Targeted protein degradation

Abstract

This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt thereof) that degrade and / or otherwise modulate (e.g., inhibit) NIMA Related Kinase 7 (NEK7). Said chemical entities are useful, e.g., for treating a subject (e.g., a human subject) having one or more disorders or diseases associated with NLRP3 inflammasome activation. Said disorders or diseases include but are not limited to, autoinflammatory and autoimmune disorders (e.g., gout, inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis), neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease), cardiovascular and metabolic disorders (e.g., pericarditis, atherosclerosis, Type 2 diabetes, obesity, metabolic syndrome, lysosomal storage diseases, MASH and Wilson disease), fibrotic disorders (e.g. interstitial lung disease, chronic kidney disease), eye disorders (e.g. macular degeneration) and haematology disorders (e.g. anaemia of inflammation).. In embodiments, and while not wishing to be bound by theory, it is believed that the chemical entities described herein directly target (e.g., directly bind to) NEK7, thereby altering (e.g., attenuating) the inflammatory response modulated by the NLRP3 inflammasome. This disclosure also features compositions containing the same as well as methods of using and making the same.

Description

[0001] TARGETED PROTEIN DEGRADATION

[0002] TECHNICAL FIELD

[0003] This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt thereof) that degrade and / or otherwise inhibit NIMA Related Kinase 7 (NEK7). Said chemical entities are useful, e.g., for treating a subject (e.g., a human subject) having a disorder or disease associated with NLRP3 inflammasome activation. This disclosure also features compositions containing the same as well as methods of using and making the same.

[0004] BACKGROUND

[0005] The ubiquitin proteasome system can be manipulated with different small molecules to trigger targeted degradation of specific proteins of interest. Promoting the targeted degradation of pathogenic proteins using small molecule degraders is emerging as a new modality in the treatment of diseases. One such modality relies on redirecting the activity of E3 ligases such as cereblon (a phenomenon known as E3 reprogramming) using low molecular weight compounds, which have been termed molecular glues to promote the poly-ubiquitination and ultimately proteasomal degradation of new protein substrates involved in the development of diseases. The molecular glues bind to both the E3 ligase and the target protein, thereby mediating an alteration of the ligase surface and enabling an interaction with the target protein. Particularly relevant compounds for the E3 ligase cereblon are the IMiD (immunomodulatory imide drugs) class including Thalidomide, Lenalidomide and Pomalidomide. These IMiDs have been approved by the FDA for use in haematological cancers. However, compounds for efficiently targeting other diseases are still required.

[0006] Inflammasomes are multi-protein complexes whose activation plays a central role in innate immunity and inflammation. NLRP3 inflammasome activation occurs in response to infectious or cell damage-related stress and acts to initiate or amplify inflammation. The NLRP3 inflammasome is composed of NLRP3, ASC, and caspase-1, which, when activated forms an intracellular complex that cleaves gasdermin D and the cytokines IL-ip and IL- 18 to release their active forms1,2. Cleaved gasdermin D then forms pores in the cell membrane, which allows the release of active IL-ip and IL- 18 and, in most cases, the rupture of the cell membrane in a highly inflammatory process known as pyroptosis3. NLRP3 activation is known to contribute to many settings of inappropriate or unwanted inflammation that is associated with autoinflammatory and autoimmune disease4,5. NEK7 is a serine / threonine kinase and a member of the family of NIMA- related kinases (NEKs) that are associated with mitotic entry, cell cycle progression, cell division, and mitotic progression. NEK7 is expressed in a variety of tissues and acts as an NLRP3-binding protein to facilitate its oligomerization and activation6.

[0007] References:

[0008] 1. Fu J & Wu H. Structural mechanisms of NLRP3 inflammasome assembly and activation.

[0009] Ann Rev Immunol . 2023; 41 :301-316

[0010] 2. McKee CM & Coll RC. NLRP3 inflammasome priming: A riddle wrapped in a mystery inside an enigma. J Leuk Biol. 2020; 108:937-952

[0011] 3. Devant P & Kagan JC. Molecular mechanisms of gasdermin D pore-forming activity. Nat Immunol. 2023; 24: 1064-1075

[0012] 4. Mangan MSJ, Olhava EJ, Roush WR, Seidl HM, Glick GD, Latz E. Targeting the NLRP3 inflammasome in inflammatory diseases. Nat Rev Drug Discov. 2018; 17:588-606

[0013] 5. Mullard A. NLRP3 inhibitors stoke anti-inflammatory ambitions. Nat Rev Drug Discov.

[0014] 2019; 18:405-407

[0015] 6. Sharif H, Wang L, Wang WL, Magupalli VG, Andreeva L, Qiao Q, Hauenstein AV, Wu Z, Nunez G, Mao Y, Wu H. Structural mechanism for NEK7-licensed activation of NLRP3 inflammasome. Nature 2019; 570(7761):338-343

[0016] SUMMARY

[0017] This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt thereof) that degrade and / or otherwise modulate (e.g., inhibit) NIMA Related Kinase 7 (NEK7). Said chemical entities are useful, e.g., for treating a subject (e.g., a human subject) having one or more disorders or diseases associated with NLRP3 inflammasome activation. Said disorders or diseases include but are not limited to, autoinflammatory and autoimmune disorders (e.g., gout, inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis), neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson’s disease) , cardiovascular and metabolic disorders (e.g., pericarditis, atherosclerosis, Type 2 diabetes, obesity, metabolic syndrome, metabolic dysfunction-associated steatohepatitis (MASH)), fibrotic disorders (e.g. interstitial lung disease, chronic kidney disease), eye disorders (eg. macular degeneration), and haematology disorders (eg. anaemia of inflammation). The disorder or disease may also be Wilson disease (also known as Wilson’s disease)). In embodiments, and while not wishing to be bound by theory, it is believed that the chemical entities described herein directly target (e.g., directly bind to) NEK7, thereby altering (e.g., attenuating) the inflammatory response modulated by the NLRP3 inflammasome. This disclosure also features compositions containing the same as well as methods of using and making the same.

[0018] In one aspect, this disclosure features compounds of Formula (I), or a pharmaceutically acceptable salt thereof; wherein A, X, R3a, R3b, and R4can be as defined anywhere herein.

[0019] In another aspect, this disclosure features pharmaceutical compositions that include one or more of the compounds described herein, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.

[0020] In a further aspect, this disclosure features methods of modulating (e.g., inhibiting) NIMA Related Kinase 7 (NEK7) in a subject, which include administering to the subject an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0021] In still another aspect, this disclosure features methods altering (e.g., attenuating) the inflammatory response modulated by the NLRP3 inflammasome in a subject, which include administering to the subject an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0022] In one aspect, this disclosure features methods of degrading NIMA Related Kinase 7 (NEK7) in a subject, which include administering to the subject an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0023] In another aspect, this disclosure features methods of degrading NIMA Related Kinase 7 (NEK7), which include one or both of the following: (i) contacting a compound described herein or a pharmaceutically acceptable salt thereof with an E3 ligase; and (ii) interacting the contacted E3 ligase with NEK7, thereby degrading NEK7.

[0024] In a further aspect, this disclosure features methods of treating a disorder associated with NLRP3 inflammasome activation in a subject in need thereof, which includes administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof.

[0025] Compounds and pharmaceutical compositions described herein can be used in the treatment of disorders in subjects in need thereof. Said disorders include, but are not limited to, those disorders caused by or associated with increased (e.g., excessive) NLRP3 inflammasome activation.

[0026] Accordingly, in one embodiment, described herein is a method of treating a disorder caused by or associated with NLRP3 inflammasome activation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof.

[0027] In some embodiments, the disorder is a disorder of the immune system, joints, central nervous system, cardiovascular system, endocrine system, renal system, eye, skin, respiratory system, hematopoietic system, hepatic system, and / or gastro-intestinal tract.

[0028] In some embodiments, the disorder is selected from the group consisting of: (i) inflammatory reactions in the joints; (ii) central nervous system diseases; (iii) cardiovascular diseases; (iv) metabolic diseases; (v) autoimmune diseases; (vi) kidney diseases; (vii) ocular diseases; (viii) hyperactive inflammation with underlying genetic mutations; (ix) respiratory diseases; (x) cancers; (xi) inflammatory reactions in the skin; (xii) diseases of the hematopoietic system; (xiii) liver disease; (xiv) viral infections and subsequent immune hyperactivation; (xv) allergic disease; and (xvi) infectious diseases.

[0029] In certain embodiments, the disorder is inflammatory reactions in the joints.

[0030] In certain of these embodiments, the disorder is acute or chronic gout.

[0031] In certain of these embodiments, the disorder is tophaceous gout.

[0032] In certain of these embodiments, the disorder is pseudo-gout or calcium pyrophosphate deposition disease.

[0033] In certain of these embodiments, the disorder is osteoarthritis.

[0034] In certain of these embodiments, the disorder is psoriatic arthritis. In certain of these embodiments, the disorder is systemic juvenile idiopathic arthritis.

[0035] In certain of these embodiments, the disorder is adult-onset Still’s disease.

[0036] In certain of these embodiments, the disorder is relapsing polychondritis.

[0037] In certain of these embodiments, the disorder is tendonitis.

[0038] In certain of these embodiments, the disorder is frozen shoulder.

[0039] In certain of these embodiments, the disorder is pyogenic arthritis.

[0040] In some embodiments, the disorder is selected from the group consisting of: (ii) central nervous system diseases; (iii) cardiovascular diseases; (iv) metabolic diseases; (v) autoimmune diseases; (vi) kidney diseases; (vii) ocular diseases; (viii) hyperactive inflammation with underlying genetic mutations; and (ix) respiratory diseases.

[0041] In certain embodiments, the central nervous system disease is selected from the group consisting of Parkinson’s disease, Alzheimer’s disease, motor neuron disease, Huntington’s disease, cerebral malaria, post-traumatic brain and / or spinal cord injury, sub-arachnoid haemorrhage, aneurysm, brain injury from pneumococcal meningitis, cerebral amyloid angiopathy, migraine, depression, and psychological stress.

[0042] In certain embodiments, the cardiovascular disease is selected from the group consisting of pericarditis including Dressier syndrome, myocarditis, inflammatory cardiomyopathy, transthyretin amyloidosis, atherosclerosis, stroke, myocardial infarction, heart failure, heart failure with preserved ejection fraction, ischemia reperfusion injury, hypertension, abdominal aortic aneurism, thromboembolism, and vasculitis.

[0043] In certain embodiments, the metabolic disease is selected from the group consisting of obesity, metabolic syndrome, MASH, and Type 2 diabetes and related morbidities including diabetic foot ulcers, atherosclerosis, diabetic cardiomyopathy, and diabetic retinopathy. The metabolic disease may also be Wilson disease.

[0044] In certain embodiments, the autoimmune disease is selected from the group consisting of multiple sclerosis (MS), rheumatoid arthritis, Behget’s disease, Sjogren’s syndrome, systemic sclerosis, mixed connective tissue disease, myositis, vasculitis, lupus, including systemic and cutaneous forms, lupus nephritis, type-1 diabetes, psoriasis, neuromyelitis optica, anti -myelin oligodendrocyte glycoprotein disease (MOG), autoimmune encephalitis, acute disseminated encephalomyelitis (ADEM), chronic meningitis, CNS vasculitis, Hashimoto’s encephalitis, steroid responsive encephalopathy associated with autoimmune thyroiditis, neurosarcoidosis, optic neuritis, transverse myelitis, Schnitzler’s syndrome, inflammatory bowel disease, colitis, and Crohn’s disease.

[0045] In certain embodiments, the kidney disease is selected from the group consisting of chronic kidney disease (CKD), including CKD associated with high uric acid, APOL1 mutations, complement-mediated kidney diseases such as C3 glomerulopathy, IgA nephropathy, atypical haemolytic uremic syndrome and membranous nephropathy, idiopathic nephrotic syndrome, oxalate nephropathy and diabetic nephropathy.

[0046] In certain embodiments, the ocular disease is selected from the group consisting of those of the ocular epithelium, age-related macular degeneration (AMD), corneal infection, uveitis and dry eye.

[0047] In certain embodiments, the hyperactive inflammation with underlying genetic mutations is selected from the group consisting of cryopyrin-associated periodic syndrome (CAPS): Muckle- Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS) and neonatal -onset multisystem inflammatory disease (NOMID); familial Mediterranean fever (FMF), TNF receptor associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MVK), hyperimmunoglobulinemia D and periodic fever syndrome (HIDS), deficiency of interleukin 1 receptor antagonist (DIRA), VEXAS syndrome, Majeed syndrome, pyoderma gangrenosum, acne, hidradenitis suppurativa, haploinsufficency of A20, paediatric granulomatous arthritis (PGA), PLCG2-associated antibody deficiency and immune dysregulation (PLAID), sideroblastic anaemia with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD), Sweet’ s syndrome, chronic non-bacterial osteomyelitis (CNO), chronic recurrent multifocal osteomyelitis (CRMO) and synovitis, pustulosis, hyperostosis, osteitis syndrome (SAPHO) and any disease where an individual has been determined to carry a germline or somatic non-silent mutation in NLRP3 or NEK7.

[0048] In certain embodiments, the respiratory disease is selected from the group consisting of chronic obstructive pulmonary disorder (COPD), acute respiratory distress syndrome (ARDS), steroid-resistant asthma, asbestosis, silicosis, sarcoidosis, cystic fibrosis and interstitial lung disease (ILD), including, but not limited to idiopathic pulmonary fibrosis (IPF), fibrotic hypersensitivity pneumonitis, rheumatoid arthritis-associated ILD, autoimmune myositis- associated ILD, systemic sclerosis-associated ILD, idiopathic interstitial pneumonia and progressive fibrosing ILD. In some embodiments, the disorder is a cancer, tumour or other malignancy.

[0049] In one aspect, this disclosure features methods of degrading NIMA Related Kinase 7 (NEK7) in a subject suffering from any one or more of the disorders described herein, comprising administering to the subject an effective amount of a compound of described herein or a pharmaceutically acceptable salt thereof.

[0050] In any of the embodiments described herein, the compound may be present in free, unsalted form, such as a free-base. In any of the embodiments described herein, the compound may be present in the form of a pharmaceutically acceptable salt.

[0051] Embodiments can include one or more of the following features. The compounds described herein can include any one or more of the structural features delineated throughout this specification and / or the claims. The compounds described herein can mediate the interaction of a NEK7 protein with an E3 ligase, e.g., thereby increasing degradation of the NEK7 protein. NEK7 can be an activator of an NLRP3 inflammasome. The compounds described herein can interact with the E3 ligase prior to the interaction of NEK7 with the E3 ligase. The E3 ligase can include cereblon (CRBN). The methods described herein can further include identifying a subject in need thereof. Additional details of one or more embodiments of the invention are set forth in the description below. Other features and advantages of the compounds, compositions, and methods featured herein will be apparent from the description and the claims.

[0052] DESCRIPTION OF DRAWINGS

[0053] FIG. 1 depicts the effects of administration of Compound 322 versus selnoflast on Caspase- 1 activity, measured using Caspase-Gio® 1 Inflammasome Assay, and inhibition of cytokine release, measured using the MSD immunoassay. Compound 322 inhibited caspase-1 activity with an average IC50 of 0.00233 pM and inhibited the release of IL-ip, IL-la, and IL-18 with average IC50 values of 0.00125 pM, 0.00105 pM, and 0.00126 pM, respectively.

[0054] FIG. 2A depicts the effects of administration of Compounds 303, 333, 353 and 382 on Caspase- 1 activity in human monocyte-derived macrophages, measured using Caspase-Gio® 1 Inflammasome Assay. Compounds 303, 333, 353 and 382 inhibited caspase-1 activity with an average ICso of 0.00176 pM, 0.00453 pM, 0.00788 pM and 0.00419 pM, respectively. FIG. 2B depicts the effects of administration of Compounds 303, 333, 353 and 382 on inhibition of cytokine release, measured using the Lumit® IL-ip Human / Mouse Immunoassay. Compounds 303, 333, 353 and 382 inhibited IL-ip release with an average ICso of 0.00165 pM, 0.00491 pM, 0.00733 pM and 0.00397 pM, respectively.

[0055] FIG. 3 depicts the effects of administration of Compound 322 on Caspase-1 activity in human iCell® microglia, measured using Caspase-Gio® 1 Inflammasome Assay, and inhibition of cytokine release, measured using the Lumit® IL-ip Human / Mouse Immunoassay. Compound 322 inhibited caspase-1 activity with an IC50 value of 0.00964 pM and inhibited the release of IL-ip with an IC50 value of 0.00158 pM.

[0056] FIG. 4 depicts the effects of Compound 322 versus selnoflast on plasma membrane integrity, assessed using the membrane impermeable nucleic acid stain, SYTOX™ Green. Compound 322 inhibited pyroptotic membrane permeabilization with an IC50 of 0.00132 pM compared to selnoflast with an IC50 of 0.455 pM.

[0057] FIG. 5 depicts a model of NEK7 MGD action that is relevant to NLRP3 -driven diseases. In this model, NLRP3 and NEK7-driven pyroptosis is depicted (left panel), showing activation and release of IL-ip and IL- 18 directly downstream of NLRP3 activation, but also showing how gasdermin D pore formation ultimately leads to cell lysis and release of multiple other factors, inclusive of IL-la and other danger molecules. These could include, but are not limited to, HMGB- 1, nucleic acids, and ATP.

[0058] The middle panel shows how targeted biologies can contribute downstream to reducing this inflammation by binding to and inactivating either IL-ip, in the case of canakinumab, for example, or both forms of IL-1 in the case of rilonacept, for example. In this case, ongoing pyroptosis is not addressed. In contrast, the NEK7 MGD approach (right panel) targets the upstream instigator of this form of cell death and can rescue the cell from not only the active release of IL-ip and IL-18, but also from the highly inflammatory cell death event itself. Thus, the NEK7 MGD approach could be a potent resolver of the types of inflammation where NLRP3 biology and this type of cell death is a key driver of pathology. FIG. 6 depicts the effects of Compound 322 on NEK7, IL-ip and IL-6 protein levels in mouse brains in an LPS-induced model of neuroinflammation. Compound 322 induces NEK7 degradation and inhibits IL-ip and IL-6 production in brains of CRBN 139 IV mice.

[0059] FIG. 7 depicts the effects of Compound 322 in non-human primate (NHP) cynomolgus monkey peripheral blood mononuclear cells (PBMCs) and cerebrospinal fluid (CSF), as well as the effects of Compound 322 on IL-ip levels post ex vivo stimulation of whole blood.

[0060] DETAILED DESCRIPTION

[0061] This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt thereof) that degrade and / or otherwise modulate (e.g., inhibit) NIMA Related Kinase 7 (NEK7). Said chemical entities are useful, e.g., for treating a subject (e.g., a human subject) having one or more disorders or diseases associated with NLRP3 inflammasome activation. Said disorders or diseases include but not limited to, autoinflammatory and autoimmune disorders (e.g., gout, inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis), neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson’s disease), cardiovascular and metabolic disorders (e.g., Wilson disease, pericarditis, atherosclerosis, Type 2 diabetes, obesity, metabolic syndrome, MASH), fibrotic disorders (e.g. interstitial lung disease, chronic kidney disease), eye disorders (e.g., macular degeneration), and haematology disorders (e.g., anaemia of inflammation). In embodiments, and while not wishing to be bound by theory, it is believed that the chemical entities described herein directly target (e.g., directly bind to) NEK7, thereby altering (e.g., attenuating) the inflammatory response modulated by the NLRP3 inflammasome. This disclosure also features compositions containing the same as well as methods of using and making the same.

[0062] Compounds

[0063] In one aspect, this disclosure features compound having formula (I): or a pharmaceutically acceptable salt thereof; wherein:

[0064] X is N, CH, CD, or CF;

[0065] A is defined according to (i), (ii), or (iii) below:

[0066] (

[0067] A is: ed according to (A) or (B) below: each of R1and R2is independently selected from the group consisting of H and RA; wherein: each occurrence of RAis independently selected from the group consisting of:

[0068] • Ci-6 alkyl optionally substituted with from 1-6 Ra;

[0069] • Ci-6 alkoxy optionally substituted with from 1-6 Ra;

[0070] • C2-6 alkenyl optionally substituted with from 1-6 Ra;

[0071] • C2-6 alkynyl optionally substituted with from 1-6 Ra; and

[0072] • -(L1)a-RB; a is 0 or 1;

[0073] L1is Ci-8 alkylene;

[0074] RBis selected from the group consisting of:

[0075] • C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rb, and Rc;

[0076] • heterocyclyl or heterocycloalkenyl including 3-10 ring members, wherein 1-3 ring members are heteroatoms or heteroatomic groups, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rb, and Rc;

[0077] • heteroaryl including 5-10 ring members, wherein 1-4 ring members are heteroatoms or heteroatomic groups, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc; and

[0078] • Ce-io aryl optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc;

[0079] (B)

[0080] R1and R2taken together with the nitrogen atom to which each is attached forms:

[0081] • heterocyclyl or heterocycloalkenyl including 3-12 ring atoms, wherein 0-4 ring atoms (aside from the N linking R1and R2) are ring heteroatoms, each independently selected from the group consisting of: N, N(H), N(Rd), O, and S, wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents each independently selected from the group consisting of: oxo, Rb, and Rc; and

[0082] • heteroaryl including from 9-14 ring atoms, wherein 0-4 ring atoms (aside from the N linking R1and R2) are ring heteroatoms, each independently selected from the group consisting of: N, N(H), N(Rd), O, and S, wherein the heteroaryl is optionally substituted with 1-4 substituents each independently selected from the group consisting of: oxo, Rb, and Rc; or

[0083] (ii) A is heteroaryl including 5-6 ring members, wherein 2-4 ring atoms are heteroatoms or heteroatomic groups, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-2 substituents independently selected from the group consisting of halo, -CN, Ci-ealkyl, Ci-4haloalkyl, Ci- 4alkoxy, Ci-4haloalkoxy, Ci-4hydroxyalkyl, phenyl, or 3-6 membered heterocyclyl containing one heteroatom, wherein the heteroatom is oxygen, wherein said phenyl may be optionally substituted with one or more of halo, CN, Ci-3alkyl, Ci-shaloalkyl, Ci-3alkoxy, or Ci-3haloalkoxy; or

[0084] (iii)

[0085] R3aand R3btaken together with the carbon atom to which each is attached forms:

[0086] • C3-5 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rb; or

[0087] • heterocyclyl including 3-5 ring members, wherein 1-2 ring members are heteroatoms or heteroatomic groups, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rb; or each of R3aand R3bis independently selected from the group consisting of:

[0088] • H;

[0089] • C1-3 alkyl optionally substituted with optionally substituted with 1-3 substituents independently selected from the group consisting of -F, -Cl, and -CN; and

[0090] • C3-4 cycloalkyl which is optionally substituted with 1-2 substituents independently selected from the group consisting of oxo and Rb;

[0091] R4is H, F, CH3, OCH3, CN, or Cl; each occurrence of Rais independently selected from the group consisting of: -OH; - halo; -NReRf; Ci-4alkoxy; Ci-4haloalkoxy; -C(=O)O(Ci-4alkyl); -C(=O)(Ci-4alkyl); - C(=O)OH; -CONR’R”; -S(O)I-2NR’R”; -S(O)i-2(Ci-4alkyl); and cyano; each occurrence of Rbis independently selected from the group consisting of: halo; cyano; Ci-io alkyl which is optionally substituted with from 1-6 independently selected Ra; C2-6 alkenyl; C2-6 alkynyl; Ci-4alkoxy; -(C1-3 alkylene)-(C3-6 cycloalkyl); -O(Ci-3 alkylene)-(C3-6 cycloalkyl); Ci-4haloalkoxy; -S(0)o-2(Ci-4alkyl); -NReRf; -OH; -S(O)I-2NR’R”; -NO2; -C(=0)(Ci-io alkyl); - C(=O)O(Ci-4alkyl); -C(=O)OH; and -C(=O)NR’R”; each occurrence of Rcis independently selected from the group consisting of:

[0092] • C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rb;

[0093] • heterocyclyl or heterocycloalkenyl including 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rb;

[0094] • heteroaryl including 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with from 1-4 Rb; and

[0095] • Ce-io aryl optionally substituted with from 1-4 Rb; each occurrence of Rdis independently selected from the group consisting of: C1-6 alkyl optionally substituted with from 1-3 independently selected Ra; -C(O)(Ci-4alkyl); -C(O)O(Ci-4alkyl); -CONR’R”; -S(O)I-2NR’R”; -S(O)i-2(Ci-4alkyl); -OH; and Ci-4alkoxy; and each occurrence of Reand Rfis independently selected from the group consisting of: H; C1-6 alkyl; -C(O)(Ci-4alkyl); -C(O)O(Ci-4alkyl); -CONR’R”; -S(O)I-2NR’R”; -S(O)i-2(Ci-4alkyl); -OH; and Ci-4alkoxy, and each occurrence of R’ and R” is independently selected from the group consisting of: H; and Ci-4 alkyl.

[0096] In another aspect, this disclosure features compound having formula (I): or a pharmaceutically acceptable salt thereof; wherein:

[0097] X is N, CH, CD, or CF;

[0098] A is defined according to (i) or (ii) below:

[0099] (

[0100] A is: ed according to (A) or (B) below: each of R1and R2is independently selected from the group consisting of H and RA; wherein: each occurrence of RAis independently selected from the group consisting of:

[0101] • Ci-6 alkyl optionally substituted with from 1-6 Ra;

[0102] • Ci-6 alkoxy optionally substituted with from 1-6 Ra;

[0103] • C2-6 alkenyl optionally substituted with from 1-6 Ra; • C2-6 alkynyl optionally substituted with from 1-6 Ra; and

[0104] • -(L1)a-RB; a is 0 or 1;

[0105] L1is Ci-8 alkylene;

[0106] RBis selected from the group consisting of:

[0107] • C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rb, and Rc;

[0108] • heterocyclyl or heterocycloalkenyl including 3-10 ring members, wherein 1-3 ring members are heteroatoms or heteroatomic groups, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rb, and Rc;

[0109] • heteroaryl including 5-10 ring members, wherein 1-4 ring members are heteroatoms or heteroatomic groups, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc; and

[0110] • Ce-io aryl optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc;

[0111] (B)

[0112] R1and R2taken together with the nitrogen atom to which each is attached forms:

[0113] • heterocyclyl or heterocycloalkenyl including 3-12 ring atoms, wherein 0-4 ring atoms (aside from the N linking R1and R2) are ring heteroatoms, each independently selected from the group consisting of: N, N(H), N(Rd), O, and S, wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents each independently selected from the group consisting of: oxo, Rb, and Rc; and

[0114] • heteroaryl including from 9-14 ring atoms, wherein 0-4 ring atoms (aside from the N linking R1and R2) are ring heteroatoms, each independently selected from the group consisting of: N, N(H), N(Rd), O, and S, wherein the heteroaryl is optionally substituted with 1-4 substituents each independently selected from the group consisting of: oxo, Rb, and Rc; or (ii)

[0115] A is heteroaryl including 5-6 ring members, wherein 2-4 ring atoms are heteroatoms or heteroatomic groups, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-2 substituents independently selected from the group consisting of F, -Cl, -CH3, -CFH2, -CF2H, -CF3, -CH2CH3, -CF2CH3, -CH2CF3, -OCH3, -OCFH2, -OCF3, and -CN;

[0116] R3aand R3btaken together with the carbon atom to which each is attached forms:

[0117] • C3-5 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rb; or

[0118] • heterocyclyl including 3-5 ring members, wherein 1-2 ring members are heteroatoms or heteroatomic groups, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rb; or each of R3aand R3bis independently selected from the group consisting of:

[0119] • H;

[0120] • C1-3 alkyl optionally substituted with optionally substituted with 1-3 substituents independently selected from the group consisting of -F, -Cl, and -CN; and

[0121] • C3-4 cycloalkyl which is optionally substituted with 1-2 substituents independently selected from the group consisting of oxo and Rb;

[0122] R4is H, F, CH3, OCH3, CN, or Cl; each occurrence of Rais independently selected from the group consisting of: -OH; - halo; -NReRf; Ci-4alkoxy; C1-4 haloalkoxy; -C(=O)O(Ci-4alkyl); -C(=O)(Ci-4alkyl); - C(=O)OH; -CONR’R”; -S(O)I-2NR’R”; -S(O)i-2(Ci-4alkyl); and cyano; each occurrence of Rbis independently selected from the group consisting of: halo; cyano; Ci-10 alkyl which is optionally substituted with from 1-6 independently selected Ra; C2-6 alkenyl; C2-6 alkynyl; Ci-4alkoxy; -(C1-3 alkylene)-(C3-6 cycloalkyl); -O(Ci-3 alkylene)-(C3-6 cycloalkyl); Ci-4 haloalkoxy; -S(0)o-2(Ci-4alkyl); -NReRf; -OH; -S(O)I-2NR’R”; -NO2; -C(=0)(Ci-io alkyl); - C(=O)O(Ci-4 alkyl); -C(=O)OH; and -C(=O)NR’R”; each occurrence of Rcis independently selected from the group consisting of:

[0123] • C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rb;

[0124] • heterocyclyl or heterocycloalkenyl including 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rb;

[0125] • heteroaryl including 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with from 1-4 Rb; and

[0126] • Ce-io aryl optionally substituted with from 1-4 Rb; each occurrence of Rdis independently selected from the group consisting of: C1-6 alkyl optionally substituted with from 1-3 independently selected Ra; -C(O)(Ci-4 alkyl); -C(O)O(Ci-4 alkyl); -CONR’R”; -S(O)I-2NR’R”; -S(O)i-2(Ci-4alkyl); -OH; and C1-4 alkoxy; and each occurrence of Reand Rfis independently selected from the group consisting of: H; C1-6 alkyl; -C(O)(Ci-4alkyl); -C(O)O(Ci-4alkyl); -CONR’R”; -S(O)I-2NR’R”; -S(O)i-2(Ci-4alkyl); -OH; and C1-4 alkoxy, and each occurrence of R’ and R” is independently selected from the group consisting of: H; and C1-4 alkyl.

[0127] Variables A, R1, R2, RA, and RB

[0128] In some embodiments, A is defined according to (i) or (ii) above.

[0129] In some embodiments, A is defined according to (i) above, wherein A is:

[0130] In some embodiments, R1and R2are defined according to (A).

[0131] In some embodiments, one of R1and R2is H, and the other of R1and R2is RA.

[0132] In certain embodiments, RAis -(L1)a-RB. In some embodiments, RAis selected from the group consisting of

[0133] In certain embodiments, a is 0.

[0134] In other embodiments, a is 1.

[0135] In some embodiments, RBis selected from the group consisting of:

[0136] • Ce-io aryl optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc; and

[0137] • heteroaryl including 5-10 ring members, wherein 1-4 ring members are heteroatoms or heteroatomic groups, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc.

[0138] In certain embodiments, RBis Ce-io aryl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of Rband Rc.

[0139] In certain embodiments, RBis Ce-io aryl, which is optionally substituted with 1-4 independently selected Rb.

[0140] In certain embodiments, RBis phenyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of Rband Rc. In certain embodiments, RBis phenyl, which is optionally substituted with 1-4 independently selected Rb.

[0141] In certain embodiments, RBis phenyl, which is optionally substituted with 1-2 independently selected Rb. For example, RBcan be:

[0142] In certain embodiments, each occurrence of Rbis independently selected from the group consisting of:

[0143] • halo;

[0144] • -CN; • Ci-4 alkyl which is optionally substituted with from 1-6 independently selected Ra

[0145] (optionally wherein Rais C1-2 alkoxy or F); and Ci-4 alkoxy or C1-4 haloalkoxy;

[0146] In certain embodiments, each occurrence of Rbis independently selected from the group consisting of -F, CH3, CH2F, CHF2, CF3, -CN, CH2OCH3, CF2CH3, OCH3, and OCF3. In certain embodiments, one occurrence of Rbis -F.

[0147] For example, RBcan

[0148] In certain embodiments, RBis: wherein Rblis F; and each of Rb21, Rb22, and Rb23is, independently, selected from the group consisting of -F, CH3, CH2F, CHF2, CF3, -CN, CH2OCH3, CF2CH3, OCH3, and OCF3.

[0149] For example, RBcan be:

[0150] In certain embodiments, RBis heteroaryl including 5-10 ring members, wherein 1-4 ring members are heteroatoms or heteroatomic groups, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc, optionally wherein the heteroaryl is optionally substituted with 1-4 independently selected Rb. In certain embodiments, RBis heteroaryl including 5-6 ring members, wherein 1-4 ring members are heteroatoms or heteroatomic groups, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 independently selected Rb.

[0151] In certain embodiments, RBis heteroaryl including 6 ring members, wherein 1-3 ring members are N, and wherein the heteroaryl is optionally substituted with 1-4 independently selected Rb;

[0152] In certain embodiments, RBcan be pyridyl or pyrimidinyl, each of which is optionally substituted with 1-3 independently selected Rb.

[0153] For example, RBcan be: , wherein 1 ■2 of Y1, Y2, and Y3are N, and the other(s) are independently CH or CRb.

[0154] In certain embodiments, Y1is N. In certain of these embodiments, Y2and Y3are CH or

[0155] CRb. E.g., Y2and Y3are both CH. E.g., one of Y2and Y3is CH, and the other is CRb.

[0156] In certain embodiments, Y2is N. In certain of these embodiments, Y1and Y3are CH or CRb. E.g., Y1and Y3are both CH. E.g., one of Y1and Y3is CH, and the other is CRb.

[0157] In certain of the foregoing embodiments, Rbof (Rb)o-2 is present. For example, Rb, or each occurrence of Rb, can be F. CHF2, or CF3 (e.g., F).

[0158] For example, RBcan be: In other embodiments, RBis heteroaryl including 5 ring members, wherein 1-3 ring members are heteroatoms or heteroatomic groups, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-2 independently selected Rb.

[0159] In certain embodiments, RBis thiazolyl or oxadiazolyl, each of which is optionally substituted with 1-2 independently selected Rb.

[0160] In certain of the foregoing embodiments, each occurrence of Rbis independently selected from the group consisting of:

[0161] • halo;

[0162] • -CN;

[0163] • Ci-4 alkyl which is optionally substituted with from 1-6 independently selected Ra(optionally wherein Rais C1-2 alkoxy or F); and

[0164] • C1-4 alkoxy or haloalkoxy;

[0165] For example, each occurrence of Rbcan be independently selected from the group consisting of -F, CH3, CH2F, CHF2, CF3, -CN, CH2OCH3, CF2CH3, OCH3, and OCF3.

[0166] In some embodiments, RBis C3-io cycloalkyl or C3-io cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rb, and Rc.

[0167] In some embodiments, RBis C3-io cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rb, and Rc.

[0168] In certain embodiments, RBis C3-8 cycloalkyl, which is optionally substituted with 1-4 independently selected Rb, or optionally substituted with 1-2 independently selected Rb, or optionally substituted with 1 Rb.

[0169] In certain embodiments, RBis C5-7 cycloalkyl, which is optionally substituted with 1-4 independently selected Rb, or optionally substituted with 1-2 independently selected Rb, or optionally substituted with 1 Rb.

[0170] In certain embodiments, RBis Ce cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rb, and Rc. In certain embodiments, RBis Ce cycloalkyl, which is optionally substituted with 1-4 independently selected Rb,

[0171] In certain embodiments, RBis Ce cycloalkyl, which is optionally substituted with 1-2 independently selected Rb, In certain embodiments, RBis Ce cycloalkyl, which is optionally substituted with 1 Rb.

[0172] In certain embodiments, RBis Ce cycloalkyl, which is optionally substituted with 1 Rb. In certain of these embodiments, RBis:

[0173] As another example, RBcan be:

[0174] In certain of these embodiments, RBis:

[0175] For example, RBcan be:

[0176] In certain of these embodiments, RBis:

[0177] As another example, RBcan be:

[0178] In certain of the foregoing embodiments, each occurrence of Rbis independently selected from the group consisting of:

[0179] • -OH;

[0180] • -NR’R”;

[0181] • Ci-4 alkyl which is optionally substituted with from 1-2 (optionally 1) independently selected Ra(optionally wherein Rais OH or F);

[0182] • Ci-4 alkoxy;

[0183] • halo; and

[0184] • -CO2R’.

[0185] For example, each occurrence of Rbcan be -OH, -NH2, -N(CH3)2, -NHSO2CH3, - NHC(O)CH3, -CH3, -CF3, -CH2OH, -CH(OH)(CH3)2, F, -Cl, -0CH3, -0CHF2, or -OCF3.

[0186] In some embodiments, RBis heterocyclyl including 3-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rb, and Rc.

[0187] In certain embodiments, each of R1and R2is an independently selected RA.

[0188] In some embodiments, R1and R2are defined according to (B), wherein:

[0189] R1and R2taken together with the nitrogen atom to which each is attached forms:

[0190] • heterocyclyl or heterocycloalkenyl including 3-12 ring atoms, wherein 0-4 ring atoms (aside from the N linking R1and R2) are ring heteroatoms, each independently selected from the group consisting of: N, N(H), N(Rd), O, and S, wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents each independently selected from the group consisting of: oxo, Rb, and Rc; and • heteroaryl including from 9-14 ring atoms, wherein 0-4 ring atoms (aside from the N linking R1and R2) are ring heteroatoms, each independently selected from the group consisting of: N, N(H), N(Rd), O, and S, wherein the heteroaryl is optionally substituted with 1-4 substituents each independently selected from the group consisting of: oxo, Rb, and Rc.

[0191] In certain embodiments, R1and R2taken together with the nitrogen atom to which each is attached forms: heterocyclyl including 3-12 ring atoms, wherein 0-4 ring atoms (aside from the N linking R1and R2) are ring heteroatoms, each independently selected from the group consisting of: N, N(H), N(Rd), O, and S, wherein the heterocyclyl is optionally substituted with 1-4 substituents each independently selected from the group consisting of: oxo, Rb, and Rc.

[0192] In certain embodiments, R1and R2taken together with the nitrogen atom to which each is attached forms: heterocyclyl including 5-8 (e.g., 6) ring atoms, wherein 0-4 ring atoms (aside from the N linking R1and R2) are ring heteroatoms, each independently selected from the group consisting of: N, N(H), N(Rd), O, and S, wherein the heterocyclyl is optionally substituted with 1-4 substituents each independently selected from the group consisting of: oxo, Rb, and Rc.

[0193] In certain embodiments, R1and R2taken together with the nitrogen atom to which each is attached forms heterocyclyl or heterocycloalkenyl selected from the group consisting of:

[0194]

[0195] In some embodiments, A is defined according to (ii) above.

[0196] In some embodiments, A is heteroaryl including 5 ring members, wherein 2-4 ring atoms are heteroatoms or heteroatomic groups, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-2 substituents independently selected from the group consisting of halo, -CN, Ci-ealkyl, Ci- 4haloalkyl, Ci-4alkoxy, Ci-4haloalkoxy, Ci-4hydroxyalkyl, phenyl, or 3-6 membered heterocyclyl containing one heteroatom, wherein the heteroatom is oxygen, wherein said phenyl may be optionally substituted with one or more of halo, CN, Ci-3alkyl, Ci-shaloalkyl, Ci-3alkoxy, or Ci- shaloalkoxy. The heteroaryl ring may include 5 ring members, wherein 2-3 ring atoms are heteroatoms or heteroatomic groups.

[0197] In some embodiments, A is heteroaryl including 5-6 ring members, wherein 2-4 ring atoms are heteroatoms or heteroatomic groups, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-2 substituents independently selected from the group consisting of -F, -Cl, -CH3, -Ph, -CFH2, -CF2H, -CF3, -CH2CH3, -CF2CH3, -CH2CF3, -CH2OMe, -CH(Me)OMe, -CH2CHF2, -CH2CF2CH3, -CH2Ph, -CH(CH3)2, -C(CH3)3, -OCH3, -OCFH2, -OCF3, C(Me)2(OH) , -CN,

[0198] 6

[0199] O , and O . The heteroaryl ring may include 5 ring members, wherein 2-3 ring atoms are heteroatoms or heteroatomic groups.

[0200] In some embodiments, A is defined according to (ii) above, wherein A is heteroaryl including 5-6 ring members, wherein 2-4 ring atoms are heteroatoms or heteroatomic groups, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-2 substituents independently selected from the group consisting of -F, -Cl, -CH3, -CFH2, -CF2H, -CF3, -CH2CH3, -CF2CH3, -CH2CF3, -OCH3, -OCFH2, -OCF3, and -CN.

[0201] In some embodiments, A is heteroaryl including 5 ring members, wherein 2-3 ring atoms are heteroatoms or heteroatomic groups, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-2 substituents independently selected from the group consisting of -F, -Cl, -CH3, -CFH2, -CF2H, - CF3, -CH2CH3, -CF2CH3, -CH2CF3, -OCH3, -0CFH2, -OCF3, and -CN.

[0202] In some embodiments, A has the formula: wherein:

[0203] X6is NH, NCH3, O, or S;

[0204] X7is N, C, CH, CF, CCF3, CCH2F, CCHF2, CF2CH3, CH2CH3, or CCH3;

[0205] X8is N, C, CH, or CCH3;

[0206] X9is N, C, CH, or CCH3; and

[0207] X10 is N, C, CH, CCF3, CCHF2, or CCH3.

[0208] In some embodiments, A has the formula: wherein:

[0209] X6is NH, NCH3, O, or S; X7is N, CH, CF, CCF3, CCH2F, CCHF2, CF2CH3, CH2CH3, or CCH3;

[0210] X8is N, CH, or CCH3; and

[0211] X9is N, CH, or CCH3.

[0212] In certain embodiments, X8is N.

[0213] In certain embodiments, X9is N.

[0214] In certain embodiments, Xe is O.

[0215] In certain embodiments, X7is CH, CCF3, CCHF2, CCH2CH3, or CCH3. For example, X7can be CH.

[0216] In certain embodiments, X8is N, and X9is N.

[0217] In certain embodiments, X8is N, X9is N, and Xe is O.

[0218] In certain embodiments, X8is N, X9is N, Xe is O, and X7is CH, CCF3, CCHF2, CCH2CH3, or CCH3. In certain of these embodiments, X7can be CH.

[0219] For example, A can have the following formula:

[0220] In certain embodiments, X9is N, and X8is CH, or CCH3.

[0221] In certain embodiments, X7is N, CCF3, CCHF2, CCH2CH3, or CCH3.

[0222] In certain embodiments, X9is N, X8is CH, or CCH3, and X7is N, CCF3, CCHF2,

[0223] CCH2CH3, or CCH3.

[0224] In certain of these embodiments, Xe is O.

[0225] For example, A can have one of the following formulas:

[0226] For example, A can have one of the following formulas:

[0227] In a certain embodiment, A is:

[0228] Variables R3aand R3b

[0229] In some embodiments, R3aand R3btaken together with the carbon atom to which each is attached forms:

[0230] • C3-5 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rb; or

[0231] • heterocyclyl including 3-5 ring members, wherein 1-2 ring members are heteroatoms or heteroatomic groups, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rb;

[0232] In certain embodiments, R3aand R3btaken together with the carbon atom to which each is attached forms C3-5 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rb.

[0233] In certain embodiments, R3aand R3btaken together with the carbon atom to which each is attached forms C3 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rb. In certain embodiments, R3aand R3btaken together with the carbon atom to which each is attached forms unsubstituted C3 cycloalkyl.

[0234] In certain embodiments, R3aand R3btaken together with the carbon atom to which each is attached forms C4 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rb.

[0235] In certain embodiments, R3aand R3btaken together with the carbon atom to which each is attached forms unsubstituted C4 cycloalkyl.

[0236] In some embodiments, each of R3aand R3bis independently selected from the group consisting of H and C1-3 alkyl, which is optionally substituted with 1-3 substituents independently selected from the group consisting of -F, -Cl, and -CN.

[0237] In certain embodiments, each of R3aand R3bis independently selected from the group consisting of H and C1-3 alkyl, which is optionally substituted with 1-3 substituents independently selected from the group consisting of -Cl - and -CN.

[0238] In certain embodiments, each of R3aand R3bis independently selected from the group consisting of H and C1-3 alkyl, which is optionally substituted with 1-3 F.

[0239] In some embodiments, one of R3aand R3bis H, and the other is C1-3 alkyl, which is optionally substituted with 1-3 substituents independently selected from the group consisting of - F, -Cl, and -CN.

[0240] In some embodiments, one of R3aand R3bis H, and the other is C1-3 alkyl, which is optionally substituted with -F, -Cl, or -CN.

[0241] In some embodiments, one of R3aand R3bis H, and the other is CH3, which is optionally substituted with -F, -Cl, or -CN.

[0242] In some embodiments, one of R3aand R3bis H, and the other is unsubstituted C1-3 alkyl.

[0243] In some embodiments, one of R3aand R3bis H, and the other is CH3.

[0244] In some of the foregoing embodiments, the carbon attached to R3aand R3bhas the R- configuration.

[0245] In some of the foregoing embodiments, the carbon attached to R3aand R3bhas the S- configuration. Variable R4

[0246] In some embodiments, R4is Cl

[0247] In some embodiments, R4is F.

[0248] In some embodiments, R4is H.

[0249] Non-Limiting Combinations

[0250] In some embodiments, the compound has formula (Ila):

[0251] In some embodiments, the compound has formula (lib):

[0252] In some embodiments, the compound has formula (Illa):

[0253] In some embodiments, the compound has formula (Illb):

[0254]

[0255] In some embodiments, the compound or pharmaceutically acceptable salt thereof is of

[0256] Formula IIIc: or a pharmaceutically acceptable salt thereof; wherein:

[0257] R1is pyridyl, which may be optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc.

[0258] In some embodiments of Formula (IIIc), the pyridyl is optionally substituted with 1, 2, 3, or 4 Rb, preferably the pyridyl is substituted with 1 or 2 Rb.

[0259] In some embodiments of Formula (IIIc), the pyridyl is optionally substituted with 1, 2, 3, or 4 Rbselected from the group consisting of halo, and Ci-3alkyl which is optionally substituted with 1, 2, 3, or 4 fluoro and / or chloro.

[0260] In some embodiments of Formula (IIIc), the pyridyl is optionally substituted with 1, 2, 3, or 4 Rbselected from the group consisting of F and CH3, wherein the CH is optionally substituted with 1 or 2 F.

[0261] In some embodiments of Formula wherein Rbl, Rb2and Rb3are each independently selected from H, halo, Ci-3alkyl or Ci-shaloalkyl; and Rb4is selected from

[0262] H or Ci-3alkyl. In some embodiments, Rblis H, halo, or Ci-shaloalkyl, Rb2is H or halo, Rb3is H, and Rb4is H or Ci-3alkyl.

[0263] In some embodiments, Rblis H, F, or Cifluoroalkyl, Rb2is H, Rb3is H, and Rb4is H or CH3. In some embodiments, the compound has formula (IVa):

[0264] In some embodiments of formula (IVa), RBhas formula: certain of these embodiments, RBhas formula B-2, B-

[0265] 3, B-4, B-5, B-6, B-7, or B-8. In still other embodiments, RBhas one of the specific formulas delineated herein that fall with the scope of formula B-l, B-2, B-3, B-4, B-5, B-6, B-7, or B-8.

[0266] In some embodiments of formula (IVa), RBis: , wherein 1 ■2 of Y1, Y2, and Y3are N, and the other(s) are independently CH or CRb.

[0267] In certain embodiments, Y1is N. In certain of these embodiments, Y2and Y3are CH or

[0268] CRb. E.g., Y2and Y3are both CH. E.g., one of Y2and Y3is CH, and the other is CRb. In certain embodiments, Y2is N. In certain of these embodiments, Y1and Y3are CH or CRb. E.g., Y1and Y3are both CH. E.g., one of Y1and Y3is CH, and the other is CRb.

[0269] In certain of the foregoing embodiments, Rbof (Rb)o-2 is present. For example, Rb, or each occurrence of Rb, can be F. CHF2, or CF3 (e.g., F).

[0270] In some of the foregoing embodiments of formula (IVa), is

[0271] In some of the foregoing embodiments of formula (IVa), > > mil

[0272] In some of the foregoing embodiments of formula (IVa), R4is Cl. wherein can be as defined anywhere herein.

[0273] In certain embodiments of formula (IVb), Xs is N.

[0274] In certain embodiments of formula (IVb), X9 is N.

[0275] In certain embodiments of formula (IVb), Xe is O.

[0276] In certain embodiments of formula (IVb), X7 is CH, CCF3, CCHF2, CCH2CH3, or CCH3. For example, X7 can be CH.

[0277] In certain embodiments of formula (IVb), Xs is N, and X9 is N.

[0278] In certain embodiments of formula (IVb), Xs is N, X9 is N, and Xe is O.

[0279] In certain embodiments of formula (IVb), Xs is N, X9 is N, Xe is O, and X7 is CH, CCF3, CCHF2, CCH2CH3, or CCH3. In certain of these embodiments, X7 can be CH. In certain embodiments of formula (IVb), A has the following formula:

[0280] In certain embodiments of formula (IVb), X9 is N, and Xs is CH, or CCH3. In certain embodiments of formula (IVb), X7 is N, CCF3, CCHF2, CCH2CH3, or CCH3.

[0281] In certain embodiments of formula (IVb), X9 is N, Xs is CH, or CCH3, and X7 is N, CCF3, CCHF2, CCH2CH3, or CCH3.

[0282] In certain of these embodiments, Xe is O.

[0283] In certain embodiments of formula (IVb), A has one of the following formulas:

[0284] In certain embodiments of formula (IVb), A has one of the following formulas:

[0285] In certain embodiments of formula (IVb), A is either:

[0286] In some of the foregoing embodiments of formula (IVb), js

[0287] In some of the foregoing embodiments of formula (IVb), is "HI . In some of the foregoing embodiments of formula (IVb), R4is Cl.

[0288] In some embodiments, the compound has formula (Va):

[0289] In some embodiments, the compound has formula (Vb):

[0290] In some embodiments, R4is Cl or F. In some embodiments, R4is Cl.

[0291] In some embodiments, the compound has formula (Ilaa):

[0292] In some embodiments, the compound has formula (Ilbb):

[0293] In some embodiments, the compound has formula (Illaa):

[0294] In some embodiments, the compound has formula (Illbb):

[0295] In some embodiments, the compound has formula (IVaa): In some embodiments, the compound has formula (IVbb):

[0296] In some embodiments, the compound has formula (Vaa):

[0297] In some embodiments, the compound has formula (Vbb):

[0298] In some embodiments of formulas (Ilaa), (Ilbb), (Illaa), (Illbb), (IVaa), (IVbb), (Vaa), and (Vbb), one of R1and R2is H, and the other of R1and R2is RA.

[0299] In some embodiments of formulas (Ilaa), (Ilbb), (Illaa), (Illbb), (IVaa), (IVbb), (Vaa), and (Vbb), RAis -(L1)a-RB. In some embodiments of formulas (Ilaa), (Ilbb), (Illaa), (Illbb), (IVaa), (IVbb), (Vaa), and (Vbb), a is 0.

[0300] In some embodiments of formulas (Ilaa), (Ilbb), (Illaa), (Illbb), (IVaa), (IVbb), (Vaa), and (Vbb), RBis Ce cycloalkyl, which is optionally substituted with 1-2 independently selected Rb,

[0301] In some embodiments of formulas (Ilaa), (Ilbb), (Illaa), (Illbb), (IVaa), (IVbb), (Vaa), and (Vbb), RBis Ce cycloalkyl, which is optionally substituted with 1 Rb.

[0302] In some embodiments of formulas (Ilaa), (Ilbb), (Illaa), (Illbb), (IVaa), (IVbb), (Vaa), and (Vbb), RBis:

[0303] In some embodiments of formulas (Ilaa), (Ilbb), (Illaa), (Illbb), (IVaa), (IVbb), (Vaa), and (Vbb), RBis:

[0304] In some embodiments of formulas (Ilaa), (Ilbb), (Illaa), (Illbb), (IVaa), (IVbb), (Vaa), and (Vbb), RBis:

[0305] In some embodiments of formulas (Ilaa), (Ilbb), (Illaa), (Illbb), (IVaa), (IVbb), (Vaa), and (Vbb), RBis: In some embodiments of formulas (Ilaa), (Ilbb), (Illaa), (Illbb), (IVaa), (IVbb), (Vaa), and

[0306] (Vbb), RBis: In some embodiments of formulas (Ilaa), (Ilbb), (Illaa), (Illbb), (IVaa), (IVbb), (Vaa), and

[0307] (Vbb), RBis:

[0308] In some embodiments of formulas (Ilaa), (Ilbb), (Illaa), (Illbb), (IVaa), (IVbb), (Vaa), and (Vbb), RBis:

[0309] In some embodiments of formulas (Ilaa), (Ilbb), (Illaa), (Illbb), (IVaa), (IVbb), (Vaa), and (Vbb), RBis: In some embodiments of formulas (Ilaa), (Ilbb), (Illaa), (Illbb), (IVaa), (IVbb), (Vaa), and (Vbb), RBis:

[0310] In some embodiments of formulas (Ilaa), (Ilbb), (Illaa), (Illbb), (IVaa), (IVbb), (Vaa), and (Vbb), each occurrence of Rbis independently selected from the group consisting of:

[0311] • -OH;

[0312] • -NR’R”;

[0313] • Ci-4 alkyl which is optionally substituted with from 1-2 (optionally 1) independently selected Ra(optionally wherein Rais OH or F);

[0314] • Ci-4 alkoxy;

[0315] • halo; and

[0316] • -CO2R’.

[0317] In some embodiments of formulas (Ilaa), (Ilbb), (Illaa), (Illbb), (IVaa), (IVbb), (Vaa), and (Vbb), Rbis -OH.

[0318] In some embodiments of formulas (Ilaa), (Ilbb), (Illaa), (Illbb), (IVaa), (IVbb), (Vaa), and (Vbb), Rbis -NH2, -N(CH3)2, -NHSO2CH3, or -NHC(O)CH3.

[0319] In some embodiments of formulas (Ilaa), (Ilbb), (Illaa), (Illbb), (IVaa), (IVbb), (Vaa), and (Vbb), Rbis -CH3, -CF3, -CH2OH, or -CH(OH)(CH3)2.

[0320] In some embodiments of formulas (Ilaa), (Ilbb), (Illaa), (Illbb), (IVaa), (IVbb), (Vaa), and (Vbb), Rbis -F.

[0321] In some embodiments of formulas (Ilaa), (Ilbb), (Illaa), (Illbb), (IVaa), (IVbb), (Vaa), and (Vbb), R4is Cl. Stereochemistry

[0322] The compounds generically or specifically disclosed herein include all stereoisomeric forms, including all diastereomeric and entantiomeric forms, unless it is specifically stated or the context indicates otherwise. Compounds with chiral centers can occur as racemates, individual enantiomers (e.g. as the (R) enantiomer or (S) entantiomer) or diastereomers, and mixtures thereof. All such stereoisomeric forms are included within the embodiments disclosed herein, including mixtures thereof.

[0323] Further, compounds of one enantiomeric form may epimerise into the other enantiomeric form. Thus, unless it is specifically stated or the context indicates otherwise, disclosure of one enantiomer encompasses the isolated enantiomer and a mixture, such as a racemic mixture, of the (R) and (S) enantiomers if the enantiomers epimerise.

[0324] Stereochemistry is represented in the structural formulas provided herein using conventional solid and dashed wedges or lines

[0325] For the avoidance of doubt, the use of solid and dashed wedges or lines in conjunction with the carbon atom attached to R3aand R3bis intended to indicate absolute stereochemistry in accordance with the Cahn-Ingold-Prelog priority rules for the following compounds:

[0326]

[0327] For the avoidance of doubt, and unless otherwise indicated, the use of solid and dashed wedges or lines in conjunction with the chiral carbon atom in the glutarimide ring (i.e., the CH that serves as the point of attachment of the glutarimide ring to the remainder of formula (I)), is intended to indicate arbitrarily assigned and / or relative stereochemistry.

[0328] For the avoidance of doubt, and unless otherwise indicated, the use of solid and dashed wedges or lines in conjunction with one or more substituted carbon atoms present in R1and / or R2is intended to indicate relative stereochemistry (see, e.g., in compound 1, in which R1is RB, and

[0329] RBis 2-fluorocyclohexyl, and R2is H:H) except for the following compounds, where absolute stereochemistry for R1and / or R2has been determined in accordance with the Cahn- Ingold-Prelog priority rules:

[0330] Pharmaceutical Compositions

[0331] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound described herein, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises an effective amount of the compound. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the compound.

[0332] The pharmaceutical compositions provided herein can be administered by a variety of routes including, but not limited to, oral (enteral) administration, parenteral (by injection) administration, rectal administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous (SC) administration, intravenous (IV) administration, intramuscular (IM) administration, and intranasal administration.

[0333] Compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. In some embodiments, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules, or the like in the case of solid compositions. In such compositions, the compound is usually a minor component with the remainder being various vehicles or excipients and processing aids helpful for forming the desired dosing form.

[0334] Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavours and the like. 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 sweetening agent such as sucrose or saccharin; or a flavouring agent such as peppermint, methyl salicylate, or orange flavouring.

[0335] Injectable compositions are typically based upon injectable sterile saline or phosphate- buffered saline or other injectable excipients known in the art. As before, the active compound in such compositions is typically a minor component with the remainder being the injectable excipient and the like.

[0336] Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s). When formulated as a ointment, the active ingredients will typically be combined with either a paraffinic or a water -miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base. Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or Formulation. All such known transdermal formulations and ingredients are included within the scope of the disclosure provided herein.

[0337] 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.

[0338] The above-described components for orally administrable, injectable or topically administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington ’s Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0339] Methods of Use

[0340] Compounds and pharmaceutical compositions described herein can be used in the treatment of disorders in subjects in need thereof. Said disorders include, but are not limited to, those disorders caused by or associated with NLRP3 inflammasome activation. Accordingly, in one embodiment, described herein is a method of treating a disorder caused by or associated with NLRP3 inflammasome activation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof.

[0341] In some embodiments, the disorder is a disorder of the immune system, joints, central nervous system, cardiovascular system, endocrine system, renal system, eye, skin, respiratory system, hematopoietic system, hepatic system, and / or gastro-intestinal tract.

[0342] In some embodiments, the disorder is an autoinflammatory or autoimmune disorder.

[0343] In certain of these embodiments, the disorder is inflammatory bowel disease.

[0344] In certain of these embodiments, the disorder is rheumatoid arthritis.

[0345] In certain of these embodiments, the disorder is multiple sclerosis.

[0346] In certain of these embodiments, the disorder is gout (e.g., acute and chronic gout, tophaceous gout, or pseudo-gout).

[0347] In some embodiments, the disorder is a neurodegenerative disorder (e.g., Alzheimer's disease or Parkinson’s disease).

[0348] In some embodiments, the disorder is a cardiovascular or metabolic disorder (e.g., Wilson disease, pericarditis, atherosclerosis, Type 2 diabetes, obesity metabolic syndrome or MASH or a lysosomal storage disease). In some embodiments, the disorder is a cardiovascular or metabolic disorder (e.g., Wilson disease, pericarditis, atherosclerosis, Type 2 diabetes, obesity or metabolic syndrome). In some embodiments, the disorder is a cardiovascular or metabolic disorder (e.g., pericarditis, atherosclerosis, Type 2 diabetes, obesity or metabolic syndrome).

[0349] In some embodiments, the disorder is a fibrotic disorder (e.g., interstitial lung disease or chronic kidney disease).

[0350] In some embodiments, the disorder is an eye disorder (e.g., macular degeneration). In some embodiments, the disorder is a disorder associated with haematology (e.g., anaemia of inflammation).

[0351] In some embodiments, the disorder is a disorder of the immune system, hematopoietic system, joints, renal system, gastro-intestinal tract, skin, eye, respiratory system, central nervous system, cardiovascular system, hepatic system, and / or endocrine system.

[0352] In some embodiments, the disorder is a cancer, tumour or other malignancy. In some embodiments, the disorder is selected from the group consisting of

[0353] (i) inflammatory reactions in the joints including acute and chronic gout, tophaceous gout, pseudo-gout (calcium pyrophosphate deposition disease), osteoarthritis, psoriatic arthritis, systemic juvenile idiopathic arthritis, adult-onset Still’s disease, relapsing polychondritis, tendonitis, frozen shoulder and pyogenic arthritis;

[0354] (ii) central nervous system diseases including Parkinson’s disease, Alzheimer’s disease, motor neuron disease, Huntington’s disease, cerebral malaria, post- traumatic brain and / or spinal cord injury, sub-arachnoid haemorrhage, aneurysm, brain injury from pneumococcal meningitis, cerebral amyloid angiopathy, migraine, depression, psychological stress;

[0355] (iii) cardiovascular diseases including pericarditis (including Dressier syndrome), myocarditis, inflammatory cardiomyopathy, transthyretin amyloidosis, atherosclerosis, heart failure, heart failure with preserved ejection fraction, stroke, myocardial infarction, ischemia reperfusion injury, hypertension, abdominal aortic aneurism, thromboembolism, vasculitis;

[0356] (iv) metabolic diseases including obesity, metabolic syndrome, and Type 2 diabetes and related morbidities including diabetic foot ulcers, atherosclerosis, diabetic cardiomyopathy and diabetic retinopathy; or metabolic diseases including obesity, metabolic syndrome, a lysosomal storage disease, MASH, Wilson disease, and Type 2 diabetes and related morbidities including diabetic foot ulcers, atherosclerosis, diabetic cardiomyopathy and diabetic retinopathy;

[0357] (v) autoimmune diseases including multiple sclerosis (MS), rheumatoid arthritis, Behget’s disease, Sjogren’s syndrome, systemic sclerosis, mixed connective tissue disease, myositis, vasculitis, lupus, including systemic and cutaneous forms, lupus nephritis, type-1 diabetes, psoriasis, neuromyelitis optica, anti-myelin oligodendrocyte glycoprotein disease (MOG), autoimmune encephalitis, acute disseminated encephalomyelitis (ADEM), chronic meningitis, CNS vasculitis, Hashimoto’s encephalitis, steroid responsive encephalopathy associated with autoimmune thyroiditis, neurosarcoidosis, optic neuritis, transverse myelitis, Schnitzler’s syndrome, inflammatory bowel disease, colitis, Crohn’s disease; (vi) kidney disease including chronic kidney disease (CKD), including CKD associated with high uric acid, AP0L1 mutations, complement-mediated kidney diseases such as C3 glomerulopathy, IgA nephropathy, atypical haemolytic uremic syndrome and membranous nephropathy, idiopathic nephrotic syndrome, oxalate nephropathy and diabetic nephropathy;

[0358] (vii) ocular diseases including those of the ocular epithelium, age-related macular degeneration (AMD), corneal infection, uveitis and dry eye;

[0359] (viii) hyperactive inflammation with underlying genetic mutations, including auto- inflammatory diseases such as cryopyrin-associated periodic syndrome (CAPS): Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS) and neonatal-onset multisystem inflammatory disease (NOMID); familial Mediterranean fever (FMF), TNF receptor associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MVK), hyperimmunoglobulinemia D and periodic fever syndrome (HIDS), deficiency of interleukin 1 receptor antagonist (DIRA), VEXAS syndrome, Majeed syndrome, pyoderma gangrenosum, acne, hi dradenitis suppurativa, haploinsufficency of A20, paediatric granulomatous arthritis (PGA), PLCG2-associated antibody deficiency and immune dysregulation (PLAID), sideroblastic anaemia with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD), Sweet’s syndrome, chronic non -bacterial osteomyelitis (CNO), chronic recurrent multifocal osteomyelitis (CRMO) and synovitis, pustulosis, hyperostosis, osteitis syndrome (SAPHO) and any disease where an individual has been determined to carry a germline or somatic non-silent mutation in NLRP3 or NEK7

[0360] (ix) respiratory diseases including chronic obstructive pulmonary disorder (COPD), acute respiratory distress syndrome (ARDS), steroid-resistant asthma, asbestosis, silicosis, sarcoidosis, cystic fibrosis and interstitial lung disease (ILD), including, but not limited to idiopathic pulmonary fibrosis (IPF), fibrotic hypersensitivity pneumonitis, rheumatoid arthritis-associated ILD, autoimmune myositis-associated ILD, systemic sclerosis-associated ILD, idiopathic interstitial pneumonia and progressive fibrosing ILD; (x) cancers including lung cancer and lung cancer metastasis, pancreatic cancers, gastric cancers, myelodysplastic syndrome, leukaemia and melanoma; polymyositis; graft-versus-host disease and transplant rejection;

[0361] (xi) inflammatory reactions in the skin including contact hypersensitivity and sunburn, psoriasis, hidradenitis suppurativa (HS) and other cyst-causing skin diseases, dermatomyositis, pemphigus, pyoderma gangrenosum;

[0362] (xii) diseases of the hematopoietic system including anaemia of inflammation (anaemia of chronic disease), paroxysmal nocturnal haemoglobinuria (PNH), sickle cell disease;

[0363] (xiii) liver diseases including non-alcoholic steatohepatitis, alcoholic liver disease and drug-induced liver injury;

[0364] (xiv) viral infections and subsequent immune hyperactivation including alpha virus including Chikungunya and Ross River virus, and flavivirus including Dengue and Zika viruses, COVID-19 / SARS-CoV-2, influenza, HIV;

[0365] (xv) allergic diseases and Type 2 inflammation-associated diseases including asthma, atopic dermatitis, eosinophilic esophagitis, chronic obstructive pulmonary disease, chronic sinusitis, nasal polyps; and

[0366] (xvi) infectious diseases including bacterial infections, including Clostridium species, viral infections, helminth infections; wound healing; sepsis; gangrene.

[0367] In some embodiments, the disorder is selected from the group consisting of pericarditis, gout, atherosclerosis, obesity, MASH, Alzheimer’s disease, Parkinson’s disease, and Wilson’s disease.

[0368] In some embodiments, the metabolic disorder is a lysosomal storage disease, which includes sphingolipidoses, oligosaccharidoses, mucopolysaccharidoses (MPS), neuronal ceroid lipofuscinoses (NCL) (Batten disease), sialic acid disorders, mucolipidoses, and glycogenoses.

[0369] The sphingolipidosis may be GM2 gangliosidosis (such as Type A - Tay Sachs disease; Type O - Sandhoff disease; or Type AB - GM2 activator deficiency); Niemann-Pick disease (such as Type A, B, or C); Gaucher disease (such as Type 1, 2, or 3); Fabry disease (such as classic, or late-onset); metachromatic leukodystrophy; globoid leukodystrophy (Krabbe disease); GM1 gangliosidosis (such as Type 1, 2, or 3); or multiple sulfatase deficiency. The oligosaccharidosis may be alfa mannosidosis; Schindler disease; asphartylglucosaminuria; or fucosidosis.

[0370] The mucopolysaccharidosis may be Hurler syndrome (Type I); Scheie syndrome (Type I); Hunter syndrome (Type II); Sanfilippo syndrome (Type III) Morquio syndrome (Type IV); Maroteaux-Lamy syndrome (Type VI); Sly syndrome (Type VII); or Natowicz syndrome (Type IX).

[0371] Batten disease may be of the CLN1, CLN2, CLN3, CLN4, CLN5, CLN6, CLN7, CLN8, CLN9, CLN10, CLN11, CLN12, CLN13 or CLN14 designation.

[0372] The sialic acid disorder may be galactosialidosis; free sialic acid storage disorder (FSASD); Salla disease; or sialuria.

[0373] The mucolipidosis may be Type I, II, III or IV.

[0374] The glycogenosis may be Pompe disease; or Danon disease.

[0375] The lysosomal storage disease may be lysosomal acid lipase deficiency (such as infantile and childhood / adult types); or cystinosis.

[0376] NLRP3, Caspase-1 and / or IL-ip are implicated in lysosomal storage disease, as demonstrated in:

[0377] (1) Platt N, Shepherd D, Smith DA, Smith C, Wallom K-L, Luqmani R, Churchill GC, Galione A, Platt FM, Dysregulation of the NLRP3 inflammasome and promotion of disease by IL-ip in a murine model of Sandhoff disease. Cells, 2025 Jan 1; 14(1):35 ;

[0378] (2) Aflaki E, Moaven N, Borger DK, Lopez G, Westbroek W, Chae JJ et al., Lysosomal storage and impaired autophagy lead to inflammasome activation in Gaucher macrophages. Aging Cell, 2015 Oct 21; 15(l):77-88. doi: 10.1111 / acel.12409

[0379] (3) Panicker LM, Miller D, Awad O, Bose V, Lun Y, Park TS, Zambidis ET, Sgambato JA, Feldman RA, Gaucher iPSC-derived macrophages produce elevated levels of inflammatory mediators and serve as a new platform for therapeutic development. Stem Cells, 2014 Sep; 32(9):2338-2349.

[0380] (4) Ormazabal ME, Pavan E, Vaena E, Ferino D, Biasizzo J, Mucci JM, Serra F, Cifu A, Scarpa M, Rozenfeld PA, Dardis AE, Exploring the pathophysiologic cascade leading to osteoclastogenic activation in Gaucher disease monocytes generated via CRISPR / Cas9 technology. Int J Mol Sci, 2023 Jul 7; 24(13): 11204. (5) Polgreen LE, Chen AH, Pak Y, Luzzi A, Morales Garval A, Acevedo J, Bitan G, lacovino M, O’Neill C, Eisengart JB, et al., Anakinra in Sanfilippo syndrome: a phase 1 / 2 trial. Nature Medicine, 2024; 30:2473-2479.

[0381] (6) Parker H, Ellison SM, Holley RJ, O’Leary C, Liao A, Asadi J, Glover E, Ghosh A, Jones S, Wilkinson FL, Brough D, Pinteaux E, Boutin H, Bigger BW, Haematopoietic stem cell gene therapy with IL-IRa rescues cognitive loss in mucopolysaccharidosis IIIA. EMBO Mol Med, 2020 Mar 6; 12(3):el 1185.

[0382] (7) Burkovetskaya M, Bosch ME, Karpuk N, Fallet R, Kielian T, Caspase 1 activity influences juvenile Batten disease (CLN3) pathogenesis. J Neurochem, 2019 Mar; 148(5):652— 668.

[0383] (8) Prencipe G, Caiello I, Cherqui S, Whisenant T, Petrini S, Emma F, De Benedetti F, Inflammasome activation by cystine crystals: implications for the pathogenesis of cystinosis. J Am Soc Nephrol, 2014 Jun; 25(6): 1163-1169.

[0384] In another embodiment, described herein is a method of degrading NIMA Related Kinase 7 (NEK7) in a subject suffering from an autoinflammatory disorder, a neurodegenerative disease, diabetes, or a liver disease, comprising administering to the subject an effective amount of a compound of described herein or a pharmaceutically acceptable salt thereof.

[0385] NEK7 Degradation

[0386] The compounds described herein can act as degraders of NIMA-Related Kinase 7 (NEK7). NEK7 is an activator of the NLRP3 inflammasome, a central regulator of cellular inflammatory responses to pathogens, damage and stress. The NLRP3 inflammasome is a multiprotein complex that serves as a central node to integrate cellular signals generated by pathogens, damage and stress, and triggers the generation of pro-inflammatory cytokines. The assembly of NLRP3 / NEK7 with ASC and pro-caspase 1 in a multi -protein complex induces cleavage of pro-caspase 1, which then activates multiple inflammatory responses including release of the cytokines interleukin- ip and interleukin- 18 and induction of pyroptosis. Additionally, multiple activating NLRP3 mutations have been shown to be associated with Cryopyrin-associated periodic syndromes.

[0387] NEK7, a serine / threonine-protein kinase, activates the NLRP3 inflammasome in a kinase independent manner. Increased (e.g., excessive) NLRP3 inflammasome activation has been implicated in the pathogenesis of several of the disorders described herein (e.g., disorders of the immune system, hematopoietic system, joints, renal system, gastro-intestinal tract, skin, eye, respiratory system, central nervous system, cardiovascular system, hepatic system, and / or endocrine system). In certain embodiments, the increased (e.g., excessive) NLRP3 inflammasome activation is chronically increased (e.g., excessive) NLRP3 inflammasome activation. In certain embodiments, the NLRP3 / NEK7 inflammasome activation occurs in the brain or central nervous system (CNS). NEK7 binding to NLRP3 has been shown to be involved in promoting the assembly of the NLRP3 inflammasome. While not wishing to be bound by theory, by being able to degrade NEK7, the compounds described herein may be used to treat disorders caused by or associated with increased (e.g., excessive) NLRP3 inflammasome activation.

[0388] In an embodiment, described herein is a method of degrading NIMA Related Kinase 7 (NEK7) in a subject, comprising administering to the subject an effective amount of a compound described herein (e.g., Compound 1), or pharmaceutically acceptable salt thereof. In some embodiments, the compound mediates the interaction of a NEK7 protein with an E3 ligase, thereby increasing degradation of the NEK7 protein. In some embodiments, NEK7 is an activator of an NLRP3 inflammasome. In an embodiment, the compound interacts with the E3 ligase prior to the interaction of NEK7 with the E3 ligase. In some embodiments, the E3 ligase comprises cereblon.

[0389] In another embodiment, described herein is a method of degrading NIMA Related Kinase 7 (NEK7), comprising: (i) contacting a compound described herein (e.g., Compound 1) or a pharmaceutically acceptable salt thereof with an E3 ligase; and (ii) interacting the contacted E3 ligase with NEK7, thereby degrading NEK7.

[0390] In other embodiments, the compounds described herein (e.g., Compound 1) are capable of selectively binding to a specific amino acid sequence of NEK7, thereby causing degradation of NEK7. In other embodiments, such degradation of NEK7 is mediated by the compound interacting with both the specific amino acid sequence of NEK7 and an E3 ligase. In other embodiments, the E3 ligase comprises cereblon.

[0391] Degrader Conjugates

[0392] In an aspect is a conjugate comprising a compound of Formula (I) as defined anywhere herein. For instance, in an aspect is an antibody-degrader conjugate or pharmaceutically acceptable salt thereof comprising a compound of Formula (I). The conjugate includes a compound of Formula (I) or pharmaceutically acceptable salt thereof which is conjugated to an antibody via a linker structure moiety.

[0393] In some embodiments, the conjugate has a structure according to Formula (A) below:

[0394] Bm - (- M- I)a

[0395] Formula (A) in which I is a compound of Formula (I) or any subformula defined herein, or a pharmaceutically acceptable salt thereof, M is a linker moiety, Bm is a binding moiety that is capable of specifically binding to an antigen, and a is from 1 to 10. The binding moiety may be an antibody, antibody fragment or an antibody-binding fragment.

[0396] In some embodiments, I is one of Compounds 1-336.

[0397] Thus, in some embodiments of Formula (A), the disclosure provides an antibody -drug conjugate or pharmaceutically acceptable salt thereof according to formula (Al): in which X, Ri, R2, R3a, R3b, and R4can be as defined anywhere herein, M is a linker moiety, Bm is a binding moiety that is capable of specifically binding to a protein, as defined above, and a is from 1 to 10. In some embodiments, X, Ri, R2, R3a, R3b, and R4are defined to provide a compound selected from any one of Compounds 1-336. In some embodiments, the disclosure provides an antibody -drug conjugate or pharmaceutically acceptable salt thereof according to Formula (A4): in which X, Ri, R2, R3a, R3b, and R4can be as defined anywhere here, M is a linker moiety, Bm is a binding moiety that is capable of specifically binding to a protein, as defined above and a is from 1 to 10. In some embodiments, X, Ri, R2, R3a, R3b, and R4are defined to provide a compound selected from any one of Compounds 1-336.

[0398] In some embodiments, M is a linker as defined in WO 2021 / 198966, which is incorporated by reference in its entirety. The linker may be a cleavable linker or non-cleavable linker. In certain aspects, the linker can contain a heterobifunctional group. In the present disclosure, the term "heterobifunctional group" refers to a chemical moiety that connects the linker of which it is a part to the binding moiety. Heterobifunctional groups are characterized as having different reactive groups at either end of the chemical moiety. Attachment to Bm can be accomplished through chemical or enzymatic conjugation, or a combination of both. Chemical conjugation involves the controlled reaction of accessible amino acid residues on the surface of the binding moiety with a reaction handle on the heterobifunctional group. Examples of chemical conjugation include, but are not limited to, lysine amide coupling, cysteine mediated coupling, and coupling via a nonnatural amino acid incorporated by genetic engineering, wherein non-natural amino acid residues with a desired reaction handle are installed onto Bm. In enzymatic conjugation, an enzyme mediates the coupling of the linker with an accessible amino residue on the binding moiety. Examples of enzymatic conjugation include, but are not limited to, transpeptidation using sortase, transpeptidation using microbial transglutaminase, and N-glycan engineering. Chemical conjugation and enzymatic conjugation may also be used sequentially. For example, enzymatic conjugation can also be used for installing unique reaction handles on Bm to be utilized in subsequent chemical conjugation.

[0399] In some embodiments, M is a linker as defined in WO 2023 / 037268, which is incorporated by reference in its entirety. M may have the structure: indicates the point of attachment of M to I (preferably attached as shown in formula (A4) above);

[0400] R5is selected from the group consisting of hydrogen, -(CH2CH2O)V-CH3, C2-Cealkenyl, Ci- Cealkyl; C2-Cealkynyl, benzyl, Cs-Cecycloalkyl, and C3-C6cycloalkyl(Ci-C3alkyl), wherein v is from 1 to 24; and L is selected from the group consisting of wherein: q is from 2 to 10; Z1, Z2, Z3, Z4, and Z5are each independently absent or a naturally occurring amino acid residue in the L- or D-configuration, provided that at least two of Z1, Z2, Z3, Z4, and Z5are amino acid residues; the point of attachment of L to NR5-CH2-I; and ★ is the point of attachment to the binding moiety Bm.

[0401] In some embodiments, Z1, Z2, Z3, Z4, and Z5are independently absent or selected from the group consisting of L-valine, D-valine, L-citrulline, D-citrulline, L-alanine, D-alanine, L- glutamine, D- glutamine, L-glutamic acid, D-glutamic acid, L-aspartic acid, D-aspartic acid, L- asparagine, D- asparagine, L-phenylalanine, D-phenylalanine, L-lysine, D-lysine, and glycine; provided that at least two of Z1, Z2, Z3, Z4, and Z5are amino acid residues.

[0402] The term “binding moiety” as used herein refers to any molecule that recognizes and binds to a cell surface marker or receptor. The binding moiety may be an antibody, antibody fragment, or an antigen-binding fragment. An antibody is a protein generated by the immune system that is capable of recognizing and binding to a specific antigen. A target antigen generally has numerous binding sites, also called epitopes, recognized by CDRs on multiple antibodies. Each antibody that specifically binds to a different epitope has a different structure. Thus, one antigen may have more than one corresponding antibody. The term "antibody" herein is used in the broadest sense and specifically covers monoclonal antibodies, single domain antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, so long as they exhibit the desired biological activity. Antibodies may be murine, human, humanized, chimeric, or derived from other species. A monoclonal antibody (mAb) to an antigen-of-interest can be prepared by using any technique known in the art which provides for the production of antibody molecules by continuous cell lines in culture. These include, but are not limited to, the hybridoma technique, the human B cell hybridoma technique, and the EBV-hybridoma technique. Such antibodies may be of any immunoglobulin class including IgG, IgM, IgE, IgA, and IgD and any subclass thereof. The hybridoma producing the mAbs of use in this disclosure may be cultivated in vitro or in vivo. The skilled person would understand how to provide an appropriate binding moiety for use in a conjugate depending on the intended therapeutic use. This is described, for example, in Nature Reviews Drug Discovery volume 22, pages 641-661 (2023), which is incorporated by reference in its entirety. In particular, an antibody, antibody fragment or an antibody -binding fragment used as a binding moiety must be capable of targeting a particular cell surface marker or receptor associated with the disorder to be treated. For example, the antibody trastuzumab can be employed if the desired target is HER2.

[0403] In some embodiments, the binding moiety is capable of binding to an antigen selected from CDl lb, CD68, CD14, CDla, CD141, CDlc, CD15, CD66b, CD49d, CSF1R, CD64, CX3CR1, CD206, CD33, CD20, CD 19, BAFFR , CD38, a4p7 integrin, IL6R, TSLPR, CD40, IFNAR1, or combinations thereof. In preferred embodiments, the binding moiety is capable of binding to an antigen selected from CDl lb, CD68, CD14 and CD15.

[0404] In some embodiments, the binding moiety comprises an antibody selected from Vedolizumab, Etrolizumab, Gemtuzumab, Rituximab, Ublituximab, Ofatumumab, Ocrelizumab, Inebilizumab, Tafasitamab, Loncastuximab, Isatuximab, Daratumumab, Tocilizumab, Iscalimab, Bleselumab, Anifrolumab.

[0405] In some embodiments, the binding moiety is capable of binding to CD 19 and is preferably Tafasitamab, Loncastuximab or Inebilizumab. In some embodiments, the binding moiety is capable of binding to CD20 and is preferably Rituximab, Ublituximab, Ofatumumab, Ocrelizumab or Inebilizumab. In some embodiments, the binding moiety is capable of binding to CD33 and is preferably Gemtuzumab. In some embodiments, the binding moiety is capable of binding to CD38 and is preferably Isatuximab or Daratumumab.

[0406] Exemplary combinations of antibodies, target antigens, and associated therapeutic indications are listed in the table below. In some embodiments, the binding moiety of the antibody-drug conjugate comprises an antibody listed in the table below and targets an antigen listed in the table below. In some aspects, the disclosure provides a method of treating a disorder listed in the table below comprising administering to a subject in need thereof an antibody -drug conjugate comprising an antibody listed in the table below.

[0407] Definitions

[0408] The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1-19. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(Ci-4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0409] A “subject” to which administration is contemplated includes, but is not limited to, humans (z.e., a male or female of any age group, e.g., a paediatric subject (e.g, infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and / or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms “human,” “patient,” and “subject” are used interchangeably herein.

[0410] Disease, disorder, and condition are used interchangeably herein.

[0411] As used herein, and unless otherwise specified, the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition (“therapeutic treatment”), and also contemplates an action that occurs before a subject begins to suffer from the specified disease, disorder or condition (“prophylactic treatment”).

[0412] The terms “NASH”, “MASH”, “non-alcoholic steatohepatitis” and “metabolic dysfunction-associated steatohepatitis” are interchangeable.

[0413] In general, the “effective amount” of a compound refers to an amount sufficient to elicit the desired biological response. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of the present disclosure may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and condition of the subject. As used herein, and unless otherwise specified, a “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0414] The present disclosure, in an alternative embodiment, also embraces isotopically labelled compounds which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as2H,3H,13C,14C,15N,18O,17O,31P,32P,35S,18F, and36C1, respectively. For example, a compound of the disclosure may have one or more H atom replaced with deuterium.

[0415] The term "halo" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

[0416] The term "alkyl" refers to a saturated acyclic hydrocarbon radical that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, Ci-io indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it. Alkyl groups can either be unsubstituted or substituted with one or more substituents. Non-limiting examples include methyl, ethyl, / .w-propyl, tert-butyl, / / -hexyl. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms and other available valences occupied by hydrogen and / or other substituents as defined herein.

[0417] The term "haloalkyl" refers to an alkyl, in which one or more hydrogen atoms is / are replaced with an independently selected halo.

[0418] The term "alkoxy" refers to an -O-alkyl radical (e.g., -OCH3).

[0419] The term "alkylene" refers to a divalent alkyl (e.g., -CH2-).

[0420] The term "alkenyl" refers to an acyclic hydrocarbon chain that may be a straight chain or branched chain having one or more carbon-carbon double bonds. The alkenyl moiety contains the indicated number of carbon atoms. For example, C2-6 indicates that the group may have from 2 to 6 (inclusive) carbon atoms in it. Alkenyl groups can either be unsubstituted or substituted with one or more substituents.

[0421] The term "alkynyl" refers to an acyclic hydrocarbon chain that may be a straight chain or branched chain having one or more carbon-carbon triple bonds. The alkynyl moiety contains the indicated number of carbon atoms. For example, C2-6 indicates that the group may have from 2 to 6 (inclusive) carbon atoms in it. Alkynyl groups can either be unsubstituted or substituted with one or more substituents.

[0422] The term "aryl" refers to a 6-20 carbon mono-, bi-, tri- or polycyclic group wherein at least one ring in the system is aromatic (e.g., 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system); and wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, dihydro- IH-indenyl and the like.

[0423] The term "cycloalkyl" as used herein refers to cyclic saturated hydrocarbon groups having, e.g., 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons, wherein the cycloalkyl group may be optionally substituted. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl may include multiple fused and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyl includes: bicyclofl.1.0]butanyl, bicyclo[2.1.0]pentanyl, bicyclofl.1.1 ]pentanyl, bicyclo[3.1.0]hexanyl, bicyclo[2.1.1]hexanyl, bicyclo[3.2.0]heptanyl, bicyclo[4.1.0]heptanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[4.2.0]octanyl, bicyclo[3.2.1]octanyl, bicyclo[2.2.2]octanyl, and the like. Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentanyl, spiro[2.5]octanyl, spiro[3.5]nonanyl, spiro[3.5]nonanyl, spiro[3.5]nonanyl, spiro[4.4]nonanyl, spiro[2.6]nonanyl, spiro[4.5]decanyl, spiro[3.6]decanyl, spiro[5.5]undecanyl, and the like. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms.

[0424] The term "cycloalkenyl" as used herein means partially unsaturated cyclic hydrocarbon groups having 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons, wherein the cycloalkenyl group may be optionally substituted. Examples of cycloalkenyl groups include, without limitation, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. As partially unsaturated cyclic hydrocarbon groups, cycloalkenyl groups may have any degree of unsaturation provided that one or more double bonds is present in the ring, none of the rings in the ring system are aromatic, and the cycloalkenyl group is not fully saturated overall. Cycloalkenyl may include multiple fused and / or bridged and / or spirocyclic rings.

[0425] The term “heteroaryl”, as used herein, means a mono-, bi-, tri- or polycyclic group having 5 to 20 ring atoms, alternatively 5, 6, 9, 10, or 14 ring atoms; and having 6, 10, or 14 pi electrons shared in a cyclic array; wherein at least one ring in the system is aromatic, and at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, and S (but does not have to be a ring which contains a heteroatom, e.g. tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl). Heteroaryl groups can either be unsubstituted or substituted with one or more substituents. Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-t ]pyrimidinyl, pyrrolo[2,3-Z>]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4- Z>]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[4,3-Z>]pyridinyl, tetrazolyl, chromanyl, 2,3-dihydrobenzo[Z>][l,4]dioxinyl, benzo[ ][l,3]dioxolyl, 2,3- dihydrobenzofuranyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[Z>][l,4]oxathiinyl, isoindolinyl, and others. In some embodiments, the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl.

[0426] The term "heterocyclyl" refers to a mono-, bi-, tri-, or polycyclic saturated ring system with 3-16 ring atoms (e.g., 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system) having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like. Heterocyclyl may include multiple fused and bridged rings. Non-limiting examples of fused / bridged heteorocyclyl includes: 2-azabicyclo[1.1.0]butanyl, 2-azabicyclo[2.1.0]pentanyl, 2-azabicyclo[l. l. l]pentanyl, 3-azabicyclo[3.1.0]hexanyl, 5-azabicyclo[2.1.1]hexanyl, 3- azabicyclo[3.2.0]heptanyl, octahydrocyclopenta[c]pyrrolyl, 3-azabicyclo[4.1.0]heptanyl, 7- azabicyclo[2.2.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 7-azabicyclo[4.2.0]octanyl, 2- azabicyclo[2.2.2]octanyl, 3-azabicyclo[3.2.1]octanyl, 2-oxabicyclo[1.1.0]butanyl, 2- oxabicyclo[2.1.0]pentanyl, 2-oxabicyclo[l. l. l]pentanyl, 3-oxabicyclo[3.1.0]hexanyl, 5- oxabicyclo[2.1.1]hexanyl, 3-oxabicyclo[3.2.0]heptanyl, 3-oxabicyclo[4.1.0]heptanyl, 7- oxabicyclo[2.2.1]heptanyl, 6-oxabicyclo[3.1.1]heptanyl, 7-oxabicyclo[4.2.0]octanyl, 2- oxabicyclo[2.2.2]octanyl, 3-oxabicyclo[3.2.1]octanyl, and the like. Heterocyclyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic heterocyclyls include 2-azaspiro[2.2]pentanyl, 4- azaspiro[2.5]octanyl, l-azaspiro[3.5]nonanyl, 2-azaspiro[3.5]nonanyl, 7-azaspiro[3.5]nonanyl, 2- azaspiro[4.4]nonanyl, 6-azaspiro[2.6]nonanyl, l,7-diazaspiro[4.5]decanyl, 7-azaspiro[4.5]decanyl 2,5-diazaspiro[3.6]decanyl, 3-azaspiro[5.5]undecanyl, 2-oxaspiro[2.2]pentanyl, 4- oxaspiro[2.5]octanyl, l-oxaspiro[3.5]nonanyl, 2-oxaspiro[3.5]nonanyl, 7-oxaspiro[3.5]nonanyl, 2-oxaspiro[4.4]nonanyl, 6-oxaspiro[2.6]nonane, l,7-dioxaspiro[4.5]decanyl, 2,5- dioxaspiro[3.6]decanyl, l-oxaspiro[5.5]undecanyl, 3-oxaspiro[5.5]undecanyl, 3-oxa-9- azaspiro[5.5]undecanyl and the like. The term “saturated” as used in this context means only single bonds present between constituent ring atoms and other available valences occupied by hydrogen and / or other substituents as defined herein.

[0427] The term "heterocycloalkenyl" as used herein means partially unsaturated cyclic ring system with 3-16 ring atoms (e.g., 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system) having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent. Examples of heterocycloalkenyl groups include, without limitation, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl. As partially unsaturated cyclic groups, heterocycloalkenyl groups may have any degree of unsaturation provided that one or more double bonds is present in the ring, none of the rings in the ring system are aromatic, and the heterocycloalkenyl group is not fully saturated overall. Heterocycloalkenyl may include multiple fused and / or bridged and / or spirocyclic rings. As used herein, when a ring is described as being “aromatic”, it means said ring has a continuous, delocalized 7t-electron system. Typically, the number of out of plane 7t-electrons corresponds to the Hiickel rule (4n+2). Examples of such rings include: benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thiazole, isoxazole, isothiazole, and the like.

[0428] As used herein, when a ring is described as being “partially unsaturated”, it means said ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation attributed to the ring itself; e.g., one or more double or triple bonds between constituent ring atoms), provided that the ring is not aromatic. Examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like.

[0429] For the avoidance of doubt, and unless otherwise specified, for rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, cycloalkyl, and the like described herein) containing a sufficient number of ring atoms to form bicyclic or higher order ring systems (e.g., tricyclic, polycyclic ring systems), it is understood that such rings and cyclic groups encompass those having fused rings, including those in which the points of fusion are located (i) on adjacent ring atoms (e.g., [x.x.O] ring systems, in which 0 represents a zero atom stems having

[0430] In addition, atoms making up the compounds of the present embodiments are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include13C In addition, the compounds generically or specifically disclosed herein are intended to include all tautomeric forms. Thus, by way of example, a compound containing the moiety:

[0431] 0 N encompasses the tautomeric form containing the moiety:Hb Similarly, a pyridinyl or pyrimidinyl moiety that is described to be optionally substituted with hydroxyl encompasses pyridone or pyrimidone tautomeric forms.

[0432] As used herein, the phrase “optionally substituted” when used in conjunction with a structural moiety (e.g., alkyl) is intended to encompass both the unsubstituted structural moiety (i.e., none of the substitutable hydrogen atoms are replaced with one or more non-hydrogen substituents) and substituted structural moieties substituted with the indicated range of nonhydrogen substituents. For example, “C1-C4 alkyl optionally substituted with 1-4 Ra” is intended to encompass both unsubstituted C1-C4 alkyl and C1-C4 alkyl substituted with 1-4 Ra.

[0433] 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.

[0434] Non-Limiting Exemplary Compounds

[0435] In some embodiments, the compound is selected from the group consisting of the compounds delineated in Table Cl or a pharmaceutically acceptable salt thereof.

[0436] Table Cl

[0437]

[0438]

[0439]

[0440]

[0441]

[0442]

[0443]

[0444]

[0445]

[0446] * Compounds 145, 146 and 147 are included as reference compounds falling outside the scope of Formula (I).

[0447] In some embodiments, the compound is selected from Table C2, or a pharmaceutically acceptable salt thereof. Table C2

[0448] In some embodiments, the compound is selected from Table Cl, or a pharmaceutically acceptable salt thereof, but is not a compound from Table C2, or a pharmaceutically acceptable salt thereof.

[0449] In some embodiments, the compound is selected from Table C3, or a pharmaceutically acceptable salt thereof.

[0450] In some embodiments, the compound is selected from Table C4, or a pharmaceutically acceptable salt thereof. Table C4

[0451]

[0452] Table C5

[0453]

[0454] Formula (I).

[0455] Compounds of Table C5 did not provide a readout when tested according to the HTRF assay described in Example 2, or the NanoBiT assay described in Example 3.

[0456] In the invention, the compound or pharmaceutically acceptable salt thereof is not a compound of Table C5, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is selected from Table Cl, or a pharmaceutically acceptable salt thereof, but is not a compound from Table C4 or C5, or a pharmaceutically acceptable salt thereof.

[0457] In some embodiments, the compound is selected from Table Cl, or a pharmaceutically acceptable salt thereof, but is not a compound from Table C2, C4, or C5, or a pharmaceutically acceptable salt thereof.

[0458] Preferably, the compound or pharmaceutically acceptable salt thereof such pharmaceutically acceptable salt thereof, or a mixture, preferably a racemic mixture, of pharmaceutically acceptable salt thereof. Preferably, the compound or pharmaceutically acceptable salt thereof such or a pharmaceutically acceptable salt thereof, pharmaceutically acceptable salt thereof, or a mixture, preferably a racemic mixture of pharmaceutically acceptable salt thereof a pharmaceutically acceptable salt thereof.

[0459] EXAMPLES

[0460] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (ie., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization.

[0461] Abbreviations: DCM: dichloromethane; DIEA: N,N-diisopropylethylamine; DMF: dimethylformamide; DMSO: dimethyl sulfoxide; EtOH: ethanol; ESI: electrospray ionization; h: hours; HATU: l-[bis(dimethylamino)methylene]-lH-l,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; TEA: tri ethylamine; and THF : tetrahydrofuran. General synthetic schemes:

[0462] General Scheme 1 ula I

[0463] A general synthetic strategy that may be used to prepare compounds of formula I is depicted in scheme 1. The desired compounds can be prepared using an amide coupling reaction starting from

[0464] AA-X with reagents such as: Mukaiyama’s reagent, HATU, EDCI / HOBt, T3P, or T4P in the presence of a base such as DIEA, in a solvent such as DMF. Alternatively, POCI3 in pyridine may be used. The coupling reaction can also be carried out with AB-X in the presence of DIEA, in a solvent such as DCM. AB-X can be obtained from AA-X via chlorination with typical chlorinating reagents (for example, oxalyl chloride and catalytic DMF).

[0465] Alternatively, starting from compound AC-X (where W1is OH or Cl), the amide coupling can be performed as described above to afford AD-X, followed by removal of PG1to afford compounds of formula I. PG1is a protecting group which can be removed by sequential treatment with an acid

[0466] (such as TFA) then a base (such as NH3), for example, SEM.

[0467] The specific groups are selected on the basis of the desired groups in the compound of formula I.

[0468] General Scheme 2

[0469] AE-X An alternative synthetic strategy for preparing compounds of formula AD-X, which may be used for the synthesis of compounds of formula I (Scheme 1), is depicted in scheme 2. An amide of formula AE-X, where W2is OH or a suitable halogen (for example Br), can be reacted with phenol AF-X using reagents suitable for a nucleophilic substitution reaction (for example, a base such as K2CO3) or reagents suitable for a Mitsunobu reaction (for example, PPI13 and DEAD). General Scheme 3 ormu a

[0470] A general synthetic strategy that may be used to prepare compounds of formula II is depicted in scheme 3. A carboxylic acid AA-X may be coupled with a hydrazine using any suitable coupling conditions, such as Mukaiyama’ s reagent / DIEA or EDCI / HOBt, in a solvent such as DMF at a temperature of 15-20 °C, to obtain intermediate AB. The specific groups are selected on the basis of the desired groups in Formula II. Compound AB may be converted into final compound of formula II upon treatment with:

[0471] • a dehydrating reagent such as Burgess reagent, in a solvent such as THF at elevated temperatures (for example, 100 °C);

[0472] • triflic anhydride with a base such as pyridine, in a solvent such as DCM at a temperature of 10-15 °C;

[0473] Trimethoxymethane with strong acid such as MeSChOH, in a solvent such as THF at elevated temperatures (for example, 80 °C)

[0474] General Scheme 4 A general synthetic strategy that may be used to prepare compounds of formula III / IV is depicted in scheme 4. A carboxylic acid AA-X may be coupled with N-hydroxyacetimidamide using any suitable coupling reagents such as EDCI / HOBt, in a solvent such as DMF at elevated temperatures (for example 100 °C) to obtain compounds of formula III.

[0475] Alternatively, a carboxylic acid AA-X may be converted into the corresponding carboxamide AC using any suitable coupling conditions and ammonium chloride. Compound AD may be obtained by treating intermediate AC with DMA-DMF at elevated temperatures such as 100 °C. Treatment of intermediate AD with hydroxylamine hydrochloride in solvents such as dioxane / acetic acid at elevated temperatures (90 °C) yields desired compounds of formula IV.

[0476] General Scheme 5

[0477] A general synthetic strategy that may be used to prepare compounds of formula V is depicted in scheme 5.

[0478] A carboxylic acid AA-X may be coupled with an amine using any suitable coupling conditions, such as Mukaiyama’ s reagent / DIEA or EDCI / HOBt, in a solvent such as DMF at a temperature of 15-20 °C, to obtain intermediate AE. The specific groups are selected on the basis of the desired groups in Formula V.

[0479] Compound AE may be converted into final compound of formula V upon treatment with:

[0480] • Zinc triflate in solvent such as toluene at high temperature (for example 100 °C);

[0481] • Treatment with acid such as HC1 in THF and subsequent treatment with a dehydrating reagent such as Burgess reagent, in a solvent such as THF at elevated temperatures (for example, 70 °C). General scheme 6

[0482] AG Formula VI

[0483] A general synthetic strategy that may be used to prepare compounds of formula VI is depicted in scheme 6. A carboxylic acid AA-X may be converted into the corresponding carboxamide AC using any suitable coupling conditions and ammonium chloride. Upon treatment with a dehydrating agent such as Burgess reagent in DCM, compound AF may be obtained. Treatment of compound AF with hydroxylamine hydrochloride and a base such as TEA, in a solvent such as EtOH at elevated temperatures (for example 90 °C) yields compound AG. Desired compound of formula VI may be obtained by treating intermediate AG with trifluoroborane diethyl ether in a solvent such as trimethoxymethane and THF, at low temperatures such as 0 °C.

[0484] General scheme 7

[0485] General scheme 7 provides a synthetic strategy for preparing compounds of formula AN-X, which may be used as starting materials AA-X in General scheme 1. Compound AH-X may be prepared from AG-X via alkylation with PGJ-Hal, where Hal is any suitable halogen (i.e., Cl or Br). PG1is a protecting group which can be removed by sequential treatment with an acid then a base, for example, SEM. Aryl boronate AI-X may be prepared from AH-X using Bis(pinacolato)diboron and a catalyst such as Pd(dppf)C12. A weak base such as potassium acetate in a solvent such as dioxane may be used. The reaction may be performed at an elevated temperature, for example, 85 degrees Celsius. Boronate AI-X may be treated with an oxidizing agent to afford phenol AJ-X. A reagent such as H2O2 may be used, in a polar aprotic solvent such as THF. AJ-X may be alkylated with intermediates such as AK-X to afford esters of formula AL-X. Aik is an alkyl group, for example, methyl, ethyl or tert-butyl. W2is OH or a suitable halogen (for example Br). In cases where W2= Br, the transformation can be carried out using reagents suitable for a nucleophilic substitution reaction (for example, a base such as K2CO3). In cases where W2= OH, the transformation can be carried out using reagents suitable for a Mitsunobu reaction (for example, PPF13 and DEAD). PG1can be removed via sequential treatment with an acid (such as TFA) then a base (such as NH3) to afford compounds of formula AM-X Ester AM-X may be hydrolysed with a strong acid (for example, HC1 6M) to afford carboxylic acid AN-X. Characterization of key intermediates

[0486] Table C5

[0487] General synthetic procedure for preparation of selected intermediates from Table C4

[0488] Synthetic procedure for preparation of intermediate AA-2, (2S)-2-(3,5-dichloro-4-(2,6- dioxopiperidin-3-yl)phenoxy)propanoic acid

[0489] Step 1

[0490] To a solution of 5-bromo-l,3-dichloro-2 -methylbenzene (30.0 g, 125 mmol, 1.00 eq.) in carbon tetrachloride (200 mL) was added N-bromosuccinimide (23.4 g, 131 mmol, 1.05 eq.) followed by benzoic peroxyanhydride (1.51 g, 6.25 mmol, 0.05 eq.) in portions. The mixture was stirred at 80

[0491] °C for 3 h under nitrogen atmosphere (Two batches were performed in parallel). The reaction mixture was cooled to room temperature. It was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluting with petroleum ether) to give 5-bromo-2-(bromomethyl)-l,3-dichlorobenzene (86.7 g, 245 mmol, 98% yield) as a white solid.

[0492] Step 2

[0493] To a solution of 5-bromo-2-(bromomethyl)-l,3-dichlorobenzene (43.3 g, 136 mmol, 1.00 eq.) and trimethyl silyl cyanide (20.2 g, 204 mmol, 1.50 eq.) in acetonitrile (100 mL) was added a solution of tetrabutylammonium fluoride (1 M in tetrahydrofuran, 204 mL, 1.50 eq.) dropwise at 0 °C over 30 min. The mixture was stirred at 20 °C for 30 min (Two batches were performed in parallel).

[0494] I l l Then the mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluting with petroleum ether / ethyl acetate = 10 / 1) to give 2-(4-bromo-2,6- dichlorophenyl)acetonitrile (63.7 g, 216 mmol, 80% yield) as a white solid.

[0495] Step 3

[0496] To a solution of 2-(4-bromo-2,6-dichlorophenyl)acetonitrile (78.8 g, 297 mmol, 1.00 eq.) in tetrahydrofuran (400 mL) were added tert-butyl acrylate (38.1 g, 297 mmol, 1.00 eq.) and sodium methoxide (1.61 g, 29.7 mmol, 0.10 eq.) at 0 °C. Then the mixture was stirred at 20 °C for 1.5 h. The mixture was diluted with water (500 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with brine (150 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl 4-(4-bromo-2,6-dichlorophenyl)-4- cyanobutanoate (115.3 g, crude) as a yellow oil.

[0497] Step 4

[0498] To a solution of tert-butyl 4-(4-bromo-2,6-dichlorophenyl)-4-cyanobutanoate (115 g, 293 mmol, 1.00 eq.) in acetic acid (500 mL) was added sulfuric acid (109 mL). The reaction mixture was stirred at 90 °C for 2 h. The reaction mixture was cooled to room temperature and poured into ice water (500 mL). The resulting precipitate was filtered and washed with ethyl acetate (200 mL). The solid was dried under reduced pressure to give 3-(4-bromo-2,6-dichlorophenyl)piperidine-2,6- dione (88.0 g, 248 mmol, 85% yield) as a white solid.

[0499] Step 5

[0500] To a solution of 3-(4-bromo-2,6-dichlorophenyl)piperidine-2, 6-dione (44.0 g, 131 mmol, 1.00 eq.) and 3,4,5,7,8,9,10,10a-octahydropyrido[l,2-a][l,4]diazepine (39.8 g, 261 mmol, 2.00 eq.) in tetrahydrofuran (300 mL) was added (2-(chloromethoxy)ethyl)trimethylsilane (32.7 g, 196 mmol, 1.50 eq.) dropwise at 0 °C for 30 min. Then the mixture was stirred at 20 °C for 2 h (two batches were performed in parallel). The mixture was quenched with water (500 mL) and extracted with ethyl acetate (2 x 300 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, eluent of 0 ~ 12% ethyl acetate / petroleum ether gradient @ 100 mL / min) to give 3-(4-bromo-2,6- dichlorophenyl)-l-((2-(trimethylsilyl)ethoxy)methyl) piperidine-2, 6-dione (99.0 g, 191 mmol, 73% yield) as a colourless oil.

[0501] Step 6

[0502] To a solution of 3-(4-bromo-2,6-dichlorophenyl)-l-((2-(trimethylsilyl)ethoxy)methyl)piperidine- 2, 6-dione (99 g, 212 mmol, 1.00 eq.) in dioxane (500 mL) were added 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (64.6 g, 254 mmol, 1.20 eq.), potassium acetate (62.4 g, 636 mmol, 3.00 eq.). Then [1,1- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (7.75 g, 10.6 mmol, 0.05 eq.) was added to the mixture under nitrogen. The mixture was stirred at 110 °C for 12 h. After cooling to room temperature, the mixture was concentrated to remove dioxane. The residue was purified by flash silica gel chromatography (eluent of 0-16% ethyl acetate / petroleum ether) to give 3-(2,6-dichloro- 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-l-((2-(trimethylsilyl)ethoxy) methyl)piperidine-2, 6-dione (86.0 g, 150 mmol, 71% yield) as a yellow solid.

[0503] Step 7

[0504] To a solution of 3-(2,6-dichloro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-l-((2- (trimethyl silyl) ethoxy)methyl)piperidine-2, 6-dione (85.0 g, 165 mmol, 1.00 eq.) in tetrahydrofuran (400 mL) was added sodium hydroxide (1 M, 165 mL, 1.00 eq.) at 0 °C. Then hydrogen peroxide (28.56 g, 252 mmol, 24.2 mL, 30% purity, 1.52 eq.) was added slowly to the mixture at 0 °C over 30 min. The reaction mixture was stirred at 20 °C for 1 h. The mixture was diluted with water (500 mL) and extracted with ethyl acetate (3 x 250 mL). The combined organic layers were washed with saturated sodium thiosulfate (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography on silica gel (eluent of 0 - 20% ethyl acetate / petroleum ether) to give 3 -(2,6- dichloro-4-hydroxyphenyl)-l-((2-(trimethylsilyl) ethoxy)methyl)piperidine-2, 6-dione (44.4 g, 107 mmol, 65% yield) as a colourless oil.

[0505] Step 8

[0506] To a solution of 3-(2,6-dichloro-4-hydroxyphenyl)-l-((2-

[0507] (trimethylsilyl)ethoxy)methyl)piperidine-2, 6-dione (2.00 g, 4.95 mmol, 1.00 eq.) and methyl (R)- 2-hydroxypropanoate (960 pL, 10.1 mmol, 2.03 eq.) in tetrahydrofuran (20 mL) was added triphenylphosphane (2.00 g, 7.63 mmol, 1.54 eq.) followed by the solution of diethyl (E)-diazene- 1,2-dicarboxylate (1.40 mL, 7.70 mmol, 1.56 eq.) in tetrahydrofuran (2 mL) at 0 °C under nitrogen atmosphere. The mixture was stirred at 25 °C for 16 h under nitrogen (22 batches were performed in parallel). The mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 600 g SepaFlash®Silica Flash Column, eluent of 30-40% ethyl acetate / petroleum ether gradient @ 100 mL / min) twice to give methyl (2S)-2-(3,5- dichloro-4-(2,6-dioxo-l-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)phenoxy)propanoate (48.1 g, 91.8 mmol, 89% yield) as a colourless oil.

[0508] Step 9

[0509] A mixture of methyl (2S)-2-(3,5-dichloro-4-(2,6-dioxo-l-((2-

[0510] (trimethylsilyl)ethoxy)methyl)piperidin-3-yl)phenoxy)propanoate (42.0 g, 85.6 mmol, 1.00 eq.) in di chloromethane (420 mL) and trifluoroacetic acid (84 mL) was stirred at 15 °C for 1 h. The mixture was concentrated under reduced pressure. The residue was suspended in acetonitrile (400 mL) and ammonium hydroxide (20 mL) and stirred at 15 °C for 0.5 h. The mixture was adjusted to pH = 3 with formic acid, then acetonitrile was removed under reduced pressure. The remaining aqueous mixture was diluted with water (300 mL) and extracted with ethyl acetate (3 x 100 mL) followed by dichloromethane (2 x 60 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give methyl (2S)- 2-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)propanoate (30.7 g, 80.1 mmol, crude) as a white solid.

[0511] Step 10

[0512] A mixture of methyl (2S)-2-[3,5-dichloro-4-(2,6-dioxo-3-piperidyl)phenoxy]propanoate (26.0 g, 72.2 mmol, 1.00 eq.) in hydrochloric acid (200 mL), water (200 mL) and 1,4-dioxane (130 mL) was stirred at 60 °C for 12 h (note: the reaction was completed after 0.5 h on 5 g scale). The mixture was concentrated under reduced pressure at 45 °C to remove dioxane. The residue was diluted with acetonitrile (200 mL) and concentrated under reduced pressure at 45 °C to remove acetonitrile. The mixture was diluted with water (300 mL) and lyophilized to give (2S)-2-[3,5- dichloro-4-(2,6-dioxo-3-piperidyl)phenoxy]propanoic acid (23.3 g, 59.2 mmol, 82% yield) as a white solid. Synthetic procedure for preparation of intermediate AA-10 (compound 399), l-(3,5- dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclopropane-l-carboxylic acid Step 1

[0513] To a solution of methyl 1-hydroxycyclopropane-l -carboxylate (22.6 g, 194 mmol, 1.50 eq.) in tetrahydrofuran (200 mL) was added sodium hydride (7.77 g, 194 mmol, 60% purity, 1.50 eq.) in portions at 0 °C. The mixture was stirred at 0 °C for 0.5 h, then 2,6-dichloro-4-fluorobenzaldehyde (25.0 g, 130 mmol, 1.00 eq.) was added in portions at 0 °C. The mixture was stirred at 20 °C for 1 h. The reaction was quenched with saturated aqueous ammonium chloride (150 mL) at 0 °C and extracted with ethyl acetate (3 * 150 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO ®; 330 g Sepa Flash ® Silica Flash Column, eluent of 0-10% ethyl acetate / petroleum ether gradient @ 150 mL / min) to give methyl l-(3,5-dichloro-4-formylphenoxy)cyclopropane-l-carboxylate (32.0 g, 99.6 mmol, 77% yield) as a yellow solid. Step 2

[0514] To a solution of methyl l-(3,5-dichloro-4-formylphenoxy)cyclopropane-l-carboxylate (21.5 g, 74.4 mmol, 1.00 eq.) in tetrahydrofuran (210 mL) was added sodium borohydride (4.15 g, 110 mmol, 1.48 eq.) in portions at 0 °C under nitrogen atmosphere. The mixture was stirred at 0 °C under nitrogen atmosphere for 1 h. The reaction mixture was quenched with saturated ammonium chloride solution (200 mL) at 0 °C and diluted with ethyl acetate (200 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (2 x 200 mL). The combined organic layers were washed with brine (400 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO ®; 220 g Sepa Flash ® Silica Flash Column, Eluent of 0-20% Ethyl acetate / Petroleum ether gradient @ 150 mL / min) to give methyl l-(3,5-dichloro-4-

[0515] (hydroxymethyl)phenoxy)cyclopropane-l -carboxylate (19.5 g, 60.3 mmol, 81% yield) as a white solid.

[0516] Step 3

[0517] To a solution of methyl l-(3,5-dichloro-4-(hydroxymethyl)phenoxy)cyclopropane-l-carboxylate (19.0 g, 62.0 mmol, 1.00 eq.) in dichloromethane (200 mL) was added tribromophosphane (50.4 g, 186 mmol, 3.00 eq.) at 0 °C under nitrogen atmosphere. The mixture was stirred at 20 °C under nitrogen atmosphere for 16 h. The mixture was poured into water (200 mL) and adjusted to pH = 7 with saturated aqueous sodium bicarbonate, then it was extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by flash silica gel chromatography (ISCO ®; 220 g Sepa Flash ® Silica Flash Column, Eluent of 0-9% Ethyl acetate / Petroleum ether gradient @ 150 mL / min) to give methyl l-(4-(bromomethyl)-3,5-dichlorophenoxy)cyclo-propane-l-carboxylate (17.0 g, 45.6 mmol, 74% yield) as a white solid.

[0518] Step 4

[0519] To a solution of methyl l-(4-(bromomethyl)-3,5-dichlorophenoxy)cyclopropane-l-carboxylate (17.0 g, 45.6 mmol, 1.00 eq.) and trimethyl silyl cyanide (7.72 g, 77.8 mmol, 1.62 eq.) in acetonitrile (200 mL) was added tetrabutylammonium fluoride (1 M in tetrahydrofuran, 48.0 mL, 1.00 eq.) dropwise at 0 °C under nitrogen atmosphere. The mixture was stirred at 20 °C for 5 h. The mixture was poured into water (200 mL), and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 220 g Sepa Flash® Silica Flash Column, eluent of 0-20% ethyl acetate / petroleum ether gradient @ 150 mL / min) to give methyl l-(3,5-dichloro-4- (cyanomethyl)phenoxy)-cyclopropane-l -carboxylate (11.0 g, 34.8 mmol, 73 % yield) as a white solid.

[0520] Step 5

[0521] To a solution of methyl l-(3,5-dichloro-4-(cyanomethyl)phenoxy)cyclopropane-l-carboxylate (10.0 g, 33.3 mmol, 1.00 eq.) and methyl acrylate (57.5 mmol, 5.18 mL, 1.73 eq.) in tetrahydrofuran (100 mL) was added sodium methanolate (5.4 M in methanol, 1.23 mL, 0.2 eq.) at 0 °C under nitrogen atmosphere. The mixture was stirred at 20 °C under nitrogen atmosphere for 2 h. The mixture was poured into water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO ®; 120 g Sepa Flash ® Silica Flash Column, Eluent of 0-14% Ethyl acetate / Petroleum ether gradient @ 150 mL / min) to give methyl l-(3,5-dichloro-4-(l-cyano-4- methoxy-4-oxobutyl)phenoxy)cyclopropane-l -carboxylate (10.2 g, 23.8 mmol, 70 % yield) as a colourless oil.

[0522] Step 6

[0523] To a solution of methyl l-(3,5-dichloro-4-(l-cyano-4-methoxy-4- oxobutyl)phenoxy)cyclopropane-l -carboxylate (8.20 g, 21.2 mmol, 1.00 eq.) in acetic acid (140 mL) was added sulfuric acid (35.0 mL) dropwise at 20 °C. The mixture was stirred at 90 °C for 48 h. The mixture was cooled to 20 °C and poured into water (200 mL) at 0 °C. The resulting precipitate was filtered, washed with water (8 x 60 mL), and dried under reduced pressure. The crude product was triturated with ethyl acetate / N,N-dimethylformamide (5 / 1, 50 mL) at 20 °C for 3 h twice. The mixture was filtered, and the solid was dried under reduced pressure to give 1 -(3,5- dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclopropane-l-carboxylic acid (6.60 g, 16.9 mmol, 78% yield) as a white solid. Example 1. Synthesis of final compounds

[0524] Synthesis of 2-(3-chloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-N-methyl-N-(l,2,3,4- tetrahydronaphthalen-l-yl)propanamide (compound 88):

[0525] Step 1. To a solution of 3,4-dihydronaphthalen-l(2J7)-one (200 mg, 1.37 mmol, 1.00 eq.) and methanamine hydrochloride (277 mg, 4.10 mmol, 3.00 eq.) in methanol (5 mL) were added triethylamine (554 mg, 5.47 mmol, 4.00 eq.) and sodium cyanoborohydride (774 mg, 12.3 mmol, 9.00 eq.). The mixture was stirred at 15 °C for 42 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by re / ?-TLC (silica gel, petroleum ether: ethyl acetate = 1 : 1) to give 7V-m ethyltetralin- 1 -amine (139 mg, 862 pmol, 63% yield) as a yellow oil.

[0526] Step 2. To a solution of 2-(3-chloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)propanoic acid (50.0 mg, 160 pmol, 1.00 eq.) in dimethylformamide (1 mL) was added O-(7-azabenzotriazol-l-yl)- 7V,7V,7V,7V-tetramethyluronium hexafluorophosphate (73.2 mg, 192 pmol, 1.20 eq.) and N,N- diisopropylethylamine (62.2 mg, 481 pmol, 3.00 eq.) at 0 °C. The mixture was stirred at 15° C for 10 min, then 7V-methyl-l, 2,3, 4-tetrahydronaphthalen-l -amine (25.9 mg, 160 pmol, 1.00 eq.) was added. The mixture was stirred at 15 °C for 2 h. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with sodium bicarbonate (3 x 10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by / Vc -HPLC (formic acid condition, column: Phenomenex luna C18 150*25mm* 10pm; mobile phase: [water(formic acid)-acetonitrile]; B%: 48%-68%, 8 min.) and lyophilized to afford 2-(3-chloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-7V- methyl-7V-(l,2,3,4-tetrahydronaphthalen-l-yl)propanamide (18.6 mg, 40.5 pmol, 25% yield) as a white solid.

[0527] Synthesis of 2-(3-chloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-N-methyl-N-(3-methyl-l- phenylbutyl)propanamide (compound 138):

[0528] To a solution of 2-(3-chloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)propanoic acid (50 mg, 160 pmol, 1.00 eq.) in dimethyl formamide (3 mL) were added 7V,7V-diisopropylethylamine (62.2 mg, 481 pmol, 3.00 eq.) and < -(7-Azabenzotriazol-l-yl)-7V,7V,7V’,7V’-tetramethyluronium Hexafluorophosphate (73.2 mg, 192 pmol, 1.20 eq.) at 0 °C. Then 7V,3-dimethyl-l-phenylbutan- 1-amine (30.6 mg, 162 pmol, 1.01 eq.) was added and stirred at 20 °C for 2 h. The mixture was diluted with water (20 mL) and ethyl acetate (30 mL). The layers were separated. Then the organic phase was washed with saturated sodium bicarbonate (2 ^ 30 mL) and brine (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C / c -HPLC (column: phenomenex luna Cl 8 150 * 25 mm * 10 pm; mobile phase: [water (formic acid)-acetonitrile]; B%: 46% - 76%, 2 min). The desired fraction was collected and lyophilized to give 2-(3-chloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-7V-methyl-7V-(3-methyl-l- phenylbutyl)propanamide (34.8 mg, 73.2 pmol, 46% yield) as a white solid.

[0529] Synthesis of (2R)-N-cyclohexyl-2-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-3- fluoro-N-methylpropanamide (compound 12):

[0530] Step 1. To a solution of (7?)-2-((benzyloxy)methyl)oxirane (2.00 g, 12.2 mmol, 1.00 eq.) in heptane (40 mL) were added potassium bifluoride (1.90 g, 24.4 mmol, 2.00 eq.) and tetrabutylammonium fluoride (IM in tetrahydrofuran, 36.5 mL, 3.00 eq.). The reaction mixture was stirred at 130 °C for 5 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (100 mL) and water (50 mL). The organic phase was washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 24 g SepaFlash® silica flash column, eluent of 0-30% ethyl acetate / petroleum ether gradient @ 40 mL / min) to give ( 5)-l -(benzyl oxy )-3- fhioropropan-2-ol (1.70 g, 8.77 mmol, 72% yield) as a colourless oil.

[0531] Step 2. To a solution of (.S’)- 1 -(benzyl oxy) -3 -fluoropropan -2-ol (1.00 g, 5.43 mmol, 1.00 eq.), 3- (2, 6-di chi oro-4-hydroxyphenyl)-l-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2, 6-dione (2.20 g, 5.43 mmol, 1.00 eq.) and triphenylphosphine (2.14 g, 8.14 mmol, 1.50 eq.) in tetrahydrofuran (10 mL) was added a solution of diethyl azodicarboxylate (1.42 g, 8.14 mmol, 1.50 eq.) in tetrahydrofuran (5 mL) at 0 °C. The reaction mixture was stirred at 20 °C under nitrogen atmosphere for 12 h. The mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent of 0-30% ethyl acetate / petroleum ether gradient @ 25 mL / min) to give 3 -(4-(((7?)-l -(benzyloxy)- 3-fluoropropan-2-yl)oxy)-2,6-dichlorophenyl)-l-((2-(trimethylsilyl)ethoxy)methyl)piperidine- 2, 6-dione (3.00 g, 5.10 mmol, 94% yield) as a colourless oil.

[0532] Step 3. To a solution of 3-(4-((( / ?)-l-(benzyloxy)-3-fluoropropan-2-yl)oxy)-2,6-dichlorophenyl)- l-((2-(trimethyl silyl) ethoxy)methyl)piperidine-2, 6-dione (3.00 g, 5.26 mmol, 1.00 eq.) in ethyl alcohol (150 mL) was added Raney-Ni (3.00 g, 5.26 mmol, 1.00 eq.) under nitrogen atmosphere. The mixture was stirred at 20 °C under hydrogen atmosphere (15 psi) for 12 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent of 0-30% ethyl acetate / petroleum ether gradient @ 35 mL / min) to give 3-(2,6-dichloro-4-(((7?)-l-fluoro-3- hydroxypropan-2-yl)oxy)phenyl)-l-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2, 6-dione (1.90 g, 3.80 mmol, 72% yield) as a colourless oil.

[0533] Step 4. To a solution of 3-(2,6-dichloro-4-(((7?)-l-fluoro-3-hydroxypropan-2-yl)oxy)phenyl)-l- ((2-(trimethyl silyl) ethoxy)methyl)piperidine-2, 6-dione (1.00 g, 2.08 mmol, 1.00 eq.) in acetonitrile (10 mL), water (5 mL) and phosphate buffer (pH = 6.5, 10 mL) were added 2, 2,6,6- tetramethylpiperidine 1-oxyl free radical (65.0 mg, 416 pmol, 0.20 eq.), sodium hypochlorite (1.04 mmol, 1.28 mL, 5% purity, 0.50 eq.) and sodium chlorite (376 mg, 4.16 mmol, 2.00 eq.) at 0 °C. The reaction mixture was stirred at 20 °C for 2 h. The mixture was diluted with water (50 mL) and ethyl acetate (50 mL). The layers were separated. Then the organic phase was washed with brine (40 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 10 g SepaFlash® silica flash column, eluent of 0-50% ethyl acetate / petroleum ether gradient @ 40 mL / min) to give (2R)-2-(3,5- di chi oro-4-(2,6-di oxo-1 -((2-(trimethylsilyl)ethoxy)methyl)piperi din-3 -yl)phenoxy)-3- fluoropropanoic acid (400 mg, 800 pmol, 38% yield) as a colourless oil.

[0534] Step 5. To a solution of (27?)-2-(3,5-dichloro-4-(2,6-dioxo-l-((2- (trimethylsilyl)ethoxy)methyl)piperidin-3-yl) phenoxy)-3-fhioropropanoic acid (200 mg, 404 pmol, 1.00 eq.) and dimethyl formamide (30.0 mg, 404 pmol, 1.00 eq.) in dichloromethane (8 mL) was added oxalyl dichloride (102 mg, 809 pmol, 2.00 eq.) dropwise at 20 °C. The reaction was stirred at 20 °C for 1 h. The mixture was concentrated under reduced pressure to give (25)-2-(3,5- di chi oro-4-(2,6-di oxo-1 -((2-(trimethylsilyl)ethoxy)methyl)piperi din-3 -yl)phenoxy)-3- fluoropropanoyl chloride (200 mg, 358 pmol, 88% yield) as a yellow oil. Step 6. To a solution of 7V-methylcyclohexanamine (61.0 mg, 538 pmol, 1.50 eq.) and N,N- diisopropylethylamine (139 mg, 1.08 mmol, 3.00 eq.) in dichloromethane (8 mL) was added (25)- 2-(3,5-di chi oro-4-(2,6-di oxo-1 -((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)phenoxy)-3- fluoropropanoyl chloride (200 mg, 358 pmol, 92% purity, 1.00 eq.) at 0 °C. Then reaction mixture was stirred at 20 °C for 12 h. The mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica flash column, eluent of 0-35% ethyl acetate / petroleum ether gradient @ 25 mL / min) to give (2A)-7V-cyclohexyl- 2-(3,5-di chi oro-4-(2,6-di oxo-1 -((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)phenoxy)-3- fluoro-7V-methylpropanamide (80.0 mg, 108 pmol, 30% yield) as a colourless oil.

[0535] Step 7. To a solution of (2A)-7V-cyclohexyl-2-(3,5-dichloro-4-(2,6-dioxo-l-((2- (trimethylsilyl)ethoxy)methyl) piperidin-3-yl)phenoxy)-3-fhioro-A-methylpropanamide (80.0 mg, 135 pmol, 1.00 eq.) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL). The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give (2A)-7V-cyclohexyl-2-(3,5-dichloro-4-(l -(hydroxymethyl)-2,6-dioxopiperidin-3- yl)phenoxy)-3-fluoro-7V-methylpropanamide (80.0 mg, crude) as a yellow oil.

[0536] Step 8. A solution of (2A)-7V-cyclohexyl-2-[3,5-dichloro-4-[l-(hydroxymethyl)-2,6-dioxo-3- piperidyl]phenoxy]-3-fluoro-7V-methyl-propanamide (80.0 mg, 163 pmol, 1.00 eq.) in acetonitrile (5 mL) was added ammonium hydroxide (0.25 mL, 28% purity). The mixture was stirred at 25 °C for 1 h. The pH was adjusted to 6 with formic acid. The mixture was concentrated under reduced pressure. The residue was purified by C / c -HPLC (column: Phenomenex luna Cl 8 150 * 25 mm * 10 pm; mobile phase: [water (formic acid) - acetonitrile]; B%: 36% - 66%, 10 min). The desired fraction was collected and lyophilized to give (2A)-7V-cyclohexyl-2-(3,5-dichloro-4-(2,6- dioxopiperidin-3-yl)phenoxy)-3-fluoro- / ' / -methylpropanamide (31.14 mg, 67.0 pmol, 41% yield) as a white solid.

[0537] Synthesis of N-(chroman-4-yl)-2-(3,5-dichloro-4-(2,6-dioxopiperidin-3- yl)phenoxy)propanamide (compound 157):

[0538] To a solution of 2-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)propanoic acid (100 mg, 288 pmol, 100 eq.) in dimethyl formamide (2 mL) were added 7V,7V-diisopropylethylamine (112 mg, 866 pmol, 3.00 eq.), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (66.5 mg, 346 pmol, 1.20 eq.), 1 -hydroxybenzotriazole (46.8 mg, 346 pmol, 1.20 eq.) and chroman-4-amine (43.0 mg, 288 pmol, 1.00 eq.). The reaction mixture was stirred at 20 °C for 12 h. The mixture was diluted with water (30 mL) and ethyl acetate (50 mL), and the layers were separated. Then the organic phase was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C / c -HPLC (column: Phenomenex luna Cl 8 150 * 25 mm * 10 pm; mobile phase: [water (formic acid) - acetonitrile]; B%: 37% - 67%, 10 min). The desired fraction was collected and lyophilized to give 7V-(chroman-4-yl)-2-(3,5- dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)propanamide (18.11 mg, 37.5 pmol, 13% yield) as a white solid.

[0539] Synthesis of 2-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-N-((R)-l,2,3,4- tetrahydronaphthalen-l-yl)propanamide (compound 133): Step 1. To a solution of 2-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)propanoic acid (50.0 mg, 144 / mol, 1.00 eq.) in dimethyl formamide (1 mL) were added 7V1-((ethylimino)methylene)- 7V3,7V3-dimethylpropane-l,3-diamine hydrochloride (33.2 mg, 173 / mol, 1.20 eq.), 1H- benzo[ ][l,2,3]triazol-l-ol (23.4 mg, 173 / / mol, 1.20 eq.) and diisopropylethylamine (56.0 mg, 433 / / mol, 3.00 eq.) in one portion at 20 °C. The mixture was stirred at 20 °C for 0.5 h then (17?)- tetralin-1 -amine (21.3 mg, 144 / / mol, 1.00 eq.) was added. The mixture was stirred at 20 °C for 12 h. The mixture was poured into water (10 mL), then it was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by C / c -HPLC (column: Phenomenex luna Cl 8 150 mm x 25 mm x 10 / / m; mobile phase: [water (formic acid)- acetonitrile]; B%: 36%-66%, 10 min) and lyophilized to give 2-(3,5-dichloro-4- (2,6-dioxopiperidin-3-yl)phenoxy)-7V-((7?)-l,2,3,4-tetrahydronaphthalen-l-yl)propanamide (13.1 mg, 27.3 / / mol, 18% yield) as a white solid.

[0540] Synthesis of 2-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-N-((S)-l,2,3,4- tetrahydronaphthalen-l-yl)propanamide (compound 50):

[0541] Step 1. To a mixture of 2-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)propanoic acid (50.0 mg, 144 / / mol, 1.00 eq.) in dimethyl formamide (1 mL) were added 7V1-((ethylimino)methylene)- 7V3,7V3-dimethylpropane-l,3-diamine hydrochloride (33.2 mg, 173 / / mol, 1.20 eq.), 1H- benzo[d][l,2,3]triazol-l-ol (23.4 mg, 173 / / mol, 1.20 eq.) and diisopropylethylamine (56.0 mg, 433 / / mol, 3.00 eq.) in one portion at 20 °C. The mixture was stirred at 20 °C for 0.5 h, then (15)- tetralin-1 -amine (21.3 mg, 144 / / mol, 1.00 eq.) was added. The mixture was stirred at 20 °C for 12 h. The mixture was cooled to 20 °C and poured into water (10 mL). The mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by / c -HPLC (column: YMC Triart Cl 8 150 mm x 25 mm x 5 / / m; mobile phase: [water (formic acid)- acetonitrile]; B%: 23%-53%, 10 min) then lyophilized to give 2-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-7V-((5)-l,2,3,4- tetrahydronaphthalen-l-yl)propanamide (14.0 mg, 29.1 / / mol, 20% yield) as a white solid.

[0542] Synthesis of 2-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-N-methyl-N-(l,2,3,4- tetrahydronaphthalen-2-yl)propanamide (compound 21):

[0543] Step 1. To a solution of 3,4-dihydronaphthalen-2(U7)-one (500 mg, 3.42 mmol, 1.00 eq.) in methanol (10 mL) was added 2-methylpyridine borane (731 mg, 6.84 mmol, 2.00 eq.) and methanamine hydrochloride (277 mg, 4.10 mmol, 1.20 eq.). The mixture was stirred at 50 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (0.1% NHs’LBO condition) to afford 7V-methyl-l, 2,3,4- tetrahydronaphthalen-2-amine (190 mg, 1.18 mmol, 34% yield) as a yellow oil.

[0544] Step 2. To a solution of7V-methyl-l,2,3,4-tetrahydronaphthalen-2-amine (27.9 mg, 173 pmol, 1.20 eq.) in dimethyl formamide (2.0 mL) was added 1 -(3 -dimethylaminopropyl)-3 -ethylcarbodiimide hydrochloride (30.5 mg, 158 pmol, 1.10 eq.), 7V,7V-diisopropylethylamine (56.0 mg, 433 pmol, 75.4 pL, 3.00 eq.), 2-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)propanoic acid (50.0 mg, 144 pmol, 1.00 eq.) and 1 -hydroxybenzotriazole (21.4 mg, 158 pmol, 1.10 eq.). The mixture was stirred at 25 °C for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by C / c -HPLC (column: Phenomenex luna Cis 150 * 25 mm * 10 um; mobile phase: [water (formic acid) - acetonitrile]; B%: 43%-73%, 10 min) and lyophilized to afford 2-(3,5- dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)- 7V-methyl-7V-(l,2,3,4-tetrahydronaphthalen-2- yl)propanamide (12.74 mg, 25.8 pmol, 17% yield) as a white solid.

[0545] Synthesis of 3-(2,6-dichloro-4-((l-(3,4-dihydroisoquinolin-2(lH)-yl)-l-oxopropan-2- yl)oxy)phenyl)piperidine-2, 6-dione (compound 103):

[0546] To a solution of 2-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)propanoic acid (100 mg, 288 pmol, 1.00 eq.) in dimethyl formamide (3 mL) were added 7V,7V-diisopropylethylamine (112 mg, 866 pmol, 3.00 eq.) and 2-chloro-l -methylpyridinium iodide (88.0mg, 346 pmol, 1.20 eq.). Then 1,2,3,4-tetrahydroisoquinoline was added and the reaction mixture was stirred at 70 °C for 12 h. The mixture was diluted with water (10 mL) and ethyl acetate (30 mL). The layers were separated. Then the organic phase was washed with brine (20 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 of 0-40% ethyl acetate / petroleum ether gradient @ 25 mL / min) followed by C / c -HPLC (column: Phenomenex luna Cl 8 150 * 25 mm * 10 pm; mobile phase: [water (formic acid) - acetonitrile]; B%: 33% - 63%, 10 min). The desired fraction was collected and lyophilized to give 3-(2,6-dichloro-4-((l-(3,4-dihydroisoquinolin- 2(177)-yl)-l-oxopropan-2-yl)oxy)phenyl) piperidine-2, 6-dione (17.68 mg, 37.0 pmol, 13% yield) as a white solid.

[0547] Synthesis of V-(chroman-4-yl)-2-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-7V- methylpropanamide (compound 117):

[0548] Step 1. To a solution of chroman-4-amine (100 mg, 670 pmol, 1.00 eq.) in dichloromethane (5 mL) were added triethylamine (135 mg, 1.34 mmol, 2.00 eq.) and a solution of di- / crt-butyl dicarbonate (175 mg, 804 pmol, 1.20 eq.) in dichloromethane (2 mL) at 0 °C. The reaction mixture was stirred at 20 °C for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica flash column, eluent of 0-30% ethyl acetate / petroleum ether gradient @ 25 mL / min) to give / crt-butyl chroman- 4-ylcarbamate (130 mg, 495 pmol, 73% yield) as a yellow oil.

[0549] Step 2. Tert-butyl chroman-4-ylcarbamate (130 mg, 521 pmol, 1.00 eq.) was added slowly to a suspension of lithium aluminium hydride (100 mg, 2.61 mmol, 5.00 eq.) in tetrahydrofuran (5 mL) at 0 °C under nitrogen atmosphere. The mixture was heated at 70 °C for 3 h. After cooling, sodium sulfate decahydrate (1.00 g) and ethyl acetate (30 mL) were added to the mixture. The resulting mixture was stirred at room temperature for 10 min, filtered through a pad of celite and concentrated under reduced pressure. Hydrochloric acid (1 M, 20 mL) and ethyl acetate (20 mL) were added to the residue. The organic layer was separated and discarded. The aqueous layer was basified with 1 M sodium hydroxide and extracted with ethyl acetate (25 mL). The combined extract was washed with water (50 mL), dried over sodium sulfate and concentrated under reduced pressure to give A-methylchroman-4-amine (60.0 mg, 330 pmol, 63% yield) as a colourless oil.

[0550] Step 3. To a solution of 2-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)propanoic acid (100 mg, 288 pmol, 1.00 eq.) in dimethyl formamide (2 mL) were added 7V,7V-diisopropylethylamine (112 mg, 866 pmol, 3.00 eq.), A-[3-(Dimethylamino)propyl]-7V-ethylcarbodiimide hydrochloride (66.0 mg, 346 pmol, 1.20 eq.) and 1 -Hydroxybenzotriazole (47.0 mg, 346 pmol, 1.20 eq.). The reaction was stirred at 20 °C for 10 min. Then A-methylchroman-4-amine (50.0 mg, 306 pmol, 1.06 eq.) was added, and the mixture was stirred at 20 °C for 12 h. The residue was purified by / c -HPLC (column: Phenomenex Luna Cl 8 150 * 25 mm* 10 pm; mobile phase: [water (formic acid)-acetonitrile]; B%: 36% - 66%, 10 min) followed by re / ?-HPLC (column: Waters Xbridge C18 150 * 50 mm* 10 pm; mobile phase: [water-acetonitrile]; B%: 34% - 64%, 10 min) to give a crude product. Then the crude product was re-purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica flash column, eluent of 0-100% ethyl acetate / petroleum ether gradient @ 18 mL / min). The desired fraction was concentrated under reduced pressure. And it was diluted with acetonitrile (3 mL) and water (30 mL), and then lyophilized to give A-(chroman-4-yl)-2-(3,5- dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-A-methylpropanamide (23.26 mg, 46.8 pmol, 16% yield) as a white solid.

[0551] Synthesis of 2-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-N-methyl-N-((R)-l,2,3,4- tetrahydronaphthalen-l-yl)propanamide (compound 108):

[0552] Step 1. A mixture of (A)-l,2,3,4-tetrahydronaphthalen-l-amine (2.00 g, 13.6 mmol, 1.00 eq.) in ethyl formate (20 mL) was stirred at 60 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0-100% ethyl acetate / petroleum ether gradient @ 50 mL / min) to give (A)-A-(l,2,3,4-tetrahydronaphthalen-l-yl)formamide (2.55 g, crude) as an off- white solid.

[0553] Step 2. To a suspension of aluminium(III) lithium hydride (650 mg, 17.1 mmol, 3.00 eq.) in tetrahydrofuran (20 mL) was added (A)-A-(l,2,3,4-tetrahydronaphthalen-l-yl)formamide (1.00 g, 5.71 mmol, 1.00 eq.) at 0 °C under nitrogen atmosphere. The mixture was stirred at 70 °C for 16 h under nitrogen atmosphere. After cooling to 0 °C, sodium sulfate decahydrate (6.62 g, 3.60 eq.) was added to the mixture. The mixture was stirred at 20 °C for 10 min. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in water (50 mL) then the mixture was adjusted to pH = 5 with 1 M hydrochloric acid. The mixture was extracted with ethyl acetate (2 x 50 mL), and the combined organic layers were discarded. The aqueous layer was adjusted to pH = 9 with 1 M sodium hydroxide. The mixture was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give (7?)-7V-methyl- 1,2,3,4-tetrahydronaphthalen-l-amine (130 mg, 774 pmol, 14% yield) as a pale yellow oil.

[0554] Step 3. To a solution of 2-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)propanoic acid (100 mg, 289 pmol, 1.00 eq.) in 7V,7V-dimethylformamide (2 mL) were added N,N- diisopropylethylamine (862 pmol, 150 pL, 2.98 eq.), l-(3-Dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (67.0 mg, 350 pmol, 1.21 eq.) and 1 -Hydroxybenzotriazole (47.0 mg, 348 pmol, 1.20 eq.) at 0 °C. The mixture was stirred at 25 °C for 10 min. Then ( ’j-A-methyl- 1,2,3,4-tetrahydronaphthalen-l-amine (47.0 mg, 292 pmol, 1.01 eq.) was added to the mixture. The resulting mixture was stirred at 25 °C for 16 h. The mixture was filtered. The filtrate was purified by C / c -HPLC (Phenomenex luna Cl 8 150 x25 mm x 10 pm; mobile phase: [water(0.225% formic acid)-acetonitrile]; B%: 43%-73%, 10 min) and lyophilized to give 2-(3,5- di chi oro-4-(2,6-dioxopiperi din-3- yl)phenoxy)-7V-methyl-7V-((7?)-l,2,3,4-tetrahydronaphthalen-l- yl)pr-opanamide (42.1 mg, 85.3 pmol, 21% yield) as a white solid.

[0555] Synthesis of 2-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-N-methyl-N-((S)-l,2,3,4- tetrahydronaphthalen-l-yl)propanamide (compound 14):

[0556] Step 1. To a solution of (5)-l,2,3,4-tetrahydronaphthalen-l-amine (500 mg, 3.40 mmol, 1.00 eq.), potassium carbonate (938 mg, 6.79 mmol, 2.00 eq.) in acetonitrile (10 mL) was added ethyl carb onochlori date (640 mg, 5.90 mmol, 1.74 eq.) at 0 °C. The reaction mixture was stirred at 20 °C for 1 h. The mixture was quenched with water at 0 °C. Then it was extracted with ethyl acetate (50 mL). The organic phase was washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 10 g SepaFlash® silica flash column, eluent of 0-10% ethyl acetate / petroleum ether gradient @ 25 mL / min) to give ethyl (S)-(l,2,3,4-tetrahydronaphthalen-l- yl)carbamate (530 mg, 2.39 mmol, 71% yield) as a yellow solid.

[0557] Step 2. (5)-7V-methyl-l,2,3,4-tetrahydronaphthalen-l-amine (300 mg, 1.37 mmol, 1.00 eq.) was added slowly to a suspension of lithium aluminium hydride (155 mg, 4.10 mmol, 3.00 eq.) in tetrahydrofuran (5 mL) at 0°C under nitrogen atmosphere. The mixture was heated at 70 °C for 2 h. After cooling, sodium sulfate decahydrate (1.0 g) and ethyl acetate (30 mL) were added to the mixture. The resulting mixture was stirred at room temperature for 10 min, filtered through a pad of celite and concentrated under reduced pressure. Hydrochloric acid (1 M, 20 mL) and ethyl acetate (20 mL) were added to the residue. The organic layer was separated and discarded. The aqueous layer was basified with 1 M sodium hydroxide and extracted with ethyl acetate (2 x 25 mL). The combined extract was washed with water (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give (S)-A-methyl-l,2,3,4-tetrahydronaphthalen-l- amine (150 mg, 883 pmol, 64% yield) as a white solid.

[0558] Step 3. To a solution of 2-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)propanoic acid (100 mg, 288 pmol, 1.00 eq.) in dimethyl formamide (2 mL) were added 7V,7V-diisopropylethylamine (112 mg, 866 pmol, 3.00 eq.), 7V-[3-(Dimethylamino)propyl]-7V-ethylcarbodiimide hydrochloride (66.0mg, 346 pmol, 1.20 eq.) and 1 -Hydroxybenzotriazole (46.0 mg, 346 pmol, 1.20 eq.). The reaction mixture was stirred at 20 °C for 10 min. Then (5)-A-methyl-l,2,3,4-tetrahydronaphthalen- 1-amine (46.0 mg, 288 pmol, 1.00 eq.) was added, and the mixture was stirred at 20 °C for 12 h. The mixture was filtered. The filtrate was purified by / c / i-HPLC (column: Phenomenex luna C18 150 * 25 mm * 10 pm; mobile phase: [water (formic acid)-acetonitrile]; B%: 43% - 73%, 10 min). The desired fraction was collected and lyophilized to give 2-(3,5-dichloro-4-(2,6-dioxopiperidin- 3-yl)phenoxy)-A-methyl-A-((5)-l,2,3,4-tetrahydronaphthalen-l-yl)propanamide (28.82 mg, 58.0 pmol, 20% yield) as a white solid. Synthesis of 3-(2,6-dichloro-4-((l-(3,4-dihydro-l,5-naphthyridin-l(2H)-yl)-l-oxopropan-2- yl)oxy)phenyl)piperidine-2, 6-dione (compound 236):

[0559] To a solution of 2-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)propanoic acid (93.8 mg, 271 pmol, 1.00 eq.) in dimethyl formamide (3.00 mL) were added 7V,7V-diisopropylethylamine (35.0 mg, 271 pmol, 1.00 eq.), 2-chloro-l-methyl-pyridin-l-ium iodide (83.1 mg, 325 pmol, 1.20 eq.) and l,2,3,4-tetrahydro-l,5-naphthyridine (40.0 mg, 298 pmol, 1.10 eq.). The mixture was stirred at 70 °C for 12 h. The mixture was filtered. The filtrate was purified by / c -HPLC (column: Phenomenex Luna C18 150 * 25 mm * 10 pm; mobile phase: [water (formic acid)-acetonitrile]; B%: 12% - 42%, 10 min). The desired fraction was collected and lyophilized to give 3-(2,6- dichloro-4-((l-(3,4-dihydro-l,5-naphthyridin-l(2J7)-yl)-l-oxopropan-2- yl)oxy)phenyl)piperidine-2, 6-dione (65.71 mg, 141 pmol, 52% yield) as a white solid.

[0560] Synthesis of 3-(2,6-dichloro-4-((l-(3,4-dihydrobenzo[b] [l,4]oxazepin-5(2H)-yl)-l- oxopropan-2-yl)oxy)phenyl)piperidine-2, 6-dione (compound 239): Step 1. To a solution of 2,3,4, 5-tetrahydrobenzo[Z>][l,4]oxazepine (43.0 mg, 288 pmol, 1.00 eq.) and 2-(3,5-dichloro- 4-(2,6-dioxopiperidin-3-yl)phenoxy)propanoic acid (100 mg, 289 pmol, 1.00 eq.) in -di methyl form am ide (1 mL) were added 2-chloro-l-methylpyridin-l-ium iodide (89.0 mg, 348 pmol, 1.21 eq.) and 7V,7V-diisopropylethylamine (112 mg, 867 pmol, 3.00 eq.). The resulting mixture was stirred at 70 °C for 16 h. After cooling to 25 °C, the mixture was filtered. The filtrate was purified by re / ?-HPLC (column: Phenomenex luna Cl 8 150 * 25 mm x 10 pm; mobile phase: [water (0.225% formic acid) - acetonitrile]; B%: 34%-64%, 2 min) and lyophilized to give 3-(2,6-dichloro-4-((l-(3,4-dihydrobenzo[Z>][l,4]oxazepin-5(2J7)-yl)-l-oxopropan-2- yl)oxy)phenyl)piperidine-2, 6-dione (39.5 mg, 81.9 pmol, 78% yield) as an off-white solid.

[0561] Synthesis of 3-(2,6-dichloro-4-((l-oxo-l-(pyrrolidin-l-yl)propan-2- yl)oxy)phenyl)piperidine-2, 6-dione (compound 140):

[0562] Step 1. To a solution of 2-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)propanoic acid (100 mg, 288 pmol, 1.00 eq.) in dimethyl formamide (3 mL) were added 7V-[3-(dimethylamino)propyl]- 7V-ethylcarbodiimide hydrochloride (66.5 mg, 347 pmol, 1.20 eq.), 1 -Hydroxybenzotriazole (46.8 mg, 347 pmol, 1.20 eq.), 7V,7V-diisopropylethylamine (75.0 mg, 578 pmol, 2.00 eq.) and pyrrolidine (21.0 mg, 289 pmol, 1.00 eq.). The mixture was stirred at 25 °C for 12 h. The mixture was filtered. The filtrate was purified by re / ?-HPLC (column: Phenomenex luna Cl 8 150 * 25 mm * 10 pm; mobile phase: [water (formic acid) - acetonitrile]; B%: 25% - 55%, 10 min) followed by Prep- HPLC (column: waters Xbridge 150 * 25 mm * 5 pm; mobile phase: [water-acetonitrile]; B%: 25% - 55%, 8 min). The desired fraction was collected and lyophilized to give 3-(2,6-dichloro-4- ((l-oxo-l-(pyrrolidin-l-yl)propan-2-yl)oxy)phenyl)piperidine-2, 6-dione (41.28 mg, 102 pmol, 35% yield) as a white solid. Synthesis of N-cyclopentyl-2-(3,5-dichloro-4-(2,6-dioxopiperidin-3- yl)phenoxy)propanamide (compound 83):

[0563] To a solution of 2-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)propanoic acid (50.0 mg, 144 pmol, 1.00 eq.) in dimethyl formamide (1 mL) were added 7V,7V-diisopropylethylamine (56.0 mg, 433 pmol, 3.00 eq.), 7V-[3-(Dimethylamino)propyl]-7V-ethyl carbodiimide hydrochloride (33.0 mg, 173 pmol, 1.20 eq.) and 1 -Hydroxybenzotriazole (23.0 mg, 173 pmol, 1.20 eq.). The reaction mixture was stirred at 20 °C for 10 min. Then cyclopentanamine (12.0 mg, 144 pmol, 1.00 eq.) was added to the mixture. The mixture was stirred at 20 °C for 12 h. The mixture was filtered. The filtrate was purified by / c / i-HPLC (column: Phenomenex luna C18 150 * 25 mm * 10 pm; mobile phase: [water (formic acid) - acetonitrile]; B%: 29% - 59%, 10 min). The desired fraction was collected and lyophilized to give 7V-cyclopentyl-2-(3,5-dichloro-4-(2,6-dioxopiperidin-3- yl)phenoxy)propanamide (27.63 mg, 66.0 pmol, 45% yield) as a white solid.

[0564] Synthesis of 2-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-N-isopropylpropanamide (compound 90):

[0565] To a solution of 2-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)propanoic acid (104 mg, 301 pmol, 1.00 eq.) in dimethyl formamide (3 mL) were added 7V-[3-(Dimethylamino)propyl] -TV- ethylcarbodiimide hydrochloride (69.3 mg, 361 pmol, 1.20 eq.), 1 -Hydroxybenzotriazole (48.8 mg, 361 pmol, 1.20 eq.) and 7V,7V-diisopropylethylamine (77.8 mg, 602 pmol, 2.00 eq.). The mixture was stirred at 20 °C for 10 min. Then propan-2-amine (21.4 mg, 361 pmol, 1.20 eq.) was added to the mixture. The mixture was stirred at 20 °C for 1 h. Ethyl acetate (20 mL) and water (20 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (20 mL). Combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by E / c -HPLC (column: Phenomenex luna Cl 8 150 * 40 mm * 15 pm; mobile phase: [water (formic acid) - acetonitrile]; B%: 24% - 54%, 9 min). The desired fraction was collected and lyophilized to give 2-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-7V-isopropylpropanamide (14.9 mg, 38 pmol, 13% yield) as a white solid.

[0566] Synthesis of 2-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-N-(tetrahydro-2H-pyran- 4-yl)propanamide (compound 129):

[0567] To a solution of 2-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)propanoic acid (50.0 mg, 144 pmol, 1.00 eq.) in dimethyl formamide (1 mL) were added 7V,7V-diisopropylethylamine (56.0 mg, 433 pmol, 3.00 eq.), 7V-[3-(Dimethylamino)propyl]-7V-ethyl carbodiimide hydrochloride (28.0 mg, 144 pmol, 1.00 eq.) and 1 -Hydroxybenzotriazole (19.0 mg, 144 pmol, 1.00 eq.). The reaction mixture was stirred at 20 °C for 10 min. Then tetrahydro-27 / -pyran-4-amine (15.0 mg, 148 pmol, 1.03 eq.) was added to the mixture. The mixture was stirred at 20 °C for 12 h. The mixture was filtered. The filtrate was purified by / c / i-HPLC (column: Phenomenex luna Cl 8 150 * 25 mm * 10 pm; mobile phase: [water (formic acid) - acetonitrile]; B%: 16% - 46%, 10 min). The desired fraction was collected and lyophilized to give 2-(3,5-dichloro-4-(2,6-dioxopiperidin-3- yl)phenoxy)- / ' / -(tetrahydro-27 / -pyran-4-yl)propanamide (11.68 mg, 26.0 pmol, 18% yield) as a white solid.

[0568] Synthesis of 2-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-7V-methylpropanamide (compound 143):

[0569] To a solution of 2-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)propanoic acid (100 mg, 289 pmol, 1.00 eq.) in dimethyl formamide (3 mL) were added 7V-[3-(Dimethylamino)propyl]-7V- ethylcarbodiimide hydrochloride (66.5 mg, 347 pmol, 1.20 eq.), 7V,7V-diisopropylethylamine (149 mg, 1.16 mmol, 4.00 eq.) and 1 -Hydroxybenzotriazole (46.8 mg, 347 pmol, 1.20 eq.). The mixture was stirred at 20 °C for 10 min. Then methanamine hydrochloride (23.4 mg, 347 pmol, 1.20 eq.) was added to the mixture. The mixture was stirred at 20 °C for 12 h. The mixture was filtered. The filtrate was purified by / c / i-HPLC (column: Phenomenex luna C18 150 * 40 mm * 15 pm; mobile phase: [water (formic acid)-acetonitrile]; B%: 16% - 46%, 9 min). The desired fraction was collected and lyophilized to give 2-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-7V- methylpropanamide (17.81 mg, 49.1 pmol, 17% yield) as a white solid.

[0570] Synthesis of 2-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-N,N-dimethylpropanamide (compound 84): To a solution of 2-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)propanoic acid (100 mg, 289 pmol, 1.00 eq.) in A'A -di methyl form am ide (3 mL) were added l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (55.4 mg, 289pmol, 1.00 eq.), 1 -hydroxybenzotriazole (46.9 mg, 347 pmol, 1.20 eq.) and 7V,7V-diisopropylethylamine (149 mg, 1.16 mmol, 201 pL, 4.00 eq.). The mixture was stirred at 25 °C for 10 min. Then dimethylamine hydrochloride (28.3 mg, 347 pmol, 1.20 eq.) was added, and the reaction was stirred at 25 °C for 12 h. The mixture was quenched with water (30 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by C / c / -HPLC (column: Phenomenex luna Cl 8 150 * 25 mm * 10 pm; mobile phase: [water (formic acid) - acetonitrile]; B%: 16% - 46%, 10 min). The desired fraction was collected and lyophilized to give 2-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-7VpV- dimethylpropanamide (48.8 mg, 131 pmol, 45% yield) as a white solid.

[0571] Synthesis of 3-(4-((l-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-l-oxopropan-2-yl)oxy)-2,6- dichlorophenyl) piperidine-2, 6-dione (compound 124):

[0572] To a solution of 2-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)propanoic acid (100 mg, 261 pmol, 1.11 eq.) and 6-oxa-3-azabicyclo[3.1.1]heptane hydrochloride (32.0 mg, 236 pmol, 1.00 eq.) in 7V,7V-dimethylformamide (1 mL) were added 7V,7V-diisopropylethylamine (746 pmol, 130 pL, 3.16 eq.) and 2-chloro-l-methylpyridin-l-ium iodide (73.0 mg, 286 pmol, 1.21 eq.). The mixture was stirred at 70 °C for 16 h. After cooling to 20 °C, the mixture was filtered. The filtrate was purified by C / c / -HPLC (column: Phenomenex luna Cl 8 150 x 25 mm x 10 pm; mobile phase: [water(0.225% formic acid) - acetonitrile]; B%: 22% - 42%, 10 min) and lyophilized to give 3-(4- ((l-(6-oxa-3-azabicyclo[3.1.1]heptan- 3-yl)-l-oxopropan-2-yl)oxy)-2,6- dichlorophenyl)piperidine-2,6- dione (18.9 mg, 41.7 pmol, 18% yield) as a white solid. Synthesis of 3-(4-((l-(2-oxa-5-azabicyclo [2.2.1] heptan-5-yl)-l-oxopropan-2-yl)oxy)-2,6- dichlorophenyl)piperidine-2, 6-dione (compound 142):

[0573] Step 1. To a solution of 2-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)propanoic acid (60.0 mg, 173 pmol, 1.00 eq.) in dimethylformamide (3 mL) were added 7V,7V-diisopropylethylamine (100 pL, 574 pmol, 3.30 eq.) and l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (42.0 mg, 219 pmol, 1.26 eq.) and 1 -hydroxybenzotriazole (30.0 mg, 222 pmol, 1.28 eq.) at 0 °C under nitrogen. The mixture was stirred at 0 °C for 10 min. Then 2-oxa-5-azabicyclo[2.2. l]heptane hydrochloride (30.0 mg, 221 pmol, 1.28 eq.) was added to the mixture and stirred at 25 °C for 16 h. Then the mixture was concentrated under reduced pressure. The residue was purified by Prep- HPLC (column: phenomenex luna Cl 8 150*25mm*10pm; mobile phase: [water(formic acid)- acetonitrile]; B%: 16%-46%, 10 min) and lyophilized to afford 3-(4-((l-(2-oxa-5- azabicyclo[2.2. l]heptan-5-yl)-l-oxopropan-2-yl)oxy)-2,6-dichlorophenyl)piperidine-2, 6-dione (46.45 mg, 108 pmol, 62% yield) as a white solid. Synthesis of 3-(4-((l-(3-azabicyclo[3.1.0]hexan-3-yl)-l-oxopropan-2-yl)oxy)-2,6- dichlorophenyl)piperidine-2, 6-dione (compound 76): To a solution of 2-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)propanoic acid (100 mg, 289 pmol, 1.00 eq.) in dimethylformamide (3 mL) were added 7V,7V-diisopropylethylamine (160 pL, 928 pmol, 3.20 eq.), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (70.0 mg, 365 pmol, 1.26 eq.) and 1 -hydroxybenzotriazole (50.0 mg, 370 pmol, 1.28 eq.) at 0 °C under nitrogen atmosphere. The mixture was stirred at 0 °C for 10 min. Then 3-azabicyclo[3.1.0]hexane hydrochloride (52.0 mg, 435 pmol, 1.51 eq.) was added to the mixture and stirred at 25 °C for 16 h. Then the mixture was concentrated under reduced pressure. The residue was purified by Prep- HPLC (column: phenomenex luna Cl 8 150*25mm*10pm; mobile phase: [water(formic acid)- acetonitrile]; B%: 26%-56%, 10 min) and lyophilized to afford 3-(4-((l-(3- azabicyclo[3.1.0]hexan-3-yl)-l-oxopropan-2-yl)oxy)-2,6-dichlorophenyl)piperidine-2, 6-dione (69.17 mg, 165 pmol, 57% yield) as a white solid.

[0574] Synthesis of 3-(4-((l-(3-azabicyclo[3.1.1]heptan-3-yl)-l-oxopropan-2-yl)oxy)-2,6- dichlorophenyl)piperidine-2, 6-dione (compound 102):

[0575] To a solution of 2-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)propanoic acid (50.0 mg, 144 / mol, 1.00 eq.) and diisopropylethylamine (74.7 mg, 578 / mol, 4.00 eq.) in dimethyl formamide (1 mL) was added 2-chloro-l-methyl-pyridin-l-ium;iodide (44.3 mg, 173 / / mol, 1.20 eq.) in one portion at 20 °C. The mixture was stirred at 20 °C for 1 h, then 3-azabicyclo[3.1.1]heptane hydrochloride (19.3 mg, 144 / / mol, 1.00 eq.) was added. The mixture was stirred at 70 °C for 12 h. The mixture was cooled to 20 °C and poured into water (10 mL). The mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by C / c -HPLC (column: Phenomenex Luna C18 150 mm x 25 mm x 10 / / m; mobile phase: [water (formic acid)-acetonitrile]; B%: 31%-61%, 10 min) then lyophilized to give 3-(4-((l-(3-azabicyclo[3.1.1]heptan-3-yl)-l-oxopropan-2-yl)oxy)-2,6- dichlorophenyl)piperidine-2, 6-dione (12.9 mg, 29.9 / / mol, 20% yield) as a white solid.

[0576] Synthesis of 3-(2,6-dichloro-4-((l-(4-hydroxy-4-methylpiperidin-l-yl)-l-oxopropan-2- yl)oxy)phenyl)piperidine-2, 6-dione (compound 122):

[0577] To a solution of 2-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)propanoic acid (100 mg, 289 pmol, 1.00 eq.) in dimethyl formamide (3 mL) were added l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (66.5 mg, 347 pmol, 1.20 eq.), 1 -hydroxybenzotriazole (46.8 mg, 347 pmol, 1.20 eq.), and 7V,7V-diisopropylethylamine (74.7 mg, 578 pmol, 2.00 eq.). The mixture was stirred at 25 °C for 10 min. Then 4-methylpiperidin-4-ol (33.3 mg, 289 pmol, 1.00 eq.) was added to the mixture. The reaction was stirred at 25 °C for 12 h. The mixture was filtered. The filtrate was purified by C / c -HPLC (column: Phenomenex Luna Cl 8 150 * 25 mm * 10 pm; mobile phase: [water (formic acid)-acetonitrile]; B%: 19% - 49%, 10 min). The desired fraction was collected and lyophilized to give 3-(2,6-dichloro-4-((l-(4-hydroxy-4-methylpiperidin-l-yl)- l-oxopropan-2-yl)oxy)phenyl)piperidine-2, 6-dione (44.91 mg, 100 pmol, 35% yield) as a white solid.

[0578] Synthesis of 3-(2,6-dichloro-4-((l-(4,4- difluoropiperidin-l-yl)-l-oxopropan-2- yl)oxy)phenyl)piperidine-2, 6-dione (compound 134):

[0579] To a mixture of 2-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)propanoic acid (100 mg, 288 / mol, 1.00 eq.) in dimethyl formamide (1.5 mL) were added diisopropylethylamine (149 mg, 1.16 mmol, 4.00 eq.) and 2-chloro-l-methyl-pyridin-l-ium iodide (88.5 mg, 346 / mol, 1.20 eq.) in one portion at 20 °C. The solution was stirred at 20 °C for 0.5 h, and then 4,4-difluoropiperidine (38.4 mg, 317 / / mol, 1.10 eq.) was added, and the reaction was stirred at 70 °C for 12 h. The mixture was cooled to 20 °C and poured into water (10 mL). The mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by / c -HPLC (column: Phenomenex luna C18 150 mm x 25 mm x io / / m; mobile phase: [water (formic acid)- acetonitrile]; B%: 35%-65%, 10 min) then lyophilized to give 3-(2,6-dichloro-4- ((l-(4,4- difluoropiperidin-l-yl)-l-oxopropan-2-yl)oxy)phenyl)piperidine-2, 6-dione (20.0 mg, 44.1 / / mol, 15% yield) as a white solid.

[0580] Synthesis of 3-(2,6-dichloro-4-((l-(4-hydroxypiperidin-l-yl)-l-oxopropan-2- yl)oxy)phenyl)piperidine-2, 6-dione (compound 101): A mixture of 2-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)propanoic acid (70.0 mg, 202 pmol, 1.00 eq.), piperidin-4-ol (22.5 mg, 222 pmol, 1.10 eq.), 3 -(3 -dimethylaminopropyl)- 1- ethylcarbodiimide (46.5 mg, 243 pmol, 1.20 eq.), 1 -hydroxybenzotriazole (32.8 mg, 243 pmol, 1.20 eq.) and diisopropylethylamine (52.3 mg, 404 pmol, 2.00 eq.) in dimethyl formamide (700 pL) was stirred at 25 °C for 2 h under nitrogen atmosphere. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate ('4 - 10 mL). The combined organic layers were concentrated to give a yellow oil. The yellow oil was purified by re / ?-HPLC(Phenomenex luna C18 150*25mm* lOum; mobile phase: [water(formic acid)-acetonitrile]; B%: 12%-42%, 10 min) and lyophilized to give 3-(2,6-dichloro-4-((l-(4-hydroxypiperidin-l-yl)-l-oxopropan-2- yl)oxy)phenyl) piperidine-2, 6-dione (48.1 mg, 112 pmol, 55% yield) as a white solid.

[0581] Synthesis of 3-(4-((l-(4-acetylpiperazin-l-yl)-l-oxopropan-2-yl)oxy)-2,6- dichlorophenyl)piperidine-2, 6-dione (compound 217):

[0582] Step 1. To a solution of 2-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)propanoic acid (100 mg, 289 pmol, 1.00 eq.) in dimethyl formamide (3 mL) were added l-(3-dimethylaminopropyl)- 3 -ethylcarbodiimide hydrochloride (66.5 mg, 347 pmol, 1.20 eq.), 1 -hydroxybenzotriazole (46.8 mg, 347 pmol, 1.20 eq.) and 7V,7V-diisopropylethylamine (112 mg, 867 pmol, 3.00 eq.). The mixture was stirred at 25 °C for 10 min. Then aniline (32.3 mg, 347 pmol, 1.20 eq.) was added. The mixture was stirred at 25 °C for 12 h. The mixture was quenched with water (30 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by / c -HPLC (column: Phenomenex Luna C 18 150 * 25mm * 10 pm; mobile phase: [water (formic acid) - acetonitrile]; B%: 38% - 68%, 10 min) followed by / c / i-HPLC (column: Phenomenex Luna C18 150 * 25 mm * 10 pm; mobile phase: [water (formic acid) - acetonitrile]; B%: 32% - 62%, 10 min). The desired fraction was collected and lyophilized to give 2-(3,5-dichloro-4-(2,6- dioxopiperidin-3-yl)phenoxy)-A-phenylpropanamide (18.01 mg, 42.8 pmol, 15% yield) as a white solid.

[0583] Synthesis of l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-7V-(2- fluorophenyl)cyclopropane-l-carboxamide (compound 287)

[0584] To a solution of l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclopropane-l-carboxylic acid (150 mg, 419 pmol, 1.00 eq.) in N,N-dimethyl formamide (3 mL) were added N,N- diisopropylethylamine (219 pL, 1.26 mmol, 3.00 eq.) and 2-chloro-l-methyl-pyridin-l-ium iodide (129 mg, 503 pmol, 1.20 eq.). After addition, the mixture was stirred at 25 °C for 30 min, and then

[0585] 2-fluoroaniline (57.0 mg, 508 pmol, 1.00 eq.) was added. The resulting mixture was stirred at 25 °C for 13 h. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with water (3 x 10 mL) and brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC [column: YMC - Actus Triart C 18 150 * 30 mm x 7 pm; mobile phase: [water (formic acid) - acetonitrile]; gradient: 43% - 73% B over 10 min). The desired fraction was collected and lyophilized to give l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-N-(2- fluorophenyl)cyclopropane-l -carboxamide (102.48 mg, 225 pmol, 54% yield) as a white solid.

[0586] Synthesis of 3-(4-(l-(l,3,4-oxadiazol-2-yl)cyclopropoxy)-2,6-dichlorophenyl)piperidine-2,6- dione (compound 322)

[0587] Step 1

[0588] To a solution of l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclopropane-l-carboxylic acid (500 mg, 1.40 mmol, 1.00 eq.) in N,N-dimethylformamide (10 mL) was added 2-chloro-l- methyl-pyridin-l-ium iodide (390 mg, 1.53 mmol, 1.09 eq.) and N,N-diisopropylethylamine (750 pL, 4.31 mmol, 3.08 eq.). The mixture was stirred at 20 °C for 0.5 h. Then tert-butyl hydrazinecarboxylate (190 mg, 1.44 mmol, 1.03 eq.) was added, and the reaction was stirred at 20 °C for 1.5 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic extracts 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 (eluent of 0-50% ethyl acetate / petroleum ether) to afford tert-butyl 2-( 1 -(3,5- dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclopropane-l-carbonyl)hydrazine-l-carboxylate (550 mg, 815 pmol, 58% yield) as a colourless gum.

[0589] Step 2

[0590] To a solution of tert-butyl 2-(l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclopropane- l-carbonyl)hydrazine-l -carboxylate (500 mg, 741 pmol, 1.00 eq.) in dichloromethane (6 mL) was added trifluoroacetic acid (2 mL). The mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure to afford l-(3,5-dichloro-4-(2,6-dioxopiperidin-3- yl)phenoxy)cyclopropane-l -carbohydrazide trifluoroacetate (600 mg, 617 pmol, 83% yield) as a yellow gum. Step 3

[0591] To a solution of l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclopropane-l- carbohydrazide trifluoroacetate (300 mg, 403.01 pmol, 1.00 eq.) in trimethoxymethane (3 mL) and tetrahydrofuran (3 mL) was added methanesulfonic acid (11.0 pL, 154 pmol, 0.50 eq.). The mixture was stirred at 80 °C for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic extracts were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: Waters Xbridge Prep OBD Cl 8 150 x 40 mm x 10 pm; mobile phase: [water (ammonium bicarbonate) - acetonitrile]; gradient: 16%-46% B over 15 min) and lyophilized to afford 3-(4-(l-(l,3,4-oxadiazol-2-yl)cyclopropoxy)-2,6- dichlorophenyl)piperidine-2, 6-dione (62.76 mg, 162 pmol, 52% yield) as a white solid.

[0592] Synthesis of (2S)-N-(4-cyano-2-fluorophenyl)-2-(3,5-dichloro-4-(2,6-dioxopiperidin-3- yl)phenoxy)propenamide (compound 213)

[0593] Step 1

[0594] To a solution of (25)-2-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)propanoic acid (200 mg, 578 pmol, 1.00 eq.) in dichloromethane (5 mL) was added oxalyl dichloride (360 mg, 2.84 mmol, 4.91 eq.) followed by three drops of dimethyl formamide (42.0 mg, 578 pmol, 1.00 eq.) at 20 °C. The mixture was stirred at 20 °C for 1 h. The mixture was concentrated under reduced pressure to give (2S)-2-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)propanoyl chloride (0.2 g, crude) as a brown foam. It was used directly in the next step. Step 2

[0595] To a solution of 4-amino-3 -fluoro-benzonitrile (75.0 mg, 551 pmol, 2.01 eq.) and diisopropylethylamine (106 mg, 823 pmol, 3.00 eq.) in dimethyl formamide (2 mL) was added a solution of (25)-2-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)propanoyl chloride (100 mg, 274 pmol, 1.00 eq.) in dichloromethane (2 mL) dropwise at 0 °C. The mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by / c / i-HPLC (column: Phenomenex luna C18 150x25mm>< 10 pm; mobile phase: [water(formic acid)-acetonitrile]; gradient: 38%-68% B over 9 min) and lyophilized to give (2S)-7V-(4-cyano-2- fluorophenyl)-2-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)propanamide (25.34 mg, 54.0 pmol, 20% yield) as a white solid.

[0596] Synthesis of 3-(2,6-dichloro-4-((l-(2,3-dihydro-4H-benzo[b] [l,4]oxazin-4-yl)-l-oxopropan- 2-yl)oxy)phenyl)piperidine-2, 6-dione (compound 253)

[0597] Step 1

[0598] To a solution of 3,4-dihydro-2J / -benzo[Z>][l,4]oxazine (300 mg, 2.22 mmol, 1.00 eq.) and triethylamine (620 pL, 4.45 mmol, 2.01 eq.) in dichloromethane (10 mL) was added 2- bromopropanoyl chloride (230 pL, 2.28 mmol, 1.03 eq.) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at 20 °C for 1 h. Then the reaction was quenched with water (10 mL). The mixture was extracted with ethyl acetate (2 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0-40% ethyl acetate / petroleum ether) to afford 2 -bromo- 1 -(2, 3- dihydro-4 / / -benzo[A][ l ,4]oxazin-4-yl)propan- l -one (105 mg, 377 pmol, 17 % yield) as a white solid.

[0599] Step 2

[0600] To a solution of 2-bromo-l-(2,3-dihydro-4J / -benzo[Z>][l,4]oxazin-4-yl)propan-l-one (90.0 mg, 333 pmol, 1.00 eq.) and 3-(2,6-dichloro-4-hydroxy-phenyl)-l-(2- trimethylsilylethoxymethyl)piperidine-2, 6-dione (135 mg, 334 pmol, 1.00 eq.) in dimethylformamide (3 mL) was added potassium carbonate (135 mg, 977 pmol, 2.93 eq.) and sodium iodide (5.40 mg, 36.0 pmol, 0.10 eq.). The reaction mixture was stirred at 80 °C for 2 h. The reaction was quenched with water (10 mL). The mixture was extracted with ethyl acetate (2 xlO mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0-60% ethyl acetate / petroleum ether) to afford 3-(2,6- dichloro-4-((l-(2,3-dihydro-4J7-benzo[Z>][l,4]oxazin-4-yl)-l-oxopropan-2-yl)oxy)phenyl)-l-((2- (trimethyl silyl)ethoxy)methyl)- piperidine-2, 6-dione (100 mg, 151 pmol, 45% yield) as a yellow oil.

[0601] Step 3

[0602] To a solution of 3-(2,6-dichloro-4-((l-(2,3-dihydro-4J / -benzo[Z>][l,4]oxazin-4-yl)-l-oxopropan- 2-yl)oxy)phenyl)-l-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2, 6-dione (100 mg, 168 pmol, 1.00 eq.) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL) at 0 °C. Then the reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in acetonitrile (5 mL) and ammonium hydroxide (0.5 mL) was added at 0 °C. The mixture was stirred at 20 °C for 1 h. The pH of the mixture was adjusted to 6 with formic acid at 0 °C, and then concentrated under reduced pressure. The residue was purified by C / c -HPLC (column: phenomenex luna Cl 8 150*25mm*10pm; mobile phase: [water(formic acid)-acetonitrile]; B%: 33%-63%, 10 min) and lyophilized to afford 3-(2,6-dichloro-4-((l-(2,3- dihydro-4J / -benzo[Z>][l,4]oxazin-4-yl)-l -oxopropan-2-yl)oxy)phenyl)piperidine-2, 6-dione (11.72 mg, 25.0 pmol, 15% yield) as a white solid. Synthesis of 2-(3-chloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-N-cyclohexyl-3,3,3-trifluoro-

[0603] N-methylpropanamide (compound 69)

[0604] Step 1 To a solution of ethyl 3,3,3-trifluoro-2-oxopropanoate (5.00 g, 29.4 mmol, 1.00 eq.) in dichloromethane (50 mL) was added 4-methylbenzenesulfonohydrazide (5.47 g, 29.4 mmol, 1.00 eq.). The mixture was stirred at 25 °C for 18 h. Then phosphorus oxychloride (38.2 mmol, 3.55 mL, 1.30 cv / J and pyridine (38.2 mmol, 3.08 mL, 1.30 eq.) were added, and the reaction was stirred at 25 °C for 18 h. The mixture was quenched with water (200 mL) and extracted with di chloromethane (200 mL). The organic layer was separated and washed with brine (200 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 20 / 1 to 10 / 1) to give ethyl 3,3,3-trifluoro-2-(2-tosylhydrazineylidene)propanoate (8.40 g, 23.6 mmol, 80% yield) as a white solid. Step 2

[0605] To a solution of ethyl 3,3,3-trifluoro-2-(2-tosylhydrazineylidene)propanoate (1.00 g, 2.96 mmol, 1.00 eq.) in di chloromethane (10 mL) was added triethylamine (3.25 mmol, 452 pL, 1.10 eq.). The mixture was stirred at 60 °C for 1 h. The mixture was diluted with dichloromethane (20 mL). Then it was washed with hydrochloric acid (1 M, 20 mL) and brine (3 x 20 mL), dried over sodium sulfate, and filtered to give a solution of ethyl 2-diazo-3,3,3-trifluoropropanoate in dichloromethane (0.148 M, 20 mL). The solution was used in the next step directly.

[0606] Step 3

[0607] To a solution of 3-(2-chloro-4-hydroxyphenyl)-l-((2-(trimethylsilyl)ethoxy)methyl)piperidine- 2, 6-dione (300 mg, 811 pmol, 1.00 eq.) in dichloromethane (5 mL) was added Rhodium(II) acetate dimer (35.9 mg, 81.1 pmol, 0.10 eq.). Then a solution of ethyl 2-diazo-3,3,3-trifhioropropanoate (0.148 M in dichloromethane, 11.0 mL, 2.00 eq.) was added to the mixture over a period of 1 h at 60 °C. After the addition, the mixture was stirred at 60 °C for 0.5 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to give ethyl 2-(3-chloro-4-(2,6-dioxo-l- ((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)phenoxy)-3,3,3-trifluoropropanoate (150 mg, 229 pmol, 28% yield) as a yellow oil.

[0608] Step 4

[0609] To a solution of ethyl 2-(3-chloro-4-(2,6-dioxo-l-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3- yl)phenoxy)-3,3,3-trifluoropropanoate (140 mg, 267 pmol, 1.00 eq.) in 1,2-di chloroethane (5 mL) was added hydroxyl (trimethyl)stannane (242 mg, 1.34 mmol, 5.00 eq.). The mixture was stirred at 85 °C for 16 h. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by / c -HPLC (column: YMC Triart C18 150 * 25 mm * 5 pm; mobile phase: [water (trifluoroacetic acid) - acetonitrile]; B%: 62% - 82%, 10 min). The desired fraction was collected and lyophilized to give 2 -(3 -chi oro-4 - (2,6-dioxo-l-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)phenoxy)-3,3,3-trifluoropropanoic acid (30.0 mg, 57.5 pmol, 22% yield) as a yellow solid.

[0610] Step 5

[0611] To a solution of 2-(3-chloro-4-(2,6-dioxo-l-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3- yl)phenoxy)-3,3,3-trifluoropropanoic acid (20.0 mg, 40.3 pmol, 1.00 eq.) in N,N- dimethylformamide (1 mL) were added 2-chloro-l-methyl-pyridin-l-ium iodide (12.4 mg, 48.4 pmol, 1.20 eq.) and A,A-diisopropylethylamine (121 pmol, 21.1 pL, 3.00 eq.). Then N- methylcyclohexanamine (4.56 mg, 40.3 pmol, 1.00 eq.) was added. The mixture was stirred at 70 °C for 12 h. The mixture was filtered, and the filtrate was purified by / Vc -HPLC (column: Phenomenex luna C18 150 * 25 mm * 10 pm; mobile phase: [water (formic acid) - acetonitrile]; B %: 67% - 97%, 10 min). The desired fraction was collected and lyophilized to give 2-(3-chloro- 4-(2,6-dioxo-l-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)phenoxy)-7V-cyclohexyl-3,3,3- trifluoro-7V-methylpropanamide (25.0 mg, 40.2 pmol, 99% yield) as a yellow solid.

[0612] Step 6

[0613] To a solution of 2-(3-chloro-4-(2,6-dioxo-l-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3- yl)phenoxy)-7V-cyclohexyl-3,3,3-trifluoro-7V-methylpropanamide (25.0 mg, 42.3 pmol, 1.00 eq.) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL). The mixture was stirred at 25 °C for 0.5 h. The mixture was concentrated to give 2-(3-chloro-4-(l-(hydroxymethyl)-2,6- dioxopiperidin-3-yl)phenoxy)-7V-cyclohexyl-3,3,3-trifluoro-7V-methylpropanamide trifluoroacetate (26.0 mg, crude) as a yellow oil, and it was used into next step directly.

[0614] Step 7

[0615] To a solution of 2-(3-chloro-4-(l-(hydroxymethyl)-2,6-dioxopiperidin-3-yl)phenoxy)-7V- cyclohexyl-3,3,3-trifluoro-7V-methylpropanamide trifluoroacetate (26.0 mg, crude) in acetonitrile (5 mL) was added ammonium hydroxide (250 pL, 25% purity). The mixture was stirred at 25 °C for 0.5 h. The mixture was acidified with formic acid until pH = 6, then it was filtered, and the filtrate was purified by / c / i-HPLC (column: Phenomenex luna C18 150 * 25 mm * 10 pm; mobile phase: [water (formic acid) - acetonitrile]; B%: 40% - 70%, 10 min). The desired fraction was collected and lyophilized to give 2-(3-chloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-7V-cyclohexyl- 3,3,3-trifhioro-N-methylpropanamide (10.58 mg, 22.5 pmol, 52% yield) as a white solid.

[0616] Synthesis of (2S)-2-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-N,N- dimethylpropanamide (compound 66)

[0617] Step 1 To a solution of (2S)-2-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)propanoic acid (100 mg, 289 pmol, 1.00 eq.) in N,N-dimethylformamide (1 mL) were added N,N- diisopropylethylamine (1.15 mmol, 200 pL, 3.97 eq.) and 2,4,6-tripropyl-l,3,5,2,4,6- trioxatriphosphinane 2,4,6-trioxide (368 mg, 580 pmol, 50% purity, 2.00 eq.) at 0 °C. The mixture was stirred at 25 °C for 10 min. Then dimethylamine hydrochloride (36.0 mg, 441 pmol, 1.53 eq.) was added, and the mixture was stirred at 25 °C for 16 h. The mixture was filtered. The filtrate was purified by / c / i-HPLC (column: Phenomenex luna C18 150 * 25 mm x 10 pm; mobile phase: [water (0.225% formic acid) - acetonitrile]; B%: 20% - 50%, 10 min) and lyophilized to give (2S)- 2-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-N,N-dimethylpropanamide (20.9 mg, 54.5 pmol, 19% yield) as a white solid.

[0618] Synthesis of (S)-2-(3,5-dichloro-4-((S)-2,6-dioxopiperidin-3-yl)phenoxy)-N,N- dimethylpropanamide (compound 27) and (S)-2-(3,5-dichloro-4-((R)-2,6-dioxopiperidin-3- yl)phenoxy)-N,N-dimethylpropanamide (compound 131)

[0619] Compound 66 Compound 27 Compound 131

[0620] (25 -2-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-7V,7V-dimethylpropanamide (100 mg, 268 pmol, 1.00 eq.) was separated by Chiral SFC (column: DAICEL CHIRALPAK IC(250 mm x 30 mm, 10 pm); mobile phase: [IPA / ACN]; B%: 50%-50%, 3.5 min) to give two peaks. Peak 1 was purified by / c / i-HPLC (column: Phenomenex luna Cl 8 150 x 25 mm x 10 pm; mobile phase: [water(0.225% formic acid)-acetonitrile]; B%: 20%-50%, 10 min) and lyophilized to give (5)-2- (3,5-dichloro-4-((5)-2,6-dioxopiperidin-3-yl)phenoxy)-A,A-dimethylpropanamide (Compound 27, 22.5 mg, 59.7 pmol, 22% yield) as a white solid.

[0621] Peak 2 was re-purified by Chiral SFC (column: DAICEL CHIRALPAK IC(250mm x 30mm, 10pm); mobile phase: [IPA / ACN]; B%: 50%-50%, 6.5 min) followed by / c / i-HPLC (column: Phenomenex luna Cl 8 150 x 25 mm x 10 pm; mobile phase: [water(0.225% formic acid)- acetonitrile]; B%: 28%-48%, 10 min) and lyophilized to give (S)-2-(3,5-dichloro-4-((7?)-2,6- dioxopiperidin-3-yl)phenoxy)-7V,7V-dimethylpropanamide (Compound 131, 21.8 mg, 55.0 pmol, 21% yield) as a white solid.

[0622] Synthesis of (2S)-2-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-N-((lr,4S)-4- hydroxycyclohexyl)propenamide (compound 38)

[0623] Compound 38

[0624] To a solution of (25)-2-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)propanoic acid (1.00 g, 2.89 mmol, 1.00 eq.) and 7V,7V-diisopropylethylamine (1.01 g, 7.80 mmol, 3.21 eq.) in dimethylformamide (15 mL) was added 2,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphinane 2,4,6- trioxide (1.36 mL, 50% purity, 3.10 eq.) at 0 °C. The reaction mixture was stirred at 25 °C for 15 min. Then 4-aminocyclohexanol (850 mg, 7.38 mmol, 3.08 eq.) was added, and the reaction was stirred at 50 °C for 16 h. The reaction mixture was diluted with ethyl acetate (20 mL) and water (30 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by C / c -HPLC (column: Phenomenex luna C18 150x25mmxl0 pm; mobile phase: [water(formic acid)- acetonitrile]; B%: 20%-50%, 10 min) and lyophilized to afford (25)-2-(3,5-dichloro-4-(2,6- dioxopiperidin-3-yl)phenoxy)-7V-((lr,4 )-4-hydroxycyclohexyl)propanamide (284.5 mg, 0.64 mmol, 22% yield) as a white solid. Synthesis of (S)-2-(3,5-dichloro-4-((S)-2,6-dioxopiperidin-3-yl)phenoxy)-N-((lr,4S)-4- hydroxycyclohexyl)propanamide (compound 16) and (S)-2-(3,5-dichloro-4-((R)-2,6- dioxopiperidin-3-yl)phenoxy)-N-((lr,4S)-4-hydroxycyclohexyl)propanamide (compound

[0625] Compound 38 Compound 106 Compound 16

[0626] (25)-2-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-7V-((lr,45)-4- hydroxycyclohexyl)propanamide (170 mg, 383 pmol, 1.00 eq.) was separated by Chiral SFC (column: DAICEL CHIRALCEL OJ(250mm x 30mm, 10pm); mobile phase: [carbon dioxide - isopropanol]; B%:30%, isocratic elution mode) to give two peaks. Peak 1 was purified by E / c / -HPLC (column: Phenomenex luna Cl 8 150 x 25mm x 10pm; mobile phase: [water(formic acid) - acetonitrile]; gradient: 15%-45% B over 10 min) and lyophilized to afford (5)-2-(3,5-dichloro-4-((7?)-2,6-dioxopiperidin-3-yl)phenoxy)-7V-((lr,45)-4- hydroxycyclohexyl)propanamide (Compound 106, 55.9 mg, 125 pmol, 33% yield) as a white solid. Peak 2 was purified by re / ?-HPLC (column: Phenomenex luna Cl 8 150 x 25mm x 10pm; mobile phase: [water(formic acid) - acetonitrile]; gradient: 15%-45% B over 10 min) and lyophilized to afford (S)-2-(3,5-dichloro-4-((5)-2,6-dioxopiperidin-3-yl)phenoxy)-7V-((lr,45)-4- hydroxycyclohexyl)propanamide (Compound 16, 57.45 mg, 128 pmol, 33% yield) as a white solid. Synthesis of (2S)-2-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-N-(2,6-difluoro-3- hydroxyphenyl)propanamide (compound 176)

[0627] Step 1 To a solution of 2, 6-difluoro-3 -methoxy-aniline (200 mg, 1.26 mmol, 1.00 eq.) in dichloromethane (10 mL) was added tribromoborane (1.89 g, 7.54 mmol, 6.00 eq.) dropwise at 0 °C. The solution was stirred at 0 °C for 1 h, and then warmed to 20 °C and stirred for 2 h. The solution was poured into ice water (20 mL) very slowly and extracted with dichloromethane (2 x 20 mL). The water layer was collected and adjusted to pH = 8-9 with ammonium hydroxide. The mixture was extracted with ethyl acetate (3 x 20 mL), and the combined organic layers were washed with brine (40 mL), dried over anhydrous 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 of 0-20% ethyl acetate / petroleum ether gradient @ 20 mL / min) to give 3-amino- 2,4-difluorophenol (200 mg, crude) as a white solid. Step 2

[0628] To a solution of 3-amino-2,4-difluorophenol (200 mg, 1.38 mmol, 1.00 eq.) in di chloromethane (5 mL) were added tert-butylchlorodimethylsilane (623 mg, 4.13 mmol, 3.00 eq.), triethylamine (418 mg, 4.13 mmol, 3.00 eq.) and 7V,7V-dimethylpyridin-4-amine (16.8 mg, 138 / / mol, 0.10 eq.) in one portion at 0 °C. The solution was stirred at 20 °C for 6 h. The mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, eluent of 0~5% ethyl acetate / petroleum ether gradient @ 20 mL / min) to give 3-((tert-butyldimethylsilyl)oxy)-2,6-difluoroaniline (300 mg, 1.16 mmol, 83% yield) as a colourless oil.

[0629] Step 3

[0630] To a solution of 3-((tert-butyldimethylsilyl)oxy)-2,6-difluoroaniline (213 mg, 823 / / mol, 2.00 eq.) and diisopropylethylamine (159 mg, 1.23 mmol, 3.00 eq.) in dimethyl formamide (2 mL) was added a solution of (25)-2-[3,5-dichloro-4-(2,6-dioxo-3-piperidyl)phenoxy]propanoyl chloride (150 mg, 411 mol, 1.00 eq.) in dichloromethane (2 mL) dropwise at 0 °C. The solution was stirred at 20 °C for 1 h. The mixture was poured into water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by C / c / i-HPLC (column: Welch Xtimate Cl 8 150 mm x 25 mm x 5 / / m; mobile phase: [water (hydrochloric acid)-acetonitrile]; gradient: 58%-88% B over 9 min) then concentrated under reduced pressure to give (25)- / V-(3-((tert-butyldimethylsilyl)oxy)-2,6-difluorophenyl)-2-(3,5- dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)propanamide (60.0 mg, 102 / / mol, 24% yield) as a white solid.

[0631] Step 4

[0632] To a solution of (25)-W(3-((tert-butyldimethylsilyl)oxy)-2,6-difluorophenyl)-2-(3,5-dichloro-4- (2,6-dioxo-piperidin-3-yl)phenoxy)propanamide (55.0 mg, 93.6 / / mol, 1.00 eq.) in acetonitrile (1 mL) was added hydrochloric acid (3 mL, 36% purity) dropwise at 20 °C. The solution was stirred at 20 °C for 12 h. The mixture was poured into water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by C / c / i-HPLC (column: Phenomenex luna C18 150 mm x 25 mm x 10 / / m; mobile phase: [water (hydrochloric acid)-acetonitrile]; gradient: 20%-50% B over 10 min) then lyophilized to give (25)-2-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-7V-(2,6-difluoro-3- hydroxyphenyl)propanamide (35.0 mg, 73.2 / / mol, 78% yield) as a white solid. Synthesis of 3-(2,6-dichloro-4-(l-(3-methyl-l,2,4-oxadiazol-5- yl)cyclopropoxy)phenyl)piperidine-2, 6-dione (compound 315)

[0633] Step 1 To a solution of l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclopropane-l-carboxylic acid (120 mg, 302 pmol, 1.00 eq.) in dimethylformamide (2.5 mL) were added l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (69.0 mg, 360 pmol, 1.19 eq.) and 1- Hydroxybenzotriazole hydrate (49.0 mg, 363 pmol, 1.20 eq.). The mixture was stirred at 20 °C for 1 h. Then / f-hydroxyacetimidamide (34.0 mg, 459 pmol, 1.52 eq.) was added, and the mixture was stirred at 100 °C for 12 h. The reaction mixture was diluted with ethyl acetate (10 mL) and water (10 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Dimethylformamide (1 mL) was added to the residue. The mixture was filtered over filter paper, and the remaining solid was washed with methanol (3 x 3 mL) and acetonitrile (3 x 3 mL). The solid was dissolved in water and lyophilized to afford 3-(2,6-dichloro-4-(l-(3-methyl-l,2,4-oxadiazol-5-yl)cyclopropoxy)phenyl)piperidine- 2,6-dione (7.05 mg, 16.9 pmol, 5.61% yield) as a white solid.

[0634] Synthesis of 3-(4-(l-(l,2,4-oxadiazol-3-yl)cyclopropoxy)-2,6-dichlorophenyl)piperidine-2,6- dione (compound 323)

[0635] Step 1 To a solution of l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclopropane-l-carboxylic acid (500 mg, 1.40 mmol, 1.00 eq.) in A( A -di methyl form am ide (15 mL) were added triethylamine (1.41 g, 14.0 mmol, 10.0 eq.) and 2-chloro-l-methyl-pyridin-l-ium iodide (534 mg, 2.09 mmol, 1.50 eq.) at 0°C. The reaction was stirred at 20 °C for 0.5 h. Then ammonium chloride (373 mg, 6.98 mmol, 5.00 eq.) was added, and the reaction was stirred at 80 °C for 3 h. Then 2-chloro-l- methyl-pyridin-l-ium iodide (356 mg, 1.40 mmol, 1.00 eq.) was added at 0 °C. The reaction was stirred at 20 °C for 0.5 h. Then ammonium chloride (373 mg, 6.98 mmol, 5.00 eq.) was added, and the mixture was stirred at 80 °C for 16 h. (The reaction was carried out with 6 batches in parallel.) All the reaction mixtures were combined and diluted with water (100 mL), then extracted with ethyl acetate (3 x 100 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 (5: 1), filtered and concentrated under reduced pressure to give l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclopropane-l-carboxamide (1.48 g, 3.94 mmol, 47 % yield) as a yellow solid.

[0636] Step 2 To a solution of l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclopropane-l- carboxamide (1.28 g, 3.58 mmol, 1.00 eq.) in dichloromethane (100 mL) was added methoxycarbonyl-(triethylammonio)sulfonyl-azanide (5.12 g, 21.5 mmol, 6.00 eq.). The reaction mixture was stirred at 40 °C for 2 h. Then methoxycarbonyl-(triethylammonio)sulfonyl-azanide (3.42 g, 14.3 mmol, 4.00 eq.) was added and stirred at 40 °C for 16 h. The reaction mixture was washed with water (50 mL) and brine (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: Phenomenex luna C18 150 * 25 mm * 10 pm; mobile phase: [water (formic acid) - acetonitrile]; B%: 32% - 62%, 10 min). The desired fraction was collected and lyophilized to give l-(3,5- dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclopropane-l-carbonitrile (520 mg, 1.49 mmol, 41% yield) as a white solid.

[0637] Step 3

[0638] To a solution of l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclopropane-l-carbonitrile (400 mg, 1.18 mmol, 1.00 eq.) in ethanol (15 mL) were added hydroxylamine hydrochloride (163 mg, 2.36 mmol, 2.00 eq.) and triethylamine (238 mg, 2.36 mmol, 2.00 eq.). The mixture was stirred at 90 °C for 0.5 h. The resulting precipitate was filtered and washed with ethanol (10 mL). The filtrate was concentrated under reduced pressure to give a residue. The residue and the precipitate were combined and purified by reversed phase column chromatography (Cl 8, 40 g; condition: water / acetonitrile = 1 / 0 to 0 / 1, 0.1% formic acid) and lyophilized to give l-(3,5-dichloro-4-(2,6- dioxopiperi din-3 -yl)phenoxy)-7V-hydroxycy cl opropane-l-carboximidamide (230 mg) as a yellow solid.

[0639] Step 4

[0640] To a solution of l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-7V -hydroxy cyclopropane-1- carboximidamide (190 mg, 510 pmol, 1.00 eq.) in trimethoxymethane (3 mL) and tetrahydrofuran (3 mL) was added boron trifluoride etherate (787 mg, 2.55 mmol, 46% purity, 5.00 eq.) at 0 °C under nitrogen atmosphere. After stirring at 25 °C for 4 h, it was quenched with tri ethylamine (15.0 eq.) at 0 °C, then diluted with water (15 mL) and extracted with ethyl acetate (20 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Isopropyl ether (10 mL) was added to the residue, and a large amount of solid formed. The solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was triturated with isopropyl ether (10 mL), and the solid was collected by filtration. Then the solid was dissolved in acetonitrile (3 mL) and concentrated under reduced pressure. The residue was triturated with isopropyl ether (10 mL), the solid was collected and concentrated under reduced pressure to give 3-(4-(l-(l,2,4-oxadiazol-3-yl)cyclopropoxy)-2,6- dichlorophenyl)piperidine-2, 6-dione (122.72 mg, 311 pmol, 61% yield) as a white solid.

[0641] Synthesis of 3-(2,6-dichloro-4-(l-(5-(l,l-difluoroethyl)-l,3,4-oxadiazol-2- yl)cyclopropoxy)phenyl)piperidine-2, 6-dione (Compound 324)

[0642] Step 1

[0643] A solution of tert-butyl 2-(l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclopropane-l- carbonyl)hydrazine-l -carboxylate (see Compound 338) (400 mg, 847 pmol, 1.00 eq.) in hydrogen chloride / ethyl acetate (2 M, 16 mL) was stirred at 20 °C for 2.5 h. The reaction mixture was concentrated in vacuo to give l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclopropane- 1 -carbohydrazide hydrochloride (320 mg, 705 pmol, 83% yield) as a white solid.

[0644] Step 2

[0645] (3 batches.) To a solution of 2,2-difluoropropanoic acid (121 mg, 1.10 mmol, 3.00 eq.) and l-(3,5- dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclopropane-l-carbohydrazide hydrochloride (150 mg, 367 pmol, 1.00 eq.) in A -di methyl form am ide (6 mL) were added N-(3- dimethylaminopropyl)-7V-ethylcarbodiimide (105 mg, 550 pmol, 1.50 eq.) and benzotriazol-l-ol (74.4 mg, 551 pmol, 1.50 eq.). The reaction was stirred at 20 °C for 1 h. The combined 3 batches were diluted with water (20 mL) and extracted with ethyl acetate (2z20 mL). Combined extracts were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, eluent of 0-80% ethyl acetate / petroleum ether gradient @ 30 mL / min). The residue was diluted with ethyl acetate (20 mL) and washed with water (3 x 20 mL). Then it was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give l-(3,5-dichloro-4- (2,6-dioxopiperidin-3-yl)phenoxy)-7V-(2,2-difluoropropanoyl)cyclopropane-l-carbohydrazide (180 mg, 310 pmol, 84% yield, 80% purity) as a white solid.

[0646] Step 3

[0647] To a solution of l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-7V-(2,2- difluoropropanoyl)cyclopropane-l -carbohydrazide (160 mg, 345 pmol, 1.00 eq.) in dichloromethane (10 mL) were added pyridine (82.0 mg, 1.03 mmol, 3.00 eq.) and trifluoromethanesulfonic anhydride (146 mg, 516 pmol, 1.50 eq.) at -15 °C. The reaction was stirred at 15 °C for 12 h. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 20 mL). Combined extracts were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by C / c -HPLC (column: YMC-Actus Triart C18 150 mm x 30 mm x7 pm; mobile phase: [water (formic acid) - acetonitrile]; gradient:43%-73% B over 10 min). The desired fraction was collected and lyophilized to give 3-(2,6-dichloro-4-(l-(5-(l,l-difhioroethyl)-l,3,4-oxadiazol-2- yl)cyclopropoxy)phenyl)piperidine-2, 6-dione (80.0 mg, 175 pmol, 51% yield) as a white solid.

[0648] Synthesis of 3-(4-(l-(l,2,4-oxadiazol-5-yl)cyclopropoxy)-2,6-dichlorophenyl)piperidine-2,6- dione (compound 328)

[0649] Step 1

[0650] To a solution of l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclopropane-l-carboxylic acid (1.00 g, 2.79 mmol, 1.00 eq.) in 7V,7V-dimethylformamide (12 mL) were added 2-chloro-l- methyl-pyridin-l-ium iodide (1.07 g, 4.19 mmol, 1.50 eq.) and triethylamine (2.84 g, 28.0 mmol, 10.0 eq.) at 20 °C. The reaction mixture was stirred at 20 °C for 0.5 h. Then ammonium chloride (747 mg, 14.0 mmol, 5.00 eq.) was added. The reaction mixture was stirred at 80 °C for 2 h. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with water (2 x 20 mL) and brine (40 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~100%Ethyl acetate / Petroleum ether gradient @ 40 mL / min). Then the product was further purified by reversed phase column chromatography (0.1% formic acid condition). The desired fraction was collected and concentrated under reduced pressure to give l-(3,5-dichloro-4-(2,6-dioxopiperidin-3- yl)phenoxy)cyclopropane-l -carboxamide (410 mg, 1.09 mmol, 39% yield) as a white solid.

[0651] Step 2

[0652] A solution of l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclopropane-l-carboxamide (200 mg, 560 pmol, 1.00 eq.) in 7V,7V-Dimethylformamide dimethyl acetal (3 mL) was stirred at 100 °C for 0.5 h. The resulting precipitate was filtered, washed with ethyl acetate (20 mL), and dried under vacuum to give l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-7V- ((dimethylamino)methylene)cyclopropane-l -carboxamide (150 mg, 346 pmol, 62% yield) as a white solid. It was used directly in the next step.

[0653] Step 3

[0654] To a solution of l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-7V- ((dimethylamino)methylene) cyclopropane-l-carboxamide (140 mg, 340 pmol, 1.00 eq.) in dioxane (4 mL) and acetic acid (0.4 mL) was added hydroxylamine hydrochloride (94.4 mg, 1.36 mmol, 4.00 eq.). The mixture was stirred at 90 °C for 16 h. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with water (2 x 20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: Welch Xtimate Cl 8 150 * 25 mm * 5 pm; mobile phase: [water (formic acid) - acetonitrile]; gradient: 28% - 58% B over 10 min). The desired fractions were collected and lyophilized under reduced pressure to give 3-(4-(l-(l,2,4-oxadiazol-5- yl)cy cl opropoxy)-2,6-di chi orophenyl)piperidine-2, 6-dione (24.45 mg, 60.1 pmol, 18% yield) was obtained as a white solid. Synthesis of l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-N-(2-

[0655] (difluoromethyl)pyridin-3-yl)cyclopropane-l-carboxamide (compound 333)

[0656] Step 1

[0657] To a solution of l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclopropane-l-carboxylic acid (208 mg, 582 pmol, 0.700 eq.) in dimethylformamide (3.00 mL) were added 2-chloro-l- methylpyridiniumiodide (263 mg, 1.03 mmol, 1.24 eq.) and A-diisopropylethylamine (326 mg, 2.52 mmol, 439 pL, 3.03 eq.). The mixture was stirred at 20 °C for 0.5 h. 2- (difluoromethyl)pyri din-3 -amine (120 mg, 832 pmol, 1.00 eq.) was added, and the mixture was stirred at 80 °C for 2 h. The mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 ^ 10 mL). The combined organic layers were washed with brine (20 mL), and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by C / c / -HPLC (column: Phenomenex luna Cl 8 150*25mm* 10um;mobile phase: [water(formic acid)- acetonitrile];gradient:30%-60% B over 9 min) and lyophilized to afford l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-7V-(2-(difluoromethyl)pyridin-3- yl)cyclopropane-l -carboxamide (197 mg, 402.72 pmol, 48% yield) as an off-white solid.

[0658] Synthesis of 3-(2,6-dichloro-4-(l-(4-methyloxazol-2-yl)cyclopropoxy)phenyl)piperidine-2,6- dione (compound 337) Step 1

[0659] To a solution of l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclopropane-l-carboxylic acid (200 mg, 558 pmol, 1.00 eq.) in A, / f-di methyl formamide (3 mL) were added 2-chloro-l- methyl-pyridin-l-ium iodide (214 mg, 838 pmol, 1.50 eq.) and MA-diisopropylethylamine (1.72 mmol, 0.3 mL, 3.08 eq.) at 20 °C. The reaction mixture was stirred at 20 °C for 0.5 h, then 2- aminopropan-l-ol (84.0 mg, 1.12 mmol, 2.00 eq.) was added. The reaction mixture was stirred at 20 °C for 1 h. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (15 mL). The organic layer was washed with water (2 x 20 mL) and brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO ®; 4 g Sepa Flash ® Silica Flash Column, eluent of 0-80% ethyl acetate / petroleum ether gradient @ 18 mL / min) to give l-(3,5-dichloro-4-(2,6-dioxopiperidin-3- yl)phenoxy)-N-(l-hydroxypropan-2-yl)cyclopropane-l -carboxamide (180 mg, 420 pmol, 75% yield) as a white solid.

[0660] Step 2

[0661] To a solution of l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-N-(l-hydroxypropan-2- yl)cyclo-propane-l -carboxamide (170 mg, 409 pmol, 1.00 eq.) in dichloromethane (5 mL) was added 3-oxo-lX5-benzo[d][l,2]iodaoxole-l,l,l(3H)-triyl triacetate (208 mg, 490 pmol, 1.20 eq.) at 20 °C. The reaction mixture was stirred at 20 °C for 2 h. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (15 mL). The organic layer was washed with water (2 x 20 mL) and brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO ®; 4 g Sepa Flash ® Silica Flash Column, eluent of 0-100% ethyl acetate / petroleum ether gradient @ 18 mL / min) to give l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-N-(l-oxopropan-2-yl)cyclopropane-l- carboxamide (115 mg, 250 pmol, 61% yield) as a white solid.

[0662] Step 3

[0663] A solution of l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-N-(l-oxopropan-2- yl)cyclopropane-l -carboxamide (105 mg, 152 pmol, 1.00 eq.) in phosphoryl trichloride (3 mL) was stirred at 100 °C under nitrogen atmosphere for 1 h. The reaction mixture was cooled to 20 °C then poured into water (10 mL) and stirred at 20 °C for 3 min. The mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (15 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: Phenomenex luna C 18 150 mm x 25 mm x 10 pm; mobile phase: [water (formic acid) - acetonitrile]; gradient: 35%-65% B over 10 min) and lyophilized to give 3-(2,6- dichloro-4-(l-(4-methyloxazol-2-yl)cyclopropoxy)phenyl)piperidine-2, 6-dione (28.1 mg, 69.8 pmol, 34% yield) as a white solid.

[0664] Synthesis of 3-(2,6-dichloro-4-(l-(5-(trifluoromethyl)-l,3,4-oxadiazol-2-yl)cyclopropoxy) phenyl)piperidine-2, 6-dione (compound 338)

[0665] Step 1

[0666] To a solution of l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclopropane-l-carboxylic acid (500 mg, 1.40 mmol, 1.00 eq.) in dimethyl formamide (5 mL) were added tert-butyl hydrazine carboxylate (221 mg, 1.68 mmol, 1.20 eq.), 2-chloro-l-methylpyridin-l-ium;iodide (392 mg, 1.54 mmol, 1.10 eq.) and diisopropylethylamine (541 mg, 4.19 mmol, 3.00 eq.). The mixture was stirred at 20 °C for 1 h, then it was diluted with water (75 mL) and extracted with ethyl acetate (3 x 25 mL). The combined organic layers were washed with water (35 mL) and brine (35 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl 2- (l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclopropane-l-carbonyl)hydrazine-l- carboxylate (705 mg, crude) as a yellow solid.

[0667] Step 2

[0668] To a solution of tert-butyl 2-(l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclopropane- l-carbonyl)hydrazine-l -carboxylate (705 mg, 1.49 mmol, 1.00 eq.) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL). The mixture was stirred at 20 °C for 4 h, then it was concentrated under reduced pressure. The residue was purified by reversed phase column chromatography (Cl 8, 80 g; condition: water / acetonitrile = 1 / 0 to 0 / 1, 0.1% formic acid) and lyophilized to give l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclopropane-l- carbohydrazide (240 mg, 612 pmol, 37% yield) as a white solid.

[0669] Step 3

[0670] To a solution of l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclopropane-l- carbohydrazide (240 mg, 644 pmol, 1.00 eq.) and N,N-dimethylpyridin-4-amine (7.88 mg, 64.4 pmol, 0.10 eq.) in di chloromethane (5 mL) was added tri ethylamine (97.8 mg, 967 pmol, 1.50 eq.) dropwise at 0 °C. Then the mixture was warmed to 20 °C, and trifluoroacetic anhydride (203 mg, 967 pmol, 1.50 eq.) was added dropwise. The mixture was stirred at 20 °C for 1 h. The mixture was poured into water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: Waters Xbridge 18 150 mm x 25 mm x 5 pm; mobile phase: [water (ammonium bicarbonate) - acetonitrile]; gradient: 38%-68% B over 10 min) then lyophilized to give 3-(2,6-dichloro-4-(l-(5- (trifluoromethyl)-l,3,4-oxadiazol-2-yl)cyclopropoxy)phenyl) piperidine-2, 6-dione (100 mg, 220 pmol, 34% yield) as a white solid.

[0671] Synthesis of 3-(2,6-dichloro-4-(l-(5-ethyl-l,3,4-oxadiazol-2-yl)cyclopropoxy)phenyl) piperidine-2, 6-dione (compound 339)

[0672] Step 1

[0673] To a solution of l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclopropane-l-carboxylic acid (200 mg, 558 pmol, 1.00 eq.) in AW-di methyl form am ide (5 mL) were added N,N- diisopropylethylamine (217 mg, 1.68 mmol, 3.00 eq.), 2-chloro-l-methyl-pyridin-l-ium iodide (214 mg, 838 pmol, 1.50 eq.). The mixture was stirred at 20 °C for 0.5 h. Then propionohydrazide (148 mg, 1.68 mmol, 3.00 eq.) was added, and the reaction was stirred at 80 °C for 1 h. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with water (2 x 20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 5 g SepaFlash® Silica Flash Column, Eluent of 0-70% Ethyl acetate / Petr oleum ether gradient @ 25 mL / min) to give l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-N' -propionylcyclopropane- 1 -carbohydrazide (250 mg, 525 pmol, 94% yield, 90% purity) as a white solid.

[0674] Step 2

[0675] A solution of l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-N'-propionylcyclopropane-l- carbohydrazide (200 mg, 467 pmol, 1.00 eq.) in phosphorus oxychloride (5 mL) was stirred at 100 °C for 2 h. The mixture was concentrated to give a residue. The residue was diluted with ethyl acetate (20 mL) and washed with water (20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: Welch Xtimate Cl 8 150 * 25 mm * 5 pm; mobile phase: [water (formic acid) - acetonitrile]; gradient: 28% - 58% B over 10 min). The desired fraction was collected and lyophilized under vacuum. The crude product was further purified by slurrying with water (20 mL) at 100 °C. The mixture was filtered, and the solid was dried under vacuum to give 3-(2,6- dichloro-4-(l-(5-ethyl-l,3,4-oxadiazol-2-yl)cyclopropoxy) phenyl)piperidine-2, 6-dione (54.13 mg, 128 pmol, 27% yield) as a white solid.

[0676] Synthesis of (S)-3-(4-(l-(l,3,4-oxadiazol-2-yl)cyclopropoxy)-2,6-dichlorophenyl)piperidine- 2, 6-dione (compound 340) and (R)-3-(4-(l-(l,3,4-oxadiazol-2-yl)cyclopropoxy)-2, 6- dichlorophenyl)piperidine-2, 6-dione (compound 341)

[0677] Compound 340 Compound 341

[0678] 3-(4-(l-(l, 3, 4-oxadiazol-2-yl)cyclopropoxy)-2,6-dichlorophenyl)piperidine-2, 6-dione (420 mg, 1.1 mmol) was purified by prep-HPLC (DAICEL CHIRALPAK IC (250 mm * 30 mm, 10 um); mobile phase : [carbon dioxide - isopropanokacetonitrile = 4: 1]; B%:40%, isocratic elution mode) and lyophilized to afford Compound 341 (R)-3-(4-(l-(l,3,4-oxadiazol-2-yl)cyclopropoxy)-2,6- dichlorophenyl)piperidine-2, 6-dione (137.16 mg, 351 pmol, 32% yield, 98% purity, Rt 1.293 min) as a white solid, and Compound 340 (S)-3-(4-(l-(l,3,4-oxadiazol-2-yl)cyclopropoxy)-2,6- dichlorophenyl)piperidine-2, 6-dione (165.36 mg, 424 pmol, 38% yield, 98% purity, Rt 1.646 min) as a white solid.

[0679] Note: The absolute configuration was assigned arbitrarily.

[0680] Synthesis of 3-(2,6-dichloro-4-(l-(5-(2,2,2-trifluoroethyl)-l,2,4-oxadiazol-3- yl)cyclopropoxy)phenyl)piperidine-2, 6-dione (compound 343)

[0681] Step 1

[0682] To a solution of 3,3,3-trifluoropropanoic acid (51.6 mg, 403 pmol, 35.6 pL, 1.50 eq.) in butyl acetate (1.00 mL) was added N-butyl phosphate anhydride (581 mg, 806 pmol, 50% purity, 3.00 eq.). The reaction was stirred at 25 °C for 1.5 h, then (Z)-l-(3,5-dichloro-4-(2,6-dioxopiperidin-3- yl)phenoxy)-7V-hydroxycyclopropane-l-carboximidamide (0.100 g, 269 pmol, 1.00 eq.) was added, and the reaction was stirred at 120 °C for 12 h. The mixture was extracted with ethyl acetate (20 mL), washed with water (10 mL) and brine (10 mL). The organic phase was concentrated under reduced pressure to give a residue. The residue was purified by C / c -HPLC (column: Phenomenex luna Cl 8 150*25mm*10um; mobile phase: [water (0.225% formic acid)- acetonitrile]; gradient: 31%-61% B over 10.0 min) and lyophilized to afford Compound 343 3- (2,6-dichloro-4-(l-(5-(2,2,2-trifluoroethyl)-l,2,4-oxadiazol-3- yl)cyclopropoxy)phenyl)piperidine-2, 6-dione (44.28 mg, 94.43 pmol, 35.15% yield, 99% purity) as a white solid. Synthesis of 3-(4-(l-(l,2,4-thiadiazol-3-yl)cyclopropoxy)-2,6-dichlorophenyl)piperidine-2,6- dione (compound 345)

[0683] Step 1. To a solution of l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclopropane-l- carboxylic acid (2.00 g, 5.58 mmol, 1.00 eq.) in dimethylformamide (20.0 mL) were added ammonium chloride (1.79 g, 33.5 mmol, 6.00 eq.), l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (1.61 g, 8.38 mmol, 1.50 eq.), lJ / -benzo[t ][l,2,3]triazol-l-ol (1.13 g, 8.38 mmol, 1.50 eq.) and 7V,7V-diisopropylethylamine (2.17 g, 16.8 mmol, 2.92 mL, 3.00 eq.) at 0 °C. The reaction mixture was stirred at 20 °C for 2 h. The mixture was diluted with water (250 mL) and extracted with ethyl acetate (3 x 90 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclopropane-l- carboxamide (1.98 g, 5.54 mmol, 99.2% yield) as a white solid.

[0684] Step 2. To a solution of l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclopropane-l- carboxamide (1.00 g, 2.80 mmol, 1.00 eq.) in toluene (45.0 mL) and dioxane (15.0 mL) were added potassium carbonate (348 mg, 2.52 mmol, 0.900 eq.) and carb onochlori die hypochlorous thioanhydride (1.47 g, 11.2 mmol, 931 pL, 4.00 eq.). The reaction was stirred at 100 °C for 12 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed phase chromatography (C18, 120 g; condition: water / acetonitrile = 100:0 to 0: 100, 0.1% formic acid) and lyophilized to afford 3-(2,6-dichloro-4-(l-(2-oxo-l,3,4-oxathiazol-5- yl)cyclopropoxy)phenyl)piperidine-2, 6-dione (440 mg, 1.06 mmol, 37.9% yield) as a brown solid. Step 3. A mixture of 3-(2,6-dichloro-4-(l-(2-oxo-l,3,4-oxathiazol-5- yl)cyclopropoxy)phenyl)piperidine-2, 6-dione (100 mg, 241 pmol, 1.00 eq.) in ethyl carbonocyanidate (2.00 mL) was stirred at 160 °C for 2 h by microwave. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed phase chromatography (C18, 40 g; condition: water / acetonitrile = 100:0 to 0: 100, 0.1% formic acid) and lyophilized to afford ethyl 3-(l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclopropyl)- l,2,4-thiadiazole-5-carboxylate (100 mg, 213 pmol, 88.3% yield) as a yellow solid.

[0685] Step 4. To a solution of ethyl 3-(l-(3,5-dichloro-4-(2,6-dioxopiperidin-3- yl)phenoxy)cyclopropyl)-l,2,4-thiadiazole-5-carboxylate (90.0 mg, 191 pmol, 1.00 eq.) in dimethylsulfoxide (2.00 mL) was added lithium chloride (81.1 mg, 1.91 mmol, 39.2 pL, 10.0 eq.). The reaction was stirred at 140 °C for 3 h. The mixture was filtered, and the filtrate was purified by / c / i-HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (0.225% formic acid) - acetonitrile]; gradient:28%-58% B over 9.0 min) and lyophilized to afford Compound 345 3-(4-(l-(l,2,4-thiadiazol-3-yl)cyclopropoxy)-2,6-dichlorophenyl)piperidine-2,6- dione (22.59 mg, 56.15 pmol, 29.4% yield, 99% purity) as an off-white solid.

[0686] Synthesis of 3-(2,6-dichloro-4-(l-(5-ethyloxazol-2-yl)cyclopropoxy)phenyl)piperidine-2,6- dione (compound 347)

[0687] Step 1. To a solution of tert-butyl A-ami nocarb am ate (2.00 g, 15.1 mmol, 1.00 eq.) in dichloromethane (30.0 mL) were added triethylamine (4.59 g, 45.4 mmol, 6.32 mL, 3.00 eq.) and 3,3,3-trifluoropropanoyl chloride (3.33 g, 22.7 mmol, 1.50 eq.) at 0 °C. The reaction was stirred at 25 °C for 2 h, then it was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, petroleum ether / ethyl acetate=l / O to 3 / 1) to afford tertbutyl 2-(3,3,3-trifluoropropanoyl)hydrazine-l-carboxylate (1.40 g, 5.78 mmol, 38.2% yield) as a white solid.

[0688] Step 2. To a solution of tert-butyl A-(3,3,3-trifluoropropanoylamino)carbamate (1.00 g, 4.13 mmol, 1.00 eq.) in dioxane (20.0 mL) was added 2,4-bis(4-Methoxyphenyl)-l,3-dithia-2,4- diphosphetane-2,4-disulfide (1.50 g, 3.72 mmol, 0.900 eq.). The reaction was stirred at 70 °C for 2 h, then it was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, petroleum ether / ethyl acetate=l / O to 3 / 1) to afford tert-butyl 2- (3,3,3-trifluoropropanethioyl)hydrazine-l-carboxylate (400 mg, 1.55 mmol, 37.5% yield) as colourless oil.

[0689] Step 3. A mixture of tert-butyl 2-(3,3,3-trifluoropropanethioyl)hydrazine-l-carboxylate (200 mg, 774 pmol, 1.00 eq.) in hydrochloric acid in dioxane (2 M, 3.00 mL) was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to afford 3,3,3- trifluoropropanethiohydrazide (150 mg, crude, hydrochloride) as a white solid.

[0690] Step 4. To a solution of l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclopropane-l- carboxylic acid (60.0 mg, 167 pmol, 1.00 eq.) and 3,3,3-trifluoropropanethiohydrazide (130 mg, 670 pmol, 4.00 eq., hydrochloride) in N, A-di methyl form am ide (2.00 mL) were added N- (chloro(dimethylamino)methylene)-A-methyl methanaminium hexafluorophosphate(V) (70.5 mg, 251 pmol, 1.50 eq.) and I -methyl - I / / -imidazole (68.7 mg, 837 pmol, 66.7 pL, 5.00 eq.). The mixture was stirred at 50 °C for 12 h. Water (20 mL) was added, and the resulting mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by / Vc -HPLC (column: Phenomenex luna Cl 8 150*25mm*10um; mobile phase: [water (0.225% formic acid) - acetonitrile]; gradient: 30%-60% B over 9.0 min) and lyophilized to afford 3-(2,6-dichloro-4-(l-(5-ethyloxazol-2- yl)cyclopropoxy)phenyl)piperidine-2, 6-dione (50.0 mg, 100 pmol, 59.9% yield) as a white solid.

[0691] Step 5. To a solution of 3-(2,6-dichloro-4-(l-(5-ethyloxazol-2- yl)cyclopropoxy)phenyl)piperidine-2, 6-dione (40.0 mg, 80.2 pmol, 1.00 eq.) in dioxane (1.00 mL) was added sulfuric acid (39.3 mg, 401 pmol, 21.3 pL, 5.00 eq.). The mixture was stirred at 60 °C for 0.5 h, then it was concentrated under reduced pressure to give a residue. The residue was purified by C / c / -HPLC (column: Phenomenex Luna Cl 8 150*25mm*10um; mobile phase: [water (0.225% formic acid) - acetonitrile]; gradient: 35%-65% B over 15.0 min) and lyophilized to afford Compound 347 3-(2,6-dichloro-4-(l-(5-ethyloxazol-2-yl)cyclopropoxy)phenyl)piperidine-2,6- dione (13.87 mg, 28.88 pmol, 35.98% yield, 99% purity) as a white solid.

[0692] Synthesis of 3-(2,6-dichloro-4-(l-(5-ethyl-l,2,4-oxadiazol-3- yl)cyclopropoxy)phenyl)piperidine-2, 6-dione (compound 350)

[0693] Step 1. To a solution of (Z)-l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-7V- hydroxycyclopropane-l-carboximidamidee (0.200 g, 537 pmol, 1.00 eq.) in acetic acid (3.00 mL) were added / ?-toluenesulfonic acid (9.25 mg, 53.7 pmol, 0.100 eq.) and 1,1,1 -tri ethoxypropane (947 mg, 5.37 mmol, 1.07 mL, 10.0 eq.). The reaction was stirred at 90 °C for 1 h, then it was concentrated under reduced pressure to give a residue. The residue was purified by / c -HPLC (column: Phenomenex Luna Cl 8 150 x 25 mm x 10 um; mobile phase: [water (0.225% formic acid) - acetonitrile]; gradient:33%-63% B over 12.0 min) and lyophilized to give a crude product. The crude product was purified by C / c -HPLC (column: Waters X bridge Cl 8 150 x 25 mm x 5 um; mobile phase: [water (10 mM ammonium bicarbonate) - acetonitrile]; gradient:28%-58% B over 15.0 min) and lyophilized to afford Compound 350 3-(2,6-dichloro-4-(l-(5-ethyl-l,2,4- oxadiazol-3-yl)cyclopropoxy)phenyl)piperidine-2, 6-dione (41.93 mg, 100.16 pmol, 18.6% yield, 98% purity) as a white solid.

[0694] Synthesis of l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-7V-(4-fluoro-6- methylpyridin-3-yl)cyclopropane-l-carboxamide (compound 351)

[0695]

[0696] Step 1. To a solution of 6-chloro-4-fluoropyri din-3 -amine (0.500 g, 3.41 mmol, 1.00 eq.) and methylboronic acid (1.02 g, 17.1 mmol, 5.00 eq.) in dioxane (10.0 mL) were added [2-(2- aminophenyl)phenyl]palladium(l+); bi s( 1 -adamantyl)-butyl-phosphane;methanesulfonate (249 mg, 341 pmol, 0.100 eq.) and potassium phosphate (2.17 g, 10.2 mmol, 3.00 eq.) in water (2.00 mL). The mixture was stirred at 100 °C for 12 h under nitrogen atmosphere. The mixture was concentrated under reduced pressure to give a residue. The residue was added to saturated ammonium chloride (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to afford 4-fluoro-6- methylpyri din-3 -amine (0.300 g, 1.66 mmol, 48.8% yield, 70% purity) as a brown solid.

[0697] Step 2. To a solution of l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclopropane-l- carboxylic acid (150 mg, 419 pmol, 1.00 eq.) in dimethylformamide (2.00 mL) were added 2- chloro-l-methyl-pyridin-l-ium;iodide (128 mg, 503 pmol, 1.20 eq.) and N,N- diisopropylethylamine (162 mg, 1.26 mmol, 219 pL, 3.00 eq.). Then 4-fluoro-6-m ethylpyri din-3 - amine (100 mg, 555 pmol, 1.33 eq.) was added at 25 °C. The mixture was stirred at 80 °C for 2 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by C / c / -HPLC (column: Phenomenex Luna Cl 8 150 x 25 mm x 10 um; mobile phase: [water (0.225% formic acid) - acetonitrile]; gradient: 14%-44% B over 10.0 min) and lyophilized to give a crude product. The crude product was purified by C / v -NPLC (column: Welch Ultimate XB- silicon hydroxide 150 x 40 mm x 10 um; mobile phase: [hexane- ethanol]; gradient: 5%-35% B over 12.0 min) and lyophilized to afford Compound 351 l-(3,5-dichloro-4-(2,6-dioxopiperidin- 3 -yl)phenoxy)-7V-(4-fluoro-6-m ethylpyri din-3 -yl)cy cl opropane-1 -carboxamide (25.23 mg, 53.57 pmol, 12.79% yield, 99% purity) as a white solid.

[0698] Synthesis of 3-(2,6-dichloro-4-(l-(4-ethyloxazol-2-yl)cyclopropoxy)phenyl)piperidine-2,6- dione (compound 352)

[0699] Step 1. To a solution of l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclopropane-l- carboxylic acid (300 mg, 838 pmol, 1.00 eq.) and 2-aminobutan-l-ol (149 mg, 1.68 mmol, 2.00 eq.) in acetonitrile (5.00 mL) was added 1-methyl-UT-imidazole (344 mg, 4.19 mmol, 5.00 eq.). The mixture was purged by nitrogen and then was added a solution of N- (chloro(dimethylamino)methylene)-7V-methylmethanaminium hexafluorophosphate(V) (353 mg, 1.26 mmol, 1.50 eq.) in acetonitrile (5.00 mL). The reaction was stirred at 50 °C for 3 h, then it was concentrated under reduced pressure to give a residue. Then the residue was diluted with saturated sodium bicarbonate (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by chromatography on silica gel (commercial hexanes / ethyl acetate=3 / l to 1 / 1 to dichloromethane / methanol = 20 / 1) to afford l-(3,5-dichloro- 4-(2,6-dioxopiperidin-3-yl)phenoxy)-7V-(l-hydroxybutan-2-yl)cyclopropane-l-carboxamide (270 mg, 629 pmol, 75% yield) as a white solid.

[0700] Step 2. To a solution of l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-7V-(l-hydroxybutan- 2-yl)cyclopropane-l -carboxamide (220 mg, 512 pmol, 1.00 eq.) in dichloromethane (3.00 mL) was added l,l-bis(acetyloxy)-3-oxo-3J7-125,2-benziodaoxol-l-yl acetate (261 mg, 615 pmol, 1.20 eq.). The mixture was stirred at 20 °C for 2 h, then it was concentrated under reduced pressure to give a residue. The residue was purified by re / ?-TLC (dichloromethane: methanol = 10: 1, Rf=0.66) to afford l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-7V-(l-oxobutan-2- yl)cyclopropane-l -carboxamide (160 mg, 374 pmol, 73% yield) as off-white oil.

[0701] Step 3. To a solution of l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-7V-(l-oxobutan-2- yl)cyclopropane-l -carboxamide (150 mg, 351 pmol, 1.00 eq.) in 1,2-di chloroethane (3.00 mL) was added burgess reagent (251 mg, 1.05 mmol, 3.00 eq.). The reaction was stirred at 70 °C for 2 h. The mixture was diluted with saturated sodium bicarbonate (10 mL) and extracted with di chloromethane (2 x 10 mL). The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by C / c -HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 um;mobile phase: [water (0.225% formic acid)- acetonitrile]; gradient: 35%-65% B over 15.0 min) and lyophilized to afford Compound 352 3-(2,6-dichloro-4-(l-(4-ethyloxazol-2-yl)cyclopropoxy)phenyl)piperidine-2,6- dione (27.91 mg, 67.5 pmol, 19.2% yield, 99% purity) as a white solid.

[0702] Synthesis of 3-(2,6-dichloro-4-(l-(5-(2,2-difluoroethyl)-l,3,4-oxadiazol-2- yl)cyclopropoxy)phenyl)piperidine-2, 6-dione (compound 354)

[0703] Step 1. To a solution of 3,3-difluoropropanoic acid (0.200 g, 1.82 mmol, 1.00 eq.) in dichloromethane (2.00 mL) were added tert-butyl hydrazinecarboxylate (480 mg, 3.63 mmol, 2.00 eq.), oxalyl di chloride (277 mg, 2.18 mmol, 191 pL, 1.20 eq.), 7V,7V-diisopropylethylamine (470 mg, 3.63 mmol, 633 pL, 2.00 eq.) and dimethylformamide (13.3 mg, 182 pmol, 14.0 pL, 0.100 eq.). The mixture was stirred at 25 °C for 1 h, then it was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (column: Waters Xbridge Cl 8 150*25mm*5um; mobile phase: [water (lOmM ammonium bicarbonate)- acetonitrile]; gradient:3%-33% B over 15.0 min) and lyophilized to afford tert-butyl 2-(3,3- difluoropropanoyl)hydrazine-l -carboxylate (0.270 g, 1.20 mmol, 66.3% yield) as yellow oil.

[0704] Step 2. To a solution of tert-butyl 2-(3,3-difluoropropanoyl)hydrazine-l-carboxylate (0.260 g, 1.16 mmol, 1.00 eq.) in dioxane (3.00 mL) were added l-(3,5-dichloro-4-(2,6-dioxopiperidin-3- yl)phenoxy)cyclopropane-l -carboxylic acid (415 mg, 1.16 mmol, 1.00 eq.) and phosphorus oxychloride (889mg, 5.80 mmol, 541 pL, 5.00 eq.). The mixture was stirred at 25 °C for 0.5 h, then at 100 °C for 5 h. The reaction was quenched with sodium bicarbonate sat. sol. (10 mL) and extracted with ethyl acetate (3 ^ 10 mL). The combined organic layers were washed with sodium bicarbonate sat. sol. (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by C / c -HPLC (column: Phenomenex luna Cl 8 150*25mm*10um; mobile phase: [water (0.225% formic acid)- acetonitrile]; gradient:25%-55% B over 9.0 min) to give a crude product. The crude product was purified by C / c / -HPLC (column: Phenomenex luna Cl 8 150*25mm* lOum; mobile phase: [water (0.05% hydrochloric acid)- acetonitrile]; gradient:20%-50% B over 13.0 min) and lyophilized to afford Compound 354 3-(2,6-dichloro-4-(l-(5-(2,2-difhioroethyl)-l,3,4-oxadiazol-2- yl)cyclopropoxy)phenyl)piperidine-2, 6-dione (24.36 mg, 54.0 pmol, 4.66% yield, 99% purity) as a white solid.

[0705] Synthesis of 3-(2,6-dichloro-4-(l-(5-methoxy-l,3,4-oxadiazol-2-yl)cyclopropoxy)phenyl) piperidine-2, 6-dione (compound 355)

[0706] Step 1. To a solution of l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclopropane-l- carboxylic acid (300 mg, 838 pmol, 1.00 eq.) in dioxane (2.00 mL) were added phosphorus oxychloride (642 mg, 4.19 mmol, 390 pL, 5.00 eq.) and methyl hydrazinecarboxylate (90.5 mg, 1.01 mmol, 1.20 eq.). The reaction was stirred at 90 °C for 4 h. The reaction was quenched by pouring into water (4 mL) slowly under nitrogen atmosphere. Then the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (2 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by reversed phase chromatography (Cl 8, 40 g; condition: water / acetonitrile = 1 / 0 to 0 / 1, 0.1% formic acid) and lyophilized to afford methyl 2-(l-(3,5-dichloro-4-(2,6- dioxopiperidin-3-yl)phenoxy)cyclopropane-l-carbonyl)hydrazine-l-carboxylate (180 mg, 410 pmol, 48.9% yield, 98% purity) as a white solid.

[0707] Step 2. To a solution of methyl 2-(l-(3,5-dichloro-4-(2,6-dioxopiperidin-3- yl)phenoxy)cyclopropane-l-carbonyl)hydrazine-l -carboxylate (0.150 g, 349 pmol, 1.00 eq.) in dichloromethane (2.00 mL) were added triethylamine (318 mg, 3.14 mmol, 437 pL, 9.00 eq.) and 4-methylbenzenesulfonyl chloride (199 mg, 1.05 mmol, 3.00 eq.). The reaction was stirred at 25 °C for 2 h, then it was concentrated under reduced pressure to give a residue. The residue was purified by / c / i-HPLC (column: Phenom enex Luna Cl 8 150*25mm*10um; mobile phase: [water (0.225% formic acid)- acetonitrile]; gradient:23%-53% B over 12.0 min) and lyophilized to afford Compound 355 3-(2,6-dichloro-4-(l-(5-methoxy-l,3,4-oxadiazol-2-yl)cyclopropoxy)phenyl) piperidine-2, 6-dione (19.71 mg, 47.34 pmol, 13.58% yield, 99% purity) as a white solid.

[0708] Synthesis of 3-(4-(l-(5-(tert-butyl)-l,3,4-thiadiazol-2-yl)cyclopropoxy)-2,6- dichlorophenyl)piperidine-2, 6-dione (compound 357)

[0709] Step 1. To a solution of l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-7V- pivaloylcyclopropane-1 -carbohydrazide (see compound 338) (0.100 g, 219 pmol, 1.00 eq.) in dioxane (2.00 mL) was added 2,4-bis(4-methoxyphenyl)-l,3,2,4-dithiadiphosphetane 2,4- disulfide (133 mg, 329 pmol, 1.50 eq.). The reaction was stirred at 50 °C for 12 h under nitrogen atmosphere. The reaction was quenched by addition of IM hydrochloric acid (5 mL) at 25 °C, diluted with water (10 mL), and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by C / c -HPLC (column: Test-Column ODS C18 150*30mm*2.4um; mobile phase: [water (0.225% formic acid)- acetonitrile]; gradient:40%-70% B over 13.0 min) and lyophilized to afford Compound 357 3-(4- (l-(5-(tert-butyl)-l,3,4-thiadiazol-2-yl)cyclopropoxy)-2,6-dichlorophenyl)piperidine-2,6-dione (33.29 mg, 72.5 pmol, 33.1% yield, 99% purity) as a white solid.

[0710] Synthesis of 3-(2,6-dichloro-4-(l-(l-methyl-lH-benzo[d]imidazol-2- yl)cyclopropoxy)phenyl)piperidine-2, 6-dione (compound 359)

[0711] Step 1. To a solution of l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclopropane-l- carboxylic acid (400 mg, 893 pmol, 1.00 eq.) and / C-methylbenzene- l ^-di amine (567 mg, 3.57 mmol, 527 pL, 4.00 eq., hydrochloride) in dimethylformamide (4.00 mL) was added l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (514 mg, 2.68 mmol, 3.00 eq.), 1H- benzo[ ][l,2,3]triazol-l-ol (362 mg, 2.68 mmol, 3.00 eq.) and A-di isopropyl propan- l -amine (346 mg, 2.68 mmol, 467 pL, 3.00 eq.). The reaction was stirred at 60 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed phase chromatography (C18, 80 g; condition: water / acetonitrile = 100:0 to 0: 100, 0.1% formic acid) to afford l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-7V-(2- (methylamino)phenyl)cyclopropane-l -carboxamide (290 mg, 627 pmol, 70.2% yield) as a yellow solid.

[0712] Step 2. A solution of l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-7V-(2- (methylamino)phenyl)cyclopropane-l -carboxamide (150 mg, 324 pmol, 1.00 eq.) in acetic acid (1.00 mL) was stirred at 25 °C for 1 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by / c -HPLC (column: Phenomenex luna Cl 8 150 x 25mm x 10um;mobile phase: [water(0.225% formic acid)- acetonitrile]; gradient: 25%-55% B over 15.0 min) to give a crude product. The crude product was purified by C / c / -HPLC (column: Phenomenex luna Cl 8 150 x 25mm x 10um;mobile phase: [water(0.225% formic acid)- acetonitrile]; gradient: 25%-55% B over 15.0 min) and lyophilized to afford Compound 359 3-(2,6-dichloro-4-(l-(l-methyl-17 / -benzo[d]imidazol-2- yl)cyclopropoxy)phenyl)piperidine-2, 6-dione (42.61 mg, 95.52 pmol, 29.44% yield, 99.6% purity) as an off-white solid.

[0713] Synthesis of 3-(2,6-dichloro-4-(l-(5-methyl-l,3,4-thiadiazol-2- yl)cyclopropoxy)phenyl)piperidine-2, 6-dione (compound 360)

[0714] Step 1. To a solution of acetohydrazide (207 mg, 2.79 mmol, 2.00 eq.) and l-(3,5-dichloro-4-(2,6- di oxopiperi din-3 -yl)phenoxy)cy cl opropane-1 -carboxylic acid (500 mg, 1.40 mmol, 1.00 eq.) in dimethylformamide (5.00 mL) were added 1 -(3 -dimethylaminopropyl)-3 -ethylcarbodiimide hydrochloride (401 mg, 2.09 mmol, 1.50 eq.) and 17 / -benzo[t ][l,2,3]triazol-l-ol (283 mg, 2.09 mmol, 1.50 eq.). The reaction was stirred at 20 °C for 2 h, then it was concentrated under reduced pressure to give a residue. The residue was purified by reversed phase chromatography (Cl 8, 80 g; condition: water / acetonitrile = 100:0 to 0: 100, 0.1% formic acid) and lyophilized to afford N'- acetyl-l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclopropane-l-carbohydrazide (440 mg, 1.06 mmol, 76.1% yield) as a white solid.

[0715] Step 2. To a solution of 7V'-acetyl-l-(3,5-dichloro-4-(2,6-dioxopiperidin-3- yl)phenoxy)cy cl opropane-1 -carbohydrazide (300 mg, 724 pmol, 1.00 eq.) in dioxane (3.00 mL) was added 2,4-bis(4-methoxyphenyl)-2,4-dithioxo-l,3,2,4dithiadiphosphetane (278 mg, 688 pmol, 0.95 eq.). The reaction was stirred at 50 °C for 3 h, then it was concentrated under reduced pressure to give a residue. The residue was purified by reversed phase chromatography (Cl 8, 80 g; condition: water / acetonitrile = 100 / 0 to 0 / 100, 0.1% formic acid) and lyophilized to afford 1- (3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-7V'-ethanethioylcyclopropane-l- carbohydrazide (150 mg, 349 pmol, 48.1% yield) as a yellow oil.

[0716] Step 3. To a solution of l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-7V- ethanethioylcy cl opropane-1 -carbohydrazide (150 mg, 349 pmol, 1.00 eq.) in dioxane (1.00 mL) was added sulfuric acid (171 mg, 1.74 mmol, 93.0 pL, 5.00 eq.). The mixture was stirred at 65 °C for 1 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by / c -HPLC (column: Phenomenex luna C18 150 x 25mm x 10um; mobile phase: [water(0.225% formic acid)- acetonitrile] ;gradi ent: 25%-55% B over 9.0 min) and lyophilized to afford Compound 360 3-(2,6-dichloro-4-(l-(5-methyl-l,3,4-thiadiazol-2- yl)cyclopropoxy)phenyl)piperidine-2, 6-dione (125.67 mg, 301.76 pmol, 86.57% yield, 99% purity) as a white solid.

[0717] Synthesis of 3-(2,6-dichloro-4-(l-(5-isopropyl-l,3,4-oxadiazol-2- yl)cyclopropoxy)phenyl)piperidine-2, 6-dione (compound 363)

[0718] Step 1. To a solution of l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclopropane-l- carboxylic acid (250 mg, 698 pmol, 1.00 eq.) in dimethylformamide (2.00 mL) were added isobutyrohydrazide (214 mg, 2.09 mmol, 3.00 eq.), triethylamine (212 mg, 2.09 mmol, 291 pL, 3.00 eq.), hydroxybenzotriazole (141 mg, 1.05 mmol, 1.50 eq.) and l-(3-dimethylaminopropyl)- 3 -ethylcarbodiimide hydrochloride (201 mg, 1.05 mmol, 1.50 eq.). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed phase column chromatography (C18, mobile phase: [water (0.1% formic acid) -acetonitrile]; B%: 45%-65%, 25 min) and lyophilized to give l-(3,5-dichloro-4-(2,6- dioxopiperidin-3-yl)phenoxy)-7V-isobutyrylcyclopropane-l-carbohydrazide (290 mg, 623 pmol, 89% yield, 95% purity) as a white solid.

[0719] Step 2. To a solution of l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-7V- isobutyrylcyclopropane-l-carbohydrazide (260 mg, 588 pmol, 1.00 eq.) in tetrahydrofuran (5.00 mL) was added burgess reagent (560 mg, 2.35 mmol, 4.00 eq.) in a sealed tube. The mixture was stirred at 100 °C for 5 h in the sealed tube. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by C / c -HPLC (column: Phenomenex Luna Cl 8 150 * 25 mm * 10 um; mobile phase: [water (0.225% formic acid) - acetonitrile];gradient:33%-63% B over 10.0 min) and lyophilized to afford Compound 363 3- (2,6-dichloro-4-(l-(5-isopropyl-l,3,4-oxadiazol-2-yl)cyclopropoxy)phenyl)piperidine-2,6-dione (35.15 mg, 81.2 pmol, 29% yield, 98% purity) as a white solid.

[0720] Synthesis of l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-N-methylcyclopropane-l- carboxamide (compound 366)

[0721] Step 1. To a solution of l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclopropane-l- carboxylic acid (120 mg, 335 pmol, 1.00 eq.) in dimethylformamide (1.00 mL) were added 1H- benzo[ ][l,2,3]triazol-l-ol (67.9 mg, 503 pmol, 1.50 eq.) and l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (96.3 mg, 503 pmol, 1.50 eq.) methanamine;hydrochloride (45.2 mg, 670 pmol, 2.00 eq.), 7V,7V-diisopropylpropan-l -amine (130 mg, 1.01 mmol, 175 pL, 3.00 eq.) was added. The mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by C / c -HPLC (column: Phenomenex luna Cl 8 150 x 25mm x 10um;mobile phase: [water(0.225% formic acid)- acetonitrile];gradient:3%-33% B over 15.0 min)- acetonitrile]; gradient: 15%-45% B over 9.0 min) and lyophilized to afford Compound 366 l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)- / f-methylcyclopropane- l -carboxamide (79.28 mg, 212.07 pmol, 63.30% yield, 99.3% purity) as a white solid.

[0722] Synthesis of 3-(4-(l-(4H-l,2,4-triazol-3-yl)cyclopropoxy)-2,6-dichlorophenyl)piperidine-2,6- dione (compound 372) Step 1. To a mixture of l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclopropane-l- carbohydrazide (200 mg, 537 pmol, 1.00 eq.) in acetic acid (2.00 mL) was added formimidamide acetate (279 mg, 2.69 mmol, 5.00 eq.). The reaction was stirred at 120 °C for 24 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep- HPLC (column: Phenomenex Luna Cl 8 150*25mm*10um; mobile phase: [water (0.225% formic acid) - acetonitrile]; gradient:23%-43% B over 10.0 min) and lyophilized to give a crude product. The crude product was purified by / Vc -NPLC (column: Welch Ultimate XB-CN 250*50mm*10um; mobile phase: [hexane-isopropanol]; gradient:20%-60% B over 15.0 min) and concentrated under reduced pressure to give a white solid. The white solid was further purified by C / c -HPLC (column: Waters xbridge 150*25mm lOum; mobile phase: [water (lOmM ammonium bicarbonate)- acetonitrile]; gradient: 15%-45% B over 9.0 min) and C / c / -HPLC (column: Phenomenex Luna Cl 8 150*25mm*10um; mobile phase: [water (0.05% ammonium hydroxide) - acetonitrile]; gradient: 6%-36% B over 16.0 min) and lyophilized to afford Compound 372 3-(4- (1-(47Z-1, 2, 4-triazol-3-yl)cyclopropoxy)-2,6-dichlorophenyl)piperidine-2, 6-dione (9.7 mg, 23.92 pmol, 18% yield, 94% purity) as a white solid.

[0723] Synthesis of 3-(4-(l-(l,2,4-thiadiazol-5-yl)cyclopropoxy)-2,6-dichlorophenyl)piperidine-2,6- dione (compound 373)

[0724] Step 1. To a solution of l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclopropane-l- carboxamide (0.295 g, 825 pmol, 1.00 eq.) in dioxane (8.00 mL) was added 2,4-bis(4- methoxyphenyl)-2,4-dithioxo-l,3,2,4dithiadiphosphetane (0.317 g, 784 pmol, 0.950 eq.). The mixture was stirred at 50 °C for 48 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by C / c -HPLC (column: Phenomenex luna Cl 8 150 x 40mm x 15um; mobile phase: [water (0.225% formic acid) - acetonitrile]; gradient: 32%-62% B over 15.0 min) and lyophilized to afford l-(3,5-dichloro-4- (2,6-dioxopiperidin-3-yl)phenoxy)cyclopropane-l-carbothioamide (0.0900 g, 241 pmol, 29.2% yield) as a white solid. Step 2. A solution of l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclopropane-l- carbothioamide (0.0700 g, 187 pmol, 1.00 eq.) in 1,1 -dimethoxy -A, A-dimethyl-m ethanamine (0.446 g, 3.75 mmol, 0.500 mL, 20.0 eq.) was stirred at 25 °C for 1 h. After the organic solution was removed, the residue was dissolved in dichloromethane (10.0 mL). Amino hydrogen sulfate (0.0636 g, 562 pmol, 3.00 eq.) in dimethylformamide (5.00 mL) and pyridine (0.0445 g, 562 pmol, 45.4 pL, 3.00 eq.) was added to the mixture at 0 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by C / c / -HPLC (column: Phenomenex luna Cl 8 150 x 25mm x 10um; mobile phase: [water (0.225% formic acid) - acetonitrile]; gradient: 32% -62% B over 9.0 min) and lyophilized to afford Compound 373 3-(4-(l-(l,2,4-thiadiazol-5-yl)cyclopropoxy)-2,6- di chi orophenyl)piperidine-2, 6-dione (60.24 mg, 151.2 pmol, 80.65% yield, 99% purity) as a white solid.

[0725] Synthesis of l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-N-(2-fluoro-6- methylpyridin-3-yl)cyclopropane-l-carboxamide (compound 374)

[0726] Step 1. To a solution of l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclopropane-l- carboxylic acid (100 mg, 279 pmol, 1.00 eq.) in dimethylformamide (3.00 mL) were added N,N- diisopropylethylamine (108 mg, 838 pmol, 146 pL, 3.00 eq.) and 2-chloro-l-methyl-pyridin-l- ium;iodide (88.5 mg, 346 pmol, 1.24 eq.). The mixture was stirred at 20 °C for 0.5 h. Then 2- fluoro-6-methylpyri din-3 -amine (52.8 mg, 419 pmol, 1.50 eq.) was added, and the mixture was stirred at 80 °C for 0.5 h. The mixture was poured into water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by C / c -HPLC (column: Phenomenex Luna Cl 8 150*25mm*10um; mobile phase: [water (0.225% formic acid) - acetonitrile]; gradient: 29%-59% B over 10.0 min) and lyophilized to afford 1 -(3 , 5- dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)-7V-(2-fluoro-6-methylpyridin-3-yl)cyclopropane-l- carboxamide (121.23 mg, 257.39 pmol, 92.19% yield, 99% purity) as a white solid.

[0727] Synthesis of 3-(2,6-dichloro-4-(l-(3-ethyl-l,2,4-oxadiazol-5-yl)cyclopropoxy)phenyl) piperidine-2, 6-dione (compound 375)

[0728] Step 1. To a solution of l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclopropane-l- carboxylic acid (100 mg, 279 pmol, 1.00 eq.) in dimethylformamide (1.00 mL) were added N- hydroxypropanamidine (36.9 mg, 419 pmol, 1.50 eq.), 7V,7V-diisopropylethylamine (108 mg, 838 pmol, 146 pL, 3.00 eq.) and 2-(3J / -[l,2,3]triazolo[4,5-Z>]pyridin-3-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate(V) (212 mg, 558 pmol, 2.00 eq.). The mixture was stirred at 60 °C for 12 h. The reaction mixture was cooled to 25 °C, diluted with water (5 mL) and extracted with ethyl acetate (3 ^ 10 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by C / c / -HPLC (column: Phenomenex luna Cl 8 150*25mm*10um; mobile phase: [water (0.225% formic acid) - acetonitrile]; gradient: 32%-62% B over 9.0 min) and lyophilized to afford 7V-((l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclopropane-l- carbonyl)oxy)propionimidamide (40.0 mg, 90.60 pmol, 32.45% yield, 97% purity) as a white solid.

[0729] Step 2. A solution of 7V-((l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclopropane-l- carbonyl)oxy)propionimidamide (40.0 mg, 93.4pmol, 1.00 eq.) in pyridine (1.00 mL) was heated at 100 °C for 16 h. The reaction mixture was diluted with acetonitrile (1.00 mL) and the solids were filtered. The solid was dissolved in dimethylformamide (0.500 mL) and purified by Prep- HPLC (column: Phenomenex luna Cl 8 150*25mm*10um; mobile phase: [water (0.225% formic acid) - acetonitrile]; gradient: 32%-62% B over 9.0 min) and lyophilized to afford Compound 375 3-(2,6-dichloro-4-(l-(3-ethyl-l,2,4-oxadiazol-5-yl)cyclopropoxy)phenyl)piperidine-2,6-dione (30.04 mg, 71.03 pmol, 76.05% yield, 97% purity) as a white solid. Synthesis of 3-(4-(l-(lH-pyrazol-3-yl)cyclopropoxy)-2,6-dichlorophenyl)piperidine-2,6- dione (compound 376)

[0730] Step 1. To solution of 3-iodo-l-methyl-lJ7-pyrazole (3.00 g, 14.4 mmol, 1.00 eq.) in tetrahydrofuran (30.0 mL) was added isopropyl magnesium chloride - lithium chloride complex (1.3 M in tetrahydrofuran, 22.2 mL, 2.00 eq.) at 0 °C, and the mixture was stirred at 0 °C for 1 h. Then a solution of l-(phenylsulfonyl)cyclopropan-l-ol (1.72 g, 8.65 mmol, 0.600 eq.) in tetrahydrofuran (30.0 mL) was added at 0 °C, and the mixture was stirred at 25 °C for 0.5 h. The reaction was quenched with ammonium chloride (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, commercial hexanes: ethyl acetate=O / l to 1 / 1) to afford 1 -( 1 -methyl- 1 / / - pyrazol-3-yl)cyclopropan-l-ol (0.500 g, 3.62 mmol, 25.1% yield) as a green oil.

[0731] Step 2. To a solution of l-(l-methyl-17 / -pyrazol-3-yl)cyclopropan-l-ol (0.400 g, 2.90 mmol, 1.00 eq.) and 2,6-dichloro-4-fluorobenzaldehyde (559 mg, 2.90 mmol, 1.00 eq.) in dimethylformamide (5.00 mL) was added cesium carbonate (1.41 g, 4.34 mmol, 1.50 eq.), and the mixture was stirred at 25°C for 16 h. The mixture was diluted with ethyl acetate (20 mL) and washed with brine (10 mL). The organic phase was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, commercial hexanes: ethyl acetate=5 / l to 1 / 1) to afford 2,6-dichloro-4-(l-(l-methyl-17 / -pyrazol-3-yl)cyclopropoxy)benzaldehyde (0.200 g, 643 pmol, 22.2% yield) as a yellow solid. Step 3. To a solution of potassium tert-butoxide (289 mg, 2.57 mmol, 4.00 eq.) in tetrahydrofuran (5.00 mL) was added a solution of tosylmethyl isocyanide (251 mg, 1.29 mmol, 2.00 eq.) in tetrahydrofuran (5.00 mL) under -78°C. The mixture was stirred at -78 °C for 30 min. Then a solution of 2,6-dichloro-4-(l-(l-methyl-lrt-pyrazol-3-yl)cyclopropoxy)benzaldehyde (0.200 g, 643 pmol, 1.00 eq.) in tetrahydrofuran (5.00 mL) was added at -78 °C. The mixture was stirred at -78 °C for 1.5 h. Then methanol (0.800 mL) was added, and the mixture stirred at 70 °C for 30 min. The reaction was quenched with ammonium chloride aqueous solution (10%, 10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, commercial hexanes: ethyl acetate=20 / l to 5 / 1) to afford 2-(2,6-dichloro-4-(l-(l-methyl-lrt-pyrazol-3-yl)cyclopropoxy)phenyl)acetonitrile (0.100 g, 310 pmol, 48.29% yield) as a white solid.

[0732] Step 4. To a solution of 2-(2,6-dichloro-4-(l-(l-methyl-lrt-pyrazol-3- yl)cyclopropoxy)phenyl)acetonitrile (0.100 g, 310 pmol, 1.00 eq.) in tetrahydrofuran (5.00 mL) was added sodium methylate (33.5 mg, 621 pmol, 2.00 eq.) and tert-butyl acrylate (119 mg, 931 pmol, 135 pL, 3.00 eq.) at 0 °C. The mixture was stirred at 25 °C for 2 h. The mixture was quenched with ammonium chloride aqueous solution (10 mL) and extracted with ethyl acetate (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford tert-butyl 4-(4-( l -( IT / -pyrazol-3-yl)cyclopropoxy)-2,6- dichlorophenyl)-4-cyanobutanoate (0.150 g, crude) as a yellow oil.

[0733] Step 5. To a solution of tert-butyl 4-(4-(l-(U / -pyrazol-3-yl)cyclopropoxy)-2,6-dichlorophenyl)- 4-cyanobutanoate (0.150 g, 333 pmol, 1.00 eq.) in acetic acid (5.00 mL) was added sulfuric acid (0.500 mL). The mixture was stirred at 80 °C for 2 h. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by / c / i-HPLC (column: Phenom enex Luna Cl 8 150*25mm*10um; mobile phase: [water (0.225% formic acid) - acetonitrile]; gradient: 28%-58% B over 15.0 min) and lyophilized to afford Compound 376 3-(4-(l-(U / -pyrazol-3-yl)cyclopropoxy)-2,6-dichlorophenyl)piperidine-2,6- dione (57.1 mg, 141.93 pmol, 42.61% yield, 98% purity) as a white solid. Synthesis of 3-(2,6-dichloro-4-(l-(3-(methoxymethyl)-l,2,4-thiadiazol-5- yl)cyclopropoxy)phenyl)piperidine-2, 6-dione (compound 388)

[0734] Step 1. l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclopropane-l-carbothioamide (75.0 mg, 201 pmol, 1.00 eq.), aluminium tricchloride (53.5 mg, 401 pmol, 2.00 eq.) and butyl acetate (1.00 mL) were added into a 8 mL reaction tube charged with a magnetic stirrer; then it was heated to 70°C, and the 2-methoxyacetonitrile (28.5 mg, 401 pmol, 29.8 pL, 2.00 eq.) was added portion-wise into the tube. The tube was sealed and stirred at 70°C for 5 h in the first step. After cooling to room temperature, water (0.300 mL) and iodine (102 mg, 401 pmol, 2.00 eq.) were added into the tube. The mixture was stirred at 25 °C for 12 h. The reaction was quenched with brine (10 mL) at 0 °C and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by / c -HPLC (column: Waters xbridge 150*25mm lOum; mobile phase: [water (lOmM sodium bicarbonate) - acetonitrile]; gradient: 25%-55% B over 10.0 min) and lyophilized to afford Compound 388 3- (2,6-dichloro-4-(l-(3-(methoxymethyl)-l,2,4-thiadiazol-5-yl)cyclopropoxy)phenyl)piperidine- 2,6-dione (48.00 mg, 106.35 pmol, 52.93% yield, 98% purity) as a yellow solid.

[0735] Synthesis of 3-(2,6-dichloro-4-(l-(4-(methoxymethyl)thiazol-2- yl)cyclopropoxy)phenyl)piperidine-2, 6-dione (compound 390) Step 1. A solution of l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclopropane-l- carbothioamide (130 mg, 348 pmol, 1.00 eq.) and 1,3 -dibromopropan -2-one (75.2 mg, 348 pmol, 1.00 eq.) in ethanol (3.00 mL) was stirred at 90 °C for 2 h. The mixture was concentrated under reduced pressure to afford 3-(4-(l-(4-(bromomethyl)thiazol-2-yl)cyclopropoxy)-2,6- dichlorophenyl)piperidine-2, 6-dione (170 mg, crude) as yellow oil.

[0736] Step 2. To a solution of 3-(4-(l-(4-(bromomethyl)thiazol-2-yl)cyclopropoxy)-2,6- dichlorophenyl)piperidine-2, 6-dione (170 mg, 346 pmol, 1.00 eq.) in methanol (3.00 mL) was added silver(I) oxide (161mg, 694 pmol, 2.00 eq.). The mixture was stirred at 90 °C for 2 h under nitrogen atmosphere. The reaction mixture was filtered and washed with di chloromethane: methanol = 10: 1 (30 mL), and the filtrate was concentrated in vacuum to give the crude product. The crude product was purified by / Vc -HPLC (column: Phenomenex Luna Cl 8 150*25mm*10um; mobile phase: [water (0.225% formic acid) - acetonitrile]; gradient:32%-62% B over 15.0 min) and lyophilized to afford Compound 390 3-(2,6-dichloro-4-(l-(4- (methoxymethyl)thiazol-2-yl)cyclopropoxy)phenyl)piperidine-2, 6-dione (49.25 mg, 110.48 pmol, 31.9% yield, 99% purity) as a white solid.

[0737] Synthesis of 3-(2,6-dichloro-4-(l-(3-methyl-l,2,4-thiadiazol-5- yl)cyclopropoxy)phenyl)piperidine-2, 6-dione (compound 391)

[0738] Step 1. A solution of l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclopropane-l- carbothioamide (0.120 g, 321 pmol, 1.00 eq.) in 1,1 -dimethoxy -N, A-dimethylethan-1 -amine (0.856 g, 6.43 mmol, 0.940 mL, 20.0 eq.) was stirred at 25 °C for 1 h. The organic solution was concentrated under reduced pressure to give a residue. The residue was dissolved in dichloromethane (10.0 mL). Amino hydrogen sulfate (0.109 g, 961 pmol, 3.00 eq.) in dimethylformamide (5.00 mL) and pyridine (0.076 g, 964 pmol, 77.8 pL, 3.00 eq.) were added to the mixture at 0 °C. The mixture was stirred at 25 °C for 11 h. The reaction mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by C / c -HPLC (column: Phenomenex luna Cl 8 150 x 25mm x 10um; mobile phase: [water (0.225% formic acid) - acetonitrile]; gradient: 32%-62% B over 9.0 min) and lyophilized to afford Compound 391 3-(2,6-dichloro-4-(l-(3-methyl-l,2,4-thiadiazol-5-yl)cyclopropoxy)phenyl) piperidine-2, 6-dione (63.53 mg, 152.5 pmol, 47.45% yield, 99% purity) as an off-white solid.

[0739] Table C6 - Characterization of final compounds

[0740] Example 2. Compound binding to CRBN by HTRF assay:

[0741] Compound activity was monitored in a Homogenous Time-Resolved Fluorescence (HTRF) assay using l-[5-({2-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-4- yl]oxy}acetamido)ethoxy]ethyl}carbamoyl)pentyl]-3,3-dimethyl-2-[(lE,3E)-5-[(2E)-l,3,3- trimethyl-5-sulfo-2,3-dihydro-lH-indol-2-ylidene]penta-l,3-dien-l-yl]-3H-indol-l-ium-5- sulfonate as a fluorescent probe. Biochemical assays were conducted in Greiner white 384 well HiBase plates (Cat. No 784075-25) in 20 pL total volume. A one pot detection solution of CRBN- DDB1 (2.5 nM), Anti-His Terbium Cryptate Gold (IX, PerkinElmer Cat.#: 61HI2TLB), and Cy5- Thalidomide (lOOnM, Tenova Cat.: T52461) was prepared in 20 mM HEPES, 20 mM NaCl, 0.2 mM TCEP, 0.2 mM EDTA, and 0.005% Tween20 was dispensed to each assay plate. Compounds were stored in dry, ambient temperatures at 10 mM. An 11 -point, 1 :3 dilution series was prepared from 10 mM stock concentrations in Echo-compatible LDV plates. lOnL of each compound dilution series was dispensed into assays wells using an Echo 650 (Labcyte inc. USA). 20 nL of 10 mM Lenalidomide was transferred into the active -control wells for the assay and 20 nL of DMSO was transferred into the neutral -control wells. The assay was then allowed to incubate for 30 min at ambient temperature after transferring compound. Plate measurements were taken on a Pherastar FSX (BMG Labtech, Germany) using the HTRF Red filter (Ex. 337 nm, eml : 620 nm, em2: 665 nm) (Flashes: 50, Integration time: 60-400 us, Z-height: 10 mm, Ratio-multiplier: 10,000). The HTRF signal was then subsequently normalized to the neutral and active controls. Analysis and EC50 values were derived using KNIME analytics (KNIME Zurich) transformation and fitting within Collaborative Drug Discovery (Collaborative Drug Discovery USA). Ki was derived from the geometric mean of the EC 50 values using the Cheng-Prustoff transformation.

[0742] Example 3. Experimental for NanoBiT

[0743] Cal51 NEK7 NanoBiT cell line was generated via CRISPR Knock-In of the HiBiT tag in NEK7 gene and stable infection with a lentivirus carrying LgBiT protein. The cell line was generated in house. For the experiment, cells were plated in 384-well white flat bottom plates (Corning, 3570BC) at 2500 cells per well using Multiflo (BioTek / Agilent) and in 25 pl volume in DMEM experimental medium: DMEM (DMEM, high glucose, HEPES, no phenol red (ThermoFisher Scientific, 21063029) supplemented with 10% FBS (Coming, 35-075-CV), 1% Penicillin / Streptomycin ((ThermoFisher Scientific, 15140-122), and 1% Endurazine (Nano-Gio Endurazine Live Cell Substrate (Promega, N2571)). Cells were incubated for 16 hours at 37 °C, 5% CO2 before compound addition. For dose response determination, 2.5nL of a compound at different concentrations (stock compound concentration range: lOmM to 0.5pM, final concentration range inside cell plate: I M to 0.05nM) were dispensed into the plate using an Echo® 650 liquid handling device (Backman Coulter / Labcyte). Cells were incubated at 37 °C, 5% CO2 for 24 hours and then signal was read on a Pherastar FSX using “LUM plus” optic module with 4095 gain and measurement interval time 0.2 seconds.

[0744] Analysis was performed in Genedata Screener (Genedata, Basel, CH). Luminescence response (R) was calculated by the formula: response = 100 * (S - N) / (P-N) where S is the signal of the well, N and P the mean negative and positive control values respectively of the same plate. The luminescence response was then fitted in Genedata using a 4-parameter antagonist logistic fit (hill slope unconstrained, EC50 > 0, top / bottom unconstrained).

[0745] The results are included in Table 1.

[0746] Table 1: HTRF Binding of compounds to CRB N and Activity for NEK7 degradation.

[0747] Example 4. Functional assays for caspase-1 activity and IL-ip, IL-la, and IL-18 cytokine release in human monocyte-derived macrophages in response to inflammasome stimulation

[0748] Human monocytes were enriched and isolated from buffy coats from two healthy donors using RosetteSep™ Human Monocyte Enrichment Cocktail (Cat.No. 15068, StemCell) and Ficoll- Plaque PLUS (Cat.No. 17144003, Cytiva). Monocytes were differentiated into macrophages by treatment with 100 ng / mL M-CSF (Cat. No 78057, StemCell) for 6 days at 37 °C, 5% CO2. Differentiated macrophages were seeded overnight (50,000 cells / well) in 100 pL of medium in a 96-well, white, flat-bottom plate at 37 °C, 5% CO2. Cells were treated for 24 h with a concentration range of compound 322, or the NLRP3 inhibitor, selnoflast (Cat. No HY-132831, MCE). Macrophages were then primed with 1 pg / mL or 0.1 pg / mL LPS (Cat. No L2630, Sigma) for 3 h followed by 1 h stimulation with 10 pM nigericin (Cat. No TLRLNIG, Invivogen). Media of stimulated macrophages were collected, and a portion was used to assay for caspase- 1 activity using the Caspase-Gio® 1 Inflammasome Assay (Cat. No G9951, Promega) according to manufacturer’s instructions. The remaining media were stored at -20°C, then thawed at 4°C before assaying for release of IL-ip, IL-la, and IL- 18 cytokines using the MSD immunoassay according to manufacturer’s instructions. Compound 322 inhibited caspase-1 activity with an average IC50 of 0.00233 pM and inhibited the release of IL-ip, IL- la, and IL- 18 with average IC50 values of 0.00125 pM, 0.00105 pM, and 0.00126 pM, respectively (FIG.l). Compounds 303, 333, 353 and 382 inhibited caspase-1 activity with an average ICso of 0.00176 pM, 0.00453 pM, 0.00788 pM and 0.00419 pM, respectively (FIG.2A).

[0749] In FIG.l and FIG.2A, caspase- 1 activity was measured using Caspase-Gio® 1 Inflammasome Assay. The release of IL-ip, IL-la, and IL-18 cytokines was measured using the MSD immunoassay. Data represent the mean ± standard error from two separate donors run in technical quadruplicate. Human monocyte-derived macrophages were isolated from healthy donor buffy coats and plated as described above, followed by 24 h treatment with compounds listed in Table 2. Caspase-1 activity was assayed as described above, while IL-ip release was measured using the Lumit® IL- ip Human / Mouse Immunoassay (Cat. No W6011, Promega). Compounds exhibited dosedependent inhibition of caspase-1 activity and IL-ip release in this assay of NLRP3 inflammasome activation (Table 2, FIG.l and FIG.2B).

[0750] Table 2: Functional assay for Caspase-1 activity and IL-ip release of compounds in human monocyte-derived macrophages in response to inflammasome stimulation.

[0751] In Table 2 IC50 values (concentration at which inhibition of 50% is achieved) for each compound in caspase-1 and IL-ip assays are shown, n denotes the number of monocyte donors in which the compound was tested; a: two independent studies with the same donor, b: three independent studies with two separate donors.

[0752] Example 5. Functional assays for caspase-1 activity and IL-ip cytokine release in human iCell® microglia in response to inflammasome stimulation

[0753] Human iCell® microglia (Cat. No. R1131, FujiFilm Cellular Dynamics) were seeded in quadruplicate into 96-well, clear, poly-D-Lysine coated, flat-bottom plates (Cat. No. 152039, ThermoFisher Scientific) at a concentration of 15,000 cells / well in 100 pL of Complete Maintenance Medium and maintained at 37 °C, 5% CO2 as recommend by the vendor’s protocol. After 48 hours, 50% of the medium in each well was replaced with fresh medium and cells were then treated with a concentration range of compound 322. After 24 hours, cells were primed with 100 ng / mL lipopolysaccharides (LPS) (Cat No. L2630, Millipore Sigma) for 3 hours followed by stimulation with 5 mM ATP (Cat No. trl-atpl, InvivoGen) for 1 hour. 50 uL of media from the stimulated microglia were then collected and used to assess caspase- 1 activity using the Caspase- Gio® 1 Inflammasome Assay (Cat. No G9951, Promega) according to manufacturer’s instructions. 30 uL of the remaining media were stored at -20°C, then thawed at 4°C and used to assess IL-ip levels using the Lumit® IL-ip Human / Mouse Immunoassay (Cat. No. W6012, Promega) according to manufacturer’s instructions. Compound 322 inhibited caspase-1 activity with an IC50 value of 0.00964 pM and inhibited the release of IL-ip with an IC50 value of 0.00158 pM (FIG.3)

[0754] Example 6. Pyroptotic membrane permeabilization in human monocyte-derived macrophages in response to inflammasome stimulation

[0755] Human monocytes were enriched and isolated from buffy coats from two healthy donors using RosetteSep™ Human Monocyte Enrichment Cocktail (Cat.No. 15068, StemCell) and Ficoll- Plaque PLUS (Cat.No. 17144003, Cytiva). Monocytes were differentiated into macrophages by treatment with 100 ng / mL M-CSF (Cat. No 78057, StemCell) for 6 days at 37 °C, 5% CO2. Differentiated macrophages were seeded overnight (50,000 cells / well) in 100 pL of medium in a 96-well, black, flat-bottom plate at 37 °C, 5% CO2. Cells were treated for 24 h with a concentration range of compound 322, or the NLRP3 inhibitor, selnoflast (Cat. No HY-132831, MCE). Macrophages were then primed with 1 pg / mL LPS (Cat. No L2630, Sigma) for 3 h followed by 1 h stimulation with 10 pM nigericin (Cat. No TLRLNIG, Invivogen) to induce pyroptosis. Immediately after nigericin addition, the cell-impermeable nucleic acid dye, SYTOX™ Green (Cat. No S7020, Invitrogen), was added to each well at 5 pM. Plates were incubated for 1 hour after which the green fluorescence was measured to assess plasma membrane integrity. Compound 322 inhibited pyroptotic membrane permeabilization with an IC50 of 0.00132 pM compared to selnoflast with an IC50 of 0.455 pM (FIG. 4).

[0756] In FIG. 4, plasma membrane integrity was assessed using the membrane impermeable nucleic acid stain, SYTOX™ Green. Data represent the mean ± standard error of the mean of 4 technical replicates from 3 healthy donors. Example 7. Experimental Evidence of CNS Exposure

[0757] Male Balb / c mice were orally administered with a single dose of the selected NEK7 MGD at 10 mg / kg and plasma and brain samples were collected at various time points post-dose, n=2 or n=3 per time point. Compound formulation was prepared on the day of administration in 0.5% methyl cellulose (4000 cps) in water (Formulation A); 5% DMSO+50% PEG300+ 5% Tween 80 + 40% water (Formulation B) or 10% DMSO and 90% of 0.5% methyl cellulose (4000 cps) in water (Formulation C).

[0758] Plasma and brain samples collected post dose were analysed using a non-GLP LC / MS / MS bioanalytical method to evaluate the compound concentration. Mice were fully exsanguinated prior to brain collection and total plasma concentration in ng / mL and total brain concentration in ng / g were reported.

[0759] Table 3. Brain penetration study of selected MGDs following oral administration in male Balb / c mice.

[0760] Example 8. Compound 322 induces NEK7 degradation and inhibits production of inflammatory cytokines in mouse brains in LPS-induced mouse model of neuroinflammation.

[0761] Naive female CRBN I391V mice were orally administered either Compound 322 at 30 mg / kg, twice a day (BID), selnoflast at 50 mg / kg once a day (QD), or vehicle for five consecutive days. On the third, fourth and fifth days, following the dosing of Compound 322 or selnoflast, 1 mg / kg of lipopolysaccharide (LPS) was administered intraperitoneally (i.p.) to induce brain inflammation as a model.

[0762] Compound formulation was prepared fresh on the day of administration in 0.5% methyl cellulose (4000 cps) in water. Four hours after the final LPS dose, animals were euthanized under CO2. Mouse brains were perfused with PBS via cardiac perfusion to remove red blood cells. The left hemisphere was isolated and processed for protein extraction with M-PER lysis buffer supplemented with Halt™ Protease and Phosphatase Inhibitor Cocktail (100X). Protein concentration was measured using a BCA assay.

[0763] Brain lysates were analysed for NEK7 protein levels using JESS, normalized to P-actin and referenced to vehicle + LPS condition. Brain cytokine levels were also measured using a multiplex mesoscale discovery (MSD) assay.

[0764] Dosing with Compound 322 (LPS + Compound 322) significantly reduced NEK7 levels to 17.73% in the brains of CRBN I391V mice compared to LPS + vehicle condition on day 5. In contrast, selnoflast, an NLRP3 inhibitor, did not reduce NEK7 levels. (Table 4A, and FIG. 6, left panel).

[0765] Table 4A. NEK7 levels in brain lysate of CRBN I391V mice

[0766] In Table 4A, Compound 322 induced NEK7 degradation in mouse brains in vivo. NEK7 protein levels were assessed in brains of CRBN I391V mice after five days of oral dosing of Compound 322 (30 mg / kg, BID), selnoflast (50 mg / kg, QD), or vehicle (QD), combined with intraperitoneal (i.p.) injection of LPS (1 mg / kg) for the final three days (LPS + Compound 322, LPS + Selnoflast, LPS + Vehicle, respectively). An additional group received vehicle orally for five days (QD) and PBS, i.p. for three days (PBS + Vehicle). NEK7 levels were quantified using JESS, normalized to P-actin, and expressed as a percentage relative to LPS + vehicle condition. In an LPS-induced model of neuroinflammation, LPS was administered at 1 mg / kg, i.p., over three days, leading to an increase in IL-10 levels to 164.10 pg / pg of brain lysates from CRBN 1391 V mice (LPS + Vehicle). Oral dosing with Compound 322 for five days, with LPS administered during the final three days, significantly reduced IL-10 levels to 57.29 pg / pg of brain lysates (LPS + Compound 322), (Table 4B, and FIG. 6, middle panel).

[0767] Table 4B. IL-10 in in brain lysate of CRBN I391V mice

[0768] Table 4B shows Compound 322 inhibits IL-ip production in mouse brains in an LPS-induced model of neuroinflammation in vivo. IL-ip cytokine levels were measured in brain lysates of CRBN I391V mice after oral administration for five consecutive days of Compound 322 at 30 mg / kg, BID, selnoflast at 50 mg / kg, QD, or vehicle, QD, and injected with 1 mg / kg LPS, i.p. for three days (LPS + Compound 322, LPS + Selnoflast, LPS + Vehicle, respectively). An additional group was orally dosed with vehicle for 5 consecutive days, QD, and injected with PBS, i.p. for three days (PBS + Vehicle). IL-ip levels were measured using MSD assay, normalized to pg of brain lysate, as measured by BCA assay.

[0769] In the same study, LPS (1 mg / kg, i.p.) administered over three days lead to an increase in IL-6 levels to 758.80 pg / pg of brain lysates from CRBN 1391 V mice (LPS + Vehicle). Oral dosing with Compound 322 for five days, with LPS administered during the final three days, significantly reduced IL-6 levels to 157.30 pg / pg of brain lysates (LPS + Compound 322), (Table 4C, and FIG. 6, right panel). Table 4C. IL-6 in brain lysate of CRBN I391V mice

[0770] Table 4C shows Compound 322 inhibits IL-6 production in mouse brains in an LPS-induced model of neuroinflammation in vivo. IL-6 cytokine levels were measured in brain lysates of CRBN 1391 V mice after oral administration for five consecutive days of Compound 322 at 30 mg / kg, BID, selnoflast at 50 mg / kg, QD, or vehicle, QD, and injected with 1 mg / kg LPS, i.p. for three days (LPS + Compound 322, LPS + Selnoflast, LPS + Vehicle, respectively). An additional group was orally dosed with vehicle for 5 consecutive days, QD, and injected with PBS, i.p. for three days (PBS + Vehicle). IL-6 levels were measured using MSD assay, normalized to pg of brain lysate, as measured by BCA assay.

[0771] In FIG. 6, Compound 322 induces NEK7 degradation and inhibits IL-ip and IL-6 production in brains of CRBN I391V mice in an LPS-induced model of neuroinflammation. NEK7 protein (left panel), IL-ip (middle panel), and IL-6 (right panel) levels were measured in mouse brains after oral administration for five consecutive days of Compound 322 (30 mg / kg, BID), selnoflast (50 mg / kg, QD), or vehicle (QD), combined with i.p. injection of LPS (1 mg / kg) for the final three days (LPS + Compound 322, LPS + Selnoflast, LPS + Vehicle, respectively). An additional group was orally dosed with vehicle for 5 consecutive days, QD, and injected with PBS, i.p. for three days (PBS + Vehicle). NEK7 levels were measured by JESS, normalized to LPS + vehicle condition. IL-ip and IL-6 levels were measured using MSD assay, normalized to pg of brain lysate, as measured by BCA assay. Example 9. Multiple-dose study with Compound 322 induces NEK7 degradation in vivo and inhibits NLRP3 inflammasome activation ex vivo in non-human primates

[0772] Non-naive male and female non-human primate (NHP) cynomolgus monkeys were orally administered with 5 consecutive daily doses of Compound 322 at 0.5 mg / kg, n=2 per dose group, 1 male and 1 female. Compound formulation was prepared on the day of administration in 0.5% methyl cellulose (4000 cps) in water and animals were fasted overnight. Plasma collected post dose were analysed using a non-GLP LC / MS / MS bioanalytical method to evaluate the compound concentration. Whole blood collected post dose were processed to PBMC. Cerebrospinal fluid (CSF) and PBMCs were analysed using JESS or western blot, respectively. Plasma pharmacokinetics and PBMC pharmacodynamics were assessed longitudinally throughout dosing and following dosing cessation.

[0773] For the ex vivo stimulation, within 0.5 h of blood collection from animals that received Compound 322 at 0.5 mg / kg, blood was aliquoted into two 0.25 mL aliquots. One aliquot was used as baseline, and the other as the ex vivo stimulated condition. For stimulation, whole blood was incubated with 100 ng / mL Lipopolysaccharide from Escherichia coli 0111 :B4 (LPS-EB) for 3 h, followed by 10 pM nigericin for 2 h. Plasma was then isolated and IL-ip levels were measured using the IL-ip ELISA R&D Systems kit (Cat. # DY1318), with 50 pL per sample diluted with 50 pL reagent diluent / well. After reading absorbance on plate reader, standard curve and sample IL-ip levels were analysed using 4PL method. The percent decrease in IL-ip was quantified based on IL-ip levels from whole blood of Compound 322-dosed animals relative to each animal’s predose level after stimulation.

[0774] At 6 h after the final dose, a single oral gavage of Compound 322 at 0.5 mg / kg showed similar mean plasma concentration in comparison to 5 consecutive days of dosing (Table 5A).

[0775] Table 5A. Mean Plasma and CSF Concentration (ng / mL) of Compound 322 dosed orally at 0.5 mg / kg In Table 5A, plasma was isolated 4 h post dose (dosed once or over five consecutive days), n=2. Plasma collected post dose were analysed using a non-GLP LC / MS / MS bioanalytical method to evaluate the compound concentration. PBMC NEK7 degradation showed reduction to 6.36% of pre-dose levels on day 1, that was further reduced to 2.89% by day 5, relative to predose levels (Table 5B, and FIG. 7, left panel).

[0776] Table 5B. NEK7 level from PBMC of NHP In Table 5B Compound 322 induces NEK7 degradation in vivo. NEK7 protein levels were assessed in PBMC isolated from NHP after oral administration for 5 consecutive days of Compound 322 at 0.5 mg / kg, n=2 per dose group. NEK7 levels were normalized to P-actin, as determined by western blot, at the indicated time points. NEK7 level at predose was normalized to 100%. Day 15 corresponds to recovery period, 10 days after drug administration. CSF NEK7 degradation showed reduction to 9.59% of pre-dose levels on day 1, and remained at 9.96% at day 5, relative to predose levels (Table 5C, and FIG. 7, middle panel).

[0777] Table 5C. NEK7 level from CSF of NHP

[0778] In Table 5C Compound 322 induces NEK7 degradation in CSF. NEK7 protein levels were assessed in CSF isolated from NHP after oral administration for 5 consecutive days of Compound 322 at 0.5 mg / kg, n=2 per dose group. NEK7 levels were normalized to P-actin, as determined by JESS, at the indicated time points. NEK7 level at predose was normalized to 100%. Day 15 corresponds to recovery period, 10 days after drug administration.

[0779] Commensurate with NEK7 levels, production of IL-1 P was inhibited in an ex vivo whole blood stimulation assay (Table 5D, and FIG. 7, right panel). The deep and sustained inhibition of IL-ip release in the ex vivo assay after oral administration over five consecutive days suggests that Compound 322 can control inflammation driven by NLRP3 inflammasome. The inhibition of IL- ip in this ex vivo stimulation assay by NEK7 MGD dosed in NHP serves as a proof-of-concept for the therapeutic use of NEK7 MGD for the treatment of multiple inflammatory diseases in which IL-ip plays a pathogenic role.

[0780] Table 5D. Percent decrease in IL-10 relative to predose

[0781] In Table 5D, suppression of ex vivo inflammasome activation following degradation of NEK7 in NHP is reported. Whole blood was isolated at the indicated time points from NHP dosed orally 0.5 mg / kg of Compound 322 over 5 days (day 1 through 5), n=2. Day 15 corresponds to recovery period 10 days after drug administration. Whole blood was stimulated ex vivo with 100 ng / mL LPS for 3 h and 10 pM nigericin for 2 h. Plasma was isolated and IL-ip was measured by monkey- specific ELISA. Percent decrease in IL-ip was quantified based on IL-ip levels from whole blood of Compound 322-dosed animals relative to each animal’s predose level.

[0782] In FIG. 7, Compound 322 induces NEK7 degradation in PBMC and CSF, and inhibits IL-ip release after in vivo dosing. Whole blood and CSF were isolated at the indicated time points from

[0783] NHP dosed orally 0.5 mg / kg of Compound 322 over 5 days (day 1 through 5), n=2. Day 15 correspond to recovery period 10 days after drug administration (left and middle panel). Whole blood was stimulated ex vivo with 100 ng / mL LPS for 3 h and 10 pM nigericin for 2 h. Plasma was isolated and IL-ip was measured by monkey-specific ELISA. Percent decrease in IL-ip was quantified based on IL-ip levels from whole blood of Compound 322-dosed animals relative to each animal’s predose level (right panel).

[0784] EQUIVALENTS

[0785] Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein.

[0786] Such equivalents are intended to be encompassed in the scope of the following claims.

Claims

WHAT IS CLAIMED IS:

1. A compound having formula (I):or a pharmaceutically acceptable salt thereof; wherein:X is N, CH, CD, or CF;A is defined according to (i) or (ii) below:(A is: ed according to (A) or (B) below:each of R1and R2is independently selected from the group consisting of H and RA; wherein: each occurrence of RAis independently selected from the group consisting of:• Ci-6 alkyl optionally substituted with from 1-6 Ra;• Ci-6 alkoxy optionally substituted with from 1-6 Ra;• C2-6 alkenyl optionally substituted with from 1-6 Ra;• C2-6 alkynyl optionally substituted with from 1-6 Ra; and• -(L1)a-RB;a is 0 or 1;L1is Ci-8 alkylene;RBis selected from the group consisting of:• C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rb, and Rc;• heterocyclyl or heterocycloalkenyl including 3-10 ring members, wherein 1-3 ring members are heteroatoms or heteroatomic groups, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rb, and Rc;• heteroaryl including 5-10 ring members, wherein 1-4 ring members are heteroatoms or heteroatomic groups, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc; and• Ce-io aryl optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc;(B)R1and R2taken together with the nitrogen atom to which each is attached forms:• heterocyclyl or heterocycloalkenyl including 3-12 ring atoms, wherein 0-4 ring atoms (aside from the N linking R1and R2) are ring heteroatoms, each independently selected from the group consisting of: N, N(H), N(Rd), O, and S, wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents each independently selected from the group consisting of: oxo, Rb, and Rc; and• heteroaryl including from 9-14 ring atoms, wherein 0-4 ring atoms (aside from the N linking R1and R2) are ring heteroatoms, each independently selected from the group consisting of: N, N(H), N(Rd), O, and S, wherein the heteroaryl is optionally substituted with 1-4 substituents each independently selected from the group consisting of: oxo, Rb, and Rc; or(ii)A is heteroaryl including 5 ring members, wherein 2-4 ring atoms are heteroatoms or heteroatomic groups, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-2 substituents independently selected from the group consisting of halo, -CN, Ci-ealkyl, Ci-4haloalkyl, Ci- 4alkoxy, Ci-4haloalkoxy, Ci-4hydroxyalkyl, phenyl, or 3-6 membered heterocyclyl containing one heteroatom, wherein the heteroatom is oxygen, wherein said phenyl may be optionally substituted with one or more of halo, CN, Ci-3alkyl, Ci-shaloalkyl, Ci-3alkoxy, or Ci-3haloalkoxy;R3aand R3btaken together with the carbon atom to which each is attached forms:• C3-5 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rb; or• heterocyclyl including 3-5 ring members, wherein 1-2 ring members are heteroatoms or heteroatomic groups, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rb; or each of R3aand R3bis independently selected from the group consisting of:• H;• C1-3 alkyl optionally substituted with optionally substituted with 1-3 substituents independently selected from the group consisting of -F, -Cl - and -CN; and• C3-4 cycloalkyl which is optionally substituted with 1-2 substituents independently selected from the group consisting of oxo and Rb;R4is H, F, CH3, OCH3, CN, or Cl; each occurrence of Rais independently selected from the group consisting of: -OH; - halo; -NReRf; C1-4 alkoxy; C1-4 haloalkoxy; -C(=O)O(Ci-4alkyl); -C(=O)(Ci-4alkyl); - C(=O)OH; -CONR’R”; -S(O)I-2NR’R”; -S(O)i-2(Ci-4 alkyl); and cyano; each occurrence of Rbis independently selected from the group consisting of: halo; cyano; Ci-10 alkyl which is optionally substituted with from 1-6 independently selected Ra; C2-6 alkenyl;C2-6 alkynyl; C1-4 alkoxy; -(C1-3 alkylene)-(C3-6 cycloalkyl); -O(Ci-3 alkylene)-(C3-6 cycloalkyl); C1-4 haloalkoxy; -S(0)o-2(Ci-4alkyl); -NReRf; -OH; -S(O)I-2NR’R”; -NO2; -C(=0)(Ci-io alkyl); - C(=O)O(Ci-4 alkyl); -C(=O)OH; and -C(=O)NR’R”; each occurrence of Rcis independently selected from the group consisting of:• C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rb;• heterocyclyl or heterocycloalkenyl including 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rb;• heteroaryl including 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with from 1-4 Rb; and• Ce-io aryl optionally substituted with from 1-4 Rb; each occurrence of Rdis independently selected from the group consisting of: C1-6 alkyl optionally substituted with from 1-3 independently selected Ra; -C(O)(Ci-4 alkyl); -C(O)O(Ci-4 alkyl); -CONR’R”; -S(O)I-2NR’R”; -S(O)i-2(Ci-4alkyl); -OH; and C1-4 alkoxy; and each occurrence of Reand Rfis independently selected from the group consisting of: H; C1-6 alkyl; -C(O)(Ci-4alkyl); -C(O)O(Ci-4alkyl); -CONR’R”; -S(O)I-2NR’R”; -S(O)i-2(Ci-4alkyl); -OH; and C1-4 alkoxy, and each occurrence of R’ and R” is independently selected from the group consisting of: H; and C1-4 alkyl.

2. The compound or pharmaceutically acceptable salt of claim 1, wherein A is:

3. The compound or pharmaceutically acceptable salt of claim 1 or 2, wherein R1and R2are defined according to (A).

4. The compound or pharmaceutically acceptable salt of any one of claims 1-3, wherein one of R1and R2is H, and the other of R1and R2is RA.

5. The compound or pharmaceutically acceptable salt of any one of claims 1-4, wherein RAis -(L1)a-RB.

6. The compound or pharmaceutically acceptable salt of any one of claims 1-5, wherein a is 0.

7. The compound or pharmaceutically acceptable salt of any one of claims 1-5, wherein a is 1.

8. The compound or pharmaceutically acceptable salt of any one of claims 1-7, wherein RBis selected from the group consisting of:• Ce-io aryl optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc; and• heteroaryl including 5-10 ring members, wherein 1-4 ring members are heteroatoms or heteroatomic groups, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc.

9. The compound or pharmaceutically acceptable salt of any one of claims 1-8, wherein RBis Ce-io aryl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of Rband Rc.

10. The compound or pharmaceutically acceptable salt of any one of claims 1-9, wherein RBis Ce-io aryl, which is optionally substituted with 1-4 independently selected Rb.

11. The compound or pharmaceutically acceptable salt of any one of claims 1-10, wherein RBis phenyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of Rband Rc.

12. The compound or pharmaceutically acceptable salt of any one of claims 1-11, wherein RBis phenyl, which is optionally substituted with 1-4 independently selected Rb.

13. The compound or pharmaceutically acceptable salt of any one of claims 1-12, wherein RBis phenyl, which is optionally substituted with 1-2 independently selected Rb.

14. The compound or pharmaceutically acceptable salt of any one of claims 1-13, wherein RBis:

15. The compound or pharmaceutically acceptable salt of any one of claims 1-14, wherein RBis:

16. The compound or pharmaceutically acceptable salt of any one of claims 8-15, wherein each occurrence of Rbis independently selected from the group consisting of: • halo;• -CN;• Ci-4 alkyl which is optionally substituted with from 1-6 independently selected Ra(optionally wherein Rais C1-2 alkoxy or F); and• C1-4 alkoxy or C1-4 haloalkoxy;17. The compound or pharmaceutically acceptable salt of any one of claims 8-16, wherein each occurrence of Rbis independently selected from the group consisting of -F, CH3, CH2F, CHF2, CF3, -CN, CH2OCH3, CF2CH3, OCH3, and OCF3.

18. The compound or pharmaceutically acceptable salt of any one of claims 8-17, wherein one occurrence of Rbis -F.

19. The compound or pharmaceutically acceptable salt of any one of claims 1-18,20. The compound or pharmaceutically acceptable salt of any one of claims 1-18, wherein RBis:wherein Rblis F; and each of Rb21, Rb22, and Rb23is, independently, selected from the group consisting of -F, CH3, CH2F, CHF2, CF3, -CN, CH2OCH3, CF2CH3, OCH3, and OCF3.

21. The compound or pharmaceutically acceptable salt of any one of claims 1-18 and20, wherein RBis:

22. The compound or pharmaceutically acceptable salt of any one of claims 1-8, wherein RBis heteroaryl including 5-10 ring members, wherein 1-4 ring members are heteroatoms or heteroatomic groups, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc, optionally wherein the heteroaryl is optionally substituted with 1-4 independently selected Rb.

23. The compound or pharmaceutically acceptable salt of any one of claims 1-8 and 22, wherein RBis heteroaryl including 5-6 ring members, wherein 1-4 ring members are heteroatoms or heteroatomic groups, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 independently selected Rb.

24. The compound or pharmaceutically acceptable salt of any one of claims 1-8, 22, and 23, wherein RBis heteroaryl including 6 ring members, wherein 1-3 ring members are N, and wherein the heteroaryl is optionally substituted with 1-4 independently selected Rb; optionally wherein RBis pyridyl or pyrimidinyl, each of which is optionally substituted with 1-3 independently selected Rb.

25. The compound or pharmaceutically acceptable salt of any one of claims 1-8 and 22-24, wherein RBis:, wherein 1 -2 of Y1, Y2, and Y3are N, and the other(s) are independently CH or CRb;26. The compound or pharmaceutically acceptable salt of any one of claims 1-8 and 22-24, wherein RBis heteroaryl including 5 ring members, wherein 1-3 ring members are heteroatoms or heteroatomic groups, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-2 independently selected Rb; optionally wherein RBis thiazolyl or oxadiazolyl, each of which is optionally substituted with 1-2 independently selected Rb.

27. The compound or pharmaceutically acceptable salt of any one of claims 22-26, wherein each occurrence of Rbis independently selected from the group consisting of:• halo;• -CN;• Ci-4 alkyl which is optionally substituted with from 1-6 independently selected Ra(optionally wherein Rais C1-2 alkoxy or F); and• C1-4 alkoxy or haloalkoxy;28. The compound or pharmaceutically acceptable salt of any one of claims 22-27, wherein each occurrence of Rbis independently selected from the group consisting of -F, CH3, CH2F, CHF2, CF3, -CN, CH2OCH3, CF2CH3, OCH3, and OCF3.

29. The compound or pharmaceutically acceptable salt of any one of claims 1-7, wherein RBis C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rb, and Rc.

30. The compound or pharmaceutically acceptable salt of any one of claims 1-7 and 29, wherein RBis C3-10 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rb, and Rc.

31. The compound or pharmaceutically acceptable salt of any one of claims 1-7 and 29-30, wherein RBis C3-8 cycloalkyl, which is optionally substituted with 1-4 independently selected Rb, or optionally substituted with 1-2 independently selected Rb, or optionally substituted with 1 Rb.

32. The compound or pharmaceutically acceptable salt of any one of claims 1-7 and 29-31, wherein RBis C5-7 cycloalkyl, which is optionally substituted with 1-4 independently selected Rb, or optionally substituted with 1-2 independently selected Rb, or optionally substituted with 1 Rb.

33. The compound or pharmaceutically acceptable salt of any one of claims 1-7 and 29-32, wherein RBis Ce cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rb, and Rc.

34. The compound or pharmaceutically acceptable salt of any one of claims 1-7 and 29-33, wherein RBis Ce cycloalkyl, which is optionally substituted with 1-4 independently selected Rb,35. The compound or pharmaceutically acceptable salt of any one of claims 1-7 and 29-34, wherein RBis Ce cycloalkyl, which is optionally substituted with 1-2 independently selected Rb,36. The compound or pharmaceutically acceptable salt of any one of claims 1-7 and 29-35, wherein RBis Ce cycloalkyl, which is optionally substituted with 1 Rb.

37. The compound or pharmaceutically acceptable salt of any one of claims 29-36, wherein each occurrence of Rbis independently selected from the group consisting of:• -OH;• -NR’R”;• Ci-4 alkyl which is optionally substituted with from 1-2 (optionally 1) independently selected Ra(optionally wherein Rais OH or F);• Ci-4 alkoxy;• halo; and• -CO2R’.

38. The compound or pharmaceutically acceptable salt of any one of claims 29-37, wherein Rbis -OH, -NH2, -N(CH3)2, -NHSO2CH3, -NHC(O)CH3, -CH3, -CF3, -CH2OH, - CH(OH)(CH3)2, F, -Cl, -OCH3, -OCHF2, or -OCF3.

39. The compound or pharmaceutically acceptable salt of any one of claims 1-7, wherein RBis heterocyclyl including 3-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rb, and Rc.

40. The compound or pharmaceutically acceptable salt of any one of claims 1-7, wherein each of R1and R2is an independently selected RA.

41. The compound or pharmaceutically acceptable salt of claim 1 or 2, wherein R1and R2are defined according to (B), wherein:R1and R2taken together with the nitrogen atom to which each is attached forms:• heterocyclyl or heterocycloalkenyl including 3-12 ring atoms, wherein 0-4 ring atoms (aside from the N linking R1and R2) are ring heteroatoms, each independently selected from the group consisting of: N, N(H), N(Rd), O, and S, wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents each independently selected from the group consisting of: oxo, Rb, and Rc; and• heteroaryl including from 9-14 ring atoms, wherein 0-4 ring atoms (aside from the N linking R1and R2) are ring heteroatoms, each independently selected from the group consisting of: N, N(H), N(Rd), O, and S, wherein the heteroaryl is optionally substituted with 1-4 substituents each independently selected from the group consisting of: oxo, Rb, and Rc.

42. The compound or pharmaceutically acceptable salt of claim 1, wherein A is heteroaryl including 5 ring members, wherein 2-4 ring atoms are heteroatoms or heteroatomic groups, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o- 2, and wherein the heteroaryl is optionally substituted with 1-2 substituents independently selected from the group consisting of halo, -CN, Ci-ealkyl, Ci-4haloalkyl, Ci-4alkoxy, Ci- 4haloalkoxy, Ci-4hydroxyalkyl, phenyl, or 3-6 membered heterocyclyl containing one heteroatom, wherein the heteroatom is oxygen, wherein said phenyl may be optionally substituted with one or more of halo, CN, Ci-3alkyl, Ci-shaloalkyl, Ci-3alkoxy, or Ci-3haloalkoxy.

43. The compound or pharmaceutically acceptable salt of claim 42, wherein the heteroaryl includes 5 ring members, wherein 2-3 ring atoms are heteroatoms or heteroatomic groups.

44. The compound or pharmaceutically acceptable salt of claim 42 or 43, wherein the heteroaryl is optionally substituted with 1-2 substituents independently selected from the group consisting of -F, -Cl, -CH3, -Ph,-CFH2, -CF2H, -CF3, -CH2CH3, -CF2CH3, -CH2CF3, -CH2OMe, -CH(Me)OMe, -CH2CHF2, -CH2CF2CH3, -CH2Ph, -CH(CH3)2, -C(CH3)3, -OCH3, -OCFH2, -OCF3, C(Me)2(OH) , -CN, vvv 6 ' OZand OJ.

45. The compound or pharmaceutically acceptable salt of claim 1, wherein A is heteroaryl including 5 ring members, wherein 2-4 ring atoms are heteroatoms or heteroatomic groups, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o- 2, and wherein the heteroaryl is optionally substituted with 1-2 substituents independentlyselected from the group consisting of -F, -Cl, -CH3, -CFH2, -CF2H, -CF3, -CH2CH3, -CF2CH3, - CH2CF3, -OCH3, -OCFH2, -OCF3, and -CN.

46. The compound or pharmaceutically acceptable salt of claim 45, wherein A is heteroaryl including 5-6 ring members, wherein 2-3 ring atoms are heteroatoms or heteroatomic groups, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o- 2, and wherein the heteroaryl is optionally substituted with 1-2 substituents independently selected from the group consisting of -F, -Cl, -CH3, -CFH2, -CF2H, -CF3, -CH2CH3, -CF2CH3, - CH2CF3, -OCH3, -OCFH2, -OCF3, and -CN.

47. The compound or pharmaceutically acceptable salt of claim 1, or 42-46, wherein A has the formula:wherein:X6is NH, NCH3, O, or S;X7is N, C, CH, CF, CCF3, CCH2F, CCHF2, CF2CH3, CH2CH3, or CCH3;X8is N, C, CH, or CCH3;X9is N, C, CH, or CCH3; andX10 is N, C, CH, CCF3, CCHF2, or CCH3.

48. The compound or pharmaceutically acceptable salt of any one of claims 1 and 42- 47, wherein A has the formula:wherein:X6is NH, NCH3, O, or S;X7is N, CH, CF, CCF3, CCH2F, CCHF2, CF2CH3, CH2CH3, or CCH3;X8is N, CH, or CCH3; and X9is N, CH, or CCH3.

49. The compound or pharmaceutically acceptable salt of claim 47 or 48, wherein Xs is N.

50. The compound or pharmaceutically acceptable salt of any one of claims 47-49, wherein X9 is N.

51. The compound or pharmaceutically acceptable salt of any one of claims 47-50, wherein Xe is O.

52. The compound or pharmaceutically acceptable salt of any one of claims 47-51, wherein X7 is CH, CCF3, CCHF2, CCH2CH3, or CCH3.

53. The compound or pharmaceutically acceptable salt of any one of claims 47-52, wherein X7 is CH.

54. The compound or pharmaceutically acceptable salt of any one of claims 47-53, wherein A has the formula:

55. The compound or pharmaceutically acceptable salt of claim 47 or 48, wherein X9 is N, and X8is CH, or CCH3.

56. The compound or pharmaceutically acceptable salt of claim 47, 48, or 55, wherein X7is N, CCF3, CCHF2, CCH2CH3, or CCH3.

57. The compound or pharmaceutically acceptable salt of claims 47, 48, 55, or 56, wherein Xe is O.

58. The compound or pharmaceutically acceptable salt of claims 1-57, wherein R3aand R3btaken together with the carbon atom to which each is attached forms:• C3-5 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rb; or• heterocyclyl including 3-5 ring members, wherein 1-2 ring members are heteroatoms or heteroatomic groups, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rb;59. The compound or pharmaceutically acceptable salt of claims 1-58, wherein R3aand R3btaken together with the carbon atom to which each is attached forms C3-5 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rb.

60. The compound or pharmaceutically acceptable salt of claims 1-59, wherein R3aand R3btaken together with the carbon atom to which each is attached forms C3 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rb.

61. The compound or pharmaceutically acceptable salt of claims 1-60, wherein R3aand R3btaken together with the carbon atom to which each is attached forms unsubstituted C3 cycloalkyl.

62. The compound or pharmaceutically acceptable salt of claims 1-59, wherein R3aand R3btaken together with the carbon atom to which each is attached forms C4 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rb.

63. The compound or pharmaceutically acceptable salt of claims 1-59 and 61, wherein R3aand R3btaken together with the carbon atom to which each is attached forms unsubstituted C4 cycloalkyl.

64. The compound or pharmaceutically acceptable salt of any one of claims 1-57, wherein each of R3aand R3bis independently selected from the group consisting of H and C1-3 alkyl optionally substituted with from 1-6 Ra.

65. The compound or pharmaceutically acceptable salt of any one of claims 1-64, wherein R4is Cl.

66. The compound or pharmaceutically acceptable salt of any one of claims 1-64, wherein R4is F.

67. The compound or pharmaceutically acceptable salt of any one of claims 1-64, wherein R4is H.

68. The compound or pharmaceutically acceptable salt of any one of claims 1-67, wherein the compound has formula (Ila):pharmaceutically acceptable salt thereof.

69. The compound or pharmaceutically acceptable salt of any one of claims 1-67, wherein the compound has formula (lib) :(lib), or a pharmaceutically acceptable salt thereof.

70. The compound or pharmaceutically acceptable salt of any one of claims 1-63 and 65-67, wherein the compound has formula (Illa):(Illa), or a pharmaceutically acceptable salt thereof.

71. The compound or pharmaceutically acceptable salt of any one of claims 1-63 and 65-67, wherein the compound has formula (Illb):(Illb), or a pharmaceutically acceptable salt thereof.

72. The compound or pharmaceutically acceptable salt of any one of claims 1-63 and65-67, and 70-71, wherein the compound is:, or a pharmaceutically acceptable salt thereof.

73. The compound or pharmaceutically acceptable salt of any one of claims 1, 42-61 and 65, wherein the compound is:pharmaceutically acceptable salt thereof.

74. The compound or pharmaceutically acceptable salt of claim 73, wherein the compound is:or a pharmaceutically acceptable salt thereof.

75. The compound or pharmaceutically acceptable salt of claim 73, wherein the compound is:, or a pharmaceutically acceptable salt thereof.

76. The compound or pharmaceutically acceptable salt of claim 73, wherein the compound or pharmaceutically acceptable salt is an enantiomeric mixture, such as a racemic, or a p armaceut ca y accepta e sa t t ereo .

77. The compound or pharmaceutically acceptable salt of claim 1, wherein the compound is of Formula (IIIc):Formula (IIIc) or a pharmaceutically acceptable salt thereof; wherein:R1is pyridyl, which may be optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc.

78. The compound or pharmaceutically acceptable salt of claim 77, wherein the pyridyl is optionally substituted with 1, 2, 3, or 4 Rb, preferably the pyridyl is substituted with 1 or 2 Rb.

79. The compound or pharmaceutically acceptable salt of claim 77 or 78, wherein Rbis selected from the group consisting of halo, and Ci-salkyl which is optionally substituted with 1, 2, 3, or 4 F and / or Cl.

80. The compound or pharmaceutically acceptable salt of any of claims 77-79, wherein the compoundpharmaceutically acceptable salt thereof.

81. The compound or pharmaceutically acceptable salt of claim 80, wherein the compound or pharmaceutically acceptable salt is an enantiomeric mixture, such as a racemicpharmaceutically acceptable salt thereof,or pharmaceutically acceptable salt thereof.

82. The compound or pharmaceutically acceptable salt of claim 1, wherein the compound or pharmaceutically acceptable salt is selected from the group consisting of the compounds in Table Cl, C2, C3, or C4 or a pharmaceutically acceptable salt thereof.

83. A pharmaceutical composition comprising the compound of any one of claims 1- 82, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

84. A method of degrading NIMA Related Kinase 7 (NEK7) in a subject, comprising administering to the subject an effective amount of a compound as claimed in any one of claims 1-82, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in claim 83.

85. The method of claim 84, wherein the compound mediates the interaction of a NEK7 protein with an E3 ligase, thereby increasing degradation of the NEK7 protein.

86. The method of claim 84 or 85, wherein NEK7 is an activator of an NLRP3 inflammasome.

87. The method of claim 85 or 86, wherein the compound interacts with the E3 ligase prior to the interaction of NEK7 with the E3 ligase.

88. The method of any one of claims 85-87, wherein the E3 ligase comprises cereblon.

89. A method of degrading NIMA Related Kinase 7 (NEK7), comprising:(i) contacting the compound of any one of claims 1-82 or a pharmaceutically acceptable salt thereof with an E3 ligase; and(ii) interacting the contacted E3 ligase with NEK7, thereby degrading NEK7.

90. A method of treating a disorder caused by or associated with NLRP3 inflammasome activation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound as claimed in any one of claims 1 -82, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in claim 83.

91. The method of claim 90, wherein the disorder is a disorder of the immune system, joints, central nervous system, cardiovascular system, endocrine system, renal system, gastrointestinal tract, eye, skin, respiratory system, hematopoietic system, and / or hepatic system.

92. The method of claim 90 or 91, wherein the disorder is selected from the group consisting of:(i) inflammatory reactions in the joints;(ii) central nervous system diseases;(iii) cardiovascular diseases;(iv) metabolic diseases;(v) autoimmune diseases;(vi) kidney diseases;(vii) ocular diseases;(viii) hyperactive inflammation with underlying genetic mutations;(ix) respiratory diseases;(x) cancers;(xi) inflammatory reactions in the skin;(xii) diseases of the hematopoietic system;(xiii) liver diseases;(xiv) viral infections and subsequent immune hyperactivation;(xv) allergic disease; and(xvi) infectious diseases.

93. The method of any one of claims 90-92, wherein the disorder is inflammatory reactions in the joints.

94. The method of claim 93, wherein the disorder is acute or chronic gout.

95. The method of claim 93, wherein the disorder is tophaceous gout or pseudo-gout, including calcium pyrophosphate deposition disease.

96. The method of claim 93, wherein the disorder is rheumatoid arthritis.

97. The method of claim 93, wherein the disorder is osteoarthritis.

98. The method of claim 93, wherein the disorder is psoriatic arthritis.

99. The method of claim 93, wherein the disorder is systemic juvenile idiopathic arthritis.

100. The method of claim 93, wherein the disorder is adult-onset Still’s disease.

101. The method of claim 93, wherein the disorder is relapsing polychondritis.

102. The method of claim 93, wherein the disorder is tendonitis.

103. The method of claim 93, wherein the disorder is frozen shoulder.

104. The method of claim 93, wherein the disorder is pyogenic arthritis.

105. The method of any one of claims 90-92, wherein the disorder is selected from the group consisting of:(i) central nervous system diseases;(ii) cardiovascular diseases;(iii) metabolic diseases;(iv) autoimmune diseases;(v) kidney diseases;(vi) ocular diseases;(vii) hyperactive inflammation with underlying genetic mutations; and(viii) respiratory diseases.

106. The method of claim 105, wherein the central nervous system disease is selected from the group consisting of:(i) Parkinson’s disease;(ii) Alzheimer’s disease;(iii) motor neuron disease;(iv) Huntington’s disease;(v) cerebral malaria;(vi) post-traumatic brain and / or spinal cord injury;(vii) sub-arachnoid haemorrhage;(viii) aneurysm;(ix) brain injury from pneumococcal meningitis(x) cerebral amyloid angiopathy;(xi) migraine;(xii) depression; and(xiii) psychological stress.

107. The method of claim 105, wherein the cardiovascular disease is selected from the group consisting of pericarditis including Dressier’s syndrome, myocarditis, inflammatory cardiomyopathy, transthyretin amyloidosis, atherosclerosis, heart failure, heart failure with preserved ejection fraction, stroke, myocardial infarction, ischemia reperfusion injury, hypertension, abdominal aortic aneurism, thromboembolism, and vasculitis108. The method of any one of claims 90-92, wherein the disorder is a metabolic disease.

109. The method of claim 108, wherein the metabolic disease is selected from the group consisting of obesity, metabolic disease, Type 2 diabetes and related morbidities including diabetic foot ulcers, atherosclerosis, obesity, diabetic cardiomyopathy and diabetic retinopathy.

110. The method of claim 108, wherein the metabolic disease is Wilson disease.

111. The method of claim 108, wherein the metabolic disease is a lysosomal storage disease.

112. The method of claim 108, wherein the metabolic disease is MASH.

113. The method of claim 105, wherein the autoimmune disease is selected from the group consisting of multiple sclerosis (MS), rheumatoid arthritis, Behget’s disease, Sjogren’s syndrome, systemic sclerosis, mixed connective tissue disease, myositis, vasculitis, lupus, including systemic and cutaneous forms, lupus nephritis, type-1 diabetes, psoriasis, neuromyelitis optica, anti-myelin oligodendrocyte glycoprotein disease (MOG), autoimmune encephalitis, acute disseminated encephalomyelitis (ADEM), chronic meningitis, CNS vasculitis, Hashimoto’s encephalitis, steroid responsive encephalopathy associated with autoimmune thyroiditis, neurosarcoidosis, optic neuritis, transverse myelitis, Schnitzler’s syndrome, inflammatory bowel disease, colitis, and Crohn’s disease.

114. The method of claim 105, wherein the kidney disease is selected from the group consisting of chronic kidney disease (CKD), including CKD associated with high uric acid, APOL1 mutations, complement-mediated kidney diseases such as C3 glomerulopathy, IgA nephropathy, atypical haemolytic uremic syndrome and membranous nephropathy, idiopathic nephrotic syndrome, oxalate nephropathy and diabetic nephropathy.

115. The method of claim 105, wherein the ocular disease is selected from the group consisting of those of the ocular epithelium, age-related macular degeneration (AMD), corneal infection, uveitis and dry eye.

116. The method of claim 105, wherein the hyperactive inflammation with underlying genetic mutations is selected from the group consisting of cryopyrin-associated periodic syndrome (CAPS): Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS) and neonatal-onset multisystem inflammatory disease (NOMID); familial Mediterranean fever (FMF), TNF receptor associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MVK), hyperimmunoglobulinemia D and periodic fever syndrome (HIDS), deficiency of interleukin 1 receptor antagonist (DIRA), clonal haematopoiesis of indeterminate potential (CHIP), VEXAS syndrome, Majeed syndrome, pyoderma gangrenosum, acne, hi dradenitis suppurativa, haploinsufficency of A20, paediatric granulomatous arthritis (PGA), PLCG2-associated antibody deficiency and immune dysregulation (PLAID), sideroblastic anaemia with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD), Sweet’s syndrome, chronic non-bacterial osteomyelitis (CNO), chronic recurrent multifocal osteomyelitis (CRMO) and synovitis, pustulosis, hyperostosis, osteitis syndrome (SAPHO) and any disease where an individual has been determined to carry a germline or somatic non-silent mutation in NLRP3 or NEK7.

117. The method of claim 105, wherein the respiratory disease is selected from the group consisting of chronic obstructive pulmonary disorder (COPD), acute respiratory distress syndrome (ARDS), steroid-resistant asthma, asbestosis, silicosis, sarcoidosis, cystic fibrosis and interstitial lung disease (ILD), including, but not limited to idiopathic pulmonary fibrosis (IPF), fibrotic hypersensitivity pneumonitis, rheumatoid arthritis-associated ILD, autoimmune myositis- associated ILD, systemic sclerosis-associated ILD, idiopathic interstitial pneumonia and progressive fibrosing ILD.

118. A method of degrading NIMA Related Kinase 7 (NEK7) in a subj ect suffering from a disorder as claimed in any one of claims 90-117, comprising administering to the subject an effective amount of the compound as claimed in any one of claims 1-74, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in claim 75.

119. The method of any one of claims 84-118, wherein the subject is a human.

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