2.56(br t,J=3.6Hz,1H),2.40-2.26(m,3H),2.08-2.01(m,1H),1.75(br t,J=3.2Hz,4H). MS(ESI)m / z 411.1[M+H] +

[0595] Example 41. Synthesis of 3-(2-chloro-4'-(pyridin-2-ylmethyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 169) [ka] 1-Bromo-4-(bromomethyl)benzene (791 mg, 3.16 mmol, 1.00 equiv.) was added dropwise to a suspension of activated zinc (2.07 g, 31.7 mmol, 10.0 equiv.) in tetrahydrofuran (50.0 mL) under nitrogen. After the temperature reached 25°C, 2-bromopyridine (500 mg, 3.16 mmol, 301 µL, 1.00 equiv.) and tetrakis[triphenylphosphine]palladium(0) (731 mg, 633 µmol, 0.200 equiv.) were then added portionwise to the mixture under nitrogen. The mixture was stirred at 25°C for 12 hours. The mixture was filtered. The filtrate was diluted with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was purified by reverse phase (C18, 120 g; conditions: water / acetonitrile = 100:0 to 0:100, 0.1% formic acid) to give 2-(4-bromobenzyl)pyridine (120 mg, 484 μmol, 15% yield) as a colorless oil. [ka]

[0596] 3-(2-chloro-4'-(pyridin-2-ylmethyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione was prepared from 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione and 2-(4-bromobenzyl)pyridine according to general scheme 1. 1H NMR(400MHz,DMSO-d6)δ=10.92(br s,1H),8.52(d,J=4.0Hz,1H),7.74(dt,J=1.6,7.6Hz,1H),7.41-7.32(m,7H),7.31-7.27(m,1H),7.26-7.21(m,1H),4 .34(dd,J=5.2,12.0Hz,1H),4.14(s,2H),2.86-2.74(m,1H),2.59-2.55(m,1H),2.39-2.26(m,1H),2.11-1.97(m,1H). MS(ESI)m / z 391.1[M+H] +

[0597] Example 42. Synthesis of 3-(2-chloro-4'-(pyrazin-2-ylmethyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 159) [ka] To a solution of 4-bromobenzaldehyde (2.00 g, 10.8 mmol, 1.00 equiv) and 2,2-dimethoxyethanamine (1.25 g, 11.9 mmol, 1.30 mL, 1.10 equiv) in methanol (20.0 mL) was added acetic acid (64.9 mg, 1.08 mmol, 61.8 μL, 0.100 equiv). The mixture was stirred at 20° C. for 0.5 hours. The mixture was concentrated under reduced pressure to give (E)-N-(4-bromobenzylidene)-2,2-dimethoxyethanamine (2.94 g, crude) as a colorless oil. [ka]

[0598] A solution of (E)-N-(4-bromobenzylidene)-2,2-dimethoxyethanamine (2.94 g, 10.8 mmol, 1.00 equiv) in 2,2,2-trifluoroacetic acid (4.00 mL) was stirred at 75 °C under a nitrogen atmosphere for 20 minutes. The reaction mixture was concentrated under reduced pressure to give a residue. Saturated sodium bicarbonate solution was added to the residue until pH = 7, and then the residue was extracted with dichloromethane (3 × 80 mL). The combined organic layers were washed with saturated sodium bicarbonate solution (90 mL) and water (90 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a brown oil. The brown oil was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give 2-(4-bromobenzyl)pyrazine (334 mg, 1.34 mmol, 12% yield) as a brown solid. [ka]

[0599] 3-(2-Chloro-4'-(pyrazin-2-ylmethyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione was prepared from 2-(4-bromobenzyl)pyrazine and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione according to general scheme 1. 1H NMR(400MHz,DMSO-d6)δ=10.88(br s,1H),8.68(d,J=1.2Hz,1H),8.59-8.52(m,1H),8.49(d,J=2.4Hz,1H),7.40-7.20(m,7H),4.30(dd,J=4.8,12. MS(ESI)m / z 392.1[M+H] +

[0600] Example 43. Synthesis of 3-(2-chloro-4'-((4-fluoro-2-oxopyridin-1(2H)-yl)methyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 170) [ka] 1-(4-Bromobenzyl)-4-fluoropyridin-2(1H)-one was prepared from 4-fluoropyridin-2(1H)-one and 1-bromo-4-(bromomethyl)benzene according to general scheme 8. [ka]

[0601] 3-(2-chloro-4'-((4-fluoro-2-oxopyridin-1(2H)-yl)methyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione was prepared according to general scheme 1 from 1-(4-bromobenzyl)-4-fluoropyridin-2(1H)-one and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione. 1 H NMR(400MHz,DMSO-d6)δ=10.91(br s,1H),8.06(t,J=8.0Hz,1H),7.40-7.33(m,6H),7.29(d,J=7.2Hz,1H),6.41-6.35(m,1H),6.26(dd,J=2.4,11.6Hz,1H),5.16 (s,2H),4.33(dd,J=4.8,12.4Hz,1H),2.80-2.75(m,1H),2.68-2.55(m,1H),2.33-2.27(m,1H),2.06-2.02(m,1H);MS(ESI)m / z 425.1[M+H] +

[0602] Example 44. Synthesis of 3-[2-chloro-3-[4-[(4-methoxy-2-oxo-1-pyridyl)methyl]phenyl]phenyl]piperidine-2,6-dione (Compound 175) [ka] 1-[(4-Bromophenyl)methyl]-4-methoxy-pyridin-2-one was prepared according to general scheme 8 from 4-methoxy-1H-pyridin-2-one and 1-bromo-4-(bromomethyl)benzene. [ka]

[0603] 3-[2-Chloro-3-[4-[(4-methoxy-2-oxo-1-pyridyl)methyl]phenyl]phenyl]piperidine-2,6-dione was prepared from 1-[(4-bromophenyl)methyl]-4-methoxy-pyridin-2-one and 3-[2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyriperidine-2,6-dione according to general scheme 1. 1 H NMR(400MHz,DMSO-d6)δ=10.91(s,1H),7.74(d,J=7.6Hz,1H),7.41-7.33(m,4H),7.33-7.26(m,3H),6.01(dd,J=2.8,7.6Hz,1H),5.85(d,J=2. 8Hz,1H),5.09(s,2H),4.40-4.28(m,1H),3.74(s,3H),2.86-2.70(m,1H) ),2.58-2.52(m,1H),2.36-2.29(m,1H),2.10-1.98(m,1H);MS(ESI)m / z 437.2[M+H] +

[0604] Example 45. Synthesis of 3-(2-chloro-4'-((2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)methyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 171) [ka] 3-(2-chloro-4'-((2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)methyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione was prepared according to general scheme 1 from 1-(4-bromobenzyl)-4-(trifluoromethyl)pyridin-2(1H)-one and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione. 1 H NMR(400MHz,DMSO-d6)δ=10.92(s,1H),8.18(d,J=7.2Hz,1H),7.42-7.34(m,6H),7.31-7.25(m,1H),6.85(s,1H),6.56(dd,J =1.6,7.2Hz,1H),5.22(s,2H),4.37-4.29(m,1H),2.79-2.63(m,1H),2.67-2.55(m,1H),2.35-2.31(m,1H),2.08-1.98(m,1H) MS(ESI)m / z 475.1[M+H] +

[0605] Example 46. Synthesis of 3-(2-chloro-4'-(((1-methyl-1H-pyrazol-3-yl)oxy)methyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 160) [ka] To a solution of 1-bromo-4-(bromomethyl)benzene (3.06 g, 12.2 mmol, 1.20 equiv) in N,N-dimethylformamide (15.0 mL) was added 1-methyl-1H-pyrazol-3-ol (1.00 g, 10.2 mmol, 1.00 equiv) and potassium carbonate (1.70 g, 12.3 mmol, 1.21 equiv) at 0° C. The mixture was stirred at 25° C. for 1.5 hours. Then, the mixture was stirred at 55° C. for 4 hours. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (100 mL), and the organic layer was washed with brine (50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by reverse phase (C18, 80 g; conditions: water / acetonitrile = 100:0 to 0:100, 0.1% formic acid) and lyophilized to give 3-((4-bromobenzyl)oxy)-1-methyl-1H-pyrazole (160 mg, 497 μmol, 5% yield, 83% purity) as a white solid and 2-(4-bromobenzyl)-1-methyl-1,2-dihydro-3H-pyrazol-3-one (350 mg, 1.30 mmol, 13% yield, 99% purity) as a white solid.

[0606] 3-(2-Chloro-4'-(((1-methyl-1H-pyrazol-3-yl)oxy)methyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione was prepared according to general scheme 1 from 3-((4-bromobenzyl)oxy)-1-methyl-1H-pyrazole and 3-(2-chloro-4'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione. MS(ESI)m / z 410.1[M+H] +

[0607] Example 47. Synthesis of 3-(2-chloro-4'-(2-oxopiperidin-1-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 161) [ka] To a solution of 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione (139 mg, 399 μmol, 1.20 equiv.) in dimethylformamide (4.00 mL) was added 1-(4-iodophenyl)piperidin-2-one (100 mg, 332 μmol, 1.00 equiv.), potassium phosphate (211 mg, 996 μmol, 3.00 equiv.), and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (24.3 mg, 33.2 μmol, 0.100 equiv.). The reaction mixture was stirred at 100° C. under a nitrogen atmosphere for 16 hours. The reaction mixture was concentrated under reduced pressure to provide a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 2 / 1) and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [water (formic acid)-acetonitrile]; B%: 28% to 58%, min) and lyophilized to give 3-(2-chloro-4'-(2-oxopiperidin-1-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (9.92 mg, 24.5 umol, 7% yield, 98% purity) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ=10.92(br s,1H),7.45-7.30(m,7H),4.35(dd,J=4.8,12.4Hz,1H),3.66(t,J=5.6Hz,2H),2.80(ddd,J=5.2,12.4,17.2Hz,1H ),2.59-2.53(m,1H),2.42(t,J=6.4Hz,2H),2.37-2.27(m,1H),2.10-2.01(m,1H),1.94-1.81(m,4H);MS(ESI)m / z 397.1[M+H] +

[0608] Example 48. Synthesis of 3-(2-chloro-4'-(2-oxopyrrolidin-1-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 162) [ka] 3-(2-chloro-4'-(2-oxopyrrolidin-1-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione was prepared from 1-(4-bromophenyl)pyrrolidin-2-one and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione according to general scheme 1. 1 H NMR(400MHz,MeOD)δ=7.69(d,J=8.8Hz,2H),7.45-7.41(m,2H),7.40-7.35(m,1H),7.34-7.29(m,2H),4.39(dd,J=5.2,12.0Hz,1H),3.98( MS(ESI)m / z 383.1[M+H] +

[0609] Example 49. Synthesis of 3-(2-chloro-4'-(2-oxoazetidin-1-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 163) 3-(2-chloro-4'-(2-oxoazetidin-1-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione was prepared from 1-(4-iodophenyl)azetidin-2-one and 3-[2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine-2,6-dione according to general scheme 1. MS(ESI) m / z=369.0[M+H] +

[0610] Example 50. Synthesis of 3-(2-chloro-4'-(1-methyl-1H-pyrazol-3-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 164) 3-(2-Chloro-4'-(1-methyl-1H-pyrazol-3-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione was prepared from 3-(4-bromophenyl)-1-methyl-1H-pyrazole and 3-[2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine-2,6-dione according to general scheme 1. MS(ESI)m / z 380.1[M+H] +

[0611] Example 51. Synthesis of 3-(2-chloro-4'-((2-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)methyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 158) [ka] 3-(2-chloro-4'-((2-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)methyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione was prepared according to general scheme 1 from 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione and 2-(4-bromobenzyl)-1-methyl-1,2-dihydro-3H-pyrazol-3-one. 1 H NMR(400MHz,DMSO-d6)δ=10.9(br s,1H),7.68(d,J=3.6Hz,1H),7.41-7.33(m,4H),7.31-7.27(m,1H),7.24(s,1H),7.22(s,1H),5.28(d,J=3.2Hz,1H),5.03(s,2H), 4.33(dd,J=5.2,12.0Hz,1H),3.32(s,3H),2.85-2.72(m,1H),2.57-2.53(m,1H),2.36-2.26(m,1H),2.09-1.99(m,1H);MS(ESI)m / z 410.1[M+H] +

[0612] Example 52. Synthesis of 3-(2-fluoro-4'-((2-oxopyridin-1(2H)-yl)methyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 149) 3-(2-Fluoro-4'-((2-oxopyridin-1(2H)-yl)methyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione was prepared according to general scheme 1 from 3-(3-bromo-2-fluorophenyl)piperidine-2,6-dione and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyridin-2(1H)-one. MS(ESI)m / z 391.1[M+H] +

[0613] Example 53. Synthesis of 3-(2-chloro-4'-(2-(2-oxopiperidin-1-yl)propan-2-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 197) [ka] To a solution of 2-(4-bromophenyl)propan-2-amine (500 mg, 2.34 mmol, 1.00 equiv) and triethylamine (473 mg, 4.67 mmol, 650 uL, 2.00 equiv) in dichloromethane (6 mL) was added 5-bromopentanoyl chloride (559 mg, 2.80 mmol, 375 uL, 1.20 equiv) at 0° C. The mixture was then stirred at 25° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to provide a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent 0-100% ethyl acetate / petroleum ether gradient @ 60 mL / min) to give the compound 5-bromo-N-[1-(4-bromophenyl)-1-methyl-ethyl]pentamide (1.71 g, 4.49 mmol, 96% yield) as a white solid. [ka]

[0614] To a solution of sodium hydride (127 mg, 3.18 mmol, 60% purity, 1.20 equiv.) in tetrahydrofuran (5 mL) was added 5-bromo-N-(2-(4-bromophenyl)propan-2-yl)pentanamide (1.00 g, 2.65 mmol, 1.00 equiv.) at 0° C. The mixture was then stirred at 70° C. under a nitrogen atmosphere for 16 hours. The reaction mixture was cooled to 25° C. and quenched with saturated ammonium chloride solution (15 mL) at 0° C. The reaction mixture was concentrated under reduced pressure to remove tetrahydrofuran and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent 0-50% ethyl acetate / petroleum ether gradient @ 40 mL / min) to afford 1-(2-(4-bromophenyl)propan-2-yl)piperidin-2-one (550 mg, 1.84 mmol, 69% yield) as a colorless oil.

[0615] 3-(2-chloro-4'-(2-(2-oxopiperidin-1-yl)propan-2-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione was prepared according to general scheme 1 from 1-(2-(4-bromophenyl)propan-2-yl)piperidin-2-one and 3-[2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine-2,6-dione. MS(ESI) m / z=439.2[M+H] +

[0616] Example 54. Synthesis of 3-(4'-(azetidin-1-yl)-2-chloro-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 195) 3-(4'-(azetidin-1-yl)-2-chloro-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione was prepared from 1-(4-bromophenyl)azetidine and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione according to General Scheme 1. MS(ESI) m / z 355.1 [M+H] +

[0617] Example 55. Synthesis of 3-(2-chloro-4'-(2-(1-methyl-1H-pyrazol-3-yl)ethyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 194) 3-(2-chloro-4'-(2-(1-methyl-1H-pyrazol-3-yl)ethyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione was prepared from 4-(2-(1-methyl-1H-pyrazol-3-yl)ethyl)phenyl trifluoromethanesulfonate and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione according to General Scheme 1. MS(ESI) m / z 408.0 [M+H] +

[0618] Example 56. Synthesis of 3-(2-fluoro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 234) [ka] A mixture of (4-bromophenyl)boronic acid (3.00 g, 14.9 mmol, 1.00 equiv), pyridin-2(1H)-one (1.70 g, 17.9 mmol, 1.20 equiv), copper acetate (2.71 g, 14.9 mmol, 1.00 equiv), and triethylamine (4.53 g, 44.8 mmol, 6.24 mL, 3.00 equiv) in dichloroethane (5 mL) was degassed and purged with oxygen three times, then the mixture was stirred at 25° C. for 3 h. The reaction mixture was concentrated under reduced pressure to provide a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent 0-80% ethyl acetate / petroleum ether gradient @ 40 mL / min) to give 1-(4-bromophenyl)pyridin-2(1H)-one (1.6 g, 6.33 mmol, 42% yield) as a white solid. [ka]

[0619] 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridin-2(1H)-one was prepared from 1-(4-bromophenyl)pyridin-2(1H)-one and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane according to general scheme 6. [ka]

[0620] 3-(2-Fluoro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione was prepared according to general scheme 1 from 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridin-2(1H)-one and 3-[2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine-2,6-dione. 1 H NMR(400MHz,DMSO-d6)δ=10.92(s,1H),7.74-7.63(m,3H),7.56-7.48(m,4H),7.41-7.35(m,1H),7.34-7.28(m,1H),6.51(d,J=9.3Hz,1H ),6.34(dt,J=6.8,1.2Hz,1H),4.16(dd,J=12.4,5.2,Hz,1H),2.84-2.72(m,1H),2.62-2.55(m,1H),2.35-2.21(m,1H),2.14-2.02(m,1H) MS(ESI)m / z 377.1[M+H] +

[0621] Example 57. Synthesis of 3-(2-chloro-4'-(((1-methyl-1H-pyrazol-3-yl)amino)methyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 196) To a solution of 4-bromobenzaldehyde (1.00 g, 5.40 mmol, 1.00 equiv) and 1-methyl-1H-pyrazol-3-amine (525 mg, 5.40 mmol, 1.00 equiv) in dichloromethane (15.0 mL) was added acetic acid (325 mg, 5.40 mmol, 309 μL, 1.00 equiv) dropwise at 25° C. The mixture was stirred at 25° C. for 1 hour. Sodium triacetoxyborohydride (2.29 g, 10.8 mmol, 2.00 equiv) was then added portionwise at 25° C. The mixture was stirred at 25° C. for 11 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate (3×30.0 mL). The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate=5 / 1) to give N-(4-bromobenzyl)-1-methyl-1H-pyrazol-3-amine (1.19 g, 4.47 mmol, 82% yield) as a white solid.

[0622] 3-(2-Chloro-4'-(((1-methyl-1H-pyrazol-3-yl)amino)methyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione was prepared according to general scheme 1 from N-(4-bromobenzyl)-1-methyl-1H-pyrazol-3-amine and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione. MS(ESI)m / z 409.0[M+H] +

[0623] Example 58. Synthesis of 3-(2-chloro-4'-(oxetan-3-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 198) 3-(2-chloro-4′-(oxetan-3-yl)-[1,1′-biphenyl]-3-yl)piperidine-2,6-dione was prepared from 3-(4-bromophenyl)oxetane and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione according to general scheme 1. MS(ESI)m / z 356.0[M+H] +

[0624] Example 59. Synthesis of 3-(2-chloro-3'-methyl-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 199) 1-(4-Bromo-2-methylphenyl)pyridin-2(1H)-one was prepared according to general scheme 7 from 4-bromo-1-iodo-2-methylbenzene and pyridin-2(1H)-one.

[0625] 3-(2-Chloro-3'-methyl-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione was prepared according to general scheme 1 from 1-(4-bromo-2-methylphenyl)pyridin-2(1H)-one and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione. MS(ESI)m / z 407.1[M+H] +

[0626] Example 60. Synthesis of 3-(2-chloro-4'-(2-methyl-6-oxopiperidin-1-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 200) [ka] To a mixture of 4-bromoaniline (1.00 g, 5.81 mmol, 1.00 equiv) in toluene (10.0 mL) was added 5-oxohexanoic acid (756 mg, 5.81 mmol, 694 μL, 1.00 equiv), indium acetate (17.0 mg, 58.1 μmol, 0.0100 equiv), and phenylsilane (629 mg, 5.81 mmol, 717 μL, 1.00 equiv). The mixture was stirred at 120° C. for 4 hours. The mixture was poured into water (80 mL) and extracted with ethyl acetate (3×60 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=0:1 to 3:1) to give 1-(4-bromophenyl)-6-methyl-piperidin-2-one (1.31 g, 4.89 mmol, 84% yield) as a yellow oil. [ka]

[0627] 3-(2-chloro-4'-(2-methyl-6-oxopiperidin-1-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione was prepared according to general scheme 1 from 1-(4-bromophenyl)-6-methyl-piperidin-2-one and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione. 1 H NMR(400MHz,DMSO-d6)δ=10.92(s,1H),7.48-7.32(m,5H),7.29-7.24(m,2H),4.35(dd,J=5.2,12.0Hz,1H),4.06-3.94(m, 1H),2.87-2.74(m,1H),2.46-2.31(m,4H),2.16-2.02(m,2H),1.99-1.84(m,1H),1.83-1.63(m,2H),1.03(d,J=6.4Hz,3H). MS(ESI)m / z 411.2[M+H] +

[0628] Example 61. Synthesis of 3-(2-chloro-3-(6-(2-(1-methyl-1H-pyrazol-3-yl)ethyl)pyridin-3-yl)phenyl)piperidine-2,6-dione (Compound 249) 3-(2-chloro-3-(6-(2-(1-methyl-1H-pyrazol-3-yl)ethyl)pyridin-3-yl)phenyl)piperidine-2,6-dione was prepared according to general scheme 1 from 3-(2-chloro-4'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione and 6-(2-(1-methyl-1H-pyrazol-3-yl)ethyl)pyridin-3-yl trifluoromethanesulfonate. MS(ESI)m / z 409.0[M+H] +

[0629] Example 62 Synthesis of (S)-3-(2-chloro-4'-((2-oxopyridin-1(2H)-yl)methyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 202) and (R)-3-(2-chloro-4'-((2-oxopyridin-1(2H)-yl)methyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 201) [ka] 3-(2-Chloro-4'-((2-oxopyridin-1(2H)-yl)methyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (150 mg, 369 μmol, 1.00 equiv.) was purified by SFC (column: DAICEL CHIRALPAK AS (250 mm x 30 mm, 10 μm); mobile phase: [propan-2-ol / acetonitrile]; B%: 70% to 70%, 6 min). The desired fractions were concentrated under reduced pressure to give two crude products. The crude product 1 was purified by preparative HPLC (column: YMC-Actus Triart C18 150x30mmx7µm; mobile phase: [water(formic acid)-acetonitrile]; B%: 35%-65%, 10 min) and lyophilized to give (S)-3-(2-chloro-4'-((2-oxopyridin-1(2H)-yl)methyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (46.4 mg, 113 µmol, 31% yield) as a white solid. The crude product 2 was purified by preparative HPLC (column: YMC-Actus Triart C18 150x30mmx7µm; mobile phase: [water(formic acid)-acetonitrile]; B%: 35%-65%, 10 min) and lyophilized to give (R)-3-(2-chloro-4'-((2-oxopyridin-1(2H)-yl)methyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (47.8 mg, 116 µmol, 32% yield) as a white solid. Compound 202: 1H NMR(400MHz,DMSO-d6)δ=10.91(s,1H),7.86(dd,J=1.6,6.8Hz,1H),7.45(ddd,J =1.6,6.8,8.8Hz,1H),7.41-7.32(m,6H),7.28(dd,J=1.6,6.8Hz,1H),6.44(d,J =8.8Hz,1H),6.27(dt,J=1.2,6.8Hz,1H),5.16(s,2H),4.33(dd,J=4.8,12.4Hz, 1H),2.85-2.70(m,1H),2.58-2.52(m,1H),2.40-2.26(m,1H),2.09-1.97(m,1H). MS(ESI)m / z 407.2[M+H] + Compound 201: 1 H NMR(400MHz,DMSO-d6)δ=10.91(br s,1H),7.86(dd,J=1.6,6.8Hz,1H),7.45(ddd,J=1.6,6.8,8.8Hz,1H),7.41-7.31(m,6H),7.28(dd,J=1.6,6.8Hz,1H),6.44(d,J=8.8Hz,1H),6.2 7(dt,J=1.2,6.8Hz,1H),5.16(s,2H),4.33(dd,J=4.8,12.4Hz,1H),2.8 6-2.71(m,1H),2.58-2.52(m,1H),2.39-2.26(m,1H),2.10-1.97(m,1H). MS(ESI)m / z 407.2[M+H] +

[0630] Example 63. Synthesis of 3-(4'-((1H-pyrazol-3-yl)methoxy)-2-chloro-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 203) [ka] tert-Butyl 3-((4-iodophenoxy)methyl)-1H-pyrazole-1-carboxylate was prepared from (1H-pyrazol-3-yl)methanol and 4-iodophenol as in Example 16.

[0631] tert-Butyl 3-(((2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-4-yl)oxy)methyl)-1H-pyrazole-1-carboxylate was prepared according to general scheme 1 from tert-butyl 3-((4-iodophenoxy)methyl)-1H-pyrazole-1-carboxylate and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione. [ka]

[0632] To a mixture of tert-butyl 3-(((2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-4-yl)oxy)methyl)-1H-pyrazole-1-carboxylate (100 mg, 181 μmol, 90% purity, 1.00 equiv) in ethyl acetate (2.00 mL) was added hydrochloric acid / ethyl acetate (4 M, 2 mL) dropwise at 0° C. The mixture was stirred at 25° C. for 2 hours. Saturated sodium bicarbonate solution (3 mL) was added to the mixture, which was diluted with water (10 mL) and extracted with ethyl acetate (3×20 mL). The organic layer was washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (formic acid)-acetonitrile]; B%: 28%~58%, 10 min) and lyophilized to give 3-(4'-((1H-pyrazol-3-yl)methoxy)-2-chloro-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (25.43 mg, 63.6 umol, 35% yield, 99% purity) as a white solid. MS(ESI)m / z 396.1[M+H] +

[0633] Example 64. Synthesis of 3-(2-chloro-4'-(2-oxooxazolidin-3-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 212) [ka] A mixture of 4-iodoaniline (1.00 g, 4.57 mmol, 1.00 equiv), 1,3-dioxolan-2-one (2.41 g, 27.4 mmol, 1.83 mL, 6.00 equiv), and 1,4-diazabicyclo[2.2.2]octane (1.02 g, 9.13 mmol, 1.00 mL, 2.00 equiv) was stirred at 100° C. under a nitrogen atmosphere for 5 hours. The reaction mixture was diluted with water (200 mL) and extracted with dichloromethane (4×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 10 g SepaFlash® silica flash column, eluent 0-30% ethyl acetate / petroleum ether gradient @ 18 mL / min) to give 3-(4-iodophenyl)oxazolidin-2-one (1.31 g, 3.99 mmol, 87% yield) as a yellow solid. [ka]

[0634] 3-(2-Chloro-4'-(2-oxooxazolidin-3-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione was prepared from 3-(4-iodophenyl)oxazolidin-2-one and 3-[2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine-2,6-dione according to general scheme 1. 1H NMR(400MHz,DMSO-d6)δ=10.92(s,1H),7.68(d,J=8.4Hz,2H),7.48-7.42(m,2H),7.40-7.28(m,3H),4.47(t,J=8.0Hz,2H),4.34(dd,J=4 .8,12.0Hz,1H),4.12(t,J=8.0Hz,2H),2.79(ddd,J=5.2,12.4,17.6Hz,1H),2.56(d,J=3.6Hz,1H),2.38-2.27(m,1H),2.12-1.99(m,1H). MS(ESI)m / z 385.1[M+H] +

[0635] Example 65. Synthesis of 3-(2-chloro-4'-(6-methyl-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 214) [ka] To a solution of 4-hydroxy-6-methyl-2H-pyran-2-one (5.00 g, 39.7 mmol, 1.00 equiv.) in water (10 mL) and acetic acid (10 mL) was added 4-bromoaniline (8.18 g, 47.6 mmol, 1.20 equiv.). The mixture was stirred at 110° C. for 12 hours. The reaction mixture was cooled to 25° C., then filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by reverse-phase column chromatography (0.1% FA). The desired fractions were then collected and lyophilized to obtain 1-(4-bromophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one (2.82 g, 9.67 mmol, 24% yield) as a yellow solid. [ka]

[0636] To a solution of 1-(4-bromophenyl)-4-hydroxy-6-methyl-pyridin-2-one (1.50 g, 4.71 mmol, 88% purity, 1.00 equiv.) in pyridine (10 mL) was added triflic anhydride (1.99 g, 7.07 mmol, 1.17 mL, 1.50 equiv.) dropwise at 0° C. After the addition, the resulting mixture was stirred at 25° C. for 2 hours. The reaction mixture was quenched at 25° C. by adding water (20 mL) and then extracted with dichloromethane (3×25 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent 0-100% ethyl acetate / petroleum ether gradient @ 35 mL / min) to give 1-(4-bromophenyl)-6-methyl-2-oxo-1,2-dihydropyridin-4-yl trifluoromethanesulfonate (1.89 g, 4.54 mmol, 96% yield) as a pale yellow solid. [ka]

[0637] A mixture of [1-(4-bromophenyl)-2-methyl-6-oxo-4-pyridyl]trifluoromethanesulfonate (2.00 g, 4.80 mmol, 99% purity, 1.00 equiv.), palladium(II) acetate (53.9 mg, 240 μmol, 0.0500 equiv.), and 1,3-bis(diphenylphosphino)propane (99.1 mg, 240 μmol, 0.0500 equiv.) in dimethylformamide (20 mL) was degassed and purged with nitrogen three times. The mixture was then stirred at 60° C. for 10 minutes, followed by the addition of triethylsilane (1.40 g, 607 μmol, 96.9 μL, 2.50 equiv.). The reaction mixture was then stirred at 60° C. for an additional 12 hours. The reaction mixture was concentrated under reduced pressure to remove dimethylformamide. The residue was diluted with ethyl acetate (30 mL) and filtered through a Celite plug. Water (50 mL) was added and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent 0–100% ethyl acetate / petroleum ether gradient @ 35 mL / min) to give 1-(4-bromophenyl)-6-methyl-pyridin-2-one (660 mg, 2.47 mmol, 52% yield) as a white solid. [ka]

[0638] 3-[2-Chloro-3-[4-(2-methyl-6-oxo-1-pyridyl)phenyl]phenyl]piperidine-2,6-dione was prepared according to general scheme 1 from 1-(4-bromophenyl)-6-methyl-pyridin-2-one and 3-[2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine-2,6-dione. 1H NMR(400MHz,DMSO-d6)δ 10.94(s,1H),7.56(d,J=8.0Hz,2H),7.46-7.38(m,4H),7.35(d,J=8.4Hz,2H),6.37(d,J=9.2Hz,1H),6.26(d,J=6.4 Hz,1H),4.20-4.40(m,1H),2.84-2.75(m,1H),2.62-2.57(m,1H),2.37-2.31(m,1H),2.10-2.05(m,1H),1.96(s,3H). MS(ESI)m / z 407.1[M+H] +

[0639] Example 66. Synthesis of 3-(2-chloro-4'-(((1-methyl-1H-pyrazol-4-yl)methyl)amino)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 193) 3-(2-chloro-4'-(((1-methyl-1H-pyrazol-4-yl)methyl)amino)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione was prepared according to general scheme 1 from 4-bromo-N-((1-methyl-1H-pyrazol-4-yl)methyl)aniline and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione. MS(ESI)m / z 409.4[M+H] +

[0640] Example 67. Synthesis of N-[4-[2-chloro-3-(2,6-dioxo-3-piperidyl)phenyl]phenyl]-1-methyl-pyrazole-3-carboxamide (Compound 207) [ka] A mixture of 4-iodoaniline (500 mg, 2.28 mmol, 1.00 equiv.), 1-methylpyrazole-3-carboxylic acid (302.30 mg, 2.40 mmol, 1.05 equiv.), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (V) (1.30 g, 3.42 mmol, 1.50 equiv.), and N-ethyl-N-isopropylpropan-2-amine (885 mg, 6.85 mmol, 1.19 mL, 3.00 equiv.) in N,N-dimethylformamide (10 mL) was degassed and purged with nitrogen three times, and then the mixture was stirred under a nitrogen atmosphere at 25° C. for 4 hours. The reaction mixture was concentrated under reduced pressure to provide a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent: 0-100% ethyl acetate / petroleum ether gradient @ 40 mL / min). The desired fractions were collected and lyophilized to give N-(4-iodophenyl)-1-methyl-pyrazole-3-carboxamide (710 mg, 2.15 mmol, 94% yield, 99% purity) as a pale yellow solid.

[0641] N-[4-[2-chloro-3-(2,6-dioxo-3-piperidyl)phenyl]phenyl]-1-methyl-pyrazole-3-carboxamide was prepared according to general scheme 1 from N-(4-iodophenyl)-1-methyl-pyrazole-3-carboxamide and 3-[2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine-2,6-dione. MS(ESI)m / z 423.2[M+H] +

[0642] Example 68. Synthesis of 1-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-4-yl)piperidine-2,6-dione (Compound 205) (4-bromophenyl)piperidine-2,6-dione (2.24 g, 8.29 mmol, 79% yield) was obtained as a white solid.

[0643] 1-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-4-yl)piperidine-2,6-dione was prepared from 1-(4-bromophenyl)piperidine-2,6-dione and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione according to general scheme 1. MS(ESI)m / z 411.1[M+H] +

[0644] Example 69. Synthesis of 3-(2-chloro-4'-(2-oxo-1,3-oxazinan-3-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 204) [ka] A mixture of 3-(4-bromophenyl)-1,3-oxazinan-2-one (100 mg, 390 μmol, 1.00 equiv.), 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione (170 mg, 390 μmol, 80% pure, 1.00 equiv.), potassium phosphate (249 mg, 1.17 mmol, 3.00 equiv.), and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (28.6 mg, 39.1 μmol, 0.100 equiv.) in dioxane (5 mL) was degassed and purged with nitrogen three times, and then the mixture was stirred at 100° C. for 16 h. The mixture was cooled to 25° C., filtered, and concentrated to a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent: 0-100% ethyl acetate / petroleum ether gradient @ 30 mL / min), followed by preparative HPLC (column: Phenomenex luna C18 150x25 mmx10 μm; mobile phase: [water (formic acid)-acetonitrile]; B%: 30%-50%, 10 min) and lyophilized to give 3-(2-chloro-4'-(2-oxo-1,3-oxazinan-3-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (31.2 mg, 77.4 μmol, 20% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ=10.92(s,1H),7.49-7.29(m,7H),4.45-4.28(m,3H),3.73(t,J=6 .0Hz,2H),2.87-2.72(m,1H),2.56(d,J=3.6Hz,1H),2.40-2.29(m,1H),2.19-2.01(m,3H) MS(ESI)m / z 399.1[M+H] +

[0645] Example 70. Synthesis of 3-(2-chloro-4'-((2-oxopyrrolidin-1-yl)methyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 206) 3-(2-chloro-4'-((2-oxopyrrolidin-1-yl)methyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione was prepared from 1-(4-bromobenzyl)pyrrolidin-2-one and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione according to general scheme 1. 1 H NMR(400MHz,DMSO-d6)δ=10.92(s,1H),7.44-7.33(m,4H),7.33-7.26(m,3H),4.43(s,2H),4.34(dd,J=5.2,12.4Hz,1H),3.33-3.29( m,2H),2.79(ddd,J=5.2,12.4,17.2Hz,1H),2.59-2.53(m,1H),2.40-2.26(m,3H),2.09-2.01(m,1H),1.96-1.87(m,2H);MS(ESI)m / z 397.3[M+H] +

[0646] Example 71 Synthesis of (S)-3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 211) and (R)-3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 210) [ka] 3-(2-Chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (150 mg, 383 μmol, 1.00 equiv.) was purified by SFC (column: DAICEL CHIRALPAK IC (250 mm x 30 mm, 10 μm); mobile phase: [isopropyl alcohol-acetonitrile]; B%: 75% to 75%, 4.7 min). The desired fractions were concentrated under reduced pressure to give two crude products. The crude product 1 was purified by preparative HPLC (column: Welch Xtimate C18 150x25mmx5μm; mobile phase: [water(formic acid)-acetonitrile]; B%: 25%-55%, 8 min) and lyophilized to give (S)-3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (37.0 mg, 93.2 μmol, 24% yield) as a white solid. The crude product 2 was purified by preparative HPLC (column: YMC-Actus Triart C18 150x30mmx7µm; mobile phase: [water(formic acid)-acetonitrile]; B%: 30%-60%, 10 min) and lyophilized to give (R)-3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (44.8 mg, 113 µmol, 30% yield) as a white solid. Compound 211: 1 H NMR(400MHz,DMSO-d6)δ=10.94(s,1H),7.73(dd,J=1.6,6.8Hz,1H),7.59-7.48(m,5H),7.47-7.33(m,3H),6.51(d,J=9.2Hz,1H), 6.34(t,J=6.4Hz,1H),4.38(dd,J=5.2,12.4Hz,1H),2.88-2.73(m,1H),2.61-2.53(m,1H),2.38-2.28(m,1H),2.11-2.02(m,1H). MS(ESI)m / z 393.3[M+H] + Compound 210: 1H NMR(400MHz,DMSO-d6)δ=10.94(s,1H),7.77-7.69(m,1H),7.58-7.48(m,5H),7.47-7.33(m,3H),6.51(d,J=9.2Hz,1H),6.34( t,J=6.4Hz,1H),4.37(dd,J=5.2,12.4Hz,1H),2.89-2.73(m,1H),2.57(d,J=3.6Hz,1H),2.38-2.28(m,1H),2.14-2.00(m,1H) MS(ESI)m / z 393.3[M+H] +

[0647] Example 72. Synthesis of (S)-3-(2-chloro-4'-((1-methyl-1H-pyrazol-3-yl)methoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 209) [ka] 3-(2-chloro-4'-((1-methyl-1H-pyrazol-3-yl)methoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (150 mg, 366 μmol, 1.00 equiv.) was purified by SFC (column: DAICEL CHIRALPAK IC (250 mm x 30 mm, 10 μm); mobile phase: [propan-2-ol / acetonitrile]; B%: 50% to 50%, 5.2 min). The desired fractions were concentrated under reduced pressure to give two crude products. The crude product 1 was purified by preparative HPLC (column: YMC-Actus Triart C18 150x30mmx7μm; mobile phase: [water(formic acid)-acetonitrile]; B%: 40%-70%, 10 min) and lyophilized to give (S)-3-(2-chloro-4'-((1-methyl-1H-pyrazol-3-yl)methoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (43.0 mg, 104 μmol, 28% yield) as an off-white solid. 1H NMR(400MHz,DMSO-d6)δ=10.92(s,1H),7.67(d,J=2.0Hz,1H),7.40-7.26(m,5H),7.13-7.04(m,2H),6.33(d,J=2.0Hz,1H),5.04(s,2H) ),4.33(dd,J=4.8,12.0Hz,1H),3.84(s,3H),2.85-2.72(m,1H),2.58-2.52(m,1H),2.40-2.26(m,1H),2.08-1.99(m,1H);MS(ESI)m / z 410.2[M+H] +

[0648] Example 73. Synthesis of (R)-3-(2-chloro-4'-((1-methyl-1H-pyrazol-3-yl)methoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 213) [ka] 3-(2-chloro-4'-((1-methyl-1H-pyrazol-3-yl)methoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (150 mg, 366 μmol, 1.00 equiv.) was purified by SFC (column: DAICEL CHIRALPAK IC (250 mm x 30 mm, 10 μm); mobile phase: [propan-2-ol / acetonitrile]; B%: 60%-60%, 3.9 min) to give two crude products. The crude product 2 was purified by preparative HPLC (column: YMC-Actus Triart C18 150x30mmx7µm; mobile phase: [water(formic acid)-acetonitrile]; B%: 40%-70%, 10 min) and lyophilized to give (R)-3-(2-chloro-4'-((1-methyl-1H-pyrazol-3-yl)methoxy)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (62.6 mg, 151 µmol, 41% yield) as a white solid. 1H NMR(400MHz,DMSO-d6)δ=10.92(s,1H),7.67(d,J=2.0Hz,1H),7.40-7.27(m,5H),7.13-7.06(m,2H),6.33(d,J=2.0Hz,1H),5.04(s,2H) ),4.33(dd,J=4.8,12.0Hz,1H),3.84(s,3H),2.85-2.73(m,1H),2.58-2.52(m,1H),2.40-2.26(m,1H),2.10-1.99(m,1H);MS(ESI)m / z 409.9[M+H] +

[0649] Example 74. Synthesis of 3-(2-chloro-4'-((R)-4-methyl-2-oxooxazolidin-3-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 217) [ka] A mixture of 1-bromo-4-iodobenzene (923 mg, 3.26 mmol, 1.10 equiv.), (R)-4-methyloxazolidin-2-one (300 mg, 2.97 mmol, 1.00 equiv.), potassium phosphate (1.26 g, 5.93 mmol, 2.00 equiv.), copper(II) acetate (53.9 mg, 297 μmol, 0.100 equiv.), and 3,4,7,8-tetramethyl-1,10-phenanthroline (105 mg, 445 μmol, 0.150 equiv.) in dimethyl sulfoxide (5 mL) was degassed and purged with nitrogen three times, and then the mixture was stirred under a nitrogen atmosphere at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure to remove dimethyl sulfoxide. The residue was diluted with water (20 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue that was purified by flash silica gel chromatography (ISCO®; 10 g SepaFlash® silica flash column, eluent: 0–35% ethyl acetate / petroleum ether gradient @ 35 mL / min) to give (R)-3-(4-bromophenyl)-4-methyloxazolidin-2-one (1.89 g, 4.54 mmol, 96% yield) as a pale yellow solid. [ka]

[0650] 3-(2-chloro-4'-((R)-4-methyl-2-oxooxazolidin-3-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione was prepared according to general scheme 1 from (R)-3-(4-bromophenyl)-4-methyloxazolidin-2-one and 3-[2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine-2,6-dione. 1H NMR(400MHz,DMSO-d6)δ ppm 11.09-10.67(m,1H),7.59(d,J=8.4Hz,2H),7.45(d,J=8.8Hz,2H),7.43-7.30(m,3H),4.77-4.67(m,1H),4.58(t,J=8.4Hz,1H),4.35(dd ,J=12.0,8.8Hz,1H),4.06(dd,J=8.4,5.6Hz,1H),2.85-2.75(m,1H),2.60-2.53(m,1H),2.39-2.28(m,1H),2.09-1.99(m,1H),1.27(d,J =6.4Hz,3H);MS(ESI)m / z 399.1[M+H] +

[0651] Example 75. Synthesis of 3-(2-chloro-4'-((S)-4-methyl-2-oxooxazolidin-3-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 216) [ka] (S)-3-(4-Bromophenyl)-4-methyloxazolidin-2-one was prepared from 1-bromo-4-iodobenzene and (S)-4-methyloxazolidin-2-one using a method similar to Example 74. [ka]

[0652] 3-(2-chloro-4'-((S)-4-methyl-2-oxooxazolidin-3-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione was prepared according to general scheme 1 from (S)-3-(4-bromophenyl)-4-methyloxazolidin-2-one and 3-[2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine-2,6-dione. 1H NMR(400MHz,DMSO-d6)δ=10.92(s,1H),7.62-7.55(m,2H),7.48-7.43(m,2H) ,7.42-7.30(m,3H),4.77-4.65(m,1H),4.58(t,J=8.4Hz,1H),4.35(dd,J=12. 4,5.2Hz,1H),4.06(dd,J=8.4,5.2Hz,1H),2.85-2.73(m,1H),2.60-2.52(m, 1H),2.38-2.29(m,1H),2.10-2.00(m,1H),1.27(d,J=6.0Hz,3H);MS(ESI)m / z 399.1[M+H] +

[0653] Example 76. Synthesis of 3-(2-chloro-4'-(pyridin-2-ylamino)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 215) [ka] To a solution of 2-fluoropyridine (1.00 g, 10.3 mmol, 885 μL, 1.00 equiv.) and 4-bromoaniline (2.66 g, 15.5 mmol, 1.50 equiv.) in tetrahydrofuran (10 mL), potassium bis(trimethylsilyl)amide (1.00 M, 15.5 mL, 1.50 equiv.) was added, and the mixture was stirred at 100° C. under a nitrogen atmosphere for 4 h. The reaction mixture was filtered, washed with tetrahydrofuran (3×10 mL), and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent: 0–60% ethyl acetate / petroleum ether gradient @ 18 mL / min) to give N-(4-bromophenyl)pyridin-2-amine (1.96 g, 7.16 mmol, 70% yield) as a brown solid.

[0654] 3-(2-Chloro-4'-(pyridin-2-ylamino)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione was prepared from N-[2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyridin-2-amine and 3-(4-bromophenyl)piperidine-2,6-dione according to general scheme 1. MS(ESI)m / z 392.3[M+H] +

[0655] Example 77. Synthesis of 3-(2-chloro-4'-(3-fluoro-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 247) [ka] A mixture of 1-methyltetrahydropyrimidin-2(1H)-one (500 mg, 4.38 mmol, 1.00 equiv.), 1-bromo-4-iodobenzene (1.49 g, 5.26 mmol, 1.20 equiv.), copper iodide (167 mg, 876 μmol, 0.200 equiv.), potassium phosphate (1.86 g, 8.76 mmol, 2.00 equiv.), and N,N-dimethylethane-1,2-diamine (154 mg, 1.75 mmol, 189 μL, 0.400 equiv.) in dioxane (7 mL) was degassed and purged with nitrogen three times, and then the mixture was stirred under a nitrogen atmosphere at 110° C. for 16 h. The reaction mixture was cooled to 25° C., then diluted with water (70 mL), and extracted with ethyl acetate (5×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue that was purified by flash silica gel chromatography (ISCO®; 10 g SepaFlash® silica flash column, eluting with a 0...

Claims

1. Formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, wherein L １ teeth, - is a bond; *-O(C ０ ~C ４ alkylene)-, *-S(C ０ ~C ４ alkylene)-, *-C １ ~C ４ Alkylene-, or *-NR'(C ０ ~C ４ alkylene)-, -(C １ ~C ４ alkylene)-C(=O)-*, *-(C １ ~C ４ alkylene)-C(═O)—, wherein the alkylene is selected from 1 to 2 R ａ and * represents L to the ring containing X and Y. １ indicates the point of attachment of -(C=O)-; or together with Y, form an additional ring fused to the ring containing X and Y, said fused ring system containing 9 or 10 ring atoms, 1 to 4 ring atoms in said additional ring being heteroatoms, each independently selected from N, N(H), N(R ｄ ) and O, wherein said additional ring is selected from the group consisting of R １ substituted with oxo and R ｃ optionally further substituted with 1 to 4 substituents independently selected from the group consisting of: each of X and Y is independently selected from the group consisting of N and CH; R １ is hydrogen, deuterium, R ｂ , -OR ｂ , -S(O) ０～２ R ｂ , -N(R')R ｂ , CN, halo, and —NR′C(O)R″; R ２ is hydrogen, deuterium, CH ３ , CHF ２ , C.F. ３ , OMe, F, Cl and Br; R ３ , R ４ and R ５ each independently represents hydrogen and R ｃ is selected from the group consisting of R ６ each independently represents deuterium, halo; cyano; 1 to 6 independently selected R ａ C optionally substituted with １～１０ alkyl; 1 to 4 independently selected R ａ C optionally substituted with ３～６ Cycloalkyl; C ２～６ Alkenyl; C ２～６ Alkynyl; C １～４ Alkoxy; -S(O) ０～２ (C １～４ alkyl); -NR ｅ R ｆ ;-OH;-S(O) １～２ NR'R'';-NO ２ -C(=O)(C １～１０ alkyl); -C(=O)O(C １～４ alkyl); -C(=O)OH; -N(R')C(=O)(C １～４ alkyl), —C(═O)NR′R″,R ｇ , and -(CH ２ ) １～２ R ｇ is selected from the group consisting of n is selected from 0, 1, 2 and 3; R ７ is hydrogen, deuterium, CH ３ , CHF ２ , C.F. ３ , OMe, F, Cl and Br; R ａ each occurrence is independently selected from -OH; -halo; -NR ｅ R ｆ ; C １～４ Alkoxy; C １～４ Haloalkoxy; —C(═O)O(C １～４ alkyl); -C(=O)(C １～４ alkyl); -C(=O)OH; -CONR'R''; -S(O) １～２ NR'R'';-S(O) １～２ (C １～４ alkyl); and cyano; R ｂ Each occurrence of is independently - oxo and R respectively ｃ C optionally substituted with 1 to 4 substituents independently selected from the group consisting of ３～１０ Cycloalkyl or C ３～１０ cycloalkenyl; a heterocyclyl or heterocycloalkenyl containing 3 to 10 ring atoms, in which 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R ｄ ), O and S(O) ０～２ wherein said heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R ｃ heterocyclyl or heterocycloalkenyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R ｄ ), O, and S(O) ０～２ wherein at least one ring in said system is aromatic and said heteroaryl is selected from the group consisting of oxo and R ｃ heteroaryl, optionally substituted with 1 to 4 substituents independently selected from 1 to 4 independently selected substituents R ｃ C optionally substituted with ６～１０ Aryl is selected from the group consisting of R ｃ each occurrence is independently selected from deuterium; halo; cyano; 1 to 6 independently selected R ａ C optionally substituted with １～１０ alkyl; 1 to 4 independently selected R ａ C optionally substituted with ３～６ Cycloalkyl; C ２～６ Alkenyl; C ２～６ Alkynyl; C １～４ Alkoxy; -S(O) ０～２ (C １～４ alkyl); -NR ｅ R ｆ ;-OH;-S(O) １～２ NR'R'';-NO ２ -C(=O)(C １～１０ alkyl); -C(=O)O(C １～４ alkyl); -C(=O)OH; -N(R')C(=O)(C １～４ alkyl), —C(═O)NR′R″,R ｇ , and -(CH ２ ) １～２ R ｇ is selected from the group consisting of R ｄ Each occurrence of is independently selected from hydrogen, deuterium, 1 to 3 independently selected R ａ C optionally substituted with １～６ Alkyl; —C(O)(C １～４ alkyl); -C(O)O(C １～４ alkyl); -CONR'R''; -S(O) １～２ NR'R'';-S(O) １～２ (C １～４ alkyl); —OH; and C １～４ alkoxy; R ｅ and R ｆ Each occurrence of is independently H; deuterium; C １～６ Alkyl; —C(O)(C １～４ alkyl); -C(O)O(C １～４ alkyl); -CONR'R''; -S(O) １～２ NR'R'';-S(O) １～２ (C １～４ alkyl); —OH; and C １～４ alkoxy; R ｇ Each occurrence of is independently - oxo and R respectively ａ C optionally substituted with 1 to 4 substituents independently selected from the group consisting of ３～７ Cycloalkyl or C ３～７ cycloalkenyl; a heterocyclyl or heterocycloalkenyl containing 3 to 7 ring atoms, of which 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R ｄ ), O and S(O) ０～２ wherein said heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R ａ heterocyclyl or heterocycloalkenyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R ｄ ), O and S(O) ０～２ wherein at least one ring in said system is aromatic and said heteroaryl is selected from the group consisting of 1 to 4 oxo or R ａ heteroaryl, optionally substituted with ・1 to 4 R ａ C optionally substituted with ６～１０ Aryl is selected from the group consisting of Each occurrence of R′ and R″ is independently hydrogen; and C １～４ Alkyl selected from the group consisting of A compound of formula (I) or a pharmaceutically acceptable salt thereof.

2. Formula (II): 【Chemistry 2】 or a pharmaceutically acceptable salt thereof, wherein L is, - is a bond; *-O(C ０ ~C ４ alkylene)-, *-S(C ０ ~C ４ alkylene)-, *-C １ ~C ４ Alkylene, or *—NR′(C ０ ~C ４ alkylene)-, *-NR'(C=O)(C ０ ~C ４ alkylene)-, -(C １ ~C ４ alkylene)-C(=O)-*, *-(C １ ~C ４ alkylene)-C(═O)—, wherein the alkylene is selected from 1 to 2 R ａ and * represents L to the ring containing X and Y. １ indicates the point of attachment of -(C=O)-; or together with Y, form an additional ring fused to the ring containing X and Y, said fused ring system containing 9 or 10 ring atoms, 1 to 4 ring atoms in said additional ring being heteroatoms, each independently selected from N, N(H), N(R ｄ ) and O, wherein said additional ring is selected from the group consisting of R １ substituted with oxo and R ｃ optionally further substituted with 1 to 4 substituents independently selected from the group consisting of: each of X and Y is independently selected from the group consisting of N and CH; R １ is hydrogen, deuterium, R ｂ , -OR ｂ , -S(O) ０～２ R ｂ , -N(R')R ｂ , CN, halo, and —NR′C(O)R″; R ２ is hydrogen, deuterium, CH ３ , CHF ２ , C.F. ３ , OMe, F, Cl and Br; R ３ , R ４ and R ５ each independently represents hydrogen and R ｃ is selected from the group consisting of R ６ each independently selected from deuterium, halo; cyano; 1 to 6 independently selected R ａ C optionally substituted with １～１０ alkyl; 1 to 4 independently selected R ａ C optionally substituted with ３～６ Cycloalkyl; C ２～６ Alkenyl; C ２～６ Alkynyl; C １～４ Alkoxy; -S(O) ０～２ (C １～４ alkyl); -NR ｅ R ｆ ;-OH;-S(O) １～２ NR'R'';-NO ２ -C(=O)(C １～１０ alkyl); -C(=O)O(C １～４ alkyl); -C(=O)OH; -N(R')C(=O)(C １～４ alkyl), —C(═O)NR′R″,R ｇ , and -(CH ２ ) １～２ R ｇ is selected from the group consisting of n is selected from 0, 1, 2 and 3; R ａ each occurrence is independently selected from -OH; -halo; -NR ｅ R ｆ ; C １～４ Alkoxy; C １～４ Haloalkoxy; —C(═O)O(C １～４ alkyl); -C(=O)(C １～４ alkyl); -C(=O)OH; -CONR'R''; -S(O) １～２ NR'R'';-S(O) １～２ (C １～４ alkyl); and cyano; R ｂ Each occurrence of is independently - oxo and R respectively ｃ C optionally substituted with 1 to 4 substituents independently selected from the group consisting of ３～１０ Cycloalkyl or C ３～１０ cycloalkenyl; a heterocyclyl or heterocycloalkenyl containing 3 to 10 ring atoms, in which 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R ｄ ), O and S(O) ０～２ wherein said heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R ｃ heterocyclyl or heterocycloalkenyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R ｄ ), O, and S(O) ０～２ wherein at least one ring in said system is aromatic and said heteroaryl is selected from the group consisting of oxo and R ｃ heteroaryl, optionally substituted with 1 to 4 substituents independently selected from 1 to 4 independently selected substituents R ｃ C optionally substituted with ６～１０ Aryl is selected from the group consisting of R ｃ each occurrence is independently selected from deuterium; halo; cyano; 1 to 6 independently selected R ａ C optionally substituted with １～１０ alkyl; 1 to 4 independently selected R ａ C optionally substituted with ３～６ Cycloalkyl; C ２～６ Alkenyl; C ２～６ Alkynyl; C １～４ Alkoxy; -S(O) ０～２ (C １～４ alkyl); -NR ｅ R ｆ ;-OH;-S(O) １～２ NR'R'';-NO ２ -C(=O)(C １～１０ alkyl); -C(=O)O(C １～４ alkyl); -C(=O)OH; -N(R')C(=O)(C １～４ alkyl), —C(═O)NR′R″,R ｇ , and -(CH ２ ) １～２ R ｇ is selected from the group consisting of R ｄ Each occurrence of is independently selected from hydrogen, deuterium, 1 to 3 independently selected R ａ C optionally substituted with １～６ Alkyl; —C(O)(C １～４ alkyl); -C(O)O(C １～４ alkyl); -CONR'R''; -S(O) １～２ NR'R'';-S(O) １～２ (C １～４ alkyl); —OH; and C １～４ Alkoxy is selected from the group consisting of R ｅ and R ｆ Each occurrence of is independently H; deuterium; C １～６ Alkyl; —C(O)(C １～４ alkyl); -C(O)O(C １～４ alkyl); -CONR'R''; -S(O) １～２ NR'R'';-S(O) １～２ (C １～４ alkyl); —OH; and C １～４ alkoxy; R ｇ Each occurrence of is independently - oxo and R respectively ａ C optionally substituted with 1 to 4 substituents independently selected from the group consisting of ３～７ Cycloalkyl or C ３～７ cycloalkenyl; a heterocyclyl or heterocycloalkenyl containing 3 to 7 ring atoms, of which 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R ｄ ), O and S(O) ０～２ wherein said heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R ａ heterocyclyl or heterocycloalkenyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R ｄ ), O and S(O) ０～２ wherein at least one ring in said system is aromatic and said heteroaryl is selected from the group consisting of 1 to 4 oxo or R ａ heteroaryl, optionally substituted with ・1 to 4 R ａ C optionally substituted with ６～１０ Aryl is selected from the group consisting of Each occurrence of R′ and R″ is independently hydrogen; and C １～４ Alkyl selected from the group consisting of A compound of formula (II) or a pharmaceutically acceptable salt thereof:

3. Formula (III): 【Transformation 3】 or a pharmaceutically acceptable salt thereof, wherein L １ teeth, - is a bond; *-O(C ０ ~C ４ alkylene)-, *-S(C ０ ~C ４ alkylene)-, *-C １ ~C ４ Alkylene, or *—NR′(C ０ ~C ４ alkylene)-, *-NR'(C=O)(C ０ ~C ４ alkylene)-, -(C １ ~C ４ alkylene)-C(=O)-*, *-(C １ ~C ４ alkylene)-C(═O)—, wherein the alkylene is selected from 1 to 2 R ａ and * represents L to the ring containing X and Y. １ indicates the point of attachment of -(C=O)-; each of X and Y is independently selected from the group consisting of N and CH; R １ is hydrogen, deuterium, R ｂ , -OR ｂ , -S(O) ０～２ R ｂ , -N(R')R ｂ , CN, halo, and —NR′C(O)R″; However, -L １ -R １ does not contain O—O, N—O, N—N, O—S, S—S or N—S bonds, and R １ When is CN, halo, or —NR′C(O)R″, L １ must be a bond, with the further proviso that R １ is hydrogen, L １ cannot be a bond, R ２ is hydrogen, deuterium, CH ３ , CHF ２ , C.F. ３ , OMe, F, Cl and Br; R ３ , R ４ and R ５ each independently represents hydrogen and R ｃ is selected from the group consisting of R ６ each independently represents deuterium; halo; cyano; 1 to 6 independently selected R ａ C optionally substituted with １～１０ alkyl; 1 to 4 independently selected R ａ C optionally substituted with ３～６ Cycloalkyl; C ２～６ Alkenyl; C ２～６ Alkynyl; C １～４ Alkoxy; -S(O) ０～２ (C １～４ alkyl); -NR ｅ R ｆ ;-OH;-S(O) １～２ NR'R'';-NO ２ -C(=O)(C １～１０ alkyl); -C(=O)O(C １～４ alkyl); -C(=O)OH; -N(R')C(=O)(C １～４ alkyl), —C(═O)NR′R″,R ｇ , and -(CH ２ ) １～２ R ｇ is selected from the group consisting of n is selected from 0, 1, 2 and 3; R ａ each occurrence is independently selected from -OH; -halo; -NR ｅ R ｆ ; C １～４ Alkoxy; C １～４ Haloalkoxy; —C(═O)O(C １～４ alkyl); -C(=O)(C １～４ alkyl); -C(=O)OH; -CONR'R''; -S(O) １～２ NR'R'';-S(O) １～２ (C １～４ alkyl); and cyano; R ｂ Each occurrence of is independently - oxo and R respectively ｃ C optionally substituted with 1 to 4 substituents independently selected from the group consisting of ３～１０ Cycloalkyl or C ３～１０ cycloalkenyl; a heterocyclyl or heterocycloalkenyl containing 3 to 10 ring atoms, in which 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R ｄ ), O and S(O) ０～２ wherein said heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R ｃ heterocyclyl or heterocycloalkenyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R ｄ ), O, and S(O) ０～２ wherein at least one ring in said system is aromatic and said heteroaryl is selected from the group consisting of oxo and R ｃ heteroaryl, optionally substituted with 1 to 4 substituents independently selected from 1 to 4 independently selected substituents R ｃ C optionally substituted with ６～１０ Aryl is selected from the group consisting of R ｃ each occurrence is independently selected from deuterium; halo; cyano; 1 to 6 independently selected R ａ C optionally substituted with １～１０ alkyl; 1 to 4 independently selected R ａ C optionally substituted with ３～６ Cycloalkyl; C ２～６ Alkenyl; C ２～６ Alkynyl; C １～４ Alkoxy; -S(O) ０～２ (C １～４ alkyl); -NR ｅ R ｆ ;-OH;-S(O) １～２ NR'R'';-NO ２ -C(=O)(C １～１０ alkyl); -C(=O)O(C １～４ alkyl); -C(=O)OH; -N(R')C(=O)(C １～４ alkyl), —C(═O)NR′R″,R ｇ , and -(CH ２ ) １～２ R ｇ is selected from the group consisting of R ｄ Each occurrence of is independently selected from hydrogen, 1 to 3 independently selected R ａ C optionally substituted with １～６ Alkyl; —C(O)(C １～４ alkyl); -C(O)O(C １～４ alkyl); -CONR'R''; -S(O) １～２ NR'R'';-S(O) １～２ (C １～４ alkyl); —OH; and C １～４ alkoxy; R ｅ and R ｆ each occurrence of is independently H; C １～６ Alkyl; —C(O)(C １～４ alkyl); -C(O)O(C １～４ alkyl); -CONR'R''; -S(O) １～２ NR'R'';-S(O) １～２ (C １～４ alkyl); —OH; and C １～４ alkoxy; R ｇ Each occurrence of is independently - oxo and R respectively ａ C optionally substituted with 1 to 4 substituents independently selected from the group consisting of ３～７ Cycloalkyl or C ３～７ cycloalkenyl; a heterocyclyl or heterocycloalkenyl containing 3 to 7 ring atoms, of which 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R ｄ ), O and S(O) ０～２ wherein said heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R ａ heterocyclyl or heterocycloalkenyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R ｄ ), O and S(O) ０～２ wherein at least one ring in said system is aromatic and said heteroaryl is selected from the group consisting of 1 to 4 oxo or R ａ heteroaryl, optionally substituted with ・1 to 4 R ａ C optionally substituted with ６～１０ Aryl is selected from the group consisting of Each occurrence of R′ and R″ is independently hydrogen; and C １～４ Alkyl selected from the group consisting of A compound of formula (III) or a pharmaceutically acceptable salt thereof:

4. Formula (IV): 【Chemistry 4】 or a pharmaceutically acceptable salt thereof, wherein L １ teeth, - is a bond; -O(C ０ ~C ４ alkylene)-, *-S(C ０ ~C ４ alkylene)-, *-C １ ~C ４ Alkylene, or *—NR′(C ０ ~C ４ alkylene)-, *-NR'(C=O)(C ０ ~C ４ alkylene)-, -(C １ ~C ４ alkylene)-C(=O)-*, *-(C １ ~C ４ alkylene)-C(═O)—, wherein the alkylene is selected from 1 to 2 R ａ and * indicates an attachment of L to the ring containing X and Y. １ indicates the point of attachment of -(C=O)-; each of X and Y is independently selected from the group consisting of N and CH; R １ is hydrogen, R ｂ , -OR ｂ , -SR ｂ , -N(R')R ｂ , CN, halo, and —NR′C(O)R″; However, -L １ -R １ does not contain O—O, N—O, N—N, O—S, S—S or N—S bonds, and R １ When is CN, halo, or —NR′C(O)R″, L １ must be a bond, with the further proviso that R １ is hydrogen, L １ cannot be a bond, R ２ is hydrogen, CH ３ , CHF ２ , C.F. ３ , OMe, F, and Cl; R ３ , R ４ and R ５ each independently represents hydrogen and R ｃ is selected from the group consisting of R ６ Each of R is independently selected ｃ and n is selected from 0, 1, 2 and 3; R ａ each occurrence is independently selected from -OH; -halo; -NR ｅ R ｆ ; C １～４ Alkoxy; C １～４ Haloalkoxy; —C(═O)O(C １～４ alkyl); -C(=O)(C １～４ alkyl); -C(=O)OH; -CONR'R''; -S(O) １～２ NR'R'';-S(O) １～２ (C １～４ alkyl); and cyano; R ｂ Each occurrence of is independently - oxo and R respectively ｃ C optionally substituted with 1 to 4 substituents independently selected from the group consisting of ３～１０ Cycloalkyl or C ３～１０ cycloalkenyl; a heterocyclyl or heterocycloalkenyl containing 3 to 10 ring atoms, in which 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R ｄ ), O and S(O) ０～２ wherein said heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R ｃ heterocyclyl or heterocycloalkenyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R ｄ ), O and S(O) ０～２ and 1 to 4 substituents R ｃ heteroaryl, optionally substituted with 1 to 4 independently selected substituents R ｃ C optionally substituted with ６～１０ Aryl is selected from the group consisting of R ｃ each occurrence of is independently selected from halo; cyano; 1 to 6 independently selected R ａ C optionally substituted with １～１０ Alkyl; C ２～６ Alkenyl; C ２～６ Alkynyl; C １～４ Alkoxy; -S(O) ０～２ (C １～４ alkyl); -NR ｅ R ｆ ;-OH;-S(O) １～２ NR'R'';-NO ２ -C(=O)(C １～１０ alkyl); -C(=O)O(C １～４ alkyl); -C(=O)OH; -N(R')C(=O)(C １～４ alkyl), —C(═O)NR′R″,R ｇ , and -(CH ２ ) １～２ R ｇ is selected from the group consisting of R ｄ Each occurrence of is independently selected from hydrogen, 1 to 3 independently selected R ａ C optionally substituted with １～６ Alkyl; —C(O)(C １～４ alkyl); -C(O)O(C １～４ alkyl); -CONR'R''; -S(O) １～２ NR'R'';-S(O) １～２ (C １～４ alkyl); —OH; and C １～４ alkoxy; R ｅ and R ｆ each occurrence of is independently H; C １～６ Alkyl; —C(O)(C １～４ alkyl); -C(O)O(C １～４ alkyl); -CONR'R''; -S(O) １～２ NR'R'';-S(O) １～２ (C １～４ alkyl); —OH; and C １～４ alkoxy; R ｇ Each occurrence of is independently - oxo and R respectively ａ C optionally substituted with 1 to 4 substituents independently selected from the group consisting of ３～７ Cycloalkyl or C ３～７ cycloalkenyl; a heterocyclyl or heterocycloalkenyl containing 3 to 7 ring atoms, of which 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R ｄ ), O and S(O) ０～２ wherein said heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R ａ heterocyclyl or heterocycloalkenyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R ｄ ), O and S(O) ０～２ wherein said heteroaryl is selected from the group consisting of 1 to 4 R ａ heteroaryl, optionally substituted with ・1 to 4 R ａ C optionally substituted with ６～１０ Aryl is selected from the group consisting of Each occurrence of R′ and R″ is independently hydrogen; and C １～４ Alkyl selected from the group consisting of A compound of formula (IV) or a pharmaceutically acceptable salt thereof:

5. L １ is a bond, -(C=O)-, *-O(C ０ ~C ４ alkylene)-, *-C １ ~C ４ Alkylene-, *-NR'(C ０ ~C ４ alkylene)-, *-NR'(C=O)(C ０ ~C ４ alkylene), or *-(C １ ~C ４ alkylene)-C(=O)-, wherein the alkylene is 1 to 2R ａ and * is optionally substituted with L １ indicates the point of attachment to the ring of together with Y to form an additional ring fused to the ring containing X and Y, said fused ring system containing 9 or 10 ring atoms, wherein 1 to 4 ring atoms in said additional ring are heteroatoms, each independently selected from N, N(H), N(R ｄ ) and O, wherein said additional ring is selected from the group consisting of R １ substituted with oxo and R ｃ and optionally further substituted with 1 to 4 substituents independently selected from the group consisting of: X and Y are both CH, or one of X and Y is N and the other is CH; R １ is R ｂ and R ２ is hydrogen, chloro, fluoro or methyl, R ３ , R ４ and R ５ is hydrogen or halo, R ６ represents deuterium, halo and unsubstituted C １～１０ is selected from the group consisting of alkyl, R ｂ teeth, a heterocyclyl or heterocycloalkenyl containing 3 to 10 ring atoms, in which 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R ｄ ), O and S(O) ０～２ wherein said heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R ｃ heterocyclyl or heterocycloalkenyl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R ｄ ), O and S(O) ０～２ wherein at least one ring in said system is aromatic and heteroaryl is selected from the group consisting of oxo and R ｃ heteroaryl optionally substituted with 1 to 4 substituents independently selected from The compound according to any one of claims 1 to 4,

6. L １ is a bond, -(C=O)-, *-O(C ０ ~C ４ alkylene)-, *-C １ ~C ４ Alkylene-, *-NR'(C ０ ~C ４ alkylene)-, *-NR'(C=O)(C ０ ~C ４ alkylene), or *-(C １ ~C ４ alkylene)-C(=O)-, wherein the alkylene is 1 to 2R ａ and * is optionally substituted with L １ indicates the point of attachment to the ring of L １ together with Y form a further ring fused to the ring containing X and Y, said fused ring system containing 9 or 10 ring atoms, and 1 to 4 ring atoms in said further ring are heteroatoms, each independently selected from N, N(H), N(R ｄ ) and O, wherein said further ring is selected from the group consisting of R １ Optionally substituted, oxo and R ｃ and optionally further substituted with 1 to 4 substituents independently selected from the group consisting of: X and Y are both CH, or one of X and Y is N and the other is CH; R １ is R ｂ and R ２ is hydrogen, chloro, fluoro or methyl, R ３ , R ４ and R ５ is hydrogen or halo, R ６ represents deuterium, halo and unsubstituted C １～１０ is selected from the group consisting of alkyl, R ｂ contains a hydrogen bond acceptor within seven atoms of the carbon atom between X and Y, The compound according to any one of claims 1 to 5.

7. L １ is a bond, -(C=O)-, *-O(C ０ ~C ４ alkylene)-, *-C １ ~C ４ Alkylene-, *-NR'(C ０ ~C ４ alkylene)-, *-NR'(C=O)(C ０ ~C ４ alkylene), or *-(C １ ~C ４ alkylene)-C(=O)-, wherein the alkylene is 1 to 2R ａ and * is optionally substituted with L １ indicates the point of attachment to the ring of L １ together with Y form a further ring fused to the ring containing X and Y, said fused ring system containing 9 or 10 ring atoms, and 1 to 4 ring atoms in said further ring are heteroatoms, each independently selected from N, N(H), N(R ｄ ) and O, wherein said further ring is selected from the group consisting of R １ Optionally substituted, oxo and R ｃ and optionally further substituted with 1 to 4 substituents independently selected from the group consisting of: X and Y are both CH, or one of X and Y is N and the other is CH; R １ is R ｂ and R ２ is hydrogen, chloro, fluoro or methyl, R ３ , R ４ and R ５ is hydrogen or halo, n is 0, R ｂ teeth, a heterocyclyl or heterocycloalkenyl containing 5 to 10 ring atoms, in which 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R ｄ ), O and S(O) ０～２ wherein said heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R ｃ heterocyclyl or heterocycloalkenyl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R ｄ ), O and S(O) ０～２ wherein at least one ring in said system is aromatic and heteroaryl is selected from the group consisting of oxo and R ｃ heteroaryl optionally substituted with 1 to 4 substituents independently selected from The compound according to any one of claims 1 to 5,

8. R ｃ are independently halo; 1 to 6 independently selected R ａ C optionally substituted with １～１０ Alkyl; C １～４ Alkoxy; R ｇ and -(CH ２ ) １～２ R ｇ The compound according to any one of claims 1 to 7, selected from the group consisting of:

9. L １ is a bond, -(C=O)-, *-O(C ０ ~C ４ alkylene)-, *-C １ ~C ４ Alkylene-, *-NR'(C ０ ~C ４ alkylene)-, *-NR'(C=O)(C ０ ~C ４ alkylene), or *-(C １ ~C ４ alkylene)-C(═O)—, wherein the alkylene is one to two R ａ and * is L to said ring. １ 9. A compound according to any one of claims 1 to 8, exhibiting a point of attachment of

10. L １ is a bond, -(C=O)-, *-O(C ０ ~C ４ alkylene)-, *-C １ ~C ４ Alkylene-, *-NR'(C ０ ~C ４ alkylene)-, *-NR'(C=O)(C ０ ~C ４ alkylene), or *-(C １ ~C ４ The compound according to any one of claims 1 to 9, wherein the alkylene group is -C(=O)-.

11. L １ is a bond, -(C=O)-, *-O(C １ ~C ４ Alkylene, *-C １ ~C ４ Alkylene-, *-(C １ ~C ４ alkylene)-C(=O)-, *-NH'(C ０ ~C ４ alkylene)-, or *-NH'(C=O)(C ０ ~C ４ alkylene)-, wherein the alkylene is one to two R ａで optionally substituted, and * indicates a linkage between L and said ring １ 11. The compound of claim 1, wherein the compound exhibits a point of attachment of

12. L １ is a bond, -(C=O)-, *-O(C １ ~C ４ Alkylene, *-C １ ~C ４ Alkylene, or *-(C １ ~C ４ The compound according to any one of claims 1 to 11, wherein the alkylene group is C(=O)-C(=O)-.

13. L １ is a bond, *-OCH ２ -, *-OCH ２ CH ２ , -CH ２ -, -CH(CH ３ ) -, -C(CH ３ ) ２ -, -CH ２ CH ２ CH ２ -, -(C=O)- or *-(CH ２ 13. The compound according to any one of claims 1 to 12, wherein the compound is —C(═O)—.

14. L １ is a bond or -CH ２ The compound according to any one of claims 1 to 13, wherein

15. L １ The compound of any one of claims 1 to 14, wherein is a bond.

16. 15. The compound of any one of claims 1 to 14, wherein X and Y are both CH, or one of X and Y is N and the other is CH.

17. 17. The compound of any one of claims 1 to 16, wherein X and Y are both CH.

18. R １ is R ｂ The compound according to any one of claims 1 to 17,

19. R ｂ 19. The compound of any one of claims 1 to 5 or 8 to 18, wherein X is a hydrogen bond acceptor within 7 atoms of the carbon atom between X and Y.

20. R ｂ contains a hydrogen bond acceptor within 7 atoms of the carbon atom between X and Y, and the hydrogen bond acceptor is selected from a carbonyl group, a sulfonyl group, a nitrogen-containing heteroaromatic group, an oxygen-containing heteroaromatic group, and an oxygen-containing aliphatic or alicyclic group.

21. R ｂ 21. The compound of any one of claims 6 or 8 to 20, wherein the compound comprises a hydrogen bond acceptor within 7 atoms of the carbon atom between X and Y, and the hydrogen bond acceptor is selected from an amide, lactam, carbamate, pyridone, pyrimidinone, piperazinone, pyridazinone, urea, sulfonamide, sulfone, pyrimidine, pyrazine, pyridazine, pyridine, oxazole, isoxazole, oxadiazole, thiazole, thiadiazole, imidazole, pyrazole, oxazole, isoxazole, oxadiazole, oxetane, tetrahydrofuran, tetrahydropyran, or a methoxyalkyl group.

22. R ｂ but, a heterocyclyl or heterocycloalkenyl containing 3 to 10 ring atoms, in which 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R ｄ ), O and S(O) ０～２ wherein said heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R ｃ heterocyclyl or heterocycloalkenyl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R ｄ ), O and S(O) ０～２ wherein at least one ring in said system is aromatic and said heteroaryl is selected from the group consisting of oxo and R ｃ heteroaryl optionally substituted with 1 to 4 substituents independently selected from The compound according to any one of claims 1 to 21,

23. R ｂ but, a heterocyclyl or heterocycloalkenyl containing 5 to 10 ring atoms, in which 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R ｄ ), O and S(O) ０～２ wherein said heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R ｃ heterocyclyl or heterocycloalkenyl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R ｄ ), O and S(O) ０～２ wherein at least one ring in said system is aromatic and said heteroaryl is selected from the group consisting of oxo and R ｃ heteroaryl optionally substituted with 1 to 4 substituents independently selected from The compound according to any one of claims 1 to 22,

24. R ｂ but, Heterocyclyl or heterocycloalkenyl containing 5 to 10 ring atoms, 1 to 3 of which are N, N(H), N(R ｄ ), O and S(O) ０～２ and at least one heteroatom is N or N(R ｄ ) wherein heterocyclyl or heterocycloalkenyl is selected from oxo and R ｃ heterocyclyl or heterocycloalkenyl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R ｄ ), O and S(O) ０～２ and at least one heteroatom is selected from the group consisting of N or N(R ｄ ), wherein at least one ring in the system is aromatic and heteroaryl is selected from oxo and R ｃ heteroaryl optionally substituted with 1 to 4 substituents independently selected from The compound according to any one of claims 1 to 23, wherein

25. Each R ｃ is optionally substituted with halo, 1 to 3 independently selected halo atoms; １～４ Alkyl and C １～４ 25. The compound of any one of claims 1 to 24, independently selected from alkoxy.

26. Rb is 【Transformation 5】 【Transformation 6】 each of which is selected from the group consisting of 1 to 4 independently selected substituents R ｃ 26. The compound of any one of claims 1 to 25, optionally substituted with

27. R ｂ is a heteroaryl containing 5 to 10 ring atoms, and 1 to 4 ring atoms are selected from N, N(H), N(R ｄ ), O and S(O) ０～２ and the heteroaryl is selected from 1 to 4 independently selected R ｃ 27. The compound of any one of claims 1 to 26, optionally substituted with:

28. R ｂ is a heteroaryl containing 5 to 6 ring atoms, and 1 to 4 ring atoms are N, N(H), N(R ｄ ), O and S(O) ０～２ and the heteroaryl is selected from 1 to 4 independently selected R ｃ 28. The compound of any one of claims 1 to 27, optionally substituted with:

29. R ｂ is a heteroaryl containing 5 ring atoms, and 1 to 4 ring atoms are selected from N, N(H), N(R ｄ ), O and S(O) ０～２ and the heteroaryl is selected from 1 to 2 independently selected R ｃ 29. The compound of any one of claims 1 to 28, optionally substituted with:

30. R ｂ is a heteroaryl containing 5 ring atoms, 1 to 4 ring atoms being heteroatoms, each independently selected from N, N(H), N(R ｄ ), O and S(O) ０～２ 30. The compound of any one of claims 1 to 29, selected from the group consisting of:

31. R ｂ but, 【Transformation 7】 each of which is selected from the group consisting of 1 to 2 independently selected R ｃ 31. The compound of any one of claims 1 to 30, optionally substituted with:

32. R ｂ but, 【Transformation 8】 and optionally R ｄ is CH ３ The compound according to any one of claims 1 to 31,

33. R ｂ but, 【Chemistry 9】 and optionally R ｄ is CH ３ The compound according to any one of claims 1 to 32,

34. R ｂ but, 【Chemistry 10】 The compound according to any one of claims 1 to 33, selected from:

35. R ｂ but, 【Chemistry 11】 The compound according to any one of claims 1 to 34, wherein

36. R ｂ but, 【Chemistry 12】 32. The compound of any one of claims 1 to 31, selected from the group consisting of:

37. R ｂ but, 【Chemistry 13】 37. The compound of any one of claims 1 to 31 or 36, selected from the group consisting of:

38. R ｃ is 1 to 6 independently selected R ａ and -NR ｅ R ｆ C optionally substituted with １～１０ alkyl, and optionally R ｃ is methyl or -NH ２ 38. The compound of claim 36 or 37, wherein:

39. R ｂ but, 【Chemistry 14】 32. The compound of any one of claims 1 to 31, selected from the group consisting of:

40. R ｂ but, 【Chemistry 15】 The compound according to any one of claims 1 to 31,

41. R ｂ but, 【Chemistry 16】 41. The compound of any one of claims 1 to 31 or 40, wherein

42. R ｃ is 1 to 6 independently selected R ａ and -NR ｅ R ｆ C optionally substituted with １～１０ alkyl, and optionally R ｃ 42. The compound of claim 40 or 41, wherein is methyl.

43. R ｂ but, 【Chemistry 17】 43. The compound according to any one of claims 1 to 31 or 40 to 42,

44. R ｂ is a heteroaryl containing 6 ring atoms, and 1 to 4 ring atoms are N, N(H), N(R ｄ ), O and S(O) ０～２ and the heteroaryl is selected from 1 to 4 independently selected R ｃ 29. The compound of any one of claims 1 to 28, optionally substituted with:

45. R ｂ is a heteroaryl containing 6 ring atoms, 1 to 4 ring atoms being heteroatoms, each independently selected from N, N(H), N(R ｄ ), O and S(O) ０～２ 45. The compound of any one of claims 1 to 28 or 44, selected from the group consisting of:

46. R ｂ but, [Chemistry 18] 46. ​​The compound of any one of claims 1 to 28 or 44 to 45, selected from the group consisting of:

47. R ｂ but, 【Chemistry 19】 46. ​​The compound of any one of claims 1 to 27 or 43 to 45,

48. R ｂ is a heteroaryl containing 7 to 10 ring atoms, 1 to 4 ring atoms being heteroatoms, each independently selected from N, N(H), N(R ｄ ), O and S(O) ０～２ wherein at least one ring in said system is aromatic and said heteroaryl is selected from the group consisting of 1 to 4 independently selected oxo or R ｃ 28. The compound of any one of claims 1 to 27, optionally substituted with:

49. R ｂ is a heteroaryl containing 9 to 10 ring atoms, 1 to 4 ring atoms are heteroatoms, and each independently is selected from N, N(H), N(R ｄ ), O and S(O) ０～２ wherein at least one ring in said system is aromatic and said heteroaryl is selected from the group consisting of 1 to 4 independently selected oxo or R ｃ 49. The compound of any one of claims 1 to 27 or 48, optionally substituted with:

50. R ｂ is a heteroaryl containing 9 ring atoms, wherein at least one ring in said system is aromatic and 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R ｄ ), O and S(O) ０～２ wherein said heteroaryl is selected from the group consisting of oxo and R ｃ 50. The compound of any one of claims 1-27 or 48-49, optionally substituted with 1-4 independently selected from the list consisting of:

51. R ｂ but, 【Chemistry 20】 each of which is selected from the group consisting of 1 to 4 independently selected R ｃ 51. The compound of any one of claims 1 to 27 or 48 to 50, optionally substituted with:

52. R ｂ but, 【Chemistry 21】 52. The compound of any one of claims 1 to 27 or 48 to 51, selected from the group consisting of:

53. R ｂ is a heteroaryl containing 10 ring atoms, 1 to 4 ring atoms being heteroatoms, each independently selected from N, N(H), N(R ｄ ), O and S(O) ０～２ wherein at least one ring in said system is aromatic and said heteroaryl is selected from the group consisting of 1 to 4 independently selected oxo or R ｃ 50. The compound of any one of claims 1 to 27 or 48 to 49, optionally substituted with:

54. R ｂ but, 【Chemistry 22】 each of which is selected from the group consisting of 1 to 4 independently selected R ｃ 54. The compound of any one of claims 1 to 27 or 48 to 49 or 53, optionally substituted with:

55. R ｂ but, 【Chemistry 23】 55. The compound of any one of claims 1 to 27, 48 to 49 or 53 to 54, selected from the group consisting of:

56. R ｂ is a heterocyclyl or heterocycloalkenyl containing 3 to 10 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R ｄ ), O and S(O) ０～２ wherein said heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R ｃ 27. The compound of claims 1-22, 25 or 26, optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

57. R ｂ is a heterocyclyl or heterocycloalkenyl containing 4 to 6 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R ｄ ), O and S(O) ０～２ wherein said heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R ｃ 57. The compound of claims 1-22, 25, 26 or 56, optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

58. R ｂ is a heterocyclyl or heterocycloalkenyl containing 5 to 6 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R ｄ ), O and S(O) ０～２ wherein said heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R ｃ 58. The compound of any one of claims 1-26 or 56-57, optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

59. R ｂ is a heterocyclyl or heterocycloalkenyl containing 6 ring atoms, 1 to 3 of which are heteroatoms, each independently selected from N, N(H), N(R ｄ ), O and S(O) ０～２ wherein said heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R ｃ 59. The compound of any one of claims 1-26 or 56-58, optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

60. R ｂ is a heterocycloalkenyl containing 6 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R ｄ ), O and S(O) ０～２ wherein said heterocycloalkenyl is selected from the group consisting of oxo and R ｃ 60. The compound of any one of claims 1-26 or 56-59, optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

61. R ｂ but, 【Chemistry 24】 61. The compound of any one of claims 1 to 26 or 56 to 60, wherein

62. R ｄ is CH ３ 62. The compound of claim 61, wherein:

63. R ｂ but, 【Chemistry 25】 and one to two independently selected R ｃ 62. The compound of any one of claims 1 to 26 or 56 to 61, optionally substituted with a substituent.

64. R ｂ but, 【Chemistry 26】 64. The compound of any one of claims 1 to 26 or 56 to 61 or 63, wherein

65. R ｂ but, 【Chemistry 27】 64. The compound of any one of claims 1 to 26, 56 to 61 or 62 to 63, wherein

66. R ｃ or R ｃ each occurrence of ａ , C １～４ Alkoxy, halo and -NR ｅ R ｆ C optionally substituted with １～１０ 65. The compound of claim 63 or 64, wherein the compound is selected from the group consisting of alkyl.

67. R ｃ Methyl, ethyl, -CHF ２ , -CF ３ , methoxy, fluoro, chloro and NH ２ 66. The compound of any one of claims 63 to 65, selected from the group consisting of:

68. R １ but, 【Chemistry 28】 68. The compound of any one of claims 1 to 26, 52 to 61, 63 to 64 or 66 to 67, selected from the group consisting of:

69. R ｂ is a heterocyclyl containing 6 ring atoms, 1 to 3 ring atoms being heteroatoms, each independently selected from N, N(H), N(R ｄ ), O and S(O) ０～２ wherein said heterocyclyl is selected from the group consisting of oxo and R ｃ 60. The compound of any one of claims 1-26 or 56-59, optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

70. R ｂ but, 【Chemistry 29】 each of which is selected from the group consisting of oxo and R ｃ 70. The compound of any one of claims 1-26, 56-59, or 69, optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

71. R ｃ is methyl, halo, methoxy or CF ３ 71. The compound of claim 70, wherein:

72. R ｂ but, 【Transformation 30】 72. The compound of any one of claims 1 to 26, 56 to 59 or 69 to 71, selected from the group consisting of:

73. R ｂ but, 【Chemistry 31】 73. The compound of any one of claims 1 to 26, 56 to 59 or 69 to 72, selected from the group consisting of:

74. R ｄ is CH ３ 74. The compound according to any one of claims 70 or 72 to 73,

75. R ｂ but, 【Chemistry 32】 74. The compound of any one of claims 1 to 26, 56 to 59 or 69 to 73, wherein

76. R ｂ is a heterocyclyl or heterocycloalkenyl containing 5 ring atoms, 1 to 3 of which are heteroatoms, each independently selected from N, N(H), N(R ｄ ), O and S(O) ０～２ wherein said heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R ｃ 59. The compound of any one of claims 1-26 or 56-58, optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

77. R ｂ is a heterocyclyl containing 5 ring atoms, 1 to 3 ring atoms being heteroatoms, each independently selected from N, N(H), N(R ｄ ), O and S(O) ０～２ wherein said heterocyclyl is selected from the group consisting of oxo and R ｃ 77. The compound of any one of claims 1-26 or 56-58 or 76, optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

78. R ｂ but, 【Transformation 33】 each of which is selected from the group consisting of 1 to 4 R ｃ 80. The compound of any one of claims 1-26, 56-58 or 76-77, optionally substituted with:

79. R ｃ is halo or C １～６ 79. The compound of claim 78, which is alkyl.

80. R ｂ but, 【Transformation 34】 80. The compound of any one of claims 1-26, 56-58 or 76-78, selected from the group consisting of:

81. R ｂ but, 【Chemistry 35】 80. The compound of any one of claims 1-26, 56-58 or 76-78, selected from the group consisting of:

82. R ｂ but, 【Transformation 36】 82. The compound of any one of claims 1 to 26, 56 to 58, 76 to 78, or 81, wherein

83. R ｂ is a heterocycloalkenyl containing 5 ring atoms, 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R ｄ ), O and S(O) ０～２ wherein said heterocycloalkenyl is selected from the group consisting of oxo and R ｃ 77. The compound of any one of claims 1-26, 56-58, or 76, optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

84. R ｂ teeth, 【Chemistry 37】 and optionally R ｂ teeth, 【Transformation 38】 85. The compound of any one of claims 1 to 26, 56 to 58, 76 or 84, wherein

85. R ｂ but, 【Chemistry 39】 27. The compound of any one of claims 1 to 22, 25 or 26, selected from the group consisting of:

86. R ｂ is a heterocyclyl or heterocycloalkenyl containing 7 to 10 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R ｄ ), O and S(O) ０～２ wherein said heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R ｃ 57. The compound of claims 1-26 or 56, optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

87. R ｂ is a heterocyclyl containing 7 to 10 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R ｄ ), O and S(O) ０～２ wherein said heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R ｃ 87. The compound of claims 1-26, 56, or 86, optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

88. R ｂ is a heterocyclyl containing 7 ring atoms, 1 to 3 ring atoms being heteroatoms, each independently selected from N, N(H), N(R ｄ ), O and S(O) ０～２ and the heterocyclyl is selected from the group consisting of 1 to 4 independently selected substituents R ｃ 88. The compound of claims 1-26, 56 or 86-87, optionally substituted with

89. R ｂ but, 【Chemistry 40】 each of which is selected from the group consisting of 1 to 4 independently selected substituents R ｃ 89. The compound of claims 1-26, 56 or 86-88, optionally substituted with

90. R ｂ but, 【Chemistry 41】 90. The compound of claim 89, selected from the group consisting of:

91. R ｂ is a heterocyclyl containing 8 ring atoms, 1 to 3 ring atoms being heteroatoms, each independently selected from N, N(H), N(R ｄ ), O and S(O) ０～２ and the heterocyclyl is selected from the group consisting of 1 to 4 independently selected substituents R ｃ 88. The compound of any one of claims 1-26, 56 or 86-87, optionally substituted with

92. R ｂ but, 【Chemistry 42】 each of which is selected from the group consisting of 1 to 4 independently selected substituents R ｃ 92. The compound of claim 91, optionally substituted with:

93. R ｂ but, 【Chemistry 43】 93. The compound of any one of claims 91 or 92, selected from the group consisting of:

94. R ｂ is a heterocyclyl containing 9 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R ｄ ), O and S(O) ０～２ wherein said heterocyclyl is selected from the group consisting of oxo and R ｃ 88. The compound of any one of claims 1-26, 56, or 86-87, optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

95. R ｂ but, 【Chemistry 44】 each of which is selected from the group consisting of 1 to 4 independently selected substituents R ｃ 95. The compound of claim 94, optionally substituted with:

96. R ｄ is CH ３ 96. The compound of claim 95, wherein:

97. R ｂ but, 【Chemistry 45】 97. The compound of claim 95 or 96, selected from the group consisting of:

98. R ｂ is C ３～１０ Cycloalkyl or C ３～１０ cycloalkenyl, each of which is oxo and R ｃ 23. The compound of any one of claims 1 to 22, optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

99. R ｂ but, 【Chemistry 46】 and one R ｃ 99. The compound of claim 98, optionally substituted with:

100. R ２ 100. The compound of any one of claims 1 to 99, wherein is hydrogen, chloro, fluoro or methyl.

101. R ２ The compound of any one of claims 1 to 100, wherein is chloro.

102. R ３ , R ４ and R ５ The compound of any one of claims 1 to 101, wherein is hydrogen or halo.

103. R ３ is halo or hydrogen, and R ４ and R ５ The compound of any one of claims 1 to 102, wherein is hydrogen.

104. R ３ , R ４ and R ５ The compound of any one of claims 1 to 103, wherein is hydrogen.

105. R ２ is chloro and R ３ , R ４ and R ５ The compound of any one of claims 1 to 104, wherein is hydrogen.

106. The compound of any one of claims 1 to 105, wherein n is 0.

107. n is 0, and R ３ , R ４ and R ５ is hydrogen, and / or L １ is a bond, -(C=O)-, *-C １ ~C ４ Alkylene-, *-NR'(C ０ ~C ４ alkylene)-, *-NR'(C=O)(C ０ ~C ４ alkylene), or *-(C １ ~C ４ alkylene)-C(═O)—, wherein the alkylene is selected from 1 to 2 R ａ and * indicates a L １ 107. A compound according to any one of claims 1 to 106, exhibiting a point of attachment of

108. The compound of any one of claims 1 to 107, wherein n is 1 or 2.

109. R ６ is deuterium, halo; cyano; 1 to 6 independently selected R ａ C optionally substituted with １～１０ Alkyl; C １～４ Alkoxy, C １～４ haloalkoxy; and —NR ｅ R ｆ and optionally wherein R ６ is deuterium, cyano, chloro, fluoro, methyl, ethyl, -CHF ２ , methoxy, -OCHF ２ and -NH ２ The compound of any one of claims 1 to 108, selected from the group consisting of:

110. R ６ is deuterium, halo and unsubstituted C １～１０ The compound of any one of claims 1 to 109, wherein the compound is selected from the group consisting of alkyl.

111. R ６ The compound of any one of claims 1 to 110, wherein is selected from the group consisting of deuterium, fluoro, and methyl.

112. R ６ is deuterium, and optionally n is 4.

113. Formula (I-1) 【Chemistry 47】 The compound according to any one of claims 1 to 107,

114. Formula (I-2) 【Chemistry 48】 is a compound of wherein X is —NH— or —O—; 114. A compound according to any one of claims 1 to 107 or 113.

115. 115. The compound of claim 114, wherein X is -O-.

116. Formula (I-3) 【Chemistry 49】 114. The compound of any one of claims 1 to 107 or 113,

117. The compound is represented by formula (I-4): [Transformation 50] 114. The compound of any one of claims 1 to 107 or 113,

118. R ２ The compound of any one of claims 113 to 117, wherein is chloro.

119. R ｂ is a heterocyclyl or heterocycloalkenyl containing 3 to 10 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R ｄ ), O and S(O) ０～２ and heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R ｃ optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Heteroaryl containing 5 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R ｄ ), O and S(O) ０～２ wherein at least one ring in said system is aromatic and said heteroaryl is selected from the group consisting of oxo and R ｃ 119. The compound of any one of claims 113-118, wherein the compound is selected from the group consisting of heteroaryl, optionally substituted with 1 to 4 substituents independently selected from:

120. R ｂ is a heterocycloalkenyl containing 6 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R ｄ ), O and S(O) ０～２ wherein said heterocycloalkenyl is selected from the group consisting of oxo and R ｃ 120. The compound of any one of claims 113 to 119, optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

121. R ｂ but, 【Chemistry 51】 each of which is selected from 1 to 2 substituents R ｃ 121. The method of any one of claims 113 to 120, optionally substituted with

122. R ｂ but, 【Chemistry 52】 which is represented by 1 to 2 independently selected R ｃ 122. The compound of any one of claims 113 to 121, optionally substituted with:

123. R ｂ but, 【Chemistry 53】 The compound according to any one of claims 113 to 122,

124. R ｂ but, 【Chemistry 54】 The compound according to any one of claims 113 to 123,

125. R ｃ or R ｃ each occurrence of ａ , C １～４ Alkoxy, halo and -NR ｅ R ｆ C optionally substituted with １～１０ 124. The compound of claim 122 or 123, wherein the compound is selected from the group consisting of alkyl.

126. R ｃ Methyl, ethyl, -CHF ２ , -CF ３ , methoxy, fluoro, chloro and NH ２ 126. The compound of any one of claims 122-123 or 125, selected from the group consisting of:

127. R ｂ but, 【Transformation 55】 121. The compound of any one of claims 113 to 120, selected from the group consisting of:

128. R ｂ is a heteroaryl containing 5 ring atoms, and 1 to 4 ring atoms are selected from N, N(H), N(R ｄ ), O and S(O) ０～２ and the heteroaryl is a heteroatom independently selected from the group consisting of 1 to 4 independently selected substituents R ｃ 120. The compound of any one of claims 113 to 119, optionally substituted with:

129. R ｂ but, 【Transformation 56】 each of which is selected from the group consisting of 1 to 2 independently selected R ｃ 129. The compound of any one of claims 113 to 119 or 128, optionally substituted with

130. R ｂ but, 【Chemistry 57】 and optionally R ｄ is CH ３ 130. The compound according to any one of claims 113 to 119 or 128 to 129,

131. R ｂ but, 【Transformation 58】 and optionally R ｄ is CH ３ The compound according to any one of claims 113 to 119 or 128 to 130,

132. R ｂ but, 【Chemistry 59】 132. The compound according to any one of claims 113 to 119 or 128 to 131,

133. R ｂ is a heterocyclyl containing 6 ring atoms, 1 to 3 ring atoms being heteroatoms, each independently selected from N, N(H), N(R ｄ ), O and S(O) ０～２ wherein said heterocyclyl is selected from the group consisting of oxo and R ｃ 119. The compound of any one of claims 113 to 118, optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

134. R ｂ but, 【Transformation 60】 134. The compound of any one of claims 113-118 or 133, selected from the group consisting of:

135. R ｂ but, 【Chemistry 61】 135. The compound of any one of claims 113-118 or 133-134, selected from the group consisting of:

136. R ｄ is CH ３ 136. The compound of claim 134 or 135,

137. R ｂ but, 【Transformation 62】 136. The compound of claim 134 or 135,

138. R ｂ is a heteroaryl containing 6 ring atoms, and 1 to 4 ring atoms are N, N(H), N(R ｄ ), O and S(O) ０～２ and the heteroaryl is selected from 1 to 4 independently selected R ｃ 120. The compound of any one of claims 113 to 119, optionally substituted with:

139. R ｂ is a heteroaryl containing 6 ring atoms, 1 to 4 ring atoms being heteroatoms, each independently selected from N, N(H), N(R ｄ ), O and S(O) ０～２ 139. The compound of any one of claims 113 to 119 or 138, selected from the group consisting of:

140. R ｂ but, 【Transformation 63】 140. The compound of any one of claims 113-119 or 138-139, selected from the group consisting of:

141. R ｂ but, 【Chemistry 64】 141. The compound according to any one of claims 113 to 119 or 138 to 140,

142. R ｂ is a heteroaryl containing 9 ring atoms, 1 to 4 ring atoms being heteroatoms, each independently selected from N, N(H), N(R ｄ ), O and S(O) ０～２ wherein at least one ring in said system is aromatic and said heteroaryl is selected from the group consisting of oxo and R ｃ 120. The compound of any one of claims 113 to 119, optionally substituted with 1 to 4 independently selected from the group consisting of:

143. R ｂ but, 【Transformation 65】 each of which is selected from the group consisting of 1 to 4 independently selected R ｃ 143. The compound of any one of claims 113-119 or 142, optionally substituted with:

144. R ｂ but, 【Chemical Formula 66】 144. The compound of any one of claims 113-119 or 142-143, selected from the group consisting of:

145. R ｂ is a heteroaryl containing 10 ring atoms, 1 to 4 ring atoms being heteroatoms, each independently selected from N, N(H), N(R ｄ ), O and S(O) ０～２ wherein at least one ring in said system is aromatic and said heteroaryl is selected from the group consisting of 1 to 4 independently selected oxo or R ｃ 120. The compound of any one of claims 113 to 119, optionally substituted with:

146. R ｂ but, 【Transformation 67】 each of which is selected from the group consisting of 1 to 4 independently selected R ｃ 146. The compound of any one of claims 113-119 or 145, optionally substituted with

147. R ｂ but, 【Transformation 68】 147. The compound of any one of claims 113-119 or 145-146, selected from the group consisting of:

148. R ｂ is a heterocyclyl containing 7 to 10 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R ｄ ), O and S(O) ０～２ wherein said heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R ｃ 120. The compound of any one of claims 113 to 119, optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

149. R ｂ is a heterocyclyl containing 7 ring atoms, 1 to 3 ring atoms being heteroatoms, each independently selected from N, N(H), N(R ｄ ), O and S(O) ０～２ wherein said heterocyclyl is selected from the group consisting of 1 to 4 independently selected substituents R ｃ 149. The compound of any one of claims 113-119 or 148, optionally substituted with

150. R ｂ but, 【Transformation 69】 each of which is selected from the group consisting of 1 to 4 independently selected substituents R ｃ 150. The compound of any one of claims 113-119 or 148-149, optionally substituted with

151. R ｂ but, 【Transformation 70】 151. The compound of any one of claims 113-119 or 148-150, selected from the group consisting of:

152. R ｂ is a heterocyclyl containing 8 ring atoms, 1 to 3 ring atoms being heteroatoms, each independently selected from N, N(H), N(R ｄ ), O and S(O) ０～２ and the heterocyclyl is selected from the group consisting of 1 to 4 independently selected substituents R ｃ 149. The compound of any one of claims 113-119 or 148, optionally substituted with

153. R ｂ but, 【Chemistry 71】 each of which is selected from the group consisting of 1 to 4 independently selected substituents R ｃ 153. The compound of any one of claims 113-119, 148 or 152, optionally substituted with:

154. R ｂ but, 【Chemistry 72】 154. The compound of any one of claims 113-119, 148, or 152-153, selected from the group consisting of:

155. R ｂ is a heterocyclyl containing 9 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R ｄ ), O and S(O) ０～２ wherein said heterocyclyl is selected from the group consisting of oxo and R ｃ 149. The compound of any one of claims 113-119, or 148, optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

156. R ｂ but, 【Transformation 73】 each of which is selected from the group consisting of oxo and R ｃ 156. The compound of any one of claims 113-119, 148, or 155, optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

157. R ｄ is CH ３ 157. The compound of claim 156, wherein:

158. R ｂ but, 【Chemistry 74】 158. The compound of any one of claims 113-119, 148, or 155-157, selected from the group consisting of:

159. R ２ The compound of any one of claims 113 to 158, wherein is chloro.

160. The compound is represented by formula (Ia) 【Chemistry 75】 160. The compound of any one of claims 1 to 159,

161. The compound is represented by formula (Ib) 【Transformation 76】 160. The compound of any one of claims 1 to 159,

162. 10. The compound of claim 1 selected from the group consisting of the compounds of Table C1 or a pharmaceutically acceptable salt thereof.

163. The compound is 【Chemical 77】 or a pharmaceutically acceptable salt thereof.

164. The compound is 【Transformation 78】 or a pharmaceutically acceptable salt thereof.

165. The compound is 【Transformation 79】 or a pharmaceutically acceptable salt thereof.

166. 166. The compound of any one of claims 163 to 165, which is present in a racemic mixture.

167. The compound is 【Chemistry 80】 10. The compound of claim 1, which is:

168. 168. A pharmaceutical composition comprising a compound according to any one of claims 1 to 167, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

169. A method for degrading the proto-oncogene vav1 protein (VAV1) in a subject, comprising administering to the subject an effective amount of a compound described in any one of claims 1 to 167 or a pharmaceutically acceptable salt thereof.

170. The method of claim 169, wherein the compound mediates the interaction of the VAV1 protein with E3 ligase, thereby increasing the degradation of the VAV1 protein.

171. 171. The method of any one of claims 169 to 170, wherein VAV1 is a lymphocyte regulator.

172. 172. The method of claim 171, wherein the lymphocyte is a T cell.

173. 172. The method of claim 171, wherein the lymphocyte is a B cell.

174. 171. The method of any one of claims 169 to 170, wherein the compound interacts with E3 ligase prior to the interaction of VAV1 with E3 ligase.

175. 175. The method of any one of claims 170-174, wherein the E3 ligase comprises cereblon.

176. A method for degrading the proto-oncogene vav1 protein (VAV1), comprising: (i) contacting a compound according to any one of claims 1 to 167 or a pharmaceutically acceptable salt thereof with an E3 ligase; (ii) allowing the contacted E3 ligase to interact with VAV1, thereby degrading VAV1; A method for degrading the proto-oncogene vav1 protein (VAV1), comprising:

177. 168. A method of treating a disorder caused by or associated with dysregulated 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 to 167 or a pharmaceutically acceptable salt thereof.

178. 178. The method of claim 177, wherein the lymphocyte is a T cell.

179. 178. The method of claim 177, wherein the lymphocyte is a B cell.

180. 168. A method 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 of any one of claims 1 to 167 or a pharmaceutically acceptable salt thereof.

181. 181. The method of claim 180, wherein the T cell receptor signaling is IFNγ, CD69 and / or IL-2.

182. 168. A method of treating a disorder caused by or associated with a VAV1 polymorphism in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 167 or a pharmaceutically acceptable salt thereof.

183. 168. A method of treating a disorder caused by or associated with immunopathology in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 167 or a pharmaceutically acceptable salt thereof.

184. 184. The method of claim 182 or 183, wherein the disorder is an autoimmune disorder.

185. The method of claim 184, wherein the autoimmune disorder is selected from the group consisting of multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I or type II diabetes mellitus and disorders related thereto, vasculitis, pernicious anemia, Sjogren's syndrome, uveitis, psoriasis, Graves' ophthalmopathy, alopecia areata, and the like, allergic diseases (e.g., allergic asthma, atopic dermatitis, allergic rhinitis / conjunctivitis, allergic contact dermatitis), inflammatory diseases optionally with underlying abnormal responses (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, skin symptoms of immune-mediated disorders, inflammatory eye diseases, keratoconjunctivitis, myocarditis, or hepatitis.

186. 184. The method of claim 182 or 183, wherein the disorder is a cancer, tumor or other malignancy, and optionally the disorder is a hematological malignancy (e.g., a T- or B-cell malignancy).

187. 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 of unknown origin, adult T cell leukemia / lymphoma (HTLV1+), anaplastic large cell lymphoma, primary cutaneous CD-30 positive T cell lymphoproliferative disorder, 187. The method of claim 186, wherein the lymphoma is selected from the group consisting of cutaneous T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, intestinal T-cell lymphoma (+ enteropathy), hepatosplenic gamma / delta T-cell lymphoma, and non-Hodgkin's lymphoma (e.g., B-cell non-Hodgkin's lymphoma; e.g., Burkitt's lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), diffuse large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma).

188. 184. The method of claim 182 or 183, wherein the disorder is selected from the group consisting of type I or type II diabetes, pernicious anemia, uveitis, psoriasis, alopecia areata, ulcerative colitis, Crohn's disease, atherosclerosis, myocarditis, pericarditis, pulmonary fibrosis, systemic sclerosis, morphea, Alzheimer's disease, acute graft-versus-host disease, or T-cell mediated renal disease.

189. 184. The method of claim 182 or 183, wherein the disorder is selected from the group consisting of multiple sclerosis, rheumatoid arthritis, myasthenia gravis, Sjogren's syndrome, Graves' disease, an allergic disorder, an autoimmune liver disease, a chronic inflammatory demyelinating polyradicular neuropathy, macular degeneration, systemic lupus erythematosus, Hashimoto's thyroiditis, amyloidosis, an inflammatory eye disease, pemphigus, systemic lupus erythematosus, chronic graft-versus-host disease, lupus nephritis, pulmonary arterial hypertension, or vasculitis.

190. 190. The method of claim 182, 183, or 189, wherein the disorder is selected from the group consisting of multiple sclerosis, rheumatoid arthritis, myasthenia gravis, Sjogren's syndrome, Graves' disease, asthma, allergic contact dermatitis, rhinitis, contact dermatitis, biliary sclerosis, sclerosing cholangitis, chronic inflammatory demyelinating polyradicular neuropathy, macular degeneration, systemic lupus erythematosus, Hashimoto's thyroiditis, amyloidosis, inflammatory eye disease, pemphigus, systemic lupus erythematosus, chronic graft-versus-host disease, lupus nephritis, pulmonary arterial hypertension, or vasculitis.

191. 184. The method of claim 182 or 183, wherein the disorder is selected from the group consisting of ulcerative colitis, rheumatoid arthritis, psoriasis, multiple sclerosis, myasthenia gravis, cutaneous lupus, or axial spondyloarthritis.

192. 184. The method of claim 182 or 183, 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.

193. 184. The method of claim 182 or 183, wherein the disorder is ulcerative colitis.

194. 184. The method of claim 182 or 183, wherein the disorder is chronic lymphocytic leukemia.

195. 10. A method for treating a transplant-related disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof.

196. 194. The method of claim 193, wherein the transplant-related disease is selected from the group consisting of graft-versus-host disease, chronic graft rejection, acute graft rejection, transplant vasculopathy, transplant vascular disease, graft atherosclerosis, and transplant coronary artery disease.

197. A method for degrading the proto-oncogene vav1 protein (VAV1) in a subject suffering from an autoimmune disease or post-transplant disease, comprising administering to the subject an effective amount of a compound described in claim 1 or a pharmaceutically acceptable salt thereof.

198. The method of claim 195, wherein the autoimmune disorder is selected from the group consisting of multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I or type II diabetes mellitus and disorders related thereto, vasculitis, pernicious anemia, Sjogren's syndrome, uveitis, psoriasis, Graves' ophthalmopathy, alopecia areata, and the like, allergic diseases (e.g., allergic asthma, atopic dermatitis, allergic rhinitis / conjunctivitis, allergic contact dermatitis), inflammatory diseases optionally with underlying abnormal responses (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, skin symptoms of immune-mediated disorders, inflammatory eye diseases, keratoconjunctivitis, myocarditis, or hepatitis.

199. 197. The method of claim 196, wherein the transplant-related disease is selected from the group consisting of graft-versus-host disease, chronic graft rejection, acute graft rejection, transplant vasculopathy, transplant vascular disease, graft atherosclerosis, and transplant coronary artery disease.

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